TW413675B - Substituted 4-biarylbutyric or 5-blarylpentanoic acids and derivatives matrix metalloprotease inhibitors - Google Patents

Abstract

Inhibitors for matrix metalloproteases, pharmaceutical compositions containing them, and a process for using them to treat a variety of physiological conditions. The compounds of the invention have the generalized formula (T)xA-B-D-E-G, wherein A and B are aryl or heteroaryl rings; each T is a substituent group; x is 0, 1, or 2; the group D represents formulas, the group E represents a two or three carbon chain bearing one to three substituent groups which are independent or are involved in ring formaiton, possible structures being shown in the text and claims; and the group G represents -PO3H2, -M, formulas, in which M represents -CO2H, -CON(R11)2, or -CO2R12; and R13 represents any of the side chains of the 19 noncyclic naturally occurring amino acids, and include pharmaceutically acceptable salts thereof.

Description

V. Description of the invention (99)

A7 B7

On the first day of this month, between ethyl acetate / digas (Na2S04) and concentrated to a yellow solid, and subjected to flash column chromatography (gradient dissociation of '1 gas methane to 98: 2 digas methane-formase), the required substance is produced. White solid "MP 148 ° -149 ° C. The examples in Table IX were prepared from Example 1 36 using the general procedure of Example 1 37, using the appropriate commercially available saponifier product. Hydrolysis was carried out from the tritiated product of ethyl ester of Example 136, resulting in Examples 140-141. Table IX The organic phase was dehydrated with water and brine

Examples of isomers Ϊ36 137 138 139 140 141 (T) x

NJH2.HC] PhOCONH / -BuOCONH CH3CONH n-BuCONH i-BuCH2CONH R, R, R, r, r, r, mp (° C) / Other characteristics 222.0-224.0 148-149 167- 168 209.5-211 168- 169.5 180.5-182.5 —. Water ——1 — Order, f > v (Please read the notes on the back before filling this page) Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives -102- The standard of this paper is applicable to China Standard () M specification (2! 〇X 297 mm) 413675 A7 ____ B7 _ —___ V. Description of the invention (丨) This case is a series of applications No. 08 / 339,846 which was filed on November 15, 1994. In some consecutive cases, the case has been incorporated into the McCaw literature of this article. Technical Field The present invention relates to enzyme inhibitors, and more specifically, to novel 4-diarylbutanoic acid or 5-diarylvaleric acid compounds or derivatives thereof, which are used to inhibit matrix metalloproteinases. Background Matrix metalloproteinases (matrix metalloproteinases or MMPs) are a type of zinc endoproteinases, including (but not limited to): interstitial gliases (MMP-1), matrix lysins (proteoglycans, iransin, or MMP-3) Gelatinase A (72kDa-gelatinase or MMP-2) and Gelatinase B (95kDa-gelatinase or MMP-9). These MMPs are secreted by many types of cells, including fibroblasts and chondrocytes, and they also secrete natural protein inhibitors known as TIMPs (tissue inhibitors of metalloproteinases). Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. All these MMPs can destroy articular cartilage or connective tissue of the basement membrane. Each MMP is an inactivated zymogen, which must be lysed in subsequent steps before it can exhibit its original proteolytic activity. In addition to the damage to the matrix, 'some of these MMPs such as: MMP-3 have been used as in vivo activators of other MMPs (such as with MMP-9) (a. Ho, H, Nagase, Arch. Biochem. Biophys. , 262, 211-16 (1988); Y. Ogata, JJ Enghild, H. Nagase, J. Biol. Chem., 262, 3581-84 (1992)) ® Therefore excess MMP-3 will trigger a series of protein hydrolysis Activity d should therefore be specific MMP-3 inhibitors to limit the activity of other MMPs that are not directly inhibited by these inhibitors. -4- ί The paper size is applicable to the Chinese National Standard Li (CMS) Α4 specification [" ΙΓίΠ 2 ^ 7 mm) -J ·-This: The page of the Central Bureau of Standards, Ministry of Economic Affairs, consumer cooperation, Du Yinzhen 413675 at Β7 I} _ j- — Explanation (130) Example 1 96 Using the method described in Example 1 3 3 above, Example 1 96 was prepared using the thiophenol of Example 2 3. MP 125-126 ° C. Example 197 An acetone (150 ml) solution containing Example 196 (24 g, 0.058 mol) and (+)-Cinconic '0.034 mol) was allowed to stand at room temperature for 46 hours. The white precipitate was removed by filtration, suspended in ethyl acetate, and washed sequentially with 2N HC1 (150 ml) and a saturated aqueous NaCl solution (100 ml). The organic phase was dehydrated (II) (MgS04), filtered and concentrated under reduced pressure to give a white solid (8-4 grams, isomer ratio 9 5.3: 4.7 (Example 1 9 7 _ Example 1 9 8). Repeated a second time (Sin Kynin, 6.75 g; acetone, 140 ml) was then simply crystallized from an ethyl acetate / hexane mixture (1: 2) to give Example 197 (6.67 g: W of theory, isomer ratio 99.3: 0.7) of white crystals; > [<3; 115 + 84.8 ° (〇K 5, acetone). Example 1 98 This heterogeneous purified sample can be used on a Chiralpak® AD column (cm x 25 cm). Ethanol / hexane (1: 9 0,15% trifluoroacetic acid added to ethanol) was obtained by HPLC. Under these conditions, the second dissolution example 1 9 8 can only be injected and shot by a very small amount. Pure substance is obtained. According to D. Art, B. Boemer, R. Grosser, and W. Lange, Angew. Chem. Int. Ed. Engl. 30 (1991) No. 12, p. 1662-1664 General Process' Using a patented stationary phase of stationary phase, which produces a large amount of pure material, the ratio of isomers < 1: > 9 9. Take the best chromatographic dissolution Serving The residue (830 mg) was recrystallized from an ethyl acetate / hexane mixture to produce -133-% of paper. National Financial Standards (CNS) of Japan (210χ? ΊΫϋ " (Please first listen Read the notes on the back and fill in this page again)-Order ^ 1κίϋ75 Α7 _____ Β7 V. Description of the invention (2) It has been reported that MMP-3 can cleave other proteases (such as pingxinsu) due to intrinsic inhibitors. Inactivation (p G Winyard, Z. # (Zhang), K. Chidwick_, DR Black, RW Carrell, G. Murphy (Murphy ), FEBS Letts., 279, 1, 91-94 (1991)). Therefore, inhibitors of MMP-3 can change the concentration of intrinsic inhibitors of other destructive proteases, and then affect the activity of these proteases. Many diseases It is thought to be regulated by excessive or unnecessary matrix metalloproteinase activity, or by an imbalance in the ratio of M M Ps to TI M Ps. These diseases include: a) Osteoarthritis (Vosno ( Woessner) and others, J. Biochelogical Chem. 259 (6). 3633-3638 (1984); J. Member of the Central Standards Bureau, Ministry of Economic Affairs Printed by Industrial and Consumer Cooperatives (Please read the notes on the back before filling this page)

Rheumatol., 10, 852-860 (1883); b) Rheumatoid arthritis (D_E. Mullins, et al., Biochim. Biophys. Acta, 695, 117-214 (1983), Arthritis and Rheumatism, 20, 1231-1239 (1977); Arthritis and Rheumatism, 34, 1076-1105 (1991)); c) septic arthritis (R. J, Williams, et al., Arthr. Rheum_ 33, 533-41 (1990)), d) Tumor metastasis (R. Reich et al., Cancer Res ·, 48, 3307-33 12 (1988) and L · M, Matrisian, et al.?!·· Nat'l. Acad. Sci. USA, 83, 9413-7 (1986)), e) periodontal disease (CM Overall et al., J. Periodontal Res, 22, 81-88 ( 1987)), f) corneal ulceration '(FR Burns et al., Invest. Opthalmol., 30, 1569-1575 (1989)), g) proteinuria (WH Baricos et al., Et al. , Biochem. J., 254. 609-612 (1988)), h) Coronary arterial blood test caused by ruptured atherosclerotic plaque (A. Henney et al., Proc. Nat'l. Acad. Sci. USA, 88, 8154-8158 (1991)), i) aortic aneurysm disease (n. Weber & Scale Universal China® Home Associate (CNS) A4 size (210X 297 male t)

W A7 B7 Master !, Description of the Invention (204), i ^ 0 '50 / 〇 acetic acid) 'produced 0.14 g (88%) Example 1 5-9 7 9 9 gray' white solid . MP 15TC. The following biphenyl product was prepared from Example 40 or Example 134 and the appropriate 1-determined compound using the method of Step 1 of Example 3 5 1 above (Table XXIV).

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

The Central Bureau of Standards, Ministry of Economic Affairs, Shellfish Consumer Cooperation, Du Printing Equipment Step 1 The method of Step 1 in Example 351 above was used to prepare propargylmethoxyacetylene as Preparation Example 3 5 3, Example 3 5 4 and Example 3 5 5 Starter. MP 151X :.

Winter paper size is applicable to China National Standards (CNS) M specifications (210X297 mm) 413675 A 7 B7 V. Description of the invention (3) Vine and J, T. Powdl, Clin. Sci ·, 81, 233-9 (1991)), j) birth control (Woessner et al. 'Steroids, 54, 49 499 (1989)), k) dystrophic epidermis to release water scars (A. Kronberger et al., J. Invest. Dermatol., 79, 208-21 1 (1982)), and 1) degenerative cartilage loss due to joint trauma, diseases that cause inflammatory reactions, MMP activity-modulated osteopenia, temporomandibular joint disease, demyelination of the nervous system, etc. (J. Neurochem., 50, 688-694 (1988)). New treatments are particularly needed for joint diseases. 4 The main inability effect of osteoarthritis (OA), rheumatoid arthritis (RA), and septic arthritis is the progressive loss of articular cartilage, thereby losing normal joint function. There are no tinctures on the market to prevent or slow this patella loss, although nonsteroidal anti-inflammatory drugs (NASIDs) are available to control pain and swelling. The end result of these diseases is a complete loss of joint function, which can only be treated with joint replacement surgery. MMP inhibitors may be able to arrest or reverse the gradual loss of cartilage and avoid or delay surgery. Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs t Please read the notes on the back and fill in the wooden cards] During the development of metastatic cancer, there are several stages that require protease as an important element. During this process, protein degradation of structural proteins in the basement membrane will cause the + tumor to expand in the primary part, leave this part and return and invade the distant secondary part. In addition, tumor growth requires tumor-induced angiogenesis and relies on the transformation of proteolytic tissue. Transfection experiments with various proteases have shown that matrix metalloproteinases play an important role in these processes, specifically gelatinases A and B (MMP-2 and MMP-9, respectively) ° References in this section References can be found in Biochimica et Biophysiea Acta. This paper applies the Chinese National Standard (CNS) μ specification (2i0x 297)-• ΤΓ

OH A7 B7 I, Ma Ming (248) Step 7 Dissolve the snail · 6 diacid (1.66 g, 5.90 mmol) in glacial acetic acid (16 ml), and add the whole amount of fruit (712 mg, 11.8 millimoles). Heat to reflux at 150 aC for 3 hours. The acetic acid was removed by emptying, and the residue was suspended in water. The solid was filtered and dried in vacuo to give 4,5-methylenedioxyg taurolimide (214 mg, 19%) as a yellow-brown solid. TLC Rf 0.5 5 (50% ethyl acetate: hexane).

0 " Example 419 The method of making 8 examples 419. According to the method of steps 4 to 5 in Example 40.5, Example 4 19 was synthesized, MP 196-198 ° C. Example 420 Step 1 Take a suspension of dioxin (4 ml) containing 10% Pd / C (40 mg, 20% w / w), rinse with Η 2 (g) for 4 5 minutes, and then add the Example 405 A suspension of 5 dioxin (7 ml) solution of the diester (200 mg, millimolar) in step 7 of 5 was stirred at room temperature and 112 ° C for 3 days. The mixture was filtered through Celite 'and washed with ethyl acetate, and the filtrate was adsorbed on silica. Purification by flash chromatography (1: 1: 3 ethyl acetate: digas methane: hexane) gave a colorless solid that replaced the di-tertiary butyl malonate (168 mg, 94%). 251-The paper size is suitable for financial affairs (n,! S)-· ^ (210Χ-297 ^ · --------- 1 ------ IT ------ 't {{(Please read the notes on the back before filling out this page) Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of Invention (4) 695 (1983)), 177-214; Eur. Respir. J. 7 (1994), 2062-2072;

Critical Reviews in Oral Biology and Medicine 4 (1993), 197-2.5. In addition, it has been shown that the inhibition of the degradation of the extracellular matrix by the natural matrix metalloproteinase inhibitor TIM P_2 (a protein) can suppress cancer growth (cancer

Res. 52, 701-7〇8, 1992) 'and TIMP-2 can inhibit tumor-induced ▲ tube formation in the real system (Science 248, 140 8-1410, 1990). Its reference literature can be found in AnnaisoftheNewYorkAcademyofSciences ^ 1994, 222-232. It has been further confirmed that when a synthetic matrix metalloproteinase inhibitor: batimastat is administered intraperitoneally, it can inhibit the growth and spread of colon-like tumors in hairless mice in the Orthotopic model (Cancer Res. 54, 4726-4728, 1994 "and prolong the survival of mice with human ovarian cancer tumor allografts (Cancer Res 53, 2087-2091, 1993). The use of this compound and related compounds has been described At WO-A-9321942. The Central Standards Bureau of the Ministry of Economic Affairs has published several patents and patent applications for metalloproteinase inhibitors to prolong metastatic cancer, promote tumor regression, inhibit cancer cell proliferation, slow down or Patent rights to prevent cartilage loss associated with osteoarthritis or use in the treatment of other diseases mentioned above (for example: WO-A-9519965, WO-A-95 19956 > WO-A-9519957-WO-A-9519961 ^ WO-A-9321942 ^ WO-A-9421625 > US Pat. No. 4,599,361; US Pat. No. 5,190,937; EP 0 574 758 Al, published on December 22, 1993; EP 026 436 Al, August 1988 Announcement on March 3; and EP 0 5 20 573 A1. Announcement dated December 30, 1992). The preferred compounds in these patents have peptide backbones, and the meaning of this paper on one end of the paper applies the Chinese National Standard (CNS) A4 standard (21ϋ × 297 mm) 21 A7 B7 V. Description of the invention (5) With a zinc complex (isohydroxyelbanoic acid, thiol, carboxylic acid or phosphinic acid) and many fluorene chains, these side chains include those common to natural amino acids and newer functions These small peptides are usually not easy to absorb, the oral bioavailability is low β, and the rate of proteolytic metabolism is also fast, so the half-life is short ^ For example: w〇_A_ 9321942 As explained by Batimus ( > 31 丨 1 ^ $ 1 & 1) can only be administered intraperitoneally. 0 It has been shown in the literature that certain 3-benzylbenzoic acid and 4-diarylbutyric acid are anti-inflammatory agents, antiplatelet coagulants, Anti-inflammatory agents, anti-proliferative agents, such as hypolipidemic agents, antirheumatic agents, analgesics, and cholesterol lowering agents. None of these examples mention the use of an MMP inhibitory effect as a mechanism for the claimed medical effect. Some related The compounds are also used as intermediates in the preparation of liquid crystals. It is explicitly stated that US Patent 3,784,701 applies for certain Substituted benzamidinepropionic acid for the treatment of inflammation and pain. These compounds include 3-biphenylamidine propionic acid (fenbufen) of the following formula. (Please read the notes on the back before filling in this education).

Du-Cheng Du-Cheng Bureau of Standards, Ministry of Economic Affairs and Consumer Cooperation, printed by RG, Child, et al. 'J_ Phartn. Sci., 466-476 (1977) illustrates the structure and activity of several phenbuphene analogs . It includes several compounds in which a biphenyl ring system or a propionic acid moiety is substituted with a phenyl, halide, oxo or methyl group, or a carboxylic acid or carbonyl functional group into many derivatives. Among them, the compound e containing 4'-substituted biphenyl and substituted propionic acid moiety in one molecule is not described. Among them, the phenyl group of the formula shown below is used. A4 specification (2) 0 + < 291 mm) ^ 13675 ι A7 B7 5. Description of the invention (6) * XLIV and LXXVII) and compounds substituted with methyl (compound XLVIII) have no activity.

(Please read the notes on the back before filling this page) Printed by K. K. Cameo et al., Chem. Pharm. Bull. M, 2050-2060, and JP Patent case 62132825 describes certain substituted 3-biphenylhydrazone propionic acid derivatives and their analogs, including the following compounds. It also describes various compounds in which the propionic acid moiety has other substituents, but all do not contain biphenyl residues.

Η. Cousse et al., Eur. J. Med. Chem., 22_, 45-57 (1987) describe the following 3-biphenylphosphonium propionic acid and -acrylic acid substituted with methyl and methylene groups. The corresponding compounds in which the carbonyl group is replaced by CHOH or CH2 are also illustrated. This paper ruler applies the Ning National Standard (CNS) A4 specification (210 X 297 t centimeters) ^ 3675 A7 B7 V. Description of the invention (7)

X = H, Cl, Br, CH30, F and NH2 Tomae German Patent Application No. 1957 750 also illustrates some of the methylene substituted biphenylarsine propionic acids mentioned above. M. A. El-Hashsh et al., Revue Roum Chim "23, 1581-1588 (1978) describes products derived from hydrazone-acrylic acid epoxide, including the following biphenyl groups Compound a is a compound in which a biphenyl moiety is not illustrated.

Du Yinlai (Please read the notes on the back before filling this page) T. Kitamura et al. Japanese Patent Application No. 84-65795 840404 Describes the use of certain phenyl compounds The intermediates for the manufacture of liquid crystals include the following compounds. The biphenyls of these intermediates are unsubstituted "-10- This paper size applies to the Chinese national standard: Standard ((:: Post) 6 4 Regulation 4 (210 > < 297 mm) A7 B7 Central Standard Rate of the Ministry of Economic Affairs Printing of the Bureau's Consumer Cooperatives V. Invention Description (η

OH German Patent No. 28 54 475 uses the following compounds as intermediates. This biphenyl group is unsubstituted.

A. Sammou et al. 'Egypt J. Chem., 311-327 (1972) and J' Couquelet et al., Bull Soc. Chim. Fr_, 1 3196-9 (1971) Explains some diphenylamino substituted biphenyl propionic acids, including the following compounds. None of its biphenyl groups is unsubstituted.

Ri R2

Does OH and nitrogen co-form a ring? Therefore, it needs an effective M P inhibitor with improved bioavailability and biostability than the peptide-based compounds of the prior art. Specific target MMPs. These compounds are the subject of this application. SUMMARY OF THE INVENTION I!-This paper standard is in accordance with Chinese Standard (CNS) A4C (210 × 297 mm) --------------- 1Τ ------ f (((( Please read the notes on the reverse side before filling out this page) 413675 A7 __ B7 _ V. Description of the invention (9) The present invention is a 合物 compound with matrix metalloproteinase inhibitory activity of the following formula '(T) XA- BDEG. (I) In the above general formula (I), (T) XA represents a substituted or unsubstituted aromatic 6-membered ring or a 5- to 6-membered ring containing 1 to 2 N, 0 or S atoms. T Represents one or more substituents, and the subscripts indicate the number of such substituents, and A represents an aromatic or heteroaromatic ring, which is called A ring or A unit. When N is combined with S or O in A ring, these Heteroatoms are separated by at least one carbon atom. Substituents T are each selected from the following: halogen; alkyl; haloalkyl; alkenyl; decyl; _ (CH2) pQ, where P is 0 or an integer from 1 to 4. And -alkenyl-Q, in which the alkenyl moiety contains 2 to 4 carbons. Q in the latter two groups is selected from the group consisting of: aryl, heteroaryl, -CN, -CHO, -N02,- C02R2, -OCOR2, -S0R3, -S02R3, -C0N (R:) 2, -S02N (R2) 2, -C0R2, -n (r2) 2, -n (r2) cor2, -n (r2) co2r3, -n (r2) con (r2) 2, · Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs ----- -/ ------ tr Jft. (Please read the notes on the back before filling this page) CHN4, -OR4, and -SR4. In this equation, R2 represents H, alkyl, aryl, heteroaryl Group, aralkyl, or heteroaryl-alkyl; R3 represents alkyl, aryl, heteroaryl, aralkyl, or heteroaryl · alkyl; R4 represents fluorene, alkyl, aryl, heteroaryl Base, aralkyl, or heteroaryl-alkenyl, alkenyl, bulk, dentyl, fluorenyl, or alkyleneoxy or polyalkyleneoxy with fluorene, alkyl, or phenyl. The unsaturated part connected to Q or Q-part is separated from any N, 0 or S in Q by at least one carbon atom. The A ring may be unsubstituted or may have up to 2 substituents T. Therefore, the subscript X It is 0, 1 or 2. In the general formula (I), B represents an aromatic 6-membered ring or a heteroaromatic 5 to 6-membered ring containing 1 to 2 N, 0 or S atoms, and is called a B ring or a B unit. .When the N and B rings -12- this paper ▲ ruler national standard (CNS) Α4 «297χ 297 mm) ^ A7 V. Description of the invention (10 in =: When: male atom _ less, child : C =: square; C: Η

OH Η, or • c = s printed by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives in the general formula '' E represents a substituent with h carbon atoms in which the Rs group is an independent substituent, or constitutes a spiro ring or Non-spiral. Rings can be formed in two ways: a) the two R6 bases are combined, and the two R <! groups are attached to the chain atom and any interspersed chains originally constitute a 3 to 7 member ring, or b ) An R6 group is bonded to the chain where this R6 group is located, and forms a 3 to 7-membered ring with the chain atom to which the 牝 Re group is attached and any intervening chain atoms. The number of carbon atoms η in the chain is 2 or 3, and the number of substituents m of R6 is an integer of 1 to 3. The total number of carbon atoms in the R6 group is at least two. Each R6 group is selected from the following: * alkyl, but the limitation is that if A is phenyl, B is phenyl, m is 1 and η is 2, then X is 1 or 2; * aryl But the restriction condition is that if the A unit is phenyl, the B unit is phenyl, the aryl is phenyl, π is 2, and m is 1 or 2, then X is 1 or 2; * Heteroaryl; * aralkyl; * heteroaryl-alkyl; * alkenyl;-! 3-This paper size applies to China's national standard (CNS standard t 210X297 mm) -------- -. 乂 ------ II ------ β — (((Please read the notes on the back before filling out this page) Central Bureau of Standards, Ministry of Economic Affairs, Consumer Affairs Cooperation, Printing A7 B7- ---- 一 ------------ 5. Description of the invention (丨!) * Alkenyl substituted by aryl; * Alkenyl substituted by heteroaryl; 'Block group: * Aryl group Substituted alkynyl; * heteroaryl substituted alkynyl; * _ (CH2) tR7, where t is an integer of 0 or 1 to 5, and R7 is selected from the following. * ^-Phthaloiminoimino ; * N · (1,2, benzenedicarboxyimidofluorenyl); * N_ (2,3-fluorenedicarbodiimidoglycosyl); * Ν-(1,8-fluorenedicarbodiimidofluorenyl) ; * Ν-»? | ; * Ν-(2-pyrrolidinyl); * Ν-succinimidine; maleimide imino; * 3 -hydantoinyl; * 1,2,4-uridine * Amine group; * Fleane; * Urea; and * Non-aromatic substituted or unsubstituted heterocyclic ring, which contains N, and is connected via N atom, and contains another 0 or s; and * amine group ; * And the corresponding heteroaryl part, which contains aryl-14 in the R7 group containing aryl group. This paper applies the Chinese national standard (CMS > A4 specification (210 乂 ^^^ 7)

(Please read the precautions on the back before filling out this FC-order ^ 3675 A7 B7 V. Invention description (part 12 contains 4 to 9 carbons and at least one ^^, 0 or 3 heteroatoms, but its restrictions Is when R7 is a non-aromatic fluorene-based heterocyclic ring or an amine group, and t is 0, m is 1 and η is 2, then jc is 1 or 2; and (CH2) VZR8, where ν is 0 or 1 to 4 Integer, Z represents 0II -S- 〇, 〇 \ ff and the policy R8 of the Consumer Cooperatives of the Central Sample Bureau of the Ministry of Economic Affairs is selected from the following: * alkyl;-* * aryl; * heteroaryl; * aralkyl ; * Heteroaryl-alkyl; and * -C (0) R9, where R9 represents an alkyl group of at least two carbon atoms, aryl, heteroaryl, aryl, or heteroaryl-alkyl; and The limiting conditions are:-when R8 is -C (0) R9, Z is S or 0;-when Z is 0, R8 can also be an alkylene oxide or a terminal of fluorene, alkyl or phenyl Alkylene oxide; and-when the A unit is a phenyl group, the B unit is a dialkyl group, m is 1, η is 2 and ν is 0, then X is 1 or 2; Substituted alkyl. In addition, the aryl or heteroaryl portion of any T or 1 ^ group may carry up to two as needed From the following substituents:-(CH2) yC (R ") (Rl1-) 〇H, -15- This paper size applies to China National Standard (CNS) A4 (2 W x 297 public directors) --- ------ ^ ------- Order (Please read the notes on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 413675 at _____ Β7_ V. Description of the Invention (13) (CH2) yOR! 1,. (CH2) ySR11 »-(CH2) yS (0) Rn»-(CH ^ JySiO) ^ 11?-(CH2) yS02N (R11) 2 .- (CH2) yN (Rll) 2 >-(CH2) yN (Rn) COR12; -〇C (RlI) 2〇- where both oxygen atoms are connected to the aryl ring: _ (CH2) yCORn '-(CH2) yCON (Ru) 2'- (CH2) yC02R11,-(CH2) y0COR11, halogen, -CHO, -CF3, -N02, -CN, and -R12, where y is 0 to 4; R11 represents H or a low number alkyl group. And R12 represents In the general formula (I), G represents -PO3Η2, -M,, 9 0 H R13 ΗΝ—ΝΝ · · "〆 where M represents -co2H, and R" represents 19 kinds of non- Any side chain β of a cyclic natural amino acid. The pharmaceutically acceptable salts of these compounds are also included in the scope of the present invention. Among the most relevant reference compounds in the prior art, the molecular Unsubstituted phenyl part, and propionic acid or butyric acid-based part having an unsubstituted or methyl or phenyl. It has been reported that when it contains a larger bulky group, the compound of the prior art will not have the activity as an anti-inflammatory analgesic. See, for example, R. G. Child and others, J. Pharm. Sci., Division, 466-476 (1977). On the contrary, it has been found that compounds having a strong μ P inhibitory activity have considerable substituents in the propionic acid or butanidine moiety in the molecule. The V position of the biphenyl moiety of the best MMP inhibitor also contains a substituent at most, but when the propionic or butyric acid moiety is appropriately substituted, the present invention is unsubstituted-16-II \ /, C- NC—Μ II • c · Ν · or {Please read the notes on the back before filling this page) This paper size applies to China National Standard (CNS) Α4 specification (210X297 mm). Cooperative printed 413675 A7 _____B7_ 5. Description of the invention (Η) Biphenyl compounds still have sufficient activity, which can be considered as candidate drugs. In addition to the above compounds, the present invention also relates to pharmaceutical compositions with matrix metalloproteinase inhibitory activity These compositions include the compounds of the invention described above and in more detail below, and a pharmaceutically acceptable carrier. The present invention also relates to a method for treating humans to achieve a certain effect. The cause and effect means: reducing osteoarthritis, rheumatoid arthritis, septic arthritis, periodontal disease, corneal ulcer, proteinuria, aortic aneurysm disease, Malnourished epidermal blistering, conditions that can cause inflammatory reactions, regulated by MMP activity ~ Osteopenia, temporomandibular joint disease or neurological deutschau deleuser: Delayed tumor metastasis or caused by joint trauma Degenerative cartilage loss; reduction of coronary arterial gold plugs caused by ruptured arterial plaques; or improved fertility control; the method comprises administering a compound of the invention as described above and in more detail below 'the compound may inhibit at least- The activity of a matrix metalloproteinase to achieve the desired effect. The description of the figure can be better understood by combining the following detailed description with the diagram, wherein: Circle 1 shows the inhibitory effect of the compound of the invention at 40 mg / kg (po) on the experimental B1U10 metastatic transfer of male BDF1 + mice: Figure 2 shows The inhibitory effect of the compound of the present invention on spontaneous transfer of B16.F10 in male BDF1 mice at i0 mg / kg (p0); and circle 3 shows that the compound of the present invention has a male Balb / c nu at 40 mg / kg (po) / nu Inhibition of SKK 0-3 water abdomen in mice. Detailed description-17- This paper size is suitable for cattle S country 4 孓 (〇 ^) person 4 see the case (210 \ 297 mm 7 (Please read the precautions on the back before filling in this page) Order A7 B7 41cG7 ^ Five, DESCRIPTION OF THE INVENTION (15 More specifically, the compounds of the present invention are compounds having matrix metalloproteinase inhibitory activity of the formula: '(T) xABDEg (I) where (T) XA represents a substituted or unsubstituted aromatic selected from the following: Department or Department of Heteroaromatics:

Order (please read the notes on the back before filling out this page) Seal of the Male Workers Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Α7 Β7 V. Description of the invention (16) where R1 represents Η or 1 to 3 carbons. In these structures, the aromatic ring is called A ring or A unit, and each T represents a substituent: called a T group or T unit. The substituent T group is selected from: halogen-F, -Cl'-Br, and -I; 1 to 10 complete alkynyl groups; 1 to 10 complete haloyl groups; 2 to 10 carbon alkenyl groups; 2 to 10 carbon alkynyl groups;-(CH2) pQ, where p is 0 Or an integer of 1 to 4; and -alkenyl-Q, in which the alkenyl moiety contains 2 to 4 carbons, each Q of the latter two groups is selected from the following: an aryl group of 6 to 10 carbons

; Heteroaryl containing 4 to 9 carbons and at least one N, O or S heterogen; -CN-one; -CHO; -N02; -C02R2; -OCOR2: -SOR3; -S02R3; -CON (R2) 2; -SO, N (R2) 2; -0 (O) R2; -N (R2) 2; -N (R2) COR2; -N (R2) C02R3; -N (R2) CON (R2) 2; -CHN4; -OR4; and -SR4. The R2, R3 and R4 groups are as defined below. R2 represents Η; an alkyl group of 1 to 6 carbons; an aryl group of 6 to 10 carbons; a heteroaryl group containing 4 to 9 carbons; and at least one N, 0 or S heteroatom; an aralkyl group in which aryl The base portion contains 6 to 10 fluorene and the alkyl portion contains 1 to 4 carbons; or a heteroaralkyl group in which the heteroaryl portion contains 4 to 9 carbons and at least one N, 0 or S heteroatom and The alkyl portion contains 1 to 4 carbons. R3 represents an alkyl group of 1 to 4 carbons; an aryl group of 6 to 10 carbons; a heteroaryl group containing 4 to 9 carbons and at least one N, 0 or S heteroatom: an aralkyl group in which the aryl portion Contains 6 to 10 carbons and the alkyl portion contains 1 to 4 carbons; or a heteroaralkyl group in which the heteroaryl portion contains 4 to 9 carbons and at least one N'0 or S heteroatom and the alkyl portion Servings contain 1 to 4 carbons. R4 represents Η; an alkyl group of 1 to 12 carbons; an aryl group of 6 to 10 carbons; a heteroaryl · aralkyl group containing 4 to 9 carbons and at least one N, 0 or S heteroatom, -19 ^ This paper size applies to China National Standards (CNS) A4 specifications (2 丨 〇 × 297 mm) (Please read the notes on the back before filling out this page) Order 413675 A7 ______87_ 5. Description of the invention () 7 Parts contain 6 to 10 carbons and the alkyl moiety contains 1 to 4 carbons; heteroaralkyl, where the heteroaryl moiety contains 4 to 9 carbons and at least one N, 0 or S heteroatom and the alkyl moiety Parts contain i to 4 carbons; alkenyl groups of 2 to 12 carbons; alkynyl groups of 2 to 12 carbons;-(CqH2qO) rR5, where q is 1 to 3, r is 1 to 3, and R5 is fluorene, But its limiting condition is that q is greater than 1 * or R5 is an alkyl group of 1 to 4 carbons, or a benzyl group:-(CH2) SX, where s is 2 to 3, and X is halogen; or -C (0) R2 〇 * Attached to Q or any unsaturated part of the Q-part is separated from any N, _- 〇 or S of Q by at least one carbon atom, and the number of substituents represented by X is 0, 1 or 2 〇 In the general formula (I), B represents an aromatic ring or a heteroaromatic ring selected from: ( (Please read the notes on the back before filling this page) Printed by the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Male Workers' Consumer Cooperatives | Zhang-Paper Standard One I National Standard A7 B7 V. Invention Description (18 Central Ministry of Economic Affairs Standards Bureau employee consumption cooperation

(Please read the notes on the back before filling in this page) The size of the paper is applicable to the China National Standard (CNS) A4 (210X 297 mm). Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 4x3675 A7 B7 5. Invention Explanation (19) wherein R1 is as defined above. These rings are called B rings or B units. In the general formula (I), D represents the following:

In the general formula (I), E represents a chain of n carbon atoms with m R6 substituents, and is called an R6 radical or R6 unit. The R6 group is an independent substituent or forms a spiro or non-spiro ring. A ring can be formed in two ways: a) two R6 groups are combined with-two R6 groups attached to the chain atom and any The interspersed chain atoms together form a 3- to 7-membered ring; or b) an R6 group is combined with the chain where the R6 base graph is located, and is formed with the bond atom attached to the R6 group and any interspersed bond atom. 3 to 7 member ring. The number of carbon atoms η of the chain is 2 or 3, and the number of R6 substituents 01 is an integer of 1 to 3 to. The total number of carbon atoms in the R6 group is at least two. Each group is selected from the substituents in the following items 1) to 14): 1) The R6 group may be an alkyl group of 1 to 10 carbons, but the limitation is that if the A unit is a phenyl group and the B unit Is a phenyl group, m is 1, η is 2, and the pit group is located at an α carbon position relative to the D unit, then X is 1 or 2. 2) The R6 group may be an aryl group of 6 to 10 carbons, but the limitation is that if the A unit is phenyl, the B unit is phenyl, the aryl is phenyl, η is 2, and m is 1 or At 2, X is 1 or 2. 3) The R6 group may be a heteroaryl group containing 4 to 9 carbons and at least one n, 0 or s heteroatom. 4) The R6 group may be an aryl-alkyl group in which the aryl portion contains 6 to 10 carbons and the alkyl portion contains 1 to 8 carbons. -22- $ ^ metric 3 3 Family Standard (CNS) A4 Regulation; 210X297 Public Holiday) ----— ^^^^ 1 —Jn ^^^^ 1 ^^^^ 1 ^^^^ 1 Ettf I ( Please read the notes on the back before filling out this page) Order B7 V. Description of the invention (20) 5) The R6 group can be heteroaryl-alkyl, in which the heteroaryl part contains 4 to 9 carbons and at least one N, O or S heteroatoms, and the base portion contains 1 to 8 carbons. 6) The R6 group may be an alkenyl group of 2 to 10 carbons = 7) The R6 group may be an aryl-alkenyl group, wherein the aryl portion contains 6 to 10 carbons and the alkenyl portion contains 2 to 5 8 carbons) 8) The R6 group may be a heteroaryl-alkenyl group, where the heteroaryl portion contains 4 to 9 carbons and at least one N, 0 or S heteroatom—and the feminine portion contains 2 to 5 "Carbon", 9) The R6 group may be an alkynyl group of 2 to 10 carbons. 10) The R6 group may be an aryl-alkynyl group, wherein the aryl portion contains 6 to 10 carbons and the alkynyl portion contains 2 to 5 carbons. 11) The 1 ^ group may be a heteroaryl-alkynyl group. Where the heteroaryl moiety contains 4 to 9 carbons and at least one N, O or S heteroatom and the alkynyl moiety contains 2 to 5 carbons. 12) The basic difficulty of R6 can be-(CH2) tR7, where t is an integer from 1 to 5, and R7 is selected from the following:

-23 · The size of this paper applies to the Chinese National Standard (210X297 mm) grid 41210ϋ7 Α7 Β7 V. Description of the invention (21 —N: 〇 0 6

|, —N

I Y

/ ~ V (R1) U 〇R2 〇I II -N-c——CR3 R2 OI II • N-C-R2, R2 〇R2 · I II IN—c ~~ N-R2 (Please read the notes on the back first Fill out this page again) and specify the corresponding heteroaryl moiety, in which the aryl moiety in the R7 group containing the aryl group contains 4 to 9 carbons and at least one ν, 0, or s heteroatom. In these R7 groups, Y represents 0 or S; R1, R2, and R3 are as defined above; and u is 0, 1, or 2; but the restriction is that when the reverse is

-N

Y (R \ or · R2 -N-Rp when printed by the central standard of the Ministry of Economic Affairs and Consumer Cooperatives, and the A unit is phenyl, the B unit is phenyl, the melon is 丨, η is 2 and t is 0; Then X is 1 or 2. 13) The R6 group may be-(CH2) VZR8, where ν is 0 or an integer from 1 to 4; z represents -S-, -S (o)-, -SOy, or 0- And R8 is selected from the following: an alkyl group of 1 to 12 carbons; an aryl group of 6 to 10 carbons; a heteroaryl group containing 4 to 9 carbons and at least one N, 0 or S heteroatom; aryl- Alkyl, 24- This paper uses the National Standard of the Cabinet of Ministers {CNS) A4 (210X297 mm) 413675 at B7 V. Description of the invention (22) where the aryl part contains 6 to 12 carbons and the alkyl part Parts contain 1 to 4 carbons; heteroaryl-alkyl, where the aryl moiety contains 4 to 9 carbons and at least one N, 0 or S heteroatom and the alkyl moiety contains 1 to 4 carbons; C (0) R9, where R »represents an alkyl group of 2 to 6 carbons, an aryl group of 6 to 10 carbons, a heteroaryl group containing 4 to 9 carbons and at least one N, 0 or S heteroatom, or Aryl-alkyl, where the aryl moiety contains 6 to 10 carbons, or 4 to 9 carbons and at least one N, 0 or S heterogen Heteroaryl, and the alkyl portion contains 1 to 4 carbons, but the restrictions are:-when R8 is -C (0) R9, Z is -S- or-when Z is -0- , R8 can also be-(CqH: qO) rR5, where q, r and R5 are as defined above; and • when A unit is phenyl, B unit is phenyl, m is 1, η is 2, and ν is When 0, X is 1 or 2; and 14) the R6 group may be-(CH2) wSiR1G3; wherein w is an integer of 1 to 3, and R1G represents an alkyl group of 1 to 2 carbons. In addition, the aryl or heteroaryl portion of any T or R6 group may bear up to 2 substituents selected from the following:-(〇 ^ 2: ^ (:( 1111) (1112;) 011,- (CH2) y〇Rl >,-(CH2) ySRu »-(CH2) yS (0) R ^,-(CH2) yS (0) 2Rn '-(CH2) ySOiN (R11) 2 >-(CH2) yN (Ru) 2?-(CH2) yN (Rl ^ COR12 '-OC (Ru) 2〇_ where two oxygen atoms are connected to the aryl ring,-(ch ^ coru,-(CHjyCONiR11; ^,-(CUdyCC ^ R11,-(CHdyOCOR11, · halogen, _CHO, _CFi, "N02, _CN, and Ι112, where y is 0 to 4; r11 represents H or 1 to 4 carbons; and R1- represents 1 to 4 Carbon pit base In the general formula (I), G stands for -P〇3H2, -M, 25- The size of the paper is applicable to the Chinese solid sample (CNS) A4 specification (210X 297 mm) (please read the note on the back first) Please fill in this page for further details), τ Printed by the staff of the Central Bureau of Standards of the Ministry of Economic Affairs 41367; A7 B7 V. Description of the invention (23) 0 〇0 H R. 13 Ν-Ν Ν—S—Μ, 丨 or Η

Ν Ordered by the Ministry of Economic Affairs, the staff of the Central Bureau of Standards and Consumers, printed M where -C02H, -CON (Ru) 2, or <: 02ϋ12, and R13 represents any side chain of 19 non-cyclic natural amino acids . The pharmaceutically acceptable salts of the compounds of the general formula (1) are also within the scope of the present invention. Among the compounds of the present invention, the following compounds are preferred β is preferred, and the substituent T group 圑 is halogen or ether OR4, which + R4 An alkyl or aryl-alkyl group of 1 to 12 carbons, in which the aryl portion is 6 to 10 carbons and the alkyl portion contains 1 to 4 carbons is preferred. Most preferably, T is halogen, And when T is OR4, R4 is an alkyl group of 1 to 6 carbons, or a fluorenyl group. The subscript of T represents the subscript number or 2 is preferred, and 1 is the most preferred, and this substituent is located in the A ring 4- In position, ring A is preferably a benzene ring or a phene ring, and phenyl is most preferred. Ring B is 1 * 4-phenylene or a 2,5-phene ring, and 1,4-benzene is preferred. The best D group is the best carbonyl group. More preferably, the R6 group is: 1) an aryl-pit group where the aryl moiety contains 6 to 10 carbons and the alkyl moiety contains 1 to 8 Carbon: "· (CHAR7, where t is 0 or an integer from 1 to 5, and R7 is an iminofluorenyl group containing an aromatic residue; or 3)-(CH2) vZR8 'where v is 0 or 1 to 4 Integer, z is s or 0, and -26 · This paper is JM-returned with the national standard (CNS 丨 A4 specification ( 21QX 297 Public IH--nn I— n-, at -I / v \ (Please read the notes on the back before filling in this page) Printed by the Central Government Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, 413675 a? ____B7 5 Explanation of the invention (24) R8 is an aryl group of 6 to 10 carbons, or an arylalkyl group, in which the aryl part contains 6 to 12 carbon atoms and the radical part contains 1 to 4 carbon atoms. 'R6 group is the following group' and any aromatic moiety is preferably substituted: 1) arylalkyl, wherein the aryl moiety is phenyl and the alkyl moiety contains 1 to 4 carbons; 2) -(CH2) tR7 'wherein t is an integer from 1 to 3, and R7 is N-phthaloiminoamido, N- (l, 2-fluorenedicarboximidoamido), N- (2,3- Stilbene diimide. Fluorenyl group) or N- (l, 8- fluorinated dicarboximide fluorenyl group); or '' 3)-(CH2) vZR8, where an integer to 3, Z is S and R8 is stupid The G unit is preferably a carboxylate. It is understood that the term "alkyl" as used herein refers to straight-chain, branched, cyclic, and polycyclic materials. The term "11-dent alkyl" refers to the part Portions or complete functional alkyl groups such as, for example, (CH2) 2C1, -CF3, and -C6Fi3. The B ring of the general formula (I) is a substituted or unsubstituted aromatic ring or heteroaromatic ring, wherein any substituent is an active position that will not cause the molecule to fail to cooperate with the target enzyme or interfere with the relative configuration of the A and B rings Harmless group. These groups may be, for example, lower-carbon alkyl groups, lower-carbon alkoxy groups, CN, N02 ′ halogen, and the like, but are not limited to these groups β. Among the specific embodiments, The invention relates to compounds of general formula (I), in which at least one A, B, T and R6 unit contains a heteroaromatic ring. Preferred heteroaromatic ring-containing compounds are those in which the heteroaryl group is 4 to 9 carbon heteroaryl groups, which contains 5 containing N, S or when the ring is 5 members) or N (when the ring is 6 members) 6-membered heteroaromatic ring. Particularly good aromatic heterocyclic compounds are among them. -27- The paper size is applicable because of the national standard (CNS) M specification (210X29? Public holiday) (Please read the precautions on the back before filling this page) Order 4130 Printed by A7 B7, Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (25) At least one A and B unit contains a pyrimidine ring. When the A unit is phenol, it is connected to the B unit at the 2-position and has a substituent τ group at the 5-position. The weight is good = > When the B unit is p-phene, it is via positions 2 and 5. It is better to connect with d and A units respectively. In the general formula (I), it is preferred that the A and β rings are a phenyl group and a phenylene group, respectively. The a ring bears: > A substituent T group is preferred, and its position is the distance from the position connecting the b ring. A distant position is preferred, a D unit is preferably a carbonyl group, and a G unit is preferably a carboxyl group. In another embodiment, the present invention relates to a compound of the general formula (丨), wherein η is 2 in the E unit and m is 1. These compounds therefore contain at least two carbon atoms' between the D unit and the G unit and the two carbon chain carries a substituent. In another specific embodiment, the present invention relates to a compound of the general formula (1), wherein ring A is a substituted or unsubstituted phenyl group, ring b is a p-phenylene group, and any T and R6 containing an aryl group The aryl moiety of the Ministry of Examination only contains carbon. These compounds therefore do not contain heteroaromatic rings. In another embodiment, the present invention relates to compounds of general formula (ί), wherein m is 1 and R6 is an independent substituent. These compounds are substances which contain only one R6 substituent in the ε unit, and this substituent is not in the ring. The preferred compounds belong to subgroups such as T

》 —C—Ch ^ -OR ^ COgH where x is 1 or 2 and a substituent τ group is located in ring a relative to rings A and B • 28 · This paper standard applies to Shiyuanyuanzuka Standard (CNS) A4 (21〇χ297 public epidemic (please read the notes on the back before filling out this page) -s 413i > 75 A7 B7 V. Description of the invention (26) (Please read the notes on the back before filling out this page) Link At the 4-position of the point. The substituent τ of this subgroup is halogen_Cl, .Br, or -I, or 眯 -or · ♦. The best compound is only on the A ring, and is connected to the B ring. In the 4-position of the point, a substituent τ > In the compound of the general formula (I), R6 is-(CH2) tR7, and t is an integer of 1 to 5. In the compound of the general formula (I), R6 is-(CH2) VZR8, v is an integer from 1 to 4 and Z is -S- or -O-. Preferred compounds of general formula (I), Han 6 is an alkyl group containing 4 or more carbons and Among them, R6 is an arylalkyl group. The alkyl portion contains 2 to 3 carbons. In another embodiment, the present invention relates to compounds of general formula (I), wherein the number of substituents on the E unit is 2 Or 3; and when m is 2, the two base graphs are independent Substituents, or together form a spiro ring, or one & 6 group is an independent substituent, and the other forms a spiro ring • and when m is 3, two R6 groups are independent substituents, one R6 group Groups form a ring, or two groups are formed, and one R6 group is an independent substituent, or three R6 groups are independent substituents. Therefore, this subgroup includes the E unit of two Or tri-substituted compounds, if di-substituted, any ring formed by one or two R6 groups is a spiro ring; if tri-substituted, the R6 group may form a spiro ring or a non-spiro ring In another specific embodiment of the quasi-stationary shellfish consumer cooperation and cooperative system, the present invention relates to compounds of general formula (I), in which the E unit has a substituent or 2; and when m is 1, the rs group When m is 2, two R6 groups together form a non-spiro ring or one R6 group is an independent substituent and the other forms a non-spiro ring. Therefore, this subgroup includes the E unit band Compounds that have one or two R6 substituents, and at least one of these substituents involves a non-spirocyclic ring. Ruler Yan used Ning's Family Standard Li (CNS) A4 specification (210X297, 4136 ^ A7 B7) V. Description of the invention (3) More specifically, representative compounds of general formula (I), in which one or more substituents The R6 group is involved in the formation of non-spiro rings, and the structure of the E unit is as follows: (H2-aR6a〇) c rCR1 (Hf.b ^ C) — (CRGb 5aH2-a) d ~ i U, (R14) k: ( CeH2e-f <);-( H2.aR6aC) c 广 V ， 2_ 丄 0 * ib ^ bC) — (CFlVVb) -V (RM) k ^ ~ (Hlb ^ C) (CgH2g-2kr (^) a ,) 2-a 4- (R14) k (ChH2h-2-k) '(Please read the notes on the back before filling in this 苋);-{H2aR6aC) c (CR6aH2.a) d ~ (H1bR «bC) -~ (CR6bH, .b) V (H14) k, (CiH2i.kU〆,

14 > (R ^) a ^) 2-a (H2-aR6aC) c

(CR6aH2.a) dI (H1b ^ b9) (CR6bH, .b) (H,, b R6 ^) ^ (CRGb H, _b) — ^ H. (R14) k Off-site Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs Print

(H2.aR6aC) c ”V 丨 2a) d — :( Hi.b ^ bC) — (CH6bH | b); (Cz 丨 丨 2A > (R ") a (H) 2.a; — {H , bf ^ bC) ^ (CR6bH, _b y ~ \, A ((CzHJ) \ = ^ (R14) k where t is 0, 1 or 2: b is () or 1: c is (j or 1: d 0 or 1: C + d is 0 or 1; e is 1-5; f is 1-4; g is 3-5; h is 2-4; i is 0 · 4; 丨 is 0-• 30 · The size of this paper is in accordance with the Chinese National Standard (CNS) Λ4 specification (; M () × 297 mm) V. Description of the invention (A7 B7 ----- the total number of R 6 groups is 0, 1 or 2: U stands for n 2 Each R14 radical is selected from: 1 to 9 ?, R :; and if the base of the courtyard contains i to 7 carbons and aryl heptahedral, square radical said 'its ^^% Contains 6 to 10 carbons: 2 to 9 carbons of alkenyl: aryl substituted alkenyls, where the alkenyl portion contains 2 to 4 carbons and the aryl portion contains 6 to 10 carbons: 2 To 9 fluorenyl: sialyl substituted alkynyl, in which the alkynyl moiety contains 2 to 4 carbons and the aryl moiety contains 6 to 10 carbons, 6 to 10 fluorene aryl groups. COR: ., _ CCkr3 CON (R ~):-(CUR /, where t is 0 or an integer from 1 to 4; and-(CH 2) v Z Rs' where V is an integer from 1 to 3, and Z represents _ s-or -Ο-'R1, R7 and R8 are as defined above. In the compound of the general formula (I), one or more substituents R < 5 are involved. For the formation of non-spiro rings, the structure of the E unit is as follows: ^ (H2.aR6aC) c -V (RH) kf \-(R14H (C0H2ekK ^ (CgH2t 2g-2-k

Packing ------ Ordering ** (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs " ~ (H2aR6aC) c (CR6aH2.a) d —; ( Hi-b ^ bC) ~ (OTbH, ^) (RH) k

And, (CjH2i.kU) where a, h, e, d, (c d), e, g, i, k 'R are all general meanings, (丨 and R 1 4 are more modified as defined above Among the compounds of the general formula (I), one «« or a substituent R " Jige involved ● 3 paper size applicable to the Chinese National Standard (CNS) Λ4 specifications (;; 0 X 2V7 mm > / / 413675 A7 -----__ B7 V. Description of the invention (29) The non-spiral ring of the following formula.

Where the subscript X is 1 or 2;-a substituent τ is located at the 4-position of ring A relative to the connection point between rings A and B: e is 2 or 3; and R14 is as defined above. The invention also includes certain intermediates suitable for the synthesis of some of the patented inhibitors. These intermediates are compounds of the following formula ^ (Please read the precautions on the back before filling out this page).

Printed by the Central Laboratories of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives, where E represents T and substituents, and X is 1 or 2. Relevant art experts understand that many of the compounds of the present invention can be in the form of enantiomers or diastereomers, and that these stereoisomers usually have different activities in biological systems. The present invention encompasses all possible stereoisomers with inhibitory activity on M MP, regardless of their stereoisomerism, and mixtures of stereoisomers' at least one member of which has inhibitory activity. Name of the best compound of the invention The description is as follows: -32 ^ This paper rule / 1 thorn t ϋ ϋ ϋ ϋ (Λ4 ^ (21 Gx 297 mm) 413075 A7 _B7_______ V. Description of the invention (30) 196 4 · [4- (4-Gaphenyl) Phenyl] -4-oxo-2- (phenylsulfanyl) butyric acid197 4- [4- (4-Gaphenyl) phenyl] -4-oxo-2S · (phenylsulfanyl) butyric acidΓ98 4- 丨 4- (4-Gaphenyl) phenyl] -4-oxo-2R · (phenylthiomethyl) butyric acid 114 4- [4- (4-Gaphenyl) phenyl] -4-oxo -2_ (3-phenylpropyl) butanoic acid 115 4- [4- (4-phenylphenyl) phenyl1-4-oxo-2R- (3-phenylpropyl) butanoic acid 116 4- [4- ( 4 · Phenyl) phenylphenyl 4-oxo-2S- (3-phenylpropyl) butanoic acid144 4- [4- (4-phenyl) phenyl] -4-oxo-2- [2- (3-N, N-diethylaminomethylamidino) phenyl] butanoic acid 145 4- [4- (4-Gaphenyl) phenyl] -4-oxo-2S- [2- (3- N, N-diethylaminomethylmethyl) phenyl] butanoic acid 146 4- [4- (4-Gaphenyl) phenyl] -4 · oxy-2R- [2- (3-N 'N -Diethylamino Fluorenyl) phenyl I butyric acid 85 4- 丨 4- (4-pentyloxyphenyl) phenyl] -4-oxo-2- (3-phenylpropyl) butyric acid 86 4- [4- (4- Pentyloxyphenyl) phenyl] -4-oxo-2S- (3-phenylpropyl) butyric acid 87 4- [4- (4-pentyloxyphenyl) phenylj 4-oxo-2R- (3 -Phenyl) butyric acid 99 4- [4- (4-Phenyloxyphenyl) phenyl] -4-oxo-2- (3-phenylpropyl) butanoic acid 100 4- [4- (4- 芊Oxyphenyl) benzyl] -4-oxo-2S- (3-phenylpropyl) butanoic acid 101 4- [4- (4-fluorenyloxyphenyl) phenyl] -4-oxo-2R- (3- Benthyl) butyric acid 267 4- [4- (4-Gaphenyl) phenyl] -4-oxo-2- (2 • phthalimideethyl) butyric acid Central sample bureau of the Ministry of Economic Affairs, employee consumption cooperation Du printed ^^ 1 ^^^ 1 n · — i n_l n ^ i ϋ ^^^ 1 「V y / 9. (Please read the precautions on the back before filling this page) 268 4- [4- (4 -Phenyl) benzyl] -4-Ga-2S- (2-Phenylimineethyl) butanoic acid 269 4- [4- (4-Gaphenyl) phenyl1-4-oxy-2R- (2-phthalimidoethyl) butyric acid 294 trans-5- [4- (4-phenylphenyl) benzenecarbonyl] -trans-2-benzylthio-cyclopentanecarboxylic acid 296 (IS, 2R, 5S) -trans-5- [4- (4-Gas-benzyl) benzylcarbonyl, trans-1,2 · 1 33- 'This paper size applies to China National Standard for Translation (CNS) A4 210X 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7________ V. Description of the Invention (31) Phenylthio-cyclopentanecarboxylic acid 297 (1R, 2S, 5R) -trans-5- [4- (Heart gas phenyl) benzyl carbonyl] • trans Ί * phenylthio-cyclopanecarboxylic acid 298 trans-5- [4- (4-Gaphenyl) benzyl] -cis-2 · ( 2-Methoxycarbonyl Basic Sulfuryl) -Cyclopentanecarboxylic Acid 299 (IS, 2S, 5S) -trans-5- [4- (4-Phenyl) benzyl cis_ 2 · (2 -Methoxycarbonylphenylthio) · cyclopentanecarboxylic acid 3 00 (1R_ '2R, 5R) -trans- 5- [4- (4 -aminobenzyl) expressing group] -cis- 2-. (2-methoxycarbonylbenzylthio) -cyclopanecarboxylic acid '360 trans-5- [4- (4-chlorophenyl) phenylcarbonyl] -trans-2-phthaloimide methylcyclopentane Alkyl carboxylic acid 361 (IS, 2R, 5S) -trans-5- [4- (4-phenylphenyl) phenylcarbonyl] -trans-2-phthaloimide f-based cyclohexyl carboxylic acid 362 (1R , 2S, 5R) -trans-5- [4- (4-Gaphenyl) benzenecarbonylcarbonyl trans-2-phthalimideiminomethylcyclopentanecarboxylic acid General preparation method: The compounds of the present invention may be known Chemical reaction and process preparation. Although this' still describes the following methods to assist readers in synthesizing inhibitors, the experimental section below will explain the operation examples in more detail with specific examples. If the meaning is not specified hereinafter, all variable groups of these methods are represented by a generic term. The variable index η is defined independently with each method. If in a given structure, the designated code (ie, R6 or D) represents a changeable group more than times, it is understood that these groups are independently changed within the definition of the code. As defined above, the unit of pounds contained in the compound of the present invention is 34. What paper size is applicable + National National Standard (CNS) ------------- -Installation-/ 1., (Please read the precautions on the back before filling out this page) Order A7 A7 Printed by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives ______B7 V. Description of the invention (32) with 1 to 3 The 2 or 3 carbon chain of each substituent R6, the definition of R6 is not Η. On the contrary, it should be noted that the definition of the R6 group used in the general reaction diagram below includes Η, to indicate that these R6 groups may be Exist in Structure 10 and be easy to represent by diagrams. However, this non-standard usage will still not change the definition of R 6 β. Therefore, it is only for the convenience of the general reaction diagram shown below. R6 except for the part specified by the definition of R < S In addition, it may be Η »The final compound contains 1 to 3 non-hydrogen groups R6.

General Method A-Preparation of the compound of the present invention, in which the A and B rings are substituted phenyl and phenylene, respectively, which uses the Friedel-Crafts reaction ~ (Friedel-Crafts reaction), Benzene II and intermediates containing activated gap groups such as: succinic anhydride or glutaric anhydride derivative 111 or fluorene radical j V, in the presence of Lewis acid catalysts such as aluminum trioxide, in aprotic solvents such as : 1,1,2,2-Siqi Yipo Ling. The familiar Friedel-Crafts reaction can also be accomplished using many other alternative dissolution and acid catalysts, as described in £. Berliner, Org. React., 229 (1949) and H. Henney ( fje_ney), Comp. Org. Synth., 2, 733 (1991) 0 Method A

-35- Applicable to China National Standard (CNS) A4 specifications (2ΐ〇κ297 mm) (Please read the precautions on the back before filling out this page).-Packing. Order 413675 at _______B7 V. Description of Invention (33)

If the anhydride III is monosubstituted or polysubstituted in an asymmetric manner, the crude product A is often reacted with one of the two carbonyl groups of the anhydride, and a mixture of isomers appears. The isomers obtained can be used by relevant technical experts. The known standard method is divided into pure forms by crystallization or chromatography. Printed by the Consumer Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs ^ — ^ 1 n ^ i — ^^ 1 ^^^ 1 1 ^ —— «ϋ nn ::-.......... II l ^ i — N iaJ f (please read the precautions on the back before filling this page) If it is not available from commercially available products, the production method of succinic anhydride Πϊ can be obtained through Stobbe condensatin, which is derived from dibasic acid. The ester is reacted with a zirconium network (producing a side chain R0), followed by catalytic hydrogenation, which hydrolyzes the half-ester intermediate to form a diacid, and then reacts with acetonitrile or acetic anhydride to convert it into an anhydride. Alternatively, the half-ester intermediate is treated with thionine or grass gas to be converted into thorium-based gas IV. For a list of Stober condensation reactions, including a list of suitable solvents and bases, see W.S. Johnson and G.H. Daub, Org., P. 63, 1-1 (1951). This method for preparing 111 (1 ^ = 11, isobutyl, and 11'-n-pentyl) has been described in U.S. Patent No. 4S771,038 by D. Hualanin et al. (September 13, 1988 day). Method A is particularly suitable for preparing cyclic compounds such as: I-A-3, in which two R6 groups are connected to a methylene chain to form a 3 to 7-membered ring. Small ring (3- to 5-membered) anhydrides are susceptible only to the cis isomers, producing the cis compound I-A-3 of the present invention. Anti-36- This paper adopts the Chinese National Standard (CNS) A4 specification (210X297). &Quot; " " " " " Central Standards Bureau of the Ministry of Economic Affairs®: Printing for industrial and consumer cooperation J13675 A7 B7 V. Description of the invention (34) The compound of formula IA-4 is prepared by treating IA-3 with a base such as DBU in THF. The substituted 4-membered ring starting acid anhydride is as follows: III-A-1 is formed by photochemical 2 ^ 2 reaction as shown below. This method is particularly suitable for the preparation of compounds where R14 is ethoxyl or ethoxymethylene. "Following the Friedrich-Crafts reaction, hydrolyzation can be used to remove acetate and convert it to 2- ( Trimethyl stilbene) ethyl ester, protecting the carboxyl group. The obtained intermediate R14 = CH2OH can be converted into the compound of the present invention containing other R14 groups by using the general method K

When a double bond appears between C-2 and C.-3 of the Poberzyl chain (for example: from maleic anhydride or 1-cyclopinene-1, 2-dicarboxylic anhydride) or a double bond appears in the side chain (Eg: Itaconic anhydride is used as the starting material) When the 'Frieder-Crafts method is used, two R6 groups are present on a carbon chain to form a plug-in T subgroup (= CH2) The product of a group. The continuation of these compounds is described in Methods D and E. "General Method B-or 'In the preparation of Compound 1, dipokyl malonate V 1 and tiger τ halide can be singulated to form an intermediate. After the compound v I 丨, it is alkylated with the commercial methyl benzophenone V 111 to produce intermediates! χ. The compound of structural formula [χ] is then hydrolyzed by picking up an aqueous solution, and then heated to remove the carboxylic acid intermediate of the malonic acid intermediate to produce 1-B-2 (Method B-1). Using one equivalent of an alkaline aqueous solution, an ester can be obtained, in which R12 is an alkyl group, and when using more than 2 equivalents of an alkali, an acid compound (R = Η) can be obtained. If necessary, without heating, diacid or acid ester i-B-1 can be obtained. -37. This M standard is applicable to the Chinese National Standard (CMS) A4 specification (297 public ** — " ~ --------- #-/ V (Please read the precautions on the back before filling in this Page), 17 413675 at Β7 5. Description of the invention (35) Alternatively, the diester intermediate IX can be heated with strong acid such as concentrated hydrochloric acid in acetic acid in a sealed test tube at about 110 ° C for about 24 hours, I__b-2 (R12 =: H) is produced. Alternatively, VI and VIII are first reacted, and then reacted with a halogenated halide to produce the same IX (Method B-2). The intermediate VIII is composed of biphenyl 11 and Buddha. In the Reed-Claffert reaction, it is formed by reacting with acetofluorenyl halides such as bromoacetamido bromide or acetylacetamido gas, or biphenyl can be reacted with acetamido gas or rhenium acetate. For example: halogenation of bromine produces intermediate VIII (X ^ Br). 'The attack point of method B is to produce a single specific orientation isomer, while method a produces a mixture. "When the side chain R6 contains an aromatic ring or a heteroaromatic ring At this time, if method A is used, it may participate in the intramolecular deuteration reaction and generate by-products, so method B is particularly applicable at this time. When containing heteroatoms such as oxygen and sulfur Nitrogen or more complex functional groups such as: the carboxyl group of the final product of the imine ring is adjacent to the R6 group, this method is also particularly applicable β (please read the precautions on the back before filling this page), * Central Ministry of Economic Affairs Printed by the bureau / consumer cooperative -38- j The size of this paper applies to the Chinese National Standard (CNS) Α4 size (mm) A7 B7 ______ V. Description of the invention (36

Method B

Ft6

VI

Η [-Ο # H ^ 〇R12 Anhydrous so X_r6 (B-2)

(Please read the notes on the back before filling in this education.) 4 Order General Printing Method C for the Consumer Cooperatives of the China Standards Bureau of the Ministry of Economic Affairs-Particularly suitable for the use of palmar η p LC to separate the enantiomeric mixtures of racemic products Structure (see for example: £). Arlt, B. Boemer, R. Grosser and W. Lange, Angew, Chem_Int. Ed. Engl. 1991) No. 12). The compounds of the present invention are made into pure enantiomers by using the palladium-assisted pathway, see, for example, DA Evans, Aidrichimica Acta, 11 (2), 23 (1982) • 39- paper protractor / fcit5 + ϋ S standards 丨 CNS) A4 specifications (2iOX29T ;, S Guang ^ — Duty printing and consumer cooperation of the Central Bureau of Standards, Ministry of Economic Affairs, Du printed A7 ____B7 V. Description of invention (37) and similar references familiar to relevant technical experts C-1 is formed by the reaction of fluorenyl halide X with the lithium salt xI (R is usually isopropyl or fluorenyl) of palmitic auxiliary to form intermediate XH, and then at low temperature (typically -50 ° C) Bottom), alkylation with a halogen-tertiary butyl ethyl fluorenyl compound xj π to produce the pure isomer XIV. Using the opposite pair of palms X i yields the opposite pair of palms XI ν. XIV forms pure enantiomers The conversion of the acidic diacid X v is treated by lithium hydroxide / hydrogen peroxide in THF / water, followed by treatment with an acid such as trifluoroacetic acid a. Compound XV is then treated with acetylene gas to convert to pure enantiomers. Acid III-A. According to Method A, the Friedrich-Crafts reaction is used to convert ^ -B to I-C-1. C-2 biphenyl initiator II can also perform the Friedel-Crafts reaction with succinic anhydride as described above, and then carry out Fisher esterification in the presence of a low carbon number alcohol such as formazan, in the presence of a strong acid such as sulfuric acid, to form amidine Carbonyl derivative. The carbonyl group of this substance is recondensed and capped, and it is composed of 1,2-bis-trimethyl stilbene ethoxylate, which is used in a catalyst such as: It can be formed by treatment in a suitable solvent. Many other ketal derivatives and reaction conditions known to the relevant technical experts can also be used in this step. After the ester is hydrolyzed, the obtained IC.-3 and XI in the amine coupling agent such as: The reaction in the presence of 1_ (3_dimethylaminopropyl) _ 3 -ethyl degraded diimine yields amidine i_c_4. This palmaramide and alkylating agents such as: alkyl or aralkyl trifluoro The reaction of methanesulfonate or phthalate produces' enantiomerically rich product I_c_5, which can be converted into the final product hCd after sequential treatment with weak bases such as lithium hydroxide / hydrogen peroxide and acid. .These steps of unblocking can be performed in an order. -40- — —- ___ This paper is within the standard + national standard (CNS ) Grid (25x297 mm) '---------------, 玎 (Please read the notes on the back before filling this page) A7 B7

V. Description of the invention (3S method c -1

X X base + HN,

XI

r »6

(Please read the note on the back before filling out this page) M. Order the staff consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Seal -41-This paper applies the Chinese National Ladder (CTNS) A4 specification (210X 297 mm) A7 B7 V. Description of the invention (39 Method C-2 0) Λ

◦Ύ〇 πι (_η)) Lewis acid

2 to 3 Sentences I2) ct ^ otf ΓΠκ sit 丨 Heart 2 Q OCH3

-OTMS CFjS ^ TMS 1) Test solution

i-C-4 Guang 1) Strong base 2) R6OTf

(CH2jn-i q R lC-5 --------- install --------- order (please read the precautions on the back before filling this page) I) THF / li2〇LiOH / iljO. 2 > acid

iC-6 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, 42, the standard of this paper is applicable to China National Standard (CNS) A4 (21 (V29 · / mm) ___B7 V. Description of the invention (4〇) General method D -A method similar to that of WO 90/05719, in which compounds are prepared in which R6 is alkyl- or aryl- or heteroaryl- or fluorenyl- or heteroarylcarbonyl-thiol methyl. Therefore, it is substituted by Itikang The acid anhydride XVI (n = 1) is reacted under a Friedrich-Crafts paper to produce acid ID-1, which can be separated by chromatography or crystallization to a small amount of isomeric IDS. Alternatively, the compound of the present invention can be derived from method A Any one of the methods to C) react with methyl alcohol in the presence of a base to obtain ID-5 ° compound I-D -1 or I-D-5 and then with argon thio derivatives χνπ and χνιι, at the catalyst Such as: potassium carbonate, ethyldiisobutylamine 'tetrabutylammonium fluoride or free radicals_ initiators such as: azobis-isobutyronitrile (AIBN) in the presence of solvents such as: dimethylmethaneamine Or in tetrahydrofuran to produce a compound of the invention ^^-], ^ D-3, I · D6 or I-D-7. (Please read the precautions of the back page before filling out this page.) Printed by the Central Consumers ’Bureau of the Ministry of Economic Affairs, a consumer cooperative. 43 This paper ruler also uses the Chinese National Standard (CNS) Λ4 specification (210X297 mm: 413675 A7 B7. 5 、 Invention description (41

Method D

-Re

rb

H XVU Binding / 1 (Please read the notes on the back before filling in this page) ID-5 Printed by the Consumers ’Cooperative of the Central Standards Bureau, Ministry of Economic Affairs

XVUI

-44- This paper applies Chinese National Standards (CNS > M specifications mm) Consumer Co-operation Du Yin of the Central Bureau of Standards, Ministry of Economic Affairs 3 ^ A7 ______ B7____ V. Description of the Invention (42) General Method E-Replaced as necessary The maleic anhydride XIX is reacted with II under the conditions of Friedel-Crafts to produce the compound IE-1 of the present invention, and then the hydrogenthio derivative XVII or XVIII is reacted to produce the compound IE-2 or Ι-Ε -3, or reaction with substituted amine XX to produce the compound of the present invention ° IE-1 (R6 = H) is esterified with CH3I / DBU and reagent XXI and AgF, and hydrolyzed by inspection to produce the p-biloxo compound of the present invention IE-5. R14 can be a variety of different environmental or aryl pit groups, including _ group. The vinegar intermediate (from step 2) reacts with acetic acid in T H F _. After refluxing, the T is hydrolyzed to produce the compound of the present invention, wherein R14 is benzyloxycarbonyl. Method Ε

^ nf «n ^ 1 ^ 1. ^^^ 1 Hr— ml -1 -5 (谙 Please read the precautions on the back before filling in this page) 1 45-The paper size is related to the country ’s drunk freshness (CNS) A4g (210X297 ^) Consumption cooperation by employees of the Central Bureau of Standards, Ministry of Economic Affairs, printed A7 ______B7___ V. Description of the invention (43) General methods Stille) cross-coupling reaction, consisting of aryl or heteroaryl tomb metal compounds, where the metal is zinc, tin, magnesium, lithium, boron, silicon, _, cadmium, etc. 'with aryl or heteroaryl halide or trifluoro Methanesulfonate and the like. In the following reaction formulas, one of Met or X is a metal, and the other is a halide ion or trifluorocarbamate. Pii (com) is a soluble complex of JI, such as: (triphenylphosphine) palladium (0) or bis (triphenylphosphine) palladium (11) gaseous. These methods are expert knowledge of the relevant art. See, for example: A. Suzuki, Pure Appl. Chem "said 213-222 (1994); A. Suzuki, Pure Appl. Chem •, Red 419-422 (1991); and V. Farina (Farina ) And G. Roth, "Metal-Organic Chemistry", Vol. 5 (Chapter 1), 1994 (in press). The starting material XXIII (B = 1,4-benzyl) is easily similar to method a, B, or C, but is replaced with benzene instead of biphenyl as the starting material. If necessary, the halogens can be converted into substances in which χ is a metal according to the reactions of experts in related arts, such as: bromine intermediate through hexamethylditin and triphenylphosphine palladium, Treatment in toluene at reflux produces a trimethyltin intermediate. The starting material XIII (B = heteroaryl) is most suitable for preparation according to method C, but a readily available heteroaryl compound is used instead of the biphenyl starting material. Intermediate χχπ can be obtained from commercial products, or it can be easily made from commercially available materials according to the methods known to relevant technical experts. The compounds made by these general methods will produce mixtures with different biaryl tritiated forms if they are subjected to the Friedel-Crafts reaction as described in Method A, β, C, D or E F is also particularly suitable for the preparation of aryl A -46-This paper size is applicable to China National Standard (C " NS) A4 specification (210X 297 male |-(Please read the precautions on the back before filling this page) Order A7 B7 V. Description of the invention (44 or B products containing one or more heteroatoms (heteroaryl) such as: they contain fenphene, squeak,? Bibite, pbilo, attack, suffocation, beta secretion Or p ratio 0 well ring and other products do not contain phenyl compounds.

