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CN109071420B - Amide derivatives, preparation method and medical application thereof - Google Patents

Amide derivatives, preparation method and medical application thereof Download PDF

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CN109071420B
CN109071420B CN201780027911.5A CN201780027911A CN109071420B CN 109071420 B CN109071420 B CN 109071420B CN 201780027911 A CN201780027911 A CN 201780027911A CN 109071420 B CN109071420 B CN 109071420B
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phenyl
compound
trifluoromethoxy
benzoylamino
oxo
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CN109071420A (en
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关东亮
白骅
盛首一
陈磊
赵伟峰
陈明孝
孟力陈
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Zhejiang Hisun Pharmaceutical Co Ltd
Shanghai Aryl Pharmtech Co Ltd
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Shanghai Aryl Pharmtech Co Ltd
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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Abstract

Provides an amide derivative, a preparation method thereof and application thereof in medicine. In particular to an amide derivative shown in a general formula (I) or a pharmaceutically acceptable salt thereof, a preparation method thereof, and application of the amide derivative or the pharmaceutically acceptable salt thereof as a therapeutic agent, especially as a pancreatic hyperglycemia receptor antagonist

Description

Amide derivatives, preparation method and medical application thereof
Technical Field
The invention relates to a novel amide derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and application of the derivative as a therapeutic agent, in particular as a GCGR antagonist.
Background
Glucagon (Glucagon) is a linear polypeptide consisting of 29 amino acids secreted by pancreatic islet alpha cells, with a molecular weight of 3485; the concentration in serum is 50-100ng/L, and the half-life in plasma is 5-10 min. Glucagon specifically binds to a B-type G protein-coupled receptor (glucagon receptor, GCGR) on the surface of a target cell such as liver or kidney, activates a downstream signal transduction pathway, and exerts a physiological effect. It is a hormone for promoting catabolism, and has strong effects of promoting glycogenolysis and gluconeogenesis, and can obviously raise blood sugar. 1mol/L of hormone can make 3X 106mol/L of glucose rapidly decomposes from glycogen (Johnson et al, J.biol.chem.1972, 247, 3229-3235).
Glucagon receptors are located on the cell surface, and G-protein coupled receptors with 7 transmembrane sequences are distributed mainly in the liver, and also in the kidney, heart, muscle, etc.
The major target organ for glucagon action is the liver. When combined with the receptor, the protein interacts with guanine nucleotide binding regulatory protein Gs, so that the subunit A of Gs releases and activates adenylate cyclase, and ATP is catalyzed to be converted into cAMP to play a biological effect. The pharmacological dose of glucagon can increase cAMP content in myocardial cells and enhance myocardial contraction. Glucagon receptor antagonists 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 nephropathy, retinopathy, hypertension, stroke, and heart disease. 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 one potential treatment for diabetes and other diseases involving dysglycemia is glucagon receptor antagonist blocking the glucagon receptor to increase insulin response, to reduce the rate of gluconeogenesis and/or to lower plasma glucose levels by reducing hepatic glucose output rate in the patient.
A series of GCGR antagonists have been disclosed, including WO2008042223, WO2010098994a1, WO2015066252, WO2012009226a1, WO2012009226a1, etc., and not all compounds that are GCGR antagonists have the property of being useful therapeutic drugs. Some of these properties include high affinity for the glucagon receptor, duration of receptor activation, oral bioavailability, and stability (e.g., ability to formulate or crystallize, shelf life). Such characteristics can lead to increased safety, tolerability, efficacy, therapeutic index, patient compliance, cost effectiveness, ease of preparation, and the like. It has been unexpectedly discovered that the particular stereochemistry and functional groups of the compounds of the present invention exhibit one or more of these desirable characteristics, including significantly improved receptor binding properties, oral bioavailability and/or other advantageous features that enhance their suitability for therapeutic use.
GCGR antagonist drugs currently under investigation include: PF-06291874 (feigen) and LGD-6972(Ligand) in clinical phase II, while MK-3577 was developed by merck corporation and disclosed in WO2015066252 that 3- (4- ((1R, 2S) -1- (5-chloro-7-fluoro-1H-indol-3-yl) -1- (4- (trifluoromethoxy) phenyl) pent-2-yl) benzoylamino) propanoic acid (FORM1) is an MK-3577 analogue structure, involving the following structure of specific compounds:
Figure GPA0000254629200000031
disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a novel amide derivative shown in a general formula (I), a tautomer, an enantiomer, a diastereomer, a racemate, a pharmaceutically acceptable salt, a metabolite, a metabolic precursor or a prodrug thereof, the compound has larger structural difference with the specifically disclosed compounds in the prior art, and shows excellent anti-diabetic effect and action, and the general formula (I) has the following structure:
Figure GPA0000254629200000032
wherein:
l is selected from-C (O) NH-or-NH-C (O) -;
A1、A2、A3、A4and A5Each independently selected from CH, C or N, with the proviso that A1、A2、A3、A4And A5And the number of N contained in a ring formed by carbon atoms connected with the N and N is 0-2;
R1selected from alkyl or cycloalkyl, wherein said alkyl or cycloalkyl is optionally further substituted by one or more groups selected from hydroxy, halo, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8or-NR6C(O)R7Substituted with the substituent(s);
R2selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8or-NR6C(O)R7Wherein said alkyl groupAlkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8or-NR6C(O)R7Substituted with the substituent(s); when A is3When selected from N, R2Is absent;
R3each independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, alkoxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8or-NR6C(O)R7Wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8or-NR6C(O)R7Substituted with the substituent(s);
R4each independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, alkoxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8or-NR6C(O)R7Wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8or-NR6C(O)R7Substituted with the substituent(s);
R5each independently selected from hydrogen atom, alkyl, halogen, hydroxyl, alkoxy, cyano, nitro, -NR6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8or-NR6C(O)R7Wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8or-NR6C(O)R7Substituted with the substituent(s);
R6selected from a hydrogen atom or an alkyl group;
R7selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from the group consisting of hydroxy, halogen, haloalkyl, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR9R10、-C(O)R9R10、-C(O)R11、-SO2R11、-C(O)OR11or-NR9C(O)R10Substituted with the substituent(s);
or, R6And R7Together with the linking N atom form a 4-to 8-membered heterocyclic group containing one or more N, O, S (O)qAnd said heterocyclyl is optionally further substituted with one or more groups selected from alkyl, halo, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR9R10、-C(O)R9R10、-C(O)R11、-SO2R11、-C(O)OR11or-NR9C(O)R10Substituted with the substituent(s);
R8selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl isOptionally further substituted with one or more groups selected from hydroxy, halogen, haloalkyl, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR9R10、-C(O)R9R10、-C(O)R11、-SO2R11、-C(O)OR11or-NR9C(O)R10Substituted with the substituent(s);
R9、R10and R11Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, haloalkyl, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid ester;
m is 0, 1, 2, 3, 4 or 5;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4; and is
q is 0, 1 or 2.
A preferred embodiment of the present invention is a compound of formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which is a compound of formula (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:
Figure GPA0000254629200000041
wherein: r1～R5M, n and p are as defined in formula (I).
A preferred embodiment of the present invention is a compound of formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which is a compound of formula (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:
Figure GPA0000254629200000051
wherein: r1～R5M, n and p are as defined in formula (I).
A preferred embodiment of the present invention is a compound of formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which is a compound of formula (IV) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:
Figure GPA0000254629200000052
wherein: r1～R5M, n and p are as defined in formula (I).
A preferred embodiment of the present invention is a compound of formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which is a compound of formula (V) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:
Figure GPA0000254629200000053
wherein: r1～R5M, n and p are as defined in formula (I).
A preferred embodiment of the present invention is a compound of formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which is a compound of formula (VI) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:
Figure GPA0000254629200000054
wherein: r1～R5M, n and p are as defined in formula (I).
A preferred embodiment of the present invention is a compound of formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which is a compound of formula (VII) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:
Figure GPA0000254629200000061
wherein: r1～R5M, n and p are as defined in formula (I).
A preferred embodiment of the present invention is a compound of formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which is a compound of formula (VIII) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:
Figure GPA0000254629200000062
wherein: r1～R5M, n and p are as defined in formula (I).
A preferred embodiment of the present invention is a compound of formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which is a compound of formula (IX) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:
Figure GPA0000254629200000063
wherein: r1～R5M, n and p are as defined in formula (I).
A preferred embodiment of the present invention is a compound of formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which is a compound of formula (X) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:
Figure GPA0000254629200000064
wherein: r1～R5M, n and p are as defined in formula (I).
A preferred embodiment of the present invention is a compound of formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which is a compound of formula (XI) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:
Figure GPA0000254629200000071
wherein: r1～R5M, n and p are as defined in formula (I).
A preferred embodiment of the present invention is a compound of any one of the general formulae (I) to (XI) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: r1Is selected from C3-6Alkyl, preferably n-propyl.
A preferred embodiment of the present invention is a compound of any one of the general formulae (I) to (XI) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R is2Selected from phenyl, wherein said phenyl is optionally further substituted with one or more substituents selected from alkyl, halo, cyano, nitro, alkoxy, haloalkyl or haloalkoxy, and further preferred wherein said phenyl is further substituted with one or more methyl, trifluoromethyl or trifluoromethoxy.
A preferred embodiment of the present invention is a compound of any one of the general formulae (I) to (XI) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R is2Selected from 5-8 membered heteroaryl, wherein said heteroaryl is optionally further substituted with one or more alkyl, halo, cyano, nitro, alkoxy, haloalkyl or haloalkoxy substituents.
A preferred embodiment of the present invention is a compound of any one of the general formulae (I) to (XI) or a stereoisomer, tautomer or mixture thereofA structure or a pharmaceutically acceptable salt thereof, wherein R2Further selected from pyrrole, furan, thiophene, pyrazole, imidazole, thiazole, benzimidazole, benzofuran, or benzoxazole, wherein said pyrrole, furan, thiophene, pyrazole, imidazole, thiazole, benzimidazole, benzofuran, or benzoxazole is optionally further substituted with one or more substituents selected from alkyl, halogen, cyano, nitro or alkoxy, wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, preferably F.
A preferred embodiment of the present invention is a compound of any one of the general formulae (I) to (XI) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R is2Selected from the group consisting of alkynyl, wherein said alkynyl is further substituted with cycloalkyl, wherein said cycloalkyl is preferably cyclopropyl.
A preferred embodiment of the present invention is a compound of any one of the general formulae (I) to (XI) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R is3Is selected from alkoxy, wherein said alkoxy is optionally further substituted with one or more substituents selected from alkyl, halo, cyano, nitro or alkoxy.
A preferred embodiment of the present invention is a compound of any one of the general formulae (I) to (XI) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R is3Selected from fluoroalkoxy groups, preferably trifluoromethoxy or trifluoroethoxy groups.
A preferred embodiment of the present invention is a compound of any one of the general formulae (I) to (XI) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R is3Attached to the 3 (meta) or 4 (para) position, m is 1.
A preferred embodiment of the present invention is a compound of any one of the general formulae (I) to (XI) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R is4Selected from hydrogen atoms, halogens or alkyl groups.
A preferred embodiment of the present invention is a process for preparing a compositionA compound of any one of the general formulae (I) to (XI) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R is4Selected from F, n is 1.
A preferred embodiment of the present invention is a compound according to any one of the general formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,
wherein:
A3is selected from C;
R1selected from n-propyl;
R2selected from alkyl, halogen, cyano, nitro, alkoxy, haloalkyl, haloalkoxy, phenyl or 5-8 membered heteroaryl, said alkyl, alkoxy, phenyl or 5-8 membered heteroaryl being optionally further substituted with one or more substituents of alkyl, halogen, cyano, nitro, alkoxy, haloalkyl or haloalkoxy;
R3is selected from trifluoromethoxy;
R4selected from hydrogen atoms or halogens;
R5each independently selected from a hydrogen atom, an alkyl group, a halogen, an alkoxy group, a haloalkyl group or a haloalkoxy group;
m is 0, 1 or 2;
n is 0, 1 or 2; and is
p is 0, 1 or 2.
Typical compounds of the invention include, but are not limited to:
Figure GPA0000254629200000081
Figure GPA0000254629200000091
Figure GPA0000254629200000101
typical compounds of the invention include, but are not limited to:
Figure GPA0000254629200000102
Figure GPA0000254629200000111
or a stereoisomer, tautomer, mixture tautomer, or pharmaceutically acceptable salt thereof.
Typical compounds of the invention include, but are not limited to:
Figure GPA0000254629200000112
Figure GPA0000254629200000121
Figure GPA0000254629200000131
Figure GPA0000254629200000141
Figure GPA0000254629200000151
Figure GPA0000254629200000161
Figure GPA0000254629200000171
Figure GPA0000254629200000181
Figure GPA0000254629200000191
or a stereoisomer, tautomer, mixture tautomer, or pharmaceutically acceptable salt thereof.
Further, the present invention provides a process for the preparation of a compound of general formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which comprises:
Figure GPA0000254629200000192
reacting the general formula (IC) with the general formula (ID) or a salt thereof to obtain a compound of the general formula (IA);
Figure GPA0000254629200000193
reacting the general formula (IA) with the general formula (IB), and further hydrolyzing the obtained compound to obtain a compound of the general formula (I);
wherein:
L1selected from-C (O) X;
L2is selected from-NH2；
X is selected from hydroxyl or halogen;
Rcselected from alkyl groups;
l is selected from-NH-C (O) -; and is
R1～R5、A1～A5M, n and p are as defined in formula (I).
Further, the present invention provides a process for the preparation of a compound of general formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which comprises:
Figure GPA0000254629200000201
reacting the general formula (IC) with the general formula (IB) or a salt thereof to give a compound of the general formula (IE);
Figure GPA0000254629200000202
reacting the general formula (IE) with the general formula (ID) or a salt thereof, and further hydrolyzing the obtained compound to obtain a compound of the general formula (I);
wherein:
x is selected from hydroxyl or halogen;
Rcselected from alkyl groups;
L1is selected from-NH2；
L2Selected from-C (O) X;
l is selected from-C (O) -NH-; and is
R1～R5、A1～A5M, n and p are as defined in formula (I).
The present invention provides a compound of general formula (IA) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:
Figure GPA0000254629200000211
wherein:
L1selected from-C (O) X;
x is selected from hydroxyl or halogen;
Rcselected from alkyl groups; and is
R1，R3，R4M and n are as defined in formula (I).
Typical compounds of formula (IA) include, but are not limited to:
Figure GPA0000254629200000212
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
Typical compounds of formula (IA) include, but are not limited to:
Figure GPA0000254629200000213
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
Typical compounds of formula (IA) include, but are not limited to:
Figure GPA0000254629200000214
Figure GPA0000254629200000221
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
The present invention provides a compound of general formula (IE) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:
Figure GPA0000254629200000222
wherein:
x is selected from hydroxyl or halogen;
l is selected from-C (O) -NH-; and is
R1～R5、A1～A5M, n and p are as defined in formula (I).
Typical compounds of formula (IE) include, but are not limited to:
Figure GPA0000254629200000223
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
The invention provides a method for preparing a compound of a general formula (IIA), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which comprises the following steps:
Figure GPA0000254629200000231
reacting a compound of formula (IIa) with a compound of formula (IIb) under basic conditions to give a compound of formula (IIc);
Figure GPA0000254629200000232
hydrolyzing the compound (IIc) under alkaline conditions to obtain a compound (IId);
Figure GPA0000254629200000233
reacting the compound of the general formula (IId) with the compound of the general formula (IIe) in the presence of a condensation agent to obtain a compound of the general formula (IIf);
Figure GPA0000254629200000234
hydrolyzing the compound (IIf) in alkaline condition to obtain a compound (IIA);
wherein:
x is selected from hydroxyl or halogen;
Ra，Rband RcEach independently selected from alkyl;
R1、R3、R4m and n are as defined in formula (I).
In the above preparation method, the basic condition is provided by an organic base or an inorganic base, the organic base is selected from diisopropylethylamine, pyridine, triethylamine, piperidine, N-methylpiperazine, 4-dimethylaminopyridine or potassium tert-butoxide, preferably diisopropylethylamine, triethylamine or potassium tert-butoxide; the inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide or potassium hydride, preferably sodium hydroxide or lithium hydroxide.
In the above preparation methods, the condensing agent includes, but is not limited to: bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride, N-dicyclohexylcarbodiimide, N-diisopropylcarbodiimide, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, o-benzotriazol-N, N' -Tetramethyluronium Borate (TBTU), preferably 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride or bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride.
The present invention provides a process for the preparation of a compound of general formula (IIIA), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which process comprises:
Figure GPA0000254629200000241
reacting the compound of formula (IIIa) in the presence of tetraisopropyl titanate and aminomethanol to obtain a compound of formula (IIIb);
Figure GPA0000254629200000242
carrying out condensation reaction on the general formula compound (IIIb) and the general formula (IIIc) to obtain a general formula compound (IIId);
Figure GPA0000254629200000243
carrying out hydrolysis reaction on the compound (IIId) in the general formula under an acidic condition to obtain a compound (IIIA) in the general formula;
wherein:
x is selected from hydroxyl or halogen;
Ra、Rband RcSelected from alkyl groups; and is
R1～R5、A1～A5M, n and p are as defined in formula (III)The above-mentioned processes are described.
In the above preparation method, the acidic condition is provided by an inorganic acid or an organic acid, and the inorganic acid is selected from hydrochloric acid or phosphoric acid.
Further, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of any one of the general formulae (I) to (III), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.
The invention provides a method for inhibiting a glucagon receptor in vitro, which comprises the step of contacting the glucagon receptor with any one of general formulas (I) to (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the stereoisomer, the tautomer or the pharmaceutically acceptable salt thereof.
The invention provides an application of a compound of any one of general formulas (I) to (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing medicaments for treating type I diabetes, type II diabetes, hyperglycemia, obesity or insulin resistance.
The invention provides an application of a compound of any one of general formulas (I) to (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing a glucagon receptor antagonist or inverse agonist.
The invention provides an application of a compound of any one of general formulas (I) to (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing a medicament for treating hyperlipidemia, dyslipidemia, hypercholesterolemia, atherosclerosis and metabolic syndrome.
The compounds of any one of the general formulae (I) to (III) of the present invention, or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, inhibit the glucagon receptor in vitro and are therefore useful for the preparation of glucagon receptor antagonists or inverse agonists, while the present invention further provides methods for treating type I diabetes, type II diabetes, hyperglycemia, obesity, insulin resistance, hyperlipidemia, dyslipidemia, hypercholesterolemia, atherosclerosis or metabolic syndrome comprising the step of administering to an animal a therapeutically effective amount of a compound of any one of the general formulae (I) to (III) of the present invention, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.
Detailed description of the invention
Unless stated to the contrary, some of the terms used in the specification and claims of the present invention are defined as follows:
"alkyl" when taken as a group or part of a group means including C1-C20Straight-chain or branched aliphatic hydrocarbon groups. Preferably C1-C10Alkyl, more preferably C1-C6An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be optionally substituted or unsubstituted.
"alkynyl" as a group or part of a group refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, and can be straight or branched. Preferably selected is C2-C10Alkynyl of (2), more preferably C2-C6Alkynyl, most preferably C2-C4Alkynyl. 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 be optionally substituted or unsubstituted.
"cycloalkyl" refers to saturated or partially saturated monocyclic, fused ring, bridged ring, and spiro carbocyclic rings, i.e., including monocyclic cycloalkyl, fused ring alkyl, bridged cycloalkyl, and spirocycloalkyl. Preferably C3-C12Cycloalkyl, more preferably C3-C8Cycloalkyl, most preferably C3-C6A cycloalkyl group. Examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cyclopropyl, cyclohexenyl being preferred.
"spirocycloalkyl" refers to a 5 to 18 membered polycyclic group having two or more cyclic structures with single rings sharing a single carbon atom (called the spiro atom) with each other, containing 1 or more double bonds within the ring, but no ring has a completely conjugated pi-electron aromatic system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified according to the number of spiro atoms shared between rings into mono-spiro, di-spiro, or multi-spiro cycloalkyl groups, preferably mono-spiro and di-spiro cycloalkyl groups, preferably 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro [4.5] decyl, spiro [4.4] nonyl, spiro [3.5] nonyl, spiro [2.4] heptyl.
"fused cycloalkyl" refers to a 5 to 18 membered all carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of "fused ring alkyl" 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 tetradecaphenanthryl.
"bridged cycloalkyl" means a 5 to 18 membered all carbon polycyclic group containing two or more cyclic structures sharing two non-directly attached carbon atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12, more preferably 7 to 10. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of "bridged cycloalkyl" groups include, but are not limited to: (1s, 4s) -bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, (1s, 5s) -bicyclo [3.3.1] nonyl, bicyclo [2.2.2] octyl, and (1r, 5r) -bicyclo [3.3.2] decyl.
The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted.
"Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably herein and all refer to non-aromatic heterocyclic groups in which one or more of the ring-forming atoms is a heteroatom, such as oxygen, nitrogen, sulfur, and the like, including monocyclic, fused, bridged, and spiro rings, i.e., including monocyclic heterocyclic groups, fused heterocyclic groups, bridged heterocyclic groups, and spiro heterocyclic groups. Preferably having a 5 to 7 membered monocyclic ring or a 7 to 10 membered bi-or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, thiomorpholinyl, tetrahydropyranyl, 1, 1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo [3.2.1] octyl, and piperazinyl. The heterocyclic group may be optionally substituted or unsubstituted.
"spiroheterocyclyl" refers to a 5-to 18-membered polycyclic group having two or more cyclic structures wherein the individual rings share an atom with one another and which contains 1 or more double bonds within the ring, but none of the rings have a fully conjugated pi-electron aromatic system wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-memberedA 6-membered, 5-membered/5-membered or 5-membered/6-membered single spiroheterocyclyl group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1, 7-dioxaspiro [4.5]]Decyl, 2-oxa-7-azaspiro [4.4]Nonyl, 7-oxaspiro [3.5]]Nonyl and 5-oxaspiro [2.4]]A heptyl group.
"fused heterocyclyl" refers to an all-carbon polycyclic group containing two or more ring structures sharing a pair of atoms with each other, one or more of the rings may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron aromatic system in which one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to: octahydropyrrolo [3, 4-c]Pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo [3.1.0]Hexyl, octahydrobenzo [ b ]][1，4]Dioxins (dioxines).
"bridged heterocyclyl" means a 5-to 14-membered, 5-to 18-membered polycyclic group containing two or more cyclic structures sharing two atoms not directly attached to each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen, or S (O)q(wherein q is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. 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-azabicyclo [3.3.2]A decyl group.
The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl. The heterocyclic group may be optionally substituted or unsubstituted.
"aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion. The term "aryl" includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferably aryl is C6-C10Aryl, more preferably aryl is phenyl and naphthyl, most preferably phenyl. The aryl group may be optionally substituted or unsubstituted. The "aryl" may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples include, but are not limited to:
Figure GPA0000254629200000261
"heteroaryl" refers to an aromatic 5-to 6-membered monocyclic or 9-to 10-membered bicyclic ring, which may contain 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-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, benzodioxolyl, benzimidazolyl, indolyl, isoindolyl, 1, 3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, and benzisoxazolyl. Heteroaryl groups may be optionally substituted or unsubstituted. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples include, but are not limited to:
Figure GPA0000254629200000271
"alkoxy" refers to a radical of (alkyl-O-). Wherein alkyl is as defined herein. C1-C6Alkoxy groups of (4) are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy and isopropoxyAlkyl, n-butoxy, isobutoxy, t-butoxy, and the like.
