TW391958B - Substitued 4-hydroxy-phenylalcanoic acid derivatives with agonist activity to ppar-gamma - Google Patents

Description

Patent application No. 86102826 ___ ^ Chinese manual amendment page (10 ~ B of 1988;-'' V. Description of the invention (118) I read and write 'month q W'lnrr — ”(MH); High Resolution MS ( FAB) c26h27N2 04 of m / e: calculated value 431.1938; measured value 431.1965 (^ «1+); that is, book 1 ^ (〇711 please ^ 60A C-18 83-201-C, 25 cm X 4.6 mm 15-80% CH3CH in H20 with 0.1% TFA buffer, 30 minutes; 15 ml / min): tr = 18.7 points (t0 = 1.7 points). Example 27 3- {4- [2- (Benzo Oxazol-2-yl-methyl-amino) _ethoxy] _phenyl} _2_ (2-bromo-benzyl) -trifluoroethyl propionate (31 mg) is from 5 1.9 mg (0.099 1 millimolar) Intermediate 16 was prepared according to the method of Example 2.6 and then purified by preparative reverse-phase HPLC with 15-80% CHsCN / E ^ O with 1% TFA buffer as the eluent: m NMR ( CD3OD, 300 MHz) 5 7.51 (d, 1H, J = 7.9), 7.44 (d, 1H, J-8.0), 7.37-7.33 (m, 2H), 7.31-7.18 (m, 3H), 7.11-7.06 ( m, 3H), 6.81 (d, 2H, J = 8.5), 4.29 (t, 2H, J = 5.1), 4.02 (t, 2H, J = 5.1), 3.37 (s, 3H), 3.02-2.88 (m , 4H), 2.76-2.71 (m, 1H); low resolution MS (ES) m / e 507 (MH); high resolution MS (FAB) m / e C26H26BrN204: calculated 509.1075; found 509.1085 (MH +); RP-HPLC (Dynamax-60A C-18 83-201-C, 25 cm X4_6 mm; 15-80% CH3CH in H20 with 0.1% TFA buffer Liquid; 30 minutes; 1.5 ml / min): tr = 20.8 points (t0 = 1.8 points). Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Example 28 3- {4- [2- (benzohumazole -2-yl-methyl-amino) -ethoxy] _phenyl} _2 (s) _ [4-oxo-4H-benzo / 5-sulfan-3-yl) -amino] -Propionic acid will be 990 mg (3.0 mmol) of N-methyloxycarbonyl-L-carboxylic acid methyl ester! 〇-121-This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) A7 ___ B7 V. Description of the invention (1) The present invention relates to specific novel compounds, their preparation methods, their pharmaceutical compositions and Its use in medicine. More specifically, it has an active effect on the activation of proteasome receptor gamma (ppAR_gamnla) on cellular enzyme bodies, including anti-activity, so that it can regulate the blood glucose of mammals. Although insulin, sulfonylurea (e.g., chloropromide > opamide), tolbutamide (tolbutamide, tolazamide)), and biguanide (e.g., benzene Formic acid (phenformin, metaformin) as oral hypoglycemic agents, type! Treatment of non-insulin-dependent diabetes mellitus (NIDDM) is still not very satisfactory. The treatment of NIDDM usually starts with a combination of diet control and exercise, followed by oral hypoglycemic drugs (such as diurethrin) and more severe cases, insulin. Unfortunately, the available hypoglycemic agents are limited by the undesired toxic effects of Guangfanyuan, which can limit its effectiveness in the treatment of NIDDM. There is therefore a clear need for the development of novel hypoglycemic bodies that can be less toxic or can have activity not found in other agents. Over the past decade, compounds known as tetrahydropyrazole dione grades (such as U.S. Pat. The insulin activity of the target tissues (bone frontal muscle, liver, fat) also reduced lipids and insulin pupae in these test animals. Recently, tetrahydrothiazole _ troglitazone has been shown to have the same political and political effects in human patients with defective glucose tolerance (metabolism that occurred before niddm) and in patients with NIDC) M (J. j Nolan et al., N. Eng. J. Med. 1188-1193, 331 (1994)). However, the mechanism of action is not clear, tetrahydro distant dione is not -4- the size of this paper is appropriate) 彳] China National Standard (CNs jr ^ grid (210x297 mm) " ~ '------- -© 装 I _ (Please read the precautions on the back before filling in the clothes page) Order A7 in Section A7 if X'j li x 消 t: 合 竹 卬 ____ B7 5. Description of the invention (2) Insulin Increased secretion or increased number of affinities at the binding site of insulin receptors. Therefore, tetrahydroxazolidone should clearly increase postreceptors in insulin signaling (J. R. Colca and DR Morton, '' Antihyperglycemic thiazolidinediones: ciglitazone and .its analogs, " in New Antidiabetic Drugs, CJ Bailey and PR Flatt, eds., Smith-Gordon, New York, 255-261 (1990)) ° Tetrahydrothiazolidinedion also defies in vivo Adipocyte differentiation of adipocyte lines (A. Hiragun, et al. J. Cell. Physiol. 124-130, 134 (1988); RF Kleitzen, et al., Mol. Pharmacol. 393-398, 41 (1992)). Tetrahydro-p-plugin dione pioglitazone treatment of preadipocytes leads to specific genes aP2 and adipsin and grape of preadipocytes Glycotransfer proteins GLUT-1 and GLUT-4, which show that the hypoglycemic effect of tetrahydrothiazole dione in vivo can be regulated by adipose tissue. Recently, steroids / thyroid / retinal-like proteins that activate ligand transcription factors The solitary element of the receptor superfamily, which has been transformed into cellular enzyme body activated proliferative receptor gamma (PPAR-gamma) has been discovered. PPAR-gamma is one of the superfamilies close to related PPARs encoded by independent genes (C. Dreyer, et al., Cell 879-887, 68 (1992); A. Schmidt, et al., Mol.

Endocrinol. 1634-1641, 6, (1992); Y. Zhu ,. et al., Chem. 26817-26820, 268 (1993); SA Kliewer et al., Proc. Nat. Acad. Sci, United States, 7355- 7359, 91, (1994)). Three mammalian PPARs were isolated and converted into pPAR-α, PPAR-, and NUC · 1. The expression of these PPARs by binding to a DNA sequence element regulatory target gene 'is transformed into a PPAR response element (ppRE). So far, PPRE'S has been regarded as several types -5-This paper is suitable for China National Standard (CNS) A4 (210X 297mm) (Please read the precautions on the back before filling this page)

1T A7 B7 V. Description of the invention (3) Advanced products of genes encoding proteins that regulate lipid metabolism, which makes PPARs play a pillar role in fat-producing signals and lipid homeostasis (Η. Keller and W Wahli, Trends Endocrin. Met. 291-296, 4 (1993)). Tetrahydroxazole dione has been reported as a useful and selective PPAR-gamma activator and directly binds to the PPAR-gamma receptor (JM Lehmann et al., J. Biol. Chem. 12953-12956, 270 (1995 )), Providing evidence of possible targets for the therapeutic effect of PPAR-gamma as tetrahydrotetradione. We have now discovered a novel group of compounds that bind and activate the PPAR-r receptor. These compounds also show good blood glucose lowering activity and are therefore useful for the treatment and / or prevention of hyperglycemia, dyslipidemia, and especially for the treatment of type 11 diabetes. 3 These compounds have also been indicated for the treatment and / or prevention of other diseases Including type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertension, and cardiovascular disease, especially atherosclerosis. Furthermore, these compounds are indicated for the regulation of appetite and food intake in subjects suffering from, for example, obesity, anorexia and anorexia nervosa. Accordingly, the present invention relates to compounds of formula (I): CO ^ R1 (Please read the precautions on the back before filling this page)

, 1T A — B — 0

Aik · 2 (丨) where A is selected from the group consisting of: -6-The size of this paper conforms to the Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of the invention (4) (i) (ii) Phenyl 'wherein the phenyl optionally has one or more halogen atoms, Cl-67 ^ 8, Cl-3 alkoxy, Ci-3 fluoroalkoxy, nitrile, or -NR R8 ( Wherein r7 & rS is each hydrogen or ci 3 alkyl) substituted; a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur; and (iii) a fused bicyclic ί

, Where ring C is as defined in item (ii) above, i ?. i \ '· and ίί-Τ 消 竹 卬 t 的 heterocyclyl' wherein the bicyclic ring is connected to the group via the ring atom of ring C B; B is a radical of the following composition: (iv) CU6 alkylene; (v) alkylene or Cw alkylene MCN6 alkylene, where M is 0, S, or -NR2 where R2 represents hydrogen Or Cl_3 alkyl; (vi) a 5 · or 6-membered heterocyclic group containing at least one nitrogen heteroatom and optionally at least another heteroatom selected from oxygen, nitrogen, and sulfur and optionally substituted with Cl_3 alkyl; And (vii) Het-Cw alkyl, wherein Het represents a heterocyclic group as defined in point (vi) above; Aik represents C! · 3 alkyl; R1 represents hydrogen or Ch3 alkyl; Z is selected from the group consisting of Groups: (viii) alkyl) phenyl, where phenyl is optionally substituted with one or more halogen atoms; and (IX) NκΊ4, where R3 represents hydrogen or C! -3 alkyl , And R4 table -Y- (C = 0) -TR; > 'or -Y- (CH (OH))-T-R5, where: The paper size meets the Chinese National Standard (CNS) M specification (2 丨〇.x297mm) --------. © 策-(Please read the notes on the back before filling in this page j

、 1T A7 B7 Central part of warp &"-^^ m τ · 消 于 合 竹 d 卬 ^; V. Description of the invention (5) (a) Y tab, Cu alkylene, C2_6 alkenyl, C4_6 ring Alkylene or cycloalkenyl, heterocyclyl as defined in point (vi) above, or phenyl optionally substituted with one or more Cw alkyl groups and / or one or more halogen atoms; _ (b) T-bond, Cw alkoxy, -0- or -N (R6)-, where R6 represents hydrogen or Cw alkyl; (c) Epicenter · 6: phenyl, C4-6 ring Ethyl or cycloalkenyl, phenyl (optionally substituted with one or more of the following: halogen atom, C3_3 alkyl, Cw alkoxy, C0-3 alkylene-NR9R10 where each of R9 and R10 Hydrogen, Ci-3 alkyl, -S02Ci_3 alkyl, or -C02CU3 alkyl, -SC ^ NHCw alkyl, C0-3 alkyl C02H, CQ_3 alkyl C02Ci-3 alkyl, or -0CH2C (0) NH2), 5_ or 6-membered heterocyclic group, as defined in item (ii) above, Λ or double fused ring wherein the ring D table contains at least one heteroatom selected from oxygen, nitrogen and sulfur and optionally Substituted by (= 〇), where the bicyclic system is connected to T via the ring atom of ring D, or _c extends MR ", M is 0, S, or _NR2 where r2 & r " each is ^ C! -3 alkyl; or its isomeric form, and / or a medically acceptable salt or solvate thereof. A person skilled in the art can recognize that the stereocenter exists in the compound of formula (1). Accordingly, the present invention includes all possible stereoisomers and geometric isomers of formula (I) and includes not only racemic compounds but also optically active isomers. When various compounds of fluorene are required to be mono-enantiomers, they can be ordered by isolation of the product or ^ I (please read the precautions on the back before filling this page)

Ｍ ________ Β7 V. Description of the invention (6) A '· — ~ Pure isomers or any convenient intermediates are obtained by stereospecific synthesis. Isolation of the final product, intermediate or starting material can be performed by methods known in the appropriate art. For example, $ _tgI.e〇chemistry 0f_ Carbon Compomih of EL LHD (Megraw HiI1, 1962) is H. Wilen-^ Iable ^ _of Resolving Agents. Furthermore, in the case where a compound of formula (I) may exist in isomers, the present invention is intended to include all isomeric forms of the compound. Those skilled in the art also recognize that the compounds of the present invention can be used in their medically acceptable form as salts or solvates. The physiologically acceptable salt of the compound of formula (1) includes a conventional salt formed from a pharmaceutically acceptable inorganic or organic acid or base and a salt of a fourth amino acid. More specific examples of suitable acid salts include hydrochloric acid, hydrobromic acid, sulfurous acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, Tartaric acid, citric acid, pamoic, malonic acid, maleic acid, phenylacetic acid, glutamic acid, phenylarsine acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, lindenyl-2-sulfonic acid Acids, benzenesulfonic acid, hydroxyarsolic acid, hydroiodic acid, malic acid, steroic Yuhan salt and the like. Other acids such as oxalic acid, although not in themselves pharmaceutically acceptable salts, can be used to prepare useful salts as intermediates for obtaining the compounds of the present invention and their pharmaceutically acceptable salts. Specific examples of suitable alkali salts include sodium, sodium, sodium, magnesium, calcium, zinc, n, n1 + + ethynylamine, chirocaine, bile test, Alcohol amines ethylene monoamine, N-methylglucamine, and jincaine salt. Subsequent references to compounds according to the invention include compounds of formula (i) and their pharmaceutically acceptable salts and solvates. -9- This paper scale coffee icNsTMmTi 210X291 ^) C, please read the precautions for back-healing and fill in this education) -0 pack 'A7 B7 V. Description of invention (7) I ......... I ... ...-: 1 t ^ n 1-! 1 f,: -Λ 士. I— —i----In HI i (Please read the precautions on the back before filling this page) The terms Cw alkyl or alkylene and Cl_6 alkyl or alkylene respectively contain 1 to 3 or 1 to 6 carbon atoms and suitably include straight or branched alkyl or alkylene, typically methyl, ethylene Fluorenyl, ethyl and ethynyl. And straight bonds and branched propyl, propyl, butyl and butyl. The term "c26" or "alkenyl" as used herein contains 2 to 6 carbon atoms and suitably includes linear or branched fluorenyl and alkenyl, especially propyl or the like. " -3 alkoxyethyl word list -O-Cu alkoxy-, its "alkylene" is essentially as defined above, for example, -0_CH2-, etc. C: 4-6 cycloalkyl, C4 The terms -6 cycloalkane, c4-6 cycloalkenyl, and C4-6 cycloalkenyl include cyclic groups containing 4 to 6 carbon atoms, such as cyclopentane, cyclopentyl, cyclohexane, cyclohexane Pentyl, cyclohexane, and cyclohexyl. The halogen term used for this includes fluorine, gas, bromine, and hydrogen. The 5- or 6-membered 5-actyl term used for this includes 5- or 6-membered Substituted heterocyclic groups and substituted or unsubstituted heteroaryl groups, for example, substituted or unsubstituted tetrahydroimidyl group, 0 base group, hexahydro P ratio P well group, P billow bite Base, molybdenyl, eryl, β 荅 P-based, yodolide, P-to-P-based, p-toloyl, VP-to-based, imidazolyl, piperanyl, furyl, pyrimyl, Hexazolyl, isoxazolyl, oxadiazolyl, 1 oxazolyl, oxadiazolyl, triazolyl, or tetrazole A substituted heterocyclyl means a 5 or 6-membered heteroaryl group substituted by one or more of the following: a halogen atom, a Cw alkyl group, a Cw alkyl group, an oxo group, and a C0-3 alkyl group NR9R10. (Wherein R9 and R10 are hydrogen, Ci.3 alkyl, -SC ^ Cu alkyl or C02Ci_3; fe group, -S〇2NHCi_3 ^ group), 匸 0.3 elongation group CO2H, C0.3 Alkyl CC ^ Cw alkyl, -0CH2C (0) NH2, -Cu fluoroalkyl, -CN or SCi.6 alkyl. -10- This paper is suitable in size; 1] Chinese National Standard (CMS) A4 specification ( 210X 297 mm. A7 B7

V. Description of the invention (8) In the above formula (I), when Y represents a bond, the nitrogen atom of '_NR3R4 is directly connected to-(C = 0) or (CH (OH)) of R4, that is, the Z table -2 (113)-(〇〇)-丁 -R or -N (R) (CH (OH))-T-R5. Similarly, when the τ table is bonded, (4) (0) or (CH (OH)) of r4 is directly connected to R5, that is, z table -N (R3) _Y_ (C = 0) -R3 or _n (R3 ) -Y- (CH (OH))-R5. It can be the case where both γ and τ are tabular I, then Z table -N (R3)-(C = 0) -R54; _n (R3HCH (0H))-R5. Appropriate A represents any phenyl, heteroaryl (such as pyridyl) or a 5-membered heterocyclic group wherein the fused ring C contains at least one nitrogen heteroatom and optionally another heteroatom selected from nitrogen and oxygen ( (Eg, pyrazolyl, imidazolyl). In particular, A means any phenyl, pyridyl, hexahydropyridyl, or benzohumazolyl 'any of which may be optionally substituted with one or more 3 alkyl groups, especially phenyl, hexahydropyridine Or pyridyl. B is suitable for any Cw alkylene (such as methylene), _N (CH3) Ci3 alkylene (such as -N (CH3) (CH2) 2-), or Het-Cw alkylene, where the Het table contains at least- Each nitrogen atom and, optionally, at least another 5-membered heterocyclic group selected from heteroatoms of oxygen and sulfur (for example, pyrrolidinyl, pyrazolyl, and thiazolyl) and suitably substituted with a CN3 alkyl group. In particular, b represents -N (CH3) (CH2) 2, pyrazolyl-Ci-6 elongation group, in which the octyl group is optionally substituted by Cw alkyl, or optionally substituted by cN3 alkyl. Azole. Appropriate Aik epimethylene. Suitable R1 is hydrogen, methyl or ethyl, especially hydrogen. Appropriate Z-covinyl one or more _ prime atoms substituted by-(c.u-streptyl) phenyl, such as benzyl substituted as appropriate. The better z table is essentially the same as the previous 11-the paper size is appropriate / 1] Chinese National Standard (CNS) A4 specification (210X297 mm) ---------.— 0¾ .------ Order (Please read the precautions for backing first and then fill in the large t page) A7 B7 Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. NR3R4 described in the description of invention (9). Usually R3 represents hydrogen. _As mentioned before, the table _y_ (c = 〇) _t_ R5 or -Y- (CH (OH))-T-R5, especially -Y (C = 0) _t_r5, and especially the base represented by R4 Includes: Y epiphenyl (. Optionally substituted by one or more self-prime atoms, or one or more heart-3 alkyl, such as methyl), T bonds or oxygen atoms, and R5 represents Cl_3 A base or phenyl group (optionally substituted with one or more _ prime atoms or one or more Cw alkyl groups); Y represents a heterocyclic group (such as a farphenyl group) substantially as described above, τ is a bond and R5 is a phenyl group (. optionally substituted by one or more halogen atoms or-or more alkyl groups); Y is a C2-6 alkylene group (such as propylene), and a τ table R5 represents phenyl (substituted by one or more _ prime atoms as appropriate); Y represents C4 · 6 cycloalkynyl- (such as cyclohexyl), T represents a bond and R5 represents phenyl; Y represents Phenyl, T-bond and R5 are essentially heterocyclic groups as described above (such as hexahydrophyllyl); Y-bond, T-bond and R5 are essentially bicyclic as described above (eg, D represents 6-membered Heterocyclic, especially piperanyl substituted with (C = 0); Y represents phenyl, T represents a bond and R5 represents a Cw cycloalkyl (such as cyclohexyl); Y represents benzene T represents Cw alkoxy (such as -0-CH2-) or N (R6)-(such as _NH-) and R5 represents phenyl "preferably when Z represents NR3R4 (R3 represents Η and R4 represents Y- (C = 0) -T-R5), the NH and the (〇0) are located adjacent to each other on γ (which is a phenyl group), τ is a bond or -0-'R3 is Ci · 6; ^ Phenyl group, or phenyl group (depending on one or more of the following -12- this paper size, using Chinese National Standard (CNS) A4 specifications (21〇 > < 297 mm) ~~~~

(Please read the notes on the back before filling in the book I ·) 1 ------ Ϊ ”: 1 -......- ·-, 11

L A7

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy Each independently is hydrogen, Cl_3 alkyl, -SO ^ -W group, or -CC ^ Cw alkyl, -SOsNHCw alkyl, co-3 alkyl C02H, Co-3 alkyl C02CN3 alkyl, or -OH2C (0) NH2). Particularly suitable for the epitope Y, phenyl T, or -0 ·, and ^^ for the alkyl or benzene ring, such as R4 Table i:

Ru wherein R13 represents phenyl or OCH3. Suitable subgroups of the compounds according to the invention can be represented by the formula (I a)

Wherein A and B are substantially as described above, and Ar represents a phenyl group or a 5- or 6-membered heteroaryl group containing at least one hetero atom selected from oxygen, nitrogen i, and sulfur; and a salt or a solvent thereof. Suitably in formula (la), A is selected from the group consisting of phenyl, pyridyl, and phenylazolium. In particular, A is phenyl or pyridyl in formula (la). Furthermore, b in -13- This paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) ^ binding ^ binding., Λ »α (Please read the precautions on the back before filling this page) A7 B7 V. Description of the invention (In formula (la), it is appropriately selected from -NVCk alkyl groups substantially as described above and Het-Cw alkyl groups substantially substituted as described above with Cw alkyl groups as appropriate) In particular, B is represented by -N (CH3) (CH2) 2- or oxazolyl-Ckalkylene in formula (la), wherein the azole group 17 is optionally Ci_3 alkyl, such as methyl A special subgroup of compounds of formula 1 is the compound of formula (I): wherein: A is selected from the group consisting of: (i) a phenyl group optionally substituted with one or more halogen atoms; ( ϋ) A 5- or 6-membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen, and sulfur; and (please read the weeping matter on the back first and fill in this tile separately)) Packing-(iii) Condensation Double ring: c where ring C is as defined in item (ii) above

1T heterocyclic group, where the bicyclic system is connected to the group B via the ring atom of ring C; B is selected from the group consisting of: (iv) (v) (vi) CN6 alkylene; economic, which central Standard Bureau employee consumer cooperatives print alkylene, where R2 represents hydrogen or Cw alkyl; contains at least one nitrogen heteroatom and optionally at least one heteroatom selected from oxygen, nitrogen and sulfur and optionally Cw alkyl Substituted 5- or 6-membered heterocyclic groups; and (vii) Het-Cu stretch group, wherein Het represents a heterocyclic group as defined in point (vi) above; Or alkyl

.-J -14 L · This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) A7 B7 V. Description of the invention (9 Z is selected from the group consisting of: (viii)-(Cw extended (Phenyl) phenyl, where phenyl is optionally substituted with one or more halogen atoms; and (ix) -NR3R4, where R3 represents hydrogen or Cl, 3 alkyl, and Chi 4 represents _Y_ (c; = 〇) -T-R3, or -Y- (CH (OH))-T-R5, where: (a) Y represents a bond, Cw alkylene, (: 2-6 alkenyl, c4-6 cyclo secondary alkyl or ring An alkenyl group, a heterocyclic group as defined in point (vi) above, or a phenyl group substituted by one or more C 3 alkyl groups and / or—or more halogen atoms, as appropriate; (b) T table bond, Cw alkoxy group, -0_ or · n (r6) _, where R6 represents hydrogen or CU3 alkyl group; (c) ^ epicenter · 6 alkyl group, (: 4-6 cycloalkyl group or ring Fluorenyl, as the case may be, a phenyl substituted with one or more halogen atoms or one or more c13 edge groups, such as a 5- or 6-membered heterocyclic fluorene or difluorene as defined in (ii) above Ring

The ring D list contains at least one heteroatom selected from the group consisting of oxygen nitrogen and sulfur and optionally substituted by (= 0). Heterocyclic ring, wherein the bicyclic ring system is connected to τ via the ring atom of ring D Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy or its isoforms' and / or its pharmaceutically acceptable salts or solvates. Special compounds according to the present invention include: 3- (4-Wordoxy-phenyl) -2 (SH1-methyl_3_oxo_3_phenyl-propenylamino) _dicyclohexyl propionate Amine salt 3- (4 ^ oxy-phenyl) _2 (SH1 • methyl_3_oxo_3_phenyl_propanamido) _ Methyl propionate-15- This paper is for Chinese national standard Standard (CNS) A4 (210X 297 mm) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. * A7 _________B7 V. Description of the invention (13) 2 (S)-(2-benzylfluorenyl-cyclohexene-1 -Ylamino) -3- (4-benzyloxy-phenyl) -dicyclohexylamine propionate 2- (2-methylaminomethylamino) -3_ (4-methylaminophenyl) propyl Acid O- (4-methoxyphenyl) -2- (2-. + Oxy-anilinopropanoic acid methyl ester 3- (4-ethanoxy-phenyl) -2- (phenylamine -Anilino) _formamidine propionate 3- (4-pyridyloxy-phenyl) -2- [2- (xuanhydroedian-1_jiji _) _ aniline] _methyl propionate 2 -(3-benzylfluorenyl-thiophen-2-yl-amino) -3- (4-fluorenyloxy-phenyl) -propanoic acid 2- (2-mercapto-thioxy-3-yl- Amine) -3- (4-Methoxy-phenyl) -propionic acid 3- (4- ¥ oxy-phenyl) -2 (S)-[(4-oxo-4H-benzo /? -Piperan-3-quinyl) -amino] -propyl Acid ester 2- (2-benzylfluorenyl-aniline) _3- {4- [2- (methyl-pyridin_2_yl-amino) _ethoxy] -phenyl} propanoic acid 2 (3 )-(2- + Bromo-curtainamino) -3- {4- [2- (methyl_p ratio_2-yl-amino) _ethoxy] -phenyl} propanoic acid 2- (2-Amino acid group_aniline group) _3_ (4_ [2- (methyl_p ratio_2_yl_amino group) _ethoxy] •• phenyl} ethyl propionate 2- (1- Methyl-3-oxo-3-phenyl-propenylamino) -3- {4- [2- (fluorenyl-pyridin-2-yl-amino) -ethoxy] -phenyl} -propyl Acid dicyclohexylamine salt j- {4- [2- (benzinazole_2_yl-fluorenyl-amino) _ethoxy] _phenylbenzene 2_ (2_benzyl S & yl-lignamine ) Propionic acid 3- {4- [2- (benzoxazol_2_yl_fluorenyl_amino) _ethoxy] _phenyl} _2_ (2_benzylfluorenyl-aniline) propionic acid 3- {4- [2- (benzoxazol_2_yl_methyl_amino) _ethoxy] -phenyl} _2 (s) _ -16- This paper applies the standard specifications (210 > < 297 public epidemic)----------- G ^ .— (Please read the precautions on the back before filling this page), π

D Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (14) (1-methyl-3-oxo-3-phenyl-propenylamino) _dicyclohexylamine propionate 3- {4-p- (Benzoxazole_2_yl · fluorenyl-aminohexylethoxy] -phenylbenzene 2 (s) _ [3- (3-iodo-phenyl) _methylmethyl_3 _Oxo-propenylamino) _dicyclohexylamine propionate > {4- [2- (benzoxazole_2_yl-methyl-amino) _ethoxy] _phenylbenzene 2_ (2_fluorenyl-4-methyl-anilino) _propionic acid 3- {4- [2- (benzoxazol_2_yl-methyl_amino) _ethoxy] -phenyl BU 2_ (2_methylamino-4-chloro-aniline) _propionic acid 3- (4- (1-benzopyrazol_2_yl-pyrrolidine_3_yloxyphenyl) _2_ (2 _Benzylfluorenyl-aniline) -propionic acid 3- [4_ (1-benzoxazol_2_yl) -pyrrolidine-2R-yl-methoxy) -phenyl] -2- (2-benzyl Linyl-benzylamino) · propionic acid 3- [4_ (1-phenylhydrazine P-zol-2-yl) -pyrrolidine-2S-yl-methoxy) -phenyl] -2- (2-fluorene Alkyl group_amido group) _propionic acid MM2- (benzoxazol-2-yl-methyl-aminoethoxy) -phenylphenyl 2- (2-cyclohexanecarbonyl-aniline) -propionic acid 3- {4-〇 (benzohumazol_2_yl_methyl-amino) _ethoxy] -phenylbenzene 2_ (2_ Stilbene-thiophenyl-3-ylamino) -propionic acid 3- {4- [2- (benzoxazol_2_yl-methyl-amino) _ethoxy] -phenylbenzene 2 _ 爷 基 _ Trifluoroethyl propionate 3- {4- [2- (benzoxazol_2_yl_fluorenyl-amino) _ethoxy] -phenyl) _2_ (2 • Bromo-Ye ) -Trifluoroethyl propionate > {4- [2- (benzinazole_2_yl-fluorenyl-aminoethoxyphenylphenyl) _2 (s) _ [4-oxo- 4H-phenylpyrene_3_carbonylamino] _propionic acid-17- This paper size is applicable to China National Standard (CNS) A4 specification (21〇 '乂 297mm) --------- -© Pack ----- 丨 Order ------- (Please read the notes on the back before filling out this page) Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs-A7 B7 V. Description of the Invention (15 > 2 (S)-(2-fluorenyl-aniline) -3- {4_ [2- (5 · fluorenyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -Propionic acid 2- (2-Bromo-aniline) -3- {4- [2- (4-chlorophenyl) -p-sed-4-ylmethoxy] -phenyl} -propionic acid 3- [4- (2- (Benzotriol-1-yl-ethoxy) -phenyl] -2- (2-enoyl-aniline propanoic acid 2 (S)-(2-benzidine -Anilino) -3- {4- [2- (5-methyl-2- (4-methoxy) -phenyl thiophene-4-yl) -ethoxy] _benzene. Propionate 2 (S)-(2-fluorenyl-aniline) _3- {4- [2- (5-methyl-2- (4-fluoro) -phenyl-humto-4 · yl) -Ethoxy] -phenyl} -propionic acid 2 (S)-(2-benzylfluorenyl-aniline) _3- {4- [2- (5-methyl-2- (5-methyl-Da Phen-2-yl) -pyrazol-4-yl) -ethoxy;]-phenylbutanoic acid 2 (S)-(2-benzylfluorenyl-aniline) _3 · {4- [2- ( 5-methyl-1-phenyl_ih-pyrazol-3-yl) -ethoxy] -phenyl} -propionic acid 2 (S) -oxenyl-aniline) _3_ {4- [2_ (5-methyl_2_hexahydropyridine-i_yl_ stilbene-4-yl) -ethoxy] _phenyl} _propionic acid 2 (S)-(2-word fluorenylanilidemethyl) _2_morpholine_4_yl-thiazole- 4-yl) -ethoxy] • phenyl} _propionic acid 2 (S)-(2-; SS group · aniline group) _3_ {4_ [2_ (5 _Methyl_2_ (4_pyridyl) _pyrazol-4-yl) -ethoxy] -phenylpropanoic acid 2 (S)-(2-fluorenyl_aniline) _3_ {4_ [2_ ( 2_dimethylamino_5_fluorenyl-fluoren-4-yl) -ethoxy] _phenylpropanoic acid 2 (S) _ (2_fluorenyl-aniline) -3- { 4- [2_ (5-Methyl-2- (5-fluorenyl-isopurazol-3-yl) -olfactory_4-yl) _ethoxy] _phenylpropionic acid-18- This paper Standards apply to China) M specifications (2 丨 〇 < 297 public directors) ------ ^ ---- © packing ------ order ----- -. 'L ·, (Please read the precautions on the back before filling this page) Α7 Β7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (16) 2 (S)-(2-Yu brewing -Anilino) -3- (4- {2- [5-methyl-2- (4-methyl [1 2 3] p-sedyl-5-yl) -fluorene-4-yl]- Ethoxyphenyl) -bisacid 2 (S)-(2- = f S-S-S-yl-aniline) -3- (4- {2_ [5-fluorenyl-2- (4-methyl_hexahydro On the dagger. I-1-yl) -Iso-4-yl] -ethoxyphenyl) -propionic acid 2 (S)-(2-fluorenyl-aniline) -3- (4- {2- [2 -(3-dimethylamino_propylamino) -5-methyl-p-sec-en-4-yl] -ethoxy] -phenyl) -propionic acid 2 (S)-(2-benzylfluorenyl -Anilino) _3_ (4_ {2_ [2_ (2_methoxy_ethylamino) _5_methyl-p-stein_4_yl] _ethoxy} _phenyl) _propionic acid 2- ( 1-Carboxy-: 2- {4- [2- (5-methyl_2_phenyl_p_ol_4_yl) _ethyl.oxy.yl] _phenyl} -ethylamino) benzoic acid Ethyl ester 2- (1-amino group · 2- {4- [2- (4-Gaphenylphenyl Sulfanyl) _ethoxy] _phenylphenylethylamino) -benzoic acid methyl ester 2- {1-Chi Methyl-2- [4- (l-phenyl · pyrrolidin-2-ylmethoxy) _phenyl] _ethylamino} -benzoic acid methyl ester 3- {4- [2- (benzoxazole _2-yl-methyl · amino) ethoxyphenylphenyl} _2_ (2_cyclopentylbenzyl-aniline) -propionic acid 3- {4- [2- (benzopyrene_2 _Yl_methyl_aminoethoxy] _phenyl} _2_ (2_cyclooctanecarbonyl-aniline propanoic acid 3- {4- [2- (benzoxazol_2_yl-methyl- Amine) _ethoxy] _phenyl} _2_ (2_cyclohexyl-5-fluoro-aniline) _propionic acid 3- {4- [2- (benzoxazol_2_yl-methyl) -Amino) _ethoxy] · phenylphenyl 2- (4-cyclohexylcarbonyl-2-methyl _2H-pyrazol-3-ylamino) -propionic acid 3- {4- [2- (benzoxazol_2_yl-methyl-amino) _ethoxy] -phenyl} _2_ (3 · Methenyl-P-phenphen-2-ylamino group) -propionic acid-19- This paper size applies Chinese National Standard (CNS) Congwei (am97 male thin

In— ml mtt§f ffn nn tl · (Please read the precautions on the back before filling out this page) • In t ^^ — · ϋ ^ — m Kn --Order—Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. .. A7 _____B7 V. Description of the invention (17) 2- (2-¾Hexyl-benzylamino) -3- {4- [2- (5-methyl-2-phenyl-sakibit-4 -Yl) -ethoxy] -phenyl} -propanoic acid 2- (2-cyclohexylcarboxy-aniline) -3- {4- [2- (5-methyl-2-phenyl-izazol -4-ylethoxy] -phenylpropanoic acid '3- [4- (1-benzoxazol-2-yl-pyrrolidine_3_yloxy) _phenyl] _2_ (2-benzyl Fluorenyl-aniline propanoic acid 3- {4- [2- (5-methyl-2-phenyl-oxazol-4-yl) _ethoxy] _phenyl} _2 (S)-[2- (Pyridine-4-carbonyl) _aniline > propanoic acid 3- {4- [2- (5-methyl-2-phenyl-oxazole_4_yl) _ethoxy] _phenyl}- 2 (S)-[2- (pyridine N-oxide-4-carbonyl) -aniline μpropanoic acid 3- {4-1; ι2- (5-methyl-2-phenyl-pyrazole_4_ ) _Ethoxy] _phenylphenyl 2 (s) _ [2_ Bibitz-3-methyl) -anilino] _propionic acid 3- {4- [2- (5-methyl_2_ Phenyl-oxazole_4_yl) _ethoxy] _phenylbu 2 (s) _ [2_ (pyridine-N-oxide_3-carbonyl) -aniline] -propionic acid 2S_ (2_ Acid group- Amine) -3- {4- [2- (5-methyl-3-phenyl-pyrazol-1-yl) -ethoxylactyl] -epibupropionate 2S- (2-fluorenyl- Aniline) _3_ [4_ (丨 _pyridin_2_yl-pyrrolidin-2S_yl-methoxy) _imidyl] -propionic acid 2S- (2-fluorenyl-anilinomethyl-4_benzene _M-imidazole_2_yl) _ethoxy] 'phenyl} -propionic acid 2S_ (2-benzylfluorenyl_aniline) -3- {4- [2- (3-furan-2-yl- 5-fluorenyl-pyrazole_1-yl) -ethoxyphenyl} _propionic acid 2ύ_ (2_fluorenyl-anilino) -3- {4- [2- (5-methyl-3- Phenyl [1,2,4] triazole-1_yl) -ethoxy] -phenyl} -propionic acid-20- Specification (2Η) × 297297 嫠 (Please read the notes on the back before filling (This page) Order printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs; A7 _ · B7 V. Description of the invention -Methoxymethyl_5_methyl_2_phenyl-3 Η -Weijun · 4-yl) -ethoxy] -phenylpropanoic acid 2S- (2-ramanyl-aniline)- 3- {4- [2- (5-methyl_2_phenyl_3Η_imidyl_4_yl) -ethoxy] -phenyl} _propionic acid hydrogenation salt 2S- (2-benzylfluorenyl -Anilino) -3- {4- [2- (5-methyl · 2-phenyloxazole_4-yl) _ethoxy] -phenyl} -propionic acid 2 (S)-(2- Fluorenyl-aniline) -3- {4- [2- (5-methyl_2_ (3_fluorenyl farphen_2 · yl) -oxazol-4-yl) -ethoxy] -phenyl } -Propionic acid 2 (S)-(2- {4_ [2- (5-nitro-2-pyridinylfluorenyl) _ethoxy] _phenylbbumethoxymethoxy-ethylamino)- Benzoic acid 2 (8)-(2- {4- [2- (5-chloro-2-? Pyridyl 511 1171) -ethyl.oxy] _phenyl} _1_methoxycarbonyl-ethylamine ) -Benzoic acid 2 (S) -〇 {4- [2- (N-ethyl-2_methyl-tolylamino) _ethoxy] _phenylbubmethoxy-ethylamino) -Benzoic acid 3- [4- (3-benzoxazol-2-yl-tetrahydrooxazole_4 (R) _ylmethoxy) -phenyl] -2 (S)-(2- Anilino) _propionic acid 3- {4- [2- (benzoxazol_2_yl-methyl-amino) _ethoxy] _phenyl} _2_ [2_ (4-trifluorofluorenyl Fluorenyl) _anilino-propionic acid 3- {4- [2- (benzinazole_2_yl-methyl-amino) _ethoxy] _phenyl} _2_ [2_ (2-thiophene Carbonyl) -anilino-propionic acid 3- {4- [2- (benzoxazol_2_yl-methyl-amino) _ethoxy] -phenyl} _2_ [2_ (3-thienylcarbonyl) -Anilino-propionic acid 3- {4- [2- (benzoxazol_2_yl-methyl-aminoethoxy] • phenyl} _2_ [2_ (3-difluoromethylbenzyl) ) _ Aniline-propionic acid-21-Applicable for this paper size China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

B7 V. Description of the invention (19) 3- {4- [2- (benzoxazin-2-yl-methyl-amino) _ethoxy] -phenyl} _2- [2- (2-tri Fluoromethylbenzylfluorenyl) _anilino-propionic acid 3- {4- [2_ (benzylazole · 2-yl-methyl-amino) _ethoxy] _phenyl (3-fluorenyloxy -Fluorenyl) _anilino-propionic acid 3- {4- [2- (benzoxazol_2_yl · methyl-amino group> ethoxy] -phenyl} _2- [2- ( 2-methoxy-benzylfluorenyl) _anilino-propionic acid 3- {4- [2- (benzoxazol · 2-yl-methyl-amino) _ethoxy] _phenyl (3 νmethyl-benzylfluorenyl) -aniline-propionic acid 2- [2- (4-diamidylaminemethyl-benzylfluorenyl) _aniline] · 3_ {4_ [2_ (5_methyl_2_ Phenyl-yinjun-4-yl) -ethoxy] -phenylpropionate hydrochloride 2_ [2- (4-aminomethyl-benzyl) _aniline] _3_ {4_ [2_ (5 -Methyl_2_phenyl-Qiaojun-4-yl) · ethoxy] -phenyl} -propionic acid hydrochloride 3- {4- [2- (benzo, oxazole_2_yl- Methyl-amino) _ethoxy] _phenyl} _2 · [2- (2,6-dimethylbenzylideneanilide-propionic acid 3- (2_ {1-carboxy-2- [4- (2- {5-methyl-2_phenyl-indazole-4_ylbuthoxy) _private] -ethylamino)-; 2-propionic acid 2- [2- (3-hydroxymethyl) -Lymphyl) _aniline] _3_ {4_ [ 2_ (5_methyl_2_phenyl_oxazole · 4-yl) _ethoxy] -phenylpropanoic acid 2- [2- (3-aminofluorenyl-φfluorenyl) _aniline] · 3_μ_ [2_ (5_ 曱 基 _2_phenyl_ printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) oxazole-4-yl) -ethoxy] -Phenylpropionate phosphonium chloride 2- [2- (j-monomethylaminemethyl-rammyl) _benzylamino] _3_ {4_ [2_ (5_methyl-2_phenyl-pyrazole)- 4-yl) -ethoxy] -phenyl} _propanoic acid hydrogenate 2 (S)-(trimethyl-2- {4- [2- (5-methyl_2-phenyl-oxazole_4) _Base) _Ethoxy] _ Phenylethylamino) -methyl phenylacetate, 22- This paper size applies to China National Standard (CNS) A4 specifications (210X 297 mm) A7 B7

Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs I. Description of the invention (20) 2 (S)-(BUC-2- (4- [2- (5_methyl_2_phenyl_P # azole_4 _Ylethoxy] _phenyl} -ethylamino) -benzoic acid 2-aminoethylamidoamine hydrochloride 2 (S)-(1-carboxy-2- {4- [2- (5- 曱2-_2-phenyl-pyrazol-4-yl) -ethoxy J-phenyl} -ethylamino) -benzoic acid 3-aminopropylamidamine hydrochloride 2- (1-carboxy-2- {4_ [2- (5_methyl_2_phenyl-oxazole_4_yl) _ethoxybuphenyl} -ethylamino) -formamide benzoate 3- {4- [2- (Benzimidazole_2_yl-methyl-amino) _ethoxy] _phenyl} _2_ [2_ (3-hydroxy-fluorenyl) _aniline] _propionic acid 3- {4- [ 2- (5-Methyl · 2_phenyl_ "Hazol_4_yl" _ethoxy] _phenylbenzene 2_ [2_ (4_propylamine and fluorenyl-fluorenyl) _aniline] _Propionic acid 2- [2_ (3-amino-benzylfluorenyl) _aniline] 3_ {4_ [2_ (5_methyl_2_phenyl-humazol-4-yl) -ethoxy] -Phenylphenylpropanoic acid 2- [2- (3-Methylalcohol, ggamine, aryl_franyl) _aniline] methyl_2_phenyl-3thazol-4-yl) -ethoxy]- Phenyl} _propionic acid 2- [2- (j-methoxycarbonylamino group_producer group) _aniline group] _3_ {4_ [2_ (5-methyl_2-benzyl group _4_ group ) _B []] Phenylphenylpropanoic acid 2- [2- (3-hydroxy-fluorenyl) _anilino ρ3 · {4_ [2_ (5-methyl_2_phenyl_ ρ-olol-4-yl) -Ethoxy] -phenylpropanoic acid 2- [2- (3-carboxyfluorenylmethoxy_methylamino) _aniline] _3_ {4_ [2_ (5_methyl_2_phenyloxazole- 4-yl) -ethoxy] -phenyl} -propionic acid 2 (8)-(2_ramanyl-aniline) _3- {4-[. 2- (5 -methyl-2- 2-ρ ratio Yodo_4_yl number vo_4yl) -ethoxy] -phenyl} -propionic acid 2 (S)-(2-benzyl-aniline) _3_ (4- {2_ [5-fluorenyl_ 2_ (4_methyl_hexahydroecogen-1-yl) -oxazol-4-yl] -ethoxy} -phenyl) -propionic acid argon gas 23- (Please read the precautions on the back first (Fill in this page again.) · -〇 Loading— --- Order I 1-............ I- I; Hi- This paper size applies Chinese National Standard (CNS) A4 specification (210 '乂 297 mm) )

Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs I A7 B7 V. Description of the invention () 2 (S)-(2-fluorenyl-aniline) -3- (4- {2_ [5-methyl-2- ( 4-Third · butoxycarbonyl-hexahydropyridin-1-yl) -oxazol-4-yl] -ethoxy} -phenyl) -propionic acid 2 (S)-(2-ffluorenyl- Aniline) -3- {4- [2- (5-methyl-2-hexahydropyridine-1-yl-p-sedin-4-yl) · ethoxy I-yl] -benzyl} •- Propane (S)-(2-fluorenyl-aniline) -3- (4- {2- [5-methyl-2- (4-fluorenylsulfonyl-hexazyl p ratio 11-well-1-yl ) Sejun-4 -yl] -ethoxy} -phenyl) -propionic acid 2 (s)-(l-carboxy-2 · {4- [2- (4-dimethylamino-phenyl)- Ethoxy] -phenyl} -ethylaminopropionate methyl 2 (s)-[l-methoxycarbonyl-2- (4- {2- [5-methyl-2- (4-methyl- Hexahydropyridin-1-yl) -oxazol-4-yl] -ethoxy} -phenyl) -ethylamino] -benzoic acid 2 (S) -H-carboxy-2- {4- [2 -(4-Gas-phenyl) -ethoxy] -phenyl} -ethylamino) _ methyl benzoate 2 (s)-[l-carboxy-2- {4- [2- (4-tri Fluoromethoxy-phenyl) -ethoxy] -phenyl} _ethylamino) -methyl benzoate 3- (4- [2_ (benzoxazol_2-yl-methylamino) -ethyl Oxy] -phenyl} -3- (4-fluorethenylamino) -propionic acid 3- {4- [2- (benzofluorene -2-yl-methylamino) -ethoxy] -phenylbenzene 2- (2- (4-bixylamyl) -aniline) -propionic acid 3- {4- [2- (phenylhydrazone p Azole_2_yl-methylamino) _ethoxy] _phenylbenzene 2_ (2_ (4-methoxy-fluorenyl) -aniline) _propionic acid 3- {4- [2- ( Benzoxazole_2_yl_fluorenylamino) _ethoxy] _phenylphenyl 2_ (2_ (4_fluorenyl-benzylfluorenyl) -aniline) _propionic acid •?-{4- [2 -(Benzoxazole_2_yl_methylamino) _ethoxy] _phenyl 丨 _2_ (2_ (2-methyl-benzylfluorenyl) -aniline propionic acid-24- This paper size Applicable_ 家 榇 准 (CNS) M Specification (21〇 > < 297 Gongchu) (Please read the notes on the back before filling this page)

• Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. A7 ____B7. V. Description of the invention (Gas 2- (2-fluorenyl-aniline) -3- {4_ [2- (4-chloro · phenyl} _ethoxy] -phenyl} -propionic acid 2 -(2-benzylfluorenyl-aniline) -3- {4- [2- (4-methyl-oxazole-5_yl) -ethoxy] -phenyl 丨 -propionic acid 2- (2- Benzamidine_aniline) -3- {4- [2- (4-chloro-phenylsuifanyl) ethoxy] _private group 丨 -propionic acid 2- (2-benzylfluorenyl-aniline) -3 -[4- (4-isopropyl_benzyloxy) _phenyl] -propanoic acid 2- (2-benzylfluorenyl-aniline) -3 · [4_ (4-gas-benzyloxy) _benzene Group] -propanoic acid 2- (2-benzylfluorenyl-aniline) _3_ {4- [3- (4-methoxy-phenyl) _propoxy] -phenyl} -propionic acid 2- (2 -Benzylidene_aniline) _3_ {4_ [2_ (4_dimethylamino_phenyl) _ethoxy] _phenyl} -propionic acid 2- (2-benzylidene-aniline) _3_ { 4_ [2_ (4_bromo-phenoxy) _ethoxy] _phenyl} -propionic acid 2- (2-fluorenyl_aniline) _3_ {4_ [2_ (5_nitro_pyridine_2_yl ) _Ethoxy] -phenyl} -propionic acid 2- (2-benzylfluorenyl_aniline) _3_ (4_ {2_ [3_ (6_methyl_pyridine_2_ylpropoxy] -ethoxy } _ 表 基） _propionic acid 2- (2-loweryl-anilinopyridine_3_yl_ethoxy] -phenylbutanoic acid 2- (2-benzylfluorenyl_aniline) _3_ { 4_ [2_ (3_methyl_6_oxygen _6h-dacroyl) -ethoxy] -phenylpropanoic acid 2- (2-benzylfluorenyl_aniline) _3_ {4_ [2_ (4_ (trifluoromethoxy-phenyl) > ethoxy ] -Phenylpropanoic acid 2- (2-benzylfluorenyl_aniline) _3_ {4_ [2_ (3_nitrile, phenoxyethoxyphenylbenzene-25- This paper is suitable for CNS) A4g (21〇 > < 297 male thin) (Please read the notes on the back before filling in this J) ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— A7 B7 Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Preparation of the fifth, description of the invention (gas group) -propionic acid 2_ (2_fluorenyl-aniline group) _3_ "4_ [2_ (6_methoxy-pyridine_2_ylsulfanyl) -ethoxy] _phenyl} _Propionic acid 2- (2-benzylfluorenyl_aniline nitrophenylpyrrolidine_2_ylmethoxy] • phenyl} -propionic acid. A special group of compounds according to the present invention includes: 2 (s)- (i-Leptyl_2_μ_ [2_ (5_methyl_2_phenyl-humazol_4_ylethoxy) _epiyl} ethylamino) _methane acid 3- (4- [2 -(Benzoxazol_2_yl_methyl_aminoethoxyphenylphenyl) _2 (s) _ (2-hexyl-anilino) _propionic acid; 3- (4- [2- (Benzoxazole_2_yl-methyl-amino) _ethoxy] _phenyl} _2_ (2_cyclohexylcarbonyl-aniline) _propionic acid; > {4- [2- ( benzene Oxazole_2_yl_methyl_amino) _ethoxy] -phenylbenzene 2_ (2-fluorenyl-thien-3-ylamino) _propionic acid; 2 (s)-[i- Methoxycarbonyl_2_ (4_ {2_ [5_methyl_2_ (4_methyl-hexahydropyridine_butyl) -thiazol-4-yl] -ethoxybenzyl) ethylamino] _benzene Formic acid; 2 (S)-(2-benzylfluorenyl_aniline) _3_ {4_ [2_ (methyl-hexahydropyridin_2_yl-amino) _ethoxy] -phenylpropionic acid; 2 ( S) (2-loweryl_aniline) _3_ {4_ [2_ (5 · fluorenylphenyl-slogan bite_cardiyl) -ethoxy] _phenylpropionic acid; and pharmaceutically acceptable Salts and solvates. 〆 The present invention further provides a compound of formula or (la), or a pharmaceutically acceptable salt or solvate thereof, for use in therapy, and particularly to human medicine. According to another feature, the present invention provides a compound of formula (1) or (1 &), or --------------- 1T (please read the precautions on the back before filling in this tile · -26

Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (24) / W Use of pharmaceutically acceptable salts or solvates for the manufacture of improved pharmaceutical products with therapeutic effects on PPAR-gamma . According to another feature of the present invention, there is provided a method for treating mammals, including humans, and in particular for treating ameliorative & conditions that have a therapeutic effect on the effect of PPAR_gamma, which method comprises subjecting a patient to a therapeutically effective amount of formula The compound of (I) or (la), or a pharmaceutically acceptable salt or solvate thereof. Those skilled in the art can know that the treatments mentioned here can be extended to the diseases or symptoms obtained, prevention and treatment. Furthermore, it is also known that the amount of the compound of the present invention required for treatment will vary with the nature of the condition being treated and the age of the patient, and will be determined by the accompanying doctor or veterinarian. In general, however, the dosage used in adult treatment is typically in the range of 2,000-50,000 mg per day, such as 1-1500 mg per day. The required dose may conveniently be presented in a single dose or in divided doses administered at appropriate intervals, such as two, three, four or more doses per day. However, the compounds of the present invention may be administered therapeutically as the raw chemical, preferably as active ingredients of pharmaceutical formulations. Accordingly, the present invention further provides a compound comprising formula (I) or (la) or a pharmaceutically acceptable salt or solvate thereof in one or more pharmaceutically acceptable carriers and, as appropriate, other therapeutic and / or preventive ingredients Pharmaceutical formulations. The carrier must be in an "acceptable" form that is compatible with the other ingredients of the formulation and non-toxic to its container. The invention further provides the preparation of a pharmaceutical formulation comprising a compound of formula (I) or (la), the method comprising combining formula (I) or (la) or a pharmaceutically acceptable salt thereof with one or more drugs Carriers are acceptable, and other therapeutic and / or preventive ingredients are premixed as appropriate. -27- The size of this paper is applicable to China National Standard (CNS) A4 (210X297mm). Please read the notes on the back first to write this page.

T7 B7 B7 5. Description of the invention (2S) Inventions include those that are especially oral, buccal, non-oral: transdermal, inhaled, nasal, transmucosal, infused or = administered: . However, oral administration is preferred. For side-like administration, it is formulated as a key or tablet. For oral capsules may contain customary excipients such as binding agents (e.g., sugar packs, acacia gum: ia), colloidal 'sorbitol, tragacanth gum, powder-saving glue or polyethylenimide (slightly), filling Agents (for example, lactose, sugar, microcrystalline cellulose, corn :::,: acidic sorbitol lubricants (for example, magnesium stearate, hard: B: stone polyethylene glycol or dream stone), split Agent (for example, Dianyan Dianfen) or soup emollient, such as sodium lauryl sulfate. Bonding technology = coating method known. This second = the compound of the invention can be incorporated into oral liquid preparations, such as water or = = money , Emulsion, syrup dispersant. In addition, including these, quotients can be dry products in one week to mix with water or other brake before use. This body preparation can contain all additives such as suspending agents such as mountain: two go Syrup, methyl cellulose, glucose / syrup, gel, hydroxyethyl cellulose, stearic acid or hydrogenated edible fat; # 7 " @t _ cooking oil) such as almond oil; fractionation Cocoa butter, oily nature: jealous-alcohol, ethanol; and preservatives such as gas-hydroxybenzoic acid methyl or propyl ester With suppositories, e.g., containing conventional suppository bases such as coconut oil or your other glycerides. Outer: 1 'The formulation of the present invention is formulated as an intestine by injection or continuous infusion. Wang Shezhi's formulations can be suspensions, solutions or emulsions in oily or -28- Please read the precautions before you pay for the printing of this paper by the China National Standards Bureau Staff Consumer Co-operative Society. (210X297 mm) A7 B7 V. Description of the invention (26) Type t in the aqueous carrier, and may include formulation agents such as suspension, stabilization and / or dispersant. Alternatively, the active ingredient may be a powder combined with a suitable carrier (e.g., sterilized, essence-free water) before use. The formulations according to the invention can also be formulated as storage preparations. This long acting formulation can be administered by infusion (for example, subcutaneously or intramuscularly or by intramuscular injection. Accordingly, the compounds of the present invention can be combined with appropriate polymeric or hydrophobic substances (such as emulsions in acceptable oils), Ion exchange resins or sparingly soluble derivatives, such as sparingly soluble salts, are formulated. The formulations according to the present invention may contain 0. 9% of active ingredients, conveniently 30-95% in tablets and capsules and 3 _5. % In liquid formulation. The present invention also provides a method for preparing a compound of formula (I). Unless otherwise indicated, A, B, Aik, R, and Z (and other substituents represented by them) are substantially as described above. According to the general method (A), the compound of the formula (I) can be obtained from the compound of the formula (π) m · m nn —m. Nim tm nn nn UK 1, J i (Please read the precautions on the back before filling this page) — Aik · HO— CO ^ R1 2 (II) Printed directly or indirectly by one or more steps of the consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A_B_x (where χ is a leaving group or a hydroxyl group, and Table B contains CN6 extension It is prepared by the reaction of alkyl group, B directly bonding X to CN6 alkylene group. Reaction conditions suitable for i The companion examples are described below. For details, such as Selective Functionalization of (S) -Tyrosine, Tetrahedton, 49 (26), pp. 5767-5776, ( 1993) The selectivity of amino acids by Solar et al. Seiective O-Alkylation -29- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) A7 B7 V. Description of the invention ( 27) of Tyrosine) Journal of Organic Chemistry, 31, pp. 1996-1997 (1966), 0. Mitsunobu, Synthesis, p 1 (1981) and DL Hughes, Org. React. Vol. 42, p 335 (1992). A is preferably phenyl, pyridyl, benzoxazolyl or hexahydropyridyl, any of which may be substituted with one or more Ci_3 alkyl groups. More preferred A is phenyl, and p is better than Benzene, Benzazine, and Junki (hexahydrop is better than P. Well.) B is preferably Het-Cu alkyl as described above and Z is preferably -NH-Y- (C = 0)- T-R5, where Y is phenyl, optionally substituted by one or more Cl_3 alkyl groups and / or one or more halogen atoms; T is a bond or _〇_ and r5 is shown in Table 6 Base (optionally via one or more , Cw alkyl, Ci-3 alkoxy, C0-3 alkyl NR9R10 (where each R9 and R10 are hydrogen, Ci-3 alkyl, -SOzCw alkyl, SOsNHCu alkyl, CG-3 alkyl Alkyl CO2H, C0-3 alkylene COsCu alkyl, or -0CH2C (0) NH2 substituted). Preferably X represents a compound or alkyl- or arylfluorenyl group and R1 represents hydrogen. More preferred compounds of formula ABX and formula (II) are:

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) where OMs are mesylate leaving groups and R13 is phenyl or 0CH3. -30-This paper size applies to China National Standard (CNS) A4 (210 ×: 297 mm)

* A7 B7 V. Description of the invention (2δ) Compounds of formula (II) (where R1 represents CN3 alkyl, preferably methyl, and X represents warp group), reactions of ABX and compounds of formula (II) include Mitsunobu reaction The alkyl ester group is then hydrolyzed to the corresponding acid without dissociating the ester. The preferred Mitsunobu reaction mixture contains toluene. More preferred compounds of formula ABX and (II) are:

0H

Wherein R13 is a phenyl group or an OCH3 group. When the following compounds are listed in the Z table: m- nn ϋϋ m nn m i m ^--.

The compound of formula (II) printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs is the first preparation of compounds of formula (II), where Z is

-31-This paper size applies Chinese National Standard (CNS) A4 (2I0X 297mm) A7 B7 (Ilf). CH, V. Description of the invention (29) Then dehydrogenation catalyst in the presence of hydrogen acceptor preparation. A preferred amidine acceptor is an aromatic nitro compound. Compounds of formula (I) can be reacted by ABX (B is the direct bond of X to Ck alkylene as described above and wherein X is a hydroxyl group or a suitable leaving group such as a halogen or a hydroxy group or an aryloxy group (E.g., 曱 Ι; mesylate) and i. Alternatively, in the case where B is -NR2Cb6 alkylene, the compound of formula (I) can be appropriately derived from the compound of formula (II) by formula ( III) Protected intermediates represented by CO'R1 P — Aik-N — C1_galkylene-〇— (where p represents a protecting group such as an alkoxycarbonyl group such as a third-butoxycarbonyl group or the like) are described in the subsequent examples Technology and representative protection and deprotection reactions known in the art, such as those described in TW Green & PGM Wuts (1991), Protecting Groups in Organic Chemistry, John Wiley & Sons, are prepared. Compounds of formula (II) Yes, for example, from the compound of formula (IV) CO ^ R1 (Please read the precautions on the back before filling this page)

Aik.

HO NH, (IV) Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs Properly prepared by reacting with a dione, such as 2-benzylfluorenyl-cyclohexanone, in the presence of a metal catalyst, such as palladium. Preferably, R1 is an alkyl group, and the diketone is first reacted with an amine, and then dehydrogenated in the presence of a metal catalyst and a hydrogen acceptor. A preferred hydrogen acceptor is an easily reduced aromatic nitro compound, such as p-nitrofluorene. If R1 is hydrogen, the compound (where R1 is 32-Chinese paper standard (CNS) A4 size (210X297 mm) is used for this paper size. A7 B7 V. Description of the invention (30) Alkyl group) Hydrolysis in a solvent mixture of water and a polar-protonic, inert solvent. Compounds of formula (IV) are commercially available or can be prepared as described in Med. Chem. 1978, 21 (5), 430-7. Compounds of formula (I) according to another general method (B) 'can be prepared from compounds A-B-0 (V) of formula (v) suitably with NWH tile. For example, the reaction can be suitably performed by using a metal catalyst such as a gold catalyst (acetic acid dimer), and appropriately by refluxing in the presence of a solvent such as toluene or the like. This will allow Method B to produce a compound of formula (I) wherein Z Table -NR3R4. Compounds of formula (V) can be diazotized compounds of formula (VI) A — B — 〇

(VI) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. The recombination reaction is carried out by refluxing a compound of formula (VI) in the presence of a nitrile, such as isovaleronitrile, which is commercially available, such as 0-fluorenyl-tyrosine. Alternatively, the compound of formula (VI) can be prepared from a known starting material, such as the t-benzoxazolium compound and amine alcohol described in the hind foot example. However, the compound of formula VII can be directly derived from the compound of formula (VI) Prepared by method) (C). For example, a compound of formula (VI) may be a compound of the general formula CH (CH2) n-(= 〇) -CH2 (C = 〇) -T-R5 (where η is ^ selected from 0 to 3) Continued- 33 This paper size applies Chinese National Standard (CNS) Μϋ7ΐΓ〇χ297 ^ (Please read the precautions on the back before filling this page)

::: ui A7 B7 V. Description of the invention (31 numbers) reaction to produce a compound of formula (I) (whose z table is _nh_C2_6 alkylene_ (C 0) -TR = In another example, formula (VI) The compound can be obtained by using r5_ (CO) -X, (where X is a suitable leaving group substantially as described above), suitably in the presence of a base such as a third amine such as triethylamine or the like, The reaction is carried out and the propionate g is converted. According to another method (D), the compound of formula (I) can be derived from the compound of formula (νπ),

A— B

co2r, (VI!) is prepared by reacting with a strong base, suitably an alkali metal amine, followed by reaction with the formula ζ_χ (where X is a suitable leaving group as previously described). In particular, the method (D) is used for the preparation of a compound of the formula (wherein the ζ table is substantially as previously described-(Ci.3alkylene) phenyl). Suitably, the reaction is carried out by stirring in an ether solvent such as tetrahydrofuran for several hours. Suitably, compounds of formula (VII) can be derived from compounds of formulas (νΙΠ) and (Ιχ)

A— b——P (VIII) — Aik — C〇2R 'HO (IX) --------- install -------- order ------ /' X (read first 闉(Please read the notes on the back and fill in this page again.) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, where P can be an appropriate protective group, substantially as described above, and prepared. Compounds of formula (IX) are commercially available. Compounds of formula (VIH) can be prepared from known starting materials using, for example, the techniques described above starting with benzimidazole and amine alcohol. According to another general method (E), the compounds of formula (I) can be cyclized by formula (X). 32) Compound-N-! 丨 丨; Η Β — 〇

CO, R1 (X) to give a compound of formula (I) (wherein A represents a bicyclic ring

Contains two nitrogen heteroatoms ($ 0 or 6%) to be prepared. Cyclization is usually carried out in an acidic environment. The compound of formula (X) can be appropriately derived from the compound of formula (XI) CO, R1 (Please read the precautions on the back before filling this page}

Aik '8-0- (XI) is prepared by reacting with 1,2-benzyl diamine' appropriately in the presence of an alkali metal carbonate such as potassium carbonate or the like. X is a leaving group substantially as described above, particularly a mesylate. Compounds of formula (XI) can be derived from compounds of formula (XII)

, 1T good furnace, ministry of inflammation «. 丰 ^ · ,; ί.τ. Eliminated by cooperation it India f co〆 'τ (XII) η〇 ~ β—〇 ___ L Jj. ~ ————... _ _ 1C is locally prepared by reacting with, for example, an alkyl or arylsulfonyl compound, such as methanesulfonate SS chloride, in an ether solvent such as tetrahydrofuran and a third amine such as triethylamine. Formula (χπ) The compound may suitably be from 35- • 111 I of the formula (II) substantially as previously described.

麫 米 '部 中 头 "-^^,']ί-τ; 7ίYu 乂 :: Bamboo " India W A7 ------------- B7 V. Description of Invention (33) ~ The compound is prepared 'for example by reaction with an alkylene carbonate in the presence of an alkali metal carbonate such as potassium osmate. According to another feature of the present invention, the compound of the formula) can be converted into the first compound of the formula (I). In particular, the internal conversion reaction involves the appropriate use of hydrolysis techniques such as metal hydroxides, in the presence of ether solvents such as tetrahydrofuran and alcohol solvents such as methanol or the like, to convert compounds of formula (where ... Table ^^ 3 alkyl) into Compounds of formula (1) (wherein R1 represents hydrogen) "Therefore," a person skilled in the art knows that compounds belonging to the general formula (!) Can sink in some cases "as described in the intermediate section below, which is used to prepare other formula Compound of (I). Sensitive or reactive groups may be needed and / or desired to be protected for any of the aforementioned general methods and schemes. The protecting group is used according to the standard method of organic synthesis (TW Green and P. G. Wuts (1991) Protecting Gmnpg £££-^ Ilic Svnthesi, s, John Wiley & Sons). These groups are removed at the customary stage of the synthesis by methods known in the art. Thus, for example, the amine group can be selected from the group consisting of aryl (such as fluorenyl), self-substituted, or fluorenyl, such as sulfopropylsulfonyl, third butoxycarbonyl, phthalimide, or The tosyl group is protected; then the protective group is removed by hydrolysis or hydrogenolysis under standard conditions of appropriate use when needed. So, for example, tertiary butoxycarbonyl is removed by hydrolysis under sexual conditions. The meridian and the radical may be protected by any conventional meridian or carboxy protecting group. Suitable hydroxy and carboxy protecting groups include those selected from alkyl, such as methyl, tert-butyl or oxomethyl, aralkyl, such as benzyl, diphenylmethyl, or triphenylmethyl, hetero Cyclic groups such as tetrahydropiperanyl'Ss groups such as acetate or acetic acid groups, and wheat alkyl groups such as trisalyl radicals, -36-; paper size applies to Chinese National Standard (〇 阳) 8 4 specifications (2丨 0 '乂 297 mm)'-(Please read the precautions on the back before filling this page)-© 装 ·-Order I n IL L · A7 B7 V. Description of the invention (34) Such as the third _ 丁A group of a dimethyl dialkyl group. The hydroxyl protecting group can be removed by conventional techniques. Thus, for example, an alkyl group, a fluorenyl group, an alcohol group, and a heterocyclic group can hydrolyze fluorene under acidic or residual conditions. Fangxian such as trityl can also be removed by hydrolysis under acidic conditions. Aralkyl groups such as fluorenyl groups can be cleaved by sulfolysis in the presence of a noble metal catalyst such as palladium / carbon. Silyl groups can also be easily removed using sources of fluoride ions such as tetra-n-butylammonium fluoride. The above reactions and synthetic routes can be completed on a solid support. For example, R of formula (11) may represent a suitable solid phase support, for example, R1 may be a 2-chlorotrityl chloride polystyrene resin. After carrying out the appropriate reaction, the desired compound of formula (I) can be separated from the solid support by cleavage. The following examples are presented to illustrate the synthesis of certain specific compounds of the invention and further specifically illustrate the application of the general examples described above. Accordingly, the following example sections are by no means intended to limit the scope of the invention herein. The codes and terms used in these method diagrams and examples are the same as those used in contemporary scientific literature, such as the journal of the American Chemical Society. Unless otherwise noted, all starting materials are obtained from commercial suppliers and require further purification before use. In particular, the following simple nests can be used in the examples and throughout the specification: g (grams); mg (milligrams); L (liters); m 丄 (milliliters); " L (microliters); psi (lbs / per Square feet); μ (molar concentration); mm (¾ molar concentration); iv. (Intravenous); Hz (hertz); MHz (mega hertz); moi (mole); RT or rt (room temperature); min (minutes); h (hours); mp. (melting point); TLC (thin layer chromatography); HPLC (high pressure liquid chromatography); tr (delay time); RP (reverse phase); MeOH (methanol); TFA (trifluoroacetic acid); THF (tetrahydrofuran 37-) This paper size is applicable to China National Standard (CNS) A4 specifications (210X297 mm) --------- G Pack- ---- 1T -------- L (Please read the notes on the back before filling this page) 屮 Jk il: j 1 \ -I 厶 卬 A7 B7 spear. Ministry head ii .T As-it ii ΐ5. Description of the invention (35) ran); DMSO (dimethylformamide); EtOAc (ethyl acetate); DCM (dichloromethane); DMF (dimethylamine amine); Et3N (triethylamine); 1,1-carbonyldiimidazole (CDI); isobutyl chloroformate (iBuCF); N_ HOSu .; N-hydroxyb.enztriazole (HOBT); azodicarboxylic acid diester (DEAD); di-tertiary-butyric acid dicarbonate ( (B0C2) 0); Ethylcarbonylimine hydrochloride (EDC); Bis (2-oxo-3-olinolinyl) phosphine chloride (BOP); Third-butoxycarbonyl (B0C); two Cyclohexylcarbonylimine (DCC); benzyloxycarbonyl (Cbz); NaHC03 (saturated aqueous sodium sulphate carbonate). All ethers are referenced to ether; brine refers to saturated aqueous Naci solution. Unless otherwise indicated, all temperatures are in ° c (Celsius ). Unless specifically if? S2 »'All reactions are performed at room temperature. H NMR spectra. Recorded with Varian VXR-3 00, Varian Unity-3 00 or Varian Unity-400 instruments. Chemical shifts are in parts per million (Ppm, Θ units). The coupling constant is in Hertz (Hz) units. The number of split peaks is specified as s, singlet; d, double-octyl; t, three-peak; q, four-peak; m, multimodal; br, Wide cold. Low-resolution mass spectrometer (MS) was recorded in JOEL JMS-AX505HA, JOEL SX-102 or SCIEX-APIiii spectrometer. All mass spectrometry are derived from positron models of electrospray ionization (ES), chemical ionization (C1), electron impact (EI), or rapid atomic bombardment (FAB) methods. Infrared (IR) spectra were obtained using a Nicolet 510 FT-IR spectrometer. Optical rotation is recorded on a Perkin-Elmer 241 polarimeter. All reactions were detected by thin-phase chromatography on a 0.25 mm E. Merck Shixi gel disc (60F-254), and detected by UV light, 7% ethanol to molybdate or -anisldehyde. Flash tube 38- This paper size is applicable to Chinese National Standard (CNS) A4 (21.0X297mm) ------ ~~ 0 batch of clothes-(Please read the precautions on the back before filling this page) Order A7 ____ B7 V. Description of the invention (36) Column chromatography was performed on silica gel (230-400 mesh, Merck). The product was prepared by preparative reverse-phase high-pressure liquid chromatography (RP-HPLC) with Waters Model 3000 Pelta. Prep was fitted with a Delta-pak radiation compression cartridge (C18, 300 A, 15 m, 47 mm x 300 mm) or a Pharmacia LKB system for purification using Merck Lobar lithotripsy or reverse-phase C18 columns. A linear gradient is used in all cases and the flow rate is 10_100 m L / min (10 = 5.0 minutes). All solvents contain 0.1% TPA. Analytical purity was evaluated by RP-HPLC using a Waters 600E system equipped with a Waters 990 diode barrier spectrometer (I range 200-400 nM) or a Hewlett Packard Series 1050 system equipped with a diode array spectrometer. The stationary phase is a Dynamax C8 column (25 cm X 4.1 mm), a Dynamax 60A C18 column (25 cm X 4.6 mm), a Vydac C18 column (5 cm; 4.6 mm X 250 mm) or a Rainin C18 column (5 Cm, 4.6 mm X 250¾ m). The flow rate was ι · 〇 to i.5 mL / min (tO = 2.8 or 3.0 minutes.) And the solvent system is described below. Enantiomeric purity was measured using a Chiralpak AD column (25 cm x 4.6_Aimi) or a Chiralpak OD column (25 cm x 4.6 mm) on a Hewlet Packard series 1050 HPLC system equipped with a two-tube array spectrometer or on a supercritical Fluid (SFC) system is evaluated using C02 / methanol as a mobile phase. 0 ^ i? '^ X'Jh-T'; fi 贽 cangzhu ^ cr ow m nfn 11 · — · m ^ i ^ — m am n—1 nn ^^^^ 1 tm ", i (Please read the notes on the back before filling this page) Intermediate Intermediate 1 3- (4-Benzyloxyphenyl) _2_diazopropionic acid Methyl ester 2.5 g (8.77 mmol) methyl 0-fluorenyl tyrosine, 1,03 g (8.77 mmol) isovaleronitrile, and 1.57 g (26.2 mmol) glacial acetic acid in chloroform (6 5 -39- This paper is suitable for Chinese National Standard (CNS) A4 size (210X: 297mm) A7 B7 V. Description of the invention (37) liters) The solution is stirred and refluxed for 5 minutes and then cooled To room temperature (RT). The solution was concentrated to an oily residue and dissolved in EtoAc. ⑼mL) and washed with 5% NaHC03. The organics were then dried (MgS04); filtered, and concentrated to an oily residue, which was chromatographed in Meng Gum with hexane / EtOAc (1: 1) to give the target compound. 1HNMR (CDCh) e 7.43-7.31 (m, 5H) 7.14 (d, 2H, J = 8.7) 6.90 (m, 2H) 5.03 (s, 2H) 3.76 (s, 3H) 3_56 (s, 2H). Intermediate 2 2- (4-Cyloxymethyl) -3_superyl_3 • phenyl_2,3_dihydro_iH, indole_2_carboxylic acid ethyl esters 〇2 millimoles, 0-24 equivalent) of rhodium (11) dimer with 250 pens (0.84 mole) of intermediate 1 and 316 mg (丨 59 millimoles) of 2-aminobenzophenone Toluene (5 ml) was refluxed. The residual liquid was refluxed for 1 minute, cooled to room temperature, poured into 2N HC1 (10 ml), and extracted with EtOAc. The organics were dried (MgS04), filtered, concentrated, and chromatographed on silica gel with hexane / EtOAc (3: 1) to give the title compound as a yellow oil. 1H NMR (CDC13) 7.6 (s, 1H) 7.60 (s, 1H) 7.43-7.24 (m, 9H) 7.11-7.09 (d, 1H, J = 7.2) 6.92-6.82 (m, 7H) 5.01 (s, 2H ) 3.77 (s, 3H) 2.66 (s 1H) 2.45 (ABq, 2H, JAB-13.5,

DnAB = 40.2) ° Intermediate 3 2- (3-fluorenyl-fluoren-2-yl-amino group) _3_ (cardiacoxyphenyl) _methyl propionate 3 mg (0.0067 mmol) rhodium acetate (II) Dimer at 80. 〇Add 300 mg (1.01 millimolar) Intermediate 1 (Kawamatsu, Y. et al.-40- (Please read the precautions on the back before filling out this page)-1 ° 丕 The paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) A7 ---___________ B7 _ ^ __ 5. Description of the invention (38)

Arzneim.-Forsch, 1980, 30 (4), 585-9) and 110 mg (0.57 mmol) (2-amino-fluoren-3-yl) -phenyl-methanone (Robba, M , Et al. Bull Soc. Chim. Fr. 1997, 12 (2), 2864-70) in 10 ml of toluene with stirring. The mixture was warmed to reflux for 5 minutes and then cooled to room temperature. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography using CH2C12 (pure) as the eluent to obtain 120 mg of the target compound; TLC (CH2CI2): Rf = 0.40) 0 Intermediate 4 2 -(2-fluorenyl-thiophene_3_yl-amino) _3_ (4_benzyloxy_phenyl) _methyl propionate The target compound (280 mg) is from 600 mg (2.02 mmol) Ear) Intermediate 1 (Kawamatsu, Y. et al., Arzneim_Försch 198, H, 585_9) and 203 mg (1.0 millimolar) (3_amino_fluorene_2_yl) _benzene -Ketone (Kiehne, H. (Bayer AG) Ger. Offen. 1945964 (March 25, 1971), according to the method of Intermediate 3 followed by (pure) as a dissolution method by flash chromatography. Prepared by purification · TLC (pure))

Rf = 0.45) ° Intermediate 5 N-2_ (N-methylaminoethanol) -1,3_benzofluorene Sniff 10 g (65.2 mmol) 2-chlorobenzoxazole at 0 r. To a stirred solution of 10 g (133 mol) of N-methylaminoethanol was added dropwise. The resulting solution was stirred for 1 hour and diluted with water (250 ml) and extracted with EtoAc. Organic matter was washed with brine, dried (Mgs04), filtered and concentrated to give I2 · 2 g brown oil, which hardened during storage, melting point 56_58 „c. Intermediate 6 -41-This paper is scaled to China State Standard (CMS) ) A4 specifications (210X297 male (please read the notes on the back before filling out the supplier's page). ¾-Order A7 B7 V. Description of the invention (λ il in the ministry f: 4, for N-2-[( N-methylamine ethyl-1-fluorenylsulfonium ester) 4,3-benzohumidazole] 17.6 ml (126.3 mmol) of TEA was added dropwise at 22 ° C (U4.6 mmol Ear) Intermediate 5 and a stirred solution of 14.43 g (126 mmol) of sulfonium chloride in dichloromethane (100 ml). The resulting suspension was stirred for 1 hour with water (200 ml) and a 1M solution of 3P04 ( 100 ml) was diluted. The organic phase was separated, dried (MgS04), filtered, and concentrated to give 20 g of a white solid with a melting point of 94-96 ° C. T_g_.lt 7. 2-amino-3- {4- [2- (Benzoxazole_2_ylmethyl-amino) -ethoxy] -phenyl} -propionic acid methyl ester. 5.0 g (18.5 mmol) of intermediate 6 at room temperature Add 3 61 g (18 5 pen ears) (S) -Tyramine and 8 丨 g (204 mmol) sodium cyanide (60% suspension in petroleum) in 50 ml of a stirred solution of DMF. The resulting solution was heated to 100Ό for 2 hours. After cooling to room temperature, the solution It was quenched with water and extracted with EtOAc. The combined organics were dried (MgS04) and the solvent was removed in the air. The residue was subjected to silica gel chromatography with hexane / EtoAc (ingredients 3: 7 to 0: 1 ) Purified as an eluent to obtain 45 g (2)% yield of the target compound: low resolution MS (ES) m / e 370 (MH). Intermediate 8 2 (S) -amino (benzene Ayasaki Bite_2_yl_methyl-aminopoethoxy] -phenyl} -propionic acid Add 131 ml (13.5 mmol) of 1 N sodium hydroxide solution to 5.00 g (^ 3.5 mmol) Body 7 (Fall% A. et al. WO 94/29285) in a stirred solution of 25 MMe0H, and the resulting solution was stirred at room temperature. Small -42- This paper button towel_Home Standard (CMS) A7S7 ^ _29_7 Li) — (Please read the notes on the back before filling out this page) ------- ®. 策 —

1T ---- I--5-I: -... vm K · Air: ^ -i.Je.T in the Ministry of Economy and Purification of Bamboo-Bass A7 B7 5. Explanation of the invention (40). The MeOH was removed under reduced pressure and the residue was diluted with 25 ml of water. The solution was extracted three times with 2.5 ml of diethyl ether, and the aqueous phase was acidified with 14 ml of 1 n hydrochloric acid. The obtained white solid was filtered, washed with 3 × 2 5 ml of water and dried under reduced pressure to obtain 4.02 g of the target compound; low resolution ms (AP1 +) m / e 356 (MH +) 〇2-diazo_3_ {4 · The reaction of [2- (benzoxazol-2-yl-methyl-amino) _ethoxy] -phenyl} -propionate was carried out after a blast screen. 0.5 ml (3 93 mmol) of isovaleronitrile was added to 1.45 g of Intermediate 7 and 0.7 ml (η.8 mmol) of glacial acetic acid in a solution of 40 ml of chloroform. The resulting solution was heated to 60 TO 25 hours. The solution turned orange / brown upon heating. The solution was cooled to room temperature and extracted with water and then washed with a saturated solution of sodium bicarbonate. The organics were then dried (MgS04) and the solvent was removed in the air to quantitatively yield the target compound, which was used without further purification: low-resolution Ms (ES) m / e (ΜΗ +), 353. .Intermediate 10 3- {4- [2- (Benzene group _2_yl_methyl_amino) _ethoxy] _phenylbenzene 2- (2_Yeryl private amino group)- The target compound (110 mg) of formazan succinate was prepared from 0.17 g (0.5 mmol) of intermediate 9 and 0 '11 g (0.5 mmol) of 2-aminodiphenyl ketone according to intermediate 3 The method was then prepared by the purification of Erica gel chromatography using Et〇Ac / hexane (components 37 to 1: 0): low resolution MS (ES) m / e 550 (MH +). Intermediate 11 ---- ---- Φ (Please read the notes on the back before filling in this page}

, 1T -t -1 -1 m 1 ^ 11 · -43-

V. Description of the invention (41) B7 3- {4- [2- (benzoxazin-2-yl-methyl-amino) _ethoxyphenyl} _2_ (2_benzyl-4-methyl -Anilino) -methyl acetate propionate (100 mg) is based on 0.13 g (0.3 mmol) of intermediate 9 and 0.10 g (0.5 mmol) of 2-amino_5_ Diphenyl ketone was prepared according to the method of Intermediate 3 and then purified by silica gel chromatography using t0Ac / hexane (components 3: 7 to 1: 1): low resolution MS (ES) m / e 564 (MH +) . Intermediate 12 3- {4- [2- (benzoxazol_2_yl_methyl_amino) _ethoxy] _phenylcyclohexanyl-anilino) _methyl propionate The target compound (61 mg) is derived from 125 mg (0.33 mmol) of Intermediate 11 and 87 '9¾ g (0.46 mmol, 14 equivalents) (2-amino_phenyl) _cyclohexyl-fluorenone The method of volume 3 was prepared by using hexane / EtoAc 3/1 to 丨 / 丨 as the eluent and purified by silica gel flash column chromatography: low resolution (API) m / e 556.3 (MH +). Intermediate 13 3- {4- [2-benzoxazol_2_yl_methyl_amino) _ethoxy] _phenylbenzene 2_ (2-benzylfluorenyl-fluoren-3-ylamine ) _Mercaptopropionate (130 mg) is based on 200 mg (0.53 mmol) of intermediate 9 and M9 mg (0.74 mmol, i 4 equivalents) (3-amino-thiophene _2 = base-formamidine according to the method of intermediate 3, followed by purification with Yasuo Kasumi / Shanxin as the eluent and purification by Jing steam column chromatography: low-resolution 'MS (API) m / e 556.2 ( MH +). Intermediate 14 3- {4- [2- (Benzazine-2_2-yl-methyl-amino) _ethoxy] • phenylbutyric acid methylan-44-(Please read first Note on the back page, please fill in this page) .0 ^ — ti —.νκ I v — ^ — · Order ------- Paper size is suitable / j] Chinese National Standard (cNS) A4 Specification (210X297mm ) A7 B7 V. Description of the invention (42) Disperse 310.7 mg (77 77 millimoles,) 〇 Prepared in 0 Τ: ΤΓ · Λ field) Sodium cyanide in 60% of oil Add 1.40 g (7.77 mmol of molyl propionate under C) to 15.5 ml of brittle = 2 methyl 4 Chuyl-benzene. Add 2.31 g (8.55 mmol, u equivalent) of middle f "The resulting solution was warmed to room temperature and removed & < two removers. By steam column chromatography to burn / should. / 1 as a solution of local analysis and purified to obtain 16i grams of low-resolution MS (ES) m / e 355 _ +). Main translucent oil. Intermediate 15 3- {4- [2- (Benzamidine number _2_yl-methylqimaiqi, 7 1 >. Methyl propionate §Purpose-synthetic group) -Ethyl lactyl] _phenyl} _2_ character group private 1-7 70 liters (1.70 millimolar,] 2 equivalents)! 〇% of it-as still soluble in THFi "mc 5022 mg (142 mmol) of intermediate 14 was added to a stirred solution of 10 mmol of THF t. The resulting solution was stirred for 15 minutes, and 315.1 g (1.84 mmol, 1.3 equivalents) of bromine were added. 4.0 ml of benzyl butyl HF. The solution was warmed to room temperature in a bath and stirred for 4 hours, then quenched with water. The reaction mixture was extracted with EtOAc. The organic layer was dried (M ^ S04) 'jl The solvent was removed in the air. Purified by Shixi gel flash column chromatography with hexane / EtOAc j / 2 as the eluent to obtain 908 mg of the target compound as a transparent oil: low resolution MS (ES) m / e 445 (MH +). Intermediate 16 I ·. ·. J Benzozazole_2-yl-methyl-amino) _ethyl Jibu Jibu 2_ benzene (2_ _ • bromo-yl) - propionic acid methyl -45- Cool the present paper suitable scale Sichuan 210X297 ^) (wide first read the read back surface and then fill Note Page}

A7 ______________ B7_ _ V. Description of the Invention (43) Add 2.26 ml (3.39 mmol, 12 equivalents) of 15 MLdA cyclohexane / mixture at -78 C and add 1.00 g (2.82 mmol) of middle gift. 5 of 5 0 ml of THF was stirred in the falling liquid. The resulting solution was stirred for 1 minute, and 846 3 mg (3.39¾ mole, 1.2 equivalents) of 2-bromo-benzyl bromide 40 ml butyl HF was added to the solution. The solution was warmed in the bath. Stir at room temperature for 4 hours and then quench with water. The reaction mixture was quenched with EtOAc. The organic layer was dried (MgS04) and the solvent was removed in the air. Purified by silica gel flash column chromatography with hexane / Et〇Ac 3/2 as eluent to obtain 3 18.5 mg of the target compound as a transparent oil: low resolution MS (ES) m / e 523 (ΜΗ +) . Intermediate 17 {4- [2- (Methyl-P Bidian_2_yl-amino) _ethoxy] _phenyl Add sodium cyanoborohydride (0.5 g '13.2 mmol) to 5.12 G (20 mmol) 4- [2- (methyl-pyridin-2-yl-amino) -ethoxy] -benzaldehyde (Camelio, B c C. et al., J_ Med. Chem_ 1994 , 37, 3977-85) in 50 ml of a stirred solution of absolute ethanol. The mixture was stirred at 20 ° C for 2 hours. 10 ml of water was added to the mixture 'and allowed to stand for 30 minutes. The ethanol was removed under reduced pressure, and 50¾ liters of water and 100¾ liters of diacetic acid were added to the residue. The mixture was stirred for minutes and then 100 ml of ether was added. The phases were separated, and the organic phase was extracted three times with 100 ml of water, dried over anhydrous magnesium sulfate, and then reduced. The solution was concentrated under reduced pressure in an oven to obtain 5.06 g of the target compound. TLC (hexane / Et0Ac (1: 1)): Rf = 0.50). Intermediate 18 [2- (4-Bromofluorenyl-phenoxy) -ethyl] -methyl-pyridine-2-yl-amine Dibromotriphenylphosphine (422 mg, 1.0 mmol) was added to 5. (: Add 258 milli-46-I paper size suitable for 7 family standards (CNS) M specifications (210x297 mm) ~~~~ &quot; (Please read the precautions on the back before filling out this page) ^ vm ml lit- ·· flu ^ i ^^^^ 1 m tm · --- 5 clothing — Ding ______, speech m ^ — tm mt l ^ n Jing &quot;-部 屮 呔 ^^ ， ^ ， '^ 丁- Elimination of the combination of bamboo ^ India 4 · '1 ^ · A7 —---- ~~~ 一 ~ ___ B7-_ V. Description of the invention (44) grams (1¾ mole) of intermediate 17 in 10 ml of dichloromethane Stir the solution. Stir the milk mixture for 30 minutes and allow the temperature to rise to 2 (rc, then add additional <422 mg (1 mmol) dibromotriphenylphosphine in one portion. Stir the mixture for an additional 30 minutes, then add 20 ml of dichloromethane, and the solution was cooled to 0.000 ^ 30 liters of a saturated aqueous sodium carbonate solution was added to the mixture, followed by stirring for 30 minutes. The phases were separated, and the aqueous phase was extracted with 20 ml of dichloromethane. Then, the organic phase was combined and dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure when the temperature was maintained below 20 C. The residue was subjected to flash chromatography with hexane / EtoAc (4: 1) as the eluent Purified. Fractions at 15_2〇 »C Concentration under reduced pressure gave 260 g of the standard compound: TLC (ethane / EtAc (1: 1)): 0.90). Intermediate 19 2-diphenylimideneamino_3- {4- [2- ( Amidino-pyridin-2-yl-amino) _ethoxy] -phenyl] -ethyl propionate 4.0 g (71.4 mol) potassium hydroxide in 4 ml of aqueous solution was added over 3 minutes to 3'50 g ( 10.9 millimoles) intermediates 18,370 grams (138 millimoles) ~ (diphenylmethylene) -glycine ethyl ester and 43 grams (161 millimoles) tetrabutyl hydrogen sulfate Record in a cold (0. (:) solution. The resulting yellow mixture was stirred at 5-0. 0 for 1 hour, then 10 g of anhydrous magnesium sulfate was added, and the suspension was filtered. It was concentrated under reduced pressure without external heating. The filtrate. The residue was transferred to a silica gel-filled tube pre-washed with a solvent mixture containing hexane / EtOAc / NEt3 (40: 10: 1). Hexane / EtOAc (4: 1) then hexane / Et 〇Ac (2: 1) was purified by flash chromatography to obtain 5.66 g of the standard compound. TLC (hexane / EtOAc (5: 1)): Rf = 0.30). -47- National standard ((: milk) 厶 4 size (210 '乂 297mm) (Please read the back Precautions to fill out this page)

A7 V. Description of the invention (45) Intermediate 20 ---------—— (Read the precautions on the back and then fill out this page} 2-Amine-3- {4- [2- ( Methyl-pyridine_2_yl-amino) _ethoxy] _phenylpropionate ethyl ester 20 ml of concentrated hydrochloric acid was added at 2.0 ° C over a period of 15 minutes to add 566 g (111 moles) of intermediate 19 In a stirred solution of 200 ml of ethanol, the mixture was stirred at room temperature for 1 hour. 400 ml of a saturated sodium bicarbonate solution was added dropwise to the solution, and 200 ml of dichloromethane was added when the carbon dioxide stopped emitting. The phases were separated, and the aqueous phase was extracted three times with 100 ml of dioxane. The organic phases were combined, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was subjected to hexane / Et by flash chromatography. 〇Ac (丨: 丨), (pure), and then the EtOAc / EtOH (9: 1) solvent mixture was purified as the eluent to obtain 3.19 g of the target compound: TLC (hexane / Et〇Ac)

Rf = 0.10). Intermediate 2 1 3- ¾l-2- {4- [2- (methyl-pyridin_2_yl_amino) _ethoxy] _fluorenyl 3 • benzyl_2,3_dihydro -1H-ind11 ethyl 2--2-chinoate ethyl ester target compound pa mg) is from 29 l mg (085 millimolar) intermediate 20 according to the method of intermediate} followed by the method of intermediate 3 and 197 mg ( / Maurol) 2-aminodiphenyl ketone reaction and then purified by silica gel flash chromatography with hexane EtOAc (4: 1) and then hexane: EtOAc (} :) as the eluent to prepare: Low Resolution MS (ESP +) m / e 524 (MH +). Intermediate 22_ 2 kis_ 3 seven examples of methyl "specific bite _2_yl_amino" _ethoxy] _phenylpropanoic acid will be 2¾ g (2 mmol) potassium hydroxide in 丨 ml Water was added to 160 mg-48- national standard (cns774 regulations in the Ministry of il and 1V for printing A7 B7 '—-________ — · ιιι ·' &II; 5. Description of the invention (46) (〇 · 46 millimoles) of intermediate 20 in 3.2 ml of a stirred solution of MeOH. The mixture was stirred at 2 (TC for 5 hours, then the MeOH was removed under reduced pressure. 240 mg (2 millimoles) of sodium hydrogen sulfate was added to the mixture in 5 ml of water and stir the slurry at 20 ° C for 30 minutes. The precipitate was filtered and washed three times with 5 ml of water. The filtrate was adjusted to p Η = 5 with saturated sodium bicarbonate solution, the precipitate was filtered and washed with 5 ml of water Three times. The solids were combined and dried under reduced pressure to produce 15 mg of the target compound: TLC (EtOH (pure)): Rf = 0.05). Intermediate 2.3 (S) -2- (2-benzylfluorenyl-aniline)- 3- (4-Hydroxy-phenyl) -propionic acid methyl ester 92 g (0-45 mol) of 2-fluorenyl-cyclohexane, (Denny, WA et al., J. Med. Chem. 1978, 21 (5), 43 0-7), 7 8 g (0.40 (Ear) L-methyl tyrosine, a stirred mixture of 17.0 g of palladium / activated carbon (10%) was refluxed in 1 liter of methoxybenzene for 2 hours, and the resulting water was removed by a Dean-Sark device The mixture was cooled to 80 ° C and filtered with Pd / C and washed three times with 50 ml of methoxybenzene. The mixture was cooled to 40 ° C, 1 liter of hexane was added and kept at -20 ° C for 4 8 hours. The solid Filtration and washing five times with 200 ml of hexane gave 89.0 g of crude (S) -2- (2-benzylfluorenyl-aniline) -3- (4-hydroxy-phenyl) -propionic acid methyl ester. This solid Mix with 220 ml of MeOH and reflux the slurry <30 minutes. The mixture was cooled to 0, the product was filtered and washed twice with 50 ml of cold (-20 C) MeOH, and then dried under reduced pressure to yield 67.4 g Target compound. Melting point 185-6 ° C; low resolution MS (ESP +) m / e 376 (MH +) 〇 Intermediate 242- (N-third-butoxycarbonyl-N_methyl-amino) ethanol-49- This paper is suitable for China National Standard (CNS) Α4 size (210X297 mm) (Please read the precautions on the back before filling this page)

--------------------- Order I tut m · mi • ---- 1 .......-- 1 —i 经 &quot; Clip &quot; 'M, -i: Jhx eliminate A cooperation. ^ 印 ¥ ^ A7 B7 V. Description of the invention (47) a _ "Take 29.U (〇.m Mol) B〇c2〇 processing under 2rc 1 A solution of 0 g (〇133 旲) of 2- (methylamino) ethanol in 266 ml of ^ 2012. After stirring for 3 hours, the reaction was concentrated in 眞. Silica chromatography was performed on hexane / EtAc. (1: 1 / E 1: 2 / E 1: 4) eluted to give 23.3 g (100%) of the target compound as a clear oil: low resolution MS (ES) m / e 198 (MNa +). Intermediate 25 2 (S )-(2-Legenyl-aniline) _3_ {4_ [2 · (Third_butoxycarbonyl_methyl-amino) -ethoxy] -phenyl} -propionic acid methyl ester will be 1-5 g ( 3.99 mol) Intermediate 2 3,770 mg (4.39 mmol, 1.1 equivalents) of Intermediate 24 and 7 g O &M; millimolar, u equivalent) Triphenylphosphine in 40 ml of THF The solution was treated dropwise at 25 »C with 0944 ml (5% mmol, 1.5 eq.) DEAD. The reaction was stirred at 25 ° C for 48 hours and then concentrated in the air. The residue was passed through a silica gel flash column. Chromatography using hexane / EtO Ac (2: 1) as eluent 37 g (65%) of the target compound was purified as a viscous yellow oil: low resolution MS (ES) m / e 555 (MNa +), 553 (MH +). Intermediate 26 2 (S)-(2_benzyl) Fluorenyl-aniline) -3- {4- [2- (methyl_pyridin_2_yl-amino) _ethoxy] -phenyl} -propionic acid methyl ester in 56 ml (0.73 moles, 152 equivalents) of a solution of 256 g (4.81 mmol) of intermediate 25 in 56 ml of ch2C12 under TFAk25 »c. After 30 minutes of incubation, the solution was dropped with saturated NaHC0 followed by solid NaHC03. And It was extracted with CHfb. Combined with organic matter drying (Na2S〇4), filtered and concentrated in the air. Crude amine was immediately used for the bottom-reaction. Obtained from the above. 2008-50- This paper size applies to Chinese national standards ) A4 (210x297 mm) nn n —I— vm ^ mml ^ n ml TJ ， 1 (Please read the notes on the back before filling this page) A7 B7 V. Description of the invention (48) grams (4 · 8 1 millimolar) of a solution of crude amine in 480 ml of 2-fluoropyridine for 16 hours and then concentrated in the air. Purified by silica gel flash column chromatography with hexane / EtOAc (2: 1) as the eluent. 85 g (76%) of the target compound was obtained. Yellow oil · · Low resolution MS (Cl) m / e 511 (MH +), 510 (M +) 〇 Intermediate 27 3- {4- [2- (benzoxazol_2-yl-methyl-amino) -Ethoxy] -phenyl} -2 (S)-(2 · Bromo-amido) _methyl propionate was treated with 7 ml (90.9 mmol, 152 equivalents) of TFA at 25 ° C 319 mg (0.60 mmol) of Intermediate 25 was extracted in 7 ml of CH2C12. The organic phase was dried (Na2S04), filtered, and concentrated in the air. Add 0.250 ml (1.80 mmol, 3 eq) of EtsN, then 0.103 ml (0.90 mmol, 1.5 eq) of 2-chlorobenzohumazole at 25 ° C and add 259 mg (0.60 mmol) of the above amine to 6 ml of THF solution. After stirring for 24 hours, the reaction was diluted with EtOAc, poured into saturated NaHC03, and extracted with EtOAc. The combined organic phases were dried (Na2SO4), filtered, and concentrated in vacuo. 244 mg (74%) of the target compound was purified as a yellow solid by lysing with hexadecane l / EtOAc (2: 1 / E 1: 1) by column chromatography on a silica gel flash column chromatography. Low resolution MS (ES) m / e 572 (MNa +), 550 (MH +). Intermediate 28 Toluene-4-sulfonic acid benzobenzozol-2-yl-pyrrolidine-2S-yl methyl ester 3.0 ml (21.8 mmol, 2.2 equivalents) of Et3N, followed by 124 ml (10.9 mmol, 1.1 equivalents) 2-chlorobenzothiazole at 0 ° C was added 10 g (9.89 mmol) of L-prolinol (thin solution of 19-8 ml of thf) -51- This paper is suitable in size; 1) 0 National Standard ((: Yang) 6 4 specifications (21〇 &lt; 297 mm) -------- Οτι (Please read the precautions on the back before filling out this page), 1T A7 B7 V. Description of the invention (49). The reaction was washed with THF and filtered, and the filtrate was concentrated in the air. The residue was dissolved in 10 ml of Edian and 1.9 g (9.89 millimoles, 1 equivalent) of p-phenylbenzene was released. Treatment. After 2 to 4 hours of incubation, the reaction was poured into water and the product was extracted with EtOAc. The combined organic phases were dried (MgS04), filtered, and concentrated in the air. By silica gel flash column column analysis. Hexane / Et〇Ac (2: 1) was eluted and purified to obtain 2.76 g (75%) of the target compound as a white solid: 1H NMR (CDC13, 300 MHz) d Ί.61 (d, 2Η, J = 12.3), 7.33-6.94 (m, 6H), 4.46 (dd, 1H, J = 7.8, 16.2), 4.30-4.10. (M, 2H), 3.60 (m, 2H), 2.16 (s, 3H), 2.25-1.90 (m, 4H); low-resolution MS (ES) m / e 395 (MNa +), 373 (MH +); Analysis (C19H20N2O4S) Calculated C, 61.27; H, 5.41; N, 7.52; S, 8.61 Found C, 61.20; H, 5.46; N, 7.46; S, 8.55; TLC ( Calcined / EtOAc (2: 1)): Rf = 0.28. _ Intermediate 29 Toluene-4-sulfonic acid 1-benzozazol_2_yl-pyrrolidine_2R_ylhydrazone ester compound (1.6 g ) Is prepared from 1.0 g (9.89 millimoles) of D-prolinol: according to the method of intermediate 28, followed by purification by solid treatment with hexane / EtOAc (1: 1): low-resolution MS (ES) m / e 395 (MNa +), 373 (MH +).. A ii -T in intermediate 3 0 and f: As printed Hi (Please read the precautions on the back before filling this page) Order 3- [4 -(l-benzohumazolyl) _pyrrolidin_2S-yl-fluorenyloxy) -phenyl] _2_ (2_ epimethyl-epiamino) _methyl propionate at 2.08 g (6.4 mmol , 1-2 equivalents) 匚 52 (: 03 to 25. (: Processing 2.0 g (5.33 mmol) of intermediate 23 and 1.98 g (5.33 mmol): [equivalent] of a solution of intermediate 28 in 21.3 ml of DMF. The reaction was heated to 80 ° C and -52-this Paper Size Applicable Standard (CNS) A4 Specification (210X 297mm) A7

V. Description of the invention (50) Granted for 24 hours. Upon cooling to 25t :, the reaction was poured into water and hexane / EtOAc (1: 1) and extracted with hexane / EtoAc (J: j). The organic coherence (NajO4) was combined, filtered, and concentrated in the air. Purified by silica gel flash column chromatography with hexane / EtAc (15: 1) and purified to give 26 g (74%) of the target compound as a yellow solid: low resolution MS (ES) m / e 598 (MNa + ), 576 (MH +). Interstitial 3 1 ^ [4- (1-benzoxazol_2_yl) _pyrrolidine_2R-yl-methoxy &gt; phenyl] ΐ Ssfc-anilino) _methyl propionate. Subject The compound (285 mg) was obtained from 0.25 g (0.67 mmol) of intermediate 23 and 0.248 g (0.667 mmol, J equivalent) of intermediate 29 according to the method of “intermediate” followed by silica gel flash column chromatography. Prepared by hexane / EtOAc (1.5: 1) elution and purification: low-resolution Ms (ES) _ 598 (Gu + (MH +).. T W ft 32 &quot; 1 1 Ben 17 No. 2_2-yl -p bilo bite_3_ol will grams (49.0 millimoles, i] equivalent) (R) _3-hydroxypyrrolidine and 4.42 liters ^ .2 millimoles, 0.72 equivalent) triethylamine in. X: Add 5.1 milliliter: (44, Mole) 2-Gas benzoxazole in 35 milliliters of agitated solution of hydrazine = agar solution, stir at room temperature for 12 hours, precipitate and filter with HF (3 X 5¾ liters), and the filtrate was concentrated under empty air. Using silica gel flash = hexane = one to ship c as the eluent to obtain 3.74; the target low-resolution MS (ESP) m / e 205 (MH +). __-53-; .. 297 mm) (Please read the precautions on the back before filling in the tiles) -1-ί In !! I-I .......-^^ I _ -I-. 1—i- ---&quot; .Ministry Central i?-^ ;: Jh 3 Elimination of 贽 合 竹, ^ 卬 —owing to A7 B7 浐 浐 中 中 ^ &quot;-^^'-;! τ_ 消 队 合 竹 女 印 ¥ V. Description of the invention (51) Intermediate 3 3 Methanesuccinic acid 1-phenylhydrazone &quot; Nozol-2-yl-pyrrolidine_3_yl ester 1.37 liters (17 8 millimoles, 0.093 equivalents) of methane Sulfonium chloride was added to a stirred solution of 3.74 g (18.3 mmol) of intermediate 32 in 30 ml of eridine. The resulting solution was stirred at room temperature for 3 hours and then stirred in ice water (100 ml). Cold. Extract the reaction mixture with DCM (3 X 50 ml). Combine the organic solvent and wash with saturated NaHC03, brine, and dry (and remove the solvent in the air. Triturate with isopropanol to obtain 371 g of the target compound. : Low-resolution MS (ESP) m / e 283 (MH +). Intermediate 34 3 [4-y · Benzoquinone_2_yl_pyrrolidin_3_yloxy) _phenyl] fluorenyl- The aniline) -ammonium propionate 'compound (156 pens) was obtained from 188 mg (050 millimoles) of intermediate 23 and 1 :) 5 gram (0.55 moles, 1 丨(Equivalent) Intermediate 3 3 According to the method of intermediate 30, followed by silica gel flash column chromatography Purification was performed by using hexane / EtoAc3 / i to 1/1 as an eluent. Low-resolution MS (ESP) m / e562 (MH +). Intermediate 3 5 2 (s)-(2-Leptino-anilinofluorene) 4 ## fluorenylphenyl-humazol-4-yl) -ethoxy] -phenyl] -propionic acid 0.25 g of Intermediate 23 (0.67 millitors, woolen bucket), 0.20 grams of 2- (5-methyl-2-phenylhumazol-4-yl) ethanol (0.98 millimoles, I5 equivalent, Maybndge), and 0.35 g of triphenylphosphine (1.33 millimoles, 2.0 also 2.0 equivalents) in 10 milliliters of aqueous THF. The valley solution was cooled to 0 C and formed at 0 2 i units per liter. Diethyl N-Dicarboxylate 54- This paper is suitable for China National Standard (CNS) A4 size (210X297 Gongli (please read the precautions on the back before filling out this page) — 0¾ clothing.,-= 5 A7 A7 Λ ^: ί? · ^: = &Lt; .τ 消 抡 合 竹 ii 卬 袈 B7 '&quot;. one' ~ 'one ------------ five, invention Note (52) (1.33 mmol, 2.0 equivalents) was processed. The reaction was warmed to room temperature for 8 hours, concentrated in the air, and purified by silica gel chromatography (7_3 hexane: EtOAc). 0_26 g (70%) of the target compound is yellow bubble: melting point 55-60 ° C; low resolution MS (ES) m / e 561 (MH +). Intermediate 36 2- (2-Bromo group- Anilinyl) -3- {4- [2- (4-chlorophenyl) -Psep_4_ylmethoxy] -phenyl} -propionic acid methyl ester The standard compound (210 mg) is from 150 mg (0.40 millimolar) intermediate 23 and 107 mg (0.44 millimolar, 1.1 equivalent) of 4-chloromethyl_2 ((4-chlorophenyl) pyrimazole) according to the method of intermediate 30, followed by flash evaporation with silicone Purification by column chromatography using hexane / EtOAc 8/1 as eluent: low resolution Ms (fab) m / e 584 (MH +), 583 (M +) 〇 Intermediate 3 7 2- (2-benzylfluorenyl -Anilino) -3- [4-O alkyl-ethoxy) -phenylbutyric acid methyl ester 400 mg (1.06 mmol) intermediate 23, 93.0 mg (106 mmol) 10_0 Hours 1) Carbon: 1 g of ethylene glycol and 175 mg (1.28 millimoles, 1? Equivalent) of KK 3 in 10 ml of DMF suspension and heated with stirring for 3 hours to 95T. The reaction mixture was cooled to room temperature, poured into 100 ml of Et20 and extracted with (3 x 50 t liters). The organic phase was separated, dried (MgS04), and the solvent was removed at 26. A yellow solid was purified by silica gel flash chromatography with hexane / EtOAc 2/1 as the eluent to obtain 440 mg of the target compound as a transparent yellow oil: 1H NMR (CDC13, 300 ΜΗζ) β 8.90 (d, 1H J = , 7.60 (m, 2H), 7.52-7.31 (m, 5H), 7.20 (dd, 2H J =? 〇. ', ZA 6.5), 6.83 (dd, 2H, J = 2.2, 6.5), 6.60 (m, 2H), 4.51 (s, 1H), 4 38 -55- This paper is suitable for Sichuan National Standard Half- (CNS) / ΰί 格格 (210X 297 mm) ------_ ----- --------- 1T (Please read the precautions on the back before filling in the supplier's page) Good: the middle folder &quot; •-^ and, only h-; / i ^ cooperation &quot; jealous A7 ____ __ B7 V. Description of the invention (53) (dd, 1H, J = 5.9, 5.9), 4.04 (m, 2H), 3.94 (m, 2H), 370 (s, 3H), 3-l7 (m, 2H) ). Body 38 2- (2-Methylsulfonyl-aniline) -3_ [4- (2-Methylsulfonyl-Soxy-ethoxy) _phenyl] -propionic acid methyl ester will be 0.23 ml ( 1.67 millimoles, 2.0 equivalents of Et3N, followed by 0.13 ml (1.67 millimoles, 2.0 equivalents) of methanesulfonyl chloride was added at room temperature to 35 mg (〇 ·· 83 mmol) of intermediate 3 7 in 8 ml In a stirred solution of THF. The resulting mixture Stir at room temperature for 90 minutes and then heat to 45 ° C for 1 hour. The reaction mixture is cooled to room temperature, poured into 50 ml E ^ 0 and extracted with water (2 × 50 ml). The organic layer is separated, dried (KsCO3), and 430 mg of the target compound was removed as a transparent yellow oil in the air. It was used without further purification: low resolution MS (Cl) m / e 499 (MH +), 498 (M +). Intermediate 3 9 ”-{ 4- [2- (2-Amino_anilino_ethoxy] _phenyl) _2_ (2_benzyl_anilino) -propionic acid · formamidine 590 mg (4.27 mmol, 5.0 (Equivalent) K2C03 and 462 mg (4.27 millimoles, 50 equivalents), 2-phenylenediamine was added at room temperature to 425 milligrams (0.85 moles) of intermediate 38 in 5 ml of a dry dmf stirred solution. The resulting solution Heat to 80 ° C for 17 hours. Cool the reaction mixture to room temperature, pour 50 ml of Et20 and pour in HC1 (1 X 20 ml), NaHC03 (1 X 20 liters), and Η &quot; (2 X 5 0 ml) and extracted. The organic layer was separated, dried (K2CO3), and the solvent was removed in the air. The crude material was purified by silica gel flash column chromatography using hexane / Et0Ac 2/1 as eluent to obtain 90 mg _________-56-This paper is suitable for iiTii '^ (cNS) A4 specifications (--- (Read the precautions on the back before filling in this page) ----- ^ nn taflu tmv-one n · ^ — j · ^ — &gt; ml tm mt nn tm--l {1-A7 ----- ------- B7 V. Description of the invention (M) — = Chemical yellow transparent oil, which is decolorized after being placed and should be used after purification. Low-resolution MS (Cl) m / e 5 11 (MH +), 520 (M +) .. ± _S_S_40_ [(2'-amidol · 1-yl-ethoxy) -phenyl] -2- (2-benzyl-aniline) -propionic acid In order to add 5 g of p-formamidine to 90 mg (ο. "Mmol) of intermediate 39 in a stirred solution of ethyl acetate orthoformic acid, it produced a white precipitate. Stir suspension The liquid was heated to 8 (rC for 2 hours, during which most precipitation disappeared. The reaction mixture was cooled to room temperature, poured into 20 ml of Et20 / dichloromethane 1: 1 and washed with 1 N NaOH (1 × 20 ml). Organic layer It was washed with h20 (1 x 20 liters), separated, dried (MgS04) and emptied. The solvent was removed. The product was purified by silica gel flash column chromatography with EtOAc as the eluent to obtain 94 mg of the target compound as a transparent yellow oil: low resolution MS (C1) m / e 521 (MH +), 520 (M +) 〇Intermediate 41 1- (3_Qi-Phenyl) -Dinghu_1,3_Dibremus 知 4.0 g (100 mol) cyanide fishing (60%) added 13.8 G (50 mmol) of ethyl gallate and 12 ml (160 mmol) of acetone in a stirred solution of 25 ml of anhydrous THF. The mixture was stirred at 25 ° C for 20 minutes, then slowly warmed to 3 0 C. Antithermal reaction started and the temperature was kept below 30 ° C in a water bath, 1 hour after the hydrogen evolution ceased, the mixture was cooled to 5 ° C, and quenched with 150 ml of aqueous hydrochloric acid. 200 ml of ethyl acetate The solution was added to the solution, and the phases were separated. The organic phase was washed three times with 100 liters of water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was mixed with 200 ml of hydration. State, Central Park National Sample Standard (CNS) Α4 Specification (210 × 297 mm) ______________ D (Please read the precautions on the back before filling this page ·) Good Central &quot; '-4,-^ 丁丁 ， 消 贤 合 竹 ^ 印 ¥. A7 B7 V. Fen Ming explained (55) and then passed Shen; Dian. Wash hair three times with hexane. The filtrate was concentrated under reduced pressure and flashed. Column chromatography was performed with hexane (pure), then hexane_

Et. (4: 1) was purified as an eluent to obtain 7q g of the title compound, which was crystallized at -4 (TC itself; TLr f, ^-EtOAc (4: 1)): Rf = 0.65). Body 42 [2- (4-methoxy-phenyl) -5-methyl-pyrazole_4-yl] methyl acetate will be 7Z5 mg (4.80 mmol) 4-methoxybenzidine and 0 g (480 mil) of 4-bromo-3-oxo-valeric acid methyl ester was heated at 12 (rc for 2 hours. The residual deep slurry was cooled to room temperature, diluted with 2 ml of dichloromethane and borrowed from silica gel. Purification by flash column chromatography using hexane / EtOAc 3/1 as eluent yielded 189 mg of the target compound as a yellow solid: low resolution MS (FAB) m / e 285 (MH +), 284 (M). Middle Body 43 2- [2- (4-methoxy_phenyl) _5_methylhao_4_yl] _ethanol will be 0.71 ml (〇_71mmol, 1.0 equivalent) of LiAlH4 in THF ·· 0 M solution was added to a stirred solution of 185 mg (0.71 mmol) of intermediate 42 in 5 ml of THF at 0 C. The residual solution was stirred at room temperature for 4 5 minutes and then cooled to 0 C and added carefully. 〇27 house litre 20, then add 0.027 ml of 15% NaOH and 0.080 ml of Η20 to quench. The obtained in Polymerization was carried out to remove solids and the filtrate was concentrated in the air to obtain 164 mg of the target compound as a pale yellow oil: NMR (CDC13, 400 ΜΗζ) β 7.92 (d 2Η, J = 8.8), 6.94 (d, 2Η, J = 8.8), 3.92 (dt, 2Η, J = 5.7, 11.5), 3.86 (s, 3H), 3.35 (t, 1H, J = 6.2), 2.71 (t, 2H, J = 5.7), 2.32 (s, 3H ) 〇-58- 一-_ This paper is suitable in size / i] Chinese country; ^ _ (CNS) A4 size (2 丨 〇 &gt; &lt; 297 public ^ &quot; (Please read the precautions on the back before filling in this page)

A7 B7 ii .- ^-XJvii.T in the sacral part of the cymbal lining. 5 、 Instruction of the invention (5e) i_S_ ^ 44_ 2 (S) 卞 '醯 yl · aniline group]] 4 · [25 _Methyl; yl_2, · methoxy) _phenyl-atomazol-4-yl) _ethoxy] _phenyl} _methyl propionate will be 17 grams (0.67 mmol *, 〇95 (Equivalent) diazonium diazodiacetate was added 19) pen grams (0.74¾ mole, 1.05 equivalent) of triphenylphosphine in 5 liters I mixed the solution towel. The resulting color solution was then placed in the chamber Gradually, add 265 mg (0.71 mmol) of Intermediate 23 II; (0.71 ¾ mole) of Intermediate 43 in 5 ml of thf solution. The resulting solution was allowed to stand for 18 hours at 1:50 and then the solvent was removed in the air. The residue was stirred vigorously in a 30-liter 2: 1 diethyl ether "N Li0H two-phase solution to selectively remove the residual intermediate 23. The layers were separated and the organic layer was washed with water, dried (MgSa〇, The solvent was removed in the air. A yellow solid was purified by Zhen Xia flash column chromatography with hexane / Et〇Ae 2/1 as the eluent to obtain 200 mg of the target compound as a yellow solid: low-resolution Ms (FAB) m ^ 501 (MH +). Intermediate 45 [2- (4_oxy-phenyl) _5_methyl · zizine_4 · yl] _formyl acetate 667 mg (4.80 mmol) 4_fluorophenylhydrazone A solution of amine and gram (4.80 mol) of 4-bromo-3-oxo-valeric acid methyl ester in 6 ml of anhydrous toluene was heated to ° C for 16 hours. The resulting solution was deeper than the mud and cooled to room temperature. Diluted with 〇mL, and washed with NaHC03 (1x10mL). The organic phase was separated, dried (MgSOO, and the solvent was removed in the air. The material was purified by silica gel flash column chromatography with hexane / EtOAc 4 / 1 Purified as an eluent to obtain 308 mg of the target compound as a transparent oil: 4 NMR (CDCI3, 400 ΜΗζ) β 7.97 (m 2H) -59 This paper is in accordance with Chinese National Standards (CNS) A4 regulations (210X 297 mm) Θ --------- ^ --- 1 --- ΐτ ------ ^ (Please read the notes on the back before filling out this page) A7 B7 V. Description of the invention ( 57) Minyang ir-5i- ^ hT of the Ministry of Economic Affairs disappeared in Hezhu · Private Seal ti 7-11 (m, 2H) 3 3.73 (s, 3H), 3.56 (s, 2H), 2.36 (s 3H) = ί_Ε_Ε46_ 2 · [2_ (4-fluoro-phenyl)-: 5-methyl-yinjun · 4-yl μ ethanol target compound system, from 300 mg (1.20 mmol) of intermediate 45 according to the preparation of intermediate 43 248 mg of the compound was prepared in the step as a white solid: low-resolution MS (FAB) m / e 221 (M +). ^ 47 2 (SH2-familyl_aniline) _3- {4_ [2_ (5 _Methyl_2_ (4 ') _ phenyl, ol-4-yl) -ethoxy] -phenylpropionate methyl ester (298 mg) is derived from 407 mg (108 mmol) Ear) Intermediate 23 and 240 mg (1.08 mmol) of Intermediate 46 according to the method of Intermediate 44 ^ By Shi Xijiao flash column chromatography with hexane / Et〇Ac 2/1 as the eluent Preparation: Low-resolution MS (FAB) m / e 580 (NH +), 579 (M +). Interstitial 48 2- (5-fluorenyl-1-phenyl_exo-? Biol-3-yl) -ethanol Add 104 mg (0.96 mmol) of phenylhydrazine, followed by 10 mg It was added under temperature π f _ acid 150 mg (0.96 mmol) 3,5_ dioxohexanoate stirred solution of MeOH in a 5 liter pen. The reaction mixture was stirred at room temperature for 1 minute and then refluxed for 2 hours. The reaction was cooled to room temperature, diluted with 100 mL of Eto-Ac, and washed with NaHC03 (1 X 10 mL). The organic phase was separated, dried (MgSO4), and the solvent was removed in the air. The material was purified by a dream gel flash column chromatography using hexane / EtOAc 3/1 as the eluent to obtain 180 mg of cyclized vinegar. This material was then reduced in accordance with the procedure for preparing intermediate 43. NMR (CDC13, 400 MHz) d 7.41 (m, 5H), 6.10 (s, 1H) 3 81 to dry formazan (1 -60- this paper Standards apply 1 丨, National Standards (CNS) Α4 specifications (21 〇 × 297 mm) (Please read the precautions on the back before filling {¾ page)

In the rage department, ir ^-^ "; iT eliminates 71 cooperation ?! A7 ____________; __B7 _ V. Description of the invention (58ϊ ~ 2Η, J = 6.5), 2.89 (t, 2Η, J = 6.5), 2.32 (s, 3Η). _Intermediate 49 2 (S)-(2-benzylfluorenyl_aniline) _3 · {4_ [2_ (5_methylphenyl_1H-pyrazole_3 · yl) -ethyl Dairy] -phenyl} -propanoic acid methyl I The target compound (100 mg) is derived from 275 mg (0 74 mmol) of intermediate 23 and 150 mg (0.74 mmol) of intermediate 48 according to intermediate 44 Method, followed by purification by silica gel flash column chromatography with a gradient of hexane / EtOAc 4/1 to hexane / EtOAc 2/1 as the eluent for purification: low resolution (FAB) m / e 561 (MH +), 560 (M +). Intermediate 50 [2. (2- ', hydrogen u ratio _ι_ group) _5_methyl_p number what_4_yl] _acetic acid ^ .72 g (13.40 mmol, 4.0 equivalents) of hexahydropyridinecarboxamide and 700 g (3.35 mmol) of 4-bromo-3-oxo-pentanoate 3 ml of anhydrous DMF The mixture was heated at 12 ° C for 15 hours. The resulting dark slurry was cooled to 罜 temperature, diluted with 10 ml of EtOAc and washed with Η &quot; (1 X 10 ml). The organic layer was separated and dried ( MgS〇4), and the solvent was removed in the air. Substance 2 was purified by silica gel flash column chromatography using hexane / EtAc 2/1 as the eluent, and 192 g of the standard compound was obtained as an orange oil: low. Analyze ms (fab) m / e 24〇 (MH +), 239 (M +). Intermediate 5 1 2- [5-methyl-2-hexamethylpyridinyl ^ oxazolyl] _ethanol standard compound (145 mg) It was prepared from 190 mg (080 mmol) of intermediate 50 according to the method of intermediate 43: HNMR (CDCl3, 400MHz) 5.03 (t, in, J = 5.8), 3.90 (d, 2H, J = 5.9), 3.73 (m, 4H), -61-This paper size is suitable for Shiba Zhongbai 5 ^ standard (cNsTA4i ^ (210x297) (Please read the precautions on the back before filling this page)

IB—. .. loll A7-* — V. B7 Invention Description (59 ')-Free from the Ministry of Central &quot;' ^^ h- · 1 '&quot; · 贽 Cooperation * 71 Printed 2-83 (t, 2H, J = 5.9), 2.19 (s, 3H), 1.71 (m, 6H).体 体 52 2 (S)-(2-fluorenyl-aniline) -3- {4- [2- (5-methyl-2-hexahydropyridin-1-yl-oxazol-4-yl ) -Ethoxy] -phenyl} -propionate (280 mg) is based on 250 mg (0.67 mmol) of intermediate 23 and 140 mg (0.67 mmol) of intermediate 5 1 Method 44 was then prepared by silica gel flash column chromatography with hexane / EtOAc 2/1 as the eluent: low resolution MS (FAB) m / e 568 (MH +), 567 (M +). Body 53 1-morpholin thiosulfate ssamine Add 932 mg (10.70 mmol) of morpholine at room temperature to 2.0 g (11.20 halitres, 1.15 equivalents) of thioxanthyl diimide is less than 3.0. Ml of THF in a stirring solution. The reaction mixture was stirred at room temperature for 2 hours and then heated to 55 ° C for 1 hour. The reaction mixture was cooled to room temperature and about 20 ml of THF was removed under vacuum, then 10 ml of a 2.0 M solution of ammonia in MeOH was added, and the reaction mixture was sealed and stirred for 15 hours. Then add another 10 ml of 2.0 M ammonia in MeOH, and stir the reaction in a warm water bath for 8 hours. During this time a white precipitate occurred. The precipitate was filtered, washed with diethyl ether, collected and dried to give 745 mg of the target compound: Low Resolution Milk (FAB) m / e 147 (MH +). Intermediate 54 2- (2-morpholin-4-yl_5 · methyl_Pselazole_4_yl) _methyl acetate will be 375 gram (2.56 mmol) intermediate 53 and 536 mg (2.56 Millimoles) 4-Bromo-3-oxo-valeric acid methyl ester in a mixture of 5 ml of anhydrous ethyl acetate reflux -62- This paper is suitable for each size / species (21Gx297 cm) (Fill in this page) ------— I 1 I lm-° -511 _s :. A7 B7 V. Description of the invention (60) 5 hours 3 The reaction is cooled to room temperature, and then ethanol is removed in the air. Residue The material was diluted with 10 mL of EtOAc and washed with NaHC03 (1 × 10 mL). The organic layer was separated, dried (MgS04), and the solvent was removed in the air. The material was subjected to flash chromatography on a silica gel column. Hexane / EtOAc 2/1 was purified as the eluent to obtain 590 mg of the target compound as a clear oil: ifj NMR (CDC13, Hall 400), 3.79 (m, 4H), 3.69 (s, 3H), 3.47 (s, 2H), 3.38 (m, 4H), 2.23 (s, 3H). Intermediate 55 2- [5-methyl_2-morpholin-1-yl-humazol-4-yl] -ethanol standard compound (487 Mg) was prepared from 590 mg (2.27 mmol) of Zhongxia 54 according to the method of intermediate 43: iH NMR ( Cdc13, 400 MHz) cJ 4.29 (t, 1H, J = 5.9), 3.90 (d, 2H, J = 5.9), 3.82 (m, 6H), 3.37 (m, 4H), 2.68 (t, 2H, J = 5.4), 2.22 (s, 3H). Intermediate 56 2 (S) _ (2-benzylfluorenyl-aniline) -3- {4- [2- (5-methyl-2-morpholine-4- -Pyrimazole_4-yl) -ethoxy] -phenyl} -propionic acid methyl ester (81 mg) is derived from 760 mg (2.02 mmol) of intermediate 23 and 480 mg (2.02 mmol) Ear) Intermediate 55 was prepared according to the method of Intermediate 44 and then purified by silica gel flash column chromatography with hexane / EtOAc 2/1 as the eluent: NMR (CDC13, 400 MHz) d 8.89 (d, 1H, J = 7.3), 7.59 (d, 2H, J = 8.6), 7.47 (m, 3H), 7.33 (dd, 1H, Bu 7.2, 7.2), 7.17 (d, 2H, J = 8.6 ), 6_82 (d, 2H, J = 8.6), 6.63 (d, 1H, J = 8.5), 6.57 (dd, 1H, J = 7.5, 7.5), 4.37 (dd, 1H, J = 7.2, 13.3), 4.15 (t, 2H, J = 7.1), 3.78 (m, 4H), 3.69 (s, 3H), 3.36 _ 63 degrees depending on China A4 specification (210X297 mm) &quot; (Please read the notes on the back before filling in (This page)

A7 _ ^ ________ B7_ V. Description of the invention (61) ^ ~~ (m, 4H), 3.19 (dd, 1H, J = 6.0, 13.9), 3.11 (dd, 1H, J = 7 3 13.9), 2.93 (t, 2H, J = 7.1), 2.23 (s, 3H). , Intermediate 57 [2- (2_pyridin_4_yl) -5-amidino-thiazol-4-yl] -methyl acetate 800 mg (5.79 mmol) thioisonicotamine and 1.21 g ( 5.79 mmol) of 4-bromo-3-oxo-valeric acid methyl ester in 20 ml of toluene / anhydrous ethanol was heated to 100 ° C for 18 hours. The reaction was cooled to room temperature, diluted with 20 mL of EtOAc, and washed with NaHC03 (1 X 10 mL). The organic phase was separated, dried (MgSCU), and the solvent was removed in the air. The material was purified by silica gel flash column chromatography with hexane / EtOAc 1/1 as eluent to obtain 63 mg of the target compound as an orange solid: NMR (CDC13, 400 MHz) d 8.64 (d, 2H, J = 6.1 ), 7.70 (d, 2H, J = 6.1), 3.82 (s, 2H), 3.71 (s, 3H), 2.45 (s, 3H) ° intermediate 58 2- [5-fluorenyl-2- ( 4-p specific bite) -p Saiye-4-yl] ethanol standard compound is from 620 mg (2.50 millimolars) of intermediate. Body 57 according to the method of intermediate 4 3, and then borrowed; ε gel flash column EtOAc to

A gradient of EtOAc / MeOH 30/1 was prepared as the eluate purification: 1 η nmr (CDC13, 400 MHz) (ί 8.66 (d, 2Η, J = 6.1), 7.71 (d, 2H, J = 6.1), 4.01 (m, 2H), 3.57 (t, 1H, J = 6.0), 2.93 (t, 2h, J = 5.8), 2.46 (s, 3H). Intermediate 59 2 (S)-(2- ^ Beryl -Anilino) -3- {4- [2- (5-methyl_2- (4_p than oxanyl) _p-sechon-4-yl) -ethoxy] -phenyl} -propionic acid methyl ester- 64- ______________ This paper size applies to Chinese national standard ((: Can) 6 4 size (2! 0 '乂 297mm)'---- _ 0 pack-I (Please read the notes on the back before filling in (This page)

* 1T A7 A7-Central part of the crotch ir'4'-x'J "Ji-Ti7i compound bamboo &quot; &quot; ϋ ________________-_ B7 V. Description of the invention (62) ~~~ The target compound is from 255 mg (〇 .68 mmol) Intermediate 23 and 150 mg (0.68 mmol) Intermediate 5 8 Follow the procedure of Intermediate 4 4 followed by column chromatography with hexane / Et0Ac 3 / 2 Prepared as eluent purification: Analytical (C34H31N304S) calculated C, 70.69; H, 5.41; N, 7.27, found C, 70.44; H, 5.50; N, 7.03. Intermediate 60 [2_ (2 · monomethyl Amine) _5_methyl_p-severyl] _methyl acetate will be 750 mg (7.20 millimoles, 5 equivalents) N, N_dimethylthiourea and 1.00 g (4.80 millimoles) A mixture of 4-bromo-3-oxo-valeric acid methyl ester in 10 ml of dioxane was heated to reflux for 3 hours. The reaction was cooled to room temperature, diluted with 20 ml of EtOAc, and diluted with NaHC03 (1 X 1 (ML) was washed. The organic layer was separated, dried (MgS04), and the solvent was removed in the air. The substance was subjected to silica gel flash chromatography column chromatography hexane / EtOAc 1/5 to EtOAc / MeOH 20/1 gradient as The eluate was purified to obtain 210 mg of the target compound. Yellow oil: low-resolution MS (FAB) m / e 216 (MH +), 215 (M +). Intermediate 61 2- [2-dimethylamino group · 5_fluorenyl group-sakijun_4_ group] -The ethanol target compound is from 210 mg (0-98 millimoles). Intermediate 6 is prepared according to the intermediate 43 method: low resolution MS (FAB) m / e 188 (ΜΗ +), 187 (M +). Intermediate 62 2 (S)-(2-Bromoglylaniline) _3- {4- [2- (2-Difluorenylamino_5_methyl_! 7Sepam-4-yl) -ethoxy μ Phenyl propionate standard compound (168 mg) is derived from 390 mg (1.00 mmol) of intermediate -65-4.. Our standard is applicable to China National Standard (CNS) A4 specification (2 丨 0X297 mm) ) -------------- IT (Please read the notes on the back before filling this page) The central part of the warp section «. ^ • ^ • .Ji.T disappeared in 4 ' Deduction, f A7 &quot; ------------- —__ B7___ V. Description of the invention (63) 23 ^ 185 pen grams (丨, 00 mmol) Intermediate 6 1 According to Intermediate 44 This method was followed by purification by steam column chromatography with hexane / EtOAc 2/1 as the eluent to purify the desired product in% unless the polarity was impure and then eluate the desired product with chloroform / MeOH: low-resolution Ms ( FAB) m / e 54 4 (M +). Intermediate 63 5-methylisopyrazole_3_thiocarboxamide 525 gross (4.16 moles) 5-methylisomycin _3_ Rebel S &amp; amine and 185 grams (4 ') 8 pens Moore, U equivalent) A suspension of Lawesson's reagent in 15 ml of anhydrous toluene was heated to reflux for 5 hours, during which the reaction mixture turned clear yellow. The reaction mixture was cooled to room temperature and the solvent was removed in the air. The material was purified by silica gel flash column chromatography with a gradient of hexane / EtoAc 5/1 to hexane 1/1 I as the eluent, then triturated with acetonitrile, filtered to remove solid Lawesson's reagent by-products and removed After removing the solvent, 614 mg of the target compound was obtained as a yellow oil: iH NMR (CDC13, 300 MHz) J 8.05 (s, br, 2H), 6.52 (s, 1H), 2.46 (s, 3H). '' Intermediate 64 2- [5-Methyl-2- (5-methyl-isopurazol-3_yl) _oxazole_4_yl] _methyl acetate The target compound (375 mg) is from 591 mg (4 · 15 mmol) 63 and 950 mg (4.47 mmol, 1.10 equivalents) of 4-bromo_3_oxo_valeric acid methyl acetate according to the method of intermediate 4, 5 Steam column chromatography was prepared by purification with hexane / EtOAc 5/1 as eluent: low resolution Ms (fab) m / e 216 (MH +), 215 (M +). Intermediate 65 2- (5-Methyl-2- (5_fluorenyl-isohumazol-3-yl) -oxazole ethanol-66-i The scale is suitable, and the family scale (⑽) A4 Specification (21GX297 Gift: ---- ______________T (Please read the notes on the back before filling out this page) A7 B7 V. Description of the invention (64) The subject compound (187 mg) is derived from 375 mg (149 mmol) of intermediate 64 4) i method: H NMR (CDC ^, 400MHz) ^ 6.50 (s, 1H), 3 97 (m, 2H), 3 46 (t, m ,; = 6 2), 2.92 (t, 2H, J = 5.6), 2.49 (s, 3H), 2.44 (s, 3H). Intermediate 66 2 (S)-(2-elastyl-aniline) _3_ {4_ [2_ (5_ Methyl_2_ (5_methyl-isosialyl-3-yl) -oxazol-4-yl) -ethoxy] _phenyl} _methyl propionate (470 mg) 530 mg (1,45 mmol) of intermediate 23 and 317 mg (1.45 mmol) of intermediate were converted according to the method of intermediate, followed by flash column chromatography to obtain 4㈣ 敝/ Et0Ac 2/1 <The gradient was prepared as an eluent for purification: low-resolution MS (FAB) m / e 582 (MH +). Intermediate 67 [5-methyl-2- (4-methylπ, 2, 3 ] 远 二 哭 _5_ 基) _ Ah Dongji] -The target compound of formamidine acetate (56 mg) is derived from [〇g (7.00 mmol) 4_ 甲某. Shu ^ 'Ministry-Under Taxi ^ "::: -1' · Consumer Hezhu &quot; 卬 f (Please read the precautions on the back before filling this page) =. = The agent is prepared according to the method of Intermediate 63, then borrowed from Intermediate 45 4/1 and then by gel flash column chromatography Hexane / C (M +) was prepared. Low-resolution MS (FAB) m / e 270 Intermediate 68 H5-methyl-2. 35.mg) is from 56.67 according to the method of intermediate 43, and the glue is flashed. D :: -67- this paper; the standard ^ A4 specification has been approved by "_ 部 中 ^ &quot; • ^^-， ^ 了-Consumer cooperation ^ 卬 ow A7 __: ____________ B7 V. Description of the invention (65) / MeOH 9/1 is prepared as the eluent purification: 1h nmr (CDC13, 400 MHz) d 3.99 (m, 2H), 3.02 (s , br, 1H), 2.94 (m, 5H), 2.49 (s, 3H). Intermediate 69 2 (S)-(2-fluorenyl_aniline) _3_ (4_ {2_ [5_methyl_2 · (4-Methyl [^ 2,3] pyridazol-5-yl) -pyrimazole_4-yl] _ethoxybphenyl) _propionic acid target compound (235 mg) is from 560 mg (1 49 millimoles) middle Body 2 0 and j60 pen grams (ι · 49 mmol) intermediate 6 8 according to the method of intermediate 4 4 followed by silica gel flash column chromatography with hexane / Et〇Ac 4/1 to hexane / A gradient of Et〇Ac 3/1 was prepared as the eluent purification: lH NMR (CDCi3, 400MHz) ^ 8.88 (d, 1H, J = 7.3), 7.59 (dd, 2H, J = 1.6, 8.4) , 7.48 (m, 3H), 7.33 (dd, 1H, J = 7.3, 7.3), 7.17 (d, 2H, J = 8.5), 6.80 (d, 2H, J = 8.5), 6.62 (d, 1H, J = 8.6), 6.58 (dd, 1H, J = 7.6, 7.6), 4.38 (m, 1H), 4.25 (t, 2H, J = 6.5), 3.69 (s, 3H), 3.16 (m, 4H), 2.92 (s, 3H), 2.50 (s, 3H). '' Intermediate 70 [5-methyl-2_ (4-methyl-hexahydropyridyl) ^ sedazole_cardiyl] _acetic acid acetate target compound (490 mg) is from 18.7 g (104 8 mmol) (Ear) thiocarbonyldiimidazole and 10 g (99.8 millimoles) of 1-methylhexahydropyridine intermediate 53, followed by a method for preparing intermediate 60 and MeOH / EtOAc (3:17 ) As an eluent and purified by silica gel chromatography: tlc (MeOH / EtOAc (1: 9)): Rf = 0.15. Intermediate 7 1 2 (5methyl-2- (4-methyl-hexa · or p ratio p well-bukey) Sai Ye _ heart base] _ ethanol-68- CNS) A 槪 Grid (21GX297 male thin) (Please read the precautions on the back before filling this page)

1T A7 B7 V. Description of the invention (66) The target compound (2.20 g) is from 2 87 g according to the method of Intermediate 43, and then the silica gel (Ion Moore) intermediate 70 / MeOH 1G / 1 is used as the eluent Purified by column analysis with chloroform 400MHzH 4.42 (s, br, 1H), 3 85 (2H position (CD ~ 0, n. ^ TT T vm, 2Η), 3.41 (in, 4H), = ( t, 2H, J = 5.4), 2.49 (m, 4H) 2 34 (s 3H) 2 20h _intermediate 72 [M3-dimethylamino-propylaminofluorenyl-pyrimazole_4-yl] -Methyl acetate target compound (S54 mg) is derived from L0 g (62 mol)% dimethylaminopropylsulfur sausage and 1.30 g (6.20 mmol) 4_brook_3_oxo_ 戍Methyl acetate was prepared according to the method of intermediate 45: low resolution MS (FAB) m / e272 (M +) 〇Intermediate 73 2- [2- (j-monomethylamino-propylamino) _5_methyl_ p 塞 Jun_4_yl] • The ethanol target compound (608 mg) was prepared from 850 mg (3.14 mmol) Intermediate Li 72 according to the method of intermediate 43: iH NMR (CDC13, 400 MHz) d 6.18 (s, br, 1H), 4.40 (s, br, 1H), 3.83 (t, 2H, J = 5.5), j. 28 (m, 2H), 2.65 (t, 2H, J = 5.5), 2.39 ( t, 2H, J = 6.4), 2.23 (s, 6H), 2.18 (s, 3H), 1.76 (m, 2H). Intermediate 74 2 (S)-(2 · fluorenyl-aniline) -3- (4- {2-〇 ( 3-Difluorenylamino-propylamino) -5-methyl-oxazol-4-yl] -ethoxy} -phenyl) -methyl propionate will be 715 mg (2.73 mmol, 1.10 equivalents) Triphenylphosphine, 929 mg (2.48 mmol) of intermediate 23, and 600 mg (2.48 mmol) of intermediate -69 This paper is in accordance with China National Standard (CNS) A4 size (210X297 mm) (please first Please read the notes on the back of the page and fill in this page) HI ml I--d ^ 1 Central part of the order department / /; ϋ .Τ ί / ί A 卬 B7 B7 V. Description of the invention (67) 73 in 25 ml of anhydrous toluene The suspension was heated to 95.15 minutes to dissolve intermediate 23 to obtain a transparent yellow falling liquid. 452 mg (2.60 mmol, L05 equivalent) of ethyl azodicarboxylate was added dropwise to the solution over 5 minutes. The reaction was then cooled to room temperature and stirred for 16 hours. Toluene was removed in the air, and the residue was purified by silica gel flash column chromatography with EioAc / MeOH M and 1% ammonium hydroxide as the eluent. , Get 770 mg of the underlying compound as a more color oil: low Resolution MS (FAB) m / e 602 (ΜΗ +), 601 (Μ +). _Intermediate 75 2- [2- (2-Methoxy-Ethylamino) _5-methyl_Pethazole_4_yl] _Ethanol standard compound (800 g) is from 75 mg (5 59 Mmol) 2_methoxyethylthiourea and 1.17 g (5.59 mmol) of 4-bromo-3_oxo-pentanoic acid phosphonate according to the method of intermediate 60, and then the intermediate 4 4 is prepared in outline. This step was purified by silica gel flash column chromatography using aerosol / Me0H 9/1 as eluent.

And preparation · NMR (CDC13, 400 MHz) 3.82 (t, 2H, J = 5 5) 3.58 (t, 2H, J = 6,9), 3.41 (m, 2H), 3.36 (s, 3H), 2.65 (t, 2H, J = 6.9), 2.19 (s, 3H). 't ^ ft 76 2 (S)-(2-benzylfluorenyl-aniline) · 3_ (4_ {2_ [2 · (2_methoxy_ethylaminofluorenyl-p-sec-4-yl) -Ethoxyphenyl) _formaldehyde methylpropionate compound (907 mg) is based on 1.38 g (3.70 mmol) of intermediate 23 and 800 mg (3.70 mmol) of intermediate 75 Method 74, followed by purification by MPLC (Merck Lobar Si60 column, diethyl ether / dichloromethane 1/4 as eluent) and preparation: low resolution ms (FAB) m / e 574 (M +).- 70- This paper is compliant with the Chinese National Standard (CNS) A4 size (210X 297mm) (please read the precautions on the back before filling in this page)

A7 B7 V. Explanation of the invention (68) Intermediate 77 3- (4- [2- (benzohumazol_2_yl · methylchipentyl-anilinopropanoic acid M oxyphenylphenyl) -2 -(2_ ring-labeled compound (referred to as mg) is / from 6650 mg α7 mM), intermediate 9,646 g (3.42 mol, 2.0 Mutian Li 2.0 mM) (2_amino group _ _ Methyl ketone and 15 mg (0_003 millimolar, denier,) Yi's volume ,, · 01 n) ethyl methacrylate intermediate 3 ethyl methacrylate ', and then by silica gel flash tube λ ,, / 瘵 e 枉 chromatography Hexane / EtOAc 7/3 was used as the eluent for purification. You cut, ^ +, 乂 prepared. Low-resolution MS (ES) m / e 542 ″ (ΜΗ). Intermediate 78 benzoxazole- 2-yl_methyl_amino) · ethoxy] _phenyl} _2_ (2_cycloheptyl-aniline) _methyl propionate (13 mg) is from 65. Milligram (171 millimoles) of intermediate 9,742¾ grams (3.42 millimoles *, 20 equivalents) (2-amino-phenyl) _cycloheptyl: ketone and milligrams of germanium acetate according to the method of Intermediate 3, then Purified by Mengjiao flash column chromatography with hexane / EtOAe 7/3 as eluent: low (ES) m / e 569.9 (MH +). Intermediate 79 Benzoxazolyl-methyl-amino) -ethoxy] -phenylbenzene 2- (2-cyclohexanecarbonyl-5-fluoro-aniline) _propionic acid methyl ester The target compound (392 mg) is from 400 mg (1.71 millimolar) of intermediate 9, 325 pens (47 耄 mol, i 4 equivalents) (2-amino_cardiofluoro-benzyl) _cyclofluorenyl-methanone and 10 mg of acetic acid The rhodium is prepared according to the method of intermediate 3, and then purified by silica gel flash column chromatography using hexane / Et0AC 7/3 as the eluent. 71-Please read the note on the back first

Re-fill the items with% of this JT reference. The paper size is (CNS) A4 (210x297 mm). A7B7 V. Description of the invention (69) Preparation: Low-resolution MS (ES) m / e 574 (MH +). Intermediate 80 3- {4- [2_ (Benzo from 2 · ιmethyl · amino) _ethoxybenzene-Detailed hexamethylene group> 2-methyl, _xin_3 ylamino group) _ Methylazeptopropionate-The target compound (278 mg) is derived from Chemg (10.5 mmol 9, 287 mg (1.47 mmol), 4 Shedan, ρgan · qi 1-4 Tianli) (5 ~ Amino_1-methyl-1Η-P ratio β-Diethylhexyl-methamine and 10 mg of acetic acid are recorded according to the method of Intermediate 3 '. Then I Shijiao flashover column chromatography was performed with Jihu / Et〇 & amp Knife 3 was prepared as a solution for purification: low-resolution MS (ES) m / e56G.2 (MH +). Intermediate 8 1 3- {心 [2- (phenopterin_2_yl_methyl-amine-amino group ) _Ethoxy] -phenyldecadecyl-fluoren-2-ylamino) · Substituted compounds of propyl propionate (145 mg) are from 137 mg (0,36 mmol) of Middle Bay 9, 104¾ g (0.51 * Mole, i 4 equivalents) (2-amino'phenyl-methyl- and 5 ^: g of germanium acetate, according to the method of intermediate 3, was subjected to hair gel flash column chromatography and burned / EtOAc 7/3 was prepared as an eluent for purification: MS (ES) m / e 556.0 (MH +). Intermediate 83 2- (2-cyclohexanecarbonyl-aniline) _3_ {4_ [2_ (5 _Fluorenyl_2_phenylfluorene Azole &lt; yl) -ethoxy] -phenyl} -propionate (2.89 g) is based on 3.03 g of 75 millimoles) and intermediate fluorene 121, 2.07 g (10.51 millimoles, 14 equivalents) ) (2_Amine_phenyl) _Ring = yl-fluorenone and 69¾g of rhodium acetate according to the method of intermediate 3, followed by silica gel flash column chromatography with DCM to 1/99 diethyl ether / DCM as the solvent Analytical liquid -72 This paper size is applicable to China National Standards (CNS) A4 specifications (2 丨 οχ29? Gongchu, please read the precautions on the back before filling in this tile)

A7 ------------- B7_____ V. Description of the invention (70) Preparation: low resolution MS (ES) m / e 567.4 (MH +); then the enantiomer of this substance is in prep OD Separation on a column; Enantiomer 1: NMR, MS, HPLC are the same as the racemate. Enantiomer 2: NMR, MS, HPLC are the same as the racemate. Intermediate 84 mesitate (S)-(-)-benzyl-pyrrolidin-3-yl ester mesylate (2.03 ml, 26.2 mmol, 0.93 equivalent) was added dropwise to (S) ( -)-L-benzyl-3-pyrrolidinone (5 g, 28.2 mmol) in eridine (40 ml). The reaction mixture was stirred for 3 hours, poured into ice water (100 mL) and extracted with DCM (3 × 50 mL). The combined organic extracts were washed with saturated aqueous NaHC03, brine and dried (MgS04) to give 3 g of the target compound. Low Resolution MS (ES) m / e 256.0 (MH +). Intermediate 85 2- (2-benzylfluorenyl_aniline benzyl-pyrrolidin_3.yloxy) _phenyl] -propionic acid methyl ester 0.95 g (2.95 mmoles; 1.1 equivalents) And 747 mg (2.93 mmol, 1.1 equivalents) of intermediate 84 were added to a stirred solution of 1.0 g (2.66 mmol) of intermediate 23 in 30 ml of DMF. The resulting solution was at 45. It was stirred for 24 hours at 0 ° C and then quenched in 10 ml of water. The reaction mixture was poured into 25 liters of EtOAc and 25 ml of Et20 and extracted with H20 (3 X 10 ml). The organic layer was dried (MgSCU) and the solvent was removed in the air. Purified by silica gel flash column chromatography with hexane / EtOAc 7/3 as the eluent to obtain 0.88 g of the target compound: low resolution MS (API) m / e 535.1 (MH +). Intermediate 86 -73- This paper size applies to Chinese National Standard (CNS) A4 (210x297 mm) (Please read the notes on the back before filling this page)

In the middle of the meridian ^: quasi-,-;}. Τ eliminates the combination of bamboo snoring 1 '! A7 B7 V. Description of the invention (71) ^ [4- (1-benzoxazole_2_yl_pyrrole Pyridine_3_yloxyphenyl] _2_ (2_Erytyl-aniline) -methyl propionate Ethyl chloroformate (0.24 ml, 2 24 mmol, 2 equivalents) was added at 0 ° C. 0.60 g of intermediate 85 (12 mmol) in 2 DCM (100 mL). The reaction mixture was stirred at TC for 30 minutes and then concentrated to dryness. The resulting residue was dissolved in MeOH (100 ml), refluxed for 25 hours, and then concentrated to dryness. Triethylamine (0.47 ml, 3 36 mmol) Ear, 3 eq) was added to this crude ^ (0.71 g, M2 mmol). The reaction mixture was stirred for 5 minutes, then 2-Ga-benzoxazole in THF (2 ml) was added dropwise. Stir for 12 hours at room temperature and concentrate in the air. Purify after purification by silica gel ^ steam column chromatography with ET20 / DCM i 〇 / 90 to obtain 200 mg of the target product: low-resolution MS (ES) m / e 562.1 (Μί〇. Intermediate 87 3- {4- [2- (5-methyl-2-phenyl-hydrazone_4-yl) _ethoxy] _phenyl} _2 (s) _ [2_ (p 比 咬 _4_fluorenyl) _aniline] _Methyl propionate target compound (2.92 g) is derived from the intermediate 丨 20 (3 65 g, 9 61 mmol) and 2- (Pyridoxine-4-carbonyl) -cyclohexanone (2922 g, 961 mmol) according to the method of intermediate 23, followed by silica gel flash column chromatography with dcm / MeOH 98/2 as the eluent Purification and preparation: low resolution MS 546.0 (MH +). Intermediate 8 8 3- {4- [2- (5-methyl-2- -Pyrazol-4-yl) -ethoxy] _phenyl} _2_ [2_ (pyridine N-oxide-4-carbonyl) -anilino] -methyl propionate mCPBA (185 mg, 1_〇 7 millimoles, 3 equivalents) -74 at room temperature- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) C Read the notes on the back before filling this page)

A7 B7 ^ &quot; ^ 而 1; ::;-&quot; &quot; '于 合 竹 ^ 卬 ^ V. Description of the invention (72) Intermediate 8 7 (200 mg, 0.36 mmol) tDCM (5 ml). 24. After time, the reaction mixture was concentrated in the air. Purification by silica gel flash column chromatography using DCM / MeOH 98/2 to 90/10 as eluent yielded 90 mg of the target compound: low resolution MS (ES) m / e 578.1 (MH +). Intermediate 89 3- {4- [2- (5-methyl-2-phenyl-oxazole_4_yl) _ethoxy] _phenylbenzene 2 (s) _ [2_ (pyridine-3- Carbonyl) -anilino] -methyl acetate propionate (540 mg) is derived from intermediate 120 (30 g, 20 mF) and 2- (pyridine-3-carbonyl) · cyclohexanone ( 107 g, 5 26 millimolar intermediate 23, followed by purification by silica gel flash column chromatography with hexane to ... Hexafe / EtOAc as eluent: low resolution msm / e 562.2 ( ΜΗ +) .; Intermediate 90 2- (5_methyl_3_phenyl-p ratio benzyl) _ethanol 497 pens (3.14 mmol) 夂 methyl_5_phenylpyrazole at 26 A solution of mM DMF at TC at 138 mg (3 45 mM,

Treat your legs. After stirring for 15 minutes, 38 grams (157 milli-ears) of acid was added, and the reaction was warmed up to the reaction mixture to release the product and the product was extracted with hexane / Et0Ac (1: 1). The organic phase was dried (MgS04), filtered and concentrated in the air. The residue was purified by flash gel column chromatography with hexane / Et0Ac (1: 3) as the eluent to obtain 305 true (48%) of the target compound: low resolution MS (ES) m / e 225 ( MNa +), 203 (MH +). J Intermediate 91 -75- This paper New i! Finance Standard (CN'sTX ^ TTf〇x297mm I-C1 binding (read the precautions on the back before filling in this page) ^ 'x, Jh-T elimination cooperation. ^ 卬 A7 B7 V. Description of the invention (73) 2S- (2-Bromo group-private amino group) -3- {4- [2- (5-methyl -3-phenyl-p than fluoren-1-yl) _ethoxy] -phenyl} -propionic acid methyl ester 169 mg (0_45 mmol) intermediate 23, 100 mg (〇_49 mmol) Ear) Intermediate 90 and 177 mg (0.67 mmol) of triphenylphosphine in 4.5 ml of THF were treated dropwise at 25 ° C with 0.106 ml (0.67 mmol) of DEAD. The reaction was stirred at 25 ° C. 24 hours and concentrated in the air. The residue was purified by silica gel flash column chromatography with hexane / EtOAc (2: 1) as the eluent to obtain 116 mg (46%) of the title compound as a thick yellow oil: low Analytical MS (ES) m / e 582 (MNa +), 560 (MH +). Intermediate 92 2S- (2-fluorenyl-aniline) _3_ [4_ (1_third-butoxycarbonyl_pyrrolidin_2S_ Methyl-methoxy) -phenyl] -propionate (g) The target compound (1.62 g) is derived from 2.82 g (7.5 mmol) of intermediate 23 and 1.66 g (8.25 耄Mol) N-third-butoxycarbonyl 丨 _prolinol was prepared according to the method of intermediate 91, and then purified by silica gel flash column chromatography with hexane / (3: ι) as the eluent. : Low resolution MS (ES) m / e 58ι (MNa +), 559 (MH +). Intermediate 93 2S- (2-fluorenyl-aniline) _3_ [4_ (1_pyridin_2_yl-pyrrolidine-2s _Yl-methoxy) -phenyl] -propionate 2.95 g (5.3 mmol) of intermediate 9 2 in 62 ml of CHA was treated with 62 ml of trifluoroacetic acid and stirred! Hours. 2 diluted and tested with Na2CO3. The water layer was treated with CH2Cl2, combined with the organic phase and dried (Ma2S04), and concentrated in the air. Residual material 210ml-76- &gt; Paper size applicable to China Standard specifications (~~-: — ~~ _______ — .1—-11: i nn In a ^ D-I_ = 1-......... ^ J. (Please read the precautions on the back before Fill in this 1) A7 B7 V. Description of the invention (74) 2-Fluoropiridine is heated under reflux for 24 hours. When cooled to ^^, the reaction is concentrated in the air and the residue is separated by Korean flash column chromatography. ^ Et〇A, c (2: 1) purification, 1.2 g (42%) of the target compound was viscous Color oil: Low-resolution MS (ES) m / e 558 (MNa +), 53 6 (; MΗ +) »Intermediate 94 2- (1-methyl-4-benzyl-1 Η-taste-2-yl ) _ Ethanol will be 674 mg (4.26 mmol) p-methyl 4-phenyl flavor also (leg, c;

Harada 'Y_; Hosomi, A. Heterocycles 1993, 35, 433) in 8_5 ml of THF solution at -78 ° C with ΐ · 9 ml (4 69 mmol) 2 5 M "_ BuLi in hexane Handle D and stir! After 0 minutes, ^ ml (21.3 mmol) of ethylene oxide was added. The reaction was stirred for 5 minutes and then warmed to 25C and stirred for 1 hour. Upon cooling down, hl milliliters (213 millimoles) of ethylene oxide were added and the reaction was warmed to 25. 〇 and stir overnight. The reaction was poured into water and extracted with EhO. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography with EtOAc / MeOH (95: 5) 'and the collected product was recrystallized from CH2Cl2 / EtOAc to obtain 178 grams (21%) of the target compound as White solid: low resolution Ms (ES) m / e 225 (MNa +), 203 (MH +). Intermediate 95 2S_ (2-benzyl-aniline) -3- {4- [2- (l-methyl-4-phenyl-1H-imidazol-2-yl) -ethoxy} -propionic acid The methyl ester-based compound (90 mg) is derived from 93 mg (4.25 mmol) of intermediate 23 and 50 mg (0.25 mmol) of intermediate 9 4 according to the method of intermediate 91, borrowing Xi Xisheng Flash column chromatography with hexane / Et〇Ac (1: 3) as the eluent for purification -77- This paper size applies to China National Standard (CNS) A4 size (210X297 mm) (read first M read (Notes on the back, please fill in this page)

— 0 私 ------ T nn —m · — · tm uttB · »! 1 ·--tnn ....... · A7B7 Bu), 560 (MH +) V. Description of the invention (75) Preparation: Low-resolution MS (ES) m / e 582 (MN intermediate 96 3-crean-2-yl-: 5-methyl, 0.442 ml (14_G7 mmol) of hydrazine at 25 °. Next, iQ7 g (7.03 mol) of H2_, alkanoyl) _1; 3_ butane were added to a solution of dysprosium in redundant milliliters. The reaction was stirred for 24 hours and then concentrated in the air. The residue was purified by Shixi gel flash column chromatography using hexane / e (1: 1) as eluent to obtain 1.02 g (98%) of the target compound: low-resolution Ms (ci) m / ei49_ intermediate 97 2- (3 · bite_2-yl_5_methyl-pbicyl- 丨 _yl) _ ethanol standard compound (189 mg) is from! 〇1g (6 82 millimolar) intermediate 96 series intermediate 90 method, followed by silica gel flash column chromatography and purification with hexane / EtOAc (1: 3) as the eluent: low resolution m / e 215 (MNa +), 93 (MH +). ) Intermediate 98 2- (5-methyl-3_phenyl- [I, 2,4] Sanjun _ 丨 _yl) _ethanol standard compound (14 mg) is from 55 mg (3 45 mmol) (Ear) Hong phenyl-5-methyl- and 4] triturate (Francis: £; G〇 called l

Mazzenga, GC; Meckler, H. Tetrahedron Lett 1987 28? 5 is called according to the method of intermediate 90 by Shi Xijiao flash column chromatography with .Ac; MeOH (95: 5) as the eluent and purified O recrystallization was prepared: low resolution MS (Cl) m / e 204 (MH +). Intermediate 99 2S- (2-elastyl-aniline) _3_ {4- [2_ (5_methyl_3_benzyl [I,〗 〆]] three vomit--78 paper size; t] China National Standard (CNS) Α4 specification (210X297 mm) (Jing first read the precautions on the back and spray before filling this ear)

Js ° via S :: 'Ministry of Time i?' ^ I: JhT, Elimination &quot; made. ^ 卬 * ,; person-melon ^ A7 _________ _ _B7 V. Description of the invention (76) ^-) Methyl] -phenylpropionate (186 mg) is based on 196 mg (0.52 mmol) of intermediate 23 and 106 mg (0.52 mmol) of intermediate 44 Methods Silica gel flash column chromatography was used to purify hexane / Et0Ac (1: 1, 1: 2) as eluent: low-resolution MS (ES) m / e583 (MNa +), 561 (MH +). Interstitial 100 3-methoxymethyl-5-methyl-2-phenyl-3H-imidazole Add 278 ¾ g (6.95 mmol, 60% in oil) of NaH at 0 ° C to 1.0 g (6.32 (Dimole) 4-methyl-2-phenyl imidazole in 25 ml of DMF solution. After stirring for 5 minutes, 0.528 ml (6.95 mmol) of methyl methyl ether was added, and the reaction was heated to 25 ° C and stirred for 4 hours. The reaction was poured into water and the product was extracted with hexane / EtOAc (1: 1). The organic layer was dried (NaJCU), filtered, and concentrated in the air, and purified by silica gel flash column chromatography using hexane / EtOAc (5:95) as the eluent to obtain 816 mg (64%) of the target compound: Low resolution MS (ES) m / e 225 (MNa +), 203 (MH +). Intermediate 101 2- (3-Methoxyfluorenyl-5_methyl-2-phenyl-3H-imidazol-4-yl) _ethanol standard compound (433 mg) is from 7 10 mg (3.5 mg Moore) middle ^ 100 according to the method of intermediate 9 4 followed by purification by lithography flash column chromatography with EtOAc / MeOH (93: 7) as the eluent: low resolution ms (ES) m / e 269 (MNa +), 247 (MH +). -79- 'Scale shift' / fl Chinese National Standard (CNS) A4 specification (210X 297 mm) -—- t · n Kn -1 1 ·· 1 tn. ^ 1 ^ 1 nn--1 · in —I —I 1--1 ·-r «. Jc ^ i (Read the precautions on the back first and then fill in the clothing page) A7 Jing 7 Rong Zhong Rong 4.r. ^. ^ L = cT 消 几 合 卄 = il Envy 5. Description of the invention (77) Intermediate 102 2S- (2-fluorenyl-benzylamino) _3_ {4_ [2_ (3_methoxymethyl_5_fluorenyl_2_phenyl_ jH- The imidazol-4-yl) -ethoxy] -phenylbutyric acid methyl ester target compound (347 mg) was obtained from 314 mg (〇84 mmol) of intermediate 23 and 207 mg (0.884 mmol). Ear) Intermediate 1 (n according to the method of Intermediate 44, followed by silica gel flash column chromatography and purification with Et0Ac / hexane (3: 丨) as the eluent to obtain 347 mg (69%) Target compound: Low resolution MS (ES) m / e 604 (MNa +), 626 (MH +). Intermediate 103 2- (3-Dimethyenylethoxymethyl_5_methyl_2_phenyl_ 3H-imidazole 4-yl ethanol 1.04 g (6.57 moles) 2-phenylfluorenimidazole in 25 ml of DMF solution at 0 ° (: 289 mg (7.23 mmoles, 60% in oil) ) Chemical treatment 11. Stir 5 After 22 minutes, 28 ml (7 23 mmol) of 2- (trimethylsilyl) ethoxymethyl gas was added. The reaction was stirred for 0 minutes and then heated to 25 C and stirred overnight. The reaction was poured into water, and the product was Hexane / EtOAc (1: 1) extraction. The combined organic phases were dried (N ^ 04), filtered, and concentrated in the air. The residue was subjected to silica gel flash column chromatography with EtO &amp; / MeOH (98: 2) Purified as an eluent to obtain 18 g (62%) of protected intermediates. This material was then passed through a silica gel flash tube according to the method of intermediate 94, and chromatographed with EtOAc / MeOH (95: 5 / E 9 : 1) Converted into the target Z compound (S51 mg) as the eluent: low-resolution MS (ES) me 233 (MH +). Intermediate 104 2S- (2-famidino-anilino) -3_ {4 · [2- (5-Methyl-2-phenylphenylimidazole, yl) -ethoxy] -phenylbutyric acid methyl ester -80- This standard is suitable 丨 彳 丨 ^ National standard (CNS ^ ^ 7_210X29_7 (Please read the precautions on the back before filling this page) ------ Order

'-5--: UBC A7 B7: ¾ &quot;. Part of the sub-i?-^^ m, ivi in He M. ^ _ 卬 ow: V. Description of the invention (78) The subject compound (542 mg) is from 931 mg (2.48 mmol) of intermediate 23 and 825 grams (2.48 mmol) of intermediate 103 were processed by intermediate 44 'followed by column chromatography on a silica gel flash column with hexane / EtOAc (2: (Where L)) was purified as a decanter to obtain 867 mg of pure intermediate. A solution of 830 mg (12 μmol) of this material in 2 mL was treated with 0 222 mL U · 8 millimolar) BF3. OEk. At 0. (: After stirring for 30 minutes and then 25 ° C for 1 hour, another 0.444 ml (3.6 mmol) of Bf3 · 0Et2 was added and stirring was continued for 3 5 minutes. The reaction was poured into saturated NaHC0 3 and the product was extracted with sodium hydroxide. Combined with organic phase drying (NkSOj, filtration, and concentration in the air). The residue was purified by silica gel column chromatography using hexane / EtoAc (1: 1) as the eluent: low-resolution Ms (ES) m / e 56〇 (MH +). Intermediate 105 5-methyl-2-phenyl-4-Petylacetate g The target compound (827 mg) is from 〇 g (4 78 mmol) 4_Bromo_3_oxo-pentyl methyl ester and 2.6 g (19.14 mmol) of thioanilide according to the method of intermediate 42, followed by silica gel flash column chromatography with hexane / Et〇Ac (3: i) Prepared as an eluent for purification: low resolution MS (ES) m / e 27〇 (MNa +), 248 (MH +) ° intermediate 106 2- (5-methyl-2-phenyl_ρ Jijun_4-yl) _ethanol standard compound (538 mg) is from 817 mg (330 mmol) of intermediate 105. According to the method of intermediate 43, followed by silica gel flash column chromatography to Ethane / EtOAc (1: 2) was prepared as a lysate purification: low resolution (es) m / e 242 (MNa +) »219 (MH +) 〇 -81-Sheet size suitable for Jfl China National Standard (CNS) Α4 ^ ΤΤ ^ 297

In l II. II-111 —I —I— II — ^ '' ^^-In..! ^ I |-* T-mouth (read the precautions on the back before filling this page) &quot;-^ 而 ";; 3 ;; 1 · Zhazhuzhu and 卬 f A7 ———________ B7 ~ _________ _ V. Description of the invention (79) — ~ 土 逆 体 107 2S- (2-benzidine -Anilino) · 3_ {4- [2- (5-methyl_2_phenyl-oxazolyl-4-yl) -ethoxy] -phenyl} -propionate (3? 8 mg) is based on 3M mg (〇93mmol) of intermediates 23 and 203 ^: g (〇9393mol) of intermediate 106 according to the method of intermediate 43, followed by the silica gel flash tube column layer The analysis was prepared by purification with hexane / EtOAc (3: U as eluent: low resolution Ms (Es) m / e 599 (MN & +), 577 (MH +). Intermediate 108 3- (5- 曱1_2 methylphenamino group) _4_oxovaleric acid methyl ester 19.0 g (0.136 moles) 5-methyl-2-thiophenecarboxylic acid in 200 ml of toluene with a slurry of 10.9 Milliliter (0.15 mol) of chlorinated sulfuric acid group treatment. The resulting mixture was heated to 70. (: 16 hours, and then concentrated in the air. The resulting oil fraction | million, 0 C and at a rate to maintain h degrees &lt; 丨 0C Add to 25 gram (0,36 mol) b-methylaspartic acid hydrogenate in a solution of 80 ml of ton. After the addition is complete, the solution is stirred at 25. (: under stirring! Hours, treated with 5G ml of hepatitis B And heated to 9 ° C for 2 hours. The mixture was cooled to hunger, poured into 700 ml of bait, and taken three times with EtOA0. Combined organic phase & 3nhci was washed three times, once forever and once with 5% water. Finally, the solution was washed with brine. The solution was dried (NaSO), and then chromatographed on silica gel with hexane: EtOAc 3/2 and chromatographed to obtain 9. g (25%) of the subject compound as a transparent yellow oil: MS. (ES) m / e 270 (MH +). Intermediate 109 (5-methyl-2- (5-fluorenyl_2_fluorenyl) _σ # azole_4_yl) methyl acetate-82-Ben Paper size is suitable for China National (CNS) A4 specification (210X297 mm) (Please read the notes on the back before filling this page) ------ ΐτ A7 V. Description of the invention (80)-3.97 grams (H. 7 millimoles) Intermediate 108 solution in 100 milliliters of anhydrous acetonitrile was treated with 4.1 milliliters (44.2 millimoles) of phosphine gas and heated to reflux for 5 hours. The solution was cooled to 25 ° C and from the bottom of the Erlenmeyer flask decanted away The dyed oil was isolated. The solution was concentrated in vacuo and diluted with water and EtOAc. The aqueous phase was saturated with KHC03, the layers were separated and the solution was extracted twice more with EtOAc. The combined organic phases were dried and dehydrated (504) and concentrated in Xingkong to give an orange oil, which was chromatographed on silica gel with dichloromethane: 20/1. The residue was concentrated in the air and dissolved in silica gel with hexane: EtOAc 2/1 and re-chromatographed to obtain 2.94 g (79%) of the title compound as a pink-orange oil: MS (ΑΡΙ +) m / e 252 (ΜΗ +). _Intermediate 110 2- (5-methyl-2- (5-fluorenyl-2-p sephenyl) -yinjun_4_yl) ethanol standard compound (1.05 g) is derived from 2.94 g (11.7 mmol) Ear) Intermediate 10 was prepared according to the method of Intermediate 43, and then purified by silica gel chromatography with hexane: EtoAcium, eluent: MS (ΑΡΙ +) m / e 224 (ΜΗ +). Intermediate 1 Π 2 (S)-(2-benzyl-anilino) _3- {4- [2-5 -methyl-2- (5-methyl_2-ppluga) &quot; 'Ifx, J'-Ji-T; ii in cooperation ^! 卬 ^; (read the precautions on the back before filling in this page)

Group) azole-4-yl) -11-ethoxy] -phenyl} -propionic acid methyl ester The target compound (440 mg) is derived from 700 mg (3.13 mmol) of intermediate 110 and 1.18 g (3.13 mmol) Mol) Intermediate 23 was prepared according to the method of Intermediate 44 and then purified by silica gel chromatography with toluene: EtOAc 2〇 / 1: MS (ES +) m / e 581 (MH +); TLC (PhMe: Et〇Ac / 90: 10): Rf = 0.25. .Intermediate 112 2 (S)-(2- + fluorenyl-aniline) -3- {4- [2- (5-methyl-2- (3-methyl-p-phenen-2-yl) -p # azole-4-yl] -phenyl} -fluorenyl propionate-83- This paper size applies to Chinese National Standard (CNS) A4 specifications_ (210X297 mm) A7 B7 V. Description of the invention (81) Target compound (100 mg) was prepared from 3.7 g of methyl (5-methyl-2- (3-methyl-2-thiafluorenyl) -azol-4-yl) acetate (prepared similar to intermediate 10) ) According to the method of intermediate 43, followed by the method of intermediate 44 and 375 mg (ιmmol) of intermediate 23, and then purified by silica gel chromatography 95: 5 / toluene: EtOAc to prepare: Ms (ES +) _ training (mh +); similar to (PhMe: EtOAc / 90: 10): 0.38 produced by R. Intermediate 113 2- (2-iodo-phenyl) -3_ {4_ [2_ (benzoxazole) _ 2-yl-fluorenyl-amino) _ethoxy] -phenyl] · -methyl propionate_ A solution of 26.3 ml of a 1.0 M intermediate in 10 in toluene, followed by 58 pens (0.132 ¾ Mol) Germanium acetate (π) dimer was added under a nitrogen pressure of 25.0 g and 2.88 g (13.15 mmol) of 2-iodoaniline was stirred in a solution of 50 ml of toluene. The resulting solution was at 25 ° C. (: It was stirred for 6 hours, and then concentrated in the air to a dark brown oil. The crude product was chromatographed on silica gel with CH2C12 to obtain 12 g (75%) of the standard compound: MS (Api) m / e 573 (MH +), 572 ( M +). Intermediate 114 4 (R) -light methyl-tetrahydro-p-plug bite "3-Leptanoic acid tertiary-butyl ester 466 g (20 millimolars) meaning cardiothioproline and 3.84 ml ( (22 mmol) DIEA in 10 ml THF was cooled to and treated with 21 ml (22 mmol) ethyl formate. After 30 minutes at room temperature, the white precipitate was filtered off and the solution was cooled. To 0 ° C and dropwise added a solution of 8.32 g (220 millimoles) of sodium hydride in 30 ml of HzO. The reaction was stirred for 24 hours, then cooled to 0 ° C and quenched by the addition of acetic acid dropwise. Et〇Ac Extraction-84- This paper is suitable for the standard / fl Chinese national standard mound fcNS) A4 size (210X 297 mm) ~ '© · 衣 — (Read the precautions on the back before filling this page) "^^^" in the ministry. Only 5 eliminates the combination of bamboo. Xinyinfan A7 ~ ------------ --- B7 _ 5. Description of the invention (82) The product, combined The organic phase is continuously washed with hydrogen steel and citrate-like acid. Sulfuric acid. Dry slowly, rinse and remove the solvent in air to obtain 2 μg of the target compound: MS (ES +) m / e 242 (M + 23), 120 (M_B () e + 1). Soil Έbody 115 4 (HH4- [2 (SH2-: f 醯 yl · anilino) _2_methoxycarbonyl_ethyl] _phenoxymethyl} -tetrahydrothiazolium tri-butyl ester 0.95 ml (6.03 mmol) DEAD was added dropwise at 0 ° C. 20 grams (5.48 moles) of Intermediate 114, 2.05 grams (5 48 mmoles) of Intermediate 23 and 1.58 grams (6.03 mmoles) (Ear) Triphenylphosphine in 7 ml of THF solution. The reaction mixture was stirred at room temperature for one hour, the solvent was removed under vacuum and the crude product was subjected to silica gel column chromatography with EtoAc / hexane 1/3 as The eluate was purified, 530 I gram of compound: ms (ES +) m / e (M + 23). Intermediate Π 6 3- [4- (3-benzoxazole_2_yl_tetrahydro Thiazole_4 (R) _ylmethoxy) _phenyl] 2 (S)-(2-benzylfluorenyl-anilino) _methyl propionate intermediate 115 (500 mg, 0.868 mmol) 5 ml of 4 N HC1 (-Yin Yu treatment for 1.5 hours. Then the solvent was evaporated and the crude hydrogenated salt was dissolved in 20 ml of dichloromethane. 767 mg (50 mmol) of chlorobenzine peak and 1.29 g ( 10.0 mmol) DIEA to this solution and the resulting solution was allowed to simmer for 36 hours at room temperature. The volatiles were removed in the air, and Silica gel column chromatography was used to purify the solid residue with EtOAc / hexanes 1: 1 as the eluent. # 128 mg of the target compound: MS (ES +) m / e 594 (MH +). Intermediate 117 2 (S) -(2-Sheep Brethyl · Anilino) -3- (4-Phenyl) -propionic acid. -85- This paper is suitable for jliTiil home standard (CNS) A4 specification (210X297 mm) (please read the back first) Please note this page before filling in this page) Φ-. Order ^^. ^. ^ ¾ ^^^^^^^^^ ¾ A7 ---_________ ^ _____ B7 V. Description of the invention (83) • Target compound (I · 63g) is from 79gM% millimolar) Intermediate η Prepared according to the method of Example 3 2: He 5 (] ^ +) 111/6 384 (1 ^ 1 ^ + 23). 土 间 体 118 2 (S)-(2-Lyme &amp; yl-aniline) _3_ (4 • Si · phenyl) _propionic acid (2 prepared phenyl) _diphenyl-methyl acetate will be attached to a polyethylene resin i.63 grams (4.4 * mole) of intermediate 1 17 in 10 ml of MeOHt and 5 ml of water was treated with 0 · δ52 (4.4 mole) of cesium hydrogen carbonate. Dissolved at room temperature Stir for 10 minutes, and then remove the solvent and dry the known solid cesium salt under the air. Take 480 mg of C1_trityl_polystyrene (ps). Zhi Mao 1.5 mole / g) in 4 ml of dry DMF at 60 in the slurry in Pico (pen about 1 mole) of cesium salt of the above reaction 5〇 C 2 billion hours. The resin was then filtered off and washed successively with 10xDMF, 1: 1 DMF / ethanol, ethanol and ether to obtain 550 mg of dried product. The substituted fluorene (0_49 mmol / g) of this derivative resin was then calculated based on combustion analysis (Cf0Und 79.%, HfQund 5.94%, NfQund 0.88%). Intermediate Π 9 2 (S)-(second-butoxycarbonyl-amino) _3_ {4_ [2_ (5-methyl_2_phenyl-oxazole_ 4-yl) -ethoxy] _ Methyl propionate (15.9 g) is derived from 15.0 g (73.8 mmol) of 2- (5-methyl-2-phenyloxazole-4-yl) _ethanol and 21_8 g (73_8 mmol) Ear) 2 (S)-(Third-butoxycarbonyl-amino) -3- (4-hydroxyphenyl) -propionic acid methyl ester, according to the method of intermediate 4 4 followed by silica gel chromatography with diethyl ether / Digas methane (丨: 丨 9) purification and preparation: low resolution MS (ES) m / e 481 (MH +). -86- This paper is in accordance with China State Standard (<:: 1 ^) and 8 specifications (210 &gt; &lt; 297 mm). (Please read the precautions on the back before filling this page)

In the Ministry of Justice ^ &quot; '^^^^-7-7 于 合 竹' ^ 卬 Father A7 ___________B7 V. Description of the invention (84) ί_Μ. 体 120 2 (S) -amino-3- {4- [2 -〇methyl-2_phenyl-humazol_4-ylethoxy] • phenyl} -methyl propionate 33 liters (10% by volume) of difluoroacetic acid was added at room temperature% g (33 .〗 Mmole) Intermediate U9 in 300 ml of dichloromethane with stirring. After stirring for 5 hours, the reaction was quenched with 0.1 n NaOH and the phases were separated. The organics were washed with water, the layers were separated, and the organics were dried (MgSa0, and the solvent was removed in the air to obtain the target compound as monotrifluoroacetate: low resolution ms (ES) m / e 381 (MH +). 体 121 2- 重Nitrogen-3- {4- [2- (5-methyl-2-phenyl-oxazole_4-yl) _ethoxy] -phenyl} _ methyl propionate t compound (240 pens) It was prepared from 500 mg (〖〇 丨 mmol) of intermediate 120 according to the method of intermediate 9, and then purified by silica gel chromatography with EtOAc / hexane (• ^ 7) as the eluent. Low-resolution MS (ES) m / e ΜΑ (M_N2), intermediate 1 9 9 2- [2-iodo-aniline] _3_ {4_ [2_ (5_methyl_2_phenyl-oxazole_4_yl The compound (3.93 g) of ethoxy] -phenyl} -ammonium propionate is derived from intermediate 121 (3.08 g, 7 87 mmol), 2-iodoaniline (2.07 g, 9 44 mmol) Moore) and Rh20Ac4 (100 mg) according to the method of Intermediate 3, followed by silica gel chromatography with hexane / EtOAc (85:15), and the preparation of low-resolution MS (ES + ) m / e 583 (MH +). tm ft 17-, -87- The paper size is suitable for standard (CNS) Λ4 specification (2j〇x297 is clear. (Please read the notes on the back before filling (Write this page)

A7 B7 if- part t A il $ and ii JT elimination f: yf · '卬 5. Description of the invention (85) 2- [2- (4-methylsynthyl-benzylfluorenyl) _aniline] _3 · {4_ [ 2 — (5_fluorenyl_2_phenyl_p Jun-4-yl) -ethoxy] _phenyl} _methyl propionate KfO3 (356 mg, 2.58 mmol) is included in the intermediate 122 (500 mg, 0.86 mmol), 4-formamylphenyl acid (193 mg, 1.29 mmol) and Pd (Cl) 2 (PPh3) 2 (18.0 mg, 26 mmol) The suspension in No. 57 (13 liters) was heated (100 m) at 1 atmosphere c0 for 24 hours. After cooling to room temperature, the EtOAc solution was washed with 0.5 M NaOH (50 mL), water (50 mL), and brine (25 mL). This solution was dried over MgS04 and concentrated to a brown oil, which was flash chromatographed on silica gel (50 grams) with hexane / EtOAc (85:15) to give the unreacted starting broken compound (0 32 grams). , 64% yield) and the target compound (99j mg, 168 millimoles, 20% yield) as a yellow oil: low resolution MS (ES) m / e 589 (MH +). Intermediate 124 2- [2-(: &gt; -Branch-Branchyl) -Amino group] _3- {4- [· 2- (5-methyl_2_benzene some p number Jun-4- Group) -ethoxy] -phenylbuprofen. Formic acid was prepared by the step of connecting 3-intermediate phenylboronic acid with intermediate 3, and the target compound was isolated (25% yield) as a yellow oil: low resolution ms ( ES +) m / e 589 (MH +). Intermediate 125 2 (S)-(1-methoxycarbonyl-2- {4- [2- (5-methyl-2-phenyl-oxazole_cardiyl) _ethoxy] -epoxy}- Ethylamino) -Methylanthic acid intermediate 120 (664 mg, 1.75 mmol) and methyl cyclohexanone 2-carboxylate (300 mg, 1.92 mmol) in toluene (50 ml) It was regenerated for 6 hours in a Dean-Stark trap (oil bath temperature not). Toluene was removed by rotary evaporation and substituted with methoxybenzene (50 ml). Will be -88 This paper is compliant with China National Standard (CNS) A4 size (210X 297mm) (Please read the notes on the back before filling this page) Φ-. Order ^ '部 中 荣 &quot;' ^^ '-^'-: Consumption and combination of bamboo ^ India &quot; A7 ________________ -----: _________: __ 5. Description of the invention (86) 10% palladium / carbon (250 mg) was added to this solution and the resulting suspension was heated To 190 C and stirred for 6 hours at &amp; After cooling to room temperature, the catalyst was removed by filtration through a pad of Celite (5 g) and washed with tAc (200 ml). The filtrate was concentrated to a brown oil, which was purified by silica gel (100 g) with hexane / EtoAc (4/1) flash chromatography to obtain the target compound (590 mg, 66%) as a white solid: melting point 102-103 ° C; low resolution MS (ES +) m / e 515 (MH +). Intermediate 126 2 (S)-(1-methoxycarbonyl-2- {4_ [2_ (5_methyl_2_phenylidazole_4_yl) _ethoxy] -phenyl} -ethylamine Benzyl) -benzoic acid KK / 〇3 (267 mg, 1.9 mmol) containing intermediate 122 (375.2 mg, 0.64 mmol) and Pd (C1) 2 (PPh3) 2 (22 6 mg, 0.032 mmol) A suspension of dioxane (50 ml) and water (0.01 ml) in a volume of 250 ml Parr was bombarded at 125 ° C under CO (200 psi) for 16 hours. After cooling to room temperature and passing CO, the resulting mixture was diluted with TOA (250 mL) and washed with 2.0 M HC1 and brine (50 mL each). The organic solution was dried over MgS04 and concentrated to a brown oil, which was flash-chromatographed on gin (50 g) with EtOAc / hexane (1/1 at 0.10 /. HOAc) to give the title compound (110 mg, 34%) as a white solid: melting point i73-174 ° C; low resolution Ms (ES +) me 501 (MH +) 〇Intermediate 127

(2S) -2- (l-methyllactyl-2- (4-¾phenyl} -ethylamino) -benzyl acid g 20 g (0.10 mole) (L) -carboxylic acid methyl ester A solution of 28.8 g (0 18 mol, 1.8 equivalents) of cyclohexanone-2-carboxylic acid methyl ester in 300 ml of toluene was heated under reflux for 2 hours, and water was removed through a Ding-Stark trap. The resulting yellow solution A- 89- This paper size is in accordance with Chinese National Standard (〇 奶) 8 4 specifications (210/297 mm) ~ ~~-~--------- ¢ 11 (Please read the precautions on the back before filling in this page)

, TT A7 B7 V. Description of the invention (87) However, the toluene was removed to the room temperature and in the air. The residue was dissolved in 250 ml of methoxy 'and 5.0 g of 10% Pd / C was added. The resulting mixture was heated to 2000C for 7 hours' and cooled to room temperature, another 5.0 g of 10% Pd / C was added and the mixture was heated to 200 ° C for another 7 hours. The reaction mixture was cooled to room temperature and filtered through a plug of celite to remove Pd. The filtrate was concentrated in the air at 60 ° C, and the residue was purified by gelatin flash column chromatography with hexane / EtOAc 7/3 as the eluent to obtain a pale yellow solid. This material was triturated with diethyl ether / hexane 1 / 丨 and filtered to give 15.75 g (47%) of the title compound as a white solid: low resolution ms (ES +) m / e 330 (MH +). Intermediate 128 2- {4- [2- (Benzozazol-2-yl-methyl-amino group> -ethoxy] • benzyl} _3_ (3_benzyloxy-phenyl) -3 -Hydroxy-2,3-dihydro-1H-indole-2-carboxylic acid methyl ester (1.45 g) is derived from 2.09 g (5.49 mmol) of intermediate 9, 2.0 g (6.59 Millimolar) (2-amino-phenyl) _ (4-benzyloxy-phenyl) _methanone (J.

Org. Chem., 1991, 56 (11), 3750-3752) and 120 mg (〇27 mM) diacetate (II) dimer according to the method of Intermediate 3 followed by silica gel chromatography with EtOAc / hexane. Calcination (gradient 2: 3 to 1: 1) was prepared as eluent purification: ^ analytical MS (ES) m / e 678 (MNa +), 656 (MH +). Intermediate 129 3- {4- [2- (benzohumazol_2_yl_fluorenyl_amino) _ethoxy] _phenylb 2_ [2_ (3-fluorenyl-benzyl) _ Aniline propionate 1.1 ml (7.52 mmol) L8-diazobicyclo [5. 4 〇] undecyl_7_ 晞 Add 1.45 g (2.21 mmol) of intermediate 128 in 2 ml toluene Stir the solution. The resulting solution was heated at reflux for 16 hours. After cooling to room temperature, -90- Use Chinese National Standard (c ^ T ^ i ^ r ^ ox 297mm) --------- _______ ^ —— JQ (Please read the notes on the back before filling this page) Order After the ministry of the Ministry of Civil Affairs ^-and Ding _; 71 抡 合 竹. ^ 印 ^: A7 B7 V. Description of the invention (88) Remove the solvent in the air. The residue was purified by silica gel chromatography with EtoAc / hexane (gradient 2-3 to 1: 1) to obtain 102 g (70% yield) of the target compound: low resolution MS (ES) m / e 678 (M + Na +), 656 (ΜΉ +). Intermediate 1 3 0 3- {4- [2- (benzoxazol-2-yl-methyl-amino) _ethoxy] _phenyl} · 2_ [3-hydroxy-benzylfluorenyl Aniline] -methyl propionate A solution of 600 mg (0.91 mmol) of intermediate 129 in 9 ml of EtOAc was evacuated and purged with argon. 300 mg (50% by weight) of palladium / Ling (10%) was added In solution. The resulting slurry was evacuated and purged with argon. After stirring for 16 hours under 1 atmosphere of hydrogen, the reaction was filtered through a plug of nitrogen under a stream of nitrogen. The organic phase was collected and the solvent was removed in the air to produce the target compound. , Which can be used directly without further purification. Low-resolution MS (ES) m / e 588 (MNa +), 566 (MH +). Intermediate. 13 1 3- {4- [2- (5-fluorenyl_2- Phenyl-Hexazole_4_yl) _Ethoxy] _phenylpropylamine-methylbenzyl-benzylfluorenyl) _aniline] _propionic acid methyl ester The target compound (70 mg) is from 190 mg (0.77 mmol) Mol) 4-propylamine and S-blue-phenylboronic acid and 300 mg (0.52 mmol) of intermediate 122 according to the method of intermediate 126, followed by silica gel chromatography with EtOAc / hexane (1: 2) Prepared as eluent for purification: low resolution Ms (ES) m / e 7〇4 (MNa +), 682 (MH +) = intermediate 132 2- [2- (3-Amino-; fluorenyl) _aniline] _3_ {4_ [2_ (5_methyl_2_phenyl_u # -4--4-yl) -ethoxy]- Phenylbutyrate propionate-91-This paper size applies to China National Standard (CNS) A4 (210X297 mm) -------- Φ —I (Please read the precautions on the back before filling this page ) Order A7 B7 V. Description of the invention (89) / ticket of compound (640 mg) is based on 400 mg (2 58 mmol) of 3-aminophenylboronic acid and 1.0 g (1.72 mmol) of intermediate 122 This method was prepared by silica gel chromatography using EtOAc / W (2: 3) as the eluent for purification: low resolution MS (ES) m / e 598 (MNa +), 576 (MH +). Intermediate〗 33 2 [2- (3-Methanesulfonamido_fluorenyl) _anilino] methylcardiol_phenyl-oxazolyl-4-yl) -ethoxy] _phenyl} _propyl Acid methyl ester soil, milliliter (0.78 millimolar) pyridine and 0.02 milliliter (〇29 millimolar) formazan, continual acid chloride and 150 mg (0.26 millimolar) intermediate body was added to / In a stirred solution of liter of methylene chloride. After warming to room temperature for 125 hours, the reaction was washed with saturated NaHC03 and water, the layers were separated, the organics (2 4) were dried and removed in the whole. The solvent was removed, and the residue was chromatographed with Acetyl acetate as Purification) was purified as an eluent to obtain 60 mg (35% yield) of the target compound: low-resolution MS (ES) m / e 6M (MH +). Intermediate 134 2_ [2; (3_methoxycarbonylamino_benzylfluorenyl) _anilino] _3_ {4_ Division-methylfluorenyl-phenylsulfonyl-4-yl) · ethoxy] -benzene Methyl} -propionate @ 65 ml (0.47 mmol) triethylamine was added to 180 mg (〇31 mmol of intermediate b2) in a stirred solution of 3 ml of dichloromethane. The solution was cooled to ^ 0_27 ml (〇34mmol) of methyl chloroformate. After warming to room temperature, the solvent was removed in Xinghuang and purified by silica gel chromatography using Et〇Ac / hexane (2: 3) as the eluent. The residue yielded 50 mg (25% yield) of the target 2 compound; low-resolution MS (ES) m / e 634 (MH +). -92- The paper size is suitable / i China A4 size (2) OX297 mm) (Please read the notes on the back before filling this page)

, 1T A7 B7

By: ^ Department ^ ^ ^ and ^ ^ elimination of the combination of bamboo ^ India fu 1_ body 135 2- [2- (3-methoxy-benzyl} -aniline] _3_ {4_ [2_ (5 _Methyl · 2_phenyl_ No. Jun-4-yl) -ethoxy] -phenyl "_Methyl acetate propionate compound (580 mg) is based on 480 mg (2.06 mmol) of 3-benzyl Oxyphenylboronic acid and 0.8 g (1.37 mmol) of intermediate 122 were removed from intermediate 126, followed by chromatographic chromatography with Et0Ac / hexane (gradient 3:17 to 1: 4) as the base The eluate was prepared by purification: low resolution Ms (fab) m / e 667 (MH +). ί-Μ 136 2 · [2- (3-Hydroxy-benzylfluorenylbenzylamino) _3] 4_ [2_ (5_methyl_2_phenylazine on 4-yl) -ethoxyl] _phenylpropyl 100 mg ((M5 mmol) of methyl acetate intermediate 135 in! 5 ml of a solution of EtOAc was evacuated and purged with argon. 110 mg (100% by weight) palladium / carbon (ι0%) was added In the mixture. The resulting slurry was evacuated and purged with argon. After stirring for 16 hours under 1 atmosphere of hydrogen, the reaction was filtered through a plug of nitrogen under a nitrogen stream. The organic phase was collected and the solvent was removed in Xing 2. The residue was purified by silica gel chromatography using EtOAc / hexanes (3.7) as the eluent to obtain 56 mg (3 7% yield) of the target compound: low resolution MS (FAB) m / e 577 (MH +) _ 少 间 体 132_ 2-I &gt; (3-Carbofluorenyloxy-benzylfluorenyl) _anilino] _3_ {4_ [2_ (5_methyl_2_phenylsulconazole_4_yl) _ethyl Oxy] -phenylphenylpropionate-8 g (0.19 mmol) of 6 0% NaH suspension was added at a temperature of 0.000 g (0.017 mol) ) Intermediate 136 was eliminated in 2 ml of a stirred solution of anhydrous THF for 15 minutes, and 24 mg (0.17 mmol) of 2-bromoacetamide was added to the slurry. , Diluted with water to room temperature and extracted with Et〇Ac -93- Zhang ⑽) A4 size (2iQx297 public clock -) - - ^^ clothes - (Please read the notes and then fill in the back of this page)

1T A7 B7 V. Description of the invention (91) Take. The layers were separated and the organics dried to a yellow tincture. Solid ^ i f⑹, and the solvent was removed in the air. Low shovel λ Β ′ Yuan milled 73 gram (66 ° / 〇 yield) target chemical: material. MS (ES) m / e 656 2 _ _ Intermediate 13 8) 3-Azido-4-oxo-valeric acid methyl ester 690 gram (1067 mol) sodium azide was added to the gram (1 °; 7 mmol) Monooxo-valeric acid methyl acetate was prepared in ηmL of acetic acid. After warming to room temperature for 2.5 hours, the reaction was diluted with water and diethyl ^ without L1). The 0 layer was separated, and the organic matter was dried (NaJCXO, and Yuxing The solvent was removed in 2. The residue was purified by gel chromatography with diethyl ether / hexane (gradient: .4 to 2_3) to obtain 107 g (58% yield) of the target compound: low-resolution MS (FAB) m / e 172 (mh +). Intermediate 139 3-Amino-4-oxo-propyl propionate ^ ,. {House mol 彡 intermediates 丨 published in "ml ^ ⑷ ^ solution was evacuated and washed with hydrogen 290 mg (30% by weight) of palladium / carbon (10%) was added to the solution. The resulting slurry was evacuated and flushed with hydrogen. Stirred under hydrogen for 4 hours and then reacted under a nitrogen stream and filtered through a plug of plastic. The organics were collected and the solvent was removed in 眞 ^ to obtain 94.0 mg (90% yield Yield) the target compound, which is used without further purification: low resolution Ms (ES) m / e M6 (μη +) t ^ J $ _U0_ 4-oxo-3-[(pyridine_4-carbonyl) -amino ] -Methyl valerate, 2.9 liters (20.72 mol) triethylamine was added to 0.90 mmol (5.18 mmol) of intermediate 13 at 0.9, and stirred in 5 2 ml of dichloromethane 94 This paper hates people to pass through Chinese National Standards (CNS) A4 specifications (210X 297 Gongchu (read the precautions on the back first and then fill out this page) -5 Available A7 B7 In the Ministry of Economics ^ Hit ^^ to eliminate &quot; Bamboo &quot; Yin · &quot;, V. Inventive Note (92). After stirring for 5 minutes, add 丨 0g (5 69 black hydrochloride and make the anti-reflection 3 ch, D Mao Wuer) It is different from the separation of the alkali chloride layer, and there is ^^. The dilution solution is diluted with water, the knife is dried, the organic matter is dried (M s04), and the fresh stone ㈣M is also removed in Xingyuan. The residual field物 猎 # Chromatography is based on Me◦Thief (the diluted compound of 360 mg (28% yield), the target compound _) 付 付 (MH +). Substance · Low Resolution MS㈣xn / e251 Intermediate 141 (5-methyl-2 -Pyridin-4-yl-oxazole_4_yl) _methyl acetate 0.28¾ Liters (3〇 蒡, · υ 毛 旲 ear) ρ〇α3 (fresh ampoules) was added to 25 mg (1.0 emole) intermediate just in 7 ml of anhydrous toluene solution and the reaction was heated to reflux 16 hours. After cooling to room temperature, the reaction was diluted and the organics were washed with saturated NaHC03, dried (MgS04), and the solvent was removed in the air. The residue was purified by Shijiao chromatography using Me0B080 (1:19 and 0.1% nH4 0h) as the eluent to obtain 180 mg (78% yield) of the target compound: low-resolution MS (ES) m / e 233 (MH +). Intermediate 142 2- (5-Methyl-2-eren-4-yl_p # jun_4_yl) _ethanol standard compound (200 mg) is from 285 mg (1 23 mmol) Intermediate 1 4 I was prepared according to the method of Intermediate 43 and then purified by silica gel column chromatography using MeOH / EtOAc (1.19) as the eluent: low-resolution Mg (es) m / e 205 (MH +). Intermediate 143 2 (s)-(2-N-SS-anilino) _3_ {4_ [2_ (5_methyl_2_pbidian_4_yl_p # -4--4-yl) -ethoxy] -Phenyl} -methyl propionate g-95 This paper is compliant with the national standard (CNS) A4 size (210X297 mm) of this paper (Please read the precautions on the back before filling this page) ij police uniform- ---- IT1 · A7 B7 I &quot; &quot; 丨 丨 _ I 1 1 · V. Description of the invention (93) (Please read the notes on the back before filling in the wooden page) The target compound (210 mg) is from 〇_ 15 g (0.73 mmol) of intermediate 142 and 0.27 g (0.73 mmol) of intermediate 23 according to the method of intermediate 44 followed by silica gel chromatography with EtOAc / hexane (gradient 1: 1 to 9: 1) ) Purified and prepared: low resolution MS (ES) m / e 562 (MH +). Intermediate 144 4-Third-butoxycarbonylhexamidine

The target compound (1-5 grams) is a method from 3.01 grams (16-91 millimoles) of the thiocarbonyl diweijun and 3.0 grams (16.12 millimoles) of the third-butoxycarbonyl-hexahydropyrhoyl intermediate 53, It was then purified by trituration with diethyl ether: low resolution MS (ES) m / e 246 (MH +). Intermediate 145 [5methyl-2- (4-Second-butoxycarbonyl-hexahydro-p-pyridine_ 丨 _yl) Secyl] · The compound of acetic acid acetate (h 18 g) is from 1.2 g ( 4.89 mmol) intermediate 144 and 1.02 g (4.89 mmol) of methyl 4-bromo-3-oxo-valerate according to the method of intermediate 60, followed by silica gel chromatography with MeOH / Digas methane (ι: 9) was prepared as a 'separated solution': low resolution MS (ES) m / e 35ό (MH +). Intermediate I4fi [fluorenyl 2- (4-second-butoxycarbonyl_hexahydro? Than _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ group _ _ _ _ _ _ _ _ group _ _ _ _ _ _ group _ _ _ _ _ _ _ _ group _ _ _ _ _ _ _ _ _ _ _ _) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __________ group which is the base of the compound 820 mg) is derived from 1.0 g (2.81 mmol) Intermediate 14 :) was prepared according to the method of Intermediate 43 and then purified by silica gel chromatography with Me0H / digas methane (1:19) as the eluent: low resolution ms 328 (M + H &quot;). This paper is suitable for scale-96-: A i &quot; in Part A: 41 · Λ 消 j '* 合 竹 卬 t A7 B7 V. Description of the invention (94) ί- 体 147 2 (S)-(2-爷Fluorenyl-aniline) -3-) (4- {2- [5-methyl-2- (4-third-butoxycarbonyl-hexahydropyridin-1-yl) -pyrazol-4-yl ] -Ethoxy} -phenyl) _methyl propionate The target compound (490 mg.) Is from 300 mg (0.92 mmol) of intermediate 146 and 330 mg (0.87 mmol) of intermediate 23 45 method, followed by silica gel chromatography and purification with MeOH / dichloromethane (1:49) as the eluent: low resolution MS (ES) m / e 707 (MNa +), 685 (MH +) intermediate 148 2 (S)-(2-benzylfluorenyl-aniline-methylhexahydropyridin-4-yl) -ethoxy] -phenylbutyric acid methyl ester · 1¾ liters of difluoro 65〇 mg of acid was added (ο ·% mmol) in. The grant 147 intermediate two liters of methane gas mixed solution of the pen 10. After stirring for 5 hours, the reaction was washed with water and saturated NaHC0. The layers were separated, the organics were dried (MgSO), and the agent was removed in a stand. The residue was purified by silica gel chromatography using MeOH / Et〇Ac (1: 4) as the eluent to obtain 176 mg (32% yield) of the target compound: low resolution MS (ES) m / e 607 (MNa +) , 585 (MH +). Intermediate 149 2 (s)-(2-Legenyl_anilinemethyl_2_ (4_methanesulfonyl-hexahydropyridin-1-yl)-, thiazolyl_4-yl] _ethoxy Benzyl phenyl) -methyl propionate 0.07 ml (0.87 mmol) pyridine and 025 ml (0 32 mmol) methyl formaldehyde was suffocated at zero. (: Add 170 mg (029 mmol) of intermediate 148 in a stirred solution of 3 * liters of dioxane. After warming to room temperature, the reaction was washed with water and saturated NaHCO. The layers were separated. Organic matter is dry and howling, and the paper is on-97- Chinese national standard 7 ^ 77 ^^ (21 () χϋ ^ 7 (Please read the notes on the back before filling in the reference page)

-Free, Ministry of Fire &quot; '^^, |,-^ 二 消 于 合 竹 &quot; 印 &quot; * A7 -_________—___ B7 V. Description of Invention (95) 移除 Remove the solvent from the air. The residue was purified by silica gel chromatography with EtoAc / hexane (2: 1) as the eluent to obtain 140 mg (74% yield) of the target compound: low resolution MS (ES) m / e 663 (MH +). Intermediate 150 2 (S)-(2- {4- [2- (5-methyl-2-phenyl-oxazole-4_ylethoxyphenyl group ^ methoxymethyl-ethylamino) -Methyl Arthroate aims to combine 350 mg (1.37 mmol, 1-10 equivalents) of triphenylphosphine, 395 mg (1-20 mmol) of Intermediate 127, and 29 mg (丨 32 mmol) of Intermediate 106 in A suspension of 10 ml of anhydrous toluene was heated to the ribs for 5 minutes to dissociate the intermediate 127 to obtain a transparent colorless solution. 25 mg (126 mmol, 1.05 equivalent) of diisopropyl azodicarboxylate was used for 5 minutes. This solution was added dropwise in minutes. The reaction was cooled and the mixture was stirred for 16 hours. The toluene was removed in the air, but the residue was vigorously stirred in 10 ml of a 1: 1 diethyl ether / N Li0H two-phase solution. 1 hour to selectively remove residual intermediate 12 7. The layers were separated and the organic layer was washed with EtOAc, dried (MgSO4), and the solvent was removed in the air. The material was subjected to silica gel flash column chromatography with hexane. / Et0Ac 5/1 was purified as an eluent to obtain 400 mg of the target compound as a white solid: low resolution MS (FAB) m / e53i (MH +). Intermediate 15 1 2 (sM2- {4- [2- (4- Gas-phenyl suifanyi) _ethoxy] _phenylbenzene 丨 · Methoxycarbonyl · ethylamino) -methyl benzyl ester (118 mg) is based on 100 mg (0.30 mmol) of intermediate 127 and 69 mg (0.36 mmol) of 2- (4-chlorobenzene) Thio) _ethanol according to the method of intermediate i50, followed by silica gel flash column chromatography with hexane / Et〇Ac 5/1-98- This paper is applicable to the national standard (CMS) A4 specification (2 * ι〇χ 297 公 俊) (Please read the notes on the back before filling this page) .Θ 装

1T A7 B7 V. Description of the invention (96) Prepared as eluent purification: low resolution MS (Fab) m / e 500 (M +). .J-body 152 2 (S) -2- {4- [2_ (5-nitro-2-pyridyloxy) -ethoxy] -phenyl} -i_methoxycarbonyl-ethylamino)- Methyl gallate standard compound (109 mg) is derived from 139 mg (0.754 mmol) of 2- (5-nitro-2-pyridyloxy) ethanol and 248 mg (0_754 mmol) of intermediate U7 The method was followed by purification by flash chromatography (2: 1 Hex: EtoAc): low-resolution MS m / e 496 (MH +). Interstitial body 153 2⑻- (2_ {4_ [2_ (5-Ga_2-p ratio s.ulfanyl) -ethoxy] -phenyl} -1-methoxycarbonyl-ethylamino) _Formaldehyde g The target compound (155 mg) is based on 156 mg (0 824 mmol) of 2- (5-Aceto-2-ylthio) ethanol and 27 μml (〇824 mmol) of intermediate 127 Method 150, followed by purification by flash chromatography (4: 1 Hex: EtoAc) to prepare 1H NMR (CDC13, 400 MHz) β 8.39 (d, 1H, 2.3), 8.19 (d, 1H), 7.89 (dd, 1H, J = 1.5, 8.0), 7.78 (d, 1H, J = 2.5), 7.45 (dd, 1H, J = 2.4, 8.5), 7.14 (d, 4H, J = 8.5), 6.86 (d , 2H, 8.5), 6.62 (t, 1H, 7.6), 6.54 (d, 1H, J = 8.4), 4.33 (q, 1H, J = 耔: &quot; · Shaozhong 1 夂 i? '^ X'J ,-;! T-elimination combination bamboo. ^ 卬 Ϊ -IG pack—I (read the precautions on the back and then write this page) 6-7), 4.19 (t5 2H, J-6.7), 3.85 ( s, 3H), 3.67 (s, 3H), 3.52 (t, 2H, J = 6.7), 3.12 (ddd, 2H, J = 5.4, 7.1, 7.1). Intermediate 154 2 (S)-(2- {4- [2_ (N_ethyl_2_methyl_tolylamino) _ethoxy] _phenylbenzene ^ methoxycarbonyl-ethylamino)- Methyl gallate standard compound (90 mg) is from α mg (0687 mmol) 2_ (N_ -99- this A-scale standard Shizhou National Standard (CNS) A4 specification (2 ^ 〇 &gt; &lt; 297 millimeters of trauma '^ &quot;-^^,-^5; / 1'synthetic bamboo perch A7 _____; _; ___________B7 V. Description of the invention (97) Ethyl-m-toluidine) ethanol And 226 mg (0 687 mmol) of intermediate 127 according to the method of intermediate 150, followed by purification by flash chromatography (4: 1 Hex: EtooAc): low-resolution MS m / e 491 (MH +) Intermediate 155 2 (S)-(2- {4- [2- (4-Dimethylamino-phenyl) _ethoxy] _phenylb] -methoxylyl-ethylamino) -Methyl acetate standard compound (290 mg) is from 110 mg (0.64 mmol) of 4- (dimethylamino) phenethyl alcohol and 200 mg (〇61 mmol) of intermediate 127 and intermediate 150 Method, followed by silica gel chromatography using triethylamine; valence hexane / hexane (1: 4: 15) as the eluent purification and preparation; low resolution (ES) m / e 499 (MNa +) 〇 156 2 (S)-[1-methoxycarbonyl · 2_ (4 „{2_ [5_fluorenyl_2_ (4_methyl-hexahydropyridine_butyl) -Hipjun-4-yl]- Ethoxyphenylethylamino] -benzoic acid methyl ester target compound (360 mg) is based on 187 mg (0.77 mmol) of intermediate 7 1 and 240 mg (〇_74 mmol) of intermediate 127 The method of volume 15 was prepared by silica gel chromatography using MeOH / EtOAc (1: 9) as the eluent. Low-resolution MS (ES) m / e 553 (MH +). Intermediate 157 ... 1 &quot; _ 2 (^)-(2- {4- [2- (4-chloro_phenyl) _ethoxy] _phenylbenzene 1_methoxysulfanyl_ethylamino) -formic acid @ Purpose target compound (230 mg) is from 500,000 mg 64 millimoles) 4-Gaphenethyl alcohol and 200 mg (0.61 millimoles) intermediate 127 according to the method of intermediate 150 followed by a silicone layer Analysis using Et0Ac / hexane (丨: 3 with TEA) as the solvent -100- This paper is suitable for size (CNS) 210x297 mm —— :: (Please read the precautions on the back before filling this page)

A7 A7 V. Ministry of Economic Affairs, IrifXJ ·. Only T- eliminates the combination of bamboo ii-yin, owe 'B7 Description of the invention (98: Xuan solution purification and preparation: low resolution MS (ES) m / e 49〇 (MNa + ), 468 (ΜΗ +) ο loyal "body 158 2- (4-trifluoromethoxy-phenyl) &gt; ethanol 9 ml (9.08 millimolar) 1 3113 but 1 ^ dropwise at 0. Joined 1.0

G (4.54 mmol) 4- (trifluoromethoxy) _phenylacetic acid in a 15 ml solution of anhydrous THF, and the reaction was warmed to room temperature! 6 hours. The mixture was cooled back to 0 ° F and the reaction was quenched with 15 ml of water / acetic acid / Thf (1: 1: 3). After warming to room temperature, the solvent was removed in the air, the residue was diluted with water and the solution was extracted with EtOAc. The layers were separated, the organics were washed with NaHC03, the layers were separated 'and the organics were dried (MgS04), and the solvent was removed in the air. The residue was purified by silica gel chromatography using EtOAc / hexane (1: 1) as the eluent to obtain 54 mg (57% yield) of the target compound: TLC-Ac / hexane (1: 1). R yielded 0.43 ° Intermediate 159 2 (S)-(1-methoxycarbonyl_2_ {4_ [2_ (4_trifluoromethoxy-phenylethoxybuphenyl} -ethylamino) -benzoic acid methyl ester target compound (280 mg) is based on 130 mg (0-64 mmol) of intermediate 158 and 200 mg (0.61 mmol) of intermediate 127 according to the method of intermediate 15, followed by silica gel chromatography with Et0Ac / hexane. (1: 3) was prepared as an eluent for purification: low resolution MS (ES) m / e 540 (MNa +). Intermediate 160 benzoxazole_2_yl_methylamino) _ethoxy] _ Benzylbenzene 3 _Hydroxy-3_ phenyl_2,3_dihydro-1Η-ρ thiophene [3,4-b] pyrrole-2carboxylic acid methyl ester 101 This paper is suitable for standard] China National Standards (CNS ) M size (210 &gt; &lt; 297mm) (Please read the precautions on the back before filling this page)

Better than the Ministry ^ iJ.iv-XJmT, Xiaoxian Hezhu it 卬; ^ A7 B7 V. Description of the invention (99) The target compound (100 mg) is from 198 mg (0.52 mmol) of intermediate 9 and 160 ¾ g (0.79¾ Mol) 2-Amino-3_benzylidene ruthenium (Hromatka, 〇 et al '1 \ / [〇1 ^ 511.〇 ^ 111.1973, 104 (6), 1513-19) The method of Intermediate 3 'followed by 1 to 5; / 〇 Et〇Ac's own entertainment: eluted and purified to prepare: low-resolution Ms (C1) m / e 556 (MH +). t-intermediate 161 3- (4-hydroxyphenyl) -2- (2- (4-diphenylcarbonyl) _aniline) _methyl propionate The target compound (830 mg) is from 83 g (57 mg) Mol) 〇_benzyl_ L-carbamate and 1.59 g (5.7 mmol) 2- (4-phenylbenzylfluorenyl) cyclohexanone (Child, RG et al., J. Pharm Sci 1977 , 66 (4), 466_76) were prepared according to the method of Intermediate 23, and then purified by silica gel chromatography with 1/9 EtoAc / hexane to elute: low-resolution MS (Cl) m / e 452 (MH +). Intermediate 162 3- {4- [2- (benzozazol_2_yl_fluorenylamino) _ethoxy] _phenylphenyl 2_ (2_ (4_diisopropyl) -aniline)- Methyl propionate adds 5 7 g of 80% NaH followed by 0.47 g (1.73 mmol) of 5 ml of DMF to intermediate D161 (; 0.78 g, 73 mmol) of DMF solution (5 ml) . Mix at 80. (: Stir down! 8 hours, quench with water (5 mL), concentrate to dryness, and extract from 30 mL of water with EtO Ac (3 × 30 mL). Dry the organics (MgSCU), concentrate, and chromatograph with silica gel and EtOAc / Hexane elution and purification to obtain 0.90 g of the target compound: low resolution MS (Cl) m / e 626 (MH +). Intermediate 163 3- (cardiohydroxyphenyl-2- (2- (4-methyl) Oxybenzyl) -aniline) _methyl propionate-102- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling in the clothing page)

好 浐 部 * ^ λ ^^^ 1, ί! -Τ ·; / ί 于 A 口 竹. ^-卬? i A7 --- ____________ ^ ___- 5. Description of the invention (10 () subject compound (2.31 g) is derived from 4.64 (20 mmol) 2- (4-methoxy-Si group) _cyclohexanone (Howard, AS et al., Tetrahedron Lett. 1979, (15), 1339-40) and 6.43 g (20 mmol) o-benzyl-L-carbamate hydrochloride as a yellow solid, such as the intermediate 61 Prepared as described: Low-resolution MS (Cl) m / e 406 (MH +). _ Intermediate 164 3- {4- [2- (benzoxazole_2_yl-methylamino) _ethoxy ] _Phenylb 2_ (2_ (4_fluorenyloxy) -anilino) -methyl propionate The target compound (0.34 g) is derived from intermediate 163 (0.5 g, 1.23 mmol) and the middle Body 6 (0.33 g, 1-23 mmol) was prepared as described above for intermediate 162: low resolution MS (Cl) m / e 581 (ΜΗ +). Intermediate 165 3- {4- [2- (benzopyrene) The azole_2-yl-methylamino) -ethoxy] -phenylbenzene 2- (2- (4-methylbenzyl) -aniline) -methyl propionate standard compound (8-10 mg) was obtained from 0.1%. 6 g (1.58 mmol) of intermediate 9 and 1.0 g (4.73 mmol) of 2-amino-4, -fluorenyldiphenyl ketone (Frye, SV et al. 'J. Org. Chem. 1991, 5 6 (11), 3750-52) According to the method of Intermediate 3 ', it was prepared by silica gel chromatography and purified by 30-50% EtOAc in hexane: low-resolution MS (ESP +) m / e 586 (M + Na +). Intermediate 166 3- {4- [2- (benzoxazol_2_yl-methylamino) _ethoxy] _phenylbenzene 2_ (2_ (2_methylamidino) -aniline)- The methyl propionate compound (800 mg) is derived from 628 mg (1.65 mmol) of intermediate 9 and 523 mg (2.48 mmol) of 2-amino-2, -methyldiphenyl ketone (Frye,- 103- The size of this paper is suitable for the National Standard (CMS) A4 (210X297mm) in Shizhou (Please read the precautions on the back before filling in this page)

A7 V. Description of the invention (10) 'SV et al., J. Org · Chem 1991, 56 (11), 3750-52) according to the intermediate 3 method, followed by silica gel chromatography, 20-40% EtoAc Prepared by hexane elution purification. · Low-resolution MS (Cl) m / e 564 (MH +). Examples Example 1 3- (4-Methoxy-phenyl) _2 (SH 丨 -methyl_3_oxo_3_phenyl-propenylamino) _ Dicyclohexylamine propionate 5.42 g (20¾ Mole) Stirred mixture of o-fycyl l-amino acid, 4.4 ml (22 mmol) of dicyclohexylamine and 3.24 g (20 mmol of benzylfluorenyl ethyl ketone) in 100 liters of MeOH Reflux for 24 hours. Then slowly add 500 ml of anhydrous ethyl ketone to the solution and distill MeOH from the reaction Erlenmeyer flask at the same rate. Then the solution is cooled to 0.0, stirred for 30 minutes, and then Filtered. The white solid was washed three times with 15 ml of cold (-20X) absolute ethanol and then dried to yield 7.60 g of the standard europium compound: iH NMR (; DMS0_d6, 400 MHz) 11.38 (d, 1H, J = 8.9) 7.76 (d, 2H , J = 5.8) 7.3 m (8H), 7.09 (d, 2H, J = 8.5), 6.84 (d, 2H, J = 8.5) 5.53 (s, 1H), 5.00 (s, 2H), 4.02 (m, 1H), 3.05 (dd, 1H, J = 4.4, 12.9) 2.93 (m, 2H), 2.76 (dd5 1H, J = 8.4, 13.7), 1.92 (m, 4H), 1.71 (s, 3H), l. 66 (called 4H), L53 (d, 2H, J-12.7), 1.2 (m, 8H), 1.03 m (2H); low resolution ⑽ (FAB +) m / e 597 (MH +), 182 (DCAH +); analysis値 (C3sH48N2〇4) Calculate 値 C, 76.47; H, 8.10; N, 4.69 Measured 値 C, 76.44; H, 8.16; N, 4.63. Example 2 3- (4-Benzyloxy-phenyl) _2 (S) _ (bumethyl _3_oxo_3_phenyl-acrylamido) _ Methyl Propionate-104- This paper is suitable for deducting the national solid standard (CNS) A4 (2) 0X297 mm) (please first W (Read the notes on the back and fill in the reference page)

A7 B7 &quot; · * _ 一-一 __ 5. Description of the invention (10 $ 0.37 ml (6 millimoles) methyl Qi is added to 2 98 grams (5 millimoles) at a time Example 1 and 1.50 grams (10.8 millimoles) Mol) Anhydrous potassium carbonate in 30 ml of a suspension of anhydrous dimethylformamidine. The mixture was stirred for 1 hour, then an additional 0.5 ml (8 mmol) of methyl iodide suspension was added and stirred for an additional minute. Then, it was diluted with 100 ml of ether. 100 ml of brine was added, and the phases were separated. The organic phase was extracted 6 times with 200 ml of brine, then the organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was flashed Chromatography (Si〇2, eluate ·· Hexane / Et0Ac (5: 1) and then hexane / Et〇Ac (ι ·· υ) 'yielded ι · 4 g of the target compound: 1HNMR (DMS〇_d6 , 400MHz) d Π.42 (d, 1H, J = 8.8) 7.80 (d, 2H, J = 6.6) 7.38 m (8H), 7.11 (d, 2H, J = 8_6), 6.90 (d, 2H, J2 8.5) 5.74 (vlH), 5.02 (s, 2H), 4.65 (m, 1H), 3.65 (s, 3H), 3.07 (dd, 1H, J = 5.3, 13.8) 2.96 (dd, 1H, J = 7.7, 13.9), 1.85 (s, 3H); low-resolution MS (ESP +) m / e 43〇 analysis 値 ((: 2? 1127 &gt; 104) Calculate 値 (:, 75.50;] 9,6_33; Team 3.26 Measured 値 C, 75.41; H, 6.35; N, 3.28. Example 3 2 (S)-(2-Benzylfluorenyl_cyclohexene _;! _ Amino group) _3_ (4_caroxy_phenyl) _dicyclohexylamine propionate 4rl.35 g (5 Mole) o-.fylyl l-carboxylic acid, 1.0 ml ( 5 mmol) dicyclohexylamine and 1.01 g (5 mmol) 2-benzylfluorenylcyclohexanone (Denny, William A .; Cain, Bruce F .; J, Med. Chem. (1978), 21 (5), 430-7) The stirred mixture in 25 ml of MeOH was refluxed for 24 hours ^, then the solution was cooled to 20 ° C, and the solvent was evaporated under reduced pressure. The residue was subjected to flash chromatography

Hexane / EtO Ac (1 __ 1), then EtOAc (pure), and finally CHCl3 / MeOH -105- ___ This paper size is suitable for 'standards (CNS) A4 size (210X297 km)' ~ (please 闳(Read the notes on the back and fill in the last page)

A 7 --______ B7 V. Description of the invention (10 ^ ~~~ d〇: i) Purified as an eluent to obtain ι_4 g of the target compound. 1HNMR (DMS0-d6, 400 MHz) ^ 12.00 (d, 1H, J = 8.4) j 7.3 (m, i〇H), (read the precautions on the back before filling this page) 7.b (d, 2H, J = 8.5), 6.85 (d, 2H, J = 8.5) 3 5_01 (s, 2H), 4,02 (m, called, 3.05 (m, 1H), 2.89 (m, 2H), 2.73 (dd, 1H, J = 8.5, 13.7), 2.25 (m, 1H), 2.03 (m, 3H), 1.93 (m, 3H), 1.66 (m, 3H), 1.53 ((2H, J = 12_3) , 1.30 (m, 2H), 1.20 (m, 12H) 3 103 m (; H); low resolution MS (ESP +) m / e 456 (MH +). Example 4 2- (2-benzylfluorenylanilide ) -3- (4-benzyloxyphenyl) propionic acid Add 500 mg (11.9 mmol) of lithium hydroxide monohydrate to 85 mg (〇_62 mmol) of intermediate 2 In 8 ml (1: 1; dioxane: water) solution. The resulting suspension was stirred at 50 ° C. for 1 hour and then cooled to room temperature. 1 M phosphoric acid solution was added until p Η was 5_5 to make the resulting suspension Extract with 080 (2 x 25 ml). Combine the organic extracts and dry (Mgs04), filter, and concentrate and chromatograph on silica gel with CHsCh / MeOH (9: 1) to yield 133 mg of the target compound. 1H NMR (CDC13) β 8.87 (bs, 1H), 7.60-7.58 ( d, 2H, J = 6), 7.94-7.32 m (10H), 7.23-7.21 (d, 2H, J = 3.9), 6.90-6.88 (m, 2H), 6.67-6.56 (m, 2H), 4.98 ( s, 2H), 4.39 (m, 1H), 3.30-3.10 (m, 2H); low resolution MS (FAB +) m / e (MH +) 452.1 〇 Example 5 3- (4-Methoxy-phenyl)- 2- (2-Benzyloxy-aniline) -propionate. 3 mg (0.0067. Mmol) of rhodium (II) acetate: 150 mg (0.50 mmol) of the polymer at 80 ° C. Moore) Intermediate 1 (.Kawamatsu, Y. et al., -106- The paper size is suitable for China National Standard (CNS) A4 specification (210X297 mm) A7 _____ B7 V. Description of the invention (104

Arzneim.-Forsch, 1980, 30 (4), 585-9) and 113 mg (0.50 mmol) of 2-amino-benzoic acid ethyl ester in a stirred solution of 5 ml of toluene. The mixture was allowed to stir at C for 5 minutes and then cooled to room temperature. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using hexadecane i / Et〇Ac. (_ 5: 1) as the eluent to produce 130 mg of the target compound 1H NMR (CDC13, 400 MHz) β 8.19 (d, 1H, J = 7.3), 7.95 (dd, 1H, J = 1.4, 7.9), 7.35 (m, ΠΗ), 7.12 (d, 2H, J = 8.5), 6.87 (d, 2H , J = 8.5), 6.60 (t, 1H, J = 7.5), 6.53 (d, 1H, J = 8.6), 5.30 (s, 2H), 5.01 (s, 2H), 4.32 (q, 1H, J = 6.4), 3.65 (s, 3H), 3.14 (dd, 1H, J = 6.0, 13.6), 3.08 (dd, 1H, J = 7.2, 13_7); low resolution MS (ESP +) m / e 496 (MH +). Example 6 3- (4- + oxy_phenyl) _2_ (phenylaminophenyl-anilino) _formamidine propionate The target compound is from 150 mg (0.50 millimolar) Intermediate 1 (Kawamatsu, Y · Et al., Arzneim.-Forsch, 1980, 30 (4), 585-9) and 10 mg (0.51 mmol) of 2-amino-benzidine aniline were prepared according to the method of Example 5: 1 H NMR ( CDC13, 400 ΜΗζ) β 7.83 (s, 1H), 7.66 (d, 1Η, J = 7.9), 7.54 (d, 2U, J = 8.0), 7.47 (d, 1H, J = 7.9), 7.35 (m, BH), 7.13 (m, 3H), 6.85 (d, 2H, J = 8.6), 6.68 (t, 1H, J = 7.5), 6.61 (d, 1H, J = 8.4), 4.96 (s, 2H), 4.30 (q, 1H, J = 7.2), 3.64 (s, 3H), 3.10 (m, 2H); low resolution MS (ESP +) m / e 481 (MH +). Example 7 3- (4-Benzyloxy-phenyl) -2- [2- (hexahydropyridine-1-carbonyl) -aniline] -propionic acid methyl ester The subject compound system (90 mg) from 150 mg (0.50 Millimoles) Intermediate 1 -107- This paper is suitable for / 1] Chinese National Standard (CNS) A4 (210X 297 mm) 1 1 ..... —II-H—:-I ϋ (Please First read the notes on the back and then fill out this page) Order 7 «-·; Central 4T. ^-^" = C Er Xiao Yu Zhu Zhuan 卬 A7 B7 V. Description of the invention (10 ^ (Kawamatsu, Y Et al., Arzneim.-Forsch, 1980, 30 (4), 585-9) and 103¾ g (0.50 mol) 2- (amino-phenyl) -hexahydropyridyl-methanone (Ahern, TP , Et al., Can. J. Chem. 1976, 54 (2), 290-6) Purified according to the method of Example 5 by silica gel flash chromatography with hexane / EtOAc (丨 :) as the eluent. 1H NMR (CDC13, 40MHz) J 7.40 (m, 5H), 7.21 (t, 1H, J = 8.2), 7.15 (m, 3H), 6.93 (d, 2H, J = 8.7), 6.73 (t , 1H, J = 7.4), 6.59 (d, 1H, J = 8.2), 5.21 (d (broad), 1H, J = 8.3), 5.06 (s, 2H), 4.30 (dd, 1H, J = 7.9, 8.8), 3.69 (s, 3H), 3.45 (m, 4H), 3.10 (m, 2H), 1.55 ( m, 6H); low resolution MS (ESP +) m / e 473 (MH +). Example 8 2- (3-fluorenyl-thien-2-yl-aminobenzyloxy_phenyl) _propionic acid will be 100 A solution of 1 g (1.78 mmol) of potassium hydroxide in 1 ml of water was added to a stirred solution of 120 ng (0.25 Φ Mor) of intermediate 3 in 10 ml of MeOH. The mixture was stirred at 20 ° C for 2 hours and then Adjust the pH = 2 with 5% aqueous hydrochloric acid. Add 50 ml of water to the mixture and extract three times with 20 ml of dichloromethane. Combine the organic phases, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure. The residue is flash-siliconized Chromatography was purified with Et0Ac (pure) and then EtOAc / EtOH (1: 1) solvent mixture as the eluent to obtain 27 mg of the target

Compound. 1 H NMR (DMSO-d6, 400 MHz) β .9.68 (d 1H J = 6.9), 7.45 (m, l〇H), 7.14 (d, 2H, J = 8.0), 6.86 (d, 2H, J = 8.0), 6.80 (d, 1H, J-5.6), 6.27 (d, 1H, J = 5.5), 5.03 (s, 2H), 3.80 (m, 1H), 3.23 (d, br, 1H, J = 9.0 ), 3.06 (d, 1H, J = 9.5); low resolution MS (ESP +) m / e 458 (MH +). -108- This paper size is deducted from Chinese National Standard (CNS) A4 (210X297mm) (Please read the precautions on the back before filling this page)

A7 A7 In the 7th part of the ^ &quot; ^ and; :: ;;-&quot; eliminate 4 'bamboo ^ India Su V. Description of the invention (an example 9 2- (2 卞 酉 S 基-口 塞芬 _3 -Its ha · ^,, mono-amino group) -3- (4-benzyloxy-phenyl) -propionic acid

A solution of tun jOO pen grams (5.05 millimoles) of potassium hydroxide in 2 ml of water was added to a stirred solution of 280 ¾ grams (0.59 ¾ mole) of intermediate 4 in 10 ml MeOH. The mixture was stirred at 2 ° C for 2 ° J, and then 50 ml of water, hexane: brine and 3 ml of acetic acid were added. The resulting emulsion was extracted three times with 2G ml of dichloromethane. The organic phases were combined and dried over anhydrous magnesium sulfate, It was then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using (pure), Eto-Ac / Eto-H (9: 1) and finally EtOH (pure) as eluent to obtain 90 mg of the 1H NMR (DMS0-d6, 400 MHz) ί 8_95 (d, 1 ，, J = 7.7), 7.62 (m, 3H), 7.45 (m, 3H), 7.30 (m, 5H), 7.09 (d , 2H, J = 8.4), 6.80 (d, 2h, J-8.2), 6.60 (d, 1H, J = 5.5), 4.96 (s, 2H), 4.05 (m, 1H), 3.13 (d, br, 1H, 1 = 11.8), 2.90 (dd, 1H, 1 = 1.6, 3.4); Analytical MS (ESP +) m / e 458 (MH +). Example 10 3- (4-Benzyloxy-phenyl) _2 (5 ) _ [(4_oxo_4H_phenylhydrazone0_piperan_3_carbonyl) _amino] -formyl propionate A few drops of DMF followed by 2 ml of grass gas in CH2Cl2 solution. Add 360 milligrams (2 millimoles) of Chromium _3_ meta-acid in 25 ml of CH2C12 stirred solution under r. Stir the resulting solution at room temperature for 3 hours and add 643 mg (2 millimoles) of o-benzyl -L-carboxylic acid methyl ester hydrogenate 0.2 g (2.0 mmol) of 15 mL of CH ^ Cl2 of triethylamine, and continuously stirred overnight. The solvent was removed under reduced pressure. The product was purified by LCC ^ S102 (hexane: EtOAc ^: 7) 83 mg of the target compound was obtained as a white solid: 1 H NMR (CDC13, -109- (CNS) A4im (210X297 ^ #) (Please read the precautions on the back before filling in the clothing page). For example, clothing-T mm 、- 0 A7 A7 Clip in the anger-free department ^ 1?-,,,;!-&Quot; Diminish in harmony ^ B7 V. Description of the invention (ioi 400 MHz) δ 9.77 (d, 1H, J = 7.3) 8.90 (s, 1H), 8.28 (dd, 1H, J = 8.1, J = 1.6) 7.74 (m, 1H), 7.54-7.26 (m, 8H), 7.14 (d, 1H, J = 8.5), 6.89 ( d, 1H, J = 8.5), 5.00 (s, 2H), 4.98-4.92 (m, 1H), 3.71 (s, 3H), 3.22-3.07 (m, 2H); low resolution MS (ES + (M + H ), 458; RP-HPLC (Dynamax C-8 25 cm X 4.1 mm; 50-90% CH3CN in H2O with 0.1% D? Eight buffers; 15 minutes; 2 ml / min): 1 ^ = 10.44 cm. Example 11 2- (2-Benzylfluorenyl-anilino) -3- {4_ [2- (methyl-pyridin-2-yl-amino) -ethoxy] -phenyl} propanoic acid will be 300 mg ( 0.57 mmol;) Intermediate 21 and 300 mg (5.2 mmol) of potassium hydroxide in 10 ml of a stirred solution of ethanol under reflux for 30 minutes. The yellow solution was cooled to 20 ° C, 0.3 ml (5.2 mmol) of acetic acid was added to the solution, and 30 ml of water was added dropwise. The mixture was stirred at 20 ° C for 30 minutes. The solid was filtered and washed three times with 20 ml of water to produce 180 mg of the target compound: 1 H NMR (DMSO-d6, 400 ΜΗζ) β 13.02 (s, 1H), 8_66 ( d, 1H, J = 7.5) 8.07 (d, 1H, J = 3.5), 7.45 m (8H), 7.11 (d, 2H, 1 = 8.2), 6.80 (m, 3H), 6.58 (m, 3H), 4.54 (m, 1H), 4.07 (t, 2H, J = 5.8), 3.87 (t, 2H, J = 5.7), 3.16 (dd, 1H, J = 5.5, 14.2) 3.05 (m, 4H); low resolution MS (ESP +) m / e 496 (MH +); Analytical 値 (C3OH29N304 1 / 2H2〇) Calculated 値 C, 71.41; H, 5.99; N, 8.33 Measured 値 C, 71.97; H, 5.98; N, 8.33 » Example 12 2 (S)-(2-fluorenyl-aniline) -3- {4- [2- (methyl-pyridin-2-yl-amino) _ethoxy] -phenyl} propanoic acid -110- The size of this paper is / 1] Chinese National Standard (CNS) A4 size (210X297mm) --------- 3 packs-C (Please read the precautions on the back before filling this page) Order ___ ____B7 V. Description of the invention (10 ^ Take 5_45 ml (5.45 mmol, 1.5 equivalents) lMLiOH at 0 ° C and then process 1.85 g (3.63 mmol) of intermediate 26 in 30 ml of THF 0 ml of water and 10 ml of MeOH. After warming to 25 ° F and stirring for 2 hours, the volatiles were removed under reduced pressure (&lt; 25 ° C). The residual aqueous layer was treated with EtOAc, acidified to pH 1 with 1 N HC1, and extracted with EtOAc. The organics were combined with浓缩 Concentrated in the air and triturated with EtOAc. Filtered to give 1.24 g of the target compound as a yellow solid. An additional 0.50 g (97% total yield) of the product was concentrated from the filtrate, triturated with EtOAc and filtered: 1 H NMR (DMSO -d6, 300 MHz) ά 13.04 (s, 1Η), 8.71 (d, 1H, J = 7.5), 8.11 (dd, 1H, J = 1.2, 5.1), 7.69-7.52 (m, 6H), 7.48 (t , 1H, J = 7.8), 7.41 (dd, 1H, J = 1.8, 8.0), 7.15 (d, 2H, J = 8.7), 7.73-6.81 (m, 3H), 6.75 (d, 1H, J = 8 7), 6.71-6.60 (m, 2H), 4.59 (m, 1H), 4.12 (t, 2H, J = 5.9), 3.93 (t, 2H, J = 5.9), 3.15 (m, 2H), 3.11 ( s, 3H); Low-resolution MS (Cl) m / e 518 (MNa +), 496 (MH +); Analyze 値 (C30H29N30.4. 0_8H2O) Calculate 値 c, 70.65; H, 6.05; N, 8.24 Measured 値 (: , 70.74; 15, 6.25; 1 ^, 7.92 · TLC (EtOAc / AcOH (99: l)): Rf = 〇.i3; SFC (chiralpak AD, 4.6 mm x 25 cm; 75% C02 / 25% MeOH with 0.1 % DEA; 35 minutes; 1 ml / min · 3000 psi, 40 ° C): tr = 24 .3 points (to = 3 points); &gt; 99% ee. Example 13 2- (2-Pentyl group_present amine group) _3_ {4_ [2- (methyl_ (1 ratio bite_2-yl_amino group) _ethoxy] -phenyl} propionic acid ethyl g The purpose is to mix 100 mg (0.19 mmol) of intermediate 21 and 100 mg (CD65 mmol) of I, 8-azabicyclo [5.4.〇] 11_7_ diluted in 5 ml of toluene Reflux the solution for 12 hours. The solvent was removed under reduced pressure, and the residue was flashed with silica gel-111-This paper size applies Chinese National Standard (CNS) A4 (210X297 mm A7 B7) V. Description of the invention (10 $ Distillation chromatography with hexane / EtOAc (4: 1) Purified to obtain 70 mg of the target compound: 1H NMR (CDC13, 400 MHz) 8.89 (d, 1H, J = 7.3), 8.12 (d, 1H, J = 4.9), 7.58 (d, 2H, J = 7.0), 7.45 (m, 5H), 7.31 (t, 1H, J = 7.0), 7.16 (d, 2H, J = 8.5), 6.80 (d, 2H, J = 8.5) 6.64 (d, 1H , J = 8.6), 6.50 (m, 2H), 4.35 (q, 1H, J = 6.3), 4.15 (m, 4H), 3.93 (t, 2H, J = 5.6), 3.16 (dd, 1H, J = 5.8, 13.5), 3_10 (s, 3H), 3.08 (m, 1H), 1.18 (t, 3H, J = 7.2); low resolution MS (ESP +) m / e 524 (MH +): TLC (hexane / EtOAc (4: 1)): Rf = 0.30). Example 14 2- (1-fluorenyl-3-oxo-: 3-phenyl-propenylamino) -3_ {4- [2- (methyl_p Biyodo_2_yl-amino) -ethoxy] -phenyl} -propionic acid dicyclohexylamine salt 105 mg (0.33 mmol) intermediate 22, 58.5 mg (0.36 mmol) 1-section Isopropylethyl g, 0.066 ml. (0.33 mmol) dicyclohexylamine was refluxed in 7 ml of M e 0 2 for 24 hours. 1 2 0 ml of absolute ethanol was added to the solution, and the MeOH-ethanol mixture was distilled from the conical flask under atmospheric pressure. When the remaining reaction volume was about 5 ml, the mixture was concentrated under reduced pressure. Then 3 ml was added at 0 ° C Anhydrous ether was in the residue, and the resulting slurry was stirred at -5 to 0 ° C for 30 minutes. The solid was filtered and washed three times with 5 ml of cold (-50 ° C) ether to obtain 105 mg of the target compound: !! η NMR_ '(CDC13, 400 MHz) (ί 11.58 (d, 1Η, J = 9.6), 8.11 (d, 1Η, J = 5.8) 7.79 (d, 2H, J = 7.9), 7_40 (m, 4H), 7.13 (d, 2H, J = 8.3), 6.75 (d, 2H, J = 8.5), 6.50 (m, 2H), 5.49 (s, 1H), 4.19 (dt, 1H, J = 3.5, 9.6), 4.10 (t, 2H, J = 5.7), 3.92 (t, 2H, 1 = 5.7), 3.27 (dd, 1H, J-3.4, 13.7), 3.l〇 (s, 3H), 2.97 (t (broad) , 2H, J = ll.l), 2.86 (dd, 1H, J = 9.6, 13.5) -112- The paper size is suitable for China National Standard (CNS) A4 specification (210X297 mm) ----: --- -9! (谙 Read the precautions on the back before filling this page),? Τ. 二 &quot; llrmfluui _EJ I.-? &Quot; '部 t-JA &quot; -iv-x'J,' Ji-T &quot; A ^ &quot; &quot; 卬 震 A7 --______ _—__ B7____ 5. Description of the invention (11 ^ ~! -96 (m? 4H), 1.71 (m, 4H), 1.57 (s, 3H), 1.54 (m, 2H), 1.35 (m, 4H), ι · ΐ2 (m, 6H); TLC (EtOH (neat)): Rf = 0.05); low resolution. MS (ESP +) m / e 460 (MH-DCA +), i 82 (DCAH +); analysis (C39H52N404) calculations 値c, 73.09; H, 8-18; N, 8.74 Measured 値 C, 73.07; H, 8.13; N, 8.72. 2- (1-methyl-3-oxo_3-phenyl-propenylamino) _3- {4_ [2- (methyl-pyridine-2-yl-amino) -ethoxy] -phenyl } _ The enantiomers of dicyclohexylamine propionate were separated by palm chromatography (method: SFC, column: Semi_Prep ChiralpakAD (25 x 2 cm), mobile phase: C02 / methanol 1% Et3NH) (75 : 25), flow: 5_0 ml / min, pressure: 300 psi, injection volume: 500 ml, temperature: 4 (TC, detector wavelength: 350 nM, injection volume: 15 mg) to obtain 4.7 mg (S) -2- (l-methyl-3-oxo_3-phenyl-propenylamino [2- (methyl-pyridin-2-yl-amino) _ethoxy] _phenyl } _Dicyclohexylamine propionate (1: temperature: 61.5 minutes) and 5.5 ml (R) _2- (l-methyl-3-oxo-3-phenyl-propenylamino) -3- {4 -[2- (fluorenyl-pyridin-2-yl-amino) -ethoxy] -phenyl} _cyclohexylamine propionate (room temperature: 69.8 minutes): 1H NMR (CDC13, 400 MHz) 11.76 (d, 1H, J = 8.9), 9.46 (s (broad), 2H), 8.11 (d, 1H, J = 4.2), 7.77 (d, 2H, J = 7.8), 7.40 (m, 2H), 7.37 (d, 2H, J = 7.5), 7.09 (d, 2H, J = 8.3), 6.75 (d, 2H, J = 8.2), 6.50 (m, 2H), 5.52 (s, 1H), 4.24 (m, 1H), 4.08 (t, 2H, J = 5.3), 3.92 (t, 2H, J = 5.4), 3.21 (m, 1H), 3.10 (s, 3H), 2.96 (m, 5H), 1.61 (s, 3H), 1.33 (m, 6H). Example 15 j- {4- [2- (Benzyin-2-yl-methyl-amino) · ethoxy] _phenyl} _2_ (2_ 芊 -113- not paper scale suitable state China Standard (CNS) A4 specification (210X297mm) (Read the precautions on the back before filling in this yellow)

The "呔" in the crotch &quot;-and ',]! 3 is less than the combination of bamboo and bamboo &quot; A7 B7 V. Description of the invention (11) fluorenyl-aniline) propionic acid-standard compound ... mg) is from 011 Grams (02 millimoles) of intermediate 10 and 0.11 grams (2_1 moles) of hydroxide but following the method of Example η followed by reverse-phase HPLC with acetonitrile / water (15% to 80% gradient over 0.05 hours) Prepared as a lysate for purification. 1Η NMR (acetone d6, 400MΗζ) $ 8 83 (melon, 1H), 7.55 (m, 3H), 7.48 (m, 2H), 7 38 (m, 2H), 7 24 (m, 4Η), 7 μm (m, 1H), 6.96 (m, 1H), 6.83 (m, 3H), 6.58 (t, 1H, JN7.7), 4.54 (m, 1H), 4.223 (t, 2H, J = 5.6), 3.91 (t, 2H, &gt; 5.5), 3.27 (s, 3H), 3.24 (m, 1H), 3.11 (m, 2H); low resolution Ms (FAB) m / e 536 (MH +); high resolution MS (FAB) 536.283 (MH +), C32H29N305 requires 536.2185; reverse phase HPLCtrUJ points, 1 ;. : 1477 points. Example 16 3- {4- [2- (Benzozazol-2-yl-methyl-amino) _ethoxy] _phenylbenzene 2_ (2_fluorenyl-aniline) propionic acid target compound (209 mg) was prepared from 234 g (0.43 mmol) of Intermediate 10 according to the method of Example 2 followed by preparation of 20 / hexanes: iH NMR (DMSO-d6, 300 MHz) δ 13.1 ( br s, 1H), 8.71 (d, 1H, J = 7.5), 7.68-7.36 (m, 8H), 7.32 (d, 1H, J = 7.2), 7.23-7.12 (m, 3H), 7.03 (dt, 1H, J-2.1, 7.7), 6.92-6.82 (m, 3H), 6.66 (t, 1H, J = 7.5), 4.58 (m, 1H), 4.23 (t, 2H, J = 5.4), 3.91 (t , 2H, J = 5.4), 3.25 (s, 3H), 3.15 (m, 2H); low-resolution MS (Cl) m / e 558 (MNa +), 536 (MH +); analysis (C32H29N30.5. 1.1 · 20 ) Calculated 値 C, 69.20; H, 5.66; N, 7.57 Measured 値 C, 69.45; H, 5.82; N, 7.18; TLC (EtOAc / MeOH (9: 1)): Rf = 0.23; HPLC (Chiralcel OD-H , 4.6 mm X 25 cm; 23% EtOH / -114- ___________________ This paper size is IKEA Standard (CNS—) A4 specification (210X297 cm i) (Please read the precautions on the back before filling this page)

A7 ---____ Β7 &quot; '― * __ ___ V. Description of the invention (4 already dry / 0.1% TFA; 45 points; 1 ml / min): tr = 9.3 points (t〇 = 3 points); & gt 94% ee. 3- {4- [2- (benzoxazole_2_yl_methyl-amino) _ethoxy] _phenyl} _2 (s) _ (1-methyl-3-oxo_3 _Phenyl-propanamido) _ Dicyclohexyl propionate The target compound is from 0.35 g (1.0 millimolar) of intermediate 8,022 ml (M millimolar) of dicyclohexylamine And 0-18 g (1 n millimolar) ^ benzamidine ethyl steel was prepared according to the method of Example 14: 1H NMR (DMS0-d6, 300 ΜΗζ) β η · 47 (d, 1Η, J = 8.9) 7.84 (m, 2H), 7.45 (m, 4H), 7.31 (d, 1H, J-7.5), 7.18 (m, 3H), 7.03 (t, 1H, J = 7.5), 6.86 (d, 2H, J = 8.3), 5- 6〇 (s, 1H), 4.25 (t, 2H, J = 4.9), 4.07 (m, 1H), 3.91 (t, 2H, J-4.8), 3.26 (s, 3H), 3.14 (dd, 1H, J = 4.3, 14.2), 3.01 (m, 2H), 2 81 (dd, 1H, J = 8.8, 13.7), 1.99 (s, 3H), 1.80-1.05 (m, 20 H); Low resolution MS (FAB +) m / e 500 (MH-DCA +), 182 (DCAH +) ° Example 18 3- {4- [2- (benzoxazol_2_yl-methyl_amino) _ethoxy Group] _phenyl} _2 (s) _ [3- (3-daily-phenyl) _ 丨 _fluorenyl_3_oxo-propylamino] -dicyclohexylamine propionate standard compound ( (370 mg) is derived from 0.35 g (1.0 mmol) of intermediate 8, 0.22 ml (ΐ · ιmmol) Cyclohexylamine and 〇29g (丨 〇mmol) 1- (3-iodo-phenyl) -butane-1,3-dione were prepared according to the method of Example 14: NMR (DMSO-d6, 300 MHz) d 11.48 (d, 1H, J = 8.9) 7.84 (m, 2H), 7.42 (d, 1H, J = 7.8), 7.20 (m, 4H), 7.03 (t, 1H, J-7.5), 6- 86 (m, 3H), 5.59 (s, 1H), 4.25 (t, 2H, J = 5.1), 4.08 (m, 1H), -115- This paper size applies to China National Standard (CNS) A4 specifications (210X 297 mm) (%) A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy and Economy V. Invention Description (113 ^ .92 (t, 2H, J = D.4), 3.27 (s, 3H), 3.15 (dd, 1H, J = 3.8, 13.4), 3.02 (m, 2H), 2.82 (dd, 1H, J = 8.8, 13.7), 2.00 (s, 3H), 1.80-1.10 (m, 20H); low resolution MS (FAB +) m / e 626 (MH_DCA +), 182 (DCAH +) 〇 Example 19 3- {4- [2- (Benzene molybdenum_2_yl · methyl_amino group K ethoxyphenyl group M · word Cishengji- 5-Methyl-aniline) -propionic acid target compound 5 mg is from 0.10 g (02 millimolar) intermediate 丨 丨 According to the method of Example 1 1 followed by reverse phase HPLC with acetonitrile / water (丨5% to 80% gradient over 0.5 hours) was prepared as a lysate purification: ιη ν · ㈣crypto, Paper) r8.61 (m, 1H), 7 55 (m, 3H), 7 48 (m, 2h), — 24 6H), 7.14 (m, 1H), 6.97 (m &gt; 1H), 6.79 (m, 3H), 4.50 (m, 1H), 4.23 2H3 1 = 5.6), 3.91 (t, 2H, J = 5.5); 3.27 (s, 3H), 3.23 (m, 1H), 3.09 (m, 2H), 2 ”2 (s, 3H); low-resolution MS (FAB) m / e 55〇 (mh +); high-resolution MS _) m / e 550.2349 _ +), QUA requires 55 ％; reverse phase HPLC tr = 22.4 points, t〇 = 2.2 points. Example 20 3- {4- [2- (Benzazine sulfonyl-2-methyl-amino group) _ethoxyphenyl group (fluorenyl_4-gas-aniline group) -propionic acid reaction is based on the drum After the wind is different. Add 2.4 mg (53 millimolar (II) dimer to 8 (TC) 0.20 g (0.5 亳 Mor π Α 毛毛 耳) intermediate 9 and .g (0.6 ¾ Mo) 2-amine -5-Gas diphenyl ketone in 10 ml of toluene in 2 solution. Nitrogen was immediately released from the reaction. The solution was heated for 2 hours and narrowed to a room temperature. The solvent was removed in the air. The residue was borrowed. The tomography is based on 116 paper sizes that are in accordance with Chinese National Standards (CNS) A4 specifications (2 丨 0 X 297 mm (#not the precautions on the back of the page before filling in this page)

A7 __________B7___ V. Description of Invention (114)

EtOAc / hexane (gradient 3: 7 to 6: 4) was purified as eluent. The purified residue was then taken up in 10 ml of ethanol and added with 100 g (20 mmol) of hydrogen peroxide. The resulting mixture was heated to 8 (rc for 2 hours. The solution was cooled to room temperature = 20 ml of water and diluted. Then glacial acetic acid was added dropwise to pH 5_6. The fork-colored precipitate was collected and washed with water and then with hexane. The solids were left under vacuum 4 Dry for 0.5 hours at 0 ° C and further purify by silica gel with MeOH / dichloromethane (1: 9) as eluent, collect the solid, and then recrystallize it from dichloromethane (containing 1% MeOH) to obtain 29.7 mg of the target compound: m nMR (DMSO-d6? 300 MHz). 8.52 (d, lHj J = 7.8) 7.56 (m, 5H), 7.45 (m, 1H) '7.35 (m, 1H), 7.25 (m, 2H), 7.10 (m, 3H), 6 97 (m, 1H), 6-88 (m, 1H), 6.78 (m, 2H), 4.55 (m, 1H), 4.15 (t5 2H5 J = 5 3 83 (t, 2H, J = 5_4), 3 ″ (s, 3H), 3.12 (m, 1H), 3 〇2 (m, m); low resolution ms (FAB) m / e 570 (MH +); reverse phase HPLC tr = 8.0min; IR (Kbr pelle〇 = 96, not 1649, i633 cm-1; analysis of C32h28N3 05C1), calculated, C, 67, 43%, H, 4.95%, N, 7.37%. Found 値 c, 67 36%, H, 4.95%, N, 7.35%. Example 21 3- [4- (l-Benzoxazole_2_yl_pyrrolidinyloxy) _phenyl] _2_ (2_benzylfluorenyl-aniline )-Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Propionic Acids --------- Packing-a # first ^ read the back of the book and fill in this page) will be 10 mg (0.23 mmol) , 1.0 equivalent) lithium hydroxide was added to 130 mg (0.23 * mole) of intermediate 34 in a solution of 3 ml of dioxane and 3 ml of h20. The resulting solution was stirred at room temperature! 2 hours and then acidified to 2. Pour the reaction mixture into 50 mL £ t0Ac and wash with brine (丨 χ 丨 mL). The organic phase is separated, dried (MgS04), and dissolved in the air -117- This paper is for China National Standards (CNS) A4 Specification (210X297 mm) After the Ministry of M &A; &quot; ^ Λ,-&quot; -1 · &quot; ^ &quot; &quot; '^ &quot; &quot;' A7 ________'_________ B7__ V. Invention Explanation (Today's reagent ° C was purified by gel column flash chromatography with D cm / MeOH / HOAc 9/1 / 0.1 as the solution to obtain I27 mg of the target compound: m NMR (d6-DMS0, 400 MHz) d 8.56 (d , 1H, J = 7.5), 7.52 (m, 5H), 7.40 (m, 4H), 7.25 (d, 2H, J = 7.7) s 7.13 (d, 2H, J = 7.0), 6.99 (m, 1H) , 6.86 (m, 2H), 6.61 (m, 1H), 5.10 (bs, 1H), 4.54 (bs, 1H), 3 .76 (bm5 4H), 3.15 (m, 2H), 2.25 (m, 2H); low resolution (£ 8?) 111 / ^ 548.0 (1 ^ +). 11? -HPLC (Vydac C-18, 25 cm x 4.6 mm; 10-90% CH3CN in H2O with 0.1% TFA buffer; 25 points; 1 ml / min); ^ = 13 46 points (t〇 = 3 Minute). Example 22 3- [4- (l-benzoxazol_2_yl) _pyrrolidin_2Ryl_methoxy) _phenyl] _2_ (2_benzyl-aniline) _propionic acid 'underlying compound (15 mg) was prepared from 0.17 g (0.30 mil) of Intermediate 31 according to the method of Example 12: m NMR (DMSO-d6, 300 MHz) d 8.72 (d, 1H, J = 7.2), 7.68 -7.32 (m, 9Η), 7.25-7 · 14 (m, 3H), 7 〇7 (t, m, J = 7.2), 6.97-6.85 (m, 3H), 6.66 (t, 1H, J = 7.5 ), 4.60 (m, iH), 4.39 (m, 1H), 4.20 (dd, 1H, J = 3_5, 9.2), 4.07 (dd, 1H, j = 7.5, 9 2), 3 80_ 3.40 (m, 2H ), 3_16 (m, 2H), 2.24_198 (m, 4H); low resolution ms (es) m / e 562 (M +); TLC (EtOAc) / MeOH (9: 1)): R 34. Example 23; 3- {4- [l- (benzoxazol_2_yl) _pyrrolidine _ ^ _ yl_fluorenyloxy] · phenylbenzene 2_ (2-fluorenyl_aniline) _propyl The acid earth standard compound (2.14 g) was prepared from 2 26 g (3 93 mmol) of the intermediate W according to the method of Example 12, followed by purification by hexane / Et20 milling: -118- CNS) A4 size (210X297mm) '------- .. (Please read the notes on the back before filling this page}

A7 B7 V. Description of the invention (116) 1H NMR (DMS0-d6, 300 MHz) ^ 8.72 (d, 1H, J = 7.2), 7.68-7.32 (m, 9H), 7.25-7.13 (m, 3H), 7.06 (t, 1H, j = 7.7), 6.98-6.86 (m, 3H), 6.67 (t, 1H, J = 7.8), 4.60 (m, 1H), 4.39 (m, 1H), 4.27-4.14 (m, 1H), 4.07 (dd, 1H, J = 7.5, 9.0), 3.82-3.40 (m, 2H), 3.16 (M, 2H), 2.30-1_98 (M, 4H); low resolution MS (ES) m / e 562 (M +); Analyze 値 (C34H31N305.0.9 H20) Calculate 値 c, 70.67; H, 5.72; N, 7.27 Measured 値 C, 70.65; H, 6.01; N, 7.28; TLC (EtOAc / MeOH (9: 1) ): Rf = 0.31; RP-HPLC (C-18, 4.6 mm X 25 cm; 50-100% Ch3CH in H20 with 0.1% TFA; 30%; q ml / min) ': tr = 10.6 points (t〇 = 3 points). Example 24 3- {4- [2- (benzoxazol_2_yl-methyl_amino) _ethoxy] _phenyl} _2_ (2-cyclohexyl-2-yl-phenylaminopropionic acid The target compound (44 g) was obtained from 61 mg (〇 丨 丨 mmol) of intermediate 1 2 according to the method of Example 21 1 followed by column chromatography on a silica gel column with d cm /

MeOH 9/1 was prepared as the eluent for purification: a NMR (CDC13, 400 MHz) ^ 9.36 (d, 1H, J = 6.1), 7.81 (d, 1H, J = 7.8), 7.26 (m5 6H), 7.02 (m, 1H), 6.70 (bm, 4H), 4.23 (m, 3H), 3.91 (m, 2H), 3.25 (s, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (read the precautions on the back before reading) Fill in this page) 3H), 乂 16 (m, 2H), 1_5 (bm, 11H); low resolution MS (API) m / e 542.3 (MH +), RP-HPLC (Vydac C-18 · '25 cm x 4.6 Mm; i0_90% CH3CN in H20 with 0.1% TFA buffer; 25 points; j ml / min); tr = 14.51 points (tQ = 3 points). Example 25 3- {4- [2- (Benzhumazol-2-yl-fluorenyl-amino) _ethoxy] _phenylbenzene 2_ (2_ -119- This paper size applies to the Chinese National Standard (CNS ) A4 specification (210X297 mm) 5. Description of the invention (117 A7 B7 ¾ Printed by the Consumer Cooperative of the Central Bureau of Justice of the Ministry of Economic Affairs + Coupling-p-phenphen-3-ylamino group) _propionic acid standard compound (44 mg ) Was prepared from 113 mg (0200 mmol) of intermediate 13 according to the method of Example 21 and purified by hair gel flash column chromatography with D cm / Me0H 19/1 as the eluent: m NMR (CD% Exactly w 8.98 (d, 1H, 1 ^ 7.6), 7.77 (d, 2H, J = 7.4), 7.42 (m, 5H) 3 7.15 (m, 4H), 7.00 (m, 1H), 6.81 (m, 2H) 5 6.61 (ms 1H), 4.37 (ln, 1Ηχ 4.16 (m, 2H), 3.87 (m, 2H), 3.24 (s, 3H), 3 2〇 (m, 2H); low resolution ms (API-1 ) M / e 542.2 (MH +); Rp_HpLC (Vydac c_i8, μ cm x 4 · 6 milli ^ 10_90% CH3CN in 〇i% tfa buffer solution; μ knife, 1 pen / min); tr = 12.60 points (T0 = 3 points). Example 26 3- {4- [2- (Benzobenzo_2_yl-methyl_amino) _ethoxy] -phenyl} _2-octyl-propionate Fluoroethyl 'will be 9.8 mg (0.4085 millimoles, 20%). Amount) uOH was added 90 mg (0.2042 millimoles) of intermediate at room temperature 5 in a stirred solution of 20 ml of THF: H2O mixture. The resulting solution was stirred at 60 τ for 19 hours' It was then extracted with EtOAc. The aqueous layer was acidified with On HC1 and extracted with EtOAc. The organic layer was dried (MgSat) and removed in the air. Reverse phase HPLC was prepared using 15-80% CH3CN / H20 with 1% ΤΤΛ solution. Purified as an eluent to obtain 87.3 mg of the target compound as a white non- "solid: 1H NMR (CD3OC, 300 ΜΗζ) ί 7.44 (d, 1H, J = 8.0), (d, 1H, J = 7.7), 7.31 (t, 1H, J = 7.7), 7.26-7.14 (m, 6H), 7.07 2H, J = 8.5), 6.80 (d, 2H, J = 8.5), 4.28 (t, 2H, J-5.1), 4.02 (t, • ^ 5 · 1), 3.37 (s, 3H), 2.90 · 2 · 69 (m, 5H); low-resolution MS (ES) m / e mixed with 00 (d, 2H, 429 ; ❹Private Book II (谙 Please read the notes on the back before filling in this page) -120-This paper size relative towel (CNS) A4 specification (210X297 mm 86102826 patent application ___ ^ Chinese manual amendment Page (10 ~ B in 88; ---) V. Description of the invention (118) I read and write 'month q W'lnrr— (MH); High Resolution MS (FAB) m / e c26h27N2 04: Calculated value 431.1938; Measured value 431.1965 (^ «1+); that is, Book 1 ^ (〇711 Please ^ 60A C-18 83-201- C, 25 cm x 4.6 mm; 15-80% CH3CH in H20 with 0.1% TFA buffer, 30 minutes; 15 ml / minute): tr = 18.7 minutes (t0 = 1.7 minutes). Example 27 3- {4- [2- (Benzoxazol-2-yl-methyl-amino) _ethoxy] _phenyl} _2_ (2_bromo-benzyl) -trifluoroethyl propionate The ester-labeled compound (31 mg) was obtained from 5 1.9 mg (0.099 1 mmol) of intermediate 16 according to the method of Example 2.6 followed by preparative reverse phase HPLC with 15-80% CHsCN / E ^ O with 1% TFA. Buffer was prepared as an eluent for purification: m NMR (CD3OD, 300 MHz) 5 7.51 (d, 1H, J = 7.9), 7.44 (d, 1H, J-8.0), 7.37-7.33 (m, 2H), 7.31-7.18 (m, 3H), 7.11-7.06 (m, 3H), 6.81 (d, 2H, J = 8.5), 4.29 (t, 2H, J = 5.1), 4.02 (t, 2H, J = 5.1) , 3.37 (s, 3H), 3.02-2.88 (m, 4H), 2.76-2.71 (m, 1H); low resolution MS (ES) m / e 507 (MH); high resolution MS (FAB) m / e C26H26BrN204: Calculated 509.1075; Found 509.1085 (MH +); RP-HPLC (Dynamax-60A C-18 83-201-C, 25 cm x 4-6 mm; 15-80% CH3CH in H20 with 0.1% TFA buffer solution; 30 points 1.5 ml / min): tr = 20.8 points (t0 = 1.8 points). Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 28 3- {4- [2- (Benzhumazol-2-yl-methyl-amino) -ethoxy] _phenyl} _2 (s) _ [4-Oxo-4H-benzo / 5-sulfan-3-yl) -amino] -propionic acid will be 990 mg (3.0 mmol) N-fluorenyloxy-L-carboxylic acid Methyl of it! 〇-121-This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) A7 B7 V. Description of the invention (（liter DMF is added with 12 mg 60% NaH under TC and stirred in 10 ml DMF The resulting mixture was stirred until clear. Then 10 ml of n_ (2 _ [(N-methylamineethyl-methylsulfonate) ^-benzoxazole 810 mg (30 pen moles) was added. DMF. The solvent was removed under reduced pressure, the residue was dissolved in EtOAc and washed with IN HC1, saturated NaHCOyJc solution and water. EtoAc was evaporated to give 300 mg of a yellow oil (MS (ES +) (M + H = 5 〇4). The oil was redissolved in EtOAc, 50 mg of 10% Pd / C was added and the reaction mixture was hydrogenated at atmospheric pressure overnight. The catalyst was filtered and the solvent was evaporated to give 90 mg of amine vinegar as a yellow oil, which can be used without further Purified for use. A few drops of DMf followed by 0.25 ml of 2 M chloracetone in CK ^ Cl2 solution at 90 ° C was added with 90 mg (0.5 mmol) chromone-3-carboxylic acid in 15 ml CH2C12 in a stirred solution. The resulting solution was stirred at room temperature for 3 hours and 190 mg (0.5 mmol) of the previously prepared amine ester and 50 mg (0.5 mmol) Moore) 15 ml of CH2C12 triethylamine was poured in continuously and stirred overnight. The solvent was removed under reduced pressure and the residue was dissolved in a mixture of THF and water, and 1 N NaOH was added and the mixture was stirred for 3 hours. Add 30 mg (0.5 mmol) of acetic acid and remove the solvent under reduced pressure. The crude material was purified by RP preparative HPLC to obtain 11 mg of the target compound: 1H NMR (CDC13, 400 MHz) d 9.92 (d, 1H, J = 7.5), 8.85 (s 1H), 8.24-8.20 (m, 1H), 7.80-7.72 (mlH), 7.63-7.28 (m, 6H), 7.18 (d, 1H, J = 8.6), 6.88 (d, 1H, J = 8.6), 4.98-4.88 〇, 1H), 4.26-3.92 (m, 4H), 3_42 (s, 3H), 3.33-3.12. (m, 2H), low resolution Ms (ES +) (M + H +), 528; RP-HPLC (Dynamax C-8 25 cm x 4 ″ mm; 50-90% CH3CN in H20 with 0.1% TFA buffer; 15 points; 2 ml / min.): Tr = 3 _20 points. -122- This paper size is suitable for China National Standard (CNS) A4 specification (210X297mm) ~~~~ <Please read the precautions on the back before filling in &quot; this page)

A7 B7 V. Explanation of the invention (120) Example 29 2 (S)-(2-benzyl-anilino) _3_ {4_ [2 · (5_methyl_2_phenyl-crazy-4-yl) -Ethoxy] -phenyl} -bisacid. 0.21 g (0.37 mmol) of intermediate 3 5 in 20 ml of a 6: 4 THF: water solution at 13 mg (0.56 mmol); 15 equivalents) LiOH. After stirring at room temperature for 3 hours, tLC (Si02; 7: 3 hexane: EtOAc) showed a large amount of starting material at Rf = 0.5 and a major new component at the origin. The solution was treated with another 6 mg of LiOH and stirred for another 2 hours, at which point TLC showed no residual starting material. The solution was neutralized by adding 1 ml of 1 N aqueous HC1 and it was rotary evaporated to remove THF. A yellow mixture was obtained, which was extracted with CHCI3 (3 × 20 ml). The combined extract was washed with water (3 × 50 ml), dried with MgSCU, and concentrated in the air to obtain 0.20 g (99〇 / 〇) of the target compound as a yellow foam: melting point 85-9. (^; 出 _ ^ 1 ^ foot (〇1 ^ 0-d6, 200 MHz) ά 8.66 (d 1H, J = 7.8), 7.91 (m, 2H), 7.64-7.33 (m, 10H), 7.13 (d , 2H, J = 8.3), 6.82 (m, 3H), 6.62 (t, 1H, J = 7.5), 4.54 (m, 1H), 4.15 (t, 2H, J = 6.5), 3.10 (m, 2H) , 2.90 (t '2H, J = 6.5), 2_34 (s, 3H); low-resolution MS (ES) _ 547 (MH +)' analysis 値 (C34H3 () N205_0.3.H2〇) to calculate 値 c, 73.98; H, 5.59; N, 5.07 Measured 値 C, 73,91; H, 5.62; N, 5.00; TLC (CH2C12 / Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs I -------- Q Pack —I (Read the first note on the back, then fill out this page)

MeOH (95: 5)): Rf = 0.49. Example 3 0 2- (2-word Si-anilino) _3_ {4_ [2_ (4_chlorophenyl) _oxazole_4_ylmethoxy] -phenyl 丨 -propionic acid compound (1 :> 4 pens) are from 200 mg (〇34mmol) Intermediate-123 · This paper size is applicable to China National Standard Rate (CNS) A4 ^ grid (2 丨 〇X 297 public holiday- &Quot; ---- Employees' cooperatives of the Central Bureau of Standards of the Ministry of Economy printed A7 B7 jade, invention description (121 3 6 according to the method of Example 12 and then prepared by acetonitrile / gasoline 1: 1 in the production process : 1H NMR (CDC13, 300 ΜΗζ) β 8.82 (d, 1H, J = 6.2), 7.87 (dd, 2H, J = 1.9, 6.8), 7.61-7.24 (τη, 13H), 6.93 (d, 2H , J = 8.6), 6.64 (m, 2H), 5.18 (s, 2H), 4.39 (m, 1H), 3.21 (m, 2H); low resolution Ms (FAB) m / e 572 (MH ++ 2), 571 (MH ++ 1), 570 (MH +), 569 (M +); Analyze 値 (C32H25C1N204S) Calculate 値 C, 67.54; H, 4.43; N, 4.92, Measured 値 C, 67.36; H, 4.51; N, 4.90. Example 3 1 3- [4- (2- (benzimidazol-1-yl-ethoxy) _phenyl] -2- (2-benzylfluorenyl-aniline) -propionic acid target compound (58 mg) From 90 mg (0.17 mmol) Intermediate 40 by example 1 2 method, followed by EtOAc milling purification and reverse phase MPLC purification using C_ i 8 column and acetonitrile / H2 03/2 as eluent: 1H NMR (CDC13, 300 MHz) d 8_72 (d , 1H, J = 7.0), 8.30 〇, br, 1H), 7.73-7.13 (m, 14H), 6.81 (m, 2H), 6.62 (dd, 1H, J = 7.5, 7.5), 4.65 (t, 2H , J = 5.1), 4.47 (s, br, 1H), 4.31 (t, 2H, J = 5_l), 3.11 (m, 2H); low resolution MS (Cl) m / e 506 (MH +), 460, 281 145; High-resolution MS (C31H27N304) calculated 値 506.2080, found 値 506.2091. Example 32 2 (S)-(2-fluorenyl-aniline) _3_ {4- [2_ (5-methyl_2- (4-methyl (Oxyl) -phenyl-azir-4-yl &gt; ethoxy] -phenylpropanoic acid 0.5 ml (0.50 mmol, L6 equivalent) of a solution of 丨 OM LiOHsH2O at room temperature Next, 190 mg (032 mmol) of intermediate 44 was added to 7 ml of a stirred solution of THF / MeOH / j ^ O (6: 0.1: 1). The resulting solution is applied to -124 private paper scales in accordance with Chinese National Standards (CNS) A4 specifications (210X297 mm (#xianwen read the notes on the back before filling this page)

Produced by the Consumer Standards Department of the Central Bureau of Economics, printed by Du A7 B7 V. Description of the invention (122) Stir at main temperature for 18 hours, then pour into 50 ml of EtOAc and extract with 1N HC1 (2x50 ml). The organic layer was separated, dried (MgS04), and the solvent was removed in the air. The yellow solid was triturated in EtOAc / diethyl ether 1: 1 and purified by vacuum filtration and dried in the air to obtain 96 mg of the target compound as a yellow amorphous solid: 1H NMR (DMSO-d6, 400 MHz) d 8.62 d , 1H, J = 7.5), 7.81 (d, 2H, J = 8.8), 7.52 (m, 5H), 7.40 (dd, 1H, J = 7.7, 7.7), 7.33 (d, 1H, J = 7.7), 7.09 (d, 2H, J = 8.6), 7.02 (d, 2H, J = 8.8), 6.80 (m, 3H), 6.59 (dd, 1H, J = 7.5, 7.5), 4.50 (m, 1H), 4.10 (t, 2H, J = 6.6), 3.79 (s, 3H), 3.11 (dd, 1H, J = 5.3, 13.8), 3.01 (dd, 1H, J = 6.5, 13.8), 2.83 (t, 2H, J = 6.6), 2.28 (s, 3H); low resolution MS (FAB) m / e 578 (MH +), 577 (M +); RP-HPLC (Dynamax C-8 25 cm x 4_1 mm; 30-80% CH3CNKH2. Its 0.1% TFA buffer solution; 30 minutes; 1 ml / min): tr = 25_59 points; Analytical tritium (C35H32N2〇6) Calculated value C, 72.90; Tritium, 5_59; N, 4_86, Found 値 c, 72.78; H, 5.55; N, 4.83 〇 Example 33 2 (S)-(2-benzylfluorenyl-aniline) _3- {4- [2- (5-methyl-2- (4-fluoro) -phenyl · ·· Ling-4-yl) -ethoxy] -phenylpropanoic acid (205 mg) was derived from 280 mg (0.48 mmol) Ear) Intermediate 4 7 and 0.73 ml (0.73 mmol, 1-5 equivalents) of a solution of LiOH in H20 was prepared according to the method of Example 32: iH NMR (DMSO-d6, 400 MHz) δ 8.62 (d , 1Η, J = 7.6) 7.93 (dd, 2H, J = 5.4, 8.7), 7.50 (m, 4H), 7.31 (m, 3H), 7.09 (d, 2H, J = 8.5), 6.80 (m, 3H ), 6.59 (dd, 1H, J = 8.5, 8.5), 4.50 (m, 1H), 4.11 (t, 2H, J = 6.6), 3.11 (dd, 1H, J = 5.3, -125- This paper size applies China National Standard (CNS) A4 size (210x297 metric) (read the precautions on the back first, then fill in this purchase), βτ A7 A7: Part A in the wood? J'l • τ elimination f: together η printed B7 five Description of the invention (, 13-9), 3.02 (dd, 1H, J = 6.5, 13.9), 2.85 (t, 2H, 1 = 6.6), 2.29 (s, 3H); low resolution MS (FAB) m / e 566 (MH +), 566 (M +); RP-HPLC (Dynamax C-8 25 cm x 4.1 mm; 50-100% CH3CN in H20 with 0.1% TFA buffer; 30 minutes; 1 ml / minute): tr = 17.58 points; Analyze 値 (C34H29FN205) Calculate 値 C, 72.33; H, 5.18; N, 4.96, Measured 値 C, 72_24; H, 5.23; N, 4.89 ° Example 34 2 (S)-(2-fluorenyl -Anilino) -3- {4- [2- (5-methyl-2- (5- -Pyrimidin-2-yl) -oxazole-4-yl) -ethoxy] -phenyl} -propionic acid (297 mg) was obtained from 440 mg (0.76 mmol) of intermediates 111 and 1.10 A solution of 1_0 M UOH in H20 (1.10 millimoles, 1.5 equivalents) was prepared according to the method of Example 32: 1H NMR (DMSO-d6, 400 MHz) d 8 70 (d, 1H, JN7.5) 7.65 -7.40 (m, 9H), 7.18 (d, 2H, 6), 6.89 (m, 4H), 6.66 (dd, 1H, J = 7.5, 7.5), 4.58 (m, 1H), 4.15 (t, 2H, J = 6.6); 3.20 (dd, 1H, J = 5.4, 14.0), 3.08 (dd, 1H, J = 6.5, 14.0), 2.89 (t, 2H, J = 6.6), 2.54 (s, 3H), 2.33 (s, 3H); Low Resolution MS (FAB) m / e 568 (MH +), 567 (M +); RP-HPLC (Dynamax C-8 25 cm &gt; &lt; 4.1 mm; 30-80% 〇 ^ 3 ( : 11 in 1120 with 0.1% D? Eight buffers; 30 minutes; 1 ml / minute): v = 27.70 minutes; Analyze 値 (C33H30N2O5S) Calculate 値 C, 69.95; H, 5.34; N, 4.94, Measured 値 C, 69.31; H, 5.37; N, 4.91 ° Example 35 2 (S)-(2-benzylfluorenyl-aniline) _3- {4- [2- (5-fluorenyl-1-phenyl-1H-pyrazol-3-yl) -ethoxy Base] -phenyl} -propionic acid 126 The paper size is in the state of China (CNS) A4 specification (210X297 mm) (read first, read the precautions on the back, then fill out this page)

A7 B7 V. Description of the invention (Mb compound (74 g) is from 1000 mg (〇 丨 8mmol) of intermediate 49 and 0.27¾ liters (0.27¾ Mol., 1.5 equivalents) ^ jyj [The solution of LiOH in H20 was prepared according to the method of Example 32: iH NMR (DMSO-d6, 400 MHz) ^ 8.64 (d, 1H, 1 = 1.1), 7.57-7.33 (m, 12H), 7.11 (d, 2H, J = 8.6), 6.81 (d, 3H, J = 8.4), 6.59 (dd, 1H, J = 7.5, 7.5), 6.18 (s, 1H), 4.52 (m, 1H), 4.14 (t, 2H , J = 6.8), 3.12 (dd, 1H, J = 5.3, 13.8), 3.02 (dd, 1H, &gt; 6.5, I3 · 8), 194 (t, 2H, J = 6.8), 2.27 (s , 3h); low resolution MS (FAB) m / e 547 (MH +), 546 (M +); RP-HPLC (Dynamax C-8 25 cm x 4.1 mm; 30_80% in H20 with 0.1% TFA buffer solution 30 minutes; 1 ml / min); tr = 14.73 minutes; analysis of 値 (c34H31N304) calculation 値 C, 74_84; H, 5.73; N, 7.70, measured 値 c, 74_89; H, 5_79; N, 7.62 ° Example 3 6 2 (S)-(2-fluorenyl-aniline) -3_ {4_ [2- (5-methyl-2-hexahydropyridin-1-yl-pyrazole ~ 4_yl) -ethoxy [] -Phenyl} -propionic acid target compound (47 mg) is from 270 mg (0.48 mmol) of intermediate 52 and 0_70 ml 0.70 mmol, 1.5 eq.) Of ΐ · Μ LiOH in H20 in accordance with the method of Example 32: 1H NMR (DMSO-d6, 400 MHz) J 8.69 (d, 1H, J-7.4), 7.50 (m, 3H), 7.33 (m, 3H), 7.09 (d, 2H, J = 8.6), 6.78 (m, 3H), 6.59 (m, 1H), 4.33 (m, 1H), 3.98 (t , 2H, J = 6.6), 3.11 (dd, 1H, J = 5.3, 13.8), 2.99 (dd, 1H, J = 6.5, 13.8), 2.61 (t, 2H, J = 6_6), 2.06 (s, 3H ), 1_49 (m, 6h); low resolution MS (FAB) m / e 555 (MH +), 554 (M +); RP-HPLC (Dynamax C-8 25 cm x 4.1 mm; 3〇_8〇 % CH3CN has 0.1% TFA buffer solution in H20; 30 -127- I m I =---—I— I---n (please read the precautions on the back before filling this page),-° scales are suitable for China National Standard (cns) a4 specification (21〇'297 mm) ~ A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (125 points; 1 ml / min); tr = 18.54 points. Example 37 Yeah)-(24fluorenyl · anilino) -3_ {4_ [2_ (5_methyl · 2, morpholinyl_thiajun_4-yl) -ethyllactyl] -phenylpropionic acid (456 mg) was prepared from 81.0 mg (138 mmol of interstitial 56 and 2.0 ml (2.00 mmol, M equivalent)) of a solution of L10H in HA according to the method of Example 32. Preparation: Bitter Benbarbar, purified by silica gel flash column chromatography with aerosol / MeOH 12/1 as eluent, followed by milling in EtoAc / diethyl ether 1: 1 to obtain yellow amorphous form. Solid: Erbium point; 1H NMR (DMSO-d6, 400 MHz) d 8.70 (d, lH; J = 7 2) 7 54 (m 1H), 7.49 (m, 3H), 7.34 (dd, 1H, 1 = 7.7 , 7.7), 7.i9 (d 1H J ^ 7 7.07 (d, 2H, J = 8.2), 6.76 (d, 1H, ㈣5), 6 71 (d, 2h, ㈣2), 6 5i (dd, 1H , 1 = 7.7, 7.7), 4.32 (m, 1H), 4.03 (t) 2H, J = 6.7), 3.64 (m, 4H), 3.23 (m, 4H), 3.12 (dd, 1H, J = 4.8, 14.0), 2.96 (dd lH, J = 6 4, 14.0), 2.78 (t, 2H, J = 6.7), 2.15 (s, 3H); low-resolution MS (FAB) m / e 573 (MH) '572 ( M +) RP-HPLC (Dynamax C-8 25 cm x 4.1 mm; 30- 80% CH3CHSH20 with 0.1% TFA buffer; 30 minutes; ): Tr = 16.26 points; analysis of 値 (C32H33N3〇5S · HC1) calculates 値 C, 63.20; Η, 5.64; N, 6.91 'to measure 値 C, 63.68; Η, 5.70; N, 6 73. Example 3 8 2 (S)-(2- + 6Atido-epiamino) -3- {4_ [2- (5-methyl-2- (4-p than ydoyl) -p ) -Ethoxy] -phenyl} • propionic acid target compound (102 mg) is derived from 165 mg (0,29 mmol) of intermediate 59 and 0.43 ml (0.43 mmol), 1.5 equivalents. 10μ of LiOH at -128- This paper size applies to the Chinese National Standard (CNS) M specification (210X297 mm) ^ ------- 0 ^ .-- (谙 Please read the notes on the back before filling in this Page) Order printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. A7 '---_____ B7 V. Description of Invention 1 — ~ -— The solution of ^ 0 was prepared according to the method of Example 32. Purified by silica gel flash column chromatography with mouse imitation / MeOfi 9/1 as eluent and then milled in EtOAc / diethyl ether 1: 1 to obtain a yellow amorphous solid: melting point 155_i58 „c; yang nmr (DMS0-d6, 400 MHz). 8.75 (dj 1H, J = 7.2), 8.62 (d, 2H, J = 6.0), 7.75 (d, 2H, J = 6.0), 7_53 (m, 1H), 7.47 (m, 4H), 7.27 (m, 2H), 7.07 (d &gt; 2H, J = 8.5), 6.72 (m, 3H), 6.44 (dd, 1H, J = 7.5, 7.5), 4.17 (m, 3H ), 3.15 (dd, 1H, J = 4_7, 13.6), 3.07 (t, 2H, J = 6.5), 2.93 (dd, 1H, J = 6.3, 13.6), 2.41 (s, 3H); Low-resolution MS ( FAB) 564 (M +); RP HPLC (Dynamax C-8 25 cm x 4-mm); 30-80% ch3CH in 0.1% TFA buffer; 30 minutes; i ml / min): tr = 16 92 points; analysis of radon (C33H29N304S. 2HC1) calculates C, 62.16; H, 5'06; N, 6.59, measured C, 62.41; H, 4.82; N, 6.83. Example 3 9 2 (s)-( 2_benzylfluorenyl_aniline) _3_ {4_ [2_ (2_dimethylamino_5_methyl_oxazol-4-yl) -ethoxy] -phenylpropanoic acid will be 0_42 ml (0.42 millimoles, 1.5 eq.) Of 1.0 μ 之 of UOH in H 2 0 aqueous solution was added at room temperature (150 mg (0 .27 mmol) of intermediate 62 in 7 ml of a stirred solution of THF / Me0H / H20 (6: 0.1: 1). The resulting solution was stirred at room temperature for 5 hours, and then the solvent was removed in the air. The residue was dissolved It was acidified in THF with 0.022 ml (0.42 mmol, 1-5 equivalents) of concentrated hydrochloric acid. The yellow oil was purified by silica gel flash column chromatography with EtOAc / MeOH 1/1 and 1% hydroxide drum as the eluent. 39 mg of the target compound was obtained as a yellow amorphous solid: 1H NMR (DMSO-d6, 400 ΜΗζ) β 8.70 (d, 1Η, J = 7.0), 7.51 (m, 4Η), 7.33 (dd, 1Η, J = 7.3, 7.3), 7.28 -129- This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) (read the precautions before reading the first page and then fill in this page) • 0 pack.

, TT printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Α7 Β7 5. Invention Description (127) (d, 1H, J = 8.1), 7.07 (d, 2H, J = 8.2), 6.75 (m, 3H), 6.49 (dd, 1H, J = 7.4, 7.4), 4.29 (m, 1H), 3.94 (t, 2H, J = 6.4), 3.17 (s, 3H), 3.13 (m, 1H), 2.96 (m, 1H) , 2.85 (t, 2H, J = 6.4), 2.79 (s, 3H), 2.01 (s, 3H), low resolution MS (FAB) m / e. 531 (MH +), 530 (M +); RP-HPLC ( Dynamax C-8 25 cm x 4.1 mm; 30- 80% CH3CH in H20 with 0.1% TFA buffer; 30 minutes; 1 ml / min): tr = l5.85 minutes; analysis of 値 (C3qH31N304S. H20) calculation 値 C , 65.79; H, 6.07; N, 7.67, measured 値 C, 65.74; H, 5.87; N, 7.54. Example 40 2 (s)-(2-benzyl-anilino) -3_ {4- [2- (5-methyl_2 · (5_methyl_isop # also_3-yl) -thiazole -4-yl) -ethoxy] -phenyl} -propionic acid_h compound (220 mg) is derived from 450 mg (0.77 mmol) of intermediate 66 and 1.20 ml (1.2 mmol), L5 equivalent ) A solution of 10 μL of LiOH was prepared according to the method of Example 32.2. Purified by silica gel flash column chromatography with chloroform / MeOH 9/1 as eluent and then triturated with diethyl ether to obtain a yellow, footless solid. 1H NMR (DMSO-d6, 400 MHz) β 8.73 (d, 1H, J = 7 2) 7.49 (m, 4H), 7.26 (m, 2H), 7.07 (d, 2H, J = 8.6), 6.69 (m, 3H), 6.44 (dd, 1H, J = 7.5, 7.5), 4.42 (m, 1H), 4.10 (m, 2H), 3.13 (dd, 1H, J-4.7, 13.9), 3_05 (t, 2H, J = 6.5), 2.94 (dd, 1H, J = 6.3, 13.9) , 2.43 (s, jH), 2.37 (s, 3H); low resolution ms (FAB) m / e 568 (MH +); RP-HPLC (Dynamax C-8 25 cm x 4 j mm; 30.8% ch3CH 0.1% TFA buffer solution in H20; 30 minutes; 丨 ml / min): tr = 25 21 minutes; analysis of 値 (C32H29N305S. Η20) calculated 値 c 65.62; H, 5.34; N, 7.17, measured 实 C, 65.64; Hf, 5.13; N, 7.13. -130- This paper size applies Chinese National Standard (CNS) Α4 specification (21〇 &gt; &lt; 297 public dream)

A7 B7 V. Description of the invention (128) Example 41 2 (S)-(24 Si-anilino) _3 · (4_ {2_ [5_methyl_2_ (4_methyl mouth and outer thiadiazole_5 -Yl) -Petazole_4-yl] -ethoxy} -phenyl) -propionic acid target compound (120 g) is from 230 mg 38 mmol) Intermediate 69 and 0.575 ¾ liter (0.58 Millimoles, 15 equivalents) 10M uHi H20 solution was prepared according to the method of Example 32. Purified by silica gel flash column chromatography with chloroform / MeOH9 / H as the eluent to obtain a yellow amorphous solid: m NMR (DMSO-d6, 400 MHz) ^ g. 71 (d, 1H, J = 7.0) , 7.50 (m, 4H), 7.28 (m, 2H), 7.06 (d, 2H, J-8.5), 6.72 (m, 3H), 6.47 (m, 1H), 4.55 (m, 1H), 4.14 (m , 3H), 3.08 (m, 3H), 2.95 (m, 1H), 2.84 (s, 3H),

2.44 (s, 3H); low-resolution MS (FAB) m / e 585 (MH +); RP-HPLC (Dynamax C-8 25 cm x 4.1 mm; 50-10% CH3cNkH2) with 0.1% TFA buffer ; 30 points; i ml / min): tr = 16 52 points. Example 42 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy Methyl_2_ (4_fluorenyl_hexahydropyridin-1-yl) -tetramethylene_4_yl] -ethoxyb-phenyl) -propionic acid A suspension of triphenylphosphine, 251 g (67 mm mol) of intermediate 23, and 2.20 g (6.70 mmol) of intermediate 7 i in 40 ml of anhydrous toluene were heated to 95X: 15 minutes The intermediate 23 was dissolved to obtain a transparent yellow solution. 23 grams (7 millimoles, 1.05 equivalents) of dimethyl azodicarboxylate were added dropwise over 10 minutes. The reaction was then cooled to room temperature and allowed to stir for 16 hours. Toluene was removed in the air, and the residue was purified by silica gel flash column chromatography with EtOAc / MeOH 10/1 and 1% ammonium hydroxide as the eluent to obtain 3-6 grams of the target compound as a yellow oil. About 丨 30 mg of the standard -131- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of the invention (129 compounds are dissolved in diethyl ether and by adding 1.0 mM The solution of HCI in the diethyl bond was adjusted to ρ Η to 1.0. The obtained yellow precipitate was dried and dried in the air to obtain 100 mg of HC1 salt: 1Η NMR (MeOH-d4, 400 ΜΗζ) β 7.57 (m 3H), 7.50 ( m, 2H), 7.41 (m, 2H), 7.09 (d, 2H, J = 8.5), 6.77 (m, 3H) 6.61 (dd, 1H, J = 7.5, 7.5), 4.62 (t, 1H, J = 5.7), 4.19 (t, 2H, J = 5.8) 5 3.73 〇, 3H), 3.30 (m, 4H), 3.20 (dd, 1H, J = 5.3, 13.9), 3,11 (dd, 1H, J = 6.2, 13.9), 3.04 (t, 2H, J = 5.8), 2.97 (s, 3H), 2.26 (s, 3H &gt;; low-resolution MS (FAB) m / e 599 (MH +); RP-HPLC (Dynamax C-8 25 cm X 4.1 mm; 30-80% CH3CN in H20 with 0.1% TFA buffer; 30 minutes; 1 ml / minute): tr = 17.79 minutes. Example 43 2 (S)-(2 · Yejiji Amino) -3- (4- {2- [2_ (3-Diamidinoamino-propylamino) -5-amidino-thiazol-4-yl] -ethoxy} -phenyl) -propionic acid The target compound (522 mg) is from 695 mg (1.15 mmol) Ear) Intermediate 74 and 1.75 ml (1.75 mmol, 1.5 eq) of a 1.0 M solution of LiOH in H20 were prepared as in Example 32. Silica gel flash column chromatography was performed using MeOH as the eluent for purification followed by milling with EtOAc. Preparation to obtain a yellow amorphous solid: 1H NMR (MeOH-d4, 400 ΜΗζ) β 7.52 (m, 3H), 7.46 〇, 2H), 7.33 (m, 2H), 7.13 (d, 2H, J = 8.5) 6.73 (m, 3H), 6.48 (dd, 1H, J = 7.5, 7.5), 4.23 (dd, 1H, &gt; 5.0, 6.7), 4.08 (t, 2H, J = 6.8), 3.26 (m, 3H), 3.03 (dd, 1H, J = 6.9, 14.7), 2.82 (t, 2H, J = 6_5), 2.74 (t, 2H, J = 7.8), 2_48 (s, 6H), 2.13 (s, 3H), 1.84 (m, 2H); Low-resolution MS (FAB) m / e 587 (MHT); RP-HPLC (Dynamax C-8 25 cm x 4.1 mm); 30-80% CH3CH in H20 with 0.1% TFA buffer; 30 minutes; 1 ml / minute): tr = 18.10 -132- Use Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling in this page j. ---

、 1T A7 B7 Description of invention (130 Analysis printed by the 130 Economic · Shao Central Bureau of Staff Consumer Cooperative, Γ81 analysis, ~ Η38N4045. HC1. H2〇) Calculate 値 C, 61.81; &amp; 6. Clock, 8.7 "found 値 C, 61.93; H, 6.20; N, 8.77. Iilil 2 (S)-(2-benzylfluorenyl_benzylamino) · 3_ (4_ {t, Methylamino-ethylamino) _5-methyl-thiazole- 4-yl] -ethoxyphenyl) -propionate propionate compound (473 mg) was obtained from 907 milliseconds. The milliliter (2.40 millimoles, i mormol) middle-u ^) Tian I) 1.0M UOH = 0% was prepared according to the method of Example 32. Hard gel flash column chromatography was performed with chloroform MeOil 9/1 as the eluent to purify the gray solid (MΗ NMR PMSO-d6, 400 MHz), 8.69 (d, 1H, J = 7.3) j? 55 (m 1H)? 49 = 3H), 7.35 (m, 3H), 7 Q8 ⑷ 2H, ㈣ 6), 6 ^ ㈦ 邱, &amp; 1H, J = 7.5, 7.5), 4.34 (m, 1H), 4.02 (t 2H τ “, '” u, ^ 2Η, 1 = 6.9), 3.48-3.08 (m ΗΧ 2.97 (dd, 1Η, Μ.5, 13.7), 2.72 (t, J = 6 9) 2 〇g (§; low-resolution MS (FAB) m / e 56Ό (Mir); Rp_Hpu: (_aa) , Cm xu mm; 30_80% .i% tfa buffer solution 30 minutes; i ml / min): ㈣6.56 points; analysis of 値 (C3) H33N3 05s · Hα H2〇) Calculate 値 C, 60.63; H, 5.91; N, 6.84, measured 値c, 6〇6i 5.55; N, 6.83. 'Example 45 2- (1-carboxy-2- {4- [2- (5-methylphenyl "selazol-4-yl) _ethoxy]- Phenyl} -ethylamino) -methyl benzate earth compound (290 mg) is from 400 mg (0 75 mmol) and 150 and U ml (1.50 mmol, 2.0 equivalents) ◦The solution was prepared according to the method of Example 32. Shixi gel flash column column, 25 H, body gas imitation 1---1 1 »-3 packs-(谙 Please read the precautions on the back 11 and then (Fill in this page) -133- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7

V. Description of the invention (13D / MeOH 9/1 as a rosanolysis purification to obtain a white solid: m NMR (DMS〇_ d6, 400 MHz) (ί 8.00 (d, 1H, J = 7.2), 7.82 (m, 2H) , 7.72 (dd, 1H, -------- 0 clothing—I (谙 first read the notice on the back and then fill out this page) J = 1.4, 8.1), 7.42 (m, 3H), 7.26 ( dd, 1H, J = 7.3, 7.3), 7.06 (d, 2H, J = 8.4), 6.75 (d, 2H, J = 8.〇), 6 62 (d, m, J =; 8 6), 6 48 ㈣, m, J = 7.4, 7.4), 4.19 (m, jH), 3.72 (s, 3H), 3.06 (m, 3H), 2_90 (dd, 1H, J = 6.7, 13.7), 2.38 (s, 3H); low-resolution Ms (FAB) m / e 517 (MH +); HP-HPLC (Dynamax C-8 25 cm x 4 '' mm; 30-80% CH3cH in H20 with 0.1% TFA buffer; 3 Points; j ml / min): hit = 26 80 minutes; analysis of 値 (C29H28N205S. H20) calculation 値 c, 65 15; H, 5 65; N, 5 24, measured 値 C, 65.60; H, 5_35; N , 5.23. Example 46 2- (1-Carboxy-2- (4- [2- (4-Gasphenylsulfanyl) _ethoxy] _phenylbethylamino) -benzoic acid methyl ester title compound (4 0 mg) is from! 丨 8 mg (〇24mmol) of intermediate 151 and 0.47 ml (0.47 mmol, 20 equivalents) of 10Mt uOH The H20 solution was prepared according to the procedure of Example 3.2. The silica gel flash column chromatography was purified by chloroform / MeOH 9/1 as the precipitation to obtain a light brown solid: m Nmr (DMSO-d6, 400 MHz) d 7.98 (d, 1H, J = 7.1), 7.71 (d, 1H, J = 8.0), 7.69 (d, 1H, J = 18.5), 7.62 (d, 1H, J = 8.5), 7.37 (m, 3H), 7.29 (m , 1H), 7.Q6 (d, 2H, &gt; 8.4), 6.73 (d, 2H, &gt; 8.4), 6.64 (d, 1H, _J = 8.6), 6.52 (dd, 1H, J = 7.5, 7.5 ), 4.20 (m, 1H), 4.07 (t, 2H, J = 6.4), 3.74 (s, jH), 3.32 (t, 2H, J = 6.4), 3.07 (dd, 1H, J-4.8, 13.7) , 2.93 (dd, 1H,

J = 6.5, 13.7); Low-resolution MS (FAB) m / e 486 (M +); RP-HPLC (Dynamax C-8 25 cm X 4.1 mm; 5 (M00% Ch3CN in h2〇 with -134- this paper size I7 standard storehouse in Shizhou (CNS> mm) A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (132) O · 1% TFA buffer solution; 30 points; 1 ml / min): tr = 16 81 points. 2- (l-carboxy-2- [4- (l-phenyl-pyrrolidin-2-ylmethoxy) _phenyl] _ethylamino} ~ 95 mg (0.36 mmol, 1.10 equivalents) of triphenylphosphine, ΙΟΟΟΟ (0.30 mmol) of intermediate 127, and 80 mg (〇_36 mmol) (s) _ (_) _ Ό- A phenyl group) _2_ said pyridine MeOH in 5 ml of anhydrous toluene was heated to 80 ° C for 15 minutes to dissolve intermediate 127 to obtain a transparent yellow solution. 68 mg (0.33 mmol) was added dropwise over 5 minutes. Moore, 12 equivalents) azo-isopropyl diisopropyl ester. The reaction was then cooled to room temperature and stirred for 16 hours. The toluene was removed in the air, and the residue was then removed in 10 ml of 1: 1 ethylene glycol. Ether / 1 N LiOH two-phase solution was stirred vigorously for 1 hour to selectively remove residuals Body 127. The layers were separated and the organic phase was washed with HA, dried (MgS04), and the solvent was removed in the air. The material was purified by silica gel flash column chromatography with hexane / EtOAc 3/1 as the eluent. 94 mg of the target compound was obtained as a yellow solid. This material was dissolved in 5 ml of THF / MeOH / H2O (4: 0.1: 1) at room temperature and 0.35 ml (0 35 mmol, 2.0) was added. 10 M (LiOH in H2O). The resulting solution was stirred at room temperature for 4 hours. Then poured into 20 ml of EtOAc and extracted with 1 N HC1 (2 X 10 ml). The organic layer was separated and dried (MgSCU), and the solvent was removed in the air. The material was purified by chromatographic flash column chromatography using chloroform / MeOH 9/1 as the eluent to obtain 30 mg of the target compound as a yellow solid: m NMR pMSO-d6, 400 MHz) "8.02 (m, 2H), 7.72 (d, 1H, J = 7.0), 7.26 (dd, 1H, J = 7.2, 7.2), 7.04 (d, 2H, J = 8.6), 6.73 (m, 3H), 6.62 (d, 1H, J = 8.6), 6.48 -135- This paper size applies the Chinese National Standard (CNS) from the specifications (2 丨 0 &gt; &lt; 297 mm) (Notes on the back then fill out this page)

Α7 Β7 Printed by the Consumer Cooperatives of the Central Bureau of Standards and Assistance of the Ministry of Economic Affairs 5. Description of the Invention (133) (dd, 1H, J 7 ", 7 ·)), 4.29 (m, 1H), 3.89 (m, 2H), 3.72 ( s, 3H), 3.52 (m, 1H) '3.30 (m, 2H), 3.06 (dd, 1H, J = 4.8, 13.9), 2.89 (dd, 1H, J 6.5, 13.9) 2.0) 〇, 4H); Low-resolution MS (FAB) m / e 52〇 (MH +); RP HPLC (Dynamax C-8 25 cm x 4 "mm; 5 〇 i 〇 ％ CH3cH in H2〇 with 0.1% Tingba buffer; 30 points; 〖ml / min）: tr = i4 54 points; analysis of 値 (C28H29N307 .AO) calculation 値 c, 62 56; H, 5 81; N, 7 82, measured 値 C, 62.18; H, 5.50; N , 7.86. Example 48 3- {4- [2- (Benzoxazole_2_yl_methyl_amino) _ethoxy] _phenylbenzene 2_ (2_cyclopentanecarbonyl-aniline) _propionic acid The target compound (66 mg) was obtained from 0,55 grams (107 millimoles) of intermediate 77 and 67.5¾ grams (1.61, ¾ mole, 1 "equivalent) of the hydroxide bell following the method of Example 32. Gel flash column chromatography was prepared using D cm / MeOH 98/2 as the eluent. 1H NMR (DMS〇_d6, 400MHz) β 9,05 (d, 1Η, J = 7.7) , 7.88 (d, 1Η, J = 7.2), 7.34 (m, 2Η), 7.24 (m, 1Η), 7.11 (m, 1H), 7.03 (m, 2H), 6.97 (m, 1H), 6.78 (m , 2H), 6.72 (m, 1H), 6.61 (t, 2H, J = 7.6), 4.40 (m, 1H), 4.19 (m, 2H), 3.19 (s, 3H), 3.06 (m, 1H), 2.96 (m, 1H), 1.79 (m, 2H), 1.56 (bm, 6H); low resolution MS (ES) m / e 526 · 2 (MHT); RP-HPLC (Vydac C-18, 25 cm x 4_6 Mm; 30-80% CH3CN in H20 with 0.1% TFA buffer; 25 points; 1 ml / min): tr = 21.29 points (t0 = 3 points). Example 49 3- {4- [2- (Benzo-β-fluorenyl-2-fluorenyl-fluorenyl-amino) -ethoxy] -phenyl} -2- (2-cyclooctylfluorenyl 51-aniline Propanoic acid-136- (# M-tt Mouth's note before humming this page) • Bookbinding • nn nn mf 1---mt— · This paper size applies Chinese National Standard (CNS) Α4 specification (210 × 297 mm) A7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs --- ^^ _ V. The description of the invention (134) 'Huakou (39 9 grams) is from 0u grams (023 millimoles) ) Intermediate 7 &amp; and 14.5 * winter (0.35 millimolar '丄 5 equivalents) of the hydroxide bell in accordance with the method of Example 3 2 followed by Shixijia flash column chromatography to test D cm 98/2 Up to 90 / H) as a lysate for purification: 1H NMR (should be mhzW 9.03 (d, 1H, J = 7.2), 7 83 (d, flood μ), 7 34 (m, 2H), 7.24 (m, 1H), 7.11 (m, 1H), 7.02 (m, 3H), 6.79 (m, 2H), 6.70 (m,

1H), 6.61 (m, 1H), 4.39 (m, 1H), 4 17 (m, 2H), 3 50 °, 1H), 3 19 (s, 3H), 3.06 (m, 1H), 2.97 ( m, 1H), 5 (bm, 10H); low resolution MS ㈣ m / e 554.! (ΜΗ.); RP_HPLC (Vydac c_18, 25 cm x 4 6 pen meters' 30-80% CH3CN in H20 With .io / oTFa buffer; 25 points; 1 litre / minute): tr = 24.86 points (t0 = 3 points). Example 50 3- {4- [2- (benzoxazol-2-yl-methyl-amino) _ethoxybuphenyl} _2_ (2 • cyclohexyl gauge • carboxy-5-fluoro-aniline group ) _ Propionic acid target compound (139 mg) was obtained from 0 39 g (0_68 mmol) of intermediate 79 and 34.4 mg (0,82 mmol, 12 equivalents) of lithium hydroxide according to the method of Example 32 ' Purified by silica gel column chromatography with D cm / Me0H 98/2 to% / 5 as the eluent: m nmr (DMS〇-d6, 300 MHz) d 8.86 (d, 1H, J = 7.6), 7.68 (dd, 1H, J = 2.9, 10.5), 7.34 (m, 1H), 7.24 (m, 2H), 7.01 (m, 4H), 6.80 (m, 3H), 4.39 (m, 1H) , 4.17 (m, 2H), 3.84 (m, 2H), 3.19 (s, 3H), 2.96 (m, 2H), 1.66 (m, 5H), 1.34 (m, 5H &gt;; Low Resolution MS (ES) m / e 558_0 (MH-); RP-HPLC (Vydac C-18, 25 cm x 4.6 mm; 30-80% CH3CN in H2 with 0.1% TFA buffer; 25 points; 1 ml / min): tr = 22.62 Points (t〇 = 3 -137- This paper size applies to China's national standard (CNS) A4 size U10X297 mm) '--------- clothing ------ order (please read the back first (Notes on this page, please fill out this page) A7 B7 V. Invention Description (135 points). Example 5 1 3- {4- [2- (Benzhumazol_2_yl-methyl-amino) _ethoxy] -phenyl} _2_ (4_cyclohexylcarbonyl-2-methyl- 2H-esial-3-ylamino) -propionic acid target compound (68 mg) is based on 175 g (0.3 1 mmol) of intermediate 80 and 16 mg (0.37 mmol, L2 equivalent) of hydrogen Lithium oxide was prepared according to the method of Example 32 and then purified by silica gel flash column chromatography using D cm / MeOH 98/2 to 90/10 / 0.1 D cm / MeOH / HOAc as the eluent. 1H NMR (DMSO -d6, 300 MHz) δ 7.74 (s, 1H), 7.36 (d, 1H, J = 7.9), 7.25 (d, 1H, J = 7.9), 7.10 (m, 5H), 6.78 (m, 2H), .4.77 (m, 1H), 4.18 (m, 2H), 3.85 (m, 1H), 3.59 (s, 3H), 3.20 (s, 3H), 2.95 (m, 2H), 2.81 (bs, 1H), 1.65 (m, 5H), 1.26 (m, 5H); low-resolution MS (ES) m / e 544.1 (MH—); RP-HPLC (Vydac C-18, 25 cm X 4.6 mm; 30-80% CH3CN at H20 with 0.1% TFA buffer; 25 points; 1 liter /. Points): tr = 14.66 points (t0 = 3 points). Example 52 3- {4- [2- (Benzazinazole_2_yl_methyl-aminoethoxy] _phenyl} _2_ (3_benzylfluorenyl-thien-2-ylamino) _ Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Propionic Acid (please read the precautions on the back before filling out this page) The target compound (77 mg) is from 0.145 g (0.26 mmol) of intermediate 8 1 and 14 mg (〇 , 34 millimoles, 13 equivalents) Lithium hydroxide was prepared according to the method of Example 32, and then purified by silica gel flash column chromatography and purified by D cm / MeOH 95/5 to 90/1 0 as the eluent. : M NMR (DMS〇_d6, 300MHz) 9.44 (d, 1H, J = 8.2), 7.54 (m, 5H), 7.36 (d, 1H, J = 7.9), 7.25 (d, 1H, J = 7.7), 7.14 (m, 3H), 6.96 (m, 1H), 6.84 (m, 3H), 6.40 -138- This paper size applies the Chinese National Standard (CNS) A4 specification (21〇χ 297 mm Ministry of Economy Printed by the Consumer Standards Cooperative of the Central Standards Bureau A7 B7 V. Description of the invention (136) (d '1H' J-5.7), 3.85 (m, 2H), 3.20 (m, 4H), 3.17 (m, 1H); low resolution MS (ES) m / e 539.9 (ΜΗ ·); RP_HPLC (Vydac c_18, 25 cm x 4.6 pen meters,) 0-80% CHsCN in H20 with 0.1% TFA buffer; 25 points; 1 ml / min): tr = 18.16 (t0 = 3 points). Example 53 2- (2-Hexanecarbonyl-aniline) _3_ {4_ [2_ (5_methyl_2_phenyl) -Oxazole_4_yl) -ethoxy] -phenyl} • propionic acid (750 gram) is based on 0.88 (90 mol) intermediate 83 and 120 mg (2.86 Millimolar, 15 equivalents) Lithium hydroxide was prepared according to the method of Example 32, and then purified by silica gel flash column chromatography with D cm / Me0H 95/5 as the bath eluent: 1H NMR (DMSO-d6, 400 MHz ) β 9.10 (d, 1H, J = 7.4), 7.88 (m, 3H), 7.46 (m, 3H), 7.28 (m, 1H), 7.03 (d, 2H, J = 8.4), 6.75 (d, 2H , J = 8.6), 6.66 (d, 1H, J = 8.4), 6.55 (m, 1H), 4.12 (m, 3H), 3.17 (m, 1H), 2.87 (m, 3H), 2.31 (s, 3H ), 1.68 (bm,) H), 1.30 (bm, 5H); low-resolution Tha Yang) 111/6 551.2 (1 ^-); 11? -HPLC (Vydac C-18, 25 cm x 4 · 6 mm; 30-80% CH3CN in H20 with 0.1% TFA buffer; 25 points; 1 ml / min): tr = 18-22 points (t0 = 3 points). Daicel Chiral OD-H (4.6X250 mm, 5 &quot;; 0.7 ml / min; injection volume 3 ml UV 230 nM; 60/40 IPA / hexane; 30 points); tr = 7.44 points, 99.99% ee. Example 54 2- (2-cyclohexanecarbonyl-aniline) _3_ {4- [2- (5-methyl-2-phenyl-azazol-4-yl) -ethoxy] -phenyl}- Propionic acid-standard compound (78 mg) is derived from 220 mg (0.39 mmol) of intermediate -139- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) (# 先 闵 读 后背Note: Please fill in this page again.) Order A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. 5. Description of the invention (137) Enantiomer 2 of 83 and 24 mg (0.58 mmol, 15 equivalents) Follow the method in Example 32, and then take the dream gel flash column chromatography at .d cm /

MeOH 95/5 was prepared as an eluent purification: ms, HPLC was the same as in Example 53. Daicel Chiral OD-H (4.6 X 250 mm, 5 &quot; 〇7 ml / min; injection volume 3 ml UV 23 0 nM; 60/40 IPA / hexane; 30 points); tr = 11.67 points, 99.3% ee. Example 55. 3- [4- (1-Benzoxazole_2_yl-pyrrolidin-3-yloxy) -phenyl] _2_ (2_benzyl-benzyl) -propionic acid Compound (115 mg) is derived from 200 mg (0.36 mmol) of 3- [4- (bubenzozol-2-yl-pyrrolidine_3_yloxy) _phenyl] _2_ (2_benzyl Fluorenyl_aniline) -methyl propionate and 18 mg (0.43 mmol, ι · 2 equivalents) of hydroxide were prepared according to the method of Example 32, followed by silica gel flash column chromatography at 0 cm /

MeOH 90/10 was prepared as an eluent for purification: iH NMR (DMSO-d6, 400 MHz) d 8.72 (m, 1H), 7.53 (m, 5H), 7.36 (m, 4H), 7.13 (m, 3H) , 6.97 (m, 1H), 6.82 (m, 3H), 6.51 (m, 1H), 5.07 (s, 1H), 4.30 (bs, 1H), 3.83 (m, 1H), 3.66 (m, 3H), 3.13 (m, 1H), 2.98 (m, 1H), 2.23 (bm, 2H); low resolution MS (ES) m / e 546.0 (MH.); RP-HPLC (Vydac C-18, 25 cm x 4.6 mm; 30-80% CH3CN in H20 with 0.1% TFA buffer; 25 points; 1 ml / min): tr = 1792 points (t0 = 3 points). Daicel Chiral OD-H (4.6 X250 points, 5 meters, · 0.7 ml / min; injection volume 3 ^: liter UV 230 nM; 40/60 / 0.1 IPA / appearance / TEA; 30 points); tr 2 6.8 points and lo.o cents. Example 56 -140- This paper size applies Chinese National Standard (CNS) A4 specification (210X297). --------- θ clothing 丨 丨 (Please read the precautions on the back before filling this page) Order A7 B7 V. Description of the invention (US) 3- {4- [2- (5-fluorenyl-2-phenyl-yinjun-4-yl) _ethoxy] _phenyl} _2 (s) _ [ 2_ (pyridine-4-carbonyl) -aniline] -propionic acid target compound (8Γ5 mg) is from ^ gmen ^ mmol) Intermediate 87 and 192 mg (4.57 mmol, L5 equivalent) of lithium hydroxide The method of "example" is then prepared by rolling in D cm: 1HNMR (DMs0_d6, 300MHz) d 9.10 (d, 1H, J = 6.9), 8.67 (dd, 2H, J ^ l.3, 4.4), 7.87 (m, 2H), 7.45 (m, 3H), 7.38 (d, 2H, J = 5.8), 7.23 (m, 1H), 7.10 (m, 1H), 7.04 (d, 2H, J = 8.4), 6.72 (d, 2H, J = 8.6), 6.64 (m3 1H), 6.34 (t; 1H, J = 7.4), 4.10 (t, 2H, J = 6.5), 3.83 (m, 1H) S 3.04 (m, 1H), 2.85 (m, jH), 2.) 0 (s, 3H); low resolution 1 ^ (£ 8) 111 / ^ 546 (1 ^ 11-); 11? -HPLC (Vydac C-18, 25 Cm x 4.6 mm; 30-80% CH3CN with 0.1% TFA buffer in H2O; 25 minutes; 1 ml / minute): tr = 16.3 5 minutes (t0 = 3 minutes). Daicel Chiral OD-H (4.6X250min, 5m; 0.7ml / min 'injection volume 3ml UV 230 nM; 40/60 / 0.1 IPA / hexane / TEA' 30min); tr = 9.21min, 96% ee. Example 57 3- {4- [2- (5-methyl_2_phenyl-humazol_4_yl) _ethoxy] -phenylbenzene 2 (s) _ [2_ (Edian N-oxide _4_carbonylaniline] _ Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Propionic Acid (Notes on the back of the poem before reading this page and then filling out this page) The target compound (52 mg) is from 70 g (0.12 mmol) Ear) Intermediate 8 8 and 10 mg (0.24 mmol, 2 equivalents) of lithium hydroxide according to the method of Example 32 'followed by purification by silica gel flash column chromatography with D cm / MeOH 90/10 as eluent Preparation: 1H NMR (DMSO-d6 400MHz) &lt; 1 8.69 (d, 1H, 7.2), 8.26 (d, 2H, J = 7.1), 7.85 (m, 3H), 7.46 (m, 4H), 7.38 ( m, 2H), 7,05 (d, 2H, J = 8.4), 6.74 (m, 2H), 6.49 (m, -141-This paper applies the National Standard (CNS) iron grid (2IQX297) Printed by the Consumer Cooperatives of the China Standards Bureau of the Ministry of Economic Affairs A7 -------- _B7_ V. Description of the Invention (139) 1H), 4.10 (m, 2H), 3.15 (m, 2H), 2.9 6 (m, 1H), 2.85 (m, 2H), 2.49 (s, 3H); low resolution ms (ES) m / e 562 (ΜΗ—); RP-HPLC (Vydac C-18 '25 cm x 4 6 Millimeter; 30-80% ch3CN in H20 with 0-1% TFA buffer; 25 points; 1 ml / min): tr = 15_92 points (t0 = 3 points). Example 3- {4_ [2- (5-methyl, _2_phenyl_oxazolyl) _ethoxyphenylphenyl 2 (s) _ [2_ (eridine-3-carbonyl) -aniline] _ Propionic acid target compound (506 mg) was obtained from 0.54 g (0.96 mmol) of intermediate 89 and 122 mg (2.88 mmol, 3_ equivalent) of lithium hydroxide according to the method of Example 32. Flash column chromatography was prepared with D cm / MeOH 90/10 as the eluent: 1H NMR (DMSO-d6, 300MHz) β 8.92 (d, 1Η, J = 6.9), 8.70 (s, 1 ，), 8.64 (s, 1Η), 7.87 (m, 2Η), 7.46 (m, 6H), 7.33 (m, 1H), 7.24 (d, 1H, J = 7.9), 7.08 (d, 2H, J = 8.4), 6.74 (d, 2H, J = 8.4), 6.47 (m, 1H), 4.18 (bs, 1H), 4.09 (m, 2H), 3.15 (m, 1H), 2.93 (m, 1H), 2.85 (m, 2H), 2.30 (s, 3H); low resolution MS (ES) m / e 546 (MH); RP-HPLC (Vydac. C-18, 25 cm x 4_6 mm; 30-80% CH3CN in H20 with 0.1% TFA buffer; 25 points; 1 ml / min): tr = 17.3 1 point (t0 = 3 points). Daicel Chiral OD-H (4.6 X 250min, 5m; 0.7ml / min; injection volume 3ml uV 23〇nM; 40/60 / 0.1 IPA / hexane / TEA; 30min); tr = 8.98min, 78% ee. Example 59 j- {4- [2- (5-methyl_2_phenyl-stilbene_4_yl) _ethoxy] _phenylbenzene 2 (s) _ [2_ -3-Carbonyl) -aniline] -propionic acid-142- The paper scale is applicable to the Chinese National Standard (CNS) A4 specification (ZIOXW7 mm) (Read the precautions on the back of the first cabinet and then fill out this page) Order A7 B7 V. Description of the invention (ι4) mCPBA (57 mg, 0.33 mmol, 1.5 equivalents) was added to intermediate 8 9 (100 mg, 0'18 mmol) (5 ml) at room temperature. After 24 hours, a second 1.5 mCBA was added. The reaction mixture was stirred for one hour and shrunk to dryness. Borrowed; epsilon. Gel flash column chromatography. Dcm / MeOH 95/5 was used as The solution was purified to obtain 50 mg of intermediate N-oxide; 1H NMR (DMSO-d6, 300MHz) J 9.00 (m, 1H), 8.40 (d, 1H, J-5.9), 8.33 (s, 1H), 7.95 (m, 3H), 7.56 (m, 4H), 7.44 (m, 3H); 7.15 (d, 2H, 1 = 8.3), 6.83 (in, 3H), 6.57 (m, 1H), 4.38 (m, 1H ), 4.20 (m, 2H), 3.22 (m, 1H), 3.04 (m, 1H), 2.94 (m, 2H), 2.38 (s 3H) 'Low Resolution MS (ES) m / e 578.3 (MH +). Hydrolyzed according to the method of Example 3 2 and then borrowed the gel flash tube column layer D in cm / Me〇H 90/10 Eluant Mao purified to give 20 g of the target compound: Low Resolution MS (ES) m / e 562 (MH-);

RP-HPLC (Vydac C-18 '25 cm x 4'6 mm; 30-80% CH3CN in H20 with 0.1% TFA buffer; 25 points; i ml / min): tr = 15 7〇min (t〇 = 3 points) = &gt; Example 60 2S- (2-benzylfluorenyl-aniline) -3- {4- [2- (5-fluorenyl_3-phenyl-pyrazolyl) _, ethoxy] -Phenylpropionic acid passed through the middle part of the head xj.-JiT, and eliminates the cooperative women's seal $: QIT (read the precautions on the back before filling this page) The target compound (7 7 mg) is from 11 Mg (0 20 mmol) of Intermediate 91 and 0.295 ml (0.0295 mmol) of 1 ^^]] »According to the method of Example 32 'followed by silica gel flash column chromatography with chloroform / Me〇H (9: 1) Purified as an eluent and prepared by EtzO / hexane milling: 1H NMR (DMSO-d6, 400ΜΗζ) (ί 8.68 (d, 1Η, J = 7.2), 7.70 (d, 2H, J = 7.6), 7.60-7.20 (m, 10H, 7.08 (d, 2H, J = 8.4), 6.80-6.70 (m, 3H), 6_52 (t, 1H, J = 7.2), -143- Sichuan China National Standard) M specification (2H) X297 mm) — ~ 'A7 B7 V. Description of invention (14)

6.42 (s, 1H), 4.46-4.30 (m, 3H), 4.30-4.16 (m, 2H), 3.12 (dd, 1H, J = 13.8, 5.2), 2.97 (dd, 1H, J = 13.8, 6.6) , 2.28 (s, 3H); low-resolution MS (ES) m / e 546 (MH +); analysis of 値 (C34H3iN3〇4. I 2H2〇) calculation of 値 c, 71.99; H, 5.94; N, 7.41 measured 41 c, 71 · 96; H, 5.85; N, 7.33; RP-HPLC (C-18 '4,6 mm x 25 cm; 50-100% CH3CN at H20 with 0.1% TFA; 30 min; 1 ml / min) : Tr = 14 5 points (t0 = 3 points). Example 6 1 2S- (2-fluorenyl-aniline) _3_ [4_ (bupyridin_2_yl_pyrrolidin_2S • yl · methoxy) -phenyl] -propionic acid target compound (1.17 mg) was obtained from 1.2 g (2.24 mmol) of intermediate 93 and 3-4 ml (3.4 mmol) of 1 ^^ 1 ^ 〇1 ^ were prepared according to the method of Example 32 followed by purification by milling with CHC13 / Et20: iH NMR (DMSO -d6, 400MHz) 8.60 (d, 1H, J = 7.6), 7.96 (d, 1H, J = 6.4), 7.93 (t, 1H, J-8.0), 7.62-7.46 (m, 5H), 7.41 (t , 1H5 J = 7.2), 7.33 (dd, 1H, 1 = 8.0, 1.2), 7.19 (br s, 1H), 7.08 (d, 2H, 1 = 8.4), 6.89 (t, lH, J = 6.4), 6.82 (d, 2H, 1 = 8.8), 6.74 (d, 2H, J-8.4), 6.59 (t, 1H, J ^ 7.6) 5 4.66-4.56 (m, 1H), 4.53 (dt, 1H, J = 6.4, 6.0), 3.98 (d, 2H, J = 6.0), 3.69 (t, 1H, J = 8.8), 3.45 (dt, 1H, J = 9.2, 7.6), 3.14 (dd, 1H, J = 13.8, 5 2), 3 〇1 (dd, m, ㈣.8, 6.4), 2.24_L98 (m, 4H); low resolution ms ⑽ m / e 522 (M +); analysis 値 (C32H3lN30.4. 〇6H2〇) Calculate 値 c, 67 h, 5.88; N, 7.39; Cl, 6_23 Measured 値 C, 67.57; H, 5.87; N, 7 31; C1, 6.46; RP-HPLC (C_18, 4.6 mm x 25 cm; 3 〇_8〇% Suction ⑶ . H20 square with 1% TFA; 30 minutes; 1 ml / min): Bian = 15.6 min (t〇 = 3 min). -144-Zhang scale is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling in this buttercup)

A7 _ _ B7 ______ ^ V. Description of the invention (1 叼 Z_tl62_ · 2S- (2-benzylfluorenyl-aniline) -3- {4- [2- (l-methyl-4-phenyl-1H-imidazole- 2-yl) -ethoxy] -phenyl} -propionic acid (70 mg) is based on 83 mg (0.15 mmol) of intermediate 95 and 0.223 ml (0.223 mmol) of 1 N LiOH according to Example 32 The method was followed by purification by milling with EtOAc: 1H NMR (DMSO-d6, 400MHz) 8.62 (d, 1H, J = 7.6), 8.06 (s, 1H), 7.78 (d, 2H, J = 7.6), 7-6〇-7.30 (m, 10H), 7.11 (d, 2H, J = 8.4), 6.86-6.78 (m, 3H), 6.59 (t, 1H, J = 7.4), 4.58-4.47 (m, 1H ), 4.32 (t, 2H, J = 6.0), 3.83 (s, 3H), 3-47 (t, 2H, J = 6.0), 3.14 (dd, 1H, J = 13.8, 5.2), 3.02 (dd, 1H, J = 13,8, 6.8); low resolution MS. (ES) m / e 546 (MH +); analysis. 値 (C34H31N3 04. HC1 · 0.5H2 0) Calculate 値 C, 69.09; H, 5.63; N, 7.11; Cl, 6-0. Measured c, 69.08; H, 5.63; N, 7.04; Cl, 6.04; RP-HPLC (C-18, 4 mm X 25 cm; 30- 80% CH3CHKH20 with 0.1% TFA 30 points; 1 ml / min): tr = 17.1 points (to = 3 points). Example 63 2S (2-fluorenyl group_aniline group) _3_ {4- [2- (3-octane-2-yl group) - 5-Methyl-ρbi_ 1_yl) -ethoxy] -phenyl} -propionic acid 9¾ g (0.911 mmol) of triphenylphosphine in 1.8 ml of anhydrous THF at 0 ° C 014 3 ml (0.911 mmol) of DEAD was processed dropwise. After 10 minutes of incubation, 342 mg (0.911 mmol) of intermediate 23 and 175 mg (〇911 mmol) were added to the reaction mixture at 25 ° C. Ear) Intermediate 97 is in 1.8 ml of anhydrous thf solution. The reaction is stirred at 25 ° C for 15 hours and then concentrated in the air (@ S25 ° C. The residue is passed through a silica gel flash column column -145- This sheet Ruler (CNS) Λ4 specification (210X297 public love) ~~~ ': ~~ One (Please read the precautions on the back before filling this page)

A7 V. Description of the invention (14) Analytical purification of EtOAc / hexane (1: 1) as the impure medium crude crude was performed by the method of Example 32, and then passed through the silica gel flash column core: CHCl3 / Me0H (9: purified as an eluent followed by a standard compound called 斤 ^ mg (37%) as a yellow solid: m _ _ MHzp 8.75 (d, 1H, J = 7.2), 7.62 (s, 1H), 7 Qin 7 42 plus 5_, 7.34-7.22 (m, 2H), 7.08 (d, 2H, J = 8.4), 6.76-6.64 (m, 3H) 6 59 (d 1H, 1 = 3.6), 6.50 (m5 1H ), 6.45 (t, 1H, J = 7.6), 6.24 (s, 1H)} 4.42; 4.10 (m, 5H), 3.20-3.08 (m, m), 2.95 (dd, 1H, J = 13.6, 6 〇 ), 2 26 (s, 3H); low resolution 1 ^^ 5) 1 ^ 558 (] \ 1 仏 +), 536 (^ 1) 9+); analyze 値 (C32H29N305.1 · 2Η20) to calculate 値 C, 68 · 98; H, 5 68; N, 7 54 Measured 値 C, 68 · 65; H, 5.29; N, 7.76; TLC (CHci3 / Me〇H ㈤)) · R product 0.24; RP- HPLC (C_18, 4.6 mm X 25 cm; 30% of the genus CU is 0.1% TFA; 30 minutes; 1 ml / minute): tr = 22 2 minutes ... "minutes. Example 64 2S- (2- 芊Fluorenyl_aniline) _3_ {4 _ [; 2_ (5_methyl_3_phenyl-nqtriazole_1-yl) -ethenyl] -benzene.yl} -propionic acid The compound (141 g) was prepared from 180 mg (0 32 mmol) of intermediate 99 and 0.482 ml (0.482 mmol) of LiOH according to the method of Example 32 followed by purification using Et2O: iH NMR ( DMSO-d6, 400 MHz) ά 8.62 (br d, 1H, J = 6.8), 7.93 (d, 2H, J = 6.8), 7.62-7.30 (m, 10H), 7.10 (d, 2H, J = 8.8) , 6.84-6.76 (m, 3H), 6.58 (t, 1H, 3 = 7.6), 4.55-4.44 (m3 3H), 4.28 (t, 2H, J = 4.8), 3.13 (dd, 1H, J = 14.0, 5.6), 3.01 (dd, 1H, J = 14.0, 6.8), 2.45 (s, 3H); low resolution] VIS (ES) m / e 569 (MNa +), 547 (MH +); analysis 値 (C32h3qN4〇4 〇m2〇) Calculate 値 c, -146-This paper size applies the Chinese National Standard (CNS) A4 specification (210X297mm) (Please read the precautions on the back before filling in this tile)

A7 B7 V. Description of the invention (14 7〇 · 20; Η, 5.71; N, 9.92 found value c, 705; h, 5 7〇; n, 9 98; TLC (CHCl3 / Me0H (9 : 1)): Rf = 〇% Rp_HpLc (c_i8, 4 6mm χ (Please read the notes on the back before filling out this page) 25 cm; 50_100% CH3CH at η2〇 with 0 %% fafa; 30%; i Ml / min): tr = 10_6 points (to = 3 points). 'Example 65 2S- (2-benzylfluorenyl-aniline) _3_ {4_ [2_ (3_methoxymethyl_5_methyl_ 2-Phenyl-3H-imidazol-4-yl) -ethoxy] -phenylpropionate target compound (324 mg) is based on 34.0 mg (0% mmol) of intermediates 102 and 0.1. S45 ml (0.S45 millimolar)} NuOH was prepared according to the method of Example η and then purified by milling with Et20: 1H NMR (DMS〇_d6 400MHz). 8.63 (d, 1H, ^ 8.0), 7.76-7.46 (m, l〇H) j 7.42 (t! 1H, J-7.2), 7.35 (d, 1H, J = 8.0), 7.11 (d, 2H, J = 8.4), 6.82 (t , 3H, J = 8.8), 6.60 (t, 1H, J = 7.2), 5.39 (s, 2H), 4.54 (dd, 1H, J = 6.8, 6.0), 4.10 (t, 2H, J = 6.0), 3.25-3.10 (m, 3H), 3.19 (s, 3H), 3.03 (dd, 1H, J = 14.0, 6.4), 2.29 (s, 3H); low resolution MS (ES) m / e 612 (MNa +), 590 (MH +); analysis of tritium (C36H35N30.5. 0. 3H2 0) calculation of c, 68_47; H, 5.84; N, 6.65 found C, 68.46; H 614; N, 6 41; TLC (CHCh / MeOH ( 9: 1).): Rf = 0.20. Example 66 2S- (2-benzylpentyl_aniline) _3_ (4_ [2_ (5_methyl_2_phenyl_3H-imidon_4_yl ) -Ethoxy] -phenyl} -propionic acid hydrochloride standard compound (162 mg) is based on 200 mg (0.36 mmol) of intermediate 104 and 0.536 ml (0.536 mmol) of 1 N UOH according to the example The method of 3 2 was then prepared by purification with EtOAc / Et20 treatment: iH NMR (DMSO- -147- This paper size applies to China's standard ^ standard (〇 阳) 8 4 specifications (2 丨 0/297 mm ) — A7 quasi-X; A2 in the A7 part; II print fr A n printed B7. V. Description of the invention (1414M 牴 ζ) π U.72 (br s, 1H), 13 〇Ga &amp; m), 8 62 ⑷ m, J = 8.0), 8.08 (dd, 2H, 1 = 8.0, 2.4), 7.65-7.45 (m, 8Ηχ 7.4〇 (, 1H, J-7.6), 7.33 (dd, 1H, 1 = 8.0 , 1.2), 7.10 (d, 2H, J = 8.4), 6.81 (d, 3H, 1 = 8.4), 6.58 (t, 1H, 1 = 7.6), 4.52 (dd5 1H, J = 6.8, 6.4) &gt; 4.18 (, 2H, J = 6'4), 3.20-2.95 (m, 4H), 2_28 (s, 3H); low solution ms (es) m / e 546 (sec. 〇; analysis 値% Yifan 〇 4 丨 Gu 刈 calculation 値 c, 68 〇5; H, 5.71; N, 7 〇〇; Cl, 5.91 found C , 68 〇3; H, 5% N, 6% 5_98; HPLC (ChiralcelOD_H, 4.6 mm x 25 cm; 80% isopropanol / hexane with 0_1% Et3N / (U% TFA; 30 points; 〇5 Ml / min): beat = 123 points (to = 3 points); &gt; 99〇 / 〇ee 〇 Example 67 2S- (2-benzylfluorenyl-aniline) -3_ {4_ [2_ (5dimethyl_ 2-Phenyl-thiazole-4-yl) _ethoxy] -phenylpropionate target compound (283 mg) is derived from 350 mg (〇61mmol) of intermediate 107 and 0.91 ml ( 〇 丨 mmole) 1N u〇h was prepared according to the method of Example 32 and then purified by EUO / hexane burned soil: m nmr (DMS〇_d6, 400 MHz) ^ 8.62 (d, 1H, 1 = 8.0) , 7.82 (dd; 2H, J = 6.0, &lt; 1.0), 7.60- 7.36 (m, 9H), 7.33 (d, 1H, 1 = 8.0), 7.09 (d, 2H, J = 8.8), 6_80 (t , 3H, J = 8.4), 6.58 (t, 1H, J-7.6), 4.50 (dd, 1H, J = 7 2? 6.0), 4.19 (t, 2H, J = 6.8), 3.18-2.94 (m, 4H), 2,37 (s, 3H); low resolution MS (ES) m / e 586 (MNa +), 563 (M +); analysis of (C34h3C) N2 04S · 〇 3H2〇) Calculated 値 c, 71.89, H, 5.4j, N, 4.93; S, 5.64 Measured 値 c, 7i 9i. H 5 44. N 4.9j, .S, 5.62, RP-HPLC (C-18, 4.6 Indica x 25 cm; 3〇_ g〇y〇CH3CHKH20 with 0.1% TFA; 30 points; 1 ml / min): tr = 28 9 points (t〇 = 3 -148- This paper size applies to Chinese national standards (CNS ) A4 size (210X297mm) (Please read the notes on the back before filling in this page)

A7 B7 V. Description of invention (14 points).

AjH_68_ 2 (S)-(2-benzylfluorenyl · aniline) _3_ 《4_ [2- (5-methyl-2- (3-methyl-thienyl_2_yl) -oxazol-4-yl)- Ethoxy] -phenylpropanoic acid target compound (90 mg) is based on 100 mg (〇7 7 mol) of intermediate 112 and 10.8 mg (0.258 mol, 1.5 equivalents) of LiOH according to Example 32 Method: low-resolution MS (ES-) m / e 565.0 (MH-); analysis of 値 (C33H3QN205S. 0,4 EtOAc) calculation 値 C, 69.04; H, 5.56; N, 4.65 found 値 C, 69.45; H, 5.95; N, 4.33. Example 69 2 (S)-(2- {4- [2- (5-nitro-2-gadolideyloxy) -ethoxy] · phenyl] methoxycarbonyl-ethylamino) -benzoic acid A solution of 109 mg (0.220 mmol) of intermediate 152 in THF (2 mL) and EtOH (2 mL) was treated with 1 μL of LiOH (1 mL). The reaction was stirred for 4 5 minutes. Water (10 ml) and 1 N HC1 (1 ml) were added. The reaction was extracted with EtOAc (2 × 30 mL). The combined organic phases were washed with brine (3 x 30 liters), dried (MgSO4), filtered and concentrated. The material was purified by flash chromatography with EtOAc + 0.1% AcOH as the eluent to obtain 25 mg (24%) of the target compound: 1H NMR (CDC13, 400 MHz) d 9.07 (d, 1H, J = 2.7), 8.36 ( dd, 1H, J = 2.8, 6.3), 7.91 (dd, 1H, J = 1.6, 6.3), 7.35 (t, 1H, J = 7.4), 7.20 (d, 2H, J = 8.7), 6.88 (dd, 3H, J = 2.7, 7.7), 6.68 (t, 1H, J = 7.4), 6.58 (d, 1H, J = g. 3), 4.77 (t, 2H, J = 4.6), 4.32 (m, 3H) , 3.86 (s, 3H), 3.20 (ddd, 2H, J = 5.1, 7.7, 7.7); low resolution MS m / e 480 (MH-). -149-The size of this paper conforms to Chinese National Standard (CNS) A4 specification (210X297 mm) -i— ....... I-iri--HI I-- 衣 -—I— 1 ·-- ---- 1 I j— (Please read the notes on the back before filling in the clothing page) A7 _____________B7 V. Description of the invention (ί_ϋ7〇ι_ 2 (S)-(2- {4- [2- (5- (5- Chloro-2-pyridyl: sulfanyl) -ethoxy] -phenyl} -oxooxycarbonyl-ethylamino) -benzoic acid standard compound (90 mg) is from 155 mg (0,31 mmol) Ear) Intermediate I53 was prepared according to the method of Example 69: low-resolution m NMR (CDC13, 400 MHz) ^ 8.38 (d, lH3J = 2.4), 8.19 (d, lH, J = 5.9), 7.91 (d, 1H , J = 8.1), 7.46 (dd, 1H, J = 2.5, 7), 7.34 (t, 1H &gt; J = 7-1), 7.19 (d, 2H, J = 8.5), 7.13 (d, 1H) J = 8.6), 6.87 (d, 2H, J = 7.5), 6.67 (t, 1H, J = 7.5), 6.57 (d, 1H; J = 8.4), 4.30 (m, 1H), 4.18 (t, 2H, J = 6.8), 3.85 (s; 3H), 3.52 (t, 2H, J = 6.8), 3 / .18 (ddd, 2H, J = 5 ″, 7.5, 7.5); low resolution MS _ 485 (MH: ), 486 (M). Example 71 2 (SH2- {4- [2- (N-ethyl_2 · fluorenyl-tolylamino) _ethoxy] -phenyl} _oxocarbonyl-ethyl Amine)- The formate compound (16 mg) was prepared from 90 mg (0184 mmol) of intermediate 154 according to the method of Example 69: low resolution 1HNmr (cdc13, 400 MHz) ci 8.19 (s, 1H), 7.91 (d , 1H, J = 6.7), 7.33 (t, 1H, J = 8.4), 7.18 (d, 2H, J = 7.9), 7.11 (m, 1H), 6 82 (m, m), 6 67 (t, 2H, J = 8.5), 6.56 (d, 2H, J = 8.4), 6.53 (m, 1H), 4.30 (q, 1H, J = 6.9), 4.07 (m, 2H), 3.85 (s, 3H), 3.69 (m 2H) 3 43 MS m / e 475 (MH-), 476 (M). Example 72 -150- (Please read the precautions on the back before filling this page)

This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 Five 'invention description (14 3_ [4- (3_Benzogas_2_2-based-tetrahydro p stoper _4 (R ) -Ylmethoxy) _phenyl] _ 2 (S)-(2-benzylfluorenyl-aniline) -propionic acid -------------- Order (Please read the back first Note for refilling this page) Dissolve 100 mg (0_168 mmol) of intermediate in 5 ml of 2/2/1 (v / v) acetonitrile / MeOH / water solution at room temperature with Π · 5 mg ( 〇_337 millimolar) LiOH H20 was treated for 2 hours. The reaction was quenched with excess citric acid, the volatiles were evaporated and the product was distributed between EtOAc and water. The organic phase was then combined, dried and left behind after rotary evaporation. The solid residue was further purified by preparative C18 HPLC to obtain 50 mg of the target compound: 1H NMR (CDC13, 300 MHz) ^ 7.58-7.15 (m, 14H), 6.78 (d, 2H, J = 11.3), 6.60 (m, 2H), 5.03 (m, 1H), 4.87 (d, 1H, J = 9.4), 4.73 (d, 1H, J = 9.4), 4.40 (m, 1H), 4.14 (m, 2H), 3.40-3.05 ( m, 4H), C18RPHPLC YMC 250 X4.6 mm ID S-5 micron, 〇-1〇00 / 〇b more than 30 minutes, flow rate 1.5 ml / minute, B = 0.1% TFA in acetonitrile, A = 0 .1% TFA in water, tr = 21.45 points (t〇 = 2.9 points), purity 100%; TLC: Rf = 0.41 (aeroform / MeOH 9/1); MS (ES +) m / e 580 (M +1); Analysis of 値 (C33H29N305S. 2TFA) Calculate 値 C, 5502; H, 3.87; N, 5.20; S, 3.97, measured 値 C, 54 38; η, 3.90; N, 5.19; S 3.91. Example 73 3 -{4- (2- (benzoxazol_2_yl-methyl-amino) _ethoxy] -phenyl} _2- [2- (4-trifluorofluorenylbenzylfluorenyl) aniline -Propionic acid intermediates 1 13 (250 mg, 0.44 mmol), K2C03, (182 mg, 1.3 mmol), Pd (Ci) 2 (Pph3) 2 (92 mg, 0.013 mmol) and 4 -Tri. A solution of fluoromethylphenylboronic acid (9ΐ · 4 mg, 0.48 mmol) in No. 2 垸 (4.4 ml) at CO (1 atmosphere, spherical bottle) and stirred at 100 ° C for 20 hours. The obtained brown heterogeneous mixture was in water (50 ml) and EtOAc -151-this paper is compliant with Chinese National Standards (CNS) A4 size (210X297 mm) in the paper. Il X'j ii .T • j'c λ -Ugly print A7 B7 V. Description of the invention (14 "(50 ml). The EtOAc solution was washed with 2.0 M NaOH and brine (25 mL each), dried over MgS04 and concentrated to a brown oil. This material was chromatographed on Shixijiao (75 g) with EtOAc / hexane 1/2 as the eluent to obtain 3_ {4- (2- (benzobenzazole_2_yl-methyl-amino) _ethyl Oxy] -phenyl [2- (4-trifluoromethyl-lower alcohol) -anilino-methyl propionate (206.9 mg, 76%) as a yellow oil: MS (ES +) with low resolution m / e 618 (MH +); TLC (EtOAc / hexane, (1/1)): Rf = 0.51. Methyl ester (206.9 mg, 0.335 mmol) in THF / EtOH / 1.0 M LiOH (3/1 / 1,5 ml) solution was hydrolyzed according to the conditions described in Example 32 to obtain the target compound (175 mg, 86%) as a yellow solid: Hyun point 177-178 ° C; 1H NMR (CDC13, 400 MHz) d 9.13 (d , 1H, J = 7.0), 7.66- 7.61 (m, 4H), 7.45-7.38 (m, 3H), 7.24 (d, 1H, J = 7.9), 7.16-7.11 (m, 3H), 7.01 (t, 1H, J = 7.8), 6.80 (d, 1H, J = 8.6), 6.77 (d, 2H, J = 8.6), 6.61 (t, 1H, J = 7.6), 4.06-4.01 (m, 1H), 3.85 -3.78 (m, 3H), 3.27 (s, 3H), 3.24-3.18 (m, 2H); low-resolution MS (ES +) m / e 604 (MH +); analysis 値 'calculation 値 C33H28F3N305. 1.0 H20: C, 63.76; H, 4.86; N, 6.76; Found 値: C, 63.44; H, 4.71; N, 6.52. Example 74 3- {4- [2- (benzohumazol-2-yl- -Amino group) _ethoxy] _phenyl (2-thienylcarbonyl) -anilino-propionic acid, using the scheme of Example 73, the subject compound was synthesized from the intermediate U3 and 2-thienyl boron '27 % Total yield and isolated yellow solid: melting point 76_ 80 C; 1H NMR (CDC13, 400 MHz) d 8.34 (br s, 1H), 7.83 (d, 1H, J = 6.8), 7.59 (d, 1H , J = 5_0), 7.50 (d, 1H, J = 3.6), 7.43-7.36 (m, 2H), 7.23 (d, 1H, J = 7.9), 7.17-7.10 (m, 3H), 7.07 (t, 1H, J = 4.3), 7.00 (t, 152 --ί-i— fm tnn n · ^ — HI— _ I '--HH I _ m ml It-OJ (please read the precautions on the back first, then Qi 筇This paper) The size of this paper is suitable] Chinese National Standard (CNS) A4 specification (210X297 mm) Good &quot; '部 ^ JA ^^ i: J ,, i!未 Ｍ-~ ________ Β7 V. Description of the invention (_ lK J = 7.8), 6.77 (d, 1H, J = 8.4), 6.75-6.68 (m, 3H), 4.42 (br s, 1H),

4-03-3.73 (m, 4H), 3.26 (s, 3H), 3.22-3.14 (m, 2H); low-resolution MS (ES) m / e 542 (MH +); high-resolution Ms (FAB +) calculation 値 ( (MH +): 542.1750; Found: 542 1750. ijH75_ 3_ {4- [2- (benzozazol-2_yl-methyl-amino) _ethoxyphenyl} _2_ [2_ (3-pyridylcarbonyl) _aniline-propionic acid. Examples of use In the scheme of 73, the target compound was synthesized from the intermediate 113 and 3_distanoboric acid, with a total yield of 28% and a yellow solid was isolated: melting point 85_; 1H NMR (CDC13s 400 MHz) d 8.70 (d, 1H, J = 6.1), 7.73- 7.70 (m, 2H), 7.43-7.36 (m, 3H), 7.31 (dd, 1Η) J = 2.9, 4.9), 7.24 (d, 1H, J = 7.8), 7.17 · 7 .η (m, 3H), 7.0 (t, 1H, J = 7 4), 6 77_6% (m, 3H), 6.68 (t, 3H, 1 = 7.6), 4.44-4.38 (m5 1H); 4.08-4.02 (m, 1H), 3.97-0.90 (m, ih), 3.83-3.79 (m, 2H), 3.26 (s, 3H), 3 23-3.28 (m, 2H); low resolution MS (ES +) m / e 542 (MH +); analysis of tritium, calculation of tritium C3OH27N305Sl. uhw: C, 63.37; H, 5 32; &amp; 7 39; Found: C, 63, 48; H, 4.97; N, 7.08. Example 76 Benzo, bite_2_yl_methyl_amino) _ethoxy] _phenylbenzene 2_ [2_ (3_trifluoromethylbenzyl) -anilino-propionic acid Use Example 73 Scheme, the target compound was synthesized from intermediate 113 and 3-trifluorobenzene acetic acid, with a total yield of 63% and a yellow solid was isolated: melting point 159-16〇r; 1H NMR (CDCI3, 400 MHz) d 9 〇1 rd 1H J = 7 0)-(-H) ;, 74 (djlH, J =, 9), 7,4 (t3lH3j = 7_ ^ -153- —-— _____ · This paper is suitable for the standard) (CNS) M size (21〇'297mm) (Please read the precautions on the back before filling this page)

A7 —___________ ^ V. Description of the invention (15) 3H), 7.23 (d '1H, J = 8.0), 7.18-7.11 (m, 3H), 7.00 (t, iH, J = 7 7) 6.80-6.76 (m , 3H), 6.61 (t, 1H, J = 7.6), 4.48-4.46 (m, ih), 4 04_ 3.98 (m, 2H), 3.83-J.81 (m, 2H), 3.26 (s, 3H), 3.23-3.21 (m, 2H) · Low-resolution MS (ES +) m / e 604 (MH +) ·, analyze 値, calculate 値 C33H28N305.0 · 5Η20: C, 64.70; H, 4.77; N, 6.86; Measured Jun: C, 64.77; H, 4.75; N, 6.83. Fuhu 77 3- {4- [2- (benzohumazol-2-yl-methyl-amino) _ethoxyphenyl} _2_ [2_ (2-difluoromethylpyridine)- Aniline-propionic acid was synthesized from the intermediates 113 and 2 monofluoromethylphenylboronic acid using the scheme of Example 7 3's target compound. It showed a total yield of 70% and a yellow solid was isolated:

102-106 X; 1H NMR (CDC13, 400 MHz) d 9.30 (d, 1H J = 7.0), 7.74-7.72 (m, 1H), 7.58-7.55 (m, 2H), 7.40-7.32 (m, 3H ), 7.24 (d5 1H, 1 = 8.0), 7.17-7.10 (m, 4H), 7.00 (t, 1H, J = 8.0), 6.78 (d, 2H, J = 8.5), 6.74 (d, 1H5 J = 8.5), 6.52 (t, 1H, J = 7.6), 4.47-4.45 (m 1H), 4.10-4.07 (m, 2H), 3.87-3.84 (m, 2H), 3.27 (s, 3H), 3.25-3.19 (m, 2H); Low-resolution Ms (ES +) m / e 604 (MH +) ·, Analyzed value, Calculated 値 C33H28F3N305. 1 · 〇Η20: C, 63.76; H, 4.86; N, 6.76; Measured 値: C, 63.82 H, 4_72; N, 6.58. Example 78 3- {4- [2- (Benzozazol_2-yl-methyl-amino) -ethoxy] _phenyl} _2_ [2_ (3-methoxy-benzylfluorenyl) _ Aniline-propionic acid was used in the scheme of Example 73. The target compound was synthesized from intermediate 13 and 3-methoxyphenylboronic acid. It showed a total yield of 61% and isolated a yellow solid: melting point -154.-Paper size Applicable to China National Standard (CNS) A4 (2l0 × 297mm) i «^^ pn · I .....-1 &quot; H… · · ftn n (Please read the precautions on the back before filling this page ) Νβ A7 B7 V. Description of the invention (office (please read the precautions on the back before filling this page) 76-80 ° C '· 1H NMR (CDC13, 400 ΜΗζ) Θ 8.94 (d, 1H, J = 6.7 ), 7.52 (d, 1H, J = 7.9), 7.41-7.36 (m, 2H), 7.31 (t, 1H, J = 8.0), 7.23 (d, 1H, J = 8.0), 7.18-7.11 (m, 5H), 7.06-6.97 (m, 2H), 6.79-6.74 (m, 3H), 6.62 (t, 1H, J = 7.5), 4.46-4.42 (m, 1H), 4.05-3.95 (m, 2H), 3.82-3.79 (m, 2H), 3.80 (s, 3H), 3.26 (s, 3H), 3.21 (d, 2H, J = 6.0); low-resolution MS (ES +) m / e 566 (MH +); analysis値, calculate 値 C33H31N3〇6 · 1.5Η20: C, 66.88; Η, 5.78; N, 7.09; measured 値: C, 66.53 pyrene, 5_45; N, 6.78. Example 79 3- {4- [2- (Dongpeng p-2 -yl-methyl-amino) -ethoxy] -phenyl} -2- [2_ (2-methoxy-benzylfluorenyl) -aniline-propionic acid The scheme of Example 73 was used. The subject compound was synthesized from intermediate 113 and 2-methoxyphenylphenylboronic acid in a total yield of 49% and Isolated yellow solid: melting point 98-102Ό; 1H NMR (CDC13, 400 ΜΗζ) β 9.38 (d, 1H, J = 6.7), 7.43-7.31 (m, 4H), 7.23-7.21 (m, 2H), 7.18- 7.12 (m, 3H), 6.78 (d, 2H, J = 8.5), 6.74 (d, 1H, J = 8.6), 6.55 (t, 1H, J = 7.6), 4.45-4.43 (m, 1H), 4.00 -3.95 (m, 2H), 3.81-3.79 (m, 2H), 3.72 (s, 3H), 3.26 (s, 3H), 3.23-3.21 (m, 2H); low resolution MS (ES +) m / e 566 (MH +); Analyze plutonium, and calculate plutonium C33H31N30.6 · 2.0H2O: C, 65.88; H, 5.86; N, 6.98; Found puppet: C, 65.98; H, 5.50; N, 6.64. Example 8 0 3- {4- [2- (Winter p-jun-2-yl-methyl-amino) -ethoxy] -phenyl] · _2- [2- (3-fluorenyl-fluorene Fluorenyl) -aniline-propionic acid using the scheme of Example 73, the target compound is from the intermediate 113 and 3-methyl-155- This paper is suitable for the state of China. National Standard (CNS) A4 size (210X297 mm)浐 部-^ JA &quot; 'iv-x'J *' Ji-T; ii'frAD bamboo; ^ 卬 ΊAΊ ___________ Β7_ V. Description of the invention (_ phenylphenylboronic acid synthesis, 52% total yield and isolated Yellow solid: melting point 80-85 ° C; 1H NMR (CDC13, 400 MHz) d 10.8 (br s, 1H), 8.91 (br s, 1H), 7.50 (d, 1H, J = 8.0), 7.41-7.35 ( m, 4H), 7.32-7.28 (m, 2H), 7.24 (d, 1H, J = 8.0) 5 7.19-7.12 (m, 3H), 7.01 (t, 1H, J = 7.7), 6.77 (d, 2H , J = 8.6), 6.72 (d, 1H, J = 8.5), 6.61 (t, 1H, J = 7.5), 4.42 (m, 1H), 4.09-4.01 (m, 2H), 3.85 (m, 2H) , 3.28 (s, 3H), 3.25-3.19 (m, 2H), 2.38 (s, 3H); low-resolution MS (ES +) m / e 550 (MH +); analysis of radon, calculation of C33H31N305. Ι · 5η2〇: C, 68.74; H, 5.94; N, 7.29; Found 値: C, 68.49 H, 5.66; N, 7.00. Example 8 1 2- [2- (4_Difluorenyl Methyl_benzylfluorenylaniline] _3_ {4_ (2_ (5-methyl_2_phenyl-oxazol-4-yl) -ethoxy] _phenylpropionate hydrochloride Sodium chloride (20 mg, 0.33 mmol) was added to the intermediate 丨 23 (96 mg, 1.63 mmol), diamine (0.85 ml, 〇17 mmol)

Ear), and HOAc (3.7 ml, 0.065 mmol) in a solution of MeOH / THF ((3/1) '4 ml). The resulting solution was stirred under n2 for 6 hours. The solution was diluted with EtOAc (50 mL) and washed with 10% NaHCO3 (20 mL) and brine (20 mL). The solution was dried over MgS04 and concentrated to a yellow semi-solid 'which lysed the low-polar product with EtOAc by dream gel flash chromatography and then the product dimethylamidomethyl ester with EtOAc / MeOH 98/2: Low resolution Ms (ES) m / e618 (MH +); TLC (EtOA): Rf0_l3. This material was hydrolyzed according to the method described in Example 32 to obtain the target compound (28.0 mg, 27% in two steps) as a yellow solid: melting point 103-105. 〇 m NMR (CD3OD, 400MHz) &lt; 5- 7.94 (br s, 2H), 7.90-7.36 (m, 9H), 7.16 (d, 2H, J = 8.2), 6.82- -156 -2l0x 29Ί ^ &amp;) ---- ~ --------- I — (Read the notes on the back first and then fill out this page)

, 1T A7 B7 five 'invention description (say 6.77 (m, 3H), 6.57 (t, 1H, J = 7.3), 4.52 (t, 1H, J = 5.4), 4.39 (s, 2H), 4.18 (t, 2H, J = 6.3), 3.24 (dd, 1H, J = 4.6, 13.7), 3.10 (dd, 1H, j = 6.8, 13.8), 2.94 (t, 2H,> 6.3), 2.89 (s, 6H) , 2.33 (s, 3H); low-resolution MS (ES) m / e 604 (MH +); high-resolution ms (FAB +) m / e (MH +) calculation 値 C37H37N305: 604.281 1, measured 値: 604.2816. A case 82 2_ [2- (4-Aminemethyl-benzylfluorenyl) _aniline] _3_ {4_ [2_ (5 • methyl_2_phenyl_amidine-4-yl) -ethoxylated] -benzene Propionate Hydrochloride Sodium borohydride (11 mg, 284 mmol) was added to a solution of intermediate 123 (167 ul g '0.284 ¾ mol) in THF (20 ml). The resulting solution was under N2 Stir for 30 minutes and quench with acetone (1 mL). After stirring for another 30 minutes, the mixture is diluted with EtOAc (50 mL) and diluted with 2.0 μ NaOH, 1.0 M NaHC0 and brine (each 2.0 μL).耄) Washing. This solution was dried at ^; §0.4 and concentrated to a dark brown oil, which was flash-chromatographed on silica gel with EtOAc / hexane 2/3 as the eluent to obtain fluorenyl alcohol ( 129 mg, 77% yield Rate) was a yellow oil: low resolution MS (ES +) m / e 591 (MH +); TLC (EtOAc / hexane (1: 1));

Rf = 0_33. Methanesulfonium gas (140 ml, 0.18 mmol) was added to the above-mentioned fluorenyl alcohol (97 mg, 0.165 mmol) and triethylamine (27.5 ml, 0.20 mmol) in CH2C12 ( 3 ml). The resulting solution was stirred under n2 for 3 hours. The liquid was diluted with EtO Ac (50 ml) and washed with 2.0 M HC1, water, 1.0 M NaHC0 3 and brine (20 ml each). The solution was dried over MgS 04 and concentrated to give the corresponding mesylate. (MesWate) (105 mg) main yellow oil. Low resolution MS (ES +) m / e 669 (MH +); TLC (EtOAc / toluene (1/3)); R yield 0.74. (31 mg, 0.18 mmol -157- This paper ruler / ϊΤΤguan standard (CNS) A4 size (2lGxY97 mm) (read the precautions on the back before filling in this page)

-¾. 1 in the ministry quot; · ^ · ^, · ^, and disappeared in combination with the bamboo shoots-India A7 B7 V. Description of the invention (~ ear) Add the above-mentioned mesylate (10.5 mg) (0 U6 mmol) in a solution of dmf (2.5¾ liters). The resulting solution was stirred under N2 for 6 hours. M NaHC03 (after 1 ml) was added, the solvent was removed by rotary evaporation and the residue was distributed between = (20 ml) and Et0Ac (50 ml). The EtOAc solution was washed with water and brine (20 liters each), dried over MgSCU, and concentrated to give a benzyl azide (96.3 mg) as a yellow oil: low dissociation Ms (ES +) m / e 616 (MH +); TLC (EtOAc / hexane (1/2)); R-45. Triphenylphosphine (45 mg, 0.172 mol) was added to a solution of the above azide (96 mg, 0156 mol) in THF (5 ml). The resulting solution was stirred under n2 for one hour. The liquid was then diluted with EtOAc (50 mL) and washed with 2.0 μ NaOH (100 μL) and brine (25 μL). The organic solution was dried over MgS04 and concentrated to give a yellow oil, which was flash-chromatographed on silica gel with CHCl3 / MeOH 95/5 as the eluent to obtain benzylamine sulfonate (73 mg, 75% yield from fluorenyl alcohol). Yellow oil: low-resolution MS (ES +) m / e 590 (MH +); TLC (CHCl3 / MeOH (9/1); R. 0.23. The above sulfonamides were dissolved in THF / EtOH / lO M LiOH (3/1 / 1.5 ml) solution was stirred under Ns for 16 hours. The solvent was removed by rotary evaporation and the residue was dissolved in water (15 ml) and washed with ether (25 ml). The aqueous layer was acidified with 2.0 M HC1 to A flocculent suspension was obtained at pH 2. The mixture was concentrated to 5 ml and centrifuged (7100 rpm, 5 minutes). The aqueous solution was decanted and the resulting yellow flakes were resuspended in water (10 ml) and centrifuged (3X) as described above. The yellow solid thus obtained was suspended in water (2 ml) and lyophilized. The obtained yellow solid was suspended in EtOAc and centrifuged (3X). The obtained flakes were dried in the air to obtain the target compound (56.8 mg, 82% yield). Yellow powder: melting point 134-136 ° C; lHNMR (DMSO-d6,400 MHz) d 8.86 (d, -158- This paper is in accordance with China National Standard (CNS) A4 regulations (2lOX 297 mm) (W Please read precautions on the back of reloading awakened this page)

A7 __ B7 V. Description of the invention (埘 ~~~ 1H, J = 7.1), 7.89-7.86 (m, 2H), 7.53-7.41 (m, 7H), 7.34 (t, 1H J = 7.2), 7.25 (d , 1H, J = 8.0), 7.10 (d, 2H, J = 8.4), 6.81 (d 1H J = 8.7), 6.76 (d, 2H, J = 8.6), 6.45 (t, 1H, J = 7.5), 4.22-4.19 (m, m) 4.08 (t, 2H, J = 6.5), 3.96 (s, 2H), 3.09 (dd, 1H, J = 5.5, 13.7), 2 94 (dd, 1H, J = 6.1, 13.3), 2.84 (t, 2H, J = 6.5), 2.30 (s, 3H); low resolution Ms (ES +) m / e 576 (MH +); high resolution MS (FAB +) m / e (MH +) calculation 値 C35H33N305 : 576.2498; Found 値: 576.2495; TLC (CHClVMeCm (4/1) + 1 drop of HOAc); Rf = 0.30. Example 83 3- {4- [2- (Benzamenzazol-2-yl-methyl-amino) _ethoxy] _phenyl (2,6-dimethylpentanogfyl) -aniline- Propionic acid was used in the scheme of Example 73. The target compound was synthesized from intermediate 1 η and 2,6-dimethylphenylboronic acid. The total yield was 13% and a yellow solid was isolated: melting point 85-9 (TC; 1H NMR (CDC13, 400 MHz) d 9.46 (d, 1H, J = 7.0), 7.34-6.93 (m, 12H), 6.69 (m, 3H), 6.44 (t, 1H, J = 7.6), 4.40-4.38 ( m, 1H), 3.99 (br s, 2H), 3.81 (br s, 2H), 3.23 (s, 3H), 3.22-3.11 (m, 2H), 2.05 (s, 3H), 1.99 (s, 3H) ; Low-resolution MS (ES +) m / e 564 (MH +); Calculated by analytic MS (FAB +); C34H33N305 (MH +): 564.2498; Found: 564 2484. Example 84 3- (2_ {1-carboxy_2_2 -[4- (2- {5-Methyl-2-phenyl-oxazole_4-yl} -ethoxy) -phenyl] -ethylamino) -benzylbenzylbenzoic acid will be 2.67 M Jones ( J0ne, s) reagent (48 ml, 128 mmol) was added dropwise to intermediate 124 (75 mg, 128 mmol) in acetone (5 ml) -159- This paper is suitable for household materials (CNS.) A4 specifications (21GX297 mm) A7 B7 V. Description of the invention (to -------- ^ --- Q — I (please first Note Complete this page and then read it back)

Falling liquid. The resulting dark green solution was allowed to stir for 2 hours. The reaction was quenched with the addition of isopropanol (1 liter). After stirring for another 15 minutes, the mixture was diluted with EtOAc (50 mL) and washed with 1.0 M HC1 (20 mL), water (20 mL) and brine (10 mL). This solution was dried over MgS04 and concentrated to a brown oil. It was chromatographed on silica gel with CHCl3 / MeOH (98/2 containing ο!% H0Ac) and chromatographed to give 3_ (2- {1-carboxy-2- [4_ (2 · {5-fluorenyl-2-phenyl-oxazol-4-ylbuthoxy) · phenyl] -ethylamino) -benzyl methylsulfonyl methyl ester (25 mg, 33%) is yellow Oil: Low resolution MS (ES) m / e 605 (ΜΗ +); TLC (CHCl3 / Me0H (95/5)); Rf = 0.2. The above methyl ester was hydrolyzed according to the procedure of Example 32 to obtain the target compound (24 mg, 98%) as a yellow solid: melting point ι07_ιιο ° C; 1H NMR (DMSO-d6, 400 MHz) cy 13.15 (brs, 1H), 13.〇〇 (br s, 1H), 8.58 (d, 1H, J = 7.8), 8_U (d, 1H, J = 7, 8), 8 〇1 (s, 1H), 7 grab 7_87 (m, 2H), 7.77 (d, 1H, J = 7_8), 7.63 (t, ih, J = 7.6), 7.49_74〇 (m, 4H), 7.31 (d, 1H, J = 6.6), 7.08 (d, 2H3 J = 8.5), 6.84 (d 1H J = 8.5), 6.79 (d, 2H, J = 8.5), 6.60 (t, 1H, J = 7.5), 4.55-4.52 1H) 5 4.11 (t, 2H, J = 6_6), 3_31 (s, 3H), 3.14 (dd, 1H, J = 5.4, 13 9) '3 like ⑽, m, m.6, 14.2), 2.85 (t, 2H, J = 6.6 ), 2 29 (s, 3H); Low-resolution · (ES-) m / e 589 (M-Η '); Analyze plutonium, calculate C35H3〇N207. 0.5H2O: C, 70 n; H, 5 21; N, 4 67; Found 値 c, 6 5.28; N, 4.51 ^. ,, Example 85 2- [2- (3-hydroxymethyl-familyl) _aniline] _3_ {4_ [2_ ( 5_Methyl — No.-4-yl) _ethoxy] _phenyl} _propionate topsoil Sodium borohydride (16.5 mg, 0.43 mmol) was added to the intermediate Η * -160- Paper Zhang scale is applicable to China Standard (CNS) A4 specification (210X297 mm) ΑΊ ~ ___ B7 V. Description of the invention (1 Wei (257 mg, 0.43 mmol) in THF (10 ml) solution. The resulting solution was stirred for 45 minutes under N2 It was quenched with acetone (1 mL) and mixed for 10 knives. After adding 1 _ 0 M NaHC0 3 (1 mL), the solvent was removed by rotary evaporation and the residue was taken up in EtOAc (50 mL) and Water (20 mL) was distributed. The EtOAc layer was washed with water (20 mL) and brine (; [0 mL) and dried over MgSO. This solution was concentrated to give a yellow oil, which was added to dream gum (30 g). EtOAc / hexane (2/3) flash chromatography to obtain 2- [2- (3-hydroxymethyl_fluorenylaniline] _3_ {4_ [2- (5-methyl-2-phenyl -Hemazole_4-yl) _ethoxymethylphenylphenylpropionate (21 1 mg, 82% yellow oil: low resolution MS (ES +) m / e (MH +); TLC (EtOAc / hexane (1: 1)); Rf = 0 39. A solution of methyl ester (45 mg) was hydrolyzed according to the procedure described in Example 32 to obtain the target compound (43 mg, 97%). The main yellow solid: melting point 87-9CTC; 1H NMR (DMS0-d6, 400 MHz) ^ 12.98 (s, 1H), 8.60 (d, 1H, J = 7.7), 7.89 (d, 1H, J = 7.9), 7.47- 7.33 (m, 9H), 7.10 (d, 2H, J = 8.5), 6.82- 6.79 (m, 3H), 6.59 (t, 1H, J-7.6), 5.30 (t, 1H, J = 5.6), 4.55 (d, 2H, J = 5.9), 4.54-4.48 (m, 1H), 4.12 (t, 2H, J = 6.8), 3.13 (dd, 1H, &gt; 5.2, 14.0), 3.02 (dd, 1H, 6.4, 14.0), 2.87 (t, 2H, J = 6.8), 2.31 (s, 3H ); Low-resolution MS (ES +) m / e 575 (M-Η ·); Analyze 値, calculate 値 (c35H32N2 0 6 〇5Η2〇) c, 71% H, 5.68; N, 4.78; Measured 値 c , 7 1.70; H, 6.60; N, 4.45. Example 86 2_ [2_ (3-Aminemethyl-benzylfluorenyl) _aniline] -3- {4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy Phenyl}}-propionic acid hydrogenate was converted to the target compound by the same synthetic method as h A Example 8 2 · melting point 138-14. 〇: 1H NMR (dms〇_ 必, 400MHz) -161-This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297mm) (Please read the precautions on the back before filling in the cover page)- --- 、 1T .-- .. ^^ 本 ^ *,;!-&Quot; Eliminated in Cangzhu ^ 卬% A7 B7 V. Description of the invention (15 纟 ^ 8.68 (d, 1H, J = 7.4), 7.88-7.28 (m, 11H), 7.08 (d, 2H, J = 8 5) 6.76-6.73 (m, 3H), 6.49 (t, 1H, J = 7.5), 4.29-4.25 (m, 1H ), 4.09 (t, 2H, J = 6.7), 3.09 (dd, 1H, J = 5.0, 13.9), 2.95 (dd, 1H, J = 6.7, 13.9) 2.29 (s, 3H); Low-resolution MS (ES + ) m / e 576 (MH +); Analyze Jun, calculate 値 C35H33N305. Ηα. 0 · 75Η2〇) C, 67.19; H, 5.72; N, 6.72; Found 値 C, 67.25; H, 5.92; N, 6.35. t Example 87 2- [2- (3-Dimethylaminomethyl-benzyl) _aniline] _3_ {4_ [2_ (5_methylphenyl-17 # -4-yl) -ethoxy Group] -phenyl} -propionate hydrochloride was used in a similar manner to Example 81 to convert intermediate 124 to the target compound: melting point 120-124Ό; lHNMR (DMSO-d6,400 MHz) β 9.98 (s 1H ), 8.66 (d3 1H, J-7.6), 7.89-7.34 (m, 11H), 7.11 (d, 2H, J = 8.5), 6.84-6.80 (m, 3H), 6.60 (t, 1H, J = 7.5 ), 4.55-4.52 (m, 1H), 4.33 (d, 2H, J = 5.4), 4.12 (t, 2H, J = 6.7), 3.14 (dd, 1H, J = 6.7, 14.0), 3 〇] ( dd, 1H, 1 = 6.7, 14.0), 2.87 (t, 2H, 1 = 6.5), 2.70 (d, 6H, J = 3.5), 2.31 (s, 3H); low-resolution low-resolution MS (ES +) m / e 604 (MH +); Analyze tritium, and calculate C37H37N3O5 .HCI.3H2O) C, 64.01; H, 6.39; N, 6.05; Measured tritium C, 63.62; H, 6.03; N, 5.78. Example 88 2 (S)-(1-Leptyl-2- {4- [2- (5-methyl-2-phenyl-azine-4-yl) -ethoxy] _phenyl} -ethyl Amine) -methyl benzoate A solution of intermediate 125 (582 mg, 1-13 mmol) in THF / EtOH / 10 M LiOH (3/1/1, 15 ml) was searched under N 2 for 2 hours. Add 0.4 M HC1 (25 ml) solution and then extract and mix with EtOAc (150 ml) -162- This paper is sized to China National Standard (CNS) A4 size (210X297 mm) (Please read the notes on the back first Fill in clothes again &quot;)

A7 B7 V. Description of the invention. This extract was washed with brine (25 ml) and dried over Na2S04 and concentrated to a white solid. This material was flash-evaporated in a silica gel with Eto The target compound (450 mg, 80%) was isolated as a white solid: melting point 140-14TC; 1H NMR (DMSO-d6, 400 MHz) δ 12.95 (br s, 1H), 7.94-7.88 (m, 3H), 7.77 ( d, 1H, J = 8.0), 7.49-7.45 (m, 3H), 7.35 (t, 1H, J = 7.9), 7.08 (d, 2H, J = 8.5), 6.82 (d, 1H, J = 8.6) , 6.69 (d, 1H, J = 8.6), 6.59 (t, 1H, J = 7.5), 4.42-4.38 (m, 1H), 4.15 (t, 2H, J-6.7), 3.75 (s, 3H), 3.09 (dd, 1H, J = 5.3, 13.9), 2.96 (dd, 1H, J = 6.1, 14.0), 2.89 (t, 2H, J = 6.6), 2.32 (s, 3H); Low-resolution MS (ES + ) m / e 501 (MH +); TLC (EtOAc): Rf = 0.51; Palmar chromatography (Chiralcel OD-H, 4.6 X 250 mm, EtOH / hexane (3/7) and 0.1% TFA, 0.7 ml / Min): tr = 7.8 points (main enantiomer), 7.2 points (secondary enantiomer): 88% ee; [a] D = -9.8., A = -0.1〇9., C = 1. ll (CH_2C12) (uncorrected.ee); analysis, calculation: C, 69.51; H, 5.68; N, 5.54; found: C69.40; H, 5.7 4; N, 5.42. Example 89 in the middle of the head H 乂 'J ϋ -X 消 i: a print I --- ^ --------I-n-^ (Please read the note on the back first Please fill in this page for more information) 2 (S)-(1-carboxy-2_ {4_ [2_ (5_fluorenyl_2_phenyl-oxazole_4_ylethoxy] -phenyl} -ethylamino ) _Benzoic acid 2-amineethylamidamine hydrochloride Add 1-ethyl-3- (3-diamidinoaminopropyl) carbonyldiimide (22.4 mg, 117 mol) to intermediate 126 (48.9 Mg, 0.98 mmoles), HOBt (5 mg, 37 mmoles), triethylamine (20.4 ml, 146 mmoles), and tert-butyl N- (2-aminoethyl) carbamate (169 Ml, mol (7 ml), in a solution of CH2C12 (5 ml). The resulting solution was stirred under n2 for 16 hours and then diluted with EtOAc (50 ml) and 25 ml each of 0.5 M HC1 -163. This paper is standard; 1] National Standard (CNS) A4 specification (21 χ 297 mm A7 B7 Five 'invention description (16)

(2x) Wash and saturate with NH4C1, water and 2.0 M NaHC03 (2X) and brine (10 mL). This solution was dried over MgS04 and concentrated to a brown oil, which was flash-chromatographed on a crushed gel with EtOAc / hexane 1/1 as the eluent to obtain the target compound (37 mg, 59%) as a colorless oil: low resolution MS (ES +) m / e 643 (MH +); TLC (hexane / EtOAc (1/1)): Rf = 0-35. A solution of this material in THF / EtOH / l.o M LiOH (3/1/1, 5 ml) was stirred under n2 for 16 hours. The solvent was removed by rotary evaporation and the residue remaining in water (10 mL) was absorbed and acidified with 2.0 M HC1 (2 mL). The resulting mixture was extracted with EtOAc (50 mL). The extract was washed with brine (10 ml), dried over MgS04 and concentrated to a colorless solid. This material was dissolved in 4.0 M HC1 bisaki Yu: (2 ml) and mixed under N2 for 1 hour. Dioxane removed the target compound in the air (4.2 mg; 100%) as a wet white solid: melting point 1-15. 〇; iH NMR (DMS0-d6, 400 MHz) δ 8.47 (m, 1H), 7.92-7.88 (m, 3H), 7.63 (d, 1H, J = 7.4), 7.48-7.47 (m, 3H), 7.25 (t, 1H, J = 7.7), 7.11 (d, 2H, J-8.5), 6.82 (d, 2H, J = 8.5), 6.62-6.56 (m, 2H), 4.26 (m, 1H), 4.15 ( t, 2H, J = 6.5), 3.68-3.66 (m, 1H), 3.48-3.43 (m, 3H), 3.02-2.87 (m, 4H), 2.33 (s, 3H); low resolution MS (ES +) m / e 529 (MH +); High resolution MS (FAB) C3OH32N4〇5 (MH +): 529.2451; Found 値: 529.2454; TLC (CHCl3 / MeOH (9/1)): Rf = 〇04. Example 90 2 (S)-(1-carboxy-2- {4- [2_ (5_methyl_2_phenyl_azazole_cardiyl) · ethoxy] _phenyl} -ethylamino) -Benzoic acid 3-Aminopropylamidoamine hydrochloride Using a similar method to that described in Example 89, the target compound was obtained in 95% yield from intermediate 126 and N- (3-aminopropyl) carbamic acid third butyl Made of wet white -164-This paper is suitable for Chinese National Standard (CNS) A4 size (210X297). -11-1 1 I 11 ϋ nn 1 ---- -1 (Please read the Please fill out this page again) ^ ϋϋ ^^^^ 1 Hit 3 * ^ m «IMl .nn

T Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 _: _B7_ V. Description of the invention (162) Color solid · Melting point 95-98Ό; 1H NMR (DMS0-d6, 400 ΜΗζ) ί 8.47-8.44 (m, 1H) , 7.90-7.80 (m, 4H), 7.56 (d, 1H, J = 6.8), 7.50-7.46 (m, 3H), 7.24 (t, 1H, J = 7.3), 7.12 (d, 2H, 1 = 8.5 ), 6.83 (d, 2H, J = 8.6), 6.62-6.56 (m, 2H), 4.27-4.24 (m, 1H), 4.16 (t, 2H, J = 6.7), 3.28-3.25 (in, 2H) 3.04-2.81 (m, 6H), 2,34 (s, 3H), 1.79-1.76 (m, 2H); low resolution MS (ES +) m / e 543 (MH +); high resolution MS (FAB +) calculation C31H34N405 (MH +): 543.2607; found tritium: 543.2609; TLC (CHCl3 / MeOH (9/1)): Rf = 0.04. Example 91 · 2- (S)-(l-carboxy-2- {4- [2- (5-methyl-2-phenyl-yin-4-yl) -ethoxy] _phenyl} • Ethylamino) -Methyldonylamine Benzoate Add 1-ethyl-3- (3-dimethylaminopropyl) carbonyldiimide (22.7 mg, 0.12 mmol) to intermediate 1 26 (49 · 5 Mg, 0.10 mmol, HOBt (6.7 mg, 49 mmol), triethylamine (41.3 ml, 0-30 mmol) and methylamine (12.8 ml (40% solution in water), 0.15 mmol Mol) in CH ^ Cl2 solution. The resulting solution was stirred under n2 for 16 hours and then

Diluted with EtOAc (50 mL) and washed with 20 mL of 0.5 M HC1 (2x0, saturated NHK1, water and 2.0M NaHC03 (2x). This solution was dried over MgSO and concentrated to give a yellow oil. 33.8 mg (67%) of colorless oil in Mengjiao (10 g) with EtoAc / hexane (1/1) flash chromatography: low resolution MS (ES +) m / e 514 (MH +) TLC (hexane / EtOAc (1/1): Rf = 031. This material was hydrolyzed according to the procedure described in Example 32 to obtain the target compound (33.4 mg, 100%) as a white solid. La85-9 (TC; mNMR (; DMSO- d6, 400 MHz) Θ 12.71 (s, m), 8.24-8.20 〇, 2H), 7.90-7.88 -165- This paper size applies Chinese National Standard (CNS) Α4ϋΓ (210X297 公 楚) '~~ ~-(Please read the precautions on the back before filling this page) Order printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 ---------- B7 V. Invention Description (163) (m '2H) , 7.49-7.45 (m, 4H), 7.21 (t, 1H, J = 7.2), 7.10 (d, 2H, J 8.5), 6.82 (d, 2H, J = 8_5), 6.60-6.53 (m, 2H) , 4.23-4.22 (m, 4.15 (t, 2H, J = 6.5), 3.02 (dd, 1H, J = 5.6, 13.8), 2.92 -2.87+ (m, 3H), 2.69 (d, 3H, J = 4_5 ),2 _33 (s, 3H); low-resolution MS (ES) m / e 500 (MH +); TLC (Hexane / EtOAc (2/1)): Hf = 0 06. Order 3- {Anal [2- (benzene Benzoxazole_2_yl-fluorenyl-amino) _ethoxy] _phenylbenzene 2_ [2 -_ (3-¾yl-benzyl) _aniline] _propionic acid standard compound (140 g) Based on 500 mg (088 mmol) of intermediate and 111 Aike (2.65 mmol) hydroxide chain monohydrate according to the method of Example 32 followed by silica gel flash column chromatography with MeOH. / Dichloromethane 丨: 19 was prepared as an eluent for purification: 1H NMR (DMS〇_d6) β 12 97 gamma, 1H), 9.74 (s, 1H), 8.54 (d, 1H, J = 7.7) , 7.36 (m, 3H), 7.25 (m, 2H), 7.09 (m, 3H), 6.93 (m, 4H), 6.79 (d, 3H, J = 8.7), 6.57 (t, 1H, J 7.5 ), 4.48 (m, 1H), 4.16 (t, 2H, J = 5.3), 3,83 (t, 2H, J = 5.3), 3.11 (m, 4H), 2.99 (m, 1H); low-resolution milk (Yang) 111/6 552 (^ 1 mine); 111> -hplc (50-100% ch3cn in water with 0 1% TFA buffer, 25 points): tr = 7.46 points. Example 93 3- {4- [2_ (5-Methenyl-2_phenyl-oxazole_4_ylethoxyphenyl) 2_ [2_ (4_propylaminesulfonyl-benzyl)- Aniline] _propionic acid target compound (31 mg) is derived from 70 mg (.02 mmol) of Intermediate 1: &gt; 1 and 21 g (0.31 ΐ: Mo. ear) hydroxide list The hydrate was in accordance with the method of Example 32, followed by MeOH / hexane (1:19) and then EtOAc / hexane-166- this k-sheet scale applies the Chinese National Standard (CNS) A4 specification &quot; Γ2ι〇 × 297 mm) &quot; '' ~~ (Please read the precautions on the reverse side before filling out this page), π ^ 7 ^ 中 ^ &quot; '^ And,-only Ding, eliminate' &quot; made, ^ 卬 4 '' : ^ · A7 B7 V. Description of the invention ((1:19) Milled and purified to prepare it. \ Yong 侑. 1Η NMR (DMS0-d6) with D20 exchange, 300 Mhz) ά 7.88 (d 4Η ί q η ^ 4Η , J = 8.4), 7.68 (d, 2Η, J = 8.1), 7.43 (m, 4Η), 7.27 (d, 1Η, J = 7 9, 7η〇η, ττ) &gt; 7.09 (d, 2H, J = 8.4), 6.80 (m, 3H), 6.58 (t, 1H, 1 = 7.5), 4.52 (m A, 1H), 4.12 (t, 2H, J = 6.3), 3.00 (dd, 1H, J = 6.5 , 14.1), 2.84 (t 2H T ~ a ο q π, t V 5 j-6.5), 2.72 (t, 2H, J = 7.1 ), 2.28 (s, 3H), 1.38 (m, 2H), 0.77 (t 3H T-7 u π &amp; λ V, state, J-7.3); low resolution ms (ES) m / e 668 3 (MH + ); RP-HPLC (50-_CH3CN in water with 0% TFA buffer, 25 minutes): 14.52 points; analytical value aw o '0.5H20) C, 65.66; H, 5.66 · N 6 ^ ^ With 6.21, 値 C, 65 82; H, 5 61; N, 6.18 〇 Example 94 2- (2- (3-Amino_fluorenyl) _anilino] _3_ {4_ [2-methyl group _2_Phenyl-chryso-4-yl) -ethoxy] -phenylpropionate (35 mg) was derived from 73 mg (〇13mmol) of intermediate B2 and 19 grams ( 〇39 耄 mol) 氲 Lithium oxide monohydrate according to the method of Example 32, followed by silica gel flash column chromatography with ethyl Me0H /: aeroline (gradient 1.19 to 1: 4) Purified as a precipitation solution, and then prepared by milling with MeOH / hexane (1: 9): 11 ^ 11 (〇? ^ 〇- (16,300) ^ 112) (5'8.64 ((1, 1H , J = 7.1), 7.88 (m, 2H), 7.46 (m, 3H), 7.27 (m, 2H), 7.08 (m, 3H), 6.69 (m, 4H), 6.56 (d, 1H, J = 7.3 ), 6.42 (m, 1H), 5.28 (br s, 2H), 4.09 (m, 3H), 3.09 (m, 1H) 2.87 (m, 3H), 2.29 (m, 3H); low resolution MS (ES) m / e 562 (MH +); RP-HPLC (0-100% CH3CN in water with 0.1% TFA buffer, 25 points): tr = 16_51 points; high resolution MS (FAB) m / e 562.2348 (MH + ), C34H31N305 requires 562.2342. -167- This paper size applies to China's National Standards (CNS) A4 size (210 × 297 mm) (Xu Xianmin read the note on the back _ ^ 4 more pages)

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 __ ___—— _ B7 V. Description of the Invention (165 ^ '： — Example 95 2- [2- (3-Methanesulfonamidofluorenyl) _aniline] _3_ {心 [2_ (5_methyl_2, phenyl-oxazol-4-yl) -ethoxy] _phenylpropionate The target compound (23 mg) is from 60 mg (〇〇〇〇mmol) Ear) Intermediate 133 and 1 μg (0.28 mmol) of lithium hydroxide monohydrate according to the method of Example 3 2 'followed by silica gel flash column chromatography with MeOH / dichloromethane (丨: 9 1% acetic acid) was prepared as an eluent for purification: iH NMR (DMS〇_d6, 400 MHz) (y 8.74 (d, 1H) J = 6.9), 7.87 (m, 2H), 7.37 (m, 8H) , 7.18 (m, 1H), 7.07 (m, 2H), 6.72 (m, 3H), 6.44 (m, 1H), 4.20 (br m, 1H), 4.07 (m, 2H), 3.13 (m, 1H) , 2.96 (m, 4H), 2.84 (m, 2H), 2.29 (s, 3H); low resolution MS (ES) m / e 640.2 (MH +); RP-HPLC (50-100〇 / o CH3CN in water with 〇.1% TFA buffer solution, 25 points): tr = 12.02 points; 咼 MS (FAB) m / e 640.2116 (MH +), C35H33N307S requires 640.2117. Example 96 2- [2- (3- -Carboxamide _Benzylsulfonyl) _ Amine] _3_ {4_ [2_ (5_methyl_2_phenyl-humazol-4-yl) -ethoxy] -phenyl} -propionic acid target compound (28 mg) is from 50 mg (0.79 mmol) Intermediate I34 and 12 gram (0.28 mmol) of lithium hydroxide monohydrate were prepared according to the method of Example 32, followed by silica gel flash column chromatography with MeOH / II. Air roasting (1: 9 with 0.1% B) was purified as an eluent, and then prepared by milling with Eto-Ac / hexane (1: 9): m NMR (abdominal 50-shaped with 0 2 〇⑽ ^ Hey, 400 MHzH 9.80 (s, 1H), 7.86 (m, 2H), 7 57 (m, 2H) 7 45 (m, 3H), 7.32 (m, 3H), 7.05 (m, 3H), 6.72 (m, 3H), 6.48 (m, 1H), 4_24 (br m, -168-this .. The Zhang scale is applicable to the Chinese National Standard (CNS) M specification (21〇 &gt; &lt; 297 public director) f please (Read the notes on the back before filling out this page)

Order _ Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs Α7 Β7 V. Description of the Invention (166) 1H), 4.08 (m, 2H), 3.61 (s, 3H), 2.92 (m, 1H), 2.82 (m, 2H ), 2.25 (s,

jH), low resolution MS (ES) m / e 642 (MNa +), 620 (MH +); RP-HPLC (50-100% CH3CN in water with 0.01% TFA buffer, 25 points):% = 13.73 points; South analysis Ms (FAB) m / e wo 2384 (MH +), 匸 36: «33 ^ [307 requires 620.2397. Example 97 2- [2- (3-hydroxy-benzylfluorenyl) _aniline] _3_ {4_ [2_ (5_methyl_2_phenyl · fluoren-4-yl) -ethoxy] -benzene The compound (13 g) of gadolinium propionate is based on 50 mg (0.087 mmol) of intermediate 136 and 13.6 mg (0.32 mmol) of lithium hydroxide monohydrate. According to Example 32 I method Then, it was purified by MesoH / digas methane (gradient 1.9 to 1: 9 + 0.1% acetic acid) as the eluent by Shijiao flash column chromatography, and then MeOH / hexane ( 1:19) prepared by milling: m NMR (DMS〇_d6, MHz). 9.77 (br s, 1H), 8.66 (m, 1H) 3 7.87 (m, 2H), 7.46 (xn ^ SH), 7.26 (m, 3H), 7.06 (m, 2H), 6.89 (m, 3H), 6.72 (m, 3H), 6.45 (m,

1H), 4.10 (t, 2H, &gt; 6.6), 3.12 (m, 2H), 2.85 (m, 3H), 2.30 (s, 3H); low resolution MS (ES) m / e 561 (MH) +; RP-HPlc (50_100% CH3CN buffered in water, 25 points): tr = 12121 points; high-resolution MS (FAB) m / e 563.2186 (MH +), C34H3ON2〇 ^ Mum. Example 98 2- [2- (3-Carboxyfluorenylmethoxy-benzylfluorenyl) _aniline] _3_ {4_ [2 · (5_methyl · 2_phenyl-humazol-4-yl) -ethyl Oxy] -phenylpropionate target compound (16 mg) is derived from 73 mg (0 12 mmol) of intermediate 13? And 16.0 mg (0.38 mmol) of lithium hydroxide monohydrate according to Examples 32 -169 -This paper rule relies on financial rewards (⑽) (Please read the notes on the back before filling in this page). Booklet V. Invention Description (16 owing methods, then borrow silica gel Λ / Menluo official column chromatography Purified with EtOAc / hexane (1: 9) as the eluent. Τ u χΤΛ NMR (CDC13, 400 MHz) d 8.67 (m, 1H), 7.89 (m, 2H) 7 37 k rTT, 5 (m, 6H), 7.05 (m, 5H), 6.76 (m, 2H), 6.60 (m, 2H), 4.47 (s, 2H), 4.31 (m, 1H), 4.07 (m, 2H), 3 1〇 (m, 2H), 2.88 (m, 2H), 2.29 (s, 3H); low-resolution MS (ES) m / e 618 (M_H) +; RP-HPLC (50-100% ck r &gt; j 'Human T H3CN has 0.1% TFA buffer in water, 25 knives) tr 10 06 knives, while MS (FAB) m / e 620.2384 (MH +), C36H33N3O7 requires 620.2397 〇2 (S)-(2- (fe 基- Aniline &gt; 3_ {4_2_5_methyl_2_ Pyridin-4-yl-oxazole- 4-yl) -ethoxy] -phenylpropanoic acid compound (191 g) was obtained from 21 mg (0 37 mmol) of intermediate H3 and 49.0¾ g (1.12¾ Mol) lithium hydroxide monohydrate was prepared according to the method of Example 32, and then purified by silica gel flash column chromatography using MeOH / dichloromethane (i: 9) as the eluent to prepare: m NMR (DMSO-d6, 400 MHz) ^ 8.75 (d, 1H, J = 7.0), 8.68 (m, 2H), 7.76 (m, 2H), 7.52 (m, 1H), 7.46 (m, 4H), 7.28 (m, 2H), 7.08 (m, 2H), 6.73 (m, 3H), 6.45 (m, 1H), 4.22 (br m, 1H), 4.07 (br m, 2H), 3.17 (m, 1H), 2.96 (m, 1H), 2.86 (m, 2H), 2_31 (s, 3H); RP-HPLC (50-100% CH3CN in water with 0.1% TFA buffer, 25 points): tr = 7.579 points; Chiral HPLC (Daicel chiralcel OD-H, 4.6 x 250 ml, 5 mm, 25% ethanol / hexane with 0, i 0/0 TFA, 1 ml / min, 30 minutes): tr = 9.45 minutes, 96% ee; Low resolution MS (ES) m / e 548 (MH +); high resolution MS (El) m / e 548.2194 (MH +), C33H29N305f 548.2185. Example 100 --------------- Order (Please read the precautions on the back before writing this page carefully) 170-

A7 Β7 V. Description of the invention (16 in this part of the head rate η.Τ elimination of λ-imprint 2 (s)-(2_ + g surplus-aniline) —3_ (4_ {2_ [5_methyl-M.A Hexahydropyridine H'yl) -fluorenyl] -ethoxy} • phenyl) -propionic acid hydrochloride The target compound (429 mg) is based on 500 mg (〇84 mmol) Example M and 110 ^: g (2.52 mol) of lithium hydroxide monohydrate according to the method of Example 32, followed by silica gel flash column chromatography with MeOH / Et〇Ac (gradient U to 3. 2 to 4_1) was purified as a precipitant and prepared with 0.75 ml (0.74 mmol) of 1 M (HC1 acidified in diethyl ether. The hydrochloride of the target compound was removed by removing the solvent in the air: 1Η NMR (CDCl3, 400 MHzK 9 〇5 (d, 1H, J 6.1), 7.56 (m, 2H), 7.40 (m, 2H), 7.30 (m, 1H), 7.02 (m, 2H), 6.80 (m, 1H), 6.47 ( m, 3H), 4.42 (m, 1H), 4.31 (m, 2H), 3.11 (m, 6H), 2.77 (m, 6H), 2.43 (s, 3H), 2.21 (s, 3H); TLC (MeOH / EtOAc ^)) Rf 〇17 'RP-HPLC (50-% CH3CN in water with 0.1% TFA buffer wave, ^ minutes): tr = 6.177 points; chiral HPLC (Daicel dnralcel OD-H, 4.6 X 25. a liter, 5 M, 25% ethanol / hexane with 0 ″% TEA and 〇1% TFA, old liter / knife +5 30 for tr = 7.908 minutes, 96% ee; low resolution MS (ES) m / e 585 ( MH) 'A resolution Ms swall 585 "M (should +), C33H36N4〇4S requires 585.2536. Example 101 2 (SH2_H group-aniline group> 3- (4- {2- [5-methyl-2_ (4 -Third-butoxy- /, hydropyrin-1-yl &gt; thiazole_4-kiboxyethoxyphenyl) _propionic acid target compound (80 mg) is from 140 mg (0.20 MM) 147 and 26 grams (0.60 mol) of lithium hydroxide monohydrate in accordance with Example 32 followed by silica gel flash column chromatography with MeOH / Et〇Ac (gradient to 1: 1) Prepared as a lysate for purification; m (DMS〇 Renegade 3: 7 -d6 171-This paper is suitable for the standard / i) Chinese national standard (read the precautions on the back before filling this page)

210X297 mm) A7 _________B7 V. Description of the invention (16〗 400 MHz) cy 8.76 (m, 1H), 7.53 (m, 1H), 7.49 (m, 4H), 7.28 (m,

2H), 7.05 (m, 2H), 6.70 (m, 3H), 6_44 (m, 1H), 4.03 (t, 2H, J = 6.9), 3.39 (m, 4H), 3.25 (m, 4H), 3.09 (dd, 1H, J = 5.2, 13.7), 2.91 (dd, 1H, J-6.0, 13.5), 2.78 (t, 2H, J = 6_9), .RJP-HPLC (50-100% CH3CN in water 0.1 % TFA buffer, 25 points): v = 10.72 points; chiral HpLC (Daicd. 1 ^ to 100- ° 4, 6 \ 250 mm, 5 mm, 25% ethanol / hexane: 〇〇１〇 / 〇 £ 7; eight, 1 ml / min, 30 points) K78 points, 98% ee; low resolution MS (ES) m / e 669 (MH) +; high resolution MS (FAB) m / e 671.2951 (MH +), C37H42 .N406S requires 671.2903. Example 102 2 (S)-(2-Benzylfluorenyl-aniline) -3_ {4- [2- (5-methyl_2_hexahydropyridin_1_yl_thiazol-4-yl) -ethyl Oxy] -phenyl} -propionic acid Add 1.5 ml of 4 M HC1 to 1,4-dioxane and add 65 mg (0.10 mmol) of Example 101 to 1 ml of 1,4-digin. Stir the solution. After stirring for 3 hours at room temperature, the solvent was removed in the air. The residue was purified by reverse-phase HPLC using acetonitrile / water 0.1% TFA buffer (gradient 30-50% over 30 minutes) as the eluent to obtain the monotrifluoroacetate of the target compound: 1HNMR (; DMS0-d6, 400 MHz) c5 '8.90 (br s, 2H), 8.63 (m, 1H), 7.58 (m5 1H), 7.53 (m, 4H), 7.41 (m, 1H), 7.34 (d, 1H, J-7.9) , 7.09 (d, 2H, J = 8.4), 6.82 (d, 1H, J = 8.6), 6.76 (d, 2H, J = 8.4), 6.59 (t, 1H, J = 7.5), 4.51 (m, 1H ), 4.07 (t, 2H, J = 6.7), 3.50 (m, 4H), 3.15 (m, 5H), 3.01 (dd, 1H, J = 13.8, 6.3), 2.82 (t, 2H, J = 6.5) , 2.18 (s, 3H); chiral HPLC (Daicel chiralcel OD-H, 4.6 X 250 mm, 5 mm, 25% ethanol / hexane with 0.1% TEA and 0.1% TFA, 1 ml / minute, 30 minutes): tr = 6.23 points, 98% ee; RP- -172- The size of this paper is the national standard of China (CNS) A4 (210X297 mm) I -------- OI— Note for this page, please fill in this page) Order A7 Β7 V. Invention Description (17ά Forgiveness: ^ but in the middle ^-/: J: Ji-T Elimination: ^ 合 竹 &quot; 卬 HPLC (30-50% CH3CN in water 〇1% TFA preparation, ”/. 1FA edge red night, 30 points): tr = 9 79 points; low resolution MS (ES) m / e 57.1.2 (MH +). Ancient jealousy &amp;, W), MS (FAB) m / e 571.2382 (MHi, C32H34N4〇4S requires 571 2379. Example 103 2 (S)-(2-benzyl) S &amp; yl-aniline) -3 ^ 4_ 丨 2_ 丨 5_ ^ 7 ,,,-, 1 L5 methyl-2- (4-methylsulfonyl-hexaoxopyryl-1-yl)-喽Azole-4-yl] -ethoxybenzyl) -propionic acid target compound (123 mg) is from 14 mg (0.2 mmol) of intermediate M9 and 26 g (0.6 mg) Ear) Hydroxide was prepared by monohydrate according to the method of Example η, and was then milled by £ 己 / hexane (1:19): ihnmr (CDC13, 300 MHz) d 8.73 (br τη im η λΊ (, m, (Out), 7.47 (m, 2Η), 7.38 (m, 4Η), 7.24 (ra, 1H), 7.10 (m, 2H), 6 69 rm 2W, aa / Λ. Milk (m, 2H), 6.56 (m, 2H), 4.26 (br m, 1H), 4.02 (t, 2H, J = 6.5), 3 43 rm ^ λπ r) &gt; (m, 4H), 3.17 ( m, 5H), 3.05 (m, 1H), 2.83 (t, 2H, J 6.6), 2.68 (s, 3H), 2.14 (s, 3H); RP-HPLC (30-80% CH3CH in water. 1% TFA buffer, 25 points, 6.74 points; —I HPLC (Da1Cel OD-H, 25% ethanol / hexane with 0.01% TEA and 0% tfa, 60 points.) Tr = 18 · 94 Points, &gt; 9S% ee; low resolution MS (ES) m / e (m_h) +; high resolution MS (FAB) m / e 649 2151, nu xT ^ ”zidi (MH), C33H36N406S2 requires 649.2155. Example 10 4 2 (s)-(i-carboxy-2_μ_ρ_ (4_dimethylamino_phenyl) _ethoxy] -phenylbethylamino) -methyl propionate (30 mg) is from 290 mg (〇61 mmol) of intermediate 155 and 714 g (1.83 mol) of monohydroxide hydroxide. Following the method of Example 3.2, followed by silica gel flash column chromatography Me〇H / Et〇Ac (gradient U soil 1.9) was used as the co-eluent to purify and prepare: old NMR (DMS〇_d6, (read the precautions on the back before filling this page) I— I— i I--1 --- --I:

— ^ Ϋ ί nn n ^ — ....... In ^ i ^ nm tm m ^ i VJ Λ,, T 1 II 1--~ -173- bu il Mj li .r.; /) F : Bamboo print t A7 B7 V. Description of the invention (171) 400 MHz) 8.06 (d, 1H, J = 7.1), 7.72 (d, 1H, J = 8.0), 7.25 (m, 1H), 7.07 (t, 4H , J = 9.4), 6.73 (d, 2H, J = 8.4), 6.63 (m5 3H), 6.46 (m, 1H), 4.00 (br m, 3H), 3.73 (s, 3H), 3.07 (m, 1H ), 2.86 (m, 9H); TLC (MeOH / EtOAc (l: 9)): Rf = 0.74; chiral HPLC (Daicel AD, 30% ethanol / hexane with 0.1% TEA and 0.1% TFA, 30 minutes ): Tr = 5.53 points, &gt; 99% ee; RP-HPLC (30-80% CH3CN in water with 0.1% TFA buffer, 25 points): tr = 13.37 points; low resolution MS (ES) m / e 461 (MH) +; High Resolution MS (FAB) m / e 463.2288 (MH +), C27H30N2O5 requires 463.2233. Example 105 2 (S)-[1-methoxycarbonyl_2_ (4_ {2_ [5_methyl_2_ (cardiomethyl-hexahydropyridine-butyl) -distant bite-4-yl] -ethoxy Phenyl) _ethylamino] _benzene f acid standard compound (150 mg) is from 360 mg (〇65 mmol) intermediate 156 and 92 mg (2.19 mmol) lithium hydroxide monohydrate Nong The method of Example 3 2 was followed by silica gel flash column chromatography using MeOH / EtOAc (gradient 3: 2 to 3: 2 with 1% NH4OH as eluent to 4: 1 with 1% NH4OH and 1% water Purified and prepared: 1H NMR (DMS0_d6, 400mHz) β 8.04 (d, 1Η, J = 6.8), 7.72 (d, 1H, J = 8.0), 7.26 (t, 1H, J-7.2), 7.04 (d, 2H, J = 8.4), 6.72 (d, 2H, J = 8.5), 6.59 (d, 1H, J = 8.7), 6.47 (t, 1H, J = 7.2), 4.06 (m, 3H), 3.74 (s, 3H), 3.26 (m, 4H), 3.03 (dd, 1H, J = 5.1, 13.8), 2.87 (dd, 1H, J = 6.5, 13.7), 2.79 (t, 2H, J = 6.8) , 2.34 (m, 4H), 2.19 (s, 3H), 2.17 (s, 3H); TLC (MeOH / EtOAc (2: 3)): Rf-〇.n; RP-HPLC (30-80% CI ^ CN in water 〇1% TFA buffer, 25 points) tr = ii 〇8 points; chiral HPLC (Daicel chiralcel OD-H, 4-6 x 250 mm, 5 milli-174 paper) Assassination 'Bu Lai family standard (called eight [4 Specifications (210 \ 297 male Chu) (Please read the notes and then fill in the back of this page)

浐 部 屮 it; 4.?. ^-XJ, -JiT-Yuzhu Heyin Long Μ _________— __ Β7 V. Description of the invention % TEA and 〇ι% τρΑ, 1ml / min, 30%). ΓΓ-1 · 3.59 points, 92% ee; low resolution MS (ES) m / e 537 (Μ- ^ ί); 咼 analytic MS (FAB) m / e 539 2328 (MH +), C28H34N405S requires 539: 2328. Example 106 2 (S)-(1-Bromo-2- {4- [2- (4-chloro-phenyl) _ethoxy] _phenylbethylamino) benzoic acid target compound (142 Mg) are from 230 mg (049 mmol) of intermediate 157 and 70 g (1-67 mmol) of lithium hydroxide monohydrate according to the method of Example 32, followed by the silica gel flash tube column layer The analysis was prepared by purification with MeOH / Et〇Ac (gradient 0:] to 1.19 main 1: 9 1% NH4OH) as the eluent: 1H NMR (DMSO-d6, 400 MHz) d δ.07 (d, 1Η, J = 7.0), 7.71 (d, 1H, J = 8.1), 7.33 (m, 4H), 7.24 (m, 1H), 7.05 (d, 2H, J = 8.5), 6.73 (d, 2H, J-8.6), 6.59 (d, 1H, J = 8.6), 6.45 (t, 1H, J = 7.4), 4.08 (m, 2H), 3.72 (s, 3H), 3.07 (m, 1H), 2.97 (t, 2H, 1 = 6.6), 2.88 (m, 1H); TLC (Me0H / EtOAc (1: 19)): R produced 0.55; rP_hplc (30_80〇 / 〇ch3CN in water 0.1% TFA buffer, 25 points): tr = 26.11 points; chiral HPLC (Daicel chiralcdOD-H, 4.6 x 250 mm, 30% ethanol / hexane with 0_1% TFA and 0.1% ΤΕ; 0.7 ml / min, 45 Points): tr = 7.20 points, 94% ee; low resolution MS (ES) m / e 452 (ΜΗ); 咼 analysis MS (FAB) m / e 454.1421 (MH) +, C25H24N05C1 requires 454.1421. Example 107 2 (S)-(1-¾yl-2- {4- [2- (4-trifluoromethoxy-phenyl) -ethoxy] -phenylbethylamino) -benzoic acid, Methyl ester-175- This paper is suitable for Chinese National Standard (CNS) A4 (210X297 mm) (read the precautions on the back before filling this page), ιτ

-I A7 ---___________ 5. Description of the invention (17 ^ bar compound (128 mg) is from 280 mg (0.54 mmol) intermediate 159 and 72 mg (1.72 mmol) lithium hydroxide The monohydrate was prepared according to the method of Example 32, followed by purification by gel column flash chromatography using MeOH / EtOAc (gradient 0: 1 to 1-19 with 1% NH4OH) as the eluent for purification: NMR (DMSO -d6, 400 MHz) ^ 8.04 (m, 1H), 7.71 (d, 1H, J = 8.0), 7.41 (d, 2H, J = 8.4), 7.25 (m, 3H), 7.04 (d, 2H, J = 8.4), 6.74 (d) 2H, J-8.2), 6.59 (m, 1H), 6.47 (m, 1H), 4.11 (t, 2H, J = 6.7), 3.72 (s, 3H), 3_03 (m , 3H), 2.89 (m, 1H); low resolution 1 ^ jin 3) 1114 502 (1 ^ -H) +; RP-HPLC (50-100% CH3CN in water with 0.1% TFA buffer, 25 minutes): tr-16.89 points; chiral HPLC (Daicel chiralcel OD-H, 4.6 X 250 mm, 30% ethanol / hexane with 0.1% TFA and 0 "TEA, 0.7 ml / minute, 20 minutes): w% Min, 92% ee; high resolution MS (FAB) m / e 504.1647 (MH +), C26H24N06F3 requires 504.1634; TLC (MeOH / EtOAc (1:19)): Rf = 0.63. Example 108 3- {4- [2- (Benzoxazole_2-yl-methylaminoethoxybenzene } _3_ (4-benzylfluorenyl_p-cephenamino-propionic acid) A solution of 100 mg (0.18 mmol) of intermediate 160 in 5 ml of ethanol and 1 ml of water was heated under reflux with 30 mg of KOH for 4 5 minutes. The solution was concentrated to an oil 'acidified to pH = 5 with 0.1 N HC1 and extracted with aerobic (2 X 20 ml). Concentrated and purified by silica gel chromatography with EtOAc followed by 1% acetic acid in EtOAc to obtain the title compound (4 5 mg) as a yellow solid: 1H NMR (CDC13, 400 MHz) 7.72 (m, 3H), 7.55 (t, 1H, J = 7.4), 7.44 (m, 4H), 7.26 (m, 1H), 7.2 (d , 2H, J = 8.8), 7.19 (m, 1H), 7.04 (t, 1H, J = 7.7), 6.80 -176- The size of this paper is suitable / fl China National Standard (CNS) Λ4 specification (210X297 mm ) In the ministry H. r. &Gt; 1 \ .T eliminator fr A7 B7 V. Description of the invention (17 $ (d, 2H, J = 8.6), 4.15 (m, 3H), 3.9 (m, 2H), 3.32 (s, 3H), 3.2 (m, 2H); low resolution MS (ESP +) m / e 542 (MH +); TLC (EtOAc with 1% AcOH): Rf = 0.38. Example 109 3- {4- [2- (benzoxazol-2-yl-methylamino) _ethoxy] _phenyl} _2_ (2_ (4_biphenylcarbonyl) -aniline) -propionic acid 0.6 grams (14. 4 millimoles) of LiOH was added to a solution of 0.9 grams (1.44 millimoles) of intermediate 髂 162 in 5 ml of water and 50 ml of MeOH. The mixture was refluxed for 0.5 hours, concentrated, and distributed between a phosphate buffer solution at pH 7 and valence. Concentrated organics were purified by silica gel chromatography at 0-5% Me0H in CH2C12 to obtain the target compound as a yellow solid: 1H NMR (CDd, 2 MHz) · 00 (br s, 1H), 7.7-7.6 (m, 7H), 7.5-7.35 (m, 5H), 7.2-6.95 (m, 5H), 6.75 (m, 3H), 6.63 (t5 1H, J = 7.5), 4.45 (br s, 1H), J.27 (s, 3H ), 3.2 (d, 2H, J = 5_7; low resolution MS (Cl) m / e 612 (MH +). Example 110 3- {4- [2- (benzoxazole_2_yl_methylamino) ) _Ethoxy] phenylphenyl 2- (2_4-methoxy-benzylfluorenyl) -aniline) -propionic acid The target compound is from 0.29 g (0.05 mmol) intermediate 164 and 31 mg UOH (0.75 millimolar) was prepared following the procedure described in Example 32 followed by purification by milling with hexane: HNMR (DMSO_d65200 MHz) J 8 35 (d, 2Η, J-7.3), 7.55 (d, 2H, J = 8.6), 7.39-7.25 (m &gt; 5H), 7.15-6 · 9 (m, 5Η), 6.8 (m, 3H), 6.6 (m, 1H), 4.3 (m, iH), 4.15 ( m, 2H), j. 8 〇, 5H), 3.2 (s, 3H), 3.0 (m, 2H); low-resolution Ms (Cl) 177- This paper standard is applicable to the national standard (CNS) A4 specification ( 210X297 mm (Please read the notes on the back before filling this page)

The tick is passed through the central part of the Ministry of Shanghai ^ ";! Ding Xiao Yu 'Hezhu ^-卬 ¥ A7 B7 V. Description of the invention (17 ^ m / e 566 (MH +). Example 111 3- {4- [2- (benzene Oxazol-2-yl-methylamino) -ethoxy] -phenyl-2- (2- (4-methyl-geranyl) -anilide propionic acid) 0.57 g (13.5 mmol) Ear) LiOH was added to 760 mg (1.35 mmol) of intermediate 165 in a solution of 70 ml of MeOH and 15 ml of water. The solution was stirred at reflux for 4 hours, concentrated, and dissolved in water (15 ml) and CH3C1 (15 ml). It was absorbed in 1.0 N HC1 and adjusted the pp of the aqueous phase to 6-7. Extraction with CHC13 followed by silica gel chromatography was first purified with EtOAc and then with EtOAc with 0.5% AcOH to obtain 90 mg of the target compound: tlC (EtOAc with 0.5% AcOH): Rf = 0.44; low resolution MS (ESP +) m / e 550 (MH +) 〇tji 112 · 3- {4- [2_ (benzoσ number azole_2_yl-fluorenamine) ) -Ethoxy] -phenyl} -2- (2- (2-methyl-benzylfluorenyl) -anilino) -propionic acid The target compound is from Intermediate 166 (687 mg, 1.22 mmol) 500 mg of crude product was prepared as described in Example 111. Silica gel chromatography was first performed with 40-50% EtOAc in hexane followed by 10% MeO H 2 CH2C12 precipitation and purification to obtain 200 mg of the target compound "Pure fraction (21 mg) is from preparative DLC (2000 microns, eluate with 0.5% AcOH in EtOAc): TLC (MeOH / CH2Cl2, 1 / 9): obtained with Rf = 0.35; low resolution MS (Cl) m / e 550 (MH +). 1 The general procedure of Example 113-1 28 was performed on a Watterman-178-Ben with a glass microfiber 0.45 mm PTFE film. Paper size suitable for home standard (CNS) A4 (210X 297mm) (Please read the precautions on the back before filling this page)

, A7 B7: Jk in Part A: J eliminate bamboo 卬 V. Description of the invention (17 @ (Whatman) PTFE without syringe 遽 自动 自动 "automatic bottle (Autovial), | Pour 100 mg into a 12 ml volume 1〗 Mole) intermediate 118, followed by 4 liters of THF, appropriate amount of alcohol (5mmol), DEAD (5mmol), and Pl or TBP (5 ^: Mol) TMAD (1,1'-azobis (N, N-dimethylformamidine) (5 mmol) and i: i CH2C12: THF as solvents. Rotate the automatic vial on the shaker for about 5 After hours, the resin was treated with a series of solvent lotions in the following order: THF, MeOH, THF, DMF, CH2C12, and then dried for 30 minutes .. Treated with 10% trifluoroacetic acid in CH ^ ci2 for 1 hour to crack Resin. The filtrate was collected in a Baker spe-24G glass column processor unit under vacuum, evaporated at%, and dried under high vacuum for 24 hours to obtain the crude product. Then the compound was further subjected to HPLC Cis Waters Delta Prep. 3000, purification column: YMC-Pack ODS AA12S05-2520WT 250 X 20 mm IDS-5 mm, 120A, 0-100% B (for 1/2 hour), flow rate 1 8 ml / min, detected at 220, B = 0.1% trifluoroacetic acid in acetonitrile, a = 0.1% trifluoroacetic acid in water. Analysis column: YMC-Pack ODS AA1 2S05-2520WT 250 X4.6 mm ID S- 5 mm, 120A, 0-100% B and 1.5 ml / min (30 minutes), detected at 220 'B = 0.1% trifluoroacetic acid in acetonitrile, α = 0. 1% trifluoroacetic acid in water 0 Example 113 2- (2-Benzylfluorenyl-aniline) -3- {4- [2- [4-chloro-phenyl} -ethoxy] -phenylpropanoic acid The intermediate 118 and 2- (4 -Phenylphenyl) ethanol reacted in the above general steps to obtain a yellow solid: 1H NMR (DMS〇-d6, 400 MHz) d 8.63 (m, 1H), -179 This paper is applicable to China National Standard (CNS) A4 specifications (210X297 mm) (谙 First read the notes on the back and then fill out this page) Order A7 B7 _ V. Description of the invention (17 $ 7.59-6.49 (m, 16H), 4.49 (m, 1H)? 4.11 (m, 2H), 2.97 (m, 2H); MS (ESP +) m / e 538 (MH +); analytical tritium (C30H26NO4Cl. TFA); HPLC: tr = 22.43 points. Example 114 2- (2-Benzylfluorenyl-anilino) -3- {4- [2- (4-methyl-thiazol-5-ylbutethoxy] -phenyl 丨 -propionic acid_ will be in the middle Isomer 118 reacted with 2- (4-methyl-oxazole_5-yl) ethanol in the general procedure described above to obtain a yellow solid: 1H NMR (DMS0-d6, 400 MHz) d 8.82 (d, 1H), 7.81-6.62 (m, 12H), 4.51 (b, 1H), 4.09 (m, 2H), 3.15 (m, 4H), 2.31 (s, 3H); MS (ESP +) m / e 487 (MH +); Analyze (C28H26N204S) TFA); HPLC: tr = 17.43 min. 115 2- (2-benzylfluorenyl-aniline) -3- {4- [2- (4-Gas-phenylsulfanyl) ethoxy] -phenylbenzene Propionate reacts intermediate 11 8 with 2- (4-chlorophenylsulfanyl) ethanol in the general procedure described above to obtain a yellow solid: 1H NMR (DMSO-d6, 400 MHz) d 8.72 (d, 1H), 7.57-7.29 (m, 8H), 7.11 (d, 2H), 6.76 (m, 4H), 6.52 (t, 1H), 4.98 (s, 2H), 4.34 (b, 1H), 3.13 (m, 1H), 2.98 ( m, 1H); MS (ESP +) m / e 532 (MH +); Analytical tritium (C30H26C1N04S · TFA); HPLC: tr = 22.65 points. Example 1 16 2- (2-benzylfluorenyl-aniline) 3- [4- (4-Isopropyl-benzyloxy,}-phenyl] -propionic acid The intermediate 11 8 is reacted with 4-isopropylbenzyl alcohol in the above general procedure to give yellow Color solid: 1H NMR (DMSO-d6, 400 ΜΗζ) β 8.69 (d, 1H), -180- This paper is suitable for China National Standard (CNS) A4 specification (210X297). (Please read the precautions on the back before reading) (Fill in this page)

, Λ in the 1T good silt section &quot; '^ · Λ · ,; ί3 valence combination bamboo &quot; 卬 7 A7 B7 _ 5. Description of the invention 2H), 6.57 (t, 1H), 4.94 (s, 2H), 4.47 (fc, 1H), 3.13 (m, 1H), 3.03 (m, 1H), 2.85 (m, 2H), 1.16 (d, 6H ); MS (ESP +) m / e 516 (M + Na +), 494 (MH +); Analytical tritium (C32H31N04. TFA); HPLC: tr = 23.36 minutes. 117 2- (2-benzylfluorenyl-aniline)- 3- [4- (4-Chloro-benzyloxy) -phenyl] -propionic acid The intermediate 118 and 4-chlorofluorenyl alcohol were reacted in the above general procedure to obtain a yellow solid: lHNMR (DMSO-d6,400 MHz ) (y8.72 (d, lH), 757-7.29 (m, 8H), 7.11 (d, 2H), 6.76 (m, 4H), 6.52 (t, 1H), 4.98 (s, 2H), 4.34 ( b, 1H), 3.13 (m, 1H), 2.98 (m, 1H); MS (ESP +) m / e 486 (MH +); Analytical tritium (C29H24C1N04.TFA); HPLC: tr = 21.95 points "Example 118 2- (2-benzylfluorenyl-aniline) _3- {4- [3- (4-methoxy-phenyl} -propoxy] -phenyl} -propionic acid Intermediate 118 and 3- (4- Methoxyphenyl) propanol was reacted according to the above general procedures to obtain a yellow solid: MS (ESP +) m / e 510 (MH +); Analytical 値 (C32H31N05. TFA); HPLC: tr = 23.48 points. Example 119 2- ( 2-benzyl -Anilino) -3- {4- [2- (4-dimethylamino-phenyl} -ethoxy] -phenyl} -propionic acid will be intermediate 118 and 2- (4-N, N -Dimethylaminophenyl) ethanol was reacted in the above general procedure to obtain a yellow solid: MS (ESP +) m / e 509 (MH +); Analytical tritium (C32H32N204. TFA); HPLC: tr = 16.81 points. Examples 120 -181 -National Standards of Ten Countries (CNS) A4 (210 X 297 mm) (Read the first note on the back and then fill out this page)

A7 ___— ___ B7 V. Description of the invention (17 from 2_ (Section § &amp; yl-aniline) -3- {4- [2 · (4-bromo-phenoxy} •• ethoxy]- Phenylpropionic acid reacts intermediate 118 with 2- (4-bromophenoxy) ethanol in the general procedure described above to obtain a yellow solid: 1H NMR (DMS0-d6, 400_MHz) d 8_65 (d, 1H), 7.65-7.26 (m, 8H), 7.13 (d, 1H), 6.91 (d, 1H), 6.81 (m, 2H), 6.58 (t, 1H), 4.52 (m, 1H), 4.22 (m, 2H), 3.15 ( m, 1H), 3.05 (m, 1H); MS (ESP +) m / e 560 (MH +); analytical tritium (C30H26BrN05 · TFA); HPLC: tr = 21.28 points. Example 121 2- (2-卞 g Saponyl-anilino) -3- {4- [2- (5-Schottky-p-Hydroxy-2-yl} -ethoxy] _phenyl} -propionic acid. Intermediate 118 and 2- (5 -Nitropyridin-2-yloxy) ethanol was reacted according to the above general procedures to obtain a yellow solid: MS (ESP +) m / e 528 (MH +); Analytical tritium (C29H25N307. TFA); HPLC: tr = 20.02 points Example 122 2- (2-Bromo-anilino) -3- (4- {2- [3- (6-methyl- | ?? bita-2 -ylpropoxy..yl) -ethoxy } -Phenyl) -propionic acid Intermediate 118 and 2- [3- (6-methylpyridin-2-yl) propoxy) ethanol A yellow solid was obtained: MS (ESP +) m / e 539 (MH +); Analytical tritium (C33H34N205 · TFA); HPLC: tr = 16.35 points. Example 123 2- (2-benzylfluorenyl-aniline) -3- [ 4- (2-Pyridin-3-yl-ethoxy] _phenyl} _propionic acid The intermediate 118 was reacted with 2- (2-p-pyridyl) ethanol in the above general procedure to give a yellow solid: MS ( ESP +) m / e 467 (MH +); Analysis 値 -182- This paper size is suitable for China National Standard (CNS) Λ4 Specification (210X297 mm) A7 B7 V. Description of the Invention (18 () (C29H26N2〇4 · TFA ); HPLC: tr = 15.84 points. Example 124 (Read the notes on the back of the page before filling out this page) 2- (2-benzylfluorenyl-aniline) -3- {4- [2- (3-form 6-6-oxo-6H-tachhen-1-yl) -ethoxy] -phenylpropanoic acid, intermediate 118 and 2- (3-fluorenyl-6-oxo-6H-tachhen- 1-based) ethanol was reacted in the above general procedure to obtain a yellow solid: MS (ESP +) m / e 498 (MH +); analytical value (C29H27N305 · TFA); HPLC: tr = 18.64 minutes. Example 125 · 2- (2-Benzylfluorenyl-aniline) -3- {4- [2- [4-trifluoromethoxy-phenyl} -ethoxy] -phenyl} -propionic acid Isomer 118 reacted with 2- (4-trifluoromethoxyphenyl) ethanol in the general procedure described above to obtain a yellow solid: MS (ESP +) m / e 550 (MH +); Analytical (C3IH26N05F3 · TFA). Example 126 2- (2-benzylfluorenyl-aniline) -3- {4- [2- [3-nitryl-phenoxy} -ethoxy] -phenyl} -propionic acid intermediates 118 and 2- (3-Nitrilephenoxy) ethanol was reacted in the general procedure described above to obtain a yellow solid: MS (ESP +) m / e 507 (MH +); analysis of rhenium (C31H26N205. TFA). Example 127 2- (2-benzyl Fluorenyl-aniline) -3- {4- [2- (6-methoxy · pyridin-2-ylsulfanyl) -ethoxy] -phenyl 丨 -propionic acid intermediates 118 and 2- (6 -Methoxy-p ratio of 2-methylsulfanyl) ethanol to a yellow solid by the above general procedure: MS (ESP +) m / e 534 -183- This paper is suitable for the size of the paper / Π Chinese National Standard (CMS) A4 (210X297 mm)-# '部 中 JA ^ 5? -X'Jh-T Eliminates the need to combine with bamboo &quot; 卬% A7 B7 V. Description of the invention (18i (MH +); Analysis 値 (C3〇H28N2〇5S · TFA ); HPLC ·· tr = 21, 88 points. Example 128 2- (2-Membenyl-anilino) -3- {4- [1- (4-nitrophenyl) -pyrrolidin-2-ylmethoxy] -phenyl} -propanoic acid intermediates 118 and ( S) -㈠-1- (4-nitrophenyl) -2-pyrrolidine MeOH was reacted according to the above general procedures to obtain a yellow solid: MS (ESP +) m / e 566 (MH +); analysis of thallium (C33H31N306. TFA); HPLC: tr = 22.07 minutes. Substituted Intermediate 2 3 Intermediate 2 3 was prepared by the following substitution method. L · -carbamate nitrile (1.00 equivalent, 0.96 weight), 2-geranyl-cyclohexanone (WA Denny et al., J. Med. Chem., 21 (5), pp. 430-437 (1978)) (1.00 equivalent, 1-00 weight) and dimethoxyethane (5 volumes), combined and heated Reflux overnight. 2-2.5 volumes of the volume were removed by distillation, and the suspension was cooled to ambient temperature. The product was collected by vacuum filtration, washed with 0.5 volume of cold dioxane and dried overnight in the room. This product (1.00 weight, 1.00 equivalent) combined with 10% palladium / carbon (0.10 weight), p-nitrotoluene (0.75 equivalent, 0.27 weight), and butanol (8.0-12.0 vol) under nitrogen atmosphere Heat to vigorous reflux for 4 to 18 hours. The suspension was filtered hot through a plastic plug under nitrogen, the plastic pad was washed with hot butanol (2-5 vol.) And the filtrate was cooled to the ambient temperature. After cooling, the crystals were collected by vacuum filtration, washed once with cold anhydrous ethanol, and dried under air. Substituted Intermediate Π 7 Intermediate 1 17, Acid analogue of methyl ester intermediate 2 3 was prepared from the following substitution method. Dissolve sodium oxide (2.2 equivalents, 0.24 weight) in water (1.2-1.4 -184-This paper is suitable for Sichuan National Standard (CNS) A4 specification (210X 297 mm)) (Read the precautions on the back before reading (Fill in this page)

Λ ^ &quot; Λ, · ^^ ί7ί 贽 竹 in the good part of the Ministry of Justice & A7 --__ B7-· * — V. The invention's description (1 ~ with the product) drops to keep the temperature less than 25X: The intermediate was added at a rate of 23,000 ng (1.0 wt.) In tetrahydrofuran (2.2 eq., 0.24 wt.) Of luteolin. After the addition is complete, the solution is warmed to 15-25 ° C and stirred until no starting material remains by TLC. 2_3 rat hydrochloric acid (22_26 equivalents, 27_s bean product) was added to the soil to reach p Η &lt; 3 ', and the temperature was kept below 25 ° C. Ethyl acetate (6.0-7.0 volumes) was added, and the mixture was stirred vigorously for 0.3-1.0 hours, then the layers were separated and the aqueous layer was discarded. The organic layer was extracted with brine (2.0-3.0 volumes) and the aqueous organic layer was concentrated to 1 · 5 -2 · 5 volumes and crystallized. Add hept k (4.0-5.0 volumes) to complete crystallization. The crystals were collected by filtration, washed with heptane (4.0-5.0 volumes) and dried. Intermediate 167 was prepared from Maybndge's oxazolol mesylate analog using the following method. At 20-25X: add sulfane sulfonium gas (〖· ;! equivalents, 0 42 vol.) To increase the temperature to 4 (TC at the rate of 2_ (5_methyl_2_phenylazazol_4_ Based) ethanol (commercially available from Maybridge) (1.0 equivalent, 1.0 weight) in a suspension of toluene (10 vol) and triethylamine (11 equivalent, 0 75 vol). After the addition is complete, the reaction history! Cool to 20-25t in 1 hour: The organic phase was washed with water (35 volumes) and brine (1.2 volumes). The resulting solution was concentrated to 5 volumes and stirred at 25 C until crystals formed. Add heptane (5 volumes) to complete Crystallized, and the mixture was stirred at 25 ° C for 1 hour. The solid was collected by filtration, washed with heptane (4.0 vol) and dried in an empty oven at 50 ° C. Alternative Example 2 9 Compound of Example 2 9 It is prepared from the following alternative method. Solid NaOH (2.4 equivalents, 0.26 weight) is added to the test, intermediate 117 (丨 equivalent, 10-185-standard (CNS)) Λ4 specification (_210X297 public (read first read the back Please fill in this page for the matters needing attention) ---- Order I ---------------------- A7 A7 Department &quot; —Ministry of Order i? ^-X ' Jj τ · & qu ot; '; ^ 合 ^. ^ 印 ¥ B7 V. Description of the invention (18 ^ weight) in a slurry of dimethylarsine (1. 0 volume water (20 volume). The resulting solution is at 50 ° C Stir and add dropwise a solution of mesylate, intermediate 167 (28 equivalents, i 0 weight) in dimethylsulfinium (3.0 vol.) At a rate maintaining a temperature of 48-52 ° C. The mixture is at 48 Stir for 2 2 hours at -52 t, cool to 25 ° C, and wash three times with methyl tertiary-butyl ether (60 vol.). The aqueous phase is first with ethanol (2.0 vol.) And then with glacial acetic acid (20 vol.). ) Dilute, and then add water (60 ml) dropwise with vigorous stirring. Add seed when the solution becomes cloudy and turbid. The resulting precipitate is filtered, filtered with water (60 vol) and then ethanol: water / 50: 50 (12.0 (Vol.) Was washed and dried at 50. (: below. The resulting yellow solid was recrystallized from ethanol: water / 95: 5 (18 vol.) And dried at 50 ° C. to a constant weight. Second alternative example 2 9 The compound of Example 2 9 was prepared by the following second substitution method. Diisopropyl azodicarboxylate (0 66 vol) was added at 40 ° C. A solution of benzene (0 vol) was added dropwise at a rate to maintain the temperature between 40 and 5 &lt; rC, phenol ester, intermediate aa23 (1 weight), 2- (5-fluorenyl-2-phenyl stilbene _4_ Ethyl) ethyl alcohol (commercially available from Mayhridge) (0,65 weight), and a mixture of triphenylphosphine (0 88 weight) in toluene (3.5 volume). After the reaction was completed (HpLC), the resulting solution was concentrated in a vacuum at 5 (TC by removing toluene (2 volumes), cooled to room temperature, and diluted with fluorenyl tertiary-butyl ether (4 volumes) and cooled. After 0. 0 hours, the mixture was filtered to remove triphenylphosphine phosphine oxide and the filter pad was washed with cold (0 C) methyl second-butyl ether (2 volumes). The resulting solution was washed with 2 Wash with $ N NaOH (2.5 vol., 0.0). Add 2 5 ν NaOH (2.5 vol.) And stir the mixture at room temperature until the hydrolysis is complete (HpLC). Add: -186- Ben '.. The scale of the scale is appropriate 'National National Standard (CNS) A4 Specification (2 丨 Gongjun) (Please read the precautions on the back before filling this page)

Jing :, &quot; '部 中 次 &quot;' ^^, '; ί-τ ·; / ί 抡 合 竹 社 卬? i A7 B7 V. Description of the invention (18 ^ fluorenyl fluorene (5 volumes) and phase separation. The aqueous phase is washed with fluorenyl tertiary-butyl ether (3 volumes), first with ethanol (2.0 volumes) followed by glacial acetic acid (2.0 vol) Dilute and then add water (6.0 vol) dropwise to the solution and stir vigorously. Add seed when the solution becomes cloudy and cloudy. The resulting precipitate is filtered and then ethanol: water / 50: 50 (6 vol) And filtered at 70 ° C. The resulting yellow solid was recrystallized from ethanol: water / 95: 5 (13.0 vol) and dried in air to a constant weight at 50 ° C. _ Compound efficacy demonstration scheme 1 · PPARga mm a moment Transient Cotransfection assay: pSG5-mPPARg and pSG5-hPPARg chimeric receptors show plasma and (USA) 5-tk-CAT. Communication blood cells have been described previously and (Kliewer, SA, et al. Cell 83 8 13-8 19 (1995); JM Lehmann et al., J. Biol. Chem. 12953-12956, 270 (1995)) ° Transient co-transfection using these plasmas was performed as previously described (Kliewer, SA , Et al. 61183, 813-819 (1995); JM Lehmann et al., J. Biol. Chem. 12953-12956, 270 (1995)) 2. hPPARga mm a coordination bond test: PPAR-ga mm a coordination bond range (amino acid 195-475) was labeled with N-terminal 10x-histidine in E. coli (E (E. coli) cells. Cells were lysed and the receptors were purified by antigen-determining markers. Protein stock solution was prepared in assay buffer (50 mm Tris, 50 mm KC1, pH 8 20 mm CHAPS, 2 mm EDTA) before use. 10 mm DTT (fresh)) diluted to 20 OnM. The test compound was prepared into a 6 mm stock solution in DMSO. Two consecutive 10-187- This paper size is in accordance with China National Standard (CNS) A4 specifications (210X297 mm) ） (谙 Please read the notes on the back before filling in this page) ΙΛ% /

、 1T • 1, A7 B7 V. Description of the invention (18 ～~ dilution diluted to make test buffer to obtain compounds of 6 0 &quot; μ and 1% and DMSO concentration. Add 12.5 microliters of diluted compound to contain 67.5 In the well of the leftmost end of the microtiter plate of the microliter test buffer, mix the contents of the well and transfer 25 microliters of this solution to the next well, which is mixed with 50 microliters of test buffer (3 times Dilution) mixing. Repeat this method to obtain each test compound in a concentration of 96 well plates arranged in rows. The rightmost column is the control group. In each experiment, an appropriate amount of 3H-BRL 49,653 Blow to dryness in a glass vial suspended in test buffer (50 mm Tris, 50 mm KC1, pH 8 20 mm CHAPS, 2 mm EDTA 10 mm DTT (fresh)) to a concentration of 400 nM. Sonicated for 10 seconds. Radioligand ([3H] -BRL 49,653) and the receptor were added to each well of the plate containing the test compound. The plate was incubated at room temperature for 2 hours and cooled on ice for 30 minutes. Zymak Rapidplate automatic pipette to transfer 50 microliters of sample from a single test Each well was simultaneously aired to the equilibrium AGTC 96-well gel filtration block. The fragments were placed on a clean microtiter plate and centrifuged @ 込 丨 ⑼Xg for 4 minutes. 200 microliters of shiny fluid was added to each well. The discs were sealed and equilibrated for at least 4 hours before counting in a Wallac 1250 Microbeta counter. For example, non-specific binding of control wells containing excess [3H] -BRL 49,653 was subtracted from all wells, and compound concentrations were plotted against CPM binding Ki, s is a simple competitive binding mode measured from the data of the nonlinear minimum squares fit. For data analysis purposes, [3H] -BRL 49,653 Kd of 200 nM is used. • 5 · / Tongue evaluation: experimental It was performed with db / db mice (n = 40-48), about 60 days old, and divided into vehicle or treatment groups. 8_ 丨 2 animals were taken from each group and placed in -188. National Standards (CNS) A4 Specification (210X297 Gongchu) (Read the precautions on the back before filling this page). "'Ίι-' Order A7 B7 ~ &quot; 一 * ''. 5. Description of the invention (18❽

Nalgene metabolic cages, two per cage. The remaining animals are in standard feed cages; 3-4 per cage. The test compound is dissolved in a suitable vehicle. Animals were administered orally by gavage at 5 ml / kg; b.i, d ·, vehicle or compound (metering = 5 g / kg) for 14 days. Food and water consumption, urination and glucose excretion and changes in body weight were measured daily in rats in metabolic cages. About animal cages in the feed cages, body weight changes were measured every 4 days. Animals from each cage were sampled on days 0, 4, 7 and 14. Mice were anesthetized and blood-sampled heart punctures were obtained and analyzed to determine grape blood content, insulin, total cholesterol, triglycerides, and unesterified free fatty acids (NEFA's). (Please read the notes on the back before filling this page)

Good 1T: λ-ii.ifx in the middle of the ministry; elimination of bamboo.

Ns Secret V. Description of the invention (.1S force A7 B7 Example 1-128 Biological data instance number PPARg PPARg PPARg Fold. Active EC50 (nM) K; (nM) Plasma glucose · Reduced% Lighter than the middle ^ &quot;- ^ 沁 ',: ^ 1,; / 1-porch &quot; bamboo &quot; 卬 ¥ 012 3 456789012 3 456789012 3 4567890 2 3 45678911111111-1 1-.. ^ 222222222233333 33 3334 Examples Example Example Example Example Example Example Example Example Example Example Example Example Example Example Example Example Example Example Example Example Example Example Example Example Example Example Example Example 6 3 ο ο 2 2 3 2 14 5 3 8 2 1 ο ο ο ΙΑ 55 1000 3000 1000 9000 &gt; 3000 ο ο ο 2 3 7 0 7 6 11 ο 5 6 11 Ίχ 11 11 ο ο 5 2 5 11 ΤΑ ο 2 11 11 ΙΑ ο ο 7 0 6 4 ο 5,: ο 5 ο 2 054100541 2 5 5 6 18 5 21 700 300 110 20 1300 80 40 20 80 10 185 180 530 65 50 30 70 1900 300 20 300 145 25 30 10 1 380 50 160 3000 70 5 8% 63% 70% -190- (Read the notes on the back before filling in this page)

This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 5. Description of the invention (18 $ 1234567890123456789012 3 456789012 45678901234 44444444455555555556666666666777777777788888 Examples Examples Examples Examples Examples Examples Examples Examples Examples Examples Examples Examples Examples Examples Examples Examples 5 5 08 0000050 5 11195215 3 82 ο 0 5 ο ο ο 5 6 2 4

ο 5 IX ο 5 5 00043 20 0 0 5 5500 5 0000565 91122112011215251162 14 215 ο ο 2 ο ο ο ο ο 5 A7 B7 701000153075024011580390140100703000140010124530100151020305040201010290250301158007511015540501013065350 / 1] Chinese National Standard (CNS) A4 specification (210X297 mm) V. Description of the invention "(18 $ Example 85 20 Example 86 30 Example 87 465 Example 88 0.5 Example 89 60 Example 90 Example 91 20 Example 92 400 Example 93 55 Example 94 10 Example 95 700 Example 96 300 Example 97 20 Example 98 375 Example 99 1 Example 100 1 Example 10 1 1 Example 102 80 Example 103 180 Example 104 900 Example 105 35 Example 106 300 Example 107 190 Example 108 20 Example 109 200 Example 1 10 65 Examples Π 1 10 Examples 112 10 Palm Examples 113 80 Examples 1 14 250 Examples 115 165 Examples 116 165 Examples 117 1000 Examples 118 500 Examples 119 470 Examples 120 350 Examples 121 320 Examples 122 500 Examples 123 620 Examples 124 810 Examples 125 200 Examples 126 800 Examples 127 460 Examples 128 20 A7 B 7 650 1160 50 3000 3000 ο ο ο 0 0 0 8 8 ooooo 21432517472 3000 140 140 40 80 700 50 70 130 150 140 200 470 655 730 3000 65 100 625 280 130 160 370 160 70 192-(Read first read the (Please fill in this page again)

This paper size applies to Chinese National Standard (CNS) Λ4 specification (210X297 mm)

Claims (1)

Case No. 86102826 patent application ~ _ _ Chinese patent application scope repairs stupid (10 groups of years-, ^ 8 A8 patent application scope Compound of formula (I) A. Aik CO, R 'B — .〇Z (I) Printed by the Consumer Cooperative of the 4-Central Standards Bureau of the Ministry of Economic Affairs where A is selected from the group consisting of: phenyl, where Phenyl is optionally substituted by one or more hydrogen atoms, α · 6 alkyl groups, Cl 3 alkoxy groups, moxy groups, nitriles, or ^ (wherein, and ... are ^^ alkyl ^ pounds; 'Contains at least one 5_ or 6_ heterocyclic group selected from oxygen, nitrogen and heteroatoms; and (called fused bicyclic OQ in which ring c represents. It is connected to the group B via a ring atom of ring C; B is selected from the group consisting of: (iv) Cu-alkylene '; -MCp-dt alkyl or Ci 6-alkylene M (: ι, 6-alkylene 0, S, or -NR2 where R2 | A Ci-3 ′ ^ group; a 5-betyl group containing at least one heteroatom and optionally at least another heteroatom selected from the group consisting of oxygen, nitrogen and sulfur and optionally substituted with a Ci 3 alkyl group; and ( VII) Het-Cu alkynyl group's heterocyclic group whose $ Het table is as defined in point (vi) above; Aik table fluorenyl group; (ϋ) (v) (vi) This paper is suitable for financial standards (CNS ) Α4 is now 72101α97 mm) of which double where M is the patent No. 86102826 p _ Chinese patent case ~_ range Pi Xiu stupid (paste of 10 group -, ^ 8 A8 patented range Compound of formula (I) A. Aik CO, R 'B — .〇Z (I) Printed by the Consumer Cooperative of the 4-Central Standards Bureau of the Ministry of Economic Affairs where A is selected from the group consisting of: phenyl, where Phenyl is optionally substituted by one or more hydrogen atoms, α · 6 alkyl groups, Cl 3 alkoxy groups, moxy groups, nitriles, or ^ (wherein, and ... are ^^ alkyl ^ pounds; 'Contains at least one 5_ or 6_ heterocyclic group selected from oxygen, nitrogen and heteroatoms; and (called fused bicyclic OQ in which ring c represents. It is connected to the group B via a ring atom of ring C; B is selected from the group consisting of: (iv) Cu-alkylene '; -MCp-dt alkyl or Ci 6-alkylene M (: ι, 6-alkylene 0, S, or -NR2 where R2 | A Ci-3 ′ ^ group; a 5-betyl group containing at least one heteroatom and optionally at least another heteroatom selected from the group consisting of oxygen, nitrogen and sulfur and optionally substituted with a Ci 3 alkyl group; and ( VII) Het-Cu alkynyl group's heterocyclic group whose $ Het table is as defined in point (vi) above; Aik table fluorenyl group; (ϋ) (v) (vi) This paper is suitable for financial standards (CNS ) Α4 is now 72101α97 mm) where double is where M is A8 B8, C8 D8. Patent Fanyuan R1 expresses hydrogen or Cw alkyl; Z is selected from the group consisting of the following groups ... Group: (viii)-(Ci.3 alkylene) phenyl group, of which Phenyl is optionally substituted with a halogen atom; and (ix) -NR_3R4, where R3 represents hydrogen, and K4 represents -Y- (C = 0) -T-R5, where: (a) the Y-bond, ( : 2_6 alkenyl, C4_6 cycloalkylene, heterocyclic group as defined in point (vi) above, or optionally one or more Cw groups and 7 .. or one qin._ more ... ... a ...: a prime. A proton. A substituted phenyl group "(b) T-tab, -0 or -NXR6)-, its soil R6--oxygen or Cw alkane ..... · · — —............ group; (c) —R5 represents Cu alkyl group, (: 4-6 cycloalkyl group, phenyl group (depending on the situation, e &quot; one or more) A plurality of the following are substituted: CU3 alkyl, Cw alkoxy, C0_3 alkylene-NR9R10 (wherein each of R9 and R10 (wherein each of R9 and R10 are hydrogen, Cw alkyl, -SC ^ CkJ ^ Group, or -COWw alkyl group, -SC ^ NHCu alkyl group), C0-3 secondary group C02H, or -0CH2C (0) NH2), or a 6-membered heterocyclic group as defined in item Ji (ii), --------- 装 — _ (Please read the notes on the back first. Printed by quasi-station employee consumer cooperatives or double fused rings Wherein ring D represents a double ring system connected to T .. 'or -Ci_6 via a ring D bead ring atom so that the group MR11, M is 0, S, or -NR2 where R2 and R11 are each hydrogen or Ci.3 alkane Base; or its isomeric form, and / or its medically acceptable salt or solvate 0 -2- This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm) A8 51 — ~ ---- ------ D8: 、 Scope of patent application2. Compounds according to item 1 of the patent application park,-each of them is 5- or 6-membered heterocyclic-ring straight-system. Choose one separately Fen—Cryptyl, hexahydropyracyl, pyrrolidinyl, morphyl, pyruvyl, pyrrolyl, pyrazolyl, pyrimyl, pyranyl, hydrazone, pyrene Group consisting of triphenyl, triphenyl, isothiopyridyl, sigma, thiadiazolyl, and triazolyl. 3 ’The compound according to item 1 or 2 of the scope of the applied patent, wherein A is epiphenyl. Bi ° ... or benzo.zolyl, any of which may optionally be substituted with one or more Cl-3 alkyl groups. 4. A compound according to item 3 of the patent application, wherein a is phenyl, hexahydropyridyl or pyridyl. 5. The compound according to item 1 or 2 of the scope of the application for patent, wherein b represents Cl_3 alkene, alkynyl or Het-Ci., .6 ... alkynyl, wherein the Het table contains at least one nitrogen atom and Optionally, at least one other heteroatom selected from oxygen and sulfur 'is substituted with a ci-3 alkyl group or an unsubstituted 5-membered cyclic group. 6. The compound according to item 5 of the scope of application for patents, wherein B Table N (&lt;: Η3) ((: ΙΙ 2) 2, oxazolyl-Cw-secondary fluorenyl, wherein the eosinophil is as appropriate C1 · 3 pyrimidyl group, or C1 _3 alkyl substituted pyrazolyl group. 7 · The compound of the scope of patent application for item 1 in which the methylene group is methylene. 8. According to the scope of patent application The compound according to item 1, wherein Ri represents hydrogen, methyl or ethyl. 9. The compound according to item 8 of the scope of patent application, wherein Ri is hydrogen. Ο · The compound according to item 1 of scope of patent application, wherein z represents nr And 4, where R3 and R4 are as defined in item 1 of the scope of the application. -3- National Standard (cnsTT ^ TFox297 mm) --------- Installation-(Please read the precautions on the back first ^ € ^ This line is printed by the employee consumer cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. ABCD is printed and patented by the Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs. Is hydrogen.. According to the i 0 or u compounds of the scope of the patent application, where R4 Table 13 strokes! ΓQ) TR 'where r 5As defined in item 1 of the scope of patents. 1 According to the benefits of item _ item 8, "as the case may be-^ more Cw health noodles, or one or more benzene substituted with a prime atom,棊. 14 · * ^ tn II ® ^ 9 ^ ^ -t--T λ il -0- 〇5 · According to the compound in the scope of the patent application No. 12 of which 5 is shown in Table ^ or phenyl (as appropriate by _. Or Park., ^ Or Qi replaced by ice-based). A 16, Gen Hai Shen # # ®, ^ or phenyl (depending on the essence-the classics. By-more-poly-and, prime atom, or a Or more substituted by cN3 alkyl). Π. The root of the U.S. patent application scope of the U.S. 2 R5 | Ci 3 alkyl or phenyl (optionally via one or more _ prime atoms, or one or More grass-based substitutions). '8. According to the application of the compound named the 10th scope of the patent, in which the NH and the (= 0) are ortho to each other on Y (which is phenyl), D is a bond or _〇_, R5 is a Cw alkyl group, or a phenyl group (substituted by one or more of the following as appropriate: a halogen atom, a Cl_31 group, a Cn3 alkoxy group, and a c03 secondary alkyl group NR R, where R9 And Ri〇 are each independently hydrogen, and Ci3 alkane is: _s〇2Ci3 alkyl, or _C〇 2CN3 alkyl, -SOrNHCw-alkynyl, cO-j-alkynyl-C02H, CQ-3 alkynyl-C ^ Cufe-based, or -Och2C (0) NH2). 19. According to the 18th in the scope of patent application The compound of the item, __. 矣 ._ in r4 Table -4- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210 &gt; &29; 29 &lt; 7mm) -β (Please read the precautions on the back page first A8 B8 C8 D8 Patent Application Scope 0 R1 where R13 is phenyl 4 0CHj. 2〇_ Compound of formula 1 (a) according to item 丨 of the scope of patent application (1a) '--------- ^-(Please read the notes on the back before G: this book) where A and B. are as described in item 丨. Of the scope of patent application and A ^ table Phenyl or a 5 or 6 ... membered heterocyclic group containing at least one atom selected from oxygen, nitrogen and sulfur, and solvates thereof. 21. The compound according to item i of the scope of the patent application, which is selected from the group consisting of: 3_ (4-methoxy-2-phenylmethyl-3_oxo-3-phenyl-propanamine ) -Dicyclohexylamine propionate. Salt 3- (4-Methoxy-phenyl) _2 (S)-(1-methyl-3-oxo_3-phenyl-propenylamino) -propyl Acrylic acid ester 2 (S)-(2-fluorenyl · cyclohexyl-i-ylaminobenzyloxy_phenylpropyl. Acid dicyclohexanylamine salt 1 2- (2-fluorenylanilide ) -3- (4-Methoxyphenyl) propionic acid 3- (4-; oxy-phenyl) -2- (2-Methoxy-aniline) _propionyl acetate 5-paper size Applicable to China National Standard (CNS) A4g (210X297mm) Printed by the Consumers 'Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, printed A8 B8 C8 —------- D8 VI. Patent Application Scope ^-(',- Benzyl phenylamine (zoyl-aniline) _ methyl propionate. (Oxybenzyl.)-2- [2- (hexahydro p ratio -1-carbonyl) _ aniline] _Methyl propionate_2 (3: Si group-lumben_2_yl-amino group) _3_ (4_benzyloxy-phenyl) _propionic acid 2_ (bu = fluorenyl-thiol_3_yl _Amine) _3_ (4_benzyloxy-phenylpropanoic acid 3_ (4_fluorenylmethylbenzyloxy-4H-benzene Pyridoxan_3_carbonyl) -amino] -methyl propionate 2Γ (2-lowerylbenzylamino) -3- {4- [2- (methyl-pyridin-2-yl-amine ) -Ethoxy] -benzyl} _propionic acid 2 (S) _ (2-narrow fluorenyl-benzylamino) -3- {4- [2- (methyl-, pyridin-2-yl- Amino) -ethoxy] -phenyl} -propionic acid 2- (2-fluorenyl · aniline) -3- {4- [2- (methyl-pyridin-2-yl-amino) -ethoxy ] -Phenyl} -acetic acid propionate (methato 3oxo-3 · -phenyl-propionamine _)-3-{4- [2- (methyl-ρ than bite 2-yl- Amine) _ethoxy] _phenylcyclopropane dicyclohexylamine salt. 3- {4_ [2_ (benzoxazol-2-yl-methyl-amino) -ethoxy] -phenyl } -2- (2-fluorenyl-benzylamino) -propionic acid 3- {4_ [2- (benzoxazol-2-yl-methyl-amino) -ethoxy] -phenyl} -2- (2-fluorenyl-benzylamidopropionic acid, printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, 3- {4- [2- (benzimidazole_2_yl-methyl-amino) _Ethoxy] _phenyl} _2 (s) _ (1-methyl-3-oxo_3_phenyl-propenylamino) _dicyclohexylamine propionate 3_ {4- [2- ( Stupid. No. azole_2_yl-methyl-amino) _ethoxy] _phenyl 丨 _2 (s) _ [3- (3-mothyl-phenyl) methyl_3_oxo -Allylamine Based) _Dicyclohexylamine propionate-6-Applicable to this paper size (CNS) A4 ^ (21QX297 public director) A8 B8 C8 D8 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 6. Application for patents 3- { 4- [2- (benzoxazol-2-yl-methyl-amino)> ethoxy] _phenyl} _2_ (2_fluorenyl-4-methyl-aniline) _propionic acid 3- {4- [2- (benzoxazol-2-yl-methyl_amino) _ethoxy] _phenyl} _2_ (2_fluorenyl-4-chloro-benzylamino) _propionic acid 3 -{4- (1-Benzoline-2-yl-pyrrolidin-3-yloxy) -phenyl] "2- (2-fluorenyl-peptidyl) -propionic acid 3- [4 -(1-benzoxazol_2_yl) _pyrrolidine_2 &amp; _yl'methyl..oxy) _phenyl] _2_ (2_fluorenyl-pentylamino.propionic acid 3- [4 -(1-.Benzo) izol_2-yl) -pyrrolidin-28-yl-methoxy) -phenyl] _2_ (2-fluorenyl-aniline) _propionic acid 3- {4- [24 Benzozol-2, yl-methyl-amino) _ethoxy such as phenyl} _2_ (2_cyclohexyl.storyl-aniline) -propionic acid. 3- {4- [2- (Benzoxazol_2_yl-methyl-aminoxoxy) _phenyl} _2_ (2_bucket SS-thiophenyl-3 -ylamino) -propionic acid 3- {4- [2- (Benzoxazol_2_yl · fluorenyl-amino) _ethoxy] _cumyl} _2_benzyl- Trifluoroethyl 3- {4- [2- (benzoxazol_2-yl-fluorenyl-amino) _ethoxy] _benzylb 2_ (2_ bromo-fluorenyl) -propionate Fluoroethyl 3- {4- [2- (benzohumazol-2-yl-methyl-amino) _ethoxybenzoyl} _2 (s) _ [4-oxo-4H-benzo / 5-pyridan-3-carbonyl) -amino] -propionic acid 2 (S)-(2-fluorenyl-aniline) _3- {4- [2- (5-methyl-2-phenyl -Oxazole_4_yl) -ethoxy] -phenyl 丨 -propionic acid 2_ (2_fluorenyl-aniline) -3- {4- [2- (4-Gaphenyl) -p _4_Methoxy] -phenyl} -propionic acid> (Please read the precautions on the back first, then this page) Gutter This paper size applies to China National Standard (CNS) A4C ^ · (210X297 mm ) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A8 B8 C8 D8 6. Application for patents 3- [4- (2- (benzimidazol-1-yl-ethoxy) -phenyl] -2- (2 -Fluorenyl-aniline propionic acid 2 (S)-(2-fluorenyl-aniline) -3- {4- [2- (5-methyl-2- (4-methoxy) -benzene .-P-number _4_yl) -ethoxy] -phenyl} -propionic acid 2 (3)-(2-benzylfluorenyl-, aniline) -3- {4- [2- (5 -Fluorenyl. 2- (4-fluoro-)-phenyl-oxazol-4-yl) -Goxy] -phenyl} -propionic acid 2 (S)-(2-benzylfluorenyl-benzene Amine) -3- {4- [2- (5-methyl-2- (5-methyl-fluoren-2-yl) -pyrazol-4-yl) -ethoxy] -phenyl} -Propionic acid &quot; 2 (S)-(2-benzylfluorenyl-aniline) -3- {4- [2- (5-methyl &lt; 1-phenyl-1H-pyrazol-3-yl) -Ethoxy] -phenyl} -propionic acid '2 (S)-(2-fluorenyl-aniline) -3- {4- [2- (5-methylfluorene-2-hexahydropyridine-1 -Yl-11 咢 η--4-yl) -ethoxy. Hydrazone,} -phenyl} -propionic acid, 2 (S)-(2-fluorenyl-aniline) -3- {4- [ 2- (5-methyl-yl-2-morpholin-4-yl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid 2 (S)-(2-fluorenyl-aniline ) -3- {4- [2- (5-methyl-2- (4-pyridyl) -thia. .-4-ethoxy] -phenyl} -propionic acid 2 (3)-(2 -Fluorenyl-aniline) -3- {4- [2- (2-dimethylamino-5-methyl-oxazol-4-yl) -ethoxy] -phenylpropanoic acid 2 (S)-(2-benzylfluorenyl-aniline) -3- {4- [2- (5-earthyl-2- (5-methylisocyanato-3-1) -pyrazole-4- ) -Ethoxy] -phenyl} -propanoic acid, 2 (S)-(2-famidino-anilino) -3- (4- {2- [5-methyl-2- (4- Fluorenyl [1,2,3] oxadiazol-5-yl &gt; --- thiazol-4-yl] -ethoxy} -phenyl) -propionic acid 2 (S)-(2-oxalyl- Aniline) -3- (4- {2- [5-fluorenyl-2- (4-methyl-hexahydropyridine-1-yl) -Pyrimazol-4-yl] -ethoxy} -phenyl) -propionic acid-8-(Please read the precautions on the back before Ci page). Binding-Binding This paper size applies to Chinese National Standard (CNS ) A4 specification (210X297 mm) 8888 ABCD 6. Application scope of patent 2 (s)-(2-word fluorenyl-anilinomethylamino-propylamino) -5-methyl-oxazolyl-4-yl] -Ethoxy} _phenyl) _propanoic acid 2 ($)-(2-fluorenyl_aniline) _3_ (4_ {2_ [2 · (2_methoxy_ethylamino) -methyl- Pyrimazol-4-yl] -ethoxyphenylphenyl) -propionic acid, 2: (1-carboxy-'2- {4- [2, (5-methyl_2_phenyl_ ~ 4_yl) _ethoxy] _Daddy \}-Ethylamino) -acid acid 2- (1-1-. 基 -2- {4- [2- (4-chlorophenylsulfanyl) _ Ethoxy] -phenylethylamino) -benzylic acid methyl 2- {1-carboxy-2- [4- (l-phenyl-pyrrolidinylmethoxy) _phenyl] -ethylamino} -Ethyl phosphonate 3- {4- [2- (Benzoxazolyl-methyl-amino) _ethoxy] _phenylbenzene 2_ (2_cyclopentanecarbonyl-aniline) _propionic acid 3 -{4- [2- (Benzoxazole_2_yl-methyl_amino) _ethoxy] _phenylbenzene 2_ (2_ liximidine molybdenyl_phenyl-aniline) _propionic acid 3- {4- [2- (benzoxazole_2_yl-methyl_ Amine) _ethoxy] _phenyl} _2_ (2_ hexanehexane I-5 -fluoro-fluorenylpropanoic acid 3 .- {4- [2-(_ Benzofluorene_2_ | _methyl_amine Based) _ethoxy]] phenylphenyl 2_ (4_cyclohexyl ... fe.agro-2-2 fluorenylamino) -propionic acid. Printed by the Consumers' Cooperative of the Central Standardization Bureau of the Ministry of Economic Affairs, 1, 4- [2- (benzyl.pyridazol_2-yl-methyl-amino) _ethoxy] _phenyl} _2_ (3_ 笮 .61-p-phenphen-2-ylaminopropionic acid 2- (2-cyclohexanecarbonyl-benzylamino) _3_ {4_ [2_ (5_methyl_2_benzyl-pyrazole_4-yl) -ethoxy] -phenyl} -propionic acid $-( 2-cyclohexanecarbonyl-anilino) -3- {4- [2- (5-methyl-2-phenyl-No. 4-4,)-ethoxy] -phenyl} -propionic acid 1 This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) A8 B8 C8 D8 々, patent application scope 3- [4- (l-benzoxazol-2-yl-pyrrolidin-3-yl (Oxy) -phenyl] -2- (2-benzyl-anilino) -propionic acid 3- {4- [2- (5-methyl-2-phenyl-oxazol-4-yl)- Ethoxy] -phenyl} -2 (S &gt;-[2- (pyridine-4-carbonyl) -aniline] -propanoic acid 3- {4- [2- (5-methyl-2-phenyl- Purazol-4-yl) -ethoxy] -phenyl} -2 (S)-[2- (pyridine N-oxide-4-carbonyl) -benzene Group] · • propionic acid 3- {4- [2, (5-methyl-2-phenyl, oxazole_4-yl) -ethoxy] -phenyl} -2 (S)-[2- (Pyridine-3-carbonyl) -aniline] -propionic acid 3bis {4- [2- (5-methyl-2-phenyl-triazol-4-yl-ethoxy] -phenyl} -2 (S)-[2- (pyridine-N-oxide-3 diacidyl) -anilino] -propionic acid 23- (2 di-n-fluorenyl-anilino) -3- {4- [2- (5 -Methyl-3 _-. Benzyl-oxazole-1: yl) -ethoxy] -phenyl} -propionic acid · 2S- (2-cocofluorenyl-aniline) -3- [4- ( 1-pyridin-2-yl-pyrrolidin-2S-yl-methoxy) -phenyl] -propionic acid 2S- (2-benzylfluorenyl-aniline) -3- {4- [2- (1- Methyl-4-phenyl-1H-imidazol-2-yl) -ethoxy] -phenyl} -propionic acid 2S- (2-fluorenyl-aniline) -3- {4- [2- ( 3-furan-2-yl-5-methyl-pyridine. -1 -yl,) .- ethoxy] -benzene ~ yl} -propanoic acid 2S- (2r benzamidine-aniline-yl) -3 -{4, [2- (5-formamidine-3-phenyl [1,2,4] triazol-1-yl) -ethoxy] -phenyl} -propionic acid 2S- (2-benzyl Fluorenyl-aniline) -3- {4- [2- (3-methoxymethyl-5-methyl-yl--2--2-yl-3H-imidazole-4-, yl) -ethoxy] -Phenylphenylpropionic acid 2S- (2-fluorenyl-aniline) -3- {4- [2- (5-methyl-2, -phenyl-3H-imidazole-4_yl) -ethoxy base ] -Benzene; &}-Hydrochloric acid propionate. Salts-10- This paper is in accordance with Chinese National Standard (CNS) A4 standard (210X: 297 mm) --------- pack —- Please read the precautions on the back of this page and then print the line printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed A8 B8 C8 DB ) _3_ {4_ [2- (5_methyl, 2-diphenyl'stein_4_yl) -ethoxy] -phenyl} -two bees ~ 2 (S)-(2., — Word: cool -Benzyl) _3_ {4- [2- (5 _-_ 1 2-yl) -oxazol-4-yl) -ethoxy] -phenylpropanoic acid 2 (| H2- {4- [2 -(5-nitro-2-pyridyloxy) -ethoxy] -phenylbutanyl-methyllactate-ethylamino) -benzoic acid 2 (S)-(2- {4- [2- (5 -Chloro-2-pyridinesulfany-1) -ethoxy-9-phenyl} _1_methoxycarbonyl-ethylamino) -benzoic acid 2 (S)-(2_ {4_ [2_ (N-ethyl 2-_2-methyl-formamido &gt; ethoxy] -phenylb-1-methoxycarbonyl-ethylamino) -benzoic acid 3- [4- (1., — Benzopyrene-2- -Tetrahydropyrazole-4 (R), .-ylmethoxyphenyl;? (8)-(2-familyl_yl-aniline) _propionic acid 3- {4- [2- (benzene Andazin-2-yl- -Amino) _ethoxy] _phenyl} _2_ [2_ (4-trifluoromethylfluorenyl) _anilino-propionic acid di 3- {4- [2- (benzoxazole-2 -Yl-methyl-amino) -ethoxy ~ yl; μphenyl} _2_ [2_ (2-pyrimidinecarbonyl) -anilino-propionic acid 3- {4- [2- (benzoxazole-2 -Yl-methyl-amino) _ethoxy] -phenyl} _ ?: [2_ (3-fluorenylcarbonyl) -anilino-propionic acid 3- {4-.1.2- (benzopazole 2-yl-methyl-amino) -ethoxy] -phenylbenzene 2- [2- (3-trifluoromethylfluorenyl) _anilino-propionic acid 3- {4- [20 Benzoinol-2-yl-methyl-aminob-ethoxy] _benzyl} _2: [2_ (2-trifluoromethylbenzyl) -anilino-propionic acid 3- {4- [2- (benzohumazol-2-yl-fluorenyl-amino) _ethoxy] -phenyl} _2_ [2 di., (3 -... methyl, oxy-I, ethyl) -benzyl Amine-propionic acid, -11-This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before this page-Pack. 、 -Β Line Central Bureau of Standards, Ministry of Economic Affairs Printed by employees' consumer cooperatives C8 _____ D8 VI. Application scope of patents' '~ 3- {4-. [2-. (Benzene number, sitting _2_yl_fluorenyl'amino) _ethoxy] • benzene Base} _2_ [2- (2- 甲-Yl-donyl.)-Anilino-propionic acid 3- {4- [2-(^ n ^ &amp; [2- (3-methyl-benzyl.yl) -anilino-propionic acid 2.- [2- (4--methylpyridinyl_benzylfluorenyl) _phenylenyl] _3_ {4_ [2_ (5_fluorenyl_ 2; phenyl-0 咢 σ--4-yl) -ethoxy []] Bun_1 | _—propane-acid chloride 2- [2- (4-Aminemethyl-yl) · aniline] small (4_ [2_ (5_methyl_2 · phenyl_yinu) -4-yl) -Ethoxy] -benzene.'yl} _propanoic acid. Hydrochloride. 3: pyrene [[2- (benzonopyrene-2'yl. ^^^ (2,6-Dimethylfluorenyl) -aniline.yl-.. propyl..acid 3- (2_ {1-carbonyl-2- [4- (2-. {5-_. Methyl-2-phenyl-oxazole-4_ylbethoxy, yl) -phenyl] -ethyl.amino) _- pyridyl acid 2- [2- (3-light methyl-benzyl Fluorenyl) _aniline] _3_ {4_ [2_ (5_methyl_2_phenyl-azazol_4_yl) -ethoxy] -phenylpropanoic acid '2- [2- (3-amine Methyl-wordyl) _aniline] _3_ 乂 4_ [2_ (5_methyl_2_phenyl-yinol_4_yl) -ethoxy] • phenylpropanoic acid hydrogenate 2- [2- (3-Dimethylaminemethyl-benzylfluorenyl) _aniline] _3_ (4_ [2_ ^ 2-phenylpyridin-4-yl) -ethoxy] _phenyl} _two acids— Hydrogen_chloride 2 (S,)-(1-carboxy-2- {4- [2- (5-methyl-2-phenyl Azole_4-yl) -ethoxy] -oxylethylamino) -benzoyl-acid methyl ester 2isH_L: retyl-2- {4- [2- (5-fluorenyl_2_phenyl- Hexazol-4-yl) -Ethyl ... 4-phenyl..yl} -ethylamino) _- benzene.methyl——acid-2-aminoethylamidamine hydrochloride. '2 (S) -(llyl-2- {4- [2- (5-methyl-2-phenyl-slogazol-4-yl) -ethoxy..yl] -phenylh.ethylamino) -benzene, 3-Aminopropylamidine hydrogen formic acid. Chloride. _ -12- Please read the precautions on the back of this page and then on this page)-Binding. Binding This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) ) A8 B8 C8 D8 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 6. Application for patents 2- (1-carboxy-2- {4- [2- (5-methyl-2-phenyl-pyrazole_4) _Yl) -ethoxy] _phenyl} -ethylamino) -benzylmethoxamine 3- {4- [2- (benzo.pyrazol_2_yl: methyl'aminoethyl ~ Oxyphenyl (3-meryl-benzyl, yl) -phenyl'amine.yl-propenyl 3- {4-['2- (5-methyl-2-phenylhydrazone-σ # azole-4- ) -Ethylpyridine] -phenyl} _2- [2- (4-propylamine transverse acid.yl theophylyl) _aniline .... yl] -propionic acid, ... 2- [2- (3 -Amine-Amidino) _Extracting Amine] _3_μ_ [2_ [5_methyl_2_ _ Hydrazol_4.yl) -ethoxyl] -phenylpropanoic acid 2- [2- (3-hydrazine peak amine_amidino) _aniline] _3_ {4_ [2_ (5 _Methyl_ 2_phenyl-dizole_4_ylethoxyj_phenyl} _propan-2- [2-, (3-methyl..oxycarbonylamino_fluorenyl) _aniline ], 3_ | 4_ [2_ (5_fluorenylphenyl-pyrazole_4_yl) -ethoxyphenyl} • propane 2-[2- (3 · hydroxy-benzyl) _benzene, Amine] _3_ (4_ [2_ (5-Methylphenylphenylazol-4-yl) -ethoxy] -phenylpropanoic acid 2- [2 '-(3-Carbohydrazone-benzyl alcohol Group) _aniline group μ3_ {4_ [2_ (5_methyl_2_phenyl-oxazole_4_yl) _ethoxy] _phenyl} _propionic acid 2 (S)-(2-fluorenyl -Anilino_2_pyridine_4_yl-oxazole-4yl) -ethoxy] -phenylpropanoic acid 2 (3)-(2-benzyl-anilino) _3_ (4- {2 -[5-Methyl_2- (4-methyl_hexahydrop ratio than 1-yl) -p-sigma-4-yl] -ethoxyphenylphenyl bis ... acid ~ hydrochloride 2 (S)-(2-fluorenyl-aniline) _3 · (4_ {2_ [5_methyl_2_ (4_third_ τoxocarbonyl-hexahydropyridine -1 -yl)-喽Azole_4_yl] • ethoxybifluorene) _propionic acid 2 (δ)-(2_fluorenyl-aniline) -3- {4- [2- (5-methyl-2-hexahydro_pyridine Geng-l_ kis (sigma-4-yl) -ethoxy ... yl] -phenylpropionic acid (Please read the precautions on the back first, then this page) Gutter-13- This paper size applies Chinese National Standard (CNS) A4g (210X297mm) Printed by A8 B8 C8 D8 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, Application Patent scope 2 (S)-(2-fluorenyl-aniline) -3- (4- {2- [5-methyl-: 2- (4-methanesulfonyl-hexahydropyrylene-1- ) -Thienyl-4-yl] -ethoxy} -phenyl) -propionic acid. 2 (S)-(1-carboxy-2- {4- [2r (4-diamidoamino-phenyl) ) -Ethoxy] -phenyl} -ethylamino) -propionic acid methyl ester 2 (S)-[1-methoxycarbonylfluorene-2- (4- {2- [5-methyl-2- ( ^ Methyl-hexahydropyridine-butyl) _Pethazol-4-yl] -ethoxy} -phenyl) -ethylamino] -benzoic acid 2S)-[l-carboxy-2- { 4- [2- (4-Chloro-phenyl) -ethoxy] -benzyl} -ethylamino) -benzoic acid acetoacetate 2 (S) 41- | yl-2- {4-zozotrifluoro Methoxy-benzyl) -ethoxy-yl] -benzene.yl} -ethylamino) -phenylbenzoic acid methyl ester &gt; {4- [2- (benzoxazol-2-yl-methylamine ) -Ethoxy] -phenyl} -3- (4-fluorenyl-thienylaminopropionic acid / 3- {4- [2- (benzoxazol-2-yl-fluorenylamino)- Ethoxy] -phenyl} -2- (2- (4-biphenylcarbonyl) -aniline) -propionic acid 3- {4- [2- (benzo Azole-2-yl-methylamino) -ethoxy] -phenyl} -2- (2- (4-methoxy-benzylfluorenyl) -aniline) -propionic acid 3- {4- [2 -(Benzohum-2-yl-fluorenylamino) -eth-oxy] -phenyl} -2- (2- (4-methyl-benzylfluorenyl) -aniline) -propionic acid di 3 -. {4- [2- (benzohumazol-2-yl-methylamino) -ethoxy] -phenyl} -2- (2- (2-methyl-.. gamma'fluorenyl-1 _)-Aniline.yl.)-Propionic acid 2- (2-fluorenyl-aniline) -3- {4- [2- (4-chloro-phenyl} -ethoxy] -phenyl 丨- Propionate 2- (2-presyl-aniline) -3- {4- [2 .- (4-fluorenyl. Sedazol-5-yl) -ethoxy] -phenylpropanoic acid. -14- (Please read the precautions on the back first, then this page) • Binding. The size of the paper is applicable to the Chinese National Standard (CNS) A4 (210X297 mm). Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A8 B8 C8 D8 VI. Application scope of patent 2- (2- ^ fluorenyl · aniline) -3- {4- [2- (4-chloro-benzene, phenyl-s-ulf-a-ny 丄) —- ethoxy , 棊] -phenyl} -propionic acid 2- (2-benzylfluorenyl-aniline) -3- [4- (4-isopropyl-benzyloxy) -phenyl] -propion ... .... V 〆-- ·, acid_ 2- (2-benzylfluorenyl-phenylenediyl) -3- [4- (4-chloro-benzyloxy) -phenyl] -propionic acid 2- ( 2-fluorenyl-aniline) -3- {4- [3- (4-methoxy--phenyl) -propoxy]-.. phenyl} -propionic acid- 2- (2-benzyl Fluorenyl-aniline) -3- {4- [2- (4-dimethylamino-phenyl) -ethoxy] -phenylpropanoic acid 2- (2-benzylfluorenyl-aniline)- 3- {4- [2- (4-Bromo-phenoxy.yl) -ethyl__hydrogen, yl] -derived} -propionic acid 2- (2-fluorenyl-aniline) -3- {4 -[2- (5-nitro-pyridine) 2-ethoxy] -ethoxy] -phenyl} -propionic acid 2- (2-fluorenyl-aniline) -3- (4- {2- [ 3- (6-methyl-pyridin-2-yl) -dioxy] -ethoxy} -phenyl) -propionic acid 2- (2-octyl Fluorenyl-aniline) -3- [4- (2-pyridin-3-yl-ethoxy] -benzyl} -propanoic acid 2- (2-benzylfluorenyl-aniline) -3- {4- [2- (3-Methyl-6-oxo-6H-dagen-1 耕) -ethoxy] -phenylpropanoic acid 2-. (2-fluorenyl-aniline) -3- {4- [2- (4-trifluoromethoxy-phenyl) -ethoxy] -phenyl} -propionic acid 2- (2-benzylfluorenyl-aniline) -3- {4- [2 -(3-Benzyl Iphenoxy) -ethoxy; K phenyl} -propionic acid 2- (2-benzyl.fluorenyl-aniline) -3- {4- [2- (6-fluorenyloxy -Pyridin-2-yl. -15-This paper size applies to the Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before this page) Packing. Line 391958 as B8 C8 Range — 'sulfanyl) -ethoxy] -phenyl} -propionic acid 2- (2-benzyl_yl_aniline nitrophenyl) · pyrrolidine_2_ylmethoxy] -phenyl} -propionic acid 22. The compound according to item 21 of the scope of patent application, which is selected from the group consisting of: 2 (.SH1-quinyl-2- {4- [2- (5-fluorenyl-2_phenylyl] -Phenyl} ethylamino) -fluorenic acid ester 3 (4 [2- (benzo) azol-2-yl-methyl-amino) _ethoxy] -phenyl} _2 (s) _ (2-fluorenyl-aniline) _propionic acid; 3 {4 [2- (Benzo) azole_2-yl-methyl-amino) _ethoxy] _phenylbenzene 2_ (2_cyclohexanecarbonyl-aniline) -propionic acid; 3 ^ { 4- [2- (benzoxazol_2_yl-methyl-amino) _ethoxy] _phenylbenzene 2_ (2_ unmethyl-pyrimidine_3_ylamino) _propionic acid; 2 (S)-[1-methoxycarbonyl · 2 -_ (4- {2- [5-methyl-2- (4-methyl-hexahydropyridin-1-yl) -p-supposition 1 ^ -4- Group] -ethoxy} _phenyl) ethylamino] _benzoic acid; 2 (S)-(2-benzylfluorenyl_aniline) _3_ {4_ [2_ (methyl-hexahydropyridine_2_yl -Amine) _ethoxy] -phenylpropanoic acid; -2 (S)-(2-fluorenyl-aniline) _3_ "4_ [2_ (5_methyl_2_phenyl-humazole" 4 _)) _ Ethoxy] -phenylpropionic acid; and its pharmaceutically acceptable salts and solvates. ~ 3.—A pharmaceutical composition for treating or preventing a disease or condition of a gamma (PPAR-gamma) -mediated proliferative receptor activated by a cellular enzyme body, comprising a compound according to item 1 of the scope of patent application or Its pharmaceutically acceptable salt or solvate and a pharmaceutically acceptable carrier. -16- A4 Specification ('210X297 mm) 391958 A8 B8 C8 D8 Patent Application Scope Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 4 Types of medical composition for reducing blood sugar, including application according to the scope of patent application Compound of item 1. '— 25. Two types are used for the treatment or prevention of hyperglycemia, dyslipidemia, type η diabetes, type I diabetes, hypertriglyceridemia, χ syndrome, insulin resistance, heart failure, diabetic lipemia, high fat Anemia, hyper * sterolemia, hypertension, obesity, anorexia nervosa, anorexia nervosa, and cardiovascular disease, especially the pharmaceutical composition of atherosclerosis, which includes administration according to the patent application Compounds in scope i. '-26. The compound according to the patent application No. circ.}, Which is used for the preparation of pharmaceuticals for the treatment of diseases related to the activation of proliferative receptor gamma (ppAR_gamma) of thin beer bodies. 27. The compound according to item i of the scope of patent application, which is only used for the preparation of a pharmaceutical for treating an individual who has obtained a blood glucose level. · '2.8. The compound according to item i of the scope of the patent application, which is used for the preparation of' 治疗 blood glucose, dyslipidemia, type II diabetes, type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, Heart failure, glucosamine, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertension, obesity, anorexia—starvation and anorexia nervosa and cardiovascular disease, especially atherosclerosis Pharmaceutical products. 29. A method for preparing a compound according to item 丨 of the patent application park, which comprises reacting a compound of the formula ABX with a compound of the formula (π), co, r 'Please read the notes on the back and then this page]. Binding • Aik Η0 (II) -17- Standard for this paper ruler (CNS) A4 ^ TT—Dong 391958 I ------ D8 VI. Application scope of patents where A, B, Aik 'R1, and Z are as applied The scope of the patent stipulates that Qin and B include Cu alkylene and X is a leaving group or a hydroxyl group. 30. The method of claim 29 in the scope of patent application, wherein X is a hydroxyl group, a halide, or an alkyl- or aryl-continyloxy group, and A is a phenyl group, a pyridyl group, or a benzo-oxazolyl group, B is Korean Het-Cu alkylene, and Z is -NH_Y (C = 0) -T-R5 'where Y is phenyl, optionally through one or more Cl_3 alkyl groups and / or-or more Substituted by a halogen atom; τ is a bond or -0- and Table 115 shows a CV.6 alkyl or phenyl group (optionally via one or more halogen atoms, Cu alkyl, cu 3 alkoxy, C 0.3 butane NR9R10 (wherein each of R9 and R10 is hydrogen, A-3 alkyl, -sOaCu alkyl, SC ^ NHCu alkyl, CG.3 butane 4C02H, Cq.3 butane CC ^ Cu alkane (Or substituted with -0CH2C (0) NH2). The method according to item 29 or 30 of the application, wherein R1 is hydrogen and X is halogen, or alkyl- or aryl-sulfonyloxy. 32. Root. According to the application-the method of claim No. 3 丨, where mx 苳 The compound of formula (π) is: (Please read the precautions on the back first, then this page)-installed. • 1T Ministry of Economy Printed by the Central Consumers Association Consumer Cooperative OMs where OMs is a mesylate leaving group and R13 is a phenyl or —CH3 group. 33. The method according to item 29 or 30 of the scope of patent application, where reverse 1 is Cl_3 alkane line -18- ~~ This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) A8 B8 C8 D8 391958 ^ 2. The scope of patent application and X is a hydroxyl group. 34. The method according to item 33 of the scope of patent application, wherein the 矣 should include three extensions. ...... * (Mi-tsunobu) reaction 'and then the said system is separated by ester-free separation The cluster breaks down into the corresponding acid. 35. The method according to item 34 of the application, wherein the Mitsunobu reaction is performed in a reaction mixture containing toluene. 36. The method according to item 35 of the scope of patent application, wherein the A-B-X and the compound of formula (II) are: R 'Wxl OH wherein R13 is a phenyl or -OH3 group. 37. The method according to item 29 or 30 of the patent application, wherein the compound of formula (II) Printed by the Central Standards Bureau of the Ministry of Economics and Consumers Cooperative, and where the compound of formula (II) consists of the first compound of formula (Π), where Z is -19- This paper size is applicable to China National Standard (CNS) A4 (210x297 mm) 391958 A8 B8 C8 D8. The scope of patent application is followed by a dehydrogenation catalyst, and the dehydrogenation step is performed in the presence of a catalyst preparation. 38. The method according to item 37 of the application, wherein the hydrogen acceptor is an aromatic disc-based compound. Please read the memorandum of attention first. Binding line. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. -20 This paper size applies to China National Standard (CNS.) Α4 size (210 × 297 mm).