Method F

ΓΟχΑ-Met + X-B-E-G-(T) XA-B-D-E-G

XXIII D, 乂, VIII, 8, £ and 0 as structural formula 1 '

Met = metal and X = halide or trifluorofsulfonate or

Met = halide or trifluoromethanesulfonate, and X = metal General method G-When the R6 group of method F together forms a 4 to 7 shell carbon ring of the intermediate XXV as shown below, it can pass 2 equivalents of strong base such as: Lithium diisopropylamide or lithium hexamethylsilylamine, etc. are treated to remove the double bond from the conjugate of the keto group, and then the reaction is stopped by acid to produce a compound of structural formula XXVI. XXVI is similar to the general method D, and the thiol derivative is reacted to produce a cyclic compound I-G-1 or I-G-2. !--I-I I I i!-* 衣--I 1-- I--1 ......., 1τ (Please read the precautions on the back before filling this page)

Pd (com)

XXII

I, F Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs -47- The standard of this paper is applicable to China® Biaofeng (CNS) A4 specifications (2 丨 G X 297mm) 4 × 0ϋ f ο Α7 _____________ Β7 5. Invention description (45)

Method G

(Please read the precautions on the back before filling this page). Packing. Printed by the Central Standards Bureau of the Ministry of Economic Affairs and printed by the Consumer Cooperative—General Method Η-According to Method Η, the compounds of the present invention are prepared, in which two R 6 groups are formed as follows 4- to 7-membered carbocyclics of formula IH are alkyl or aralkyl. The starting material XXVII reacts with 2 equivalents of a strong base such as: lithium diisopropylamide (LDA) to react with an alkyl or aralkyl halide (R "X) to produce an intermediate XX VIII. This material is then subjected to Reducing agents that can selectively reduce ketones, such as sodium hydride, reduce to alcohol, and then combine with tribenzylfluorene / diethyl azodicarboxylate-48- Common Chinese National Standard (CNS) A4 Specification (2 丨 〇 × 29Ϊί) A7 B7 V. Description of the invention (46) (DE AD) 'Dehydration is performed in a suitable solvent such as Thf under reflux, and the XXIX 〇 ester is hydrolyzed with an alkaline aqueous solution, and is reacted with r12 〇NhrU (r is low The carbon number is Yaoyl, but it is usually CH3). In the presence of a coupling agent such as: dicyclohexyldiimine (DCC), amidine is formed to produce XXX. Other amyl activation base diagrams known to relevant technical experts can be used instead. For example: fluorene-based gas or mixed acid anhydride instead of XXX. The substituted fluorene phenyl halide XXXI reacts with alkyl lithium such as: 2 equivalents of tertiary butyl lithium to produce lithiated biphenyl XXXII, and then activate the fluorene-based compound XXX reaction. The obtained intermediate XXXIII is then treated with diethylaluminum cyanide, and the intermediate XXXIV produced is further processed. The aqueous solution is hydrolyzed to produce the compound I-Η of the present invention, which is purified by silica gel chromatography to produce pure isomers. (Please read the notes on the back before filling in this page). Du Yin 褽 i This paper applies Chinese National Standard (CNS) A4 specifications (210X207 mm) A7 B7 413675 V. Description of the invention (47 methods)

R

1) 2 pawn

2) RmX

R] 丨 > Aqueous solution acid 3) RI2〇NHRi2 pseudo-joint surface

R

R 14 (Please read the precautions on the back before filling out this page) Equipment. Consumption cooperation among employees of the Central Bureau of Standards, Ministry of Economic Affairs. Printed by Du

X

R14 order -50- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 413675 A7 _B7_ V. Description of the invention (4S) General method I-According to method I, the compound of the present invention is prepared, two of which The R 6 groups together form a pyrrolidine ring. The starting material XXX V (L-pyroglutamine) is reacted with benzaldehyde XXX VI (which can be substituted) under acid catalysis to produce a bicyclic derivative χχχνπ = and then the phenyl field method (phenvlselenenyl), which is well known in the art methodology), introducing a double bond to produce χχχνπι, and then reacting with the vinylidene steel (I) complex to produce a conjugate addition product χχχχχ. In these reactions, Lig can be, for example, another equivalent of a vinyl or halide known to the relevant artisan. After performing the hydride reduction reaction (gasification of lithium aluminum, etc.), XXXIX is subjected to a standard such as: tertiary butyl disilyl gas. The XXXX produced by the end-capping reaction is then substituted with benzyl gas formic acid if necessary. An ester XXXXI is reacted to produce XXXXII. After the intermediate is ozonated, reduction is performed (dimethylsulfide, zinc / acetic acid ', etc.) to produce an aldehyde xxxxm. This group reacts with organometallic biphenyls such as: XXXII to produce alcohol XXXXIV. For example, tetrabutylammonium fluoride is used to release the silyl group and then oxidized with, for example, pyridine dichromate, etc., to produce a patented compound i_I_i, which makes R14 a fluorenyl ester group. Printed by the Shellfish Consumer Cooperative of the Central Sample Industry Bureau of the Ministry of Economic Affairs --------- ^ ------ ir f (Please read the precautions on the back before filling this page) or 'To remove the ester At base time, it reacts with gas and catalysts such as: Pd / C to produce unsubstituted compounds 1-1-2 of the present invention. If necessary, N-alkylation is then performed to produce compounds 1 -1 -3. These final steps are those skilled in the relevant art. Alternatively, the intermediate X X X X may be directly treated with ozone and then subjected to other steps of the method to produce 1-1-3, where R14 is a substituted fluorenyl group as required, which is different from that of 1-1. This method is particularly suitable for the preparation of mono-enantiomers, as the starting material XXX V can be in the isomeric form shown or in the form of pyroglutanol, giving an enantiomeric product. -51-Applicable to China National Standard (CNS j A4 specification (210 × 2ο7 mm)) 5. Description of the invention (49

Method I

NH

0H A7 B7

OTBDMS

/ CuLig-

XXXXI OTBDMS

XXXX1I

HO OTBDMS

1) hydride 4 original effect THF, heating 2) TBDMS-C1 / Ifese

1) Unblocking 2 > Oxidation (Please read the precautions on the back before filling this page) Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs [^ mU * 1-1-3 r14x

1-1-2 -52-This paper size applies Chinese National Standard (CNS) Ad Torgue (210 X 2 mm) 413675 A7 B7 V. Description of the invention (50) General method J-Preparation of the compound according to method J , Where E represents a substituted chain of 3 carbons. If the intermediate XXXXVII cannot be obtained from the commodity, the activated biphenylcarboxylic acid derivative χχχχν reacts with the substituted acetic acid XXXXX. The latter has passed 2 equivalents, such as: LDA, converted to its bis-anion, and then heated. To remove the carboxyl group of the intermediate keto acid. XXXXVII is generated and then treated with the methylene malonate derivative χχχχνίΙΙ, and reacted in the presence of a strong base such as sodium hydride to produce substituted malonate XXXXIX. This malonate can be alkylated under similar conditions familiar to experts in related arts to produce L, which can be heated after acid treatment to produce the compound 1-J-1 of the present invention. Alternatively, the final alkylation can be omitted. Among the products produced, R6 adjacent to several groups is fluorene. Alternatively, from xxxxvh and 3-propionate LI in the test such as: the presence of LD Α is down-graded 'producing ester 丨 _ j _ 2, after the hydrolysis of empirical aqueous solution' with acid, the compound of the present invention is produced ^ If any R6 This method is particularly useful when the base map contains aromatic residues. 11. 15 ^ Order {Please read the notes on the back before filling in this ear) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs -53- This paper method is applicable to Chinaϋ ^^ Τ3ίϋ7Ί4ϋ〇 × 297 mm 413675 V. Invention Note (51) A7 B7 Printed by the Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

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

--II Good 54. The paper size is in accordance with the Chinese National Standard (CNS) A4 (210X297 mm) A7 B7 V. Description of the invention (52) Method K-Method K is most suitable for the preparation of the compounds of the present invention. Combine to form a substituted 5-membered ring. In this method, Tetrahedrón, Vol. 37, SuppU 1981, 4Π was used to prepare the acid LII (R ^ H). The acid is based on a coupling agent such as: 1- (3-dimethylaminopropyl). 3-ethylcarbodiimide hydrochloride and an ester formed according to a process known to experts in related technologies (R = benzyl or 2 ( Trimethylsilyl) ethyl). The substituted bromofluorene L is treated with magnesium to convert it to Grignard reagent, and then reacts with LII to produce alcohol LIV. According to the conditions known to the relevant technical experts, the mesylate is treated with alkali to remove the alcohol LIV and produce olefin LV. Alternatively, at low temperature (_78 ° C), LIII is converted into trimethyltin intermediate through the initial metallization of -bromide and n-butyllithium, and then treated with trimethyltin, LII and 2_ [N , N-bis (trifluoroacidyl) amino] -5 -pyridine is reacted in the presence of an aprotic strong base to be converted into enol triflate. The intermediate of tin and enol triflate is further coupled with Pd ° catalyst in the presence of Cul and AsPh3 to directly produce the intermediate LV. The ozonation of LV (using sulfenyl sulfur operation) produces aldehyde LVI. Alternatively, after treatment with 0s04, LV was converted into LVI through ΗΙ04. The conversion of the key intermediary substance L VI into the patented compound I κ can depend on the functional group X of the side chain and can be accomplished in several ways. After the LVI is reacted with Wittig reagent and hydrogenated ', x is an alkyl group, an aryl group or an arylalkyl group. Aldehyde L VI is reduced by LA Η to produce alcohol I-K (X = 0 Η) 3 alcohol, which is converted into a benzyl ester or Mitsunobu condition using appropriate starting materials and related techniques. N-phthaliminoimide compound; see Synthesis, 1, Miz. (198 1). Or IK alcohol (X = OH) can be converted into free radicals according to the conditions known to experts in related arts. -55-This paper uses the Chinese National Standard (CNS) M specifications (2 丨 0X297 mm) (please first (Please read the notes on the back and fill out this page)

Ya printed by Central Standards Bureau of the Ministry of Economic Affairs—Industrial and Consumer Cooperatives A7 ___B7 V. Description of Invention (53) Such as: Toluate (X = OTs) or Bromide (X = Br) The nucleating agent displaces the detached group to produce X = thionine or azide-bearing poplar, which is then reduced and fermented to produce amidine (X = NH-fluorenyl). The direct fermentation of alcohol I-K (X = OH) produces the compound of the present invention, where X = 0, and the alcohol reacts with various alkyl autogenates in the presence of a base to produce an alkyl ether (X = OR2). In each of the above cases, the end step of the acid removes the acid end-blocking group r 'to produce an acid (R = H). The conditions used depend on the stability of R and X, but they are all known to relevant technical experts Conditions, such as: when the benzyl group is removed, the hydrolyzation is performed, or when the 2- (trimethylsulfanyl) ethyl group is removed, it is treated with tetrabutylmonoammonium fluoride.

Method K (Please read the notes on the back before filling this page}

IT * 56 ^ This paper is compliant with the national standard (CNSyA4, current A7, B7, printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, and printed on the 5' invention description (54) Method L- When preparing the amidine of the acid compound of the present invention, It is prepared by treating primary or secondary amines and coupling * agents such as dicyclohexylcarbodiimide in solvents such as: digas methane or dimethylformamide. These reactions are studied by relevant technical experts Known = The amine component may be simply substituted with an alkyl or aralkyl group, or it may be an amino acid derivative in which the carboxyl group is blocked and the amine group is free. Suitable pharmaceutically acceptable salts of the compounds of the present invention Classes include addition salts with organic or inorganic bases. Salt-forming ions from these bases can be metal ions', for example, tricks, test metal ions, such as: Na or A, test earth metal ions--ions such as : Calcium or magnesium, or amine salt ions, many of which are known to users for this purpose. Examples include: ammonium salts, arylamines such as: diamine and Ν, Ν-diamidylethylenediamine Low amines such as methylamine, tertiary butylamine, general Because of (procaine), low-carbon alkyl hexahydropyridines such as: N-ethyl hexahydropyridine; ), Or derived from; arginine, lysine, etc. salts of amino acids. Physiologically acceptable salts such as sodium or potassium salts and amino salts can be used in medicine as described below, These salts and other salts that are not necessarily physiologically acceptable are suitable for use in the isolation or purification of acceptable products for the purposes described below, such as the use of commercially available pure enantiomers in suitable solvents. Isomers of amines 'e.g.-cinchonine, can produce a single enantiomeric salt crystal of the compound of the invention, leaving the opposite enantiomer in solution' This method is generally Called, the traditional analytic method ". If the physiological effect of an enantiomer of a particular compound of the present invention is significantly greater than its enantiomer, the active isomer can be purified into crystals or produced as a liquid phase a salt by the acid form of the compound of the present invention and —S7- Equivalent can be provided -S7- Use a moderate ruler I sheet of paper, a season-like sample I centimeter: Male 7 9 2 (Please read the precautions on the back before filling this page) fc- -3

T% A7 B7 V. Description of the invention (55) A base that requires alkaline ions is reacted in a medium in which salts can be precipitated or in an aqueous medium, and then freeze-dried. The free acid form can be prepared by neutralizing the salt with conventional neutralization techniques, such as neutralizing with potassium hydrogen sulfate, hydrochloric acid, and the like. It has been found that the compounds of the present invention can inhibit matrix metalloproteinases MMP-3, MMP-9 and MMP-2, and to a lesser extent MMP-1, and are therefore suitable for treating or preventing diseases mentioned in the technical background. Since other MMPs not mentioned above are highly homogeneous with the MMPs mentioned above, especially at the catalytic position, the compounds of the present invention can indeed inhibit these other M MPs to varying degrees. Changing the substituent on the diaryl portion of the molecule and the substituent on the propionic or butyric acid chain of the patent-pending compound proves that it can affect the relative inhibitory effects of the MMPs listed above. Therefore, it is possible to select specific substituents, and adjust &quot; this general compound, so that the inhibition of specific M M P s can be enhanced with specific pathological conditions, leaving no M M Ps unaffected. Methods for treating matrix metalloproteinase-mediated disorders can be performed on mammals (including humans) suffering from such disorders. Printed by the Shellfish Consumer Cooperative of the Central Kezhun Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) The inhibitor of the present invention can be used in animals and humans. For these purposes, it is used as a pharmaceutical composition, which contains the active ingredient and one or more pharmaceutically acceptable carriers, diluents, additives, binding agents, and other excipients, depending on the mode of administration and dosage form It depends. Inhibitors can be administered in any suitable manner known in the relevant arts. Examples of parenteral administration of the combination include: intravenous, intraarterial, subcutaneous, and intramuscular routesa. Intravenous administration can be used to acutely regulate plasma drugs Peak concentration. Embedding the drug in the microfat granules helps to improve the drug in the joint cavity -58- This paper size applies to the Chinese National Standard (CNS) Λ4 specification (2 丨 〇 X 297 public celebration) A7 _____ B7 V. Description of the invention (56) ~~ '~ half-life and aiming. Ligands can also be introduced on the periphery of the liposomes to combine with macromolecules specific to the synovium to improve the selectivity of the liposomes for joint cavity targets. Alternatively, microspheres can be embedded or undegradable, for example, drugs in microspheres containing poly (DL-lactide · co-glycolide) can be injected into intramuscular 'arteries or stored subcutaneously. Continuous release of prolonged drugs. In order to improve the convenience of the dosage form, a reservoir and a diaphragm implanted intraperitoneally can be used, such as the Percuseal system of Pharmacia. You can also use an injection pen (such as Novo Pin or Q-pen) or a needleless injection syringe (such as from Bioject, Mediject, or Becton Dickison) to improve convenience and patient adaptability. It is also possible to use an implantable pump to deliver the drug to the synovial cavity through a catheter to extend zero-order release or other precisely controlled releases such as pulsation release. Examples include subcutaneously implantable osmotic pumps from ALZ A, such as ALZET osmotic pumps. Nasal administration involves mixing the drug into a bioadhesive granular carrier (<200 microns), such as those containing cellulose, polyacrylate, or polycarbophi, and using appropriate enhancements such as squatting fat or pancreas. Base meat poison test. Available systems include those developed by Dan Biosys or Scios Nova. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs --------- ^ ------ '玎 (Please read the notes on the back before filling this page) The compound of the present invention is different from this application in The importance of the various peptide compounds mentioned in the technical background section can be demonstrated by the oral activity of the compounds of the invention. Oral bioavailability of certain compounds in different animal models is as high as 90-98%. . Oral administration can be achieved by mixing discarded tablets, coated tablets, dragees, hard and soft gelatine capsules' solutions, emulsions or suspensions. Drugs can also be mixed into enteric-coated capsules to reach -59- This paper size is applicable to the National Standard for Household Standards (CNS) A4 (210 X297 mm) Printed by the Consumers ’Cooperative of the Central Standardization Bureau of the Ministry of Economic Affairs A7 B7 5. Description of the invention (57) The purpose of oral administration is designed to release the drug in the colon with low digestive protease activity. Examples include the ROS-CT / OsmetTM &amp; PULSINCAPTM system from ALZA and Scherer drug return systems, respectively. Other systems use polymers crosslinked with nitrogen, which can be degraded by colon-specific bacterial azo reductases, or use pH-sensitive polyacrylate polymers that can be activated by elevated pH in the colon. The system described above can be used in combination with many available enhanced absorbents. Rectal administration is performed by mixing the drug into a suppository. The compound of the present invention can be prepared by adding various medical inert, inorganic or organic carriers known to relevant technical experts. Examples of such substances include (but are not limited to): lactose, corn starch or derivatives thereof, talc, vegetable oils, soils, fats, polyhydric alcohols such as polyethylene glycol, water, sucrose, alcohols, glycerol 'and the like. Various preservatives, emulsifiers, dispersants, flavors, wetting agents, antioxidants, sweeteners, pigments, stabilizers, salts, buffers, etc. can also be added as needed to help stabilize the formulation or help improve The bioavailability of the active ingredient or, if taken orally, the formulation can produce an acceptable fragrance or discouragement. The amount of the pharmaceutical composition to be used will depend on the recipient and the condition to be treated. The required amount can be determined by methods known to the relevant art experts without additional experiments. Alternatively, 'the required amount can be calculated based on the measured amount of the target enzyme that must be inhibited in order to treat the condition. The matrix metalloproteinase inhibitor of the present invention is not only suitable for treating the above-mentioned physiological conditions, but also suitable for, for example, purifying metalloproteinases and testing matrix metalloproteinase activity. These activity tests can use natural or synthetic enzyme preparations in living -60- this paper size "t H household materials (CNsl A4 ^ (210X297 ^ 1 (Please read the precautions on the back before filling out this page) Order-Α7 Β7 五(5S) (Please read the precautions on the back before filling out this page), or use, for example: naturally occurring (animals using genetic mutations or introduction of foreign genes) or induced or administered by the administration of exogenous agents The animal model that destroys joint stability and has abnormal destructive enzyme concentration is tested in vivo: General process: All reactions are performed in a flame-drying or oven-drying glass breaker under positive argon pressure, and unless Otherwise, all are mechanically stirred.-'Sensitive liquids and solutions are transferred into the reaction bottle via syringe or catheter through rubber stoppers. Unless otherwise stated, the reaction product solution is concentrated using a Buchi evaporator · Materials: Commercial grade reagents and solvents are used without further purification, but diethyl ether and tetrahydrofuran are usually distilled from benzophenone ketyl under argon. Digas methane is distilled from calcium argon under argon. Many special organic or organometallic starting materials and reagents are from Aldrich (Aldrich, 1001 West Saint Paul Avenue, Milwaukee, WI 53233). Solvents Often come from EM Science, which is locked by VWR Scientific. Chromatography from the Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives: Precoated Silicone 60 A F-254 on Whatman® A 250-micron glass plate was subjected to analytical grade thin layer chromatography (TLC). The dissolving point was detected using one of the following techniques: (a) UV light: (b) Exposure to iodine vapor: (0 immerse the plate in 10% phosphorus After the ethanol solution of molybdic acid is heated, and (d) the board is immersed in a standard containing -61-IS, which applies the Chinese National Standard (CNS) A4 specification (2 丨 Kung Chu) A7 ___ 87_ V. Description of the invention (59) 0.5% After being concentrated in 3% p-methoxybenzaldehyde in ethanol solution of concentrated sulfuric acid, the column chromatography method was used to perform analytical-grade high performance liquid chromatography (HPLC) using EM Science® crushed gel with a mesh size of 230 × 400. HPLC) at 1 ml / min in a 4.6 x 25 mm Microsorb® tube It was performed at 288 nm, while semi-preparative HPLC was performed at 24 ml / min on a 21.4 x 250 mm Micrsorb * &gt; column and performed at 288 nm. • Instrument:,, 'The dazzle point (mp) was measured using a Thomas-H over marry point tester and has not been corrected. Proton (VII) nuclear magnetic resonance (NMR) spectrum was measured with a general-purpose electronic GN-OMEGA 300 (300 MHz) spectrometer, and carbon 13 (13C) NMR spectrum was measured with a general-purpose electronic GN-OMEGA 300 (75 MHz) spectrometer. Most of the compounds synthesized in the experiments below were analyzed by NMR, and their spectra corresponded to their structural formulas. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). Mass spectrometry (MS) data are from Kratos Concept 1-H spectrometer, using liquid absolute secondary ions (LCIMS) for the latest fast atom. Obtained by FAB. Most of the compounds synthesized in the following real powders were analyzed by mass spectrometry, and their spectra conformed to their structural formulas. General instructions In a multi-step process, the continuous steps are numbered. Changes in steps are indicated by letters. Dashed lines of data in the table indicate connection points. It should be 2. Case 3, Case 4, Case 5 and Case 6: -62- Water-paper scale system t ® (CNS) A4 # ^ S- (210X297 ^ # &quot;} Consumption by the Central Government Bureau of the Ministry of Economic Affairs · Cooperation Du Yinshang A7 _B7 V. Description of Invention (60)

Weigh 4-gas biphenyl (2.859 g, 15'154 millimoles, provided by TCI) to a 500 ml flask that has been flushed with argon. In this flask add dihydro-3- (2-methyl Propyl) -2,5-sweetened dimesh (1 997 g, 15.1 10 mmol). See below for its preparation method. 1 '1' 2 '2-Siqi Yipo (50 ml) s solution in an ice bath Cool in the middle, and slowly add the solid aluminum trioxide (4.09 g). Leave the ice cream and allow the reaction to return to room temperature. The mixture was heated in the oil bath for a total of 2.5 hours, and the reaction was cooled in the ice bath to 10 % HC 1 solution (200 ml) stopped the reaction. The aqueous mixture was extracted 3 times with ethyl acetate, and the combined organic extracts were washed with brine. The β solution was washed once and dehydrated with MgS04, and concentrated in vacuo. Purified by flash chromatography ( Hexane · Ethyl acetate) The oil produced was recrystallized twice (Hexane-ethyl acetate), yielding 1.358 g of a light orange solid, mainly a substance. Chromatography of a small amount of this substance (ethyl acetate-hexane) Yielding 5 2 · 0 mg of Example 1 (MP

138.5- 139.5 ° C) as a white wooly solid, and 4.0 mg of Example 6 (MP 185.5- 186.5 ° C) as a by-product from succinic anhydride, containing a small amount of impurities dihydro-3- (2-methylpropyl) -2,5-difuran (prepared by Wolanin et al., U.S. Patent No. 4,771,038 (September 13, 1988, Real 6 and 5c)). The mother liquor from Example 1 was also concentrated in the air, and the residue was analyzed by NMR spectroscopy. It was found that its main component was the isomer 5-methyl-3- [oxy- (4agger gas-4-biphenyl) methyl]. Hexanoic acid "This residue was subjected to flash chromatography (Digas A Pit-Methanol) to remove foreign impurities and then separated on C Hirapak AD®. Through an HPLC column (65% n-heptane, 35% (1% water + 0.2% TFA in ethanol)), a specific orientation isomer is produced to the isomer (Example 4 / Example 5 mixed ) And Example 1. Pure Example 1 was separated on a homogeneous system and only the isomers of this compound were produced -63- This paper is moderate in size 1; National Standard (CNS) A4 (2 丨 0 X 297 mm) (Please read the back first Please note this page before filling in this page) 4¾ A7 B7 V. Description of the invention (61) (Please read the notes on the back before filling this page), Example 2 (first dissolution) and Example 3 (second dissolution) The specific orientation isomer mixture was rechromatographed on a Chiralcel 0J® column to produce pure samples of Example 5 (sound dissociation first) and Example 4 (second dissociation). In another experiment, similar to Method, using pure succinic anhydride instead of the above anhydride, only produces Example 6. Example 1-The latter pear and the general process order Weigh 4 -biphenyl (14.8 mmol, 1 equivalent) and add it to the argon flush In a 250 ml flask. Take dihydro-3- (2-methylpropyl) -2,5-furamine. Dione (14.9 mmol, 1 equivalent) and 1,1,2,2-tetragas Ethane (50 ml) was transferred to a-flask. After the solution was cooled in an ice bath, aluminum trioxide (30.8 mmol, 2.07 equivalents) was added slowly as a solid. After 30 minutes, leave the ice bath, allow the reaction to warm to room temperature and stir for at least 24 hours. Then pour into a cold 10% HC1 solution and extract with chloroform 3 to 5 times. The combined organic extracts are washed once with brine, It was dehydrated with M g S 0 4 and concentrated in vacuo. Purified by flash chromatography (digas methane-methanol) and the resulting oil was recrystallized twice (ethyl acetate hexane) to give 1.066 g of a white solid (Example 1). The recrystallized mother liquor is a mixture containing a specific orientated isomer and a small amount of Example 6. Using the method described above for the preparation of Example 1, using the appropriately substituted acid anhydride and the appropriately substituted biphenyl, the following biphenyl products were prepared (Table U 6 Consumption Cooperation by Employees of Central Bureau of Standards, Ministry of Economic Affairs, Du-64-This paper size applies to China National Standard (CNS) A4 (110X297 mm)

Printed by Shelley Consumer Cooperative of the Central Bureau of the Ministry of Economic Affairs 23456a7a8a9a10alla12a1314151617181920212223a24a25a26b ί-Bu i-Bu i-Bu HHHHHHHHHH i-Bu ί-Bu i-Bu i-Bu / -Bu i-Bu i-Bu f-Bu i- Bu i-Bu = CH2 = CH2 -Me n-pent HHH-B-BUHHHHHHHHHHHHHHHHHHHHH * 1 · ai

4-0 4 * CI 4-CI 4-C1 4-CI 4-CI 4-Br 4-F 2-F 2- C1 2.4- (F) 2 3- C1 H 4- Dr 4-F 4-Et 2 -F 2-C1 4-MeO 2.4- (F) 2 4-Me 4-n-Pent 4-CI 2-0 4-CI 4-CI bR, SSSSS5SS ss s sR, R, R, R, R, R , R, R, R.'R. 'R, R, 138.5- 139.5 [a] D = -26.3 (MeOH) [a] D = +25.4 (MeOH) ia] 〇-26.3 (MeOH) (a) 〇 +26.1 (MeOH) 185.5- 186.5 201.5- 202.0 176.5- 177.0 158.0- 159.0 175.0- 176.0 133.0- 134.0 147.0- 148.0 134.5- 135.0 149.0- 150.0 117.5- 118.5 153.0 119.0- 120.0 118.0- 119.0 141.0- 142.0 133.0- 134.0 131.5- 132.5 101.0- 102.0 169-170 186.0-187.5 196-197 141-142 a Reference compound. B This acid needle (2-n-pentyl broken 1 beat acid) 彳 $ to prepare two gas according to the above--3- (2- Methylpropyl) -2,5-succinone monoketone method, but replaced with isobutyraldehyde instead of acetaldehyde ° -65- ϋ scale suitable for China National Standard (CNS) Α4 specifications &lt; 210 乂 mm) --------- A ------ ΪΤ ------ 1, / i ../ (Please read the notes on the back before filling this page) 413675 A7 &lt; _B7 V. Description of the Invention (63) The method of Preparation Example 1 described above is used, using the acidic acid and A substituted aryl group of the starting material, the following preparation (Table [pi]) stupid group-containing product.

'' Table II

a Reference compound The following olefin-containing products were prepared by the method of Preparation Example 1 described above using the appropriately substituted acid residues and the appropriately substituted aryl starting materials (Table III).

Table III Examples

n \ .p. (° C) / Other characteristics ------------ Shiyi ------ Order / 1 ^ (Please read the precautions on the back before filling this page) 29a 30a a Reference Compound α-〇 · -c, -〇 ·. -123.5-124.5 144.0-145.5% Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

-66. This paper has a common national standard (CNS) A4 specification (210X297 mm). Member of the Central Bureau of Standards of the Ministry of Economic Affairs M Consumer Cooperative Cooperative Imprint 4i0675 A7 ^ _B7 _ V. Description of the invention (64) 复 M 丄Take Example 19 (5 2 '2 mg' 0, 1 3 3 mol) dissolved in 25 ml of ice vinegar and 1.5 ml, the agricultural compound B 丨 middle '' this compound at the temperature After falling overnight, the gas was returned for 13 hours: the reaction was allowed to cool before adding water, and the crude solid precipitated. This solid was dissolved in ethyl acetate and washed with brine. The solution was dehydrated with MgSO and concentrated. The resulting solid was recrystallized from hexane-ethyl acetate to produce 24.6 mg of white crystals, MP 18S.0-189 ° C «

Example 32 Compound j 3 2 (reference compound): Take Example 6 (127.2 mg '0.441 mmol) and dissolve it in 2 ml of pyridine. 3 Add 3 mg of paraformaldehyde and 0.5 ml of hexahydropyridine to this solution. . After heating the mixture in an oil bath at 5 5-60 ° C for 6 hours, stir the mixture at ambient temperature overnight. The reaction was poured into 10% H C 1, extracted with Et. Ac, washed with saturated salt forever, dehydrated with MgSO_t, and filtered? The solvent was removed in the air, and the crude solid was found. This solid was dissolved in E tOAc and filtered through a cotton pad to remove insoluble residues from "Jihu. EtO Ac recrystallized to produce 5 4.4 mg (41%) white. Crystal, M p 1 2 7.0-1 2 8.0 C-

This paper size applies to China National Standards (CNS) Λ4 specifications (210 X 297 mm) --------- U ------ iT ------ / {/ f (please first Read the notes on the back and fill out this page} A7 __B7 V. Description of the Invention (65) Example 33 Isomer A- Firstly Dissolved From Chromatographic Column D Example 34 Isomer B- Secondly Dissolved From Chromatographic Column Example 3 3 and Example 3 4 Example 1 (103.5 mg, 0.300 mmol) was dissolved in 20 ml of water, and 30.0 mg (0.687 mmol) of sodium hydroxide was added. After the solution was cooled in an ice bath, 'Add 13 , 0 mg (0.344 mmol) sodium borohydride solid. Continue stirring for 1 hour. TLC (digas methane-2.5% methanol) showed that it still contained the starting material, so the reaction was allowed to warm to room temperature overnight (16.5 The starting material was still contained for 1 hour, so 13.0 mg of sodium borohydride was added at room temperature. The reaction was stirred for 2 hours, and then the reaction was stopped with 10% HC1. Extracted twice with ethyl acetate. Combined The organic extract was washed once with brine and dehydrated with MgS04. The solution was emptied of concentration to produce 57.0 mg of a crude solid. Purified by silica gel chromatography (digas-methanol-methanol) to produce two Three main products, Example 33 (7.9 mg) and Example 34 (19.1 mg). Example 33: h NMR (MeOD-d3) d 7.56 (m, 4H), 7.38 (m, 4H), 4.66 (dd, J = 9 Hz,] = 3 Hz, 1H), 2.77 (m, 1H), 1.95 (m, 1H), 1.75, 1.57 (m, 3H), 1.26 (m, 1H), 0.85 (d, J = 6 Hz , 3H) r 0.79 (d, J = 6 Hz, 3H). Example 34: NMR (MeOD ~ d3) d 7.58 (m, 4H), 7.40 (m, 4H), 4.64 (t, J = 6 Hz, 1H ), 2.34 (m, 1H), 2.10 (m and solvent), 1.74 (m, 1H), 1.54 (m, 2H), 1.28 (m, 2H), 0.87 (d, J = 6 Ηζ, ^ Η), 0.77 (d, J = 6 Hz, 3H). (锖 Please read the precautions on the back before filling this page)

, 1T Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs

-68- This paper size is applicable to China A standard (CNS) A4 specification (2 丨 0X297 mm) Printed by A7 B7, Consumer Cooperatives of the China Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (66) Example 35 and Example 36 Example The method for preparing lactones in Example 3 6 (reference compound), Example 3 5 and Example 3 6 is to dissolve the mixture containing Example 3 3 and Example 3 4 (51 mg) and camphorsulfonic acid (11 mg) together. 25 ml of benzene-This mixture was refluxed for 12 hours using a Dean-Stark trap. The resulting solution was washed with aqueous sodium bicarbonate solution, dehydrated with MgS04, and evaporated in vacuo. The residue was purified by silica gel chromatography with hexane-EtO Ac to give isolated lactones. Example lH NMR (CDC13) d 7.3-7.7 (m, 8Η &gt;, 5.6 (m, 1H), 2.75 (m, 1H), 2.45 (m, 2H), 2.20 (capacitor 1.75 (m, 2H), 1.45 (m, 1H), 1.01 (d, .J = 7 Hz, 3H), 0.87 (d, J = 7 Hz, 3H); MS (FAB-LSIMS) 329 (M + H) + (C2〇H21 〇2〇FW = 328.87). 'Example 29; NMR (CDCI3) d (m, 8H), (m, 1H), (m, 1H), 2 (m, 2H), 2.20 (solution), 1.75 ( m, 2H), 1.45 (m, LH), 1.01 (d,; T = 7 Hz, 3H), 0 · 37 (d, J = 7 Hz, 3H); MS (FAB-LSIMS) 328 fMJ + (C20H21O2CI FW = 328.87). Example 3 7 Example 3 7 (Intermediate) The general method of Example 23 was used to replace itaconic anhydride with acetone gas instead of itaconic anhydride. M P 1 0 0-1 〇1 ° C.

〇 Example 3 8 -69- This paper size is applicable to China (CNS) A4 specification (2 丨 0 · × 297 public epidemic) --------- i ------ IT / V {Please read the back first Please fill in this page before printing) A7 B7 printed by the Central Bureau of Standards, Ministry of Economic Affairs and Industrial Cooperatives _ V. Description of Invention (67) Example 3 8 (Reference Compound): Take Example 23 (97.9 mg, 0.325 mmol) It was dissolved in 1.0 ml of 0.446 M aqueous potassium hydroxide solution. Slowly add 76.8 mg (2.030 mmol) of sodium borohydride 3 mixture and stir at room temperature for 15 hours = add 6N HC1 to stop the reaction, extract twice with ethyl acetate, and wash the combined organic extracts once with brine. The solution was dehydrated with MgS04 and concentrated in vacuo. The white solid was recrystallized (hexane-ethyl acetate) to give 57.1 mg of Example 38 as a white solid. MP 118-120 ° C.

Example 3 9 Example 39 (reference compound): Example 39 was prepared from Example 9 in the same manner as in Example 38. Analysis: C: Calculated 値 6 7 8 3; Measured 値: 6 7 · 80. Η: Calculate 値 5. 1 2; Measured 値: 5. 50, Calculate 値 containing 0.5 Η 2 〇 Example 4 0 Step 1 Add 5 ml DME containing trimethyltin chloride (5.5 g, 27.60 mmol) The solution was stirred under a stream of argon and 15 ml of D M E containing small pieces of metallic sodium (1.9 g, 8 264 mg) in an ice bath. When the addition was complete, the mixture was stirred and cooled in an ice bath for 2 hours (turned green). The mixture was transferred via a cannula to another dry round bottom flask under argon, the excess sodium was eliminated, and cooled to 0 ° C. Contains 4 -Chinese biphenyl (5.4 g, -70-) This paper size applies Chinese national standards ((210X 297mm) (Please read the precautions on the back before filling this page) Order A7 B7 V. Description of the invention ( 6S): 22,70 millimoles) in 14 ml of solution from £ solution to low-temperature cooled 1 ^ 8111 ^ 3 solution. The resulting solution was stirred at room temperature, and TLC analysis showed that the skin should be complete. Rf = 0.44 for the methyl tin product (silica, hexane reaction mixture was cooled in an ice bath and treated with iodine (66 g, 26.0 millimoles). Stir at room temperature for 15 hours' to Et The mixture was diluted with 0 Ac, washed with water and brine, and dehydrated with M g S 0 *, and the solvent was eliminated. The crude product was purified by column chromatography using hexane to yield 5.5 g (86% yield) of a white solid. TLC (Silica, Hexane) Rf = 0.54. (Please read the notes on the back before filling out this page) 乂 Staff Consumer Cooperatives, Central Bureau of the Ministry of Economic Affairs, India, India, India, India, Japan 2: Han (醯) 0.47 ml, 5.21 millimoles) treatment with step 2 of 4-iodobiphenyl (1.35 g, 4.82 millimoles) of 2 ml of anhydrous digas The solution was cooled to 0eC under an argon stream, and the cooled mixture was treated with A1C1S (0.77 g, 5.77 mmol) and stirred overnight at room temperature. The reaction mixture was poured into cold 10% HC1, Extraction by gas beaker 3 times. The combined extracts were washed with brine, dehydrated with M g S 0 4; concentrated under reduced pressure. Crystallized from E t OA c / Hexane to produce 1.1 g (yield 5 8 〇 / 0) light brown fine needles 9 4ί NMR (CD30D) d 8.17 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 8.4 Hz. 2H), 7.94 (d, J-8.7 Hz. 2H ), 7.66 (d, J = 8.1 Hz, 2H), 5.05 (s, 2H).

-71-order -1

This paper uses Chinese National Standard i CNS) A4 (210X297 mm)

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A7 B7 V. Description of Invention (69

Step Su 3 was treated with NaH (0.12 g, 4.95 mmol) in a stream of argon, containing diethyl (3-phenyl) propylmalonate (the product of step 1 of Example H4, Γ. 5 克 ， 5 · 28 millimolar) 1 1 ml of anhydrous r HF solution. The mixture was stirred at room temperature for 30 minutes, at which time a homogeneous mixture was obtained, and gas evolution stopped. 20 ml of anhydrous THF solution containing 2-bromo-4- (4-iodophenyl) acetophenone (from step 2) (1.85 g, 4.6 1 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours At this time, TLC analysis showed that the reaction was complete. &amp; 2N HC1 stopped the reaction, diluted with EtOAc, and separated widely. The aqueous layer was extracted twice with EtOAc, and the combined extracts were washed with brine, dried over MgS0 4 and the solvent was removed under reduced pressure. The crude product was subjected to 3%-40% E10 A c hexane beech solution chromatography to produce 2,28 g (83% yield) of pure product. TLC (silica; EtOAc: hexane 1: 4) Rf = 0.37 Step 4 Treat 5 ml of water containing 5 equivalents of NaOH to 1% of the diethyl ester (2.28 g, 3.81 mmol) obtained from Buluo 3 ^ (5 ml) / £ 101 (15 ml) solution, stir overnight at room temperature. At this time, the reaction mixture was acidified with 2 N H C1, and the solvent was removed under reduced pressure. The solid formed was filtered, washed with water, and dried to give 1.6 g (77 ° / °) of pure product. TLC (silica, CH2Cl2: MeOH 9: 1) Rf = 0.14. · Ί7 · This paper size applies to China National Standard (CNS) Α4 size (2: 0X297mm) {Please read the precautions on the back before filling this page)

Α7 Β7 V. Description of the invention (70) Step 5 Example 40 Production method β Take the diacid from step 4 (1.6 g, 2.95 mmol) and dissolve in 30 ml of 1,4-dioxolane and reflux for 36 hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The resulting residue was crystallized from EtOAc / hexane to yield 0.6 g (41% yield) = MP 1 6 5-1 6 5.5 ° C.

CO2H Example 4 1 Example 4 1 This compound was prepared in a similar manner to Example 40, except that diethyl isobutylmalonate was used instead of diethyl (3-phenyl) propylmalonate. Elementary analysis calculation: 5: C 5 5.0 6, Η 4.85; Measured 値: C 54.9 0 Η 4.79 ° --------- ^ ------ 1T / i \ {Please read the precautions on the back first (Fill in this page again)

Printed by the Consumer Cooperative of the Central Bureau of the Ministry of Economic Affairs, Example 4 2 Example 4 2 Take Example 40 (300 mg, 0.6 0 mmol) and dissolve it in DMF (3 ml). Ethyl acrylate (0 '15 ml, I · 38 mmol), Pd (〇Ac) 2 (15 mg, 0-07 mmol). Sodium argon carbonate (126 mg, 1.50 mmol) and tetrabutylammonium gas (69 mg '0-24 mmol) were treated. The mixture was refluxed for 3 days, diluted with ethyl acetate, transferred to a separating funnel, and the organic layer was washed with water and brine, dehydrated with MgS04, and the solvent was removed under reduced pressure. The crude product is 〇_ 4 〇 / 0 methanol digas -7 ^-This paper is again applicable to China National Standard 4 *. (CNS} A4 size (210X297 mm) printed by the Shell Standard Consumer Cooperative of the Central Standardization Bureau of the Ministry of Economic Affairs Packing A7 B7 V. Description of the invention (71) Chromatography of an alkane solution yielded 120 mg of product. MP i55-157 ° C.

JT—Example 43 A solution of NaOH (14 mg, 0.35 mmol) in water (0.3 ml) was used to treat an ethanol suspension (1.5 ml) containing Example 42 (28 mg, 0.06 mmol) in a suspension. Stir overnight at room temperature. At this time, the reaction was stopped with 2N HC1, and the combined extracts were washed with brine (2 × 10 ml), dehydrated with MgS04, and the solvent was removed under reduced pressure, yielding 23 mg (87%) of the product. MP 230-232 X :.

Example 44 An ethanol (2 ml) solution containing Example 42 (60 mg, 0.13 mmol) was treated with 10% Pd / C (10 mg), and the mixture was stirred at room temperature under a hydrogen balloon overnight. At this time, the reaction mixture was filtered through celite, and the solvent was removed under reduced pressure, yielding 43 mg of an oil product. MS (FAB-LSIMS) 458 [M] +.

-74- S ------ Order ------ Λ. (Please read the notes on the back before filling this page) • This paper size applies to Chinese national standard (CNS pit grid {210X297 public 嫠&gt; A7 ___B7____ V. Description of the Invention (72) Example 45 Treatment of a solution containing Example 44 (15 mg, 0.03 mmol) with a solution of sodium argon oxide (9 mg, 0.2 3 mmol) in water (0.2 ml) Ethanol ethanol) suspension, stirred at room temperature for 1.5 days = the reaction mixture was stopped with 2N HC1, diluted with ethyl acetate, and the layers were separated. The organic layer was washed with brine, dried over MgS04, and the solvent was removed to reduce the yield, yielding 12 mg of product. MP 131-132 ° C.

Example 4 6 Example 41 (50 mg, 0.12 mmol), Cu (I) CN (36 mg, 0.40 mmol) and 0.7 ml of I-methyl-2-pyrrolidone were mixed at 125 ° C. Heat for 24 hours. The reaction mixture was diluted with digas methane, and the crude β product was evaporated under reduced pressure. Chromatography of 4 plc with 0-8% methanol in digas methane yielded 26.5 mg (yield 66%) of the product. HRMS (FAB): C21H22N05S [M + H] + Calculated 値 336.15997, Example 値 336.16129. Example 4 7 (Please read the notes on the back before filling in this f) Order Printed by the Consumer Cooperative of the Central Sample Bureau of the Ministry of Economic Affairs

Buyin 1 was similar to the method in Example 40, but it was replaced with 2,4, -dibromoacetamidine instead of 2-Han-4- (4-iodophenyl) acetamidine to prepare this intermediate. TLC (dichloromethane_ 10% methanol) r f 5 2. -75-

ί, Paper Magic 1 Applicable to China National Cricket (CNS) (T B7 V. Invention Description (73) B7

Step 2 involves methylation of the product from step 1 with diazomethane in acetic acid to produce methyl ester in full yield. TLC (hexane, 10% ethyl acetate) r f 0.2 1

Step 3 contains the product of Step 2 (1.85 g, 4.75 mmol), hexamethylditin (2-00 g, 5.80 mmol), and tris-benzylphosphine palladium (44 mg, 0.038 mmol) 7 ml of methylbenzene was refluxed for 3 hours under argon. TLC showed that the reaction was complete. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the residue was subjected to MPLC chromatography with 3-30% ethyl acetate in hexane to give 2.25 g (100% yield) of trimethyltin product. TLC (hexane-10% ethyl acetate) Rf 0.26. (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs in step 4 containing 4-bromo-N-Boc-aniline (0.61 g, 2.24 mmol), the product of step 3 (0.51 g, 1.08 mmol) and tri-benzene 9 ml of methylphosphine palladium (94 mg, 0.08 mmol) was heated under reflux for 3 hours under argon. After TLC showed that the reaction was complete, the reaction mixture was filtered, concentrated under reduced pressure, and chromatographed with 3-60% ethyl acetate in hexane to give 180 mg of the product (yield 33%) as methyl ester. T L C (hexane-20% ethyl acetate) R f 0.26. -76- The paper scales are generally in accordance with China's K-standard standard (CNS) A4 specifications (210X297 mm) A7 B7____ _ V. Description of the invention (74) Step 5 Example 47 method. This methyl ester (93 mg) was dissolved in 3 ml of ethanol and treated with 0.5 milliwell H20 containing 5 equivalents of sodium argon oxide. The mixture was stirred at room temperature for 10 hours, at which time TLC showed that methyl vinegar had completely hydrolyzed. The reaction mixture was acidified with 2N HCI and diluted with ethyl acetate 'and the layers were separated. The organic layer was washed with brine, dehydrated with MgS04, and the solvent was evaporated to yield 82 mg of product. : MP 169-171X :. Using the method described in Preparation Example 47 above, and using the appropriate bromide instead of 4-bromo-Boc-aniline in Step 4, the following biphenyl powders were prepared (Table IV).

Form IV /-\ (Please read the notes on the back before filling this page}

47484950515253545556

NHBoc / -Bu CH2NHB0C CH2CN SMe 0 (CH2) 2CI CH2OH 0 (CH2) 2〇H _ CH2CH2 CN S5SSSSSSSSR &quot; R, R, R &quot; R, R, R, R, R, R / 169-171 124-125 156 139-140 174.5-175 155- 156 165-166 167-168 156- 157 199-200 J5 Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs11

-77- This paper size applies the Chinese National Standard (CNS) A4 * See grid (格 χ297 公 蝥) A7 ----B7 V. Description of the invention (Yes) Example 5 7 Take the methyl ester of Example 56 (81 mg, 〇 2 millimoles, prepared by treating the ethanol solution of Example 56 with diazocarbamate (prepared by evaporation of the solvent in air), dissolved in 1 ml of toluene, and dimethyltin azide (62 mg, 0.3 millimoles) )deal with. The reaction mixture was refluxed for 5 days. At this time, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, 'washed with brine' and dehydrated with MgS04. The crude product was chromatographed with 0-20% methanol in methane solution to produce 56 mg of methyltetrazole product. The methyl vinegar product was suspended in ethanol, treated with 2N NaOH solution (0.5 milliwell), and searched and stirred at room temperature. The reaction mixture was stopped for 3 hours with 2 NHCI, diluted with ethyl acetate, and the layers were separated. The organic layer was washed with water, dehydrated with MgSO4 'and crystallized from ethyl 6 acid / hexane, yielding 34 mg of Example 57. MP 176-177SC. (Please read the notes on the back before filling this page)

Example 5 8 Ordered by the Central Bureau of Standards, Consumer Cooperatives, Printing Example 5 8 Take Example 47 (46 mg, 0.094 mmol) dissolved in methane digas methane 'with trifluoroacetic acid (0.16 ml, 2.06 Millimoles). The mixture was stirred at room temperature for 32 hours until TLC showed that the reaction was complete. The solid obtained by removing the solvent 'under reduced pressure was washed with ethyl acetate / hexane to give 40 mg of the product as a TFA salt. MP 170-174 ° C (decomposed).

Example 59 -78 · Zhang scale is applicable to Chinese national standard; CNS) A4 size (210X297 mm) Printed by the Central Laboratories Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative A7 —___ B7 V. Description of the invention (76) Example 5 9 Similar example 5 8 Method 'but using Example 4 9 instead of Example 4 7 to prepare the compound "MP 146-148 ° C.

Example 6 0 Example 60 was treated with 37% aqueous formaldehyde (0.11 ml, 1.46 mmol), glacial acetic acid (0.032 ml), and sodium cyanoborohydride (0.32 ml, 1.0 M THF solution, 0.32 mmol) Methanol / tetrahydrofuran (0.7 ml / 0.4 ml) containing Example 58 methyl ester (50 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and saturated potassium carbonate was added to the residue. Ethyl acetate was added to the mixture, and layer D was separated and extracted with ethyl acetate. The combined extracts were washed with brine, dried over 804 at 804, and the solvent was evaporated under reduced pressure to yield 47 mg (88% yield) of methyl ester. product. TLC (hexane-20% ethyl acetate) Rf 0.3 5. The methyl vinegar product (47 mg, 0.11 mmol) was suspended in ethanol (2 ml) and treated with Η 2 0 (1 ml) containing 40 equivalents of sodium hydroxide. The mixture was stirred at room temperature for 16 hours, at which time TLC showed that the reaction was complete. The ethanol 'residue was removed under reduced pressure and diluted with ethyl acetate, and the mixture was acidified with 2N HCI. At this time, the layers were separated, and the organic layer was washed with brine, dehydrated with M g S 0 4, and the solvent was evaporated under reduced pressure to produce 48 mg (yield 96 ° / 0) of the hydrochloride of the product. MP 166-168X: -79- This paper has a national standard (CNS) A4 size (210X 297mm (please read the precautions on the back before filling out this page). Order 5. Description of the invention (77 Examples 6 1

OEt A7 B7 ο OEt Printing steps 1, 2 and 3 from the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs Under argon milk, add a tertiary butanol clock / tertiary butanol solution (800 ml, iO to the attached mechanical stirrer) In a three-necked 2 liter flask, return to reflux. Combine isobutyraldehyde (66.2 ml, 729 mmol) with diethyl citrate (151 ml, 907 mmol) and drip over 0.5 hour. Add. The reaction solution was refluxed for another 1.5 hours, cooled to ambient temperature, diluted with ethyl acetate (800 ml), and washed with 2N hydrochloric acid solution (500 ml). The ethyl acetate solution was separated by 1 0% sodium carbonate solution (6 X 2000 ml) was washed. The test lotions were combined and acidified with concentrated M acid. The product was extracted with ethyl acetate (5 X 250 ml) and the combined washings were dehydrated with tritium sulfate. , And thick plum. Take a portion of this material and immediately use a Parr apparatus to vaporize it with Pd / c to produce 90.18 grams of the desired ester compound as shown above. This material is refluxed with grass gas (1 equivalent) Into the corresponding ester shovel base gas. Step 4 Add trimethyltin-containing gas (21.8 g, 10 · 9 · 5 mmol) of freshly distilled dimethoxyethane (50 ml) solution to argon atmosphere, sodium-containing (7.6 g, 330 ml) that has been cooled to -20 ° C '荇 (200 mg, 1.56 ml Mol) and dimethoxyethane in suspension. After 2.5 hours, the suspension turned dark green ° Decanting the excess sodium in the solution. Under 0 and argon, the solution containing 1 was added dropwise over a period of 0.3 hours. , 4-dibromopyridine (10 g, 4 2 2 mol) and dioxoane paper standard 逋 A f 囡 National Standard (CNS &gt; A4 now standard (Ή0 × 297 mm) 1 --- ---- Order (Please read the precautions on the back before filling this page) A7 _____B7 V. Description of the invention (78) Solution. After the solution slowly rises to the ambient temperature, pour it into 500 ml of water. Wash with methane (4 X 250 ml), combine the extracts, dehydrate with MgS04 and concentrate to give a brown solid, which is recrystallized from acetonitrile to yield 13.8 g, 4_ bis-trimethylsilicotinylpyridine.

Example 6 1 ′ Steps 5, 6 and 7-The method of Example 61. Take potassium carbonate (loo mg) and suspend it in a solution containing the tritium base gas of step 3 (1.91 g, 9,6 mmol), the product of step 4 (3.9 g, 9.6 mmol), and methylbenzyl (50 ml) . After refluxing for 48 hours, it was cooled to the ambient temperature 'and diluted with ethyl acetate. The solid was filtered off and the solvent was eliminated. The remaining oil was chromatographed on silica using ethyl acetate / hexane eluent chromatography D and p-iodoethylbenzyl (1 equivalent) in a gaseous product containing bis (tribenzylphosphine) palladium (u) (2 0 Coupling was carried out by refluxing in a tetrahydrofuran solution (mol%). The coupling product was chromatographed on silica with ethyl acetate / hexane, and sodium argon oxide was added to the aqueous ethanol solution to perform tritiation. Acidified to pH 5 and the yellow solid produced was filtered out and printed by the Central Standard of the Ministry of Economic Affairs for Shellfish Consumer Cooperative (please read the note on the back before filling out this page) and recrystallize the ethyl acetate / hexane card. Yield 5 3 mg of Example 61. MP ^^-ΐ 1 2 6C. Real 6 2 Real 6 6 Real 6 6

-81-The size of this paper is applicable to China Standards (CNS) A # specifications (2; 0x297 mm) A7 ___B7 V. Description of the invention (79) Step 1 (A) is attached to the rubber stopper and argon needle inlet. Add 7 ml of THF and sodium hydride (0.058 g, 2.42 mmol) to a single-head 50 ml round-bottomed flask, and then cool to 0 ° C. While using a syringe, add isobutylmalonic acid dropwise over about 2 minutes. Diethyl ester (0_476 g, 0.491 ml, 2.20 mmol) = The resulting mixture was stirred at (TC for 30 minutes' and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 ° C while using a tube to about 1 A solution of 2,4-dibromoacetophenone (0.556 g '2.00 mmol in 3 ml of THF) was added dropwise in minutes. The resulting mixture was stirred at 0 ° C for 30 minutes and stirred at room temperature for 13 hours. A mixture containing water (30 ml) and hexane (50 ml) was added, and the resulting aqueous phase was extracted with a second portion of -20 ml of hexane. The combined organic phases were dehydrated with MgS04, filtered and concentrated to give a yellow oil. Column chromatography on 30 g of silica gel (dissolved in a gradient of i_5% ethyl acetate / hexane) to yield 0.53 g (64%) of the product The colorless oil. TLC (5% ethyl acetate-brewing has burned) Rf = 0.24. (Please read the notes and then fill in the back of this page)

Step 1 (B) According to the general alkylation process of Step 1 (A), ethyl phenylpropylmalonate (1 r0 0 g '3 5 9 mmol) is processed to produce 1.1 1 g (7 1) Colorless oil product> TLC (10% ethyl acetate-hexane) Rf = 0.19. Printed by male laborers in the Central Standards Bureau of the Ministry of Economic Affairs

This paper uses Chinese National Standard (CNS) A4 specifications: 2 丨 PX297 mm

A7 _B7____ 5. Description of the invention (80) Step 2 (A) In a single-necked 10 ml round bottom flask equipped with a reflux condenser with argon in P, add 4 ml of toluene and step 1 (A) product ( 0.100 grams, CT.242 millimoles), hexamethylene ditin (0.159 grams, 0.484 millimoles), (triphenylphosphine> palladium (0.014 grams, 0.0171 millimoles), and heated at reflux for 24 hours. The resulting The mixture was concentrated to give a black oil. Column chromatography (dissolved with 5% ethyl acetate-hexane) through 15 g of silica gel yielded 0.107 g (89%) of a colorless oil product. TLC (5% ethyl acetate hexane) &gt; Rf = 0.33.

Ph Step 2 (B) According to the general procedure of Step 2 (A), the product of Step 1 (B) (0.1 50 g, 0.3 16 mmol) is processed to produce 0.1 55 g (88%) of a colorless oil product. Ding LC (10.0 ?. Ethyl acetate. Hexane) Rf = 0.19 ---------- I (Please read the precautions on the back before filling this page)

Step 3 (A) of male laborer's consumer cooperation with the Central Bureau of Standards of the Ministry of Economic Affairs. Add 1 ml of dimethoxyethane or toluene to a single-headed 10 ml round bottom flask with a reflux condenser equipped with an argon inlet. 1. Product from step 2 (A) (0.107 g, 0.215 mmol), 1-bromo-3,4-dichlorobenzene (0.097 g, 0.429 mmol), palladium (triphenylphosphine) palladium (0.025 g, 0.0216 millimolar) and heated at reflux for 24 hours. The resulting mixture was concentrated to give a black oil. 15 grams of silicone • 83- This paper conforms to the Chinese Standard (CNS) A4 for 2 ^ X297 ^ F1 'V. Description of the invention (8) A7 B7 column chromatography (with 5% acetic acid) Ethyl-hexane was isolated) to give 0.058 g (57%) of product as a white solid. TLC (10% ethyl acetate-hexane) Rf = 〇26 β Ph

OEt) Step 3 (B) According to the general coupling process of Step 3 (A), the product of Step 2 (b) (0.079 g, 0'04 1 mmol) and 4-bromobenzotrifluoride The reaction in toluene yielded 0.069 g (91%) of a white solid product e TLC (100/0 ethyl acetate-hexane) Rf = 0.8.

0Et &gt;

Ph --------- J ------ # /% (Please read the notes on the back before filling out this page) Staff Consumer Cooperation of the Central Standards Bureau of the Ministry of Economic Affairs Du Ke 3 (C) According to the general coupling process of step butterfly 3 (A), the product of step disc 2 (B) (0.058 g '〇'104 millimoles) was reacted with 1-o_4-nitrobenzene in toluene. This gave 0.042 g (78%) of a white solid product. TLC (10% ethyl acetate-hexane) Rf = 0.06.

Example 6 2 84- Each paper size applies Chinese National Standard (CNS) A4 specification (2 丨 0XD7 mm) Consumption cooperation between employees of the Central Bureau of Standards of the Ministry of Economic Affairs of the People's Republic of China A7 B7 5. Description of the invention (82) Step 4 (B ) Implementation of the 62 method. To a single-headed 10 ml round bottom flask with an argon inlet was added 3 ml of methanol, the product of step 3 (B) (0.069 g, θΓ.128 mmol) and 1 ml of a 25% aqueous sodium hydroxide solution. The resulting mixture was stirred at room temperature for 10 hours. The reaction mixture was acidified with 10% H C 1 solution and extracted 3 times with 20 ml of ether each. The organic phase was dehydrated with MgS04, filtered, and concentrated to produce a yellow solid, which was dissolved in 2 ml of 1,4-dioxolane and heated in a single-necked 10 ml round bottom flask equipped with a reflux condenser equipped with an argon inlet. Reflux for 24 hours. The resulting mixture was concentrated to give a yellow solid. After 10 g of crushed gel column chromatography (dissolved in 40% ethyl acetate-hexane containing 1% acetic acid), ~ 0.033 g (59%) of Example 62 was produced and recrystallized from ethyl acetate-hexane Once, a white solid> MP 165 ° C was produced. Ph

Example 6 3 The method of step 4 (C) Example 63. According to the general procedure of Example 62, the product of step 3 (C) (0.042 g, 0.081 mmol) was buried to produce 0.023 g (68%) of Example 6 3, which was recrystallized once from ethyl acetate-hexane, Produces white

Example 6 4 (Please read the notes on the back before filling in this page j 乂 定 乂 ^ 85- This paper size is applicable to the national standard of China (CNS) A4 specifications (210X297 mm) 5. Description of the invention (83 A7 B7 steps 4 (A) Production method of Example 64. According to the general procedure of Example 62, the product of step 3 (A) (0.050 g, 0.0 mmol) was processed to produce 0.010 g (15%) of Example 64. Recrystallize once from ethyl acetate-hexane to give a white solid. MP 13 2 ° C 〇 Example 6 5

OH

Ph Step 1 According to the general process of Example 62 and Step 4 (B), the product of Step 1 (B) (13.34 g, 28.06 mmol) of the method of Example 62 is processed to produce 4.36 g (4 1%) of the above 4-bromophenyl Intermediate, recrystallized from 1-butane to give a white solid. MP 147 ° Ce times (Please read the notes on the back before filling in this education) Order

OH Ο Printed by the Shellfish Consumer Cooperative of the Central Sample Bureau of the Ministry of Economic Affairs

Ph Step 2 According to the general process of Example 6 4 Step 2 (A), the 4-bromophenyl intermediate (1.00 g, 2.66 mmol) in step 1 is treated in the presence of anhydrous K 2 C 0 3 to produce- 0.706 g (58%) of 4-trimethylstannylphenyl compound as a white solid. TLC (30% ethyl acetate-1% acetic acid in hexane) Rf = 0.47. Add the 3 ml of toluene, the product of step 2 (0.050 g, 0.108 mmol) to the necked 10 ml round bottom flask equipped with a reflux condenser equipped with an argon inlet. Bromo-3,4-difluorobenzene (0.049 g, 0'217 mmol) and palladium (triphenylphosphine) palladium (0.013 g, 00 U2 mmol). 86 · This paper is again applicable to the China National Standard (CNS) (210X297 ^^) 413675 Α7 _________ Β7_ V. Description of the Invention (84) --------- / | _ (Please read the precautions on the back before Fill in this page] The resulting mixture was heated under reflux for 24 hours and concentrated to give a black oil. After 15 g of silica gel column chromatography (dissolved in 20% ethyl acetate-hexane containing 0.5% acetic acid), 0.033 was produced. G (69%) of Example 65, recrystallized from ethyl acetate · hexane one time to give a white solid, mp 137. (: Using the method described in Example 65 above, using the appropriate bromide in step 3, the following was prepared Biphenyl products (Table V).

