CN105152977A

CN105152977A - D-hydroxy phenylglycine derivative and preparation method and application

Info

Publication number: CN105152977A
Application number: CN201510641211.8A
Authority: CN
Inventors: 杨大成; 曹园; 范莉; 杨龙; 刘晓华; 蒋佳; 黄亚兰; 叶晶晶; 吴晓霞; 曹丽君; 周围
Original assignee: Southwest University
Current assignee: Southwest University
Priority date: 2015-09-28
Filing date: 2015-09-28
Publication date: 2015-12-16
Anticipated expiration: 2035-09-28
Also published as: CN105152977B

Abstract

The invention discloses a D-hydroxy phenylglycine derivative. Please see the formula of the D-hydroxy phenylglycine derivative in the specification. D-hydroxy phenylglycine serves as a parent body, amino groups and carboxyl groups of the D-hydroxy phenylglycine are reasonably modified, a phenolic hydroxyl group is connected with an aromatic nucleus type hydrophobic group through a connector, the D-hydroxy phenylglycine derivative which is novel in structure is constructed, compounds capable of promoting the secreting activity of GLP-1 and/or inhibiting the activity of Nav1.7 are screened out, the preparation method of the compounds is simple and can be used for preparing GLP-1secernent and/or Nav1.7 inhibitors, and the D-hydroxy phenylglycine derivative has potential application prospects in the fields of diabetes treatment drugs and/or neuropathy pain treatment drugs. Please see the formula in the specification.

Description

D-pHPG derivative and its preparation method and application

Technical field

The invention belongs to technical field of medicine synthesis, relate to a class new compound, its preparation method and the application in pharmacy thereof.

Background technology

D-pHPG (D-PHPG) is as a kind of medicine intermediate, be mainly used in the production of beta-lactam semisynthetic antibiotics at present, in producing in the synthesis of the Broad spectrum antibiotics such as amoxycillin (amoxycilline Trihydrate bp), cephalo hydroxyl benzyl (Ou Yi), cephalo chlorobenzene (pioneer IV), cefoperazone, cephalo Luo Qi, SKF-60771, Cefaclor, Cephradine (Ancef I), cefatrizine, Cefalexin, D-pHPG is absolutely necessary side-chain acid.But it is less at present to the research of D-pHPG derivative both at home and abroad.

Summary of the invention

In view of this, the object of the invention is to take D-pHPG as parent, by protecting it and modifying, synthesize the D-pHPG derivative of a class formation novelty, more therefrom filter out the target molecule with pharmacologically active.

After deliberation, the invention provides following technical scheme:

1.D-D-pHPG derivative, has following structural formula:

R ¹for methyl, ethyl, n-propyl or normal-butyl, Y is O, Ar is 3-Fonnylphenyl, 2-Fonnylphenyl, 4-Fonnylphenyl, 4-methoxycarbonyl phenyl, 4-(2-oxo-2-methoxyl group) ethylphenyl, 4-(3-oxo-3-methoxyl group) propyl group phenyl, 4-propionylphenyl, 4-acetylphenyl, 2-acetylphenyl, 3-acetylphenyl, 5-formyl radical-2-p-methoxy-phenyl, 4-formyl radical-2-p-methoxy-phenyl, 4-acetylamino phenyl, phenyl, naphthalene-2-base or 2-oxo-2H-chromene-4-base;

Or, R ¹for methyl, ethyl, n-propyl or normal-butyl, Y is S, Ar is benzo [d] oxazole-2-base, 1H-benzo [d] imidazoles-2-base, 5-amido-1,3,4-thiadiazoles-2-base or 4-hydroxyl-6-aminopyrimidine-2-base;

Or, R ¹for methyl, ethyl, n-propyl or normal-butyl, Y is SO ₂, Ar is 1H-benzo [d] imidazoles-2-base;

Or, R ¹for hydrogen, Y is O, Ar is 3-Fonnylphenyl, 2-Fonnylphenyl, 4-Fonnylphenyl, 4-carboxyl phenyl, 4-carboxymethyl phenyl, 4-carboxyethyl phenyl, 4-propionylphenyl, 4-acetylphenyl, 2-acetylphenyl, 3-acetylphenyl, 5-formyl radical-2-p-methoxy-phenyl, 4-formyl radical-2-p-methoxy-phenyl, 4-acetylamino phenyl, phenyl, naphthalene-2-base or 2-oxo-2H-chromene-4-base;

Or, R ¹for hydrogen, Y is S, Ar is benzo [d] oxazole-2-base or 1H-benzo [d] imidazoles-2-base.

Preferably, R ¹for methyl, Y is O, Ar is 3-Fonnylphenyl, 2-Fonnylphenyl, 4-methoxycarbonyl phenyl, 4-propionylphenyl, 4-acetylphenyl, 2-acetylphenyl, 3-acetylphenyl, 5-formyl radical-2-p-methoxy-phenyl, 4-formyl radical-2-p-methoxy-phenyl, phenyl or 2-oxo-2H-chromene-4-base;

Or, R ¹for ethyl, Y is O, Ar is 2-Fonnylphenyl, 2-acetylphenyl, 3-acetylphenyl or phenyl;

Or, R ¹for n-propyl, Y is O, Ar is 4-acetylphenyl, phenyl or naphthalene-2-base;

Or, R ¹for normal-butyl, Y is O, Ar is 2-Fonnylphenyl or phenyl;

Or, R ¹for methyl or ethyl, Y is S, Ar is benzo [d] oxazole-2-base, 1H-benzo [d] imidazoles-2-base or 4-hydroxyl-6-aminopyrimidine-2-base;

Or, R ¹for n-propyl, Y is S, Ar is 1H-benzo [d] imidazoles-2-base, 5-amido-1,3,4-thiadiazoles-2-base or 4-hydroxyl-6-aminopyrimidine-2-base;

Or, R ¹for normal-butyl, Y is S, Ar is 1H-benzo [d] imidazoles-2-base or 4-hydroxyl-6-aminopyrimidine-2-base;

Or, R ¹for methyl, ethyl or n-propyl, Y is SO ₂, Ar is 1H-benzo [d] imidazoles-2-base;

Or, R ¹for hydrogen, Y is O, Ar is 4-acetylamino phenyl, phenyl or naphthalene-2-base;

Or, R ¹for hydrogen, Y is S, Ar is benzo [d] oxazole-2-base.

Preferred, R ¹for methyl, Y is O, Ar is 4-acetylphenyl or 2-acetylphenyl;

Or, R ¹for ethyl or normal-butyl, Y is O, Ar is 2-Fonnylphenyl or phenyl;

Or, R ¹for n-propyl, Y is O, Ar is phenyl or naphthalene-2-base;

Or, R ¹for methyl, Y is S, Ar is 1H-benzo [d] imidazoles-2-base or 4-hydroxyl-6-aminopyrimidine-2-base;

Or, R ¹for ethyl, Y is S, Ar is benzo [d] oxazole-2-base, 1H-benzo [d] imidazoles-2-base or 4-hydroxyl-6-aminopyrimidine-2-base;

Or, R ¹for methyl or ethyl, Y is SO ₂, Ar is 1H-benzo [d] imidazoles-2-base.

The preparation method of 2.D-D-pHPG derivative, step is as follows:

1) D-pHPG and benzene methoxy carbonyl acyl succinimide Z-OSu are reacted under base catalysis generate intermediate compound I M1, IM1 again with alcohol R ¹oH reacts and generates intermediate compound I M2 under sulfur oxychloride effect;

2) intermediate compound I M2 and 1,3-dibromopropane are reacted under base catalysis generate intermediate compound I M3;

3) intermediate compound I M3 and aromatic compound A is reacted under base catalysis generate D-pHPG derivative TM1;

4) D-pHPG derivative TM1-18 and metachloroperbenzoic acid and mCPBA are reacted generate D-pHPG derivative TM2;

5) after being hydrolyzed under base catalysis by D-pHPG derivative TM1, acidifying generates D-pHPG derivative TM3;

Alcohol R ¹in OH, intermediate compound I M2 and IM3, R ¹for methyl, ethyl, n-propyl or normal-butyl;

In aromatic compound A and D-pHPG derivative TM1, R ¹for methyl, ethyl, n-propyl or normal-butyl, Y is O, Ar is 3-Fonnylphenyl, 2-Fonnylphenyl, 4-Fonnylphenyl, 4-methoxycarbonyl phenyl, 4-(2-oxo-2-methoxyl group) ethylphenyl, 4-(3-oxo-3-methoxyl group) propyl group phenyl, 4-propionylphenyl, 4-acetylphenyl, 2-acetylphenyl, 3-acetylphenyl, 5-formyl radical-2-p-methoxy-phenyl, 4-formyl radical-2-p-methoxy-phenyl, 4-acetylamino phenyl, phenyl, naphthalene-2-base or 2-oxo-2H-chromene-4-base; Or, R ¹for methyl, ethyl, n-propyl or normal-butyl, Y is S, Ar is benzo [d] oxazole-2-base, 1H-benzo [d] imidazoles-2-base, 5-amido-1,3,4-thiadiazoles-2-base or 4-hydroxyl-6-aminopyrimidine-2-base;

In D-pHPG derivative TM2, R ¹for methyl, ethyl, n-propyl or normal-butyl;

In D-pHPG derivative TM3, R ¹for hydrogen, Y is O, Ar is 3-Fonnylphenyl, 2-Fonnylphenyl, 4-Fonnylphenyl, 4-carboxyl phenyl, 4-carboxymethyl phenyl, 4-carboxyethyl phenyl, 4-propionylphenyl, 4-acetylphenyl, 2-acetylphenyl, 3-acetylphenyl, 5-formyl radical-2-p-methoxy-phenyl, 4-formyl radical-2-p-methoxy-phenyl, 4-acetylamino phenyl, phenyl, naphthalene-2-base or 2-oxo-2H-chromene-4-base; Or, R ¹for hydrogen, Y is S, Ar is benzo [d] oxazole-2-base or 1H-benzo [d] imidazoles-2-base.

Preferably, step 1) be by D-pHPG and benzene methoxy carbonyl acyl succinimide Z-OSu in boiling mixed solvent, salt of wormwood catalysis, 15-35 DEG C, react under pH8-9 condition generate intermediate compound I M1, IM1 again with alcohol R ¹oH reacting by heating under sulfur oxychloride effect generates intermediate compound I M2.

Preferably, step 2) be by intermediate compound I M2 and 1,3-dibromopropane in acetonitrile, salt of wormwood catalysis, react under 45-55 DEG C condition and generate intermediate compound I M3.

Preferably, step 3) be by intermediate compound I M3 and aromatic compound A in DMF, salt of wormwood catalysis, react under 15-35 DEG C condition and generate D-pHPG derivative TM1.

Preferably, step 4) be by D-pHPG derivative TM1-18 and mCPBA in methylene dichloride, under 15-35 DEG C condition reaction generate D-pHPG derivative TM2.

Preferably, step 5) be by D-pHPG derivative TM1 in tetrahydrofuran (THF), lithium hydroxide catalysis, generate D-pHPG derivative TM3 with hcl acidifying after the reaction of 15-35 DEG C Water Under solution.

3.D-D-pHPG derivative is preparing the application in glucagon-like-peptide-1 (glucagon-likepeptide1, GLP-1) secernent, and described D-pHPG derivative has following structural formula:

R ¹for methyl, Y is O, Ar is 3-Fonnylphenyl, 2-Fonnylphenyl, 2-acetylphenyl, 4-formyl radical-2-p-methoxy-phenyl, 4-acetylamino phenyl, phenyl or 2-oxo-2H-chromene-4-base;

Or, R ¹for ethyl, Y is O, Ar is 3-Fonnylphenyl, 2-Fonnylphenyl, 4-Fonnylphenyl, 4-methoxycarbonyl phenyl, 4-(2-oxo-2-methoxyl group) ethylphenyl, 4-(3-oxo-3-methoxyl group) propyl group phenyl, 4-acetylphenyl, 2-acetylphenyl, 3-acetylphenyl, 4-acetylamino phenyl, phenyl, naphthalene-2-base or 2-oxo-2H-chromene-4-base;

Or, R ¹for n-propyl, Y is O, Ar is 3-Fonnylphenyl, 2-Fonnylphenyl, 4-Fonnylphenyl, 4-(3-oxo-3-methoxyl group) propyl group phenyl, 4-acetylphenyl, 3-acetylphenyl, 5-formyl radical-2-p-methoxy-phenyl, 4-formyl radical-2-p-methoxy-phenyl, phenyl, naphthalene-2-base or 2-oxo-2H-chromene-4-base;

Or, R ¹for normal-butyl, Y is O, Ar is 2-Fonnylphenyl, 4-Fonnylphenyl, 4-(3-oxo-3-methoxyl group) propyl group phenyl, 2-acetylphenyl, 5-formyl radical-2-p-methoxy-phenyl, 4-formyl radical-2-p-methoxy-phenyl, 4-acetylamino phenyl, phenyl or 2-oxo-2H-chromene-4-base;

Or, R ¹for methyl, Y is S, Ar is benzo [d] oxazole-2-base;

Or, R ¹for ethyl or n-propyl, Y is S, Ar is benzo [d] oxazole-2-base or 1H-benzo [d] imidazoles-2-base;

Or, R ¹for methyl, n-propyl or normal-butyl, Y is SO ₂, Ar is 1H-benzo [d] imidazoles-2-base;

Or, R ¹for hydrogen, Y is O, Ar is 3-Fonnylphenyl, 2-Fonnylphenyl, 4-Fonnylphenyl, 4-carboxyl phenyl, 4-carboxymethyl phenyl, 4-propionylphenyl, 4-acetylphenyl, 2-acetylphenyl, 3-acetylphenyl, 5-formyl radical-2-p-methoxy-phenyl, 4-acetylamino phenyl, phenyl, naphthalene-2-base or 2-oxo-2H-chromene-4-base;

Preferably, in the structural formula of described D-pHPG derivative,

R ¹for methyl, Y is O, Ar is 2-acetylphenyl, phenyl or 2-oxo-2H-chromene-4-base;

Or, R ¹for ethyl or normal-butyl, Y is O, Ar is 2-Fonnylphenyl or phenyl;

Or, R ¹for n-propyl, Y is O, Ar is phenyl or naphthalene-2-base;

Or, R ¹for ethyl, Y is S, Ar is benzo [d] oxazole-2-base;

Or, R ¹for n-propyl, Y is SO ₂, Ar is 1H-benzo [d] imidazoles-2-base;

Or, R ¹for hydrogen, Y is O, Ar is phenyl or naphthalene-2-base;

Or, R ¹for hydrogen, Y is S, Ar is benzo [d] oxazole-2-base.

Preferred, in the structural formula of described D-pHPG derivative,

R ¹for ethyl or normal-butyl, Y is O, Ar is 2-Fonnylphenyl or phenyl;

Or, R ¹for n-propyl, Y is O, Ar is phenyl or naphthalene-2-base;

Or, R ¹for ethyl, Y is S, Ar is benzo [d] oxazole-2-base.

4.D-D-pHPG derivative is preparing the application in Voltage-gated sodium channels Nav1.7 inhibitor, and described D-pHPG derivative has following structural formula:

R ¹for methyl, Y is O, Ar is 3-Fonnylphenyl, 2-Fonnylphenyl, 4-Fonnylphenyl, 4-methoxycarbonyl phenyl, 4-(2-oxo-2-methoxyl group) ethylphenyl, 4-(3-oxo-3-methoxyl group) propyl group phenyl, 4-propionylphenyl, 4-acetylphenyl, 2-acetylphenyl, 3-acetylphenyl, 5-formyl radical-2-p-methoxy-phenyl, 4-formyl radical-2-p-methoxy-phenyl, phenyl, naphthalene-2-base or 2-oxo-2H-chromene-4-base;

Or, R ¹for ethyl, Y is O, Ar is 3-Fonnylphenyl, 4-acetylphenyl, 2-acetylphenyl, 3-acetylphenyl or phenyl;

Or, R ¹for n-propyl, Y is O, Ar is 2-Fonnylphenyl, 4-acetylphenyl, 2-acetylphenyl, 5-formyl radical-2-p-methoxy-phenyl, 4-formyl radical-2-p-methoxy-phenyl, 4-acetylamino phenyl or 2-oxo-2H-chromene-4-base;

Or, R ¹for normal-butyl, Y is O, Ar is 2-Fonnylphenyl, 4-Fonnylphenyl, 4-methoxycarbonyl phenyl, 4-propionylphenyl, 2-acetylphenyl, 3-acetylphenyl, 4-acetylamino phenyl, naphthalene-2-base or 2-oxo-2H-chromene-4-base;

Or, R ¹for hydrogen, Y is O, Ar is 4-carboxymethyl phenyl, 4-carboxyethyl phenyl, 4-acetylphenyl, 2-acetylphenyl, 4-formyl radical-2-p-methoxy-phenyl, 4-acetylamino phenyl or naphthalene-2-base;

Preferably, in the structural formula of described D-pHPG derivative,

R ¹for methyl, Y is O, Ar is 3-Fonnylphenyl, 2-Fonnylphenyl, 4-methoxycarbonyl phenyl, 4-propionylphenyl, 4-acetylphenyl, 2-acetylphenyl, 3-acetylphenyl, 5-formyl radical-2-p-methoxy-phenyl, 4-formyl radical-2-p-methoxy-phenyl, phenyl or 2-oxo-2H-chromene-4-base;

Or, R ¹for ethyl, Y is O, Ar is 2-acetylphenyl, 3-acetylphenyl or phenyl;

Or, R ¹for n-propyl, Y is O, Ar is 4-acetylphenyl;

Or, R ¹for methyl, Y is S, Ar is benzo [d] oxazole-2-base, 1H-benzo [d] imidazoles-2-base or 4-hydroxyl-6-aminopyrimidine-2-base;

Or, R ¹for ethyl or normal-butyl, Y is S, Ar is 1H-benzo [d] imidazoles-2-base or 4-hydroxyl-6-aminopyrimidine-2-base;

Or, R ¹for hydrogen, Y is O, Ar is 4-acetylamino phenyl.

Preferred, in the structural formula of described D-pHPG derivative,

R ¹for methyl, Y is O, Ar is 4-acetylphenyl or 2-acetylphenyl;

Or, R ¹for methyl or ethyl, Y is S, Ar is 1H-benzo [d] imidazoles-2-base or 4-hydroxyl-6-aminopyrimidine-2-base;

Or, R ¹for methyl or ethyl, Y is SO ₂, Ar is 1H-benzo [d] imidazoles-2-base.

Beneficial effect of the present invention is: the present invention take D-pHPG as parent, its amino and carboxyl are reasonably modified, and be connected with the ring-like hydrophobic grouping of fragrance by a connexon (linker) on phenolic hydroxyl group, construct the D-pHPG derivative of a class formation novelty, and therefrom filtered out the compound with short GLP-1 secretion activity and/or Nav1.7 inhibit activities, these compounds process for production thereof are simple, may be used for preparation GLP-1 secernent and/or Nav1.7 inhibitor, at Remedies for diabetes and/or neurogenic pain medicine field, there is potential application prospect.

Embodiment

In order to make object of the present invention, technical scheme and beneficial effect clearly, will be described in detail the preferred embodiments of the present invention below.

The synthesis of embodiment 1 intermediate compound I M1 and IM2

SM83.55g (499.84mmol) and 2mol/LK is added in 2L round-bottomed flask ₂cO ₃aqueous solution 300mL, the lower stirring and dissolving of ice bath cooling, then add the acetone soln 200mL of Z-OSu130.11g (522.07mmol), use 2mol/LK ₂cO ₃the aqueous solution regulates pH=8-9, and (15-35 DEG C) stirring reaction under envrionment temperature, keeps pH constant in reaction process, tlc (TLC) monitors reaction process.After reaction terminates, 3mol/L hydrochloric acid regulates pH=7, revolves and steams removing acetone, saturated K ₂cO ₃the aqueous solution regulates pH=9, add ethyl acetate (EtOAc) extraction (2 × 150mL), aqueous phase ice bath cools, concentrated hydrochloric acid regulates pH=3-4, a large amount of solid is separated out, and adds EtOAc extraction (3 × 250mL), collects and merge organic phase, saturated sodium-chloride water solution (3 × 200mL), water (3 × 200mL) is used to wash successively, anhydrous Na ₂sO ₄drying, suction filtration, filtrate revolves steaming, obtains intermediate compound I M1, yield 95%.

In the round-bottomed flask of suitable size, appropriate alcohol R is added under ice bath ¹oH, slowly drips appropriate SOCl ₂, activation 30min, remove ice bath, add design flow IM1, move into reacting by heating in oil bath after stirring, TLC monitors reaction process.After reaction terminates, vacuum rotary steam, except desolventizing, adds appropriate 5wt%NaHCO ₃the aqueous solution stirs, then adds appropriate EtOAc and dissolves, layering, collection organic phase, aqueous phase EtOAc extracts 1 time, merges organic phase, adds appropriate saturated sodium-chloride water solution, regulates pH=5-6 with saturated aqueous citric acid solution, layering, organic phase uses saturated sodium-chloride water solution and water washing successively, anhydrous Na ₂sO ₄drying, suction filtration, filtrate revolves steaming, obtains intermediate compound I M2.

