TWI328585B - Oxazol derivatives - Google Patents

Description

1328585 A7 B7 V. Scope of the station The present invention relates to novel azole derivatives, their manufacture and their use as pharmaceuticals. The invention relates in particular to compounds of formula (I)

And pharmaceutically acceptable salts and esters thereof, wherein R1 is aryl or heteroaryl; R2, R3, R4 and R6 are independently of each other hydrogen, hydroxy, lower sulfhydryl, halogen, lower alkyl or a lower alkoxy group, wherein at least one of R2, R3, R4 and R6 is not hydrogen, or R3 and R4 are bonded to each other, and together with the carbon atom to which they are attached form a ring' and R3 and R4 are -CH =CH-S-, -S-CH=CH-' -CH=CH-0- > -0-CH=CH-, -CH=CH-CH=CH·, -((:Η2)3·5 -, -〇-(cH2)2.3- or -(CH2)2.3-0-, and R2 and R6 are as defined above; R5 is lower alkoxy, lower alkoxy,

R R- or Ϊ

R 10 -5 - This paper size is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1328585 A7 B7 V. Description of invention (2 R7 hydrogen or lower alkyl R8 hydrogen or lower alkyl R9 Hydrogen or lower alkyl R10 aryl: η system 1, 2 or 3; wherein the bond between the carbon atom <^ and the carbon atom Cbi is a single bond or a double bond of a carbon-carbon. Proliferation by peroxidase Peroxisome Proliferator Activated Receptors (PPAR's) are members of the nuclear hormone receptor superfamily, which regulate gene expression by ligand-activated transcription factors. Various subtypes have been identified and selected. These include PP AR a, PP AR /3 (also known as PPAR 5 ) and PPAR r. They exist as major isoforms of at least two PPAR 7. Although PPAR r 1 is expressed in most tissues that are ubiquitous, Almost only the long isoform PPAR τ 2 is found in fat cells. In contrast, PPAR α is preferentially expressed in the liver, kidney and heart. PPAR's regulate various body reactions, including glucose- and lipid-body balance, cell differentiation. , inflammatory response and cardiovascular events. Diabetes is a patient control A disease in which the ability to make a glucose value in the blood is impaired because the patient has lost some of the ability to respond appropriately to insulin. In type 2 diabetes (T2D), often referred to as non-supplementation-dependent diabetes mellitus (NIDDM) In all developed countries, 80-90% of all diabetic patients suffer from it, and the island of Lang's in the pancreas still produces insulin. However, the target is, the main muscle, liver and fat tissue will show A cumbersome anti-skin stimulating effect and compensates for the body by producing non-physiologically high insulin values. However, in the later stages of the disease, insulin secretion is reduced due to pancreatic depletion _ R - _ This paper scale applies China National Standard (CNS) A4 Specification (210X 297 mm) 1328585 A7 . B7__ V. Invention Description ( ) 3 ' Low. In addition, T2D is a metabolic cardiovascular disease syndrome. Among them, it is related to Ding 2 D. The comorbidities are insulin resistance, dyslipidemia, hypertension, vascular endothelial function abnormalities, and inflammatory atherosclerosis. The current first-line treatment for diabetes usually involves a low-fat- and low-glucose diet and exercise. The progress of the disease has eased 'But the progress of the disease has become a need for treatment with hypoglycemic drugs, such as 'sulfonate urea or YE Dexiang. A promising new type of drug has been introduced to re-sensitize the patient's own insulin (insulin sensitizer) ), in order to reverse the amount of blood glucose and triglyceride to normal, and thus abolish or at least reduce the demand for exogenous insulin. Pioglitazone (ActosTM) and Josigliazone (rosiglitazone) ( AvandiaTM) belongs to PPAR r ·activator. It is a type of thiazolidinedione (TZD) and has been approved by many countries as the first representative drug for NIDDM. However, these compounds suffer from side effects, including rare, but severe hepatotoxins (such as the experience of troglitazone) and cause weight gain in humans. Therefore, there is an urgent need for new, better and more effective NIDDM treatments. Recent studies have provided evidence that the co-promoting action of ppARa and PPAR 7 may lead to evidence that the compound has enhanced therapeutic potential, namely improved lipid profile effects with positive glucose and valerin values (Keller and (Keller) Wahli: Trends Endocrin. Metab. 1993, 4:291-296, Macdonald and Lane: Current Biology v〇l.5 pp 618-621 (1995)) - The novel compound of the present invention goes beyond the skill Known compounds, because they combine and simultaneously and very effectively activate both PPAr α and ppar 。. Therefore, the anti-glycemic effect of these compounds combined with PPART activation is applicable to the Chinese National Standard (CNS) Α4 specification. (210X 297 mm) 1328585 A7 B7 V. Description of the invention (should be associated with PPAR 〇: activation of anti-lipidemia. The result will reduce blood glucose and adenosine (= insulin sensitivity), reduce triglyceride and increase HDL cholesterol (= improved lipid profile). In addition, these compounds can also lower LDL cholesterol, increase blood pressure and fight inflammatory atherosclerosis. Because of the common agonist pursuit of PPAR α and PPAR 7 The multifaceted nature of the 2D disease syndrome is expected to have enhanced therapeutic potential compared to compounds known in the art. The compounds of the present invention exhibit improved pharmacological properties as compared to known compounds. There are other indications, which are exemplified and defined by the definitions set forth below to illustrate the meaning and scope of the various terms of the invention. In this specification, the use of "low carbon," terminology represents from 丨 to 7 carbon atoms. The group 'preferably has 1 to 4 carbon atoms. The term "halogen" means fluorine, chlorine, bromine and a block. The order line is expressed in terms of "protecting group" such as, for example, a mercapto group, an alkoxycarbonyl group, an aryloxy group. a group such as a carbonyl group, a methoxyalkyl group or an imine derivative, which is used to temporarily block the reactivity of the g thiol group. A well-known protecting group can be used, for example, to protect the amine group, the third butoxycarbonyl group, the fluorenyloxy group, the hydrazine. Methoxycarbonyl or dibenzylidene' or a lower alkyl group for use in protecting the group, a p-trimethylformamidoethyl group and/or a tris-ethyl-ethyl ester, alone or in combination with Other group combinations of "alkyl," A branched or linear monovalent saturated aliphatic hydrocarbon group having from 2 to 5 carbon atoms, preferably from 16 to 16 carbon atoms, more preferably from 1 to 10 carbon atoms, and the alkyl group may be, for example, a hydroxyl group. Lower alkoxy, lower alkoxycarbonyl, NH2, N (H, lower alkyl) and 1,328585 A7 ______B7 V. Inventive description (c) or N (lower alkyl) 2 substituted. Separately or in combination with others The "lower alkyl" term of the group combination means a branched or straight-chain monovalent alkyl group of 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms. The term is further illustrated by a group such as methyl 'ethyl, n-propyl, isopropyl, n-butyl, t-butyl 't-butyl and the like. The lower alkyl group may have a substitution pattern of the alkyl group " as described in connection with the previously stated. The term 'alkoxy' refers to R|_〇_ group..., wherein R is an alkyl group. The term "lower alkoxy" refers to R1 - fluorenyl, wherein R is lower alkyl. Examples of the lower alkoxy group are, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group and a hexyloxy group. The term "low carbon thiol", alone or in combination, means a straight or branched hydrocarbon residue containing an olefinic bond and up to 8 carbon atoms (up to 6 preferably up to 4 particularly preferred). base. Examples of the alkenyl group are a vinyl group, a propylene group, a 2-propyl group, an isopropenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group and an isobutenyl group. A preferred example is 2-ethyl-propyl group. By ''lower carbyloxy,' the term stands for R" hydrazino, wherein R" is a lower olefin. An example of a "lower carbon epoxide group" is a butoxy group, especially a butyl 3 oxy group. The aryl term is phenyl or tea based, preferably phenyl, which can be self-primed, trans-based, CN, CF3, Ν〇2, ΝΑ, N (H, low carbon, environmental). , N (lower alkyl h, carboxy 'amine carbonyl, lower alkyl, lower alkoxy ' aryl and / or aryloxy group by mono- or poly-, especially mono- or di-substituted. Good substituents are self-priming, Ch 'lower alkyl and/or lower alkoxylated. This paper is suitable for use in the g @家标准(CNS) A4 specification (21Q χ 297^爱) 心〇:>谷5 A7

B7 base. The term "aryl" refers to an aromatic 5 or 6-membered ring which may contain fluorene, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur, such as a thiol group, a pyridyl group, 1, 1,3- and oxime, 4-didecyl, pyrimido-isoxazolyl, σ-zolyl, imidazolyl or pyrrolyl. The "heteroaryl" terminology refers to a double % aromatic group containing two 5 or 6-membered garments, wherein the or two rings may include hydrazine, 2 or 3 selected from nitrogen, An atom of oxygen and/or sulfur, such as, for example, an anthracene or a quinolinyl group; or a partially hydrogenated double % aromatic group such as, for example, an indanyl group. The heteroaryl group may have the substitution pattern of the term "aryl group" as described in conjunction with the above, and the preferred heteroaryl group such as fluorenyl and furyl groups may be substituted as described above, with halogen, CFS. , a lower alkyl group and/or a lower alkoxy group is preferred. The term 'medicinally acceptable salt' includes organic acids (eg hydrogen acid 'hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, lemon). Salts of the compounds of formula (I) of acids, formic acid, maleic acid, acetic acid, fumaric acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluene acid and the like, which have no maternity to living organisms. Preferred are acid salts of formate, maleate, citrate, hydrochloride, hydrobromide and decane sulfonate. Further compounds of formula j are pharmaceutically acceptable The base forms salts such as alkali salts (for example, Na- and sulfonium salts), alkaline earth salts (for example, Ca and Mg• salts), and substituted or substituted ammonium salts (such as, for example, trimethylammonium salts). ). "The pharmaceutically acceptable salt " terminology is also about these salts. _ can also be combined with Formula I Hydration, ie hydration. The solvation can be completed during the manufacturing process, or hydrated (hydrated), for example due to the hygroscopic nature of the initially anhydrous hydrazine compound. The pharmaceutically acceptable salt term is also included in the medicine. -- *10- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) ΓΙ328585 Α7

1328585 A7 B7 V. INSTRUCTION DESCRIPTION (8) wherein R1 is an aryl or heteroaryl group, and _R2, R3 and R4 are independently of each other hydrogen, halogen, lower alkyl or lower alkoxy, wherein R2, R3 and At least one of R4 is not hydrogen, or R3 and R4 are bonded to each other, and together with the carbon atom to which they are attached, form a ring, and R3 and R4 are -CH=CH-S-, -S-CH=CH-, -CH=CH-0-, -0-CH=CH-, -CH=CH-CH=CH- or -(CH2)3-5-, and R2 is as defined above, R5 is lower alkoxy Or -N Η 〇

And pharmaceutically acceptable salts thereof. In a particularly preferred embodiment, the invention relates to a compound of formula (I) characterized by formula (Ibb)

(Ibb) -12 - This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 1328585

Wherein R, R, R3, R4 and R5 are as defined above, and a pharmaceutically acceptable salt thereof. According to Cahn-Ingold-Prel〇g_Convention, the formula (11?13) represents an asymmetric carbon atom C* with an S configuration. Further, a compound having a phenyl group as defined above wherein R is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, CF3, lower alkyl group and lower alkoxy group is preferred. It is especially good with an unsubstituted phenyl group. Further, a compound of the formula wherein R is substituted with i to 3 substituents independently selected from the group consisting of halogen, CF;, lower alkyl and lower alkoxy as defined above Preferably, the unsubstituted π thiol group is particularly preferably β in which R 3 and R 4 are bonded to each other, and together with the carbon atom to which they are attached, form a ring ' and R 3 and R 4 together are _CH=CH-CH=CH- And the compounds of formula (I) of R2 and R are preferably β. These compounds therefore comprise the following

Binding

Further, wherein R3 and R4 are bonded to each other, together with the carbon atom to which they are attached, form a ring, and R3 and R4 together are _CH=CH-S-, and R2 and R6 are hydrogen compounds of formula (I). good. These compounds therefore contain the following parts —^— ------ 13 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) j 『1328585 A7

Further, the towels r2, r3 & r4 are each independently hydrogen or a lower carbon group. The compound as defined above is preferred, and those wherein R2 and R3 are methyl, ruthenium and R4 are particularly preferred. It is a particularly preferred compound of the formula (1): those in which R2 is a methyl group and r3&r4 is a hydrogen. More particularly preferred compounds of formula (I) are those wherein R4 is methyl, and quaternary 2 and amp 3 are hydrogen. Those compounds of formula I in which the R6 is methyl are particularly preferred. . The formula (") wherein R is a lower alkoxy group represents a preferred embodiment of the invention, wherein those wherein R5 is methoxy, ethoxy 'propoxy, butoxy or hexyloxy The compound of formula (1) represents a particularly preferred embodiment of the invention. Other preferred compounds are those in which the R5 system

The compound of the formula I according to the invention and its pharmaceutically acceptable salts are preferred. Compounds of formula I are especially preferred. A preferred aspect of the invention is a compound according to the formula, wherein the compound. · This paper scale is suitable for the standard of financial assets (CNS) Α 4 specifications (21GX 297 public) A7 - _ - B7 V. Invention description (~~) R2, R3 and R4 are independent, hydrogen and fang a lower alkyl group or a lower alkoxy group wherein at least one of R, R3 and IV» is not hydrogen or R and R are bonded to each other, and a carbon atom attached thereto forms a ring, and R3 and R4 It is _(:]^=(;^冬,^心^ ' -CH=CH-°- ' -〇-CH=CH- ^ -CH=CH-CH=CH- or -(CH2)3,5 ·, and where the rule 2 is as defined above; R5 is lower alkoxy or

R6 is hydrogen; R7 is methyl; η is 2; wherein a bond between a ruthenium atom (:3 and a carbon atom cbt is a single carbon-carbon bond; and a pharmaceutically acceptable salt thereof) One or more (1 to 3 preferred) compounds of formula I substituted independently of a phenyl or thiol group substituted with a substituent selected from the group consisting of a trifluoromethyl, an aryl, an alkyl 'alkoxy and a functional group Preferably, the compound is based on a compound wherein Ri is a phenyl group or a phenyl group substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy groups and trifluoromethyl groups. Another preferred aspect of the invention is Formula I a compound in which R2, R3, R4 and R6 are independently of each other hydrogen, hydroxy, lower alkyl or ____-15 - The paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1328585 A7 B7 12 5. Description of the invention (lower alkoxy, wherein at least one of R2, R3, R4 and R0 is not hydrogen, or R3 and R4 are bonded to each other' and the carbon atom to which they are attached - forms a ring' and R3 and R4 The starting point is _(:11=〇^_3, _3^=^^-CH CH 〇, _0-CH=CH- or -CH=CH-CH=CH-, and wherein R2 and R6 are as defined above.Wherein r2, r3, and Rm are each independently hydrogen, hydroxy 'lower alkyl or lower alkoxy, and at least one of the intermediates of the Chinese 2, Ri, and the ruler 6 is not hydrogen.佳"x where r3#r4 is bonded to each other, and forms a ring with the attached carbonogen, and R3 and R4 are -CH=CH-S-, _S_CH=CH., _CH=CH 〇, _〇 Ch=ch• or -CH=CH-CH=CH·, and its tR\R6 is as defined above. [The compound is more particularly preferred. The compound of the formula (4) is hydrogen. The compound is also particularly preferred. And R6 is hydrogen, and ^r3#r4 is bonded to each other, and forms a ring together with the carbon atom, and ... and the ruler 4 is _ch=ch -S-CH^CH-, and the compound according to the formula is better. - or a compound in which R3W is a report together! These compounds therefore have the following chemical formula

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Description of the invention (13) Another preferred aspect of the invention is a compound according to formula j, wherein R5 is a lower alkane Oxyl or

The compounds of the formula wherein R5 is a lower alkoxy group are particularly preferred. A compound according to the formula wherein R5 is a decyloxy group, an ethoxy group or a propoxy group is more preferred. A further preferred aspect of the invention is a compound wherein R7 is alkyl. Those compounds in which the R-form methyl group is based on the formula are particularly preferred. The compound of the formula wherein R8 is a low carbon fluorenyl group, particularly a methyl group, is also preferred. The compound of the formula wherein R9 is hydrogen is also preferred. The compound of formula I wherein r9 is a low carbon compound is preferred. It is more preferable to use a compound having a R system, a phenyl group or a stupid group substituted with a low carbon group. Among them, those having a phenyl group of phenyl group are particularly preferred. Among them, a compound of the formula ί is preferred. It is a formula of 2 or 3. The compound is more preferable. Those compounds in which η is 2 are particularly preferred. The compound of the formula may include many asymmetric centers, and may be optically pure to U such as a racemate, Optically pure non-parallel isomers, non-isomeromers; a mixture of quinone racemates or diastereomeric racemates, such as dissociation of racemates, asymmetric synthesis Or asymmetry of color ^ 14 5, invention description A7 B7 away, 〆I (in the form of the active layer for the separation of palmar adsorbents or leaching agents. 忖 from carbon to asymmetric carbon, (C*) stands for Cahn-Ingold-Prelog Convention with 4 different substituents, asymmetric carbon atoms Has a "R" or "S" configuration. The palm-like compound of formula (I) characterized by formula (la) is preferred R1-N-

CT -(CH2)

(la) = RI, r2, r3, r4, r5, r6Wwui a) represents an asymmetric carbon atom c* with s configuration. 》 R1- 〇-

(la) A compound according to formula (Ia) wherein R1, R2, R3, r4, r6, 5 R R and n are as defined above and wherein R represents a lower carbon group is particularly preferred. - a carbon-carbon double bond in which the carbon atom is 匸3 and hard; and you are between C (according to -18 - this paper size is suitable for national standards (CNS) A4 specification 13258585 A7 B7 V. Description of invention (15)

Formula 1 compounds of Cahn-Ingold-Prelog-Convention or E- or Z-configuration are preferred. Therefore, those compounds have the following chemical formula (Ic)

It is better to use E-configuration. With Z-configuration special. · k Further is particularly preferred as the compound of the formula I in which the bond between the carbon atom ca and the carbon atom cb is a single bond of carbon. Therefore, those compounds have the following chemical formula (Id)

〇/\R7 R_ FT order

Preferred compounds of the formula (1) are those selected from the group consisting of: 1. 2-Methoxy-3-{4-[2-(5.methyl-2-phenyl-s-zole- 4-yl)-ethoxy]-benzo[b]porphin-7-yl}-propionic acid; 2. 2-ethoxy-3-{4-[2-(5-methyl-2- Phenyl-[#]-4-yl)-ethoxy]-benzo[b]indole -7-yl}-propionic acid; 3. 3-{4-[2-(5-methyl) -2-phenyl-oxazol-4-yl)-ethoxy]-benzo[15]"cephen-7-yl}-2-propoxy-propionic acid; 4 . 2 -butoxy - 3- {4-[2-(5 -Methyl-2-phenyl-indazol-4-yl)-ethoxy---- - 19 -_______ This paper size applies to the Chinese National Standard (CNS) A4 specification. (210X 297 public) 1328585 A7 B7 V. Description of invention (16) Base]-year and [b]B thiophene-7-yl}-propyl from the father, 5. 2 -isobutoxy- 3- {4 -[2-(5-T-yl-2-yl-[beta]-S--4-yl)-ethoxy]-private [b]pj-phen-7-yl}-propionic acid; 6. 2 - Hexyloxy-3-{4-[2-(5-fluorenyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]4-phen-7-yl}-prop Acid; 7. 2-methoxyl-3-{4-[2-(5-methyl-2-phenyl-indazol-4-yl)-ethoxy]na-1-yl}-propyl > 8. 2-Ethoxy-3-{4-[2-(5-methyl-yl-2- Phenyl-oxazol-4-yl)-ethoxy]-naphtho-1-yl}-propane@艾, 9. 3-{4-[2-(5-methyl-2-phenyl-oxime) Zyridin-4-yl)-ethoxy]-indole-l-yl}-2-propoxypropionic acid: 10. 2-butoxy-3-{4-[2-(5-methyl-2) -, phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-propionic acid: 11. (S)-2-methoxy-3-{4-[2-(5 -methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]porphin-7-yl}-propionic acid; 12. (S)-2-ethoxy- 3-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]4-phen-7-yl}-propionic acid; (S)-2-indolyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethane group]-}-propionic acid; S)-2-ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-yl-1-yl}-propionic acid , 15· 2-(2-Benzyl-phenylamino)-3-{4-[2-(5-methyl-2-phenyl-indazol-4-yl)-ethoxy]-荇-1 -yl}-propionic acid; 16. 2-(2-phenylhydrazino-phenylamino)-3-{4-[2-(5-methyl-2-phenyl-indole--20) -__ The national standard (CNS) A4 specification (210 X 297 mm) 1328585 A7

All-4-yl)-ethoxy]-p- and [b]p-sept.7·kibpropionic acid; 17·3-{3,)-dimethyl·4_[2(5·methyl· 2·Phenyl·carbazole_4·yl ethoxy]-styl}-2-ethoxypropionic acid; H 2 -ethoxy _3_{3_ fluorenyl _4_[2_(5-A Base 2_phenyl-carbazole·4·yl)·ethoxy]-styl}_propionic acid; 19. 2-(2-stupyl-phenylamino)_3_{3,5_two Methyl _4 [2 (5-methyl-2-phenyl-pyrazole·4-yl)·ethoxy]-phenyl-propionic acid: 2〇. 2-(2-Benzyl-phenylamine ))--3-{3.-Methyl-4-[2-(5-methyl.2_phenyloxazol-4-yl)-ethoxy]-phenyl}-propionic acid; S)-2-methoxy·3_(4_{2·[5_methyl_2(4trimethylmethylphenyl) qiaojun-4-yl]ethoxy}anthracene-yl)propionic acid ; (S)-2-Ethoxy·3_(4_{2·[5•methyl·2·(4_trifluoromethylphenyl)oxazol-4-yl]ethoxy}^- i•yl)propionic acid; 23. (S)-2-methoxy_3·(4_{2[5methyl_2(4)trifluoromethylphenyl)oxazol-4-yl]ethoxylate }Benzo[b](>cetin-7(7)-propionic acid; 24. =)-2-ethoxy-3-3((4·{2_[5_methyl_2(4trifluoromethyl) Phenyl) °oxazol-4-yl]ethoxy}benzo[b]porphin-7-propionic acid 25. (S)-3-{4-[2-(2·Biphenyl-4-yl-5-methylcarbazole_4•yl)ethoxy] +1-yl.} - 2-B Oxypropionic acid; 26. (S)-3-{4-[2-(2-biphenyl·4·yl·5·methylcarbazole-4-yl)ethoxy]tea-1-yl} -2 -propoxypropionic acid; 27. (S)-3-{4-[2-(2-biphenyl-4-yl·5·methylcarbazole-4)ethoxy]benzo [b]-cerebral-7-ylindole-2·propoxypropionic acid; 8·(S) 3 {4-[2-(2-diphenyl-4-yl-5-methyl) 4-yl)ethoxy]

1328585 A7 ______B7 V. INSTRUCTIONS (18) 荇-1 -yl} - 2 -methoxypropionic acid: 29. (S)-3- {4-[2-(2-biphenyl-4-yl-5) -methyl.oxazol-4-yl)ethoxy]indol-1-yl}-2-(2,2,2-trifluoroethoxy)propionic acid; 3〇_ (S)-3-{ 4-[2-(2-biphenyl-4-yl-5-methyloxazol-4yl)ethoxy]benzo[b]dexh-7-yl}-2-ethoxypropane Acid; 31· (S)-3-(4-{2-[2-(4-isopropylphenyl)-5-methyloxazol-4-yl]ethoxy}benzo[b]pyrene Benz-7-yl)-2-methoxypropionic acid; 32. (S)-3-(4-{2-[2-(4-isopropylphenyl)-5-methylcarbazole-4 -yl]ethoxy} benzo[b] porphin-7-yl)-2-(2,2,2-trifluoroethoxy)propionic acid; 33. (S)-3-(4-{ 2-[2-(3,5-Dimethylphenyl)-5-methyloxazol-4-yl]ethoxy}bromo[b μcephen-7-yl)-2-methoxy Propionic acid: 34. (S)-3-(4-{2-[2-(3,5-Dimethoxyphenyl)-5-indolyloxazol-4-yl]ethoxy}benzo [b].cephen-7-yl)-2-methoxypropionic acid; 35. (S)-3-(4-{2-[2-(3,5-dimethylphenyl)-5 -methyl. oxazol-4-yl]ethyl lactyl}^-1-yl)-2-methoxypropionic acid; 36. [racemic]-3 - (4 - { 2 - [ 2 - (3,5 - two gas (5)-methyl-oxazol-4-yl]ethoxy}benzo[b]thiophen-7-yl)-2-methoxypropionic acid; 37. [racemic.]-3 (4 _{ 2 - [ 2 - ( 3 , 5 -difluorophenyl)-5 -methylcarbazole · 4 -yl]ethoxy}benzo[b]porphin-7-yl)·2 - Methoxypropionic acid; 38_ [racemic]-2-butoxy-3-(4-(2-[2-(3,5-difluorophenyl))-5-methylcarbazole-4 -yl]ethoxy}benzo[b]thiophen-7-yl)propanoic acid; 39. [racemic]-2 -butoxy-3 - ( 4 - { 2 - [ 2 - ( 3, 5-Dimethoxyphenyl)-5-methyloxazol-4-yl]ethoxy} benzo[b]pyrimidin-7-yl)propene___-22 -__ ^paper scale for China National Standard (CNS) A4 Specification (210 X 297 mm) 1328585 A7 B7 V. Description of the Invention (Acid; 40. [Rapex]-2 - Butoxy_ 3 - (4 - { 2 - [ 2 - (3,5-Dimethylphenyl)·5-methyl.唆-4-yl]ethoxy}phenylhydrazine [b]e-sept-7-yl)propionic acid; 41. [racemic]-3 - ( 4 - { 2 - [ 2 - ( 3, 5-difluorophenyl)-5-methylcarbazole-4-yl]ethoxy}benzo[b]P-sept-7-yl)_2-ethoxypropionic acid; 42. [racemic -2 -Methoxy-3 -(4 - { 3 - [ 2 - (4-methoxyphenyl)- 5-methylindole-4-yl]propoxypropionic acid; 43. [ Racemic]_ 3 - ( 4 - { 3 - [ 2 乂 4 -chlorophenyl)· 5 _methylcarbazole-4 _yl]propoxy}pyridin-1-yl)-2-methoxy Propionate; 44. [Racea]-2-methoxy-3 - (4 - { 3 - [5 -methyl-2 - (4-trifluoromethylphenyl) 17 -propyl]propoxy}benzo[b]eseptene-7-yl)propanoic acid; 45. [Racemic]-2 -ethoxy-3 - (4 - { 3_- [ 5 - A -2 -(4-trifluoromethylphenyl). oxime-4-yl]propoxy} benzo[b]thiophene-7-yl)propanoic acid; 46. [racemic]-3 - ( 4 - { 3 - [ 2 - (4 - chlorophenyl)_ 5 -methyl oxazol _ 4 _ yl] propoxy octenyl-1- yl)-2 -isopropoxypropionic acid: 47_ (S)-2-methoxy-3-(4-{3-[5-methyl_2_(4.trifluoromethyl)-based 2-hydroxy-4-yl]propenyl)propionic acid 48. [Outside Cyclosyl]-3-(4 - { 3-[2-(4 - phenylphenyl) 5_methyl oxime _4. yl] propyloxy] yl) and [b] 4 phen-7-yl 2·methoxypropionic acid; 49. [racemic]-2 -ethoxy-3-(4-{3-[2-(4-methoxyphenyl)· 5-methyl " oxazol-4-yl]propoxy-yl}naphthyl-fluorenyl-propionic acid; 〕 〇. [racemic]-2 -ethoxy-3-(4-{3_[2-(4 _isopropylphenyl b 5-methyloxazol-4-yl]propoxy} 荇-丨·yl)propionic acid; 51. [racemate]-3 - ( 4 - { 3 - [ 2 - (4-Phenylphenyl)_ 5 _methylcarbazole _ 4 _ -23 -

]]propyl aryl}tea-1-yl)-2-ethoxypropionic acid; 3 2 [racemic]-3 - (4 - { 3 - [ 2 - (4-isopropylphenyl) -5-methylcarbazole-4-yl]propoxy}indole-1_yl)_2-methoxypropionic acid; 53,[racemic]-3-(4 - {2-[2- (3,5-Dimethylphenyl)-5-methylindol-4-yl]ethoxy}benzoxeno-7-yl)_2-ethoxypropionic acid: 54. [Rectone -3(4-{2-[2-(3,5.dimethoxyphenyl)-5-methyl~deoxy-4-yl]ethoxy}benzo[b]lI _7_yl)_2_ethoxypropionic acid; - 55·[racemic]-2-ethoxylated 3-(4-{3-[2-(4-methoxyphenyl) - 5-methyloxazol-4-yl]propoxy}benzo[b]sulfon-7-yl)propionic acid; %·[racemic]-2-methoxy- 3-(4 -{3-[2-(4-methoxyphenyl)- 5-methyl. oxime _4_yl]propoxy}benzo[b]thiophen-7-yl)propanoic acid; 57. Racemic]-2 -ethoxy-3 -(4 - { 3 - [ 2 - (4-isopropylphenyl)-5 -methyloxazol-4-yl]propoxy} benzo [b]Pcetin-7-yl)propionic acid; 58-[racemic]-3-(4-{3-[2-(4-isopropylphenyl)-5-methylcarbazole -4 -yl]propoxy}benzo[b]thiophen-7-yl)_2-methoxypropionic acid 59. [Racecycline]-3-(4-{3-[2-(4-Phenylphenyl)-5-methyloxazol-4-yl]propoxy}benzo[b]pyrene Benz-7-yl)-2-ethoxypropionic acid; 60. [racemic]-3 - ( 4 - { 3 - [ 2 - ( 4 - phenyl)-5 -methyl β azole -4 -yl]propoxy}benzo[b]»cephen-7-yl)-2-methoxypropionic acid: 61. [Racemic]-2 -ethoxy- 3-(4 -{3-[2-(4-Methoxyphenyl)-5-methyloxime-4-yl]propoxy-polyalkyl-propionic acid; 62-[racemic]-2 -Ethoxy-3 - ( 4 - { 3 - [ 2 - ( 4 -isopropylphenyl)-5-methyloxazol-4-yl] propoxypropionic acid; This paper scale applies to China Standard (CNS) A4 size (210X 297 mm) 1328585 A7 B7 V. Description of invention (21 63. [Racecyclin]-3 - (4 - { 3 - [ 2 - (4-chlorophenyl)-5 · mercaptoin-4 -yl]propoxy}-1-yl)-2-ethoxypropionic acid; 64·[racemic]-2 -ethoxy_3_(4_{2_[ 2_(4•isopropylphenyl)_ 5-methyl. Zyzol-4-yl]ethoxy}benzo[b]sulfonyl-7-yl)propionic acid; 65. (5)-2-but-3-enyloxy-3-(4_{2-[ 2_(4_isopropylphenyl)_5_methyl^.#-4-yl]ethoxy}benzo[b].sept.7-yl)propionic acid; 66. [racemic] -3 - (4 - { 2 - [ 2 -(4-isopropylphenyl) 5 -methylcarbazole-4-yl]ethoxy}su-1-yl)_2-nooxypropionic acid 67. [Racecycline]-2-ethoxy-3-(4-{2-[2-(4-isopropylphenyl)-5-methyloxazol-4-yl]ethoxylate Propionate; 68. [Racecycline]-3-(4-{2-[2-(3,5-dimethoxyphenyl)-5-methyl]carbazole 4-yl]ethoxy}benzo[b]thiophene-7-yl)-2-isopropoxypropionic acid; 69. (5)-3-(4-{2-[2-(3, 5-dimethoxyphenyl).5-methyl oxime _4_yl]ethoxy}phenylhydrazine [b]°cephen-7-yl)-2-isopropoxypropionic acid; [Racea]-3 - (4 - { 3 - [ 2 - (4-isopropylphenyl) _ 5 _methyl oxazol-4-yl] propoxy} phenyl hydrazine [b]. Tomb Benz-7-yl)-2-propoxypropionic acid; 71. [Racemic]-3 - (4 - { 2 - [ 2 - (3,5 · Dimethoxyphenyl)_ 5 - Methyl oxime 4-.yl]ethoxy} oxime-1 _)-2 ethoxy propyl 72. [Racecycline]-3-(4-{2-[2-(3,5-dimethoxyphenyl)·5-methyloxazol-4-yl]ethoxy}荇-1-yl)-2-propoxypropionic acid; 73. [racemic]-3 - (4 - { 2 - [ 2 - ( 3,5 -dimethoxyphenyl)-5 - Base <7 ° 坐-4-yl]ethyl keto}}-1-yl)-2-isopropoxypropionic acid; 74_ [racemic]-2 -isopropoxy-3 - ( 4 - { 2 - [ 2 - ( 4 -isopropylphenyl)- _- 25 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Description of invention (22 5 -Methyl"oxazol-4-yl]ethoxy}tea-1-yl)propionic acid '75. 2Z-ethoxyl 3-{2_methyl_4_[2-(5-A Base 2_phenyloxazol-4-yl)-ethoxy]-phenyl}-propionic acid; 76. [racemic]· 2 -ethoxy-3- 3 - { 2 -methyl- 4-(2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid; 77. 2(S)-ethoxy-3-{ 2·曱基·4_[2-(5-methyl-2.phenyl-oxazolyl-4-yl)-ethoxy]-phenylpropanoic acid; 78. 2 (R)-ethoxy _ 3_{2_methyl-.4_[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxyphenyl phenylpropanoid; 79. 3-{2,3 - Methyl-4_[2-(5.methyl-2-phenyloxazol-4-yl)-ethoxy]-p-styl}-2Ζ·ethoxyacrylic acid; '80. [racemic] -3 - { 2,3 -Dimethyl-4 2 -(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy;]·Phenyl-2-ethoxypropionic acid 81. 3-{2,6-Dimethyl-4_[2_(5-methyl-2-phenyl-oxazol-4-yl)-ethyl lactyl]-year's base}·2Ζ·ethoxy Acetyl acid; 82. [racemic]-3-{2,6-dimethyl-4-[2-(5-methyl-2-phenyl- -4-yl)-ethoxy ] _ 2 2 · ethoxy propionic acid; 83. 2 Ζ - ethyl lactyl - 3- {4-[2-(5 -methyl-2·phenyl-σ)-4-yl) Ethoxy]-benzopyran-7-yl}-propanoid; 84. 2Ε-ethoxy-3--{4-[2-(5-methyl-2-phenyl) -4- ()-ethoxy]-benzofuran-7-yl}-acrylic acid; 85. [Racemic]-2-ethoxy-3-(5-[4-[2-(5-methyl-2-) Phenyl-carbazole·4_yl)-ethylidyl]-winter-p-pentan-7-yl}-propionic acid; 86. [racemic]-2-ethoxy·3 - { 4 - [ 2 - ( 5 -Methyl-2-phenyl-carbazole · This paper scale applies to China National Standard (CNS) Α 4 specifications (21〇Χ297 mm) 1328585 A7

4-yl)ethoxy]-2,3-dihydrobenzopyranyl}}propionic acid; 87. 2Z-ethoxy-3_{7-[2_(5-methyl_2•phenyl , carbazole 4 kibethoxy]-benzofuran-4-yl acrylic acid; 88. 2E-ethoxy-3-{7_[2.(5_methyl_2_ 笨基斗主·4基 ethoxy]-benzopyranyl acryl; Di [racemic]-2_ethoxy_3-{7_[2 (5-methyl-2-phenyl]carbazole-4-yl )-ethoxy]- benzofuran-4_yl}propionic acid; 90. [racemic]-2-ethoxy. 3-{2_[2_(5-methyl-phenyl) Oxazide 4-yl)ethoxy]_2,3·dihydrobenzobenzoin_4_yl}-propionic acid; 9L [racemic]-2-ethoxy-3-.{7·[2· (5 methyl small phenyl gas s-7-yl) ethoxy]eji full-4 - kipropropanoic acid; 92. Cyclonic] ethoxy _3_(4 {2 [2_(5 methyl _ 2 phenyl, benzoate-4-yl)ethoxy]·5,6,7 8 tetrachlorocha·bubupropionic acid; 93. -(4-{2-[2-(4-^) .5_ f ethoxy] benzo[b] phenanthrene _7_yl)·2·ethoxypropionic acid; 94. [racemic]·2-ethoxylated.3_(4_{ 2_[2_(4-fluorophenyl)5-methyloxazol-4-yl]ethoxy} benzo[b]thiophene-7-yl)propanoic acid; 95. [Racemic]-2-B Oxy _ 3 _ (4 - { 2 - [ 2 -(2-ethoxy-4 fluorophenyl)-5-methyloxazol-4-yl]ethoxy}benzo[b]p-sept.7-yl)propionic acid 96_ [racemic]-2 -ethoxy--3 - (4 - { 2 - [ 2 - ( 4 -methoxyphenyl) - 5 -methyl. oxazol-4-yl] Oxy}benzo[b]p-cephen-7-yl)propanoic acid; 97. [Racemic]-2-ethoxy-3 - (4 - { 2 - [ 2 - (4-isopropyl) Oxyphenyl) 5-methyl-methyl. Sodium-4-yl]ethoxy}benzo[b]p-cetin-7-yl)propionic acid; ___- 27 - This paper scale applies to China Standard (CNS) A4 size (210X 297 mm)

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Line 1328085 A7 B7 V. Description of the invention (24) 98. (5)-2-decyloxy-3-{7-[2-(5-mercapto-2-phenyl-.oxazol-4-yl) -ethoxy]-benzo[b]»»cephene: 4-yl}-propionic acid; 99_ 2Z-ethoxy-3-{7-[2-(5-methyl-2-phenyl- (oxazol-4-yl)ethoxy]indan-4-yl}-propionic acid: 100. (S)-2 -decyloxy-3-{7-[2-(5-methyl-2) -Phenyl-oxazol-4-yl)ethoxyl> base]indan-4-yl}•-propyl@parent, 101. [racemic]-3-(4 - {2-[2- (2-ethoxy-4-fluorophenyl)-5-methyloxazol-4-yl]ethoxy}indole-1-diyl)-2-methoxypropionic acid; 102. Cyclos]-2-oxooxy-3-(4-{2-[2-(4-methoxyphenyl)-5-fluorenyl. oxazol-4-yl]ethoxy} oxime-1 -yl)propionic acid; 103.2Z-ethoxy-3-(7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-private [b] P-cephen-4-yl}-propanoid-acid, 104. [racemic]-2 -ethoxy-3 - { 7 - [ 2 - ( 5 -methyl-2-phenyl-carbazole -4 -yl)-ethane group]-benzo[b]>»j-phen-4-yl}-propionic acid; 105. [racemic]-2 - [1-methyl-3-oxo 3-phenyl-(Z)-acrylamido]-3-{4-[2-(5-methyl-2-phenyl-indazol-4-yl)-B Oxy]-benzoquinone [b]p-cephen-7-yl}-propionic acid; 106. [Racemic]-2-[1-methyl-3-oxo-3-(4-trifluoro) Methylphenyl)-(Z)-acrylamido]-3-{4-[2-(5-methyl-2-phenyl-indazol-4-yl)-ethoxy]-private b]!1 phene-7-yl}-propionic acid; 107. [Racemic]-3 - { 4 - [ 2 - ( 5 -methyl-2-phenyl-carbazol-4-yl) -ethoxy]-benzo[b]4phen-7-ylbu 2-[3-oxo-3-phenyl-1-trifluoromethyl-(2)-propyl-amino-propionic acid]-propionic acid 108. [Racea]-2 -ethoxy- 3-{4-[2-(4-isopropylphenyl)-5-甲__-28 -_ This paper size applies to China Standard (CNS) A4 size (210 X 297 mm) (· Binding

1328585 A7 B7 V. Description of the invention (25) carbazol-4-ylmethoxy]-5,6,7,8-tetrahydroindole-l-yl}-propionic acid; 109. [racemic] -2 -ethoxy-3-[4-(5-methyl-2-phenyl-indazol-4-ylmethoxy)-5,6,7,8-tetrahydronaphthalen-1-yl] -propionic acid; 110. [racemic]-2 -ethoxy-3 - ( 4 - { 2 - [ 2 - (2-ethoxy-4-fluorophenyl)-5 -methylcarbazole 4-yl]ethoxy}-5,6,7,8-tetrahydroindol-1-yl)propionic acid; 111. [racemic]-2-ethoxylated 3-(4 - { 2-[2-(4-Fluorophenyl)-5-mercaptoindazole-4-yl]ethoxy}-5,6丄7,8-tetrahydroindol-1-ylpropionic acid; 112. [Racecyclin]-2 -ethoxy-3-(4 - {3-[2-(4-oxophenyl)-5-methylcarbazol-4yl]propoxy}- 5,6,7,8-tetrahydroindol-1-yl)propionic acid; 113. [Racemic]-2 -ethoxy-3-(4 - {2_-[5-methyl-2- (4-trifluoromethylphenyl)oxazol-4-yl]ethoxy}-5,6,7,8-tetrahydronaphthalen-1-yl)propanoic acid; 114. [racemic]- 2-methoxy-3-({3-methyl-4-[2-(5-fluorenyl-2-phenyl-soxazol-4-yl)-ethoxy]-phenyl}-propionic acid; 115. [Racea]-2 -decyloxy-3 - { 3 -methoxy-4 - [ 2 - ( 5 -Methyl-2 -•^------------ 4-ethoxy)-ethoxy]-benzyl}-propionic acid, 116. [Racemic]-2-Ethoxy 3- 3-[3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid lithium; 117. [Racecyclin]-3 - { 3,5 -Dimethyl- 4-[2-(5-fluorenyl-2-phenyl-oxazol-4yl)-ethoxy]-phenyl} -2-methoxypropionic acid; Π 8. [racemate]-3 - { 2 -hydroxy-4 - [ 2 - ( 5 -methyl-2-phenyl-oxazol-4-yl)-B乳基]-phenyl}-2 -decyloxypropionic acid; _-29 -_ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) k

1328585 A7 B7 V. INSTRUCTIONS (26) 119. [Racecyclic]-3·{3·Methyl·4·[2_(5-methyl·2_phenyl-p-azol-4-yl) -ethoxy benzene|factor 2_(1-methyl-3-oxy-3_phenyl)(propenyl)-propenyl)propionic acid; 120. [racemic]-2 -ethoxy -3-[4-(5-methyl-2-phenyl-2-carbazole.4-yl-methyl), acetyl- 7-yl]-propionic acid; 121. [racemic]-2 - Ethoxy-3-[4-(5-methyl-2-4-phen-2-yl, keto-4-ylmethoxy)benzofuran-7-yl]-propionic acid; 122. Racemic] _ 2 -ethoxy 3 -_{- 4 - [_2 - (4-ethylphenyl)-5-methyl °. Sodium-4-ylmethoxy]benzofuran_·7-yl}-propionic acid; 123. [Racecyclic]_3_{4-[2-(4-tributylphenyl)·5- Methylcarbazole _ 4-methoxymethoxy]benzofuran-7-yl}-2-ethoxypropionic acid; 124. [Racemic]-2·Ethoxy-3-{4-[ 2·-(4-Isopropoxyphenyl)_5-methyloxazol-4-ylmethoxy]benzofuran-7-yl}-propionic acid; 125. [Racemic]·2 - B Oxy-3-[4-(5-methyl-2-phenyl-sodium benzo-4-yloxy)-2,3-dihydrobenzofuran-7-yl]-propionic acid; 126. [ Racemic]·2-ethoxy-3-{4-[2-(4-ethylphenyl)-5-methyloxazol-4-ylmethoxy]-2,3-dihydro Benzofuran-7-yl}-propionic acid; 127. [Racemic]-3 - { 4 - [ 2 - (4-tributylphenyl)-5-methyl oxime. Sodium 4-methyloxy]-2,3-dihydrobenzofuran-7-yl}-2.ethoxypropanol, 128. [racemic]-2-ethoxy-3 -{4-[2-(4-isopropoxyphenyl).5-methyl. Isoazol-4-yl-methoxy]·2,3-dihydrobenzofuran-7-ylpropanoic acid; 129. [Racemic]-2-ethoxy-3- [2-methyl - 4- (5 -Methyl-2-phenyl] ___- 30 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Invention description (°号峻-4 -yloxy)phenyl]•propionic acid; 130. [racemate]-2 -ethoxy_3 _[ 2 -methyl-4 - ( 5 -mercapto-2 · b-septene _ 2-(4-cyclo-4-ylmethoxy)phenylpropanoic acid; 131. [Racemic]-2 -ethoxy-3-{4-[2 _ (4-ethylphenyl) -5 -methyl °°°4·ylmethoxy]-2-methylphenyl}-propionic acid; 132. [racemic]-3-{4-[2-(4 - Tributylphenyl)-5-methyl.oxazole-4-ylmethoxy]-2-methylphenyl-2-ethoxypropionic acid: 133. [racemic]-2 - B Oxy-3 [2-(4-isopropoxyphenyl)-5-methyloxazol-4-ylmethoxy]_2-methylphenyl}-propionic acid; 134. (S)-2 - But-3-enyloxy-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-carbazole-4-yl)-ethoxy]benzene Propionate; 135. 3-{3,5-Dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-B ]]-phenyl}-2Z-ethoxypropionic acid; 136. [Racemic]-3 - { 4 - [ 2 - (4-chlorophenyl)-5 -methylcarbazole-4 - Methoxy]benzofuran-7-yl}-2-ethoxypropionic acid: 137. [Racemic]-3-{4-[2-(4-chlorophenyl)-5-A Ketrazole-4-ylmethoxy]-2-methylphenyl}-2-ethoxypropionic acid; 138. [Racemic]-3 - { 4 - [ 2 - (3 , 5 - Dimethoxyphenyl)-5-methyloxazol-4-yl.methoxy]benzofuran-7-yl} _2-ethoxypropionic acid; 139. 2Z-ethoxy-3- {4-[2-(4-isopropylphenyl)-5-methylindole-4-ylmethoxy]-2-methylphenyl}-propanyl r-acid; M0.[racemic -2 -ethoxy-3 - [ 3 -mercapto-4 - (2-phenyl-oxazol-4-ylmethoxy)phenyl]-propionic acid; 141_(5)-3-{ 3,5-Dimethyl-4-[2-(5-methyl-2-phenyl-indazole-4- ___- 31 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1328585 A7 ____B7 _____ V. Description of the invention (28) yl)-ethoxy]-styl}-2-propoxypropionic acid; 142. 2Z-but-3-enoxy-3-{3,5 -Dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy bphenyl Acene acid; 143.2E - butyl-3·alkenyl-3-{3,5·dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-B Oxy]-phenyl-acrylic acid: 144. [racemic]-3-{4-[2-(2-chlorophenyl)-5-mercaptoindazole-4-ylmethoxy]-2 -methyl stupid ibu- 2 -ethoxypropionic acid; I45 ·[racemic]-3 - { 4 - [ 2 _( 3 _ phenylene)-5 -methyl succinyl 4 - yl Oxy]-2-methylphenyl- 2-ethoxypropionic acid; 146. [racemate]-2 -ethoxy-3 - { 2 -methyl-4 - [ 3 - ( 5 - Methyl-2-phenyl-oxazol-4-yl)propoxy]phenylpropionic acid; 147_ [racemic]·2-ethoxy-3 - { 4 - [ 2 --(4 -fluoro-3-methylphenyl)-5-methyloxazol-4-ylmethoxy]-2-methylphenyl}-propionic acid; 148. [Racemic]-2 - B Oxy-3 - { 4 - [ 2 - (2-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]-2-methylphenylpropionic acid; 149. Racemic]-3 - (4 - { 2 - [ 2 - (4-chlorophenyl)-5 -methylcarbazol-4-yl]ethoxy}-5,6,7,8-tetrahydrogen荇-1-yl)-2-ethoxypropionic acid; 150. [racemic]-2 -ethoxy-3 - [ 4 - ( 5 -methyl-2-phenyl-carbazole-4 - 基甲Naphthyl-1-yl]-propionic acid; 151. [racemic]-2 -ethoxy-3 - [ 7 - ( 5 -methyl-2-phenyl-oxazol-4-yl) Oxy)benzo[b]·»cephen-4-yl]-propionic acid; 152_ [racemic]-2 -ethoxy-3 - { 7 - [ 2 - (4-isopropoxy) Phenyl)-5-methyloxazol-4-ylmethoxy]benzo[b] «cephen-4-yl}-propionic acid; 153. [racemic]-2-ethoxy- 3 - ( 7 - { 2 - [ 2 - (2-ethoxy-4-fluorobenzene_-32 -___) This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V , Description of the invention (29-)-5-methylcarbazole-4-yl]ethoxy}phenylhydrazine [b]p-cephen-4-yl)propanoid; 154. [Racemic]-3 - ( 7 - { 2 - [ 2 - (4-Phenylphenyl)-5-methylcarbazole-4 _yl]ethoxy} benzo[b]thiophen-4-yl)-2-ethoxypropane Acid; 155. [Racecycline]-3 - { 7 - [ 2 - ( 4 -th-butylphenyl)-5 -methyloxazol-4-yl decyloxy]benzo[b]pyrene塞 _ 4-yl}-2·ethoxypropionic acid; 156. (S)-2-ethoxy-3-{3-methyl-4-[2-(5-methyl-2-benzene) Base No. 4 -yl)-ethoxy]-phenylpropionic acid _; _ 157. (2S)-3-{ 3,5-dimethyl_4_ [2_(5 - Methyl-2-phenyl-oxazolyl-4-yl)-ethoxy]-phenyl}-2-ethoxypropanoic acid; 158. [Racemic]-2-ethoxy-3 { 3 -Fluoro-4 - [ 2 - ( 5 -methyl - 2 -phenyloxazol-4-yl)-ethoxyphenyl]-propionic acid; 159. [Racemic]-2 -ethoxy-4-({4-[2-(5-methyl-2-phenyl-]oxazolyl-4-yl)ethoxy]-3-propylphenyl}-propionic acid; 160. (2S)-2-ethoxy-3-{3-decyloxy-4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxyphenylphenyl Propionic acid; 161. (2S)-2-ethoxy-3-{2-methoxy-4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy ].-Phenylpropionic acid; 162. [Racecycline]-2-isopropoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl) )-ethoxy]-benzo[b]4 phen-7-yl}-propionic acid: 163. (5)-2-Isopropyl-3-{4-[2-(5-methyl- 2-phenyl-# is also -4 yl)-ethoxy]- benzo[b]thiophen-7-yl}-propionic acid; 164. [racemic]-3-{3 - isopropyl Base - 4- [2-(5-methyl-phenoxy-^). Sit _ 4 -yl)-ethoxy]-tea-1-yl}_2-ethoxy diacid, ___- 33 - This paper scale is based on the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. INSTRUCTION DESCRIPTION (30) Particularly preferred compounds of formula (1) are selected from the group consisting of 2-methoxy-3-(4-[2-(5-methyl-2-yl), No.^Sit_4-yl)-ethoxy]_benzo[b]sulfon-7-kibpropionic acid: 3-{4-[2-(5-mercapto-2-phenyl-saki (oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-2-propoxypropionic acid; (S)-2-methoxy-3-{4-[2- (5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]·1 ceto-7-yl}-propionic acid; (S)-3-(4 -{ 2-[2-(3,5-Dioxalyl-phenyl)-5-methyl-11-oxazol-4-yl]ethoxy}benzo[b]deceno-7-yl)- 2-methyl-1-propionic acid; (8)-2-decyloxy-3-(4-{3-[5-methyl-2-(4-trifluoromethylphenyl)-oxazole-4 - (1,4-methoxy-4-[2-(5-methyl-2-phenyloxazole·4-yl) )-ethoxy]-phenyl}-acrylic acid; 2(S)-ethoxy-3-{2-methyl-4-[2-(5-methyl-2-phenyl-carbazole-4) · yl)-ethoxy]-phenyl}-propionic acid; 2Z-ethoxy- 3-{4-[2-(5-Methyl-2-phenyloxazol-4-yl)-ethoxy bromoxyfuran-7-ylbu-acrylic acid; [external/cyclonic]-2- [l-Methyl-3-oxo-3-phenyl-(Z)-propionylamino]_3_ {4-[2-(5-fluorenyl-2-phenyl-oxazol-4-yl) -ethoxy benzo[b]thiophene-7-yl}-propionic acid; [racemic]-3-{2-hydroxy-4-[2-(5-fluorenyl-2.phenyl- Breathing ·4_yl)· Ethoxy]-phenyl}-2-methoxypropanoic acid 外 [racemic]-3-{3-methyl-4-[2-(5-methyl) -2- stupyl-oxime _4_yl)_ethoxy bphenyl}-2-(1-indolyl-3-oxy-3-phenyl-U)-propyl-aminoamine) ____ 34 - The paper dare to pass the GG family material (CNS) A4 specifications (2lQX297 public) ~ - 1328585 A7 B7 V. Description of invention (31) Propionic acid; [racemicity 2-ethoxy-3- (2-mercapto-4-(5-fluorenyl-2-phenyloxazole-4-ylindoleoxy)phenyl]-propionic acid; [racemic]-2-ethoxy-3- {4-[2-(4-Isopropoxy)]-5-methyl-[oxazol-4-ylmethoxy]-2-methylphenylpropanoic acid; (2S)-3-{3 ,5-monodecyl-4-[2-(5-fluorenyl-2-phenylphonyl)-ethoxy]-phenyl}-2-ethoxypropionic acid; and (2S)-2 -ethoxy-3-{3-methoxy gas]2_(5-methyl_2_ Phenyl-carbazole-4-yl)-ethoxy]-phenyl}-propionic acid. - (S)-2-Methane-3·{4-[2-(5-fluorenyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]pyrene The phen-7-yl}-propionic acid and its pharmaceutically acceptable salts and esters are more particularly preferred. (S)-2-decyloxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]pyrimidine _7_Kippropionic acid is the best. The compound of formula (I) may have one or more asymmetric carbon atoms and may exist as an optically pure enantiomer or as a racemate. The present invention encompasses all of these forms. It is to be understood that the compound of the formula (1) which can be derivatized in the present invention on a functional group to provide a derivative which can be converted into a parent compound in vivo. A further aspect of the invention is a process for the manufacture of a compound of formula I, which comprises deprotection of a compound of formula II

____- 35 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Inventions (& ) where R1, R2, R3, R4, R5, R6, " The present invention also relates to a process for the production of a compound of formula (!) as defined above, which process comprises removing a deprotecting group in a compound of formula (Ila).

