CN113149941A - Ether compound and pharmaceutical application thereof in preventing and treating diabetes and metabolic syndrome - Google Patents

Ether compound and pharmaceutical application thereof in preventing and treating diabetes and metabolic syndrome Download PDF

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CN113149941A
CN113149941A CN202010074613.5A CN202010074613A CN113149941A CN 113149941 A CN113149941 A CN 113149941A CN 202010074613 A CN202010074613 A CN 202010074613A CN 113149941 A CN113149941 A CN 113149941A
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unsubstituted
substituted
alkyl
cycloalkyl
haloalkyl
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沈建华
冷颖
叶阳亮
黄素玲
许惕非
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
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    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
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    • 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
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

The invention relates to an ether compound and a pharmaceutical application thereof in preventing and treating diabetes and metabolic syndrome. Specifically, the invention provides a compound shown as a formula (I), an isomer, a racemate and a prodrug thereofThe medicament, solvate thereof, deuteron or pharmaceutically acceptable salt thereof, wherein Ar1, Ar2, X, Y and R are defined in the specification.

Description

Ether compound and pharmaceutical application thereof in preventing and treating diabetes and metabolic syndrome
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a novel ether compound, application of the compound in preventing and treating diabetes and metabolic syndrome diseases, and a composition containing the compound.
Background
As is well known, diabetes is the third chronic disease after tumor and cardiovascular and cerebrovascular diseases, seriously threatening human health, and according to the eighth global diabetes map released by the International Diabetes Federation (IDF), 4.25 hundred million diabetics exist in the world at present, and nearly 7 hundred million diabetics are expected to exist in 2045 years. According to 2017, The Journal of The American Medical Association (JAMA), The Chinese population has a diabetes prevalence of up to 10.9%, and The prediabetes prevalence is even more up to 35.7%. The number and incidence rate of Chinese diabetics are at the forefront of the world, and the incidence form of diabetes is not optimistic. Diabetes mellitus is a serious and frequent chronic disease, and is a group of clinical syndromes caused by the interaction of genetic and environmental factors, and is caused by a series of metabolic disorders such as sugar, protein, fat, water and electrolyte and the like due to absolute or relative insufficiency of insulin secretion and reduced sensitivity of target tissue cells to insulin. Diabetes mellitus is generally classified into two types, type 1 diabetes (insulin-dependent diabetes mellitus, IDDM) and type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM), wherein type 2 diabetes accounts for 90% of the total number of diabetic patients, and is characterized by hypofunction of islet beta cells and resistance of peripheral tissues such as liver, skeletal muscle, fat and the like to insulin, which causes glycolipid metabolism disorder.
Hyperglycemia is a major characteristic of diabetes and also a major cause of chronic complications; the abnormal enhancement of hepatic gluconeogenesis function is one of the main causes of hyperglycemia of diabetic patients. Since endogenous sugars are mainly derived from glycogenolysis and gluconeogenesis, and since liver glycogen and muscle glycogen storage is limited, they are decomposed and exhausted in a short time in a starved state, and gluconeogenesis is one of the main causes of hyperglycemia. Studies have shown that most of the hepatic glucose synthesis in normal humans is from hepatic gluconeogenesis, which is even higher in type 2 diabetic humans. In the insulin resistant state, the gluconeogenic substrate content is increased to cause abnormal enhancement of gluconeogenic function; meanwhile, the balance of insulin and glucagon in the body of a diabetic patient on the regulation of hepatic glucose metabolism is damaged, the liver is in an insulin resistant state, and insulin cannot normally inhibit hepatic gluconeogenesis, so that hepatic glucose output is increased. Effectively inhibits the excessive gluconeogenesis of the liver and reduces the generation of endogenous glucose, and is one of important means for treating type 2 diabetes. Therefore, the research and development of the medicine for effectively inhibiting the hepatic gluconeogenesis have important significance for improving the hyperglycemia symptoms of the diabetes patients.
The incidence of fatty liver of a diabetic patient is 3-5 times higher than that of a common person, when insulin resistance occurs to an organism, lipolysis of adipose tissues is accelerated, a large amount of free fatty acid is generated, and at the moment, triglyceride is synthesized and stored in the liver in a large amount to form the fatty liver, so that the normal structure or function of the liver is damaged. Meanwhile, fatty liver can further affect the conditions of insulin resistance, glucose metabolism disorder and the like of the diabetic, and aggravate the conditions of the diabetic. Particularly, when severe fatty liver or liver cirrhosis is developed, liver function is obviously abnormal, normal glycometabolism cannot be performed, and the body cannot normally convert blood sugar into liver glycogen for storage, so that the blood sugar is in a continuous high-level state, diabetes is aggravated, and a vicious circle is formed. Therefore, the effective prevention and treatment of the fatty liver can reduce the occurrence of liver cirrhosis, diabetes and cardiovascular and cerebrovascular events to a certain extent.
Therefore, the development of a novel medicine which can simultaneously inhibit hepatic gluconeogenesis and improve liver lipid metabolism has important significance for treating glycolipid metabolic disorder of diabetes patients and preventing fatty liver. There is an urgent need in the art to develop a drug having a good effect on preventing or treating diabetes or metabolic syndrome in order to improve the quality of life of a wide range of patients.