Table one intermediate compound I M2 generated data

IM1 (R)-2-(((benzyloxy) carbonyl) is amino)-2-(4-hydroxy phenyl) acetic acid: white solid; M.p.:140-141 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 5.01 (s, 2H, PhCH ₂-), 5.04 (s, 1H, * CH), 6.71 (d, 2H, J=8.4Hz, Ar-H), 7.19 (d, 2H, J=7.8Hz, Ar-H), 7.35 (s, 5H, Ar-H), 7.93 (d, 1H, J=7.8Hz, CONH), 9.47 (s, 1H,-OH), 12.60 (s, 1H ,-COOH).

IM2-a (R)-2 – (((benzyloxy) carbonyl) is amino)-2-(4-hydroxy phenyl) methyl acetate: white solid; M.p.:125-127 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 3.60 (s, 3H ,-CH ₃), 5.04 (s, 2H, PhCH ₂-), 5.12 (d, 1H, J=7.8Hz, * CH), 6.72 (d, 2H, J=8.4Hz, Ar-H), 7.18 (d, 2H, J=8.4Hz, Ar-H), 7.31-7.34 (m, 5H, Ar-H), 8.14 (d, 2H, J=7.8Hz, CONH).

IM2-b (R)-2 – (((benzyloxy) carbonyl) is amino)-2-(4-hydroxy phenyl) ethyl acetate: white solid; M.p.:131-133 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 1.10 (t, 3H, J=7.2Hz ,-CH ₃), 4.06 (m, 2H, J=7.2Hz ,-CH ₂-), 5.04 (s, 2H, PhCH ₂-), 5.07 (d, 1H, J=7.8Hz, * CH), 7.71 (d, 2H, J=8.1Hz, Ar-H), 7.17 (d, 2H, J=8.1Hz, Ar-H), 7.35 (s, 5H, Ar-H), (8.09 d, 1H, J=7.5Hz, CONH), (9.52 s, 1H ,-OH).

IM2-c (R)-2 – (((benzyloxy) carbonyl) is amino)-2-(4-hydroxy phenyl) propyl acetate: white solid; M.p.:125-127 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 0.75 (t, 3H, J=7.5Hz ,-CH ₃), 1.45-1.52 (m, 2H ,-CH ₂-), 3.97 (t, 2H, J=6.0Hz ,-OCH ₂), 5.04 (s, 2H, PhCH ₂-), 5.08 (d, 1H, J=7.8Hz, * CH), 6.71 (d, 2H, J=7.8Hz, Ar-H), 7.18 (d, 2H, J=7.8Hz, Ar-H), 7.35 (s, 5H, Ar-H), 8.11 (d, 1H, J=7.5Hz, CONH).

IM2-d (R)-2 – (((benzyloxy) carbonyl) is amino)-2-(4-hydroxy phenyl) butylacetate: white solid; M.p.:131-133 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 0.86 (t, 3H, J=7.2Hz ,-CH ₃), 1.25 (m, 2H ,-CH ₂-), 1.55 (t, 2H, J=6.3Hz ,-CH ₂-), 4.13 (d, 2H, J=5.4Hz ,-OCH ₂), 5.10 (d, 2H, J=2.4Hz, PhCH ₂-), 5.85 (d, 1H, J=6.6Hz, * CH), 6.76 (d, 2H, J=7.8Hz, Ar-H), 7.21 (d, 2H, J=7.8Hz, Ar-H), 7.35 (s, 5H, ArH).

The synthesis of embodiment 2 intermediate compound I M3

The anhydrous K of appropriate IM2, acetonitrile, porphyrize is added in the round-bottomed flask of suitable size ₂cO ₃, stir, then add 1,3-dibromopropane (IM2:K ₂cO ₃: 1,3-dibromopropane mol ratio is 1:4:6), 50 DEG C of oil bath heating, TLC monitors reaction process.After reaction terminates, suction filtration, filtrate revolves steaming, obtains pale tan oil, silica gel column chromatography, elutriant concentrated by rotary evaporation, natural cooling crystallization, suction filtration, and vacuum-drying, obtains intermediate compound I M3.

Table two intermediate compound I M3 generated data

IM3-a (R)-2-(((benzyloxy) carbonyl) is amino)-2-(4-(3-bromine propoxy-) phenyl) methyl acetate: white solid; M.p.:84-85 DEG C; ¹hNMR (600MHz, DMSO-d ₆) δ: 2.21-2.25 (m, 2H ,-CH ₂-), 3.61 (s, 3H, OCH ₃), 3.66 (t, 2H, J=6.6Hz ,-CH ₂br), 4.07 (t, 2H, J=6.0Hz ,-OCH ₂), 5.06 (s, 2H, PhCH ₂), 5.21 (d, 1H, J=7.2Hz, * CH), 6.93 (d, 2H, J=8.4Hz, Ar-H), 7.30-7.37 (m, 7H, Ar-H), 8.22 (d, 1H, J=7.8Hz, CONH).

IM3-b (R)-2-(((benzyloxy) carbonyl) is amino)-2-(4-(3-bromine propoxy-) phenyl) ethyl acetate: white solid; M.p.:89-90 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 1.22 (t, 3H, J=6.3Hz ,-CH ₃), 2.33-2.34 (m, 2H ,-CH ₂-), 3.61 (t, 2H, J=6.0Hz ,-CH ₂br), 4.11 (t, 2H, J=5.4Hz ,-OCH ₂), 4.21 (t, 2H, J=9.9Hz ,-OCH ₂), 5.10 (s, 2H, PhCH ₂-), 5.30 (d, 1H, J=7.2Hz, * CH), 6.89 (d, 2H, J=6.9Hz, Ar-H), 7.31 (m, 7H, Ar-H), 8.03 (s, 1H, CONH).

IM3-c (R)-2-(((benzyloxy) carbonyl) is amino)-2-(4-(3-bromine propoxy-) phenyl) propyl acetate: white solid; M.p.:94-95 DEG C; ¹hNMR (600MHz, CDCl ₃) δ: 0.83 (t, 3H, J=7.2Hz, CH ₃), 1.56-1.61 (m, 2H ,-CH ₂-), 2.29-2.33 (m, 2H ,-CH ₂-), 3.59 (t, 2H, J=6.0Hz ,-CH ₂br), 4.05-4.10 (m, 4H, 2-OCH ₂), 5.09 (q, 2H, J=12.6Hz, 31.2Hz, PhCH ₂-), 5.30 (d, 1H, J=7.2Hz, * CH), 5.82 (d, 1H, J=6.6Hz, CONH), 6.88 (d, 2H, J=8.4Hz, Ar-H), 7.28-7.37 (m, 7H, Ar-H).

IM3-d (R)-2-(((benzyloxy) carbonyl) is amino)-2-(4-(3-bromine propoxy-) phenyl) butylacetate: white solid; M.p.:121-123 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 0.86 (t, 3H, J=7.2Hz, CH ₃), 1.24-1.26 (m, 2H ,-CH ₂-), 1.52-1.59 (m, 2H ,-CH ₂-), 2.27-2.35 (m, 2H ,-CH ₂-), 3.60 (t, 2H, J=6.3Hz ,-CH ₂br), 4.07-4.13 (m, 4H, 2-OCH ₂), 5.07 (q, 2H, J=12.3Hz, 18.9Hz, PhCH ₂-), 5.29 (d, 1H, J=6.9Hz, * CH), 5.81 (d, 1H, J=6.9Hz, CONH), 6.88 (d, 2H, J=8.4Hz, Ar-H), 7.26-7.34 (m, 7H, Ar-H).

The synthesis of embodiment 3 compound TM1

In round-bottomed flask, add aromatic compound A and 5-15mLN, dinethylformamide (DMF), after stirring and dissolving, add powdery K ₂cO ₃, stir and add IM3 after 30 minutes, (15-35 DEG C) stirring reaction under envrionment temperature, TLC monitors reaction process.After reaction terminates, pour in frozen water, EtOAc extracts, and collects organic phase, washing, anhydrous Na ₂sO ₄drying, suction filtration, filtrate decompression concentrated by rotary evaporation, silica gel column chromatography, obtains object compound TM1.

Table three compound TM1 generated data

TM1-1a (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(3-formvlphenoxv) propoxy-) phenyl) methyl acetate: white solid; M.p.:87-88 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 9.97 (1H, s, CHO), 7.17-7.46 (11H, m, Ar-H), 6.89 (2H, d, J=8.4Hz, Ar-H), 5.77 (1H, d, J=6.3Hz, NH), 5.30 (1H, d, J=6.3Hz, * CH), 5.09 (2H, d, J=4.8Hz, PhCH ₂-), 4.14-4.22 (4H, m ,-OCH ₂), 3.71 (3H, s, OCH ₃), 2.24-2.32 (2H, m ,-CH ₂-); ¹³cNMR (75MHz, CDCl ₃) δ: 191.7,171.1,159.0,158.6,154.9,137.3,135.7,129.7,128.4,128.1,128.0,127.8,127.7,123.2,121.4,114.4,112.3,66.7,64.1,63.8,56.9,52.4,28.6; HRMS:C ₂₇h ₂₇nO ₇[M+Na] ⁺calculated value 500.1680, measured value 500.1683.

TM1-1b (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(3-formvlphenoxv) propoxy-) phenyl) ethyl acetate: white solid; M.p.:72-74 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 9.97 (1H, s, CHO), 7.46-7.27 (11H, m, Ar-H), 6.98 (1H, d, J=8.4Hz, Ar-H), 5.81 (1H, d, J=7.2Hz, NH), 5.29 (1H, d, J=6.9Hz, * CH), 5.14-5.04 (2H, m, PhCH ₂-), 4.24-4.08 (6H, m ,-OCH ₂), 2.30-2.26 (2H, m ,-CH ₂-), 1.20 (3H, t, d=7.2Hz, CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 192.10,171.07,159.55,159.05,155.45,137.98,136.35,130.17,129.20,128.60,128.49,128.22,123.59,121.92,114.98,113.08,67.14,64.81,64.42,61.91,57.56,29.27,14.10; HRMS:C ₂₈h ₂₉nO ₇[M+H] ⁺calculated value 492.2017, measured value 492.2020.

TM1-1c (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(3-formvlphenoxv) propoxy-) phenyl) propyl acetate: white solid; M.p.:55-56 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 9.97 (1H, s, CHO), 7.34-7.26 (11H, m, Ar-H), 6.88 (2H, d, J=7.8Hz, Ar-H), 5.81 (1H, d, J=6.3Hz, NH), 5.29 (1H, d, J=6.9Hz, * CH), 5.14-5.03 (2H, m, PhCH ₂-), 4.22 (2H, t, J=5.4Hz ,-OCH ₂-), 4.15 (2H, t, J=5.7Hz ,-OCH ₂-), 4.10-4.04 (2H, m ,-OCH ₂-), 2.30-2.26 (2H, m ,-CH ₂-), 1.62-1.55 (2H, m ,-CH ₂-), 0.82 (3H, t, J=7.2Hz, CH ₃); ¹³cNMR (75MHz, CDCl ₃) δ: 192.26,171.17,159.45,158.95,155.41,137.84,136.24,130.17,129.16,128.61,128.46,128.28,128.25,123.69,121.97,114.85,112.81,67.43,67.12,64.65,64.27,57.48,29.17,21.87,10.25; HRMS:C ₂₉h ₃₁nO ₇[M+Na] ⁺calculated value 528.1993, measured value 528.2002.

TM1-1d (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(3-formvlphenoxv) propoxy-) phenyl) butylacetate: white solid; M.p.:61-63 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 9.97 (1H, s, CHO), 7.46-7.17 (11H, m, Ar-H), 6.98 (1H, d, J=8.1Hz, Ar-H), 5.81 (1H, d, J=6.6Hz, NH), 5.29 (1H, d, J=6.9Hz, * CH), 5.14-5.03 (2H, m, PhCH ₂-), 4.22 (2H, t, J=5.7Hz ,-OCH ₂), 4.15 (2H, t, 6.0Hz ,-OCH ₂), 4.10-4.01 (2H, m ,-OCH ₂), 2.30-2.26 (2H, m ,-CH ₂-), 1.59-1.50 (2H, m ,-CH ₂-), 1.28-1.21 (2H, m ,-CH ₂-), 0.85 (3H, t, d=7.2Hz ,-CH ₃); ¹³cNMR (75MHz, CDCl ₃) δ: 192.26,171.16,159.45,158.95,155.41,137.83,136.23,130.16,129.14,128.61,128.45,128.28,128.25,123.69,121.96,114.85,112.81,67.12,65.75,64.64,64.27,57.47,30.44,29.16,18.95,13.67; HRMS:C ₃₀h ₃₃nO ₇[M+H] ⁺calculated value 520.2330, measured value 520.2333.

TM1-2a (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(2-formvlphenoxv) propoxy-) phenyl) methyl acetate: white solid; M.p.:85-86 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 10.40 (1H, s, CHO), 8.22 (1H, d, J=7.5Hz, NH), 7.62-7.70 (2H, m, Ar-H), 7.23-7.35 (m, 8H, Ar-H), 7.7 (1H, t, J=7.2Hz, Ar-H), 6.93 (2H, d, J=7.8Hz, Ar-H), 5.20 (1H, d, J=7.5Hz, * CH), 5.05 (2H, s, PhCH ₂-), 4.18-4.29 (4H, m ,-OCH ₂), 3.60 (3H, s, OCH ₃), 2.22-2.25 (2H, m ,-CH ₂-); ¹³cNMR (75MHz, DMSO-d ₆) δ: 189.3,171.6,160.9,158.4,155.9,136.9,136.5,129.2,128.4,127.9,127.8,127.7,114.5,113.4,65.7,65.1,64.3,57.4,52.2,28.5; HRMS:C ₂₇h ₂₇nO ₇[M+Na] ⁺calculated value 500.1680, measured value 500.1679.

TM1-2b (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(2-formvlphenoxv) propoxy-) phenyl) ethyl acetate: white solid; M.p.:65-66 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 10.49 (1H, s, CHO), 7.85-7.79 (1H, m, Ar-H), 7.58-7.49 (1H, m, Ar-H), 7.40-7.14 (7H, m, Ar-H), 7.08-7.00 (2H, m, Ar-H), 6.98 (2H, d, J=9Hz, Ar-H), 5.80 (1H, d, J=6Hz, NH), 5.28 (1H, d, J=9.3Hz, * CH), 5.16-5.00 (2H, m, PhCH ₂-), 4.28 (2H, t, J=6.9Hz ,-OCH ₂), 4.23-4.02 (4H, m ,-OCH ₂), 2.38-2.30 (2H, m ,-CH ₂-), 0.85 (3H, t, J=7.5Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 189.64,171.06,161.27,158.97,155.46,136.35,136.03,129.35,128.65,128.63,128.55,128.25,125.12,120.96,114.96,112.63,67.16,65.18,64.36,61.94,57.56,29.29,14.11; HRMS:C ₂₈h ₂₉nO ₇[M+Na] ⁺calculated value 514.1836, measured value 514.1840.

TM1-2c (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(2-formvlphenoxv) propoxy-) phenyl) propyl acetate: white solid; M.p.:69-70 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 10.49 (1H, s, CHO), 7.95-7.76 (1H, m, Ar-H), 7.59-7.46 (1H, m, Ar-H), 7.42-7.13 (7H, m, Ar-H), 7.09-6.93 (2H, m, Ar-H), 6.98 (2H, d, J=7.8Hz, Ar-H), 5.82 (1H, d, J=6.6Hz, NH), 5.30 (1H, d, J=3.6Hz, * CH), 5.16-5.00 (2H, m, PhCH ₂-), 4.28 (2H, t, J=5.7Hz ,-OCH ₂), 4.17 (2H, t, J=5.7Hz ,-OCH ₂), 4.08 (2H, t, J=6.0Hz ,-OCH ₂), 2.43-2.24 (2H, m ,-CH ₂-), 1.64-1.46 (2H, m ,-CH ₂-), 0.82 (3H, t, J=7.2Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 189.63,171.15,161.27,158.96,155.47,136.36,136.02,129.43,128.66,128.62,128.53,128.23,125.13,120.96,114.95,112.64,67.46,67.16,65.20,64.38,57.57,29.29,21.92,10.23; HRMS:C ₂₉h ₃₁nO ₇[M+Na] ⁺calculated value 528.1993, measured value 528.1998.

TM1-2d (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(2-formvlphenoxv) propoxy-) phenyl) butylacetate: white solid; M.p.:82-84 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 10.49 (1H, s, CHO), 7.87-7.79 (1H, m, Ar-H), 7.59-7.49 (1H, m, Ar-H), 7.40-7.12 (7H, m, Ar-H), 7.07-6.96 (2H, m, Ar-H), 6.88 (2H, d, J=8.7Hz, Ar-H), 5.84 (1H, d, J=7.9Hz, NH), 5.28 (1H, d, J=7.5Hz, * CH), 5.17-5.01 (2H, m, PhCH ₂-), 4.28 (2H, t, J=6.0Hz ,-OCH ₂), 4.18 (2H, t, J=6.0Hz ,-OCH ₂), 4.14-4.01 (2H, m ,-OCH ₂), 2.40-2.25 (2H, m ,-CH ₂-), 1.59-1.47 (2H, m ,-CH ₂-), 0.92-0.78 (5H, m ,-CH ₂-,-CH ₃); ¹³cNMR (75MHz, CDCl ₃) δ: 189.61,189.51,171.09,161.19,158.86,155.41,136.28,136.03,135.94,129.28,128.52,128.46,128.17,124.91,120.86,114.83,112.52,67.05,65.70,65.12,65.03,64.31,64.24,57.49,30.42,29.74,29.17,18.91,13.62,13.56.

TM1-3a (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(4-formvlphenoxv) propoxy-) phenyl) methyl acetate: white solid; M.p.:91-92 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 9.88 (1H, s, CHO), 7.83 (2H, d, J=8.7Hz, Ar-H), 7.26-7.34 (7H, m, Ar-H), 7.01 (2H, d, J=8.4Hz, Ar-H), 6.89 (2H, d, J=8.4Hz, Ar-H), 5.79 (1H, d, J=6.6Hz, NH), 5.30 (1H, d, J=6.9Hz, * CH), 5.09 (2H, d, J=5.7Hz, PhCH ₂-), 4.13-4.24 (4H, m, H-6 ,-OCH ₂), 3.71 (3H, s, OCH ₃), 2.27-2.31 (2H, m ,-CH ₂-); ¹³cNMR (75MHz, CDCl ₃) δ: 190.5,171.1,163.4,158.5,155.0,135.7,131.6,129.5,128.5,128.1,127.8,127.7,114.4,114.3,66.6,64.3,63.7,56.9,52.4,28.6; HRMS:C ₂₇h ₂₇nO ₇[M+Na] ⁺calculated value 500.1680, measured value 500.1685.

TM1-3b (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(4-formvlphenoxv) propoxy-) phenyl) ethyl acetate: white solid; M.p.:85-86 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 9.88 (1H, s, CHO), 7.83 (2H, d, J=8.4Hz, Ar-H), 7.34-6.99 (7H, m, Ar-H), 7.01 (2H, d, J=8.4Hz, Ar-H), 6.88 (2H, d, J=8.4Hz, Ar-H), 5.81 (1H, d, J=6.9Hz, NH), 5.28 (1H, d, J=7.5Hz, * CH)), 5.14-5.03 (2H, m, PhCH ₂-), 4.24 (2H, t, J=6.0Hz ,-OCH _2-), 4.18 (2H, t, J=6.0Hz ,-OCH _2-), 4.26-4.09 (2H, m ,-OCH _2-), 2.33-2.26 (2H, m ,-CH ₂-), 1.20 (3H, t, J=6.0Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 190.84,171.07,164.00,158.99,155.45,136.33,132.10,130.18,129.32,128.63,128.53,128.25,114.96,114.90,77.37,77.16,76.95,67.17,64.90,64.28,61.95,57.55,29.21,14.11; HRMS:C ₂₈h ₂₉nO ₇[M+Na] ⁺calculated value 514.1836, measured value 514.1840.

TM1-3c (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(4-formvlphenoxv) propoxy-) phenyl) propyl acetate: yellow oil; ¹hNMR (300MHz, CDCl ₃) δ: 9.88 (1H, s, CHO), 7.83 (2H, d, J=8.4Hz, Ar-H), 7.36-7.26 (7H, m, Ar-H), 7.01 (2H, d, J=8.4Hz, Ar-H), 6.88 (2H, d, J=8.4Hz, Ar-H), 5.82 (1H, d, J=6.9Hz, NH), 5.29 (1H, d, J=7.5Hz, * CH), 5.14-5.03 (2H, m, PhCH ₂-), 4.24 (2H, t, J=6.0Hz ,-OCH ₂-), 4.15 (2H, t, J=6.0Hz ,-OCH ₂-), 4.11-4.04 (2H, m ,-OCH ₂-), 2.31-2.18 (2H, m ,-CH ₂-), 1.62-1.53 (2H, m ,-CH ₂-), 0.82 (3H, t, J=7.5Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 190.85,171.16,164.01,158.98,155.46,136.32,132.11,130.19,129.40,128.63,128.50,128.25,114.94,114.90,77.37,77.16,76.95,67.46,67.17,64.91,64.30,57.55,29.21,21.92,10.23; HRMS:C ₂₉h ₃₁nO ₇[M+Na] ⁺calculated value 528.1993, measured value 528.1996.