Wherein R, R2, R3, 'R4 and R5 are as defined above, and a pG-based protecting group, and the resulting compound of formula (I) is converted to a pharmaceutically acceptable salt as needed. Possible protecting groups PG in the compound of the formula (II) are, for example, lower alkyl-, p-dimethylamino>5-thyl-ethyl- and /3-trichloroethyl-ester, which can be used Protect the corresponding carboxyl group. The low carbon can be removed in a temperature range such as 丨〇 501 in an organic solvent such as, for example, hO, ethanol, tetrahydrofuran or dioxane, or a mixture of these solvents in the presence of a base (e.g., wLiOH or Na〇H) Alkyl-bulk factor. The protecting group can be removed in the presence of Zn in the presence of Zn at a temperature of, for example, 1 〇·5 》. In the tetrahydrofuran in the presence of vaporized tetrabutyl, for example, 20-651 The point-trimethylformamidoethyl-ester protecting group is removed at a temperature range. Methods of converting a compound of formula (I) as defined above into a pharmaceutically acceptable salt are known in the art. The invention further relates to the application of the Chinese Standard (CNS) A4 specification (210X 297 mm) according to the method as defined above, such as _____- 36 - the paper silver scale 1328585

The compound of the formula (i) above. As explained above, it is possible to use the compound of the formula 本) of the present invention as a treatment and/or prevention of a disease modulated by PPAR α / 弋 dd a η · „ .. „“ and/or PPAR^K kinetics. Pharmacy. Examples of these diseases are 搣 头 头 头 、 、 、 、 、 、 头 头 头 头 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 头 头 头It is preferred to use as an agent for the treatment and/or prevention of non-insulin type diabetes. The invention accordingly also relates to a pharmaceutical composition comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant. The present invention relates to the use of a compound as defined above as a therapeutically active substance, in particular as a therapeutically active substance for the treatment and/or prevention of a disease modulated by a ppARQ/ or PPARr agonist. These diseases are diabetes ( In particular, non-insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus, blood pressure, lipid and cholesterol, atherosclerotic disease, and metabolic syndrome are preferred. In an embodiment, the invention relates to a method of treating and/or preventing a disease modulated by a PPARa and/or PPARr activator, the method comprising administering a compound of formula I to a human or an animal. A preferred example of such a disease is diabetes (particularly Non-insulin-dependent diabetes mellitus, elevated blood pressure, decreased lipid and cholesterol levels, atherosclerotic disease, and metabolic signs are preferred for treating and/or preventing non-insulin-dependent diabetes mellitus. The present invention further relates to The use of a compound as defined above for the treatment and/or prophylaxis of diseases mediated by PPARa and/or PPARt agonists. A preferred example of these diseases is diabetes (especially non-insulin dependent urinary _37). Standard (CNS) A4 size (210X 297 mm) Gutter 34 1328585 V. Description of the invention (disease), increased blood pressure, decreased lipid and cholesterol values 'Atherosclerosis and metabolic syndrome, non-Island Dependent-type diabetes is preferred. Further, the invention relates to the use of a medicament for the preparation of a medicament as defined above for treatment and/or prevention. ppARa and βρρΑΐ 促 促 促 《 《 《 《 《 《 《 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Groups, preferably non-alked-dependent diabetes mellitus. These agents comprise a compound as defined above. The method of the present invention can be produced by the method provided below by the method provided in the examples or by a similar method. Suitable reaction conditions for each reaction step are known. The starting materials are either commercially available or can be prepared analogously to the methods provided below or in the examples or by methods known in the art, for example, from wo 94/27995, w 〇98/427〇4 and Ερ 1〇78923 and the references cited therein and the references cited in the following. The racemate of the compound of formula (1) can be synthesized, for example, according to the method described in Equation 1, Equation 2 and Equation 3 or in a similar manner (compound 在 in equation ^, compound 8 in equation 2, in the equation The compound in 3 is racemic-6) and the non-p-palphatic olefin compound having an alkoxy substituent R5 (compound 1 in Formula 1). The racemate and optically pure analog (compound 6 in Equation 3) of the compound of the formula (I) having an amino substituent R 5 can be synthesized, for example, according to the method described in Equation 3 or in a similar manner. . A single pair of palm compounds of formula (1) having an alkoxy substituent R5 can be prepared according to the method described in Equation 4 or in a similar manner (in Equation 4^-38, this paper scale applies to the Chinese National Standard (CNS)). Α4 specifications (210X297 public) 1328585 A7 B7

1328585 A7 B7

1328585 A7 ____B7 V. INSTRUCTION DESCRIPTION (37) Phenol 1 and/or aldehyde 6 are known or can be synthesized by methods known in the art. Examples of possible synthesis of these phenols and aldehydes are provided in Million 5-10. The aryl-carbazole compound 2 (prepared as shown in the formula )-^) and phenol 1 or aldehyde 6 are concentrated according to known procedures, and if R12 represents a hydroxyl group, via triphenylphosphine and azodicarboxydi The Mitsunobu-reaction of tributyl-, di-isopropyl or diethyl-ester as a reagent is preferably carried out at room temperature in a solvent such as methyl or tetrahydrofuran. Or if it represents a tooth, a sulfonate or a toluene sulfonate-previously, the presence of the aryl azole compound 2 and the phenol 1 or aldehyde 6 in a weak base such as cesium carbonate or potassium hydride The solvent such as hydrazine, hydrazine dimethyl carbamide, acetone or methyl ethyl ketone is reacted at a temperature ranging from room temperature to 14 Torr C (preferably at about 50 ° C), thereby obtaining an ether compound 3 or an aldehyde 5 (Step a). The former is then subjected to mercaptomethylation, for example, in an inert solvent (preferably dioxane methane) of trioxane and HBr (preferably 62% aqueous HBr). (lower (preferred) treatment to obtain highly reactive, often very unstable, electrophilic material 4 (step b). Electrophilic feed 4 is suitable for alkoxy-acetic acid brewing 7 (Ru = lower alkyl) The enolate is alkylated to treat 7 of the lithium enolates prepared by treatment with a strong non-nucleophilic base such as lithium diisopropylguanidinium in a reagent such as tetrahydrofuran. The reactivity of the alcoholated electrophile, so in the presence of a cosolvent such as hexamethylenephosphonium dimethyl 3,4,5,6·tetrahydro-2(1Η)-pyrimidinone (DMPU) The reaction is preferably carried out to obtain ester 9 (step d). Alternatively, it may also be vnsmeier for caramification or via formazanization in the presence of titanium tetrachloride (for at between -78. Preferably, the aldehyde compound 5 (step c) and the enolate of the alkoxy-acetate (7) are obtained in the dioxane at a temperature between the mud back temperatures (for example, in---- 41 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585

It is preferred to treat the lithium enolate prepared by treating a strong non-nucleophilic base such as lithium diisopropylguanidinium at -78 C in a tetrahydrofuran/valid in a solution such as tetrahydrofuran. The temperature of -78 C is preferred to give the diastereomeric product a fulleraldehyde product 8 . Triethylmethane in the presence of a Lewis acid such as boron trifluoride or an aprotic acid such as tri-acetic acid in a suitable solvent such as trifluoroacetic acid itself or dichloromethane . 〇 to 6〇. The benzylic hydroxyl group in 8 is removed between the oximes to give the racemic ester 9 (step f). Or a Wittig salt (such as chlorinated (ethoxy: ethoxycarbonyl-methyl)-triphenyl) in a solvent such as isopropanol, dichloromethane or tetrahydrofuran or a mixture thereof. Base or brominated (methoxy-methoxycarbonyl-methyl)-triphenyl scales in, for example, potassium carbonate or 1,8 吖 %% [5.4.0] 十一_7_埽 (DBU) The reaction is carried out in the presence of a base, preferably at a reflux temperature of 〇c to the falling agent, to obtain a propionate H) which is a beta and/or z isomer (step g). The hydrogenation of acrylate oxime as a catalyst on charcoal (preferably at room temperature and hydrogen pressure at atmospheric pressure) is used in a solvent such as methanol, tetrahydrofuran, vinegar I, monomethane and mixtures thereof. Racemic ester 9 (step h). Hydrogenation of a compound in which R3-R4 forms a benzofuran moiety with a benzene ring attached thereto can be carried out for a predetermined period of time to provide a corresponding stupid dihydrofuran analog. In the compound in which R3-R4 forms a benzophenan moiety together with the benzene ring to which it is attached, the double bond is carried out at a reflux temperature from room temperature to the solvent in magnesium in a solvent mixture such as tetrahydrofuran/methanol. The reduction is preferred. The esters 9 and 〇 can be hydrolyzed according to standard procedures, for example, by treatment with an alkali hydroxide such as LiOH or NaOH in a polar solvent mixture such as tetrahydrofuran/ethanol/water to form the carboxylic acid 1 1 (step i) . ____- 42 - This paper size applies to Chinese national standards (CNS> A4 size (210x 297 mm)

Binding

Line 1328585 A7 B7

1328585 A7 _________ B7____ V. INSTRUCTION DESCRIPTION (40) Metathylation in the presence of titanium is preferred in methylene chloride at a reflux temperature of from -78 ° C to the solvent (step b). The aldehyde 3 can then be combined with a Wittig salt (such as chlorinated (ethoxy-ethoxycarbonyl-methyl)-triphenyl scale or brominated in a solvent such as isopropanol, di-methane or tetrahydrofuran or a mixture thereof. (Methoxy-oxiranyl-fluorenyl)-trisyl scales are reacted in the presence of a base such as potassium carbonate or i.8.bi-bicyclo[5.4.0]indole-7-ene (DBU). Preferably, it is at a temperature of from 〇 ° C to the temperature of the solvent to obtain an acrylate 4 which is an E and/or z isomer (step c). The acrylate 4 is hydrogenated by a catalyst to produce phenol 5 in a solvent such as decyl alcohol, ethanol or tetrahydrofuran on charcoal (step d). In the case where R3 and R4 form a benzothiophene or a benzofuran moiety together with the benzene ring to which it is attached, it is preferably carried out in two steps: in the first reaction, magnesium in a mixture of methanol and tetrahydrofuran is used. The double bond of the acrylate is reduced at a temperature ranging from room temperature to the reflux temperature of the solvent. Next, the protecting group such as benzyl ester is cleaved, for example, using dimethyl sulfide and boron trifluoride-ethyl bromide in a solvent such as dichloromethane to cleave between room temperature and the reflux temperature of the solvent to obtain a phenolic compound 5 . The known procedure described in the equation 丨 for concentrating phenolphthalein or 4-hydroxy-benzene chain 6 with an aryl group is then used to concentrate those self-dividing compounds with the aryl 3 azole 6 to give the ether compound 7 (step e) . Ester 7 can be colored into acid 8 using standard conditions of alkaline hydrolysis as needed (step. This paper scale applies to China M specification (2ι〇χ2=治-------- 1328585 A7 B7)

1328585

The preparation of the α-amino group gs 4 can be carried out by treating the glycinate as a strong non-nucleophilic base such as lithium diisopropylguanidinium in an inert solvent of tetrahydrofuran. Preferably, N-(diphenylmethylene)glycolate is converted to a corresponding decanoate (preferably lithium decanoate) under _78; η) will form a The alcoholate is reacted with the sulfhydryl group U in the compound 4) of the formula 1, preferably between -78 t and room temperature, in order to increase, for example, hexamethylphosphoniumamine (HMPA) or 1,3-methyl-methyl _3,4,5,6-tetrahydro-2( 1H) - the co-solvent of the electrophile of the benzoic ketone (DMPU) - preferably the following: iH) imine intermediate and acid Hydrolysis (for example, dilute aqueous hydrogen chloride solution) (step a). Alternatively, the alpha amino ester 4 can be prepared from aldehyde 2 (compound 5 in the formula ,) by using 1) a diphosphoric acid glycinate suitable for use in a solvent such as di-methane or tetrahydrofuran (for example, hydrazine- (Mercaptooxycarbonyl)_α_trioxophosphoric acid trimethyl ester) is concentrated in the presence of a base such as Huenig's base at room temperature to reflux of the solvent to form an enamine amine group. Formate; 3; 丨i) Hydrogenation and deprotection of enamine urethane 3 in a solvent such as ethyl acetate, tetrahydrofuran or methanol using, for example, hydrogen in the presence of palladium on charcoal (Step b, c) ° by i) Separation into enantiomers by preparative chromatographic HPLC column chromatography or ii) hydrazinocarbamic acid g3 in the presence of ι,2·双[( 2S,5S)-2 5_Diethylphosphinyl]phenyl to a palmitic ligand in the presence of a catalyst such as methanol in a solvent such as methanol hydrogenated [Comparative J. Am. Chem. Soc. (2000) ), 122(16), 3830-3838] 'The Z-protecting group is then removed using standard reaction conditions such as catalyst-free hydrogenolysis. Next, the α-amino ester 4 is reacted with a suitable ketone in an inert solvent such as toluene and at a reflux temperature, if necessary, in the presence of a catalyst such as p-toluenesulfonic acid to be converted into the enamine 5. In wood-46 paper scale applicable Chinese national standard (CNS) Α4 specification (210X297 mm) 1328585 A7 B7 V. Description of invention (in the presence of Pd on carbon and about 18 (using benzoyl group at TC temperature) The cyclohexanone is used as a ketone component in an inert solvent such as anisole, followed by aromatization to form an enamine (step d). The enamino ester racemization _ 5 or (S)- can be optionally used. 5 saponification to acid racemic _6 or (S)-6 using standard conditions of alkaline hydrolysis (step e)e

1328585 A7 B7

1328585 A7 _____ B7 V. Inventive Statement 45) - A single pair of palmitic alpha alkoxyphenylpropionic acid compounds of formula 8 can be prepared according to the methods described in Equation 4 or analogously known in the art. The well-known pair of palmitic adjuvant 2 [( s) _ 4 -mercaptooxazolidine 2 - ketone] and alkoxy oxime 1 in the presence of, for example, n-butyllithium in an inert solvent such as tetrahydrofuran Concentrate at a temperature of about -78 C to produce chunk 3 (step a). The latter is then reacted with dibutyl boron-trifluoromethanesulfonate in di-methane and a secondary amine such as triethylamine according to the additional procedure [Tetrahedron Asymmetry (1999), 10, 1353-1 367] To produce the corresponding-enolated boron, which is then reacted with benzaldehyde 4 (Compound 5 in Equation!) at low temperature to give compound (5) (step b). Among the compounds 5, all of the four possible stereoisomers are extremely dominant (there is no strict proof of the stereochemistry shown). The benzylic hydroxyl group is then removed in a reduced manner, as illustrated by the conversion of compound 8 to compound 9 in Equation 1, to produce the penultimate intermediate 6 (step c). Finally, the alcohol is carefully decomposed in a corresponding alcohol as a solvent or in a reagent such as tetrahydrofuran or dioxane at a temperature of about 〇t (step d) or diluted Na〇H in tetrahydroanhydride/water. By careful alcoholysis (step e) at 〇 ° C, ester 7 or acid compound 8 ' can be obtained without racemization. The optical rotation of compounds 7 and 8 can be determined by the presence of palmar hplc or 1H-NMR light in the presence of a palmitic solvent such as 1·(9-fluorenyl)_2,2,2-trifluoroethanol. Purity, and found in all case examples to be of high purity. It is known or can synthesize phenol 1 and/or aldehyde 6 (Equation 1), phenol 1 and/or protected 2 and/or protected aldehyde 3 (Equation 2) and 嗤 2 in a method known in the art. (Equation 1). A possible synthesis example of these key intermediates is provided in Equation 5_丨2. This paper scale applies to China National Standard (CNS) Α4 specification (210 X 297 mm) 1328585 A7 B7 V. Invention description (46)

4-Hydroxybenzofuran 5 [Synthetic Communications (1986), 16(13), 1635-1640; Helvetica Chimica Acta (1933), 16, 121-129] and 4-hydroxybenzophenone 8 [Jpn. Kokai Tokkyo Koho (2001), 2〇01048876A2]. Therefore, 'cyclohexane-1,3-dione 1 carrying a different substituent R6 at the 5_ position can be interposed with bromopyruvate in methanol in the presence of, for example, a hydroxide desorption test. Hey. The temperature reaction between the reflux temperature of hydrazine and decyl alcohol is then treated with hydrogen acid at about 1 Torr to obtain furan-carboxylic acid 3 (step a). These furan-carboxylic acid 3s are treated in an inert solvent such as decahydrocha in the presence of a hydrogen acceptor of dodecene and palladium on carbon, preferably under reflux to provide carboxybenzofuran 4 (step b), decarboxylation to benzofuran 5, for example, at 2 Torr. (: to 24 〇. (: used between temperatures

1328585 A7 B7 V. Description of invention (47)

Copper powder in porphyrin (step c). Treating 2-nonylcarboxyaldehyde 6 with a vinyl lithium- or vinyl magnesium-derivative suitable in a solvent such as tetrahydrofuran or 1,2 dimethoxyethane, at a distance of from 78 to The temperature between room temperature is preferred, followed by treatment with acetic anhydride to produce thiophene 7 having a different substituent R6 (step d) » with carbon monoxide (preferably at a pressure of 2 to 6 bar), such as acetic acid Palladium-based palladium catalyst, such as trisphosphine phosphine, in a solvent blend (which typically includes acetic acid liver, diethylamine, methyl bromide or tetrahydropyrene) to treat p-septene 7 at The temperature between 1 and 60 C is preferably such that benzo-4 phen 8 is supplied after the saponification of the -acetate function (step e). Equation 6

-51 -

1328585

Conversion of 2-hydroxy-3-methoxybenzaldehyde i substituted with bromine at position 5 to benzo[b]phenylsulfonyl-7-phenol 6 or 5-bromobenzo[b]benzenesulfide _7• Phenol 6. This sequence is carried out as described in J. Chem. Soc., Perkin Trans. 1 1983 (12), 2973-7. Regarding the conversion of 2-hydroxyl-% methoxybenzaldehyde to stupid [b] phenylsulfan-7-phenol: in the presence of an aqueous base such as potassium hydroxide in water or in the presence of, for example, diisopropyl In the presence of an amine organic base, it is treated with hydrazine, dimethyl-dimethyl thiocarbamidine gas in a solvent such as tetrahydrofuran, preferably at a temperature between 〇r and chamber to produce Sulfur urethane 2 (step a); between 2 Torr. (: to 28 〇. (: between the temperature, the thermal recombination with no solvent or in an inert solvent such as diphenyl ether (preferably) 2 to produce S · aryl thiocarbamic acid formic acid 3 ( Step b); followed by a coloration of, for example, a hydroxide or potassium in a solvent such as an alcohol; benzene sulphur age 4, preferably at a temperature between 1 temperature and the reflux temperature of the solvent (steps) ^, reacting thiophenol 4 in sodium or sodium chloroacetate in a water or hydroalcohol mixture at a temperature between room temperature and the reflux temperature of the solvent in the presence of a base such as sodium or potassium hydroxide, followed by Producing benzo-1>cepheno-carboxylic acid 5 (step phantom; decarboxylation effect, for example, in quinoline in the presence of copper in the form of a temperature between 2 〇〇. 匚 to 24 〇 ec, #着甲Functional cleavage, for example, treatment of aqueous hydrazine in acetic acid under reflux to produce benzo[b]phenylsulfan-7-朌6 (step e). 7-Mercaptobenzopyran Is known and commercially available when Chem. (1987), 卯), in the order similar to the above, '5-carbyl-3-methoxybenzene can be used to prepare 5-formyl homologues, Its system is like , Ν-dimethyl kegs · neck > six 丨丄 丨丄,, ^ . 丞T makeup foot 'glutamine 2-hydroxy-3-methoxybenzene chain 1 and chloroacetic acid ethyl The existence of the unloading test is based on the 6th generation to the paper scale. The standard (CNS) A4 specification (21QX297; ^-------________ 1328585 A7 B7

V. Description of the invention (!20. (: reaction between temperatures to produce stupid and furancarboxylic acid 7 (step f). Next with decarboxylation as described above and defined ether solution leaving (at room temperature) The lower pyridine hydrochloride is preferred to give 5-bromo-7-hydroxybenzofuran 8 (step g).

Hydroxaquinone 1 and 2,3-linked phenol 2 having 5, 6 and 7 ring sizes are commercially available or known [Ref. J. Am. C hem. Soc. (1988), 110 (19) ), 6471-6480; US (2000) 6121397; PCT Int. Αρρ1·(1999) WO99/10339]. Available from 3-nitro-1·methoxynaphthalene 3 [ivlonatsh.

Chem. (1992), 123 (6-7), 637-645] Prepared by the complete established step _- 53 - This paper string scale applies to the China National Standard (CNS) A4 specification (210X297 public) 1328585 A7 B7 50 V. INSTRUCTION DESCRIPTION (In the final stage, the synthetically improved intermediates of the functionally modified intermediates 3_Moji_i- via tea 4' are reduced by nitro-functionality, for example, in the presence of a catalyst Subsequent hydrogenation followed by diazotization, reaction and methyl ether functional cleavage to give 3-amino-based small hydroxy tea 4 (step & bc). 2,3-linked carboxylic acid 5 is known. It is known that its 3-bromo homologue 6, or can be prepared by bromination of an established aromatic nucleus [j. 0rg. Chem (1987), 43 (11夂2167-70; Ger· Offen_(i977) , DE 2633905] (step d). It is then possible to post-degrade 3-oxalylphthalic acid to the corresponding phenol 7 in a known manner, such as by using a destructive ring of, for example, borane to form the corresponding alcohol. For example, using Swern conditions (early helium/dimethyl _5 wind/triethylamine in two mouse mitochonds, -78eC to room temperature) is oxidized to p-aldehydes followed by peracetic acid in acetic acid (4 〇%) of Baeyer Vill Eriger oxidation (steps e, f, g). — Equation 8 '0 X),

Ordering

_ - 54 - This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1328585 A7 B7

Alkyl methoxylates characterized by a hexahydro oxane ring are known [Can. j. chem. (1982), 60(16), 2〇93·8]. The methoxy ether-functional cleavage of pyridine hydrochloride at about 2 Torr (t) yields 3-bromophenol 2 (step a). The isomer block can be obtained as follows: the carboxylic acid 3[1; s (丨999) can be brominated to give the 3-bromo derivative 4 (step ..., similar to the compound 6 in the equation 7) Converted to the order illustrated by compound 7, which can be converted to 朌5 (step c, d, e). Equation 9 - Plant" 3 ^4

The 3-bromophenol 1 carrying a protective functional group may be converted into a homologous phenol 2 carrying a different functional group R6, and the bromine compound is first converted into a corresponding aryl lithium derivative (for example, used in, for example, tetrahydrofuran) The alkyllithium reagent in the solvent, preferably at a temperature of about -78. (and preferably), and then using various methods well known in the art, to neutralize the latter with various electrophiles (step a). Synthesis of R6=OH) by reacting an aryllithium compound with trimethylborane at a temperature between _78eC and the reflux temperature of tetrahydroanthracene, followed by small oxidation with, for example, N-methylmorpholine The oxidation of the material is preferably carried out at the reflux temperature of tetrahydrofuran [Compared to Syn丨ett 1995 (09), 93 1-932]. These phenols 2 having R6 = OH can then be converted into corresponding genomic compounds by well-known methods.

Equation 1 ο

The beverage 1 can be functionalized with a protective functional group as desired by a known electrophilic aromatic substitution method to form an age 2 carrying an additional substituent R2. It will be opened in many coats, and will be substituted with o-/p-substituted products and o-/p-substituted products, the ratio of which depends on the precise reaction conditions. In these cases, the highest possible single ortho-product can be achieved with the most complete reaction conditions; the product can also be separated into pure isomers by well-known methods (eg (4) gel layer separation). a). τ is the age of protective functional groups as needed! Obtaining 4*-mercapto-based compound 3 with known formazamylation (such as Vi丨smeier formazonization) or for the formazanization of di-p-methyl ether in the presence of titanium tetra-carbide The temperature between the methyl chloride and the reflux temperature between -781 and the solvent is preferred (step b). Then, the methyl mercapto compound 3 can be reused as a raw material for the known electrophilic aromatic substitution method. Generating a formulation with an additional R2 substituent

Line The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) —--- 1328585 A7 B7 V. Inventive Note (53) Compound 4 (Step c). Equation 1 1

Aldehyde 1 is commercially available or known. According to the literature procedure (Diels, 0.; Riley, K.; Chem Ber (1915), 48, 897), the diketone monofluorene 2 is present in the presence of a strong acid (formulae HC1) and as in AcOH Concentrate in a polar solvent to produce carbazole-N-oxide 3 (step a). POCI in digas methane under reflux; followed by treatment to provide the corresponding primary gasification 4 (Goto, Y.; Yamazaki, M.; Hamana, M.; Chem Pharm Bull (1971), 1, 9,2050 'Step b). Or use the original look of these intermediates, according to the method established by redundancy, to convert to the corresponding alcohol or activated alcohol, such as methyl sulfonate or ____ - 57 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) ----- 1328585 A7 ____B7 V. Description of the invention (e) x 54 sulfonate, or converted to bromide or iodide, or finally further via SN2 reaction with NaCI to obtain Block 7 via nitrile 5 (step c), destruction of f-water % effect (step d), and kinetic action (eg, with boron boron in tetrahydropyrene) (step e). As described, for example, in Bioorg. Med. Chem. Lett. (2000), 10 (17), 2041- 2044, with corresponding aryl or heteroaryl carboxamide and 匕3_dichloroacetone having r7=hydrogen The 4-chloromethyl-2-aryl or 2-heteroaryl group is preferred. Equation 丨 2 • Two -

___- 58 - This paper size is applicable to China National Standard (CNS) Α4 specification (210X297 mm) 1328585 A7 B7 V. Invention description (~"" ~ N- SS-glycolate 1 or commercially available product , or known, or can be prepared by standard N-cooling. Will be double deprotonated by a non-nucleophilic base such as LiHMDS in a solvent such as THF, typically at -78 Monoc-propylated ester 2 can be readily obtained by treatment with guanidinium bromide at ° C to selectively produce C-alkylated product 2 (step a). Intermediate acid 3 is produced by standard hydrolysis (step 骡b), then converted to compound 4 (step c) in a completely established procedure (J Med Chem. (1996), 39, 3897). Using tri-acetic acid and trifluoroacetic anhydride as reagents, the ring is closed to carbazole. A key intermediate 5 is produced (step d) 'finally via oxidative chlorination of, for example, 9-BBN in THF and continued oxidative finishing with H 2 〇 2 and NaOH to achieve the target alcohol 6 (step e). The following test was carried out to determine the activity of the compound of formula I. It can be developed in Nichols JS et al. Development of scintillation proximity assay f〇r peroxisome proliferator-activated receptor gamma ligand binding domain", (1998) Anal. Biochem. 257:1 12- 1 Background information for the assay was found in 19. The full-length cdNA strains of human PPAR α and mouse PPAR 7 were obtained by RT-PCR of human fat and mouse liver fat cRNA, respectively, and cloned into plasmid vector and confirmed by DNA sequence. Bacterial and mammalian expression vectors to produce glutathione-s-transferase (GST) and Gal4 DN A in the ligand-binding domain (LBD) of fused synthetic PPARr (aa 174 to 476) and PPARa (aa 167 to 469) Binding region protein. In order to accomplish this, PCR amplification of full-length ______- 59 -___ This paper scale applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 1328585 A7 B7 V. Invention description (56) The LBD site encoded by the cloning sequence was ligated into plasmid vectors pGEX4T-2 (Pharmacia) and pFA-CMV (Stratagene), and the final strain was confirmed by DNA sequence analysis. Standard method in E. coli strain BL21 (pLysS) cells (Reference: Current edited by Ausubel et al. by Wiley Press et al.

Protocols in Molecular Biology) Induction, expression and purification of GST-LBD fusion proteins. Radioligand binding assay _ PPARa was assayed in TKE10· (10 mg molecular weight Tris-HCl, pH 8, 50 mg molecular weight KC1, 2 mg molecular weight EDTA, 0.1 mg/ml BSA-free fatty acid and 10 mg molecular weight DTT) Body combination. Add 2.4 μg of GST-PPARa-LBD fusion protein and radioligand per 96 wells (eg '400-dpm of 2(S)-(2-phenylmercapto-phenylamino)-3-{4-[ 1,1-ditritio-2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl-propionic acid) was incubated for 2 hours at room temperature in a volume of 100 μl . The bound ligand was removed from the unbound ligand by solid phase separation using a Multiscreen flat disk (Millipore) filled with 80 microliters of SG25 according to the manufacturer's recommendations. In TKE50 (50 mg molecular weight Tris-HCl, pH 8, 50 mg molecular weight KC1, 2 mg molecular weight EDTA, 0.1 mg/ml BSA-free fatty acid and 10 mg molecular weight DTT) assay? ? Eight-foot 7 receptor binding. Each 96 wells were combined with 140 μg of equivalent GST_PpaR r - LBD fusion protein and 1 μg of UV beads into a final volume of 50 μl. The resulting slurry was incubated at room temperature for 1 hour and at 13 〇 (^ Minute centrifugation removes the supernatant containing unbound protein and dissolves the semi-dry sheet containing the beads coated with the receptor at -60 - This paper scale applies to China National Standard (CNS) A4 specification (21 〇X 297 public 〉

Order

1328585

50 microliters of TKE. Regarding radioligand binding, for example, adding 2OO(S)-(2: phenylhydrazine-stupylamine-based honghongqi seven mountains dur mountain ο·2·(5-methyl-) in the micro-liter 2-Phenyl-oxazol-4-yl)·ethoxy]-phenyl}•propionic acid, the reaction was incubated at room temperature, and the scintillation proximity count was performed. All were carried out in a 96 well plate. The binding assay was performed and the number of bound ligands was measured on a Packard TopCount using 〇ptiputes (Packard)'. Non-specific binding was determined in the presence of 1 〇4 g of molecularly unlabeled compound. Dosage response curve was repeated 3 times in the concentration range of 10-4^ molecular weight. The luciferase transcription receptor was detected in 95% of the kidney cells of the large cheek pups (ΒΗΚ21 ATCC CCL10) at 37t. 02: 5% C02 atmosphere was grown in DMEM medium containing i〇〇/oFbs. Cells were seeded at a density of 10 cells/well in a 6 well plate, followed by either pFA-PPARr-LBD or pFA-PPARa - LBD expression plasmid plus pFR-luc receptor plasmid (Stratagene) and a conserved shape of a basic luciferase encoding a plasmid as a normalization control (SEAP) was transfected by batch. Transfection was performed according to the proposed style 'Fugene 6 reagent (Roche Molecular Biochemicals). 6 hours after transfection, cells were harvested by digestion, and at a density of 104 cells/well Inoculated in a flat well of 96. After allowing the cells to adhere for 24 hours, the medium was removed and replaced with 1 〇〇 microliter of medium-free phenol red (final 〇·1% DMSO) containing the test substance or control ligand. After incubating the cells with the substance for 24 hours, 50 μl of the supernatant was recovered and analyzed for its SEAP activity (Roche Molecular Biochemicals). The remaining portion of the supernatant was discarded and 50 μl of PBS was added to each well-61 - this The paper scale applies to the China National Standard (CNS) A4 specification (210X 297 mm). Ordering 1328585

In the Packard T〇pCount, the amount of SEAP is taken in the Packard T〇pCount And the luminescence of both luciferase. The luciferase activity was determined by SEAP. ί 仫 正规 正规 regularization, and will be experimenting

The transcriptional activity under the object = is expressed as a multiple activity exceeding the cells cultured in the absence of substance. The EC50 value was calculated using the XLfit program (5) β Ltd. UK). S The compound of the present invention exhibits an IC5 enthalpy value of ppar α and ~PPARr (milligram molecular weight to 50 microgram molecular weight, pen gram knife A 1 gram gram weight to 1 〇 micro name 八子量 is better, especially 1_ 3500 mg knife ^ θ δ .. See the knife amount 'is better than 1-500 ng. The compound is ppar brother knives κ α and pp AR r into - gram molecular weight to 50 micrograms of the amount of Ic 'Pen Μ eight early ... soil IC50 value, - 1 ng to the amount to 1 〇 micro knives read good, to (10) nanograms. SOO Taiwan 檄 right 厶 county _ 里 & 1 main iff 疋 1 -

PPARa IC5〇 Example 1 117 nanomole/liter example 2 II·7 milligrams m/liter example 7 Η4 nanomole/liter example 11 38.2 nano velvet/liter instance 48 nd instance 83 109 nanometer Ear / liter example 106 259 nanometers per liter if siglia it is inactive L13 milli ^ 1L70 nanometer / male # 21i«WiL

丄 8 8 nanomoles / male and 94 nanometers of m / liters of liters 21 nanometers 68 nanometers / male 4 1 _ 21 nanometers / male 4 8 nanomoles / liters 746 nanometers Mohr / Gongdou 464 nanometers per liter 188 nanometers per liter

Booking line 丄j厶03δ:)

V. INSTRUCTIONS (-63 - The compound and its pharmaceutically acceptable M and g classes are used as medicaments: for example, in the form of a medicinal preparation for enteral, parenteral or topical administration; For example, by oral administration, for example, in the form of a tablet coated tablet, a dragee pill, a hard or soft white gelatin capsule, a solution, an emulsion or a suspension, a rectal administration, such as a 'suppository form, is administered parenterally, for example, In the form of an ointment, cream or oil. The manufacture of a pharmaceutical product can be achieved in a manner familiar to those skilled in the art, which is described as a formula and a pharmaceutically acceptable, suitable non-toxic Sexual, inert, therapeutically compatible solid or liquid carrier materials and, if necessary, pharmaceutical adjuvants, complete the pharmaceutical form of administration. / Suitable carrier materials are not only inorganic carrier materials, but also organic carriers. For example, lactose, corn starch or a derivative thereof, talc, stearic acid or a salt thereof can be used as a tablet, a coated tablet, a dragee, and a hard white gelatin capsule. Suitable for soft white gelatin. The carrier materials of the capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the unsupported active ingredient required in the case of soft white gelatin capsules). Suitable carrier materials for the production of solutions and syrups. For example, water, polyols, cane, invert sugar and the like. Carrier materials suitable for injectable solutions are, for example, water, alcohols, poly 7C alcohols, glycerol and vegetable oils. Carrier materials suitable for suppositories are, for example, natural or hardened oils. , waxes, fats and semi-solid and liquid polyols. Suitable carrier materials for topical products are glycerides, semi-synthetic and synthetic glycerols - hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, ρ ethylene glycols. And cellulose derivatives. Water-based paper scale applicable to China National Standard (CNS) A4 specification (210X297 mm) Ordering 1328585 A7 B7 V. Description of invention (60) Consider common stabilizers, preservatives, wetting agents and emulsification Agent, consistency improver, gas improver, salt with different osmotic pressure, buffer, solvent, colorant, masking agent and antioxidant as medicine The dosage of the compound of formula 1 can vary within the broad limits depending on the disease, age and individual condition of the patient to be controlled and the mode of administration, and of course meet the individual needs in each particular application. In particular, a dose of from about 1 mg to about 1 000 mg, especially from about 1 mg to about 100 mg, is considered. Depending on the dosage, it is convenient to administer the dose in many dosage units. - 500 mg of the compound of the formula I, preferably 0.5 to 100 mg. The following examples illustrate the utility of the invention in more detail, but are not intended to limit the scope of the invention in any way. - Example abbreviations. nBu2BOTf = dimethyl Acid difluoride, acid side, br = wide, DBAD = di-tertiary dicarboxylic acid di-t-butyl ester ' DBU = 1,8-di-bi-bicyclo[5 4.〇] -j---7-埽, DEAD = azo bis, so the second brewing 'DIAD = azobis acid diisopropyl hydrazine, DMPU = 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone , _= equivalent, HPLC =. High performance liquid chromatography, LDA = lithium diisopropyl amide 'P0C13 = phosphonium chloride, quint. = five weight, rt = room temperature, sept = Seven weights, sext. = six weights, THF = tetrahydro puffan. Example 1 al2-methyl-yl- 3-{4-『2-(5-methyl-2- stupid--a certain plant oxy 1-stupid|~blp thiophene-7-yl fluorene-propionic acid Vinegar ____-64 -___- This paper size is suitable for the standard of the goods S standard WNS) A4 specifications ((10) X 297 mm) '' 1328585 A7 ______B7____ V. Description of the invention (61) 1.0 ml of nBuLi (1.5 g molecular weight, hexane LDA was prepared by adding a solution of 0.162 g (1.6 mmol) of diisopropylamine in 3 ml of absolute THF at -5 °C via a syringe. Cool to -78. Thereafter, 0.177 grams of methoxyethyl acetate (1.50 mmol) dissolved in 1 ml of absolute THF was added and maintained at room temperature for 15 minutes to confirm complete deprotonation. Next, 0.343 g of 4-[2-(7.bromomethyl benzo[[pitophen-4-yloxy)ethyl]-5-methyl-2-phenyl-indole dissolved in 5 ml of absolute THF was added. The azole (〇.80 mmol) was then added to 3 ml of DMPU. After stirring at dry ice temperature for 15 minutes and at 〇 ° C for 30 minutes, the reaction mixture was poured onto iced ice, extracted twice with AcOEt, washed with water, dried over sodium sulfate and evaporated to dryness. After crystallization of the pit at 0 C, 0.206 g of the title compound was obtained as a white solid, m.p.: 59-61. MS: 465.1 (M) +, 348.0, 186.0. NMR : (CDC13 ' 1H, 5, TMS) 1.21 (t, J = 7, 3H), 2.43 (s, 3H), 3.09 (t, J = 6.5, 2H), 3.15-3.3 (m, 2H), 3.33 (s, 3H), 4.15 (m, lH), 4.17 (q, J=7, 2H), 4.40 (t, J=6.5, 1H), 6.74 (d, J=8, 1H), 7.12 (d, J=8.5, 1H), 7.32 (d, J=5.5, 1H), 7.42-7·50 (m, 4H), 8.01 (br d, J=8, 2H). ί>12-甲气基-3-{4-|~2-(5-甲某-2-笨基-p号岭-4·一乙1基卜本·丨丨blp tomb-7-based丨-C-age will be 0. 丨 84 grams of 2-methoxy-3-{4-[2-(5-methyl-2-phenyl-». sit-4-yl)-ethoxy] • Benzo[b]p-cephen-7-yl}-propionic acid ethyl vinegar (〇·4〇 mmol) dissolved in 13⁄4 liters of THF/MeOH = l/l and at 0.670 ml of 3N NaOH ______ - 65 - The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Description of the invention (62). Maintain the reaction mixture at room temperature overnight, and then pour in The crushed ice/HC 中 was suspended. It was extracted twice with AcOEt, washed with water, dried over sodium sulfate and evaporated to give a crude product which was purified from crystals from EtOAc to hexane to afford white solid. 〇1 58 g of the title compound, m.p. 12 1- 122°. ISP MS : (MNa) + 460.3, (MH) + 438.3. IR (cm): 3078, 2922, 2853, 1737, 1653, 1554, 1462, 1 378, 1341, 1272, 1185, 1125, 1-064, 1025, 719, 688. NMR: (DMS0-d6, lH, δ, TMS) 2.40 (s, 3H), 3.02 (t, J = 6.5, 2H), 3.00-3.10 (m,1H), 3.13 (dxd' J=5, J=14.5,1H), 3-20 (s, 3H), 4.06 (m,lH), 4.34 (t, J=6.5 , 2H), 6.89 (d, J=8, 1H), 7.15 (d, J=8, 1H), 7.39 (d, J=5.5, 1.H), 7.42-7.52 (m, 3H), 7.63 ( d, J=5.5, 1H), 7.92 (br d, J=8, 2H), 12.8 (br s, 1H). Example 2 2-Ethyl-3 - {4-"2-(5-methyl) -2· Stupid-p ton _4. yl)-ethane group i 冬 冬 Γ 1 1 1 1 1 1 1 1 1 1 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题Ethyl ethoxyacetate was used instead of the methoxy derivative, and white crystals having a melting point of 147-148° were obtained. ISP MS : (M+Na) + 474.2, (M+H) + 452.4. NMR : DMSO-d6, lH, δ, TMS) 0.99 (t, J=7, 3H), 2.39 (s, 3H), 3-02 (t, J=6.5, 2H), 3.00-3.10 (m, ih), 3.12 (dx, J=5, J=14.5, 1H), 3.22-3.32 (m, ih), 3.48-3.58 (m, 1H), 4.12 (m.lH). 4.35 (t, J=6.5. 2H) , 6.90 (d, J=8, 1H), 7.15 (d, J=8, _ - 66 -___ This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm)

Binding

Line 1325885 63 V. Description of the invention (1H), 7.39 (d, J=5 1Η^ η IH, 7 9» ..., 5_7·53 (m, 3H), 7.63 (dj=5 5 lH).7.9l (brd5J =8,2H)>12 7(br SjlH)〇,; 5.5, Example 3 11_[丨丨2-(5-甲-4_::2-炙炙- *, 7 ... in a manner similar to the example! Prepare the title compound using propoxy acetoacetate instead of Qin (10). Gray (four) body. Creature, and get this point · (Μ+Κ)+ Μ.2' (Μ,)+ 488.2, (M+H) + 466.3. I:: base 3, (appendix-咩乙气一一-beng and fb] 喵-7-7- 呙 呙 呙 (4) The title compound was prepared in the manner of Example 1, but used in step a] The butyl acetoacetate is intended to be a volcanic ketone, and it is obtained as a grayish white solid having a melting point of 123° (dec.) MS: (MH). 478.3. Example 5 1: isobutoxy a -3-{4 bis 2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ In the case of using isobutoxyacetic acid, the T-oxyl derivative was replaced with a white solid which became the melting point I 02 (dec.) MS : (MH) 478.3. 1R (cm-1): 2924, 2853' 1 737,1 653' 1 555,1461,1384, -67 - 1328585 A7 ______B7 V. Description of invention (64) 1342. 1271, 1174, 1121, 1〇 66, 1030, 718, 689 NMR: (CDC13, 1H, δ, TMS) 0.78, 0.79 (2xd, J=7, 2x3H), 1.75 (septett, J=7, 1H), 2.40 (s, 3H), 3.06 (t, J=6.5, 2H), 3.00-3.10 (m, 1H), 3.19 (dxd, J=8, J=14.5, 1H), 3.27 (m, 1H), 3.36 (dxd, J=4.5, J =i4.5, 1H), 4.24 (m,lH), 4.37 (t, J=6.5,2H), 6.74 (d' J=8,1H), 7.15 (d, J=8,1H), 7.32 ( d, J=5.5,1H), 7.38- 7.48 (m,3H), 7.48 (d, J=5.5, 1H), 7.98 (br d, J=8, 2H), 9_5 (very wide -l 1H) . Example ό - hexyloxydi- 3 - { 4-f 2-( 5--methyl-2-pyrene-carbazole-4-)-Ethyl-l-this and "big base _7· base The title compound was prepared in a similar manner to Example 1 except that in the step a], the methoxyacetic acid was used in place of the methoxy derivative, and a pale yellow solid which became a bright spot of 79 to 82 was obtained. [SP MS : (M+K) + 546.1, (M+Na) + 530.2, (M+H) + 508.4. Example 7 Correction 4 丨2丨2-(4-bromomethylnaphthalene-fluorenediyl) Ethylaminopheny-2•stupid-arsenic arsenic 0.494 g 5-methyl-4-[2-(naphthalene- 1-Oxo)ethyl]_2-phenyl-tetrazole (1.503⁄4 mol) was dissolved in 6 ml of CH2Cu under argon and cooled to zero. . 0: 455 ml of 62% aqueous HBr was added followed by 58 mg of trioxane (0.644 mmol, 丨.29 equivalent). After 2 hours, an additional 0 '45) soaring 62% aqueous HBr was added and the total stirring was continued under strict temperature control: > hours. The reaction mixture is then diluted with CHfh, washed with NaHCO; saturated aqueous solution, and the aqueous layer is further extracted with cH/丨2 - times ____- 68 - This paper scale is applicable to China National Standard (CNS) A4 specification (210X 297 MM)

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Line 1328585 A7 !__ _____B7 ___ Five 'Inventive Notes (65) The combined organic phases were dried over sodium sulfate and evaporated to dryness to leave a crude title compound as the title compound. The product is very unstable and cannot be purified by column chromatography on SiO 2 , which is also easily decomposed on TLC-plates. Helium base-[2-(5-A 芡 芡 - 碟 _ 4 4 4 4 丄 笨 笨 笨 笨 笨 笨 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0. LD A was prepared via a syringe in a solution of 0.02 g (1.6 mmol) of diisopropylamine in 3 ml of absolute THF at _ 5 ° C. After cooling to -78. 0.177 grams of methoxyethyl acetate (1.50 mmol) in 1 mL absolute THF' and the mixture was maintained at room temperature for 5 minutes to confirm complete deprotonation. Then added to dissolve in 6 mL absolute THF 0.38 g of crude 4-[2-(4-bromomethylindol-1-oxy)ethyl]·5-methyl_2·phenyl-π-isoxazole (&lt;〇9〇 millimoles] 1 mM of the above obtained, then add 3 ml of dmpu. Stir at dry ice temperature for 15 minutes and stir for 3 〇 minutes under the armpit, then pour the reaction mixture onto crushed ice 'extracted with ^0 £1 Two times, washed with water, dried over sodium sulfate and evaporated to dryness by two flash chromatographic separations (Si〇2, hexane/eight (: 0 £1 = 74/26, followed by 76/24) Produced 145 grams of title compound as a colorless oil MS : 459.2 (M) + , 386.1, 342.1 〇gJ2-methyllacyl- 3-{4-f2-(5-methyl-2-phenyl---------- Rain S will be 0_丨37 grams of 2·methoxy-3-{4-[2-(5-methyl-2-phenyl-carbazole-4-yl)-ethoxy]-荇-丨- Base}-ethyl propionate (0.298 mmol) dissolved in 2 ___-69 -__ This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) --- 1328585 A7 B7 V. Invention (66) THF/EtOH = 1/1 </ RTI> and treated with 〇 745 mL of 2N NaOH. The reaction was carried out; the compound was maintained at room temperature for 24 hours and then quenched on crushed ice/HC1. It was extracted twice with AcOEt, washed with water, dried over sodium sulfate and evaporated to dryness eluting eluting eluting eluting of of , melting point 128-130° » MS : (MH). 430.5. IR (cm.1) : 2924,2854,17^3, .1650,1 585, 1553,1460, 1381.丨343, 1270,1249,1165 , 1112, 1094, 1026, 766, 714, 692., NMR: (DMSO-d6, lH, &lt;5, TMS) 2.42 (s, 3H), 3.08 (t, J = 6 2H) ' 3.17 (s,3H), 3.19 (dxd,1H), 3.36 (dxd, J=5' J=i4.5, 1H), 3.96 (m,1H), 4.38 (t, J=6.5, 2H), 6.94 (d, J=8,1H) 7.26 (d, J=8, 1H), 7.45- 7.55 (m, 4H), 7.57 (t, J=7, 1H) 7.92 (br d, J=8, 2H ), 8.01 (d, J=8 5, 1H), 8 18 (d, J=8, (1) 12.8 (br s, 1H) » ' Factory example 8 2-Ethyl-based-3~{4-丨2- (5-^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Ethylene is substituted for the methoxy derivative and is obtained as an off-white crystal of 105-108. · MS : ( M)+ 445.3 « Example 9 This paper music scale applies to China National Standard (CNS) A4 specification ^70 - 1328585

3-{4-f2-(5-A&quot;-2-ylpropanolpropionic acid was prepared in a similar manner to Example 7 using the ethyl propoxyacetate instead of methoxy λ 103-105° white. Crystal. - A certain 彳-Λ Λ 卜 笨 -1- 1- some 1-, but the derivative in step b], and obtained into the melting point MS: 459.2 (M) + , 415.2, 372.2, 342,1 〇 Example 1 0 2· X·乳基-3- {_!-丨2- ( stupid 咩岫-4 · group)· B M Ί _ 苫-1 - a certain propionic acid prepared in a similar manner to Example 7 Compound 'But in the step... ethyl butoxyacetate was used instead of the methoxy derivative, and white crystals having a melting point of 88-90 were obtained. MS : (Μ-Η)· 472.2. Example 1 1 §l. -g&gt;4-Benzyl-K(2S,3R_hJ-捋某-2-甲氮)-3- 4-Γ2-(^-methylphenyl-°号°皇四-基)-基〗 And "blp dictates to ___} and 醢 、, ° 吐 炫 will 0.24.9 grams (S) -4- 基 -3- 曱 曱 乙 临 。 。 。 。 。 -2- 1.00 1.00 1.00 Mol) dissolved in 2.5 ml of absolute CH2C12 under argon and treated with 167 ml of triethylamine (1.2 eq.) "after cooling to -78. Thereafter, slowly add nBu2BOTf (1.1 Raise 1 gram of molecular weight solution in CH2C12) and allow 50 minutes of enol borate formation for 50 minutes at -78. After re-cooling, add 3.5 ml absolute via a dropper. 0.363 g in CH2C12 4-[2-(5-methyl-2-indolyl-4-yl). B_________- 71 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297) Public love)

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1328585 A7 ______B7 V. INSTRUCTION DESCRIPTION 1 68^ '~~~oxy]-benzo[bp-sept-7-carboxaldehyde (io millimolar), and the mixture is maintained at -78 ° for 30 minutes and in 〇 . Maintain for 6 minutes. Pour on crushed ice, extract two/under s with AcOEt to remove salt water and water, dilute with 35 acid acid and obtain solvent, then use flash chromatography to separate the layer (silicone, hexane/Ac〇Et=7 /3') Finally, 0.259 g of the title compound was added as a pale yellow foam. According to NMR, one of the four isomers is extremely dominant. According to Tetrahedr〇n Asyminetry 1999, 1353, the configuration is temporarily named 2S, 3R. Μί5Ι-4-^.3-((2$)-2- Ψ Μ-Γ2-Γ5- ^ ^ - 7- ^ ^ - P oxazolyl)-ethane carbazyl and fh14吟-7- (5)-4-mercapto-3-((28,311)-3-hydroxy-2-indolyl-3-{4-[2-()夂Methyl-2-phenyl _ _ _ _ 4 _ _ _ ethoxy] benzo [1); | 11 thiophene-7-yl} propyl hydrazino) oxazolidin-2-one (0.255 G, 0.42 mmol, dissolved in 2.2 ml of trifluoroacetic acid at 0. It was treated with 663 663 ml of triethylmethane (10 eq.) and then maintained at room temperature for 3 hrs, when TLC showed no material. The reaction mixture was poured onto crushed ice / EtOAc / EtOAc / EtOAc (EtOAc)EtOAc. The title compound was obtained as a colorless foam by flash chromatography (SiO 2 , hexanes / EtOAc / 7 / 3). MS: 596.4 (M) +, 564.3, 348.2. NMR : (CDC13, 1H, δ, TMS) 2.39 (s, 3H), 2.78 (dxd, J = 9.5, J = 13.5, 1H), 3.05 (t, J = 6.5, 2H), 3.25-3.31 (m, 3H), 3.41 (s, 3H), 3.91 (t, J=8, 1H), 4.07 (m, lH), 4.37 (t, J=6.5, 2H), 4.42 (m, 1H), 5.42 (t, J=6.5, 1H), 6.75 (d, J=8, 1H), 7.17- -72 - This paper scale applies to Chinese National Standard (CMS) A4 specification (210 X 297 mm) 1328585 A7 ___ B7 V. Invention Description (6g) 7.4 (m, 7H), 7.40-7.46 (m, 4H), 7.98 (br d, J = 8, 2H).丨2-Liz 甲棊-2二笨某莘,-production. To _^1-stupid and fbl唣--7-a}--propyl vinegar (0.1) prepared by 0.195 grams or more (S) _ 4-mercapto-3_ ( (2s) 2·曱oxy% &gt; 4- [2-( 5 -Mercapto-2-phenyl-»-azol-4-yl)-ethoxy]•benzo[b]thiophene-7· The oxazolidine-2-one (0.32 mmol) was dissolved in 2 25 mL of THF and treated with 0.81 mL of IN Na〇H (2.5 eq.). The reaction mixture was maintained at hydrazine. Under and carry out hydrolysis - followed by TLC. After 丨 hours, the reaction mixture was quenched on crushed ice/HC1, and the two 'people' were extracted with Ac〇Et and washed with water and brine, dried over magnesium sulfate and evaporated to leave a crude product. Purification by crystallization from AcOEt/hexane twice to remove the antagonistic adjuvant. Thus, a white solid was obtained as a white solid title compound, m.p.: 118-120. . The excess of the enantiomer was identified according to iH_NMR in the presence of &gt;95% of very excess optically active pure trifluoromethylmercaptoethanol. Based on palmar HPLC (Chiralpak-AD), which totals 99.3% » MS : 436.3 (MH)·, 404.3 NMR : (CDCI3, 1H, (5, TMS) 2.40 (s, 3H), 3.06 (t, J =6.5, 2H), 3.20 (dxd, J=7.5, J=14.5, 1H), 3.32 (s, 3H), 3.36 (dxd, 1H), 4.20 (m,lH), 4.36 (t, J=6.5, 2H), 6.74 (d, J=8, 1H), 7.15 (d, J=8, 1H), 7.32 (d, -J=5.5, 1H), 7.40-7.45 (m, 3H), 7.48 (d, J=5.5, 1H), 7.97 (br d, J=8, 2H), COOH is very wide. Example 1 2 (S)-2-E gas a-3· {4-『2-(5-甲某- 2-苳- oxazol-4-yl)-r, g _- 73 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1328585 A7 B7