Disclosure of Invention
The present inventors have made extensive and intensive studies and experiments, and have unexpectedly found that a class of ether compounds has an extremely excellent effect of preventing or treating diabetes and metabolic syndrome, and have completed the present invention.
The invention aims to provide a novel ether compound.
Another object of the present invention is to provide a composition comprising the ether compound.
The invention also aims to provide the application of the ether compound in preventing and treating diabetes and metabolic syndrome.
It is another object of the present invention to provide a method for preventing or treating diabetes and metabolic syndrome.
In a first aspect of the present invention, there is provided a compound represented by formula (I), an isomer, a racemate, a prodrug, a solvate, a deuteride or a pharmaceutically acceptable salt thereof:
Figure BDA0002378170860000021
r is selected from: H. c substituted or unsubstituted with 1-3Q 11-10An alkyl group;
x is selected from: o, NH, NQ1, CH2Or CHQ 1;
y is selected from: o, NH or NQ 1;
ar1, Ar2 are heteroaryl, aryl, benzoheterocyclyl or benzoalicyclic groups, substituted or unsubstituted with 1-10Q 1;
wherein said substituent Q1 is selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C3578 unsubstituted or substituted with 1 to 5Q 42-C10 alkenoxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenoxy, C2-C10 haloalkynoxy; the following groups substituted or unsubstituted with 1 to 5Q 2: heteroaryl containing one to two oxygen or nitrogen atoms, heteroaryl (C1-C6) alkyl containing one to two oxygen or nitrogen atoms, (C6-C12) fused heterocyclyl (C1-C6) alkyl containing one to two oxygen or nitrogen atoms, C5-C12 aryl (C1-C6) alkyl, phenoxy, benzyloxycarbonyl,
wherein the substituent Q2 is selected from halogen, oxo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, amino, mercapto, cyano, nitro, hydroxy, phenyl or phenoxy which is substituted or unsubstituted by 1-3Q 3,
wherein the substituent Q3 is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, amino, mercapto, cyano and hydroxyl,
wherein R ', R' are independently selected from: H. phenyl substituted or unsubstituted with 1 to 3Q 4, benzyl substituted or unsubstituted with 1 to 3Q 4, C1-10 alkyl substituted or unsubstituted with 1 to 3Q 4, C1-10 haloalkyl substituted or unsubstituted with 1 to 3Q 4, C2-10 alkenyl substituted or unsubstituted with 1 to 3Q 4, C2-10 alkynyl substituted or unsubstituted with 1 to 3Q 4; alternatively, the radicals R 'and R' are joined together to form a 4-to 7-membered ring,
wherein said substituent Q4 is selected from the group consisting of halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R′、-SO2NR′R″、-SOR′、-SO2R′、-NO2、-OCF3、-CF3、-C2F5、-C3F7or-CN.
In a second aspect of the invention, there is provided a composition comprising:
(a) an effective amount of a compound of the present invention, its isomer, racemate, prodrug, solvate, deuteride or pharmaceutically acceptable salt thereof; and
(b) a dietetic or pharmaceutically acceptable carrier or excipient.
In a third aspect of the present invention, there is provided a use of the compound of the present invention, its isomer, racemate, prodrug, solvate thereof, deutero-compound or pharmaceutically acceptable salt thereof for the prevention and treatment of diabetes and metabolic syndrome.
In a fourth aspect of the present invention, there is provided a method for preventing or treating diabetes or metabolic syndrome in a mammal, comprising the steps of: administering to a mammalian subject in need thereof an effective amount of a compound of the present invention, its isomer, racemate, prodrug, solvate thereof, deutero-derivative or pharmaceutically acceptable salt thereof.
Detailed Description
The "halogen" as referred to herein means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like. Fluorine atom and chlorine atom are preferred.
The term "halo" as used herein means that any atom in the group which can be substituted is substituted by halogen, and can be perhalogenated, i.e., the halogen atom is substituted at all positions in the group which can be substituted.
Said "C" of the present invention1-10Alkyl "means a straight-chain or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. Preferably C1-8Alkyl, more preferably C1-6Alkyl radical, C1-4Alkyl or C1-3An alkyl group.