"hydroxy" refers to an-OH group.
"halogen" means fluorine, chlorine, bromine and iodine, preferably chlorine, bromine and iodine.
"amino" means-NH2。
"cyano" means-CN.
"nitro" means-NO2。
"benzyl" means-CH2-phenyl.
"carboxy" refers to-C (O) OH.
"carboxylate" refers to-C (O) O (alkyl) or (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
As used herein, "substituted" or "substituted," unless otherwise specified, means that the group may be substituted with one or more groups selected from: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, ═ O, -NR, carboxyl6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8or-NR6C(O)R7Wherein R is6、R7And R8The definition of (A) is described in the general formula (I).
The definition and convention of stereochemistry in the present invention is generally used with reference to the following documents:
S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-HillBook Company, New York; and Eliel, E.and Wilen, S., "stereoschemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. All stereoisomeric forms of the compounds of the present invention, including but in no way limited to diastereomers, enantiomers, atropisomers and mixtures thereof, such as racemic mixtures, form part of the present invention. Diastereomers may be separated into individual diastereomers on the basis of their physicochemical differences by chromatography, crystallization, distillation, sublimation, or the like. Enantiomers can be separated, such that a chiral isomeric mixture is converted into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers to the corresponding pure enantiomers. The intermediates and compounds of the invention may also exist in different tautomeric forms and all such forms are included within the scope of the invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to designate the sign of the rotation of plane polarized light of the compound, with (-) or l indicating that the compound is left-handed and the prefix (+) or d indicating that the compound is right-handed. The atoms or groups of these stereoisomers are attached to each other in the same order, but they differ in their steric structure. A particular stereoisomer may be an enantiomer, and a mixture of isomers is commonly referred to as a mixture of enantiomers. A50: 50 mixture of enantiomers is called a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.
"tautomer" or "tautomeric form" means that isomers of structures of different energies can be interconverted through a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include tautomers that move through protons, such as keto-enol and imine-enamine isomerizations. Valence (valence) tautomers include tautomers that recombine into bond electrons. Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers): such as the R, S configuration containing an asymmetric center, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers thereof are intended to be within the scope of the present invention.
"pharmaceutically acceptable salts" refers to certain salts of the above compounds which retain their biological activity and are suitable for pharmaceutical use. Pharmaceutically acceptable salts of the compounds represented by formula (I) may be metal salts, preferably alkali metal, alkaline earth metal salts, amine salts formed with suitable acids, including inorganic and organic acids, 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, with the hydrochloride salt being most preferred.
"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, in admixture with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
Synthesis of the Compounds of the invention
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
the preparation method of the compound or the salt thereof of the general formula (II) comprises the following steps:
Figure GPA0000254629200000281
reacting a compound of formula (IIa) with a compound of formula (IIb) under basic conditions to give a compound of formula (IIc); hydrolyzing the compound (IIc) under alkaline conditions to obtain a compound (IId); reacting a compound of the general formula (IId) with a compound of the general formula (IIe) or a salt thereof in the presence of a condensing agent to give a compound of the general formula (IIf); hydrolyzing and acidifying the compound (IIf) with the general formula under alkaline condition to obtain a compound (IIA) with the general formula; the compound of formula (IIA) is reacted with a compound of formula (IIB), optionally further hydrolyzed, to give a compound of formula (II).
Wherein:
x is selected from hydroxyl or halogen;
Ra、Rband RcSelected from alkyl groups; and is
R1～R5、A1～A5M, n and p are as defined in formula (II).
In the above preparation method, the basic condition is provided by an organic base or an inorganic base, the organic base is selected from diisopropylethylamine, pyridine, triethylamine, piperidine, N-methylpiperazine, 4-dimethylaminopyridine or potassium tert-butoxide, preferably diisopropylethylamine, triethylamine or potassium tert-butoxide; the inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide or potassium hydride, preferably sodium hydroxide or lithium hydroxide.
In the above preparation methods, the condensing agent includes, but is not limited to: bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride, N-dicyclohexylcarbodiimide, N-diisopropylcarbodiimide, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, o-benzotriazol-N, N' -Tetramethyluronium Borate (TBTU), preferably 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride or bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride.
The preparation method of the compound or the salt thereof of the general formula (III) comprises the following steps:
Figure GPA0000254629200000291
reacting the compound of formula (IIIa) in the presence of tetraisopropyl titanate and aminomethanol to obtain a compound of formula (IIIb); carrying out condensation reaction on the general formula compound (IIIb) and the general formula (IIIc) to obtain a general formula compound (IIId); carrying out hydrolysis reaction on the compound (IIId) in the general formula under an acidic condition to obtain a compound (IIIA) in the general formula; the compound of formula (IIIA) is reacted with the compound of formula (IIe) or a salt thereof, optionally further hydrolyzed, to give the compound of formula (III).
Wherein:
x is selected from hydroxyl or halogen;
Ra、Rband RcSelected from alkyl groups; and is
R1～R5、A1～A5M, n and p are as defined in formula (III).
In the above preparation method, the basic condition is provided by an organic base or an inorganic base, the organic base is selected from diisopropylethylamine, pyridine, triethylamine, piperidine, N-methylpiperazine, 4-dimethylaminopyridine or potassium tert-butoxide, preferably diisopropylethylamine, triethylamine or potassium tert-butoxide; the inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide or potassium hydride, preferably sodium hydroxide or lithium hydroxide.
The acidic condition is provided by an inorganic acid or an organic acid, and the inorganic acid is selected from hydrochloric acid or phosphoric acid.
In the above preparation methods, the condensing agent includes, but is not limited to: bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride, N-dicyclohexylcarbodiimide, N-diisopropylcarbodiimide, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, o-benzotriazol-N, N' -Tetramethyluronium Borate (TBTU), preferably 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride or bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride.
Drawings
FIG. 1 is a graph of the change in blood glucose levels upon 28 days administration of preferred compounds of the present invention to db/db mice, wherein the ordinate is the blood glucose level (mmol/L) and the abscissa is the time of administration (days).
Detailed Description
The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.
Examples
The examples show the preparation of representative compounds represented by formula (I) and the associated structural identification data. It must be noted that the following examples are intended to illustrate the invention and are not intended to limit the invention.1The H NMR spectrum was obtained using a Bruker instrument (400MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00ppm) was used.1Method for H NMR expression: s is singlet, d is doublet, t is triplet, m is multiplet, br is broadened, dd is doublet of doublet, dt is doublet of triplet. If a coupling constant is provided, it is in Hz.
The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai 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 commercially available or synthesized according to known methods, and none of the commercially available materials and reagents are used without further purification, and unless otherwise indicated, commercially available manufacturers include, but are not limited to, Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Prov Chemical science Inc. and Sci Chemical science Inc., among others.
CD3OD: deuterated methanol.
CDCl3: deuterated chloroform.
DMSO-d6: deuterated dimethyl sulfoxide.
The argon atmosphere means that the reaction flask is connected with an argon balloon having a volume of about 1L.
In the examples, the solution in the reaction is an aqueous solution unless otherwise specified.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a developing solvent system of: a: petroleum ether and ethyl acetate system, B: dichloromethane and ethyl acetate system, C: dichloromethane and methanol, and the volume ratio of the solvent is adjusted according to the polarity of the compound.
The system of eluents for column chromatography or thin layer chromatography plates comprises: a: petroleum ether and ethyl acetate system, B: n-hexane and ethyl acetate system, C: dichloromethane and methanol system, D: petroleum ether and methanol systems. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of ammonia water, acetic acid and the like can be added for adjustment.
Example 1
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 1
3- (4- ((2R, 3S) -1- ((4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-in-3-yl) benzoylamino) propanoic acid 1A
3- (4- ((2S, 3R) -1- ((4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 1B
Figure GPA0000254629200000311
Figure GPA0000254629200000321
First step of
4- (1-hydroxybutyl) benzoic acid methyl ester
Methyl 4-formylbenzoate 1a (10.00g, 60.92mmol) was dissolved in 100mL of tetrahydrofuran, the reaction mixture was cooled to-78 ℃, propylmagnesium bromide 1b (33.50mL, 67.00mmol) was added dropwise, and after completion of the addition, the mixture was stirred at room temperature for 3 hours. The reaction was quenched by addition of 100mL of water, extracted with ethyl acetate (100 mL. times.3), the combined organic phases were washed with saturated ammonium chloride solution (200mL) and sodium chloride solution (200mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to give methyl 4- (1-hydroxybutyl) benzoate 1c (7.50g, colorless liquid), yield: 59.1 percent.
1H NMR(400MHz，CDCl3)：δ7.99(d，J＝8.28Hz，2H)7.39(d，J＝8.03Hz，2H)4.73(t，J＝6.53Hz，1H)3.89(s，3H)1.80-2.25(m，1H)1.59-1.82(m，2H)1.21-1.50(m，2H)0.92(t，J＝7.40Hz，3H)
Second step of
4- (1-Bromobutyl) benzoic acid methyl ester
Methyl 4- (1-hydroxybutyl) benzoate 1c (7.50g, 36.00mmol) was dissolved in 100mL of dichloromethane, and carbon tetrabromide (23.88g, 72.00mmol) and triphenylphosphine (18.88g, 72.00mmol) were added with stirring, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was further isolated and purified by silica gel column chromatography (eluent: system a) to give methyl 4- (1-bromobutyl) benzoate 1d (6.49g, brown liquid) in yield: 66.5 percent.
1H NMR(400MHz，CDCl3)：δ8.01(d，J＝8.28Hz，2H)7.46(d，J＝8.28Hz，2H)4.96(t，J＝7.53Hz，1H)3.92(s，3H)2.23-2.28(m，1H)2.06-2.13(m，1H)1.46-1.54(m，1H)1.29-1.37(m，1H)0.94(t，J＝7.40Hz，3H)
The third step
2- (4- (trifluoromethoxy) phenyl) acetic acid tert-butyl ester
Magnesium sulfate (21.86g, 182mmol) was dissolved in 100mL of dichloromethane, concentrated sulfuric acid (2.66mL, 50mmol) was added dropwise, and after stirring for 10 minutes, 1e (10g, 45.4mmol) of 2- (4- (trifluoromethoxy) phenyl) acetic acid and t-butanol (4.9mL, 50mmol) were added in this order, and the mixture was stirred at room temperature for 24 hours. The reaction solution was poured into 100mL of a saturated sodium bicarbonate solution, the reaction solution was extracted with ethyl acetate (100mL × 3), the combined organic phases were washed with a saturated ammonium chloride solution (200mL) and a sodium chloride solution (200mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give tert-butyl 2- (4- (trifluoromethoxy) phenyl) acetate 1f (8.84g, brown liquid), yield: 70.7 percent.
1H NMR(400MHz，CDCl3)：δ7.29(d，J＝8.28Hz，2H)7.16(d，J＝8.03Hz，2H)3.53(s，2H)1.44(s，9H)
The fourth step
4- (1- (tert-butoxy) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoic acid methyl ester
Tert-butyl 2- (4- (trifluoromethoxy) phenyl) acetate 1f (7.11g, 25.7mmol) and potassium tert-butoxide (6.98g, 25.7mmol) were dissolved in 50mL of N, N-dimethylformamide, and methyl 4- (1-bromobutyl) benzoate 1d (6.98g, 25.7mmol) was added with stirring and stirred at room temperature for 5 hours. The reaction was quenched by adding 100mL of water, extracted with ethyl acetate (100mL × 3), the combined organic phases were washed with sodium chloride solution (200mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system a) to give methyl 4- (1- (tert-butoxy) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoate 1g (4.27g, white solid) in yield: 35.6 percent.
MS m/z(ESI)：410.9[M-57]
The fifth step
4- (1- (tert-butoxy) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoic acid
Methyl 4- (1- (tert-butoxy) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoate 1g (4.27g, 9.2mmol) was dissolved in 30mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1: 1), and 5mL of a solution of sodium hydroxide (1.83g, 45.8mmol) was added with stirring, and the mixture was stirred at room temperature for 3 hours. The reaction was concentrated under reduced pressure, the pH of the solution was adjusted to 6 with 2M hydrochloric acid, extracted with ethyl acetate (200mL), the combined organic phases were washed with sodium chloride solution (100mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system a) to give 4- (1- (tert-butoxy) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoic acid 1h (4g, white solid) with yield: 96.6 percent.
MS m/z(ESI)：452.46[M-57]
The sixth step
3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoic acid tert-butyl ester 1k
((2R, 3S)/(2S, 3R)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoic acid tert-butyl ester 1p
((2R, 3R)/(2S, 3S)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoic acid tert-butyl ester 1q
4- (1- (tert-butoxy) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoic acid 1h (4.00g, 8.84mmol), ethyl 3-aminopropionate hydrochloride 1j (1.25g, 10.60mmol), 1-hydroxybenzotriazole (1.79g, 13.30mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.54g, 13.30mmol) were dissolved in 50mL tetrahydrofuran, triethylamine (7.8mL, 44.2mmol) was added with stirring and stirred at room temperature for 24 hours. The reaction solution was quenched by adding 50mL of water, extracted with ethyl acetate (200mL), the combined organic phases were washed with sodium chloride solution (100mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give tert-butyl 3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoate 1k (2.352g, white solid), which was further purified by silica gel column chromatography to give slower elution ((2R, 3S)/(2S, 3R)) -tert-butyl 3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoate 1p (1.61g, white solid) and faster elution tert-butyl ((2R, 3R)/(2S, 3S)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoate 1q (742mg, white solid), yield: 35.1 percent.
1k：MS m/z(ESI)：552.9[M+1]
1p：MS m/z(ESI)：552.9[M+1]
1H NMR(400MHz，CDCl3)δ＝7.72(d，J＝8.0Hz，2H)，7.47(d，J＝8.5Hz，2H)，7.34(d，J＝8.0Hz，2H)，7.20(d，J＝8.0Hz，2H)，6.84(br.s.，1H)，4.23-4.13(m，2H)，3.78-3.61(m，3H)，3.20(dt，J＝3.8，10.9Hz，1H)，3.27-3.14(m，1H)，2.70-2.60(m，2H)，1.62(br.s.，2H)，1.68-1.55(m，2H)，1.27(t，J＝7.2Hz，5H)，1.05(s，9H)，0.93(tt，J＝7.8，15.0Hz，2H)，0.72-0.61(m，3H).
1q：MS m/z(ESI)：552.9[M+1]
1H NMR(400MHz，CDCl3)δ＝7.50(d，J＝8.0Hz，2H)，7.11(d，J＝8.5Hz，2H)，6.99(d，J＝8.0Hz，2H)，6.92(d，J＝8.3Hz，2H)，6.70(br.s.，1H)，4.15(d，J＝7.0Hz，2H)，3.72-3.57(m，2H)，3.28(br.s.，1H)，2.59(t，J＝5.6Hz，2H)，1.81-1.64(m，1H)，1.87-1.60(m，2H)，1.44(s，9H)，1.25(t，J＝7.2Hz，3H)，1.13-1.04(m，2H)，0.87-0.80(m，3H).
Seventh step
((2R, 3S)/(2S, 3R)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoic acid 1m
((2R, 3R)/(2S, 3S)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoic acid 1S
Tert-butyl ((2R, 3S)/(2S, 3R)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoate 1p (1.61g, 2.90mmol) was dissolved in 20mL of trifluoroacetic acid and stirred at room temperature for 0.5 h. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a)) to give ((2R, 3S)/(2S, 3R)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoic acid 1m (1.40g, light yellow oil), yield: 97.2 percent.
MS m/z(ESI)：495.9[M+1]
Tert-butyl ((2R, 3R)/(2S, 3S)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoate 1q (742.00mg, 1.35mmol) was dissolved in 20mL of dichloromethane, trifluoroacetic acid (0.20mL, 2.69mmol) was added, and after stirring at room temperature for 0.5 hour, 5mL of trifluoroacetic acid was added, and the reaction was continued for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give ((2R, 3R)/(2S, 3S)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoic acid 1S (663.00mg, light yellow viscous substance), yield: 99.48 percent.
MS m/z(ESI)：495.9[M+1]
Eighth step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionic acid ethyl ester
((2R, 3S)/(2S, 3R)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoic acid 1m (80.00mg, 0.16mmol), 4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl ] -4-amine 1n (52.00mg, 0.24mmol), 1-hydroxybenzotriazole (43.00mg, 0.32mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (61mg, 0.32mmol) were dissolved in 20mL of dichloromethane, triethylamine (0.14mL, 0.80mmol) was added with stirring and stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-ane-3-yl) benzoylamino) propionate 1t (58.00mg, white solid), yield: 51.8 percent.
MS m/z(ESI)：695.8[M+1]
The ninth step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid
Ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoate 1t (50.00mg, 0.072mmol) was dissolved in 6mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1: 1), and 1mL of a solution of sodium hydroxide (14.40mg, 0.36mmol) was added with stirring and stirred at room temperature for 3 hours. The reaction was concentrated under reduced pressure, the pH was adjusted to 3 with 1M hydrochloric acid, extracted with ethyl acetate (60mL), the combined organic phases were washed with sodium chloride solution (30mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system a) to give 1(4.00g, white solid) of 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 1(4.00g, yield: and (4) 64.5%.
MS m/z(ESI)：668.7[M+1]
1H NMR(400MHz，DMSO-d6)δ10.07(s，1H)，8.45(s，1H)，7.76(d，J＝7.9Hz，2H)，7.69(d，J＝8.4Hz，2H)，7.48-7.35(m，6H)，7.32(s，1H)，7.24(d，J＝7.9Hz，1H)，7.16-7.07(m，3H)，4.11(d，J＝11.8Hz，1H)，2.47(s，2H)，2.14(s，3H)，0.96-0.89(m，2H)，0.85(t，J＝6.5Hz，2H)，0.64(t，J＝7.4Hz，3H).
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl)]-4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 1 was further prepared by using preparative equipment and a chiral column to resolve chiral isomers using Supercritical Fluid Chromatography (SFC) method ((1) chiral column ChiralPak AD, 25 × 3cm, 80 mL/min; mobile phase A for CO2and B for Ethanol; or/and (2) Whelk O1(S, S), 25X 3cm, 65 mL/min; mobile phase A for CO2and B for Ethanol; or/and (3) Whelk O1(S, S), 25X 3cm, 70 mL/min; mobile phase A for CO2and B for Ethanol)) to obtain 3- (4- ((2R, 3S) -1- ((4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl)]-4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) Propionic acid 1A and 3- (4- ((2S, 3R) -1- ((4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl)]-4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionic acid 1B.
1A：MS m/z(ESI)：668.7[M+1]
1B：MS m/z(ESI)：668.7[M+1]
Example 2
3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) hex-3-yl) benzoylamino) propanoic acid 2
3- (4- ((2R, 3S) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) hex-3-yl) benzoylamino) propanoic acid 2A
3- (4- ((2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) hex-3-yl) benzoylamino) propanoic acid 2B
Figure GPA0000254629200000351
Figure GPA0000254629200000361
First step of
3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) hex-3-yl) benzoylamino) propionic acid ethyl ester
((2R, 3S)/(2S, 3R)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoic acid 1m (100.00mg, 0.20mmol), 2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-amine 2a (63.00mg, 0.3mmol), 1-hydroxybenzotriazole (41.00mg, 0.30mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (43.00mg, 0.32mmol) were dissolved in 10mL of dichloromethane and N, N-diisopropylethylamine (0.09mL, 0.50mmol) was added with stirring and stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to obtain ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) hex-3-yl) benzoylamino) propionate 2B (50.00mg, white solid), yield: 36.3 percent.
MS m/z(ESI)：689.9[M+1]
Second step of
3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) hex-3-yl) benzoylamino) propanoic acid
Ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) hex-3-yl) benzoylamino) propanoate 2b (50.00mg, 0.072mmol) was dissolved in 6mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1: 1), and 1mL of a solution of sodium hydroxide (14.40mg, 0.36mmol) was added with stirring and stirred at room temperature for 3 hours. The reaction was concentrated under reduced pressure, the pH was adjusted to 3 with 1M hydrochloric acid, extracted with ethyl acetate (20mL), the combined organic phases were washed with sodium chloride solution (20mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to give 2- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) hex-3-yl) benzoylamino) propanoic acid (20.00mg, white solid) in yield: 42.0 percent.
MS m/z(ESI)：661.9[M+1]
1H NMR(400MHz，DMSO-d6)δ10.00(s，1H)，8.45(s，1H)，7.77(d，J＝7.7Hz，2H)，7.69(d，J＝7.9Hz，2H)，7.52-7.31(m，6H)，6.96-6.79(m，4H)，4.11(d，J＝10.8Hz，1H)，3.42(d，J＝5.8Hz，3H)，2.49-2.44(m，2H)，1.84(s，5H)，0.95-0.80(m，4H)，0.65(t，J＝7.2Hz，3H).
3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2 ', 4', 6 '-trimethyl- [1, 1' -bi-ethyl)Benzene and its derivatives]-4-yl) amino) hex-3-yl) benzoylamino) propionic acid 2 was further prepared by using a preparation apparatus and a chiral column to resolve chiral isomers using a Supercritical Fluid Chromatography (SFC) method ((1) chiral column ChiralPak AD, 25 × 3cm, 80 mL/min; mobile phase A for CO2and B for Ethanol; or/and (2) Whelk O1(S, S), 25X 3cm, 65 mL/min; mobile phase A for CO2and B for Ethanol; or/and (3) Whelk O1(S, S), 25X 3cm, 70 mL/min; mobile phase A for CO2and B for Ethanol)) to obtain 3- (4- ((2R, 3S) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl)]-4-yl) amino) hex-3-yl) benzoylamino) propionic acid 2A (white solid) and 3- (4- ((2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl]-4-yl) amino) hex-3-yl) benzoylamino) propanoic acid 2B (white solid).
2A：MS m/z(ESI)：668.7[M+1]
2B：MS m/z(ESI)：668.7[M+1]
Example 3
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (benzofuran-2-yl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 3
3- (4- ((2R, 3S) -1- ((4- (benzofuran-2-yl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hexan-3-yl) benzoylamino) propanoic acid 3A
3- (4- ((2S, 3R) -1- ((4- (benzofuran-2-yl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hexan-3-yl) benzoylamino) propanoic acid 3B
Figure GPA0000254629200000371
First step of
4- (benzofuran-2-yl) anilines
4-iodoaniline 3a (448.00mg, 2.05mmol), 2- (benzofuran-2-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxolane 3b (500.00mg, 21.10mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (1.54g, 2.11mmol) and sodium carbonate (652.00mg, 6.15mmol) were dissolved in 28mL of a mixed solvent of dimethyl ether, ethanol and water (V/V/V ═ 5: 1), and the reaction mixture was reacted at 100 ℃ for 5 hours under the protection of argon. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 4- (benzofuran-2-yl) aniline 3c (150.00mg, white solid) in yield: 35 percent.
MS m/z(ESI)：210.9[M+1]
Second step of
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (benzofuran-2-yl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-en-3-yl) benzoylamino) propanoic acid
((2R, 3S)/(2S, 3R)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoic acid 1m (80mg, 0.16mmol), 4- (benzofuran-2-yl) aniline 3c (50mg, 0.24mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (61mg, 0.24mmol) were dissolved in 10mL dichloromethane and N, N-diisopropylethylamine (0.14mL, 0.8mmol) was added with stirring and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (benzofuran-2-yl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionate 3d (61mg, white solid) in yield: 55.6 percent.