5. Description of the invention (a certain benzoquinone fblp porphin-7-yl}-propionate The title compound was prepared in a similar manner to Example 1 1 but using (S)-4-mercapto-3 in step a] - Ethoxyethyl π-oxazolidine _ 2 - ketone in place of the methoxy oxime derivative, and obtained as a white crystal having a melting point of 1 33 - 34. (dec.). Chiracel- ODH), total enantiomeric excess &gt; 99%. The compound was chemically contaminated with a small amount of palmitic adjuvant. MS: (MH) · 450.3. DiNMR: (CDC13, 1H, (5, TMS ) 1.09 (t, J=7, 3H), 2.40 (s 3H), 3.07 (t, J=6.5, 2H), 3.18 (dxd, J=4.5, J=14.5, iH) 3 . j - 3.3 9 ( m,2 H), 3.5 2 ( m,1 H),4.2 7 (m,1H), 4 3 7 (t J=6.5, 2H), 6.74 (d, J=8, 1H), 7.15 (d, J=7.5, 1H), 7.32 (d J-5.5, 1H), 7.41-7.48 (m, 3H), 7.48 (d, J=5.5, 1H), 7.98 (br d, J=8, 2H), COOH Very wide. Example 1 3 (S)-2-Methylsyl- 3-{4-|~2-(5-Methyl-2-3⁄4:yl-p咢&lt;-4_ _)_ethoxy b The title compound was prepared in a similar manner to Example 1 1 but using 4-[2:(5-methyl-2) in step a]. -Phenyl azole·4-yl)ethoxy]naphthalene-indole-carboxaldehyde instead of 4-[2-(5-methyl-2-indolyl-oxazol-4-yl)·ethoxy bromide And [b] porphin-7-carboxaldehyde aldehyde and obtain white crystals having a melting point of 1 32-33. According to 1 H· NMR, a very excess optical rotation of pure trifluoromethyl mercaptoethanol at &gt; 95% Excess enantiomers were identified in the presence of a total of 99.4% according to the palmitic Hplc (Chiralpak-AD). The compound was subjected to a small amount of palmarity ______- 74 - This paper scale applies to the Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) 1328585 A7 B7 V. INSTRUCTIONS (71) Chemical contamination of adjuvants MS: (Μ-ΗΓ 430.4. IR (cm-1): 2926, 2854,1 773,1650,1 585 , 1552, 1461, 138 1, 1 343, 1270, 1249, 1164, 1110, 1095, 1026, 766, 714, 693 NMR: (CDC13, 1H, δ, TMS) 2.42 (s, 3H), 3.12 (t , J=6, 2H). 3.24 (s, 3H), 3.26 (dxd, 1H), 3.62 (dxd, J=4, J=14.5, , '· **—-1H), 4.11 (m, 1H) , 4.41 (t, J=6^5, 2H), 6.78 (d, J=7.5, 1H), 7.28 (d, J=8, 1H), 7.40- 7.50 (m, 4H), 7.55 (d, J =7, 1H), 7.92 (br d, J=7, 2H), 8.00 (d, J=8.5, 1H ), 8.30 (d, J=8, 1H). Example 1 4 _ (S)-2-Ethoxy-3-{4-"2-(5-methyl-2-indolyl- 4-yl-ethyl. Kibbi-丨-丨--- The title compound was prepared in a similar manner to Example 13 except that in step a], (S)-4-(4-)-3-ethoxyethyl- s- The derivative was obtained as a white crystal having a melting point of 1 33 - 34. (dec.). According to the HPLC (Chiralpak-AD), the total amount of the enantiomer was &gt; 99%. The compound was subjected to a small amount of palm. Chemical cold dyeing of sex adjuvants MS : 445.4 (M) +, 401.3, 3 72.2, 342.3 Example 1 5 al2-(二笨甲甲胺基)-3- {4-[2-(5-甲某- 2^_基_ @ 啥_4_ base)_B&amp; base 1-strip-l-yl}-propionic acid y is intended to add 2.0 ml of nBuLi (1.5 g molecular weight, hex) via needle steam at 1 〇

__- 75 - This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 1328585 A7 ____B7_ V. Invention description (~~ --- °C 0.324 g in 6 ml absolute THF (32 mmol) To the solution of diisopropylamine to prepare LDA. After cooling to _78, 〇.802 g of N_(diphenylmethylene)glycine ethyl ester dissolved in 2 ml of absolute THF was added dropwise. (3.0 Torr), and the mixture was maintained at this temperature for 5 minutes to determine complete deprotonation. Then, 0.81 g of crude 4-[2-(4-bromo) dissolved in 12 ml of absolute THF was added. Methyl hydrazine _ _ oxy) ethyl b 5 methyl 2 - phenyl - β oxime (&lt; 0.20 house Moule, 2.06 millimolar amount as prepared in [Example 7a] above), and then added 5 ml of DMPU. After stirring at dry ice temperature for 3 minutes and stirring at 0 C for 90 minutes, the homogeneous reaction mixture was poured onto crushed ice/N^C丨, extracted twice with AcOEt, and washed with nhj丨 until pH7, dried over sodium sulfate and evaporated to dryness. <RTI ID=0.0># </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Compound: MS: (M) + 608.3 〇bl2 -amino-3 - {4-"2-(5-methyl-2-phenyl-.equequence _._4 - ethoxylated 1_ 茗-丨-yl Ethyl propionate 2-(diphenylfluorenylamino)-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]- Ethyl 荇-1- kibpropanoate was dissolved in 2 mL of THF and treated with 5 mL of 2 Ν HCl at 0°. The cleavage of the protecting group was monitored by TLC. After 5 hours, the reaction mixture was poured on crushed ice. /NaHC03 on 'and extracted twice with AcOEt. Wash with water, dry with sodium sulfate and remove the solvent with 1. V. to yield 0.505 g of colorless oil by flash chromatography (Si02, AcOEt). Compound ISP MS : (M+Na)+ 467.3, (M+H)+ 445.4 » __- 76 - This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x 297 mm) 1328585 A7 _ B7 , invention description (~ NMR: (CDC13, 1H, (5, TMS) 1.22 (t, J=7, 3H), 1.49 (br s, 2H), 2.43 (s, 3H), 3.05 (dxd, J=8.5 , J=14, 1H), 3.13 (t, J=6.5, 2H), 3.58 (dxd, J=5, J=U, 1H), 3.83 (dxd, J=5, J=8.5, 1H), 4.14 (q, J=7, 2H), 4.42 (t, J=6.5, 2H), 6.79 (d, J=7.5. 1H). 7.23 (d. J=7.5, 1H), 7.40-7.50 (m, 4H), 7.54 (br t, J=7, 1H), 7.96- 8.02 (m, 3H), 8.30 ( d, J=8.5, 1H) 1£1..2- (2-cracked 苽 苽 胺 胺 丨 丨 丨 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Dibasic-ethoxylated-l-yl}-propionic acid-ethyl-branched 0.345 g 2-amino- 3-{4-[2-(5-methyl-2-phenyl-carbazole- 4-yl)-ethoxy]-yl-1-yl}-propionic acid ethyl acetate was dissolved in 6 ml of the scent chain and continuously fed with 0.181 g (1.15 equivalents) of 2-benzofluorenylcyclohexanone and 60 mg. Pd/C (10. /. ) Treatment 'and heating to 180 to 1 85 under Ar. . After 80 minutes, add an additional 60 mg of fresh catalyst and continue to reheat for 3.5 hours. Cool to room temperature, pour on crushed ice 'extract twice with AcOEt, wash with water, dry over sodium sulfate' and prepare by flash chromatography (Si〇2, 7/3 hexanes/AcOEt) The title compound of 0.075 g of the low polarity fraction and 0.285 g of the intermediate compound of the snail amine were subjected to the same treatment as above. The final purification leaves a yellow viscous oil-like 〇22 1 gram combined 2-(2-phenylhydrazino-phenylamino)-3-{4-[2-(5-methyl-2- A phenyl-oxazol-4-yl)-ethoxy]-tea-oxime-yl}-propionic acid ethyl ester product. ISP MS : (M+Na)+ 647.2, (-M+H)+ 625.1 NMR: (CDCI3, 1H, &lt;5, TMS) 1.13 (t, J=7, 3H), 2.41 (s, 3H) , 3.10 (t, J=6.5, 2H), 3.44 (dxd, J=8.5, J=14, 1H), 3.71 (dxd, J=5.5, J=14, 1H), 4.13 (q, J=7, 2H), 4.38 (t, J=6.5, _^77 - This paper scale is suitable for the g standard (CNS) A4 specification (21G X 297 public) 1328585 A7 B7 V. Invention description (74) 2H), 4.52 (q, J=7, 1H), 6.52 (m, 2H), 6.76 (d, J=8, 1H), 7.23 (t, J = 7.5, 1H), 7.35-7.6 (m, 12H), 7.97 (br d, J=7..5, 2H), 8.04 (d, J=8.5, 1H), 8.28 (d, J=8.5, 1H), 8.96 (d, J=7, 1H). d~|2-(2-phenylindolyl-stupylamino-methyl-2-stupyl-p-substitudin-4-yl)-ethoxy-yl-indole-3⁄4 age will be 0.21 3 g (0.341 m Mo)) 2-(2-phenylhydrazino-phenylamino)-3-{4-[2-(5-methyl-2-phenylindole-4-yl'-ethoxy-) The tea-l-yl}-propionic acid ethyl ester was dissolved in 1.6 ml of THF/EtOH = 1 / 1 and treated with 0.568 ml of 3N NaOH (5 eq.). The reaction flask was stirred at room temperature for 20 hours. The mixture was poured onto crushed ice / NH4C, extracted twice with AcOEt, washed with brine, dried over sodium sulfate and evaporated to dryness. hexane/AcOEt was crystallized twice to yield yellow crystals. 1 99 g of title product , melting point 125° (dec.) ISP MS : (M+K)+ 635.1, (M+Na)+ 619.1, (M+H)+ 597.1 = IR (cm.1) : 3318,2925,2854, 1 734,1622,1 585,1514, 1460,1379,1336,1249,1157,1090,1047,1025,938,701, 643. NMR: (DMSO-d6, 1H, δ, TMS) 2.40 (s, 3H) , 3.03 (t, J=6, 2H), 3.41 (dxd, 1H), 3.70 (dxd, 1H), 4.29 (m, 1H), 4.31 (t, J=6, 2H), 6.37 (t, J= 7.5, 1H), 6.46 (d, J=8.5, IH), 6.85 (d, J=8, 1H). 7.13 (t, J=7.5 , 1H), 7.20 (d, J=7.5, 1H), 7.31 (d, J=8. 1H). 7.40- 7.60 (m, 10H), 7.91 (br d, J=8, 2H), 8.12 (t , J = 7.5, 2H), 8.87 (d, J=7, 1H), 14 (very wide s, 1H). _- 78 -__ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297) MM)

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Line 1328085 A7 B7 V. Description of the invention (75) Example 16 M2- + 喔-capped diphenylamine )) ^_{4-『2彳5_methyl-2·indolyl-carbazole-4-oxime)- The helium cap 1 - stupid and rb]d%, -7 - even 1 and the title compound was prepared in a similar manner to Example 15 but using 4-[2-(7-bromoindole) in step a] Benzo[b] porphin-4-yloxy)ethyl]_5methyl-2-phenyloxazole instead of 4_[2_(4_bromoindolyl 荇 oxy)ethyl b 5 methyl _ 2 -Phenyl-carbazole' is obtained as the melting point 丨24_丨27. Yellow solid. ISP MS: (M+K)+ 641.1, (M+N3)+ _625.1, (M+H)+ 603.0. 1R (cm.1): 3303,2925,2854,1732,1624,1574,1516, 1460, 1379, 1346, 1258, 1 179, 1095, 1047, 1027, 937, 701, 643 · NMR : (DMSO-d6 , 1H, δ , TMS) 2.35 (s, 3H), 2.98 (t, J=6.5, 2H), 3.24 (dxd, J=7.5, J=14.5, 1H), 3.37 (dxd, J=4.5, J= 14.5, 1H), 4.30 (t, J=6.5, 2H), 4.63 (m, 1H), 6.54 (t, J=7.5, 1H), 6.76 (d, J=8.5, 1H), 6.84 (d, J =8, 1H), 7.20 (d, 1=8, !H), 7.29 (d, J=8, 1H), 7.30- 7.40 (m, 2H), 7.45-7.60 (m. 9H). 7.90 (br d, J=6, 2H), 8.73 (d, J=7.5, 1H), 13.5 (very wide s, 1H). Example 1 7 gl4-丨2-(2.6-dimethyl oxime) B. _-5_A-2-mercapto-p-oxazole 1.1 g of 2,6-dimethylphenol, _ 2.0 1 Glucose 2-(5-methyl-2-phenyl-°oxazol-4-yl)ethanol and 2-6 g of triphenylphosphine were dissolved in 30 ml of THF at 0. It was treated with 16 ml of DEAD (diethyl azodicarboxylate). The mixture was maintained at room temperature overnight and "water was added. Extracted twice with AcOEt's salt water __- 79 - This paper scale applies Chinese National Standard (CNS) A4 specification (210X297 public)

Line 1328085 Α7 Β7 V. Description of the invention (76) Washing, drying over sodium sulphate and providing the crude product as evaporating solvent, which is purified by chromatography (Si 2 , ether / cyclohexane) to yield Yellow by 0.89 g of the title compound. MS: (M) + 307.2. NMR (DMSO-d6, 1H, TMS) 2.14 (s, 6H), 2.39 (s 3H) 2.93 (t, J=7, 2H), 3.99 (t, J=7, 2H), 6.87-7.02 (m&gt; 3H)^ 7.45- 7.55 (m, 3H), 7.90-7.97 (m, 2H). '1) 14-丨2-(4-bromomethyl-2,6-dimethyl argon argon) 匕 1 1 甲甘 2 基-carbazole - ^ ~~ Allowed in acetic acid (33%) 0.86 g of 4-[2-(2.6-dimethylphenoxy)ethyl]-5-mercapto-2-yl azole and 0.19 g of a p-chain in HBr were placed at room temperature 3 days. The mixture was poured onto crushed ice and extracted with a second gas. The combined organic layers were extracted with a saturated aqueous solution of sodium hydrogen sulfate and washed with brine. The obtained crude product was purified by chromatography (yield: EtOAc, hexanes) to afford crystals of hexanes as a white solid. MS : (Μ)+ 399”. NMR (CDC13, 1H, δ, TMS) 2.20 (s, 6H), 2.39 (s, 3H), 2.98 (t, J-6.5, 2H), 4.04 (t, J=6.6, 2H), 4.41 (s, 2H), 7.02 (s, 2H), 7.4 Bu 7.44 (m, 3H), 7.97-8.01 (m, 2H) 〇c]3-{375-一..y base - 4-·(~2-(5 -. A-2-phenyl group -4- 茱) gas-based hydrazine-2-ethoxypropionic acid The title compound was prepared in a similar manner to Example 2, but using 4_[2_(4-bromomethyl) - 2,6-dimethylphenyloxy)ethyl]·5-methyl·2·phenylazole

· OU This paper scale applies to China National Standard (CNS) Α4 specification (210X297 public) 1328585 A7 B7 V. Invention description ( 77 )

Instead of 4-[2-(7-bromomethylbenzo[13] porphin-4-yloxy)ethyl]_5_methyl_2-m-yl-indole as a raw material, it was obtained as a pale yellow oil. The title compound. ISP MS: (M+K) + 462.2, (M+Na) + 446.3, (M+H) + 424.4. NMR (CDC13, lH, δ, TMS) 1.16 (t, J=6.9, 3H), 2.18 (s, 6H) 2.39 (s,3H), 2.85 (dxd, J=14.1 7.8, 1H), 2.95-3.03 ( m,3H) 3.39-3.50 (m,1H), 3.52-3.60 (m,iH), 3.99-4.04 (m,3H) 6.85 (s,2H), 7.40-7.45 (m,3H),7.96-8.00 ( m, 2H). Example 18 - 1^Oxygen-..3-{3-Methyl-4-"-(5-A very-2-苽-咩地_4_某)·, oxy 1-stup The title compound was prepared in the same manner as in Example 17 except that o-cresol was used instead of 2,6-dimethylphenol as a starting material, and a white compound was obtained. ISN MS : (M-H)· 408.4. Surface R (DMSO-d6, m, TMS): i.03 (t, 〇, 3H), 2 〇6 (s 3H), 2·35 (s, 3H), 2.74 (dxd, J=12 8, ih ), 2 83 2, J = 12.8, 1H), 2.92 (t, J=7, 2H), 3.22-3.39 (nij 1H)&gt; 3 41. 3-56 (m, 1H), 3.87-3.95 (m , 1H), 4.17 (t, J=7&gt;2H)&gt; J g4 ((j&gt; J=8, 1H), 6.97 (s, 1H), 6.98 (d, J=7, 1H)&gt; 7.45- 7 55 (m, 3H), 7.87-7.96 (m, 2H). (Example 19: A _2_ ethoxy oxime 1-phenyl hydrazine-propionic acid) The title compound was prepared in a similar manner to Example 15 but Use ----- 81 - This paper scale applies towel S g Jia Pi ((10)) A4 ^ grid (21〇^^-------- 1328585 A7 B7 V, invention description (78 (4-bromo Methyl-2,6-dimethylphenyloxy)ethyl]_5-methyl-2-phenyl-oxazole (Example 丨7b) instead of 4-[2-(7-bromomethylbenzo[b] ] 喽 -4- -4-oxy)ethyl]_ 5·methyl-2-phenyl-σ azole as a starting material to produce pale yellow crystals. 1SN MS : (Μ-Η)· 573.2. NMR (DMSO- D6, 1H, TMS) : 2.02 (s, 6H), 2.35 (s, 3H), 2.88 (t, J=6.3, 2H), 2.94 (dxd, J=13.8 6.6, 1H), 3.07 (dxd, •1 =13.8 5.1, 1H), 3.91 (t, J=6.3, 2H), 4.52 (dxd, J-7.2 7.2j 1H), 6.60 (t, 1=7.2, 1H), 6.81J: s,. 2H), 6.83 (d, J=9, 1H), 7.34- 7.58 (m, 10H), 7.89- 7.92 (m, 2H) ), 8.64 (d, J=7.8, 1H) 13 (very wide s, 1H). ' ' Example 20 U 2 - broth base - winter base amine) -3-{3-甲某·: 4- [~2-(5-Methyl-2) 3 oxi-4-)-ethoxy 1-indole}-propanoid The title compound was prepared in a similar manner to Example 15 but using 4_ (4- &gt;Smelly methyl-2-methylphenoxy)ethyl]-5-methyl-2-phenyl azole (similar to the synthesis of 4-[2-(4-molyl-2,6_) Dimethyl[2-bromomethylbenzo[b]thiophene-4-oxo prepared by the method of dimethyloxy)ethyl, methyl-2-phenyl]carbazole (Example 17) The ethyl]ethyl]_5_methyl-2-phenyl oxazole is used as a raw material to produce pale yellow crystals. '' ISP MS : (M+K)+ 599.1, (M+Na)+ 583.1, (M+H)+ 561 3 (CDa3, m,TMS) : 2.n (s,3H)' 2 34 (s , 3H), 2.96 (t" = 6.3. 2H). 3.H (dxd. &gt;13.8 6 9, 1H), 3 22 (dxd, ' J=13.8 6.0' 1H), 4.13 (t, &gt; 6.3 , 2H), 4·36 (dxd, Bu 6 6, 1H)' 6.61 (t, J=8, 1H), 6.71 (t, J=7.5, 2H), ?.〇6 (s&gt; 1H)) 7.07 ___- 82 -

This paper scale applies to China National Standard (CNS) A4 specification (210X297 public I) 1328585 A7 •_ B7_ V. Invention description (79 ) J=8.7, 1H), 7.34- 7.60 (m, 1〇Η), 7.93- 7.96 (m, 2H), 8.82 (brd, J = 6,1 Η). Example 2 1 al 4,S-dimethyl"2-(4-trimethylmethyl) a nickname p sits 3 _ oxygen servant will 17.4 grams of 4-trifluorodecylbenzaldehyde (丨00 mmol) Dissolved in 5 ml of AcOH' and treated with 1 equivalent of diethyl hydrazide in a single month (ι〇·ι). The reaction flask was cooled to zero. ' And dry HC1 vapor is bubbled through the solution for 3 minutes (slightly exothermic). After a further 1/4 hour~, 15 ml of EtEEt was added and the precipitate was separated by filtration. Thus, 1 8 · 6 g of the title molecule which became a white crystal was obtained, and the melting point was 179 - 81 °.

El MS : (M) + 257_1, (M-OH) + 240. Bl 4-Oxomethyl-5-mercapto-2-(4-trimethyl.methyl benzoxazole 4,5-dimethyl-2·(4-trifluoromethyl) prepared over 1 8.5 g Phenyl) oxazole 3 oxide (72 mmol) was dissolved in 250 ml of CH2C12 and treated with 7.909 ml of 〇 (: 13 (86 _ 4 mmol). The reaction mixture was refluxed overnight and then carefully poured The reaction was stopped on crushed ice / 3N NaOH. The layers were separated and the aqueous phase was extracted with CH.sub.2.sub.2 and the combined organic layers were dried over magnesium sulfate. After evaporation of solvent, 1 .78 g of crude product was obtained as light brown crystals. Use the following procedure as it is. ISP MS : ( M+H) + 276.2. cU5·methyl-2-(4-trifluoromethyl) oxazole-4-one acetonitrile will be in 144 ml of DMSO A solution of 4-methylmethyl-5-methyl-2-(4-trifluoromethylphenyl)»azole prepared above 19.57 g was added via a pipette to 5.3 9 dissolved in 72 ml of 〇^5〇. Gongke 1^3 (: 丨10 millimoles) (slightly placed ________-83 -______ This paper scale applies to Chinese National Standard (CMS) A4 specification (210 X 297 mm) 1328585 A7

heat). The reaction mixture was then maintained at 35 t for an hour and at a price of 1 night. The reaction mixture was then poured onto crushed ice/AeC) Et. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated to dry. The 8.8 1 g of the title compound was transferred to a light yellow crystal by flash chromatography (Si 〇 2, hexane / Ac0Et = 8/2). .

El MS : (M)+ 266.1 〇H f methyl-2· (4·difluoromethyl stupid) gp full _ 4_ a [cool vinegar will be prepared above 8.69 grams [5_又基·2_(4 • Trifluoromethylphenyl)-oxazol-4-yl]acetonitrile (32.6 mmol) was dissolved in 1 mL of water/water and treated with 10 equivalents of NaOH tablets (13 g). Allow overnight hydrolysis at 85«c. Pour on crushed ice/HC丨, extract twice with gossip, wash with water, dry over magnesium sulfate, evaporate solvent, then recrystallize from Ac〇Et/hexane to produce 7 3 5 as grayish white crystals. The gram title is sour. El MS : (M)+ 285.1 〇兰12-[5-methyl-2-(4-three gas benzophenanyl)" 崠-4- certain 1 yeast will be prepared for 7.33 grams or more [5_甲Base-2-(4-trifluoromethylphenyl) oxime-4-yl]acetic acid (25.7 mmol) dissolved in 12 mL of absolute THF and 1 g of 64 ml at 0 °C Molecular weight bh3 · THF (2.5 eq.). The reaction mixture was maintained at room temperature overnight, carefully quenched with MeOH and ice, extracted twice with AcOEt, washed with water and brine, dried over magnesium sulfate and evaporated The crude product was left to reflux in MeOH for 30 min to yield quantitative free alcohol. &lt;RTI ID=0.0&gt;&gt;&gt;&gt; 84 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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Line 1325885 A7 ________ B7 V. Description of the invention (81) Methyl-2-μ-trifluoromethyl 苽 喵岫, 喵岫-4·莘1 ethane base} Article-1 - Read 2.00 gram 2-[5- Methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]ethanol (7_37 Nym) was dissolved in 37 ml of toluene and was continuously dried at 丨·27 g 4· Hydroxy hydrazine 1-carboxyaldehyde (7.37 mmol), 1.93 g triphenylphosphine (7,37 mmol) and 1.49 g (7.37 mmol) DIAD treatment. The cooling bath was then removed and stirring was continued for 2 hours. The reaction mixture was then evaporated in vacuo to dryness. After boiling in ether, </ br> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Compound.

Sl^ii_5L^-3-"(2S.3RH荈一-2-甲氪一甲fluoromethylphenyl) ° carbazole-4-yl 1 ethyl group} stupid-1-some) propyl sfe its 1 g Oxazolidine _ Dissolving 0.374 g of (S)-4-mercapto-3-methoxyethyl aryl group - 2 - 嗣 (1.503⁄4 mol) in argon under μl absolute ch2ci2, Treated with 0.2:) 1 ml of triethylamine (1.2% equivalent). After cooling to 78., nBu2BOTf (1.65 ml of a 1 gram molecular weight solution in CH2C12) was slowly added and allowed to proceed at -78. The enol borate formation was carried out for 15 minutes at 15 minutes and in 〇. After re-cooling, 0.638 g of 4-{2-[5-methyl-2-(4-) in 12 ml of absolute CH 2 Cl 2 was added. A solution of trifluoromethylphenyl)carbazole-4-yl]ethoxy}brown-branched chain (L 5 mmol) was added via a dropper and the mixture was maintained at -78 for 30 minutes and in hydrazine. Maintain for 60 minutes. Pour on crushed ice, extract twice with AcOEt, wash with salt water and water, dry with magnesium sulfate and evaporate the solvent, then flash-separate method (矽胶,己虎_ - 85 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297) 1328585 A7 B7 V. INSTRUCTIONS (82) / AcOEt = 1/ 1) Finally left 0.840 g of the title compound as a white foam. ISP MS : (M+H) + 675.1, (M+Na) + 697 HL(S)-4-芊篡- 3-US)-2-Methyl-yl- 3-(4-(2-Γ5-甲某- 2-(4-三气甲一装某)啐峡- 4_Base 1 Ethoxy} Stupid-1•A) Propionyl 1 Soxazolidine-2- § (S)-4-Mercapto-3-([23,311)-3- prepared with 0.837 g or more Hydroxy-2-methoxy-3-(4-{2-[5-methyl-2:1_4-trifluoromethylphenyl)oxazol-4-yl]ethoxy}indole-1 -yl) Propionyl] oxazolidin-2-one (1.23 mmol) was dissolved in 3.2 mL of trifluoroacetic acid and treated with 0.977 mL of triethylmethane (5 eq.) and then maintained at room temperature. 1 6 hours, when TLC showed no material appeared. Then the reaction mixture was poured on crushed ice / AcOEt / NaHC03 'The organic layer was washed with water and brine (pH ~ 8 of water phase), dried by sulfuric acid and Evaporation to dryness, 0.702 g of the title compound was obtained as a white foam by flash chromatography (Si.sub.2, hexane/AcOEt = 7/3). ISP MS : (M+H) + 659.1, (M+Na )+ 681.1 〇 il(S)-2-methoxy- 3-(4-{2-[5-methyl- 2-(4-three-suspension. A certain benzene) 咩 °-4-yl~|B (S)-4-mercapto-3-([S)-2-methoxy-3 (4-{2-[ 5-Methyl-2-(4-trifluoromethylphenyl). Isoazyl-4-yl]ethoxy)indole-1-yl)propanyl]oxazolidine-2-one (丨03 mmol) dissolved in 7 5 ml of THF with 2_57 mL of IN NaOH (2.5 equivalents) treatment. The reaction mixture was maintained at zero. Lower and proceed to hydrolysis' followed by TLC. After 1 hour, the reaction mixture was poured onto crushed ice and extracted with mystery to remove the palmar aid. -86 -_ This paper scale applies the Chinese national standard (CNS>A4 specification (210X297 public))

Line 1328085 A7 __B7___ V. Inventive Note (83) Agent" The aqueous layer is then acidified with HC1, extracted with eight (1) twice, washed with water, dried with magnesium silicate and evaporated to dry β from Ac〇Et crystal, finally Produced as a white crystal 0.356 g of the title product, dazzling 丨 67_68. . 1SN-MS: 498.2 (M-H)+. NMR : (CDC13, 1H, (5, TMS) 2.44 (s, 3H), 3.14 (t, S=6.5, 2H), 3.25 (s, 3H), 3.28 (dxd, J=9, J=14.5, 1H ), 3.61 (dxd, J=14.5, J = 4,1H), 4.11 (m,m), 4.41 (t, J=6.5, 2H), 6.78 (d, J=8, 1H), 7.30 (d, J=8, lH), -7.49. (m, 1H), 7.55 (m, 1H), 7.68 (d, J=8.5, 2H), 8.02 (d, J=8.5, 1H), 8.09 (d, J =8.5, 2H), 8.2 8 (d, J=7, 1H), COOH is very wide. Example 22 B - 3- (4- { 2- f 5-甲 t 2- (4-三一甲甲苽) Oral oxazol-4-yl 1 ethane group 丨萁-l-m) propylene was prepared in a similar manner to Example 2 1 as white crystals having a melting point of 1 5 3 _ 5 5 , but in step g] Replace the oxirane derivative with (S)-4-benzyl·3·ethoxyethyl oxazolidine-2·one. ISN-MS : 512.2 (Μ-Η)+. NMR : (CDC13, 1Η, &lt;5, TMS) l.〇15 (t, J=7, 3Η), 2.45 (s, 3H), 3.14 (t, J-6.5, 2H), 3.2-3.3 (m, 2H), 3.44 (m, 1H), 3.63 (dxd, J=14.5, J=4, 1H), 4.17 (m, 1H), 4.42 (t, J=6.5, 2H). 6.79 (d, J=8, IH), 7,29 (d, J=8, 1H), 7,48 (m,1H), 7.55 (m, 1H), 7.68 (d, J-8.5, 2H), 8.03 (d, J=8.5, 1H) , 8.09 (d. J=8.5, 2H), 8.28 ( d, J=8.5, 1 H), COOH is very wide. Example 23 ____- 87 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1328585

Base _·3·(4·{2-丨Trifluoromethane) arsenic· } stupid f bl4 phen-7-芊丨 Θ $ Prepared in a manner similar to Example 21 to a melting point of 173·75. It is an off-white crystal, but in the step f], 4· benzyl benzo[b]B thiophene _7__[Ger 〇^η·(1998) DE 19711617 Αι] is used instead of 4 hydroxy tea·丨carboxyl aldehyde. ISN-MS: 504.2 (MH), NMR: (CDC13, 1H, 5, TMS) 2.43 (s, 3H), 3.08 (t, J=6.5, 2H), 3.21 (dxd, J=8, J=14.5, IH), 3.33 (s, 3H), 3.38 (dxd, J-14.5, J=4.5, lH), 4.20 (m, lH), 4.38 (t, 1=6.5, 2H), 6.74 (d. J=8 , 1H), 7.15 (d, J=8.5, 1H), 7.33 (d, J=5.5, 1H), 7.47 (d, J=5.5, 1H), 7.68 (d, J=8, 2H), 8.08 ( d, J=8 5 2H) COOH is very wide. Example 24 (sp-ethoxyl (heart trimethyl ketone) 4-yl 1 ethane benzophenone bl 唭-7-, while hydrazine was prepared in a similar manner to Example 22 as melting point 126 • White crystals of 28. However, in the step f], 4-hydroxybenzo[b] porphin-7 carboxaldehyde [Offen. (1998) DE 19711617 A1] was used instead of 4-hydroxyindole-indole-carboxaldehyde. 1SN-MS : 518.1 (Μ·Η)+. NMR : (CDCI.3, 1Η, 6, TMS) 1.09 (t, J=7, 3H), 2.42 (s, 3H).3.07(t,J-6.5 , 2H), 3-.20 (dxd, J=8, J=14.5, lH)3 3- 3.4 (m, 2H), 3.51 (m, 1H), 4.27 (m, 1H), 4.38 (t, j =6.5, 2H), 6.74 (d, J=8, 1H), 7.15 (d, J=8, 1H), 7.33 (d, J=5, 1H), 7.48 (d, J=5, 1H), 7.68 (d, J=8.5, 2H), 8.08 (d, J=8.5, I_- 88 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) V. Description of the invention ( 85 A7 B7 1H), COOH is very wide &lt; Example 25 bis 4_-yl) ethoxy. Some 1 竿- LS)-3^.4-f 2-(2j_^4^ · 1-yl}-2-ethoxylated rain The age was similar to that of Example 22 -/Nikko became the melting point of 140-45. The white polysteroids, but the 4-styl aldehydes were substituted for white solids. 瞀4-Difluoromethylbenzaldehyde began to reverse Should be cis-ISN-MS: 520.3 (MH) + 〇.. Example 26 - (S)-3-M-f2-(2-diphenyl-1-yl}-2-propenyl propylene age similar to Example 25 The way gentleman · Α - l 々 表 表 备 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 _3_ propyl most acetamidooxazolidine-2-one in place of ethoxy analog. ISN-MS: 534.2 (MH)+. Example 27 fbl4 phen-7-yl}-2-propanyl _ The ash b ochre solid which became the melting point 丨47_5丨 was prepared in a manner similar to Example 26, but the 4-hydroxybenzo[b] porphin 7 a chain was used in the Mitsunobu reaction [Ger. Offen. (1998) DE 19711617 A1] Instead of 4-hydroxy tea": aldehyde. 夂1SN-MS: 540.2 (MH)+. Example 28 89 - This paper size applies to the Chinese Painter Standard (CNS) A4 specification (210 X 297 mm) 1328585

Oxy 1 - i^L-3 bis { 4-丨2-(2-biphenyl-4 bis-4^methyl carbazole-4·, Λ 丄-yl 丨-2-methoxypropionic acid A white solid which became a melting point of 1 56-59 was prepared in a similar manner to Example 26, but (S)_4H3. methoxyethinyloxazolidine-2-one was used instead of Oxygen derivative. ISP-MS : 508.4 (M+H)+ 〇Example 2 9 111:.3- { 4-丨2-(2-biphenyl-4di^.嗤-4-) B _^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Replace the methoxy derivative with (8)-4-benzyl-3-[(2,2,2-dioxaethoxy)ethinyl]oxazolidine-2-one. ISN-MS : 574.0 (MH)+ Example 30

Lg)-3-{4-[2-(2-biphenyl-4di-4_^methyl呤咄-4·very)Λ氲一苽苽[1)1喝苯-7-yl丨-2- Ethylene was prepared in a manner similar to Example 27 to mp 163 164. The white solid is used, but in the butanol coupling step, (s) _4•benzyl-3 ethoxylated oxazolidin-2-one is used in place of the propoxy derivative. ISN-MS: 526_0 (M-H)+. Example 3 1 (5)-3-(4-{2-11-(4-isomethyl oxazol-4-yl 1 ethyl group} phenylhydrazine fb porphin-Z-yl)-2-methyl What is prepared in a manner similar to that of Example 23 to a melting point of 95_97. The pale yellow crystal-90 - paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X29741) 1328585 A7 B7

5. Inventive Note (87) Body, but using 4·isopropyl stupid hair. Instead of 4-trifluoromethyl stupid as the original 1SN-MS: 478.2 (MH) + 〇 Example 32 (S)-3-(4-{2-f2-(4-isopropyl stupid and fbl mouth phenophene -7-based - base mouth 全口 全-4- tail 乙乳) 13⁄4 S will be prepared in a manner similar to the case of Example 31, which is a mp 181-182. The intermediate alcohol (four) combined step, using (s) _ 4-word base = trifluoroethoxy) ethyl thiol] ten sit burning _2, instead of the methoxy derivative. ''2· ISP-MS : 548.2 (M+H)+ 〇Example 33 (S)-3-(4-(2-[2-(3,5-Dimethyl | , . - --- Ψ Λ. .f 1 ^ ^ steamed}%&gt; and 丨.b]·»sep-7-yl)·2-f-hydrogen propyl g was prepared in a similar manner to Example 23 as the melting point 丨84 185. Jingyue a, but 疋 starts the entire reaction sequence with 3,5-methyl aldehyde. ISN-MS: 464.2 (MH)+ 〇Example 34 0_&gt;(4-{2-『2-(3,5-II ^^phenyl bromide 5- _ 其 地 地 丨 并 并 并 并 f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f 194 194 194 However, the whole reaction sequence was started by replacing 3,5-dimethoxybenzaldehyde with 4-trifluoromethylbenzaldehyde = 1SN-MS : 496.0 (Μ-Η)+. Example 35 ---1_91 - Paper scale Applicable to China National Standard (CNS) Α4 specification (210X 297 mm)

Binding

Line 1325885 A7 B7 V. Description of the invention (88) ^^11^{2-[2-(3.5-Dimethylbenzene- gt;&gt;_5_曱基0 azole-4-one 1 ethyl)- 2-Methane was prepared in a manner similar to Example 28 to a melting point 丨97-198. The white crystal's but the replacement of 4-phenylbenzaldehyde with 3,5-dimethylalbenal started the entire reaction sequence. 1SN-MS: 458.3 (M-H)+. Example 3 6 ^111111_2-丨2-(3,5-dichlorophenyl-)_5-methyl carbazole-4_yl 1 ethyl hydrazide} ^ΙΜζ^ι_-7-yl)-3· with a - 2-A Μ Μ 呙绐 呙绐 呙绐 呙绐

Prepared in THF at -10 C according to the standard procedure '0.171 g of diisopropylamine (丨.69 house mole) and 2 ml of i 5 g molecular weight nBuLi (hexane) in 3 ml absolute THF. LDA solution. - Cool down to -78. Thereafter, 〇 18 丨 g of methoxyacetic acid ethyl ester (1·1 mmol) was added to THF in THF and stirring was continued for 15 minutes to complete the enolate formation. Add 0.166 g of 4-{2-[2-(3,5-di-phenylphenyl)-5-methyl"-thin-4-yl]ethoxy}in a 1.5 ml THF solution -7• Carboxaldehyde (〇38 mmol) and the mixture was maintained at this temperature for an additional 3 minutes. Pour on the crushed ice / NHeCI 'extracted with AcOEt twice' with water and brine, dried over magnesium sulfate and evaporated solvent, then flash chromatographic separation (Si 〇 2, hexane ' AcOEt = 7 / 3 Transfer to the same/reverse-isostructure. 1 74 g of the title compound. Preparation of the necessary aldehyde (4_{ 2 -[ 2 (5,5-diphenyl)-5-methyloxazol-4-yl]ethoxy}benzene as described in Example 2 1 a] - f] The -7-carboxyl chain, but the replacement of 4-trifluoromethylbenzaldehyde with 3,5-dichlorobenzaldehyde, the entire reaction sequence and the 4-pyrimido[b]-cephen-7-carboxaldehyde [Ger. Offen. ( 1998) DE ___- 92 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) B7 89 V. Invention description (19111617 A1) instead of 4-3⁄4 base-1 Several strands were used for the [yjitsunobu reaction] ISP MS: 550.1 (M+H)+. · IL racemate_1-3-(4-{2-12-(3.5-difluorobenzene)-5-A峄峙 丄 丄 丄 丄 丨 -7 丨 -7 -7 -7 -7-7-))-2-f gas ethyl propionate will be 0.173 grams above prepared 3-(4-{2-[2-(3, 5-diphenylphenyl)-5-methyl ° oxazol-4-yl]ethoxy} benzo[b] porphin _7_yl)_3_hydroxy_2·methoxypropanethyl ester (0.31 Millions were dissolved in ίο ml of trifluoroacetic acid and treated with 0.250 ml of diethylformanium (5 liters) under hydrazine and then maintained at this temperature for 4 hours when TLC showed disappearance of starting material. The reaction mixture is then poured onto crushed ice / AcOEt / NaHC 3 (pH of the aqueous layer ~ 7 5), the organic layer was washed with water and brine (pH of the aqueous phase ~ 8) ' dried over magnesium sulfate and evaporated to dry. Separation by flash chromatography (Si〇 2, hexane / Ac 〇 Ei == 85 / 15) supplied as a white crystal 0 · 143 g of the title compound, dazzle 1 〇〇 _ 丨〇 2. ISP MS: 535.3 (M+H) +. £1_1 ^ 沩 性 3- 3-(4-{2.-[?:-(3,5-diphenylene)-5-methyl oxazol-4-ylindole 丄 丨 bp sept-7- Base y | Gao Shi will be 0. 丨 42 grams above prepared [racemic] _3_(4·( 2_ [2_(3,5-dichlorophenyl)-5-methyloxazol-4-yl] Ethoxy}benzo[b] is dissolved in 4 ml of THF/EtOH=l/l and is 0:68 when phenanthyl-7-yl)_2-methoxypropane s-g-g (0.27 mmol) ML <RTI ID=0.0># </RTI> NaOH (2.5 eq.). The reaction mixture was stirred at room temperature and hydrolyzed, followed by TLC. After 2 hrs, the reaction mixture was poured on crushed ice/diluted HC hydr. The two layers were extracted. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated to dryness. Crystallized from AcOEt/hexanes to give white crystals. 7 -93 - 1328585 A7 B7 V. invention is described in (g title product, melting point 160-61. . ISN-MS : 504.1 (MH) + 〇' NMR : (CDCI3, 1H, δ, TMS) 2.41 (s, 3H), 3.06 (t, J=6.5, 2H), 3.21 (dxd, J=8, J= 14.5, 1H), 3.34 (s, 3H), 3.36 (m-, 1H), 4.20 (m,lH), 4.37 (t, J=6.5, 2H), 6.74 (d, J=8, 1H), 7.15 (d, J=8, 1H), 7.33 (d, J=5.5, 1H), 7.37 (s, 1H), 7.46 (d, J=5.5. m), 7.86 (d, J=1.5, 2H), COOH is very wide. Example 37 - 111 卜4 旋旋]-.3-(4-{2-『2-(_^二|1苽&amp;)_5_甲某[&gt;夸崦-4-一一虱棊} The wheat bran fb~|嚷 -7-7-base)·2·-methylpropionic acid was prepared in a manner similar to Example 36 to a melting point of 14 1 _ 142. The white crystal, but 疋 replaced 3,5-difluorobenzaldehyde with 3,5-difluorobenzaldehyde to start the entire reaction sequence. ISP-MS: 474.3 (Μ+Η), Example 3 8 (4)^ 生Η-丁氧笨甲甲圭-4-基丄ethoxy}荇 and 1 prepared in a manner similar to Example 37 to become dazzling From the point of forbearance 95-96. White crystal ethyl ester

Coupling partner for the aldol reaction ISN-MS: 514.2 (MH) + Example 39 L_racemic 1-2-butyryl-3-M £_ carbazole-4-one 1 氲 氲 茇And "V sa ', but use butyl acetonate to replace oxime _ milk 42- a certain glutenyl) -5 - 94 - This paper scale applies Chinese National Standard (CNS) A4 specification (210X297 mm) ) 1328585

Preparation of difluorobenzaldehyde in a manner similar to Example 38 began with the entire reverse κ as melting point 161-162. The white crystal fla ’ is replaced by 3,5 - 2 曱 笨 笨 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 ' 1SN-MS : 538.2 (M-H)+. Example 40 [External 1-2-butyryl- 3- (4. (2 r 〇 / 〇-j~^Uip, 5-dimethyl oxime, -s-methyl H4-yl 1 ethoxy) Phenyl phenyl) propionic acid was prepared in a manner similar to that of Example 38 to give a white crystal of 174 _ 175 ', but 3,5-dimethylbenzaldehyde was used to produce — ς 3,5- Difluorophenylaldehyde starts the entire reaction sequence. ISN-MS: 506.2 (Μ-Η)+. Example 4 1 L1 Bu 4 green 1,3-(4-{2-"2-(丄^^phenyl)- 5_甲其。 。 _ _ _ _ _ _ _ _ _ _ 棊丨 - -7 - - - - - - - - -2- -2- -2- -2- -2- -2- -2- 148 148 148 148 148 148 148 148 148 148 148白色5〇. White crystal, but using ethoxyethyl acetate instead of methoxyethyl acetate as a coupling partner for the aldol reaction. ISN-MS : 486.2 (MH)+ « Example 42 gj 2- ( 4 -Methoxy-benzoylamine even 戍-4. enoate ethyl ester 11.7 g (4-methoxyphenylhydrazino) ethyl acetate (49.6 mmol) in 250 ml absolute THF The solution was cooled to -78. and treated with 2.1 equivalents of lithium hexamethyldifluoride (1. 4 mL, 1 g molecular weight [hexanes]). After that, the equivalent of allyl bromo bromide (4.62 ml) is applied via the -95 - paper scale to the Chinese National Standard (CNS) A4 specification (210X297 public) 1328585 A7

_____BT V. INSTRUCTIONS (92) The cartridge is added' and the reaction mixture is maintained at _78. Kneeling for 5 minutes and squatting. The next 3 knives are in the middle. Pour on crushed ice, extract twice with ^(^, wash twice with water, dry with sodium citrate and evaporate the solvent, then flash-separate (Si02, ruin/AcOEt=85/15) Provided in addition to 2 74 g of the dialkylated product as a yellow oil, 1 〇56 g of the title compound 'melting point 76-78.'. ISP-MS: 278.2 (M+H)+. KLlii 4·Methoxy benzoquinone, an amine, even to -j-峥酩 2·(4-methoxyphenylhydrazino) pentanoic acid (38.1 mmol) prepared above 10.56 g ) Dissolved in 12 mL of THF/EtOH = 1/l and at 0. It was treated with 3 8 ml of 2N NaOH. The reaction mixture was maintained at this temperature for 3 hours. It was then poured onto crushed ice/HCi, extracted twice with Ac〇Et, washed with brine and dried over sodium sulfate. The solvent was evaporated, and then crystallized from AeOEt at -20 to yield 8.41 g of the title acid as white crystals, melting point 121-124. . ISN-MS : 248.1 (MH) + p丄N- ( 1 -ethenyl 3- 3-baked) -4 ·Methoxy amidoxime 21.2 ml of acridine and 15.95 ml of Ac20 (5 equivalents) were continuously added 8.41 g or more of a solution of 2-(4-decylphenylphenylamino)pent-4-enoic acid (3 3.7 mmol) prepared. The reaction mixture was maintained at 9 Torr. Next 45 minutes. After cooling, 15.8 ml of water was added and the mixture was maintained at 85. The next 3 minutes&apos; is determined to determine the hydrolysis. It was then poured onto crushed ice/HCM, extracted twice with AcOEt, washed with 2N EtOAc and water and dried over sodium sulfate. Evaporate the solvent and then use flash chromatographic separation (Si〇2, hexane/Ac〇Et=7/3) _________- 96 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 93 V. INSTRUCTIONS (available as a yellow solid, 6.45 g of the title compound, melting point 58_ 5 9 .. ISP-MS: 248.3 (M+H)+ 〇' phantom propyl-2-ί 4-methoxy Its us us us us 将 将 将 将 us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us A mixture of acetic acid (22 eq.) and 2 1.75 liters of trifluoroacetic anhydride (6 eq.) was stirred for 7 hours, stirred at room temperature for 16 hours, poured over crushed ice and extracted twice with EtOEt. It was washed three times with Na2C〇3 solution, dried with sulfur-sodium and evaporated, and then finally purified by flash chromatography (Si〇2, hexane/AcOEt=9/1) to be 4.5 1 g of colorless oil. Title compound: EI-MS: 229.2 (M) + gj_3 - 丨2-(4_甲气基基基)甲坐基·[丙-1·醇 The 4-allyl-2-(4) prepared above 4-decyloxyphenyl)-5-methylcarbazole (4.51 Gram, 丨 9.7 mM) dissolved in 60 ml of absolute THF and treated with 100 ml of 9-BBN solution (0.5 g of molecular weight hexane) in a solution of 100 ml of BBN. Allow for 2 hours of hydroboration at room temperature. Then add 56 ml of 3N NaOH and 114.5 ml of 30% Η2〇2, thereby raising the initial temperature to 45. After the time, the mixture is diluted with ice and water to Ac. The extract was extracted twice with EtOAc (EtOAc) EtOAc (EtOAc). _ E 卜 MS : 247.1 (M) + NMR : (CDC13, 1H, δ, TMS) 1.89 (quint, J=5.5, 2H), 2.31 (s, 3H), 2.62 (t, J=6.5, 2H) , 3.55 (br s, OH), 3.75 (t, J=5.5, _ - 97 - This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 public) A7 B7

V. Description of the invention (94 2H), 3.85 (s, 3H), 6 94 Μ τ,. ), to 4 (d, J=7, 2Η), 7 89 (df) 4-{3-Γ2-Γ4-Ψ oxygen parent bowl, c; ?(4) ~ 1 propylene gas one} stupid will be 1 · 〇0 3-[2-(4-Methoxyphenyl)-5-methyl s-propyl]propan-1-ol (4.G4 mmol) prepared above gram was dissolved in 2! Next, continue to 〇, 696 grams 4- via base m disk (4·04 millimoles), 1.061 grams of triphenylphosphine (4.04 millimoles) and 〇818 grams (4 〇 4 millimoles) DIAD^. Remove the cooling and keep stirring for 3 hours. Pour on the crushed ice: extract the heart (4) twice, with 3Νν&amp;〇η and water clear. First, dry with sulfuric acid, beauty and Luofa ♦, then with flashing color layer The separation method (fragmented, burned/AcOEt 7/3) was finally left as a pale yellow gum (〇84 g of the title compound. ISP-MS: 402.5 (M+H)+. 3夂棊·2·甲苹华·3·(4·丨3_“2_(4_methoxy) υ 甲 甲 甲 氧 荇 荇 基 基 基 基 基 基 基 基 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据Diisopropylamine (1.64 mmol) and 964·964 ml i 5 g molecular weight 』 heart (Hyun) Prepare lDA solution in THF at _ 10 C. Cooling _78. Thereafter, 0.177 g of ethyl decyloxyacetate (丨.49 mmol) in 1.3 ml of THF was added and stirring was continued for 15 minutes to complete the formation of the enolate. 4_{3_[2-(4-Methoxyphenyl)-5-methyloxazol-4-yl]propoxy} 荇·丨_carboxaldehyde prepared in 0 ml of THF in 2 ml of THF · 5 〇 millimolar, and maintain the mixture at this temperature for another 3 minutes. Pour on crushed ice / NHqCl 'extracted with AcOEt twice' with water, dried with sodium sulfate _____- QS - paper Scale applicable @国标准(CNS) A4 specification (210 X 297 mm)

k order

1328585 A7 B7 V. Description of the invention (95 and evaporating solvent, then 0.228 g of the title compound as a homo/reverse isomer by means of flash chromatography (Si〇2, hexane/AcOEt = 1/1) Colorless glue) 1SP-MS : 520.3 (M+H)+. 111丨 岣 性 1 - 2-甲甲. 基-3- (4- { 3-"2-(4-methoxy) )-5-玉_基°号号 _4·基1丙气基} 笨_卜) Ethyl propionate 3-light ketone-2-oxime _3-(4- prepared by 0.228 g or more {3-[2·(4-Methoxyphenyl)-5-methyloxazol-4-diyl]propoxy-yl)propionic acid ethyl hydrazide (0.443⁄4 mol) dissolved in 2.3 ml of trifluoro In the sour acid, it is treated with 697, 697 liters of diethyl guanidine pit (1 〇 equivalent) and then maintained at 〇0 for 4 hours. Then the reaction mixture is poured on crushed ice / Ac〇Et/NaHC 〇3±, the organic layer was washed twice with water, dried over sodium sulfate and evaporated to dryness to give a colorless oil by flash chromatography (Si〇2 'hexane/Ac〇Et=7/3). 〇·丨43 g of the title compound. 1SP-MS : (M+H)+ 504.4. Ιΐ ί racemic 1.-2-methoxy-3-(4- f 3-Γ2-Μ-甲气Base Base [# w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w -Methoxyphenyl)-5-methylcarbazole·4·yl]propoxy}荇_1_yl)propionic acid ethyl acetate (0.28 mmol) dissolved in ι·5 ml THF/EtOH=l /l, and treated with 0.47 ml of 3N NaOH (5 eq.) "The reaction mixture was stirred at room temperature for 2 hours" and then poured onto crushed ice / diluted 9 Torr and extracted twice with AcOE. The organic layer was washed with water, dried over sodium sulfate and evaporated to dryness. Crystallized from AcOEt/hexane pit, and finally supplied as white crystals. 〇12〇 public L_______ - 9a. This paper scale applies to China National Standard (CNS) A4 specification ( 210 X 297 public) ----

k Order 1328585 A7 _______B7 ___ V. Description of the invention (96) g title product, melting point 67-70 °. ISN-MS : (M+H)+ 474.1 NMR: (CDCI 3. 1H, (5, TMS) 2.22 (s, 3H), 2.29 (quint, J=6.5, 2H), 2.79 (t, J=6.5, 2H), 3.26 (s,3H), 3.28 (dxd, J=8.5. J=14.5, 1H), 3.63 (dxd, J=i4.5, J=4, 1H), 3.86 (s, 3H), 4.1 -4.2 (m, 3H), 6.72 (d, J=8j 1H), 6.94 (d, J=9, 2H), 7.28 (d, J=8, 1H), 7.48 (m, 1H), 7.55 (m , 1H), 7.92 (d, •1=8.5, 2H), 8.35 (d, J=8.5, 1H·) 8.35 (d, J=8.5, 1H), COOH is very broad. · Example 43 [racemic Sex Bu 3 - (4 - { 3 -『2 - (4-Cyanide y芊)-甲某崎p sit-4-yl 1 propanyl}}-1-yl)-2-methoxypropane vinegar 7 A compound which became a white foam was prepared in a similar manner to Example 42 except that 4-methoxyphenyl acid was used in place of 4-methoxy aldehyde to initiate the reaction sequence. ISN-MS: 478.2 (MH)+ = Example 44 f racemic 〗 〖_2 methoxy oxime-3 bis (4-(3-"s_A A - 7"4 · San Gu. Methyl stupid) ° No. 〖Jin 丨 丨 丨 丨 丨 丨 丨 丨 〇 吟 吟 吟7-m) propionic acid was prepared in a similar manner to Example 42 as a white crystal of melting point 丨丨5_丨丨6, but starting with 4-trifluoromethylbenzaldehyde instead of 4-methoxybenzaldehyde And 4-cyclopyridyl-丨- complex chain is used in the Mitsun〇bu reaction when 4-phenyl group and [b] phen-7-carboxaldehyde [Ger. 〇ffen. (1998) DE 19711617 A1] Step η). 1SN-MS : 5 18.0 (Μ-Η)+. ______- 100 - This paper scale applies to Chinese National Standard (CNS) Α4 specification (210X 297 mm) 1328585 A7 B7 V. Invention Description (97) Example 45 | racemic] -2 · ethoxy group 2 "4 r: the parent family of worms] oxazol-4-yl 1 propoxy _1 benzopyrene blP^__7_ a) A white crystal having a melting point of 丨12_丨14 was prepared in a similar manner to Example 44, but ethyl ethoxyacetate was used in place of methoxyethyl acetate as a coupling partner for the aldol reaction (step g)) ISN-MS : 532.1 (MH)+ 〇 Example 46 - f racemic 〖-3 - (4- { 3 - [ 2- (4- gas stupid % A certain g azole -4- a 1 C The hydrazine η7_1 58 was prepared in a manner similar to that of Example 43. The crystal was off-white, but ethyl isopropylacetate was used in place of ethyl methoxyacetate for the aldol reaction (step g)). ISN-MS: 506.2 (MH) + 〇 Example 47 (S)-2-Jfoxy- 3-(4- { tri-argonmethyl phenyl, 垵4 -4-yl 1-propoxy fluorene-1- A compound which became a colorless foam was prepared in a similar manner to Example 21, but 3-[5-fluorenyl-2-(4-trifluoromethylphenyl)carbazole-4-yl] Propyl-co-alcohol (prepared in analogous to Examples 42a]-e) was substituted for 2·[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]ethanol Mitsunobu reaction (step f)). iSN-MS: 512.3 (MH) +. Example 48 f racemic bucker 3- ( 4_ {.3 J: 2-丄N-sodium I s-methyl carbazole · 4 - 1 and _-101 -___ This paper size applies to China National Standard (CNS) A4 specification (210X297 public) " 1328585 A7 B7 V. Invention description (98) 1 violent benzo" b〗 ·» 7_基)_2·A. The ruthenium was prepared in a manner similar to that of Example 43 as a white crystal of melting point 1〇5_1〇7. However, 4-hydroxybenzo[b]thiophene-7-carboxaldehyde [Ger 〇ffen (1998) DE 19711617 A1] Instead of 4-hydroxyindole·carboxaldehyde, sMitsun〇bu reaction (step f)) 1SN-MS: 484.1 (MH)+. Example 49 1_ Racemic Bu 2 - ethoxylated g茉5) _5_methyl oxazol-4-yl 1 propoxy} 茬-1-, and 1 was prepared in a similar manner to Example 42 as the melting point M 丨 M 2 . Ethyl acetate was used as a coupling partner for the aldol reaction with ethyl acetate. ISN-MS: 488.2 (MH)+. Example 5 0 [outer cyclonicity 2 ethoxy] 3 (earth昱 昱 其 其 i i i i i i i -4- -4- 基 基 基 丙 · · · 1- 1- 1- 1- 丙 丙 丙 以 以 以 以 以 以 以 以 以 以 以 以 以 以 以 以 以The reaction sequence was started instead of 4-decyloxy aldehyde. ISN-MS : 500.3 (MH) + Example 5 1 f external cyclonic 1-3-(4· { 3_[2-丄^phenylmethyl oxazole _ 4. 某 而 而 而 - - - ) -2- -2- 某 某 某 某 某 某 某 某 某 某 某 某 某 147 147 147 147 147 147 147 147 147 147 147 147 147 147 147 147 147 147 147 147 147 147 Methoxybenzaldehyde begins to react cis __- 102 -