Said "C" of the present invention2-10The "alkenyl group" means a straight-chain, branched or cyclic alkenyl group having 2 to 10 carbon atoms and containing a double bond, and preferably "C2-6Alkenyl ", i.e. a linear, branched or cyclic alkenyl group having 2 to 6 carbon atoms containing a double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, vinyl, or a vinyl group, or a hydroxy group, containing a hydroxy group, or a hydroxy group,1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1-dimethyl-2-propenyl, 1, 2-dimethyl-1-propenyl, 1, 2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1-dimethyl-2-butenyl, 1-dimethyl-3-butenyl, 1, 2-dimethyl-1-butenyl, 1, 2-dimethyl-2-butenyl, 1, 2-dimethyl-3-butenyl, 1, 3-dimethyl-1-butenyl, 1, 3-dimethyl-3-butenyl, 2-pentenyl, 3-pentenyl, 4-methyl-pentenyl, 1-methyl-4-pentenyl, 1-dimethyl-2-butenyl, 1-dimethyl-3-butenyl, 1, 2-dimethyl-3-butenyl, 1, 2-pentenyl, 2-methyl-pentenyl, 3-methyl-pentenyl, 4-methyl-2-pentenyl, 1, 2-dimethyl-butenyl, 1, 2-pentenyl, 1, 2-pentenyl, and 2-pentenyl, 1, 3-dimethyl-2-butenyl, 2-dimethyl-3-butenyl, 2, 3-dimethyl-1-butenyl, 2, 3-dimethyl-2-butenyl, 2, 3-dimethyl-3-butenyl, 3-dimethyl-1-butenyl, 3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-butyl-, 2-ethyl-1-butenyl, 2-methyl-3-butenyl, 2-methyl-butyl-, 2-methyl-butyl-, 2-butenyl, 2-butyl, 2-methyl-butyl, 2-methyl-1-butyl, 1,1, 2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, 1-ethyl-2-methyl-2-propenyl, 1, 3-butadienyl, 1, 3-pentadienyl, 1, 4-pentadienyl, 2, 4-pentadienyl, 1, 4-hexadienyl, 2, 4-hexadienyl, cyclopentenyl, 1, 3-cyclopentadienyl, cyclohexenyl, 1, 4-cyclohexadienyl and the like. The double bond may optionally be cis and trans.
Said "C" of the present invention2-10Alkynyl means a straight or branched chain alkynyl group of 2 to 10 carbon atoms containing a triple bond, preferably "C2-6Alkynyl ", i.e. containing threeStraight chain or branched alkynyl having 2 to 6 carbon atoms in the bond, such as ethynyl, 1-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 4-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-2-pentynyl, 2-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 1-dimethyl-2-butynyl, 1-dimethyl-3-butynyl, 1, 2-dimethyl-3-butynyl, 2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl and the like.
Said "C" of the present invention1-10Alkoxy "means" C1-10Alkyl "radicals attached to other structures via oxygen atoms, preferably C1-6Alkoxy radicals ", i.e. C1-6Alkyl "a group bonded to another structure through an oxygen atom, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1-dimethylethoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1-dimethylpropyloxy, 1, 2-dimethylpropyloxy, 2-dimethylpropyloxy, 1-ethylpropyloxy, hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1-dimethylbutyloxy, 1, 2-dimethylbutyloxy, 1, 3-dimethylbutyloxy, 2-dimethylbutyloxy, 1-methylpropyloxy, 1-dimethylbutyloxy, 2-dimethylbutyloxy, 1-methylpropyloxy, 1-ethylbutoxy, 2-dimethylbutyloxy, 1-methylbutoxy, 2-methylbutoxy, etc, 2, 3-dimethylbutyloxy, 3-dimethylbutyloxy, 1-ethylbutoxy, 2-ethylbutoxy, 1, 2-trimethylpropoxy, 1,2, 2-trimethylpropoxy, 1-ethyl-1-methylpropyloxy and 1-ethyl-2-methylpropyloxy. The term "C1-4The "alkoxy group" refers to a specific example containing 1 to 4 carbon atoms among the above examples.
Said "C" of the present invention1-6Alkylcarbonyl "refers to the term" C1-6Alkyl "radicals attached to other structures via a carbonyl group, e.g. methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl,Butylcarbonyl group, isobutylcarbonyl group, tert-butylcarbonyl group, sec-butylcarbonyl group, pentylcarbonyl group, neopentylcarbonyl group, hexylcarbonyl group, and the like.
Said "C" of the present invention1-6Alkoxycarbonyl "is the term" C1-6Alkoxy "a group bonded to another structure through a carbonyl group, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, etc.
The "3-14 membered cycloalkyl" as referred to herein means a cyclic alkyl group derived from a cyclic alkane moiety of 3 to 14 carbon atoms by removing one hydrogen atom, and includes 3-8 membered monocyclic cycloalkyl, 6-14 membered fused cycloalkyl, 7-12 membered bridged cyclic group and 7-12 membered spiro cyclic group. Preferably C3-8Cycloalkyl radical, C3-6Cycloalkyl and C5-6A cycloalkyl group. The term "C3-8Cycloalkyl group "," C3-6Cycloalkyl group "," C5-6Cycloalkyl "is a specific example containing 3 to 8, 3 to 6, and 5 to 6 carbon atoms in the following examples, respectively.
3-8 membered monocyclic cycloalkyl groups, including 3-8 membered saturated monocyclic cycloalkyl groups and 3-8 membered partially saturated monocyclic cycloalkyl groups. 3-8 membered saturated monocyclic cycloalkyl, meaning that the monocyclic ring is fully saturated carbocyclic, examples of which include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, methylcyclopropane, dimethylcyclopropane, methylcyclobutane, dimethylcyclobutane, methylcyclopentane, dimethylcyclopentane, methylcyclohexane, dimethylcyclohexane, etc. 3-8 membered partially saturated monocyclic cycloalkyl, meaning that the monocyclic ring is a partially saturated carbocyclic ring, examples of which include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1, 4-cyclohexadienyl, cycloheptenyl, 1, 4-cycloheptadienyl, cyclooctenyl, 1, 5-cyclooctadienyl, and the like;
"C" according to the invention3-8Cycloalkoxy "refers to the term" C3-8Cycloalkyl "radicals attached to other structures via an oxygen atom, e.g. cyclopropyloxy, cyclobutyloxy, 1-methylcyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptylOxy, cyclooctoxy, and the like. "C3-8Cycloalkoxy "is preferably C3-6A cycloalkoxy group.