TM1-3d (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(4-formvlphenoxv) propoxy-) phenyl) butylacetate: white solid; M.p.:77-79 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 9.88 (1H, s, CHO), 7.83 (2H, d, J=8.7Hz, Ar-H), 7.34-7.26 (7H, m, Ar-H), 7.01 (2H, d, J=8.7Hz, Ar-H), 6.88 (2H, d, J=8.7Hz, Ar-H), 5.82 (1H, d, J=6.9Hz, NH), 5.29 (1H, d, J=7.5Hz, * CH), 55.14-5.03 (2H, m, PhCH ₂-), 4.24 (2H, t, J=6.0Hz ,-OCH ₂-), 4.17-4.06 (4H, m ,-OCH ₂-), 2.33-2.26 (2H, m ,-CH ₂-), 1.59-1.49 (2H, m ,-CH ₂-), 1.28-1.21 (2H, m ,-CH ₂-), 0.85 (3H, t, J=7.2Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 190.82,171.14,163.98,158.96,155.44,136.32,132.09,130.16,129.37,128.61,128.48,128.24,114.92,114.88,67.14,65.76,64.88,64.28,57.54,30.49,29.19,18.97,13.64; HRMS:C ₃₀h ₃₃nO ₇[M+H] ⁺calculated value 520.2330, measured value 520.2332.

TM1-4a (R)-4-(3-(4-(1-((carbobenzoxy-(Cbz)) is amino)-2-methoxyl group-2-oxoethyl) phenoxy group) propoxy-) methyl benzoate: white solid; M.p.:83-84 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.98 (2H, d, J=8.7Hz, Ar-H), 7.26-7.34 (7H, m, Ar-H), 6.90 (4H, t, J=8.4Hz, Ar-H), 5.78 (1H, d, J=6.9Hz, NH), 5.30 (1H, d, J=6.9Hz, * CH), 5.09 (2H, d, J=5.4Hz, PhCH ₂-), 4.15-4.22 (4H, m ,-OCH ₂-), 3.88 (3H, s ,-OCH ₃), 3.71 (3H, s ,-OCH ₃), 2.23-2.31 (2H, m ,-CH ₂-); ¹³cNMR (75MHz, CDCl ₃) δ: 171.1,166.4,162.1,158.5,154.9,135.7,131.2,128.4,128.1,128.0,127.8,127.7,122.2,114.4,113.6,66.7,64.0,63.8,56.9,52.4,51.5,28.6; HRMS:C ₂₈h ₂₉nO ₈[M+Na] ⁺calculated value 530.1785, measured value 530.1789.

TM1-4b (R)-4-(3-(4-(1-((carbobenzoxy-(Cbz)) is amino)-2-oxyethyl group-2-oxoethyl) phenoxy group) propoxy-) methyl benzoate: white solid; M.p.:79-81 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 8.01 (2H, d, J=8.7Hz, Ar-H), (7.99-7.28 7H, m, Ar-H), (6.95-6.89 4H, m, Ar-H), (5.82-5.80 1H, m, NH), 5.31-5.29 (1H, m, * CH), 5.16-5.05 (2H, m, PhCH ₂-), 4.24-4.11 (6H, m ,-OCH ₂-), 3.90 (3H, s ,-OCH ₃), 2.31-2.27 (2H, m ,-CH ₂-), 1.20 (3H, t, J=6.9Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 171.09,166.92,162.74,159.06,155.46,136.36,131.73,129.28,128.63,128.52,128.31,128.26,122.88,114.99,114.23,67.17,64.71,64.43,61.93,57.58,51.92,29.28,14.11; HRMS:C ₂₉h ₃₁nO ₈[M+Na] ⁺calculated value 544.1942, measured value 544.1946.

TM1-4c (R)-4-(3-(4-(1-((carbobenzoxy-(Cbz)) is amino)-2-oxo-2-Among) phenoxy group) propoxy-) methyl benzoate: white solid; M.p.:68-71 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 8.00 (2H, d, J=8.7Hz, Ar-H), (7.97-7.26 7H, m, Ar-H), (6.93-6.86 4H, m, Ar-H), (5.82-5.80 1H, m, NH), 5.30-5.28 (1H, m, * CH), 5.14-5.03 (2H, m, PhCH ₂-), 4.22-4.11 (6H, m ,-OCH ₂-), 3.88 (3H, s ,-OCH ₃), 2.29-2.26 (2H, m ,-CH ₂-), 1.57-1.55 (2H, m ,-CH ₂-), 0.82 (3H, t, J=7.5Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 171.17,166.92,162.74,159.05,155.46,136.37,131.73,129.36,128.63,128.49,128.27,122.88,114.98,114.23,67.45,67.17,64.72,64.44,57.58,51.93,29.81,29.28,21.93,10.24; HRMS:C ₃₀h ₃₃nO ₈[M+Na] ⁺calculated value 558.2098, measured value 558.2102.

TM1-4d (R)-4-(3-(4-(1-((carbobenzoxy-(Cbz)) is amino)-2-oxo-2-butoxyethyl group) phenoxy group) propoxy-) methyl benzoate: white solid; M.p.:91-93 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 8.00 (2H, d, J=8.7Hz, Ar-H), (7.97-7.26 7H, m, Ar-H), (6.93-6.86 4H, m, Ar-H), (5.82-5.80 1H, m, NH), 5.30-5.27 (1H, m, * CH), 5.14-5.03 (2H, m, PhCH ₂-), 4.22-4.07 (6H, m ,-OCH ₂-), 3.88 (3H, s ,-OCH ₃), 2.31-2.24 (2H, m ,-CH ₂-), 1.56-1.49 (2H, m ,-CH ₂-), 1.28-1.21 (2H, m ,-CH ₂-), 0.85 (3H, t, J=7.2Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 171.15,166.91,162.73,159.04,155.46,136.37,131.72,129.35,128.62,128.48,128.25,128.25,122.88,114.97,114.22,67.15,65.75,64.71,64.45,57.58,51.91,30.52,29.27,18.99,13.64; HRMS:C ₃₁h ₃₅nO ₈[M+Na] ⁺calculated value 572.2255, measured value 572.2260.

TM1-5a (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(4-(2-methoxyl group-2-oxoethyl) phenoxy group) propoxy-) phenyl) methyl acetate: white solid; M.p.:70-72 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.17-7.34 (9H, m, Ar-H), 6.84-6.89 (4H, m, Ar-H), 5.78 (1H, d, J=6.9Hz, NH), 5.30 (1H, d, J=7.2Hz, * CH), 5.09 (2H, d, J=5.1Hz, PhCH ₂-), 4.12-4.15 (4H, m ,-OCH ₂-), 3.71 (3H, s ,-OCH ₃), 3.68 (3H, s ,-OCH ₃), 3.56 (2H, s ,-CH ₂-), 2.20-2.28 (2H, m ,-CH ₂-); ¹³cNMR (75MHz, CDCl ₃) δ: 172.0,171.1,158.6,157.5,154.9,135.7,129.9,128.3,128.1,128.0,127.8,125.7,114.5,114.1,66.7,64.0,63.8,56.9,52.4,51.6,39.9,29.3; HRMS:C ₂₉h ₃₁nO ₈[M+Na] ⁺calculated value 544.1942, measured value 544.1946.

TM1-5b (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(4-(2-oxyethyl group-2-oxoethyl) phenoxy group) propoxy-) phenyl) methyl acetate: white solid; M.p.:73-75 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.34-7.17 (9H, m, Ar-H), 6.94-6.83 (4H, m, Ar-H), 5.80-5.78 (1H, m, NH), 5.29-5.27 (1H, m, * CH), 5.14-5.04 (2H, m, PhCH ₂-), 4.29-4.02 (6H, m ,-OCH ₂-), 3.68 (3H, s ,-OCH ₃), 3.56 (2H, s ,-CH ₂-), 2.31-2.17 (2H, m ,-CH ₂-), 1.20 (3H, t, J=6.6Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 172.40,171.12,159.15,158.12,155.47,136.38,130.40,129.11,128.62,128.49,128.25,126.36,120.45,115.01,114.78,67.15,64.65,64.53,61.91,57.59,52.05,40.41,29.39,14.11; HRMS:C ₃₀h ₃₃nO ₈[M+Na] ⁺calculated value 558.2098, measured value 558.2101.

TM1-5c (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(4-(2-oxo-2-Among) phenoxy group) propoxy-) phenyl) methyl acetate: white solid; M.p.:49-51 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.34-7.17 (9H, m, Ar-H), 6.93-6.81 (4H, m, Ar-H), 5.83-5.81 (1H, m, NH), 5.30-5.28 (1H, m, * CH), 5.14-5.04 (2H, m, PhCH ₂-), 4.15-3.98 (6H, m ,-OCH ₂-), 3.68 (3H, s ,-OCH ₃), 3.56 (2H, s ,-CH ₂-), 2.26-2.22 (2H, m ,-CH ₂-), 1.62-1.55 (2H, m ,-CH ₂-), 0.82 (3H, t, J=7.5Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 172.40,171.19,159.13,158.12,155.47,136.37,130.40,129.20,128.61,128.46,128.24,126.36,120.44,114.99,114.78,67.42,67.15,64.65,64.53,57.59,52.04,40.40,29.39,21.92,10.23; HRMS:C ₃₁h ₃₅nO ₈[M+Na] ⁺calculated value 572.2255, measured value 572.2260.

TM1-5d (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(4-(2-oxo-2-butoxyethyl group) phenoxy group) propoxy-) phenyl) methyl acetate: white solid; M.p.:59-62 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.34-7.17 (9H, m, Ar-H), 6.96-6.73 (4H, m, Ar-H), 5.82-5.79 (1H, m, NH), 5.29-5.27 (1H, m, * CH), 5.14-5.04 (2H, m, * CH), 4.15-3.98 (6H, m ,-OCH ₂-), 3.68 (3H, s ,-OCH ₃), 3.56 (2H, s ,-CH ₂-), 2.26-2.22 (2H, m ,-CH ₂-), 1.56-1.52 (2H, m ,-CH ₂-), 1.25-1.17 (2H, m ,-CH ₂-), 0.85 (3H, t, J=7.5Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 172.40,171.20,159.14,158.12,155.47,136.38,130.40,129.20,128.62,128.46,128.25,128.23,126.36,115.00,114.78,67.15,65.74,64.67,64.54,57.60,52.05,40.41,30.53,29.39,18.99,13.65; HRMS:C ₃₂h ₃₇nO ₈[M+Na] ⁺calculated value 586.2411, measured value 586.2416.

TM1-6a (R)-3-(4-(3-(4-(1-((carbobenzoxy-(Cbz)) is amino)-2-methoxyl group-2-oxoethyl) phenoxy group) propoxy-) phenyl) methyl propionate: yellow oil; ¹hNMR (300MHz, CDCl ₃) δ: 7.26-7.34 (7H, m, Ar-H), 7.11 (2H, d, J=8.4Hz, Ar-H), 6.81-6.89 (4H, m, Ar-H), 5.78 (1H, d, J=6.9Hz, NH), 5.30 (1H, d, J=6.9Hz, * CH), 5.09 (2H, d, J=4.8Hz, PhCH ₂-), 4.09-4.15 (4H, m ,-OCH ₂-), 3.71 (3H, s ,-OCH ₃), 3.66 (3H, s ,-OCH ₃), 2.89 (2H, t, J=7.5Hz ,-CH ₂-), 2.59 (2H, t, J=7.5Hz ,-CH ₂-), 2.20-2.25 (2H, m ,-CH ₂-); ¹³cNMR (75MHz, CDCl ₃) δ: 173.0,171.1,158.7,156.9,154.9,135.7,132.3,128.8,128.3,128.1,128.0,127.8,127.7,114.5,114.1,66.7,64.0,63.8,56.9,52.3,51.2,35.6,29.7,28.8; HRMS:C ₃₀h ₃₃nO ₈[M+H] ⁺calculated value 536.2279, measured value 536.2281.

TM1-6b (R)-3-(4-(3-(4-(1-((carbobenzoxy-(Cbz)) is amino)-2-oxyethyl group-2-oxoethyl) phenoxy group) propoxy-) phenyl) methyl propionate: white solid; M.p.:53-54 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.37-7.26 (7H, m, Ar-H), 7.10 (2H, d, J=8.4Hz, Ar-H), (6.89-6.81 4H, m, Ar-H), (5.81-5.79 1H, m, NH), 5.29-5.27 (1H, m, * CH), 5.14-5.04 (2H, m, PhCH ₂-), 4.19-4.10 (6H, m ,-OCH ₂-), 3.66 (3H, m ,-OCH ₃), 2.89 (2H, t, J=6.6Hz ,-CH ₂-), 2.59 (2H, t, J=6.0Hz ,-CH ₂-), 2.26-2.22 (2H, m ,-CH ₂-), 1.20 (3H, t, J=7.2Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 173.45,171.10,159.15,157.47,155.45,136.37,132.88,129.33,129.09,128.63,128.60,128.47,128.23,114.99,114.70,67.14,64.67,64.50,61.89,57.57,51.62,36.08,30.22,29.42,14.10; HRMS:C ₃₁h ₃₅nO ₈[M+H] ⁺calculated value 550.2435, measured value 550.2440.

TM1-6c (R)-3-(4-(3-(4-(1-((carbobenzoxy-(Cbz)) is amino)-2-oxo-2-Among) phenoxy group) propoxy-) phenyl) methyl propionate: white solid; M.p.:50-51 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.37-7.27 (7H, m, Ar-H), 7.10 (2H, d, J=8.4Hz, Ar-H), (6.89-6.81 4H, m, Ar-H), (5.83-5.80 1H, m, NH), 5.30-5.28 (1H, m, * CH), 5.14-5.04 (2H, m, PhCH ₂-), 4.15-4.04 (6H, m ,-OCH ₂-), 3.66 (3H, m ,-OCH ₃), 2.89 (2H, t, J=6.6Hz ,-CH ₂-), 2.59 (2H, t, J=6.0Hz ,-CH ₂-), 2.26-2.22 (2H, m ,-CH ₂-), 1.62-1.55 (2H, m ,-CH ₂-), 0.82 (3H, t, J=7.5Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 173.46,171.19,159.14,157.48,155.46,136.37,132.88,129.34,129.16,128.64,128.60,128.44,128.23,114.98,114.70,67.41,67.14,64.69,64.52,57.59,51.62,36.08,30.22,29.42,21.92,10.22; HRMS:C ₃₂h ₃₇nO ₈[M+Na] ⁺calculated value 586.2411, measured value 586.2415.

TM1-6d (R)-3-(4-(3-(4-(1-((carbobenzoxy-(Cbz)) is amino)-2-oxo-2-butoxyethyl group) phenoxy group) propoxy-) phenyl) methyl propionate: white solid; M.p.:44-46 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.37-7.26 (7H, m, Ar-H), 7.10 (2H, d, J=8.4Hz, Ar-H), (6.89-6.81 4H, m, Ar-H), (5.82-5.79 1H, m, NH), 5.29-5.27 (1H, m, * CH), 5.14-5.04 (2H, m, PhCH ₂-), 4.15-4.06 (6H, m ,-OCH ₂-), 3.66 (3H, m ,-OCH ₃), 2.89 (2H, t, J=6.6Hz ,-CH ₂-), 2.59 (2H, t, J=7.2Hz ,-CH ₂-), 2.26-2.20 (2H, m ,-CH ₂-), 1.57-1.50 (2H, m ,-CH ₂-), 1.29-1.21 (2H, m ,-CH ₂-), 0.85 (3H, t, J=7.5Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 173.46,171.19,159.15,157.49,155.46,136.38,132.90,129.35,129.18,128.65,128.61,128.45,128.25,114.99,114.71,67.15,65.74,64.71,64.52,57.59,51.63,36.09,30.52,30.23,29.43,18.99,13.64; HRMS:C ₃₃h ₃₉nO ₈[M+Na] ⁺calculated value 600.2568, measured value 600.2572.

TM1-7a (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(4-propionyl phenoxy group)-propoxy-) phenyl) methyl acetate: white solid; M.p.:86-87 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.93 (2H, d, J=8.7Hz, Ar-H), 7.26-7.34 (6H, m, Ar-H), 6.87-6.95 (5H, m, Ar-H), 5.79 (1H, d, J=6.9Hz, NH), 5.29 (1H, d, J=7.2Hz, * CH), 5.09 (2H, q, J=12.3Hz, 18.6Hz, PhCH ₂-), 4.13-4.24 (6H, m ,-OCH ₂-), 2.55 (3H, s ,-OCH ₃), 2.24-2.32 (2H, m ,-CH ₂-), 1.20 (3H, t, J=6.9Hz ,-CH ₃); ¹³cNMR (75MHz, CDCl ₃) δ: 196.4,170.6,162.3,158.4,154.9,135.7,130.2,129.9,128.6,128.1,128.0,127.8,127.7,114.4,113.7,66.6,64.1,63.7,61.5,57.0,29.3,26.0,13.6; HRMS:C ₂₉h ₃₁nO ₇[M+Na] ⁺calculated value 528.1993, measured value 528.2000.

TM1-7b (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(4-propionyl phenoxy group)-propoxy-) phenyl) ethyl acetate: white solid; M.p.:93-95 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 1.18-1.23 (m, 6H, 2-CH ₃), 2.24-2.32 (m, 2H ,-CH ₂-), 2.95 (q, 2H, J=7.2Hz, 14.4Hz, CH ₂), 4.13-4.23 (m, 6H, 2-OCH ₂), 5.08 (q, 2H, J=12.3Hz, 18.6Hz, PhCH ₂), 5.28 (d, 1H, J=7.2Hz, * CH), 5.79 (d, 1H, J=6.9Hz, CONH), 6.87-6.94 (m, 4H, Ar-H), 7.26-7.34 (m, 6H, Ar-H), 7.94 (d, 2H, J=8.7Hz, Ar-H); ¹³cNMR (75MHz, DMSO-d ₆) δ: 198.8,171.6,162.2,158.4,155.9,136.9,130.1,129.1,128.4,127.9,127.8,114.5,114.3,65.7,64.6,64.1,57.4,52.2,30.8,28.5,8.3; HRMS:C ₃₀h ₃₃nO ₇[M+Na] ⁺calculated value 542.2149, measured value 542.2152.

TM1-7c (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(4-propionyl phenoxy group)-propoxy-) phenyl) propyl acetate: white solid; M.p.:86-87 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.94 (2H, d, J=8.7Hz, Ar-H), 7.34-7.26 (7H, m, Ar-H), 6.93 (2H, d, J=8.7Hz, Ar-H), 6.88 (2H, d, J=8.7Hz, Ar-H), 5.81 (1H, d, J=7.2Hz, NH), 5.29 (1H, d, J=6.9Hz, * CH), 5.14-5.03 (2H, m, PhCH ₂-), 4.21 (2H, t, J=6.0Hz ,-OCH ₂-), 4.15 (2H, t, J=6.0Hz ,-OCH ₂-), 4.11-4.04 (2H, m ,-OCH ₂-), 2.95 (2H, q, J=7.2Hz ,-CH ₂-), 2.32-2.24 (2H, m ,-CH ₂-), 1.62-1.55 (2H, m ,-CH ₂-), 1.21 (3H, t, J=7.2Hz ,-CH ₃), 0.82 (3H, t, J=7.5Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 199.59,171.18,162.72,159.04,155.46,136.35,130.37,130.27,129.35,128.65,128.50,128.28,114.97,114.29,67.48,67.19,64.73,64.40,57.57,31.54,29.28,21.93,10.25,8.58; HRMS:C ₃₁h ₃₅nO ₇[M+Na] ⁺calculated value 556.2306, measured value 556.2309.

TM1-7d (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(4-propionyl phenoxy group)-propoxy-) phenyl) butylacetate: white solid; M.p.:75-76 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.94 (2H, d, J=7.1Hz, Ar-H), 7.34-7.26 (7H, m, Ar-H), 6.95-6.87 (4H, m, Ar-H), 5.81 (1H, d, J=6.6Hz, NH), 5.29 (1H, d, J=7.2Hz, * CH), 5.14-5.03 (2H, m, PhCH ₂-), 4.21 (2H, t, J=5.7Hz ,-OCH ₂-), 4.15 (2H, t, J=6.0Hz ,-OCH ₂-), 4.17-4.07 (2H, m ,-OCH ₂-), 2.95 (2H, q, J=7.2Hz ,-CH ₂-), 2.30-2.26 (2H, m ,-CH ₂-), 1.59-1.50 (2H, m ,-CH ₂-), 1.26-1.19 (2H, m ,-CH ₂-), 0.85 (3H, t, J=7.2Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 199.57,171.16,162.70,159.03,155.45,136.34,130.35,130.26,129.34,128.63,128.49,128.26,114.96,114.28,67.17,65.78,64.72,64.41,57.57,31.52,30.52,29.26,18.99,13.65,8.57; HRMS:C ₃₂h ₃₇nO ₇[M+Na] ⁺calculated value 570.2462, measured value 570.2466.

TM1-8a (R)-2-(4-(3-(4-acetyl phenoxy group) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) methyl acetate: white solid; M.p.:99-100 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 8.22 (1H, d, J=7.8Hz, NH), 7.92 (2H, d, J=8.7Hz, Ar-H), 7.29-7.35 (7H, m, Ar-H), 7.05 (2H, d, J=8.7Hz, Ar-H), 6.93 (2H, d, J=8.7Hz, Ar-H), 5.19 (1H, d, J=7.5Hz, * CH), 5.04 (2H, s, PhCH ₂-), 4.10-4.23 (4H, m ,-OCH ₂-), 3.59 (3H, s ,-OCH ₃), 2.50 (3H, s ,-CH ₃), 2.16-2.20 (2H, m ,-CH ₂-); ¹³cNMR (75MHz, DMSO-d ₆) δ: 196.3,171.6,162.4,158.4,155.9,136.9,130.5,129.9,129.2,128.4,128.3,127.9,127.8,114.5,114.3,65.7,64.6,64.1,57.4,52.2,28.5,26.4; HRMS:C ₂₈h ₂₉nO ₇[M+Na] ⁺calculated value 514.1836, measured value 514.1842.