MS m/z(ESI)：687.8[M+1]
The third step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (benzofuran-2-yl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-en-3-yl) benzoylamino) propanoic acid
Ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (benzofuran-2-yl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoate 3d (60mg, 0.087mmol) was dissolved in 6mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1: 1), and 1mL of a solution of lithium hydroxide monohydrate (73mg, 1.75mmol) was added with stirring and stirred at room temperature for 3 hours. The reaction was adjusted to pH 3 with 1M hydrochloric acid, extracted with ethyl acetate (50mL), the combined organic phases were washed successively with saturated ammonium chloride solution (50mL × 2), sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to give 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (benzofuran-2-yl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 3(50mg, white solid), yield: 87.3 percent.
MS m/z(ESI)：658.9[M+1]
1H NMR(400MHz，CDCl3)：δ1H NMR(400MHz，DMSO-d6)δppm 7.73(td，J＝15.56，8.28Hz，8H)7.54-7.63(m，3H)7.38-7.48(m，6H)7.21-7.28(m，2H)4.11(d，J＝11.29Hz，1H)3.37-3.50(m，2H)2.43-2.48(m，1H)1.23-1.32(m，3H)1.18(d，J＝4.77Hz，1H)0.93(d，J＝6.53Hz，2H)0.84-0.90(m，2H)0.65(t，J＝7.15Hz，3H)
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (benzofuran-2-yl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 3 further the chiral isomer was resolved by using a preparative apparatus and a chiral column by using a Supercritical Fluid Chromatography (SFC) method ((1) chiral column ChiralPak AD, 25X 3cm, 80 mL/min; mobile phase A for CO2and B for Ethanol; or/and (2) Whelk O1(S, S), 25X 3cm, 65 mL/min; mobile phase A for CO2and B for Ethanol; or/and (3) Whelk O1(S, S), 25X 3cm, 70 mL/min; mobile phase A for CO2and B for Ethanol)) to give 3- (4- ((2R, 3S) -1- ((4- (benzofuran-2-yl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 3A (white solid) and 3- (4- ((2S, 3R) -1- ((4- (benzofuran-2-yl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 3B (white solid).
3A：MS m/z(ESI)：658.9[M+1]
3B：MS m/z(ESI)：658.9[M+1]
Example 4
3- (4- ((2R, 3S)/(2S, 3R) -1- ((3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-ane-3-yl) benzoylamino) propanoic acid 4
3- (4- ((2R, 3S) -1- ((3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 4A
3- (4- ((2S, 3R) -1- ((3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 4B
Figure GPA0000254629200000391
First step of
3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-amine
2-fluoro-4-iodoaniline 4a (5g, 21.1mmol), 2, 4, 6-trimethylphenylboronic acid 4b (3.46g, 21.1mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (1.54g, 2.11mmol) were dissolved in 100mL of N, N-dimethylformamide, and 20mL of a sodium hydroxide solution (2.53g, 63.3mmol) were added with stirring, and the reaction mixture was reacted at 100 ℃ for 4 hours under the protection of argon. The reaction solution was extracted with ethyl acetate (100mL × 3), the combined organic phases were washed with sodium chloride solution (100mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to obtain 3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-amine 4c (4.8g, white solid), yield: 96.2 percent. MS m/z (ESI): 230.0[ M +1]
Second step of
3- (4- ((2R, 3S)/(2S, 3R) -1- ((3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-ane-3-yl) benzoylamino) propionic acid ethyl ester
((2R, 3S)/(2S, 3R)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoic acid 1m (5.00g, 10.09mmol), 3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-amine 4c (2.31g, 10.09mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (3.84g, 15.13mmol) were dissolved in 50mL of dichloromethane and N, N-diisopropylethylamine (8.79mL, 50.45mmol) was added with stirring and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionate 4d (2.10g, white solid), yield: 29.5 percent.
MS m/z(ESI)：706.9[M+1]
The third step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-ane-3-yl) benzoylamino) propanoic acid
Ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hexan-3-yl) benzoylamino) propanoate 4d (5.20g, 7.35mmol) was dissolved in 120mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1: 1), and 10mL of a solution of lithium hydroxide monohydrate (6.10g, 147mmol) was added with stirring and stirred at room temperature for 2 hours. 500mL of ethyl acetate was added, washed with 0.3M dilute hydrochloric acid to pH 5-6, then washed with saturated sodium chloride solution (300mL), concentrated under reduced organic pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system a) to give 4- ((2R, 3S)/(2S, 3R) -1- ((3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 4(4.50g, white solid) in yield: 90.18 percent. MS m/z (ESI): 678.9[ M +1]
1H NMR(400MHz，CDCl3)：9.78(s，1H)8.45(t，J＝5.14Hz，1H)7.77(d，J＝8.03Hz，2H)7.68(d，J＝8.53Hz，2H)7.53-7.62(m，1H)7.41(dd，J＝13.05，8.28Hz，4H)6.82-6.94(m，2H)4.39(d，J＝11.54Hz，1H)4.01(q，J＝7.11Hz，2H)3.38-3.47(m，2H)2.17-2.26(m，2H)1.93-2.01(m，2H)1.83(d，J＝10.29Hz，3H)1.11-1.25(m，3H)0.79-0.93(m，4H)0.56-0.68(m，3H)
3- (4- ((2R, 3S)/(2S, 3R) -1- ((3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl)]-4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 4 was further prepared by using a Supercritical Fluid Chromatography (SFC) method to resolve chiral isomers using preparative equipment and a chiral column ((1) chiral column ChiralPak AD, 25 × 3cm, 80 mL/min; mobile phase A for CO2and B for Ethanol; or/and (2) Whelk O1(S, S), 25X 3cm, 65 mL/min; mobile phase A for CO2and B for Ethanol; or/and (3) Whelk O1(S, S), 25X 3cm, 70 mL/min; mobile phase A for CO2and B for Ethanol)) to obtain 3- (4- ((2R, 3S) -1- ((3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl)]-4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 4A and 3- (4- ((2S, 3R) -1- ((3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl)]-4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionic acid 4B.
4A：MS m/z(ESI)：678.9[M+1]
1H NMR(400MHz，DMSO-d6)δ＝9.79(s，1H)，8.53-8.40(m，1H)，7.79(d，J＝8.0Hz，2H)，7.70(d，J＝8.5Hz，2H)，7.58(t，J＝8.4Hz，1H)，7.43(dd，J＝8.4，11.9Hz，4H)，6.94-6.82(m，3H)，6.73(d，J＝8.0Hz，1H)，4.47-4.34(m，1H)，3.50-3.38(m，4H)，3.17(s，2H)，2.22(s，3H)，1.85(d，J＝10.0Hz，6H)，1.06(t，J＝7.0Hz，2H)，0.96-0.85(m，2H)，0.64(d，J＝14.3Hz，3H).
4B：MS m/z(ESI)：678.9[M+1]
1H NMR(400MHz，DMSO-d6)δ＝9.80(s，1H)，8.47(t，J＝5.4Hz，1H)，7.79(d，J＝8.0Hz，2H)，7.71(d，J＝8.5Hz，2H)，7.59(t，J＝8.3Hz，1H)，7.44(dd，J＝8.3，12.8Hz，4H)，6.94-6.85(m，3H)，6.73(d，J＝8.3Hz，1H)，4.42(d，J＝11.5Hz，1H)，3.52-3.30(m，6H)，2.22(s，3H)，1.86(d，J＝10.5Hz，7H)，1.42-1.29(m，1H)，1.19(br.s.，1H)，1.06(t，J＝7.0Hz，3H)，0.91(d，J＝7.5Hz，2H)，0.70-0.58(m，3H).
Example 5
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2-fluoro-4- (trifluoromethyl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 5
3- (4- ((2R, 3S) -1- ((2-fluoro-4- (trifluoromethyl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-ane-3-yl) benzoylamino) propanoic acid 5A
3- (4- ((2S, 3R) -1- ((2-fluoro-4- (trifluoromethyl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-ane-3-yl) benzoylamino) propanoic acid 5B
Figure GPA0000254629200000411
First step of
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2-fluoro-4- (trifluoromethyl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionic acid ethyl ester
((2R, 3S)/(2S, 3R)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoic acid 1m (60mg, 0.12mmol), 2-fluoro-4- (trifluoromethyl) aniline 5a (25mg, 0.13mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (46mg, 0.18mmol) were dissolved in 20mL dichloromethane, triethylamine (0.085mL, 0.6mmol) was added with stirring and stirred at room temperature for 2 hours. To the reaction solution were added 15mL of ethyl acetate and 10mL of water, the pH was adjusted to 1 with 3M hydrochloric acid, the aqueous layer was extracted with ethyl acetate (15mL × 2), the combined organic phases were washed successively with a saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to obtain ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((2-fluoro-4- (trifluoromethyl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionate 5B (20mg, white solid) in yield: 25.6 percent.
Second step of
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2-fluoro-4- (trifluoromethyl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid
Ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((2-fluoro-4- (trifluoromethyl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoate 5b (20mg, 0.03mmol) was dissolved in a mixed solvent of 3mL tetrahydrofuran and water (V/V ═ 2: 1), and added to lithium hydroxide monohydrate (3mg, 0.06mmol) with stirring and stirred at room temperature for 24 hours. The reaction was adjusted to pH 3 with 1M hydrochloric acid, extracted with ethyl acetate (15mL), the combined organic phases were washed successively with saturated ammonium chloride solution (10mL), saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system C) to give 3- (4- ((2R, 3S)/(2S, 3R) -1- ((2-fluoro-4- (trifluoromethyl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionic acid 5(18mg, white solid) in yield: 94.7 percent.
MS m/z(ESI)：629.8[M+1]
1H NMR(400MHz，DMSO-d6)：δ10.08(br.s.，1H)，8.45(br.s.，1H)，7.85(br.s.，1H)，7.76(d，J＝7.0Hz，2H)，7.69(d，J＝7.3Hz，2H)，7.59(d，J＝10.8Hz，1H)，7.42(br.s.，5H)，4.47(d，J＝11.3Hz，1H)，3.56-3.42(m，5H)，1.41-1.23(m，4H)，0.64(br.s.，3H)
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2-fluoro-4- (trifluoromethyl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 5 Compound the chiral isomer was further resolved by using a preparative and chiral column using a Supercritical Fluid Chromatography (SFC) method ((1) chiral column ChiralPak AD, 25X 3cm, 80 mL/min; mobile phase A for CO2and B for Ethanol; or/and (2) Whelk O1(S, S), 25X 3cm, 65 mL/min; mobile phase A for CO2and B for Ethanol; or/and (3) Whelk O1(S, S), 25X 3cm, 70 mL/min; mobile phase A for CO2and B for Ethanol)) to give 5A (white solid) of 3- (4- ((2R, 3S) -1- ((2-fluoro-4- (trifluoromethyl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid and 3- (4- ((2S, 3R) -1- ((2-fluoro-4- (trifluoromethyl) phenyl) hex-3-yl) benzoylamino)Yl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionic acid 5B (white solid).
5A：MS m/z(ESI)：629.8[M+1]
5B：MS m/z(ESI)：629.8[M+1]
Example 6
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2, 5-difluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 6
3- (4- ((2R, 3S) -1- ((2, 5-difluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 6A
3- (4- ((2S, 3R) -1- ((2, 5-difluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 6B
Figure GPA0000254629200000431
First step of
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2, 5-difluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-en-3-yl) benzoylamino) propionic acid ethyl ester
((2R, 3S)/(2S, 3R)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoic acid 1m (80mg, 0.16mmol), 2, 5-difluoroaniline 6a (33.3mg, 0.24mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (61mg, 0.24mmol) were dissolved in 10mL dichloromethane and N, N-diisopropylethylamine (0.11mL, 0.64mmol) was added with stirring and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to obtain ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((2, 5-difluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionate 6B (50mg, white solid) in yield: 51.0 percent.
MS m/z(ESI)：607.9[M+1]
Second step of
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2, 5-difluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-en-3-yl) benzoylamino) propanoic acid
Ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((2, 5-difluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoate 6b (48mg, 0.097mmol) was dissolved in 4mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1: 1), and 1mL of a solution of sodium hydroxide (19.4mg, 0.49mmol) was added with stirring, and stirred at room temperature for 2 hours. The reaction solution was partially removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, 2 drops of 3M hydrochloric acid were added dropwise to adjust the pH, extraction was performed with ethyl acetate (10mL × 3), the combined organic phases were washed with a sodium chloride solution (10mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developer: system C) to give 3- (4- ((2R, 3S)/(2S, 3R) -1- ((2, 5-difluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionic acid 6(21mg, white solid) in yield: 46.0 percent.
MS m/z(ESI)：579.8[M+1]
1H NMR(400MHz，DMSO-d6)：δ12.90(s，1H)，10.04(s，1H)，8.44(t，J＝5.1Hz，1H)，7.89(s，1H)，7.79(s，1H)，7.75(d，J＝8.0Hz，2H)，7.70(d，J＝8.5Hz，2H)，7.44(d，J＝8.0Hz，2H)，7.40(d，J＝8.0Hz，2H)，7.33(d，J＝8.8Hz，1H)，7.11(d，J＝8.8Hz，1H)，4.16(d，J＝11.3Hz，1H)，3.52-3.40(m，5H)，2.45(t，J＝7.0Hz，2H)，1.18(d，J＝8.0Hz，2H)，0.96-0.87(m，2H)，0.67-0.61(m，3H)
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2, 5-difluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 6 the chiral isomer was further resolved by using a preparative apparatus and a chiral column using a Supercritical Fluid Chromatography (SFC) method ((1) chiral column ChiralPak AD, 25X 3cm, 80 mL/min; mobile phase A for CO2and B for Ethanol; or/and (2) Whelk O1(S, S), 25X 3cm, 65 mL/min; mobile phase A for CO2and B for Ethanol; or/and (3) Whelk O1(S, S), 25X 3cm, 70 mL/min; mobile phase A for CO2and B for Ethanol)) to obtainTo 6A 3- (4- ((2R, 3S) -1- ((2, 5-difluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hexan-3-yl) benzoylamino) propanoic acid (white solid) and 6B 3- (4- ((2S, 3R) -1- ((2, 5-difluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hexan-3-yl) benzoylamino) propanoic acid (white solid).
6A：MS m/z(ESI)：579.8[M+1]
6B：MS m/z(ESI)：579.8[M+1]
Example 7
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2, 4-difluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 7
3- (4- ((2R, 3S) -1- ((2, 4-difluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 7A
3- (4- ((2S, 3R) -1- ((2, 4-difluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 7B
Figure GPA0000254629200000441
First step of
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2, 4-difluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-en-3-yl) benzoylamino) propionic acid ethyl ester
((2R, 3S)/(2S, 3R)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoic acid 1m (80mg, 0.16mmol), 2, 4-difluoroaniline 7a (0.024mL, 2.4mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (61mg, 0.24mmol) were dissolved in 20mL dichloromethane and N, N-diisopropylethylamine (0.11mL, 0.64mmol) was added with stirring and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((2, 4-difluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionate 7B (40mg, white solid) in yield: 41.2 percent.
MS m/z(ESI)：607.9[M+1]
Second step of
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2, 4-difluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-en-3-yl) benzoylamino) propanoic acid
Ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((2, 4-difluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoate 7b (40mg, 0.066mmol) was dissolved in 6mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1: 1), and 1mL of a solution of sodium hydroxide (14.4mg, 0.36mmol) was added with stirring, and stirred at room temperature for 1.5 hours. The reaction was concentrated under reduced pressure, pH was adjusted to 3 with 1M hydrochloric acid, ethyl acetate was extracted (60mL), the combined organic phases were washed with sodium chloride solution (60mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to give 7- (4- ((2R, 3S)/(2S, 3R) -1- ((2, 4-difluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid (31mg, white solid) yield: 81.3 percent.
MS m/z(ESI)：579.8[M+1]
1H NMR(400MHz，DMSO-d6)δ9.78(s，1H)，8.55(s，1H)，7.75(s，2H)，7.68(s，2H)，7.41(s，4H)，7.33(s，1H)，7.16(s，1H)，6.88(s，1H)，4.30(d，J＝11.4Hz，2H)，4.18-4.08(m，1H)，2.40(s，2H)，0.97-0.81(m，4H)，0.64(s，3H).
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2, 4-difluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 7 further the chiral isomer was resolved by using a preparative apparatus and a chiral column using a Supercritical Fluid Chromatography (SFC) method ((1) chiral column ChiralPak AD, 25X 3cm, 80 mL/min; mobile phase A for CO2and B for Ethanol; or/and (2) Whelk O1(S, S), 25X 3cm, 65 mL/min; mobile phase A for CO2and B for Ethanol; or/and (3) Whelk O1(S, S), 25X 3cm, 70 mL/min; mobile phase A for CO2and B for Ethanol)) to obtain 3- (4- ((2R, 3S) -1- ((2, 4-difluorophenyl) amino) -1-oxo-7A 2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid (white solid) and 7B 3- (4- ((2S, 3R) -1- ((2, 4-difluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid (white solid).
7A：MS m/z(ESI)：579.8[M+1]
7B：MS m/z(ESI)：579.8[M+1]
Example 8
3- (4- ((2R, 3S)/(2S, 3R) -1- ((3, 4-dimethoxyphenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-en-3-yl) benzoylamino) propanoic acid 8
3- (4- ((2R, 3S) -1- ((3, 4-dimethoxyphenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 8A
3- (4- ((2S, 3R) -1- ((3, 4-dimethoxyphenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 8B
Figure GPA0000254629200000461
First step of
3- (4- ((2R, 3S)/(2S, 3R) -1- ((3, 4-dimethoxyphenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-en-3-yl) benzoylamino) propionic acid ethyl ester
((2R, 3S)/(2S, 3R)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoic acid 1m (80mg, 0.16mmol), 3, 4-dimethoxyaniline 8a (25mg, 0.16mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (61mg, 0.24mmol) were dissolved in 20mL of dichloromethane, N-diisopropylethylamine (0.11mL, 0.64mmol) was added with stirring and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((3, 4-dimethoxyphenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionate 8B (41mg, white solid) in yield: 40.6 percent.
MS m/z(ESI)：607.9[M+1]
Second step of
3- (4- ((2R, 3S)/(2S, 3R) -1- ((3, 4-dimethoxyphenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-en-3-yl) benzoylamino) propanoic acid
Ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((3, 4-dimethoxyphenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoate 8b (41mg, 0.065mmol) was dissolved in 6mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1: 1), and 1mL of a solution of sodium hydroxide (14.4mg, 0.36mmol) was added with stirring, and stirred at room temperature for 1.5 hours. The reaction was concentrated under reduced pressure, pH was adjusted to 3 with 1M hydrochloric acid, ethyl acetate was extracted (60mL), the combined organic phases were washed with sodium chloride solution (60mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to give 3- (4- ((2R, 3S)/(2S, 3R) -1- ((3, 4-dimethoxyphenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionic acid 8(30mg, white solid) in yield: 76.6 percent.
MS m/z(ESI)：603.9[M+1]
1H NMR(400MHz，DMSO-d6)δ9.90(s，1H)，8.55(s，1H)，7.75(d，J＝7.6Hz，2H)，7.67(d，J＝8.5Hz，2H)，7.41(t，J＝8.6Hz，4H)，6.88(s，1H)，6.82(d，J＝8.8Hz，1H)，6.72(d，J＝8.4Hz，1H)，4.09(d，J＝10.9Hz，1H)，3.61(d，J＝8.7Hz，6H)，2.41-2.34(m，2H)，0.88(ddd，J＝14.7，12.8，5.8Hz，4H)，0.63(t，J＝7.0Hz，3H).
3- (4- ((2R, 3S)/(2S, 3R) -1- ((3, 4-dimethoxyphenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 8 the chiral isomer was further resolved by using a preparative and chiral column using Supercritical Fluid Chromatography (SFC) method ((1) chiral column ChiralPak AD, 25X 3cm, 80 mL/min; mobile phase A for CO2and B for Ethanol; or/and (2) Whelk O1(S, S), 25X 3cm, 65 mL/min; mobile phase A for CO2and B for Ethanol; or/and (3) Whelk O1(S, S), 25X 3cm, 70 mL/min; mobile phase A forCO2and B for Ethanol)) to give 8A (white solid) 3- (4- ((2R, 3S) -1- ((3, 4-dimethoxyphenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid and 8B (white solid) 3- (4- ((2S, 3R) -1- ((3, 4-dimethoxyphenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid.
8A：MS m/z(ESI)：603.9[M+1]
8B：MS m/z(ESI)：603.9[M+1]
Example 9
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4-trifluoromethoxyphenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-en-3-yl) benzoylamino) propanoic acid 9
3- (4- ((2R, 3S) -1- ((4-trifluoromethoxyphenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 9A
3- (4- ((2S, 3R) -1- ((4-trifluoromethoxyphenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 9B
Figure GPA0000254629200000471
First step of
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4-trifluoromethoxyphenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-en-3-yl) benzoylamino) propionic acid ethyl ester
((2R, 3S)/(2S, 3R)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoic acid 1m (80mg, 0.16mmol), 4-trifluoromethoxyaniline 9a (28mg, 0.16mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (61mg, 0.24mmol) were dissolved in 20mL of dichloromethane and N, N-diisopropylethylamine (0.11mL, 0.64mmol) was added with stirring and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4-trifluoromethoxyphenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionate 9B (64mg, white solid) in yield: 60.6 percent.
MS m/z(ESI)：655.8[M+1]
Second step of
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4-trifluoromethoxyphenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-en-3-yl) benzoylamino) propanoic acid
Ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4-trifluoromethoxyphenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoate 9b (64mg, 0.097mmol) was dissolved in 6mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1: 1), and 1mL of a solution of sodium hydroxide (19.4mg, 0.49mmol) was added with stirring, and stirred at room temperature for 1.5 hours. The reaction was concentrated under reduced pressure, the pH was adjusted to 3 with 1M hydrochloric acid, ethyl acetate was extracted (60mL), the combined organic phases were washed with a saturated ammonium chloride solution (60mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to give 9- (4- ((2R, 3S)/(2S, 3R) -1- ((4-trifluoromethoxyphenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid (27mg, white solid), yield: 44.4 percent. MS m/z (ESI): 628.7[ M +1]
1H NMR(400MHz，DMSO-d6)δ10.35(s，1H)，8.48(s，1H)，7.74(d，J＝8.2Hz，2H)，7.69(d，J＝8.5Hz，2H)，7.41(t，J＝9.1Hz，6H)，7.16(d，J＝8.7Hz，2H)，4.17(d，J＝10.9Hz，2H)，2.38(t，J＝7.2Hz，2H)，0.99-0.76(m，4H)，0.63(t，J＝7.1Hz，3H).
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4-trifluoromethoxyphenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 9 further the chiral isomer was resolved by using a preparative apparatus and a chiral column using a Supercritical Fluid Chromatography (SFC) method ((1) chiral column ChiralPak AD, 25X 3cm, 80 mL/min; mobile phase A for CO2and B for Ethanol; or/and (2) Whelk O1(S, S), 25X 3cm, 65 mL/min; mobile phase A for CO2and B for Ethanol; or/and (3) Whelk O1(S, S), 25X 3cm, 70 mL/min; mobile phase A for CO2and B for Ethanol)) to give 9A 3- (4- ((2R, 3S) -1- ((4-trifluoromethoxyphenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid (white solid) and 9B 3- (4- ((2S, 3R) -1- ((4-trifluoromethoxyphenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid (white solid).