The term "aryl" as used herein refers to a cyclic aromatic group, preferably a 6-to 14-membered aryl group. "6-14 membered aryl" means a cyclic aromatic group having 6-14 membered carbon atoms in the ring atoms, including 6-8 membered monocyclic aryl and 8-14 membered fused ring aryl. The 6-8 membered monocyclic aryl group means an all unsaturated aryl group such as phenyl, cyclooctatetraenyl and the like. The 8-to 14-membered fused ring aryl group means a cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms with each other and having at least one ring being an all unsaturated aromatic ring, and includes 8-to 14-membered all unsaturated fused ring aryl, naphthyl, anthryl, phenanthryl and the like, and also includes 8-to 14-membered partially saturated fused ring aryl groups such as benzo 3-to 8-membered saturated monocyclic cycloalkyl, benzo 3-to 8-membered partially saturated monocyclic cycloalkyl, and specific examples thereof are 2, 3-dihydro-1H-indenyl, 1,2,3, 4-tetrahydronaphthyl, 1, 4-dihydronaphthyl and the like. Preferably 6-to 10-membered aryl, more preferably benzene or a benzo 3-to 8-membered saturated monocyclic cycloalkyl, a benzo 3-to 8-membered partially saturated monocyclic cycloalkyl. The term "6-to 10-membered aryl" refers to a specific example of the above-mentioned "aryl" having 6 to 10 ring atoms.
The term "heteroaryl" refers to an aromatic group whose ring atoms include one or more heteroatoms in addition to carbon atoms, including, but not limited to, oxygen, nitrogen, and sulfur atoms. Heteroaryl groups may be bonded through carbon or a heterocyclic atom. Heteroaryl can be 5-14 membered heteroaryl; including 5-8 membered monocyclic heteroaryl and 8-14 membered fused heterocyclic aryl. 5-8 membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 3-triazinyl, 1,2, 4-triazinyl, tetrazolyl, oxadiazolyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 2H-1, 3-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 2H-1, 4-oxazinyl, 4H-1, 4-oxazinyl, isooxazinyl, pyridazinyl, pyrimidinyl, pyrazinyl and the like; 8-14 membered fused heterocyclic aryl groups include, but are not limited to, benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, indolizinyl, indazolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzimidazolyl, pyridopyridyl, pyrazolo [3,4-b ] pyridyl, purinyl, acridinyl, xanthenyl, and the like.
The term "3-14 membered heterocyclic group" as used herein means a 3-14 membered cyclic group containing one or more heteroatoms, wherein the "heteroatom" means N, S, O, SO and/or SO2And the like. Including saturated, partially saturated, unsaturated having 1-4 substituents selected from N, S, O, SO and/or SO2And saturated, partially saturated, unsaturated, 5-14 membered heteromonocyclic group. Also included are the heteroaryl groups mentioned above and their dihydro and tetrahydro analogs. 5-14 membered diheterocyclyl includes saturated, partially saturated, unsaturated having 1-4 substituents selected from N, S, O, SO and/or SO2Fused, spiro, bridged rings of heteroatoms of (a). Preferred is a 3-to 8-membered heterocyclic group, and further preferred is a saturated, partially saturated, unsaturated 3-to 8-membered heteromonocyclic group. More preferred is a 5-8-membered, 5-7-membered, 5-6-membered heterocyclic group, and further preferred is a saturated, partially saturated, unsaturated 5-8-membered, 5-7-membered, 5-6-membered heteromonocyclic group.
The term "3-to 8-membered heterocyclyl" as used herein means a compound containing 3 to 8 ring atoms (at least one heteroatom selected from N, S, O, SO and/or SO)2) The monocyclic heterocyclic group of (1) includes a 3-8-membered unsaturated monocyclic heterocyclic group, a 3-8-membered partially saturated monocyclic heterocyclic group and a 3-8-membered saturated monocyclic heterocyclic group. 3-8 membered unsaturated heteromonocyclic group and 3-8 membered partially saturated heteromonocyclic group, which means 3-8 membered heterocyclic group in which unsaturated bond exists in ring, preferably 5-7 membered unsaturated heteromonocyclic group and 5-7 membered partially saturated heteromonocyclic group, specific examples include, but are not limited to, including, but not limited to, for example, the following groups: azetidine, 1, 2-diazacyclobutene, pyrrole, 4, 5-dihydropyrrole, 2, 5-dihydropyrrole, imidazole, 4, 5-dihydroimidazole, pyrazole, 4, 5-dihydropyrazole, 1,2, 3-triazole, 1,2, 4-triazole, pyridine, 2-pyridone, 4-pyridone, pyridabenOxazines, pyrimidines, pyrazines, 1,2, 3-triazines, 1,2, 4-triazines, azepantrienes, 1, 2-diazepatrienes, 1, 3-diazepatrienes, 1, 4-diazepatrienes, azacyclooctatetraenes, 1, 4-dihydro-1, 4-diazacyclooctatrienes, 1, 2-dithiocyclobutenes, furans, 4, 5-dihydrofurans, 2, 5-dihydrofurans, thiophenes, 2, 5-dihydrothiophenes, 4, 5-dihydrothiophenes, 1, 2-dithiocyclopentenes, 1, 3-dithiocyclopentenes, 2H-pyrans, 2H-pyran-2-ones, 3, 4-dihydro-2H-pyrans, 4H-pyran-4-ones, azacycloheptatrienes, 1, 2-diazepatrienes, 1, 5-dihydrofurans, 2-dihydropyrans, 3, 4H-pyrans, 4-ketones, 1, 4-dioxadiene, 1, 4-dithiine, 1, 4-oxathiahexadiene, oxepitriene, thieptatriene, 1, 4-dioxacyclooctatriene, oxazole, 4, 5-dihydrooxazole, 2, 3-dihydrooxazole, isoxazole, 4, 5-dihydroisoxazole, 2, 3-dihydroisoxazole, 1,2, 3-oxadiazole, 1,2, 5-oxadiazole, thiazole, 4, 5-dihydrothiazole, 2, 3-dihydrothiazole, isothiazole, 1,2, 3-thiadiazole, 2H-1, 2-oxazine, 4H-1, 2-oxazine, 6H-1, 2-oxazine, 2H-1, 3-oxazine, 4H-1, 3-oxazine, 2H-1, 3-oxazine, 5, 6-dihydro-4H-1, 3-oxazine, 6H-1, 3-oxazine, 2H-1, 4-oxazine, 4H-1, 4-oxazine, 2H-1, 3-thiazine, 4H-1, 3-thiazine, 5, 6-dihydro-4H-1, 3-thiazine, 6H-1, 3-thiazine, 2H-1, 4-thiazine, 4H-1, 4-thiazine group, and the like. Among them, preferred are azetidine, 1, 2-diazacyclobutene, pyrrole, dihydropyrrole, imidazole, 4, 5-dihydroimidazole, pyrazole, 4, 5-dihydropyrazole, pyridine, 2-pyridone, 4-pyridone, pyridazine, pyrimidine, pyrazine, azepane, 1, 2-dithiacyclobutene, furan, thiophene, 2, 5-dihydrothiophene, 1, 2-dithiacyclopentene, 2H-pyran-2-one, 3, 4-dihydro-2H-pyran, 4H-pyran-4-one, 1, 4-dioxadiene, 1, 4-dithiadiene, 1, 4-oxathiadiene, oxepine, 1, 4-dioxacyclooctatriene, Oxazole, 4, 5-dihydrooxazole, isoxazole, 4, 5-dihydroisoxazole, 2, 3-dihydroisoxazole, 1,2, 3-oxadiazole, 1,2, 5-oxadiazole, thiazole, 4, 5-dihydrothiazole, isothiazole, 1,2, 3-thiadiazole, 2H-1, 2-oxazine, 4H-1, 2-oxazine, 6H-1, 2-oxazine, 2H-1, 3-oxazine, 4H-1, 3-oxazine, 5, 6-dihydro-4H-1, 3-oxazine, 6H-1, 3-oxazine, 2H-1, 4-oxazine, 4H-1, 4-oxazine, 2H-1, 3-thiazine, 4H-1, 3-thiazine, 2H-1, 3-oxazine, 2H-1, 3-thiazine, 2H-1, 3-oxa, 5, 6-dihydro-4H-1, 3-thiazine, 6H-1, 3-thiazine, 2H-1, 4-thiazine, 4H-1, 4-thiazine, morpholine, 1,3, 4-thiadiazole radicals. More preferred are pyrrole, dihydropyrrole, imidazole, 4, 5-dihydroimidazole, pyrazole, 4, 5-dihydropyrazole, pyridine, pyridazine, pyrimidine, pyrazine, furan, thiophene, 2, 5-dihydrothiophene, 2H-pyran-2-one, 3, 4-dihydro-2H-pyran, 4H-pyran-4-one, 1, 4-dioxadiene, 1, 4-dithiahexadiene, 1, 4-oxathiolane, oxazole, 4, 5-dihydrooxazole, isoxazole, 4, 5-dihydroisoxazole, 2, 3-dihydroisoxazole, 1,2, 3-oxadiazole, 1,2, 5-oxadiazole, thiazole, 4, 5-dihydrothiazole, and the like, Isothiazole, 1,2, 3-thiadiazole, 1,2, 4-thiadiazole, 1,3, 4-thiadiazole group, etc.; 3-8 membered saturated heteromonocyclic group means a heteroatom-containing cyclic group having all saturated bonds, preferably 5-7 membered saturated heteromonocyclic group, specific examples include but are not limited to: aziridine, azetidine, 1, 2-diazetidine, pyrrolidine, imidazolidine, pyrazolidine, hydropyridone, piperidine, piperazine, ethylene oxide, thietane, oxetane, 1, 2-dioxetane, thietane, tetrahydrofuran, tetrahydrothiophene, 1, 3-dioxolane, 1, 3-dithiolane, tetrahydropyran, 1, 4-dioxane, 1, 3-oxathiane, oxazolidine, morpholine groups, and the like; among them, aziridine, azetidine, pyrrolidine, imidazolidine, pyrazolidine, hydropyridone, piperidine, piperazine, ethylene oxide, tetrahydrofuran, tetrahydrothiophene, 1, 3-dioxolane, 1, 3-dithiolane, tetrahydropyran, 1, 4-dioxane, 1, 3-oxathiane, oxazolidine, morpholine group and the like are preferable.
The terms 3-8 membered heterocyclic group, 5-7 membered heterocyclic group, 5-6 membered heterocyclic group mean specific examples in which the number of ring atoms in the above-mentioned "3-14 membered heterocyclic group" is 3-8 membered, 5-7 membered, 5-6 membered.
The "5-to 7-membered heterocyclic group" according to the present invention includes, but is not limited to, for example, aziridine, azetidine, 1, 2-diazetidine, pyrrolidine, imidazolidine, pyrazolidine, hydropyridone, piperidine, piperazine, ethylene oxide, thietane, oxetane, 1, 2-dioxetane, thietane, tetrahydrofuran, tetrahydrothiophene, 1, 3-dioxolane, 1, 3-dithiolane, tetrahydropyran, 1, 4-dioxane, 1, 3-oxathiane, oxazolidine, morpholine group and the like; among them, aziridine, azetidine, pyrrolidine, imidazolidine, pyrazolidine, hydropyridone, piperidine, piperazine, ethylene oxide, tetrahydrofuran, tetrahydrothiophene, 1, 3-dioxolane, 1, 3-dithiolane, tetrahydropyran, 1, 4-dioxane, 1, 3-oxathiane, oxazolidine, morpholine group and the like are preferable.
"C" according to the invention3-C6Heterocycloalkyl "includes, but is not limited to, a pyrrole ring, a piperidine ring, a morpholine ring, a piperazine ring, or similar groups.
The term "halo (C)1-6Alkyl) group "means the above-mentioned C substituted by the same or different 1 to 6 of the above-mentioned halogen atoms1-6Alkyl groups such as trifluoromethyl, pentafluoroethyl, or the like.
The term "C1-4The acyl group "means a straight or branched acyl group having 1 to 4 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, or the like.
The term "aralkyl" refers to C substituted with an aryl group as described above1-6An alkyl group.
The term "aromatic heterocyclic ring containing one to two oxygen or nitrogen" means furan ring, pyridine ring, pyrimidine ring, pyrrole ring, pyrazine ring, pyridazine ring, triazine ring, or the like.
The term "benzoheterocyclyl" refers to a fused ring of benzene with a 3-10 membered heterocyclic ring containing 1 to 3 heteroatoms, which is partially saturated. The heteroatom may be selected from N, O, S, SO and/or SO2Etc., the 3-to 10-membered heterocyclic ring is preferably a 3-to 8-membered monocyclic heterocyclic ring, more preferably a 5-to 7-membered monocyclic heterocyclic ring. "3-8 membered heteromonocyclic group" means a compound containing 3 to 8 ring atoms (at least one heteroatom selected from N, S, O, SO and/or SO)2) The monocyclic heterocyclic group of (1) includes a 3-8-membered unsaturated monocyclic heterocyclic group, a 3-8-membered partially saturated monocyclic heterocyclic group and a 3-8-membered saturated monocyclic heterocyclic group. 3-8 Yuan BuSaturated heteromonocyclic group and 3-8 membered partially saturated heteromonocyclic group, means a 3-8 membered heterocyclic group in which an unsaturated bond is present in the ring, preferably a 5-7 membered unsaturated heteromonocyclic group and a 5-7 membered partially saturated heteromonocyclic group, specifically as described above in the definition of "3-8 membered heteromonocyclic group". The benzoheterocyclyl group can be a dihydro analog, a tetrahydro analog, a hexahydro analog, an octahydro analog of a heteroaryl group, and the like, for example, chromanyl, tetrahydroquinolinyl, indolinyl, tetrahydropyridoquinolinyl, and the like. Preferably, the "benzoheterocyclyl" does not include heteroaryl.
The term "benzoalicyclic group" refers to a fused ring of benzene with a 3-to 10-membered carbocyclic ring, which may be fully saturated, partially saturated, or unsaturated. The 3-to 10-membered carbocyclic ring does not contain a heteroatom, preferably a 3-to 8-membered carbocyclic ring, more preferably a 5-to 7-membered carbocyclic ring. "3-8 membered carbocyclic" means a monocyclic group containing 3-8 ring carbon atoms and includes 3-8 membered unsaturated monocyclic groups, 3-8 membered partially saturated monocyclic groups, and 3-8 membered saturated monocyclic groups. Preferably, the benzoaliphatic ring can be a dihydro analog, a tetrahydro analog, a hexahydro analog, an octahydro analog of an aryl group, and the like, such as tetrahydronaphthyl, indanyl, indenyl, and the like. Preferably, the "benzoalicyclic group" does not include an aryl group.
The term "3-to 8-membered" as used herein means 3,4,5,6,7, 8-membered, preferably 5-to 8-membered. Further preferably 5 to 7 membered. Even more preferably 5-6 membered. The 5-8 yuan means 5,6,7 and 8 yuan, and the 5-7 yuan means 5,6 and 7 yuan.