TM1-8b (R)-2-(4-(3-(4-acetyl phenoxy group) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) ethyl acetate: white solid; M.p.:106-107 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.93 (2H, d, J=8.7Hz, Ar-H), 7.26-7.34 (6H, m, Ar-H), 6.87-6.95 (5H, m, Ar-H), 5.79 (1H, d, J=6.9Hz, NH), 5.29 (1H, d, J=7.2Hz, * CH), 5.09 (2H, q, J=12.3Hz, 18.6Hz, PhCH ₂-), 4.13-4.24 (6H, m ,-OCH ₂-), 2.55 (3H, s ,-CH ₃), 2.24-2.32 (2H, m ,-CH ₂-), 1.20 (3H, t, J=6.9Hz ,-CH ₃); ¹³cNMR (75MHz, CDCl ₃) δ: 196.4,170.6,162.3,158.4,154.9,135.7,130.2,129.9,128.6,128.1,128.0,127.8,127.7,114.4,113.7,66.6,64.1,63.7,61.5,57.0,29.3,26.0,13.6; HRMS:C ₂₉h ₃₁nO ₇[M+Na] ⁺calculated value 528.1993, measured value 528.1996.

TM1-8c (R)-2-(4-(3-(4-acetyl phenoxy group) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) propyl acetate: white solid; M.p.:79-81 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.93 (2H, d, J=7.8Hz, Ar-H), 7.34-7.26 (7H, m, Ar-H), 6.95-6.87 (4H, m, Ar-H), 5.82 (1H, m, NH), 5.29 (1H, m, * CH), 5.14-5.03 (2H, m, PhCH ₂-), 4.22 (2H, t, J=6.0Hz ,-OCH ₂-), 4.15 (2H, t, J=6.0Hz ,-OCH ₂-), 4.24-4.13 (2H, m ,-OCH ₂-), 2.56 (3H, s ,-CH ₃), 2.32-2.24 (2H, m ,-CH ₂-), 1.57-1.49 (2H, m ,-CH ₂-), 0.85 (3H, t, J=7.2Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 196.85,171.16,162.88,159.00,155.46,136.31,130.70,130.55,129.33,128.61,128.47,128.23,114.94,114.28,77.37,77.16,76.95,67.44,67.15,64.74,64.36,57.55,29.23,26.37,21.90,10.22; HRMS:C ₃₀h ₃₃nO ₇[M+Na] ⁺calculated value 542.2149, measured value 542.2154.

TM1-8d (R)-2-(4-(3-(4-acetyl phenoxy group) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) butylacetate: white solid; M.p.:66-69 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.93 (2H, d, J=9.0Hz, Ar-H), 7.34-7.26 (7H, m, Ar-H), 6.95-6.87 (4H, m, Ar-H), 5.82 (1H, m, NH), 5.30 (1H, m, * CH), 5.15-5.05 (2H, m, PhCH ₂-), 4.23 (2H, t, J=5.7Hz ,-OCH ₂-), 4.17 (2H, t, J=6.0Hz ,-OCH ₂-), 4.13-4.04 (2H, m ,-OCH ₂-), 2.57 (3H, s ,-CH ₃), 2.32-2.28 (2H, m ,-CH ₂-), 1.61-1.57 (2H, m ,-CH ₂-), 1.45-1.41 (2H, m ,-CH ₂-), 0.84 (3H, t, J=7.2Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 196.84,171.17,162.90,159.03,155.46,136.34,130.73,130.59,129.36,128.63,128.49,128.26,114.97,114.30,67.18,65.78,64.76,64.40,57.57,30.52,29.26,26.40,18.99,13.66; HRMS:C ₃₁h ₃₅nO ₇[M+Na] ⁺calculated value 556.2306, measured value 556.2311.

TM1-9a (R)-2-(4-(3-(2-ethanoyl phenoxy group) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) methyl acetate: yellow oil; ¹hNMR (300MHz, CDCl ₃) δ: 7.73 (2H, d, J=6.3Hz, Ar-H) .7.26-7.47 (7H, m, Ar-H), 6.96-7.02 (2H, m, Ar-H), 6.88 (2H, d, J=8.4Hz, Ar-H), 5.79 (1H, d, J=6.9Hz, NH), 5.31 (1H, d, J=6.9Hz, * CH), 5.09 (2H, q, J=12.3Hz, 17.7Hz, PhCH ₂-), 4.15-4.26 (4H, m ,-OCH ₂-), 3.71 (3H, s ,-OCH ₃), 3.62 (3H, s ,-CH ₃), 2.29-2.37 (2H, m ,-CH ₃); ¹³cNMR (75MHz, CDCl ₃) δ: 199.3,171.1,158.5,157.6,154.9,135.7,133.3,130.0,128.5,128.1,127.9,127.8,127.7,120.3,114.4,111.9,66.7,64.6,63.9,56.9,52.4,31.6,28.8; HRMS:C ₂₈h ₂₉nO ₇[M+Na] ⁺calculated value 514.1836, measured value 514.1841.

TM1-9b (R)-2-(4-(3-(2-ethanoyl phenoxy group) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) ethyl acetate: yellow oil; ¹hNMR (300MHz, CDCl ₃) δ: 7.73 (1H, d, J=4.2Hz, Ar-H), 7.50-7.49 (1H, m, Ar-H), 7.38-7.20 (7H, m, Ar-H), 7.05-6.92 (2H, m, Ar-H), 6.92-6.79 (2H, m, Ar-H), 5.81 (1H, d, J=6.3Hz, NH), 5.28 (1H, d, J=6.9Hz, * CH), 5.15-5.01 (2H, m, PhCH ₂-), 4.30-4.07 (6H, m ,-OCH ₂-), 2.62 (3H, s ,-CH ₃), 2.40-2.24 (2H, m ,-CH ₂-), 1.22-1.08 (3H, m ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 199.69,171.05,158.96,158.16,155.45,136.34,133.68,130.49,129.35,128.59,128.53,128.23,128.21,120.83,114.93,76.95,67.13,65.28,64.58,61.91,57.55,31.96,29.37,14.09; HRMS:C ₂₉h ₃₁nO ₇[M+Na] ⁺calculated value 528.1993, measured value 528.1996.

TM1-9c (R)-2-(4-(3-(2-ethanoyl phenoxy group) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) propyl acetate: yellow solid; M.p.:71-72 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.73 (1H, d, J=4.2Hz, Ar-H), 7.47-7.42 (1H, m, Ar-H), 7.38-7.21 (7H, m, Ar-H), 7.02-6.96 (2H, m, Ar-H), 6.89-6.86 (2H, m, Ar-H), 5.81 (1H, d, J=6.9Hz, NH), 5.28 (1H, d, J=7.2Hz, * CH), 5.14-5.04 (2H, m, PhCH ₂-), 4.27 (2H, t, J=6.0Hz ,-OCH ₂-), 4.17 (2H, t, J=5.7Hz ,-OCH ₂-), 4.12-4.04 (2H, m ,-OCH ₂-), 2.62 (3H, s ,-CH ₃), 2.37-2.30 (2H, m ,-CH ₂-), 1.60-1.55 (2H, m ,-CH ₂-), 0.84 (3H, t, J=7.8Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 199.69,171.13,158.95,158.17,155.45,136.35,133.68,130.50,129.44,128.60,128.51,128.25,128.22,126.67,120.84,114.92,112.52,67.43,67.14,65.29,64.60,57.57,31.97,29.38,21.91,10.21; HRMS:C ₃₀h ₃₃nO ₇[M+Na] ⁺calculated value 542.2149, measured value 542.2152.

TM1-9d (R)-2-(4-(3-(2-ethanoyl phenoxy group) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) butylacetate: white solid; M.p.:82-84 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.73 (1H, d, J=4.2Hz, Ar-H), 7.48-7.42 (1H, m, Ar-H), 7.34-7.26 (7H, m, Ar-H), 7.02-6.96 (2H, m, Ar-H), 6.89-6.86 (2H, m, Ar-H), 5.82 (1H, d, J=7.2Hz, NH), 5.29 (1H, d, J=7.2Hz, * CH), 5.14-5.04 (2H, m, PhCH ₂-), 4.27 (2H, t, J=6.0Hz ,-OCH ₂-), 4.25-4.07 (4H, m ,-OCH ₂-), 2.62 (3H, s ,-CH ₃), 2.36-2.32 (2H, m ,-CH ₂-), 1.57-1.52 (2H, m ,-CH ₂-), 1.29-1.21 (2H, m ,-CH ₂-), 0.85 (3H, t, J=7.5Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl3) δ: 199.67,171.11,158.94,158.16,155.44,136.35,133.67,130.49,129.42,128.59,128.50,128.23,128.21,120.83,114.91,112.51,67.13,65.74,65.29,64.60,57.55,31.96,30.50,29.37,18.96,13.62; HRMS:C ₃₁h ₃₅nO ₇[M+H] ⁺calculated value 534.2486, measured value 534.2490.

TM1-10a (R)-2-(4-(3-(3-ethanoyl phenoxy group) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) methyl acetate: white solid; M.p.:94-95 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.26-7.55 (10H, m, Ar-H), 7.11 (1H, d, J=8.1Hz, Ar-H), 6.89 (2H, d, J=8.4Hz, Ar-H), 5.77 (1H, d, J=6.0Hz, NH), 5.30 (1H, d, J=6.0Hz, * CH), 5.09 (2H, q, J=12.3Hz, 17.1Hz, PhCH ₂-), 4.14-4.20 (4H, m ,-OCH ₂-), 3.72 (3H, s ,-OCH ₃), 2.59 (3H, s ,-CH ₃), 2.25-2.29 (2H, m ,-CH ₂-); ¹³cNMR (75MHz, CDCl ₃) δ: 198.0,171.7,159.1,159.1,155.4,138.5,136.2,129.7,128.9,128.6,128.5,128.3,128.2,121.3,120.1,115.0,113.1,67.2,64.6,64.3,57.4,52.9,29.8,26.9; HRMS:C ₂₈h ₂₉nO ₇[M+Na] ⁺calculated value 514.1836, measured value 514.1837.

TM1-10b (R)-2-(4-(3-(3-ethanoyl phenoxy group) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) ethyl acetate: white solid; M.p.:81-83 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.57-7.45 (2H, m, Ar-H), 7.41-7.24 (8H, m, Ar-H), 7.14-7.09 (1H, m, Ar-H), 6.92-6.85 (2H, m, Ar-H), (5.87-5.76 1H, m, NH), 5.33-5.24 (1H, m, * CH), 5.15-5.02 (2H, m, PhCH ₂-), 4.27-4.07 (6H, m ,-OCH ₂-), 2.59 (3H, s ,-CH ₃), 2.32-2.21 (2H, m ,-CH ₂-), 1.20 (3H, t, J=2.9Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 197.94,171.09,159.21,159.08,155.46,138.69,136.36,129.69,129.17,128.60,128.49,128.24,128.22,121.28,120.07,114.99,113.32,77.37,77.16,76.95,67.13,64.73,64.47,61.90,57.57,29.31,26.75,14.09; HRMS:C ₂₉h ₃₁nO ₇[M+Na] ⁺calculated value 528.1993, measured value 528.1996.

TM1-10c (R)-2-(4-(3-(3-ethanoyl phenoxy group) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) propyl acetate: white solid; M.p.:87-89 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.57-7.46 (2H, m, Ar-H), 7.42-7.21 (8H, m, Ar-H), 7.15-7.07 (1H, m, Ar-H), 6.93-6.82 (2H, m, Ar-H), 5.87-5.78 (1H, m, NH), 5.32-5.25 (1Hm, * CH), 5.16-5.02 (2H, m, PhCH ₂-), 4.25-4.00 (6H, m ,-OCH ₂-), 2.59 (3H, s ,-CH ₃), 2.33-2.21 (2H, m ,-CH ₂-), 1.63-1.50 (2H, m ,-CH ₂-), 0.82 (3H, t, J=7.5Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 197.91,171.14,162.63,159.18,159.03,155.44,138.66,136.34,129.66,129.22,128.56,128.44,128.20,121.26,120.04,114.94,113.30,77.37,77.16,76.95,67.38,67.09,64.71,64.46,57.56,29.28,26.71,21.88,10.19; HRMS:C ₃₀h ₃₃nO ₇[M+H] ⁺calculated value 520.2330, measured value 520.2332.

TM1-10d (R)-2-(4-(3-(3-ethanoyl phenoxy group) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) butylacetate: white solid; M.p.:69-70 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.59-7.42 (2H, m, Ar-H), 7.41-7.17 (8H, m, Ar-H), 7.14-7.06 (1H, m, Ar-H), 6.94-6.79 (2H, m, Ar-H), (5.89-5.72 1H, m, NH), 5.33-5.21 (1H, m, * CH), 5.16-5.00 (2H, m, PhCH ₂-), 4.25-4.00 (6H, m ,-OCH ₂-), 2.59 (3H, s ,-CH ₃), 2.34-2.18 (2H, m ,-CH ₂-), 1.57-1.44 (2H, m ,-CH ₂-), 1.30-1.15 (2H, m ,-CH ₂-), 0.87 (3H, t, J=7.2Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 197.96,171.18,159.24,159.09,155.46,138.72,136.37,129.71,129.28,128.63,128.48,128.27,128.26,121.31,120.10,115.00,113.33,77.37,77.16,76.95,67.16,65.76,64.75,64.52,57.59,30.53,29.34,26.78,19.00,13.65; HRMS:C ₃₁h ₃₅nO ₇[M+Na] ⁺calculated value 556.2306, measured value 556.2311.

TM1-11a (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(5-formyl radical-2-methoxyphenoxy) propoxy-) phenyl) methyl acetate: white solid; M.p.:113-115 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 9.83 (1H, s, CHO), 7.26-7.47 (9H, m, Ar-H), 6.97 (1H, d, J=8.1Hz, Ar-H), (6.89 2H, d, J=8.7Hz, Ar-H), (5.77 1H, d, J=6.9Hz, NH), (5.30 1H, d, J=7.2Hz, * CH), 5.09 (2H, d, J=4.8Hz, PhCH ₂-), 4.27 (2H, t, J=6.0Hz ,-OCH ₂-), 4.17 (2H, t, J=6.0Hz ,-OCH ₂-), 3.93 (3H, s ,-OCH ₃), 3.71 (3H, s ,-OCH ₃), 2.29-2.37 (2H, m-CH ₂-); ¹³cNMR (75MHz, CDCl ₃) δ: 190.5,171.1,158.6,154.9,154.4,148.4,135.7,129.6,128.3,128.1,128.0,127.8,127.7,126.4,114.5,110.2,110.0,66.6,65.0,63.8,56.9,55.7,52.4,28.5; HRMS:C ₂₈h ₂₉nO ₈[M+Na] ⁺calculated value 530.1785, measured value 530.1789.

TM1-11b (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(5-formyl radical-2-methoxyphenoxy) propoxy-) phenyl) ethyl acetate: white solid; M.p.:124-126 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 9.84 (1H, s, CHO), 7.47-7.44 (2H, m, Ar-H), 7.34-7.12 (7H, m, Ar-H), 6.97 (1H, d, J=7.2Hz, Ar-H), 6.89 (2H, d, J=8.4Hz, Ar-H), 5.80-5.78 (1H, m, NH), 5.29-5.27 (1H, m, * CH), 5.14-5.04 (2H, m, PhCH ₂-), 4.29-4.05 (6H, m ,-OCH ₂-), 3.94 (3H, s ,-OCH ₃), 2.37-2.30 (2H, m ,-CH ₂-), 1.20 (3H, t, J=7.2Hz ,-CH ₃); ¹³cNMR (75MHz, CDCl ₃) δ: 191.02,171.09,158.99,155.40,154.87,148.92,136.25,130.09,128.99,128.59,128.44,128.26,128.23,126.94,114.90,110.71,110.56,67.10,65.51,64.33,61.92,57.49,56.20,29.07,14.09; HRMS:C ₂₉h ₃₁nO ₈[M+H] ⁺calculated value 522.2122, measured value 522.2127.

TM1-11c (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(5-formyl radical-2-methoxyphenoxy) propoxy-) phenyl) propyl acetate: white solid; M.p.:88-90 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 9.84 (1H, s, CHO), 7.47-7.44 (2H, m, Ar-H), 7.34-7.12 (7H, m, Ar-H), 6.97 (1H, d, J=8.1Hz, Ar-H), 6.89 (2H, d, J=8.7Hz, Ar-H), 5.82-5.80 (1H, m, NH), 5.30-5.28 (1H, m, * CH), 5.14-5.04 (2H, m, PhCH ₂-), 4.27 (2H, t, J=6.0Hz ,-OCH ₂-), 4.17 (2H, t, J=5.7Hz ,-OCH ₂-), 4.08-4.04 (2H, m ,-OCH ₂-), 3.94 (3H, s ,-OCH ₃), 2.37-2.29 (2H, m ,-CH ₂-), 1.64-1.53 (2H, m ,-CH ₂-), 0.82 (3H, t, J=7.2Hz ,-CH ₃); ¹³cNMR (75MHz, CDCl ₃) δ: 191.03,171.18,158.98,155.41,154.88,148.93,136.26,130.10,129.09,128.61,128.42,128.27,128.25,126.96,114.89,110.72,110.58,67.42,67.11,65.54,64.35,57.50,56.21,29.08,21.87,10.25; HRMS:C ₃₀h ₃₃nO ₈[M+Na] ⁺calculated value 558.2098, measured value 558.2102.

TM1-11d (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(5-formyl radical-2-methoxyphenoxy) propoxy-) phenyl) butylacetate: white solid; M.p.:95-97 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 9.84 (1H, s, CHO), 7.47-7.44 (2H, m, Ar-H), 7.34-7.12 (7H, m, Ar-H), 6.97 (1H, d, J=7.2Hz, Ar-H), 6.89 (2H, d, J=8.4Hz, Ar-H), 5.82-5.80 (1H, m, NH), 5.30-5.27 (1H, m, * CH), 5.14-5.04 (2H, m, PhCH ₂-), 4.27 (2H, t, J=6.0Hz ,-OCH ₂-), 4.17 (2H, t, J=5.7Hz ,-OCH ₂-), 4.13-4.08 (2H, m ,-OCH ₂-), 3.93 (3H, s ,-OCH ₃), 2.35-2.31 (2H, m ,-CH ₂-), 1.57-1.50 (2H, m ,-CH ₂-), 1.29-1.21 (2H, m, H-26-CH ₂-), 0.85 (3H, t, J=7.4Hz, H-27-CH ₃); ¹³cNMR (75MHz, CDCl ₃) δ: 191.00,190.94,171.13,158.96,155.38,154.87,148.91,136.25,130.08,130.05,129.05,128.55,128.38,128.20,126.87,114.86,110.72,67.05,65.68,65.52,64.35,57.48,56.15,30.41,29.05,18.91,13.62; HRMS:C ₃₁h ₃₅nO ₈[M+H] ⁺calculated value 550.2435, measured value 550.2440.

TM1-12a (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(4-formyl radical-2-methoxyphenoxy) propoxy-) phenyl) methyl acetate: white solid; M.p.:98-99 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 9.85 (1H, s, CHO), 7.26-7.44 (9H, m, Ar-H), 7.00 (1H, d, J=7.8Hz, Ar-H), 6.89 (2H, d, J=8.4Hz, Ar-H), 5.77 (1H, d, J=6.9Hz, NH), (5.30 1H, d, J=7.2Hz, * CH), 5.09 (2H, d, J=5.7Hz, PhCH ₂-), 4.29 (2H, t, J=6.0Hz ,-OCH ₂-), 4.17 (2H, t, J=6.0Hz ,-OCH ₂-), 3.91 (3H, s ,-OCH ₃), 3.71 (3H, s ,-OCH ₃), 2.31-2.39 (2H, m ,-CH ₂-); ¹³cNMR (75MHz, CDCl ₃) δ: 190.5,171.1,158.5,154.9,153.4,149.4,135.7,129.9,128.4,128.1,128.0,127.8,127.7,126.4,114.4,111.1,108.7,66.6,65.1,64.9,63.7,56.9,55.5,52.4,28.5.HRMS:C ₂₈h ₂₉nO ₈[M+Na] ⁺calculated value 530.1785, measured value 530.1785.

