WO2017008681A1 - Amide derivative, and preparation method and pharmaceutical use thereof - Google Patents

Abstract

The present invention relates to an amide derivative, and the preparation method and pharmaceutical use thereof. In particular, the present invention relates to the amino derivative as represented by general formula (I), the preparation method and a pharmaceutically acceptable salt thereof, and the use thereof as a therapeutic agent, in particular, the use thereof 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. 1 mol/L of hormone can rapidly decompose 3 × 10 ⁶ mol / L of glucose from glycogen.

The glucagon receptor is located on the cell surface and is a G-protein coupled receptor 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 GCGR antagonists have been published, 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 present invention provides a novel GCGR receptor antagonist designed to have a compound represented by the general formula (I), and the compound of the present invention has a large structural difference with the compound specifically disclosed in the prior art, and exhibits excellent resistance. Diabetes effects and effects.

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), as well as their tautomers, enantiomers and diastereoisomers. Body, racemate and pharmaceutically acceptable salts, as well as metabolites and metabolic precursors or prodrugs:

among them:

R ^{1 is} selected from aryl, wherein said aryl group is further optionally further selected from one or more selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclic, aryl a substituent of a heteroaryl group, -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O)R ¹² , -C(O)OR ¹² or -NR ¹⁰ C(O)R ¹¹ Substituted, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, Cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O)R ¹² , -C(O)OR ¹² or -NR ¹⁰ Substituted by a substituent of C(O)R ¹¹ ;

R ^{2 is} selected from the group consisting of:

(i) a phenyl group, wherein said phenyl group is further selected from the group consisting of an alkynyl group, a heterocyclic group,

的取代基所取代；

Substituted by a substituent;

Wherein said alkynyl group is further substituted by one or more substituents selected from cycloalkyl or alkoxy; preferably substituted by cyclopropyl;

The heterocyclic group described therein is preferably a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group,

(ii) a heterocyclic group or

R ^{3 is} selected from a hydrogen atom, a halogen, an alkyl group or an alkoxy group, wherein the alkyl group or alkoxy group is further further selected from one or more selected from the group consisting of an alkyl group, an alkoxy group, a halogen group, a hydroxyl group, and a cyano group. Nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O)R ¹² , -C(O)OR ¹² or Substituted by a substituent of -NR ¹⁰ C(O)R ¹¹ ;

R ⁴ are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a hydroxyl group, a cyano group or a nitro group, preferably selected from F or Cl, wherein the alkyl group or alkoxy group is optionally further one or Substituting a plurality of substituents selected from -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O)R ¹² , -C(O)OR ¹² or -NR ¹⁰ C(O)R ¹¹ ;

One or two of R ⁵ , R ⁶ and R ⁷ are selected from -C(CX ₃ )=N-OH; the other is selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a hydroxyl group, a cyano group or a nitrate And wherein said alkyl or alkoxy group is further further selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, - Substituted by a substituent of NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O)R ¹² , -C(O)OR ¹² or -NR ¹⁰ C(O)R ¹¹ ;

Alternatively, R ⁵ and R ⁶ , or R ⁶ and R ⁷ may also form a 4 to 14 membered cycloalkyl or heterocyclic group together with a carbon atom to which they are attached, preferably 5 to 7 members, wherein said cycloalkyl group Or a heterocyclic group optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =0, - Substituted by a substituent of NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O)R ¹² , -C(O)OR ¹² or -NR ¹⁰ C(O)R ¹¹ ;

R ^5a and R ^6a , or R ^6a and R ^7a may form a 4- to 14-membered cycloalkyl or heterocyclic group together with a carbon atom to which they are bonded, preferably 5 to 7 members, wherein the heterocyclic group contains one or more N, O, S(O)n atoms, and the cycloalkyl or heterocyclic group optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, hetero Cyclo, aryl, heteroaryl, =0, -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O)R ¹² , -C(O)OR ¹² or -NR ¹⁰ C( O) substituted with a substituent of R ¹¹ ;

R ^{8 is} each independently selected from the group consisting of:

(i) F, Cl, Br, I, hydroxy, cyano, nitro, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , —C(O)R ¹² , —C(O)OR ¹² or —NR ¹⁰ C(O)R ¹¹ , wherein said alkoxy group, cycloalkyl group, heterocyclic group, aryl group or hetero group The aryl group is optionally further selected from one or more selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ¹⁰ R ¹¹ , Substituted by a substituent of -C(O)NR ¹⁰ R ¹¹ , -C(O)R ¹² , -C(O)OR ¹² or -NR ¹⁰ C(O)R ¹¹ ;

(ii) an alkyl group, wherein said alkyl group is further selected from one or more selected from the group consisting of alkoxy, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, - Substituted by a substituent of NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O)R ¹² , -C(O)OR ¹² or -NR ¹⁰ C(O)R ¹¹ ;

R ^{9 is} each independently selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)NR ¹⁰ R ¹¹ , -C(O) R ¹² , -C(O)OR ¹² , preferably a tert-butyl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is further further selected from one or more selected from an alkyl group , alkoxy, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O Substituting a substituent of R ¹² , -C(O)OR ¹² or -NR ¹⁰ C(O)R ¹¹ ;

R ¹⁰ , R ¹¹ and R ¹² 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, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ¹⁴ R ^{15, -C (O) NR 14} R 15, -C (O) R 16, -C (O) oR 16 or -NR ¹⁴ C (O) R ^15, substituted with a substituent;

Alternatively, R ¹⁰ and R ¹¹ together with the N atom to which they are attached form a 4 to 8 membered heterocyclic group, wherein the 4 to 8 membered heterocyclic ring contains one or more N, O, S(O) n atoms, and 4 The ～8 membered heterocyclic ring is further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =0, - Substituted by a substituent of NR ¹⁴ R ¹⁵ , -C(O)NR ¹⁴ R ¹⁵ , -C(O)R ¹⁶ , -C(O)OR ¹⁶ or -NR ¹⁴ C(O)R ¹⁵ ;

R ¹⁴ , R ¹⁵ and R ¹⁶ 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, cycloalkyl group, heterocyclic group, aryl group Or a heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxy Substituted by a substituent of the acid ester;

X is selected from halogen, preferably F;

m is selected from 1, 2, 3 or 4;

n is selected from 0, 1 or 2;

p is selected from 0, 1, 2, 3 or 4.

In a preferred embodiment of the invention, the compound of the formula (I), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, is a compound of the formula (II) or Stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

Wherein: R ¹ to R ⁴ and p are as defined in the formula (I).

In a preferred embodiment of the invention, the compound of the formula (I), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, is a compound of the formula (III) or Stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

Wherein: R ¹ to R ⁴ and p are as defined in the formula (I).

In a preferred embodiment of the invention, the compound of the formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, R ^{1 is} selected From phenyl, wherein said phenyl group is optionally further substituted with a substituent selected from an alkyl group or a halogen, preferably substituted with methyl, ethyl, propyl, butyl, F, Cl, Br or I, It is preferably substituted by methyl, F or Cl, and the remaining groups are as defined in the general formula (I).

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

R ^{1 is} selected from phenyl, wherein said phenyl group is optionally further substituted with a substituent selected from an alkyl group or a halogen, preferably methyl, ethyl, propyl, butyl, F, Cl, Br or I. Substituted, more preferably substituted with methyl, F or Cl;

取代；且R ^{2 is} selected from a phenyl group, and the phenyl group is further

Replace

R ⁵ and R ⁶ , or R ⁶ and R ⁷ together with the carbon atom to which they are bonded form a 5- to 7-membered cycloalkyl or heterocyclic group, wherein said cycloalkyl or heterocyclic group is optionally further substituted by one or A plurality of substituents selected from an alkyl group, a halogen, a hydroxyl group, a cyano group, a nitro group, a cycloalkyl group or a heterocyclic group are substituted, and the remaining groups are as defined in the formula (I).

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

R ^{1 is} selected from phenyl, wherein said phenyl group is optionally further substituted with a substituent selected from an alkyl group or a halogen, preferably methyl, ethyl, propyl, butyl, F, Cl, Br or I. Substituted, more preferably substituted with methyl, F or Cl;

取代；R ^{2 is} selected from a phenyl group, and the phenyl group is further

Replace

R ^{8 is} selected from fluorine;

m is 2, and the remaining groups are as defined in the formula (I).

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

R ^{1 is} selected from phenyl, wherein said phenyl group is optionally further substituted with a substituent selected from an alkyl group or a halogen, preferably methyl, ethyl, propyl, butyl, F, Cl, Br or I. Substituted, more preferably substituted with methyl, F or Cl;

取代，其余基团的定义如通式(I)中所述。R ^{2 is} selected from a phenyl group, and the phenyl group is further

Substituted, the remaining groups are as defined in the general formula (I).

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

R ^{1 is} selected from phenyl, wherein said phenyl group is optionally further substituted with a substituent selected from an alkyl group or a halogen, preferably methyl, ethyl, propyl, butyl, F, Cl, Br or I. Substituted, more preferably substituted with methyl, F or Cl;

取代；R ^{2 is} selected from a phenyl group, and the phenyl group is further

Replace

R ^{8 is} selected from cycloalkyl, wherein the cycloalkyl group is further substituted with an alkyl group.

m is 1, and the remaining groups are as defined in the general formula (I).

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

R ^{1 is} selected from phenyl, wherein said phenyl group is optionally further substituted with a substituent selected from an alkyl group or a halogen, preferably methyl, ethyl, propyl, butyl, F, Cl, Br or I. Substituted, more preferably substituted with methyl, F or Cl;

取代；R ^{2 is} selected from a phenyl group, and the phenyl group is further

Replace

R ^{8 is} selected from cyclopropyl, wherein the cyclopropyl group is further substituted with an alkyl group.

m is 1, and the remaining groups are as defined in the general formula (I).

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

R ^{1 is} selected from phenyl, wherein said phenyl group is optionally further substituted with a substituent selected from an alkyl group or a halogen, preferably methyl, ethyl, propyl, butyl, F, Cl, Br or I. Substituted, more preferably substituted with methyl, F or Cl;

取代，其余基团的定义如通式(I)中所述。R ^{2 is} selected from a phenyl group, and the phenyl group is further

Substituted, the remaining groups are as defined in the general formula (I).

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

R ^{1 is} selected from phenyl, wherein said phenyl group is optionally further substituted with a substituent selected from an alkyl group or a halogen, preferably methyl, ethyl, propyl, butyl, F, Cl, Br or I. Substituted, more preferably substituted with methyl, F or Cl;

取代；R ^{2 is} selected from a phenyl group, and the phenyl group is further

Replace

R ^{8 is} selected from an alkyl group, preferably a tert-butyl group;

m is 1, and the remaining groups are as defined in the general formula (I).

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

R ^{1 is} selected from phenyl, wherein said phenyl group is optionally further substituted with a substituent selected from an alkyl group or a halogen, preferably methyl, ethyl, propyl, butyl, F, Cl, Br or I. Substituted, more preferably substituted with methyl, F or Cl;

取代；R ^{2 is} selected from a phenyl group, and the phenyl group is further

Replace

选自：among them,

From:

Wherein R ¹³ are each independently selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O)R ¹² , -C(O)OR ¹² or -NR ¹⁰ C(O)R ¹¹ wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group Further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O) Substituted with a substituent of R ¹² , -C(O)OR ¹² or -NR ¹⁰ C(O)R ¹¹ ; R ¹³ is preferably an alkyl group;

n is 0, 1, 2 or 3, and n is preferably 0 or 1; the remaining groups are as defined in the formula (I).

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

R ^{1 is} selected from phenyl, wherein said phenyl group is optionally further substituted with a substituent selected from an alkyl group or a halogen, preferably methyl, ethyl, propyl, butyl, F, Cl, Br or I. Substituted, more preferably substituted with methyl, F or Cl;

取代；R ^{2 is} selected from a phenyl group, and the phenyl group is further

Replace

选自：among them,

From:

Wherein R ^{13 is} each independently selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , —C(O)R ¹² , —C(O)OR ¹² or —NR ¹⁰ C(O)R ¹¹ , wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group Optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C ( O) is substituted with a substituent of R ¹² , -C(O)OR ¹² or -NR ¹⁰ C(O)R ¹¹ ; R ¹³ is preferably an alkyl group;

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

The remaining groups are as defined in the general formula (I).

In a preferred embodiment of the invention, the compound of the formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, R ^{2 is} selected From the phenyl group, the phenyl group is further substituted with an alkynyl group which is further substituted with a substituent selected from a cycloalkyl group or an alkoxy group.

In a preferred embodiment of the invention, the compound of the formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, R ^{2 is} selected From the phenyl group, the phenyl group is further substituted by an ethynyl group or a propynyl group, preferably by an ethynyl group, wherein the ethynyl group or propynyl group is further substituted with a cyclopropyl group.

In a preferred embodiment of the invention, the compound of the formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, R ² is :

其中

选自下列基团：

among them

Selected from the following groups:

Wherein R ^{13 is} each independently selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , —C(O)R ¹² , —C(O)OR ¹² or —NR ¹⁰ C(O)R ¹¹ , wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group Optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C ( O) is substituted with a substituent of R ¹² , -C(O)OR ¹² or -NR ¹⁰ C(O)R ¹¹ ; R ¹³ is preferably an alkyl group;

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

The remaining groups are as defined in the general formula (I).

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

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

Further, the present invention provides a process for the preparation of a compound of the formula (I), which comprises:

a compound of the formula (IA)

The reaction with 2-aminoethanesulfonic acid in the presence of a condensation reagent provides a compound of the formula (I)

Wherein the condensation reagent is preferably (2-oxo-3-oxazolidinyl)phosphoryl chloride;

Wherein: R ¹ to R ⁴ and p are as defined in the formula (I).

Further, the present invention provides a process for the preparation of a compound of the formula (II), which comprises:

a compound of the formula (IIA)

Carrying out the reaction with 2-aminoethanesulfonic acid in the presence of a condensation reagent to obtain a compound of the formula (II)

Wherein the condensation reagent is preferably (2-oxo-3-oxazolidinyl)phosphoryl chloride;

Wherein: R ¹ to R ⁴ and p are as defined in the formula (II).

Further, the present invention provides a process for the preparation of a compound of the formula (III), which comprises:

Compound of formula (IIIA)

The reaction with 2-aminoethanesulfonic acid in the presence of a condensation reagent provides a compound of the formula (III)

Wherein the condensation reagent is preferably (2-oxo-3-oxazolidinyl)phosphoryl chloride;

Wherein: R ¹ to R ⁴ and p are as defined in the formula (III).

The invention also provides a method of preparing the general formula (IA), the method comprising:

Condensation of a compound of formula (IC) with (ID)

Obtaining a compound of the formula (IB)

Hydrolysis of a compound of formula (IB) to give a compound of formula (IA)

Wherein: R ¹ to R ⁴ , R ¹² and p are as defined in the formula (I).

The invention also provides a method of preparing the general formula (IIA), the method comprising:

Condensation of a compound of the formula (IIC) with (IID)

Obtaining a compound of the formula (IIB)

Hydrolysis of a compound of the formula (IIB) to give a compound of the formula (IIA)

Wherein: R ¹ to R ⁴ , R ¹² and p are as defined in the formula (II).

The invention also provides a method of preparing the general formula (IIIA), the method comprising:

Condensation of a compound of the formula (IIIC) with (IID)

Obtaining a compound of the formula (IIIB)

Hydrolysis of a compound of the formula (IIIB) to give a compound of the formula (IIIA)

Wherein: R ¹ to R ⁴ , R ¹² and p are as defined in the formula (III).

Furthermore, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of the formula (I), (II) or (III) or a stereoisomer thereof, tautomerism thereof Or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

The present invention also provides a method for inhibiting a glucagon receptor in vitro or in vivo, which comprises the glucagon receptor as described in formula (I), (II) or (III) or Its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is contacted.

The present invention also provides a compound of the formula (I), (II) or (III), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof Use in the preparation of a medicament for the treatment of type 2 diabetes, hyperglycemia, obesity or insulin resistance.

The present invention also provides a compound of the formula (I), (II) or (III), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof Use in the preparation of a glucagon receptor inhibitor.

The present invention also provides a compound of the formula (I), (II) or (III), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof Use in the treatment of type 2 diabetes, hyperglycemia, obesity or insulin resistance.

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 may optionally be 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. The alkynyl group may optionally be 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, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like. The cycloalkyl group may optionally be 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 optionally be 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), and 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 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) _m (where m 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 optionally be 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 may optionally be 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, and 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, isothiazolyl, 1,2,3-thiadiazolyl, benzo-di Oxolyl, benzimidazolyl, fluorenyl, isodecyl, 1,3-dioxo-isoindolyl, quinolyl, oxazolyl, benzisothiazolyl, benzo Oxazolyl and benzoisoxazolyl. The heteroaryl group can optionally be 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 ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O)R ¹² , -C(O)OR ¹² , -NR ¹⁰ C(O)R ¹¹ , -OC(O)NR ¹⁰ R ¹¹ or -NR ¹⁰ C(O)R ¹¹ . Wherein R ¹⁰ , R ¹¹ and R ¹² are as defined in the formula (I).

"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 (I) or a salt thereof of the present invention comprises the following steps:

The compound of the formula (IC) and (ID) are subjected to a condensation reaction in the presence of a condensation reagent under basic conditions to obtain a compound of the formula (IB); the compound of the formula (IB) is further hydrolyzed to obtain a compound of the formula ( IA); the compound of the formula (IA) and 2-aminoethanesulfonic acid are reacted in the presence of a condensation reagent to obtain To the compound of formula (I).

Wherein R ¹ to R ⁴ , R ¹² and p are as defined in the formula (I).

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

在碱性条件下，将通式化合物(IIC)与(IID)在缩合试剂存在的条件下进行缩合反应，得到通式化合物(IIB)；通式化合物(IIB)进一步水解，得到通式化合物(IIA)；通式化合物(IIA)与2-氨基乙磺酸在缩合试剂存在的条件下进行反应，得到通式(II)化合物。

The compound of the formula (IIC) and the (IID) are subjected to a condensation reaction in the presence of a condensation reagent under basic conditions to obtain a compound of the formula (IIB); the compound of the formula (IIB) is further hydrolyzed to obtain a compound of the formula (IIB) IIA); the compound of the formula (IIA) and 2-aminoethanesulfonic acid are reacted in the presence of a condensation reagent to give a compound of the formula (II).

Wherein R ¹ to R ⁴ , R ¹² 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 (IIIC) and the (IID) are subjected to a condensation reaction in the presence of a condensation reagent under basic conditions to obtain a compound of the formula (IIIB); the compound of the formula (IIIB) is further hydrolyzed to obtain a compound of the formula (IIIB). IIIA); the compound of the formula (IIIA) and 2-aminoethanesulfonic acid are reacted in the presence of a condensing reagent to give a compound of the formula (III).

Wherein R ¹ to R ⁴ , R ¹² and p are as defined in the formula (III).

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, Preferred are diisopropylethylamine and triethylamine; the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, preferably sodium carbonate and sodium hydride.

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 Alkyl carbodiimide, o-benzotriazole-N,N,N'N'-tetramethyluronium borate (TBTU), preferably bis(2-oxo-3-oxazolidinyl) Phosphorus chloride.

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 an LC/MS instrument, and the ionization method was electrospray (ESI) or atmospheric pressure chemical ionization (APCI).

Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao Ocean Chemical GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.2mm. The specifications for thin layer chromatography separation and purification are 0.4mm to 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 purity of commercially available materials and reagents is greater than 98%, unless otherwise specified, commercially available from 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.

Unless otherwise stated in the examples, the reactions were all carried out under an argon atmosphere.

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.

Example 1

2-(4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2,3-di) Hydrobenzofuran-5-yl)phenyl)-3-oxopropyl)benzoylamino)ethanesulfonic acid

first step

2-(4-(2,3-dihydrobenzofuran-5-yl)acetate

(2,3-Dihydrobenzofuran-5-yl)boronic acid 1a (5 g, 30.5 mmol), ethyl 2-(4-bromophenyl)acetate 1b (7.4 g, 30.5 mmol), sodium carbonate (12.9) g, 122 mmol), bis(tris(p-methylphenyl)phosphine)palladium chloride (1.2 g, 1.53 mmol) was dissolved in a mixed solvent of 80 mL of tetrahydrofuran, 40 mL of ethanol and 20 mL of water, and heated under reflux for 2 hours. The reaction solution was filtered while hot, and the filter cake was washed with ethyl acetate (50 mL×2), and the THF was evaporated. The obtained solution was adjusted to pH=6 with 1M hydrochloric acid solution and extracted with ethyl acetate (100 mL×3). The organic phase was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Purification of 15:1 and 10:1) to give ethyl 2-(4-(2,3-dihydrobenzofuran-5-yl)acetate 1c (8.4 g, pale yellow oil). .

