WO2017215586A1

WO2017215586A1 - Amide derivatives, preparation process thereof and use thereof in medicine

Info

Publication number: WO2017215586A1
Application number: PCT/CN2017/088015
Authority: WO
Inventors: 关东亮; 白骅; 盛首一; 陈磊; 赵伟峰; 陈明孝; 孟力陈
Original assignee: 浙江海正药业股份有限公司
Priority date: 2016-06-14
Filing date: 2017-06-13
Publication date: 2017-12-21
Also published as: CN109071420B; TW201742857A; CN109071420A; TWI654169B

Abstract

Provided are amide derivatives, a preparation process thereof and a use thereof in medicine. More specifically, provided are amide derivatives represented by the general formula (I) or pharmaceutically acceptable salts thereof, a process for the preparation thereof, and the use thereof as a therapeutic agent, in particular as a glucagon receptor antagonist.

Description

Amide derivative, preparation method thereof and use thereof in medicine

Field of invention

The present invention relates to a novel amide derivative, a process for its preparation and a pharmaceutical composition containing the same and its use as a therapeutic agent, in particular as a GCGR antagonist.

Background of the invention

Glucagon is a linear polypeptide consisting of 29 amino acids secreted by islet alpha cells with a molecular weight of 3485; a concentration of 50-100 ng/L in serum and a half-life of 5-10 minutes in plasma. Glucagon specifically binds to the type B G-protein coupled receptor (glucagon receptor, GCGR) on the surface of target cells such as liver and kidney, activates downstream signal transduction pathways, and exerts physiological effects. Contrary to the action of insulin, it is a hormone that promotes catabolism, and has a strong promotion of glycogenolysis and gluconeogenesis, resulting in a marked increase in blood sugar. A 1 mol/L hormone can rapidly decompose 3 x 10 ⁶ mol/L glucose from glycogen (Johnson et al., J. Biol. Chem. 1972, 247, 3229-3235).

The glucagon receptor is located on the cell surface and has G-protein coupled receptors with seven transmembrane sequences, mainly distributed in the liver, and also distributed in the kidney, heart, muscle, and the like.

The main target organ for glucagon action is the liver. When bound to the receptor, it interacts with the guanine nucleotide to regulate the protein Gs, causing the release of the A subunit of Gs to activate adenylate cyclase, which catalyzes the conversion of ATP to cAMP to exert its biological effects. Pharmacological doses of glucagon can increase cAMP content in cardiomyocytes and increase myocardial contraction. A glucagon receptor antagonist can compete with glucagon for the receptor, thereby blocking its action.

Diabetes is a disease characterized by high levels of plasma glucose. Uncontrolled hyperglycemia is associated with an increased risk of microvascular and macrovascular disease, including kidney disease, retinopathy, hypertension, stroke, and heart disease. The control of glucose homeostasis is the primary method of treating diabetes. It has been shown in healthy animals and animal models of type I and type II diabetes that removal of circulating glucagon with selective and specific antibodies results in a decrease in blood glucose levels. Thus a potential treatment for diabetes and other diseases involving abnormal blood glucose is that the glucagon receptor antagonist blocks the glucagon receptor to increase the insulin response, to reduce the rate of gluconeogenesis and/or to reduce the patient's The hepatic glucose output rate is used to lower plasma glucose levels.

A series of literatures on GCGR antagonists have been published, including WO2008042223, WO2010098994A1, WO2015066252, WO2012009226A1, WO2012009226A1, etc., and not all compounds that are GCGR antagonists have properties that are useful therapeutic agents. Some of these properties include high affinity for the glucagon receptor, duration of receptor activation, oral bioavailability and stability (eg, ability to formulate or crystallize, shelf life). Such properties can lead to improvements in safety, tolerability, effectiveness, therapeutic index, patient compliance, cost effectiveness, ease of preparation, and the like. Surprisingly, it has been found that the specific stereochemistry and functional groups of the compounds of the invention exhibit one or more of these desirable properties, including significantly improved receptor binding properties, oral bioavailability, and/or other enhancements for therapeutic use. An advantageous feature of the suitability of the use.

The GCGR antagonist drugs currently under investigation include: PF-06291874 (Pfizer) and LGD-6972 (Ligand) in clinical phase II, while Merck has developed MK-3577, and 3-(4-) is disclosed in WO2015066252. ((1R,2S)-1-(5-chloro-7-fluoro-1H-indol-3-yl)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzene Formylamino)propionic acid (FORM1), which is an analog of MK-3577, relates to the structure of a specific compound as follows:

Summary of the invention

In order to overcome the deficiencies of the prior art, it is an object of the present invention to provide a novel class of amide derivatives of the formula (I), and their tautomers, enantiomers, non-pairs Enantiomers, racemates and pharmaceutically acceptable salts, as well as metabolites and metabolic precursors or prodrugs, the compounds of the invention have large structural differences from the compounds specifically disclosed in the prior art and exhibit excellent anti-diabetes Effect and effect, the structure of the general formula (I) is as follows:

among them:

L is selected from -C(O)NH- or -NH-C(O)-;

A ₁ , A ₂ , A ₃ , A ₄ and A ₅ are each independently selected from CH, C or N, provided that A ₁ , A ₂ , A ₃ , A ₄ and A ₅ and the carbon atom to which they are attached The number of N in the ring is 0 to 2;

R ^{1 is} selected from an alkyl group or a cycloalkyl group, wherein the alkyl group or cycloalkyl group is further further selected from one or more selected from the group consisting of a hydroxyl group, a halogen, a nitro group, a cyano group, an alkoxy group, a cycloalkyl group, and a heterocyclic group. Cyclo, aryl, heteroaryl, -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -C(O)R ⁸ , -SO ₂ R ⁸ , -C(O)OR ⁸ or -NR Substituted by a substituent of ⁶ C(O)R ⁷ ;

R ^{2 is} selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -C(O)R ⁸ , -SO ₂ R ⁸ , -C(O)OR ⁸ or -NR ⁶ C(O)R ⁷ , wherein the alkyl group, Alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy , haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -C(O)R ⁸ , -SO ₂ Substituted with a substituent of R ⁸ , -C(O)OR ⁸ or -NR ⁶ C(O)R ⁷ ; when A _{3 is} selected from N, R ² is absent;

R ^{3 is} each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogen, a hydroxyl group, an alkoxy group, a cyano group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -NR ⁶ R ⁷ , -C (O)NR ⁶ R ⁷ , -C(O)R ⁸ , -SO ₂ R ⁸ , -C(O)OR ⁸ or -NR ⁶ C(O)R ⁷ , wherein the alkyl group, alkoxy group Or a cycloalkyl, heterocyclyl, aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, Heterocyclyl, aryl, heteroaryl, -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -C(O)R ⁸ , -SO ₂ R ⁸ , -C(O)OR ⁸ or - Substituted by a substituent of NR ⁶ C(O)R ⁷ ;

R ⁴ are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogen, a hydroxyl group, an alkoxy group, a cyano group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -NR ⁶ R ⁷ , -C (O)NR ⁶ R ⁷ , -C(O)R ⁸ , -SO ₂ R ⁸ , -C(O)OR ⁸ or -NR ⁶ C(O)R ⁷ , wherein the alkyl group, alkoxy group Or a cycloalkyl, heterocyclyl, aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, Heterocyclyl, aryl, heteroaryl, -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -C(O)R ⁸ , -SO ₂ R ⁸ , -C(O)OR ⁸ or - Substituted by a substituent of NR ⁶ C(O)R ⁷ ;

R ^{5 is} each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogen, a hydroxyl group, an alkoxy group, a cyano group, a nitro group, -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -C(O)R ⁸ And -SO ₂ R ⁸ , -C(O)OR ⁸ or -NR ⁶ C(O)R ⁷ , wherein said alkyl or alkoxy group is further further selected from one or more selected from the group consisting of hydroxyl, halogen, and nitrate , cyano, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -C( Substituting a substituent of O) R ⁸ , -SO ₂ R ⁸ , -C(O)OR ⁸ or -NR ⁶ C(O)R ⁷ ;

R ^{6 is} selected from a hydrogen atom or an alkyl group;

R ^{7 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, aryl group or heteroaryl group is further optionally further selected from one or more selected from the group consisting of hydroxyl groups, Halogen, haloalkyl, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ⁹ R ¹⁰ , -C(O)R ⁹ R ¹⁰ ,- Substituted by a substituent of C(O)R ¹¹ , -SO ₂ R ¹¹ , -C(O)OR ¹¹ or -NR ⁹ C(O)R ¹⁰ ;

Alternatively, R ⁶ and R ⁷ together with the N atom to which they are attached form a 4 to 8 membered heterocyclic group, wherein said heterocyclic group contains one or more N, O, S(O) _q atoms, and said The heterocyclic group is optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ⁹ R ¹⁰ , -C Substituting (O) a substituent of R ⁹ R ¹⁰ , -C(O)R ¹¹ , -SO ₂ R ¹¹ , -C(O)OR ¹¹ or -NR ⁹ C(O)R ¹⁰ ;

R ^{8 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further one Or a plurality selected from the group consisting of hydroxyl, halogen, haloalkyl, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ⁹ R ¹⁰ , -C(O Substituting a substituent of R ⁹ R ¹⁰ , -C(O)R ¹¹ , -SO ₂ R ¹¹ , -C(O)OR ¹¹ or -NR ⁹ C(O)R ¹⁰ ;

R ⁹ , R ¹⁰ and R ¹¹ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group Or a heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, haloalkyl, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy Substituted by a substituent of an acid or a carboxylic acid ester;

m is 0, 1, 2, 3, 4 or 5;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

q is 0, 1 or 2.

A preferred embodiment of the invention is a compound of the formula (I), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, which is a compound of the formula (II) a compound or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof:

Wherein: R ¹ to R ⁵ , m, n and p are as defined in the formula (I).

A preferred embodiment of the invention is a compound of the formula (I) or a stereoisomer, tautomer thereof or pharmaceutically acceptable thereof a salt which is a compound of the formula (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

Wherein: R ¹ to R ⁵ , m, n and p are as defined in the formula (I).

A preferred embodiment of the invention is a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, which is a compound of the formula (IV) Or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

Wherein: R ¹ to R ⁵ , m, n and p are as defined in the formula (I).

A preferred embodiment of the invention is a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, which is a compound of the formula (V) a compound or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof:

Wherein: R ¹ to R ⁵ , m, n and p are as defined in the formula (I).

A preferred embodiment of the invention is a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, which is a compound of the formula (VI) a compound or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof:

Wherein: R ¹ to R ⁵ , m, n and p are as defined in the formula (I).

A preferred embodiment of the invention is a compound of the formula (I) or a stereoisomer, tautomer thereof or pharmaceutically acceptable thereof a salt which is a compound of the formula (VII) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof:

Wherein: R ¹ to R ⁵ , m, n and p are as defined in the formula (I).

A preferred embodiment of the invention is a compound of the formula (I), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, which is a compound of the formula (VIII) a compound or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof:

Wherein: R ¹ to R ⁵ , m, n and p are as defined in the formula (I).

A preferred embodiment of the invention is a compound of the formula (I), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, which is a compound of the formula (IX) a compound or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof:

Wherein: R ¹ to R ⁵ , m, n and p are as defined in the formula (I).

A preferred embodiment of the invention is a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, which is a compound of the formula (X) a compound or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof:

Wherein: R ¹ to R ⁵ , m, n and p are as defined in the formula (I).

A preferred embodiment of the invention is a compound of the formula (I) or a stereoisomer, tautomer thereof or pharmaceutically acceptable thereof a salt which is a compound of the formula (XI) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof:

Wherein: R ¹ to R ⁵ , m, n and p are as defined in the formula (I).

A preferred embodiment of the invention is a compound of any one of the formulae (I) to (XI), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein: R ^{1 is} selected from C _3-6 alkyl, preferably n-propyl.

A preferred embodiment of the invention is a compound of any one of the formulae (I) to (XI), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R ² Selected from a phenyl group, wherein the phenyl group is optionally further substituted with one or more substituents of an alkyl group, a halogen, a cyano group, a nitro group, an alkoxy group, a halogenated alkyl group or a halogenated alkoxy group, further preferred, The phenyl group described therein is further substituted by one or more methyl, trifluoromethyl or trifluoromethoxy groups.

A preferred embodiment of the invention is a compound of any one of the formulae (I) to (XI), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R ² Selected from a 5- to 8-membered heteroaryl group, wherein the heteroaryl group is optionally further substituted with one or more alkyl, halo, cyano, nitro, alkoxy, haloalkyl or haloalkoxy groups. Replace.

A preferred embodiment of the invention is a compound of any one of the formulae (I) to (XI), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R ² Further selected from the group consisting of pyrrole, furan, thiophene, pyrazole, imidazole, thiazole, benzimidazole, benzofuran, or benzoxazole, wherein the pyrrole, furan, thiophene, pyrazole, imidazole, thiazole, benzimidazole The benzofuran or benzoxazole is optionally further substituted with one or more substituents of an alkyl, halogen, cyano, nitro or alkoxy group, wherein said alkyl or alkoxy group is optionally Further substituted with one or more halogen substituents, said halogen is preferably F.

A preferred embodiment of the invention is a compound of any one of the formulae (I) to (XI), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R ² It is selected from alkynyl groups wherein the alkynyl group is further substituted by a cycloalkyl group, wherein the cycloalkyl group is preferably a cyclopropyl group.

A preferred embodiment of the invention is a compound of any one of the formulae (I) to (XI), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R ³ It is selected from alkoxy groups, wherein the alkoxy group is optionally further substituted with one or more substituents selected from the group consisting of alkyl, halogen, cyano, nitro or alkoxy.

A preferred embodiment of the invention is a compound of any one of the formulae (I) to (XI), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R ³ It is selected from a fluoroalkoxy group, preferably a trifluoromethoxy group or a trifluoroethoxy group.

A preferred embodiment of the invention is a compound of any one of the formulae (I) to (XI), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R ³ Connect to 3 bits (inter-digit) or 4 bits (para), m is 1.

A preferred embodiment of the invention is a compound of any one of the formulae (I) to (XI), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R ⁴ It is selected from a hydrogen atom, a halogen or an alkyl group.

A preferred embodiment of the invention is a compound of any one of the formulae (I) to (XI), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R ⁴ It is selected from F and n is 1.

A preferred embodiment of the invention is a compound of any one of formula (I), or a stereoisomer, tautomer thereof or Medicinal salt,

among them:

A _{3 is} selected from C;

R ^{1 is} selected from n-propyl;

R ^{2 is} selected from alkyl, halogen, cyano, nitro, alkoxy, haloalkyl, haloalkoxy, phenyl or 5- to 8-membered heteroaryl, alkyl, alkoxy, phenyl or The 5- to 8-membered heteroaryl group is optionally further substituted with one or more substituents of an alkyl group, a halogen, a cyano group, a nitro group, an alkoxy group, a halogenated alkyl group or a halogenated alkoxy group;

R ^{3 is} selected from the group consisting of trifluoromethoxy;

R ^{4 is} selected from a hydrogen atom or a halogen;

R ⁵ are each independently selected from a hydrogen atom, an alkyl group, a halogen, an alkoxy group, a halogenated alkyl group or a halogenated alkoxy group;

m is 0, 1 or 2;

n is 0, 1, or 2;

p is 0, 1, or 2.

Typical compounds of the invention include, but are not limited to:

Typical compounds of the invention include, but are not limited to:

Or a stereoisomer, tautomer, mixture tautomer thereof or a pharmaceutically acceptable salt thereof.

Typical compounds of the invention include, but are not limited to:

Further, the present invention provides a process for the preparation of a compound of the formula (I), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the process comprising:

The general formula (IC) and the general formula (ID) or a salt thereof are reacted to obtain a compound of the formula (IA);

The compound of the formula (I) is reacted with the formula (IB), and the obtained compound is further hydrolyzed to obtain a compound of the formula (I);

among them:

L _{1 is} selected from -C(O)X;

L _{2 is} selected from -NH ₂ ;

X is selected from a hydroxyl group or a halogen;

R ^{c is} selected from an alkyl group;

L is selected from -NH-C(O)-;

R ¹ to R ⁵ , A ₁ to A ₅ , m, n and p are as defined in the formula (I).

The general formula (IC) and the general formula (IB) or a salt thereof are reacted to obtain a compound of the general formula (IE);

The compound of the formula (I) is further hydrolyzed by reacting the compound of the formula (IE) with the formula (ID) or a salt thereof;

among them:

X is selected from a hydroxyl group or a halogen;

R ^{c is} selected from an alkyl group;

L _{1 is} selected from -NH ₂ ;

L _{2 is} selected from -C(O)X;

L is selected from -C(O)-NH-;

R ¹ to R ⁵ , A ₁ to A ₅ , m, n and p are as defined in the formula (I).

The present invention provides a compound of the formula (IA): or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof:

among them:

L _{1 is} selected from -C(O)X;

X is selected from a hydroxyl group or a halogen;

R ^{c is} selected from an alkyl group;

R ¹ , R ³ , R ⁴ , m and n are as defined in the formula (I).

Typical compounds of formula (IA) include, but are not limited to:

Or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof.

Typical compounds of formula (IA) include, but are not limited to:

Typical compounds of formula (IA) include, but are not limited to:

The present invention provides a compound of the formula (IE) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

among them:

X is selected from a hydroxyl group or a halogen;

L is selected from -C(O)-NH-;

R ¹ to R ⁵ , A ₁ to A ₅ , m, n and p are as defined in the formula (I).

Typical compounds of the general formula (IE) include, but are not limited to:

The present invention provides a process for the preparation of a compound of the formula (IIA), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, the process comprising:

The compound of the formula (IIa) is reacted with the compound of the formula (IIb) under basic conditions to give the formula (IIc);

The compound of the formula (IIc) is hydrolyzed under basic conditions to give a compound of the formula (IId);

The compound of the formula (IId) is reacted with the compound of the formula (IIe) in the presence of a condensation reagent to give a compound of the formula (IIf);

The compound of the formula (IIf) is hydrolyzed under basic conditions to give the compound of the formula (IIA);

among them:

X is selected from a hydroxyl group or a halogen;

R ^a , R ^b and R ^c are each independently selected from an alkyl group;

R ¹ , R ³ , R ⁴ , m and n are as defined in the formula (I).

In the above preparation method, the basic condition is provided by an organic base or an inorganic base selected from the group consisting of diisopropylethylamine, pyridine, triethylamine, piperidine, N-methylpiperazine, 4-dimethylaminopyridine or Potassium tert-butoxide, preferably diisopropylethylamine, triethylamine or potassium t-butoxide; the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide Or potassium hydride, preferably sodium hydroxide or lithium hydroxide.

In the above preparation method, the condensation reagent includes, but is not limited to, bis(2-oxo-3-oxazolidinyl)phosphoryl chloride, N,N-dicyclohexylcarbodiimide, N,N-diisopropyl Carbodia, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, o-benzotriazole-N,N,N'N'-tetramethyluronium boron The acid ester (TBTU) is preferably 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride or bis(2-oxo-3-oxazolidinyl)phosphoryl chloride.

The present invention provides a process for the preparation of a compound of the formula (IIIA), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, which comprises include:

The compound of the formula (IIIa) is reacted in the presence of tetraisopropyl titanate and ammonia methanol to obtain the formula (IIIb);

The condensation reaction of the compound of the formula (IIIb) with the formula (IIIc) gives the compound of the formula (IIId);

The compound of the formula (IIId) is subjected to a hydrolysis reaction under acidic conditions to obtain a compound of the formula (IIIA);

among them:

X is selected from a hydroxyl group or a halogen;

R ^a , R ^b and R ^{c are} selected from an alkyl group;

R ¹ to R ⁵ , A ₁ to A ₅ , m, n and p are as defined in the formula (III).

In the above production method, the acidic condition is provided by an inorganic acid or an organic acid selected from hydrochloric acid or phosphoric acid.

Furthermore, the present invention provides a pharmaceutical composition comprising an effective amount of a compound according to any one of the formulae (I) to (III) or a stereoisomer or tautomer thereof. Or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

The present invention provides a method for inhibiting a glucagon receptor in vitro, the method comprising the step of administering the glucagon receptor to any one of the formulae (I) to (III) or a stereoisomer thereof The body, tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is contacted.

The present invention provides a compound according to any one of the above formulas (I) to (III), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of type I Use in medicines for diabetes, type 2 diabetes, hyperglycemia, obesity, or insulin resistance.

The present invention provides a compound according to any one of the above formulas (I) to (III), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preparing a pancreas Use in a glucose receptor antagonist or inverse agonist.

The present invention provides a compound according to any one of the above formulas (I) to (III), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a therapeutic high Use in drugs for lipemia, dyslipidemia, hypercholesterolemia, atherosclerosis, and metabolic syndrome.

The compound of any one of the above formulas (I) to (III), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, can inhibit glucagon in vitro The receptor can therefore be used to prepare a glucagon receptor antagonist or inverse agonist, while the invention further provides for the treatment of type 1 diabetes, type 2 diabetes, hyperglycemia, obesity, insulin resistance A method of hyperlipemia, dyslipidemia, hypercholesterolemia, atherosclerosis or metabolic syndrome, the method comprising administering to the animal a therapeutically effective amount of any of the general formulae (I) to (III) of the present invention Or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

Detailed description of the invention

Unless otherwise stated, some of the terms used in the specification and claims of the invention are defined as follows:

When "alkyl" as a group or part of a group is meant to include C ₁ -C ₂₀ linear or branched aliphatic hydrocarbon group with a chain. It is preferably a C ₁ -C ₁₀ alkyl group, more preferably a C ₁ -C ₆ alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1, 1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait. The alkyl group can be optionally substituted or unsubstituted.

"Alkynyl" as a group or part of a group refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight or branched. Preference is given to C ₂ -C ₁₀ alkynyl groups, more preferably C ₂ -C ₆ alkynyl groups, most preferably C ₂ -C ₄ alkynyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like. An alkynyl group can be optionally substituted or unsubstituted.

"Cycloalkyl" means a saturated or partially saturated monocyclic, fused, bridged, and spiro carbon ring, ie, comprising a monocyclic cycloalkyl, a fused cycloalkyl, a bridged cycloalkyl, and a spirocycloalkyl. It is preferably a C ₃ -C ₁₂ cycloalkyl group, more preferably a C ₃ -C ₈ cycloalkyl group, and most preferably a C ₃ -C ₆ cycloalkyl group. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene The alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group.

"Spirocycloalkyl" means a polycyclic group of 5 to 18 members, two or more cyclic structures, and a single ring sharing a carbon atom (referred to as a spiro atom), and the ring contains one or more A double bond, but none of the rings have a fully conjugated π-electron aromatic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl group is classified into a monospiro, a spiro- or a spirocycloalkyl group, preferably a mono- and bi-spirocycloalkyl group, preferably 4 yuan/5 yuan, 4, depending on the number of common spiro atoms between the rings. Yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan. Non-limiting examples of "spirocycloalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]decyl, spiro[3.5]decyl, spiro[2.4]heptyl.

"Fused cycloalkyl" means 5 to 18 members, an all-carbon polycyclic group containing two or more cyclic structures that share a carbon atom with each other, and one or more rings may contain one or more double bonds, However, none of the rings have a fully conjugated π-electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of "fused cycloalkyl" include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetradecafluorophenanyl.

"Bridge cycloalkyl" means 5 to 18 members, containing two or more cyclic structures, sharing two all-carbon polycyclic groups that are not directly bonded to each other, and one or more rings may contain one or A plurality of double bonds, but none of the rings have a fully conjugated π-electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s, 4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-di Ring [3.3.1] fluorenyl, bicyclo [2.2.2] octyl, (1r, 5r)-bicyclo[3.3.2] fluorenyl.

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, Restrictive examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. The cycloalkyl group can be optionally substituted or unsubstituted.

"Heterocyclyl", "heterocyclic" or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group wherein one or more of the ring-forming atoms are heteroatoms such as oxygen, The nitrogen, sulfur atom and the like include a monocyclic ring, a fused ring, a bridged ring and a spiro ring, that is, a monocyclic heterocyclic group, a fused heterocyclic group, a bridged heterocyclic group and a spiroheterocyclic group. It preferably has a 5- to 7-membered monocyclic ring or a 7- to 10-membered double- or tricyclic ring which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo- Piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl. The heterocyclic group may be optionally substituted or unsubstituted.

"Spiroheterocyclyl" means a polycyclic group of 5 to 18 members, two or more cyclic structures, and a single ring sharing one atom with each other, and the ring contains one or more double bonds, but no An aromatic system having a fully conjugated π-electron, wherein one or more ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) _m (where m is selected from 0, 1 or 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to, 1,7-dioxaspiro[4.5]fluorenyl, 2-oxa-7-azaspiro[4.4]decyl, 7-oxo Heterospiro[3.5]decyl and 5-oxaspiro[2.4]heptyl.

"Fused heterocyclic group" means an all-carbon polycyclic group containing two or more cyclic structures that share a pair of atoms with each other, and one or more rings may contain one or more double bonds, but none of the rings have complete A conjugated π-electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to, octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindenyl, 3-azabicyclo[3.1. 0] hexyl, octahydrobenzo[b][1,4]dioxine.

"Bridge heterocyclyl" means 5 to 14 members, 5 to 18 members, containing two or more cyclic structures, sharing two polycyclic groups which are not directly connected to each other, and one or more rings may be used. An aromatic system containing one or more double bonds, but none of which has a fully conjugated π-electron, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) _q (where q is an integer from 0 to 2) Of the heteroatoms, the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-aza-di Ring [3.3.2] sulfhydryl.

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group. The heterocyclic group may be optionally substituted or unsubstituted.