Table V

Ministry of Economic Affairs, Central Standards Bureau, Employee Consumer Cooperatives, Policy… R, S 137 1 Order I 66 α R, 5 123 1 1 1 I 67a R, S 131 1 1 68 R, S 120 (Gas 1 69 H〇, C — R, S 154 1 I 70 _ 3-pyridyl R, S MS (FAB-LSIMS) 374 [M + H] + 1 I 71 H = / R, S MS (FAB-LSIMS) 460 [M + H] + 1 I 72 4- (n-pentylS) phenyl R, S 113 1 1 -87- This paper size is applicable to China National Standard (CNS) A4 specification (ϋ 10X 297 mm) A7 B7 ___ V. Invention Note (85) 3 Production method of ethylacetoxy-4-bromobenzene: In a single-head 25 milliliter round bottom flask with an argon inlet, add 5 ml of pyridine and 4-bromophenol (1.00 g, 5.78 mmol) Mol) and acetic anhydride (2.80 g, 27.4 mmol). The resulting mixture was stirred at room temperature for 12 hours. A mixture of water (20 ml) and ether (50 ml) was added. Washing with milliliters of water = The organic phase is dehydrated with MgS04, filtered and concentrated to produce a colorless oil. TLC (10% ethyl acetate-hexane) Rf = 0.54 »Example 73 In a reflux condenser with an argon inlet One-necked 100 ml round bottom. To the flask, add 30 ml of toluene, Example 6 5 Product from Process Step 1 (1,000 g, 2.66 mmoles) '4-methoxybenzenedihydroxyboronic acid (1.60 g, 10.5 mmoles), sodium carbonate or potassium carbonate (1.60 g, 11.6 mmoles) And palladium (triphenylphosphine) palladium (0.300 g '0 260 mmol). The resulting mixture was heated at reflux for 12 hours. After cooling to room temperature, 5 ml of a 30% hydrogen peroxide solution was added, and the resulting mixture was stirred for 1 hour. Add a mixture containing ether (300 ml) and a 10% HC1 solution (300 ml). The resulting organic phase was washed with 300 ml of a saturated sodium gaseous solution, and the organic phase was dehydrated with MgS04, filtered and concentrated to yield 0.879 g 82%) Example 73. Recrystallization from 1-butane once to give a white solid. M pi 6 9 乇. Using the method of Example 73 above, using the appropriate dihydroxyboronic acid, the following biphenyl products were prepared (Table VI) ----------, &lt; ------- tr (Please read the notes on the back before filling this page) Printed on the 88-f paper by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Rogue scale 1¾cai g g Ϊ standard (CNS) A4 specifications (2iOx297 public magic A7

B7 V. Description of Invention (86) Table VI

74 R, S 141 75a 76 77 78 79 R, S 144 R, S 145 R, S 138 R, 5 174 R, S 145 --------- Water-(Please read the precautions on the back first (Fill in this page again) Order 82 t &gt; -CHOA · '^ NMR (CDCI3, 300 MHz) d 7.94 (d, / = 8.8 Hz, 2H), 7.67 (d, / = 8.8 Hz, 2H), 7.41 (br d, / = 3.7 Hz, 1H), 7.36 (br d, / = 5.2 Hz, 1H), 7.09-7.28 (m, 6H), 3.43 (dd, / = 8.1, 16.5 Hz, 1H), 3.03-3.12 (mf 2H), 2.64 (brt, / = 7.0 Hz, 2H), and 1.69-1.78 (m, 4H) R, S 118 R 'S lH NMR (CDCI3, 300 MHz) d 9.94 (s, 1H), 8.04 (d, / = 8.5 Hz, 2H), 7.49-7.66 (m, 3H), 7.47 (d, / = 8.5 Hz, 2H), 7.42 (d,) = 8.1 Hz, 1H), 7.14-7.30 (m, 5H), 3.49 (dd, / = 8.1, 16.5 Hz, 1H), 3.05-3.13 (m, 2H), 2.66 (brt, / = 7.0 Hz, ZH), and 1.71- 1.80 (m, 4H) 89- This paper is suitable for Chinese National Standard (CNS) Ad Standard U1 OX 297 mm. Α7 Β7 V. Description of the invention (87) a4-ethoxybenzyl dihydroxyboric acid: A single-headed 25 ml round-bottomed flask equipped with a reflux condenser with a radon inlet was charged with magnesium powder (0.255 g, * 10.5 millimoles, _50 mesh), 7 milliliters of dibutyl ether, and 4-bromobenzyl ether (1.41 grams of '1 '00 milliliters' 7.00 millimoles). The resulting mixture was heated to reflux for 3 hours. In a second single-necked 25 ml round bottom flask with a rubber stopper and an argon inlet needle, triisopropyl borate (3.95 g, 4.85 ml, 21.00 mmol) was added and cooled. At -78 ° C, the Grignard reagent prepared as described above was added dropwise through the catheter for about 5 minutes. After leaving the cooling bath, the reaction mixture was stirred at room temperature for 3 hours. A mixture of ether (50 ml) and 10% H C1 solution (50 ml) was added, and the resulting organic phase was washed with a portion of 100 ml of water. The organic phase was dehydrated with MgS04, filtered and concentrated. The resulting yellow solid was recrystallized from ether-hexane to yield 0.783 g (67%) of a white solid. 1H NMR (CDC13, 300 Mhz) d 8_14 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 8.5 Hz. 2H) »4.11 (q. J = 7.0 Hz, 2H), and 1.45 (t, J = 7.〇Hz, 3H) (Please read the precautions on the back before filling this tile) Order

Example 83 Duty-packing cooperation with the Central Standards Bureau of the Ministry of Economic Affairs Example 8 3: Adding 3 5 ml of acetic acid to a single-head 100 ml round bottom flask with a reflux condenser, Example 73 (0.751 g, 1.86 mmol) Ear) and 20 ml of 48% hydrobromic acid. The resulting mixture was heated at 90 ° C for 12 hours. After cooling to room temperature, 100 ml of ethyl acetate was added, and the resulting mixture was washed and washed twice with 100 ml of water, at -90-this paper rule ^ Applicable to Chinese national standards (CNS ϋΐ 格 (1110X 297 mm) ^ 4136/5 A7 B7 produced by the Central Bureau of Standards of the Ministry of Economic Affairs and Consumer Cooperation Du Yin. 5. Description of the invention (88> 100 ml of saturated sodium gas solution was washed once. The organic phase was dehydrated with MgS04, filtered and concentrated to produce a brown solid. After 50 g of silica gel column chromatography (5% methanol-digas methane), 0.530 g (73%) of the white solid of Example 83 was produced. MP 189 ° C = Example 84 The rubber stopper and argon inlet needle were attached A single-necked 10 ml round bottom flask was charged with 1 ml of DMF and Example 83 (0.100 g, 0.257 mmol). Sodium hydride (0.014 g, 0.583 mmol) was added and the reaction mixture was stirred at room temperature for 10 minutes. Add 1-iodopropane (0.130 g, 0.075 ml, 0.765 mmol), the resulting mixture was heated to 60 ° C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with 50 ml of ethyl acetate and 20 ml Wash twice with water and once with 20 ml of a saturated sodium gas solution. The organic phase was dehydrated with MgS04, filtered and concentrated to produce oil. In a second single-headed 10 ml round-bottomed flask with a rubber stopper and an argon inlet needle, add the above oil substance, 1 ml of THF, 1 ml of methanol, and 2 Ml of a 1M sodium hydroxide solution. The resulting mixture was stirred at room temperature for 10 minutes, dissolved in 20 ml of ethyl acetate, and washed twice with 20 ml of a 10% HC1 solution. The organic phase was dehydrated with MgS04, filtered and After concentration and purification by HPLC, 0.014 g (13%) of the white solid of Example 84 was produced. Μ P 12 6 * C.-Using the method of Preparation Example 84 above, using the appropriate generalizing agent, the following composition was prepared. Benzene products (table V u). -9!-Chinese paper standard (CNS) A4 size (2)! 3X 297 mm for paper size (please read the notes on the back before filling this page) Description of the invention (89) Λ7B7

Table VII

Duty printing cooperation between the Central Bureau of Standards of the Ministry of Economic Affairs and Du Dupin 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 n-propyl n-pentyl n-pentyl rt-pentyl /! -hexyl n * butvl Ph (CH2) 3 n-hept〇i-Bu allyl isoamyl 2-pentyl PhCH2 PhCH2 PhCH2 Ph (CH2) 2 ~ 0 ~ ch, B # 〇H0 ~ CHa 5S)) SSSSSS S5SS SS R'R. , G i R, r, r., R., R, r., R'r, r 'r, r, r, 126 110 (a) D = -27.3 (CHCh) 0 9 8 2 4 1 9307 04 153Z14 14 12 2 Φ 111 111 1111 1 1 (Read the precautions on the back before filling this page) -I .: Order 5 s R, R, s R, sR, s R, s R, [a] D = +26.7 (CHCI3) 152 136 166 153 128 150 This paper uses Chinese National Standard (CNS) A4 specifications (2! GX 297 mm) A7 B7 V. Description of the invention (90) 108 109 n-decyl R, SR , S 108 178 110 cycH, R, S 166 111 HCy〇Ht R, S 187 112 h, moc-fy-ch3 R, S 208 113 HOjC-f 7 ~ CHj R, S 236 Example 1 1 4:

(Please read the precautions on the back before filling out this page) Step 1 Add sodium hydride (8.4 g 95 % NaH; ~ 0.33 ml) suspension in anhydrous THF (700 ml) and cooled in an ice water bath. Diethyl malonate (48.54 g, 0.30 mmol) was added dropwise to the dropping funnel over a period of 25 minutes. After continuing to stir for 1.5 hours, using a dropping funnel, 1-bromo-3_phenylpropane (47 ml, ~ 61 g, ~ 0. 30 mol) was added over a period of 10 minutes. Add the rinse solution of the funnel (THF, 2 X 10 ml) to the reaction mixture and continue stirring for 30 minutes. Use a reflux condenser and stopper instead of the dropping funnel and thermometer, and heat the reaction for 19 hours under reflux. After the mixture was cooled to room temperature, it was cooled in an ice water bath. Slowly stir and add distilled water (400 ml layered, extract the aqueous phase with aerosol (100 ml) &quot; combine the organic phases and wash with 10% HC1 (250 ml), separate the aqueous phase and return to aerosol (100 ml) Extraction. The combined organic phases were washed with saturated NaHC0 0, 250 ml), and the separated aqueous phase was re-extracted with aerosol (100 ml). The organic phase was dehydrated. CNS) 8 rules and 1 grid (210X297 mm) Ordered by the Central Bureau of Standards of the Ministry of Economic Affairs for consumer cooperation Du printed A7 B7 V. Description of the invention (91) (NajO4) and enrichment, the yellow oil produced was passed through the Vigro pipe column ( column) Distilled and purified under minus (0.4). At 124_138. The boiling fraction is the desired product for clarification (57.21 g, 0.206 mole, 68% closed). TLC Gas methane, i: i) Rf = 0.32.

Printed by the Consumers ’Co-operative Cooperative of the Ministry of Economic Affairs and the Central Bureau of Procurement, step 2 In a 2-liter three-necked round-bottom flask with a mechanical stirrer, thermometer, and argon inlet, add 4-gas biphenyl (48.30 g, 0.256 moles) ·) No. 2 Gas A_ So (500 ml, freshly opened bottle) solution. Add Ogilvy (23 ml, ~ 53.5 g, ~ 0.26 mol) via syringe, and the solution was cooled in an ice-water bath to an internal temperature of 3 eC. The thermometer was temporarily taken out, and A1 C was added in batches over a period of 5 minutes. The internal temperature rose to 10 ° C. A white gas emerged from the opaque heart-colored green reaction mixture. After stirring for 24 hours, carefully pour into cold 10% HC1 (1 liter) to stop the reaction. The organic layer turned cloudy yellowish green. Adding gas imitation promotes the dissolution of solids, but the organic layer cannot be turned transparent. The organic layer was concentrated on a rotary evaporator and dried under high vacuum. The crude product was a light green solid (~ 82 g), which was recrystallized from ethyl acetate to give a brown needle (58.16 g) of 1- (2-bromoethyl ketone) -4- (4- phenylphenyl) benzene. . After the mother liquor was concentrated, hexane was added to produce a second crystal (11.06 g), the NMR spectrum of which was the same as the first crystal. The total yield of the title product was 87%. TLC (hexane-digas methane, 2: 1) Rf 0,30. Using the general production method of 1-(2 -bromoethyl ketone) -4-(4-gasophenyl) benzene, 1 · (2-bromoethyl ketone) -4- (4-bromophenyl) benzene, 1- ( 2-Bromoethyl ketone) -4- (4-nitrophenyl) benzene and 1- (2-Au-copper) -4- (4-aminoamido) benzene ° -94- This paper is applicable to China @ 准(CNS) A4 size (210 X 297 mm) (Please read the notes on the back before filling out this page) Order printed in the Ministry of Economic Affairs, Bureau of Shellfish Consumer Cooperatives, printed A7 ___B7 V. Description of the invention (92)

Step 3 Install a 1-liter three-necked round-bottomed flask with a magnetic stir bar, thermometer, argon inlet, and a dripping funnel. To the flask was added an anhydrous ThF (400 ml) suspension containing sodium argon (4.7 g of 95% NaH; ~ 0.185 mol), and the malonate product of step 1 (46.76 g, 0.168 mol) was added to the dropping funnel. ear). The reaction flask was cooled in an ice-water bath, while malonate was added dropwise over a period of 18 minutes. After stirring for 45 minutes, an anhydrous THF (200 ml) solution containing the bromomethyl ketone product of step 2 (52.00 g, 0.18 mol) was added via a dropping funnel over 20 minutes. The dark orange reaction mixture was stirred overnight under hydrogen while slowly warming to room temperature. The reaction flask was cooled in an ice-water bath while carefully adding distilled water (300 ml). The layers were separated and the aqueous phase was extracted with methane (100 ml). The combined organic phases were washed sequentially with 10% HC1 and saturated sodium bicarbonate (200 ml). The combined aqueous phases were back-extracted with methane (50 ml). The combined organic phases were dehydrated (Na2S04) and concentrated to give a dark orange oil (84.07 g). This crude material was used in the next step without purification. Take a portion of the crude oil (24.09 g, ~ 47,5 mol) and dissolve it in ethanol (400 ml; the sample is not completely dissolved) ^ In this mixture, add NaOH solution (19.0 g of 50% by weight aqueous NaOH solution, ~ 23 8 mmol), the reaction was stirred overnight under argon and room temperature. After stirring for 20 hours, no diacetic acid remained in the reaction by tlc. Add concentrated HC 1 (~ 20 ml) to the mixture and adjust it to ρ η ~ 1, -95- This paper is in accordance with Chinese national standard (CNsT 孓 4 specification (210X297 mm)) * (Please read the notes on the back before filling (This page) -1- · Order A7 A7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs j ---------- B7___ V. Description of Invention (93) and then concentrated to dryness. Attempts were made to distribute this substance Between aerosol (200 ml) and water (100 ml) 'but cannot dissolve all solids. Collect the undissolved solids by drying under high airspace to produce the desired product (1238 g, 27') 46 millimoles) The water and organic phases were examined with tlc, showing only a negligible amount of the desired product. The remaining crude diester (59.47 g, ~ 117 moles) was weighted and then converted to an organic compound. Parts of diacid (28 34 g, 62.85 moles). The total yield of the diacid product produced by the alkylation-saponification process was 54%. TLC (aeroform-methanol 9: 1, still containing trace acetic acid) Rf = 0.45 Step 4 Example II4 Preparation Method 6 Take the diacid product from Step 3 (28.34 g, 62_85 mmol) and dissolve it in 1,4-dioxolane (1,2 liters). It was kept under reflux overnight under gas concentration. The crude product was concentrated to give a yellow-white solid (27.60 g), which was recrystallized from methylbenzyl and dried overnight in an air-conditioned oven at 100 ° C to give the yellow-brown solid of the title compound of Example 1 1 4 ( 21 · 81 g, 53.60 mmol). Repeat the decarboxylation with the remaining diacid (12.38 g) from step 3 to produce a recrystallized product (7.60 g, 18.68 mmol). Decarboxylation step The total yield of tritium is 80%. Even after the final product is dried in a high-temperature air oven at 100 ° C, it still contains 5 mole% of toluene. Analytical C25H: 303C1 »0.05C7HS: C Calculated 値 73-99, found 値: 73.75; Η: Calculated 値 5.73; Measured 5.74. Example 115-Step 騣 1 Preparation of dehydrorosinamine. At room temperature, a toluene (55 ml) solution containing glacial acetic acid (24 ml) was treated with argon desaturated rosin. A solution of amine (60% 100 g, 0: mol) in benzene (170 ml). The mixture was stirred overnight at room temperature. The crystalline salt was collected by filtration, washed with cold toluene, and boiled toluene (1 5 2 ml). The crystals were collected by filtration, washed with n-hexane, air-dried, and produced. Go to -96- _ -------- — I-— ^ — — __ The paper roll scale is applicable to the Chinese National Standard (cns) A4 specification (210 &gt;: 297297)-! I-I- ---: ^ _! |. ..... II] — / V (Please read the notes on the back before filling out this purchase) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ________B7_ V. Description of the invention ( 94) White crystals of hydrorosinamine acetate (47 g, 78%). Water (1 ml) of dehydrorosinamine acetate (47 g, 0.16 g mole) was warmed gently until the solution was homogeneous. Carefully add aqueous Na O Η solution (10% w / v, 61 mL). After cooling to room temperature ', the aqueous solution was extracted with diethyl ether, dehydrated with MgSO, filtered and concentrated to give dehydrorosinamine (35 g, 58%) shoe oil, which solidified when left standing. MP 44-45 ° C. Step 2 illustrates the method of making U5. An acetone / ethanol / water mixture (1260 ml on 50:20) was added to a solution containing Example 114 (45 g, 0.1 mole) and dehydrorosinamine (32 g, 0. [mol]). Warm until the solution is clear (1 hour), cool to room-warm and let stand for 42 hours, filter to remove solids. The solid product, which was crystallized for the first time, was diluted with 10% dichloromethane / ethyl acetate leak (700 ml) and treated with 10% phosphoric acid (300 ml). After stirring at room temperature for 1 hour, the mixture was added to a separation funnel, and diluted with a saturated Nac 丨 aqueous solution (200 ml). After the aqueous phase was separated, the precipitate was filtered out from the organic layer and dried to give 9.2 g of nearly disappearance. Rotating solids with an isomer ratio of 48: 5 2 (Example 116: Example 115). The remaining solution was passed through a short period of silica gel and concentrated to give Example 1 15 (13.3 g, 60% of theoretical tritium: isomer ratio 0.8: 99.2 (Example 116; Example 115)). MP 125-126 ° C; [from] d + 25.7-(c 1.4, C network). Example U 6 The filtrate of the first crystallization of Step 2 in the manufacturing method of Example 1 15 was concentrated under reduced pressure, and the obtained solid was operated according to the same process as in Example 15. ^ A racemate was produced according to a similar procedure (8. 0 g 'isomer ratio 5 7: 4 3) and actual 洌 1 丨 6 (丨 3, 5 g, 60% of theoretical 値; isomer ratio 99.1: 0.9). He 125-126 ^ :, [called 15-25,6 ° -07. The standard is applicable to Chinese national standards (CNS &gt; A4 generation; &quot; ^ 〇 &gt; Q97 ^ i7 (Please read the precautions on the back before filling in this Page) Order A7 B7 V. Description of the invention (95) (c 1.4, acetone). Using the method for preparing Example 1 1 4, Example 1 5 and Example 1 16 above, use an appropriate alkylating agent in step 1, step 3 Using the appropriately substituted diaryl starting materials, the following biphenyl-containing products are prepared (Table VIII) = {Please read the notes on the back before filling this page). 4 Each-Order Central Bureau of Standards, Ministry of Economic Affairs Printed by the Consumer Cooperatives-98- This paper music standard is applicable to 3 Chinese standards (CNS) A4 specification ui 〇 X 297 mm) A7 B7 V. Description of the invention (96 Form V 111 O R6a

OH example R6a (butyl) x isomer r mpC ° C) / other characteristics 114 Ph (CH2) 3 115 Ph (CH2) 3 116 Ph (CH2) 3 117 Ht 118 n-propyl 119 allyl 120, * i-butyl 121 propargyl 122 n-heptyl 123 n-decyl 124 Ph (CH2) 2 2 1 —i 1 —i It n 14 li ti «1c cccccccccw

S

CN S5SSSSSS S οί R, R &quot; c £ iR ·, KR, R, Rr A Analysis C: Calculation said 73. Bean 9; Measured value, 73.75. Η: Calculated 値, 5.73; 値, 5,74 la] D + 25.7〇 (c 1.4 ,; propyl ie) ia] 〇-25.6 ° (c 1.4, ne) 15M52 127-128, _ 133-134- — 152-153 130-132 118-120 108-110 A C: Calculation basis, 71,45; 1 Measured radon, 71.41. H: Calculated radon, 5.25; Measured radon, 5.23. N: Calculated value 3.47; Measured radon, 3.46 HRMS calculation 値 383.1521, Measured value 383.1531 ^ — ^ 1 Ε-Ε-«HI. _-_-.M I. ------- I-. I-1aJ / V (please read the notes on the back before filling this page) Printed by Bureau Consumers Cooperative

125 Ph (CH?) 2 126a Q- (CH2h Cl R, S 189-190 127a &lt; P ^ ~ (CH2h 1 Cl R, S 171-173 128a i-〇- (CH2) 2 Cl R, S 163.5- 165 1293 MeO Cl R, S 160-161-(CHj), MeO, 〇9. This paper size is applicable to Chinese group standard (CNS) A4 specification (210X297 mm axoϋ / 〇 A 7 B7 V. Description of the invention (97) 130b Ph Cl S NMR (MeOD) d 8.03 (d, Bu 8.8 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 6.6 Hz, 2H), 7.28 (m, 5H), 4.19 (dd, J = 10.3, 4.1 Hz, 1H), 3.91 '(dd, J = 14.0, 10.3 Hz, 1H), 3.27 (dd, J = 14.0, 4.1 Hz, 2H). 131 132 133 134 135 430

PhCH2 Ph (CH2) 2 Me3SiCH2 Ph (CH2) 3 Ph (CH2) 3 NHAc

Cl Cl Cl Dr H Cl R 'R, R, R / 167-171 179 134-136 174 HRMS calculation 1 372.1725; measured value, 372.1735. 141-142 Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs a2- ( Method for preparing 2-iodophenyl) ethyl bromide: A solution of phosphorus and phenylacetic acid (19.87 g, 75.83 mmol) in anhydrous tetrahydrofuran (110 ml) was added dropwise over 41 minutes until it was cooled in an ice water bath Boron-containing tetrahydrocondensate (151 ml of a 1M solution, about 151.0 mmol). The reaction was stirred at 0 to 10 ° C for 2 hours and 15 minutes. After the reaction mixture was cooled to 0 ° C, the reaction was stopped by carefully adding (foaming!) 10% by volume of methanol in acetic acid over 20 minutes. After stirring for another 25 minutes, the reaction was concentrated on a rotary evaporator. The residue was dissolved in ethyl acetate and washed sequentially with saturated ammonium vaporized and saturated sodium bicarbonate. The organic phase was dehydrated (Na 2 S 0 4) and concentrated to a yellow oil (8 07 g), which was used in the next step without further purification. Phosphorus tribromide (3.5 ml, 3 6.8 5 mmol) was added dropwise over 6 minutes to treat solvent-free 2- (2-iodobenzyl) ethanol (17.75 g, 71.55 mmol) while reacting The bottle was placed in a water bath to adjust the exothermic reaction. After stirring at room temperature for 15 minutes, the mixture was heated in an i 0 0 t oil bath for 2 hours. The reaction was cooled to warm to dilute with a chain and carefully stop the reaction with water (foaming / exothermic 丨). The layer 'organic phase was washed with saturated sodium bicarbonate and dehydrated (Na2S04). The yellow oil produced by the 'concentration' is distilled by a tube (丨 40/70000 Duo) to produce a colorless oil 100- this standard is suitable for the Chinese Lai Chuan Pi (CNS) class 297 grid meal) (Please read the back first Please pay attention to this page and fill in this page again.) Printed A7 ___ B7 by Shellfish Consumer Cooperation of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (98) (19.50 grams, 62.71 millimoles; the yield of the above two steps is S3%) e MS (EI) 310,312 [M] + 〇 Using the general method for the preparation of 2- [2- Qiphenyl> ethyl bromide, 2_ (3_iodophenyl) ethyl bromide '2- (4-iodobenzene Group> ethyl bromide and 2- (3,5-dimethoxyphenyl) ethyl bromide.

Example 1 36: In a 125 ml Parr reaction bottle containing Example 124 (1.15 g, 2.85 mmol), 10%? <1 / &lt;: (0.06 g) and sorbic acid <50 ml) Add 55 psi of hydrogen 'and shake in a Parr until it stops absorbing hydrogen. The Parr reaction flask was then flushed with argon, and the reaction mixture was filtered through a celite pad and rinsed with acetone. The solution was subjected to rotary evaporation, azeotroped with hexane and acetic acid, and concentrated to dryness. The solid was dissolved in hot 10% H C1, filtered and concentrated to dryness by rotary evaporation. The crude hydrochloride was recrystallized from ethanol to produce off-white crystals. When dried in an empty oven (80eC, 3 days), it turned purple (0.18 g, 17%). ΜΡ 222.0-224.0 ° C »Example 137 Making Example 1 36 (0.30 g) was suspended in ethyl acetate (7 ml) * treated sequentially with K2C03 aqueous solution (1.93 g in 7 ml) and ethyl formate (0.165 ml). The mixture is stirred for a weekend. The reaction is distributed at I0% HC 丨 and -101-This paper applies the standard of China National Standards (CNS) A4 (210X297 mm) ------ n-/ rffv (please first Read the notes on the back and fill out this page) Order V. Description of the invention (99)

A7 B7

On the first day of this month, between ethyl acetate / digas (Na2S04) and concentrated to a yellow solid, and subjected to flash column chromatography (gradient dissociation of '1 gas methane to 98: 2 digas methane-formase), the required substance is produced. White solid "MP 148 ° -149 ° C. The examples in Table IX were prepared from Example 1 36 using the general procedure of Example 1 37, using the appropriate commercially available saponifier product. Hydrolysis was carried out from the tritiated product of ethyl ester of Example 136, resulting in Examples 140-141. Table IX The organic phase was dehydrated with water and brine

Examples of isomers Ϊ36 137 138 139 140 141 (T) x

NJH2.HC] PhOCONH / -BuOCONH CH3CONH n-BuCONH i-BuCH2CONH R, R, R, r, r, r, mp (° C) / Other characteristics 222.0-224.0 148-149 167- 168 209.5-211 168- 169.5 180.5-182.5 —. Water ——1 — Order, f &gt; v (Please read the notes on the back before filling this page) Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives -102- The standard of this paper is applicable to China Standard (M) specifications (2.0 × 297 mm) Printed by the Central Bureau of Standards of the Ministry of Economic Affairs and Industrial Cooperatives Ί __ B7 V. Description of the invention (100) Actual 1 1 2 The acid of Example 1 2 6 was dissolved Dimethylarsine (1.5 ml) and methanol (1 ml). Add triethylamine (0.21 ml, 1.5 1 mmol), palladium (Π) acetate (12.8 mg '0.057 mmol), and 1,3-bis (dibenzylphosphino) propane (23.0 mg') in this order. 0.056 millimolar). An emulsified carbon was passed through the solution for 3 minutes. The lamp-colored solution is placed in an atmosphere of carbon oxide and heated in an oil bath at 70-75 ° C. After heating for 20 hours and 45 minutes, the reaction was operated. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed sequentially with 10% HC1 and water. The organic phase was dehydrated (Na2S04) and concentrated to a yellow solid. This material was purified by crystallization from hot hexane / ethyl acetate or from auto-toluene / hexane to give the title compound as a yellow 'brown solid (109.6 mg, 0.243 mmol, 50% "MP 129 °-130eC. Example 143 Take the half ester of Example 1 42 and dissolve it in ethanol (3 ml), tetrahydrofuran (3 ml) and aqueous NaOH solution (0.20 g in 1 ml). After stirring for 4.5 hours, the mixture still contains the starting material. Add 5 0% N aO Η aqueous solution (1 ml), machine-mix the mixture overnight. The mixture was acidified with 10% H C1 and extracted with ethyl acetate / aerosol. The extract was dehydrated (Na2S04) and concentrated to a black solid, which could not be completely dissolved. In fresh ethyl acetate. The suspension was filtered through yin salt and concentrated to a yellow solid (354 mg). Purified by flash column chromatography (degree dissolution, 1% 0% 1% gas imitation) Methanol of acetic acid to 20: 1 chloroform-methanol containing 1% acetic acid) to give the desired product as an off-white solid (218.6 mg). MP 178. -186Ό (darkened). Palladium adjusted carbonyl according to 142 The reaction was changed to water or an appropriate amine instead of methanol, and the examples in Table X were prepared. 1 44 ethyl ester, carbonyl-103 in Example 142- This paper size applies the Chinese National Standard (CNS A4 size, 2T0 × 297 mm) &quot; -1 1 ^ 1 I- —1 ^^ 1 m I -ΛΤ 1 ^ 1 In »-HI Only τ ° / tlv (Please read the notes on the back before filling in this page) t A7 B7 V. Description of the invention (丨 01) Water is used in the basicization method, and then according to Example 143 The process was hydrolyzed, and Preparation Example 1 5 3 ° Examples 1 4 5 and 1 4 6 were isolated from the racemate of Example 1 4-«stereoisomers. The separation process was performed on a Chiralpak AS column (65:35 Hexane-absolute ethanol with 10/0 acetic acid), and the relative activity of other defined isomer pairs specifies the stereochemistry of each isomer.

Form X --------- 4 .------- Order IV (Please read the notes on the back before filling out this page)

The annual scale is applicable to the Chinese National Standard (CNS) A4 specification U10XW7 mm) Ministry of Economic Affairs + Central Procurement Bureau employee consumption cooperation Du printed A7 B7 V. Invention Description (102) 145 ElfHOC R 123.5-124.5 146 EIjMOC ^ S 124 -124.5 147 (CHt)? CONHn-Bu R, S 164-165 148 HOjC R, S 239-240 149 C ^-{cH &gt; h CONEl, R, S 85.5-88.5 150 rvBuHNOC, R, S 67-69.5 151 EI, N〇C— ^ ^ — (CHj), R, S 123-124 152 n-BuHNOC — (〉 — fCHj), R, S 195.5-196.5 153 H〇tC rCH by R, S 246-248 438 / V-tCH, », R, S 209-210; Case 154:

(Please read the precautions on the back before filling in this page) I —---- Reorder-105-The paper scale is applicable to China National Standards (CNS) A4 specifications (210X297 mm) A7_____B7 V. Description of the invention (103) Step Dish 1 uses the general method of step 65 in the production method of Example 65. Using phenethylmalonate as a starting material, a white solid of the desired product is produced, which is then crystallized from ether. M P 1 4 8 · 5. -1 4 9.5 ac &gt;

Step 2 Production Method of Example 154 According to the general process of Example 73, the product of Step 1 was reacted to produce the yellow crystal of Example 1 54. MP 177,5U -178 ° C.

I-I l ^ i. If II _-n: ^-II— I ^^ 1 I— i \-(Please read the precautions on the back before filling out this page) Staff Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs Printing example 1 5 5 According to the general process of real 83, the methyl ether of real 54 is cracked, and the white solid of example 1 5 5 is cracked. MP 165.5. -166 ° C. According to the general procedure of Example 84, Example 15 was reacted with an appropriate alkylating agent to produce Examples 15 6-15 9 (Table XI). According to the general procedure of Example 84, the ethyl ester of Example 155 was reacted as an alkylating agent to produce Examples 16 and 6 !. -106-Standards of this paper & National Standards (CNS) 八 蜣 210 (210X297 mm) A7 B7 V. Description of the invention (104) Awards R4 Table XI 'R—〇

Isomers i.p. (° C) / other properties 156 157 158 159 160 161

Et: JL two groups 1. n-fluorenyl group 丨 n-hexyl group •• n-butyl PhCH2

R, 5 R, SR, SR, SR, SR, S 160.5- 161 147.5- 148.5 140.5- 141 135.5- 137.5 149.5- 151.5 156-157 I ^^^^ 1 n ^^^^ 1 n I / -1 \ fPlease read the notes on the back before considering this page j tn 162:

Ac〇

-1T Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Step 1 Add a single-necked 1000 ml round bottom flask with an argon inlet: 00 ml CH2C12, 4-phenylbenzylacetic acid 〇g, 235 millimoles), ethidium bromide (73_2 grams, 31-6 milliliters, 363 millimoles), cooled to, while adding aluminum trioxide (94 2 grams, 7 in small portions) over about 5 minutes The resulting mixture was stirred at 0 ° C for 30 minutes and at room temperature for 12 hours. The reaction mixture was added to a cold 10% HC1 solution (500 ml), each at -107 -Applicable to Zhongwei National Standard (CNS) A4 specification (mm) A7 __ B7 V. Description of the invention (丨 05) Extracted 3 times with 200 ml of ethyl acetate. The organic phase is dehydrated with MgS04, dried and concentrated ' A black solid was produced. It was recrystallized from ethyl acetate-hexane to give 4 4.3 g (56%) of the desired compound as a brown solid. Τ LC (10% ethyl hexanoate-hexanoate) Rt, = 0.1 4 =

Step 2 is similar to the method of Example 14 except that 2- (3-iodophenyl) ethylhan is used instead of 1-bromo-3-phenylpropane, and the desired compound is synthesized from the product of step 1 above. TLC (hexane-ethyl acetate, 3: 1) Rf = 0.49. --------- ZΛ-- yi-f. (Please read the notes on the back before filling this page)

Ordered by the Central Bureau of Standards of the Ministry of Economic Affairs for the printing of employee cooperatives. Step 3 Process a solution containing the product of Step 2 (18.4 g) in tetrahydrofuran (400 ml) and ethanol (50 ml) at a rate of 2 at 于 under argon and room temperature. Mix overnight. Since a significant amount of the starting material remained, the reaction volume was reduced by half, and an additional ruler 2 &lt;: 03 (12 g) was added. The reaction was completed after 3 hours. The reaction was concentrated, acidified with 10% HC1 and the product was extracted with ethyl acetate, dehydrated (Na2S04) and concentrated to a brown oily residue. Purification by flash chromatography (hexane-ethyl acetate, 3: 1) gave the product as a yellow oil (14.8 g, 86%). TLC (hexane-ethyl acetate, 3: 1) Rf = 0.20.

-! 08-逋 Using Chinese National Umbrella ICNS) Eight 4 threats (210X297 male thin T A7 ___ _______B7 V. Description of the invention (106)

Example 1 6 2 Step 4 Example 1 2 2 method. According to the general procedure of Example 84, the product of Step 3 was reacted with amyl iodide to produce Example 162. MP 156. -157 ° C. (Please read the notes on the back before filling this page

Example 163 Order Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs Example 163 According to the general process of Example 84, the product of Example 102, Step 3 is alkylated with bromide to produce Example 163. MP 173. -174 ° C.

Example 164 Example 164 was prepared according to the palladium-modified carbonylation method of Example 162, using diethylamine as the nucleophile. Analysis (c "η 4 i N 〇5. 〇75 -109- Fit teeth China ^ | quasi (specification (; diaphragm \ tT a &quot; -A7 B7 V. Description of the invention (107) H2〇) C: calculation 73.29: actual measurement 73.35, H: calculated 7.76; measured 7.43; N: calculated 2.51; measured 2.33 a

Example 165 Example 165 was prepared from Example 16 3 according to the palladium-mediated carbonylation method of Example 14 2 using diethylamine. As a nucleophile. MP 92 ° -95 ° C. Instance 166 f, please read the notice on the back first (and then fill out this page): Yu r ----

Step 1 Similar to the two-step method described in the literature (see j. Am. Chem_Soc. 1989, ill, 1525-1527), the above-mentioned a'b-unsaturated intrinsic hydrazone was prepared from commercially available L-pyroglutamine fermentation products. amine. TLC (Hexane-ethyl acetate, 3: 2) Rf = 0.29-Step 2 Install a dry 500 ml three-necked round bottom flask with a magnetic stir bar, two-way switch, low temperature thermometer and Teflon stopper. The flask was flushed with argon, and tetravinyltin (5.9 ml, 32.3 mmol) and 50 ml of freshly distilled ether were added. The cooled (0 C) solution was treated with methylamine (86 9 mL of 1.43 M ether solution; 124.3 mmol) over a period of 20 minutes. The mixture was stirred at 〇χ: 3〇 〇〇. The paper size is applicable to China &: Home Standard (CNS &gt; A4 specification (210 × 2) 7)

, 1T

Printed by the Ministry of Economic Affairs _ Central Standards Bureau Consumer Cooperative A7 ___B7 V. Description of the invention (108) minutes ′ Cool to-786C and treat it with CuCN (4.45 g, 49.7 millimoles) in full. The reaction was allowed to rise back to -301 over a period of 1 hour and 35 minutes, and continued at -300%: 亍 stirred for 40 minutes. Use a dry dropping funnel instead of the stopper, and add the ether (150 ml) solution containing the enone (5.0 g, 24.85 mmol) of step 1 to the funnel. Add Tiumex to the reaction mixture over a period of 30 minutes while maintaining the internal temperature of _3 (TC. After 40 minutes, the reaction was judged to be complete by TLC. Saturated ammonium vaporization (350 ml) was added and the stirred mixture was returned to 0. The gray solid formed was filtered through a medium salt on a moderately porous glass funnel. The filter block was washed with fresh ether. The filtrate was separated and the aqueous phase was extracted with fresh ether (2 X 100 ml.). The combined extracts were dehydrated (MgSOJ and concentrated to a yellow oil, purified by flash column chromatography (hexane-ethyl acetate, 3: 1) 'to give a yellow oil product (4.6 g, 81%). TLC (ethyl acetate's appearance) 3: l): Rf = 〇.34. (Please read the notes on the back before filling in this page)

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Step 3 Add an anhydrous tetrahydrofuran (100 milliwell) solution containing the product of Step 2 (8.20 g, 35.8 mmol) to the reflux, containing lithium aluminum hydride (204 g, 5 36 mmol) in anhydrous tetrahydrofuran (100 ml). Continue to reflux for 1 hour 15 minutes. The reaction mixture was cooled, and treated with saturated Na2S04 solution until it was formed; the thick and thick house was added. Ethyl acetate (1 QQ ml) was added. After the mixture was briefly stirred, it was filtered through yin salt: washed with ethyl acetate. Filter block. The combined filtrates were dehydrated (NajOJ, and concentrated ^ vegetable yellow oil (667 g '86%) without further purification and used in the next step. TLC (hexane-ethyl acetate f 3: l) Rf = 0.21 ° -Ill-The paper ruler A is used in til national standard (CNS) A4 (2i × 297mm 1 A7) 5. Description of the invention (109)

Consumption cooperation among employees of the Central Bureau of Standards of the Ministry of Economic Affairs

Step Knee 4 In a dry 250 ml round bottom flask, add anhydrous dichloromethane (60 ml), tertiary butyldimethylsilyl gas (4.9 g, 32.03 mmol) and imidazole (4.54 g, 66.73 mmol) ear). After the mixture was stirred for 10 minutes, it was treated with a solution of the product of Step 3 (5.8 g, 26.69 mmol) in anhydrous digas solution (50 ml). 4 The reaction was stirred under argon for 1 hour. The mixture was concentrated and the residue was purified by flash column chromatography (hexane-ethyl acetate, H) to give a yellow oil (9-19 g, 100%). TLC (hexane-ethyl acetate, 9]). qj082 LOTBS Step 5 Keep a solution of benzyl chloroacetate (13.34 ml, 93.42 mmol) and the product of step 4 (8.85 g, 26.69 mmol) in tetrahydrofuran (190 ml) at reflux for several hours. The mixture was cooled to room temperature, diluted with diethyl ether (250 ml), and washed sequentially with 10% HC1 (2 x 150 ml) and saturated NaHCC ^ nO ml). The aqueous layer was extracted back with ether. The combined organic phases were dehydrated (Na2S04) and concentrated. Purified by flash f column chromatography (gradient dissolution, 99: 1 to 95: 5 hexane-ethyl acetate) to give a clear desired material (76, 2, 7600) »TLC (hexane -Ethyl acetate, 9: 1): R. 0.40 〇 ^ NV-〇TTBS -112- This paper reports the standard "Zhonglai Jiaxian (CNS) (21Qx297) ^^ (Please read the precautions on the back before filling this page )

'1T Printed by A7 ____B7 ____ of the Consumer Cooperatives of the Ministry of Economic Affairs of the Ministry of Economic Affairs of the People's Republic of China. 5. Description of the invention (110) Step 6 takes 5% methanol containing the product of Step 5 (丨, 225g, 3,26 mmol). _ CH2C12 (20 ml) solution is cooled to -78. (:, Flush with argon. Pass in ozone in the mixture until the blue color does not turn on. The mixture is flushed with argon and treated with dimethylsulfide (1.2 ml, 16.3 mmol). The mixture is pulled for 2 hours. Stir back to room temperature, concentrate to dryness, and leave to stand at high altitude overnight. The crude product is purified by flash column chromatography (degree dissolution, 9: 1 to 7: 3, jihu-ethyl acetate) to produce Colorless oil of the required substance (890 mg, 73 0'0) »TLC (hexane-ethyl acetate, 9: l) Rf = 0.11. J,

OH

Step 7 Under argon, add 4-bromo-4'-chlorobiphenyl (4.17 g, 15.58 mmol) anhydrous tetrahydrofuran (50 ml solution to -78 aC, drop to Add n-butyllithium (5.65 ml of 2.64 M hexane solution, 14.92 mmol). The mixture was stirred at -78 ° C for 1 hour and 45 minutes. The product containing step 6 (4.9 g, 12.98 mmol) was added via a cannula. Anhydrous tetrahydro. Squeaking (20 ml) solution. The reaction was stirred to rise to = 20 ° C over 2 hours and 10 minutes, and stirred at -20 ° C for 50 minutes. Saturated gasified ammonium ( 150 ml) to stop the reaction and transfer to a separation funnel. The mixture was extracted with methane (3x80 ml), and the combined extracts were dehydrated (MgS04) and concentrated to a yellow oil. Flash column chromatography (gradient dissolution, 9: 1) To 3: 2 hexane-ethyl acetate) to give a diastereomeric mixture of the desired material (5.21 g, 71%). TLC (hexane-ethyl acetate, 3: 1). Paper size: China same standard (CM'S) A4 specification (2 丨 0X297 mm), -------- order f V (Please read the precautions on the back before filling this page ) A7 __ B7 V. Description of the invention (111)

Step 8: Treat tetrahydrofuran (60 ml) containing acetic acid 7 product (3.25 g, 5.74 mmol) with acetic acid (〇 ··) with tetrabutylfluoride (1 4.3 5 ml of 100 N tetrahydrofuran solution). 85 ml) solution and stirred overnight. The mixture was diluted with Erqi Jiapo (120 ml) and washed with water (75 ml). The organic phase is dehydrated (N a2 S Ο '} and concentrated to produce a yellow oil. Impatient column chromatography (gradient dissolution' off '3: 2 hexane-acetic acid to 100 *% ethyl acetate) produces a clear Diol (2.00 g, 77%). Ding [(:( Hexit-ethyl acetate, 1: 3). (Please read the Weeping Matters on the back first and fill in this page)

Ordered by the Central Bureau of Standards of the Ministry of Economic Affairs and printed by the Shellfish Consumer Cooperatives. Treat acetone with Step 8 diol (1.50 g, 3.32 mmol) cooled to _40SC at 40 min with C r 〇3 / ac Ο 2 (24 ml '0.083 g Cr03 / ml AcOH solution) (40 ml) solution. After stirring the dark brown gram mixture for 4 hours, it was diluted with water (300 ml), and extracted with aerated (3 x 100 ml). The combined organic phases were dehydrated (N a 2 s 0 4), concentrated to a green residue, and concentrated in hexane to remove residual acetic acid. ^ Flash column chromatography (aeroform-formaldehyde '95: 5) produced _ acid Gray solid (1.1 g, 73%). Analysis (C26h22C1n05) c: Calculated radon, 67 3 2; Measured radon, 67.10; Η: Calculated radon, 4 7 8; Measured radon: 4 9 7; N: Calculated radon, 3 〇2;- 114- The size of this paper is suitable for 5 towels (CNS) A4 size (2IGX297 mm) 413675 A7 B7 V. Description of the invention (112) Actual measurement: 3. 1 1

CI Example 1 6 7 Example 1 6 7 The method similar to that of Example 1 6 6 was used to prepare the compound from the market 隹 D 隹 軚 越, alcohol. The spectral analysis of Example 167 is the same as that of Example 166. Example 1 6 8

HBr (please read the notes on the back before filling in this page). I: Each, the consumer cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs, Du Printing Step 1 Take the example 166 (1.2 g, 2.59 mmol) dissolved in ice Acetic acid (30 ml) and 30% ΗBr in ice-cold acid solution (35 ml). Solution stir-night. The reaction> Kun compound was diluted with a chain (250 ml), and the resulting suspension was stirred for several minutes' to break up a large solid. The mixture was filtered and the collected solid was suspended in fresh bonds and stirred for 1 hour. The solid was collected by filtration and dried overnight. The crude product (790 mg, 75 ° / ί &gt;) was used without purification in the next step a TLC (ethyl acetate-formic acid-water, 8: 1: l) Rf 0.63. Step 2 Example 168 method. The product from Step 1 (1,000 mg, 0.25 mmol) was dissolved in anhydrous tetrahydrofuran (3.2 ml). Triethylamine (73 ml) was added and the resulting suspension was cooled in an ice bath. Isocyanate (34 mL) was added 'and left the ice bath, and the mixture was stirred and warmed to room temperature over 3 hours. Dilute the mixture with tetrahydrofuran, filter, and concentrate. ○ Flash column chromatography (including -1) 5- This paper size applies to China National Standards (CNS) A4 specifications (210X297 male_%) Order 413675 A7 B7 V. Invention Description (U3) 2. /. Gas simulation of acetic acid) gave the desired material as a colorless solid (43.8 mg, 38/0). MP 132.0-134.0 ° C. • Use the appropriate chelating agent in Example 168-General Method to make an example of Table X11.

Form XII (Please read the notes on the back before filling out this page) Printed by the Central Bureau of Standards, Ministry of Economic Affairs, Consumers and Consumers Cooperatives Example 1 7 4:

0 〇

R4 mp (° C) / Other characteristics 168 PhCH2〇CO 132.0 -134.0 169 PhCH2CH2CO 75-78 170 PKCH2CO 77-79 171 i-BuCH2CO 182 -185 172 ί-BuOCO 160-163 173 PhNHCO 231 -232 -116- This paper size is in accordance with the Chinese standard (CNS) A4 (21ϋ × 297mm) B7 V. Description of the invention (m) Step 1 Take Example 29 (10g, 34.9 mmol) under argon and suspend in water Tetragonal squeak (100 mL) was cooled to 0 t. Sequentially add 1 * '8-diazobicyclo [5_4.0] undec-7-ene (5.2 ml, 34.9 mmol) and methyl lysate (6.5 ml, 104.6 mmol) via the syringe; reaction The mixture was stirred overnight and warmed to room temperature. The reaction mixture was filtered and the filter cake was washed with water. After filtration, the concentrated residue was dissolved in dichloromethane and washed with 100/3 H c 1 (2 X 1 2 5 ml). The organic phase was dehydrated (Na2S04) and concentrated to a yellow solid (9_08 g, 87%). TLC (gas-methanol, 97.5: 2.5): Rf = 0.90 P .— 〇 Step 骒 2 under argon to make Ν-fluorenyl-N- (cyanomethyl) -N-[(trimethylsilyl) methyl Amine] amine (4-6 g, 17,5 mmol) and the product from step 1 (5.0 g, 16.6 mmol) were suspended in acetonitrile (40 ml), and a sufficient amount of methane was added to dissolve all solids. Wrap the flask with aluminum foil and add AgF (2.32 g, 18.3 mmol). The mixture was stirred in the dark for overnight. The black mixture was filtered through yin salt, and the filtrate was concentrated to a brown oily residue. Flash chromatography (gradient dissolution, hexane-ethyl acetate, 9: 1 to 75:25), yellow oil that produces the required substance, printed by the Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs (read the precautions on the back first) Fill out this page again) (3.87 g, 54%). Butanyl (aqueous-co-alcohol, 97_5: 2.5) 1 == 0.48.

This paper uses the Chinese National Standard 210 X297. A7 B7 V. Description of the invention (115) Step 3 Add benzyl chloroformate (1.77 g, 10.4 mmol) to the product containing Step 2 (1_5 g '3.46 mmol) Mol) in tetrahydrosqueak (20 ml) solution. The solution was heated back to k overnight. Add Rujia et al. (3 ml). After stirring the mixture for 10 minutes, it was concentrated to a yellow oil. Flash chromatography (hexane-ethyl acetate 3 · 丨) gave a pale yellow foam (1.07 g '65%) e TLC (hexane-ethyl acetate, 3: l) Rf = 0.27 »° γ〇 ^ 0洌 174 Step 4 Example 1 * 74 method. Treat the mixture containing the methyl ester of step 3 (201 mg, 042 mmol) with a 1: 1 solution of tetrahydrofuran-ethanol (10 ml) in 11SI NaOH (2.1 ml) and stir overnight at room temperature. The reaction was concentrated to dryness and the residue was partitioned between 10% HC and ethyl acetate. The organic phase was separated and dehydrated (NhSOJ, concentrated to a semi-crystalline residue. Flash chromatography (hexane-ethyl acetate, 1: 1. Contains 1% acetic acid), which produces the required off-white solid (62 2 mg). MP 1 3 7 -1 5 8 ° C. (Please read the precautions on the back before filling this page). 1 Product '• Ordered by the Central Bureau of Standards of the Ministry of Economic Affairs

Real 1 7 5

-I- II— -I I1S · The paper size is applicable to the national standard I CNS) A4 specification (210X 297 mm) A 7 B7 V. Description of the invention (n6) Example 1 7 5 According to Example 1 7 4 Step 4 General Procedure 'Example 174 Step 2 material (202 mg, 0.47 mmol) was hydrolyzed to give the title compound as a colorless solid. Analysis (C 2 5 H 2 2 N C1 Ο 3): C: Calculated 7, 7 1. 5 1; Measured 値, 7 1.42; Η: Calculated 値, 5.28; Measured 値, 5. · 30; Ν: Calculated 値, 3.34; Measured radon, 3.33. Examples 176 and 177: Step 1 A mixture of Examples 176 and 177. Take dicyclopentadiene through a Vigro tube. Column fractionation (190 ° C oil bath), collect cyclocyclodiene at 40 ° C. Cyclopentadiene (1.25 ml, 15.13 mmol) was added to a suspension of methane (15 ml) and tetrahydrofuran (15 ml) containing the dihydrophile (3.30 g) of Example 29. The mixture was stirred under argon at room temperature for 2.5 hours, and then concentrated to a white solid. TLC (aeroform-methanol, 100: 1, containing acetic acid) Rf = 0.47. (Please read the notes on the back before filling in this book), τ

Ministry of Economic Affairs_Information Bureau—Industrial-Consumption Cooperation Du Yin177 Example 177 Step 2 The method of 177. Take the product mixture from step 1 (2.29 g, 6.49 mmol) and dissolve it in tetrahydrofuran (50 ml) and treat it with NaHC03 aqueous solution (50 ml). Quickly add iodine (3.11 g, 12.25) in 3 minutes. Mol) and KI (2.17 g, 13.07 mol) in water-tetrahydrofuran (2: 1,50 ml), the brown mixture was stirred overnight under argon to saturate NaHSO; the reaction was quenched with acetic acid Ethyl acetate extraction. Merged organic -119- This paper is again applicable to Chinese National Standard (CNS) A4 (HJX297 mm) Printed by the Shell Standard Consumer Cooperative of the Ministry of Economy, Central Bureau of Standards and Printing Α7 Β7 V. Description of the invention (1Π) The phase is dehydrated and concentrated The yellow foamy substance β was purified by a flash column (degree dissolution, ethyl acetate-hexane 6: 1, containing 0.5% eight &lt; 011, to 3: 1 containing 0.5% eight (; 〇11), Samples of poorly produced semi-pure exo-aciiiKOJ rabbits) and iodine forging (0.88 g). The plug-in acid was then chromatographed (gradient dissolution, ΙΟΟΜ aerosol · acetone to 100: 1 aeroform-ethanol containing 0.5% acetic acid to 100: 1: 1 aeroform-ethanol. Methanol produced pure Example 177 (4264 mg). Analysis (C21H17C103): C: calculated radon, 71.49: measured radon, 71.20; H: calculated radon, 4.86; measured radon, 4.72. 0

Example 176 Step 3 Example 1 76 method. Take the iodolactone (0.93 g, ι 94 mmol) from step 2 and dissolve it in tetrahydrofuran (20 ml) and glacial acetic acid (15 ml). The solution was treated with a full amount of zinc powder (1.27 g, 19.43 mmol) at one time, and stirred under argon for 2.5 hours. The mixture was diluted with ethyl acetate and filtered through celite. The filter phase was washed with 10% H C, and the organic phase was dehydrated (Na: SO4) and reduced to a yellow solid. Trituration with a mixture of osmium and ethyl acetate gave a yellow-brown powder (425 mg, 62%). Analysis (c21H17C103 «〇. 2 5H2〇) C: Calculated 値, 7 0 · 5 9; Measured 値, 7 0.6 8; Η · Calculated 値, 4.94; Measured 値, 4.94» Example 1 7 8 0

This paper size applies to Chinese national standards (CMS M4 specification (210X297 mm) ---------- 乂 —— fv (Please read the notes on the back before filling this page) • Order 413G75 A7 B7 V. Description of the Invention (I18 Step 1 Take 4-bromobiphenyl (11.6 g, 50 mmol) and dissolve it in 1,2-dichloroethane (25 ml) and add it to a solution containing succinic anhydride (5.0 g, 50 mmol) ) In a suspension of 1,2-digas L hexane (70 ml), the mixture was cooled to 0 «6 times the gasification of ammonium solids (14.0 g, 105 mmol) was added to produce a dark green solution, 10 minutes After that, the reaction was warmed to room temperature and stirred under argon for 72 hours. The reaction mixture was poured into a beaker containing 200 ml of crushed ice / water. Hexane (200 ml) was added, and the mixture was stirred for 1 hour. Hours. The light-colored solid was decanted, yielding 16.8 g (100%) of crude acid. A portion of this acid (7.0 g) was suspended in methanol (25 ml) / methylbenzyl (25 ml). To the solution was added dropwise concentrated H2S04 (2.5 ml). The mixture was stirred at room temperature for 14 hours, and then heated to 7 5 ° C for 3 hours. The solvent was removed and the residue was dissolved in CH2Ci2 and slowly poured into saturated hydrogen carbonate. Sodium water solution and mixture with ice. The ester was extracted with dichloromethane and dehydrated with MgS04. The solvent was filtered and emptied to yield 6.44 g (88%) of a light yellow powder. 1H NMR (300 MHz, CDC13) d 2.81 (t , J = 6.6 Hz, 2 H)? 3.36 (t, J-6.6 Hz, 2 H), 3.73 (s, 3 H), 7.49 (m, 2 H), 7.59 (m. 4 H), S.07 (ddf J = lg, 6.6 Hz, 2 H). Gate

OMe {Please read the notes on the back before copying this page) Order Printed Silver 2 by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 2 Take 1,2-bis (trimethylsiloxy) ethane (4.8 ml, 20 C. 2 C 12 (1 ml) solution cooled to -7 (TC »Add catalytic trimethylsilyl trifluoromethanesulfonate (10 microwells, .05 mmol) and step 1 A solution of the ester blight (1.70 g, 5 mmol) in CHiChG), forming a thick slurry. Allow the ice bath to rise to room temperature (over 3 hours), and then stir for 2 and 4 hours. After that, add • m- the size of the paper is suitable for the Chinese national standard. CNS (210X297 mm) A7 _____B7 V. Invention Instructions (119) Water. The product was extracted with CH2C12, and the organic layer was dried over sodium sulfate. After filtration, the solvent was emptied and the residue was purified by MPLC (15% ethyl acetate / 85% hexane) to give 1.71 g (85%) of a colorless powder of the ester. NMR (3 00 MHz, CDC13) d 2.28 (m, 2 H), 2.46 (m, 2H), 3.65 (s, 3 H), 3.81 (m3 2 H), 4.04 (m; 2 H), 7.45 (dd , 3 = 2.2, 6.6 Hz, 2 H), 7.51 (m, 4 H), 7'57 (dd, J = 2.2, 6.6 Hz, 2 H).

Printed by the Consumer Samples Cooperative Bureau of the Central Bureau of the Ministry of Economic Affairs 1 In — ^^ 1:--^^^ 1 In · ^^^ 1 f--I --- fiv (Please read the precautions on the back before filling This page) Step 3 Take the ketal from Step 2 (4.6 1 g, 12 mmol) in THF (45 ml) and 10 (15 ml) at room temperature. NaOH (480 mg, 12 mmol) was added, and the reaction was stirred at room temperature for 19 hours. TLC showed that it still contained esters, so an additional portion of NaOH (2iO mg) was added. After another 2 hours, it was acidified to pH 3 with 4 M HC1 at 0 ° C, and the product was extracted with ethyl acetate. The solvent was removed by emptying, yielding 4.63 g of a colorless solid. Used in the next step without purification. Take two portions of acid (2.50 g, 6.6 mmol) and dissolve in (: 1 (: 丨 2 (37 ml). At room temperature, add (S)-(-)-4 -benzyl-2- Oxazolidone (1.44 g, 11.1 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.56 g, 8.1 mmol) and dimethylamine Pyridyl (181 mg, 1.5 mmol). After adding DMAP for several minutes, all solids were dissolved. After stirring at room temperature for 3 hours, poured into abalone and NH 4 C 1 aqueous solution. With CH 2 C 1: The product was extracted and dehydrated with sodium sulfate. After the solvent was emptied, the residue was 122- This paper size is suitable for Ning Dong-Jun {CNS) A4 specification (2 丨 0X 297 mm) ^ A7 ____87 ____ V. Description of the invention (12〇) Purified by MPLC (2 ° / 〇CH s 〇Η / 98% C Η 2 C h), yielding 2.64 g (74%) of a colorless solid hydrazidone of the above formula NMR (300 ΙνϊΗζ, CDClj ) d 2.38 (m, 2 H), 2.72 (dd, J = 9.6, 13.2 Hz, 1 H), 13.3 (m, 2 H), 3.29 (dd, J = 3.3, 13.6 Hz. 1 H), 3.82 ( m, 2 H), 4.08 (m, 2 H), 4.17 (m, 2 H), 4.52 (m, 1 H), 7.19-7.33 (comp m, 5 H), 7.45 (m, 2 H), 7.56 (m, 6 H) 0

Step 4: Take a solution of pyridine (0.90 ml, 11 mmol) in CH2CU (33 ml) and cool to -70 X :. Trifluorofsulfonic anhydride (1.68 ml, 10 mmol) was added over a period of 6 minutes, resulting in a yellow mud-like solution. After 5 minutes, 3-phenyl-1-propanol (1.40 ml, 10 mmol) was added over 4 minutes. The reaction was stirred at -7 0 aC for 30 minutes and then returned to -20 ° C for 75 minutes. The cold solution was poured through a porous glass funnel containing silicone. The silica was washed with CHiCU, and the solvent was removed under vacuum to produce a light orange liquid with trifluoromethanesulfonate, which was stored under vacuum until used for the next reaction (about 1 hour). -I -----I i Ά-- fv (Please read the notes on the back before filling out this page) Order Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

-123 · This paper size is applicable to the National Standard Car (CNS) A4 specification (2 丨 ox 297 mm) Α7 Β7 V. Description of the invention () 21) Step 5 Take the step 3 humenone (1 0 g, L9 mmol) was dissolved in THF (5 ml) and cooled to -7 (TC. Over a period of 5 minutes, sodium bis (trit-silyl) amide (1 M THF solution, 2.0 ml) , 2 millimolar) to the rickets' reaction for another 30 minutes. Add the THF (5ml) solution containing the phenylpropyl trifluorometarate (2.7 g, 10 mmol) in step 4 and Diisopropylethylamine (1.8 ml, 10 mmol) was added to the sodium anion, and the reaction was stirred at -700 ° C for 2 hours. The reaction was stopped at -70 ° C with a saturated aqueous solution of nh4C1 (100 ml). The flask was warmed up to room temperature. The solvent was emptied and the residue was dissolved in ethyl acetate. The vinegar was washed with saturated N Η 4 C 1 aqueous solution. The aqueous layer was extracted with ethyl acetate. Dehydrated with sodium sulfate. After filtration, the solvent was emptied and emptied. The residue was purified by MPLC (20% ethyl acetate / 80% hexane to 30% ethyl acetate / 70% hexane), yielding 66 mg of recovered pyrazolidone, 34 mg R)-diastereomeric product and 630 mg (S)-diastereomeric product (as above formula). 13C NMR (75 MHz, CDC13) d 28.6; 33.6, 35.8, 38.3, 42.3, 55.6, 64.3, 64.8, 65.9, 109.6, 119.7, 121.8, 125.8, 126.5, 126.7, 127.3, 128.3, 128.5, 128.7, 129.0, 129.5, 132.0, 135.4, 139.7, 141.6, 142.1, 153.3, 177.1 = (Please read the back first Note: Please fill in this page before filling in this page.)

• 124- This paper has a common Chinese standard (CNS) A4 specification (: Π0 × 297 male flower) A7 B7 V. Description of the invention (122) Step 6 Take the product from step 5 (350 mg, 0.53 mmol) THF (3.75 mL) and 1120 (1.25 mL) were cooled to 0 ° C. Sequentially add hydrogen peroxide Γ: 30%, 485 ml, 4.2 mmoles) and lithium hydride monohydrate (90 mg, 2.1 mmoles). After 30 minutes, leave the ice bath and react at room temperature. Stir for 6 hours. Aqueous sodium bisulfite solution (10%) was added, and the mixture was stirred overnight. The aqueous layer was extracted with C H 2 C12 and the organic solution was dried over sodium sulfate. After filtration, the residue was purified by M PLC (20% ethyl acetate / 80% hexane), yielding 31 mg of pure acid of the above formula and 103 mg of the starting material fluorenazolidone and the exact combination of the product. Thing. The mixed solution was dissolved in 30% ethyl acetate and 70% hexane. • The crystals formed were known to be 70 0 / ozazolidinone from PBS, and the mother liquor was a pure acid product a 13C NMR (75 MHz, CDCl3) d 28.9, 32.7, 35.6, 40.3, 42.8, 64.7, 64.8, 109.4, 125.8, 126.2, 126.8, 128.3, 128.3, 128.4, 128.4, 128.8, 132.0, 139.8, 142.0, 142.1, 181.4---- -I-! ---- --- I (Please read the precautions on the back before filling out this page) Order the consumer cooperation agreement of the Central Government Bureau of the Ministry of Economic Affairs

Example 178 -125- Winter Paper Standards Applicable ㈣ National Standards (CNS) (21GX297) Every day, Central Bureau of Standards of the Ministry of Economic Affairs®; printed by Industrial and Consumer Cooperatives 413675 i7 A7 B7 V. Description of Invention (123) Step 7 Example 178 . Take the reduced size of step 6 (38 mg, 0.08 mmol) in CH2Ci2 (475 ml) and cool to 0 ° C. Add a drop of HCI04 (9.4 ml) and stir the reaction at TC for 3.5 hours. Add saturated sodium bicarbonate and extract the product with methane gas. The combined organic fractions are dehydrated with sodium sulfate. Empty the solvent * to eliminate the substances produced (29 mg , 84%) Analysis by analytical HPLC showed pure substance e [e] D_22.1 ° (c 1.2, CHC13) = 179:

Step 1 R = Me. Diethyl malonate (2.46 ml, 16.2 mmol) was added dropwise over 20 minutes to a suspension of sodium argon (0.43 g, 17.8 mmol) in THF (24 ml) at 0 ° C. After the solution was stirred for 20 minutes, a solution of 4- (4 · -phenyl-bromoacetophenone (5.0 g, 16_2 mmol)) in THF (24 ml) was added over 20 minutes. The reaction was warmed to room temperature, After stirring for another 12 hours, it was poured into EtOAc (2 50 ml) and water (250 ml). The layers were separated and the aqueous phase was extracted with EtOAc (2 X 100 ml). The combined organic phases were treated with 1 M phosphoric acid (2 X 2 00 ml). ), Saturated sodium bicarbonate (2 X 200 ml) and brine (100 ml), and then dehydrated (MgS04), filtered, and concentrated in vacuo. The resulting oil was subjected to flash chromatography on sand gel using ethyl acetate / hexane ( 10% to 50% acetate) gradient dissolution, the resulting crystals are recrystallized from alkane and ethyl acetate to give 2-ethylacetyl-4- [4 '-(4 &quot; -aminophenyl) progenyl ] -4-Oxybutyric acid ethyl alcohol (ι · 24g, 20%) ^ LH NMR (CDCI3) d 8.06 (d, J = 8.1 Hz, 2 H), 7.66 (d, -126- This paper is applicable to China a home standard (CNS &gt; A4 specification (210 X297 mm) (Please read the notes on the back before filling in this I)

ST A7 413675 _B7____ V. Description of the invention (124) J = 8.5 Hz, 2 Η), 7.56 (d, J = 8.5 Hz, 2 H), 7.45 (d, J = 8.1 Hz, 2 H), 4.26 (q , J = 7.4 Hz, 4 H), 4.09 (t, J = 7.0 Hz, 1 H), 3_66 (d, · ί = 7.0 Hz, 2 H), 1.31 (t, J = 7.0 Hz, 6 H, CH3). Step 1 (A) Add the entire amount of dimethyl malonate (5'7 ml, 50.0 mmol) to a D ME (45 ml) solution containing sodium methoxide (66 g, 500 mmol) at room temperature. t, stir for 15 minutes. In another reaction flask, dissolve 4- (4, -aminophenyl) -β-bromoacetophenone (M.0 g, 45.0 mmol) with sodium iodide (6.7 g, 45.0 mmol). In DM £ (136 ml). The Nal solution was allowed to stir at room temperature for 15 minutes. A solution of dimethyl malonate sodium was added dropwise to a 4-(4 1 -phenyl) -α-bromoacetophenone solution through a catheter, and stirring was continued at room temperature for 1 hour. The solvent was emptied and the resulting oil was dissolved in .1: 1 digas methane: ethyl ether (700 ml). The organic phase was washed with water (250 ml) and a saturated sodium chloride solution (250 ml). The organic layer was washed (MgS04), filtered, and the oil was concentrated. The obtained oil was used 4: chloroform containing hexane; methanol was recrystallized to make 2-methyl-4- [4 '-(4 ”-phenylphenyl) Phenyl] -4-oxobutanoic acid methyl ester precipitated (10.43 g, 64%). IH NMR (DMSO) d 8.06 (d, J = 8.1 Hz, 2 Η), 7.66 (Mountain J = 8'5 Hz, 2 Η), 7.56 (d, J = 8.5 Hz, 2Η), 7'45 (d, J = 8.1 Hz, 2H); 3.95 (t, J = 7.0 Hz, 1H), 3.70 (s, J = 7.〇 Hz, 6H), 3.66 (s, 2H) 〇-

Step 2 4 -Phenyl-1-machine · Dingmao production method. Add broken sodium (89 grams, 59.2 moles) and 4-phenyl-1-ebutanol (5.0 grams, 29.6 moles) to room temperature C-127- This paper wave scale is applicable to China's Takarazuka; ^ Rate (―CNS) A4 Specification (21ftX 297mm) --One-One &quot; One &quot; &quot; '(Please read the precautions on the back before filling this page)

___ II I ^ ϋ II Order printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 __B7_ V. Description of the invention (125) 嗣 (2 9 · 6 ml). The mixture was heated to 70 ° C for 1 2 hours. The resulting solution was gravity filtered to remove salts. The solvent was removed under reduced pressure, and excess salt was dissolved in water (100 ml). Add pits (100 ml) to the aqueous mixture. The aqueous phase was separated. The organic phase was washed with a saturated sodium sulfite solution (3 x 50 ml), treated with decolorized carbon, and gravity filtered. The organic layer was dehydrated (MgS04), filtered and concentrated in vacuo to produce 4-phenyl-1-iodobutane (6.94 g, 90%). General production method of 4 · phenyl-1-iodobutane, using commercially available 5-benzyl-1-pentane '6-phenyl-1-gashexane and 4- (gas methyl) biphenyl products Preparation of 5-benzyl-1-pentamyl pit, 6-benzyl-1-ethexol and 4- (brominated methyl) biphenyl. -I -------- ^ 11 (Please read the notes on the back before filling this page)

Bu Man 2 (B) 3- (p-methylbenzyl) -1-bromine entertainment ”method of adding o Fahua (0.90 g, 5.4 mmol) and 3- (p-methylbenzyl) propane-1- Alcohol (0.4 g, 2.7 mmol) into 85% phosphoric acid (5.4 ml) at room temperature. The reaction was cooked to 120 ° C for 3 hours. During this period, the oil layer separated from the acid layer. The mixture was cooled to room temperature and poured into 150 ml of water and 150 ml of ether. Separate the airfield, decolorize with saturated sodium bisulfite solution (100 ml), and wash with saturated sodium gas solution (100 ml-). The organic layer was dehydrated (MgS04), filtered, and concentrated in vacuo to produce 3- (4-tolyl) -1-iodopropyl tiger (0.48 g, 68%). Using the general method of 3- (4-tolyl) -1-iodopropane, 3- (4-Gaphenyl) propan-1-ol is used to prepare 3- (4-Gaphenyl) -1-propanone 1 And use commercially available 3- (4-hydroxyphenyl) -1-propanol, 4-hydroxyphenylethanol, and 3-hydroxybenzyl alcohol to prepare 3- (4-hydroxyphenyl) -propiodopropane and 4-hydroxyphenyl, respectively. Benzyl ethyl iodide and 3-hydroxybenzyl ethyl iodide "-128- The standard of this paper is applicable to the Chinese National Standard (CNS) A4 Regulations: 丨 〇χ &quot; 297 ^ ϋ ~ Order the cooperation of employee consumption of the Central Bureau of Standards of the Ministry of Economic Affairs System A7 B7 V. Description of Invention (126)

OM «¥ Can2 (C) 3- (p-methoxybenzyl 1-iodopropane production method. Add anhydrous potassium acid breaker (4.14 g, 30.0 mmol), methyl iodide (374 ml, 600 mmol) Ear) and 3- (4-hydroxyphenyl) -i-iodopropane (158 g, 6 mM) to acetone (25 ml) at room temperature. The mixture was heated to i7 (rc 8 hours. The resulting solution was gravity The salt was removed by filtration, and the solution was concentrated in the night sky to produce 3- (4-methoxyphenyl) -iodopropane (1-222 g, 730 / 〇). Using 3- (4-methoxyphenyl) · 〖-iodopropane In general, 4_methoxyphenethyl iodide and 3-methoxyphenethyl t are prepared from 4-hydroxyphenyl f-iodine and 3-hydroxyphenethyl iodide. Please read the notes on the back first and fill in this page)- ---- Printing method of step 2 (D) 1-phenyl-3-bromo-1 · propyne produced by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, adding phosphorus tribromide (2 62 ml, 27.6 mmol) Ear) to a solution of 3-phenyl-2-propyne · alcohol (100 g, "mmol) and pyridine (0.14 ml, i.77 mmol) in ether (22 mwell), The addition rate needs to be kept at reflux. After the addition, the mixture is heated at 40 ° C for 2 hours. The mixture is cooled Pour onto ice. Separate the organic layer, dilute with diethyl ether (100 mL), wash with saturated sodium bicarbonate (2 x 50 mL) and saturated sodium vaporized (20 mL T. The organic layer is dehydrated (MgS04), Filtration and concentration in vacuo gave 1-phenyl-3-bromo-1-propyne (13.4 g, 90 / 〇) »

Br &gt; 0 Step 2 (E) 2- (oxy) bromoethane production method. Contains -129- in the form of i-minutes. This paper size is applicable to the Chinese National Ginseng Standard (CNS) A4 standard (21〇, Dog 297 at public expense).