MS m/z (ESI): 283.0 [M+1]

Second step

tert-Butyl 4-(2-(4-(2,3-dihydrobenzofuran-5-yl)phenyl)-3-ethoxy-3-oxopropyl)benzoate

Ethyl 2-(4-(2,3-dihydrobenzofuran-5-yl)acetate 1c (4 g, 14.17 mmol) was dissolved in 150 mL of tetrahydrofuran and cooled to -78 ° C with aq. 1M lithium hexamethyldisilazane solution (17 mL, 17 mmol) was added dropwise, and the reaction temperature was controlled to not exceed -60 ° C. After the completion of the dropwise addition, stirring was continued at -78 ° C for 1 hour, and then 2-(4-(bromo) was added dropwise. Tert-butyl methyl phenyl)acetate 1d (broad, 4.22g, 15.58mmol), controlled temperature does not exceed -60 ° C. Stir for 30 minutes, naturally warm, monitor the progress of the reaction with TLC. Add saturated chlorine to the reaction solution The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) -(2-(4-(2,3-Dihydrobenzofuran-5-yl)phenyl)-3-ethoxy-3-oxopropyl)benzoic acid tert-butyl ester 1e (6.5 g, white Solid), the product was directly subjected to the next reaction without purification.

third step

3-(4-(tert-Butoxycarbonyl)phenyl)-2-(4-(2,3-dihydrobenzofuran-5-yl)phenyl)propanoic acid

tert-Butyl 4-(2-(4-(2,3-dihydrobenzofuran-5-yl)phenyl)-3-ethoxy-3-oxopropyl)benzoate 1e (6.5 g , 14.17 mmol) was dissolved in a mixed solvent of 120 mL of tetrahydrofuran, 40 mL of methanol and 40 mL of water, and lithium hydroxide monohydrate (3 g, 70.85 mmol) was added under stirring, and stirred at room temperature overnight, and the reaction was monitored by TLC. The reaction mixture was adjusted to pH=6 with 3M potassium hydrogen phosphate, and extracted with methyl tert-butyl ether (100 mL×2). The combined organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate Concentration under pressure gave 3-(4-(tert-butyloxycarbonyl)phenyl)-2-(4-(2,3-dihydrobenzofuran-5-yl)phenyl)propanoic acid 1f (4 g , yellow solid), yield: 65.5%.

^{1 H NMR (400MHz, CDCl3)} : δ7.85 (d, J = 8.0Hz, 2H), 7.47-7.30 (m, 6H), 7.16 (d, J = 8.4Hz, 2H), 6.83 (d, J = 8.0 Hz, 1H), 4.63-4.59 (m, 2H), 3.91–3.87 (m, 1H), 3.49–3.44 (m, 1H), 3.28–3.21 (m, 2H), 3.14–3.10 (m, 1H) , 1.56(s,9H)

the fourth step

4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2,3-dihydrobenzo) Tert-butyl furan-5-yl)phenyl)-3-oxopropyl)benzoate

3-(4-(tert-Butoxycarbonyl)phenyl)-2-(4-(2,3-dihydrobenzofuran-5-yl)phenyl)propanoic acid 1f (1.0 g, 2.32 mmol Dissolved in 15 mL of dichloromethane, and then added triethylamine (1 mL, 6.96 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (805 mg, 3.48 mmol) and 4'-. Chloro-2'-methyl-[1,1'-diphenyl]-4-amine 1 g (500 mg, 2.32 mmol) was stirred at room temperature overnight. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. Silica gel column chromatography (eluent system: cyclohexane: ethyl acetate = 10:1 and 5:1) was further separated and purified to give 4-(3-((4'-chloro-2'-methyl-[ 1,1'-diphenyl]-4-yl)amino)-2-(4-(2,3-dihydrobenzofuran-5-yl)phenyl)-3-oxopropyl)benzoic acid tert-Butyl ester 1 h (800 mg, yellow solid), yield: 61%.

the fifth step

4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2,3-dihydrobenzo) Furan-5-yl)phenyl)-3-oxopropyl)benzoic acid

4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2,3-dihydrobenzene) And tert-butyl furan-5-yl)phenyl)-3-oxopropyl)benzoate 1 h (800 mg, 1.27 mmol) was dissolved in 15 mL of dichloromethane, and 4 mL of trifluoroacetic acid and 2 mL of concentrated hydrochloric acid were added with stirring. Stir at room temperature overnight. The reaction mixture was added with 10 mL of water, EtOAc (3 mL, EtOAc) Crude 4-(3-((4'-chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2,3-dihydrobenzene) And furan-5-yl)phenyl)-3-oxopropyl)benzoic acid 1j (746 mg, yellow solid).

Step 6

2-(4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2,3-di) Hydrobenzofuran-5-yl)phenyl)-3-oxopropyl)benzoylamino)ethanesulfonic acid

4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2,3-dihydrobenzene) And furan-5-yl)phenyl)-3-oxopropyl)benzoic acid 1j (746 mg.1.27 mmol) was dissolved in 10 mL of dichloromethane, triethylamine (0.6 mL, 3.81 mmol), and stirred at room temperature After 10 minutes, the obtained reaction solution was used. Bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (484 mg, 4.5 mmol) was added to a reaction flask, and diaminoethanesulfonic acid (175 mg, 1.4 mmol) was added thereto with stirring, and the resulting mixture was added to the above. The reaction mixture was stirred at room temperature for 24 hours. The reaction solution was poured into 50 mL of 2.4 M hydrochloric acid to precipitate a solid, which was filtered with suction, and the obtained cake was recrystallized from methanol to give 2-(4-((4)-chloro-2'-methyl-[1 ,1'-diphenyl]-4-yl)amino)-2-(4-(2,3-dihydrobenzofuran-5-yl)phenyl)-3-oxopropyl)benzoyl Amino)ethanesulfonic acid 1 (350 mg, white solid), yield: 40%.

MS m/z (ESI): 697.2 [M+1]

¹ H NMR (400 MHz, MeOD-d ₄ ): δ 10.0 (s, 1H), 8.43 (s, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.52-7.44 (m, 7H), 7.35 -7.31 (m, 3H), 7.25-7.10 (m, 5H), 4.58-4.54 (m, 2H), 4.05-4.02 (m, 1H), 3.78-3.75 (m, 2H), 3.58-3.52 (m, 1H), 3.25-3.21 (m, 2H), 3.17-3.11 (m, 1H), 3.08-3.04 (m, 2H), 2.20 (s, 3H)

Example 2

2-(4-(3-((2',4',6'-Trimethyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2,3) -dihydrobenzofuran-5-yl)phenyl)-3-oxopropyl)benzoylamino)ethanesulfonic acid

first step

2',4',6'-trimethyl-[1,1'-diphenyl]-4-amine

4-iodoaniline (21.9 g, 0.1 mol), 2,4,6-trimethylbenzeneboronic acid (16.4 g, 0.1 mol), bis(tris(p-methylphenyl)phosphine) palladium chloride under argon atmosphere (7.86 g, 10 mmol), sodium carbonate (42.4 g, 0.4 mol) was dissolved in a mixed solvent of 20 mL of dichloromethane, 15 mL of ethanol and 8 mL of water, and the mixture was replaced with argon gas three times, and heated to reflux for 5 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with 50 mL of ethyl acetate. The solvent was added to 100 mL of water, EtOAc (EtOAc) (EtOAc) =15:1) Further purification gave 2',4',6'-trimethyl-[1,1'-diphenyl]-4-amine 2c (5.2 g, off-white solid), yield: 25 %.

MS m/z (ESI): 212.1 [M+1]

Second step

4-(3-((2',4',6'-Trimethyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2,3-dihydro) Tert-butyl benzofuran-5-yl)phenyl)-3-oxopropyl)benzoate

3-(4-(tert-Butoxycarbonyl)phenyl)-2-(4-(2,3-dihydrobenzofuran-5-yl)phenyl)propanoic acid 1f (1.0 g, 2.32 mmol Dissolved in 15 mL of dichloromethane, and then added triethylamine (1 mL, 6.96 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (805 mg, 3.48 mmol) and 2', with stirring. 4',6'-Trimethyl-[1,1'-diphenyl]-4-amine 2c (490 mg, 2.32 mmol) was stirred at room temperature for 24 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. Further separation and purification by silica gel column chromatography (eluent system: cyclohexane: ethyl acetate = 10:1 and 5:1) gave 4-(3-((2', 4', 6'- -[1,1'-diphenyl]-4-yl)amino)-2-(4-(2,3-dihydrobenzofuran-5-yl)phenyl)-3-oxopropyl tert-Butyl benzoate 2d (800 mg, yellow solid), yield: 54.1%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.13 (s, 1H), 7.78 (d, J = 8.4Hz, 2H), 7.59-7.47 (m, 7H), 7.39-7.34 (m, 3H) , 4.56-4.52 (m, 2H), 3.63-3.47 (m, 1H), 3.21 (d, J = 8.4 Hz, 2H), 3.18-3.15 (m, 1H), 3.11-3.01 (m, 1H), 2.22 (s, 3H), 1.91 (s, 6H), 1.50 (s, 9H)

third step

4-(3-((2',4',6'-Trimethyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2,3-dihydro) Benzofuran-5-yl)phenyl)-3-oxopropyl)benzoic acid

4-(3-((2',4',6'-Trimethyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2,3-di) Hydrogen benzofuran-5-yl)phenyl)-3-oxopropyl)benzoic acid tert-butyl ester 2d (700 mg, 1.09 mmol) was dissolved in 15 mL of dichloromethane, and 4 mL of trifluoroacetic acid and 2 mL Hydrochloric acid was stirred at room temperature overnight and the progress of the reaction was monitored by TLC. The reaction mixture was added with 10 mL of water, EtOAc (3 mL, EtOAc) 4-(3-((2',4',6'-Trimethyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2,3-dihydro) Benzofuran-5-yl)phenyl)-3-oxopropyl)benzoic acid 2e (500 mg, yellow solid), yield: 78%.

the fourth step

2-(4-(3-((2',4',6'-Trimethyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2,3) -dihydrobenzofuran-5-yl)phenyl)-3-oxopropyl)benzoylamino)ethanesulfonic acid

4-(3-((2',4',6'-Trimethyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2,3-di) Hydroxybenzofuran-5-yl)phenyl)-3-oxopropyl)benzoic acid 2e (368 mg.1.09 mmol) was dissolved in 10 mL of dimethylformamide and triethylamine (0.7 mL, 4. The mixture was stirred at room temperature for 10 minutes, and the resulting reaction solution was used. Bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (579 mg, 2.27 mmol) was added to a reaction flask, and 2-aminoethanesulfonic acid (150 mg, 1.2 mmol) was added with stirring, and the obtained mixture was added. The above reaction solution was stirred at room temperature overnight, and the reaction was monitored by TLC. The reaction mixture was poured into EtOAc (3 mL) (EtOAc (EtOAc) (3-((2',4',6'-Trimethyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2,3-dihydrobenzo) Furan-5-yl)phenyl)-3-oxopropyl)benzoylamino)ethanesulfonic acid (350 mg, white solid), yield: 46.6%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.18 (s, 1H), 7.66 (d, J = 8.4Hz, 2H), 7.61 (d, J = 8.4Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.50-7.48 (m, 3H), 7.39-7.32 (m, 4H), 7.26 (d, J = 1.6 Hz, 1H), 7.25 (d, J = 2.0 Hz, 2H), 7.15 (d, J=8.0 Hz, 1H), 4.57-4.51 (m, 2H), 4.09-4.05 (m, 1H), 3.54-3.48 (m, 3H), 3.23-3.15 (m, 2H), 3.08-3.02 (m,1H), 2.67-2.63 (m, 2H), 2.31 (s, 3H), 1.97 (s, 6H)

Example 3

2-(4-(2-(4-(benzo[d][1,3]diox-5-yl)phenyl)-3-oxo-3-((2',4',6) '-Trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoylamino)ethanesulfonic acid

first step

2-(4-(benzo[d][1,3]diox-5-yl)phenyl)acetate

Benzo[d][1,3]diox-5-ylboronic acid 3a (16.6 g, 100 mmol), ethyl 2-(4-bromophenyl)acetate 1b (22 g, 91 mmol), sodium carbonate (38.6 g, 364 mmol), bis(tris(p-methylphenyl)phosphine)palladium chloride (3.6 g, 4.55 mmol) was dissolved in a mixed solvent of 240 mL of tetrahydrofuran, 120 mL of ethanol and 60 mL of water, and the mixture was heated to reflux for 3 hours. The reaction solution was filtered while hot-packed with Celite, washed with ethyl acetate (100 mL×2), and evaporated, and evaporated to EtOAc EtOAc EtOAc EtOAc The combined organic phase was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. :1,5:1) purification to give ethyl 2-(4-(benzo[d][1,3]diox-5-yl)phenyl)acetate 3b (10.5 g, white solid) Rate: 41%.

^{1 H NMR (400MHz, CDCl3)} : δ8.98 (s, 1H), 8.21 (s, 1H), 7.99-7.93 (m, 1H), 7.76 (d, J = 8.8Hz, 1H), 7.51 (d, J=11.2Hz, 1H)

Second step

4-(2-(4-(Benzo[d][1,3]diox-5-yl)phenyl)-3-ethoxy-3-oxopropyl)benzoic acid tert-butyl ester

Ethyl 2-(4-(benzo[d][1,3]diox-5-yl)phenyl)acetate 3b (5.7 g, 20 mmol) was dissolved in 150 mL of THF. After cooling to -78 ° C, 1 M lithium hexamethyldisilazane solution (24 mL, 24 mmol) was added dropwise with stirring. After the addition was completed, stirring was continued at -70 ° C for 1 hour, then 2-(4-(bromomethyl) was added dropwise. Phenyl)acetate tert-butyl ester 1d (broad, 6g, 22mmol), controlled temperature does not exceed -60 ° C. Stir for 30 minutes and heat up naturally. The reaction solution was quenched by adding a saturated ammonium chloride solution, and 50 mL of water was added to clarify. The reaction mixture was evaporated under reduced pressure. EtOAc (EtOAc m. Concentration to give the crude 4-(2-(4-(benzo[d][1,3]diox-5-yl)phenyl)-3-ethoxy-3-oxopropyl)benzoic acid tert-Butyl ester 3c (6.5 g, white solid).

MS m/z (ESI): 419.2 [M+1]

third step

2-(4-(Benzo[d][1,3]diox-5-yl)phenyl)-3-(4-(tert-butyloxycarbonyl)phenyl)propanoic acid

tert-Butyl 4-(2-(4-(benzo[d][1,3]diox-5-yl)phenyl)-3-ethoxy-3-oxopropyl)benzoate 3c (9.2 g, 20 mmol) was dissolved in a mixed solution of 120 mL of tetrahydrofuran, 40 mL of methanol and 40 mL of water, and lithium hydroxide monohydrate (2.52 g, 60 mmol) was added under stirring, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was added with 50 mL of water and extracted with EtOAc. EtOAc (EtOAc) (EtOAc) Drying with sodium sulfate, filtration and concentration under reduced pressure afforded crude 2-(4-(benzo[d][1,3] dioxin-5-yl)phenyl)-3-(4-(tert-butyl) 3-oxocarbonyl)phenyl)propanoic acid 3d (2.72 g, yellow solid).

MS m/z (ESI): 390.9 [M+1]

the fourth step

4-(2-(4-(benzo[d][1,3]diox-5-yl)phenyl)-3-oxo-3-((2',4',6'-three) Tert-butyl methyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoate

2-(4-(Benzo[d][1,3]diox-5-yl)phenyl)-3-(4-(tert-butyloxycarbonyl)phenyl)propanoic acid 3d (1.08 g, 2.5 mmol) was dissolved in 15 mL of dichloromethane, and triethylamine (1.045 mL, 7.5 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (950 mg, 3.75 mmol) was added sequentially with stirring. And 2',4',6'-trimethyl-[1,1'-diphenyl]-4-amine 2c (580 mg, 2.75 mmol), stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 3:1) to afford 4-(2-(4-( Benzo[d][1,3]diox-5-yl)phenyl)-3- Oxo-3-(2',4',6'-trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoic acid tert-butyl ester 3e (1.3 g, Yellow solid), Yield: 83%.

MS m/z (ESI): 584.3 [M+1]

the fifth step

4-(2-(4-(benzo[d][1,3]diox-5-yl)phenyl)-3-oxo-3-((2',4',6'-three) Methyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoic acid

4-(2-(4-(Benzo[d][1,3] dioxin-5-yl)phenyl)-3-oxo-3-((2',4',6'-) tert-Butyl trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoate 3e (1.0 g, 1.56 mmol) was dissolved in 20 mL of dichloromethane, and 5 mL Fluorineacetic acid and 2.5 mL of concentrated hydrochloric acid were stirred at room temperature overnight, and the reaction was monitored by TLC. The reaction solution was concentrated under reduced pressure to give 4-(2-(4-(benzo[d][1,3] dioxin-5-yl)phenyl)-3-oxo-3- ((2',4',6'-Trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoic acid 3f (900 mg, off-white solid), yield: 98 %.

MS m/z (ESI): 584.2 [M+1]

Step 6

2-(4-(2-(4-(benzo[d][1,3]diox-5-yl)phenyl)-3-oxo-3-((2',4',6) '-Trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoylamino)ethanesulfonic acid

4-(2-(4-(Benzo[d][1,3]diox-5-yl)phenyl)-3-oxo-3-((2',4') under argon atmosphere , 6'-Trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoic acid 3f (800 mg.1.37 mmol) dissolved in 5 mL of dimethylformamide, added to triethyl The amine (0.6 mL, 3.81 mmol) was stirred at room temperature for 10 minutes and the obtained mixture was evaporated. Bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (484 mg, 4.5 mmol) was added to a reaction flask, and diaminoethanesulfonic acid (524 mg, 2.06 mmol) was added thereto with stirring, and the resulting mixture was added to the above. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified and purified by silica gel column chromatography (dichloromethane:methanol=8:1) to give 2-(4-(4-(benzo)[d] ][1,3] dioxin-5-yl)phenyl)-3-oxo-3-((2',4',6'-trimethyl-[1,1'-diphenyl]] 4-(4-amino)amino)propyl)benzoylamino)ethanesulfonic acid 3 (310 mg, white solid), yield: 33%.

MS m/z (ESI): 691.3 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) = 10.16 (s, 1H), 8.41 (t, J = 5.1Hz, 1H), 7.67 (d, J = 8.0Hz, 2H), 7.60-7.53 (m, J = 8.8 Hz, 4H), 7.52-7.47 (m, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.21 (s, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.97 (d) , J=8.0 Hz, 3H), 6.86 (s, 2H), 6.03 (s, 2H), 3.53-3.44 (m, 3H), 3.12-3.02 (m, 3H), 2.68-2.60 (m, 2H), 2.22(s,3H), 1.87(s,6H)

Example 4

2-(4-(2-(4-(benzo[d][1,3]diox-5-yl)phenyl)-3-((4'-chloro-2'-methyl-[ 1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoylamino)ethanesulfonic acid

first step

4-(2-(4-(Benzo[d][1,3]diox-5-yl)phenyl)-3-((4'-chloro-2'-methyl-[1,1 '-Diphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid tert-butyl ester

2-(4-(Benzo[d][1,3]diox-5-yl)phenyl)-3-(4-(tert-butyloxycarbonyl)phenyl)propanoic acid 3d (1.08 g, 2.5 mmol) was dissolved in 15 mL of dichloromethane, and triethylamine (1.045 mL, 7.5 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (950 mg, 3.75 mmol) was added sequentially with stirring. And 1'-chloro-2'-methyl-[1,1'-diphenyl]-4-amine 1 g (580 mg, 2.75 mmol), and stirred at room temperature for 24 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. Silica gel column chromatography (eluent system: cyclohexane: ethyl acetate = 8:1 and 6:1) was further separated and purified to give 4-(2-(4-(benzo[d][1,3]] Dioxo-5-yl)benzene Tert-butyl 4-((4'-chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoate 4a ( 1.3 g, white solid), yield: 83%.

MS m/z (ESI): 589.8 [M+1]

Second step

4-(2-(4-(Benzo[d][1,3]diox-5-yl)phenyl)-3-((4'-chloro-2'-methyl-[1,1 '-Diphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid tert-butyl ester

4-(2-(4-(Benzo[d][1,3]diox-5-yl)phenyl)-3-((4'-chloro-2'-methyl-[1, 1'-Diphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid tert-butyl ester 4a (1 g, 1.56 mmol) was dissolved in 15 mL of dichloromethane and 5 mL of trifluoroacetic acid was added with stirring. 2.5 mL of concentrated hydrochloric acid was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to give crude 4-(2-(4-(benzo[d][1,3] dioxin-5-yl)phenyl)-3-((4'-chloro) -2'-Methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid tert-butyl ester 4b (900 mg, off-white solid), yield: 98 %.

third step

2-(4-(2-(4-(benzo[d][1,3]diox-5-yl)phenyl)-3-((4'-chloro-2'-methyl-[ 1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoylamino)ethanesulfonic acid

4-(2-(4-(Benzo[d][1,3]diox-5-yl)phenyl)-3-((4'-chloro-2'-methyl-[1, 1'-Diphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid tert-butyl ester 4b (730 g. 1.24 mmol) was dissolved in 10 mL of dichloromethane and triethylamine (0.52 mL, 3.72 mmol), stirred at room temperature for 10 minutes, and the resulting reaction solution was used. Bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (474 mg, 1.86 mmol) was added to a reaction flask, and diaminoethanesulfonic acid (170 mg, 1.36 mmol) was added thereto with stirring, and the resulting mixture was added to the above. The reaction mixture was stirred at room temperature overnight, and the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane:methanol = 40:1 to 10:1) to give 2-(4-(2-(4-) Benzo[d][1,3]diox-5-yl)phenyl)-3-((4'-chloro-2'-methyl-[1,1'-diphenyl]-4- Amino)-3-oxopropyl)benzoylamino)ethanesulfonic acid 4 (406 mg, white solid), yield: 47.0%.

