CN109071420A - Amide derivatives, preparation method and its purposes in medicine - Google Patents

Amide derivatives, preparation method and its purposes in medicine Download PDF

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CN109071420A
CN109071420A CN201780027911.5A CN201780027911A CN109071420A CN 109071420 A CN109071420 A CN 109071420A CN 201780027911 A CN201780027911 A CN 201780027911A CN 109071420 A CN109071420 A CN 109071420A
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compound
phenyl
base
trifluoromethoxy
alkyl
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CN109071420B (en
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关东亮
白骅
盛首
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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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/83—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates

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Abstract

Amide derivatives, preparation method and its application in medicine are provided.Specifically, provide amide derivatives shown in a kind of logical formula (I) or its pharmaceutical salt, preparation method and they as therapeutic agent, especially as the purposes of pancreas HGF receptor antagonist

Description

Amide derivatives, preparation method and its purposes in medicine Invention field
The present invention relates to a kind of new amide derivatives, preparation method and pharmaceutical composition containing the derivative as well as therapeutic agents especially as the purposes of GCGR antagonist.
Background of invention
Glucagon (Glucagon) is the straight-chain polypeptide of alpha Cell of islet secretion being made of 29 amino acid, molecular weight 3485；Concentration in serum is 50-100ng/L, and the half-life period in blood plasma is 5-10 minutes.Glucagon activates downstream signal transduction access, plays physiological effect by being specifically bound with the Type B g protein coupled receptor (glucagon receptor, GCGR) of the target cell surfaces such as liver kidney.Its effect with insulin has very strong promotions decomposition of glycogen and gluconeogenesis, makes blood glucose apparent increase on the contrary, be a kind of hormone for promoting catabolism.The hormone of 1mol/L can make 3 × 106The glucose of mol/L comes out (Johnson etc., J.Biol.Chem.1972,247,3229-3235) from decomposition of glycogen rapidly.
Glucagon receptor is located at cell surface, and the G- G-protein linked receptor with 7 cross-film sequences is distributed mainly on liver, is in addition also distributed in kidney, heart, muscle etc..
The first target organs of glucagon effect are livers.After in conjunction with receptor, regulatory protein Gs interacts in conjunction with guanylic acid, and the A subunit of Gs is made to discharge activated adenyl cyclase, and catalysis ATP is converted into cAMP and plays its biological effect.The glucagon of pharmacological dose can be such that cAMP content in cardiac muscle cell increases, myocardial contraction enhancing.Glucagon receptor antagonist can compete this receptor with glucagon, to block its effect.
Diabetes are a kind of disease of high level characterization by plasma glucose.Uncontrolled hyperglycemia is related with capilary and macrovascular diseases risk increase, and the disease includes nephrosis, retinopathy, hypertension, apoplexy and heart disease.The control of glucose homeostasis is to treat the main method of diabetes.Show in the animal model of healthy animal and I type and type-2 diabetes mellitus: removing the glucagon in circulation with selectivity and specific antibody causes blood glucose level to reduce.Therefore a kind of potential treatment method of diabetes and other diseases for being related to pathoglycemia is that glucagon receptor antagonist blocks glucagon receptor to improve insulin replies, to reduce gluconeogenesis rate and/or to reduce plasma glucose levels by hepatic glucose output speed in reduction patient.
The document of a series of GCGR antagonist has been disclosed at present, including WO2008042223, WO2010098994A1, WO2015066252, WO2012009226A1, WO2012009226A1 etc., not all compound as GCGR antagonist all has the characteristic as useful therapeutic agent.Some in these characteristics include duration, oral administration biaavailability and the stability (such as preparation or ability of crystallization, shelf-life) acted on high-affinity, the receptor activation of glucagon receptor.This class feature can lead to safety, tolerance, validity, therapeutic index, patient's compliance, cost effective, preparation easiness etc. and improve.Surprisingly find that the specific spatial chemistry of the compounds of this invention and functional group show one of these required characteristics or a variety of, including significantly improved receptor binding matter, oral administration biaavailability and/or other favorable characteristics for enhancing its well-formedness for being used for therapeutical uses.
It include: at present PF-06291874 (Pfizer) and LGD-6972 (Ligand) in the clinic II phase in the GCGR antagonist pharmaceuticals ground, Merck & Co., Inc. once researches and develops MK-3577 simultaneously, and 3- (4- ((1R is disclosed in WO2015066252,2S) -1- (the fluoro- 1H- indol-3-yl of the chloro- 7- of 5-) -1- (4- (trifluoromethoxy) phenyl) amyl- 2- yl) benzamido) propionic acid (FORM1), for MK-3577 analog structure, the structure for being related to particular compound is as follows:
Summary of the invention
Place for overcome the deficiencies in the prior art, the purpose of the present invention is to provide a new class of amide derivatives shown in a kind of logical formula (I), and their tautomer, enantiomer, diastereomer, raceme and pharmaceutical salt, and metabolite and metabolic precursor thereof or prodrug, the compounds of this invention has biggish architectural difference compared with compound specifically disclosed in technology, and excellent anti-diabetic effect and effect are shown, it is as follows to lead to formula (I) structure:
Wherein:
L is selected from-C (O) NH- or-NH-C (O)-；
A1、A2、A3、A4And A5It is each independently selected from CH, C or N, on condition that A1、A2、A3、A4And A5And the quantity in ring composed by carbon atom in connection containing N is 0~2；
R1Selected from alkyl or cycloalkyl, wherein the alkyl or cycloalkyl is optionally further selected from hydroxyl, halogen, nitro, cyano, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl ,-NR by one or more6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8Or-NR6C(O)R7Substituent group replaced；
R2Selected from hydrogen atom, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, cyano, nitro, naphthenic base, heterocycle, aryl, heteroaryl ,-NR6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8Or-NR6C(O)R7, wherein alkyl, alkenyl, alkynyl, alkoxy, naphthenic base, heterocycle, aryl or the heteroaryl are optionally further selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy, naphthenic base, heterocycle, aryl, heteroaryl ,-NR by one or more6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8Or-NR6C(O)R7Substituent group replaced；Work as A3When selected from N, R2It is not present；
R3It is each independently selected from hydrogen atom, alkyl, halogen, hydroxyl, alkoxy, cyano, nitro, naphthenic base, heterocycle, aryl, heteroaryl ,-NR6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8Or-NR6C(O)R7, wherein alkyl, alkoxy, naphthenic base, heterocycle, aryl or the heteroaryl are optionally further selected from hydroxyl, halogen, nitro, cyano, alkoxy, halogenated alkyl, halogenated alkoxy, naphthenic base, heterocycle, aryl, heteroaryl ,-NR by one or more6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8Or-NR6C(O)R7Substituent group replaced；
R4It is each independently selected from hydrogen atom, alkyl, halogen, hydroxyl, alkoxy, cyano, nitro, naphthenic base, heterocycle, aryl, heteroaryl ,-NR6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8Or-NR6C(O)R7, wherein alkyl, alkoxy, naphthenic base, heterocycle, aryl or the heteroaryl are optionally further selected from hydroxyl, halogen, nitro, cyano, alkoxy, halogenated alkyl, halogenated alkoxy, naphthenic base, heterocycle, aryl, heteroaryl ,-NR by one or more6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8Or-NR6C(O)R7Substituent group replaced；
R5It is each independently selected from hydrogen atom, alkyl, halogen, hydroxyl, alkoxy, cyano, nitro ,-NR6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8Or-NR6C(O)R7, wherein the alkyl or alkoxy are optionally further selected from hydroxyl, halogen, nitro, cyano, alkoxy, halogenated alkyl, halogenated alkoxy, naphthenic base, heterocycle, aryl, heteroaryl ,-NR by one or more6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8Or-NR6C(O)R7Substituent group replaced；
R6Selected from hydrogen atom or alkyl；
R7Selected from hydrogen atom, alkyl, naphthenic base, aryl or heteroaryl, wherein alkyl, naphthenic base, aryl or the heteroaryl are optionally further selected from hydroxyl, halogen, halogenated alkyl, nitro, cyano, alkyl, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl ,-NR by one or more9R10、-C(O)R9R10、-C(O)R11、-SO2R11、-C(O)OR11Or-NR9C(O)R10Substituent group replaced；
Alternatively, R6And R74~8 circle heterocyclic ring bases are formed together with the N atom being connected, wherein containing one or more N, O, S (O) in the heterocycleqAtom, and the heterocycle is optionally further selected from alkyl, halogen, hydroxyl, cyano, nitro, naphthenic base, heterocycle, aryl, heteroaryl ,-NR by one or more9R10、-C(O)R9R10、-C(O)R11、-SO2R11、-C(O)OR11Or-NR9C(O)R10Substituent group replaced；
R8Selected from hydrogen atom, alkyl, naphthenic base, heterocycle, aryl or heteroaryl, wherein the alkyl, naphthenic base, heterocycle, aryl or heteroaryl are optionally further selected from hydroxyl, halogen, halogenated alkyl, nitro, cyano, alkyl, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl ,-NR by one or more9R10、-C(O)R9R10、-C(O)R11、-SO2R11、-C(O)OR11Or-NR9C(O)R10Substituent group replaced；
R9、R10And R11It is each independently selected from hydrogen atom, alkyl, naphthenic base, heterocycle, aryl or heteroaryl, wherein the alkyl, naphthenic base, heterocycle, aryl or heteroaryl are optionally further selected from replaced the substituent groups of hydroxyl, halogen, halogenated alkyl, nitro, cyano, alkyl, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl, carboxylic acid or carboxylate by one or more；
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
Q is 0,1 or 2.
A preferred embodiment of the invention is, compound or its stereoisomer, tautomer or its pharmaceutical salt described in a kind of logical formula (I), for compound or its stereoisomer, tautomer or its pharmaceutical salt described in logical formula (II):
Wherein: R1~R5, m, n and p definition as described in logical formula (I).
A preferred embodiment of the invention is, compound described in a kind of logical formula (I) or its stereoisomer, tautomer or its is pharmaceutical Salt, to lead to compound or its stereoisomer, tautomer or its pharmaceutical salt described in formula (III):
Wherein: R1~R5, m, n and p definition as described in logical formula (I).
A preferred embodiment of the invention is, compound or its stereoisomer, tautomer or its pharmaceutical salt described in a kind of logical formula (I), for compound or its stereoisomer, tautomer or its pharmaceutical salt described in logical formula (IV):
Wherein: R1~R5, m, n and p definition as described in logical formula (I).
A preferred embodiment of the invention is, compound or its stereoisomer, tautomer or its pharmaceutical salt described in a kind of logical formula (I), for compound or its stereoisomer, tautomer or its pharmaceutical salt described in logical formula (V):
Wherein: R1~R5, m, n and p definition as described in logical formula (I).
A preferred embodiment of the invention is, compound or its stereoisomer, tautomer or its pharmaceutical salt described in a kind of logical formula (I), for compound or its stereoisomer, tautomer or its pharmaceutical salt described in logical formula (VI):
Wherein: R1~R5, m, n and p definition as described in logical formula (I).
A preferred embodiment of the invention is, compound described in a kind of logical formula (I) or its stereoisomer, tautomer or its is pharmaceutical Salt, to lead to compound or its stereoisomer, tautomer or its pharmaceutical salt described in formula (VII):
Wherein: R1~R5, m, n and p definition as described in logical formula (I).
A preferred embodiment of the invention is, compound or its stereoisomer, tautomer or its pharmaceutical salt described in a kind of logical formula (I), for compound or its stereoisomer, tautomer or its pharmaceutical salt described in logical formula (VIII):
Wherein: R1~R5, m, n and p definition as described in logical formula (I).
A preferred embodiment of the invention is, compound or its stereoisomer, tautomer or its pharmaceutical salt described in a kind of logical formula (I), for compound or its stereoisomer, tautomer or its pharmaceutical salt described in logical formula (IX):
Wherein: R1~R5, m, n and p definition as described in logical formula (I).
A preferred embodiment of the invention is, compound or its stereoisomer, tautomer or its pharmaceutical salt described in a kind of logical formula (I), for compound or its stereoisomer, tautomer or its pharmaceutical salt described in logical formula (X):
Wherein: R1~R5, m, n and p definition as described in logical formula (I).
A preferred embodiment of the invention is, compound described in a kind of logical formula (I) or its stereoisomer, tautomer or its is pharmaceutical Salt is compound or its stereoisomer, tautomer or its pharmaceutical salt described in general formula (XI):
Wherein: R1~R5, m, n and p definition as described in logical formula (I).
A preferred embodiment of the invention is a kind of logical formula (I)~(XI) described in any item compounds or its stereoisomer, tautomer or its pharmaceutical salt, in which: R1Selected from C3-6Alkyl, preferably n-propyl.
A preferred embodiment of the invention is a kind of logical formula (I)~(XI) described in any item compounds or its stereoisomer, tautomer or its pharmaceutical salt, wherein R2Selected from phenyl, wherein the phenyl is optionally further replaced the substituent group of one or more alkyl, halogen, cyano, nitro, alkoxy, halogenated alkyl or halogenated alkoxy, further preferred scheme, wherein the phenyl is further replaced one or more methyl, trifluoromethyl or trifluoromethoxy.
A preferred embodiment of the invention is a kind of logical formula (I)~(XI) described in any item compounds or its stereoisomer, tautomer or its pharmaceutical salt, wherein R2Selected from 5~8 unit's heteroaryls, wherein the heteroaryl is optionally further replaced the substituent group of one or more alkyl, halogen, cyano, nitro, alkoxy, halogenated alkyl or halogenated alkoxy.
A preferred embodiment of the invention is a kind of logical formula (I)~(XI) described in any item compounds or its stereoisomer, tautomer or its pharmaceutical salt, wherein R2It is further selected from pyrroles, furans, thiophene, pyrazoles, imidazoles, thiazole, benzimidazole, benzofuran or benzoxazoles, wherein pyrroles, furans, thiophene, pyrazoles, imidazoles, thiazole, benzimidazole, benzofuran or the benzoxazoles are optionally further replaced the substituent group of one or more alkyl, halogen, cyano, nitro or alkoxy, wherein optionally further replaced the substituent group of one or more halogens, the halogen is preferably F for the alkyl or alkoxy.
A preferred embodiment of the invention is a kind of logical formula (I)~(XI) described in any item compounds or its stereoisomer, tautomer or its pharmaceutical salt, wherein R2Selected from alkynyl, wherein the alkynyl is further replaced naphthenic base, wherein the naphthenic base is preferably cyclopropyl.
A preferred embodiment of the invention is a kind of logical formula (I)~(XI) described in any item compounds or its stereoisomer, tautomer or its pharmaceutical salt, wherein R3Selected from alkoxy, wherein the alkoxy is optionally further selected from replaced the substituent groups of alkyl, halogen, cyano, nitro or alkoxy by one or more.
A preferred embodiment of the invention is a kind of logical formula (I)~(XI) described in any item compounds or its stereoisomer, tautomer or its pharmaceutical salt, wherein R3Selected from fluoroalkyl, preferably trifluoromethoxy or trifluoro ethoxy.
A preferred embodiment of the invention is a kind of logical formula (I)~(XI) described in any item compounds or its stereoisomer, tautomer or its pharmaceutical salt, wherein R3It is connected to 3 (meta positions) or 4 (contraposition), m 1.
A preferred embodiment of the invention is a kind of logical formula (I)~(XI) described in any item compounds or its stereoisomer, tautomer or its pharmaceutical salt, wherein R4Selected from hydrogen atom, halogen or alkyl.
A preferred embodiment of the invention is a kind of logical formula (I)~(XI) described in any item compounds or its stereoisomer, tautomer or its pharmaceutical salt, wherein R4Selected from F, n 1.
A preferred embodiment of the invention is, a kind of logical described in any item compounds of formula (I) or its stereoisomer, tautomer or its can Medicinal salt,
Wherein:
A3Selected from C；
R1Selected from n-propyl；
R2Selected from alkyl, halogen, cyano, nitro, alkoxy, halogenated alkyl, halogenated alkoxy, phenyl or 5~8 unit's heteroaryls, the alkyl, alkoxy, phenyl or 5~8 unit's heteroaryls are optionally further replaced the substituent group of one or more alkyl, halogen, cyano, nitro, alkoxy, halogenated alkyl or halogenated alkoxy；
R3Selected from trifluoromethoxy；
R4Selected from hydrogen atom or halogen；
R5It is each independently selected from hydrogen atom, alkyl, halogen, alkoxy, halogenated alkyl or halogenated alkoxy；
M is 0,1 or 2；
N is 0,1 or 2；And
P is 0,1 or 2.
Typical compound of the invention includes, but are not limited to:
Typical compound of the invention includes, but are not limited to:
Or its stereoisomer, tautomer, mixture tautomer or its pharmaceutical salt.
Typical compound of the invention includes, but are not limited to:
Or its stereoisomer, tautomer, mixture tautomer or its pharmaceutical salt.
Further, the present invention provides the preparation method of a kind of logical formula (I) compound or its stereoisomer, tautomer or its pharmaceutical salt, this method comprises:
General formula (IC) and general formula (ID) or its reactant salt, obtain general formula (IA) compound；
General formula (IA) is reacted with general formula (IB), and obtained compound further hydrolyzes, and obtains logical formula (I) compound；
Wherein:
L1Selected from-C (O) X；
L2Selected from-NH2；
X is selected from hydroxyl or halogen；
RcSelected from alkyl；
L is selected from-NH-C (O)-；And
R1~R5、A1~A5, m, n and p definition as described in logical formula (I).
Further, the present invention provides the preparation method of a kind of logical formula (I) compound or its stereoisomer, tautomer or its pharmaceutical salt, this method comprises:
By general formula (IC) and general formula (IB) or its reactant salt, general formula (IE) compound is obtained；
General formula (IE) and general formula (ID) or its reactant salt, obtained compound further hydrolyze, and obtain logical formula (I) compound；
Wherein:
X is selected from hydroxyl or halogen；
RcSelected from alkyl；
L1Selected from-NH2；
L2Selected from-C (O) X；
L is selected from-C (O)-NH-；And
R1~R5、A1~A5, m, n and p definition as described in logical formula (I).
The present invention provides compound or its stereoisomer, tautomer or its pharmaceutical salt described in a kind of general formula (IA):
Wherein:
L1Selected from-C (O) X；
X is selected from hydroxyl or halogen；
RcSelected from alkyl；And
R1, R3, R4, the definition of m and n are as described in logical formula (I).
The typical compound of general formula (IA) includes, but are not limited to:
Or its stereoisomer, tautomer or its pharmaceutical salt.
The typical compound of general formula (IA) includes, but are not limited to:
Or its stereoisomer, tautomer or its pharmaceutical salt.
The typical compound of general formula (IA) includes, but are not limited to:
Or its stereoisomer, tautomer or its pharmaceutical salt.
The present invention provides compound or its stereoisomer, tautomer or its pharmaceutical salt described in a kind of general formula (IE):
Wherein:
X is selected from hydroxyl or halogen；
L is selected from-C (O)-NH-；And
R1~R5、A1~A5, m, n and p definition as described in logical formula (I).
The typical compound of general formula (IE) includes, but are not limited to:
Or its stereoisomer, tautomer or its pharmaceutical salt.
The present invention provides the preparation method of a kind of general formula (IIA) compound or its stereoisomer, tautomer or its pharmaceutical salt, this method comprises:
General formula compound (IIa) reacts under alkaline condition with general formula compound (IIb), obtains general formula (IIc)；
General formula compound (IIc) hydrolyzes under alkaline condition, obtains general formula compound (IId) compound；
General formula compound (IId) compound reacts in the presence of condensation reagent with general formula compound (IIe), obtains general formula compound (IIf) compound；
General formula compound (IIf) hydrolyzes under alkaline condition, obtains general formula compound (IIA)；
Wherein:
X is selected from hydroxyl or halogen；
Ra, RbAnd RcIt is each independently selected from alkyl；
R1、R3、R4, m and n definition as described in logical formula (I).
In above-mentioned preparation method, alkaline condition is provided by organic base or inorganic base, and organic base is selected from diisopropylethylamine, pyridine, triethylamine, piperidines, N methyl piperazine, 4- dimethylamino pyridine or potassium tert-butoxide, preferably diisopropylethylamine, triethylamine or potassium tert-butoxide；Inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide or hydrofining, preferably sodium hydroxide or lithium hydroxide.
In above-mentioned preparation method, condensation reagent includes, but it is not limited to: bis- (2- oxo -3- oxazolidinyls) secondary phosphoryl chloride phosphorus oxychloride, N, N- dicyclohexylcarbodiimide, N, two Asia of N- diisopropyl carbon, 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride, o- benzotriazole-N, N, N ' N '-tetramethylurea borate (TBTU), preferably 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride or bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychlorides.
The present invention provides the preparation method of a kind of general formula (IIIA) compound or its stereoisomer, tautomer or its pharmaceutical salt, this method Include:
General formula compound (IIIa) reacts in the presence of tetraisopropyl titanate and ammonia methanol, obtains general formula (IIIb)；
General formula compound (IIIb) and general formula (IIIc) carry out condensation reaction, obtain general formula compound (IIId) compound；
Reaction is hydrolyzed in general formula compound (IIId) compound in acid condition, obtains general formula compound (IIIA)；
Wherein:
X is selected from hydroxyl or halogen；
Ra、RbAnd RcSelected from alkyl；And
R1~R5、A1~A5, m, n and p definition as described in logical formula (III).
In above-mentioned preparation method, acid condition is provided by inorganic acid or organic acid, and inorganic acid is selected from hydrochloric acid or phosphoric acid.
Further, the present invention provides a kind of pharmaceutical composition, the pharmaceutical composition contains compound described in logical formula (I)~(III) any one of effective dose or its stereoisomer, tautomer or its pharmaceutical salt and pharmaceutical carrier, excipient or their combination.
The present invention provides a kind of method of external glucagon suppression receptor, this method includes by the glucagon receptor and logical formula (I)~(III) be described in any item or its stereoisomer, tautomer or its pharmaceutical salt or its pharmaceutical composition are in contact.
The present invention provides a kind of logical formula (I)~(III) described in any item compounds or its stereoisomer, tautomer or its purposes of pharmaceutical salt or its pharmaceutical composition in the drug for preparing type-1 diabetes mellitus, type-2 diabetes mellitus, hyperglycemia, obesity or insulin resistance.
The present invention provides a kind of logical formula (I)~(III) described in any item compounds or its stereoisomer, tautomer or its pharmaceutical salt or its pharmaceutical composition is preparing the purposes in glucagon receptor antagonist or inverse agonist.
The present invention provide a kind of logical formula (I)~(III) described in any item compounds or its stereoisomer, tautomer or its pharmaceutical salt or its pharmaceutical composition preparation treatment hyperlipidemia, dyslipidemia, hypercholesterolemia, atherosclerosis, metablic syndrome drug in purposes.
The present invention leads to formula (I)~(III) described in any item compounds or its stereoisomer, tautomer or its pharmaceutical salt, or its pharmaceutical composition can external glucagon suppression receptor, therefore it can be used for preparing glucagon receptor antagonist or inverse agonist, invention further provides can be used for treating type-1 diabetes mellitus simultaneously, type-2 diabetes mellitus, hyperglycemia, obesity, insulin resistance, hyperlipidemia, dyslipidemia, hypercholesterolemia, the method of atherosclerosis or metablic syndrome, the method includes the present invention to animal application therapeutically effective amount to lead to formula (I)~(III) described in any item compounds or its stereoisomer, tautomer or its pharmaceutical salt, or the step of its pharmaceutical composition.
Detailed description of the invention
Unless stated to the contrary, otherwise used part term is defined as follows the present invention in the specification and in the claims:
Refer to when " alkyl " is as a part of a group or a group including C1-C20Straight chain or aliphatic hydrocarbon group with branch.Preferably C1-C10Alkyl, more preferably C1-C6Alkyl.The embodiment of alkyl group includes but is not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1, 1- dimethyl propyl, 1, 2- dimethyl propyl, 2, 2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl propyl, 1, 1, 2- thmethylpropyl, 1, 1- dimethylbutyl, 1, 2- dimethylbutyl, 2, 2- dimethylbutyl, 1, 3- dimethylbutyl, 2- ethyl-butyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 2, 3- dimethylbutyl etc..Alkyl can be optionally substituted or unsubstituted.
Refer to the aliphatic hydrocarbon group containing a triple carbon-carbon bonds when " alkynyl " is as a part of a group or a group, can also have branch for straight chain.That preferentially select is C2-C10Alkynyl, more preferable C2-C6Alkynyl, most preferably C2-C4Alkynyl.The embodiment of alkynyl group includes, but are not limited to acetenyl, 1- propinyl, 2-propynyl, 1-, 2- or 3- butynyl etc..Alkynyl can be optionally substituted or unsubstituted.
" naphthenic base " refer to the monocycle of saturation or fractional saturation, condensed ring, bridged ring and loop coil carbocyclic ring, that is, include monocyclic cycloalkyl, cycloalkyl, bridge ring alkyl and spiro cycloalkyl group.Preferably C3-C12Naphthenic base, more preferably C3-C8Naphthenic base, most preferably C3-C6Naphthenic base.The embodiment of monocyclic cycloalkyl includes but is not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc., preferably cyclopropyl, cyclohexenyl group.
" spiro cycloalkyl group " refers to 5 to 18 yuan, two or more cyclic structures, and the polycyclic moiety of a carbon atom (claiming spiro-atom) is shared between monocycle each other, contain one or more double bonds in ring, but none ring has the aroma system of the pi-electron of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Spiro cycloalkyl group is divided into single spiral shell, double spiral shells or more spiro cycloalkyl groups according to the number for sharing spiro-atom between ring and ring, preferably single spiral shell and double spiro cycloalkyl groups, preferably 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan.The non-limiting embodiment of " spiro cycloalkyl group " includes but is not limited to: spiral shell [4.5] decyl, spiral shell [4.4] nonyl, spiral shell [3.5] nonyl, spiral shell [2.4] heptyl.
" cycloalkyl " refers to 5 to 18 yuan, full carbon polycyclic moiety containing two or more cyclic structures public a pair of of carbon atom each other, one or more rings can contain one or more double bonds, but none ring has the aroma system of the pi-electron of total conjugated, preferably 6 to 12 yuan, more preferably 7 to 10 yuan.Bicyclic, tricyclic, Fourth Ring or polycyclic fused ring alkyl, preferably bicyclic or tricyclic, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic alkyl can be divided into according to a group cyclic number.The non-limiting embodiment of " cycloalkyl " includes but is not limited to: two rings [3.1.0] hexyl, two rings [3.2.0] hept- 1- alkenyl, two rings [3.2.0] heptyl, decahydronaphthalene naphthalene or ten tetrahydro phenanthryl.
" bridge ring alkyl " refers to 5 to 18 yuan, contain two or more cyclic structures, two full carbon polycyclic moieties for not being connected directly carbon atom are shared each other, one or more rings can contain one or more double bonds, but none ring has the aroma system of the pi-electron of total conjugated, preferably 6 to 12 yuan, more preferably 7 to 10 yuan.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, tricyclic, Fourth Ring or polycyclic bridge ring alkyl, preferably bicyclic, tricyclic or Fourth Ring can be divided into according to a group cyclic number, be more selected as bicyclic or tricyclic.The non-limiting embodiment of " bridge ring alkyl " includes but is not limited to: (1s, 4s)-two rings [2.2.1] heptyl, two rings [3.2.1] octyl, (1s, 5s)-two rings [3.3.1] nonyl, two rings [2.2.2] octyl, (1r, 5r)-two ring [3.3.2] decyl.
The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocyclic ring, wherein be naphthenic base with the ring that precursor structure links together, it is non- Restricted embodiment includes indanyl, tetralyl, benzocyclohepta alkyl etc..Naphthenic base can be optionally substituted or unsubstituted.
" heterocycle ", " heterocycle " or " heterocycle " is used interchangeably in this application, all refer to non-aromatic heterocyclyl groups, the atom of wherein one or more cyclization is hetero atom, such as oxygen, nitrogen, sulphur atom, it including monocycle, condensed ring, bridged ring and loop coil, that is, include monocyclic heterocycles base, condensed hetero ring base, bridge heterocycle and spiro heterocyclic radical.It is preferred that having 5 to 7 unit monocycles or 7 to 10 yuan pairs-or tricyclic, 1,2 or 3 atom in nitrogen, oxygen and/or sulphur may include.The example of " heterocycle " includes but is not limited to morpholinyl, thio-morpholinyl, THP trtrahydropyranyl, and 1,1- dioxo-thiomorpholinyl, piperidyl, 2- oxo-pipehdinyl, pyrrolidinyl, 2- oxo-pyrrolidine, piperazine -2- ketone, 8- oxa- -3- aza-bicyclo [3.2.1] octyl and piperazinyl.Heterocycle can be optionally substituted or unsubstituted.
" spiro heterocyclic radical " refers to 5 to 18 yuan, two or more cyclic structures, and the polycyclic moiety of an atom is shared between monocycle each other, contain one or more double bonds in ring, but none ring has the aroma system of the pi-electron of total conjugated, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is selected from 0,1 or 2), remaining annular atom are carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Spiro heterocyclic radical is divided into single spiro heterocyclic radical, double spiro heterocyclic radicals or more spiro heterocyclic radicals according to the number for sharing spiro-atom between ring and ring, preferably single spiro heterocyclic radical and double spiro heterocyclic radicals.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro heterocyclic radicals.The non-limiting embodiment of " spiro heterocyclic radical " includes but is not limited to: 1,7- dioxo spiro [4.5] decyl, 2- oxa- -7- azaspiro [4.4] nonyl, 7- oxaspiro [3.5] nonyl and 5- oxaspiro [2.4] heptyl.
" condensed hetero ring base " refers to the full carbon polycyclic moiety containing two or more cyclic structures public a pair of of atom each other, one or more rings can contain one or more double bonds, but none ring has the aroma system of the pi-electron of total conjugated, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atom are carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, tricyclic, Fourth Ring or polycyclic condensed hetero ring base, preferably bicyclic or tricyclic, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic condensed hetero ring bases can be divided into according to a group cyclic number.The non-limiting embodiment of " condensed hetero ring base " includes but is not limited to: octahydro pyrrolo- [3,4-c] pyrrole radicals, octahydro -1H- isoindolyl, 3- azabicyclic [3.1.0] hexyl, octahydro benzo [b] [Isosorbide-5-Nitrae] dioxin (dioxine).
" bridge heterocycle " refers to 5 to 14 yuan, 5 to 18 yuan, contain two or more cyclic structures, the polycyclic moiety of two atoms not being connected directly is shared each other, one or more rings can contain one or more double bonds, but none ring has the aroma system of the pi-electron of total conjugated, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)qThe hetero atom of (wherein q is integer 0 to 2), remaining annular atom are carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, tricyclic, Fourth Ring or polycyclic bridge heterocycle, preferably bicyclic, tricyclic or Fourth Ring can be divided into according to a group cyclic number, be more selected as bicyclic or tricyclic.The non-limiting embodiment of " condensed hetero ring base " includes but is not limited to: 2- azabicyclic [2.2.1] heptyl, 2- azabicyclic [2.2.2] octyl and 2- azabicyclic [3.3.2] decyl.
The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, wherein being heterocycle with the ring that precursor structure links together.Heterocycle can be optionally substituted or unsubstituted.
" aryl " refers to the carbocyclic aromatic system containing one or two rings, wherein the ring can be linked together in a manner of condensed.Term " aryl " includes the aromatic group of such as phenyl, naphthalene, tetralyl.Preferred aryl groups are C6-C10Aryl, more preferable aryl are phenyl and naphthalene, most preferably phenyl.Aryl can be optionally substituted or unsubstituted." aryl " can be with heteroaryl, heterocycle or Cycloalkylfused, wherein linking together with precursor structure is aryl rings, non-limiting embodiment includes but is not limited to:
" heteroaryl " refers to 5 to 6 unit monocycle of aromatic series or 9 to 10 membered bicyclics, may include 1 to 4 atom in nitrogen, oxygen and/or sulphur.The embodiment of " heteroaryl " includes but is not limited to furyl, pyridyl group, it is 2- oxo -1,2- dihydropyridine base, pyridazinyl, pyrimidine radicals, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazoles base, imidazole radicals, pyrrole radicals, pyrazolyl, triazolyl, tetrazole radical, thiazolyl, different Thiazolyl, 1,2,3- thiadiazolyl groups, benzodioxole group, benzimidazolyl, indyl, isoindolyl, 1,3- dioxo-isoindolyl, quinolyl, indazolyl, benzisothia oxazolyl, benzoxazolyl and benzo isoxazolyl.Heteroaryl can be optionally substituted or unsubstituted.The heteroaryl ring can be condensed on aryl, heterocycle or cycloalkyl ring, wherein the ring to link together with precursor structure is heteroaryl ring, non-limiting embodiment includes but is not limited to:
" alkoxy " refers to the group of (alkyl-O-).Wherein, alkyl is shown in related definition herein.C1-C6Alkoxy be preferential selection.The example includes, but are not limited to: methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy etc..
" hydroxyl " refers to-OH group.
" halogen " refers to fluorine, chlorine, bromine and iodine, preferably chlorine, bromine and iodine.
" amino " refers to-NH2。
" cyano " refers to-CN.
" nitro " refers to-NO2。
" benzyl " refers to-CH2Phenyl.
" carboxyl " refers to-C (O) OH.
" carboxylate " refers to-C (O) O (alkyl) or (naphthenic base), and wherein alkyl, naphthenic base are as defined above.
" substituted " refers to that one or more hydrogen atoms in group, preferably at most 5, more preferably 1~3 hydrogen atom are replaced by the substituent group of respective number independently of one another.Self-evident, substituent group is only in their possible chemistry position, and those skilled in the art can determine in the case where not paying and excessively making great efforts and (pass through experiment or theory) possible or impossible substitution.It may be unstable when for example, amino or hydroxyl with free hydrogen are in conjunction with the carbon atom with unsaturated (such as olefinic) key.
" substitution " or " substituted " described in this specification, as without particularly pointing out, each mean that group can be substituted with one or more groups selected from the following: alkyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, dredges base, hydroxyl, nitro, cyano, naphthenic base, heterocycle, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, amino, halogenated alkyl, hydroxyalkyl, carboxyl, carboxylate ,=O ,-NR at alkenyl6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8Or-NR6C(O)R7, wherein R6、R7And R8Definition as described in logical formula (I).
The definition of neutral body chemistry of the present invention and the use of convention are typically referenced to following documents:
S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-HillBook Company,New York；And Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley&Sons, Inc., New York, 1994. the compound of the present invention may include asymmetric center or chiral centre, therefore there are different stereoisomers.All stereoisomer forms of the compound of the present invention, including but not limited to diastereomer, enantiomter, atropisomer and its their mixture, such as racemic mixture constitute a part of the invention.Diastereoisomer can be separated into individual diastereoisomers by the methods of chromatography, crystallization, distillation or distillation based on its physical chemical differences.Enantiomter can pass through separation, chiral photo-isomerisation mixture is set to be converted into diastereomeric mixtures, its mode is and appropriate optically active compound (such as chiral adjuvant, for example chiral alcohol or MosherShi acyl chlorides) reaction, diastereoisomer is separated, and individual diastereoisomers is made to be converted into corresponding pure enantiomter.Intermediate of the invention can also exist from compound with different tautomeric forms, and all such form is comprised in the scope of the present invention.Many organic compounds all exist with optical active forms, i.e. the plane of their capable Plane of rotation polarised lights.When describing optically active compound, prefix D, L or R, S are used to indicate the exhausted of molecular chiral center To configuration.The symbol that prefix d, l or (+), (-) are used to that compound linearly polarized light is named to rotate, (-) or l refer to compound be it is left-handed, prefix (+) or d refer to that compound is dextrorotation.It is identical that the atom or atomic group of these stereoisomers interconnect order, but their stereochemical structure is different.Specific stereoisomer can be enantiomer, and the mixture of isomers is commonly referred to as enantiomeric mixture.The mixture of enantiomers of 50:50 is referred to as racemic mixture or racemic modification, this, which may cause in chemical reaction process, does not have stereoselectivity or stereoselectivity.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomters, lack optical activity.
" tautomer " or " tautomeric form " refers to that the isomer of the structure of different-energy can be by the mutual inversion of phases of low energy barrier.Such as proton tautomer (i.e. prototropic tautomer) includes the interconversion by proton transfer, such as the isomerization of keto-enol and imine-enamine.Valence (chemical valence) tautomer includes the interconversion for recombinating bonding electrons.Unless other aspects show, structural formula described in the invention includes all isomeric forms (such as enantiomerisms, diastereo-isomerism, and geometrical isomerism): such as R, S configuration containing asymmetric center, (Z), (E) isomers of double bond, and the conformer of (Z), (E).Therefore, the mixture of the single three-dimensional chemical isomer or its enantiomter of the compound of the present invention, diastereoisomer or geometric isomer belongs to the scope of the present invention.
" pharmaceutical salt " refers to that above compound is able to maintain original bioactivity and is suitable for certain salts of medical usage.The pharmaceutical salt of compound represented by formula (I) can be metal salt, the amine salt formed with suitable acid, metal salt preferred as alkali, alkali salt, suitable acid includes inorganic acid and organic acid, such as acetic acid, benzene sulfonic 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-methyl benzenesulfonic acid etc..Particularly preferably hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, most preferably hydrochloride.
" pharmaceutical composition " indicates mixture and the pharmaceutical carrier of other components such as physiology and excipient containing one or more compounds described herein or its physiologically pharmaceutical salt or pro-drug and other chemical constituents.The purpose of pharmaceutical composition is the administration promoted to organism, plays bioactivity in turn conducive to the absorption of active constituent.
The synthetic method of the compounds of this invention
In order to complete the purpose of the present invention, the present invention adopts the following technical scheme:
The present invention leads to the preparation method of compound or its salt described in formula (II), comprising the following steps:
General formula compound (IIa) reacts under alkaline condition with general formula compound (IIb), obtains general formula (IIc)；General formula compound (IIc) is under alkaline condition Hydrolysis, obtains general formula compound (IId) compound；General formula compound (IId) compound, which exists with general formula compound (IIe) or its salt in condensation reagent, to react, and obtains general formula compound (IIf) compound；General formula compound (IIf) hydrolyzes under alkaline condition, and acidification obtains general formula compound (IIA)；General formula compound (IIA) is reacted with general formula compound (IIB), optionally further hydrolysis, obtains logical formula (II) compound.
Wherein:
X is selected from hydroxyl or halogen；
Ra、RbAnd RcSelected from alkyl；And
R1~R5、A1~A5, m, n and p definition as described in logical formula (II).
In above-mentioned preparation method, alkaline condition is provided by organic base or inorganic base, and organic base is selected from diisopropylethylamine, pyridine, triethylamine, piperidines, N methyl piperazine, 4- dimethylamino pyridine or potassium tert-butoxide, preferably diisopropylethylamine, triethylamine or potassium tert-butoxide；Inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide or hydrofining, preferably sodium hydroxide or lithium hydroxide.
In above-mentioned preparation method, condensation reagent includes, but it is not limited to: bis- (2- oxo -3- oxazolidinyls) secondary phosphoryl chloride phosphorus oxychloride, N, N- dicyclohexylcarbodiimide, N, two Asia of N- diisopropyl carbon, 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride, o- benzotriazole-N, N, N ' N '-tetramethylurea borate (TBTU), preferably 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride or bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychlorides.
The present invention leads to the preparation method of compound or its salt described in formula (III), comprising the following steps:
General formula compound (IIIa) reacts in the presence of tetraisopropyl titanate and ammonia methanol, obtains general formula (IIIb)；General formula compound (IIIb) and general formula (IIIc) carry out condensation reaction, obtain general formula compound (IIId) compound；Reaction is hydrolyzed in general formula compound (IIId) compound in acid condition, obtains general formula compound (IIIA)；General formula compound (IIIA) and general formula compound (IIe) or its reactant salt, optionally further hydrolysis, obtain logical formula (III) compound.
Wherein:
X is selected from hydroxyl or halogen；
Ra、RbAnd RcSelected from alkyl；And
R1~R5、A1~A5, m, n and p definition as described in logical formula (III).
In above-mentioned preparation method, alkaline condition is provided by organic base or inorganic base, and organic base is selected from diisopropylethylamine, pyridine, triethylamine, piperidines, N methyl piperazine, 4- dimethylamino pyridine or potassium tert-butoxide, preferably diisopropylethylamine, triethylamine or potassium tert-butoxide；Inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide or hydrofining, preferably sodium hydroxide or lithium hydroxide.
Acid condition is provided by inorganic acid or organic acid, and inorganic acid is selected from hydrochloric acid or phosphoric acid.
In above-mentioned preparation method, condensation reagent includes, but it is not limited to: bis- (2- oxo -3- oxazolidinyls) secondary phosphoryl chloride phosphorus oxychloride, N, N- dicyclohexylcarbodiimide, N, two Asia of N- diisopropyl carbon, 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride, o- benzotriazole-N, N, N ' N '-tetramethylurea borate (TBTU), preferably 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride or bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychlorides.
Detailed description of the invention
Fig. 1 is preferred compound of the present invention to 28 days administration blood glucose value change curves of db/db mouse, wherein ordinate is blood glucose value (mmol/L), and abscissa is administration time (day).
Specific embodiment
With reference to embodiments for further describing the present invention, but these embodiments not limit the scope of the present invention.
Embodiment
Embodiment gives preparation and the dependency structure appraising datum of representative compound represented by formula (I).Mandatory declaration, following embodiments are for illustrating the invention and not limiting the invention.1H NMR spectra is to be measured and obtained with Bruker instrument (400MHz), and chemical shift is indicated with ppm.It uses tetramethylsilane internal standard (0.00ppm).1The representation method of H NMR: s=is unimodal, d=doublet, t=triplet, m=multiplet, what br=broadened, the doublet of dd=doublet, the doublet of dt=triplet.If coupling constant is provided, unit Hz.
Mass spectrum is to measure to obtain with LC/MS instrument, and Ionization mode can be ESI or APCI.
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, and the specification that the silica gel plate that thin-layered chromatography (TLC) uses uses is 0.15mm~0.2mm, and the specification that thin-layer chromatography isolates and purifies product use is 0.4mm~0.5mm.
Column chromatography is generally carrier using 200~300 mesh silica gel of Yantai Huanghai Sea silica gel.
In following Examples, unless otherwise specified, all temperature are Celsius temperature, and unless otherwise specified, various starting materials and reagent come from commercially available or synthesize according to known methods, marketable material and reagent directly use without further purification, unless otherwise specified, commercially available producer includes but is not limited to Aldrich Chemical Company, ABCR GmbH&Co.KG, Acros Organics, Guang Zan Chemical Industry Science Co., Ltd and Jing Yan Chemical Industry Science Co., Ltd etc. purchase.
CD3OD: deuterated methanol.
CDCl3: deuterated chloroform.
DMSO-d6: deuterated dimethyl sulfoxide.
Argon atmospher refers to that reaction flask connects the argon gas balloon of an about 1L volume.
Without specified otherwise in embodiment, the solution in reaction refers to aqueous solution.
The monitoring of reaction process in embodiment uses thin-layered chromatography (TLC), the system of solvent used in reacting has: A: petroleum ether and ethyl acetate system, B: methylene chloride and ethyl acetate system, C: the volume ratio of methylene chloride and methanol system, solvent is different according to the polarity of compound and is adjusted.
The system of column chromatography or the eluant, eluent of thin layer chromatography board includes: A: petroleum ether and ethyl acetate system, B: normal hexane and ethyl acetate system, C: methylene chloride and methanol system, D: petroleum ether and methanol system.The volume ratio of solvent is different according to the polarity of compound and is adjusted, and a small amount of ammonium hydroxide and acetic acid etc. can also be added and be adjusted.
Embodiment 1
3- (4- ((2R, 3S)/(2S, 3R) -1- ((the chloro- 2'- methyl-of 4'- [1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 1
3- (4- ((2R, 3S) -1- ((the chloro- 2'- methyl-of 4'- [1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 1A
3- (4- ((2S, 3R) -1- ((the chloro- 2'- methyl-of 4'- [1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 1B
The first step
4- (1- hydroxybutyl) methyl benzoate
4- acyl radical methyl benzoate 1a (10.00g, 60.92mmol) is dissolved in 100mL tetrahydrofuran, reaction solution is cooled to -78 DEG C; propyl magnesium bromide 1b (33.50mL is added dropwise; 67.00mmol), it after being added dropwise, is stirred at room temperature 3 hours.The quenching of 100mL water is added in reaction solution, ethyl acetate extraction (100mL × 3) is added, combined organic phase is washed with saturated ammonium chloride solution (200mL) and sodium chloride solution (200mL), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 4- (1- hydroxybutyl) methyl benzoate 1c (7.50g, colourless liquid), yield: 59.1%.
1H NMR (400MHz, CDCl3): δ 7.99 (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
4- (1- brombutyl) methyl benzoate
By 4- (1- hydroxybutyl) methyl benzoate 1c (7.50g, it 36.00mmol) is dissolved in 100mL methylene chloride, it is added with stirring carbon tetrabromide (23.88g, 72.00mmol) and triphenylphosphine (18.88g, 72.00mmol), it stirs 24 hours at room temperature.Reaction solution is concentrated under reduced pressure, obtained residue is further isolated and purified by silica gel column chromatography (eluant, eluent: system A), obtain 4- (1- brombutyl) methyl benzoate 1d (6.49g, brown liquid), yield: 66.5%.
1H NMR (400MHz, CDCl3): δ 8.01 (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)
Third step
2- (4- (trifluoromethoxy) phenyl) tert-butyl acetate
Magnesium sulfate (21.86g, 182mmol) is dissolved in 100mL methylene chloride, is added dropwise the concentrated sulfuric acid (2.66mL, 50mmol), is stirred 10 minutes After sequentially add 2- (4- (trifluoromethoxy) phenyl) acetic acid 1e (10g, 45.4mmol) and the tert-butyl alcohol (4.9mL, 50mmol), at room temperature stir 24 hours.Reaction solution is poured into 100mL saturated sodium bicarbonate solution, (100mL × 3) are extracted with ethyl acetate in reaction solution, combined organic phase is washed with saturated ammonium chloride solution (200mL) and sodium chloride solution (200mL × 2), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 2- (4- (trifluoromethoxy) phenyl) tert-butyl acetate 1f (8.84g, brown liquid), yield: 70.7%.