This paper scale applies to China National Standard (CNS) A4 specification (210X297 public I 1328585 A7 B7. V. Invention description (99) Preface 0 ISN-MS: 492.1 (MH) + 〇 Example 52 } stupid-1-base)- 2-Methane "Essence of 1-3-(4-{3-"2-丄£^ 羞 _ phenyl)-5 bis-carbazol-4_ a 1 similar to Example 50 The compound was prepared as a white foam, and p was replaced by ethoxyacetic acid ethyl acetate as the coupling partner for the aldol reaction. -- ISN-MS : 486.3 (MH) + 〇 Example 53 生卜3-(4-{2二1_2-_〇^^基茉)_%甲芊|?止4 /| 荇和[bi^i^二二乙i A certain rain 硓 is similar to the example 40 The method was prepared as a white crystal having a melting point of 149 Å 丨 5 ,, but using ethyl ethoxyacetate instead of butyl butyl ethoxide as a coupling partner for the aldol reaction. ISN-MS: 478.2 (MH), Example 54

LiLiUm Bu 3&lt;4]2 Diyl 苽 卜 5 - - - 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备Become a melting point 1 58丨59. The white crystals were replaced with ethyl ethoxyacetate in place of butoxybutyl butyl acetate as a coupling partner for the aldol reaction. 1SN-MS: 510.2 (M-H)+. Example 5 5 ____- 103 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1328585

100

this.圭-4- some 1 propylene gas and "bloi: _ _ · 7 τ ^) C. age similar to the method of Example 49 to prepare 忐·ά h 尔 into the melting point 121-123. Gray-white crystal, but 4-Hydroxybenzo[b]thiophene 7 is obtained by J s H竣蛀 [Ger. 〇ffen. (1998) DE 1 97 1 1 6 1 7 A 1 ] instead of 4-hydroxy stupid _]. The road is used for the Mitsunobu reaction (step f)). ISN-MS: 494.1 (MH)+. Example 56 - methoxy-3-i^u^^甲氲一策!i_啥-4-棊1 propoxy}benzoxanyl) propylene was prepared in a similar manner to Example 55 as a white crystal of the melting point 丨27_ ι29, but was used as a coupling partner with methoxyacetic acid ethyl acetate instead of ethoxyacetic acid ethyl vinegar. Aldol reaction: 13 ISN-MS: 480.2 (MH)+. Example 5 7

Lfh. Racemic 丄oxy-3-丨^_〇^2-(4•Tomb and even 茇 某 slogan. Sit-4-yl 1 propoxy} benzopyrene bl 4 -7-7- 〉 Two-stage preparation of a white solid having a melting point of 9〇_93 was prepared in a similar manner to Example 55, but starting the reaction sequence with 4-isopropylbenzaldehyde instead of 4-methoxybenzaldehyde. ISN-MS : 506.2 (MH ) + 〇. Example 58 1_ Racemic Bu 3-(4-{3-[2-(1 diisopropyl 氲 苇 苇 小 小 小 小 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ "bp stopper-7-"-2-A, its propionic acid-104 This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 ____B7 V. Invention description (101) A white crystal having a melting point of 丨〇3·丨〇5 was prepared in a manner similar to Example 57 except that ethyl ethoxyacetate was used in place of ethoxyethyl acetate as a coupling partner for the aldol reaction. ISN-MS : 492.2 (Μ-Η)+ 〇Example 59 『External 4-spinning hKi-{3-丄g-丄Benzene A A certain g-azole oxime ^oxy}phenylhydrazine bl 4 -7-7 base: Diethyl propyl hydrazine was prepared in a manner similar to that of Example 57. ???~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The propyl benzene chain begins the reaction sequence. ISN-MS: 498.0 (MH)+. Example 60 A ke singling ·4_ &amp; yl} + and fblp 篆 -7-7-yl)-2-oxy and two A white carcass was prepared in a manner similar to that of Example 59, but was replaced by methoxyacetic acid in the form of an acetoxyacetate as an oxime partner for the aldol reaction. ° ISN- MS: 484.1 (MH)+ « Example 6 1 1 racemic -2- ethoxy oxime and oxazol-4-yl 1 propyl group} 茬 -1- was prepared in a similar manner to Example 42丨 4 142. Gray crystal, but with ethoxyacetate instead of methoxyacetic acid acetate for the aldol reaction. θ ISN-MS : 488.2 (MH) + = 105 - the paper scale Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1328585

102 Example 62 ^Exo β oxy·3 2^^_ί2_ί4·昱咼 苽 苽 甲基 甲基 以 以 以 苽 苽 苽 苽 苽 以 以 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于The base of benzaldehyde starts the reaction sequence. ISN-MS: 500.3 (M-H)+. Example 63 ^External ^ 旋 ^ 某 、, -5 - A g gazole -4- a 1 propyl hydrazine}. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The manner of preparation became the melting point μ, 149. It is grayish white, but the reaction sequence begins with 4-methoxybenzaldehyde instead of 4-methoxybenzaldehyde. ISN-MS: 492.1 (M-H) + 〇 Example 64 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The white crystal was replaced by 4-isopropylbenzaldehyde instead of 3,5-dimethylbenzaldehyde. ISN-MS : 492.1 (MH)+ 〇Example 65 LS)-2-丁二3-"咏_礼基-3-(土异一一茇一ι &lt;^_^ oxazol-4-yl 1 B The oxy-! benzo is prepared in a manner similar to the example 3丨 as the melting point 丨24·丨26. White crystal-106 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 public) 1328585 A7 - -- B7 V. Inventions ( &quot;) &quot; '~ V 103 &gt; body, but in the aldol aldol unit coupling step with (S)-4-mercapto-3-but-enyloxyacetamidine Substituting oxazolidine-2-one for (S)-4-benzyl-3-methoxy-3-indenyl-2-oxazolone. ISN-MS: 518.1 (Μ-Η)+. The necessary block (s) _ 4_ thiol · 3 _ _ 3 alkenyloxy acetyl oxazolidin-2-one: § 1 T · 3 dipolar oxygen vinegar age will be 72 丨 克 3-丁ι·ι_alcohol (1〇mmol-荖耳) was added to 480 mg of NaH (in 50% mineral oil, ~2 〇 millimolar) in 丨〇ml absolute THF, and the mixture was stirred. 5 minutes (release H2) ^ then add 1.39 grams of bromoacetic acid (1 mM millimolar) dissolved in THF, and maintain the mixture at 0 ° for 5 minutes The mixture was shaken on crushed ice/diluted HC® at room temperature for 2 hours, extracted twice with AcOHt, washed with brine, dried over sodium sulfate and evaporated solvent to afford 1.65 g of title compound, which was obtained from mineral oil. Contamination, but sufficient purity for the following steps. Butyl-3-enoxyacetamidine g-oxazolidine-2-one will be 1·6 g or more of D-3·-enoxyacetic acid (9 9 mmol) Ear) Treated with 3 35 liters - 5,03 grams of grass cockroach (4 equivalents) and 1 drop of absolute dmF. Immediately begin to vent the gas and maintain the reaction mixture for 3 hours. Carefully evaporate excess reagent and dry to produce hydrazine. 3 5 g of hydrazine base gas, using the product without further purification in the following procedure _ 1.77 g (S)-4 - benzyl-2-p eat; 13⁄4 min mil) dissolved in 30 ml absolute THF And cooled to -78°. 6.67 ml of 1. 5 g of molecular weight nBuLi (hexane) (strong exotherm) was added via a syringe to deprotonate NH. In ____-107 -_______ The original Zhang Jianqi towel National Painter Standard (CNS) A4 specification (210X 297 mm) ' ' 1328585 A7 B7 V. Invention description (104 1 〇 minutes, after adding dissolved in 丨〇 The above prepared crude base gas in THF was continuously stirred at -78 ° C for 3 minutes and stirred at 〇, c for 3 minutes. Pour on crushed ice / Nha, extract with eight (1) twice It was washed with water, dried over sulphur sulphate and evaporated, and then purified by flash chromatography (SiO2, hexane / AcOEt = 7/3) to afford to afford the title compound as a colorless viscous oil. -MS : 290.3 (M+H) +, 307.4 (M+NH) + NMR · (CDClj, 1H, δ, TMS) 2.46 (m, 2H), 2.81 (dxd, J=9.5) J-13.3, 1H ) ' 3·34 (dxd, J=3, j=13 5, 1H), 3 66 (t, J=7, .2H), 4.20-4.34 (m, 2H), 4.62-4.76 (m, 3H) , 5.09 (d, J=l〇.5, 1H), 5.15 (d, J-17, 1H), 5.86 (m, ih), 7.20-7.39 (m, 5H) 〇Example 66 L·racemic Bu 丙 苽 苽 卜 5 _ _ 5 5 5 5 5 - 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚[ The small secret of the cymbal is used for =. The second reaction 'in the more coupling step of the butanol, the ethyl ethoxyacetate is used instead of the ethoxyacetic acid. 1SN-MS: 5Q0.2 (M-H)+. Example 67 [External &gt; 旋旋性1-2-乙fi芊Μ Ά η,,田^计^ Τ~~ΓΤΤ -1~~~ pedestal A)-5-A very/similar to the way of Example 66 Preparation of a compound that becomes a white foam, but the use of ethoxyacetate in the butyl aldehyde coupling step in place of the propoxy group is suitable for the Chinese scale - 1328585

Ethyl acetate. 1SN-MS: 486.3 (M-H)+. Example 68 ί Racemic 1 - 3 - (4 - ί - - f 9 - r 7 c ~~~~1~ Oxygen 苽 U U 5- 5- 5- 5- 5- 5- 5- 5- 5- - - - - - - - - - Bl 窠 窠 -7-7 tf, . ^ ~ 2-isopropyl gas a propionic acid in a manner similar to the example of 3 Α Α p. , I became the melting point of 148 _ 15 〇. The white crystal, but in Ding The meta-aldehyde enters the bovine BS·A u 咚 if the σ step uses ethyl isopropoxyacetate instead of butyl butoxyacetate. As above, w-iD ^ττ ν 珧 is ^r〇H, NaH and bromo Acetic acid, followed by acid catalyzed esterification with EtOH, μ &quot;# u ϋ 用 用 成 成 3 3 3 3 ( ( ( ( ( ( ( ( ( ( ( ( I I I I I I I I I I I 4.1 4.1 4.1 4.1 4.1 4.1 4.1 4.1 4.1 (MH)+ = Example 69 (_g&gt;3-(4-{2-f2-(3,5-dimethoxymethyl 噚 -4-4•芊1 聚oxy} winter 丨 丨 b~|pg phen -7-yl)-2-iso-gas _ a compound which became a white solid was prepared in a similar manner to Example 33, but 3,5-dimethylbenzaldehyde was replaced by 3,5-dimethoxybenzaldehyde. Start the entire reaction sequence and use the Μ)·4•benzylisopropoxyethyl 4 wowane-2-indole instead of the (S)-4-section in the interbutol coupling step. _3-methoxyethyl hydrazine gas 1 pit-2 ketone. The melting point was not determined because the product was contaminated with a slight contamination of the palm adjuvant. ISN-MS: 524.1 (MH)+.-Example 70 『racemic Sex 1 - 3 - (4 -丨3 -丨_2 - (4-isopropylphenyl)_ s _甲芊$岭_ 4 Propylene base 丨 并 and "bl嵝 -7-7"-2 - Propylene is given

__- 109 - This paper size applies to China National Standard (CNS) A4 specification (210 X 297 public) 1328585 A7 B7 V. Description of invention (1〇6) Prepared as a melting point 72-73 in a manner similar to Example 58 . The white crystals were used, but in the step of the dibutyl alcohol (tetra), ethyl acetoxyacetate was used instead of methoxyethyl acetate. 1SN-MS : 520_2 (M-H)+. Example 7 1

LiLjl^#l·3パ4_{2q2-U^1^^ Oxygen 芡 u u u5-A certain carbazole-棊1 ethyl lactyl} 碁-1-碁)·2· ethoxylate is similar to The preparation of Example 54 - the coupon was a melting point of 1 64 丨 65. The white crystal, but 4-hydroxycha-1-carboxylate was substituted for the 4·1 benzyl[b]p-septene-7-carboxyl chain for the Mitsunobu reaction. 1SN-MS: 504.2 (M-H)+. Example 72 L-exhibition 1 - 3_- (4- { 2_ [2-丄^^曱气茇茇甲甲喵崦喵崦-ii1一乙孔基}Naphthalene-1-yl)_2: Propoxyl Propionate was prepared as the melting point 丨4〇_ 14丨 in the same manner as in Example 71. It was white crystal, but ethyl propoxyacetate was used instead of ethyl ethoxyacetate in the aldol coupling step. 1SN-MS: 518.1 (M-H)+. Example 73 丄 丄 丄 丄 υ υ υ 甲 甲 甲 甲 甲 甲 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The white crystal, but 4-hydroxyindole-1 -carboxaldehyde was substituted for 4-hydroxyl bromide [b] b-cetin-7 carboxylic acid for the Mitsunobu reaction. ____ 110 - This paper size applies to the 圉@家标竿(CMS) A4 specification (210X297 公1328585 A7 ______B7 V. Invention description (107) ISN-MS : 518.1 (MH)+. Example 74 [External ^ 旋性卜 2 - propyl-oxo-3·(4]2-丨2-f4-isopropyl oxime)-5-methylcarbazole-4-oxime was prepared in a similar manner to Example 73 as a white foam compound. However, the entire reaction sequence was started by substituting 4-isopropylphenyl aldehyde for 3,5-dimethoxybenzaldehyde. ISN-MS: 500.2 (MH) + 〇-- Example 75 - 3.50 g in 190 ml of THF a solution of cresol, 9 87 g of 2-(5-methyl-2-phenyl-oxazol-4-yl)ethanol and 12 73 g of triphenylphosphine under the reaction of 8 · 4 5 g in 75 ml of THF Diethyl azodicarboxylate (DEAD) was treated for 20 minutes and the brown solution was stirred at 22 Torr for 24 hours. The solution was evaporated and the residue was partitioned between CH2C12 (3 mL) and EtOAc. Between NaOH (100 ml). The organic layer was washed twice with water (2 χ 〇〇 mL), dried and evaporated, and the residue was chromatographed on silica gel (20:1 n-hexane / Ac0Et ) to get 7 43 g (78%) of the title compound: MS: (Μ+Η)+ 294.3. NMR (CDC13, lH, TMS): 7.97 (m, 2H), 7.45-7.35 (m, 3H). 7.14 (t, J=7.6, 1H), 6.77- 6.67 (m, 3H), 4.23 (t, 3=6 8 2H). 2·97 (t, J=6.8, 2H), 2.38 (s, 3H) , 2.21 (s, 3H). »212 2. 5.-4-(2-(5-methyl-2-phenyl-° azole-4-some, -,. sound | 1_stupple chain _ ____- 111 - This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1328585 A7 _________B7_____ V. Description of invention (1〇8) 6.00g 5-methyl-2- to be in 30ml CH2C12 A solution of phenyl-4-(2-m-tolyloxyethyl)carbazole and 4.70 g of dichloromethyl methyl ether was treated at 11.2 ml of TiCl4 for 15 minutes at 0 ° C. Stir for 2.5 hours. Treat the red solution with 6 mL of water in HCl. The organic layer was washed with 0.1 N aqueous NaOH and washed twice with brine. The organic layer was dried to evaporate solvent and residue The material was chromatographed on silica gel (7:1 hexanes/EtOAc) to afford 3.42 g (52%) of the title compound as a pale yellow solid. -- MS : (M)+ 321,2 » IR (liquid stone ants): 1691s and 1679s (C=0) NMR (CDC13, 1H, δ, TMS) : 10.10 (s, 1H), 7.96 (m, 2H ), 7.73 (d, J=8.6, 1H), 7.45-7.36 (m, -3H), 6.84 (dxd, J=8.6, 2.8, 1H), 6.73 (d, J=2.8, 1H), 4.32 (t , J=6.8, 2H), 3.00 (t, J=6.8, 2H), 2.62 (s, 3H), 2.38 (s, 3H). Cl 2g diethoxy- 3-{2-甲某-4- "2-(5-methyl-2-pyranazole-4-yl)-ethoxy-1-phenylindole-propanol L cool will be 1.50 grams of 2-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde in 30 ml of i-PrOH, 3 〇〇 克 wittig salt [gasification (ethyl lactyl ethyl) diphenyl scales, Tetrahedron 50 (25), 7543-56 (1994)] and 0.97 grams of potassium carbonate suspension at 22. (: Stir for 6 days. Add another 1.50 grams of Wittig salt and 48 kg of potassium carbonate, and continue mixing overnight at 60. Add another 1.50 grams of Wittig salt and 0.48 grams of potassium carbonate at 60 °. Stirring was continued overnight at C, after which time the conversion was completed. The mixture was evaporated and the residue was dissolved in 4 mL of CH2Cl2 - 112 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Inventive Note (109) Between 40 ml of saturated aqueous nh4C 。. The organic layer was washed with 40 ml of water, dried and evaporated. The residue was chromatographed on s. Hexane/AcOEt) to give a pale yellow solid 1 53 g (75%) of the title compound MS: (M) + 435.2 〇1R (liquid paraffin): 1715 s (c = 0) NMR (CDC13, 1H, δ, TMS): 8.05 (d, J = 8.8, (1), 7.97 (m, 2H) (q, J=6.8, 2H), 4.27 (t, J=6.8, 2H), 3.89 (q, J=6.8„ 2H), 2.98 (t, J=6.8, 2H), 2.3 8 (s, 3H) , 2.35 (s, 3H), 1.35 (t, J=6.8, 3H), 1.28 (t, J=6.8 3H). 'iLJZ-Ethoxy Screen: 3- {2-A - 4-f A茱-啐 sleeve_4 diyl)-ethyl lactyl I-benzin-propionic acid 〇·丨丨6 g LiOHxH20 was added to 〇·40 in 10 ml of THF, 5 ml of MeOH and 5 ml of water at 22 t.克 2Z_ethoxy _3 {2•methyl·[2-(5-methyl-2-phenyl-carbazole_4_yl)-ethoxyphenyl)}-propionic acid In the cold liquid, continue to stir for 2 days. The yellow solution was evaporated, the residue was dissolved in water (20 ml), and the pH was adjusted to 3 using about 26 ml of 1N aqueous HC. The suspension was filtered, and the residue was washed with water and dried to afford white crystals. MS: (M+H) + 408.3. 1R (liquid paraffin): 3100-2500m, br. (COOH), 1 705s (C=0). 'R (CDC13, 1H, (5, TMS): 1〇·5 (s, very wide, 1H), 8 〇 3 (d, -113 - This paper scale applies to the g national standard (CNS) A visual ( 21GX297 mm) 1328585 A7 B7 V. INSTRUCTIONS (110) J=8.8. 1H), 7.98 (m, 2H), 7.47- 7.37 (m, 3H), 7.31 (s, 1H), 6.77 (dxd. J= 8.8, 2.8, 1H), 6.73 (d, J=2.8, 1H), 4.27 (t, J = 6.8, 2H), 3.91 (q, )=1.2, 2H), 2.99 (t, J=6.8, 2H) , 2.38 (s, 3H), 2.35 (s, 3H), 1.30 (t, J=7.2, 3H) « Example 76 Γ Racemic Bud 2-Ethyl Hydrogen-3- {2-Methyl-4- [2-(5-曱--2-Butyl-oxazol-4-yl)-Ethylene-l-yl}-propanthene will be 100 mM 2 ethoxy-3- in 2 ml of MeOH {2-Methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl-propionic acid and 26 mg Pd/C (10% The suspension was argonized at 22 ° C / 1 bar for 2 days. The suspension was filtered, and the filtrate was evaporated and evaporated to crystals crystals - MS : (M+H)+ 410.4 〇1R (MIR) : 3100-2400m, br. (COOH), 1 725m (C=0) NMR (CDC13, 1H, &lt;5, TMS) : 10.5 (s , very wide, 1H), 7.96 (m, 2H), 7.45- 7.35 (m, 3H), 7.09 (d, J=8.4, 1H), 6.68 (s, br·, 1H), 6.66 (d, br. J=8.4, 1H), 4.19 (t, J=6.8, 2H), 3.96 (m, 1H), 3.50 (m, 1H), 3.27 (m, 1H), 3.07 (m, 1H), 2.95 (t, J = 6.8, 2H), .2.87 (m, 1H), 2.36 (s, 3H), 2.30 (s, 3H), 1.08 (t, J = 7.2, 3H). Example 77, 78 - al [racemate 1-2-ethane-yl-3-(2-methyl-4-|~2-(5-methyl-2-phenyl-[[iota]-4]- Base) - Ethyl bromide - ethyl propionate will be 400 mg - -114 &quot; in 8 ml of MeOH, 2 ml of THF and 0.5 ml of AcOH - This paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210X297 mm)

Binding

Line 1328085 A7 B7 111 V. Description of the invention (22-ethoxy-3-{2-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy A suspension of ethyl streptoacetate and 98 mg of Pd/C (10%) was hydrogenated overnight at 22 ° C / 。 bar. The suspension was filtered, and the filtrate was evaporated and dried to give Become a colorless oil of 38 mg (95%) of the title compound. MH)· and KR)-E.glycosis-3-{2-methyl-4-f2-(5-甲某-2-苽篡-^吐-4 - 乙h乙乙一1 ·苽一丨_ethyl propionate on the preparative column ((: 1^31 mouth 3^8, 98:2 n-hexane / £1〇11) dissociation [ Racemic]-2-ethoxy-3-{2-dimethyl-4-[2-(5-methyl-2-phenyl-&quot; 峻-4-yl)-ethoxy • Phenyl propyl propionate to prepare two of the title compounds 'dissolved 2(S)-enantiomers. ?(3)- and 2(ugly)-ethane--3_^2_A a -4_『2彳&lt;;-methyl_2_苽__;&gt; azole-4 -棊)--ethoxy bromide-propionium _ as described in Example 75d] hydrolysis of the ester The effect is to obtain two title compounds with e_e_&gt;99% (chiralpakAD, 97:3 of the genus / EtOΗ). Spectroscopic data and The data for the racemic compounds described in Example 76 were identical. The 2(s)-acid was analyzed by X-ray to establish an absolute configuration. Crystals were grown from CHCIV n-hexane at 22 ° C. Example 79 g_L; U2-(2,3-Dimethylphenoxyhydrazide)methan-2-bromo-arsenic arsenic The title compound was prepared in a similar manner to Example 75a], but using 2 3 dimethyl phthalocyanine instead of m-methylhydrazine, To give a pale yellow solid (6 72 g, 67%). MS: (M, 307.3. NMR (CDC.3, 1H, TMS): 7.97 (m &gt; 2H), 7.45 - 7.35 (m, , 115 - The paper size is applicable to the China National Standard (CNS) A4 specification (210X297 public if 1328585 A7 B7 5. Invention description (112) 3H), 7.02 (t, i=7.6, IH), 6.77-6.70 (m, 2H), 4.23 (t, J=6.8, 2H), 2.99 (t, J = 6.8, 2H), 2.38 (s, 3H), 2.25 (s, 3H), 2.11 (s, 3H). bl 2,3-dimercapto · 4__丨2-(5-methyl--···苽-»-oxazol-4-yl)-acetamyl 1- aldehyde The title compound was prepared in a similar manner to Example 75b], but using 4· [ 2-(2,3-Dimethylphenoxy)ethyl]·5·methyl-2-phenyl·carbazole as a starting material to give a pale yellow solid (4 · 12 ng, 7%, 7 1 %) . MS: (M) + 335.1. IR (liquid paraffin): 1689s (C=〇). NMR (CDCI3, (5, TMS): 10.13 (s, 1H), 7.98 (m, 2H), 7.64 (d, J=8.4, 1H), 7.46-7.36 (m, 1H), 6.85 (d, J= 8.4, 1H), 4.33 (t, J-6.4, 2H), 3.〇3 (t, J=6.4, 2H), 2.58 (s, 3H), 2.39 (s, 3H), 2.16 (s, 3H) 〇cl -"_2,3-dimethylazole_4, Ethyl]-phenylindole-2Z-ethoxyl Acrylic acid c Cooling Prepare the titled dimethyl o--(in a similar manner to Example 75c) 5-Methyl-2-phenyl. Ten "_yl" - Ethylene as the starting material to give a white solid (50 mg, 54%). MS ·· (M+H)+ 450.4 〇1R (liquid paraffin) ): 1709s (C=0) NMR (CDCh, 1H, 6, TMS): 7.97 (m, 2H), 7.81 (d, J=8.8, 1H), 7.45- 7.35 7.24(s, lH) 5 6.76 ( d, J=8.8, 1H), 4-29 (q, J=7.2, 2H), 4.27 (t, J=6 2H)j 3 g4 j=6 -116 - 1328585 A7 B7 113 V. Description of invention (2H ), 3.00 (t, J-6.4, 2H), 2.38 (s, 3H), 2 26 (s, 3H), 2 15 (s, 3H). L36(t, &gt;7.2, 3H), 12Mu=6.8 , 2H). &quot;-1...Dim 2, 笨 某 哼吔 · · · · · · · · 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备The title compound but uses 3· {—2.3- — Base 4-[2-(5-methyl-2-phenyl-2-carbazole-4-yl)-ethoxy]- phenyl 2Z-ethoxypropionate as raw material to obtain white Solid (0-32 g, 86%) -, MS: (M+H-)+ 422.3 » ' 1R (liquid paraffin wax 31 〇 0-2500 m, br_ (C〇〇H), 1698s (c=〇). NMR (CDC13, 1H, δ, TMS) : U_1〇(s, very wide, 1H), 7 98 (m. 2H), 7.80 (d, J=8.8, 1H), 7.46-.7.36 (m, 4H), 6.77 (d, J=8.8, 1H), 4.28 (t, J=6.4, 2H), 3.85 (q, 1=7.2, 2H), 3.02 (t, J-6.4, 2H), 2.39 (s, 3H) , 2.27 (s, 3H), 2.15 (s, 3H), 1.26 (t, J=7.2, 3H). Example 80: yl)-ethyllacyl 1-phenylidene-2-ethoxyl.propionic acid The title compound was prepared in a similar manner to that of Example 76, but using 3_{2,3-didecyl-4-[2 -(5-Methyl-2-phenyl-oxazole·4-yl)·ethoxy]- aryl}-2Z-ethoxypropionic acid was used as a starting material to give a white solid (92 mg, 91%). MS : (Μ+Η)+ 424·4 » IR (liquid paraffin): 3 100-2500m, br. (COOH), 1724s (0〇)》 -117 - This paper scale applies to China National Standard (CNS) A4 Specification (210X 297 public) 1328585 114 Description of the invention (NMR (CDCI3, 1H, &lt;5, IMS): (1_ 10 (s, very wide, 1H), 7.97 (m, 2H), 7.46- 7.36 (m, 3H),6 9r _ J=8.4. 1H),4· 19 (t,J=6,4, 2H, (d, J 8'4> 1H), 6.66 (d, 3.29 (m, 1H), 3.15 (dxd, J=l4 4 97 (m, 1H), 3.49 (m, 1H), 2.91 (dxd, J= 14.4, 8.8, 1H), 2 3 5 1H), 2,98 (t, J=6.4, 2H), (s, 3H), 1.09 (" J=6.8, 3H). 7 (S' 3H), 2.23 (S, 3H), 2·13 r Example 8 1 al 4] 2-(3,.5 - 2_1 base pen is made in a manner similar to that of example 75a], 7/~~ slit. Work-sitting, I prepare the title compound, 彳曰 is to make dimethylphenol instead of m-cresol, use ρ, 彳3,5· 乂钤 to pale yellow oil (g, 59%). Second brother MS : (M+H)+ 308.2 NMR (CDCb, 1H, 5, TMS) : 7 ^ J 7-97 (m, 2H ), 7.43- 7.33 (m, 3H), 6.59 (s, br., 1H), 6.53 (s br .〇Λ , br.s 2H), 4.20 (tj=6 4 2U) 2.96 (t, J=6.4 ,2H), 2.38 (s,3H)52.26 (Ss6H) ; ' )' bl 2,6-Dimethyl-4-f2-(5-formamidine-g.diyl)·ethylhydrogen]· aldehyde The title compound was prepared in a similar manner to Example 75b]. [2-(3,:)-Dimethylphenoxy)ethyl b.methyl-2-phenyl-carbazole as a starting material to give a light yellow solid: a positive isomer of 1 Mixture (83 mg, 78%). The title compound (jjjjjjjjjjjjjjjjjjjj 335.2. ___ - 118 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1328585 A7 B7 V. Description of invention (115) IR (liquid paraffin): 1672. NMR (CDC13, 1H, 6, TMS): 10.46 (s, 1H), 1.9 Ί (m, 2H), 7.46- 7.36 (m, 3H), 6.59 (s, 2H), 4.30 (t, J=6.4, 2H), 2.99 (t, J=6.4, 2H), 2.58 (s, 6H), 2.38 (s, 3H). c| 3 - ! 2,6-dimethyl-4-l~2-(5-methyl-2-pyrene-4-a)-pybylhydrazine-2Z-ethane Cooling a suspension of 2.88 grams of Wittig salt [ethoxy(ethoxyethoxycarbonylmethyl)triphenyl scale, Tetrahedron 50 (25), 7543--6 (1994) and 15 ml of THF to -78 °C Treated with 6.7 ml of LiN (TMS) 2 (1 gram molecular weight in THF), the yellow solution was warmed to 221 over 1 hour and cooled to -78 °C. The solution was 1.40 grams of 2,6-dimethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy-]benzaldehyde in 15 ml of THF. The solution was treated and stirring was continued for 7 days at 70 °. The mixture was treated with 1.44 g of Wittig salt and 3.35 ml of LiN (TMS) 2 (1 g molecular weight in THF) at 70. Stirring was continued for 6 days. The reaction mixture was evaporated and the residue was partitioned between CH/H and sat. The organic layer was washed with water, dried and evaporated. The residue was chromatographed on silica gel (8:1 hexanes / EtOAc) to afford y. MS: (M) + 449.2. IR (pure): 1721 s (C = 0). _ NMR (CDCI3, !Η, δ, TMS): 1.91 (m, 2H), 7.46-7.36 (m 3H), 7.03 (s, 1H), 6.60 (s, 2H), 4.30 (q, J=7.2, 2H), 4.23 (t J=6.4, 2H), 3.56 (q, J=7.2, 2H), 2.97 (t, 5=6.4, 2H), 2.37 (s, ____- 119 - This paper scale applies to Chinese national standards (CNS) A4 size (210 x 297 mm) 1328585 A7 B7 V. Description of invention (116) 3H), 2.22 (s, 6H), 1.35 (t, 7.2, 3H), 1.05 (t, J = 7.2, 3H ). Dl..3- { 2,6-di-T-group-U2-〇甲_^2-笨某-咩^-yl 1 -epi}-2Ζ-ethane-based di-acid is similar to Example 75d] The title compound was prepared in the same manner, but using 3·{ 2,6-dimethyl-4-[2-(5-methyl-2-phenyl· oxazolyl-4-yloxy)-phenyl} - 2Ζ-ethoxypropionate as a starting material to give a white solid (1 5 5 mg, 41%) MS: (Μ+Η)+ 422.3. - -%» · 1R (liquid stone soil) ): 3100-2500m, br. (COOH), 1716s (C=0). NMR (CDCI3.1H. δ, TMS): 9.50 (s, br., 1H), 7.98 (m, 2H), 7.46- 7.36 (m, 3H), 7.15 (s, 1H), 6.61 (s, 2H), 4.23 〇, J=6.4, 2H), 3.54 (q, J=7.2, 2H), 2.98 (t, J=6.4, 2H ), 2.38 (s, 3H), 2.21 (s, 6H), 1.10 (t, J = 7.2, 3H) 〇 Example 82 al [racemic]-3-{ 2,6-dimethyl-4- Γ2-(A-2-pyryl^4-yl)-ethyllacyl-1-epi--2-ethylene-based acesulfame-methyl 13⁄4 gram and 17 mg hydrazine were added to 1.5 ml of methanol. 3 { 2,6-monomethyl- 4-[2-(5-methyl-2-phenyl-σ- oxime)-ethoxy]-phenyl}- 2Ζ-ethoxy acrylate In the solution, and continue to stir for 3 hours. Another 67 mg of magnesium was continuously stirred for 1.5 hours. The suspension was filtered, the filtrate was evaporated and the residue was purified on preparative HPLC (RP-1, CH3CN/H.sub.2 gradient). 2 mg (7%) of the title compound as a white solid. NMR (CDC13, 1H, TMS): 7.98 (m, 2H), 7.45-7.35 (m __- 120 - This paper scale applies to the Chinese National Standard (CNS) A4 Specifications (21〇x 297 mm)

1328585 V. INSTRUCTIONS (3H), 6.57 (S) 2H), 4.20 (t, J=6 4 1H) 3 72 ( ar ' 2H), 3.92 (dxd, 8.8, 4.8, 1H), 3.72 (s, 3H), 3.52 (τη, (m, 4H), 2.38 (s, 3H), 2.31 (s 6m . m> lH), 3.05-2.93 'H), 1.09 (t, 7 9 fly)4, similar to Example 7 The title compound was prepared in the same manner as the title compound. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Phenyl}-2-ethoxy-propanium &amp; white solid (1. 4 g, 72%). ~ Acidic as a starting material to give MS: (M+H) + 424.3 » NMR (CDCl3, 1H,5,TMS): 7.97 (m, 2H), 7 46_7 36 (m, 3H), 6·59 (s, 2H), 4.21 (t, J=6 4, 2H), 3 % (m, ih) ),3 45 (m,1H)' 3.18(m' 1H)' 3.10 (m,1H),3 〇5 2 94 (m,4H) 2.38 (s,3H),2.33 (s,6H),1.05 ( t, J=7 2, 3H). 'Example 83, 84 aj 4-丨2-(benzofuran 4-oxy)ϋ [ _ %甲甲-2-苽A certain arsenic is similar to Example 75a] The title compound was prepared in the manner but using 4 hydroxy cumene furan [Synthetic Communications (1986), 16 (13) 1635-1640; Helvetica Chimica Acta (1993) 16,121-129] Instead of m-cresol to give a white solid (2.41 g, 76%) MS: (M) + 319.1 - NMR (CDC13, 1H, δ, TMS): 7.97 (m, 2H ), 7.52 (d, J=2.4, 1H), 7.46-7.36 (m, 3H), 7.19 (t, J=8.0, 1H), 7.12 (d, J=8.0, 1H), 6.83 (d, J= 2.4, 1H), 6.68 (d, J=8.0, 1H), 4.39 (t, ____- 121 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 public)

Binding

1328585 A7 B7

J = 6.4, 2H), 3.06 (t, J = 6.4, 2H), 2.40 (s, 3H) kL._4 bis Ll-H 甲 琴 琴 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Compound, but using 4 [2-(benzofuran-4-oxy)ethyl]-5-methyl-2-phenyl-oxazole as a white solid (yield: 82 g, 3 3%). ..... MS : (M+H)+ 348.4. IR (MIR): 1680s (C=0). -- NMRCCDC.3. 1H, 5, TMS): Γ〇.21 (s, 1H), 7.98 (m 2H) 7.74 (d, J^8.4, lH), 7.67 (d, J=2.〇5 1 H), 7.46- 7.3 8 (m, 3H) 6.89 (d, &gt; 2.0, 1H), 6.81 (d, 4, ih), 4 49 〇, j=6 4, 2H), 3.09 (t, J= 6.4, 2H), 2.41 (s, 3Fl). c,l. „2,Z-^2E- 6 A certain -2-芡某-碟砵 j 芊,· s milk base.1 - + and pfu -7-7 - 丨 丨 · 丙 g g# ,. spray The title compound was prepared in the manner of (4) m5e], but using the [2-(5-methyl-2-*-yl-s-s--4-yl-ethoxy)-benzopyran- 7 aldehyde as the aldehyde The starting material was obtained as a 2Z isomer (yield: 64 g, 65 〇 / 〇) as a white solid to obtain an isomer (79 mg, 8%) as a colorless oil in the second fraction. Number of substances _ : MS : ( M+H). 462.3. IR (liquid paraffin): 1713s and 1704s (C=〇). NMR (CDCI3, IH, (5, TMS): 8.14 (d, J=8.4, IH), 7.98 (m, 2H), 7o6 (d, J=2, 1H), 7.52 (s, 1H), 7.46- 7.36 (m, 3H), the paper size applies to the Chinese National Standard (CMS) A4 specification (2l〇x 29^mm)----- Set the line Λ 1328585 A7 B7

6.84 (d, J=2, 1H), 6,2 (d, J=8.4&gt;1H)&gt;4 43 (tj=64 4-3. (q. J=7.2. 2H), 4.03 (q, j=7 2( 2H), 3.06 〇;=6 5 ::;;2·40- 139 (t&gt; — 3H), , 3S (t; J=7; 2; 2E-isomer teaching: MS: (M+H)+ 462.3. IR (p.): 1732s, br. (c = 0). NMR (CDC, 3, 1H, ,, TMS): ^7.99 (m, 2H)j 7&gt;49 (d J==2 1H), 7,6-7.36 (m, 3H), 7.07 (d, J=8&gt;1H)&gt;6.82(;.j=; ΐΗ),6·63(υ—-8,iH ), 6.22(slH) 4 37 (tj=“ , 4.05 (...2' 2H), 4.00 (....2, 2H) ·;, ;:;···40 (S' 3H)*,43 ^ — 3H ), 〇,6;t;J=:;;; ethoxy... 4 milyl 1-benz and pentyl-7-ylindole-propene; the title compound was prepared in a similar manner to Example 75d.仏 and 2E-ethoxy- 3-{4-[2-(5-methyl_2-phenylidazolyl)-ethoxy]-benzopyran-7-yl}•propionic acid f is used as a raw material to obtain 2 isomers (0.53 g, 94%) of the color solid and 2E_isomer (40 g, 67%) which becomes a white solid. Number of 2Z-isomers : . MS : ( Μ- H)· 432.4. IR (liquid paraffin): 3 100-2500w, br. (C O〇H), 1709s (C=0). NMR (CDC13, 1H, (5, TMS): 10.5 (s, very wide, 1H), 8.15 (d, _____- 123 - This paper scale applies to Chinese national standards (CNS) A4 size (210X 297 mm)

Binding

1328585 A7 B7 V. INSTRUCTIONS (120 J = 8.8, IH), 7.99 (m, 2H), 7.68 (s, 1H), 7.55 (d, J = 2, 1H), 7.46-7.36 (m, 3H), 6.83 (d, J=2,1H), 6.74 (d, J=8,8, 1H), 4.45 (t, J=6.4, 2H), 4.05 (q, J=7.2, 2H), 3.09 (t, J = 6.4, 2H), 2.41 (s, 3H), 1.38 (t, J = 7.2, 3H). 2 E · Number of isomers: MS : (M-H). 432.4. IR (MIR): 3 100-2500w, br. (COOH), 1712m, br. (C=0). NMR (CDC13, 1H, &lt;5, TMS): 0-1 (s, very broad, 1H), 7.95 (m, 2H), 7.48 (d, J=2, 1H), 7.45-7.35 (m, 3H) ), 7.32 (d, J=8.4, 1H), 6.78 (d, J = 2, 1H), 6.58 (d, J=8.4, 1H), 6.38 (s, 1H), 4.28 (t. J=6.4, 2H), 4.04 (q, J=7.2, 2H), 3.02 (t, J=6.4, 2H), 2.39 (s, 3H), 1.45 (t, J=7.2, 3H) « . Example 85 f racemic卜 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- - propionic acid will be 50 mg of 2Z-ethoxy-3-{4-[2-(5-methyl-2-indolyl)-4-ethoxy) in 1 ml of MeOH and 1 ml of CH2C12 A suspension of benzo[p-p-pyran--7-ylbu-acrylic acid and 12 mg of Pd/C (丨0%) was hydrogenated at 22 ° C / 1 bar over 1 hour. The suspension was filtered, EtOAc EtOAc m. MS: (M-H)· 434.4. 1R (MIR) : 3100-2500w, br. (COOH), 1724s, br. (C=0) 〇NMR (CDC13, 1H,(5, TMS) : 9.5 (s, very wide, 1H), 7.98 (m _____- 124 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm)

% order

1328585 A7 r-----5!__ _ V. Description of invention (121) 2H), 7.53 (d, J=2.4, 1H), 7.46-7.36 (m, 3H), 7.06 (d, J=8 , ^), 6.82 (d, J=2.4, 1H), 6.61 (d, J=8, 1H), 4.35 (t, J=6.4, 2H). 4.26 (m, IH), 3.57-3.41 (m, 3H), 3.19 (m, 1H), 3.〇6 (t, ·ί = 6·4· 2H)· 2.40 (s. 3H)· 1.08 (t. J=7.4, 3H). Example 8 6 Ethoxy-3-(4-"2-(5-methyl-2-pyrene-carbazole-4-pin, 1-2T3-two-button. Stupid and p-fu--7-some The two acids will be 100 mg of 2Z-ethoxy-3'{heart [2-(5, decyl-2-phenyl-«oxazol-4-yl) in 2 ml of MeOH and 2 ml of CH-2_C12. a suspension of -ethoxy]-benzofuran-7-yl}-acrylic acid and 25 mg of Pd/C (10%) at 22 ° C / 1 bar • blanket overnight hydrogenation ^ filter the suspension and filter The mixture was re-slued with 25 mg of fresh solvent over night. The suspension was filtered, and the filtrate was evaporated,jjjjjjjjjjjjjjjjjj Compound (56 mg, 56%) MS: ( Μ-H)· 436.4 (liquid paraffin): 3 1 00-2400w, br. (COOH), 1715s, br. (〇〇) Ο NMR (CDC13, 1Η , (5, TMS) : 9.5 (S, very wide, 1Η), 7.97 (m, 2H), 7.46- 7.35 (m, 3H), 6.90 (d, J=8.4, 1H), 6.34 (d, J= 8.4, 1H), 4.56 (d, J=8.8, 2H), 4.23 (t, J=6.4, 2H), 4.15 (m, 1H), 3.53 (m, 2H), 3.15-3.05 (m, 3H), 2.96 (t, 6.4, 2H), 2.88 (m, 1H), 2.37 (s, 3H), 1.14 (t, J=7.2, 3H) « Example 87, 88 al 4 -丨2-(furfuran-7-gas-based) B-1-5-methyl-2-carbazole _- 125 - This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1328585 A7 B7 122 V. Description of the Invention (The title compound was prepared in a similar manner to Example 75a), but was replaced with 7-hydroxybenzofuran [J. Med. Chem. (1987), 30(1), 62-7]. M-cresol to give a white solid (2.54 g, 80%) MS: (M) + 319.1 NMR (CDC13, 1H, δ, TMS): 7.97 (m, 2H), 7.61 (d, J=2.0 , 1H), 7.45-7.35 (m, 3H), 7.18 (d, J=7.8, 1H), 7.14 (d, J=7.8, 1H), 6.83 (d, J=7.8, 1H), 6.75 (d, J=2.0, 1H), 4.47 (t, J=6.4, 2H), 3.09 (t, J=6.4, 2H), ".40 (s, 3H). Preparation of the title compound by bl 7 -"2-(5-methyl-2-phenyl-[N-methyl-2-phenyl]- ethoxy-4-yl-l-benzofuran- 4-carboxaldehyde in a similar manner to Example 75b] , but using 4_[2-(benzofuran-7-oxy)ethyl]-5-methyl-2-phenyl-oxazole as a starting material. Instead of chromatographic separation by crystallization from CHzCl2/n-hexane Purification was carried out to give a white solid (1·5 7 g, 71%) » MS : (M) + 347.1 » IR (liquid paraffin): 1690s (c=0). NMR (CDCI3, 1H, account, TMS ) : 10.03 (s, IH), 7.97 (m, 2H), 7.77 (d, J=2.0, 1H), 7.65 (d, J=8, 1H), 7.52 (d, J=2, 1H), 7.47 -7.37 (m, 3H), 6.93 (d, J=8, 1H), 4.57 (t, J=6.4, 2H), 3.13 (t. J = 6.4, 2H), 2.42 (s, 3H). ' c ] 2Z- and 2E-ethylglycol-3 - { 7-丄甲一-2·benzoquinone_p-azole _4p_ ethylhydro benzofuran-4- 丨-acryl hydrazine The title compound was prepared in the manner of 75c], but using 7_[2-(5-methyl-t-phenylphenyl-tetrayl)-ethoxy]-benzene-furan-4. CNS) Α4 size (210 X 297 mm) Setting line 126 - 1328585 A7 B7 V. It is indicated that (123 is used as a raw material to obtain a 2Z isomer which is a white solid (〇93 g, 80%). In the second fraction, 2E•isomer (85 mg, 7%) which is a colorless oil is obtained. The number of gZ-isomers: MS: (M+H) + 462.3. 1R (liquid paraffin): 1715s and 1703s (C=〇). NMR (CDC13, lH, δ, TMS): 7.99 (m, 3H), 7.65 (d, J=2.0, 1H), 7.45- 7.35 (m, 3H), 7.26 (s, lH), 6.98 (d, J=2.0, 1H), 6.86 (d, J=7.2, 1H ), 4.51 (t, J=6.4, 2H), 4.32 (q, J-7.2, 2H), 3.96 (q, J=7.2, 2H), 3.10 (t, J=6.4, 2H), 2.40 (s, 3H), 1.38 (t, J=7.2, 3H), 1.33 (t, J=7.2, 3H). The number of 2E-isomers: MS: (M) + 461 _2. IR (neat): 1730s (C=0) 〇NMR (CDC13? 1H, (5, TMS): 7.97 (m, 2H), 7.60 (d, J=2.0, 1H), 7.46- 7.35 (m, 3H) , 6.97 (d, J=8, 1H), 6.76 (d, J=8, 1H), 6.70 (d, J=2.0, 1H), 6.23 (s, 1H), 4.45 (t, J=6.4, 2H ), 4.02 (q, J-7.2, 2H), 3.98 (q, J=7.2, 2H), 3.09 (t, J=6.4, 2H), 2.40 (s, 3H), 1.44 (t, J=7.2, 3H), 0.95 (t, J=7.2, 3H). _2Z- and 2E-ethyl lactyl- 3- {7-"-2-(5-methyl-2-phenyl-°°°-4- a) ethoxy 1-benzocypan-4-ylindole-acrylic acid The title compound was prepared in a similar manner to the compound of Example 75d], but using 2Z- and 2E-ethoxy-3-{7- [2-(5-Methyl-2-phenyl-»-oxazol-4-yl)-ethoxy___- 127 - This paper scale applies to Chinese national standards (CNS> A4 specification (210X297 public) 1328585 A7 B7