MS m/z (ESI): 697.2 [M+1]

¹ H NMR (400 MHz, DMSO-d ₆ ) = 10.20 (br.s., 1H), 8.41 (br.s., 1H), 7.67 (d, J = 6.3 Hz, 2H), 7.57 (dd, J = 7.0, 17.6 Hz, 4H), 7.49 (br.s., 2H), 7.33 (br.s., 3H), 7.28-7.17 (m, 4H), 7.17-7.07 (m, J = 9.0 Hz, 2H) , 6.96 (d, J = 7.3 Hz, 1H), 6.03 (br.s., 2H), 5.74 (br.s., 1H), 3.48 (br.s., 3H), 3.05 (d, J = 7.3 Hz, 1H), 2.66 (br.s., 2H), 2.17 (br.s., 3H)

Example 5

(R)-2-(4-(2-(4-(benzo[d][1,3]diox-5-yl)phenyl)-3-((4'-chloro-2'-) Methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoylamino)ethanesulfonic acid

first step

4-(2-(4-bromophenyl)-3-((4'-chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxo Propyl) tert-butyl benzoate

(R)-2-(4-Bromophenyl)-3-(4-(tert-butyloxycarbonyl)phenyl)propanoic acid 5b (1.9 g, 4.69 mmol, obtained according to CN102292316) , 4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-amine 1 g (1.07 g, 4.92 mmol), bis(2-oxo-3-oxazolidinyl) The subphosphoryl chloride (1.79 g, 7.03 mmol) and N,N-diisopropylethylamine (2.5 mL, 14.06 mmol) were dissolved in 20 mL of dichloromethane, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The residue was further purified by silica gel column chromatography (hexane: ethyl acetate = 5:1) to give 4-(2-(4-bromophenyl)-3-((4'-chloro-2) -Methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid tert-butyl ester 5c (2.4 g, white solid), yield: 85.7%.

^{1 H NMR (400MHz, CDCl3)} : δ7.85 (d, J = 8.0Hz, 2H), 7.47-7.43 (m, 4H), 7.23-7.15 (m, 7H), 7.09-7.05 (m, 2H), 3.78-3.66 (m, 2H), 3.72-3.61 (m, 2H), 3.10-3.05 (m, 1H), 2.23 (s, 3H), 2.00-1.94 (m, 2H) 1.57 (s, 9H)

Second step

(R)-4-(2-(4-(benzo[d][1,3]diox-5-yl)phenyl)-3-((4'-chloro-2'-methyl-) tert-Butyl [1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoate

(R)-4-(2-(4-bromophenyl)-3-((4'-chloro-2'-methyl-[1,1'-diphenyl]-4-) under a nitrogen atmosphere Tert-butyl)amino)-3-oxopropyl)benzoate 5c (850 mg, 1.4 mmol) dissolved in 20 mL of dichloromethane, benzo[d][1,3]diox-5-ylboronic acid 5d (233mg, 1.4mmol), bis(tris(p-methylphenyl)phosphine)palladium chloride (98mg, 0.12mmol) and sodium carbonate (526mg, 4.96mmol) dissolved in 20mL dimethyl ether, 10mL ethanol and 5mL water The reaction solution was heated to reflux for 4 hours in a mixed solvent. The reaction mixture was added with EtOAc (EtOAc) (EtOAc (EtOAc. The residue obtained is further separated and purified by silica gel column chromatography (cyclohexane: ethyl acetate = 10:1 to 5:1) to give (R)-4-(2-(4-(benzo[d]]] [1,3] dioxin-5-yl)phenyl)-3-((4'-chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)- tert-Butyl 3-oxopropyl)benzoate 5e (700 mg, yellow solid), yield: 77.4%.

^{1 H NMR (400MHz, CDCl3)} : δ7.86 (d, J = 8.0Hz, 2H), 7.50-7.45 (m, 4H), 7.23 (s, 2H), 7.37 (d, J = 8.0Hz, 2H) , 7.23-7.17 (m, 4H), 7.12-7.04 (m, 4H), 6.88 (d, J = 8.8 Hz, 1H), 6.01 (s, 2H), 3.81-3.69 (m, 2H), 3.16-3.11 (m, 1H), 2.20 (s, 3H), 1.57 (s, 9H)

third step

(R)-4-(2-(4-(benzo[d][1,3]diox-5-yl)phenyl)-3-((4'-chloro-2'-methyl-) [1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid

(R)-4-(2-(4-(Benzo[d][1,3]diox-5-yl)phenyl)-3-((4'-chloro-2'-methyl) -[1,1'-Diphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid tert-butyl ester 5e (700 mg, 1.08 mmol) was dissolved in 10 mL dichloromethane. Trifluoroacetic acid and 1 mL of concentrated hydrochloric acid were stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to give crude (R)-4-(2-(4-(benzo[d][1,3] dioxin-5-yl)phenyl)-3-(( 4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid 5f (500 mg, yellow solid), yield: 78.2 %.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.20 (s, 1H), 7.83 (d, J = 8.4Hz, 2H), 7.60-7.55 (m, 4H), 7.49 (d, J = 8.4Hz , 2H), 7.38 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 1.6 Hz, 1H), 7.27-7.20 (m, 4H), 7.15-7.10 (m, 2H), 6.97 (d, J=8.4 Hz, 1H), 6.03 (s, 2H), 4.11-4.07 (m, 1H), 3.54-3.50 (m, 1H), 3.10-3.05 (m, 1H), 2.20 (s, 3H)

the fourth step

(R)-2-(4-(2-(4-(benzo[d][1,3]diox-5-yl)phenyl)-3-((4'-chloro-2'-) Methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoylamino)ethanesulfonic acid

(R)-4-(2-(4-(benzo[d][1,3]diox-5-yl)phenyl)-3-((4'-chloro-2'-methyl-) [1,1'-Diphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid 5f (526 mg.0.89 mmol) was dissolved in 5 mL of dimethylformamide. -oxo-3-oxazolidinyl)phosphoryl chloride (340 mg, 1.34 mmol), N,N-diisopropylethylamine (0.9 mL, 5.34 mmol), stirred at room temperature for 10 min, then added to the reaction flask Diaminoethanesulfonic acid (123 mg, 0.98 mmol) was added with stirring, and the resulting mixture was added to the mixture, and stirred at room temperature for 24 hr. The reaction mixture was added with 10 mL of water, EtOAc (EtOAc) (EtOAc) Purification by silica gel column chromatography (dichloromethane:methanol = 50:1 to 20:1) gave (R)-2-(4-(2-(4-(benzo[d][1,3]] Dioxo-5-yl)phenyl)-3-((4'-chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropan Benzo)benzoylamino)ethanesulfonic acid 5 (40 mg, white solid), yield: 7.3%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.27 (s, 1H), 8.43-8.40 (m, 1H), 7.66 (d, J = 7.6Hz, 2H), 7.60 (d, J = 8.4Hz , 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 6.4 Hz, 3H), 7.25 (d, J = 8.4 Hz, 1H) ), 7.20 (d, J = 7.2 Hz, 3H), 7.12-7.10 (m, 2H), 6.96 (d, J = 8.4 Hz, 1H), 6.03 (s, 2H), 4.11-4.08 (m, 1H) , 3.51-3.47 (m, 3H), 3.12-3.03 (m, 1H), 2.67-2.63 (m, 2H), 2.20 (s, 3H)

Example 6

(R)-2-(4-(2-(4-(benzo[d][1,3]diox-5-yl)phenyl)-3-oxo-3-((2', 4',6'-Trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoylamino)ethanesulfonic acid

first step

(R)-4-(2-(4-bromophenyl)-3-((2',4',6'-trimethyl-[1,1'-diphenyl]-4-yl)amino )-3-Oxopropyl)benzoic acid tert-butyl ester

(R)-2-(4-Bromophenyl)-3-(4-(tert-butyloxycarbonyl)phenyl)propanoic acid 5b (3 g, 7.4 mmol), 2', 4' , 6'-trimethyl-[1,1'-diphenyl]-4-amine 2c (1.563 g, 7.4 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (2.826) g, 11.1 mmol) and N,N-diisopropylethylamine (3.9 mL, 22.2 mmol) were dissolved in 20 mL dichloromethane, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The residue was further separated and purified by silica gel column chromatography (hexane: ethyl acetate = 5:1) to afford (R)-4-(2-(4-bromophenyl)-3-((2', 4',6'-Trimethyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid tert-butyl ester 6a (3.2 g, white solid) Rate: 72.7%.

Second step

(R)-4-(2-(4-(benzo[d][1,3]diox-5-yl)phenyl)-3-((2',4',6'-trimethyl) Tert-butyl ester of benzyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoate

4-(2-(4-bromophenyl)-3-((2',4',6'-trimethyl-[1,1'-diphenyl]-4-yl)) under nitrogen atmosphere tert-Butylamino 6-oxopropyl)benzoate 6a (500 mg, 0.84 mmol) was dissolved in 20 mL of dichloromethane, benzo[d][1,3]diox-5-ylboronic acid 5d ( 139 mg, 0.84 mmol), a mixture of bis(tris(p-methylphenyl)phosphine)palladium chloride (66 mg, 0.084 mmol) and sodium carbonate (354 mg, 3.34 mmol) dissolved in 16 mL of dimethyl ether, 8 mL of ethanol and 4 mL of water The solvent was heated to reflux for 4 hours in a solvent. The reaction mixture was added with EtOAc (EtOAc) (EtOAc (EtOAc. The residue obtained is further separated and purified by silica gel column chromatography (cyclohexane: ethyl acetate = 10:1 to 5:1) to give (R)-4-(2-(4-(benzo[d]]] [1,3] dioxin-5-yl)phenyl)-3-((2',4',6'-trimethyl-[1,1'-diphenyl]-4-yl)amino tert-Butyl 3-oxopropyl)benzoate 6b (430 mg, yellow solid), yield: 80.5%.

^{1 H NMR (400MHz, CDCl3)} : δ7.86 (d, J = 8.0Hz, 2H), 7.51-7.45 (m, 4H), 7.38 (d, J = 8.0Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.11 (s, 1H), 7.06-7.04 (m, 4H), 6.92–6.87 (m, 3H), 6.01 (s, 2H), 3.80-3.72 (m, 2H), 3.17-3.12 (m, 1H), 2.31 (s, 3H), 1.96 (s, 6H), 1.57 (s, 9H)

third step

(R)-4-(2-(4-(benzo[d][1,3]diox-5-yl)phenyl)-3-((2',4',6'-trimethyl) --[1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid

(R)-4-(2-(4-(Benzo[d][1,3] dioxin-5-yl)phenyl)-3-((2',4',6'-three Methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid tert-butyl ester 6b (430 mg, 0.67 mmol) dissolved in 10 mL of dichloromethane and stirred 2 mL of trifluoroacetic acid and 1 mL of concentrated hydrochloric acid were added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to give crude (R)-4-(2-(4-(benzo[d][1,3] dioxin-5-yl)phenyl)-3-(( 2',4',6'-Trimethyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid 6c (300 mg, yellow solid), yield : 76.5%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.16 (s, 1H), 7.83 (d, J = 8.0Hz, 2H), 7.58-7.55 (m, 4H), 7.49 (d, J = 8.0Hz , 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.22 (s, 1H), 7.11 (d, J = 8.4 Hz, 3H), 6.97 (d, J = 8.0 Hz, 2H), 6.03 (s , 2H), 4.11-4.07 (m, 1H), 3.54-3.49 (m, 1H), 3.10-3.05 (m, 1H), 2.20 (s, 3H), 1.87 (s, 6H)

the fourth step

(R)-2-(4-(2-(4-(benzo[d][1,3]diox-5-yl)phenyl)-3-((2',4',6') -Trimethyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoylamino)ethanesulfonic acid

(R)-4-(2-(4-(Benzo[d][1,3] dioxin-5-yl)phenyl)-3-((2',4',6'-three Methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid 6c (300 mg.0.52 mmol) was dissolved in 5 mL of dimethylformamide and stirred. Bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (196 mg, 0.77 mmol), N,N-diisopropylethylamine (0.6 mL, 3.08 mmol), stirred at room temperature for 10 min, In the reaction flask, diaminoethanesulfonic acid (71 mg, 0.57 mmol) was added under stirring, and the resulting mixture was added to the mixture and stirred at room temperature for 24 hr. The reaction mixture was added with 10 mL of water, EtOAc (EtOAc) (EtOAc) Purification by silica gel column chromatography (dichloromethane:methanol = 50:1 to 20:1) gave (R)-2-(4-(2-(4-(benzo[d][1,3]] Dioxo-5-yl)phenyl)-3-((2',4',6'-trimethyl-[1,1'-diphenyl]-4-yl)amino)-3-oxo Propyl)benzoylamino)ethanesulfonic acid 6 (60 mg, white solid), yield: 18.8%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.16 (s, 1H), 8.42-8.41 (m, 1H), 7.67 (d, J = 8.0Hz, 2H), 7.59-7.54 (m, 4H) , 7.49 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.21 (s, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 8.0 Hz, 3H), 6.86 (s, 2H), 6.03 (s, 2H), 4.11-4.07 (m, 1H), 3.51-3.47 (m, 3H), 3.11-3.07 (m, 1H), 2.66-2.62 (m, 2H), 2.20 (s, 3H), 1.87 (s, 6H)

Example 7

(R)-2-(4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-morpholine) Phenyl)-3-oxopropyl)benzoylamino)ethanesulfonic acid

first step

(R)-4-(2-(4-bromophenyl)-3-oxo-3-((2',4',6'-trimethyl-[1,1'-diphenyl]- 4-yl)amino)propyl)benzoic acid tert-butyl ester

(R)-2-(4-Bromophenyl)-3-(4-(tert-butyloxycarbonyl)phenyl)propanoic acid 5b (1.08 g, 2.5 mmol) was dissolved in 20 mL of dichloromethane and stirred. N,N-diisopropylethylamine (3.9 mL, 22.2 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (2.862 mg, 7.4 mmol) and 2',4 were added in this order. ',6'-Trimethyl-[1,1'-diphenyl]-4-amine 2c (1.563 g, 7.4 mmol), stirred at room temperature overnight, and the reaction was monitored by TLC plate. The reaction mixture was quenched with EtOAc (EtOAc m. The residue was concentrated and purified by silica gel column chromatography (eluent: hexanes: ethyl acetate = 20:1 and 15:1) to afford (R)-4-(2-(4-) Bromophenyl)-3-oxo-3-((2',4',6'-trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoic acid Butyrate 7a (3.2 g, white solid), Yield: 72.7%.

MS m/z (ESI): 642.2 [M-57]

Second step

(R)-4-(2-(4-morpholinophenyl)-3-oxo-3-((2',4',6'-trimethyl-[1,1'-diphenyl) ]-4-yl)amino)propyl)benzoic acid

(R)-4-(2-(4-bromophenyl)-3-oxo-3-((2',4',6'-trimethyl-[1,1'-) under argon atmosphere Diphenyl]-4-yl)amino)propyl)benzoic acid tert-butyl ester 7a (1 g, 1.7 mmol), morpholine (163 mg, 1.87 mmol), bis(tris(p-methylphenyl)phosphine) chloride Palladium (156 mg, 0.17 mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (162 mg, 0.34 mmol) and potassium t-butoxide (672 mg, 5.1 mmol) were dissolved in 10 mL 1,4 In the dioxane, the reaction solution was heated to reflux. The reaction mixture was filtered through celite, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (dichloromethane:methanol = 80:1 to 50:1) to afford (R)-4- (2-(4-morpholinylphenyl)-3-oxo-3-((2',4',6'-trimethyl-[1,1'-diphenyl]-4-yl)) Amino)propyl)benzoic acid 7b (1.02 g, yellow solid), yield about 100%.

MS m/z (ESI): 549.3 [M+1]

third step

(R)-2-(4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-morpholine) Phenyl)-3-oxopropyl)benzoylamino)ethanesulfonic acid

(R)-4-(2-(4-morpholinophenyl)-3-oxo-3-((2',4',6'-trimethyl-[1,1'-diphenyl) 4-yl)amino)propyl)benzoic acid 7b (548 mg.1 mmol) and bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (382 mg, 1.5 mmol), N,N-di Isopropylethylamine (0.496 mL, 3 mmol) was dissolved in 10 mL of dichloromethane and stirred at room temperature for 10 min. After adding to the reaction flask, diaminoethanesulfonic acid (125 mg, 1 mmol) was added thereto, and the resulting mixture was added to the above reaction mixture, and stirred at room temperature overnight, and the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to afford (R)-2-(4-(3-((4)) -Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-morpholinylphenyl)-3-oxopropyl)benzoylamino Ethyl sulfonic acid 7 (104 mg, white solid), yield: 15.9%.

MS m/z (ESI): 656.3 [M+1]

¹ H NMR (400 MHz, DMSO-d ₆ ) = 10.3 (s, 1H), 8.44 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.3) Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 7.5 Hz, 2H), 6.99 (d, J = 8.3 Hz, 2H), 6.90 (s, 2H), 4.02 (t, J = 7.5 Hz, 1H), 3.80 (br.s., 4H), 3.55-3.41 (m, 3H), 3.23 (br.s., 4H) , 3.10-2.99 (m, 1H), 2.68 (t, J = 7.0 Hz, 2H), 2.25 (s, 3H), 1.90 (s, 6H)

Example 8

(R)-2-(4-(3-((2',4',6'-trimethyl-[1,1'-diphenyl]-4-yl)amino)-2-(4') , 4'-Difluoro-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzoylamino) Sulfonic acid

first step

2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane

4,4-Difluorocyclohexanone 8a (26.8 g, 0.2 mol) and p-methylbenzenesulfonyl hydrazide 8b (37.2 g, 0.2 mol) were dissolved in 150 mL of ethanol and heated to reflux for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filtered cake was washed with EtOAc EtOAc EtOAc EtOAc .

MS m/z (ESI): 303.3 [M+1]

Second step

N'-(4,4-difluorocyclohexylene)benzenesulfonyl urea

2-(4,4-Difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane 8c (15.1 g, 0.05 mol) was dissolved in 150 mL of tetrahydrofuran, and tetramethylethylenediamine (154 mL, 1 mol) was added with stirring, and the mixture was cooled to -78 ° C dropwise with n-butyllithium (80 mL, 0.2 mol). After the completion of the dropwise addition, the mixture was further stirred at -78 ° C for 30 minutes, and then allowed to warm to room temperature. The mixture was further stirred at 20 ° C for 1 hour, cooled to -78 ° C, and 2-isopropoxy-4,4,5,5 was added dropwise. Tetramethyl-1,3,2-dioxaborane (40.8 mL, 0.2 mol) was stirred at -78 °C for 30 minutes and then allowed to warm to room temperature overnight. The reaction mixture was adjusted to pH = 7 with a 1M aqueous solution of hydrochloric acid, and the mixture was extracted with ethyl acetate (300mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification (cyclohexane: ethyl acetate = 80:1 to 50:1) to give 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetra Methyl-1,3,2-dioxaborane 8d (742 mg, pale yellow solid), yield: 6%.

third step

(R)-4-(2-(4',4'-difluoro-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)- 3-oxo-3-((2',4',6'-trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoic acid tert-butyl ester

(R)-4-(2-(4-bromophenyl)-3-oxo-3-((2',4',6'-trimethyl-[1,1'-diphenyl]] -4-yl)amino)propyl)benzoic acid tert-butyl ester 7a (605 mg, 1.0 mmol), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5, 5-tetramethyl-1,3,2-dioxaborane 8d (269 mg, 1.1 mmol), di(tris(p-methylphenyl)phosphine)palladium chloride (79 mg, 0.1 mmol) and sodium carbonate ( 424 mg, 4.0 mmol) was dissolved in a mixed solvent of 4 mL of dichloromethane, 2 mL of ethanol and 1 mL of water, and the reaction mixture was heated to reflux for 3 hours. The reaction mixture was filtered over Celite (EtOAc) (EtOAc (EtOAc) Methyl chloride: methanol = 50:1 to 20:1), isolated and purified to give (R)-4-(2-(4',4'-difluoro-2',3',4',5'-four Hydrogen-[1,1'-diphenyl]-4-yl)-3-oxo-3-((2',4',6'-trimethyl-[1,1'-diphenyl]] tert-Butyl -4-yl)amino)propyl)benzoate 8e (430 mg, pale yellow solid), yield: 67.0%.

^{1 H NMR (400MHz, CDCl3)} : 7.84 (d, J = 7.8Hz, 2H), 7.44 (d, J = 8.3Hz, 2H), 7.36 (d, J = 8.0Hz, 2H), 7.24 (br.s .2H), 7.18 (d, J = 8.3 Hz, 5H), 7.13 - 7.06 (m, 2H), 6.15 (br.s., 1H), 3.79-3.64 (m, 2H), 3.11 (dd, J =7.4, 13.2 Hz, 1H), 2.54-2.35 (m, 2H), 2.31-2.22 (m, 1H), 2.20 (s, 3H), 1.99 (d, J = 9.5 Hz, 2H), 0.94-0.90 ( m, 9H), 0.83-0.77 (m, 2H)

the fourth step

(R)-4-(2-(4',4'-difluoro-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)- 3-oxo-3-((2',4',6'-trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoic acid

(R)-4-(2-(4',4'-Difluoro-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl) 3-Oxo-3-(2',4',6'-trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoic acid tert-butyl ester 8e ( 381 mg, 0.6 mmol) was dissolved in 10 mL of dichloromethane, and 2.5 mL of trifluoroacetic acid and 1 mL of concentrated hydrochloric acid were added under stirring, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was extracted with methylene chloride (30 mL, EtOAc). (4',4'-Difluoro-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxo-3-(( 2',4',6'-trimethyl-[1,1'-diphenyl]-4- Base amino)propyl)benzoic acid 8f (390 mg, yellow solid), yield about 100%.