9A：MS m/z(ESI)：628.7[M+1]
9B：MS m/z(ESI)：628.7[M+1]
Example 10
3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2, 4, 6-trifluorophenyl) amino) hex-3-yl) benzoylamino) propanoic acid 10
3- (4- ((2R, 3S) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2, 4, 6-trifluorophenyl) amino) hex-3-yl) benzoylamino) propanoic acid 10A
3- (4- ((2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2, 4, 6-trifluorophenyl) amino) hex-3-yl) benzoylamino) propanoic acid 10B
Figure GPA0000254629200000481
Figure GPA0000254629200000491
First step of
3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2, 4, 6-trifluorophenyl) amino) hex-3-yl) benzoylamino) propionic acid ethyl ester
((2R, 3S)/(2S, 3R)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoic acid 1m (80mg, 0.16mmol), 2, 4, 6-trifluoroaniline 10a (35mg, 0.24mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (61mg, 0.24mmol) were dissolved in 20mL dichloromethane and N, N-diisopropylethylamine (0.11mL, 0.64mmol) was added with stirring and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to obtain ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2, 4, 6-trifluorophenyl) amino) hex-3-yl) benzoylamino) propionate 10B (29mg, white solid) in yield: 29.0 percent.
MS m/z(ESI)：625.8[M+1]
Second step of
3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2, 4, 6-trifluorophenyl) amino) hex-3-yl) benzoylamino) propanoic acid
Ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2, 4, 6-trifluorophenyl) amino) hex-3-yl) benzoylamino) propanoate 10b (29mg, 0.05mmol) was dissolved in 6mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1: 1), and 1mL of a solution of sodium hydroxide (9.3mg, 0.25mmol) was added with stirring, and stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure, extracted with ethyl acetate (60mL), the combined organic phases were washed with a saturated ammonium chloride solution (60mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to give 10(8mg, white solid) of 3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2, 4, 6-trifluorophenyl) amino) hex-3-yl) benzoylamino) propionic acid (yield: 26.7 percent.
MS m/z(ESI)：597.8[M+1]
1H NMR(400MHz，CDCl3)：1H NMR(400MHz，DMSO-d6)：δ9.95(s，1H)，8.46(s，1H)，7.76(d，J＝7.8Hz，2H)，7.68(d，J＝8.3Hz，2H)，7.41(t，J＝6.9Hz，5H)，7.22-7.12(m，1H)，6.84(s，1H)，4.43(d，J＝11.3Hz，1H)，2.49-2.44(m，2H)，1.34(d，J＝6.0Hz，1H)，1.22(s，6H)，1.16(s，1H)，0.94-0.86(m，2H)，0.62(t，J＝7.0Hz，3H)
3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2, 4, 6-trifluorophenyl) amino) hex-3-yl) benzoylamino) propanoic acid 10 further by using Supercritical Fluid Chromatography (SFC) method with preparative equipment and chiral column for adversaryThe sex isomers are resolved ((1) chiral column ChiralPak AD, 25X 3cm, 80 mL/min; mobile phase A for CO)2and B for Ethanol; or/and (2) Whelk O1(S, S), 25X 3cm, 65 mL/min; mobile phase A for CO2and B for Ethanol; or/and (3) Whelk O1(S, S), 25X 3cm, 70 mL/min; mobile phase A for CO2and B for Ethanol)) to give 10A (white solid) 3- (4- ((2R, 3S) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2, 4, 6-trifluorophenyl) amino) hex-3-yl) benzoylamino) propanoic acid and 10B (white solid) 3- (4- ((2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2, 4, 6-trifluorophenyl) amino) hex-3-yl) benzoylamino) propanoic acid.
10A：MS m/z(ESI)：597.8[M+1]
10B：MS m/z(ESI)：597.8[M+1]
Example 11
3- (4- (1- (2-methoxy-4- (trifluoromethyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid
Figure GPA0000254629200000501
First step of
4- (1-amino-1- (4- (trifluoromethoxyphenyl) pentan-2-yl) benzoic acid tert-butyl ester
Under the protection of argon, dissolving tert-butyl 4- (1-oxo-1- (4- (trifluoromethoxyphenyl) pent-2-yl) benzoate 11a (1.50g, 3.55mmol) and tetraisopropyl titanate (2.10mL, 7.10mmol) in 7N ammonia methanol (20mL), reacting at room temperature for 18 hours, cooling the reaction solution to 0 ℃, adding sodium borohydride (230mg, 6.03mmol), heating to room temperature, reacting for 2 hours, slowly dropwise adding 1N sodium hydroxide solution into the reaction solution until no obvious solid is formed, filtering, concentrating the filtrate, adding 20mL water, extracting with ethyl acetate (10mL multiplied by 3), combining the organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying the obtained residue with silica gel column chromatography (eluent: system A) to obtain tert-butyl 4- (1-amino-1- (4- (trifluoromethoxyphenyl) pentan-2-yl) benzoate 11b (1.02) g, yellow viscous liquid), yield: 68.0 percent.
1H NMR(400MHz，CDCl3)δ7.96(d，J＝7.4Hz，2H)，7.38(d，J＝8.0Hz，2H)，7.29(d，J＝7.7Hz，2H)，7.19(d，J＝7.9Hz，2H)，4.07(d，J＝8.9Hz，1H)，2.82(d，J＝6.4Hz，1H)，2.32(s，2H)，1.60(s，9H)，1.26(s，2H)，0.94(d，J＝6.5Hz，2H)，0.75-0.58(m，3H).
Second step of
4- (1- (2-methoxy-4- (trifluoromethyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid tert-butyl ester
Tert-butyl 4- (1-amino-1- (4- (trifluoromethoxyphenyl) pentan-2-yl) benzoate 11b (700mg, 1.65mmol), 2-methoxy-4- (trifluoromethyl) benzoic acid 11c (512mg, 1.50mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (573mg, 2.25mmol) and N, N-diisopropylethylamine (1.05mL, 6.00mmol) were dissolved in a mixed solvent of 12mL of dichloromethane and N, N-dimethylformamide (V/V ═ 5/1), the reaction mixture was reacted at room temperature for 18 hours, 20mL of water was added to the reaction mixture, extraction was performed with ethyl acetate (10mL × 3), anhydrous sodium sulfate was dried, filtration was performed, concentration was performed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a), tert-butyl 4- (1- (2-methoxy-4- (trifluoromethyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoate 11d (790mg, light yellow solid) was obtained, yield: 86.0 percent. MS m/z (ESI): 557.8[ M +1-56]
The third step
4- (1- (2-methoxy-4- (trifluoromethyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid
Tert-butyl 4- (1- (2-methoxy-4- (trifluoromethyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoate 11d (790mg, 1.29mmol) and 85% phosphoric acid (1.20g, 10.3mmol) were dissolved in 10mL of acetonitrile, and the reaction was reacted at 80 ℃ for 5 hours. The filtrate was concentrated, then 30mL of water was added, extracted with ethyl acetate (10mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 11e (720mg, light yellow liquid) of 4- (1- (2-methoxy-4- (trifluoromethyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid, yield: 99.0 percent.
MS m/z(ESI)：557.8[M+1]
The fourth step
3- (4- (1- (2-methoxy-4- (trifluoromethyl) benzoylamino) -2- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid ethyl ester
11e (720mg, 1.29mmol) of 4- (1- (2-methoxy-4- (trifluoromethyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid, ethyl 3-aminopropionate hydrochloride (1.0g, 6.50mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (1.994mg, 7.8mmol) and N, N-diisopropylethylamine (2.20mL, 1.89mmol) were dissolved in a mixed solvent of 11mL of dichloromethane and N, N-dimethylformamide (V/V ═ 9/2), and the reaction solution was reacted at 35 ℃ for 38 hours. The reaction solution was concentrated under reduced pressure, then 20mL of water was added, extraction was performed with ethyl acetate (10mL × 3), the combined organic phases were washed successively with a saturated sodium carbonate solution (20mL × 1), a 1N hydrochloric acid solution (20mL × 1) and a saturated saline solution (20mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol system) to give ethyl 3- (4- (1- (2-methoxy-4- (trifluoromethyl) benzoylamino) -2- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionate 11f (530mg, white solid), yield: 62.0 percent.
MS m/z(ESI)：656.8[M+1]
The fifth step
3- (4- (1- (2-methoxy-4- (trifluoromethyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid
Ethyl 3- (4- (1- (2-methoxy-4- (trifluoromethyl) benzoylamino) -2- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionate 11f (530mg, 0.81mmol) and 0.80mL of lithium hydroxide monohydrate (170mg, 4.05mmol) were dissolved in 10mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1: 1), and the reaction mixture was reacted at 30 ℃ for 18 hours. The reaction solution was concentrated under reduced pressure to remove a part of the solvent, pH was adjusted to 2-3 with 1M hydrochloric acid, extraction was performed with ethyl acetate (10mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate system) to give 11- (4- (1- (2-methoxy-4- (trifluoromethyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propanoic acid (200mg, white solid), yield: 40.0 percent.
MS m/z(ESI)：640.0[M+1]
1H NMR(400MHz，DMSO)δ12.20(s，1H)，8.52(d，J＝8.5Hz，2H)，7.82(d，J＝7.9Hz，2H)，7.58(d，J＝8.2Hz，2H)，7.40(d，J＝7.9Hz，2H)，7.35(d，J＝8.3Hz，3H)，7.30(s，1H)，7.23(d，J＝7.7Hz，1H)，5.30(t，J＝8.9Hz，1H)，3.76(s，3H)，3.47(d，J＝5.7Hz，2H)，3.14(t，J＝8.3Hz，1H)，2.53(d，J＝6.9Hz，2H)，1.58(d，J＝9.7Hz，1H)，1.15(s，1H)，0.98-0.84(m，2H)，0.65(t，J＝7.0Hz，3H).
Example 12
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (tert-butyl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-en-3-yl) benzoylamino) propanoic acid 12
3- (4- ((2R, 3S) -1- ((4- (tert-butyl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 12A
3- (4- ((2S, 3R) -1- ((4- (tert-butyl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 12B
Figure GPA0000254629200000521
First step of
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (tert-butyl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-en-3-yl) benzoylamino) propionic acid ethyl ester
((2R, 3S)/(2S, 3R)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoic acid 1m (80mg, 0.16mmol), 4-tert-butylaniline 12a (28mg, 0.19mmol), 1-hydroxybenzotriazole (1.79g, 13.3mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (40mg, 0.21mmol) and N, N-diisopropylethylamine (52mg, 0.4mmol) were dissolved in 10mL of tetrahydrofuran and stirred at room temperature for 24 hours. The reaction was extracted with ethyl acetate (60mL), the combined organic phases were washed with sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to give ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (tert-butyl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionate 12B (32mg, white solid), yield: 35.1 percent.
MS m/z(ESI)：626.9[M+1]
Second step of
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (tert-butyl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-en-3-yl) benzoylamino) propanoic acid
Ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (tert-butyl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoate 12b (32mg, 0.05mmol) was dissolved in 6mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1: 1), and 1mL of a solution of sodium hydroxide (10mg, 0.25mmol) was added with stirring, and stirred at room temperature for 1.5 hours. The reaction solution was subjected to removal of a part of the solvent under reduced pressure, pH was adjusted to 3 with 1M hydrochloric acid, extraction was performed with ethyl acetate (20mL × 3), the combined organic phases were washed with a saturated ammonium chloride solution (30mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent dichloromethane: methanol ═ 9: 1), the obtained residue was purified by silica gel column chromatography (eluent: system B) to obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (tert-butyl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 12(7mg, white solid) in yield: 23.4 percent.
MS m/z(ESI)：599.9[M+1]
1H NMR(400MHz，DMSO-d6)δ9.86(s，1H)，8.47(s，1H)，7.74(d，J＝8.5Hz，2H)，7.66(d，J＝8.6Hz，2H)，7.40(dd，J＝8.3，5.1Hz，4H)，7.17(dd，J＝16.5，9.0Hz，6H)，5.33(d，J＝3.8Hz，1H)，4.05(t，J＝10.0Hz，2H)，2.42-2.36(m，2H)，0.94-0.81(m，4H)，0.63(t，J＝7.5Hz，3H).
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (tert-butyl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 12 further the chiral isomer was resolved by using a preparative and a chiral column using Supercritical Fluid Chromatography (SFC) method ((1) chiral column ChiralPak AD, 25X 3cm, 80 mL/min; mobile phase A for CO2and B for Ethanol; or/and (2) Whelk O1(S, S), 25X 3cm, 65 mL/min; mobile phase A for CO2and B for Ethanol; or/and (3) Whelk O1(S, S), 25X 3cm, 70 mL/min; mobile phase A for CO2and B for Ethanol)) to give 12A 3- (4- ((2R, 3S) -1- ((4- (tert-butyl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid (white solid) and 12B 3- (4- ((2S, 3R) -1- ((4- (tert-butyl) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid (white solid).
12A：MS m/z(ESI)：599.9[M+1]
12B：MS m/z(ESI)：599.9[M+1]
Example 13
3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) amino) hex-3-yl) benzoylamino) propanoic acid 13
3- (4- ((2R, 3S) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) amino) hex-3-yl) benzoylamino) propanoic acid 13A
3- (4- ((2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) amino) hex-3-yl) benzoylamino) propanoic acid 13B
Figure GPA0000254629200000531
Figure GPA0000254629200000541
First step of
1- (4-nitrophenyl) -4- (trifluoromethyl) -1H-pyrazole
1-fluoro-4-nitrobenzene 13a (1.35g, 9.55mmol), 4- (trifluoromethyl) -1H-pyrazole 13b (1g, 7.35mmol) and potassium carbonate (2.03g, 14.7mmol) were dissolved in 10mL of acetonitrile, and the reaction mixture was reacted at 85 ℃ for 7 hours. The reaction was filtered and concentrated under reduced pressure to give crude 1- (4-nitrophenyl) -4- (trifluoromethyl) -1H-pyrazole 13c (1.2g, light yellow solid), yield: 63.5 percent of
MS m/z(ESI)：257.9[M+1]
Second step of
4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) aniline
1- (4-Nitrophenyl) -4- (trifluoromethyl) -1H-pyrazole 13c (257mg, 1mmol) and 10% palladium on carbon (128mg) were dissolved in 10mL of methanol, and the reaction mixture was stirred at room temperature for 5 hours. The reaction solution was filtered and concentrated under reduced pressure to give crude 4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) aniline 13d (230mg, colorless liquid).
MS m/z(ESI)：227.9[M+1]
The third step
3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) amino) hex-3-yl) benzoylamino) propanoic acid ethyl ester
((2R, 3S)/(2S, 3R)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoic acid 1m (90mg, 0.22mmol), 4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) aniline 13d (66mg, 0.29mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (100mg, 0.26mmol) and N, N-diisopropylethylamine (0.12mL, 0.66mmol) were dissolved in 5mL tetrahydrofuran and stirred at room temperature for 18 hours. Adding 15mL of water to the reaction solution, extracting with ethyl acetate (8 mL. times.3), drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying the obtained residue with silica gel column chromatography (eluent: System C) to obtain
Ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) amino) hex-3-yl) benzoylamino) propanoate 13e (155mg, yellow solid), yield: 99.9 percent.
MS m/z(ESI)：704.8[M+1]
The fourth step
3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) amino) hex-3-yl) benzoylamino) propanoic acid
Ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) amino) hex-3-yl) benzamido) propanoate 13e (155mg, 0.22mmol) was dissolved in 5mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 4: 1), and 0.22mL of a solution of lithium hydroxide monohydrate (50mg, 1.1mmol) was added with stirring, and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to remove a part of the solvent, pH 2-3 was adjusted with 1M hydrochloric acid, extraction was performed with ethyl acetate (6mL × 3), the combined organic phases were washed successively with a saturated ammonium chloride solution (5mL × 2), a sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 13(8mg, yellow solid) of 3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) amino) hex-3-yl) benzoylamino) propionic acid, yield: 5.4 percent.
MS m/z(ESI)：676.8[M+1]
1H NMR(400MHz，DMSO)δ10.14(s，1H)，9.00(s，1H)，8.43(s，1H)，8.11(s，1H)，7.76(d，J＝7.4Hz，2H)，7.68(d，J＝7.8Hz，5H)，7.47-7.38(m，6H)，4.09(d，J＝11.5Hz，1H)，3.52-3.44(m，2H)，3.22-3.16(m，1H)，2.47-2.43(m，2H)，1.98-1.94(m，2H)，1.15-1.13(m，2H)，0.64(t，J＝6.4Hz，3H).
3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) amino) hex-3-yl) benzoylamino) propanoic acid 13 further obtained by resolving a chiral isomer using a preparative instrument and a chiral column by using a Supercritical Fluid Chromatography (SFC) method ((1) chiral column ChiralPak AD, 25X 3cm, 80 mL/min; flow column ChiralPakPhase A for CO2and B for Ethanol; or/and (2) Whelk O1(S, S), 25X 3cm, 65 mL/min; mobile phase A for CO2and B for Ethanol; or/and (3) Whelk O1(S, S), 25X 3cm, 70 mL/min; mobile phase A for CO2and B for Ethanol)) to give 13A 3- (4- ((2R, 3S) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) amino) hexan-3-yl) benzoylamino) propanoic acid (white solid) and 13B 3- (4- ((2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) amino) hexan-3-yl) benzoylamino) propanoic acid (white solid).
13A：MS m/z(ESI)：676.8[M+1]
13B：MS m/z(ESI)：676.8[M+1]
Example 14
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (2-methylthiazol-5-yl) phenyl) amino (1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 14
3- (4- ((2R, 3S) -1- ((4- (2-methylthiazol-5-yl) phenyl) amino (1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-en-3-yl) benzoylamino) propanoic acid 14A
3- (4- ((2S, 3R) -1- ((4- (2-methylthiazol-5-yl) phenyl) amino (1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 14B
Figure GPA0000254629200000561
First step of
4- (2-methylthiazol-5-yl) aniline
5-bromo 2-methylthiazole 14a (840mg, 4.72mmol), 4-aminophenylboronic acid hydrochloride 14b (900mg, 5.19mmol), tetrakistriphenylphosphine palladium (273mg, 0.24mmol) and sodium carbonate (1.90g, 17.9mmol) were dissolved in 50mL of a mixed solvent of toluene, ethanol and water (V/V/V ═ 2: 1), and the reaction mixture was reacted at 90 ℃ for 6 hours with the replacement of gas with argon. The reaction solution was concentrated, 15mL of water was added, extraction was performed with ethyl acetate (10 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System C) to give 4- (2-methylthiazol-5-yl) aniline 14C (630mg, yellow solid) in yield: 70.0 percent
MS m/z(ESI)：190.9[M+1]
Second step of
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (2-methylthiazol-5-yl) phenyl) amino (1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionic acid ethyl ester
((2R, 3S)/(2S, 3R)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoic acid 1m (248mg, 0.50mmol), 4- (2-methylthiazol-5-yl) aniline 14c (114mg, 0.60mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (380mg, 1.00mmol) and N, N-diisopropylethylamine (0.35mL, 2.00mmol) were dissolved in 6mL of a mixed solvent of dichloromethane and N, N-dimethylformamide (V/V ═ 5/1), and the reaction liquid was reacted at room temperature for 18 hours. To the reaction solution, 20mL of water was added, and extraction was performed with ethyl acetate (10 mL. times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System C) to obtain ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (2-methylthiazol-5-yl) phenyl) amino (1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionate 14d (166mg, off-white solid) with a yield of 49.7%.
MS m/z(ESI)：667.9[M+1]
The third step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (2-methylthiazol-5-yl) phenyl) amino (1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid
Ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (2-methylthiazol-5-yl) phenyl) amino (1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoate 14d (166mg, 0.25mmol) was dissolved in 8mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 4: 1), 0.25mL of a solution of lithium hydroxide monohydrate (53mg, 1.25mmol) was added with stirring, stirring was carried out at room temperature for 18 hours, the reaction solution was concentrated under reduced pressure to remove part of the solvent, pH was adjusted with 1M hydrochloric acid to 2-3, extracted with ethyl acetate (10mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system C), to give 14(100mg, white solid) of 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (2-methylthiazol-5-yl) phenyl) amino (1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid in a yield of 62.0%.
MS m/z(ESI)：639.9[M+1]
1H NMR(400MHz，DMSO)δ12.40-11.89(m，1H)，10.07(s，1H)，8.42(s，1H)，7.85(s，1H)，7.75(d，J＝8.0Hz，2H)，7.67(d，J＝8.4Hz，2H)，7.38(dd，J＝21.0，8.6Hz，8H)，4.08(d，J＝11.0Hz，1H)，3.47(dd，J＝3.4，2.1Hz，1H)，3.45-3.41(m，2H)，2.62(s，3H)，2.46(d，J＝7.1Hz，2H)，1.38(dd，J＝10.5，4.8Hz，2H)，0.93-0.84(m，2H)，0.64(t，J＝7.2Hz，3H).
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (2-methylthiazol-5-yl) phenyl) amino (1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 14 further the chiral isomer was resolved by using a preparative and chiral column using a Supercritical Fluid Chromatography (SFC) method ((1) chiral column ChiralPak AD, 25X 3cm, 80 mL/min; mobile phase A for CO2and B for Ethanol; or/and (2) Whelk O1(S, S), 25X 3cm, 65 mL/min; mobile phase A for CO2and B for Ethanol; or/and (3) Whelk O1(S, S), 25X 3cm, 70 mL/min; mobile phase A for CO2and B for Ethanol)), 14A 3- (4- ((2R, 3S) -1- ((4- (2-methylthiazol-5-yl) phenyl) amino (1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid (white solid) and 14B 3- (4- ((2S, 3R) -1- ((4- (2-methylthiazol-5-yl) phenyl) amino (1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid (white solid).
14A：MS m/z(ESI)：639.9[M+1]
14B：MS m/z(ESI)：639.9[M+1]
Example 15
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2-fluoro-4- (trifluoromethoxy) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 15
3- (4- ((2R, 3S) -1- ((2-fluoro-4- (trifluoromethoxy) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-ane-3-yl) benzoylamino) propanoic acid 15A
3- (4- ((2S, 3R) -1- ((2-fluoro-4- (trifluoromethoxy) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-ane-3-yl) benzoylamino) propanoic acid 15B
Figure GPA0000254629200000581
First step of
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2-fluoro-4- (trifluoromethoxy) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionic acid ethyl ester
1m (200mg, 0.40mmol) of ((2R, 3S)/(2S, 3R)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl-2- (4- (trifluoromethoxy) phenyl) hexanoic acid, 2-fluoro-4- (trifluoromethoxy) aniline 15a (116mg, 0.60mmol) and N, N-diisopropylethylamine (0.28mL, 1.60mmol) were dissolved in 6mL of dichloromethane, bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (152mg, 0.60mmol) was finally added, the reaction solution was reacted at room temperature for 18 hours, the reaction solution was concentrated under reduced pressure, 60mL of ethyl acetate was added, washed with a saturated sodium bicarbonate solution (30 mL. times.2) and a saturated ammonium chloride solution (30 mL. times.2) in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (developing solvent: system a) to give ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((2-fluoro-4- (trifluoromethoxy) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionate 15b (155mg, white solid), yield: 16.4 percent.