TM1-12b (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(4-formyl radical-2-methoxyphenoxy) propoxy-) phenyl) ethyl acetate: yellow oil; ¹hNMR (300MHz, CDCl ₃) δ: 9.85 (1H, s, CHO), 7.45-7.26 (9H, m, Ar-H), 7.01 (1H, d, J=8.1Hz, Ar-H), 6.89 (2H, d, J=8.4Hz, Ar-H), 5.82-5.80 (1H, m, NH), 5.29-5.27 (1H, m, * CH), 5.14-5.03 (2H, m, PhCH ₂-), 4.30 (2H, t, J=6.0Hz ,-CH ₂-), 4.17 (2H, t, J=5.7Hz ,-CH ₂-), 4.21-4.09 (2H, m ,-OCH ₂-), 3.91 (3H, s ,-OCH ₃), 2.37-2.33 (2H, m ,-CH ₂-), 1.20 (3H, t, J=7.2Hz, H-25-CH ₃); ¹³cNMR (75MHz, CDCl ₃) δ: 191.07,171.06,158.91,155.39,153.92,149.87,136.22,130.16,129.13,128.60,128.47,128.28,128.24,126.90,114.87,111.56,109.23,67.12,65.61,64.21,61.95,57.46,56.04,29.03,14.09; HRMS:C ₂₉h ₃₁nO ₈[M+Na] ⁺calculated value 544.1942, measured value 544.1946.

TM1-12c (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(4-formyl radical-2-methoxyphenoxy) propoxy-) phenyl) propyl acetate: yellow oil; ¹hNMR (300MHz, CDCl ₃) δ: 9.85 (1H, s, CHO), 7.45-7.26 (9H, m, Ar-H), 7.01 (1H, d, J=8.1Hz, Ar-H), 6.89 (2H, d, J=8.7Hz, Ar-H), 5.83-5.81 (1H, m, NH), 5.31-5.28 (1H, m, * CH), 5.14-5.03 (2H, m, PhCH ₂-), 4.30 (2H, t, J=6.0Hz ,-OCH ₂-), 4.17 (2H, t, J=5.7Hz ,-OCH ₂-), 4.11-4.09 (2H, m ,-OCH ₂-), 3.91 (3H, s ,-OCH ₃), 2.37-2.33 (2H, m ,-CH ₂-), 1.60-1.55 (2H, m ,-CH ₂-), 0.82 (3H, t, J=7.5Hz ,-CH ₃); ¹³cNMR (75MHz, CDCl ₃) δ: 191.07,171.06,158.91,155.39,153.92,149.87,136.22,130.16,129.13,128.60,128.47,128.28,128.24,126.90,114.87,111.56,109.23,67.12,65.61,64.21,61.95,57.46,56.04,29.03,14.09; HRMS:C ₃₀h ₃₃nO ₈[M+H] ⁺calculated value 536.2279, measured value 536.2289.

TM1-12d (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(4-formyl radical-2-methoxyphenoxy) propoxy-) phenyl) butylacetate: yellow solid; M.p.:85-86 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 9.85 (1H, s, CHO), 7.45-7.26 (9H, m, Ar-H), 7.01 (1H, d, J=8.1Hz, Ar-H), 6.89 (2H, d, J=8.4Hz, Ar-H), 5.83-5.81 (1H, m, NH), 5.30-5.27 (1H, m, * CH), 5.14-5.03 (2H, m, PhCH ₂-), 4.30 (2H, t, J=6.0Hz ,-OCH ₂-), 4.17 (2H, t, J=5.7Hz ,-OCH ₂-), 4.13-4.07 (2H, m ,-OCH ₂-), 3.91 (3H, s ,-OCH ₃), 2.37-2.33 (2H, m ,-CH ₂-), 1.60-1.55 (2H, m ,-CH ₂-), 1.57-1.50 (2H, m ,-CH ₂-), 0.85 (3H, t, J=7.5Hz ,-CH ₃); ¹³cNMR (75MHz, CDCl ₃) δ: 191.05,171.12,158.87,155.37,153.89,149.85,136.20,130.14,129.19,128.58,128.42,128.26,128.22,126.89,114.83,111.54,109.21,67.08,65.73,65.59,64.21,57.45,56.02,30.41,29.01,18.92,13.65; HRMS:C ₃₁h ₃₅nO ₈[M+H] ⁺calculated value 550.2435, measured value 550.2438.

TM1-13a (R)-2-(4-(3-(4-kharophen phenoxy group) propoxy-) phenyl)-2 – ((carbobenzoxy-(Cbz)) is amino) methyl acetate: yellow oil; ¹hNMR (300MHz, CDCl ₃) δ: 7.25-7.38 (10H, m, NH, Ar-H), 6.86 (4H, t, J=8.7Hz, Ar-H1), 5.80 (1H, d, J=6.3Hz, NH), 5.29 (1H, d, J=6.6Hz, * CH), 5.09 (2H, q, J=8.1Hz, PhCH ₂-), 4.12-4.13 (4H, m ,-OCH ₂-), 3.71 (3H, s ,-OCH ₃), 2.15-2.26 (5H, m ,-CH ₃and-CH ₂-); ¹³cNMR (75MHz, CDCl ₃) δ: 171.1,168.3,158.6,155.1,155.0,135.7,130.9,128.7,128.0,127.8,127.7,121.5,114.5,114.3,66.7,64.0,63.9,57.0,52.4,28.2,23.7; HRMS:C ₂₈h ₃₀n ₂o ₇[M+Na] ⁺calculated value 529.1945, measured value 529.1948.

TM1-13b (R)-2-(4-(3-(4-kharophen phenoxy group) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) ethyl acetate: white solid; M.p.:134-136 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.49-7.10 (9H, m, Ar-H), 6.97-6.70 (4H, m, Ar-H), 5.84 (1H, s, NH), 5.29 (1H, s, * CH), 5.19-5.00 (2H, m, PhCH ₂-), 4.40-3.99 (6H, m ,-OCH ₂-), 2.37-2.09 (5H, m ,-CH ₃and-CH ₂-), 1.27-1.14 (3H, m ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 171.09,168.49,159.13,155.71,155.52,136.30,131.44,128.99,128.59,128.45,128.26,128.17,121.98,115.00,114.91,77.37,77.16,76.95,67.15,64.77,64.61,61.91,57.60,29.38,24.27,14.07; HRMS:C ₂₉h ₃₂n ₂o ₇[M+H] ⁺calculated value 521.2282, measured value 521.2286.

TM1-13c (R)-2-(4-(3-(4-kharophen phenoxy group) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) propyl acetate: white solid; M.p.:137-138 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.44-7.19 (9H, m, Ar-H), 6.94-6.79 (4H, m, Ar-H), 5.85 (1H, d, J=6.9Hz, NH), 5.29 (1H, d, J=6.9Hz, * CH), 5.16-5.01 (2H, m, PhCH ₂-), 4.16-3.95 (6H, m ,-OCH ₂-), 2.30-2.19 (2H, m ,-CH ₂-), 2.15 (3H, s ,-CH ₃), 1.65-1.50 (2H, m ,-CH ₂-), 0.82 (3H, t, J=7.5Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 171.19,168.65,162.82,159.10,155.68,155.52,136.29,131.47,129.06,128.58,128.41,128.24,128.16,121.96,114.97,114.89,77.37,77.16,76.95,67.42,67.14,64.77,64.62,57.59,31.58,29.36,24.20,21.87; HRMS:C ₃₀h ₃₄n ₂o ₇[M+H] ⁺calculated value 535.2439, measured value 535.2446.

TM1-13d (R)-2-(4-(3-(4-kharophen phenoxy group) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) butylacetate: white solid; M.p.:124-125 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.49-7.12 (9H, m, Ar-H), 6.95-6.75 (4H, m, Ar-H), 5.85 (1H, d, J=6.0Hz, NH), 5.28 (1H, d, J=6.9Hz, * CH), 5.19-5.00 (2H, m, PhCH ₂-), 4.26-3.95 (6H, m ,-OCH ₂-), 2.31-2.18 (2H, m ,-CH ₂-), 2.18-2.09 (3H, s ,-CH ₃), 1.54 (2H, t, J=6.6Hz ,-CH ₂-), 1.30-1.19 (2H, m ,-CH ₂-), 0.85 (3H, t, J=7.2Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 171.16,168.48,159.11,155.68,155.50,136.30,131.47,129.07,128.59,128.41,128.24,128.17,121.95,114.98,114.90,77.37,77.16,76.95,67.13,65.73,64.77,64.63,57.59,30.48,29.37,24.26,18.94,13.61; HRMS:C ₃₁h ₃₆n ₂o ₇[M+Na] ⁺calculated value 571.2415, measured value 571.2418.

TM1-14a (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-Phenoxypropoxy) phenyl) methyl acetate: white solid; M.p.:68-70 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.26-7.34 (10H, m, Ar-H), 6.87-6.97 (4H, m, Ar-H), 5.78 (1H, d, J=6.3Hz, NH), 5.30 (1H, d, J=6.9Hz, * CH), 5.09 (2H, q, J=12.3Hz, 17.1Hz, PhCH ₂-), 4.13-4.17 (4H, m ,-OCH ₂-), 3.72 (3H, s ,-OCH ₃), 2.21-2.29 (2H, m ,-CH ₂-); ¹³cNMR (75MHz, CDCl ₃) δ: 171.1,158.7,158.3,154.9,135.7,129.1,128.1,128.0,127.8,120.3,114.5,114.0,66.7,64.1,63.7,56.9,52.4,28.8; HRMS:C ₂₆h ₂₇nO ₆[M+Na] ⁺calculated value 472.1731, measured value 472.1743.

TM1-14b (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-Phenoxypropoxy) phenyl) ethyl acetate: white solid; M.p.:97-99 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.44-7.07 (9H, m, Ar-H), 7.01-6.78 (5H, m, Ar-H), 5.80 (1H, d, J=6,9Hz, NH), 5.28 (1H, d, J=7.2Hz, * CH), 5.17-5.00 (2H, m, PhCH ₂-), 4.29-4.00 (6H, m ,-OCH ₂-), 2.30-2.19 (2H, m ,-CH ₂-), 1.20 (3H, d, J=7.2Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 171.11,162.63,159.16,158.96,155.46,136.38,129.56,129.11,128.61,128.48,128.25,120.90,115.01,114.66,77.37,77.16,76.95,67.14,64.68,64.38,61.89,57.58,29.42,14.10; HRMS:C ₂₇h ₂₉nO ₆[M+Na] ⁺calculated value 486.1887, measured value 486.1891.

TM1-14c (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-Phenoxypropoxy) phenyl) propyl acetate: white solid; M.p.:52-54 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.41-7.10 (9H, m, Ar-H), 7.00-6.90 (5H, m, Ar-H), 5.97-5.75 (1H, m, NH), 5.34-5.23 (1H, m, * CH), 5.16-5.02 (2H, m, PhCH ₂-), 4.20-3.99 (6H, m ,-OCH ₂-), 2.32-2.19 (2H, m ,-CH ₂-), 1.66-1.52 (2H, m ,-CH ₂-), 0.82 (3H, t, J=7.2Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 171.20,159.14,158.96,155.47,136.38,129.56,129.19,128.61,128.45,128.25,127.06,120.90,115.00,114.66,77.37,77.16,76.95,67.41,67.14,64.70,64.39,57.59,29.42,21.92,10.23; HRMS:C ₂₈h ₃₁nO ₆[M+Na] ⁺calculated value 500.2044, measured value 500.2046.

TM1-14d (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-Phenoxypropoxy) phenyl) butylacetate: white solid; M.p.:57-59 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.41-7.17 (9H, m, Ar-H), 7.02-6.91 (5H, m, Ar-H), 5.86-5.79 (1H, m, NH), 5.34-5.27 (1H, m, * CH), 5.18-5.04 (2H, m, PhCH ₂-), 4.23-4.00 (6H, m ,-OCH ₂-), 2.34-2.20 (2H, m ,-CH ₂-), 1.62-1.50 (2H, m ,-CH ₂-), 1.32-1.19 (2H, m ,-CH ₂-), 0.87 (3H, t, J=7.2Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 171.18,159.14,158.95,155.45,136.37,129.55,129.17,128.60,128.44,128.23,127.04,120.89,114.99,114.66,77.37,77.16,76.95,67.12,65.71,64.70,64.38,57.58,30.51,29.41,18.97,13.63.

TM1-15a (R)-2-(((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(naphthalene-2-base oxygen base) propoxy-) phenyl) methyl acetate: white solid; M.p.:87-88 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 8.22 (1H, d, J=7.5Hz, NH) .7.80 (3H, t, J=8.1Hz, Ar-H), 7.15-7.47 (11H, m, Ar-H), 6.96 (2H, d, J=8.7Hz, Ar-H), 5.20 (1H, d, J=7.5Hz, * CH), 5.05 (2H, s, PhCH ₂-), 4.15-4.27 (4H, m ,-OCH ₂-), 3.60 (3H, s ,-OCH ₃), 2.22-2.26 (2H, m ,-CH ₂-); ¹³cNMR (75MHz, DMSO-d ₆) δ: 172.0,158.8,156.8,156.3,137.2,134.7,129.7,129.7,129.6,128.9,128.8,128.7,128.3,128.2,127.9,127.1,126.8,124.0,119.2,114.9,107.1,66.1,64.7,57.9,52.6,29.0; HRMS:C ₃₀h ₂₉nO ₆[M+Na] ⁺calculated value 522.1887, measured value 522.1890.

TM1-15b (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(naphthalene-2-base oxygen base) propoxy-) phenyl) ethyl acetate: yellow solid; M.p.:93-95 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.85-7.50 (3H, m, Ar-H), 7.49-6.97 (11H, m, Ar-H), 6.95-6.78 (2H, m, Ar-H), 5.78 (1H, d, J=6.6Hz, NH), 5.29 (1H, d, J=7.3Hz, * CH), 5.15-4.99 (2H, m, PhCH ₂-), 4.27 (2H, t, J=5.7Hz ,-OCH ₂-), 4.22-4.05 (2H, m ,-OCH ₂-), 2.37-2.25 (2H, m ,-CH ₂-), 1.22-1.09 (3H, m ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 171.11,159.17,158.96,156.93,155.46,136.38,134.70,129.52,129.16,128.62,128.51,128.26,127.75,126.85,126.48,123.75,118.96,115.03,106.92,77.37,77.16,76.95,67.16,64.72,64.56,61.91,57.59,29.40,14.11; HRMS:C ₃₁h ₃₁nO ₆[M+Na] ⁺calculated value 536.2044, measured value 536.2047.

TM1-15c (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(naphthalene-2-base oxygen base) propoxy-) phenyl) propyl acetate: yellow solid; M.p.:90-92 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.82-7.60 (3H, m, Ar-H), 7.54-7.18 (9H, m, Ar-H), 5.80 (1H, d, J=5.4Hz, NH), 5.29 (1H, d, J=6.3Hz, * CH), 5.16-5.00 (2H, m, PhCH ₂-), 4.37-3.91 (6H, m ,-OCH ₂-), 2.32 (2H, t, J=5.1Hz ,-CH ₂-), 1.35-1.11 (2H, m ,-CH ₂-), 0.85-0.75 (3H, m ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 171.20,159.16,158.95,156.94,155.47,136.38,134.71,129.53,129.24,129.17,128.63,128.49,128.27,127.76,126.86,126.49,123.76,118.96,115.03,106.94,77.37,77.16,76.95,67.47,67.45,67.17,64.75,64.58,57.60,32.45,29.41,21.94; HRMS:C ₃₂h ₃₃nO ₆[M+Na] ⁺calculated value 550.2200, measured value 550.2204.

TM1-15d (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(naphthalene-2-base oxygen base) propoxy-) phenyl) butylacetate: yellow solid; M.p.:68-70 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.81-7.63 (3H, m, Ar-H), 7.49-7.21 (9H, m, Ar-H), 7.14 (2H, d, J=7.2Hz, Ar-H), 6.90 (2H, d, J=8.4Hz, Ar-H), 5.82 (1H, d, J=6.9Hz, NH), 5.28 (1H, d, J=7.2Hz, * CH), 5.10-5.00 (2H, m, PhCH ₂-), 4.27 (2H, t, J=6.0Hz ,-OCH ₂-), 4.19 (2H, t, J=6.0Hz ,-OCH ₂-), 4.09 (2H, t, J=9.3Hz ,-OCH ₂-), 2.32 (2H, t, J=6.0Hz ,-CH ₂-), 1.60-1.45 (2H, m ,-CH ₂-), 1.27-1.21 (2H, m ,-CH ₂-), 0.84 (3H, t, J=4.2Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 171.18,162.63,159.13,156.91,155.47,136.36,134.68,129.50,129.20,129.14,128.60,128.46,128.24,127.73,126.83,126.46,123.73,118.93,115.00,106.92,77.37,77.16,76.95,67.13,65.72,64.73,64.55,57.59,30.50,29.37,18.97,13.62; HRMS:C ₃₃h ₃₅nO ₆[M+Na] ⁺calculated value 564.2357, measured value 564.2361.

TM1-16a (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-((2-oxo-2H-chromene-4-base) oxygen base) propoxy-) phenyl) methyl acetate: white solid; M.p.:120-122 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.80 (2H, d, J=7.8Hz, Ar-H), 7.56 (1H, t, J=8.4Hz, Ar-H), 7.24-7.34 (8H, m, Ar-H), 6.89 (2H, d, J=8.4Hz, Ar-H), 5.79 (1H, d, J=6.6Hz, NH), 5.72 (1H, s, COCH-), 5.31 (1H, d, J=7.2Hz, * CH), 5.08 (2H, d, J=6.0Hz, PhCH ₂-), 4.17-4.34 (4H, m ,-OCH ₂-), 3.71 (3H, s ,-OCH ₃), 2.35-2.43 (2H, m ,-CH ₂-); ¹³cNMR (75MHz, CDCl ₃) δ: 171.0,165.0,162.4,158.3,154.9,152.9,135.7,132.0,128.7,128.1,127.8,127.7,123.5,122.5,116.4,115.2,114.4,90.3,66.6,65.4,63.4,56.9,52.4,28.1; HRMS:C ₂₉h ₂₇nO ₈[M+Na] ⁺calculated value 540.1629, measured value 540.1627.

TM1-16b (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-((2-oxo-2H-chromene-4-base) oxygen base) propoxy-) phenyl) ethyl acetate: white solid; M.p.:127-128 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.80 (1H, d, J=7.8Hz, Ar-H), 7.62-7.49 (1H, m, Ar-H), 7.41-7.08 (9H, m, Ar-H), 6.89 (2H, d, J=8.4Hz, Ar-H), 5.81 (1H, d, J=6.9Hz, NH), 5.72 (1H, s, COCH-), 5.28 (1H, d, J=7.2Hz, * CH), 5.15-5.00 (2H, m, PhCH ₂-), 4.34 (2H, t, J=6.0Hz ,-OCH ₂-), 4.26-4.02 (4H, m ,-OCH ₂-), 2.47-2.31 (2H, m ,-CH ₂-), 1.20 (3H, t, J=6.9Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 171.00,165.51,162.82,158.79,155.43,153.48,136.32,132.50,129.54,128.59,128.55,128.25,128.20,123.95,122.99,116.90,115.77,114.93,90.82,77.37,77.16,76.95,67.13,66.02,64.06,61.92,57.53,28.69,14.08; HRMS:C ₃₀h ₂₉nO ₈[M+Na] ⁺calculated value 554.1785, measured value 554.1790.

TM1-16c (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-((2-oxo-2H-chromene-4-base) oxygen base) propoxy-) phenyl) propyl acetate: white solid; M.p.:142-144 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.80 (1H, d, J=7.5Hz, Ar-H), 7.60-7.51 (1H, m, Ar-H), 7.41-7.14 (9H, m, Ar-H), 6.88 (2H, d, J=8.4Hz, Ar-H), 5.83 (1H, d, J=6.9Hz, NH), 5.72 (1H, s, COCH-), 5.29 (1H, d, J=7.2Hz, * CH), 5.16-5.00 (2H, m, PhCH ₂-), 4.34 (2H, t, J=5.7Hz ,-OCH ₂-), 4.19 (2H, t, J=5.7Hz ,-OCH ₂-), 4.12-3.99 (2H, m ,-OCH ₂-) 2.45-2.32 (2H, m ,-CH ₂-), 1.61-1.51 (2H, m ,-CH ₂-), 0.82 (3H, t, J=8.7Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 171.07,165.50,162.82,158.77,155.43,153.48,136.32,132.49,129.61,128.58,128.52,128.23,128.19,123.95,122.98,116.90,115.77,114.91,90.82,77.37,77.16,76.95,67.43,67.12,66.03,64.07,57.53,28.69,21.89,10.20; HRMS:C ₃₁h ₃₁nO ₈[M+Na] ⁺calculated value 568.1942, measured value 568.1945.

TM1-16d (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-((2-oxo-2H-chromene-4-base) oxygen base) propoxy-) phenyl) butylacetate: white solid; M.p.:122-125 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.80 (1H, d, J=4.8Hz, Ar-H), 7.61-7.48 (1H, m, Ar-H), 7.41-7.13 (9H, m, Ar-H), 6.98 (2H, d, J=8.7Hz, Ar-H), 5.83 (1H, d, J=6.9Hz, NH), 5.72 (1H, s, COCH-), 5.29 (1H, d, J=7.2Hz, * CH), 5.17-4.99 (2H, m, PhCH ₂-), 4.34 (2H, t, J=6.0Hz ,-OCH ₂-), 4.22-3.99 (4H, m ,-OCH ₂-), 2.47-2.32 (2H, m ,-CH ₂-), 1.59-1.46 (2H, m ,-CH ₂-), 1.2-1.19 (2H, m ,-CH ₂-), 0.84 (3H, t, J=7.5Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 171.08,165.52,162.83,158.79,155.44,153.50,136.33,132.51,129.63,128.60,128.53,128.26,128.22,123.96,122.99,116.92,115.78,114.93,90.84,77.37,77.16,76.95,67.14,66.03,65.77,64.09,57.55,30.50,28.70,18.97,13.62; HRMS:C ₃₂h ₃₃nO ₈[M+Na] ⁺calculated value 582.2098, measured value 582.2103.