MS m/z (ESI): 602.2 [M+Na]

the fifth step

(R)-2-(4-(3-((2',4',6'-trimethyl-[1,1'-diphenyl]-4-yl)amino)-2-(4') , 4'-Difluoro-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzoylamino) Sulfonic acid

(R)-4-(2-(4',4'-Difluoro-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl) 3-oxo-3-((2',4',6'-trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoic acid 8f (347 mg, 0.6 Methyl) was dissolved in 7 mL of dichloromethane and added with bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (229 mg, 0.9 mmol), N,N-diisopropylethylamine (0.3). The mixture was stirred at room temperature for 30 minutes, and added to a reaction flask. Diaminoethanesulfonic acid (75 mg, 0.6 mmol) was added thereto with stirring, and the resulting mixture was added to the above reaction mixture, and stirred at room temperature for 24 hours, TLC Monitor the reaction. The reaction mixture was added with 10 mL of water, EtOAc (EtOAc)EtOAc. Purification by silica gel column chromatography (dichloromethane:methanol = 100:1 to 50:1) gave (R)-2-(4-(3-((2',4',6'- trimethyl) -[1,1'-diphenyl]-4-yl)amino)-2-(4',4'-difluoro-2',3',4',5'-tetrahydro-[1,1 '-Diphenyl]-4-yl)-3-oxopropyl)benzoylamino)ethanesulfonic acid 8 (99 mg, white solid), yield: 24.0%.

^{1 H NMR (400MHz, DMSO-} d6): 10.18 (br.s., 1H), 8.42 (br.s., 1H), 7.73-7.56 (m, 4H), 7.46-7.28 (m, 6H), 6.98 (d, J = 8.0 Hz, 2H), 6.88 (s, 2H), 6.14 (br.s., 1H), 4.07 (br.s., 1H), 3.57-3.42 (m, 3H), 3.09-2.98 (m, 1H), 2.66 (t, J = 6.5 Hz, 2H), 2.41-2.13 (m, 5H), 2.00-1.92 (m, 2H), 1.89 (s, 6H), 1.36-1.14 (m, 2H) )

Example 9

2-(4-((2R)-3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4'-( 1-methylcyclopropyl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzoyl Amino)ethanesulfonic acid

first step

4-(1-methylcyclopropyl)cyclohex-1-en-1-yl trifluoromethanesulfonate

4-(1-Methylcyclopropyl)cyclohexanone 9a (2.7 g, 17.7 mmol, prepared according to the published patent application WO2010039789) was dissolved in 80 mL of dry tetrahydrofuran, and the reaction was cooled to -78 ° C. Lithium bis(trimethylsilyl)amide (36 mL, 35.5 mmol) was added with stirring, and the mixture was stirred at -78 °C for 30 minutes. The reaction solution was added dropwise to a solution of 20 mL of 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (6.3 g, 17.7 mmol) in tetrahydrofuran at room temperature. Stir under 3 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The residue obtained was purified by silica gel column chromatography (cyclohexane:ethyl acetate = 100:1 to 50:1) to give 4-(1-methylcyclopropyl)cyclohex-1-ene-1 - Benzyl triflate 9b (1.1 g, colorless oil), yield: 22%.

^{1 H NMR (400MHz, CHLOROFORM-} d): 5.75 (br.s., 1H), 2.41-2.27 (m, 2H), 2.13 (d, J = 2.3Hz, 2H), 1.88 (td, J = 2.7, 12.9 Hz, 1H), 1.75 (s, 1H), 1.71-1.53 (m, 2H), 0.93 (s, 2H), 0.91 - 0.82 (m, 1H), 0.27 (d, J = 2.8 Hz, 3H)

Second step

4,4,5,5-tetramethyl-2-(4-(1-methylcyclopropyl)cyclohex-1-en-1-yl)-1,3,2-dioxaborane

4-(1-Methylcyclopropyl)cyclohex-1-en-1-yltrifluoromethanesulfonate 9b (1.1 g, 3.9 mmol), potassium acetate (1.14 g, 11.6 mmol), 1,1 '-bis(diphenylphosphino)ferrocene (237 mg, 0.43 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride (285 mg, 0.39 mmol) and 4, 4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (1.09 g, 4.3 mmol) is soluble In the 1,4-dioxane, the reaction solution was stirred at 100 ° C for 3 hours. The reaction mixture was poured into ethyl acetate (30 mL), EtOAc (EtOAc m. The residue was concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 20:1) to give 2-(4-(2-methoxypropyl-2-yl)cyclohexyl 1-(1-yl-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane 9c (605 mg, white oil), yield: 59.3%.

^{1 H NMR (400MHz, CHLOROFORM-} d): 6.59 (br.s., 1H), 2.34-2.10 (m, 2H), 2.09-1.98 (m, 2H), 1.93-1.49 (m, 2H), 1.43- 1.28 (m, 2H), 1.28-1.23 (m, 12H), 0.92 (s, 2H), 0.90-0.82 (m, 1H), 0.29-0.15 (m, 3H)

third step

(2R)-3-(4-(tert-Butoxycarbonyl)phenyl)-2-(4'-(1-methylcyclopropyl)-2',3',4',5'-four Hydrogen-[1,1'-diphenyl]-4-yl)propionic acid

(R)-2-(4-Bromophenyl)-3-(4-(tert-butyloxycarbonyl)phenyl)propanoic acid 5b (448 mg, 1.1 mmol) was dissolved in 20 mL of dichloromethane Medium, 4,4,5,5-tetramethyl-2-(4-(1-methylcyclopropyl)cyclohex-1-en-1-yl)-1,3,2-dioxaboron Alkane 9c (290 mg, 1.1 mmol), bis(tris(p-methylphenyl)phosphine)palladium chloride (86 mg, 0.11 mmol) and sodium carbonate (446 mg, 4.4 mmol) dissolved in 4 mL dimethyl ether, 2 mL ethanol and 1 mL In a mixed solvent of water, the reaction liquid was heated to reflux for 2 hours. The reaction mixture was added with EtOAc (EtOAc) (EtOAc (EtOAc. The residue obtained is further separated and purified by silica gel column chromatography (cyclohexane: ethyl acetate = 10:1 to 5:1) to give (2R)-3-(4-(tert-butyloxycarbonyl)benzene. 2-(4'-(1-methylcyclopropyl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl) Acid 9d (370 mg, white solid), yield: 73%.

the fourth step

4-((2R)-3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4'-(1-A) Cyclopropyl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzoic acid tert-butyl ester

7a (605 mg, 1.0 mmol), (2R)-3-(4-(tert-butyloxycarbonyl)phenyl)-2-(4'-(1-methylcyclopropyl)-2',3 ',4',5'-Tetrahydro-[1,1'-diphenyl]-4-yl)propanoic acid 9d (370 mg, 0.8 mmol), bis(2-oxo-3-oxazolidinyl) The subphosphoryl chloride (305 mg, 1.2 mmol), triethylamine (0.34 mL, 2.4 mmol) was dissolved in 5 mL dichloromethane, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was extracted with methylene chloride (15 mL×3), and the combined organic phase was washed with water (5 mL) and brine (5 mL) Alkane: ethyl acetate = 20:1 to 10:1), isolated and purified to give 4-((2R)-3-((4'-chloro-2'-methyl-[1,1'-diphenyl) ]-4-yl)amino)-2-(4'-(1-methylcyclopropyl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl] -4-yl)-3-Oxopropyl)benzoic acid tert-butyl ester 9e (403 mg, mp.

^{1 H NMR (400MHz, CHLOROFORM-} d): 7.84 (d, J = 8.0Hz, 2H), 7.44 (d, J = 8.3Hz, 2H), 7.35 (d, J = 8.0Hz, 2H), 7.24 (br .s., 2H), 7.18 (d, J = 8.0 Hz, 5H), 7.14-7.06 (m, 2H), 6.16 (br.s., 1H), 3.80-3.65 (m, 2H), 3.11 (dd , J=7.3, 13.1 Hz, 1H), 2.54-2.45 (m, 1H), 2.35-2.27 (m, 1H), 2.24-2.19 (m, 4H), 2.15 (d, J = 10.5 Hz, 1H), 2.06-1.87 (m, 1H), 1.82-1.71 (m, 1H), 1.53-1.48 (m, 1H), 1.45-1.41 (m, 1H), 1.26 (s, 9H), 1.02 (s, 2H), 0.98(s,3H),0.96(d,J=6.8Hz,1H),0.83-0.77(m,2H)

the fifth step

4-((2R)-3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4'-(1-A) Cyclopropyl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzoic acid

4-((2R)-3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4'-(1- Methylcyclopropyl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzoic acid tert-butyl ester 9e (381 mg, 0.6 mmol) was dissolved in 4 mL of 1,4-dioxane, and potassium t-butoxide (343 mg, 3.05 mmol) was added with stirring, and the reaction mixture was stirred at 100 ° C for 1 hour. The reaction solution was concentrated under reduced pressure to drynessnessnessnessnesssssssssssssssssssssssssssssssssssssssssssssss Wash (30 mL), dry over anhydrous sodium 4-yl)amino)-2-(4'-(1-methylcyclopropyl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl [-4-yl)-3-oxopropyl)benzoic acid 9f (313 mg, yellow solid).

Step 6

2-(4-((2R)-3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4'-( 1-methylcyclopropyl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzoyl Amino)ethanesulfonic acid

4-((2R)-3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4'-(1- Methylcyclopropyl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzoic acid 9f (313 mg , 0.52 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (200 mg, 0.78 mmol), triethylamine (0.22 mL, 1.56 mmol), stirred at room temperature for 30 min, then added to the reaction flask Diaminoethanesulfonic acid (75 mg, 0.6 mmol) was added thereto with stirring, and the resulting mixture was added to the mixture and stirred at room temperature for 24 hr. The reaction mixture was added with 25 mL of ethyl acetate and 10 mL of water, and the mixture was adjusted to pH 1 with 3M hydrochloric acid, ethyl acetate (15 mL, 3), and the combined organic phase was washed with brine (30 mL) Filtration and concentration under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane:methanol = 30:1 to 20:1) to give 2-(4-((2)) (4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4'-(1-methylcyclopropyl)-2',3 ',4',5'-Tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzoylamino)ethanesulfonic acid 9 (150 mg, white solid) Yield: 40.5%.

¹ H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.42 (t, J = 5.0 Hz, 1H), 7.70-7.55 (m, 4H), 7.42-7.10 (m, 11H), 6.13 (br.s., 1H), 4.08-4.01 (m, 1H), 3.59-3.40 (m, 3H), 3.12-2.98 (m, 4H), 2.68 (t, J = 7.0 Hz, 2H), 2.48- 2.22(m,2H), 2.18(s,3H),2.08(d,J=19.8Hz,1H),1.99(s,1H),1.92-1.72(m,1H),0.94(s,3H),0.34 -0.17(m,3H)

Example 10

(R)-2-(4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2) ,3-dihydrobenzo[b][1,4]dioxan-6-yl)phenyl)-3-oxopropyl)benzoylamino)ethanesulfonic acid

first step

(R)-2-(4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2) , 3-dihydrobenzo[b][1,4]dioxan-6-yl)phenyl)-3-oxopropyl)benzoic acid tert-butyl ester

(R) 4-(2-(4-Bromophenyl)-3-((4'-chloro-2'-methyl-[1,1'-diphenyl]-4-yl) under a nitrogen atmosphere Amino)-3-oxopropyl)benzoic acid tert-butyl ester 5c (600 mg, 0.99 mmol), (2,3-dihydrobenzo[b][1,4]dioxan-6-yl)boronic acid 10c (179mg, 0.99mmol), bis(tris(p-methylphenyl)phosphine)palladium chloride (78mg, 0.099mmol) and sodium carbonate (421mg, 3.97mmol) dissolved in 16mL dimethyl ether, 8mL ethanol and 4mL water The reaction solution was heated to reflux for 6 hours in a mixed solvent. The reaction mixture was quenched with EtOAc EtOAc EtOAc (EtOAc m. Filtration and concentration under reduced pressure, and the residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 10:1 to 5:1) to afford (R)-2-(4-(3) -((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2,3-dihydrobenzo[b][ 1,4] tert-butyl dioxane-6-yl)phenyl)-3-oxopropyl)benzoate 10a (500 mg, white solid), yield: 76.3%.

^{1 H NMR (400MHz, CDCl3)} : δ7.86 (d, J = 8.0Hz, 2H), 7.52-7.45 (m, 4H), 7.36 (d, J = 8.4Hz, 2H), 7.23-7.16 (m, 6H), 7.11-7.06 (m, 3H), 6.93 (d, J = 8.4 Hz, 1H), 4.30 (s, 4H), 3.81-3.68 (m, 2H), 3.16-3.11 (m, 1H), 2.20 (s, 3H), 1.57 (s, 9H)

Second step

(R)-2-(4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2) ,3-dihydrobenzo[b][1,4]dioxan-6-yl)phenyl)-3-oxopropyl))benzoic acid

(R)-2-(4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-() 2,3-Dihydrobenzo[b][1,4]dioxan-6-yl)phenyl)-3-oxopropyl)benzoic acid tert-butyl ester 10a (500 mg, 0.76 mmol) dissolved in 10 mL In dichloromethane, 2 mL of trifluoroacetic acid and 1 mL of concentrated hydrochloric acid were added under stirring, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give crude (R)-2-(4-(3-((4'-) Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2,3-dihydrobenzo[b][1,4] dioxins Alkyl-6-yl)phenyl)-3-oxopropyl))benzoic acid 10b (380 mg, white solid), yield: 83.3%.

^{1 H NMR (400MHz, DMSO-} d 6): δ12.82-12.77 (m, 1H), 10.18 (s, 1H), 8.43-8.40 (m, 1H), 7.82 (d, J = 8.0Hz, 2H) , 7.59-7.52 (m, 4H), 7.48 (d, J = 8.0 Hz, 2H), 7.39-7.33 (m, 3H), 7.27-7.20 (m, 3H), 7.14-7.08 (m, 3H), 6.90 (d, J=8.0 Hz, 1H), 4.25 (s, 4H), 4.10-4.06 (m, 1H), 3.53-3.40 (m, 1H), 3.10-3.05 (m, 1H), 2.17 (s, 3H) )

third step

(R)-2-(4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2) ,3-dihydrobenzo[b][1,4]dioxan-6-yl)phenyl)-3-oxopropyl)benzoylamino)ethanesulfonic acid

(R)-2-(4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-() 2,3-Dihydrobenzo[b][1,4]dioxan-6-yl)phenyl)-3-oxopropyl))benzoic acid 10b (380 mg.0.63 mmol) dissolved in 5 mL of dimethyl To the carbamide, bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (240 mg, 0.95 mmol), N,N-diisopropylethylamine (0.4 mL, 1.89 mmol), After stirring for 10 minutes at room temperature, it was added to a reaction flask, and diaminoethanesulfonic acid (83 mg, 0.66 mmol) was added thereto with stirring, and the resulting mixture was added to the above reaction mixture, and stirred at room temperature for 24 hours, and the reaction was monitored by TLC. The reaction mixture was added with 10 mL of water, EtOAc (EtOAc) (EtOAc) Purification by silica gel column chromatography (dichloromethane:methanol = 50:1 to 20:1) afforded (R)-2-(4-(3-((4'-chloro-2'-methyl-[ 1,1'-diphenyl]-4-yl)amino)-2-(4-(2,3-dihydrobenzo[b][1,4]dioxan-6-yl)phenyl) 3-Oxopropyl)benzoylamino)ethanesulfonic acid 10 (50 mg, white solid), yield: 11.2%.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.27 (s, 1H), 8.44 - 8.42 (m, 1H), 7.66 (d, J = 7.6 Hz, 2H), 7.60 (d, J = 8.4 Hz) , 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 6.4 Hz, 3H), 7.25 (d, J = 8.4 Hz, 1H) ), 7.20 (d, J = 7.2 Hz, 3H), 7.12-7.10 (m, 2H), 6.96 (d, J = 8.4 Hz, 1H), 4.24 (s, 4H), 4.11-4.08 (m, 1H) , 3.51-3.47 (m, 3H), 3.12-3.03 (m, 1H), 2.67-2.63 (m, 2H), 2.17 (s, 3H)

Example 11

(R)-2-(4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2) ,3-dihydrobenzofuran-5-yl)phenyl)-3-oxopropyl)benzoylamino)ethanesulfonic acid

first step

(R)-4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-dihydrobenzofuran-5-yl) Tert-butyl phenyl)-3-oxopropyl)benzoate

(R) 4-(2-(4-Bromophenyl)-3-((4'-chloro-2'-methyl-[1,1'-diphenyl]-4-yl) under a nitrogen atmosphere Amino)-3-oxopropyl)benzoic acid tert-butyl ester 5c (850 mg, 1.4 mmol) dissolved in 20 mL of dichloromethane, dihydrobenzofuran-5-ylboronic acid 5d (233 mg, 1.4 mmol), (Tris(p-methylphenyl)phosphine)palladium chloride (98 mg, 0.12 mmol) and sodium carbonate (526 mg, 4.96 mmol) were dissolved in a mixed solvent of 20 mL of dimethyl ether, 10 mL of ethanol and 5 mL of water, and the reaction liquid was heated. Until reflux for 4 hours. The reaction mixture was added with EtOAc (EtOAc) (EtOAc (EtOAc. The residue obtained is further separated and purified by silica gel column chromatography (cyclohexane: ethyl acetate = 10:1 to 5:1) to give (R)-4-(3-((4'-chloro-2'). -methyl-[1,1'-diphenyl]-4-yl)amino)-dihydrobenzofuran-5-yl)phenyl)-3-oxopropyl)benzoic acid tert-butyl ester 11a ( 700 mg, yellow solid), Yield: 77.4%.

^{1 H NMR (400MHz, CDCl3)} : δ7.86 (d, J = 8.0Hz, 2H), 7.51 (d, J = 8.4Hz, 2H), 7.47-7.42 (m, 3H), 7.37-7.33 (m, 3H), 7.23-7.17 (m, 6H), 7.12-7.08 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H), 4.65 - 4.60 (m, 2H), 3.81-3.69 (m, 2H) , 3.29-3.25 (m, 2H), 3.17–3.12 (m, 1H) 2.20 (s, 3H), 1.57 (s, 9H)

Second step

(R)-4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-dihydrobenzofuran-5-yl) Phenyl)-3-oxopropyl)benzoic acid

(R)-4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-dihydrobenzofuran-5-yl) Benzyl)-3-oxopropyl)benzoic acid tert-butyl ester 11a (700 mg, 1.08 mmol) was dissolved in 10 mL of dichloromethane, and 2 mL of trifluoroacetic acid and 1 mL of concentrated hydrochloric acid were added under stirring, and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to give crude (R)-4-(3-((4'-chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino) -Dihydrobenzofuran-5-yl)phenyl)-3-oxopropyl)benzoic acid 11b (500 mg, yellow solid), yield: 78.2%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.19 (s, 1H), 7.82 (d, J = 8.4Hz, 2H), 7.59 (d, J = 8.4Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.0 Hz, 3H), 7.39-7.33 (m, 4H), 7.27-7.20 (m, 3H), 7.13 (d, J = 8.4 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 4.56-4.51 (m, 2H), 4.10-4.07 (m, 1H), 3.54-3.48 (m, 2H), 3.22-3.18 (m, 1H), 3.10-3.05 (m, 1H), 2.17 (s, 3H)

third step

(R)-2-(4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2) ,3-dihydrobenzofuran-5-yl)phenyl)-3-oxopropyl)benzoylamino)ethanesulfonic acid

(R)-4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-dihydrobenzofuran-5-yl) Phenyl)-3-oxopropyl)benzoic acid 11b (526 mg.0.89 mmol) was dissolved in 5 mL of dimethylformamide and bis(2-oxo-3-oxazolidinyl)phosphorus was added with stirring. The acid chloride (340 mg, 1.34 mmol), N,N-diisopropylethylamine (0.9 mL, 5.34 mmol) was stirred at room temperature for 10 min, then added to the reaction flask, and diaminoethanesulfonic acid (123 mg, 0.98) was added with stirring. Mmol), the obtained mixture was added to the above reaction solution, and stirred at room temperature for 24 hours, and the reaction was monitored by TLC. The reaction mixture was added with 10 mL of water, EtOAc (3 mL, EtOAc) The residue was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 20:1) to afford (R)-2-(4-(3-((4')) -[1,1'-diphenyl]-4-yl)amino)-2-(4-(2,3-dihydrobenzofuran-5-yl)phenyl)-3-oxopropyl Benzoylamino)ethanesulfonic acid 11 (40 mg, white solid), yield: 7.3%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.19 (s, 1H), 7.66 (d, J = 8.4Hz, 2H), 7.60 (d, J = 8.4Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.50-7.47 (m, 3H), 7.39-7.31 (m, 4H), 7.26 (d, J = 1.6 Hz, 1H), 7.24 (d, J = 2.0 Hz, 2H), 7.14 (d, J=8.0 Hz, 1H), 4.56-4.51 (m, 2H), 4.09-4.05 (m, 1H), 3.54-3.48 (m, 3H), 3.23-3.15 (m, 2H), 3.08-3.02 (m, 1H), 2.67-2.63 (m, 2H), 2.17 (s, 3H)

Example 12

(R)-2-(4-(2-(4-(2,3-dihydrobenzo[b][1,4]dioxan-6-yl)phenyl)-3-oxo-3 -((2',4',6'-trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoylamino)ethanesulfonic acid

first step

(R)-(4-(2-(4-(2,3-dihydrobenzo[b][1,4]dioxan-6-yl)phenyl)-3-oxo-3-() (2',4',6'-Trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoic acid tert-butyl ester

4-(2-(4-Bromophenyl)-3-((2',4',6'-trimethyl-[1,1'-diphenyl]-4-yl)amino)-3 -Oxopropyl)tert-butyl benzoate 6a (600 mg, 1.002 mmol) dissolved in 20 mL of dichloromethane, (2,3-dihydrobenzo[b][1,4]dioxan-6-yl Boric acid 12a (180 mg, 1.002 mmol), bis(tris(p-methylphenyl)phosphine)palladium chloride (79 mg, 0.1 mmol) and sodium carbonate (424 mg, 4.0 mmol) dissolved in 16 mL of dimethyl ether, 8 mL of ethanol and The reaction solution was heated to reflux for 6 hours in a mixed solvent of 4 mL of water. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The sodium was dried, filtered, and concentrated under reduced pressure. EtOAc m. -(4-(2,3-dihydrobenzo[b][1,4]dioxan-6-yl)phenyl)-3-oxo-3-((2',4',6' Tri-tert-butyl trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoate 12b (430 mg, yellow solid), yield: 81.0%.