1H NMR (400MHz, CDCl3): δ 7.29 (d, J=8.28Hz, 2H) 7.16 (d, J=8.03Hz, 2H) 3.53 (s, 2H) 1.44 (s, 9H)
4th step
4- (1- (tert-butoxy) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) methyl benzoate
By 2- (4- (trifluoromethoxy) phenyl) tert-butyl acetate 1f (7.11g, 25.7mmol) and potassium tert-butoxide (6.98g, 25.7mmol) it is dissolved in 50mLN, in dinethylformamide, it is added with stirring 4- (1- brombutyl) methyl benzoate 1d (6.98g, 25.7mmol), it stirs 5 hours at room temperature.The quenching of 100mL water is added in reaction solution, (100mL × 3) are extracted with ethyl acetate, combined organic phase is washed with sodium chloride solution (200mL × 2), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 4- (1- (tert-butoxy) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) methyl benzoate 1g (4.27g, white solid), yield: 35.6%.
MS m/z (ESI): 410.9 [M-57]
5th step
4- (1- (tert-butoxy) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzoic acid
By 4- (1- (tert-butoxy) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) methyl benzoate 1g (4.27g, 9.2mmol) it is dissolved in the in the mixed solvent of 30mL tetrahydrofuran and methanol (V/V=1:1), it is added with stirring 5mL sodium hydroxide (1.83g, 45.8mmol) in solution, stir 3 hours at room temperature.Reaction solution is concentrated under reduced pressure, with 2M hydrochloric acid conditioning solution pH=6, (200mL) is extracted with ethyl acetate, combined organic phase is washed with sodium chloride solution (100mL × 2), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 4- (1- (tert-butoxy) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzoic acid 1h (4g, white solid), yield: 96.6%.
MS m/z (ESI): 452.46 [M-57]
6th step
3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hecanoic acid t-butyl ester 1k
((2R; 3S)/(2S, 3R)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hecanoic acid t-butyl ester 1p
((2R; 3R)/(2S, 3S)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hecanoic acid t-butyl ester 1q
By 4- (1- (tert-butoxy) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzoic acid 1h (4.00g, 8.84mmol), 3- alanine carbethoxy hydrochloride 1j (1.25g, 10.60mmol), I-hydroxybenzotriazole (1.79g, 13.30mmol) and 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride (2.54g, it 13.30mmol) is dissolved in 50mL tetrahydrofuran, it is added with stirring triethylamine (7.8mL, 44.2mmol), it stirs 24 hours at room temperature.It goes out 50mL water quenching is added in reaction solution, (200mL) is extracted with ethyl acetate, combined organic phase is washed with sodium chloride solution (100mL × 2), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hecanoic acid t-butyl ester 1k (2.352g, white solid), silica gel column chromatography separating purification can further be passed through, respectively obtain slower elution ((2R, 3S)/(2S, 3R)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hecanoic acid t-butyl ester 1p (1.61g; white solid) and very fast elution ((2R; 3R)/(2S; 3S)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hecanoic acid t-butyl ester 1q (742mg; white solid), yield: 35.1%.
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) .
7th step
((2R, 3S)/(2S, 3R)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) caproic acid 1m
((2R, 3R)/(2S, 3S)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) caproic acid 1s
By ((2R; 3S)/(2S; 3R)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hecanoic acid t-butyl ester 1p (1.61g; it 2.90mmol) is dissolved in 20mL trifluoroacetic acid, stirs 0.5 hour at room temperature.Reaction solution is concentrated under reduced pressure; obtained residue is with silica gel column chromatography (eluant, eluent: system A)) purifying; obtain ((2R; 3S)/(2S; 3R)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) caproic acid 1m (1.40g; light yellow oil), yield: 97.2%.
MS m/z (ESI): 495.9 [M+1]
By ((2R; 3R)/(2S; 3S)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) hecanoic acid t-butyl ester 1q (742.00mg; it 1.35mmol) is dissolved in 20mL methylene chloride; trifluoroacetic acid (0.20mL is added; 2.69mmol); after stirring 0.5 hour at room temperature; 5mL trifluoroacetic acid is added, the reaction was continued 3 hours.Reaction solution is concentrated under reduced pressure; obtained residue is purified with silica gel column chromatography (eluant, eluent: system A); obtain ((2R; 3R)/(2S; 3S)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) caproic acid 1s (663.00mg; faint yellow dope), yield: 99.48%.
MS m/z (ESI): 495.9 [M+1]
8th step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((the chloro- 2'- methyl-of 4'- [1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzene first
Acylamino-) ethyl propionate
By ((2R, 3S)/(2S, 3R)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) caproic acid 1m (80.00mg, 0.16mmol), the chloro- 2'- methyl-[1 of 4'-, 1'- biphenyl] -4- amine 1n (52.00mg, 0.24mmol), I-hydroxybenzotriazole (43.00mg, 0.32mmol) and 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride (61mg, it 0.32mmol) is dissolved in 20mL methylene chloride, it is added with stirring triethylamine (0.14mL, 0.80mmol), it stirs 24 hours at room temperature.Reaction solution is concentrated under reduced pressure, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- ((the chloro- 2'- methyl-[1 of 4'-, 1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 1t (58.00mg, white solid), yield: 51.8%.
MS m/z (ESI): 695.8 [M+1]
9th step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((the chloro- 2'- methyl-of 4'- [1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzene first
Acylamino-) propionic acid
By 3- (4- ((2R, 3S)/(2S, 3R) -1- ((the chloro- 2'- methyl-[1 of 4'-, 1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 1t (50.00mg, 0.072mmol) it is dissolved in the in the mixed solvent of 6mL tetrahydrofuran and methanol (V/V=1:1), it is added with stirring 1mL sodium hydroxide (14.40mg, 0.36mmol) in solution, stir 3 hours at room temperature.Reaction solution is concentrated under reduced pressure, pH=3 is adjusted with 1M hydrochloric acid, (60mL) is extracted with ethyl acetate, combined organic phase is washed with sodium chloride solution (30mL × 3), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- ((the chloro- 2'- methyl-[1 of 4'-, 1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) 1 (4.00g of propionic acid, white solid), yield: 64.5%.
MS m/z (ESI): 668.7 [M+1]
1H NMR(400MHz,DMSO-d6) δ 10.07 (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- ((the chloro- 2'- methyl-[1 of 4'-, 1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 1 is further by using supercritical fluid chromatography (SFC) method, ((1) chiral column ChiralPak AD is split with Preparation equipment and the chiral isomers of chiral column, 25 × 3cm, 80mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (2) Whelk O1 (S, S), 25 × 3cm, 65mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (3) Whelk O1 (S, S), 25 × 3cm, 70mL/min；Mobile phase A for CO2And B for Ethanol)) it is split, obtain 3- (4- ((2R, 3S) -1- ((the chloro- 2'- methyl-[1 of 4'-, 1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 1A and 3- (4- ((2S, 3R) -1- ((the chloro- 2'- methyl-of 4'- [1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 1B.
1A:MS m/z (ESI): 668.7 [M+1]
1B:MS m/z (ESI): 668.7 [M+1]
Embodiment 2
3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) hexane -3- base) benzamido) propionic acid 2
3- (4- ((2R, 3S) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) hexane -3- base) benzamido) propionic acid 2A
3- (4- ((2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) hexane -3- base) benzamido) propionic acid 2B
The first step
3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) hexane -3- base) benzamido) ethyl propionate
By ((2R, 3S)/(2S, 3R)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) caproic acid 1m (100.00mg, 0.20mmol), 2', 4', 6'- trimethyl-[1, 1'- biphenyl] -4- amine 2a (63.00mg, 0.3mmol), I-hydroxybenzotriazole (41.00mg, 0.30mmol) and 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride (43.00mg, it 0.32mmol) is dissolved in 10mL methylene chloride, it is added with stirring N, N- diisopropylethylamine (0.09mL, 0.50mmol), it stirs 24 hours at room temperature.Reaction solution is concentrated under reduced pressure, obtained residue is purified with silica gel column chromatography (eluant, eluent: system B), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) hexane -3- base) benzamido) ethyl propionate 2b (50.00mg, white solid), yield: 36.3%.
MS m/z (ESI): 689.9 [M+1]
Second step
3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) hexane -3- base) benzamido) propionic acid
By 3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) hexane -3- base) benzamido) ethyl propionate 2b (50.00mg, 0.072mmol) it is dissolved in the in the mixed solvent of 6mL tetrahydrofuran and methanol (V/V=1:1), it is added with stirring 1mL sodium hydroxide (14.40mg, 0.36mmol) in solution, stir 3 hours at room temperature.Reaction solution is concentrated under reduced pressure, pH=3 is adjusted with 1M hydrochloric acid, (20mL) is extracted with ethyl acetate, combined organic phase is washed with sodium chloride solution (20mL × 3), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system B), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2', 4', 6'- trimethyl-[1, 1'- biphenyl] -4- base) amino) hexane -3- base) benzamido) 2 (20.00mg of propionic acid, white solid), yield: 42.0%.
MS m/z (ESI): 661.9 [M+1]
1H NMR(400MHz,DMSO-d6) δ 10.00 (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'- biphenyl] -4- base) amino) hexane -3- base) Benzamido) propionic acid 2 further by using supercritical fluid chromatography (SFC) method, split ((1) chiral column ChiralPak AD, 25 × 3cm, 80mL/min with Preparation equipment and the chiral isomers of chiral column；Mobile phase A for CO2and B for Ethanol；Or/and (2) Whelk O1 (S, S), 25 × 3cm, 65mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (3) Whelk O1 (S, S), 25 × 3cm, 70mL/min；Mobile phase A for CO2And B for Ethanol)) it is split, obtain 3- (4- ((2R, 3S) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2', 4', 6'- trimethyl-[1, 1'- biphenyl] -4- base) amino) hexane -3- base) benzamido) 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- base) amino) hexane -3- base) benzamido) propionic acid 2B (white solid).
2A:MS m/z (ESI): 668.7 [M+1]
2B:MS m/z (ESI): 668.7 [M+1]
Embodiment 3
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (benzofuran -2- base) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 3
3- (4- ((2R, 3S) -1- ((4- (benzofuran -2- base) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 3A
3- (4- ((2S, 3R) -1- ((4- (benzofuran -2- base) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 3B
The first step
4- (benzofuran -2- base) aniline
By 4- Iodoaniline 3a (448.00mg; 2.05mmol), 2- (benzofuran -2- base) -4; 4; 5; 5- tetramethyl -1; 3; penta ring 3b (500.00mg of 2- dioxy boron; 21.10mmol), 1; 1'- bis(diphenylphosphino) ferrocene dichloropalladium (II) (1.54g, 2.11mmol) and sodium carbonate (652.00mg, 6.15mmol) are dissolved in the in the mixed solvent of 28mL dimethyl ether, second alcohol and water (V/V/V=5:1:1); under argon gas protection, reaction solution reacts 5 hours at 100 DEG C.Reaction solution is concentrated under reduced pressure, obtained residue is purified with silica gel column chromatography (eluant, eluent: system B), obtains 4- (benzofuran -2- base) aniline 3c (150.00mg, white solid), yield: 35%.
MS m/z (ESI): 210.9 [M+1]
Second step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (benzofuran -2- base) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid
By ((2R; 3S)/(2S; 3R)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) caproic acid 1m (80mg; 0.16mmol), 4- (benzofuran -2- base) aniline 3c (50mg; 0.24mmol), bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (61mg; it 0.24mmol) is dissolved in 10mL methylene chloride; it is added with stirring N; N- diisopropylethylamine (0.14mL; 0.8mmol), it stirs 1 hour at room temperature.Reaction solution is concentrated under reduced pressure, obtained residue is purified with silica gel column chromatography (eluant, eluent: system B), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (benzofuran -2- base) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 3d (61mg, white solid), yield: 55.6%.
MS m/z (ESI): 687.8 [M+1]
Third step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (benzofuran -2- base) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid
By 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (benzofuran -2- base) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 3d (60mg, 0.087mmol) it is dissolved in the in the mixed solvent of 6mL tetrahydrofuran and methanol (V/V=1:1), it is added with stirring mono- hydronium(ion) lithia (73mg of 1mL, 1.75mmol) in solution, stir 3 hours at room temperature.Reaction solution 1M hydrochloric acid is adjusted into pH=3, (50mL) is extracted with ethyl acetate, combined organic phase successively uses saturated ammonium chloride solution (50mL × 2), sodium chloride solution (50mL) washing, anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system B), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (benzofuran -2- base) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) 3 (50mg of propionic acid, white solid), yield: 87.3%.
MS m/z (ESI): 658.9 [M+1]
1H NMR(400MHz,CDCl3):δ1H NMR(400MHz,DMSO-d6) 7.73 (td of δ ppm, 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) 1.18 (d, J=4.77Hz of 1.23-1.32 (m, 3H), 1H) 0.93 (d, J=6.53Hz, 2H) 0.65 (t of 0.84-0.90 (m, 2H), J=7.15Hz, 3H)
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (benzofuran -2- base) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 3 is further by using supercritical fluid chromatography (SFC) method, ((1) chiral column ChiralPak AD is split with Preparation equipment and the chiral isomers of chiral column, 25 × 3cm, 80mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (2) Whelk O1 (S, S), 25 × 3cm, 65mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (3) Whelk O1 (S, S), 25 × 3cm, 70mL/min；Stream Dynamic phase A for CO2And B for Ethanol)) it is split, obtain 3- (4- ((2R, 3S) -1- ((4- (benzofuran -2- base) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 3A (white solid) and 3- (4- ((2S, 3R) -1- ((4- (benzofuran -2- base) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 3B (white solid).
3A:MS m/z (ESI): 658.9 [M+1]
3B:MS m/z (ESI): 658.9 [M+1]
Embodiment 4
3- (4- ((2R, 3S)/(2S, 3R) -1- ((the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 4
3- (4- ((2R, 3S) -1- ((the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 4A
3- (4- ((2S, 3R) -1- ((the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 4B
The first step
3- fluoro- 2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- amine
By the fluoro- 4- Iodoaniline 4a (5g of 2-, 21.1mmol), 2,4,6- trimethylbenzene boric acid 4b (3.46g, 21.1mmol), 1,1'- bis(diphenylphosphino) ferrocene dichloropalladium (II) (1.54g, 2.11mmol) it is dissolved in 100mL N, in dinethylformamide, it is added with stirring 20mL sodium hydroxide (2.53g 63.3mmol) in solution, under argon gas protection, reaction solution reacts 4 hours at 100 DEG C.(100mL × 3) are extracted with ethyl acetate in reaction solution, combined organic phase is washed with sodium chloride solution (100mL × 2), and anhydrous sodium sulfate dries, filters, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system B), obtains the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- amine 4c (4.8g, white solid), yield: 96.2%.
MS m/z (ESI): 230.0 [M+1]
Second step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate
By ((2R, 3S)/(2S, 3R)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) caproic acid 1m (5.00g, 10.09mmol), the fluoro- 2' of 3-, 4', 6'- trimethyl-[1, 1'- biphenyl] -4- amine 4c (2.31g, 10.09mmol), bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (3.84g, it 15.13mmol) is dissolved in 50mL methylene chloride, it is added with stirring N, N- diisopropylethylamine (8.79mL, 50.45mmol), it stirs 3 hours at room temperature.Reaction solution is concentrated under reduced pressure, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- ((the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 4d (2.10g, white solid), yield: 29.5%.
MS m/z (ESI): 706.9 [M+1]
Third step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid
By 3- (4- ((2R, 3S)/(2S, 3R) -1- ((the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 4d (5.20g, 7.35mmol) it is dissolved in the in the mixed solvent of 120mL tetrahydrofuran and methanol (V/V=1:1), it is added with stirring mono- hydronium(ion) lithia (6.10g of 10mL, 147mmol) in solution, stir 2 hours at room temperature.500mL ethyl acetate is added, it is washed with the dilute hydrochloric acid of 0.3M to pH=5~6, then it is washed with saturated sodium chloride solution (300mL), the lower concentration of organic phase decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- ((the fluoro- 2' of 3-, 4', 6'- trimethyl-[1, 1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) 4 (4.50g of propionic acid, white solid), yield: 90.18%.
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- ((the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 4 is further by using supercritical fluid chromatography (SFC) method, ((1) chiral column ChiralPak AD is split with Preparation equipment and the chiral isomers of chiral column, 25 × 3cm, 80mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (2) Whelk O1 (S, S), 25 × 3cm, 65mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (3) Whelk O1 (S, S), 25 × 3cm, 70mL/min；Mobile phase A for CO2And B for Ethanol)) it is split, obtain 3- (4- ((2R, 3S) -1- ((the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 4A and 3- (4- ((2S, 3R) -1- ((the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) 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=8.5 Hz, 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)
Embodiment 5
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2- fluoro- 4- (trifluoromethyl) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 5
3- (4- ((2R, 3S) -1- ((2- fluoro- 4- (trifluoromethyl) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 5A
3- (4- ((2S, 3R) -1- ((2- fluoro- 4- (trifluoromethyl) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 5B
The first step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2- fluoro- 4- (trifluoromethyl) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate
By ((2R; 3S)/(2S, 3R)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) caproic acid 1m (60 Mg, 0.12mmol), the fluoro- 4- of 2- (trifluoromethyl) aniline 5a (25mg, 0.13mmol), bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (46mg, it 0.18mmol) is dissolved in 20mL methylene chloride, it is added with stirring triethylamine (0.085mL, 0.6mmol), it stirs 2 hours at room temperature.15mL ethyl acetate and 10mL water will be added in reaction solution, pH=1 is adjusted with 3M hydrochloric acid, aqueous layer with ethyl acetate extracts (15mL × 2), combined organic phase is successively washed with saturated sodium chloride solution (10mL), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system B), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- ((2- fluoro- 4- (trifluoromethyl) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 5b (20mg, white solid), yield: 25.6%.
Second step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2- fluoro- 4- (trifluoromethyl) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid
By 3- (4- ((2R, 3S)/(2S, 3R) -1- ((2- fluoro- 4- (trifluoromethyl) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 5b (20mg, 0.03mmol) it is dissolved in the in the mixed solvent of 3mL tetrahydrofuran and water (V/V=2:1), it is added with stirring a hydronium(ion) lithia (3mg, in 0.06mmol), stir 24 hours at room temperature.Reaction solution 1M hydrochloric acid is adjusted into pH=3, (15mL) is being extracted with ethyl acetate, combined organic phase successively uses saturated ammonium chloride solution (10mL), saturated sodium chloride solution (10mL) washing, anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system C), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- ((2- fluoro- 4- (trifluoromethyl) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) 5 (18mg of propionic acid, white solid), yield: 94.7%.
MS m/z (ESI): 629.8 [M+1]
1H NMR (400MHz, DMSO-d6): δ 10.08 (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) hexane -3- base) benzamido) propionic acid 5 compound further by using supercritical fluid chromatography (SFC) method, ((1) chiral column ChiralPak AD is split with Preparation equipment and the chiral isomers of chiral column, 25 × 3cm, 80mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (2) Whelk O1 (S, S), 25 × 3cm, 65mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (3) Whelk O1 (S, S), 25 × 3cm, 70mL/min；Mobile phase A for CO2And B for Ethanol)) it is split, obtain 3- (4- ((2R, 3S) -1- ((2- fluoro- 4- (trifluoromethyl) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 5A (white solid) and 3- (4- ((2S, 3R) -1- ((2- fluoro- 4- (trifluoromethyl) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 5B (white solid).
5A:MS m/z (ESI): 629.8 [M+1]
5B:MS m/z (ESI): 629.8 [M+1]
Embodiment 6
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2,5- difluorophenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 6
3- (4- ((2R, 3S) -1- ((2,5- difluorophenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 6A
3- (4- ((2S, 3R) -1- ((2,5- difluorophenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 6B
The first step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2,5- difluorophenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate
By ((2R; 3S)/(2S; 3R)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) caproic acid 1m (80mg; 0.16mmol), 2; 5- difluoroaniline 6a (33.3mg; 0.24mmol), bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (61mg; it 0.24mmol) is dissolved in 10mL methylene chloride; it is added with stirring N; N- diisopropylethylamine (0.11mL; 0.64mmol), it stirs 1 hour at room temperature.Reaction solution is concentrated under reduced pressure, obtained residue is purified with silica gel column chromatography (eluant, eluent: system B), obtain 3- (4- ((2R, 3S)/(2S, 3R) ((2-1-, 5- difluorophenyl) amino)-1- oxo-2- (4- (trifluoromethoxy) phenyl) hexane-3- base) benzamido) ethyl propionate 6b (50mg, white solid), yield: 51.0%.
MS m/z (ESI): 607.9 [M+1]
Second step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2,5- difluorophenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid
By 3- (4- ((2R, 3S)/(2S, 3R) ((2-1-, 5- difluorophenyl) amino)-1- oxo-2- (4- (trifluoromethoxy) phenyl) hexane-3- base) benzamido) ethyl propionate 6b (48mg, 0.097mmol) it is dissolved in the in the mixed solvent of 4mL tetrahydrofuran and methanol (V/V=1:1), it is added with stirring 1mL sodium hydroxide (19.4mg, 0.49mmol) in solution, stir 2 hours at room temperature.Reaction solution is removed into partial solvent under reduced pressure, 5mL ethyl acetate and 5mL water is added, 2 drop 3M salt acid for adjusting pH value are added dropwise, (10mL × 3) are extracted with ethyl acetate, combined organic phase is washed with sodium chloride solution (10mL × 3), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with thin layer chromatography (solvent: system C), obtain 3- (4- ((2R, 3S)/(2S, 3R) ((2-1-, 5- difluorophenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) Propionic acid 6 (21mg, white solid), yield: 46.0%.
MS m/z (ESI): 579.8 [M+1]
1H NMR(400MHz,DMSO-d6): δ 12.90 (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) ((2-1-, 5- difluorophenyl) amino)-1- oxo-2- (4- (trifluoromethoxy) phenyl) hexane-3- base) benzamido) propionic acid 6 is further by using supercritical fluid chromatography (SFC) method, ((1) chiral column ChiralPak AD is split with Preparation equipment and the chiral isomers of chiral column, 25 × 3cm, 80mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (2) Whelk O1 (S, S), 25 × 3cm, 65mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (3) Whelk O1 (S, S), 25 × 3cm, 70mL/min；Mobile phase A for CO2And B for Ethanol)) it is split, obtain 3- (4- ((2R, 3S) ((2-1-, 5- difluorophenyl) amino)-1- oxo-2- (4- (trifluoromethoxy) phenyl) hexane-3- base) benzamido) propionic acid 6A (white solid) and 3- (4- ((2S, 3R)-1- ((2,5- difluorophenyl) amino)-1- oxo-2- (4- (trifluoromethoxy) phenyl) hexane-3- base) benzamido) propionic acid 6B (white solid).
6A:MS m/z (ESI): 579.8 [M+1]
6B:MS m/z (ESI): 579.8 [M+1]
Embodiment 7
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2,4 difluorobenzene base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 7
3- (4- ((2R, 3S) -1- ((2,4 difluorobenzene base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 7A
3- (4- ((2S, 3R) -1- ((2,4 difluorobenzene base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 7B
The first step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2,4 difluorobenzene base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate
By ((2R; 3S)/(2S; 3R)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) caproic acid 1m (80mg; 0.16mmol), 2; 4- difluoroaniline 7a (0.024mL; 2.4mmol), bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (61mg; it 0.24mmol) is dissolved in 20mL methylene chloride; it is added with stirring N; N- diisopropylethylamine (0.11mL; 0.64mmol), it stirs 1 hour at room temperature.Reaction solution is concentrated under reduced pressure, obtained residue is purified with silica gel column chromatography (eluant, eluent: system B), obtain 3- (4- ((2R, 3S)/(2S, 3R) ((2-1-, 4- difluorophenyl) amino)-1- oxo-2- (4- (trifluoromethoxy) phenyl) hexane-3- base) benzamido) ethyl propionate 7b (40mg, white solid), yield: 41.2%.
MS m/z (ESI): 607.9 [M+1]
Second step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2,4 difluorobenzene base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid
By 3- (4- ((2R, 3S)/(2S, 3R) ((2-1-, 4- difluorophenyl) amino)-1- oxo-2- (4- (trifluoromethoxy) phenyl) hexane-3- base) benzamido) ethyl propionate 7b (40mg, 0.066mmol) it is dissolved in the in the mixed solvent of 6mL tetrahydrofuran and methanol (V/V=1:1), it is added with stirring 1mL sodium hydroxide (14.4mg, 0.36mmol) in solution, stir 1.5 hours at room temperature.Reaction solution is concentrated under reduced pressure, pH=3 is adjusted with 1M hydrochloric acid, ethyl acetate extracts (60mL), combined organic phase is washed with sodium chloride solution (60mL × 3), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system B), obtain 3- (4- ((2R, 3S)/(2S, 3R) ((2-1-, 4- difluorophenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) 7 (31mg of propionic acid, white solid), yield: 81.3%.
MS m/z (ESI): 579.8 [M+1]
1H NMR(400MHz,DMSO-d6) δ 9.78 (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) ((2-1-, 4- difluorophenyl) amino)-1- oxo-2- (4- (trifluoromethoxy) phenyl) hexane-3- base) benzamido) propionic acid 7 is further by using supercritical fluid chromatography (SFC) method, ((1) chiral column ChiralPak AD is split with Preparation equipment and the chiral isomers of chiral column, 25 × 3cm, 80mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (2) Whelk O1 (S, S), 25 × 3cm, 65mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (3) Whelk O1 (S, S), 25 × 3cm, 70mL/min；Mobile phase A for CO2And B for Ethanol)) it is split, obtain 3- (4- ((2R, 3S) ((2-1-, 4- difluorophenyl) amino)-1- oxo-2- (4- (trifluoromethoxy) phenyl) hexane-3- base) benzamido) propionic acid 7A (white solid) and 3- (4- ((2S, 3R)-1- ((2,4- difluorophenyl) amino)-1- oxo-2- (4- (trifluoromethoxy) phenyl) hexane-3- base) benzamido) propionic acid 7B (white solid).
7A:MS m/z (ESI): 579.8 [M+1]
7B:MS m/z (ESI): 579.8 [M+1]
Embodiment 8
3- (4- ((2R, 3S)/(2S, 3R) -1- ((3,4- Dimethoxyphenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 8
3- (4- ((2R, 3S) -1- ((3,4- Dimethoxyphenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 8A
3- (4- ((2S, 3R) -1- ((3,4- Dimethoxyphenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 8B
The first step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((3,4- Dimethoxyphenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate
By ((2R; 3S)/(2S; 3R)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) caproic acid 1m (80mg; 0.16mmol), 3; 4- dimethoxyaniline 8a (25mg; 0.16mmol), bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (61mg; it 0.24mmol) is dissolved in 20mL methylene chloride; it is added with stirring N; N- diisopropylethylamine (0.11mL; 0.64mmol), it stirs 1 hour at room temperature.Reaction solution is concentrated under reduced pressure, obtained residue is purified with silica gel column chromatography (eluant, eluent: system B), obtain 3- (4- ((2R, 3S)/(2S, 3R) ((3-1-, 4- Dimethoxyphenyl) amino)-1- oxo-2- (4- (trifluoromethoxy) phenyl) hexane-3- base) benzamido) ethyl propionate 8b (41mg, white solid), yield: 40.6%.
MS m/z (ESI): 607.9 [M+1]
Second step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((3,4- Dimethoxyphenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid
By 3- (4- ((2R, 3S)/(2S, 3R) ((3-1-, 4- Dimethoxyphenyl) amino)-1- oxo-2- (4- (trifluoromethoxy) phenyl) hexane-3- base) benzamido) ethyl propionate 8b (41mg, 0.065mmol) it is dissolved in the in the mixed solvent of 6mL tetrahydrofuran and methanol (V/V=1:1), it is added with stirring 1mL sodium hydroxide (14.4mg, 0.36mmol) in solution, stir 1.5 hours at room temperature.Reaction solution is concentrated under reduced pressure, pH=3 is adjusted with 1M hydrochloric acid, ethyl acetate extracts (60mL), combined organic phase is washed with sodium chloride solution (60mL × 3), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system B), obtain 3- (4- ((2R, 3S)/(2S, 3R) ((3-1-, 4- Dimethoxyphenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) 8 (30mg of propionic acid, white solid), yield: 76.6%.
MS m/z (ESI): 603.9 [M+1]
1H NMR(400MHz,DMSO-d6) δ 9.90 (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) ((3-1-, 4- Dimethoxyphenyl) amino)-1- oxo-2- (4- (trifluoromethoxy) phenyl) hexane-3- base) benzamido) propionic acid 8 is further by using supercritical fluid chromatography (SFC) method, ((1) chiral column ChiralPak AD is split with Preparation equipment and the chiral isomers of chiral column, 25 × 3cm, 80mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (2) Whelk O1 (S, S), 25 × 3cm, 65mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (3) Whelk O1 (S, S), 25 × 3cm, 70mL/min；Mobile phase A for CO2And B for Ethanol)) it is split, obtain 3- (4- ((2R, 3S) ((3-1-, 4- Dimethoxyphenyl) amino)-1- oxo-2- (4- (trifluoromethoxy) phenyl) hexane-3- base) benzamido) propionic acid 8A (white solid) and 3- (4- ((2S, 3R)-1- ((3,4- Dimethoxyphenyl) amino)-1- oxo-2- (4- (trifluoromethoxy) phenyl) hexane-3- base) benzamido) propionic acid 8B (white solid).
8A:MS m/z (ESI): 603.9 [M+1]
8B:MS m/z (ESI): 603.9 [M+1]
Embodiment 9
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- Trifluoromethoxyphen-l) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 9
3- (4- ((2R, 3S) -1- ((4- Trifluoromethoxyphen-l) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 9A
3- (4- ((2S, 3R) -1- ((4- Trifluoromethoxyphen-l) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 9B
The first step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- Trifluoromethoxyphen-l) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate
By ((2R; 3S)/(2S; 3R)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) caproic acid 1m (80mg; 0.16mmol), 4- trifluoro-methoxyaniline 9a (28mg; 0.16mmol), bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (61mg; it 0.24mmol) is dissolved in 20mL methylene chloride; it is added with stirring N; N- diisopropylethylamine (0.11mL; 0.64mmol), it stirs 1 hour at room temperature.It will Reaction solution is concentrated under reduced pressure, obtained residue is purified with silica gel column chromatography (eluant, eluent: system B), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- Trifluoromethoxyphen-l) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 9b (64mg, white solid), yield: 60.6%.
MS m/z (ESI): 655.8 [M+1]
Second step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- Trifluoromethoxyphen-l) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid
By 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- Trifluoromethoxyphen-l) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 9b (64mg, 0.097mmol) it is dissolved in the in the mixed solvent of 6mL tetrahydrofuran and methanol (V/V=1:1), it is added with stirring 1mL sodium hydroxide (19.4mg, 0.49mmol) in solution, stir 1.5 hours at room temperature.Reaction solution is concentrated under reduced pressure, pH=3 is adjusted with 1M hydrochloric acid, ethyl acetate extracts (60mL), combined organic phase is washed with saturated ammonium chloride solution (60mL × 3), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system B), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- Trifluoromethoxyphen-l) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) 9 (27mg of propionic acid, white solid), yield: 44.4%.
MS m/z (ESI): 628.7 [M+1]
1H NMR(400MHz,DMSO-d6) δ 10.35 (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- Trifluoromethoxyphen-l) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 9 is further by using supercritical fluid chromatography (SFC) method, ((1) chiral column ChiralPak AD is split with Preparation equipment and the chiral isomers of chiral column, 25 × 3cm, 80mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (2) Whelk O1 (S, S), 25 × 3cm, 65mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (3) Whelk O1 (S, S), 25 × 3cm, 70mL/min；Mobile phase A for CO2And B for Ethanol)) it is split, obtain 3- (4- ((2R, 3S) -1- ((4- Trifluoromethoxyphen-l) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 9A (white solid) and 3- (4- ((2S, 3R) -1- ((4- Trifluoromethoxyphen-l) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 9B (white solid).
9A:MS m/z (ESI): 628.7 [M+1]
9B:MS m/z (ESI): 628.7 [M+1]
Embodiment 10
3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2,4,6- trifluorophenyl) amino) hexane -3- base) benzamido) propionic acid 10
3- (4- ((2R, 3S) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2,4,6- trifluorophenyl) amino) hexane -3- base) benzamido) propionic acid 10A
3- (4- ((2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2,4,6- trifluorophenyl) amino) hexane -3- base) benzamido) propionic acid 10B
The first step
3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2,4,6- trifluorophenyl) amino) hexane -3- base) benzamido) ethyl propionate
By ((2R; 3S)/(2S; 3R)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) caproic acid 1m (80mg; 0.16mmol), 2; 4; 6- trifluoromethyl aniline 10a (35mg; 0.24mmol), bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (61mg; it 0.24mmol) is dissolved in 20mL methylene chloride; it is added with stirring N; N- diisopropylethylamine (0.11mL, 0.64mmol) stirs 1 hour at room temperature.Reaction solution is concentrated under reduced pressure, obtained residue is purified with silica gel column chromatography (eluant, eluent: system B), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2,4,6- trifluorophenyl) amino) hexane -3- base) benzamido) ethyl propionate 10b (29mg, white solid), yield: 29.0%.
MS m/z (ESI): 625.8 [M+1]
Second step
3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2,4,6- trifluorophenyl) amino) hexane -3- base) benzamido) propionic acid
By 3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2,4,6- trifluorophenyl) amino) hexane -3- base) benzamido) ethyl propionate 10b (29mg, 0.05mmol) it is dissolved in the in the mixed solvent of 6mL tetrahydrofuran and methanol (V/V=1:1), it is added with stirring 1mL sodium hydroxide (9.3mg, 0.25mmol) in solution, stir 2 hours at room temperature.Reaction solution is concentrated under reduced pressure, (60mL) is extracted with ethyl acetate, combined organic phase is washed with saturated ammonium chloride solution (60mL × 3), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system B), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2, 4, 6- trifluorophenyl) amino) hexane -3- base) benzamido) 10 (8mg of propionic acid, white solid), yield: 26.7%.
MS m/z (ESI): 597.8 [M+1]
1H NMR(400MHz,CDCl3):1H NMR(400MHz,DMSO-d6): δ 9.95 (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) hexane -3- base) benzamido) propionic acid 10 further by using supercritical fluid chromatography (SFC) method, split ((1) chiral column with Preparation equipment and the chiral isomers of chiral column ChiralPak AD,25×3cm,80mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (2) Whelk O1 (S, S), 25 × 3cm, 65mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (3) Whelk O1 (S, S), 25 × 3cm, 70mL/min；Mobile phase A for CO2And B for Ethanol)) it is split, obtain 3- (4- ((2R, 3S) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2,4,6- trifluorophenyl) amino) hexane -3- base) benzamido) propionic acid 10A (white solid) and 3- (4- ((2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2,4,6- trifluorophenyls) amino) hexane -3- base) benzamido) propionic acid 10B (white solid).
10A:MS m/z (ESI): 597.8 [M+1]
10B:MS m/z (ESI): 597.8 [M+1]
Embodiment 11
3- (4- (1- (2- methoxyl group -4- (trifluoromethyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid
The first step
4- (1- amino -1- (4- (Trifluoromethoxyphen-l) pentane -2- base) t-butyl perbenzoate
Under protection of argon gas; by 4- (1- oxo -1- (the amyl- 2- yl of 4- (Trifluoromethoxyphen-l)) t-butyl perbenzoate 11a (1.50g; 3.55mmol) and tetraisopropyl titanate (2.10mL; it 7.10mmol) is dissolved in the ammonia methanol (20mL) of 7N, reacts at room temperature 18 hours.Reaction solution is cooled to 0 DEG C, is added sodium borohydride (230mg, 6.03mmol), is warmed to room temperature reaction 2 hours.The sodium hydroxide solution of 1N is slowly added dropwise into reaction solution, go out to without obvious solid system, it filters, 20mL water is added after filtrate concentration, it is extracted with ethyl acetate (10mL × 3), it is dry with anhydrous sodium sulfate to merge organic phase, it is concentrated under reduced pressure, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 4- (1- amino -1- (4- (Trifluoromethoxyphen-l) pentane -2- base) t-butyl perbenzoate 11b (1.02g, yellow viscous liquid), yield: 68.0%.
1H NMR (400MHz, CDCl3) δ 7.96 (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
4- (1- (2- methoxyl group -4- (trifluoromethyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate
By 4- (1- amino -1- (4- (Trifluoromethoxyphen-l) pentane -2- base) t-butyl perbenzoate 11b (700mg, 1.65mmol), 2- methoxyl group -4- (trifluoromethyl) benzoic acid 11c (512mg, 1.50mmol), bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (573mg, 2.25mmol) and N, N- diisopropylethylamine (1.05mL, 6.00mmol) it is dissolved in 12mL methylene chloride and N, the in the mixed solvent of dinethylformamide (V/V=5/1), reaction solution react 18 hours at room temperature.20mL water is added into reaction solution, (10mL × 3) are extracted with ethyl acetate, anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 4- (1- (2- methoxyl group -4- (trifluoromethyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate 11d (790mg, faint yellow solid), yield: 86.0%.MS m/z (ESI): 557.8 [M+1-56]
Third step
4- (1- (2- methoxyl group -4- (trifluoromethyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid
By 4- (1- (2- methoxyl group -4- (trifluoromethyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate 11d (790mg, 1.29mmol) phosphoric acid (the 1.20g with 85%, it 10.3mmol) is dissolved in 10mL acetonitrile, reaction solution reacts 5 hours at 80 DEG C.30mL water is added after filtrate concentration, (10mL × 3) are extracted with ethyl acetate, it is dry with anhydrous sodium sulfate to merge organic phase, it is concentrated under reduced pressure, obtain 4- (1- (2- methoxyl group -4- (trifluoromethyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid 11e (720mg, weak yellow liquid), yield: 99.0%.
MS m/z (ESI): 557.8 [M+1]
4th step
3- (4- (1- (2- methoxyl group -4- (trifluoromethyl) benzamido) -2- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate
By 4- (1- (2- methoxyl group -4- (trifluoromethyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid 11e (720mg, 1.29mmol), 3- alanine carbethoxy hydrochloride (1.0g, 6.50mmol), bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (1.994mg, 7.8mmol) and N, N- diisopropylethylamine (2.20mL, 1.89mmol) it is dissolved in 11mL methylene chloride and N, the in the mixed solvent of dinethylformamide (V/V=9/2), reaction solution was at lower at 35 DEG C reaction 38 hours.20mL water is added after being concentrated under reduced pressure in reaction solution, (10mL × 3) are extracted with ethyl acetate, merge organic interdependent secondary saturated sodium carbonate solution (20mL × 1), the hydrochloric acid solution (20mL × 1) and saturated salt solution (20mL × 1) of 1N washs, anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: methylene chloride: methanol system), obtain 3- (4- (1- (2- methoxyl group -4- (trifluoromethyl) benzamido) -2- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate 11f (530mg, white solid), yield: 62.0%.
MS m/z (ESI): 656.8 [M+1]
5th step
3- (4- (1- (2- methoxyl group -4- (trifluoromethyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid
By 3- (4- (1- (2- methoxyl group -4- (trifluoromethyl) benzamido) -2- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate 11f (530mg, 0.81mmol) and mono- hydronium(ion) lithia (170mg of 0.80mL, 4.05mmol) solution is dissolved in the in the mixed solvent of 10mL tetrahydrofuran and methanol (V/V=1:1), and reaction solution reacts 18 hours at 30 DEG C.Reaction solution is concentrated under reduced pressure removing partial solvent, pH=2-3 is adjusted with 1M hydrochloric acid, (10mL × 3) are extracted with ethyl acetate, combined organic phase is dry with anhydrous sodium sulfate, filtering, the lower concentration of decompression, obtained residue are purified with silica gel column chromatography (eluant, eluent: petroleum ether: ethyl acetate system), obtain 3- (4- (1- (2- methoxyl group -4- (trifluoromethyl) benzene first Acylamino-) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid 11 (200mg, white solid), yield: 40.0%.
MS m/z (ESI): 640.0 [M+1]
1H NMR (400MHz, DMSO) δ 12.20 (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=9.7H Z, 1H), 1.15 (s, 1H), 0.98-0.84 (m, 2H), 0.65 (t, J=7.0Hz, 3H)
Embodiment 12
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (tert-butyl) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 12
3- (4- ((2R, 3S) -1- ((4- (tert-butyl) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 12A
3- (4- ((2S, 3R) -1- ((4- (tert-butyl) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 12B
The first step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (tert-butyl) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate
By ((2R, 3S)/(2S, 3R)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) caproic acid 1m (80mg, 0.16mmol), 4- tert-butyl aniline 12a (28mg, 0.19mmol), I-hydroxybenzotriazole (1.79g, 13.3mmol) and 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride (40mg, 0.21mmol) and N, N- diisopropylethylamine (52mg, it 0.4mmol) is dissolved in 10mL tetrahydrofuran, it stirs 24 hours at room temperature.(60mL) is extracted with ethyl acetate in reaction solution, combined organic phase is washed with sodium chloride solution (30mL), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system B), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (tert-butyl) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 12b (32mg, white solid), yield: 35.1%.
MS m/z (ESI): 626.9 [M+1]
Second step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (tert-butyl) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid
By 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (tert-butyl) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 12b (32mg, 0.05mmol) it is dissolved in the in the mixed solvent of 6mL tetrahydrofuran and methanol (V/V=1:1), it is added with stirring 1mL sodium hydroxide (10mg, 0.25mmol) in solution, stir 1.5 hours at room temperature.Reaction solution is removed into partial solvent under reduced pressure, pH=3 is adjusted with 1M hydrochloric acid, , (20mL × 3) are extracted with ethyl acetate, combined organic phase is washed with saturated ammonium chloride solution (30mL × 3), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent is methylene chloride: methanol=9:1), obtained residue is purified with silica gel column chromatography (eluant, eluent: system B), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (tert-butyl) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) 12 (7mg of propionic acid, white solid), yield: 23.4%.
MS m/z (ESI): 599.9 [M+1]
1H NMR(400MHz,DMSO-d6) δ 9.86 (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) hexane -3- base) benzamido) propionic acid 12 is further by using supercritical fluid chromatography (SFC) method, ((1) chiral column ChiralPak AD is split with Preparation equipment and the chiral isomers of chiral column, 25 × 3cm, 80mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (2) Whelk O1 (S, S), 25 × 3cm, 65mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (3) Whelk O1 (S, S), 25 × 3cm, 70mL/min；Mobile phase A for CO2And B for Ethanol)) it is split, obtain 3- (4- ((2R, 3S) -1- ((4- (tert-butyl) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 12A (white solid) and 3- (4- ((2S, 3R) -1- ((4- (tert-butyl) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 12B (white solid).
12A:MS m/z (ESI): 599.9 [M+1]
12B:MS m/z (ESI): 599.9 [M+1]
Embodiment 13
3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) phenyl) amino) hexane -3- base) benzamido) propionic acid 13
3- (4- ((2R, 3S) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) phenyl) amino) hexane -3- base) benzamido) propionic acid 13A
3- (4- ((2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) phenyl) amino) hexane -3- base) benzamido) propionic acid 13B
The first step
1- (4- nitrobenzophenone) -4- (trifluoromethyl) -1H- pyrazoles
By the fluoro- 4- nitrobenzene 13a (1.35g of 1-, 9.55mmol), 4- (trifluoromethyl) -1H- pyrazoles 13b (1g, 7.35mmol), potassium carbonate (2.03g, it 14.7mmol) is dissolved in 10mL acetonitrile, reaction solution reacts 7 hours at 85 DEG C.Filtering reacting liquid is concentrated under reduced pressure, and obtains crude product 1- (4- nitrobenzophenone) -4- (trifluoromethyl) -1H- pyrazoles 13c (1.2g, faint yellow solid), yield: 63.5%
MS m/z (ESI): 257.9 [M+1]
Second step
4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) aniline
By 1- (4- nitrobenzophenone) -4- (trifluoromethyl) -1H- pyrazoles 13c (257mg, 1mmol), 10% palladium carbon (128mg) is dissolved in 10mL methanol, reaction solution is stirred at room temperature 5 hours.Filtering reacting liquid is concentrated under reduced pressure, and obtains crude product 4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) aniline 13d (230mg, colourless liquid).
MS m/z (ESI): 227.9 [M+1]
Third step
3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) phenyl) amino) hexane -3- base) benzamido) ethyl propionate
By ((2R, 3S)/(2S, 3R)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) caproic acid 1m (90mg, 0.22mmol), 4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) aniline 13d (66mg, 0.29mmol), 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (100mg, 0.26mmol) and N, N- diisopropylethylamine (0.12mL, it 0.66mmol) is dissolved in 5mL tetrahydrofuran, it stirs 18 hours at room temperature.15mL water will be added in reaction solution, (8mL × 3) are extracted with ethyl acetate, anhydrous sodium sulfate dries, filters, and depressurizes lower concentration, and obtained residue is purified with silica gel column chromatography method (eluant, eluent: system C), obtained 3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) phenyl) amino) hexane -3- base) benzamido) ethyl propionate 13e (155mg, yellow solid), yield: 99.9%.
MS m/z (ESI): 704.8 [M+1]
4th step
3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) phenyl) amino) hexane -3- base) benzamido) propionic acid
By 3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) phenyl) amino) hexane -3- base) benzamido) ethyl propionate 13e (155mg, 0.22mmol) it is dissolved in the in the mixed solvent of 5mL tetrahydrofuran and methanol (V/V=4:1), it is added with stirring mono- hydronium(ion) lithia (50mg of 0.22mL, 1.1mmol) in solution, stir 1 hour at room temperature.Reaction solution is concentrated under reduced pressure removing partial solvent, pH=2-3 is adjusted with 1M hydrochloric acid, (6mL × 3) are extracted with ethyl acetate, combined organic phase successively uses saturated ammonium chloride solution (5mL × 2), sodium chloride solution (5mL) washing, anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system B), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) phenyl) amino) hexane -3- base) benzamido) 13 (8mg of propionic acid, yellow solid), yield: 5.4%.
MS m/z (ESI): 676.8 [M+1]
1H NMR (400MHz, DMSO) δ 10.14 (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) hexane -3- base) benzamido) propionic acid 13 is further by using supercritical fluid chromatography (SFC) method, ((1) chiral column ChiralPak AD is split with Preparation equipment and the chiral isomers of chiral column, 25 × 3cm, 80mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (2) WhelkO1 (S, S), 25 × 3cm, 65mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (3) Whelk O1 (S, S), 25 × 3cm, 70mL/min；Mobile phase A for CO2And B for Ethanol)) it is split, obtain 3- (4- ((2R, 3S) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) phenyl) amino) hexane -3- base) benzamido) propionic acid 13A (white solid) and 3- (4- ((2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) phenyl) amino) hexane -3- base) benzamido) propionic acid 13B (white solid).
13A:MS m/z (ESI): 676.8 [M+1]
13B:MS m/z (ESI): 676.8 [M+1]
Embodiment 14
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (2- methylthiazol -5- base) phenyl) amino (1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 14
3- (4- ((2R, 3S) -1- ((4- (2- methylthiazol -5- base) phenyl) amino (1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 14A
3- (4- ((2S, 3R) -1- ((4- (2- methylthiazol -5- base) phenyl) amino (1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 14B
The first step
4- (2- methylthiazol -5- base) aniline
By 5- bromine 2- methylthiazol 14a (840mg, 4.72mmol), 4- aminobenzene boric acid hydrochloride 14b (900mg, 5.19mmol), tetra-triphenylphosphine palladium (273mg, 0.24mmol) and sodium carbonate (1.90g, 17.9mmol) it is dissolved in the in the mixed solvent of 50mL toluene, second alcohol and water (V/V/V=2:2:1), with argon gas substitution gas, reaction solution reacts 6 hours at 90 DEG C.Reaction solution concentration, 15mL water is added, it is extracted with ethyl acetate (10mL × 3), merge organic phase, it is dry with anhydrous sodium sulfate, it is concentrated under reduced pressure, obtained residue silica gel column chromatography (eluant, eluent: system C) purifying obtains 4- (2- methylthiazol -5- base) aniline 14c (630mg, yellow solid), yield: 70.0%
MS m/z (ESI): 190.9 [M+1]
Second step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (2- methylthiazol -5- base) phenyl) amino (1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate
By ((2R, 3S)/(2S, 3R)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) caproic acid 1m (248mg, 0.50mmol), 4- (2- methylthiazol -5- base) aniline 14c (114mg, 0.60mmol), bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (380mg, 1.00mmol) and N, N- diisopropylethylamine (0.35mL, 2.00mmol) it is dissolved in 6mL methylene chloride and N, the in the mixed solvent of dinethylformamide (V/V=5/1), reaction solution reacts 18 hours at room temperature.20mL water is added into reaction solution, is extracted with ethyl acetate (10 ML × 3), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system C), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (2- methylthiazol -5- base) phenyl) amino (1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 14d (166mg, off-white powder), yield: 49.7%.
MS m/z (ESI): 667.9 [M+1]
Third step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (2- methylthiazol -5- base) phenyl) amino (1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid
By 3- (4- ((2R, 3S)/(2S, 3R) -1- ((4- (2- methylthiazol -5- base) phenyl) amino (1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 14d (166mg, 0.25mmol) it is dissolved in the in the mixed solvent of 8mL tetrahydrofuran and methanol (V/V=4:1), it is added with stirring mono- hydronium(ion) lithia (53mg of 0.25mL, 1.25mmol) in solution, stir 18 hours at room temperature.Reaction solution is concentrated under reduced pressure removing partial solvent, pH=2-3 is adjusted with 1M hydrochloric acid, (10mL × 3) are extracted with ethyl acetate, combined organic phase is dry with anhydrous sodium sulfate, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system C), obtain 3- (4- ((2R, 3S)/(2S, 3R) 14 (100mg of -1- ((4- (2- methylthiazol -5- base) phenyl) amino (1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid, white solid), yield: 62.0%.
MS m/z (ESI): 639.9 [M+1]
1H NMR (400MHz, DMSO) δ 12.40-11.89 (m, 1H), 10.07 (s, 1H), 8.42 (s, 1H), 7.85 (s, 1H), 7.75 (d, J=8.0Hz, 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- base) phenyl) amino (1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 14 is further by using supercritical fluid chromatography (SFC) method, ((1) chiral column ChiralPak AD is split with Preparation equipment and the chiral isomers of chiral column, 25 × 3cm, 80mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (2) Whelk O1 (S, S), 25 × 3cm, 65mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (3) Whelk O1 (S, S), 25 × 3cm, 70mL/min；Mobile phase A for CO2And B for Ethanol)) it is split, 3- (4- ((2R, 3S) -1- ((4- (2- methylthiazol -5- base) phenyl) amino (1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 14A (white solid) and 3- (4- ((2S, 3R) -1- ((4- (2- methylthiazol -5- base) phenyl) amino (1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 14B (white solid).
14A:MS m/z (ESI): 639.9 [M+1]
14B:MS m/z (ESI): 639.9 [M+1]
Embodiment 15
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2- fluoro- 4- (trifluoromethoxy) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 15
3- (4- ((2R, 3S) -1- ((2- fluoro- 4- (trifluoromethoxy) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 15A
3- (4- ((2S, 3R) -1- ((2- fluoro- 4- (trifluoromethoxy) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 15B
The first step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2- fluoro- 4- (trifluoromethoxy) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate
By ((2R; 3S)/(2S; 3R)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl -2- (4- (trifluoromethoxy) phenyl) caproic acid 1m (200mg; 0.40mmol), the fluoro- 4- of 2- (trifluoromethoxy) aniline 15a (116mg; 0.60mmol) and N; N- diisopropylethylamine (0.28mL; it 1.60mmol) is dissolved in 6mL methylene chloride; it is eventually adding bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (152mg; 0.60mmol), reaction solution reacts 18 hours at room temperature.Reaction solution is concentrated under reduced pressure, 60mL ethyl acetate is added, successively washed with saturated sodium bicarbonate solution (30mL × 2) and saturated ammonium chloride solution (30mL × 2), anhydrous sodium sulfate is dry, the lower concentration of decompression, obtained residue is purified with silicon thin-layer chromatography (solvent: system A), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- ((2- fluoro- 4- (trifluoromethoxy) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 15b (155mg, white solid), yield: 16.4%.
MS m/z (ESI): 672.8 [M+1]
Second step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2- fluoro- 4- (trifluoromethoxy) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid
By 3- (4- ((2R, 3S)/(2S, 3R) -1- ((2- fluoro- 4- (trifluoromethoxy) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 15b (44mg, 0.065mmol) it is dissolved in the in the mixed solvent of 6mL tetrahydrofuran and methanol (V/V=1:1), it is added with stirring 1.0mL sodium hydroxide (13mg, 0.33mmol) in solution, stir 12 hours at room temperature.Reaction solution is concentrated under reduced pressure removing partial solvent, pH=3 is adjusted with 1M hydrochloric acid, it is extracted with 60mL ethyl acetate, organic phase is washed with saturated ammonium chloride solution (30mL × 3), organic phase is dried, filtered with anhydrous sodium sulfate, depressurizes lower concentration, obtained residue is purified with silicon thin-layer chromatography (solvent: system A), is obtained 3- (4- ((2R, 3S)/(2S, 3R) -1- ((2- fluoro- 4- (trifluoromethoxy) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) 15 (19mg of propionic acid, white solid), yield: 45.3%.
MS m/z (ESI): 644.7 [M+1]
1H NMR (400MHz, MeOD) δ 7.79 (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) hexane -3- base) benzamido) propionic acid 15 is further by using supercritical fluid chromatography (SFC) method, ((1) chiral column ChiralPak AD is split with Preparation equipment and the chiral isomers of chiral column, 25 × 3cm, 80mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (2) Whelk O1 (S, S), 25 × 3cm, 65mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (3) Whelk O1 (S, S), 25 × 3cm, 70mL/min；Mobile phase A for CO2And B for Ethanol)) it is split, obtain 3- (4- ((2R, 3S) -1- ((2- fluoro- 4- (trifluoromethoxy) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 15A (white solid) and 3- (4- ((2S, 3R) -1- ((2- fluoro- 4- (trifluoromethoxy) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 15B (white solid).
15A:MS m/z (ESI): 644.7 [M+1]
15B:MS m/z (ESI): 644.7 [M+1]
Embodiment 16
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2- methyl -4- (trifluoromethoxy) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 16
3- (4- ((2R, 3S) -1- ((2- methyl -4- (trifluoromethoxy) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 16A
3- (4- ((2S, 3R) -1- ((2- methyl -4- (trifluoromethoxy) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 16B
The first step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2- methyl -4- (trifluoromethoxy) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate
By ((2R, 3S)/(2S, 3R)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl -2- (4- (trifluoromethoxy) phenyl) caproic acid 1m (200mg, 0.40mmol), 2- methyl -4- (trifluoromethoxy) aniline 16a (116mg, 0.61mmol) and N, N- diisopropylethylamine (0.28mL, it 1.60mmol) is dissolved in 6mL methylene chloride, argon gas substitution gas is three times, then bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (155mg are added, 0.61mmol), reaction solution reacts 18 hours at room temperature.Reaction solution is concentrated under reduced pressure, 60mL ethyl acetate is added, successively washed with saturated sodium bicarbonate solution (30mL × 3) and saturated ammonium chloride solution (30mL × 3), anhydrous sodium sulfate is dry, the lower concentration of decompression, obtained residue is purified with silicon thin-layer chromatography (solvent: system A), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- ((2- methyl -4- (trifluoromethoxy) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 16b (44mg, white solid), yield: 16.5%.
MS m/z (ESI): 668.9 [M+1]
Second step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((2- methyl -4- (trifluoromethoxy) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid
By 3- (4- ((2R, 3S)/(2S, 3R) -1- ((2- methyl -4- (trifluoromethoxy) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 16b (44mg, 0.066mmol) it is dissolved in the in the mixed solvent of 6mL tetrahydrofuran and methanol (V/V=1:1), it is added with stirring 1.0mL sodium hydroxide (13.2mg, 0.33mmol) in solution, stir 1.5 hours at room temperature.Reaction solution is concentrated under reduced pressure removing partial solvent, pH=3 is adjusted with 1M hydrochloric acid, the extraction of 60mL ethyl acetate is added, it is washed with saturated ammonium chloride solution (30mL × 3), organic phase is dry with anhydrous sodium sulfate, filtering, the lower concentration of decompression, obtained residue is purified with silicon thin-layer chromatography (solvent: system C), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- ((2- methyl -4- (trifluoromethoxy) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) 16 (28mg of propionic acid, white solid), yield: 66.2%.
MS m/z (ESI): 640.8 [M+1]
1H NMR (400MHz, MeOD) δ 7.83 (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) hexane -3- base) benzamido) propionic acid 16 is further by using supercritical fluid chromatography (SFC) method, ((1) chiral column ChiralPak AD is split with Preparation equipment and the chiral isomers of chiral column, 25 × 3cm, 80mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (2) Whelk O1 (S, S), 25 × 3cm, 65mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (3) Whelk O1 (S, S), 25 × 3cm, 70mL/min；Mobile phase A for CO2And B for Ethanol)) it is split, obtain 3- (4- ((2R, 3S) -1- ((2- methyl -4- (trifluoromethoxy) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 16A (white solid) and 3- (4- ((2S, 3R) -1- ((2- methyl -4- (trifluoromethoxy) phenyl) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 16B (white solid).
16A:MS m/z (ESI): 640.8 [M+1]
16B:MS m/z (ESI): 640.8 [M+1]
Embodiment 17
3- (4- ((2R, 3S)/(2S, 3R) -1- ((the chloro- 2- fluorophenyl of 4-) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 17
3- (4- ((2R, 3S) -1- ((the chloro- 2- fluorophenyl of 4-) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 17A
3- (4- ((2S, 3R) -1- ((the chloro- 2- fluorophenyl of 4-) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 17B
The first step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((the chloro- 2- fluorophenyl of 4-) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate
By ((2R; 3S)/(2S; 3R)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl -2- (4- (trifluoromethoxy) phenyl) caproic acid 1m (100mg; 0.20mmol), the chloro- 2- fluoroaniline 17a (44mg of 4-; 0.30mmol) and N; N- diisopropylethylamine (0.14mL; it 0.80mmol) is dissolved in 3mL methylene chloride; argon gas substitution gas is three times; then bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (76mg are added; 0.30mmol), reaction solution reacts 5 hours at room temperature.Reaction solution is concentrated under reduced pressure, 60mL ethyl acetate is added, successively washed with saturated sodium bicarbonate solution (30mL × 2) and saturated ammonium chloride solution (30mL × 2), anhydrous sodium sulfate is dry, the lower concentration of decompression, obtained residue is purified with silicon thin-layer chromatography (solvent: system A), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- ((the chloro- 2- fluorophenyl of 4-) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 17b (17mg, white solid), yield: 13.6%.
MS m/z (ESI): 622.8 [M+1]
Second step
3- (4- ((2R, 3S)/(2S, 3R) -1- ((the chloro- 2- fluorophenyl of 4-) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid
By 3- (4- ((2R, 3S)/(2S, 3R) -1- ((the chloro- 2- fluorophenyl of 4-) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 17b (36mg, 0.058mmol) it is dissolved in the in the mixed solvent of 6mL tetrahydrofuran and methanol (V/V=1:1), it is added with stirring 1.0mL sodium hydroxide (12.0mg, 0.29mmol) in solution, stir 16 hours at room temperature.Reaction solution is concentrated under reduced pressure removing partial solvent, pH=3 is adjusted with 1M hydrochloric acid, the extraction of 60mL ethyl acetate is added, organic phase is washed with saturated ammonium chloride solution (30mL × 3), organic phase is dried, filtered with anhydrous sodium sulfate, depressurizes lower concentration, obtained residue is purified with silicon thin-layer chromatography (solvent: system A), is obtained 3- (4- ((2R, 3S)/(2S, 3R) -1- ((the chloro- 2- fluorophenyl of 4-) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) 17 (19mg of propionic acid, white solid), yield: 55.1%.
MS m/z (ESI): 594.8 [M+1]
1H NMR (400MHz, MeOD) δ 7.78 (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- ((the chloro- 2- fluorophenyl of 4-) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 17 is further by using supercritical fluid chromatography (SFC) method, ((1) chiral column ChiralPak AD is split with Preparation equipment and the chiral isomers of chiral column, 25 × 3cm, 80mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (2) Whelk O1 (S, S), 25 × 3cm, 65mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (3) Whelk O1 (S, S), 25 × 3cm, 70mL/min；Mobile phase A for CO2And B for Ethanol)) it is split, obtain 3- (4- ((2R, 3S) -1- ((the chloro- 2- fluorophenyl of 4-) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 17A (white solid) and 3- (4- ((2S, 3R) -1- ((the chloro- 2- fluorophenyl of 4-) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 17B (white solid).
17A:MS m/z (ESI): 594.8 [M+1]
17B:MS m/z (ESI): 594.8 [M+1]
Embodiment 18
3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl -1- ((6- (trifluoromethyl) pyridin-3-yl) amino) hexane -3- base) benzamido) propionic acid 18
3- (4- ((2R, 3S) -1- oxo -2- (4- (trifluoromethoxy) phenyl -1- ((6- (trifluoromethyl) pyridin-3-yl) amino) hexane -3- base) benzamido) propionic acid 18A
3- (4- ((2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl -1- ((6- (trifluoromethyl) pyridin-3-yl) amino) hexane -3- base) benzamido) propionic acid 18B
The first step
3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl -1- ((6- (trifluoromethyl) pyridin-3-yl) amino) hexane -3- base) benzamido) ethyl propionate
By ((2R, 3S)/(2S, 3R)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl -2- (4- (trifluoromethoxy) phenyl) caproic acid 1m (200mg, 0.40mmol), 6- (trifluoromethyl) pyridine -3- amine 18a (98mg, 0.60mmol) and N, N- diisopropylethylamine (0.28mL, it 1.60mmol) is dissolved in 6mL methylene chloride, argon gas substitution gas is three times, then bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (152mg are added, 0.60mmol), reaction solution reacts 18 hours at 35 DEG C.Reaction solution is concentrated under reduced pressure, 60mL ethyl acetate is added, successively washed with saturated sodium bicarbonate solution (30mL × 2) and saturated ammonium chloride solution (30mL × 2), anhydrous sodium sulfate is dry, the lower concentration of decompression, obtained residue is purified with silicon thin-layer chromatography (solvent: petroleum ether: ethyl acetate=1:1), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl -1- ((6- (trifluoromethyl) pyridin-3-yl) amino) hexane -3- base) benzamido) ethyl propionate 18b (34mg, white solid), yield: 13.3%.
MS m/z (ESI): 639.9 [M+1]
Second step
3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl -1- ((6- (trifluoromethyl) pyridin-3-yl) amino) hexane -3- base) benzamido) propionic acid
By 3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl -1- ((6- (trifluoromethyl) pyridin-3-yl) amino) hexane -3- base) benzamido) ethyl propionate 18b (34mg, 0.053mmol) it is dissolved in the in the mixed solvent of 6mL tetrahydrofuran and methanol (V/V=1:1), it is added with stirring 1.0mL sodium hydroxide (11.0mg, 0.27mmol) in solution, stir 18 hours at room temperature.Reaction solution is concentrated under reduced pressure removing partial solvent, pH=3 is adjusted with 1M hydrochloric acid, the extraction of 60mL ethyl acetate is added, organic phase saturated ammonium chloride solution (30mL × 3) washing, organic phase is dry with anhydrous sodium sulfate, filtering, the lower concentration of decompression, obtained residue is purified with silicon thin-layer chromatography (solvent: system A), obtain 3- (4- ((2R, 3S)/(2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl -1- ((6- (trifluoromethyl) pyridin-3-yl) amino) hexane -3- base) benzamido) 18 (8mg of propionic acid, white solid), yield: 25.0%.
MS m/z (ESI): 694.8 [M+1]
1H NMR (400MHz, DMSO) δ 10.66 (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) hexane -3- base) benzoyl Amino) propionic acid 18 further by using supercritical fluid chromatography (SFC) method, split ((1) chiral column ChiralPak AD, 25 × 3cm, 80mL/min with Preparation equipment and the chiral isomers of chiral column；Mobile phase A for CO2and B for Ethanol；Or/and (2) Whelk O1 (S, S), 25 × 3cm, 65mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (3) Whelk O1 (S, S), 25 × 3cm, 70mL/min；Mobile phase A for CO2And B for Ethanol)) it is split, obtain 3- (4- ((2R, 3S) -1- oxo -2- (4- (trifluoromethoxy) phenyl -1- ((6- (trifluoromethyl) pyridin-3-yl) amino) hexane -3- base) benzamido) propionic acid 18A (white solid) and 3- (4- ((2S, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl -1- ((6- (trifluoromethyl) pyridin-3-yl) amino) hexane -3- base) benzamido) propionic acid 18B (white solid).
18A:MS m/z (ESI): 694.8 [M+1]
18B:MS m/z (ESI): 694.8 [M+1]
Embodiment 19
3- (4- (1- (4- (trifluoromethoxy) phenyl) -1- (2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) pentane -2- base) benzamido) propionic acid
3- (4- ((1R, 2R) -1- (4- (trifluoromethoxy) phenyl) -1- (2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) pentane -2- base) benzamido) propionic acid 19A
3- (4- ((1S, 2S) -1- (4- (trifluoromethoxy) phenyl) -1- (2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) pentane -2- base) benzamido) propionic acid 19B
The first step
4- (1- (4- (trifluoromethoxy) phenyl) -1- (2', 4,6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) pentane -2- base) t-butyl perbenzoate
By 4- (1- amino -1- (4- (Trifluoromethoxyphen-l) pentane -2- base) t-butyl perbenzoate 11b (600mg, 1.42mmol), 2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- carboxylic acid 19a (442mg, 1.84mmol), bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (723mg, 2.84mmol) and N, N- diisopropylethylamine (1.0mL, 5.68mmol) it is dissolved in 12mL methylene chloride and N, the in the mixed solvent of dinethylformamide (V/V=5/1), reaction solution react 18 hours at room temperature.15mL water is added after being concentrated under reduced pressure in reaction solution, (10mL × 3) are extracted with ethyl acetate, merge organic phase to be washed with water (20mL × 2), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 4- (1- (4- (trifluoromethoxy) phenyl) -1- (2', 4,6'- trimethyls-[1,1'- biphenyl] -4- base formamido group) pentane -2- base) t-butyl perbenzoate 19b (820mg, yellow solid), yield: 89.4%.
MS m/z (ESI): 589.9 [M+1-56]
Second step
4- (1- (4- (trifluoromethoxy) phenyl) -1- (2', 4,6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) pentane -2- base) benzoic acid
By 4- (1- (4- (trifluoromethoxy) phenyl) -1- (2', 4,6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) pentane -2- base) t-butyl perbenzoate 19b (820mg, 1.27mmol) phosphoric acid (the 1.20g with 85%, it 10.2mmol) is dissolved in 12mL acetonitrile, reaction solution reacts 4 hours at 80 DEG C.15mL water is added after reaction solution concentration, it is extracted with ethyl acetate (10mL × 3), merge organic phase, it is dry with anhydrous sodium sulfate, it is concentrated under reduced pressure, obtain crude product 4- (1- (4- (trifluoromethoxy) phenyl) -1- (2', 4,6'- trimethyls-[1,1'- biphenyl] -4- base formamido group) pentane -2- base) benzoic acid 19c (750mg, white solid), yield: 100%.
MS m/z (ESI): 589.9 [M+1]
Third step
3- (4- (1- (4- (trifluoromethoxy) phenyl) -1- (2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) pentane -2- base) benzamido) ethyl propionate
By 4- (1- (4- (trifluoromethoxy) phenyl) -1- (2', 4,6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) pentane -2- base) benzoic acid 19c (750mg, 1.27mmol), 3- alanine carbethoxy hydrochloride (293mg, 1.91mmol), 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (726mg, 1.91mmol) and N, N- diisopropylethylamine (0.90mL, it 5.08mmol) is dissolved in bis- n,N-Dimethylformamide of 10mL, reaction solution reacts 4 hours at room temperature.25mL water is added into reaction solution, is extracted with ethyl acetate (10mL × 3), merges organic phase and is washed with water (30mL × 1), anhydrous sodium sulfate is dry, filtering, depressurizes lower concentration, and obtained residue is with silica gel column chromatography (eluant, eluent: system C) Purifying, obtain 3- (4- (1- (4- (trifluoromethoxy) phenyl) -1- (2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) pentane -2- base) benzamido) ethyl propionate 19d (854mg, yellow liquid), yield: 97.6%.
MS m/z (ESI): 688.9 [M+1]
4th step
3- (4- (1- (4- (trifluoromethoxy) phenyl) -1- (2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) pentane -2- base) benzamido) propionic acid
By 3- (4- (1- (4- (trifluoromethoxy) phenyl) -1- (2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) pentane -2- base) benzamido) ethyl propionate 19d (854mg, 1.24mmol) and mono- hydronium(ion) lithia (260mg of 1.20mL, 6.20mmol) solution is dissolved in the in the mixed solvent of 12mL tetrahydrofuran and methanol (V/V=1/5), and reaction solution reacts 18 hours at room temperature.Reaction solution is concentrated under reduced pressure, pH=2-3 is adjusted with 1M hydrochloric acid, (10mL × 3) are extracted with ethyl acetate, combined organic phase is dry with anhydrous sodium sulfate, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system C), obtain 3- (4- (1- (4- (trifluoromethoxy) phenyl) -1- (2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) pentane -2- base) benzamido) 19 (750mg of propionic acid, white solid), yield: 91.7%.
MS m/z (ESI): 660.9 [M+1]
1H NMR(400MHz,CDCl3) δ 12.25 (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- base formamido group) pentane -2- base) benzamido) propionic acid 19 is further by using supercritical fluid chromatography (SFC) method, (chiral column WhelkO1 (S is split with Preparation equipment and the chiral isomers of chiral column, S), 300 × 50mm I.D.10 μm, mobile phase A for CO2And B for methanol (0.1%NH3H2O), flow velocity 200mL/min) it is split, obtain 3- (4- ((1R, 2R) -1- (4- (trifluoromethoxy) phenyl) -1- (2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) pentane -2- base) benzamido) propionic acid 19A (retention time: 4.57min；And 3- (4- ((1S ee value: 100%), 2S) -1- (4- (trifluoromethoxy) phenyl) -1- (2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) pentane -2- base) benzamido) propionic acid 19B (retention time: 10.56min；Ee value: 100%).
19A:MS m/z (ESI): 660.9 [M+1]
19B:MS m/z (ESI): 660.9 [M+1]
Embodiment 20
3- (4- (1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid
The first step
4- (1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) methyl benzoate
By 4- (1- amino -1- (4- (Trifluoromethoxyphen-l) pentane -2- base) t-butyl perbenzoate 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) secondary phosphoryl chloride phosphorus oxychloride (611mg, 2.40mmol) and N, N- diisopropylethylamine (0.84mL, 4.80mmol) it is dissolved in 12mL methylene chloride and N, the in the mixed solvent of dinethylformamide (V/V=5/1), reaction solution reacts 18 hours at room temperature.20mL water is added after being concentrated under reduced pressure in reaction solution, (10mL × 3) are extracted with ethyl acetate, merge organic phase to be washed with water (15mL × 2), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 4- (1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) methyl benzoate 20b (260mg, white solid), yield: 31.4%.
MS m/z (ESI): 633.8 [M+1-56]
Second step
4- (1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid
By 4- (1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) methyl benzoate 20b (260mg, 0.38mmol) phosphoric acid (the 350mg with 85%, it 3.00mmol) is dissolved in 8mL acetonitrile, reaction solution reacts 4 hours at 80 DEG C.15mL water is added after reaction solution concentration, it is extracted with ethyl acetate (10mL × 3), merge organic phase, it is dry with anhydrous sodium sulfate, it is concentrated under reduced pressure, obtains crude product 4- (1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid 20c (240mg, weak yellow liquid), yield: 100%.
MS m/z (ESI): 633.8 [M+1]
Third step
3- (4- (1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate
By 4- (1- (3, 5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid 20c (240mg, 0.38mmol), 3- alanine carbethoxy hydrochloride (117mg, 0.76mmol), 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (217mg, 0.57mmol) and N, N- diisopropylethylamine (0.30mL, 1.52mmol) it is dissolved in bis- N of 5mL, in dinethylformamide, reaction solution reacts 4 hours at room temperature.25mL water is added into reaction solution, (10mL × 3) are extracted with ethyl acetate, Merge organic phase to be washed with water (50mL × 2), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system C), it obtains 3- (4- (1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate 20d (278mg, off-white powder), yield: 100%.
MS m/z (ESI): 732.9 [M+1]
4th step
3- (4- (1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid
By 3- (4- (1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate 20d (278mg, 0.38mmol) and mono- hydronium(ion) lithia (80mg of 0.40mL, 1.90mmol) solution is dissolved in the in the mixed solvent of 6mL tetrahydrofuran and methanol (V/V=1/2), and reaction solution reacts 18 hours at room temperature.Reaction solution is concentrated under reduced pressure, pH=2-3 is adjusted with 1M hydrochloric acid, (10mL × 3) are extracted with ethyl acetate, combined organic phase is dry with anhydrous sodium sulfate, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system C), obtain 3- (4- (1- (3,5- dimethyl -4- (4- (trifluoromethyl) -1H- pyrazol-1-yl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) 20 (197mg of propionic acid, white solid), yield: 73.8%.
MS m/z (ESI): 704.9 [M+1]
1H NMR (400MHz, DMSO) δ 12.25 (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)
Embodiment 21
3- (4- (1- (4- Cyanophenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid
The first step
4- (1- (4- Cyanophenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate
By 4- (1- amino -1- (4- (Trifluoromethoxyphen-l) pentane -2- base) t-butyl perbenzoate 11b (423mg, 1.00mmol), 4- cyanobenzoic acid 21a (162mg, 1.10mmol), bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (510mg, 2.00mmol) and N, N- diisopropylethylamine (0.70mL, 4.00mmol) it is dissolved in 12mL methylene chloride and N, the in the mixed solvent of dinethylformamide (V/V=5/1), reaction solution react 18 hours at room temperature.20mL ethyl acetate and 20mL water is added after being concentrated under reduced pressure in reaction solution, layering, (20mL × 3) are extracted with ethyl acetate in water phase, merge organic phase to be washed with water (10mL × 2), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 4- (1- (4- Cyanophenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate 21b (406mg, white solid), yield: 73.5%.
MS m/z (ESI): 496.9 [M+1-56]
Second step
4- (1- (4- Cyanophenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid
By 4- (1- (4- Cyanophenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate 21b (406mg, it 0.73mmol) is dissolved in 3mL methylene chloride, 3mL trifluoroacetic acid is added, reaction solution reacts 18 hours at room temperature.20mL ethyl acetate is added after reaction solution concentration, it is washed with water (20mL × 3), merge organic phase, it is dry with anhydrous sodium sulfate, it is concentrated under reduced pressure, obtain crude product 4- (1- (4- Cyanophenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid 21c (337mg, white solid), yield: 93.0%.
MS m/z (ESI): 496.9 [M+1]
Third step
3- (4- (1- (4- Cyanophenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate
By 4- (1- (4- Cyanophenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid 21c (337mg, 0.68mmol), 3- alanine carbethoxy hydrochloride (261mg, 1.70mmol), bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (432mg, 1.70mmol) and N, N- diisopropylethylamine (0.56mL, it 3.39mmol) is dissolved in 9mL methylene chloride, reaction solution reacts 18 hours at room temperature.Reaction solution is concentrated under reduced pressure, 30mL ethyl acetate is added, successively washed with 1M hydrochloric acid solution (30mL) and water (30mL × 2), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), it obtains 3- (4- (1- (4- Cyanophenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate 21d (51mg, off-white powder), yield: 12.6%.
MS m/z (ESI): 595.9 [M+1]
4th step
3- (4- (1- (4- Cyanophenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid
By 3- (4- (1- (4- Cyanophenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate 21d (51mg, 0.086mmol) and mono- hydronium(ion) lithia (18mg of 1.0mL, 0.428mmol) solution is dissolved in the in the mixed solvent of 5mL tetrahydrofuran and methanol (V/V=1/4), and reaction solution reacts 18 hours at room temperature.30mL ethyl acetate is added into reaction solution, with 1M salt acid for adjusting pH to solution in acidity, layering, (20mL) is extracted with ethyl acetate in water phase, combined organic phase is washed with water (20mL × 2), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silicon thin-layer chromatography (solvent: system C), obtain 3- (4- (1- (4- Cyanophenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid 21 (17mg, white solid), yield: 34.8%.
MS m/z (ESI): 567.9 [M+1]
1H NMR (400MHz, DMSO) δ 8.92 (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)
Embodiment 22
3- (4- (1- (3,5- dimethyl phenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid
The first step
4- (1- (3,5- dimethyl phenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate
By 4- (1- amino -1- (4- (Trifluoromethoxyphen-l) pentane -2- base) t-butyl perbenzoate 11b (423mg, 1.00mmol), 3,5 mesitylenic acid 22a (165mg, 1.10mmol), bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (510mg, 2.00mmol) and N, N- diisopropylethylamine (0.70mL, 4.00mmol) it is dissolved in 12mL methylene chloride and N, the in the mixed solvent of dinethylformamide (V/V=5/1), reaction solution react 18 hours at room temperature.20mL ethyl acetate and 20mL water is added after being concentrated under reduced pressure in reaction solution, layering, (20mL × 2) are extracted with ethyl acetate in water phase, merge organic phase to be washed with water (10mL × 3), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 4- (1- (3,5- dimethyl phenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate 22b (389mg, white solid), yield: 70.0%.
MS m/z (ESI): 557.0 [M+1]
Second step
4- (1- (3,5- dimethyl phenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid
By 4- (1- (3,5- dimethyl phenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate 22b (260mg, it 0.38mmol) is dissolved in 3mL methylene chloride, 3mL trifluoroacetic acid is added, reaction solution reacts 18 hours at room temperature.20mL ethyl acetate is added after reaction solution concentration, it is washed with water (20mL × 3), merge organic phase, it is dry with anhydrous sodium sulfate, it is concentrated under reduced pressure, obtains crude product 4- (1- (3,5- dimethyl phenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid 22c (327mg, white liquid), yield: 93.5%.
MS m/z (ESI): 499.9 [M+1]
Third step
3- (4- (1- (3,5- dimethyl phenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate
By 4- (1- (3,5- dimethyl phenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid 22c (327mg, 0.65mmol), 3- alanine carbethoxy hydrochloride (251mg, 1.64mmol), bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (417mg, 1.64mmol) and N, N- diisopropylethylamine (0.54mL, 3.27mmol) it is dissolved in bis- N of 5mL, in dinethylformamide, reaction solution reacts 18 hours at room temperature.Reaction solution is concentrated under reduced pressure, 30mL ethyl acetate is added, successively washed with 1M hydrochloric acid solution (30mL) and water (30mL × 2), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system C), obtain 3- (4- (1- (3,5- dimethyl phenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate 22d (128mg, white solid), yield: 32.8%.
MS m/z (ESI): 598.9 [M+1]
4th step
3- (4- (1- (3,5- dimethyl phenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid
By 3- (4- (1- (3,5- dimethyl phenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate 22d (128mg, 0.31mmol) and mono- hydronium(ion) lithia (72mg of 1.0mL, 1.71mmol) solution is dissolved in the in the mixed solvent of 5mL tetrahydrofuran and methanol (V/V=1/4), and reaction solution reacts 18 hours at room temperature.Reaction solution is concentrated under reduced pressure, 30mL ethyl acetate and 10mL water is added, with 1M salt acid for adjusting pH to solution in acidity, layering, (20mL) is extracted with ethyl acetate in water phase, combined organic phase is washed with water (30mL × 3), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtain 3- (4- (1- (3,5- dimethyl phenacyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid 22 (98mg, white solid), yield: 81.8%.
MS m/z (ESI): 570.9 [M+1]
1H NMR (400MHz, DMSO) δ 8.50 (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)
Embodiment 23
3- (4- (1- (5- chloropyridine acylamino-) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid
The first step
4- (1- (5- chloropyridine acylamino-) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate
By 4- (1- amino -1- (4- (Trifluoromethoxyphen-l) pentane -2- base) t-butyl perbenzoate 11b (423mg, 1.00mmol), 5- chloropyridine formic acid 23a (175mg, 1.10mmol), bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (510mg, 2.00mmol) and N, N- diisopropylethylamine (0.70mL, 4.00mmol) it is dissolved in 10mL methylene chloride and N, the in the mixed solvent of dinethylformamide (V/V=4/1), reaction solution react 18 hours at room temperature.20mL water is added after being concentrated under reduced pressure in reaction solution, (10mL × 3) are extracted with ethyl acetate, merge organic phase to be washed with water (30mL × 3), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 4- (1- (5- chloropyridine acylamino-) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate 23b (470mg, faint yellow solid), yield: 83.5%.MS m/z (ESI): 584.8 [M+23]
Second step
4- (1- (5- chloropyridine acylamino-) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid
By 4- (1- (5- chloropyridine acylamino-) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate 23b (470mg, it 0.83mmol) is dissolved in 6mL methylene chloride, 6mL trifluoroacetic acid is added, reaction solution reacts 2 hours at 25 DEG C.20mL water is added after reaction solution concentration, it is extracted with ethyl acetate (10mL × 3), merge organic phase, it is washed with water (30mL × 3), anhydrous sodium sulfate is dry, is concentrated under reduced pressure, obtains crude product 4- (1- (5- chloropyridine acylamino-) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid 23c (423mg, yellow liquid), yield: 100%.
MS m/z (ESI): 506.8 [M+1]
Third step
3- (4- (1- (5- chloropyridine acylamino-) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate
By 4- (1- (5- chloropyridine acylamino-) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid 23c (423mg, 0.83mmol), 3- alanine carbethoxy hydrochloride (255mg, 1.66mmol), 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (473mg, 1.24mmol) and N, N- diisopropylethylamine (0.60mL, 3.32mmol) it is dissolved in bis- N of 8mL, in dinethylformamide, reaction solution reacts 3 hours at 25 DEG C.30mL water is added into reaction solution, (10mL × 3) are extracted with ethyl acetate, merge organic phase to be washed with water (30mL × 3), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system D), obtain 3- (4- (1- (5- chloropyridine acylamino-) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate 23d (340mg, white solid), yield: 67.6%.
MS m/z (ESI): 605.8 [M+1]
4th step
3- (4- (1- (5- chloropyridine acylamino-) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid
By 3- (4- (1- (5- chloropyridine acylamino-) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate 23d (340mg, 0.56mmol) and mono- hydronium(ion) lithia (120mg of 0.50mL, 2.80mmol) solution is dissolved in the in the mixed solvent of 8mL tetrahydrofuran and methanol (V/V=1/4), and reaction solution reacts 18 hours at room temperature.Reaction solution is concentrated under reduced pressure, adjusts pH=2-3, ethyl acetate (10mL × 3) extraction with 1M hydrochloric acid, merge organic phase, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, obtained residue is purified with silica gel column chromatography (eluant, eluent: system C) Obtain 23 (290mg of 3- (4- (1- (5- chloropyridine acylamino-) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid, white solid), yield: 89.5%.
MS m/z (ESI): 577.8 [M+1]
1H NMR (400MHz, DMSO) δ 12.18 (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=11.5 Hz, 1H), 1.15-1.04 (m, 1H), 0.86 (dd, J=15.7,9.5Hz, 2H), 0.63 (t, J=7.2Hz, 3H)
Embodiment 24
3- (4- (1- (4- chloro-2-methyl benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid
The first step
4- (1- (4- chloro-2-methyl benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate
By 4- (1- amino -1- (4- (Trifluoromethoxyphen-l) pentane -2- base) t-butyl perbenzoate 11b (423mg, 1.00mmol), the chloro- 2 methyl benzoic acid 24a (190mg of 4-, 1.10mmol), bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (510mg, 2.00mmol) and N, N- diisopropylethylamine (0.70mL, 4.00mmol) it is dissolved in 10mL methylene chloride and N, the in the mixed solvent of dinethylformamide (V/V=4/1), reaction solution react 18 hours at room temperature.20mL water is added after being concentrated under reduced pressure in reaction solution, (10mL × 3) are extracted with ethyl acetate, merge organic phase to be washed with water (30mL × 3), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 4- (1- (4- chloro-2-methyl benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate 24b (460mg, white solid), yield: 79.9%.
MS m/z (ESI): 597.8 [M+23]
Second step
4- (1- (4- chloro-2-methyl benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid
By 4- (1- (4- chloro-2-methyl benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate 24b (460mg, 0.80mmol) phosphoric acid (the 553mg with 85%, it 4.80mmol) is dissolved in 5mL acetonitrile, reaction solution reacts 4 hours at 80 DEG C.20mL water is added after reaction solution concentration, it is extracted with ethyl acetate (10mL × 3), merge organic phase, it is dry with anhydrous sodium sulfate, it is concentrated under reduced pressure, obtain crude product 4- (1- (4- chloro-2-methyl benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid 24c (416mg, yellow liquid), yield: 100%.
MS m/z (ESI): 519.8 [M+1]
Third step
3- (4- (1- (4- chloro-2-methyl benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate
By 4- (1- (4- chloro-2-methyl benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid 24c (416mg, 0.85mmol), 3- alanine carbethoxy hydrochloride (250mg, 1.60mmol), 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (456mg, 1.20mmol) and N, N- diisopropylethylamine (0.60mL, 3.20mmol) it is dissolved in bis- N of 8mL, in dinethylformamide, reaction solution reacts 3 hours at 25 DEG C.30mL water is added after being concentrated under reduced pressure in reaction solution, (10mL × 3) are extracted with ethyl acetate, merge organic phase to be washed with water (30mL × 3), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtain crude product 3- (4- (1- (4- chloro-2-methyl benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate 24d (495mg, white solid), yield: 100%.
MS m/z (ESI): 618.90 [M+1]
4th step
3- (4- (1- (4- chloro-2-methyl benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid
By 3- (4- (1- (4- chloro-2-methyl benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate 24d (495mg, 0.80mmol) and mono- hydronium(ion) lithia (170mg of 0.80mL, 4.00mmol) solution is dissolved in the in the mixed solvent of 9mL tetrahydrofuran and methanol (V/V=2/7), and reaction solution reacts 18 hours at room temperature.Reaction solution is concentrated under reduced pressure, pH=2-3 is adjusted with 1M hydrochloric acid, methylene chloride (15mL × 3) extraction, merge organic phase, anhydrous sodium sulfate is dry, it is concentrated under reduced pressure, obtained residue is purified with silica gel column chromatography (eluant, eluent: system C), obtain 24 (270mg of 3- (4- (1- (4- chloro-2-methyl benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid, white solid), yield: 57.1%.
MS m/z (ESI): 590.8 [M+1]
1H NMR (400MHz, DMSO) δ 12.17 (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)
Embodiment 25
3- (4- (1- (2- fluoro- 4- (trifluoromethyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid
The first step
4- (1- (2- fluoro- 4- (trifluoromethyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate
By 4- (1- amino -1- (4- (Trifluoromethoxyphen-l) pentane -2- base) t-butyl perbenzoate 11b (423mg, 1.00mmol), 2- fluoro- 4- (trifluoromethyl) benzoic acid 25a (230mg, 1.10mmol), bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (510mg, 2.00mmol) and N, N- diisopropylethylamine (0.70mL, 4.00mmol) it is dissolved in 10mL methylene chloride and N, the in the mixed solvent of dinethylformamide (V/V=4/1), reaction solution react 18 hours at room temperature.20mL water is added after being concentrated under reduced pressure in reaction solution, (10mL × 3) are extracted with ethyl acetate, merge organic phase to be washed with water (30mL × 3), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 4- (1- (2- fluoro- 4- (trifluoromethyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate 25b (500mg, white solid), yield: 81.6%.
MS m/z (ESI): 557.8 [M+1-56]
Second step
4- (1- (2- fluoro- 4- (trifluoromethyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid
By 4- (1- (2- fluoro- 4- (trifluoromethyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate 25b (500mg, 0.82mmol) phosphoric acid (the 753mg with 85%, it 6.53mmol) is dissolved in 10mL acetonitrile, reaction solution reacts 4 hours at 80 DEG C.20mL water is added after reaction solution concentration, it is extracted with ethyl acetate (10mL × 3), merge organic phase, it is dry with anhydrous sodium sulfate, it is concentrated under reduced pressure, obtain crude product 4- (1- (2- fluoro- 4- (trifluoromethyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid 25c (457mg, yellow solid), yield: 100%.
MS m/z (ESI): 557.8 [M+1]
Third step
3- (4- (1- (2- fluoro- 4- (trifluoromethyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propanoic acid tert-butyl ester
By 4- (1- (2- fluoro- 4- (trifluoromethyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid 25c (457mg, 0.82mmol), 3- alanine t-butyl ester hydrochloride (300mg, 1.64mmol), 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (470mg, 1.23mmol) and N, N- diisopropylethylamine (0.60mL, 3.28mmol) it is dissolved in bis- N of 8mL, in dinethylformamide, reaction solution reacts 3 hours at 25 DEG C.30mL water is added into reaction solution, (15mL × 3) are extracted with ethyl acetate, merge organic phase to be washed with water (50mL × 2), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtain crude product 3- (4- (1- (2- fluoro- 4- (trifluoromethyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propanoic acid tert-butyl ester 25d (560mg, yellow solid), yield: 100%.
MS m/z (ESI): 571.90 [M+1]
4th step
3- (4- (1- (2- fluoro- 4- (trifluoromethyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid
By 3- (4- (1- (2- fluoro- 4- (trifluoromethyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propanoic acid tert-butyl ester 25d (560mg, 0.82mmol) phosphoric acid (the 570mg with 85%, it 4.92mmol) is dissolved in 20mL acetonitrile, reaction solution reacts 4 hours at 80 DEG C.Reaction solution has a large amount of solids to be precipitated, filtering, successively filter cake is washed with water (15mL × 2) and methylene chloride (15mL × 2), filter cake is dissolved in the mixed liquor of 20mL methanol and toluene (V/V=3/1), it is concentrated to dryness, vacuum drying, obtain 25 (340mg of 3- (4- (1- (2- fluoro- 4- (trifluoromethyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid, white solid), yield: 66.0%.
MS m/z (ESI): 628.8 [M+1]
1H NMR (400MHz, DMSO) δ 12.06 (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)
Embodiment 26
3- (4- (1- (different nicotinoyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid
The first step
4- (1- (different nicotinoyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate
By 4- (1- amino -1- (4- (Trifluoromethoxyphen-l) pentane -2- base) t-butyl perbenzoate 11b (423mg, 1.00mmol), isonicotinic acid 26a (150mg, 1.20mmol), bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (510mg, 2.00mmol) and N, N- diisopropylethylamine (0.70mL, 4.00mmol) it is dissolved in 11mL methylene chloride and N, the in the mixed solvent of dinethylformamide (V/V=8/3), reaction solution react 18 hours at room temperature.20mL water is added after being concentrated under reduced pressure in reaction solution, is extracted with ethyl acetate (10mL × 3), merges organic phase and is washed with water (30mL × 3), anhydrous slufuric acid Sodium is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 4- (1- (different nicotinoyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate 26b (450mg, yellow solid), yield: 85.2%.
MS m/z (ESI): 528.9 [M+1]
Second step
4- (1- (different nicotinoyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid
By 4- (1- (different nicotinoyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate 26b (450mg, it 0.85mmol) is dissolved in 4mL methylene chloride with 4mL trifluoroacetic acid, reaction solution reacts 2 hours at 25 DEG C.20mL water is added after reaction solution concentration, it is extracted with ethyl acetate (10mL × 3), merge organic phase, it is washed with water (30mL × 3), anhydrous sodium sulfate is dry, is concentrated under reduced pressure, obtains 4- (1- (different nicotinoyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid 26c (400mg, yellow solid), yield: 100%.
MS m/z (ESI): 472.9 [M+1]
Third step
3- (4- (1- (different nicotinoyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate
By 4- (1- (different nicotinoyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid 26c (400mg, 0.85mmol), 3- alanine carbethoxy hydrochloride (261mg, 1.70mmol), 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (485mg, 1.28mmol) and N, N- diisopropylethylamine (0.60mL, 3.40mmol) it is dissolved in bis- N of 8mL, in dinethylformamide, reaction solution reacts 4 hours at 25 DEG C.30mL water is added after being concentrated under reduced pressure in reaction solution, (15mL × 3) are extracted with ethyl acetate, merge organic phase to be washed with water (50mL × 2), anhydrous sodium sulfate is dry, filtering depressurizes lower concentration, obtains crude product 3- (4- (1- (different nicotinoyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate 26d (485mg, white solid), yield: 100%.
MS m/z (ESI): 571.90 [M+1]
4th step
3- (4- (1- (different nicotinoyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid
By 3- (4- (1- (different nicotinoyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate 26d (485mg, 0.85mmol) and mono- hydronium(ion) lithia (180mg of 0.80mL, 4.25mmol) solution is dissolved in the in the mixed solvent of 12mL tetrahydrofuran and methanol (V/V=1/5), and reaction solution reacts 4 hours at 25 DEG C.Reaction solution is concentrated under reduced pressure, pH=2-3 is adjusted with 1M hydrochloric acid, there are a large amount of solids to be precipitated, filtering, successively filter cake is washed with water (15mL × 2) and methylene chloride (15mL × 2), filter cake is dissolved in the mixed liquor of 20mL methanol and toluene (V/V=3/1), it is concentrated to dryness, vacuum drying, obtain 26 (350mg of 3- (4- (1- (different nicotinoyl amino) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid, white solid), yield: 75.8%.
MS m/z (ESI): 543.8 [M+1]
1H NMR (400MHz, DMSO) δ 12.26 (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)
Embodiment 27
3- (4- (1- (tert-butyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid 27
The first step
4- (1- (tert-butyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate
By 4- (1- amino -1- (4- (Trifluoromethoxyphen-l) pentane -2- base) t-butyl perbenzoate 11b (423mg, 1.00mmol), 4- (tert-butyl) benzoic acid 27a (215mg, 1.20mmol), bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (510mg, 2.00mmol) and N, N- diisopropylethylamine (0.70mL, 4.00mmol) it is dissolved in 10mL methylene chloride and N, the in the mixed solvent of dinethylformamide (V/V=4/1), reaction solution react 18 hours at room temperature.20mL water is added after being concentrated under reduced pressure in reaction solution, (10mL × 3) are extracted with ethyl acetate, merge organic phase to be washed with water (30mL × 3), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 4- (1- (tert-butyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate 27b (260mg, yellow solid), yield: 68.6%.
MS m/z (ESI): 527.9 [M+1-56]
Second step
4- (1- (tert-butyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid
By 4- (1- (tert-butyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) t-butyl perbenzoate 27b (400mg, it 0.68mmol) is dissolved in 4mL methylene chloride with 4mL trifluoroacetic acid, reaction solution reacts 2 hours at 25 DEG C.30mL water is added after reaction solution concentration, it is extracted with ethyl acetate (10mL × 3), merge organic phase, it is washed with water (30mL × 2), anhydrous sodium sulfate is dry, is concentrated under reduced pressure, obtains crude product 4- (1- (tert-butyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid 27c (362mg, yellow liquid), yield: 100%.
MS m/z (ESI): 527.9 [M+1]
Third step
3- (4- (1- (tert-butyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate
By 4- (1- (tert-butyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzoic acid 27c (362mg, 0.68mmol), 3- alanine carbethoxy hydrochloride (210mg, 1.36mmol), 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (390mg, 1.02mmol) and N, N- diisopropylethylamine (0.50mL, 2.72mmol) it is dissolved in bis- N of 6mL, in dinethylformamide, reaction solution reacts 4 hours at room temperature.25mL water is added into reaction solution, is extracted with ethyl acetate (10mL × 3), merges organic phase and is washed with water (30mL × 2), nothing Aqueous sodium persulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system C), obtain 3- (4- (1- (tert-butyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate 27d (170mg, white solid), yield: 39.9%.
MS m/z (ESI): 627.0 [M+1]
4th step
3- (4- (1- (tert-butyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) propionic acid
By 3- (4- (1- (tert-butyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) ethyl propionate 27d (170mg, 0.27mmol) and mono- hydronium(ion) lithia (60mg of 0.30mL, 1.40mmol) solution is dissolved in the in the mixed solvent of 8mL tetrahydrofuran and methanol (V/V=3/1), and reaction solution reacts 4 hours at 25 DEG C.Reaction solution is concentrated under reduced pressure, pH=2-3 is adjusted with 1M hydrochloric acid, (10mL × 3) are extracted with ethyl acetate, combined organic phase is dry with anhydrous sodium sulfate, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system C), obtain 3- (4- (1- (tert-butyl) benzamido) -1- (4- (trifluoromethoxy) phenyl) pentane -2- base) benzamido) 27 (110mg of propionic acid, white solid), yield: 68.3%.
MS m/z (ESI): 598.9 [M+1]
1H NMR (400MHz, DMSO) δ 12.20 (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)
Embodiment 28
3- (4- ((2R, 3R)/(2S, 3S) -1- ((the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 28
3- (4- ((2R, 3R) -1- ((the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 28A
3- (4- ((2S, 3S) -1- ((the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 28B
The first step
3- (4- ((2R, 3R)/(2S, 3S) -1- ((the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate
By ((2R, 3R)/(2S, 3S)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) caproic acid 1s (82.0g, 165.5mmol), the fluoro- 2' of 3-, 4', 6'- trimethyl-[1, 1'- biphenyl] -4- amine 4c (37.9g, 165.5mmol), bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (83.8g, it 329.8mmol) is dissolved in 820mL methylene chloride, it is added with stirring N, N- diisopropylethylamine (145.7mL, 827.7mmol), it stirs 18 hours at room temperature.Reaction solution is concentrated under reduced pressure, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 3- (4- ((2R, 3R)/(2S, 3S) -1- ((the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 28a (110.0g, white solid), yield: 94.0%.
MS m/z (ESI): 706.9 [M+1]
Second step
3- (4- ((2R, 3R)/(2S, 3S) -1- ((the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid
By 3- (4- ((2R, 3R)/(2S, 3S) -1- ((the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 28a (110.0g, 155.6mmol) it is dissolved in the in the mixed solvent of 1200mL tetrahydrofuran and methanol (V/V=1:1), it is added with stirring mono- hydronium(ion) lithia (65.0g of 65mL, 1.56mol) in solution, stir 2 hours at room temperature.1000mL ethyl acetate is added, it is washed with 1M dilute hydrochloric acid (1500mL), then it is washed with saturated ammonium chloride solution (1000mL), organic phase is dry with anhydrous sodium sulfate, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 3- (4- ((2R, 3R)/(2S, 3S) -1- ((the fluoro- 2' of 3-, 4', 6'- trimethyl-[1, 1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) 28 (82.0g of propionic acid, white solid), yield: 77.7%.
MS m/z (ESI): 678.9 [M+1]
3- (4- ((2R, 3R)/(2S, 3S) -1- ((the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) and propionic acid 28 further by chiral column further by using supercritical fluid chromatography (SFC) method, ((1) chiral column ChiralPak AD is split with Preparation equipment and the chiral isomers of chiral column, 25 × 3cm, 80mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (2) Whelk O1 (S, S), 25 × 3cm, 65mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (3) Whelk O1 (S, S), 25 × 3cm, 70mL/min；Mobile phase A for CO2And B for Ethanol)) it is split, obtain 3- (4- ((2R, 3R) -1- ((the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 28A and 3- (4- ((2S, 3S) -1- ((the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) 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), and 8.01 (t, J=8.3Hz, 1H), 7.70-7.57 (m, 2 ), H 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)
Embodiment 29
3- (4- ((2R, 3R)/(2S, 3S) -1- ((the chloro- 2'- methyl-of 4'- [1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 29
3- (4- ((2R, 3R) -1- ((the chloro- 2'- methyl-of 4'- [1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 29A
3- (4- ((2S, 3S) -1- ((the chloro- 2'- methyl-of 4'- [1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 29B
The first step
3- (4- ((2R, 3R)/(2S, 3S) -1- ((the chloro- 2'- methyl-of 4'- [1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate
By ((2R; 3R)/(2S, 3S)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) caproic acid 1s (80 Mg, 0.16mmol), the chloro- 2'- methyl-[1 of 4'-, 1'- biphenyl] -4- amine 1n (52mg, 0.24mmol), I-hydroxybenzotriazole (43mg, 0.32mmol) and 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride (61mg, 0.32mmol) are dissolved in 20mL methylene chloride, it is added with stirring N, N- diisopropylethylamine (0.14mL, 0.8mmol) stirs 24 hours at room temperature.Reaction solution is concentrated under reduced pressure, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 3- (4- ((2R, 3R)/(2S, 3S) -1- ((the chloro- 2'- methyl-[1 of 4'-, 1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 29a (58mg, white solid), yield: 51.8%.
MS m/z (ESI): 695.8 [M+1]
Second step
3- (4- ((2R, 3R)/(2S, 3S) -1- ((the chloro- 2'- methyl-of 4'- [1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid
By 3- (4- ((2R, 3R)/(2S, 3S) -1- ((the chloro- 2'- methyl-[1 of 4'-, 1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) ethyl propionate 29a (58mg, 0.083mmol) it is dissolved in the in the mixed solvent of 6mL tetrahydrofuran and methanol (V/V=1:1), it is added with stirring 1mL sodium hydroxide (17mg, 0.42mmol) in solution, stir 3 hours at room temperature.Reaction solution is concentrated under reduced pressure, (50mL) is extracted with ethyl acetate, combined organic phase with saturated ammonium chloride (50mL) and sodium chloride solution (50mL) with successively being washed, anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtain 3- (4- ((2R, 3R)/(2S, 3S) -1- ((the chloro- 2'- methyl-[1 of 4'-, 1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 29 (40m g, white solid), yield: 71.0%.
MS m/z (ESI): 667.8 [M+1]
1H NMR(400MHz,DMSO-d6) δ 10.46 (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- ((the chloro- 2'- methyl-[1 of 4'-, 1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 29 is further by using supercritical fluid chromatography (SFC) method, ((1) chiral column ChiralPak AD is split with Preparation equipment and the chiral isomers of chiral column, 25 × 3cm, 80mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (2) Whelk O1 (S, S), 25 × 3cm, 65mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (3) Whelk O1 (S, S), 25 × 3cm, 70mL/min；Mobile phase A for CO2And B for Ethanol)) it is split, obtain 3- (4- ((2R, 3R) -1- ((the chloro- 2'- methyl-[1 of 4'-, 1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 29A and 3- (4- ((2S, 3S) -1- ((the chloro- 2'- methyl-of 4'- [1,1'- biphenyl] -4- base) amino) -1- oxo -2- (4- (trifluoromethoxy) phenyl) hexane -3- base) benzamido) propionic acid 29B.
29A:MS m/z (ESI): 667.8 [M+1]
29B:MS m/z (ESI): 667.8 [M+1]
Embodiment 30
3- (4- ((2R, 3R)/(2S, 3S) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) hexane -3- base) benzamido) propionic acid 30
3- (4- ((2R, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) hexane -3- base) benzamido) propionic acid 30A
3- (4- ((2S, 3S) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) hexane -3- base) benzamido) propionic acid 30B
The first step
3- (4- ((2R, 3R)/(2S, 3S) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) hexane -3- base) benzamido) ethyl propionate
By ((2R, 3R)/(2S, 3S)) -3- (4- ((3- ethyoxyl -3- oxopropyl) carbamoyl) phenyl) -2- (4- (trifluoromethoxy) phenyl) caproic acid 1s (80mg, 0.16mmol), 2', 4', 6'- trimethyl-[1, 1'- biphenyl] -4- amine 2a (63.4mg, 0.3mmol), I-hydroxybenzotriazole (40.5mg, 0.3mmol) and 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride (49.8mg, it 0.26mmol) is dissolved in 10mL methylene chloride, it is added with stirring N, N- diisopropylethylamine (0.09mL, 0.5mmol), it stirs 24 hours at room temperature.Reaction solution is concentrated under reduced pressure, obtained residue is purified with silica gel column chromatography (eluant, eluent: system B), obtain 3- (4- ((2R, 3R)/(2S, 3S) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) hexane -3- base) benzamido) ethyl propionate 30a (50mg, white solid), yield: 45.4%.
MS m/z (ESI): 690.0 [M+1]
Second step
3- (4- ((2R, 3R)/(2S, 3S) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) hexane -3- base) benzamido) propionic acid
By 3- (4- ((2R, 3R)/(2S, 3S) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) hexane -3- base) benzamido) ethyl propionate 30a (50mg, 0.072mmol) it is dissolved in the in the mixed solvent of 6mL tetrahydrofuran and methanol (V/V=1:1), it is added with stirring 1mL sodium hydroxide (14.4mg, 0.36mmol) in solution, stir 3 hours at room temperature.Reaction solution is concentrated under reduced pressure, (30mL) is extracted with ethyl acetate, combined organic phase is washed with ammonium chloride solution (30mL × 3), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with thin layer chromatography (solvent: system A), obtain 3- (4- ((2R, 3R)/(2S, 3S) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2', 4', 6'- trimethyl-[1, 1'- biphenyl] -4- base) amino) hexane -3- base) benzamido) 30 (17mg of propionic acid, white solid), yield: 29.4%.
MS m/z (ESI): 661.9 [M+1]
1H NMR (400MHz, DMSO) δ 10.42 (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- base) amino) hexane -3- base) benzamido) propionic acid 30 is further by using supercritical fluid chromatography (SFC) method, ((1) chiral column ChiralPak AD is split with Preparation equipment and the chiral isomers of chiral column, 25 × 3cm, 80mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (2) Whelk O1 (S, S), 25 × 3cm, 65mL/min；Mobile phase A for CO2and B for Ethanol；Or/and (3) Whelk O1 (S, S), 25 × 3cm, 70mL/min；Mobile phase A for CO2And B for Ethanol)) it is split, obtain 3- (4- ((2R, 3R) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) hexane -3- base) benzamido) propionic acid 30A and 3- (4- ((2S, 3S) -1- oxo -2- (4- (trifluoromethoxy) phenyl) -1- ((2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base) amino) hexane -3- base) benzamido) propionic acid 30B.
30A:MS m/z (ESI): 661.9 [M+1]
30B:MS m/z (ESI): 661.9 [M+1]
Embodiment 31
3- (4- (1- (3- fluoro- 2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) -1- (4- (trifluoromethoxy) phenyl)-pentane -2- base) benzamido) propionic acid
3- (4- ((1R, 2R) -1- (the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) -1- (4- (trifluoromethoxy) phenyl)-pentane -2- base) benzamido) propionic acid 31A
3- (4- ((1S, 2S) -1- (the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) -1- (4- (trifluoromethoxy) phenyl)-pentane -2- base) benzamido) propionic acid 31B
The first step
4- (1- (3- fluorine 2', 4,6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) -1- (4- (trifluoromethoxy) phenyl)-pentane -2- base) t-butyl perbenzoate
By 4- (1- amino -1- (4- (Trifluoromethoxyphen-l) pentane -2- base) t-butyl perbenzoate 11b (5.50g, 13.0mmol), the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- carboxylic acid 31a (3.95g, 15.3mmol), bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride (6.00g, 23.6mmol) and N, N- diisopropylethylamine (8.2mL, 47.2mmol) it is dissolved in 60mL methylene chloride and N, the in the mixed solvent of dinethylformamide (V/V=5/1), reaction solution react 18 hours at 30 DEG C.50mL water is added after being concentrated under reduced pressure in reaction solution, (25mL × 3) are extracted with ethyl acetate, merge organic phase to be washed with water (50mL × 3), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: system A), obtain 4- (1- (3- fluorine 2', 4,6'- trimethyls-[1,1'- biphenyl] -4- base formamido group) -1- (4- (trifluoromethoxy) phenyl)-pentane -2- base) t-butyl perbenzoate 31b (7.13g, faint yellow solid), yield: 82.8%.
MS m/z (ESI): 607.9 [M+1-56]
Second step
4- (1- (the fluoro- 2' of 3-, 4,6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) -1- (4- (trifluoromethoxy) phenyl)-pentane -2- base) benzoic acid
By 4- (1- (3- fluorine 2', 4,6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) -1- (4- (trifluoromethoxy) phenyl)-pentane -2- base) t-butyl perbenzoate 31b (7.13g, 10.7mmol) phosphoric acid (the 4.5mL with 85%, it 66.0mmol) is dissolved in 50mL acetonitrile, reaction solution reacts 4 hours at 80 DEG C.50mL water is added after reaction solution concentration, it is extracted with ethyl acetate (25mL × 3), merge organic phase, it is dry with anhydrous sodium sulfate, it is concentrated under reduced pressure, obtain crude product 4- (1- (the fluoro- 2' of 3-, 4,6'- trimethyls-[1,1'- biphenyl] -4- base formamido group) -1- (4- (trifluoromethoxy) phenyl)-pentane -2- base) benzoic acid 31c (6.50g, yellow solid), yield: 100%.
MS m/z (ESI): 607.9 [M+1]
Third step
3- (4- (1- (3- fluoro- 2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) -1- (4- (trifluoromethoxy) phenyl)-pentane -2- base) benzamido) ethyl propionate
By 4- (1- (the fluoro- 2' of 3-, 4,6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) -1- (4- (trifluoromethoxy) phenyl)-pentane -2- base) benzoic acid 31c (6.50g, 10.7mmol), 3- alanine t-butyl ester hydrochloride (3.90g, 21.4mmol), 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (6.10g, 16.1mmol) and n,N-diisopropylethylamine (7.50mL, 42.8mmol) it is dissolved in bis- N of 60mL, N- In dimethylformamide, reaction solution reacts 3 hours at 25 DEG C.250mL water is added into reaction solution, (80mL × 3) are extracted with ethyl acetate, merge organic phase, it is washed with water (300mL × 3), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtained residue is purified with silica gel column chromatography (eluant, eluent: methylene chloride: methanol system), it obtains 3- (4- (1- (the fluoro- 2' of 3-, 4', 6'- trimethyl-[1, 1'- biphenyl] -4- base formamido group) -1- (4- (trifluoromethoxy) phenyl)-pentane -2- base) benzamido) ethyl propionate 31d (7.86g, yellow solid), yield: 100%.
MS m/z (ESI): 678.9 [M+1-56]
4th step
3- (4- (1- (3- fluoro- 2', 4', 6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) -1- (4- (trifluoromethoxy) phenyl)-pentane -2- base) benzamido) propionic acid
By 3- (4- (1- (the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) -1- (4- (trifluoromethoxy) phenyl)-pentane -2- base) benzamido) ethyl propionate 31d (7.86g, 10.7mmol) phosphoric acid (the 4.5mL with 85%, it 64.2mmol) is dissolved in 100mL acetonitrile, reaction solution reacts 4 hours at 80 DEG C.Reaction solution concentration, pH=3 is adjusted with 3M hydrochloric acid, (40mL × 3) are extracted with ethyl acetate, combined organic phase, it is washed with water (120mL × 3), anhydrous sodium sulfate is dry, filtering, the lower concentration of decompression, obtains 3- (4- (1- (the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) -1- (4- (trifluoromethoxy) phenyl)-pentane -2- base) benzamido) propionic acid 31 (7.10g, faint yellow solid), yield: 97.8%.
MS m/z (ESI): 678.9 [M+1]
1H NMR(400MHz,CDCl3) δ 7.98 (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), 1.6 6 (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- (the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) -1- (4- (trifluoromethoxy) phenyl)-pentane -2- base) benzamido) propionic acid 31 is further by using supercritical fluid chromatography (SFC) method, (chiral column Whelk O1 (S is split with Preparation equipment and the chiral isomers of chiral column, S), 250 × 4.6mm I.D., mobile phase A for CO2and B for Ethanol；A for CO2And B (50%) for Methanol (0.05%DEA)) it is split, obtain 3- (4- ((1R, 2R) -1- (the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) -1- (4- (trifluoromethoxy) phenyl)-pentane -2- base) benzamido) propionic acid 31A (retention time: 4.95min；And 3- (4- ((1S ee value: 100%), 2S) -1- (the fluoro- 2' of 3-, 4', 6'- trimethyl-[1,1'- biphenyl] -4- base formamido group) -1- (4- (trifluoromethoxy) phenyl)-pentane -2- base) benzamido) propionic acid 31B (retention time: 11.28min；Ee value: 100%).
31A:MS m/z (ESI): 678.9 [M+1]
1H NMR (400MHz, DMSO) δ 12.19 (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) δ 12.21 (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=10.9H Z, 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 assessment
The inhibition that test case 1, the compounds of this invention generate the cAMP intracellular that glucagon induces
This method tests test-compound in cellular level to the antagonism of glucagon receptor using the HEK293 cell strain (being purchased from Shanghai Inst. of Life Science, CAS cell resource center) of high expression source of people glucagon receptor (hGCGR) as test model.HEK293-hGCGR cell adds 10% fetal calf serum (FBS, GIBCO article No. 10099141) with F12 culture medium (Invitrogen article No. #11765047), at 37 DEG C, 5%CO2Under the conditions of cultivated.When experiment, cell is inoculated in 384 porocyte culture plates (OptiPlate-384, white, PerkinElmer article No. 6007290) with 3000/hole.Compound is first dissolved in DMSO, subsequent gradient dilution to required test concentrations, and each compound sets 10 concentration points, respectively 50 μM, 16.7 μM, 5.56 μM, 1.85 μM, 0.62 μM, 0.21 μM, 69nM, 23nM, 7.5nM and 2.5nM.After cell gives compound, then with glucagon (Sigma, 0.05nM) stimulation cell, it is incubated at room temperature 1 hour.It is then added after detection liquid by Lance cAMP384Kit kit (PerkinElmer, article No. #AD0263) operating instruction and continues to be incubated for 1 hour at room temperature and illustrate to measure cyclic adenosine monophosphate intracellular (cAMP) level by kit.It is compared by the cAMP level with blank control cell, determine the inhibition level that test-compound generates cAMP under each concentration, amount effect relation curve figure is then made with compound log concentration (logarithm of compound concentration)-suppression level (inhibiting rate), and carries out the IC that nonlinear regression analysis calculates compound50Value.Similar method is suitable for testing the cell strain of high expression source of people glucogan-like peptide 1 receptor (hGLP-1R) and Gastrin Inhibitory Peptide receptor (GIPR), to measure compound to the selectivity of GCGR.
The IC that preferred compound of the present invention inhibits GCGR50Numerical value is as shown in table 1.
The IC that the preferred compound of the present invention of table 1 inhibits GCGR50Value
Compound number 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
Conclusion: preferred compounds of the invention significantly inhibits GCGR.
The pharmacokinetics of test case 2, the compounds of this invention 4A and compound 4B is tested
1, it makes a summary
Using SD rat as animal subject, after giving compound 4A and compound 4B compound using LC/MS/MS method measurement rat oral gavage, the drug concentration in its different moments blood plasma is measured, studies the compounds of this invention in the intracorporal Pharmacokinetic Characteristics of rat.
2, experimental program
2.1 experimental drugs and animal
Compound 4A and compound 4B；Healthy adult SD male rat 6, purchased from dimension experimental animal Technology Co., Ltd., tonneau China, production licence number: 11400700109943.
2.2 medicine ordinances and administration
The experimental drug of 3mg is weighed, 1mL ethyl alcohol is added, ultrasound to solution is added 1.5mL PEG400 and 2.5mL water, while vortex mixed, is configured to 0.6mg/mL；
Healthy adult SD male rat 6, gastric infusion, dosage 3mg/kg are distinguished after overnight fasting.
The acquisition of 2.3 samples
15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours throat venous blood collection 0.15mL before administration and after administration, it is placed in heparinised tubes, 5500 revs/min, is centrifuged 10 minutes, it is saved in -30 DEG C, administration is fed after 4 hours.
2.4 sample treatment
Plasma sample handles (For plasma samples):
20 μ L samples are taken, IS is added and (contains Verapamil 5ngmL-1With glibenclamide 50ngmL-1) 100 μ L acetonitriles solution in, vortex mixed 0.2 minute, 13000 revs/min be centrifuged 8 minutes, then take 70 μ L supernatants be added 70 μ L water in, vortex mixed 10 minutes, the supernatant of 10 μ L mixed liquors is taken to be analyzed into LC-MS/MS system.
It is administered sample treatment (For dose sample):
The administration sample mixed solvent of first alcohol and water (1:1, v/v) is diluted to concentration as 100ngmL-1, sample and 100 μ L inner mark solution (100ngmL after taking 100 μ L to dilute-1) be added to the IS solution and 600 μ L water of 500 μ L, then vortex mixed, takes the supernatant of 10 μ L mixed liquors to be analyzed into LC-MS/MS system.
3, pharmacokinetic parameter result
The pharmacokinetic parameter of preferred compounds of the invention is as shown in table 1.
The pharmacokinetic data table of table 2 compound 4A and compound 4B
Conclusion: currently preferred compound 4A and 4B has preferable pharmacokinetic property.
The influence to db/db mouse random blood sugar is administered in test case 3, the compounds of this invention single oral
Experiment purpose
Observe the influence after preferred compound single oral of the present invention is administered to type-2 diabetes mellitus model db/db mouse random blood sugar, using tail portion blood taking method, blood glucose numerical value is measured by portable glucose meter, and then the internal blood sugar reducing function of test-compound is evaluated.
Animal subject
Male db/db mouse 42 9-10 weeks, is provided, credit number by model animal research institute, Nanjing University: SCXK (Soviet Union) 2010-0001, and positive controls and solvent control group are arranged.
Tested material
(the 4- ((1R of 3- disclosed in compound 4,4A, 5,19,23,25 and 28A, WO20150662521,2S) -1- (the fluoro- 1H- indol-3-yl of the chloro- 7- of 5-) -1- (4- (trifluoromethoxy) phenyl) amyl- 2- yl) benzamido) propionic acid (FORM1), with ethyl alcohol: PEG400: concentration needed for water=20:30:50 is prepared.
Administration mode
Oral administration gavage administration, blank control group fill the ethyl alcohol for giving same volume: PEG400: water=20:30:50, administered volume 10ml/kg, dosage 30mg/kg.
Test method
Male db/db mouse is grouped, every group 6, the respectively administration group of solvent control and different compounds by non-fasting blood glucose and weight.Single oral gives test medicine and solvent to groups of animals respectively, and 1h, 2h, 4h, 6h, 8h, 12h and progress tail portion blood glucose value detection for 24 hours, observe tested material hypoglycemic effect and hold time, and draw 24 hours blood glucose curves before administration and after administration.Compound determines the adjustment effect of blood glucose and compared with the blood glucose of db/db mouse for being given only Vehicle controls.
Experimental result
The blood glucose rate of descent of preferred compound of the present invention is as shown in table 3.
The blood glucose rate of descent table of the preferred compound of the present invention of table 3
Conclusion: preferred compound of the present invention all shows preferable blood sugar reducing function 4 hours and 6 hours.
Influence of the oral administration in test case 4, preferred compound of the present invention continuous 28 days to db/db mouse random blood sugar
Experiment purpose
Influence after observation oral administration in preferred compound of the present invention continuous 28 days to type-2 diabetes mellitus model db/db mouse random blood sugar, using tail portion blood taking method, blood glucose numerical value is measured by portable glucose meter, and then the internal blood sugar reducing function of test-compound is evaluated.
Animal subject
Male db/db mouse 100 9-10 weeks, is provided, credit number by model animal research institute, Nanjing University: SCXK (Soviet Union) 2010-0001, and positive controls and solvent control group are arranged.
Tested material
Compound 4A, 28A, sitagliptin (marketed drug), 3- (4- ((1R disclosed in WO20150662521,2S) -1- (the fluoro- 1H- indol-3-yl of the chloro- 7- of 5-) -1- (4- (trifluoromethoxy) phenyl) amyl- 2- yl) benzamido) propionic acid (FORM1), with ethyl alcohol: PEG400: water=20:30:50 prepares institute Need concentration.
Administration mode
Oral administration gavage administration, blank control group fill the ethyl alcohol for giving same volume: PEG400: water=20:30:50, administered volume 10ml/kg, dosage 30mg/kg.
Test method
Male db/db mouse is grouped, every group 8, the respectively administration group of solvent control and different compounds by non-fasting blood glucose and weight.Groups of animals takes orally give test medicine and solvent respectively for continuous 28 days, 8h carries out the detection of tail portion blood glucose value after the 1st day, the 7th day, the 14th day, the 21st day, administration in the 28th day, it observes tested material hypoglycemic effect and holds time, and draw 28 days blood glucose curves.Compound determines the adjustment effect of blood glucose and compared with the blood glucose of db/db mouse for being given only Vehicle controls.
Experimental result
Db/db mouse continuous 28 days oral to give the compound (FORM1) of preferred compound 4A of the present invention, compound 28B and sitagliptin and WO2015066252, in comparison, compound 4A and compound 28B has apparent hypoglycemic effect, it is specific as shown in Figure 1 better than sitagliptin and FORM1.
All references mentioned in the present invention is incorporated herein by reference, as if each reference was individually incorporated by reference.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can make various modifications or changes to the present invention, these equivalent forms also fall within the scope of the appended claims of the present application.

Claims (36)

  1. A kind of logical formula (I) compound represented or its stereoisomer, tautomer or its pharmaceutical salt:
    Wherein:
    L is selected from-C (O) NH- or-NH-C (O)-；
    A1、A2、A3、A4And A5It is each independently selected from CH, C or N, on condition that A1、A2、A3、A4And A5And the quantity in ring composed by carbon atom in connection containing N is 0~2；
    R1Selected from alkyl or cycloalkyl, wherein the alkyl or cycloalkyl is optionally further selected from hydroxyl, halogen, nitro, cyano, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl ,-NR by one or more6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8Or-NR6C(O)R7Substituent group replaced；
    R2Selected from hydrogen atom, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, cyano, nitro, naphthenic base, heterocycle, aryl, heteroaryl ,-NR6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8Or-NR6C(O)R7, wherein alkyl, alkenyl, alkynyl, alkoxy, naphthenic base, heterocycle, aryl or the heteroaryl are optionally further selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy, naphthenic base, heterocycle, aryl, heteroaryl ,-NR by one or more6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8Or-NR6C(O)R7Substituent group replaced；Work as A3When selected from N, R2It is not present；
    R3It is each independently selected from hydrogen atom, alkyl, halogen, hydroxyl, alkoxy, cyano, nitro, naphthenic base, heterocycle, aryl, heteroaryl ,-NR6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8Or-NR6C(O)R7, wherein alkyl, alkoxy, naphthenic base, heterocycle, aryl or the heteroaryl are optionally further selected from hydroxyl, halogen, nitro, cyano, alkoxy, halogenated alkyl, halogenated alkoxy, naphthenic base, heterocycle, aryl, heteroaryl ,-NR by one or more6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8Or-NR6C(O)R7Substituent group replaced；
    R4It is each independently selected from hydrogen atom, alkyl, halogen, hydroxyl, alkoxy, cyano, nitro, naphthenic base, heterocycle, aryl, heteroaryl ,-NR6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8Or-NR6C(O)R7, wherein alkyl, alkoxy, naphthenic base, heterocycle, aryl or the heteroaryl are optionally further selected from hydroxyl, halogen, nitro, cyano, alkoxy, halogenated alkyl, halogenated alkoxy, naphthenic base, heterocycle, aryl, heteroaryl ,-NR by one or more6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8Or-NR6C(O)R7Substituent group replaced；
    R5It is each independently selected from hydrogen atom, alkyl, halogen, hydroxyl, alkoxy, cyano, nitro ,-NR6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8Or-NR6C(O)R7, wherein the alkyl or alkoxy are optionally further selected from hydroxyl, halogen, nitro, cyano, alkoxy, halogenated alkyl, halogenated alkoxy, naphthenic base, heterocycle, aryl, heteroaryl ,-NR by one or more6R7、-C(O)NR6R7、-C(O)R8、-SO2R8、-C(O)OR8Or-NR6C(O)R7Substituent group replaced；
    R6Selected from hydrogen atom or alkyl；
    R7Selected from hydrogen atom, alkyl, naphthenic base, aryl or heteroaryl, wherein alkyl, naphthenic base, aryl or the heteroaryl are optionally further selected from hydroxyl, halogen, halogenated alkyl, nitro, cyano, alkyl, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl ,-NR by one or more9R10、-C(O)R9R10、-C(O)R11、-SO2R11、-C(O)OR11Or-NR9C(O)R10Substituent group replaced；
    Alternatively, R6And R74~8 circle heterocyclic ring bases are formed together with the N atom being connected, wherein containing one or more N, O, S (O) in the heterocycleqAtom, and the heterocycle is optionally further selected from alkyl, halogen, hydroxyl, cyano, nitro, naphthenic base, heterocycle, aryl, heteroaryl ,-NR by one or more9R10、-C(O)R9R10、-C(O)R11、-SO2R11、-C(O)OR11Or-NR9C(O)R10Substituent group replaced；
    R8Selected from hydrogen atom, alkyl, naphthenic base, heterocycle, aryl or heteroaryl, wherein the alkyl, naphthenic base, heterocycle, aryl or heteroaryl are optionally selected from hydroxyl, halogen, halogenated alkyl, nitro, cyano, alkyl, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl ,-NR by one or more9R10、-C(O)R9R10、-C(O)R11、-SO2R11、-C(O)OR11Or-NR9C(O)R10Substituent group replaced；
    R9、R10And R11It is each independently selected from hydrogen atom, alkyl, naphthenic base, heterocycle, aryl or heteroaryl, wherein the alkyl, naphthenic base, heterocycle, aryl or heteroaryl are optionally selected from replaced the substituent groups of hydroxyl, halogen, halogenated alkyl, nitro, cyano, alkyl, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl, carboxylic acid or carboxylate by one or more；
    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
    Q is 0,1 or 2.
  2. Compound according to claim 1 or its stereoisomer, tautomer or its pharmaceutical salt, to lead to compound or its stereoisomer, tautomer or its pharmaceutical salt described in formula (II):
    Wherein: R1~R5, m, n and p definition as described in the appended claim 1.
  3. Compound according to claim 1 or its stereoisomer, tautomer or its pharmaceutical salt, to lead to compound or its stereoisomer, tautomer or its pharmaceutical salt described in formula (III):
    Wherein: R1~R5, m, n and p definition as described in the appended claim 1.
  4. Compound according to claim 2 or its stereoisomer, tautomer or its pharmaceutical salt, for logical formula (IV) or (V) Or compound described in (VI) or (VII) or its stereoisomer, tautomer or its pharmaceutical salt:
    Wherein: R1~R5, m, n and p definition as described in the appended claim 1.
  5. Compound according to claim 3 or its stereoisomer, tautomer or its pharmaceutical salt, to lead to compound or its stereoisomer, tautomer or its pharmaceutical salt described in formula (VIII) or (IX) or (X) or (XI):
    Wherein: R1~R5, m, n and p definition as described in the appended claim 1.
  6. Described in any item compounds or its stereoisomer, tautomer or its pharmaceutical salt according to claim 1~5, wherein R1Selected from C3-6Alkyl, preferably n-propyl.
  7. Described in any item compounds or its stereoisomer, tautomer or its pharmaceutical salt according to claim 1~5, wherein R2Selected from phenyl, wherein the phenyl is optionally further replaced the substituent group of one or more alkyl, halogen, cyano, nitro, alkoxy, halogenated alkyl or halogenated alkoxy, further preferred scheme, wherein the phenyl is further replaced one or more methyl, trifluoromethyl or trifluoromethoxy.
  8. Described in any item compounds or its stereoisomer, tautomer or its pharmaceutical salt according to claim 1~5, wherein R2Selected from 5~8 unit's heteroaryls, wherein the heteroaryl is optionally further replaced the substituent group of one or more alkyl, halogen, cyano, nitro, alkoxy, halogenated alkyl or halogenated alkoxy, wherein R2Further preferably pyrroles, furans, thiophene, pyrazoles, imidazoles, thiazole, benzimidazole, benzofuran or benzoxazoles, wherein pyrroles, furans, thiophene, pyrazoles, imidazoles, thiazole, benzimidazole, benzofuran or the benzoxazoles are optionally further replaced the substituent group of one or more alkyl, halogen, cyano, nitro or alkoxy, wherein optionally further replaced the substituent group of one or more halogens, the halogen is preferably F for the alkyl or alkoxy.
  9. Described in any item compounds or its stereoisomer, tautomer or its pharmaceutical salt according to claim 1~5, wherein R3Selected from alkoxy, wherein the alkoxy is optionally further selected from replaced the substituent groups of alkyl, halogen, cyano, nitro or alkoxy by one or more, R3Preferably fluoroalkyl, more preferably trifluoromethoxy or trifluoro ethoxy.
  10. Compound according to claim 9 or its stereoisomer, tautomer or its pharmaceutical salt, wherein R33 (meta positions) or 4 (contraposition) are connected to, m is preferably 1.
  11. Described in any item compounds or its stereoisomer, tautomer or its pharmaceutical salt according to claim 1~5, wherein R4Selected from hydrogen atom, halogen or alkyl, preferably F, n is preferably 1.
  12. Compound according to claim 1 or its stereoisomer, tautomer or its pharmaceutical salt, in which:
    A3Selected from C；
    R1Selected from n-propyl；
    R2Selected from alkyl, halogen, cyano, nitro, alkoxy, halogenated alkyl, halogenated alkoxy, phenyl or 5~8 unit's heteroaryls, the alkyl, alkoxy, phenyl or 5~8 unit's heteroaryls are optionally further replaced the substituent group of one or more alkyl, halogen, cyano, nitro, alkoxy, halogenated alkyl or halogenated alkoxy；
    R3Selected from trifluoromethoxy；
    R4Selected from hydrogen atom or halogen；
    R5It is each independently selected from hydrogen atom, alkyl, halogen, alkoxy, halogenated alkyl or halogenated alkoxy；
    M is 0,1 or 2；
    N is 0,1 or 2；And
    P is 0,1 or 2.
  13. Compound according to claim 1 or its stereoisomer, tautomer or its pharmaceutical salt, wherein the compound includes:
  14. Compound according to claim 1 or its stereoisomer, tautomer or its pharmaceutical salt, wherein the compound includes:
  15. 4 described in any item compounds or its stereoisomer, tautomer, its raceme or its pharmaceutical salt according to claim 1, wherein the compound includes:
  16. Compound according to claim 1 or its stereoisomer, tautomer or its pharmaceutical salt, wherein the compound includes:
  17. 6 described in any item compounds or its stereoisomer, tautomer or its pharmaceutical salt according to claim 1, wherein the compound includes:
  18. A kind of preparation method of formula according to claim 1 (I) compound, which comprises
    General formula (IA) is reacted with general formula (IB), and obtained compound further hydrolyzes, and obtains logical formula (I) compound；
    Wherein:
    L1Selected from-C (O) X；
    L2Selected from-NH2；
    X is selected from hydroxyl or halogen；
    RcSelected from alkyl；
    L is selected from-NH-C (O)-；And
    R1~R5、A1~A5, m, n and p definition as described in the appended claim 1.
  19. The preparation method of preparation method according to claim 18, formula of (IA) includes:
    General formula (IC) and general formula (ID) or its reactant salt, obtain general formula (IA) compound；
    Wherein:
    L1Selected from-C (O) X；
    X is selected from hydroxyl or halogen；
    RcSelected from alkyl；And
    R1、R3、R4, m, n definition as described in the appended claim 1.
  20. A kind of preparation method of formula according to claim 1 (I) compound, which comprises
    General formula (IE) and general formula (ID) or its reactant salt, obtained compound further hydrolyze, and obtain logical formula (I) compound；
    Wherein:
    X is selected from hydroxyl or halogen；
    RcSelected from alkyl；
    L is selected from-C (O)-NH-；And
    R1~R5、A1~A5, m, n and p definition as described in the appended claim 1.
  21. The preparation method of preparation method according to claim 20, formula of (IE) includes:
    By general formula (IC) and general formula (IB) or its reactant salt, general formula (IE) compound is obtained；
    Wherein:
    L1Selected from-NH2；
    L2Selected from-C (O) X；
    X is selected from hydroxyl or halogen；
    L is selected from-C (O)-NH-；And
    R1~R5、A1~A5, m, n and p definition as described in the appended claim 1.
  22. Compound or its stereoisomer, tautomer or its pharmaceutical salt described in a kind of general formula (IA):
    Wherein:
    L1Selected from-C (O) X；
    X is selected from hydroxyl or halogen；
    RcSelected from alkyl；And
    R1、R3、R4, m and n definition as described in the appended claim 1.
  23. Compound according to claim 22 or its stereoisomer, tautomer or its pharmaceutical salt, wherein the compound includes:
  24. Compound according to claim 22 or its stereoisomer, tautomer or its pharmaceutical salt, wherein the compound includes:
  25. Compound or its stereoisomer, tautomer or its pharmaceutical salt described in a kind of general formula (IE):
    Wherein:
    X is selected from hydroxyl or halogen；
    L is selected from-C (O)-NH-；And
    R1~R5、A1~A5, m, n and p definition as described in the appended claim 1.
  26. Compound according to claim 25 or its stereoisomer, tautomer or its pharmaceutical salt, wherein the compound includes:
  27. A kind of preparation method of formula according to claim 22 (IA) compound, wherein the compound of the formula (IA) is the compound with formula (IIA):
    The described method includes:
    General formula compound (IIa) reacts under alkaline condition with general formula compound (IIb), obtains general formula (IIc)；
    General formula compound (IIc) hydrolyzes under alkaline condition, obtains general formula compound (IId) compound；
    General formula compound (IId) compound reacts in the presence of condensation reagent with general formula compound (IIe), obtains general formula compound (IIf) compound；
    General formula compound (IIf) hydrolyzes under alkaline condition, obtains general formula compound (IIA)；
    Wherein:
    X is selected from hydroxyl or halogen；
    Ra, RbAnd RcIt is each independently selected from alkyl；
    R1、R3、R4, m and n definition as described in the appended claim 1.
  28. Preparation method according to claim 27, wherein, the condensation reagent is selected from bis- (2- oxo -3- oxazolidinyls) secondary phosphoryl chloride phosphorus oxychloride, N, N- dicyclohexylcarbodiimide, N, two Asia of N- diisopropyl carbon, 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride and o- benzotriazole-N, N, N ' N '-tetramethylurea borate (TBTU)；Preferably 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride or bis- (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychlorides.
  29. Preparation method according to claim 27, wherein, the alkaline condition is provided by organic base or inorganic base, the organic base is selected from diisopropylethylamine, pyridine, triethylamine, piperidines, N methyl piperazine, 4- dimethylamino pyridine and 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 and hydrofining, preferably sodium hydroxide or lithium hydroxide.
  30. A kind of preparation method of formula according to claim 25 (IE) compound, wherein formula (IE) compound is the compound with formula (IIIA):
    The described method includes:
    General formula compound (IIIa) reacts in the presence of tetraisopropyl titanate and ammonia methanol, obtains general formula (IIIb)；
    General formula compound (IIIb) and general formula (IIIc) carry out condensation reaction, obtain general formula compound (IIId) compound；
    Reaction is hydrolyzed in general formula compound (IIId) compound in acid condition, obtains general formula compound (IIIA)；
    Wherein:
    Ra、RbAnd RcSelected from alkyl；And
    R1~R5, m, n and p definition as described in the appended claim 1.
  31. Preparation method according to claim 30, wherein the acid condition is provided by inorganic acid or organic acid, and the inorganic acid is selected from hydrochloric acid or phosphoric acid.
  32. A kind of pharmaceutical composition, the pharmaceutical composition contain effective dose according to claim 1~any one of 17 described in compound or its stereoisomer, tautomer or its pharmaceutical salt and pharmaceutical carrier, excipient or their combination.
  33. A kind of method of external glucagon suppression receptor, including by the glucagon receptor with according to claim 1~any one of 17 described in compound or its stereoisomer, tautomer or its pharmaceutical salt or pharmaceutical composition according to claim 32 be in contact.
  34. Compound described according to claim 1~any one of 17 or its stereoisomer, tautomer or its pharmaceutical salt, or Purposes of the pharmaceutical composition according to claim 32 in the drug for preparing type-1 diabetes mellitus, type-2 diabetes mellitus, hyperglycemia, obesity or insulin resistance.
  35. According to claim 1, compound described in~any one of 17 or its stereoisomer, tautomer or its pharmaceutical salt or pharmaceutical composition according to claim 32 are preparing the purposes in glucagon receptor antagonist or inverse agonist.
  36. The purposes of compound described according to claim 1~any one of 17 or its stereoisomer, tautomer or its pharmaceutical salt or pharmaceutical composition according to claim 32 in the drug that hyperlipidemia, dyslipidemia, hypercholesterolemia, atherosclerosis, metabolic syndrome are treated in preparation.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003048109A1 (en) * 2001-12-03 2003-06-12 Novo Nordisk A/S Novel glucagon antagonists
WO2008098244A1 (en) * 2007-02-09 2008-08-14 Metabasis Therapeutics, Inc. Novel antagonists of the glucagon receptor
WO2010093535A1 (en) * 2009-02-12 2010-08-19 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use

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TW200821284A (en) * 2006-10-03 2008-05-16 Merck & Co Inc Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
US8436015B2 (en) * 2008-09-15 2013-05-07 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
US8318667B2 (en) * 2009-02-25 2012-11-27 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
EP3065736B1 (en) * 2013-11-04 2018-11-14 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions thereof, and methods of use

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003048109A1 (en) * 2001-12-03 2003-06-12 Novo Nordisk A/S Novel glucagon antagonists
WO2008098244A1 (en) * 2007-02-09 2008-08-14 Metabasis Therapeutics, Inc. Novel antagonists of the glucagon receptor
WO2010093535A1 (en) * 2009-02-12 2010-08-19 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use

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