5. Description of the invention (124-)-benzofuran-4-yl}-ethyl acrylate as a starting material to obtain a 2Z-isomer as a white solid (0.61 g '97%) and 2e_isomeric as a white solid (48 mg, 72%). j Z - Number of isoforms: MS: (M-Η)· 432_3 (liquid paraffin): 3 100-2500W, br. (COOH), 1708s (C=0 NMR (CDC13, 1H, (5, TMS): 11 (s, very wide, ΐΗ), 7·99 (m, 3H), 7.66 (d, J=2.0, 1H), 7.47- 7.37 (m, 4H), 6.97 (d, J=2.0, 1H), 6.88 (d, J=8.8, 1H), 4.52 (t, J=6.4, 2H), 3.99- (q, J=7.2, 2H), 3.12 ( t, J=6.4, 2H), 2.42 (s, 3H), 1.24 (t, J=7.2, 3H). Number of 2E-isomers: _ MS : (MH)· 432.3. 1R (liquid paraffin) :3 100-2500w,br. (COOH), 1710s (〇0). NMR (DMSO-d6, 1H, δ, TMS) : 13.0 (s, 1H), 7.95 (d, J=2.0, 1H), 7.91 (m, 2H), 7.55-7.45 (m, 3H), 7.01 (d, J=8, 1H), 6.96 (d, J = 2.0, 1H), 6.88 (d, J=8, 1H), 6.17 ( s, 1H), 4.39 (t, J=6.4, 2H), 3.95 (q, J=7.2, 2H), 3.00 (t, J=6.4, 2H), 2_38 (s, 3H)., 1.32 (t, J = 7.2, 3H). Example 89, 90 i racemic buns 2-acetamidine -3-(-7-丨2-(5-methyl-2- benzo-carbazole-4-yl)-ethyl benzoyl 1-indeno-pyran-4-yl hydrazine-propionic acid Racemic Bu 7 - Indolyl-3-(7-"2-(5-methyl-2-pyrene-o-oxazol-4-yl)---a certain 1-7夂di-benzopyran -4-A certain propionic acid __- 128 - This paper size applies to Chinese National Standard (CMS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Description of invention (125) will be in 2 ml of MeOH and 2 ml of CH2C12 100 mg of 2Z-ethoxy-3_{7-[2-(5-methyl-2-phenyl"oxazol-4-yl)-ethoxy]-benzofuran-4-ylpropanoid A suspension of acid and 25 mg Pd/C (10%) was hydrogenated overnight at 22 °C / 1 bar. The suspension was filtered, the filtrate was evaporated, and the mixture was purified by preparative HPLC (EtOAc, EtOAc, EtOAc (EtOAc) 2-( 5-Mercapto-2-phenyl-°oxazol-4-yl)ethoxy]-2,3-dihydrobenzofuran-4-yl}-propionic acid (12.5 mg, 12%) . In the second fraction, it is included as a white solid [racemic 2-ethoxy-3-(7-[2-(5-methyl-2-phenyl-oxazol-4-yl) )-Ethoxy]-benzofuran-4-yl}-propionic acid (50 mg, 50%) » f racemic 1-2-fluorenyl-3-(7-『2-(5- Methyl-2-phenyl-oxazol-4-yl) Ethyl lactate 1-2,3 - 2 chaotic winter p-Pan-4-ylindole-propionic acid data MS: (M+H)+ 438.4 〇IR (liquid paraffin): 3100-2500w, br. (COOH), 1 736s and 1716s (C = Ο). NMR (CDCI3,1Η,5, TMS) : 10 (s, very wide, 1Η), 7· 97 (m, 2H), 7.46- 7.36 (m, 3H), 6.72 (d, J=8.4, 1H), 6.66 (d, J=8.4, 1H), 4.61 (t, J=8.8, 2H), 4.29 (t, J=6.4, 2H), 4.04 (m, 1H), 3.57 (m, 1H), 3.42 (m, 1H), 3.21 (m, 2H), 3.06-2.97 (m, 3H), 2.88 (m ,1H), 2.36 (s,3H), 1.16 (t, J=7.2, 3H) » f 卜卜-racemic 1-2-ethane -3- (7-丨2-( 5-A) -2- 芡 呤 - oxazole - 4- 棊 h ethoxy group 1 - 笨 咭 咭 甚 甚 甚 甚 甚 摅 MS : ( M + H) + 436.4 ° IR (liquid paraffin): 3 100- 2500w,br. (CO〇H),1 733s, br. (C = _____- 129 -___ This paper scale applies to China National Standard (CNS) A4 Specifications (210 x 297 mm) 1328585 A7 B7 V. Description of invention (126 0) NMR (CDC13, 1H, 5, TMS): 10 (s, very wide, 1H), 7.97 (m, 2H), 7.61 ( d, J=2.0, 1H), 7.46- 7.36 (m, 3H), 7.00 (d, J-8, 1H), 6.85 (d, J=2.0, 1H), 6.76 (d, J=8, 1H) , 4.43 (t, J=6.4, 2H), 4.11 (m, 1H), 3.52 (m, 1H), 3.40- 3.27 (m, 2H), 3.13 (m, 1H), 3.08 (t, J=6.4, 2H), 2.40 (s, 3H), ll〇(t, J=7.2, 3H) 〇' Example 91 -- g丄4-(2-(茆满-4-气某)ethyl 5_甲某- 2_茇其-喵〇 will also be 4.00 grams of 2-(5-methyl-2-phenyl-carbazole-4-yl) methanesulfonate [PCT Int. Appl. (2000) W00008002] (14.22 mil Mohr), 2.00 g of 4-indanol (14.93 mmol) and 487.6 mg of tetrabutylammonium hydrogen sulfate dissolved in 65 ml of stupid and heated to 8 〇 it then slowly added ΚΟΗ (10·66^ A solution of 2 grams of molecular weight in h20, 21.33 millimolar) was maintained at a temperature of 75-80 C. The resulting mixture was stirred for 4 hours. 35 ml of water was added, and the mixture was further stirred at 80 ° C for 5 minutes, and then the aqueous phase was removed. 20 ml of water was added to the toluene phase, and the mixture was stirred at 8 ° C for 5 minutes' and the aqueous phase was removed. The aqueous phase was extracted 3 times with two gas. The combined organic phase was dried and evaporated by MgS〇4 to supply 4 to 90 g (1%) of 4-[2-(indan-4-yloxy)ethyl]·5_A as a color solid. Base-2-phenyl-°. sit. _ MS : 3 19.2 (M)+, 186.2 (M-indanol)+. NMR : (CDC13, 1H, δ, TMS, 300MHz) 2.05 (quint., J=7 5 2H), 2.36 (s, 3H), 2.83 (t, J=7.5, 2H), 2.90 (t, J=7.5 , 2H) ____- 130 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 ___B7 V. Invention description (127) 2.98 (t. J=6.5, 2H), 4.25 ( t, J=6.5, 2H), 6.66 (d, J=7.5, 1H), 6.82 (d, J=7.5, 1H), 7.08 (t, J=8, 1H), 7.25-7.45 (m, 3H) , 7.97 ( br d, J= 8,2H). Kl.2-丨2-(5-formaldehyde-2-benzoxazole-4·m) Λ荦其忒湍i44_斿趑 4.00 g 4-[2-(indan-4-ol) Ethyl]·5-methyl-2-phenyl-anthracene (12.52 mmol) and 2.29 ml of dichloromethyl methyl ether (25. 5 mmol) were dissolved in 300 ml of di-methane. The solution was cooled to 〇〇c and 5 mmol of titanium tetrachloride (44 69 mmol) in 75 ml of di-methane was slowly added. The resulting dark solution was stirred at 0 °C for 30 minutes, and then 200 mL of IN HC1 was slowly added under the sputum. The mixture was stirred at 〇 °c for 3 , minutes, the two phases were separated, and the aqueous phase was washed 3 times with di-methane. The combined organic phases were dried and evaporated by MgS 4 to provide 4 · 5 g of a beige solid β as a flash chromatographic separation method (silicone, cyclohexane / ethyl acetate = 9 / 1 , followed by cyclohexane) / Acetate acetate = 4 / 1) Finally left as a beige crystal 2 96 grams (68%) 7-[2-(5-methyl-2-phenyloxazole-4-yl)ethoxy] Indane·4-carboxylic acid. MS : 347.3 (Μ) + , 187.2 » NMR : (CDC13, 1Η, 5, TMS, 300MHz) 2.12 (quint., J=7.5 2H), 2.39 (s, 3H), 2.82 (t, J=7.5, 2H ), 3.02 (t, J=6.5, 2H) 3.28 (t, J=7.5, 2H), 4.35 (t, J=6.5, 2H), 6.81 (d, J=8.4, 7.43 (m, 3H), 7.62 (d, J=8.-5, 1H), 7.96-7.99 (m 2H), 9.98 (s, 1H). 5 cl 2Z-ethyl lactyl- 3-{7-[2-(5-methyl- 2-笨某-芊)Ethoxy..羡·丄印满-4 -基丨-Acrylic acid g--131 - -The original Zhang scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) &quot; ------ 1328585 A7 B7 V. Description of the invention (128 will 1.39 grams of 7-[2-(5-methyl-2-phenyl-indazol-4)yl)ethoxy] 4-Carboxaldehyde (4.00 mmol) and 1.89 g of gasified (ethoxyethoxycarbonylmethyl) diphenyl scale [Tetrahedron 50 (25), 7543-56 (1994)] (4.40 mmol) in argon Dissolve in 9 ml of di-methane methane / 2 -propanol (ι / 丨, volume / volume). Cool the solution to -1 (TC, and add 855 mg of potassium carbonate (6.00 mmol). The resulting suspension was stirred overnight and allowed to reach room temperature. An additional 1.89 g of gasification (ethoxyethoxycarbonyl) was added. Triphenyl hydrazine (4·4 〇 millimolar), the solution was cooled to -1 〇 ° C, and S5~5 mg potassium carbonate (6.00 mmol) was added. The resulting suspension was stirred for 60 hours and allowed to reach At room temperature, add 89 g of gasification (ethoxyethoxycarbonylmethyl) to three scales (44 〇 millimolar), and cool the solution to -10 ° (:, and add 855 mg of potassium carbonate (6, The resulting suspension was taken up overnight and allowed to reach room temperature. The mixture was filtered, washed with di-methane and evaporated. The residue was dissolved in dichloromethane and washed with brine. Sulfur 33⁄4 magnesium was dried 'and the solvent was evaporated' and then flash chromatographic separation (silica gel, cyclohexane followed by cyclohexane / ethyl acetate = 95/5, followed by cyclohexane / ethyl acetate = 4 / 1) Finally, 1.215 g (65.8%) of 22-ethoxy-3-{7-[2-(5-fluorenyl-2-phenyl-.oxazol-4-yl)-B was obtained as a beige crystal. Ethyloxy]indan-4-yl}-propionate ethyl ester MS: 461.2 (M) + , 186.1 NMR: (CDC13, 1H, &lt;5, TMS, 300 MHz) 1.33 (t, J = 6.6, 3H), 1.36 (t, J=6.6, 3H), 2.07 (quint., J=7.5, 2H), 2.38 (s, 3H) 2.86 (t, J=7.5, 2H), 2.99 (t, J=6.9, 4H), 3.93 (q, J=7.i5 2H), 4.28 (q, J=7.2 , 2H), 4.29 (t, J~7Hz, 2H), 6.73 (d, J=8.7, 1H), 7.05 (s, 1H), 7.39-7.46 (m, 3H), 7.96-7.99 (m, 2H) , L.______- 132 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Description of invention (129 8.05 (d, J=8.7, 1H). Red 1丨 racemic 1-2-ethane group-'3-{7·"2-(5-methyl-2-phenyl-oxazol-4-yl)ethane gas 1 - ethyl bromopropionate 250 mg of Pd/C was added under argon to 850 mg of 2Z-ethoxy-3 - {7-[2-(5-mercapto-2-) dissolved in 1 ml of tetrahydrofuran Phenyloxazol-4-yl)ethoxy]indol-4-yl}-ethyl acrylate (1.84 mmol). The atmosphere was replaced by Η2, and the suspension was rapidly dried at room temperature Η2 atmosphere. Stir for 4 hours, filter through dicalite, and evaporate the solvent to leave 850 mg (99.6%) as a brown oil [racemic]-2-ethoxy-3-{7-[ Ethyl 2-(5-methyl-2-phenyl-σoxazol-4-yl)ethoxy]indan-4-yl}-propanoate MS: 464·4 (Μ+Η)+. NMR : (CDC13, 1H, δ, TMS, 300MHz) 1.14 (t, J=6.9, 3H), 1.21 (t, J=7.1, 3H), 2.04 (quint., J=7.5, 2H), 2.38 (s , 3H), 2.84 (t, J=7.5, 2H), 2.95 (m, 6H), 3.32 (m, 1H), 3.56 (m, 1H), 3.95 (t, J=6.8, 1H), 4.15 (q , J=7.1, 2H), 4.22 (t, J=6.4, 2H), 6.61 (d, J=8.3, 1H), 6.95 (d, J=8.2, 1H), 7.40-7.46 (m, 3H), 7.96- 7.99 (m, 2H). g_l f external play〗 -2- -3- {7-『2-(5-甲其-2-基基-p号吃-4-yl)ethyl lactyl 1 full-4 -ylindole-propionic acid [racemic]-2 -ethoxy-3-{ 7- [2-( 5-methyl-2-phenyl-3-oxazol-4-yl)ethoxy]phenanthyl-4-ylpropanoate (85〇 Milligram, 1 83 mmol.) Dissolve in 丨0 liters of dioxane, then slowly add 5 ml of water and LiOH (4_58 ml of ι solution in water, 4 58 mmol) at room temperature. The mixture was stirred overnight at room temperature and then poured onto ice to obtain the Chinese National Standard (CNS) A4 specification in Ηα( 1N) 133 paper scales (210X29·^公爱1 1328585 A7 ____ _B7 V. Invention Description (130) and pH 4 and extraction with AcOEt 3 times. The combined organic phases were washed with water, dried over magnesium sulfate and evaporated to give a colorless solid, which was then wet-purified for 5 min, filtered and dried to give 47〇mg (58.9%) [racemic]-2-ethoxy-3_{7-[2_(5_methyl_2_phenyl·^ bit-4-yl) ethoxylate as a colorless crystal Base] indole-4 -yl}-propionic acid. MS : 434.4 (MH)· » NMR ·· (CDC13, 1H, δ, TMS, 30〇MHz) 1.14 (t, J=7, 3H), 2.04 (quint., J=7.4, 2H), 2.38-^ , 3H), 2.84 (t, J-7.5, 2H), 2.88- 2.90 (m, 3H), 2.93 (t, 1=6.3, 2H), 3.01 (dxd, 1=4.8^9, 1H), 3.37 ( m, 1H), 3.55 (m, ,H), 4.01 (dxd, 1=4.8^8.1, 1H), 4.21 (t, J=6.3, 2H), 6.62 (d, J=8.l, 1H), 6.98 (d, J=8丄1H), 7.39-7.46 (m, 3H), 7.95_ 7 98 (m, 2H), c〇〇H non, always wide. Example 92 a] 4-"2-(t A violent argon argon N5.6.7J-four-bank stupid-1 - furfural

In a procedure similar to that described in Examples 9U] and b], 5,6 7 8·tetrahydroindole-bupropanol and methanesulfonic acid 2-(5-methyl-2-phenyloxazole-4-yl) Ethyl ester [pcT

Int. Appl. (2000) W00008002] Reaction to give 5 mercapto-2-phenyl-2-[2-(5,6,7,8-tetrahydroindol-1-oxy)ethyl]. No. azole. Treatment of 5-methyl-2-phenyl_4-[2·(5,6,7,8-tetrahydroindol-1-oxy)ethyl]anthracene with dichloromethyl methyl ether and titanium tetra-titanate The azole is then obtained as a yellow solid 4 [2 (5•methyl-2-phenyl)-oxazol-4-yl)ethoxy] 5,6 7 8·tetrahydroindole. MS: 361 · 2 (Μ) +, 186.2. -----134 - This paper size applies to China National Standard (CNS) Α4 specifications (210 X 297 public) %

Line 1328585 A7

NMR: (CDC13, ιΗ, 0, D, MS, 300MHz) 1 76 "(s,3H), 2.63 (br,2H . . 6 (br,4H),2.3ί 3.02 (t,J=6.5,2H) i , 4.32 (t, J=6.5, 2H), 6 Rn rat , 3·17 (br, 2H) °-80 (d, J=8.5, 1H), 7 4〇7^ . 7·62(^8· 5,1Η),7 95 _ · ·4 (m,3H) Some-2·, (S,1H) Some 1-5.6,7,8 - four-story 14·, Gan,-Acrylic acid ethyl ester is similar to the example 9 1 ci present nH t CJ in the step described, 4_mercapto-oxazol-4-yl)ethoxy-indenyl-2.ylethoxycarbonyl fluorenyl) long-term and sputum The reaction is carried out to obtain beige 2Z-ethoxy-3-{4-Γ2 r^ only solid l2-(5_f-based 2•phenyl-carbazole 5,6,7,8·tetrahydro tea]- Ethyl propyl acetoacetate. Milk-based MS: 476.2 (M+H)+ NMR: (CDC13, 1H, TMS &gt; 3〇〇MHz) 1.27 (t&gt; j=7 1? 3H 1.35 〇' J=7.1,3H ), h76 (br,4H),2 38 (s,3h),2 J=5.8, 2H)' 2.75 (t,J=5.8, 2H), 2 99 (t,J=6 4, 2h),3 ^ J=7.0, 2H), 4.28 (m, 4H), 6.71 (d, J=8.7, lH), 7.18 (s, iH 7.39- 7.46 (m, 3H), 7.90 (d, J=8.7, 1H) , 7.96-7.99 (, 2H). c] [racemicity 2-2-ϋ-3-Μ·"2·(5_基-2_笨某峄地j基)乙气基卜 5,6,7,8-四'奇笨-ΐ·丨-propionic acid in a procedure similar to that described in Example 9 1 d] and e] , 2Ζ-ethoxy_3_ {4·[2-(5-methyl-2-phenyl-oxazol-4-yl)ethoxy]_5,6,7,8-tetrahydro-1 -yl}-propionic acid ethyl ethane is hydrogenated to give [racemic]-2-ethoxy-3-(4-[2-(5-methyl-2-phenyl-carbazole-4) -yl)ethoxy]-5,6,7,8-tetrahydro___- 135 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm)

Pack ··· order

Line 1328085 A7 B7 V. Description of the invention (132) Tea-1 -yl}-ethyl propionate followed by [racemic]-2-ethoxy-3-{4-[2-(5-A) Saponification of ethyl-2-phenyl oxime-4-yl)ethoxy]-5,6,7,8-tetrahydrosol-buki}-propionate into colorless crystals [racemic]- 2-Ethoxy-3-{4-[2-(5-methyl 2-phenyl-o. g--4-yl)ethoxy]-5,6,7,8-tetrahydro tea- L-based}••propionic acid. MS: 450.4 (M+H)+. NMR : (CDC13) 1H, δ , TMS, 300MHz) 1.12 (t, J=6.9, 3H), 1.74 (br, 4H), 2.37 (s, 3H), 2.62 (br, 2H), 2.72 (br, 2H) ), 2.89 (dxd, J=14.4, 8.7, 1H), 2.98 (t, J=6, 2H), 3.05 (dxd, J=14.4, 4.2, 1H), 3.31 (quasi-quint, J~7, 1H) ), 3.52 (quasi-quint, J~7,1H), 3.98 (dxd, J=8.7, 4.2,1H), 4.19 (t, J=6.3, 2H), 6.63 (d, J=8.1, 1H), 6.98 (d, J=8.4, 1H), 7.39-7.46 (m, 3H), 7.96-7.99 (m, 2H), COOH is very broad. Example 93 a] ( 3-(4·芊 笨 笨 Γ & & & 1 1 1 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Ε 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 4-decyloxybenzo[bp-sept-7-carboxaldehyde [Ger. Offen. (1998) DE 19711617 A1] dissolved in 15 ml of 2-propanol under argon. β after cooling to -20 C' Add 0.944 g (2 20 mmol) of gasified (ethoxyethoxycarbonyl fluorenyl) triphenyl scale [Tetrahedr〇n 50 (25), 7543-56 (1994)] and 0.44 丨 5 g (3.00) Millions of anhydrous potassium carbonate. The resulting suspension was stirred in an ice bath&apos; and allowed to reach room temperature and stirred at room temperature overnight. A second addition of the Witting reagent and potassium carbonate was carried out a second time at -20 ° C as described above. After filtration and evaporation of the solvent, the residue -136 - the paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 public) ' -- 1328585 A7 B7 to flash, color layer; 7 away from the law (Shi Xisheng Purification of yttrium from the sloping/Et〇Ac) to 0.586 g (77%) of a diffuse yellow oil (3-(4-ethoxybenzobenzo-7.)_2(Z e) ethoxy propyl Acetate vinegar MS: 382.2 (M) + , 29l2 i89i NMR . (CDC13, 1H, TMSi 3〇〇MHz) 1.36 (t, J=7, 3H), 140 〇' Bu 7' 3H)' 4 ·〇1 (q, J=7, 2H), 4.34 (q, J=7, 2H),

)_26 (S. 2H)' 6.88 (d, J=8, 1H), 7.23 (s, 1H), 7.35- 7.45 (m, 4H), 7·) 〇 (m, 2H), 7·59 (d , 1H), 8.19 (d, 1 = 8, 1H). Bl [.external-spinning 氡 some loading ~ and rbl4 phen·7·some) · 2_ethyl ethionyl propionate 〇·383 g (1.00 mmol) (3-(4-decyloxybenzene) And [b] thiophen-7-yl)-2(Z'E)-ethoxy acrylate was dissolved in 2 mL of THF/MeOH (1:1) under argon. Add 〇248 g (1) 〇 2 millimoles of magnesium, and ordered

The reaction mixture was warmed to 5 (rc. After 3 min, it was cooled to warmness and stirred overnight at ambient temperature. Add 5 ml of hci (25% in water) at 25 &lt;3 (:) Afterwards, the reaction mixture was vigorously stirred. Then, it was extracted with EtOAc (secondary); the organic phase was washed with brine, dried over MgS 4 and filtered and evaporated. 9: 丨 to 4: 〗 hexanes / EtOAc) Purified yellow oil to supply 366 g (99%) of yttrium as a yellow oil [racemic] _3_(4·芊 oxybenzo[b] porphin -7·yl)_2_ethoxypropionic acid methyl ester. _ MS : 370.1 (M) + , 3 1 1.2, 253.1 » NMR : (CDCI3, 1H, δ , TMS, 300MHz) 1.13 (t, J=8 , 3H), 3.23 (m, 2H), 3.35 (m, 1H), 3.60 (m, 1H), 3.70 (s, 3H), _____- 137 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 134 B7 V. Description of invention (

4.24 (m,1H), 5.21 (s 2H, A, 2Η), 6.78 (d, J = 9, 1H), 7.13 (d, J=9, H), 7 38- 7 48 (m, 6H ), W(d, &gt;6, 1H). c] L racemate 1 -2 - λ oxygen, its W/1, Pak _ 〖bh thiophene-7-some) two 醢ϋι - ^4.68^(12.6^莫耳)[racemic]3( M-based benzene (tetra) ancient 7 soil) 2 ethoxypropionate methyl ester dissolved in argon and room temperature in I liter CH2C12 towel drop added 23 9 ml dimethyl sulfide and ^ ml three nipples puzzle 纟 room temperature After stirring for 5 hours, the reaction mixture was stopped by pouring on crushed ice water and then extracted three times with CHaCI. The organic phase was washed with water, dried with MgS 4, (iv) and evaporated to supply (92 g). The color oil was purified by flash chromatography (Shixi gum, cH2Cl2 and Me〇H) to give a &lt;yellow solid of 3..5 1 g (99%) [racemic] 2 Methyl 3-(4-methoxybenzo[b]B-tomb-7-yl)propionic acid methyl ester. MS _· 279.1 (M-Η). NMR : (CDC13, 1H, TMS, 300MHz) 1.13 (t, J=7, 3H), 3.22 (m, 2H), 3.35 (m, iH), 3.61 (m, 1H), 3.71 (s, 3H), 4.24 (m, 1H), 5.32 (s, 1H ), 6.66 (d, J=8, 1H), 7.07 (d, J=8, 1H), 7.35 (d, J=5, 1H), 7.48 (d, J=5, 1H) » d] 1~ ^ Racemic Bu 3-(4-{_2-[2-(4- 苽 ))-5-methyl oxazole-4-even 1 oxy} stupid 丨bh吩-7·某)· 2-Ethene a certain propionate in a procedure similar to that described in Example 1 7a], [racemic] _ 2_ethoxy-3-(4-hydroxybenzo[b] 4 phen-7-yl)methyl propionate with 2-[2-(4-chlorophenyl)-5-methyl" ox-4-yl]ethanol (similar to in Example 2 丨a) to 2 1 e] Description of the sequence 'conversion of 4-vaporaldehyde to 2-[2-(4-phenylphenyl)-5-methyl", etc. _____- 138 - This paper scale applies to Chinese national standards ( CNS) A4 size (210X297 mm) 1328585 A7 B7 V. Description of the invention (135 gram-4-yl) ethanol prepared in the presence of triphenylphosphine and dead (diazo azodicarboxylate) To produce [racemate]_ 3 _ ( 4_丨2_ [ 2· ( 4 chlorophenyl) 〇-methyl phenyl oxazol-4-yl] ethoxy} benzo[b] β phenanthrene _7_基)·2_ethoxypropyl ketone methyl ester, which was further saponified in a procedure similar to that described in Example 9.1 e] to produce a racemic buckling 3_(4·{ 2_[2·(4_gas + f )-5-fluorenyl) oxazol-4-yl]ethoxy}benzo[b]thiophene-7-ylethoxypropionic acid. MS: 484, 3 (M-H)·, 438.3. -~ NMR · (CDC13, 1H, δ, TMS, 300MHz) 1.09 (t, J=7, 3H), 2.39 (s, 3H), 3.06 (t, J=6, 2H), 3.18 (m, 1H) , 3.28-3.43 (m, 2H), 3.50- 3.63 (m, 1H), 4.20-4.29 (d, J=5, 1H), 4.35 (t, J = 6, 2H), 6.74 (d, J=8 , 1H), 7.11-7.24 (m, 3H), 7.32 (d, J=6, 1H), 7.47 (d, J=6, 1H), 7.88 (d, J=9, 2H), COOH# f 0 Example 94 I. Outer. Milk 1 Sex 2-Base-3·(4·{2]?-(4-Air 茇 篡 篡 嗑 _..4H Ethoxy) Poor _ and f bh -7- its, stone starting in a procedure similar to that described in Example 17a], [racemic 2 - ethoxy-3-(4-hydroxybenzo[13] cumphin-7-yl) propyl Methyl ester with 2_[2_(4_fluorophenyl)-5-methyloxazol-4-yl]ethanol [j_ Med. Chem (1998), 41 ((9), 5037-5054] in triphenylphosphine and DEAD Reaction in the presence of (diethyl azodicarboxylate) to give [racemic]-3-(4-{2-[2·(4-fluorophenyl)·5·methylcarbazole- Methyl 4-ethyl]ethoxy}phenylhydrazine [b] porphin-7-yl) 2 ethoxypropionate, which was further saponified in a similar manner to that described in Example 9 丨e]

Binding

Line 1328085 A7 B7 V. INSTRUCTION DESCRIPTION (136) [Racecyclic]-3-(4-{2-[2-(4-fluorophenyl)-5-methylcarbazole-) 4-yl]ethoxylated benzo[b]&quot;cephen-7-yl)-2-ethoxypropionic acid. MS: 468.2 (MH)', 422.2 NMR: (CDCl3, 1H, 6, TMS, 300 MHz) 1.10 (t, J=7, 3H), 2.39 (s, 3H), 3.05 (t, J=6, 2H ), 3.16-3.24 (m, 1H), 3.31-3.43 (m, 2H), 3.51-3.63 (m, 1H), 4.23-4.29 (m, 1H), 4.35 (t, J=6, 2H), 6.72 (d, J=8, 1 H), _7.05-7.16 (m, 3H), 7.32 (d, J=5, 1H), 7.48 (d, J=5, 1H), 7.93-7.99 (m, 2H), COOH is very wide. Example 95 ί racemic 2-Ethoxy-3-(4-(2-丨2-(2-ethane)-4-methylindole-5-methylcarbazol-4-yl 1 Ethene and a certain amount of 丨 并 『 bl bl 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢And [b]thiophene-7-yl)propionic acid methyl ester and 2-[2-(2-ethoxy-4-fluorophenyl)-5-methyl B-oxazol-4-yl]ethanol (i) Treatment of 4-fluoro-2-hydroxybenzaldehyde with ethyl iodide and potassium carbonate in N,N-dimethylformamide [J.

Chem. Soc., Perkin Trans. 1 (1994), (13), 1823-3 1] to give 2-ethoxy-4-fluorobenzaldehyde; ii) similar to in Examples 21a] to 21e] Illustrated sequence, converted to 2-[2-(2-ethoxy-4-fluorophenyl)-5-methyloxazol-4-yl]ethanol with 2-ethoxy-4-fluorobenzaldehyde To obtain 2-[2·(2-ethoxy-4-cyclophenyl)-5-methyl "Wow-4-yl]ethanol) in triphenylphosphine and DEAD (azodicarboxylic acid II) Reaction in the presence of ethyl ester) to give [racemic] 2-ethoxy-3-(4-{2-[2-(2-ethoxy-4-fluorophenyl)-5- Methylcarbazol-4-yl]B______- 140 -_______ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) &quot; ' 1371328585 A7 B7 V. Invention Description ( Oxygen Benzene [ It is called _7_yl) propionic acid methyl g §, which is further stepped in a step similar to the example to give a [racemic]-2-ethoxy group. (4_{2·[2.(2_ethoxy-4-4 fluorophenyl)_5 methyl^. -4-yl]ethoxy}benzo[b]porphin-7-yl)propionic acid MS: 512.2 (MH)·, 494.1, 466.2. NMR: (CDCI3, 1H, 5, TMS, 300MHz): i.〇9 (t, j=7&gt; 3H), 1-44 (t, J=7, 3H), 2.38 (s, 3H), 3.09 (t, J=6, 2H), 3.12-3.39 (m, 3H), 3.51-3.61 (m, 1H ), '4.08 (q, J=6, 2H)&gt; 4 25 (m 1H), 4.36 (t, J=6j 2H), 6.64-6.75 (m, 3H), 7.11 - 7.24 ( 1H), 7.29 ( d, J=6Hz, 1H), 7.48 (d, J=6, 1H), 7.80 (dxd 1H), COOH is very broad. Example 96 QLM. Rotational l-2-_^oxy-3-(4- {上丄2_(4_甲氪很笨某)_5_?气坐-4-基1乙氧某}苽# r hl〇塞吩-夂,壬 given in the steps similar to the example 17a], [Racemic 2-Ethoxy-3-(4-hydroxybenzo[b]sulfonyl-7-yl)propanoic acid methyl ester with 2 [2 (4-methoxyphenyl)-5-A Ketrazole-4-yl]ethanol [j Med Chem (丨998), 41(25), 503 7- 50 54] reacts in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate), To produce [racemate]_2_ethoxy_3_(4_{2_[2, (4-methoxyphenyl)-5-methyl)oxazol-4-yl]ethoxy}benzene [b]»cetin-7, yl)methyl propionate, which was further saponified in a procedure similar to that described in Example 9 1 e] to give [racemic] to 2-color as a colorless amorphous solid. Oxyl, 3-(4_ { 2·[2·(4-methoxybenzene) ) -5 Yue Well-yl-4-yl] ethoxy} stupid Bing [b] ° -7 plug Yu-yl) propionic acid. _- -___- 141 - This paper size applies to Chinese National Standard (CNS) Α4 specification (210X297 mm) 1328585 A7 B7 V. Description of invention (138) MS: 480.3 (M-H)., 434.3. NMR : (CDClj, 1H, &lt;5, TMS, 300MHz) : 1.09 (t, J=7, 3H), 2.38 (s, 3H), 3.05 (t, J=6, 2H), 3.13-3.60 (m , 4H), 3.85 (s, 3H), 4.25 (m, 1H), 4.33 (t, J=6, 2H), 6.71 (d, J=8, 1H), 6.93 (d, J=9, 2H) , 7.13 (d, J=8, 1H), 7.31 (d, J=5, 1H), 7.64- 7.73 (m, 1H), 7.91 (d, J= 9, 2H), COOH is very wide. Example 97 [Racemic Bu-2-Ethoxy-3·(4·(2二"2·(4_isopropyl gas 茇 some methyl carbazole · 4 _ 1 ethane group 丨 stupid # fbl4岭-7-)propionic acid in a procedure similar to that described in Example 1 7a], [racemic] _ 2 ethoxy-3-(4-hydroxybenz[b]thiophen-7-yl ) decyl propionate and 2-[2-(4-isopropoxyphenyl)-5-methyl.oxazol-4-yl]ethanol_[PCT Int. Appl. (2000), WOOOO8002 A 1 ] Reacts in the presence of triphenylene and DEAD (diethyl azodicarboxylate) to produce [racemicity 2_ethoxy_3_(4·{2_[2·(4•isopropoxy) Phenylphenyl)-5-mercaptooxazol-4-yl]ethoxy}benzo[b]sulfon-7-yl)methyl propionate's steps as described in Example 9 1 e] Further saponification to produce [racemic 2-2-ethoxy-3_(4-{2-[2-(4-isopropoxyphenyl)-5-methyl) as a pale yellow amorphous solid, Isoazol-4-yl]ethoxy}^ and [b]B-secen-7-yl)dioic acid MS: 508.3 (MH)·, 462.3. NMR: (CDC13, 1H, 5, TMS, 300MHz) 1.09 (t, J=6, 3H), 1.35 (d, 1=6, 6H), 2.37 (s, 3H), 3.04 (t, J=6, 2H), 3.12-3.40 (m, 3H), 3.52 -3.61 (m, 1H), 4.2 2-4.29 (m, 1H), 4.35 (t, J = 6, 2H), 4.55-4.67 (m, 1H), 6.72 (d, J=7, 1H), 6.89 (d, __- 142 -___ The paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm)

Line invention description (J=8, 2H), 7.15 (d, J=8, 1H), 7.31 (d, J=5, 1H), 7.63-7.73 (m. 1H). 7,88 (d. J= 8, 2Ηί, COOH is very broad. Example 98 a] h.·丨2-(5-methyl-2-phenyl H)-ethoxy oxime and 卜 1 ^ H furfural in a similar example 91a In the steps described in b], benzo[b]thiophene-7-ol [J. Chem. Soc., Perkin Trans. 1 (1983), (12), 2973-7] and methylate 2- (5-methyl-2-phenyl ol-4-yl)ethyl ester [pct int Appl. (2000) W00008002] reaction to produce 4-[2-(benzoquinone [b] ketone-7-gas Ethyl]-5-methyl-2-phenyl no. Jun 4-[2-(benzo[b]sulfon-7-oxy) treated with dichloromethyl mystery and titanium tetrachloride Ethyl]-5-fluorenyl-2-phenylene-carbazole, followed by 7-[2_(5-methyl-2-phenyl-indole 0--4-yl)-ethoxy]-benzene as a yellow solid And [b]&lt;»cetin _4 - 叛 〇 NMR : (CDC13, 1H, 5, TMS, 300MHz) 2.45 (s, 3H), 3.12 (t, J-6, 2H), 4.55 (t, J=6, 2H), 6.92 (d, J=8, 1H), 7.39-7.46 (m, 3H). 7.66 (d, J=5, 1H), 7.80 (d, J=8, 1H), 7.95 -7.99 (m, 2H), 8.35 (d, J=5,1H), 10.1 (s, 1H) 〇bl(S)-2-methyl-oxy-3- { 7- |~2-(5-甲棊)2-茉茱-噚口Φ - 4_其, _ oxy 1-benzopyrene bl»»Shanxi-4-some 丨-Bing in a similar example 1 1 In the step described by a] to 1 1 c], 7_[ 2 —( 5-methyl-2-phenyloxazol-4-yl)·ethoxy bromide[b]D-cephen-4-carboxylate The aldehyde reacts with (S)-4-pyryl-3-methoxyethoxyethyloxazolidine-2·one and nBu2B〇Tf to produce (S)-4-benzyl-3-[(2S,3R) )-3-hydroxy-2-methoxy-3-{ 7-(2-(5-methyl-2-phenyloxazol-4-yl)·ethoxy]-benzo[flash porphin -143 - 1328585 A7 B7 V. Description of the Invention (140 4-yl}propanyl]°oxazolidine-2-one (according to NMR, one of the four isomers is predominant, according to Tetrahedron Asymmetry 1999, 1353, temporarily configure the configuration to 2S, 3R). (s)-4-benzyl-3-[(2S,3R)-3-yl-2-yloxy-3-{7-[2-(5-mercapto-2-phenyl) -4-yl)-ethoxy]-benzo[bp-cet-4-yl}propanyl]- oxo-2-ketone is reduced with triethylmethane in trifluoroacetic acid, followed by S)-4-benzyl-3-(2(S)-2-methoxy-3-{ 7-[2-(5-methyl-2-indolyl-oxazol-4yl)-B Oxy]-benzoquinone [b] phen-4-yl}propanyl 81) ° 唆 - pain _ 2 ketone. Next, (S)-4·Germanyl-3-(2(8)-2-methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl) )-ethoxy]-benzo[b]&quot;cephen-4-yl}propyl aryl) 〇 烧 _2 - 纲 纲 _2 IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN s)-2-methoxy-3-{7-[2-(5-methyl-2-phenyl-»-oxazol-4-yl)-ethoxy]-benzo[b] porphin- 4-yl}-propionic acid. MS: 436.4 (M-Η)·. NMR : (CDC13, 1H, δ, TMS, 300MHz) 2.44 (s, 3H), 3.06 (t, J=6, 2H), 3.21-3.31 (m, 4H), 3.40-3.46 (dxd, Ji = 4, J2=14, 1H), 4.04-4.08 (m, 1H), 4.38 (t, J=6, 2H), 6.73 (d, J=8, 1H), 7.17 (d, J=8, 1H), 7.40 - 7.47 (m, 5H), 7.95-7.98 (m, 2H), COOH is very wide. Example 99 2Z-Ethoxy-3-indolyl-7-"2-(5-methyl-2-pyano-indol-4-yl)ethoxy 1 indane-4-yl}-propanoic acid 2Z-ethoxy-3-{7-[2-(5-methyl-2-phenyl-indazole-4(yl)ethoxy]]indol-4-yl}-propionate ethyl ester (Example 91c)) (i5〇mg, 0.325m________ 144 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1328585 A7 B7 V. Invention description (141) Moer) In 7 ml of dioxane, 9 ml of water and LiOH (0.812 ml of a 1 Torr solution in water, 0.813 mmol) were slowly added at room temperature. The resulting mixture was stirred at room temperature overnight. It was then poured onto ice, neutralized with HCI (IN) to form ρΗ4 and extracted with AcOEt three times. The combined organic phases were washed with water, dried over magnesium sulfate and evaporated to give &lt;RTI ID=0.0&gt;&gt; -2-Phenyl-oxazol-4-yl)ethoxy]imprint-4-yl}-propionic acid. MS: 432.5 (M-Η). NMR : (CDC13, 1H, (5, TMS, 300MHz) 1.32 (t, J=7.1, 3H), 2.08 (quint., J=7.5, 2H), 2.39 (s, 3H), 2.86 (t, J= 7.5, 2H), 3.00 (m, 4H), 3.95 (q, J=7.1, 2H), 4.30 (t, J=6.5, 2H), 6.74 (d, J=8.7, 1H), 7.20 (s, 1H) ), 7.39- 7.46 (m, 3H), 7.96-7.99 (m, 2H), 8.02 (d, J=8.7, 1H), COOH is very broad. Example 100 (_S)-2-methoxy--3- 7_〖2-(5-methyl-2-stupid-啐咄-4-) Ethyl argon 1 phenanthrene-4-some: 丨- and vinegar is similar to the example 1 1 a] to 1 1 c] In the illustrated step, 7-[2-(5-methyl-2-phenyl-indazol-4-yl)ethoxy]indano-4_carboxaldehyde (Example 9ib)) and (S)- 4-mercapto-3-methoxyethenyl. Isooxazol-2-one and nBu2BOTf are reacted to give (S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2 -Methoxy-3-{7-[2-(5-methyl-2-phenylazol-4-yl)ethoxy]indan-4-yl}propanyl]°oxazolidine-2 - Ketone (according to NMR, one of the four isomers is predominant; according to Tetrahedron Asymmetry 1999, 1 353, the configuration is temporarily named 2S, 3R). (S)-4-Benzyl-3- [(2S,3R)-3 -hydroxy-2-methyl__- 145 -___ This paper size is suitable for the garden (CNS) A4 size (210 X 297 mm) 1328585 A7 B7 V. Description of invention (142) Oxy- 3-{7-[2-(5-methyl-2-phenyl-form _4_yl) Ethoxy]indan-4-yl}propanyl]oxazolidine-2·one is reduced with triethylformamidine in trifluoroacetic acid, followed by (S)-4-mercapto-3-() 2(S)-2-methoxy-3-{7-[2-(5-methyl-2-phenyl-B-oxazol-4-yl)ethoxy]indan-4_yl-propyl Mercapto) σ oxo-2-one followed by benzyl-3-(2(S)-2-methoxy-3-{7-[2-(5.methyl-2-phenyl-oxime) Zin-4-yl)ethoxy]indan-4-yl}propan-2-one is saponified with IN NaOH in THF to give a colorless solid after crystallization from AcOEt/hexane. ·(poly)-2-indolyl_3-{7-[2-(5-methyl-2-indolyl-cinazole-4-yl)ethoxy]phenanthrene-4_gibr acid. The excess enantiomer was 97.7% identified by HPLC (Chiralpak-AD). MS : 420.4 (M-Η)· » NMR : (CDCl3, 1H, 6, TMS) 2.05 (quint., J=7.5, 2H), 2.38 (s, 3H), 2.84 (t, J-7.5, 2H) , 2.87-3.00 (m, 5H), 3.05 (dxd, J-14.4, 4.8, 1H), 3.35 (s, 3H), 3.95 (dxd, J=7.8, 4.8, 1H), 4.21 (t, J=6.3 , 2H), 6.63 (d, J=8.4, 1H), 6.98 (d, J=8.4, 1H), 7.40-7.46 (m, 3H), 7.95- 7.99 (m, 2H), COOH is very wide. Example 1 0 1 a 1_L racemic 1 - 3 - ( 4 -yl-based tea-1 -yl)-2 -methoxy-propionic acid A cool in a procedure similar to that described in Example 93a], 4-笮Oxyquinone-1 _Junjun (prepared from 4-hydroxyindole-1·carboxaldehyde, sulfhydryl gas and potassium carbonate in N,N-dimethylformamide at room temperature) and bromine (methoxy methoxycarbonylmethyl) triammonium [Tetrahedron 53 (50), 17097-171 14 (1997)] reaction to produce 3-(4-benzyloxynaphthalene-bu)-2 (Z , E) - Methyl methacrylate. For example ___- 14R -____ This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm): ' 1328585 A7 B7 V. Description of invention (143) 91d] '3' (4_benzyl Hydrogenation of methoxy hydrazine-hydrazinyl)·2(ζ,ε)_methoxy methacrylate to produce [racemic]_3_(4-hydroxyindol-1-yl)-2 in light rose oil Methyl methoxypropionate. MS: 259.1 (M-H)·, 229.2. NMR : (CDC13, 1H, δ, TMS, 300MHz) : 3.31-3.38 (m, 4H), 3.44-3.49 (q, J=5, 1H), 3.72 (s, 3H), 4.09-4.13 (dxd, J , = 5, J2=8, 1H), 5.63 (s, 1H), 6.71 (d, J=7, 1H), 7.18 (d, J=8, 1H), 7.47-7.58 (m, 2H), 8.00 '-'8.03 (m, 1H), 8.23- 8.26 (m, 1H) 〇5 i exogenous 1 - 3 - ( 4 - { 2 -『2 - ( 2- 乙某-4 - suffering, stupid a) _% A certain ° sitting -4- group 1 氲 氲 萁 萁 基 基 基 基 -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于_3_(4-Hydroxyindol-1-yl)-2-decyloxypropionate oxime ester and 2·[2_(2-ethoxy-4-cyclofluoro)-5-methyloxazol-4-yl Ethanol (Example 95) was reacted in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to give [racemic] _ 3_ (4_ {2-[2-(2-ethoxy) 4-merylphenyl)-5-methyl 唆 唆 _ 4-yl] ethoxy} 荇 1 -yl)-2 - methoxypropionic acid 甲 g 'will be similar to Example 91 e] The steps described are further saponified to produce [racemate]_3_(4-{2-[2-(2-ethyllacyl-4-oxadonyl)·5-methyl as a colorless solid 》号〇 _4_基]Ethoxy} 荇-1-yl)-2-methoxypropane acid. MS: 492.2 (M-Η)·. — NMR : (CDC13, 1H, δ , TMS, 300MHz) : \ A2 (t J=7, 3H), 2.41 (s, 3H), 3.12 (t, J-6, 2H), 3.23-3.31 4H), 3.52- 3.58 (dxd, Ji = 4, J2=14, 1H), 4.04-4.11 (m, 3H), 4 37 (t, -147 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 public ) ~ ---

Line 1328585 A7

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Line 1328085 A7 B7 145 V. INSTRUCTION DESCRIPTION (Winter 『 ^ 嚷 -4 -4 - - - - - - - -4 -4 -4 -4 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在(Ethoxyethoxymethyl)triphenyl scale [Tetrahedron 50 (25), 7543. 56 (1994)] Treatment of 7_[2·(5-methyl·2-phenyl) in the presence of potassium carbonate No. 0 sitting -4 -yl)-ethoxy]-benzo[b] ν» septene · 4-single (example 98a)), to produce, produce 2Z-ethoxy-3-{7·[ 2·(5-Methyl__2_Phenyl-Sakiji·4·yl)·Ethoxy]-benzo[b]nonphen-4-yl}-propionate ethyl ester. 22•Ethoxy_3_{7_[2-(5-methyl-2-phenyl-oxazol-4-yl-j-ethoxybenzo[b]IJ-septene_4_yl}-- Ethyl citrate was further coated in a similar manner to that described in Example 99 to give 2Z-ethoxy-3-{7-[2-(5-mercapto-2-phenyl-jun) as a hot solid. -4 -yl)-ethoxy]-when-[b]p-phenylphen-4-yl}-propionic acid MS: 448.2 (MH)·, 376.2. NMR: (CDC13, 1H, &lt;5, TMS, 300MHz) 1.33 (t, J=6, 3H), 2.45 (s, 3H), 3.11 (t, J=5, 2H), 3.99 (q, J=6, 2H), 4·5〇(t , J-5, 2H), 6.87 (d, J=7, 1H), 7.39- 7.46 (m, 3H), 7, 49-7, 57 (m, 2H), 7.64 (s, 1H), 7.97- 8.00 (m, 2H), 8.24 (d, J=7, 1H), COOH is very broad. 'Example 104 f racemic 2-2-hydrogen-3-{7-"2-(5-A -2-苽--carbazole-4_yl)-ethyl lactyl 1 - acetonyl hydrazide {31. porphin-4 - hydrazino-propionic acid will be 0_175 g (0.39 mmol) 2Z-ethoxy- 3-{ 7-[2-(5-methyl-2-phenyl-.oxazol-4-yl)-ethoxy]-benzo[b]4-phen-4-yl}-propionic acid ( Example 103) hydrogenation with a racemic Ru(〇Ac) 2 [3 5_xyl_ MeOBIPHEP] catalyst in ethanol at 60 ° C and a pressure of 60 bar To become -149 - This paper scale applies Chinese National Standard (CNS) A4 specification (210X297 mm) 1328585 A7 B7 V. Invention description (~~) ~ ~ ' Light gray solid 0. 167 g [racemic] -2-ethoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[bp tomb.4 base 丨Acid 0 MS : 450.2 (MH)·, 404.0. NMR: (CDC13, 1H, 5, TMS, 300 MHz) 1.06 (t, J=6j 3H) 2.44 (S, 3H), 3.07 (t, J=5, 2H ), 3.22-3.31 (m, 2H), 3.4〇. 3.55 (m, 2H), 4.10-4.14 (m, 1H), 4.38 (t, J=5, 2H)5 6.72 (d J=7, 1H) , 7.16 (d, J=7, 1H), *7_.40.-7.47 (m, 6H), 7.95.7.98 (m, 2H) » - Example 105 a~LLj 岣 Ί Ί - 2- Π -Methyl -3- gas a-3 - stupid - (Z) - and · beeamine a i _ 3- {4-『2-(5-methyl 茱-2-phenyl-carbazole-4 - a certain ethane Ι_不和[bl 4 phen-7-yl}-propionyl b will be 0.334 g (0.75 mmol) [racemic 2-amino-3·{4·[2_ (5-methyl-) 2-Phenyl-oxazol-4-yl)-ethoxy]-benzo[b]p-sept.7-yl}·ethyl propionate (in a similar order to that described in Examples 15a) and 15b] To 4_[2_(7-bromoindolyl][b]nonphen-4-oxy)ethyl]-5-fluorenyl -2-Phenyl-carbazole [PCT Int. Appl. (200I) W001/79202] and N-(dimethylmethylene) ethyl glycinate) and 0.161 g (0.97 mmol) Benzoylacetone was dissolved in 25 ml of toluene. Next, 0.2 mL (0.55 mmol) of triethylamine and 0.026 g (0.15 mmol) of 4-toluenesulfonic acid were added, and the reaction mixture was heated under reflux for 2 hours. After removing the solvent under reduced pressure, the residue was diluted with water / sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The combined organic phases were dried over MgSO4 and evaporated. Flash-separated layer separation method (矽 ____- 150 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 public) 1328585 A7 B7 V. Description of invention (

147 Glue, Eluent: Gradient of hexanes and ethyl acetate) Purify the residue to give 0.38 g (85 %) as a light yellow oil [racemic]-2 - [ 1 -methyl·3 Oxy-3-phenyl-(Z)-propenylamino]-3-{4-[2-(5-methyl-2-indolyloxazol-4-yl)-ethoxy]-benzene And [b]. Ethyl-7-yl}-propionic acid ethyl ester. MS: 595.1 (M+H)+ NMR: (CDC13, 1H, δ, TMS, 300 MHz) 1.26 (t, J=6, 3H) 1.64 (s, 3H), 2.39 (s, 3H), 3.03-3.08 (t, J=6, 2H), 3 17 3.25 (dxd, J, = 8, J2=13, 1H)/3.44-3.5 1 (dxd, J, = 5, J2=12 1H), 4.19-4.26 ( q, J=6, 2H), 4.34-4.39 (t, J=5, 2H), 4 58_' 4.66 (m, 1H), 6.70-6.73 (d, J=7, 1H), 7.12-7.14 (d , j=7 1H), 7.26- 7.52 (m, 9H), 7.84-7.99 (m, 4H), 11.73-11, 76 (d J=8, 1H) 〇' bl [. racemicity 2- _f 1-methyl-3-chloro-3-oxo-(Z, · and 3-{4-[2-(5-methyl:2-styl-oxazol-4-yl)-B Very 1-phenyl-7-yl}•propionic acid will be 0.333 g (0.56 mmol) [racemate]_2_ [1-indolyl-3-oxy 3 phenyl-(Ζ)-propionium Amino group]·3·{4·[2-(5-methyl-2-phenyl-indazol-4-yl)-ethoxy]- benzo[b]thiophen-7-ylpropanoic acid The ethyl ester was dissolved in 1:1 THF / EtOH (10 mL) and was taken &lt;RTI ID=0.0&gt; Bu], then, acidified with IN hydrogen acid and extracted with di-methane. The combined organic phase The MgSCU was dried and evaporated, and purified by flash chromatography (methylene gel, elutant, gradient of methane and methanol) to afford 0.218 g (69 〇/〇) as a pale yellow amorphous solid. ]Methyl _3oxy-Hong ____- 151 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm)

Participation

1328585 A7 B7 V. INSTRUCTIONS (148 phenyl-(Z)-propenylamino]-3· {4-[2-(5-nonyl-2-phenyl-indazole-4-yl)·B乳基]-表[b]B-cephen-7-yl}-propionic acid MS: 565.1 (MH)·, 521.2. NMR: (CDCI3, 1H, (5, TMS, 300MHz) 1.56 (s, 3H ), 2.38 (s, 3H). 3.03-3.07 (t, J=6, 2H), 3.20-3.28 (m, 1H), 3.54-3.59 (m, 1H), 4.30-4.32 (t, J=6, 2H), 4.64 (m, 1H), 5.55 (s, 1H), 6.66-6.69 (d, J=7, 1H), 7.10-7.13 (d, J=7, 1H), 7.26-7.53 (m, 9H ), 7.84- 7.98 (m, 4H), 11:85-. 1 1.88 (d, 8, 1H) » Example 106 - 谷 l.„l-(4-Trifluoromethane) Butadiene-i, 3_二_ 3.94 ml (40 mmol) of ethyl acetate and then 〇丨ml of ethanol was added to a stirred suspension of U70 g (39 mmol) sodium hydride in 20 ml of THF maintained under argon. Then, a solution of 3.76 g (20 mmol) of 4-trifluoromethylacetamidine in 2 ml of THF was added below 25 «c, and finally 0.12 g (0.32 house mole) diphenyl hydrazine was added. _18 • Coronal _6, and the reaction mixture is heated under reflux for 90 minutes. After cooling to about 〇χ: The mixture was acidified with 20 ml of sulfuric acid (丨〇% solution in water) and the reaction product was separated by ether extraction. The combined organic phases were dried over MgSO 4 and evaporated. The residue formed was flashed. Chromatography (purine, eliminator: gradient of hexanes and ethyl acetate) was purified to give 3.54 g (77%) of 1-(4-trifluoromethylphenyl)butane as a yellow crystal. 3 diketone MS: 230.1 (M), 215.0, 173.0. NMR: (CDC13, 1H, 5, TMS, 300 MHz) 2.24 (s, 3H), 6.20 (s, 1H), 7.69-7.72 (d, J= 7, 2H), 7.96-7.99 (d, J=7, 2H), 15.99

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(s, 1 Η) 〇

A certain )) - 旋性卜 2 - Γ丨-甲其_ ^-^Α^Αΐι,3-{4-ί2-〇. y 1 ^ a tr i JTT . % base-°carbazole-4 - a)-Ethylene phen-7-a certain 丨-- in a similar manner to the example 丨05a] to illustrate ± -I f / l, in the step, [racemic]-2-amino-3-{4-[ 2-(5-methyl-2-phenyl-indole-^) Sorb-7 oxazol-4-yl)-ethoxy]-benzo[b], 1-(4-tri) Fluoromethylphenyl) butyl 1,3-1,3-dione is reacted in the presence of a catalytic amount of p-nonanoic acid and under reflux to give [racemic]-2·[kappamethyl-3 Oxyphenyl)-(Ζ)·(tetra)ylamino Η.Μ·[2·(5·η_2.«.^坐4_yl)-ethoxy]·benzo[b]4 phen.7. }_propionic acid (10), which was subjected to a procedure similar to that described in Example 丨(4)] to give [cyclomic]-2-Μ-methyl·3.oxy_3_ as a pale yellow solid. (4_Trifluoromethylphenyl)_(Ζ)-propyl-denylamino]-3_{4_[2-(5-methyl 2phenyloxazol-4-yl)·ethoxy]-stupid And [b]p-cephen-7-yl}-propionic acid. MS : 635.1 (M+H) + , 591.1 NMR: (CDC13, 1H, &lt;5, TMS, 300 MHz) 1.59 (s, 3H), 2.39 (s, 3H), 3.04-3.09 (t, J=6 , 2H), 3.23- 3.28 (m, 1H), 3.53.3.59 (m, 1H), 4.30-4.34 (t, J=6, 2H), 4.67 (m, 1H), 5.53 (s, 1H) 6.67- 6.70 (d, J=7,1H), 7.10-7.12 (d, J=7,1H), 7.29-7.31 (d, J=5,1H), 7.40- 7.48 (m,4H), 7.61-7.64 ( d, J=7, 2H) 7.92-7.97 (m, 4H), 1 1.93- 1 1.96 (d, J=8, 1H), COOH Very see 0 Example 107 __- 153 - This paper scale applies to Chinese national standards ( CNS) A4 specification (21〇X 297 mm) 1328585 A7 B7 150 V. Invention description (~~~- 4 - a) - Ethyl thiophene-7m_r3-language 3 - Ganzi J private ~^· - 3 - the original -1 - three i - even - 0.41 ml (2.3 m moles) of N_ethyl diisopropylamine at less than 5 &lt;&gt;c to add 347·347 g in the illusion. .77 mmoler) [racemic]-2-amino 3-{4-[2-(5-methyl_2-phenyl" No. _4_yl)-ethoxy]_ Benzo[b]bend _7-yl}. Propionic acid ethyl vinegar and 〇322 g (ι 16 mmol) (E/z) _ 3 bromo 4'4,4-difluoro 丨 苯 benzene -Dodd·2·Conclusion_ι·ketone [pcT... appl(2_),W In the solution of 0__2A1], the reaction mixture was stirred under a dish for 18 hours. It was then diluted with water and extracted with ethyl acetate. Will. The organic phase was dried over MgS04 and evaporated. The resulting residue was purified by flash chromatography (yield, eluting solvent: gradient of hexanes and ethyl acetate) to yield a yel of 49 g (98%) as a light yellow solid. 3-{4-[2-(5-Methyl-2-phenyl-carbazole-4-yl)-ethoxy]benzo[b]thiophen-7-yl}-2-[3-oxy _3_Phenyl-indole-trifluoromethyl·(ζ)_propyl-phenylamino]-propionic acid B. MS: 649.2 (Μ+Η)+. NMR : (CDClj, 1H, δ, TMS, 300MHz) 1.15 (t, J=6, 3H), 2.38 (s, 3H), 3.03-3.07 (t, J=6, 2H), 3.27- 3.34 (m, 1H), 3.40-3.47 (m, 1H), 4.10-4.17 (q, J = 6, 2H), 4.37 (t, J=6' 2H), 4.70-4.73 (m, 1H), 6.22 (s, 1H) ), 6.71-6.74 (d, J=7' 1H), 7.11-7.14 (d, J=7, 1H), 7.30-7.32 (d, J=5, 1H), 7.40- 7.49 (m, 7H), 7.87- 7.99 (m, 4H), 10.96- 10.99 (d, J=95 1H) » ' ___- 154 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 public) 1328585 A7 B7 Description of invention (