"Aryl" means a carbocyclic aromatic system containing one or two rings wherein the rings may be joined together in a fused manner. The term "aryl" includes aryl groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferably, the aryl group is a C ₆ -C ₁₀ aryl group, more preferably the aryl group is a phenyl group and a naphthyl group, and most preferably a phenyl group. The aryl group can be optionally substituted or unsubstituted. The "aryl" may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the parent structure is attached to an aryl ring, non-limiting examples include, but are not limited to:

"Heteroaryl" means an aromatic 5 to 6 membered monocyclic or 9 to 10 membered bicyclic ring which may contain from 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, iso Thiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzimidazolyl, fluorenyl, isodecyl, 1,3-dioxo-isoindole Base, quinolyl, oxazolyl, benzisothiazolyl, benzoxazolyl and benzisoxazolyl. The heteroaryl group can be optionally substituted or unsubstituted. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include, but are not limited to:

"Alkoxy" means a group of (alkyl-O-). Among them, the alkyl group is defined in the relevant definition herein. Alkoxy groups of C ₁ -C ₆ are preferred. Examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.

"Hydroxy" refers to an -OH group.

"Halogen" means fluoro, chloro, bromo and iodo, preferably chloro, bromo and iodo.

"Amino" means -NH ₂ .

"Cyano" means -CN.

"Nitro" means -NO ₂ .

"Benzyl" refers to -CH ₂ - phenyl.

"Carboxy" refers to -C(O)OH.

"Carboxylic acid ester group" means -C(O)O(alkyl) or (cycloalkyl) wherein alkyl, cycloalkyl are as defined above.

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

As used herein, "substituted" or "substituted", unless otherwise indicated, means that the group may be substituted by one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy. , alkylthio, alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =O, -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -C(O)R ⁸ , -SO ₂ R ⁸ , -C(O)OR ⁸ or -NR ⁶ C(O)R ⁷ , wherein R ⁶ , R ⁷ and R ⁸ are as defined in the formula (I).

The use of definitions and conventions of stereochemistry in the present invention generally refers to the following documents:

SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-HillBook Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York 1994. The compounds of the invention may contain asymmetric centers or chiral centers, and thus different stereoisomers are present. All stereoisomeric forms of the compounds of the invention, including but not limited to diastereomers, enantiomers, atropisomers and mixtures thereof, such as racemic mixtures, constitute the invention portion. Diastereomers can be separated into individual diastereomers by chromatography, crystallization, distillation or sublimation based on their physicochemical differences. The enantiomers can be converted into diastereomeric mixtures by separation, by reaction with a suitable optically active compound such as a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride. Separation of the diastereomers and conversion of the individual diastereomers to the corresponding pure enantiomers. The intermediates and compounds of the invention may also exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Many organic compounds exist in optically active forms, that is, they have the ability to rotate planes of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to indicate the molecular chiral center. For the configuration. The prefix d, l or (+), (-) is used to designate the sign of the plane-polarized light rotation of the compound, (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed. The atoms or radicals of these stereoisomers are connected in the same order, but their stereostructures are different. A particular stereoisomer can be an enantiomer, and a mixture of isomers is often referred to as a mixture of enantiomers. The 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lack optical activity.

"Tautomer" or "tautomeric form" means that the isomers of the structure of different energies can be converted into each other by a low energy barrier. For example, proton tautomers (i.e., proton-shifted tautomers) include interconversions by proton transfer, such as keto-enol and imine-enamine isomerization. The valence (valence) tautomer includes the interconversion of recombination bond electrons. Unless otherwise indicated, the structural formulae described herein include all isomeric forms (eg, enantiomeric, diastereomeric, and geometric isomerism): for example, the R, S configuration containing an asymmetric center, The (Z), (E) isomers of the double bond, and the conformational isomers of (Z) and (E). Thus, individual stereochemical isomers of the compounds of the invention, or enantiomers, diastereomers, or mixtures of geometric isomers thereof, are within the scope of the invention.

"Pharmaceutically acceptable salt" refers to certain salts of the above compounds which retain their original biological activity and are suitable for pharmaceutical use. The pharmaceutically acceptable salt of the compound represented by the formula (I) may be a metal salt, an amine salt formed with a suitable acid, a metal salt preferably an alkali metal or an alkaline earth metal salt, and a suitable acid including an inorganic acid and an organic acid such as acetic acid. , benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, malic acid, maleic acid , mandelic acid, methanesulfonic acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. Particularly preferred are hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, and most preferred is the hydrochloride salt.

"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or a physiologically pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and Shape agent. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.

Method for synthesizing the compound of the present invention

In order to accomplish the object of the present invention, the present invention adopts the following technical solutions:

The preparation method of the compound of the formula (II) or a salt thereof of the present invention comprises the following steps:

The compound of the formula (IIa) is reacted with the compound of the formula (IIb) under basic conditions to obtain the formula (IIc); the compound of the formula (IIc) is under basic conditions. Hydrolysis to obtain a compound of the formula (IId); a compound of the formula (IId) and a compound of the formula (IIe) or a salt thereof are reacted in a condensation reagent to obtain a compound of the formula (IIf); the compound of the formula (IIf) is Hydrolysis and acidification under basic conditions affords the compound of the formula (IIA); the compound of the formula (IIA) is reacted with the compound of the formula (IIB), optionally further hydrolyzed to give the compound of the formula (II).

among them:

X is selected from a hydroxyl group or a halogen;

R ^a , R ^b and R ^{c are} selected from an alkyl group;

R ¹ to R ⁵ , A ₁ to A ₅ , m, n and p are as defined in the formula (II).

The preparation method of the compound of the formula (III) or a salt thereof of the present invention comprises the following steps:

The compound of the formula (IIIa) is reacted in the presence of tetraisopropyl titanate and ammonia methanol to obtain the formula (IIIb); the compound of the formula (IIIb) is subjected to a condensation reaction with the formula (IIIc) to obtain a compound of the formula (IIId). a compound; a compound of the formula (IIId) is subjected to a hydrolysis reaction under acidic conditions to obtain a compound of the formula (IIIA); a compound of the formula (IIIA) is reacted with a compound of the formula (IIe) or a salt thereof, optionally further hydrolyzed, to give a pass. a compound of formula (III).

among them:

X is selected from a hydroxyl group or a halogen;

R ^a , R ^b and R ^{c are} selected from an alkyl group;

The acidic conditions are provided by an inorganic or organic acid selected from the group consisting of hydrochloric acid or phosphoric acid.

DRAWINGS

Figure 1 is a graph showing changes in blood glucose levels of a preferred compound of the present invention administered to db/db mice for 28 days, wherein the ordinate is the blood glucose level (mmol/L) and the abscissa is the administration time (days).

detailed description

The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.

Example

The examples give the preparation of representative compounds represented by formula (I) and related structural identification data. It is to be understood that the following examples are intended to illustrate the invention and not to limit the invention. ^{The 1} H NMR spectrum was measured using a Bruker instrument (400 MHz) and the chemical shift was expressed in ppm. The internal standard of tetramethylsilane (0.00 ppm) was used. ¹ H NMR representation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If a coupling constant is provided, its unit is Hz.

Mass spectrometry was measured by LC/MS, and the ionization method was ESI or APCI.

Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.2mm. The specification for thin layer chromatography separation and purification is 0.4mm. ~0.5mm.

Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

In the following examples, all temperatures are in degrees Celsius unless otherwise indicated, and unless otherwise indicated, the various starting materials and reagents are either commercially available or synthesized according to known methods, and the commercially available starting materials and reagents are not further purified. Direct use, unless otherwise specified, commercially available, including but not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd. and Jingyan Chemical Technology Co., Ltd., etc.

CD ₃ OD: Deuterated methanol.

CDCl ₃ : deuterated chloroform.

DMSO-d ₆ : deuterated dimethyl sulfoxide.

The argon atmosphere means that the reaction flask is connected to an argon balloon having a volume of about 1 L.

There is no particular description in the examples, and the solution in the reaction means an aqueous solution.

The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The system used for the reaction was: A: petroleum ether and ethyl acetate system, B: dichloromethane and ethyl acetate system, C: In methylene chloride and methanol systems, the volume ratio of the solvent is adjusted depending on the polarity of the compound.

The system of eluent for column chromatography or thin layer chromatography plates includes: A: petroleum ether and ethyl acetate systems, B: n-hexane and ethyl acetate systems, C: dichloromethane and methanol systems, D: petroleum Ether and methanol systems. The volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of ammonia water, acetic acid or the like.

Example 1

3-(4-((2R,3S)/(2S,3R)-1-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-) 1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 1

3-(4-((2R,3S)-1-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-1-oxo-2 -(4-(Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 1A

3-(4-((2S,3R)-1-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-1-oxo-2 -(4-(Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 1B

first step

Methyl 4-(1-hydroxybutyl)benzoate

Methyl 4-formylbenzoate 1a (10.00 g, 60.92 mmol) was dissolved in 100 mL of tetrahydrofuran, the reaction solution was cooled to -78 ° C, and propyl magnesium bromide 1b (33.50 mL, 67.00 mmol) was added dropwise. After completion, it was stirred at room temperature for 3 hours. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) The residue was purified by silica gel column chromatography (eluent: EtOAc) to afford ethyl 4-(1-hydroxybutyl)benzoate 1c (7.50 g, colorless liquid). Yield: 59.1%.

^{1 H NMR (400MHz, CDCl3)} : δ7.99 (d, J = 8.28Hz, 2H) 7.39 (d, J = 8.03Hz, 2H) 4.73 (t, J = 6.53Hz, 1H) 3.89 (s, 3H) 1.80-2.25(m,1H)1.59-1.82(m,2H)1.21-1.50(m,2H)0.92(t,J=7.40Hz, 3H)

Second step

Methyl 4-(1-bromobutyl)benzoate

Methyl 4-(1-hydroxybutyl)benzoate 1c (7.50 g, 36.00 mmol) was dissolved in 100 mL of dichloromethane and then added with carbon tetrabromide (23.88 g, 72.00 mmol) and triphenylphosphine ( 18.88 g, 72.00 mmol), stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjj Liquid), yield: 66.5%.

¹ H NMR (400 MHz, CDCl 3 ): δ 8.01 (d, J = 8.28 Hz, 2H) 7.46 (d, J = 8.28 Hz, 2H) 4.96 (t, J = 7.53 Hz, 1H) 3.92 (s, 3H) 2.23-2.28(m,1H)2.06-2.13(m,1H)1.46-1.54(m,1H)1.29-1.37(m,1H)0.94(t,J=7.40Hz,3H)

third step

Tert-butyl 2-(4-(trifluoromethoxy)phenyl)acetate

Magnesium sulfate (21.86 g, 182 mmol) was dissolved in 100 mL of dichloromethane, concentrated sulfuric acid (2.66 mL, 50 mmol) was added dropwise and stirred for 10 min. Then, 2-(4-(trifluoromethoxy)phenyl)acetic acid 1e (10 g, 45.4 mmol) and tert-butanol (4.9 mL, 50 mmol) were added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was poured into 100 mL of a saturated sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate (100 mL×3), and the combined organic phase was saturated with ammonium chloride (200mL) and sodium chloride solution (200mL×2) The organic layer was dried (MgSO4). ) tert-butyl acetate 1f (8.84 g, brown liquid), yield: 70.7%.

^{1 H NMR (400MHz, CDCl3)} : δ7.29 (d, J = 8.28Hz, 2H) 7.16 (d, J = 8.03Hz, 2H) 3.53 (s, 2H) 1.44 (s, 9H)

the fourth step

Methyl 4-(1-(tert-butoxy)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoate

tert-Butyl 2-(4-(trifluoromethoxy)phenyl)acetate 1f (7.11 g, 25.7 mmol) and potassium tert-butoxide (6.98 g, 25.7 mmol) were dissolved in 50 mL of N,N-dimethyl To the amide, methyl 4-(1-bromobutyl)benzoate 1d (6.98 g, 25.7 mmol) was added under stirring, and stirred at room temperature for 5 hr. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) The residue was purified by silica gel column chromatography (eluent: System A) to give 4-(1-(tert-butoxy)-1-oxo-2-(4-(trifluoromethoxy)benzene Methyl hexane-3-yl)benzoic acid 1 g (4.27 g, white solid), yield: 35.6%.

MS m/z (ESI): 410.9 [M-57]

the fifth step

4-(1-(tert-Butoxy)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoic acid

Methyl 4-(1-(tert-butoxy)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoate 1 g (4.27 g, 9.2 Methyl) was dissolved in a mixed solvent of 30 mL of tetrahydrofuran and methanol (V/V = 1:1), and added to a solution of 5 mL of sodium hydroxide (1.83 g, 45.8 mmol) under stirring, and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. The residue was purified by silica gel column chromatography (eluent: system A) to give 4-(1-(tert-butoxy)-1-oxo-2-(4-( Trifluoromethoxy)phenyl)hexane-3-yl)benzoic acid 1 h (4 g, white solid).

MS m/z (ESI): 452.46 [M-57]

Step 6

tert-Butyl 3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(trifluoromethoxy)phenyl)hexanoate 1k

((2R,3S)/(2S,3R))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(trifluoro) Methoxy)phenyl)hexanoic acid tert-butyl ester 1p

((2R,3R)/(2S,3S))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(trifluoro) Methoxy)phenyl)hexanoic acid tert-butyl ester 1q

4-(1-(tert-Butoxy)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoic acid 1 h (4.00 g, 8.84 mmol) , 3-aminopropionic acid ethyl ester hydrochloride 1j (1.25 g, 10.60 mmol), 1-hydroxybenzotriazole (1.79 g, 13.30 mmol) and 1-ethyl-(3-dimethylaminopropyl) The carbodiimide hydrochloride (2.54 g, 13.30 mmol) was dissolved in 50 mL of tetrahydrofuran, and triethylamine (7.8 mL, 44.2 mmol) was added with stirring, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc)EtOAc. The residue was purified by silica gel column chromatography (eluent:EtOAc) to afford 3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-( 4-(Trifluoromethoxy)phenyl)hexanoic acid tert-butyl ester 1k (2.352g, white solid), which can be further purified by silica gel column chromatography to give slow elution ((2R,3S)/( 2S,3R))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(trifluoromethoxy)phenyl)hexyl Tert-butyl acid ester 1p (1.61g, white solid) and faster elution ((2R,3R)/(2S,3S))-3-(4-((3-ethoxy-3-oxopropyl) tert-Butyl carbamoyl)phenyl)-2-(4-(trifluoromethoxy)phenyl)hexanoate 1q (742 mg, white solid), yield: 35.1%.

1k: MS m/z (ESI): 552.9 [M+1]

1p: MS m/z (ESI): 552.9 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.72 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.20 (d) , J=8.0Hz, 2H), 6.84 (br.s., 1H), 4.23-4.13 (m, 2H), 3.78-3.61 (m, 3H), 3.20 (dt, J=3.8, 10.9Hz, 1H) , 3.27-3.14 (m, 1H), 2.70-2.60 (m, 2H), 1.62 (br.s., 2H), 1.68-1.55 (m, 2H), 1.27 (t, J = 7.2 Hz, 5H), 1.05 (s, 9H), 0.93 (tt, J = 7.8, 15.0 Hz, 2H), 0.72-0.61 (m, 3H).

1q: MS m/z (ESI): 552.9 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.50 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 6.92 (d) , J = 8.3 Hz, 2H), 6.70 (br.s., 1H), 4.15 (d, J = 7.0 Hz, 2H), 3.72-3.57 (m, 2H), 3.28 (br.s., 1H), 2.59 (t, J = 5.6 Hz, 2H), 1.81-1.64 (m, 1H), 1.87-1.60 (m, 2H), 1.44 (s, 9H), 1.25 (t, J = 7.2 Hz, 3H), 1.13 -1.04 (m, 2H), 0.87-0.80 (m, 3H).

Seventh step

((2R,3S)/(2S,3R))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(trifluoro) Methoxy)phenyl)hexanoic acid 1m

((2R,3R)/(2S,3S))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(trifluoro) Methoxy)phenyl)hexanoic acid 1s

((2R,3S)/(2S,3R))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(III) The fluoromethoxy)phenyl)hexanoic acid tert-butyl ester 1p (1.61 g, 2.90 mmol) was dissolved in 20 mL of trifluoroacetic acid and stirred at room temperature for 0.5 hour. The reaction mixture was concentrated under reduced pressure and purified residue purified eluted eluted elut elut elut elut elut elut elut elut ((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(trifluoromethoxy)phenyl)hexanoic acid 1 m (1.40 g, pale yellow oil) , Yield: 97.2%.

MS m/z (ESI): 495.9 [M+1]

((2R,3R)/(2S,3S))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(3) Fluoryloxy)phenyl)hexanoic acid tert-butyl ester 1q (742.00 mg, 1.35 mmol) was dissolved in 20 mL of dichloromethane, trifluoroacetic acid (0.20 mL, 2.69 mmol) was added and stirred at room temperature for 0.5 hour. 5 mL of trifluoroacetic acid was continued for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjj (3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(trifluoromethoxy)phenyl)hexanoic acid 1s (663.00 mg, pale yellow viscous) , yield: 99.48%.

MS m/z (ESI): 495.9 [M+1]

Eighth step

3-(4-((2R,3S)/(2S,3R)-1-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-) 1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzene

Amidoethyl propionate

((2R,3S)/(2S,3R))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(III) Fluoromethoxy)phenyl)hexanoic acid 1m (80.00 mg, 0.16 mmol), 4'-chloro-2'-methyl-[1,1'-biphenyl]-4-amine 1n (52.00 mg, 0.24 mmol ), 1-hydroxybenzotriazole (43.00 mg, 0.32 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.32 mmol) dissolved in 20 mL of dichloro To the methane, triethylamine (0.14 mL, 0.80 mmol) was added under stirring, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and purified residue purified crystallililililililililililililililililili ((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl) Ethyl hexane-3-yl)benzoylamino)propanoate 1t (58.00 mg, white solid), yield: 51.8%.

MS m/z (ESI): 695.8 [M+1]

Step 9

Amido aminopropionic acid

3-(4-((2R,3S)/(2S,3R)-1-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino) Ethyl-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoate 1t (50.00 mg, 0.072 mmol) was dissolved in 6 mL of THF. In a mixed solvent of methanol (V/V = 1:1), a solution of 1 mL of sodium hydroxide (14.40 mg, 0.36 mmol) was added under stirring, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc (EtOAc m. The residue was purified by silica gel column chromatography (eluent: system A) to afford 3-(4-((2),3S) -Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3 -yl)benzoylamino)propionic acid 1 (4.00 g, white solid), yield: 64.5%.

MS m/z (ESI): 668.7 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ10.07 (s, 1H), 8.45 (s, 1H), 7.76 (d, J = 7.9Hz, 2H), 7.69 (d, J = 8.4Hz, 2H) , 7.48 - 7.35 (m, 6H), 7.32 (s, 1H), 7.24 (d, J = 7.9 Hz, 1H), 7.16 - 7.07 (m, 3H), 4.11 (d, J = 11.8 Hz, 1H), 2.47 (s, 2H), 2.14 (s, 3H), 0.96 - 0.89 (m, 2H), 0.85 (t, J = 6.5 Hz, 2H), 0.64 (t, J = 7.4 Hz, 3H).

3-(4-((2R,3S)/(2S,3R)-1-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-) 1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 1 further prepared by using supercritical fluid chromatography (SFC) method Resolution with chiral column chiral isomers ((1) chiral column ChiralPak AD, 25 × 3 cm, 80 mL / min; mobile phase A for CO ₂ and B for Ethanol; or / and (2) Whelk O1 ( S, S), 25 × 3 cm, 65 mL / min; mobile phase A for CO ₂ and B for Ethanol; or / and (3) Whelk O1 (S, S), 25 × 3 cm, 70 mL / min; mobile phase A for CO ₂ and B for Ethanol)) were resolved to give 3-(4-((2R,3S)-1-((4'-chloro-2'-methyl-[1,1'-biphenyl]-) 4-yl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 1A and 3-(4-(( 2S,3R)-1-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-1-oxo-2-(4-(trifluoro) Methoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 1B.

1A: MS m/z (ESI): 668.7 [M+1]

1B: MS m/z (ESI): 668.7 [M+1]

Example 2

3-(4-((2R,3S)/(2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2',4',6) '-Trimethyl-[1,1'-biphenyl]-4-yl)amino)hexane-3-yl)benzoylamino)propanoic acid 2

3-(4-((2R,3S)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2',4',6'-trimethyl-) [1,1'-biphenyl]-4-yl)amino)hexane-3-yl)benzoylamino)propionic acid 2A

3-(4-((2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2',4',6'-trimethyl-) [1,1'-biphenyl]-4-yl)amino)hexane-3-yl)benzoylamino)propionic acid 2B

first step

3-(4-((2R,3S)/(2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2',4',6) '-Trimethyl-[1,1'-biphenyl]-4-yl)amino)hexane-3-yl)benzoylamino)propionic acid ethyl ester

((2R,3S)/(2S,3R))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(III) Fluoromethoxy)phenyl)hexanoic acid 1m (100.00 mg, 0.20 mmol), 2',4',6'-trimethyl-[1,1'-biphenyl]-4-amine 2a (63.00 mg, 0.3 mmol), 1-hydroxybenzotriazole (41.00 mg, 0.30 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (43.00 mg, 0.32 mmol) were dissolved. In 10 mL of dichloromethane, N,N-diisopropylethylamine (0.09 mL, 0.50 mmol) was added under stirring, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and purified residue purified silicagel elut elut elut elut elut elut elut Oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2',4',6'-trimethyl-[1,1'-biphenyl]-4-yl) Ethylamino)hexane-3-yl)benzoylamino)propionic acid ethyl ester 2b (50.00 mg, white solid), yield: 36.3%.

MS m/z (ESI): 689.9 [M+1]

Second step

3-(4-((2R,3S)/(2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2',4',6) '-Trimethyl-[1,1'-biphenyl]-4-yl)amino)hexane-3-yl)benzoylamino)propionic acid

3-(4-((2R,3S)/(2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2',4', 6'-Trimethyl-[1,1'-biphenyl]-4-yl)amino)hexane-3-yl)benzoylamino)propionic acid ethyl ester 2b (50.00 mg, 0.072 mmol) dissolved in 6 mL A mixed solvent of tetrahydrofuran and methanol (V/V = 1:1) was added to a solution of 1 mL of sodium hydroxide (14.40 mg, 0.36 mmol) with stirring, and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc (EtOAc m. The residue was purified by silica gel column chromatography (eluent: system B) to afford 3-(4-((2),3S) -(4-(Trifluoromethoxy)phenyl)-1-((2',4',6'-trimethyl-[1,1'-biphenyl]-4-yl)amino)hexane -3-yl)benzoylamino)propionic acid 2 (20.00 mg, white solid), yield: 42.0%.

MS m/z (ESI): 661.9 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ10.00 (s, 1H), 8.45 (s, 1H), 7.77 (d, J = 7.7Hz, 2H), 7.69 (d, J = 7.9Hz, 2H) , 7.52–7.31 (m, 6H), 6.96–6.79 (m, 4H), 4.11 (d, J = 10.8 Hz, 1H), 3.42 (d, J = 5.8 Hz, 3H), 2.49–2.44 (m, 2H) ), 1.84 (s, 5H), 0.95 - 0.80 (m, 4H), 0.65 (t, J = 7.2 Hz, 3H).

3-(4-((2R,3S)/(2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2',4',6) '-Trimethyl-[1,1'-biphenyl]-4-yl)amino)hexane-3-yl)benzoylamino)propanoic acid 2 further by using supercritical fluid chromatography (SFC) Preparation equipment and chiral column chiral isomers were resolved ((1) chiral column ChiralPak AD, 25 × 3 cm, 80 mL / min; mobile phase A for CO ₂ and B for Ethanol; or / and (2) Whelk O1 (S, S), 25 × 3 cm, 65 mL / min; mobile phase A for CO ₂ and B for Ethanol; or / and (3) Whelk O1 (S, S), 25 × 3 cm, 70 mL / min; mobile phase A for CO ₂ and B for Ethanol)) was resolved to give 3-(4-((2R,3S)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1- ((2',4',6'-Trimethyl-[1,1'-biphenyl]-4-yl)amino)hexane-3-yl)benzoylamino)propanoic acid 2A (white solid) And 3-(4-((2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2',4',6'-trimethyl) -[1,1'-Biphenyl]-4-yl)amino)hexane-3-yl)benzoylamino)propanoic acid 2B (white solid).

2A: MS m/z (ESI): 668.7 [M+1]

2B: MS m/z (ESI): 668.7 [M+1]

Example 3

3-(4-((2R,3S)/(2S,3R)-1-((4-(benzofuran-2-yl)phenyl)amino)-1-oxo-2-(4-( Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 3

3-(4-((2R,3S)-1-((4-(benzofuran-2-yl)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)) Phenyl)hexane-3-yl)benzoylamino)propionic acid 3A

3-(4-((2S,3R)-1-((4-(benzofuran-2-yl)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)) Phenyl)hexane-3-yl)benzoylamino)propionic acid 3B

first step

4-(benzofuran-2-yl)aniline

4-iodoaniline 3a (448.00 mg, 2.05 mmol), 2-(benzofuran-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan 3b (500.00 mg, 21.10 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride (1.54 g, 2.11 mmol) and sodium carbonate (652.00 mg, 6.15 mmol) dissolved in 28 mL In a mixed solvent of dimethyl ether, ethanol and water (V/V/V = 5:1:1), the reaction solution was reacted at 100 ° C for 5 hours under argon gas. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj , yield: 35%.