The invention also comprises isomers, racemes, prodrugs, solvates and deuterides of the compounds or pharmaceutically acceptable salts thereof. The pharmaceutically acceptable salt refers to a salt generated by reacting an ether compound of the formula with an inorganic acid, an organic acid, an alkali metal or an alkaline earth metal and the like. These salts include (but are not limited to): (1) salts with the following inorganic acids: such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid; (2) salts with organic acids such as acetic acid, oxalic acid, succinic acid, tartaric acid, methanesulfonic acid, maleic acid, or arginine. Other salts include those formed with alkali or alkaline earth metals (e.g., sodium, potassium, calcium or magnesium), in the form of esters, carbamates, or other conventional "prodrugs". The compounds have one or more asymmetric centers. Thus, these compounds may exist as racemic mixtures, individual enantiomers, individual diastereomers, mixtures of diastereomers, cis or trans isomers.
The term "precursor of a compound" refers to a compound which, when administered by a suitable method, undergoes a metabolic or chemical reaction in the patient to convert the precursor to a compound of formula (I), or a salt or solution of a compound of formula (I).
Compound (I)
The invention firstly provides a compound shown in (I), an isomer, a racemate, a prodrug, a solvate, a deutero-compound or a pharmaceutically acceptable salt thereof:
Figure BDA0002378170860000101
r is selected from: H. c substituted or unsubstituted with 1-3Q 11-10An alkyl group;
x is selected from: o, NH, NQ1, CH2Or CHQ 1;
y is selected from: o, NH or NQ 1;
ar1, Ar2 are heteroaryl, aryl, benzoheterocyclyl or benzoalicyclic groups, substituted or unsubstituted with 1-10Q 1;
wherein said substituent Q1 is selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; C1-C10 alkyl, C2-C10 alkenyl, C1-C10 substituted or unsubstituted with 1 to 5Q 42-C10 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy; the following groups substituted or unsubstituted with 1 to 5Q 2: heteroaryl containing one to two oxygen or nitrogen atoms, heteroaryl (C1-C6) alkyl containing one to two oxygen or nitrogen atoms, (C6-C12) fused heterocyclyl (C1-C6) alkyl containing one to two oxygen or nitrogen atoms, C5-C12 aryl (C1-C6) alkyl, phenoxy, benzyloxycarbonyl,
wherein the substituent Q2 is selected from halogen, oxo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, amino, mercapto, cyano, nitro, hydroxy, phenyl or phenoxy which is substituted or unsubstituted by 1-3Q 3,
wherein the substituent Q3 is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, amino, mercapto, cyano and hydroxyl,
wherein R ', R' are independently selected from: H. phenyl substituted or unsubstituted with 1 to 3Q 4, benzyl substituted or unsubstituted with 1 to 3Q 4, C1-10 alkyl substituted or unsubstituted with 1 to 3Q 4, C1-10 haloalkyl substituted or unsubstituted with 1 to 3Q 4, C2-10 alkenyl substituted or unsubstituted with 1 to 3Q 4, C2-10 alkynyl substituted or unsubstituted with 1 to 3Q 4; alternatively, the radicals R 'and R' are joined together to form a 4-to 7-membered ring,
wherein said substituent Q4 is selected from the group consisting of halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R′、-SO2NR′R″、-SOR′、-SO2R′、-NO2、-OCF3、-CF3、-C2F5、-C3F7or-CN.
Preferably, X is selected from: o, NH or CH2。
Preferably, Y is selected from: o or NH.
Preferably, Ar1, Ar2 are independently selected from 5-14 membered heteroaryl, 6-14 membered aryl, benzo 3-10 membered heterocyclyl or benzo 3-10 membered alicyclic ring substituted or unsubstituted with 1-5 of Q1; more preferably, Ar2 and Ar1 are independently selected from phenyl, naphthyl, tetrahydronaphthyl, indanyl, benzoxazolyl, chromanyl, tetrahydroquinolinyl, indolyl, indolinyl, tetrahydropyridoquinolinyl, indenyl, benzopyranyl, quinolinyl, substituted or unsubstituted with 1-5Q 1; most preferably, Ar2 is selected from phenyl, naphthyl, tetrahydronaphthyl, indanyl, benzoxazolyl, chromanyl, tetrahydroquinolinyl, indolyl, indolinyl, tetrahydropyridoquinolinyl, indenyl, benzopyranyl, quinolinyl, substituted or unsubstituted with 1-5Q 1; ar1 is preferably phenyl, pyridyl, furyl, substituted or unsubstituted with 1 to 5Q 1.
Preferably, the substituent Q1 is selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO ', C-10 haloalkynyloxy, -COOR', -O ', -SO', C-alkoxy-C-2 haloalkoxy, C-3-C-3-C2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, which are unsubstituted or substituted by 1 to 5Q 4;
more preferably, the substituent Q1 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkinyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkinyloxy, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C2-C6 haloalkenyloxy, C2-C6 haloalkynyloxy, -COOR ', -NR ' R ', -OR ', -COR ', -CONR ' R ', -O, -SR ', -SO ', -2R′、-SO3R′、-NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C2-C6 haloalkenyloxy, C2-C6 haloalkynyloxy, which are unsubstituted or substituted by 1 to 5Q 4;
wherein R ', R' are each independently selected from: H. phenyl substituted or unsubstituted with 1 to 3Q 4, benzyl substituted or unsubstituted with 1 to 3Q 4, C1-10 alkyl substituted or unsubstituted with 1 to 3Q 4, C1-10 haloalkyl substituted or unsubstituted with 1 to 3Q 4, C2-10 alkenyl substituted or unsubstituted with 1 to 3Q 4, C2-10 alkynyl substituted or unsubstituted with 1 to 3Q 4; alternatively, the groups R 'and R' are joined together to form a 4-7 membered ring, preferably R ', R' are each independently selected from: H. phenyl substituted or unsubstituted with 1 to 3Q 4, benzyl substituted or unsubstituted with 1 to 3Q 4, C1-6 alkyl substituted or unsubstituted with 1 to 3Q 4, C1-6 haloalkyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkenyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkynyl substituted or unsubstituted with 1 to 3Q 4; alternatively, the groups R 'and R' are joined together to form a 4-7 membered ring.