Its 1. base II·! ΐ diylethyl I cap _L_^_ and 丨bl44-7- 丄-2 r , —. - 3 - ^ ^ - 1 -; acute methyl _ G) - propyl A Bu 呙 e e 1 A 4 In a procedure similar to the semi-precise J 说明 described in Example 1 〇 5b], [racemic] _3 {4_ [-(5-methyl: 2 phenyl, VII 4) .) ethoxy] benzo (10) phenan _7_ _} 2 [3 oxy-3-phenyl·ι_trifluoromethyl (7) propylamino) propionic acid ethoxylated as a rose solid [Racecycline]-3-Η-[2-(5-Methyl-2-jujuazol-4-yl)-ethoxy]• Stupid~[b]B-Septene_7-base} 2_[3_oxy. 3-phenyl-1·trifluoromethyl_(Z)-propionylamino]•propionic acid. MS: 619.0 (M-H)-, 575.0. NMR. (CDC13, 1H, &lt;5, TMS, 300 MHz) 2.37 (s, 3H), 3.02-3.06 (t, J = 6, 2H), 3.39 - 3.45 (m, 2Ji), 4.22-4.26 (t, J=6, 2H), 4.77-4.81 (m, 1H), 6.23 (s, 1H), 6.65-6.68 (d, J=7, 1H), 7.15-7.18 (d, J=7, 1H), 7.26 - 7.28 (d, J=5, 1H), 7.38- 7.51 (m, 7H), 7.85- 7.95 (m, 4H), 11.01-11.04 (d, J=9, 1H), COOH is very wide. Example 108 3~|4-decyloxy-5,6,7,8-tetra. Stupid-1-Lemoral Disk In a procedure similar to that described in Example 91b], 5-decyloxy-1,2, 3,4-tetrahydroanthracene [J. Org. Chem. (2001), 66(5), 1775-1780] is treated with di-n-methyl oxime ether and titanium tetra-titanate to obtain a yellow solid. -decyloxy-5,6,7,8-tetrahydroindole-1-carboxaldehyde. MS: 266_2 (M), 91.2. NMR : (CDC13, 1H, δ , TMS, 300MHz) 1.78- 1.82 (m, 4H), -155 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 public) 1328585 A7 _ B7______ V. Invention Description (152) 2.74-2.76 (m, 2H), 3.18-3.20 (m, 2H), 5.16 (s, 2H), 6.84- 6.87 (d, J=7, 1H), 7.34- 7.45 (m, 5H) , 7.63-7.66 (d, J=7, 1H), 10.12 (s, 1H). Bl丨 racemic 2-ethyl-2-yl- 3-(4- with a certain-5,6.7 tetradec-1-yl; propylacetate in a procedure similar to that described in Example 93 a], 4 -benzyloxy-5,6,7,8-tetrahydrocha-1-carboxyaldehyde and gasified (ethoxyethoxycarbonylmethyl)triphenyl scale [Tetrahedron 50 (25), 7543-56-(J_994 The reaction was carried out to give ethyl 3-(4-decyloxy-5,6,7,8-tetrahydroindol-1-yl)-2(Z,E)-ethoxypropionate. Description of 91(1), with 3-(4-benzyloxy-5,6,7,8-tetrahydroindol-1-yl)-2-(Z,E)-ethoxypropionate Hydrogenation produces [racemic]-2-ethoxy-3-(4-cyano-5,6,7,8-tetrahydrocha-1-yl)propanoic acid ethyl ester as a pale yellow oil. : 310.4 (M+NH4) + , 293.4 (M+H) + , 247.3, 201.2 » NMR : (CDC13, 1H, δ, TMS, 300MHz) 1.14-1.17 (t, J=7, 3H), 1.21-1.25 (t, J=7, 3H), 1.79- 1.80 (m, 4H), 2.64-2.79 (m. 4H). 2.92-2.94 (d, J=6, 2H), 3.29-3.36 (m, 1H), 3.53-3.61 (m, 1H), 3.94-3.97 (t, J=6, 1H), 4.14-4.20 (q, J=7, 2H), 4.58 (s, 1H), 6.55-6.57 (d, J= 8, 1H), 6.90-6.92 (d, J=8, 1H) cl丨 racemic 1-2-ethenyl-3-indole 4-indole 2-(4-isopropyl hydrazine a certain -5-argon-based oxazol-4-one methyl group 1-5,6,7,8-four arrow 茬-l-yl hydrazine-propionic acid ethyl ester will be 0.037 grams (1·54 millimolar Sodium hydride is added in small portions at less than 30 ° C and under argon in 5.0 ml of Ν, Ν-dimethylformamide. 公 30 kg ___ - 156 -____ This paper scale applies to Chinese national standards (CNS) Α4 size (210 X 297 mm) 1328585 A7 __- —__B7 V. Description of the invention ((1.03 mmol) [racemic] _2 ethoxy·3 (4 via _ 5 6 7, 8 tetrahydroindole-diyl) ethyl propionate solution. After 1 minute, 〇384 g (丨.54 mol) 4·chloromethyl-2-(4-isopropylphenyl) was added. 5-5-methylcarbazole (in a procedure similar to that described in Examples 2 1 a) and 2 1 b], 4- isopropyl benzaldehyde and diethyl hydrazino monohydrazine, and then treated with P 〇 Cl 3 Derived), and then the reaction / 1⁄2. The material was mixed for a while under the temperature. It is then diluted with water and extracted by key. The combined organic phases were dried over MgSO4 and evaporated. The residue thus formed was purified by flash chromatography (yield: lysing: gradient of hexanes and ethyl acetate) to afford to be a colorless oil of 3-5 g (67%) [racemic 2-Ethoxy-3-{4-[2-(4-isopropylphenyl)-5-oxyindole_4•ylmethoxy]-5,6,7,8-tetrahydroanthracene- 1_base}_ethyl propionate. MS: 506.5 (M+H) +, 528.4 (M+Na). NMR · (CDC13, 1H, δ, TMS, 300MHz) 1.14-1.1 7 (t, J=7 3H), 1.20- 1.24 (t, J=7,3H), 1.27- 1.28 (d, J=7, 6H ), 1.76 (m, 4H), 2.42 (s, 3H), 2.70-2.75 (m, 4H), 2.94-2.96 (m, 3H), 3.31-3.35 (m, 1H), 3.55- 3.59 (m, 1H) ), 3.96-3.99 (t| j=7, 1H), 4.14-4.19 (q, j=7, 2H), 4.97 (s, 2H), 6.74-6.76 (d, 3=S, 1H), 6.98- 7.00 (d, J=8, 1H), 7.29-7.31 (d, J=8 2H), 7.92-7'94 (d, J=8, 2H). ' cn 丨 丨 性 卜 · · · · · · i i i i i i i i i i i i i i i i i i i i i i i i i i 某 某 某 某 某 某 某 某 某 某91e] In the illustrated step, [racemic ethoxy-3-{4-[2-(4-isopropylphenyl)-5.oxy). Saponin-4_ylmethoxy]5,6'7,8-tetrahydroindole-indole-yl}-propionic acid ethyl ester saponified into a colorless solid [external-157 - This paper scale applies to Chinese national standards ( CNS) Α4 size (210 X 297 mm) ' ------- 1328585 A7 B7 V. Description of the invention (154 旋性)-2-ethoxy- 3-{ 4-[2-(4- Propyl strepto)·5-oxycarbazole_4-ylmethoxy]-5,6,7,8-tetrahydroindole-indole_yl}•propionic acid MS: 476.2 (Μ-Η), NMR : (CDCI3, 1H, δ, TMS, 300MHz) I. I 1 - 1.1 5 (t, J=9, 3H), 1.26- 1.29 (d, J=8, 6H), 1.74- 1.76 (m, 4H ), 2.43 (s, 3H), 2.65-2.97 (m, 6H), 3.07-3.12 (dxd, 丨=4, J2=13, ih) 3.29-3.35 (m, 1H), 3.50-3.56 (m, 1H), 3.98-4.03 (dxd, 1, = 4, J2=8, 1H), 4.97 (s, 2H), 6.75-6.78 (d, J=7, 1H), 7.〇l-7.〇4 (d, J-7, 1H), 7.28-7.31 (d, J=7, 2H), 7.91-7.94 (d, j=7 2H), COOH is very broad. ' ' Example 109 L racemic 1 II 2-Ethoxy-J^·(5_甲篡-2•苇--oxy)-5,6,7,8-tetrakis-preparation-1-kib is similar to Example 1 08c] In the illustrated step, 4-chloromethyl-5-methyl-2-phenyl-α in hydrazine, hydrazine-dimethyl ketoamine Treatment of [racemic]-2-ethoxy-3-(4-hydroxy-5,6,7,8•tetrahydroindole-yl)propionic acid ethyl ester with azole and sodium hydride to produce [examination .Cyclosyl]-2-ethoxy 3-(4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-5,6,7,8-tetrahydroanthracene Ethyl propionate, which was saponified to a colorless solid [r-[rho]]-2-ethoxy-3-[4-(5-methyl-2-) -Phenyl-carbazole_4·ylmethoxy^5,6,7,8-tetrahydroindol-1-yl]-propionic acid_. ^ MS : 434.3 (M-Η)·. NMR : (CDCI3 , 1H, δ , TMS, 300MHz) 1.1 1 - 1. ι 5 (t J=? 3H), 1.69- 1.82 (m, 4H), 2.44 (s, 3H), 2.66-2.94 (m, 5H)' - 158 - 1328585 A7 B7 155 V. INSTRUCTIONS (3-07-3.12 (m, 1H), 3.29-3.37 (m 1H)j 3.5〇-3.57 (m, 1H), 4.00-4.03 (m,1H), 4.99 (s, 2H) 6 76 6 78 (8), Bu 8, ih), ^02-7.04 (d, J=8, 1H), 7.43-7.47 (m, 3H), 8.00-8.02 (m, 2H), COOH Very wide. Example 1 10 • Ethene gas. In a step-sound similar to that described in Example Ha], [racemic]·2 ethoxy 3 (4-3⁄4-yl-5,6,7,8- Tetrahydroindole_丨_yl)ethyl propionate (example (7)❿]) and 2-[2-(2-ethoxy-4-fluorophenyl)_5-methylcarbazole-4-yl]ethanol (example) 95) reacting in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to produce [racemic] 2 -ethoxy _3_(4_{2-[2_(2_ ethoxy) Ethyl 4-(fluorophenyl)-5-mercaptoindazole-4-yl]ethoxy bromide 5 6,7 8 · tetrahydroindenyl) propionic acid ethyl ester, which is similar to Example 9le] The step is further saponified to give [racemic]_2_ethoxy·3·(4-{2-[2-(2-ethoxy-4-fluorophenyl)-5) as a typical solid. - thiol &quot; No. -4-yl]ethoxy}-5,6,7,8-tetra or naphthyl-1-yl)propionic acid. MS: 510.3 (M-H)_. NMR : (CDCI3, 1H, 6 , TMS, 300MHz) 1.10-1.14 (t, J=7&gt; 3H), 1.44-1.47 (t, J=7, 3H), 1.67-1.82 (m, 4H), 2.36 ( s, 3H), 2.63- 2.75 (m, 4H), 2,86- 2.92 (m, 1H), 2.97-3.00 (t, J=6, 2H), 3.06-3.10 (m, 1H), 3.30-3.36 (m, 1H), 3.47-3.55 (m, 1H), 3.97-4.00 (m, 1H), 4.07-4.13 (q, J=7, 2H), 4.18-4.21 (t, J=7, 2H), 6.62-6.64 (d, J=8, 1H), 6.67-6.72 (m, -159 This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) Gutter 1328585 A7 B7 V. Description of invention (156) 2H), 6.97-6.99 (d, J=8, 1H), 7, 80-7.84 (m, 1H), COOH is very broad.

Example III L-external 1-2-ethoxy group. Stupid ·) -5-A 1] 噢-4-yl 1 ethoxy b 5,6,7,8 -tetraxin - 丨-其)propionic acid in a procedure similar to that described in Example 1 7a], [racemic] _ 2 ethoxy 3-(4-1⁄2 yl - 5, 6, 7, 8 - 4 Wind tea-i_base) propionic acid ethyl vinegar (example i〇8b)) with 2-[2-(4-fluoro-secretyl)-5-mercapto-dimethyl-4-yl]ethanol [j. Med Chem. (1998), 41(25), 5037-5054] reacts in the presence of triphenylphosphine and DEAD (azodi-acid-ethyl) to produce [racemic]-2-ethoxy 3-(4-{2-[2-(4-fluorophenyl)-5-methyl). sit-4-yl]ethoxy) 5,6,7,8-tetrahydroindole-1 -yl)ethyl propionate, which was further saponified in a procedure similar to that described in Example 9ie] to give [racemic] 2-ethoxy-3-(4-{2-[2 -(4-Fluorophenyl)-5-methyloxazole_4.yl]ethenyl-5,6,7,8-tetranorazin-1-yl)propanoic acid. MS: 466.2 (Μ-Η) —, 422.3. NMR : (CDC13, 1H, 5, TMS, 400MHz) l.i2 (t, J=7 2 3H) 1.74 (m, 4H), 2.37 (s, 3H), 2.62-2.92 (m, 5H), 2.97 ( / J=6.4,2H),. 3.09 (dxd,Ji = 4, J2= 14.4,1H)' 3.3 i_ 3 35 ' 1H), 3.49- 3.53 (m,1H), 3.98-4.01 (m,1H), 418·4 23 阳, 2H), 6.63'(d, J=8, 1H), 6.98 (d, J=8, 1H), 7 〇9 7 13 (7)' 2H), 7.94-7.98 (m, 2H) , COOH is very wide. (Print, example 1 12 i outside M-sex 2-ethoxy a stupid

_____- 160 - This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1328585 A7 ______B7 V. Invention description (~~) ' !g 吐-4-一一丙氧卜5.6,7, 8-tetramine 芄 丨 某 某 丙 丙 丙 丙 丙 丙 丙 丙 丙 丙 丙 丙 丙 丙 丙 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 外 外 外 外 外 外 外 外 外 外 外 外 外 外 外 外,8-tetrahydroanthracene-fluorenyl-propionate ethyl ester (Example 1〇8b]) with 3-[2-(4-methoxyl)·5-methylηη吐_心基]丙Alcohol (Example 42e)) is reacted in the presence of diphenylphosphine and DEAD (diethyl azodicarboxylate) to give [racemic]-2-ethoxy-3-(4-{3- [2-(4-Methoxyphenyl)-5-mercapto-3-oxazol-4-yl]propoxybu 5,6,7,8-tetrahydroindole-1-yl)propionic acid ethyl ester, It is further saponified in a similar manner to that described in Example 9 1 e] to give [racemic]-2-ethoxy_3_(4-{3-[2-(4-) as a coloring solid.曱oxyphenyl)-5-methyl. oxazol-4-yl]propoxy}· 5 6 7 8_tetrahydroindole_丨_yl)propionic acid. MS: 492.2 (Μ-Η)·, 448.3. NMR : (CDC13, 1H, 5, TMS, 400MHz) 1.11 (t,3H), 1.74 (m,4H), 2.13 (t,J=6.4,2H), 2.24 (s,3H),2.66-2.93 (m , 7H), 3.08 (d, J = 12.4, 1H), 3.32 (m, 1H), 3.55 (m, 1H), 3.84- 3.98 (m, 6H), 6.57 (d, J=8.4, 1H), 6.93 (d, J=8.8, 2H) 6.99 (d, J=8.4' 1H), 7.90 (d, J=8.8, 2H), COOH is very wide. Example 1 1 3

Li 纳旋旋卜 2-ethoxy- 3-(4-(2 - "5-甲某- 2-(4-三病甲节节赢丄哇哇-4-yl 1 ethoxy.} 5,6,7,8 2 stupid-丨·, and in the steps similar to the example 丨7a], [racemic]_ 2_ethoxy-3-(4-3⁄4 base- 5,6,7,8-tetrahydrocha-1-yl)propionic acid ethyl ester (example i〇8b)) with 2-[5-mercapto-2-(4-trifluoromethylphenyl)carbazole _4_yl]ethanol (in a similar manner to Examples 2U) to 21e], converted with 4-trifluoromethylbenzaldehyde __- 161 - This paper scale uses Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 1328585 A7 B7

Manufactured as 2-[5-fluorenyl-2-(4-trifluorodecylphenyl)" azole-4-yl]ethanol) in triphenylphosphine and DEAD (diethyl azodicarboxylate) Reaction in the presence of ) to give [racemic]-2-ethoxy-3-(4· {2-[ 5-methyl·2·(4-trifluoromethyl) carbazole-4 -Ethyl]ethoxy}-5,6,7,8-tetrahydroindole. 1-yl)propionic acid ethyl ester: it was further subjected to a procedure similar to that described in Example 9丨e] to give a colorless Solid [racemate]-2-ethoxy-3-(4-{2-[5-methyl_2(4-difluoromethylphenyl)"oxazol-4-yl]ethoxylate Base}-5,6,7,8-tetrahydronaphthalene·bupropion) Propionic acid. - Soil MS : 516.2 (MH)*, 472.1 NMR : (CDC13, 1H, TMS, 300MHz) I.13 (t, J=7.〇, 3H) 1.69-1.80 (m, 4H), 2.40 (s , 3,,,,, 4.20 (t, J=6.4, 2H), 6.63 (d, J=8.4, 1H), 6.99 (d, J=8.4, 1H), 7.66 (d, J=8.2, 2H), 8.08 (d, J =8.1, 2H), COOH is very wide. , , Example 丨14 al gasification (benzyloxycarbonyl oxime, a methyl group), three 苽 将 一 一 一 一 一 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Mohr) Dissolve 5 ml of dioxane and 5 ml of water at 〇 °c and place the reaction mixture in hydrazine. (: stirring for 3 minutes and stirring at room temperature for 0.75 hours. Then it was diluted with tBuOMe and washed with i mole of ice. The aqueous layer &amp; was converted to pH 2 and extracted with AcOEt three times, the combined organic phase was NasSO4 is dried and evaporated to give a dimethoxyacetic acid (600 mg) as a yellow oil. The dimethoxy acetic acid obtained in a similar manner is used. 162 - This paper scale applies to the Chinese National Standard (CNS) A4 size (210 X 297 mm) 1328585 A7 ._______B7 V. Description of the invention (159) (8.86 g, 73·8 mmol) dissolved in 1 ml of acetonitrile at 0 ° C, followed by sterol (7.33⁄4 liters, 70 millimoles), EDCI (15 &amp; gram, 8 mM molars) and DMAP (855 mg, 7 millimoles) and maintain the reaction mixture at room temperature for 18 hours. It is diluted with AcOEt, washed with water, 1 gram of molecular weight HCI, brine, NaaCOd 1 〇%) and then with brine, and the combined organic phases are dried over NadO4 and evaporated to give benzyl dimethoxyacetate ( 10.4 grams). Ethyl xenon (2 ml) and iodine (1 mg) as a catalyst were added to the crude dimethyl dimethoxyacetate (4.86 g-g), and the mixture was heated at 65 for 4 hours while being added. After evaporation of 100 ml of ether, it was diluted with EtOAc (m.sub.2) (CH.sub.2), and added to a solution of triphenylphosphine (25 mM, 6.63 g) in 50 ml of CH2C12 and stirred at room temperature for 24 hours. The chlorinated (芊 oxycarbonylmethoxymethyl) triphenyl scale (6.87 g. 62°) was obtained as a white foam by chromatography (chromium sulphate '0.6 kg, dissolved in AcOEt/amp; l/l of AcOEt/ethanol). /.). MS: (M+H+)+ 442.3. NMR (CDC13, 1H, 6 , TMS) 3.91 (s, 3H), 4.92-5.17 (d, 2H), 6.98 (dxd, 2H), 7.19-7.31 (m, 3H), 7.55-7.90 (m, 15H) , 8.64 (br.d, 1H) » U 3-甲某-4-丨2-(5-甲某-2-苽某-哼azole-4-某)-乙气一一笨醛 will be at 400 4-hydroxy-3-methylbenzaldehyde (9 g '.66.10 mmol), methane, acid 2-(5-methyl-2-phenyl-carbazole) -4-yl) Ethyl ester [PCT Int. Appl. (2000) W00008002] (22.5 g, 80 mmol) 'ΚΟΗ (80 mmol, 4.48 g) and tetrabutylammonium hydrogen sulfate (2 g) Heat at 80 ° C for 17 hours. The reaction mixture was then cooled to zero. (:, with water ------163 -____ This paper scale applies Chinese National Standard (CNS) A4 specification (21〇x 297 mm) 1328585 A7 B7 160 V. Invention description (/Ice and saline cleaning The aqueous layer was extracted with tBuOMe, and the combined organic layers were dried over Na 2 S 〇 4 and evaporated. The crude product was purified by chromatography (Si 〇 2 : AcOEt / hept) and crystallized from heptane to produce 5 克 (72%) of the title compound as a white solid. MS: (M+H+) + 322.3, (2M+H+) + 643.2. NMR (CDCl3, lH, 5, TMS): 2.23 (s, 3H), 2.38 (s, 3H), 3.03 (t, 2H), 4.35 (t, 2H), 6.94 (dxd, 1H), 7.40-7.45 (m5 3H), 7.66-7.68 (m, 2H), 7.96-. (m, 2H), 9.83 (s, 1H). (:12(27£)-1_oxy-3-{3-甲某_442_(5-甲某-2-苽某-噚岫· 4..-Shame)-Ethoxy-1-moxa-l-butene g* oxime ester 3-methyl-4-[2-(5-methyl-2-phenyl-indazole-4·yl) )-ethoxy]-benzene station (540 mg ' 1.68 mmol) dissolved in 2 ml of ch2C12 and cooled at 0 ° C 'added gasification (benzyloxycarbonyl methoxymethyl) triphenyl scale (丨. 04 grams, 2. 丨 8 millimoles) 'Next join 丨I,3,3_tetramethylguanidine, and the reaction mixture was stirred at room temperature for 3 days, more of the two sulfonium salts and bases (1 equivalent each) were added. The reaction mixture was diluted with AcOEt to a molecular weight of 1 gram. HC1 ice and brine were washed, the aqueous layer was extracted with AcOEt, and the combined organic phases were dried over Na 2 SO 4 and evaporated. The crude product was purified by chromatography (Si〇2; AcOEt/heptane) to leave 6 〇 5 mg (74%) of the title compound. MS: (M+H+) + 484.4 NMR (DMSO-d6, 1H, &lt;5, TMS): 2.10 (s, 3H), 2.36 (s, 3H), 2.96 (t, 2H), 3.67 (s, 3H), 4.25 (t, 2H), 5.25 (s, 2H), 6.81 (s, 1H), 7.00 (dxd, 1H), 7.30- 7.63 (m , 10H), 7.90-7.92 (m, 2H). 164 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm). Ordering 1328585 A7 B7 V. Invention Description (161) Magic _.丄 and racemic 1-2-A 氲-3 "3-methyl-4-"? -(5-甲某-2-苽一-°号°坐·4_棊)--A certain gas, a certain dipropionic acid, treated with 10% Pd-C, dissolved in 5 ml of ethanol, 2 (Ζ, Ε) -Methoxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-°oxazol-4-yl)-ethoxy]-phenyl}-propyl hoof Benzyl acetate (6 mg, 1 - 24 mmol) was stirred vigorously at room temperature under a pressure of 7 hr. This was then evaporated over EtOAc EtOAc (EtOAc) (EtOAc:EtOAc: MS : (Μ-Η.)· 394.2. NMR (DMSO-d6, 1H, TMS): 2.05 (s, 3H), 2.36 (s, 3H), 2.71-2.76 (2xdxd, 2xlH), 2.92 (t, 2H), 3.20 (s, 3H), 3.81- 3.85 (m, 1H), 4.16 (t, 2H), 6.84 (dxd, 1H), 6.95-6.97 (m, 2H), 7.48-7.50 (m, 3H), 7.90-7.92 (m, 2H), 12.80 ( Br.s, 1H). Example 1 1 5 f racemic 2-methoxy-3-oxime 3-methylhydro-4-"2-(5-methyl-2-pyrimidin-4-yl)-B I. The base of the vanillyl group and the methanesulfonic acid 2-(5-methyl-2-phenyl-indoleazole-- 4-yl)ethyl ester [PCT Int. Appl_(2000) W00008002] to give 3-methoxy-4-[2-(5-methyl-2-phenyl-phenylindole-4-yl)- Ethoxy]-benz. Treatment of 3-methoxy-4-[2-(5-methyl-2-phenyl-oxazole) with gasification (octyloxymethyloxymethyl)triphenyl 4-yl)-ethoxy]•benzaldehyde, followed by 2(Z,E)-methoxy-3·{3-methoxy-4-[2-(5-methyl-2-benzene) Base-carbazol-4-yl)-ethoxy]-phenyl}-propyl_- 165 -_____ This paper size applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) Binding

线1328585 A7 '____B7 V. INSTRUCTION DESCRIPTION (162) Iridinium + ester, which is hydrogenated to give a colorless solid [racemic 2-methoxy-3-methoxy- 4- [2-(5-Methyl-2-phenyl]-oxazole-4-yl)-ethoxy]-phenyl}-propionic acid. MS : ( Μ-Η)· 410.4. NMR (DMSO-d6, 1H, δ, TMS): 2.36 (s, 3H), 2.76 (dxd, 1H), 2.86 (dxd, 1H), 2.91 (t, 2H), 3.21 (s, 3H), 3.71 ( s, 3H), 3.84- 3.88 (m, 1H), 4.14 (t, 2H), 6.70 (dxd, 1H), 6.82 (d, 1H), 6.85 (d, 1H), 7.46-7^.52-( m, 3H), 7.89-7.92 (m, 2H), 12.90-(br.s, 1H). Example 1 1 6

Ll i exogenous, spin, axillary ΐ - 2 · ethoxy storm - 3_ (4--3-methyl free & benzophenone) propionic acid BIL. In a procedure similar to that described in Example 93a], 4_ The reaction of methoxy_3_methoxybenzene with gasified (ethoxyethoxycarbonylmethyl)triphenylhydrazine [Tetrahedr〇n 50(25), 7543-56 (1 994)] to give 3_( 4-octyloxy-3-methoxyphenyl)-2(Z,E)-ethoxypropionic acid. As illustrated in Example 9 1 d], hydrogenation of ethyl 3-(4-benzyloxy-3-methoxyphenyl)-2(Z,E)-ethoxy acrylate yielded a colorless solid. Racemic] _ 2_ethoxy-3-(4-hydroxy-3-methoxyphenyl)propanoic acid ethyl ester β MS : (Μ) + 268.1. NMR (DMSO-d6, 1H, δ, TMS): l.〇3 (t, 3H), 1.12 (t, 3H), 2.80 (dxd, 2H), 3.30-3.40 (m, 1H), 3.42-3.52 ( m, 1H), 3.73 (s, 3H), 4.01-4.09 (m, 3H), 6.57 (dxd, 1H), 6.65 (d, 1H), 6.77 (d, 1H), 8.74 (br.s, 1H) . __- 166 - This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1328585 A7 B7 V. Invention description (163) k!_L racemicity]-2-Ethyl -3- ( 3-methyl hydrazine -4- "2-(5-methyl-2-pyridyl-p-azol-4-yl)-ethyl acesulfame ethyl ester in a similar example 丨7a] In the step, [racemic]-2-ethoxy-3-(4-hydroxy-3-methoxyphenyl)propanoic acid ethyl ester with 2-(2-phenyl-5-methylindole) Zyzol-4-yl)ethanol is reacted in the presence of triphenylphosphine and DBAD (di-tert-butyl azodicarboxylate) to produce [racemate]-2-ethoxy-3- as a colorless oil {3-Methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester. - II. MS : (M+H+)+ 454.3,(M+2H+)+ 455.2. gl ί racemic 1-2-ethane a certain -3-U-methyl -4-(2-[5-methyl-2) - mercapto azole _4_yl)-ethyl benzene 1-phenyl hydrazine-lithium propionate [racemic]-2-ethoxy-3-{3-methyl-oxy-4-[ 2-(5-Methyl-2-pyromyl-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester (306 mg, 0.67 mmol) dissolved in 3 mL of dioxane and Add 2 mg to 2 ml of water Lithium oxide was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was then chromatographed with a lithium salt (MCI-gel; CH.sub.3CN/H.sub.2) to give a white powder of 125 mg (43%). MS: (MH) · 424.4. NMR (DMSO-d6, 1H, 5, TMS): 0.98 (t, 3H), 2.36 (s, 3H), 2.55 (dxd, 1H), 2.80 (dxd, 1H) , 2.85 (t, 2H), 3.05-3.15 (m, 1H), 3.48 (dxd, 1H), 3.52--3.62 (m, 1H), 3.70 (s, 3H), 4.13 (t, 2H), 6.67 ( Dxd, 1H), 6.80- 6.83 (m, 2H), 7.47-7.51 (m, 3H), 7.92 (dxd, 2H). Example 1 1 7 _- 1β7 - Table paper scale applicable to China National Standard (CNS) A4 specification (210x 297 mm) 1328585 A7 B7

V. INSTRUCTIONS OF THE INVENTION (f-external) -3 -yl)-ethoxy 1-indole-2-carbopropionic acid in a procedure similar to that described in Examples 1 14b], c] and d] , 3 5 dimethyl-4-hydroxybenzaldehyde and 2-(5-fluorenyl-2-phenyl-azain-4-yl)ethyl methanesulfonate [PCT Int· Appl. (2000) W00008002] The reaction was carried out to obtain 3 5 · dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxytomb]-benzaldehyde. Treatment of 3,5-dimethyl-4_[2_(5-methyl-2-methylene-hydroxy-4-yl)-&lt; gas base with gasification (芊 oxycarbonylmethoxymethyl)triphenyl scale ]-benzoic acid, followed by 3_{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}- 2 (Ζ,Ε)·benzyl methacrylate, which is hydrogenated to give [racemic]-3-{3,5-dimethyl-4-[2-(5) as a pale yellow oil. -Methyl-2.phenyl-indazol-4-yl)-ethoxy]-phenyl-2-methyl-propionic acid. MS: (M-H)· 408.2. NMR (DMSO-d6, 1H, 5, TMS): 2.09 (s, 6H), 2.38 (s, 3H), 2.67-2.80 (2xdxd, 2xlH), 2.91 (t, 2H), 3.20 (s, 3H), 3.84-3.90 (m, 1H), 3.95 (t, 2H), 6.82 (s, 2H), 7.45-7.55 (m, 3H), 7.92 (dxd, 2H), 12.8 (br.s, 1H). Example 1 1 8 al 2 -Lightyl-4-"2-(5-methyl-2-phenyl-co-g-all-4-yl)-ethoxy. Some: Bu will be in 20 ml of THF A solution of 2,4-dihydroxybenzaldehyde (2 g, 14.5 mmol) was cooled to 0 ° C. Triphenylphosphine (9.7 g, 37 mmol), 2-(2-phenyl-5-A) Ketrazole-4-yl.)ethanol (2.84 g, 14 mmol) and finally dibutyl azodicarboxylate (8.5 2 g, 3 7 m) in 20 ml of THF over a period of 0.75 h A solution of Mohr) is added to the solution. Mix the reaction ------ ifift - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) 1328585 A7 ____ B7 V. Description of invention (165 The material is allowed to stand at room temperature: it is stirred overnight, evaporated to dryness, purified by chromatography (Si 〇 2; AcOEt / heptane), and the product is crystallized from AcOEt / ether / heptane to give a smear solid. 2.2 g (46%) product NMR (CDC13, 1H, 5, TMS): 2.37 (s, 3H), 2.97 (t, 2H), 4·31 (t, 2H), 6.44 (d, 1H), 6.53 (dxd, 1H), 7.39-7.43 (m, 4H), 7.95-7.99 (m, 2H), 9.70 (s, 1H), 11.42 (s, 1H). 2-(4-methoxyindenyl) -4-"2-( 5-A-A-2-Butm-S-oxazol-4-yl)-I-oxyl-furfural will be 2-amino-4-[2-(5-A) in 6 ml of acetaminophen and 5 ml of water Benzyl-2-phenyl-[嗤-4-yl)-ethoxy]benzaldehyde (54 mg, 0.167 mmol), 4-methoxybenzyl gas (58 mg, 0.368 mmol) The mixture of hydrazine (56 mg, 1 mmol) and tetrabutyl hydrogen sulphate (5 〇 mg) was heated at 8 〇ec for 6 hours. The reaction mixture was then cooled to 〇t with water/ice and salt. Water-washing' The aqueous layer was extracted with AcOEt, and the combined organic layers were dried and evaporated over Na.sub.2, and the crude product was purified by chromatography (Si.sub.2; AcOEt/heptane) and crystallized from heptane. To give a product of 25 mg (34%) as a white solid. MS: (M+H+) + 444.4, (M+Na+)+ 466.3 = NMR (CDC13, 1H, δ, TMS): 2.37 (s, 3H) , 2.99 (t, 2H), 3.82 (s, 3H), 4.31 (t, 2H), 5.06 (s, 2H), 6.52 (d, 1H), 6.55 (dxd, 1H), 6.91 (d, 2H), 7:33 (d, 2H), 7.40-7.43 (m, 3H), 7.80 (d, 1H), 7.98 (dxd, 2H), 10_32 (s, iH). £]2(2,£)-Methane-based-3-{2-(4-Methane-based oxime)-4『2_(5_Methyl_ 夺基-坐-4-yl)-Ethoxy Base 1 - Packing 丨 - 丙余 brewing y啼 ____ - 169 - This paper scale applies to China National Standard (CNS) A4 specification (210 K 297 mm) 1328585 A7 __B7 V. Invention Description (166) (4-methoxydecyloxy)_4-[2-(5-methyl-2-phenyl-σ-oxazol-4-yl)-ethoxy]-benzaldehyde (400 mg, 0.90 mmol) Dissolve 2 ml of CH2C12 and cool to 〇 °C 'Add chlorinated (benzyloxycarbonylmethoxymethyl) triphenyl scale (Example 114a)) (1.04 g, 2.18 mmol), then add l, l, 3,3-Tetramethylhydrazine (丨 ml '8 mmol), and the reaction mixture was stirred at room temperature for 3 days, then diluted with AcOEt, washed with HC1 (1 g molecular weight) / ice and brine The aqueous layer was extracted with AcOEt. The combined organic phases were dried over Na 2 SO 4 and evaporated. The crude product was purified by EtOAc (EtOAc) (EtOAc) elute -MS : (M+H+)+ 606.0, (M+Na+)+ 628.1. 41 f racemic 1-3-(2-鼗-4-(2-(5-methyl-2-methyl-oxazol-4-yl)-ethoxy 1-phenyl]-2 -Methane a propionic acid - 2(Z,E)-methoxy-3-{2-(4-methoxyindolyl)-4-[2-(5-methyl-2-phenyl) -carbazole _4·yl)-ethoxy]-phenyl benzyl acrylate (360 mg, 0.6 mmol) dissolved in 5 mL of AcOEt and the reaction mixture in the presence of 10% Pd-C And vigorously stirring for 18 hours at room temperature under H2 pressure. Then it was filtered through C salt, evaporated, chromatographed (MCI-gel, CH3CN, H20) and crystals (AcOEt/heptane) to give 30 mg (1 3%) of the title compound as a white solid. MS: (M+H+) + 398.3 ° NMR (DMSO-d6, 1H, 6, TMS): 2.36 (s, 3H), 2.55 (dxd, 1H), 2.87-2.92 (m, 3H), 3.25 (s, 3H), 3.46 (m, 1H), 4.10 (t, 2H), 6.24-6.26 (m, 2H), 6.90 (d, 1H), 7.48-7.50 ( m, 3H), 7·90·7_92 (m, 2H), 12.80 (br.s, 2H). ____- 170 -__ This paper scale applies to Chinese national standards (CNS> A4 size (210 x 297 mm) 1328585 A7 B7 V. INSTRUCTIONS (167 EXAMPLE I 1 9 ^(2, £)-._X-Oxocarbonylamine A-3-{3- -4-"2-(5-甲某-2-莫甚-4 -yl)-ethoxy oxabene 丨 锍 锍 锍 将 将 将 N N (卞 羰 carbonyl) · α - dioxophos Trimethyl sulphate (773 mg, 2 33 moles) and then added to the 3-methyl-4-[2] cooled to 2 mL and 1 mL of THF. -(5-Methyl-2-phenyl-5-prop-4-yl)-ethoxybenzaldehyde (5 mg, 156 mmol) (Example 1 14b)) The admixture was stirred at room temperature for 6 hours. It was then diluted with AcOEt, washed with HC1 1 g molecular weight/ice and brine, and the aqueous layer was extracted with AcOEt. The combined organic phases were dried over 1×3D4. And evaporation. The crude product was purified by chromatography (EtOAc: EtOAc (EtOAc): EtOAc (EtOAc) : (M+H+)+ 527.2 NMR (DMSO-d6, 1H, (5, TMS): 2.06 (s, 3H), 2.36 (s, 3H), 2.96 (t, 2H), 3.69 (s, 3H) , 4.26 (t, 2H), 5.10 (s, 2H), 6.99 (d, 1H), 7.23-7.40 (m, 6H), 7.45- 7.55 (m, 5H), 7.90-7.92 (m, 2H), 9.01 (br.s, 1H). Kl "external 1-2-amino-3-{3-methyl- 4-f2-(5-methyl-2- laughing group? sit-4-)-ethane group 1-stupyl group - Propionate A Kubo Pound will dissolve in 2 ml of AcOEt - 2 (Z, E) -benzyloxycarbonylamino 3 - 3] 3 - methyl-4-[2-(5 -methyl-2-benzene Ketrazole-4-yl)-ethoxy]-phenyl methacrylate (552 mg, 1.05 mmol) was vigorously stirred in the presence of Pd-C at room temperature under a pressure of 16 hours. The reaction mixture is then applied to the Chinese National Standard (CNS) A4 specification (210X 297 mm) via c _____- 171 - this scale.

Binding

Line 1328085 A7 -------B7 V. Description of the invention (168) Salt 遽 'evaporation' by chromatographic separation (Si〇2; AC〇Et) and crystalline product (HC1 in the chain)' 174 mg (40 〇 / 〇) of the title compound as a white solid. MS : (m+H+)+ 395.4 » NMR (DMSO-d6, 1H, δ, TMS) : 2.07 (s, 3H), 2.37 (s, 3H), 2 93 (t, 2H), 2.95-3.06 (m , 2H), 3.67 (s, 3H), 4.18 (t, 2H), 6.89-6.99 (m, 3H), 7.47-7.52 (m, 3H), 7.90-7.92 (m, 2H), 8.45 (br.s , 3H). -- 卜消旋-性卜3-{3-Methyl·4·"2"5_甲某_2_芡某-Sakizol·4· Shame)-Ethoxyphene phenyl}-2-( 1-methyl-3-oxan-3-indole-m-propenylamino)propanoxime methyl ester in the anisole (20 ml) [racemic]_ 2_amino group · 3_ { 3 Methyl 4-[2-(5-methyl-2-phenyl-»oxazol-4-yl)-ethoxy]-phenyl}-propionic acid methyl ester [1.83 g] 4.64 mmol a mixture of phenylhydrazinone (7.52 g, 46 mmol) obtained by extraction of HC1 salt (dioxethane, aqueous sodium carbonate) was refluxed at 1 90 ° C for 3 days, evaporated, and colored. The layers were separated (Si 〇 2 ; AcOEt / heptane) and crystallized to afford 840 mg (33%) of the title compound as white powder. MS: (M+H+)+ 539.3. NMR (DMS0-d6, 1H, &lt;5, TMS): 1.88 (s, 3H), 2.03 (s, 3H), 2.33 (s, 3H), 2.93 (t, 2H), -2.95 (dxd, 1H) , 3.02 (dxd, 1H), 3.67 (s, 3H), 4.17 (t, 2H), 4.63-4.69 (m, 1H), 5.76 (s, 1H), 6.87 (d, 1H), 6.97-6.99 (m , 2H), 7.40-7.49 (m, 6H), 7.82 (dxd, 2H), 7.91 (dxd, 2H), 11.4 (s, 1H). __- 172 -_____ This paper size applies to Chinese National Standard (CNS) A4 specification (210x 297 mm) 1691328585 -173 - Description of invention (A-2-2 4, -4 base) propionic acid, disease conversion η: ο μ -^-Ώ-^k. In a procedure similar to that described in the example], [racemic methyl-4-[2·^5-methyl_2·phenyl, ..4·yl) Ethoxy phenyl bromide 2-(1-methyl-3-oxy_3_phenyl.(ζ)_propyl-propylamino)propionic acid methyl hydrazide to give W racemability] -3-{3·Methyl·4_[2·(5•methyl_2phenyl fluorenyl)-ethoxy]-phenyl}-2-(1-indolyl 2 oxy) 3-Phenyl-(indolyl)propanyl)propionic acid (0.798 g' Κ52 mmol) was dissolved in 1 mL of ethanol in the presence of triethylamine (2.28 mmol). The reaction mixture was heated to 60 ° C for 70 minutes, cooled to room temperature, and added to a solution of Ca(CH3CO?) 2 (i.sup.32 mg, 〇 84 mM) in 5 ml of water over 15 minutes. The suspension was diluted with 50 ml of water, cooled and (iv) 1 hour. The salt was separated by hydrazine, washed with 50 ml of water and dried to give an off-white solid (62 g, 75%) 〇 MS : (M-H) _ 523.1. NMR (DMSO-d6 &gt; 1H, 5, TMS): 1.65 (s, 3H), 2.01 (s, 3H), 2.33 (s, 3H), 2.68 (dxd, 1H), 2.89 (t, 2H), 3.12 ( Dxd, 1H), 3.95-4.02 (m, 1H), 4.14 (t, 2H), 5.15 (s, 1H), 6.81 (d, 1H), 6.97-6.99 (m, 2H), 7.37-7.49 ( 2m, 2x3H), 7.76 (dxd, 2H), 7.90 (dxd, 2H), 1 1.4 (d, 1H). Example 120 al 4- y oxo and 4 _ 4-hydroxybenzofuran in N,N-dimercaptocaramine (8 ml) (2.6 paper scale applicable to Chinese National Standard (CNS) A4 Specification (2 〇χ 〇χ 297 mm) Setting line 1325885 A7 B7 V. Description of invention (170) Solution of gram '1 9.4 millimoles (for preparation of 4_ benzopyrene) Reference. G. ICneen, P, J. Maddocks, Syn. Commun. 1986, 1 6,1 63 5- 1 640) Potassium carbonate in n,N-dimethylformamide (8 ml) was added under argon at 2C (2.68) In the suspension of grams ' 19.4 millimoles'. After stirring at 2 ° C for 50 minutes, benzyl bromide (3.3 ml liter ' 19.4 mmol) was added over 15 minutes at 2 °C. Place the suspension at 2. (: stirring for another 30 minutes and stirring at room temperature for another 1.5 hours. After adding ice water (20 ml), the solution was extracted twice with diethyl ether. The combined extracts were washed three times with brine and sulfuric acid. The title compound was obtained as a colorless oil (yield: EtOAc, hexane). 224.1 (M) +, 91.2. NMR: (CDC13, 1H, 400MHz, (5, TMS) 5.21 (s, 2H), 6.72 (d, J=8, 1H), 6.91 (d, J=2, 1H ), 7.14-7.26 (m, 2H), 7.31-7.42 (m, 3H), 7.48 (d, J=8, 2H), 7.54 (d, J=2,1H). bl gas base stupid and puff -7-Rolled anhydrous N,N-dimethylformamide (12.1 g, 166 mmol) was added dropwise with stirring and cooling under argon (1 1.4 g, 75 mmol) In this case, the addition speed is such that the temperature does not exceed 1 〇 ° C. After 30 minutes at 1 〇 ° c, 4- in N,N-dimethylformamide (9 ml) is added within 30 minutes. a solution of decyloxyfuran (9.3 g, _41 mmol). Stir at room temperature for 30 minutes and then continue heating to 100. (: After 10 minutes at 10 ° C, the mixture was heated at 85 ° C for 3 hours and cooled to 10 ° (:, 25% aqueous) Sodium acetate is neutralized by cooling and extracted with diethyl ether. _____- 174 -_____ This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm)

Line 1328585 A7 B7 V. Description of the invention ( 171 The extract is washed with saturated aqueous sodium hydrogencarbonate and water, and dried over sodium sulfate. The solvent is removed under reduced pressure to give a brown oil, which is obtained by column chromatography. Purification to give the title compound as a yellow oil (1.8 g, 7 mmol, 17%). MS: 252.1 (M) +, 91.1. NMR: (CDC13 , 1H, 400MHz, 5 , TMS) 5.30 (s, 2H), 6.85 (d, J=8, 1H), 6.97 (d, J=2, 1H), 7.36-7.48 (m, 5H), 7.69 (d , J=2, 1H), 7.75 (d, J=8, 1H), lO:24-(s,1H). Spit (4-benzyloxybenzopyran-7-yl)-2Z-ethyl argon I uric acid acetyl chloride (ethoxy ethoxycarbonyl. fluorenyl) triphenyl scale (2.04 g, 4.8 mmol) and 〇811 (0.8 g, 5.2 mmol) in THF (40 ml) The suspension of the ear) was argon at room temperature: mixing for 10 minutes [for the preparation of chlorinated (ethoxyethoxymethyl) methyl triphenyl scales, reference: Κ. K. Bach, H. R EI. Seedi, Η. Μ. Jensen, Η. Β. Nielsen, I. Thomson, Κ.. Β G Torssell, Tetrahedron 1994, 50, 7543-7556]. Benzofuran-7-carboxylate (〇_8 g, 3.2 mmol), and the mixture was heated under reflux for 12 h. The solvent was concentrated under reduced pressure and the residue was treated with ethyl acetate. ^C丨Aqueous saturated aqueous solution and washed twice with brine. The organic layer was dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane, hexane/Ac 〇Et = 9/l) Purification to give 0.8 g (2·2 mmol, 69%) of the title compound as a colorless oil. MS: 366.1 (Μ) +, 275.1, 173.0, 91.1. NMR : (CDC13, 1H, 400ΜΗζ , δ , TMS) 1.3 7- 1.45 (m, 6H), 4.04 (q, J=8, 2H), 4.32 (q, J=8, 2H), 5.24 (s, 2H), 6.77 (d,

Order

Line 1328585 A7 _____B7 V. Description of invention (172) J=9, 1H), 6.92 (d, J=2&gt; 1H), 7.33-7.49 (m, 5H), 7.53 (s, 1H), 7.58 (d, J =2, 1H), 8.Ϊ5 (d, J=8, 1H). Rainbow [External #旋性卜3- dy oxybenzoquinone-7·a u 2_ Λ敉 曱 两 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 In a stirred solution of ethyl 3-(4-decyloxybenzofuran-7-yl)-2-indole•ethoxy acrylate (0.8 g, 2.18 mmol) in THF and THF (13 mL). The suspension was warmed to 40 ° C until the start of hydrogen evolution. The additional magnesium dust (1 gram, 41 2 millimoles) was then heated in a water bath instead of the heating bath and the reaction mixture was continuously stirred for 12 hours. The suspension was cooled to the hydrazine and then 25% aqueous hydrochloric acid was added until all solids dissolved. The mixture was extracted twice with ethyl acetate, and the combined ethyl acetate solution was washed three times with water and dried over sodium sulfate. The solvent was evaporated to give the title compound (j.j. MS: 354.2 (M) +, 237.2, 91_2. NMR : (CDC13, 1H, 400MHz, 5 , TMS) M2 (t, J=7.2, 3H) 3.19-3.38 (m, 3H), 3.55-3.61 (m, 1H), 3.68 (s, 3H), 4.23 ( Dxd, J=8.8, J=6.4, 1H), 5.18 (s, 2H), 6.65 (d, 1H), 6.90 (d, J=2.4, 1H), 7.05 (d, J=8.8, 1H), 7.34 -7 42 (m 3H) 7.47 (d, J=8, 2H), 7.55 (d, J=2.4, 1H). ' 'g"i racemic 1·2-ethoxy-3-(4-indolyl)propanyl dimethyl sulfide (4·4 ml '6G$mol) and boron trifluoride diethyl乡纯纯-176 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1328585

173 degrees, 3.3 ml, 12 mmol), squash, gt;,,, f,,...,,,,,,,,,,,,,,,,,,,,,,, Spiral-3 (4-; 蚤其^•姓特土, (丁丁基冬和furan-7-yl)-2-ethoxypropionic acid formazan (0.85 grams, 24 tombs Jt, Shi, L· , person, . . . Moer) 疋 ice in the cold liquid. Stir the mixture at room temperature for 6 hours, pour on the ice water and _ - long after taking a scorpion to take three times. The combined extracts in saline After cleaning and aging for a long time, the work stone 4 is dried by sodium. The solvent is removed under reduced pressure to obtain a ochre oil, which will be separated by a tube layer (矽, hexane/AcOEt=4). /l) Purification, to obtain 刭成.# 乂付A becomes a light-page oil 〇45 g 7 Xuan Mo Er '71 %) Title compound.--MS : 263.0 (M-Η)·. NMR · (CDC13 , 1H, 400MHz, (5 , TMS) 1.13 (t, J=7.2, 3H) 3.19-3.41 (m,3H), 3.56- 3.65 in ' 'im, 1H), 3.67 (s, 3H), 4.22 (dxd , J=8, J=7.2, 1H), 5.04 (s, 1H), 6.54 (d, J=8.8, 1H), 6.83 (d, J=2.4, 1H), 6.99 (d, J=8:S , 1H), 7.56 (d J=2 4 1H). , Fl f 外消绿性卜2-Ethylene shy two stupid - 呤岫 · 4_ its methoxy) benzocypan -7 - a 1-two broken potassium carbonate (37 mg, 300 micromoles , 14 equivalents) and potassium iodide (mg mg, 30 micromoles, 0.1 equivalent) added to [racemic]-2-ethoxy_3_(4) in dimethyl dimethylformamide (〇5 ml) Methyl hydroxybenzofuran-7-propionate (503⁄4 g, 189 micromolar) and 4-methyl-3-methylphenyl-2-pyrazole (39 mg, 189 micromolar, ! equivalent) In the solution, the mixture was shaken at 8 Torr for 12 hours, filtered and the filtrate was evaporated in vacuo to give [racemic]-2-ethoxy-3-[4-(5-methyl) 2_Phenyl-indole _4_ylmethoxy)benzofuran-7-yl]-propionic acid methyl ester. Crude [racemic] _2 ethoxy _&gt; ____- 177 - paper Zhang scale applies to China National Standard (CNS) A4 specification (210X 297 public). Ordering 1328585 V. Invention description (174 A7 B7

[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)benzofuran_7-yl]•propionic acid A brewed in THF/ethanol/water 2: 1: 1 In the mixture. Lithium oxide (40 mg, 945 micromolar, 5 equivalents) was added and the solution was shaken at room temperature for 12 hours. The title compound (28 mg, 66 micromoles, 35%) was obtained as a white solid. MS: 420.2 (M-Η)·, 374.2, 249.1. NMR: (DMSO-d6, 1H, 400MHz, 5, TMS) l.〇〇(t&gt; J=? 2 3H). 2.46 (s, 3H), 3.09 (dxd, J=15.2, J=8, 1H) , 3.19 (dxd J=15.2, j=6.4, 1H), 3.28-3.30 (m, 1H), 3.47-3.53 (m&gt; ^ 4.13 (dxd, J=8.8, 1=5.6, 1H), 5.13 (s, 2H), 6.90 (d, j=8.〇1H), 6.91 (d, J=2.4, 1H)} 7.12 (d, J-8.0, 1H), 7.52-7.54 (m, 3H), 7.90 (d&gt; J=2.4, 1H), 7.94-7.97 (m, 2H), 12.69 (s 1H) 〇' Example 1 2 1 Ethyl-3- "4-(5-methyl-2-4) Oral.d shy ^methyl keto and p denor-7-yl 1-propionic acid in a procedure similar to that described in Example 120f], 2-ethoxy _3_(4_ via phenyl). -7-yl)methyl propionate (Example I20e)) and 4-chloromethyl-5-methyl-2-heptan-2-ylcarbazole (similar to Example 2 1 a)) and b] a step of reacting with potassium phenoxide and potassium iodide in the presence of potassium bromide and potassium iodide to produce [racemic t] -2-ethyllactyl- 3- [4-(5-methyl-2-ene-2-phenoxy-2-yloxy)-4-phenyloxy-7-yl]-propionic acid An oxime ester, which is _____-178 as described in Example 1 2〇f] - This paper size applies to the Chinese National Standard (CMS) A4 specification (210X297 public)

Binding

Line 1328585 A7 B7

The step is further saponified to give a white solid [racemic I ethoxy-3·[4-(5-methyl-2-B-sept. 2-ylcarbazole-4-ylmethoxy)) Benzo-n--7-yl]-propionic acid. MS: 426.2 (M-Η)', 380.2, 249.0 NMR NMR (DMSO-d6, 1H, 400MHz, δ, TMS) 1.00 (t, j= 7 2 3H), 2.43 (s, 3H), 3.07 ( Dxd, J=15.2, J=8, 1H), 3.19 (dxd J=15.2, J=6.4, 1H), 3.28- 3.32 (m, 1H), 3.49-3.53 (m, i^) 4·12 (dxd , J=8, J=6.4, 1H), 5.TQ (s, 2H), 6.87 (d, J=8',, 6.90 (d, J=2.4, 1H), 7.12 (d, J=8, 1H), 7.21 (t, J=4, 1H), 7.66 (d, J=4, 1H), 7.76 (d, J=4, 1H), 7.90 (d, J=2.4, 1H/ 12.70 (br. s, 1H). ' ), Example 122 _ al 4- 曱 曱 -2- (4-ethyl benzene 甲基 甲基 g 去 去 去 在 在 在 类似于 类似于 类似于 4 4 4 4 4 The aldehyde is reacted with diethyl hydrazine in the presence of glacial acetic acid and anhydrous vaporized hydrazine vapor to produce 2-(4-ethyl phenyl)-4,5-dimethylcarbazole 3 _ oxide, In a step similar to that described in Example 2 1 b], further treatment with phosphonium chloride in di-methane to produce 4-chloromethyl-2-(4-ethylphenyl)-5- as a colorless crystal Methyl Sigma No. MS: 236.2 (Μ+Η) +, 200.3, 129.0. NMR: (CDC13, 1H, 400MHz, 5, TMS) 1.26 (t, J=7.2, 3H), 2.42 (s, 3H) , 2.69 ( q, J=7.2, 2H), 4.55 (s, 2H), 7.27 (d, J=8, 2H), 7.91 (d, J=8, 2H). y_L racemic J-2-ethoxy oxime -3-_{4-Γ2-ί4- Λ其 y rong 15-A akisaki L------ 17Q, this paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public)