TM1-17a (R)-2-(4-(3-(benzo [d] oxazole-2-base sulfenyl) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) methyl acetate: white solid; M.p.:101-103 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 8.22 (1H, d, J=7.5Hz, NH), 7.30-7.36 (11H, m, Ar-H), 6.94 (2H, d, J=8.7Hz, Ar-H), 5.20 (1H, d, J=7.2Hz, * CH), 5.05 (2H, s, PhCH ₂-), 4.11 (2H, t, J=6.0Hz ,-OCH ₂-), 3.60 (3H, s ,-OCH ₃), 3.48 (2H, t, J=6.9Hz ,-SCH ₂-), 2.21-2.29 (2H, m ,-CH ₂-); ¹³cNMR (75MHz, DMSO-d ₆) δ: 171.6,164.2,158.3,155.9,151.2,141.3,136.9,129.2,128.4,128.3,127.9,127.8,124.6,124.2,118.2,114.5,110.2,65.8,65.7,57.4,52.2,28.6,28.5; HRMS:C ₂₇h ₂₆n ₂o ₆s [M+Na] ⁺calculated value 529.1404, measured value 529.1410.

TM1-17b (R)-2-(4-(3-(benzo [d] oxazole-2-base sulfenyl) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) ethyl acetate: white solid; M.p.:89-91 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.60 (1H, d, J=7.2Hz, Ar-H), 7.22-7.44 (10H, m, Ar-H), 6.88 (2H, d, J=8.7Hz, Ar-H), 5.78 (1H, d, J=6.6Hz, NH), 5.29 (1H, d, J=7.2Hz, * CH), 5.10 (2H, q, J=12.3Hz, 18.0Hz, PhCH ₂-), 4.11-4.20 (4H, m ,-OCH ₂-and-SCH ₂-), 3.51 (2H, m ,-OCH ₂-), 2.31-2.39 (2H, m ,-CH ₂-), 1.21 (3H, t, J=6.9Hz ,-CH ₃); ¹³cNMR (75MHz, DMSO-d ₆) δ: 170.6,164.2,158.4,154.9,151.4,141.4,135.7,128.7,128.1,128.0,127.8,123.9,123.5,118.0,114.6,114.4,109.5,66.6,65.3,61.5,57.0,28.5,28.5,13.6; HRMS:C ₂₈h ₂₈n ₂o ₆s [M+Na] ⁺calculated value 543.1560, measured value 543.1565.

TM1-17c (R)-2-(4-(3-(benzo [d] oxazole-2-base sulfenyl) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) propyl acetate: white solid; M.p.:97-98 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.62-7.49 (1H, m, Ar-H), 7.44-7.09 (10H, m, Ar-H), 6.90-6.77 (2H, m, Ar-H), 5.93-5.69 (1H, m, NH), 5.32-5.20 (1H, m, * CH), 5.15-4.97 (2H, m, PhCH ₂-), 4.14-3.93 (4H, m, OCH ₂-andCOCH ₂-), 3.46 (2H, t, J=2.9Hz, SCH ₂-), 2.39-2.22 (2H, m ,-CH ₂-), 1.63-1.47 (2H, m ,-CH ₂-), 0.83-0.70 (3H, m ,-CH ₃); ¹³cNMR (75MHz, CDCl ₃) δ: 171.18,164.74,158.90,155.42,151.93,128.64,128.48,128.31,128.28,126.83,124.42,124.02,118.48,114.89,109.98,77.58,77.16,76.74,67.46,67.16,65.79,57.50,29.06,28.98,21.90,10.27; HRMS:C ₂₉h ₃₀n ₂o ₆s [M+H] ⁺calculated value 535.1897, measured value 535.1901.

TM1-17d (R)-2-(4-(3-(benzo [d] oxazole-2-base sulfenyl) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) butylacetate: white solid; M.p.:86-88 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.68 (1H, d, J=7.2Hz, Ar-H), 7.42 (1H, d, J=7.8Hz, Ar-H), 7.40-7.10 (9H, m, Ar-H), 6.93-6.91 (2H, m, Ar-H), 5.98-5.73 (1H, m, NH), 5.35-5.23 (1H, m, * CH), 5.17-5.02 (2H, m, PhCH ₂-), 4.21-4.00 (4H, m ,-OCH ₂-andCOCH ₂-), 3.50 (2H, t, J=2.9Hz ,-SCH ₂-), 3.41-2.28 (2H, m ,-CH ₂-), 1.61-1.46 (2H, m ,-CH ₂-), 1.31-1.17 (2H, m ,-CH ₂-), 0.95-0.79 (3H, t, J=7.2Hz ,-CH ₃); ¹³cNMR (75MHz, CDCl ₃) δ: 171.16,164.71,158.89,155.41,151.92,129.27,128.60,128.45,128.26,124.39,123.99,118.47,114.89,109.95,77.58,77.16,76.74,67.13,65.81,65.75,57.50,30.46,29.07,28.97,18.96,13.67; HRMS:C ₃₀h ₃₂n ₂o ₆s [M+H] ⁺calculated value 549.2054, measured value 549.2058.

TM1-18a (R)-2-(4-(3-((1H-benzo [d] imidazoles-2-base) sulfenyl) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) methyl acetate: white solid; M.p.:95-96 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.18-7.48 (11H, m, Ar-H), 6.82 (2H, d, J=8.4Hz, Ar-H), 5.84 (1H, d, J=6.3Hz, NH), 5.28 (1H, d, J=6.6Hz, * CH), 5.10 (2H, q, J=12.3Hz, 18.3Hz, PhCH ₂-), 4.09-4.19 (4H, m ,-OCH ₂-and-SCH ₂-), 3.71 (1H, s, NH), 3.49 (3H, s ,-OCH ₃), 2.24-2.27 (2H, m ,-CH ₂-); ¹³cNMR (75MHz, CDCl ₃) δ: 170.6,158.4,155.2,149.8,135.6,128.3,128.1,128.0,127.9,127.9,127.7,121.8,114.4,114.4,66.8,65.3,61.6,57.1,52.4,28.8.

TM1-18b (R)-2-(4-(3-((1H-benzo [d] imidazoles-2-base) sulfenyl) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) ethyl acetate: white solid; M.p.:96-97 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.18-7.51 (11H, m, Ar-H), 6.82 (2H, d, J=8.4Hz, Ar-H), 5.85 (1H, d, J=6.9Hz, NH), 5.28 (1H, d, J=7.2Hz, * CH), 5.10 (2H, q, J=12.3Hz, 18.3Hz, PhCH ₂-), 4.06-4.21 (5H, m ,-OCH ₂-,-SCH ₂-andNH), 3.50-3.52 (2H, m ,-OCH ₂-), 2.24-2.28 (2H, m ,-CH ₂-), 1.20 (3H, t, J=6.9Hz ,-CH ₃); ¹³cNMR (75MHz, CDCl ₃) δ: 170.6,158.3,155.1,149.7,135.6,128.1,127.9,127.7,121.9,114.3,113.6,66.7,65.3,61.5,57.1,28.8,28.7,13.6; HRMS:C ₂₈h ₂₉n ₃o ₅s [M+Na] ⁺calculated value 542.1720, measured value 542.1723.

TM1-18c (R)-2-(4-(3-((1H-benzo [d] imidazoles-2-base) sulfenyl) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) propyl acetate: yellow oil; ¹hNMR (300MHz, CDCl ₃) δ: 7.54-7.45 (2H, m, Ar-H), 7.38-7.13 (9H, m, Ar-H), 6.94-6.74 (2H, m, Ar-H), 5.91 (1H, d, J=9Hz, NH), 5.28 (1H, d, J=9Hz, * CH), 5.17-5.00 (2H, m, PhCH ₂-), 4.14-3.97 (4H, m ,-OCH ₂-andCOCH ₂-), 3.48 (2H, t, J=7.5Hz ,-SCH ₂-), 2.27-2.18 (2H, m ,-CH ₂-), 1.65-1.49 (3H, m ,-CH ₂-), 0.81 (3H, t, J=7.2Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 171.07,158.77,155.58,150.03,138.54,136.13,129.04,128.53,128.32,128.21,128.09,122.65,114.84,114.03,77.28,77.07,76.86,67.42,67.17,65.83,57.55,29.31,29.23,21.79,10.11; HRMS:C ₂₉h ₃₁n ₃o ₅s [M+H] ⁺calculated value 534.2057, measured value 534.2060.

TM1-18d (R)-2-(4-(3-((1H-benzo [d] imidazoles-2-base) sulfenyl) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) butylacetate: yellow solid; M.p.:105-107 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.55-7.42 (2H, m, Ar-H), 7.41-7.11 (9H, m, Ar-H), 6.86-6.75 (2H, m, Ar-H), 5.93-5.79 (1H, m, NH), 5.33-5.22 (1H, m, * CH), 5.17-5.00 (2H, m, PhCH ₂-), 4.21-3.93 (4H, m ,-OCH ₂-), 3.56-3.41 (2H, m, SCH ₂-), 2.33-2.16 (2H, m ,-CH ₂-), 1.61-1.45 (2H, m ,-CH ₂-), 1.29-1.14 (2H, m ,-CH ₂-), 0.85 (3H, t, J=7.5Hz ,-CH ₃); ¹³cNMR (75MHz, CDCl ₃) δ: 171.12,158.75,155.60,150.18,139.42,136.05,128.77,128.54,128.31,128.24,128.11,122.24,114.72,114.09,77.58,77.16,76.74,67.16,65.74,57.55,30.33,29.17,18.86,13.59; HRMS:C ₃₀h ₃₃n ₃o ₅s [M+H] ⁺calculated value 548.2214, measured value 548.2217.

TM1-19a (R)-2-(4-(3-((5-amino-1,3,4-thiadiazoles-2-base) sulfenyl) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) methyl acetate: yellow oil; ¹hNMR (300MHz, CDCl ₃) δ: 7.34-7.27 (7H, m, Ar-H), 6.85 (2H, d, J=8.4Hz, Ar-H), 5.96 (1H, d, J=6.6Hz, NH), 5.30 (1H, s, * CH), 5.13-5.04 (2H, m, PhCH ₂-), 4.13-4.07 (2H, m ,-OCH ₂-), 3.71 (3H, s ,-CH ₃), 3.40-3.28 (2H, m, SCH ₂-), 2.22-2.18 (2H, m ,-CH ₂-); ¹³cNMR (75MHz, CDCl ₃) δ: 171.56,167.15,158.80,156.33,155.49,136.15,128.84,128.60,128.53,128.30,128.20,114.99,67.18,65.60,57.43,52.92,29.77,14.27.

TM1-19b (R)-2-(4-(3-((5-amino-1,3,4-thiadiazoles-2-base) sulfenyl) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) ethyl acetate: white solid; M.p.:87-90 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.34-7.26 (7H, m, Ar-H), 6.85 (2H, d, J=8.4Hz, Ar-H), 5.95 (1H, d, J=6.6Hz, NH), 5.27 (1H, d, J=6.9Hz, * CH), 5.14-5.04 (2H, m, PhCH ₂-), 4.22-4.06 (4H, m ,-OCH ₂-andCOCH ₂-), 3.30 (2H, t, J=6.9Hz, SCH ₂-), 2.22-2.18 (2H, m ,-CH ₂-), 1.20 (3H, t, J=7.2Hz ,-CH ₃); ¹³cNMR (75MHz, CDCl ₃) δ: 171.09,158.76,155.50,136.16,128.94,128.60,128.46,128.29,128.19,114.93,67.14,65.61,62.00,57.52,31.58,29.05,14.08; HRMS:C ₂₃h ₂₆n ₄o ₅s ₂[M+H] ⁺calculated value 503.1417, measured value 503.1420.

TM1-19c (R)-2-(4-(3-((5-amino-1,3,4-thiadiazoles-2-base) sulfenyl) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) propyl acetate: white solid; M.p.:59-61 DEG C; ¹hNMR (600MHz, DMSO) δ: 8.14 (1H, d, J=7.8Hz, NH), 7.41-7.27 (9H, m, Ar-H), 6.93-6.99 (2H, d, J=9.0Hz, NH ₂), 5.19-5.16 (1H, m, * CH), 5.09-5.02 (2H, m, PhCH ₂-), 4.06 (3H, t, J=6.0Hz ,-OCH ₂-), 3.99 (2H, t, J=6.6Hz, COCH ₂-), 3.19 (2H, t, J=6.6Hz ,-SCH ₂-), 2.10-2.04 (2H, m ,-CH ₂-), 1.54-1.46 (2H, m ,-CH ₂-), 0.77 (3H, t, J=4.2Hz ,-CH ₃); HRMS:C ₂₄h ₂₈n ₄o ₅s ₂[M+H] ⁺calculated value 517.1574, measured value 517.1580.

TM1-19d (R)-2-(4-(3-((5-amino-1,3,4-thiadiazoles-2-base) sulfenyl) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) butylacetate: white solid; M.p.:84-89 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.41-7.17 (7H, m, Ar-H), 6.90-6.77 (2H, m, Ar-H), 5.94 (1H, d, J=6.6Hz, NH), 5.27 (1H, d, J=6.9Hz, * CH), 5.15-5.01 (2H, m, PhCH ₂-), 4.20-4.02 (4H, m ,-OCH ₂-andCOCH ₂-), 3.30 (2H, t, J=6.9Hz, SCH ₂-), 2.21 (2H, t, J=6.0Hz ,-CH ₂-), 1.60-1.45 (2H, m ,-CH ₂-), 1.34-1.14 (2H, m ,-CH ₂-), 0.85 (3H, t, J=7.2Hz ,-CH ₃); ¹³cNMR (75MHz, CDCl ₃) δ: 171.17,158.77,155.49,136.17,129.04,128.62,128.42,128.30,128.21,114.94,77.58,77.16,76.74,67.16,65.81,65.64,57.53,31.59,30.42,29.08,18.94,13.68; HRMS:C ₂₅h ₃₀n ₄o ₅s ₂[M+Na] ⁺calculated value 553.1550, measured value 553.1554.

TM1-20a (R)-2-(4-(3-((4-hydroxyl-6-aminopyrimidine-2-base) sulfenyl) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) methyl acetate: white solid; M.p.:81-84 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.42-7.12 (7H, m, Ar-H), 6.91-6.81 (2H, m, Ar-H), 5.95-5.86 (1H, m, NH), 5.33-5.25 (1H, m, * CH), 5.15 (1H, s, Ar-H), 5.12-5.00 (2H, m, PhCH ₂-), 4.56 (1H, s, OH), 4.06 (2H, t, J=5.4Hz, OCH ₂), 3.72 (3H, s ,-CH ₃), 3.28 (2H, t, J=6.9Hz ,-SCH ₂-), 2.24-2.11 (2H, m ,-CH ₂-); ¹³cNMR (75MHz, CDCl ₃) δ: 171.60,166.18,163.23,161.39,158.89,155.53,136.14,128.65,128.56,128.52,128.24,128.14,114.86,83.62,77.59,77.16,76.74,67.11,65.87,57.43,52.85,28.98,26.89; HRMS:C ₂₄h ₂₆n ₄o ₆s [M+H] ⁺calculated value 499.1646, measured value 499.1650.

TM1-20b (R)-2-(4-(3-((4-hydroxyl-6-aminopyrimidine-2-base) sulfenyl) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) ethyl acetate: white solid; M.p.:76-83 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.34-7.26 (7H, m, Ar-H), 6.86 (2H, d, J=8.1Hz, Ar-H), 5.92 (1H, d, J=6.9Hz, NH), 5.26 (1H, d, J=6.9Hz, * CH), (5.14 1H, s, Ar-H), 5.10-5.03 (2H, m, PhCH ₂-), 4.54 (1H, s, OH), 4.21-4.10 (2H, m, COCH ₂-), 4.06 (2H, t, J=5.7Hz, OCH ₂), 3.34-3.22 (2H, m ,-SCH ₂-), 2.24-2.10 (2H, m ,-CH ₂-), 1.20 (3H, t, J=7.2Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 171.05,166.20,163.18,161.56,158.93,155.54,136.29,129.08,128.61,128.49,128.27,128.18,114.93,83.77,77.37,77.16,76.95,67.15,65.96,61.97,57.58,29.13,27.03,14.09; HRMS:C ₂₅h ₂₈n ₄o ₆s [M+H] ⁺calculated value 513.1802, measured value 513.1807.

TM1-20c (R)-2-(4-(3-((4-hydroxyl-6-aminopyrimidine-2-base) sulfenyl) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) propyl acetate: yellow oil; ¹hNMR (300MHz, CDCl ₃) δ: 7.39-7.21 (7H, m, Ar-H), 7.00-6.91 (2H, m, Ar-H), 6.00-5.94 (1H, m, NH), 5.22 (1H, s, OH), 5.30-5.24 (1H, m, * CH), 5.15-5.00 (3H, m, Ar-HandPhCH ₂-), 4.12-3.99 (4H, m ,-OCH ₂-andCOCH ₂-), 3.27 (2H, t, J=5.4Hz ,-SCH ₂-), 2.22-2.11 (2H, m ,-CH ₂-), 1.63-1.52 (2H, m ,-CH ₂-), 0.94-0.80 (3H, m ,-CH ₃); ¹³cNMR (75MHz, CDCl ₃) δ: 171.14,166.23,163.18,161.44,158.83,155.51,136.18,129.02,128.60,128.44,128.27,128.19,114.79,83.67,77.58,77.16,76.74,67.46,67.12,65.82,57.49,29.76,29.06,21.84,10.24; HRMS:C ₂₆h ₃₀n ₄o ₆s [M+H] ⁺calculated value 527.1959, measured value 527.1962.

TM1-20d (R)-2-(4-(3-((4-hydroxyl-6-aminopyrimidine-2-base) sulfenyl) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) butylacetate: yellow oil; ¹hNMR (300MHz, CDCl ₃) δ: 7.43-7.12 (7H, m, Ar-H), 6.92-6.79 (2H, m, Ar-H), 5.97-5.87 (1H, m, NH), 5.32-5.21 (1H, m, * CH), 5.14 (1H, s, Ar-H), 5.12-5.00 (2H, m, PhCH ₂-), 5.52 (1H, s, OH), 4.20-3.97 (4H, m ,-OCH ₂-andCOCH ₂-), 3.37-3.20 (2H, m ,-SCH ₂-), 2.25-2.10 (2H, m ,-CH ₂-), 1.61-1.46 (2H, m ,-CH ₂-), 1.32-1.16 (2H, m ,-CH ₂-), 0.85 (3H, t, J=7.2Hz ,-CH ₃); ¹³cNMR (75MHz, CDCl ₃) δ: 171.12,166.24,163.17,161.46,158.86,155.50,136.20,129.07,128.61,128.44,128.28,128.20,114.83,111.54,83.78,77.58,76.73,67.14,65.80,57.51,30.43,29.76,29.11,26.92,18.94,13.66; HRMS:C ₂₇h ₃₂n ₄o ₆s [M+H] ⁺calculated value 541.2115, measured value 541.2120.

The synthesis of embodiment 4 compound TM2

In round-bottomed flask, add TM1-18, after dissolving with q. s. methylene chloride (DCM), add the metachloroperbenzoic acid (mCPBA) of 2 times of molar weights, stirred at ambient temperature reacts, and TLC monitors reaction process.After reaction terminates, concentrated, silica gel column chromatography, obtains object compound TM2.

Table four compound TM2 generated data

TM2-a (R)-2-(4-(3-((1H-benzo [d] imidazoles-2-base) alkylsulfonyl) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) methyl acetate: white solid; M.p.:96-97 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 2.32 (m, 2H ,-CH ₂-), 3.70 (s, 3H, OCH ₃), 4.02-4.20 (m, 5H, SCH ₂, NH, OCH ₂), 5.09 (q, 2H, J=12.0Hz, 13.8Hz, PhCH ₂), 5.27 (d, 1H, J=6.3Hz, * CH), 5.87 (d, 1H, J=6.3Hz, CONH), 6.76 (m, 2H, Ar-H), 7.21-7.45 (m, 9H, Ar-H), 7.75 (m, 2H, Ar-H); ¹³cNMR (75MHz, CDCl ₃) δ: 22.2,51.8,57.0,61.6,64.8,66.8,114.3,114.4,127.7,127.8,128.0,128.1,128.1,135.6,146.7,155.2,157.9,170.7.

TM2-b (R)-2-(4-(3-((1H-benzo [d] imidazoles-2-base) alkylsulfonyl) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) ethyl acetate: white solid; M.p.:98-99 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 1.20 (t, 3H, J=6.9Hz, CH ₃), 2.34 (m, 2H ,-CH ₂-), 3.71 (m, 2H ,-CH ₂-), 4.04-4.15 (m, 5H, SCH ₂, NH, OCH ₂), 5.09 (d, 2H, J=5.1Hz, PhCH ₂), 5.27 (d, 1H, J=6.9Hz, * CH), 5.84 (d, 1H, J=6.9Hz, CONH), 6.77 (d, 2H, J=8.1Hz, Ar-H), 7.22-7.73 (m, 11H, Ar-H); ¹³cNMR (75MHz, CDCl ₃) δ: 13.6,22.2,29.3,51.7,57.0,61.6,64.7,66.7,114.3,125.1,127.7,127.8,128.0,128.1,128.8,135.6,146.6,155.0,157.9,170.6.