.1T Printed A7 ____B7 by the Consumers' Cooperative of Yin Yangxun Associate Bureau of the Ministry of Economic Affairs 5. Description of the invention (127) Triphenylphosphine (2,1 g, 7.9 mmol) solution of anhydrous digas methane (16 ml) to -78 Anhydrous methane (23 ml) containing N-bromosuccinimide (14 g, 7.9 mmol) was stirred at ° C, and the reaction was kept in the dark until the N-bromoamber was stirred. 0 minutes until the imine is dissolved). Add a solution of 2- (fluorenyloxy) acetic acid in anhydrous digas methane) dropwise, leave the cooling tank, and continue stirring at room temperature for 12 hours. The organic layer was condensed in the air and dissolved through silica gel 'with 1: 1 hexane: digas methane to produce 2- (fluorenyloxy) bromide.

Step 3 At room temperature, add the entire amount of 2-ethylethyl-4- [4 '-(4 &quot; -aminophenyl) phenyl] -4-oxobutanoic acid ethyl ester (0.40 g, 1.02 mmol) To a solution of sodium ethoxide (0.08 g, 1.2 mmol) in DME (1 ml). After 15 minutes, a solution of 4-phenyl-1-iodobutane (0.24 g, 0.93 mmol) in D ME (3 ml) was added. The resulting solution was stirred for 18 hours = the solvent was concentrated and the remaining oil was dissolved in CH2C12 (100 ml) and washed with water (100 ml). The layers were separated. The aqueous phase was extracted with CH 2 C 2 (2 X 50 mL). The combined organic phases were dehydrated (from gS04), filtered and concentrated in vacuo. The resulting oil was subjected to flash chromatography on silica gel using ethyl acetate / hexane (10% to 250/0 ethyl acetate), and the resulting crystals were crystallized from hexane and ethyl acetate to give a phenyl gas group. ] -3,3-diethylethyl-1-oxo-7-phenylheptane (0.272 g '28%). 67-69. . . Step 4 and 5 Example 1 79 method. Follow the steps 4 and 5 of Example 40—The general method. 130- -—____—— ----- This paper size is applicable to the Chinese National Standard (CNS) Yasugi 4 cells (2 丨 OX297) «(Please read the back first (Notes on this page, please fill in this page) Order 413675 A7 B7 V. Description of the invention (128), the diester of step 3 is converted into monoacid. λίΡ 127-130 ° C. Using the method described in Example 1 79 above, the following biphenyl-containing products were prepared using the appropriate alkylating agent and the appropriate diaryl starting material (Table XI11)

Example R6a Foreign matter m.p. (° C) / Other properties 179 180 181 182 183 184 185 186 187 188

Ph (CH2) 4 Ph (CH2) 5 Ph (CH2) 6 4-Ph-PhCH2

CH, ssss SR, R &quot; R, R, R, s S R &quot; R / s SR, R, 127-130 131-132 104-105 228-230 171-172 158-159 U8-149 125-126 127- 129 155-156 (Please read the notes on the back before filling out this page) Printed by the Staff of the Central Standards Bureau of the Ministry of Economic Affairs, Cooperative 189 190 191 192

PhClCCH2 PhCH2〇 (CH2) 2 CH3〇 (CH2) 2〇CH2 PhCH2〇CH2 141-142 99-100 95-97 A] Analysis C: Calculated 値, 70,50; Measured value, 70.73. Η: Calculated 値, 5.18 ; Measurement 値, 5.14 -131 This paper size is applicable to Chinese national standards; CMS ') A4 size U! 〇X207 mm) Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 ___ B7 V. Description of the invention (〖29 ) Example 1 9 3 A method similar to Chem. Pharm. Bull. H (6), 2050-2060 (1988), Preparation Example 193 was as follows: In a 250 ml round bottom flask, 9.84 g (32.77 mmol) was taken. Example 23 was dissolved in 48 ml of DMF. The flask was placed under Ar. After adding thiotetramic acid (8.4 ml, 66.09 mmol, 2 equivalents) to the flask via a syringe, 3.2 ml of a 1.93 M ICO3 aqueous solution was added. The mixture was stirred at 25 t for 2 3 hours. The reaction was diluted with 200 ml of H20, acidified with 10% HC1 to pH = 1 »The mixture was extracted with ethyl acetate (100 ml X 3). The combined organic extracts were washed with water (100 ml x 4), dehydrated with magnesium sulfate, and concentrated in vacuo to produce a crude product (13.16 g, purity 969 / 〇). The crude material was dissolved in ethanol, treated with activated carbon, filtered and concentrated in vacuo. . The residue was recrystallized from ethyl acetate and hexane to give 112 g (81%) of white crystals. MP 119-120. . . Example 194 and Example 195 Take Example 193 (injected several times, 1, 38 grams) through a Cirairace 1 * 〇J HPLC column (2 cm x 25 cm), using 9 ml / min 85% hexane Chromatographic separation was performed at 15% (ethanol containing -0.2% trifluoroacetic acid), and the absorption peak was detected at 3 2 0 nm with UV light. The best eluate fractions for each isomer were combined and each material was recrystallized from ethyl acetate / hexane to yield 520 mg of pure Example 194 (first dissociation) and 504 mg of pure Example 195 (second dissociation). Example 194: ["] 13 + 26.4 (&lt;: 11 (: 13). Example 195: [〇 ^]! 5-27.0 ((: ^ 1 &lt;: 13). -I32-

Zhang scale is applicable to China @ 家 标准 (CNS) A4 regulations Pan \ 2 \ 〇7ϊ ^ Έ) W (Please read the notes on the back before filling out this page) Shiyi. Dingquan-J ·-This: Page Central Ministry of Economic Affairs Consumer cooperation of Bureau of Standards Bureau Du Yinzhen 413675 at Β7 I} _ j- — Explanation (130) Day Example 1 96 The above method of Example 1 3 3 was used, and Example 2 3 was used to prepare Example 1 96. MP 125-126 ° C. Example 197 An acetone (150 ml) solution containing Example 196 (24 g, 0.058 mol) and (+)-Cinconic '0.034 mol) was allowed to stand at room temperature for 46 hours. The white precipitate was removed by filtration, suspended in ethyl acetate, and washed sequentially with 2N HC1 (150 ml) and a saturated aqueous NaCl solution (100 ml). The organic phase was dehydrated (II) (MgS04), filtered and concentrated under reduced pressure to give a white solid (8-4 grams, isomer ratio 9 5.3: 4.7 (Example 1 9 7 _ Example 1 9 8). Repeated a second time (Sin Kynin, 6.75 g; acetone, 140 ml) was then simply crystallized from an ethyl acetate / hexane mixture (1: 2) to give Example 197 (6.67 g: W of theory, isomer ratio 99.3: 0.7) of white crystals; &gt; [&lt;3; 115 + 84.8 ° (〇K 5, acetone). Example 1 98 This heterogeneous purified sample can be used on a Chiralpak® AD column (cm x 25 cm). Ethanol / hexane (1: 9 0,15% trifluoroacetic acid added to ethanol) was obtained by HPLC. Under these conditions, the second dissolution example 1 9 8 can only be injected and shot by a very small amount. Pure substance is obtained. According to D. Art, B. Boemer, R. Grosser, and W. Lange, Angew. Chem. Int. Ed. Engl. 30 (1991) No. 12, p. 1662-1664 General Process' Using a patented stationary phase of stationary phase, which produces a large amount of pure material, the ratio of isomers &lt; 1: &gt; 9 9. Take the best chromatographic dissolution Serving The residue (830 mg) was recrystallized from an ethyl acetate / hexane mixture to produce -133-% of paper. National Financial Standards (CNS) of Japan (210χ? ΊΫϋ &quot; (Please first listen (Read the notes on the back and fill out this page)-Ordered by the Consumers' Cooperative of the Nakaya Standards Bureau, Ministry of Economic Affairs

Α7 _'_ Β7_ V. Description of the invention (131) Pure substance (479 mg). ["] 0-79.8 ° (c 1.0, acetone was prepared by the method described in Examples 193-198 above, using the appropriate mercaptan-containing reagent k Example 23, to prepare the following bibenzyl-containing products (Table XIV). Table XIV 5193194195196197198199200201202203204205206207208209210211212213214215216217218219

Cl ~ (CHij ^ cco (CH3) 3CCO (CH3) 3CCO Ph Ph Ph 2- * Yuanfen Ac 4-Methylsulfonyl PhCO FhCH2 4-hydroxyphenyl 2-phenethyl 4-methoxy + yl 3-benzyl Propyl 4-fluoropentyl 4-phenyl 4-edgebenzyl 4-fphenyl 4-ethylbenzyl 4-tripolar butylphenylcyclohexyl 3,4-dimethylbenzyl 3, winter digas Phenyl 2-hydroxyf-benzyl 2-fluorobenzyl 2-bromophenyl S-H®

Isomers iri.p.PC) / Other characteristics ss C.-SSSSSSSSSSSSSS5 SSSSSR R, R, R., R, R, R, R., R, R., R., R., R, R, R, R, R, R, r, r., R, r, r / 119-120 [a] 〇 + 26.4 (CHCI3) [a] 〇-27.0 (CHCI3) 125- 126 [a] D + 84- 8〇 (c C W) 136 ^ 137 140-141 126- 127 162-164 155- 157 162-163 105-106 13S-139 82-83 112-113 152- 153 153- 154 125-127 122-123 122 -123 MS (FAB-LSIMS) 417 [M + H] + 144-145 156- 157 ΠM12 131-132 159-160 (Please read the precautions on the back before filling this page) -134- This paper ruler China National Standard (CNS) Λ4 specification (2 丨 0X 297 mm) V. Description of the invention (132) A 7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 220 2-ethylphenyl221 2-cumyl 222 4 -»Specific group 223 4-acetamidobenzyl 224 4-nitrobenzyl 225 〇226 \ mmm / 2 2-theanyl 227] -phenyl228 3-bromophenyl229 .2-methylphenyl 230 2 -Fluorenyl 231 3-fluorenyl 232 2-methylbenzyl 233 / Ο # 234 3-methoxyphenyl 235.3, 5-dimethoxyphenyl 236 3-trifluorof benzyl 237 4 &gt; f Ester benzyl 238 HO-C ^^ n / V ... * \ * / 239 i-Pr 240 2-hydroxyphenyl 241 φ 242 3-Gas Benzene ▲-243 244 3-Fluorophenyl 432 433 2,6-Di-f-benzyl 434 CO ^ I * 435 EI, ΝΟΟ 6 ... 436 &amp; · This paper is applicable to the standard of CNI (CNS) ) Ah see (210X297 male) ssss S 5 R, R, R, CrT R, 134-135 149-150 190-191 165-166 211-212 172-173 sssssssss r, r, r, r, r / r'r, r. sss sssss R, R, KiR, R, R / R,

sss R- &quot; RiCET sss R &quot; R 's R, s R, 155-156 168-169 167-168 Π5-116 153-154 137-138 130-131 221-222 143-144 175-176 114-115 152-153 162-163 110-111 148-149 172-173 164-165 135-136 167-168 132-133 190-191 160161 165-166 (Please read the notes on the back before filling this page) Order

A7 ______B7 V. Description of the Invention (Π3) 437 R'S 15M37 6-. Example 444:

0H 0 Step 1 According to the procedure of Example 23, the desired product β MP 200-201 ° C was prepared from acetamidine and itaconic anhydride.

〇 Step 2 example 444 method. Example 444 was prepared from the product of step 1 and thiophenol according to the method of Example 193. The reaction conditions caused the cleavage of the acetamidine group and the addition of thiophenol to the acrylate. MP 137-138 ° C ° (Please read the precautions on the back before filling this page)

, 1T

Printed by the Employees' Cooperative of the Central Bureau of Standards of the Ministry of Economics-Example 245 Example 2 4 5 Take the mother liquor of the crude material of Example 196 and subject it to silica gel chromatography to produce a pure sample of the product of Example 2 45 isomer. Analysis: C calculation 値: 6 7.2 3; actual measurement 値: 6 6.9 2; Η calculation 値: 4.66; actual measurement 値: 4 · 6 6; C1: calculation 値 8.6 3; actual measurement 値: 8.7 2; S: calculation 値: 7.80: Measured radon: 7.69. -136- Standard Chinese Standard for this paper (CNS:) A4g (Magic 0X297 mm) A 7 B7 V. Description of the Invention (134)

a] d-99.7 (c 0.6, acetone) ϋΙΜZ: [a] D + 100.6 (c 0.6, acetone) Don [called D-9 7.4 (c 0'6, acetone) weight α] D +9 5 6 (c 0 · 6, acetone) Example 2 4 6 、 Example 2 4 7 、 Example 2 4 S and Example 2 4 9: Sample 1 9 6 Form a solution in a mixed solvent containing tetragas furan and a significant amount of peroxide, and store for several days. As a result, a significant amount of heterogeneous sublayers were formed. Examples 2 4 6 and 2 4 7 'Examples 2 4 8 and 2 4 9 were separated into pure fractions by HPLC stationary phase chromatography. These same compounds can also be isolated from aged samples of Example 196 or its isomerized Examples 197 or 198 or samples of the same substance in a solution to which peroxide gas is added. In the aged air-oxidized samples of Example 19 7 ', two subarsenides of Example 2 4 8 and Example 2 4 9 are also often found, so they must have the same C-2 stereochemistry as Example 丨 9 but The stereochemistry on oxygen is different. Similarly, Example 246 [〇 /] 〇_997 ((; 〇6, Acetone) and Example 2 4 7 were also found in the aging samples of actual sample 198, so it must be the same c_ 2 stereo as Example 丨 9 8 'Chemical', but the stereochemistry of Yazi is different. • 137, this paper ruler · Caimucai County (C-NS) A4 · (210X297 male thin) A7 ______B7 V. Description of the invention (135) 0

Example 2 50 Consumption Cooperation of Employees of Ningyang Municipal Quasi-Bureau of the Ministry of Economic Affairs ‘Social Policy’ Example 2 50 Take a solution of Example 244 (20.9 mg, 0.0445 mmol) in THF (1.5 ml) and cool in a dry ice / acetone bath. Seal the reaction flask with a rubber stopper and let methylamine. Gas pass for about 1 minute. The reaction was warmed to room temperature, stirred for several hours, concentrated under reduced pressure, and recrystallized from ethyl acetate and hexane to give the white crystal of Example 250. MP 185-186 ° C. Example 251 In a 25 ml round bottom flask, 209.8 mg (0.732 mmol) of Example 29 was dissolved in a 5 ml 1 '4-dioxolane beta flask and placed under argon. 0.1 ml of thiophenol (0.934 mmol, 1.33 eq) was added to the flask through a syringe, and the mixture in the flask was stirred at 25 * C. After 10 hours, 0.1 ml of thiophenol was added through the syringe. The mixture was stirred for a total of 2 5 hours. The reaction was concentrated in vacuo, and the residue was recrystallized from ethyl acetate and hexane to give 93.0 mg (32%) of white crystals. MP 168-169 ° C. Using the method described in Example 2 51 above, using Example 29 and the appropriately substituted thiol starting materials, the following biphenyl-containing products (Table χ V) -138-in this paper are prepared in g;: turn (CNS ) 2lOX 297 ^ t) (Please read the notes on the back of Jing and fill in this page first) Order five 'invention description (136) A7 B7

Table XV

Example 2 5 3 (Reference compound) This compound was prepared in a manner similar to that of Example 193 except that thiolactic acid was used instead of thiopivalic acid, and Example 2 8 was used instead of Example 23. MP 94 ° -95.0. . . Using the method of Preparation Example 253 described above, using the thiol acetic acid and an appropriately substituted olefin starter, the following benzyl-containing products were prepared (Table XVI). Form XVI (Please read the notes on the back before filling in this I) -vs

253a 254d Me c, -〇-c R, SR, S 94-95 91-92 Central Standards Bureau of the Ministry of Economic Affairs; a reference compound printed by the Industrial and Commercial Cooperative Example 2 5 5 Take 19.3 mg (0.665 mmol) Ear) Example 32 and 120 · 9 mg of 2-hydrothiophene were dissolved in 3 ml of distilled Thf. The reaction was flushed with argon gas. It was printed on Zhou-139-paper scale (3 countries, 1 country, standard (CNS), 8 TB, 2 丨 0X297 mm) A7 A7, printed by the Central Bureau of Standards, Ministry of Economic Affairs and Consumer Cooperatives. ------- -------- 5. Description of the invention (137) Stir overnight at warm temperature. The volatile components were removed by emptying, and the resulting coarse solid recrystallized (EtOAc-hexane) 'yielded 140.0 mg (52%) of Example 255. MP Ϊ60.0-161.0 ° C. Using the method described in Preparation Example 255 above, using the appropriate serthiol reagent and Example 32, the following bibenzyl-containing products were prepared (Table XVII). Table X V11 0

255 2-Sephen R, S 160-161 256 (CH3) 3CCO R, S 106-107.5 257 Ph R, S 135-136 258a Ac R, S 118-119 Reference compound example 2 5 9 Take example 29 (0.36 mmol Mol) was dissolved in 10 ml of 1 '4-dioxolane under argon at room temperature. Add 1.06 equivalents of thiomorpholine to the solution, and within 5 minutes, a precipitate began to form. Add some 1,4-dioxozone to make the mixture easier to stir. Continue stirring overnight. The solid was removed by filtration, and dried to produce 1 1 2 mg of the free base solid product of Example 2 59. The primary solid was suspended in EtOH, and HC1 gas was passed through until clarified to form a hydrochloride salt of the product. The salt was precipitated using Et20 and collected by filtration to give Example 259 final product. MS (FAB-LSIMS) 390 [M + H] + ° Using the method described above for the preparation of plutonium 259, using Example 29 and an appropriate amine starter, the following biphenyl group-containing products were prepared (Table X V 111). Each phase product is in accordance with • 140 winter paper, which is also applicable to Chinese National Standard (CNS) A4. ^ (210 &gt; &lt; 297) ^ (Please read the precautions on the back before filling this page} Order A7 B7 413675 5 2. Description of the invention (138) The above method is first analyzed after being converted into the hydrochloride salt as an inhibitor of M MP s.

'Form XVIII (Please read the notes on the back before filling out this page) 〇

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

Example R6a Isomers Other properties 259 Factory 1 Η \ / R, S MS (FAB-LSIMS) 390 [M + H] +. 260 ΝΗ 0 ^ 0 R, S MS (FAB-LSIMS) 470 [M + H ] + 261 \ -— / 4X3 Ν_ f η- \ Μςχ R, S MS (FAB-LSIMS) 402 [M + H] + 0 Η This paper is based on China's national standard: CNS) A4 wash grid (210X297) (1) Consumption cooperation by employees of the Central Bureau of Standards, Ministry of Economic Affairs, Du Yin 4Ϊ3675 A1 B7 V. Description of the invention (139) Shizhao 26 2 General process of use case 144 ', but use a commercially available 2_ (3_N_phthalimide imine b group ) This compound was prepared by replacing dimethyl malonate with ethyl 2-ethyl- 5-phenylvalerate. The following process is also used instead of the steps (and subsequent steps) for treating crude oil with NaOH in ethanol / water. In a closed container, take the substituted diester (products from the first half of steps 1, 2 and 3) and dissolve it in a concentrated solution of acetic acid: glacial acetic acid 1: 4 and heat to 110 ° C for 18 hours. After cooling, deduct the solvent. The residue was taken up in hexane (2 x 25 ml) and toluene (2 x 25 ml). Concentration, the resulting solid was chromatographed on silica gel using 3% acetic acid / ethyl acetate. 19 1-1 92aC »Example 263 Step Touch_1 Take Example 114 Step 2 Plate 2 The methyl ketone product was recrystallized from ethyl acetate. In a 50 ml round bottom flask, take 1.2 2 g (3.94 mmol) of this purified material and dissolve it in 12 ml of dimethoxyethane (DME) *. Add sodium iodide, 6 18.9 mg (4.13 mmol, 1.05 equivalent) into the flask to produce solution 1. In another flask, take 1.00 g (4.34 millimolars, equivalent) of commercially available (2-dimethylamine ethyl) diethyl malonate in 4 ml Add acetic acid. Sodium (336 mg, 4.69 mmol) to the flask to produce solution 2. Add solution 1 to solution 2. The mixture was stirred at 25 for 1.5 hours. The reaction was concentrated in vacuo and the residue The gas-soluble layer was washed twice with 10% carbonic acid solution and once with sodium sulfite solution. The organic layer was dehydrated with sulfuric acid, filtered, and concentrated in vacuo. Step 2 Take the residue from step 1 and dissolve it. 20 ml 1: 1: 1 ethanol / water / tetrahydro, Fu Nan ·; Kun-142- This paper is a Chinese standard (CNS) Α4ίΜ§ (210X297g / £) {Please read the notes on the back first Fill out this page again) Order A7 _____B7_____ V. Description of the invention (140) Add 6 ml 1. 〇n N a Ο Η to the compound. The mixture was refluxed for several days, diluted with water, acidified to pH 3 with 10% HC1, and concentrated. According to the method of Example 263 in Step 3, the obtained solid was mixed with 100 ml of HC1 and refluxed for 8 hours = the mixture was filtered, and the solid was washed with hot ethanol. The ethanol washes were concentrated and the crystals were collected. The filtrate was concentrated to dryness and recrystallized from ethyl acetate to give 156 mg (3.7%) of white crystals of Example 263. MP 207-20 8. . . Using the method of Preparation Example 263 described above, the following biphenyl-containing products were prepared (Table XIX). Each initial product was first converted into the hydrochloride salt as described above before being analyzed as an inhibitor of MMPs.

Form XIX (Please read the notes on the back before filling this page) 〇

264 HCl * Et2N (CH2) 2 R, S 185-186 265 CF3CO2H · Et2N (CH2) R, S MS (FAB-LSIMS) 402 [M + H] + 3 Order the shellfish consumer cooperation cooperation of the Central Sample Bureau of the Ministry of Economic Affairs Printing

Example 2 6 6 -143 · This paper size applies the China National Standard (CNS) (210X 297 male diamond) A7 __ B7___ V. Description of the invention (141) Example 2 6 6 A method similar to Example 2 6 3, but using 2 instead -(3-Methylthiopropyl) malonic acid di-6 ester was used instead of (2-dimethylaminoethyl) diethyl malonate to prepare Example 266. The crude product of the diester intermediate was not washed with alkali 3 and was chromatographed on silica gel using hexane and ethyl acetate. After final acidification, the product was extracted with ethyl acetate and concentrated. The residue was dissolved in 1,4-dioxolane, refluxed, and the carboxyl group was removed. The crude product was chromatographed on silica gel using ethyl acetate and acetic acid. The product was recrystallized from ethyl acetate and hexane. MP 134-135 ° C. Example 267: ο Step 1 Treat an allyl alcohol (250 ml) solution containing malonic acid (100 g, 0.96 mol) with sulfuric acid (0.25 ml) and heat to 70 ° C for 12 hours. After cooling to room temperature, the solution was concentrated to about 1/3 of its original volume and diluted with hexane (500 ml). The mixture was washed sequentially with saturated aqueous K2C03 solution and NaCl. The organic layer was dehydrated with Na2S04, filtered and concentrated. Purification by distillation (85 ° C @ 〇_〇1 mm Hg) gave diallyl malonate (156 g, 88%) as a colorless oil. NMR (300 MHz, C.DClj) d 5.85 (tn, 2H), 5.30 (m, 2H), 5.20 (m, 2H), 4'60 (m, 4H), 3.40 (s, 2H). (Please read the notes on the back before filling this page) Order Print

• 144- This paper size is applicable to the Chinese Standards (CNS) A4 size f 210X297 mm) // A7 A7

Printed as B7 by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (142) Step 2 Take a freshly distilled THF (100 milliwell) solution containing sodium hydride (4.35 g, 0.18 mol) and cool to 0 ° C, via a dropping funnel, for 40 minutes: treated with diallyl malonate (35 g, 0.19 mol) a After stirring at room temperature for 30 minutes, add N- (2- The entire amount of bromoethyl) phthalimide (43.9 g, 0.1 7 mol) was added to the solution, and the mixture was heated to reflux. After 48 hours, the solution was cooled to 0 ° C and reacted with 2 N H C 1 in middle soil, and concentrated to about 20% of the original volume. The concentrate was diluted with ethyl acetate (300 ml), washed sequentially with saturated reverse 2 &lt; 03 and NaCl, and the organic layer was dehydrated with MgS04, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (5-25% ethyl acetate: hexane) yielded 2-phthaloiminoethyl malonate diallyl (41.2 g, 67%) as a colorless oil. 1Η NMR (300 MHz, CDC13) d 7.82 (m, 2H), 7.72 (m, 2H), 5.85 Cm, 2H) f 5.30 (m, 2H), 5.22 (m, 2H), 4.60 (m, 4H), 3.80 (t? J = 6.6 Hz, 2H), 3.46 (t, J = 7.2 Hz, 1H), 2.30 (dd, J-13.8, 6.9 Hz, 2H) 〇a Step 3 What is the 2-phthalimide ethyl A solution of freshly distilled thF (200 ml) of diallyl malonate (38.0 g, 0.106 mole) was cooled to 0aC and added to 0 via a cannula. (: Below, in a solution of NaH (2.5 g, 0.106 mole) in THF (50 ml). After warming up to room temperature, stir for 40 minutes, add Example 14 in three minutes in 5 minutes, step 2 product (36.1 g, 0.1 17 mol) The mixture was heated to reflux. After 12 hours, the solution was cooled to 0 t, at -145- each paper ruler and the standard (A) A4, Miscellaneous (2lQx29? Male thin) (Please read the precautions on the back before filling this page)

T Λ Printed by the Shellfish Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs A7 ____B7_ V. Description of the invention (143) 2 N HC 丨 The reaction was stopped and concentrated under reduced pressure. The concentrate was diluted with digas-methane (250 ml) 'and washed sequentially with a planer and K2C3 and NaC1 aqueous solution. The organic layer was dehydrated with M g S 0 *, filtered and concentrated. Crystallization from ethyl acetate yielded (2-phthaloiminoethyl) 4 ·-(4'-phenyl) acetamidophenylmalonate (49.1 g '83%) as an off-white crystal ( Recrystallize once more and recover another portion): Rf = 0_4 (30% 6-acetic acid: hexaneρ Step 4 of Example 267. Take the disubstituted propionate containing disubstituted malonate (45.6 g, 77.5 millimoles) of 1'4. Dioxoland / aqueous solution (300ml-, 5% water) to full amount of (triphenylphosphine) palladium (0.5g, 0.4 millimoles )-After treatment, add Eleusis (1 4.2 ml, 171 millimoles) dropwise over 1 hour. After stirring for another 30 minutes, dilute the solution with ethyl acetate (600 ml) to 2 NHC 1 Wash. The organic layer is concentrated and reduced to yield white crystals of the corresponding diacid. This diacid is easily recrystallized from aerosol or ethyl acetate, but is usually used in the next step without further purification 1,4-dioxolium (300 ml), heated to reflux for 36 hours. After cooling to room temperature, the solution was concentrated 'from 1,4-dioxolium: methylbenzene, recrystallized to produce the Desired acid (31 g , 86%) of white crystals. Mp 209-210Ό. Example 268: Take Example: 267 (racemate) on a Pirkle L-leucine type HPLC column 'use ethanol / digas methane containing 2% acetic acid / Hexane mixture (2/25/73) dissociated into the most active (Example 2 6 8 dissolves first from the column) and the less active (Example 2 6 9 the second dissolves from the column). Enantiomers. Example 2 6 8: [a] D-9 7 ° (e 1 · 3, DMF). Using the method described in Preparation Example 2 6 7-2 6 9 above, use -140 as appropriate in Step 3. 'This paper music scale is applicable to Chinese Standards (CNS) M specifications (;;: 〇ίΐ9_7 公 董)' (Please read the precautions on the back before filling this page)-, 1Τ A7

B7 V. Description of the invention (144) α-halones, to prepare the following fluorene-containing phenyl products (Table XX). Table XX

R, 5 6 6 6 2 2 2

c c C

270 Br 271 a PnCH2〇 272a M-pentO 273a EtO

R, SR, SR, SR, S 209-210 [a] 〇-9.7〇 (c 1.3, DMF). The second one was 223 210 163-164 106-107 from the PirldeL-leucine mosquito plastic HPLC column. (Please read the precautions on the back before filling out this page) Order printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs -147- This paper size is 0 ^ 1 Chinese National Standard (0guanidine) 8 4 specifications (210 '乂 297 1-) Ministry of Economic Affairs _ Central Standards Bureau, Off-line Work and Consumer Cooperation Co-print A7 _____B7_ V. Description of the Invention (145) al- (2-i4 ethyn) -4- (4-oxophenyl) benzene Production method: Step 1 In a single-headed, 250-ml round-bottomed flask equipped with an argon inlet, add 50 liters of acetone, 50 ml of acetone: 4 · -Cyclo-4 · 聨 -benzonitrile (100 g, 51 2 mmol) Mol), benzyl bromide (3 5.0 g, 24.3 ml '20.5 mmol) and potassium carbonate (2,8 g, 230 mmol). The resulting mixture was heated at reflux for 12 hours. When cooled to room temperature, white hexahedral crystals appear in the acetone layer. Exclude the water layer 'filter, the total yield of 4 · -methoxyl_4 · bibenzonitrile "MP 151 Step 2 Add 70 ml of single display 250ml round bottom winding with rubber stopper and argon needle inlet. Ml of THF, 4'-fluorenyl-4-bibenzonitrile (10.0 g, 35.0 mmol), cooled to 0, and at the same time, the methyl solution (1.4M ethyl chain) was added dropwise via a syringe in about 2 minutes. Solution, 37.5 ml, 52.5 mmol). The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was added to an ice-cold solution of water and concentrated sulfuric acid (600 ml), and extracted with ethyl acetate. The resulting organic phase was dehydrated with Na 2 S 0 4, filtered, and concentrated to give a yellow solid which was recrystallized from ethyl acetate to yield the desired methyl ketone in full yield. T LC (50% acetic acid ethyl acetate *) 1 ^ = 0.64. Step 3 In a single-necked 100 ml round-bottomed flask equipped with a rubber stopper and an argon needle inlet, add 35 ml of THF, 4'-methoxy-4-benzyl ketone (1.0 g, 3 · 31 1 mol), cooled to -7 8 ° C, while using a needle to add L i Η MDS solution (0 · 1 M THF, 3, 3 1 ml, 3.3 1 millimolar). After leaving the cooling bath, the resulting mixture was stirred at room temperature until the solution was clear. The reaction mixture was cooled to -78 ° C, and trimethylsilyl gas (0.39 5 g, 0.461 ml, 3.64 mmol-148) was added dropwise over a period of about 1 minute using a syringe. CMS &gt; Α4 specification (210X297 mm) (Please read the notes on the back before filling this page) Order λ A7 B7 Five 'Invention Note (H6) Mor) ° The resulting mixture. Stir at -78 ° C for 30 minutes The reaction mixture was added to an ice-cold * mixture containing hexane (100 ml) and NaHC03 solution (100 ml). The resulting organic phase was dehydrated with Na 2 S 0 4 and filtered and concentrated to give a yellow solid. A transformation reaction. TLC. (C_-18 silica, MeCN) Rf = 0.59. Step 4: Add a single-head 100ml round bottom with a coarsely broken yetyl allozyme as the entrance of the needle and argon needle. Add 25 ml to the flask, cool to 0 ° C, and add the entire amount of N- 涘 succinimide (0.587 g, 3.30 mmol) at one time. After 15 minutes, it is difficult to open the cooling bath and the reaction mixture is added to ethyl acetate. (50 ml) and water (100 ml). The organic phase obtained was Dehydrate, filter, and concentrate to produce 1- (2-bromoethyl ketone) -4- (4-oxophenyl) benzene, suitable for immediate use as a calciner. TLC (C-18 silica, MeCN) Rf = 0.71 This method is also used to prepare 1- (2-bromoacetamidine) -4- (4-ethoxyphenyl) benzene and 1- (2, bromoethyl ketone) -4- (4-pentoxyphenyl) benzene (Read the notes on the back before filling out this page) • ys Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

Example 276 The method of Example 2 67 was used, and a commercially available N- (bromomethyl) S dazaimine product was used in step 骒 2 to prepare Example 276. MP P 190-193 ° C. • 149- The paper size is in accordance with China National Standards (CNS) A4 specifications (2) 0 × 297 mm A7 _____ — — B7 V. Description of the invention (147) 〇

〇 Example 4 3 1 Example 4 3 1: Using the method of Example 267, commercially available ν · (4-xibutyl) scopolamine imide was used in Bulu 2 to prepare Example 431. MP 168-169 ° C. (Please read the notes on the back before filling this page)

0 Order M * Ministry Central Bureau of Standards Consumer Cooperatives Printed Example 279 Treasure Example 279 Take Example 267 (50 mg, 0.11 mmol) Suspended in 5 ml of water β Add Na 〇Ή (9 _ 1 mg '0.2 3 mmol Mol) in 5 ml of aqueous solution and stir for 18 hours. Concentrated H C 1 was added dropwise until the solution was acidified. The precipitate was filtered off and air-dried to give 33 mg (64%) of the desired product. MP 93-1001. -150- This paper size applies to Chinese National Standards (CNS; 8-shaped (210X297 mm) A7 B7 V. Description of the invention (48)

Example 280 Example 2 80 &quot; Using the method of Example 279, a pure enantiomeric example 2 80 was prepared from the pure enantiomeric example 2 68. MP 79-89 '. (Please read the notes on the back before filling this page}

〇 Printed by the Consumer Standards Bureau of the Ministry of Economic Affairs, Bureau of Laboratories, Cooperative Society 282 Example 282 A method similar to Example 23 was used, but 2,2-dimethylsuccinic anhydride was used instead of itaconic anhydride to prepare the compound. MP 179-180X :. Using the method described in Preparation Example 2 8 2 above, the following biphenyl-containing products were prepared (Table XXI). -151-The size of this paper is in accordance with Chinese National Standard (CNS) A4 size Ui〇297mm. V. Description of the invention (149) Real 6 R e € f MM Η 2Jala 2828284

Α7 Β7

Table XXI 0 Rea

Isomer o ^ ti π mprC) / Other persistent racemic 179-180 157-159 165-167 a2,3-dimethylsuccinic anhydride production method: At room temperature, add acetamidine gas (8_27, G, 7.49 ml, 105 millimoles) to 2,3-dimethylsuccinic acid (5.13 grams, 3 5.1 millimoles). The reaction mixture was refluxed at about 65 ° C for 2 hours. Concentrated and highly air-dried. The desired product (4.95 g, containing a small amount of acetic acid impurities) was obtained as a white solid. H-NMR (CDCh) d isomer # 1: 1.25 (d, 6H), 3.18-3.23 (m, 2H); isomer # 2: 1.36 (d, 6H), 2.71-2.77 (m, 2H) . Example 285, Example 286, and Example 2 87 The process was similar to that in Example 1, but the specified anhydride was used instead of digas_3_ (2-methylpropyl) -2,5-furandifluorene to prepare these compounds: (Please (Read the notes on the back before filling out this page)

Printed by the Shellfish Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

L

Example 2 8 5 (racemate) Prepared from trans · cyclohexane-1,2-dicarboxylic anhydride: MP 187_188 -152- This paper is suitable for the β standard national standard (CNS) A4 pit (210X297) %) A7 B7 V. Description of the invention (150) ° c

Example 286 (racemate) f Example 2 8 6: Prepared from cis-cyclohexyl-1,2-dicarboxylic anhydride: MP 180-181 (Please read the precautions on the back before filling this page)

Example 287 Example 287: Preparation from phthalic anhydride: MP &gt; 23 (TC Example 2 8 8:

Η

Printed in Step 1 by the Central Consumer Bureau of the Ministry of Economic Affairs and Consumer Cooperatives. Add acetic anhydride (10 ml) to trans-cyclopentane-1,2-dicarboxylic acid (1.16 g, 7.33 mmol) at room temperature. . The reaction mixture was refluxed at about 165 ° C for 14 hours. Concentrated by vacuum and co-evaporated 3 times with toluene. This gave a crude product (1.0 g, ~ 100%, with minor acetic anhydride impurities) as a brown oily solid. lH NMR (CDC13) d 3.55-3.35 (m, 2H), 2.4-2.2 (m, 2H), 2.15.1.75 (m, 5H), 1.55- 1.35 (m, 1H) ° -153- This paper size applies to China National Standards (CNS) Α4 specifications (210X297 male) A7 B7 V. Description of the invention (151

Example 2 8 8 (racemate) The method of Step 2 Example 288. Following the general method of Example 1, but using i '2-digasethane as the solvent and using the anhydride prepared in step 1 instead of dihydro-3- (2-methylpropyl) -2,5-furan Dione preparation. The product (1.0 g, 43%) was purified by silica gel chromatography to give a residue containing cis and trans isomers. "After several recrystallizations, the cis isomer was isolated. Example 2 8 8 (1 60 ml). MP 176-178. (:. {Please read the notes on the back before filling this page) • \ ls

Printing example 289 (racemate) of the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs 洌 2 8 9 Add 1,8-diazobicyclo [5,4,0] + -carbon-7-ene (75 Ml, 0.502 mmol) to a solution of the mother liquor containing trans isomers (110 mg, 0.334 mmol) in THF (5 ml). The reaction mixture was stirred under argon for 154-pieces, and it was used as a standard sheet. "^ 0 Drawing Standard (CNS) A4 size (2DX297 mm). Printed by A7 B7, Consumer Work Cooperative of Central Bureau of Standards, Ministry of Economic Affairs. V. Invention Instructions (152) Mix for 48 hours. The operation process includes: diluting with dClji (5 ml), adding 1 N HCI (15 ml), 'separating', and extracting water with CH2CI: 2 (15 ml x 3). The combined organic layers are dehydrated with MgS04, filtered, and concentrated in vacuo. The crude product was purified by H PLC to give pure white compound of Example 2 89. MP 169-mOC.

Example 290 (racemate) Example 291 (racemate) Example 2 9 0 Example 2 9 1 Following the general method of Example 1, but using 1,2-digas ethane as the solvent and cyclobutane di These compounds are prepared by replacing the dihydro-3- (2-methylpropyl) -2,5-furandione with an acid anhydride. The crude product (0.72 g, 30%) contains a mixture of cis-trans-isomers (cis: trans = 2/1) ^ ms (fab-lSims) 3 1 5 [M + H], Example 2 9 0: The crude product was purified by silica gel, yielding 40 mg of cis isomer as a white solid. MP 154-156 ° C. Example 291: Excess K2C03 was added to a MeOH (250 ml) suspension of a two-component crude product (14.5 g, 46.06 mmol) at room temperature. The reaction mixture was stirred at room temperature for 48 hours. The operation process includes adding 2 NHC (500 ml), extracting the aqueous layer with CH2C12 (7 X 100 ml), washing the combined organic layers with saturated NaCl (1200 ml), dehydrating with N'igS04, and passing -J55- This paper size applies the China National Standard (CNS) A4 specification (U〇V29lZ £) (please read the notes on the back before filling this page) Order A7 ___B7_ 5. Description of the invention (153) Filtration and air concentration. Crude product (1 3.2 g, 9 1 ° / 0 &gt; is an 84% de off-white solid that favors the trans isomers. After recrystallization, 9.1 g of pure trans material are depleted of white crystals. Mp 1 84-1 86 &quot; C. Real 292:

H02C CO2H Step 1 At room temperature, add IN NaOH (150 ml) to a solution of 1,2_cis-dimethylcyclopropane dicarboxylic acid ester (4.71 g, 29.8 mmol) in THF_ (100 ml) in. The reaction mixture was stirred under argon for 14 hours. The operation process includes: separating the aqueous layer and the THF layer, washing the aqueous layer with diethyl ether, acidifying, acidifying the aqueous layer with 2N HC 丨, concentrating to dryness, diluting with EtOAc, diluting and emptying. concentrate. The desired product (3.5 g, 90%) was obtained as a white solid. iH-NMR (DMSO-d6) d 4.21 (bs, 2H), 1.29-1.24 (m, 1H), 0.71-0.65 (m, 1H) 0 〇

o Printed by the Shell Standard Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Step 2 Add acetic anhydride (30 ml) to cyclopropane-1,2-dicarboxylic acid at room temperature (3 2 4 g, 2 4.9 mmol). The reaction mixture was refluxed for 4 hours. Concentrated in air 'to produce the desired product. iH-NMR (DMSO-d6) d 2.00 (dd, j = 4.04, J '= 8.08, 2H), 0.90-0.83 (m, 2H) -156- This paper applies to 13 countries 棰 CMS) ΜίΙ ^ (210X 297 / ^ · ^) A7 B7 Five 'invention description (154)

Example 292 (racemate) Preparation method of step% 3 (reference compound) β According to the general method of Example 1, but using 1'2-digas ethane as the solvent and using the anhydride of step 2 above instead of dihydro- 3- (2-Methylpropyl, 5-furanedion) MP 175-176 ° C., 0

f Please read the precautions on the back before filling this page) Order the printed example 293 (racemate) of the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 293 (Spring Compound 1 at room temperature, add excess K2C03 to Example 292 (50 mg, 0.166 mmol) in MeOH (20 ml). The reaction mixture was stirred at room temperature for 48 hours. The medium was added by adding 1N HC1 (25 ml) to CH2C12 (4 X 25 ml). ) Extract the aqueous layer, wash the combined organic layers with saturated NaCi (50 ml), dehydrate with MgS04, filter, and concentrate in vacuo. The product of pseudo trans isomers (50 mg, 100%) is obtained, which is> 99% De white solid. MP P 1 8 1 -1 8 3 ° C -Example 2 9 4 and Example 2 9 5: -157- This paper has a suitable wave size; National Standard (CNS) A4 Specification (210 × 297 mm) A7 _____B7 V. Invention Description (155)

Step 1 follows the general method of Example 1, but uses 1,2-digasethane as the solvent and cyclopentene-1'2-dicarboxylic anhydride instead of dihydro-3- (2-methylpropyl ) -2,5-furan dinetwork to obtain the above compound (27 7 g) as white crystals in a yield of 91%. MP 226-227 ° C. '' Example 43 9 (Please read the precautions on the back before filling this page)

&quot; Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Example 439 Step Knee 2 Example 439 method. Add n-butylamine (7 § ml, 125 mmol) to -78 ° C in a solution of diisopropylamine (19 ml, 130 mmol) in THF (60 ml). After the LDA was stirred at -78 ° C for 30 minutes, it was treated with a solution of the product from Step 1 (10.2 g, 31.2 mmol) in THF (100 ¾ liter). The reaction mixture was stirred under argon and -78 for 1.5 hours, and the reaction was quenched with Ac Η (21 ml, 375 mmol). The resulting mixture was allowed to warm to room temperature over a period of 2 hours. The operation process includes: adding IN HCl (100 ml), -158, i paper wave X degree applies Chinese national standards ϋ Ϊϋ (210Ϊϋ> α97 mm) ~ A7 B7 Central Ministry of Economic Affairs Central Bureau of Quasi Bureau Shellfisher Consumer Cooperative Printing 5. Description of the invention (156) CH2C12 (3 X 150 ml) extracts the aqueous layer, and condenses it in air. The crude product was recrystallized from EtOAc to yield 6.22 g of the above compound as off-white crystals, QP 202-204 ° C ° Step 3 Example 294 and Example 295 Production Method a Add thiophenol (433 ml '4.22 mmol) and K2C03 in water (2M, 141 ml, 0.281 mmol) to room temperature and argon in DMF (6 ml) containing the product of Step 2 (919 mg, 2.81 mmol). The reaction mixture was stirred under argon at room temperature for 18 hours. The operation process includes: diluting with c H 2 C 12 (15 ml), acidifying with 2 N. HC 丨, adding Η20 (20 ml), αΗ20 (3 × 40 ml) and absolute NaCl (30 ml), washing the organic layer with MgS04 was dehydrated, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography to produce two separated diastereoisomers, trans-trans Example 2 9 4 and trans-cis Example 2 9 5, total. Rate 4 6% 0 Example 294: MP 177-178eC Example 295: MP 184-185 ° C Example 296 and Example 297 Using Diacel® AD semi-preparative column (2 cm x 2 5 cm) at 15% IPA (Containing 1% Η 20 and 0.1% TFA) The enantiomers of Example 2 9 4 were separated to yield &gt; 98% ee Example 2 9 6 enantiomers and &gt; 97% ee Example 297 Enantiomer. Example 2 9 6: (+) enantiomer: MP 1 6 5-1 6 71, Example 2 9 7: (-) enantiomer: MP 1 6 8-1 6 9 C,洌 2 9 8 Use the manufacturing method of Example 294 above to use appropriate mercaptan merchandise, -159- This paper size is common Chinese National Standard (CNS) Λί specification (210x297 mm) (Please read the precautions on the back before (Fill in this page)-**

I

I A7 ____B7 V. Description of the Invention (157) Preparation Example 298. MP 227-228 ° C. Example 299 and Example 300 were chromatographed on a Chira pak AD HPLC column to separate the isomers of Example 298, resulting in the enantiomers 2 9 9 and Example 3 0 0. Example 299: MP 124-125 ° C; [aID + 18.69 (c 0,73, Cgang) Example; Ϊ 0 0: MP 1 3 2-1 3 3. (:; [A] D-1 7 '9 2 (c 1. 1.6, acetone) Example 3 0 1 Take 0.6 ml of 1 N sodium hydroxide and add it to 100 ml of 3 ml of methanol suspended in Example 2 9 8 After stirring at ambient temperature, T LC analysis showed that it still contained the starting material, so 0.3 ml of Na 2 O solution was added and stirring was continued for a total of 40 hours. The residue was mixed with water and 10 ° / 〇IIC1 Mix and extract several times with ethyl acetate. The combined extracts are dehydrated (MgS04) and evaporated in vacuo. The residue is recrystallized from ethyl acetate / hexane to give 72.6 mg of the white powder of Example 31. MP 216-217 ° C (decomposition). Using the method described in Preparation Example 294-30 1 above, the following biphenyl-containing products (Table XXII) were prepared. ____ ^ χλΊΓ --------- / ------ Order (please (Please read the notes on the back before filling in this page) Printed by the Shellfish Consumer Cooperation Department of the Central Bureau of Standards of the Ministry of Economic Affairs, ί, 4,56 7 8 &quot; 292929292929s

Rsphphphph Γ Γd ° d °

«Chemical properties 1,2 mp &lt; ° C) / Other properties 2,3 Isomers trans trans, 179-180 trans cis racemic 184-185 trans trans. (+ ) 165-167 trans-trans, (-) 168-169 trans-cis-dissipative 227-228 trans-clear (+) acetone) 160-% Paper size applies Nakazukuni-tsuka standard (CTNS) Α4 see Lattice (210 × 297 mm) V. Description of the invention (158) 300 &amp;-trans 301 &amp; trans 302.4 = fluorophenyl cis 303 -4-gasphenyl trans 304 2-f phenyl trans Formula 305 2-T Phenyl 306 2-methylphenvl trans 307 co · v trans 308 d ... cis 309 4-fluorophenyl trans 310 4-gas phenyl trans 311 4-fluorenyl trans 440 PhCH2 trans 441 PhCH2 trans cis-PN -ru tcv ulv Ji 3 3 3 anti-reverse sleeve anti-(-) [a] 〇-17.92 (c U6, Cis-racemic 216-217 (dec) racemic MS (FAB-LSIMS) 455 ~ [M + H] + racemic 211-212 racemic 175-176 racemic MS (FAB-LSIMS) 451 [M + H] + Racemic 196-197 Racemic MS (FAB-LSIMS) 495 [M + H] + Cyclic MS (FAB-LSIMS) 495 [M + HJ + Racemicity 164-166 Racemicity 213-214 Racemicity 210-211 Racemicity 155-156 Racemicity --------- Top ------ Order ------ '/ | \ / (please read the note on the back first and then fill out this page) The Central Slope Bureau, Ministry of Economic Affairs, Industrial and Consumer Cooperation Du printed

Example 313 The paper music standard is in accordance with the Chinese National Standard (CNS) A4 specification (2 丨 OX 297 mm). Printed by the Shelling Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 _ B7 _ V. Description of the invention (〖59) Example 3 1 2 3 1 3 The racemate of Example 295 was chromatographed on a Chiralpak AD® PLC column and separated into enantiomers. Example 312 was first eluted. The 1H-N MR spectrum was the same as in Example 2 95.

Example 3 1 4 Example 3 1 4 5 ml of a 30% aqueous hydrogen peroxide solution was added to 25 ml of an acetic acid / water (1: 1) suspension containing 2.0 g of Example 197. After the mixture was stirred overnight, another 2 ml of a hydrogen peroxide solution was added, and the mixture was further stirred for 24 hours. The mixture was heated to 40-6 (2.5 hours after TC, stirred at room temperature overnight. The resulting solution was diluted with water, extracted three times with ethyl acetate, and extracted three times with dichloromethane. The combined extracts were dehydrated (MgS04) , And evaporated in vacuo. The residue was recrystallized from ethyl acetate and hexane. Three times, 1.64 g of white powder of Example 3 1 4 was collected. 'Mp 159.5-161: 0 ° C; ia] D + l9'59 ( c = 0.485, acetone). Example 313 and Example 316:

-162- This paper size applies to Chinese national standards ((210X297mm) (please read the precautions on the back before filling out this page) -a The Central Bureau of Standards, Ministry of Economic Affairs, Shellfisher Consumer Cooperation Du printed A7 B7 V. Invention Instructions (16〇) Step Mania 1 Add 4.5 eq. 2 &lt; ^ 〇3 (4.0 \ 4, 18 ml, 73.3 mmol) of water and 4'0 equivalent of ethyl iodide (5.26 ml, 65.2 mmol) At room temperature, 4- (4-bromophenyl) phenol (4,06 g, 16.3 mmol) in acetone (30 ml) was dropped into the reaction mixture. The reaction mixture was stirred overnight and heated to reflux for 6 hours. Product Crystals were precipitated from the solution and filtered. The crude product was recrystallized from itself to give ethyl 4- (4-bromophenyl) phenyl ether (4.1 g, 91%) as white crystals. 1H NMR (CDClj) d 7.53 (d , J = 8.83 Hz, 2H), 7.47 (d? J = 6.62 Hz? 2H), 7.41 (d? J = 8.46 Hz, 2H), 6.96 (d, J = 8.82 Hz, 2H), 4.07 (q ?. J = 6.99 Hz, 2H)? 1.44 (t5 1 = 6.99 Hz, 3H) ° ~

Step 2 Under -781, add ^ 8111 ^ (1.7% 54.6 ml, 92.87 mmol) to ethyl 4- (4-bromophenyl) phenyl ether (12.87 g '46.43 mmol) in THF (90 Ml) solution. The reaction mixture was stirred under argon at -78 ° C for 3 hours and treated with 1 · cyclopentene-1,2-dicarboxylic anhydride (6.73 g, 48.75 mmol). The resulting mixture was stirred at -78 ° C for 2 hours and then 'returned to room temperature. The procedure included the addition of 1 N HC 1 (150 ml) 'and recrystallization from EtOAc to give an fluorenyl acrylic intermediate (6.8 g, 43%) as an off-white solid. 1 H NMR (CDC13) d 7.88 (d? J = 8.09 Hz. 2H)? 7.63 (d, J = 8.45 Hz. 2H)? 7.56 (d, J = 8.82 Hz, 2H) 7 6.98 (d, J-9.19 Hz, 2H), 4.09 (q, J = 6.99 Hz, 2H)? 2.84 (m, 4H), 2.10 (m, 2H), 1.45 (t, 5 = 6.99) This paper standard applies to Chinese National Standard (CNS) AGi # (2! 0X297A ^ &gt; — I ------- Shiyi ------- Order (Please read the notes on the back before filling this page) V. Description of the invention (161)

Hz, 3H) A7 B7

0 COOH

Step 3 Add 4.0 equivalents of 1 ^ called Ding 5 ^) 2 (1! ^, 41.03 ml, 41.03 millimoles). To -78 ° C, containing intermediate from step 2 (3.45 g, 10.25 millimoles) depleted THF (100-ml) solution. The resulting yellow mixture was stirred under argon and -78 ° C for 18 hours. The reaction was quenched with AcOΗ (~ 10 ml) and then allowed to warm to room temperature. The procedure included the addition of IN HC1 (120 mL), extraction with EtOAc (4 X 130 mL), the combined organic layers were washed with saturated NaCl (250 mL), dehydrated with MgS04, filtered and concentrated in vacuo. The crude product was purified by recrystallization from EtOAc to give a recombinant acrylic intermediate (2.40 g, 70%) as an off-white solid. 1H NMR (CDCl0d 7.89 (d, J = 8.64 Hz, 2H), 7.50 (d, J = 8.09 Hz, 2H), 7.42 (d, J-8.83 Hz, 2H), 6.85 (Sj 1H), 6.83 ( d, J = 8.83 Hz, 2H)? 4.64 (ra, 1H), 3.94 (q, J = 6.99 Hz, 2H), 2.47 (m, 2H), 2.35 (m, 1H), 1.85 (m, 1H), 1.29 (t. J = 6'99 Hz, 3H). (Please read the notes on the back before filling out this page) &quot; ^ 1 --- · r Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Example 3 15 (racemate)

Example 316 (racemate) -ie, 4- This paper wave scale applies the Chinese National Standard (CNS) AUt grid (2 丨 0 &gt; &lt; 297 mm) A7 B7 V. Description of the invention (丨 62) Step 4 Example 3 15 The same method as in Example 3 16 was added thiophenol (311 ml, 3.0 3 mmol) and a freshly prepared solution of K 2 C 0 ′ 』Η 2 0 (2 μM, 7 5 table liters' 0.1 5 mmol) to A solution of the intermediate in step 3 (5 μ 0 mg, 1.5 2 mmol) in DMF (2 mmol) at room temperature under argon. The homogenized solution was stirred overnight at room temperature. The procedure includes: acidification with 2N HC1 (1 ml), addition of arsenic 20 (10 ml), extraction with CH2C12 (2 x 15 ml), filtration through silica, and air concentration. The crude product was purified by HPLC (0-8% EtOAc / CH2Cl2) to give two separated diastereomers, trans-trans isomer example 3 1 5 and trans-cis isomer example 3 1 6. '' Example 3 1 5: Analysis C: Calculation 値, mi: Measured 値, 72.74: H: Calculation 値, 5.87; Measured 値, 5.84 »Example 3 〖6: Analysis C: Calculation 値, 72, 62; Measured 値, 72 39; Η: calculated 値, 5.87; measured 値, 5.87. (Please read the notes on the back before filling this page)

Example 442 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Example 4 4 2 Follow the example 3 1 5 Example 3 1 6 Steps of the manufacturing method 1-3 Preparation of 4 4 2 3 1VIP 172-173 ° C. -Ifi5- Chinese paper standard (CNS) A4 specification (210 &gt; i W7 mm) applicable to each paper size 5. Description of invention (丨 63) Λ7 87

Example 4 4 3 Example 443 Example 443 MP 174-177 was prepared according to steps 1-3 of the manufacturing method of Example 3 15 and Example 3. (:.

----------- Water-- (Please read the precautions on the back before filling this page

、 1T Consumption Cooperation with Male Workers, Central Standards Bureau, Ministry of Economic Affairs · Du Printing Example 317 (racemic) Example 318 (racemic) Example 317 and 318 Similar to the method of Examples 315 and 316, but use 1-iodopentan These materials were prepared by replacing the iodoethane in step 1. All intermediates and end products were identified by ιΗ NMR. Example 3 17: MP 1 48-15 0 4C. Example 3 19, Example 3 2 0, Example 3 2 1 and Example 3 2 2: A mixture (1.8 g) containing 洌 317 and Example 318 was taken and analyzed by &lt;: 1 ^ 31〇4 0} Separation yielded the enantiomers of each compound. The 1Η-NMR spectrum of the enantiomers of each compound is the same as that of its respective racemate. Example 319: 105 mg: (.) Isomer of Example 318. -166- The size of this paper is in accordance with Chinese national standard (210 × 297 mm)

A7 B7_ V. Description of the invention (丨 64) Example 3 2 0 ·· 7 5 mg: (ten) isomers of real 3 i 8. Example 321: 160 mg; (·) isomer of Example 317. Example 3 22: 115 mg; (3) 7 (+) isomers. Example 3 2 3-〇〇production 0 Step 1 Add n-BuLi (2M, 100 ml, 200 mmol) to -7S ° C containing di; isopropylamine (30.8 ml, 220 mmol) in THF ( 100 ml) solution. The LDA solution was stirred at -78aC for 30 minutes, and then 2-oxocyclopentanecarboxylic acid acetic acid (15,6 g, 14.8 ml, 100 mmol) was added. After the reaction mixture was allowed to rise to 0-30 minutes, after cooling to -7 ° C, the reaction mixture was treated with benzyl gas (12.66 g, 1 1.51 ml, 100 mmol). The resulting mixture was raised to 0aC for 3 hours. The operation process includes: acidification with 2N HC1 (100 ml), extraction with EtOAc (4 x 100 ml), dehydration with MgS04, filtration and vacuum concentration. The crude product was purified by MPLC (5-15% EtOAc / hexanes) to give the specified intermediate (7.1 g, 29%) as a clear oil. Yield 0 Step 2 Add NaBH4 (1.12 g, 29_56 millimoles) to 0 ° C, in a solution of 1011 (50 ml) containing the intermediate from Step 1 (7.28 g, 29.56 millimoles). The reaction mixture was stirred at argon and room temperature for 3 hours, and then saturated with -167- (Please read the precautions on the back before filling in this page).

Ο OH

This paper size applies the Chinese National Standard (CNS) Ai specification (210 &gt; &lt; 297 mm) 5. Description of the invention (丨 65) A7 B7 NH4C1 (100 ml) &gt; Stop the reaction. The operation process includes the following: £; 〖〇 八£: (4) {100 mL) extracted 'dehydrated with MgSO4, filtered and concentrated in vacuo. 6 The crude product was a yellow oil. 〇, cr

Step 3 Add a thf (~ 50 ml) solution containing the intermediate from Step 2 (6.30 g, 2 5.3 7 mmol) to room temperature &gt; containing triphenylphosphine (i4 64 g, 55 s mmol) with The £ 6-80 (7.99 ml, 50.74 mmol) solution of dioxin (100 ml) was 6-the reaction mixture was refluxed overnight under argon. The operation process includes air concentration. The crude product was purified twice by MPLC (20 / i> EtO Ac / hexane) to produce the above intermediate (2.85 g, 49%). 1HNMR (CDCl3) d735-715 (m, 5H), 6.68 (bs, 1H)? 4.20 (q, 2H), 3.15 (m, 1H), 2.80-2.45 (m, 4H), 2.10 (m, 1H), 1.65 (m, 1H), 1.29 (t, 3H) O

(Please read the precautions on the back before filling this page) Order the printed steps of the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 4 Add 1120 (~ 35 ml) containing UOH. H20 (5.1 g, 121.6 mmol) to At room temperature, in DM E (35 mL) solution containing the intermediate from step 3 (2.8 g, 12.16 mmol). The resulting mixture was heated to reflux for 3 hours. The operation includes acidification with 2N HC 1 (~ 100 ml), extraction with EOAc (4 x 100 ml), the combined organic layers are washed with saturated NaC, dehydrated with MgS04, filtered, concentrated, and toluene (3x50 ml) Co-evaporated. The intermediate (2.35 g, 96%) was obtained as a white solid. 1 H NMR (CDCi3) d 7.35-7.15 -168- This paper size is applicable to Chinese garden (CNS) A4 specifications (210 × 297 mm) A7 B7 V. Description of the invention (166) (m, 3H), 3.15 (m? 1H), 2.80-2.63 (m, 2H), 2.65-2.45 (m, 2H), 2.15 (m, 1H), 1.70 (m, 1H).

Step 5 Add DCC (2.82 g, 13.65 mmol) and HOBT (1 84 g '13 .65 mmol) to 〇eC, containing step 4 intermediate (23 g, 11.34 mmol) ) In THF (80 ml). After the resulting mixture was stirred for about f hours, N, O-dimethyl-hydroxylamine hydrochloride (222 g, 2274 mmol) and £ 1 (3_96 ml, 28.43 mmol) were added to bring the reaction mixture back to the chamber. Warm and stir overnight. The operation includes filtration, washing the filter block with EtO Ac, and concentrating in the air. The crude product was purified by HPLC (dissolution: 7-15% EtOAc / CH2Cl2) to give an intermediate of the formula (2.56 g, 92%) as a pale yellow oil. 1HNMR (CDC13) d, 7.25 (m; 2H), 7.15 (m, 3H), 6.38 (m, 1H), 3.55 (s, 3H), 3.20 (s, 3H), 3.10 (m, 1H), 2.65 (m? 4H), 2.05 (m, 1H), 1.60 (m, 1H ). ----------------------- 京 y {-i (Please read the notes on the back before filling out this page) Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs Print

O

-16S- The size of this paper is applicable to the Chinese National Standard (CKS) A4 (210X297 mm)

Seal of the Shelling Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (167) Step 6 at -78. (: Add 1-3111 ^ (1.7 ~ 丨, 3.52 ml, 5.99 mmol) to THF containing ethyl 4- (4-bromophenyl) phenylhydrazone (830 mg '2.99 mmol) Ml) solution. The reaction mixture was stirred under argon at -78 ° C for 1 hour and treated with the intermediate from step 5 (770 mg, 3.14 mmol). The resulting mixture was stirred at -78 ° C for 30 minutes at 0 ° Stir for 30 minutes at room temperature and 30 minutes at room temperature. The operation includes adding IN HC1 (25 ml), extraction with EtOAc (4x20 ml), filtering through silica, and concentrating in vacuo. The crude product is purified by HPLC (dissolution: 5 -20% EtOAc / hexane) 'yielded the above-formed intermediate (400 mg, 35%) as an off-white solid. 1H NMR (CDC1;) d 7.80 (d, J = 8.46 Hz. 2H), 7.62 (d. J = 8.46 Hz. 2H), 7.57 (d, J-8.83 Hz, 2H), 7.29 (m, 2H), 7.21 (m, 3H), 7.00 (d, J-8.82, 2H); 6.46 (bs, 1H ), 4.10 (q, 3 = 6.99 Hz, 2H), 3.30 (m, 1H), 2.84 (m, 4H), 2.20 (m, 1H), 1.75 (m, 1H), 1.46 (t, J = 6.99 Hz , 3H).

O Step 7 Add diethyl aluminum containing diethylaluminum cyanide (IN, 2.1 ml, 2.1 mmol) (at TC, containing step 6 intermediate (205 mmol, 0.5 3 mmol)) In toluene (5 ml) solution. The reaction mixture was stirred at room temperature under argon for 2 hours. The operation process included the addition of 1 N HC1 (20 ml) to Et〇Ac (4x -170-. This paper applies Chinese national standards. (CNS / Rong 4 generation grid (210X29 * 7mm) --------- 1 ------- Order (Please read the notes on the back before filling this page) A7 B7_ V. Invention Explanation (168) 20 ml) extraction, the combined organic layers were washed with absolute Na C 1, dehydrated with MgS04, filtered, and the crude β-rolled product was used for the next step.

Plant 0 Step 8 Add 50% H2SO4 (5 ml) to the dioxin (5 ml) -solution containing the crude substance from step 7 at room temperature. The reaction mixture was refluxed for 18 hours. The operation included the addition of EtOAc (25 ml), the organic layer was washed with β320 (3 × 15 ml), dehydrated with MgS04, filtered and evaporated. The crude product is used for the next step. 〇

--------- * 衣 --- 广 '(Please read the precautions on the back before filling in this page) Example 3 2 3 (racemate) Central Government Bureau of Economic Affairs, Ministry of Economic Affairs Step 9 is an example of the method of step 323. Add excess DBU to a THF (5 ml) solution containing the crude intermediate from step 8 at room temperature. The reaction mixture was stirred overnight. The operation included dilution with EtOAc (30 mL), washing with 2N HC1 (2 x 10 mL), filtration through silica and concentration in vacuo. The crude product was purified by HPLC and recrystallized from EtO Ac: to give an off-white solid of Example 3 23, MP 138-13 9X :. -17]-Chinese paper kneading standard (CNS) for this paper size Λ4 size (210x297 mm) A 7 B7

V. Invention Description (169)

CjH

Example 3 2 4 Example 3 2 5 Example 324 and Example 325 are similar to the method of Example 323, but in step IX, amyl 4- (4-bromobenzyl) benzylfluorene is used instead (prepared according to the synthesis method of Example 3 17) Instead of 6-based 4- (4-pyridyl) benzylpyrene, a racemate was prepared. Using a Chiralpak AD column, racemic 4 was separated into the paired, enantiomers, which were first eluted from Example 3 2 4. Identify intermediates with 1 Η-N M R 0

Example 3 26 (racemate) Example 3 2 6 Following the same synthetic sequence as in Example 323, but step silver 6 was replaced with 4-bromo-4 · -air coupling instead of ethyl ~ 4-(4-bromophenyl) benzene Ether to give Example 3 2 6. MP 170-nrc. -172- This paper is suitable for China National Standard (CNS) A4 specification (210X297mm)

--------- Put ------- Order (Please read the note on the back first and then fill out this page; I Yin Yang Bid Rate Bureau Shellfish Consumer Cooperative Co., Ltd. Printed η

OH Example 327 (racemate) A7-B7 _____ ^ printed by the consumer cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (丨 70) Actual 327 Added 2 '3-dimethyl-1,3-butane (2.69 g, 3.7 bml, 32.8 mmol) to room temperature 'containing 4-oxy-4-bibenzyl) butenoic acid (Example 2 9) (0,9 4 1 g, 3.2 8 MM) in λΙe〇Η (5 ml) suspension = the reaction mixture was refluxed for a total of 2.5 hours under argon. The operation process includes air densification. The crude product was purified by recrystallization from MeO Η, yielding 950 mg of 3MP 217.0-220 ° C as a white solid.