MS m/z(ESI)：672.8[M+1]
Second step of
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2-fluoro-4- (trifluoromethoxy) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid
Ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((2-fluoro-4- (trifluoromethoxy) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoate 15b (44mg, 0.065mmol) was dissolved in a mixed solvent of 6mL tetrahydrofuran and methanol (V/V ═ 1: 1), and 1.0mL sodium hydroxide (13mg, 0.33mmol) was added to the solution with stirring and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to remove a part of the solvent, pH-3 was adjusted with 1M hydrochloric acid, extracted with 60mL of ethyl acetate, the organic phase was washed with a saturated ammonium chloride solution (30mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (developing solvent: system a) to give 15(19mg, white solid) of 3- (4- ((2R, 3S)/(2S, 3R) -1- ((2-fluoro-4- (trifluoromethoxy) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionic acid, yield: 45.3 percent.
MS m/z(ESI)：644.7[M+1]
1H NMR(400MHz，MeOD)δ7.79(d，J＝7.9Hz，2H)，7.70(d，J＝8.5Hz，2H)，7.48(d，J＝8.2Hz，2H)，7.43(d，J＝8.3Hz，1H)，7.33(d，J＝8.6Hz，2H)，7.05(d，J＝11.6Hz，1H)，6.95(d，J＝7.7Hz，1H)，4.12(d，J＝11.2Hz，1H)，3.63(t，J＝6.6Hz，2H)，3.52-3.44(m，1H)，2.63(t，J＝6.5Hz，2H)，1.06-0.95(m，2H)，0.89(ddd，J＝8.0，7.1，4.8Hz，2H)，0.73(t，J＝7.1Hz，3H).
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2-fluoro-4- (trifluoromethoxy) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 15 further the chiral isomer was resolved by using a preparative apparatus and a chiral column by using a Supercritical Fluid Chromatography (SFC) method ((1) chiral column ChiralPak AD, 25X 3cm, 80 mL/min; mobile phase A for CO2and B for Ethanol; or/and (2) Whelk O1(S, S), 25X 3cm, 65 mL/min; mobile phase A for CO2and B for Ethanol; or/and (3) Whelk O1(S, S), 25X 3cm, 70 mL/min; mobile phase A for CO2and B for Ethanol)) to give 15A (white solid) of 3- (4- ((2R, 3S) -1- ((2-fluoro-4- (trifluoromethoxy) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid and 3- (4- ((2S, 3R) -1- ((2-fluoro-4- (trifluorom ethoxy) phenyl) hex-3-yl) benzoylamino)Methoxy) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 15B (white solid).
15A：MS m/z(ESI)：644.7[M+1]
15B：MS m/z(ESI)：644.7[M+1]
Example 16
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2-methyl-4- (trifluoromethoxy) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 16
3- (4- ((2R, 3S) -1- ((2-methyl-4- (trifluoromethoxy) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hexan-3-yl) benzoylamino) propanoic acid 16A
3- (4- ((2S, 3R) -1- ((2-methyl-4- (trifluoromethoxy) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hexan-3-yl) benzoylamino) propanoic acid 16B
Figure GPA0000254629200000591
First step of
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2-methyl-4- (trifluoromethoxy) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionic acid ethyl ester
1m (200mg, 0.40mmol) of ((2R, 3S)/(2S, 3R)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl-2- (4- (trifluoromethoxy) phenyl) hexanoic acid, 2-methyl-4- (trifluoromethoxy) aniline 16a (116mg, 0.61mmol) and N, N-diisopropylethylamine (0.28mL, 1.60mmol) were dissolved in 6mL of dichloromethane, the gas was replaced three times with argon, then bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (155mg, 0.61mmol) was added, the reaction solution was reacted at room temperature for 18 hours, the reaction solution was concentrated under reduced pressure, 60mL of ethyl acetate was added, and washed with a saturated sodium bicarbonate solution (30 mL. times.3) and a saturated ammonium chloride solution (30 mL. times.3) in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (developing solvent: system a) to give ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((2-methyl-4- (trifluoromethoxy) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionate 16b (44mg, white solid), yield: 16.5 percent.
MS m/z(ESI)：668.9[M+1]
Second step of
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2-methyl-4- (trifluoromethoxy) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid
Ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((2-methyl-4- (trifluoromethoxy) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoate 16b (44mg, 0.066mmol) was dissolved in a mixed solvent of 6mL tetrahydrofuran and methanol (V/V ═ 1: 1), and 1.0mL sodium hydroxide (13.2mg, 0.33mmol) was added to the solution with stirring and stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to remove a part of the solvent, pH-3 was adjusted with 1M hydrochloric acid, 60mL of ethyl acetate was added for extraction, and washed with saturated ammonium chloride solution (30mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (developing solvent: system C) to give 3- (4- ((2R, 3S)/(2S, 3R) -1- ((2-methyl-4- (trifluoromethoxy) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionic acid 16(28mg, white solid), yield: 66.2 percent.
MS m/z(ESI)：640.8[M+1]
1H NMR(400MHz，MeOD)δ7.83(d，J＝8.2Hz，2H)，7.72(d，J＝8.6Hz，2H)，7.51(d，J＝8.1Hz，2H)，7.35(d，J＝8.7Hz，2H)，6.99(s，1H)，6.93(d，J＝8.4Hz，1H)，6.75(d，J＝8.6Hz，1H)，4.03(d，J＝11.7Hz，1H)，3.66(t，J＝6.7Hz，2H)，3.52-3.44(m，1H)，2.64(t，J＝6.4Hz，2H)，1.65(s，3H)1.62-1.39(m，2H)，1.06-0.97(m，2H)，0.73(t，J＝7.3Hz，3H).
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2-methyl-4- (trifluoromethoxy) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 16 further chiral isomers were resolved by using a preparation apparatus and a chiral column using a Supercritical Fluid Chromatography (SFC) method ((1) chiral column ChiralPak A)D, 25 multiplied by 3cm, 80 mL/min; mobile phase A for CO2and B for Ethanol; or/and (2) Whelk O1(S, S), 25X 3cm, 65 mL/min; mobile phase A for CO2and B for Ethanol; or/and (3) Whelk O1(S, S), 25X 3cm, 70 mL/min; mobile phase A for CO2and B for Ethanol)) to give 16A 3- (4- ((2R, 3S) -1- ((2-methyl-4- (trifluoromethoxy) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid (white solid) and 16B 3- (4- ((2S, 3R) -1- ((2-methyl-4- (trifluoromethoxy) phenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid (white solid).
16A：MS m/z(ESI)：640.8[M+1]
16B：MS m/z(ESI)：640.8[M+1]
Example 17
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4-chloro-2-fluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 17
3- (4- ((2R, 3S) -1- ((4-chloro-2-fluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 17A
3- (4- ((2S, 3R) -1- ((4-chloro-2-fluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 17B
Figure GPA0000254629200000611
First step of
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4-chloro-2-fluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionic acid ethyl ester
1m ((2R, 3S)/(2S, 3R)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl-2- (4- (trifluoromethoxy) phenyl) hexanoic acid (100mg, 0.20mmol), 4-chloro-2-fluoroaniline 17a (44mg, 0.30mmol) and N, N-diisopropylethylamine (0.14mL, 0.80mmol) were dissolved in 3mL of dichloromethane, argon gas was substituted three times, then bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (76mg, 0.30mmol) was added, the reaction solution was reacted at room temperature for 5 hours, the reaction solution was concentrated under reduced pressure, 60mL of ethyl acetate was added, and washed with a saturated sodium bicarbonate solution (30 mL. times.2) and a saturated ammonium chloride solution (30 mL. times.2) in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (developing solvent: system a) to give ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4-chloro-2-fluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionate 17b (17mg, white solid) in yield: 13.6 percent.
MS m/z(ESI)：622.8[M+1]
Second step of
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4-chloro-2-fluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid
Ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4-chloro-2-fluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoate 17b (36mg, 0.058mmol) was dissolved in 6mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1: 1), and 1.0mL of a solution of sodium hydroxide (12.0mg, 0.29mmol) was added with stirring, and stirred at room temperature for 16 hours. Concentrating the reaction solution under reduced pressure to remove part of the solvent, adjusting pH to 3 with 1M hydrochloric acid, adding 60mL of ethyl acetate, extracting, washing the organic phase with saturated ammonium chloride solution (30 mL. times.3), drying the organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying the obtained residue with silica gel thin layer chromatography (developing agent: system A) to obtain
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4-chloro-2-fluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 17(19mg, white solid), yield: 55.1 percent.
MS m/z(ESI)：594.8[M+1]
1H NMR(400MHz，MeOD)δ7.78(d，J＝8.2Hz，2H)，7.70(d，J＝8.6Hz，2H)，7.48(d，J＝8.0Hz，2H)，7.36(d，J＝8.6Hz，1H)，7.33(d，J＝7.8Hz，2H)，7.11(d，J＝12.7Hz，1H)，7.00(d，J＝8.5Hz，1H)，4.11(d，J＝11.6Hz，1H)，3.63(t，J＝6.9Hz，2H)，3.51-3.43(m，1H)，2.61(s，2H)，1.61-1.37(m，2H)，1.06-0.95(m，2H)，0.72(t，J＝7.3Hz，3H).
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4-chloro-2-fluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 17 the chiral isomer was further resolved by using a preparative and chiral column using Supercritical Fluid Chromatography (SFC) method ((1) chiral column ChiralPak AD, 25X 3cm, 80 mL/min; mobile phase A for CO2and B for Ethanol; or/and (2) Whelk O1(S, S), 25X 3cm, 65 mL/min; mobile phase A for CO2and B for Ethanol; or/and (3) Whelk O1(S, S), 25X 3cm, 70 mL/min; mobile phase A for CO2and B for Ethanol)) to give 17A of 3- (4- ((2R, 3S) -1- ((4-chloro-2-fluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid (white solid) and 17B of 3- (4- ((2S, 3R) -1- ((4-chloro-2-fluorophenyl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid (white solid).
17A：MS m/z(ESI)：594.8[M+1]
17B：MS m/z(ESI)：594.8[M+1]
Example 18
3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl-1- ((6- (trifluoromethyl) pyridin-3-yl) amino) hex-3-yl) benzoylamino) propanoic acid 18
3- (4- ((2R, 3S) -1-oxo-2- (4- (trifluoromethoxy) phenyl-1- ((6- (trifluoromethyl) pyridin-3-yl) amino) hex-3-yl) benzoylamino) propanoic acid 18A
3- (4- ((2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl-1- ((6- (trifluoromethyl) pyridin-3-yl) amino) hex-3-yl) benzoylamino) propanoic acid 18B
Figure GPA0000254629200000621
Figure GPA0000254629200000631
First step of
3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl-1- ((6- (trifluoromethyl) pyridin-3-yl) amino) hex-3-yl) benzoylamino) propanoic acid ethyl ester
1m (200mg, 0.40mmol) of ((2R, 3S)/(2S, 3R)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl-2- (4- (trifluoromethoxy) phenyl) hexanoic acid, 6- (trifluoromethyl) pyridin-3-amine 18a (98mg, 0.60mmol) and N, N-diisopropylethylamine (0.28mL, 1.60mmol) were dissolved in 6mL of dichloromethane, the gas was replaced three times with argon, then bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (152mg, 0.60mmol) was added, the reaction solution was reacted at 35 ℃ for 18 hours, the reaction solution was concentrated under reduced pressure, 60mL of ethyl acetate was added, and washed with a saturated sodium bicarbonate solution (30 mL. times.2) and a saturated ammonium chloride solution (30 mL. times.2) in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (developing solvent: petroleum ether: ethyl acetate 1: 1) to give ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl-1- ((6- (trifluoromethyl) pyridin-3-yl) amino) hex-3-yl) benzoylamino) propionate 18b (34mg, white solid) in 13.3% yield.
MS m/z(ESI)：639.9[M+1]
Second step of
3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl-1- ((6- (trifluoromethyl) pyridin-3-yl) amino) hex-3-yl) benzoylamino) propanoic acid
Ethyl 3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl-1- ((6- (trifluoromethyl) pyridin-3-yl) amino) hex-3-yl) benzoylamino) propanoate 18b (34mg, 0.053mmol) was dissolved in 6mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1: 1), 1.0mL of a sodium hydroxide (11.0mg, 0.27mmol) was added with stirring, stirring was carried out at room temperature for 18 hours, the reaction solution was concentrated under reduced pressure to remove part of the solvent, pH was adjusted to 3 with 1M hydrochloric acid, 60mL of ethyl acetate was added for extraction, the organic phase was washed with a saturated ammonium chloride solution (30mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the obtained residue was purified by silica gel thin layer chromatography (developing solvent: system a) to give 18(8mg, white solid) of 3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl-1- ((6- (trifluoromethyl) pyridin-3-yl) amino) hex-3-yl) benzoylamino) propanoic acid in a yield of 25.0%.
MS m/z(ESI)：694.8[M+1]
1H NMR(400MHz，DMSO)δ10.66(s，1H)，8.60(s，1H)，8.45(s，1H)，8.04(d，J＝8.0Hz，1H)，7.76(s，1H)，7.74(s，1H)，7.72(s，1H)，7.69(s，1H)，7.67(s，1H)，7.44(s，2H)，7.42(s，2H)，4.16(d，J＝11.8Hz，1H)，3.66(t，J＝6.7Hz，2H)，3.52-3.44(m，1H)，2.46(t，J＝7.0Hz，2H)，1.20-1.12(m，2H)，0.88(dd，J＝15.7，7.0Hz，2H)，0.64(t，J＝7.4Hz，3H).
3- (4- ((2R, 3S)/(2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl-1- ((6- (trifluoromethyl) pyridin-3-yl) amino) hex-3-yl) benzoylamino) propanoic acid 18 further the chiral isomer was resolved by using a preparative and chiral column using a Supercritical Fluid Chromatography (SFC) method ((1) chiral column ChiralPak AD, 25X 3cm, 80 mL/min; mobile phase A for CO2and B for Ethanol; or/and (2) Whelk O1(S, S), 25X 3cm, 65 mL/min; mobile phase A for CO2and B for Ethanol; or/and (3) Whelk O1(S, S), 25X 3cm, 70 mL/min; mobile phase A for CO2and B for Ethanol)) to give 18A 3- (4- ((2R, 3S) -1-oxo-2- (4- (trifluoromethoxy) phenyl-1- ((6- (trifluoromethyl) pyridin-3-yl) amino) hex-3-yl) benzoylamino) propanoic acid (white solid) and 18B 3- (4- ((2S, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl-1- ((6- (trifluoromethyl) pyridin-3-yl) amino) hex-3-yl) benzoylamino) propanoic acid (white solid).
18A：MS m/z(ESI)：694.8[M+1]
18B：MS m/z(ESI)：694.8[M+1]
Example 19
3- (4- (1- (4- (trifluoromethoxy) phenyl) -1- (2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-ylcarboxamido) pentane-2-yl) benzamido) propionic acid
3- (4- ((1R, 2R) -1- (4- (trifluoromethoxy) phenyl) -1- (2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-ylcarboxamido) pentan-2-yl) benzoylamino) propionic acid 19A
3- (4- ((1S, 2S) -1- (4- (trifluoromethoxy) phenyl) -1- (2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-ylcarboxamido) pentan-2-yl) benzoylamino) propionic acid 19B
Figure GPA0000254629200000641
Figure GPA0000254629200000651
First step of
4- (1- (4- (trifluoromethoxy) phenyl) -1- (2 ', 4, 6 ' -trimethyl- [1, 1 ' -biphenyl ] -4-ylcarboxamido) pentan-2-yl) benzoic acid tert-butyl ester
Tert-butyl 4- (1-amino-1- (4- (trifluoromethoxyphenyl) pentan-2-yl) benzoate 11b (600mg, 1.42mmol), 2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-carboxylic acid 19a (442mg, 1.84mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (723mg, 2.84mmol) and N, N-diisopropylethylamine (1.0mL, 5.68mmol) were dissolved in 12mL of a mixed solvent of dichloromethane and N, N-dimethylformamide (V/V ═ 5/1), the reaction mixture was reacted at room temperature for 18 hours, the reaction mixture was concentrated under reduced pressure, 15mL of water was added, extracted with ethyl acetate (10mL × 3), the combined organic phases were washed with water (20mL × 2), dried over anhydrous sodium sulfate, filtration and concentration under reduced pressure gave a residue which was purified by silica gel column chromatography (eluent: system a) to give tert-butyl 4- (1- (4- (trifluoromethoxy) phenyl) -1- (2 ', 4, 6 ' -trimethyl- [1, 1 ' -biphenyl ] -4-ylcarboxamido) pentan-2-yl) benzoate 19b (820mg, yellow solid) in yield: 89.4 percent.
MS m/z(ESI)：589.9[M+1-56]
Second step of
4- (1- (4- (trifluoromethoxy) phenyl) -1- (2 ', 4, 6 ' -trimethyl- [1, 1 ' -biphenyl ] -4-ylcarboxamido) pentan-2-yl) benzoic acid
Tert-butyl 4- (1- (4- (trifluoromethoxy) phenyl) -1- (2 ', 4, 6 ' -trimethyl- [1, 1 ' -biphenyl ] -4-ylcarboxamido) pentan-2-yl) benzoate 19b (820mg, 1.27mmol) and 85% phosphoric acid (1.20g, 10.2mmol) were dissolved in 12mL of acetonitrile, and the reaction was reacted at 80 ℃ for 4 hours. After the reaction solution was concentrated, 15mL of water was added, and extracted with ethyl acetate (10mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 4- (1- (4- (trifluoromethoxy) phenyl) -1- (2 ', 4, 6 ' -trimethyl- [1, 1 ' -biphenyl ] -4-ylcarboxamido) pentan-2-yl) benzoic acid 19c (750mg, white solid) in yield: 100 percent.
MS m/z(ESI)：589.9[M+1]
The third step
3- (4- (1- (4- (trifluoromethoxy) phenyl) -1- (2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-ylcarboxamido) pentan-2-yl) benzoylamino) propionic acid ethyl ester
19c (750mg, 1.27mmol) of 4- (1- (4- (trifluoromethoxy) phenyl) -1- (2 ', 4, 6 ' -trimethyl- [1, 1 ' -biphenyl ] -4-ylcarboxamido) pentan-2-yl) benzoic acid, ethyl 3-aminopropionate hydrochloride (293mg, 1.91mmol), 2- (7-azobenzotriazol) -N, N, N ', N ' -tetramethyluronium hexafluorophosphate (726mg, 1.91mmol) and N, N-diisopropylethylamine (0.90mL, 5.08mmol) were dissolved in 10mL of di-N, N-dimethylformamide, and the reaction mixture was reacted at room temperature for 4 hours. To the reaction solution, 25mL of water was added, extraction was performed with ethyl acetate (10mL × 3), the combined organic phases were washed with water (30mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system C) to obtain ethyl 3- (4- (1- (4- (trifluoromethoxy) phenyl) -1- (2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-ylcarboxamido) pentan-2-yl) benzoylamino) propionate 19d (854mg, yellow liquid), yield: 97.6 percent.
MS m/z(ESI)：688.9[M+1]
The fourth step
3- (4- (1- (4- (trifluoromethoxy) phenyl) -1- (2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-ylcarboxamido) pentane-2-yl) benzamido) propionic acid
Ethyl 3- (4- (1- (4- (trifluoromethoxy) phenyl) -1- (2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-ylcarboxamido) pentan-2-yl) benzamido) propionate 19d (854mg, 1.24mmol) and 1.20mL of a solution of lithium hydroxide monohydrate (260mg, 6.20mmol) were dissolved in 12mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1/5), and the reaction solution was reacted at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, the pH was adjusted to 2-3 with 1M hydrochloric acid, extraction was performed with ethyl acetate (10mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system C) to give 19- (4- (1- (4- (trifluoromethoxy) phenyl) -1- (2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-ylcarboxamido) pentan-2-yl) benzoylamino) propionic acid (750mg, white solid), yield: 91.7 percent.
MS m/z(ESI)：660.9[M+1]
1H NMR(400MHz，CDCl3)δ12.25(s，1H)，8.71(d，J＝8.9Hz，1H)，8.45(t，J＝5.3Hz，1H)，7.79(d，J＝8.2Hz，2H)，7.72(d，J＝8.7Hz，2H)，7.53(dd，J＝13.1，8.2Hz，4H)，7.40(d，J＝8.1Hz，2H)，7.10(d，J＝8.1Hz，2H)，6.90(s，2H)，5.33-5.25(m，1H)，3.42(dd，J＝12.6，6.9Hz，2H)，3.30-3.22(m，1H)，2.47(d，J＝7.2Hz，2H)，1.91(s，3H)，1.85(s，6H)，1.52(dd，J＝18.6，7.5Hz，1H)，1.09(dd，J＝16.2，6.6Hz，1H)，0.87(dd，J＝23.8，10.3Hz，2H)，0.63(t，J＝7.2Hz，3H).
3- (4- (1- (4- (trifluoromethoxy) phenyl) -1- (2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl)]-4-ylcarboxamido) pentan-2-yl) benzoylamino) propionic acid 19 was further resolved by using Supercritical Fluid Chromatography (SFC) method using preparative equipment and chiral column (chiral column Whelk O1(S, S), 300X 50mm I.D.10 μm, mobile phase A for CO2and B for methanol (0.1% NH3H2O) at a flow rate of 200mL/min to give 3- (4- ((1R, 2R) -1- (4- (trifluoromethoxy) phenyl) -1- (2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl)]-4-ylcarboxamido) pentan-2-yl) benzoylamino) propionic acid 19A (retention time: 4.57 min; ee value: 100%) and 3- (4- ((1S, 2S) -1- (4- (trifluoromethoxy) phenyl) -1- (2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl)]-4-ylcarboxamido) pentan-2-yl) benzathinesAmido) propionic acid 19B (retention time: 10.56 min; ee value: 100%).
19A：MS m/z(ESI)：660.9[M+1]
19B：MS m/z(ESI)：660.9[M+1]
Example 20
3- (4- (1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid
Figure GPA0000254629200000661
Figure GPA0000254629200000671
First step of
4- (1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid methyl ester
Tert-butyl 4- (1-amino-1- (4- (trifluoromethoxyphenyl) pentan-2-yl) benzoate 11b (560mg, 1.32mmol), 3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) benzoic acid 20a (340mg, 1.20mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (611mg, 2.40mmol) and N, N-diisopropylethylamine (0.84mL, 4.80mmol) were dissolved in 12mL of a mixed solvent of dichloromethane and N, N-dimethylformamide (V/V ═ 5/1), the reaction mixture was reacted at room temperature for 18 hours, after the reaction mixture was concentrated under reduced pressure, 20mL of water was added, extraction was performed with ethyl acetate (10mL × 3), the combined organic phases were washed with water (15mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system a) to give methyl 4- (1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoate 20b (260mg, white solid) in yield: 31.4 percent.
MS m/z(ESI)：633.8[M+1-56]
Second step of
4- (1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid
Methyl 4- (1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoate 20b (260mg, 0.38mmol) and 85% phosphoric acid (350mg, 3.00mmol) were dissolved in 8mL of acetonitrile, and the reaction solution was reacted at 80 ℃ for 4 hours. After the reaction solution was concentrated, 15mL of water was added, and extracted with ethyl acetate (10mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 4- (1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid 20c (240mg, pale yellow liquid), yield: 100 percent.