TM2-c (R)-2-(4-(3-((1H-benzo [d] imidazoles-2-base) alkylsulfonyl) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) propyl acetate: yellow oil; ¹hNMR (300MHz, CDCl ₃) δ: 8.00-7.65 (2H, m, Ar-H), 7.47-7.09 (9H, m, Ar-H), 6.83-6.71 (2H, m, Ar-H), 5.93-5.90 (1H, m, NH), 5.32-5.25 (1H, m, * CH), 5.16-5.00 (2H, m, PhCH ₂), 4.14-3.95 (4H, m, OCH ₂andCOCH ₂), 3.69 (2H, t, J=7.5Hz, SCH ₂), 2.40-2.26 (2H, m ,-CH ₂-), 1.63-1.51 (2H, m ,-CH ₂-), 0.81 (3H, t, J=7.5Hz ,-CH ₃); ¹³cNMR (151MHz, CDCl ₃) δ: 171.20,163.10,158.51,155.63,147.46,136.24,129.45,128.59,128.46,128.26,128.17,125.26,120.43,114.90,77.37,77.16,76.95,67.50,67.22,65.40,57.56,52.20,22.72,21.86,10.19; HRMS:C ₂₉h ₃₁n ₃o ₇s [M+Na] ⁺calculated value 588.1775, measured value 588.1780.

TM2-d (R)-2-(4-(3-((1H-benzo [d] imidazoles-2-base) alkylsulfonyl) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) butylacetate: white solid; M.p.:111-112 DEG C; ¹hNMR (300MHz, CDCl ₃) δ: 7.78-7.67 (2H, s, Ar-H), 7.49-7.40 (2H, m, Ar-H), 7.39-7.15 (7H, m, Ar-H), 6.91-6.71 (2H, m, Ar-H), (5.90-5.82 1H, m, NH), 5.32-5.24 (1H, m, * CH), 5.15-5.03 (2H, m, PhCH ₂), 4.19-3.98 (4H, m, OCH ₂andCOCH ₂), 3.76-3.65 (2H, m ,-SCH ₂-), 2.40-2.24 (2H, m ,-CH ₂-), 1.60-1.44 (2H, m ,-CH ₂-), 1.31-1.15 (2H, m ,-CH ₂-), 0.84 (3H, t, J=6Hz ,-CH ₃); ¹³cNMR (75MHz, CDCl ₃) δ: 171.27,158.44,155.68,155.65,147.22,136.13,129.31,128.63,128.47,128.33,128.22,127.87,125.41,114.79,77.58,77.16,76.74,67.28,65.90,65.26,57.52,52.21,30.42,22.67,18.94,13.67; HRMS:C ₃₀h ₃₃n ₃o ₇s [M+H] ⁺calculated value 580.2112, measured value 580.2116.

The synthesis of embodiment 5 compound TM3

In round-bottomed flask, add TM1, after dissolving with 1-3mL tetrahydrofuran (THF) (THF), drip 1NLiOH, (15-35 DEG C) stirring reaction under envrionment temperature, TLC monitors reaction process.After reaction terminates (about 2h), drip 1NHCl and regulate pH=7, vacuum rotary steam removing tetrahydrofuran (THF), drips 1NHCl and regulates pH=5, reaction solution is muddy, obtains viscous solid gradually, and ethyl acetate (10mL) extracts, collect organic phase, washing, anhydrous Na ₂sO ₄drying, suction filtration, filtrate decompression is revolved and is steamed except desolventizing, and obtain stickiness product, freezing precipitation solid after adding ether, suction filtration, obtains object compound TM3.

Table five compound TM3 generated data

TM3-1 (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(3-formvlphenoxv) propoxy-) phenyl) acetic acid: white solid; M.p.:85-87 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 2.17-2.21 (m, 2H ,-CH ₂-), 4.12-4.23 (m, 4H, 2-OCH ₂), 5.04 (s, 2H, PhCH ₂), 5.09 (d, 1H, J=8.4Hz, * CH), 6.94 (d, 2H, J=8.7Hz, Ar-H), 7.30-7.52 (m, 11H, Ar-H), 8.06 (d, 1H, J=8.1Hz, CONH), 12.76 (s, 1H, COOH); ¹³cNMR (75MHz, DMSO-d ₆) δ: 28.5,57.5,64.2,64.6,65.6,113.7,114.4,121.4,127.8,128.4,129.1,130.4,136.9,137.6,155.8,158.2,159.0,172.4,193.0; HRMS:C ₂₆h ₂₅nO ₇[M+Na] ⁺calculated value 486.1523, measured value 486.1528.

TM3-2 (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(2-formvlphenoxv) propoxy-) phenyl) acetic acid: yellow oil; ¹hNMR (300MHz, DMSO-d ₆) δ: 2.22-2.26 (m, 2H ,-CH ₂-), 4.17-4.31 (m, 4H, 2-OCH ₂), 5.05 (s, 2H, PhCH ₂), 5.09 (d, 1H, J=8.1Hz, * CH), 6.94 (d, 2H, J=8.1Hz, Ar-H), 7.08 (t, 1H, J=7.5Hz, Ar-H), 7.24-7.70 (m, 10H, Ar-H), 8.06 (d, 1H, J=7.8Hz, CONH), (12.71 s, 1H, COOH); ¹³cNMR (75MHz, DMSO-d ₆) δ: 28.5,57.5,64.3,65.2,65.6,113.4,114.3,120.7,124.3,127.7,127.8,127.9,128.3,129.0,129.1,136.4,137.0,155.8,158.2,160.9,172.4,189.3; HRMS:C ₂₆h ₂₅nO ₇[M+Na] ⁺calculated value 486.1523, measured value 486.1527.

TM3-3 (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(4-formvlphenoxv) propoxy-) phenyl) acetic acid: white solid; M.p.:156-158 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 2.18-2.22 (m, 2H ,-CH ₂-), 4.11-4.25 (m, 4H, 2-OCH ₂), 5.04 (s, 2H, PhCH ₂), 5.09 (d, 1H, J=8.1Hz, * CH), 6.93 (d, 2H, J=8.4Hz, Ar-H), 7.14 (d, 2H, J=8.7Hz, Ar-H), 7.30-7.35 (m, 7H, Ar-H), 7.86 (d, 2H, J=8.7Hz, Ar-H), 8.05 (d, 1H, J=8.1Hz, CONH), 9.86 (s, 1H, CHO), 12.75 (s, 1H, COOH); ¹³cNMR (75MHz, DMSO-d ₆) δ: 28.4,57.4,64.1,64.8,65.5,109.5,109.7,114.4,115.0,121.9,123.8,127.8,127.9,128.4,129.0,129.1,129.7,131.9,136.9,155.8,158.1,163.5,172.4,191.4; HRMS:C ₂₆h ₂₅nO ₇[M+Na] ⁺calculated value 486.1523, measured value 486.1527.

TM3-4 (R)-4-(3-(4-(((carbobenzoxy-(Cbz)) is amino) (carboxyl) methyl) phenoxy group) propoxy-) phenylformic acid: white solid; M.p.:178-180 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 2.16-2.20 (m, 2H ,-CH ₂-), 4.12 (t, 2H, J=6.0Hz, OCH ₂), 4.19 (t, 2H, J=6.0Hz, OCH ₂), 5.07 (t, 3H, PhCH ₂, * CH), 6.93 (d, 2H, J=8.4Hz, Ar-H), 7.04 (d, 2H, J=9.0Hz, Ar-H), 7.29-7.35 (m, 6H, Ar-H), 7.88 (d, 2H, J=8.7Hz, Ar-H), 8.00 (d, 1H, J=8.1Hz, CONH); ¹³cNMR (75MHz, DMSO-d ₆) δ: 28.5,57.6,64.2,64.6,65.6,114.3,114.4,123.0,127.7,127.8,128.4,129.0,129.4,131.4,136.9,155.8,158.1,162.1,167.1,172.4; HRMS:C ₂₆h ₂₅nO ₈[M+Na] ⁺calculated value 502.1472, measured value 502.1479.

TM3-5 (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(4-(carboxymethyl) phenoxy group) propoxy-) phenyl) acetic acid: white solid; M.p.:138-140 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 2.13-2.15 (m, 2H ,-CH ₂-), 3.48 (s, 2H, COCH ₂-), 4.10-4.12 (m, 4H, 2-OCH ₂), 5.04 (s, 2H, PhCH ₂), 5.09 (d, 1H, J=7.8Hz, * CH), 6.87-6.90 (m, 4H, Ar-H), (7.16 d, 2H, J=8.4Hz, Ar-H), 7.30-7.36 (m, 7H, Ar-H), 8.06 (d, 1H, J=7.8Hz, CONH), (12.48 s, 2H, COOH); ¹³cNMR (75MHz, DMSO-d ₆) δ: 28.6,39.8,57.5,64.1,64.3,65.6,114.2,114.4,127.1,127.8,127.8,128.4,129.1,130.4,137.0,155.8,157.3,158.2,172.4,173.0.

TM3-6 (R)-3-(4-(3-(4-(((carbobenzoxy-(Cbz)) is amino) (carboxyl) methyl) phenoxy group) propoxy-) phenyl) propionic acid: white solid; M.p.:125-126 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 2.12-2.16 (m, 2H ,-CH ₂-), 2.45-2.47 (m, 2H, CH ₂), 2.74 (t, 2H, J=7.5Hz, CH ₂), 4.02-4.13 (m, 4H, 2-OCH ₂), 5.04 (s, 2H, PhCH ₂), 5.09 (d, 1H, J=7.8Hz, * CH), 6.85 (d, 2H, J=8.1Hz, Ar-H), 6.93 (d, 2H, J=8.1Hz, Ar-H), 7.12 (d, 2H, J=8.1Hz, Ar-H), 7.30-7.35 (m, 7H, Ar-H), 8.06 (d, 1H, J=7.8Hz, CONH), 12.40 (s, 2H, COOH); ¹³cNMR (75MHz, DMSO-d ₆) δ: 28.6,29.5,35.6,57.4,64.1,64.3,65.6,114.3,114.3,127.8,127.8,128.4,129.0,129.2,132.9,136.9,155.8,156.8,158.2,172.4,173.9; HRMS:C ₂₈h ₂₉nO ₈[M+Na] ⁺calculated value 530.1785, measured value 530.1792.

TM3-7 (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(4-propionyl phenoxy group) propoxy-) phenyl) acetic acid: white solid; M.p.:93-95 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 1.06 (t, 3H, J=7.2Hz, CH ₃), 2.16-2.20 (m, 2H ,-CH ₂-), 2.97 (q, 2H, J=7.2Hz, 12.3Hz, COCH ₂), 4.13-4.23 (m, 4H, 2-OCH ₂), 5.04 (s, 2H, PhCH ₂), 5.09 (d, 1H, J=8.1Hz, * CH), 6.93 (d, 2H, J=8.4Hz, Ar-H), 7.05 (d, 2H, J=8.7Hz, Ar-H), 7.30-7.35 (m, 7H, Ar-H), 7.93 (d, 2H, J=8.7Hz, Ar-H), 8.05 (d, 1H, J=8.1Hz, CONH), 12.76 (s, 1H, COOH); ¹³cNMR (75MHz, DMSO-d ₆) δ: 8.3,28.5,30.8,57.4,64.1,64.6,65.6,114.3,114.4,127.7,127.8,128.4,129.0,130.1,137.0,155.8,158.1,162.2,172.4,198.8; HRMS:C ₂₈h ₂₉nO ₇[M+H] ⁺calculated value 492.2017, measured value 492.2021.

TM3-8 (R)-2-(4-(3-(4-ethanoyl phenoxy group) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) acetic acid: white solid; M.p.:120-122 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 2.16-2.20 (m, 2H ,-CH ₂-), 2.50 (s, 3H, COCH ₃), 4.12-4.23 (m, 4H, 2-OCH ₂), 5.03 (s, 2H, PhCH ₂), 5.08 (d, 1H, J=8.1Hz, * CH), 6.92 (d, 2H, J=8.4Hz, Ar-H), 7.05 (d, 2H, J=8.4Hz, Ar-H), 7.29-7.34 (m, 6H, Ar-H), 7.92 (d, 2H, J=8.7Hz, Ar-H), 8.05 (d, 1H, J=8.1Hz, CONH), 12.76 (s, 1H, COOH); ¹³cNMR (75MHz, DMSO-d ₆) δ: 26.4,28.4,57.5,64.1,64.6,65.6,114.3,114.4,127.8,127.9,128.4,129.1,130.5,136.9,155.9,158.2,162.4,172.4,196.4.

TM3-9 (R)-2-(4-(3-(2-ethanoyl phenoxy group) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) acetic acid: yellow oil; ¹hNMR (300MHz, DMSO-d ₆) δ: 2.20-2.28 (m, 2H ,-CH ₂-), 2.55 (s, 3H, COCH ₃), 4.14-4.27 (m, 4H, 2-OCH ₂), 5.04 (s, 2H, PhCH ₂), 5.09 (d, 1H, J=7.8Hz, * CH), 6.94 (d, 2H, J=8.7Hz, Ar-H), 7.02 (t, 1H, J=7.5Hz, Ar-H), 7.18 (d, 1H, J=8.1Hz, Ar-H), 7.30-7.60 (m, 9H, Ar-H), (8.06 d, 1H, J=8.1Hz, CONH); ¹³cNMR (75MHz, DMSO-d ₆) δ: 28.6,31.8,57.5,64.5,65.2,65.6,113.1,114.3,120.4,127.7,127.8,128.4,129.1,129.6,133.9,136.9,155.8,157.8,158.2,172.4,198.8; HRMS:C ₂₇h ₂₇nO ₇[M+H] ⁺calculated value 478.1860, measured value 478.1864.

TM3-10 (R)-2-(4-(3-(3-ethanoyl phenoxy group) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) acetic acid: white solid; M.p.:115-116 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 2.16-2.20 (m, 2H ,-CH ₂-), 2.56 (s, 3H, COCH ₃), 4.13-4.21 (m, 4H, 2-OCH ₂), 5.04 (s, 2H, PhCH ₂), 5.09 (d, 1H, J=7.8Hz, * CH), 6.94 (d, 2H, J=8.4Hz, Ar-H), 7.25-7.53 (m, 11H, Ar-H), 8.05 (d, 1H, J=7.8Hz, CONH), 12.75 (s, 1H, COOH); ¹³cNMR (75MHz, DMSO-d ₆) δ: 26.9,28.5,57.0,57.5,64.2,64.4,65.6,113.3,114.4,119.6,120.8,127.8,128.4,129.0,129.9,138.2,158.2,158.6,172.4,197.8; HRMS:C ₂₇h ₂₇nO ₇[M+Na] ⁺calculated value 500.1680, measured value 500.1685.

TM3-11 (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(5-formyl radical-2-methoxyphenoxy) propoxy-) phenyl) acetic acid: white solid; M.p.:106-107 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 2.17-2.21 (m, 2H ,-CH ₂-), 3.86 (s, 3H, OCH ₃), 4.13-4.19 (m, 4H, 2-OCH ₂), 5.04 (s, 2H, PhCH ₂), 5.09 (d, 1H, J=7.8Hz, * CH), 6.94 (d, 2H, J=8.4Hz, Ar-H), 7.18 (d, 1H, J=8.1Hz, Ar-H), 7.30-7.35 (m, 7H, Ar-H), 7.43 (s, 1H, Ar-H), 7.56 (d, 1H, J=8.1Hz, Ar-H), 8.05 (d, 1H, J=8.1Hz, CONH), 9.83 (s, 1H, CHO), 12.77 (s, 1H, COOH); ¹³cNMR (75MHz, DMSO-d ₆) δ: 28.5,55.9,57.5,64.2,65.0,65.6,110.8,111.5,114.3,126.1,127.8,127.9,128.4,129.0,129.6,136.9,148.3,154.4,155.8,158.2,172.4,191.4; HRMS:C ₂₇h ₂₇nO ₈[M+Na] ⁺calculated value 516.1629, measured value 516.1632.

TM3-12 (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(4-formyl radical-2-methoxyphenoxy) propoxy-) phenyl) acetic acid: white solid; M.p.:191-193 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 2.17-2.21 (m, 2H ,-CH ₂-), 3.87 (s, 3H, OCH ₃), 4.11-4.21 (m, 4H, 2-OCH ₂), 5.02 (d, 3H, PhCH ₂, * CH), 6.92 (d, 2H, J=7.5Hz, Ar-H), 7.19 (d, 1H, J=8.4Hz, Ar-H), 7.29-7.44 (m, 8H, Ar-H), 7.57 (d, 1H, J=8.1Hz, Ar-H), 7.91 (d, 1H, J=7.2Hz, CONH), 9.84 (s, 1H, CHO); ¹³cNMR (75MHz, DMSO-d ₆) δ: 28.5,55.9,57.5,64.2,65.0,65.5,110.8,111.5,114.3,126.1,127.7,127.8,128.4,129.0,129.6,137.0,148.3,154.4,155.8,158.1,172.4,191.4; HRMS:C ₂₇h ₂₇nO ₈[M+Na] ⁺calculated value 516.1629, measured value 516.1632.

TM3-13 (R)-2-(4-(3-(4-kharophen phenoxy group) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) acetic acid: white solid; M.p.:144-145 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 1.99 (s, 3H, COCH ₃), 2.11-2.15 (m, 2H ,-CH ₂-), 4.07-4.10 (m, 4H, 2-OCH ₂), 5.04 (s, 3H, PhCH ₂, * CH), 6.90 (q, 4H, J=9.0Hz, 10.8Hz, Ar-H), 7.29-7.35 (m, 9H, Ar-H), 7.97 (d, 1H, J=7.5Hz, CONH), 9.78 (s, 1H, COOH); ¹³cNMR (75MHz, DMSO-d ₆) δ: 23.8,28.6,57.5,64.3,65.5,114.3,114.4,120.5,127.7,127.8,128.4,129.0,129.1,132.6,137.0,154.2,155.8,158.2,167.8,172.4; HRMS:C ₂₇h ₂₈n ₂o ₇[M+Na] ⁺calculated value: 515.1789, measured value 515.1794.

TM3-14 (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-Phenoxypropoxy) phenyl) acetic acid: white solid; M.p.:73-74 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 2.13-2.20 (m, 2H ,-CH ₂-), 4.06-4.12 (m, 4H, 2-OCH ₂), 5.04 (s, 2H, PhCH ₂), 5.08 (d, 1H, J=7.5Hz, * CH), 6.94-6.95 (m, 4H, Ar-H), 7.25-7.35 (m, 6H, Ar-H), 8.05 (d, 1H, J=7.5Hz, CONH), 12.76 (s, 1H, COOH); ¹³cNMR (75MHz, DMSO-d ₆) δ: 28.63,57.45,64.03,64.29,65.56,114.37,114.45,120.58,127.8,128.4,129.0,129.5,137.0,155.8,158.2,158.5,172.4; HRMS:C ₂₅h ₂₅nO ₆[M+Na] ⁺calculated value 458.1574, measured value 458.1579.

TM3-15 (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-(naphthalene-2-base oxygen base) propoxy-) phenyl) acetic acid: white solid; M.p.:94-96 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 2.22-2.26 (m, 2H ,-CH ₂-), 4.17-4.27 (m, 4H, 2-OCH ₂), 5.04 (s, 2H, PhCH ₂), 5.09 (d, 1H, J=8.1Hz, * CH), 6.95 (d, 2H, J=8.1Hz, Ar-H), 7.18 (d, 1H, J=8.7Hz, Ar-H), 7.31-7.83 (m, 13H, Ar-H), 8.06 (d, 1H, J=7.5Hz, CONH), (12.75 s, 1H, COOH); ¹³cNMR (75MHz, DMSO-d ₆) δ: 28.6,57.5,64.3,65.6,106.7,114.4,118.7,123.6,126.4,126.7,127.5,127.7,127.8,128.4,128.5,129.0,129.1,129.3,134.3,137.0,155.9,156.4,158.2,172.4; HRMS:C ₂₉h ₂₇nO ₆[M+Na] ⁺calculated value 508.1731, measured value 508.1734.

TM3-16 (R)-2-((carbobenzoxy-(Cbz)) is amino)-2-(4-(3-((2-oxo-2H-chromene-4-base) oxygen base) propoxy-) phenyl) acetic acid: white solid; M.p.:98-99 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 2.26-2.30 (m, 2H ,-CH ₂-), 4.19-4.37 (m, 4H, 2-OCH ₂), 5.07 (t, 3H, PhCH ₂, * CH), 5.94 (s, 1H, COCH-), 6.95 (d, 2H, J=8.4Hz, Ar-H), 7.30-7.38 (m, 9H, Ar-H), 7.66 (t, 1H, J=7.5Hz, Ar-H), 7.85 (d, 2H, J=7.8Hz, Ar-H), 8.05 (d, 1H, J=8.1Hz, CONH), 12.74 (s, 1H, COOH); ¹³cNMR (75MHz, DMSO-d ₆) δ: 28.0,57.5,64.2,65.6,66.4,90.6,114.3,114.4,115.2,115.2,116.4,122.9,124.2,127.8,127.8,128.3,129.0,129.1,129.2,132.7,136.9,152.8,155.8,158.1,161.7,164.9,172.4; HRMS:C ₂₈h ₂₅nO ₈[M+Na] ⁺calculated value 526.1472, measured value 526.1476.