^{1 H NMR (400MHz, CDCl3)} : δ7.86 (d, J = 8.0Hz, 2H), 7.52-7.45 (m, 4H), 7.36 (d, J = 8.4Hz, 2H), 7.23-7.16 (m, 6H), 7.11–7.06 (m, 3H), 6.93 (d, J=8.4 Hz, 1H), 4.30 (s, 4H), 3.81-3.68 (m, 2H), 3.16-3.11 (m, 1H), 2.31 (s, 3H), 1.98 (s, 6H), 1.59 (s, 9H)

Second step

(R)-(4-(2-(4-(2,3-dihydrobenzo[b][1,4]dioxan-6-yl)phenyl)-3-oxo-3-() (2',4',6'-Trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoic acid

(R)-(4-(2-(4-(2,3-Dihydrobenzo[b][1,4]dioxan-6-yl)phenyl)-3-oxo-3- ((2',4',6'-Trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoic acid tert-butyl ester 12b (530 mg, 0.81 mmol) dissolved in 10 mL In dichloromethane, 2 mL of trifluoroacetic acid and 1 mL of concentrated hydrochloric acid were added with stirring, and the mixture was stirred at room temperature overnight. The reaction mixture was extracted with dichloromethane (30 mL×3), and the combined organic The organic layer was dried over sodium sulfate, filtered, and evaporated, evaporated, evaporated,363363363363363363363363363363363363363363363363363363363363363363 2,3-Dihydrobenzo[b][1,4]dioxan-6-yl)phenyl)-3-oxo-3-((2',4',6'-trimethyl- [1,1'-Diphenyl]-4-yl)amino)propyl)benzoic acid 12c (450 mg, yellow solid), yield: 93.0%.

^{1 H NMR (400MHz, DMSO-} d 6): δ12.79 (s, 1H), 10.15 (s, 1H), 7.83 (d, J = 8.0Hz, 2H), 7.59-7.48 (m, 6H), 7.38 (d, J = 8.0 Hz, 2H), 7.12 - 7.08 (m, 2H), 6.97 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 6.86 (s, 3H) , 4.25 (s, 4H), 4.10-4.06 (m, 1H), 3.53-3.40 (m, 1H), 3.10-3.05 (m, 1H), 2.48 (s, 3H), 1.87 (s, 6H)

third step

(R)-2-(4-(2-(4-(2,3-dihydrobenzo[b][1,4]dioxan-6-yl)phenyl)-3-oxo-3 -((2',4',6'-trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzene Formylamino)ethanesulfonic acid

(R)-(4-(2-(4-(2,3-Dihydrobenzo[b][1,4]dioxan-6-yl)phenyl)-3-oxo-3- ((2',4',6'-Trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoic acid 12c (450mg.0.75mmol) dissolved in 5mL dimethyl To the formamide, bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (287 mg, 1.13 mmol), N,N-diisopropylethylamine (0.4 mL, 2.26 mmol). After stirring for 10 minutes, it was added to a reaction flask, and diaminoethanesulfonic acid (99 mg, 0.79 mmol) was added thereto with stirring, and the resulting mixture was added to the above reaction solution, and stirred at room temperature for 24 hours, and the reaction was monitored by TLC. After adding 10 mL of water and extracting with ethyl acetate (30 mL × 3), the combined organic phase was washed with brine (30 mL) Further analysis and purification (dichloromethane:methanol = 30:1 to 20:1) gave (R)-2-(4-(2-(4-(2,3-dihydrobenzo[b][1, 4] Dioxane-6-yl)phenyl)-3-oxo-3-((2',4',6'-trimethyl-[1,1'-diphenyl]-4-yl) Amino)propyl)benzoylamino)ethanesulfonic acid 12 (100 mg, white solid), yield: 18.8%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.20 (s, 1H), 8.44-8.42 (m, 1H), 7.83 (d, J = 8.0Hz, 2H), 7.59-7.48 (m, 6H) , 7.38 (d, J = 8.0 Hz, 2H), 7.12 - 7.08 (m, 2H), 6.97 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 6.86 (s, 3H), 4.24 (s, 4H), 3.50-3.48 (m, 3H), 3.07-3.02 (m, 1H), 2.71-2.65 (m, 2H), 2.21 (s, 3H), 1.87 (s, 6H)

Example 13

(R)-2-(4-(2-(4-(2,3-dihydrobenzofuran-5-yl)phenyl)-3-oxo-3-((2',4',6) '-Trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoylamino)ethanesulfonic acid

first step

(R)-(4-(2-(4-(2,3-dihydrobenzofuran-5-yl)phenyl)-3-oxo-3-((2',4',6'-) Tert-butyl trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoate

4-(2-(4-Bromophenyl)-3-((2',4',6'-trimethyl-[1,1'-diphenyl]-4-yl)amino)-3 -Oxopropyl)benzoic acid tert-butyl ester 6a (600 mg, 1.002 mmol) dissolved in 20 mL of dichloromethane, (2,3-dihydrobenzofuran-5-yl)boronic acid 13c (165 mg, 1. Di(tris(p-methylphenyl)phosphine)palladium chloride (79 mg, 0.1 mmol) and sodium carbonate (424 mg, 4.0 mmol) were dissolved in a mixed solvent of 16 mL of dimethyl ether, 8 mL of ethanol and 4 mL of water. Heat to reflux for 6 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The sodium was dried, filtered, and concentrated under reduced pressure. EtOAc m. -(4-(2,3-dihydrobenzofuran-5-yl)phenyl)-3-oxo-3-((2',4',6'-trimethyl-[1,1' -Diphenyl]-4-yl)amino)propyl)benzoic acid tert-butyl ester 12b (350 mg, white solid), yield: 53.8%.

^{1 H NMR (400MHz, CDCl3)} : δ7.86 (d, J = 8.0Hz, 2H), 7.51 (d, J = 8.4Hz, 2H), 7.47-7.42 (m, 3H), 7.37-7.33 (m, 3H), 7.23-7.17 (m, 6H), 7.12-7.08 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H), 4.65-4.60 (m, 2H), 3.81-3.69 (m, 2H) , 3.29-3.25 (m, 2H), 3.17-3.12 (m, 1H), 2.31 (s, 3H), 1.98 (s, 6H), 1.59 (s, 9H)

Second step

(R)-(4-(2-(4-(2,3-dihydrobenzofuran-5-yl)phenyl)-3-oxo-3-((2',4',6'-) Trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoic acid

(R)-(4-(2-(4-(2,3-dihydrobenzofuran-5-yl)phenyl)-3-oxo-3-((2',4',6') - Trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoic acid tert-butyl ester 12b (350 mg, 0.55 mmol) was dissolved in 10 mL of dichloromethane, and 2 mL The fluoroacetic acid and 1 mL of concentrated hydrochloric acid were stirred at room temperature overnight. The reaction mixture was extracted with methylene chloride (30 mL×3). The residue obtained was further separated and purified by silica gel column chromatography (dichloromethane: methanol = 10:1) to afford (R)-(4-(2-(4-(2,3-dihydrobenzofuran)- 5-yl)phenyl)-3-oxo-3-((2',4',6'-trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl) Benzoic acid 12c (315 mg, white solid), yield: 98.7%.

1H NMR (400MHz, DMSO-d ₆ ): δ 10.19 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.0 Hz, 3H), 7.39-7.33 (m, 4H), 7.27-7.20 (m, 3H), 7.13 (d, J = 8.4 Hz, 1H), 6.80 ( d, J=8.4 Hz, 1H), 4.56-4.51 (m, 2H), 4.10-4.07 (m, 1H), 3.54-3.48 (m, 2H), 3.22-3.18 (m, 1H), 3.10-3.05 ( m, 1H), 2.31 (s, 3H), 1.98 (s, 6H)

third step

(R)-2-(4-(2-(4-(2,3-dihydrobenzofuran-5-yl)phenyl)-3-oxo-3-((2',4',6) '-Trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoylamino)ethanesulfonic acid

(R)-(4-(2-(4-(2,3-dihydrobenzofuran-5-yl)phenyl)-3-oxo-3-((2',4',6') -Trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoic acid 12c (315 mg.0.54 mmol) was dissolved in 5 mL of dimethylformamide and added with stirring (2) -oxo-3-oxazolidinyl)phosphoryl chloride (207 mg, 0.81 mmol), N,N-diisopropylethylamine (0.3 mL, 1.63 mmol), stirred at room temperature for 10 min, then added to the reaction flask Diaminoethanesulfonic acid (71 mg, 0.57 mmol) was added under stirring, and the obtained mixture was added to the reaction mixture, and the mixture was stirred at room temperature for 24 hours, and the reaction was monitored by TLC. 30 mL × 3), the combined organic phases were washed with brine (30 mL) From 30:1 to 20:1), (R)-2-(4-(2-(4-(2,3-dihydrobenzofuran-5-yl)phenyl)-3-oxo-3 is obtained -((2',4',6'-trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoylamino)ethanesulfonic acid 13 (100 mg, white solid ), yield: 26.8%.

1H NMR (400MHz, DMSO-d ₆ ): δ 10.19 (s, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.50-7.47 (m, 3H), 7.39-7.31 (m, 4H), 7.26 (d, J = 1.6 Hz, 1H), 7.24 (d, J = 2.0 Hz, 2H), 7.14 ( d, J=8.0 Hz, 1H), 4.56-4.51 (m, 2H), 4.09-4.05 (m, 1H), 3.54-3.48 (m, 3H), 3.23-3.15 (m, 2H), 3.08-3.02 ( m,1H), 2.67-2.63 (m, 2H), 2.31 (s, 3H), 1.98 (s, 6H)

Example 14

(R)-2-(4-(2-(4-(4-(tert-butyl)piperidin-1-yl)phenyl)-3-oxo-3-((2',4',6) '-Trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoylamino)ethanesulfonic acid

first step

(R)-4-(2-(4-(4-(tert-butyl)piperidin-1-yl)phenyl)-3-oxo-3-((2',4',6'-three Methyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoic acid

(R)-4-(2-(4-bromophenyl)-3-oxo-3-((2',4',6'-trimethyl-[1,1'-) under argon atmosphere tert-Butyl diphenyl]-4-yl)amino)propyl)benzoate 7a (598 mg, 1.0 mmol), 4-tert-butylpiperidine hydrochloride (187 mg, 1.05 mmol), two (three) Phenylphenyl)phosphine) palladium chloride (92 mg, 0.17 mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (96 mg, 0.2 mmol) and potassium t-butoxide (337 mg, 3.0 Methyl) was dissolved in 15 mL of 1,4-dioxane and the reaction was heated to reflux for 6 h. The reaction mixture was filtered through celite, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 20:1) to afford (R)-4- (2-(4-(4-(tert-butyl)piperidin-1-yl)phenyl)-3-oxo-3-((2',4',6'-trimethyl-[1, 1'-Diphenyl]-4-yl)amino)propyl)benzoic acid 14a (400 mg, yellow solid), yield: 66.6%.

MS m/z (ESI): 604.4 [M+1]

Second step

(R)-2-(4-(2-(4-(4-(tert-butyl)piperidin-1-yl)phenyl)-3-oxo-3-((2',4',6) '-Trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoylamino)ethanesulfonic acid

(R)-4-(2-(4-(4-(tert-butyl)piperidin-1-yl)phenyl)-3-oxo-3-((2',4',6'-three Methyl-[1,1'-diphenyl]-4-yl)amino)propyl)benzoic acid 14a (400 mg.0.66 mmol) was dissolved in 5 mL of dimethylformamide and bis(2-oxygen) was added with stirring. </RTI> <RTIgt; Diaminoethanesulfonic acid (151 mg, 0.70 mmol) was added thereto, and the resulting mixture was added to the mixture and stirred at room temperature for 24 hr. The reaction mixture was added with 10 mL of water, EtOAc (EtOAc)EtOAc. Purification by silica gel column chromatography (dichloromethane:methanol = 30:1 to 20:1) afforded (R)-2-(4-(2-(4-(4-(tert-butyl))piperidine- 1-yl)phenyl)-3-oxo-3-((2',4',6'-trimethyl-[1,1'-diphenyl]-4-yl)amino)propyl) Benzoylamino)ethanesulfonic acid 14 (100 mg, white solid), yield: 21.1%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.13 (s, 1H), 10.03 (s, 1H), 8.41-8.39 (m, 3H), 7.65-7.63 (m, 3H), 7.57-7.55 ( m,3H), 7.45-7.43 (m, 2H), 7.35-7.22 (m, 8H), 6.97-6.94 (m, 4H), 6.86-6.85 (m, 5H), 4.05-4.01 (m, 2H), 3.92-3.88 (m, 2H), 3.71-3.67 (m, 3H), 3.62-3.58 (m, 5H), 2.65-2.49 (m, 4H), 2.22 (s, 4H), 1.87 (s, 9H), 0.84(s,9H)

Example 15

2-(4-((2R)-3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4'-( 2-methoxypropyl-2-yl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxypropyl Benzoylamino)ethanesulfonic acid

first step

2-(1,4-Dioxaspiro[4.5]decane-8-yl)propan-2-ol

Ethyl 4-oxocyclohexylcarboxylate 15a (50 g, 293.96 mmol), ethylene glycol (65 ml, 1.18 mol), p-toluenesulfonic acid (5 g, 29.4 mmol) was dissolved in 300 mL of toluene, and the reaction mixture was heated to It was refluxed and stirred for 8 hours. The reaction mixture was concentrated under reduced pressure. EtOAc m. The residue obtained was further separated and purified by silica gel column chromatography to give 2-(1,4-dioxaspiro[4.5]decane-8-yl)propan-2-ol 15b (43 g, white oil). Rate: 69.3%

^{1 H NMR (400MHz, CDCl3)} : δ4.075 (q, 2H), 3.89 (s, 4H), 1.90-1.87 (m, 2H), 1.79-1.71 (m, 4H), 1.54-1.47 (m, 2H ), 1.20(s,3H).

Second step

Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate

2-(1,4-Dioxaspiro[4.5]decane-8-yl)propan-2-ol 15b (43 g, 75 mmol) was dissolved in 100 mL of dry tetrahydrofuran, and the reaction mixture was reduced to -78 ° C, Methylmagnesium chloride (100 mL, 0.3 mol) was added dropwise, and the temperature was controlled at -78 ° C. After the completion of the dropwise addition, the mixture was allowed to warm to room temperature and stirred overnight. The temperature was lowered to -78 ° C, and the reaction was quenched with EtOAc (EtOAc) (EtOAc) Filtration and concentrating under reduced pressure afforded crude 1,4-dioxaspiro[4.5] decane-8-carboxylic acid ethyl ester 15c (12.23 g, white oil). The next step is to react.

¹ H NMR (400 MHz, CDCl 3 ): δ 3.93 (s, 4H), 2.03 (s, 4H), 1.80-1.78 (m, 2H), 1.54-1.48 (m, 2H), 1.19 (s, 6H).

third step

8-(2-methoxypropyl-2-yl)-1,4-dioxaspiro[4.5]decane

Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate 15c (4.2 g, 20.97 mmol) was dissolved in 50 mL of tetrahydrofuran, and 60% sodium hydride (3.35 g, 83.88 mmol), iodomethane (13 mL, 20.97 mmol). The reaction mixture was cooled to -78 ° C, and the mixture was evaporated to dryness eluted Dryed over sodium sulfate, filtered and concentrated under reduced vacuoielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielieliel ), the yield is about 100%.

^{1 H NMR (400MHz, CDCl3)} : δ3.92 (s, 4H), 3.16 (s, 3H), 1.79-1.69 (m, 4H), 1.53-1.43 (m, 2H), 1.35-1.24 (m, 2H ), 1.12 (s, 6H).

the fourth step

4-(2-methoxypropyl-2-yl)cyclohexanone

8-(2-Methoxypropyl-2-yl)-1,4-dioxaspiro[4.5]decane 15d (4.5 g, 2.99 mmol) was dissolved in 60 mL of tetrahydrofuran, and 60 mL of 4M was added with stirring. In a hydrochloric acid solution, the reaction solution was stirred at room temperature overnight. The reaction mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride, and the mixture was evaporated to ethyl acetate (50 mL × 3). Concentration under reduced pressure gave crude 4-(2-methoxypropyl-2-yl)cyclohexanone 15e (4.6 g, m.

^{1 H NMR (400MHz, CDCl3)} : δ3.19 (s, 3H), 2.42-2.26 (m, 2H), 2.10-2.04 (m, 2H), 1.90-1.84 (m, 2H), 1.52-1.44 (m , 2H), 1.07 (s, 6H).

the fifth step

4-(2-methoxypropyl-2-yl)cyclohexyl-1-en-1-yl 2,2,2-trifluoromethanesulfonate

4-(2-methoxypropyl-2-yl)cyclohexanone 15e (2.6 g, 15.27 mmol) was dissolved in 30 mL of dry tetrahydrofuran, the reaction solution was cooled to -78 ° C, and then added to the mixture. Methylsilyl) lithium amide (19 mL, 18.32 mmol) was stirred at -78 °C for 30 min. The reaction solution was added dropwise to a solution of 20 mL of 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (4.9 g, 13.74 mmol) in tetrahydrofuran at room temperature. Stir under 3 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 10:1) to give 4-(2-methoxypropyl-2-yl)cyclohexyl-1-ene-1 - 2,2,2-trifluoromethanesulfonate 15f (2.14 g, white oil), yield: 46.5%.

^{1 H NMR (400MHz, CDCl3)} : δ3.18 (s, 3H), 2.40-2.33 (m, 2H), 2.22-2.18 (m, 1H), 2.40-2.29 (m, 2H), 2.03-1.94 (m , 2H), 1.24 (s, 6H).

Step 6

2-(4-(2-methoxypropyl-2-yl)cyclohexyl-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxo Heteroborane

4-(2-Methoxypropyl-2-yl)cyclohexyl-1-en-1-yl 2,2,2-trifluoromethanesulfonate 15f (2.14 g, 7.08 mmol), sodium acetate ( 1.7 g, 21.3 mmol), 1,1'-bis(diphenylphosphino)ferrocene (275 mg, 0.49 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (II) ) (311 mg, 0.42 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (2.16 g, 8.49 mmol) was dissolved in 1,4-dioxane, and the reaction mixture was stirred at 80 ° C for 3 hours. The reaction mixture was poured into ethyl acetate (30 mL), EtOAc (EtOAc m. The residue was concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 20:1) to give 2-(4-(2-methoxypropyl-2-yl)cyclohexyl 1-(1-yl-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane 15 g (892 mg, white oil), yield: 45.1%.

¹ H NMR (400 MHz, CDCl 3 ): δ 3.04 (s, 3H), 2.16-2.10 (m, 2H), 1.91-1.81 (m, 2H), 1.78-1.73 (m, 2H), 1.69-1.58 (m) , 1H), 1.28-1.22 (m, 12H), 1.06-0.96 (m, 6H).

Seventh step

4-((2R)-3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4'-(2-A) Oxypropyl-2-yl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzoic acid Tert-butyl ester

(R)-4-(2-(4-Bromophenyl)-3-((4'-chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino) tert-Butyl 3-oxopropyl)benzoate 5c (604 mg, 1.0 mmol), 2-(4-(2-methoxypropyl-2-yl)cyclohex-1-en-1-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane 15h (250mg, 0.89mmol), bis(tris(p-methylphenyl)phosphine)palladium chloride (79mg 0.1 mmol) and sodium carbonate (319 mg, 3.0 mmol) were dissolved in a mixed solvent of 16 mL of dichloromethane, 16 mL of ethanol and 8 mL of water, and the reaction mixture was heated under reflux for 3 hours. The reaction mixture was filtered over Celite (EtOAc) (EtOAc (EtOAc) Methyl chloride:methanol = 50:1 to 20:1), isolated and purified to give 4-((2R)-3-((4'-chloro-2'-methyl-[1,1'-diphenyl]] 4-yl)amino)-2-(4'-(2-methoxypropyl-2-yl)-2',3',4',5'-tetrahydro-[1,1'-di Tert-butyl phenyl]-4-yl)-3-oxopropyl)benzoate

15j (270 mg, yellow oil), yield: 45.8%.