MS m/z (ESI): 210.9 [M+1]

Second step

3-(4-((2R,3S)/(2S,3R)-1-((4-(benzofuran-2-yl)phenyl)amino)-1-oxo-2-(4-( Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid

((2R,3S)/(2S,3R))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(III) Fluoromethoxy)phenyl)hexanoic acid 1m (80mg, 0.16mmol), 4-(benzofuran-2-yl)aniline 3c (50mg, 0.24mmol), bis(2-oxo-3-oxazolidine The bisphosphoryl chloride (61 mg, 0.24 mmol) was dissolved in 10 mL of dichloromethane, and N,N-diisopropylethylamine (0.14 mL, 0.8 mmol) was added with stirring, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and purified residue purified silicagel elut elut elut elut elut elut elut ((4-(benzofuran-2-yl)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino Ethyl propionate 3d (61 mg, white solid), yield: 55.6%.

MS m/z (ESI): 687.8 [M+1]

third step

3-(4-((2R,3S)/(2S,3R)-1-((4-(benzofuran-2-yl)phenyl)amino)-1-oxo-2-(4-) Ethyl (trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoate 3d (60 mg, 0.087 mmol) dissolved in 6 mL of tetrahydrofuran and methanol (V/V = 1:1) To the solvent, 1 mL of a lithium hydroxide monohydrate (73 mg, 1.75 mmol) was added with stirring, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was adjusted to pH = 3 with 1M hydrochloric acid, and ethyl acetate (50 mL), and the combined organic phase was washed successively with saturated aqueous ammonium chloride (50mL×2), sodium chloride solution (50mL), anhydrous sodium sulfate Drying, filtration and concentration under reduced pressure. ((4-(benzofuran-2-yl)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino Propionic acid 3 (50 mg, white solid), yield: 87.3%.

MS m/z (ESI): 658.9 [M+1]

^{1 H NMR (400MHz, CDCl3)} : δ 1 H NMR (400MHz, DMSO-d 6) δppm 7.73 (td, J = 15.56,8.28Hz, 8H) 7.54-7.63 (m, 3H) 7.38-7.48 (m, 6H ) 7.21-7.28(m,2H)4.11(d,J=11.29Hz,1H)3.37-3.50(m,2H)2.43-2.48(m,1H)1.23-1.32(m,3H)1.18(d,J= 4.77 Hz, 1H) 0.93 (d, J = 6.53 Hz, 2H) 0.84-0.90 (m, 2H) 0.65 (t, J = 7.15 Hz, 3H)

3-(4-((2R,3S)/(2S,3R)-1-((4-(benzofuran-2-yl)phenyl)amino)-1-oxo-2-(4-( Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 3 is further removed by supercritical fluid chromatography (SFC) using preparative equipment and chiral column chiral isomers Fractions ((1) Chiral Pak AD, 25 x 3 cm, 80 mL/min; mobile phase A for CO ₂ and B for Ethanol; or / and (2) Whelk O1 (S, S), 25 x 3 cm, 65 mL/ Min; mobile phase A for CO ₂ and B for Ethanol; or / and (3) Whelk O1 (S, S), 25 × 3 cm, 70 mL / min; mobile phase A for CO ₂ and B for Ethanol)) , 3-(4-((2R,3S)-1-((4-(benzofuran-2-yl)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)) Phenyl)hexane-3-yl)benzoylamino)propionic acid 3A (white solid) and 3-(4-((2S,3R)-1-((4-(benzofuran-2-) Phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 3B (white solid).

3A: MS m/z (ESI): 658.9 [M+1]

3B: MS m/z (ESI): 658.9 [M+1]

Example 4

3-(4-((2R,3S)/(2S,3R)-1-((3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4 -yl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 4

3-(4-((2R,3S)-1-((3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4-yl)amino)- 1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 4A

3-(4-((2S,3R)-1-((3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4-yl)amino)-) 1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 4B

first step

3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4-amine

2-Fluoro-4-iodoaniline 4a (5 g, 21.1 mmol), 2,4,6-trimethylphenylboronic acid 4b (3.46 g, 21.1 mmol), 1,1'-bis(diphenylphosphino)di Ferrocene palladium(II) chloride (1.54 g, 2.11 mmol) was dissolved in 100 mL of N,N-dimethylformamide, and 20 mL of sodium hydroxide (2.53 g, In a solution of 63.3 mmol), the reaction solution was reacted at 100 ° C for 4 hours under argon gas protection. The reaction mixture was extracted with ethyl acetate (100 mL×3), and the combined organic phase was washed with sodium chloride (100mL×2), dried over anhydrous sodium sulfate, filtered and evaporated. Purification by chromatography (eluent: System B) to give 3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4-amine 4c (4.8 g, white Solid), yield: 96.2%.

MS m/z (ESI): 230.0 [M+1]

Second step

3-(4-((2R,3S)/(2S,3R)-1-((3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4 -yl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid ethyl ester

((2R,3S)/(2S,3R))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(III) Fluoromethoxy)phenyl)hexanoic acid 1m (5.00g, 10.09mmol), 3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4-amine 4c (2.31 g, 10.09 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (3.84 g, 15.13 mmol) dissolved in 50 mL of dichloromethane and added with N,N-diisopropyl Ethylethylamine (8.79 mL, 50.45 mmol) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and purified residue purified crystallililililililililililililililililili ((3-Fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4-yl)amino)-1-oxo-2-(4-(trifluoromethyl) Ethyl phenyl) hexane-3-yl)benzoylamino)propanoic acid ethyl ester 4d (2.10 g, white solid), yield: 29.5%.

MS m/z (ESI): 706.9 [M+1]

third step

3-(4-((2R,3S)/(2S,3R)-1-((3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4 -yl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid

3-(4-((2R,3S)/(2S,3R)-1-((3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]- Ethyl 4-amino)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoate 4d (5.20 g, 7.35 mmol It was dissolved in a mixed solvent of 120 mL of tetrahydrofuran and methanol (V/V = 1:1), and 10 mL of a lithium hydroxide monohydrate (6.10 g, 147 mmol) was added thereto with stirring, and the mixture was stirred at room temperature for 2 hours. After adding 500 mL of ethyl acetate, it was washed with 0.3 M of dilute hydrochloric acid to pH = 5-6, then washed with saturated sodium chloride solution (300 mL), and the organic phase was concentrated under reduced pressure. Eluent: System A) was purified to give 3-(4-((2R,3S)/(2S,3R)-1-((3-fluoro-2',4',6'-trimethyl-[ 1,1'-biphenyl]-4-yl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid 4 (4.50 g, white solid), yield: 90.18%.

MS m/z (ESI): 678.9 [M+1]

^{1 H NMR (400MHz, CDCl3)} : 9.78 (s, 1H) 8.45 (t, J = 5.14Hz, 1H) 7.77 (d, J = 8.03Hz, 2H) 7.68 (d, J = 8.53Hz, 2H) 7.53- 7.62(m,1H)7.41(dd,J=13.05,8.28Hz,4H)6.82-6.94(m,2H)4.39(d,J=11.54Hz,1H)4.01(q,J=7.11Hz,2H)3.38 -3.47(m,2H)2.17-2.26(m,2H)1.93-2.01(m,2H)1.83(d,J=10.29Hz,3H)1.11-1.25(m,3H)0.79-0.93(m,4H) 0.56-0.68 (m, 3H)

3-(4-((2R,3S)/(2S,3R)-1-((3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4 -yl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 4 further by using supercritical fluid chromatography (SFC) Method, using preparative equipment and chiral column chiral isomers for resolution ((1) chiral column ChiralPak AD, 25 × 3 cm, 80 mL / min; mobile phase A for CO ₂ and B for Ethanol; or / and (2) Whelk O1 (S, S), 25 × 3 cm, 65 mL / min; mobile phase A for CO ₂ and B for Ethanol; or / and (3) Whelk O1 (S, S), 25 × 3 cm, 70 mL / Min; mobile phase A for CO ₂ and B for Ethanol)) is resolved to obtain 3-(4-((2R,3S)-1-((3-fluoro-2',4',6'-tri-) -[1,1'-biphenyl]-4-yl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino Propionic acid 4A and 3-(4-((2S,3R)-1-((3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4- Amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 4B.

4A: MS m/z (ESI): 678.9 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ = 9.79 (s, 1H), 8.53-8.40 (m, 1H), 7.79 (d, J = 8.0Hz, 2H), 7.70 (d, J = 8.5 Hz, 2H), 7.58 (t, J = 8.4 Hz, 1H), 7.43 (dd, J = 8.4, 11.9 Hz, 4H), 6.94 - 6.82 (m, 3H), 6.73 (d, J = 8.0 Hz, 1H), 4.47-4.34(m,1H), 3.50-3.38(m,4H), 3.17(s,2H), 2.22(s,3H),1.85(d,J=10.0Hz,6H),1.06(t,J= 7.0 Hz, 2H), 0.96-0.85 (m, 2H), 0.64 (d, J = 14.3 Hz, 3H).

4B: MS m/z (ESI): 678.9 [M+1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.80 (s, 1H), 8.47 (t, J = 5.4 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H), 7.59 (t, J = 8.3 Hz, 1H), 7.44 (dd, J = 8.3, 12.8 Hz, 4H), 6.94 - 6.85 (m, 3H), 6.73 (d, J = 8.3 Hz, 1H), 4.42 (d, J = 11.5 Hz, 1H), 3.52-3.30 (m, 6H), 2.22 (s, 3H), 1.86 (d, J = 10.5 Hz, 7H), 1.42-1.29 (m, 1H) ), 1.19 (br.s., 1H), 1.06 (t, J = 7.0 Hz, 3H), 0.91 (d, J = 7.5 Hz, 2H), 0.70-0.58 (m, 3H).

Example 5

3-(4-((2R,3S)/(2S,3R)-1-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-1-oxo-2-(4- (trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 5

3-(4-((2R,3S)-1-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)) Phenyl)hexane-3-yl)benzoylamino)propionic acid 5A

3-(4-((2S,3R)-1-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)) Phenyl)hexane-3-yl)benzoylamino)propionic acid 5B

first step

3-(4-((2R,3S)/(2S,3R)-1-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-1-oxo-2-(4- (Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid ethyl ester

((2R,3S)/(2S,3R))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(III) Fluoromethoxy)phenyl)hexanoic acid 1m (60 Mg, 0.12 mmol), 2-fluoro-4-(trifluoromethyl)aniline 5a (25 mg, 0.13 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (46 mg, 0.18 mmol) It was dissolved in 20 mL of dichloromethane, and triethylamine (0.085 mL, 0.6 mmol) was added under stirring, and the mixture was stirred at room temperature for 2 hours. 15 mL of ethyl acetate and 10 mL of water were added to the reaction mixture, and the mixture was adjusted to pH 1 with 3M hydrochloric acid, and the aqueous layer was extracted with ethyl acetate (15 mL×2), and the combined organic phases were washed sequentially with saturated sodium chloride solution (10 mL). Drying over anhydrous sodium sulfate, filtration, and EtOAc mjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -1((2-fluoro-4-(trifluoromethyl)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl Benzoylamino)propionic acid ethyl ester 5b (20 mg, white solid), yield: 25.6%.

Second step

3-(4-((2R,3S)/(2S,3R)-1-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-1-oxo-2-(4- (trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid

3-(4-((2R,3S)/(2S,3R)-1-((2-Fluoro-4-(trifluoromethyl)phenyl)amino)-1-oxo-2-(4) -(Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid ethyl ester 5b (20 mg, 0.03 mmol) dissolved in 3 mL of tetrahydrofuran and water (V/V = 2:1) To the mixed solvent, lithium hydroxide monohydrate (3 mg, 0.06 mmol) was added under stirring, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was adjusted to pH = 3 with 1M hydrochloric acid, and ethyl acetate (15 mL), and the combined organic phase was washed successively with saturated aqueous ammonium chloride (10 mL) Drying, filtration and concentration under reduced pressure. ((2-Fluoro-4-(trifluoromethyl)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoyl Amino)propionic acid 5 (18 mg, white solid), yield: 94.7%.

MS m/z (ESI): 629.8 [M+1]

^{1 H NMR (400MHz, DMSO-} d6): δ10.08 (br.s., 1H), 8.45 (br.s., 1H), 7.85 (br.s., 1H), 7.76 (d, J = 7.0 Hz, 2H), 7.69 (d, J = 7.3 Hz, 2H), 7.59 (d, J = 10.8 Hz, 1H), 7.42 (br.s., 5H), 4.47 (d, J = 11.3 Hz, 1H) , 3.56-3.42 (m, 5H), 1.41-1.23 (m, 4H), 0.64 (br.s., 3H)

3-(4-((2R,3S)/(2S,3R)-1-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-1-oxo-2-(4- (Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid 5 compound further by using supercritical fluid chromatography (SFC) method, using preparation equipment and chiral column chiral isomer Resolution (1) Chiral Pak AD, 25 x 3 cm, 80 mL/min; mobile phase A for CO ₂ and B for Ethanol; or / and (2) Whelk O1 (S, S), 25 x 3 cm, 65 mL/min; mobile phase A for CO ₂ and B for Ethanol; or / and (3) Whelk O1 (S, S), 25 x 3 cm, 70 mL/min; mobile phase A for CO ₂ and B for Ethanol)) Resolution to give 3-(4-((2R,3S)-1-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-1-oxo-2-(4-(3) Fluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid 5A (white solid) and 3-(4-((2S,3R)-1-((2-fluoro-4-) (trifluoromethyl)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 5B (white solid) ).

5A: MS m/z (ESI): 629.8 [M+1]

5B: MS m/z (ESI): 629.8 [M+1]

Example 6

3-(4-((2R,3S)/(2S,3R)-1-((2,5-difluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Phenyl)hexane-3-yl)benzoylamino)propionic acid 6

3-(4-((2R,3S)-1-((2,5-difluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane -3-yl)benzoylamino)propionic acid 6A

3-(4-((2S,3R)-1-((2,5-difluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane -3-yl)benzoylamino)propionic acid 6B

first step

3-(4-((2R,3S)/(2S,3R)-1-((2,5-difluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Ethyl phenyl)hexane-3-yl)benzoylamino)propionic acid ethyl ester

((2R,3S)/(2S,3R))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(III) Fluoromethoxy)phenyl)hexanoic acid 1m (80mg, 0.16mmol), 2,5-difluoroaniline 6a (33.3mg, 0.24mmol), bis(2-oxo-3-oxazolidinyl)phosphorus The acid chloride (61 mg, 0.24 mmol) was dissolved in 10 mL of methylene chloride, and N,N-diisopropylethylamine (0.11 mL, 0.64 mmol). The reaction mixture was concentrated under reduced pressure and purified residue purified silicagel elut elut elut elut elut elut elut ((2,5-Difluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid ethyl ester 6b (50 mg, white solid), yield: 51.0%.

MS m/z (ESI): 607.9 [M+1]

Second step

3-(4-((2R,3S)/(2S,3R)-1-((2,5-difluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Phenyl)hexane-3-yl)benzoylamino)propionic acid

3-(4-((2R,3S)/(2S,3R)-1-((2,5-Difluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Ethyl phenyl)hexane-3-yl)benzoylamino)propionic acid ethyl ester 6b (48 mg, 0.097 mmol) was dissolved in 4 mL of tetrahydrofuran and methanol (V/V = 1:1) in a mixed solvent. A solution of 1 mL of sodium hydroxide (19.4 mg, 0.49 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was partially evaporated under reduced pressure, and 5 mL of ethyl acetate and 5 mL of water were added, and 2 drops of 3 M hydrochloric acid were added dropwise to adjust the pH value, and extracted with ethyl acetate (10 mL × 3), and the combined organic phase was sodium chloride solution (10 mL × 3) washed, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography (developing solvent: system C) to give 3-(4-((2R,3S) /(2S,3R)-1-((2,5-difluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl Benzoylamino) Propionic acid 6 (21 mg, white solid), yield: 46.0%.

MS m/z (ESI): 579.8 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6): δ12.90 (s, 1H), 10.04 (s, 1H), 8.44 (t, J = 5.1Hz, 1H), 7.89 (s, 1H), 7.79 (s , 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H) ), 7.33 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 4.16 (d, J = 11.3 Hz, 1H), 3.52-3.40 (m, 5H), 2.45 (t) , J=7.0 Hz, 2H), 1.18 (d, J=8.0 Hz, 2H), 0.96-0.87 (m, 2H), 0.67-0.61 (m, 3H)

3-(4-((2R,3S)/(2S,3R)-1-((2,5-difluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Phenyl)hexane-3-yl)benzoylamino)propionic acid 6 is further resolved by supercritical fluid chromatography (SFC) using preparative equipment and chiral column chiral isomers ((1) Chiral Pak AD, 25 x 3 cm, 80 mL/min; mobile phase A for CO ₂ and B for Ethanol; or / and (2) Whelk O1 (S, S), 25 x 3 cm, 65 mL/min; mobile phase A For CO ₂ and B for Ethanol; or / and (3) Whelk O1 (S, S), 25 × 3 cm, 70 mL / min; mobile phase A for CO ₂ and B for Ethanol)), to obtain 3-( 4-((2R,3S)-1-((2,5-Difluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3- Benzoylamino)propionic acid 6A (white solid) and 3-(4-((2S,3R)-1-((2,5-difluorophenyl)amino)-1-oxo-2- (4-(Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 6B (white solid).

6A: MS m/z (ESI): 579.8 [M+1]

6B: MS m/z (ESI): 579.8 [M+1]

Example 7

3-(4-((2R,3S)/(2S,3R)-1-((2,4-difluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Phenyl)hexane-3-yl)benzoylamino)propionic acid 7

3-(4-((2R,3S)-1-((2,4-difluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane -3-yl)benzoylamino)propionic acid 7A

3-(4-((2S,3R)-1-((2,4-difluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane -3-yl)benzoylamino)propionic acid 7B

first step

3-(4-((2R,3S)/(2S,3R)-1-((2,4-difluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Ethyl phenyl)hexane-3-yl)benzoylamino)propionic acid ethyl ester

((2R,3S)/(2S,3R))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(III) Fluoromethoxy)phenyl)hexanoic acid 1m (80mg, 0.16mmol), 2,4-difluoroaniline 7a (0.024mL, 2.4mmol), bis(2-oxo-3-oxazolidinyl)phosphorus The acid chloride (61 mg, 0.24 mmol) was dissolved in dichloromethane (20 mL), and N,N-diisopropylethylamine (0.11 mL, 0.64 mmol). The reaction mixture was concentrated under reduced pressure and purified residue purified silicagel elut elut elut elut elut elut elut ((2,4-Difluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid ethyl ester 7b (40 mg, white solid), yield: 41.2%.

MS m/z (ESI): 607.9 [M+1]

Second step

3-(4-((2R,3S)/(2S,3R)-1-((2,4-difluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Phenyl)hexane-3-yl)benzoylamino)propionic acid

3-(4-((2R,3S)/(2S,3R)-1-((2,4-difluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Ethyl phenyl)hexane-3-yl)benzoylamino)propionic acid ethyl ester 7b (40 mg, 0.066 mmol) was dissolved in 6 mL of tetrahydrofuran and methanol (V/V = 1:1) in a mixed solvent. A solution of 1 mL of sodium hydroxide (14.4 mg, 0.36 mmol) was added and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. Concentration under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: system B) to give 3-(4-((2R,3S)/(2S,3R)-1-((2,4) -difluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 7 (31 mg, white solid) , Yield: 81.3%.

MS m/z (ESI): 579.8 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ9.78 (s, 1H), 8.55 (s, 1H), 7.75 (s, 2H), 7.68 (s, 2H), 7.41 (s, 4H), 7.33 ( s, 1H), 7.16 (s, 1H), 6.88 (s, 1H), 4.30 (d, J = 11.4 Hz, 2H), 4.18 - 4.08 (m, 1H), 2.40 (s, 2H), 0.97 - 0.81 (m, 4H), 0.64 (s, 3H).

3-(4-((2R,3S)/(2S,3R)-1-((2,4-difluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Phenyl)hexane-3-yl)benzoylamino)propionic acid 7 is further resolved by supercritical fluid chromatography (SFC) using preparative equipment and chiral column chiral isomers ((1) Chiral Pak AD, 25 x 3 cm, 80 mL/min; mobile phase A for CO ₂ and B for Ethanol; or / and (2) Whelk O1 (S, S), 25 x 3 cm, 65 mL/min; mobile phase A For CO ₂ and B for Ethanol; or / and (3) Whelk O1 (S, S), 25 × 3 cm, 70 mL / min; mobile phase A for CO ₂ and B for Ethanol)), to obtain 3-( 4-((2R,3S)-1-((2,4-difluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3- Benzoylamino)propionic acid 7A (white solid) and 3-(4-((2S,3R)-1-((2,4-difluorophenyl)amino)-1-oxo-2- (4-(Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 7B (white solid).

7A: MS m/z (ESI): 579.8 [M+1]

7B: MS m/z (ESI): 579.8 [M+1]

Example 8

3-(4-((2R,3S)/(2S,3R)-1-((3,4-dimethoxyphenyl)amino)-1-oxo-2-(4-(trifluoro)) Oxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 8

3-(4-((2R,3S)-1-((3,4-dimethoxyphenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)) Hexane-3-yl)benzoylamino)propionic acid 8A

3-(4-((2,4-Dimethoxyphenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl) Hexane-3-yl)benzoylamino)propionic acid 8B

first step

3-(4-((2R,3S)/(2S,3R)-1-((3,4-dimethoxyphenyl)amino)-1-oxo-2-(4-(trifluoro)) Ethyloxyphenyl)hexane-3-yl)benzoylamino)propionic acid ethyl ester

((2R,3S)/(2S,3R))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(III) Fluoromethoxy)phenyl)hexanoic acid 1m (80mg, 0.16mmol), 3,4-dimethoxyaniline 8a (25mg, 0.16mmol), bis(2-oxo-3-oxazolidinyl) Phosphorous oxychloride (61 mg, 0.24 mmol) was dissolved in 20 mL of dichloromethane, and N,N-diisopropylethylamine (0.11 mL, 0.64 mmol). The reaction mixture was concentrated under reduced pressure and purified residue purified silicagel elut elut elut elut elut elut elut ((3,4-Dimethoxyphenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid Ethyl ester 8b (41 mg, white solid), yield: 40.6%.

MS m/z (ESI): 607.9 [M+1]

Second step

3-(4-((2R,3S)/(2S,3R)-1-((3,4-dimethoxyphenyl)amino)-1-oxo-2-(4-(trifluoro)) Oxy)phenyl)hexane-3-yl)benzoylamino)propionic acid

3-(4-((2R,3S)/(2S,3R)-1-((3,4-Dimethoxyphenyl)amino)-1-oxo-2-(4-(trifluoro)) Ethyl methoxy)phenyl)hexane-3-yl)benzoylamino)propanoate 8b (41 mg, 0.065 mmol) was dissolved in a mixture of 6 mL of tetrahydrofuran and methanol (V/V = 1:1). 1 mL of a solution of sodium hydroxide (14.4 mg, 0.36 mmol) was added thereto with stirring, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. Concentration under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: system B) to give 3-(4-((2R,3S)/(2S,3R)-1-((3,4) -dimethoxyphenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 8 (30 mg, white Solid), Yield: 76.6%.

MS m/z (ESI): 603.9 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ9.90 (s, 1H), 8.55 (s, 1H), 7.75 (d, J = 7.6Hz, 2H), 7.67 (d, J = 8.5Hz, 2H) , 7.41 (t, J = 8.6 Hz, 4H), 6.88 (s, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 4.09 (d, J = 10.9 Hz, 1H), 3.61 (d, J = 8.7 Hz, 6H), 2.41-2.34 (m, 2H), 0.88 (ddd, J = 14.7, 12.8, 5.8 Hz, 4H), 0.63 (t, J = 7.0) Hz, 3H).

3-(4-((2R,3S)/(2S,3R)-1-((3,4-dimethoxyphenyl)amino)-1-oxo-2-(4-(trifluoro)) Oxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 8 is further resolved by supercritical fluid chromatography (SFC) using preparative equipment and chiral column chiral isomers (( 1) Chiral Pak AD, 25 x 3 cm, 80 mL/min; mobile phase A for CO ₂ and B for Ethanol; or / and (2) Whelk O1 (S, S), 25 x 3 cm, 65 mL/min; Phase A for CO ₂ and B for Ethanol; or / and (3) Whelk O1 (S, S), 25 × 3 cm, 70 mL / min; mobile phase A for CO ₂ and B for Ethanol)) -(4-((2R,3S)-1-((3,4-dimethoxyphenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)) Alkyl-3-yl)benzoylamino)propionic acid 8A (white solid) and 3-(4-((2S,3R)-1-((3,4-dimethoxyphenyl)amino)-1) - Oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 8B (white solid).

8A: MS m/z (ESI): 603.9 [M+1]

8B: MS m/z (ESI): 603.9 [M+1]

Example 9

3-(4-((2R,3S)/(2S,3R)-1-((4-Trifluoromethoxyphenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Phenyl)hexane-3-yl)benzoylamino)propionic acid 9

3-(4-((2R,3S)-1-((4-Trifluoromethoxyphenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)) Alkyl-3-yl)benzoylamino)propanoic acid 9A

3-(4-((2S,3R)-1-((4-Trifluoromethoxyphenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)) Alkyl-3-yl)benzoylamino)propanoic acid 9B

first step

3-(4-((2R,3S)/(2S,3R)-1-((4-Trifluoromethoxyphenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Ethyl phenyl)hexane-3-yl)benzoylamino)propionic acid ethyl ester

((2R,3S)/(2S,3R))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(III) Fluoromethoxy)phenyl)hexanoic acid 1m (80mg, 0.16mmol), 4-trifluoromethoxyaniline 9a (28mg, 0.16mmol), bis(2-oxo-3-oxazolidinyl)phosphinus The acid chloride (61 mg, 0.24 mmol) was dissolved in dichloromethane (20 mL), and N,N-diisopropylethylamine (0.11 mL, 0.64 mmol). Will The reaction mixture was concentrated under reduced pressure and purified residue purified silicagel elut elut elut elut elut elut (4-Trifluoromethoxyphenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid ethyl ester 9b (64 mg, white solid), yield: 60.6%.