Example 32δ (racemate) Example 328 Add excess butadiene to the bottom, containing oxygen · 4_ (4_-gas-4-bibenzyl) but-2-enoic acid (Example 29) (1.01 g, After 3.53 mmol of MeOH (5 mL) was added, DMF (5 mL) was added. The reaction mixture was refluxed under argon for a total of 72 hours. The operation process included diluting with EtOAc ((15 ml) and adding water to 5 ml) and extracting the aqueous layer with EtO Ac (3 to 1 ml). The combined organic layers were washed with Na and C a, dehydrated with M g S 0 4, and: ¾, concentrated. The crude product was purified by chromatography (EtOAc / Hexane) to give 140 mg of a white solid, Example 3 28. M p 1 8 5.0-1 8 6.0 C.

The size of this paper applies to the Chinese National Standard (CNS) Λ4 specification (210X297 mm) I n It ί ^ ί nnn I ^ I-nn T / -V (Please read the notes on the back first and fill in this card) 413675 A7 B7 V. Description of the invention (171) Real frjj 2 9 Add isoprene (2.87 g, 4.21 ml, 42.1 mmol) to room temperature, containing 4-oxy-4- (4'-qi_4 -Biphenyl) but-2-enoic acid (Example 29) (1.208 g, 4.21 mmol) in a &! 6011 (5 ml) solution 1 &gt; The reaction mixture was refluxed overnight under argon. The operation process includes air concentration. The crude product was purified by chromatography (EtOAc / hexane) 'and recrystallization (three times) to yield 20 mg of Example 329 as a white solid. MP 174.0-1 77.aC.

Example 33 (racemate) Example 330 Add 5 equivalents of 1,3-cyclohexadiene (1.87 ml, 19.577 mmol) to room temperature, containing 4-oxy-4- (4'-gas- 4-Biphenyl) but-2-enoic acid (Example 29) (1.123 g, 3.915 mmol) in THF (7 ml). The reaction mixture was stirred at reflux for 18 hours. The operation process includes air concentration. The crude product was purified by HPLC to give the desired product Example 330 (5 70 mg, 40%) as a white solid containing two isomers. MP 174-176 ° C. (Please read the precautions on the back before filling out this page) Binding-Book Spring Seal of Shellfish Consumer Cooperative, Central Marking Bureau, Ministry of Economic Affairs

Example 331 (racemate) -174- The paper Λ degree is applicable to the National Standard of China® House Standard (CNS) A4 (210x297). Printed on the A7 B7 by the Shellfish Consumer Cooperative of the Central Bureau of Standardization of the Ministry of Economic Affairs _ V. Description of the invention (172) Example 3 3 1 A mixture containing Example 330 (299 mg, 0.815 mmol) and p-toluenesulfonylhydrazine '(1.5 g, 8.15 mmol) was dissolved in dimethoxyethane (20 ml). Let it warm to reflux. A solution of sodium acetate (1.0 g &apos; 12.2 mmol) in water (16 ml) was added over a period of 4 hours. The reaction mixture was cooled to room temperature, poured into water (120 ml), and extracted with CH2C12 (4x70 ml). The combined organic layers were washed with 150 ml of water, dried over M g S 0 4 and concentrated in vacuo. The crude product was purified by HPLC to give the desired product Example 3 31 (85 mg, -2%) ^ MP 191-193 ° C 0 Example 332 Take 4-chlorobiphenyl (0.76 g, 4 mmol) A 50 ml flask was mixed with a solution of 3-methylglutaric anhydride (0.52 g, 4 mmol) in anhydrous digas methane (10 ml) and cooled in an ice bath. For several minutes, the gasified aluminum solid (1.1 g, 8 mmol) was carefully added. The reaction mixture was stirred for 20 hours while warming to room temperature. After 20 hours, the reaction mixture was cooled in an ice bath again, and the reaction was stopped with 10% H C 1 (10 ml). The layers were separated and the aqueous phase was extracted back with methane (2 x 10 mL). The combined organic fractions were washed with brine (25 mL), dried (Na2SO0, and concentrated in vacuo. The resulting yellow-white solid was recrystallized (ethyl acetate-hexane)-to give the small crystals of Example 332. MP 140.5- 142.5X: Using the production method of Example 3 32 above, the following biphenyl-containing products (Table XXIII) were prepared => -J75- This paper method is applicable to the national standard ΐ CNL) / U Appearance (210X 297 mm &gt; --------- ^ ------- ΪΤ ------ ^ / i /% (Please read the precautions on the back before filling this page) A7B7 V. Description of the invention (173)

Table XXIII

333 ^ 334 335 a Mecox Η Me Et Η Me Me

R, S 174-176 152-154.5 130.0-131.0

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

r1T Printed by the Consumer Cooperatives of the Central Bureau of Samples of the Ministry of Economic Affairs -176 This paper size applies to Chinese national standards (CNS &gt; A4 size (2 丨 0 X 297 mm) A7 A7 Printed by the Consumer Cooperatives of the China Standards Bureau of the Ministry of Economic Affairs _B7_ V. Explanation of the invention (174) Example 3 3 6 A method similar to that of Example 1 except that 3 '3 -tetramethyleneglutaric anhydride was used instead of trihydro-3- (2-methylfluorenyl, 5-furan Dione 'to prepare this compound. MP 139-140 ° C =

Example 337 Example 3 3 7 A method similar to that of Example 1 except that 2,2-dimethylglutaric anhydride was used instead of dihydro-3- (2-methylpropyl) -2,5-furandione to prepare the present compound. Compound. The crude product was purified by flash column chromatography (gradient dissolution, methane to methane-methanol-methanol (9 9.5: 0.5)) and recrystallization (ethyl acetate-hexane) in order to produce white micro-particles of Example 337. Crystal. MP 163.5 · 164.0 ° C.

洌 33 8 Step 1 In a 25 ml round bottom flask, 'add diethyl isobutylmalonate (2.82 g, 13 mmol), secondary butanol (86 ml) and 30% &amp; ( ^ Methanol solution (0 · 25ml, 丨 3mmol). Acrylonitrile-177- is added via a syringe. The scale is applicable to China National Standard Season (CNS) Α4 specification (2 ^ 2 * ^^^ ---- ---------- Λ ------- Order ------ 卞 (Please read the notes on the back before filling this page) A7 B7 V. Description of the invention (175) (0.8 6 ml, 1 3 mmol), the reaction mixture was heated to 3 3 ° C using an oil bath. Stir in an inert atmosphere for 3 hours, stop the reaction mixture with 2 μ HC [(1 ml) 'with distilled water (15 ml ) And ether (20 mL). The separated aqueous layer was extracted back with ether (2 x 20 mL). The combined organic fractions were dehydrated (Na, · S 0 4) and concentrated in vacuo to produce a solid precipitate containing oil. (3.42 g). The crude material was used in the next step without further purification. A portion of crude oil and solid (1.5 g) was dissolved in 48% Hbr (6 ml). The solution was kept in an atmospheric atmosphere After refluxing for 2 4 · 5 hours, the solution was concentrated to almost dryness The residue was partitioned between distilled water (20 ml) and ether (20 ml). The separated aqueous layer was back extracted with ether (2 X 20 ml). The combined organic parts were dehydrated and concentrated to produce an oil. Residue (1.5 g). The reaction was completed by 1H NMR, so the crude crude diester (1,9 g) was subjected to the above hydrolysis conditions to produce a substituted crude product of adipic acid (I. 5 g). The combined crude products (30 g in total) were combined and purified by flash column chromatography (gradient dissolution, methane to methane: methanol: 98: 2) to give the desired compound as a white solid ( 1.64 g, 69%). * H NMR (DMSO-d6) d 0.83 (dd, J = 6.6 Hz, 2.9 Hz? 6H), 1.16 (m, 1H), 1.36-1.56 (m, 2H); 1,61 (q J-7.4 Hz. 2H), 2.17 (m, 2H), 2.28 (m, 1H), 12.11 (s? 2H) ^ Step 2 Add step 1. Product (1.62 g, 8.6 mmol) and B Acid anhydride (10 ml) to 100 ml 圚 bottom flask. The reaction mixture is kept at reflux for 2 hours. 178- This paper is scaled to the national standard (CNS, M dead grid (210X297 mm)) (please read the back first) Please fill in the matters needing attention P), \ $

Printed by Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs

〇 A7 _____B7______ 5. After description of the invention (丨 76), cool to room temperature. Volatile matter was removed by air distillation (0.1 tor, 20-60 ° C). The crude product was dried at 80X: air-dried (0.1 tau) for 14 hours, yielding the desired it: brown oil of the compound, which was used without further purification (1.15 g, 79%). I R (solvent-free) 1805, 1762 cnT1: 〇 〇 Preparation method of step 3 example 3 38. The general process of Example 3 3 4 was used, but 2-isobutyl succinic anhydride was used instead of 3-methylglutaric anhydride. The crude product was subjected to flash tube digestion [gradient dissociation, dioxane to dichloromethane- Methanol (98.5: 1.5)] and recrystallization (ethyl acetate-hexane) were sequentially purified to produce white fine crystals of Example 3 38. MP 129. (M30.5 ° C. Example 339 Step 1 In a 100 ml round bottom flask, add 1, i • cyclohexanediacetic acid (2.03 g '9.99 mmol) and acetic anhydride (116 ml p After the reaction mixture was kept at reflux for 2 hours, the reaction mixture was cooled to room temperature. 5 The volatiles were removed by vacuum distillation (0.06 ° C, 20-6 CTC). The obtained crude product was dried at 80 ° C for 14 hours, Generate a white solid of the desired compound for further purification and use (1.75 g, 96%), IR (solvent-free) 1813, 1770 cm l. -179- This paper size applies to China National Standards (CNS), 4 specifications (210 &gt; &lt; 297 Modi) '(Please read the notes on the back before filling out this page) .- Again. Order the U3675 A7 B7 printed by the Shell Specimen Consumer Cooperative of the Central Ministry of Economic Affairs Printed by Industrial and Commercial Cooperatives V. Description of Invention (177)

Step 2 Example 339 method. The general method of Example 332 was used, but 3,3-pentamethylene glutaric anhydride was used instead of 3 -methyl glutaric anhydride β. The crude product was subjected to flash column chromatography (gradient dissolution, methane to methane). -Methanol (97: 3)) and recrystallization (ethyl acetate-hexane) were sequentially purified to produce white fine crystals of Example 339. MP 129.0-131.5aC. Example 3 4 0:

Step i Add the amount of p-toluenesulfonic acid monohydrate to the benzene (150 ml, ~ 15.7 g, 0.145 mole) containing 3-bromopropionic acid (20.49 g, 0.134 mole) Ml) of the solution. "Add a Dean-Stark collector to the reaction flask, and keep the solution stirred at reflux overnight. After 16 hours at reflux, the reaction was cooled, washed with saturated carbonate: sodium bicarbonate, dehydrated (Na2S04), and concentrated to an oil (28.78 g). Partial distillation under reduced pressure (0,18 Duo) produces a colorless liquid (18.49 g, 56%) of the desired product with a boiling range of 99-109 ° C. Install ------ order ------ Quan V (Please read the precautions on the back before filling this page)

A7 B7 V. Description of the invention (178) Step 2 The 4-gas biphenyl (3.57 g, 18.9 mmol) and cycloheptane carbonyl gas (2.6 g, 18.9 mmol) were contained in a 100 ml flask. ) Of anhydrous digas methane (50 ml) solution was cooled using an ice bath. For several minutes, carefully add the gasified aluminum solid (5 g, 3 7.7 mmol). The reaction mixture was stirred for 6 hours while warming up to room temperature. After 6 hours, the reaction mixture was cooled in an ice bath to 100%. HC1 (50 ml) stopped the reaction. The layers were separated and the aqueous layer was extracted back with methane (2 x 50 mL). The combined organic portions were washed with brine (100 mL), dried (Na2S04), and concentrated under air. The resulting yellow solid was used without further purification (5.5 g, 100%). TLC (hexane-ethyl acetate, 3: l): Rf: 0.22 (Please read the precautions on the back before filling this page) &quot; 衣 '

Order Printed by the Consumers Cooperative of the Central Economic and Technical Bureau of the Ministry of Economic Affairs Step 3 Add n-butyl (2.64M hexane solution, 0.8 ml, 2.16 mmol) to 0 ° C and argon in fresh atmosphere Diisopropylamine (0.3 ml '0.22 g' 2.16 mmol) in anhydrous tetrahydrocran (4 ml). After 30 minutes of searching, the solution was cooled to -7 0 Τ !. Using a syringe, a tetragas furan solution (1 ml, rinsed with 0.5 ml) containing the product of Step 2 (0,59 g, 2.06 mmol) was added over a period of 20 minutes. Continue stirring at -7 0 ° C for 7 5 minutes. Tetrahydrofuran solution (1 ml, rinsed in 0.05 ml) containing 3_bromopropionic acid vinegar (0.50 g, 2.0 6 mmol) from step 1 was added via a syringe over 20 minutes. After stirring at -7 ° C for 1 hour, slowly raise the temperature to room temperature overnight. Stir in inert atmosphere for 14.2 5 hours, wash with ether (25 ml) and digas (1 5 -f81-Zhang scale applies to China's national standard (CNS &gt; A4 specification mm) '----- ---- A7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ___ B7 V. Invention Description (179 ml) After dilution, the reaction mixture was stopped with 10% H C1 (10 ml). The separated organic phases were washed sequentially with 10% HC1 (10 ml), saturated sodium bicarbonate ('2 X 100 ml) and brine (2 X 100 ml). The combined aqueous washings were washed with dichloromethane (10 ml) ) Back extraction. Combined organic phase deionization (Na2S04) and air-concentration to produce an orange-yellow residue, purified by flash column chromatography [gradient dissolution, hexane-digas methane (1: 1) to hexane -Digas methane (2: 3)], giving off-white solid (0.18 g, 20%) of the desired product. TLC (hexane-digas methane, 1: 1): Rf: 0.45. 〇〇

Example 3 4 0 Step 4 Example 3 40 method. An aqueous solution of sodium hydroxide (1M, 0.46 ml, 0.46 mmol) was added to a solution of absolute ethanol (0.6 2 ml) containing the ethyl ester of step 3 (0.14 g, 0.31 mmol). After stirring for 3 hours, the reaction mixture was diluted with ethyl acetate (10 ml) and distilled water (10 ml). The aqueous layer was separated and acidified to pH 1 with concentrated H C1, extracted with ethyl acetate (2x10 ml), and the combined extracts were combined, deaerated (N a 2 S 0 4), and concentrated in vacuo to give the product (0.0 8 grams, 73%) 〇MP 161.0-164.〇3C 〇 洌 341 〇

This paper size applies to China National Standard Apple (CNS) A4 specifications (21〇 '&297; |) (Please read the precautions on the back before filling this page) Order ^ A7 B7 V. Description of the invention (180) Step butterfly i An anhydrous 1,2-diethylacetate (300 ml) containing 4-gas biphenyl (22.64 g, millimoles) and acetonitrile gas (9.6 g, 120 millimoles) in a 500 ml flask was made. ) The solution was cooled with an ice bath. The gasified aluminum solid (1 7.8 g, 132 mmol) was carefully added over 10 minutes: the reaction mixture was stirred for 20 hours while warming to room temperature. After 20 hours, the reaction mixture was slowly added to a stirred low-temperature cooling solution (300 ml) of 10% H C1 to stop the reaction. Add ethyl acetate (200 mL) to help dissolve the solid. The layers were separated and the aqueous layer was extracted back with ethyl acetate (200 mL). The combined organic fractions were washed with brine (300 mL), dried (Na2SO4) and concentrated in vacuo. The resulting yellow-white solid was recrystallized (ethyl acetate-Hittig), and multiple crystals of the desired ketone (25,66 g, 93%) were collected. Butane LC (hexane-digas methane, 2: 1): Rf: 0.61. (Please read the notes on the back and fill in this page) C \ r \

1T Step 2 In a dry 100 ml round-bottomed flask, add anhydrous N, N · dimethyl famine (43 ml) containing sodium argon (0.24 g 95% NaH, ~ 9_1 mmol). Suspension,-Ling Que to 'within 15 minutes' "N, N-di, containing step 1 4- (4 · -Aminobenzyl) methyl ketone (2.0 g, 8_67 mmol) was added via a syringe. A solution of methylformamide (7 ml) was stirred at 0 ° C for 1 hour under an inert atmosphere. Add di-tertiary butyl methylene malonate (1.98 g, 8.67 mmol) using a canister over a period of 5 minutes (the preparation and purification method of this compound is based on reference: Robert (Roberts) et al. 'J. Org. Chem-! 83-Applicable-Standard (CNS ϋ (210 × 297 mm)-Printed by the Consumers Cooperative of the Sample Procurement Bureau of the Ministry of Economic Affairs 413675 A7 B7 V. Description of the invention (181) 1983, 48, 3603) solution of N, N-dimethylformamidine (5 ml). After stirring for 5.5 hours and gradually returning to room temperature, the reaction mixture was released with tritium (350 ml) and 10 % HC 丨 (500 ml) to stop the reaction. The separated aqueous layer was back extracted with ether (100 ml). The organic phase of 3 x 3 was washed with salt forever (2 x 500 ml). The combined aqueous phase Extract again with ether (100 ml). The combined organic phases are dehydrated (Na2S04) and emptied and rolled. The resulting orange solid is purified by recrystallization (hexane) to produce the desired product as white flocculent crystals (1.64 G). A significant amount of the desired compound remained in the mother liquor 'was purified by flash column chromatography [gradient dissolution. Hexane-digas methane ( 1: 1) to digas methane-methanol (98: 2)], and regenerating one part of the desired material as an off-white solid (0.47 g, 2.11 g, 53%). TLC (hexane-ethyl acetate, 9: 1) R produced 0.43. (Please read the precautions on the back before filling this page)-

Ordered by the Central Bureau of Standards, Ministry of Economic Affairs, Shellfish Consumer Cooperation, Du Printing Step 3 In a dry 25 ml round bottom flask, add sodium methoxide (0.26 g 95% 1 ^ 〇 ^^, ~ 4.75 mmol) and the pure product from step 2 (2.0 g, 4.36 mmol) in a suspension of anhydrous dimethoxyethane (4.7 ml). At the same time, an anhydrous methyl formate containing 1-bromo-3-phenylpropane (0.67 ml, 0.87 g '4.36 mmol) and sodium iodide (0.66 g, 4.36 mmol) was formed in a ml round bottom flask. Oxygen pit (13,5 ml) suspended ash. After stirring for 40 minutes in an inert atmosphere, 'using an syringe, add the orange associating salt suspension to .184- this paper music standard universal Chinese letter 圉 family standard (CNS) A4 size (210X297) (Centi) A7 B7 5. Description of the invention (182) Yellow &gt; odorant · decomposed matter suspension. After 40 hours of searching, the reaction was judged to be incomplete by TLC, and an additional portion of sodium methanol (0.13 g, 2.38 mmol) was added. 1-Bromo-3-phenylpropane (0.33 ml, 0.44 g, 2.i8 millimoles). After stirring for 24 hours, the reaction mixture was allowed to shrink to dryness. The residue was dissolved in ethyl acetate (50 ml) and the reaction was stopped with 10% HC1 (50 ml). The separated organic phase was washed with 10% H C 1 (50 ml). The combined aqueous phases were extracted back with dichloromethane (50 mL). The combined organic phases were dehydrated (N a 2 s 0 4) and concentrated in vacuo. The resulting orange oil was purified by flash dish column chromatography [gradient dissociation, hexane to hexane. Alkane-ethyl acetate (19: 1)] , Giving the desired product as an off-white solid (166 g, 66%). MS (FAB-LSIMS) 577 [M + H] +. (Please read the notes on the back before filling this page)

Order

Step 4: Take the product from Step 3 (1.66 g, 2.88 mmol), anisole (7.81 ml, 7.77 g, 71.90 mmol) and trifluoroacetic acid (2, 22 ml, 3.28 g, 28.76 mmol) Ear) of methane (10 ml) solution was stirred in a 50 ml 酽 bottom flask for 55 hours. The reaction mixture was partitioned between ether (50 ml) and brine (50 ml). Add some distilled water to dissolve the precipitated salt. The organic phase was separated, dehydrated (Na2S04), and concentrated in vacuo to give a white-pink solid, which was purified by flash column chromatography [gradient dissolution, ethyl acetate-hexane-acetic acid (25: 74: 1) to ethyl acetate Ester-hexane-acetic acid (49: 50: 1)] to give the desired product as an off-white solid (0.53 g, 39%). MP -185- This paper.υίΰΐChina National Tomb Standard (CNS) Λ4 specification (2 丨 0 X 297 public no. J _ Ai Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

ΐ4Zίί〇ν〇 Α7 Β7 V. Description of the invention (183)

168.5-170.0 ° C Example 341 Step 5 The method of making Example 341. A solution of 1,4-dioxolane (7.5 ml) containing the diacid of step 4 (0.4 g, 0.86 mmol) was kept under inert atmosphere. Refluxed for 4 hours. The reaction mixture was concentrated to dryness, Purification by flash column chromatography [ethyl acetate-hexane-acetic acid (24: 75: 1)] gave the title compound as a white solid (0.25 g, 69%) »MP 97.0-98.51. Example 342 Step 1 A mixture of 4-chlorobiphenyl (7.06 g, 37.4 mmol) and g-methylpentazone (5.0 g, 37.4 mmol) was contained in a 250 ml flask. A solution of anhydrous dichloromethane (9 3 to 5 ml) was cooled using an ice bath. Carefully add the gasified aluminum solid (9.97 g, 74.8 mmol) over 10 minutes. Continue stirring for 23 hours while slowly warming to room temperature. The reaction mixture was slowly added to a stirred low-temperature cooling solution (100 ml) of 10% H C1 to stop the reaction. The layers were separated and the aqueous phase was extracted back with methane (2 x 50 mL). The combined organic portions (turbidity) were washed with brine (50 ml), dried (N a: S 0 4), and filtered. With digas methane (10086- this paper A degree applies to the Chinese national standard ^ (CNS) A4 specifications (210X297 mm) --------- support ------, order- ---- ^ / • V (Please read the notes on the back before filling in this I) The Central Government Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative Du printed 413675 A7 B7 α V. Description of the invention (184) ml) diluted, and finally The solution was clarified with ethyl acetate (100 mL), and then dehydrated (Na2SO4) and concentrated in vacuo to give a yellow solid (! 33 g). A portion of this crude product (2.97 g) was purified by flash column chromatography [digas methane-hexane (2: 3)] to give the desired product as a pale yellow solid (2.54 g, 82%). TLC (hexane ethyl acetate, 9: 1): Rf 0.54. 0

V Step 2 In a dry 25 ml round-bottomed flask, add anhydrous sodium hydride (0.044 g, 95 &lt;) / (^ 3 [1, ~ 1.74 mmol), dimethylformamide (7.9 ml) ) The suspension was cooled to 0 ° C. Carefully add the ketone solid from step 1 (0.5 g, 1.74 mmol) to the suspension, and continue stirring at 0 ° C for 1 hour under an inert atmosphere. Using a syringe, add N, N-dimethylformamidine containing di-methylene malonate di-tert-butyl ester (0.4 g, 1.74 mmol) from step 2 of Example 3 4 1 over 15 minutes. Amine (3 ml) solution. After stirring for 19 hours and gradually returning to room temperature, the reaction mixture was diluted with osmium (70 ml), and the reaction was stopped with 10% HCI (120 ml). The separated organic phase was washed with brine (2x100 ml), dehydrated (Na2S04-) and concentrated in vacuo to give a yellow oil. The crude product was purified by flash column chromatography (gradient dissociation, hexane-digasmethane (3: 1) to hexane-dichloromethane (1: 2)) 'yielding the desired product in two fractions Firstly, the high Rf dissociation point (0.36 points, 40%) containing some micro impurities was dissociated first, and the pure substance (determined by TLC) was dissociated secondly (0.22 g, 24% (64%)). TLC (Hexane-digas, 1: 2) Rf 0.20. 187- The size of this paper is applicable to the Chinese National Standard (cns Γ) ΰ specifications (2 丨 ο X297 mm) --------- A ------ Order ------ ^ / ί / {Please read the notes on the back before filling this page) Printed by the Central Laboratories of the Ministry of Economic Affairs, Printed by the Shellfish Consumer Cooperatives 413675 A7 B7 Printed by the Offshore Consumers Cooperatives of the China ’s Ministry of Economic Affairs, Standards Bureau

002H Step 3 In this step, two separate fractions of the product of Step 2 are reacted separately. The order of the stoichiometry in parentheses refers to the amount of the first and second dissolving fractions, respectively. In a 25-ml round-bottomed flask, the dissolution fractions containing step 2 (0.36 g, 0.7 mmol and 0.22 g, 0.43 mmol), anisole (1.9 ml, 1.9 g, 17.5 mmol) were formed. And 1.17 ml, 116 g, 10.75 mmoles) and trifluoro 6 acid (0.54 ml, 0 g, 7.0 mmoles and 0.33 ml, 0.49 g, 4.3 mmoles) of digas methane (4.6 ml and 2.9 Ml) solution. After stirring under an inert atmosphere for 2 2 hours, the reaction mixture was partitioned between ethyl acetate (20 ml) and brine (20 ml). Add some distilled water to dissolve the precipitated salt. 6 Separate the organic phases, combine the two fractions, wash with distilled water (2x15 ml), dehydrate (Na2S04), and concentrate in the air to produce a light pink oil. Chromatographic purification [gradient dissociation, ethyl acetate-hexane-acetic acid (25: 74: 1) to ethyl acetate-hexane-acetic acid (49r5 0: 1)], the resulting fractions are shown by 1H-NMRS, The reaction is still incomplete. The fractions were combined again and subjected to reaction conditions for another 16 hours. When TLC showed that the reaction was complete, the reaction mixture and chromatography were operated under the same conditions as above to produce the desired off-white solid (0,2 g, 44%) of the diacid. TLC (gas-methanol, 9: 1, with a small amount of acetic acid): Rf 0.17. -188- This paper uses the Chinese Standard (CNS) A4 size (210 &gt; &297; men Λ ------ order -------- 订 ί) (Please read the note on the back first) Please fill in this page again) Printed by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives Α7 ___ Β7 V. Description of Invention (186)

Step 4: Example 342. A 1,4-dioxoline (9_1 ml) solution containing the diacid of step 3 (02 g '05 mmol) was stirred and refluxed under an inert atmosphere for 15 hours. The reaction mixture was rolled to dryness, followed by a rapid Purification by column chromatography (digas-methyl-f-ol (99: 1)) gave the title compound as a white solid (0 μg ·, 61%). MP 102.0-103.0 ° C. Example 343

Step Butterfly 1 Add bromine (5.6 ml, 17.3 g, 108.35 mmol) to 0. (: Distilled water (75.8 ml) containing sodium hydroxide (5-2 grams) 379 millimoles), stir for 15 minutes. To this reagent mixture is added a sample containing Example 3 4 1 Step 1-( 4'-Gas biphenyl) methyl ketone (5.0 g, 21.67 mmol) in 1 'L dioxozone (54.2 ml). The reaction mixture was heated at 40 ° C for 18 hours using an oil bath , Cool to room temperature. Add distilled water (60 milliwell) solution containing sodium thiosulfate pentahydrate (21_5 g, 86.68 mmol) to the reaction mixture, and stop the remaining bromoform reaction (~ 2 5 ml) Acidified to ρ η ~ 1, it will foam. The precipitated solid is separated by filtration, -m-gjgf 窣 ϋ CNS in the paper method scale 从 from Waki (2 丨 .χ297 公 庆)- ------- install ------ order ------ l ^ riv. Jl \ (please read the back of the book first; fill in this page with the meanings) V. Description of the invention (187) A7B7 was recrystallized (ethyl acetate) and the title compound (4.44 g, 88%) was collected from multiple crystallizations. MP 286.0-; 288.0 ° C.

Ν ', 0, Member of the Central Bureau of the Ministry of Economic Affairs, Consumer Cooperation, printing step 2 so that 4- (4 · -air-linked phenyl) carboxylic acid (3.7 g, 15.9 mmol), Ν, 0 -A solution of dimethylhydroxylamine hydrochloride (2.34 g, 23,85 mmol) and '1-hydroxybenzotriazole (2.36 g, 17.49 mmol) in anhydrous digas methane (66 ml) In a 100 ml 圚 bottom flask, cool using an ice bath and stir for several minutes. N-methylmorpholine (2.62 ml, 2.41 g, 23.85 mmol) was rapidly added sequentially via a syringe, and solid ethyl-3- (3-difaminopropyl) carbodiimide (3.36 g, 17.49 Mol). The reaction mixture was stirred at 0 aC under an inert atmosphere for several hours. Continue stirring while warming to room temperature overnight. After a total of 3 hours of stirring, the reaction was judged to be incomplete by TLC. Anhydrous N, N-dimethylformamide (2 ml) was added at 0 ° C to clarify the reaction mixture. After 1 hour, τlc showed no more conversion effect. Therefore, other reagents (N, 0-dimethylhydroxylamine hydrochloride (0.46 g), 1 · hydroxybenzotrisine (0.47 g), N-methyl? 11 lin (0.52 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (0.66 g)] TLC after 1 hour showed that Complete conversion, so the reaction mixture was diluted with dioxane (20 () ml), and then sequentially with sodium bicarbonate (2 X 100 ml), 10% HC 丨 (100 ml), and Saturated sodium bicarbonate (100 ml) was washed. The combined aqueous layer was ether (50 ml-190-). This paper size is suitable for China Hunshen (CNS) M specifications (210/297 mm. ---- ----- 1 ------ ΐτ ------ 't ί (please read the precautions on the reverse side before filling out this page)) back to extraction. The combined organic phases are dehydrated (Na ^ SOj and Concentrated in the air to produce a light-colored solid, which was purified by impatient column chromatography (gradient dissociation, digas T2 to digas methyl pit methanol (99.5: 0.5), yielding the desired product as a white solid (3.89 g, 89%) , \ 18 (卩 八 8-1 ^ 服 8) 276 [1 ^ + 11] + »0

A7 __ — B7 V. Description of the invention (188) α Step 骅 3 dropwise add n-butyl lithium (2_64M hexane solution, 10.2 ml, 26.98 mmol) to -40 ° C and argon atmosphere, containing freshly distilled Diisopropylamine (3.78 ml, 2.73 g, 26.98 mmol) in anhydrous tetrahydrocran (50 ml). The solution was stirred for 25 minutes and returned to · 20. (: After that, it was cooled to · 40 ° C. Using a syringe, tetrahydrofuran (4 ml, washed with 1 ml) containing 5 phenylvaleric acid (2.40 g, 13.49 mmol) was added over 7 minutes. The solution caused solid precipitation. The stirred solution was heated at 50 ° C for 2 hours and then cooled to -40 ° C. Using a syringe, the product containing step 2 (3.1 g '11.24 mmol) was added over a period of 8 minutes. ) Tetrahydrosquenching solution (4ml, 1ml ·; wash). After the reaction was stirred at -40 0C for 3 hours, carefully decanted to 10% HC1 (50ml) to stop the reaction. The mixture was extracted with mystery (50 ml). The aqueous phase was separated and extracted with ethyl acetate (2 x 50 ml). The combined organic phases were washed with brine (75 ml) and dehydrated (Na 2 s 0 4). ), And the light-colored solid produced by air concentration was purified by flash column chromatography (gradient dissolution, hexane-digasmethane (3: 1) to hexane_digasmethane (3: 2)) to produce What you need to check -191-This paper size applies to Chinese national standards (CNS Ding ----- --------- ± Yu ------------ ^ --- ~ L. / V (Please read the notes on the back first (Fill in this page) Shellfish Consumption Cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs Printed by the Shellfish Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 _B7_____ V. Description of Invention (189) Yellow-white solid (1.80 g, 46% ). MS (FAB-LSIMS) 349 [Μ + ΗΓ 0 〇

Step 4 In a dry 50 ml round-bottomed flask, add an anhydrous N, N-dimethylformamide (20 ml) suspension containing sodium hydride (0.15 g.-95% NaH, ~ 5.8 mmol), Cool to 0t. Using a syringe, an N, N-dimethylfamidamine (10 ml) solution containing the ketone product of Step 3 (1.93 g, 5.53 mmol) was added over a period of 10 minutes. Continue mixing at 0 ° C for 1 hour under inert atmosphere. Using a syringe, add the di-tertiary butyl methylene malonate (1.26 g, 5.53 mmol) containing Step 2 of Example 341 over 4 minutes. Solution of N, N-dimethylformamide (3 ml) into a dark orange reaction mixture. After stirring for 15 hours and gradually warming to room temperature, the reaction mixture was diluted with ether (300 ml) and the reaction was stopped with 10% HC1 (500 ml). The separated organic phase was washed with brine (2x500 ml), dehydrated (Na;! SO), and concentrated in vacuo. The resulting yellow oil was purified by flash column chromatography [gradient dissolution, hexane_digas methane (4: 1) to hexane-digas methane &lt; 1: 1)] to produce an off-white solid (2. 13 g, 67 ...) η MS (FAB-LSIMS) 557 of the desired substance. 192- The scale of this paper is applicable to the national floating year (CNS) A4 specifications of the country &quot; ΰΐ〇Χ297 公 ft) —ί II — 1!--N In I --Λn Hr _ _ _ _ T ^ &quot; * . ((Please read the notes on the back before filling out this page) Printed by the Consumers Cooperative of the Central Government Bureau of the Ministry of Economic Affairs A7 ______B7 V. Description of Invention (190)

Example 343 Step 5 Example 343. Digasformamidine containing the product from step 4 (2 "g, 3 64 mmoles), phenyl ether (9.9 ml, 91 mmoles), and trifluoroacetic acid (.28 ml, 36.4 mmoles) (15 ml) of the solution was stirred in a 50 ml tritium flask. After 72 hours, the reaction was not complete. Trifluoroacetic acid (5 ml, 65 mmol) was added. After stirring for an additional 4,5 hours, the reaction mixture was partitioned between ethyl acetate (75 ml) and brine (75 ml). Add some distilled water to dissolve the salt in the temple. The organic phase was separated, dehydrated (Na 2 S 〇 4) and concentrated in vacuo to produce a search brown oil, which was purified by flash column chromatography [gradient dissociation, ethyl acetate-hexane-acetic acid (25: 74: 1) To ethyl acetate-hexane-acetic acid (49: 50: 1)], which produces the desired diacid plus decarboxylated compound (after air-drying) 'is a white solid (1.35 g, ~ 80% , MP 4 5 _ 0-5 1.0 ° C (decomposition)] TLC (Yi: imitation · methanol 9 -1, containing a small amount of acetic acid rf 0.34. Take U.0 g with partially converted diacid, ~ 2_15 millimoles) of 1,4_ dioxin (18 ml) solution was stirred under reflux in an atmospheric atmosphere for 20 hours, and the reaction mixture was concentrated to dryness and purified by flash column chromatography (ethyl acetate -Hexaneacetic acid (19: 80: 1)) to give the title compound as a transparent gum (0.75 g, 83%). Analysis C: Calculated hydrazone, 7 4. 19: Measured uranium, 7 3. 9 5. Η: Calculate 値, 5.9 9: -193- This paper size is based on Chinese national standard 1, (: 1 ^) 八 4 (210 乂 297 mm) --------- /- ----- Order ------ 1 (Please read the notes on the back before filling this page) 413675 A7 B7 V. Description of the invention (191 0

Br measured 値, 5.82 Example 3 4 4

(Please read the precautions on the back before filling out this page} Step 1 Make a solution containing p-bromobiphenyl (20.0 g. 0.0858 mol &gt; and 3-bromoacetylidene (7.5 ml, 0.0858 mol, 1_0 equivalent). (^ 2 (: 11 (400 ml) of the solution was cooled to 0 ° C under argon, and A1C 丨 2 (240 g, 0.180 mol, 2'1 equivalent) was added in four portions. The resulting dark green solution was slowly Return to room temperature and stir for 14 hours. The reaction was cooled to 0 aC, and the reaction was stopped with 10 ϋ /. HC 1 solution (200 ml). The aqueous layer was separated and extracted with CH2C12 (3x100 ml). Combined The organic layer was washed with saturated NaCl solution (150 ml), dehydrated (anhydrous MgS04), and concentrated under reduced pressure to give a brown solid (29.3 g, 96 0 / ό), which was used in the next step without further purification. 〇PPh3 Central Ministry of Economic Affairs Printed by the Bureau of Consumers Cooperatives, Step 2 contains the intermediates from Step 1 (29.3 g, 0.027 mol) and ^^ (2 33 g, 0.09 10 mol, 1.1 equivalent). The anhydrous Dingcho (400 ml) was heated at reflux temperature for 14 hours. The solid obtained was removed by filtration and washed with ether to produce bromide (4 6 · 7 , 9 2%). The mixture containing the bromide (7.60 g '1.23 mmol), CH: C12 (50 ml) and 10% NaOH solution (20 ml) was stirred vigorously for 30 minutes, and the aqueous layer Extracted with c η 2 C 12 (30 ml), and the combined organic phases were washed with η 2 0 (30 ml). 'Dehydrated-194- This standard is used in China Standards (CNS) 8-4 ( 210 × 297 mm Printed by the Central Bureau of Standards, Ministry of Economic Affairs, Shellfish Consumer Cooperative, A7 __ B7 V. Description of the invention (〖92) (anhydrous MgS04). The obtained solid was ground with EtOAc to produce a light brown powder of the desired alkylene compound (5. 17 g '78%), which is used in the next step: TLC Rf (EtOAc) 0.55 0

Step 3 Add 4-Phenylbutanol (10.2 ml, 0.0696 mole) and 4 ί sieve powder (2.0 g &gt; to N-methyl? 11 Lin oxide (11.4 g, 0.0973 mole '1_40) Equivalent) in a solution of CH2C12 (200 ml). After stirring for 10 minutes—, tetrapropylammonium perruthenate (0.218 g, 6.20 mmol, 9 mole%) was added, and the resulting mixture was a saturated Na2S03 solution (200 ml ), Saturated NaCl solution (200 ml) '1M &lt;: 1 ^ 04 solution (200 ml) was washed, dehydrated (anhydrous MgS04). After concentrated under reduced pressure, it was distilled through a bulb to check the aldehyde colorless oil (9.3 G, 90%) 'will gradually oxidize when exposed to air' TLC Rf (25% EtOAc / hexane) 0.60.

Step 4: A mixture of the compound from Step 2 (12.5 g, 0.0233 moles) and the compound from Step 3 (4.13 g, 0.0280 moles, 1.5 equivalents) in anhydrous THF (230 ml) was heated at reflux temperature for 80 hours. The resulting mixture was concentrated under reduced pressure and dissolved in acetone (250 ml). 'Cool to 0X:' Drop-on's reagent (jones -195- this paper rule j [applicable ^ National Standard (CNS) A4 size (210X297 ^^ 7 '--- ----------------- Order ------ t -ί (Please read the notes on the back before filling this page) A7 Ministry of Economic Affairs Printed by the Bureau of Consumers of the Bureau of Standards B7 V. Invention Description (193) &quot; ~~ reagent) processing until TLC analysis shows that all the starting aldehydes have been consumed. The acetone mixture is concentrated under reduced pressure and dissolved in E t 〇A c (250 ml), washed with saturated NaHC03 solution (〖50 ml), dehydrated (anhydrous MgS〇 ^) 3 The solution was concentrated under reduced pressure, dissolved in dC 丨 2, with a small amount; ^^, borrowed 25% EtOAc / Due to the extinction, removal of residual 4-benzyl butyric acid and Ph ^ PO 'yielded the single diastereomer of the desired enone (385 g, 41%). Analyze C24H21BrO: Calculate 値 C '71.05; H, 5.22: 0, Br; 19.71. Found 値: C, 70.77; Η, 5.23; 0, 19.56. 0

Step 5 Slowly add a solution containing KCN (0.130 g, 2.00 mmol, 2.0 equivalents) of only 20 (1.2 ml) to 35 ° &lt;: containing the product of Step 4 (0.405 g, 1.00 mmol Mol) and acetic acid (0.060 ml, 1.0 mmol, 1.0 equivalent) in anhydrous EtOH (15 ml). The mixture was stirred at 35 ° C for 14 hours, and the resulting slurry was partitioned into CHC.13 (50 ml ) And 112 (50 ml). The aqueous layer was extracted with 13 (2 x 20 ml). The combined organic phases were washed with H 2 0 (3 x 40 ml) and dehydrated (anhydrous M g S 〇 4), and concentrated under reduced pressure. The precipitated solid was recrystallized using EtOAc / hexane to give a white powder of cyano product (0.2 52 g, 58%). MP 139-141X: -196- ik Zhang scale applicable to China Due to family standards (CNS> regulations (210x? 97 mm) (Please read the precautions on the back before filling out this page)

, 1T V. Description of the invention (194) A7 B7 ~ --- 〇

N Η Example 3 4 4 Step 6 Example 3 4 4 The method of preparing toluene (25 ml) containing the product of step 5 and trimethyltin azide (0.180 g, 0.874 mmol, 2.00 eq) was mixed in i 0 5 SC heated for 60 hours. The volatiles were then removed at 0 5 3C to produce a single compound of trimethylstannyltetrazole. The foamy brown solid was re-dissolved in toluene (10 ml) and treated with HC1 (4.0 M dioxin solution, 0.33 ml, 1.32 mmol, 3.02 equivalents). The resulting mixture was stirred at room temperature for 14 hours and then partitioned between EtO Ac (50 ml) and H20 (50 ml). The organic phase was washed with H, _O (2 x 50 mL) and saturated NaCt solution (2 x 50 mL), and concentrated to give the desired tetrazolide as a yellow solid (0.2 11 g, 100%). ? 11? 175-180 ° &lt;: (decomposition). Example 345- Day 0, (Please read the precautions on the back before filling this page)-Order. Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs P—〇SiM03

EtO Step 1 Using a syringe, slowly add freshly distilled trimethylsilyl gas (3.3 ml, 0.0260 moles, 1.2 equivalents) to 0. Below 〇, containing diethyl phosphite (0.8 ml, 0.02 17 mol) and triethylamine (9 ml, 0.06 5 mol '3.0 equivalents -197 I paper size applicable Chinese National Standard (CNS) A4 specification (210 297 male thin) A7 B7 V. Description of the invention (195)) in a mixture of anhydrous ether (250 ml). The resulting slurry was slowly warmed to room temperature and then raised to 4 5 ° C for 14 hours. Use 5 5 'C oil bath distillation to remove volatiles. The resulting mixture was diluted with oxane (150 ml), filtered to remove the triethylammonium salt, and concentrated under a normal pressure using a 5 5 #C oil bath. The resulting oil was distilled to produce a colorless oil of trimethyl palpityl diethyl sulfite (364 g, 80%). BP 60'C (5 mm Hg). Ο (Please read the notes on the back before filling this page)-Order

OEt P-OEt η 0 Step 2 under argon in a dry NMR tube, using 5 (TC sonication tank, containing the product of Step 4 of Example 344 (0.200 g, 0.490 mmol)) A slurry of diethyl phosphonate (0.105 g, 0.490 mmol, i.0 equivalent) was dissolved, and then heated at 5 (TC for 14 hours. The mixture was concentrated under reduced pressure, and a portion of trimethylsilyl phosphorous acid was dissolved. Treated with diethyl ether (0.5 ml) and heated at 50 ° C for 24 hours. The reaction mixture was reduced in ink and dissolved in ^ d C 13 (apparently cleavable silyl enol ether) at 1 mm Hg And concentrated at 50 ° C for 3 hours, yielding the above-mentioned viscous pale yellow oil of diethyl ester (0.23 g, 95%). Analytical's calculations: C 2 8 Η 3:; B r 〇 4 P : C, 6 1 · 8 3; Η, 5 · 9 4. Measured 値: C, 62.05; Η, 6.11. -198 This paper size applies to China National Standard (CNS) Α4 specification (210X 297 mm East Ministry of Economic Affairs) Printed by the Consumer Samples Cooperative of the Central Bureau of Samples B7 V. Invention Description (196) 0

0H

P-OH Example 3 4 5 Step 3 Preparation method of Example 3 4 5 β Add trimethylsilicone tomb bromide (0.4 8 ~ milli well, 3.64 mmol, 7.4 equivalent) to the product containing step 2 (0.243 g) via a syringe. , 0.490 millimoles) of anhydrous CH2C 2 (15 ml), dissolved in liquid. Stir at room temperature for 14 hours. The resulting solution was rolled under reduced pressure to about 8 ml, and then treated with MeOΗ (10 ml). This concentration / dilution process was repeated more than 5 times, after which the reaction mixture was concentrated. The resulting solid was triturated with hexane to produce the desired phosphonic acid (0.150 g, 63%). MP 150-152 ° C. H,

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) Example 346 Example 3 4 6 In a 10 ml round bottom flask containing Example 1 (0 · 2 5 g ' 〇 7 2 5 Million paper scales are applicable to China (CNS) A4 specifications (210X2 public directors) Printed by the Consumers Cooperatives of the China Prospective Bureau of the Ministry of Economic Affairs A7 _____B7 V. Description of the invention (丨 97) Mole), Proline Acid Nf-methylamidamine hydrochloride (0.48 g, 2.90 mmol) and a solution of hydroxybenzotriazole (0.10 g, 0.725 mmol) in anhydrous dichloromethane (3 ml) were cooled in an ice bath and stirred for several minutes. minute. After rapid addition of N-methyl? Via a syringe (# 32 ml, 0.29 g, 2.90 mmol), ethyl ethyl 3- (3-dimethylaminopropyl) carbodiimide solid ( 146 grams, 0.76 millimoles). The reaction mixture was stirred for several hours under argon and then returned to room temperature overnight. The reaction mixture was diluted with aeroform (30 mL) and washed with 10% HCI (10 mL). The separated aqueous layer was back-extracted with aerosol (5 mL). The combined organic phases were washed with NaHC0 (10 mL), dehydrated (NkS04), and concentrated in vacuo. The crude oil material was purified by flash column chromatography (2 gas compasse · methanol (98: 2)] 'to give the title compound as a white solid (0.26 g, 79%). MP 75.5-78.CTC. Example 3 4 7 — AO .. Step 1 Reflux 6 ml of toluene solution containing 2,4'-dibromoethyl benzene (〇_62 g, 2.19 mmol) and acetamide (0.20 g, 3.32 mmol) for 3 days. The solvent was removed under reduced pressure and the residue was chromatographed with 0-30% ethyl acetate in hexane to give 0 20 mg (38%) of a white solid product „τ LC, (Dimethyl formaldehyde) R 0.42. 1 Step 2 Add χ.ι £ -200 containing dimethyltin gas (0.8 1 g, 406 millitorles)-This paper size applies Chinese National Standard (CNS) A4 specification 210x297-^^ 7 J nnn -nn 1 ^ 1 __ 士 L -------- J I --- 1 _ IT i IIII _ Qi I --β Vi / V (Please read the precautions on the back before filling this page) 413675 A7 _____B7 V. Description of the invention (is »8) (15 ml) solution. An ice-cooled round-bottomed flask under argon flow containing small pieces of metallic sodium (0.3 g, 1 · 3.0 mmol) D M E ( 2.5 ml) of the stirred suspension when the mixture turned green, The mixture was stirred in an ice bath for 3.5 hours. The mixture was transferred via a syringe to a cooled round bottom flask and treated with a DME (4 ml) solution containing the product of step 1 (0.8 g, 3.36 mmol). The reaction mixture was then warmed and stirred at room temperature overnight. At this time, it was diluted with ethyl acetate, washed with water and brine, and dehydrated with MgS04. The crude product was chromatographed with 3-20% ethyl acetate in hexane. Yield 0.7 6 g (70%) oily product "T LC (hexane-20% ethyl acetate) R, '0_37 ° &quot;'

GO 20 (Please read the precautions on the back before filling this page) c Step 騄 3 Take the product containing Step 2 (0.21 g, 0.65 mmol), Example 61, and sample 3 base gas (0.16 g, 0.74 mmol) Mol) and 1,2-dichloroethane (1-5 ml) solution of PdCl2 (PPh3) 2 (0.078 g, 0.14 mmol) were refluxed overnight. The reaction mixture was diluted with ethyl acetate and filtered. After filtering under reduced pressure and rolling, chromatography was performed with 3-50% ethyl acetate in hexane to give 66 mg of a solid product. HRMS (FAB) calculated 値 C20H26NO4 [M + H] + 344.18618, measured 値 344,18600.

CO2H is printed by the Ministry of Economic Affairs, Central Tezawa, and Off-line Consumer Cooperatives. 347 Step 4 Example 347. Take the product from step 3 (56 mg '0.16 mmol) and -20)-Kt scale of this paper is applicable to Chinese National Standard (CNS) A4 specification (21〇κ &gt; 9, νΑ'centi) A7 B7 V. Description of the invention (199) Float in ethanol (1.3 ml) and treat with 4 N na 〇Η (0.4 ml). The mixture was stirred at room temperature. The reaction mixture was stopped with 2N H CM, diluted with ethyl acetate, The layers were separated. The organic layer was washed with brine and dehydrated with Mgs. 04. The product was layered with 0-12% methanol in digas rotane to give 40 mg (78%) of the solid of Example 248. MP 120 g.

COjH Example 348 Example 348: A method similar to Example 3 4 7 'but using thioacetamide instead of acetamide. HRMS (FAB) Cl8H22N03S [M + H] + Calculate 値 332.13204, Measured 値 332.13287 ° Example 349: (Read the precautions on the back before filling out this page) 41 Central Government Bureau of Ministry of Economic Affairs Shellfish Consumer Cooperation Du Printing Steps 1 A solution containing 2-ethylammonio-5bromoquine (PPhA) (0.55 g, 2.64 mmol) in Benzene (5 ml) was stirred at room temperature for 30 minutes. At this time, 4 was added. -Pyrophthalic acid (0 46 g, 2 91 mmol) and NaOMetMeOH (1.21 ml, 25% wt, 5 29 mmol). ^ The mixture should be refluxed for 4 hours. The mixture was cooled to At room temperature, add 2N NaOH (3ml) 'continued for 2 hours.) The Kun compound was diluted with dichloromethane, and the national paper standard (CNS; Μ ^ ΛΤΤί 29Ί / ^ A7 B7) was used as the paper standard. 2. Description of the invention (200) Wash and dehydrate with M g S 0 4. The crude product is chromatographed with 0-30% ethyl acetate solution of Tiger, yielding 0.5 1 g (82%) of the product. Alkane-10% ethyl acetate) * Rf 0.24. Step 2 Take the product from Step 1 (0.51 g, 2.17 mmol) and dissolve in THF (10 ml), cool to 0 ° C, and then use phenyltrimethylammonium three Bromide (0.84 g, 2.17 mmol) was treated. The reaction mixture was stirred at room temperature for 5 hours. The mixture was quenched with H20 and extracted with ethyl acetate (2x15 ml). The chapter solution was washed with brine, dehydrated with MgS04, Crystallized from ether / hexane, producing 0.62% (91%). TLC (hexane-10% ethyl acetate) R f 0.2 7. (Please read the precautions on the back first and fill in this page) ί ,.

Ordered by the Ministry of Economic Affairs of the People's Republic of China Bureau of Consumer Cooperation Du printed step 3 under the argon flow, treated with NaOH (0.068 g, 2.81 mmol) containing 3 -phenyl-propyldiethyl malonate (0.85 G, 3.05 mmol) in THF (10 ml). The solution was stirred at room temperature for 30 minutes. At this time, a solution of the product from Step 2 (0-62 g, 1.98 mmol) in THF (14 ml) was added dropwise. After the addition, the reaction mixture was stirred at room temperature for 15 minutes, the reaction was stopped with H20, diluted with ethyl acetate, the organic layer was washed with brine and dehydrated with MgS0 4. The residue was chromatographed with 0-40% ethyl acetate in hexane to give 0.63 g of product TLC (hexane-20% ethyl acetate) Rf 0.39. 203 * The size of this paper mark is applicable to China National Standard (CNS) A4 (2i × 297mm) 413675 A7 B7 V. Description of the invention (20l)

Employees of the Central Bureau of Standards, Ministry of Economic Affairs, Consumer Cooperation Du Printing Step 4 Treat H20 (0.5 ml) containing sodium hydroxide (0.24 g, 6.16 mmol) with the product from step 3 (0.63 g, 1.23 mmol) Of ethanol (5 ml), and the mixture was stirred at room temperature for 2 hours. At this time, the reaction mixture was acidified with 2N HC1, diluted with ethyl acetate, and the layers were separated. The organic layer was washed with brine, dehydrated with Mg S04, and decolorized with activated carbon to produce 0.5 4 g of a diacid product. TLC (digas methane · 10% methanol). r f 〇 · 1 3.

002 «Example 3 4 9 Step 5 Example 349 method. The product from Step 4 (50 mg, 0.1 mmol) was dissolved in anhydrous acetonitrile (1.5 ml); treated with copper oxide (2 mg, 0.01 mmol). The mixture was refluxed under a stream of argon for 36 hours. At this time, it was diluted with ethyl acetate, and the reaction was stopped with 2N HC1. The layers were separated, and the organic phase was washed with brine, dehydrated with M g S 0 4, and crystallized from Myrtle / hexane to give 34 mg of Example 349. MP 149〇C 〇 Example 3 50 door 〇 Step 1 take methyl 5-bromofuroate (204 mmol, 0.9 9 mmol) dissolved in DME (3.5 ml), and then add Pd ( 0 Ac): (24 mg, 0.1 1 mol), P (o-tolyl) 2 (60 mg, 0.20 mol) '4-Gaben 204-This paper size applies Chinese National Standard (CNS) A4 specifications (2 丨 OX 297 mm) --------- ί ------, 玎 ------ ^, y (. Y £ \ {Please read the notes on the back first Refill this page) A7 B7 printed by Shelley Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs 5. Description of the invention (202) Dihydroxyboric acid (168 mg, 1.07 mmol) and sodium decomposing solution (1.0 ml, 2N Η 2 〇 solution , 2 millimoles). The reaction mixture was refluxed for 1 hour, at which time the thin layer method showed that the reaction was complete. The mixture was cooled to room temperature, diluted with water, and extracted with methane (2 x 15 ml). The tritium-containing extract was washed with brine, dehydrated with MgS04, and the solvent was reduced to reduce the baby's content, yielding 1 70 mg (72%) of the methyl ester product. This methyl ester was suspended in 2 ml of 6 alcohol, and treated with 5 equivalents of NaOH aqueous solution, and the mixture was stirred at room temperature for 1 hour. At this time, the reaction mixture was stopped with 2N HC1, diluted with ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate, and the combined extracts were washed with brine, dehydrated with M g S 0 4 and drained under reduced pressure to remove the solvent, and 140 mg of the product was found. TLC (digas methane-1 0% methanol) Rf 0.17 ^

Step 2 Treat the dichloromethane suspension 3 mixture containing the product from Step 1 (1.42 g, 6.38 mmol) with argon (3.5 ml, 2M CH2C 2 solution, 7.00 mmol) and 1 drop of DMF. Under reflux for 1 hour 3 at this time, the mixture was cooled to 0 π and transferred via a cannula to an ice-cold solution of diazomethane (50 ml, 0.6M Et20 solution, 30 mmol). After the reaction mixture was stirred at 0 ° C for 1 hour, the reaction was stopped with HC1 (30 ml, IN Et20 solution, 30 mmol). The mixture was stirred at room temperature for 1.5 hours 'and transferred to a separating funnel containing ethyl acetate, washed with a saturated sodium bicarbonate solution and brine' and dehydrated with M g S 0 4. The crude product was chromatographed with a acetic acid solution of acetic acid, resulting in 1.28 g (79%) of the product ^ TLC (hexanox-10% ethyl hexanoate) Rr 0.13. -205-This paper size applies the Chinese National Standard (OS) A4 (2i〇. 乂 W 公 *〉 (Please read the note on the back before filling this page) • ^ 'Order-Line I. V. Invention Instructions (203) A7 B7

Step 3 Example 3 50 method. The method of Example 3 4 9 was similar, but the product of Step 2 was used instead of the corresponding product in the method of Example 349. MP l29-l30 ° C »Example 3 5 1

〇 (Please read the precautions on the back before filling this page) The Central Ministry of Economic Affairs must print the clothes for employees' consumer cooperatives. Step 1 Insert a rubber stopper and argon needle into the 〇 and a single neck 10 ml containing 4 ml of triethylamine. Example 40 (0.200 g, 0.401 mmol) was added to the round-bottomed flask. Mol) and trans-digas bis (triphenylphosphine) palladium (0.011 g, 0.016 mmol). The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated, and column chromatography was performed on 100 g of silica gel (20% ethyl acetate-hexane containing 0.05% acetic acid) to isolate the product, yielding 0.1 to 63 g (87%) of the coupled product. White solid. MP 149 ° C. Step 2 Example 35 1 production method. To a 2 ml vial with a screw cap was added silanol acetylene (0.150 g, 0.320 mmol) and a solution of KOH in methanol (2 ml, 0.3 2 mmol). The resulting mixture was stirred at room temperature for 12 hours = the reaction mixture was acidified to ρ Η 1 and extracted with ethyl acetate (10 ml). The resulting organic phase was dehydrated with NTa2S04, filtered, and concentrated to give the crude product of Example 1 5-9 9 9 9. After 20 grams of silica gel column analysis (20% ethyl acetate. Contains 206-This paper size applies to Chinese national standard (CN ;;) A4 specification (2! 0X297 mm) Order

W A7 B7 Master !, Description of the Invention (204), i ^ 0 '50 / 〇 acetic acid) 'produced 0.14 g (88%) Example 1 5-9 7 9 9 gray' white solid . MP 15TC. The following biphenyl product was prepared from Example 40 or Example 134 and the appropriate 1-determined compound using the method of Step 1 of Example 3 5 1 above (Table XXIV).

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

The Central Bureau of Standards, Ministry of Economic Affairs, Shellfish Consumer Cooperation, Du Printing Equipment Step 1 The method of Step 1 in Example 351 above was used to prepare propargylmethoxyacetylene as Preparation Example 3 5 3, Example 3 5 4 and Example 3 5 5 Starter. MP 151X :.

The winter paper scale is applicable to the Chinese National Standard (CNS) M specification (210X297 mm) Α7 ___ Β7 V. Description of the invention (205) Step 2 Example 3 5 3, Example 3 5 4 and Example 3 5 5 In a single-head 10 ml round bottom flask equipped with a rubber stopper and an argon balloon connected through the needle inlet, add 2 ml of M eOH. The acetylene substrate in step 1 (0.030 g, 0.068 mmol) and 0.0 02 g 5% ie / carbon. The resulting mixture was stirred at room temperature for 12 hours, at which time a second portion of 0.02 g of catalyst was added. After the reaction mixture was stirred at room temperature for 24 hours, half of the material was taken and filtered through celite and concentrated. Example 3 53 (0.00 1 g), Example 3 54 (0.003 g), and Example 3 5 5 (0.00 1) were isolated by HPLC (Si02 column, 1% ethyl acetate-2 gas f slope containing οορ / oTFA). G) "/ Example 3 5 2: HPLC (dissolution: 1% ethyl acetate-2.0% TFA in two gas pits) tR = 17.6 minutes; MS (FAB-LSIMS) 443 [M + N] +. Example 354: HPLC (dissociation: 1% ethyl acetate-0.01% TFA in digaszine) tR = 15.5 minutes; MS (FAB-LSIMS) 443 [M + N] +. Example 355: HPLC (dissociation: 1% ethyl acetate-0.01% TFA in digaszine) tR = 20.6 minutes; MS (FAB-LSIMS) 445 [M + N] +. ---------------- Order (Please read the precautions on the back before filling out this page) Printed by the Consumers' Cooperative of the Central Government Bureau of the Ministry of Economic Affairs

Example 3 5 6 Example 3 5 7 Example 3 5 6 and Example 3 5 7: Using the above-mentioned Preparation Example 3 5 3, Example 3 5 4 and Example 3 5 5 Step Can 2 &gt; '1 208 Paper Size Applicable to China National Standards (CNS) A4 specification (2 丨 0 · 〆297mm) A7 B7 V. Description of the invention (206) Method to prepare examples 3 5 6 and 3 5 7 Example 356: HPLC (dissolution: 10/0 ethyl acetate-digas methane containing o.op / oTFA) * tR = 11, 5 minutes; MS (FAB-LSIMS) 455 [M10N] 10. Example 357: HPLC (dissolution: 1% ethyl acetate-methane gas with 0.01% tfa) 4 = 3.2 minutes; MS (FAB-LSIMS) 442 [M + N] ten. Example 3 5 8 Example 3 5 9

In step 1, the method of step 1 in Example 351 was used to prepare benzylacetylene as the starting material for preparing Examples 3 5 8 and 3 5 9. Μ P 1 5 4. (:. (Please read the notes on the back before filling out this page)-Order

Ph

Printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs Example 3 5 8 Example 359 Step 2 Example 3 5 8 and the method of 3 5 9 Using the method for preparing Example 3 5 3, Example 3 5 4 and Step 2 of Example 3 5 5 above, Example 3 5 8 and Example 3 5 9 were prepared. Example 358: HPLC (dissolution: 1% ethyl acetate-digas methane containing 0.01% TFA) tR = 13.9 minutes: MS (FAB-LSIMS) 475 [M + NΓ. • 209-This paper rule; ^ Xiaoyong China National Standards (CNS) A4 specifications (210X297) A7 ——___ V. Description of the invention (207) Example 359: HPLC (Dissolution: ι〇々ethyl acetate n 〇i% TFA methane) tR = 25.2 minutes; MS (FAB-LSIMS) 477 [M + N] +. Greed 3 6 0

Step 1 Make the oxo-2-oxobicyclo [2,2,1] heptane-7 · carboxylic acid (prepared by the method described in Tetrahedron, Vol. 37, SuppL, 1981, 411.) (3 _ 0 4 g , 1 9.7 millimoles) of C H 2 C12 (45 ml) solution was cooled to Γ 3C with 2- (trimethylsilyl) ethanol (27 milliliters, 186 millimoles), EDC (3.94 grams, 2 0.5 5 mmol) and DMAP (0.1 1 g, 0.9 mmol). After warming to room temperature, the reaction mixture was stirred for 2 hours. The reaction was stopped in water and diluted with CH ^ Cl2. After layering, the organic phase Washed with saturated aqueous NaCl solution, dehydrated with MgS04, and concentrated. Purified by MPLC (0-25% EtOAc / hexane) to give the target compound (3.9 g, 78%) as a colorless oil "1 η NMR (CDC13 ) d, 4.18 (m, 2H), 2.88 (m, 2H), 2.76 (m, 1H); 2.05 (m, 4H), 1.50 (m, 2H), 0.99 (t, J = 8.4 Hz, 2H ), 0.09 (s, 9). (Please read the notes on the back before filling out this page) Order printed by the Central Consumers' Bureau of the Ministry of Economic Affairs, Consumer Cooperatives

Step 2 Take the ketone (3. IS g, 12.50 mmol) from Step 1 and 2- [N, Ν · bis (trifluoromethylfluorenyl) amino group 5-5-pyridine (6.6 g, 16.30 mmol) Ear) of THF was cooled to -7 C, and carefully treated with 0.5 μM KΗMDS in methylbenzyl (24 ml '12 mmol). After the addition is completed, the solution is stirred -210- This paper size is in accordance with the Chinese Standard (CNS) A4 (2IOX 297 mm) Printed by A7 __B7, the Consumer Work Cooperative of the China Standard and Quasi-Bureau of the Ministry of Economic Affairs. After stirring for 2 hours, the reaction mixture was quenched with water (30 mL), warmed to room temperature, and diluted with EtOAc. Separate the two phases. The organic layer was washed with a saturated aqueous NaCl solution, dried over M g S 0 4, and concentrated. Purification by μP L C (0-15% EtO Ac / hexane) gave the target compound (42 g, 91%) as a colorless oil. NMR CCDC13) d, 5.75 (d: J-4.8 Hz, 1H), 4.13 (t, J = 9.0 Hz, 2H), 3.18 (m, 2H), 2.62 (m, 1H), 1.89 (m, 2H ), 1.4: (t J = 9.3 Hz, 1H), 1.23 (t, J = 9, l Hz '1H), 0.96 (t, J = 8.4 Hz, 2H), 0.04 (s, 9H).

Step 3 At room temperature, carefully treat a solution of 4-fluorofluorene (3.0 g, 15.9 mmol) in acetic acid (50 mL) with bromine (1.1 mL, 2 0.7 mmol), and heat the reaction mixture. To reflux for 4 hours. Cool to room temperature and treat with excess propylene until the mixture is clear. The solution was concentrated to a thick slurry, diluted with CH2C12 (50 ml), and washed sequentially with water and 2N NaOH. The organic extract was dehydrated with MgS04, filtered and concentrated, and purified by recrystallization from EtOAc to give aryl bromide (3.57 g, 84%) as white crystals. j NMR (CDC1J d, 7.57 (m, 2H), 7.48 (m, 2H), 7.41 (m, 4H).