^{1 H NMR (400MHz, CDCl3)} : δ7.83 (d, J = 8.0Hz, 2H), 7.44 (d, J = 8.0Hz, 2H), 7.35 (d, J = 8.0Hz, 2H), 7.24-7.22 (m, 2H), 7.18-7.14 (m, 6H), 7.08 (d, J = 8.4 Hz, 1H), 6.16-6.15 (m, 1H), 3.77 - 3.65 (m, 2H), 3.21 (s, 3H) ), 3.13-3.08 (m, 1H), 2.48-2.40 (m, 2H), 2.35-3.32 (m, 1H), 2.28-2.19 (m, 3H), 2.08-1.99 (m, 2H), 1.98-1.83 (m, 1H), 1.56 (s, 9H), 1.52-1.49 (m, 1H), 1.48-1.42 (m, 1H), 1.19-1.14 (m, 6H)

Eighth step

4-((2R)-3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4'-(2-A) Oxypropyl-2-yl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzoic acid

4-((2R)-3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4'-(2- Methoxypropyl-2-yl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzene Tert-butyl formate 15j (270 mg, 0.40 mmol) and potassium t-butoxide (268 mg, 2.39 mmol) were dissolved in 5 mL of 1,4-dioxane, and the reaction mixture was heated to reflux for 2 hr. The reaction mixture was cooled, EtOAc (EtOAc m. The resulting crude 4-((2R)-3-((4'-chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4'-( 2-methoxypropyl-2-yl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl Benzoic acid for 15 h (270 mg, yellow solid).

^{1 H NMR (400MHz, DMSO-} d 6): δ12.50 (s, 1H), 10.15 (s, 1H), 7.80 (d, J = 8.0Hz, 2H), 7.57 (d, J = 8.4Hz, 2H ), 7.45- 7.36 (m, 7H), 7.35-7.19 (m, 3H), 7.13 (d, J = 8.0 Hz, 1H), 6.16-6.15 (m, 1H), 4.05-4.02 (m, 1H), 3.52-3.46 (m, 2H), 3.08 (s, 3H), 3.06-3.01 (m, 1H), 2.45-2.41 (m, 3H), 2.20 (s, 3H), 2.19-2.13 (m, 1H), 2.01-1.88 (m, 3H), 1.70-1.60 (m, 1H), 1.32-1.29 (m, 1H), 1.19-1.14 (m, 6H)

Step 9

2-(4-((2R)-3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4'-( 2-methoxypropyl-2-yl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxypropyl Benzoylamino)ethanesulfonic acid

4-((2R)-3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4'-(2- Methoxypropyl-2-yl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzene Formic acid 15h (280mg.0.43mmol) was dissolved in 5mL dimethylformamide, and bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (163mg, 0.65mmol), triethylamine (0.2) The mixture was stirred at room temperature for 10 minutes, and then added to a reaction flask, and diaminoethanesulfonic acid (57 mg, 0.46 mmol) was added thereto with stirring, and the resulting mixture was added to the above reaction mixture, and stirred at room temperature for 24 hours, TLC Monitor the reaction. The reaction mixture was added with 10 mL of water, EtOAc (EtOAc)EtOAc. Further analysis and purification by silica gel column chromatography (dichloromethane:methanol = 100:1 to 50:1) afforded 2-(4-((2R)-3-((4'-chloro-2'-methyl-[ 1,1'-diphenyl]-4-yl)amino)-2-(4'-(2-methoxypropyl-2-yl)-2',3',4',5'-four Hydrogen-[1,1'-diphenyl]-4-yl)-3-oxypropyl)benzoylamino)ethanesulfonic acid 15 (130 mg, white solid), yield: 41.5%.

^{1 H NMR (400MHz, DMSO-} d 6): δ12.24 (s, 1H), 8.41-8.39 (m, 1H) 7.65-7.58 (m, 4H), 7.39-7.19 (m, 8H), 7.14 (d , J=8.4 Hz, 3H), 6.16-6.15 (m, 1H), 4.05-4.02 (m, 1H), 3.52-3.46 (m, 3H), 3.08 (s, 3H), 3.06-3.01 (m, 2H) ), 2.65-2.61 (m, 2H), 2.45-2.41 (m, 3H), 2.20 (s, 3H), 2.19-2.13 (m, 1H), 2.01-1.88 (m, 3H), 1.70-1.60 (m) , 2H), 1.32-1.29 (m, 1H), 1.19-1.14 (m, 6H)

Example 16

(S)-2-(4-(2-(4-(benzo[d][1,3]diox-5-yl)phenyl)-3-((4'-chloro-2'-) Methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoylamino)ethanesulfonic acid

first step

4-(2-(4-bromophenyl)-3-((4'-chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxo Propyl) tert-butyl benzoate

(S)-2-(4-Bromophenyl)-3-(4-(tert-butyloxycarbonyl)phenyl)propanoic acid 16a (1.9 g, 4.69 mmol, obtained according to CN102292316) , 4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-amine 1 g (1.07 g, 4.92 mmol), bis(2-oxo-3-oxazolidinyl) The subphosphoryl chloride (1.79 g, 7.03 mmol) and N,N-diisopropylethylamine (2.5 mL, 14.06 mmol) were dissolved in 20 mL of dichloromethane, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The residue was further purified by silica gel column chromatography (hexane: ethyl acetate = 5:1) to afford (S)-4-(2-(4-bromophenyl)-3-((4'-) tert-Butyl chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoate 16b (2.23 g, white solid) 79.6%.

^{1 H NMR (400MHz, CDCl3)} : δ7.87 (d, J = 8.0Hz, 2H), 7.45-7.43 (m, 4H), 7.23-7.15 (m, 7H), 7.09-7.05 (m, 2H), 3.79-3.65 (m, 2H), 3.72-3.63 (m, 2H), 3.11-3.05 (m, 1H), 2.24 (s, 3H), 2.00-1.94 (m, 2H) 1.58 (s, 9H)

Second step

(S)-4-(2-(4-(Benzo[d][1,3]diox-5-yl)phenyl)-3-((4'-chloro-2'-methyl-) tert-Butyl [1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoate

(S)-4-(2-(4-bromophenyl)-3-((4'-chloro-2'-methyl-[1,1'-diphenyl]-4-) under a nitrogen atmosphere Tert-butyl)amino)-3-oxopropyl)benzoate 16b (850 mg, 1.4 mmol) dissolved in 20 mL of dichloromethane, benzo[d][1,3]diox-5-ylboronic acid 5d (233mg, 1.4mmol), bis(tris(p-methylphenyl)phosphine)palladium chloride (98mg, 0.12mmol) and sodium carbonate (526mg, 4.96mmol) dissolved in 20mL dimethyl ether, 10mL ethanol and 5mL water In a mixed solvent, The reaction was heated to reflux for 4 hours. The reaction mixture was added with EtOAc (EtOAc) (EtOAc (EtOAc. The residue obtained is further separated and purified by silica gel column chromatography (cyclohexane: ethyl acetate = 10:1 to 5:1) to give (S)-4-(2-(4-(benzo[d]]] [1,3] dioxin-5-yl)phenyl)-3-((4'-chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)- tert-Butyl 3-oxopropyl)benzoate 16c (551 mg, yellow solid), yield: 60.9%.

^{1 H NMR (400MHz, CDCl3)} : δ7.87 (d, J = 8.0Hz, 2H), 7.50-7.45 (m, 4H), 7.24 (s, 2H), 7.37 (d, J = 8.0Hz, 2H) , 7.24 - 7.17 (m, 4H), 7.13 - 7.04 (m, 4H), 6.89 (d, J = 8.8 Hz, 1H), 6.01 (s, 2H), 3.81-3.69 (m, 2H), 3.16-3.11 (m, 1H), 2.21 (s, 3H), 1.58 (s, 9H)

third step

(S)-4-(2-(4-(Benzo[d][1,3]diox-5-yl)phenyl)-3-((4'-chloro-2'-methyl-) [1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid

(S)-4-(2-(4-(Benzo[d][1,3]diox-5-yl)phenyl)-3-((4'-chloro-2'-methyl) -[1,1'-Diphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid tert-butyl ester 16c (700 mg, 1.08 mmol) was dissolved in 10 mL dichloromethane. Trifluoroacetic acid and 1 mL of concentrated hydrochloric acid were stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to give crude (S)-4-(2-(4-(benzo[d][1,3] dioxin-5-yl)phenyl)-3-(( 4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid 16d (416 mg, yellow solid), yield: 65.1 %.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.21. (s, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.61 - 7.56 (m, 4H), 7.49 (d, J = 8.4 Hz , 2H), 7.38 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 1.6 Hz, 1H), 7.27-7.20 (m, 4H), 7.15-7.10 (m, 2H), 6.98 (d, J=8.4 Hz, 1H), 6.04 (s, 2H), 4.11-4.08 (m, 1H), 3.54-3.50 (m, 1H), 3.10-3.05 (m, 1H), 2.21 (s, 3H)

the fourth step

(S)-2-(4-(2-(4-(benzo[d][1,3]diox-5-yl)phenyl)-3-((4'-chloro-2'-) Methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoylamino)ethanesulfonic acid

(S)-4-(2-(4-(Benzo[d][1,3]diox-5-yl)phenyl)-3-((4'-chloro-2'-methyl-) [1,1'-Diphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid 16d (526mg.0.89mmol) was dissolved in 5mL of dimethylformamide and added to the mixture under stirring (2) -oxo-3-oxazolidinyl)phosphoryl chloride (340 mg, 1.34 mmol), N,N-diisopropylethylamine (0.9 mL, 5.34 mmol), stirred at room temperature for 10 min, then added to the reaction flask Diaminoethanesulfonic acid (123 mg, 0.98 mmol) was added with stirring, and the resulting mixture was added to the mixture, and stirred at room temperature for 24 hr. The reaction mixture was added with 10 mL of water, EtOAc (EtOAc) (EtOAc) Purification by silica gel column chromatography (dichloromethane:methanol = 50:1 to 20:1) gave (S)-2-(4-(2-(4-(benzo[d][1,3]] Dioxo-5-yl)phenyl)-3-((4'-chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropan Benzo)benzoylamino)ethanesulfonic acid 16 (58 mg, white solid), yield: 10.6%.

^{1 H NMR (400MHz, DMSO-} d 6): δ10.28 (s, 1H), 8.45-8.42 (m, 1H), 7.68 (d, J = 7.6Hz, 2H), 7.60 (d, J = 8.4Hz , 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 6.4 Hz, 3H), 7.25 (d, J = 8.4 Hz, 1H) ), 7.21 (d, J = 7.2 Hz, 3H), 7.13-7.10 (m, 2H), 6.96 (d, J = 8.4 Hz, 1H), 6.03 (s, 2H), 4.11-4.08 (m, 1H) , 3.51-3.47 (m, 3H), 3.12-3.03 (m, 1H), 2.67-2.64 (m, 2H), 2.21 (s, 3H)

Example 17

(R)-2-(4-(3-((4'-chloro-3-fluoro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-() 4',4'-Difluoro-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzoyl Amino)ethanesulfonic acid

first step

(R)-3-(4-(tert-Butoxycarbonyl)phenyl)-2-(4',4'-difluoro-2',3',4',5'-tetrahydro-[1, 1'-diphenyl]-4-yl)propionic acid

(R)-2-(4-Bromophenyl)-3-(4-(tert-butyloxycarbonyl)phenyl)propanoic acid 5b (685 mg, 1.69 mmol), 2-(4, 4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane 8d (413 mg, 1.69 mmol), two (three (p-methylphenyl)phosphine)palladium chloride (134 mg, 0.17 mmol) Sodium carbonate (540 mg, 5.10 mmol) was dissolved in a mixed solvent of 20 mL of dimethyl ether, 10 mL of ethanol and 5 mL of water, and heated at 100 ° C for 8 hours under argon atmosphere. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. (cyclohexane: ethyl acetate = 10:1 to 5:1) further isolated and purified to give (R)-3-(4-(tert-butoxycarbonyl)phenyl)-2-(4',4' -Difluoro-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)propanoic acid 17a (580 mg, white solid), yield: 77.6%.

Second step

(R)-4-(3-((4'-chloro-3-fluoro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-2-(4',4 '-Difluoro-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzoic acid tert-butyl ester

(R)-3-(4-(tert-Butoxycarbonyl)phenyl)-2-(4',4'-difluoro-2',3',4',5'-tetrahydro-[1 ,1'-diphenyl]-4-yl)propionic acid 17a (580 mg, 1.32 mmol), 4'-chloro-3-fluoro-2'-methyl-[1,1'-biphenyl]-4 -Amine 17b (339 mg, 1.44 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (504 mg, 1.98 mmol), triethylamine (543 mg, 5.28 mmol) dissolved in dichloromethane The reaction solution was stirred at room temperature for 3 hours. After adding 1 mL of hydrochloric acid (20 mL), EtOAc (EtOAc) (EtOAc) 1 to 10:1), isolated and purified to give (R)-4-(3-((4'-chloro-3-fluoro-2'-methyl-[1,1'-biphenyl]-4-yl) Amino)-2-(4',4'-difluoro-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxo Propyl) tert-butyl benzoate 17c (480 mg, white solid), yield: 55.1%.

^{1 H NMR (400MHz, CHLOROFORM-} d): δ8.34 (t, J = 8.16Hz, 1H), 7.97 (d, J = 5.77Hz, 1H), 7.87 (d, J = 8.03Hz, 2H), 7.30 -7.42 (m, 5H), 7.26 (br.s., 2H), 7.21 (d, J = 8.03 Hz, 3H), 7.01 - 7.12 (m, 2H), 6.97 (d, J = 1.54 Hz, 1H) , 5.95 (br.s., 1H), 3.84 (t, J = 7.28 Hz, 2H), 3.70 (dd, J = 7.40, 13.43 Hz, 1H), 3.16 (dd, J = 7.53, 13.55 Hz, 1H) , 2.54-2.45 (m, 1H), 2.65-2.82 (m, 5H), 2.12-2.29 (m, 6H), 0.89 (d, J = 6.78 Hz, 6H).

third step

(R)-4-(3-((4'-chloro-3-fluoro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-2-(4',4 '-Difluoro-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzoic acid

(R)-4-(3-((4'-chloro-3-fluoro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-2-(4', 4'-Difluoro-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzoic acid tert-butyl ester 17c (450 mg, 0.68 mmol) was dissolved in 10 mL of dichloromethane, then added 4 mL of trifluoroacetic acid and 2 mL of hydrochloric acid, and stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc m. Drying over anhydrous magnesium sulfate, filtration and concentration under reduced pressure to give crude (R)-4-(3-((4'-chloro-3-fluoro-2'-methyl-[1,1'-biphenyl) ]-4-yl)amino)-2-(4',4'-difluoro-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl ?-oxopropyl)benzoic acid 17d (410 mg, yellow solid).

the fourth step

(R)-2-(4-(3-((4'-chloro-3-fluoro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-() 4',4'-Difluoro-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzoyl Amino)ethanesulfonic acid

(R)-4-(3-((4'-chloro-3-fluoro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-2-(4', 4'-Difluoro-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzoic acid 17d (400mg, 0.66 mmol), 1-hydroxybenzotriazole (135 mg, 0.99 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (229 mg, 0.79 mmol), aminoethyl Sulfonic acid (75 mg, 0.6 mmol) and diisopropylethylamine (426 mg, 3.3 mmol) were dissolved in 3 mL of N,N-dimethylformamide and stirred at room temperature for 5 hours. To the reaction mixture was added 1 mL of EtOAc (EtOAc) (EtOAc (EtOAcj. (dichloromethane: methanol = 30:1 to 20:1) to give (R)-2-(4-(3-((4'-chloro-3-fluoro-2'-methyl-[1,1] '-Diphenyl]-4-yl)amino)-2-(4',4'-difluoro-2',3',4',5'-tetrahydro-[1,1'-diphenyl ]-4-yl)-3-oxopropyl)benzoylamino)ethanesulfonic acid 17 (22 mg, off-white solid), yield: 4.7%.

¹ H NMR (400 MHz, CDCl ₃ -d) δ 8.25 (t, J = 8.16 Hz, 1H), 8.09 (d, J = 8.03 Hz, 1H), 8.00 (t, J = 7.78 Hz, 3H), 7.60 (d, J = 8.28 Hz, 1H), 7.50 (d, J = 8.03 Hz, 1H), 7.32 - 7.47 (m, 5H), 7.17 - 7.27 (m, 2H), 6.91 - 7.16 (m, 3H), 6.08(br.s.,1H),5.96(br.s.,1H), 4.18(q,J=7.03Hz,1H),3.86-4.00(m,1H),3.73(dd,J=13.43,7.65 Hz, 1H), 3.13-3.30 (m, 1H), 2.65-2.84 (m, 3H), 2.44 (d, J = 12.80 Hz, 3H), 2.22 (s, 6H), 1.22-1.39 (m, 3H)

Example 18

2-(4-((2R)-2-(4'-(tert-butyl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4- 3-((4'-chloro-3-fluoro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoyl Amino)ethanesulfonic acid

first step

(2R)-3-(4-(tert-Butoxycarbonyl)phenyl)-2-(4'-(tert-butyl)-2',3',4',5'-tetrahydro-[1, 1'-diphenyl]-4-yl)propionic acid

(R)-2-(4-Bromophenyl)-3-(4-(tert-butyloxycarbonyl)phenyl)propanoic acid 5b (1.20 g, 3.00 mmol), 2-(4-(tert-butyl) (cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane 18b (872 mg, 3.30 mmol), two (three (pair) Methylphenyl)phosphine)Palladium chloride (259 mg, 0.33 mmol) and sodium carbonate (954 mg, 9.00 mmol) were dissolved in a mixed solvent of 20 mL of dimethyl ether, 10 mL of ethanol and 5 mL of water under argon atmosphere and heated at 100 ° C. Reaction for 4 hours. The reaction mixture was stirred for 20 mL of a saturated aqueous solution of ammonium chloride, and then the mixture was evaporated to ethyl acetate and ethyl acetate (20 mL). Drying, filtration and concentration under reduced pressure afforded crude (2R) <RTIgt; (&lt;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot; ',5'-Tetrahydro-[1,1'-diphenyl]-4-yl)propanoic acid 18b (1.38 g, yellow solid).

Second step

4-((2R)-2-(4'-(tert-butyl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-3 -((4'-Chloro-3-fluoro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid tert-butyl ester

(2R)-3-(4-(tert-Butoxycarbonyl)phenyl)-2-(4'-(tert-butyl)-2',3',4',5'-tetrahydro-[1 , 1'-diphenyl]-4-yl)propionic acid 18b (1.38 g, 3.00 mmol), 4'-chloro-3-fluoro-2'-methyl-[1,1'-biphenyl]- 4-Amine 17b (705 mg, 1.44 mmol) and bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (1.14 g, 4.50 mmol) were dissolved in 20 mL dichloromethane and diisopropylethylamine was added. (1.58 g, 12.0 mmol), the reaction mixture was stirred at room temperature for 3 hr. 20 mL of dichloromethane and 1 N of hydrochloric acid (20 mL) were added, and the organic phase was dried over anhydrous magnesium sulfate. 1), isolated and purified to obtain 4-((2R)-2-(4'-(tert-butyl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl] 4-yl)-3-((4'-chloro-3-fluoro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxopropyl)benzene Tert-butyl formate 18c (770 mg, white solid), yield: 38.5%.

third step

4-((2R)-2-(4'-(tert-butyl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-3 -((4'-chloro-3-fluoro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid

4-((2R)-2-(4'-(tert-butyl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)- 3-((4'-Chloro-3-fluoro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid tert-butyl ester 18c ( 770 mg, 1.13 mmol) was dissolved in 10 mL of dichloromethane, and 2 mL of trifluoroacetic acid and 1 mL of hydrochloric acid were added and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to give crude 4-(((2))-(4'-(tert-butyl)-2',3',4',5'-tetrahydro-[1,1' -biphenyl]-4-yl)-3-((4'-chloro-3-fluoro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxo Propyl)benzoic acid 18d (700 mg, white solid).

the fourth step

2-(4-((2R)-2-(4'-(tert-butyl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4- 3-((4'-chloro-3-fluoro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoyl Amino)ethanesulfonic acid

4-((2R)-2-(4'-(tert-butyl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)- 3-((4'-Chloro-3-fluoro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid 18d (700mg, 1.12 Methyl) is dissolved in 5 mL of N,N-dimethylformamide, bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (427 mg, 1.68 mmol), aminoethanesulfonic acid (167 mg, 1.34 mmol) and Diisopropylethylamine (578 mg, 4.48 mmol) was stirred at room temperature for 5 hours. 20 mL of 2M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL×3). (dichloromethane:methanol = 30:1 to 20:1) to give 2-(4-((2R)-2-(4'-(tert-butyl)-2',3',4',5' -tetrahydro-[1,1'-diphenyl]-4-yl)-3-((4'-chloro-3-fluoro-2'-methyl-[1,1'-diphenyl]- 4-(4-amino)-3-oxopropyl)benzoylamino)ethanesulfonic acid 18 (60 mg, white solid).