1328585 V. INSTRUCTIONS (176) —~~ 甲甲乳基13⁄4•和咕叫-7-甚·}- 丙龄 In the steps similar to the example 12〇f], 2_ethoxy_3_ Methyl (4hydroxybenzofuran-7-yl)propanoate (Example 12〇6)) and 4-chloromethyl-2(4-ethylphenyl)-5-methylcarbazole in potassium carbonate and potassium iodide The reaction is carried out to give [racemate]_2_ethoxy-3_丨4_[2_(4ethylphenyl)5.methyloxazol-4-ylmethoxy]benzofuran_7 Methyl ketopropionate, which was further packaged in a similar manner to that described in Example 120 to give [racemic] 2 -ethoxy-- 2...ethylbenzene as a white solid. Base)·5 methyl 17 oxazol-4-ylmethoxy]benzofuran-7- kipropropionic acid. MS: 448.2 (Μ-Η)·, 375.1, 281.2 » NMR: (DMSO-d6, 1H, 400MHz, 5, TMS) l.〇〇(t, j=7.2} 3H), 1.21 (t, J=8 , 3H), 2.45 (s, 3H)5- 267 (q, J=8j 2H), 3.06 (dxd, J=15.2, J=8, 1H), 3.19 (dxd, J=15.2, J=6.4, 1H ), 3-28-3.32 (m, 1H), 3.49-3.53 (m, lH), 4.12 (dxd, J=8! J=6.4, 1H), 5.12 (s, 2H), 6.90 (d, J= 8, 1H), 6.91 (d, J=2.4} 1H), 7.12 (d, J=8, 1H), 7.36 (t, J=8, 2H), 7.86 (d, J=8, 2H), 7.90 (d, J = 2.4, 1H), 12.70 (br.s, 1H). 'Example 123 ?--(4-Tertibutylbenzene)·4-氪甲一-5-甲甲喵a In a procedure similar to that described in Example 21a], 4•t-butylbenzaldehyde was Diethyl hydrazine is reacted in the presence of glacial acetic acid and anhydrous hydrogenated hydrogen vapor to produce 2-(4-t-butylphenyl)-4,5-dimethylcarbazole 3•oxide, which is similar In the step illustrated in Example 21b], further treated with phosphonium chloride in dichloromethane to produce 2_(4th butylphenyl)-180 which is a colorless solid. The paper scale applies to the Chinese national standard ( CNS) A4 size (210X297 mm) 1328585 A7 _ B7 V. Description of invention (177) 4-Chloromethyl-5-methylcarbazole. MS : 264.3 (M+H) + , 228.3, 187.2 NMR: (CDC13, 1H, 400 MHz, δ, TMS) 1.34 (s, 9H), 2.42 (s, 3H), 4.56 (s, 2H), 7.45 ( d, J = 8.8, 2H), 7.92 (d, J = 8.8, 2H). . , bl 『racemic 1 - 3- { 4-"2-(4-t-butyl 某 κ κ S-methyl 噚岫 _ 4 diyl methoxy 1 stupid and wow -7 - some Methyl 2-ethoxy-3-(4-3⁄4-ylbenzofuran-7-yl)propanoate (Example 120e) in a step similar to that described in Example 120f] ]) reacting with 2-(4-t-butylphenyl)-4-chloromethyl-5-methyloxazole in the presence of potassium carbonate and potassium iodide to produce [racemic]-3-{ 4-[2-(4-Tertiary phenyl)-5-methyloxazol-4-yl decyloxy]benzopyran-7·yl} 2-ethoxypropionate methyl ester, It was further saponified in a procedure similar to that described in Example 120f] to give [racemic]-3-{4-[2-(4-t-butylphenyl)-5-methyl succin as a white solid. Ollenyl-4-ylmethoxy]benzoin-7-yl}-2-ethoxypropionic acid MS: 476.2 (MH)', 430.3, 381.1. 281.2 « NMR : (DMSO-d6, 1H, 400MHz, 5, TMS) 1.00 (t, 3=7.2, 3H), 1.31 (s, 9H), 2.45 (s, 3H), 3.07 (dxd, J=15.2, J=8, 1H), 3.19 (dxd, J=15.2, J=6.4, 1H), 3.26-3.32 (m, 1H), 3.48-3.55 (m, 1H), 4.12 (dxd, J=8, J=6.4, 1H), 5.12 (s, 2H) , 6.89 (d, J=8, 1H) , 6.90 (d, J=2.4, 1H), 7.11 (d, J=8, 1H), 7.54 (d, J=8, 2H), 7.88 (d, J=8, 2H), 7.90 (d, J =2.4, 1H), 12.70 (br.s, 1H). Example 124 -181 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Description of invention ( 178 Isopropoxy _^^)-5-methyl carbazole in the procedure similar to that described in Example 21a], the presence of 4 isopropyloxybenzaldehyde in the presence of glacial acetic acid and vaginal hydrogen vapor The next reaction is carried out to give 2-(4-isopropoxyphenyl)-4,5-dimethyl.oxazole % oxide, which is further in the step similar to that described in Example 21b] in dichloromethane Treatment with hydrazine chloride to give 4-chloromethyl-2-(4-isopropoxyphenyl)-5-methylcarbazole as a colorless liquid MS : 266.3 (M+H) +, 224.2, 18-8.3. NMR : (CD-C13, 1H, 400MHz, 5; TMS) 1.36 (d, J=7.2, 6H), 2.40 (s, 3H), 4.54 (s, 2H), 4.61 (sept., J=7.2, 1H ), 6.92 (d, J=8, 2H), 7.91 (d, J=8, 2H). kU racemic 1-2-ethoxy, two different, two dad, its shameful, sputum, methoxy, 1 benzofuran, -7, and sulphate, in a procedure similar to that described in Example 1 20f] , 2 ethoxy_ 3_(4-hydroxybenzofuran-7-yl)propanoic acid methyl ester (Example 12〇6)) and 4-chloromethyl_2_(4-isopropylisophenyl)-5- Methylcarbazole is reacted in the presence of potassium carbonate and potassium iodide to give [racemic]-2-ethoxy_3_{4_[2·(4•isopropoxyphenyl)-5-methyl Methyl oxazol-4-ylmethoxy]benzofuran. 7- propylpropanoate, which was further encapsulated in a procedure similar to that described in Example 120f] to give [racemic] as a white solid. -2-ethoxy-3-{4-[2-(4-isopropoxyphenyl)-5-methyloxazol-4-ylmethoxy]benzofuran-7-yl}•C acid. Soil MS : 478.2 (M-H)·, 432.6, 375.2, 281.2. NMR: (DMSO-d6, 1H, 400MHz, &lt;5, TMS) l. 〇〇(t, J=7.2, 3H), 1.29 (d, J=6.4, 6H), 2.43 (s, 3H), 3.07 (dxd, J=15.2, -182 - This paper size applies to China National Standard (CNS) A4 specification (210X297 mm)

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Line 1328085 A7 B7 179 V. Description of invention (J=8, 1H), 3.19 (dxd, J=15.2, J=6.4, 1H), 3.27- 3.33 (m, 1H), 3.48- 3.55 (m, 1H), 4.13 (dxd, J=8, J=6.4, 1H), 4.70 (sept., ^=6.4, 1H), 5.10 (s, 2H), 6.89 (d, J=8, 1H), 6.91 (d, J =2.4, 1H), 7.03 (d, J=8.8, 2H), 7.11 (d, J=8, 1H), 7.85 (d, J=8.8, 2H), 7.90 (d, J=2.4, 1H), 12.70 (br.s, 1H). Example 1 2 5 ethoxybenzopyranyl-7-yl)ethyl propionate - 3-(4-benzyloxybenzofuran-7-yl)2Z-ethoxypropionic acid in methanol (17 ml) A solution of ethyl ester (420 mg, 1.15 mmol) (Example 12〇c)) was hydrogenated at room temperature with 10% palladium (100 mg) on charcoal over 2 hrs. The catalyst was filtered, and the solvent was evaporated under reduced pressure, and the residue was separated by chromatography (yield: EtOAc/EtOAc/EtOAc/EtOAc/EtOAc) MS: 279.1 (MH)., 265_2, 217.1, 141.0. NMR: (CDC13, 1H, 400 MHz, d, TMS) l.i6(t) J=7.2&gt; 3H) 1-22 (t, J= 7.2,3H), 2.87-2.97 (^2^, 3.15(1, 2H/ 3.36-3.44 (m,1H), 3.55- 3.62 (m,1H),4 〇8 〇j=7 2' ih)' 4.15 (q, J = 7.2, 2H), 4.59 (t, δ, 2H), 4.64 (b, s &gt;1H; 6 (d, J = 8, 1H), 6.84 (d, J = 8, 1H). LLLtLii 旋性卜 2-ethoxyoxindole·4_2,3-dihydrobenzobenzopyran-7-l-dipropionic acid will be [racemic] in a procedure similar to that described in Example 120f] Sexuality] 2 Ethyl-3-7-trans-based-2,3-dihydro benzopyran.7·yl)propionic acid B and 4_gas = 183 - This paper scale applies to Chinese National Standard (CNS) A4 size (21〇x 297 mm) 1328585 A7 B7 V. Description of the invention (18〇) Group 5-methyl-2-phenyl-oxazole is reacted in the presence of potassium carbonate and potassium iodide to produce [examination Rotyl]-2-ethoxy-3-(4-( 5-indolyl-2-phenyl-oxazol-4-yl) Ethyloxy-2,3-dioxabenzofuran-7-ylpropanoic acid ethyl ester, which was further saponified in a similar manner to that described in Example 120f] to give [racemic] as a white solid. 2-Ethoxy_3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-2,3-dihydrobenzofuran-7-yl-propionic acid. MS: 422.2 (M-Η)·, 378.3, 251.1. NMR: (DMSO-d6, 1H, 400 ΜΉζ, &lt;5, TMS) 1.03 (t, J=7.2, 3H), 2.44 (s, 3H), 2.71 (dxd, J=15.2, J=8, 1H), 2.83 (dxd, J=15.2, J=6.4, 1H), 3.06 (t, J=8, 2H), 3.25-3.32 (m, 1H), 3.45 -3.52 (m, 1H), 3.96 (dxd, J=8, J=6.4, 1H), 4.52 (t, J=8, 2H), 5.00 (s, 2H), 6.58 (d, J=8, 1Ή) ), 6.93 (d, J=8, 1H), 7.48-7.55 (m, 3H), 7.93-7.96 (m, 2H), 12.55 (br.s, 1H) e Example 126 f racemic 1-2 -Ethoxy-3-indole 4-"2-(4-ethyl acetonide U5-methyl fluorene 4-ylmethyl group 1-2,3 - dihydro cumin and -7-something - rain In a similar procedure to that described in Example 120f], [racemic] 2-ethoxy-3-(4-amino-2,3-dihydrobenzoin-7-yl)-propyl Ethyl acetate (example 丨25 a)) and 4-chloromethyl-2-(4-ethylphenyl)-5-fluorenyl number. Sit (example i22a)) in the presence of potassium bromate and potassium iodide to give [racemic] _2 ethoxy-3-{4-[4-(4-ethylphenyl)-5- Methyl 1» 岐-4-ylmethoxy]-2,3-dihydrobenzoin-7-yl}-propionic acid ethyl ester, which is further described in a procedure similar to that described in Example 12〇f] Saponification to give [racemic]-2-ethoxy-3-{4-[2-(4-ethylphenyl)-5-methyl"-oxazol-4-yl as a white solid A-184 - This paper size is applicable to China National Standard (CNS) Α4 specification (210Χ 297 mm) Binding

1328585 V. Description of the invention (181 A7 B7

Oxy]-2,3-monohydrobenzopyran_7_ylindole·propionic acid. MS: 450.3 (M-H)·, 406_2, 251.1. NMR : (DMS〇_d6, 1H, 4〇〇MHU, TMS) 1 〇3 〇, J=7 2 3H), 1.21 (t, J=8, 3H), 2.43 (s, 3H), 2.64-2.74 (m 3H) 2.83 (dxd, J=15.2, J=6.4, 1H), 3.06 (t, j=8, 2H)&gt; 3 25 3 32 (% 1H), 3·45-3.52 (m, 1H) , 3.96 (dxd, J=8, J=6 4, 1H) 4.51 (t, J=8, 2H), 4.98 (s, 2H), 6.58 (d, J=8> lH), 6.92 J=8, lH), 7.36 (d, J=8, 2H), 7.-, 5(,, J=8, 2H), 12.6〇(br; 1H). ' 5 Example 127 f external charm 1 p sitting _ 4_ a 甲 巩 d3-二虱乙氢和^ In the procedure similar to the example l20f], [racemic] _2 ethoxy-3- (4·(4)_2,3·: Hydrogen benzene _7-based) Propionic acid (iv) (example) and 2-(4-dibutyl butyl)-methyl-3-methylcarbazole ( Example 123a)) Reacts in the presence of a post-acid clock and a moth, to give [racemic]-3-匕[2-(4·t-butylphenyl) 5-methylindole~yl Ethyl bromide 2,3-dihydron-benzoic acid 7-yl}-2-ethoxypropionic acid ethyl acetonate, which was further saponified in a procedure similar to that described in Example 120f] to give a white solid. Racemic]-3-{4-[2-(4-t-butylphenyl)·5-methylcarbazole·4ylfoxy]-2,3-dihydrobenzofuran_7_ _ _ 2 ethoxypropionic acid. MS . 478.2 (MH)·, 434.4, 375.1, 299.1, 281.2, 251.1 » NMR ·· (DMSO-d6, lH, 40〇MHz, TMS) 1·〇3 (t , J=7·2, 3H), 1.31 (s, 9H), 2.43 (s, 3H), 2.71 (dxd, J = 15.2, J=8, lH), the paper ruler (CNS) A4 size (210 x 29匕茇)

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Line 1328085 A7 B7 V. Description of invention (182) 2.S3 (dxd, J=15.2, J=6.4, 1H), 3.06 (t, J=g, 2H), 3.25-3.32 (m, 1H), 3.45- 3.52 (m, 1H), 3.95 (dxd, J=8, J=6.4, 1H) 4.51 (t, J=8, 2H), 4.99 (s, 2H), 6.58 (d, J=8, 1H), 6.92 (d, J=8, 1H), 7.54 (d, J=8, 2H), 7.87 (d, J=8, 2H), 12.60 (br.s, 1H). Example 128 ΓExhaustive 'spinning〗 -2-Ethylhydro-3-j[ 4- [2-(_4-isopropyl 氲 节 ) ) ) ) ) ) ) ) ) ) ) ) ) ) 某 某 某 某 某 某 某 某 1- 1- 1- 1- 1- 1- 2,3-Dihydro benzopyrene. -7-7- ί - 呙 - in the procedure similar to that described in Example 120f], [racemic 2 - ethoxy-3-(4-hydroxy-) Ethyl 2,3-dihydrobenzofuran-7-yl)propionate (Example 1253)) with 4-chloromethyl-2-(4-isopropyllactyl)-5-methyl Example 124a]) Reaction in the presence of potassium carbonate and potassium iodide to give [racemic] _ 2 ethoxy-3-{4-[2-(4-isopropoxyphenyl)-5- base. No. decyl methoxy] 2,3-dihydrobenzopyran--7-yl}-propionic acid ethyl acetonate, which was further saponified in a procedure similar to that described in Example 120f] to give a white solid. Racemic]-2-ethoxy-3-{4-[2-(4-isopropoxyphenyl)_5•methyl σ ° °-4--4-methoxy]-2,3 - Two wind leather and bite 7-based}-propionic acid. MS: 480.3 (Μ-Η)', 436.7, 281.2, 251·1. NMR: (DMSO-d6, 1 Η, 400 MHz, &lt;5, TMS) 1·〇3 (t, J=7 2 3H), 1.29 (d, J=7.2, 6H), 2.41 (s, 3H), 2.71 (dxd, J=l5.2 J=8, 1H), 2.83 (dxd, J=15.2, J=6.4, 1H), 3.06 (t, J=8, 2H) 3.25-3.32 (m, 1H), 3.45 -3.52 (m, 1H), 3.96 (dxd, J=8 J=6.4, 1H), 4.51 (t, J=8, 2H), 4.70 (sept., J=7.2, 1H), 4 97 (s, 2H), 6.57 (d, J=8, 1H), 6.92 (d, J=8, 1H), 7.03 j~g-186 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) ) -----

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V. Description of the invention (183 2H), 7.84 (d, J=8, 2H), 12.60 (br.s, 1H). Example 129 al 4-Hydrazine Hydrogen-2_- f furfural Anhydrous N,N-dimethylformamide (34.2 ml, 444 mmol) was added dropwise with stirring and cooling under a gas atmosphere. In the case of (1 8.3 ml, 200 mmol), the addition speed is such that the temperature does not exceed 10 °C. At 0. After 30 minutes of squatting, dipoxy-3-methylbenzene (22 g, 1 丄 1 mM) in N,N-dimethylformamide (22 ml) was added dropwise over 30 minutes. Solvent (for the preparation of oxime oxy-3-methylbenzene, see: D. Bogdal, J. Pielichowski, A. Boron, Syn. Commun. 1998, 28, 3029-3039). The reaction mixture was stirred at room temperature for 30 minutes and then continuously heated to 110 °C. After 10 minutes at I 1 〇 C, the mixture was maintained at 9 for 3 · 5 hours' cooling to 10 ° C, neutralized with 25% aqueous sodium acetate, and taken with vinegar. The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give a brown oil, which was purified by column chromatography (EtOAc, hexane/AcOEt = 19 </ RTI> </ RTI> </ RTI> to afford a 4.3 g (19 mM, 17%) as a yellow solid. Title compound. MS : 226.1 (M) + , 91.2 » NMR : (CDCI3, 1H, 400MHz, (5, TMS) 2.65 (s, 3H), 5.13 (s, 2H), 6.83 (d, J=1.6, 1H),- 6.91 (dxd, J=8.8, J=1.6, 1H), 7.32- 7.44 (m,5H), 7.75 (d,J=8.8, 1H), 10.12 (s, 1H). kl_3-(4-benzyloxy -2-methyl stupid) _2Z-ethyl hydrogen ethyl acrylate will chlorinate (ethoxyethoxycarbonylmethyl) three stupid scale (379 grams, 8.8 millimoles ------ 1»7 - this The paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇x297 mm) 1328585 A7 B7 184 V. Invention description (ear) and \acid _ .46 g, } 〇 6 m Mo) in } 〇.〇 Addition under chlorine, 4 ethoxy· 2 _methyl phenyl chain (7) gram in isopropyl S| (10 ml), 3 Å mAh / in solution [on gasification (ethoxy ethoxylate) Discussion on the preparation of trimethylbenzene triphenyl scales. Reference: κ κ Β 吨 H rΗ Μ

Jensen, Η. B. Nielsen, I. Thomson, K. B. G. Torssell, Tetfahedton 1994’ 50’ 7543_7556]. Heat the suspension to (9) 乞. At 1 = J and after 20 hours, add gasification (ethoxyethoxymethomethyl) benzene scale (each 3.79 grams, 88 milligrams - tomb) and potassium carbonate (146 grams each time) , 10.63⁄4-mole) After 36 hours, the suspension was filtered and the filtrate was decompressed under reduced pressure. The residue was dissolved in methylene chloride to be washed with saturated water f-vaporized ammonium and ice water, and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (yield: EtOAc) to afford the title compound. MS: 340.2 (M)' 249.2, 147 Mountain 91". NMR : (CDC13, 1H, 400MHz, 5 , TMS) 1.31 (t, J=7.2, 3H), 1-37 (t, J=7.2, 3H), 2.37 (s, 3H), 3.91 (q, J= 7.2, 2H), 4.30 (q, J=7.2, 2H), 5.07 (s, 2H), 6.82-6.85 (m, 2H), 7.18 (s, 1H), 7.33-7.44 (m, 5H), 8.08 ( d, J=8.8, 1H). Lu 2 - ethoxy (4_ with a · 2 · methyl oxime 1) and vinegar, ester will be in ethanol (50 ml) of 3 · (4 • benzyloxy · 2 methyl phenyl) 2 Z A solution of ethyl oxyacrylate (1 g, 2 9 mmol) was hydrogenated at room temperature over 1% palladium on charcoal (250 mg) over 2 hours. The catalyst is filtered, and the solvent is released under reduced pressure to obtain 6 〇〇 mg which becomes a yellow liquid (2 4 mAh paper size 财 财@时职 CNS) A4 threat (210X29$爱) 1328585 A7 _'____B7 V. INSTRUCTIONS (185) Ear '81%) of the title compound, which was used in the next stage without further purification. MS: 270·4 (M+NH4) +, 253 (M) +, 207.2, 165.3. NMR: (CDC13, lH, 400MHz, &lt;5, TMS) 1.15 (t, J=7.2, 3H), 1.22 (t, J=7.2, 3H), 2.30 (s, 3H), 2.95 (d, J= 7.2, 2H), 3.28-3.36 (m, 1H), 3.54-3.62 (m, 1H), 3.95 (t, J=7.2, 1H), 4.16 (^&gt; J-7.2, 2H), 4.54 (s, 1H), 6.59 (dxd, J=8, J= 1 6 1H) 6.63 (d, J=1.6, 1H), 7.04 (d. JU). Dl f racemate b 2-ethoxy-3-"2-甲某-4-ί5· f某·2-section-oxazole-4-some hyperthyroidism) stupid base 1-propanoid Similar to the procedure illustrated in Example 1 20f], [racemic] 2 ethoxy-3-(4-hydroxy-2-methylphenyl)propanoic acid ethyl acetonate and 4 qi methyl group 5 Methyl-2_ phenyl-pyrazole is reacted in the presence of potassium carbonate and potassium iodide to give [racemic]-2-ethoxy-3-[2-methyl-4-(5-methyl) -2-Phenyl-oxazol-4-ylmethylidyl)-propionic acid]-propionic acid B was further saponified by a procedure similar to that described in Example 12 〇f] to give a pale yellow solid [ Racemic] _ 2_ethoxy-3-(2-methyl-4-(5-fluorenyl-2-phenyl-D-indole-4-ylmethoxy)phenyl]-propionic acid. MS : 394.2 (M-Η)', 348.5 〇 NMR · (CDCI3, 1H, 300MHz, 5 , TMS) 1.13 (t} J=7 2 3H), 2.34 (s, 3H), 2.44 (s, 3H), 2.93 (dxd, J=15.2, J=8, 1H), 3.11 (dxd, J=15.2, J=4, 1H), 3.30-3.36 (m, 1H), 3.50-3.57 (m, 1H), 4.01 ( Dxd, J=8, J=4, 1H), 4.97 (s, 2H), 6.79 (dxd, J=8, J=1.6, 1H), 6.83 (d, J=i.6, 1H), 7.13 ( d, J=8, 1H), I_____ - 1ftQ - the paper scale With China National Standard (CNS) A4 size (210X 297 Kimiyoshi) 1328585 A7 B7 invention described five (186 7.43-7.46 (m, 3H), 8.00-8.03 (m, 2H) · 130 · Example

Lil: racemic Bu 2-ethoxy-3_"2_甲-4-(5-甲某·2··· oxazol-4-ylmethoxy) 苽 高 高 高 在 在 类似于 类似于 类似于 类似于In the indicated procedure, [racemic]_2_ethoxy-3-(4-hydroxy-2-mercaptophenyl)propanoic acid ethyl ester (Example 129c)) and 4•chloromethyl-5 -Methyl-2-decenophen-2-ylcarbazole is reacted in the presence of potassium carbonate and potassium iodide to give [racemic]-2-ethoxyxo-3-[2-indolyl-4-( Ethyl 5-methyl-2-thiophen-2-yloxazol-4-ylmethoxy)phenyl]-propanoate, which was further saponified in a procedure similar to that described in Example 1 20f] to give a shallow [Racecycling]-2-ethoxyl_3_[2_indolyl-4_(5-methyl-2•喽 _-2-yloxazol-4-ylmethoxy)phenyl Propionate MS: 400.3 (M+H)·, 354.1, 281.2. NMR: (CDC13, 1H, 300MHz, 5, TMS) 1.13 (t, J=7.2j 3H) 2.34 (s, 3H), 2.41 ( s, 3H), 2.93 (dxd, J=15.2, J=g.8j 1H) 3.12 (dxd, J=15.2, J=4, 1H), 3.30-3.38 (m,1H), 3.49.3 57 (m , 1H), 4.01 (dxd, J=8, J=4.8, 1H), 4.94 (s, 2H) 6 78 (dxd, J=8, J=1.6, 1H), 6.82 (d, lH)) 7.08- 7.14 (m 2H), 7.40 (dxd, J-4.8, J=〇.8, lH), 7.64 (dxd, J=4 0 J=〇/ 1H) . , 5 Example 131 . Ethyl oxalate will be [racemic]-2-ethoxyl i Racemic 1-2-E gas U- {4_"2^4 4 -ylmethoxy 1-2-methyl phenyl]_ two domains in a similar manner to the steps described in Example 12〇f] The scale applies to the Chinese National Standard (CNS) A4 specification (210X297 public 1328585 A7 _____ —______B7 V. Invention description (187) 〇·(4·趣基·2_methylphenyl)propionate ethyl ester (example 129c) Reaction with 4-chloromethylethylphenyl)-5-indoleazole (Example 122a)) in the presence of potassium carbonate and an iodide clock to yield [racemic]-2-ethoxy- 3-{4-[2-(4-Ethylphenyl)_5-methyl oxime _4_ylmethoxy]_2-decylphenylpropionic acid ethyl ester, similar to the example 120f The procedure described is further saponified to give [racemic]·2·ethoxy-3_丨4_[2-(4-ethylphenyl)-5-indenylcarbazole as a pale yellow solid. Methoxy] 2 methyl phenylpropionic acid. .. MS : 422.2 (Μ-Η)', 376.3. NMR : (CDC13, 1H, 300MHz, 5 , TMS) 1.12 (t, 1=7.2, 3H), 1.26 (t, J=8, 3H), 2.33 (s, 3H), 2.42 (s, 3H), 2.69 (q, j=8&gt; 2H), 2.93 (dxd, J=15.2, J=8.8, 1H), 3.11 (dxd, J=15.2, J=4} 1H), 3.30-3.35 (m, 1H), 3.49 -3.57 (m, 1H), 4.00 (dxd, J=8, J=4, 1H), 4.95 (s, 2H), 6.79 (dxd, J=8, J=1.6, 1H), 6.82 (d^ J =1.6, 1H), 7.12 (d, J=8, 1H), 7.27 (d, J=8, 2H), 7.92 (d J=8, 2H). 'Example 132 生卜3- M-"2-(4- m三丁某苽基)·5·甲篡碟ΐ. Milk-based 1-2-methyl stupidin-2-ethyl hydrazine propionic acid [Racemic]_2ethoxy-3-(4-hydroxy-2-methylphenyl)-propionic acid ethyl ester (Example 129 (;) in a procedure similar to that described in Example 12]. Reaction with 2__(4_2t-butylphenyl)-4-chloromethyl-5-methylcarbazole (Example 123a)) in the presence of potassium carbonate and potassium hydride to produce [racemic ]_3_{4_[2(4_T-butylphenyl)-5-methyloxazol-4-ylmethoxy]-2-methylphenyl b 2•B

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1328585 A7 ___ B7 V. INSTRUCTION DESCRIPTION (188) Ethyl oxypropionate, which is further saponified in a procedure similar to that described in Example l2〇f] to produce [racemic]·3_{ as a pale yellow solid 4_[2_(4·t-Butylphenyl)-5•mercaptoindazole-4-ylmethoxy]-2-methylphenyl- 2-ethoxypropionic acid. MS: 450.3 (Μ-Η)*, 422.2, 404.3. NMR : (CDC13, 1H, 300MHz, ό, TMS) 1.12 (t, J=7.2, 3H), 1.35 (s, 9H), 2.34 (s, 3H), 2.43 (s, 3H), 2.93 (dxd, J =15.2, J=8.8, 1H), 3.13 (dxd, J=15.2^ J=4.8, 1H), 3.26-3.38 (m, 1H), 3.48-3.58 (m,ih), 4.00 (dxd, J=8 , J=4, 1H), 4.96 (s, 2H), 6.79 (dxd, J=8, J=1.6, 1H), 6.82 (d5 J=1.6, 1H), 7.12 (d, J=8, 1H) , 7.45 (d, J=8, 2H), 7.93 (d, J=8, 2H) « Example 133 _

LjBu racemic l-2- Γϋ-3- Μ-Γ2-Μ-isopropyl 氲 Some stupid U-甲篡:f_吃-4·基甲氧一1-2-甲某笨基卜Acid in a similar procedure to that described in Example 120f], [Racemic 2-Ethoxy-3-(4-hydroxy-2-methylphenyl)propanoic acid ethyl ester (Example 129 £;]) Reaction with 4-chloromethyl-2-(4-isopropoxyphenyl)-5-methylcarbazole (Example 1243) in the presence of potassium carbonate and potassium iodide to give [racemic]_2_ Ethoxy_3_ {4-[2-(4-isopropoxyphenyl)_5-mercaptocarbazole-4-yloxy]_2-methylphenyl}-propionic acid ethyl ester Steps similar to those described in Example 12〇f] were further optimized to give [racemic]·2_ethoxy_3-{4-[2-(4-isopropoxybenzene) as a pale yellow solid. Base)_5•methylcarbazole_4_ylmethoxy]_2_mercaptophenylphosphonium-propionic acid. MS : .452.3 (Μ-Η)_, 406.3, 281.2 » _____ - 192 - This paper X·度适财g @家标准(CNS) Α4Specifications (21Gχ 297 公爱) --- 1328585 A7 B7 V. Invention Description (189) NMR: (CDCI3, 1H, 300MHz, 5, TMS) 1.12 (t, J=7.2, 3H), 1.36 (d, J=7.2, 6H), 2.37 (s, 3H), 2.41 (s, 3H), 2.92 (dxd, J=15.2, J=8.8, 1H), 3.12 (dxd, J=i5.2, J=4.8, 1H), 3.26- 3.36 (m, 1H), 3.48-3.58 (m, 1H), 4.〇l (dxd&gt; J=8? J=4, 1H), 4.61 (sept., J=7.2, 1H), 4.94 (s, 2H), 6.79 (dxd, J=8, 1H) , 6.83 (d, J=i.6j 1H), 6.92 (d} J=8, 1H), 7.12 (d, J=8, 2H), 7.93 (d, J=8, 2H). Example 134 (8)-2-but-3-oxo_^_3_{3,5-dimethyldi 1^2_(5_甲某-2_笨甚-g-azole-4-yl)-B Oxygen 1_茇一丨-Cailing in a procedure similar to that described in Examples 113] to 11〇], 3,5-dimethyl-4-(2-(5-methyl-2-phenyl)- Carbazole _4·yl)·ethoxy]benzaldehyde (Example Π7) and (5)-4-mercapto-3-(2-butyl-3-isopropoxyacetinyl)1»oxazolidine _2 ketone (for the preparation of (S)-4-pyryl-3-(2-but-3-enyloxyethyl) oxazolidine-2-one] Reference: Μ. T. Crimmins, AL Choy, J. Am. Chem. Soc. 1999, 121, 5653-5660) and nBu2BOTf reaction to produce (s)-4-benzyl-3-((2S,3R)-2-butyl-3-pyrene Oxy-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-phenyl b- 3 hydroxypropionate Oxazolidine-2-one (according to NMR, one of the four isomers is predominant; according to D_ Haigh, HC Birrell, B. C. C. Cantello, DS

Eggleston, R. C. Haltiwanger, R. M. Hindley, A. Ramaswamy, N. C. Stevens, Tetrahedron Asymmetry 1999, 10, 1353-1 367, temporarily named 2S, 3R). Reduction of (S)-4-mercapto-3-(( 2S,3R)-2-but-3-enyloxy-3- ____ 1Q^ - this paper scale with triethylformane in trifluoroacetic acid Applicable to China National Standard (CNS) A4 specification (210X297 mm)

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V. DESCRIPTION OF THE INVENTION (190) { 3,5-Dimethyl- 4-[2-(5-methyl-2-phenyl-σ-oxazol-4-yl)-ethoxyphenyl]} 3 -hydroxypropionyl)oxazolidin-2-one' to give (S)-4-indolyl'3-((2S)-but-3-oxooxy-3-{3,5-dimethyl -4· [2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}propenyl)oxazolidin-2-one. Next, (S)-4-benzyl-3-((2S,3R)-2-but-3-enyloxy-3-{3,5-dimethyl-4_[2-(5-methyl) -2-Phenyl-oxazol-4-yl)-ethoxy]-phenyl}-3-hydroxypropanylpolyoxazolidin-2-one is saponified with 1 gram molecular weight NaOH in THF to produce (S)-2-butoxy- 3-{3,5-dimercapto[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxylate as a colorless solid ]-Phenylpropionic acid °-MS: 438.3 (M-Η)., 394.2, 293.2, 263.1, 219.4. NMR: (DMSO-d6, 1 Η, 400 MHz, (5, TMS) 2.10 (s, 6 Η), 2.18 (q, J=7.2, 2H), 2.38 (s, 3H), 2.67-2, 77 (m, 1H), 2.81 (dxd, J = 15.2, J = 5.6, 1H), 2.91 (t, J = 7.2, 2H), 3.23-3.32 (m, 2H), 3.51-3.57 (m, 1H), 3.90-3.98 (m, 3H), 4.94 (dxd, J=8·8, J=0.8, 1H), 5.00 (dxd, J = 16.8, J = 0.8, 1H), 5.63-5.74 (m, 1H), 6.85 (s, 2H), 7.45-7.52 (m, 3H), 7.92 (dxd, J=8, J=〇 · 8» 2H), 12.65 (br.s, 1H). Example 135 - A certain - 4 · Ι ~ 2-(5-methyl-2-endyl-, scent-4 - very condensed ~ base 篆丨 Ζ Ζ Ζ 氲 氲 氲 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在5-methyl-2-phenyl-p-azole _4. yl)-ethoxy]-phenyl}_2Z-ethoxy propylene (in a similar manner to Example 1 14c), 3,5-Dimethyl-4-[2-(5-methyl_2-phenyl.carbazole-4-yl)·ethoxy]benzaldehyde (example _________- 1Q4 -_____) Zhang scale applies to China National Standard (CNS) A4 specification (210X 297 mm)

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1328585 A7 B7 V. INSTRUCTIONS (191) 11 *7) and chlorinated (ethoxyethoxycarbonylmethyl)triphenyl tungsten (KK Bach, HR ΗΙ-Seedi, Η. M. Jensen, Η. Β. Nielsen , I. Thomson, KBG Torssell, Tetrahedron 1994, 50, 7543-7556) 3-{3,5-Dimethyl-4-[2-(5-methyl-2-benzene) Base-carbazole-4-yl)-ethoxy]-phenyl}·2Ζ-ethoxy acrylic acid. MS: 420.3 (Μ-Η)·, 348.3, 281.2, 255.2, 235.2. NMR: (CDC13, 1H, 400MHz, &lt;5, TMS) 1.38 (t, J = 7.2, 3H), 2.23 (s, 6H), 2.40 (s, 3H), 3:01 (t, 5 = 1.2, 2H), 3.98 (q, 3=1.2, 2H), -4.99 (t, J-7.2, 2H), 7.02 (s, 1H), 7.41-7.46 (m, 5H), 7.99 (dxd, J=8, J = 0.8, 2H). Example 1 3 6 [Racemic 1-3- {4-『2-(4-氪Benzylmethylcarbazole-4-A$$1 1 stupid and 咭-7-kib 2-ethane a propionic acid in a procedure similar to that described in Example 2, f], [Racemic 2-ethyl-3-ethoxy-3-(4-hydroxybenzofuran-7-yl)propanoate (Example 120e) ]) with [2- (4-methylmethyl)-5-mercaptoindazole-4-yl] sterol (RC Self, WE Barber, JP Machin, JM Osbond, CE Smithen, BP Tong, JC Wickens, DP Bloxham, D. Bradshaw, CH Cashin, BB Dodge, EJ Lewis, D. Westmacott, J. Med. Chem. 1991, 34, 772-777) Reaction in the presence of triphenylphosphine and diethyl azodicarboxylate To produce [racemate]-3-{4-[2-(4-phenylphenyl)-5-methylcarbazole-4-yloxy]benzofuran-7-yl}-2 Methyl ethoxypropionate, which was further saponified in a similar manner to that described in Example 20f] to give [racemic]-3-{4-[2-(4-chlorobenzene) as a colorless solid. Base)-5-methylcarbazol-4-ylmethoxy] __- 1PR -_____ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 public)

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Line 1328585 A7 B7 V. Description of the Invention (192) Benzofuran-7-yl}-2-ethoxypropionic acid. MS ·· 454.2 (M-Η)., 408.1, 299.1, 249.1. NMR : (DMSO-d6, 1H, 400 ΜΗζ, ά, TMS) 0.99 (t, J = 7.2, 3H), 2.46 (s, 3H), 3.06 (dxd, J = 15.2, J = 8, 1H), 3.19 ( Dxd, J=15.2, J=6.4, 1H), 3.23-3.45 (m, 1H), 3.47-3.55 (m, 1H), 4.10 (t, i=1.2, 1H), 5.13 (s, 2H), 6.89 (d, J=8, 1H), 6.90 (d, J=1.6, 1H), 7.12 (d, J=8, 1H), 7.60 (d, J=8.8, 2H), 7.90 (d, J=1.6 , 1H), 7.96 (d, J=8.8, 2H)U12.90 (br.s, 1H) 〇Example 137 - Γ Ά Ά 4 4 1-3-{4-[~2-(4-气Stupid base) -5-methyl p-peak · 4_ a certain gas 1-2-methyl 苽 a 丨 -2- ethoxy propyl hydrazine in a step similar to the example 2 1 f], - [Racemic 2 -ethoxy-3-(4-3⁄4yl-2-methylphenyl)propionic acid ethyl (example 129c)) and [2-(4-chloromethyl)-5- Mercaptoin-4-yl] sterol (RC Self, WE Barber, JP Machin, JM Osbond, CE Smithen, BP Tong JC Wickens, DP Bloxham, D. Bradshaw, CH Cashin BB Dodge, EJ Lewis, D. Westmacott , J. Med. Chem. 1991, 34, 772-777) reacts in the presence of two scales and arsenic acid diethylene g, % yields [racemic]-3- {4-[ 2 -(4-phenylphenyl)-5-methylcarbazole -4-ylmethoxy]-2-yl.ylamino}_2-ethoxypropionic acid B, which was further-encapsulated in a similar manner to that described in Example 120f] to give a colorless solid. [Racecycling]-3-{4-[2-(4-Phenylphenyl)-5-fluorenyl. No. azole_4_ylindole group]-2-methylphenyl}-2-ethoxypropionic acid. MS: 428.32 (M-H)·, 384.1, 349.0, 255.4. 196 This paper scale applies to China National Standard (CMS) A4 specification (210X297 mm) 1328585 A7 ______B7 V. Invention description (193) NMR: (CDCI3, 1H, 400MHz, (5, TMS) 1.06 (t, J=7.2 , 3H), 2.23 (s, 3H), 2.36 (s. 3H), 2.88 (dxd, J=15.2, J=8, 1H), 3.05 (dxd, J=15.2, J=4.8, 1H), 3.22- 3.31 (m, 1H), 3.43-3.51 (m, 1H), 3.94 (dxd, J=8, J=4.8, 1H), 4.88 (s, 2H), 6.73 (dxd, J=8, J=1.6, 1H), 6.76 (d, J=1.6, 1H), 7.06 (d, J=8, 1H), 7.34 (d, J=8, 2H), 7.88 (d, J=8, 2H). Example 138 J : racemic 1-3- {4-"2-(3.5-di-methyl 氲) ----, 诎- 4-- • methoxy 1 benzopyran-7-yl 2-Ethylpropionic acid in a procedure similar to that described in Example 12〇f], [racemic] _ 2 ethoxy _ 3 · (4-hydroxybenzofuran-7-yl) propyl Methyl ester (Example 120e)) with 4-methylmethyl-2-(3:5-dimethoxyphenyl)-5-methyl-carbazole (in a similar manner to Example 21a) and b] Reacting in the presence of potassium carbonate and potassium iodide with a single monthly loss of 3,5-dimethoxybenzaldehyde and diethylhydrazine, followed by treatment with POCI3 to produce [racemic]_3 _{4_[2_(3,5-Dimethoxyphenyl)_5_ fluorenyl oxa-4-ylmethyl] benzopyran-7-yl hydrazine-2-ethoxypropionic acid methyl vinegar, It was further saponified in a procedure similar to that described in Example 12, to give [racemic]_3-{4-[2-(3,5-dimethoxyphenyl) as a colorless solid. -5-Methyloxazol-4-ylmethoxy]benzofuran-7-yl-2-ethoxypropane acid MS: 480.2 (MH)., 434.3, -390.2, 249.1. NMR: (DMSO -d6, 1H, 400MHz, δ, TMS) 1.00 (t, J=7.2, 3H), 2.46 (s, 3H), 3.08 (dxd, J=15.2, J=8, 1H), 3.19 (dxd, J= 15.2, J=6.4, 1H), 3.26-3.32 (m, 1H), 3.47-3.55 (m, 1H), __ - 197 - This paper size applies to the Chinese National Standard (CNS) A4 specification (4) x297 public) - - Binding

Line 1328085 A7 B7 V. Description of invention (194 3.82 (s, 6H), 4.13 (dxd, J=8, J=6.4, 1H), 5.12 (s, 2H), 6.64 (t, J=0.8, 1H), 6.89 (d, J=8, 1H), 6.91 (d, J=1.6, 1H), 7.06 (d, J=〇.8,2H), 7.12 (d, J=8, 1H), 7.90 (d, J=1.6,1H), 12,70 (br.s,1H). Example 139 22-Ethyl argon-3-{4-丨2-(4-isopropyl some stupid)-5-A „^ ^坐_4_基methoxy. base 1-2-methyl hydrazino-acrylic acid in a step similar to that described in Example 120f], 4-hydroxy-2-mercaptobenzaldehyde (about 4- Preparation of benzyl-2-methylbenzaldehyde, reference: η.. H. Hodgson, TA Jenkinson, J. Chem. Soc. 1929, 469, 1639-1641) and 4-chloromethyl-2-(4- Isopropylphenyl)-5-methylcarbazole (in a procedure similar to that described in Examples 21a) and b], treated with 4-isopropylbenzaldehyde and diethylindenyl, followed by P0C13 The resulting compound is reacted in the presence of potassium carbonate to produce 4-[2-(4-isopropylphenyl)-5-indenyl σ. 吐-4-ylmethoxy]_2-methylbenzaldehyde. Similar to the procedure illustrated in Example 12〇c], 4_[ 2_(4-isopropylphenyl)-5-methyl &quot;oxazol-4-ylmethoxy]_2-methylbenzene Aldehyde and chlorinated (ethoxyethoxycarbonylmethyl)triphenylhydrazine (for the preparation of gasified (ethoxyethoxycarbonylmethyl) triphenyl scales, reference: κ.κ·Bach, HREI-Seedi , Η. M. Jensen, Η. B. Nielsen, I. Thomson, KBG

Torssell' Tetrahedron 1994, 50, 7543-7556) reacts in the presence of DBU to give 2Z-ethoxy_3_{4_[2_(4·isopropylphenyl)·5 methyl ρ-axazole-4- Ethyl methoxy]-2-methylphenyl acrylate, which is saponified in a similar manner to that described in Example 1 20f] to give 2Z-ethoxy-3- as a light green solid. {4-[2-(4-Isopropylphenyl)-5-methylcarbazole_4_yl 1 Paper · Scale applicable to China National Standard (CNS) A4 Specification (210X291^^) ~ 1328585 A7 B7 195 V. DESCRIPTION OF THE INVENTION Methoxy]-2-methylphenyl}-acrylic acid. MS: 434.3 (M-H)·, 362.2, _293.2. NMR : (DMSO-d6, 1H, 400 ΜΗζ, δ, TMS) 1.21 (t, J=8, 3H), 1.23 (d, 1 = 1.2, 6H), 2.32 (s, 3H), 2.45 (s, 3H) , 2.95 (sept·, J=7.2, 1H), 3.90 (q, J=7.2, 2H), 5.01 (s, 2H), 6.92 (dxd, J=8, J=0.8, 1H), 6.95 (d, J=〇.8, 1H), 7.03 (s, 1H), 7.40 (d, J=8, 2H), 7.87 (d, J=8, 2H), 8.00 (d, J=8, 1H), 12.80 (br.s, 1H). - Example 140 L is externally rotated. j shengb 2-ethyl fluorenyl-3-f3_methyl methoxy) phenyl 1-propionic acid in a procedure similar to that described in Example 1 08c], in N N 4-oxomethyl-2-phenyl-oxazole in dimethylformamide [in terms of benzoguanamine and [3-3-dicarbylacetone] such as Bioorg. Med_Chem. Lett. (20〇〇), 1〇(17), prepared by the description of 2041-2044] and sodium hydride treatment [racemic]_2•ethoxy3_4_(hydroxy-3-methylphenyl)propionate ethyl ester [PCT Int Αρρ丨(2〇〇1), w〇01/40172A1], to produce [racemate]_2_ethoxy-3 [3 methyl_4·(2-phenyl-tensole_4·ylmethoxy) Phenylpropionate, which was further deuterated in a similar manner to that described in Example 9U] to give [racemic]-2·ethoxy-3-[3- Mercapto-4-(2-phenyl-carbazole-4-ylmethoxyphenyl)-propionic acid. MS : 380.2 (MH)* NMR: (CDC13 &gt; 1H, 2-25 (s, 3H) ), 2.92 400MHz, TMS) L18 J=?〇j 3h)j (dxd. J=14.4j J=7.6, 1H), 3.06 (dxd. This paper size is timely gg material (CNS) A4 specification -- ------- 1328585 A7 B7

^14·4, J=4, 1Η), 3.48 (dxq. J=13.6, J=7.2, 1H), 3.56 (dxq, 2 '6&gt; J-7.2, 1H), 4.05 (dxd. J=8, J=4.4, 1H), 5.07 (s, 2H), 6.86 (d, J=8.8, ih), 7.04 (ar〇m. H, 2H), 7 45 7 48 m· Η, 3H), 7.71 (s , 1H), 8.05 (m, arom. Η, 2H), 8-11 (very wide, 1H). Example 141: Propane gas rain ge 'In a procedure similar to that described in -Examples 11a to 11], 3,5-dimethyl-4-4[2-(5-methyl-2-phenyl-oxazole- 4-yl)-ethoxybenzaldehyde (Example 117) with (S), 4-benzyl-3-propoxyethenyl oxazolidine 2-ketone (Example 26) and nBu2B〇Tf To produce (s)_4-benzyl_3_((23,311)_3_丨3,5-dimercapto-4-[2,(5-mercapto-2-phenyl-oxazol-4-yl) · Ethoxy]•phenyl}·3_hydroxy-2-propoxypropionyl)oxazolidine-2-one (according to NMR, one of the four isomers is predominant; according to D· Haigh , hc BirrelU b. CC Cantello, DS Eggleston, RC Haltiwanger, RM Hindley, A. Ramaswamy, NC Stevens, Tetrahedron

Asymmetry 1999,10,1353- 1367 ’ temporarily configures the 2s, 3R name). Reduction of (S)_ 4_mercapto-3_((2S,3R)-3-{3,5-dimethyl-4-[2-(5) with triethylmethionine in trifluoroacetic acid - mercapto-2-phenyl-form _4·yl)-ethoxy]-phenyl}-3-transyl-2-propoxypropyl) „ 峻 . 烷 烷 烷 · ketone To give (S)-4-^yl-3-((2S)-3-{3,5-dimethyl-4-(2-(5-methyl-2-phenyloxazole-4-yl) )-ethoxy]-styl}_ 2-propoxypropionyl)oxazolidin-2-one. Next, (S)-4-mercapto-3-((2S)-3-{3 ,5-Dimethyl-4- ____- 200 - This paper size is applicable to the SS standard (CNS) A4 specification (210X297 mm)

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Line 1328085 A7 B7 V. Description of the Invention (197) [2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-propoxypropyl fluorenyl σ oxazolidin-2-one is saponified with 1 gram of molecular weight NaOH in THF to give (S)-3-{3,5-dimethyl-4-[2-(5-A) as a colorless solid Benzyl-2-phenyloxazol-4-yl)-ethoxy]-phenyl}-2-propoxypropionic acid MS: 436.4 (M-Η), 376.3, 251.1, 217.1. NMR : (DMSO-d6, 1H, 400MHz, 5, TMS) 0.87 (t, J = 7.2, 3H), 1.56 (sext., J = 7.2, 2H), 2.18 (s, 6H), 2.39 (s, 3H) ), 2.86 (dxd, J=15.2, J=8, 1H), 2'.98 (t, 1=7.2, 2H), 3.02 (dxd, J=15.2, J=4.8, 1H), 3.31-3.37 ( m, 1H), 3.44-3.50 (m, 1H) 4.01-4.04 (m, 3H), 6.85 (s, 2H), 7.40-7.45 (m, 3H), 7.98 (dxd, J=8, J=0.8, 2H) « Example 142 . a~| 2 - Butyl-3-cyclohexyl-3-{3,5-dimethyl-4-indole 2-(5-methyl-2-pyrox-oxazol-4-yl )-ethoxy bromide 丨-3-蕤ethyl propionate

A solution of ethyl 3-methoxyacetate (12 mg, 0.763⁄4 mol) in THF (3 mL) was added to THF at -78 °C; 2 g of molecular weight LDA Solution (0.383⁄4 liter, 0.76 mmol) (for preparation of buty-3_alkoxyacetic acid ethyl vinegar) Reference: AF Noe丨s, A. Dem〇nceau, N

Petiniot, A..J. Hubert, P. Teyssie, Tetrahedron 1982, 38, 2733-2739). The solution was stirred for 1 minute and then added to the 3,5 methyl 4-[2-(5-methyl-2-phenyl) _4_yl)-B in thf (3 mL) A solution of oxy]- bracelet (2543⁄4 gram '0.763⁄4 mole' example ip). The reaction mixture was stirred at -7 8 C for 30 minutes, then quenched by the addition of saturated NHjCl at -7 §. The solution was diluted with water and ethyl acetate to separate the layers, and the __- 7Π1 -___ paper size was applied to the Chinese National Standard (CNS) A4 specification (210X297 mm).