MS m/z(ESI)：633.8[M+1]
The third step
3- (4- (1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid ethyl ester
20c (240mg, 0.38mmol) of 4- (1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid, ethyl 3-aminopropionate hydrochloride (117mg, 0.76mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (217mg, 0.57mmol) and N, N-diisopropylethylamine (0.30mL, 1.52mmol) were dissolved in 5mL of dimethylformamide, and the reaction solution was reacted at room temperature for 4 hours. To the reaction solution, 25mL of water was added, extraction was performed with ethyl acetate (10mL × 3), the combined organic phases were washed with water (50mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system C) to obtain ethyl 3- (4- (1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzamido) propionate 20d (278mg, off-white solid), yield: 100 percent.
MS m/z(ESI)：732.9[M+1]
The fourth step
3- (4- (1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid
Ethyl 3- (4- (1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzamido) propionate 20d (278mg, 0.38mmol) and 0.40mL of a lithium hydroxide monohydrate (80mg, 1.90mmol) solution were dissolved in 6mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1/2), and the reaction solution was reacted at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, the pH was adjusted to 2-3 with 1M hydrochloric acid, extraction was performed with ethyl acetate (10mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system C) to give 20(197mg, white solid) of 3- (4- (1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzamido) propionic acid: 73.8 percent.
MS m/z(ESI)：704.9[M+1]
1H NMR(400MHz，DMSO)δ12.25(s，1H)，9.10(d，J＝8.7Hz，1H)，8.50(t，J＝5.3Hz，1H)，8.07(s，1H)，7.69(d，J＝8.1Hz，2H)，7.46(d，J＝8.5Hz，2H)，7.32(d，J＝8.2Hz，2H)，7.20(d，J＝8.1Hz，2H)，7.14(t，J＝7.5Hz，1H)，6.96(d，J＝7.4Hz，1H)，6.83(d，J＝7.2Hz，1H)，5.17-5.06(m，1H)，3.58-3.49(m，2H)，3.12-3.02(m，1H)，2.59(t，J＝6.9Hz，2H)，1.41(s，3H)，1.23(s，3H)，1.22-1.15(m，1H)，1.03-0.91(m，1H)，0.76(dd，J＝14.6，7.7Hz，2H)，0.55(t，J＝7.1Hz，3H).
Example 21
3- (4- (1- (4-cyanobenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid
Figure GPA0000254629200000681
First step of
4- (1- (4-Cyanobenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid tert-butyl ester
Tert-butyl 4- (1-amino-1- (4- (trifluoromethoxyphenyl) pentan-2-yl) benzoate 11b (423mg, 1.00mmol), 4-cyanobenzoic acid 21a (162mg, 1.10mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (510mg, 2.00mmol) and N, N-diisopropylethylamine (0.70mL, 4.00mmol) were dissolved in 12mL of a mixed solvent of dichloromethane and N, N-dimethylformamide (V/V ═ 5/1), the reaction mixture was reacted at room temperature for 18 hours, after the reaction mixture was concentrated under reduced pressure, 20mL of ethyl acetate and 20mL of water were added, the layers were separated, the aqueous phase was extracted with ethyl acetate (20mL × 3), the combined organic phases were washed with water (10mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: system a) to give tert-butyl 4- (1- (4-cyanobenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoate 21b (406mg, white solid), yield: 73.5 percent.
MS m/z(ESI)：496.9[M+1-56]
Second step of
4- (1- (4-cyanobenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid
Tert-butyl 4- (1- (4-cyanobenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoate 21b (406mg, 0.73mmol) was dissolved in 3mL of dichloromethane, 3mL of trifluoroacetic acid was added, and the reaction mixture was reacted at room temperature for 18 hours. After the reaction solution was concentrated, 20mL of ethyl acetate was added, washed with water (20mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 4- (1- (4-cyanobenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid 21c (337mg, white solid), yield: 93.0 percent.
MS m/z(ESI)：496.9[M+1]
The third step
3- (4- (1- (4-Cyanobenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid ethyl ester
21c (337mg, 0.68mmol) of 4- (1- (4-cyanobenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid, ethyl 3-aminopropionate hydrochloride (261mg, 1.70mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (432mg, 1.70mmol) and N, N-diisopropylethylamine (0.56mL, 3.39mmol) were dissolved in 9mL of dichloromethane, and the reaction mixture was reacted at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, 30mL of ethyl acetate was added, and washed with 1M hydrochloric acid solution (30mL) and water (30mL × 2) in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to obtain ethyl 3- (4- (1- (4-cyanobenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionate 21d (51mg, off-white solid), yield: 12.6 percent.
MS m/z(ESI)：595.9[M+1]
The fourth step
3- (4- (1- (4-cyanobenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid
Ethyl 3- (4- (1- (4-cyanobenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionate 21d (51mg, 0.086mmol) and 1.0mL of a solution of lithium hydroxide monohydrate (18mg, 0.428mmol) were dissolved in 5mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1/4), and the reaction mixture was reacted at room temperature for 18 hours. To the reaction solution was added 30mL of ethyl acetate, the pH was adjusted with 1M hydrochloric acid until the solution was acidic, the layers were separated, the aqueous phase was extracted with ethyl acetate (20mL), the combined organic phases were washed with water (20mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (developer: system C) to give 21- (17mg, white solid) of 3- (4- (1- (4-cyanobenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid (yield: 34.8 percent.
MS m/z(ESI)：567.9[M+1]
1H NMR(400MHz，DMSO)δ8.92(d，J＝9.1Hz，1H)，8.50(s，1H)，7.85(d，J＝8.5Hz，2H)，7.76(d，J＝7.9Hz，2H)，7.71(d，J＝8.6Hz，2H)，7.62(d，J＝8.3Hz，2H)，7.48(d，J＝8.3Hz，2H)，7.40(d，J＝8.2Hz，2H)，5.28(d，J＝1.8Hz，1H)，3.43-3.38(m，2H)，2.47-2.42(m，2H)，1.62-1.45(m，2H)，1.16-1.00(m，2H)，0.62(t，J＝7.2Hz，3H).
Example 22
3- (4- (1- (3, 5-dimethylbenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentane-2-yl) benzoylamino) propionic acid
Figure GPA0000254629200000701
First step of
4- (1- (3, 5-Dimethylbenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid tert-butyl ester
Tert-butyl 4- (1-amino-1- (4- (trifluoromethoxyphenyl) pentan-2-yl) benzoate 11b (423mg, 1.00mmol), 3, 5-dimethylbenzoic acid 22a (165mg, 1.10mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (510mg, 2.00mmol) and N, N-diisopropylethylamine (0.70mL, 4.00mmol) were dissolved in 12mL of a mixed solvent of dichloromethane and N, N-dimethylformamide (V/V ═ 5/1), the reaction mixture was reacted at room temperature for 18 hours, after the reaction mixture was concentrated under reduced pressure, 20mL of ethyl acetate and 20mL of water were added, the layers were separated, the aqueous phase was extracted with ethyl acetate (20mL × 2), the combined organic phases were washed with water (10mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent: system a) to give tert-butyl 4- (1- (3, 5-dimethylbenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoate (389mg, white solid), yield: 70.0 percent.
MS m/z(ESI)：557.0[M+1]
Second step of
4- (1- (3, 5-Dimethylbenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid
Tert-butyl 4- (1- (3, 5-dimethylbenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoate 22b (260mg, 0.38mmol) was dissolved in 3mL of dichloromethane, 3mL of trifluoroacetic acid was added, and the reaction mixture was reacted at room temperature for 18 hours. After the reaction solution was concentrated, 20mL of ethyl acetate was added, and washed with water (20mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude 4- (1- (3, 5-dimethylbenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid 22c (327mg, white liquid), yield: 93.5 percent.
MS m/z(ESI)：499.9[M+1]
The third step
3- (4- (1- (3, 5-Dimethylbenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid ethyl ester
4- (1- (3, 5-Dimethylbenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid 22c (327mg, 0.65mmol), ethyl 3-aminopropionate hydrochloride (251mg, 1.64mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (417mg, 1.64mmol) and N, N-diisopropylethylamine (0.54mL, 3.27mmol) were dissolved in 5mL of di-N, N-dimethylformamide, and the reaction solution was reacted at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, 30mL of ethyl acetate was added, and washed with 1M hydrochloric acid solution (30mL) and water (30mL × 2) in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system C) to give ethyl 3- (4- (1- (3, 5-dimethylbenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionate 22d (128mg, white solid), yield: 32.8 percent.
MS m/z(ESI)：598.9[M+1]
The fourth step
3- (4- (1- (3, 5-dimethylbenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentane-2-yl) benzoylamino) propionic acid
Ethyl 3- (4- (1- (3, 5-dimethylbenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionate 22d (128mg, 0.31mmol) and 1.0mL of a solution of lithium hydroxide monohydrate (72mg, 1.71mmol) were dissolved in 5mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1/4), and the reaction mixture was reacted at room temperature for 18 hours. The reaction was concentrated under reduced pressure, added 30mL of ethyl acetate and 10mL of water, adjusted to acidic pH with 1M hydrochloric acid, the layers were separated, the aqueous phase was extracted with ethyl acetate (20mL), the combined organic phases were washed with water (30mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 22- (4- (1- (3, 5-dimethylbenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propanoic acid (98mg, white solid) in yield: 81.8 percent.
MS m/z(ESI)：570.9[M+1]
1H NMR(400MHz，DMSO)δ8.50(s，1H)，8.46(d，J＝10.0Hz，1H)，7.78(d，J＝7.8Hz，2H)，7.70(d，J＝8.6Hz，2H)，7.48(d，J＝8.0Hz，2H)，7.39(d，J＝8.7Hz，2H)，7.03(s，1H)，6.99(s，2H)，5.21(d，J＝10.1Hz，1H)，3.46-3.38(m，2H)，2.47(d，J＝2.4Hz，2H)，2.20(s，6H)，1.59-1.46(m，2H)，1.14-0.99(m，2H)，0.63(t，J＝7.3Hz，3H).
Example 23
3- (4- (1- (5-chloropyridoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid
Figure GPA0000254629200000711
Figure GPA0000254629200000721
First step of
4- (1- (5-Chloropyrimidinamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid tert-butyl ester
Tert-butyl 4- (1-amino-1- (4- (trifluoromethoxyphenyl) pentan-2-yl) benzoate 11b (423mg, 1.00mmol), 5-chloropicolinic acid 23a (175mg, 1.10mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (510mg, 2.00mmol) and N, N-diisopropylethylamine (0.70mL, 4.00mmol) were dissolved in a mixed solvent of 10mL of dichloromethane and N, N-dimethylformamide (V/V ═ 4/1), the reaction liquid was reacted at room temperature for 18 hours, after concentrating the reaction liquid under reduced pressure, 20mL of water was added, extraction was performed with ethyl acetate (10mL × 3), the combined organic phases were washed with water (30mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a), tert-butyl 4- (1- (5-chloropyridylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoate 23b (470mg, pale yellow solid) was obtained in yield: 83.5 percent. MS m/z (ESI): 584.8[ M +23]
Second step of
4- (1- (5-Chloropyrimidinamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid
Tert-butyl 4- (1- (5-chloropyridoamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoate 23b (470mg, 0.83mmol) was dissolved in 6mL of dichloromethane, 6mL of trifluoroacetic acid was added, and the reaction mixture was reacted at 25 ℃ for 2 hours. After concentrating the reaction solution, 20mL of water was added, and extraction was performed with ethyl acetate (10 mL. times.3), and the organic phases were combined, washed with water (30 mL. times.3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 4- (1- (5-chloropyridylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid 23c (423mg, yellow liquid), yield: 100 percent.
MS m/z(ESI)：506.8[M+1]
The third step
3- (4- (1- (5-Chloropyrimidinamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid ethyl ester
23c (423mg, 0.83mmol) of 4- (1- (5-chloropyridylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid, ethyl 3-aminopropionate hydrochloride (255mg, 1.66mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (473mg, 1.24mmol) and N, N-diisopropylethylamine (0.60mL, 3.32mmol) were dissolved in 8mL of di-N, N-dimethylformamide, and the reaction solution was reacted at 25 ℃ for 3 hours. To the reaction solution, 30mL of water was added, extraction was performed with ethyl acetate (10mL × 3), the combined organic phases were washed with water (30mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system D) to obtain ethyl 3- (4- (1- (5-chloropyridylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionate 23D (340mg, white solid) in yield: 67.6 percent.
MS m/z(ESI)：605.8[M+1]
The fourth step
3- (4- (1- (5-chloropyridoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid
Ethyl 3- (4- (1- (5-chloropyridinamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzamido) propionate 23d (340mg, 0.56mmol) and 0.50mL of a solution of lithium hydroxide monohydrate (120mg, 2.80mmol) were dissolved in 8mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1/4), and the reaction mixture was reacted at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, the pH was adjusted to 2-3 with 1M hydrochloric acid, ethyl acetate (10mL × 3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system C) to obtain 3- (4- (1- (5-chloropyridoamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid 23(290mg, white solid), yield: 89.5 percent.
MS m/z(ESI)：577.8[M+1]
1H NMR(400MHz，DMSO)δ12.18(s，1H)，9.11(d，J＝9.2Hz，1H)，8.60(d，J＝2.1Hz，1H)，8.43(t，J＝5.4Hz，1H)，8.00(dd，J＝8.5，2.1Hz，1H)，7.81(d，J＝8.4Hz，1H)，7.73(t，J＝8.7Hz，4H)，7.46(d，J＝8.1Hz，2H)，7.37(d，J＝8.2Hz，2H)，5.29(t，J＝10.0Hz，1H)，3.50-3.37(m，3H)，2.47(d，J＝7.0Hz，2H)，1.52(d，J＝11.5Hz，1H)，1.15-1.04(m，1H)，0.86(dd，J＝15.7，9.5Hz，2H)，0.63(t，J＝7.2Hz，3H).
Example 24
3- (4- (1- (4-chloro-2-methylbenzamido) -1- (4- (trifluoromethoxy) phenyl) pentane-2-radical) benzamido) propionic acid
Figure GPA0000254629200000731
First step of
4- (1- (4-chloro-2-methylbenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid tert-butyl ester
Tert-butyl 4- (1-amino-1- (4- (trifluoromethoxyphenyl) pentan-2-yl) benzoate 11b (423mg, 1.00mmol), 4-chloro-2-methylbenzoic acid 24a (190mg, 1.10mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (510mg, 2.00mmol) and N, N-diisopropylethylamine (0.70mL, 4.00mmol) were dissolved in 10mL of a mixed solvent of dichloromethane and N, N-dimethylformamide (V/V ═ 4/1), the reaction liquid was reacted at room temperature for 18 hours, the reaction liquid was concentrated under reduced pressure, 20mL of water was added, extraction was performed with ethyl acetate (10mL × 3), the combined organic phases were washed with water (30mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a), tert-butyl 4- (1- (4-chloro-2-methylbenzamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoate 24b (460mg, white solid) was obtained in: 79.9 percent.
MS m/z(ESI)：597.8[M+23]
Second step of
4- (1- (4-chloro-2-methylbenzamido) -1- (4- (trifluoromethoxy) phenyl) pentane-2-yl) benzoic acid
Tert-butyl 4- (1- (4-chloro-2-methylbenzamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoate 24b (460mg, 0.80mmol) and 85% phosphoric acid (553mg, 4.80mmol) were dissolved in 5mL acetonitrile, and the reaction was reacted at 80 ℃ for 4 hours. After the reaction solution was concentrated, 20mL of water was added, and extracted with ethyl acetate (10mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude 4- (1- (4-chloro-2-methylbenzamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid 24c (416mg, yellow liquid), yield: 100 percent.
MS m/z(ESI)：519.8[M+1]
The third step
3- (4- (1- (4-chloro-2-methylbenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid ethyl ester
24c (416mg, 0.85mmol) of 4- (1- (4-chloro-2-methylbenzamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid, ethyl 3-aminopropionate hydrochloride (250mg, 1.60mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (456mg, 1.20mmol) and N, N-diisopropylethylamine (0.60mL, 3.20mmol) were dissolved in 8mL of bis-N, N-dimethylformamide and the reaction was reacted at 25 ℃ for 3 hours. The reaction solution was concentrated under reduced pressure, then 30mL of water was added, extracted with ethyl acetate (10mL × 3), and the combined organic phases were washed with water (30mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude ethyl 3- (4- (1- (4-chloro-2-methylbenzamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzamido) propionate 24d (495mg, white solid), yield: 100 percent.
MS m/z(ESI)：618.90[M+1]
The fourth step
3- (4- (1- (4-chloro-2-methylbenzamido) -1- (4- (trifluoromethoxy) phenyl) pentane-2-radical) benzamido) propionic acid
Ethyl 3- (4- (1- (4-chloro-2-methylbenzamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzamido) propionate 24d (495mg, 0.80mmol) and 0.80mL of a lithium hydroxide monohydrate (170mg, 4.00mmol) solution were dissolved in 9mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 2/7), and the reaction solution was reacted at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, pH was adjusted to 2-3 with 1M hydrochloric acid, dichloromethane (15mL × 3) was extracted, organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system C) to obtain 24- (4- (1- (4-chloro-2-methylbenzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid 24(270mg, white solid) in yield: 57.1 percent.
MS m/z(ESI)：590.8[M+1]
1H NMR(400MHz，DMSO)δ12.17(s，1H)，8.67(d，J＝9.4Hz，1H)，8.49(t，J＝5.1Hz，1H)，7.81(d，J＝8.0Hz，2H)，7.66(d，J＝8.3Hz，2H)，7.42(dd，J＝11.2，8.5Hz，4H)，7.19(s，1H)，7.15(d，J＝7.8Hz，1H)，6.70(d，J＝8.4Hz，1H)，5.29(t，J＝10.1Hz，1H)，3.46(dd，J＝11.9，6.0Hz，2H)，3.03(td，J＝9.8，1.3Hz，1H)，2.69(s，3H)，2.53(d，J＝7.6Hz，2H)，1.52(dd，J＝18.9，6.0Hz，1H)，1.12-1.02(m，1H)，0.90-0.77(m，2H)，0.61(t，J＝7.0Hz，3H).
Example 25
3- (4- (1- (2-fluoro-4- (trifluoromethyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid
Figure GPA0000254629200000741
Figure GPA0000254629200000751
First step of
4- (1- (2-fluoro-4- (trifluoromethyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid tert-butyl ester
Tert-butyl 4- (1-amino-1- (4- (trifluoromethoxyphenyl) pentan-2-yl) benzoate 11b (423mg, 1.00mmol), 2-fluoro-4- (trifluoromethyl) benzoic acid 25a (230mg, 1.10mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (510mg, 2.00mmol) and N, N-diisopropylethylamine (0.70mL, 4.00mmol) were dissolved in 10mL of a mixed solvent of dichloromethane and N, N-dimethylformamide (V/V ═ 4/1), the reaction mixture was reacted at room temperature for 18 hours, the reaction mixture was concentrated under reduced pressure, 20mL of water was added, extraction was performed with ethyl acetate (10mL × 3), the combined organic phases were washed with water (30mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: system a) to give tert-butyl 4- (1- (2-fluoro-4- (trifluoromethyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoate 25b (500mg, white solid), yield: 81.6 percent.
MS m/z(ESI)：557.8[M+1-56]
Second step of
4- (1- (2-fluoro-4- (trifluoromethyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid
Tert-butyl 4- (1- (2-fluoro-4- (trifluoromethyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoate 25b (500mg, 0.82mmol) and 85% phosphoric acid (753mg, 6.53mmol) were dissolved in 10mL of acetonitrile, and the reaction was reacted at 80 ℃ for 4 hours. After the reaction solution was concentrated, 20mL of water was added, and extracted with ethyl acetate (10mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude 4- (1- (2-fluoro-4- (trifluoromethyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid 25c (457mg, yellow solid), yield: 100 percent.
MS m/z(ESI)：557.8[M+1]
The third step
3- (4- (1- (2-fluoro-4- (trifluoromethyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid tert-butyl ester
25c (457mg, 0.82mmol) of 4- (1- (2-fluoro-4- (trifluoromethyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid, tert-butyl 3-aminopropionate hydrochloride (300mg, 1.64mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (470mg, 1.23mmol) and N, N-diisopropylethylamine (0.60mL, 3.28mmol) were dissolved in 8mL of bis-N, N-dimethylformamide, and the reaction solution was reacted at 25 ℃ for 3 hours. To the reaction mixture was added 30mL of water, extracted with ethyl acetate (15mL × 3), and the combined organic phases were washed with water (50mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude tert-butyl 3- (4- (1- (2-fluoro-4- (trifluoromethyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzamido) propionate 25d (560mg, yellow solid), yield: 100 percent.
MS m/z(ESI)：571.90[M+1]
The fourth step
3- (4- (1- (2-fluoro-4- (trifluoromethyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid
Tert-butyl 3- (4- (1- (2-fluoro-4- (trifluoromethyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionate 25d (560mg, 0.82mmol) and 85% phosphoric acid (570mg, 4.92mmol) were dissolved in 20mL acetonitrile, and the reaction was reacted at 80 ℃ for 4 hours. The reaction solution was precipitated as a large amount of solid, filtered, and the filter cake was washed with water (15mL × 2) and dichloromethane (15mL × 2) in this order, dissolved in a mixture of 20mL methanol and toluene (V/V ═ 3/1), concentrated to dryness under reduced pressure, and dried in vacuo to give 25(340mg, white solid) of 3- (4- (1- (2-fluoro-4- (trifluoromethyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid (yield: 66.0 percent.
MS m/z(ESI)：628.8[M+1]
1H NMR(400MHz，DMSO)δ12.06(d，J＝3.7Hz，1H)，8.89(d，J＝8.9Hz，1H)，8.50(t，J＝5.5Hz，1H)，7.80(d，J＝8.1Hz，2H)，7.70(d，J＝9.4Hz，1H)，7.64(d，J＝8.6Hz，2H)，7.53(d，J＝8.0Hz，1H)，7.48-7.34(m，4H)，7.15(t，J＝7.3Hz，1H)，5.31(t，J＝9.8Hz，1H)，3.46(dd，J＝12.6，6.7Hz，2H)，3.08(td，J＝10.9，2.5Hz，1H)，2.57-2.52(m，2H)，1.64-1.48(m，1H)，1.18-1.05(m，1H)，0.97-0.77(m，2H)，0.62(t，J＝7.2Hz，3H).
Example 26
3- (4- (1- (isonicotinamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid
Figure GPA0000254629200000761
First step of
4- (1- (Isonicotinoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid tert-butyl ester
Tert-butyl 4- (1-amino-1- (4- (trifluoromethoxyphenyl) pentan-2-yl) benzoate 11b (423mg, 1.00mmol), isonicotinic acid 26a (150mg, 1.20mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (510mg, 2.00mmol) and N, N-diisopropylethylamine (0.70mL, 4.00mmol) were dissolved in a mixed solvent of 11mL of dichloromethane and N, N-dimethylformamide (V/V ═ 8/3), the reaction mixture was reacted at room temperature for 18 hours, the reaction mixture was concentrated under reduced pressure, 20mL of water was added, extraction was performed with ethyl acetate (10mL × 3), the combined organic phases were washed with water (30mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system a), tert-butyl 4- (1- (isonicotinamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoate 26b (450mg, yellow solid) was obtained in: 85.2 percent.
MS m/z(ESI)：528.9[M+1]
Second step of
4- (1- (isonicotinamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid
Tert-butyl 4- (1- (isonicotinamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoate 26b (450mg, 0.85mmol) and 4mL of trifluoroacetic acid were dissolved in 4mL of dichloromethane, and the reaction mixture was reacted at 25 ℃ for 2 hours. After the reaction mixture was concentrated, 20mL of water was added, and extracted with ethyl acetate (10mL × 3), and the organic phases were combined, washed with water (30mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 26c (400mg, yellow solid) of 4- (1- (isonicotinamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid, yield: 100 percent.
MS m/z(ESI)：472.9[M+1]
The third step
3- (4- (1- (isonicotinamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid ethyl ester
26c (400mg, 0.85mmol) of 4- (1- (isonicotinamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid, ethyl 3-aminopropionate hydrochloride (261mg, 1.70mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (485mg, 1.28mmol) and N, N-diisopropylethylamine (0.60mL, 3.40mmol) were dissolved in 8mL of di-N, N-dimethylformamide and the reaction was reacted at 25 ℃ for 4 hours. The reaction was concentrated under reduced pressure, then 30mL of water was added, extracted with ethyl acetate (15mL × 3), and the combined organic phases were washed with water (50mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude ethyl 3- (4- (1- (isonicotinamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzamido) propionate 26d (485mg, white solid), yield: 100 percent.
MS m/z(ESI)：571.90[M+1]
The fourth step
3- (4- (1- (isonicotinamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid
Ethyl 3- (4- (1- (isonicotinamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionate 26d (485mg, 0.85mmol) and 0.80mL of a solution of lithium hydroxide monohydrate (180mg, 4.25mmol) were dissolved in 12mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1/5), and the reaction mixture was reacted at 25 ℃ for 4 hours. The reaction mixture was concentrated under reduced pressure, the pH was adjusted to 2-3 with 1M hydrochloric acid, a large amount of solid was precipitated, filtered, the cake was washed with water (15mL × 2) and dichloromethane (15mL × 2) in this order, dissolved in 20mL of a mixture of methanol and toluene (V/V ═ 3/1), concentrated to dryness under reduced pressure, and dried under vacuum to give 3- (4- (1- (isonicotinamido) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid 26(350mg, white solid), yield: 75.8 percent.
MS m/z(ESI)：543.8[M+1]
1H NMR(400MHz，DMSO)δ12.26(s，1H)，8.95(d，J＝8.3Hz，1H)，8.62(d，J＝5.5Hz，2H)，8.46(t，J＝5.1Hz，1H)，7.77(d，J＝7.9Hz，2H)，7.71(d，J＝8.2Hz，2H)，7.49(d，J＝8.3Hz，2H)，7.40(t，J＝5.8Hz，4H)，5.32-5.22(m，1H)，3.42(dd，J＝12.1，5.9Hz，2H)，3.21(t，J＝11.2Hz，1H)，2.46(d，J＝4.5Hz，2H)，1.55(dd，J＝20.5，8.8Hz，1H)，1.08(dd，J＝19.2，7.6Hz，1H)，0.88(dt，J＝15.7，6.5Hz，2H)，0.63(t，J＝7.2Hz，3H).
Example 27
3- (4- (1- (tert-butyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid 27
Figure GPA0000254629200000781
First step of
4- (1- (tert-butyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid tert-butyl ester
Tert-butyl 4- (1-amino-1- (4- (trifluoromethoxyphenyl) pentan-2-yl) benzoate 11b (423mg, 1.00mmol), 4- (tert-butyl) benzoic acid 27a (215mg, 1.20mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (510mg, 2.00mmol) and N, N-diisopropylethylamine (0.70mL, 4.00mmol) were dissolved in 10mL of a mixed solvent of dichloromethane and N, N-dimethylformamide (V/V ═ 4/1), the reaction mixture was reacted at room temperature for 18 hours, after the reaction mixture was concentrated under reduced pressure, 20mL of water was added, extraction was performed with ethyl acetate (10mL × 3), the combined organic phases were washed with water (30mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a), tert-butyl 4- (1- (tert-butyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoate 27b (260mg, yellow solid) was obtained, yield: 68.6 percent. MS m/z (ESI): 527.9[ M +1-56]
Second step of
4- (1- (tert-butyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid
Tert-butyl 4- (1- (tert-butyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoate 27b (400mg, 0.68mmol) and 4mL of trifluoroacetic acid were dissolved in 4mL of dichloromethane, and the reaction mixture was reacted at 25 ℃ for 2 hours. After the reaction solution was concentrated, 30mL of water was added, and extracted with ethyl acetate (10mL × 3), and the organic phases were combined, washed with water (30mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 4- (1- (tert-butyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid 27c (362mg, yellow liquid), yield: 100 percent.
MS m/z(ESI)：527.9[M+1]
The third step
3- (4- (1- (tert-butyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid ethyl ester
27c (362mg, 0.68mmol) of 4- (1- (tert-butyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoic acid, ethyl 3-aminopropionate hydrochloride (210mg, 1.36mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (390mg, 1.02mmol) and N, N-diisopropylethylamine (0.50mL, 2.72mmol) were dissolved in 6mL of di-N, N-dimethylformamide, and the reaction mixture was reacted at room temperature for 4 hours. To the reaction solution was added 25mL of water, extracted with ethyl acetate (10mL × 3), the combined organic phases were washed with water (30mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system C) to give ethyl 3- (4- (1- (tert-butyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionate 27d (170mg, white solid) in yield: 39.9 percent.
MS m/z(ESI)：627.0[M+1]
The fourth step
3- (4- (1- (tert-butyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid
Ethyl 3- (4- (1- (tert-butyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionate 27d (170mg, 0.27mmol) and 0.30mL of lithium hydroxide monohydrate (60mg, 1.40mmol) were dissolved in 8mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 3/1), and the reaction mixture was reacted at 25 ℃ for 4 hours. The reaction solution was concentrated under reduced pressure, the pH was adjusted to 2-3 with 1M hydrochloric acid, extraction was performed with ethyl acetate (10mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system C) to obtain 27(110mg, white solid) of 3- (4- (1- (tert-butyl) benzoylamino) -1- (4- (trifluoromethoxy) phenyl) pentan-2-yl) benzoylamino) propionic acid (yield: 68.3 percent.
MS m/z(ESI)：598.9[M+1]
1H NMR(400MHz，DMSO)δ12.20(s，1H)，8.55(d，J＝8.8Hz，1H)，8.45(t，J＝5.3Hz，1H)，7.76(d，J＝8.1Hz，2H)，7.70(d，J＝8.5Hz，2H)，7.48(d，J＝8.1Hz，2H)，7.45-7.29(m，6H)，5.29-5.19(m，1H)，3.41(dd，J＝12.8，7.0Hz，2H)，3.27-3.16(m，1H)，2.47(d，J＝7.1Hz，2H)，1.52(dd，J＝17.2，5.5Hz，1H)，1.25(s，9H)，1.07(dd，J＝15.6，8.9Hz，1H)，0.93-0.78(m，2H)，0.62(t，J＝7.2Hz，3H).
Example 28
3- (4- ((2R, 3R)/(2S, 3S) -1- ((3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-en-3-yl) benzoylamino) propanoic acid 28
3- (4- ((2R, 3R) -1- ((3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 28A
3- (4- ((2S, 3S) -1- ((3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 28B
Figure GPA0000254629200000791
Figure GPA0000254629200000801
First step of
3- (4- ((2R, 3R)/(2S, 3S) -1- ((3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-ane-3-yl) benzoylamino) propionic acid ethyl ester
((2R, 3R)/(2S, 3S)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoic acid 1S (82.0g, 165.5mmol), 3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-amine 4c (37.9g, 165.5mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (83.8g, 329.8mmol) were dissolved in 820mL of dichloromethane and N, N-diisopropylethylamine (145.7mL, 827.7mmol) was added with stirring and stirred at room temperature for 18 h. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give ethyl 3- (4- ((2R, 3R)/(2S, 3S) -1- ((3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionate 28a (110.0g, white solid), yield: 94.0 percent.
MS m/z(ESI)：706.9[M+1]
Second step of
3- (4- ((2R, 3R)/(2S, 3S) -1- ((3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-en-3-yl) benzoylamino) propanoic acid
Ethyl 3- (4- ((2R, 3R)/(2S, 3S) -1- ((3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hexan-3-yl) benzamido) propionate 28a (110.0g, 155.6mmol) was dissolved in 1200mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1: 1), and 65mL of a solution of lithium hydroxide monohydrate (65.0g, 1.56mol) was added with stirring and stirred at room temperature for 2 hours. 1000mL of ethyl acetate was added, washed with 1M dilute hydrochloric acid (1500mL) and then with a saturated ammonium chloride solution (1000mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to give 3- (4- ((2R, 3R)/(2S, 3S) -1- ((3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionic acid 28(82.0g, white solid), yield: 77.7 percent.
MS m/z(ESI)：678.9[M+1]
3- (4- ((2R, 3R)/(2S, 3S) -1- ((3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl)]-4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionic acid 28 was further resolved by using a preparative instrument and a chiral column on a chiral isomer by using a Supercritical Fluid Chromatography (SFC) method further by (1) chiral column ChiralPak AD, 25 × 3cm, 80 mL/min; mobile phase A for CO2and B for Ethanol; or/and (2) Whelk O1(S, S), 25X 3cm, 65 mL/min; mobile phase A for CO2and B for Ethanol; or/and (3) Whelk O1(S, S), 25X 3cm, 70 mL/min; mobile phase A for CO2and B for Ethanol)) to obtain 3- (4- ((2R, 3R) -1- ((3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl)]-4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 28A and 3- (4- ((2S, 3S) -1- ((3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl)]-4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionic acid 28B.
28A：MS m/z(ESI)：678.9[M+1]
1H NMR(400MHz，DMSO-d6)δ＝10.17(s，1H)，8.44-8.32(m，1H)，8.01(t，J＝8.3Hz，1H)，7.70-7.57(m，2H)，7.42(d，J＝8.5Hz，2H)，7.24-7.10(m，4H)，7.06(d，J＝11.8Hz，1H)，6.97-6.84(m，3H)，4.40(d，J＝11.3Hz，1H)，3.56-3.33(m，4H)，2.30-2.18(m，3H)，2.03-1.85(m，6H)，1.74(d，J＝15.6Hz，2H)，1.14-0.93(m，4H)，0.88-0.72(m，3H).
28B：MS m/z(ESI)：678.9[M+1]
1H NMR(400MHz，DMSO-d6)δ＝9.81(s，1H)，8.08-7.96(m，1H)，7.65(t，J＝8.3Hz，1H)，7.34-7.21(m，2H)，7.06(d，J＝8.5Hz，2H)，6.88-6.74(m，4H)，6.71(d，J＝11.8Hz，1H)，6.61-6.48(m，3H)，4.04(d，J＝11.3Hz，1H)，3.20-2.97(m，4H)，2.28-2.08(m，3H)，2.01-1.80(m，6H)，1.54(d，J＝15.6Hz，2H)，1.11-0.92(m，4H)，0.87-0.72(m，3H).
Example 29
3- (4- ((2R, 3R)/(2S, 3S) -1- ((4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 29
3- (4- ((2R, 3R) -1- ((4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 29A
3- (4- ((2S, 3S) -1- ((4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 29B
Figure GPA0000254629200000811
First step of
3- (4- ((2R, 3R)/(2S, 3S) -1- ((4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionic acid ethyl ester
((2R, 3R)/(2S, 3S)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoic acid 1S (80mg, 0.16mmol), 4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl ] -4-amine 1N (52mg, 0.24mmol), 1-hydroxybenzotriazole (43mg, 0.32mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (61mg, 0.32mmol) were dissolved in 20mL of dichloromethane and N, N-diisopropylethylamine (0.14mL, 0.8mmol) was added with stirring and stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give ethyl 3- (4- ((2R, 3R)/(2S, 3S) -1- ((4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-ane-3-yl) benzoylamino) propionate 29a (58mg, white solid), yield: 51.8 percent.
MS m/z(ESI)：695.8[M+1]
Second step of
3- (4- ((2R, 3R)/(2S, 3S) -1- ((4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid
Ethyl 3- (4- ((2R, 3R)/(2S, 3S) -1- ((4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoate 29a (58mg, 0.083mmol) was dissolved in 6mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1: 1), and 1mL of a solution of sodium hydroxide (17mg, 0.42mmol) was added with stirring and stirred at room temperature for 3 hours. The reaction was concentrated under reduced pressure, extracted with ethyl acetate (50mL), and the combined organic phases were washed with saturated ammonium chloride (50mL) and sodium chloride solution (50mL) in that order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3- (4- ((2R, 3R)/(2S, 3S) -1- ((4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl ] -4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionic acid 29(40m g, white solid), yield: 71.0 percent.
MS m/z(ESI)：667.8[M+1]
1H NMR(400MHz，DMSO-d6)δ10.46(s，1H)，8.37(br.s.，1H)，7.68(s，2H)，7.65-7.60(m，2H)，7.43-7.35(m，3H)，7.28(d，J＝8.0Hz，3H)，7.18(d，J＝8.0Hz，2H)，7.13(s，3H)，4.09(d，J＝11.3Hz，1H)，2.46(br.s.，2H)，2.22(s，3H)，1.73(br.s.，1H)，1.31-1.15(m，2H)，1.08-0.94(m，2H)，0.88-0.72(m，2H)，0.90-0.69(m，3H).
3- (4- ((2R, 3R)/(2S, 3S) -1- ((4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl)]-4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionic acid 29 was further prepared by resolving chiral isomers using a preparative instrument and a chiral column using Supercritical Fluid Chromatography (SFC) method ((1) chiral column ChiralPak AD, 25 × 3cm, 80 mL/min; mobile phase A for CO2and B for Ethanol; or/and (2) Whelk O1(S, S), 25X 3cm, 65 mL/min; mobile phase A for CO2and B for Ethanol; or/and (3) Whelk O1(S, S), 25X 3cm, 70 mL/min; mobile phase A for CO2and B for Ethanol)) to obtain 3- (4- ((2R, 3R) -1- ((4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl)]-4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propanoic acid 29A and 3- (4- ((2S, 3S) -1- ((4 ' -chloro-2 ' -methyl- [1, 1 ' -biphenyl)]-4-yl) amino) -1-oxo-2- (4- (trifluoromethoxy) phenyl) hex-3-yl) benzoylamino) propionic acid 29B.
29A：MS m/z(ESI)：667.8[M+1]
29B：MS m/z(ESI)：667.8[M+1]
Example 30
3- (4- ((2R, 3R)/(2S, 3S) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) hex-3-yl) benzoylamino) propanoic acid 30
3- (4- ((2R, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) hex-3-yl) benzoylamino) propanoic acid 30A
3- (4- ((2S, 3S) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) hex-3-yl) benzoylamino) propanoic acid 30B
Figure GPA0000254629200000831
First step of
3- (4- ((2R, 3R)/(2S, 3S) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) hex-3-yl) benzoylamino) propionic acid ethyl ester
((2R, 3R)/(2S, 3S)) -3- (4- ((3-ethoxy-3-oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hexanoic acid 1S (80mg, 0.16mmol), 2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-amine 2a (63.4mg, 0.3mmol), 1-hydroxybenzotriazole (40.5mg, 0.3mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (49.8mg, 0.26mmol) were dissolved in 10mL of dichloromethane and N, N-diisopropylethylamine (0.09mL, 0.5mmol) was added with stirring and stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to obtain ethyl 3- (4- ((2R, 3R)/(2S, 3S) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) hex-3-yl) benzoylamino) propionate 30a (50mg, white solid), yield: 45.4 percent.
MS m/z(ESI)：690.0[M+1]
Second step of
3- (4- ((2R, 3R)/(2S, 3S) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) hex-3-yl) benzoylamino) propanoic acid
Ethyl 3- (4- ((2R, 3R)/(2S, 3S) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) hex-3-yl) benzoylamino) propanoate 30a (50mg, 0.072mmol) was dissolved in 6mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1: 1), and 1mL of a solution of sodium hydroxide (14.4mg, 0.36mmol) was added with stirring and stirred at room temperature for 3 hours. The reaction was concentrated under reduced pressure, extracted with ethyl acetate (30mL), the combined organic phases were washed with ammonium chloride solution (30mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (developing solvent: system a) to give 30(17mg, white solid) of 3- (4- ((2R, 3R)/(2S, 3S) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-yl) amino) hex-3-yl) benzoylamino) propanoic acid (yield: 29.4 percent. MS m/z (ESI): 661.9[ M +1]
1H NMR(400MHz，DMSO)δ10.42(s，1H)，8.37(s，1H)，7.68(d，J＝8.1Hz，2H)，7.63(d，J＝7.5Hz，2H)，7.40(d，J＝8.6Hz，2H)，7.18(d，J＝7.9Hz，2H)，7.13(d，J＝8.3Hz，2H)，7.04(d，J＝8.3Hz，2H)，6.90(s，2H)，4.10(d，J＝11.1Hz，1H)，3.63(t，J＝6.9Hz，2H)，3.51-3.43(m，1H)，2.47(s，3H)，2.25(s，3H)，1.92(s，6H)，1.80-1.68(m，2H)，1.06-0.97(m，2H)，0.79(t，J＝7.2Hz，3H).
3- (4- ((2R, 3R)/(2S, 3S) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl)]-4-yl) amino) hex-3-yl) benzoylamino) propionic acid 30 was further prepared by using a preparation apparatus and a chiral column to resolve chiral isomers using a Supercritical Fluid Chromatography (SFC) method ((1) chiral column ChiralPak AD, 25 × 3cm, 80 mL/min; mobile phase A for CO2and B for Ethanol; or/and (2) Whelk O1(S, S), 25X 3cm, 65 mL/min; mobile phase A for CO2and B for Ethanol; or/and (3) Whelk O1(S, S), 25X 3cm, 70 mL/min; mobile phase A for CO2and B for Ethanol)) to obtain 3- (4- ((2R, 3R) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl)]-4-yl) amino) hex-3-yl) benzoylamino) propionic acid 30A and 3- (4- ((2S, 3S) -1-oxo-2- (4- (trifluoromethoxy) phenyl) -1- ((2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl]-4-yl) amino) hex-3-yl) benzoylamino) propanoic acid 30B.
30A：MS m/z(ESI)：661.9[M+1]
30B：MS m/z(ESI)：661.9[M+1]
Example 31
3- (4- (1- (3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-ylcarboxamido) -1- (4- (trifluoromethoxy) phenyl) -pentan-2-yl) benzoylamino) propionic acid
3- (4- ((1R, 2R) -1- (3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-ylcarboxamido) -1- (4- (trifluoromethoxy) phenyl) -pentan-2-yl) benzoylamino) propionic acid 31A
3- (4- ((1S, 2S) -1- (3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-ylcarboxamido) -1- (4- (trifluoromethoxy) phenyl) -pentan-2-yl) benzoylamino) propionic acid 31B
Figure GPA0000254629200000841
Figure GPA0000254629200000851
First step of
4- (1- (3-fluoro-2 ', 4, 6 ' -trimethyl- [1, 1 ' -biphenyl ] -4-ylcarboxamido) -1- (4- (trifluoromethoxy) phenyl) -pentan-2-yl) benzoic acid tert-butyl ester
Tert-butyl 4- (1-amino-1- (4- (trifluoromethoxyphenyl) pentan-2-yl) benzoate 11b (5.50g, 13.0mmol), 3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-carboxylic acid 31a (3.95g, 15.3mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (6.00g, 23.6mmol) and N, N-diisopropylethylamine (8.2mL, 47.2mmol) were dissolved in 60mL of a mixed solvent of dichloromethane and N, N-dimethylformamide (V/V ═ 5/1), the reaction mixture was reacted at 30 ℃ for 18 hours, after concentrating the reaction mixture under reduced pressure, 50mL of water was added, extraction was performed with ethyl acetate (25mL × 3), the combined organic phases were washed with water (50mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give tert-butyl 4- (1- (3-fluoro 2 ', 4, 6 ' -trimethyl- [1, 1 ' -biphenyl ] -4-ylcarboxamido) -1- (4- (trifluoromethoxy) phenyl) -pentan-2-yl) benzoate 31b (7.13g, light yellow solid), yield: 82.8 percent.
MS m/z(ESI)：607.9[M+1-56]
Second step of
4- (1- (3-fluoro-2 ', 4, 6 ' -trimethyl- [1, 1 ' -biphenyl ] -4-ylcarboxamido) -1- (4- (trifluoromethoxy) phenyl) -pentan-2-yl) benzoic acid
Tert-butyl 4- (1- (3-fluoro-2 ', 4, 6 ' -trimethyl- [1, 1 ' -biphenyl ] -4-ylcarboxamido) -1- (4- (trifluoromethoxy) phenyl) -pentan-2-yl) benzoate 31b (7.13g, 10.7mmol) and 85% phosphoric acid (4.5mL, 66.0mmol) were dissolved in 50mL acetonitrile, and the reaction was reacted at 80 ℃ for 4 hours. After the reaction solution was concentrated, 50mL of water was added, and extracted with ethyl acetate (25mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude 4- (1- (3-fluoro-2 ', 4, 6 ' -trimethyl- [1, 1 ' -biphenyl ] -4-ylcarboxamido) -1- (4- (trifluoromethoxy) phenyl) -pentan-2-yl) benzoic acid 31c (6.50g, yellow solid), yield: 100 percent.
MS m/z(ESI)：607.9[M+1]
The third step
3- (4- (1- (3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-ylcarboxamido) -1- (4- (trifluoromethoxy) phenyl) -pentan-2-yl) benzoylamino) propionic acid ethyl ester
31c (6.50g, 10.7mmol) of 4- (1- (3-fluoro-2 ', 4, 6 ' -trimethyl- [1, 1 ' -biphenyl ] -4-ylcarboxamido) -1- (4- (trifluoromethoxy) phenyl) -pentan-2-yl) benzoic acid, tert-butyl 3-aminopropionate hydrochloride (3.90g, 21.4mmol), 2- (7-azobenzotriazol) -N, N, N ', N ' -tetramethylurea hexafluorophosphate (6.10g, 16.1mmol) and N, N-diisopropylethylamine (7.50mL, 42.8mmol) were dissolved in 60mL of di-N, N-dimethylformamide and the reaction mixture was reacted at 25 ℃ for 3 hours. To the reaction solution was added 250mL of water, extracted with ethyl acetate (80mL × 3), the organic phases were combined, washed with water (300mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol system) to give ethyl 3- (4- (1- (3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-ylcarboxamido) -1- (4- (trifluoromethoxy) phenyl) -pentan-2-yl) benzoylamino) propionate 31d (7.86g, yellow solid), yield: 100 percent.
MS m/z(ESI)：678.9[M+1-56]
The fourth step
3- (4- (1- (3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-ylcarboxamido) -1- (4- (trifluoromethoxy) phenyl) -pentan-2-yl) benzoylamino) propionic acid
Ethyl 3- (4- (1- (3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-ylcarboxamido) -1- (4- (trifluoromethoxy) phenyl) -pentan-2-yl) benzoylamino) propionate 31d (7.86g, 10.7mmol) and 85% phosphoric acid (4.5mL, 64.2mmol) were dissolved in 100mL acetonitrile and the reaction was reacted at 80 ℃ for 4 hours. The reaction was concentrated, pH was adjusted to 3 with 3M hydrochloric acid, extracted with ethyl acetate (40mL × 3), and the combined organic phases were washed with water (120mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 31- (4- (1- (3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl ] -4-ylcarboxamido) -1- (4- (trifluoromethoxy) phenyl) -pentan-2-yl) benzoylamino) propionic acid (7.10g, light yellow solid), yield: 97.8 percent.
MS m/z(ESI)：678.9[M+1]
1H NMR(400MHz，CDCl3)δ7.98(t，J＝7.8Hz，1H)，7.72(d，J＝6.7Hz，2H)，7.27(d，J＝5.0Hz，2H)，7.21(d，J＝6.2Hz，2H)，7.17(d，J＝7.9Hz，2H)，7.13-7.04(m，1H)，6.98(d，J＝7.7Hz，1H)，6.91(d，J＝3.2Hz，2H)，6.87(d，J＝12.7Hz，2H)，5.48(t，J＝6.2Hz，1H)，3.73(q，J＝7.0Hz，2H)，3.10(s，1H)，2.31(s，3H)，1.98(s，3H)，1.92(s，3H)，1.66(ddd，J＝30.3，11.0，4.5Hz，2H)，1.24(t，J＝7.0Hz，2H)，1.14(dd，J＝14.4，7.1Hz，2H)，0.79(t，J＝7.1Hz，3H).
3- (4- (1- (3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl)]-4-ylcarboxamido) -1- (4- (trifluoromethoxy) phenyl) -pentan-2-yl) benzoylamino) propionic acid 31 was further resolved by using Supercritical Fluid Chromatography (SFC) method with preparative equipment and chiral column (chiral column Whelk O1(S, S), 250 × 4.6mm i.d., mobile phase a for CO2and B for Ethanol；A for CO2and B (50%) for Methanol (0.05% DEA)) to give 3- (4- ((1R, 2R) -1- (3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl)]-4-ylcarboxamido) -1- (4- (trifluoromethoxy) phenyl) -pentan-2-yl) benzoylamino) propionic acid 31A (retention time: 4.95 mim; ee value: 100%) and 3- (4- ((1S, 2S) -1- (3-fluoro-2 ', 4', 6 '-trimethyl- [1, 1' -biphenyl)]-4-ylcarboxamido) -1- (4- (trifluoromethoxy) phenyl) -pentan-2-yl) benzoylamino) propionic acid 31B (retention time: 11.28 min; ee value: 100%).
31A：MS m/z(ESI)：678.9[M+1]
1H NMR(400MHz，DMSO)δ12.19(s，1H)，8.69(d，J＝8.6Hz，1H)，8.49(t，J＝5.2Hz，1H)，7.82(d，J＝8.1Hz，2H)，7.69(d，J＝8.5Hz，2H)，7.47(d，J＝8.1Hz，2H)，7.39(d，J＝8.1Hz，2H)，7.13(t，J＝7.7Hz，1H)，6.96(d，J＝10.9Hz，1H)，6.89(m，3H)，5.31(t，J＝9.7Hz，1H)，3.45(dd，J＝12.4，6.7Hz，2H)，3.17(t，J＝9.3Hz，1H)，2.52(d，J＝7.1Hz，3H)，2.24(s，3H)，1.88(d，J＝2.0Hz，7H)，1.54(d，J＝10.1Hz，1H)，1.12(d，J＝6.9Hz，1H)，0.86(m，2H)，0.63(t，J＝7.2Hz，3H).
31B：MS m/z(ESI)：678.9[M+1]
1H NMR(400MHz，DMSO)δ12.21(s，1H)，8.68(d，J＝8.7Hz，1H)，8.49(t，J＝5.3Hz，1H)，7.82(d，J＝8.1Hz，2H)，7.69(d，J＝8.5Hz，2H)，7.47(d，J＝8.1Hz，2H)，7.39(d，J＝8.1Hz，2H)，7.13(t，J＝7.7Hz，1H)，6.96(d，J＝10.9Hz，1H)，6.89(m，3H)，5.31(t，J＝9.7Hz，1H)，3.45(dd，J＝12.6Hz，6.8Hz，2H)，3.17(dd，J＝10.9Hz，7.8Hz，1H)，2.51(s，2H)，2.24(s，3H)，1.88(d，J＝2.3Hz，6H)，1.54(d，J＝10.6Hz，1H)，1.12(d，J＝7.2Hz，1H)，0.88(m，2H)，0.63(t，J＝7.2Hz，3H).
Biological evaluation
Test example 1 inhibition of glucagon-induced intracellular cAMP production by Compounds of the present invention
The method takes a HEK293 cell strain (purchased from cell resource center of Shanghai Life sciences research institute of Chinese academy of sciences) with high expression of human glucagon receptor (hGCGR) as a test model to test the antagonism of the tested compound on the glucagon receptor at the cell level.
HEK293-hGCGR cells were supplemented with 10% fetal bovine serum (FBS, GIBCO cat # 10099141) in F12 medium (Invitrogen cat #11765047) at 37 deg.C, 5% CO2Culturing is carried out under the conditions. For the experiments, cells were seeded at 3000 cells/well in 384 well cell culture plates (OptiPlate-384, white, PerkinElmer cat # 6007290). Compounds were first dissolved in DMSO and then diluted in a gradient to the desired assay concentration, with 10 concentration points for each compound, 50. mu.M, 16.7. mu.M, 5.56. mu.M, 1.85. mu.M, 0.62. mu.M, 0.21. mu.M, 69nM, 23nM, 7.5nM and 2.5nM, respectively. After the cells were administered with the compound, the cells were stimulated with glucagon (Sigma, 0.05nM) and incubated at room temperature for 1 hour. The assay was then incubated for 1 hour at room temperature following the addition of the detection solution as indicated by the Lance cAMP384 Kit (Perkinelmer, cat # AD0263) protocolIntracellular cyclic adenosine monophosphate (cAMP) levels were determined. The extent of inhibition of cAMP production by the test compound at each concentration was determined by comparison with cAMP levels in blank control cells, and then IC of the compound was calculated by plotting the log concentration of the compound (log value of the compound concentration) -inhibition level (inhibition rate) as the dose-effect curve and performing non-linear regression analysis50The value is obtained. Similar methods are applicable to testing cell lines that highly express the human glucagon-like peptide 1 receptor (hGLP-1R) and Gastrin Inhibitory Peptide Receptor (GIPR) to determine the selectivity of compounds for GCGR.
IC for GCGR inhibition by preferred compounds of the invention50The values are shown in Table 1.
TABLE 1 IC for GCGR inhibition by preferred compounds of the invention50Value of
Compound numbering IC50(nM)
4 135
4A 52
4B 166
5 206
11 210
12 98
15 137
16 143
17 134
19 199
19A 120
19B 180
23 231
25 151
28A 42
28B 97
31A 54
31B 88
And (4) conclusion: preferred compounds of the invention have significant inhibitory effects on GCGR.
Test example 2 pharmacokinetic testing of Compound 4A and Compound 4B of the invention
1. Abstract
SD rats are used as test animals, after the compounds 4A and 4B are measured by an LC/MS/MS method, the drug concentrations in blood plasma of the rats at different times are measured, and the pharmacokinetic characteristics of the compounds in the rats are researched.
2. Experimental protocol
2.1 Experimental drugs and animals
Compound 4A and compound 4B; healthy adult SD male rats 6 purchased from viton laboratory animal technology ltd, production license number: 11400700109943.
2.2 drug formulation and administration
Weighing 3mg of experimental medicine, adding 1mL of ethanol, performing ultrasonic treatment to obtain a solution, adding 1.5mL of PEG400 and 2.5mL of water, and performing vortex mixing to prepare 0.6 mg/mL;
healthy adult SD male rats 6 were individually gavaged after overnight fasting at a dose of 3 mg/kg.
2.3 sample Collection
The throat vein blood was collected at 0.15mL before and 15 min, 30 min, 1 hr, 2 hr, 4 hr, 8 hr, 12 hr and 24 hr after administration, placed in heparinized tubes, 5500 rpm, centrifuged for 10 min, stored at-30 deg.C, and fed 4 hr after administration.
2.4 sample treatment
Plasma sample processing (For plasma samples):
a20. mu.L sample was taken and IS (containing verapamil 5 ng. mL) was added-1And glibenclamide 50 ng/mL-1) And then 70. mu.L of the supernatant was added to 70. mu.L of water, and the mixture was vortex-mixed for 10 minutes, and 10. mu.L of the supernatant of the mixture was transferred to an LC-MS/MS system for analysis.
Dosing sample treatment (For dose sample):
the dosing samples were taken with methanol and water (1: 1, v/v)) The mixed solvent of (1) is diluted to a concentration of 100 ng/mL-1100. mu.L of the diluted sample and 100. mu.L of an internal standard solution (100 ng. mL) were taken-1) Add 500. mu.L of IS solution and 600. mu.L of water, vortex mix and take the supernatant of 10. mu.L of the mixture to the LC-MS/MS system for analysis.
3. Pharmacokinetic parameter results
The pharmacokinetic parameters of preferred compounds of the invention are shown in table 1.
TABLE 2 pharmacokinetic data for Compound 4A and Compound 4B
Figure GPA0000254629200000881
And (4) conclusion: preferred compounds 4A and 4B of the present invention have better pharmacokinetic properties.
Test example 3 Effect of a Single oral administration of the Compound of the present invention on random blood glucose in db/db mice
Purpose of experiment
Observing the influence of the preferred compound of the invention on the random blood sugar of db/db mice with type II diabetes after single oral administration, adopting a tail blood sampling method, and measuring the blood sugar value by a portable glucometer so as to evaluate the in-vivo blood sugar reduction effect of the tested compound.
Test animal
Male db/db mice, 42, 9-10 weeks, were provided by the university of Nanjing model animal institute, license number: SCXK (Su) 2010-0001, and a positive control group and a solvent control group are set.
Test article
3- (4- ((1R, 2S) -1- (5-chloro-7-fluoro-1H-indol-3-yl) -1- (4- (trifluoromethoxy) phenyl) pent-2-yl) benzamido) propanoic acid (FORM1) disclosed in compounds 4, 4A, 5, 19, 23, 25 and 28A, WO20150662521, formulated at the desired concentrations with ethanol: PEG 400: water ═ 20: 30: 50.
Mode of administration
The oral administration is carried out by intragastric administration, and ethanol, PEG400 and water with the same volume are infused into a blank control group with the volume of 10ml/kg and the administration dose of 30mg/kg in proportion to 20: 30: 50.
Test method
Male db/db mice, grouped by non-fasting blood glucose and body weight, were 6 mice per group, solvent control and different compound dosing groups. The animals in each group are respectively orally administered with the tested drug and the solvent once, the tail blood sugar value detection is carried out respectively at 1h, 2h, 4h, 6h, 8h, 12h and 24h before and after the administration, the blood sugar reducing effect and the maintaining time of the tested object are observed, and a 24-hour blood sugar curve is drawn. The blood glucose modulating effect of the compounds was determined by comparison with blood glucose in db/db mice given vehicle control alone.
Results of the experiment
The blood glucose lowering rates of preferred compounds of the invention are shown in table 3.
TABLE 3 blood glucose decline Rate profiles for preferred Compounds of the invention
Figure GPA0000254629200000891
And (4) conclusion: preferred compounds of the invention exhibit good hypoglycemic effects at both 4 hours and 6 hours.
Test example 4 Effect of oral administration of preferred Compounds of the invention for 28 consecutive days on random blood glucose in db/db mice
Purpose of experiment
Observing the influence of the preferred compound on the random blood sugar of a type II diabetes model db/db mouse after continuous 28-day oral administration, adopting a tail blood sampling method, and measuring the blood sugar value by a portable glucometer so as to evaluate the in-vivo blood sugar reduction effect of the tested compound.
Test animal
Male db/db mice, 100, 9-10 weeks, were provided by the university of Nanjing model animal institute, license number: SCXK (Su) 2010-0001, and a positive control group and a solvent control group are set.
Test article
Compound 4A, 28A, sitagliptin (marketed drug), 3- (4- ((1R, 2S) -1- (5-chloro-7-fluoro-1H-indol-3-yl) -1- (4- (trifluoromethoxy) phenyl) pent-2-yl) benzamido) propionic acid (FORM1) disclosed in WO20150662521, formulated at the desired concentration with ethanol: PEG 400: water ═ 20: 30: 50.
Mode of administration
The oral administration is carried out by intragastric administration, and ethanol, PEG400 and water with the same volume are infused into a blank control group with the volume of 10ml/kg and the administration dose of 30mg/kg in proportion to 20: 30: 50.
Test method
Male db/db mice, grouped by non-fasting blood glucose and body weight, were 8 mice per group, solvent control and different compound dosing groups. The tested drugs and the solvent are orally administered to each group of animals for 28 consecutive days, tail blood sugar value detection is carried out 8 hours after administration on days 1, 7, 14, 21 and 28, blood sugar reducing effect and maintaining time of the tested substances are observed, and a 28-day blood sugar curve is drawn. The blood glucose modulating effect of the compounds was determined by comparison with blood glucose in db/db mice given vehicle control alone.
Results of the experiment
db/db mice orally administered the preferred compound 4A, compound 28B of the present invention with sitagliptin and the compound of WO2015066252 (FORM1) for 28 consecutive days, compound 4A and compound 28B have a significant hypoglycemic effect, superior to sitagliptin and FORM1, as shown in fig. 1 in particular.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (41)

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:
Figure FDA0003008885080000011
wherein:
l is selected from-C (O) NH-or-NH-C (O) -;
A1、A2、A3and A5Each is independently selected from CH or C; a. the4Selected from CH, C or N;
R1is selected from C3-C6An alkyl group;
R2selected from hydrogen atoms, C1-C6Alkyl, halogen or C1-C6Alkoxy, wherein said C1-C6Alkyl or C1-C6Alkoxy is optionally further substituted with one or more halo;
or, R2Selected from phenyl, wherein said phenyl is optionally further substituted by one or more groups selected from C1-C6Alkyl or halogen;
or, R2Selected from 5-to 6-membered monocyclic heteroaryl or 9-to 10-membered bicyclic heteroaryl, wherein said 5-to 6-membered monocyclic heteroaryl or 9-to 10-membered bicyclic heteroaryl is optionally further substituted by one or more C1-C6Alkyl substitution, wherein said C1-C6Alkyl optionally further substituted with one or more halogens;
R3each independently selected from C1-C6Alkoxy, wherein said C1-C6Alkoxy is optionally further substituted with one or more halo;
R4each independently selected from alkyl or halogen;
R5each independently selected from C1-C6Alkyl, halogen or C1-C6Alkoxy, wherein said C1-C6Alkyl or C1-C6Alkoxy is optionally further substituted with one or more halo;
m is 0, 1, 2, 3, 4 or 5;
n is 0, 1, 2, 3 or 4; and is
p is 0, 1, 2, 3 or 4.
2. The compound according to claim 1, which is a compound of the general formula (II):
Figure FDA0003008885080000012
wherein: r1～R5M, n and p are as defined in claim 1.
3. The compound according to claim 1, which is a compound of the general formula (III):
Figure FDA0003008885080000021
wherein: r1～R5M, n and p are as defined in claim 1.
4. The compound according to claim 2, which is a compound of formula (IV) or (V) or (VI) or (VII), or a pharmaceutically acceptable salt thereof:
Figure FDA0003008885080000022
wherein: r1～R5M, n and p are as defined in claim 1.
5. A compound according to claim 3, which is a compound of general formula (VIII) or (IX) or (X) or (XI) or a pharmaceutically acceptable salt thereof:
Figure FDA0003008885080000023
Figure FDA0003008885080000031
wherein: r1～R5M, n and p are as defined in claim 1.
6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R1Is n-propyl.
7. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R2Selected from phenyl, wherein said phenyl is optionally further substituted with one or more methyl groups.
8. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R2Selected from 5-6 membered monocyclic heteroaryl, wherein said 5-6 membered monocyclic heteroaryl is optionally further substituted by one or more C1-C6Alkyl, halo C1-C6Alkyl substitution.
9. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R2Is pyrrole, furan, thiophene, pyrazole, imidazole, thiazole, benzimidazole, benzofuran, or benzoxazole, wherein the pyrrole, furan, thiophene, pyrazole, imidazole, thiazole, benzimidazole, benzofuran, or benzoxazole is optionally further substituted with one or more C1-C6Alkyl substitution, wherein said C1-C6Alkyl is optionally further substituted with one or more halo substituents.
10. A compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein said halogen is F.
11. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R3Is fluoro C1-C6An alkoxy group.
12. The compound of claim 11, wherein R3Is trifluoromethoxy or trifluoroethoxy.
13. A compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein R3Attached to the 3 (meta) or 4 (para) position, m is 1.
14. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R4Selected from F, n is 1.
15. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
A3is selected from C;
R1selected from n-propyl;
R2selected from hydrogen atoms, C1-C6Alkyl, halogen or C1-C6Alkoxy, wherein said C1-C6Alkyl or C1-C6Alkoxy is optionally further substituted with one or more halo;
or, R2Selected from phenyl, wherein said phenyl is optionally further substituted by one or more groups selected from C1-C6Alkyl or halogen;
or, R2Selected from 5-to 6-membered monocyclic heteroaryl or 9-to 10-membered bicyclic heteroaryl, wherein said 5-to 6-membered monocyclic heteroaryl or 9-to 10-membered bicyclic heteroaryl is optionally further substituted by one or more C1-C6Alkyl substitution, wherein said C1-C6Alkyl optionally further substituted with one or more halogens;
R3is selected from trifluoromethoxy;
R4selected from halogens;
R5each independently selected from C1-C6Alkyl, halogen, C1-C6Alkoxy, halo C1-C6Alkyl or halogenGeneration C1-C6An alkoxy group;
m is 0, 1 or 2;
n is 0, 1 or 2; and is
p is 0, 1 or 2.
16. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is:
Figure FDA0003008885080000041
17. the compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is:
Figure FDA0003008885080000042
Figure FDA0003008885080000051
Figure FDA0003008885080000061
18. the compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein said compound is:
Figure FDA0003008885080000062
Figure FDA0003008885080000071
19. the compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is:
Figure FDA0003008885080000072
20. the compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is:
Figure FDA0003008885080000073
21. a process for the preparation of a compound of formula (I) according to claim 1, which process comprises:
Figure FDA0003008885080000081
reacting the general formula (IA) with the general formula (IB), and further hydrolyzing the obtained compound to obtain a compound of the general formula (I);
wherein:
L1selected from-C (O) X;
L2is selected from-NH2；
X is selected from hydroxyl or halogen;
Rcselected from alkyl groups;
l is selected from-NH-C (O) -; and is
R1～R5、A1～A5M, n and p are as defined in claim 1.
22. The process according to claim 21, wherein the process for the preparation of formula (IA) comprises:
Figure FDA0003008885080000082
reacting the general formula (IC) with the general formula (ID) or a salt thereof to obtain a compound of the general formula (IA);
wherein:
L1selected from-C (O) X;
x is selected from hydroxyl or halogen;
Rcselected from alkyl groups; and is
R1、R3、R4M, n are as defined in claim 1.
23. A process for the preparation of a compound of formula (I) according to claim 1, which process comprises:
Figure FDA0003008885080000083
reacting the general formula (IE) with the general formula (ID) or a salt thereof, and further hydrolyzing the obtained compound to obtain a compound of the general formula (I); wherein:
x is selected from hydroxyl or halogen;
Rcselected from alkyl groups;
l is selected from-C (O) -NH-; and is
R1～R5、A1～A5M, n and p are as defined in claim 1.
24. The method of claim 23, wherein the method of preparation of formula (IE) comprises:
Figure FDA0003008885080000091
reacting the general formula (IC) with the general formula (IB) or a salt thereof to give a compound of the general formula (IE);
wherein:
L1is selected from-NH2；
L2Selected from-C (O) X;
x is selected from hydroxyl or halogen;
l is selected from-C (O) -NH-; and is
R1～R5、A1～A5M, n and p are as defined in claim 1.
25. A compound of formula (IA):
Figure FDA0003008885080000092
wherein:
L1selected from-C (O) X;
x is selected from hydroxyl or halogen;
Rcselected from alkyl groups; and is
R1、R3、R4M and n are as defined in claim 1.
26. The compound according to claim 25, or a pharmaceutically acceptable salt thereof, wherein said compound comprises:
Figure FDA0003008885080000093
27. the compound according to claim 26, or a pharmaceutically acceptable salt thereof, wherein said compound comprises:
Figure FDA0003008885080000101
28. a compound of the general formula (IE):
Figure FDA0003008885080000102
wherein:
x is selected from hydroxyl or halogen;
l is selected from-C (O) -NH-; and is
R1～R5、A1～A5M, n and p are as defined in claim 1.
29. The compound according to claim 28, or a pharmaceutically acceptable salt thereof, wherein said compound is:
Figure FDA0003008885080000103
30. a process for the preparation of a compound of formula (IA) according to claim 25, wherein the compound of formula (IA) is a compound of formula (IIA):
Figure FDA0003008885080000104
the method comprises the following steps:
Figure FDA0003008885080000111
reacting a compound of formula (IIa) with a compound of formula (IIb) under basic conditions to give a compound of formula (IIc);
Figure FDA0003008885080000112
hydrolyzing the compound (IIc) under alkaline conditions to obtain a compound (IId);
Figure FDA0003008885080000113
reacting the compound of the general formula (IId) with the compound of the general formula (IIe) in the presence of a condensation agent to obtain a compound of the general formula (IIf);
Figure FDA0003008885080000114
hydrolyzing the compound (IIf) in alkaline condition to obtain a compound (IIA);
wherein:
x is selected from hydroxyl or halogen;
Ra，Rband RcEach independently selected from alkyl;
R1、R3、R4m and n are as defined in claim 1.
31. The method of claim 30, wherein the condensation reagent is selected from the group consisting of bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride, N-dicyclohexylcarbodiimide, N-diisopropylcarbodiimide, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, and o-benzotriazol-N, N' -Tetramethyluronium Borate (TBTU).
32. The production method according to claim 31, wherein the condensation reagent is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride or bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride.
33. The preparation method according to claim 31, wherein the basic condition is provided by an organic base or an inorganic base, the organic base being selected from diisopropylethylamine, pyridine, triethylamine, piperidine, N-methylpiperazine, 4-dimethylaminopyridine and potassium tert-butoxide; the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, and potassium hydride.
34. The preparation method according to claim 33, wherein the organic base is diisopropylethylamine, triethylamine, or potassium tert-butoxide.
35. The method of claim 33, wherein the inorganic base is sodium hydroxide or lithium hydroxide.
36. A process for the preparation of a compound of formula (IE) according to claim 28, wherein the compound of formula (IE) is a compound of formula (IIIA):
Figure FDA0003008885080000121
the method comprises the following steps:
Figure FDA0003008885080000122
reacting the compound of formula (IIIa) in the presence of tetraisopropyl titanate and aminomethanol to obtain a compound of formula (IIIb);
Figure FDA0003008885080000123
carrying out condensation reaction on the general formula compound (IIIb) and the general formula (IIIc) to obtain a general formula compound (IIId);
Figure FDA0003008885080000124
carrying out hydrolysis reaction on the compound (IIId) in the general formula under an acidic condition to obtain a compound (IIIA) in the general formula;
wherein:
Ra、Rband RcSelected from alkyl groups; and is
R1～R5M, n and p are as defined in claim 1.
37. The method of claim 36, wherein the acidic condition is provided by an inorganic acid selected from hydrochloric acid or phosphoric acid or an organic acid.
38. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.
39. Use of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 38, in the manufacture of a medicament for the treatment of type I diabetes, type II diabetes, hyperglycemia, obesity or insulin resistance.
40. Use of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 38, in the preparation of a glucagon receptor antagonist or inverse agonist.
41. Use of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 38, in the manufacture of a medicament for the treatment of hyperlipidemia, dyslipidemia, hypercholesterolemia, atherosclerosis, metabolic syndrome.
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