¹ H NMR (400 MHz, DMSO-d6): δ 0.88 (s, 9H), 1.15-1.35 (m, 6H), 1.93 (br.s., 2H), 2.21 (s, 4H), 2.28-2.40 ( m, 1H), 2.45 (br.s., 1H), 2.67 (t, J = 7.03 Hz, 2H), 2.96-3.10 (m, 1H), 3.17 (d, J = 5.27 Hz, 7H), 3.50 ( d, J = 5.77 Hz, 4H), 4.11 (d, J = 5.27 Hz, 2H), 4.30 (br.s., 1H), 6.15 (br.s., 1H), 7.08 (d, J = 8.03 Hz) , 1H), 7.21 (t, J = 8.03 Hz, 2H), 7.26-7.46 (m, 9H), 7.67 (d, J = 7.78 Hz, 2H), 7.80 - 8.01 (m, 1H), 8.44 (br. s., 1H), 9.95 (s, 1H).

Example 19

(R)-2-(4-(2-(benzo[d][1,3]dioxol-5-yl)-3-((4'-chloro-2'-methyl-) [1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoylamino)ethanesulfonic acid

first step

(S)-2-(hydroxymethyl)pyrrolidin-1-y-(R)-2-(benzo[d][1,3]dioxol-5-yl)-3-( 4-(tert-butoxycarbonyl)phenyl)propionic acid

2-(4-(Benzo[d][1,3]diox-5-yl)phenyl)-3-(4-(tert-butyloxycarbonyl)phenyl)propanoic acid 3d (3.80 g, 10.3 mmol) was dissolved in 12 mL of ethyl acetate. EtOAc (EtOAc m. Naturally, it was cooled to room temperature, stirred overnight, and the reaction mixture was filtered, and the filter cake was washed with a small ethyl acetate and dried to give (S)-2-(hydroxymethyl)pyrrolidin-1-y-(R)-2-(benzene) And [d][1,3]dioxol-5-yl)-3-(4-(tert-butoxycarbonyl)phenyl)propanoic acid 19b (2.10 g, white solid). 43.2%.

Second step

(R)-2-(benzo[d][1,3]dioxol-5-yl)-3-(4-(tert-butoxycarbonyl)phenyl)propanoic acid

(S)-2-(Hydroxymethyl)pyrrolidin-1-y-(R)-2-(benzo[d][1,3]dioxol-5-yl)-3- (4-(tert-Butoxycarbonyl)phenyl)propanoic acid 19b (2.10 g, 4.45 mmol) was dissolved in 50 mL of ethyl acetate. The layers were separated, and the aqueous layer wasjjjjjjjjjjjjjjjjjjjjjjj Oxol-5-yl)-3-(4-(tert-butoxycarbonyl)phenyl)propanoic acid 19c (1.70 g, white solid).

third step

(R)-4-(2-(4-(benzo[d][1,3]dioxol-5-yl)-3-((4'-chloro-2'-methyl-) tert-Butyl [1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoate 2-(4-(benzo[d][1,3]dioxole -5-yl)phenyl)-3-(4-(tert-butyloxycarbonyl)phenyl)propanoic acid 3d (1.70 g, 4.6 mmol), 4'-chloro-2'-methyl-[1, 1'-diphenyl]-4-amine 1 g (1.10 g, 5.0 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (1.70 g, 6.9 mmol) and triethylamine (1.40) g, 13.8 mmol) was dissolved in 30 mL of dichloromethane and stirred at room temperature for 24 hours. The reaction mixture was washed with water (50 mL) To give the crude (R)-4-(2-(4-(benzo[d][1,3]dioxol-5-yl)-3-((4'-chloro-2'-) tert-Butyl methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoate 19d (2.6 g, off-white solid). One step reaction.

MS m/z (ESI): 570.7 [M+1]

the fourth step

(R)-4-(2-(4-(benzo[d][1,3]dioxol-5-yl)-3-((4'-chloro-2'-methyl-) [1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid

(R)-4-(2-(4-(Benzo[d][1,3]dioxol-5-yl)-3-((4'-chloro-2'-methyl) -[1,1'-Diphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid tert-butyl ester 19d (2.6 g, 4.6 mmol) was dissolved in dichloromethane (60 mL) The reaction mixture was washed with water (50 mL×2) (2-(4-(Benzo[d][1,3]dioxol-5-yl)-3-((4'-chloro-2'-methyl-[1,1'-) Diphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid 19e (2.3 g, white solid), yield: 98%.

the fifth step

(R)-2-(4-(2-(benzo[d][1,3]dioxol-5-yl)-3-((4'-chloro-2'-methyl-) [1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoylamino)ethanesulfonic acid

(R)-4-(2-(4-(Benzo[d][1,3]dioxol-5-yl)-3-((4'-chloro-2'-methyl) -[1,1'-Diphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid 19e (2.0 g. 3.90 mmol), aminoethanesulfonic acid (586 mg, 4.68 mmol), 1- Hydroxybenzotriazole (790 mg, 5.85 mmol), 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride (897 mg, 4.68 mmol) and diisopropylethylamine (2.40) g, 18.72 mmol) was dissolved in 20 mL of N,N-dimethylformamide, and stirred at room temperature overnight. 150 mL of ethyl acetate and 65 mL of water were added to the reaction mixture, and the solution was adjusted to pH=1 with 3M hydrochloric acid. The mixture was extracted with 150 mL of EtOAc. (R)-2-(4-(2-(benzo[d][1,3]dioxol-5-yl)-3-((4'-chloro-2'-methyl-) [1,1'-Diphenyl]-4-yl)amino)-3-oxopropyl)benzoylamino)ethanesulfonic acid 19 (710 mg, white solid), yield: 62.5%.

^{1 H NMR (400MHz, DMSO-} d6) δ10.15 (s, 1H), 8.44-8.39 (m, 1H), 7.66 (d, J = 8.0Hz, 2H), 7.59 (d, J = 8.0Hz, 2H ), 7.35 (s, 1H), 7.33 - 7.25 (m, 3H), 7.22 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 8.0 Hz, 1H), 7.04 (s, 1H), 6.90 -6.81 (m, 2H), 5.98 (d, J = 4.3 Hz, 2H), 3.65-3.56 (m, 2H), 3.53-3.45 (m, 2H), 3.41 (dd, J = 9.0, 13.3 Hz, 1H) ), 3.00 (dd, J = 6.0, 13.3 Hz, 1H), 2.65 (t, J = 7.0 Hz, 2H), 2.19 (s, 3H).

Example 20

(R,Z)-2-(4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxo- 2-(4'-(2,2,2-Trifluoro-1-(indolyl)ethyl)-[1,1'-diphenyl]-4-yl)propyl)benzoylamino)B Sulfonic acid

first step

(R)-4-(3-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxo 2-(4'-( tert-Butyl 2,2,2-trifluoroacetyl)-[1,1'-biphenyl]-4-yl)propyl)benzoate

(R)-4-(2-(4-Bromophenyl)-3-((4'-chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino) tert-Butyl 3-oxopropyl)benzoate 5c (1.55 g, 2.56 mmol), 2,2,2-trifluoro-1-(4-(4,4,5,5-tetramethyl-1) , 3,2-dioxaborolan-2-yl)phenyl)ethanone 20a (700 mg, 2.30 mmol), bis(tris(p-methylphenyl)phosphine)palladium chloride (183 mg, 0.23 mmol) and Sodium carbonate (742 mg, 7.00 mmol) was dissolved in a mixed solvent of 60 mL of dimethyl ether, 30 mL of ethanol and 15 mL of water, and the mixture was heated at 90 ° C for 3 hours under argon atmosphere. The reaction mixture was filtered over EtOAc (EtOAc)EtOAc. The residue was purified by silica gel column chromatography (eluent: EtOAc:EtOAc: 30:1 to 20:1) to afford (R)- 4-(3-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxo 2-(4'-(2,2, 2-Trifluoroacetyl)-[1,1'-biphenyl]-4-yl)propyl)benzoic acid tert-butyl ester 20b (1.00 g, red oil), yield: 62.5%.

Second step

(R)-4-(3-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxo-2-(4'- (2,2,2-trifluoroacetyl)-[1,1'-biphenyl]-4-yl)propyl)benzoic acid

(R)-4-(3-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxo-2-(4') -(2,2,2-Trifluoroacetyl)-[1,1'-biphenyl]-4-yl)propyl)benzoic acid tert-butyl ester 20b (2.6 g, 4.6 mmol) dissolved in 15 mL dichloromethane 3 mL of trifluoroacetic acid and 1.5 mL of concentrated hydrochloric acid were added under stirring, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was washed with EtOAc (EtOAc m. -[1,1'-biphenyl]-4-yl)amino)-3-oxo-2-(4'-(2,2,2-trifluoroacetyl)-[1,1'-biphenyl ]-4-yl)propyl)benzoic acid 20c (790 mg, white solid), yield: 88%.

third step

(R)-2-4(3-((4'-chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxo-2-(4) '-(2,2,2-Trifluoroacetyl)-[1,1'-biphenyl]-4-yl)propyl)benzoylamino)ethanesulfonic acid

(R)-4-(3-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxo-2-(4') -(2,2,2-trifluoroacetyl)-[1,1'-biphenyl]-4-yl)propyl)benzoic acid 20c (790 mg, 1.23 mmol), aminoethanesulfonic acid (185 mg, 1.47 mmol) ), 1-hydroxybenzotriazole (249 mg, 1.85 mmol), 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride (283 mg, 1.47 mmol) and diisopropyl Ethylamine (763 mg, 5.90 mmol) was dissolved in 10 mL of N-N-dimethylformamide and stirred at room temperature overnight. 20 mL of ethyl acetate and 20 mL of water were added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (15 mL×2). Purification by chromatography (eluent: petroleum ether: ethyl acetate) to give (R)-2-4-(3-((4'-chloro-2'-methyl-[1,1'-biphenyl) ]-4-yl)amino)-3-oxo-2-(4'-(2,2,2-trifluoroacetyl)-[1,1'-biphenyl]-4-yl)propyl) Benzoylamino)ethanesulfonic acid 20d (310 mg, white solid), yield: 34%.

the fourth step

(R,Z)-2-(4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxo- 2-(4'-(2,2,2-Trifluoro-1-(indolyl)ethyl)-[1,1'-diphenyl]-4-yl)propyl)benzoylamino)B Sulfonic acid

(R)-2-4(3-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxo-2-() 4'-(2,2,2-Trifluoroacetyl)-[1,1'-biphenyl]-4-yl)propyl)benzoylamino)ethanesulfonic acid 20d (310mg, 0.40mmol), hydrochloric acid Hydroxylamine (57.5 mg, 0.80 mmol) and sodium acetate (78 mg, 0.95 mmol) were dissolved in 6 mL of a mixed solution of ethanol and water (V/V = 5/1), and the mixture was heated to 80 ° C for 3 hours. The reaction mixture was adjusted to pH 2 with 3M hydrochloric acid, and the residue was evaporated to dryness (yield: 4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxo-2-(4'-(2, 2,2-Trifluoro-1-(indolyl)ethyl)-[1,1'-diphenyl]-4-yl)propyl)benzoylamino)ethanesulfonic acid 20 (120 mg, white solid) ), yield: 65%.

^{1 H NMR (400MHz, DMSO-} d6) δ12.82 (s, 1H), 10.38-10.29 (m, 1H), 8.45 (br.s., 1H), 7.79 (d, J = 8.0Hz, 2H), 7.70 (d, J = 7.3 Hz, 4H), 7.66-7.60 (m, 4H), 7.58 (d, J = 4.3 Hz, 3H), 7.36 (d, J = 10.3 Hz, 3H), 7.29-7.20 (m , 3H), 7.16 (d, J = 8.3 Hz, 1H), 4.18 (br.s., 1H), 3.52 (br.s., 3H), 3.15-3.03 (m, 1H), 2.70 (t, J =6.7Hz, 2H), 2.19(s, 3H)

Example 21

2-(4-((2R)-3-((4'-chloro-3-fluoro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-( 4'-(1-Methylcyclopropyl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl Benzoylamino)ethanesulfonic acid

first step

4-((2R)-3-((4'-chloro-3-fluoro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4'- (1-Methylcyclopropyl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzoic acid Tert-butyl ester

(2R)-3-(4-(tert-Butoxycarbonyl)phenyl)-2-(4'-(1-methylcyclopropyl)-2',3',4',5'- Tetrahydro-[1,1'-diphenyl]-4-yl)propanoic acid 9d (610mg, 1.32 Ment), 4'-chloro-2'-methyl-[1,1'-biphenyl]-4-amine 17b (317 mg, 1.46 mmol), bis(2-oxo-3-oxazolidinyl) The subphosphoryl chloride (505 mg, 1.99 mmol), triethylamine (0.56 mL, 3.97 mmol) was dissolved in 10 mL dichloromethane. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl ether: ethyl acetate = 20:1 to 100:7) to afford 4-((2R)-3-(( 4'-Chloro-3-fluoro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4'-(1-methylcyclopropyl)-2 ',3',4',5'-Tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzoic acid tert-butyl ester 21a (440 mg, white solid) Yield: 49%.

Second step

4-((2R)-3-((4'-chloro-3-fluoro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4'- (1-Methylcyclopropyl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzoic acid

4-((2R)-3-((4'-Chloro-3-fluoro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4' -(1-methylcyclopropyl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzene Tert-butyl formate 21a (440 mg, 0.65 mmol) was dissolved in 5 mL of 1,4-dioxane, and potassium t-butoxide (218 mg, 1.95 mmol) was added with stirring, and the reaction mixture was stirred at 100 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure and evaporated, evaporated, evaporated, evaporated, evaporated, The organic layer was dried over sodium sulfate, filtered, and evaporated, evaporated, evaporated,462462462462462462462462462462462462462462462462462462462 '-Chloro-3-fluoro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4'-(1-methylcyclopropyl)-2' , 3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzoic acid 21b (374 mg, white solid), yield: 92.5 %.

third step

2-(4-((2R)-3-((4'-chloro-3-fluoro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-( 4'-(1-Methylcyclopropyl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl Benzoylamino)ethanesulfonic acid

4-((2R)-3-((4'-Chloro-3-fluoro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-2-(4' -(1-methylcyclopropyl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4-yl)-3-oxopropyl)benzene Formic acid 21b (374 mg, 0.60 mmol), diaminoethanesulfonic acid (75 mg, 0.60 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (305 mg, 1.20 mmol) and diisopropyl The amine (0.50 mL, 3.00 mmol) was dissolved in 5 mL of N-N-dimethylformamide and stirred at room temperature for 16 hours. The reaction solution was concentrated under pressure to remove a part of the solvent, 15 mL of water was added, pH was adjusted to 2 with 3M hydrochloric acid, and extracted with a mixed solvent of dichloromethane and methanol (V/V=10/1) (20 mL×3), combined organic The residue was dried over anhydrous magnesium sulfate, filtered and evaporated. Further analysis and purification (dichloromethane: acetone = 100:0 to 0:100) gave 2-(4-((2R)-3-((4'-chloro-3-fluoro-2'-methyl-) [1,1'-diphenyl]-4-yl)amino)-2-(4'-(1-methylcyclopropyl)-2',3',4',5'-tetrahydro-[ 1,1'-Diphenyl]-4-yl)-3-oxopropyl)benzoylamino)ethanesulfonic acid 21 (128 mg, white solid), yield: 29%.

MS m/z (ESI): 728.8 [M+1]

^{1 H NMR (400MHz, DMSO-} d6) δ9.92 (s, 1H), 8.42 (br.s., 1H), 7.86 (t, J = 8.2Hz, 1H), 7.67 (d, J = 7.8Hz, 2H), 7.41-7.26 (m, 9H), 7.23-7.17 (m, 2H), 7.07 (d, J = 8.3 Hz, 1H), 6.14 (br.s., 1H), 4.31 (d, J = 6.5 Hz, 1H), 3.55-3.40 (m, 3H), 3.03 (dd, J = 5.5, 13.3 Hz, 1H), 2.67 (t, J = 7.0 Hz, 2H), 2.21 (s, 3H), 2.15. (m, 2H), 1.48-1.21 (m, 2H), 1.15-1.07 (m, 1H), 0.95 (s, 3H), 0.36-0.15 (m, 4H)

Example 22

(R)-2-(4-(2-(4-(4-(tert-butyl)cyclohexyl)phenyl)-3-((4'-chloro-2'-methyl-[1,1') -diphenyl]-4-yl)amino)-3-oxopropyl)benzoylamino)ethanesulfonic acid

first step

4-((2R)-2-(4'-(tert-butyl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-3 -((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid tert-butyl ester

(2R)-3-(4-(tert-Butoxycarbonyl)phenyl)-2-(4'-(tert-butyl)-2',3',4',5'-tetrahydro-[1 , 1'-diphenyl]-4-yl)propionic acid 18b (500 mg, 1.08 mmol), 4'-chloro-2'-methyl-[1,1'-biphenyl]-4-amine 1 g ( 260 mg, 1.19 mmol) and bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (411 mg, 1.62 mmol) were dissolved in 20 mL of dichloromethane and diisopropylethylamine (0.76 mL, 4.32 mmol) The reaction solution was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjj -2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-3-((4'-chloro-2'-methyl-[1 , 1'-Biphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid tert-butyl ester 22a (450 mg, white solid), yield: 62.8%.

Second step

4-((2R)-2-(4'-(tert-butyl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-3 -((4'-chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid

4-((2R)-2-(4'-(tert-butyl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)- 3-((4'-Chloro-3-fluoro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid tert-butyl ester 22a ( 450 mg, 0.68 mmol) was dissolved in 10 mL of dichloromethane, added 4 mL of trifluoroacetic acid and 1 mL hydrochloric acid, and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to give crude 4-(((2))-(4'-(tert-butyl)-2',3',4',5'-tetrahydro-[1,1' -biphenyl]-4-yl)-3-((4'-chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxopropyl)benzene Formic acid 22b (412 mg, white solid).

third step

2-(4-((2R)-2-(4'-(tert-butyl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4- Benzyl-3-((4'-chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoylamino)ethanesulfonate acid

4-((2R)-2-(4'-(tert-butyl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)- 3-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxopropyl)benzoic acid 22b (412 mg, 0.68 mmol), double (2-Oxo-3-oxazolidinyl)phosphoryl chloride (260 mg, 1.02 mmol) and aminoethanesulfonic acid (102 mg, 0.82 mmol) dissolved in 5 mL of N,N-dimethylformamide, diisopropyl Ethylamine (0.5 mL, 2.72 mmol) was stirred at room temperature for 12 h. 50 mL of ethyl acetate was added to the reaction mixture, and the mixture was adjusted to pH 5 with 1M hydrochloric acid. Agent: dichloromethane: methanol) to give 2-(4-((2R)-2-(4'-(tert-butyl)-2',3',4',5'-tetrahydro-[1, 1'-diphenyl]-4-yl)-3-((4'-chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxo Propyl)benzoylamino)ethanesulfonic acid 22c (115 mg, white solid), yield: 23.7%.

the fourth step

(R)-2-(4-(2-(4-(4-(tert-butyl)cyclohexyl)phenyl)-3-((4'-chloro-2'-methyl-[1,1') -diphenyl]-4-yl)amino)-3-oxopropyl)benzoylamino)ethanesulfonic acid

2-(4-((2R)-2-(4'-(tert-butyl)-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-4 -yl)-3-((4'-chloro-3-fluoro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzamide The acylamino)ethanesulfonic acid 22c (27 mg, 0.041 mmol) was dissolved in 2 mL of methanol, and then 10% palladium carbon (0.4 mg,) was added and stirred at room temperature for 5 hours. The reaction was carried out for 12 hours at room temperature under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give (R)-2-(4-(4-(4-(4-(tert-butyl)cyclohexyl)phenyl)-3-((4'-chloro-2) '-Methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxopropyl)benzoylamino)ethanesulfonic acid 22 (10 mg, white solid), yield: 37 %.

¹ H NMR (400 MHz, DMSO-d ₆ ) 10.21 (d,J=7.53 Hz, 1H), 8.78 (br.s., 1H), 8.42 (br.s., 1H), 7.54-7.74 (m, 4H) ), 7.07-7.46 (m, 11H), 3.95-4.14 (m, 1H), 3.61 (d, J = 6.27 Hz, 4H), 3.47 (dd, J = 5.52, 13.05 Hz, 2H), 3.12 (d, J = 6.78 Hz, 2H), 2.66 (t, J = 6.90 Hz, 2H), 2.13 - 2.24 (m, 2H), 1.81 (br.s., 2H), 1.53 (br.s., 2H), 1.19 -1.36(m,9H),1.08(br.s.,1H),0.82-0.90(m,2H)

Example 23

(R)-2-(4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxo-2- (4-(1-Pentyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)propyl)benzoylamino)ethanesulfonic acid

first step

4-(((Trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

4-Oxopiperidin-1-carboxylic acid tert-butyl ester 23a (4.00 g, 20.00 mmol) was dissolved in 30 mL of tetrahydrofuran, argon-protected, cooled to -78 ° C, and lithium diisopropylamide (12.0 mL) , 24.00 mmol), reacted at -78 ° C for 1 hour. Then N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (8.60 g, 22.00 mmol) was added dropwise in 10 mL. A solution of tetrahydrofuran. The reaction was naturally raised to room temperature for 2 hours. The reaction mixture was quenched with 50 mL of EtOAc EtOAc EtOAc. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate) to afford 4-(((trifluoromethyl)sulfonyloxy)-5,6-dihydropyridine- 1(2H)-tert-butyl carboxylate 23b (4.5 g, colorless liquid), yield: 68.2%.