SnMea Step 4: Take a solution of 4-bromo-4 dagger gas coupling (8.0 color '30- 0 mmol) in thF (120 ml) and cool to -78 ° C with n-BuLi (19.7 ml, 1. 6 M hexane solution, 3 1.5 mmol. After stirring for 1 hour, -211-This paper size is applicable to the national standard of the country (CNS) Α4 (210X27) --------- support -------- order .------ ' t ί (Please read the precautions on the back before filling this page) Consumption cooperation between employees of the Central Bureau of Standards of the Ministry of Economic Affairs Du printed A7 B7 V. Description of the invention (209) Mixture of gas trimethyltin (33 ml, 1 _ 〇 〇 (M solution, 330 mmol). After another 30 minutes, the solution was warmed to room temperature and concentrated. The off-white solid vessel was diluted with C Η2 C 丨 2 (300 ml), and washed with water and saturated n a C 丨 water solution in this order. The organic layer was dehydrated with M g S 0 *, filtered, and concentrated, and purified by mplc (hexane :) to produce white crystals of aryl town (9,38 g, 89%). 1 NMR (CDC13) d 7.62 (m, 6H), 7.54 (m, 2H), 0.39 (s, 9H)

Step 5: Take the triflate (4_2 g, 10.89 mmol) from Step 2, Cul (0.215 g '1.1 mmol), AsPh3 (0.339 g, 1.1 mmol), Cl2Pd (MeCN) 2 (0.215 g, 0.56 mmol) and a few BHT crystallized 1-methyl-2-0 ratio bittenone (1 1-5 ml) solutions were placed in an oil bath preheated to 8 5 C. After 4 minutes of turning off, the full amount of step_4's biphenyltin derivative (7.3 g, 20.7 mmol) was added at once. The mixture was stirred for 30 minutes and cooled to room temperature with EtOAc.-. After the layers were separated, the aqueous layer was extracted back with EtOAc, and the organic layer was dehydrated with Mg S 0 4, filtered and shrunk. The obtained residue was adsorbed on the crushed gel and was purified by MPLC (0-15% E t OAe / hexane) to produce a white crystal of a coupling product (4.0 g, 86%). NMR (CDC13) d. 7.52 (m. 6H), 7.43 (mr 2H). 6.40 (d. J = 3.3 Hz, 1H), 4.19 (t, J = 10.2 Hz, 2H)? 3.58 (m, 1H)? 3.23 (m, 1H), 2.60 (m, 1H), 1.95 (m, 2H) f 1,20 (m, 2H)? 1.02 (d, J = 7.5 Hz, -212 · This paper size applies to Chinese national standards ( CNS) A.4 Specification (210X297mm) (Please read the notes on the back before filling this page) Ja B7 V. Invention Description (210) 2H), 0.08 (s, 9H). O co2TMSEciX> oVrCH. Printed by the Men ’s Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Step 6 Take a 10% MeOH / CH2Cl2 (200 ml) solution containing the olefin (3.60 g, 8.47 mmol) from step 5 and cool to -78. Add the ozone gas directly to The reaction mixture was worked up (10 minutes, 1 liter / minute). After TLC showed no starting material, flush the solution with argon (i 5 minutes), treat with dimethyl sulfide. (13 ml), return to room temperature ^ After stirring overnight, the solution was concentrated to a residue 'via MPLC Purification (0-15% EtoAc / hexane) 'yielded a mixture containing the desired aldehyde and the corresponding dimethylacetal. The product mixture was dissolved in acetone (45 mL) and treated with CSA (0-192 g, 0.83 mmol) and water (0.3 mL, 16.) mmol). After stirring overnight, the solution was concentrated and passed MpL (^ t (Guang Er% E: 0 AC / hexane)) to produce the desired color (3.45 g '89%) of the seeding oil. H NMR (CDri, ^ ucl3 ) d 9 78 (d, J = 6, 6 Hz, 2 H), 7,65 (d,] spoon Hz, 2 H), 7.44 (d, J = 9 0 Hz '&gt; 7.2 Hz, 1 H) , 3.15 (m 1-86 (m, b H), 1.58 (s? T H) 2 H), 0.009 h). Step 7: Read it first with 3 ethyl. Please fill in the notes of I &amp; then fill in this page H), 戍 trout (ο (d, J = 1.8 Hz, 1 H), 8.05; 6-6 Hz, 2 H ), 7.55 (d, J-9.〇4.15 (m, 3 H), 3.87 (t, (m, 1 H), 2.03 (m '1 H). (T, J = 6.9 Hz, 1 H), 0.93 (m, liter, 5.77 millimolars) For processing paper containing paper, the scale applies to Chinese national standards (------, magic 3. 413675 A7 B7 V. Description of the invention (2)!) Lithium aluminum hydride (1.9 ml , Κομ THF) in THF (6 ml), heated to gentle reflux for 1 hour, and the mixture cooled to room temperature. (Please read the precautions on the back before filling this page} Take the aldehyde intermediate containing step 6 (0.85 g, 1.86 The THF (15 ml) solution was cooled to -78 ° C, and the THF solution of LTEPA (as described above) prepared in advance was added dropwise through a catheter. After the addition was completed, the solution was at _78. After 4 hours, the reaction was quenched with 2N HC1 (4.6 mL). The reaction mixture was diluted with EtOAc 'and washed with water. The organic layer was dehydrated with Mgs 04, filtered and concentrated. MPLC (5-40% EtAc / Hexane) &gt; to produce the desired aldehyde (0.640 g 7 5%) of white crystals. 4 (〇〇 (: 1;) £ 18.05 (Mountain _ / = 8.7 1 ^, 2 11), 7.65 (d, J = 8.5 Hz, 2 H), 7.55 (d, J = 8.4 Hz, 2 H), 7.44 (d, J = 8.4 Hz, 2 H), 4.15 (m, 2 H), 3.76 (t, J-6.3 Hz, 2 H), 3.28 (t, J = 8.7 Hz , 1 H), 2.48 (m, 1 H)? 2.35 (t, J = 6 Hz, 1 H), 2.18 (m, 1 H)? 1.91 (m; 2 H), 1.57 (m, 1 H), 1.35 (t, 3 = 6.9 Hz, 1 H), 0.91 (m, 2 Η), -0.01 (s, 9 H).

〇C〇2TMSE The Central Bureau of Standards, Ministry of Economic Affairs, Shellfish Consumer Cooperation, Du Printing Step 8 Take the ch2CU containing the alcohol from step 7 (0.200 g, 0.436 mmol) and triethylamine (0.09 ml '0.65 mmol). 6 ml) solution, treated with p-toluenesulfonium (0.101 g, 0-524 mmol) and DMAP crystals. The mixture was stirred at room temperature for 16 hours, concentrated under reduced pressure, and purified by MPLC (0-20% EtOAc / hexane) 'to give methanesulfonate (0, 240 g, 89%) as a colorless oil. 1 Η (CDC13) d 8.02 (d, J = 8.4 Hz, 2 H); 7.82 (d, J = 8.1 Hz, 2 H), 7.64 (d, J = 8.4 Hz, 2 H), 7.56 (m, 2 H), 7.45 (m, 2 H), 7.36 -214 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 41S675 Μ printed by the Consumer Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs __! L__ -—- V. Description of the invention (212) (df J = 8.1 Hz, 2 Η), 4.28 (m, 1 Η), 4.10 (m, 4 Η)? 3-14 1 Η), 2.61 (m, 1 Η) ), 2.46 (s, 3 Η), 2.13 (m, 1 Η), 2. · 〇〇1 Η), 1.82 (m, 1 Η), 1.56 (m, 1 Η), 0.87 (m, 2 Η) ), 0.〇〇 (s. 9 Η)

Step 9: Take the benzenesulfonate (0.250 g, 0.408 mmol) containing step 8f '' 'potassium phthalimide (0.232 g, 1.23 mmol), 18-crown-6 (0.341 g' h29 mmol) ) Solution of DMF (3 milliwells) was heated to 40aC and stirred for 2 hours. After cooling to room temperature, the reaction mixture was diluted with EtO Ac and water and separated into layers. The organic layer was washed with a saturated Na C 1 aqueous solution, dehydrated with M g S 0 4, filtered and concentrated. Purification by] VIPLC (3-200 / 0EtoAc / hexane) to give the desired phthalimide imine (0.187 g, 78%) as white crystals. 4 NMR (CDC13) d 8.04 (d, J = 8.4 Hz, 2 H), 7.86 (dd, Jt-5.1 Hz, S2 = 3.0 Hz, 2 H), 7.71 (dd, J, = 5.4 Hz, J2 = 2.7 Hz, 2 H), 7.63 (d, J = 6.6 Hz, 2 H) f 7.55 (d, J = 8.7 Hz, 2 H), 7.44 (d. J = 8.4 Hz, 2 H), 4.20 (m, 1 H), 4.00 (m, 1 H), 3.91 (m, 2 H), 3.81 (m, 1 H)? 3.33 (dd, J ^ B. 5 Hz, J2 = 6.9 Hz, 1 H), 3.32 (dd Hz; J. = 3.9 Hz, 2 H), 2.80 (m; 1 H), 2.15 (m. 1 H), 1.94, (m, 2 H), 1-60 (m, 1 H), 0.66 ( m, 2 H), -0.08 (s, 9 H) ^ II— »---- --------* 冬 ---- / i (please read the crying items on the back first and fill in the difference) Order of this education

A7 B7 V. Description of the invention (213) Step 10 Example 360 method, TBAF (0.43 ml, 0.43 mmol) was treated with step 9 ester (0 "68 g, 0.2 86 mmol THF (5 ml) ) Solution, continued to stir off at room temperature for 2 hours. The reaction mixture was stopped with 2 NH 1 and diluted with E t 〇 A e 3 layers. The organic layer was washed with Na and aqueous solution. Purified by MPLC (0-5% MeOH / CH ^ Cl :) to produce white crystals of the desired acid (0.128 g, 92%), MP 203-205 ° C. Examples 361 and 362 on a Chiralcel &quot; AS HPLC column Using the ethanol / hexane mixture as the eluent, Example 360 (racemate) was separated into the enantiomers with the highest activity (Example 361) and the lower activity (Example 3 6 2). Example 361: [ a] D + 44 ° (c0.3, CHC13) (Please read the notes on the back before filling this page)-Example 363:

0 Q〇2TMSE -a Step 1 Take a solution of 4-methylbenzyltriphenylphosphine bromide in THF (2.5 ml) and cool it to -7 8 X: n-B u L i (0. T 3 ml, 1.6 M hexane solution) treatment ^ 'After stirring for 30 minutes, THF (1.5, 0.2 1-0.2, 5 5 mol) containing aldehydes in Example 3, 60 steps was added. Ml) solution, and the mixture was warmed to room temperature over 3 hours. The reaction mixture was diluted with ethyl acetate and the bars were washed with water. The organic layer was washed with saturated aqueous Na C 1 solution, dehydrated with M g S 0 4 and purified by flash column chromatography (0.10% EtOAc / hexane) to give the desired olefin (0.0 22 g, 16 %) Of white crystals. TLC Rf: 0.22 (silica; 10¾ EtOAe / hexane). -216- This paper size is applicable to CNS A4 specifications {210X 297 mm) -1 Printing policy of the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy Μ B7 5. Description of the invention (2Μ)

〇 C〇2H Step 2 Example 363 method. The same method as in Example 3603, Step 10 for the removal of the intermediates was used to remove Step 2-(trimethyl τ 7). MP 2 1 3 C. Example of protection of ethyl ester 3 640 CoaBnajy〇X ^ CH〇 Step 1 is similar to the corresponding 2-trimethylsilyl ester intermediate (Example 36, steps 1-6) to prepare fluorenyl esters. At this time, Use step alcohol instead of step trisilyl ethanol. 0 CQzBn

In OH step 2, the corresponding 2- (trimethylsilyl) ethanol intermediate (Example 37, step 7) was used to reduce the intermediate in step 1 using the same method. (Please read the notes on the back before filling this page) -n ___

-1T Employee Consumption Cooperatives, China Standards Bureau, Ministry of Economic Affairs, 51

0 &quot; Step 3 Treatment with gaseous methyl methyl ether (0.01 ml, .0 mmol) with the intermediate from Step 2 (0 0 2 5 g, 0 _ 0 5 5 7 mmol) and diisopropyl Ethylamine (0 0 3 -2Ϊ7- this paper wave scale applies to China National Standard Feng (C "NS) A4 specifications (210 X 297 mm) A7 B7 V. Description of the invention (215) ml, 0.167 mM) CH2C12 ( 2 ml) solution and stirred overnight at room temperature. The concentrated reaction mixture was purified by flash column chromatography (3-2'0% EtOAc / hexane) to give the desired ether (0.025 g, 91%). Rf 0.16 (silica, 25% EtOAd hexane).

Step 4 Example 364. A solution of the intermediate of Step 3 (0.023 g, 0.047 mmol) in THF (0.5 ml) and ethanol (0.4 ml) was treated with a NaOH solution (0.19 ml, 0.5 g / 10 ml of water). After stirring at room temperature for 1.5 hours, the mixture was diluted with EtOAc and the reaction was quenched with 2N aqueous HC1 (0.6 mL). The organic layer was washed with a saturated aqueous Na C 1 solution, dried over M g S 0 4, and concentrated. The residue was crystallized from ether and hexane to give the desired diacid (0.1 7 g, 90/0). MP 89-90 ° C. Example 365 C〇2Bn

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

-ji ^ n I Order Printed by Shelley Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, Step 1, with 2,2,2-trifluoroacetimidate (0.068 ml, 0.37 mmol) and BF3 'Et20 ( 7 μl) of a solution of the intermediate of Example 364, Step 2 (0.150 g, 0.334 mmol) in CH: C12 (1 ml) and cyclohexane (2 ml). After stirring for 30 minutes, NaHC03 solid was added and the solution was diluted with CH2C12. After a short period of filtration through silica gel, the solution was concentrated to a flash tube -2J8- This paper size is in accordance with Chinese National Standard (CNS) A4 ^ grid (210X 297 mm) A7 A7

B7 V. Description of the invention (216) Purification by column chromatography (0-15 0 / 〇E t 〇Acz hexane), yielding the desired compound in low yield ° R f 0.3 9 (25% E t OA c / Hexane). * 〇 C〇5 Step 2 Example 3 6.5 method. The same method as in Example 3 6 4 step 4 was used to remove the protection of the ester intermediate in step 1. MP 1 57-158 ° C. Example 366

Step 1 Treat the alcohol (0.054 g, 0.118 mmol) containing step 7 of Example 360 with diethyl azodicarboxylate (0.04 ml, 0.2 5 4 mmol), benfenol (0.015 g, 0 · 159 mmol) and triphenylphosphine (0.069 g, 0.263 mmol) in THF, and stirred at room temperature for 24 hours. After the reaction mixture was concentrated, the residue was purified by flash column chromatography (0-10% EtOAe / hexane) to give the desired benzene-phenol (0.03 1 g, 52%) = Rf: 0.41 (silica, 15 % E t O Ae / own hospital). Step 2 Example 3 6 6 method. Using the same manufacturing method of Example 3 6 0 Step 1 219- This paper is compliant with the Chinese National Standard (CNS) A4 Regulation (21J3X 297). ------ y-/ t \ ((Please read the notes on the back before filling out this page) Printed by the Department of Economics, Central Standards Bureau, Consumer Consumption Cooperation

A7 B7_ 5. Description of the invention (217), remove the deep protection of step 12-(trimethylsilyl) ethanolate intermediate 189-190 ° C. Greed 367 〇 co2tmse 〇

MP (Please read the notes on the back before filling out this page)-Step 1 Treat the alcohol containing Example 360 step 7 with Benzene (0.015 ml, 0.129 mmol) and DM AP (1 mg). 〇40 g '0.08 7 mmoles). Dissolve with triethylamine (0.02 ml, 0-144 mmoles) in CH2C12 (2 ml). After stirring at room temperature for 5 hours, the solution was concentrated and purified by flash column chromatography (0-15% EtOAc / hexane) to give the desired ester (0.044 g, 92%). R t 0.4 (silica, 25% Et O Ac / hexane).

The method of printing step 2 example 3 67 is printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economics ° The same method as in example 3 6 step 10 is used to remove the protection of 2- (trimethylsilyl) ethanol ester intermediate of step 1 . MP 166-167. (:. Example 3 6 8 〇CO2TMSE 〇〇〇2Μθ -220-This paper size applies to the national standard of China (CNS) A4 will be mm) A7 B7 V. Description of the invention (218) Step 1 contains the example 360 Alcohol from step 7 (0.39 g, 0.0085 mmol), monomethyl phthalate (0.032 g, 0.172 mmol), dimethylaminopropyl) -3-ethylcarbodiimide Iodide (CD033, 72 mmol) and N'N-dimethylaminocolloid (0.05 mg, 0.004 mmol) tCH2Cl2 (2 mL) solution at room temperature Stir for 3 2 hours. The reaction was diluted with c H 2 c and washed with water. The organic extract was dehydrated with MgSO4, filtered and purified by flash column chromatography (0-20 / 0EtoAe / hexane) to yield the desired ester (0039 g '74 ° /.) . Rf: 0.3 5 (silica, 30% EtoAe / hexane). jOaH 〇 οο, Μβ — 〇 ^ Cr ^ Yr〇A0 Step 2 Example 3 6.8. Therefore, the same method as in Example 3 60, Step 10 is used to remove the protection of step 12 ((dimethylsilyl) ethanol ester intermediate). MP 102-104. . . Example 369

9 COjTMSE Printed by the Pager Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (° ·. 62 g, .534 mmol) Disposal of gas-containing sodium (ϋ, 0 093 g, 0 fly)

After searching for 30 minutes, add 1 ml of tincture, 1 ml of suspension), 1 gram of suspension, 0.082 millimoles &gt; No. 2 to No. 3 to 60, step 6 of the toluene tank sour (0.05 and stirring for 2 hours. Reverse Heart = (003 ml) falling solution, the mixture was washed at room temperature with the organic extract ^ Et〇At, released 'with saturated NaCl water-g S 〇4 晛 water, filtered, cold shrink, after a sudden 221.2j. X297 ^^ ~ (Please read the precautions on the back before filling this page) The paper scale is applicable to Chinese family standards (413675 A7 B7 V. Description of the invention (219) Purification by column chromatography (0-5 ° / 〇E t OA e / hexane) to produce the desired product (〇 ′ 〇37 7g ′ 12%). Rf: 0 _ 2 1 (silica, 10% EtO Ac / hexane) ° * 0 COgl ·

0 COgH Step 2 Example 3 6 9 The same method as in Example 36, Step 10 was used to remove the protection of Step 1 2-(trimethylsilyl) ethanol ester intermediate. MP. 184. . . '' Example 370

CJ 0 co2tmse (Please read the notes on the back before filling out this page) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Step 1 Treat with sodium azide (0160 g, 25 mmol) with example Step 8 toluene A solution of sulfonate (0-5 g, 082 mmol) in dmf (3 ml). After being allowed to stand at room temperature for 24 hours, the vinegar was washed with acetamidine and water. The organic extract was dehydrated with M g S 04, quenched, concentrated, purified with M p ^ -10% EtOAc / Hexamine, *,. ^ Has been produced) to produce the desired azide (〇341 g, 86 .). Rf 0.22 (fascia, H)% EtOAc / hexane). α 0 co2tmse ο ======= b Paper size universal China -222-S) (2s〇X297 mm) Jihu)

CI A7 _B7 V. Description of the Invention (220) Solution. After heating to 70 ° C for 6 hours, the 'mixture was diluted with EtO Ac, washed with abalone and NaC1 aqueous solution' and dehydrated with MgS04. The obtained solution was concentrated and reduced in quantity, and 4 was dissolved in CH: C21. The mixture was treated with benzamidine gas (0.0 3 ml, 0.2 5 8 mmol) 'and stirred at room temperature for 24 hours. After the solution was concentrated, the resulting residue was purified by flash column chromatography (5-35% EtO Ac./hexane) to give the desired compound (0.025 g, 44%). Rf: 0.15 (silica, 30% EtOAc / 0 C0 2H 〇 Step Screw · 3 Example 37 ° method ^ 'Using the same method as in Example 16-7387 Step 3, remove Step 2 of 2- (Trimethylolamine Protection of ethanol-based intermediates. MP 204-206eC ° The following biphenyl-containing products (Table XXV) were prepared using the manufacturing method of Example 360-370 above. (Please read the precautions on the back before filling this page) ·- * Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs -m This paper size applies to Chinese national standards (CNS M4 specification (210X297 mm) 5. Description of the invention (221 Α7 Β7

Reward example 360 r14 ㈣ 物 mp (° C) /. Other characteristics racemic 361 362 〇 〇00 203-205 (+) (-) [a] 〇 + 48 (CHCI3) Brother 364365366367368369370370372372373374 Printed by Industrial and Consumer Cooperatives ο Racemic 213 CH2〇CH2 &lt; XH3 Racemic 89-90 CH2〇CH2Ph Racemic 157-158 CH2〇Ph Racemic 189-190 CH2〇2CPh Racemic 166- 167 ...--. 102-104 racemic 184 CH2NHCOPh racemic 204-206 CH2〇CH2〇 (CH2) 2〇Me racemic 107-108 CH2SCH2Ph racemic 145-146 CH2SPh racemic 173-175 CH2SCH2CH2CH3 Racemicity 163-165-224-This paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm) --------- True -------- Order ------ 'Λ W / (Please read the notes on the back before filling this page) 413675 V. Description of the invention (222, A7 B7 375 racemic 195-196 376 ZX) Racemic 146-147 377 〇CH jHH people. Racemic 136-137 378 0 CH, Racemic 152-154 379 〇 Racemic 150-151 380 VII. ~ Racemic 145 381 〇 OCH * C «l. Human nature 146 ~ 148 382 0 ow ^ Q-001, racemic nature 162-164 383 mediation (please read the precautions on the back before filling this page) Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 384 Racemicity 180-183 385 Now 5 Racemicity 203-204 386. Knowing 'Λ Racemicity 178-179 387 Racemicity 247-248 388 Racemicity 215-217 389 0 Racemate 19M92 〇225- The size of this paper is applicable to the specifications of Chinese Cabinet (CNS) A4 (210 X 2ί »7 mm) A7 B7 V. Description of the invention (223) 390 ° .ho, racemic

201-203 391 392 〇NHf Racemicity 257-258 220-223 (Please read the notes on the back before filling out this page) Example 393 Yushu Zhou 394: Order 0 ch3 ο Order of the Ministry of Economic Affairs Printed by Off-Working Consumer Cooperatives -226 This paper size applies to the Chinese National Standard (t; NS) A4 size (210 × 297 mm) A7 A7 Printed by Shellfish Consumer Cooperatives, Central Standards Bureau of the Ministry of Economic Affairs B7 V. Invention Description (224) Step 1 In a Rayonet apparatus, under argon, accept 120 ml of CH3CN solution containing maleic anhydride (3.99 g, 0.041 mmol) and vinyl acetate (6 ml, 0.065 mmol). Irradiate for 24 hours. The reaction mixture is concentrated and placed in a bulb still (K: uger hr) to remove residual maleic acid liver. The crude brown oil (2.0 3 g) was used in the next one without further purification. Step. 1Η N MR (CDC13) is shown as a mixture of cis and trans acetate (s, d 2.03 and 1.96 ppm).

r. ,, ',, 0, ch3 The method of step 2 of Example 393 and Example 394. Under argon, the anhydride (2.00 g '10.60 mmol) and 4-gas biphenyl (2.00 g, 10.69 mmol) were dissolved in 50 ml of CH 2 C 12. The solution was cooled in an ice bath. Add the whole amount of Sanqi Beiluo (4.03 g, 32.25 mmol) at one time to bring the reaction back to ambient temperature. After 1 hour, the reaction was stopped with ice-cold 10% HC1, and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic phases were washed with brine ', dried over MgS0 *, and concentrated. The crude product was crystallized using f: t 0 a c -hexane to produce Example 3 9 3 (93 5 mg) (decomposition of MP 202-204X). Another example of isomers is 3 9 4 (116 mg), and the filtrate uses E t OA c-227-this paper size applies to Chinese National Standard (CNS) »Maoge (21CX29: mm) -ni I- -----Soil water | --- w. F Please read the notes on the back before filling this page) Order A7 B7 V. Description of the invention (225) Alkanes are obtained by crystallization (MP 189-190 ° C).

0 CH3 Example 395 · 'Add DBU (0.15 mL, 1.003 mmol) to 5 mL of THF containing Example 393 (252 mg, 0.680 mmol) under argon, stir for 24 hours, and mix the reaction mixture with CH 2 C After the 12 dilution, it was washed with 10% HC 1 and brine, and dehydrated with M g S 0 4. Concentrated crude product using ε t Ο Ac-hexane pit yielded 1 17 mg Example 395 »MP 197-199. (: "(Decomposition)" Jing First, please read and read the legal matters of the back-sale and fill in this paper]] Printed by the Shell Consumer Cooperative of the Central Bureau of Economic Affairs, Ministry of Economic Affairs 〇

· ,,, ', 〇CH3 Example 396 The method of Example 3 95 was used to prepare Example 3 9 4 from Example 3 9 6 D Μ P 151-152.5 ° C ^ -228-This paper applies the national solid standard (CV) , S) Λ4 specification (21 × 97mm) MB7 V. Description of the invention (226)

HO

X OAc OAc

O H〇Jk ~ oo ~ r

O Example 397 Example 398 Example 3 9 7 and Example 3 9 8 are similar to Example 393 and Example 394, but step i is replaced with allyl acetate instead of vinyl acetate. The crude product is crystallized using Et O Ac-hexane as a solvent to produce an example. 3 9 7. Isomers Example 3 98 was isolated from the mother liquor via ΗPLC. --------- / --- (Please read the notes on the back before filling this page)

OAc

〇 Printed by Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs Example 3 9 9 Example 3 9 9

Clothing * J Policy Preparation Example 3 9 9. M S (FAB) M + -387 〇

• 229- The iron content of this paper applies the Chinese National Standard (CNS) A4 specification (210 · 〆297 mm) A7 B7 V. Description of the invention (227) Actual 洌 4 0 〇_ Manufactured from Example 395 using Example 398 Real 400

〇Example 4 0 1 j-Example 4 0 1 Use! ^ 匚 03-1 ^ 011 to remove the acetate of Example 39 9 and then use LiOH in ^^ 0 ^ 1-H20 to hydrolyze the methyl ester. End-former) to make this compound. Example 40 2

Printed by the Consumer Cooperative of the China Standards Bureau of the Ministry of Economic Affairs. Step 1 treats Example 401 with the concentration of propanol and catalyst 112504 to prepare this ester β 〇 0

AllylO

〇 Step 2 The phthalimide derivative is prepared from the product of Step 1 and the reagents commonly used in Step 9 of General Example 360. -230-This paper size applies to China National Standard (CNS) A4 (2i0X 297 mm)

V. Description of the invention (22S) 0 JL__

A7 B7 0

HyO 0 Example 4 0 2 Step 3 uses the method of Example 2 6 7 Step 4 to prepare Example 402 from the product of Step 2 〇 实 洌 4 0 3 --------- -o- ^ V〇H3C0— 《 —— 《》 OCH3 (Please read the notes on the back before filling out this page) The stamp of the employee consumer cooperative of the Central Sample Bureau of the Ministry of Economic Affairs Step 1 Add 1,4-dihydroxy-2-butene (10.00 in 30 minutes) Grams, 0. U mole) of 110 ml of anhydrous DMF to 170 ml of anhydrous DMF slurry containing 95% NaH (8.17 g, 0.3 4 mole). After the resulting mixture was stirred at room temperature for 2 hours, it was cooled to 0 ° C, and 170 ml of anhydrous DMF solution containing 4-methoxyfluorenyl gas (37.33 g, 0.24 mol) was added over 20 minutes, while intense gas appeared Release. The reaction mixture was stirred at 0 ° C for 15 minutes. After being stirred at room temperature for 30 minutes, it was cooled to 0 ° C. 100 ml of H2O was added dropwise to stop the reaction mixture. After vigorously stirring at room temperature for 15 minutes, the reaction mixture was stirred at 40 ° C. 0 mL of EtOAc was diluted. The aqueous layer was extracted with 2x400 mL of EtOAc. The combined organic layers were washed with NaC'n solution, dehydrated (Na2S04), and concentrated in vacuo. The crude product was purified by chromatography (11 cm x 6.5 cm silicone; hexane, then 20% EtOAc-hexane). , Yielding 34.94 grams (94%) of a colorless oil of olefin. T L C R f (30% E t O Ac -hexane) 0.4 7. -231-Paper size ii 4 Chinese National Standard (CNS) A4 specification (210X297 mm) --5 A7 B7 V. Description of the invention (229 h3c〇

In step 2, the olefin (5.00 g, 15 mmol) was taken up and dissolved in a mixture containing 225 ml of dioxin, 60 ml of gadolinium 2 and 15 ml of 2 N H 2 S 0 4. Tetraoxide moth was added and the solution was stirred for 10 minutes. Add NaI04 (13.00 g, 60 mmol) in small portions over 10 minutes. 15 ml of 2N H2S04 was added, and the mixture was stirred for 5 hours to form a white solid. To this slurry was added 250 milliliters 2 0 to obtain a clear solution, which was extracted with E 12 0 (6 × 250 ml). The organic layers were combined, washed with saturated NaCl solution, dehydrated (Na2S04), and concentrated in vacuo. The crude product was purified by chromatography (150 g of silica gel; 30 ° / ί »E t O Ac-hexane) to yield 4.69 g (8 5%) of a colorless oil. 1'1 ^ 11 {«(30〇 / 〇 £ [〇 知 —hexane) 0,25. 0.

(Please read the precautions on the back before filling this page). Packing. Order the H3CO printed by the Consumer Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs Step 3 Add nitromethane (5,53 g, 91 mmol) and ruler 〇1811 ((34g '3 millimole) to (at TC, a solution of a mixture of the aldehyde (5.44 g, 30 mmol) in freshly distilled TTH (65 ml) and anhydrous tBuOH (65 ml). The mixture is stirred. 4 hours, diluted with 200 ml of Et20, washed with 2 x 5 liters of NHjCl. The combined aqueous layers were combined with 100 ml of Et20 back to the extractor layer, washed with brine, dehydrated with Na 2 S 0 4 and emptied. Concentrated. The crude product of 4% alcohol was dissolved in 160 ml of freshly distilled c H 2CU and cooled to 0 ° C. Sulfur sulfonium gas (2.3 ml, 30 ml Mor) was added and stirred off-> 32. This paper size Applicable to Chinese national kneading tincture (CNS) A &lt; ^ specifications (210X297 mm) V. Description of the invention (230 A7 B7 6 minutes. Add fresh diethylamine (8.4 ml, 61 mmol), locust mix 1 5 Min. At 25 ° C, add 25 ml of run and n H 4 C solution to stop the reaction. The mixture was taken at 300 ml C 2 C 12 The organic layer was washed with 50 ml of a saturated ΝβΙΙ solution. The combined aqueous layer was extracted back with 100 ml of CH2C12. The combined organic layers were washed with a saturated NaCl solution, dried (Na2s04), and concentrated in vacuo. The crude product Purified by chromatography (150 g of silica gel; 20% EtOAc • hexane) to yield 5.56 g (82%) of nitroene, a colorless oil. Tlc (20% EtOAc-hexane) 0.36 .

f Please read the precautions on the back before filling in this page;--Install the central standardization bureau of the Ministry of Economic Affairs-Industrial and Consumer Cooperative Printing Step 4 to take a block containing propanol (3.14 g, 56 mmol), 1_ 澳 _4_ (4, _Gaphenyl) benzene (10.0 g, 37.3 mmol), bis (tribenzylphosphine) palladium (π) chloride (0.19 g, 0.3 mmol), triphenylsulfonium (0.3 7 g, 14 mmol) and cuprous iodide (0_37 g, i.9 mmol) of 1 500 ml of freshly distilled diethylamine i-quinate was heated at reflux temperature for 16 hours 5 Add further bis (diphenylphosphine) palladium (Π) gaseous (0'19 g, 0.3 mmol), tribenylphosphine (0 37 g, 1.4 mmol) and cuprous iodide (0.37 g) , 19 millimoles), the mixture was heated at reflux temperature for another 7 hours. The mixture was cooled to room temperature, filtered, and the filtrate was emptied and concentrated to concentrate the crude product, which was then chromatographed (丨 丨 cmχ 〖丨 cm silicone gel: CHzC! 2) and then Crystallization (from a mixture of EtOAc • hexane) yielded 7.32 g (80%) of benzyl alcohol as a yellow solid. TLC Rt (CH: el :) 48 sΗ300． * Λ-= /

-233 * Order A7 B7 V. Description of the invention (231) Step 5 Add 20 () milliliters of THF containing biphenyl alcohol (7.31 g, 30 mmol) to 95% NaH (0.72 g, 30 mmol) 50 ml of distilled THF slurry. After the mixture was stirred for 1 hour, it was cooled to -4Π. 5 of this nitroene (3-36 g, 15 mmol) was added dropwise over a period of minutes. The THF was saturated with THF. The mixture was brought back to 0- (: after addition, 100 ml of 1 NH c was added and reacted. The resulting mixture was extracted with 3 × 250 ml of E t OA c. The organic layers were combined, A 1: 1 mixture of a saturated NaHC0 3 solution and Η 2 〇 及 and Na 2 C 1 liquid washes and washed 'dehydrated (N a 2 S 〇 *)' and concentrated in 眞. The crude product was purified by chromatography. (150 grams of silicone; CH2C12; and 150 grams of silicon, 60% CH, C12_hexane), yielding 4_05 grams (58%) of Michael-adduct yellow oil. TLC Rf (80% CH2C12 · hexane) 0.36. (Please read the precautions on the back before filling this page)

CI, τ Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs Step 6 Add TM SCI (1,97 g, 18.0 mmol) with fresh steaming and freshly distilled £ 3N (1.83 g, 18.0 mmol) 10 ml of anhydrous methyl stupid slurry was added to a mixture of 14 ml of anhydrous toluene solution containing Mitchell adduct (2.8 1 g, 6.0 mmol), and after stirring for 1 hour, 15 ml of THF and 13 ml were added. 10% HC 丨. The mixture was stirred vigorously for 1.5 hours, and then extracted with Et OC (3 x 100 ml). The organic layers were combined, and the knees were washed with a saturated NaCl solution, dehydrated (NiS04), and concentrated in vacuo. The crude product was purified by decantation (100-234-paper size &amp; using China National Standard (CNS) A4 size (210X297 male cage) 413675 A7 B7) 5. Description of the invention (232) grams of silicone; 2% EtOAc- CH2Cl2), yielding 1,42 g (54%) of dihydrofuran as a yellow solid. TLC Rf (5% EtoAc-CH2Cl2). 0.46. H3CoiX0

{Please read the notes on the back before filling this page] Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 7. Add 15 mg of methyl lithium (2.6 ml, 3.7 millimeters) in 15 minutes. Moore) to 0 ° C in 15 ml of freshly distilled Et20 solution containing tetravinyltin (289 mg, 1.3 mmol). The mixture was stirred at 0 ° C for 15 minutes and then cooled to -78 ° C . Add the full amount of cuprous (228 mg, 2,5 mmol) in one portion. The mixture was allowed to rise to -30 ° C over 75 minutes and stirred at -30 ° C for 45 minutes. 24 ml of a freshly steamed Et: 0 solution containing dihydrofuran (390 mg '0.9 mmol) was added dropwise over 15 minutes, and the resulting mixture was stirred at -30 C for 45 minutes. Slowly add a mixture containing 10 ml of run and nh4C1 solution to 10 milliliter-liter H20, and keep the temperature below _2 5 ° C. At this time, the reaction mixture turns brown, and the mixture rises to 15 3C. Formula I is filtered. The ammonium salt was washed with 50 ml of acetone and 100 ml of EtOAc. The two filtrates were separated and the blue aqueous layer was washed with 100 ml of EtoAc. The organic layers were combined, washed with saturated NaCl solution, dehydrated (Na2s〇4) and emptied concentrated p. The NMR spectrum of the crude product showed that there were two isomers (trans-trans-235-Ningguan of paper size) Home Standard (CNS) A4 specification (2! 〇χχ 公, Γ order the consumer cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs Du Duanzhuang A7 _ _ _B7_____ V. Description of the invention (233) and trans-cis). Rough The mixture was purified by chromatography (15 g of silica gel; 3% EtOAc-CH2Cl2), yielding 222 mg of a yellow oil of ethylene tetrahydrofuran and 120 mg of a mixture of two vinyl tetrahydrofuran isomers. Oil (total yield 82%): major isomer TLC Rf (5% EtOAc-CH2Ci2) 0.49; minor isomer TLC Rf (5% EtOAe-CH: CU) 0,38. HO, Ο

Step 8 Add 0.S ml of Η20 and DDQ (643 mg, 2.8 mmol) to 16 ml of CHsC ^ 2 solution containing trans-trans-ethenyl isomers (874 mg, 1.9 mmol) . The mixture was stirred for 40 minutes. The precipitated solid was filtered, and washed with 150 ml of 0112 (: 丨 2. The filtrate was saturated with 50 ml] ^ 3 ^ {(: 03 solution, saturated Na C 1 solution, dehydrated (N a 2 S Ο 4) and Concentrated in vacuo. The crude mixture was chromatographed (30 g of silica gel: 10% £ 10 core- &lt; ^, &lt;: 12) to yield 534 mg (83%) of TLC EtOAe as a white solid with methylol analogues. -CH2CI2) 0.30 ^ -23fi-Standard for this paper (CNS) A4 size (210 X297 mm) —1 HI I _ _ _ D% (Please read the precautions on the back before filling this page) A7 A7

B7 V. Description of Invention (234)

CI Step 9 Add triphenylscale (324 mg, 1.24 mmol), 0 Dammine (182 mg, 1.24 mmol) and DEAD (215 mg, 1.24 mmol) to 0 ° C with Methylol analogues (303 mg, 0.88 mmol) in 18 ml of freshly distilled THF solution. The mixture was warmed to room temperature, stirred for 1 hour, and concentrated in vacuo. The crude mixture was purified by chromatography (50 g of silica gel, 2% EtO Ac-CH2C12), yielding 266 mg (64%) of a ¾ 醯 imine analog as a white solid. TLC Rf (50 /. EtOAc-CH2Cl2) 0.71. —I— I!--I--D. Shishui-—I {Please read the notes on the back before filling this page),-·

Employees ’cooperation cooperation of the Central Bureau of Standards, Ministry of Economic Affairs, printing step 10 Make 02 pass at -78 ° C, 5 ml of CH 2 C 12 containing phthalimide imide (2 62 mg, 0.5 5 mmol) In the solution for 15 minutes,-let ◦ 3 pass into the mixture until it turns gray-blue (5 minutes). Pass 02 again into the solution until the blue color disappears, then flush the mixture with Ar. Add triphenylphosphine (288 mg, [.10 millimoles), and bring the mixture back to room temperature. 'Limbi-2 :) 7- The paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X797 mm) V. Description of the invention (Ϊ35, A7 B7 overnight, crude compound was chromatographed (40 grams of silica gel; 2% E t 〇A c CH'l2 eluent), yielding 265 mg (1〇 〇0, 〇) aldehyde as a white solid. TLC Rf (5% EtO Ac-CH.Cl,) 0.35 c. 〇γΟΗ Ο

Step 11 Example 403 method. Add Strong's reagent to the bottom, in a 5 ml acetone solution containing the aldehyde (: 0 mg, 0. U mmol) until the dark yellow color persists. After the mixture was stirred for 5 minutes, 2 ml of isopropanol was added to stop the reaction. The resulting mixture was stirred at room temperature for 10 minutes and turned green, and then the crude mixture was concentrated and purified by chromatography (0 g of silica gel; 3% MeOH-0.5% AcOH-EtOAc was dissolved) to yield 44 mg (8 5% &gt; White solid of Example 403. mp ^ i 3-114ac, Example 404-(Please read the notes on the back before filling out this page) &quot; Printed by Zhengong Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs

Step Knee 1 Sequentially add a solution of tertiary butyl acetimidate tert-butyl ester (23.0 ml, 86.0 mmol) in cyclohexane (93 ml) solution BF3, Et: 0 (1.76 ml

I -238-Record ruler 丨 til Lingpi (CNS) A4 specification (M_B7_______ five 'invention description (236), 14.3 millimoles) to a solution containing 洌 267 in anhydrous THF (397 ml) . After the mixture was stirred at room temperature for 18 hours, NaHC0 3 (~ 5 g) was added to terminate the reaction. The obtained slurry was filtered, and the filtrate was concentrated under reduced pressure. The resulting crude solid was partitioned between CH2C12 (500 ml) and water (500 ml). The organic phase was washed with abalone and Na C 1 solution, dehydrated (M g S 0 4), and concentrated under reduced pressure. The resulting solid was recrystallized (EtOAc / hexane) to give a white solid (U.4 g, 5 1%) . TLC (2 5% EtOAc./hexane) Rf 0.73. (Please read the precautions on the reverse side before filling out this page)-Printing and printing by the Ministry of Economic Affairs, Bureau of Shellfish Consumer Cooperative, Step 2 Add 1 Μ N a 〇 Η solution (0.8 ml, 0.8 milliliter Mol) to a mixture of anhydrous EtOH (3.8 ml) containing the product of Step 1 (0.20 g, 0.38 mmol). The resulting slurry was stirred at room temperature for 6 hours and concentrated under reduced pressure. The resulting residue was partitioned between EtoAc (10 mL) and water (10 mL). The aqueous layer was acidified with 10% aqueous HC1 (10 mL) and extracted with Eto Ac (3 x 10 mL). The organic phase was washed with a saturated NaCI solution (10 mL), dehydrated (MgS04), and concentrated under reduced pressure to give a white solid (013 g, 6 20 / L &gt;). TLC (10% MeOH / CIt2Cl2) Rf 0.38.

Order

____-23 »-This' Recording Standard Sigma China Standard (CNS) A4 specification (210X297? ^ A7 4136 * 75 __B7 V. Description of the invention (237) Step 3 Add acetamidine solution containing diazomethane to In a solution of Et20 (50 ml) containing the product of step 2 (0.12 g '0.23 mmol) until the yellow color persists to 4 and then stop the reaction of excess diazomethane with glacial acetic acid (~ 5 ml) 3 Dilute with E t OA c (50 ml), wash the strips with water (50 ml) and abalone and Na C 1 solution (50 ml) 'dehydrate (μ g S Ο), and subtract to concentrate to produce the The yellow solid was purified by circular chromatography (Si 02, 0.5% Me 0.5 / CH2C 12) to give a colorless oil (0.10 g, 82%). TLC (50% EtOH / hexane) ) Rf 0.49.

Example 4 0 4 Step 4 Example 40 4 Production method "Take the solution containing the product of step 3 (0.1 1 g, 0.2 mmol) HC1-containing dioxolane (8.0 ml, 4M, 32 mmol) solution 'It was stirred at room temperature for 2 hours, then concentrated under reduced pressure, and the resulting residue was partitioned between EtOAc (100 mL) and water (100 mL). The organic phase was washed with a saturated NaCl solution (50 ml), dehydrated (MgS04), and concentrated under reduced pressure. The resulting half was purified using circular chromatography (si〇2, 0.5% MeOH / CH2C12). ) 'Produce a pale yellow solid (82 mg, 82%) HRMS C27H25Cm0 Calculated 値 (μ + + Η): 494 · 1370. Found 値 494.1365. Example 40 5 f &lt; X55Sitv ^ a) 2Bn χτ -240 -This paper scale system? ® Xiao Family &quot; ^ 5 · (CNS) A4 size Q10X297 male thin) (Please read the precautions on the back before filling out this page) '1Ί Printed by the Central Bureau of Standards, Ministry of Economic Affairs, Consumer Cooperatives

Central Ministry of Economic Affairs _ Printed by A7 B7, a responsible consumer cooperative --r-----------------V. Description of the invention (238) Step 1 Take the product containing 4-hydroxyphthalic acid (3.50 G, 19.2 mmoles) and K, CO3 (23.9 g, 173 mmoles) of acetone (100 ml) and water (50 ml) and stirred at room temperature for 15 minutes. Add fluorenyl bromide ( 2 0.6 ml, 173 mmol), and the mixture was heated at reflux for 3 days. The steam was evaporated in a vacuum (45-50 C / 1.1 mm) to remove residual radon, and the distillation residue was purified by gradient flash chromatography (1 〇 -30 «% ethyl acetate: hexane) to give 4-methyloxyphthalic acid dimethyl ester (7.20 g, 83%) as a pale yellow oil. TLC Rf 0.65 (25% ethyl acetate: hexane). XYTOlH-Step 2 Take 1 ^? (60 ml) containing the diester of step 1 (7.20 g, 15.5 mmol) and water (60 ml) containing LiOH'H20 (2.00 g, 47.7 mmol) in the chamber Mix for 4 days at room temperature. Remove the THF in vacuo and wash the basic layer with ether (twice). The solution is concentrated to ρ Η 3 with concentrated HC 1. The colorless precipitate is removed and dried in air to produce 4- Ethoxyphthalic acid (3,1 g, 73%) is a colorless solid. TLC Rf 0'15 (50% ethyl acetate: hexane). 0 Step 3 Add urea (1.32 g, 22 mmol) to the glacial acetic acid (3.00 g '1 1.0 mmol) containing the product of BSA 2 (3.00 g' 1 1.0 mmol). The solution was cooled to room temperature and slowly added to a dilute sodium bicarbonate solution. The resulting precipitate was collected, dissolved in acetone, filtered and air-dried to produce 4 _ benzyloxyphthalimide (1.9 8 g, 71%) as an off-white solid. Τιχ I 〇〇〇-241-This paper is in accordance with the China Garden Standard (CNS) A4 specification (210X2 ^^ y-— — (Please read the precautions on the back before filling this page) Pack 1 ^ 1 A7 A7 Printed by B7 of the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives V. Description of Invention (239) (50% ethyl acetate: hexane). 〇2tBu * &gt; ^ 〇) Dance step 4 Take a suspension of anhydrous THF (90 ml) containing NaH (1.69 g, 67.0 mmol) and cool to 0 ° C, and place it under argon for 10 minutes. Add di-tertiary butyl malonate (15.0 ml, 67 7 mmol) over time, then stir at room temperature for 20 minutes. Add 3,3-dimethylformate over 5 minutes Allyl A. (7.4 3 ml, 63. 6 mmol), stirred at room temperature for 18 hours. The reaction mixture was concentrated to a slurry and partitioned between ethyl acetate and water. Aqueous It was washed with ethyl acetate, and the combined organic extracts were washed with 10% HC 1 and brine, dehydrated with M g S 0 4, dried and rolled to a light colored oil (1 9.7 1 g, &gt; 100% Crude product>. The crude product was washed with 15 cm of silica, and washed with 30% ethyl acetate: hexane, and dried to give a yellow oil (19.37 g, &gt; 100%). TLC Rf 0.60 (20% ethyl acetate: hexane). CD2tBu m—f 002tBu Step 5 Take the solution of the crude olefin product (1 7.4 g, 6 1.2 mmol) from step 4 in a solution of methane (240 mm) and methanol (60 ml) and cool to -7 8 X, α Q 2 (g) washes for 10 minutes. O 3 (g) was passed into the solution for about 90 minutes until the blue color remained intact. Rinse the solution with 0 2 minutes, and with argon for about 20 minutes, until the solution is colorless again.-Add the entire amount of Na B Η 4 (2.31 g, 61.2 mmol), and stir the mixture overnight to make it rise again.到 室 -242- This paper is fine. Standards are in accordance with China National Standards (CNS) Α4 · (21 {) × 297 Public No. (Please read the precautions on the back before filling out this page) Installation, 1T A7 B7 V. Description of the invention (24o) temperature. The mixture was concentrated 'then diluted with two-gas solution, washed with water' 10% HC 1 (twice) and brine 'dehydrated with M§S04 and filtered and concentrated to a colorless oil (13.71 g, 86% crude Product) ° Take 400 grams of the crude material and purify it by gradient flash chromatography (15/15/7 0-2 5/2 5/50, ethyl acetate: dichloromethane: hexane) to produce 2-Colorless oil via ethyl malonate di-tert-butyl vinegar (2.g, 52¾). Ding 1 ^ ruler ('.25 (25% ethyl acetate: hexane). 〇〇〇〇2tflu 〇02tBu 〇 Step 6 Take the imine from step 3 (1.56 g, 6,15 mmol), snail 60 g of 2-hydroxyethyl malonic acid di-tertiary butyl U60 g, 6.15 mmoles and pph3 (1.6 1 g, 6.15 mmoles) were dissolved in anhydrous THF (1000 ml) , Diethyl azodicarboxylate (970 ml, 615 mmol) was added dropwise. The solution was stirred at room temperature under argon for 6 days' and then adsorbed on silica. Purified by flash chromatography (5/5 / 90-3 0/3 0/70 ethyl ethyl acetate: digas methane: hexane) to produce the recovered imine (1.03 g) and 2- (4 -narrow oxygen) Phthalideneimino) ethyl malonate di-tert-butyl ester (799 mg, 26%). TLC Rf 0.75 (1: 丨: 2 ethyl acetate: digas methyl alcohol: Jixuan ").

BnO

(Please read the precautions on the back before filling out this page) Packing. Order Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

OBn Step 7 Add anhydrous 24 containing malonate of Step 6 (2.33 g, 4.70 mmol); 1 This paper size is applicable to China National Bismuth Standard (CNS) A4 (210 X 297 mm) A7 413675 _ _ _ 5. Description of the invention (241) D 1 ^ (30 ml) solution to a THF (10 ml) suspension containing 1 '^^ (112 mg' 4.70 mmol) in argon, And stirred until a clear solution was maintained for Ih (20 minutes). The whole amount of "-bromoketone" (2.i8 g, 7.05 mmol) from Example 114 in Example 114 was added in one portion and stirred at room temperature for 2 days. The mixture was concentrated to a slurry and partitioned between methane and water. The organic layer was washed with saturated NH 4 C 1, water and brine, dehydrated with M g S 〇 4, filtered, and adsorbed on silica. Purified by flash, hard chromatography (12-20% ethyl acetate: hexane) Lake) 'yielded a disubstituted tertiary butyl malonate (730 mg, 21% &gt; colorless solid, and unreacted malonate (1.70 g) p TLC Rf 0.40 (25% Ethyl acetate: Hexane) (Please read the notes on the back before filling this page)

Printed by the Employees' Cooperative of the Central Government Bureau of the Ministry of Economic Affairs

Step 8: Treat a solution of dioxolane (7 ml) containing the diester of step 7 (84 mg, 0.11 mmol) with a solution of dioxolane (1-0 ml) in 4 M HC and heat under reflux. 10 hours. The mixture was concentrated to an oil. Purified by flash chromatography (0-5% methanol: digasmethane) to produce a solid containing trace impurities and purified by preparative H PLC (8% ethyl acetate: digasparin '〇 · 〇1 0 / 〇TFA) 'Produce Example 405 (32 mg, 49 0 / 〇) as an off-white solid iVi P 1 87-190 ° C i Using the method described above for Preparation Example 405', the following biphenyl products were prepared (Table XX VI). These imines are made from commercially available hydroxy acid products. 244- This paper size applies to Chinese national standard soap ΰ7 ^ *) M specification (21〇21mm) A7 B7 V. Description of the invention (242.

Table XXVI

406 407

R, S

R, S 79-81 93-95 (Please read the notes on the back before filling out this page) 上 4. Using the method of Example 4 0 5 Steps 6-8 to prepare the following examples from commercially available imine products (Table XX V11 ). Printed by the Central Bureau of Standards of the Ministry of Economic Affairs—Industrial and Consumer Cooperatives. 245. This paper is suitable for the National Standard (CNS) A4 (210X297 mm) A7 B7 V. Description of the invention (243.

Table XXVII 0 R * a

Isomers m.p.d) / Other properties Real M (Τ) χ 408 C1

R, S 409 Cl 410 Cl 411 Cl

R, S

R, S

R, S

241-242 (Resolve J 230 (Resolve) m-172 (Resolve) (Read the precautions on the back before filling in this page))

412 EtO

R, S 201-203 C) Order O 413 Cl 414a Cl 415a Cl

R, S

R, S

R, S 146-148

187-189 (decomposition J

190 (Decomposed by J Central Bureau of Standards, Ministry of Economy Printed by Shelley Consumer Cooperative 416a Cl 417® Cl 418b Cl

(CH,)

Br 〇

R, S

R, S

R, S 246-This paper size applies Chinese National Standard (CNS) A4 regulations (2i0X 297 mm 175 (decomposed, 153-157 214 · 215 (decomposed)) A7 —________ B7_ V. Description of the invention (244) ~~ a The imine 4 1 4 _ 4 1 7 is prepared according to the following method: a tertiary butyl g large acid rod (1.0 g '4 · 9 mmol) After heating with urea (0.60 g '10 .0 mmol) to Ϊ 5 05C 'to form a melt for 3 hours and cooling to room temperature, the crude solid was triturated twice with water and filtered. Gu Li was dissolved in acetic acid 'Dehydration with sodium sulfate and emptying of the solvent in the ethyl ester produced a colorless solid (0.83 g' 83%). Tix Rf 〇62 (25% EtOAc / 75% hexane). B Example 4 1 8 was prepared as follows Amine: A solution containing 4_bromo_, 8_flavonic acid (2'50 g'9,02 mmol) in NΝ4 0 (100 ml) was heated under reflux at 7 for 3 hours. The solution was cooled to room temperature, and a yellow-brown solid precipitated. The solid was filtered and washed with water. The crude product was recrystallized from Η Ν 03 (concentration) to produce 4-bromo-1 '8-stubble imine (2_20 g 89%) of colorless needles TLC Rf 0.2 5 (2 5% ethyl acetate: hexane) Example 419 Με0γ ^ γά) 2Η

MeO ^ X ^ Br Step 1 Using a dropping funnel, add a solution containing ruler | ^ 11〇4 (7 25 g 3 92 mmol) in water (100 ml) over 30 minutes to preheat to 7 〇, in a solution containing 6 * bromaldehyde (6 *: 00 g, 24.5 mmol) in dioxolane (i50 ml). After the addition was complete, the mixture was heated to 85 ° C for 40 minutes, and the resulting suspension was then treated with 15 ml of 1 M N a Η Η while passing through the hot salt, washed with 3 parts of hot water. When cooled to room temperature, ‘the unreacted starting material appeared in the filtrate’, the solid λ suspension was refrigerated for 16 hours in a refrigerator, and the Shendian was removed by filtration. The filtrate was acidified to pH 2 with 4M HC1, resulting in an off-white solid precipitate. Mixed -247-This paper ruler and applicable &quot;? National Standard (CNS) A4 specification (210X297 mmT ~ '' {碕 Notes on the back of the first leisure Jing, then write Fc

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the invention (245) The compound was extracted twice with methane. The organic layer was washed with brine, dehydrated with n a 2 S 0 4, filtered, and concentrated to an off-white solid (4.5 9 g, 72%. TLC Ι ^ -ό.40 (15% methanol: digas methane). 002Me

MeO 〆Br Step 2 Add a solution of K; jC03 (9.32 g '67.5 mmol) in water (25 ml) to acetone (50 ml) containing the acid of Step 1 (4.40 g' 16.9 mmol). ) Suspension * _ Stir in a liquid for 30 minutes ° Add iodomethane (4.20 ml, 67.5 mmol), stir the biphasic mixture vigorously, and heat at 7 5 SC for 16 hours. Add more iodine. (400 ml, 6 4 3 mmol), heat 4 small rides. The mixture was cooled to room temperature and concentrated in vacuo to give a pale yellow slurry, which was partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate, and the combined organic extracts were washed with brine, dried over Na 2 S ◦ 4, filtered and concentrated to a pale yellow solid (4.89 g, &gt; 100% crude product). This material was used without further purification.

Me〇 Into 〇 02Μβ Step 3 Add a stopper to the dried 3-neck round bottom flask, a condenser tightly connected to the stopper, and a three-way switch. Take the ester from step 2 (4.80 g, 17.4 mmol) and dissolve it in DMS 0 (35 mL), and add the following reactants in sequence: E13 Ν (7.30 mL '52.3 mmol), pd (OAc): ( 392 mg, 1.74 mmoles) '1,3-bis (diphenylphosphino) propane (〇ppp) (720 mg, 174 mmoles) and anhydrous methanol (〖06 ml, 2 6 2 mmoles Moore). Make a dioxin -248-This paper is standard (准) can ^ 1 () &gt; &lt; 297 male f—- (Please read the precautions on the back before filling this page} Packing. *-° A7 B7

V. Description of the invention (246) Carbonized gas was passed into the reaction mixture for 6 minutes, and then the flask was heated to 6 3-7 G C for 1 hour in the atmosphere of CO. Inflate the ball again and let ^ 〇 pass into the mixture for 5 days. The reaction is still incomplete. The mixture was poured into ethyl acetate (300 mL), washed with 10% HCI (twice), water and brine, dehydrated with Na 2 S 0 4 and filtered and concentrated to a green oil. Purification by flash chromatography (300/0 ethyl acetate: hexane) gave the starting material (1'09 g, 23%) as the 4,5-dimethoxyphthalic acid dif-ester (dioxine) ^ ... almost a colorless solid ^ D ... heart ^ ^ ethyl acetate: hexane) S ^, 002Me-OOiMe Step 4 Take 2 containing the diester of Step 3 (195g, 7 64 mmol) 0 ml of digas solution was cooled to-in a round bottom flask equipped with an air condenser. 1.0 M B B r; digas methane (306 ml) solution was added dropwise over a period of 10 minutes, and the acacia was stirred for 20 hours to bring it back to ambient temperature. The mixture was poured into .200 ml of ice water, and then extracted with methane gas. The aqueous layer was concentrated to about 60 milliliters, and dried in a cold beam to become tile-colored solid. The diacid intermediate was then heated in refluxing methanol (65 mL) and concentrated 2S 0 4 (0.1 mL) for 3 days, and then esterified again. The solvent was removed in vacuo, and the resulting yellow solid was dissolved in ethyl acetate, washed with water (twice) and brine ', dehydrated with H gSO 4, filtered, and concentrated to produce 4,5_ 2 times of oxanoic acid. Cool (172 g '99%) red oil that solidifies when left to stand. tlC Rf 0_75 (15% methanol: digas methane),

This paper standard uses China National Standards (CNS) M specifications (2 丨 0'〆297 public holidays; --------- installation ------ order ------ good, / λλ /% (Please read the notes on the back before filling in this text) Central Standards Bureau of the Ministry of Economic Affairs-Industrial and Consumer Cooperative Cooperative Printed by the Central Government Bureau of the Ministry of Economic Affairs and Industrial Cooperation Du Yin 31 A7 ______B7_______ 5. Description of the Invention (247) Step 5 Add CsF (5.78 g, 38.0 mmol) to a 0MF (6 mL) solution containing step 4 catechol (1.72 g, 7.60 mmol) to form a green 'suspension. Cool After reaching room temperature, add digas methyl pit (0.5 4 ml, 8, 36 mmol), and heat the mixture to 110-115 ° C for 90 minutes, the reaction is not complete: add digas methane (2 ml), heating was continued for 1 hour. The reaction mixture was partitioned between ether and water. The aqueous layer was washed with ether (2 times). The combined organic layers were washed with water (2 times) and brine, and μg S 0 4 Dehydration, filtration and concentration 'produce an orange oil of dimethyl 4,5-methylenedioxyphthalate (ι · 39 g, 77%), which solidifies upon standing. TLC Rf 0.75 (50% ethyl acetate: Hexane) = & gt ° ^ Χίί ^ σ〇2Η Bulu 6 溱 plus 15 ml of water containing LiOH * Η20 (3.0 g, 71.5 mmol) ▲ Liquid containing 5 vinegar (1.38 g, 5.80 mmol) Ear) in THF (30 ml), and stirred overnight. The mixture was concentrated, THF was removed, and diluted with water. The basic solution was washed with ethyl acetate 'acidified to pH 3 with concentrated HCI, cold; dried to give an orange solid. The solid was dissolved in methanol, acidified again with concentrated Hc, filtered, and the salt was removed. The filtrate was concentrated in vacuo. The weight of the crude material (58 g) showed that it still contained 4 salts, so the solid was dissolved in acetone and filtered 3 times. : Removal of the solvent yielded a pale orange solid of 4,5-methylenedioxyphthalic acid (2 38 g, &gt; 100/0). TLC Rf0 "0 (15% methanol: 85% digas fane). 1 0

The size of the clothing paper is applicable to the Chinese national rate (6 ^ 5) A4 specification (210X297 ^^ 7 --------- installation— (Read the notes on the back of the poem before filling in this page). Order ί%.-• ΤΓ

OH A7 B7 I, Ma Ming (248) Step 7 Dissolve the snail · 6 diacid (1.66 g, 5.90 mmol) in glacial acetic acid (16 ml), and add the whole amount of fruit (712 mg, 11.8 millimoles). Heat to reflux at 150 aC for 3 hours. The acetic acid was removed by emptying, and the residue was suspended in water. The solid was filtered and dried in vacuo to give 4,5-methylenedioxyg taurolimide (214 mg, 19%) as a yellow-brown solid. TLC Rf 0.5 5 (50% ethyl acetate: hexane).

0 &quot; Example 419 The method of making 8 examples 419. According to the method of steps 4 to 5 in Example 40.5, Example 4 19 was synthesized, MP 196-198 ° C. Example 420 Step 1 Take a suspension of dioxin (4 ml) containing 10% Pd / C (40 mg, 20% w / w), rinse with Η 2 (g) for 4 5 minutes, and then add the Example 405 A suspension of 5 dioxin (7 ml) solution of the diester (200 mg, millimolar) in step 7 of 5 was stirred at room temperature and 112 ° C for 3 days. The mixture was filtered through Celite 'and washed with ethyl acetate, and the filtrate was adsorbed on silica. Purification by flash chromatography (1: 1: 3 ethyl acetate: digas methane: hexane) gave a colorless solid that replaced the di-tertiary butyl malonate (168 mg, 94%). 251-The paper size is suitable for financial affairs (n,! S)-· ^ (210Χ-297 ^ · --------- 1 ------ IT ------ 't {{(Please read the notes on the back before filling out this page) Printed by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 413675 A7 B7 V. Description of the invention (249) TLC Rf 0.30 (1: 1: 3 ethyl acetate: 2 Gas fane: hexane &gt;

OH Step 2 Example 420. Example 420 was prepared from the product of step 1 above according to the method of step 405, step 8 '. \ ^ 211-215. (:(break down).

(Please read the Cautions on the back #Fill this page first) Binding Printed by the Central Bureau of Standards, Ministry of Economic Affairs, Consumption Cooperation, Du Printed Example 421 According to the method of Example 420, Example 42 1 was prepared. MP 201 ° C (decomposition) Example 422

OMe Step 1 Take an acetone (10 mL) solution containing the alcohol (94 mg, 0.15 mmol) from Step 420 in Example 420 and CS 2 C Ο 3 (145 mg, 0.4 4 mmol). After 30 minutes, it was treated with methyl iodide (5 mL, 4.0 mmol). ：: Kunhe 252-Use the tD Standards (CNS) μ specifications; 210X297 mm &gt; A7 B7 Printed by the Central Ministry of Economics, Ministry of Economics and Labor Consumer Cooperatives to the fullest paper scale. 5. Description of the Invention (25〇) The mixture was heated to 40 ° ci for 0 minutes, at which time the mixture was changed from bright yellow to colorless D. The mixture was concentrated and partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate and bismuth, and the combined organic extracts were washed with brine ', dehydrated with Mgs0 ··, concentrated under reduced pressure, and evaporated to give the desired product (86 mg' 90%) as a pale yellow solid ^ TLC Rf 0.60 ( 40% ethyl acetate: hexane).

OMβ The method for preparing Example 422 in Step 2 according to the method for preparing Step 8 in Example 405, and preparing Example 422 from the product in Step 1. MP 63-67 '.

— Example 4 2 3 Example 4 2 3 According to the manufacturing method of Example 4 2 2, Example 4 2 3, MP 1 86-19 (TC Example 42 4

The paper size ii Choi Chuan Zhuan i CNS) 2ΙΟχ 297 ^ F) ---------- button clothes ------ iT _------ 1 / ir. ((Please read first (Notes on the back page are refilled on page 44) A7 B7

OAc Ministry of Economic Affairs_Consumption Cooperation by the Employees of the Zhunzhan Bureau Du Yin 5.Invention (251) Step 1 Add the alcohol containing 420 (100 mg, millimolar) and triethylamine (65 μl, 0.47 Mol) to digas methane (1 () ml), but to 03C. Add 2-pyridinecarbonyl gas (33 μl, 0.32 mmol) and stir the mixture for 10 minutes. The solvent was emptied and the residue was dissolved in Et O A c, washed with water, and dehydrated with sodium sulfate. The solution was filtered, and the solvent was evaporated to produce a colorless powder (0.013 g, 90%). TLC Rf 0.90 5% EtOAc / 85% hexane).

Step 2 example 424 method. Example 424 was prepared from the step silver 1 product according to the method of Example 40 5 step 8. MP 181-182 ° C. Example 42 5: Step 1 treating a solution of pyridine (3 ml) containing the alcohol of Example 42 (50 mg, 0.08 mmol) with acetic anhydride (15 ml, 0.1 mmol), Stir at room temperature under air for 3 days. Add acetic anhydride (100 ml, 1.0 mmol), and stir at room temperature for 2 hours. The reaction was partitioned between water and methane gas, and the aqueous phase was washed twice with methane gas. The combined organic layers were water and saturated CuS 〇4 殳 brine -254-this paper is a common Chinese national standard i CNS) Μ Specifications (2 丨 0X 9? Mm) IM ^ u It κ ί--丁 ^ 、 言 n (Please read the precautions on the back before filling this page)

A7 B7 ___ V. Description of the invention (252) The strips were washed sequentially, dehydrated with M g S 〇 4, filtered ’and adsorbed on the crushed stone. Purification by flash chromatography (40% ethyl acetate: prostitute *) 'yielded acetate (30 mg, 57%) as a colorless solid. τ l C R 0. 5 5 (1: 1: 3 ethyl acetate: two gases methyl alcohol: hexane) °

Step 2 Example 4 2 5 method. Example 425 was prepared from the product of Step 1 above according to the method of Step 8 in Example 405. MP 176-178 ° C '. Example 426

CI Step 1 Add sodium iodide (1.5 g, 10 mmol) to Ar, containing 1- (2-bromoethyl ketone) -4- (4-nitrobenzyl) benzene (Example 1 14 Steps 2, 3, 09 grams, 10 millimoles) in DME (27 ml), the solution was stirred for 15 minutes. "In another flask, add tetrahydro-2-oxo-3 -furancarboxylic acid ethyl ester (2.1 grams, 1 1 mmol) into DME (10 ml) containing NaOEt (0 &quot; 75 g, 11 mmol) and mix for 15 minutes. This solution was added to the sodium hydroxide solution via a cannula, and the combined mixture was stirred at room temperature for 18 hours. The solvent was emptied and the residue was dissolved in dichloromethane (200 ml) and washed with two 2000 ml portions of water. The digas methane solution is dehydrated with M g S 〇4, filtered, and the solvent is emptied to produce a crude solid product. The residue is recrystallized from ethyl acetate / hexane to produce an alkylated malonate. 255- This paper size applies Chinese National Standard (CNS) A4 Regulation. Grid (: 10X2975 ^ 51 (Please read the precautions on the back before filling out this page)-丨 installed. Order 1 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 A7

B7 V. Description of the invention (253) (3.2 g, 760 / 〇). TLC R (0.50 (40% EtOAc / 60 ... hexane)

Ov 〇 &gt; -〇 Step 骧 2 The suspension of glacial acetic acid (180 ml) and concentrated HC 丨 (90 ml) containing step 1 ethoxybiphenyllactone (11.0 g, 28 mmol) was heated to reflux, At this point the starting material was dissolved and C02 was released. After 4 hours, the reaction was cooled to room temperature and the solvent was removed by emptying. The solid residue was dissolved in E.t O A c, and the washing was repeated with Na 2 H C 0 3. The organic layer was washed with brine, dehydrated with Na S 0 4 and the solvent was removed. The residue was recrystallized from EtOAc / hexane to give a yellow lactone (7.S g, 88%). Thing. MP 129-130 ° C. (Please read the notes on the back before filling this page)

0

Step 3 Example 426. Sodium hydride (97%, 0.027 g, 3 mmol) was suspended in DM F (15 ml) and cooled to 0 ° C. Stupid mercaptan (0.29 ml, 2.86 mmol) was added dropwise and gas evolved. Stir for 10 minutes at (TC) and allow the reaction to warm to room temperature. Add the lactone from step 2 (1.0 g, 3.18 mmol) in portions and slowly heat the reaction to 1000 ° C. Solution It turned dark green. After 3 hours, TLC showed a new dissolution point and no more lactone was consumed after heating. After the reaction was warmed to room temperature, 10% HC1 (10 ml) was added to stop the reaction. The reaction was diluted with water and extracted with Eto Ac. The combined E t 〇 A c layers were washed with water and brine; the strips were dehydrated with NT a 2 S 〇 4 ° The solvent was removed and the residue was purified by MPLC (90% EtOAd hexane) After that, self-heating CHClj, H-256-Too large paper size applies to Chinese national standards (CNS: A4 size (210X297 mm) i. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. Recrystallize. Filter the solid to give the desired product (0.50 g, 37'0) as yellow-brown needles. MP 179-18 Can C »

ΟΜθ Example 427 In the same manner as in Example 426, step 3 was carried out using an appropriate mercaptan product to prepare Example 427, MPBδ-ΜΟί.