MS m/z (ESI): 655.8 [M+1]

Second step

3-(4-((2R,3S)/(2S,3R)-1-((4-Trifluoromethoxyphenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Phenyl)hexane-3-yl)benzoylamino)propionic acid

3-(4-((2R,3S)/(2S,3R)-1-((4-Trifluoromethoxyphenyl)amino)-1-oxo-2-(4-(trifluoro)) Ethyloxy)phenyl)hexane-3-yl)benzoylamino)propionic acid ethyl ester 9b (64 mg, 0.097 mmol) was dissolved in 6 mL of a mixture solvent of tetrahydrofuran and methanol (V/V = 1:1) and stirred. 1 mL of a solution of sodium hydroxide (19.4 mg, 0.49 mmol) was added thereto, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The residue was purified by silica gel column chromatography (eluent: system B) to afford 3-(4-((2),3S) Trifluoromethoxyphenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 9 (27 mg, white Solid), Yield: 44.4%.

MS m/z (ESI): 628.7 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ10.35 (s, 1H), 8.48 (s, 1H), 7.74 (d, J = 8.2Hz, 2H), 7.69 (d, J = 8.5Hz, 2H) , 7.41 (t, J = 9.1 Hz, 6H), 7.16 (d, J = 8.7 Hz, 2H), 4.17 (d, J = 10.9 Hz, 2H), 2.38 (t, J = 7.2 Hz, 2H), 0.99 –0.76 (m, 4H), 0.63 (t, J = 7.1 Hz, 3H).

3-(4-((2R,3S)/(2S,3R)-1-((4-Trifluoromethoxyphenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Phenyl)hexane-3-yl)benzoylamino)propanoic acid 9 is further resolved by supercritical fluid chromatography (SFC) using preparative equipment and chiral column chiral isomers (1 ) Chiral Pak AD, 25 × 3 cm, 80 mL / min; mobile phase A for CO ₂ and B for Ethanol; or / and (2) Whelk O1 (S, S), 25 × 3 cm, 65 mL / min; mobile phase A for CO ₂ and B for Ethanol; or / and (3) Whelk O1 (S, S), 25 × 3 cm, 70 mL / min; mobile phase A for CO ₂ and B for Ethanol)), to obtain 3- (4-((2R,3S)-1-((4-Trifluoromethoxyphenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane- 3-yl)benzoylamino)propionic acid 9A (white solid) and 3-(4-((2S,3R)-1-((4-trifluoromethoxyphenyl)amino)-1-oxo) 2-(4-(Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 9B (white solid).

9A: MS m/z (ESI): 628.7 [M+1]

9B: MS m/z (ESI): 628.7 [M+1]

Example 10

3-(4-((2R,3S)/(2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2,4,6-tri) Fluorophenyl)amino)hexane-3-yl)benzoylamino)propanoic acid 10

3-(4-((2R,3S)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2,4,6-trifluorophenyl)amino)) Hexane-3-yl)benzoylamino)propionic acid 10A

3-(4-((2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2,4,6-trifluorophenyl)amino)) Hexane-3-yl)benzoylamino)propionic acid 10B

first step

3-(4-((2R,3S)/(2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2,4,6-tri) Ethyl fluorophenyl)amino)hexane-3-yl)benzoylamino)propionate

((2R,3S)/(2S,3R))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(III) Fluoromethoxy)phenyl)hexanoic acid 1m (80mg, 0.16mmol), 2,4,6-trifluoroaniline 10a (35mg, 0.24mmol), bis(2-oxo-3-oxazolidinyl) Phosphorous oxychloride (61 mg, 0.24 mmol) was dissolved in 20 mL of dichloromethane, and N,N-diisopropylethylamine (0.11 mL, 0.64 mmol). The reaction mixture was concentrated under reduced pressure and purified residue purified silicagel elut elut elut elut elut elut elut Oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2,4,6-trifluorophenyl)amino)hexane-3-yl)benzoylamino)propanoic acid Ethyl ester 10b (29 mg, white solid), yield: 29.0%.

MS m/z (ESI): 625.8 [M+1]

Second step

3-(4-((2R,3S)/(2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2,4,6-tri) Fluorophenyl)amino)hexane-3-yl)benzoylamino)propionic acid

3-(4-((2R,3S)/(2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2,4,6-) Ethyl trifluorophenyl)amino)hexane-3-yl)benzoylamino)propanoate 10b (29 mg, 0.05 mmol) was dissolved in a mixture of 6 mL of tetrahydrofuran and methanol (V/V = 1:1). A solution of 1 mL of sodium hydroxide (9.3 mg, 0.25 mmol) was added with stirring, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated with EtOAc EtOAc (EtOAc m. The residue was purified by silica gel column chromatography (eluent: EtOAc) to afford 3-(4-((2),3S)/(2S,3R)-1-oxo-2-(4-(trifluoro) Methoxy)phenyl)-1-((2,4,6-trifluorophenyl)amino)hexane-3-yl)benzoylamino)propanoic acid 10 (8 mg, white solid). 26.7%.

MS m/z (ESI): 597.8 [M+1]

^{1 H NMR (400MHz, CDCl3)} : 1 H NMR (400MHz, DMSO-d 6): δ9.95 (s, 1H), 8.46 (s, 1H), 7.76 (d, J = 7.8Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H), 7.41 (t, J = 6.9 Hz, 5H), 7.22 - 7.12 (m, 1H), 6.84 (s, 1H), 4.43 (d, J = 11.3 Hz, 1H) , 2.49-2.44 (m, 2H), 1.34 (d, J = 6.0 Hz, 1H), 1.22 (s, 6H), 1.16 (s, 1H), 0.94-0.86 (m, 2H), 0.62 (t, J =7.0Hz, 3H)

3-(4-((2R,3S)/(2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2,4,6-tri) Fluorophenyl)amino)hexane-3-yl)benzoylamino)propanoic acid 10 is further resolved by supercritical fluid chromatography (SFC) using preparative equipment and chiral column chiral isomers (( 1) Chiral Pak AD, 25 x 3 cm, 80 mL/min; mobile phase A for CO ₂ and B for Ethanol; or / and (2) Whelk O1 (S, S), 25 x 3 cm, 65 mL/min; Phase A for CO ₂ and B for Ethanol; or / and (3) Whelk O1 (S, S), 25 × 3 cm, 70 mL / min; mobile phase A for CO ₂ and B for Ethanol)) -(4-((2R,3S)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2,4,6-trifluorophenyl)amino)) Alkyl-3-yl)benzoylamino)propionic acid 10A (white solid) and 3-(4-((2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl) 1-((2,4,6-Trifluorophenyl)amino)hexane-3-yl)benzoylamino)propanoic acid 10B (white solid).

10A: MS m/z (ESI): 597.8 [M+1]

10B: MS m/z (ESI): 597.8 [M+1]

Example 11

3-(4-(1-(2-methoxy-4-(trifluoromethyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl) Benzoylamino)propionic acid

first step

4-(1-Amino-1-(4-(trifluoromethoxyphenyl)pentan-2-yl)benzoic acid tert-butyl ester

4-(1-Oxo-1-(4-(trifluoromethoxyphenyl)pentan-2-yl)benzoic acid tert-butyl ester 11a (1.50 g, 3.55 mmol) and titanium under argon The tetraisopropyl isopropyl ester (2.10 mL, 7.10 mmol) was dissolved in 7N ammonia methanol (20 mL) and allowed to react at room temperature for 18 hours. The reaction solution was cooled to 0 ° C, sodium borohydride (230 mg, 6.03 mmol) was added and the mixture was allowed to react to room temperature. 2 hours. Slowly add 1N sodium hydroxide solution to the reaction solution until no obvious solids were taken out, suction filtration, concentrate the filtrate, add 20 mL of water, extract with ethyl acetate (10 mL×3), and combine the organic phases. The organic layer was dried over anhydrous sodium sulfate (MgSO4). tert-Butyl pentan-2-yl)benzoate 11b (1.02 g, yellow viscous liquid), yield: 68.0%.

^{1 H NMR (400MHz, CDCl3)} δ7.96 (d, J = 7.4Hz, 2H), 7.38 (d, J = 8.0Hz, 2H), 7.29 (d, J = 7.7Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H), 4.07 (d, J = 8.9 Hz, 1H), 2.82 (d, J = 6.4 Hz, 1H), 2.32 (s, 2H), 1.60 (s, 9H), 1.26 (s, 2H), 0.94 (d, J = 6.5 Hz, 2H), 0.75 - 0.58 (m, 3H).

Second step

4-(1-(2-Methoxy-4-(trifluoromethyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid Tert-butyl ester

tert-Butyl 4-(1-amino-1-(4-(trifluoromethoxyphenyl)pentan-2-yl)benzoate 11b (700 mg, 1.65 mmol), 2-methoxy-4- (trifluoromethyl)benzoic acid 11c (512 mg, 1.50 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (573 mg, 2.25 mmol) and N,N-diisopropylethylamine (1.05 mL, 6.00 mmol) was dissolved in a mixed solvent of 12 mL of dichloromethane and N,N-dimethylformamide (V/V=5/1), and the reaction mixture was reacted at room temperature for 18 hours. The residue was purified by silica gel column chromatography (eluent: system A) to give 4 -(1-(2-Methoxy-4-(trifluoromethyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid Butyl ester 11d (790 mg, pale yellow solid), yield: 86.0%. MS m/z (ESI): 557.8 [M+1-56]

third step

4-(1-(2-Methoxy-4-(trifluoromethyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid

4-(1-(2-Methoxy-4-(trifluoromethyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzene Tert-butyl formate 11d (790 mg, 1.29 mmol) and 85% phosphoric acid (1.20 g, 10.3 mmol) were dissolved in 10 mL of acetonitrile, and the reaction mixture was reacted at 80 ° C for 5 hours. The filtrate was concentrated, and then added with EtOAc (3 mL, EtOAc) Methyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid 11e (720 mg, pale yellow liquid), yield: 99.0%.

MS m/z (ESI): 557.8 [M+1]

the fourth step

3-(4-(1-(2-methoxy-4-(trifluoromethyl)benzoylamino)-2-(4-(trifluoromethoxy)phenyl)pentan-2-yl) Benzoylamino)propionic acid ethyl ester

4-(1-(2-Methoxy-4-(trifluoromethyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzene Formic acid 11e (720 mg, 1.29 mmol), 3-aminopropionic acid ethyl ester hydrochloride (1.0 g, 6.50 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (1.994 mg, 7.8 mmol) And N,N-diisopropylethylamine (2.20 mL, 1.89 mmol) was dissolved in a mixed solvent of 11 mL of dichloromethane and N,N-dimethylformamide (V/V=9/2). The solution was reacted at 35 ° C for 38 hours. The reaction solution was concentrated under reduced pressure, and then water (20 mL), and ethyl acetate (10mL×3), and the organic phase was combined with saturated sodium carbonate solution (20mL×1), 1N hydrochloric acid solution (20mL×1) and saturated brine ( The residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol) to afford 3-(4-( 1-(2-Methoxy-4-(trifluoromethyl)benzoylamino)-2-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino) Ethyl propionate 11f (530 mg, white solid), yield: 62.0%.

MS m/z (ESI): 656.8 [M+1]

the fifth step

3-(4-(1-(2-Methoxy-4-(trifluoromethyl)benzoylamino)-2-(4-(trifluoromethoxy)phenyl)pentan-2- a solution of ethyl benzoylamino)propionate 11f (530 mg, 0.81 mmol) and 0.80 mL of lithium hydroxide monohydrate (170 mg, 4.05 mmol) dissolved in 10 mL of tetrahydrofuran and methanol (V/V = 1:1) In the solvent, the reaction solution was reacted at 30 ° C for 18 hours. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated, evaporated, evaporated, evaporated. The residue obtained is purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate) to give 3-(4-(2-methoxy-4-(trifluoromethyl)) Benzyl Amido)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propanoic acid 11 (200 mg, white solid), yield: 40.0%.

MS m/z (ESI): 640.0 [M+1]

^{1 H NMR (400MHz, DMSO)} δ12.20 (s, 1H), 8.52 (d, J = 8.5Hz, 2H), 7.82 (d, J = 7.9Hz, 2H), 7.58 (d, J = 8.2Hz, 2H), 7.40 (d, J = 7.9 Hz, 2H), 7.35 (d, J = 8.3 Hz, 3H), 7.30 (s, 1H), 7.23 (d, J = 7.7 Hz, 1H), 5.30 (t, J=8.9 Hz, 1H), 3.76 (s, 3H), 3.47 (d, J = 5.7 Hz, 2H), 3.14 (t, J = 8.3 Hz, 1H), 2.53 (d, J = 6.9 Hz, 2H) , 1.58 (d, J = 9.7 Hz, 1H), 1.15 (s, 1H), 0.98 - 0.84 (m, 2H), 0.65 (t, J = 7.0 Hz, 3H).

Example 12

3-(4-((2R,3S)/(2S,3R)-1-((4-(tert-butyl)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Phenyl)hexane-3-yl)benzoylamino)propionic acid 12

3-(4-((2R,3S)-1-((4-(tert-butyl)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)) Alkyl-3-yl)benzoylamino)propionic acid 12A

3-(4-((2S,3R)-1-((4-(tert-butyl)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)) Alkyl-3-yl)benzoylamino)propionic acid 12B

first step

3-(4-((2R,3S)/(2S,3R)-1-((4-(tert-butyl)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Ethyl phenyl)hexane-3-yl)benzoylamino)propionic acid ethyl ester

((2R,3S)/(2S,3R))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(III) Fluoromethoxy)phenyl)hexanoic acid 1m (80mg, 0.16mmol), 4-tert-butylaniline 12a (28mg, 0.19mmol), 1-hydroxybenzotriazole (1.79g, 13.3mmol) and 1-B Base-(3-dimethylaminopropyl)carbodiimide hydrochloride (40 mg, 0.21 mmol) and N,N-diisopropylethylamine (52 mg, 0.4 mmol) in 10 mL of tetrahydrofuran at room temperature Stir for 24 hours. The reaction mixture was extracted with EtOAc (EtOAc)EtOAc. Eluent: System B) was purified to give 3-(4-((2R,3S)/(2S,3R)-1-((4-(tert-butyl)phenyl)amino)-1-oxo- Ethyl 2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoate 12b (32 mg, white solid).

MS m/z (ESI): 626.9 [M+1]

Second step

3-(4-((2R,3S)/(2S,3R)-1-((4-(tert-butyl)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Phenyl)hexane-3-yl)benzoylamino)propionic acid

3-(4-((2R,3S)/(2S,3R)-1-((4-(tert-butyl)phenyl)amino)-1-oxo-2-(4-(trifluoro)) Ethyloxy)phenyl)hexane-3-yl)benzoylamino)propionic acid ethyl ester 12b (32 mg, 0.05 mmol) was dissolved in 6 mL of a mixed solvent of tetrahydrofuran and methanol (V/V = 1:1) and stirred. 1 mL of a solution of sodium hydroxide (10 mg, 0.25 mmol) was added thereto, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was evaporated under reduced pressure to drynessnessnessnessnessnessnesssssssssssssssssssssssssssssssssssssssssssssssssss The organic layer was dried over sodium sulfate, filtered, and evaporated, evaporated,363363363363363363363363363363363363363363363363363363363 Eluent: System B) was purified to give 3-(4-((2R,3S)/(2S,3R)-1-((4-(tert-butyl)phenyl)amino)-1-oxo- 2-(4-(Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 12 (7 mg, white solid).

MS m/z (ESI): 599.9 [M+1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.86 (s, 1H), 8.47 (s, 1H), 7.74 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 8.6 Hz, 2H) , 7.40 (dd, J = 8.3, 5.1 Hz, 4H), 7.17 (dd, J = 16.5, 9.0 Hz, 6H), 5.33 (d, J = 3.8 Hz, 1H), 4.05 (t, J = 10.0 Hz, 2H), 2.42–2.36 (m, 2H), 0.94-0.81 (m, 4H), 0.63 (t, J = 7.5 Hz, 3H).

3-(4-((2R,3S)/(2S,3R)-1-((4-(tert-butyl)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Phenyl)hexane-3-yl)benzoylamino)propanoic acid 12 is further resolved by supercritical fluid chromatography (SFC) using preparative equipment and chiral column chiral isomers (1 ) Chiral Pak AD, 25 × 3 cm, 80 mL / min; mobile phase A for CO ₂ and B for Ethanol; or / and (2) Whelk O1 (S, S), 25 × 3 cm, 65 mL / min; mobile phase A for CO ₂ and B for Ethanol; or / and (3) Whelk O1 (S, S), 25 × 3 cm, 70 mL / min; mobile phase A for CO ₂ and B for Ethanol)), to obtain 3- (4-((2R,3S)-1-((4-(tert-butyl)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane- 3-yl)benzoylamino)propionic acid 12A (white solid) and 3-(4-((2S,3R)-1-((4-(tert-butyl)phenyl)amino)-1-oxo) 2-(4-(Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 12B (white solid).

12A: MS m/z (ESI): 599.9 [M+1]

12B: MS m/z (ESI): 599.9 [M+1]

Example 13

3-(4-((2R,3S)/(2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((4-(4-(3) Fluoromethyl)-1H-pyrazol-1-yl)phenyl)amino)hexane-3-yl)benzoylamino)propanoic acid 13

3-(4-((2R,3S)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((4-(4-(trifluoromethyl))-1H) -pyrazol-1-yl)phenyl)amino)hexane-3-yl)benzoylamino)propanoic acid 13A

3-(4-((2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((4-(4-(trifluoromethyl))-1H) -pyrazol-1-yl)phenyl)amino)hexane-3-yl)benzoylamino)propanoic acid 13B

first step

1-(4-nitrophenyl)-4-(trifluoromethyl)-1H-pyrazole

1-Fluoro-4-nitrobenzene 13a (1.35 g, 9.55 mmol), 4-(trifluoromethyl)-1H-pyrazole 13b (1 g, 7.35 mmol), potassium carbonate (2.03 g, 14.7 mmol) The reaction solution was reacted at 85 ° C for 7 hours in 10 mL of acetonitrile. The reaction mixture was filtered, and then evaporated tolulujjjjjjjjjjjjjjj %

MS m/z (ESI): 257.9 [M+1]

Second step

4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)aniline

1-(4-Nitrophenyl)-4-(trifluoromethyl)-1H-pyrazole 13c (257 mg, 1 mmol), 10% palladium on carbon (128 mg) dissolved in 10 mL of methanol Stir for 5 hours. The reaction solution was filtered, and then evaporated tolululululululululululululululululululululululululululululululululu

MS m/z (ESI): 227.9 [M+1]

third step

3-(4-((2R,3S)/(2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((4-(4-(3) Fluoromethyl)-1H-pyrazol-1-yl)phenyl)amino)hexane-3-yl)benzoylamino)propionic acid ethyl ester

((2R,3S)/(2S,3R))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(III) Fluoromethoxy)phenyl)hexanoic acid 1 m (90 mg, 0.22 mmol), 4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)aniline 13d (66 mg, 0.29 mmol), 2- (7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (100 mg, 0.26 mmol) and N,N-diisopropylethylamine (0.12 mL) 0.66 mmol) was dissolved in 5 mL of tetrahydrofuran and stirred at room temperature for 18 hours. 15 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (8 mL × 3). Purify, get 3-(4-((2R,3S)/(2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((4-(4-(3) Ethyl fluoromethyl)-1H-pyrazol-1-yl)phenyl)amino)hexane-3-yl)benzoylamino)propanoate 13e (155 mg, yellow solid), yield: 99.9%.

MS m/z (ESI): 704.8 [M+1]

the fourth step

3-(4-((2R,3S)/(2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((4-(4-(3) Fluoromethyl)-1H-pyrazol-1-yl)phenyl)amino)hexane-3-yl)benzoylamino)propionic acid

3-(4-((2R,3S)/(2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((4-(4-() Trifluoromethyl)-1H-pyrazol-1-yl)phenyl)amino)hexane-3-yl)benzoylamino)propionic acid ethyl ester 13e (155 mg, 0.22 mmol) was dissolved in 5 mL of tetrahydrofuran and methanol ( In a mixed solvent of V/V = 4:1), a solution of 0.22 mL of lithium hydroxide monohydrate (50 mg, 1.1 mmol) was added under stirring, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove a solvent, and the mixture was adjusted to pH 2-3 with 1M hydrochloric acid, and ethyl acetate (6 mL×3) The mixture was washed with aq. EtOAc (EtOAc) (EtOAc m. 2R,3S)/(2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((4-(4-(trifluoromethyl)-1H-) Pyrazol-1-yl)phenyl)amino)hexane-3-yl)benzoylamino)propanoic acid 13 (8 mg, yellow solid), yield: 5.4%.

MS m/z (ESI): 676.8 [M+1]

^{1 H NMR (400MHz, DMSO)} δ10.14 (s, 1H), 9.00 (s, 1H), 8.43 (s, 1H), 8.11 (s, 1H), 7.76 (d, J = 7.4Hz, 2H), 7.68 (d, J = 7.8 Hz, 5H), 7.47-7.38 (m, 6H), 4.09 (d, J = 11.5 Hz, 1H), 3.52 - 3.44 (m, 2H), 3.22-3.16 (m, 1H) , 2.47-2.43 (m, 2H), 1.98-1.94 (m, 2H), 1.15 - 1.13 (m, 2H), 0.64 (t, J = 6.4 Hz, 3H).

3-(4-((2R,3S)/(2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((4-(4-(3) Fluoromethyl)-1H-pyrazol-1-yl)phenyl)amino)hexane-3-yl)benzoylamino)propanoic acid 13 further by using supercritical fluid chromatography (SFC), using preparative equipment and Chiral column chiral isomers are resolved (1) chiral column ChiralPak AD, 25 × 3 cm, 80 mL / min; mobile phase A for CO ₂ and B for Ethanol; or / and (2) WhelkO1 (S, S), 25 x 3 cm, 65 mL/min; mobile phase A for CO ₂ and B for Ethanol; or / and (3) Whelk O1 (S, S), 25 x 3 cm, 70 mL/min; mobile phase A for CO ₂ And B for Ethanol)) to carry out the resolution to give 3-(4-((2R,3S)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-(4- (4-(Trifluoromethyl)-1H-pyrazol-1-yl)phenyl)amino)hexane-3-yl)benzoylamino)propionic acid 13A (white solid) and 3-(4-( (2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((4-(4-(trifluoromethyl)-1H-pyrazole-1-) Phenyl)amino)hexane-3-yl)benzoylamino)propionic acid 13B (white solid).

13A: MS m/z (ESI): 676.8 [M+1]

13B: MS m/z (ESI): 676.8 [M+1]

Example 14

3-(4-((2R,3S)/(2S,3R)-1-((4-(2-methylthiazol-5-yl)phenyl)amino)(1-oxo-2-(4-) (trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 14

3-(4-((2R,3S)-1-((4-(2-methylthiazol-5-yl)phenyl)amino) 1-oxo-2-(4-(trifluoromethoxy) Phenyl)hexane-3-yl)benzoylamino)propionic acid 14A

3-(4-((2S,3R)-1-((4-(2-methylthiazol-5-yl)phenyl)amino) 1-oxo-2-(4-(trifluoromethoxy) Phenyl)hexane-3-yl)benzoylamino)propionic acid 14B

first step

4-(2-methylthiazol-5-yl)aniline

5-Bromo-2-methylthiazole 14a (840 mg, 4.72 mmol), 4-aminophenylboronic acid hydrochloride 14b (900 mg, 5.19 mmol), tetratriphenylphosphine palladium (273 mg, 0.24 mmol) and sodium carbonate ( 1.90 g, 17.9 mmol) was dissolved in a mixed solvent of 50 mL of toluene, ethanol and water (V/V/V = 2:2:1), and the gas was replaced with argon gas, and the reaction liquid was reacted at 90 ° C for 6 hours. The reaction mixture was concentrated, EtOAc (EtOAc) (EtOAc) : System C) was purified to give 4-(2-methylthiazol-5-yl)phenylamine 14c (630 mg, yellow solid), yield: 70.0%

MS m/z (ESI): 190.9 [M+1]

Second step

3-(4-((2R,3S)/(2S,3R)-1-((4-(2-methylthiazol-5-yl)phenyl)amino)(1-oxo-2-(4-) (Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid ethyl ester

((2R,3S)/(2S,3R))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(III) Fluoromethoxy)phenyl)hexanoic acid 1m (248mg, 0.50mmol), 4-(2-methylthiazol-5-yl)aniline 14c (114mg, 0.60mmol), bis(2-oxo-3-oxole) Oxylalkyl)phosphoryl chloride (380 mg, 1.00 mmol) and N,N-diisopropylethylamine (0.35 mL, 2.00 mmol) dissolved in 6 mL dichloromethane and N,N-dimethylformamide (V/ In the mixed solvent of V = 5/1), the reaction liquid was reacted at room temperature for 18 hours. 20 mL of water was added to the reaction solution, and extracted with ethyl acetate (10) The residue was purified by silica gel column chromatography (eluent: system C) to give 3-(4-((2R,3S)). /(2S,3R)-1-((4-(2-methylthiazol-5-yl)phenyl)amino(1-oxo-2-(4-(trifluoromethoxy)phenyl)) Ethyl-3-yl)benzoylamino)propanoate 14d (166 mg, off-white solid), yield: 49.7%.