TM3-17 (R)-2-(4-(3-(benzo [d] oxazole-2-base sulfenyl) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) acetic acid: gray solid; M.p.:177-178 DEG C; ¹hNMR (600MHz, DMSO-d ₆) δ: 2.21-2.26 (m, 2H ,-CH ₂-), 3.46 (t, 2H, J=7.2Hz, SCH ₂), 4.09 (t, 2H, J=6.0Hz, OCH ₂), 4.75 (d, 1H, J=6.6Hz, * CH), 5.00 (q, 2H, J=13.2Hz, 26.4Hz, PhCH ₂), 6.83-6.86 (m, 2H, Ar-H), 7.24-7.35 (m, 11H, Ar-H, CONH); ¹³cNMR (75MHz, DMSO-d ₆) δ: 28.7,58.7,65.3,65.8,68.1,110.2,113.9,114.1,114.5,117.3,118.2,124.2,124.6,127.7,127.8,128.4,137.1,141.3,151.2,155.2,157.4,164.3,171.9; HRMS:C ₂₆h ₂₄n ₂o ₆s [M-H] ^-calculated value 491.1271, measured value 491.1280.

TM3-18 (R)-2-(4-(3-(((1H-benzo [d] imidazoles-2-base) sulfenyl) propoxy-) phenyl)-2-((carbobenzoxy-(Cbz)) is amino) acetic acid: white solid; M.p.:111-112 DEG C; ¹hNMR (300MHz, DMSO-d ₆) δ: 2.17-2.21 (m, 2H ,-CH ₂-), 3.61-3.63 (m, 3H, SCH ₂, NH), 4.10 (t, 2H, J=5.8Hz, OCH ₂), 5.05 (s, 2H, PhCH ₂), 5.09 (d, 1H, J=7.8Hz, * CH), 6.91 (d, 2H, J=8.4Hz, Ar-H), 7.30-7.63 (m, 11H, Ar-H), 8.05 (d, 1H, J=8.1Hz, CONH); ¹³cNMR (75MHz, DMSO-d ₆) δ: 28.7,28.9,57.4,65.6,65.7,113.3,114.4,124.0,127.8,127.8,128.4,129.0,129.2,134.6,136.9,150.2,155.8,158.0,172.4; HRMS:C ₂₆h ₂₅n ₃o ₅s [M+H] ⁺calculated value 492.1588, measured value 492.1595.

The short GLP-1 secretion activity test of embodiment 6 object compound

GLP-1 is the intestines peptide hormone that the promoting insulin secretion that found is the strongest.After the GLP-1 receptors bind of the ripe β cell of itself and pancreas islet, can adenosine acyl cyclase, produce cyclic amp, the latter and glucose are worked in coordination with and are stimulated insulin synthesis and secretion, stimulate insulin gene transcription and proinsulin biosynthesizing, reduce Glucagon concentrations and glucagon suppression secretion, strengthen cell to the susceptibility of Regular Insulin, stimulate insulin-dependent Glycogen synthesis, reduce postprandial blood sugar concentration; All right activated protein kinase, phosphatidylinositol3 3 kinase (PI3K), mitogen activated protein kinase (MAPK) passage, before adjustment apoptosis, the expression of albumen and induction inhibitor of apoptosis protein Bcl-2 and Bcl-xL is to slow down β apoptosis, promote its regeneration, impel beta Cell of islet to break up and breed.Owing to having above good physiologically active, the research and development of GLP-1 and relevant new drug thereof are the focus of diabetes B drug research over nearly 20 years always.But GLP-1 can by the DPP IV (dipeptidylpepidiase-IV be extensively present in the tissues such as kidney, gi tract, reticular tissue, lymph in human blood circulation, DPP-4) degrade rapidly, its Half-life in vivo only about 2 minutes, causes external source GLP-1 to be difficult to obtain Clinical practice.Therefore, investigator's main relevant new drug from 3 aspect developing GLP-1 at present: GLP-1 is modified or changes structure and obtain the long-acting agonist of GLP-1; The DPP-4 inhibitor of research and development novelty is to improve the transformation period of endogenous GLP-1; Seek the GLP-1 receptor stimulant with identical physiologically active.

Compound TM1, TM2 and TM3 that the present invention synthesizes are carried out short GLP-1 secretion activity test.Test job is completed by open innovation style drug research (OpenInnovationDrugDiscovery, the OIDD) platform of Lilly pharmacy group (EliLillyandCompany).Current research shows, some cell can produce GLP-1 under chemical molecular stimulates.OIDD chooses mouse STC-1 cell (mSTC-1) and people NCI-H716 cell (hNCI-H716) studies the ability that testing molecule active cells secretes GLP-1.Wherein, hNCI-H716 cell belongs to the L-type endocrine cell in enteron aisle, has internal secretion characteristic, can secrete GLP-1 under the stimulation of lipid acid, glucosal related protein (GRP), cholinergic agonist, PKA and PKC activator.MSTC-1 cell derived, in the endocrine tumors of mouse small intestine, can secrete multiple enteron aisle hormone, comprises GLP-1, Glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK) and secretin etc.

Materials and methods

1. reagent and consumptive material

DMEM high glucose medium, RPMI1640 substratum is purchased from Hyclone company.Foetal calf serum (FBS), 4-hydroxyethyl piperazine ethanesulfonic acid (HEPES), dual anti-(penicillin, Streptomycin sulphate) is purchased from Invitrogen company.GLP-1 (7-37) is purchased from Bachem company.Bovine serum albumin (BSA) is purchased from MPBiomedicals company.AlphaLISA test kit, 384 orifice plate Proxi-platesplus are purchased from PerkinElmer company.DPP-4 inhibitor is purchased from Millipore company.Tissue Culture Plate is purchased from Greiner company.

384 orifice plates involved in test all adopt poly-lysine to carry out bag quilt before inoculating cell, and testing compound is dissolved in dimethyl sulfoxide (DMSO) (DMSO).

2. clone and culture condition

MSTC-1 clone is separated from mouse small intestine endocrine tumors.Adopt DMEM high glucose medium, add 10wt% through heat-inactivated foetal calf serum, 10mMHEPES and dual anti-, in 5%CO ₂, 37 DEG C of constant temperature culture.

HNCI-H716 clone purchased from American Type culture collection center (AmericanTypeCultureCollection, ATCC).Adopt RPMI1640 substratum, add 10wt% through heat-inactivated foetal calf serum, 2mML-glutamine, 10mMHEPES and dual anti-, in 5%CO ₂, 37 DEG C of constant temperature culture.

3. based on the GLP-1 secretion test of AlphaLISA

For mSTC-1 cell, by every hole 80 μ L about 12,000 cell is inoculated in 384 orifice plates, adherent culture.Then, with the HBSS damping fluid containing 0.1wt%BSA, attached cell is washed 3 times, remove substratum and serum.Every porocyte adds the HBSS damping fluid 50 μ L containing 0.1wt%BSA, add 100nL different concns (2 μMs again, 20 μMs) testing compound solution process cell (with DMSO treatment group for contrast) simultaneously, hatch 2 hours for 37 DEG C, under compound stimulates, emiocytosis GLP-1 is in substratum.The GLP-1 of emiocytosis adopts corresponding AlphaLISA test kit to detect, and the multi-functional plate reading machine of Envision (PerkinElmer) measures fluorescence intensity.

For hNCI-H716 cell, before test, RPMI1640 substratum is replaced by " differentiation " substratum, namely containing 10wt% heat-inactivated fetal bovine serum, 10mMHEPES and dual anti-DMEM high glucose medium.With the HBSS damping fluid containing 0.1wt%BSA and 1wt%DPP-4 inhibitor, attached cell is washed 2 times, remove substratum and serum, again with this damping fluid resuspension cell, according to every hole 50 μ L about 10,000 cell is inoculated in 384 orifice plates, and the testing compound solution of preparation different concns (2 μMs, 20 μMs) processes cell (with DMSO treatment group for contrast) respectively simultaneously, hatch 2 hours for 37 DEG C, under compound stimulates, emiocytosis GLP-1 is in substratum.The GLP-1 of emiocytosis adopts corresponding AlphaLISA test kit to detect, and the multi-functional plate reading machine of Envision (PerkinElmer) measures fluorescence intensity.

With GLP-1 (7-37) polypeptide for standard, adopt AlphaLISA kit measurement and drawing standard curve, quantitative analysis is carried out to test-results.

4. data processing and statistical study

The agonist activity (stimulation, stim) of testing compound calculates according to following formula, and wherein Max and Min is respectively the maximum of control group and minimum detection value, and Signal is test group detected value.

S t i m u l a t i o n (%) = \frac{S i g n a l - M i n}{M a x - M i n} \times 100

Half effective concentration (the EC of testing compound ₅₀) adopt 4 parameter logistic recurrence and nonlinear regression analysis to calculate.

Experimental result

The short GLP-1 secretion activity measurement result of the object of the invention compound TM1, TM2 and TM3 is in table six, in tested person compound, majority has short GLP-1 secretion activity, wherein the relatively exciting percentage of the GLP-1 of 14 compounds reaches more than 20%, and what activity was the highest is TM1-2b (test value is 57.1%).Further, to all showing short GLP-1 secretion activity at two cell strains and at the active compound more than 20% of a certain cell strain, and EC has been carried out at the active compound more than 50% of a certain cell strain ₅₀measure, the results are shown in Table six, individual compound shows lower toxicity and urgees GLP-1 secretion activity preferably.

The short GLP-1 secretion activity of table six compound TM1 ~ TM3 and EC ₅₀measurement result

Note: "-" represents undetermined.

The Nav1.7 inhibit activities test of embodiment 7 object compound

Neurogenic pain refers to the pain because neural system sustains damage or produces pathology and cause.It is different from the acute pain caused by tissue injury, usually in chronic, can last for days or the several months, and the anodyne of routine as opiates potent narcotic anodyne and non-steroidal anti-inflammatory drugs to it all without obvious curative effect.Its physiopathology feature main manifestations is the hyperergy of the pain sensation, as hyperpathia (hyperalgesia), allodynia (allodynia) and idiopathic pain (spontaneouspain) etc.A kind of hypothesis about neurogenic pain mechanism of generally acknowledging at present is thought, the spontaneous pain produced after peripheral nerve injury and bring out pain with damaged part or dorsal root ganglion neurons is spontaneous and routinely paradoxical discharge is closely related.The hormesis that this paradoxical discharge increases with the Inflammatory substances that peripheral nerve injury triggers on the one hand and causes is relevant, on the other hand in the change depending on Voltage-gated sodium channels to a greater extent.

Voltage-gated sodium channels (voltage-gatedsodiumchannels, VGSCs) is a kind of albumen composition of 6 cross-films, and its basic function unit is α subunit.According to the constructional feature of α subunit, 9 kinds of hypotypes (Nav1.1 ~ Nav1.9) can be divided into.Wherein Nav1.7 great expression in Primary Sensory Neuron and sympathetic ganglia neurons, most Nav1.7 is distributed in the nociceptive neuron of minor diameter, participates in the transmission of pain signal.Research shows, the generation of Nav1.7 passage and much pain and continue to have clear and definite relation.Such as, the born pain that lacks is subject to (CIP) patient to be because the SCN9A gene of Nav1.7 that No. 2 karyomit(e)s are encoded is undergone mutation, and causes Nav1.7 to lose activity completely; Heredity erythromelalgia (IE) patient, its SCN9A gene has 13 mutational sites, causes Nav1.7 activity to increase; Paroxysmal erythroderma (PEPD) patient, the mutational site of its SCN9A gene is different from IE patient, causes the incomplete inactivation of Nav1.7.Many experimentation on animalies show, Nav1.7 has also played important effect in inflammatory pain.Therefore, Nav1.7 passage becomes the target molecule of important pain research.Investigators think, the active size of Nav1.7 can affect the sensitivity of human body to pain, and the selective depressant of this passage almost can be used for the treatment of various pain.Thus, Nav1.7 ionic channel high selectivity inhibitor is the focus of analgesic research and development in recent years.

Compound TM1, TM2 and TM3 that the present invention synthesizes are carried out the test of Nav1.7 inhibit activities.Test job is completed by the OIDD platform of Lilly pharmacy group (EliLillyandCompany).

Materials and methods

1. reagent and consumptive material

DMEM high glucose medium is purchased from Hyclone company; Foetal calf serum (FBS), 4-hydroxyethyl piperazine ethanesulfonic acid (HEPES), dual anti-(penicillin, Streptomycin sulphate) is purchased from Invitrogen company; Tissue Culture Plate is purchased from Greiner company.

Patch clamp extracellular fluid: NaCl140mM, KCl5mM, CaCl ₂2mM, MgCl ₂1.1mM, HEPES10mM, glucose 10mM, NaOH adjust pH to 7.4.

Testing compound is dissolved in 0.5% dimethyl sulfoxide (DMSO) (DMSO).

2. clone and culture condition

Express the people source embryonic kidney cells HEK293 of people's sodium-ion channel Nav1.7 or Nav1.5 purchased from Millipore company.Adopt DMEM high glucose medium, add 10wt% through heat-inactivated foetal calf serum, 10mMHEPES and dual anti-, in 5%CO ₂, 37 DEG C of constant temperature culture.

3. sodium-ion channel Nav1.7 Patch-clamp experiments

Compound primary dcreening operation and multiple sieve adopt IonWorksQuattro (IWQ) system for automatic patch-clamp system, according to operational manual, select Perforated patch clamp method record sodium ion electric current.Test first 2 ~ 3 days, the HEK293 cell cultivated under standard conditions is seeded in T75 Tissue Culture Flask, before test, substratum is replaced by patch clamp extracellular fluid.For reference before adding with testing compound, the sealing-in resistance arranging wave filter end pulses is 25M Ω, current amplitude is that 0.5nA is to remove undesirable test group.For single concentration tests (SP), add 3 μMs of testing compound solution process cells, the current amplitude change before and after being added by control compounds, assessment compound is to the restraining effect of Nav1.7/Nav1.5 electric current.For concentration dependent test (CRC, i.e. many concentration tests), the testing compound solution of configuration different concns (0.014-30 μM) processes cell respectively, if keep current potential to be-110mV, adopt 5Hz electricimpulse interval 6 seconds continued stimuluses, according to end pulses analysis and the Use-dependence IC of computerized compound ₅₀value or percent inhibition.

Compound is checked and is adopted PatchXpress system for automatic patch-clamp system.

4. data processing and statistical study

For single concentration tests, be maximum value (Max) with 12.5 μMs of tetracaine (tetracaine) treatment group, 0.5%DMSO control group is minimum value (Min), calculates the relative inhibition (inhibition, inhib) of test group.Calculation formula is:

I n h i b i t i o n (%) = 1 - (\frac{S i g n a l - M i n}{M a x - m i n}) \times 100

Wherein Signal is test group detected value.

For concentration dependent test, adopt 4 parameter logistic regression analyses (XLFitModel), curved vertex be modified to 100% inhibiting rate and allow bottom to float.

Experimental result

The Nav1.7 inhibit activities measurement result of the object of the invention compound TM1, TM2 and TM3 is in table seven.In tested person compound, majority has Nav1.7 inhibit activities, wherein the relative inhibition percentage of the Nav1.7 of 29 compounds reaches more than 20%, the relative inhibition percentage of Nav1.7 of 8 compounds reaches more than 60%, and what activity was the highest is TM1-18b (test value is 89.4%).Further IC is carried out to 8 compounds that the relative inhibition percentage of Nav1.7 reaches more than 60% ₅₀test, the results are shown in Table seven, and the Nav1.7/Nav1.5 ratio of some molecule (as TM1-18a, TM1-18b, TM2-a, TM2-b) is comparatively large, and selectivity is better, has the potentiality of further investigation.

The Nav1.7 inhibit activities of table seven object compound TM1 ~ TM3 and IC ₅₀measurement result

Note: "-" represents undetermined.

What finally illustrate is, above preferred embodiment is only in order to illustrate technical scheme of the present invention and unrestricted, although by above preferred embodiment to invention has been detailed description, but those skilled in the art are to be understood that, various change can be made to it in the form and details, and not depart from claims of the present invention limited range.

Claims

1.D-D-pHPG derivative, is characterized in that: have following structural formula:

2. D-pHPG derivative as claimed in claim 1, is characterized in that: R ¹for methyl, Y is O, Ar is 3-Fonnylphenyl, 2-Fonnylphenyl, 4-methoxycarbonyl phenyl, 4-propionylphenyl, 4-acetylphenyl, 2-acetylphenyl, 3-acetylphenyl, 5-formyl radical-2-p-methoxy-phenyl, 4-formyl radical-2-p-methoxy-phenyl, phenyl or 2-oxo-2H-chromene-4-base;

Or, R ¹for normal-butyl, Y is O, Ar is 2-Fonnylphenyl or phenyl;

Or, R ¹for hydrogen, Y is S, Ar is benzo [d] oxazole-2-base.

3. D-pHPG derivative as claimed in claim 2, is characterized in that: R ¹for methyl, Y is O, Ar is 4-acetylphenyl or 2-acetylphenyl;

Or, R ¹for ethyl or normal-butyl, Y is O, Ar is 2-Fonnylphenyl or phenyl;

Or, R ¹for n-propyl, Y is O, Ar is phenyl or naphthalene-2-base;

Or, R ¹for methyl or ethyl, Y is SO ₂, Ar is 1H-benzo [d] imidazoles-2-base.

4. the preparation method of D-pHPG derivative described in claim 1, is characterized in that: step is as follows:

In D-pHPG derivative TM2, R ¹for methyl, ethyl, n-propyl or normal-butyl;

5. the preparation method of D-pHPG derivative as claimed in claim 4, it is characterized in that: step 1) be by D-pHPG and benzene methoxy carbonyl acyl succinimide Z-OSu in boiling mixed solvent, salt of wormwood catalysis, 15-35 DEG C, react under pH8-9 condition generate intermediate compound I M1, IM1 again with alcohol R ¹oH reacting by heating under sulfur oxychloride effect generates intermediate compound I M2;

Step 2) be by intermediate compound I M2 and 1,3-dibromopropane in acetonitrile, salt of wormwood catalysis, react under 45-55 DEG C condition and generate intermediate compound I M3;

Step 3) be by intermediate compound I M3 and aromatic compound A in DMF, salt of wormwood catalysis, react under 15-35 DEG C condition and generate D-pHPG derivative TM1;

Step 4) be by D-pHPG derivative TM1-18 and mCPBA in methylene dichloride, under 15-35 DEG C condition reaction generate D-pHPG derivative TM2;

Step 5) be by D-pHPG derivative TM1 in tetrahydrofuran (THF), lithium hydroxide catalysis, generate D-pHPG derivative TM3 with hcl acidifying after the reaction of 15-35 DEG C Water Under solution.

6.D-D-pHPG derivative is preparing the application in agent for promoting glucagon-like peptide 1 secretion, and described D-pHPG derivative has following structural formula:

Or, R ¹for methyl, Y is S, Ar is benzo [d] oxazole-2-base;

7. D-pHPG derivative as claimed in claim 6 is preparing the application in agent for promoting glucagon-like peptide 1 secretion, it is characterized in that, in the structural formula of described D-pHPG derivative,

Or, R ¹for ethyl or normal-butyl, Y is O, Ar is 2-Fonnylphenyl or phenyl;

Or, R ¹for n-propyl, Y is O, Ar is phenyl or naphthalene-2-base;

Or, R ¹for ethyl, Y is S, Ar is benzo [d] oxazole-2-base;

Or, R ¹for n-propyl, Y is SO ₂, Ar is 1H-benzo [d] imidazoles-2-base;

Or, R ¹for hydrogen, Y is O, Ar is phenyl or naphthalene-2-base;

Or, R ¹for hydrogen, Y is S, Ar is benzo [d] oxazole-2-base.

8. D-pHPG derivative as claimed in claim 7 is preparing the application in agent for promoting glucagon-like peptide 1 secretion, it is characterized in that, in the structural formula of described D-pHPG derivative,

R ¹for ethyl or normal-butyl, Y is O, Ar is 2-Fonnylphenyl or phenyl;

Or, R ¹for n-propyl, Y is O, Ar is phenyl or naphthalene-2-base;

Or, R ¹for ethyl, Y is S, Ar is benzo [d] oxazole-2-base.

9.D-D-pHPG derivative is preparing the application in Voltage-gated sodium channels Nav1.7 inhibitor, and described D-pHPG derivative has following structural formula:

10. D-pHPG derivative as claimed in claim 9 is preparing the application in Voltage-gated sodium channels Nav1.7 inhibitor, it is characterized in that, in the structural formula of described D-pHPG derivative,

Or, R ¹for ethyl, Y is O, Ar is 2-acetylphenyl, 3-acetylphenyl or phenyl;

Or, R ¹for n-propyl, Y is O, Ar is 4-acetylphenyl;

Or, R ¹for hydrogen, Y is O, Ar is 4-acetylamino phenyl.

11. D-pHPG derivatives as claimed in claim 10, preparing the application in Voltage-gated sodium channels Nav1.7 inhibitor, is characterized in that, in the structural formula of described D-pHPG derivative,

R ¹for methyl, Y is O, Ar is 4-acetylphenyl or 2-acetylphenyl;

Or, R ¹for methyl or ethyl, Y is SO ₂, Ar is 1H-benzo [d] imidazoles-2-base.