(Please read the precautions on the reverse side before filling out this page) Shiyi.-Order Example 42 8 Example 428: Make 含 42 6 (0.05 g, 0.11 mmol) with &lt;: ^ 12 &lt;: 12 ( 30 ml) of the solution was cooled to -7 8 t. Add the entire amount of m-C PB Α (0.036 g) at a time, 0.17 millimoles (calculated as m-CPBA with a purity of 85%). The reaction was allowed to rise to -3 ° C. After the reaction was stirred at -3 ° C for 2 hours, the solvent was emptied and the residue was triturated in EtOAc, dissolved in benzoic acid and the remaining m-CPBA. The insoluble product was recovered by filtration and dried in air to give a white powder of the desired product. MP 208Ό (decomposed). -257 This paper size applies to Chinese National Standard (CNS) A4 (210 X297 mm)-Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 __B7 V. Description of the Invention (255)

Example 4 2 9 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs --------- Λ ------ &quot; (Please read the precautions on the back before filling this page) Adding condensation A round bottom flask of the device was charged with anhydrous ethanol (50 ml) containing 2,3-trisuccinamine (IQ g '5.1 mmol). The mixture was gently refluxed (78 C) until most of the solids dissolved into the soil. Decant the hot ethanol solution from any dissolved solids into a conical flask containing a solution of potassium hydroxide (0.27 g, 5./ml) in water (0.27 ml>) and absolute ethanol (0.80 ml). Immediately A white precipitate formed. The mixture was stirred and quickly cooled to room temperature. The air was passed over to produce a white solid of 2,3-mosa-dicarboxyamido potassium (0.88 g, 73%). The product was used directly in the next one without analysis. Step. In a round bottom flask equipped with a condenser, add a solution of potassium 2,3-dicarbamidineimide (0.47 g, 2.0 mmol) in anhydrous DMF (1.0 ml). The solution was heated to reflux (150 aC). ). Anhydrous DMF (1.0 ml) containing the lactone (0.34 g, 1 _0 mmol) of step 2 of solid 426 was added. The mixture was heated (15 (TC)) for 18 hours and then cooled to room temperature.排除. Empty the solvent and partition the residue between ethyl acetate (50 mL) and 1 M H Cl (10 mL). Separate the layers, wash the organic phase with water (25 mL), dehydrate (MgS04), and empty. Removal of the solvent resulted in a brown oil in which an excess of potassium 2,3-dicarbamidineimine was recrystallized from hexane-ethyl acetate. The liquid was concentrated, and the resulting orange solid was purified on a silica gel column using 7.5% methanol-digasmethane as an eluent to produce a white solid of Example 4 2 9 (1 3 mg, 3%): MP 1 9 3-1 9 4 ^ -25S-Chinese paper standard (CNS) (210X297) is applicable to this paper. A7 B7 V. Description of the invention (256) Biological test method and in vitro test evidence Gelatinase · B (9 2 k D a, P -9) system improved Hibbs and others (J. B 丨 〇 丨 .ch «ί m .. 260. 2493-2 500, 1 984) and Wilhelm (Z. Biol. Chem., 264, 17213-1722 1 '1989) The method has been explained separately from mmP-9. In short, printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling out (This page) In accordance with the above, polymorphonuclear nucleus was isolated from 3 or more units of blood freshly drawn from the New York Blood Center (N ew Y t &gt; rk B 1 ο 〇d C en Ur, N. Y., NY.) White blood cell (PMN) specimens. Cells were resuspended at 37 ° C in 100 ng / ml Euphorbic Diterpenol Myristic Acid Acetate (ρ Μ A) at 50 mM fluoride. S diisopropyl purpose (the DFP), 1 g / ml and anti-protein fermentation ieUpeptin thinking too, phosphate and 1 mg / ml of catalase buffered saline (p B S) for 1 hour. The supernatant was collected by centrifugation (300 × g), and the samples were frozen at _70 ° C. All chromatography was performed at 4 aC. The thawed samples were concentrated 5 times in an 80 ^ 11 tank with a γ μ-10 membrane. Concentrate relative to 〇21 ^ 丁 1 ^ -1 ^ 1, 〇1 \ 1 NaCl, 1 mM CaCl2, 1 &quot; M ZnCl2, 〇〇〇〇1, 〇Brij -3 5, 0.02% azide Sodium chloride (N a N 3), ρ Η 7 · 5 under pressure and dialyzed at a flow rate of 0.4 ml / min to a DEAE ion exchange chromatography resin which has been equilibrated with the same buffer. 'Wash the column thoroughly with the same buffer, # 〇.〇2MTris-HC1, O.JM NaCl, imM CaCl !, 1 μM ZnCl2? 0.001% Brij-3 5' 0.02% NaN3, pH 7.5 dissolve from the column Dissolve 4 ml of gelatinase dissociation. A gelatinase-containing dissociation fraction was observed by gelatin zymography (see below), added to gelatin agarose affinity resin, and washed with the same buffer. 0.0 2 Μ Tris-HC ί, 1 mM NaCl, ImM CaCl2, 1 μ ZnCl ;, 0.001% Brij-35, -25 ί) containing 10% dimethylarsine (DMS Ο)-applicable to China National Standards (CNS) (2ί297 × 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (257)

0 '0 2% N a N 3, p Η 7.5' Divided into 1 ml according to the flow rate of 1 ml min; ^ § · Leaves' Dissolves gelatinase activity from the column η Collects gelatin-containing soluble fractions 'Compared to 0.0 0 Μ Tns-HU, 5 mM NaCMU 111 \ 1 (11; 1 (1'12, 〇.1 &quot;? ^ 211 (^ 12,0'〇〇104〇314 314-35') 117.4 Remote analysis. The protein content of the substance was determined by micro-BCA analysis (Pierce, Rockfords π), freeze-dried, and reconstituted to the required operating concentration (100 μg ml).丨 〇 口 6 口 “1 丨 (^)! ^ \ 1? -9 Inhibition analysis method: Isolated human gelatin zymogen (10 μg / ml) (as above) from human PMNs, containing 1 mM 4 -Aminophenylacetic acid multiplied by 50 mM Tris-HCl, 200 mM NaCl. 5 mM CaCl2, 0.001% Brij-35, pH 7.6, and activated at 37 sc for 16 hours. The activated enzymes are relative to the above buffer Agent to remove APMA. Modified thiopeptolide spectrophotometry (η. Weingarten, J. Fedor, Anal. Biochem., 147.437-440 &gt; 1985) With 隞 analysis mode. The activity of M NP-9 Spectrophotometric analysis requires the activation of NM P-9 (10 nanograms, 0 1 4 ηM) in HEPES containing 50 mM 4- (2-hydroxyethyl) -1-hexagonal sulfonic acid (HEPES) ), 0 · 15MNaCl, 10mMCaClh0 · 001., OBrij-3 5, pH 6.5 diluted 1000 times in the analysis buffer, enzyme analysis method diluted 100 to 1000 times, the reaction mixture used for inhibitor test contains 1111] \ 4 八 (;-.? 1'〇-1 ^ 11-Gly-S-Leu-Leu-Gly-o-ethylthiophthalein substrate with 0,5 ηΜ 5,5'-disulfide-bis- ( Nitrobenzoic acid), drugs and activating enzymes in the range of 0.5 11M to 5 &quot; M (0 ~ 1 0 0 nanograms) are dissolved in HEPES analysis buffer ρ Η 6.5, the total volume is 1 3 0 micro Liters, using an automated analysis plate reader (Molecular Devices, Menlo Park, CA), stepping on the substrate at 405 nm -260- This paper size is applicable to China National Standard (CNS_) A4 (2IOX2 ~ 7 public director) ( Please read the precautions on the back before filling out this page) * Clothing · Order A7 __________B7_ V. Hydrolysis of the description of the invention (258). Subtract the number of samples from the control group cultured without enzymes by adjusting the number of enzymes-mediated hydrolysis to correct the quality of non-enzyme hydrolysis. The drug efficiency is expressed by the general ratio of the enzyme activity calculated by the following formula: (the number of control groups 値 the number of treatment groups /) / the number of control groups 〇 X 1 〇0 active compounds with 30% or more inhibition of enzyme activity— Steps were tested at different concentrations (0.5 ηM-5 γM), and linear retrace analysis was performed on the logarithm of drug agronomy from the percentage of inhibitory effect to obtain IC5.采 *. Use two-way analysis of variance to determine the significance between experimental groups = &gt; 'Performance of recombinant truncated stromelysin (MMP-3) purification: Imahi (Mar cy) et al., Biochemistry, 30. 6476-6483, 1991, showed a soluble truncated matrix lysogen · 257 in E. coli (£. coli). Improved affinity antibody chromatography of monoclonal antibodies described in Hous 丨 ey et al., J. Biol. Chem., 268., 448 1-87, i993 to purify soluble truncated matrix lysogens . Primary Thiopeptide MMP-3 Inhibition Analysis Method: Printed by the Machining Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs -------- Shiyi -------- Order (Please read the precautions on the back before filling This page) Enzymes: Recombinant stromalysins are expressed and purified in E. coli as described above. The truncated base-plasmin is activated by heating as described in Kokalitis et al. 'Biochem. J., 216; 2 17-22 1,1991. The analysis of the compound as a matrix lysin inhibitor is the same as that of MMP-9 ', but the analysis buffer was changed to 50 mM MES, ptl containing 150 mM NaCl, 10 mM CaCl :, 0.005% Brij, and 1% DMSO. 6.5. Enzyme concentration was 13 nM matrix lysin. The substrate concentration is 6 5 S &quot; Μ, and our drug concentration is in line with MMP -9 points-ΊΜ-winter paper scale applicable to China National Standard (CNS) A4 specification (2 ω'X 297 mm) Central Ministry of Economic Affairs Standards Bureau employee consumer cooperative seal A7 B7 V. Description of invention (259) The analysis method is the same. Secondary P 2 1 8 extinction fluorescence splitting of MM P-3 inhibition: t This method is derived from Knight et al. 'FliBS Lett.ers, 296 263-2 66, 1992 as the relevant substrate The method described in this analysis was performed in a 3.0 ml photometric tube using a Perk in-Elmer LS 50 B camping spectrometer at 25aC and a continuous measurement at a concentration of 2.0 ml. P2 1 8 substrate (10 mM) in 100% DMSO in analysis buffer: containing 150 μM NaCl, 10 mM CaCl2, 0.00 5% Brij-35 and 1% (ν / ν). DMSO 50 mM MES 'pH 6.5 was diluted to a final concentration of 2 · 0 / ίΜ The test compound (10 m Μ) contained in DMSO was diluted to an initial concentration of 10 to 100 &quot; Μ in analysis buffer. Finally, the final concentration in the analytical method was diluted to 100 nM to 1 pM according to the previously measured efficacy in the primary Swiss-style analysis. Recombinant stromalysin (MM P-3) was added to start the reaction to a final concentration of 1.0 iiM. When the peptide is cleaved, the fluorescent A MC group is detected using an excitation wavelength of 3 2 8 nm and an emission wavelength of 393 nm. This analysis method is linear at 0.2 to 5 η M MMP-3 concentration, and the inhibition percentage is calculated according to the above-mentioned primary thiopeptide analysis method, and a linear and regression analysis is performed from the inhibition percentage to the logarithm of the drug concentration to determine the IC 5 値. The peptide sequence of MC A substrate (hereinafter referred to as p 2 1 8) is as follows: MC A-Pro-Lys-Pro-Leu-Ala-Leu-DPA-Ala-Arg-NH2 P218 at P Ρ 6.5, MMP- 3 The Km of the mass is 1 6 a iM! cc a t, km 56, is 56,500. MMP-2 inhibitory secondary p2 丨 8 extinction fluorescence analysis method: -262-This paper from Xincai HS! Jiaxian (CNS) A4 specification (21 (TX29 · 7 (, Ϊ1 '(Please read the note on the back first) Please fill in this page again. 4. Order A7 B7 V. Description of the invention (26〇) According to R. Fridnian 莘 人, J contender, J. Biol. Chem., 267, 1_398 (1992)- (Method, using Yangpu Form 2; &gt; Ground

-卞〗 Anti-field performance system to prepare gelatinase A (MMP-2). In accordance with the above μ μ P-3 &gt; Shi-Ye. ^ 3 million method 'using the final concentration of 〇 2 η enzyme and P 2! 8 substrate to perform the inhibition analysis of Μ ρ _ 2 in this analysis method' The conversion number of MMP-2 is Toka. In these experiments, the initial rate (nM / s) never exceeded 5% of the total substrate c. Leucinase inhibition 1 All I c 5 were expressed as n M. When &quot; I = X% ", X represents the inhibitory effect at 5 A Μ / 〇. When" χ (η) "appears, X is the IC 5 measured separately η times. 値 a (please first Read the notes on the back and fill out this page)-· Order the Central Ministry of Economic Affairs to print rewards for employee consumer cooperatives #

MMP-3 Although! C5〇 MMP-3 Fluorescent substance icso MMP-9: IC50 MMP-2 Light emitting substance IC50

-2Μ-

• II II) A4 size (210X297 mm) printed on paper and printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 19 550 1,200 20 I = 32% I = 34% 21 750 1,200 22 790 1,200 23 I = 24% 1 = 0% 24 I = 40% 1 = 0% 25 950 I = 43% 26 620 240 4,300 27 I = 11% I = 15% 28 I = 14% 1 = 0% 29 I = 28% I = 44% 30 1 = 8% I = 25% 31 I = 56% I = 29% 32 I = 58% 6,000 33 2,600 2,400 34 5,000 35 I-0% 36 1 = 0% 1 = 0% 37 1 = 9% 1 = 0% 38 10,000 I = 10% 39 I = 16% 1 = 4% 40 121 (4) 50 41 118 (3) 260 500 42 48 21 43 44 1,970 1,150 45 1 = 43% I = 56% 46 700 4,000 47 560 I = 22% 48 I = 53% I = 15% 49 750 1 = 13% 50 630 800 51 170 100 52 76 (2) 37 53 950 800 54 190 700 55 170 110 56 310 700 57 I = 16% 1 = 22 % 58 1,200 1,500 59 I = 33% 2,000 60 600 180 61 I = 35% I = 22% 62 400 4,500 63 980 500 This paper is applicable to national standards (CNS) Α44 grid (210 × 297 mm) 413675 A7 B7 V. Invention Description (2έ1) __- ------- A ------- Order / ί (please read the notes on the back before filling in this education) A7 B7 V. Description of Invention (262) Staff Consumer Cooperation of Central Standards Bureau, Ministry of Economic Affairs Printed 64 300 I ^ 29% J 65 840 I = 47% 66 1 = 7% I = 11% 67 150 780 68 280 300 73 220 600 74 2,300 I = 38% 75 78 82⑵ 76 1,000 1,800 77 I = 24% 1 = 7% 78 310 1,200 79 I = 12% 1 = 9% 80 470 800 81 1 = 30% 1 = 12% 82 I = 23% 1 = 9% 83 720 1,4〇84 150 100 (2) 85 37 I = 44% (3) 88 168⑷ I = 30% 89 111⑷ 480 90 I = 36% 1 = Π% 91 174 700 92 I = 60% I = 26% 114 244 (11) 120 (3) 285 ( 2) 25 (2) 115 I = 39% I = 31% 116 145⑷ 80 (2) 190 28 (2) 117 590 3,800 118 440 2,200 119 760 1,800 120 380 I = 60% 121 1,000 I = 45% 122 403 ( 2) 123 ~ I = 43% 124 180⑵ I = 28% 125 105 (2) 1,800 126 600⑵ 130 230 1,200 2,900 131 310⑵ 900 132 112 (4) 2,600 (2) 133 640 10,000 135 2,800 ⑵ 2,800 136 1,600 I = 50 % (2) 142 310 (2) 178 150 240 179 160 (2) 200 Use the Chinese standard (CNS) A4 size (210X297 mm) as far as the paper scale is concerned (please read the precautions on the back before filling this page) Order 5. Description of the invention (263 ) Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 180 270 360 181 330 290 182 1 = 7% I = 17% 183 270 710 184 280 I = 41% 185 220 1 = 31% 186 170 383⑶ 187 757 1,500 188 151 1,300 189 530 600 190 227 215 (2) 191 330 I = 62% 192 140 510 193 153 (3) 150⑵ 2,450 ⑵ 40⑵ 194 115⑵ 62 750 195 1 = 31% I = 20% 196 236 (12) 180⑵ 438 (5) 20 (2) 197 117 (2) 92 197 (3) 26 (2) 198 I = 23% I = 21% 199 170 200 200 640 2,300 201 340 800 202 250 500 203 247 (3) 1,200 204 213 (3) 215 (2) 205 87 (3) 170 206 950 (2) 417 (3) 207 180⑵ 290 (3) 208 140 (2) 1,050 ⑵ 209 340 390 (2) 210 500 205 (2) 211 440 280 212 650 390⑵ 213 2 ^ 00 I = 41% 214 170 2,200 215 U00 1,200 216 770 590 217 83 245 (2) 218 170 435 (2) 219 260 600 220 190 950 221 240 2,400 222 610 1,800 223 930 580 224 680 550 * 266- This paper uses China National Standard (CNS) A4 format (2 [0XU 了 公 t) (Please (Please read the notes on the back before filling this page) 4 Order 413675 A7 B7 V. Description of the invention (264) Printed by the Consumers' Cooperative of the China Standards Bureau of the Ministry of Economic Affairs 225 310 550 226 720 255 (2) 227 220 360 (2) 228 360 800 229 300 900 * 230 250 550 231 280 820 232 150 200 (2) 233 339 (2) 4,8〇234 144 (2) 600 235 1,600 236 2,000 237 2,000 238 920 239 490 I = 53% 240 96 (2) 300 (2) 241 195 (2) 340 (2) 242 490 1,300 243 360 850 244 79 (4) 27 (1) 600 7 (1) 245 1 = 55% 246 I = 14% 247 1 = 17 % 248 830 249 1,600 250 125 (2) 800 251 640 (3) 7,500 252 293 (3) 2,900 253 1 = 0% I = 21% 254 I = 10% I = 27% 255 950 2,000 256 600 3,000 257 800 2,100 258 820 2,100 259 2,600 I = 37% 260 520 I = 16% 261 900 I = 20% 262 95⑵ 76 263 I = 33% I = 21% 264 I = 48% I = 31% 265 2,900 I = 42% 266 250 650 267 38 (3) 1.8 (2) 282 1 = 2% 1 = 0% 233 2,400 7,000- (Please read the notes on the back before filling this page), * this

'1T This paper size applies Chinese National Standard (CNS) A4 specification (2j0X 297 mm) 4136V. A7 B7 V. Description of the invention (265) Printed by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 284 1 = 10% 1 = 1% 285 2 ^ 00 I = 21% 286 I = 19% 1 = 0% 287 I = 26% 1 = 3% 288 I = 40% I = 46% 289 348 (4) 910 (2) 290 I = 35% I = 15% 291 437 (3) 2, 70 (3) 292 I = 21% I = 12% 293 I = 16% 1 = 0% 294 47 (8) 14⑷ 56 (5) 4 (2 ) 295 99 600 296 26 (10) 12 (2) 25 (4) 297 640 (3) 298 50 850 302-303 310 1,400 304 55 42 (2) 305 470 1,800 306 150 550 307 33 108 (2) 308 309 73 62⑵ 310 80 32⑵ 311 340 700 315 36⑷ 316 66 (4) 323 98 (2) 326 140 (2) 327 I = 55% '12,000 328 I = 49% I = 45% 329 I = 58% 8,000 330- 1 = 9% I = 16% 331 I = 15% I = 18% 332 I = 37% I = 41% 333 I = 62% (2) I = 25% 334 I = 42% 6,000 335 I = 55% 6,000 336 1,400 600 337 I = 20% 1 = 2% 338 I = 24% I = 32% 339 1,700 1,500 340 1 = 14% I = 21% 341 2,400 3,800 342 360 700 This Weilang scale is applicable to China's national standard (CNS) Μ specification (2! Ϋ́ × 21 ·, 7 mm) (谙 Please read the precautions on the back before filling out this page) Pack- • 1T Fine A7 B7 343 500 680 344 I = 11% I = 14% 345 5,000 I = 30% 346 6,000 1 = 34% 347 I = 12% 1 = 0% 34S I = 31% I = 36% 349 550 &quot; 330 350 1 = 4% 1 = 20% automated M P P-shaped analysis This analysis method is similar to the process of M P 3 inhibition, using synthetic p 2 2 8 and each of the two enzymes, and Measure the extinction fluorescence. Each of the compounds of the present invention and three enzymes, MMP-3, MMP-9 and MMP-2, were tested on a 9-microtiter plate 'using a Hamilton AT ® workstation for &lt; well analysis of some of the compounds of the present invention. All IC50 0 値 are expressed as η μ. When appears, the following inhibitory effects. /. . Delegate on 5. (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

The size of this paper is applicable to China's national sample, CNS) A4 rules and regulations (2! Ox297 public change). Order 5 'Invention Note (267) Printed by A7 B7 104 125 1 = 18% 63 105 33 1 = 37% 14 106 57 622 43 107 32 1 = 34% 16 108 1 = 8% 1 = 4% I = 16% 109 28 1,290 6.6 110 37 I = 26% 38 111 18 4,730 3.9 112 30 884 11 113 28 1,330 44 114 246 439 68 115 &gt; 1,250 &gt; 1,250 1,750 116 137 185 38 127 605 1,220 40 128 561 715 145 129 237 771 89 134 304 358. 63 137 &gt; 1,250 1,400 548 138 905 1 = 0% 665 139 5,000 5,000 323 140 1,030 &gt; 1,250 242 141 &lt; 5,000 Τ / Λ rn 1 — \ J / 0 1,170 143 309 1,400 111 144 15 29 3.4 145 7.5 19 2.1 146 2,400 2,710 538 147 266 676 73 148 90 454 54 149 109 512 40 150 371 957 201 151 371 607 70 152 367 597 210 153 — 594 1,010 127 154 470 875 37 155 777 &gt; 1,250 50 156 126 145 21 157 111 142 35 158 37 &gt; 500 32 159 116 &gt; 1,250 42 160 147 1,060 42 161 46 1,560 38 162 181 1 = 8% 22 163 64 I = 18% 1 7 164 30 82 3.9 165 13 55 3.0 This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page) 'Order A7 B7 V. Description of the invention (268) Consumption cooperation of employees of the Central Bureau of Standards of the Ministry of Economic Affairs Du printed: 166 103 381 35 ^ 167 I = 18% I = 23% 1 = 31% '168 49 163 15 169 245 1,080 80 170 296 1,800 103 171 663 3,520 452 172 456 1,930 175 173 119 814 104 174 144 522 56 175 1 = 28% 1 = 6% 5,000 176 1 = 26% I = 24% 2,000 177 I = 11% I = 30% 4 ^ 30 196 381 955 37 197 205 504 22 267 15 3.0 2.6 268 5.73 1.15 0.91, 269 1,030 197 165 270 6.0 1.6 1.4 271 5.2 7.9 1.4 272 9.20 10.8 2.28 273 21 1.25 2.27 276 262 275 39 279 402 286 67 280 146 66 29 294 58 176 11 296 44 111 6.4 297 5,750 2,370 2,070 299 58 531 52 300 &gt; 1,230 &gt; 1,250 2 ^ 00 301 30 290 18 312 80 871 60 313 3 &gt; 330 I = 20% 2,780 314 399 555 13 317 75 808 37 318 319 30 197 4.1 320 1 = 6% 1 = 6% I = 24% 321 322 324 46 343 8.1 325 1 = 10% 1 = 0% 4,400 351 107 151 50 352 130 905 61 353 84 274 20 354 577 1,710 76 (Please read the notes on the back before filling out this page) The paper size of the paper is in accordance with the Chinese National Standard (CNS) A4 specification; 21!) & 097 mm) A7 B7 V. Description of the invention (: 69) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 355 508 1,080 90 356 I = 45% 1 = 14% 188 357 I = 15% 1 = 4% I = 38% 358 I = 39% 1 = 4% 124 359 83 1 = 16% 51 360 5.46 0.93 1.46 361 3.00 0.50 0.81 362 431 100 183 363 5,000 I = 37% &lt; 5,000 364 46 180 40 365 27 58 13 366 22 56 6.7 367 44 38 37 368 36 30 31 369 54 139 37 370 24 26 8.7 371 10 26 9.1 372 39 65 22 373 56 113 24 374 54 271 34 375 116 146 68 376 46 95 34 377 24 44 28 378 77 83 43 379 63 4β 92 380 46 40 69 381 46 97 44 382 42 39 64 383 58 53 110 384 129 167 78 385 4.22 1.12 4.26 386 ^ 8.34 0.97 11.7 387 9.4 2.0 4.9 3θ8 105 467 30 389 15 23 6.3 390 10 1.2 15 391 19 4.2 14 392 2.5 393 I = 18% ϊ = 38% 2,000 394 I = 26% I = 15% 2,000 3 95 2,200 1 = 44% 560 396 779 2,290 362 397 3,200 I = 40% 750 398 399 -272- (Please read the notes on the back before filling this page) Chinese National Standard i CNS) A4 specification (210 '&lt; 297 mm) V. Description of invention (270) A7 B7 Duplicate printing of employee cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs (4UU 401 402 403 17 5.7 6.4 404 405 75 5.8 80 406 10.3 1.7 17 407 69 36 39 408 409 12.3 1.9 30 410 104 44 80 411 116 213 27 412 84 41 10 413 39 109 10 414 37 15 79 415 12 1.2 34: 416 9.5 2.5 23 417 32 12 3.7 418 305 89 420 419 6.7 0.85 31 420 14 1.7 5.1 421 12 1,7 0.75 422 8.4 1.6 14 423 19 6.1 15 424 425 3.8 1.2 14 426 161 417 35 427 189 362 428 42 428 53 119 16 429 23 1.6 23 430 I = 28% I = 37 7〇419 431 38 50 16 432 * 1,600 &gt; 1,250 236 433 103 130 6.2 434 254 1,140 61 435 39 107 8.1 436 158 519 286 437 50 166 15 438 439 1 = 0% 1 = 3% I = 24% 440 58 380 43 441 38 149 27 442 2,760 I = 40% 962 443 I = 20% I = 16% 4,610 444 &lt; 5,000 &lt; 5,000 43 The paper size of the table is applicable to China's 'Home' (CNS) A4 specification (2 丨 0X 297 mm) {Please read the precautions on the back before filling this page)-'11 Economy Printed by A7 B7, Consumer Cooperatives of the Ministry of Standards and Prospects of the People's Republic of China 5. Description of the Invention (271) As can be seen from the table above, the significant inhibitory activity of ΝΡ Μ requires a diaryl moiety. See, for example, Example 1 of Biphenyl Compound and Phenyl Comparison of reference compound example 2 7; or comparison of biphenyl compound example 2 0 with phenyl reference compound example 2 5 3. It should also be noted that the effectiveness of the phenoxyphenyl reference compound example 254 is extremely low. It is also true that although the 4-substituent on the A ring is not necessarily a necessary condition for its effectiveness, it does significantly improve its effectiveness. See the unsubstituted examples of low potency 1 3 and 1 3 5 and Examples 1 and I 1 4 are compared. It was also found that when the R 6 substituent on the E moiety is increased, the activity is also improved, see the unsubstituted example 6 and the methyl substituted example 25 and the ethyl substituted example 丨 i 7 comparison / This also shows In comparison with Example 293, 'E represents cyclopropane, while Example 29, which is much more active, has cyclobutane. When the biphenyl and e moieties are unsubstituted (such as the reference compound phenbutene, column 1 in the table), it has only a small activity. 0 Inhibition of tumor metastasis in mouse mode in vivo Sexual metastasis mode: Male BDF1 mice from δ to 8 weeks old were injected with ΙχΙΟ B16, F10 melanoma cells from the tail vein. Compounds were administered intraperitoneally at -24 hours, _3 hours, ten 2.4 hours, and + 48 hours when cells were injected. The compound of the present invention is diluted to 4 mg in a suspension of P GG 4 0 0/1 w e e η 8 0 (9 5: 5 w / w) in scaly buffered physiological saline, and is administered orally in milliliters. In the control group, only the vehicle was administered in the same manner. On the 21st day, the animals were euthanized and the number of lung metastases was measured. When using compounds of the present invention Example 8 6 Λ u 6, 2 6 8, 296 or 299, the number of transfers relative to the vehicle control group is reduced by between 38% and 49%. 0-m paper ruler} A4g (7 ^ 97 ^ Fj ------ (Please read the precautions on the reverse side before filling out this page) Agriculture A7 B7 V. Description of the Invention (272) In the second group of experimental animals, they were vaccinated and administered as described above. Compounds It is a suspension of PEG 4 0 0/1 wee η 80 0 orally administered at 40 mg / kg. The number of lung metastases was measured on day 21. The results are shown in Fig. 1 The number of metastases in the vehicle-treated group has decreased. Β 16. F 1 0 Spontaneous metastatic pattern of melanoma 6 to 8 week old male BDF 1 mice were injected with lxlO6 B16.F10 mice from the right hind toe. Tumor cells. On the 21st day after inoculation, the initial limb tumors were taken out. On the 23rd day after the inoculation of the cells, the invention was administered daily. The compound was once ° The compound was formulated with p B s 7 PEG containing 10 mg / kg. 4 0 0 / tween 80 suspension was administered orally. Animals were euthanized, and lung nodules were measured on day 77. The results are shown in Figure 2. Relative to loading In the control group, the spontaneous metastasis has been reduced by between 45% and 63%. In human ovarian cancer tumors, the S KO V-3 xenograft model has an inhibitory effect on malignant hydrothorax:-intraperitoneal SKOV-3 tumor growth- Treatment with the compound of the present invention takes 6-8 weeks old Balb / c nu / nu mice, intraperitoneally inoculates 2xl05 SKOV-3 human ovarian cancer tumor cells. On the 3rd day after inoculation, the compound of the present invention is administered daily. 1 time until the 21st day. The compounds were administered orally as a suspension in pGE / tween vehicle. Animals were tracked every day with survival as the experimental endpoint. The results are shown in Figure 3. Those treated with the compounds of the invention Animals have a 3.8-fold higher survival rate relative to the vehicle control group.-Intraperitoneal SKOV-3 tumor growth-Compounds of the invention and treatment with Cisplatin take 6 to 8 week old females B a 丨 b '' cnu 'nu mice, injected intraperitoneally -275-This paper size applies the Chinese National Standard (CNS) λ4 specification (210X297 mm) f Please read the precautions on the back before filling this page)-' β Central Member of the Central Bureau of Standards of the Ministry of Economy A7 printed by a consumer cooperative __________B7____ 5. Description of the invention (: 73) 1 x 1 〇 6 S Κ Ο V-3 human ovarian cancer cells. On the seventh day after inoculation, the animals were treated with 5 0 mg / m 2 Shipin Once ° As of day 9, A20 mg / kg of the compound of the present invention was orally administered once a day until the animal died. Animals were tracked every day, and when they died, tumor growth was measured 'and tissues were collected for tissue analysis. When the compound of the present invention is combined with Shipin at a dose of 20 mg / kg, the survival time is prolonged by more than 4.6 times. Inhibition of sacral damage in guinea pig's osteoarthritis model 'Progressive chronic Osteoarthritis in femorotibial of guinea pig's femur and tibia joint according to "partial meniscus resection" by AM Bendele Joints of partical tnedial menisectomized guinea pigs) 5 Vet. Pathol. 1987, 24, 444-448. Partial meniscalectomy for the left knee of guinea pigs, osteoarthritis. Seven compounds of the present invention were taken. 15 mg / ml in 10 mg / ml Tween 80, 190 mg / ml PEG and 0.44 mg / ml ethanolamine in a vehicle. Dilute this concentrate 1: 1 with water before administration (final concentration 7.5 mg / ml). Ml). On the 5th day before the operation, each animal received a test compound loading agent or a vehicle only, 15 mg / kg (2 milliliters to 1 liter / kg) by intubation into the stomach tube every day until the time of surgery. Then 4 weeks after the operation (3 3 days in total) «Weigh the animals at the beginning and every 2 weeks thereafter, calculate the dose of each compound or vehicle, and adjust if necessary At the end of the experiment, the animals died of asphyxiation with CO 2, and their knees were removed, partially engraved, and placed in 10% neutral buffered formalin. The degree of damage development at the upper end of the femur was computer-assisted surface area analysis 276- This paper conforms to Chinese National Standard (CNS) Α4ΐ? ^ 72Ι〇χ 297mm) '' (Please read the precautions on the back before filling this page) 4_, va A7 7 Β V. Description of the invention ( 274) The inhibitory effects of several specific examples of the compounds of the present invention on the damaged surface area of joints after surgery in animals receiving these compounds compared to animals receiving only vehicle are as follows: Example% Inhibition of Femoral Damage Surface Guess 86 0 100 37.8 116 0 145 46.4 &quot; ~ 197 18 * 268 53 296 31 299 28 * Average of several separate experiments. (Please read the notes on the back before filling out this page) Ding 1 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs -277-This: ¾-sheet scale applies to the Chinese National Standard (CNS) A4 specification (2 丨 〇297mm) A7 A7 Printed by the Consumers' Cooperative of the China Standards Bureau of the Ministry of Economic Affairs B7 _ V. Description of the invention 275)

Table XXVUI Real Chemicals ~ Compound Numbers: Chemical Abstract (CA) Index Name 1: [1,1, Biphenyl 4-butanoic acid, 4, Qi-Han- (2-methylpropyl)-? ^ Oxygen -2: [1, Γbiphenyl] -4-butanoic acid, 4'-gas-α- (2-methylpropyl) -r-oxy-, (S) -3: [1,1 · bi Phenyl] -4-butanoic acid, 4, p-methylpropyl) -r.oxy-, (R) -4: [1, Γbiphenyl] -4-butyric acid, 4'-p-phenyl- (2 -Methylpropyl) -r-oxy ,, (S) -5: [1, Γbiphenyl] -4-butanoic acid, 4'-chloromethylpropyl) -plant-oxy-, (R) _ 6: [1,1, biphenyl] -4-butanoic acid, 4, -gas-r-oxy-7: [1,1'biphenyl] -4-butanoic acid, 4'-bromo-r -Oxygen_ 8: [1,1, biphenyl] -4-butanoic acid, 4 · -fluorooxy · 9: [1, Γbiphenyl] -4-butanoic acid, 2 · -fluoro-r-oxygen -10: [1, Γbiphenyl] -4-butanoic acid '2'-gas-r-oxygen · U: [1, Γbiphenyl] -4-butanoic acid, 2', 4, -difluoro -r-oxy 12: [1,1, biphenyl] butyric acid '3, -gas-r-oxy_ 13: [1,1, bibenzyl] -4-butyric acid, therapy- (2 -Methylpropyl) -Γ-oxy- 14: [1, Γbiphenyl] -4-butanoic acid '4'-Han-α-(2-methylpropyl) -r · oxy, 15: [ 1, 'Biphenyl M-butyric acid' 4'_fluoro- (2 · methylpropyl) r- Oxygen_½: [1, Γ biphenyl M-butyric acid, 4'-ethylmethylpropyl) -r-oxy-17: 丨 1, Γ biphenyl] -4-butyric acid '2'- Fluoro-shen- (2-methylpropyl) -Plant-oxy-18: [1, Γ 聨 benzyl M-butyric acid '2, -gas-α- (2-methylpropyl &gt; -r- Oxygen: [1,1_bibenzyl] -4-butanoic acid, oxy-π- (2-methylpropyl) -r'oxy-21): [1, Γbiphenyl] -4 -Butyric acid '2' '4' · Difluoro-shen- (2-methylpropyloxy ·-278- (Please read the precautions on the back before filling out this page)-Packing ' &quot; ^ 李 (CNS) A4 ^ (210X297 / ^ *) A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (276) 21: [1, Γ biphenyl] -4-butanoic acid, 4'-methyl-shen- (2-fluorenylpropyl) -r-oxy-22: [1, Γbiphenyl] -4-butanoic acid, α- (2-fluorenylpropyl) -r- Oxy-4 · -fluorenyl knows: [1, I1 bibenzyl] -4-butanoic acid, 4, gas-β-methylene-r-fluorene-34: [1, Γbiphenyl] -4- Butyric acid, 2, -gasmethylene-r-oxy-25: [1, Γbiphenylphenyl 4-butanoic acid, 4, gas-π-methyl-r-oxy-26: [1,1 ' Biphenyl] -4-butyric acid, 4'-Ga-r-oxy-α-pentyl 27: Phenyl butyric acid, 4 · -Ga-ίγ (2-methylpropyl) -r-oxy-2S: stearic acid, 4-methyl-α-methylene-r-oxy-29: 2-butenoic acid, 4- (4'-gas- [1, I1-Biphenylphenyl 4-yl) -4-oxo-, (E) -3ί): 2-butanoic acid, 4- [4- (4-Gaphenoxy) phenyl] -4 -Oxy-, (E) -31: [1, Γbiphenyl] -4-butanoic acid, 4'-hydroxy-α- (2 · methylpropyl) -r-oxy-32: [1, Γ Bibenzyl] -4-butanoic acid, 4_-gas-/?-Methylene-Γ-oxy-33: [1,1 · biphenyl] -4-butanoic acid, 4'-gas-r-hydroxy -β- (2-methylpropyl) -34: [1, Γ biphenyl] -4-butanoic acid, 41-gas-r-hydroxy-α- (2-Τpropylpropyl) -35: 2 (3Η) -furanone, 5- (4'-gas- [1,1'biphenyl] -4-yl) -dihydro-3- (2-methylpropyl) 36: 2 (3H)- Furan hydrazone, 5- (4'-Ga- [1, Γ biphenyl] -4-yl) -dihydro-3- (2-f-propylpropyl) 37: ethyl ketone, fluorene- (4'-Ga -[1, Γbiphenyl] -4-yl) -38: [1, Γbiphenylphenyl 4-butanoic acid, 4'-chloro-Γ-hydroxy-π-methylene-39: [1, Γ double-benzyl] -4-butyric acid, 2 fluoro-r hydroxy- 40: [1,1 'double-benzyl] -4-butyric acid, 4 | -iodine-? ^ Oxy-«-(3-benzene Propyl)-41: [1,1'biphenyl] -4-butanoic acid, 4, iodine-ίϊ- (2-methylpropyl) -Γ-oxy- 42: [1,1 · Phenyl] -4-butyric acid, f- (3-ethoxy-3-oxo-1-propenyl) -r-oxyl--279-This paper size is applicable to the Chinese National Standard (匚 chan) 8-4 specifications (2 [0 乂: 297mm; (Please read the precautions on the back before filling out this page)-Equipment-Spring Λ7 __ϋ_ 1 Description of the invention (277) β-(3-phenylpropyl)-, (E) -[1 'Γ biphenyl] ···· butyric acid' 4'-U-carboxyvinylbenzene r. Oxygen · α- (3-benzylpropyl), (Ε)-like: 丨 丨, 丨, Biphenyl] -4 · butyric acid, 4 '-(3-ethoxy-3 · oxypropyl phenyl from Xinghong phenyl internal group)-Recipient: [1,1 · biphenyl] -4-but Acid, 4 _- (2 · 殁 ethylphenylpropyl) hu: [1, Γbiphenyl] -4-butanoic acid, 4 '· amino-π- (2-methylpropyl) oxo · 4 /: [1 '1, Biphenyl] -4-butanoic acid, dimethyl ethoxy) amino] amino l · r -oxo-α- (3-phenylpropyl)-' ~ 诏: [1,1, biphenyl] -4-butanoic acid '4,-(1, 丨 -dimethylethyl) -r-oxo-butylpropyl) -milk: [1' Γ biphenyl] · 4 · butyric acid, 4 '-[[[(1,1-dimethylethoxyhexyl] amino] methyl] -Γ-oxy-^-(3-phenylpropane ) -50: [1,1-biphenyl] -4-butanoic acid , 4 '-(cyanomethyl-oxybenzylpropyl). 51: [1,1-biphenyl M-butyric acid, 4'-(methylthio) -r-oxy w (3-phenylpropyl 52) [1,1.biphenyl] -4-butanoic acid, 4 '-(2-gasethoxy) &quot; _oxyl- (3_phenylpropyl)-Central Standard of the Ministry of Economic Affairs Printed by the Bureau-Industrial and Consumer Cooperatives 50: [1, 1 · bibenzyl] -4 -butyric acid '* 4- (seryl) -plant-milk-; ^ _ (3-benzylpropyl) _ 54: [1,1, Benzyl] -4-butanoic acid, 4 ·-(hydroxyethoxy) -r · oxy-jiang_ (3-benzylpropyl)-55: [1, Γbiphenyl ] -4-butanoic acid, 4'-vinyl-r-oxy-from- (3-benzylpropyl) -56: [1,1, biphenyl] -4-butanoic acid, 4, -cyano -r _oxy-α- (3-benzylpropyl) -57: [1,1, biphenylbut 4-butanoic acid, Γ-oxy-α_ (3 · benzylpropyl) -4,- (1Η-tetrazol-5-yl) · -280-This paper size applies to China National Standard (CNS) Α4ΐί (210X297-degree) A7 B7 V. Description of the invention (278) 58: [1, 1, Phenyl] -4-butanoic acid, 4 · -amino-Γ-oxo-han- (3-phenylpropyl) _ Please read the amount of precautions on the back (Page 59: [1 ， Γ 联Phenyl] -4-butyric acid '4'-(aminomethyl) -Γ -oxy-α '· (3- Propyl) _60: [1, Γbibenzyl] -4-butyric acid '4'-(dimethylamino) _r • oxybenzylpropyl) -61: 2-pyridinebutyric acid '5- ( 4-ethylphenyl)-(21ylpropyl) -oxo. 62: [1, Γbibenzyl] -4-butanoic acid'Γ-oxyphenylpropyl MΗtrifluoromethyl) -63: [1,1 'Biphenyl] _ 4 -Butane' 4 -Chrysyl-Γ-oxy_β (3-benzylpropyl) Benzene 64: [1, ΓBiphenyl] -4-Butyric acid 1 3 '' 4 * -Digas-methylpropyl),-oxy 65: [〖, 1, biphenyl) -4-butanoic acid, 31,4 · -digas-r-oxy-α- (3 -Phenylpropyl) -66: [1, Γbiphenyl] -4-butanoic acid '3 ·' 5 ^ digas-r · oxy-α-(3-benzylpropyl) -67: [1 , Γbiphenyl] -4-butyric acid'4 ·-(ethanoyloxy) -r_oxy_α- (3 · phenylpropyl) -from phenylvaleric acid, α- [2- 丨 4- (5-Gas-2-pyrimidinyl) phenyl 1,2 · oxyethyl] -69: 2-succinic acid, 5- [4- (3-alkyl-1-oxo-6-hexyl) Hexyl) Epidyl] -70: Phenylvaleric acid, π- [2 · oxy-2- [4- (3-pyridyl) phenyl] ethyl] _71: Phenylpentanoic acid, α- [2. Oxygen- 2- [4- [6- (pentyloxy) -3 · pyridyl) phenyl] ethyl-72: [1, Γbiphenyl] -4-butanoic acid, r-oxy-4,-(戍Thio) -π- (3-phenylpropyl) · 73: [ 1, Γbiphenyl 丨 -4-butanoic acid, 4'-methoxy · r-oxy-α- (3-phenylpropyl) _ 74: [1,1 · bibenzyl] -4-but Acid, 3 * -Ga-4, -Fluoro-r-oxy-methyl- (3-benzylpropyl) 75: [1, Γbibenzyl] -4-butanoic acid, 4'-hexyloxy-r -Oxy- (3_phenylpropyl) _ 76: Benzene acid-, £ χ '-[2-Oxy-2- [4- (3-pyrimyl) benzyl] ethyl] · Central Ministry of Economic Affairs Building Cooperative Consumption and Cooperation of Building Industry Bureau, Du Yin 77: [1,1, biphenylbutanyl 4-butanoic acid, 2,, 4, -digas-r-oxya- (3-benzylpropylbutane 78: [1,1, Bibenzyl] -4-butanoic acid, 4, -methylamino-r-oxy-α- (3-phenylpropyl) _79: [1, Bibenzyl] -4-butyl Acid, r-oxy-fluorene- (3-benzylpropylbenzene 3 '' 5 · bis (monofluoromethyl) -80: glutaric acid, α · [2-oxy · 2- [4- (2_ (Phenyl) benzyl] Ethyl Bu-2RJ-This paper uses Ning Ning country sample: Xin. (CNS) A4 size (210 × 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 41367: A7 B7 V. Description of the invention (279) 81: [1, Γbiphenyl] -4-butanoic acid, r-oxy-β- (3-phenylpropyl) -3f (trifluoromethyl) -82: [1 , Γbiphenyl] -4-butanoic acid, 2'-methylamino-r · oxy-π- (3-benzylpropane ) -§3: [1, Biphenyl] -4-butanoic acid, 4'-hydroxy-r-oxyphenylpropyl) -84: [1, Γ biphenyl] -4-butanoic acid, r -Oxy w- (3-phenylpropyl) -4 · -propoxy-85: [1,1'biphenyl] -4-butanoic acid, oxygen-4 ·-(fluorenyloxy) -π- (3-Benzylpropyl) -86: [1, Γbiphenyl] -4-butanoic acid, r-oxy-4 × pentyloxy) -α- (3-phenylpropyl)-, (S) -87: [1, Γbiphenyl] -4-butanoic acid, r -oxy · 4Κ 戍 oxy) -π- (3-benzylpropyl)-, '-(R)-8S: [1, Γbiphenyl] · 4 · butyric acid, 4 '-(hexyloxy) -r-oxy-π-(3-phenylpropyl) -89: [1, Γbiphenyl] -4-butyric acid , 4 · -butoxy-r-oxy-π- (3-phenylpropyl) -90: [1, Γbiphenyl] -4-butanoic acid; r-oxy-4 '-(3- Phenylpropoxyphenyl diyl) -91: [1, Γbiphenyl] -4-butanoic acid, 4 '-(1-methylethoxy) -r-oxy-π- (3-benzene Propyl) -92: [1,1'biphenyl] -4-butanoic acid, 4 '-(heptyloxy)-? ~ Oxy-from- (3-phenylpropyl) -93: [1 , Γbiphenyl] -4-butanoic acid, 4 '-(cyclohexylmethoxyoxy-α- (3-phenylpropyl)-. 94: [1, Γbibenzyl] -4-butanoic acid , 4 '-(2-methylpropoxy) -Γ-oxy-phenylpropyl)-95: [1, Γ Group] -4-butanoic acid, r-oxy-π- (3-phenylpropyl) -4 ·-(2-propenyloxy) -96: [1, Γbibenzyl] -4-butanoic acid, 4 ·-(3-methylbutoxy) -r-oxy-a-(3-phenylpropyl)-28?-The paper size applies to the Chinese National Standard (CNii) Α4 specification (210 × 297 mm) — 1 --------- install ------- iT ------ quan. (Please read the precautions on the back before this page) (Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Preparation of A7 B7_ V. Description of the invention (280) 97: [1, Γ 聨 phenyl] -4-butanoic acid, 4 ·-(cyclopropylmethoxy) -r-oxy-α- (3-phenylpropane )-§8: [i, Γbiphenyl] -4-butyric acid'ethylpropoxy) -r-oxy · α- (3-benzylpropyl)-99: [1,1 · 聨Phenyl] -4-butanoic acid, r-oxy-cardio (phenylmethylamino) --methyl- (3-phenylpropyl)-100: [1, Γbiphenyl] -4-butanoic acid, r-oxy-4 '-(phenylmethoxy) -α- (3-phenylpropyl) -7 (S) -di_ [1, Γbiphenyl] -4-butanoic acid, r-oxy 4 '-(phenylmethoxy) -α- (3-phenylpropyl)-' (R)-102: [1, Γbibenzyl] -4-butanoic acid, 7. # oxy-4Η2- Phenylmethoxy) · π- (3-phenylpropyl)-, (S) -103: [1, Γbiphenyl] -4-butanoic acid Heart [(4-methylphenyl) methoxy] -r • oxy_α · (3-phenylpropyl)-104: [丨, 1 · biphenyl] -4-butyric acid'oxy-4 '-(3-phenylpropyl) _4' _ [[4_trifluorofyl] phenyl] methoxy] -105 ·· [1,1 · bibenzyl] -4-butanoic acid '4 · -[(4-methoxybenzyl) methoxyb r _oxo-fluorene- (3-phenylhydrazinopropyl)-106: [1, cadaveryl] -4-butanoic acid, 4,-[(3 -Phenyl) methoxyphenyl r_oxy_jiang (3_benzylpropyl)-107: [1, Γbiphenyl] -4-butanoic acid, 4 ·-[(4-fluorophenyl) methyl Oxy_oxy · 戌 _ (3-phenylpropyl) -108: [1,1, bibenzyl] -4-butanoic acid, 4Ηdecyloxy) · r_oxy-"_ (3 · phenylpropyl ) _ 109: [1, Γ double-benzyl] -4-butyric acid 'Γ-oxy-α_ (3-benzyl propyl than dian-methyl-283-water-paper scale suitable for financial SS £ (CNS) Α4 trace U1GX 297 male I) '— — ~ (Please read the precautions on the back before filling out this page} -Packing-Spring B7 V. Description of the Invention (281) Milk-based)-110: [1, Γ biphenyl] -4 -Butyric acid, r -oxy-λ ~ (3-phenylpropyl) -1- (2-pyridylmethoxy)-111: [1, Γbiphenyl] -4-butanoic acid, Γ-oxy- β- (3-Benzylpropyl) -4 '-(4-pyridylmethoxy)-112 ... [1, Γbiphenyl] -4-butanoic acid, 4 ·-[[4- (aminocarbonyl) phenyl) methoxy]-,-oxy-α- (3-benzylpropyl)-113: [1, 1'biphenyl] -4-butanoic acid, 444- (carboxyphenyl) methoxy]-; ^ oxy-from- (3-phenylpropyl) -114: [1,1, biphenyl] 4-butanoic acid, 4'-gas-oxo-from- (3-phenylpropyl) -115: [1, Γbiphenyl] -4-butanoic acid, 4 · -gas-r-oxobenzene Propyl)-, (R) -116: Π, biphenyl] -4-butanoic acid, 4'-gas-r-oxy-ο ^ (3-benzylpropyl)-, (S)- il7: [1, Γ biphenyl] -4-butanoic acid, 4'-Ga-ethyl-r-oxy-118: [1, Γ biphenyl] -4-butanoic acid, 4 · -Ga-Γ -Oxy-α-propyl- 119: [1,1'biphenyl] -4-butanoic acid, 4'-Ga-bufi-fluorene-2-propenyl-120: [1, ΓBiphenyl] 4-butanoic acid, butyl-4'-chloro-r-oxy- 121: [1, Γbiphenyl] -4-butanoic acid, 4 · -gas-r-oxy-α-2-propynyl -l22 '_ [l, 1: biphenyl] -4-butanoic acid, 4 · -gas-α · heptyl-r, oxygen_ Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 123: [1,1— Biphenyl] -4-butanoic acid, 4'-gas-α-decyl-r-oxy. 124: [1,1 &lt; biphenylbutanyl 4-butanoic acid, 4 ^ nitro-? ^-Oxy- 〇- (2-phenylethyl) -125: [1, Γbiben ] -4-butanoic acid, 4 · -cyano-r-oxo- (2-phenylethyl) -126: [1, Γbibenzyl 4-butanoic acid, 4 · -gas-π- [2- (2-Iodobenzyl) ethyl-r-oxy-127: [1, Γ 聨 phenyl] -4-butanoic acid, π- [2- (3-iodophenyl) ethyl ]-Oxygen-128: [1, Γ double-benzyl] -4-butyric acid, qi-iodine-benzyl) ethyl j-r-oxyl-284-This paper is suitable for Chinese National Standard (CNS) Μ 胡 A (210X 297 mm) A 7 B7 printed by the Consumer Cooperative of the Ministry of Economic Affairs + Central Standards Bureau V. Description of the invention (282) 129: [1, Γ biphenylbenzene 4-butyric acid, 4'-gas- π- [2- (3,5-dimethoxyphenyl) ethyl] -Γ-oxy_ Γ30: [1, Γbibenzyl] -4-butanoic acid, 4 · -gas-r-氡 -π -Benzyl-131: [1, Γbiphenyl] -4-butanoic acid, pregnant gas-r oxygen- &amp;-( benzyl) -132: [1, Γbiphenyl] -4-butanoic acid , I-Ga-r-oxybenzylethyl) -133: [1, Γbiphenyl] -4-butanoic acid, 4'-Ga-r-oxy-π-[(trimethylsilyl) methyl]- Π4: [1, Γbiphenyl] -4-butanoic acid, 4 · -bromo-r-oxy-α- (3-phenylpropyl) -i35: [l, Γbiphenylj-4-butanoic acid , Oxy-"-(3-phenylpropyl)-• 136: [1, Γbiphenyl] -4-butanoic acid, I-amino-r oxygen- (2-phenethyl)-137: [1 Γ biphenyl] -4-butanoic acid, plant oxygen-π-(2-phenethyl) -4 '· [[benzyloxy] carbonyl] amino]-138: [1, Γbiphenyl] 4-butyric acid, 4 ·-[[(1,1-dimethylethoxy) carbonyl] amino] -Γ-I 1-β-(2 -asthyl) _ 139: [1, Γ Biphenyl] -4-butanoic acid, 4 ·-(acetamido) v-oxy-π- (2-phenethyl) -140: [1, Γbiphenylj-4-butanoic acid, r- Oxyoxyphenyl) amino] -π- (2-phenethyl)-141: [1, Γbiphenyl] -4-butanoic acid, 4 ·-[(3, 3-dimethyl-1- Oxybutyl) amino] -γ-oxy-π-(2-benzylethyl)-142: [1, phenyl] -4-butanoic acid, 4 · -gas-π- [2- [2- ( Methoxycarbonyl) benzyl] ethyl] -r-oxy-143: [1, Γbibenzyl] -4-butanoic acid, carboxybenzyl) ethyl] -4 · -chloro · oxy-144: [1 ， Γbibenzyl] -4-butanoic acid, 4'-Ga-π- [2- [2- (diethylamino) carbonyl) benzyl] ethyl] -Γ -oxy_ 145: [1, Γ Bibenzyl] -4-butyric acid, 4'-gas-π- [2- [3- (diethylamino) carbonyl) phenyl] -285-Applicable to China National Standard (CNS) 8-to-4 Case (2 丨 0 × 297mm) --------- ▲ ------- Order / V (Please read the notes on the back before filling this page) Central Bureau of Standards, Ministry of Economic Affairs Printed by Consumer Cooperative A7 ___B7_ V. Description of the Invention (283) Ethyl] -r-oxy-, (S) -146: [1, Γbiphenyl] -4-butyric acid, 4'-gas, Shen- [ 2- [3- (diethylamino) carbonyl) benzyl] ethyl] oxy-, (R)-147: [1, Γbiphenyl] -cardiobutyric acid 'β- [2- [2- ( Butylamino) carbonyl) phenyl] ethyl] -4, -oxygen-148: [1, Γbiphenyl] -4-butanoic acid, π- [2- (3-carboxyphenyl) ethyl] -4. Gas-r-oxygen-149: [1, Γbiphenyl] -4-butyric acid '4' · Ga-α- [2- [3-[(diethylamino) carbonyl) phenyl} Ethylbenzene Γ-milk-150: [1, Γ biphenyl] -4-butanoic acid, α- [2- [3-[(butylamino) carbonyl) phenyl] ethyl] -4'-gas -,-Oxygen-151: [1, Γbiphenyl] -4-butanoic acid, 4'-Ga-β- [2- [4-[(Diethylamino) carbonyl) phenyl] hexyl] -Γ -Milk · 152: [1, Γbiphenyl] -4-butanoic acid, β- [2- [4-[(butylamino) carbonyl) phenyl 1ethyl] -4, gas-r-oxygen- --------- A ------- Order ------ 卞 / V ί (Please read the notes on the back before filling this page) 153 [1, 1'biphenyl ] -4-butanoic acid, «-12- (4-carboxyphenyl) ethyl] -41-gas-r-oxy-154 Π, 1'biphenyl] -4-butanoic acid, 4'-methoxy Radical -r -oxygen- -(2-phenethyl)-155 Π, 1'bibenzyl] -4-butanoic acid, 4'-Leptyl-r-oxy-α-(2-benzylethyl)-156 [1, Γ coupling Phenyl] -4-butanoic acid, 4 · -ethoxy-Γ • oxy-α-(_ 2-phenethyl)-157 [1, 1 ^ phenyl] -4-butanoic acid, r -oxy-α -(2-benzylethyl) -4 · -propoxy- 158 [1,1 · bibenzyl] -4-butanoic acid, F -oxy-f- (fluorenyl) phenethyl)-159 π , 1'bibenzyl] -4-butanoic acid, 4- (hexyloxy) -plant-lactate- (2 · benzylethyl) -160 [1, Γbiphenyl] -4-butanoic acid, 4'-butoxy-r-oxy-sand- (2-benzylethyl)-161 Π, Γbiphenyl] -4-butanoic acid, r-oxy-^-(2-phenethyl) -4 ·-(Benzyloxy)-162 [1, Γbibenzyl] -4-butanoic acid '^ [2- (3-iodobenzyl) ethyl] -γ-oxy-4'-(penta-286 -This paper uses Chinese interpreter standard (CNS &gt; A4 specification (210 × 297 mm), printed by the Consumer Cooperatives of the Bureau of Standards and Loss Standards of the Ministry of Economic Affairs, printed A7 __B7_____ V. Description of the Invention (284) Oxygen &gt; · 163: [ 1, Γbiphenyl] -4-butanoic acid, π 42- (3-iodobenzyl) ethyl] -Γ -oxy-4 ·-(benzene'methylamino)-164: [1,1 · bi Phenyl] -4-butanoic acid, α- [2- 〖3-[(diethylamino) carbonyl] Phenyl] ethyl] -Γ _oxy-4 * · (fluorenyloxy)-165: [1,1, biphenylphosphonium-butyric acid, han- [2- [3 · [(diethylamino) Carbonyl] phenyl] ethyl Γ-lactamylamino) -l66: 1, 2-sorococic acid, 3-[(4'-qi- [1, 1, biphenyl] -4- Yl) quinyl], 1- (benzyl) ester, (2S-trans) -167: 1,2-pyrrolidinedicarboxylic acid, 3-[(4'-Ga- [1, biphenyl M-yl) carbonyl]-, I- (benzyl) ester, (2R-trans) -I68: L-proline, 3-[(4 · -Ga- [1,1 · -bibenzyl ] -4 · yl) carbonyl] -1_ (benzyl) amino] carbonyl]-, trans-169: L-proline, 3-[(4 · -Ga- [1,1'-biphenyl []] '') Carbonyl]] 1- (1.oxy-3-phenylpropyl ^ trans-170: L-proline, 3-[(4'-chloro- [1,1 · -biphenyl Phenyl] -4-yl) carbonyl] -1- (phenethylfluorenyl)-, trans-171: L-cholic acid '3-[(4 · -Ga- [1' I · -Diethyl] -4-yl) Zyenyl] -1- (3,3-dibenzyl-1-¾: butyl)-, trans- 172: 1,2-diloxyl-diacid, 3-[(4 '-Gas- [1' I1-linkedyl-4-yl) yl]-, 1- (2-methylpropyl) ester, (2S-trans) -173: L-proline, 3-[(4, -Ga- [1,1, bibenzyl M-yl) carbonyl j -丨-(benzylamino) carbonyl]-, trans · 174: [, 3-? Biha bite diacid, 4-[(4'-Ga- [1 'I1- 聨 Benzyl] -4- (Base) carbon-based] · -287-This paper is suitable for financial &amp; home guide (CNS) A4A1 ^ (210X297 / &gt; t). Table -------- Order ------% ( Please read the notes on the back before filling out this page) Α7 Β7 ___ __ ^ — V. Description of the invention (285), (benzyl) ester 'trans- Bu 175: 3- · 1 bilo acid diacid, 4-[(4'-Ga- 丨 1, Γ-biphenyl] -4-yl) octyl group [small (stupid * methyl) ester, trans · 176: bicyclic [2.2.1] hept-5- Ene-2-carboxylic acid, 3-[(4.-Ga [1 '1.-biphenyl] -4-yl) carbonyl group, (2-inward' 3-outer) -177: bicyclic 〖2.2.1 ] Hept-5-en-2-chinoic acid '3-[(4, -Ga [1'Γ-biphenyl] · 4 · yl) carbonyl]-, (2-Exo-3-introversion)-178: [1, Γbibenzyl] -4-butanoic acid 'bromo-Γ-oxyphenylpropyl), (8) -179: [1,1, biphenyl] -4-butanoic acid' 4'-gas -r -oxy-α-(4-phenylbutyl) 180: [1,1'biphenyl] -4-butanoic acid, 4'-gas-r -oxy-α-(5-phenylpropyl) _ 181: [1,1 * biphenyl] -4-butanoic acid, 4'-gas-r-oxy-α- (6-phenylhexyl) 182: [1, Γbiphenyl ] -4-butanoic acid, ([1 'r-bibenzyl] -4-ylmethyl) -4'-chloro-Γ-oxy-183: [1, Γbiphenyl] -4-butanoic acid , 4, · qi-Γ-oxy-α- (3-benzyl-2-propenyl)-'(E)-Duplicate printing of work and consumer cooperation of the Central Standards Bureau of the Ministry of Economic Affairs --------- Η 水 ------ Order / | \ (Please read the notes on the back to fill in this education first) 184: [1, Γbiphenyl] -4-butyric acid '4' · chloro-α- 丨 3 -(4-Tolyl) propyl] -r-oxy-185: [1, 丨 • biphenyl] -4-butyric acid '4 · -Ga-α- [3 · (4-Gaphenyl) propane Radical] -Plant-oxygen-186: [1, Γbiphenyl] · 'butyric acid, 4'-gas-π- [3- (4-methoxyphenyl) propyl] -r-gas-187: [i, I1 phenyl] -4-butanoic acid '4f-gas-α- [2- (4-methoxyphenyl) ethyl] -oxy-188: [1, "biphenyl] -4- Butyric acid, 4 · -aminomethoxybenzyl) ethylbenzene r_oxy_ 189: [1 '1'biphenyl] _4-butyric acid' 4'-qi-r-oxy-benzyl-2 -two (Decanyl) -190: [1,1, bibenzyl] -4-butyric acid '41-qi-r-oxy-therapeutic- [2- (benzyloxy) ethyl j-191: [1,1 .Biphenyl] -4 · butyric acid '4'-Ga-π · [(2-methoxyethoxy) methyl] _Plant-oxygen 192: [1, Γbibenzyl] -4-but Acid 'Zhangqi-Γ-qi [(Stupid methoxy ) Methyl]--288-Paper ruler / 1 suitable financial item ^ 椋 椋 (CNS) Α4 + see the standard (? 10X297 mm) 413675 413675 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 28ό) 193: [i, 1'biphenyl] -4-butyric acid'4, · qi-u-[[(2,2-dimethyl-1-oxopropyl) thio] methyl] -r -Oxygen- • 194: [1,1.Biphenyll · 4-butyric acid, 4, _Ga · π-[[(2,2-Dimethyl-1 · oxypropyl) thiojmethyl] -r -oxy- 195: [I, 1, biphenyl I · 4 · butyric acid, 4'-gas · π · [[(2,2-dimethyl-oxopropyl) thio] methyl] Γ r · oxy- 196: Π, 1, fluorenyl] · 4-butyric acid '4'_chloror · oxy · α _ [(phenylthio) methylbuthyl 197: (1,1'bibenzyl Bu 4_butyric acid, 4'-qi_ r · Wu- “_ [(phenylthio) methylbu '(S) l · 198: [1,1 · biphenyl] _4_ Ding Jun' 4 * _ Gas_Oxygen [(phenylthio) methylbuth '(R) -199: [1,1, Biphenylbuth 4-butyric acid, 4L Gas-Plant Oxygen-α-[(2-pyrimidinethio) ) Methyl benzene 200: Π, 1, biphenyl] _4-butyric acid '"Ethyl alcohol" methyl] -4'-air-r _ oxygen _ 201: [1, phenyl phenyl 4- Butyric acid, 4, -air hydrazone (4_f oxyphenyl) Group] sulfur] methyl] -r-oxy 202: 丨 1, Γbiphenyl] -4-butanoic acid, "-[(benzylthio) methyl] -4 '• gas · r -oxy · 203: [1,1, bibenzyl] · 4 · butyric acid, 4'-gas * ^ oxybenzyl) methyl)]-204: [1,1 · biphenyl] · 4 · butyric acid '4, · Gas-[[[(4-hydroxyphenyl) thio] methyl] -oxo 205: [1, Γbiphenyl] -4_butyric acid, 4, _gas ·, -oxygen-precipitation -[[(2-Phenethyl) thio) pyridyl 206: [1, Γbiphenyl M-butyric acid, 4_-gas-[[[(4-methoxyphenyl) thio] methyl]- Plant oxygen one 207: [1, Γ-dibenzyl 4-butanoic acid, 4, -gas-r -oxy-"-[[(3-benzylpropyl) sulfur) methylbull 208: [1, Γ-diphenyl Phenyl] · 4-butyric acid 'gas-[[[(4_fluorobenzyl) sulfur] fluorenyl r-gas_ 209: [1, "bibenzyl] -4-butanoic acid, 4,- Fluorobenzyl) Sulfuryl methyl r-oxyl 210: [1, Γ biphenyl]-4'butyl 'dibenzyl) succinyl] carboxyl qi: _ oxygen 211: [1, Γ Bibenzyl] _4_butyric acid '4'-Ga-methylbenzyl) sulfur] methyl] oxygen] this paper size ϋ 财 关 家 办 (CNS) Α4 size (2: 0X297 mm) (Please read first (Notes on the back then fill out this page) A7 B7 printed by the Consumers 'Cooperative of the Central Provincial Bureau of Standards V. Description of the invention (: 87) μ, Γ biphenyl〗 _4_ 丁 梭' 4'- 气 -β-[[[(4_ethylphenyl) Gib-r-oxy · ni, biphenyl] -4-butanoic acid'4, -qi-[-[[[4- (1,1-dimethylethyl) phenyl.213: I 丄-] 瑞] Methylbu r-oxy-i, biphenyl] -4 · butyric acid, 4 · -gas-β-[(cyclohexylthio) methyl] _factory oxygen_ 214: I1 2ΐ5. Μ ， Γ 联Phenyl] butyric acid, 4'-gas · α-[[(3,4 · dioxophenyl) sulfur] methyl w-oxy-, M, Γbiphenyl] -4-butanoic acid, 4 ' -Gas-α-[[(3,4 · dichlorophenyl) sulfur] methyl J-216: I1 r-oxy-.-: M, i, biphenyl] -4-butanoic acid, 4 ·-气 -π-[[[(2- (hydroxymethyl) phenyl) thio] methyl 21 ^: I1 j-,-oxy_M, Γbiphenyl] · 4 · butyric acid '4'-Ga- β · [[(2-fluorophenyl) thio] methyl] -r-oxy · 218: I1 Μ, p-bibenzyl] -4-butanoic acid, bromobenzyl) sulfur] methyl] -4 ·- Gas-r-oxygen-219: I1 r1, Γ biphenyl] -4-butanoic acid '41 -gas-«-[[(2-ethylphenyl) sulfur] methyl] -r-oxygen_22〇: I1 f1, Γ biphenyl] -cardiobutyric acid, -gas-α-[[[2- (1- (methylethyl) phenyl) sulfur] 221: I1 f group] -r-oxy_ m Γ biphenylbutyric acid, 4 · -qi-r-oxy-cardio [(4- (pyridinethio) methyl] -222: L1 r ,, 丨, biphenyl] -4 · butyric acid, α- [[[4- (Ethylamino) benzyl) sulfur] methyl] benzene 223: L1 fluoro-r let r1, 1, phenyl] -4-butanoic acid, gas-π · [[4- (nitro Phenyl) sulfur] methyl]-,-oxy-224: L1, Γ bibenzyl I-4 · butyric acid, from-[[[4- (2 · carboxyethyl) benzyl) methyl] methyl 4 ·-225: I1 Chloro-oxyl-226. (1,1, bibenzyl) -4-butanoic acid, 4, -gas-π-fluoren (2-phenylthio) methyl〗 -r-oxygen -7; 27. [1, 丨, biphenyl] butyric acid, [[(thioquinone) methyl] r'oxy] 228: μ, 1 · bibenzyl] -4-butanoic acid, α · [[(3-Bromobenzyl) thio] methyl M, -Gas-r-Oxygen- -290-This paper size is generally applicable to National Standards (CNS) A4 (210 × 297 mm)) Read the precautions on the back and fill in this page) Clothing., 1T A7 A7 Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs B7__ V. Description of the invention (288) 229: [1, 1, biphenyl] -4-but Acid, gas-from-[[(2-fluorenoxyphenyl) sulfur] fluorenyl group 丨 —plant_oxy_ 23〇: [1,1, biphenyl] -4-butanoic acid, 4'_gas-α 7 2 · qi Phenyl) sulfur] methyl] Xi-oxy-2 * 31: [1,1, biphenylbutanyl 4-butanoic acid, 4 · _ππ [[3-methylbenzyl) thio _Oxygen · 232: [1,1, biphenyl] -cardiobutyric acid '4' · gas w-[(2-tolyl) sulfur] methyl-oxygen-233: [1,1, bibenzyl] -4-butyric acid 'α-[[(2-benzyl) bowl methyl]]-r-oxygen-234: [1, Γbiphenyl] -4-butyric acid'heart gas-α _ [ [(3-methoxyphenyl) sulfur] methylbutan-oxy-235: [1,1'biphenyl] -4-butanoic acid '4 * _Ga · ^ -ί [(3' 5_ 二Tolyl) sulfur 1methyl] 'r-oxy-di236: [1, Γbiphenyl 4-butanoic acid' 4 '· gas-plant_oxy-[[[3 · (fluoromethyl) phenyl ] Sulfur] methyl]-;-Oxygen-237: [1, Γbibenzyl] -4-butyric acid '4 · _qi-heart [[[4- (methoxycarbonyl) benzyl) sulfur] methyl Group]-,-Oxygen-238: [1, Γbiphenyl] -4-butanoic acid, α-[[[4- (carboxymethyl) phenyl] thio] methyl] · 4, _air-r -Oxygen-239: [1,1, bibenzyl] -4-butanoic acid, 4 &lt; -Gas-[[(1-methylethyl) sulfur] fyl] -r oxygen · 240: [1, r Biphenyl] -4-butyric acid, 4 · -oxyhydroxyphenyl) sulfur] methyl] -r-oxy-241: [1,1 · biphenyl] -4-butyric acid '4'-gas- r-oxoquinolinethio) methyl 242: [1, 1: biphenyl] -4-butyric acid '4_-gas phenyl) sulfur 1 methyl] oxy-243: [1,1, benzyl] -4-butanoic acid, 4' · gas-π-ΠΡ -Fluorophenyl) sulfur] methyl] -r-oxy-244: [1,1'bibenzyl 4-butyric acid '4_-gasmethoxycarbonyl &gt; benzyl 丨 sulfur 1 methyl] -Plant- Oxy_245: (1, Γ 聨 benzyl] -4-butanoic acid, 4'-gas-α-methyl-r-oxy · α- (benzylthio) -246: [1,1, biphenyl 】 -4 · Butyric acid 'heart gas-r-oxygen ~-[(benzylidenesulfenyl) methyl] _, stereoisomers-291- This paper size is applicable to the Chinese national standard (A4) (210X297 mm ) '—- (Please read the notes on the back before filling this page)

, 1T 413675 A7 B7 Printed by the pager and consumer cooperation of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (289) 247: [1 'Γ biphenylbu 4-butyric acid' 4'-gas-factory-oxygen-α- [(Benzylidene) methylbuthyl, stereoisomer 2'48: [1,1, bibenzylidene] -4-butanoic acid, 4 · -gas-oxy-π- 丨 (benzylidenesulfonyl) Methyl group, stereoisomer 249: [1, Γ bibenzyl] -4-butyric acid '4 · -gas-plant oxygen-α-[(benzylidenesulfenyl) methyl], stereoisomer Structure 250: [1, Γbiphenyl] -4-butanoic acid, 4 * -gas-[[[[2- (methylamino) carbonyl] phenyl) sulfur j methyl jr -oxo-251: [1 , Γbiphenyl] -4-butanoic acid, 4'-Ga-r-oxy-〇 &lt;-( phenylthio 252: [1, ΓBiphenyl] -4-butanoic acid, 4, -Ga · r oxygen-α-[(benzyl) sulfur J-253: phenylbutyric acid, [(acetamylthio) methyl l · 4 · methyl-r-oxy-254: phenylbutyric acid [(acetamidinesulfur (Methyl) methyl] -4- (4-aminophenoxy) -r-oxy-255: [1, Γbiphenyl] -4 · butanoic acid, 4 · -gas-r-oxy-point-[( 2-pyridylthio) methyl] -256: [1, Γbiphenyl] -4-butanoic acid, 4 · -qi-zhao-[[(2,2-dimethyl-1-oxopropyl ) Sulfur] methyl] -r-oxy_ 257: [1, Γbiphenyl] -4-butanoic acid, 4'-gas-r-oxygen -; 3-[(benzylthio) -258: [1, Γbibenzyl] -4-butanoic acid, /?-[(Ethylsulfanyl) methyl] -4'-chloro-r -oxyl · 259: 1-Hexahydropyridine &quot; Well acetic acid [2- (4'-Ga [1, bibenzyl] -4-yl) -2-oxoethylbutanyl 4-methyl-, monohydrochloride 260 : [1,1, biphenyl] -4-butyric acid, 4'-gas-α-[(dibenzylmethyl> amino group r * oxy-, hydrochloride 261: 4-morpholineacetic acid, α-[2- (4'-Ga [1,1, -bibenzyl 4-yl) -2-oxoethyl] 3,5-dimethyl ·, hydrochloride 262: 2H-isoamidine 2-Pyrulic acid, α- [2- (4_-Ga [1,1, -bibenzyl] -4-yl) -2-oxo-292- Jade paper standard applicable to China National Standard (CNS &gt; A4 Specifications (2 丨 0 &gt;: 297mm) (Please read the precautions on the back before filling this page) Λ. -5-% A7

Five 'invention description (290) ethyl] -1,3-diargon-1,3-dioxo said 263: [1,1, biphenyl] -4-butanoic acid, 4, -chloro-a- [ 2. (Dimethylamino) ethylbenzene Γ-oxyhydrochloride &lt; 264: [1,1.Biphenyl] -4-butanoic acid, 4, -chloro-α- [2- (diethylamine) Group) ethyl] r gas hydrochloride, 265 ·· [1,1, bibenzyl] -4-butyric acid, diethylamino dipropyl propyl oxo diacetic acid π, 266: [1, ι &gt; biphenyl] -4-butanoic acid, 4, -fluorene-cardio [3- (methylthio) propyl]: 'Rolling gas 267: 2 fluorene-isobutyrate butyric acid, α -[2- (4'- | ΐ [1 '1'-biphenyl] _4'yl) 2 group] -1,3-dihydro-1,3-dioxo- &lt; 268: 2Η-iso Indole-2-butanoic acid, han- [2- (4 '· chloro [1,1'-biphenyl] · 4-yl) 2lactyl] -1,3-dihydro-1, 3-di Oxy-'(S)-^^ 269: 2 Ortho-isobutanoic acid, heart [2- (4, -chloro [1'1, -biphenyl] -4_yl) -2_ # 1 group] -1,3-dihydro-1,3-dioxo-'(R) -Gas: 270: 2Η-Iso's · 2-butyric acid, α- [2- (4'- Mo [1,1 '-Biphenylphenyl 4-yl) _2 lactyl] -1,3-diargon-1,3-dioxo-β, 271: 2H-iso-iso-2-butanoic acid, 1,3-dihydro- I '3 · Dioxo- [2-milk-2_ [ 4 Zhongmeimei &gt; [1,1biphenylbut 4-yl) ethyl 1-—41 (戍 272: 2Η-iso 呻 Zui_2-butyric acid, 1,3-dihydro-1,3-di Oxygen w [2_oxy · 2] 4 * Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs &gt; π, 1'-bibenzyl M-yl) ethyl]-2_ 273: 2Η- 异 ♦ 朵- 2-butyric acid, called 2- (4, -ethoxy, ii-biphenylphenyl 4-yl) oxyethyl J-1,3 · dihydro-1,3-dioxo-276..2Η- Isopyridine · 2 · butyric acid, bromo [1,1 · -bibenzyl] _4_yl) _2_yl J-1,3-diargon-1,3-dioxy-293-

The size of this paper is applicable to China's National Standards (CNS) Λ ·; Specifications (210 × 2? 7 mm) 4 Printed by the Peugeot Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 13675 A7 B7______ 5. Description of the Invention (291) 279: [1 , 1, biphenyl] -4-butanoic acid, α_ [2-[(2-carboxybenzylhydrazyl) amino] ethylbu 4 · -fluorene-,-oxygen $ 80: [1,1, Biphenyl l · 4 · butyric acid, α · [2 * ί (2_dibenzylidene) amino] ethyl] _4, -gas-r-oxy_ 282: [1,1'biben Phenyl] -4-butanoic acid, 4'-chloro-π, π-dimethyl_r'oxy. 283: [1,1.biphenyl] -4-butanoic acid, 4 · -gas-α, / ? -Dimethyl-oxo _ '(R *' R *)-284: [1 '1, biphenyl] -4-butanoic acid, 4, -gas-α dimethyl · "oxy-, ( R *, _ S *)-285: cyclohexanecarboxylic acid, 2-[(4, -Ga [1,1'-biphenyl] · 4-yl) carbonyl]-, trans · 286: cyclohexyl Alkanecarboxylic acid, 2-[(4'-chloro [1, Γ-biphenyl] -4 ~ yl) carbonyl]-, cis-287: benzene f acid, 2 _ [(4, _ 气 [1,1 'Biphenyl] winteryl) Tibetanyl] · 288: cyclopentyl carboxylic acid, 2-[(4, -Ga [1, Γ-fluorenyl] * 4-yl) carbonyl]-, cis_289 : Cyclopentanecarboxylic acid, 2-[(4, -Ga [1, Γ-biphenyl] -4 · yl) carbonyl] — , Trans_290: cyclobutanecarboxylic acid '2 [[4 &lt; -Gas [〖, r-biphenyl] · 4 · yl) kisquib, cis_291: cyclobutanecarboxylic acid, 2 -[(4.-Chloro [1'biphenyl] '4-yl) spectino] *' trans' 291 cyclopropanecarboxylic acid, 2-[(4, -chloro [1, Γ-biphenyl ] _4_yl) carbonyl] ,, cis · 293: Cycloalkanecarboxylic acid, 2 _ [(4, -Ga 丨 1 'Γ_biphenyl] -4 · yl) zo], trans-294: Cyclopentanecarboxylic acid, 2-[(4, -Ga [1, Γ-bibenzyl] -4-yl) carbonyl] · 5- (phenylthio)-, (1 α, 2 / ?, 5 / ?)-295: Cyclopentanecarboxylic acid, 2-[(4, -chloroI1 ′ bibenzyl 4-yl) zoyl] · 5_ (phenylthio) ·, (1π, 2 cold, 5 &lt; ar )-296: Cyclopentanecarboxylic acid, 2-[(4, -Gas [1 'Γ_bibenzyl l-4-yl) anyl] _5 · (phenylthio) _, [1S- (1 or , 2 / ?, 5/5)]--2M-

1 paper ^ ξϋNational Standards of the Lower Countries (CNS) Λ4 «^ U10X297 public iT --------- ^ .------- ΐτ ------, t Γχ / 1 (Please Read the notes on the back of Jing before filling out this page.) 5. Description of the invention (292) A7 B7 Printed by the Male Workers Consumer Cooperatives of the quasi bureau in the Ministry of Economic Affairs 297: Cyclopentamic acid, 2-[(4 ,. 气 [ 1, biphenyl] _4-yl) carboxyl 5- (phenylthio)-, [1R- (1 from, 2 cold '5 /?) L · 98: stearic acid, 2-[[2-Endyl _3_ί (Yu-Fu [Bub-Benki-B 4-yl) carbonyl J cyclopentyl] sulfur]-, Methyl ester, (1 Han, 2 Han, 3/5) _ 299: Benzoic acid, 2- [ [2-Beryl-3-[(in Fluorine, Bubenyl) Iceyl) carbonylJcyclopentyl] sulfur]-, 1-methyl ester, [15- (1H'2Shen'3 / 5 )] · 300: Benzoic acid, 2-[[2-Chloro-3-[(4, -chloro (1, Cantonyl) -4-yl) carbonylJ cyclofluorenyl] sulfur]-, 1-formyl Vinegar, [⑽1 汉 '2 £ &quot;' 3/3) Bu-301: Phenylacetic acid, 2-Π2-Ethyl-3-K in chlorine [1, Γ_biphenyl M · yl) carbonyl] Cyclofluorenyl] sulfur]-, [is- (la, 2α, 3 Lu)!-302: Cyclovaleric acid, 2-[(4, -Ga [1, Candidylphenyl] Amino)] -5 · [(4-Gasphenyl) sulfur]-, (1 α, 2 β '5 Han)-Ring 戍Osmic acid, 2-[(4, -amino U, ι, -biphenyl] · 4-yl) zoyl] -5fluorophenyl) sulfur]-, (1 a, 2y ?, 5 α Ring 戍 pit money, 2- [… Ga Π, P-linked benzyl] winter-based) peptidyl] -5 · 1 (2-tolyl) sulfur]-, (1 α, 2 ?, V 305: ring 戍Feed acid, 2-[(4, -GaII, 1__bibenzyl] pyridyl) carboxyl] · 5 · [(2_tolyl) tellurium]-, (1 from, 306: cyclopentanecarboxylic acid, 2-[(4'-Ga [1 phenyl) thiob '(1 α, 2 ?, 5 α)-benzoic acid, 2 · [arsenic acid is corrected, Γ biphenyl] I group is returned] Cyclofluorenyl j-sulfur J-, 1-methyl ester, (1 from ,, 3) methyl benzoic acid, 2-posto-chinoic acid-3-K [fluoroI1, Γ bibenzyl] · 4-yl) carbonyl 1 Cyclofluorenyl] sulfur]-, 1-methyl ester, (1π, 2π ^^ ccY, i • -fluorenyl) -4-yl) carbonyl J-5-[(2-methyl &lt; x)--' 295-The size of this paper is suitable for China ^ Jia 橾 Standard (〇 ^) 44 (210 father 297 <dung) (please read the notes on the back first, and then fill in this page j put _, π &gt; ηκ Co-operation and Consumption Cooperation of the Central Bureau of Standards, Ministry of Economic Affairs, Du Printed 413675 V. Description of the Invention (293) Cyclopentamic Acid, State, -Gas [〖, Bubiphenylyl, Carbonyl], 4-Gaphthyl) ] -, A r / f Xupu π, 1, -. Lian Ji Bu 4-benzyl-yl) carbonyl Ji Bu 5 - [(4 _ gas

310: Cyclopeptanecarboxylic acid '2-[(HA Phenyl) sulfur 1-, (1 α, 20,5 / 5 Bu ... ^ 1 &quot; 4, _chloro [1, I1-biphenyl] -Heartyl) compound] chloro 3U: cyclopentanecarboxylic acid, M (4--phenyl) sulfur]-, (1 β, 5ίϊ) · 312: cyclopentyl acetic acid, 2-[(4,- 1 ′ (biphenylphenyl) .carbonyl)] 5 · (phenylthio)-, (1α, 2,5,5pentyl)---3Π: cyclopentyl, 2-[(4 ， -Nitrogen 丨 1, Γ · biphenylphenyl 4-yl) phenyl group] small (phenylthio)-, (1 π, 2 cold, 5 Han)-_.. &Lt; * 6,4, -argon -r-Oxy-H [[Benzene.Phenyl] methyl] 314: [1,1, Biphenyl] -4-butanoic acid, 4-amino (S) -cyclopentanoic acid, 2- [(Ethyloxy group ′ r · biphenyl] ice-based group 1 ^ phenylthio)-, (1 «, 2,5 #)-316: Cyclopentamic acid, 2-[(U oxygen [[Bubiphenyl, 4-phenyl), jiki] heptylthio)-, (1 «, 2;?, 5 outer 317: cyclohexyl carboxylic acid, 2-[[4 .- (fluorene oxygen Group) Π, Γ_biphenyl] 4 'group I phenyl group] _5_ (phenylthio.)-, (1 α, 2 /?' 5 π)-318: cyclopentanecarboxylic acid, 2- [ [4,-(fluorenyloxy) Π, 丨 '-biphenyl] -4-yl] carbonyl] -5_ (benzylidene)-, (Icy, 2y ?, 5 / 5)-319: Cyclopentanecarboxylic acid, 2-[[4,-(pentyloxy) [1, Cantonylbenzyl-4-yl] carbonyl, 5 · (benzylthio &gt;-, (1π, , 5 re)) (+)-320: cyclopentane carboxylic acid, 2-[[4,-(oxobiazole, 1, -biphenyl] yl] carbonyl group 5_ (benzylthio)-, ( 1 π, 2 ?, 5/5)-(-)--2%-This paper size is applicable to Chinese National Standards &amp; {CNS) A4 (210 乂 29? Mm) -------- -* Winter ------- order ------% / {/ i (Please read the notes on the back * first and foremost in the nose and nose education) Employees of the Central Standards Bureau of the Ministry of Economic Affairs, consumer cooperation Du printed Α7 Β7 5 2. Description of the invention (294) 321: Cyclofluorene carboxylic acid, 2-[[4,-((Moxiranium M1 ′ Γ-bibenzyl-4-yl-1, alkynyl)-, (1 Shen, 2 / ?, 5) · (+) · 3'22: Cyclic acid, 2-[[4,-(fluorenyloxy, Γ ·· 基基基 1 几 基基基 5 · (phenylthio) -, (1 α, 20 '5 α)-(-)-323: cyclohexyl carboxylic acid, 2-[(4, -ethoxy [1' Γ_biphenyl] icel) carbonyl] · 5 · (Stupid methyl)-, (1 π, 2 / ?, 5 /?)-324: Cyclopentene carboxylic acid, 2 _ [[4, _ (pentyloxy P 'Γ • bibenzyl) pyridyl] A few bases] 〇 (phenylthio), [1S- (1 β, 2; 5,5A)] —: 325: cyclopentanecarboxylic acid, 2-[[4,-(pentyloxy) P, Cantonylbenzyl] yl] 5 · (phenylthio)-, [1R- ( 1 π, 2y ?, 5β)] · 326: cyclopentyl carboxylic acid, 2-[(4, -GaII, biphenylphenyl 4-yl) jiki] -5_ (epimethyl)-, ( 1 π, 2 / ?, 5 /?)-327: 3-cyclohexyl minor enantioic acid, 6-[(4-chloro [1, [, biphenylphenyl 4-yl) quinyl] · 3,4 · Dimethyl-, trans-328: 3-cyclohexene-i-carboxylic acid, 0-[(4-Gas [1, Γbibenzyl] -4-yl) carbonyl] ·, trans · 329 : 3-cyclohexyl-I-carboxylic acid, 6-[(4-air [丨, Γbiphenyl] -4-yl) carbonyl] · 3-methyl- * trans-330: bicyclic [r2 · 2] octyl_5_ 晞 _2_chinoic acid, 3 _ [(heart gas 丨 1, Γbiphenyl] dongyl) carbonyl]-, (2R *, 3R *)-331: bicyclo [2.2.2] octane -2-carboxylic acid, 3-[(4, -GaII, 1'biphenyl] · 4-yl) carbonyl l ·, trans-332: [1, Γbiphenyl] -4-fluorenic acid, 4 ,， 气 -A 1 基 -ύ '-oxygen-333: [1,1 丨 bibenzyl] -4-valeric acid, 4, -chloro-oxygen-297-This paper size applies Chinese National Standard (CNS) Ad specifications (210 × 297 public policy) (Please read the notes on the back before filling out this page} 、-· β A7

V. Description of the invention (295) Shellfish consumer cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs Du printed 334: μ, 1 · biphenylbenzene 4-valeric acid, 4, -gas, /?-Dimethyl-gas · 335: μ, 1, biphenyl] -4-acetic acid, 4, -gas, Θ-ethyl-methyl 4-gas · 3 * 36: cyclopentaneacetic acid, Bu [2- (4._ 气 丨 1 , Γ-bibenzyl 4-yl) 2-oxoethyl 337 · [1,1'biphenyl] -4-phosphonic acid, 4'-murine- &lt; ^, 338: [丨, 1, biphenyl Yl] -4-fluoric acid, 4, -gas- «Τ-(2-methylpropyl) -ό '-oxy- 339: cyclohexyl acetic acid, 1' [2 · (4_ • 气 [1, L biphenyl] ice group) 2-oxoethyl group 340: Cyclopentyl propionate 'Ga Π' Γ biphenyl group 4-yl) Tanyl group 341: 丨 1, 1, biphenyl group l · 4 -Valeric acid, 4'-gas-d-oxy-α_ (3_phenylpropyl_ 342: [1,1_bibenzyl] · 4-valeric acid, 4'-gas-Γ · (2-methyl Propyl warfare '343: [1,1 · biphenyl] _4-gallic acid' 4 · -gas-d'-oxy-plant- (3-phenylpropyl) _ 344: 1-hexanone, Bu (4 , -Bromo [1,1 · biphenylbut 4-yl) · 6-phenyl-3 · (1Η-tetra-5-yl) · 345: Linoscale'b (2- (4'-han [ 1'1'bibenzyl 4-yl) 2-oxoethyl] -4-.privylbutyl] -346: 2-pyrrolidinylcarboxamide, M2 -[2- (4, -Ga [1,1, bibenzyl] -4-yl) 2-oxoethyl] -4-methyl-1-fluorenyl-N-methyl-, (2S ) -347: Phenylbutyric acid, 4- (2-methyl-4-hexyl) -α- (2-methylpropyl) -r-oxy-348: Phenylbutyric acid, α- (2-methyl Propyl) -4- (2-fluorenyl-4-Pethazolyl) -Γ-oxy-349: 2 · »Cybutyric acid, 5- (4-Gaphenyl) -r-oxy-α -(3-phenylpropyl) -350: 2-furan · butyric acid, 5- (4-phenyl) -r-oxy-cy- (3-phenylpropyl) -351: [1,! · Benzyl 4-butyric acid, 4 · -ethynyl-canthoxy-π- (3-phenylpropyl) · 352: [1, Γbiphenyl] -4-butanoic acid, 4 _- (1-hexane Alkynyl) _r_Ga-^ (3-benzylpropyl) -353: [1, Γbiphenyl] -4-butanoic acid, 4 '-(3-methoxy "· propanyl) -r -Oxy (3-benzylpropyl)-, (E)-354: [1, Γbibenzyl] -4-butanoic acid, 4 ·-(3-methylaminopropenyl) -r-oxygen w -2 %-This paper size is in accordance with Chinese national standard (CNS Λ4 specification (21〇X 297 mm) (Please read the notes on the back and fill in this page first) Order by the Ministry of Economic Affairs Central Standard Bureau Bureau Shellfisher Consumer Cooperatives A7 _B7________ 5 Description of the invention (296) (3-phenylpropyl +)-, (Z) -355: [1,1, fluorenyl] 4-butyric acid, 4 _- (3_methoxypropyl) -r-oxy-tritium 3-benzylpropyl), 356: [1, Γbiphenyl] -4-butyric acid '4' -(1-hexenyl) · '· Ga-α- (3-phenylpropyl, (Z)-357: [1,1, Bibenzyl 4-butanoic acid'4, Hexyl-»-(3 -Phenylphenyl)-358: [1, Γbiphenyl] -4-butyric acid, r-oxyphenylethenyl) -from-(3-phenylpropyl)-, (Z)-. _ 359: Π, factory-attached benzyl I · 4 · butyric acid 'r oxygen_4, (2-phenethyl) -yi_ (3 · benzylpropyl) ~ 360: cyclopentanecarboxylic acid, 2-[(4, -Gas [1'1, biphenyl] -4-yl) carbonyl] -5Hepta'3-dihydro-1,3-dioxo-2H-iso '^ indole-2-yl) methyl]- , (1 α, 20,000, 5 points) _ 361: cyclopentanecarboxylic acid, 2-[(4, · Gas [1,1'bibenzylM · yl) carbonyl '3-dihydro], 3- Dioxo-2'-isoindole · 2-yl) methylbull '[1S- (1 α' 2 / 3,5 β)] 362: Cyclopentamic acid * 2-[(4 ·-气 [1 'Γ biphenyl M-yl) carbonyl] -5-[(1' 3-dihydro-1,3-dioxo-2'-isofluorin-2-yl) methyl]-, [1R- (1 Suppose, 2 cold, 5 ^)] 363 .. Cyclofluorenecarboxylic acid, 2-[(4f-gas [1,1'biphenyl M-yl) carbonyl] -M2- (4-tolyl) vinyl Bu, [1 or, 20,000, 50,000 E)]-364 ·. Cyclopeptanecarboxylic acid, 2-[(4 · -Gas [1,1'bibenzyl-4-yl) carbonyl 5-[(methoxymethoxy) methyl] -, (I α, 2 / ?, 5 /?)-365: Cyclopeptanecarboxylic acid, 2-[(4'-chloro [1, factory-attached benzyl], 4-yl) carbonyl] -5- ( Benzylmethoxy) methylbutyrate, (1 «, 2nd, 5th)-366: cyclopentanecarboxylic acid, 2-[(4'-Ga [1, Γbibenzyl] -4-yl) carbonyl ] -5- (Stupid Qijia • 299- Zhang Zhiyuan uses China National Standard (CNS) A4 specifications (2. [ϋ; Η7 · ^ skinny) (Please read the precautions on the back before filling out this page-pack. Ordered by male laborers in the Central Standards Bureau of the Ministry of Economic Affairs for cooperation in printing kl ______B7____ V. Description of the invention (: 97) Kibb, (1 α, 2 ?, 5 /?), 367: Cyclopeptanecarboxylic acid, 2- [(Benzamyloxy) methyl] -5-[(4, -Ga [1,1, pyridinyl 1A-yl) strict]-, (1 α, 2 0, 5 /?)-368 : Bu 2 · benzenedicarboxylic acid, 1-[[2-carboxy-3-[(4.-Ga 丨 1, Γbiphenylfluorenyl · carbonyl) carbonyl] cyclofluorenyl] methyl] 2-methyl acetate, (Ία, 2 /? 369: Cyclopentanecarboxylic acid, 2-[(4, -Ga [1, Γbibenzyl] · 4-yl) carbonyl] -5-[(2-pyridinylthio) methyl Base]-'(1 π, 2 points, 5 /? )-370: Cyclopentanecarboxyl, 2-[(benzylamido) fluorenyl 5-[(4ι-Ga 〖1, Γ biphenyl phenyl 4-yl) quinyl]-'(1 Shen, 2; 9,5 million)-371: Cyclopeptanecarboxylic acid '2-[(4'-Gas [1,1 · biphenyl] -4-yl) carbonyl] -5-[[(2-methoxyethyl (Oxy) methoxy] methyl]-, (1 π, 2y ?, 5y?)-372: cyclopentanecarboxylic acid, 2-[(4 * -Ga [1, Γbibenzyl] -4 · Carbonyl)]-5-[[(benzyl) thio] methyl]-, (la, 2 / ?, 50,000) -373: cyclopentanecarboxylic acid, 2-[(4'-Ga [1 , 1 · biphenyl] -4-yl) carbonyl] -5-[(benzylthio) methyl 1-, (1,2,2,-)-374: cyclopentanecarboxylic acid, 2-[(4 '-Ga [1,1'biphenyl] -4-yl) carbonyl] -5-[(propylthio) methyl]-, (1 Han, 2 Lu, 5 C)-375: cyclopentamidine carboxyl Acid, 2-[(2-benzimidazolylthio) methyl] · 5-[(4 · -Ga [1, Γbiphenyl] -4-yl) carbonyl]-, (1 α, 2 Lu , 5))-376: benzoic acid, 2- [ί [2-carboxy-3-[(4'-Ga 丨 1,1'biphenyl] -4-yl) carbonyl] cyclopentyl] methyl] Sulfur]-, 1-methyl ester, (1 π, 20,000, 3 precipitates) -377: Cyclopeptanecarboxylic acid, 2-[(4'-chloro [1, Γ bibenzyl) carbonyl] 5- [ [[(Stupid methoxy) Carbonyl] amino] methyl l ·, (Id, 2 / ?, 5/5) -378: benzoic acid, 2-methyl · '[2-carboxy-3 · [(4 · -Ga [1,1 '聨 Benyl] -4-yl) carbonyl-300-National Standard S (CNS M4 (210 x 297 mm)) --------- ^ ------ -Order ------ rt yg% / (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ____B7_______ V. Description of the invention (298) Methyl acetate, (1, 2/3, 3) 379: benzoic acid, 3-F-based, [2-carboxy-3-[(4_-gas [1,1 · biphenyl] -4 -Yl) carbonyl * group J cyclofluorenyl J methyl ester, (1 from, 2 points, 3π) · 380: benzoic acid, 4-f group-, [2-carboxy-3-[(4_-Ga [1, Γ bibenzyl] -4-yl) carbonyl] cyclopentyl] methyl ester, (1 α, 220,000,3 〇-381: benzoic acid, 2-methoxy-, [2-carboxy-3- [ (4, -Ga [1,1'bibenzyl] -4-yl) carbonyl] cyclopentyl] methyl ester, (lor, 2;?, 3 «〇-382: benzoic acid, 3-methoxy- , [2-Carboxy-3-[(4, -Ga [1,1'biphenylphenyl'yl Lcarbonyl] cyclopentyl] methyl ester, (1 α, 20,3 4-methoxy-, [2-carboxy-3-[(4 -Ga [1,〗, bibenzyl] -4-yl) carbonyl] cyclopentyl] methyl ester, (le, 2y ?, 3co-384: cyclopentanecarboxylic acid, 2-[(2-benzyl Hexazolylthio) methyl I-5-[(4f-Ga [1'1'biphenyl] -4-yl) carbonyl, (1π, 2/3, 5/5) -385: cyclofluorene Alkanecarboxylic acid, 2-[(4, · Ga [1, Γbiphenyl] -cardio) carbonyl] -HG '3-dihydro-4-nitro-1,3-dioxo-2H-iso4 Indole-2-yl) methyl] _ '(1α'M, 50,000) -386: Cyclopeptanecarboxylic acid, 2-[(4, -Ga [1,1'bibenzyll · 4 · yl ) Carbonyl] -5 · [(1,3_ dihydro-5-nitro-1,3-dioxo-2H-iso '^ in-2-yl) methyl]-' (1 α '2 /?, W-387: Cyclopentanecarboxylic acid, 2-[(4, -Ga [1, Γbibenzyl-4-yl) carboxyl 5 · ... '3-dihydro-1,3-dioxo-2Η- Benyi [f] Isoindol-2 * yl) methyl] _ '(1 α' 20,000-5 / 5)-

388: cyclofluorene carboxylic acid, 2- 丨 (4, -chloro [1,1, pyridinyl I · 4 · yl) carbonyl] _5_ 丨 (4-Gaphenoxy) methyl group, (1 α , 2/5, W -301-This paper size is suitable for the homeless # 准 （CNS） Α4 ^ 格 （21.0X297 公 «) I-. I! ...... I-----k ^ .. .....- / V (Please read the precautions on the back and fill in this purchase)

, 1T Printed by A7 _B7____ of the Consumer Cooperatives of the Central Standard Vehicle Bureau of the Ministry of Economic Affairs V. Description of the Invention (299) 389: Cyclopentamic Acid, 2-[(4, -Gas [1,1 · Biphenyl M · Base] Carbonyl M — lIX1,3_diargon-1,3-dioxo-2H-isoxandol-2-yl) oxy] f group] _ '0 not, 20,000' 5 * β)-390: cyclopananecarboxyl Acid, 2-[(4, -Ga [1, Γbiphenyl] -4-yl) carbonyl] -5-[(5-Ga-1,3-dihydro-6-nitro-1,3- Dioxo-2Η-isoindol-2-yl) methyl]-'(1 π, 2β »5β) ~ 391: Cyclopeptanecarboxylic acid, 2-[(4'-Ga [1, Γbiphenyl ] -4-yl) carbonyl] -5-[(5 '6-digas-1,3-dihydro-1,3-dioxo-2Η-isofluorin-2-yl) methyl]-, ( 1 π, $ β, 392: cyclopentanecarboxylic acid, 2-[(4-amino-1,3-dihydro-1,3-dioxo-2Η-isoindole-2-yl) methyl] -5-[(4, -chloro [1, Γbiphenylj-4-yl) carbonyl]-'(1 π, 2 cold, 5 /?)-393: cyclobutanecarboxylic acid, 2- (ethyl (Methoxy) -4- 丨 (4 · -Ga [1, Γbiphenyl] -4-yl) carbonyl]-, (1H, 2α, 4α)-394: cyclobutanecarboxylic acid, 2- ( Acetyloxy) -4-[(4'-Ga [1,1'biphenyl] -4-yl) carbonyl]-, (1H, 2/3, 4tv)-395: ring Butanecarboxylic acid, 2- (ethyl $ oxy) -4-[(4, -gas [1, 丨, biphenyl] -4-yl) carbonyl, (Iπ, 2π, 4 /?)-396 : Cyclobutanecarboxylic acid, 2- (ethoxy) -4-[(4, · Ga [1 '1, biphenyl] · 4 · yl) carbonyl group, (I a, 2 treatment, 4 / 3) -397: cyclobutanecarboxylic acid, 2-[(ethoxy) methyl] -4-[(4 · -Ga [1, Γbibenzyl] · 4-yl) carbonyl j-, ( ], 2 / ?, 4α)-398: cyclobutanecarboxylic acid, 2-[(ethylacetoxy) methyl] -4-[(4, -chloro [1 ′ 1′bibenzyl M-yl ) Carbonyl]-, (i-Fan 'hr, 4 works)-* 302-_ _ ----Paper size is applicable to China Solid State Standards (CNS) A4 specifications (' 2l'〇X 297 public love) (Please read first Note on the back, please fill out this page again). Packing. Order A7 B7 Printed by the Central Government Bureau of the Ministry of Economic Affairs of the Department of Shellfish Consumer Cooperation Du printed 5. Description of the Invention (300) 399: Cyclobutanecarboxylic acid, 2-[(acetamidine oxygen Methyl) methyl 4-[(4, -Ga [1,1 • biphenylbu 4-yl) truncyl]-, (1 π, 2 y ?, 40,000)-'400: cyclobutanecarboxyl Acid, 2-[(4 · -qi [1, "bibenzyl] -4-yl) pyridyl] -4- (hydroxymethyl) _, (1 Shen, 2 ;?, 4 &quot;) _ 401 · .Cyclobutanecarboxylic acid, 2-[(acetamidine ) Fluorenyl〗 -4-[(4 · -Ga [1,1 · 1benzyl] -4-yl) carbonyl]-, (1 α ,, 4y?)-402: cyclobutanecarboxylic acid, 2- [(4 · -Ga [1,1'bibenzyl] -4-yl) carbonylcarbonyl 4-[(1,3-dihydro-1,3-dioxo-2Η-isoindolin-2-yl) Methyl]-, (1 α, 2 cold, 4 lu)-403: 3-furancarboxylic acid, 4-[(4'-Ga [1, Γbiphenyl] -4-yl) carbonyl 2- [(1,3-Diargon-1,3-dioxo-2Η-iso &quot; indole-2-yl) methyl] -tetrahydro, (2 α, 3 #, 4 α)-4〇4 : [1, Γbibenzyl] _4 · Butyric acid '4, -qiι [2-[[2 · (methoxycarbonyl) benzyl] amino] ethyl] -r-oxyl-405 ·· 2H-isoindole-2-butyric acid, α- [2 · (4, -Ga [1,1, bibenzyl] · 4 · yl) _2 孰 ethyl] -1,3-dihydro-1, 3-dioxo-5- (benzyloxy) -406: 2H-isoxanthenyl-2-butanoic acid, π- [2- (4, -qi [1, Γbiphenylphenyl 4.yl) _2 _Oxyethyl] -1,3-diargon-1'3-dilactate-5-propanoyl 407: 2H-L-indole-2 · butyric acid, β- [2- (4, -Ga [1 , 1, bibenzyl 4-yl) _2_oxoethyl] -1,3-dihydro-1,3-dioxo-4- (benzylmethoxy) -408: 2H-iso-4 -Butyric acid, 5-amino-λ ·-[2- (4'-gas fi, 1.bibenzyl 4-yl) -2-oxyethyl ] -1,3-diargon-1,3-dioxo-409: 2H-benz [f] iso4-dole-2-butanoic acid,-(2- (4 ^ -gas11, r-dibenzyl 4-yl) -2-oxoethyl] -1,3-dihydro-1,3-dioxo-410: 2H-benz [de] isobutyric acid 'cv-[2- (4 气 [1,1 Lianbenji-303-This paper ruler is applicable to the Chinese National Standard (CMS) Λ4 specification (2lOX297.i · ali 1 ~ '-------- (Please read the precautions below and fill out this Page)-Consumption cooperation between employees of the Central Standards Bureau of the Ministry of Economic Affairs, Du printed A7 and B7 V. Description of the invention (301) Bu 4-yl) -2-oxoethyl] -1,3-dioxo-411: 1- Pyrrolidine butyric acid, π- [2- (4'-Ga [1, Γbibenzyl] -4-yl) -2-oxoethyl]-• 2,5-dioxy · 412: 1-? Ratio Lorbitine ethyl lactate [1,1 · Bentyl] -4 -yl) -2 oxoethyl] -2 '5 -dilactate-413: 2H-isoamido-2-butyric acid, α-[ 2- (4, Ga [1, Γbiphenyl] -4-yl) -2-oxoethyl] -1,3,3a, 4,7,7a-hexafluorene-1,3-dioxo-,丨 Angular 414: 2H-iso &quot; indole-2-butyric acid, gas [1, Γbibenzyl 4-yl) -2-oxyethyl. -Yl] -5- (1,1-dimethyl Ethyl) -1,3-dihydro-1,3-dioxo-415: 2H-iso ^ indole-2-butanoic acid, 5,6-digas- -[2- (4, -Ga [1, Γbiphenyl] -4-yl) -2-oxoethyl] -1,3-dihydro-1,3-dioxo 416: 2H-isofluorene Indole-2-butanoic acid, α] 2- (4'-Ga [1, Γbibenzyl] -4-yl) -2-oxoethyl] -1,3-dihydro-5- subgroup-1 , 3-Dioxo-417: 2H-pyrrolo [3,4-c] pyridine-2-butanoic acid, α- [2- (4, -chloro [1, Γ biphenyl] -4 -yl) -2 -lactylethyl] -1,3 -dilactate-1 '3 -dilactate_ 418: 1pyrene-benzo [de] isopyridin-2 (3Η) -butyric acid, 6-bromo-π- [ 2- (4 · -Ga [1, Γlinkedyl] -4 -yl) -2 -lactylethyl] -1 '3 -dioxy * 419: 6H-1,3-dioxolene [4,5-Γ] Iso-4do-6-butanoic acid, π-[2- (4 · -Ga [1, fluorenylbenzyl] -4-yl) -2-oxoethyl-5,7 -Dihydro-5,7-dioxo-420: 2H-iso4-dole-2-Γ acid from-[2- (4 * -Ga 『i, Γbibenzyl j-4-yl) -2- Oxyethyl] -1,3-diargon-5-hydroxy-1 * 3-dioxo-421: 2H-isoamidine-2-butyric acid, π- [2 · (4 · -Gaμ, Γ-linked Benzyl] -4-yl) -2-oxoethyl] -1,3-dihydro-4-hydroxy-1,3-dioxo-422: 2H-isoamido-2-butyric acid, π- [ 2- (4'-Gas [1, Γbiphenyl] -4-yl) -2-oxoethyl-304-This paper is applicable to Chinese papers in China (standard) (standard) (6) 4 specifications (!! 1 0/297 mm) (Please read the notes on the back before filling out this page) Order A7 A7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs B7_ V. Description of the invention (302) Kib 1,3 · Diargon · 5 · Methoxy_1,3_dioxy_ 423: 2H-Iso &quot; Hydroxy-2-butyric acid, hydrazine] -4-yl) -2-oxyethyl'yl] -1, 3- Dihydro-4-methoxy-1,3-dioxo_ 424: 211-iso- ^ pig-2-butanoic acid, gas [1 '1'biphenyl] -4-yl) -2-oxy Ethyl ... yl] -1,3-dihydro-1,3-dioxo, 5 _ [(2 ^ sedienyl) oxyb. 425: 211-Iso-0Hydroxy-2-butyric acid '5- (2- Ethyloxy)-£ 1 /-[2- (4_-Gas [1'1_biphenylJ-4-yl) -2-oxo-Cj-1,3-dihydro], 3.2 Oxy-426: [1, Γ-bibenzyl] -4_ butyric acid, qi -r -oxybenzylthio) ethylbuthyl--427: [1, Γ-biphenyl] -4-butyrate, 4'_Ga-α- [2-[[(4 · methoxyphenyl) methyl] sulfur] ethyl] -Γ _oxy- 428: [1, Γ-biphenyl] _4_butyric acid, 4 '_Ga ·, · Oxygen · α- [2- (Benzenesulfenyl) ethyl]-429: 2fluorene-benzo [f] isokeydoline-2-butyric acid' α · [2 · (4 ' · Ethoxy [1,1, biphenyl] -4-yl) -2-oxoethyl] -1,3-dihydro ", 3_dioxy · 4 3〇: [1,1, · biphenyl] -4-butyl base, (ethyl amine amino group 4 · -gas-r-oxy-431: 2HKt2-hexanoic acid, β- [2- (4'- Gas Γ1, Γbiphenylj-4-yl) -2-oxoethyl] -1 '3 -diaza-1,3 — * milk_43L [1,1, -biphenylbut 4-butanoic acid , 4_-Ga-α · [[[3- (methoxycarbonyl) phenyl] sulfur] methyl] Γ-oxy- 433: Π, 1, -Bibenzyl 4-butanoic acid, 4'-Ga- Shen- 丨 [(2, b-dimethylbenzyl) thio] methyl] plant-oxygen-434: [1, Γ-bibenzyl] butyric acid '4 · -fluoro || (methoxycarbonyl) benzyl Group] thio] methyl] r-oxy- 435: [1 '1, -bibenzyl] -4-butanoic acid' 4, -gas-called [[3, (diethylamino) carbonyl) benzyl 305 -The size of this paper is suitable; "China Standard (CNS) A4 Specification (2 丨 0 _X 297mm;-(Please read the precautions on the back before filling this page))-Article-413675 at Β7 V. Description of the invention (303)] Sulfur] methyl] r-oxygen (Please read the notes on the back before filling this page) 436: [1,1'-biphenyl] -4-butanoic acid, 4, gas two famino) carbonyl) phenyl] sulfur] methyl] r-oxy- 437: [1,1'-biphenyl] -4-butanoic acid, 4 · -gas-α-[[[3 · (di Methylamino) carbonyl ) Phenyl 1thio] methyl] r-oxy. 438: Bicyclic [2.2.1] hepta-5- 埽 -2-carboxylic acid, 3- 丨 丨 4, (pentyloxy) [1,] 'biben Yl] -4-yl] carbonyl], (2-intro, 3-exo) _ 439: 1-cyclopentene-1-carboxylic acid, 5-[(4 匕 Ga-Π, 1, -bibenzyl] —4.yl1carbonyl] -440: cyclopentanecarboxylic acid, 2-[(4, gas [1, ι, _biphenyl] -4 · yl] carbonyl] -5-[(benzyl) sulfur] -, (1β, 2 ?, 5β)-441: cyclopentanecarboxylic acid, 2-[(4'-gas [1, ι'_biphenyl] -4-yl] carbonyl] -5-[( Benzyl) sulfur]-, (1β, 2 / ?, 5 /?)-442: 1-cyclopentyl-1-propanoic acid, 5-[[4 '-(fluorenyloxy) [1,1, -Biphenylphenyl 4-yl] carbonyl] -443: 1-cyclopentene 4-quinic acid, 5-[[4,-(hexyloxy) [1, Γ-biphenyl] -4 · yl] Carbonyl group 444: [1, Γ biphenyl] -4-butanoic acid, 4, hydroxy-r-oxy-π-[(benzylthio) carboxyl]-Other specific embodiments of the present invention are related to the technical experts The description or operation disclosed by the invention can be understood. The description and examples are just examples. The scope and connotation of the present invention are described in the following patent applications. ° Printed by the Employees' Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs -306-This paper uses Chinese National Standards (CNS) Α4 specifications (210 × 297)

Claims (1)

413675 Patent Application No. 84U2045 Chinese Patent Application Amendment (August 89) Application; please Xingli Fan f— 丨 丨 · ^ clothing a 1 'A compound of the following general formula ABDEG with inhibitory activity of matrix metalloprotein su The Ministry of Economic Affairs, the Ministry of Economic Affairs, the Central Government, the Automobile Industry, the Consumer Cooperation, and the Du Duan Printing (a) A Representative "Sephenki, Wei Keji, Jin Geji, 0 Furanji! 7-pyridyl or phenyl: wherein fluorenyl, oxazolyl, and azazolyl can be selected from one or more halogens: -F, -Cl, -Br, and I and 6-carbon alkyl groups Furanyl may be substituted by one or more substituents selected from the group consisting of halogen: -F, -Cl, -Br and I, carbon and -COOH; pyridyl may be substituted by one or Multiple substituents selected from the group consisting of halogen: -F, -Cl'-Br, and I, I-6 Λ carbon alkynyl and -CKCu) alkyl group; benzyl group may be substituted by T where T represents selected from Substituents of the group consisting of: * 1, 2 or 3 halogens: -F, -Cl'-Br and -I; * alkyl groups of 1 to 6 carbons; * alkyl groups of 1 to 6 carbons ; * 2 to 6 carbon alkenyl groups; * Unsubstituted or phenyl substituted 2 to 10 carbon alkynyl groups; *-CH〇 '_, · CN, N02,-OH, (C [-6 alkane Group) 0H '(c6 alkyl) CN, tetrazolyl, phenyl, (C6 alkyl) phenyl'-n (r2) 2'-OR4, and -S- (C 〖-6 ) Alkyl groups; and * -alkenyl-Q, wherein the alkenyl group includes 2-4 carbons; and Q is selected from the group consisting of phenyl groups -C02R2; and Car (CNS) Α4 is now available (210 × 297 mm) (please first read the "Notes on the back" and then fill out this page) 413675 Patent Application No. 84U2045 Amendment to the Chinese Patent Application Range (August 89) Application; Please Xinglifan f—- Gong · ^ yi a 1 ′ compounds with matrix metalloproteinase inhibitory activity of the following general formula ABDEG Phenyl, cleavage, oxenyl, oxanyl,! 7-pyridyl, or phenyl: wherein fluorenyl, oxazolyl, and azazolyl can be selected from one or more halogens: -F, -Cl, -Br, and a substituent consisting of a group consisting of I and P6 alkyl; furanyl may be substituted by one or more halogens: -F, -Cl, -Br and I, I carbon and -COOH is substituted by a substituent of the group; pyridyl may be composed of one or more selected from halogen: -F, -Cl'-Br and I, I-6 Λ carbon alkyl and -CKCu) alkyl Substituent group substitution; Benzo may be substituted by T wherein T represents a substituent selected from the group consisting of: * 1, 2 or 3 halogens: -F, -Cl'-Br and -I; * 1 to 6 carbon alkyl group; * 1 Alkyl from 6 carbons; * Alkenyl from 2 to 6 carbons; * Alkenyl from 2 to 10 carbons unsubstituted or substituted with phenyl; *-CH〇 '_, · CN, N02,-OH , (C [-6 alkyl) OH (C6 alkyl) CN, tetrazolyl, phenyl, (C6 alkyl) phenyl'-n (r2) 2'-OR4, and- S- (C 〖-6) alkyl; and * -alkenyl-Q, wherein the alkenyl body includes 2-4 carbons; and Q is selected from the group consisting of phenyl-C02R2; and Standards used in China "Furniture Car (CNS) Α4 is now (210 × 297 mm) (please« read memorandum * before filling in the lettuce page) Patent scope, allyl-Q, where R2 represents fluorene, an alkyl or phenyl group of 1 to 6 carbons; R3 represents an alkyl or fluorenyl group of 1 to 4 carbons; R4 represents fluorene, (C! -12) Alkyl, benzyl (Cm) alkyl, unsubstituted or Ck alkyl pyridyl, (C3.8) cycloalkyl (Cu) alkyl, (CH2) SX where s is 2-3 and X It is halogen or OH; but the limitation is that it is connected to Q or part of Q- and it is separated from Q by any N, 0 or S. At least one carbon atom; and (b) B represents a group selected from Benzy, phenenyl, furyl or pyridyl: (Please read the notes on the back before filling this page) Order. ¾ Printed by the Central Ministry of Economic Affairs of the People's Republic of China. (C) D stands for:〉 c = o or〉 cC, / ^ 0H (d) E stands for a claw! ^ One of the substituents! One of carbon atoms, where the R6 group is an independent substituent, or constitutes a ring, where: a) the two R6 groups are combined, and the chain attached to the two R6 groups Atoms and any interspersed chain atoms together form a 3- to 7-membered ring; or b) an R6 group and this R6 group are being used again in this paper * 11 standard standard (CNS f A4 size (210X 297 male sickle) Patent scope And A8 B8 C8 D8 R2 〇ί II ′ .Ν-C— R2 (please fill in this page without reading the notes on the back) where Y represents CO or s; R1 represents Η or 1-3 carbon alkyl; and R2 is as defined above ; And u is 0, 1, or 2; and the limitation is that when R7 is N Λ / ^ Ίυ V 51 R2 [Η — R2 Ordered by the Ministry of Justice * Department t printed by the Shellfish Consumer Cooperative and the unit A is When phenyl and B are 0, then A is replaced by T; *-(CH2) vZR8, where Z stands for 0 0, 0 \ &quot;, 4- This paper uses the standard to select the poor countries (CNS) ) Ｍ 洗 格 U 丨 0 X M7 mm) M ^ 部 tcentral sample 窣 扃 贝 工 consuming cooperatives printed *. Λ8 B8 C8 ------ ^ _ ~, the scope of patent application R8 is selected from the following: 1 Alkyl groups of 1 to 12 carbons; phenyl; fluorenyl; a sephenyl, 1-pyridyl; pentyl; where the moieties include 1 to 4 phenyls: and -C (0) R9, where R9 represents an alkyl or phenyl group of 2 to 6 carbons; and v is an integer of 0 or 1 to 4, with the limitation that when the a unit is a phenyl group, the B unit is a phenyl group, and ^ is! And η is 2, then when R8 is aryl or heteroaryl, V is an integer from 1 to 4; but the restrictions are: • When R8 is -C (0) R9, Z is S or 0;- When Z is 0, R8 may also be _ (CqH2q〇) '; R5, where q. R and 11 &gt; are as defined above; and-when the A unit is phenyl, the B unit is phenyl, and m is 1, When η is 2 and ν is 0, then A is substituted by T; and, where w is an integer of 1 to 3; and RIG represents an alkyl group of 1 to 2 carbons, but its limitation is any τ or R6 group The aryl or heteroaryl part of the group may bear at most 2 aR | selected from the following: _ (CH2) yC (Rll) (Rl2) OH,-(CH2) yOR! 1--(CH2) ySRn --(CH2) yS (0) R! L-(CH2) yS (0) 2R11,-(CH2) yS02N (R &quot;) 2 '_ (CH2) yN (Ru) 2,-(CH2) yN ( Rn) COR12, .〇c (R &quot;) 20--Two of the oxygen atoms are connected (please «read the precautions on the back before filling out this page) The size of the paper method is common to the Chinese national rate (CNS &gt; (210X 297 mm) The Ministry of Economic Affairs ordered the central sample bureau to cope with the work and cooperation f. Du Yince AS B8 CS -_, the scope of patent application for aryl ring:-((^ 2) 7 (: 01111,-((^ 2 \ ( : 0 call 1111) 2,-(CHjyCC ^ R1 1,-(CH2) yOC〇R11, _halo '' CHO, -CF3 '-N02, -CN and -Ri2, where y is o to 4; R11 represents fluorene or an alkyl group of 1 to 4 carbons; and R · 12 represents a base of 1 to 4 carbons; and (e) G represents -M, 0 f? «R13 丨 丨 (? Or — 2 — ί ——C—N—C—MLN— · C --Η, Η Η where M represents -C Ο 2 Η-, C Ο Ν (R 1!) 2 or -C Ο 2 R ', 12: Rn and Ri2 are as defined above; and R13 represents proline; and Its pharmaceutically acceptable salts. 2. The compound according to item 1 of the scope of the patent application, wherein at least one of the a and B units includes a β-thiophene ring. 3. The compound according to the scope of the patent application, wherein the D unit is carbonyl group 04. The compound according to item 1 of the scope of patent application, in which the E unit, n is 2 and m is 1. 5. According to the application of Cheli Fanyuan item 1, the G unit is _ C02H »6. According to _ please apply for the compound in the first item of the patent scope, in which -6 * This paper method is applicable to China® Housekeeping Standard (CNS) A4 wash grid (21 〇X 297 public dust) (Please read« (Notes should be filled in this education) Order A8 B8 C8 D8 6. Scope of patent application T B is a compound based on the 6th scope of the patent scope of the patent, and its unit is several millimeters. 8. The compound according to item 6 of the patent scope, where E unit order, 11 is 2 and in is 1 = &gt; 9. The compound according to item 6 of the patent scope, wherein the unit 0 is _ C〇2H . 10. The compound according to item 6 of the application, wherein m is 1; and R6 is an independent substituent. 11. The compound according to item i0 of the scope of patent application, which is represented by the following formula: —O-j2-o-r5-c〇2h Ministry of Tao. R Central Samples Bureau Shellfish Consumer Cooperatives ¾ where the substituent T is located at the 4_ position on the A ring relative to the connection point between the A and B rings = 12. The compound according to item 6 of the patent scope, where m is 2 or 3; and when m is 2, 'the two R6 groups are independent substituents' or together form the ft dimension of this paper. Furniture standard (CNS) Λ4M (210X297 mm) A8 B8 C8 D «Spiral ring in the scope of patent application, or one W group is an independent substituent 'and the other forms a spiro ring; and when &quot; is 3 , Two R6 groups are independent substituents, and one R6 group forms a%, or two R5 groups are formed to form a ring, and one ruler group is an independent substituent, or three R6 groups are independent Substituent 3 1 10. The compound according to item 6 of the patent is ordered, where 111 is 1 or 2; and when m is 1, the R6 group forms a non-spirocyclic ring; when m is 2, two R6 The groups are common: it is difficult to form a non-spiro ring or one R6 group is the only three substituents and the other is a non-spiro soil. H. According to the compound of the scope of application for item 13, it is necessary to have the E unit Selected from the following:, (Jing first ® Notes on the back of the ear read complete this laughing) Gamma] winged central relief section t comp dart owned cooperatives Bureau HIGHLAND dissipation plate S- The standard of this paper is applicable to the standard of a country (CNS &gt; A4) (210X297 male iTi ''-patent application scope A8 B to C8 D8 Ministry of Economic Affairs _ 央 橾 引 扃 身 工 洧 f 合作社 印 印 *. 其 ta 〇1 or 2: b is 〇 or i; c is 〇 or [; d is 〇 or [; c + d is 0 or 1; e is U; g is 3-5; i is 〇4; k is 0-2; the total number of R6 radicals is 0, 1, or 2; (J represents 0, s, or NR_; and each radical is selected from the following: an alkyl group of 1 to 6 carbons; Where the alkyl portion contains 1 to 7 carbons; * 2 to 6 alkenyl groups; * alkenyl substituted with aryl groups in which the alkenyl portion contains 2 to 4 carbons and the aryl portion contains 6 Up to 10 carbons, * 2 to 9 carbon alkynyl groups; * blocks substituted with aryl groups: the group 'wherein the alkynyl portion contains 2 to 4 carbons and the aryl portion contains 6 to 10 carbons, * BenQ; * -COR3; * -C02R3; * -CON (R2) 2; *-(CH2) tR7, where t is 0 or an integer from 1 to 4; and *-(CH2) vZR8 'where V is 0 or An integer from 1 to 3; and Z represents -S- or -0- 〇15. According to the order, the compound in the scope of patent No. 14 is represented by the following formula: (please read the precautions of `` Read V &amp; fill in (This page) Order -9- The paper * Λ degree is applicable in the "National Rubbing Standard (CNS) A4 * t Pile (2 丨 0) &lt; 297 mm) 6. Scope of Patent Application Α8 BS C8 D8 Π Employees of the Central Bureau of the Ministry of Cooperation, Ministry of Cooperation, and Du Yinze, where the substituent T is as defined in item 1 of the scope of patent application and is located at position 4_ on the ring A relative to the connection point between the rings A and b; e is 2 or 3. 16.—Saurine composition with matrix metalloproteinase inhibitory activity, which includes a compound according to item 1 of the patent scope and a pharmaceutically acceptable carrier "17 A pharmaceutical combination according to item 16 of the patent scope Material, its line: used to reduce osteoarthritis, rheumatoid arthritis, dystrophic joint k, periodontal disease, corneal ulcer, proteinuria, aortic aneurysm disease, malnutrition epidermolysis, leech, cause Inflammatory disease, osteopenia regulated by M MP activity, temporomandibular joint disease, or demyelination of the nervous system 'Delayed tumor metastasis or degenerative cartilage loss due to joint trauma: reduces arteriosclerosis Coronary arterial thrombosis caused by plaque rupture; or improved fertility control β 18. The pharmaceutical composition according to item 17 of the patent application park, wherein the effect is to reduce osteoarthritis. 19. The pharmaceutical composition according to item 17 of the application, wherein the effect is to delay tumor metastasis. 20. — A compound of the following formula (please read the precautions on the back before filling in this page), 11 / V -L0-this paper * standard universal t furniture ratio (CNS) (210 X 297 public *) 413675 ′ —One patent application scope A8 B8 CS D8 ε-co ^ H where E stands for The definition of T is as follows: Please apply for the first item of the patent scope = 21. The compound according to the first item of the profit scope of the application, which is selected from Examples 1 to 5 i 7 9 to i S i I 1------- I ^ -I / ίχ (please read the notes on the back * before filling in the wooden pages) Order the stamping of the shellfish consumer cooperation department of the Ministry of Economic Affairs *. 13 to 22, 26, 31, 33 to 34-4 to Compounds in 177, 183 to 444 ° 22. The compound in the scope of patent application of the Gen Brigade No. 21, wherein the compound is one of the following compounds: Example No. 铒 196 4- [4- (4 · -benzyl) phenyl ] -4-oxo-2- (stupid methyl) butyl 197 4 · [4- (4 · chlorophenyl) phenyl bu 4-oxo-2S- (phenylthiomethyl) butyric acid 198 4- [ 4- (4 · Phenylphenyl) phenyl] · 4-oxo-2R- (phenylsulfenyl) butyric acid 114 4- [4- (4-xenylphenyl) phenyl] _4-oxo-2- ( 3 · Phenyl) butyric acid 115 4- [4- (4 · Phenyl) phenyl] -4 · -oxo-2Han_ (3_phenylpropyl) butan 116 4-〇- (4_ Pyridyl) phenyloxy-2S- (3-benzylpropyl) butanoic acid144 4 '[4- (4 · chlorophenyl) phenyl] -4-oxo, 2- [2- (3-N, N-diethylaminomethylmethyl) phenyl] butyric acid 145 4- (4- (4-chlorobenzyl) benzyl] -4-gas, 2S ~ [2- ( 3-N, N-diethylamino glycosyl) benzyl] butyric acid-Ιί · Applicable for this paper size «National Carrier (CNS) A4 This grid (210 × 297 male *) 413675 A8 B8 C8 D8 Application Scope of patents: Ministry of Economic Affairs, Ministry of Economic Affairs, China, Gongyang, pager, consumer cooperation, Du Yin *. 1 46 85 86 87 99 100 10 1 267 268 269 294 296 29 7 298 299 3 00 3 60 3 6 1 4- [4- (4 -Phenyl) phenyl] -4-oxo-2R- [2- (3-N, N-diethylamino 1Ffluorenyl) benzyl] butanoic acid 4- [4- (4-pentyloxybenzyl ) Phenyl] -4-oxo-2- (3-phenylpropyl) butanoic acid 4- [4- (4-pentyloxyphenyl) benzyl] -4-oxo-2S- (3-phenylpropyl ) Butyric acid 4- [4- (4-pentyloxyphenyl) phenyl] -4-oxo-2R- (3-benzylpropyl) butyric acid 4- [4- (4-fluorenyloxyphenyl) phenyl ] -4-oxo-2- (3-phenylpropyl) butanoic acid 4- [4- (4-fluorenylbenzyl) phenyl 1-4-fluorene-2S- (3-benzylpropyl) butanoic acid 4 -[4- (4-Phenylbenzyl) benzyl] -4, oxy-2R- (3-benzylpropyl) butyric acid kernel [4_ (4-chlorophenyl) phenyl] -4 · oxy-2 -(2-¾ 醢 iminoethyl) butanoic acid 4- [4- (4-phenylphenyl) benzyl] -4-oxo-2S- (2-S teraiminoethyl) butanoic acid 4- (4- (4-Gaphenyl) phenyl] -4-oxo-2R- (2-phthaloiminohexyl) butanoic acid ) Phenylcarbonyl] -trans'-2-phenylthio-cyclopentanesulfonic acid. (IS, 2R, 5S) -trans-5- [4- (4-Gaphenyl) benzylcarbonyltrans- 2-phenylthio-cyclopentanecarboxylic acid (1R, 2S, 5R) -trans-5- [4- (4-phenyl) benzylcarbonyl] -trans, 2-phenylthio-cyclopentane Carboxylic acid trans-5- [4- (4-Gaphenyl) phenylcarbonyl] -cis-2- (2-methoxycarbonylphenylthio) cyclopentanecarboxylic acid (IS, 2S, 5S) -trans Formula-5- [4- (4-chlorobenzyl) phenylcarbonyl] • cis- 2- (2-Toxycarbonylphenylthio) cyclopentanecarboxylic acid (1R, 2R, 5R) -trans-5 -[4- (4-Phenylphenyl) benzylcarbonyl] -cis-2- (2-methoxycarbonylbenzylthio) cyclopentanecarboxylic acid trans_5_ [4- (4-phenylphenyl) benzyl Carbonyl] -trans-2-phthaloiminomethylcyclopentanecarboxylic acid (IS, 2R, 5S) -trans-5- [4- (4-chlorophenyl) phenylcarbonyl] trans-2- 5 Taijimide f-based cyclopentanecarboxylic acid-12- This paper method uses China «Home Picker (CNS) Α4 Washer (2 丨 〇 &gt; &297; product) / V Please read the back first * Attention Ning Xiangbi Fill out this page to order 413675 A8 B8 C8 D8 2, the scope of application for patent 3 62 (1R, 2S, 5R) -trans-5- [4 · (4-air-benzyl) phenylcarbonyl bu trans- 2-phthaliminoimide T-cyclopentanecarboxylic acid 23. A method for preparing a compound of the following general formula with matrix metalloproteinase inhibition of tongue: ^ R6 I C-i2〇iC02H which makes T represent 1 or 2 and R6 is a) a phenylalkyl group, in which the alkyl portion Contains 1 to 4 carbons; or b)-(CH2) tR7, where t is an integer from 1 to 5 and R7 is an N-imine group containing an aromatic residue; _ 'This method is based on the general method B, Including the following steps: 1) Substituted by methyl biphenyl ketone by T (please pay attention to MTtir before filling in this purchase) I &lt; I-1 — Order The Ministry of Economic Affairs ordered the employees of the vehicle to cooperate with the cooperative «. Reaction with R6 substituted dialkyl malonate to produce R6! -G ^ ChUCO 2) Convert the latter to the corresponding diacid or acid ester, and 3) heat to remove the carboxyl group to produce the desired product . 24. A method for preparing a compound having the following inhibitory activity of matrix metalloproteins with the following general formula: -13 This paper is Λ scale, and uses the Chinese National Standard Car (CNS) A4 (210X297) * 413675 A8 88 C8 08 : R6 I Gi2G-iC02H where T represents 1 or 2 halogens, and R is '(CH2) VZR8' where v is i, z is S and R8 is phenyl, benzyl or benzyl alkyl, of which the alkyl moiety Contains 1 to 4 steps. This method is based on General Method D and includes the following steps: 1) by -CC-izCC02H Γ · reacts with R8SH in the presence of a suitable catalyst to produce the desired addition product. 25. A method for preparing a compound of the general formula with matrix metalloproteinase inhibitory activity. Printed by the Industrial Cooperatives 9 Γ'Η Where T stands for 1 or 2 and R6 is-(CH ^ R7, where tt is 1 and R7 is an N-iminoyl group containing an aromatic residue, (Please read the precautions on the back first) (Fill in this card again) This paper uses CNS A «t pile (210X297 mm) ^^ 3675 Α &amp; Μ C8 D8, applied for patents Fanyuan Economic Bureau Central Samples Bureau Λ Industrial Consumer Cooperatives printed QN 〇 This The method is based on the general method K, including the following steps: 1) Q-ίο reacts with a reducing agent to convert the -CHO group into an alcohol _CH 〇Η. 2) convert the 鞟 into a derivative containing a group ^ which can be easily replaced; and ', 3) with a base and containing aromatic Residue imine treatment of the derivative produces the desired product. 26. A method for preparing a compound of the following formula having matrix metalloproteinase inhibitory activity: R6 wherein τ is 眯 -OR4, wherein R4 is an alkyl group of 1 to 6 carbons, or fluorenyl group; X is 1 or 2; and R6 Is a aryl alkyl f in which the alkyl portion contains 1 to 8 hydrazones; this method is based on the general method F and includes the following steps: 1. From an organic gold compound of formula (T) xA-Met, where T is鲢--15-Selection of ft scale of this paper «National Standards (CNS) Α4 gauge / block (h〇X297 公 A) In nn HI 1 ^ 1 i tv — ^ n 11J .....» lii IK — 1 ″ fJi / 1 · (please fill in the "Notes on reading the back first") 413675 A8 BS C8 08 type aromatic system The scope of the patent application is 0RJ, A is phenyl, and Met is a metal atom. After treatment, the following is cg-i2chco2h, where X is halogen or trifluoromethanesulfonate, which undergoes a coupling reaction in the presence of a palladium substance to form Desired compound Gu Shenghua 27.—A method for preparing a substance with matrix metalloproteinase inhibitory activity: Combining the following formulas (please read the "Notes on reading the back before filling this page") Ordered by the Ministry of Economic Affairs and the Central Government Bureau of Shellfish Consumer Cooperatives *. Where T is a prime or g ^ 〇R4, where Gen4 is an alkyl or phenylalkyl group of 1 to 12 carbons, where the alkyl portion contains 1 to 4 carbons, and R, (CH2) vZR8 * where v &gt; 〇 'Z is s' and Rs is phenyl, benzyl or phenylalkyl, wherein the alkyl portion contains 1 to 4 carbons, which The method is based on General Method G and includes the following steps: 1. Treatment with alkali Remove the double bond from the conjugation with the carbonyl group of the network to form a ** 16 paper-scale selection ® β family phase t rate (CNS) ΜΛΜ * · {210X297 公 *) G CO vH4 8 «0 S 8 ABCD VI. Application Patent scope This substance is then treated with HSRs to produce the desired addition compound. ^^^ 1 Jn ^ in ^ — ^^^^ 1 In if n ^ i it 1 ^^ 11 a-4 i (Please read the Please fill out this page again for the matter of intent) The Central Government Bureau of the Ministry of Economic Affairs and the Ministry of Economic Affairs of the People ’s Republic of China are responsible for the consumption cooperation. The printed paper X XΧ is used by the Chinese National Government (CNS} A4 Regulation Ice (2 〖〇X297mm). I