Second step

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

4-((((Trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 23b (4.50 g, 13.6 mmol), bis-pinacol Borate ester (3.45 g, 13.6 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (497 mg, 0.68 mmol) and potassium acetate (4.00 g, 40.8 mmol) The reaction was carried out at 60 ° C for 4 hours under argon atmosphere in 60 mL of 1,4 dioxane. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. EtOAcjjjjjjjjj -1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 23c (6.40 g, white solid), yield: 78% .

third step

(R)-2-(4-(1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3-(4-(tert-butoxy) Carbonyl)phenyl)propionic acid

(R)-2-(4-Bromophenyl)-3-(4-(tert-butyloxycarbonyl)phenyl)propanoic acid 5b (3.70 g, 12.0 mmol), 4-(4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 23c (4.05 g, 10.0 mmol) , bis(tris(p-methylphenyl)phosphine)palladium chloride (786 mg, 1.00 mmol) and sodium carbonate (3.18 g, 30.00 mmol) in a mixed solvent of 40 mL of dimethyl ether, 20 mL of ethanol and 10 mL of water, argon Under gas protection, heat 95 ° C anti It should be 5 hours. The reaction solution was filtered through celite, and the filtrate was evaporated to dryness to remove the organic solvent, and the organic solvent was adjusted to pH 3 to 4 with 2M hydrochloric acid, and extracted with ethyl acetate (100 mL×3). Drying, filtration, and concentration under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1) to give (R)-2-(4-(1) -(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3-(4-(tert-butoxycarbonyl)phenyl)propanoic acid 23d (3.40g , white solid), Yield: 55.9%.

MS m/z (ESI): 529.9 [M+23]

the fourth step

(R)-4-(4-(3-(4-(tert-Butoxycarbonyl)phenyl)-1-((4'-chloro-2'-methyl-[1,1'-biphenyl]] 4-yl)amino)-1-oxopropyl-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-tert-butyl benzoate

(R)-2-(4-(1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3-(4-(tert-butoxy) Benzyl)phenyl)propionic acid 23d (3.40 g, 6.7 mmol), 4'-chloro-2'-methyl-[1,1'-diphenyl]-4-amine 1 g (1.46 g, 6.7 mmol) , bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (2.56 g, 10.0 mmol) and triethylamine (2.03 g, 20.1 mmol) dissolved in 40 mL of dichloromethane, argon, at room temperature Stir for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 20:1 to 8:1) to give (R)-4-(4) -(3-(4-(tert-Butoxycarbonyl)phenyl)-1-((4'-chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)- 1-Oxopropyl-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-tert-butylbenzoate 23e (3.6 g, white solid), yield: 76%.

the fifth step

(R)-4-(3-((4'-chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxo-2-(4-( 1,2,3,6-tetrahydropyridin-4-yl)phenyl)propyl)benzoic acid

(R)-4-(4-(3-(4-(tert-Butoxycarbonyl)phenyl)-1-((4'-chloro-2'-methyl-[1,1'-biphenyl) 4--4-amino)-1-oxopropyl-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-tert-butyl benzoate 23e (3.60 g, 5.0 mmol) It was dissolved in 60 mL of dichloromethane, and 10 mL of trifluoroacetic acid was added dropwise thereto under ice-cooling, and the mixture was stirred at room temperature for 12 hours. 120 mL of n-hexane was added to the reaction solution to precipitate a large amount of solid, which was filtered, and the filter cake was washed with n-hexane (20 mL x 2), and pumped to obtain (R)-4-(3-((4'-chloro-2'-) Methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxo-2-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl) Propyl)benzoic acid 23f (3.1 g, off-white solid), yield: 93%.

Step 6

(R)-4-(3-((4'-chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxo-2-(4-( 1-pivaloyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)propyl)benzoic acid

(R)-4-(3-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxo-2-(4-) (1,2,3,6-Tetrahydropyridin-4-yl)phenyl)propyl)benzoic acid 23f (665 mg, 1.0 mmol) was dissolved in 60 mL of tetrahydrofuran, and triethylamine (0.20 mL, 1.40 mmol) ), stir for 10 minutes at room temperature. Pivaloyl chloride (181 mg, 1.5 mmol) and triethylamine (0.217 mL, 1.52 mmol) were then dissolved in 3 mL of tetrahydrofuran. The above 23f solution was added dropwise under ice bath, and slowly warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc (EtOAc m. Concentration, the obtained residue was further purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1 to 2:1) to afford (R)-4-(3-((4) -Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxo-2-(4-(1-pivaloyl-1,2,3,6 -tetrahydropyridin-4-yl)phenyl)propyl)benzoic acid 23 g (500 mg, white solid), yield: 79%.

Seventh step

(R)-2-(4-(3-((4'-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxo-2- (4-(1-Pentyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)propyl)benzoylamino)ethanesulfonic acid

(R)-4-(3-((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-3-oxo-2-(4-) (1-pivaloyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)propyl)benzoic acid 23 g (500 mg.0.79 mmol), aminoethanesulfonic acid (100 mg, 0.79 mmol), 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (305 mg, 1.20 mmol) and triethylamine (0.445 mL, 3.20 mmol) It was stirred at room temperature overnight in 5 mL of N,N-dimethylformamide. The reaction mixture was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (dichloromethane:methanol = 25:1 to 10:1) to afford (R)-2-(4-(3-((4) '-Chloro-2'-methyl-[1,1'-diphenyl]-4-yl)amino)-3-oxo-2-(4-(1-neopentyl-1,2,3 , 6-tetrahydropyridin-4-yl)phenyl)propyl)benzoylamino)ethanesulfonic acid 23 (47 mg, pale yellow solid), yield: 8.0%.

¹ H NMR (400 MHz, DMSO-d6) δ 10.21. (br.s., 1H), 8.42 (br.s., 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 4.3 Hz, 3H), 7.59 (d, J = 8.3 Hz, 2H), 7.41 (br.s., 3H), 7.36-7.29 (m, 3H), 7.27 (d, J = 8.3 Hz, 1H), 7.21. (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 1H), 6.17 (br.s., 1H), 4.18-4.05 (m, 3H), 3.73 (br.s., 2H) ), 3.49 (d, J = 5.3 Hz, 3H), 3.03 (d, J = 7.0 Hz, 2H), 2.70 - 2.63 (m, 2H), 2.19 (s, 3H), 1.23-1.19 (m, 9H)

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. No. #11765047) and cultured at 37 ° C, 5% CO ₂ . At the time of the experiment, the cells were seeded in a suitable concentration (3000 cells/well) in a 384-well plate (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 to the cells, the cells were stimulated by adding an appropriate concentration of Glucagon (purchased in Sigma, 0.05 nM) and incubated for 1 hour at room temperature. Subsequently, the test solution was added according to the Lance cAMP384 Kit Kit (PerkinElmer, #AD0263) operating instructions, and incubation was continued for 1 hour at room temperature and 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 plotted against the logarithmic concentration-inhibition level of the compound, and the nonlinear regression analysis was performed to calculate the IC ₅₀ of the compound. value. A similar method is suitable for testing HEK293 cell lines with high expression of human glucagon-like peptide 1 receptor (hGLP-1R) and gastrin inhibitory peptide receptor (GIPR) (all purchased from Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences). Cell Resource Center) to determine the selectivity of a compound for GCGR.

IC ₅₀ values for inhibition of GCGR compounds of the invention as shown in Table 2, wherein the range of IC ₅₀ <500nM (range indicated by A):

Table 2 IC _{50 of the} compounds of the invention against GCGR inhibition

Example number IC ₅₀ (nM) 5 A 6 A 8 A 9 A 10 A 11 A 14 A 15 A

Conclusion: The compounds of the present invention have a significant inhibitory effect on GCGR and have a selective inhibitory effect on GCGR.

Test Example 2: Effect of single oral administration of the compound of the present invention on random blood glucose in db/db mice

Purpose

The effect of the compound of the present invention on the random blood glucose of the type 2 diabetes model db/db mice was observed after a single oral administration, and the blood glucose level was measured by a portable blood glucose meter by using the tail blood sampling method, thereby further reducing the blood sugar in the test compound. The role is evaluated.

Test animal

50 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 solvent control group was set up.

Test substance

The compounds of Example 9 and Example 18 were formulated with 20% Solutol (polyethylene glycol stearate) to the desired concentration.

Mode of administration

Oral gavage was administered, and the solvent control group was administered with the same volume of 20% Solutol (polyethylene glycol stearate), and the administration group was administered at a volume of 10 ml/kg at a dose of 30 mg/kg.

experiment method

Male db/db mice were grouped according to non-fasting blood glucose and body weight (tail blood collection, blood collection was 5-10 μL, and blood glucose was detected in time with a stable blood glucose meter and blood glucose test paper, and the weight of the mice was weighed and made. The corresponding records were recorded, and then the mice were screened according to the blood glucose level, and the body weight was used as a reference index. Six groups in each group were the solvent control group and the administration group of different compounds. Each group of animals was given a single oral administration of the test drug and solvent, and blood glucose was measured before administration and 1 h, 2 h, 4 h, 6 h, 8 h, 12 h and 24 h after administration, and the hypoglycemic effect and maintenance time of the test substance were observed. 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.

Table 3 Table of blood glucose decline rates of the compounds of the present invention

Numbering Blood sugar drop rate (4 hours) Blood sugar drop rate (6 hours) Example 9 30.5% 33.0% Example 18 37.4% 18.0%

Conclusion: The compounds of the invention have a good hypoglycemic effect.

According to the same test conditions, the other compounds of the present invention were tested, and the GCGR was significantly inhibited and selectively inhibited, and both had good hypoglycemic effects.

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 (25)

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

among them: R ^{1 is} selected from aryl, wherein said aryl group is further optionally further selected from one or more selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclic, aryl a substituent of a heteroaryl group, -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O)R ¹² , -C(O)OR ¹² or -NR ¹⁰ C(O)R ¹¹ Substituted, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, Cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O)R ¹² , -C(O)OR ¹² or -NR ¹⁰ Substituted by a substituent of C(O)R ¹¹ ; R ^{2 is} selected from the group consisting of: (i) a phenyl group, wherein said phenyl group is further selected from the group consisting of an alkynyl group, a heterocyclic group,

Substituted by a substituent; Wherein said alkynyl group is further substituted by one or more substituents selected from cycloalkyl or alkoxy; preferably substituted by cyclopropyl; The heterocyclic group described therein is preferably a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group,

(ii) a heterocyclic group or

R ^{3 is} selected from a hydrogen atom, a halogen, an alkyl group or an alkoxy group, wherein the alkyl group or alkoxy group is further further selected from one or more selected from the group consisting of an alkyl group, an alkoxy group, a halogen group, a hydroxyl group, and a cyano group. Nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O)R ¹² , -C(O)OR ¹² or Substituted by a substituent of -NR ¹⁰ C(O)R ¹¹ ; R ⁴ are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a hydroxyl group, a cyano group or a nitro group, preferably selected from F or Cl, wherein the alkyl group or alkoxy group is optionally further one or Substituting a plurality of substituents selected from -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O)R ¹² , -C(O)OR ¹² or -NR ¹⁰ C(O)R ¹¹ ; One or two of R ⁵ , R ⁶ and R ⁷ are selected from -C(CX ₃ )=N-OH; the other is selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a hydroxyl group, a cyano group or a nitrate And wherein said alkyl or alkoxy group is further further selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, - Substituted by a substituent of NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O)R ¹² , -C(O)OR ¹² or -NR ¹⁰ C(O)R ¹¹ ; Alternatively, R ⁵ and R ⁶ , or R ⁶ and R ⁷ may also form a 4 to 14 membered cycloalkyl or heterocyclic group together with a carbon atom to which they are attached, preferably 5 to 7 members, wherein said cycloalkyl group Or a heterocyclic group optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, =0, -NR ¹⁰ R ¹¹ Substituted with a substituent of -C(O)NR ¹⁰ R ¹¹ , -C(O)R ¹² , -C(O)OR ¹² or -NR ¹⁰ C(O)R ¹¹ ; R ^5a and R ^6a , or R ^6a and R ^7a may form a 4- to 14-membered cycloalkyl or heterocyclic group together with a carbon atom to which they are bonded, preferably 5 to 7 members, wherein the heterocyclic group contains one or more N, O, S(O)n atoms, and the cycloalkyl or heterocyclic group optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, hetero Cyclo, aryl, heteroaryl, =0, -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O)R ¹² , -C(O)OR ¹² or -NR ¹⁰ C( O) substituted with a substituent of R ¹¹ ; R ^{8 is} each independently selected from the group consisting of: (i) F, Cl, Br, I, hydroxy, cyano, nitro, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , —C(O)R ¹² , —C(O)OR ¹² or —NR ¹⁰ C(O)R ¹¹ , wherein said alkoxy group, cycloalkyl group, heterocyclic group, aryl group or hetero group The aryl group is optionally further selected from one or more selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ¹⁰ R ¹¹ , Substituted by a substituent of -C(O)NR ¹⁰ R ¹¹ , -C(O)R ¹² , -C(O)OR ¹² or -NR ¹⁰ C(O)R ¹¹ ; (ii) an alkyl group, wherein said alkyl group is further selected from one or more selected from the group consisting of alkoxy, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, - Substituted by a substituent of NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O)R ¹² , -C(O)OR ¹² or -NR ¹⁰ C(O)R ¹¹ ; R ^{9 is} each independently selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)NR ¹⁰ R ¹¹ , -C(O) R ¹² , -C(O)OR ¹² , preferably a tert-butyl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is further further selected from one or more selected from an alkyl group , alkoxy, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O Substituting a substituent of R ¹² , -C(O)OR ¹² or -NR ¹⁰ C(O)R ¹¹ ; R ¹⁰ , R ¹¹ and R ¹² 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, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ¹⁴ R ^{15, -C (O) NR 14} R 15, -C (O) R 16, -C (O) oR 16 or -NR ¹⁴ C (O) R ^15, substituted with a substituent; Alternatively, R ¹⁰ and R ¹¹ together with the N atom to which they are attached form a 4 to 8 membered heterocyclic group, wherein the 4 to 8 membered heterocyclic ring contains one or more N, O, S(O) n atoms, and 4 The ～8 membered heterocyclic ring is further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =0, - Substituted by a substituent of NR ¹⁴ R ¹⁵ , -C(O)NR ¹⁴ R ¹⁵ , -C(O)R ¹⁶ , -C(O)OR ¹⁶ or -NR ¹⁴ C(O)R ¹⁵ ; R ¹⁴ , R ¹⁵ and R ¹⁶ 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, cycloalkyl group, heterocyclic group, aryl group Or a heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxy Substituted by a substituent of the acid ester; X is selected from halogen, preferably F; m is selected from 1, 2, 3 or 4; n is selected from 0, 1 or 2; p is selected from 0, 1, 2, 3 or 4. 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 ⁴ 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 ⁴ and p are as defined in claim 1. The compound according to any one of claims 1 to 3, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ^{1 is} selected from phenyl, wherein said phenyl group is optionally further Substituted by a substituent selected from an alkyl group or a halogen, it is preferably substituted with methyl, ethyl, propyl, butyl, F, Cl, Br or I, more preferably with methyl, F or Cl. The compound according to claim 4, or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R ^{2 is} selected from phenyl, said phenyl group being further

Replace R ⁵ and R ⁶ , or R ⁶ and R ⁷ together with the carbon atom to which they are bonded form a 5- to 7-membered cycloalkyl or heterocyclic group, wherein said cycloalkyl or heterocyclic group is optionally further substituted by one or A plurality of substituents selected from an alkyl group, a halogen, a hydroxyl group, a cyano group, a nitro group, a cycloalkyl group or a heterocyclic group are substituted. The compound according to claim 4, or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R ^{2 is} selected from phenyl, said phenyl group being further

Replace, among them, R ^{8 is} selected from fluorine, m is 2; Preferably, the phenyl group is

Replace. The compound according to claim 4, or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R ^{2 is} selected from phenyl, said phenyl group being further

Replace, R ^{8 is} selected from cycloalkyl, preferably cyclopropyl, wherein said cycloalkyl is further substituted with an alkyl group; More preferably, the phenyl group is

Replace. The compound according to claim 4, or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R ^{2 is} selected from phenyl, said phenyl group being

Replace R ^{8 is} selected from an alkyl group, preferably a tert-butyl group; m is 1. A compound according to claim 5, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

From:

R ^{13 is} each independently selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O)R ¹² , -C(O)OR ¹² or -NR ¹⁰ C(O)R ¹¹ wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl group is optionally further One or more selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O)R ¹² Substituted with a substituent of -C(O)OR ¹² or -NR ¹⁰ C(O)R ¹¹ ; preferably an alkyl group; n is 0, 1, 2 or 3; n is preferably 0 or 1; The definitions of R ¹⁰ , R ¹¹ and R ¹² are as set forth in claim 1. A compound according to claim 5, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

From:

Wherein R ^{13 is} each independently selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , —C(O)R ¹² , —C(O)OR ¹² or —NR ¹⁰ C(O)R ¹¹ , wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group Optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C ( O) is substituted with a substituent of R ¹² , -C(O)OR ¹² or -NR ¹⁰ C(O)R ¹¹ ; R ¹³ is preferably an alkyl group; n is 0, 1, 2 or 3; n is preferably 0 or 1; The definitions of R ¹⁰ , R ¹¹ and R ¹² are as set forth in claim 1. The compound according to claim 1 or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R ^{2 is} selected from phenyl, said phenyl group being further substituted by an alkynyl group, said The alkynyl group is further substituted with a substituent selected from a cycloalkyl group or an alkoxy group. The compound according to claim 11 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the alkynyl group is selected from the group consisting of an ethynyl group or a propynyl group, preferably an ethynyl group, wherein the acetylene group The base or propynyl group is further substituted with a cyclopropyl group. A compound according to claim 4, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ² is:

among them

Selected from the following groups:

Wherein R ^{13 is} each independently selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , —C(O)R ¹² , —C(O)OR ¹² or —NR ¹⁰ C(O)R ¹¹ , wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group Optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C ( O) is substituted with a substituent of R ¹² , -C(O)OR ¹² or -NR ¹⁰ C(O)R ¹¹ ; R ¹³ is preferably an alkyl group; n is 0, 1, 2 or 3; n is preferably 0 or 1; The definitions of R ¹⁰ , R ¹¹ and R ¹² are as set forth in claim 1. A compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein said compound comprises:

A process for the preparation of a compound of formula (I) according to claim 1, the process comprising: a compound of the formula (IA)

The reaction with 2-aminoethanesulfonic acid in the presence of a condensation reagent provides a compound of formula (I)

Wherein the condensation reagent is preferably (2-oxo-3-oxazolidinyl)phosphoryl chloride; Wherein: R ¹ to R ⁴ and p are as defined in claim 1. A process for the preparation of a compound of formula (II) according to claim 2, the process comprising: a compound of the formula (IIA)

Carrying out the reaction with 2-aminoethanesulfonic acid in the presence of a condensation reagent to obtain a compound of the formula (II)

Wherein: the condensation reagent is preferably (2-oxo-3-oxazolidinyl)phosphoryl chloride; The definitions of R ¹ to R ⁴ and p are as set forth in claim 1. A process for the preparation of a compound of formula (III) according to claim 3, the process comprising: Compound of formula (IIIA)

The reaction with 2-aminoethanesulfonic acid in the presence of a condensation reagent provides a compound of the formula (III)

Wherein the condensation reagent is preferably (2-oxo-3-oxazolidinyl)phosphoryl chloride; Wherein: R ¹ to R ⁴ and p are as defined in claim 1. A method of preparing the general formula (IA), the method comprising: Condensation of a compound of formula (IC) with (ID)

Obtaining a compound of the formula (IB)

Hydrolysis of a compound of formula (IB) to give a compound of formula (IA)

Wherein: R ¹ to R ⁴ , R ¹² and p are as defined in claim 1. A method of preparing the general formula (IIA), the method comprising: Condensation of a compound of the formula (IIC) with (IID)

Obtaining a compound of the formula (IIB)

Hydrolysis of a compound of the formula (IIB) to give a compound of the formula (IIA)

Wherein: R ¹ to R ⁴ , R ¹² and p are as defined in claim 1. A method of preparing the general formula (IIIA), the method comprising: Condensation of a compound of the formula (IIIC) with (IID)

Obtaining a compound of the formula (IIIB)

Hydrolysis of a compound of the formula (IIIB) to give a compound of the formula (IIIA)

Wherein: R ¹ to R ⁴ , R ¹² and p are as defined in claim 1. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 14, 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 comprising the glucagon receptor and the compound according to any one of claims 1 to 14, or a stereoisomer thereof, tautomerism thereof The body or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 21 is contacted. The compound according to any one of claims 1 to 14, or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 21, in the preparation of a therapeutic II Use in drugs for diabetes, hyperglycemia, obesity or insulin resistance. The compound according to any one of claims 1 to 14, or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 21, for preparing pancreatic hyperglycemia Use in receptor inhibitors. The compound according to any one of claims 1 to 14, or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 21, in the treatment of type II Use in diabetes, hyperglycemia, obesity or insulin resistance.