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Line 1328085 A7 B7 V. Description of the invention (198 The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried with thios. to evaporate solvent to give a yellow oil, which was separated by column chromatography Purification by the method (j. hexanes / EtOAc / EtOAc / EtOAc / EtOAc / EtOAc) H) +, 476.3, 446.3, 402.4, 186.4. NMR: (CDC13, 1H, 300MHz, &lt;? 'TMS) 1.16 (t, J=7.2, 3H), 2.20 (s, 6H), 2.25-2.35 (m , 2H),. 2.39 (s, 3H), 2.87 (d, J=4.8, 0.7H-), 2.98 (t, J=7.2, 2H), 3.30-3.44 (m, 1H), 3.63-3.75 (m , 1H), 3.88 (d, J=7.2, 0.3H), 3.98-4.03 (m, 2H), 4.16 (q, J=7.2, 2H), 4.76 (t, J=6.4, 0.3H), 4.84 ( t, J=6.4, 0.7H), 4.99-5.13 (m, 2H), 5.63-5.82-(m, 1H), 6.98 (s, 2H), 7.40-7.45 (m, 3H), 7.97-8.00 (m , 2H). bl 2Z-butyl- 3-# oxy-3 - {夂5·dimethyl-4-pyrene-2-(5-methyl sulphur- ° azole-4 ·yl)-ethoxy 1 - Benzene 抡 抡 抡 Λ龅 三 三 triethylamine (55 μl, 〇. 4 mmol) and decane sulfonate gas (42 μl of '0_3 6 mmol) was continuously added at 0 ° C to 2-but-3-enyloxy-3-{ 3,5-dimethyl- in di-methane (2 mL). 4-[2-(5-Methyl-2-phenyl-samily-4-yl)-ethoxy]-phenyl}-3-ylpropanoic acid ethyl ester (150 mg, 0.3 mmol) The solution was allowed to warm to room temperature overnight, and then was added with saturated NaHCO; the layer was separated and the aqueous phase was extracted twice with dichloromethane. Concentrated in vacuo to supply crude 1,3- 3 -amino-oxy-3 - { 3,5-dimethyl-4-[2-( 5-methyl-2-phenyl_ ° azole-4-yl )-Ethoxy]-phenyl phenyl 3_methanesulfonyloxypropionic acid ethyl ester, _- - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 Five Inventive Note (199) It was dissolved in THF (2 mL). DBU (139 μL, 0.9 mmol) was added at room temperature and the mixture was stirred at 501 for 8 hours. The reaction was quenched by addition of water, the layers were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, and the solvent was evaporated under reduced pressure to afford a brown oil, which was purified by column chromatography (yield, hexane / AcOEt = 9/1). 79 mg of yellow oil (0.1 66 mmol, 55%) of the title compound and 29 mg (6 1 micromolar, 20%) as a bright yellow oil. 2E-butyl 3-conoxy-3-{3, 5-Dimethyl-·4 bis[2,(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy-yl]-phenyl}-propionate acid. Number of oxime-isomers: MS: 476.3 (Μ+Η) +, 328.4, 293.4, 186.3. NMR : (CDC13, 1H, 400MHz, ¢5, TMS) 1.35 (t, J=8, 3H), 2.22 (s, 6H), 2.40 (s, 3H), 2.51 (q, J=7.2, 2H), 2.99 (t, J=7.2, 2H), 3.94 (t, J=7.2, 2H), 4.08 (t, J=7.2, 2H), 4.28 (q, J-8, 2H), 5.09 (dxd, J= 8.8, J=0.8, 1H), 5.16 (dxd, J=16.8, J=0.8, 1H), 5.84-5.94 (m, 1H), 6.89 (s, 1H), 7.39-7.46 (m, 5H), 7.99 (dxd, J=8, J= 1.6, 2H). £]_22-but-3-enyloxy-3-{3.5-dimethyl-4-[2-(5-methyl-2-benzene-oxazol-4-yl)·ethane group 1-苽A hydrazine-acrylic acid in a step similar to that described in Example 120f], 2Z-but-3-enyloxy-3-{3,5-methyl-4-[2-(5-methyl-- 2-phenylnosyl-4-yl)-ethoxy]-phenyl}-ethyl acrylate saponified to give 2Z-butyl- 3 _ lesseoxy- 3- {3,5 - one as a colorless solid Methyl-4-[2-(5-methyl-2-phenyl-wow-4-yl)-ethoxy]-phenyl}-acrylic acid. ______- 70^ - This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1328585 A7 B7 V. Invention description (200) MS : 446.0 (MH)-, 391.7, 327.1, 256.9, 212.9, 185.6 ° NMR : (CDC13, 1H, 400MHz, 5 , TMS) 2.23 (s, 6H), 2.40 (s, 3H), 2.51 (q, J=7.2, 2H), 3.01 (t, J=7.2, 2H), 3.96 (t, J=7.2, 2H), 4.09 (t, J=7.2, 2H), 5.12 (dxd, J=8.8, J=0.8, 1H), 5.18 (dxd, J= 16.8, J=0.8, 1H) , 5.84- 5.94 (m, 1H), 7.03 (s, 1H), 7.41-7.46 (m, 5H), 7.99 (dxd, J=8, J=l.6, 2H). Example 143 2E-butyl-3-ene gas -3-{3,5-dimethyl-4.-"2-(5-methyl-2-methyl-oxazol-4-yl)-ethane group 1 - Stupid hydrazine-acrylic acid in a procedure similar to that described in Example 1 20f], 2E-but-3-enyloxy-3-{ 3,5-dimercapto-4-[2-(5-曱) Ethyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenylethyl acrylate (Example 142b)) saponified to give 2E-but-3-enoxy-3 as a colorless oil - {3,5-Dimethyl-4-[2-(5-methyl-2-phenyl-indol-4-yl)-ethoxy]-phenyl}-acrylic acid. MS : 446.1 ((················· =7.2, 2H), 2.98 (t, J=7.2, 2H), 3.93 (t, J=7.2, 2H), 4.03 (t, J=7.2, 2H), 5.15 (dxd, J=8.8, J=0.8 , 1H), 5.19 (dxd, J= 16.8, J=0.8, 1H), 5.83-5.91 (m, 1H), 6.20 (s, 1H), 7.02 (s, 2H), 7.42-7.51 (m, 3H) , 7.98 (dxd, J=8, J= 1.6, 2H). - Example 144 al丨 racemic 1-3-丨4-f 2-(2-gaso)-5-methyl-carbazole- 4- Some methoxy. Kebu 2-methyl stupid}-2-Ethyl propyl propionate _- 2Q4 -_ This paper scale applies to China Standard (CNS) A4 size (210 X 297 mm)

Line 1328085 A7 B7 V. Description of the invention (2()1) Adding citric acid (97 mg, 300 micromolar, 1.5 equivalents) and a small amount of potassium citrate to [racemicity] in acetone (4 ml) Ethyl 2-ethoxy-3-(4-hydroxy-2-methylphenyl)propanoate (50 mg, 200 micromoles, 1 equivalent, example 129c)) and 4-methylmethyl-2- (2-Chlorophenyl)-5-methylcarbazole (72 mg, 3 Torr micromolar, 1.5 eq., in a procedure similar to that described in Example 2 1 a) and b], with 2-chloro A solution of the base benzaldehyde and the diethylindenyl monohydrazine followed by the P?Cl3 treatment. The mixture was heated under reflux for 12 hours, filtered and the filtrate evaporated in vacuo. The residue was treated with vinegar, brewed, and ice-cold 1 g of molecular weight hydrochloric acid. The organic layer was washed twice with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give a yellow oil, which was purified by EtOAc (EtOAc, EtOAc/EtOAc/EtOAc) %) title compound ^ MS : 458.3 (M+H) + , 414.1, 384.1, 247.1, 206.1, 179.1 &lt;· NMR : (CDC13, 1H, 300MHz, δ , TMS) 1-15 (t, J=7.2, 3H), 1.22 (t, J=8, 3H), 2.33 (s, 3H), 2.46 (s, 3H), 2.97 (d, J=7.2 2H), 3.25-3.37 (m, 1H), 3.52-3.62 (m, 1H), 3.96 (t, J=7.2, 1H), 4.16 (q, J=8, 2H), 5.00 (s, 2H), 6.79 (dxd, J=8, J=l.6&gt; 1H ), 6.83 (d, J=1.6, 1H), 7.10 (d, J=8, 1H), 7.33-7.37 (mj 2H), 7.47-7.50 (m, 1H), 7.95-7.98 (m, 1H). Bl "racemic 1 - 3- M-丨2- (2-qi 某)-5-methyl p azole-4-yl yl i 1-2-methyl phenyl -2- Argon-propionin in a procedure similar to that described in Example 120f], [racemic]-3-{4-[2-(2-phenylphenyl)-5-methyloxazol-4-yl Ethyl methoxy]-2-methylphenyl}-2-ethoxypropionate is saponified to give [racemic]-3_ as a colorless oil

Binding

Line ------- 9〇cj - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Description of invention (2〇2) {4-[2-( 2-Phenylphenyl)-5-methyloxazol-4-ylmethoxy]-2-methylphenyl- 2-ethoxypropionic acid. MS : 428.2 (MH)*, 382.0. 222.7, 176.8 ° NMR : (CDC13, 1H, 300MHz, 5 , TMS) 1.13 (t, J=7.2, 3H), 2.34 (s, 3H), 2.46 (s, 3H ), 2.93 (dxd, J=15.2, J=8.8, 1H), 3.13 (dxd, J=15.2, J=4, 1H), 3.31-3.37 (m5 1H), 3.48-3.56 (m, 1H), 4.01 (dxd, J=8.8, J=4.8, 1H), 5.30 (s, 2H), 6.81 (dxd, J=8, J=1.6, 1H), 6.85 d 1H), 7.13 (d, J=8, 1H ), 7.33-7.37 (m, 2H), 7.47-7.51 (m, 1H), 7.95-7.98 (ms 1H). Example 145 『racemic, seat 1-3- Μ-Γ2-(3-气苽)-·5-甲甲哼崦甲甲 y base 1-2-methyl 苽基卜 2-乙氲墓Acid in a similar procedure to that described in Example 144a], [[R)-2-ethoxy-3-(4-hydroxy-2-methylphenyl)propanoate (Example 129c)) 3-Chloromethyl-2-(3-chlorophenyl)-5-methyl 1&gt; No. (in a procedure similar to Example 21a) and b], 3-chlorobenzaldehyde and diethyl hydrazine The reaction is carried out in the presence of cesium carbonate and potassium iodide to produce [racemic]-3-{4-[2-(3-chlorophenyl)-5. -methylcarbazol-4-yloxy-2-ethyl-3-phenyl}-ethoxypropionic acid vinegar's further saponified in a similar manner to that described in Example 12, to give [Racecycling]_ 3_ {4-[2-(3-(phenylphenyl)-5-methylβ-indol-4-yloxy)-2-methylphenyl)_ 2 - ethoxypropionic acid. MS: 428.2 (Μ-Η)·, 382.1, 337.7, 223.0, 176.2. -206 - 'This paper scale is suitable for S S standard (CNS) A4 specification (21GX297 public) '

Packing

Line 1328085 A7 ________B7 V. Description of the invention (~~&quot; - NMR: (CDC13, 1H, 300MHz, 5, TMS) 1.13 (t, J=8, 3H), 2.34 (s, 3H), 2.44 (s, 3H ), 2.93 (dxd, J=15.2, J=8.8, 1H), 3.14 (dxd, J=15.2, J=4, 1H), 3.31-3.39 (m, 1H), 3.49-3.57 (m, 1H), 4.02 (dxd, J=8.8, J=4, 1H), 4.96 (s, 2H), 6.80 (dxd, J=8, J=0.8, 1H), 6.83 (d, J=〇.8, 1H), 7.13 (d, J=8, 1H), 7.34- 7.42 (m, 2H), 7.90 (dxt, J=7.2, J=0.8, 1H), 8.01-8.02 (m, 1H). Example 146 fill racemability卜2-ethoxyxo-3-{2-methyl_4_"3_is_methyl·2 yl. -17 -4--4-) propyl group 1 菜 丨 - 醢 醢 in similar to Example 2 In the procedure described in 1 f], [racemic] 2 ethyl ethoxy-3-(4-hydroxy-2-methylphenyl)propanoate (example 129 {;]) and 3_(5 Methyl-2-phenyl-十圭_4_yl)------- (J 乂c〇1Hns,m) heart, j A. Oplinger, A. Jeffrey, TM Willson, International Patent Appl'' Publication No. W00008002 (Al), 2000) is reacted in the presence of triphenylphosphine and diethyl azodicarboxylate to give [racemic 2·ethoxy-3-{2-methyl-4] -[3-(5- Ethyl-2-phenylazole-4-yl)propoxyl]phenyl}-propionic acid ethyl ester, which was further saponified in a similar manner to that described in Example 1 20f] to give a colorless oil. Cyclosyl 2·ethoxy 3 ( 2 decyl-4-[3-(5-methyl-2.phenyl)oxazol-4-yl)propoxy]pyridylpropionic acid. _ MS : 422.2 (MH),, 375, 9, 308.7, 222.8, 179.4. NMR: (CDC13, 1H, 300MHz, &lt;5, TMS) 1.13 (t' j=7 2 rushed 2.14 (qUint·, J=7.2, 2H ), 2 28 (s, 3Η), 2·32 (s 3h), 2 The size of the paper is applicable to the China National Standard (CNS) A4 specification (21QX297 public) -----

Binding

Line 1328085 A7 B7 V. Description of invention (2〇4) J=7.2, 2H), 2.92 (dxd, J=15.2, J=8.8, 1H), 3.13 (dxd, J=15.2, J=4, 1H), 3.29-3.40 (m, 1H), 3.47-3.58 (m, 1H), 3.95 (t, J=7.2, 2H), 4.03 (dxd, J=8.8, J=4, 1H), 6.68 (dxd, J= 8, J=1.6, 1H), 6.71 (d, J=1.6, 1H), 7.10 (d, J=8, 1H), 7.40-7.46 (m, 3H), 7.98 (dxd, J=8, J= 〇.8, 2H). Example 147 "External" Xiaolu sex]-3- f 4-Γ 2-(4- gas very-3-A certain 茇,-5-A 呤咄4-4-pentaoxy1-2-A In the procedure described in analogy to Example 144a], a certain amount of [racemic] 2 -ethoxy-3-(4-hydroxy-2-methylphenyl)propanoic acid ethyl ester ( Example 129c]) with 4-chloromethyl-2-(4-fluoro-3-methylphenyl)-5-methyl. No. (in a similar manner to Example 21 a) and b] A fluorinated 3-methylbenzaldehyde and a dihydrazino group is lost in a single month, followed by treatment with POCI3) in the presence of cesium carbonate and potassium iodide to produce [racemic] _3-{4- [2-(4-Fluoro-3-methylphenyl)_ 5-methyl "oxazol-4-ylmethoxy]-2-methylphenyl}-propionic acid ethyl ester, which is similar Further saponification was carried out in the procedure illustrated in Example 120f] to give [racemic]-3-{4-[2-(4-fluoro-3-methylphenyl)-5-methylcarbazole as a colorless solid. 4--4-methoxy]-2-methylphenylpropanoic acid MS: 426.2 (MH)·, 380.1, 336.5, 283.3, 255.4. NMR: (DMSO-d6, 1H, 300 MHz, 5, TMS) 1.02 (t,j=72 3H), 2.27 (s, 3H), 2.31 (s-, 3H), 2.43 (s, 3H), 2.79 (dx d J=15.2, J=8, 1H), 2.89 (dxd, J=15.2, J=6.4, 1H), 3.20-3 32 (m, 1H), 3.45-3.52 (m, 1H), 3.91 (dxd, J=8, J=6.4, iH) 4.94 (s, 2H), 6.78 (dxd, J=8, J=0.8, 1H), 6.83 (d, J=〇g • 208 - This paper size applies to China Standard (CNS) A4 specification (210X297 public)

Binding

Line 1328085 A7 B7 V. Description of the invention (2〇5) 1H), 7.07 (d, J=8, 1H), 7.29 (t, J=8, 1H), 7.77-7.82 (m> 1H), 7.89 (dxd , J=8, J=0.8, 1H), 12.65 (br.s, 1H). Example 148 ί external consumption. Sexuality 2 2- 氪 -3- -3- {4_丨2-(2-甲甲基甲〇〇峻_4_羞methoxy-4-E-A certain 丨- Propionic acid In a similar procedure to that described in Example 144a], [R-[rho]-2-ethoxy-3-(4-hydroxy-2-methylphenyl)propanoic acid ethyl ester (Example 129c)) With 4· chloromethyl-2-(2-methoxyphenyl)-5-methyl 1 oxime (in a similar manner to Examples 213) and 1)], 2-nonyloxybenzaldehyde and Ethyl oxime, followed by treatment with POCI3) is reacted in the presence of cesium carbonate and potassium iodide to give [racemic]-2-ethoxy-3-{4-[2-(2- Ethyloxyphenyl)_5-methylcarbazole-4-yloxy]_2-methylphenylpropionic acid ethyl ester, which was further saponified in a procedure similar to that described in Example 120f] to give white Solid [racemate]-2-ethoxy-3_{4_[2_(2-methoxyphenyl)-5-methyl-2-oxazol-4-yloxy]-2-methylphenyl Propionic acid. MS : 424.3 (MH)·, 380.3, 334.8, 299.3, 255 NMR : (CDC13, 1H, 400 MHz, d, TMS) 1.12 (t,J=7 2 3H) 2.33 (s,3H),2.44 (S,3H ), 2.91 (dxd, J is 5 2, J=8' iH)' 3.10 (dxd, J=15.2, J=4, 1H), 3.29-3.36 (m, 1H), 3.49-3.57 (m, 1H) , 3.94 (s, 3H), 3.99 (dxd, J=8, J=4, iH), 4.99 〇2H)' 6.79 (dxd, J=8, 1H), 6.83 (d, J is 6.6, 1H) · 7 w 7.05 (m, 2H), 7.12 (d, J=8, 1H), 7.41 (dxt, J=8,, J=〇: ih 7.90 (dxd, J=8, J=0.8, 1H) 〇 'Example 149 -209 -

•摹定

1328585 A7 B7 V. Description of the invention (2〇6) f racemic property 3-(4-{2-"^^^^^^^^^^^^^^^^^^^^^^^^^^ ..,-5,6,7,8-tetrahydronaphthalenyloxyl, a certain age, in a procedure similar to that described in Example 17a], [racemic] _2 ethoxy-3-(4- Ethyl hydroxy-5,6,7,8-tetrahydroindole-1-ylpropionate (Example 1〇81)]) with 2-[2-(4-chlorophenyl)-5-mercaptocarbazole _4•yl]ethanol (in a sequence similar to that described in Examples 21a) to e], the 4-chlorobenzene disk was converted to 2·[2_(4-_phenylphenyl)-5-methylcarbazole-4- (ethanol) reacts in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to produce "racemicity" _3_(4{2[2(4_chlorophenyl)-5-A) Ethyl oxazol-4-yl]ethoxy}-5,6,7,8-tetrahydroindole_丨_.yl) 2-ethyl ethoxypropionate, which is similar to Example 9 The procedure described is further saponified to give [racemic]_3_(4丨(4-chlorophenyl)-5-methyloxazol-4-yl]ethoxy brom 5,6 as a colorless oil. , 7,8_tetrahydroindole·buki)-2-ethoxypropionic acid. MS : 484.3 (M+H) + , 506.2 (M+Na) + NMR: (CDC13, 1H, 6 , TMS, 300 MHz) 1.12 (t, J=7.2, 3H) 1.73- 1.79 (m, 4H), 2.37 (s, 3H), 2.60-2.74 (m, 4H), 2.91, 3.05 (m., 4H), 3.32-3.35 (m, 1H), 3.50-3.56 (m, 1H)} 3 9g_ 4.01 (m, 1H), 4.19 (t, J=6.3, 2H), 6.61 (d, J=8.4, 1H), 6.98 (d, J=8.4, 1H), 7.39 (d, J=6.9, 2H), 7.90 (d , 8.7, 2H) COOH is very wide. 'Example 150 - _ "External Cyclonic 1-2-Ethyl-3-(4-trans-base-)-based diacids. In a procedure similar to that described in Example 93a], 4-芊 萘 萘 萘 以 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( CMS) A4 size (210 X 297 mm) ' ~-1328585 A7 _______B7 V. Description of invention (2()7) Carbonated at room temperature) and gasification (ethoxyethoxycarbonylmethyl) Tritene scale [Tetrahedron 50 (25), 7543-56 (1994)] reaction to produce 3-(4-decyloxy tea-1 -yl)-2-ethoxy(Z,E)-acrylic acid Ester. As illustrated in Example 91 d], hydrogenation of 3-(4-benzyloxynaphthalenyl-fluorenyl)-2-ethoxylate-(Z,E)-ethyl acrylate afforded a light brown oil. Racemic] _ 2_ethoxy-3-(4-pyridin-1-yl)propionic acid ethyl acetate MS: 288.3 (M), 242.2, 215.3, 157.2. NMR: (CDC13, 1H, 5, TMS, 3Ό〇ΜΗζ): 1.11 (t, J= 7.0, 3Η), 1.17 (t, J=7.1, 3H), 3.26-3.60 (m, 4H), 4.10-4.19 (m, 3H), 5.67 (s, 1H), 6.82 (d, J=7.6, 1H), 7.20 (d, J= 7.6, 1H), 7.46-7.58 (m, 2H), 8.03 (d, J=7.8, 1H), 8.24 (d, J=7.9, 1H) 〇 bl 『racemic 1 - 2-ethane- 3 甲-2 phenyl-s-azol-4- methoxy) stupid-1 - some 1 - propylene in a procedure similar to that described in Example 1 08c], in N, N-dimethyl Treatment of 4-chloromethyl-5-methyl-2-phenyl-oxazole and sodium hydride in guanamine [racemic]-2-ethoxy-3-(4-hydroxyindole-1-yl) Ethyl propionate to give [racemic]-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy) tea-1 -yl]-propionic acid ethyl ester, which was further t-formed in a similar manner to that described in Example 9 丨e] to give a racemic 2- ethoxy 3-(4-(5) -Methyl-2-phenyloxazole·4-ylmethoxy)indole-yl]-propionic acid MS: 430.3 (Μ·Η)·· - NMR : (CDC13, 1H, δ, TMS, 300MHz) 1.01 (t, J=7.0, 3H), 2.47 (s, 3H), 3.15-3.25 (m, 2H), 3.41-3.63 (m, 2H), 4.16 (dxd. J, = 3.9, J2=6.9 , 1H), 5.17 (s, 2H), 6.90 (d. J=7.9, 1H), - —— · / I i This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1328585 A7 B7

V. INSTRUCTIONS (2Q8) 7.30 (d. J-7.9, 1H), 7.44-7.57 (m, 5H), 8 〇2_8 〇5 (m, 3H), 8.34 (d, J=8.2, 1H), COOH Very wide. Example 1 5 1 "Exocyclyl-2-oxoindole-3-diylbenzene # [blg stopper _4 1 propyl hydrazine * in a step similar to the example 9 1 b], will 7-Benzyloxybenzo[b]thiophene (as benzo[b]sulfonyl-7-ol in N,N-didecylguanamine [1^£111· Soc. Perkin Trans. 1 ( 1983), (12, 2973 7], stearyl chloride and potassium carbonate produced at room temperature) and dichloromethyl methyl ether in di-methane methane are reacted under hydrazine to obtain 7-卞Oxybenzo[b] porphin-4-carboxylic aldehyde. Gasification (ethoxyethoxypyrimylmethyl)triphenyl in 2-propanol in a procedure similar to that described in Example 9.3a] Squamous treatment of 7-hydroxy benzo[_pheno-4·Μ to give 3-(7-yloxybenzo[b]4 phen·4•yl)_2(z,e)·ethoxypropane Acidic acid. In a similar manner to that described in Example 93b], the magnesium in THF/Me〇H(i:i) was reduced at 3:(7_benzyloxybenzo...thieno-4 -yl)_ 2(Z'E)-ethoxypropionic acid ethyl acetoacetate to give [racemic] oxy benzo[b] plug &gt;% ·4-yl) 2-ethoxyl Methyl acrylate, followed by a step similar to that described in Example 93c] Dimethyl sulphate and trifluoromethane in the alkane remove the aryl protecting group at room temperature to obtain a racemic 2-ethoxy-3-(7- [b]Deuterophene-4-yl) methyl propionate MS: 279.0 (M-Η)·. 'NMR: (CDC13, 1H, (5, TMS, 300MHz) 1.12 (t,j=7 〇, 3H ), 3.230.36 (m3 3H), 3.56-3.61 (m, 1H), 3.68 (s&gt; 3H)/4.11 This paper scale applies to China National Standard (CNS) A4 specification (210 X — 1 ~ -- 丄:^如

4·15 (dxd, J| = 5.5, J2=7 7 im ζ 〇, 7ns ... 2 , 1H) '5.83(s,lH), 6.63(d,J=7.8, ),7.〇8(d, J = 7.8, IH), 7.45 (s, 2h). In the step described in the example, the method is as follows: in the step described in the example, the 4-chloro-indolyl-5-methyl-2-phenyl group in the indole ·Surface and hydrogenated steel treatment [racemic]-2-ethyl lactyl-3_(7· mercaptobenzo[small-septyl)-propionic acid methyl vinegar to produce [racemic]-2 · Ethoxy ethoxy [7 ♦ methyl · 2 phenyl ... qi 4 4 methoxy) benzo [b] P ceto _ 4 yl] propionic acid methyl vinegar, similar to the example 91e The steps described are further deuterated to produce a racemic nature of 2-methyloxy_3_[7-(5-methyl-2-phenyl-s-___ylmethoxy) as a colorless solid. [b] &lt;»cephen-4-yl]-propionic acid. MS : 436.2 (M-Η)' NMR: (CDC13, 1H, TMS, 300MHz) 1.07 (t, J=7.0, 3H), 2.47 (s, 3H), 3.19-3.33 (m, 2H), 3.40- 3.55 (m, 2H), 4.10- 4.15 (dxd. J, = 4.1, J2=8.3, 1H), 5.20 (s, 2H), 6.87 (d. J=8.0, 1H), 7.19 (d. J=8.0 , 1H), 7.43- 7.48 (m, 5H), 8.00-8.03 (m, 2H), COOH is very wide. Example 152 L_Exo-racemic 2- 2-ethoxypropane argon 竿 呤 methyl oxazole-4 - a group of gas, a 1 苽砰fblp, _4-base}_ propyl hydrazine in a procedure similar to that described in Example 1 〇8c], with 4-chloroform in N,N-dimethylformamide Base-2-(4-isopropoxyphenyl)-5-mercaptocarbazole (in a procedure similar to that described in Examples 2 1 a) and b), 4-isopropoxybenzaldehyde and diethyl - This paper scale applies to China National Standard (CNS) A4 specification (210X297 public) 1328585 A7 _____B7 V. Invention description 1 base single handle, followed by P0C13 treatment) and sodium hydride treatment [racemic] - Methyl 2-ethoxy_3_(7-hydroxybenzo[b]thiophene-4-yl)propionate (Example 151a)) to give [racemic] _2 ethoxy _3_{7[2( 4isopropoxyphenyl)-5-methylcarbazole_4_ylmethoxy]benzo[b]p-septene _4_Kibupro-S parent methyl ester, which was further saponified in a procedure similar to that described in Example 9丨e] to give [racemic]-2-ethoxy-3-{ 7- as a colorless solid. [2-(4-Isopropoxyphenyl)-5-indolylcarbazole-4-yloxy]benzo[b]porphin_4_yl}-propionic acid. MS : 494.1 .( Μ- Η)' NMR (CDC13, 1H, δ, TMS, 300MHz) 1.07 (t, J=6.9, 3H), 1-36 (d, J=6.3, 6H), 2.44 ( s, 3H), 3.18-3.30 (m, 2H), 3.38-3-44 (dxd, J, = 4.2, J2=14.1, 1H), 3.49- 3.55 (m, 1H), 4.09-4.13 (dxd, J , = 3.9, J2=8.15 1H), 4.58-4.66 (m, 1H), 5.17 (s, 2H), 6.86 (d, J=7.8, 1H), 6.93 (d. J=8.7, 2H), 7.18 ( d, J-7.8, 1H), 7.42-7.47 (dxd, J, = 5.4, J2 = 9.9, 2H), 7.91-7.94 (dxd, J2 = 6.9, 2H), COOH is very wide. Example 153 1^1^性卜2-ethoxy curtain-3-(7-{立1£2_(2_乙一某_4_|1笨某)_ U_基0号 _4·基1乙Oxyquinone [bl忒 _4·) and vinegar in a procedure similar to that described in Example 17a], [racemic]_2_ethoxy-3-(7-hydroxybenzo[b] ] p-Phen-4-yl) decyl propionate (example i51a)) and 2-[2-(2-ethoxy-4-lactophenyl)-5-methyl". All-base]ethanol (Example 95) is reacted in the presence of diphenyl scales and DEAD (diethyl azo-monoacid) to give [racemic]-2-ethoxy-3-(7- { 2-[2-(2_ethoxy-4-fluorobenzene L___- 214 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Description of invention (211) )--5-mercapto-oxazol-4-yl]ethoxy}benzo[b]porphin-4-yl)propionate, which is further saponified in a similar manner to that described in Example 9 1 e] To produce a racemic 2-ethoxy-3-(7-{2-[2-(2-ethoxy-4-fluorophenyl)-5-methylcarbazole 4-yl]ethoxy benzobenzo[b]thiophene-4-yl)propanoic acid. MS: 5 12.2 (M-Η)-. NMR : (DMSO-d6, 1H, δ, TMS, 300MHz) 0.99 (t, J = 6.9, 3H), 1.33 (t, J = 6.9, 3H), 2.3 (T[s, 3H), 2.98 (t, J=6.3, 2H), 3.17-3.33 (m, 3H), 3.46-3.57 (m, iH), 3.99-4.04 (dxd,

Ji = 5.4, J2=7.5, 1H), 4.09-4.16 (q, J=6.9, 2H), 4.37 (t, J-6.3, 2H), 6.83-6.91 (m, 2H), 7.04-7.08 (dxd, 1, = 2.1, J2=11.4, 1H), 7.15 (d, J=8.1, 1H), 7.49 (d, J=5.4, 1H), 7.71 (d, J=5.4, 1H), 7.76-7.81 (dxd , J, = 6.9, J2=12, 1H), 12.67 (s, 1H) » Example 154 f. &gt; Cyclonic. 1 - 3- ( 7- { 2-『2- (4-Fluoro .5·Methyl 4 P all-4-yl·]ethoxy benzobenzo &lt; ld &lt;RTI ID=0.0&gt;&gt;&gt;&gt; [Racecyclo]_ 2_ethoxy-3-(7-hydroxybenzo[bp-desphen-4-yl)propanoate (example i5ia)) with 2-[2-(4-chloro) Phenyl)-5-methylcarbazole-4-yl]ethanol (in a sequence similar to that described in Examples 2 1 a) to 2 1 e], converting 4-chlorobenzaldehyde to 2_ [2-(4- Chlorophenyl)-5-methyloxazol-4-yl]ethanol) is reacted in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to produce [racemic]-3. ( 7_ { 2- [ 2· ( 4_ phenyl)-5-methyloxazol-4-yl]ethoxy} benzo[b]p-cephen-4-yl)·2_ __- 21S -___ This paper scale applies to the Chinese National Standard (CNS) Α4 specification (210X297 mm) 1328585 212 V. Description of the invention (^-lactyl propionic acid &quot;" is similar to the example. Step 4 to produce [racemic] ^1 phenyl)-5-methyl as a colorless oil Seven-spin-4•yl]ethoxyl} stupid and [(tetra)-pheno- 1 =-ethyllactylpropionic acid. Soil)-2-MS: 484.2 (M-Η).. NMR: (CDC, 3,1H, , , TMs, 3〇〇MH2)1〇7(tj=7〇2 44 (s,3H),3.〇5(t,Jas6,,2H) 3 22 3 3 i(m 2H) 3.45 (dxd, J , = 4.4, J2=u.2&gt; 1HL 3 513 57 &gt;8.0, 1H), 7.i6(d, J=8 〇, π)”” H '7·91 (m, 2H), COOH is very wide '), 7.87- Instance 155 ^similar to the example dirty] explained in the steps to the heart of dimethyl methyl:: 4' chaotic base 2_(4_t-butylphenyl)-5, base (four) In a similar procedure; in the steps described in Examples 2U) and b), 4: butyl benzaldehyde and diethyl 2: H) are treated with p〇cl3) and fluorinated [racemic] [oxy-3·(7-light-based benzo[b]n-secret-4-yl)-propionic acid methyl vinegar (example a]) 'to produce [racemic] 3 {7 seven (4 third butyl Phenylmethyl-methyl-n-yl-yloxy]benzo[small snail-4-yl&quot;-ethoxypropionic acid: vinegar, The procedure illustrated in Example 91e] is further enhanced to give [racemic]-3-{7-[2-(4-t-butylphenyl)-5.methyl as a colorless amorphous solid. Ten sitting -4- to oxy] stupid and (five) violent -4-yl} 士1328585 A7 B7 ___ V. Description of invention (213) ethoxypropionic acid. MS: 492.2 (MH)', 448.2 NMR: (CDC13, 1H, 6, TMS, 300 MHz) 1.07 (t, J=7.2, 3H), 1.35 (s, 9H), 2.46 (s, 3H), 3.26 ( m, 2H), 3.51 (m, 2H), 4.13 (m, 1H), 5.20 (s, 2H), 6.87 (d, J=8.1, 1H), 7.19 (d, J=8.1, 1H), 7.45- 7.48 (m, 4H), 7.94 (d, J = 8.7, 2H), COOH is very wide. Example 丨 56 . (S)-2-Ethyl aryl-3" 3-methyl-4-"2-(5-methyl-2-yl-2-yl-2-yl)-ethoxy b In a step similar to that described in Examples 1 1 a] to 1 1 c], 3-methyl-4-[2-(5-mercapto-2-phenylisoxazole-4- ))-ethoxy]-benzaldehyde (Example 114b)) reacts with (S)-4-mercapto-3-ethoxyethyl oxime 0 and the like ketone-2-one and nBi^BOTf to produce S)-4-;yl-3-((2S,3R)-2-ethoxy-3-hydroxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl) · oxazol-4-yl)-ethoxy phenyl} propyl hydrazide) oxazolidin-2-one (according to NMR, _ pole 4 of the four isomers predominate; according to Tetrahedron Asymmetry 1999, 1353, temporarily configured with 2S, 3R). Reduction of (S)-4-benzyl-3-((2S,3R)-2-ethoxy-) with triethylformane in trifluoroacetic acid 3-hydroxy-3·{3-methyl-4_[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenylindenyl). Alkan-2-one' followed by (s)-4-mercapto-3-((2S)-2-ethoxy_3_{3·methyl-4-[2-(5-methyl-2-) Phenyl-oxazol-4-yl)-ethoxyphenyl}nonyl) oxazolidine-2-one. Next (S) 4-benzyl-3-((2S)-2-ethoxy-3- 3-{3-indolyl·4· [2-(5-methyl-2-phenyl-oxazol-4-yl) ·Ethoxy]_stupid;-----217 ___ This paper scale applies to Chinese National Standard (QMS) A4 Specification (210X29^Love) — 1328585 A7 B7 V. Invention Description (214) Base} The oxazolidin-2-one is acetylated with iN Na〇H in THF to give (S)-2-ethyllacyl-3-{3-methyl-4_[2-( 5-methyl -2-phenyl-oxazol-4-yl)-ethoxy]- phenylpropionic acid. Identification of excess enantiomeric line 99 3 according to HPLC (Chiralpak-AD) 〇/〇. MS : (M+H+ 广410.5. NMR (DMSO-d6,1H,5, TMS): 1'〇3 (t,3H), 2.06 (s,3H), 2.35 (s, 3H), 2.75 (dxd, 1H), 2.82 (dxd, 1H), 2.91 (t, 2H), 3.23-3.32 (m, 1H), 3.45-3.52 Cm, 1H), 3.90 (dxd, 1H), 4.18 (t, 2H ), 6.69 (dxd, 1H), 6.95-6.99 (ms 2H), 7.47- 7.52 (m, 3H), 7.92 (dxd, 2H), 12_6 (s, 1H). Example 157 (5)-3-{3,5-dimethyl-4-(2-(5-methyl-2-. macro, dish-4-a)-hydrogenyl 1-styl -2-E gas. A certain age of 3,5-dimethyl-4-[2-(5-mercapto-2-phenyl) in a procedure similar to that described in Examples 1 1 a] to 1 1C] Zyzol-4-yl)-ethoxy]-benzaldehyde (Example 117) is reacted with (S)-4-benzyl-3-ethoxyethyl oxazolidin-2-one and nBu2BOTf to produce (S)-4-benzyl-3-((2S,3R)-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-carbazole-4- ()-ethoxy]-phenyl}-2-ethoxy-3-hydroxypropionyl)oxazolidin-2-one (according to NMR, one of the four isomers is predominant; Tetrahedron Asymmetry 1999, 1 353, temporarily named 2S, 3R). _Reducing (3)-4-mercapto-3-((23,311)-3-{3,5-dimethyl-4-[2-(5-A) with triethylformane in trifluoroacetic acid Benzyl-2-phenyl-oxazole-4-yl)-ethoxy]•phenyl}·2-ethoxy-3-hydroxypropanyl) ° oxazolidine-2-one, followed by (s )-4-mercapto-3-((2S)-3-{3,5-

Binding

Line _ - 218 - This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1328585

Dimethyl-4-[2-(5-methyl-2-indolyl-oxazol-4-yl)-ethoxy]-phenyl b-2-ethoxypropenylpolyoxazolidine_2 ketone. Next, (s)-4_芊基·3_((2S)-3-{3,5-dimercapto-4·[2·(5_methyl_2·phenyl-σ-azole·4 base) · Ethoxy]-phenyl} 2-ethoxypropenyl) oxazolidine-2-one is saponified with IN NaOH in THF to produce (s)_3_{3,5• as a colorless solid. Dimethyl_ 4-[2·(5-fluorenyl-2-phenyl-benzazosin-4-yl)-ethoxy]phenyl}·2 ethoxy propyl § again. According to the palmar HPLC ( Chiralpak·ad) identified 98.8% of the excess enantiomeric system. -- MS : (M-Η)· 422.2 〇NMR (DMS〇-d6, 1H, TMS): l.〇3 (t, 3H), 2.09 (s, 6H), 2- 38 (s, 3H), 2.72 (dxd, 1H), 2.80 (dxd, 1H), 2.91 (t, 2H), 3- 23- 3.32 (m, 1H), 3.45- 3.52 (m, iH), 3.90-4.02 (m, 3H), 6.84 (s, 2H), 7.47-7.52 (m, 3H), 7.92 (dxd, 2H), 12 8 (s 1H). 'Example 158 f On the eve of the race, 1-2-ethoxy _3_丨% gas ι^_"2·(5A 芊芊 芊芊 _ wow-4 - yl)- ethane group 1 _ 丨 丨 · 醢 醢 in a similar In the steps illustrated in Examples 114b], c] and d], 3-fluoro-4-tetrahydroxybenzaldehyde and 2-(5-methyl-2-phenyl-carbazolyl)ethyl methanesulfonate [ PCT Int. APP1. (2000) W00008002] Reaction. To get 3·fluoroyl_4·[2-(5-methyl-2-phenyl-carbazole·4·yl)·ethoxy]benzaldehyde. Gasification (benzyloxycarbonylethoxymethyl) 3-trifluoro-4-[2-() prepared by the procedure described for the synthesis of gasified (benzyloxycarbonylmethoxymethyl)triphenyl cast in a similar manner as in Example n 4a) 5-methyl-2-phenyl-carbazole _4_yl)-ethoxyl]benzaldehyde,

Install ίτ

1328585 A7 B7 V. Description of invention (

216 followed by 2(2/)-ethoxy-3-{3-fluoro-4-[2-(5-methyl-2-phenylene)

Benzyl-4-yl)-ethoxy]-phenyl benzyl acrylate, which is produced as a colorless solid oil [racemic]-2-ethoxy·3_丨3 _ gas 4 [2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy bupidopropionic acid f · MS : (MH) · 412.2 NMR (DMSO-d6 , 1H, TMS) : 1.03 (t, 3H), 2.35 (s, 3H) 2.78 (dxd, 1H), 2.88 (dxd, 1H), 2.95 (t, 2H), 3.23-3.32 (m 1H), 3.45- 3.52 (m, 1H), 3.95: 1.00 (m, iH), 4 26 (t, 2H)' 6.95 (d, 1H), 7.04-7.10 (m, 2H), 7.47-7.52 (m, 3H), 7 92' (dxd, 2H), 12.7 (s, 1H). Example 159 1_外..消禄性卜2-乙气基-3-{4-[2-(5-甲一^Phenyl-喵〇4^^ ethoxyl 1-3-propyl 芨 some }- two hundred will be in a procedure similar to that described in Examples 1 14b], c] and d], 3- propyl propyl 4-hydroxybenzaldehyde and 2-( 5-methyl-2-phenyl methanesulfonate -carbazole _ 4_yl) acetamidine t [PCT Int. Appl. (2000) W00008002] reaction to obtain 3_ propyl-4-(2-(5-methyl-2- ingyl-11-deficient 0 sitting 4-yl)-ethoxy]-benzene chain. Gasification by gasification (r-oxy-ethoxymethyl)triphenyl scale (similar to in Example 1丨4a) 3-methoxy-4-[2-(5-fluorenyl-2-phenyl-oxazol-4-yl)-ethoxylate prepared by the procedure described for methoxyfluorenyltriphenyl scales Benzoaldehyde' then gives 3-{3-allyl-yl-4-[2-(5-methyl-2-phenyl-indenyl-4-yl)-ethoxy]-phenyl b 2 ( Ζ,Ε)-decyl ethoxy acrylate, hydrogenated to produce [racemic]_2-ethoxy-3-indole-4_[2-(5-methyl-2) as a colorless solid oil -Phenyl-oxazol-4-yl)ethoxy]-3-propylphenyl}_propene 220 - This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 13285 85 A7 B7 V. INSTRUCTIONS (217) Acid MS: (MH)·436.3. NMR (DMSO-d6, 1H, &lt;5, TMS): Ο.77 (t&gt; 3H), 1.03 (t, 3H) , 1.32- 1.42 (m, 2H), 2.35 (s, 3H), 2.35-2.45 (m, 2H), 2.76 (dxd, 1H), 2.85 (dxd, 1H), 2.92 (t, 2H), 3.23-3.32 (m, 1H), 3.45-3.52 (m, 1H), 3.90 (dxd, 1H), 4.19 (t, 2h), 6.82 (d, 1H), 6.92 (d, 1H), 6.97 (dxd, 1H), 7.47-7.52 (m, 3H), 7.92 (dxd, 2H), 12.7 (s, 1H). Example 160 - (2.S)-2-B I Keshi { 3 -Methoxy-4_ [A _2_Phenyl-g-biting - 4 'yl)-ethyllacyl 1-styl}-propionic acid in a procedure similar to that illustrated by Examples lla] to lie], 3-methoxy_4_ [2 -(5-methyl-2-phenylisoxazin-4-yl)-ethoxybenzaldehyde (in a procedure similar to that of greek 1 14b), 4-hydroxy-3-methoxybenzene (2-) 5-(4-methyl-2-phenyl-oxazol-4-yl)ethyl acetate 〇 烧 _2 _2 ketone and nBU2B 〇 Tf reaction to produce (5)-4-mercapto-3-((23,311)-2-ethoxy-3-hydroxy-3-{3-methoxy _4- [2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl} Acyl) Well-2-one (according to NMR, one of the four isomers of the dominant pole; according to Tetrahedron Asymmetry 1999,1353, configured to temporarily named 2 5,311). Reduction of (3)- 4-mercapto-3-((23,311)-2-ethoxy-3-hydroxy-3-{3-methoxy-4-[3] with triethylformane in trifluoroacetic acid 2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}propenyl)oxazolidin-2-one' followed by (S)-4-芊Base-3-((2S)-2-ethoxy-3-{3-methoxy- ___- 221 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Order

Line 1328085 A7 B7 V. Description of the Invention (218) 4-[2-(5-Methyl-2.phenyl-oxazol-4-yl)-ethoxyphenyl}propenyl) 11-oxazolidine -2-ketone. Next, (S)-4-mercapto-3-((2S)-2-ethoxy_3_{3-methoxy-4-[2-(5-methyl-2-phenyl-carbazole) 4-yl)-ethoxy]phenyl)propanyl)oxazolidin-2-one is saponified with IN NaOH in THF to give (S)-2-ethoxy-3 as a colorless solid. -{3-Methoxy-4-[2-(5-methyl-2-phenyl-)-yl-4-yl]-ethoxy]-phenyl}-propionic acid. The excess enantiomer was 98.7% identified based on palmitic hplC (Chiralcel-OJ). MS: (M-Η)· 424'3. NMR (DMSO-d6, 1ΗΓ δ , TMS) : l.〇4 (t, 3Η), 2.36 (s, 3H), 2.75-2.87 ( 2xdxd, 2xlH), 2.91 (t, 2H), 3.27-3.32 (m, 1H), 3.49-3.52 (m, 1H), 3.72 (s, 3H), 3.94-3.96 (m, 1H), 4.14 (t, 2H), 6.71 (dxd, 1H), 6.84-6.87 (m , 2H), 7.48-7.50 (m, 3H), 7.90-7.92 (m, 2H), 12.7 (s, 1H). Example 1 6 1 (2S)-2-Ethyl-3- (2-methyl 氲 -4- Γ Η 甲 甲 甲 2- 2- 2- 2- 4 4 4 4 4 4 4 4 4 4 4 a certain propionic acid in a procedure similar to that described in Examples 1 1 a] to 11 c], 2·methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl) )-ethoxy]-stanoaldehyde (in a procedure similar to that described in Example 1 14b), 4-hydroxy-2.methoxybenzaldehyde and 2-(5-methyl-2-phenylmethanesulfonate) - (#) 4-yl) ethyl ester prepared by reacting with (s) 4- 4-mercapto-3-ethoxyethyl ketone beta oxet-2-one and nBi^BOTf to produce 5) 4-mercapto-3-((2 5,311)-2-ethoxy-3-carbyl-3-{2-decyloxy-4-[2-(5-methyl-2-benzene) Base-oxazol-4-yl)-ethoxy]-phenylpyridinyl)oxazolidin-2-one (according to NMR, one of the four isomers is predominant; _____-000 - ___________ This paper ruler S (materials) S (materials) A4 specifications (21G X 29ϋ &quot;&quot; 1328585 A7 B7 V, invention description (219) According to Tetrahedron Asymmetry 1999, 1 353, the configuration will be temporarily named 2S, 3R) Reduction of (s)_4_benzyl-3-((25,311)-2-ethoxy-3-hydroxy- by triethylformane in trifluoroacetic acid 3-{2-decyloxy-4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-phenyl}propanyl oxazol-2_ketone Next, (S)-4-mercapto-3-((2S)-2-ethoxy-3-{2-methoxy-4--[2-(5-methyl-2-phenyl) Sodium 4-(yl)-ethoxy]-phenylpropionate) oxazolidin-2-one followed by (S)-4-mercapto-3-((2S)-2-ethoxy -3_ρ·methoxy-4-[2-(5-methyl-2-phenyl-·5oxa-4-yl)-ethoxy]•phenyl}propenyl)oxazolidine-2- The ketone is saponified with IN NaOH in THF to give (S)-2-ethoxy-3-{2-methoxy-4-[2-(5-methyl-2-whenyl) as a colorless solid - 吟 ° all-4-yl)-ethane group]-phenyl}-propionic acid MS: (Μ-H)- 424.5. NMR (DMSO-d6, 1H, (5, TMS): 1.01 (t, 3H), 2.36 (s, 3H), 2.72 (dxd, 1H), 2.84 (dxd, 1H), 2.92 (t, 2H), 3.22-3.29 (m, 1H), 3.41-3.49 (m, 1H), 3.75 (s, 3H), 3.89-3.92 (m, 1H), 4.19 (t, 2H), 6.44 (dxd, 1H), 6.50 (d, 1H), 6.99 (d, 1H), 7.48- 7.50 (m, 3H ), 7.90-7.92 (m, 2H), 12.6 (s, lH). Example 1 62 i Racemic 1- 2 -isopropenyl-3-M-indole 2-(5-methyl-2-indole-carbazol-4-yl)-ethoxy 1-stup Fbl·» 实-7-7- 丨- and aged to a melting point of 146-147 in a manner similar to Example 68. An off-white solid' but using an unsubstituted 4_[2_(5-methyl-2-phenylno-4-yl)-ethoxy]-benzo[b]e in the aldol process吩7-chain [to 4-hydroxybenzo[b] in tetrahydrofuran. Cerebral-7-carboxaldehyde [Ger. Offen. ( 1998) _- 223 - This paper scale applies to the Chinese Standard (CNS) A4 specification (210X 297 public) ~ one

Binding

line

DE 1971 1617 A1] and 2-(5-phenylphosphine and DEAD (Azodicarboxylic acid electronic coupling partner methyl-2-phenyloxazole-4-yl)ethanol in the presence of diethylene ester) Derived as a pro-ISN-MS: 464.1 (MH) + 〇 instance 163

Ll)-2-isopropyl wrap. -3-(4-"om a-~~~苽- oxazole-4_ its i. oxy 1 -benzofb sept-7 - a certain propyl hydrazine - prepared in a manner similar to the example η, as the melting point 167-168. The off-white crystal 'but- in step a] is replaced with (s) _4m·isopropoxyacetinyl 10 to 垸-2-鲷 (SM4 base _ 3. Methoxyethyl sulfhydryl sulphide is a coupling partner. In a manner similar to that described in Example 65 above, isopropoxyacetic acid and (S)-4-mercapto-2-oxazolidinone Prepare the former. ISN-MS: 464.2 (MH)+. Example 1 6 4 ill racemic 1 - 3_ ( 3-埽 芏 芏 丨 丨 美 美 2- 2- 2- 2- 2- 2- 2- 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 2.65 millimoles) [racemic] _3·(4-allyloxyindenyl)-2-.ethyl ethoxypropionate [as [racemic]_2•ethoxy 3_(4 • Hydroxy tea · 1-yl) ethyl propionate (example 丨 50a)) and guanidinium bromide with carbonic acid in acetone at 60 ° C] stirred at 160 ° C for 2 hours without any solvent The dark residue was purified by flash chromatography (yield, EtOAc/EtOAc: 4:1) to yield a yield of 0.82 g (94%) as a yellow oil. Ethyl 3-(3-allyl-4-hydroxyindol-1-yl)-2-ethoxypropanoate MS: 327.2 (M-Η). L------ 79Λ - This paper scale applies to the Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1328585 A7 B7 221 V. Description of the invention (NMR: (CDCI3, 1H, &lt;5, TMS) 1.1〇(t, J=7, 3H), 1.18 (t, J-7, 3H), 3.23- 3.35 (m, 3H), 3.42-3.44 (d, J=5, 1H), 3.53-3.57 (m, 2H), 4.10-4.18 (m , 3H), 5.20-5.27 (m, 2H), 5.47 (s, 1H), 6.02-6.11 (m, 1H), 7.13 (s, 1H), 7.47-7.54 (m, 2H), 8.00-8.03 (m , 1H), 8.20- 8.23 (m, 1H). kl-L1K. Racemic 1-3-Π-ene-ene-1 某-2- 苽- oxazol-4-yl)·ethoxy萘naphthalene-1 -..1卜2_B, in the same step as described in Example 1 7a], [racemic]-3-(3-allyl-4-hydroxyl) Ethyl phthal-1-yl)-2-ethoxypropionate with 2-(5-methyl-2-phenyl-oxazolyl-4-yl)ethanol in tetrahydrofuran in triphenylphosphine &amp; DBad ( Reaction in the presence of di-tert-butyl azodicarboxylate) to give [racemic oxime {3-晞propyl-4-[2-(5-methyl-2-phenyl-唠-wow) _4_Kib ethoxy bnaphthalene 1-yl b 2-ethoxyl Ethyl acetate, which was further saponified in a similar manner to that described in Example 91e] to give a racemic, 3, 3- allyl-4-[2-(5-methyl-2) -Phenyl-carbazole-4-yl)-ethoxynaphthalene 1-yl}-2-ethoxypropionic acid. MS: 484.3 (M-Η). NMR : (CDC13, 1H, TMS) 0.97- 1.02 (t, J=7 3m 0 (s, 3H), 3.08-3.22 (m, 4H), 3.43-3.59 (m, 4H), 4.12 * ^ · 1 6 (dxd, J, = 3.5, J2=9, 1H), 4.23-4.27 (t, J=6.5, 2H), 5.〇〇.5 〇6 (m, 2H), 5.92-6.01 (m, 1H) , 7.22 (s, 1H), 7.40-7 / υ (m, 5H), 8.00-8.10 (m, 4H), COOH is very wide.

Example A A tablet containing the following ingredients can be manufactured in a well-known manner. · This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Invention Description (222) Ingredients Each tablet type I Compound 10.0-100.0 mg Lactose 125.0 mg Corn starch 75.0 mg Talc powder 4.0 mg Magnesium stearate 1.0 mg Example B Capsules containing the ingredients can be made in a well-known manner: Ingredients - Each capsule I compound 25.0 mg lactose 150.0 mg corn Starch 20.0 mg talc 5.0 mg Example C The injection solution may have the following composition: Compound of formula I 3.0 mg of gelatin 150.0 mg of phenol 4.7 mg of water for injection solution about 1.0 ml -?? β - This paper scale applies to Chinese national standards (CNS) A4 size (21〇x 297 mm)

Claims (1)

1328585 VI. Application for a patent garden 1. A compound of formula (I), R\ R (CH2)-0 R7 RR wherein R1 is aryl or heteroaryl; R2, R3, R4 and R6 are independently of each other hydrogen, hydroxy, lower alkenyl, south, lower alkyl or lower alkoxy, wherein R2, R3 And at least one of R4 and R6 is not hydrogen, or R3 and R4 are bonded to each other, and together with the carbon atom to which they are attached, form a ring, and R3 and R4-S*-CH=CH-S-, -S-CH =CH-, -CH=CH-0_, -0-CH=CH-, _CH=CH-CH=CH-, -(CH2)3. 5- ' -〇-(CH2)2. 3- or -(CH2)2-3-〇-, wherein R2 and R6 are as defined above; R5 is lower alkoxy, lower alkoxy; R7 is hydrogen or low carbon alkyl; R8 is hydrogen or lower alkyl; This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A BCD VI. Apply for patent garden r9 hydrogen or a lower alkyl group; R1 (&gt; is an aryl group; n is a group 1, 2 or 3; wherein a bond between a carbon atom Ca and a carbon atom Cb is a single carbon or a double bond; and pharmaceutically acceptable Salts and esters. 2 _ The compound according to claim 1, wherein R2, R3 and R4 are independently of each other hydrogen, halogen 'lower alkyl or lower methoxyoxy' wherein R2, R3 and R4 At least one of them is not hydrogen, or R3 and R4 are bonded to each other, and together with the carbon atom to which they are attached, form a ring ' and R3 and R4, _CH=CH-0-, -〇_cH=CH-, _CH=CH-CH =CH-, -(CH2)3·5·, and wherein R2 is as defined above; R5 is lower alkoxy or R6 is hydrogen; R7 is methyl; η is 2; wherein the bond between the carbon atom Ca and the carbon atom is carbon-carbon single • Double-2 - 1328585 A8 B8 C8 _ D8 VI. Pharmaceutically acceptable salts. The compound according to claim 1, wherein Ri is a phenyl group or a phenyl group substituted with 1 to 3 substituents independently selected from alkoxy groups and trifluoromethyl groups. 4. The compound according to claim 1, wherein R2, R3, ... and R6 are each independently hydrogen, hydroxy, lower alkyl or lower alkoxy, wherein R2, R3, and at least One is not nitrogen or combines the ruler 3 and the ruler 4 with each other, and forms a ring together with the carbon atom to which it is attached, and R3 and R4 together are -CH=CH_S-, -S-CH=CH-, -CH=CH-0- , -0_CH=CH_, _CH=CH-CH=CH_, and its definition is as above. 5. A compound according to claim 1, wherein R2 and R6 are hydrogen, and R3 and R4 are bonded to each other' together with a carbon atom to which they are attached to form a ring, and R3 and R4 are -CH=CH-S -or-S-CH=CH-. 6 · A compound according to the scope of claim 1 wherein R5 is a lower alkoxy group or 7 · According to the scope of the patent application! A compound of the formula wherein R5 is methoxy, ethoxy or propoxy. 8. A compound according to claim 1 wherein r7 is methyl. 9_ A compound according to the scope of claim patent, wherein R8 is a methyl group. -3 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A8 B8 C8 D8 VI. Application for patent garden 10. According to the patent application range i, the R9 hydrogen . 11_ A compound according to claim 1 wherein ri is a phenyl group. 12. A compound according to claim 1 wherein η is 2. 13. A compound according to claim 1 of the scope of the patent application, characterized by having the formula ( Wherein R1, R2, R3, R4, R5, V, R^n are as defined in claims 1 to 12. 14. A compound according to the scope of claim 4, which is selected from the group consisting of 2-methoxy-3-{4-[2-(5-methylphenyl-p-indenyl)-ethoxy]-benzene And [b]thiophen-7-yl}-propionic acid; 3-{4·[2-(5-fluorenyl-2-phenyl-oxazol-4-yl)·ethoxy]•benzo[b Thiophen-7-yl}-2-propoxypropionic acid; (3)-2-decyloxy-3-{4-[2-(5-methyl-2-phenyl-„号嗤_4 _ yl) _ ethoxy]- benzo[b]a phenan-7-yl}-propionic acid; (S)-3-(4-{2-[2-(3,5-didecyloxy) Stupid)-5-methyl „salt _4_yl] ethoxy} 弁[b]&lt;*cep-7-yl)-2-methyllactanoic acid; (S)-2-曱oxy-3-(4-{3-[5-mercapto-2-(4-trifluorodecyl)]oxazol-4-yl]propoxy}indol-1-yl)propionic acid ; 2Z-ethoxy-3-{2-methyl-4-[2-(5.indolyl-2-inscapto-saltyl-4-yl)-ethoxy]-phenyl}-acrylic acid; Zhang scale applies Chinese National Standard (CNS) Α4 specification (210Χ 297 mm) 1328585 as B8 C8 D8__ VI. Application for patent Fanyuan 2(S)-ethoxy-3-{2-methyl_4-[2_( 5-methyl-2-phenyl-1*-oxazole-4-yl)-ethoxy]-styl}-propionic acid; 2Z-ethoxy-3-{4-[2-(5-A Ke-2-phenyl-β-azol-4-yl) _Ethoxy]-benzobenzoin-7-yl}-propionic acid '[racemic]-2-[1-methyl·3-oxy-3-phenyl-(anthracene)-propene Amino]_3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[1&gt;] porphin-7-yl}-propionic acid [Racecyclic]-3-{2-hydroxy-4-[2-( 5-decyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl]-2- Methoxypropionic acid; [racemate]-3-{3-mercapto-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]- Phenyl}-2-(1-methyl-3-oxy-3-phenyl-(anthracene)-propenylamino)propanoic acid; [racemic]-2-ethoxy-3-[2 -methyl-4-(5-fluorenyl-2-phenyl-oxazol-4-ylmethoxy)phenyl]-propionic acid; [racemic]-2-ethoxy-3- 4-[2-(4-isopropoxyphenyl)· 5-indolyl β-azol-4-ylmethoxy]-2-mercaptophenyl}·propionic acid; (2S)-3-{ 3,5-dimethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-phenyl}-2-ethoxypropionic acid; 2S)-2-ethoxy-3-{3-methoxy-4-[2-(5-methyl-2-indolyl-oxazol-4-yl)-ethoxy]-phenyl} - Propionic acid. 15. A compound according to claim 1 wherein the compound is (S)-2-methoxy-3-{4-[2·(5-methyl-2-phenyl-carbazole-4) (1)-ethoxy]-benzo[b]sulfon-7-yl}-propionic acid β 16. A method for producing a compound of formula I as claimed in claim 1 Applicable to China National Standard (CNS) Α4 Specification (210X 297 mm) 1328585 A8 B8 C8 D8 VI. Patent application scope includes deprotection of compounds according to formula II Wherein R1, R2, R3, R4, R5, R6 and R^n are as defined in any one of claims 1 to 15 and a PG-based protecting group. 17. A pharmaceutical composition for treating and/or preventing a disease modulated by a ppARa and/or ppaRy agonist, comprising a compound according to claim 1 and a pharmaceutically acceptable carrier and/or Agent. 18. A compound according to claim 1 of the scope of the patent application as a therapeutically active substance for the treatment and/or prevention of diseases modulated by PPARa and/or ΡΡΑΙΙγ activators. 19· One according to the scope of the patent application! Use of a compound according to the manufacture of a medicament for the treatment and/or prevention of a disease modulated by a PPARa and/or PPARY activator. 20. A compound according to claim 8 wherein the disease is diabetes, elevated blood pressure, decreased lipid and cholesterol levels, atherosclerotic disease or metabolic syndrome. 21. The pharmaceutical composition according to claim 17, wherein the disease is diabetes, an increase in blood pressure, a decrease in lipid and cholesterol levels, an atherosclerotic disease or a metabolic syndrome. 22. According to the application of the scope of patent application No. 19, the disease is diabetes, blood pressure rises, lipid and cholesterol values decrease, atherosclerotic disease -6 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 PCT 8 8 8 8 AB c D 1328585 6. Apply for a patent garden or metabolic syndrome. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm)