TW201242594A - Diphenylmethanol derivatives, preparation process and pharmaceutical use thereof - Google Patents

Abstract

The present disclosure relates to diphenylmethanol derivatives, preparation processes and pharmaceutical compositions containing them. Specifically, the present disclosure relates to novel diphenylmethanol derivatives presented by formula (I), the uses for treatment especially for renin inhibitors and the use in the preparation of drugs for the treatment of renin related disorders, in which each substitute group of general formula (I) is as defined in the specification.

Description

201242594 6. Technical Field of the Invention: The present invention relates to a novel diphenylmethanol derivative, a process for the preparation thereof, and a pharmaceutical composition containing the same, and as a therapeutic agent, particularly as a renin inhibitor And the use of a medicament for the treatment of a disease associated with renin activity such as antihypertensive. [Prior Art] Aspartic Proteinase (Aspartic Proteinase) is a class of important φ proteolytic enzymes involved in the metabolism and biological regulation of the body. In general, their active centers consist of two highly conserved catalytic aspartic acid residues. Common aspartic proteases include: pepsin, renin, beta-secretase (β-site amyloid precursor protein cleaving enzyme, BACE) » human immunodeficiency virus protease, human T cell leukemia virus protease and the like. They are associated with the occurrence of many diseases, such as: in hypertensive patients, the angiotensin I level is elevated due to the catalytic action of renin; it is generally believed that one of the main pathogenesis of Alzheimer's disease is It is formed by the abnormal deposition of β amyloid, a product of BACE, which acts on the powder-like precursor protein. In addition, human immunodeficiency virus and human tau cell leukemia virus require the participation of their respective aspartic proteases during their maturation. Renin (Renin), also known as the angiotensinogenase, is synthesized and released by the renal glomerulus, and then cleaves angiotensinogen into angiotensin I (angitensin I, Ang I) in the blood. Under the action of angiotensin converting enzyme (ACE), Angi 95392 4 201242594 was cleaved into angiotensin II (Ang II), and highly bioactive Angl I can be directly vascularized by arterial vasoconstriction. Ascending hypertension can also indirectly increase blood pressure by regulating the release of aldosterone from the adrenal gland. This regulatory mechanism from renin to aldosterone is called renin-angiotension-aldosterone system (RAAS) ° renin-angiotensin-aldosterone system (RAAS) It is a key role for drugs in the treatment of cardiovascular diseases (Zaman Μ. A. et al. Nature ❶ Reviews Drug Discovery 2002; 1 : 621-36), which can inhibit the secretion and activity of renin, and prevent A-line angiotensin ;[[Generate and block angiotensin II receptors to achieve. Currently, angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBS) have been marketed, and some have become first-line drugs for antihypertensive drugs. However, there are still some problems with current ACEi inhibitors and ABRs. For example, the non-specificity of ACEi causes the RAAS system to be incompletely blocked, resulting in side effects such as dry cough, headache, and hyperkalemia. Since renin directly regulates the initial link in the RAAS system, Angl production, and is highly specific for endogenous angiotensin, it has been the focus of research on RASS drugs. In addition, by inhibiting renin to block RASS, in addition to lowering blood pressure, it also reduces the risk of diabetes and other cardiovascular diseases caused by hypertension. Such as blocking RAAS can be used to treat liver and kidney fibrosis (Gaedeke), etc.

Contrib Nephrol. 2001; 135: 153-60, Regina Μ. P. et al. World J Gastroenterol. 2009; 15(21): 2579-86), Artery 5 95392 201242594 Atherosclerosis, cardiac hypertrophy, myocardial fibrosis, diastolic function Disorders, complications of diabetes (such as kidney disease, eye diseases) and other diseases. The first-generation renin inhibitors are peptide matrix analogs, which have poor stability in vivo and have a short duration of action and can only be administered parenterally (Cumin F et al. J. Biol. Chem, 1985; 260(16): 9154-57. ). After that, chemical modification was carried out on the basis of the second generation of oral peptidomimetic renin inhibitors. The related patents have been disclosed: W02005051895, W02005070871, W02007031557 and so on. Currently Aliskiren has been successfully listed. Φ In recent years, with the development of drug development technology, the third generation of non-peptide small molecule renin inhibitors has been designed. The disclosed patents are: W020060U150, W02008036216, W02008156817. Although a series of Renin inhibitors have been disclosed, there is still a need to develop new compounds having better pharmacodynamics, drug metabolism results, and bioavailability. Through continuous efforts, the present invention is designed to have the structure shown by the general formula. A compound, and a compound having such a structure was found to exhibit excellent effects and effects. The present invention aims to provide a compound represented by the formula (1), and tautomers, enantiomers, diastereomers, racemates thereof and pharmaceutically acceptable salts thereof. And metabolites and metabolic precursors or prodrugs. . 95392 6 201242594 R\ Ο

Μ ΗΝ , R8

R7 wherein: R is an alkyl group; a halogen, an aryl group, a thiol group, a cycloalkyl group, a heterocyclic group, and an aryl C(0)R9, wherein each of the alkyl groups is independently selected from the group consisting of a hydrogen atom, a nitro group, Sulfhydryl, alkoxy, alkenyl, alkynyl, heteroaryl, -C(0)0R9, -〇C(〇)R9, — .Wr g; «. w,~" Any one or more selected from the group consisting of dentate, cyano, hydroxy, earth, sulfhydryl, and alkane, respectively, from the genus, the county, the alkynyl group, the thiol group, the heterocyclic group, the silk or the heteroaryl group. Oxyl, cycloalkyl, heterocyclic, aryl, heteroaryl, C(〇)〇R9, -〇C(0)R9, -C(0)R9, -NHC(0)R9, -NiTR11, - 〇C(〇3)NR1QRu, _NHC(〇)NRlQRll4_s(〇)mR9 substituted by a substituent; one of R, R4 and R5 is selected from cyano, alkyl, alkoxy, naphthenic, hetero Cyclo, aryl, heteroaryl, C(〇)〇R9, _〇C(〇)r9, —c(〇)r9, ^Hc(0)R9, _NRi〇Rn. -〇C(〇)NR10Rn ^ -NHC(O)NR10Rn ^ -SO)NR10 R11 # S,S(〇乂R9 ' wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, earth or heteroaryl group is optionally further Multiple selected from !I, Base, this, nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)0R9, -0C(0)R9, -C(0)R9, -NHC(0)R9, -NR1%11, 〜0(:(〇)服1", -MCiWNi^R11 or -S(0)mR9 substituents are substituted, the other two are selected from hydrogen atoms; 7 95392 Or 2012. a heterohalo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aroma = substituted with a substituent of an alkyl, carboxylic acid or phthalic acid ester; a heteroaryl group, R is 〜(CH2)p , R R is a hydrogen atom ' R 7 is -(CH 2 )P-R 12 , or R 7 is a hydrogen atom; R 8 is selected from a hydrogen atom or an alkyl group;

R is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group wherein the alkyl group, cyclofilament, heterocyclic group, aryl group or hetero 3 or hetero group is optionally further selected by one or more Substituted from alkyl, 4, and 2, each independently, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid =, : substituent; ruthenium R or R11 are each independently selected from a hydrogen atom, An alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group or -S(0)mR9 ' wherein the alkyl group, cycloalkyl group, heteroaryl group or heteroaryl group are each independently optionally further one or Substituting a plurality of substituents selected from the group consisting of an alkyl group, a dentate, a hydroxyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a decanoic acid or a carboxylic acid ester; or, R1() and R11 Together with the nitrogen atom to which it is attached, a heterocyclic group is formed, wherein the 3H heterocyclic group contains one or more hetero atoms selected from n, fluorene or s(〇)ra, and the heterocyclic group is optionally further subjected to one or Substituting a plurality of substituents selected from the group consisting of an alkyl group, a halogen, a hydroxyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester; R12 is selected from the group consisting of a cycloalkyl group and a heterocyclic group. Ring base An aryl or heteroaryl group, wherein the cyclohexane 95392 8 201242594 base, heterocyclic group, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, cycloalkane Substituted by a substituent of a hetero group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester; m is 0, 1 or 2; η is 1, 2, 3, 4 or 5; and ρ is 0, 1, 2 or 3;

In the case of (4) of the present invention, the compound of the formula (1) and its enantiomer, diastereomer or pharmaceutically acceptable salt thereof, including the compound represented by the formula (1)) and its enantiomer, non-pair或其 or its pharmaceutically acceptable 趟:

μ疋 I am as described in the general formula (I). A preferred embodiment of the invention, a compound of the formula (1) and a potenten enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (πι) and αν) And 1 σ pharmaceutically acceptable salt. · Body, diastereomer or its R4

Where R1 to R5, R8, p2

(IV)

η and p are as defined in the general formula (I) t 95392 9 201242594 A preferred embodiment of the invention, a compound of the formula (i) and its enantiomers, diastereomers or pharmaceutically acceptable salts thereof Wherein R4 is selected from the group consisting of cyano, alkyl, alkoxy, heterocyclyl, cycloalkyl or aryl. A preferred embodiment of the present invention, a compound of the formula (I), and an enantiomer, diastereomer thereof or a pharmaceutically acceptable salt thereof, wherein: R3 and R4 or R4*R5 together with the attached atom A 5- to 6-membered heterocyclic group is formed wherein the heterocyclic group contains a deuterium atom. A preferred embodiment of the invention, a compound of the formula (1), and an enantiomer of the enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound comprises the compound of the formula (7) and (I) and its enantiomer Body, diastereomer or pharmaceutically acceptable salt thereof:

(VI) 0 atom, or X is a halogen atom, and Y is -CH2;

Wherein X is -CH2~, γ is q is 1 or 2; and R, R2, R6 to R, n are as defined in the formula (1). Yijiajiao scheme provides a compound of the formula (1) and an enantiomer, a diastereomer or a salt thereof, wherein η is a tooth 95392 201242594

Typical compounds of the invention include, but are not limited to: Examples Numbering Structures and nomenclature 1 . Fork a ~. Άα. A N-[2-[(3_气phenyl)_[3_[[(15")-1-(cyclohexylmethyl)_2-methylamino]ethyl]aminomethylmercapto]-5 Methyl cyclopropyl-phenyl]methoxy]ethyl]carbamate 2 . ~~ Ν-[2-[(3-Phenylphenyl)-[3-[[(1 phanyl-1-(cyclohexylmethyl)-2-methylamino-ethyl]aminomethyl decyl] -5-Mercapto-phenyl]methoxy]ethyl]carbamic acid methyl ester 3, human ~ Η ά / ό Ν-[2-[(3-chlorophenyl)-[3-cyclopropyl -5-[[(2 曱-2-decylamino-3-[(3Α0-tetrahydropyran-3-yl]propyl]aminocarboxamyl]phenyl]methoxy]ethoxy Methyl carbazide 4 N-[2-[(3-Vinylphenyl)-[3-(3-methoxypropoxy)-5-[[(2 phanyl-2-methylamino)- 3-[(3A0-tetrahydropyran-3-yl)propyl]aminoindenyl]phenyl]methoxy]ethyl]carbamic acid methyl ester 5, human N~ Η ά/Ό Ν-[2-[(3-Phenylphenyl)-[3-[[cyclohexylmethyl)-2-mercaptoamino-ethyl]aminomethylindenyl]-5-(3-methoxy Propyloxy)phenyl]methoxy]ethyl]carbamic acid oxime ester 11 95392 201242594

6 〇~ ,. Human N 〜0 ά/Ό Ν_[2-[(3-Phenylphenyl)-[3_ethoxy-5-[[(25")-2-decylamino-3-[(3 皮)) -tetrahydrofuran-3-yl]propyl]aminoindenyl]phenyl]methoxy]ethyl]amino decanoic acid methyl ester 7 N-[2-[(3-chlorophenyl)- (^3-(^(25)-3-cyclohexyl-2-mercaptoamino-propyl]aminoindenyl]5-ethoxy-phenyl]decyloxy]ethyl]aminocarboxylic acid Methyl ester 8 9 .. fork [^~ Ν-[2-[(3-chlorophenyl)_[ 3-[[(15〇-1_(cyclohexylfluorenyl)-2-methylamino]ethyl ]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]] - gas phenyl)-[3_ethoxy-5-[[(25")-2_methylamino-3-[(3Λ0-tetrahydro'-pyran-3-yl]propyl]amino hydrazine Methyl phenyl] phenyl] methoxy] ethyl] carbamic acid methyl ester 10 . Η 。 。 丫 丫 丫 丫 丫 丫 丫 丫 丫 丫 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 Methyl cyclohexyl-5-[[(150-1-(cyclohexylmethyl)-2-fluorenylamino-ethyl]aminoindolyl]phenyl]decyloxy]ethyl]aminocarbamate 12 95392 201242594 ----- 11 , people ~. into the _ H & ---------. gas stupid base _ [3_ cyclohexyl _5_[[(2 _2_Methylamino-3-3 tetrahydropyran-3-yl]propyl]aminocarbamimidyl]phenyl]methoxy]ethyl] ester 12, and [J — ----- gas Phenyl)-[2-methoxy-5-[[(2β-2-methylamino-3-yl"3Λ0-tetrahydropyran-3-yl]propyl]aminomethylindenyl]benzene Methoxy]ethyl] _^ rabbit!^methyl ester 13 ,. Β Ν~[2-[(3-phenylphenyl)-[2-ethoxy-5-[[(25)) 2-methylamino-3-[(3Λ0-tetrahydropyran-3-yl]propyl]aminocarbamimidyl]phenyl]methoxy]ethyl]carbamic acid oxime ester 14 Ν_[ 2-[(3-Chlorophenyl)-[3-cyclopentyl-5-[[(15")-1-(cyclohexylmethyl)-2-methylamino-ethyl]aminocarboxamidine Methyl]phenyl]methoxy]ethyl]aminocarbamate 15 , human ~. into $ H 6 Ν-[2-[(3-chlorophenyl M3-cyclopentyl-5-^(25) -2-methylamino-3-[(3>?)-tetrahydropyran-3-yl]propyl]aminocarbamimidyl]phenyl]methoxy]ethyl]carbamic acid Ester 13 95392 201242594

16 N-[2-[(N)-(3-Phenylphenyl)-[3-cyclopropyl-5-[ [(25^-2-decylamino-3-[(3A0-tetrahydro]' • Methylpyran-3-yl]propyl]aminoindenyl]phenyl]methoxy]ethoxy]carbamic acid methyl ester 17, human ~. Named N-[2-[(5〇- (3-Phenylphenyl)-[3-cyclopropyl-5-[ [(25)-2-decylamino-3-[(3A0-tetrahydron-pyran-3-yl]propyl]amine Methylmercapto]phenyl]methoxy]ethoxy]carbamic acid methyl ester 18, Λ~死 4 Ν-[2-[ [3-butoxy-5-[ [(150-1-( Cyclohexylmethyl)-2-mercaptoamino-ethyl]aminomethylindenyl]phenyl]-(3-phenylphenyl)methoxy]ethyl]carbamic acid oxime ester 19 ?^^〇 , ,., b b ~ Ν-[2-[(3-Phenylphenyl)-[3-[[(15·)-ΐ-(cyclohexylmethyl)-2-methylamino-ethyl]amine Methylmercapto]-5-(2-methoxyethoxy)phenyl]methoxy]ethyl]carbamic acid methyl ester 20 0. Human Ν-[2_[(3_^本基)- [3-[[(1cyclohexylmethyl)-2-methylamino-ethyl]aminocarbamimidyl]-5-(cyclopropyldecyloxy)phenyl]methoxy]ethyl] Methyl urethane 14 95392 201242594 21 、, 〇/So 孴^3_[ [(150-^(cyclohexylmethyl)_2_decylamino]ethyl] Methyl fluorenyl]-5-isobutyl decyl _ phenyl] methoxy] ethyl] carbamic acid methyl ester 22, Η Η 。 。 。 / / / / / / / / / / / / / / / / / / / / / / / £ £ £ £ £ )_[5-[[(15')-(cyclohexylmethyl)-2-decylamino-ethyl]aminomethylindenyl]_2, 3-dihydroindolyl]-methoxy Ethyl]ethyl] carboxylic acid oxime ester 23, Η-[2-[(3-carbophenyl)-[5-[[(15〇-l-(cyclohexylfluorenyl)) 2- Methylamino-ethyl]aminomercapto]-3,4-dihydro-2β-benzopyran-7-yl]-methoxyl 1 ethyl]carboxylic acid methyl vinegar 24, fork Η Id N-[2-[(3-Phenylphenyl)_[4-[[(1 phanyl-1-(cyclohexylmethyl)-2-methylamino]ethyl]aminocarbazinyl) ]-2,3-Dihydrobenzofuran-6-yl]methoxy]ethyl]carboxylic acid methyl ester 25 - _ ~, .~~. Chlorophenyl)-[7 - [[ (1 幻 - 1-(cyclohexylmethyl)-2-methylamine -ethyl]aminocarbazinyl]_3,4_dihydro-2^~benzopyrene than η南-5-yl]-methoxy i !Ethyl] formic acid methyl vinegar 15 95392 201242594

26,. Fork κ~. L_[2-[(3-Phenylphenyl)-[6-[ [(15)-1-(cyclohexylmethyl)-2-methylamineethyl]aminomethylindenyl]-2, 3 - Dihydrobenzofuran-4-yl]nonyloxy]ethyl]carboxylic acid oxime ester 27, human ~ Η άα. ά Ν-[2-[(3-Phenylphenyl)-[5-(^(25)-2-methylamino-3-[(3))-tetrahydro]pyran-3-yl]-propyl Methylaminomethyl hydrazino]methyl _7-yl]methoxy]ethyl]amino decanoic acid methyl ester 28, population ~ 〇Ν-[2-[(Λ〇-(3-气phenyl) )-[3-[[(150-1-(cyclohexylmethyl)-2-methylamino-ethyl]aminoindolyl]-5-methoxy-phenyl]decyloxy]B Methyl carbamic acid methyl ester 29 -------- N-[2-[(50-(3-chlorophenyl)-[3-[ [(1^-1-(cyclohexyldecyl))) -2-Methylamino-ethyl]aminomethylindenyl]-5-methoxy-phenyl]decyloxy]ethyl]amine i methyl formate 30 〇^^〇〆, Λ~. Η ά/ ά —---- Γ^Τ^Τΰο-Ο-chlorophenyl)-[3-(3-methoxypropoxy)-5-(:1:(25)-2-methylamine Methyl-3-[(3-tetrahydropyran-3-yl)propyl]aminocarbamimidyl] phenyl]ethyl]ethyl]carbamic acid methyl ester 16 95392 201242594 31 N-[2-[ (>S)-(3-Phenylphenylindole 3-(3-decyloxypropoxy)-5-[[(25〇-2-methylamino-3-[(3))-tetrahydro)比 喃 -3- 基 基 丙基 ] ] ] ] ] ] ] ] ] ] ] ] ] 甲酯 甲酯 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 Base)-[6-[[(l magic-1-(cyclohexyl) Methyl)-2-mercaptoamino-ethyl]aminocarbamimidyl]-2,3-dihydrobenzofuran-4-yl]nonyloxy]ethyl]carboxylic acid methyl ester 33. 〇丫^·N〆N-[2-[U)-(3-Chlorophenyl)-[6-[[(15〇-1-(cyclohexylmethyl)-2-methylamino)-B Methyl]aminomethylindenyl]-2,3-dihydrobenzofuran-4-yl]methoxy]ethyl]carboxylic acid methyl ester 、, human ~vCOjX 34 0 Η 1 τ άα° 6 ν_[2- [(3-Phenylphenyl)-[3-[[(25))-2-decylamino-3-[(3Α〇-tetrahydropyridin-3-yl]propyl]aminocarboxamyl) ]-5-(2, 2, 2-Trifluoroethoxy)phenyl]methoxy]ethyl]carbamic acid methyl ester 0' 35 one gas phenyl)_[3_ethoxy-5-[ [(25")-2-Methylamino-3-tetrahydropyran-3-yl]propyl]aminocarbamimidyl]phenyl]methoxy]ethyl]amino decanoate

95392 17 201242594

36 N-[2-[(3-Chlorophenyl)_[6-[ [(2iS)-2-methylamino-3-[(3Λ〇-tetrahydro)"pyran-3-yl]-propyl Methylaminomethyl]3-dihydrobenzopyran-4-yl]methoxyl methyl 1-ethyl]carbamate 37, ν 〜 Η ά / 6 1^-[2- [(3-Chlorophenyl)_[3_methoxy_5-[[(21?)-2-methylamino-3-[(3)-tetrahydro- 0-yl]propyl] Amino methoxy]phenyl]decyloxy]ethyl] carbamic acid methyl ester 38., (Λν~〇丫ϋ·γ^Τ^Ν〆N-[2_[(3-chlorophenyl)- [3_[[(1 phan-1-(cyclohexyl fluorenyl)-2-methylamino-ethyl]aminocarbamimidyl]-5-(cyclopropylcarbonylamino)phenyl]decyloxy ]ethyl] methyl carbamate 39 〇丫口"V, Ηα/Ό base)-[3-[ [(15)-1-(cyclohexylfluorenyl)-2-methylamino group -ethyl]aminoglycolyl]_5-(cyclopropylaminoalkyl)phenyl]methoxy]ethyl]carbamic acid methyl ketone 40, human ~. True 4 Η ά / ό 11- "2-[(3-Chlorophenyl)_[3_(2-methoxyethoxy)_5_[[(2 幻_2_methyl拉kV"(3A0-tetrahydro 0-pyran-3-yl) ]phenyl]aminoglycolyl]phenyl]methoxylate 1!man methyl ester ___ 18 95392 201242594

41 〇γΝν^〇Η ,. Fork-[2-[(3-chlorophenyl)-[3-[[(150-(cyclohexyldecyl)-2-methylamino-ethyl]aminomethylindenyl]-5 Methyl (2-hydroxyethylaminocarbamimidyl)phenyl]methoxy]ethylcarbamate 42 丄N-[2-[(3-Phenylphenyl)-[3-[[(25 ·)-2-decylamino-3-K3A0-tetrahydrofuran-3-yl]propyl]aminocarbamimidyl]-5-methylsulfonyl-phenyl]methoxy]ethyl Methyl carbazate 43 〇4=〇,.H 0L/ A i[2-[(3-Phenylphenyl)-[3-[[(l-Fanta--1-(cyclohexylmethyl)-2) -Methylamino-ethyl]aminoindenyl]-5-decylsulfonyl-phenyl]methoxy]ethyl]carbamic acid methyl ester 44, .'~ N-[2-[ (3-fluorophenyl)-[6-[[(25〇-2-methylamino-3-[(3A〇-tetrahydrofuran-3-yl)propyl]amino)] -2,3-Dihydrobenzofuran-4-yl]methoxy]ethyl]carbamic acid oxime ester 45 N,. fork 〜~0γϋγΗ·ν^Ν〆ά/》 Ν-[ 2-[( 3-oxophenyl)-[3-cyano-5-[[(1^)-1-(cyclohexylmethyl)-2-indolylamino-ethyl]aminomethylindenyl]phenyl] Methyl methoxy]ethyl]carbamate 19 95392 201242594

46 N-[2-[(3-Phenylphenyl)-[3-[(2)-2,3-dihydroxypropoxy]_5-[[(2)-2-methylamino-3 -[(3A〇-tetrahydropyran-3-yl)propyl]aminocarbamimidyl] phenyl]methoxy]ethyl]carbamic acid methyl ester 47 1[2-[(3-chlorobenzene) -[3-(Hydroxymethyl)-5-[[(2 phanol-2-methylamino-3-[(3Λ0-tetrahydro)"pyran-3-yl]propyl]amino) Methyl]phenyl]methoxy]ethyl]methyl carbamate 48, .'~ Ν-[2-[(5·)-(3-phenylene)-[6-[[(2 -2-methylamino-3-indenyl-3-indanyl-3-yl]propyl]aminoindenyl]-2,3-dihydrobenzofuran-4-yl]methoxy]B Methyl carbamic acid 49, .'~ N-[2-[U)-(3-phenylphenyl)-[6-[[25()-2-methylamino-3-K3A0- Tetrahydropyran-3-yl]propyl]aminocarbamimidyl]-2,3-dihydrobenzofuran-4-yl]methoxy]ethyl]carbamic acid oxime 50. -[2-[(3-indolyl)-[3-[[(150-1-(cyclohexylfluorenyl)-2-mercaptoamino-ethyl]aminomethylindenyl]-5-( Methyl 2-dimethylaminoethoxy)phenyl]decyloxy]ethyl]carbamate 20 95392 201242594

51. ~~ N-[2-[(3-Chlorophenyl)-[3-[[(2S)-2-decylamino-3-[(3R)-tetrahydropyran-3-yl]propyl) Aminomethyl]-5-[(3-methyloxetan-3-yl)methoxy]phenyl]decyloxy]ethyl]amino decanoic acid methyl ester 52 0 . '~ Ν-[2-[(3-Phenylphenyl)-[3-[[(150-1-(cyclohexylmethyl)-2-methylamino-ethyl]aminomethylindenyl]- Methyl 5-morpholine-phenyl]methoxy]ethyl]amino decanoate 53 , human ~., 彳 0 0 ° 6 N-[2-[(50-(3-fluorophenyl)-[ 6-[[(250-2-Methylamino-3-[(3))-tetrahydropyran-3-yl]propyl]aminocarbamimidyl]-2,3-dihydrobenzofuran Methyl 4-methyl]methoxy]ethyl]carbamate 54 H忒.6 1'}-[2-[(N)-(3-fluorophenyl)-[6-[[(21$ )-2-mercaptoamino-3-[(3 and)-tetrahydropyran-3-yl]propyl]aminocarbamimidyl]-2,3-dihydrobenzofuran-4-yl] Ethyl methoxy]ethyl]carbazate 55 〇^^〇, N-[2-[U)-(3-phenylphenyl)-[3-(2-decyloxyethoxy)_5_[ [(2i9)-2-methylamino-3-[(3Λ〇-tetrahydropyran-3-yl)phenyl]aminocarboxamido; iphenyl] methoxy]ethyl]amino Ethyl formate — ——- 1 ' —-- 95392 21 201242594

56, people ~. 〇^ οΓ1 G N-[2-[(50-(3-Phenylphenyl)-[3-(2-methoxyethoxy)-5-[ [(25)-2-methylamino) -3-[(3A〇-tetrahydro)pyran-3-yl]phenyl]aminocarbamimidyl]phenyl]methoxy]ethyl]amino decanoate 57 Ν-[2-[ (3,5-di-phenyl)-[6-[[(250-methylamino-3-[(3 疋)tetrahydro-α ratio σ南_3_yl]propyl]amino] ]-2,3_Dihydrobenzo.fol-4-yl]decyloxy]ethyl]amino decanoic acid decyl ester 58 , . , ~ N-[2-[(3-chlorophenyl)- [6-[[(25〇-2-Methylamino-3-[tetrahydro 0-pyran-4-yl]propyl]aminocarbamimidyl]-2,3-dihydrobenzofuran-4 Methyl-methoxy]ethyl]aminocarbamate 59 〇~〇, Λ N-[2-[(3-chlorophenyl)-[3-(2-methoxyethoxy)- 5-[[(250-2-decylamino-3-[tetrahydropyr-4]yl]propyl]amino]]phenyl]methoxy]ethyl]amino decanoic acid Methyl ester 60 0~〇, ,.'~ Ν-[2-[(3-fluorophenyl)-[3-(2-methoxyethoxy)-5-[[(26〇-2-曱) Methylamino-3-[(3Λ0-tetrahydro"pyran-3-yl]propyl]aminoindenyl]phenyl]methoxy]ethyl]amino decanoic acid methyl ester 22 95392 201242594 61 ^ [2-[(3- gas base) -[3_(difluoromethoxy)_5-[[(215)-2-methylamino-3-[(3Λ〇-tetrahydropyran-3-yl]propyl]aminocarbamyl] Phenyl (paste) _ methoxy 1 ethyl 1 amine a formic acid methyl ketone 62 OCHF2 ' Ν-[2-[(5·)-(3-chlorophenyl)_[3_(difluoromethoxy) _5-[[(25〇-2-Methylamino-3-[(3A〇-tetrahydro- 0-yl)propyl]amino]indolyl]phenyl]methoxy]ethyl]amino Methyl formate

Or a pharmaceutically acceptable salt thereof. The present invention relates to a process for the synthesis of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which comprises:

(IB) optionally hydrolyzing a compound of the formula (IA) to a carboxylic acid and reacting a compound of the formula (π), optionally further removing the protecting group PG of the amine group, to give a compound of the formula (1); wherein: n, R1 The definition to R8 is as defined in the formula (!); G is selected from a hydroxyl group, an alkoxy group or a dentate; PG is a protecting group for an amine group, preferably a third butoxycarbonyl group. And a pharmaceutically acceptable salt thereof, wherein:

Wherein: n' R1 to R5 are as defined in the formula (1); and G is selected from a trans group, an alkoxy group or a halogen.

A process for the preparation of a compound of the formula (ΙΑ), an enantiomer thereof, a diastereomer or a pharmaceutically acceptable salt thereof, the method comprising: R4

The benzofural compound a is reacted with a substituted benzene format reagent to obtain a diphenyl sterol compound b

The condensation reaction of the compound b with the compound c gives a compound of the formula (IA) wherein n, R to R5 are as defined in the formula (;); G is selected from a hydroxyl group, an alkoxy group or a halogen. 95392 24 201242594 A process for the preparation of a compound of the formula (p) and its enantiomers, diastereomers or pharmaceutically acceptable salts thereof, the process comprising:

0·· The reaction of the benzene compound e with the substituted stupid formaldehyde to obtain the diphenyl sterol compound f;

D4

〇, · Compound g is reduced to alcohol and then reacted with methanesulfonyl chloride to give compound h;

0, Μ

〇,. Compound h undergoes azidation to give compound i; 25 95392 201242594

Reduction of compound i to give ethylamine compound j;

Compound j is converted to compound k; R4

Compound k deprotects a hydroxy protecting group to give a compound of the formula (IA); wherein n'R1 to R5 are as defined in the scope of the patent application; G is selected from a hydroxyl group, an alkoxy group or a halogen; A hydroxy protecting group, preferably a methyl or tert-butyldiphenyl fluorenyl group. Another aspect of the invention relates to a compound of the invention or a tautomer thereof, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable salt thereof for the preparation of renin Use in drugs for inhibitors. A further aspect of the invention relates to a compound of the invention, or a tautomer, a racemate, an enantiomer, a diastereomer thereof, and mixtures thereof, as a medicament for a renin inhibitor, and Medicinal salt. 95392 26 201242594 The present invention also relates to a compound of the present invention or a tautomer, a racemate, an enantiomer, a enantiomer, a mixture thereof, and a pharmaceutically acceptable salt thereof, in the preparation of a treatment and Uses in drugs for renin-related diseases, including renin-related diseases including: hypertension, atherosclerosis, unstable coronary redness, heart failure, cardiac hypertrophy, myocardial fibrosis Post-infarction cardiomyopathy, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, liver fibrosis, complications caused by diabetes (such as kidney disease, vascular disease and neuropathy), coronary artery disease, ankle after angioplasty Restenosis, elevated eye pressure, glaucoma, abnormal blood vessel growth, high (4) ketosis (4) known damage, Alzheimer's disease, treatment, anxiety, or cognitive disorder. Another aspect of the invention relates to treatment and renin a compound of the invention or a tautomer, racemate, enantiomer, diastereomer, mixture thereof, and pharmaceutically acceptable drug of a related disease Salt. Among them, diseases related to renin activity are as described above. Φ The present invention relates to a method of inhibiting renins comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the invention or a tautomer, racemate, enantiomer or diastereomer thereof. And mixtures thereof, and pharmaceutically acceptable salts. Further, another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention or a tautomer, racemate, enantiomer, diastereomer thereof, and In the form of a mixture, and a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition is used as a drug for a renin inhibitor. Use of the pharmaceutical composition for the preparation of a medicament for the treatment of a preparation of renin 95392 27 201242594. The use of the pharmaceutical composition for the preparation of a medicament for treating a disease associated with renin, wherein the renin-related diseases include: blood pressure, atherosclerosis, unstable coronary syndrome, congestion = heart failure, Cardiac hypertrophy, myocardial fibrosis, cardiomyopathy after infarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, liver fibrosis, complications caused by diabetes (such as kidney disease, vascular disease and neuropathy), coronary artery disease Restenosis after angioplasty, elevated pressure in the eye, glaucoma, abnormal blood vessel growth, hyperaldosteronism, cognitive impairment, Alzheimer's disease, dementia, anxiety, and cognitive disorders. Another aspect of the invention relates to a method of treating a condition associated with renin activity, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of the invention or a tautomer, racemate, enantiomer thereof , diastereomers, mixtures thereof, and pharmaceutically acceptable salts or pharmaceutical compositions. Among them, diseases related to renin activity are as described above. DETAILED DESCRIPTION OF THE INVENTION φ Unless otherwise stated, the following terms used in the specification and claims have the following meanings. The alkyl group means a saturated aliphatic hydrocarbon group including straight-chain and branched groups of 1 to 20 carbon atoms. Preferred are alkyl groups having from 1 to 2 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, second butyl Base, n-pentyl, 1, dicaptanylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3 -methylbutyl, n-hexyl, i_ethyl 2 -methylpropyl, ll trimethylpropyl, 1,1-didecylbutyl, L2-dimethylbutyl, 2 2 - 2 95392 28 201242594 Mercaptobutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3- Dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-decylhexyl, 5-methylhexyl, 2,3-didecylpentyl, 2,4-dimethyl Pentyl, 2, 2-dimethylpentyl, 3, 3-dimercaptopentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-didecylhexyl , 2,4-didecylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimercaptohexyl, 4,4-didecylhexyl, 2-ethyl Hexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl Base, 2-methyl-3-indolylethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl , n-decyl, 3, 3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having from j to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, Second butyl, n-pentyl, 1,1-dimethylpropyl, L 2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-mercaptobutyl , 3-methylbutyl, n-hexyl, I-ethylmercaptopropyl, 1,1,2-trimethylpropyl, 1,1-didecylbutyl, 1,2-di Butyl, 2,2-dimethylbutyl, 1,3-didecylbutyl, 2-ethylbutyl, 2-decylpentyl, 3-decylpentyl, 4-decylpentyl Base, 2, 3-dimercaptobutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl. , alkynyl, alkoxy, alkylthio, alkylamino, dentate, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy , heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, _c(〇)〇R9, 29 95392 201242594

'°C(O)NR10R -〇C(0)R9, _c(〇)R9, -NHC(〇)r9, _NR1QR11 -NHC(〇)NR1()Rn or -S(0)mR9. "Cycloalkyl" means a saturated or partially unsaturated monocyclic sm-generation group comprising from 3 to 20 carbon atoms, preferably including 3 valences, more preferably a cycloalkyl ring containing from 3 to 1 碳 carbon. atom. Carbonogens Non-restrictive additions include rings of ring, ring, and ring W ring groups. It is =7 ι.^ # -, Α'ίΐ·pentenyl, hexyl, %hexan, %hexadienyl, cycloheptyl octyl octyl, and the like. Polycyclic cycloalkyl groups include ruthenium, 葙# 一 妇 妇 “ “ “ “ “ “ “ 螺 螺 螺 螺 螺 螺 螺 螺 螺 螺 螺 螺 螺 螺 螺 螺 螺 螺 螺 螺 螺 螺 螺 螺 螺 螺 螺 螺 螺 螺 螺 螺Groups, these may contain - or more double bonds, no - rings have a complete comon system. More than 6 to 14 members, == 10 members. Rings are based on the number of shared snail atoms between the rings a silk, a double-spiral or a spirulinyl group, which is a snail 1 and a spirox group. More preferably 4 members/4 members, 4 two ft members/6 members, 5 members/5 Or a 5 member/6 member monospirocycloalkyl group. A non-limiting embodiment of a spiro% alkyl group comprises

A fused base refers to 5 to 2 employees. Each ring in the system shares (four) the all-carbon polycyclic group to the carbon atom in the ring of the system, one or more of which contain one or more A double-key, but not a ring-shaped π-electron system. It is preferably 6 to 30, more preferably 7 to 30 95392 201242594 = member. According to the number of constituent rings, it can be divided into two rings and three rings. , a tetracyclic or a multi-histylene alkyl group is preferably a bicyclic or tricyclic 'more member/6 member bicyclic alkyl group. Non-limiting examples of fused ring groups include

"Bridge cycloalkyl" refers to 5 to 2 () 贞, any _ directly connected carbon ring is fine, the material may contain one or more double bonds, but there is no one ring and preferably 6 to the employee, more preferably 7^ subsystems, which are 7 to 10 members. According to the number of constituent rings, they can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridging groups, preferably bicyclic, tricyclic or tetracyclic. Selected as a bicyclic or tricyclic ring. Non-limiting examples of bridge (four) groups include

^ ^ ^ c\ ο The cycloalkyl ring may be referred to as a green, heterochloro or heterocyclic wire ring, wherein the ring connected to the parent structure is a loop wire, and the non-compact embodiment includes a full base, Tetrahydronaphthyl, benzocycloheptyl and the like. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane. Sulfur, alkylamine, halogen, thiol, hydroxy, nitro, cyano, ring 31 95392 201242594 201242594 or -S (0% Rs alkyl, miscellaneous, aryl, heteroaryl, cyclooxygen Base, hetero-environmental oxy, cycloalkylthio, oxalinylthio, oxo, -c(〇)〇R9, _〇 〇) only 9, -C(0)R9 > -NHC(0 R9 ^ -NR^R11, ~〇C(〇)NR10Rn > -NHC(〇)Nri〇r11 "Heterocyclyl" pure or partially unsaturated monocyclic or polycyclic cyclic substituent 'includes 3 to 2G ring atoms, one or more ring atoms: a hetero atom from nitrogen, oxygen or S(G)m (where m is an integer Q to 2), but a ring portion of i〇_mS-S- The remaining ring atom y = includes 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, and more than = the alkyl ring contains 3 to 10 ring atoms. The example of Quanjiao includes fluorenylalkyl, piperidinyl, piperazinyl, and two: "It:" 艮 实施 实施 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Base, "spiroheterocyclyl", means 5 to 2. Member, single two:: and heterocyclic groups of the bridged ring. a polycyclic heterocyclic group of an atom, wherein a hetero atom of 4 atoms (called snail or S(0)p (wherein P is an integer 〇 to 2) is selected from nitrogen and oxygen, which may contain one double The bond, but no atom is carbon. The 7-turn electronic system of the yoke. It is preferably 6 to U long. The number of shared spiro atoms between the fully co-rooted rings will be = 7 to 1 。. Ring group, double lion ring base ❹ In the county, the second is a single-spiro-spirocyclic group. The group is U/4M, 4S/54, and the two-membered or five-membered/six-membered single-spindle base. The spiro ring base: ^ Non-limiting implementation 95392 32 201242594

N

O- ~lv|\ and

The second: two = two members of each ring and the π-electron system of the yoke in the system, the t-a u have a total of s(o)P (where p is an integer 〇 to 2) of the hetero atom selected from nitrogen Preferably, the oxygen is from 6 to 14 members, more preferably the atom is carbon. The target can be divided into double ring, three ring, s, fairy. Depending on the number of constituent rings, a bicyclic or tricyclic ring, more preferably 5, preferably a group, a non-limiting tenth embodiment of the ring group, a beetle/6 member bicyclic fused heterocyclic ring

0-Jr

N

6

彳uw 〇 bridge heterocyclic group means 5 to 丨4 。.* A polycyclic heterocyclic group of a directly bonded atom, a double bond, 彳m rings: a hetero atom having one or more phantoms, a sub-nitrogen A^s(10) (wherein TM is an integer 0 to 7 to (7) members. Preferably 6 to 14 members' is more preferably classified according to the number of constituent rings 雒95392 33 201242594 ring, tricyclic, tetracyclic or polycyclic A bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, is more preferably selected as a bicyclic ring or a tricyclic ring. Non-limiting examples of bridged cycloalkyl groups include: heart 5^ $ AA 4 the heterocyclic ring may be thick Occluding an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples include:

Wait. The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkene, alkynyl, alkoxy, Alkylthio, alkylamino, _, thiol, hydroxy, Schopenyl, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy , cycloalkylthio, heterocyclic sulfuryl, oxo, • _C(0)0R9, -0C(0)R9, -C(0)R9, -NHC(〇)R9, -服呷11, -OCCOHFTR11 , -NHCCO^W1 or -S(〇W. aryl refers to a 6 to 14 membered all-carbon monocyclic or fluorene polycyclic ring (that is, a ring that shares a pair of adjacent carbon atoms) having a conjugated alpha electron system a plurality (i.e., having an adjacent pair of broken atoms), preferably 6 to 1 member, such as a phenyl group and a naphthyl group. The aryl ring may be fused to a heteroaryl group, a heterocyclic group or a cyclic ring. The ring on the base ring where the bond to the parent structure is an aryl ring, non-limiting examples include: 95392 34 201242594

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, thiol, Anthranyl, a thiol, a thiol, a thiol, a decyl group, a cyano group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a cycloalkoxy group, a heterocycloalkoxy group, a cycloalkane Thio, heterocycloalkylthio, -C(0)0R9, -0C(0)R9, -C(0)R9, -NHC(0)R9, -NR1GRn, -0C(0)NR1QRn, -NHC( O) NR10Rn or -S (0% R9. "Heteroaryl" means a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. 5 to 10 members. The heteroaryl group is preferably 5 or 6 members, such as σ-fumanyl, phenanthryl, 0-to-zero, 11 to 11, fluorene-based, a thiol group, 吼°秦基', imipenem, a tetra-β-based group, etc. The heteroaryl ring may be fused to an aryl group, a heterocyclic group or a cycloalkyl ring, wherein the structure is bonded to the parent structure. The ring together is a heteroaryl ring, non-limiting examples include:

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituted 35 95392 201242594 group is preferably one or more of the following groups independently selected from the group consisting of an alkyl group, a dilute group, a block group, and an oxygenated group. Base, thiol group, alkylamino group, halogen, thiocyanium, thiol, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy Base, cycloalkylthio, heterocycloalkylthio, -C(0)0R9, -0C(0)R9, -C(0)R9, -NHC(0)R9, -NR1DRn, -0C(0)NR1QRn , -NHCCOHITR11 or -S(0)BR9. The alkyloxy group means _〇_(hospital group) and _0_(unsubstituted cycloalkyl group), wherein the alkyl group and the cycloalkyl group are as defined above. Non-limiting examples include ο oxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of an alkyl group, a dilute group, a fast group, an alkoxy group, Thio, anthranyl, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, heterocycloalkylthio, -C(0)0R9, -0C(0)R9, -C(0)R9, -NHC(0)R9, A-nWr11, -occo^fR11, -nhcco^ Wr11 or -S(0)mR9. "Hydroxy" means an -OH group. Halogen" means fluorine, gas, bromine or broken. Amine" means -NH2. Cyano" means -CN. Nitro" means -N〇2. Benzyl" means -CH2-phenyl. Oxo" means = 0 羧酸 carboxylic acid" means -C(0)0H. 36 95392 201242594 "Carboxylic acid ester" means -c(0)0 (alkyl) or (cycloalkyl). "Hydroxy protecting group" refers to a molecule containing two or more functional groups in organic synthesis. In order to protect the hydroxyl group from the reaction, a certain reagent is used to protect it first, and then the protective agent group is removed after the reaction is completed. Hydroxy protecting groups include, but are not limited to, anthracenyl, ethyl, tert-butyldiphenylindenyl, tert-butyl, benzyl, ethenyl or benzoinyl. "Amino-protecting group" refers to a molecule containing two or more functional groups in organic synthesis. In order to protect the amine group from the reaction, it is usually protected by a certain reagent, and then removed after the reaction is completed. Agent base. Amino protecting groups include, but are not limited to, a third butoxycarbonyl group, a benzyloxycarbonyl group, a decyl group or a trifluoroethyl fluorenyl group. "Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes a case where the heterocyclic group is substituted with an alkyl group and a case where the heterocyclic group is not substituted with an alkyl group. . φ "Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5', more preferably 1 to 3, hydrogen atoms are independently substituted with each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amine group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond. "Pharmaceutical composition" means a mixture of 37 95392 201242594 containing one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components and other components such as physiology/drugs. Carrier and excipients used. The purpose of the medical composition is to promote the giving of the organism, and to facilitate the absorption of the active ingredient to exert biological activity. 1. The definition of melon, η and 1^9 to Ru is as described in the compound of the formula (1). Method for synthesizing the compound of the present invention

For the purpose of the invention, the following technical solutions are used: The preparation method of the compound of the formula (I) or a salt thereof of the present invention includes the following

The phenylfurfural compound a is reacted with a substituted stabilizing reagent to obtain a diphenyl sterol compound b, and the compound b is subjected to a condensation reaction with the compound c to obtain a compound of the formula (IA). The compound of the formula (IA) is optionally hydrolyzed to a tauric acid. Reaction with a compound of the formula (IB), optionally further removal of the protecting group pG of the amine group, provides the compound of the formula (I). Wherein: n, R to R8 are as defined in the formula (I); G is selected from a hydroxyl group, an alkoxy group or a shoulder group; and PG is a protecting group for an amine group, preferably a third butoxycarbonyl group. A process for the preparation of a compound of the formula (I) or a salt thereof according to the invention, comprising 95392 38 201242594

The bromo compound e reacts with the substituted benzofuraldehyde to obtain diphenylmethanol%. The compound f 'compound f and ethyl bromoacetate are reacted under basic conditions to obtain compound g, and compound g is reduced to alcohol and then with methanesulfonate. Gas reaction to obtain compound h 'compound h to carry out azide reaction to obtain compound i, compound i is reduced to obtain ethylamine compound j, compound j is reacted with halogenated decanoate to obtain compound k 'compound k deprotected by hydroxyl group to obtain general formula (IA) A compound, a compound of the formula (ΙΑ) is oxidized to give a compound d, and a compound d is reacted with a compound of the formula (IB), optionally further deprotecting the protecting group pg of the amine group to give a compound of the formula (I). Wherein: n, R1 to R5 are as defined in the general formula (I); 39 95392 201242594 6 is selected from a hydroxyl group, an alkoxy group or a halogen; M is a hydroxy protecting group, preferably a methyl group or a tert-butyl group Benzoyl. The following examples are provided to further describe the present invention, but these examples are not intended to limit the scope of the invention. EXAMPLES The structure of the compound was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus. The oxime solvent was determined to be deuterated dimercaptosulfoxide (iZ-DMSO), deuterated gas (CDCI3), deuterated sterol (CHsOD), and the internal standard was tetrahydrogen. For decane (TMS), the chemical shift is given in units of 10 〇 6 (ppm). The MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX). The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4. 6 mm chromatography column) and a Waters 2695-2996 φ high pressure liquid chromatograph (Gimini C18 150 x 4 · 6 mm chromatography column). Kinase inhibition rate and I Cs. The value was determined using a NovoStar plate reader (BMG, Germany). The thin-layer chromatography tantalum sheet is made of Yantai Huanghai HSGF254 or Qingdao GF254 tantalum sheet' thin layer chromatography (TLC). The specifications of the Shixi rubber sheet are 5 mm to 0.2 mm, and the thin layer chromatography is used to separate and purify the product. The specifications are 〇. 4 mm to 0.5 mm silicone sheet. Tube chromatography generally uses Yantai Yellow Sea 200 to 300 mesh silicone as a carrier. The known starting materials of the present invention can be synthesized by or according to the method known in the art 95392 40 201242594' or can be purchased from ABCR GmbH & Co. KG, Acros

Organnics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Chemicals and other companies. In the examples, the reactions were carried out under an argon atmosphere or a nitrogen atmosphere unless otherwise specified. An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an air or nitrogen balloon of about 1 L volume. The hydrogen atmosphere means that the reaction flask is connected to a helium balloon of about 1 L volume. The pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenator and a clear blue QL-500 argon generator or a HC2-SS type hydrogenator. The hydrogenation reaction is usually evacuated, charged with hydrogen, and the operation is repeated 3 times. The microwave reaction uses a CEM Discover-S Model 908860 microwave reactor β. Unless otherwise stated, the solution in the reaction means an aqueous solution. In the examples, the temperature of the reaction was room temperature unless otherwise specified. Room temperature is the optimum reaction temperature and the temperature range is 2 Torr. 〇 to 3 〇 it. φ The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The system used for the reaction was: Α: methylene chloride and hexane and acetic acid, C: petroleum and ethyl acetate The volume ratio of the solvent is adjusted depending on the polarity of the compound. The system of the chromatographic eluent used for the purification of the compound and the system of the thinning catalyst of the combined method include the alcohol system and the acetic acid system, c: the normal and the propylene system, D•正己广E: acetic acid B from the purpose of 'solvent volume ratio according to the polarity of the compound = adjust ' can also add a small amount of triethylamine and acidic or test reagents etc. ^ 95392 41 201242594 ^. 〇 a Λ · / τ tune. Example 1 Ν-[2-[(3-Chlorophenyl)-(^3-1^(151)-1-(cyclohexyldecyl)-2-methylamino-ethyl]aminopurine ]]- 5-cyclopropyl-phenyl]decyloxy]ethyl]amino

Decyl citrate

42 95392 201242594 First step (251)-2-Amino-3-cyclohexyl-propionic acid methyl ester hydrochloride salt (250-2-amino-3-cyclohexylpropionic acid ia (8.55 g) , 0.050 mol) was dissolved in 70 raL of methanol, and thionyl chloride (5.4 mL, 0. 075 mol) was added dropwise. The reaction was stirred under reflux for 2 hours. 3-cyclohexyl-propionic acid methyl ester hydrochloride lb (12. 50 g, white solid). The product was taken to the next step without purification. ❶ Step 2 (25)-3-cyclohexyl-2-( Dibenzylamino) decanoyl propionate The crude (25)-2-amino-3-cyclohexyl-propionic acid methyl acetate hydrochloride η (11.10 g, 0.05 〇 111 〇 1) was dissolved in 7〇1111^, To the dimethyl decylamine, potassium carbonate (24·15 g, 0.175 mol) was added, and benzyl bromide (13.1 Å, 0.11 mol) was added dropwise, and the reaction was stirred at 50 ° C for 12 hours. The reaction solution was concentrated under reduced pressure, and a small amount of water was added, and extracted with ethyl acetate (150 mL×3), and the organic phase was combined, and the mixture was dried over anhydrous sodium sulfate, and the mixture was concentrated under reduced pressure, and washed with Shixi gum column chromatography. The obtained residue was purified by a de-bending system B to give the title product (25·)_3_ ring Benzyl-2-(dibenzylamino)propionate lc (16.00 g, pale yellow liquid), yield: 88.8%. Step (25)-3-cyclohexyl-2-(dibenzylamine) (N-methyl-propionamide) (250-3-cyclohexyl-2-(dibenzylamino) decanoate ic (16. 00 g, 0.044 mol) was dissolved in 100 mL of 40% hydrazine In the solution of the amine sterol, the reaction was carried out for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was purified by eluting with EtOAc EtOAc EtOAc EtOAc EtOAc. -2-(Dibenzylamino)-N-methyl-propionamide ld (6.6 g, white solid), Yield: 41. 7% MS m/z (ESI): 365 [M+ l] The fourth step (2«-N2, N2-dibenzyl-3-cyclohexyl-N1-methyl-propane-i,2-diamine, under ice bath, (2Λ-3-cyclohexyl-2- (Dibenzylamino)-N-methyl-propionamide ld (6. 60 g, 〇· 018 mol) was dissolved in 40 mL of tetrahydrofuran, and hydrogenated lithium (1. 72 g, 0·045 mol) was added. 5 (TC stirring reaction for 4 hours. The reaction was quenched by dropwise addition of 10% sodium hydroxide solution in an ice bath, filtered, and the filter cake was washed with four broth, and the filtrate was combined and concentrated under reduced pressure to give crude title. (25·)-Ν2, N2-dibenzyl-3-cyclohexyl-N1-methyl-propane-1,2-diamine (8.00 g, pale yellow liquid). reaction. The fifth step is N-[(25*)-3-cyclohexyl-2-(dibenzylamino)propyl]-N-methyl-amino decanoic acid tert-butyl ester under ice bath, (2 «-N2,N2-Dibenzyl-3-cyclohexyl-N1-indenyl-propanone-diamine le (6.35 g, 0.018 mol) was dissolved in 6 mL of dioxane and saturated sodium bicarbonate solution (V In a mixed solvent of /V = 1 : 2), dibutyl butyl carbonate (5. 93 g, 0.027 mol) was added, and the reaction was stirred at room temperature for 12 hours. The reaction solution was extracted with a gas purged gas. 1 〇〇^1^3), the organic phase was combined, dried over anhydrous sodium sulfate <~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ [(250-3-Cyclohexyl-2-(dibenzylamino)propyl]-N-methyl-carbamic acid tert-butyl ester If (4.40 g, pale yellow liquid), yield: 54.0%. Step 6 N-[(25*)-2-Amino-3-cyclohexyl-propyl]-N-indolyl-carbamic acid tert-butyl ester N-[(250-3-cyclohexyl- 2-(Dibenzylamino)propyl]-N-methyl-amino decanoic acid tert-butyl ester If (6.17 g, 0.014 mol) was dissolved in 50 mL of tetrahydrofuran 'Add palladium oxide palladium (2 · 44 g, 40%), three times of hydrogen, and the reaction was stirred at 50 ° C for 12 hours. The reaction mixture was filtered, and the filtrate was evaporated. Propyl] mercapto-amino decanoic acid tert-butyl ester lg (3.15 g, pale yellow oil), yield: 85.0%. MS m/z (ESI): 272 [M+l] 7-step 5-(trifluoromethylsulfonyl) phenyl-1,3-dicarboxylate φ -30 ° C, 5- phenol-1,3-dicarboxylate lh (9. 50 g , 45 mmol) and pyridine (10. 70 g, 135 mmol) were dissolved in 150 mL of toluene, trifluoromethane anhydride anhydride (25.5 g, 90 mmol) was added, and the reaction was stirred at room temperature for 12 hours. The mixture was extracted with ethyl acetate (100 mL×3), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by eluent column chromatography with eluent system B. The title product is 5-(trifluoromethylsulfonyl)benzene-1,3-dicarboxylic acid decyl ester lj (14.40 g, white solid), yield: 90.0%. NMR (400 MHz, CDCh): δ 8. 72 (s, 1Η), 8. 12 (s, 2H), 95392 45 201242594 3.99 (s, 6H) Step 8 5-cyclopropylbenzene-1,3-di-hypo-acidic hydrazine is a 5-(difluoroindolyl hydrazino) benzene-1,3-disolvate vinegar 1 j (4. 00 g, 45 mmol Dissolved in 100 mL of tetrahydrofuran, added 5 〇mL 2 Μ sodium carbonate solution 'added cyclopropylboronic acid lk (1. 20 g, 14 mmol), 1, bismuth-bis(diphenylphosphine) Ferrocene palladium chloride (ΙΙ) (〇25 g, 0.35 mmol), 1, Γ-bis(diphenylphosphino)ferrocene (0.19 g, 0.35 mmol), 5 (TC) stirred for 12 hours. The reaction solution was cooled to room temperature, extracted with ethyl acetate (5 mL mL), and the organic phase was combined, washed with saturated sodium sulfate solution (5 〇mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by EtOAc EtOAc EtOAc. R Surface R (400 MHz, CDC13): δ 8. 45 (s, 1H), 7· 92 (s, 2H), ❿ 3. 95 (s, 6Η), 2. 01 (m, 1Η), 1. 06 (m, 2Η), 0· 79 (m, 2Η) ninth step 3 1-cyclopropyl-5-methoxycarbonyl-benzoic acid 5-cyclopropylbenzene-1,3-dicarboxylate a (1.00 g, 4.27 _〇1) was dissolved in 5 mL of methanol, and stirred for 12 hours by adding sodium hydroxide (171 mg, 4.27 mmol) and 1 mL of acetone '5〇〇c. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m.) Oxycarbonyl-benzoic acid ln (54 mg, white solid 46 95392 201242594), yield: 53.0%. Step 10 - Cyclopropyl-5-(methyl) 曱 曱 自 自 3- 3- 3- 3- 3- 3- 3- 3- 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 Dissolved in 5 mL of tetrahydrofuran, and added 1 μ of borane in tetrahydrofuran (3.7 mL, 3.68 mmol). The reaction was stirred at 50 ° C for 12 hours. The reaction was quenched by the addition of decyl alcohol, concentrated under reduced pressure, and 50 mL of ethyl acetate was added, followed by 30% potassium carbonate solution (20 mL), 1M hydrochloric acid (20 mL), saturated sodium hydrogen carbonate solution (20 mL) and The saturated sodium carbonate solution was washed (2 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 3-cyclopropyl-5-(methyl-methyl)benzoate 1 〇 (440 mg, Colorless oil), Yield: 87. 1% 〇Eleventh step 3-cyclopropyl-5-carboxylic acid-benzoic acid hydrazine 3-cyclopropyl-5-(fluorenyl)benzoquinone The oxime ester ester (540 mg, 2.45 φ mmol) was dissolved in 15 mL of di-methane, and pyridine chlorochromate rust salt (1.38 g, 6.4 mmol) and sodium acetate (700 mg, 8.54 mmol) were added. The reaction was stirred for 12 hours. After adding 2.0 g of phthalocyanine, the filtrate was concentrated under reduced pressure, and the obtained residue was purified with EtOAc EtOAc EtOAc EtOAc EtOAc. Lp (240 mg, white solid), yield: 55.2%. Step 12 3-[(3-Phenylphenyl)-carbyl-indenyl]-5-cyclopropyl-benzoic acid vinegar in an ice bath, 3-cyclopropyl-5-carboxylic acid-benzene Ethyl formate lp (240 47 95392 201242594 mg, 1.18 mmol) was dissolved in 5 mL of tetrahydrofuran, and a solution of i μ 3-oxyphenylmagnesium bromide in tetrahydrofuran (1·2 niL, 1·18 mm〇l) was added dropwise. ), the reaction was stirred for 1 hour. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. The resulting residue was purified by thin layer chromatography using EtOAc (EtOAc) eluting to afford title product: 3-[(3-fluoro- propyl)- propyl propyl </ br> </ br> Mg, colorless viscous liquid) 'yield: 75.1%. 〇Step 13 N-(2-hydroxyethyl)amine decanoate citrate under ice bath 2. Dissolve 2-aminoethanol lr (15.00 g, 246 mmol) in 200 mL acetonitrile and add potassium carbonate (ιοί 8 〇g, 738 mmol), methyl formate Iss (50 mL, 647 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with EtOAc EtOAc (EtOAc)EtOAc. The filtrate was concentrated under reduced pressure. EtOAcjjjjjjjjjj , yield: 90.1%. MS m/z (ESI): 120 [M+l] 4 丽 R (400 MHz, CDC13) : δ 5. 64 (Z?r. s,1H), 3. 69 (m, 5H), 3.59 (t , /= 5.6 Hz, 1H), 3.32 (m, 2H) Step 14 3-[(3-Chlorophenyl)-[2-(decyloxycarbonylamino)ethoxy]methyl]-5 - ring 48 95392 201242594 propyl-p-decyl decanoate 3-[(3-chlorophenyl)-hydroxy-indolyl]_5_cyclopropyl-benzoic acid hydrazine lq (280 mg, 0.89 mmol) and N -(2-Hydroxyethyl)amino decanoate methyl ester lt (115 mg, 0.97 mmol) was dissolved in 25 mL of hydrazine, and the mixture was stirred and reacted with hydrazine sulfonic acid (177 mg, 0.99 mmol). 1 hour. Add 1 mL of ethyl acetate, wash with saturated sodium bicarbonate solution (2 〇 mL×2), dry <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> filtered, the filtrate is concentrated under reduced pressure, and purified by eluent column chromatography using eluent system B To give the title product 3_[(3_ succinyl) Θ-[2-(decyloxycarbonylamino)ethoxy] fluorenyl]_5_cyclopropyl- 曱 曱 曱 ( ( (200 mg, Yellow oil), Yield: 54. 〇%. The fifteenth step of 3-[(3-chlorophenyl)-[2-(decyloxycarbonylamino)ethoxy]indolyl]_5~lopinyl-benzoic acid 3-[(3-chlorobenzene) -[2-(Methoxycarbonylamino)ethoxy]methyl]cyclopropyl-benzoic acid oxime ester (197 mg, 0. 47 mmol) dissolved in 1 turbulent methanol (47 mg, 1. 18 mmol), 5 (TC was removed for 12 hours. The reaction was quenched with EtOAc EtOAc EtOAc (EtOAc) The filtrate was concentrated under reduced pressure, and the obtained residue was purified eluted eluted elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut Oxy]mercapto]-5-cyclopropyl-benzoic acid iv (190 mg, white solid). The product was taken to the next step without purification. Step 16 N_[2-[[3-[[( i))-i-[(t-butoxycarbonyl(indenyl)amino)indolyl] 95392 49 201242594-2-cyclohexyl-ethyl]aminocarbamimidyl]_5_cyclopropyl-phenyl] Methyl 3-(3-chlorophenyl)methoxy]ethyl]carbamate 3-((3-phenylphenyl)-[2-(decyloxycarbonylamino)ethoxy]methyl -5-cyclopropyl-formic acid lv (85 mg, 0.21 mmol) and ^[(25^-2.-amino-3-cyclohexyl-propyl]-N-mercapto-amino decanoic acid Butyl ester ig (75 mg, 0.27 mmol) was dissolved in 2 mL of N,N-dimethylformamide, and 1-hydroxybenzotriazole (47 mg, 1.18 mmol), 1-(3-diindole) Aminopropyl)-3-ethylcarbodiimide hydrochloride (1〇6 mg, 〇. 55 mm〇1;) and NN-® diisopropylethylamine (143·6 mg, 1.11 Mm〇i), the reaction was stirred for 12 hours. Add 50 mL of methylene chloride to dryness (2 mL mL2) and saturated sodium chloride solution (20 mL×2) dried over anhydrous sodium sulfate. The obtained residue was purified by EtOAc (EtOAc) eluting Methyl]-2-cyclohexyl-ethyl]aminocarbazinyl]-5-cyclopropyl-phenyl]-(3-chlorophenyl)methoxy]ethyl]amino decanoic acid methyl ester lw (134 Mg, white solids, yield: 96.9%. Step 17^[2-[(3-chlorophenyl)-[3-[[(151)-1-(cyclohexylfluorenyl)) _2-decylamino-ethyl]aminoindenyl]-5-cyclopropyl- Methyl methoxy]ethyl]amino decanoate N-[2-[[3-[[(iy?)-1-[(t-butoxycarbonyl(fluorenyl))) fluorenyl) ]-2-cyclohexyl-ethyl]aminomethylindenyl]_5-cyclopropyl-phenyl]-(3-hydroxyphenyl)decyloxy]ethyl]carbamic acid oxime ester lw (134 mg, 〇27 mm〇 1;) Dissolved in 1 mL of trifluoroacetic acid and stirred for 丨 hours. Add saturated carbon 95392 50 201242594 酉 钠 岭 岭 淬 , , , , , , , , , , 淬 淬 淬 淬 淬 淬 淬 淬 淬 淬 淬 淬 淬 淬 淬 淬 淬 淬 淬 淬 淬 淬 淬 淬 淬 淬 淬 95 95 95 95 95 95 95 95 95 95 95 95 Drying with anhydrous sodium sulfate, filtration, and concentrating the filtrate under reduced pressure. The obtained residue was purified by EtOAc EtOAc (EtOAc) 1^-1-(cyclohexylmethyl)_2-methylamino-ethyl]aminomethylindenyl]-5-cyclopropyl-phenyl]methoxy]ethyl]amino decanoate 1 (62 mg, white solid), Yield: 54. 8% MS m/z (ESI): 556 [M+l] ® 4 (400 MHz, CDCh): δ 8. 00-7. 12 ( m,7H),5.34 and 5.33 (2s, 1H), 5.70 (m, 1H), 4. 60 (m, 1H), 3.72-3.01 (m, 9H), 2.66 and 2.60 (2s, 3H), 1.90-0.75 (m, 18H) Example 2 N-[2-[(3-Chlorophenylcyclohexylmethyl)-2-mercaptoamino-ethyl]aminoindenyl]-5-anthracene Ethyl-phenyl]decyloxy]ethyl]aminocarbazate

51 95392 201242594

first step

5-methoxyphenyl-1,3-dicarboxylate oxime 5-oxo-1,3-1,3-dicarboxylate 1h (4.20 g, 20 mmol) was dissolved in 50 mL of C @同中, Carbonation (5.50 g, 40 mmol) and p-toluenesulfonate (5. 60 g, 30 mmol) were added, and the reaction was stirred at 50 ° C for 18 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) The filtrate was concentrated under reduced pressure. EtOAc m. The product was directly subjected to the next reaction without purification. Step 2 3-Methoxy-5-methoxycarbonyl-benzoic acid methyl ester 5-methoxyphenyl-1,3-dicarboxylate 2a (4.48 g, 20 mmol) dissolved in 50 mL of methanol A solution of 25 mL of sodium hydroxide (800 mg, 52 95392 201242594 20mraol) in methanol was added and the reaction was stirred for 24 hours. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) -5-decyloxycarbonyl-bromic acid 2b (2.20 g, white solid), yield: 52. 〇〇/〇. third step

3-(methoxymethyl)-5-methoxy-benzoic acid oxime ester 3~methoxy-5-methoxycarbonyl-benzoic acid 2b (2. 20 g, 10. 5 _〇) 1) Dissolved in 15 mL of tetrahydrofuran, added a solution of j borane in tetrahydrofuran (16 mL, 16 nmol), 5 (rc stirred for 12 hours, raised to 70 C, and stirred for 4 hours. Add methanol to quench the reaction Concentrated under reduced pressure, adding 100 mL of ethyl acetate, followed by 3 % potassium carbonate solution (2 mL), 1 mL hydrochloric acid (20 mL), saturated sodium bicarbonate (2 mL) and saturated sodium chloride The solution was washed (2 mL), dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated. Oil), yield: μ. 9%. Step 4 - 3 -Hydroxymethyl-5-methoxy-benzoic acid methyl acetonate 3 (hydroxymethyl)-5-decyloxy-benzoic acid methyl ester &amp;〇7舀&amp; 7 face 1) Dissolved in 2GmL two gas chamber, adding chloroauric acid (tetra) sulfonium salt (3 7 g, ^7·3 _) and sodium acetate (2·14 _01), mixing Reaction 12 Add 2·0 g Shixi gum, filter, and dilute the liquid under reduced pressure, and use the Shixi hose to eluent. The resulting residue was purified to give the title compound: mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Step 5 3-[(3-Phenylphenyl)-hydroxy-indenyl]-5-decyloxy-benzoic acid decyl ester under ice bath '3-carboxyl-5-methoxy-cracked acid The methyl ester 2d (550 mg, 2.85 mmol) was dissolved in 5 mL of tetrahydrofuran, and a solution of 1 Μ 3-chlorophenylmagnesium bromide in tetrahydrofuran (4.3 mL, 4.30 _ 〇1) was added dropwise, and the reaction was stirred for 1 hour. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. The residue obtained was purified by eluent column chromatography using eluent column chromatography to afford the title product 3-[(3-phenylphenyl)-carboxy-methyl]-5-methoxy-benzoic acid decyl ester 2e. (780 mg, light yellow oil), yield: 90.1%. 4 丽R (400 MHz, CDC13): δ 7. 63 (s, 1H), 7. 47 (m, U), 7. 38 (s, 1H), 7. 25 (m, 3H), 7. 13 (m, 1H), 5. 81 (s, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 2.38 (br s, 1H) ^ Step 6 3-[(3-Chlorophenyl) -[2-(Methoxycarbonylamino)ethoxy]methyl]-5-methoxy-benzoic acid methyl ester 3-((3-indolyl)-hydroxy-indenyl]-5曱 methoxy-benzoic acid oxime ester 2e (780 mg, 2.55 mmol) and methyl n-(2-hydroxyethyl)carbamate It (331 mg, 2.81 mmol) dissolved in 5 mL mL To the benzene, a hydrazine acid (509 mg, 2.68 mmol) was added, and the dehydration reaction was carried out at i30 ° C for 2 hours. The reaction was quenched by the addition of EtOAc (3 mL).曱 oxycarbonylamino) ethoxy]methyl]-5-methoxy-benzoic acid hydrazine 2f (390 mg, colorless oil), yield: 37.0%. 4 丽R (400 MHz, CDC13): δ 7. 59 (s, 1H), 7. 47 (m, 1H), 7.33 (s, 1H), 7.25 (m, 2H), 7.20 (in, 1H), 7.07 (m, 1H), 5.32 (s, 1H), 5.05 (br. s, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 3.67 (s, 3H), 3.53 (m, 2H) , 3.43 (m, 2H) Step 7 3_[(3-Phenylphenyl)-[2-(decyloxycarbonylamino)ethoxy]methyl]-5-•曱® oxy-benzoic acid 3-[(3-Indolyl)-[2-(decyloxycarbonylamino)ethoxy]indolyl]-5-nonyloxy-benzoic acid oxime ester 2f (390 mg, 0. 96 Methyl acetate was dissolved in 3 mL of methanol, sodium hydroxide (96 mg, 2.4 mmol) was added, and the reaction was stirred at 40 ° C for 36 hours. The reaction was quenched by the addition of 1 mL of EtOAc. EtOAc (EtOAc m. The residue obtained gives φ the title product 3-[(3-chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl]-5-decyloxy-benzoic acid 2 g (340 mg , White solid), Yield: 90.6%. Step 8 n~[2-[[3-[[(1t?)-1-[(T-Butoxycarbonyl(methyl)amino)methyl]~2~cyclohexyl-ethyl]amino)醯]]_5_曱oxy_phenyl(3-chlorophenyl)methoxy]ethyl]carbamic acid decyl ester 3-((3-phenylphenyl)-[2-(methoxy) Carbonylamino)ethoxy]indolyl] '5~methoxy-benzoic acid 2g (190 mg, 0. 48 mmol) and ^[(250-2- 55 95392 201242594 Amino-3-cyclohexyl-propenyl ]]-N-decyl-amino decanoic acid tert-butyl ester lg (130 mg, 0·48 mmol) dissolved in 6 mL of N,N-dimercaptocaramine and N,N-isopropyl In a mixed solvent of ethylamine (V/V = 5:1), 1-mercapto-3-trimium (130 mg, 0.96 mmol) and 1-(3-diamidinopropyl)-3-ethyl were added. Base carbodiimide hydrochloride (184 mg, 0.96 mmol), stir the reaction for 12 hours. Add 50 mL of dioxane, wash with water (20 mL×2) and saturated sodium carbonate solution (20 mL×2), anhydrous sodium sulfate Drying, filtration, and concentration of the filtrate under reduced pressure. The residue obtained was purified by thin-layer chromatography eluting with solvent A to give the title product 1^-[2-[[3-[[(1))-1-[( Third butoxycarbonyl(indenyl)amino)methyl]-2-cyclohexyl -ethyl]aminomethylmercapto]-5-methoxy-phenyl]-(3-phenylphenyl)methoxy]ethyl]carbamic acid oxime ester 2h (200 mg, colorless oil) , yield: 66. 0%. MS ra/z (ESI): 646 [M+l] ninth step N-[2-[(3-))-[3-[[(15&quot;)- L-(cyclohexyldecyl)-2-mercaptoamine φ-ethyl]aminocarbamoyl]-5-methoxy-phenyl]methoxy]ethyl]amino decanoate Under the bath 'Ν-[2-[[3-[[(1β)-1-[(t-butoxycarbonyl(indenyl)amino)indolyl]-2-cyclohexyl-ethyl]amino) Ethyl]-5-methoxy-phenyl]-(3-chlorophenyl)nonyloxy]ethyl]carbamic acid decyl ester 2h (210 mg, 0.33 mmol) dissolved in 10 mL of dichloromethane Add 2.5 mL of trifluoroacetic acid' to stir the reaction for 1.5 hours. The reaction solution is concentrated under reduced pressure, and 100 mL of dichloromethane is added. The organic phase is sequentially saturated with sodium bicarbonate (10 mL×2), water (10 mL×2) and saturated The sodium salt solution was washed (1 〇 mL x 2), dried over anhydrous sodium sulfate 56 95392 201242594, dried, filtered, and the filtrate was concentrated under reduced pressure. 3-gas phenyl)-[3_ [ [(150-1-(cyclohexylmethyl)-2-mercaptoamino-ethyl]aminoindenyl]-5-methoxy-phenyl]methoxy]ethyl]amino decanoic acid M% 2 (8 〇 mg, colorless oil), yield: 40. 0%. MS m/z (ESI): 546 [M+l] 4 NMR (400 MHz, CDC13): δ 7. 99-7· 66 (m, 2H), 7. 48 (m, 2H), 7.21 (m, 2H), 7.09-6.83 (m, 2H), 5.67 and 5.58 • (2 br. s, 1H), 5.30 and 5.26 (2 br. s, 1H), 4.61 (m, 1H), 5. 83 and 5. 81 (2 s, 3H), 3.64-3.02 (in, 10H), 2.68 and 2.67 (2 s, 3H), 1.78-.087 (m, 13H) Example 3 1^-[2-[(3-chloro) Phenyl)-[3-cyclopropyl-5-[[(251)-2-methylamino-3-[(3)-tetrahydropyran-3-yl]propyl]amino) Thiol]phenyl]decyloxy] ethoxy]amino decanoate

The first step is [(15')-1-[[[3-[(3-phenylphenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]-5-cyclopropyl) -phenylhydrazinyl]amino]methyl;|_2-[(37?)-tetrahydro 57 95392 201242594 pyran-3-yl]ethyl]-N-mercapto-amino decanoic acid tert-butyl ester 3-[(3-Lipyl)-[2-(decyloxylamino)ethoxy]methyl]-5-cyclopropyl-crackinic acid lv (85 mg, 0.21 mmol) N-[(15*)-l-(lie-ylmethyl)-2-[(3^0-tetrazo- 0-pyran-3-yl]ethyl]-N-indolyl-tartrate tert-butyl ester 3a (57. 4 mg, 0. 21 mmol, prepared by the well-known method "patent W02007070201") dissolved in 6 mL of N,N-didecylguanamine, added with 1-phenylbenzotrisole ( 57 mg, 0.42 mmol), 1-(3-diamidinopropyl)-3-ethylcarbodiimide hydrochloride (81 mg, 0.42 mmol) ® and N,N-diisopropylethylamine (109 mg, 0. 84 mmol), the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, and then ethyl acetate (25 mL) and then washed with water (20 mL×2) and saturated sodium carbonate solution (2 〇mL×2), anhydrous sodium sulfate Dry, filter, concentrate the filtrate under reduced pressure, and purify it by thin layer chromatography with developer system A Residue, the title product chlorophenyl)-[2-(methoxyaminoamino)ethoxy]methyl]-5-cyclopropyl-phenylhydrazinyl]amino]methyl]-2 -[(3友)-tetrahydropyrano-3-yl]ethyl]-N-φ decyl-amino decanoic acid tert-butyl ester 3b (137 mg, white solid), yield: 98. %. The second step N-[2-[(3-chlorophenyl)-[3-cyclopropyl-5-[[(2«-2-methylamino)-3-K3A0-tetrahydropyran-3- Methyl]propyl]amino]indenyl]phenyl]decyloxy] ethoxy]carbamic acid methyl ester under ice bath, chlorophenyl)-[2-(methoxylamino)yl Oxy]methyl]-5-cyclopropyl-phenylhydrazino]amino]methyl]-2-[(3 and)-tetradecylpyran-3-yl]ethyl]-N- Base-aminocarboxylic acid 95392 58 201242594 Tributyl ester 3b (137 mg, 〇. 21 mmol) was dissolved in 3 mL of dioxane, 1 mL of tri-acetic acid was added, and the reaction was stirred for 1 hour. The reaction was quenched by the addition of a saturated aqueous solution of sodium carbonate, and the aqueous phase was extracted with dioxane (1 〇mL×3), and the organic phase was combined, washed sequentially with water (10 mL×2) and saturated sodium chloride solution (i〇mLx2), dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure. (25·)-2-decylamino-3-[(3iP)-tetrahydropyran-3-yl]propyl]aminocarbamimidyl]phenyl]decyloxy]ethoxy]amino ® decyl citrate 3 (56 mg, white solid), yield: 40.0%. MS m/z (ESI): 558 [M+l] 4 R (400 MHz, CDC13): δ 8. 37-6. 67 (m,8H), 5. 29 (m, 2H), 3.85-3.04 (m, 16H), 2.62 (m, 3H), 2.05-1.22 (m, 7H), 0.97 (m, 2H), 0.72 (m, 2H) Example 4 N-[2-[(3-phenylphenyl) H3-(3-decyloxypropoxy)-5-[[(2«-2-曱φ-aminoamino-3-[(3-tetrahydropyran-3-yl)propyl]amino) Thiol]phenyl] methoxy]ethyl]amino decanoate

59 95392 201242594

The ninth step 3a the eighth step, 0

first step

5-(3-decyloxypropoxy) phenyl-1,3-dicarboxylate oxime ester 5-pentene-1,3-dioxalate hydrazide lh (4.20 g, 20 mmol) was dissolved in In 100 mL of acetone, potassium moth (20O mg, 1. 68 mmol), carbonic acid clock (4. 15g, 30 romo 1) and 1-di-3-methoxy-propane 4a (3. 37 g, 22 mmol), the reaction was stirred at 80 ° C for 8 hours. The reaction solution was filtered, a small amount of water was added, and the filtrate was extracted with dichloromethane (150 mL×3). The organic phase was combined, washed with water (50 mL×2) and saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, filtrate The residue was purified by EtOAc EtOAc EtOAc. (5.60 g, white solid). Step 2 3-Methoxycarbonyl-5-(3-decyloxypropoxy)benzoic acid methyl 5-(3-decyloxypropoxy)phenyl-1,3-dicarboxylate 4b 60 95392 201242594 (5.60 g, 20 mmol) was dissolved in 5 mL of methanol, and a solution of 25 虬 sodium hydroxide (800 mg, 2 〇 mm 〇 1) in decyl alcohol was added, and the reaction was allowed to stand for 24 hours. The reaction solution was concentrated under reduced pressure, and water (1 mL) was added, and the mixture was extracted with methylene chloride (20 mL×3), the aqueous phase was adjusted to pH 3 to 4 with i-acid, filtered, and the filter cake was dried in vacuo to give the title product methoxy ss. 3-methoxypropoxy)benzoic acid 4c (2.8 g, white solid), yield: 52.8%. The third step is 3-(hydroxymethyl)_5_(3-methoxypropoxy)benzoic acid methyl ester under ice/cold, 3-decyloxycarbonyl-5-(3-methoxypropoxy) Benzopyrene 4c (2. 80 g, 1 〇. 5 〇 〇 1) was dissolved in 30 mL of tetrahydroculphonic acid, and a solution of 1 borane in tetrahydrofuran (15 mL, 15 mm 〇1) was added and the reaction was stirred. 12 hours. The reaction was quenched by the addition of decyl alcohol, concentrated under reduced pressure, and ethyl acetate ethyl acetate was added, followed by 30% potassium carbonate solution (20 niL), 1 Μ hydrochloric acid (20 mL), and saturated sodium hydrogen carbonate solution (2 mL) Washing with saturated sodium sulphate solution (2) raL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give the title compound (3) (hydroxyphenyl)-5-(3-methoxypropoxy)benzene. Methyl decanoate 4d (2.0 g of colorless oil), yield: 74.9%. The fourth step is to dissolve dimethyl sulfoxide (1.00 g, 13.6 mra〇1) in 8 mL of dichloroanthracene under dry ice bath of decanoic acid-5-(3-decyloxypropoxy)benzoic acid. In the alkane, add chlorophyll chloride (1〇〇g, 816 〇1), stir the reaction for 50 minutes, and add 5 mL of 3-(sulfenyl)-5-(3-methoxypropoxy)benzene. A solution of decyl decanoate 4d (1.7 g, 6.8 mmol) in dichloromethane was stirred for 2.5 h. Quench the reaction by adding triethylamine, stirring for 5 hours, adding 95392 61 201242594 into 50 mL of water, extracting with dichlorohydrazine (2Q mLx3), combining the organic phases, followed by water (10 mLx2) and saturated sodium carbonate solution. Washed (1 〇 mL x 2), dried over anhydrous sodium sulfate, filtered, and then evaporated. Oily), Yield: 88.0%. H NMR (400 MHz, CDCI3): δ·1〇· 02 (s,1H)., 8. 10 (s,1H), 7.83 (s, 1H), 7.59 (s, 1H), 4.17 (t, / = 8.0 Hz, 2H), 3. 96 (s, 3H), 3. 57 (t, /= 8.0 Hz, 2H), 3.36 (s, 3H), ❹ 2. 10 (m, 2H) 'Step 5 Methyl 3-[(3-chlorophenyl)-hydroxy-methyl]_5_(3-methoxypropoxy)benzoate, 3-carboxylic acid-5-(3-decyloxy) Methyl propionate methyl ester 4e (1. 50 g, 5.92 mmol) was dissolved in 5 mL of tetrahydrofuran, and a solution of 1 Μ 3-chlorophenylmagnesium bromide in tetrahydrofuran (M o mL, 12) was added dropwise. 〇φ mmol), the reaction was stirred for 20 minutes. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified eluting with EtOAc EtOAc EtOAc EtOAc 0%。 oxypropoxy) benzoic acid methyl ester 4f (1.5 &amp; pale yellow oil), yield: 69.0%. Step 6 3-[(3-Chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]methyl] 95392 62 201242594 -5-(3-decyloxypropoxy)benzoic acid Methyl ester 3-((3-chlorophenyl)-transyl-methyl]_5-(3-methoxy^f^fH 4fa5〇g, formazan formic acid It (490 mg, 4.12 _ι) was dissolved in 8 〇mL is added to the toluene (10) m2 _)] 耽 · dehydration reaction for 2 hours. Add the protocol to acetic acid ethyl acetate, wash with a saturated sodium bicarbonate solution 0 raL) 'Use the column column chromatography to purify the residue obtained with eluent system b to obtain the product of 3-[(3-phenylene) _[2_(foxy County Amino): oxy]methyl]-5-(3-methoxypropoxy)benzoic acid methyl ester 4g (?2 〇,, color oil), produced Rate: 37. 〇%. Step 7 3-[(3-Chlorophenyl H2_(decyloxy)amino)ethoxy]indolyl]-5-(3-decyloxypropoxy)benzoic acid 3--(3 - gas phenyl)-[2~(methoxylamino)ethoxy]methyl](3methoxypropoxy)benzoic acid methyl vinegar 14 (10), ^ 55 〇 1) • = 5, raL sterol, adding gas oxidized sodium (10), 31 〇 1), the reaction was allowed to react for 12 hours. The reaction solution is concentrated under reduced pressure, and 2GmL of dichlorochloride is added. (2 Π yuan is added with 1 M hydrochloric acid to adjust the pH to 3 to 4, and extracted with dichloromethane for "X3) I water, sodium sulphate is dried, filtered, and decompressed. Concentration gave the product 3-U3 yl)-(decyloxyamino)ethoxy]methyldi-5 (3 methoxypropoxy)benzoic acid 4h (58 mg, pale yellow oil). Yield: 83.0%. The eighth step NU [[3-[[(2 幻_2_(3 butyloxycarbonyl)] _3_ 63 95392 201242594 [(3 left)-tetrahydro.pyran-3-yl]propyl Methylaminomethyl]-5-(3-methoxypropoxy)phenyl]-(3-phenylphenyl)nonyloxy]ethyl]amino decanoate 3-((3-chloro) Phenyl)-[2-(decyloxycarbonylamino)ethoxy]methyl]-5-(3-methoxypropoxy)benzoic acid 4h (9 mg, 0.20 mmol) and N- [(15^-1-(Aminomethyl)-2-[(3 milk-tetrahydrofuran]-3-yl]ethyl]-N-mercapto-tartrate tert-butyl ester 3a (55 mg , 0. 20 mmol) dissolved in 6 mL of N,N-didecylguanamine, added with hydroxybenzotriazole (μ, 〇. 4 mmo1) ' 1-(3-diaminopropyl) -3-ethylcarbodiimide hydrochloride (76. 4 *, 0·4 mmo1) and N,N-diisopropylethylamine (77. 5 mg, 0.6 mmol), The reaction mixture was concentrated for 12 hours. The reaction mixture was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjj Title product ^[241:3-1:1:(250-2-(T-butoxycarbonyl(indenyl)amino)- 3_ [(3-tetrahydropyran-3-yl)propyl]aminomethylindenyl]-5-(3-methoxypropoxy)phenyl]-(3-phenylphenyl)methoxy Methyl]methyl carbamate 4i φ (81 mg, colorless oil), yield: 57.0%. MS m/z (ESI): 606 [M-100+1] ninth step N- [2-[(3-indolyl)-[3-(3-methoxypropoxy)-5-[[(2«-2-methylamino-3-[(3))-tetra Hydrogen"pyran-3-yl]propyl]aminoindenyl]phenyl] methoxy]ethyl]carbamic acid decyl ester under ice bath 'N-[2-[[3-[ [ 2^-2-(t-butoxycarbonyl(indenyl)amino)-3-[(3疋)-tetrahydropyran-3-yl]propyl]aminoindenyl]-5-(3 -Methoxypropoxy)phenyl]-(3-chlorophenyl)methoxy]ethyl]carbamic acid 64 95392 201242594 Methyl ester 4i (109 mg, 0·24 mmol) dissolved in 12 mL of dichloro In decane, 3 mL of trifluoroacetic acid was added to stir the reaction for 1.5 hours. The reaction solution was adjusted to pH &lt;7&gt; with saturated sodium bicarbonate solution, and extracted with dichloromethane (50 mL×3). Wash with 10 mL×2) and saturated sodium sulphate solution (1 〇mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, using thin layer chromatography The residue obtained was purified by the title compound A to give the title product N-[2-[(3-phenylphenyl)-[3-(3-decyloxypropoxy)-541: (250-2-decylamine) Benzyl-3-[(3疋)-tetrahydropyran-3-yl]propyl]aminoindenyl]phenyl]indolyl® yl]ethyl]amino decanoate 4 (25 mg, White solid), Yield: 36.1% 〇MS m/z (ESI): 606 [M+l] !H NMR (400 MHz, CDCh): δ 8. 55-8. 35 (m, 1H), 7. 90-7. 75 (m, 1H), 7.49-6.90 (m, 6H), 5.70 (s, 1H), 5.32-5.29 (m 1H), 4. 10 {br. s, 2H), 3. 89- 3. 14 (in, 18H), 2. 77 (s, 3H), 2. 05-1. 30 (m, 9H) Example 5 N-[2-[(3-Phenylphenyl)-[3- [[(l5〇-i-(cyclohexylfluorenyl)- 2-monomethylamino-ethyl]aminocarbamimidyl]-5-(3-methoxypropoxy)phenyl]methoxy Methyl ethyl carbamate

95392 65 201242594 〇义

First step N-[2-[ tert-butoxycarbonyl(methyl)amino)methyl]-2-cyclohexyl-ethyl]aminomethylindenyl]-5-(3-methoxypropoxy) Phenyl]-(3-phenylphenyl)methoxy]ethyl]carbamic acid methyl ester 〇 3-[(3-chlorophenyl)-[2-(methoxycarbonylamino)ethoxy 4-methyl--5-(3-methoxypropoxy)benzoic acid 4h (109 mg, 0.24 mmol) and N-[(25)-2-amino-3-cyclohexyl-propyl]- N-decyl-carbamic acid tert-butyl ester lg (65 mg, 0.24 _〇1) was dissolved in 6 mL of N,N-dimethyl decylamine, and hydroxybenzotriazole (65 mg, 0·48 mmol), 1-(3-monoamidopropyl)-3-ethylcarbodiimide hydrochloride (92 mg, 0.45 mmol) and N,N-diisopropylethylamine (93 mg, 0.72 mmol), spoiled for 12 hours. The reaction mixture was concentrated under reduced pressure. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; [2_[[3_[[(1«-1-[(T-butoxycarbonyl(indenyl)amino)indolyl]_2_cyclohexyl_ethyl]aminomethylindenyl]-5-(3-曱 methoxypropoxy)phenyl]-(3-chlorophenyl) decyloxy]ethyl]amino decanoic acid decanoate 5a (113 mg, colorless oil), Yield: 67. 0°/ m MS m/z (ESI): 704 [M+l] Second step 95392 66 201242594 N-[2-[(3-chlorophenyl)-[3-[ [(150-1-(cyclohexyl) Methyl)-2-methylamino-ethyl]aminocarbamimidyl]-5-(3-methoxypropoxy)phenyl]methoxy]ethyl]carbamic acid methyl ester under ice bath , N-[2-[[3-[[(l«-l-[(T-butoxycarbonyl(methyl)amino)indolyl]-2-cyclohexyl-ethyl]aminocarbazinyl) ]-5-(3-methoxypropanyl)benyl]-(3-disorganophenyl)methoxy]ethyl]carbamic acid hydrazine 5a (112 mg, 0.19 mmol) was dissolved in In a solution of 12 mL of dichloromethane, 3 mL of trifluoroacetic acid was added to stir the reaction for 1.5 hours. The reaction solution was saturated. The sodium hydrogen hydride solution was adjusted to pH &gt; 7, extracted with dichloromethane (50 mL×3), and the combined organic phases were washed sequentially with water (10 mL×2) and saturated sodium carbonate solution (1 〇mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified to purified crystals eluted eluted eluted eluted Cyclohexyldecyl)_2-monomethylamino-ethyl]aminoindenyl]-5-(3-decyloxypropoxy)phenyl]decyloxy]ethyl]amino decanoate 5 (70 mg, white solid), Yield: 63.0%. φ MS m/z (ESI): 604 [M+l] ] NMR (400 MHz, CDCls): δ 7.8-7.6 (m, 2H ), 7.40 (m, 2H), 7.2 (m, 2H), 6.91 (m, 2H), 5.70 and 5.60 (2 s, 1H), 5.30 (m, 1H), 4.59 (m, 1H), 4.06 (t , / = 6. 0 Hz, 2H), 3.64-3.41 (m, 8H), 3.34 (s, 3H), 3.05 (m, 1H), 2.71 (s, 3H), 2.02 (m, 3H), 1.75- 0.87 (m, 14H) Example 6 ^[2-[(3-Phenylphenyl)-[3_ethoxy_5_[[(2 _2_2_曱-ylamino)-3-[(3«- Tetrahydropyran-3-yl]propyl]aminoindenyl]phenyl]decyloxy] 95392 67 201242594

Ethyl]amino decanoate

〇 6d

The first step of 5-ethoxyphenyl-1,3-dioxadic acid is to dissolve methyl 5-phenyl-1,3-dicarboxylate lh (5.00 g, 23 mmol) in 50 mL of acetonitrile. Potassium carbonate (4.90 g, 36 mmol) and moth E 6a (4.30 g, 28 mmol) were added and the reaction was allowed to react for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) The filtrate was concentrated under reduced pressure. EtOAc mjjjjjjjj , 68 95392 201242594 Yield: 84.8%. !H NMR (400 MHz , CDCh) · δ 8. 26 (s, 1Η), 7. 74 (s, 2H) 4.23 (q, /= 8.0 Hz, 2H), 3.94 (s, 3H), 1.44 (t , 8.0 Hz, 3H) Step 2 3-decyloxycarbonyl-5-ethoxybenzoic acid 5-Ethoxyphenyl-1,3-di-hypo-acidic formazan 6b (4.80 g, 2〇ramol Dissolved in 50 mL of methanol, added 25 mL of sodium hydroxide (810 mg, ❶ 20 ramol) in methanol, and stirred at 80 ° C for 24 hours. The reaction mixture was concentrated under reduced pressure. &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&&&&&&&&&&&&克-5-ethoxybenzoic acid 6c (3. 50 g, white solid), yield: 78.6%. The third step '3-(hydroxymethyl)-5-ethoxybenzoic acid oxime ester φ 3-methoxycarbonyl-5-ethoxybenzoic acid 6c (3. 50 g, 15) 6 mmol) was dissolved in 20 mL of tetrahydrofuran, and a solution of 1 borane in tetrahydrofuran (23 mL, 23 mmol) was added. (: The reaction was stirred for 5 hours. The reaction was quenched by adding decyl alcohol, concentrated under reduced pressure, and 100 mL of ethyl acetate was added, followed by 30% potassium carbonate solution (20 mL), 1 μ of hydrochloric acid (20 mL), and saturated The sodium hydrogen carbonate solution (20 mL) and a saturated sodium sulfate solution (20 mL), and dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to give the title product 3-(hydroxymethyl)-5-ethoxybenzoic acid. Ethyl ester 6d (2.9 g, colorless oil), yield: 80.0%. 95392 69 201242594 Fourth step 3 - decanoic acid-5-ethoxybenzoic acid vinegar vinegar 3~(hydroxymethyl -5-ethoxybenzoic acid methyl ester 6d (2.9 〇g, 13 8 mmol) was dissolved in 6 〇 mL of methane, and ton (tetra) chloroformate (5.90 g, 27.6 mmol) and sodium acetate were added. (3.40 g, 41.4 mm 〇1), the reaction was stirred for 12 hours. 3.0 g of hydrazine was added, filtered, and the filtrate was concentrated under reduced pressure.曱 基-5-ethoxybenzoate oxime 6e (2. 20 g yellow color solid), yield: 76. G%. ^ Step 5 3_[(3-phenylphenyl)-hydroxy- Methyl]_5-ethoxybenzoic acid formazan Methyl 3-carboxylic acid-5-ethoxybenzoate 6e (6〇〇mg 2· 9 mmo 1) was dissolved in 9 mL of tetrahydrofuran under ice bath. The 錤 虱 虱 夫 ( solution (6.0 mL, 6.0 mmol) was stirred for 5 hours. The reaction was quenched by adding water. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate (25 mL×3). The combined organic phases were washed sequentially with water (15 mL) and saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by eluent column chromatography with eluent system B. The title product 3-[(3-Phenylphenyl)-hydroxy-methyl]-5-ethoxy acenamate methyl vinegar 6f (729 mg, colorless oil), yield: 79.第六. Step 6 3-[(3-Phenylphenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]-5-ethoxybenzoic acid methyl ester 3-[(3 -Chlorophenyl)-hydroxy-methyl]-5-ethoxybenzoic acid methyl ester 70 95392 201242594 6f (729 mg, 2.27 mmol) and N-(2-Methyl)amino decanoate It (542 mg, 4. 56 mmol) was dissolved in 5 mL of hydrazine and added p-toluenesulfonic acid (431 mg, 2.27 mmol), 13 (TC stirred The dehydration reaction was carried out for 1. 2 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified to the titled product 3-[(3-chlorophenyl)-[2-(methoxy). 1%。 carbonylamino) ethoxy] decyl]-5-ethoxybenzoic acid decyl ester 6g (567 mg, colorless oil), yield: 59.1%. Step 7 3-[(3-Phenylphenyl)-[2-(decyloxycarbonylamino)ethoxy]indolyl]-5-ethoxybenzoic acid 3-[(3-Phenylphenyl) -[2-(decyloxycarbonylamino)ethoxy]methyl]-5-ethoxybenzoic acid methyl ester 6g (567 mg, 1.34 mmol) was dissolved in 1.5 mL of methanol and potassium hydroxide was added. (151, 2.7 mmol), the reaction was stirred at 50 C for 12 hours. The reaction solution was concentrated under reduced pressure '2 mL of a mixture of hexanes, and then added to 1 Μ hydrochloric acid to adjust the pH to 3 to 4, and extracted with dichloromethane (20 φ this &gt;&lt; 3), dried over anhydrous sodium sulfate, filtered The filtrate was concentrated under reduced pressure to give the title product: 3-[(3-phenylphenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]-5-ethoxybenzoic acid (440 mg) , White solid), Yield: 80.3%. The eighth step [3-[ [ (25)-2-(t-butoxycarbonyl(indenyl)amino)-3_[(3 left)-tetrahydro 11-pyranyl-3-yl]propyl]amino Methyl fluorenyl]_5_ethoxyphenyl]-(3-phenylphenyl)nonyloxy]ethyl]amino decanoic acid decyl ester 3-((3-phenylphenyl)-[2-(A Oxycarbonylamino)ethoxy]methyl] 71 95392 201242594 -5-ethoxybenzoic acid 6h (81 mg, 0.20 mmol) and n_[(25*)-2-amino-3-cyclohexyl- Propyl]-N-methyl-carbamic acid tert-butyl ester lg (70 mg, 0.26 mmol) was dissolved in 6 mL·N,N-dimethyl decylamine, and added to 1-basic (54 mg, 〇·4 mmol), 1-(3-diaminopropyl)-3-ethylcarbodiimide hydrochloride (76 mg, 〇.4 mm〇i) and n,N- Diisopropylethylamine (105 mg, 〇·8 mmol) was stirred for 18 hours. The reaction solution was concentrated under reduced pressure, and 50 mL of methylene methane was added, and then washed with water (2 〇mL×2) and saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered and filtered under reduced pressure to give the title product N. -[2-[ [3-[ [(25)-2-(T-butoxycarbonyl(indenyl)amino)-3-[(3 left)-tetrahydro]pyran-3-yl]propyl Amido fluorenyl]-5-ethoxyphenyl]-(3-phenylphenyl) decyloxy]ethyl] carbamic acid oxime ester 6i (93 mg, colorless oil), yield: 71. 〇%. MS m/z (ESI): 660 [M+l] N-[2-[(3-chlorophenyl)-[3-ethoxy-5-[[(250-2-methylamine) Methyl-3-φ[(3Λ0-tetrahydropyran-3-yl)propyl]aminoindenyl]phenyl]methoxy]ethyl]carbamic acid methyl ester under ice bath 'N-[ 2-[ [3-[ [(25)-2-(T-butoxy-yl (indenyl)amino)-3-[(3 pico)-tetrahydropyroxy-3-yl]propyl] Amino fluorenyl]-5-ethoxyphenyl]-(3-chlorophenyl)nonyloxy]ethyl]amino decanoic acid decyl ester 6i (in mg, 0·14 mmol) dissolved in 8 mL In the methylene chloride, add 2 mL of sultanic acid, and stir the reaction for 1.5 hours. The reaction solution is adjusted with a saturated sodium bicarbonate solution, pH &gt; 7, extracted with dichloromethane (50 mL×3), and the organic phases are combined, followed by water. (10 mL×2) and a saturated sodium chloride solution (10 mL×2), dried over anhydrous water, dried, filtered, evaporated, evaporated, evaporated, evaporated N_[2_[(3_Chlorophenyl M3-ethoxy-5-[[(25))-2-decylamino]_3_[(3, 4-tetrahydro 0-pyran-3-yl)propyl Aminomethyl]phenyl]methoxy]ethyl]amino decanoic acid methyl 6 (60 rag , White solid), Yield: 76.0%. MS.sup..ss.sssssssssssssssssssssssssssssssssssssssss And 5.65 (2 s, 1H), 5.32 (m, 1H), 4.64-4.54 (m, 1H), 4.07 ® (t, /= 6.0 Hz, 2H), 3.67-3.05 (m, 9H), 2.71 (s , 3H), 1.81-0.91 (m, 16H) Example 7 N_[2-[(3- disordered phenyl)-[3_[[(25&quot;)-3-cyclohexyl-2-decylamino-propyl Aminomethyl]5-ethoxy-phenyl]nonyloxy]ethyl]aminocarbamate

95392 73 201242594

❸ First step (250-2-amino-3-cyclohexyl-propionic acid ethyl ester hydrochloride under ice bath, (2W-2-amino-3-cyclohexylpropionic acid la (8.55 g, 0.050 mol) Dissolved in 70 mL of decyl alcohol, and then added chlorite (5.5 mL, 0. 075 mol), and the reaction was stirred for 2 hours under reflux. The reaction mixture was concentrated under reduced pressure to give crude title product (250-2-amine- 3-cyclohexyl-propionic acid ethyl ester hydrochloride 7a (13. 00 g, white solid). The product was taken to the next step without purification. The second step (251)- 2- (t-butoxy decylamine) The crude product (250-2-amino-3-cyclohexyl-propionic acid ethyl ester hydrochloride 7a (13 g, 0.050 mol) was dissolved in an ice bath under ice-bath. Add 50 g of dibutyl phthalate (V/V = 1 : 2) to a mixed solvent of dibutyl phthalate (16.35 g, 0.075 mol) and stir at room temperature. The reaction was carried out for 12 hours. The reaction mixture was extracted with methylene chloride (100 mL EtOAc), EtOAcjjjjjjjjjjj Carbonylamino)-3-cyclohexyl-propionic acid ethyl ester 7b (17 g, light yellow liquid), the product was directly subjected to the next reaction without purification. The third step was Ν-[(1Λ-1-(cyclohexyldecyl)-2-hydroxy-ethyl]carbamic acid tert-butyl ester ice The crude product (2«-2-(t-butoxycarbonylamino)_3_cyclohexyl-propionic acid ethyl ester 7b (17 g, 0.050 mol) was dissolved in 80 mL of ethanol under a bath, and sodium borohydride was added. (9. 50 g, 0. 25 mol), the reaction was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) The filtrate was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified to the titled product Ν-[(15·)-1-(cyclohexylfluorenyl)-2-hydroxyl. -ethyl]aminobutyl carbamic acid tert-butyl ester 7c (11. 20 g, colorless liquid), yield: 87. 〇%. MS m/z (ESI): 158 [M-100+1] fourth step pain I [(2$)-2_(2nd butoxy 1k-amino)-3-cyclohexyl-propyl] oxime acid -15 ° C, N-[(lv9)-l-(cyclohexyl Tert-butyl 2-hydroxy-ethyl]aminocarbamate 7c (6. 71 g, 0.026 mol) and triethylamine (9.05 mL, 0.065 mol) In 50 mL dioxane dichloro Yue, methanesulfonyl acyl chloride (4. 46 raL, 0. 057 mol) 'The reaction was stirred for 0.5 hours, the reaction was continued for 1 hour scrambling. The reaction was quenched by the addition of a small amount of water, and the mixture was separated and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated _2~·(T-butoxymethylamino)-3-cyclohexyl-propyl]methanesulfonic acid 7d (9. 50 g, colorless liquid), product 95392 75 201242594 The next reaction was carried out without purification. The fifth step N-Kl^-lC azide methyl)_2_cyclohexyl-ethyl]carbamic acid dibutyl ester will be crude [(2^-2-(t-butoxycarbonylamino))_3-ring Hexyl-propyl] methanesulfonic acid 7d (9. 50 g, 〇. 026 mol) was dissolved in 50 mL of hydrazine, hydrazine-dimethylformamide, and sodium azide (3.39 g, 〇〇52 m〇) was added. 1), stirring the reaction for 8 hours. Add 100 mL of ethyl acetate, and then wash the organic phase with water (5〇® mL) and saturated sodium chloride solution (5〇mL), dry with anhydrous sulfuric acid steel, and filter. The filtrate was concentrated under reduced pressure. EtOAc mjjjjjjjjjjjjjjj ^体'), Yield: 39.0%. Step 6 N [(15〇-1-(azidomethyl)_2-cyclohexyl-ethyl]:_N-methyl-aminocarbamic acid tert-butyl ester Ν-[(15*)-ΐ-(azidomethyl)-2-cyclohexyl-ethyl]carbamic acid dibutyl ester 7e (2.89 g, 0.010 mol) was dissolved in 1 mL of tetrahydrofuran, added 60% sodium hydride (615 mg, 0.015 mol), simmering reaction for 5 hours, adding iodonium (1 The reaction was stirred for 12 hours. The reaction was quenched with EtOAc (EtOAc (EtOAc)EtOAc. 〇虬), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent from EtOAc (EtOAc) EtOAc (EtOAc) Azide methyl)-2-cyclohexyl-ethyl]-N-methyl-carbamic acid tert-butyl ester 7f (2.68 g, colorless liquid), yield: 90.5%. *H NMR (400 MHz, CDCh ) : δ 4. 36 (m, 1Η), 3. 38-3. 11 (m, 2H), 2. 71 (s, 3H), 1. 87 (d, /=11. 2Hz, 1H), 1 70-0. 85 (m, 12H), 1.48 (s, 9H) Step 7 N-[ (15)-1-(Aminomethyl)-2-cyclohexyl-ethyl]-N-fluorenyl -Aminobutyl phthalate® N-[(150-1-(azidomethyl)-2-cyclohexyl-ethyl]-N-methyl-amino decanoic acid tert-butyl ester 7f ( 2.00 g, 6. 7 mmol) was dissolved in 50 mL of tetrahydrofuran, palladium on carbon (400 mg, 10%) was added, three times of hydrogen was added, and the reaction was stirred for 12 hours. The reaction mixture was filtered and evaporated tolulululululululululululululu 63 g, colorless oil), yield: 89.0%. Step 8 φ Ν-[2-[[3-[[(25))-2-(T-butoxycarbonyl) Amino)-3-cyclohexyl-propyl]aminoindenyl]-5-ethoxy-phenyl]-(3-chlorophenyl)nonyloxy]ethyl]aminocarbazate will be 3 -[(3-Chlorophenyl)-[2-(decyloxycarbonylamino)ethoxy]methyl]-5-ethoxybenzoic acid 6h (80 mg, 0.20 mmol) and amine 7-cyclohexyl-ethyl]-indole-indenyl-aminocarboxylic acid terpene vinegar 7g (69 mg, 0.26 mmol) dissolved in 4 mL of N,N-didecylamine, added 1 - benzotriazine (53 mg, 0.36 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (68 mg, 0.36 mmol) and 77 95392 201242594 N,N-isopropylethylamine (127 mg, 0. 98 mmol), spoiled for 12 hours. The reaction solution is concentrated to reduce waste, add 50 mL of methylene chloride, and then wash with water (20 mL×2) and saturated sodium carbonate solution (2〇mL×2), dry over anhydrous sodium sulfate, 'filtered' filtrate and concentrate under reduced pressure. The resulting residue was purified by EtOAc (EtOAc) eluting Methyl propyl-propyl]amino aryl]-5-ethoxy-phenyl]-(3-phenylphenyl)methoxy]ethyl]carbamic acid methyl ester 7h (93 mg, white solid) Yield: 72.0%. MS m/z (ESI): 660 [M+l] ninth step N-[2-[(3-phenylphenyl)-[3-[[(25*)- 3-cyclohexyl-2-mercaptoamino-propyl]aminoindenyl]5-ethoxy-phenyl]decyloxy]ethyl]amino decanoic acid methyl ester under ice bath, will be [ 2-[[3-[[(2«-2-(T-butoxycarbonyl(indenyl)amino)-3-cyclohexyl-propyl]aminoindolyl]-5-ethoxy-benzene Base]-(3-φ chlorophenyl)decyloxy]ethyl]amino decanoate 7h (93mg, 0.14mmol) dissolved in 8 mL of dioxane, added 3 mL of trifluoroacetic acid, stirred Reaction 1. 5 hours. The reaction solution was adjusted with a saturated sodium bicarbonate solution pH &gt; 7, with two The decane was extracted (50 mL×3), and the organic phase was combined, washed sequentially with water (10 mL×2) and saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate and filtered. The resulting residue was purified to give the title product N-[2-[(3-chlorophenyl)-[3-[[(25(3)-cyclohexyl-2-mercaptoamino-propyl]amine Ethyl decyl] 5-ethoxy-phenyl] methoxy]ethyl] carbamic acid decyl 7 (62 mg, white solid), yield: 78 95392 201242594 79·0〇/〇. MS m /z (ESI) : 560 [M+l] 沱 R (400 MHz, CDCh) : δ 8. 70-8· 40 (m,1H), 7. 94-7. 78 (m, 1H), 7.49 -6.87 (m, 6H), 5.77 {br. s, 1H), 5.32-5. 29 (m, 1H), 4. 06 (t, /=8.0 Hz, 2H), 4. 01-3. 25 ( m, 11H), 2.71 (s, 3H), 1.88-0.91 (m, 16H) Example 8 N-[2-[(3-chlorophenylcyclohexylmethyl)-2-methylamino-ethyl ]propyl]amino aryl]]5-phenyl-phenyl]decyloxyethyl]amino decanoate

79 95392 201242594 The first step is biphenyl-3, 5-di- succinic acid dimethyl hydrazine. 5-(Trifluoromethylsulfonyloxy) benzene phthalate diester E. (3.00 g, 8.77 Mm〇l)^^S,8a(1.28g&gt;1〇5〇; m〇〇 dissolved in 80 mL of tetrazole) Add 40 mL of 2 μ sodium carbonate solution, ι,ι'-bis(diphenyl Phosphine) ferrocene gasified palladium (n) (0.19g, 〇26 〇 〇ι) and 1,1'-bis(diphenylphosphino)ferrocene (0.14 g, 〇. 26 mm〇i) The reaction was carried out for 12 hours. The reaction mixture was cooled to room temperature, and then extracted with ethyl acetate (10) &lt;RTI ID=0.0&gt;&gt; The obtained residue was purified with EtOAc EtOAc EtOAc EtOAc (EtOAc) m/z (ESI): 271 [M+l] *H NMR (400 MHz, CDCh): δ 8. 65 (t, / =: l. 6 HZ) 1H) 8.46 (d, /= 1.6 Hz, 2H ), 7. 69 (m, 2H), 7.50-7. 41 (m! 3H), 3.98 (s, 6H) ' The second step of the stupid-3, 5-dicarboxylic acid-3-decyl ester will be biphenyl _3,5~2 post-acid bismuth vinegar 8 b (Ug, U mmo (10) was dissolved in a mixed solvent of 20 mL of decyl alcohol and tetrahydrofuran (V/V = 3:2), and (10).26 g, 4.7 vol. 1) was added, and the reaction was stirred under reflux for 5 hours. The reaction solution was reduced and concentrated. 150 mL of water and 50 mL of ethyl acetate were added to adjust the pH - 6 knives. The organic phase was washed with a saturated sodium carbonate solution (2 〇 mL x 2), and the anhydrous acid-coated steel was dried. The organic product was concentrated under reduced pressure to give crude title product: 95392 80 201242594 bis biphenyl-3, 5-dicarboxylic acid-3-methyl ester 8c Π η ο ο ο ο ο [Production] MS ra/z (ESI): 255 [Ml] Step 3 5-Methyl-biphenyl-3_carboxylic acid methyl hydrazine, the crude biphenyl-3, 5-dicarboxylate Acid -3~9 methyl ester 8 2. 3 mmol) was dissolved in 10 mL of tetrahydrofuran and added with 9 c (6 ng, hydrogen sulphonic solution α 5 mL, 3.5 mraol), 5 (rc bismuth: = alkane IV) The reaction was quenched with a small amount of water and concentrated under reduced pressure. EtOAc······································ 20 mL), the residue obtained by purifying the eluent system 8 to obtain a hair gel of the chromatographic group - biphenyl-3-carboxylic acid oxime ester 8d (31 〇, white $ title product 5 ~ hydroxymethyl 55. 〇% Solid) 'Yield: The fourth step 5 - broth base - biphenyl - 3 ~ decanoic acid for the purpose of 5-methyl-biphenyl- 3 - decanoic acid methyl ester 8 9 2.6 _ 〇 1) and Sodium acetate (315 mg, 38 sedation (5), 3.0 g of sputum in the mouth, filtered, the filtrate was depressurized, the reaction was carried out, 12 small chromatograms were used to purify the residue from the eluent system B, and the sputum was warned. Mercapto-biphenyl-3-carboxylic acid methyl ester 8e (250 m£r extended to the title product 5 81.0%. Solid solution in 8 mL of dioxane, add =, 1, 3 curry 1) ... a" - b bite salt (551 mg, m \ hair), yield: fifth step 95300 201242594 5 [(3 -Chlorophenyl)-substituted in the ice bath under the base of the base_'5-carboyl-biphenyl-3-s-acid methyl ester 8e (240 mg of 1 嶋υ dissolved in 5raL tetrahydroanthene) The tetrahydrogen sulfonate solution (4 mL, 2 ram〇1) of Q5M3_chlorophenyl sulfonium was added dropwise, and the reaction was stirred for 1 hour. The reaction was quenched by adding saturated sodium hydrogen hydride solution, and concentrated under reduced pressure with acetic acid. B-brew extraction (25 mLx3), combine the organic phase, wash the strips with water (15) and saturated sodium chloride solution (20 mL), dry over anhydrous sodium sulfate, pass through the sputum, filter the house to reduce the house and use the Shixi rubber column Chromatography of the residue obtained from EtOAc EtOAc (EtOAc) Yield: 9i.〇〇/0. MS m/z (ESI): 335 [M-15] Step 6 3-[(3-Phenylphenyl)-[2-(methoxycarbonylamino) Oxy]methyl]_5~styl-benzoic acid vinegar will be 3-[(3-phenylphenyl)-hydroxy-indenyl]_5_phenyl-benzene Methyl formate ❿ 8f (200 mg, 0.57 mmol) and N-(2-hydroxyethyl)aminocarbazide methyl ester lt (136 mg, 1.1 mmol) were dissolved in 20 mL of toluene. Citrate (109 mg, 0. 57 mmol), 13 (TC stirred for 3 hours. The reaction mixture was concentrated under reduced pressure and purified to purified crystals eluted eluted eluted eluted elution Methyl]-5-phenyl-benzoic acid decyl ester gg (110 mg, colorless liquid), yield: 42.0%. MS m/z (ESI): 335 [M-118] NMR (400 MHz, CDCh): δ 8. 19 (d, / = 1. 6 Hz, 1H) 95392 82 201242594 7.96 (d, /= 1.6 Hz , 1H), 7.72 (s, 1H), 7.59 (d, J = 7.0 Hz, 2H), 7.45 (m, 2H), 7.37 (m, 2H), 7.25 (in, 3H), 5.42 (s, 1H) , 5.09(Z?r. s, 1H), 3. 94 (s, 3H), 3. 65 (s, 3H), 3.57 (m, 2H), 3.46 (m, 2H) Step 7 3-[( 3-oxophenyl)-[2-(decyloxycarbonylamino)ethoxy; Imethyl]_5-phenyl-benzoic acid

3-[(3-Chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl] 罨' _5_phenyl-benzoic acid decyl 8 g (110 mg, 0.24 mmol) Dissolved in 1.5 mL of sterols 'Sodium hydroxide (19 mg, 0.49 mmol) was added and the reaction was stirred at 50 °C for 12 hours. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc) was evaporated. EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc The sodium chloride solution was washed (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title product 3-[(3-phenylphenyl)-[2-(methoxycarbonylamino)ethoxy. 0%。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。. The eighth step is Ν[[[[[[[[[[[[[[[[[[[[[[[[[[[[([[[[[[[[[ Base]_5_phenyl-phenyl]](3_qiqiji)methoxy]ethyl]amino decanoate decyl ester under ice bath '3-[(3-phenylphenyl)-[2- (曱oxycarbonylamino)ethyllacyl]mercapto]-5-phenyl-cracked acid (107 mg, 0.24 mmol) and hydrazine-[(250-2-amino-3-cyclohexyl) -propyl]-N-mercapto-amino decanoic acid tert-butyl vinegar (85 mg, 0.32 mmol) dissolved in 5 mL of N,N-dimethylhydrazine 83 95392 201242594 Amine in 'Add 1- Benzotrisole (66 mg, 0.49 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (93 mg, 0.49 mmol) and N, N Diisopropylethylamine (119 mg, 0.9 mmol) was stirred for 12 hours. The reaction was concentrated under reduced vacuo. Mercapto)amino)indenyl]-2-cyclohexyl-ethyl]amino aryl]-5-phenyl-phenyl]-(3-chlorophenyl)methoxy]ethyl]amino Methyl formate 8i G30 mg, white solid), yield: 77. 0%. ® MS m/z (ESI): 692 [M+l] Step 9 N-[2-[ (3-Phenylphenyl)_[ 3-[ [(ΐ5·)-ΐ-(cyclohexylfluorenyl)) _2 monomethylamino-ethyl]propyl]aminoindenyl]-5-phenyl-phenyl]nonyloxyethyl] guanidinium decanoate under ice bath 'N-[2- [[3-[[(15*)-l-[(t-butoxycarbonyl(methyl)amino)] yl]-2-cyclohexyl-ethyl]aminomethylindenyl]-5-phenyl -Benzyl φ-yl]-(3_chlorophenyl)methoxy]ethyl]carbamic acid methyl ester 8i (130 mg, 0·19 mmol) was dissolved in 8 mL of dichloromethane and 2 mL of trifluoroacetic acid was added. 5小时。 Stirring reaction 1. 5 hours. The reaction mixture was adjusted to pH &lt;RTI ID=0.0&gt;&gt; Drying the 'filter' of anhydrous sodium sulfate and concentrating under reduced pressure, the residue obtained was purified by EtOAc (EtOAc) 15)-1-(cyclohexylmethyl)-2-methylamino-ethyl]propyl]aminocarbamimidyl]-5-phenyl-phenyl]methoxyethyl]carbamic acid Ester 8 (1 〇〇 mg, 84 95392 201242594 white solid), yield: 90.0%. MS m/z (ESI): 592 [M+l] 'H NMR (400 MHz, CDCh): δ 8.17-7.20 (m, 12H), 5.60 (in, 1H), 5.40 (s, 1H), 4. 60 (in, 1H), 3. 62-2. 96 (m, 10H), 2.65 and 2.64 (2 s, 3H), 2.05-0.81 (m, 13H) Example 9 N_[2-[(3-milk) Phenyl)-[3-ethoxy-5-[[(251)-2-methylamino-3-[(3iP)-tetrahydro]pyran-3-yl]propyl]aminocarboxamidine Ethyl]phenyl]decyloxyethyl]urethane

The first step is Ν-[(15·)-1-[[[3-[(3-chlorophenyl)-[2-(decyloxycarbonylamino)ethoxy]indolyl]-5-ethoxy Amino-mercapto-yl]amino]mercapto]-2-[(3疋)-tetrahydrofuran-3-yl]ethyl]-anthracene-methyl-amino decanoic acid tert-butyl ester Ν-[2 -[[3-[[(2«-2-(t-butoxycarbonyl(indenyl)amino)-3-cyclohexyl-propyl]aminoindolyl]_5_ethoxy-phenyl] -(3-Chlorophenyl)decyloxy]ethyl]carbazinate 7h (70 mg, 0. Π mmol) and N-[(151)-1-(aminomercapto)_2_[(3 And)-tetrahydroindolepyran-3-yl]ethyl 85 95392 201242594 base]-N-mercapto-carboxylic acid tert-butyl ester 3a (70 mg, 0.26 mmol) dissolved in 3 mL of N,N-dimethyl In the guanamine, 1-hydroxybenzotriazole (48 mg, 0·35 mmol), 1-(3-diamidinopropyl)-3-ethylcarbodiimide hydrochloride (67 mg) , 0.35 mmol) and N,N-diisopropylethylamine (111 mg, 0.86 mmol), the reaction was stirred for 12 hours. The reaction was concentrated under reduced pressure, then 50 mL dichloromethane was added, then water (20 mL×2) and saturated The sodium solution was washed (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 1'1-[(151)-1-[[[3- [(3-Chlorophenyl)-[2-(decyloxycarbonylamino) ® ethoxy]indolyl]-5-ethoxy-benzoinyl]amino]methyl]-2-[ (3i?)-Tetrahydrofuran-3-yl]ethyl]-N-indolyl-amino decanoic acid tert-butyl ester 9a (72 mg, colorless oil), yield: 65.0%. z (ESI) : 562 [M-100 + 1] Step 2 1^_[2-[(3-乳phenyl)-[3-ethoxy-5-[[(25&lt;)-2-) Aminoamino-3-[(3N)-tetrahydropi-pyran-3-yl]propyl]aminomethylindenyl]phenyl]decyloxyethyl)-amino decyl decanoate under ice bath 'ΝΝ-[(15·)-1-[[[3-[(3-Phenylphenyl)-[2-(decyloxy) ethoxy]methyl]-5-ethoxy Alkyl-phenylhydrazino]amino]mercapto]-2-[(3 and)-tetrahydrofuranyl]ethyl]-indole-methyl-amino phthalic acid dibutyl vinegar 9a (72 mg, 〇. 11 mmol Dissolve in 8 mL of dichlorohydrazine, add 2 mL of trifluoroacetic acid, stir the reaction for 5 hours. Adjust the pH of the reaction mixture with saturated sodium bicarbonate solution, and extract with dioxane (50 mL×3). The combined organic phases were washed successively with water (10 mL×2) and saturated sodium chloride solution (1 〇mL×2) dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 5392 201242594 Spectroscopy Purification of the obtained residue in the title compound A to give the title product N-[2-[(3-chlorophenyl)-[3-ethoxy-5-1^(25^-2-decyl) Amino-3-[(3A〇-tetrahydroπ-pyran-3-yl]propyl]aminoindenyl]phenyl]decyloxyethyl]amino decanoate 9 (45 mg, white Solid,) Yield: 75.7%. MS m/z (ESI): 562 [M+l].11 NMR (400 MHz, CDCh) ' δ 8. 62-8. 41 (m, 1H), 7. 94-7. 77 (m, 1H) , 7.51-7.17 (m, 5H), 6.95-6.90 (m, 1H), 5.74 (s, 1H), 5. 33 and 5. 29 (2 s, 1H), 4. 09-3. 14 (m, 16H), ® 2.76 and 2.74 (2 s, 3H), 2.05-1.27 (m, 10H) Example 10 N-[2-[(3-Phenylphenyl)-[3-cyclohexylcyclohexylfluorenyl) 2-nonylamino-ethyl]aminoindenyl] phenyl]methoxy]ethyl]amino decyl decanoate

95392 201242594

First step 5_cyclohexyl stupyl-1,3-di-rebel vinegar vinegar 5-(trifluoromethylsulfonyl) benzene-1,3-dicarboxylic acid methyl ester lj (2.00 g, 5. 85 Ment) and cyclohexylboronic acid l〇a (0.90 g, 7 ramol) dissolved in 30 mL of toluene, 5 mL of 2 M carbonate planer (3.00 g, 9.36 mmol) • solution and M'-bis(diphenylphosphine) ) Ferrocene palladium chloride (11) (347 mg, 0.47 mmol) The reaction was stirred for 5 hours. The reaction solution was cooled to room temperature, 50 mL of water was added, and extracted with ethyl acetate (5 〇mL×3). The organic phase was combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and dried. The title product, methyl 5-cyclohexylphenyl-1,3-didecanoate (1.22 g, white solid), was obtained from EtOAc (EtOAc). Yield·· η. 〇%.曰 Step 2

8S 95392 201242594 3-Cyclohexyl-5-methoxycarbonyl-benzoic acid 5-decylphenyl-1,3-dicarboxylate 10b (1.73 g, 6.3 mmol) was dissolved in 20 mL of acetone and added 20 mL of sodium hydroxide (250 mg, 6. 3 mmol) in methanol was stirred at 50 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure. &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&&& 0%。 carbonylcarbonyl-benzoic acid l〇c (1.1 〇 g, white solid), yield: 67.0%. Step 3 - 3-cyclohexyl-5-(hydroxymethyl)benzoic acid decyl ester, 3-cyclohexyl-5-methoxycarbonyl-benzoic acid l〇c (1. 10 g, 4) 2 mmol) was dissolved in 20 mL of tetrahydrofuran, and a solution of 1 Μ borane in tetrahydrofuran (6.3 mL, 6.3 mmol), 50. The reaction was stirred for 12 hours. The reaction was quenched by the addition of decyl alcohol, and concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc) The organic layer was concentrated under reduced pressure, and the residue obtained was purified eluting with EtOAc EtOAc EtOAc EtOAc White solid), Yield: 70. 0%. Step 4 3-Cyclohexyl-5-carboxylic acid- benzoic acid oxime ester 3-Cyclohexyl-5-(fluorenyl)benzoic acid methyl ketone l〇d (500 mg, 2 mmol) dissolved in 8 mL II To the chlorodecane, pyridine chlorochromate rust salt (902 mg, 5. 2 mmol) and sodium acetate (516 mg, 6.3 mmol) were added, and the reaction was stirred at 89 95392 201242594 for 12 hours. 3.0 g of phthalocyanine was added, and the filtrate was concentrated under reduced pressure. The obtained residue was purified eluting from EtOAc EtOAc EtOAc EtOAc e (316, colorless oil) 'yield: 31.6%. Step 5 3-[(3-Chlorophenyl)-hydroxy-indenyl]_5_cyclohexyl-benzoic acid oxime ester Under ice, 3-cyclohexyl-5-decanoic acid-formic acid methyl ester 1〇 e (316, 1.28, 〇1) was dissolved in 5 mL of tetrahydrofuran, and a solution of iM3_chlorophenylmagnesium bromide in tetrahydrofuran (3 mL, 3 mm 〇1) was added dropwise, and the reaction was stirred for 2 Torr. After adding 20 mL of a saturated aqueous solution of sodium hydrogencarbonate, EtOAc (EtOAc) (EtOAc) Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified eluting from EtOAc EtOAc EtOAc EtOAc Methyl decanoate l 〇 f (509 mg, white solid), product was taken directly to the next step without purification. Step 6 3-[(3-Phenylphenyl)-[2-(methoxylamino)ethoxy]indolyl]-cyclohexyl-benzoic acid decyl ester The crude 3-[(3-chloro) Phenyl)-hydroxy-indenyl]-5-cyclohexyl-benzoic acid methyl ester 10f (509 mg ' 1.42 mmol) and methyl N-(2-hydroxyethyl)carbamate It (338 mg, 2.84 Methyl) was dissolved in 20 mL of toluene and p-toluenesulfonic acid (27 〇 1 ^, 1.42 for 1 〇 1), 130. (: stirring and dehydration reaction at 35 J. The reaction solution is depressurized and added to a saturated carbonic acid sodium solution, and extracted with a gas of 95392 90 201242594 toluene (25 mL×3). The organic phases are combined, followed by water (15 mL) and saturated chlorine. The solution was washed with a solution of sodium chloride (2 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography using eluent column chromatography to give the title product 3-[(3-chlorobenzene). — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — Step 7 _ ^[(3-Chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl]_5-cyclohexyl-benzoic acid 3-[(3-chlorophenyl) -[2-(Methoxycarbonylamino)ethoxy]indolyl] Cyclohexyl-benzoic acid oxime i〇g (373 mg, 0.81 mmol) was dissolved in 10 mL of methanol and sodium hydroxide was added. Mg, 2. 03 mmol), stir the reaction for 12 hours at 50 ° C. The reaction solution was concentrated under reduced pressure, then added 1 Μ hydrochloric acid to adjust pH = 3 to 4, extracted with dioxane (20 mL x 3), Water (10 mL x 2) and saturated chlorination The solution was washed (1 mL) &lt;2&gt;, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title product 3~[(3-phenylphenyl)-[2-(methoxyphenyl) Ethyl] decyl]-5-cyclohexyl-benzoic acid l〇h (388 mg, white solid) product was directly subjected to the next reaction without purification. Step 8 ν~·[2-[[ 3-[[(1«-1-[(t-butoxycarbonyl(indenyl)amino)indolyl]-2-cyclohexyl-ethyl]aminocarbamimidyl]-5-cyclohexyl~phenyl Methyl 3-[(3-phenylphenyl)-[2-(decyloxycarbonylamino) 95392 91 201242594 Ethoxy]indenyl]_5-indoleyl-benzoic acid 1 〇h (100 mg, 0.222 mmol) and N-[(250-2-amino-3-cyclohexyl-propyl) -N-Mercapto-aminocarboxylic acid tert-butyl ester lg (61 mg, 0.22 mmol) dissolved in 5 mL of N,N-dimethyl decylamine 'Addition of hydroxybenzotriazole (61 mg, 〇 .45mmol), l-(3-monoamidopropyl)-3-ethylcarbodiimide hydrochloride (86 mg, 0. 45 mmol) and N,N-diisopropylethylamine (〇 2 mL, 0.9 mmol), stir the reaction at room temperature for 12 hours. The solution was concentrated under reduced pressure. EtOAc (EtOAc m.) The filtrate was filtered, and the filtrate was concentrated under reduced pressure. '1-[2-[[3-[[(15')-1-[(t-butoxycarbonyl(indenyl)amino)indolyl]-2-cyclohexyl-ethyl]aminocarboxamido 5%-cyclohexyl-phenyl]-(3-phenylphenyl) decyloxy]ethyl] carbamic acid decyl ester 10i (148 mg, white solid). MS m/z (ESI): 698 [M+l] φ ninth step Ν-[2-[(3-chlorophenyl)-[3-cyclohexyl-5-[cyclohexylfluorenyl]-2-methyl胺 胺 乙基 乙基 乙基 乙基 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将 将2-cyclohexyl-ethyl]aminoindenyl]-5-cyclohexyl-phenyl]-(3-phenylphenyl)methoxy]ethyl]amino decanoic acid oxime i〇i (; 195nig , 0.28 mmol) was dissolved in 8 mL of dichlorohydrazine, and a mixed solution of 12 mL of trifluoroacetic acid and di-methane (V/V = 1: 2) was added, and the reaction was stirred at 1.5 hours 92 95392 201242594. The reaction solution was adjusted to pJJ &gt; with saturated sodium bicarbonate solution, and extracted with dioxane (50 mL×3). The organic phase was combined and washed with water (1 mL mL 2) and saturated sodium carbonate solution (10 mL×2), anhydrous sulfuric acid. The sodium was dried, filtered, and the filtrate was evaporated, evaporated, evaporated,jjjjjjjjjjjjjjjj [[(1«-1-(cyclohexylmethyl)-2-mercaptoamino-ethyl]aminoindenyl]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]] (1 〇〇 mg, white solid), Yield: 59.0%. ❶ MS m/z (ESI): 598 [M+1] 4 R (400 MHz, CDC13): δ 8. 72-7. 18 (m, 8H), 5. 84 and 5. 70 (2 s, 1H), 5. 32 and 5. 29 (2 s, 1H), 4. 59 (in, 1H), 3.62-3.26 (m, 8H), 3.00 (m, 1H), 2.60 (s, 3H), 2.49 (m, 1H), 1.81-0.88 (m, 13H) Example 11 N-[2-[(3-chlorophenyl)-[ 3-cyclohexyl-5-[[(2«-2-methylamino) φ 3-[(3Λ〇-tetrahydro&quot;pyran-3-yl]propyl]aminoindenyl]phenyl Methyloxy]ethyl]amino decanoate

93 95392 201242594

The first step is Ν-[(15·)-1-[[[3-[(3-phenylphenyl)-[2-(decyloxycarbonylamino)ethoxy]indolyl]-5-cyclohexyl -benzylidenyl]amino]methyl]-2-[(3«-tetrahydrofuran-3-yl]ethyl]-indole-indolyl-aminocarbamic acid tert-butyl ester 〇 3-[(3- Chlorophenyl)-[2-(decyloxycarbonylamino)ethoxy]indolyl]-5-cyclohexyl-benzoic acid 10h (100 mg, 0.12 mmol) and hydrazine-[(15·) 1-(aminomercapto)-2-[(3Α〇-tetrahydropyran-3-yl]ethyl]-indole-methyl-carboxylic acid tert-butyl ester 3a (61 mg, 0. 22 Ment) dissolved in 3 mL hydrazine, hydrazine-dimethylformamide, with hydroxybenzotriazole (61 mg, 0. 45 mmol), 1-(3-diamidinopropyl)-3- Ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol) and N,N-diisopropylethylamine (116 mg, 0.90 mmol), stirred at room temperature for 12 hours. Concentrated 'extracted with dichloromethane (50 mL×3). The combined organic phases were washed with water (2 mL mL 2) and saturated aqueous sodium carbonate (20 mL×2), dried over anhydrous sodium sulfate Product 1^-[(15')-1-[[[3-[(3-Phenylphenyl)-[2-(methoxycarbonylamino)) Methyl]-5-cyclohexyl-benzylidene]amino]methyl]-2-[(3iP)-tetrahydrofuran-3-yl]ethyl]-N-indenyl-amino decanoic acid Tributyl ester 11a (72 mg, colorless oil), yield: 65. 0%. MS m/z (ESI): 700 [M+1] The second step 95392 94 201242594 N-[2-[(3 -Chlorophenyl)-[3-cyclohexyl-5-[[(25)-2-methylamino-.3-[(3 pico)-tetrahydro-11-pyran-3-yl]propyl]amine曱-[(15·)-1-[[[3-[(3-chlorophenyl)-]] [2-(Methoxycarbonylamino)ethoxy]methyl]-5-cyclohexyl-adolyl]amino]indenyl]-2-[(3)-tetrahydrocarbamate-3 -yl]ethyl]-fluorenyl-fluorenyl-amino decanoic acid tert-butyl ester 11a (138 mg, 0.2 mmol) was dissolved in 6 mL of methylene chloride, 9 mL and dichloromethane (V/ Mixture of V = 1 : 2), stir the reaction for 1. 5 hours. Adjust the pH of the reaction mixture with saturated sodium bicarbonate solution. 7. Extract with dioxane (30 mL x 3). Combine the organic phases, and then use water ( 1〇mLx2) and saturated sodium chloride solution (10 mLx2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, using thin layer chromatography Purification of the residue obtained by the solvent system A to give the title product N-[2-[(3-phenylphenyl)-[3-cyclohexyl-5-[[(250-2-decylamino)-3-[(3Λ 〇-tetrahydropyran-3-yl]propyl]aminoindenyl]phenyl]decyloxy]ethyl]amino decyl decanoate u (65 mg, white φ color solid), yield: 55 · 0%. MS in /z (ESI): 600 [M+l] Ή NMR (400 MHz, CDCh): δ 8. 64-7. 07 (m, 8H), 5. 69 (br. s, 1H), 5.31 ( m, 1H), 3. 97-3. 08 (m, 14H), 2. 64 (s, 3H), 2.50 (m, 1H), 2.00-0.86 (m, 17H) Example 12 N-[2- [(3-Phenylphenyl)-[2-methoxy-5-[[(2«-2-decylamino)-3-[(3-tetrahydropyran-3-yl)propyl Ethyl mercapto]phenyl]methoxy]ethyl]carbamic acid decyl 95 95392 201242594

The first step is 3-methylmercapto-4-methoxy-benzoic acid oxime ester 3-methylmercapto-4-hydroxy-benzoic acid methyl ester 12a (2.00 g, Η. 1 mmol, using the known method "chem pharm" Bull 1983, 31 (5), 1752" was prepared by dissolving in 20 mL of N,N-dimethylformamide, adding potassium carbonate (2.30 g, 16.7 mmol) and iodonane (3.20 g, 22 2 M)) The reaction was allowed to react for 12 hours. The reaction mixture was quenched with a small amount of water and concentrated under reduced pressure. The mixture was evaporated to ethyl acetate (50 mL×3). The organic phase was combined and washed with water (20 mL×2) and saturated sodium chloride solution (2 〇mL×2). The residue obtained by purifying the residue under reduced pressure and eluting with eluent system B to give the title product 3_methylmercapto-4-indolyl-benzoic acid hydrazine. Ester 12b (1. 50 g, pale yellow solid), yield: 68. The second step is 3_[(3-phenylphenyl)-carbyl-methyl]- 4-methoxy-bromoformic acid methyl ester under ice bath, 3 methoxyl base + methoxy-benzoic acid methyl vinegar 12b (30 slightly U·1) was dissolved in 5 mL of diethyl ether, and 0.5 Μ 3-chlorobenzene was added dropwise! 95392 96 201242594 A solution of THF in tetrahydrofuran (3.4 mL, 1.7 匪〇 1) was stirred for 2 hours. The reaction was quenched by the addition of EtOAc EtOAc (EtOAc (EtOAc) Drying, filtration, and concentrating the filtrate under reduced pressure, and purifying the residue obtained by eluent column chromatography using eluent column chromatography to give the title product 3-[(3-chlorophenyl)-hydroxy-indenyl]-4-oxanium Base - benzoic acid decyl ester 12c (340 mg, white solid), yield: 70.0%. ® MS m/z (ESI): 307 [M+l] NMR (400 MHz, CDCh): δ 8.07 (d, 4. 0 Hz, 1H), 8.00 (d, /= 8.0 Hz, 1H), 7.38 ( s, 1H), 7.24 (m, 3H), 6.90 (d, /=12. 0 Hz, 1H), 6.03 (s, 1H), 3.88 (s, 3H), 3.86 (s, 3H) -[(3-chlorophenyl)-[2-(decyloxycarbonylamino)ethoxy]indolyl]_4-methoxy-benzoic acid formazan is intended to be 3-[(3-phenylphenyl) )-hydroxy-methyl]_4_decyloxy-methyl benzoate 12c (270 mg, 0.88 mmol) and N-(2-ethyl)amino decyl decanoate It (105 mg, 0·88 mmol) Dissolved in 20 mL of terpene, adding p-toluenesulfonic acid (167 mg, 0.88 mmol), refluxing and reacting with water! The store liquid is concentrated under reduced pressure, 100 mL of ethyl acetate is added, and the strip is washed with saturated carbonic acid gas (20 mL×2), dried over anhydrous sodium sulfate, filtered, filtrate is decompressed, and (10) lings product 3-[(3-phenylphenyl) -[2-(Methoxycarbonylamino)ethoxy] The residue obtained was purified by thin layer chromatography using EtOAc EtOAc (EtOAc). Ethyl benzoate I2d (280 mg, yellow oil), yield: 78.0 〇 / 〇. MS m/z (ESI): 430 [M+23] 4 NMR (400 MHz, CDCh): δ 8. 07 (s, 1H), 7.97 (d, / = 9.2 Hz, 1H), 7.36 (s , 1H), 7.23 (m, 2H), 6.89 (d, 7= 8.8 Hz, 1H), 5. 71 (s, 1H), 5. 16 (s, 1H), 3. 89 (s, 3H), 3.88 (s, 3H), 3.66 (s, 3H), 3.54-3.43 (m, 4H) Step 4® 3-[(3-Phenylphenyl)-[2-(methoxycarbonylamino)ethoxy 3-[(3-Phenylphenyl)-[2-(methoxyamino)ethoxy]methyl]-4-methoxy as methyl]-4-methoxy-benzoic acid The hydrazinyl benzoate I2d (280 mg, 0.69 mmol) was dissolved in 1 mL of methanol, sodium hydroxide (55 mg, i. 38 mmol) was added, and 5 (TC stirred for 12 hours). 1 μ of hydrochloric acid was adjusted to pH 3', extracted with dichloromethane (2 〇 mL×3), dried over anhydrous sodium sulfate, filtered, and then filtered and evaporated to give the title product 3-[(3-chlorophenyl)-[2- (Methoxy alkylamino)ethoxy]methyl]-4-methoxy-benzoic acid I2e (270 mg, yellow oil), crude material was taken directly to the next step. MS ra/z (ESI): 392 [Ml] The fifth step N_[2-[ [5-[ [(25)-2-(T-butoxycarbonyl (methyl)amino)_3_ [(3 friends)-four °Methyl-3-yl]propyl]aminocarbamimidyl]-2-methoxy-phenyl]-(3-chlorophenyl)methoxy]ethyl]amino decanoate under ice bath , 3-[(3-Chlorophenyl H2-(methoxycarbonylamino)ethyl 95392 98 201242594 oxy]methyl]-4-decyloxy-benzoic acid 12e (270 mg, 0.69 mmol) and 1 ^-[(15*)-1-(Aminomethyl)-2-[(3N)-tetrahydroranium-3-yl]ethyl]-N-indenyl-carboxylic acid tert-butyl ester 3a (186 mg, 〇. 69 mmol) was dissolved in 6 mL of N,N-dimercaptocaramine to add hydroxybenzotriazole (185 mg, 1.4 mmol), 1-(3-methylamino) Propyl)-3-ethylcarbodiimide hydrochloride (263 mg, 1.4 mmol) and N,N-diisopropylethylamine (337 mg, 2.6 mmol). Concentrate, extract with ethyl acetate (5 〇mLx3), combine the organic phase, then wash with water (20 mLx2) and saturated sodium sulphate & gluten solution (20 mL×2), dry over anhydrous sodium sulfate, filter, decompress liquid The residue was purified by EtOAc (EtOAc) eluting -3-[(3--tetrahydropyridyl) 3-yl]propyl]aminocarbazinyl;|2- 2 methoxy-phenyl]-(3-phenylphenyl)nonyloxy]ethyl]amino decanoate 12f (350 mg, White solid), Yield: 79.0%. MS m/z (ESI): 648 [M+l] Step 6 N-[2-[(3-chlorophenyl)-[2-methoxy-5-1^(250-2-methylamine Base-3-[(3-tetrahydro-α-pyran-3-yl]propyl]aminomethylindenyl]phenyl]methoxy]ethyl]amino decanoic acid formazan N-[2-[[5-[[(2^-2-(t-butoxycarbonyl(methyl)amino)-3-[(3))-tetrahydropyran-3-yl]propyl Methylaminomercapto]_2-methoxy-phenyl]-(3-phenylphenyl)methoxy]ethyl]carbamic acid methyl ester 12f (350 mg, 0.54_〇1) was dissolved in 7. 5 mL of dichlorofane, adding 2. 5 mL of difluoroacetic acid 'stirring reaction for 1 hour. The reaction solution was dissolved in saturated sodium bicarbonate 99 95392 201242594 to adjust the pH of pH &gt; 7, extracted with dichloromethane (3 〇 mL x 3) The organic phase was combined and washed with water (10 mL×2) and saturated sodium sulfate solution (1 〇^1^2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by thin layer chromatography The residue obtained gave the title product: _[2_[(3-chlorophenyl M2-methoxy-5-[[(25))-2-decylamino-3-[(3i?)- Hydrogen 0-pyran-3-yl]propyl]aminomethylindenyl] phenyl] decyloxy]ethyl]amino decyl decanoate 12 (150 mg, white solid), Yield: 51. 〇〇/0. MS m/z (ESI): 548 [M+l] ❶1H NMR (400 MHz, CDC13) : δ 8. 12 (d, / = 4. 0 Hz, 1H), 7.88 (d, /= 8.0 Hz, 1H), 7.78 (br. s, 1H), 7.35 (s, 1H), 7.18 (m, 3H), 6.85 (d, / = 8 . 0 Hz, 1H), 5.99 (s, 1H), 5.30 (s, 1H), 3.83-3.71 (m, 7H), 3.48-3.34 (in, 3H), 3.10 (m, 2H), 2.54 (s, 3H), 2.54 (s, 3H), 1.91 (1H), 1.79 (1H), 1.60-1.48 (m, 4H) Example 13 N-[2-[(3-chlorophenyl)-[2-ethoxy 5-[[(25)-2-decylamino-3-[(3left)-tetrahydropyran-3-yl]propyl]aminomethylindenyl]phenyl]decyloxy Ethyl]urethane vinegar

95392 100 201242594

The first step 4-ethoxy-3-mercapto-benzoic acid methyl hydrazine is to methyl 3-mercapto-4-hydroxy-benzoate i2a (3.5 〇g, 19 4 Ο _〇1 Dissolved in 150 mL of N,N-dimethylformamide, adding carbonic acid clock (4.00 g, 29.1 mmol) and iodoethyl bromide (6. 06 g, 38.9 mmol) to give the reaction 12 hours. The reaction mixture was quenched with less water and concentrated under reduced pressure. The obtained residue was purified by eluent column chromatography to afford the title product 4-ethoxy-3-methylpyranyl-benzoic acid methyl vinegar. I2a (1. 30 g, white solid), yield: 32. 2%. The second step is φ 3-[(3-monophenyl)-hydroxy-methyl]-4-ethoxy-benzoic acid decyl ester, 4-ethoxy-3-indolyl-benzoquinone in an ice bath The decyl ester 13a (5 〇〇 mg, 2.4 mmol) was dissolved in 1 THF, and a solution of 〇5M3_chlorophenylmagnesium bromide in tetrahydrofuran (5.3 mL, 2.65 mmol) was added dropwise, and the reaction was stirred for 1 hour. The reaction was quenched by the addition of EtOAc EtOAc (EtOAc) (EtOAc) The residue was dried over anhydrous sodium sulfate, filtered, and then evaporated tolulululululululululululululululululululululu 201242594 -4-Ethoxy-p-decanoate 13b (360 mg, white solid), Yield: 47.0%. !H NMR (400 MHz , CDCh) : δ 8. 10 (d, / = 2. 3 Hz, 1H)} 7.95 (dd, 2.3 Hz, 8.4 Hz, 1H), 7.39 (s, 1H), 7, 2l (m, 3H), 6.85 (d, / = 8.4 Hz, 1H), 5.98 (s, 1H), 4^ 〇5 (m, 2H), 3.87 (s, 3H), 1.36 (t, / = 7.0 Hz , 3H) The third step 3-[(3-chlorophenyl)-[2-(decyloxycarbonylamino)ethoxy]methyl]~4~ethyl oxy-benzoic acid methyl ester will be 3 -[(3-chlorophenyl)-carbyl-indenyl]-4-ethoxy-benzoic acid formazan 13b (360 mg, 1 · 13 mmol) and hydrazine-(2-ethyl)amine The hydrazide t It (105 mg, 0.88 mmol) was dissolved in 20 mL of toluene, p-toluenesulfonic acid (119 mg, 1.13 mmol) was added, and the mixture was refluxed for 1 hour. After adding 100 mL of ethyl acetate, it was washed with a saturated aqueous solution of sodium bicarbonate (2 〇mUu, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 3-[(3-Chlorophenyl)~[2_(methyllacylamino)ethoxy]methyl]- 4-ethoxy-benzoic acid decyl ester 13c (250 mg, colorless oil) , Yield: 53.0%. !H NMR (400 MHz, CDCh): δ 8. 11 (d, / = 2. 4 Hz, 1H), 7.95 (m, 1H), 7.39 (s, 1H), 7.37 ( s,1H), 7.22 (m,3H), 6.83 (d, /= 8.4 Hz, 1H), 5.67 (s, 1H), 5.1〇(z?r. s&gt; 1H), 4.11 (m, 2H), 3.89 (s, 3H), 3.66 (s, 3H), 3 52 (m, 2H), 3.43 (m, 2H), 1.39 (t, / = 7.0 Hz, 3H) Step 4 95392 102 201242594 3-[( 3-Chlorophenyl)-[2-(decyloxycarbonylamino)ethoxy]methyl]_4_ethinyl-benzoic acid 3-[(3-phenylphenyl)-[2-(曱oxycarbonylamino)ethoxy]methyl]4-ethoxy-benzoic acid methyl acetate i3c (250 mg, 0. 60 mmol) dissolved in 3 mL of sterol 'Add sodium hydroxide (196 mg, 4. 9 mmol), Γ) 0 ° 〇 stir the reaction for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m.) 0%。 _[2_(Methoxycarbonylamino)ethoxy]indolyl]-4-ethoxy-benzoic acid 13d (135 g, white solid), yield: 56.0%. MS ra/z (ESI): 406 [Ml] 'H NMR (400 MHz, CDCh): δ 8. 24 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H) , 7.27 (m, 3H), 6.90 (d, 8.4 Hz, 1H), 5.72 (s, 1H), 5. 20 (Z?r. s, 1H), 4.15 (m, 2H), 3.71 (s, 3H ), 3. 57 (m, 2H), 3.48(m, 2H), 1.48 • (t, / = 7.2 Hz, 3H) Step 5 N - [2-1^5-1^(2^-2- (Third butoxycarbonyl (methyl)amino)-3 -[(3^-tetrahydro.pyran-3-yl]propyl]aminoindenyl]_2_ethoxy-phenyl] - (3-Chlorophenyl)nonyloxy]ethyl]amino decanoic acid methyl ester under ice bath 3-((3-phenylphenyl)-[2-(decyloxycarbonylamino)ethoxy ]methyl]-4-ethoxy-benzoic acid 13d (135 rag, 0.33 mmol) and N-[(l«-l-(aminomethyl)-2-[(3 --tetrahydro „ 比喃_3_yl]ethyl]-N-mercapto-carboxylic acid tert-butyl ester 3a (90 mg, 0·33 mmol) was dissolved in 6 103 95392 201242594 mLN, N-dimethylformamide, force 1-Phenylbenzotrisole (90mg, 0.66_υ, Bu (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (127mg' 0.66_1) and Ν, 卜二异Propylethylamine (10), 126 mmol) 'Lin reaction for 12 hours. The reaction solution was concentrated under reduced pressure. The organic phase was extracted with ethyl acetate (50 mL×3). The organic phase was combined, washed sequentially with water (2 〇roLx2) and saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified to give the titled product N-[2-[[5-[[(2vS)-2-(t-butoxycarbonyl (anthracenyl)amino)-3-[(3«) -tetrahydroxanyl]propyl]aminoindenyl]_2_ethoxy-phenyl]-(3-chlorophenyl)methoxy]ethyl]carbamic acid decyl ester 13e (100 mg, colorless Oil), Yield: 46. 〇% MS m/z (ESI): 662 [M+l] Step 6 N-[2-[(3-Phenylphenyl)-[2-ethoxy -5-[ [(25)-2-Methylamino-3-[(3 pico)-tetrahydroindol-3-yl]propyl]aminoindolyl]phenyl]decyloxy] Ethyl phthalate

N-[2-[[5-[[(25)-2-(T-butoxycarbonyl(indenyl)amino)-3-[(3))-tetrahydropyran-3) -yl]propyl]aminomethylindenyl]-2-ethoxy-phenyl]-(3-chlorophenyl)methoxy]ethyl]amino decanoic acid decyl ester 13e (100 mg, 0. 15 mmol) was dissolved in 6 mL of dichlorohydrazine, 2 mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction mixture was adjusted to pH &lt;7&gt; with saturated sodium bicarbonate solution, and extracted with dichloromethane (30 mL×3). The organic phase was combined and washed sequentially with water (10 mL×2) and saturated sodium chloride solution (10 mL×2), anhydrous sodium sulfate Drying, filtration, and concentration of the filtrate under reduced pressure, and the residue obtained was purified by thin layer chromatography to give the title product [2_[(3_chlorophenyl M2-ethoxy-5-[ [(2Λ-2-Methylamino-3-[(3-tetrahydrofuran-3-yl)propyl]aminoindenyl]phenyl]methoxy]ethyl]aminocarbamate Ester 13 (60 mg, white solid), Yield: 71. 〇% MS m/z (ESI): 562 [M+l] 卞 ( (400 MHz, CDC13) : δ 8.35 (eg.s, 1H) , 8.26 (s, 1H), 7.88 (m, 1H), 7.37-7.13 (m, 4H), 6.79 (m, 1H), 5.98 (s, 1H), 3.99 (m, 2H), 3.86-3.09 (m , 13H), 2.63 (s, 3H), 1.99-1.22 (m, 11H)

Example 14 1^-[2-[(3-Phenylphenyl)-[3-cyclopentyl-5-[[(15&lt;)-1-(cyclohexylmethyl)-2-decylamino)- Ethyl]amino fluorenyl]phenyl]decyloxy]ethyl]amino decyl decanoate

95392 105 201242594

First step 5-cyclopentylphenyl-1,3-dicarboxylate decyl 5-(trifluoromethylsulfonyl)benzene-1,3-dicarboxylate lj (0.64 g, 1.87 mmol And cyclopentyl linonic acid 14a (256 mg, 2.24 mmol) dissolved in 20 mL of toluene, adding 5 mL of 2 M cesium carbonate (960 mg, 2.94 mmol) solution and 1, bismuth-bis(diphenylphosphine) Ferrocene palladium chloride (Π) (112 • mg, 0.15 mmol), and stirred at 110 ° C for 5 hours. The reaction mixture was cooled to room temperature, and then added with 50 mL of water, EtOAc (EtOAc)EtOAc. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc) . 0%. Step 2 3-Cyclopentyl-5-methoxycarbonyl-benzoic acid 106 95392 201242594 Dissolving methyl 5-cyclopentylphenyl-1,3-dicarboxylate 14b (334 mg, 1.27 mmol) Add 10 mL of a gas-oxidized sodium (51 mg, 1.27 mmol) in methanol solution in 1 mL of acetone. The reaction was stirred at 50 ° C for 12 hours. The reaction solution was concentrated under reduced pressure, and then taken to a mixture of &lt;RTI ID=0.0&gt;&gt; The present invention is 14c (275 mg, white solid), yield: 87.0%. Step 3® 3-Cyclopentyl-5-(methyl)-p-hydroxybenzoate, 3-cyclopentyl-5-methoxycarbonyl-benzoic acid (275 mg, 1.1 mmol) Dissolved in 5 mL of tetrahydrofuran, a solution of 1 bromo borane in tetrahydrogenate (2.2 raL, 2.2 mmol), and 503⁄4 was stirred for 12 hours. Add a small amount of sterol to quench the reaction, concentrate under reduced pressure, add 2 mL of water, extract with ethyl acetate (20 mL×3), wash with saturated sodium chloride solution (1 mL), dry over anhydrous sodium sulfate The mixture was concentrated under reduced pressure. The residue obtained was purified eluting with EtOAc EtOAc EtOAc (EtOAc) The next step is to react. Step 4 3-Cyclopentyl-5-carboxylic acid-methyl benzoic acid methyl ester The crude 3-cyclopentyl-5-(hydroxyindenyl) benzoic acid decyl ester 14d was dissolved in 8 mL of methane, and chrome was added. The pyridinium salt (477 mg, 2.2 匪〇1) and sodium acetate (272 mg '3.3 mmol) were mixed for 12 hours. Add 3·〇gzhenjiao's work, concentrate the filtrate under reduced pressure, and (4) Hose column chromatography to purify the obtained residue with 95392 107 201242594 eluent system B to obtain the title product 3_cycloindole I-formic acid 'benzoic acid A Vinegar 14e (10), colorless oil), / rate: 61. 0% 〇 fifth step 3_[(3-chlorophenyl)-hydroxy-indenyl]_5_cyclopentyl-bromide methyl ester under ice , 3-cyclopentyl-5-decanoic acid methyl benzoate i4e (eg mg, 〇·68 mmol) was dissolved in 5 mL of tetrahydrofuran, and a solution of i M 3 chlorophenylmagnesium bromide in tetrahydrofuran was added dropwise. (1.36 mL, 136 Curry 1), stir the reaction for 20 minutes. Add 20 mL of saturated sodium bicarbonate solution, concentrate under reduced pressure, and extract with ethyl acetate (25 mL×3). The organic phase is combined and washed with water (15) and saturated sodium carbonate solution (20 mL), dried over anhydrous sodium sulfate. Filtration, and the filtrate was concentrated under reduced pressure. Methyl amyl-benzoate (14 mg, 265 mg, white solid). Step 6 3-[(3-Phenylphenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]-5-cyclopentyl-benzoic acid methyl ester 3-[ (3 -Chlorophenyl)-carbyl-indenyl]-5-cyclopentyl-crackinic acid A 14f (265 mg, 0.77 mmol) and N-(2-ethyl)amino decanoic acid 5小时。 It was hydrated and stirred at 130 ° C for 3.5 hours. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) Drying over sodium sulfate, filtration, and concentrating the filtrate <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTI ID=0.0> Amino) ethoxy] decyl]-5-cyclopentyl-benzoic acid vinegar vinegar (4 mg (177 mg, white solid)) Yield: 52.0%. Step 7 3-[(3-Chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl]-5-cyclopentyl-benzoic acid* 3-[(3- gas Phenyl)-[2-(decyloxycarbonylamino)ethoxy]indolyl]-5-cyclopentyl- benzoic acid oxime i4g (177 mg, 0.40 mmol) was dissolved in 7 mL of decyl alcohol. Sodium hydroxide (4 〇 mg, 1 mmol) was stirred at 50 ° C for 12 hours. The reaction solution was concentrated under reduced pressure. The mixture was adjusted to pH 3 to 4 with hydrochloric acid, and extracted with dichloromethane (20 mL×3). The organic phase was combined and washed with water (10 mL×2) and saturated sodium carbonate solution (1 〇mL×2) Drying under anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure to give the title product: 3-[(3_ φ chlorophenyl)-[2-(decyloxycarbonylamino)ethoxy] decyl]-5-cyclopentyl - Acidic formic acid 14h (257 mg, white solid), the crude product was directly reacted. The eighth step is [2-[[3-[[(151)-1-[(t-butoxycarbonyl(methyl)amino)indolyl]-2-cyclohexyl-ethyl]aminocarboxamyl) -5-cyclopentyl-phenyl]-(3-chlorophenyl)decyloxy]ethyl]amino decanoate decyl ester 3-((3-phenylphenyl)-[2 -(methoxycarbonylamino)ethyllacyl]mercapto]-5-cyclopentyl-benzoic acid 14h (100 mg, 0.23 mmol) and hydrazine-[(25.)-2-amino-3-ring Hexyl-propyl]-N-mercapto-amino decanoic acid 109 95392 201242594 Tributyl ester lg (63 mg, 0·23 mmol) dissolved in 5 mL of N,N-didecyl decylamine 1-Phenylbenzotriazole (63 mg, 0.46 mmol) ' 1-(3-Diamylaminopropyl)-3-ethylcarbodiimide hydrochloride (88 mg, 0.46 mmol) And N,N-diisopropylethylamine (〇. 2 mL, 0.92 mmol), and the reaction was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, water was added, and extracted with methylene chloride (20 mL×3), and the organic phase was combined, and then washed with water (1 〇&gt;&lt;2) and saturated sodium carbonate solution (10 mL×2), anhydrous sulfuric acid Drying, filtration, 'concentration of the filtrate under reduced pressure, and purification of the residue by using a thin layer chromatography to afford the residue of the solvent system B to obtain the title product Ν-[2-[[[(15])-ΐ-[( Third butoxycarbonyl(indenyl)amino)indenyl]-2-cyclohexyl-ethyl]aminomethylindenyl]_5-cyclopentyl-phenyl]-(3-chlorophenyl)methoxy] Ethyl]amino carbazate i4i (111 mg, white solid), yield: 71.0%. MS m/z (ESI): 684 [M+l] ninth step N-[2-[(3-phenylphenyl)-[3-cyclopentyl-5-[[(1)己 曱 基 基 曱 曱 曱 曱 曱 曱 曱 曱 曱 曱 曱 曱 曱 第三 第三 第三 第三 第三 第三 第三 第三 第三 第三 第三 第三 第三 第三Amino)methyl]-2-cyclohexyl-ethyl]aminomethylindenyl]_5_cyclopentyl phenyl]](3-chlorophenyl)nonyloxy]ethyl]amino hydrazine Methyl ester i4i gu mg, 0· 16 mmol) was dissolved in 10 mL of di-methane, and a mixed solution of 7.5 mL of tri-acetic acid and dichlorohydrazine (V/V = 1: 2) was added to disturb the reaction. 1 5 hours. The reaction solution was adjusted to pH &lt;7 with sodium bicarbonate solution, extracted with dichloromethane (50 mL×3), and the organic phases were combined and washed sequentially with water (1 〇mL×2) and 95392 110 201242594 and sodium chloride solution (1〇) </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; Methyl-5-[[(l«-1-(cyclohexylmethyl)-2-fluorenylamino-ethyl]aminoindenyl]]yl]methoxy]ethyl]aminocarbamic acid methyl ester 14 (72 mg, white solid), Yield: 80. 0%. MS m/z (ESI): 584 [M+1] !H NMR (400 MHz, CDCh): δ 8. 09-7. 77 ( m, 3H), 7. 49-7 19 Lu (m, 5H), 5. 87 and 5. 74 (2 s, 1H), 5. 32 and 5. 29 (2 s, 1H), 4.62 (m, 1H), 3.66 (s, 3H), 3.63-3.40 (m, 4H), 3.00-2.94 (m, 2H), 2.62 (s, 3H), 2.03 (m, 2H), 1.79-0.86 (m, 21H) Example 15 N-[2-[(3-Phenylphenyl)-[3-cyclopentyl-5-[[(251)-2-decylamino-3-[(3^-tetrahydropyran) -3-yl]propyl]aminoindenyl]phenyl]methoxy]B

Methyl carbazate

111 95392 201242594 1[(1«-1-[[[3-[(3-Phenylphenyl)-[2-(decyloxycarbonylamino)ethoxy]indolyl]-5-cyclopentyl- Benzoyl]amino]mercapto]_2-[(3A〇_tetracycline-3-yl)ethyl]-N-methyl-amino decanoic acid tert-butyl ester 3-[(3 - gas phenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl] -5-1⁄4 pentyl-benzoic acid I4h (1 〇〇 mg, 0.23 mmol) and N-[ (15)-1-(Aminomethyl)-2-[(3iP)-tetrahydropyran-3-yl]ethyl]-N-indolyl-pyridinium dicarboxylate 3a (63 mg, 0. 23 mmol) dissolved in 3 mL of N,N-dimethylamine, 'add 1- mercaptobenzotrisole (63 mg, 0.646 mmol), ® 1-(3~ diammonium Propyl)-3-ethylcarbodiimide hydrochloride (88 mg, 0.446 mmol) and N,N-diisopropylethylamine (119 mg, 0.92 mmol). The reaction solution was concentrated under reduced pressure and extracted with dioxane (5 〇mL×3). The organic phase was combined, washed sequentially with water (2 〇mL×2) and saturated sodium carbonate solution (20 mL×2) dried over anhydrous sodium sulfate, filtered, filtrate Concentration under reduced pressure gave the title product [[15]-l[[[3-[(3-chlorophenyl)-[ Ethoxy]indenyl]-5-cyclopentyl-benzylidenyl]amino]methyl] φ -2-[(3 pico)-tetrahydrofuran-3-yl]ethyl]-N-indenyl- Tert-butyl carbamate 15a (103 mg, white solid), Yield: 71. 〇%. MS m/z (ESI): 686 [M+l] Step 2 N-[2-[(3- Phenyl)-[3-cyclopentyl-5-[[(25.)-2-methylamino-3-[(3Λ〇-tetradecano)-pyran-3-yl]propyl]amino Methyl fluorenyl] phenyl] decyloxy] ethyl] carbamic acid decyl ester under ice bath 'will be [[150-141^3-1:(3-phenylphenyl)-[2-(decyloxy) Carbonylamino)ethoxy]indolyl]-5-cyclopentyl-benzylidene]amino]methyl 112 95392 201242594 base]-2-[(3 and)-tetrahydrofuran-3-yl]ethyl] -N-Mercapto-amino decanoic acid tert-butyl ester 15a (103 mg, 0.15 mmol) was dissolved in 8 mL of dichloromethane, 6 mL and dichloromethane were added (V/V = 1 : 2 a mixed solution, the reaction is stirred for 1.5 hours. The reaction solution is adjusted with a saturated sodium bicarbonate solution pH &gt; 7, extracted with methylene chloride (30 raLx3), combined with organic phase, followed by water (1 〇 mL X2) and Saturated sodium chloride solution (10 mLx2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the residue obtained by the solvent system A to give the title product N-[2-[(3-phenylphenyl)-[3-(2-(2-phenylethyl)-[ 3-[(3A)-tetrahydropyran-3-yl]propyl]aminocarbamimidyl]phenyl]decyloxy]ethyl]carbamic acid decyl ester 15 (65 mg, white solid) Rate: 75.0%. MS m/z (ESI): 586 [M+l] NMR (400 MHz, CDCh): δ 8. 63-7. 15 (m, 8H), 5. 71 (s, 1H), 5.31 (s, 1H ), 3.85-3.11 (m, 14H), 2.65 (s, 3H), 2.03-0.87 (m, 16H) Example 16, 17 [2-[(〇-(3-chlorophenyl)-[3- Cyclopropyl-5-[[(251)-2-decylamino-3-[(37?)-tetrahydropyran-3-yl]propyl]aminoindolyl]phenyl]decyloxy Ethyl ethoxy]methyl carbamate Ν-[2-[(5·)-(3-chlorophenyl)-[3-cyclopropyl-5-[[(2Λ-2-decylamino)- 3-[(3Pi)-tetrahydropyran-3-yl]propyl]aminoindenyl]phenyl]decyloxy]ethoxy]carbamic acid ruthenium vinegar 113 95392 201242594

N-[2-[(3-Azyl)H3_cyclopropyl_5_[[(10)_2-methylamino-3-[(3-tetrahydropentan-3-yl]propyl]amino) Methyl phenyl] methoxy] ethoxy] carbamic acid methyl carbazide 3 (10) mg, Q36 υ υ chiral separation 'HPLC method, separation by preparative equipment and chiral column chiral isomers (Separation conditions: Chiralcel 〇DH, mobile phase: n-hexane: isopropanol: diethanolamine = 6 〇: 4 〇: 〇. Bu flow rate: 1 〇 mL / min), collect the corresponding components, rotate The solvent was evaporated to give the title product Ν-[2-[(Λ〇-(3- disordered phenyl)-[3-cyclopropyl-5-[[(25)-2-methylamino-3-[ (3i〇-tetrahydropyran-3-yl]propyl]aminoindenyl]phenyl]methoxy]ethoxy]amino decanoic acid methyl ester 16 (95. 5 mg, 0. 17 mmol ) and N-[2-

[(5)-(3-Chlorophenyl)-[3-cyclopropyl-5-[ [(2S)-2-decylamino-3-[(3疋)-tetrahydrofuran-3- And propyl]amino] decyl] phenyl] methoxy] ethoxy] carbamic acid hydrazine vinegar 17 (89. 7 mg, 0.16 mmol). 16 MS ra/z (ESI): 558 [M+l] !H NMR (400 MHz, CDCh): δ 8. 16-7. 07 (ra, 8H), 5. 40 (s, 1H), 5.30 ( s, 1H), 3.83 (m, 2H), 3.64-2.98 (m, 12H), 2.52 (s, 3H), 1.91-1.19 (m, 8H), 0.96 (m, 2H), 0.73 (m, 2H) 17 MS m/z (ESI): 558 [M+l] !H NMR (400 MHz, CDCh): δ 7. 69-7. 09 (m, 8H), 5. 41 (s, 114 95392 201242594 1H) , 5.31 (s, 1H), 4.03-2.98 (m, 11H), 2.54 (s, 3H), 1.91-0.96 (in, 8H), 0.96 (m, 2H), 0.73 (m, 2H) Example 18 N -[2-[[3-butoxy-5-[[(l«-l-(cyclohexyldecyl)-2-mercaptoamino-ethyl]aminoindolyl]phenyl]-( Ethyl 3-chlorophenyl)methoxy]ethyl]carbamate

The first step is 5-butoxybenzene-1,3-dicarboxylate. Under the ice water bath, methyl 5-phenol-1,3-dicarboxylate lh (2.50 g, 12 mmol), 1- Butanol (1. 30 g, 18 mmol) and triphenyl acid ester (4. 70 g, 18 mmol) were dissolved in 40 mL of 1,2-dioxin, and diethyl azobisphosphate was added dropwise (3 10 g, 18 mmol), the reaction was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate (50 mL), water (50 mL) and saturated sodium carbonate solution 115 95392 201242594 Washing (10)..., anhydrous sulfuric acid, dry, 摅, 遽 give Shixi rubber tube column color f# The method is to purify the lyophilized β-purified product, and the title product is 5-butoxybenzene-1&gt;3-diacid acid f 酉 (2 =, to obtain the standard), the yield: 93.0% . 'g' yellow liquid second step 3-butoxy-5- Toxycarbonyl-cracked acid 5-butoxybenzene-u-two-low-acidic methyl vinegar (2·9 jealous, ιΐ 4〇 Circle 1) was dissolved in 15 mL of methanol, and sodium chlorohydroxide (456 °, ιΐ 4 〇 mmol) was added and stirred at 50 C for 12 hours. The reaction solution was concentrated under reduced pressure, and 15 mL of water was added. The mixture was extracted (2).3), and the aqueous phase was adjusted to 3 to 4 with im hydrochloric acid to give the title product: 3-butoxy-5 methoxycarbonyl. _ 本曱 I 18b (2. 03 g, white solid), yield: 75 %. The third step is 3-butoxy-5-(fluorenyl)benzoic acid formazan. Under the ice bath, 3-butoxy-5-nonyloxycarbonyl-benzoic acid 18b (2 g, 7· 96 mmol) was dissolved in 12 mL of tetrahydrofuran, and a solution of j borane in tetrahydrofuran (12 mL, 12 mmol). The reaction was quenched by the addition of methanol, and concentrated under reduced pressure. 5 mL of ethyl acetate was then weighed, and then, with 3?% potassium carbonate solution (20 inL), 1M hydrochloric acid (2 〇mL), saturated sodium hydrogen carbonate solution (2 〇mL) Washed with saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulphate, filtered, and the filtrate was concentrated under reduced pressure to give crude title product: 3-butoxy-5-(hydroxyindole) benzoic acid methyl ester l8c (2 g, colorless oil), the product was taken to the next step without purification. The fourth step 95392 116 201242594 3-butoxy-5-decanoic acid-benzoic acid methyl ester is intended to be a crude 3-butoxy-5-(hydroxymethyl)benzoic acid (2 g, 8.40 mmol) It was dissolved in 40 mL of dioxane, and pyridine chlorochromate rust (5.42 g, 25.20 mmol) and sodium acetate (2.10 g, 25·20 mmol) were added, and the reaction was stirred for 18 hours. The title product, 3-butoxy-5-decanoic acid-benzoic acid, was obtained by the addition of 2.0 g of hydrazine, filtered, and the filtrate was concentrated under reduced pressure. Methyl ester i8d (1.60 g, colorless oil), yield: 80.8%. • Step 5 - 3-butoxy-5-[(3-chlorophenyl)-carbyl-methyl]benzoic acid methyl ester, 3-butoxy-5-decanoic acid-benzoquinone Methyl ester i8d (1. 60 g, 6.78 mmol) was dissolved in 14 raL of tetrahydrofuran, and 1 μ 3-chlorophenyl bromide in tetrahydrofuran (14 mL, 14 mmol) was added dropwise. 5小时。 The mixing reaction was 0.5 hours. The reaction was quenched with water, EtOAc (EtOAc (EtOAc)EtOAc. Concentration, the residue obtained was purified by silica gel column chromatography using EtOAc EtOAc (EtOAc) 1.90 g, colorless liquid), yield: 81.0%. Step 6 3- Butoxy-5-[(3-phenylphenyl)-[2-(decyloxycarbonylamino)ethoxy]methyl]benzoic acid decyl ester 3-butoxy- Methyl 5-[(3-chlorophenyl)-hydroxy-indolyl]benzoate 18e (1.90 g, 4.90 mmol) and methyl N-(2-hydroxyethyl)carbamate 117 95392 201242594

It (1. 20 g, 10 mmol) was dissolved in 5 mL of hydrazine, and hydrazine sulfonic acid (931 mg' 4. 90 匪〇l) was added, and the reaction was stirred under reflux for a few hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjj Carbonylamino) ethoxy]methyl]benzoic acid decyl ester 18f (11 g, colorless oil), yield: 50.0%. Step 7 3- Butoxy-5-[(3-chlorophenyl)-[2-(decyloxycarbonylamino)ethoxy]-methyl]benzoic acid 3-butoxy-5 -[(3-Phenylphenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl]benzoic acid decyl ester 18f (1.1 g, 2.40 mmol) dissolved in 50 mL 曱Add sodium hydroxide (200 mg, 4.80 mmol) in the alcohol and mix for 50 hours at 50 C. The reaction mixture was concentrated under reduced pressure. ethyl acetate (5 mL) and water (50 mL) &lt;RTI ID=0.0&gt;&gt; The title compound, 3-butoxy-5-[(3-phenylphenyl)-[2-, was purified by EtOAc EtOAc. (methoxycarbonylamino)ethoxy]methyl]benzoic acid 18 g (810 mg, white waxy), yield: 81. 0 / /. The eighth step N-[2-[[3-butoxy-tert-butoxycarbonyl(methyl)amino)indolyl]-2-cyclohexyl-ethyl]aminomethylindenyl]phenyl-chloro Phenyl) decyloxy]ethyl]carbamic acid decyl ester 3-butoxy-5-[(3-phenylphenyl)-[2-(decyloxycarbonylamino)ethyl 118 95392 201242594 oxy曱]]benzoic acid 18 bogey (104 1112, 0.24 111111〇1) and ^[(251)-2-amino-3-cyclohexyl-propyl]-N-indolyl-carbamic acid tert-butyl The base ester lg (60 rag, 0.22 mmol) was dissolved in 5 mL of hydrazine, hydrazine-dimethylformamide, and added to 1-phenylbenzotriazine (60 mg, 0.44 mmol), 1-(3-dioxime). Aminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg, 0.44 mmol) and N,N-diisopropylethylamine (142 mg, 1.10 mmo 1 ). hour. Concentrate under reduced pressure' Add 50 mL of dioxane, wash with water (20 mL×2) and saturated sodium chloride solution (20 mL×2), dry over anhydrous sodium sulfate, and then filtered and filtered. The resulting residue was purified to give the titled product N-[2-[[3-(s).sup.5-[[(15*)-1-[(t-butoxy)-yl) Ethyl]-2-cyclohexyl-ethyl]aminoindenyl] phenyl]-(3-chlorophenyl)nonyloxy]ethyl]amino decanoic acid decyl ester I8h (118 mg, light yellow Oily), yield: 77.0%. Ninth step N-[2-[[3-butoxy-5-[[(15)-1-(cyclohexylfluorenyl)-2-mercaptoamino) φ-ethyl]aminocarbinyl] Phenyl]-(3-chlorophenyl)methoxy]ethyl]amino decanoate decyl ester under ice bath, N-[2-[[3-butoxy-5-[[(15*) -1-[(t-butoxy-yl(indenyl)amino)indenyl]-2-cyclohexyl-ethyl]amino aryl]phenyl]-(3-phenylphenyl) decyloxy ] ethyl]amino phthalic acid methyl vinegar igh (118 mg, 0.17 mmol) was dissolved in 6 mL of dichloromethane, and 6 mL of dichlorohydrazine solution containing 3 mL of trifluoroacetic acid was added dropwise. Stirring reaction 1 hour. The reaction was quenched by the addition of saturated sodium sulphate solution. The aqueous phase was extracted with di-methane (2 mL mL), and the organic phases were combined and washed sequentially with water (10 mL×2) and saturated sodium chloride solution (1〇119 95392 201242594 mL×2) The organic layer was dried over sodium sulfate, filtered, and the filtrate was evaporated, evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Cyclohexylmethyl)_2-decylaminoethyl-ethyl]aminoindenyl]phenyl]-(3-phenylphenyl)methoxy]ethyl]amino decanoic acid methyl ester 18 (46 1^ , White solid), Yield: 45%. MS m/z (ESI): 558. 3[M+1] !H NMR (400 MHz, CDCh): δ 7. 96-6. 94 (m, 8H ), 5. 75 and 5.65 (2 s, 1H), 5. 34 and 5. 29 (2 s, 1H), 4.60 (m, 1H), ® 4. 01 (t, /=6. 4 Hz, 2H ), 3.67 (s, 3H), 3.57-3.06 (in, 7H), 2.72 (s, 3H), 1.75-0.87 (m, 22H) Example 19 N-[2-[(3-chlorophenyl)- [3-[[(15)-1-(cyclohexylmethyl)-2-mercaptoamino-ethyl]aminoindolyl]-5-(2-decyloxyethoxy)phenyl] Methoxy]ethyl]amino decanoate

120 95392 201242594

❸ First step 5-(2-decyloxyethoxy)benzene-1,3-dicarboxylate oxime 5-Benzene-1,3-dioxalate oxime lh (2.50 g, 12 mmol) , 1_ desert_2-decyloxy_acetone (2.5-0 g, 18 ππηοΐ), carbonic acid clock (3. 30 g, 24 mmol) and moth clock (0.30 g, 1.8 mmol) dissolved in 50 mL of acetonitrile The reaction was stirred at 50 ° C for 12 hours, and the reaction was continued at 75 ° C for 5 hours. Concentration under reduced pressure gave the crude title product 5-(2-methoxy-ethoxyethoxy)benzene-1,3-dicarboxylic acid methyl ester 19a (3. 05 g, white solid). - Step reaction. Step 2 3-Hydroxycarbonyl-5-(2-decyloxyethoxy)benzoic acid The crude methyl 5-(2-decyloxyethoxy)benzene-1,3-dicarboxylate 19a (3 g, 11.20 mmol) was dissolved in 15 mL of methanol, sodium hydroxide (448 mg, 11. 20 mmol) was added, and the mixture was stirred at 50 ° C for 12 hours. The reaction solution was concentrated under reduced pressure, and 150 mL of water was added, and the mixture was extracted with dichloromethane (20 mL×3), and the aqueous phase was adjusted to pH 3 to 4 with 1 Μ hydrochloric acid, filtered, and dried in vacuo to give the title product: Oxycarbonyl-5-(2-methoxyethoxy)benzoic acid 19b (2. 16 g, white solid), Yield: 76.0% ° Step 3 3-(Hydroxymethyl)-5-(2 Methyl 3-methoxycarbonyl-5-(2-methoxyethoxy) benzoic acid 19b (2. 10 g, 8.26 mmol) The solution was dissolved in 12 mL of tetrahydrofuran, and a solution of 2.5 mL of tetrahydro-sulphur solution G2.5 mL, 12.50 mmo 1) was added, and the reaction was stirred at 5 ° C for 12 hours. The reaction was quenched by the addition of methanol and concentrated under reduced pressure. EtOAc (EtOAc) The saturated sodium carbonate solution was washed (20 mL), dried over anhydrous sodium sulfate Ester 19c (1.87 g, colorless oil).笫 Four steps of 3-carboxylic acid methyl 5-(2-methoxyethoxy)benzoic acid methyl ester crude methyl 3-(hydroxymethyl)-5-(2-methoxyethoxy)benzoate 19c (1.87 g' 7.80 mmol) was dissolved in 4 〇 dichloro decane, salt (5.1 〇g, 23. 6 〇 curry 1) and sodium acetate (3) 95 g, and the reaction was given for 18 hours. . The mixture was purified by chromatography on a hexane column (1.40 g, colorless oil). Yield: 76 〇%. The fifth step 95392 122 201242594 3-[(3~ gas phenyl), yl-methyl]|(2-methoxyethoxy) benzoic acid oxime ester in the ice bath, 3-carboxylic acid base | (2_ Methyl methoxyethoxy)benzoate 19d (1.40g, 6mm〇1) was dissolved in 12乩 tetrahydrofuran, and a tetrahydroanthracene solution of 1 Μ 3-gas phenyl desertification was added dropwise (12仏, 12 coffee (4), stir the reaction for 0.5 hours. Add water to quench the reaction, extract with ethyl acetate (5) Heart 3) 'The organic phase is combined, then washed with water (15 mL) and saturated sodium carbonate solution (20 mL), anhydrous The residue was dried over sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to afford the product of 3-[(3-phenylphenyl)-carbyl-methyl. 5_(2-methoxyethoxy)phenylhydrazine I formazan I9e (1.80 g, white solid), yield: 89.%. Step 6 3-[(3~Chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]_5_(2-decyloxyethoxy)benzoate decyl ester [ (3-Chlorophenyl)-hydroxy-methyl]-5-(2-decyloxyethoxy) φ methyl benzoate 19e (1.80 g, 5.17 mmol) and N-(2-hydroxyethyl) Aminocarbamate A (1.22 g, 10.30 mmol) was dissolved in 50 mL of toluene. Concentration under reduced pressure, the residue obtained was purified eluting with EtOAc EtOAc EtOAc EtOAc ]] fluorenyl]-5-(2-decyloxyethoxy) benzoic acid decyl ester 19f (1.20 g, colorless oil), yield: 52. Step 7 3-[(3-Chlorophenyl)_[2_(methoxycarbonylamino)ethoxy]indolyl] 123 95392 201242594 -5-(2-methoxyethoxy)benzoic acid 3-[(3-Chlorophenyl)-[2-(methoxymethylamino)ethoxy]methyl](2-decyloxyethoxy)benzoic acid 19f (1. 20 g, 2·67 mmol) The hydrazine was dissolved in 4 hydrazine methanol, sodium hydroxide (214 mg, 5.35 mmol) was added, and C was stirred for 12 hours. Concentrate under reduced pressure, add two gas to simmer (5 〇), 1 Μ salt &amp; 〇 液 solution to adjust the pH to 3 to 4, extract with dichloromethane (10) mLx3) 'The organic phase is combined, dried with anhydrous sodium sulfate , 遽 遽, · decompression concentrated H ' shrinking' to give the crude product 3-[(3-chlorophenylmethoxyamino)ethoxy] decyl]-5-(2-methoxyethoxy) Benzoic acid 19 g (87 〇 mg, lightly colored viscous) 'yield: 75. 〇%. The eighth step is Ν-[2-[[3-[[(15.)-ι-[(t-butoxycarbonyl(methyl)amino)indolyl]- 2-cyclohexyl-ethyl]aminopurine 5-[(3-chlorophenyl)phenyl]-(3-phenylphenyl)nonyloxy]ethyl]amino decanoate decyl 3-((3-chlorophenyl) [2-(Methoxycarbonylamino)ethoxy]indolyl]% decyloxyethoxy)benzoic acid 19g (106 mg, 0·24 mmol) and N-[(2«-2-amine) Base 3 - cyclohexyl-propyl]_N_methyl-amino decanoic acid tert-butyl vinegar lg (60 mg, 〇 · 22 mm 〇l) is dissolved in 5 mL of N,N-didecyl decylamine 'Add 1-hydroxy benzotriazole (6 〇 mg, 0.44 mm 〇l), 1-(3- hydrazinopropyl)-3-ethylcarbodiimide hydrochloride (84 mg, 0. 44 mmol) and N,N-diisopropylethylamine (142 mg, 1.10 mmol), stirred for 12 hours. Concentrated under reduced pressure 'Add 5 〇 mL of dioxane, followed by water (20 mL×2) and saturated The mixture was washed with a sodium chloride solution (2 mL mL), dried over anhydrous sodium sulfate, filtered and filtered. The filtrate was concentrated under reduced pressure, and purified by EtOAc EtOAc EtOAc EtOAc. [[3-[[(15·)-1-[(第Tributyloxycarbonyl (methyl)amino)methyl]-2-cyclohexyl-ethyl]aminof-yl]-δα-methoxyethoxy)phenyl]-(3-chlorophenyl) 0%。 Methoxy]ethyl] carbamic acid methyl ester 19h (121 mg, pale yellow oil), yield: 79.0%. Nine Steps N-[2-[(3-Phenylphenyl)-[3-[[(15〇-1_(cyclohexylmethyl)-2-methylamino-ethyl]aminocarbamoyl] -5-(2-methoxyethoxy)phenyl]decyloxy]ethyl]carbamic acid methyl ester • Under ice bath, Ν-[2-[[3-[[(15·)- 1-[(T-butoxycarbonyl(methyl)amino)indolyl]-2-cyclohexyl-ethyl]aminoindolyl]-5-(2-methoxyethoxy)phenyl]- Methyl (3-phenylphenyl)methoxy]ethyl]carbamate 19h (121 mg, 0. 18 mmol) was dissolved in 6 mL of methylene methane, and 6 mL of 3 mL of trifluoroacetic acid was added dropwise. Methyl chloride solution, stirring for 1 hour. Add the saturated sodium carbonate solution to quench the reaction, the aqueous phase is extracted with dichloromethane (2〇mLx3), the organic phase is combined, and then water (10 mLx2) and saturated sodium sulfonate solution Washing (1 〇 mL x 2) dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. -[3-[[(ΐ5·)-ΐ-(cyclohexylfluorenyl)_2-methylamino-ethyl]aminoindolyl]-5-(2-methoxyethoxy)phenyl曱oxy]ethyl]amino ruthenate 19 (56 mg, mp. , 8H), 5. 75 and 5.65(2s, 1H), 5. 29 and 5. 24 (2s, 1H), 4. 60 (m, 1H), 95392 125 201242594 4.15 (s, 2H), 3.69-3.28 (m, 14H), 3.08 (m, 1H), 2.67 (s, 3H), 1.79-0.83 (in, 13H) Example 20 N-[2-[(3-Phenylphenyl)-[3-[ Hexylmethyl)-2-methylamino-ethyl]aminocarbamimidyl]-5-(cyclopropylmethoxy)phenyl]methoxy]ethyl]amino decanoate

First step 5-(cyclopropyl decyloxy) stupid-1,3-dioxalate oxime ester 5-phenol-1,3-didecanoate ih (2 5〇g, 12 mm〇1) , bromomethylcyclopropane (2.40 g, 17.80 mmol), carbonic acid clock (3·30 g, 24 mmol) and potassium iodide (〇. 30 g, 24 mmol) dissolved in 5 mL of acetonitrile, 5 〇 ° C. The reaction was carried out for 12 hours and further at 75 ° C for 5 hours. Concentration under reduced pressure gave the crude title product 5-(cyclopropylfoxy)benzene </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The next step is to react. The second step 3 (cyclopropyl decyloxy)-5-methoxycarbonyl-cracked acid will be crude 5~(cyclopropyl decyloxy)benzene-1,3-dicarboxylate 2〇a S , fine 10 丨) dissolved in 15 companies of methanol, sodium hydride (440 mg, 11 _ 〇 1) was added, 5 c 授 mixed reaction for 12 hours. The reaction solution was depressurized>Agricultural shrinkage' was added to 150 mL of water, extracted with dichloromethane (2〇mLx3), and the aqueous phase was adjusted to pH 3 to 4 with 1 Μ hydrochloric acid to give the title product 3-(cyclopropyl hydrazine). Oxy) 5-methoxycarbonyl-cracked acid 20b (2.20 g, white solid), yield: 80%. The third step 3-(cyclopropyl decyloxy)-5-(hydroxymethyl) benzoic acid oxime ester under the ice bath '3-(cyclopropyl decyloxy)-5-methoxycarbonyl-benzoquinone The acid 20b (2.20 g, 8.80 mmol) was dissolved in 13 mL of tetrahydrofuran, and a solution of borane in THF (13.5 mL, 13.20 mmol) was added, and the reaction was stirred at 50 ° for 12 hours. The reaction was quenched by the addition of methanol and concentrated under reduced pressure &lt;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot; The gasified sodium solution (20 mL) was washed with EtOAc (EtOAc) (EtOAc)jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj , colorless oil), the product was directly subjected to the next reaction without purification. The fourth step 95392 127 201242594 3-(cyclopropylmethoxy)-5-decanoic acid-methyl benzoate The crude 3-(cyclopropyl decyloxy)-5-(hydroxyindenyl)benzoate hydrazine Ester 20c (1.90 g, 8 mmol) was dissolved in 40 mL of methane toluene, and the mixture was reacted with chromic acid pyridine salt (5.20 g, 24 mmol) and sodium acetate (1.95 g, 24 mmol). hour. Add 2·〇g Shixi gum, transfer, and dilute the liquid under reduced pressure. The residue obtained by purifying the eluent system B with Shixi gum column chromatography to give the title product 3-(cyclopropylmethoxy)-5. 0%。 The decanoic acid-formic acid methyl ester 20d (1. 60 g, colorless oil), yield: 85.0%. ® Step 5 [(3-Chlorophenyl)-carbyl-indenyl]-5-(cyclopropylmethoxy)benzoic acid 曱酉 冰 冰 ' '3-(cyclopropylmethoxy) -5-formic acid-benzoic acid hydrazine 20d (1.60 g, 6.80 mmol) dissolved in 14 mL of tetrahydrocide, and added 1 Μ 3- phenylphenylmagnesium bromide in tetrahydrofuran (14 mL, 14 5小时。 The reaction was stirred for 0.5 hours. The mixture was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) The residue obtained was purified by silica gel column chromatography using EtOAc EtOAc EtOAc (EtOAc)曱% 20e (1. 85 g, colorless oil), yield: 78. 〇%. Step 6 3-[(3-Chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl]-5-(cyclopropylmethoxy)benzoic acid methyl ester 3- [(3-Chloro)-hydroxy-methyl]_5-(cyclopropylmethoxy)benzene 95392 128 201242594 Methyl formate 20e (1.85 g, 5.30 mmol) and N-(2-hydroxyethyl) Amino ruthenium citrate lt (1.26 g, 10.70 mmo 1) was dissolved in 50 mL of toluene, p-toluene acid (1 g, 5.30 mmol) was added, and the reaction was stirred under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure <yield</RTI></RTI></RTI></RTI> <RTI ID=0.0> 5-(cyclopropyl decyloxy) benzoate oxime ester 2 〇f (950 mg, colorless oil), yield: 41.3%. Step 7® 3_[(3-chlorophenyl M2-(decyloxycarbonylamino)ethoxy]indolyl]-5-(cyclopropylmethoxy)benzoic acid 3--(3- Phenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl]-5-(cyclopropyldecyloxy)benzoate oxime 2〇f (95〇, 2.10 mmol) / glutathione in 30 mL of sterols 'added sodium hydroxide (Mg mg, 4. 20 mmol), and the reaction was stirred at 50 ° C for 12 hours. The reaction solution was concentrated under reduced pressure, and dichloromethane (5 〇 mL) was added. 1 The hydrochloric acid solution of hydrazine is adjusted to a pH of 3 to 4, extracted, and combined with organic φ phase, dried over anhydrous sodium sulfate. The filtrate is concentrated under reduced pressure to give the title product 3-[(3-phenylphenyl)-[2-( 0%。 Methoxycarbonylamino) ethoxy] fluorenyl] -5-(cyclopropyl decyloxy) benzoic acid 2 〇 g (75 〇 mg, pale yellow viscous), Yield: 81.0%. The eighth step N-[2-[[3-[[(15))-1-[(t-butoxycarbonyl(indenyl)amino)methyl]-2-cyclohexyl-ethyl]aminoindole)醯]]5-(cyclopropylmethoxy)phenyl]-(3-chlorophenyl)nonyloxy]ethyl]amino decanoic acid decyl ester 3&quot;[(3-chlorophenyl)_[2 Mono(methoxycarbonylamino)ethoxy]indenyl] 129 9539 2 201242594 -5-(cyclopropylmethoxy)benzoic acid 20g (100 mg, 0.23 mmol) and N-[(25)-2-amino-3-cyclohexyl-propyl]-N-methyl- Tert-butyl butyl citrate lg (81 mg, 0.30 mmol) was dissolved in 5 mL of N,N-dimercaptocaramine to add hydroxybenzotriazole (62. 50 mg, 0.46 mmol) , 1-(3-Diaminoaminopropyl)-3-ethylcarbodiimide hydrochloride (88.70 mg, 0.46 mmol) and N,N-diisopropylethylamine (114 mg, 0.88 mmol), the reaction was stirred for 12 hours. Concentrated under reduced pressure, 50 mL of ethyl acetate was added, washed with water (20 mL×2) and saturated sodium chloride (20 mL×2) and dried over anhydrous sodium sulfate. The residue was purified by EtOAc (EtOAc) elut elut Aminomethylmercapto]-5-(cyclopropyldecyloxy)phenyl]-(3-phenylphenyl)methoxy]ethyl]carbamic acid hydrazine vinegar 20 h (107 mg, white solid) Yield: 67. 0%. Ninth step Lu N-[2-[(3-chlorobenzyl)-[3-[[(151)-1-(cyclohexylmethyl)-2-decylamino) -ethyl]amino group Acyl] -5- (cyclopropyl Yue yloxy) phenyl] Yue oxy] ethyl] carbamic acid ester Yue

Under ice bath '1[[[[[[[[[[[[[[[[[[[[[[[([[[[[[[[[[[[[[[[[[([[[[[[[[[[[[[[[[[[[[[[[[[[[[ Methyl fluorenyl]-5-(cyclopropyl decyloxy)phenyl]-(3-phenylphenyl) decyloxy]ethyl]amino decanoic acid methyl ester 2 〇匕 (107 mg, 0. 16 Methyl) was dissolved in 4 mL of dichloromethane, and 1 mL of difluoroacetic acid was added dropwise to stir the reaction for 1 hour. The reaction was quenched by the addition of saturated sodium bicarbonate solution. The aqueous phase was extracted with a gas (20 mL×3), and the organic phases were combined, followed by 95392 130 201242594, washed with water (10 mL×2) and saturated sodium chloride solution (1〇fflLx2), anhydrous The residue was dried over sodium sulfate, filtered, and then evaporated tolulululululululululululululululululululululu -(cyclohexylmethyl)_2-methylamino-ethyl;|aminomethylmercapto]-5-(cyclopropylmethoxy)phenyl]decyloxy]ethyl]aminocarbamic acid methyl ester 20 (65 mg, white solid), Yield: 71. 〇% MS m/z (ESI): 586.3 [M+l] !OMR (400 MHz, CDC13) : δ 8. 11-6. 94 (m , 8H), 5.75 and 5.65 (2 s, 1H), 5. 30 and 5. 25 (2s, 1H), 4. 61 (m, 1H), 3.82 (d, /= 6. 8 Hz, 2H ), 3.64-3.01 (ra, i〇H), 2. 68 (s, 3H), 1.79-0.89 (m, 14H), 0.61 (m, 2H), 0.33 (m, 2H) Example 21 N-[ 2-[(3-Chlorophenyl)-[3_[ [(ΐ5·)_ι —(cyclohexylfluorenyl)_2-decylamino-ethyl]aminoindolyl]-5-isobutoxy -phenyl]decyloxy]ethyl]amino decanoate

95392 131 201242594

Φ 1st 2-mercapto-propan-1-ol ice bath, 2-methylpropanal 21a (3 g, 41 mmol) was dissolved in 30 mL of tetrahydrofuran, and added to the shed. Sodium (3.10 g, 82 mmol) was stirred for 4 hours. Filtration and concentrating the filtrate under reduced pressure afforded the title compound, m.p. The second step • 5-Isobutoxybenzene-1,3-distrontium decyl ester, pentyl 5-phenol-1, 3-dicarboxylate lh (2. 50 g, 12 mmol), The crude 2-mercapto-propan-1-ol 21b (1. 30 g, 18 mmol) and the triphenyl sulphate (4.70 g, 18 mmol) were dissolved in 40 mLl, 4-:^^*, dropwise addition Diethyl ruthenate (3. 10 g, 18 mmol) was stirred at room temperature for 12 hours. Concentrate under reduced pressure, add ethyl acetate (50 mL), water (50 mL) and saturated chlorinated steel solution (50 mL), dry over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained 132 95392 201242594 residue was purified by the eluent system B to give the titled product 5-isobutoxybenzene-1,3-distronosyl ester 21c (3 g, yellow liquid), yield: 94.0%. The third step 3 - isobutoxy-5-nonyloxy-based benzoic acid is dissolved in 5-isobutoxy phenyl-1,3-dicarboxylate 21c (3 g, 11.32 curry 1) Sodium hydroxide (452 mg, 1132 mm 〇1) '50 was added to 15 mL of methanol. (: The reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure. EtOAc EtOAc EtOAc EtOAc (EtOAc) Butoxy-5-methoxy-l-capric acid 21d (2.20g, white solid), yield: 76%. Step 4 3-(Hydroxymethyl)-5-isobutoxy-benzoquinone 3-Isobutoxy-5-nonyloxycarbonyl-benzoic acid 21d (2.2 g, 8.70 mmol) was dissolved in 13 mL of tetrahydrofuran under ice-cold vinegar, and 1 M was added. 4 虱 0 喃 浴 bath (13 mL, 13 mmol), 5 〇. (^ disturb reaction) 2 _. Add methanol to quench the reaction 'decompression shrinkage, force α into 50 mL acetic acid B cool' Wash with 30% potassium carbonate solution (20 raL), 1 M hydrochloric acid (2 mL), saturated sodium bicarbonate solution (20 mL) and saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, filtered The filtrate was concentrated under reduced pressure to give the title compound, m, m. Step 5 3-Formyl-5-isobutoxy-benzoic acid The crude 3-(hydroxyindenyl)-5-isobutoxy-benzoic acid methyl ester 21e (2 g. 95392 133 201242594 8. 40 mmol) was dissolved in 40 mL of dichlorohydrazine and placed in the second place. Milk tau play, add pyridinium bismuth chromate (5.402, 25.20 leg 〇 1) and sodium acetate (2.1{) 2, 252 〇 with 〇 1), stir the reaction for 18 hours. Add 2.0 g of 矽 gel, filter, filtrate concentrated under reduced pressure The residue obtained is purified by a solvent-purifying method using an eluent system b to give the title product: 3-decanoic acid-5-isobutyloxybenzoic acid methyl ester 21f Q 5 〇g colorless oily) , Yield: 76.0 ° / «. 'Step 6 3-[(3-Phenylphenyl)-hydroxy-indolyl]-5-isobutoxy-benzoic acid oxime ester® 3_carboxylic acid 5--5-isobutoxy- Methyl benzoate 21f

5小时。 The reaction was stirred in a solution of 0. 5 hours. The reaction was quenched with water and extracted with ethyl acetate (5 〇mL×3). The organic phase was combined, washed sequentially with water (15 raL) and saturated sodium carbonate solution (20 mL), dried over anhydrous sodium sulfate Concentration, the obtained residue was purified by silica gel column chromatography using a solvent system B to give the title product 3-[(3-chlorophenyl)-hydroxy-indolyl]-5-isobutoxy-benzoic acid. Ester 21g (1.70g, colorless oil), Yield: 79, 〇%β Step 7 3-[(3-Chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]methyl ]_5_Isobutoxy-benzoic acid methyl hydrazine is a methyl 3-[(3-chlorophenyl)-carbyl-indenyl]-5-isobutoxy-benzoic acid ester 21g (1.70 g, 4 90 mmol). and N-(2-ethylethyl)carbamate, It (1. 20 g, 1 〇1〇1) were dissolved in 50 mL of toluene and p-toluene acid (0.93 g, 4.90 mmol), reflux reaction for 1 hour. The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc) Oxy]methyl]-5-isobutoxy-benzoic acid oxime ester 2lh (1.2〇g, colorless oil), yield: 54.0%. Step 8 3-K3-Phenylphenyl) -[2-(Methoxycarbonylamino)ethoxy]methyl]_5-isobutoxy-benzoic acid 3-[(3-phenylphenylH2-(methoxycarbonylamino)ethyl Oxyl;|mercapto] ® methyl isobutoxy-benzoate 21h (1.40 g, 3.10 mm〇i) was dissolved in 10 mL of sterol and sodium hydroxide (250 mg, 6.30 mmol) was added. The reaction was stirred for 48 hours at 50 C. Concentrated under reduced pressure, dioxane (5 〇 mL) was added, and 1 Μ hydrochloric acid solution was adjusted to adjust the p{j value to 3 to 4, extracted, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude product: 3-[(3-chlorophenyl)-[2-(decyloxycarbonylamino)ethoxy]indolyl]_5-isobutoxy-benzoic acid 21 i (1.20 g, light yellow solid), yield: 88.0%. φ ninth step N-[2-[t-butoxycarbonyl(indenyl)amino)indolyl]-2-cyclohexyl Methyl 3-ethyl(aminochloro) -[2-(Methoxycarbonylamino)ethoxy]methyl]-5-isobutoxy-benzoic acid 21i (100 mg, 〇. 23 mmol) *N-[(2« -2-amino) -3-cyclohexyl-propyl]-N-mercapto-carbamic acid tert-butyl ester lg (81 mg, 0.30 mmol) was dissolved in 5 inL of N,N-didecylamine, and added to the hydroxyl group. Benzotriazole (62. 50 mg, 0.446 mmol), 1-(3-dimethyl 135 95392 201242594 aminopropyl)-3-ethylcarbodiimide hydrochloride (88. 70 mg, 0.46 Methyl) and N,N-diisopropylethylamine (114 mg, 0.88 mmol), stirred for 12 hours, concentrated under reduced pressure, and then added 50 mL of ethyl acetate, followed by water (2 〇mLx2) and saturated sodium chloride Washing (20 mL x 2), dry over anhydrous sodium sulfate, filtered &lt;&quot;&quot;&quot;&quot;&quot&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Base) fluorenyl]-2-cyclohexyl-ethyl]amino fluorenyl]_5_isobutoxy-phenyl]-(3-phenylphenyl)nonyloxy]ethyl]amino decanoic acid Ester ❶21ί Π16 mg, white solid), yield: 73.4%. Step 10 N-[2-[(3-Chlorophenyl)-[3-[ [(15)-1-(cyclohexyldecyl)-2-mercaptoamino-ethyl]aminocarboxamyl) ]-5-Isobutoxy-phenyl]decyloxy]ethyl]amino decanoic acid for the treatment of N-[2-[ [3-(^(150-14) Oxycarbonyl(methyl)amino)indenyl]-2-cyclohexyl-ethyl]aminocarbamimidyl]-5-isobutoxy 0 _phenyl]_(3~·oxyphenyl)methoxy Methyl 2-ethyl]carbamate.21j (116 rag, 0.17 mmol) was dissolved in 4 mL of dichlorohydrazine, 1 mL of trifluoroacetic acid was added dropwise, and the reaction was stirred for 1 hour. Saturated sodium hydrogencarbonate was added. The solution is quenched, the aqueous phase is extracted with methylene chloride (2 mL mL), and the organic phase is combined, washed sequentially with water (1〇raLx2) and saturated sodium chloride solution (丨〇mLx), dried over anhydrous sodium sulfate, filtered The filtrate was concentrated under reduced pressure, and the obtained residue was purified to purified crystals eluted eluted elution (cyclohexylmethyl)-2-methylamino-ethyl]aminocarbamimidyl]-5-isobutoxy-phenyl]decyloxy]ethyl]amino decanoate 21 (95 136 95392 201242594 mg, white solid), yield 96. 0%. MS ra/z (ESI): 588 [M+l] 4 NMR (400 MHz, CDC13): δ 8. 05-6. 82 (m,8H),5·82 and 5.69 (2 s , 1H), 5. 30 and 5. 25 (2s, 1H), 4.65 (m, 1H), 3.77-3.00 (m, 12H), 2.67 (s, 3H), 2.04 (m, 1H), 1.86-0.86 (m, 20H) Example 22 N-[2-[(3-chlorophenyl(cyclohexylmethyl)-2-mercaptoamino-ethyl]aminomethyl]]-2,3-di Methyl benzobenzofuran-7-yl]-methoxy]ethyl]decanoate

Λ

137 95392 201242594

The first step of 7-bromo-2,3-dihydrobenzofuran-5-furfural, 2,3-dihydrobenzofuran-5-furfural 22a (1.00 g, 6. 76 mmol) Dissolved in 15 mL of acetic acid, and added sodium acetate (665 mg, 8. 1 mmol). Slowly add bromine (0.7 mL, 13.5 mmol) and react at room temperature for 3 hours. After adding 1 mL of a saturated solution of sodium thiosulfate and 20 mL of a saturated sodium hydrogencarbonate solution, ethyl acetate (3 mL mL) was evaporated. 7-Moline-2, 3-dihydrobenzofuran-5-carbaldehyde 22b (2.61 part of an oily product), the product was directly subjected to the next reaction without purification. 138 95392 201242594 The second step (7 &gt; odor-2,3-diophos benzo bite "•Nan-5-yl" methanol ice bath, the crude 7-bromo-2, 3-dihydrobenzo Bite-5-formaldehyde 22b (1.54 g, 6.76 mmol) was dissolved in 20 mL of ethanol, sodium borohydride (257 mg, 6.76 mmol) was added portionwise, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure of EtOAc (EtOAc) (EtOAc (EtOAc). 2,3-Dihydrobenzofuran-5-yl)methanol 22c (1.89 g, yellow oil). The third step (7-bromo-2,3-dihydrobenzofuran-5-yl)decyloxy-t-butyldiphenyl decane, the crude product (7-bromo-2, 3) -Dihydrobenzofuran-5-yl)nonanol 22c (1.89 g, 8.2 mmol) was dissolved in 20 mL of dichloromethane, added with imidazole (559, 8.2 _〇1), slowly added dropwise Butyl diphenyl gas decane (2.56 mL, 9.85 mmol) was stirred at room temperature for 12 hours. After adding 30 mL of water, the mixture was extracted with a gas mixture (20 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title product (7-bromo-2,3-dihydrobenzofuran-5-yl)methoxy-t-butyldiphenylnonane 22d (3. 69 g, colorless oil) :g5 8%. NMR (400 MHz, CDCh): δ 7. 76-7. 73 (ra, 4Η), 7. 50_7· 43 (m, 6H), 7.25(s, 1H), 7.12 (s, 1H), 4.75-4.69 (m, 4H), 95392 139 201242594 3. 34 (t, / = 8. 8 Hz, 2H), 1. 15 (s, 9U) The fourth step [5-[(T-butyldiphenyl fluorenyl) (7-Bromo-2,3-dihydro benzofuranyl) under oxymethyl]- 2 3 -dihydrobenzofuran-7-yl]-(3-phenylphenyl)methanol under dry ice bath曱oxy-t-butyl-stupyl Shishiyuan 22d (3.69 g, 7.89 mmol) was dissolved in 30 mL of tetrahydrofuran, and n-butyllithium was added dropwise (3.85, 7.89, stirring reaction for 45 minutes) 'Addition of 5 mL of 3-chlorobenzaldehyde (1. 〇7 mL, 9.46 ® mmol) in tetrahydrofuran and continue stirring for 5 hours. Add 4 〇虬 saturated ammonium hydride solution 'extracted with ethyl acetate ( 3 〇mLx3), the organic phase was combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography to afford the title product [5-[(2nd Benzyl phenyl sulfanyloxycarbonyl] 2,3-dihydrobenzobenzopyran-7-yl]-(3-chlorophenyl)methanol 22e (2.0 g, white solid) Yield: 48. 2%. _ H NMR (400 MHz, CDC13): δ 7.47-7.27 (m, 10H), 7 14 (s, 1H), 6. 95 (s, 1H), 5. 93 (s , 1H), 4. 69 (s, 2H), 4. 66 (t, /= 8.8 Hz, 2H), 3.24 (t, / = 8.8 Hz, 2H), 1.09 (s, 9H) Step 5 - [[5-[(T-butyldiphenylindenyl)oxymethyl]_2 3 -dihydrobenzofuran-7-yl]-(3-chlorophenyl)methoxy]acetic acid ethyl acetate Under ice bath, sodium hydride (377 mg, 15.7 mmol) was suspended in 'tetrahydrofuran, and 6. 5 mL of [5-[(t-butyldiphenylfluorenyl)oxy 95392 140 201242594 曱] was added dropwise. -2,3-Dihydrobenzofuran-7-yl]-(3-phenylphenyl)nonanol 22e (1.52 g' 2.89 mmol) in tetrahydrofuran, stirring for 1 hour, dropwise addition of 6.5 mL &gt; Ethyl acetate (〇. 96 mL, 8.66 mmo 1) of the four bite-drinking solution, the reaction was stirred under reflux for 3 hours, and cooled to 〇 °c to add sodium hydride (207 mg, 8.67 mmol). Ethyl bromoacetate (0·96 mL, 8.66 mmol) was added, and 5 (TC) was reacted for 12 hours. Cool to 〇 °c, add 20 mL of saturated ammonium chloride solution, extract with ethyl acetate (20 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and filter the filtrate to concentrate under reduced pressure. The eluent system A was purified to give the crude title product 2-[[5-[(t-butyldiphenyl-decyl)oxyindenyl]-2,3-dihydrobenzofuran- Ethyl 7-yl]-(3-chlorophenyl)methoxy]ethyl ester 22f (2 g, m. !H NMR (400 MHz , CDCh) : δ 7. 72-7. 68 (m, 4Η), 7. 42-7. 14 (m, 10H), 6.90 (s, 2H), 5.81 (s, 1H) , 4.61 (t, /= 2.4 Hz, 2H), 4.29-4.11 (m, 6H), 3.23 (t, / = 8. 8 Hz, 2H), φ 1.31 (m, 3H), 1.09 (s, 9H) Step 6 2-[[5-[(T-butyldiphenylindenyl)oxymethyl]-2,3-dihydrobenzofuran-7-yl]-(3-chlorophenyl) Ethyl methoxy]methanesulfonate ethyl ester in the ice bath, the crude 2-[[5-[(t-butyldiphenylfluorenyl)oxymethyl]-2,3-dihydrobenzofuran-7 Ethyl-(3-chlorophenyl)methoxy]ethyl acetate 22f (12.0 g, 18.25 mmol) was dissolved in methanol (180 mL), and then hydrogenated steel (6.99 g, 126 mmol). The reaction was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc) (EtOAc (EtOAc) , the product is obtained for use. Under ice bath, transfer the above residue to (10) the dichlorobenzene, and add ethylamine (7·6 mL' 69·75 _1) and a calcined brewing gas (27 mL, ΐ82· 5 _υ ' Reaction for 2 hours. Add 1 Torr of this water, use dichloro

Aromatic extraction (1GQmLx3), combined with organic phase 1 anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title product 2_[[5_[(t-butyldiphenylsinyl)oxymethyl]-2 , 3-dihydro benzoate and ketone + yl]-(3_ gasophenyl)methoxy]hydic acid to 22g (1() g, yellow oil), the product was taken to the next step without purification reaction. MS in/z (ESI): 669 [M+18] Step 7 [7-[2-azidoethyl-(3-carbophenyl)methyl]_2 3_dihydrobenzofuran-5- Methoxy]t-butyldiphenyl decane. The crude 2-[[5-[(t-butyldiphenyl)methoxymethyl] φ 2,3-dihydrobenzofuran _7-yl]_(3_ phenylene) decyloxy] decane sulfonate ethyl ester 22g (628 mg, 0.97 ramol) was dissolved in 2 〇mL N,N-dimercapto kinetic amine, added Sodium azide (189 mg, 2.9 mmol), 5 (TC reaction for 12 hours. Add 20 mL of water 'extracted with ethyl acetate (2 〇mL×3), combined organic phase dried over anhydrous sodium sulfate, filtered and filtered. Concentration, the residue obtained was purified by eluent column chromatography eluting to elute to afford the title product [7-[2-azidoethyl-(3-chlorophenyl)methyl]-2, 3- Hydroxybenzofuran-5-yl]decyloxy-t-butyldiphenylnonane 22h (551 mg, colorless oil), yield: 95. 5%. 95392 142 201242594 Step 8 2-[[ 5-[(Tertiary butyldiphenylfluorenyl)oxyindenyl]-2,3-dihydrobenzofuran-7-yl]-(3-carbophenyl)methoxy]ethylamine [7-[2-azidoethyl-(3-chloro) Phenyl) indenyl]-2,3-dihydrobenzoc--5-yl]nonyloxy-t-butyldiphenylnonane 22h (551 mg, 〇.92 ramol) dissolved in 21 mL of four Add triphenylphosphine (968 mg, 3.69 mmol) to a mixture of furfuran and water (V/V = 20:1) and allow to react for 12 hours. Add 20 mL of water and extract with ethyl acetate (20 mL×3) The product phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give the crude title product 2-[[5-[(t-butyldiphenyl-decyl)oxyindenyl]-2 , 3-dihydrobenzopyran-7-yl]-(3-carbophenyl)methoxy]ethylamine 22 j (500 mg, mp. Nine steps N-[2-[[5-[(t-butyldiphenylfluorenyl)oxyindenyl]_2, 3-dihydro cum-furan-7-yl]- (3- gas Benzyl) decyloxy]ethyl]amino decanoic acid decyl ester, the crude 2-[[5-[(t-butyldiphenylfluorenyl)oxyindenyl]-2, 3 -Dihydrobenzofuran-7-yl]-(3-chlorophenyl)methoxy]ethylamine 22j (527 mg, 0.92 mmol) was dissolved in 20 mL of dioxane, followed by diethylamine ( 1 .28 mL, 9.2 mmol, and 4-diamine. The reaction was stirred for 1 minute, and the methyl formate (0.36 mL' 4·61 mmol) was added dropwise, and the reaction was further stirred for 2 hours. Add 2 Torr of water, and extract with ethyl acetate (20 mL×3). The organic phase is combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure and purified by column chromatography with 95392 143 201242594. Residue' gave the title product n-[2-[[5-[(t-butyldiphenylindolyl)oxyindenyl]-2,3-dihydrobenzofuran-7-yl]-(3- Chlorophenyl) methoxy]ethyl] carbamic acid oxime ester 22k (409 mg, colorless oil), yield: 70. Step 10 N-[2-[(3-Chlorophenyl)-[5-(hydroxyindenyl)-2,3-dihydrobenzofuran-7-yl]nonyloxy]ethyl]amino Ethyl formate will be N-[2-[[5-[(t-butyldiphenylfluorenyl)oxyindenyl]_2,3-® dihydrobenzofuran-7-yl]-(3- gas Benzyl)nonyl]ethyl]amino decanoate 22k (409 mg, 0.65 mmol) was dissolved in 1 mL of THF, and tetrabutylammonium fluoride (308 mg, EtOAc. The reaction was stirred for 12 hours. After adding 10 mL of water, extracting with ethyl acetate (1 mL mL), the organic phase was combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system A. The crude title product N-[2-[(3-carbophenyl)-[5-(p-carbyl)-2,3-diphilehydrobenzofuran-7-yl]nonyloxy]ethyl Methyl amino decanoate 22 m (254 mg, colorless oil). The eleventh step N-[2-[(3-chlorophenyl)-[5-methyl-l-yl-2,3-dihydro cumin-5-yl] methoxy]ethyl]amino曱 曱 曱 干 干 干 ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' 25 mmol) 'Stirring reaction for 1 hour' Slowly add 5 mL of crude N-[2-[(3-carbophenyl)-[5-(transmethyl)-2,3-dihydrobenzopyran -7-yl] 95392 144 201242594 methoxy]ethyl]amino decyl decanoate 22m (223 mg, 0.57 mmol) in dioxane, stirring was continued for 1 hour, then triethylamine (0.79 mL, 5. 7 mmol), the reaction was carried out for 0.5 hours, and the reaction was stirred at room temperature for 0.5 hours. After adding 15 mL of water, the mixture was extracted with chloroform (1 mL mL). -[5-furfural-2,3-dihydrobenzofuran-7-yl]nonyloxy]ethyl]amino decanoate 22η (276 mg, colorless oil), product Purification proceeds directly to the next reaction. ® Twelfth Step 7-[(3-Chlorophenyl)-[2-(methoxyantimonylamido)ethoxy]indolyl]- 2,3-dihydrobenzopyrene β South-5 - formic acid to crude Ν-[2-[(3-carbophenyl)-[5-nonylaldehyde-2,3-dihydrobenzofuran-7-yl]nonyloxy]ethyl]aminocarboxylic acid Methyl ester 22η (276 mg, 0.71 mmol) was dissolved in 10 mL of acetonitrile, followed by 5 mL of sodium dihydrogen phosphate (863 mg, 5.53 mmol) and 5 mL of sodium hypochlorite (286 mg, 3. 16 φ then 1〇1) solution and 〇. 1 mL of hydrogen peroxide, stir the reaction for 12 hours. After adding 10 mL of water, the mixture was extracted with ethyl acetate (10 mL×3), EtOAcjjjjjjjjjj Aminooxy)amino)ethoxy]methyl]-2,3-dihydrobenzofuran-5-decanoic acid 22p (220 mg, mp. Thirteen steps Ν-[2-[[5-[[(15.)-1-[(t-butoxycarbonylmethylamino)] yl)]-2-cyclohexyl-ethyl]amino hydrazine Base]-2,3-dihydrobenzofuran-7-yl] 145 95392 201242594 -(3-Chlorophenyl)methoxy]ethyl]decanoate methyl ester under ice bath, crude 7-[( 3-chlorophenyl)-[2-(methoxyantimonylamido)ethoxy]indolyl]-2,3-dihydrobenzofuran "5-carboxylic acid 22p (100 mg, 0 · 25 mmol Dissolved in 10 mL of N, N-dimethyl decylamine, followed by the addition of Ν-[(25.)-2-amino-3-cyclohexyl-propyl]-N-mercapto-amino decanoic acid Third butyl ester lg (67 mg, 0.25 mmol), 1-hydroxybenzotriazole (67 mg, 0.45 mmol) and 1-(3-diaminopropyl)-3-ethyl carbon Diimine hydrochloride (95 mg, 0.49 mmol), added diisopropyl Ethylamine (0.17 mL, 0.94 ® mm 〇l) 'Stirring reaction for 12 hours at room temperature. Add 20 mL of water and extract with dioxane (10 mL×3). Combine the organic phase, dry over anhydrous sodium sulfate, filter, filtrate Concentration by pressure, the residue obtained was purified by eluent column chromatography using eluent system B to give the title product [(t-butoxycarbonyl decylamino) decyl]-2-cyclohexyl-ethyl]amine Methyl hydrazino]-2,3-dibenzopyrano-7-yl]-(3-chlorophenyl)decyloxy]ethyl]decanoate 22q (1 〇〇mg, colorless oil Yield: 61.6%. φ MS m/z (ESI): 658 [M+l] Step 14 N - [2-[(3-chlorophenyl)-[5-[[ (l«-(cyclohexyldecyl)-2-mercaptoamino-ethyl]aminoindenyl]-2,3-dihydroindolofuran-7-yl]-decyloxy]ethyl] Decyl citrate

N-[2-[[5-[[(l«-l-[(t-butoxycarbonyldecylamino)indolyl]-2-cyclohexyl-ethyl]amino) hydrazine under ice bath Methyl 2-(3-dihydrobenzofuran-7-yl]-(3-carbophenyl)methoxy]ethyl]carboxylic acid methyl ester 22 (1 (120 mg, 〇. 18 mmol) Dissolve in 4 mL of dichloromethane, add 6 mL of 95392 146 201242594 dioxoacetic acid and di-methane (V/V 2:1) mixed solution, stir the reaction for 1 hour. Add saturated hydrogen carbonate under ice bath. The sodium solution was adjusted to pH 8, and extracted with methylene chloride (1 mL mL). The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and purified by eluent column chromatography with eluent system B. The residue obtained gave the title product n-[2-[(3-carbophenyl)-[5-[[(1)-(cyclohexylfluorenyl)- 2 -nonylamino-ethyl]amine曱醯]] 2,3-dihydrobenzofuran-7-yl]-decyloxy]ethyl]decanoate 22 (15 mg, white solid), yield: 14.7%. m/z (ESI): 558 [M+l] Ή NMR (400 MHz, CDCh): 57. 91-7. 16 (m, 6H), 5. 50 (m, 1H), 4.60 (m, 2H) , 3.63 (s, 3H), 3.58-3.35 (m, 4H), 3.04-3.01 (m, 1H), 2.65 (s, 3H), 1.78-0.83 (m, 15H) Example 23 1^-[2-[(3-chlorophenyl)-[5-[[(151)-1-(cyclohexylmethyl))) Amino-ethyl]aminoindenyl]-3,4-dihydro-2 in benzopyranyl]-

曱oxy]ethyl]formic acid

95392 147 201242594

Oh,

Step 10

Step 12

4 The first step of 5~ allyloxybenzene-1,3-dicarboxylic acid dinonyl ester will be 5-phenyl-p-1,3-1,3-dicarboxylic acid dimethyl ester lh (8 4 〇g, 4 〇 in 80 mL of _ _ , followed by the addition of dilute propyl (7. 5 rainbow, 88_u and stone acid reflux (12. 40 g, 92 _l), 7 "c stirred reaction for 3 hours, 5 〇〇 c continued reaction for 12 hours. The product was concentrated under reduced pressure to give the crude titled product 5--propoxy-m-di-di-di-di- </ </ </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Dissolving the crude 5-allenyloxy-i,3-dicarboxylic acid dinonyl ester 23b (10 g, 40 mmol) in 50 with allyl-5-trans-p-1,3-1,3-dicarboxylic acid dinonyl ester In mL N,N-diethylaniline, stir the reaction at 220 ° C for 5 hours. Add 40 mL of saturated sodium bicarbonate solution and 160 mL of water at room temperature, wash with petroleum ether (150 mL×3), and adjust the aqueous phase with 6 Μ hydrochloric acid. The pH was 4 148 95392 201242594 to 5, solid precipitated, filtered, and the filter cake was dried in vacuo to give the crude title product 4-allyl-5-hydroxy-benzene-1,3-didecanoate dimethyl ester 23c (7. 00 g, yellow oil), the product was taken directly without purification Reaction Ή NMR (400 MHz , CDCh) : δ 8. 12 (d, 1Η), 7. 67 (d, 1H, /=4 Hz), 6.03 (m, 1H), 5.14-5.09 (m, 2H) , 3.93 (s, 3H), 3.92 (s, 3H), 3.83 (d, /= 8.0 Hz, 2H) The third step is 5-hydroxy-4-(3-hydroxypropyl)benzene-1,3-dioxin The crude diphenyl sulfonate was dissolved in 60 mL of tetrahydrofuran by dissolving the crude 4-phenylpropionate-5-yl-benzo-1,3-didecanoate 23c (3.50 g, 14 mmol). Add THF to tetrahydrogenate solution (28 mL, 28 mmol), stir the reaction for 5 hours, add 60 mL of saturated sodium bicarbonate solution and 7 mL of hydrogen peroxide, and continue to stir the reaction for 12 hours. Add 60 mL of saturation. The chlorinated solution was concentrated under reduced pressure, and the aqueous phase was extracted with ethyl acetate (100 niLx3). The organic phase was combined and washed with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified eluting with eluent column chromatography to afford the title product 5-hydroxy-4-(3-hydroxypropyl)benzene-1,3-didecanoic acid Methyl ester 23d (3. 20 g, white solid), yield: 85.1%. Step 4. 3, 4-dihydro-2 and -benzopyran-5 , 7-dicarboxylic acid dinonyl ester, 5-hydroxy-4-(3-hydroxypropyl)benzene-1,3-didecanoic acid dinonyl ester 23d (1. 30 g, 4.85 mmol) dissolved in 25 mL In the second-degree smoldering, azobisindole acid (1.27 g, 7.28 mmol) and triphenylphosphine (1.90 g, 149 95392 201242594 7.28 mmol) were added in sequence to stir the reaction for 12 hours. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc)EtOAc. Chromatography to purify the residue obtained from eluent system A to give the title product 3, 4-dihydro-2 and benzopyran-5,7-didecanoate 23e (0.98, white solid). Yield: 81.7%. Step 5 7-Methoxycarbonyl-3,4-dihydro-2#-benzopyran-5-decanoic acid and 5-decyloxy® carbonyl-3,4-dihydro-2 and-benzo Pyran-7-decanoic acid 3,4-Dihydro-2 and benzopyran-5,7-dicarboxylic acid dimethyl ester 23e (1.30 g, 5.2 mmol) were dissolved in 2.5 mL of methanol, and hydrogen was added. Sodium oxide (〇. 21 g, 5.2 mmol) was stirred at 75 ° C for 8 hours. The reaction solution is concentrated under reduced pressure. Add 20 mL of water and 30 mL of di-methane, add 1 Μ hydrochloric acid, adjust the pH to 3 to 4', and extract the aqueous phase with dichlorohydrazine (20 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. Carbonyl-3,4-dihydro-2 and-benzopyran-7-decanoic acid 23 g (1. 15 g, yellow oil). The sixth step is 5-hydroxyindolyl-3,4-dihydro-2 and-benzopyran-7-carboxylic acid, and the 7-hydroxyindenyl-3,4-dihydro-2F-benzopyran -5-methyl decanoate under ice bath' crude 7-methoxycarbonyl-3,4-dihydro-2pi-p-pyran-5-carboxylic acid 23f and 5-decyloxycarbonyl-3, 4 -Dihydro-2 polybenzopyran 150 95392 201242594 -7-decanoic acid 23g (1.15 g, 4.88 mmol) dissolved in 75 mL of tetrahydro 0 flu, 1 M shed (1. 3 mL) , 7·3 mmol) of tetrahydrofuran solution, and reacted at 50 ° C for 12 hours. Add 2 mL of methanol, mix for 1 minute, concentrate under reduced pressure, add 30 mL of ethyl acetate, and wash the organic phase with 30% cesium carbonate solution (20 mL), 1 Μ hydrochloric acid (20 mL) and saturated sodium hydrogen carbonate solution. (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by eluent column chromatography to afford the title product 5--methylmethyl-3,4- Dihydro-2 and -benzone-pyrano-7-formic acid formazan 23h ® (195 mg, white solid), yield: 18.1%, and 7-hydroxymethyl-3,4-dihydro- 2和-benzopyran-5-carboxylic acid oxime ester 23i (500 mg, white solid), Yield: 46.3%.沱NMR (400 MHz, CDC13): δ 7. 52 (s, 1H), 7· 03 (s, 1H), 4. 68 (d,7&quot; = 5· 6 Hz, 2Η), 4. 22 (t , / = 4. 8 Hz, 2Η) 3. 92 (s, 3H), 3. 13 (t, /= 6.8 Hz, 2H), 2. 03 (m, 2H) Step 7 φ 7_furfural —3,4-Dihydro-2f benzopyran-5-carboxylic acid methyl ester 7-Hydroxymethyl- 3,4-dihydro-2 and-benzopyranium methyl ester 23i (500?' 2.25 Methyl acetate was dissolved in 15 mL of dichloromethane, and sodium acetate (460 mg, 6.75 mmol) and pyridine chlorochromate rust salt (1. 45 g, 6.75 mmol) were sequentially added, and the reaction was stirred for 12 hours. The reaction mixture was dried over EtOAc, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system A to give the title product 7-furfural-3, 4-dihydro-2 in benzene. 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。. The eighth step 95392 151 201242594 7-[(3-Chlorophenyl)-hydroxy-methyl]-3, 4-dihydro-2 and -benzopyrene than methyl _5_carboxylic acid methyl ester under ice bath, will be 7 -Methylformaldehyde-3,4-dihydro-2f benzopyran-5-carboxylic acid methyl ester 23j (430 mg, 1.95 mmol) was dissolved in 6 mL of tetrahydrofuran, and 1.0 Torr of 3-gas was added dropwise. 5小时。 The reaction was stirred at room temperature for 0.5 hours. Add 20 mL of saturated sodium bicarbonate solution, extract with ethyl acetate (20 mL×3), and the organic phase is combined, washed with saturated sodium sulfate solution (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated. Column chromatography Chromatography of the obtained residue to afford the title product 7-[(3-chlorophenyl)-hydroxy-methyl]-3, 4-dihydro-2 and benzopyran 5% carboxymethyl ester 23k (570 mg, pale yellow oil), yield: 88.1%. The ninth step 7-[(3-chlorophenyl)-[2-(decyloxycarbonylamino)ethoxy]methyl]_3,4-dihydrobenzopyran-5-decanoate will be 7 -[(3-Chlorophenyl)-hydroxy-methyl]_3, 4-dihydro-2 and benzopyran-pyran-5-decanoate 23k (57〇mg, 1.77 mmol) dissolved in 30 mL In the benzene, N-(2-hydroxyethyl)amino decanoate. lt (212 mg, 1.77 mmol) and p-sulfonic acid (338 mg, 177 mm 〇1) were added in sequence, and the reaction was stirred under reflux. . 5 hours. The reaction mixture was concentrated under reduced pressure, and then purified tolulujjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj曱 卜 3 3,4 1-2 Hydrogen 2 and _benzopyran-5-carboxylic acid methyl ester 23 m (300 mg, colorless oil), yield: 40.4%. Step 10 152 95392 201242594 7-[(3-Chlorophenyl)-[2-(decyloxycarbonylamino)ethoxy]indolyl]-3,4_dihydro-2 and -benzone-5 - citric acid 7-[(3-phenylphenyl)-[2-(decyloxycarbonylamino)ethoxy]indolyl] -3,4-dihydro-2 to benzopyran-5- Methyl decanoate 23 m (300 mg, 0.69 mmol) was dissolved in 1 mL of methanol, potassium hydroxide (81 mg, 1.41 mmol) was added, and the reaction was stirred at 50 ° C for 12 hours. Add 1 mL of water, add 1 Μ hydrochloric acid to adjust the pH to 3 to 4, extract with methylene chloride (1 mL mL), combine the organic phases, dry over anhydrous sodium sulfate, 7-[(3-Phenylphenyl)-[2-(decyloxycarbonylamino)ethoxy]methyl]-3,4-dihydro-2 and-benzopyran-5-carboxylic acid 23η ( 185 mg, light yellow solid), yield: 64. 0%. Eleventh step N-tert-butoxycarbonyl-decylamino)methyl]-2-cyclohexyl-ethyl]aminocarbamimidyl]- 3,4-dihydro-2 and-benzopyran -7-yl]-(3-.chlorophenyl)methoxy]ethyl]decanoate φ ester 7-[(3-chlorophenyl)-[2-(decyloxy) under ice bath Carbonylamino)ethoxy]indolyl]-3,4-dihydro-2F benzopyran-5-decanoic acid 23n (85 mg, 0.2 mmol) was dissolved in 4 mL of N,N-dimercaptopurine In the amine, N-[(2«-2-amino-3-cyclohexyl-propyl]-N-methyl-carbamic acid tert-butyl ester lg (70 mg, 0.26 mmol), 1- Benzotriazine (54 mg, 0.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (76 mg, 0.4 mmol), diisopropyl Ethylamine (〇. 14 mL, 0.8 mmol), the reaction was stirred at room temperature for 18 hr. The reaction was concentrated under reduced pressure, and 20 mL of dioxane' organic phase was washed with water (20 mL) and sat. </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 1-[(t-butoxycarbonyl) Mercaptoamino)methyl]_2-cyclohexyl-ethyl]aminoindenyl]-3,4-dihydro-2-indole-benzopyran-7-yl]-(3-chlorophenyl) Methyl methoxy]ethyl] decanoate 23p (82 mg, yellow oil), yield: 60.3% MS m/z (ESI): 674 [M+l] Step 12® N-[ 2-[(3-Chlorophenyl)-[5-[[(150-(cyclohexylmethyl)- 2-methylamino-ethyl]amino] aryl]-3, 4- Dihydro-2 and -benzo-p-pyran-7-yl]-decyloxy]ethyl]decanoate decyl ester under ice bath, Ν-[2-[[5-[[(15·)-ΐ -[(Tertibutoxycarbonyldecylamino)indenyl]-2-cyclohexyl-ethyl]aminoindenyl]_3,4_dihydro-2#·benzo-pyran-7- ]]-(3-chlorophenyl)methoxy]ethyl]decanoic acid vinegar 23ρ (80 mg' 0. 12 mmol) was dissolved in 4 mL of dioxane, and 6 • mL of trifluoroacetic acid was added dropwise. Mixture with dichloromethane (V/V = 2:1), stir the reaction for 1.2 hours, add saturated sodium bicarbonate solution, adjust pH to 8, extract with dioxane (10 mL×3), combine organic The phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Product N-[2-[(3-Chlorophenyl)-[5_[[(1ι9) *~1-(cyclohexylfluorenyl)-2-mercaptoamino-ethyl]aminocarbinyl) _3, 4_Dihydro-2 and - benzopyran-7-yl]-decyloxy]ethyl]carboxylic acid methyl ester 23 (25 mg, white solid), yield: 36.8%. MS m/z (ESI): 572 [M+l] 95392 154 201242594 'H NMR (400 MHz, CDCla): δ 7. 67-7. 13 (m, 6H), 6. 72 (m, 1H), 5.76(^r. s, 1H), 5. 29 and 5. 23 (s, 1H), 4. 57 (^r. s, 1H), 4. 17 (m, 2H), 3. 66 and 3. 63 (s, 3H), 3.50-2.80 (m, 7H), 2.75-2.67 (m, 3H), 2.06-0.88 (ra, 15H) Example 24 N-[2-[(3-Phenylphenyl M4) -[[(l-phenan-1-(cyclohexylmethyl)-2-methylamino-ethyl]aminoindolyl]- 2,3-dihydro benzofuran-6-yl] decyloxy Ethyl]carboxylic acid decyl ester

The first step is 2-hydroxy-2,3-dihydrobenzofuran-4,6-dicarboxylic acid dinonyl ester. Under dry ice bath, 4-allyl-5-hydroxy-benzene-1,3-dicarboxylic acid曱155 95392 201242594 Ester 23c (3·50 g, 14 mmol) was dissolved in 60 mL of ethyl acetate. Ozone was added for 5 hours, air was bubbled for 2 hours, and triphenylphenyl phosphate (3. 70 g, 14 mmol) was added. The reaction was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and then purified, m.j. 24% (1. 70 g, pale yellow solid), yield: 48.6%. !H NMR (400 MHz , CDCh) : δ 8. 27 (s, 1Η), 7. 65 (s, 1H), 6.20 (m, 1H), 3. 94(s, 6H), 3.68 (dd, / = 8.0 Hz, 20.0 • Hz, 1H), 3.51 (dd, / = 4.0 Hz, 16.0 Hz, 1H) Step 2 2, 3-Dihydrobenzofuran-4,6-dicarboxylic acid dimethyl ester 2- Hydroxy-2,3-dihydrobenzofuran-4,6-dioxalate dinonyl ester 24a (1.70 g, 6.7 mmol) was dissolved in 10 mL of formic acid, and the reaction was stirred at 100 ° C for 5 hours. The reaction was further stirred at 50 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj White solid), the product was directly subjected to the next reaction without purification. In the third step, the crude product was dissolved in 80 mL of ethyl acetate, and palladium on carbon (400 mg, was added to the crude dibenzofuran-4,6-didecanoate 24b (1. 56 g, 6.6 _〇1). 10%), hydrogen was replaced three times, 5 (TC was stirred for 12 hours. The reaction solution was filtered, the filter cake was washed with 50 mL of methanol, and the filtrate was concentrated under reduced pressure to give the title product 2, 3-dihydrobenzopyran-4. 6-didecanoate 24c (1.50 g, white solid), Yield: 93.7%. 156 95392 201242594 Ή NMR (400 MHz, CDCh): δ 8. 25 (d, J = 1.2 Hz , 1H), 7. 61 (d, /=1. 6 Hz, 1H), 4. 71 (t, /= 8. 8 Hz, 2H), 3. 97 and 3.96 (2 s, 6H), 3.64 ( t, 7 = 8. 8 Hz, 2H) The fourth step 6_methoxy benzyl-2, 3-di-benzobenzoin-4-carboxylic acid and methoxy-n-yl-2, 3_-gas benzo Alpha-furancarboxylic acid 2,3-dihydrobenzofol-4,6-dioxalic acid dimethyl vinegar 24c (1. 50 g 6.3 mmol) was dissolved in 3·2 mL of sterol, sodium hydroxide was added (〇25 g, ® 6. 3 mmol), stir the reaction for 8 hours under reflux. The reaction solution was concentrated under reduced pressure, and then added with 20 mL of water, and the pH was adjusted to 3 to 4, and the aqueous phase was extracted with dichloromethane. 20 mLx3), combined with organic phase, with no Drying over sodium sulfate, filtration, and EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Dihydrobenzofuran-6-decanoic acid 24e (1.32 g, yellow oil), the product was taken to the next step without purification. </ br> Step 5 4-(Methyl) 2,3- azobenzene Bite 6-decanoic acid vinegar and 6_(sulfenyl) 2,3-diazabenzofuran-4-indole hydrazine. The crude 6-decyloxycarbonyl-2 , 3-dihydrobenzofuran-4-methyl 24d and 4-decyloxycarbonyl-2,3-dihydrofurfuran-6-decanoic acid 24e (1.50 g, 5.85 mmol) dissolved in 9 mL of tetrahydrogen Add a side-burning tetrahydrofuran solution (8.8 mL, 8.8匪〇1), and stir the reaction for 24 hours at 50 ° C. Add 2 mL of methanol, stir for 1 min, concentrate under reduced pressure, add 3〇11^ acetic acid The ester and organic phase were washed with 30% potassium carbonate solution (20 mL), 1 Μ hydrochloric acid 157 95392 201242594 (20 mL) and saturated sodium bicarbonate solution (2 mL) and saturated sodium carbonate solution (20 mL). Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified with EtOAc EtOAc (EtOAc: EtOAc: 24. 6%. 4%, and 6-(hydroxymethyl)-2,3-dihydrobenzofuran-4-furic acid decyl ester 24 g (310 mg, white solid). !OMR (400 MHz, CDC10: δ 7. 49 (s, 1H), 6. 98 (s, 1H), • 4. 67 (d, J = 4.4 Hz, 2H), 4. 62 (t, / = 8. 8 Hz, 2H), 3. 90 s, 3H), 3. 52 (t, / = 8. 8 Hz, 2H), 1. 60 (dr. s, 1H) Step 6 6-Formaldehyde- 2,3-Dihydrobenzofuran-4-indole oxime ester 6-(hydroxymethyl)-2,3-dihydrobenzofuran-4-carboxylic acid methyl ester 24 g (310 mg, 1.49 mmol) was dissolved in Sodium acetate (367 mg, 4.47 mmol) and pyridine chlorochromate rust salt (960 mg, 4.47 mmol) were sequentially added to 15 mL of dioxane, and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjj , white solid), yield: 79.8%. Step 7 6-[(3-Chlorophenyl)-hydroxy-indolyl]-2,3-dihydrobenzofuran-4-carboxylic acid methyl ester, 6-formaldehyde-2, 3-di Methyl hydrobenzofuran-4-carboxylate 158 95392 201242594 24h (245 mg, 1.19 mmol) was dissolved in 4 mL of tetrahydrofuran, and 1·〇M 3-pyrylmethane bromide (丨.8 mL) was added dropwise. , 丨. 8 mmol), stir the reaction 〇. 5 hours. Add 20 mL of water, extract with ethyl acetate (20 mL×3), combine the organic phase, wash with saturated sodium carbonate solution (2 〇mL), dry over anhydrous sodium sulfate, filter the filtrate and concentrate under reduced pressure. The obtained residue was purified with eluent A to give the title product 6-[(3-chlorophenyl)-hydroxyindolyl]-2, 3-- benzopyran-4-carboxylic acid methylacetate 24i (350 mg, Light yellow oil), Yield: 92.6%. ® Step 8 6-[(3-Chlorophenyl)-[2-(decyloxycarbonylamino)ethoxy]indolyl]-2, 3-yl-pyrene and π-fuca Dissolve 6-[(3-chlorophenyl)-hydroxy-indenyl]_2,3-dihydrobenzofuran-4-carboxylic acid oxime ester 24i (350 mg, 1.1 mmol) in 30 mL of hydrazine. N-(2-hydroxyethyl)carbamic acid decyl ester it (131 mg, 1.1 mmol) and p-behenic acid (209 mg, 1.1 mmol) were added successively, and the reaction was refluxed for φ 丨·5 hours. . The reaction mixture was concentrated under reduced pressure, and then purified and purified to the titled product to afford the title product 6-[(3-phenylphenyl)-[2-(decyloxycarbonylamino) ethoxylate. Methyl]2,3-dihydrobenzofuran-4-carboxylic acid methyl ester 24j (220 mg, colorless oil), yield: 47.7%. MS m/z (ESI): 2385-85.H NMR (400 MHz, CDCh): δ 7. 37 (d, / = 4. 0 Hz, 1H), 7. 31 (m, 2H), 7. 18 (m, 1H), 7. 12 (in, 1H), 6. 76 (s, 1H), 6.29 (s, 1H), 4.64 (t, / = 8. 0 Hz, 2H), 4.38 (t, / = 8.0 Hz, 8.0 Hz, 2H), 3.89 (s, 3H), 3.55 (t, / = 8.0 159 95392 201242594

Hz, 2H), 3. 93 (t, / = 6.0 Hz, 2H) ninth step 6-[(3-phenylphenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl] -2,3-dihydro benzofuran-4-carboxylic acid 6-[(3-chlorophenyl)-[2-(nonyloxycarbonylamino)ethoxy]methyl]-2,3-di Benzene hydrazine 曱 曱 曱 曱 24 24 24 24 (220 mg, 0. 53 mmol) dissolved in 1 mL of sterol, added potassium hydroxide (59 mg, 1.05 mmol), stirred at 50 ° C for 12 hours . Add l 〇 mL of water, add 1 Μ hydrochloric acid to adjust the pH to 3 to 4, extract with dichloromethane (1 〇 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, The product 6-[(3-chlorophenyl)-[2-(decyloxycarbonylamino)ethoxy]methyl]_2,3-dihydrobenzopyran-4-indole 24k (195 mg, Light yellow solid), Yield: 92. 0 〇 / 〇. Step 10 N-[C25V2-[[6-[(3-Phenylphenyl)-[2-(methoxycarbonylamino)ethoxyphenoxy] yl]-2, dihydrobenzofuran-4 -carbonyl]amino]-3-cyclohexyl-propyl]-N-indolyl-aminocarbamic acid tert-butyl ester under ice bath '6-[(3-gasto)-[2-(methoxy) Alkylcarbonylamino)ethoxy]indolyl]-2,3-dihydrobenzofuran_4_decanoic acid 24k (81 mg, 0.2 mmol) was dissolved in 4 mL of N,N-didecylamine , followed by the addition of N-[(2«-2-amino-3-cyclohexyl-propyl)-N-decyl-amine decanoic acid terpene vinegar lg (70 mg' 0.26 _〇1), hydroxybenzene Triazole (54 mg, 0.4 mmol) and 1-(3-diamidinopropyl)_3_ethylcarbodiimide hydrochloride (76 mg, 0.4 ramol) ' dropwise addition of diisopropylethylamine (〇. 14 mL, 0.8 mm 〇i), 160 95392 201242594 The reaction was stirred at room temperature for 18 hours. The reaction was concentrated under reduced pressure, then 20 mL dichloromethane was added and the organic phase was washed with water (20 mL) and sat. 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjj 3-chlorophenyl)- [2-(decyloxyamino)ethoxy]indolyl]-2,3-dihydrobenzoindole-4-yl]amino]-3-cyclohexyl-propyl]-N - mercapto-amino decanoic acid tert-butyl S. 24m (67 mg, colorless oil), yield: 51. 1%. • MS m/z (ESI): 658 [M+l] Step N-[2-[(3-Phenylphenyl)-[4-[ [(15)-1-(cyclohexylmethyl)-2-indolylamino-ethyl]amino]] -2,3-Dihydrobenzobenzopyran-6-yl]nonyloxy]ethyl]decanoic acid methyl hydrazine under the ice bath, gas phenyl)-[2-(decyloxyamino) Ethoxy]methyl]-2,3-dihydro cumin π 克 _4 _ yl] amide group] cyclohexyl-propyl]-N-methyl-amino decanoic acid tert-butyl ester 24m (67 mg, 0. 10 mmol) was dissolved in 6 mL of dichloromethane, and a mixed solution of 6 mL of trifluoroacetic acid and a gas-burning (V/V = 2 · 1) was added dropwise, and the reaction was disturbed for 12 hours. Saturated sodium bicarbonate solution was added dropwise, the pH was adjusted to 8, and the mixture was extracted with a gas mixture (10 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified to give the titled product N-[2-[(3-carbophenyl) (cyclohexyl) Methyl)-2-mercaptoamino-ethyl]aminocarbamimidyl] 2,3-dihydrobenzofuran-6-yl]nonyloxy]ethyl]carboxylic acid methyl ester 24 (5 〇 mg, White 95392 161 201242594 solid), yield: 80.0%. MS m/z (ESI): 558 [M+l]^ NMR (400 MHz, CDCh): δ 7. 76-6. 66 (m, 7H), 5. 82 and 5. 75 (2 s, 1H) , 5. 30 and 5. 25 (2 s, 1H), 4. 54 (m, 3H), 3.71-3.01 (m, 12H), 2.65 (s, 3H), 1.75-0.84 (m, 13H) 25 N-[ 2-[(3-Phenylphenyl)-[7-[[(151)-1-(cyclohexyldecyl)-2-methylamino-ethyl]aminocarbamoyl] -3,4-dihydro-2 and -benzopyran-5-yl.]-decyloxy]ethyl]decanoate

Step 1 5-Mercapto-3,4-dihydro-2-benzopyran-7-decanoic acid methyl ester. Dissolve diterpenoids (194 mg, 2.63 mmol) in a dry ice bath. 5 mL of dioxane, oxaloquinone chloride (334 mg, 2·63 匪ol) was added dropwise under argon atmosphere, and the reaction was stirred for 40 minutes, and 5 mL of 5_hydroxyindenyl group was added dropwise _3, 41-2162 95392 201242594 Nitrogen-2H-benzopyrene~7__carboxylic acid oxime ester 23h (195 mg, 〇88 〇1) in a solution of dichloromethane. Continue stirring for 1 hour, add 1.5 mL of triethylamine, and allow to room temperature. The reaction was carried out for 0.5 hours. The reaction solution was filtered, and the filter cake was concentrated under reduced pressure with 5 mL of dichloromethane, and the residue was purified by eluent column column chromatography to afford the title product 5_furfural. 3,4-dihydro-2H-benzopyran-7, methyl decanoate 25a (125 g, white solid), yield: 64.8%. 4 NMR (400 MHz, CDC13): δ 10. 15 (s, 1H), 8. 01 (s, 1H), • 7.69 (s, 1H), 4.23 (t, / = 8. 0 Hz, 2H), 3.94 (s, 3H), 3.24 (t, /= 8.0 Hz, 2H), 2.05 (in, 2H) Step 2 5-[(3-Phenylphenyl)-hydroxyl-methyl]_34_dihydro_2 And 5-benzoyl-3,4-dihydro-2H- benzopyran-7-decanoic acid vinegar 25a (125 mg, 〇.) under an ice bath of monobenzopyran _7_ decanoic acid vinegar. 5小时。 The reaction was stirred for 0.5 hours. The reaction was stirred for 0.5 hours. Add 20 mL of saturated sodium bicarbonate solution, extract with ethyl acetate (20 mL×3), and the organic phase is combined, washed with saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, filtered, The residue obtained was purified by eluent column chromatography eluting with eluent system A to give the title product: 5-[(3-phenylphenyl)-hydroxy-indolyl]-3, 4-dihydro-2H-benzopyrrole-7 4%。 - benzoic acid ester 25b (150 mg, light yellow oil), yield: 79.4%. The third step is 5-[(3-chlorophenyl)-[2-(decyloxycarbonylamino)ethoxy]methyl]_3,4_ 95392 163 201242594 dihydro-2 and -benzo-pyrene 7-Oxanoic acid decyl ester 5-((3-phenylphenyl)-hydroxy-methyl]-3,4-dihydro-2Η-benzo-4-pyran-7-decanoic acid methyl ester 25b (150 mg, 0·45 mmol) was dissolved in 30 mL of toluene, followed by N-(2-hydroxyethyl)amino decyl decanoate (108 mg, 0.9 mmol) and p-toluenesulfonic acid (85 mg, 0. 45小时), the water separator reflux reaction for 1.5 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjj Methyl]_3,4-dihydro- 2h-benzo-pyranyl-pyran-7-carboxylic acid methyl ester 25c (100 mg, colorless oil), yield: 51.3%. Step 4 5-[(3-Chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]_3,4_dihydro-2 and-benzopyran-7-decanoic acid 5-[(3-Phenylphenyl)-[2-(decyloxycarbonylamino)ethoxy]indolyl]-3,4-dihydro-2H-benzopyran-7-decanoate Ester 25c (100 mg, 0.23 ginseng 1) was dissolved in 1 mL of decyl alcohol, potassium hydroxide (26 mg, 0.46 mmol) was added, and 5 (TC was stirred for 12 hours. 1 mL of water was added and 1 滴 was added dropwise. Hydrochloric acid was adjusted to pH 3 to 4, and extracted with dichloromethane (1 mL mL). The organic phase was combined and dried over anhydrous sodium sulfate. -[2-(Methoxycarbonylamino)ethoxy]indolyl]-3,4-dihydro-2H-benzopyran-7-carboxylic acid 25d (98 mg, white solid) Purification proceeds directly to the next step. Step 5 -[[5-[(3-Chlorophenyl)-[2-(decyloxycarbonylamino)ethyl 164 95392 201242594 oxy]methyl]-3, 4 -Dihydro-2 and -benzopyran-7-carbonyl]-3-cyclohexyl-propyl]-N-methyl-carbamic acid tert-butyl ester under ice bath '5-[(3-chloro) Phenyl)-[2-(decyloxycarbonylamino)ethoxy]anthracene ]-3,4-Dihydro-2-benzopyran-7-decanoic acid 25d (98 mg, 0.23 mmol) was dissolved in 4 mL of N,N-didecylamine, and Ν-[ (25·)-2-Amino-3-cyclohexyl-propyl]-N-mercapto-amino decanoic acid Thirty-six 酉 1 g (82 mg, 0. 3 mmo 1) ' 1-Phenylbenzene And three β sitting (62 mg, 0. 46 _〇1) and diammonium propyl)-3-ethylcarbodiimide hydrochloride (88 mg, 0.46 mmo 1) ' Isopropylethylamine (〇. 2 mL, 0. 8 mmo 1) was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure. EtOAc (2 mL), EtOAc (EtOAc) (EtOAc) The residue obtained was purified by column chromatography eluting to afford the title product ν-[(25·)-2-[[5-[(3-chlorophenyl)-[ Ethyl]mercapto]-3,4-dihydro-2 and-benzopyrene ratio "Nan-7-yl"-3-cyclohexyl-propyl]-indole--methyl-amino group Cyanate citrate 25e (100 mg, white solid), yield: 64.9%. MS m/z (ESI): 672 [M+l] Step 6? '1-[2-[(3-Phenylphenyl)-[7-[[(151)-1-(cyclohexylmethyl) -2-methylamino-ethyl]amino aryl]]3,4-dihydro-2 and benzopyrano-5-yl]-methoxy]ethyl]decanoate Under ice bath, Ν-[(25·)-2-[ [5-[(3-carbophenyl)-[2-(methoxymethylamino)ethoxy]methyl]_3, 4-Dihydro-2 and -benzo.比喃-7-几165 95392 201242594 基]-3-Cyclohexyl-propyl]-N_decyl-aminocarbamic acid tert-butyl ester 25e (1〇〇mg' 0. 15 mmol) dissolved in 6 rainbow two In the gas-fired product, a mixed solution of 6 mL of trifluoroacetic acid and di-methane (V/V = 2: 丨) was added dropwise, and the reaction was stirred for 12 hours. Add saturated sodium bicarbonate solution, adjust {) 11 to 8, and extract with two methane (10 mL×3), combine the organic phase, dry with anhydrous sodium sulfate, and filter. The filtrate is concentrated under reduced pressure. The resulting residue was purified to give the title product N-[2-[(3-chlorophenyl(cyclohexylmethyl)-2-methylamino-ethyl]aminomethylmethyl]- 3, 4-dihydro^ _2 and ~ benzopyrano-5-yl]-decyloxy]ethyl] decanoic acid methyl ester 25 (38 mg, white solid), yield: 44. 7%. MS m / z (ESI) : 572 [M+l] !H NMR (400 MHz , CDCh) : δ 7. 90-7. 70 (m, 2H), 7. 40-7. 19 (ra, 7H), 5.80 ( 2 br. s, 1H), 5.37 (m, 1H), 4.62 (m, 1H), 4.09 (m, 2H), 3.66-3.03 (m, 9H), 2.70 (s, 3H), 2.55-2.49 (m , 2H), 1.98-0.86 (m, 15H) φ Example 26 N-[2-[(3-chlorophenyl)-[6-[[(l«-l-(cyclohexylfluorenyl)-2) -methylamino-ethyl]aminoindenyl]-2,3-difluorenylbenzo-methyl 4-methoxy]methoxy]ethyl]carboxylic acid methyl ester

166 95392 201242594

first step

4-mercapto-2, 3-dihydro benzofuran-6-carboxylic acid vinegar vinegar 4-(hydroxymethyl)-2,3-dihydrobenzofuran-6-decanoic acid decyl ester 24f (295 mg , 1.42 mmol) was dissolved in 20 mL of dichloromethane, and sodium acetate (270 mg, 4.25 mmol) and pyridinium chlorochromate (914 mg, 4.25 mmol) were sequentially added, and the reaction was stirred for 12 hours. The reaction solution was filtered, and the filtered cake was washed with 3 mL of dichloromethane, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography to afford the title product 4-mercapto-2,3- Dihydrobenzofuran-6-carboxylate 26a (240 mg, white solid), yield: 82.2%. The second step 4-[(3-phenylphenyl)-hydroxy-indolyl]-2,3-dihydrobenzofuran-6-decanoic acid decyl ester, 4-methylmercapto-2, 3 - Dihydrobenzofuran-6-decanoic acid decyl ester 26a (240 mg, 1. 16 mmol) was dissolved in 4 mL of tetrahydrofuran, and deuterated 3-oxophenylmagnesium bromide (1.8 mL, 18 〇) 1), stirring reaction 0. 5 hours ❶ adding 20 mL of saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (20 mL×3), the organic phase was combined, washed with saturated sodium chloride solution 95392 167 201242594 Γ, filtered, _ Concentration, using (4) == the agent "purification of the obtained residue to obtain the title product = two] 2,3 - dihydro cumin oxime + carboxylic acid hydrazine 2613 (315 呃, colorless oil), yield :85 4%. The third step 4-[(3-phenylphenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl]- 2 3 -1 benzoquinone-6- Calcium

4-[(3-Phenylphenyl)-hydroxy-indenyl]_2, 3_ two gas stupid and bite _6_ methyl formate 26b (315 mg, 0.99 mmol) dissolved in 3〇mL of benzene, in turn N-(2-hydroxyethyl)amino decanoate H (238 mg, 2 〇1) and p-toluenesulfonic acid (190 mg, 〇99 mm〇1) were added and refluxed for '12 hours. The reaction mixture was concentrated under reduced pressure, and the residue obtained was purified eluting from EtOAc EtOAc EtOAc EtOAc EtOAc Methyl]-2,3-dihydro benzofuran-6-carboxylic acid methyl ester 26c (280 mg, colorless oil), yield: 67.5%. The fourth step 4-[(3-phenylphenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl]-2,3-dihydrobenzofuran-6-decanoic acid 4- [(3-Phenylphenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl]-2,3-dihydrobenzoin-6-decanoate 26c (280 mg, 0. 66 mmol) Dissolved in 1 mL of methanol, and added a hydrazine clock (74 mg, 1.32 mmol). The reaction was stirred at 50 ° C for 12 hours. Add 10 mL of water, add 1 Μ hydrochloric acid to adjust the pH to 3 to 4, and extract with dioxane (10 mL×3). 168 95392 201242594 [(3-Chlorophenyl H2-(decyloxycarbonylamino)ethoxy]indolyl]-2,3-dihydrofuranfuran-6-decanoic acid 26d (250 mg, pale yellow solid ) 'Yield · · 92. 6%. The fifth step N-[(25〇-2-[[4-[(3-phenylphenyl)-[2-(decyloxycarbonyl))ethoxy) ]] mercapto]-2,3-dihydrobenzofuran-6-carbonyl]amino]-3-cyclohexyl-propyl]-N-methyl-amino decanoic acid tert-butyl ester 4-[(3-Chlorophenyl)-[2-(methoxycarbonylamino)ethyloxy]indenyl]-2,3-dihydrofuranfuran-6-carboxylic acid 26d (70 mg, 0 17 mmol) was dissolved in 4 mL of N,N-dimercaptocaramine, and N-[(2S)-2-amino-3-cyclohexyl-propyl]-N-methyl-amino group was added sequentially. Tert-butyl citrate lg (61 mg, 0.22 mmol) ' 1-Phenylbenzotris (66 mg, 0.34 _〇1) and 1-(3-diaminopropyl)- 3-ethylcarbodiimide hydrochloride (47 mg, 0.34 mmol), diisopropylethylamine (〇. 14 mL, 0. The reaction was stirred at room temperature for 18 hours. The reaction was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc) The mixture was filtered, and the filtrate was evaporated to dryness. -(methoxycarbonylamino)ethoxy]indolyl;|-2,3-dihydrobenzofuran-6-carbonyl]amino]-3-cyclohexyl-propyl]-N-methyl-amine Third butyl carboxylic acid 26e (71 mg, white solid), Yield: 62. 8%. MS m/z (ESI): 658 [M+1] Step 6 95392 169 201242594 N-[ 2-[( 3-oxo-phenyl)-[6-[[(15)-1-(cyclohexylmethyl)-2-decylamino-ethyl]aminomethylindenyl]-2,3-dihydrobenzene And furan-4-yl]methoxy]ethyl]decanoate decyl ester under ice bath 'will be Ν-[(2Λ-2-[[4-[(3-chlorophenyl)-[2-(methoxy) Alkylcarbonylamino)ethoxy]indolyl]-2,3-dihydrobenzofuran-6-carbonyl]amino]-3-cyclohexyl-propyl]-fluorenyl-fluorenyl-amino decanoic acid Tributyl ester 26e (71 mg, 〇·11 mmol) was dissolved in 6 mL of dichloromethane, and 6 mL was added dropwise. 2小时。 The mixed solution of trifluoroacetic acid and dioxane (V / V = 2: 1), stirring reaction for 1.2 hours. ® Add saturated sodium bicarbonate solution to adjust pH to 8 and extract with chloroform (1 〇mLx3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified to give the title product N-[2-[(3-chlorophenyl)-[6-[[(15)-1-(cyclohexylmethyl)-2-methyl Amino-ethyl]aminocarbamimidyl]- 2,3-dihydrobenzofuran-4-yl]nonyloxy]ethyl]decanoate 26 (42 mg, white solid), yield: 70. 0%. • MS m/z (ESI): 558 [M+l] 4 R (400 MHz, CDC13): δ 7. 90-7_ 65 (m, 2H), 7. 43-7. 22 (m, 5H) , 5.86 and 5.74 (2s, 1H), 5.30 (m, 1H), 4.59-4.51 (m, 3H), 3.66-2.94 (m, 11H), 2.71 (s, 3H), 1.77-0.86 (m, 13H) Example 27 [[2-[(3-Chlorophenyl)-[5-[[(25)]-2-methylamino-3-[(3)-tetrahydropyran-3-yl] Propyl]aminoindenyl]chroman-7-yl]nonyloxy]ethyl]carbamic acid decyl ester 170 95392 201242594

The first step φ 卜 [(15')-1-[[[7-[(3-phenylphenyl)-[2-(methoxycarbonylamino)ethoxy] fluorenyl] Retiny]amino]mercapto]-2-[(3疋)-tetrahydropyran-3-yl]ethyl]-anthracene-methyl-aminocarbamic acid tert-butyl ester 7-[(3 -Vetylphenyl)-[2-(decyloxycarbonylamino)ethoxy]indolyl]-3,4-dihydro-2 and-benzopyran-5-carboxylic acid 23η (30 mg, 0.07 mmol And N-[(150-1-(aminomethyl)-2-[(3-tetrahydrofuran-3-yl)ethyl]-N-mercapto-decanoic acid tert-butyl vinegar 3a (29 mg, 0.11 mmol) was dissolved in 3 raL·N,N-dimethylformamide, and hydroxybenzotriazole (19 mg, 0. 14 mm〇l), 1-(3) -Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27 mg, 0.14 mmol) and N,N-diisopropylethylamine (45 mg, 0.35 mmol). The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc m. Chromatography to purify the obtained residue in the solvent system A to give the title product|^-[(1 Λ -1-[[[7-[(3-chlorophenyl)-[2-( Oxycarbonylamino)ethoxy]methyl]chroman-5-carbonyl]amino]indoyl]-2-yl[(3 ate-tetrahydropyran-3-yl) 95392 171 201242594 ethyl]- N-decyl-amino decanoic acid tert-butyl ester 27a (36 mg, white oil), yield: 75.5%. Step 2^[2-[(3-chlorophenyl)-[5-[ [(21$')-2-Methylamino-3-[(3left)-tetrahydrofuran-3-yl]propyl]aminomethylindenyl]chroman-7-yl]decyloxy ]] ethyl] carbamic acid oxime ester under ice bath, N-[(l«_l-[[[7-[(3-phenylphenyl)-[2-(decyloxy) yl) Alkyl] fluorenyl]chroman-5-ylamino]amino]methyl]- 2-® [(3 and)-tetrahydro D-pyran-3-yl]ethyl]-N-methyl-amino The third butyl citrate 27a (36 mg, 0.053 mmol) was dissolved in 8 mL of dichloromethane, and 6 mL of a mixed solution of trifluoroacetic acid and dichloromethane (V/V = 2:1) was added, and the reaction was stirred. The reaction was quenched by the addition of saturated sodium carbonate solution. The aqueous phase was extracted with dichloromethane (10 mL×3). The organic phase was combined and washed with water (1 〇mL×2) and saturated sodium chloride solution (10 mL×2), anhydrous sodium sulfate Drying, filtration, and concentration of the filtrate under reduced pressure 'purified by thin layer chromatography using a developing solvent system A The resulting residual φ residue' gave the title product N-[2-[(3-chlorophenyl)-[5-[[(2Λ-2-methylamino)-3-[(3^0-tetrahydropyran) -3-yl]propyl]aminoindenyl]chroman-7-yl]methoxy]ethyl]amino decyl decanoate 27 (13 mg, white solid), yield: 42. 0% . MS m/z (ESI): 574 [M+l] NMR (400 MHz, CDCh): δ 8.11 (m, 1H), 7. 42-6. 65 (ra, 6H), 5.60 (in, 1H ), 5.22 (m, 1H), 4.11-2.70 (m, 21H), 1.92-1.22 (m, 9H) Example 28, 29 172 95392 201242594 N-[2-[U)-(3-Phenylphenyl) -[3-[[(l«-l-(cyclohexyldecyl)-2-decylamino-ethyl]aminoindolyl]-5-methoxy-phenyl]decyloxy]B Amino phthalic acid decyl Ν-[2-[(5·)-(3-chlorophenyl)-[3-[[(1)-1-(cyclohexyldecyl)-2-methylamine) --ethyl]amino aryl]-5-decyloxy-phenyl]methoxy]ethyl]

N-[2-[(3-Chlorophenyl)-[3-[ [(15)-l-(cyclohexylfluorenyl)_2-fluorenylamino-ethyl]aminoindolyl]-5 -Carboxyoxy-phenyl]methoxy]ethyl]amino decanoate 2 (300 mg '0.55 mmol) for chiral separation, using HPLC method, preparation equipment and chiral column Separation of the isomers (separation conditions: chiral column Chiralcel 0DH, mobile phase: positively burned: isopropanol: diethanolamine = 60: 40: 0. 1 'flow rate: h 〇 mL / min), collect corresponding The solvent was removed by rotary evaporation to give the title product N <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; Methyl 2-ethyl]aminocarbamimidyl]-5-decyloxy-phenyl]decyloxy]ethyl]carbamate 28 (129. 3 rag, 0.24 mmol) and ^[2-((5) )-(3-Phenylphenyl H3-[[(10)-b (cyclohexylmethyl)_2-methylamino]ethyl]aminoindolyl]-5-methoxy-phenyl]methoxy ]ethyl]carbamic acid methyl ketone 29 (108·2 mg, 0·20 mmol). 28 MS m/z (ESI): 546[M+1] 95392 173 201242594 'H NMR (400 MHz, CDCh): δ 7. 38-7. 21 (m, 6H), 6. 98 (s, 1H), 6.58 (d,, two 7.2 H z,1H), 5.34 (s, 1H), 5.23 (s, 1H), 4.39 (s, 1H), 3.86 (s, 3H), 3.69 (s, 3H), 3.57 (m, 2H), 3.47 (m , 2H), 2.78 (m, 2H), 2.49 (s, 3H), 1.85-0.91 (m, 13H) 29 MS m/z (ESI): 546[M+1] !H NMR (400 MHz , CDCh) : δ 7. 39-7. 21 (m, 6H), 6. 98 (s, 1H), 6.58 (d, /=7. 0 Hz, 1H), 5. 34 (s, 1H), 5. 23 (Z?r. s, ® 1H), 4.39 (br.s, 1H), 3.86 (s, 3H), 3.69 (s, 3H), 3.57 (m, 2H), 3.47 (in, 2H), 2.80- 2.73 (m, 2H), 2. 49 (s, 3H), 1.88-0.92 (m, 13H) Example 30, 31 1^-[2-[())-(3-Phenylphenyl)-[3 -(3-decyloxypropoxy)-5-[[(250-2-methylamino-3-[(37?)-tetrahydrofuran-3-yl]propyl]amino) Methyl]phenyl]methoxy]ethyl]amino decanoate [2-[(51)-(3-chlorophenyl)-[3-(3-decyloxypropoxy)-5_ [[(25)-2-Methylamino-3-[tetrahydropyran-3-yl]propyl]aminomethylindenyl]phenyl]decyloxy]ethyl]aminopyrudecanoate ester

Ν-[2-[(3-Chlorophenyl)-[3_(3-decyloxypropoxy)-5-[[(250-2-decylamino-3-[(3 friends)- Tetrahydropyran-3-yl]propyl]amino 174 95392 201242594 Methyl]phenyl]decyloxy]ethyl]amino decanoic acid methyl ester 4 (149 mg, 〇25 mmol) for chiral resolution Separation by preparative equipment and chiral column chiral isomers by HPLC method (separation conditions: chiral column Chiralcel 0DH, mobile phase: n-hexane: isopropanol: diethanolamine = 6〇: 4〇: 〇. J, flow rate: 1·0 mL/min), the corresponding components were collected, and the solvent was removed by rotary evaporation to give the title product N-[2-[(A〇-(3- phenylphenyl)-[3-( 3-methoxypropoxy)-5-[[(25〇-2-methylamino-3-[(3))-tetrahydro.pyran-3-yl]propyl]aminopurine Ethyl]phenyl]methoxy]ethyl]amino decanoate 30 (64.6 mg, 0.11 mmol) and N-[2-[(5〇-(3-phenylphenyl)-[3-(3) - alkoxypropoxy)-5-[[(2«-2-decylamino-3-[(3妁-tetrahydroindolepyran-3-yl)propyl]amino)] Methyl phenyl]methoxy]ethyl]amino decanoate 31 (57.8 mg, 0. 10 mmol). 30: MS m/z (ESI): 606 [M+1], retention time 12 47 minutes, ee value is 1〇〇%. 31 : MS m/z (ESI): 606 [M+1], retention time 12.42 minutes, φ ee value 99.63%. Example 32, 33 N-[2 -[(«-(3-chlorophenyl)-[6-[[(1«-1-(cyclohexyldecyl)-2-hydroxymethylamino-ethyl]amino]] , 3-dihydrobenzohaffin-4-yl]methoxy]ethyl]carboxylic acid methyl ester N-[2 - [U)_(3- gasophenyl)_[6-[[(1 «-1-(cyclohexylmethyl)-2-methylamino-ethyl]aminoglycolyl]-2,3-diazabenzophenone π-nan-4-yl]methoxy]ethyl Methyl formate 175 95392 201242594

M-[2-[(3-Vinylphenylcyclohexylmethyl)-2-methylamino-ethyl]aminocarbamimidyl]_2,3-dihydrobenzofuran_4_yl] Chiral separation of methyl methoxy]ethyl]ethyl decanoate 26 (150.4 mg, 0.27 mmol) (isolation conditions: Chiralpak IC, mobile phase: acrylonitrile: isopropanol: diethanolamine = 95: 5: 〇1, flow rate: 1 〇mL/min), the corresponding components were collected, and the solvent was removed by rotary evaporation to give the title product N-[2-[(5)-(3- phenylphenylcyclohexylmethyl) -2-methylamino-ethyl]aminoindenyl]_2,3-dihydrobenzofuran_41yl] decyloxy]ethyl]decanoic acid vinegar 32 (60.8 mg, ou curry 1 And Bu [2_ [U&gt;(3-chlorophenyl)-[6-[[(15)-1-(cyclohexylmethyl)_2-methyl-moon-l-ethyl]]] -2,3-Dihydrobenzobenzopyrano-4-yl]decyloxy]ethyl]carboxylic acid methyl ester 33 (54.8 mg, 〇·1 mmol). 32. MS m/z (ESI): 558 [M+1] ’ retention time 12. 25 minutes ee value 99. 57%. 33 : MS m/z (ESI) : 558 [M+1], retention time 12 24 minutes ee value 99. 11%. Example 34 N-[2-[(3-Phenylphenyl)H3-[[(10)-2-methyl silk|[(10)_tetraapyran-3-yl]propyl]aminomethylindenyl]-5 -(2, 2, 2-trifluoroethoxyxo)phenyl]methoxy]ethyl]carbamic acid A from the soil 95392 176 201242594

First step 2, 2, 2-trifluoroethanol 2, 2, 2-trifluoroethyl methanesulfonate # 5°c ' Dissolve 2, 2, 2-trifluoroethanol 34a (5 g, 50 mmol) Triethylamine (1〇1〇g, 1〇〇mmoi) and sulfonium sulfonate (8·60 g, 75 mmol) were successively added to 30 mL of dioxane, and the reaction was stirred at room temperature for 12 hours. The reaction mixture was poured into a 5% aqueous solution of sodium arphate and stirred for 15 minutes, and the organic layer was dried over anhydrous sodium sulfate. 0%。 The ester 34b (8.0 g, brown oil), yield: 90.0%. The second step is 5-(2,2,2-difluoroethoxy)benzene-l-dicarboxylate 95392 177 201242594 5-Benzene-1,3--------- g, 14. 3 mmol) and 2, 2, 2-trifluoroethyl formate 34b (3.31 g, 18.6 mmol) were dissolved in 40 mL of N,N-dimercaptocaramine. Carbonate planer (6. 〇6 g, 18. Θ mmol) was added, and the reaction was stirred at 80 ° C for 12 hours. The reaction solution was poured into a 250 mL ice-water mixture, and extracted with ethyl acetate (100 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by eluent column chromatography with eluent system B. The residue was obtained to give the title product: 5-(2,2,2-trifluoroethoxy)benzene, &lt;RTI ID=0.0&gt; %. The third step is 3-(f-oxycarbonyl)-5-(2,2,2-trifluoroethoxy)benzoic acid 5-(2,2,2-trifluoroethoxy)benzene- ι,3- Methyl dicarboxylate 34c (3 g, 10.3 _〇1) was dissolved in 5 mL of decyl alcohol, and 1 M sodium hydroxide solution (10 mL, 10 〇i) was added, and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. ~5-(2,2,2-Trifluoroethoxy)benzoic acid 34d (2.29 g, white solid), yield: 80. The fourth step 3 (via 'mercapto)-5-(2,2,2-trifluoroethoxy)benzoic acid methyl 3-(methoxycarbonyl)_5_(2,2,2-trifluoroethoxy Benzoic acid 34d (2. 30 g, 8. 27 mmol) was dissolved in 15 mL·tetrahydrofuran, and 1 μ borane in tetrahydrofuran (12.4 mL, 12.4 mmol) was added, 5 (TC stirring reaction 12 After adding sterol to quench the reaction, concentrate under reduced pressure, add 5 〇虬ethyl 95392 178 201242594 acid ethyl ester, followed by 30% potassium carbonate solution (20 mL), 1 M hydrochloric acid (2 〇 mL), saturated nucleus Sodium hydride solution (2 〇niL) and saturated sodium sulphate solution (2 mL) were dried over anhydrous sodium sulfate and filtered. Methyl 2-trifluoroethoxy)benzoate 34e (2.20 g, mp.). Step 5 3-Methylmethyl-5-(2,2,2-trifluoroethoxy)benzoate The crude hydroxymethyl)-5-(2, 2, 2-trifluoroethoxy) Methyl benzoate 34e (2. 20 g, &amp; 33 mmol) was dissolved in 30 mL of di-methane, and then added to the gas chromatographic I-pyridinium salt (3.60 g, 16.7 mmol) and sodium acetate (2) 〇5 g, 25 mmol), the reaction was stirred for 12 hours. 3 〇g 矽 gum was added, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by eluent system B using (4) column chromatography to give the title product: 3-carboyl _5_(2,2,2-trifluoroethyl Methyl benzoate 34f (1.54 g, white solid), yield: 7 〇. 〇%. Step 6 3-[(3-Chlorophenyl)-pyridylmethyl]_5_(2,2,2_trisethoxy)benzoic acid methyl ester ice/closed '3-曱酷基- 5-(2,2,2-Trifluoroethoxy)benzoic acid methyl vinegar 34f (l&gt;g, 3.82 mmol) was dissolved in 1G mL of tetrahydro-seven, and 1 Μ 3-gas bromide was added dropwise. A solution of magnesium in tetrahydrofuran (3. 82 Å, &amp; _ 〇 1) was given for 1 hour. Add water to quench the reaction, use acetic acid to take (25 mLX3) 'The organic phase, then use water (15 mL) and saturated sodium carbonate, wash the knees (2GmL), dry anhydrous sodium, filter, decompression Concentrate 95392 179 201242594 condensed 'The residue obtained was purified by thin layer chromatography to afford the title product 3-[(3-chlorophenyl)-hydroxy]-5-(2, 2, 2-trifluoro Methyl ethoxy) benzoate 34 g (1·19 g, colorless oil), yield: 84. 〇%. Step 7 3-[(3-Chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]-5. (2, 2, 2-trifluoroethoxy)benzoic acid Ester 3-((3-phenylphenyl)-hydroxy-methyl]-5-(2, 2, 2-trifluoroethoxy) decyl decanoate 34g (500 mg, 1.34 mmol) and N-(2-Ethyl)carbamic acid methyl acetonate lt (316 mg, 2.67 mmol) was dissolved in 25 mL of toluene, and p-benzoic acid (267 mg, 1_41 _〇1) was added. The reaction was separated by water for 1 hour. The mixture was washed with aq. The title product 3-[(3-chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]_5_(2,2,2-difluoroethoxy)benzoic acid vinegar was obtained. 34h (285 mg, colorless oil). Yield: 45.0%. Step 8 3-[(3-Chlorophenyl)-[2-(indolylcarbonylamino)ethoxy]indolyl]_5_(2,2,2-trifluoroethoxy)benzoic acid 3 -[(3-Phenylphenyl)-[2-(oximeoxycarbonylamino)ethoxy]indolyl]-5-(2,2,2-trifluoroethoxy)benzoate oxime 34h (28 〇mg, 〇6〇1) Dissolved in 1 mL of sterol, added with sodium hydroxide (47 mg, 118 with 〇1), and stirred at 50 °C for 12 hours. The reaction was quenched by the addition of 1 μ of hydrochloric acid, concentrated under reduced pressure, and extracted with hexanes (20 mL×3), dried over anhydrous sodium sulfate, and over-fishing, 95392 180 201242594 The filtrate was concentrated under reduced pressure, using a gel column chromatography to eluent The resulting residue was purified to give the title product as a crude title product: 3-[(3-(chlorophenyl)-[2-(indoleoxycarbonylamino)ethoxy]indolyl]-5-(2, 2, 2 -Trifluoroethoxy)benzoic acid 34i (220 mg, white solid). The ninth step N-[(1 幻-1_[[[3-[(3-phenylphenyl)-[2-(曱 oxycarbonylamino)ethoxy]] 曱 卜) 5- (2, 2, 2-trifluoroethoxy)phenylhydrazinyl]amino]indolyl]-2-[(3^-tetrahydropyran-3-yl]ethyl]-fluorenyl-fluorenyl-amino decanoic acid Tributyl ester will be crude 3-[(3-phenylphenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl]-5-(2,2,2-trifluoroethoxy)benzene Formic acid 34 丨 (90 mg, 0.2 mmol) and Ν-[(1^-1-(amino fluorenyl)_2_[(3 _ tetrahydropyran-3-yl)ethyl]-Ν-甲Base-teletonic acid tert-butyl ester 3a (10), 0.25 mmol) dissolved in 3 mL of N,N-dimethylformamide, added with hydroxybenzotriazole (54 mg, 0.4 mmol), 1-(3-di Methylaminopropyl)_3_ethylcarbodiimide hydrochloride (77 # mg, 〇.4 mmol) and N,N-diisopropylethylamine (99 mg, 0.76 mmol) 25 mL of dichloromethane was added to the reaction solution, and the mixture was washed with water (20 mL×2) and saturated sodium carbonate solution (2 〇mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified to give the crude title product [(3-chlorophenyl)-[2-(indoleoxycarbonylamine). Ethyl]methyl]_5_(2,2,2~trifluoroethoxy)phenylhydrazinyl]amino]indolyl]-2-[(3 phantom-tetrahydrol^3-yl] Ethyl]methyl-aminocarbamic acid tert-butyl ester 3 hydrazine (14 〇, lightly colored oil), the product was directly subjected to the next reaction without purification. 95392 181 201242594 The tenth step N-[2-[ (3-chlorophenyl)-[3-[ [(25^-2-decylamino-3-[(3))-tetrahydro 0-pyran-3-yl]propyl]amino) fluorenyl ]-5-(2, 2, 2-trifluoroethoxy) phenyl] decyl] ethyl] amide decyl decanoate under ice bath 'will be crude Ν-[(15·)-1-[ [[3-[(3-Chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]-5-(2, 2, 2-trifluoroethoxy)benzylidene Amino]methyl]-2-[(3Λ〇-tetrahydro.pyran-3-yl)ethyl]-anthracene-methyl-aminobutyric acid tert-butyl ester 34j (90 mg, 0·12 Methyl) was dissolved in 8 mL of dilucloxane, and a mixture of 6 mL of trifluoroacetic acid and dichloromethane (v/v = 2:1) was added to the reaction mixture for 1 hour. The reaction was quenched by the addition of saturated sodium carbonate solution. The aqueous phase is extracted with dichloromethane (10 mL×3), and the organic phases are combined and washed sequentially with water (10 mL×2) and saturated sodium chloride solution (1 〇mL×2) The residue was filtered and dried under reduced pressure. (25)-2-Methylamino-3-[(3/?)-tetrahydropyrano-3-yl]propyl]amine φ thiol]_5—(2, 2, trifluoroethyl Oxy)phenyl]toxy]ethyl]amino decyl decanoate 34 (12 mg, white solid), yield: 14. 〇%. MS m/z (ESI): 616 [M+l]]H NMR (400 MHz, CDCla): δ 7. 46-7. 03 (m, 8H), 5. 33 (s, 1H), 5.19 (s , 1H), 4.39 (q, / = 8. 0 Hz, 2H), 3.86 (m, 2H), 3.66 (s, 3H), 3.56-3.38 (m, 7H), 3.08 (in, 2H), 2.74 ( s, 1H), 2.43 (s, 3H), 1.90-1.21 (m, 7H) Example 35 [2-[(51)-(3-Phenylphenyl)-[3-ethoxy-5-[ [(25')-2-mercaptoamine 95392 182 201242594 -3-[(3^)-tetrahydrofuran-3-yl]propyl]aminomethylindenyl]phenyl]decyloxy] B Methyl carbazate

N-[2-[(幻-(3-chlorophenyl)_[3-ethoxy]5_[[(2 幻_2_methylamino-3-[(3))-tetrahydro" ratio N-[2-[(3-Phenylphenyl)-[3-ethoxy] methoxy-3-yl]propyl]aminomethylindenyl]phenyl]methoxy]ethyl]aminocarbamic acid -5-[ [(250-2-Methylamino-3-[(3疋)-tetrahydrofuran-3-yl]propyl]aminomethylindenyl]phenyl]methoxyethyl Amidine decyl sulfonate 9 (126 mg, 〇22 〇1) was subjected to chiral separation and separated by HPLC using preparative equipment and chiral column chiral isomers. Separation conditions: chiral tube Column Chiralpak IC, mobile phase: acrylonitrile: isopropanol: diethanolamine = 95 : 5 :, flow rate: 1 〇 mL / total knife) 'Collect the corresponding components, remove the solvent by rotary evaporation to obtain the title product N-[2 -[(«-(3-Phenylphenyl)_[3_ethoxy-5-[[(2 _2_2_ decylamino-3-[(3A〇-tetrahydropyran-3-yl)-propyl Methyl]aminomethylindenyl]phenyl]methoxy]ethyl]carbamic acid methyl ester 35 (31 mg, 〇〇55 leg 〇 1). Example 36 1 [2-[(3-chlorophenyl) )-[6-[[(251)-2-Methylamino)-3-[(3 ate-tetrahydropyran-3-yl]propyl]aminoindenyl]_2,3-dihydrobenzene And furan_4_ ] Yue oxy] ethyl] carbamic acid methyl ester 183 201 242 594 95392

first step

N-[(l«-l-[[[4-[(3-chlorophenyl)-[2-(methoxycarbonylamino)ethoxy] decyl]-2, 3-dihydrobenzofuran) -6-carbonyl]amino]methyl]-2-[(3 phantom-tetrahydropyran-3-yl]ethyl]-N-decyl-amino decanoic acid tert-butylate under ice bath 4-[(3-Chlorophenyl)-[2-(decyloxyamino)ethoxy]methyl]-2,3-dihydrobenzofuran-6-decanoic acid 26d (200 mg, 0. 51 mmol) was dissolved in 3 mL of N,N-didecylamine, and Ν-[(15·)-1-(aminomercapto)-2-[(3妁-tetrahydropyran-) was added in sequence. 3-yl]ethyl]-fluorenyl-fluorenyl _ carboxylic acid tert-butyl ester 3a (151 mg, 0.56 mmol), hydroxybenzotriazole (322 mg, 2.5 mmol) and l-(3- Diammonium propyl)-3-ethylcarbodiimide hydrochloride (191 mg, 1 〇1), diisopropylethylamine (i35 mg, 1 mmol) was added dropwise. 2 〇 mL of dichloromethane was added to the reaction mixture, and the organic phase was washed with water (20 mL) and saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The obtained residue was purified to give the title product [[15]-[[[[4-[(3-chlorophenyl)-[2-] Oxycarbonylamino)ethoxy]]indolyl]-2,3-dihydrobenzofuran-6-carbonyl]amino]methyl]_2_[(3 none)_ 95392 184 201242594 Tetrahydropyran-3- Alkyl]ethyl]-N-indolyl-aminocarbamic acid tert-butyl ester 36a (292 mg, colorless oil), yield: 88.8%. Second step N-[2-[(3- gas Phenyl)-[6-[[(2«-2-decylamino-3-[(3«-tetrahydropyran-3-yl)propyl]aminoindenyl]-2, 3- Dihydrobenzofuran-4-yl]methoxy]ethyl]amino decanoic acid decyl ester, chlorophenyl)-[2-(indolylcarbonylamino)ethoxy]indenyl] -2,3-dihydrobenzofuran-6-carbonyl]amino] ® fluorenyl]-2-[(3 pico)-tetrahydropyran-3-yl]ethyl]-N-indenyl-amine The third butyl carboxylic acid 36a (290 mg, 0.45 mmol) was dissolved in 1 mL of dioxane, and a mixture of 6 mL of trifluoroacetic acid and dioxane (V/V = 2:1) was added and stirred. The reaction was carried out for 1 hour. The reaction was quenched by the addition of saturated sodium carbonate solution, and the aqueous phase was extracted with dioxane (1 〇mL×3). The organic phase was combined and washed with water (1 〇mL×2) and saturated sodium chloride solution (1 〇HJLX2) ), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and thin The resulting residue was purified by EtOAc to EtOAc (EtOAc). (37?)-tetrahydro"pyran-3-yl]propyl]aminoindenyl]-2,3-dihydrobenzocypanto-4-yl]decyloxy]ethyl]amino Ethyl decanoate 36 (110 mg, white solid), yield: 45. 〇%. MS m/z (ESI): 560 [M+l] NMR (400 MHz 'CDCh): δ 7. 86-7. 07 (m,7H), 5.71 (s, 1H), 5.29 (s, 1H), 4.56 (m, 2H), 3.91-3.31 (m, 13H), 3.15-2.94 (m, 4H), 2.71 (in, 3H), 2.15-1.24 (m, 7H) Example 37 95392 185 201242594 ^ [2-[(3-Chlorophenyl)-[3-曱-oxy-5-[[(25')))]-2-ylylamino-3-[(3A〇-tetrahydrofuran-3-yl) Methyl]amino]indenyl]phenyl]methoxy]ethyl]amino decanoate

The first step ^[(150-1-1^1^3-1^(3-phenylphenyl)-[2-(indolyl)-ethoxy]indolyl]-5-decyloxy -benzoyl]amino]mercapto]-2-[(3 friends)-tetrahydro 0-pyran-3-yl]ethyl]-N-methyl-amino decanoic acid tert-butyl ester ice bath 3-[(3-Chlorophenyl)-[2-(decyloxycarbonylamino)ethoxy]indolyl]-5-decyloxy-benzoic acid 2 g (300 mg, 0.76 mmol) Dissolved in 1〇1111^,1^-dimercaptoamine, and then added [[151]-1-(aminomercapto)-2-[(3 friends)-tetrahydropyran-3- 3-ethyl]-N-indenyl-carboxylic acid tert-butyl ester 3a (270 mg, 0.99111111〇1), 1-hydroxybenzotriazole (20711^, 1.53 mmol) and 1-(3-diamine Propyl)-3-ethylcarbodiimide hydrochloride (293 rag, 1·5 _〇1), diisopropylethylamine (375 mg, 2.9 mmol) was added dropwise. The reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc (EtOAc m. 186 95392 201242594 Thin layer chromatography Purify the residue obtained with Developer System A to give the title product [[151]-1-[[[3-[(3-chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl]-5-methoxy-benzylidene) Amino]methyl;|1-2-[(3)?)-four gas 0-pyran-3-yl]ethyl]-N-mercapto-aminocarboxylic acid tert-butyl ester 37a (340 mg, colorless oil The yield was 69. 0%. MS m/z (ESI): 648 [M+l] Step 2 φ 1^-[2-[(3-chlorophenyl)-[3-曱oxy-5-[[(25))-2 - mercaptoamino-3-[(3)-tetrahydropyranyl-3-yl]propyl]aminomethylindenyl]phenyl]decyloxy]ethyl]amino decanoate Under the bath 'N-[(l«-l-[[[3-[(3-chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl]-5-decyloxy) -phenylhydrazinyl]amino]methyl]-2-((3 friend)-tetrahydro.pyran-3-yl]ethyl]-N-methyl-amino decanoic acid terpene vinegar 37a ( 340 mg, 0.53 mmol) was dissolved in 1 mL of dichloromethane, and a mixed solution of 6 mL of trifluoroacetic acid and dioxane (V/V = 2:1) was added, and the reaction was stirred for 1 hour. Sodium solution quenching reaction 'The aqueous phase is extracted with dichloromethane (10 mL×3), and the organic phase is combined, washed with water (10 mL×2) and saturated sodium carbonate solution (1 〇mL×2), dried over anhydrous sodium sulfate, filtered, Concentration under reduced pressure, and the residue obtained was purified by EtOAc (EtOAc) EtOAc (EtOAc) Amino-based 3-[(3/?)-tetrahydropyran-3-yl]propyl]aminoglycolyl]phenyl]decyloxy] Ethyl]amino decanoate 37 (150 mg, colorless oil), yield: 52.3%.

Ms m/z (ESI): 548 [M+1] 187 95392 201242594 4 NMR (400 MHz , CDCIO : δ 7. 42-7. 15 (m,7H), 6.97 (s, 1H), 5.41 ( s, 1H), 5.34 (s, 1H), 3.89 (m, 2H), 3.68 (s, 3H), 3.56-3.38 (m, 10H), 3.10 (m, 1H), 2.76 (m, 1H), 2.45 (s, 3H), 1.93-1.23 (m, 7H) Example 38 1^_[2-[(3-Phenylphenyl)-[3-[[(15))-1-(cyclohexylfluorenyl) 2-nonylamino-ethyl]aminoindenyl]-5-(cyclopropylcarbonylamino)phenyl]decyloxy]ethyl]amino decanoate

188 95392 201242594 First step 3-(hydroxymethyl)-5-nitro-benzoic acid decyl ester 3-methoxycarbonyl 5-nitro-benzoic acid 38a (1〇g, 44. 4 mmol) was dissolved in 120 mL of tetrahydrofuran, and a solution of 1 borane in tetrahydrofuran (89 mL, 89 mmol) was added and the mixture was stirred for 12 hours. The reaction was quenched by the addition of MeOH (1 mL EtOAc). EtOAc (EtOAc m. Concentration to give the crude title product 3-(m-decyl)-5-nitro-benzoic acid decyl ester 38b (yellow solid). Step 2 3-Methylmethyl-5-nitro-benzoate Methyl 3-(methyl)-5-nitro-benzoate 38b (9.38 g, 44.4 mmol) To 50 mL of di-gas methane, pyridine chromite rust salt (19.10 g, 88.8 mmol) and sodium acetate (10.92 g, 133.2 mmol) were added. • The reaction was stirred for 12 hours. 6.0 g of phthalocyanine was added, and the filtrate was filtered and concentrated under reduced pressure. The obtained residue was purified using eluent column chromatography to afford the title product 3-mercapto-5-nitro-benzoic acid methyl ester 38c ( 4%。 White solid), yield: 43.1%. Step 3 3-[(3-Chlorophenyl)-hydroxy-indolyl]-5-nitro-benzoic acid oxime ester 3-methylmercapto-5-nitro-absuccinate methyl ester in ice bath 38c (4 g, 19. 14 mmol) was dissolved in 40 mL of tetrahydrofuran, and a solution of h 5 M 3-phenylphenylmagnesium bromide in tetrahydrofuran (19.14 mL, 28.71 mmol) was added dropwise to 95392 189 201242594 i, time. Add the saturated gasification solution to quench the reaction, extract with ethyl acetate (50 mL×3), combine the organic phase, wash the strip with water (5) and saturated sodium chloride solution (20 mL), dry over anhydrous sodium sulfate, filter, filtrate dust reduction Purification of the obtained residue by eluent system B to give the title product 3_[(3-chlorophenyl), yl-methyl]_5-nitro-benzoic acid methyl ester 38d (3.80 g, yellow oil), yield: 62. 〇%. The fourth step 3 [(3 gas base), (2,2,2-di-iminoacetinyloxy)oxy-indenyl]-bu-fi-methyl-benzoic acid methyl ester will be 3_[(3-gas Phenyl)-hydroxy-methyl]_5_nitro-benzoic acid oxime 38d (3 g' 11.84 mm〇i) was dissolved in 4 Torr toluene, trichloroacetonitrile (8.55 g, 59.2 mmol) and dinitrogen were added. Heterobicycle (182 7 mg, 12 ramol) was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. The residue was purified by eluent column chromatography using eluent column chromatography to give the title product 3, [(3-chlorophenyl)-(2,2,2-triamine). Oxy-indenyl]-5-nitro- benzoic acid decyl ester 38e (3 g, yellow oil), yield: 54.3%. Step 5 3-[(3_Phenylphenyl)~[2_(methoxycarbonylamino)ethoxy]indolyl]_5-nitro-benzoic acid decyl ester 3-[(3-phenylphenyl) )_(2, 2, 2-triseocarbendifluorene) 氡__mercapto]-5-nitro-benzoic acid decyl ester 38e (3 g, 6 44 _〇1) and N_(2 Hydroxyethyl 95392 190 201242594 base) methyl carbamate It (760 mg, 6.44 mmol) was dissolved in 5 mL of dichloromethane and trimethyl sulfonate trifluoromethanesulfonate (1.43 g, 6.44 mmol) ), the reaction was stirred for 1 hour. The reaction was quenched with aq. EtOAc (EtOAc) (EtOAc (EtOAc) The filtrate was filtered, and the filtrate was concentrated under reduced pressure. Methyl]-5-nitro-benzoic acid methyl ketone 38f (1 I colorless, isolated), yield: 37.0%. Step 6 3-amino-5-[(3-phenylphenyl) -[2-(Methoxycarbonylamino)ethoxy]methyl]benzoic acid methyl ester 3-[(3-chlorophenyl)_[2_(methoxy-ylamino)ethoxy]- 3 - nitro-benzoic acid decyl ester 3 cubits (1 苢, 2.38 111111 〇 1) dissolved in 5 〇 this methanol 'Add Lenny Town (250 mg, 〇.6〇mmol) 'hydrogen replacement three times The reaction was stirred for 4 hours, and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the title product, 3-amino-5-[(3-chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]methyl Benzyl benzoate 38g (800 mg, colorless oil), yield: 80. 0%. Step 7 - [(3-Phenylphenyl)-[2-(indolylcarbonylamino)ethoxy]indolyl]-5-(cyclopropylcarbonylamino) benzoic acid methyl ester under ice bath '3-amino group -5-[(3-Chlorophenyl)-[2-(indolylcarbonylamino)ethylidyl]indenyl]benzic acid methyl vinegar 38g (300 mg, 0. 77 ήπιο 1) and 191 95392 201242594 Ethylamine (154.53 mg, 1.53 mmol) was dissolved in 50' dioxane, and cyproterone chloride (80. 5 mg, 0.77 mmol) was added dropwise, and the reaction was stirred at room temperature for 12 hours. Extracted with dichloromethane (5 〇 mL×3), and the combined organic phases were washed successively with water (20 mL) and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Chromatography The residue obtained was purified using eluent B to give the title product: 3-[(3- phenylphenyl)-[2-(indoleoxycarbonylamino)ethoxy]indolyl]-5-(cyclopropylcarbonylamino) Ethyl benzoate 38h (280 mg, light yellow oil), yield: y. 79.3%. MS m/z (ESI): 483 [M+23] Step 8 3-[(3-(p-phenyl)-[2-(indoleoxycarbonylamino)ethoxy]]]] 3-[(3-Phenylphenyl)-[2-(indolylcarbonylamino)ethoxy]indolyl]-5-(cyclopropylcarbonyl) under a benzylhydrazine hydrazine bath The amino) benzoic acid oxime ester (280 mg, φ 0.61 mmo1) was dissolved in 15 mL of tetrahydrofuran, and 15 mL of sodium hydroxide (24.34 11^, 0.61111111〇1) in methanol was added, and the reaction was stirred at room temperature for 12 hours. The reaction mixture was adjusted to pH 2 to 3 with 1 mL of EtOAc. EtOAc (EtOAc (EtOAc) [2-(曱Oxycarbonylamino)ethoxy]methyl]-5-(cyclopropylamino)benzoic acid 38i (240 mg, pale yellow solid). MS m/z (ESI): 446 [M+l] ninth step 192 95392 201242594 Ν-[(25·)-2-[ [3-[(3-chlorophenyl)-[2-(methoxycarbonyl) Amino)ethoxy]methyl]-5-(cyclopropylaminoamino)phenylhydrazinyl]amino]-3-cyclohexyl-propyl]-N-indenyl-amino decanoic acid Tributyl ester 3-((3-chlorophenyl)-[2-(indolylcarbonylamino)ethoxy]methyl]-5-(cyclopropylamino)benzoic acid 38i (240 Mg, 0.54 mmol) and N-[(25)-2-amino-3-cyclohexyl-propyl]-N-fluorenyl-amino decanoic acid tert-butyl ester lg (190.4 mg, 0.7 mmol) dissolved Adding hydroxy benzotriazole (146 mg, 1.08 mmol), ^ 1-(3-diaminopropyl)-3-ethylcarbamate in 10 mL of hydrazine, hydrazine-dimethyl decylamine The imine hydrochloride (207 mg, 1.08 mmol) and N,N-diisopropylethylamine (265 mg, 2.05 mmol) were stirred for 12 hours. Add 50 mL of water, extract with 2 gas (30 mL×3), wash with water (20 mL×2) and saturated sodium carbonate solution (20 mL×2), “dry over anhydrous sodium sulfate”, filter, and concentrate the filtrate under reduced pressure. Chromatography of the residue obtained by eluent B to give the title product N-[(25')-2-[[3-[(3-chlorophenyl)-[2-(methoxycarbonylamino) Oxy] φ fluorenyl]_5-(cyclopropylcarbonylamino)phenylindolyl]amino]-3-cyclohexyl-propyl]-N-decyl-amino decanoic acid tert-butyl ester 38j ( 230°, light yellow oil), yield: 61. 2 ° / 〇. MS m/z (ESI): 699 [M+l] Step 10 1^-[2-[(3-phenylphenyl)-[3-[[(151)-1-(cyclohexyl)]- 2-nonylamino-ethyl]aminocarbamimidyl]-5-(cyclopropylcarbonylamino)phenyl]decyloxy]ethyl]amino decanoate decyl ester under ice bath 'N- [(2«-2-[[3-[(3-Chlorophenyl)-[2-(曱-oxycarbonyl 193 95392 201242594 ylamino)ethoxy]methyl]-5-(cyclopropylcarbonylamine Benzyl hydrazide]amino]-3-cyclohexyl-propyl]methyl-amino decanoic acid tert-butyl ester 38j (230 mg, 0·33 mmol) was dissolved in 8 mL of dichloromethane. 6mL mixed solution of trifluoroacetic acid and dichlorodecane (V/V = 2: 1), stirring for 1 hour. Add the saturated sodium carbonate solution to quench the reaction, adjust the pH to 7 to 8, and extract with dichlorohydrazine ( 10 mL×3), the organic phase was combined, washed with water (10 mL×2) and saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue is obtained to give the title product N-[2-[(3-phenylphenyl)-[3-[[(15))-1-(cyclohexylmethyl)-2-mercaptoamino-ethyl Aminomethylmercapto]-5-(cyclopropylcarbonylamine Benzyl] decyloxy]ethyl] carbamic acid decyl ester 38 (140 mg, colorless oil), yield: 71. 1%. MS m/z (ESI): 599 [M+l] 4 R (400 MHz, CDC13): δ 8· 76-7. 01 (m, 9H), 6. 10 (m, 1H), 5.23 (m, 1H), 4.65 (m, 1H), 3.69-2.81 ( m, 13H), φ 1.67-0,78 (m, 13H) Example 39 N-[2-[(3-chlorophenyl)-[3-[[(15)-1-(cyclohexylfluorenyl)) 1-nonylamino-ethyl]aminoglycolyl]-5-(cyclopropylaminoindenyl)phenyl]decyloxy]ethyl]amino decanoic acid

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In the first step, in the ice bath of benzenetricarboxylate, isophthalic acid 39a (15 g, 〇.〇7 mol) was dissolved in 200 mL of dichlorosilane, and sulfonium sulfonate was added (15.5). mL, 0. 21 mol) 'The reaction was stirred at 60 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated. Methyl tricarboxylate 39b (17 g, white solid), 94.0%. NMR (400 MHz , CDCh) : δ 8.87 (s, 3 Η), 3.99 (S, 9H). 195 95392 201242594 Second step 3, 5-di(indolylcarbonyl)benzoic acid decyl benzene phthalate 39b (3 g, 11.9 mmol) was dissolved in 30 mL of acetone, and 20 mL of sodium hydroxide (476 mg, 11.9 mmol) in methanol was added, and the reaction was stirred at 50 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m.) , 5% (曱 羰 carbonyl) benzoic acid 39c (2.3 g, white solid), yield: 82.0%. MS m/z (ESI): 237 [M+l] Step 3 5-(Hydroxyhydrazinyl) benzyl 1,3-1,3-dicarboxylate 3,5-bis(methoxycarbonyl)benzoic acid 39c (11.30 g, 47 mmol) Dissolved in 50 mL of tetrahydroanthracene π Nan, add 1 Μ 烧 的 tetrahydrofuran solution (71 mL, 71 mmol), and stir the reaction at 50 ° C for 12 hours. The title compound 5-(hydroxyindenyl)phenyl-1,3-didecanoate was obtained by purifying φ. 39% (6 g, white solid), yield: 55.5 %. Step 4: 5-Methylmercaptophenyl-1,3-dicarboxylate Methyl 5-(hydroxymethyl)phenyl-i,3-dicarboxylate 39d (5.89 g, 26 mmol) was dissolved in To 50 methylene chloride, pyridinium chlorochromate (11.30 g, 53 mmol) and sodium acetate (6.47 g, 79 mmol) were added, and the reaction was stirred for 12 hours. 6 〇g Shishijiao was added, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by EtOAc EtOAc EtOAc EtOAc Methyl 3-dicarboxylate 39e (4. 4 g, white solid), yield: 70. 0%. * Step 5 - 5-((3-Phenylphenyl)-hydroxy-methyl]phenyl-indole, 3-dicarboxylic acid methyl ester under ice bath '5-Methylmercaptoalkyl dicarboxylate 39e (4. 〇6 g, 70 mmol) was dissolved in 50 mL of tetrahydrofuran, and a solution of M 3_gas phenylmagnesium bromide in tetrahydrofuran (040 mL, 140 mm 〇i) was added dropwise, and the reaction was stirred for 1 hour. The reaction was quenched by the addition of a saturated aqueous solution of ammonium sulphate. The mixture was extracted with ethyl acetate (50 mL×3), and the organic phase was combined and washed with water (5 mL) and saturated sodium carbonate solution (20 mL), dried over anhydrous sodium sulfate Concentration under reduced pressure, the residue obtained was purified eluting with EtOAc EtOAc EtOAc (EtOAc) 39f (4. 62 g, pale yellow oil), yield: 77. 〇%. Step 6: 3-[(3-Phenylphenyl)-hydroxy-methyl]-5_曱oxycarbonyl-benzoic acid 5-[(3-Chlorophenyl)-hydroxy-methyl]phenyl-1&gt Methyl 3-carboxylate 39f (2. 92 g' 8. 76 mmol) was dissolved in 40 mL of a mixed solvent of methanol and water (v/v = 3:1). Add lithium hydroxide solution (368 mL, 8 76 mmol), the reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure. The mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated Sodium (20 mL) dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give the title product 3-[(3-chlorophenyl)-hydroxy-indolyl]-5-methoxycarbonyl-benzene 95392 197 201242594 acid 39% (2. 78 g, colorless oil), 99.9%. Step 7 3-[(3-Phenylphenyl)-hydroxy-indenyl]-5-(hydroxyindenyl)benzoate oxime 3-[(3-chlorophenyl)-hydroxy-methyl]_5- 39 g (3 g, 9.4 mmol) of methoxycarbonyl-benzoic acid was dissolved in 5 mL of tetranitrofuran, and a solution of 1 Μ borane in tetrahydrofuran (14 mL, 14.1 mmol) was stirred at 50 ° C 12 hours. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. The filtrate was concentrated under reduced pressure to give the title compound, m,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The next reaction was carried out without purification. Step 8 3-[(3-Phenylphenyl)-[2_(indolylamino)ethoxy]indolyl]_5_(fluorenyl) benzoic acid oxime ester The crude product 3-[(3- Chlorophenyl)-trans-yl-indenyl]-5-(methyl)methyl decanoate 39h (2.77 g, 9.1 mmol) and N-(2-ethyl) carbamic acid The ester It (2.15 g, 18.1 mmol) was dissolved in 50 mL of toluene, and p-toluenesulfonic acid (1.72 g, 9.1 mmol) was added and the mixture was stirred for 3 hours. The reaction mixture was concentrated with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The obtained residue was purified by EtOAc EtOAc EtOAc (EtOAc) - (via thiol) awkward 95392 198 201242594 yttrium ester 39i (890 mg, colorless oil), yield: 24.0%. ninth step 3-[(3-phenylphenyl)-[2- (Methoxycarbonylamino)ethoxy]methyl]-5-indolyl-parabencarboxylic acid oxime ester 3-[(3-phenylphenyl)-[2-(indolylcarbonylamino)ethoxy ]]] -5-(hydroxyindenyl) benzoic acid oxime ester 39i (890 mg, 2.19 mmol) was dissolved in 30 mL of dichloromethane and (ι,ι,ι_triethoxy)- 1, dihydrogen-1,2-codden moth-3(1H)-_(1.11 g, 2.62 mmol), scrambled reaction for 3 ® hours. The reaction was quenched by adding decyl alcohol and concentrated under reduced pressure. Extract with ethyl acetate (80 mL×3), and combine organic phases, then washed with water (30 mL) and saturated sodium carbonate solution (20 mL) The sodium salt was dried, filtered, and the filtrate was evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Ethyl] ethoxy] fluorenyl] -5-fluorenyl-benzoic acid methyl ester 39 j (500 mg, colorless oil), yield: 56. 0%. Step 10 3-[(3-chloro Phenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl]-5-methoxycarbonyl-benzoic acid 3-[(3-chlorophenyl)-[2-(methoxycarbonyl) Amino)ethoxy]methyl]-5-anthracene-yl benzoate 39j (500 mg, 1.23 mmol) was dissolved in 20 mL of acetonitrile, followed by 10 mL of sodium dihydrogen phosphate (1.5 mg, 9.6 mmol). Solution, 10 mL of sodium hypochlorite (494 mg, 5.49 mmol) and 0.6 mL of hydrogen peroxide, stirred for 12 hours. Add 1 mL of water and extract with ethyl acetate (20 mL×3). 〇mL) and 199 95392 201242594 Washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated.曱Oxocarbonylamino)ethoxy]methyl]-5-methoxycarbonyl-benzoic acid 3 The crude product of 9k (520 mg, white solid) was taken directly to the next step without purification. Step 11 3-[[(15.)-1-[(T-butyloxycarbonyl(fluorenyl)amino) fluorenyl) 2-cyclohexyl-ethyl]aminocarbamimidyl]-5-[(3-phenylphenyl)-[2-(indolylcarbonylamino)ethoxy]methyl]benzoic acid decyl ester ® 3-[(3-Phenylphenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl]-5-indoleoxycarbonyl-benzoic acid 39k (518 mg, 1.23 mmol) and hydrazine -[(250-2-Amino-3-cyclohexyl-propyl]-N-indenyl-carbamic acid tert-butyl ester lg (365 mg, 1.35 mmol) was dissolved in 4 mL of N,N-dioxin To the guanamine, 1-mercaptobenzotriazine (332 mg, 2.46 mmol), 1-(3-diamidinopropyl)-3-ethylcarbodiimide hydrochloride ( 472 mg, 2.46 mmol) and N,N-diisopropylethylamine (1 mL, 4.92 mmol). Add 50 mL of water 'extracted with dioxane (30 mL×3), washed with water (20 mL×2) and saturated sodium carbonate solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and evaporated. The residue obtained was purified by chromatography to afford the title product 3-[[(150-[((((((()))))) Aminoguanidino]-5-[(3-phenylphenyl)-[2-(indolylcarbonylamino)ethoxy]indolyl] decyl benzoate 39m (585 mg, white oil) , Yield: 66.0%. Step 12 1'1-[(251)-2-[[3-[(3-Phenylphenyl)-[2-(曱.oxy)amino) Oxyl] 200 95392 201242594 methyl]-5-(cyclopropylaminomercapto)benzylidene]amino]-3-cyclohexyl-propyl]-N-methyl-aminocarboxylic acid Butyl ester will be 3_[[(15·)-1-[(t-butoxycarbonyl(methyl)amino)indolyl]_2-cyclohexyl-ethyl]aminocarbazinyl]-5-[(3- Methyl phenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]benzoic acid methyl ester 39m (195 mg, 0.25 mraol) dissolved in 10 mL of decyl alcohol, added cyclopropylamine (165 , 2. 9 mmol), stirring reaction at 50 °C After 12 hours, the reaction mixture was concentrated under reduced vacuo. —[2-(曱Oxocarbonylamino)ethoxy]indolyl]-5-(cyclopropylaminoindolyl)benzylidene]amino]_3-cyclohexyl-propyl]-N- Methyl-amino decanoic acid tert-butyl ester 39 η (25 mg, yellow), Yield: 12.0 〇 / 〇 MS m / z (ESI): 699 [M+l] Step 13 1^-[2 -[(3-chlorophenyl)-[3-[[(15')-1-(cyclohexylfluorenyl)-2-mercaptoamine φ-ethyl]aminoindolyl]-5-( Cyclopropylaminomethionyl)phenyl]decyloxy]ethyl]amino decanoate

Under ice bath, N-[(2«-2-[[3-[(3-phenylphenyl)-[2-(methoxycarbonylamino)ethoxy]] yl]-5-(cyclopropyl) Aminobenzyl hydrazino)phenylamino]amino]-3-cyclohexyl-propyl]-N-fluorenyl-amino decanoic acid tert-butyl ester 39η (30 mg, 0.14 mmol) was dissolved in 2 mL of di-gas methane, add 3 mL of a mixed solution of trifluoroacetic acid and dichlorodecane (V/V = 2:1), stir the reaction for 1 hour, add saturated sodium carbonate solution to quench the reaction, adjust the pH to 7 8. Extract with dioxane (10 mL×3), combine the organic phases, wash with water (1〇mLx2) 201 95392 201242594 and saturated sodium chloride solution (10 mL×2), dry over anhydrous sodium sulfate, transfer, decompression The residue was purified by EtOAc (EtOAc) elut elut ))-2-mercaptoamino-ethyl]aminocarbamimidyl]-5-(cyclopropylaminoindenyl)phenyl]decyloxy]ethyl]amino decanoate 39 ( 5 mg, white solid), yield: 25.0%. MS m/z (ESI): 599 [M+l] lH NMR (400 MHz, CDCh): δ 8. 57-7. 86 (ra, 5H), 7. 31-7. 18 (m, 4H), 5.64-5.54 (m, 1H), 5. 34 (m, 1H), 4. 64 (m, 1H), 3.71 - 2.69 (in, 5H), 1.72-0.76 (m, 13H) Example 40 N-[ 2-[(3-Phenylphenyl)-[3-(2-decyloxyethoxy)-5-[[(25.)-2-methylamino]_3-[(3 Friends)-Four Hydrogen π-pyran-3-yl]phenyl]aminoindenyl]phenyl]decyloxy]ethyl]amino decanoate

N-[(l«-l-[[[3-[(3-chlorophenyl)-[2-(indolylcarbonylamino)ethoxy]methyl]-5-(2-methoxy) Oxy)phenylphenyl]amino]methyl]-2- 202 95392 201242594 [(37?)-tetrahydropyran-3-yl]ethyl]-N-decylmonocarbamic acid tert-butyl 3-[(3-Phenylphenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl]-5-(2-decyloxyethoxy)phenylhydrazine Acid 19g (15() mg, 0.34 mmol) was dissolved in 1 mL of N,N-dimercaptocaramine, and 1 [(161)-1-(aminomercapto)-2-[(3) No)-tetrahydro 11-pyran-3-yl]ethyl]-N-indenyl-carboxylic acid tert-butyl ester 3a (103 mg, 0.38 mmol), hydroxy benzotriazole (55 mg, 0. 41 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (78 mg, 0.41 mmol), diisopropylethylamine ( 132 mg, 1.02 mmol), the reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. 20 mL of dioxane was added and the organic phase was washed with water (2 mL) and saturated sodium chloride solution (20 mL) Drying with sodium sulfate, transition, and concentrating the filtrate under reduced pressure. The residue obtained by purification of the solvent system A by thin layer chromatography. The title product Ν-ΙΧΙβ-Ι-Ι; [[3-[(3-Phenylphenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]-5-(2-decyloxy) Ethoxy)phenylhydrazinyl]amino]mercapto]-2-[(3-phantom-tetrahydro- 0-pyran-3-yl]ethyl]-fluorenyl-fluorenyl-amino φ decanoic acid Ester 40a (120 mg, colorless oil), yield: 51. 1%. MS m/z (ESI): 692 [M+1] Step 2 N-[2-[(3-phenylphenyl) -[3-(2-methoxyethoxy)-5-[[(2«-2-methylamino-3-[(3)-tetrahydrofuran-3-yl]phenyl]amine Methyl phenyl] phenyl] decyl] ethyl] carbamic acid methyl ester under ice bath, Ν-[(1«-1-[[[3-[(3-chlorophenyl))-[2 -(曱Oxycarbonylamino)ethoxy]methyl]-5-(2-decyloxyethoxy) adolino]amino]methyl]-2-[(3 left)-tetrahydro 0-pyran-3-yl]ethyl]-N-methyl-amino 203 95392 201242594 Dibutyl carboxylic acid 40a (100 fflg, 〇·ι5 mmol) was dissolved in 1 二 二 , ML trifluoroacetic acid and dichloromethane (v / v = 2 : ^ mixed solution, stirring reaction 丨 hours. Add saturated sodium carbonate solution to quench the reaction, the aqueous phase is extracted with di-methane (1 〇 mL x 3), combined organic phase ,according to Washing with water (10 mL×2) and a saturated sodium chloride solution (1 mL mL), dried over anhydrous sodium sulfate, filtered, filtered, and evaporated to dryness. 2_[(3_Chlorophenyl)-[3-(2-methoxyethoxy)-5-^(250-2-methylamino-3-[(3 oxime-tetrahydrofuran-3) Methyl]phenyl]aminocarbamimidyl]phenyl]methoxy]ethyl]carbamic acid methyl ester 40 (61 mg, white solid), yield: 71.7%. MS m/z (ESI): 592 [M+l] lH NMR (400 MHz, CDCh): δ 7. 47-6. 93 (m, 8H), 5. 67 (s, 1H), 5. 29 and 5. 25 (2s, 1H), 4.14 (m, 2H), 3.98-3.11 (m, 19H), 2.71 (m, 3H), 2.01-1.26 (m, 7H) Example 41 φ N-[2-[ (3-Chlorophenyl(cyclohexylfluorenyl)_2-methylamino-ethyl]aminocarbamimidyl]-5-(2-hydroxyethylaminomethylindenyl)phenyl]methoxy] Ethylaminoformate

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φ first step 3-[[(15·)-1-[(t-butoxycarbonyl(indenyl)amino)indolyl]- 2_cyclohexyl-ethyl]aminocarbazinyl]-5_[ (3-gasphenyl)_[2_(methoxycarbonylamino)ethoxy]indolyl]benzoic acid 3-[[(15·)-ΐ-[(t-butoxycarbonyl(methyl)) Amino)methyl]_2_cyclohexyl-ethyl]aminomethylindenyl]_5-[(3-gasphenyl)-[2_(methoxycarbonylamino)ethoxy]indolyl]benzoic acid Ester 39ιη (585, 0 87 mm〇1) was dissolved in a mixture of 12 mL of decyl alcohol and water (v/v = 3:1), and a solution of lithium hydride (73 mg, 1.74 mmol) was added and stirred. Reaction for 12 hours. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 6 to 7 with citric acid, 1 mL of water was added, and the mixture was extracted with ethyl acetate (1 〇mL×3), and the organic phase was combined and dried over anhydrous sodium sulfate. The residue obtained is purified by eluent column chromatography using eluent column chromatography to give the title product [(2,2,1,1,5,5,5,5,5,5,5 yl) Brewing base]-5-[(3-chlorophenyl)-[2-(decyloxycarbonylamino)ethoxy]indolyl]benzoic acid 41a (110 mg, colorless viscous liquid), 20, 0% . The second step 205 95392 201242594 ^1-[(25|)-2-[[3-[(3-Phenylphenyl)-[2-(methoxylamino)ethoxy] decyl]-5 -(2-hydroxyethylaminomethylindenyl)phenylindenyl]amino]_3-cyclohexyl-propyl]-N-indolyl-aminoindole tert-butyl ester 3-[[(15· )-1-[(t-butoxycarbonyl(indenyl)amino)indolyl]_2_cyclohexyl-ethyl]aminocarbamimidyl]-5-[(3-chlorophenyl)-[2-( Methoxycarbonylamino)ethoxy]methyl]benzoic acid 41a (110 mg, 0.17 mmol) dissolved in 10 mL of methanol. Add ethanolamine (20 mgv 0.33 mmol), 1-hydroxybenzotriazine (45 mg) , 0. 33 mmol) and 1-(3-dimethylaminopropyl)-3-® ethylcarbodiimide hydrochloride (64 mg, 0.33 mmol), diisopropylethylamine (0. 12 mL, 0. 67 mmol) 'Scatch reaction for 12 hours. The reaction mixture was quenched with EtOAc (EtOAc (EtOAc) (EtOAc (EtOAc) Chromatography Purification of the obtained residue in EtOAc EtOAc (EtOAc)曱]]-5-(2-ethylaminomethylmercapto)phenylindoleyl]][rho]amino]-3-cyclohexyl-propyl]-N-indolyl-aminocarboxamidine Ester 41b (65 mg, white solid), Yield: 56.0%. MS / / (ESI): 704 [M+1] The third step 1 '1~[2-[(3-phenylphenyl) -[3-[[(151)-1-(cyclohexyldecyl)_2-methylamino-ethyl]aminoindolyl]-5-(2-ethylaminomethyl) benzene Methyl methoxy]ethyl carbamic acid methyl ester 1^-[(25|)-2-[[3-[(3-phenylphenyl)-[2-(indoleoxycarbonylamine) Ethyl]mercapto]-5-(2-hydroxyethylaminomethylindenyl)phenylhydrazine] 95392 206 201242594 Amino]-3-cyclohexyl-propyl]-N-methyl- Aminoguanidine tert-butyl ester 41b (65 mg, 0.009 mmol) was dissolved in 1 mL of dioxane, and 6 mL of trifluoroacetic acid was added. A mixed solution of chlorodecane (V/V = 2:1), the reaction was stirred for 1 hour. The reaction was quenched by the addition of saturated sodium carbonate solution and the aqueous phase was extracted with dichloromethane (10 mL×3). 〇mLx2) and a saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by thin layer chromatography to afford the title product N-[2- [(3-Chlorophenyl)-[3-[[(15·)-1-(cyclohexyl) fluorenyl) 2-nonylamino-ethyl]aminoindenyl]-5-( 2-hydroxyethylamino fluorinyl) benzyl] methoxy] ethyl amide phthalic acid vinegar 41 (35 mg, white solid), yield: 63. 0%. MS m/z (ESI) : 603 [M+l] 4 丽R (400 MHz, CDC13) : δ 8· 92-6. 90 (m, 9H), 5. 80 (s, 1H), 5.38 (m, 1H), 4.69 (s , 1H), 3.93-2.73 (in, 15H), 2. 02-0. 87 (m, 13H) φ Example 42 N-[2-[(3-Phenylphenyl)-[3-[[(2 «-2-decylamino-3-[(3)-tetrahydropyran-3-yl]propyl]aminoindenyl]-5-mercaptosulfonyl-phenyl]methoxy Methyl]aminocarbamate

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Dissolving sodium 3,5-bis(indolylcarbonyl)phenylsulfonate 42a (5 g, φ 16.89 mmol) in an ice bath with ice-purified 5-oxosulfonylphenyl-1,3-dicarboxylate To 10 mL of hydrazine and hydrazine-dimercaptoamine, 5 mL of acetonitrile was added dropwise to a three-gas oxygen tank (5 mL, 55 mmol), and the reaction was stirred at 70 ° C for 4 hours. The reaction mixture was poured into 200 mL of ice water, and stirred for 1 hour, and filtered to give a white solid, which was dried in vacuo to give the title product 5 </RTI> </RTI> sulfonyl phenyl &lt;, 3-dicarboxylic acid oxime ester 42b (4. 70 g, pink Solid), yield: 95. 〇%. The second step is 5-indolesulfonylphenyl-indole, 3-carboxylic acid decyl ester. Dissolving sodium sulfate (2.80 g, 22.50 mmol) and sodium hydrogencarbonate (2 g, 24.1 Lithium 1) In 45 mL water, 18 mL of 5_ chlorosulfonyl phenyl hydrazine, 3 208 95392 201242594 dicarboxylate dicarboxylate 42b (4. 70 g, 16.07 mmol) in tetrahydro urethane solution 50 ° C The reaction was stirred for 24 hours. The reaction solution was filtered, and a small amount of water was added. The mash was extracted with ethyl acetate (150 ιπΙ &lt; χ 3), and the combined organic phases were washed successively with water (5 〇 mL×2) and saturated sodium chloride solution (50 mL×2). Filtration and concentration of the filtrate under reduced pressure. The obtained residue was purified eluting with EtOAc EtOAc EtOAc EtOAc. Yellow solid), yield: 84.0%. *Three-step 3-oxocarbonyl-5-nonylsulfonyl-benzoic acid. Dissolve 5-methylsulfonylphenyl-i,3-dicarboxylate 42c (3.70 g, 13.6 mmol) 10 mL of sodium hydroxide (544 mg, 13.6 mmol) in methanol was added to 30 mL of acetone, and the reaction was stirred at 50 ° C for 12 hours. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) The phase was washed with water (5 〇 mL×2) and saturated sodium sulphate (5 〇 mL×2), dried over anhydrous sodium sulfate, filtered, and filtrate was concentrated under reduced pressure to give the title product 3-methoxycarbonyl-5-methylsulfonate. Mercapto-benzoic acid 42d (3.20 g, white solid), yield: 91.4%. The fourth step is 3-(hydroxymethyl)-5-mercaptosulfonyl-p-benzoate oxime ester. 3-oxocarbonylcarbonyl-5-mercaptosulfonyl-benzoic acid 42d (3. 20 g) ' 12. 4 mm 〇 i) was dissolved in 38 mL of tetrahydrofuran, and a solution of i M borane in tetrahydrofuran (19 mL, 19 mm 〇1) was added, and the reaction was stirred for 12 hours. The reaction was quenched by the addition of EtOAc, EtOAc (EtOAc) (EtOAc) The mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate (5 mL) and saturated aqueous sodium chloride (50 mL). 5% _ _ 曱 曱 42 42 42 42 42 42 。 。 。 。 。 。 。 。 。 。. The fifth step is 3 - mercapto-5-methyl hydrazino benzoic acid methyl benzoic acid methyl 3-(hydroxymethyl)-5-nonylsulfonyl-benzoic acid methyl ester 42e (2. 85 g, 11.68 mmol) was dissolved in 25 niL of dichloromethane, and the chromic acid pyridine rust salt (6.30 g, 29.2 mmol) and sodium acetate (2.4 〇g, 29.2 mmol) were added to the reaction for 12 hours. The title product, 3-mercapto-5-methylsulfonyl group, was obtained by the addition of 6. 〇g 矽 gum, filtered, and the filtrate was reduced under reduced pressure. The residue obtained was purified by eluent column chromatography. Methyl benzoate 42f (2 g, white solid), yield: 70. H NMR (400 MHz , CDCh) : δ 10. 16 (s, 1H), 8. 84 (s, 1H), 8.8G (s, 1H), 8.64 (s' 1H), 4. G3 (s, 3H), 3. 14 (s, 3H) Step 6 3-[(3-Phenylphenyl)-hydroxy-methyl]-5-methyl hydrazino _ 曱 曱 甲酯 冰 冰 ' ' ' 3 -Methylmercapto-5-mercaptosulfonyl-benzoic acid decyl ester 42f (1 g, 4.1 mmol) was dissolved in 8.5 mL of tetrahydro-u-d-d, and 1 μ 3-chlorophenylmagnesium bromide was added dropwise. A solution of tetrahydrofuran (8.5 mL, 8.5 mmol) was stirred for 1 hour. The reaction was quenched with a saturated solution of EtOAc (EtOAc) (EtOAc (EtOAc) (EtOAc) Decompression 95392 210 201242594 Concentration 'The residue obtained was purified by eluent column chromatography eluting with eluent system B to give the title product 3-[(3-chlorophenyl)-hydroxy-methyl]methyl Methyl benzoate 42 g (1. 30 g, white solid), yield: 89. 〇%. The seventh step 3_[(3_气本基)_(2,2,2_二气胺胺乙) Oxy-indenyl]_5_methyl hydrazino-benzoic acid methyl vinegar under ice bath, will 3-[(3-Chlorophenyl)-hydroxy-methyl]_5_fluorenyl decyl-benzoic acid oxime ester 422 (1.30 §, 3.67 111111〇1) was dissolved in 121^A® benzene, added three Chloroacetonitrile (2.65 g, 18.35 mmol) and diazabicyclo(56 mg, 0.37 mmol) were stirred at room temperature for 3 h. The reaction mixture was filtered with EtOAc EtOAc (EtOAc) (EtOAcjjjjjjjj - Tris-iminoacetamido)oxy-indenyl]-5-decylsulfonyl-benzoic acid decyl ester 42h (1.90 g, yellow oil). φ Step 8 3-[(3-Chlorophenyl)-[2-(indolylcarbonylamino)ethoxy]indolyl]-5-fluorenylsulfonyl-benzoic acid decyl ester [(3-Chlorophenyl)-(2, 2, 2-trichloroiminethane)oxy-methyl]-5-mercaptosulfonyl-benzoic acid methyl ester 42h (1. 90 g, 3. 67 mmol) and N_(2-hydroxyethyl)amino decanoic acid methyl ester It (672 mg, 5.64 mmol) dissolved in 15 mL of methane toluene's addition of tri-I methyl methic acid trimethyl vinegar (896 mg, 4.04 mmol), spoiled for 1 hour. The reaction was quenched by the addition of a saturated aqueous solution of sodium bicarbonate, and extracted with dichloromethane (50 mL×3), washed sequentially with water (20 211 95392 201242594 mL) and saturated sodium carbonate solution (20 mL) dried over anhydrous sodium sulfate, filtered, filtrate Concentration under reduced pressure gave the title product 3-[(3-(3-phenylphenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]-5-decylsulfonyl----- 1%, colorless oil), yield: 59.0%. The ninth step 3-[(3-chlorophenyl)-[2-(indolylcarbonylamino)ethoxy]methyl]-5-mercaptosulfonyl-benzoic acid 3--(3- Phenyl)-[2-(methoxycarbonylamino)ethoxy]methyl] ® -5-methyl decyl-benzoic acid oxime ester 42i (1 g, 2.2 mmol) dissolved in 40 To a mixed solvent of mL sterol and water (V/V = 3:1), a hydrazine hydroxide solution (277 mg, 6.6 mmol) was added, and the reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure. EtOAc (100 mL) and water (50 mL) were added, and the pH was adjusted to less than 3 with 1M hydrochloric acid. The mixture was separated and extracted with ethyl acetate (30 mL×3). (30 mL) and saturated sodium carbonate solution (20 mL), dried over anhydrous sodium sulfate, filtered, and filtered, and then evaporated to give the title compound (3) ([3-chlorophenyl]-[2-(oxygen) Carbonylamino)ethoxy]indolyl]-5-methylsulfonyl-benzoic acid 42j (810 mg, white solid), 83.6%. The tenth step N~[(l«-l-[[[3-[(3-chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]-5-methylsulfonium) Aminobutyryl]amino]mercapto]-2-[(3i?)-tetrahydropyran-3-yl]ethyl]-N-methyl-amino decanoic acid tert-butyl ester ice bath 3-[(3-Chlorophenyl)-[2-(indolylcarbonylamino)ethoxy]methyl]-5-methylsulfonyl-benzoic acid 42j (150 mg, 0.34 mmol) Dissolved in 10 mL of N, N-dimercaptocaramine, and then added N-[(15)-1-212 95392 201242594 (aminomethyl)-2-[(3妁-tetrahydropyran-3) -yl]ethyl;|-N-methyl monocarboxylic acid, second butyl g, 3a (102 mg, 0.37 mmol), i-pyridinium triazine (91 § mg, 0.68 mmol) and 1-( 3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (130 mg, 0·68 mmol), diisopropylethylamine (132 mg, 1. 02 mmol), rt The reaction was stirred for 12 hours. The reaction was concentrated under reduced pressure. dichloromethane (20 mL), and then evaporated. Concentration, purification of the obtained residue by thin layer chromatography with a developing solvent system A, to obtain a standard The title product ^[(151)-1-[[[3-[(3-phenylphenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]-5-fluorenyl fluorenyl-phenylhydrazine) Tertyl]amino]mercapto]_2-[(3 and)-tetrahydropyran-3-yl]ethyl]-N-indolyl-amino decanoic acid tert-butyl ester 42k (127 mg, colorless oil Yield: 53.8% MS m/z (ESI): 696 [M+l] Step 11 N-[2-[(3-chlorophenyl)-[3-[[(2β-) 2-mercaptoamino-3-[(3Λ-tetrahydroφpyran-3-yl]propyl]aminoindolyl]-5-methylsulfonyl-phenyl]decyloxy]ethyl曱-[(15·)-ΐ-[[[3-[(3-chlorophenyl)-[2-(曱-oxycarbonylamino)ethoxy] oxime] ]]-5-fluorenylsulfonyl-phenylhydrazinyl]amino] fluorenyl]-2-[(3left)-tetrahydropyran-3-yl]ethyl]-fluorenyl-fluorenyl-amine Tetrabutyl phthalate 42k (127 mg, 0.18 mmol) was dissolved in 10 mL of dioxane, and a mixture of 6 mL of trifluoroacetic acid and dichloromethane (v/v = 2:1) was added. The reaction was carried out for 1 hour. The reaction was quenched by the addition of saturated sodium carbonate solution, and the aqueous phase was extracted with dichlorohydrazine (10 mL×3). The organic phase was combined with water (10 213 95392 201242594 mL×2) and saturated sodium chloride solution. The title product N_[2-[(3-chlorophenyl)_[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[ 3-[[(25〇-2_Τ-ylamino-3-[(3-phanyl-tetrahydropyran-3-yl]propyl]aminoindolyl]-5-fluorenyl)-phenyl] Ethyl methoxy]ethyl] carbamic acid decyl ester 42 (90.9 mg, white solid), yield: 83. MS m/z (ESI) : 596 [M+l]

'H NMR (400 MHz , CDCh) : δ 8. 70-7. 15 (m, 8H), 5. 55 (s, 1H), 5.45 (s, 1H), 3.95-3.15 (in, 14H), 3.10 (s, 3H), 2.75 (s, 3H), 2.00 (m, 4H), 1.31 (m, 3H) Example 43 N-[2-[(3-Phenylphenyl)-[3-[[ -1-(cyclohexylfluorenyl)_2-fluorenylamino-ethyl]aminoindenyl]-5-methylsulfonyl-phenyl]methoxy]ethyl]

Methyl amino decanoate o=s=o

?^-[(251)-2_[[3-[(3-Chlorophenyl)-[2-(indolylcarbonylamino)ethoxy]indolyl]-5-methylsulfonyl- alum Tertyl]amino]-3-cyclohexyl-propyl] 214 95392 201242594 -N-decyl-carbamic acid tert-butyl ester 3-[(3-phenylphenyl)-[2-(oximeoxycarbonyl) Amino)ethoxy]methyl]-5-mercaptosulfonyl-benzoic acid 42j (150 mg, 0.34 mmol) and N-[(2Λ-2-amino-3-cyclohexyl-propyl) -N-Mercapto-aminocarboxylic acid tert-butyl vinegar lg (101 mg, 0·37 mmol) dissolved in 6 mL of N,N-didecyl decylamine 'Addition of 1-hydroxybenzotriazole (91 . 8 mg, 0.68 mmol), 1-(3-diodinopropyl)-3-ethylcarbodiimide hydrochloride (130 mg, 0.68 mmol) and N,N-diisopropylethylamine (131. 6 mg, 1.02 mmol), stir the reaction for 12 hours. Add 50 mL of dichloromethane, wash with water (20 mL×2) and saturated sodium carbonate solution (20 mL×2), dry over anhydrous sodium sulfate and filter. Concentration by pressure, the residue obtained was purified by EtOAc (EtOAc) (EtOAc) Amino) ethoxy] fluorenyl]-5-methyl fluorenyl-benzoquinone Amino]-3-cyclohexyl-propyl]-N-indolyl-amino decanoic acid tert-butyl ester 43a (131 mg, colorless viscous), yield: 55.7 ° / 〇. _ MS m/z ( ESI) : 694 [M+l] Step 2 N-[2-[(3-Chlorophenyl)-[3-[ [(15)-1-(cyclohexyldecyl)-2-decylamino) -ethyl]fe-based fluorenyl]-5-fluorenyl fluorenyl-phenyl]methoxy]ethyl] carbamic acid hydrazine vinegar under ice bath 'will ^[(25^-2-1^3 -1^(3-chlorophenyl)-[2-(indolylamino)ethoxy]methyl]-5-methyl thiol-acidylamino]amino]_3_cyclohexyl- Propyl]-N-mercapto-amino decanoic acid terpene vinegar 43a (131 mg, 0·19 mmol) was dissolved in 10 mL of di-methane, and 6 mL of Sandun 95392 215 201242594 acid and dichloromethane was added. The mixed solution was calcined (v/v = 2:1), and the reaction was stirred for 1 hour. The reaction was quenched by the addition of saturated sodium carbonate solution, and the aqueous phase was extracted with dichloromethane (3×3), and the organic phase was combined with water (1 〇mL×2) and The mixture was washed with a saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Chlorophenyl)-[3-[ [ (15)-1-(cyclohexylmethyl)_2-methylamino-ethyl]aminoindenyl]_5-methylsulfonyl-phenyl]decyloxy]ethyl]aminocarbamate Ester 43 (91 mg, white solid), yield: mp. ® MS m/z (ESI): 594 [M+l] W NMR (400 MHz, CDC13): δ 8· 61-7, 10 (m,8H), 5. 69 and 5.60 (2s, 1H), 5.46 (s, 1H), 4.68 (m, 1H), 3.69-3.20 (in, 8H), 3. 11 {br. s, 4H), 2. 75 (s, 3H), 1. 95-0. 87 ( m, 13H) ? Example 44 N-[2-[(3-fluorophenyl)-1:6-1^(250-2-decylamino-3-[(3疋)_tetrahydro•pyridyl]喃-3-yl]propyl]aminoindenyl]-2,3-dihydrobenzofuran-4-yl]nonyloxy]ethyl]amino ruthenic acid

95392 216 201242594

ester

4-carboyl-2,3-dihydrobenzopyrano-6-nonanoic acid methyl hydrazine 26a (2 g, 9.6 mmol) was dissolved in 20 inL tetrazolium 5小时。 The reaction mixture was stirred and stirred for 0. 5 hours. Add 20 mL of saturated sodium bicarbonate solution, the aqueous phase is extracted with ethyl acetate (80 mL×3), and the organic phase is combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by eluent column chromatography eluting to afford the title product 4-[(3-fluorophenyl)-carbyl-indenyl]-2,3-dihydrobenzopyran-6- The carboxylic acid oxime ester 44a (2.40 g, pale yellow oil), yield: 83. 〇%. Step 2 4-[(3-Fluorophenyl)-[2-(indolylcarbonylamino)ethoxy]methyl]-2,3-dihydrobenzon-f--6-treazone vinegar Dissolving 4-[(3-fluorophenyl)-carbyl-methyl]-2,3-dihydro benzopyran-6-tresonic acid ester 44a (2. 40 g, 7.9 mmol) 50 mL of toluene, 217 95392 201242594 Methyl N-(2-hydroxyethyl)amine decanoate (l go g, ΐ5·8 mmol) and p-toluenesulfonic acid monohydrate (15〇g, 7) were added in sequence. 9mm〇1), i3 (rc was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure. )-[2-(methoxycarbonylamino)ethoxy]indolyl] 2,3-dihydrobenzofuran-6-carboxylic acid oxime ester 44b (2.60 g, pale yellow oil), yield : 81.5%. The third step ® 4-[(3-fluorophenyl)-[2-(indolylcarbonylamino)ethoxy]methyl]_2, 3-dihydrogen and sigma-6- Capric acid 4-((3-fluorophenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]-2,3-dihydrobenzofuran-6-carboxylate 44b ( 2.60 g, 6.45 mmol) dissolved in a mixed solvent of 33 mL of acetone and methanol (V/v = i〇: 1) Add sodium hydroxide (258 mg, 6.45 mmol), stir the reaction for 12 hours. Concentrate the reaction solution under reduced pressure, add 10 mL of water, add 1 Μ hydrochloric acid to adjust the pH to φ at 3, and extract with ethyl acetate (8 〇mLx3) The organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated 3_Dihydrobenzofuran-6-decanoic acid 44c (2.30 g, white solid), yield: 91.6%. The fourth step N-[2-[ [6-[[(250-2-) (t-butoxycarbonyl(indenyl)amino)_3_[(3 friends)-tetraapyran-3-yl]propyl]aminoindenyl]_2,3-dihydrobenzofuran-4_ Methyl]-(3-fluorophenyl)nonyloxy]ethyl]amino decanoate N-[(2«-3-cyclohexyl-2-[[4-[(3-fluorophenyl)-) [2-(曱 oxycarbonylamine 95392 218 201242594 yl) ethoxy] fluorenyl]-2,3-dihydrobenzofuran-6-carbonyl]amino]propyl]-N-methyl-amino hydrazine '3-[(3-Fluorophenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]-2,3-azabenzoflavinium under ice bath of tert-butyl acid -6-decanoic acid 44c (150 mg, 〇. 39 mmol) dissolved in 4 mL of N,N-dimethylformamide In the middle, ν-[(ι$) -1-(aminomethyl)-2-[(3Λ〇-tetrahydron-pyran-3-yl)ethyl]-fluorenyl-fluorenyl-carbonyl acid Tributyl ester 3a (115 mg, 0.42 mmol), 1-hydroxybenzotriazole (104 mg, 0.77 mmol) and 1-(3-diamidinopropyl)-3-ethylcarbodiimide salt The acid salt (147 mg, 0. 77 mmol) was added dropwise diisopropylethylamine (150 mg, 1.16 mmol). The reaction solution was concentrated under reduced pressure. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Chromatography to purify the residue obtained from the solvent system A to give the title product N-[2-1^6-(^(25)-2-(t-butoxy-yl(methyl)amino)-3-[ (3 and)-tetrahydro 0-pyran-3-yl]propyl]aminoindenyl] ^ 3-dihydrobenzoin-4-yl]-(3-fluorophenyl)decyloxy] Ethyl] carbamic acid oxime ester 44d (131 mg, colorless wax), yield: 52. 8%. MS m/z (ESI): 644 [M+l] Step 5 N-[2-[ (3-fluorophenyl)-[6-[ [(25*)-2-decylamino-3-[(3))-tetrahydropyran-3-yl]propyl]amino fluorenyl ]-2,3-Dihydrobenzofuran-4-yl]nonyloxy]ethyl]amino decanoic acid methyl ester under ice bath 'N-[2-[[6-[[(2«-2) -(t-butoxycarbonyl(methyl)amino)-3-[(3/?)-tetrahydropy ratio °N--3-yl]propyl]aminoindenyl]_2, 3- 95392 219 201242594 Benzyl benzofuran-4-yl]-(3-phenylphenyl)methoxy]ethyl]carbamic acid oxime 44d (131 mg, 0·20 mmol) dissolved in 10 mL of dichloropurine To the alkane, 6 mL of a mixed solution of trifluoroacetic acid and dichloromethane (V/V = 2:1) was added, and the reaction was allowed to stand for 1 hour. The reaction was quenched by the addition of a saturated sodium carbonate solution, and the aqueous phase was extracted with dichloromethane ( 1〇mLx3), the organic phase was combined, washed with water (1〇mLx2) and saturated sodium hydride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified to give the title product N-[2-[(3-fluorophenyl)-[6-[[(25))-2- decylamino-3-[(3)- Tetrahydropyrano-3-yl]propyl]aminoindenyl]-2,3-dihydrobenzopyrene-β-n-yl]nonyloxy]ethyl]amino decanoic acid 44 (102 mg, mp. , 5. 85 (s, 1H), 5.36 (s, 1H), 4.61-4.53 (m, 2H), 4.04-3.03 (m, 13H), 2.76 (s, 3H), 2.06-1.29 (m, 13H) % Example 45 N-[2-[(3-Chlorophenyl)-[3-cyano-5-[[(150-1-(cyclohexylmethyl)-2-decylamino-ethyl]] Amino fluorenyl]phenyl]methoxy]ethyl; I amino decyl decanoate

95392 220 201242594

3-aminomercapto-5-[(3-phenylphenyl)-[2-(indolylcarbonylamino)ethoxy]

Methyl]benzoic acid methyl ester 3-((3-chlorophenyl)-[2-(indolylcarbonylamino)ethoxy]methyl]-5-oximeoxycarbonyl-benzoic acid 39k (2 46 g, 5. 83 mmol) dissolved in 50 mL of tetrahydrofuran 'Sequentially added 1-hydroxybenzotriazole (866 mg, 6.41 mmol) and 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide hydrochloride (i.34 g, 7 mmol), aqueous ammonia (3.89 mL, 58.3 mmol) was added dropwise, and the reaction was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The residue obtained was purified by eluent column chromatography to afford the title product: 3-aminomethylmercapto-5-[(3-phenylphenyl)-[2-(indoleoxycarbonylamino) ethoxy Methyl phenyl phthalate 45a (710 mg, white powder), yield: 28.9%. The second step 3-[(3-chlorophenyl)-[2-(methoxy)amino]ethoxy]indolyl]-5-cyano-benzoic acid decyl ester under ice bath 'will 3- Aminomercapto-5-[(3-phenylphenyl)-[2-(oxime 95392 221 201242594 arunylamino)ethoxy]methyl]benzoic acid methyl ester 45a (510 mg, 1.21 mm 〇1) Dissolved in 20 mL of dichloromethane, triethylamine (368 mg, 3.64 mmol) ' Add 1 mL of trifluoroacetic anhydride (3〇4 mg, l 45 mm〇i) of dichlorodecane The solution was stirred at room temperature for 1 hour. A small amount of water was added to the reaction mixture, and extracted with dioxane (50 mL×3). The organic phases were combined, washed sequentially with hydrochloric acid (20 mL×2), saturated sodium bicarbonate (2 mL) and saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, EtOAcjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -5-Cyano-benzoic acid decyl ester 45b (480 mg, white oily liquid), yield: 98.4%. Step 3 3-[(3-Phenylphenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl]-5-cyano-benzoic acid 3-[(3-Phenylphenyl) -[2-(曱Oxocarbonylamino)ethoxy]indolyl]-5-cyano-benzoic acid oxime ester 45b (668 mg, 1.66 mmol) dissolved in 40 mL φ methanol and water (V/V A mixed solution of = 3 : 1) was added with a lithium hydroxide solution (209 mg, 5 mmol), and the reaction was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure. ethyl acetate (100 mL) and water (50 mL), and the mixture was adjusted to pH 3 with 1M hydrochloric acid, and the mixture was separated and extracted with ethyl acetate (30 mL×3). The title product 3-((3-phenylphenyl)-[2-(methoxycarbonylamine) was obtained. Ethyl] ethoxy] fluorenyl]-5-cyano-benzoic acid 45c (482 mg, colorless viscous liquid), 74.8%. Fourth step 222 95392 201242594 Ν-[(25·)-2-[[3-[(3-Phenylphenyl)-[2-(oximeoxycarbonylamino)ethoxy]methyl]-5-cyanide 3-[(3-phenylphenyl)-[2-(A) 3-aminophenylamino]-3-cyclohexyl-propyl]-N-methyl-amino decanoic acid tert-butyl ester Oxycarbonylamino)ethoxy]indolyl]-5-cyano-benzoic acid 45c (100 mg, 0.25 mmol) and hydrazine-[(25.)-2-amino-3-cyclohexyl-propane ]]-Ν-fluorenyl-amino decanoic acid tert-butyl ester lg (67. 3 mg, 〇· 25 mmol) was dissolved in 6 mL of N,N-dimethyl decylamine, and hydroxybenzobenzene was added. Triazole (67. 3 mg, 0.5 mmol), 1-(3-dimethylamine® propyl)-3-ethylcarbodiimide hydrochloride (95. 4 mg, 0.5 mmol) The reaction was stirred for 12 hours with 10 mL of N,N-diisopropylethylamine. Add 50 mL of dioxane, wash with water (20 mL×2) and saturated sodium chloride solution (20 mL×2) successively, dry over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure and purified by thin layer chromatography The residue obtained the title product N-[(250-24 0-1:(3- phenylphenyl)-[2-(indoleoxycarbonylamino)ethoxy] decyl]-5-cyano-benzoquinone醯]]amino]-3-cyclohexyl-propyl]-N-indolyl-• tert-butyl carbazide 45d (125 mg, white solid) (ESI): 641 [M+l] Step 5 N-[2-[(3-Chlorophenyl)-[3-cyano-5-[[(15*)-l-(cyclohexylmethyl)) Methyl 2-methylamino-ethyl]aminomethylindenyl]phenyl]decyloxy]ethyl]amino decanoate under ice bath 'will be Ν-[(25·)-2-[[ 3-[.(3-Chlorophenyl)-[2-(indolylamino)ethoxy]indolyl]-5-cyano-benzylidenyl]amino]-3-cyclohexyl- Propyl]-fluorenyl-mercapto-amino decanoic acid tert-butyl ester 45d (125 mg, 0. 20 mmol) 95392 223 201242594 mL of trifluoroacetic acid and dichloropurine dissolved in 10 mL of dichloromethane, 6 hexane (V/V = 2: 1) mixed solution, stir the reaction for 丨 hours. Add saturated carbonic acid. The solution was quenched, the aqueous phase was extracted with dichloromethane (1 〇 '&gt;&lt; 3), and the organic phases were combined, washed sequentially with water (1 〇mL×2) and saturated sodium carbonate solution (1 〇mL×2), anhydrous sodium sulfate The title compound N-[2-[(3-chlorophenyl)-[3-cyano-5-[[] was obtained. (150-1-(cyclohexylmethyl)_2-methylamino-ethyl]aminoindenyl]phenyl]decyloxy]ethyl]amino decanoate-45 (24 mg, white Solid), Yield: 22.7%. MS m/z (ESI): 541 [M+l] NMR (400 MHz, CDC13): δ 8. 57-7. 09 (m,8H),5. 76 (m, 1H), 5.40 (m, 1H), 4.65 (ra, 1H), 3.94-3.08 (m, 9H), 2.71 (s, 3H), 1.88-0.85 (m, 13H) Example 46 1^ -[2-[(3-Phenylphenyl)-[3-[(2)-2,3-dihydroxypropoxy]-5-•[[(25)-2-methylamino-3- [(3N)-tetrahydrofuran-3-yl]propyl]aminomethylindenyl]phenyl]methoxy]ethyl]amino decyl decanoate

224 95392 201242594

Step 3 - Meryl-5-methyl-yl-benzoic acid Methyl 5-phenol-1, dicarboxylic acid lh (10.50 g, 50 _〇1) was dissolved in 120 mL of sterol and water (V/ In a mixed solvent of V = 3 : 1), a lithium hydroxide solution (4. 70 g, 112 mmol) was added and the reaction was stirred for 12 hours. The reaction mixture was concentrated with EtOAc EtOAc m.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 71. 4%. Step 2 3-Benzyloxy-5-mercaptocarbonyl-benzoic acid 3-Hydroxy-5-methylcarbonyl-benzoic acid 46a (3 g, 15.3 mmol) was dissolved in 100 mL of water and added Potassium carbonate (5.28 g, 38.2 mmol), phenylhydrazine chloride (2.37 g, 16.8 mmol) was added dropwise, and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. Benzhydryloxy-5-mercaptocarbonyl-benzoic acid 46b (17 g, white solid). Step 3 3-Benzyloxy-5-(hydroxyindenyl)benzoate oxime ester The crude 3-benzylideneoxy-5-mercaptocarbonyl-benzoic acid® 46b (16 g) was obtained on ice. , 50 mmol) was dissolved in 200 mL of tetrahydrofuran, and 1.0 Torr of borane (75 mL, 75 mmol) was added dropwise, and the mixture was stirred and stirred at 50 ° C for 3 hours. The reaction was quenched by the addition of EtOAc (EtOAc)EtOAc. 46% (9 g, white solid), yield: 60. 0%. Step 4 3-Benzyloxy-5-fluorenyl-benzoic acid oxime ester φ 3-Benzenyloxy-5-(hydroxyindenyl)benzoate oxime ester 46c (ice bath) 9 g, 30 mmol) dissolved in 250 mL of dichlorohydrazine, adding chlorochromic acid 0 to 0 rust salt (20.30 g, 94 mmol) and sodium acetate (7.74 g, 94 mmol), stirring at room temperature for 2 hours . After adding 6.0 g of phthalocyanine, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified from EtOAc EtOAc EtOAc EtOAc The decyl decanoate 46d (9 g, gray solid) was taken to the next step without purification. The fifth step 226 95392 201242594 3-benzene f-oxyl-5-[(3-chlorophenyl)--------------------- _5_尹酿基_Benzene acid Yin 黯 46d (δ.90 g, 30 ιι 1) dissolved in 6 〇 dihydrofuran drops 1.0 Μ 3-chlorophenyl magnesium bromide (60 mL, 6〇mm〇i), the reaction was stirred for 0.5 hours. 150 mL of saturated ammonium hydride solution was added, the aqueous phase was extracted with ethyl acetate (100 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution (mL) dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Rough beam

The title product 3-cupidoxy-5_[(3_chlorophenyl)-substituted-indenyl]benzidine^methicone 46e (12.5Gg 'self-color (tetra))' product is directly purified in the next step without purification [(3-Chlorophenyl)-hydroxy-indenyl]_5-hydroxy-benzoic acid decyl ester will be crude 3-benzylideneoxy-5_[(3-chlorophenyl)-hydroxy-methyl-methine Sa 46e (12. 50 g, 30 mmol) dissolved in a mixed solvent of 16 mL of methanol water (V/V 3 '1) 'Addition of a hydroxide chain solution (1 η 28 mmol) 'Stirring reaction for 12 hours. The reaction solution is concentrated under reduced pressure: the acid is adjusted to a pH value of less than 3, 1 Torr of this water is added, and the salt of the salt can be extracted with ethyl acetate, and the organic phase is combined, dried over anhydrous sodium sulfate, and the reaction is collapsed. Purification by column chromatography eluting the residue obtained by elution of (4) of B to give the title product: 3-[(3-chlorophenyl)-silyl-methyl]_5_(tetra)-m-methyl ester 46f (7 g, white waxy solid), 76 3 %.第七文Step 7 [(3-Phenylphenyl)-indole (methoxy(tetra)amino)ethoxy]methyl]riwu-benzoic acid oxime ester ^ 95392 227 201242594 3-[(3-chlorobenzene) Methyl)-hydroxy-methyl]-5-hydroxy-p-formic acid methyl ester 46 £ (7 §, 24 111111 〇 1) and ]^-(2-hydroxyethyl) carbamic acid formic acid 11; (566 g, 47. 9 mmol) dissolved in 150 mL of toluene, adding p-toluene acid (4.55 g, 24 _ 〇 1), 13 (TC dehydration stirring reaction 丨. 5 hours. The reaction solution was concentrated under reduced pressure, using a silica gel column chromatography The obtained residue was purified with EtOAc (EtOAc) to give the title product 3-[(3-chlorophenyl)-[2-(indoleoxycarbonylamino)ethoxy]methyl]-5-hydroxy-benzoic acid Methyl ester 46g (3.50 g, yellow yttrium solid), yield: 37.0%. Step 8 3-[(3-Phenylphenyl)-[2-(methoxymethylamino)ethoxy] Methyl]_5_[(2,2-dimethyl-1,3-dioxolan-4-yl)nonyloxy]phenyl decanoate 3-((3-chlorophenyl)-[2 -(methoxycarbonylamino)ethoxy]methyl]-5-hydroxy-benzoic acid methyl ester oxime (5 〇〇, 1.27 mmol), [(450-2, 2-dimethyl-1) , 3-dioxolan-4-yl]nonanol (2〇2 mg, 153 mm〇1) and diphenylphosphine (5 00 mg, 1. 9 _〇1) Dissolved in 3 mL of tetrahydrofuran, dripping # Adding diethyl azodicarboxylate (332 mg, 1. 9 mmol), stirring for 12 hours. The reaction solution was concentrated under reduced pressure. The residue obtained was purified by eluent column chromatography to afford the title product: 3-[(3-chlorophenyl)-[2-(methoxycarbonylamino)ethoxy] decyl 2 Base &lt;, 3-dioxolan-4-yl) decyloxy] benzoic acid oxime ester (945 mg, white flaky solid), the product was directly subjected to the next reaction without purification. -[(3-Phenylphenyl)_[2-(indolylcarbonylamino)ethoxy]methyl]_5_ [(2,2-dimercapto-1,3-dioxolan-4-yl)曱oxy]benzoic acid 228 95392 201242594 3-[(3-Phenylphenyl)-[2-(methoxyamino)ethoxy]methyl]-5-[(2'2- Dimethyl-1'3-dioxolanyl)methoxy]benzoic acid formazan 46h (645 mg, 1.27 mmol) dissolved in 12 mL of methanol and water (v/v = 3: hydrazine in a solvent mixture) 'Adding a hydrazine hydroxide solution (134 mg, 3.18 mmol)' to the reaction for 12 hours. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 6 to 7 with citric acid. The mixture was extracted with ethyl acetate (1 mL) (EtOAc) (EtOAcjjjjjjj Product 3-[(3-Phenylphenyl)-[2-(methoxy)amino]ethoxy]methyl]-5-[(2,2-dimethyl-1,3-dioxolan) Ring_4-yl)methoxy]benzoic acid 46i (376 mg, colorless viscous liquid), 6 %. The tenth step N-[(l(3-chlorophenyl)-[2-(indolylcarbonylamino)ethoxy]indolyl]-5-[(2,2-dimethyl-1,3- Dioxolane-4-yl)methoxy]benzhydryl]amino]indenyl]-2-[(3 and)-tetrahydropi-pyranyl-3-yl]ethyl]decyl-amine 3-[(3-Phenylphenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]-5-[(2, 2-difluorene) under ice bath of tributyl methacrylate Benzyl-1,3-dioxolan-4-yl)methoxy]benzoic acid 46i (313 mg, 0.64 mmol) was dissolved in 4 mL of N,N-didecylamine and added sequentially卜[(1 phanyl-1-(aminomethyl)-2-[(3)-tetrahydro 0-pyran-3-yl]ethyl]-N-decyl-remediate tert-butyl ester 3a (175 mg, 0.64 mmol) '1-Hydroxybenzotriazole (丨〇4 mg, 〇·77 mmol) and di(3-diamidinopropyl)-3-ethylcarbodiimide hydrochloride (147 mg, 0.77 mmol), diisopropylethylamine (413 mg, 3.2 mmol) was added dropwise, and the mixture was stirred at room temperature for 229 95392 201242594 for 12 hours. The reaction mixture was concentrated under reduced pressure and 2 mL of dichloromethane was added. The phases were washed with water (20 raL) and saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate The resulting residue was purified by EtOAc (EtOAc) eluting [(2,2-·-Mercapto-1,3-1,3-pentyl-4-yl)methoxy]phenylindenyl]amino]indenyl]-2-[(3)-tetrahydro </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; : 748 [M+1] The eleventh step N-[2-[(3-chlorophenyl)-[3-[(2))-2,3-dihydroxypropoxy]-5-[[( 25^-2-Methylamino-3-[(3^0-tetrahydropyran-3-yl)propyl]aminoindenyl]phenyl]decyloxy]ethyl]aminocarboxylic acid Under the ice bath of methyl ester, Ν-[(1«-1-[[[3-[(3-chlorophenyl)-[2-(methoxy)amino)ethoxy]methyl]-5 -[(2,2-dimethyl-1,3-dioxolan-4-yl)nonyloxy] aryl]amino]indenyl]-2-[(3 and)-tetra Π-pyran-3-yl]ethyl]-fluorenyl-fluorenyl-amino decanoic acid tert-butyl ester 46j (199 mg, 0.27 mmol) was dissolved in 10 mL of dioxane, and 6 mL of triduronic acid was added. A mixed solution of dichlorosilane (V/V = 2:1) was stirred for 1 hour. The reaction was quenched by the addition of a saturated aqueous solution of sodium carbonate. The aqueous phase was extracted with methylene chloride (1 〇mL×3), and the organic phase was combined and washed with water (1 〇mL×2) and saturated sodium carbonate solution (10 mL×2) Filtration and concentration of the filtrate under reduced pressure. 3_di-propylpropoxy] 230 95392 201242594 -5-[ [25^-2-decylamino-3-[(3Λ〇-tetrahydro-0-pain-3-yl]propyl]amino)曱醯[]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]匪R (400 MHz , CDC13) : δ 7. 72-7. 22 (m, 7H), 6. 98 (s, 1H), 6.51 (s, 1H), 5.30 (s, 1H), 4.03 (m, 3H), 3.89-3.02 (m, 16H), 2.54 (m, 3H), 1.96-1.23 (m, 7H) Example 47

N-[2-[(3-Chlorophenyl)-[3-(hydroxymethyl)-5-[[(25*)-2-decylamino)-3-[(3)-tetrahydro Ethyl-3-yl]propyl]aminoindenyl]phenyl]decyloxy]ethyl]amino decyl decanoate

The first step is Ν-[(1ν»-1 -[[[3-[(3-chlorophenyl)-[2-(indolylcarbonylamino)ethoxy]methyl]-5-(hydroxyl yl) Benzyl hydrazinyl]amino]methyl;|_2-[(3疋)-tetrahydropyridin-5-methyl]ethyl]-N-indolyl-aminocarbamic acid tert-butyl ester under ice bath 'Methyl 3-[(3-chlorophenyl)-[2-(indolylcarbonylamino)ethoxy]methyl]-5-(hydroxyindenyl)benzoate 39i (155 mg, 0.39 mmol) 231 95392 201242594 Dissolved in 4 mL of N,N-dimercaptocarhamamine, followed by the addition of Ν[[1,1 (amino)methyl)-2-[(3 and)-tetrahydroanthracene-3 Ethyl]_N-methyl-carboxylic acid dibutyl g曰3a (107 mg, 0.39 mmol), 1-pyridylbenzotrizole (1〇6 mg, 0.77 mmol) and 1-(3-dimethyl Aminopropyl)_3_ethylcarbodiimide hydrochloride (151 mg, 0.78 _〇1), diisopropylethylamine (413 g, 3.2 mmol) was added dropwise, and the reaction was stirred at room temperature for 12 hours. The solution was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) Chromatography to purify the resulting residue with a developing solvent system a Title product ^[(119)-1-[[[3-[(3-Phenylphenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]-5-(hydroxymethyl)benzene) Tertyl]amino]methyl]- 2_[(3 and)-tetrahydropyran-3-yl]ethyl]-N-methyl-amino decanoic acid tert-butyl ester 47a (128 mg, white Solid), Yield: 5 〇. 〇% MS m/z (ESI): 648 [M+l] The second step φ [2-[(3-phenylphenyl)-[3-(hydroxyphenyl) )_5_[[(;251)-2-methylamino-3-[(3«-tetrahydropyran-3-yl]propyl]aminocarboxamyl]phenyl]methoxy]ethyl Methylamino decanoate under ice bath, N-[(l«-l-[[[3-[(3-phenylphenyl)]-[2-(oxacarbonylamino)ethoxy]) 5-(hydroxyindole)phenylhydrazinyl]amino]indolyl]-2-[(3«-tetrahydroindan-3-yl]ethyl]-N-indenylamino The acid tert-butyl ester 47a (128 mg, 〇·19 mmol) was dissolved in 1 mL of dichloromethane, and 6 mL of trifluoroacetic acid and di-methane (v/v = 2: n mixed solution was added, and the reaction was stirred 1 The reaction was quenched by the addition of saturated sodium carbonate solution. The aqueous phase was extracted with 95392 232 201242594 monochloromethane (10 mL×3), and the organic phases were combined and then purified with water (1 〇mL×2) and saturated. The solution was washed (1 〇 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. )[3_(sulfhydryl) decylamino-3-[(3疋)-tetrahydropyran-3-yl]propyl]aminoindolyl]phenyl]decyloxy]ethyl % 胺 胺 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 ❶ MS m/z (ESI): 548 [M+l]^ NMR (400 MHz, CDCh): δ 8. 63-7. 24 (m, 8H), 5. 62 (s, 1H), 5.34 (s , 1H), 4.03 (m, 3H), 4.59 (m, 2H), 3.85- 3.40 (m, 13H), 3.07 (in, 1H), 2.65 (s, 3H), 2.00-1.22 (m, 7H) Example 48, 49 N-[2-[(5·)-(3-Phenylphenyl)-[6-[[(251)-2-decylamino-3-[(3T?)-tetrahydro] Bis-butyl-3-yl]propyl]aminoindenyl]-2,3-dihydrobenzopyran-4-41yl]methoxy]ethyl]amino decanoic acid oxime [2- [(/?)-(3-Phenylphenyl)-[6-[[(25&lt;)-2-decylamino-3-[(3«-tetrahydropyran-3-yl]propyl] Methyl hydrazide]-2,3-dihydrobenzofuran-4-yl]methoxy]ethyl]amino decanoate

N-[2-[(3-chlorophenyl)-[6-[[(2«-2-methylamino)-3- 233 95392 201242594 [(3-tetrahydropyranyl-3-yl)] Methyl propyl]aminocarbamimidyl] 2,3-dihydrobenzofuran-4-yl]methoxy]ethyl]carbamic acid methyl ester 36 (6〇9邶, n just 1) for chiral demolition Separation by HPLC method using preparative equipment and chiral column chiral isomers (separation conditions: chiral column (3) (4) her 1C, mobile phase: acrylonitrile: isopropanol · diethanolamine = 95 : 5 : 〇. 1, flow rate: 1.0 mL/min) 'Collect the corresponding components, and remove the solvent by rotary evaporation to obtain the title product N-[2-[(--(3-chlorophenyl)_[6_[[(25) )) 2-methylamino _3—[(3 saponin-tetrahydrofuran-3-yl)propyl]aminocarbamimidyl]-2,3-dihydrobenzofuran-4-yl] Methyl methoxy]ethyl]carbamate 48 (24 〇 mg, 0.36 ramol) and N-[2-[(妁-(3-chlorophenyl)-[6_[[(2ι9)_2] fluorenyl) Amino-3-[(3^-tetrahydropyran-3-yl)propyl]aminocarbamimidyl]-2,3-dihydrobenzofuran-4-yl]methoxy]ethyl] Ethyl carbazate 49 (250 mg, 0. 38 mmol). 48 m. MS m/z (ESI): 560 [M+1], retention time ίο. 82 min, e e value &gt; 98% φ 49 : MS m/z (ESI): 560 [M+1 ], retention time 1 〇 77 minutes, ee value &gt; 98%. Example 50 N-[2-[( 3-chlorophenyl)-[3-[[(150-1-(cyclohexyldecyl)-2-methylamino-ethyl]aminoindolyl]-5-(2-didecylamine) Ethyl ethoxy)phenyl]methoxy]ethyl]amino decanoate 95392 234 201242594

• 3-[(3-Chlorophenyl)-[2-(indolylcarbonylamino)ethoxy]methyl]-5-(2-

Di-decylamino ethoxy) benzoic acid decyl ester 3-((3-chlorophenyl)-[2-(indolylcarbonylamino)ethoxy]indolyl]-5-superyl-ben Methyl citrate 46g (200 mg, 0.5 mmol) 'dimethylethanolamine (54 mg, 0.6 mmol) and triphenylphosphine (2 〇〇 mg, 0.76 mmol) dissolved in 1 mL of tetrahydrofuran, added dropwise Diethylene g-dicarboxylate (133 mg, 0.76 mmol) was scrambled for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue obtained was purified to purified crystals to crystals to afford the title product 3-[[3-(3-carbyl)-[2-((methoxyphenyl) ethoxy)] Methyl]-5-(2-dimethylaminoethoxy)benzoic acid vinegar 50a (132 mg, colorless viscous liquid), yield: 56.0%. Second step 95392 235 201242594 3_[(3-Chlorophenyl)-[2-(indolylcarbonylamino)ethoxy]indolyl]-5-(2-dimethylaminoethoxy)phenylhydrazine Acid 3-((3-Phenylphenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]-5-(2-didecylaminoethoxy)benzoic acid methyl ester 50a (132 mg, 0.28 mmol) was dissolved in a mixed solvent of 8 mL of methanol and water (v/V = 3:1), and a lithium hydroxide solution (30 mg, 0.71 mmol) was added, and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) The residue obtained was purified by column chromatography eluting to afford the title product: 3-[(3-chlorophenyl[2-(indoleoxycarbonylamino)ethoxy]methyl;|_5_(2-dimethyl Aminoethoxy)benzoic acid 50b (98 mg, colorless viscous liquid), 76.6%. The third step is [~[(25·)-2-[[3-[(3-chlorophenyl)- [2-(indolylcarbonylamino)ethoxy]indolyl]-5-(2-dimethylaminoethoxy)benzimidyl]amino]_3-cyclohexyl-propyl]-N - Tert-yl-carbamic acid tert-butyl ester 3-[(3-chlorophenyl)-[2-(indolylcarbonylamino)ethoxy]indolyl]-5-(2-dimethylamine Ethyl ethoxy) benzoic acid 50b (97 mg, 0.2 mmol) and N-[(25*)_2-^cyl-3-cyclohexyl-propyl]-N.-methyl-aminocarboxylic acid Butyl ester lg (58 mg, 0.2 mmol) was dissolved in 6 mL of N,N-dimethyl decylamine, and 1-butylic benzotriazole (35 mg, 〇. 26 mmol) was added, l-(3_ Diammonium propyl)-3-ethylcarbodiimide hydrochloride ( 50, 0.26 mmQl) and N,N-diisopropylethylamine (140 mg, 1 mmol), stir-fry for 12 hours. Add 50 mL of di-methane, followed by water (2〇mLX2) and saturated chlorination 95392 236 201242594 Sodium solution was washed (20 mL×2), dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated, evaporated. 2-[[3-[(3-chlorophenyl)-[2-(methoxy)amino)ethoxy]indolyl]-5-(2-didecylaminoethoxy) 0%。 Alkyl]-3-cyclohexyl-propyl]-N-decyl-amino decanoic acid tert-butyl ester 5 〇 c mg, white solid), yield: 64. 0%. MS m/z (ESI): 703 [M+1] Step 4: N-[2-[(3-chlorophenyl)-[3-[[(15&quot;)-l-(cyclohexylmethyl) —2-methylamino-ethyl]aminoindenyl]-5-(2-dimethylaminoethoxy)phenyl]methoxy]ethyl]amino decyl decanoate

Under ice, N-[(25&quot;)-2-[ [3-[(3-Phenylphenyl)-[2~(曱-oxylamino)ethoxy]indolyl]-5-( 2-Dimethylaminoethoxy)phenylhydrazino]amino]-3-cyclohexyl-propyl]-N-indolyl-amino decanoic acid tert-butyl ester 5〇c (97 mg, 0 14 mmol) was dissolved in 1 mL of methane, and a mixture of 6 mL of trifluoroacetic acid and methylene chloride (V/V = 2:1) was added and the reaction was stirred for 1 hour. The reaction was quenched by the addition of a saturated sodium carbonate solution. The aqueous phase was extracted with dichloromethane (10 mL×3). The organic phase was combined and washed with water (1 〇mL×2) and saturated sodium carbonate solution (10 mL×2), dried over anhydrous sodium sulfate. Filtration, hydration and concentration under reduced pressure, EtOAc (EtOAc) -(cyclohexyldecyl)-2-mercaptoamino-ethyl]aminoglycolyl]-5-(2-didecylaminoethoxy)phenyl]anthracene]ethyl]amine曱 R 旨 50 (35 mg, pale yellow solid), yield: 42.2%. 237 95392 201242594 MS m/z (ESI): 603 [M+l] 泔 R (400 MHz, CDC13) : δ 7. 58-7. 47 (m, 2H), 7. 34-7 26 (m, 5H), 7.03 (s, 1H), 5.39 (s, 1H), 5.28 (m, ih), 4.52 ( m, 1H), 4.12 (m, 2H), 3.68-2.80 (m, 11H), 2 60 (m 3H), 2.41 (s, 6H), 1.78-0.91 (ra, 13H) Example 51 ^^-[ 2-[(3-chlorophenylhydrazine)-[3-[[(23)-2-decylamino-3-[())-tetraazin-3-yl]propyl]amino] aryl ]-5-[(3-Methoxyoxetanyl-3-yl)methoxy]phenyl]methoxy]ethyl]amino decanoic acid

First step 3-K3-gasphenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]-5-[(3-methyloxetan-3-yl)methoxy Methyl benzoate 3-((3-chlorophenyl)-[2-(indolylcarbonylamino)ethoxy]methyl] 238 95392 201242594 Hydroxy-benzoic acid methyl ester 46g (200 mg, hydrazine · 5 _〇ι) , (3 - decyloxabutan-3-yl)methanol (62 mg, 0.61 _〇1) and triphenyl scale (10), 0.76 lysine 1) dissolved in i mL tetrahydrofuran Diethyl azodicarboxylate (133 mg '〇.76 _〇1) was added dropwise, and the reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and then purified to purified to afford to afford to afford to afford the title product 3-K3- phenylphenylH2-(indole(tetra)amino)ethoxy]indolyl]5-[ (3-Mercapto-oxetan-3-yl)methoxy]benzene. decanoic acid φ oxime ester 51a (214 mg, white solid), yield: 88%. Step 2 3-[(3-Chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]_5_[(3-methyloxetan-3-yl)methoxy Benzoic acid 3-((3-phenylphenyl)-[2-(indolylcarbonylamino)ethoxy]indolyl]-5-[(3-indolyloxyheterobutyl)_3_ Ethyl methoxy] benzoic acid oxime ester 51a (217 mg, 0.45 mmol) was dissolved in a mixed solvent of 8 mL·sterol and water (V/V = 3:1), and a lithium hydroxide solution was added (48, ι ·ΐ4 mm〇i), φ Stir the reaction for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. Column chromatography Chromatography of the obtained residue to afford the title product 3-[(3-chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]methyl] decyloxy Cyclobutyl-3-yl)nonyloxy]benzoic acid 51b (180 mg, white solid), 85.7%. The third step N-[(15*)-1-[[[3-[(3-chlorophenyl)-[2-(methoxycarbonylamino)ethoxy] 239 95392 201242594 曱]]-5- [(3-Mercaptoheterobutyl-3-yl)decyloxy]phenylhydrazinyl]amino]indolyl]-2-[(3Λ〇-tetrahydropyran-3-yl)ethyl ;|_N_decyl-amino decanoic acid tert-butyl ester 3-[(3-phenylphenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl]-5 -[(3-Mercapto-oxetan-3-yl)nonyloxy]benzoic acid 51b (180 mg, 0.39 mmol) was dissolved in 4 mL of N,N-dimethylamine, and then added ^[(150-1-(Aminomethyl)-2-[(3-tetrahydron-pyranyl-3-yl)ethyl]-indenyl-carboxylic acid tert-butyl ester 3a (117 Mg, 0.43 mmol), 1-hydroxybenzotriazine (63 mg, 0.47 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (89 mg, 0.47 Methyl), diisopropylethylamine (250 mg, 2 mmol) was added dropwise, and the reaction was stirred for 12 hours at room temperature. 20 mL of dichloromethane was added to the reaction mixture, and the organic phase was sequentially water (2 mL) and saturated gas. The sodium solution was washed (20 mL), dried over anhydrous sodium sulfate and dried over Celite. The resulting residue was purified to give the titled product 1[(1]-1-[[[3-[(3-chlorophenyl)-[2-(methyloxyamino)ethoxy]] 5-[(3-methyloxetan-3-yl) decyloxy]benzylidene]amino]indenyl]-2-[(3 friends)-tetrahydrofuran- 3-yl]ethyl]-N-mercapto-amino decanoic acid tert-butyl ester 51c (222 mg, white solid), yield: 79.6% MS m/z (ESI): 718 [M+l] The fourth step N - [2-[(3-phenylphenyl)_[3_[[(25&quot;)_2_ decylamino-3_[(3 and)_tetraapyran-3-yl]propyl] Amino fluorenyl]-5-[(3-indolyl oxetan-3-yl) decyloxy]phenyl] decyloxy]ethyl]amino decanoic acid decyl ester 240 95392 201242594 Ice bath Next, N-[(l-[3-[3-[3-chlorophenyl]-[2-(indolyloxycarbonylamino)ethoxy]indolyl]-5-[(3-methyl) Oxecyclobutyl-3-yl)methoxy]phenylhydrazinyl]amino]hydrazino 2_[(3 porcine-tetrahydropyran-3-yl]ethyl]-N-methyl-amine The third butyl carboxylic acid 51c (22 〇 mg, 〇 31 〇 〇 1) was dissolved in 10 mL of two-gas methane, and a mixture of 6 mL of trifluoroacetic acid and a second gas (V/V = 2: 1) was added. The solution was scrambled for 1 hour. The reaction was quenched by the addition of saturated sodium carbonate solution, and the aqueous phase was extracted with dioxane (1 〇mL×3). The organic phase was combined and washed with water (10 mL×2) and saturated sodium chloride solution (1 〇mL×2) The filtrate was concentrated under reduced pressure, and the obtained residue was purified to silica gel eluting to afford to afford the title product n-[2-[(3-chlorophenyl)-[3-[[(25)]- 2-mercaptoamino-3-[(3 and)-tetrahydroηpyran-3-yl]propyl]aminoindenyl]-5-[(3-indolyloxyheterobutyl- 3 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ MS m/z (ESI): 618 [M+l] φ Ή NMR (400 MHz, CDCh): δ 7. 78-7. 70 (m, 8H), 5. 3〇-5. 25 (m, 2H), 4. 62(m, 2H), 4. 45 (m, 2H), 4.04-3.02 (m, 16H), 2.62-2.55 (m, 3H), 2.01-1.25 (ra, l〇H) Example 52 1^-[2-[(3-Chlorophenyl)-[3-[[(15')-1-(cyclohexylmethyl)_2-decylamino-ethyl]aminoindolyl) ]_5-Niprin-Benyl]Methoxy]ethyl]amino decanoic acid methyl ester 95392 241 201242594

The first step of 5-nitrophenyl-1,3-dicarboxylate is dissolved in an ice bath of 3-曱-oxycarbonyl-5-nitro-benzoic acid 38a (5 g, 22. 21 mmol). In mL methanol, sulfoxide (2.33 mL, 33.31 mmol) was added, and the reaction was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc)EtOAc. The title product 5_shishen benzene-1,3-di(tetra)methyl ketone 52a (4.78 g, white solid) was obtained, yield: 90.0%. The second step is 5-aminobenzene-1,3-dicarboxylic acid vinegar 165-nitro-st-u-dicarboxylic acid methyl ester orphan (3 g, i2.6 _〇1), which is dissolved in 15 mL of methanol. Add Lanni Record (_mg, (4) Li (4), replace the hydroquinone twice, stir the reaction for 12 hours. The reaction solution is filtered, and the filtrate is concentrated under reduced pressure to give the title product 5-aminobenzene-1,3-dicarboxylic acid. Ester 52b (2. 20g, off-white solid), yield: 84.6%. Step 3 - 5-linyl phenyl-1,3-dioxalate 曱g to 5-aminobenzene-1,3- Ethyl dicarboxylate 52b (2 g, 9.6 mmol) and 2,2-bromodiethyl light (1.5 mL, 11.5 mmol) dissolved in 20 mL of N,N-dimethylamine 5小时。 The reaction solution was concentrated under reduced pressure and extracted with ethyl acetoacetate (50). </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The title product 5-morpholine phenyl-1,3-dicarboxylate methyl ester 52c (800 mg, white solid). MS m/z (ESI): 280 [M+1] Step 4 3-Mercaptocarbonyl-5-morpholine-benzoic acid 5- morpholinylphenyl-1,3-dicarboxylate 52c (630 mg, 2.26 243 95392 201242594 mmol) was dissolved in 5 mL of methanol, sodium hydroxide (90 mg, 2.26 mmol) and 10 mL of propylamine were added, and the reaction was stirred for 12 hours. The reaction was concentrated under reduced pressure and 20 mL was added. Water, 1 M hydrochloric acid was added dropwise to the reaction mixture to pH 3 to 4, which was extracted with ethyl acetate (20 mL×3). 5-morpholine-benzoic acid 52d (560 mg, light yellow solid), yield: 93.7%. MS m/z (ESI): 266 [M+l] Step 5 ® 3-(hydroxylhydrazyl) -5-morpholine-p-benzoic acid decyl ester, 3-mercaptocarbonyl-5-morpholine-benzoic acid 52d (560 mg, 2.1 mmol) was dissolved in 5 mL of tetrahydrofuran, and 1 Μ boron was added. The resulting mixture was stirred for 12 hours. The reaction was quenched with EtOAc EtOAc (EtOAc). Wash with sodium hydride solution (1 〇 mL) and saturated sodium chloride solution 10 mL) Dry over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 3-(hydroxymethyl)-5-morpholine- succinic acid ethyl ester 52e (420 mg, colorless transparent liquid), yield: 79. 2%. MS m/z (ESI): 252 [M+l] Step 6 - 曱-based 5-- 吓 benzoic acid 曱酉 将 3-(hydroxyindolyl)-5-morpholine-benzoic acid decyl ester 52e (400 mg, 1.6 mmol) was dissolved in i〇mL of dichloromethane. Pyridinium chlorochromate (685 mg, 3.2 mmol) and sodium acetate (392 mg, 4.8 mmol) were added and the reaction was stirred for 12 hours. . After adding 2.0 g of phthalocyanine, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by eluent </ br> </ br> 3%。 The decyl formate 52f (260 mg, yellow solid), yield: 65.3%. MS m/z (ESI): 251 [M+l] Step 7 3-[(3-Phenylphenyl)-carbyl-methyl]_5一吗淋_曱曱酸曱下冰冰下下3-Mercapto-5-morphine-methyl benzoate 52f (85 〇mg, 3·4 _〇1) was dissolved in 10 mL of tetrahydrofuran, and 3 chlorophenyl magnesium bromide of i 〇M was added dropwise. (6.8 mL, 6.8 mmol), stir the reaction for 5 hours. Add 50 mL of saturated ammonium hydride solution, extract the aqueous phase with ethyl acetate (5 〇mL×3), combine the organic phase, wash the mL with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and filter. Column chromatography Chromatography of the obtained residue to afford the title product 3 [(; 3 - gas phenyl) - hydroxy - fluorenyl] morpholine - succinic acid oxime ester 52 g (11 〇 g, light Yellow solid), Yield: 89.4%. Lu 8th Step 3-[(3-Phenylphenyl)-(2,2,2-trichloroiminoethylidene)oxy-indenyl]_5_?-lin-benzoic acid formazan Dissolve 3-[(3-chlorophenyl)-hydroxymethyl]-5-morpholine-benzoic acid vinegar 52g (830 mg, 2.3 mmol) in 1 mL of toluene and add diacetonitrile (1.70 g). , 115 mm 〇 1) and diazabicyclo ring (35 〇 23 〇 1), and the reaction was stirred at room temperature for j hours. The reaction solution was filtered with a guar gum. The filtrate was concentrated under reduced pressure to give the crude title product: 3-[(3- phenylphenyl H2, 2'2-tri-iminoethylidenyloxy)-indenyl]-5-morpholine-benzene Citrate 95392 245 201242594 Methyl vinegar 52h (1. 19 g, light yellow oil). The product was taken to the next step without purification. The ninth step of 3-[(3-chlorophenylmethoxycarbonylamino)ethoxy]methyl]_5-morpholine-molecular acid methyl ester will be the crude 3-[(3-chlorophenyl)-(2, 2,2-tris, imine, ethenyl)oxy-indenyl]-5-morpholine-benzoic acid oxime 52h (116 g, 2.3 mmol) and N-(2-ethyl)amino decanoic acid Methyl ester it (567 mg, 4.8 mmol) was dissolved in 10 mL of dichloromethane and trimethyl sulfonate trifluoromethanesulfonate (555 mg, 2.5 mmo 1) was added. hour. The reaction was quenched by the addition of a saturated aqueous solution of sodium hydrogencarbonate. The mixture was extracted with methylene chloride (5 mL mL), washed sequentially with water (20 mL) and saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate and filtered. Concentration, the residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc) -5-morpholine-benzoic acid oxime ester 52i (1·10 g, white φ solid), yield: 61.0%. MS m/z (ESI): 463 [M+l] Step 10 3-[(3-chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl] Acid 3-[(3-Chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl]-5-morpholine-benzoic acid methyl ester 52i (295 mg, 〇. 65 mmol Dissolved in 5 mL of methanol, added with sodium hydroxide (52 mg, 1.3 mmol), and stirred at 50 ° C for 12 hours. The reaction solution was concentrated under reduced pressure. 2 mL of water was added, and hydrochloric acid 95392 246 201242594 was added dropwise to pH 1-2 of the reaction mixture, which was extracted with ethyl acetate (20 mL×3), and the organic phase was dried over anhydrous sodium sulfate, filtered and filtered. Concentration by pressure gave the title product 3-[(3-phenylphenyl)-[2-(indoleoxycarbonylamino)ethoxy]indolyl]-5-morpholine-benzoic acid 52j (245 mg, yellow oil 7%), yield: 85.7%. MS m/z (ESI): 447 [Ml] Step 11^[(2«-2-[[3-[(3-chlorophenyl)-[2-((oxycarbonylamino))ethoxy) ] mercapto]-5-morpholine-phenylhydrazinyl]amino]-3-cyclohexyl-propyl]-N-indolyl-® tert-butyl amide phthalate 3-((3-chloro) Phenyl)-[2-(indolylcarbonylamino)ethoxy]methyl]-5-nor-benzoic acid 52j (245 mg, 0.55 mmol) and N-[(25^-2-amino- 3-cyclohexyl-propyl]-N-indenyl-carbamic acid tert-butyl ester lg (177 mg, 0.66 mmol) was dissolved in 6 mL of hydrazine, hydrazine-dimethyl decylamine, and 1-hydroxyl was added. Benzotriazine (148 mg, 1.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylhistidine hydrochloride (210 mg, 1.1 mmol) and N,N- Diisopropylethylamine (269 mg, 2.1 mmol), stir the reaction for 2 hours. Add 50 mL of methylene chloride and wash with water (20 mL×2) and saturated sodium chloride solution (20 mL×2). The sodium was dried, filtered, and the filtrate was evaporated to dryness. )-[2-(methoxycarbonylamino)ethoxy]methyl]-5-morpholine-phenylhydrazino]amino] -3-cyclohexyl-propyl]-N-methyl-amino decanoic acid tert-butyl ester 52k (334 mg, white solid), yield: 87. 2% ° MS ra/z (ESI): 701 [ M+l] 95392 247 201242594 The twelfth step N-[2-[(3-chlorophenyl)-[3-[ [(150-1-(cyclohexylmethyl)-2-decylamino)-B Methyl]amino-mercapto]-5-morpholine-phenyl]decyloxy]ethyl]amino decanoate under ice bath, Ν-[(25·)-2-[[3-[ (3-Chlorophenyl)-[2-(indolylcarbonylamino)ethoxy]methyl]-5-morpholine-phenylhydrazinyl]amino]-3-cyclohexyl-propyl]methyl - Aminobutyric acid terpene vinegar 52k (300 mg, 0.43 mmol) was dissolved in 8 mL of dioxane, 2 mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction was quenched by the addition of a saturated sodium carbonate solution. The aqueous phase was extracted with two gas (10 mL×3), and the organic phase was combined, washed with water (10 Π^χ2) and saturated sodium hydride solution (10 mL×2), dried over anhydrous sodium sulfate, and filtered. Purification of the obtained residue by thin layer chromatography to afford the title product N-[2-[(3-chlorophenyl)-[3-[[(ΐ5·)-ΐ-(cyclohexyl) ))-2-mercaptoamino-ethyl]amino fluorenyl]-5_ Morpholine-phenyl]methoxy]ethyl]amino decanoic acid methyl g 52 (245 mg, white solid), yield: 95.3%. MS m/z (ESI): 601 [M+l] H NMR (400 MHz, CDCI3): δ 8·06-7. 15 (m,7H), 6.92 (s, 1H), 5.76 and 5.63 ( 2s, 1H), 5.34 (s, 1H), 4.65 (m, 1H), 3.84-3.03 (m, 17H), 2.70 (s, 3H), 1.81-0.86 (m, 13H) Example 53, 54 [[ 24(5^-(3-fluorophenyl-2-methylamino)_3_[(3-tetrahydropyran-3-yl)propyl]aminoindenyl]-2,3-dihydro Benzofuran-4- 248 95392 201242594 methyl]methoxy]ethyl]carbamic acid methyl ester Ν-[2-[α)-(3-fluorophenyl)_[6_[[(2iS:)_2_f Amines_3_[(3 __tetrahydropyranyl)propyl]aminocarbamimidyl]-2,3-dihydrobenzofuran-4-yl]methyllactyl]ethyl]aminocarbamate vinegar

,. Human Η άΡ: • Ν-[2-[(3-fluorophenyl)-[6-[ [(25)-2-methylamino]- 3-[[3^-tetrahydro-α-pyran_3 Methyl]propyl]aminomethylindenyl]_2,3-dihydrobenzofuran-4-yl]methoxy]ethyl]amino decanoic acid methyl ester 44 (620 mg, 1.14 facial 〇1 Chiral separation, separation by HPLC and preparative equipment and chiral column chiral isomers (separation conditions: Chiralpak ic, mobile phase: acrylonitrile: isopropanol: diethanolamine = 95:5: 〇.丨, flow rate: 1.0 mL/min) 'Collect the corresponding components, and remove the solvent by rotary evaporation to obtain the title product Ν-[2-[(5Μ3-fluorophenyl)-[6-[[( 2ι9) 1-2 amino group-amino-3-[(3«-tetrahydropyran-3-yl]propyl]aminocarboxamido]_2,3-dihydrobenzofuran-4-yl] Methyl methoxy]ethyl]carbamate 53 (19 〇 mg, 0.35 mmol) and N-[2-[U〇-(3-fluorophenyl)-[6_[[(2 幻_2一曱) Aminoamino-3-[(3 and)-tetrahydropyran-3-yl]propyl]aminomethylindenyl]-2,3-dihydrobenzofuran-4-yl]methoxy]B Methyl carbazate 54 (200 mg, 0. 37 mmol) 〇 53 . MS m/z (ESI): 544 [M+l], retention time 9.77 Clock, ee value 96.33%. 95392 249 201242594 54 : MS m/z (ESI): 544 [M+l] ' Retention time 9 81 minutes, ee value 99.74%. Example 55, 56 1'1-[ 2-[(^?)-(3-chlorophenyl)-[3-(2-decyloxyethoxy)_5-[[(25)-2-methylamino-3-[(3 )-tetrahydrofuran-3-yl]phenyl]amino] aryl]yl] methoxy]ethyl]amino decanoic acid 1 1^-[2-[(5&lt;)-( 3-oxophenyl)-[3-(2-methoxyethoxy)_5_[[(2-Methylamino)-3-[(3-tetrahydro-pyran-3-yl)phenyl Aminomethyl] benzyl]methoxy]ethyl]amino decanoic acid

Ν-[2-[(3-Chlorophenyl)-[3-(2-methoxyethoxy)-5-[[(250-2-methylamino-3-[(3&gt;?) Methyl 4-tetrahydropyran-3-yl]phenyl]aminocarbamimidyl]phenyl]methoxy]ethyl]carbamate 4〇 (616, 1〇4 • mmol) for chiral demolition Separation by HPLC method using preparative equipment and chiral column chiral isomers (separation conditions · chiral column 1C 'mobile phase: acrylonitrile: isopropanol: diethanolamine = 95 : 5 : ^ , flow rate: 1.0 mL / min), the corresponding components were collected, and the solvent was removed by rotary evaporation to obtain the title product N-[2-[〇P)-(3-phenylphenyl) 43-(2-methoxyethoxy -5-[ [(25*)-2-Methylamino-3-[(3)-tetrahydroindole-pyranyl-3-yl]phenyl]aminocarboxamyl]phenyl]- Methyl oxy]ethyl]carbamate 55 (2〇7 mg, 0.35 mmol) and N_[2-[(«-(3-chlorophenyl)_[3-(2-methoxy 95392 250 201242594) Ethoxy)-5-1^(250-2-decylamino-3-[(3)-tetrahydropi-pyranyl-3-yl]] benzyl]aminomethyl]]]]]乳基]ethyl]amino decanoic acid hydrazine from the purpose of 56 (222.9 mg, 0. 38 mmol). 55 : MS m/z (ESI): 592 [M+1] ' Retention time 9 24 minutes, ee value 99·68%. 56 : MS m/z (ESI): 592 [M+1], retention time 1〇. 〇5 minutes, 6 values 99.32%.

Example 57 1[2-[(3,5-Difluorophenyl)-[6-[[(251)-2-decylamino]_3_[(3)-tetrahydropyran-3-yl) ]propyl]aminomercapto]_2,3-dihydrobenzofuran-4-yl]methoxy]ethyl]amino decanoic acid

95392 251 201242594

First step 6-(Second-butyl-indenyloxy) indenyl 2,3-dihydrobenzofuran-4-carboxylic acid decyl ester 6-(hydroxyindenyl)-2,3-dihydrogen Benzofuran-4-methyl decanoate 24 light (8 g, 38.5 mmol) dissolved in dichloromethane (15 Torr, imidazole (65)

g,96. 3 mmol), stir and dissolve, cool in ice water bath, add tert-butyl dimethyl gas Wei (8.2 g, 57.7 mmol), stir for 1 hour at room temperature, add water (50 inL), dispense, The organic layer was washed with brine (5 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to give the title product 6-(t-butyl dimethyl oxalyloxy) hydrazino 2, dihydrobenzo σ Fu _4_ citric acid methyl sulphate U4.3 g, white solid), yield 1%, directly proceed to the next reaction. The second step (6 (t-butyldimethyl oxalyl) fluorenyl-2,3-dihydrobenzofuran-4-yl) decyl alcohol 252 95392 201242594 6-(Tertiary butyl hydrazine矽 矽 oxy)methyl-2, 3-dihydro benzofuran 南 曱 曱 曱 57 57 57a (13 g, 40 mmol) dissolved in tetrahydro cp: methane (150 mL), cooling in ice water bath Lithium aluminum hydride (3.1 g, 80 mmol) was added, and the mixture was stirred at room temperature for 3 hr. EtOAc (EtOAc m. Concentration, the title product (6-(t-butyl-didecyloxy)methyl-2,3-dihydrobenzofuran-4-yl) decyl alcohol 57b (12 g, white solid) 93%, proceed directly to the next step. The third step (second butyl-fluorenyl oxetyl) fluorenyl-2,3-dihydrobenzopyran-4-carbaldehyde (6-(t-butyldidecyloxy) fluorenyl _2, 3_Dihydrobenzofuran-4-yl)methanol 57b (12 g, 40·8 mmol), sodium acetate (8.4 g, 102 mmol) dissolved in dichloromethane (bo mL), ice water bath The temperature was lowered, and the chlorochromic acid pyridinium salt (21 g, 102 mmol) was added, and the mixture was stirred at room temperature overnight, filtered, and the residue was evaporated. Dimethyl methoxy) decyl-2,3-dihydrobenzofuran 4-furaldehyde 57c (7.1 g, white solid), yield. The fourth step (6-(t-butyldi-f-kilcyl)methyl-2,3-dihydrobenzo-pyrene-_4_yl)(3,5-difluorophenyl)methanol will be 6-(the first Tributyl bisindenyl oxo)methyl-2,3-dihydrobenzopyran-4-methylate 57c (2 g' 7 _1) dissolved in four gas bites (15 mL), ice The water bath was cooled by adding 1N of 3,5-difluorophenyl desertification town (15 ' 14 95392 253 201242594 mmol), and the temperature was controlled to °C for a period of 0.5 hours, and a saturated aqueous solution of ammonium sulfate (10 mL) was added. The title compound (6-(t-butyl dimethyl fluorenyloxy) was obtained. )methyl-2,3-dihydrobenzofuran-4-yl)(3,5-difluorophenyl)nonanol 57d (2.5 g, light yellow oil), yield 99%, directly One step reaction. The fifth step (6-((tert-butyldidecyloxy)methyl)-2,3-dihydrobenzofuran-4-yl)(3,5-difluorophenyl)-2, 2 , methyl 2-trichloroimidoacetate (6-(t-butyldimethyl methoxy) fluorenyl-2,3-dihydrobenzofuran-4-yl) (3, 5-di) Fluorophenyl) decyl alcohol 57d (0.5 g, 1. 23 mmol) was dissolved in hydrazine (10 mL), tri-acetonitrile (0.27 g, 1.85 mmol) was added, and 1,8-diazabicyclo was added dropwise. [5.4.0] Undec-7-ene (1 mL), stirred at room temperature overnight, the reaction mixture was concentrated, and the residue obtained was purified by column column chromatography to afford the title product (6-((3rd) (2,5-dihydrobenzofuran-4-yl)(3,5-difluorophenyl)-2,2,2-trichloroimidoacetate 1 〇/〇. The ester 57e (0.5 g, pale yellow oil). Step 6 2-((3,5-Difluorophenyl)(6-(hydroxyindenyl)-2,3-dihydrobenzofuran-4-yl)methoxy)ethylcarbamic acid methyl vinegar (6-((Tertiary butyl fluorenyloxy)methyl)_2 3 -dihydrobenf- -4-yl)(3,5-difluorophenyl)-2, 2, 2 - Trimethylimidoacetate oxime Me (0.5 g, 0.91 mmol) was dissolved in dioxane (1 mL), and N-(2-hydroxyethyl)amino decanoate (〇.2) was added. g, 18 curry 1), ice water bath 95392 254 201242594 cooling 'drip trimethyl sulfonate triflate (0. 4 g, 1. 8 mmol), ice water bath temperature control 0 ° C 'stirring reaction 1 〇min, add saturated sodium bicarbonate solution (5 raL) 'separate, the aqueous layer was extracted with dichloromethane (5 mL×3), and the organic layer was combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to solvent system B The obtained residue was purified to give the title product 2-((5 5 -difluorophenyl)(6-(sulfenyl)-2,3-dihydrobenzofuran-4-yl)methoxy)ethylamine hydrazide. Acid vinegar 57f (〇.3g, colorless oil), yield 70 〇 / 〇. φ seventh step 4_((3,5-difluorophenyl)(2-(methoxyanthryl)ethoxy)indolyl)_2,3-dihydrobenzofuran-6-decanoic acid 2- ((3, 5-Difluorophenyl)(6-(hydroxyindenyl)-2,3-dihydrobenzofuran-4-yl)methoxy)ethylamine decanoate 57f (〇. 3g,0. 8_〇1) Dissolved in dioxane (1〇mL), added with dichromate pyridine (1 g, 2.4 mmol), stirred at room temperature overnight, and the reaction solution was washed with water (5 id) The mixture was washed with aq. EtOAc (EtOAc) (EtOAc m. 1%。 Amino) ethoxy) fluorenyl)-2, 3-dihydrobenzofuran-6-decanoic acid 57g (0 g, colorless oil), yield 65. 1%. The eighth step 1 [2-[[6-[[(251)-2-(t-butoxycarbonyl(indenyl)amino)- 3-[[3])-tetrahydrofuran-3-yl] Methyl]amino]indenyl]-2,3-dihydrobenzofuran-4-yl]-(3,5-difluorophenyl)decyloxy]ethyl]amino decanoic acid methyl ester 4 -((3,5-difluorophenyl)(2-(indolyl)-ethoxy)carboindole) -2,3-dihydrobenzobenzopyran-6-decanoic acid 57g (0.1 g , 0.24 mmol) Dissolved 95392 255 201242594 'In addition to Ν-[(15·)-1-(aminomercapto)-2_[(3)-tetrahydroanthracene-2-yl in DMF (3 mL) ]ethyl]mercapto-carboxylic acid tert-butyl ester 3a (0. 0735 g, 0.27 mmol), hydroxybenzotriazole (0 065 g, 0.48 mmol) ' 1-ethyl-(3-dimethyl Aminopropyl)carbodiimide hydrochloride (0· 092 g, 0. 48 mmol), n,N-diisopropylethylamine (〇. 158 g, 1.2 〇1), room After stirring overnight, the reaction mixture was concentrated, and the residue obtained was purified by column column chromatography to afford the title product N-[2_[[6-[[(2)-(3)-(3-butoxycarbonyl(methyl)amine ))-3-[(3 and)-tetrahydropyran-3-yl]propyl]aminoindenyl]-2,3-dihydrobenzofuran-4-yl]-(3, 5- Difluoro曱 曱 ] ] 乙基 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 ))[6_[ [(25*)~2_Methylamino-3-[(3疋)-tetrahydropyran-3-yl]propyl]aminomethylindenyl]_2, 3_dihydro N-[2-[[6-[ [(250-2-(T-butoxycarbonyl(fluorenyl))amino)]] 3-[(3N)-tetrahydrofuran-3-yl]propyl]aminomethylindenyl]_2,3-dihydrobenzofuran-4-yl]-(3, 5-difluorophenyl) Ethyl methoxy]ethyl]carbazinate 57h (0. 102 g, 154· 154 mmol) was dissolved in dichloromethane (12 mL), cooled in ice water bath, and trifluoroacetic acid (3 mL) After the addition, the temperature is controlled. 〇, the reaction is stirred for 1 hour, saturated sodium bicarbonate (5 mL) is added, and the aqueous layer is separated and extracted with a gas (5 mL×3). The residue was purified by column chromatography using EtOAc EtOAc (EtOAc). -3-[(3Λ〇-tetrahydropyran-3-yl)propyl]aminocarboxamidine ; | _2, 3_-dihydro-benzofuran-4-yl] methoxy] ethyl] methyl amine 57 (0.075 g, white solid) in a yield of 86.7%. MS m/z (ESI): 562.1 [M+l] H NMR (400 MHz, CDCh): δ 9. 39 (s, 1H), 8. 41 (m, 1H), 7. 80 (m, 1H) , 7. 42(s, 1H), 7. 09 (s, 1H), 6. 97 (s, 1H), 6.71 (s, 1H), 5. 87(d, 1H), 5. 34 (m, 2H), 4. 55 (m, 2H), φ 4·04 (m, 3H), 3.66 (s, 3H), 3.44 (in, 6H), 3. 14 (m, 3H), 2.78 (s, 3H) ), 2.05 (m, 3H), 1.31 (ra &gt; 4H) Example 58 N-[2-[(3-Phenylphenyl)-[6-[[(25^-2-decylamino)-3- [tetrahydro 0-pyran-4-yl]propyl]aminocarbamimidyl]-2,3-dihydrobenzofuran-4-yl]decyloxy]ethyl]aminocarbamic acid methyl vinegar

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The first step (S)-2-((S)-2-hydroxy-1-phenylethylamino)-3-0-pyran-4-yl)propanenitrile under argon protection of 'tetrahydropyran-4 The acetaldehyde 58a (2.6 g, 23 mmol) was dissolved in decyl alcohol (20 mL), L-phenylglycolamine (2.4 g, 17.5 mmol) was added, and trimethyl sulfonate (5.6 g) was added dropwise. , 5·5 mmol), added, and reacted at room temperature overnight, the reaction mixture was dried, and the residue obtained was purified by column chromatography to give the title product (S)-2-((S)-2-hydroxyl -1- phenylethylamino) -3 -pyran-4-yl)propanenitrile 58b (2.66 g, white solid) 'yield 51.0% 〇 second step (S)-2-amino- 3-(°Bin-4-yl))propanonitrile (S)-2-((S)-2-hydroxy-1-phenylethylamino)-3-(pyran-4-yl)propanenitrile 58b (1 g, 3.65 mmol) dissolved in dichloromethane (75 mL) and 曱258 95392 201242594

To a mixed solution of alcohol (40 mL), lead tetraacetate (16 g, 3 65 mmol) was added to stir the reaction for 2 hours, and a saturated aqueous solution of sodium hydrogencarbonate (2 mL) was added. 20 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved with 3N hydrochloric acid (50 mL) and methanol (5 虬), and the reaction was stirred for 4 hr. The extract was extracted with ethyl acetate (20 mL×3). EtOAcjjjjjjjjjj Nitrile 58c (〇·49 g, pale yellow oil), product was taken to the next step without purification. (s)-l-Cyano-2-0-pyano-4-yl)ethylaminocarbamic acid tert-butoxy ester (S)-2-amino-3-(pyran-4-yl)) Propionitrile 58c (0. 49 g, 3.2 mm 〇1) was dissolved in a mixed solution of dioxane (5 mL) and water (2 mL), and a solution of di-n-butyl succinate (0795 mL, 32 mm) was added. 〇1), sodium carbonate (〇58 g' 4.8mmol), reacted at room temperature overnight, extracted with dioxane (5mLx3), combined with 3 phases, anhydrous sulfur_dry, lye, concentrated, purified by column chromatography Residues gave the title product ((4) EtOAc (EtOAc): (S)-l-cyano-2-(pyran-4-yl A m 丞 丞) ethyl decyl carboxylic acid tert-butoxy ester under the protection of helium, (S) ~ l-cyanide 9 , ^ cyano~2-(pyran-4-yl)ethylamine 曱酉 第二 second butoxide 58d (0.27 g ηηϊ 1Ν g, 丨.06 mmol) dissolved in tetrahydrofuran ( 4 mL) in the 'ice bath cooling, add 60% sodium hydrogen (128 mg, 3. 95392 259 201242594 mmol), add the reaction, stir the reaction for 40 minutes 'Add mothane (〇. 323 g, 2. 1 Mmo 1), react at room temperature overnight, add 5 mL of water to the reaction mixture, and extract with ethyl acetate (5 mL×3). The organic phase is combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography The residue obtained was obtained as the title product (S)-l-cyano-2-(indolyl-4-yl)ethyl phthalic acid decanoate 58e (0.26 g, colorless oil). The yield was 91%. Step 5 (S)-l-Amino^-(indol-4-yl)_2-propanyl-guanidinocarboxylic acid tert-butoxy® ig (S)-l-cyano-2-( Pyran-4-yl)ethyl decyl decanoic acid tert-butoxy ester 58e (0.26 g, 0.97 mmol) was dissolved in decyl alcohol (5 mL), charged with Raney nickel (0.03 g), aqueous ammonia (1 mL) The hydrogen was replaced three times, and the reaction was carried out at room temperature overnight, filtered, and the filtrate was concentrated to give the title product crude amido-3-(pyran-4-yl)-2-propyl-methylcarbamic acid tert-butoxide 58f ( 0. 19 g, white solid), yield 72.0%. MS m/z (ESI): 273.1 [M+l] Step 6 N-[2-[(3L phenyl)-[6-[[(250-2-(3 butyloxycarbonyl)) Amino)-3-[tetrahydropyran-4-yl]propyl]aminoindenyl]-2,3-dihydroindolofuran-4-yl]nonyloxy]ethyl]aminopurine Acid oxime ester 4-[(3-chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl]-2,3-dihydrobenzopyran-6-decanoic acid 26d (0.13 g, Q.32 mmol), (S)-l-amino-3-(n-pyran-4-yl)-2-propyl-nonylaminodecanoic acid tert-butoxide 95392 260 201242594 ester 58f (0. 105 g, 0·38 mmol), 1-hydroxybenzotriazole (0. 865 g, 0.64 mmol), 1-ethyl-(3-didecylaminopropyl) carbodiimide salt The acid salt (0.122 g, 0.64 mmol) was dissolved in DMF (4 mL), N,N-diisopropylethylamine (0. 206 g, 1. 6 mmol). Concentration, the obtained residue was purified by column chromatography using solvent system A to obtain the standard product N-[2-[(3 - phenyl)-[6-[[(2)) Alkyl (methyl)amino)-3-[tetrahydrofuran-4-yl]propyl]aminomethylindenyl]_2,3-dihydrobenzofuran-4-yl]methoxy]B Ethyl decyl decanoate 58g ^ (〇· 171 g, white solid), yield 81%. Step 7 N_[2-[(3-Phenylphenyl-methylamino-3-[tetrahydropyran-4-yl]-propyl Amino[indolyl]-2,3-dihydrobenzoindol-4-yl]methoxy]ethyl]carbamic acid formazan is intended to be N-[2-[(3-phenylphenyl) )-[6-[ [(25&gt;2-(T-butoxycarbonyl(indenyl)amino)-3-[tetrahydropyran-4-yl]propyl]aminomethylindenyl]-2 , ruthenium dihydrobenzofuran-4-yl]methoxy]ethyl]amino decanoate 58g (〇. Π1 g, 0.26 mmol) dissolved in dichloromethane (12 mL), cooled in ice water bath' Trifluoroacetic acid (4.62 g, 40.52 mmol) was added dropwise, and the reaction was stirred for 1 hour under temperature control. A saturated aqueous solution of sodium hydrogencarbonate (5 s) was added, and the mixture was extracted with dichlorohydrazine (5 mL×3), and the organic phase was combined. Drying over anhydrous sodium sulfate, filtration, EtOAc (EtOAc m.) Mercaptoamino-3-[tetrahydro-α-domain]propyl]amino]carbonyl]_2,3-dihydroindolizin-4-yl]nonyloxy]ethyl]amino decanoic acid Ester ester 58 (0.119 g, white house 95392 261 201242594 solid), The yield was 82%. MS m/z (ESI): 560.1 [M+l].H NMR (400 MHz, CDCh): δ 8. 62 (m, 1H), 8. 36 (s, 1H), 7.88 (m, 1H), 7.40 (m, 2H), 7.25 (m, 3H), 5. 77 (s, 1H), 5. 34(m, 1H), 4. 60 (m, 2H), 4. 04 (m, 3H), 3. 66 (in, 3H), 3. 53(s, 3H), 3. 45(m, 3H), 3. 37 (m, 1H), 2.99 (m, 2H), 2.73 (s, 3H), 1.70 (m, 3H), 1.31 (m, 4H) Example 59 ® N-[2-[(3-Phenylphenyl)-[3-(2-decyloxyethoxy)-5-[[( 2«-2-Methylamino-3-[tetrahydropyran-4-yl]propyl]aminoindenyl]phenyl]methoxy]ethyl]amino decyl decanoate

First step ^[2-[(3-chlorophenyl)-[3-(2-decyloxyethoxy)-5-[[(2«-2-(t-butoxycarbonyl)] Amino)_3_[tetrahydron-pyranyl-4-yl]propyl]aminomethylindenyl]phenyl]decyloxy]ethyl]aminodecanoic acid decyl ester 3-[(3-phenylphenyl) -[2-(Methoxycarbonylamino)ethoxy]indolyl]-5-(2-methoxyethoxy)benzoic acid i9g (16 g, 3 67; 〇1), 262 95392 201242594 (S)-l-Amino-3-(°-pyran-4-yl)-2-propyl-methylaminodecanoic acid tert-butoxy 58f (1 g, 3.67 mmol), 1-hydroxyl Benzotriazole (0.596 g, 4. 4 mmo 1), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.843 g, 4.4 mmol) dissolved in DMF (10 mL), N,N-diisopropylethylamine (2.4 g, 18.4 mmol) was added dropwise, temperature controlled 3 (TC, stirred overnight, the reaction was concentrated, water (100 mL) and ethyl acetate (1 〇〇 mL), the liquid layer was extracted with ethyl acetate (100 mL×3), the organic layer was combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column column chromatography with solvent system A. Title product N-[2-[(3-indolyl)-[3-(2-methoxyethoxy) -5-[[(25.)-2-(t-butoxycarbonyl(indenyl)amino)-3-[tetrahydropyran-4-yl]propyl]aminomethylindenyl]phenyl] Methoxy]ethyl]amino decanoate 59a (1.8 g, yellow solid), yield 71%. Step 2 N-[2-[(3-chlorophenyl)-[3-(2-曱) Oxyethoxyethoxy)-5-[ [(250-2-methylamino-3-[tetrahydrofuran-4-yl]propyl]aminocarbazinyl]phenyl]methoxy]#] Ethyl]amino decyl decanoate will be N-[2-[(3-chlorophenyl)-[3-(2-methoxyethoxy)_5_[[(25)-2-(second butyl) Oxymethyl (meth)amino)[tetrahydro 0 to 0 _4_yl] propyl]aminomethylindenyl]phenyl]decyloxy]ethyl]carbamic acid methyl ester 59a 〇·8 g, 2. 6 mmol) dissolved in dichloromethane (3 〇 mL), cooled in an ice water bath, and a mixed solution of trifluoroacetic acid (15 mL) and dichloromethane (30 mL) was added dropwise, and the mixture was stirred for 0 C. The mixture was extracted with aq. Concentrate, use column chromatography 95392 263 201242594 to purify the residue obtained in solvent system A to obtain the title The product Ν-[2-[(3·-phenylphenyl)-[3-(2-methoxyethoxy)-5-[[(2«-2-decylamino)-3-[tetrahydro] Methyl 4-methyl]propyl]aminocarbamimidyl]phenyl]methoxy]ethyl]carbamate 59 (1.15 g, white solid), yield 75%. MS m/z (ESI): 592.2 [M+l], NMR (400 MHz, CDCH): δ 8. 23 (in, 1H), 8. 12 (m, 1H), 7.82 (m, 1H), 7.46 Cm, 3H), 7.25 (m, 2H), 7. 03 (in, 1H), 5.53 (m, 1H), 4.20 (m, 2H), 4.00 (br, 2H), 3.86 (m, • 1H) , 3.75 (br, 2H), 3.67 (m, 2H), 3.56 (m, 2H), 3.75 (s, 3H), 3.46 (s, 3H), 3.30 (br, 4H), 2.70 (m, 3H), 1.67 (m, 4H), 1.32 (m, 3H) Example 60^[2-[(3-fluorophenyl)-[3-(2-decyloxyethoxy)_5-[[(;25( _2-Methylamino-3-[(3/?)-tetrahydron-pyran-3-yl]propyl]aminomethylindenyl]phenyl]methoxy]ethyl]amino decanoic acid Vinegar

95392 264 201242594

The first step is 3-(decyloxy(decyl)aminocarbamimidyl)-5-(2-methoxyethoxy)benzoate decyl 3-phenyloxycarbonyl-5-(2-曱 ethoxyethoxy)benzoic acid 19a (42.5 g, 167 mmol), N,0-dimercaptoamine hydrochloride (97.54 g, 250.5 mmol), 〇-(IH-benzotriazole -Bu,N-N,N',N'-tetradecylisourea hexafluoride (95 g, 250.5 mmol), triethylamine (30 mL) dissolved in DMF (500 mL), room temperature After stirring overnight, the mixture was extracted with EtOAc (EtOAc (EtOAc) -(Methoxy(methyl)aminoindenyl)-5-(2-decyloxyethoxy)benzoate decyl 60a (40 g, pale yellow oil), yield 80.4. Hey. Step 2 3-(3-Fluorobenzylidene)-5-(2-decyloxyethoxy)benzoic acid methyl ester Magnesium strips (1.68 g, 70 mmol) and tetra-argon π-propan (10 mL) ) Add 265 95392 201242594 In a bottle, add dropwise a solution of m-fluorobromobenzene (8.8 g, 50 mmol) in tetrahydrofuran (20 mL), reflux, stir the reaction for 1 hour, the magnesium strips disappeared, and the fluorophenyl bromide was obtained. Magnesium solution, 3-(decyloxy(methyl)aminocarbamimidyl)-5~(2-methoxyethoxy) decanoic acid oxime 6〇a (10 g, 33.7 丽〇1) Dissolved in tetrahydrofuran (100 mL), cooled in an ice water bath, and added dropwise the obtained m-fluorophenylmagnesium bromide solution (30 mL). The reaction was stirred for 1 hour, and a saturated aqueous solution of ammonium chloride (50 mL) was added. The chloroformane (50 mL×3) was extracted, and the combined organic layer was evaporated, evaporated, evaporated, evaporated -5_(2_decyloxyethoxy)benzoic acid methyl ester 60b (11.8 g, white solid), yield 1%% = third step 3-((3-fluorophenyl)hydroxymethyl)- 5-(2-methoxyethoxy)benzoate oxime t will be 3 ( 3-fluorobenzhydryl)-5-(2-decyloxyethoxy)benzoic acid, 60b (11.18 g, 33.7 mm〇1) dissolved in methanol (5 〇) in ice water bath to cool 'batch Adding sodium sulphate (2.2 g, 57 29 _ υ, rising to room _ warm' _ reaction overnight 'concentrated anti-ship, residual money (5 () mL), extracted with acetic acid B (50 mL x 3) 'combined organic The layer was dried over anhydrous sulphuric acid, filtered, and concentrated to give the title product crude product (3 ((3-fluorophenyl)-methyl methoxy ethoxy)). , the yield is 83.6%, the crude product is directly put into the next reaction. The fourth step 3 ((3-fluorophenyl) (2, 2, 2-trichloro-1-iminoethoxy)methyl)_5_ (2-methoxyethoxy)benzoic acid methyl vinegar 3-((3-fluorophenyl)-methyl)|(2-methoxyethoxy)benzene 95392 266 201242594 decanoate 60c ( 9.2g' 28_1), trioxoacetonitrile (19 9g, l4〇_〇 dissolved in toluene (50 mL), stirred at room temperature, add 18_diazabicyclo...chuan-10-carbon+ene (four) to "stick "The mixture was stirred at room temperature overnight, and the reaction mixture was concentrated. (2,2,2-three gas-丨-iminoethoxy) fluorenyl)-5-(2-decyloxyethoxy)benzoate oxime 6〇d (12· ig colorless oil The yield is 92%. '... Step 5 3-[(3-Fluorophenyl)-[2-(indolyl)ethoxy]indolyl]_5_(2_methoxy B Alkyl benzoate is intended to be 3-((3-fluorophenyl)(2, 2, 2-tris-1-enaminoethoxy)methyl)-5-(2-oxo Ethyl ethoxy) benzoic acid oxime ester 6 〇d (121 g, 25 〇 1) dissolved in dichloromethane (50 mL), added n-(2-hydroxyethyl)amino decanoate (3·01 g, 25 mmol), the ice water bath was cooled, trimethyl decyl trifluoromethanesulfonate (0. 562 g, 2.5 mmol) was added dropwise, and the temperature was controlled in an ice water bath. 〇, disturbing the anti-φ should be 2 hours, add saturated sodium bicarbonate solution (25 mL), separate the liquid, the aqueous layer is extracted with monochloromethane (50 mL×3), the organic layer is combined, dried over anhydrous sulfuric acid, filtered, concentrated, The obtained residue was purified by column chromatography using EtOAc EtOAc (EtOAc). Methoxyethoxy)methyl benzoate 6 〇e (9 g, colorless oil), yield 81%. Step 6 3-[(3-Fluorophenyl)-[2-(methoxyxymethyl)ethoxy]methyl]_5_(2-methoxyethoxy)benzoic acid 267 95392 201242594 [(3-Fluorophenyl)-[2-(methoxyxymethyl)ethoxy]indolyl]-5-(2-methoxyethoxy)benzoic acid methyl ester 6〇e (2 g, 4.6 followed by 1) dissolved in a mixed solution of methanol (15 mL) and water (5 mL), adding hydrazine hydroxide monohydrate (0.483 g, 11.5 mmol), stirring at room temperature overnight, hank Add water (10 niL) 'Acetyl acetate (15 mL), stir vigorously, add 2N hydrochloric acid to adjust ρΗ=3 to 4, separate the liquid, and extract the aqueous layer with ethyl acetate (20 mL×3). Drying over anhydrous magnesium sulfate, filtration and concentration to give the title product 3-[(3-fluorophenyl)-[2-(methoxymethoxymethyl)ethoxy]-methyl]-5-(2-methoxy) Ethoxy)benzoic acid 60f (1.91 g, colorless oil), yield 100%. The seventh step is 1^-[2-[(3-fluorophenyl)-[3-(2-methoxyethoxy)-5-[[(25〇-2-(2 butyloxy) Mercapto)amino)_3_[(3 left)-tetrahydron-pyranyl-3-yl]propyl]aminoindenyl]phenyl]decyloxy]ethyl]aminocarbamic acid methyl ester 3- [(3-Fluorophenyl)-[2-(indolyl)ethoxy]methyl]-5- • (2-monooxyethoxy) benzoic acid 60f (1.62 g, 3.87 mmol), Ν-[(15)-1-(Aminoguanidino)-2-[(3 and)-tetrahydropyran-3-yl]ethyl]-N-indolyl-dipicolinate 3a (1.05 g, 3.87 mmol), 1-hydroxy-p-oxadiazole (1.04 g, 7.71 mmol), ethyl-(3-didecylaminopropyl)carbodiimide hydrochloride (1.48 g, 7.71 Methyl) dissolved in DMF (25 mL) < </ RTI> </ RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; (20 mL×3), the organic layer was combined, dried with EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The yield is 92%. The eighth step N-[2-[(3-fluorophenyl)-[3-(2-oxo) Ethoxy)-5-[[(250-2-decylamino-3-[(37?)-tetrahydroxanthyl]-3-yl]propyl]aminoindenyl]phenyl]methoxy Ethyl]ethyl]amino decyl decanoate 60 g (2.3 g, 3.5 mmol) was dissolved in dichloromethane (15 mL), cooled in an ice water bath, and trifluoroacetic acid (2 mL) was added dropwise. Chlorodecane (20 mL) solution was stirred for 3 hours, saturated aqueous sodium bicarbonate (2 mL) was added, and the aqueous phase was separated and extracted with di-methane (20 mL×3). The residue was purified by column chromatography eluting with EtOAc EtOAc EtOAc. 5-[[(25*)-2-decylamino-3-[(3)-tetrahydrofuran-3-yl]propyl]aminoindolyl]phenyl]decyloxy]B Methyl carbamic acid methyl ester 60 (1.3 g, white solid), yield 66%. MS m/z (ESI): 576.3[M+1] φ * NMR (400 MHz, CDCh): δ 8 . 42 {br, 1H), 7.96 (br, 1H), 7.72 (br, 1H), 7.51 (m, 3H), 7.29 (m, 3H), 7.03 (m, 1H), 6.95 (m, 1H), 5. 43 (m, 1H), 5. 34 (m, 2H), 4.02 (Μ 2H), 3.75 (s, 3H), 3.72 (m, lH), 3.71 2H), 3. 62 (m, 2H), 3.54 (m, 2H), 3.48 (s, 3H), 3.26 (brt 4H), 1.65 (m, 4H), 1.44 (m, 2H), 1.29 (m, 3H) Example 61 N-[2-[(3-Phenylphenyl)-[3-(difluoromethoxy)-5-[[(2)-2-methylamino-3-[(3))-tetrahydro) Pyran-3-yl]propyl]aminoindenyl]phenyl] 269 95392 201242594

The first step is 5-difluoromethoxybenzene-1,3-dicarboxylate. 5-Benzene-1,3-dioxanoate 61a (1. 0 g, 80 mmol) and potassium carbonate ( 22. 1 g, 160 mmol) dissolved in 100 mL of N,N-dimercaptocarhamamine and added to the N-dimethyl group of difluoroiododecane (21.5 g, 120 mmol) 270 95392 201242594 under ice bath A solution of guanamine, 8 Torr: The reaction was stirred for 16 hours. Concentrate under reduced pressure, add 100 mL of water, and extract with ethyl acetate (2 mL mL). The organic phase is combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure and purified by eluent column chromatography with eluent system B The residue was obtained to give the titled product, m.p., 5-difluoromethoxybenzene-1,3-dicarboxylic acid methyl ester 61b (6.2 g, white solid). The second step is φ 3 -difluorodecyloxy-5-nonyloxycarbonyl-benzoic acid. Methyl 5-difluorodecyloxybenzene-1,3-dicarboxylate 61b (6.2 g, 23.8 mmol) is dissolved in 11 mL of methanol and 24 mL of water were added with sodium hydroxide (85 〇 mg ' 21·8 mm 〇i). The reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and then added with 100 mL of water, and extracted with methyl butyl ether (3 〇, the aqueous phase was adjusted to pH 3 to 4 with 2 M hydrochloric acid, filtered, and the filter cake was dried in vacuo to give the title product 3~2 Fluoromethoxy-5-nonyloxycarbonyl, benzoic acid 61c (4.4 g, white solid) 'yield: 82%. #3 Step 3 3-(3-phenylphenyl)carbonyl-5-difluoromethoxy _ Benzene benzoate. To 3~ difluorodecyloxy-5-decyloxycarbonyl-benzoic acid 61c (4.4 g, 17. 9 mmol) + Add 20 mL of dichlorohydrazine*, heat reflux 3 In an hour, spin dry to a yellow mucus, add 20 mL of tetrahydrofuran under argon, and take 1 Μ 3-chlorophenyl bromide in tetrahydrogenate (goo this, 20.0 mmol) 'at ~30 °C Add to the reaction system in the next 5 minutes. After 1 hour of reaction, '30 mL of saturated ammonium chloride solution was added to quench the reaction, spin dry tetrahydrogenate' and extracted with ethyl acetate (60 mL×2). 271 95392 201242594 Washed with sodium carbonate solution (50 mL) and saturated sodium carbonate solution (5 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The crude product of methyl carbonyl-5-difluoromethoxy-clutonic acid methyl ester 61d (6.7 g, yellow oil) was applied to the next step without purification. Step 4 3-[(3-benzene Methyl 3-hydroxy-indenyl]-5-difluoromethoxy-benzoic acid The crude 3-(3-phenylphenyl)carbonyl-5-difluorodecyloxy-p-formate obtained in the previous step 61d (6. 7 g, 18 mmol) was dissolved in 20 mL of tetrahydrofuran in an 'ice bath' and 2 borane dioxane thioether solution (13. 5 mL, 27 mmol) was added dropwise. The mixture was warmed to room temperature, and the reaction was stirred overnight. EtOAc (EtOAc) was evaporated. The filtrate was filtered, and the filtrate was evaporated to dryness. Oxy-benzoic acid oxime ester 61e (2.8 g, yellow oil), φ two-step yield: 43%. Step 5 3-[(3-chlorophenyl)-[2-(methoxy)|carbon Ethylamino)ethoxy]indolyl]_5-monofluoromethoxy-benzoic acid methyl ester 3-[(3- Phenyl)-trans-yl-indenyl]-5-difluoromethoxy-one oxime I oxime ester 61e (1.1 g, 3.2 mmol) and N-(2-hydroxyethyl) carbazate formate ( 0.96 g, 8.0 mmol) was dissolved in 1 mL of toluene 'p-toluenesulfonic acid (1.22 g, 6.4 mmol), and stirred at 130 ° C for 2 hours. The reaction was quenched by the addition of 2 mL of triethylamine. EtOAc (EtOAc) Methoxycarbonylamino)ethoxy]methyl]-5-difluoromethoxyoxybenzoate 61f (300 mg, colorless oil). Yield: 22%. Step 6 3-[U)-(3-Phenylphenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]-5-difluorodecyloxy-benzoic acid methyl ester High Performance Liquid Chromatography Separation of Racemic Mixtures 3_[(3-Chlorophenyl)-[2_(methoxycarbonylamino)ethoxy]indolyl]-5-difluorodecyloxy-benzoic acid hydrazine Ester 61f (300 mg, 0. 67 mmol) gave the title product 3-[UM3-chlorophenyl)-[2-(decyloxycarbonylamino)ethoxy]] yl]-5-difluoro oxime 15%。 The methyl-benzoic acid methyl ester 61g (112 mg, 0. 25 mmol), the yield: 75%. Step 7 3-[U)-(3-Chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]-5-difluorodecyloxy-benzoic acid • 3 [U)-(3-Phenylphenyl)-[2-(decyloxycarbonylamino)ethoxy] decyl]-5-difluoromethoxy-benzoic acid methyl ester 61g (100 mg, 0.225 Methyl) dissolved in 10 mL of sterol and 3.5 mL of water, and added with sodium hydroxide (36 mg, 0.9 匪〇1). The reaction was stirred at room temperature for 6 hours. The title compound 3-((7?)-(3-) was obtained by EtOAc (EtOAc) (EtOAc) Chlorophenyl)-[2-(decyloxycarbonylamino)ethoxy]methyl]-5-difluoromethoxy-benzoic acid as a crude product (yield: 97 mg, oil) Carry out the next reaction. 273 95392 201242594 Step 8 N-[2-[(3-Phenylphenyl)-[3-(difluoromethoxy)-5-[[(2«-2-(T-butoxycarbonyl)] Amino)-3-[(3«-tetrahydropyran-3-yl]propyl]aminomethylindenyl]phenyl]-(indenyloxy)ethyl]aminopyrudecanoate The ester is 3-[U)-(3-phenylphenyl)-[2-(decyloxycarbonylamino)ethoxy]indolyl]-5-difluorodecyloxy-benzoic acid 61h (97 mg, 0.225 mmo1) and N-[(150-1-(aminomethyl)-2-[(3-tetrahydroanthran-3-yl)ethyl]-N-methyl-carboxylic acid tert-butyl) The base 3a (123 mg, 0.45 mmol) was dissolved in ® 10 mL of N,N-didecylamine, and hydroxybenzotriazole (37 mg, 0.271 mmol) was added, and the (3-dimethylamino group) was added. Propyl)-3-ethylcarbodiimide hydrochloride (52 mg, 0.271 mmol) and N,N-diisopropylethylamine (88 mg, 0.678 mmol), stirred for 20 hours. Concentration, 1 〇〇 mL of dichloromethane was added, washed with water (50 mL×2), dried over anhydrous sodium sulfate -(dioxamethoxy)-5-[[ (25)-2-(t-butoxy-yl(methyl)amino)-3-φ [(3^-four Hydrazin-3-yl]propyl]aminoindenyl]phenyl]-(and)-methoxy]ethyl]amino decanoate 61i (155 mg, colorless oil) crude, The product was directly subjected to the next reaction without purification. N-[2-[(3-chlorophenyl)-[3-(difluoromethoxy)-5-[[(2)-2-yl) Amino-3-[(3 and)-tetrahydropyran-3-yl]propyl]aminoindenyl]phenyl]-(p)-methoxy]ethyl]aminopyrudecanoate Under the ester ice bath, N-[2-[(3-phenylphenyl)-[3-(difluorodecyloxy)-5-[[(25^-2-(T-butoxy) Amino)-3-[(3A〇-tetrahydro. ί南南274 95392 201242594-3-yl]propyl]aminomethylindenyl]phenyl]-(and)-methoxy]ethyl The oxime carbazate 61 i (155 mg, 0.225 mmol) was dissolved in 30 mL of dichlorohydrazine, and 5 mL of trifluoroacetic acid was added to carry out the reaction for 2 hours. The reaction solution was adjusted with a saturated sodium hydrogencarbonate solution. &lt;9, extracted with a gas-fired gas (50 mL×3), and the organic phase was combined, washed with water (20 mL×2) and saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate Residues purified by thin layer chromatography with developer system A , the title product N_[2-[(3-chlorophenyl)-[3-(difluoromethoxy)-5-[[(25^-2-decylamine®)-3-[(3A0-) Tetrahydropyroxy-3-yl]propyl]aminoglycolyl]phenyl]-(indolyl-methoxy)ethyl]aminoglycolic acid methyl ketone 61 (62 mg, white solid), three steps Yield: 46.9%. MS m/z (ESI): 584 [M+l].H NMR (400 MHz, CDCh): δ 8. 30 (s, 1H), 7. 95 (s, 1H), 7.70-7.00 (m, 5H ), 6.58 (t, / = 8. 0 Hz, 1H), 5.30 (s, 1H), 4.05-3.05 (in, 13H), 2.68 (m, 2H), 2.10-1.20 (m, φ 9H) 62 N-[2-[ (Λ-(3-Chlorophenyl M3-(difluorodecyloxy)-5-[ [(2«-2-methylamino-3-[(3A〇-tetrahydro) "Bialm-3-yl]propyl]aminomethylindenyl]phenyl] decyloxy]ethyl]amino decyl decanoate

, cAn ~ Η 62 275 95392 201242594

first step

3-[(50-(3-Phenylphenyl)-[2-(decyloxycarbonylamino)ethoxy]methyl]-5-difluoromethoxy-benzoic acid oxime ester Separation of the racemic mixture by phase preparative chromatography 3_[(3-(phenylphenyl)-[2-(methoxycarbonylamino)ethoxy]indolyl]_5-difluorodecyloxy- decyl decanoate 61f (3 〇〇 mg, 0.67 mmol) gave the title product 3-[(3⁄4-(3-chlorophenyl)-[2-(methoxycarbonylamino)ethoxy]methyl]_5_difluoroanthracene Methyl-benzoic acid methyl ester 62a (112 mg, 0.25 mmol), yield: 75. 0% 'Chiral HPLC showed an optical purity of 99.85 〇 / 0. The second step 3 ~ [(phantom - (3-chlorophenyl) -[2-(Methoxycarbonylamino)ethoxy]indolyl]difluoromethoxy-benzoic acid 34(50-(3-phenylphenyl)-[2_(methoxylamine) Ethyl] ethoxy] methyl]-5-difluoromethoxy- benzoic acid oxime ester (1) 〇 〇, 〇 25 legs 〇 1) Dissolved in 10 mL of methanol and 3.5 raL of water, add sodium hydroxide (10), • 〇 〇 1) 'room fox stir-mixed reaction for 6 hours. Add 1 Μ of hydrochloric acid to quench the reverse ~ take dry sterol with acetic acid ethyl extraction (5 〇 heart 2), anhydrous sulphuric acid dry 95392 276 201242594 dry 'filter 'filter Concentration under reduced pressure gave the title product 3-[(5·)-(3-chlorophenyl)-[2-(decyloxycarbonylamino)ethoxy] fluorenyl; j_5_difluoromethoxy-benzene Formic acid 62b (107 mg, oil) crude product, the product was taken to the next step without purification. The third step Ν-[2-[(5·)-(3-chlorophenyl)-[3-(difluoro)曱oxy)-5-[[(2« -2-(t-butoxycarbonyl(methyl)amino)-3-[(3妁-tetrahydrofuran-3-yl]) propyl]amine Methyl phenyl] phenyl] decyloxy] ethyl] carbamic acid carboxylic acid ester 34 (50-(3-chlorophenyl)-[2-(methoxycarbonylamino)ethoxy] fluorenyl ]-5-Difluoromethoxy-benzoic acid 62b (107 mg, 0.25 mmol) and N-[(1aminomethyl)-2-[(3N)-tetrahydron. ratio. Ethyl]-hydrazine-methyl-hypo-acid tert-butyl hydrazone 3a (136 mg, 0.50 mmol) was dissolved in 10 mL of N,N-dimethylformamide and 1-hydroxybenzotriazole (41) was added. Mg, 0· 30 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58 mg, 0.30 mmol) and hydrazine, hydrazine-diisopropylethylamine (97 mg, 0.75 • mmol), stir the reaction for 20 hours. The reaction was concentrated under reduced pressure. (50 mL×2), dried over anhydrous sodium sulfate, filtered and evaporated. -[ [(250-2-(T-butoxycarbonyl(methyl)amino)-3_[(3N)-tetrahydropyran-3-yl]propyl]aminomethylindenyl]phenyl] The crude product of decyloxy]ethyl]carbamic acid carbazate 62c (171 mg, colourless oil) was taken to the next step without purification. The fourth step is Ν-[2-[(«-(3-chlorophenyl)-[3-(difluoromethoxy)-5-[[(25·)-2-methyl 277 95392 201242594) 3-[(3 and)-tetrakis-β-pyran-3-yl]propyl]amino]carbonyl]phenyl] decyloxy]ethyl]carbamic acid methyl ester under ice bath, Ν-[ 2-[(3-Chlorophenyl)-[3-(difluoromethoxy)-5-[[(25*)-2-(t-butoxycarbonyl(methyl)amino)-3-[ (3 friends)-tetrahydrofuran-3-yl]propyl]amino aryl]phenyl]-(51)-decyloxy]ethyl]amino decanoate 62c (171 mg, 0 25 mmol) dissolved in 30 mL of dioxane. 'Add 5 mL of trifluoroacetic acid, stir the reaction for 2 hours. Adjust the pH of the reaction solution with saturated sodium bicarbonate solution. 9' Extract with dichloromethane (5〇mLx3 ), ® combined organic phase 'washed with water (20 mLx2) and saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, dried over Celite, concentrated under reduced pressure, purified by thin layer chromatography The residue obtained gave the title product N-[2-[(5&quot;)-(3-murophenyl)-[3-(difluoromethoxy)-5-[[(25)-2-decylamine Base-3-[(3 friends)-tetrahydrofuran-3-yl]propyl]aminoindenyl]phenyl]methoxy]ethyl曱 carboxylate 62 (70 mg, white solid), three-step yield: 47. 9%. φ MS m/z (ESI): 584 [M+l] H fJMR (400 MHz, CDCh): δ 8· 41 (s,1H),7· 96 (s, 1H), 7.69-7.05 (m, 5H), 6.60 (t, /=7.2, 1H), 5.31 (s, 1H), 4.00-3.10 (m , 13H), 2.69 (m, 2H), 2.10-1.20 (m, 9H) Test example: Biological evaluation Test example 1. Compound inhibition of renin activity test The following method is used to determine the inhibition of renin protease activity by the inventive compound. Capacity. The half-inhibitory concentration of each compound is IC5. (Inhibiting the concentration of the compound measured when the enzyme activity is 95392 278 201242594 to 50%) is a fixed amount of enzyme mixed with a fixed amount of substrate and different concentrations of the test compound. Materials for determination of renin inhibitory activity of the compounds of the invention: 1. Black 96-well plate (Greiner bi〇~one #655087) 2. 1 OX buffer IX buffer

50 mM Tris-HCl 100 mM NaCl pH 8. 0 (Cayman #10006870) 3. Renin enzyme (sigma-aldrich #R2779) 4. Renin matrix (Cayman #100068720) 5. ddH2〇6. DMSO (Chinese medicine #30072418) Method : Proceed as follows: 1. Pre-diluted the compound to the desired final concentration with 50% DMS0 (DMS0: ddH2〇, 1:1). 2. Dilute 10X buffer to IX buffer with ddM). 37 ΐ preheated IX buffer. 3. Blank (blank control) plus 10# L substrate, 80 IX buffer, 5//L 50% DMSO to each well'.

4. Negative control (100% active control) - plus 1 〇 ^ L 95392 279 201242594 substrate, 75a L IX buffer, 5 # L 50% DMS0 to each well, set a double well control. 5. Sample (test compound group) - add 1 〇 #1 substrate, 75 &quot; L IX buffer ' 5 / zL compound (dissolved in 5 % DMSO) to each well, with a duplicate well. 6. Dilute the Renin enzyme to 8.33 ng//zL with IX buffer. 7. Add 5/zL Renin to the Negative control well and the SamPle well to initiate the reaction. The micro-oscillator is shaken for 1 〇 second to mix, and the ® sealing film is sealed and incubated at 37 ° C for 90 minutes. 8. Remove the sealing film and read the fluorescence value at excitation wavelengths of 335 to 345 nm and emission wavelengths of 485 to 510 nm. Inhibition rate calculation: IR (° / 〇) = 100-100 * (SB) / (NB) S = fluorescence value of the reaction well added to the test compound N = fluorescence value of the negative control reaction well φ B = blank well Fluorescent value ICs. The value can be calculated by measuring the IR value of the compound under a concentration gradient. Activity of the Compound of the Invention The biochemical activity of the compound of the present invention was measured by the above test, and the I Cso value measured is shown in the following table. 95392 280 201242594

Example Compound ICso Value (nM) 3 2 4 6 5 4 6 8 7 8 9 1 10 6 11 2 14 7 15 1 16 1 18 1 20 1 21 1 23 6 25 7 27 4 28 1 , 30 1 32 2 34 1 37 1 38 4 39 9 40 10 42 8 43 1 44 11 45 8 46 6 47 2 48 3 51 20 52 24 53 1 55 3 57 29 58 22 281 95392 201242594 Activity Conclusion: The compounds of the invention are specific for renin protease Significant inhibition of pharmacokinetic evaluation Test Example 2, pharmacokinetic test of the compound of the present invention 1. Abstract Rats were used as test animals, and rats were intragastrically administered by LC/MS/MS method. Example 4 was administered. Compounds of 23, 30, 48, 53, 55, and 58 are the same: the concentration of the drug in the pulp. The pharmacokinetic behavior of the compounds of the present invention in rats was investigated and their pharmacokinetic characteristics were evaluated. * 2. Test protocol 2. 1 Test drug Examples 4, 23, 30, 48, 53, 55 and 58. 2. 2 Test animals Healthy adult SD rats 28 male and female, each planted * 隹, purchased from Shanghai Xipuer - must hung experimental animal company, animal birth certificate number: SCXK (Shanghai) 2008-0016. 2. 3 drug preparation Weigh a certain amount of drug, add 5%. 5% by methyl cellulose to make a 3 〇 mg / mL suspension. 2.4 Administration 28 SD atmospheres were male and female, and each group of 4 fasted overnight after intragastric administration, the dose was 3 〇. 〇 mg/kg. 3. Operate 28 SD rats, both male and female, administered intragastrically after one night of fasting. The dose of 95392 282 201242594 was 30. 0 mg/kg, Examples 4, 23, 30, 48, 53, 55 and 58 The compound is administered before and after administration. 5 ' 1.0, 2.0, 3. 〇, 4. Ο, Μ), 8. Ο ' 12. Ο ' 24. Ο ' 36. Ο ' 48· Ο ' 72. Blood was collected from the eyelids for 2 hours, placed in a heparinized test tube, centrifuged at 10,000 rpm for 1 minute, and stored at -20 ° C for 2 hours after administration. The test compounds in rat gold paste after intragastric administration of different concentrations of the drug were measured. The blood of the rats at each time after administration was 50/zL, and the internal standard solution was added 50 y L 'methanol 1 〇〇//L. 'Thirsty for 3 minutes, centrifuge for 1 minute

(13500 rpm) The plasma samples were taken for lc/MS/MS analysis. 4. Pharmacokinetic parameters results The pharmacokinetics of the compounds of the present invention are as follows: T, 八*·* 1 · Drug metabolism test (10 mg/kg) No. Blood concentration curve area half-life retention time clearance rate table Distribution. Volume Cmax (ng/mL) AUC (ng/mL*h) tl/2(h) MRT(h) CL/F (L/h/kg) Vz/F (L/kg) Example 4 276 +90 1008+317 5.42 + 1.31 6.08+0.89 π. 0+4. 5 85. 2+40. 0 Example 23 211+155 1404+894 4.98±0.23 A 7.90+0. 99 8.77+3.48 62. 2± 23_ 1 Example 30 295+50 1063±127 4·78±1_ 82 5.73+2.1〇9.51 + 1. 19 65. 9+27. 0 Example 48 108+34 367 soil 94 3.35±1.47 4.40+1.15 28.8+ 8.3 137±68 Example 53 108+22 346+19 3.36±1. 10 4.45+1.〇1 28. 9+1.5 139+36 Example 55 378±147 9951441 4.25+1.27 4.70+0.66 12.7+8.5 85.4+ 78.7 Example 58 125+25 342±141 3.51±1.77 4.70+0.64 33. 0+12. 7 150+42 95392 283 201242594 Conclusion: The blood concentration and exposure level of the compound of the present invention in rats after oral administration Higher, longer half-life, with good pharmacokinetic characteristics. [Simple description of the diagram] None. [Main component symbol description] None.

284 95392

Claims (1)

201242594 VII. Patent application scope: 1. A compound represented by the formula (I), an enantiomer thereof, a diastereomer or a pharmaceutically acceptable salt thereof: Wherein: R1 is an alkyl group; each R2 is independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a hydroxyl group, a nitro group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, and an aromatic group. a heteroaryl group, -C(0)0R9, -0C(0)R9, -C(0)R9, wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, The aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of dentate, cyano, hydroxy, nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, hetero Aryl, -C(0)0R9, -0C(0)R9, -C(0)R9, -NHC(0)R9, -NR1GRn, -0C(0)NR1()Ru, -NHCCCONITR11 or -S( 0) Substituted by a substituent of mR9; one of R3, R4 and R5 is selected from the group consisting of cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, C(0)0R9, -0C(0)R9, -C(0)R9'-NHC(0)R9-NR10R11&gt;-〇c(〇)NR10R11'-NHC(O)NR10 R11, -SOMRWR11 or -S(〇)mR9, wherein The pendant, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further selected from one or more of 1 95392 201242594 selected from the group consisting of _, cyano, hydroxy, decyl, alkyl, alkane Oxyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(0)0R9, -〇C(〇)R9, -C(0)R9, ~NHC(〇)V, _NRl〇Ru , -OCCOjNW1, -ΝΙΚΧΟ)^%11 or S(〇)n&gt; is substituted with a substituent of R9, and the other two are selected from a hydrogen atom; or, R3 and R4 or R4 and R5 together with the attached atom form a hetero a cyclic group wherein the heterocyclic group contains a hetero atom selected from N, oxime or SCOX, and the heterocyclic group is optionally further further selected from one or more % 2 selected from the group consisting of an alkyl group, a south group, a hydroxyl group, an alkoxy group, Substituted by a substituent of a cycloalkyl, heterocyclic, aryl, heteroaryl, carboxylic acid or carboxylic acid ester; i2 R is a hydrogen atom 'R7 is a (CH2)p-R12, or R6 is -(CH2) pR r is a hydrogen atom; R 8 is selected from a hydrogen atom or an alkyl group; - R is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heterocyclic group, wherein the alkyl group, the cycloalkyl group, and the hetero Each of the cyclo, aryl or heteroaryl groups is independently further optionally further substituted by one or more substituents selected from the group consisting of alkyl, hydrazine, hydroxy, weiji, miscellaneous, secret, heterofilament, pro- or oxime Substituted; Yan R* or R1 are each independently selected from hydrogen An atom, an alkyl group, a ring-based group, a hetero-, an aryl group, a heteroaryl group or a _s(G)nR9, wherein the alkyl group, the cycloalkyl group, the :yl group, the * group or the hetero-filament are each independently optionally further Substituted by a substituent selected from the group consisting of an alkyl group, a hydrazine, a hetero group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a heteroaryl group, and a nicotinic acid vinegar; 'R1. And R&quot; together with the attached gas atom to form a heterocyclic group wherein the heterocyclic group contains one or more heteroatoms selected from N, yttrium or secret 95392 2 201242594, and the heterocyclic group optionally further Substituted by one or more substituents selected from the group consisting of an alkyl group, a hydroxyl group, a hydroxyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester; R12 is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of a halogen group, a hydroxyl group, and a hydroxyl group. Substituted by a substituent of an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester; m is 0, 1 or 2; η is 1, 2, 3, 4 or 5; and ρ is 0, 1, 2 or 3. 2. A compound of the formula (I), an enantiomer, a diastereomer thereof or a pharmaceutically acceptable salt thereof, according to the invention of claim 1, which comprises a compound of the formula (II) And its enantiomers, diastereomers or pharmaceutically acceptable salts thereof: R4 Wherein R1 to R8, η are as defined in the first item of the patent application. 3. The compound of the formula (I) and its enantiomers, diastereomers or pharmaceutically acceptable salts thereof, as defined in the scope of claim 1, including the general formulae (III) and (IV) The compound shown and its enantiomers, diastereomers or pharmaceutically acceptable salts thereof: 95392 201242594 R5 hn'r8 'R12 , Re where R 丨 to R 5 , R 8 , R 12 , n and D are M, 丄 ^ I1: f P is as described in the first item of the patent application. - General formula (I) as described in the item 4. As in the scope of claims 1 to 3 of the patent application A compound, an enantiomer thereof, a diastereomer or a pharmaceutically acceptable salt thereof, wherein R4 is selected from the group consisting of cyano, alkyl, silk, heterocyclyl, cyclofilament or aryl. A compound of the formula (1), an enantiomer, a diastereomer thereof or a pharmaceutically acceptable salt thereof, according to any one of the claims U 3, wherein p is 1. 6. The compound of the formula (1), and the enantiomer, diastereomer or pharmaceutically acceptable salt thereof, according to any one of the claims ir to 3, wherein R3 and R4 or R4 and R5 are bonded to a bonded atom to form a 5- to 6-membered heterocyclic group wherein the heterocyclic group contains a halogen atom. 7. The compound of the formula (1) and the enantiomer, diastereomer or pharmaceutically acceptable salt thereof, as defined in the scope of claim 6, including the formulae (v) and (VI) The compound shown and its enantiomers, diastereomers or pharmaceutically acceptable salts thereof: 95392 4 201242594 HN q is 1 or 2; , R8, R7 HN' R8 -CH2 The definitions of R, R R to R, n are as described in the scope of the patent application. The compound of the formula (1), and the enantiomer, diastereomer or pharmaceutically acceptable salt thereof, according to any one of the above-mentioned items, wherein n is 1, and R2 is a halogen. A compound of the formula (1), an enantiomer, a diastereomer thereof or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, wherein P is 1, and R12 is selected from the group consisting of Alkyl or heterocyclic group. A compound represented by the formula (1), and an enantiomer, a diastereomer thereof, or a pharmaceutically acceptable salt thereof, wherein R, 2 is cyclohexyl or tetrahydrogen, as described in claim 9咐^ 基基. A compound of the formula (I), an enantiomer, a diastereomer thereof or a pharmaceutically acceptable salt thereof, as described in claim 1, wherein the compound is: 95392 201242594 6 95392 201242594 〇^Ό, 7 95392 201242594 HN or HN, 12. A method of preparing a non-lethalant or a pharmaceutically acceptable salt thereof, the compound and its enantiomer, and the non-described method of the formula (1) comprising: (IB) optionally hydrolyzing a compound of the formula (IA) to a reaction of a compound of the formula (I) with a compound of the formula (ib), optionally a step-by-step removal of the amine group, to give a compound of the formula (I); , R1 to R8 are as defined in the scope of the patent application; G is selected from a hydroxyl group, an alkoxy group or a dentate; PG is a protecting group for an amine group. 13. The method of claim 12, wherein the protecting group of the amine group is a third butoxycarbonyl group. A compound of the formula (A), an enantiomer thereof, a diastereomer thereof or a pharmaceutically acceptable salt thereof, wherein: R4 95392 201242594 wherein: n'R1 to R5 are as defined in claim 1; G is selected from hydroxy, alkoxy or halogen. A method of preparing a compound of the formula (IA) described in claim 14 and an enantiomer, a diastereomer thereof or a pharmaceutically acceptable salt thereof. The method comprises: The benzaldehyde compound a is reacted with a substituted benzene format reagent to obtain a diphenylmethanol compound b; The compound b is subjected to a condensation reaction with the compound c to obtain a compound of the formula (IA): wherein: n'R1 to R5 are as defined in the first item of the patent application; G is selected from a hydroxyl group, an alkoxy group or a γ group. 16. A method of preparing a compound of the formula (IA) and an enantiomer, a diastereomer thereof or a pharmacologically acceptable salt thereof according to the invention of claim 14, the method comprising: 95392 9 201242594 R4 The bromobenzene compound e is reacted with a substituted benzaldehyde to obtain a diclofenac compound f; Compound g is reduced to alcohol and then reacted with sulfonium chloride to obtain compound h; Compound h undergoes azide reaction to give compound i; R4 R4 Reduction of compound i to give ethylamine compound j; 10 95392 201242594 R4 (R)n Λ \,ry) Compound k deprotects the hydroxy protecting group] to obtain the general formula (R)n, wherein the definition is as in the patent application:::: This is selected from the group consisting of a hydroxyl group, an alkane group or a nutrient; Said Μ is a trans-protecting group.方 The square base as described in claim 16 is methyl or tert-butylbiphenyl. The compound of the present invention, which comprises a therapeutically effective amount of the compound of any one of claims 1 to 11 and an enantiomer, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and A pharmaceutically acceptable carrier or excipient. 19. A compound according to any one of claims 1 to 5, and an enantiomer, diastereomer thereof or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 18 The use of the substance is used in the preparation of a medicament for the treatment of diseases associated with renin activity. 2. The use according to claim 19, wherein the disease associated with renin activity is selected from the group consisting of: hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy , cardiac fiber 11 95392 201242594, post-infarction cardiomyopathy, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, liver fibrosis, complications caused by diabetes, coronary artery disease, restenosis after angioplasty, Increased pressure in the eye, glaucoma, abnormal gold tube growth, high stagnation, cognitive impairment, Alzheimer's disease, dementia, anxiety or cognitive disorders, including complications of diabetes including nephropathy, vascular disease and Neuropathy. 21. The compound of any one of claims 1 to 11 and the enantiomer, diastereomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 18 The use of the substance is used in the preparation of a renin inhibitor. 2 2. A method for inhibiting renin, which comprises administering a therapeutically effective amount of a compound according to any one of claims 1 to 11 and an enantiomer, diastereomer thereof or Medicinal salt, the pharmaceutical composition described in item 18 of the patent application. 12 95392 201242594 IV. Designated representative map: (1) The representative representative of the case is: The case has no schema. (2) A brief description of the symbol of the representative figure: None. 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 3 95392