MS m/z (ESI): 667.9 [M+1]

third step

3-(4-((2R,3S)/(2S,3R)-1-((4-(2-methylthiazol-5-yl)phenyl)amino)(1-oxo-2-(4-) (trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid

3-(4-((2R,3S)/(2S,3R)-1-((4-(2-methylthiazol-5-yl)phenyl)amino)(1-oxo-2-(4) -(Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid ethyl ester 14d (166 mg, 0.25 mmol) dissolved in 8 mL of tetrahydrofuran and methanol (V/V = 4:1) Into a mixed solvent, 0.25 mL of lithium hydroxide monohydrate (53 mg, 1.25 mmol) was added thereto with stirring, and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to remove a solvent, and then adjusted to pH 2-3 with 1 M hydrochloric acid. The extract was extracted with EtOAc (EtOAc (EtOAc)EtOAc. 3-(4-((2R,3S)/(2S,3R)-1-((4-(2-methylthiazol-5-yl)phenyl)amino)(1-oxo-2-(4) -(Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 14 (100 mg, white solid), yield: 62.0%.

MS m/z (ESI): 639.9 [M+1]

¹ H NMR (400 MHz, DMSO) δ 12.40 - 11.89 (m, 1H), 10.07 (s, 1H), 8.42 (s, 1H), 7.85 (s, 1H), 7.75 (d, J = 8.0 Hz, 2H) ), 7.67 (d, J = 8.4 Hz, 2H), 7.38 (dd, J = 21.0, 8.6 Hz, 8H), 4.08 (d, J = 11.0 Hz, 1H), 3.47 (dd, J = 3.4, 2.1 Hz) , 1H), 3.45 - 3.41 (m, 2H), 2.62 (s, 3H), 2.46 (d, J = 7.1 Hz, 2H), 1.38 (dd, J = 10.5, 4.8 Hz, 2H), 0.93 - 0.84 ( m, 2H), 0.64 (t, J = 7.2 Hz, 3H).

3-(4-((2R,3S)/(2S,3R)-1-((4-(2-methylthiazol-5-yl)phenyl)amino)(1-oxo-2-(4-) (Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 14 is further carried out by using a supercritical fluid chromatography (SFC) method using preparative equipment and a chiral column chiral isomer Resolution (1) Chiral Pak AD, 25 x 3 cm, 80 mL/min; mobile phase A for CO ₂ and B for Ethanol; or / and (2) Whelk O1 (S, S), 25 x 3 cm, 65 mL /min; mobile phase A for CO ₂ and B for Ethanol; or / and (3) Whelk O1 (S, S), 25 × 3 cm, 70 mL / min; mobile phase A for CO ₂ and B for Ethanol)) , 3-(4-((2R,3S)-1-((4-(2-methylthiazol-5-yl)phenyl)amino)(1-oxo-2-(4-(trifluoro)) Oxy)phenyl)hexane-3-yl)benzoylamino)propionic acid 14A (white solid) and 3-(4-((2S,3R)-1-((4-(2-methylthiazole)) -5-yl)phenyl)amino(1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 14B (white solid).

14A: MS m/z (ESI): 639.9 [M+1]

14B: MS m/z (ESI): 639.9 [M+1]

Example 15

3-(4-((2R,3S)/(2S,3R)-1-((2-fluoro-4-(trifluoromethoxy)phenyl)amino)-1-oxo-2-(4) -(Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 15

3-(4-((2R,3S)-1-((2-fluoro-4-(trifluoromethoxy)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Phenyl)hexane-3-yl)benzoylamino)propionic acid 15A

3-(4-((2S,3R)-1-((2-fluoro-4-(trifluoromethoxy)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Phenyl)hexane-3-yl)benzoylamino)propionic acid 15B

first step

3-(4-((2R,3S)/(2S,3R)-1-((2-fluoro-4-(trifluoromethoxy)phenyl)amino)-1-oxo-2-(4) -(Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid ethyl ester

((2R,3S)/(2S,3R))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl-2-(4-(trifluoro) Methoxy)phenyl)hexanoic acid 1m (200mg, 0.40mmol), 2-fluoro-4-(trifluoromethoxy)aniline 15a (116mg, 0.60mmol) and N,N-diisopropylethylamine ( 0.28 mL, 1.60 mmol) was dissolved in 6 mL of dichloromethane, and finally bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (152 mg, 0.60 mmol) was added, and the reaction mixture was reacted at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The residue was purified by silica gel thin-layer chromatography (developing solvent: system A) to give 3-(4-((2R,3S)/(2S,3R)-1-((2-fluoro-4-(trifluoro)) Ethyl methoxy)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoate 15b (155 mg, White solid), Yield: 16.4%.

MS m/z (ESI): 672.8 [M+1]

Second step

3-(4-((2R,3S)/(2S,3R)-1-((2-fluoro-4-(trifluoromethoxy)phenyl)amino)-1-oxo-2-(4) -(Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid

3-(4-((2R,3S)/(2S,3R)-1-((2-Fluoro-4-(trifluoromethoxy)phenyl)amino)-1-oxo-2-() Ethyl 4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoate 15b (44 mg, 0.065 mmol) dissolved in 6 mL of tetrahydrofuran and methanol (V/V = 1:1) Into a mixed solvent, 1.0 mL of a solution of sodium hydroxide (13 mg, 0.33 mmol) was added under stirring, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and evaporated to dryness, evaporated, evaporated, evaporated, evaporated, evaporated , filtration, and concentration under reduced pressure, and the obtained residue was purified by silica gel chromatography (yield: system A). 3-(4-((2R,3S)/(2S,3R)-1-((2-fluoro-4-(trifluoromethoxy)phenyl)amino)-1-oxo-2-(4) -(Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 15 (19 mg, white solid).

MS m/z (ESI): 644.7 [M+1]

^{1 H NMR (400MHz, MeOD)} δ7.79 (d, J = 7.9Hz, 2H), 7.70 (d, J = 8.5Hz, 2H), 7.48 (d, J = 8.2Hz, 2H), 7.43 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 8.6 Hz, 2H), 7.05 (d, J = 11.6 Hz, 1H), 6.95 (d, J = 7.7 Hz, 1H), 4.12 (d, J = 11.2 Hz, 1H), 3.63 (t, J = 6.6 Hz, 2H), 3.52 - 3.44 (m, 1H), 2.63 (t, J = 6.5 Hz, 2H), 1.06 - 0.95 (m, 2H), 0.89 ( Ddd, J = 8.0, 7.1, 4.8 Hz, 2H), 0.73 (t, J = 7.1 Hz, 3H).

3-(4-((2R,3S)/(2S,3R)-1-((2-fluoro-4-(trifluoromethoxy)phenyl)amino)-1-oxo-2-(4) -(Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 15 further by using supercritical fluid chromatography (SFC) method, using preparative equipment and chiral column chiral isomers Resolution (1) Chiral Pak AD, 25 x 3 cm, 80 mL/min; mobile phase A for CO ₂ and B for Ethanol; or / and (2) Whelk O1 (S, S), 25 x 3 cm, 65 mL/min; mobile phase A for CO ₂ and B for Ethanol; or / and (3) Whelk O1 (S, S), 25 x 3 cm, 70 mL/min; mobile phase A for CO ₂ and B for Ethanol)) Resolution to give 3-(4-((2R,3S)-1-((2-fluoro-4-(trifluoromethoxy)phenyl)amino)-1-oxo-2-(4-) Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid 15A (white solid) and 3-(4-((2S,3R)-1-((2-fluoro-4) -(Trifluoromethoxy)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 15B ( White solid).

15A: MS m/z (ESI): 644.7 [M+1]

15B: MS m/z (ESI): 644.7 [M+1]

Example 16

3-(4-((2R,3S)/(2S,3R)-1-((2-methyl-4-(trifluoromethoxy)phenyl)amino)-1-oxo-2-( 4-(Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 16

3-(4-((2R,3S)-1-((2-methyl-4-(trifluoromethoxy)phenyl)amino)-1-oxo-2-(4-(trifluoro)) Oxy)phenyl)hexane-3-yl)benzoylamino)propionic acid 16A

3-(4-((2S,3R)-1-((2-methyl-4-(trifluoromethoxy)phenyl)amino)-1-oxo-2-(4-(trifluoro)) Oxy)phenyl)hexane-3-yl)benzoylamino)propionic acid 16B

first step

3-(4-((2R,3S)/(2S,3R)-1-((2-methyl-4-(trifluoromethoxy)phenyl)amino)-1-oxo-2-( Ethyl 4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoate

((2R,3S)/(2S,3R))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl-2-(4-(trifluoro) Methoxy)phenyl)hexanoic acid 1m (200mg, 0.40mmol), 2-methyl-4-(trifluoromethoxy)aniline 16a (116mg, 0.61mmol) and N,N-diisopropylethylamine (0.28 mL, 1.60 mmol) was dissolved in 6 mL of dichloromethane, argon gas was exchanged three times, then bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (155 mg, 0.61 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours, and the reaction mixture was evaporated to dryness. EtOAcjjjjjjjj Concentration under reduced pressure, the residue obtained was purified by silica gel chromatography (yield: system A) to give 3-(4-((2R,3S)/(2S,3R)-1-(2- Methyl-4-(trifluoromethoxy)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino) Ethyl propionate 16b (44 mg, white solid), yield: 16.5%.

MS m/z (ESI): 668.9 [M+1]

Second step

3-(4-((2R,3S)/(2S,3R)-1-((2-methyl-4-(trifluoromethoxy)phenyl)amino)-1-oxo-2-( 4-(Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid

3-(4-((2R,3S)/(2S,3R)-1-((2-Methyl-4-(trifluoromethoxy)phenyl)amino)-1-oxo-2- Ethyl 4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoate 16b (44 mg, 0.066 mmol) dissolved in 6 mL of tetrahydrofuran and methanol (V/V = 1:1 The mixed solvent was added to a solution of 1.0 mL of sodium hydroxide (13.2 mg, 0.33 mmol) with stirring, and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure to give a solvent. Concentration under reduced pressure, and the residue obtained was purified by silica gel chromatography (yield: system C) to give 3-(4-((2R,3S)/(2S,3R)-1-(2) -Methyl-4-(trifluoromethoxy)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino Propionic acid 16 (28 mg, white solid), yield: 66.2%.

MS m/z (ESI): 640.8 [M+1]

^{1 H NMR (400MHz, MeOD)} δ7.83 (d, J = 8.2Hz, 2H), 7.72 (d, J = 8.6Hz, 2H), 7.51 (d, J = 8.1Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 6.99 (s, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.6 Hz, 1H), 4.03 (d, J = 11.7 Hz, 1H) , 3.66 (t, J = 6.7 Hz, 2H), 3.52 - 3.44 (m, 1H), 2.64 (t, J = 6.4 Hz, 2H), 1.65 (s, 3H) 1.62-1.39 (m, 2H), 1.06 –0.97 (m, 2H), 0.73 (t, J = 7.3 Hz, 3H).

3-(4-((2R,3S)/(2S,3R)-1-((2-methyl-4-(trifluoromethoxy)phenyl)amino)-1-oxo-2-( 4-(Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 16 further by using supercritical fluid chromatography (SFC), using preparative equipment and chiral columns for heterogeneous isomerism Resolution (1) Chiral Pak AD, 25 × 3 cm, 80 mL / min; mobile phase A for CO ₂ and B for Ethanol; or / and (2) Whelk O1 (S, S), 25 × 3 cm , 65 mL/min; mobile phase A for CO ₂ and B for Ethanol; or / and (3) Whelk O1 (S, S), 25 x 3 cm, 70 mL/min; mobile phase A for CO ₂ and B for Ethanol)) Resolution was carried out to give 3-(4-((2R,3S)-1-((2-methyl-4-(trifluoromethoxy)phenyl)amino)-1-oxo-2-(4) -(Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid 16A (white solid) and 3-(4-((2S,3R)-1-((2-) 4-(trifluoromethoxy)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propane Acid 16B (white solid).

16A: MS m/z (ESI): 640.8 [M+1]

16B: MS m/z (ESI): 640.8 [M+1]

Example 17

3-(4-((2R,3S)/(2S,3R)-1-((4-chloro-2-fluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Phenyl)hexane-3-yl)benzoylamino)propionic acid 17

3-(4-((2R,3S)-1-((4-chloro-2-fluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)) Alkyl-3-yl)benzoylamino)propanoic acid 17A

3-(4-((2S,3R)-1-((4-chloro-2-fluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)) Alkyl-3-yl)benzoylamino)propionic acid 17B

first step

3-(4-((2R,3S)/(2S,3R)-1-((4-chloro-2-fluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Ethyl phenyl)hexane-3-yl)benzoylamino)propionic acid ethyl ester

((2R,3S)/(2S,3R))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl-2-(4-(trifluoro) Methoxy)phenyl)hexanoic acid 1 m (100 mg, 0.20 mmol), 4-chloro-2-fluoroaniline 17a (44 mg, 0.30 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.80 mmol) Dissolved in 3 mL of dichloromethane, argon gas was exchanged three times, then bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (76 mg, 0.30 mmol) was added, and the reaction was allowed to react at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The residue was purified by silica gel thin-layer chromatography (yield: system A) to give 3-(4-((2R,3S)/(2S,3R)-1-((4-chloro-2-fluorophenyl) Amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid ethyl ester 17b (17 mg, white solid) : 13.6%.

MS m/z (ESI): 622.8 [M+1]

Second step

3-(4-((2R,3S)/(2S,3R)-1-((4-chloro-2-fluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Phenyl)hexane-3-yl)benzoylamino)propionic acid

3-(4-((2R,3S)/(2S,3R)-1-((4-Chloro-2-fluorophenyl)amino)-1-oxo-2-(4-(trifluoro)) Ethyloxy)phenyl)hexane-3-yl)benzoylamino)propionic acid ethyl ester 17b (36 mg, 0.058 mmol) was dissolved in 6 mL of a mixed solvent of tetrahydrofuran and methanol (V/V = 1:1) and stirred. A solution of 1.0 mL of sodium hydroxide (12.0 mg, 0.29 mmol) was added thereto, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give a solvent. EtOAc (EtOAc m. , filtration, and concentration under reduced pressure, and the obtained residue was purified by silica gel chromatography (yield: system A). 3-(4-((2R,3S)/(2S,3R)-1-((4-chloro-2-fluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Phenyl) hexane-3-yl)benzoylamino)propanoic acid 17 (19 mg, white solid), yield: 55.1%.

MS m/z (ESI): 594.8 [M+1]

^{1 H NMR (400MHz, MeOD)} δ7.78 (d, J = 8.2Hz, 2H), 7.70 (d, J = 8.6Hz, 2H), 7.48 (d, J = 8.0Hz, 2H), 7.36 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 7.8 Hz, 2H), 7.11 (d, J = 12.7 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 4.11 (d, J = 11.6 Hz, 1H), 3.63 (t, J = 6.9 Hz, 2H), 3.51 - 3.43 (m, 1H), 2.61 (s, 2H), 1.61 - 1.37 (m, 2H), 1.06 - 0.95 (m, 2H) ), 0.72 (t, J = 7.3 Hz, 3H).

3-(4-((2R,3S)/(2S,3R)-1-((4-chloro-2-fluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy) Further, phenyl)hexane-3-yl)benzoylamino)propanoic acid 17 was further resolved by supercritical fluid chromatography (SFC) using preparative equipment and chiral column chiral isomers (1 ) Chiral Pak AD, 25 × 3 cm, 80 mL / min; mobile phase A for CO ₂ and B for Ethanol; or / and (2) Whelk O1 (S, S), 25 × 3 cm, 65 mL / min; mobile phase A for CO ₂ and B for Ethanol; or / and (3) Whelk O1 (S, S), 25 × 3 cm, 70 mL / min; mobile phase A for CO ₂ and B for Ethanol)), to obtain 3- (4-((2R,3S)-1-((4-chloro-2-fluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane- 3-yl)benzoylamino)propionic acid 17A (white solid) and 3-(4-((2S,3R)-1-((4-chloro-2-fluorophenyl)amino)-1-oxo 2-(4-(Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 17B (white solid).

17A: MS m/z (ESI): 594.8 [M+1]

17B: MS m/z (ESI): 594.8 [M+1]

Example 18

3-(4-((2R,3S)/(2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl-1-((6-(trifluoromethyl))) Pyridin-3-yl)amino)hexane-3-yl)benzoylamino)propanoic acid 18

3-(4-((2R,3S)-1-oxo-2-(4-(trifluoromethoxy)phenyl-1-((6-(trifluoromethyl)pyridin-3-yl)) Amino)hexane-3-yl)benzoylamino)propanoic acid 18A

3-(4-((2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl-1-((6-(trifluoromethyl)pyridin-3-yl)) Amino)hexane-3-yl)benzoylamino)propanoic acid 18B

first step

3-(4-((2R,3S)/(2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl-1-((6-(trifluoromethyl))) Pyridin-3-yl)amino)hexane-3-yl)benzoylamino)propionic acid ethyl ester

((2R,3S)/(2S,3R))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl-2-(4-(trifluoro) Methoxy)phenyl)hexanoic acid 1m (200mg, 0.40mmol), 6-(trifluoromethyl)pyridin-3-amine 18a (98mg, 0.60mmol) and N,N-diisopropylethylamine (0.28 mL, 1.60 mmol) was dissolved in 6 mL of dichloromethane, argon gas was exchanged three times, then bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (152 mg, 0.60 mmol) was added, and the reaction mixture was at 35 ° C. The reaction was carried out for 18 hours. The reaction mixture was concentrated under reduced pressure. ethyl acetate (60 mL), EtOAc (EtOAc) The residue was purified by silica gel chromatography (yield: petroleum ether: ethyl acetate = 1:1) to afford 3-(4-((2), (3) 1-oxo-2-(4-(trifluoromethoxy)phenyl-1-((6-(trifluoromethyl)pyridin-3-yl)amino)hexane-3-yl)benzene Acylamino)ethyl propionate 18b (34 mg, white solid), yield: 13.3%.

MS m/z (ESI): 639.9 [M+1]

Second step

3-(4-((2R,3S)/(2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl-1-((6-(trifluoromethyl))) Pyridin-3-yl)amino)hexane-3-yl)benzoylamino)propionic acid

3-(4-((2R,3S)/(2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl-1-((6-(trifluoromethyl)) Ethyl pyridin-3-yl)amino)hexane-3-yl)benzoylamino)propanoate 18b (34 mg, 0.053 mmol) dissolved in 6 mL of tetrahydrofuran and methanol (V/V = 1:1) Add 1.0 mL of sodium hydroxide (11.0 mg, 0.27 mmol) to the solution under stirring, and stir at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to remove some solvent, pH was adjusted with 3M hydrochloric acid, and 60 The ester is extracted, the organic phase is washed with saturated ammonium chloride solution (30 mL×3), the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue obtained is silica gel thin layer chromatography (developing solvent: system A Purification to give 3-(4-((2R,3S)/(2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl-1-((6-(three) Fluoromethyl)pyridin-3-yl)amino)hexane-3-yl)benzoylamino)propanoic acid 18 (8 mg, white solid), yield: 25.0%.

MS m/z (ESI): 694.8 [M+1]

^{1 H NMR (400MHz, DMSO)} δ10.66 (s, 1H), 8.60 (s, 1H), 8.45 (s, 1H), 8.04 (d, J = 8.0Hz, 1H), 7.76 (s, 1H), 7.74 (s, 1H), 7.72 (s, 1H), 7.69 (s, 1H), 7.67 (s, 1H), 7.44 (s, 2H), 7.42 (s, 2H), 4.16 (d, J = 11.8 Hz) , 1H), 3.66 (t, J = 6.7 Hz, 2H), 3.52 - 3.44 (m, 1H), 2.46 (t, J = 7.0 Hz, 2H), 1.20 - 1.12 (m, 2H), 0.88 (dd, J = 15.7, 7.0 Hz, 2H), 0.64 (t, J = 7.4 Hz, 3H).

3-(4-((2R,3S)/(2S,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl-1-((6-(trifluoromethyl))) Pyridin-3-yl)amino)hexane-3-yl)benzoylamino)propanoic acid 18 is further resolved by supercritical fluid chromatography (SFC) using preparative equipment and chiral column chiral isomers ((1) Chiral Pak AD, 25 x 3 cm, 80 mL/min; mobile phase A for CO ₂ and B for Ethanol; or / and (2) Whelk O1 (S, S), 25 x 3 cm, 65 mL/min ; mobile phase A for CO ₂ and B for Ethanol; or / and (3) Whelk O1 (S, S), 25 × 3 cm, 70 mL / min; mobile phase A for CO ₂ and B for Ethanol)), 3-(4-((2R,3S)-1-Oxo-2-(4-(trifluoromethoxy)phenyl-1-((6-(trifluoromethyl)pyridin-3-yl) Amino)hexane-3-yl)benzoylamino)propionic acid 18A (white solid) and 3-(4-((2S,3R)-1-oxo-2-(4-(trifluoromethoxy) Phenyl-1-((6-(trifluoromethyl)pyridin-3-yl)amino)hexane-3-yl)benzoylamino)propanoic acid 18B (white solid).

18A: MS m/z (ESI): 694.8 [M+1]

18B: MS m/z (ESI): 694.8 [M+1]

Example 19

3-(4-(1-(4-(Trifluoromethoxy)phenyl)-1-(2',4',6'-trimethyl-[1,1'-biphenyl]-4- Carbamoylamino)pentan-2-yl)benzoylamino)propionic acid

3-(4-((1R,2R)-1-(4-(Trifluoromethoxy)phenyl)-1-(2',4',6'-trimethyl-[1,1'- Biphenyl]-4-ylformylamino)pentan-2-yl)benzoylamino)propanoic acid 19A

3-(4-((1S,2S)-1-(4-(Trifluoromethoxy)phenyl)-1-(2',4',6'-trimethyl-[1,1'- Biphenyl]-4-ylformylamino)pentan-2-yl)benzoylamino)propanoic acid 19B

first step

4-(1-(4-(Trifluoromethoxy)phenyl)-1-(2',4,6'-trimethyl-[1,1'-biphenyl]-4-ylcarboxamido Tert-butyl pentan-2-yl)benzoate

4-(1-Amino-1-(4-(trifluoromethoxyphenyl)pentan-2-yl)benzoic acid tert-butyl ester 11b (600 mg, 1.42 mmol), 2', 4', 6' -Trimethyl-[1,1'-biphenyl]-4-carboxylic acid 19a (442 mg, 1.84 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (723 mg, 2.84 mmol) And N,N-diisopropylethylamine (1.0 mL, 5.68 mmol) was dissolved in a mixed solvent of 12 mL of dichloromethane and N,N-dimethylformamide (V/V=5/1). After the reaction was carried out for 18 hours at room temperature, the reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The residue was purified by silica gel column chromatography (eluent: 6'-Trimethyl-[1,1'-biphenyl]-4-ylformylamino)pentan-2-yl)benzoic acid tert-butyl ester 19b (820 mg, yellow solid), yield: 89.4%.

MS m/z (ESI): 589.9 [M+1-56]

Second step

4-(1-(4-(Trifluoromethoxy)phenyl)-1-(2',4,6'-trimethyl-[1,1'-biphenyl]-4-ylcarboxamido Pentane-2-yl)benzoic acid

4-(1-(4-(Trifluoromethoxy)phenyl)-1-(2',4,6'-trimethyl-[1,1'-biphenyl]-4-ylcarbonyl Amino)pentan-2-yl)benzoic acid tert-butyl ester 19b (820 mg, 1.27 mmol) and 85% phosphoric acid (1.20 g, 10.2 mmol) were dissolved in 12 mL of acetonitrile, and the reaction mixture was reacted at 80 ° C for 4 hours. After the reaction mixture was concentrated, EtOAc (EtOAc m. Phenyl)-1-(2',4,6'-trimethyl-[1,1'-biphenyl]-4-ylcarboxamido)pentan-2-yl)benzoic acid 19c (750 mg, White solid), Yield: 100%.

MS m/z (ESI): 589.9 [M+1]

third step

3-(4-(1-(4-(Trifluoromethoxy)phenyl)-1-(2',4',6'-trimethyl-[1,1'-biphenyl]-4- Ethylamino)pentan-2-yl)benzoylamino)propionic acid ethyl ester

4-(1-(4-(Trifluoromethoxy)phenyl)-1-(2',4,6'-trimethyl-[1,1'-biphenyl]-4-ylcarbonyl Amino)pentan-2-yl)benzoic acid 19c (750 mg, 1.27 mmol), 3-aminopropionic acid ethyl ester hydrochloride (293 mg, 1.91 mmol), 2-(7-azobenzotriazole)- N,N,N',N'-tetramethyluronium hexafluorophosphate (726 mg, 1.91 mmol) and N,N-diisopropylethylamine (0.90 mL, 5.08 mmol) dissolved in 10 mL of two N,N- In dimethylformamide, the reaction solution was reacted at room temperature for 4 hours. 25 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL×3). Chromatography (eluent: system C) Purification to give 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1-(2',4',6'-trimethyl-[1,1'-biphenyl] Ethyl 4-carbamoylamino)pentan-2-yl)benzoylamino)propanoate 19d (854 mg, yellow liquid), yield: 97.6%.

MS m/z (ESI): 688.9 [M+1]

the fourth step

3-(4-(1-(4-(Trifluoromethoxy)phenyl)-1-(2',4',6'-trimethyl-[1,1'-biphenyl]-4 -carbamoylamino)pentan-2-yl)benzoylamino)propionic acid ethyl ester 19d (854 mg, 1.24 mmol) and 1.20 mL of lithium hydroxide monohydrate (260 mg, 6.20 mmol) in 12 mL of tetrahydrofuran and methanol In the mixed solvent of (V/V = 1/5), the reaction liquid was reacted at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The residue was purified by silica gel column chromatography (eluent:EtOAc) to afford 3-(4-(4-(trifluoromethoxy)phenyl)-1-(2', 4', 6'-Trimethyl-[1,1'-biphenyl]-4-ylcarbonylamino)pentan-2-yl)benzoylamino)propanoic acid 19 (750 mg, white solid), yield: 91.7 %.

MS m/z (ESI): 660.9 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ 12.25 (s, 1H), 8.71 (d, J = 8.9 Hz, 1H), 8.45 (t, J = 5.3 Hz, 1H), 7.79 (d, J = 8.2 Hz) , 2H), 7.72 (d, J = 8.7 Hz, 2H), 7.53 (dd, J = 13.1, 8.2 Hz, 4H), 7.40 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.1 Hz) , 2H), 6.90 (s, 2H), 5.33 - 5.25 (m, 1H), 3.42 (dd, J = 12.6, 6.9 Hz, 2H), 3.30 - 3.22 (m, 1H), 2.47 (d, J = 7.2 Hz, 2H), 1.91 (s, 3H), 1.85 (s, 6H), 1.52 (dd, J = 18.6, 7.5 Hz, 1H), 1.09 (dd, J = 16.2, 6.6 Hz, 1H), 0.87 (dd) , J = 23.8, 10.3 Hz, 2H), 0.63 (t, J = 7.2 Hz, 3H).

3-(4-(1-(4-(Trifluoromethoxy)phenyl)-1-(2',4',6'-trimethyl-[1,1'-biphenyl]-4- Carbamoylamino)pentan-2-yl)benzoylamino)propanoic acid 19 is further resolved by supercritical fluid chromatography (SFC) using preparative equipment and chiral column chiral isomers (chirality) Column WhelkO1 (S, S), 300 × 50 mm ID 10 μm, mobile phase A for CO ₂ and B for methanol (0.1% NH ₃ H ₂ O), flow rate 200 mL / min) was resolved to obtain 3-(4-(( 1R,2R)-1-(4-(Trifluoromethoxy)phenyl)-1-(2',4',6'-trimethyl-[1,1'-biphenyl]-4-yl Formylamino)pentan-2-yl)benzoylamino)propanoic acid 19A (retention time: 4.57 min; ee value: 100%) and 3-(4-((1S,2S)-1-(4-) (trifluoromethoxy)phenyl)-1-(2',4',6'-trimethyl-[1,1'-biphenyl]-4-ylcarboxamido)pentan-2-yl Benzoylamino)propionic acid 19B (retention time: 10.56 min; ee value: 100%).

19A: MS m/z (ESI): 660.9 [M+1]

19B: MS m/z (ESI): 660.9 [M+1]

Example 20

3-(4-(1-(3,5-Dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzoylamino)-1-(4-( Trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propionic acid

first step

4-(1-(3,5-Dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzoylamino)-1-(4-(trifluoromethyl) Methyl oxy)phenyl)pentan-2-yl)benzoate

tert-Butyl 4-(1-amino-1-(4-(trifluoromethoxyphenyl)pentan-2-yl)benzoate 11b (560 mg, 1.32 mmol), 3,5-dimethyl- 4-(4-(Trifluoromethyl)-1H-pyrazol-1-yl)benzoic acid 20a (340 mg, 1.20 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (611 mg) , 2.40 mmol) and N,N-diisopropylethylamine (0.84 mL, 4.80 mmol) dissolved in 12 mL of dichloromethane and N,N-dimethylformamide (V/V=5/1) The reaction mixture was reacted for 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc) The residue was purified by silica gel column chromatography (eluent: system A) to give 4-(1-(3,5-dimethyl-4-(4-(trifluoro)) Methyl)-1H-pyrazol-1-yl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid methyl ester 20b (260 mg, white solid ), yield: 31.4%.

MS m/z (ESI): 633.8 [M+1-56]

Second step

4-(1-(3,5-Dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzoylamino)-1-(4-(trifluoromethyl) Oxy)phenyl)pentan-2-yl)benzoic acid

4-(1-(3,5-Dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzoylamino)-1-(4-(trifluoro) Methyl methoxy)phenyl)pentan-2-yl)benzoate 20b (260 mg, 0.38 mmol) and 85% phosphoric acid (350 mg, 3.00 mmol) were dissolved in 8 mL of acetonitrile and the reaction was reacted at 80 ° C. hour. After the reaction mixture was concentrated, EtOAc (EtOAc m.) 4-(4-(Trifluoromethyl)-1H-pyrazol-1-yl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzene Formic acid 20c (240 mg, pale yellow liquid), yield: 100%.

MS m/z (ESI): 633.8 [M+1]

third step

3-(4-(1-(3,5-Dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzoylamino)-1-(4-( Ethyl trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propanoate

4-(1-(3,5-Dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzoylamino)-1-(4-(trifluoro) Methoxy)phenyl)pentan-2-yl)benzoic acid 20c (240 mg, 0.38 mmol), 3-aminopropionic acid ethyl ester hydrochloride (117 mg, 0.76 mmol), 2- (7-azobenzene) Triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (217 mg, 0.57 mmol) and N,N-diisopropylethylamine (0.30 mL, 1.52 mmol) were dissolved in 5 mL In the two N,N-dimethylformamide, the reaction solution was reacted at room temperature for 4 hours. 25 mL of water was added to the reaction mixture, and extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with water (50 mL×2), dried over anhydrous sodium sulfate. -(1-(3,5-Dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzoylamino)-1-(4-(trifluoromethoxy) Ethyl phenyl)pentan-2-yl)benzoylamino)propionic acid ethyl ester 20d (278 mg, off-white solid), yield: 100%.

MS m/z (ESI): 732.9 [M+1]

the fourth step

3-(4-(1-(3,5-Dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzoylamino)-1-(4-) Ethyl (trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propanoate 20d (278 mg, 0.38 mmol) and 0.40 mL of lithium hydroxide monohydrate (80 mg, 1.90 mmol) In a mixed solvent of 6 mL of tetrahydrofuran and methanol (V/V = 1/2), the reaction solution was reacted at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The residue was purified by silica gel column chromatography (eluent: EtOAc) to afford 3-(4-(3,5-dimethyl-4-(4-trifluoromethyl)-1H- Pyrazol-1-yl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propanoic acid 20 (197 mg, white solid) Yield: 73.8%.

MS m/z (ESI): 704.9 [M+1]

^{1 H NMR (400MHz, DMSO)} δ12.25 (s, 1H), 9.10 (d, J = 8.7Hz, 1H), 8.50 (t, J = 5.3Hz, 1H), 8.07 (s, 1H), 7.69 ( d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 7.14 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 7.4 Hz, 1H), 6.83 (d, J = 7.2 Hz, 1H), 5.17 - 5.06 (m, 1H), 3.58 - 3.49 (m, 2H), 3.12–3.02 (m,1H), 2.59 (t, J=6.9 Hz, 2H), 1.41 (s, 3H), 1.23 (s, 3H), 1.22–1.15 (m, 1H), 1.03–0.91 (m, 1H), 0.76 (dd, J = 14.6, 7.7 Hz, 2H), 0.55 (t, J = 7.1 Hz, 3H).

Example 21

3-(4-(1-(4-Cyanobenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propanoic acid

First step

4-(1-(4-Cyanobenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid tert-butyl ester

4-(1-Amino-1-(4-(trifluoromethoxyphenyl)pentan-2-yl)benzoic acid tert-butyl ester 11b (423 mg, 1.00 mmol), 4-cyanobenzoic acid 21a ( 162 mg, 1.10 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (510 mg, 2.00 mmol) and N,N-diisopropylethylamine (0.70 mL, 4.00 mmol) dissolved in 12 mL The reaction solution was reacted at room temperature for 18 hours in a mixed solvent of dichloromethane and N,N-dimethylformamide (V/V = 5/1). The reaction mixture was concentrated under reduced pressure and then 20 mL ethyl acetate and 20 The organic layer was washed with water (10 mL×2), dried over anhydrous sodium sulfate, filtered and evaporated. Purification by the method (eluent: System A) gave 4-(1-(4-cyanobenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl) tert-Butyl benzoate 21b (406 mg, white solid), yield: 73.5%.

MS m/z (ESI): 496.9 [M+1-56]

Second step

4-(1-(4-Cyanobenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid

4-(1-(4-Cyanobenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid tert-butyl ester 21b (406 mg, 0.73 mmol Dissolved in 3 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, and the reaction solution was reacted at room temperature for 18 hours. After the reaction mixture was concentrated, EtOAc (EtOAc m. 1-(4-(Trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid 21c (337 mg, white solid), yield: 93.0%.

MS m/z (ESI): 496.9 [M+1]

third step

Ethyl 3-(4-(1-(4-cyanobenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propanoate

4-(1-(4-Cyanobenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid 21c (337 mg, 0.68 mmol), 3 -Aminopropionic acid ethyl ester hydrochloride (261 mg, 1.70 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (432 mg, 1.70 mmol) and N,N-diisopropylethylamine (0.56 mL, 3.39 mmol) was dissolved in 9 mL of dichloromethane, and the reaction mixture was reacted at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. Purification by eluent (eluent: System A) to give 3-(4-(1-(4-cyanobenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentane Ethyl-2-phenyl)benzoylamino)propanoate 21d (51 mg, off-white solid), yield: 12.6%.

MS m/z (ESI): 595.9 [M+1]

the fourth step

3-(4-(1-(4-Cyanobenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propanoic acid B The ester 21d (51 mg, 0.086 mmol) and 1.0 mL of lithium hydroxide monohydrate (18 mg, 0.428 mmol) were dissolved in a mixed solvent of 5 mL of tetrahydrofuran and methanol (V/V = 1/4), and the reaction solution was reacted at room temperature. hour. 30 mL of ethyl acetate was added to the reaction mixture, and the mixture was adjusted to pH with aq. EtOAc. EtOAc (EtOAc) Drying, filtration and concentration under reduced pressure, the obtained residue was purified by silica gel chromatography (yield: system C) to give 3-(4-(4-cyanobenzoylamino)-1 -(4-(Trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propanoic acid 21 (17 mg, white solid).

MS m/z (ESI): 567.9 [M+1]

¹ H NMR (400 MHz, DMSO) δ 8.92 (d, J = 9.1 Hz, 1H), 8.50 (s, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.76 (d, J = 7.9 Hz, 2H), 7.71 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H) , 5.28 (d, J = 1.8 Hz, 1H), 3.43 - 3.38 (m, 2H), 2.47 - 2.42 (m, 2H), 1.62 - 1.45 (m, 2H), 1.16 - 1.00 (m, 2H), 0.62 (t, J = 7.2 Hz, 3H).

Example 22

3-(4-(1-(3,5-dimethylbenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propane acid

first step

tert-Butyl 4-(1-(3,5-dimethylbenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoate

tert-Butyl 4-(1-amino-1-(4-(trifluoromethoxyphenyl)pentan-2-yl)benzoate 11b (423 mg, 1.00 mmol), 3,5-dimethylbenzoic acid 22a (165 mg, 1.10 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (510 mg, 2.00 mmol) and N,N-diisopropylethylamine (0.70 mL, 4.00 mmol) The reaction solution was reacted at room temperature for 18 hours in a mixed solvent of 12 mL of dichloromethane and N,N-dimethylformamide (V/V = 5/1). 20 mL of water, EtOAc, EtOAc (EtOAc (EtOAc m. Purification by chromatography (eluent: System A) to give 4-(1-(3,5-dimethylbenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentane tert-Butyl benzoate 22b (389 mg, white solid), yield: 70.0%.

MS m/z (ESI): 557.0 [M+1]

Second step

4-(1-(3,5-Dimethylbenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid

4-(1-(3,5-Dimethylbenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid tert-butyl ester 22b (260 mg , 0.38 mmol) was dissolved in 3 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, and the reaction mixture was reacted at room temperature for 18 hours. After the reaction mixture was concentrated, ethyl acetate (20 mL), EtOAc (EtOAc) Amido)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid 22c (327 mg, white liquid), yield: 93.5%.

MS m/z (ESI): 499.9 [M+1]

third step

3-(4-(1-(3,5-dimethylbenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propane Ethyl acetate

4-(1-(3,5-Dimethylbenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid 22c (327 mg, 0.65 mmol , 3-aminopropionic acid ethyl ester hydrochloride (251 mg, 1.64 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (417 mg, 1.64 mmol) and N,N-diisopropyl Ethylethylamine (0.54 mL, 3.27 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and the reaction was allowed to react at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. Purification by eluent (eluent: System C) to give 3-(4-(3,5-dimethylbenzoylamino)-1-(4-(trifluoromethoxy)phenyl) Ethylpentane-2-yl)benzoylamino)propanoate 22d (128 mg, white solid), yield: 32.8%.

MS m/z (ESI): 598.9 [M+1]

the fourth step

3-(4-(1-(3,5-Dimethylbenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino) Ethyl propionate 22d (128mg, 0.31mmol) and 1.0mL lithium hydroxide monohydrate (72mg, 1.71mmol) solution was dissolved in 5mL tetrahydrofuran and methanol (V / V = 1/4) mixed solvent, the reaction solution at room temperature The reaction was carried out for 18 hours. The reaction solution was concentrated under reduced pressure. EtOAc (3 mL, EtOAc, EtOAc, EtOAc. Washed, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-(4-(3,5-dimethylbenzoylamino)-1-(4-(trifluoromethoxy) Phenyl)pentan-2-yl)benzoylamino)propanoic acid 22 (98 mg, white solid), yield: 81.8%.

MS m/z (ESI): 570.9 [M+1]

^{1 H NMR (400MHz, DMSO)} δ8.50 (s, 1H), 8.46 (d, J = 10.0Hz, 1H), 7.78 (d, J = 7.8Hz, 2H), 7.70 (d, J = 8.6Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H), 7.03 (s, 1H), 6.99 (s, 2H), 5.21. (d, J = 10.1 Hz, 1H), 3.46–3.38 (m, 2H), 2.47 (d, J = 2.4 Hz, 2H), 2.20 (s, 6H), 1.59–1.46 (m, 2H), 1.14–0.99 (m, 2H), 0.63 (t, J = 7.3 Hz, 3H).

Example 23

3-(4-(1-(5-chloropyridylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propanoic acid

first step

Tert-butyl 4-(1-(5-chloropyridylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoate

4-(1-Amino-1-(4-(trifluoromethoxyphenyl)pentan-2-yl)benzoic acid tert-butyl ester 11b (423 mg, 1.00 mmol), 5-chloropicolinic acid 23a (175 mg) , 1.10 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (510 mg, 2.00 mmol) and N,N-diisopropylethylamine (0.70 mL, 4.00 mmol) dissolved in 10 mL In a mixed solvent of methyl chloride and N,N-dimethylformamide (V/V=4/1), the reaction mixture was reacted at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and then 20 mL of water (10 mL × 3), the combined organic phase was washed with water (30 mL×3). 4-(1-(5-Chloropyridylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid tert-butyl ester 23b (470 mg, pale yellow solid) , Yield: 83.5%. MS m/z (ESI): 584.8 [M+23]

Second step

4-(1-(5-chloropicolinylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid

Dissolve tert-butyl 4-(1-(5-chloropyridylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoate 23b (470 mg, 0.83 mmol) 6 mL of trifluoroacetic acid was added to 6 mL of dichloromethane, and the reaction solution was reacted at 25 ° C for 2 hours. After the reaction mixture was concentrated, EtOAc (EtOAc) (EtOAc (EtOAc) -Chloropyridylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid 23c (423 mg, yellow liquid), yield: 100%.

MS m/z (ESI): 506.8 [M+1]

third step

Ethyl 3-(4-(1-(5-chloropyridylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propanoate

4-(1-(5-Chloropyridylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid 23c (423 mg, 0.83 mmol), 3-amino Ethyl propionate hydrochloride (255 mg, 1.66 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (473 mg, 1.24) Methyl) and N,N-diisopropylethylamine (0.60 mL, 3.32 mmol) were dissolved in 8 mL of N,N-dimethylformamide, and the reaction mixture was reacted at 25 ° C for 3 hours. 30 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL×3). Purification by chromatography (eluent: System D) to give 3-(4-(5-chloropyridylamino)-1-(4-(trifluoromethoxy)phenyl)pentane-2 Ethyl benzoylamino)propanoate 23d (340 mg, white solid), yield: 67.6%.

MS m/z (ESI): 605.8 [M+1]

the fourth step

Ethyl 3-(4-(1-(5-chloropyridylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propanoate 23d (340 mg, 0.56 mmol) and 0.50 mL of lithium hydroxide monohydrate (120 mg, 2.80 mmol) were dissolved in a mixed solvent of 8 mL of tetrahydrofuran and methanol (V/V = 1/4), and the reaction mixture was reacted at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. Chromatography (eluent: system C) purification, 3-(4-(1-(5-Chloropyridine)amino-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propanoic acid 23 (290 mg) , white solid), Yield: 89.5%.

MS m/z (ESI): 577.8 [M+1]

^{1 H NMR (400MHz, DMSO)} δ12.18 (s, 1H), 9.11 (d, J = 9.2Hz, 1H), 8.60 (d, J = 2.1Hz, 1H), 8.43 (t, J = 5.4Hz, 1H), 8.00 (dd, J = 8.5, 2.1 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.73 (t, J = 8.7 Hz, 4H), 7.46 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 5.29 (t, J = 10.0 Hz, 1H), 3.50 - 3.37 (m, 3H), 2.47 (d, J = 7.0 Hz, 2H), 1.52 ( d, J = 11.5 Hz, 1H), 1.15 - 1.04 (m, 1H), 0.86 (dd, J = 15.7, 9.5 Hz, 2H), 0.63 (t, J = 7.2 Hz, 3H).

Example 24

3-(4-(1-(4-Chloro-2-methylbenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino) Propionic acid

first step

4-(1-(4-Chloro-2-methylbenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid tert-butyl ester

tert-Butyl 4-(1-amino-1-(4-(trifluoromethoxyphenyl)pentan-2-yl)benzoate 11b (423 mg, 1.00 mmol), 4-chloro-2-methylbenzene Formic acid 24a (190 mg, 1.10 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (510 mg, 2.00 mmol) and N,N-diisopropylethylamine (0.70 mL, 4.00 mmol) The reaction solution was dissolved in a mixed solvent of 10 mL of dichloromethane and N,N-dimethylformamide (V/V=4/1), and the reaction mixture was reacted at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and then 20 mL of water was used. The organic layer was washed with water (30 mL×3), dried over anhydrous sodium sulfate, filtered and evaporated. A) Purification to give 4-(1-(4-chloro-2-methylbenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid Butyl ester 24b (460 mg, white solid), yield: 79.9%.

MS m/z (ESI): 597.8 [M+23]

Second step

4-(1-(4-Chloro-2-methylbenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid

4-(1-(4-Chloro-2-methylbenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid tert-butyl ester 24b ( 460 mg, 0.80 mmol) and 85% phosphoric acid (553 mg, 4.80 mmol) were dissolved in 5 mL of acetonitrile, and the reaction mixture was reacted at 80 ° C for 4 hours. After the reaction mixture was concentrated, EtOAc (EtOAc m.) Benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid 24c (416 mg, yellow liquid), yield: 100%.

MS m/z (ESI): 519.8 [M+1]

third step

3-(4-(1-(4-Chloro-2-methylbenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino) Ethyl propionate

4-(1-(4-Chloro-2-methylbenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid 24c (416 mg, 0.85 Methyl), 3-aminopropionic acid ethyl ester hydrochloride (250 mg, 1.60 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluoro The phosphate (456 mg, 1.20 mmol) and N,N-diisopropylethylamine (0.60 mL, 3.20 mmol) were dissolved in 8 mL of N,N-dimethylformamide, and the reaction was reacted at 25 ° C for 3 hours. . The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. 4-(1-(4-Chloro-2-methylbenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propanoic acid B Ester 24d (495 mg, white solid), yield: 100%.

MS m/z (ESI): 618.90 [M+1]

the fourth step

3-(4-(1-(4-Chloro-2-methylbenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino Ethyl propionate 24d (495mg, 0.80mmol) and 0.80mL lithium hydroxide monohydrate (170mg, 4.00mmol) solution was dissolved in 9mL tetrahydrofuran and methanol (V / V = 2 / 7) in a mixed solvent, the reaction solution The reaction was carried out for 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. Purification by chromatography (eluent: system C) to give 3-(4-(4-chloro-2-methylbenzoylamino)-1-(4-(trifluoromethoxy)benzene Pentyl-2-yl)benzoylamino)propanoic acid 24 (270 mg, white solid), yield: 57.1%.

MS m/z (ESI): 590.8 [M+1]

^{1 H NMR (400MHz, DMSO)} δ12.17 (s, 1H), 8.67 (d, J = 9.4Hz, 1H), 8.49 (t, J = 5.1Hz, 1H), 7.81 (d, J = 8.0Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 7.42 (dd, J = 11.2, 8.5 Hz, 4H), 7.19 (s, 1H), 7.15 (d, J = 7.8 Hz, 1H), 6.70 ( d, J = 8.4 Hz, 1H), 5.29 (t, J = 10.1 Hz, 1H), 3.46 (dd, J = 11.9, 6.0 Hz, 2H), 3.03 (td, J = 9.8, 1.3 Hz, 1H), 2.69 (s, 3H), 2.53 (d, J = 7.6 Hz, 2H), 1.52 (dd, J = 18.9, 6.0 Hz, 1H), 1.12 - 1.02 (m, 1H), 0.90 - 0.77 (m, 2H) , 0.61 (t, J = 7.0 Hz, 3H).

Example 25

3-(4-(1-(2-fluoro-4-(trifluoromethyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzene Formylamino)propionic acid

first step

4-(1-(2-Fluoro-4-(trifluoromethyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid tert-butyl ester

tert-Butyl 4-(1-amino-1-(4-(trifluoromethoxyphenyl)pentan-2-yl)benzoate 11b (423 mg, 1.00 mmol), 2-fluoro-4-(3) Fluoromethyl)benzoic acid 25a (230 mg, 1.10 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (510 mg, 2.00 mmol) and N,N-diisopropylethylamine (0.70) mL, 4.00 mmol) was dissolved in a mixed solvent of 10 mL of dichloromethane and N,N-dimethylformamide (V/V=4/1), and the reaction mixture was reacted at room temperature for 18 hours. After adding 20 mL of water, it was extracted with ethyl acetate (10 mL × 3), and the organic layer was washed with water (30 mL × 3), dried over anhydrous sodium sulfate Eluent: System A) was purified to give 4-(1-(2-fluoro-4-(trifluoromethyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentyl tert-Butyl ester of alk-2-yl)benzoate 25b (500 mg, white solid), yield: 81.6%.

MS m/z (ESI): 557.8 [M+1-56]

Second step

4-(1-(2-Fluoro-4-(trifluoromethyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid

4-(1-(2-Fluoro-4-(trifluoromethyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid Butyl ester 25b (500 mg, 0.82 mmol) and 85% phosphoric acid (753 mg, 6.53 mmol) were dissolved in 10 mL of acetonitrile, and the reaction mixture was reacted at 80 ° C for 4 hours. After the reaction mixture was concentrated, EtOAc (EtOAc m.) Fluoromethyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid 25c (457 mg, yellow solid), yield: 100%.

MS m/z (ESI): 557.8 [M+1]

third step

3-(4-(1-(2-fluoro-4-(trifluoromethyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzene Formylamino)propionic acid tert-butyl ester

4-(1-(2-Fluoro-4-(trifluoromethyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid 25c (457 mg, 0.82 mmol), tert-butyl 3-aminopropionate hydrochloride (300 mg, 1.64 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-four Methylurea hexafluorophosphate (470 mg, 1.23 mmol) and N,N-diisopropylethylamine (0.60 mL, 3.28 mmol) were dissolved in 8 mL of N,N-dimethylformamide. The reaction was carried out at ° C for 3 hours. 30 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL×3). (1-(2-Fluoro-4-(trifluoromethyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propane T-butyl acid ester 25d (560 mg, yellow solid), yield: 100%.

MS m/z (ESI): 571.90 [M+1]

the fourth step

3-(4-(1-(2-Fluoro-4-(trifluoromethyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl) The benzoylamino)propionic acid tert-butyl ester 25d (560 mg, 0.82 mmol) and 85% phosphoric acid (570 mg, 4.92 mmol) were dissolved in 20 mL of acetonitrile, and the reaction mixture was reacted at 80 ° C for 4 hours. The reaction solution was precipitated with a large amount of solid, filtered, and the filter cake was washed successively with water (15 mL × 2) and dichloromethane (15 mL × 2), and the filter cake was dissolved in 20 mL of a mixture of methanol and toluene (V/V = 3/1). Concentrated to dryness under reduced pressure and dried in vacuo to give 3-(4-(2-(2-fluoro-4-(trifluoromethyl)benzoylamino)-1-(4-(trifluoromethoxy) Phenyl)pentan-2-yl)benzoylamino)propanoic acid 25 (340 mg, white solid), yield: 66.0%.

MS m/z (ESI): 628.8 [M+1]

^{1 H NMR (400MHz, DMSO)} δ12.06 (d, J = 3.7Hz, 1H), 8.89 (d, J = 8.9Hz, 1H), 8.50 (t, J = 5.5Hz, 1H), 7.80 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 9.4 Hz, 1H), 7.64 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.48 - 7.34 (m, 4H), 7.15 (t, J = 7.3 Hz, 1H), 5.31 (t, J = 9.8 Hz, 1H), 3.46 (dd, J = 12.6, 6.7 Hz, 2H), 3.08 (td, J = 10.9, 2.5 Hz, 1H), 2.57–2.52 (m, 2H), 1.64–1.48 (m, 1H), 1.18–1.05 (m, 1H), 0.97–0.77 (m, 2H), 0.62 (t, J = 7.2 Hz, 3H).

Example 26

3-(4-(1-(Iso-nicotinyl)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propanoic acid

first step

Tert-butyl 4-(1-(isonicotinido)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoate

4-(1-Amino-1-(4-(trifluoromethoxyphenyl)pentan-2-yl)benzoic acid tert-butyl ester 11b (423 mg, 1.00 mmol), isonicotinic acid 26a (150 mg, 1.20) Methyl) bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (510 mg, 2.00 mmol) and N,N-diisopropylethylamine (0.70 mL, 4.00 mmol) dissolved in 11 mL dichloromethane In a mixed solvent of N,N-dimethylformamide (V/V=8/3), the reaction mixture was allowed to react at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, then 20 mL of water ×3), the combined organic phase was washed with water (30 mL×3), anhydrous sulfuric acid The sodium was dried, filtered, and concentrated under reduced pressure. EtOAcjjjjjjjj tert-Butyl fluoromethoxy)phenyl)pentan-2-yl)benzoate 26b (450 mg, yellow solid), yield: 85.2%.

MS m/z (ESI): 528.9 [M+1]

Second step

4-(1-(Ionicotinylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid

tert-Butyl 4-(1-(isonicotinido)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoate 26b (450 mg, 0.85 mmol) and 4 mL The fluoroacetic acid was dissolved in 4 mL of dichloromethane, and the reaction solution was reacted at 25 ° C for 2 hours. After the reaction mixture was concentrated, EtOAc (EtOAc) (EtOAc (EtOAc) Amido)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid 26c (400 mg, yellow solid), yield: 100%.

MS m/z (ESI): 472.9 [M+1]

third step

Ethyl 3-(4-(1-(isonicotinido)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propanoate

4-(1-(Isoanilino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid 26c (400 mg, 0.85 mmol), 3-aminopropionic acid Ethyl ester hydrochloride (261 mg, 1.70 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (485 mg, 1.28 mmol) N,N-diisopropylethylamine (0.60 mL, 3.40 mmol) was dissolved in 8 mL of N,N-dimethylformamide, and the reaction mixture was reacted at 25 ° C for 4 hours. The reaction mixture was concentrated under reduced vacuol~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Ethyl 4-(1-(isonicotinido)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propanoate 26d (485 mg, white solid) , Yield: 100%.

MS m/z (ESI): 571.90 [M+1]

the fourth step

Ethyl 3-(4-(1-(Iso-nicotinyl)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propanoate 26d (485mg A solution of 0.85 mL of lithium hydroxide monohydrate (180 mg, 4.25 mmol) was dissolved in 12 mL of a mixed solvent of tetrahydrofuran and methanol (V/V = 1/5), and the reaction mixture was reacted at 25 ° C for 4 hours. The reaction solution was concentrated under reduced pressure, and the mixture was adjusted to pH 2-3 with 1M hydrochloric acid, and a large amount of solids was precipitated, filtered, and the filter cake was washed with water (15 mL × 2) and dichloromethane (15 mL × 2), and the filter cake was dissolved. In a mixture of 20 mL of methanol and toluene (V/V = 3/1), concentrated under reduced pressure to dryness and dried in vacuo to give 3-(4-(1-(nicotinoylamino)-1-(4-( Trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propanoic acid 26 (350 mg, white solid), yield: 75.8%.

MS m/z (ESI): 543.8 [M+1]

^{1 H NMR (400MHz, DMSO)} δ12.26 (s, 1H), 8.95 (d, J = 8.3Hz, 1H), 8.62 (d, J = 5.5Hz, 2H), 8.46 (t, J = 5.1Hz, 1H), 7.77 (d, J = 7.9 Hz, 2H), 7.71 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.3 Hz, 2H), 7.40 (t, J = 5.8 Hz, 4H) , 5.32–5.22 (m, 1H), 3.42 (dd, J = 12.1, 5.9 Hz, 2H), 3.21 (t, J = 11.2 Hz, 1H), 2.46 (d, J = 4.5 Hz, 2H), 1.55 ( Dd, J = 20.5, 8.8 Hz, 1H), 1.08 (dd, J = 19.2, 7.6 Hz, 1H), 0.88 (dt, J = 15.7, 6.5 Hz, 2H), 0.63 (t, J = 7.2 Hz, 3H) ).

Example 27

3-(4-(1-(tert-butyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propanoic acid 27

first step

Tert-butyl 4-(1-(tert-butyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoate

tert-Butyl 4-(1-amino-1-(4-(trifluoromethoxyphenyl)pentan-2-yl)benzoate 11b (423 mg, 1.00 mmol), 4-(tert-butyl)benzene Formic acid 27a (215 mg, 1.20 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (510 mg, 2.00 mmol) and N,N-diisopropylethylamine (0.70 mL, 4.00 mmol) The reaction solution was dissolved in a mixed solvent of 10 mL of dichloromethane and N,N-dimethylformamide (V/V=4/1), and the reaction mixture was reacted at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and then 20 mL of water was used. The organic layer was washed with water (30 mL×3), dried over anhydrous sodium sulfate, filtered and evaporated. A) Purification to give 4-(1-(tert-butyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid tert-butyl ester 27b ( 260 mg, yellow solid), yield: 68.6%.

MS m/z (ESI): 527.9 [M+1-56]

Second step

4-(1-(tert-butyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid

tert-Butyl 4-(1-(tert-butyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoate 27b (400 mg, 0.68 mmol And 4 mL of trifluoroacetic acid was dissolved in 4 mL of dichloromethane, and the reaction solution was reacted at 25 ° C for 2 hours. After the reaction mixture was concentrated, EtOAc (3 mL, EtOAc) was evaporated. Butyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid 27c (362 mg, yellow liquid), yield: 100%.

MS m/z (ESI): 527.9 [M+1]

third step

Ethyl 3-(4-(1-(tert-butyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propanoate

4-(1-(tert-butyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoic acid 27c (362 mg, 0.68 mmol), 3 -Aminopropionic acid ethyl ester hydrochloride (210 mg, 1.36 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (390 mg , 1.02 mmol) and N,N-diisopropylethylamine (0.50 mL, 2.72 mmol) were dissolved in 6 mL of N,N-dimethylformamide, and the reaction mixture was reacted at room temperature for 4 hours. 25 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL×3), and the organic phase was washed with water (30 mL×2). The organic layer was dried over sodium sulfate, filtered, and evaporated, evaporated, mjjjjjjjjjj Ethyl 1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propanoate 27d (170 mg, white solid), yield: 39.9%.

MS m/z (ESI): 627.0 [M+1]

the fourth step

3-(4-(1-(tert-butyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propanoic acid

3-(4-(1-(tert-Butyl)benzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propanoic acid A solution of ester 27d (170 mg, 0.27 mmol) and 0.30 mL of lithium hydroxide monohydrate (60 mg, 1.40 mmol) was dissolved in a mixed solvent of 8 mL of tetrahydrofuran and methanol (V/V = 3/1), and the reaction mixture was reacted at 25 ° C. 4 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The residue was purified by silica gel column chromatography (eluent: system C) to give 3-(4-(1-(tert-butyl)benzoylamino)-1-(4-(trifluoromethoxy) Phenyl)pentan-2-yl)benzoylamino)propanoic acid 27 (110 mg, white solid), yield: 68.3%.

MS m/z (ESI): 598.9 [M+1]

^{1 H NMR (400MHz, DMSO)} δ12.20 (s, 1H), 8.55 (d, J = 8.8Hz, 1H), 8.45 (t, J = 5.3Hz, 1H), 7.76 (d, J = 8.1Hz, 2H), 7.70 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 7.45 - 7.29 (m, 6H), 5.29 - 5.19 (m, 1H), 3.41 (dd, J = 12.8, 7.0 Hz, 2H), 3.27 - 3.16 (m, 1H), 2.47 (d, J = 7.1 Hz, 2H), 1.52 (dd, J = 17.2, 5.5 Hz, 1H), 1.25 (s, 9H) , 1.07 (dd, J = 15.6, 8.9 Hz, 1H), 0.93 - 0.78 (m, 2H), 0.62 (t, J = 7.2 Hz, 3H).

Example 28

3-(4-((2R,3R)/(2S,3S)-1-((3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4 -yl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 28

3-(4-((2R,3R)-1-((3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4-yl)amino)- 1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 28A

3-(4-((2S,3S)-1-((3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4-yl)amino)- 1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 28B

first step

3-(4-((2R,3R)/(2S,3S)-1-((3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4 -yl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid ethyl ester

((2R,3R)/(2S,3S))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(3) Fluoromethoxy)phenyl)hexanoic acid 1s (82.0 g, 165.5 mmol), 3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4-amine 4c (37.9 g, 165.5 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (83.8 g, 329.8 mmol) was dissolved in 820 mL of dichloromethane, and N,N-diisopropyl was added with stirring. Ethylethylamine (145.7 mL, 827.7 mmol) was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and purified residue purified silicagel elut elut elut elut elut elut ((3-Fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4-yl)amino)-1-oxo-2-(4-(trifluoromethyl) Ethyl phenyl) hexane-3-yl)benzoylamino)propanoic acid ethyl ester 28a (110.0 g, white solid), yield: 94.0%.

MS m/z (ESI): 706.9 [M+1]

Second step

3-(4-((2R,3R)/(2S,3S)-1-((3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4 -yl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid

3-(4-((2R,3R)/(2S,3S)-1-((3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]- Ethyl 4-amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoate 28a (110.0 g, 155.6 mmol It was dissolved in a mixed solvent of 1200 mL of tetrahydrofuran and methanol (V/V = 1:1), and 65 mL of lithium hydroxide monohydrate (65.0 g, 1.56 mol) was added thereto with stirring, and the mixture was stirred at room temperature for 2 hours. After adding 1000 mL of ethyl acetate, the mixture was washed with EtOAc EtOAc (EtOAc)EtOAc. Purification by chromatography (eluent: System A) gave 3-(4-((2R,3R)/(2S,3S)-1-((3-fluoro-2',4',6'- Methyl-[1,1'-biphenyl]-4-yl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoyl Amino)propionic acid 28 (82.0 g, white solid), yield: 77.7%.

MS m/z (ESI): 678.9 [M+1]

3-(4-((2R,3R)/(2S,3S)-1-((3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4 -yl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 28 further passed through a chiral column by using super Critical fluid chromatography (SFC) method, using preparative equipment and chiral column chiral isomers for resolution ((1) Chiral Pak AD, 25 × 3 cm, 80 mL / min; mobile phase A for CO ₂ and B for Ethanol; or / and (2) Whelk O1 (S, S), 25 × 3 cm, 65 mL / min; mobile phase A for CO ₂ and B for Ethanol; or / and (3) Whelk O1 (S, S), 25 ×3 cm, 70 mL/min; mobile phase A for CO ₂ and B for Ethanol)) was resolved to obtain 3-(4-((2R,3R)-1-((3-fluoro-2', 4', 6'-Trimethyl-[1,1'-biphenyl]-4-yl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl Benzoylamino)propionic acid 28A and 3-(4-((2S,3S)-1-((3-fluoro-2',4',6'-trimethyl-[1,1'-linked Benzene-4-yl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 28B.

28A: MS m/z (ESI): 678.9 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ = 10.17 (s, 1H), 8.44-8.32 (m, 1H), 8.01 (t, J = 8.3Hz, 1H), 7.70-7.57 (m, 2 H) , 7.42 (d, J = 8.5 Hz, 2H), 7.24-7.10 (m, 4H), 7.06 (d, J = 11.8 Hz, 1H), 6.97 - 6.84 (m, 3H), 4.40 (d, J = 11.3) Hz, 1H), 3.56-3.33 (m, 4H), 2.30-2.18 (m, 3H), 2.03-1.85 (m, 6H), 1.74 (d, J = 15.6 Hz, 2H), 1.14-0.93 (m, 4H), 0.88-0.72 (m, 3H).

28B: MS m/z (ESI): 678.9 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ = 9.81 (s, 1H), 8.08-7.96 (m, 1H), 7.65 (t, J = 8.3Hz, 1H), 7.34-7.21 (m, 2H), 7.06 (d, J = 8.5 Hz, 2H), 6.88 - 6.74 (m, 4H), 6.71 (d, J = 11.8 Hz, 1H), 6.61-6.48 (m, 3H), 4.04 (d, J = 11.3 Hz) , 1H), 3.20–2.97 (m, 4H), 2.28-2.08 (m, 3H), 2.01-1.80 (m, 6H), 1.54 (d, J = 15.6 Hz, 2H), 1.11-0.92 (m, 4H) ), 0.87-0.72 (m, 3H).

Example 29

3-(4-((2R,3R)/(2S,3S)-1-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-) 1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 29

3-(4-((2R,3R)-1-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-1-oxo-2 -(4-(Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 29A

3-(4-((2S,3S)-1-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-1-oxo-2 -(4-(Trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 29B

first step

3-(4-((2R,3R)/(2S,3S)-1-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-) Ethyl 1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoate

((2R,3R)/(2S,3S))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(3) Fluoromethoxy)phenyl)hexanoic acid 1s (80 Mg, 0.16 mmol), 4'-chloro-2'-methyl-[1,1'-biphenyl]-4-amine 1n (52 mg, 0.24 mmol), 1-hydroxybenzotriazole (43 mg, 0.32 mmol) And 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.32 mmol) dissolved in 20 mL of dichloromethane and added with N,N-diisopropyl Amine (0.14 mL, 0.8 mmol) was stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure and purified residue purified silicagel elut elut elut elut elut elut ((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl) Ethyl hexane-3-yl)benzoylamino)propanoate 29a (58 mg, white solid), yield: 51.8%.

MS m/z (ESI): 695.8 [M+1]

Second step

3-(4-((2R,3R)/(2S,3S)-1-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-) 1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid

3-(4-((2R,3R)/(2S,3S)-1-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino) Ethyl-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoate 29a (58 mg, 0.083 mmol) dissolved in 6 mL of tetrahydrofuran and methanol In a mixed solvent of (V/V = 1:1), 1 mL of a solution of sodium hydroxide (17 mg, 0.42 mmol) was added under stirring, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Concentration under reduced pressure gave 3-(4-((2R,3R)/(2S,3S)-1-((4'-chloro-2'-methyl-[1,1'-biphenyl]-4 -yl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 29 (40 g, white solid) Rate: 71.0%.

MS m/z (ESI): 667.8 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ10.46 (s, 1H), 8.37 (br.s., 1H), 7.68 (s, 2H), 7.65-7.60 (m, 2H), 7.43-7.35 ( m, 3H), 7.28 (d, J = 8.0 Hz, 3H), 7.18 (d, J = 8.0 Hz, 2H), 7.13 (s, 3H), 4.09 (d, J = 11.3 Hz, 1H), 2.46 ( Br.s., 2H), 2.22 (s, 3H), 1.73 (br.s., 1H), 1.31-1.15 (m, 2H), 1.08-0.94 (m, 2H), 0.88-0.72 (m, 2H) ), 0.90-0.69 (m, 3H).

3-(4-((2R,3R)/(2S,3S)-1-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-) 1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 29 is further prepared by using a supercritical fluid chromatography (SFC) method Resolution with chiral column chiral isomers ((1) chiral column ChiralPak AD, 25 × 3 cm, 80 mL / min; mobile phase A for CO ₂ and B for Ethanol; or / and (2) Whelk O1 ( S, S), 25 × 3 cm, 65 mL / min; mobile phase A for CO ₂ and B for Ethanol; or / and (3) Whelk O1 (S, S), 25 × 3 cm, 70 mL / min; mobile phase A for CO ₂ and B for Ethanol)) were resolved to give 3-(4-((2R,3R)-1-((4'-chloro-2'-methyl-[1,1'-biphenyl]-) 4-yl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 29A and 3-(4-(( 2S,3S)-1-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-1-oxo-2-(4-(trifluoro) Methoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid 29B.

29A: MS m/z (ESI): 667.8 [M+1]

29B: MS m/z (ESI): 667.8 [M+1]

Example 30

3-(4-((2R,3R)/(2S,3S)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2',4',6 '-Trimethyl-[1,1'-biphenyl]-4-yl)amino)hexane-3-yl)benzoylamino)propanoic acid 30

3-(4-((2R,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2',4',6'-trimethyl-) [1,1'-biphenyl]-4-yl)amino)hexane-3-yl)benzoylamino)propanoic acid 30A

3-(4-((2S,3S)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2',4',6'-trimethyl-) [1,1'-biphenyl]-4-yl)amino)hexane-3-yl)benzoylamino)propanoic acid 30B

first step

3-(4-((2R,3R)/(2S,3S)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2',4',6 '-Trimethyl-[1,1'-biphenyl]-4-yl)amino)hexane-3-yl)benzoylamino)propionic acid ethyl ester

((2R,3R)/(2S,3S))-3-(4-((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(3) Fluoromethoxy)phenyl)hexanoic acid 1s (80 mg, 0.16 mmol), 2',4',6'-trimethyl-[1,1'-biphenyl]-4-amine 2a (63.4 mg, 0.3 Methyl), 1-hydroxybenzotriazole (40.5 mg, 0.3 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (49.8 mg, 0.26 mmol) dissolved in 10 mL N,N-Diisopropylethylamine (0.09 mL, 0.5 mmol) was added to dichloromethane, and stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and purified residue purified silicagel elut elut elut elut elut elut elut Oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2',4',6'-trimethyl-[1,1'-biphenyl]-4-yl) Ethylamino)hexane-3-yl)benzoylamino)propionic acid ethyl ester 30a (50 mg, white solid), yield: 45.4%.

MS m/z (ESI): 690.0 [M+1]

Second step

3-(4-((2R,3R)/(2S,3S)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2',4',6 '-Trimethyl-[1,1'-biphenyl]-4-yl)amino)hexane-3-yl)benzoylamino)propionic acid

3-(4-((2R,3R)/(2S,3S)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2',4', 6'-Trimethyl-[1,1'-biphenyl]-4-yl)amino)hexane-3-yl)benzoylamino)propionic acid ethyl ester 30a (50 mg, 0.072 mmol) dissolved in 6 mL of tetrahydrofuran In a mixed solvent of methanol (V/V = 1:1), a solution of 1 mL of sodium hydroxide (14.4 mg, 0.36 mmol) was added under stirring, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced EtOAc. EtOAc (EtOAc m. Purification by thin layer chromatography (developer: system A) gave 3-(4-((2R,3R)/(2S,3S)-1-oxo-2-(4-(trifluoromethoxy) Phenyl)-1-((2',4',6'-trimethyl-[1,1'-biphenyl]-4-yl)amino)hexane-3-yl)benzoylamino Propionic acid 30 (17 mg, white solid), yield: 29.4%.

MS m/z (ESI): 661.9 [M+1]

^{1 H NMR (400MHz, DMSO)} δ10.42 (s, 1H), 8.37 (s, 1H), 7.68 (d, J = 8.1Hz, 2H), 7.63 (d, J = 7.5Hz, 2H), 7.40 ( d, J = 8.6 Hz, 2H), 7.18 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 7.04 (d, J = 8.3 Hz, 2H), 6.90 (s, 2H), 4.10 (d, J = 11.1 Hz, 1H), 3.63 (t, J = 6.9 Hz, 2H), 3.51 - 3.43 (m, 1H), 2.47 (s, 3H), 2.25 (s, 3H), 1.92 (s, 6H), 1.80–1.68 (m, 2H), 1.06–0.97 (m, 2H), 0.79 (t, J = 7.2 Hz, 3H).

3-(4-((2R,3R)/(2S,3S)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2',4',6 '-Trimethyl-[1,1'-biphenyl]-4-yl)amino)hexane-3-yl)benzoylamino)propanoic acid 30 further by using supercritical fluid chromatography (SFC) Preparation equipment and chiral column chiral isomers were resolved ((1) chiral column ChiralPak AD, 25 × 3 cm, 80 mL / min; mobile phase A for CO ₂ and B for Ethanol; or / and (2) Whelk O1 (S, S), 25 × 3 cm, 65 mL / min; mobile phase A for CO ₂ and B for Ethanol; or / and (3) Whelk O1 (S, S), 25 × 3 cm, 70 mL / min; mobile phase A for CO ₂ and B for Ethanol)) was resolved to give 3-(4-((2R,3R)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1- ((2',4',6'-Trimethyl-[1,1'-biphenyl]-4-yl)amino)hexane-3-yl)benzoylamino)propanoic acid 30A and 3-(( 4-((2S,3S)-1-oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2',4',6'-trimethyl-[1, 1'-Biphenyl]-4-yl)amino)hexane-3-yl)benzoylamino)propanoic acid 30B.

30A: MS m/z (ESI): 661.9 [M+1]

30B: MS m/z (ESI): 661.9 [M+1]

Example 31

3-(4-(1-(3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4-ylcarbonylamino)-1-(4-( Trifluoromethoxy)phenyl)-pentan-2-yl)benzoylamino)propionic acid

3-(4-((1R,2R)-1-(3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4-ylcarbonylamino)- 1-(4-(Trifluoromethoxy)phenyl)-pentan-2-yl)benzoylamino)propanoic acid 31A

3-(4-((1S,2S)-1-(3-Fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4-ylcarboxamido)- 1-(4-(Trifluoromethoxy)phenyl)-pentan-2-yl)benzoylamino)propanoic acid 31B

first step

4-(1-(3-Fluoro 2',4,6'-trimethyl-[1,1'-biphenyl]-4-ylcarbonylamino)-1-(4-(trifluoromethoxy) Tert-butyl phenyl)-pentan-2-yl)benzoate

4-(1-Amino-1-(4-(trifluoromethoxyphenyl)pentan-2-yl)benzoic acid tert-butyl ester 11b (5.50 g, 13.0 mmol), 3-fluoro-2', 4',6'-trimethyl-[1,1'-biphenyl]-4-carboxylic acid 31a (3.95 g, 15.3 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (6.00 g, 23.6 mmol) and N,N-diisopropylethylamine (8.2 mL, 47.2 mmol) dissolved in 60 mL dichloromethane and N,N-dimethylformamide (V/V=5/1) In the mixed solvent, the reaction solution was reacted at 30 ° C for 18 hours. The reaction solution was concentrated under reduced pressure, and then 50 mL of water was added, and ethyl acetate (25 mL × 3) was used, and the organic phase was washed with water (50 mL × 3), anhydrous sulfuric acid The sodium was dried, filtered, and concentrated under reduced pressure. The obtained residue was purified to silica gel column chromatography (eluent: system A) to give 4-(1-(3-fluoro 2', 4, 6'- Tert-butyl 1-(1,1'-biphenyl]-4-ylcarbonylamino)-1-(4-(trifluoromethoxy)phenyl)-pentan-2-yl)benzoate 31b ( 7.13 g, pale yellow solid), yield: 82.8%.

MS m/z (ESI): 607.9 [M+1-56]

Second step

4-(1-(3-Fluoro-2',4,6'-trimethyl-[1,1'-biphenyl]-4-ylcarbonylamino)-1-(4-(trifluoromethoxy) Phenyl)-pentan-2-yl)benzoic acid

4-(1-(3-Fluoro 2',4,6'-trimethyl-[1,1'-biphenyl]-4-ylformylamino)-1-(4-(trifluoromethoxy) Tert-butyl)phenyl)-pentan-2-yl)benzoate 31b (7.13g, 10.7mmol) and 85% phosphoric acid (4.5mL, 66.0mmol) were dissolved in 50mL acetonitrile, the reaction solution was at 80 ° C Reaction for 4 hours. After the reaction mixture was concentrated, EtOAc (EtOAc m.) ,6'-trimethyl-[1,1'-biphenyl]-4-ylformylamino)-1-(4-(trifluoromethoxy)phenyl)-pentan-2-yl)benzene Formic acid 31c (6.50 g, yellow solid), yield: 100%.

MS m/z (ESI): 607.9 [M+1]

third step

3-(4-(1-(3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4-ylcarbonylamino)-1-(4-( Ethyl trifluoromethoxy)phenyl)-pentan-2-yl)benzoylamino)propanoate

4-(1-(3-Fluoro-2',4,6'-trimethyl-[1,1'-biphenyl]-4-ylformylamino)-1-(4-(trifluoromethyl) Oxy)phenyl)-pentan-2-yl)benzoic acid 31c (6.50 g, 10.7 mmol), 3-aminopropionic acid tert-butyl ester hydrochloride (3.90 g, 21.4 mmol), 2-(7-even) Nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (6.10 g, 16.1 mmol) and N,N-diisopropylethylamine (7.50 mL, 42.8 mmol) ) dissolved in 60mL two N, N- In dimethylformamide, the reaction solution was reacted at 25 ° C for 3 hours. 250 mL of water was added to the reaction mixture, and the mixture was extracted with EtOAc (EtOAc (EtOAc) Purification by column chromatography (eluent: dichloromethane: methanol) afforded 3-(4-(1-(3-fluoro-2',4',6'-trimethyl-[1,1] '-Biphenyl]-4-ylformylamino)-1-(4-(trifluoromethoxy)phenyl)-pentan-2-yl)benzoylamino)propionic acid ethyl ester 31d (7.86g , yellow solid), yield: 100%.

MS m/z (ESI): 678.9 [M+1-56]

the fourth step

3-(4-(1-(3-Fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4-ylformylamino)-1-(4-) Ethyl (trifluoromethoxy)phenyl)-pentan-2-yl)benzoylamino)propanoate 31d (7.86 g, 10.7 mmol) and 85% phosphoric acid (4.5 mL, 64.2 mmol) dissolved in 100 mL In the acetonitrile, the reaction solution was reacted at 80 ° C for 4 hours. The reaction mixture was concentrated, EtOAc EtOAc (EtOAc m. 3-(4-(1-(3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4-ylcarbonylamino)-1-(4-( Trifluoromethoxy)phenyl)-pentan-2-yl)benzoylamino)propanoic acid 31 (7.10 g, pale yellow solid), yield: 97.8%.

MS m/z (ESI): 678.9 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (t, J = 7.8 Hz, 1H), 7.72 (d, J = 6.7 Hz, 2H), 7.27 (d, J = 5.0 Hz, 2H), 7.21. , J = 6.2 Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 7.13 - 7.04 (m, 1H), 6.98 (d, J = 7.7 Hz, 1H), 6.91 (d, J = 3.2 Hz) , 2H), 6.87 (d, J = 12.7 Hz, 2H), 5.48 (t, J = 6.2 Hz, 1H), 3.73 (q, J = 7.0 Hz, 2H), 3.10 (s, 1H), 2.31 (s) , 3H), 1.98 (s, 3H), 1.92 (s, 3H), 1.66 (ddd, J = 30.3, 11.0, 4.5 Hz, 2H), 1.24 (t, J = 7.0 Hz, 2H), 1.14 (dd, J=14.4, 7.1 Hz, 2H), 0.79 (t, J=7.1 Hz, 3H).

3-(4-(1-(3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4-ylcarbonylamino)-1-(4-( Trifluoromethoxy)phenyl)-pentan-2-yl)benzoylamino)propanoic acid 31 is further carried out by using a supercritical fluid chromatography (SFC) method using preparative equipment and a chiral column chiral isomer Resolution (chiral column Whelk O1 (S, S), 250 × 4.6 mm ID, mobile phase A for CO ₂ and B for Ethanol; A for CO ₂ and B (50%) for Methanol (0.05% DEA)) Resolution to give 3-(4-((1R,2R)-1-(3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4-yl group Amido)-1-(4-(trifluoromethoxy)phenyl)-pentan-2-yl)benzoylamino)propanoic acid 31A (retention time: 4.95 min; ee value: 100%) and 3 -(4-((1S,2S)-1-(3-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-4-ylformylamino)-1 -(4-(Trifluoromethoxy)phenyl)-pentan-2-yl)benzoylamino)propanoic acid 31B (retention time: 11.28 min; ee: 100%).

31A: MS m/z (ESI): 678.9 [M+1]

¹ H NMR (400 MHz, DMSO) δ 12.19 (s, 1H), 8.69 (d, J = 8.6 Hz, 1H), 8.49 (t, J = 5.2 Hz, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.13 (t, J = 7.7 Hz, 1H) , 6.96 (d, J = 10.9 Hz, 1H), 6.89 (m, 3H), 5.31 (t, J = 9.7 Hz, 1H), 3.45 (dd, J = 12.4, 6.7 Hz, 2H), 3.17 (t, J=9.3 Hz, 1H), 2.52 (d, J=7.1 Hz, 3H), 2.24 (s, 3H), 1.88 (d, J=2.0 Hz, 7H), 1.54 (d, J = 10.1 Hz, 1H) , 1.12 (d, J = 6.9 Hz, 1H), 0.86 (m, 2H), 0.63 (t, J = 7.2 Hz, 3H).

31B: MS m/z (ESI): 678.9 [M+1]

¹ H NMR (400 MHz, DMSO) δ 12.21. (s, 1H), 8.68 (d, J = 8.7 Hz, 1H), 8.49 (t, J = 5.3 Hz, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.13 (t, J = 7.7 Hz, 1H) , 6.96 (d, J = 10.9 Hz, 1H), 6.89 (m, 3H), 5.31 (t, J = 9.7 Hz, 1H), 3.45 (dd, J = 12.6 Hz, 6.8 Hz, 2H), 3.17 (dd , J = 10.9 Hz, 7.8 Hz, 1H), 2.51 (s, 2H), 2.24 (s, 3H), 1.88 (d, J = 2.3 Hz, 6H), 1.54 (d, J = 10.6 Hz, 1H), 1.12 (d, J = 7.2 Hz, 1H), 0.88 (m, 2H), 0.63 (t, J = 7.2 Hz, 3H).

Biological evaluation

Test Example 1. Inhibition of glucagon-induced intracellular cAMP production by the compound of the present invention

The method uses a HEK293 cell line (purchasing the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences) with high expression of human glucagon receptor (hGCGR) as a test model to test the test compound at the cellular level for glucagon. Receptor antagonism. HEK293-hGCGR cells were supplemented with 10% fetal calf serum (FBS, GIBCO Cat. No. 10099141) in F12 medium (Invitrogen Cat #11765047) and cultured at 37 ° C, 5% CO ₂ . At the time of the experiment, cells were seeded at 3,000 cells/well in 384-well cell culture plates (OptiPlate-384, white, PerkinElmer Cat. No. 6007290). Compounds were first dissolved in DMSO and then serially diluted to the desired concentration. Each compound was set at 10 concentrations of 50 μM, 16.7 μM, 5.56 μM, 1.85 μM, 0.62 μM, 0.21 μM, 69 nM, 23 nM, 7.5 nM. And 2.5nM. After the cells were administered with the cells, the cells were stimulated with glucagon (Sigma, 0.05 nM) and incubated for 1 hour at room temperature. Subsequently, the incubation was continued by the Lance cAMP384 Kit Kit (PerkinElmer, Cat. #AD0263), and the incubation was continued for 1 hour at room temperature and the intracellular cyclic adenosine monophosphate (cAMP) levels were determined according to the kit instructions. The degree of inhibition of cAMP production by the test compound at each concentration was determined by comparison with the cAMP level of the blank control cells, and then the dose-response curve of the compound logarithmic concentration (the logarithm of the compound concentration)-inhibition level (inhibition rate) was determined. FIG, and non-linear regression analysis to calculate IC ₅₀ values of the compounds. A similar method is suitable for testing cell lines that highly express the human glucagon-like peptide 1 receptor (hGLP-1R) and the gastrin inhibitor peptide receptor (GIPR) to determine the selectivity of the compound for GCGR.

The IC ₅₀ values for the inhibition of GCGR by the preferred compounds of the invention are shown in Table 1.

Table IC ₅₀ values of preferred compounds of the invention in an inhibition of GCGR

化合物编号Compound number	IC₅₀(nM)IC ₅₀ (nM)
44	135135
4A4A	5252
4B4B	166166
55	206206
1111	210210
1212	9898
1515	137137
1616	143143
1717	134134
1919	199199
19A19A	120120
19B19B	180180
23twenty three	231231
2525	151151
28A28A	4242
28B28B	9797
31A31A	5454
31B31B	8888

Conclusion: The preferred compounds of the invention have a significant inhibitory effect on GCGR.

Test Example 2, Pharmacokinetic Test of Compound 4A and Compound 4B of the Present Invention

1. Summary

SD rats were used as test animals, and the compounds in compound 4A and compound 4B were intragastrically administered by LC/MS/MS method. The drug concentrations in plasma were measured at different times. The compounds of the present invention were studied in rats. Generation dynamics.

2, the experimental program

2.1 Experimental drugs and animals

Compound 4A and Compound 4B; 6 healthy adult SD male rats, purchased from Vitallihua Laboratory Animal Technology Co., Ltd., production license number: 11400700109943.

2.2 drug configuration and drug delivery

Weigh 3mg of the experimental drug, add 1mL of ethanol, ultrasonically to the solution, add 1.5mL PEG400 and 2.5mL water, while vortex mixing, configured to 0.6mg / mL;

Six healthy adult SD male rats were intragastrically administered overnight after fasting, and the dose was 3 mg/kg.

2.3 sample collection

0.15 mL of laryngeal vein was collected before and 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours after administration, and placed in heparinized tubes at 5500 rpm. Centrifuge for 10 minutes, store at -30 ° C, and eat 4 hours after administration.

2.4 sample processing

For plasma samples:

Take 20 μL of the sample, add IS (containing verapamil 5 ng·mL ^-1 and glibenclamide 50 ng·mL ^-1 ) in 100 μL of acetonitrile, vortex for 0.2 minutes, 13000 rpm / separate the heart for 8 minutes, then 70 μL of the supernatant was added to 70 μL of water, vortexed for 10 minutes, and 10 μL of the supernatant of the mixed solution was taken to an LC-MS/MS system for analysis.

For dose sample:

The administered sample was diluted with a mixed solvent of methanol and water (1:1, v/v) to a concentration of 100 ng·mL ^-1 , and 100 μL of the diluted sample and 100 μL of the internal standard solution (100 ng·mL ^-1 ) were added thereto. 500 μL of the IS solution and 600 μL of water were then vortexed, and the supernatant of 10 μL of the mixed solution was taken to an LC-MS/MS system for analysis.

3, pharmacokinetic parameters results

The pharmacokinetic parameters of preferred compounds of the invention are shown in Table 1.

Table 2 Pharmacokinetic data for Compound 4A and Compound 4B

Conclusion: Preferred compounds 4A and 4B of the invention have better pharmacokinetic properties.

Test Example 3: Effect of single oral administration of the compound of the present invention on random blood glucose in db/db mice

Purpose

To observe the effect of the preferred compound of the present invention on the random blood glucose of the type 2 diabetes model db/db mice after a single oral administration, the blood glucose level was measured by a portable blood glucose meter by using the tail blood sampling method, and then the test compound was reduced in vivo. Sugar action was evaluated.

Test animal

Forty-two male db/db mice, 9-10 weeks, were provided by the Institute of Model Animals of Nanjing University, license number: SCXK (Su) 2010-0001, and a positive control group and a solvent control group were set.

Test substance

Compounds 4, 4A, 5, 19, 23, 25 and 28A, 3-(4-((1R,2S)-1-(5-chloro-7-fluoro-1H-indol-3-yl) disclosed in WO20150662521 -1 -(4-(Trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propionic acid (FORM1), prepared with ethanol: PEG400: water = 20:30:50 .

Mode of administration

Oral gavage administration, the blank control group was given the same volume of ethanol: PEG400: water = 20:30:50, the administration volume was 10 ml/kg, and the administration dose was 30 mg/kg.

experiment method

Male db/db mice were divided into groups according to non-fasting blood glucose and body weight, and each group consisted of a solvent control and a drug administration group of different compounds. Each group of animals was given a single oral administration of the test drug and solvent, and the tail blood glucose level was measured before and 1 h, 2 h, 4 h, 6 h, 8 h, 12 h and 24 h after the administration, and the hypoglycemic effect of the test substance was observed. Maintain time and draw a 24-hour blood glucose curve. The modulation of blood glucose by the compounds was determined by comparison to the blood glucose of db/db mice administered only vehicle control.

Experimental result

The blood glucose lowering rate of the preferred compounds of the present invention is shown in Table 3.

Table 3 Table of blood glucose lowering rates of preferred compounds of the invention

Conclusion: Preferred compounds of the invention show better hypoglycemic effects at both 4 and 6 hours.

Test Example 4: Effect of Oral Administration of Preferred Compounds of the Invention on Random Blood Glucose in db/db Mice for 28 Days Oral Administration

Purpose

The effect of the preferred compound of the present invention on the random blood glucose of the type 2 diabetes model db/db mice after oral administration for 28 consecutive days was observed, and the blood glucose level was measured by a portable blood glucose meter by using the tail blood sampling method, and then the test compound was in vivo. The hypoglycemic effect was evaluated.

Test animal

100 male db/db mice, 9-10 weeks, were provided by the Institute of Model Animals, Nanjing University, license number: SCXK (Su) 2010-0001, and a positive control group and a solvent control group were set.

Test substance

Compound 4A, 28A, sitagliptin (a marketed drug), 3-(4-((1R,2S)-1-(5-chloro-7-fluoro-1H-indol-3-yl) disclosed in WO20150662521 )-1-(4-(trifluoromethoxy)phenyl)pentan-2-yl)benzoylamino)propionic acid (FORM1), formulated with ethanol: PEG400: water = 20:30:50 Required concentration.

Mode of administration

experiment method

Male db/db mice were divided into groups according to non-fasting blood glucose and body weight, and each group consisted of a solvent control and a drug administration group of different compounds. Each group of animals was orally administered with the test drug and solvent for 28 consecutive days, and the tail blood glucose level was detected on the first day, the seventh day, the 14th day, the 21st day, and the 28th day after the administration, and the test article was observed. Reduce blood sugar and maintain time, and draw a 28-day blood glucose curve. The modulation of blood glucose by the compounds was determined by comparison to the blood glucose of db/db mice administered only vehicle control.

Experimental result

The db/db mice were orally administered with the preferred compound 4A of the present invention, the compound 28B, and the compound (FORM1) of sitagliptin and WO2015066252 for 28 consecutive days. In contrast, the compound 4A and the compound 28B have significant hypoglycemic effect, which is superior to Sitagliptin and FORM1 are shown in Figure 1.

All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims

A compound of the formula (I): or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

among them:

L is selected from -C(O)NH- or -NH-C(O)-;

A 1 , A 2 , A 3 , A 4 and A 5 are each independently selected from CH, C or N, provided that A 1 , A 2 , A 3 , A 4 and A 5 and the carbon atom to which they are attached The number of N in the ring is 0 to 2;

R 1 is selected from an alkyl group or a cycloalkyl group, wherein the alkyl group or cycloalkyl group is further further selected from one or more selected from the group consisting of a hydroxyl group, a halogen, a nitro group, a cyano group, an alkoxy group, a cycloalkyl group, and a heterocyclic group. Cyclo, aryl, heteroaryl, -NR 6 R 7 , -C(O)NR 6 R 7 , -C(O)R 8 , -SO 2 R 8 , -C(O)OR 8 or -NR Substituted by a substituent of 6 C(O)R 7 ;

R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 6 R 7 , -C(O)NR 6 R 7 , -C(O)R 8 , -SO 2 R 8 , -C(O)OR 8 or -NR 6 C(O)R 7 , wherein the alkyl group, Alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy , haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 6 R 7 , -C(O)NR 6 R 7 , -C(O)R 8 , -SO 2 Substituted with a substituent of R 8 , -C(O)OR 8 or -NR 6 C(O)R 7 ; when A 3 is selected from N, R 2 is absent;

R 3 is each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogen, a hydroxyl group, an alkoxy group, a cyano group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -NR 6 R 7 , -C (O)NR 6 R 7 , -C(O)R 8 , -SO 2 R 8 , -C(O)OR 8 or -NR 6 C(O)R 7 , wherein the alkyl group, alkoxy group Or a cycloalkyl, heterocyclyl, aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, Heterocyclyl, aryl, heteroaryl, -NR 6 R 7 , -C(O)NR 6 R 7 , -C(O)R 8 , -SO 2 R 8 , -C(O)OR 8 or - Substituted by a substituent of NR 6 C(O)R 7 ;

R 4 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogen, a hydroxyl group, an alkoxy group, a cyano group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -NR 6 R 7 , -C (O)NR 6 R 7 , -C(O)R 8 , -SO 2 R 8 , -C(O)OR 8 or -NR 6 C(O)R 7 , wherein the alkyl group, alkoxy group Or a cycloalkyl, heterocyclyl, aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, Heterocyclyl, aryl, heteroaryl, -NR 6 R 7 , -C(O)NR 6 R 7 , -C(O)R 8 , -SO 2 R 8 , -C(O)OR 8 or - Substituted by a substituent of NR 6 C(O)R 7 ;

R 5 is each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogen, a hydroxyl group, an alkoxy group, a cyano group, a nitro group, -NR 6 R 7 , -C(O)NR 6 R 7 , -C(O)R 8 And -SO 2 R 8 , -C(O)OR 8 or -NR 6 C(O)R 7 , wherein said alkyl or alkoxy group is further further selected from one or more selected from the group consisting of hydroxyl, halogen, and nitrate , cyano, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 6 R 7 , -C(O)NR 6 R 7 , -C( Substituting a substituent of O) R 8 , -SO 2 R 8 , -C(O)OR 8 or -NR 6 C(O)R 7 ;

R 6 is selected from a hydrogen atom or an alkyl group;

R 7 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, aryl group or heteroaryl group is further optionally further selected from one or more selected from the group consisting of hydroxyl groups, Halogen, haloalkyl, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 9 R 10 , -C(O)R 9 R 10 ,- Substituted by a substituent of C(O)R 11 , -SO 2 R 11 , -C(O)OR 11 or -NR 9 C(O)R 10 ;

Alternatively, R 6 and R 7 together with the N atom to which they are attached form a 4 to 8 membered heterocyclic group, wherein said heterocyclic group contains one or more N, O, S(O) q atoms, and said The heterocyclic group is optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 9 R 10 , -C Substituting (O) a substituent of R 9 R 10 , -C(O)R 11 , -SO 2 R 11 , -C(O)OR 11 or -NR 9 C(O)R 10 ;

R 8 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally one or A plurality selected from the group consisting of hydroxyl, halogen, haloalkyl, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 9 R 10 , -C(O) Substituted by a substituent of R 9 R 10 , -C(O)R 11 , -SO 2 R 11 , -C(O)OR 11 or -NR 9 C(O)R 10 ;

R 9 , R 10 and R 11 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group Or a heteroaryl group optionally selected from one or more selected from the group consisting of hydroxyl, halogen, haloalkyl, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid Or substituted with a substituent of a carboxylic acid ester;

m is 0, 1, 2, 3, 4 or 5;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

q is 0, 1 or 2.
The compound according to claim 1 or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, which is a compound of the formula (II) or a stereoisomer thereof, tautomerizable Or a pharmaceutically acceptable salt thereof:

Wherein: R 1 to R 5 , m, n and p are as defined in claim 1.
A compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound of the formula (III) or a stereoisomer thereof, tautomerizable Or a pharmaceutically acceptable salt thereof:

Wherein: R 1 to R 5 , m, n and p are as defined in claim 1.
A compound according to claim 2, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is of the formula (IV) or (V) Or a compound of (VI) or (VII) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

Wherein: R 1 to R 5 , m, n and p are as defined in claim 1.
The compound according to claim 3, or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, which is a compound of the formula (VIII) or (IX) or (X) or (XI) a compound or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof:

Wherein: R 1 to R 5 , m, n and p are as defined in claim 1.
The compound according to any one of claims 1 to 5, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 3-6 alkyl, preferably n-propyl .
The compound according to any one of claims 1 to 5, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 2 is selected from phenyl, wherein said phenyl group is optionally further Substituted by one or more substituents of an alkyl group, a halogen, a cyano group, a nitro group, an alkoxy group, a halogenated alkyl group or a halogenated alkoxy group, further preferred wherein the phenyl group is further protected by one or more methyl groups Substituted by trifluoromethyl or trifluoromethoxy.
The compound according to any one of claims 1 to 5, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 2 is selected from a 5- to 8-membered heteroaryl group, wherein heteroaryl is optionally further substituted by one or more alkyl, halo, cyano, nitro, alkoxy, haloalkyl or haloalkoxy substituents, wherein R 2 is more preferably pyrrole, furan, thiophene, Pyrazole, imidazole, thiazole, benzimidazole, benzofuran, or benzoxazole, wherein the pyrrole, furan, thiophene, pyrazole, imidazole, thiazole, benzimidazole, benzofuran, or benzoxazole The azole is optionally further substituted with one or more substituents of an alkyl, halogen, cyano, nitro or alkoxy group, wherein the alkyl or alkoxy group is optionally further substituted by one or more halogens Substituted, the halogen is preferably F.
The compound according to any one of claims 1 to 5, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 3 is selected from alkoxy groups, wherein said alkoxy group Further selected by one or more substituents selected from alkyl, halo, cyano, nitro or alkoxy, R 3 is preferably fluoroalkoxy, more preferably trifluoromethoxy or trifluoro Ethoxy.
The compound according to claim 9 or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R 3 is bonded to the 3-position (meta) or the 4-position (para), and m is preferably 1.
The compound according to any one of claims 1 to 5, or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a hydrogen atom, a halogen or an alkyl group, preferably F, n is preferably 1.
A compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

A 3 is selected from C;

R 1 is selected from n-propyl;

R 2 is selected from alkyl, halogen, cyano, nitro, alkoxy, haloalkyl, haloalkoxy, phenyl or 5- to 8-membered heteroaryl, alkyl, alkoxy, phenyl or The 5- to 8-membered heteroaryl group is optionally further substituted with one or more substituents of an alkyl group, a halogen, a cyano group, a nitro group, an alkoxy group, a halogenated alkyl group or a halogenated alkoxy group;

R 3 is selected from the group consisting of trifluoromethoxy;

R 4 is selected from a hydrogen atom or a halogen;

R 5 are each independently selected from a hydrogen atom, an alkyl group, a halogen, an alkoxy group, a halogenated alkyl group or a halogenated alkoxy group;

m is 0, 1 or 2;

n is 0, 1, or 2;

p is 0, 1, or 2.
A compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein said compound comprises:
A compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein said compound comprises:
A compound according to any one of claims 14 or a stereoisomer, tautomer, racemate thereof or a pharmaceutically acceptable salt thereof, wherein the compound comprises:
A compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein said compound comprises:
The compound according to any one of claims 16 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound comprises:
A process for the preparation of a compound of formula (I) according to claim 1, the process comprising:

The compound of the formula (I) is reacted with the formula (IB), and the obtained compound is further hydrolyzed to obtain a compound of the formula (I);

among them:

L 1 is selected from -C(O)X;

L 2 is selected from -NH 2 ;

X is selected from a hydroxyl group or a halogen;

R c is selected from an alkyl group;

L is selected from -NH-C(O)-;

R 1 to R 5 , A 1 to A 5 , m, n and p are as defined in claim 1.
The production method according to claim 18, wherein the preparation method of the general formula (IA) comprises:

The general formula (IC) and the general formula (ID) or a salt thereof are reacted to obtain a compound of the formula (IA);

among them:

L 1 is selected from -C(O)X;

X is selected from a hydroxyl group or a halogen;

R c is selected from an alkyl group;

R 1 , R 3 , R 4 , m, n are as defined in claim 1.
A process for the preparation of a compound of formula (I) according to claim 1, the process comprising:

The compound of the formula (I) is further hydrolyzed by reacting the compound of the formula (IE) with the formula (ID) or a salt thereof;

among them:

X is selected from a hydroxyl group or a halogen;

R c is selected from an alkyl group;

L is selected from -C(O)-NH-;

R 1 to R 5 , A 1 to A 5 , m, n and p are as defined in claim 1.
The production method according to claim 20, wherein the preparation method of the general formula (IE) comprises:

The general formula (IC) and the general formula (IB) or a salt thereof are reacted to obtain a compound of the general formula (IE);

among them:

L 1 is selected from -NH 2 ;

L 2 is selected from -C(O)X;

X is selected from a hydroxyl group or a halogen;

L is selected from -C(O)-NH-;

R 1 to R 5 , A 1 to A 5 , m, n and p are as defined in claim 1.
A compound of the formula (IA): or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

among them:

L 1 is selected from -C(O)X;

X is selected from a hydroxyl group or a halogen;

R c is selected from an alkyl group;

The definitions of R 1 , R 3 , R 4 , m and n are as set forth in claim 1.
The compound according to claim 22, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound comprises:
The compound according to claim 22, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound comprises:
A compound of the formula (IE) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

among them:

X is selected from a hydroxyl group or a halogen;

L is selected from -C(O)-NH-;

R 1 to R 5 , A 1 to A 5 , m, n and p are as defined in claim 1.
The compound according to claim 25, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound comprises:
A process for the preparation of a compound of formula (IA) according to claim 22, wherein the compound of formula (IA) is a compound of formula (IIA):

The method includes:

The compound of the formula (IIa) is reacted with the compound of the formula (IIb) under basic conditions to give the formula (IIc);

The compound of the formula (IIc) is hydrolyzed under basic conditions to give a compound of the formula (IId);

The compound of the formula (IId) is reacted with the compound of the formula (IIe) in the presence of a condensation reagent to give a compound of the formula (IIf);

The compound of the formula (IIf) is hydrolyzed under basic conditions to give the compound of the formula (IIA);

among them:

X is selected from a hydroxyl group or a halogen;

R a , R b and R c are each independently selected from an alkyl group;

The definitions of R 1 , R 3 , R 4 , m and n are as set forth in claim 1.
The production method according to claim 27, wherein the condensation reagent is selected from the group consisting of bis(2-oxo-3-oxazolidinyl)phosphoryl chloride, N,N-dicyclohexylcarbodiimide, N, N-diisopropylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and o-benzotriazole-N,N,N'N'- Tetramethyluronium borate (TBTU); preferably 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride or bis(2-oxo-3-oxazolidinyl) Hypophosphoryl chloride.
The production method according to claim 27, wherein the basic condition is provided by an organic base or an inorganic base selected from the group consisting of diisopropylethylamine, pyridine, triethylamine, piperidine, and N-methyl. Piperazine, 4-dimethylpyridine and potassium t-butoxide, preferably diisopropylethylamine, triethylamine or potassium t-butoxide; the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, hydrogenation Sodium, sodium hydroxide, potassium hydroxide, lithium hydroxide and potassium hydride are preferably sodium hydroxide or lithium hydroxide.
A process for the preparation of a compound of formula (IE) according to claim 25, wherein the compound of formula (IE) is a compound of formula (IIIA):

The method includes:

The compound of the formula (IIIa) is reacted in the presence of tetraisopropyl titanate and ammonia methanol to obtain the formula (IIIb);

The condensation reaction of the compound of the formula (IIIb) with the formula (IIIc) gives the compound of the formula (IIId);

The compound of the formula (IIId) is subjected to a hydrolysis reaction under acidic conditions to obtain a compound of the formula (IIIA);

among them:

R a , R b and R c are selected from an alkyl group;

The definitions of R 1 to R 5 , m, n and p are as set forth in claim 1.
The production method according to claim 30, wherein the acidic condition is provided by a mineral acid or an organic acid selected from hydrochloric acid or phosphoric acid.
A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 17, or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, And pharmaceutically acceptable carriers, excipients or combinations thereof.
A method for inhibiting a glucagon receptor in vitro, comprising the step of mutagenizing said glucagon receptor with a compound according to any one of claims 1 to 17, or a stereoisomer thereof The construct or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 32 is contacted.
A compound according to any one of claims 1 to 17, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or Use of the pharmaceutical composition according to claim 32 for the manufacture of a medicament for type I diabetes, type II diabetes, hyperglycemia, obesity or insulin resistance.
The compound according to any one of claims 1 to 17, or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 32, for the preparation of pancreatic hyperglycemia Use in a receptor antagonist or inverse agonist.
The compound according to any one of claims 1 to 17, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 32, for the preparation of a high fat Use in drugs for blood, dyslipidemia, hypercholesterolemia, atherosclerosis, and metabolic syndrome.