Wherein said substituent Q4 is selected from the group consisting of halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R′、-SO2NR′R″、-SOR′、-SO2R′、-NO2、-OCF3、-CF3、-C2F5、-C3F7or-CN.
Preferably Y-R is selected from-OH; -NH- (CH)aSO2OH，-NH-(CH)aCOOH, wherein a is 1,2,3,4 or 5; substituted by 1-3 substituents selected from hydroxy, -N (C1-6 alkyl)2and-SO2C1-6 alkyl or unsubstituted C1-6 alkyl.
In a preferred embodiment, the compounds of formula (I) according to the present invention have the structure shown in formula (II) below:
Figure BDA0002378170860000121
Figure BDA0002378170860000131
r is selected from: H. c substituted or unsubstituted with 1-3Q 11-10An alkyl group;
x is selected from: o, NH, NQ1, CH2Or CHQ 1;
y is selected from: o, NH or NQ 1;
n is selected from 1,2,3,4, or 5;
m is selected from 1 or 2;
Q1、R1、R2each independently selected from: H. C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, which are unsubstituted or substituted by 1 to 5Q 4;
preferably, Q1, R1、R2Each independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C2-C6 haloalkenyloxyA group, C2-C6 haloalkynyloxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; or the following groups substituted or unsubstituted with 1 to 5Q 4: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C2-C6 haloalkenyloxy, and C2-C6 haloalkynyloxy;
wherein R ', R' are each independently selected from: H. phenyl substituted or unsubstituted with 1 to 3Q 4, benzyl substituted or unsubstituted with 1 to 3Q 4, C1-6 alkyl substituted or unsubstituted with 1 to 3Q 4, C1-6 haloalkyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkenyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkynyl substituted or unsubstituted with 1 to 3Q 4; alternatively, the groups R 'and R' are joined together to form a 4-7 membered ring;
wherein said substituent Q4 is selected from the group consisting of halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R′、-SO2NR′R″、-SOR′、-SO2R′、-NO2、-OCF3、-CF3、-C2F5、-C3F7or-CN.
In a preferred embodiment, the compounds of formula (I) according to the present invention have the structure shown in formula (III) below:
Figure BDA0002378170860000141
wherein X, m, n, R1, R2 are as defined for general formula (II).
In a preferred embodiment, the compounds of formula (I) according to the present invention have the structure shown in formula (IV) below:
Figure BDA0002378170860000142
r is selected from: H. c substituted or unsubstituted with 1-3Q 11-10An alkyl group;
x is selected from: o, NH or NQ 1;
y is selected from: o, NH or NQ 1;
o is selected from 1 or 2;
p is selected from 1,2 or 3;
q is selected from 1,2,3 or 4;
Q1、R3、R4、R5each independently selected from: H. C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, which are unsubstituted or substituted by 1 to 5Q 4;
preferably, Q1, R3、R4、R5Independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C2-C6 haloalkenyloxy, C2-C6 haloalkynyloxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO ', C-6 haloalkynyloxy, -COOR', -NR 'R', -OR ', -COR', -CONR 'R', -O ', -SR', -SO ', C-S', C-2 haloalkoxy, C-C2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, or nitro,A hydroxyl group; or the following groups substituted or unsubstituted with 1 to 5Q 4: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C2-C6 haloalkenyloxy, and C2-C6 haloalkynyloxy;
wherein R ', R' are each independently selected from: H. phenyl substituted or unsubstituted with 1 to 3Q 4, benzyl substituted or unsubstituted with 1 to 3Q 4, C1-6 alkyl substituted or unsubstituted with 1 to 3Q 4, C1-6 haloalkyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkenyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkynyl substituted or unsubstituted with 1 to 3Q 4; alternatively, the groups R 'and R' are joined together to form a 4-7 membered ring;
wherein said substituent Q4 is selected from the group consisting of halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R′、-SO2NR′R″、-SOR′、-SO2R′、-NO2、-OCF3、-CF3、-C2F5、-C3F7or-CN.
In a preferred embodiment, the compounds of formula (I) according to the present invention have the structure shown in formula (V) below:
Figure BDA0002378170860000151
X、o、p、q、R3、R4、R5as defined for general formula (IV).
In a preferred embodiment, the compounds of formula (I) according to the present invention have the structure shown in formula (VI) below:
Figure BDA0002378170860000152
wherein:
r is selected from: H. c substituted or unsubstituted with 1-3Q 11-10An alkyl group;
x is selected from: o, NH or NQ 1;
y is selected from: o, NH or NQ 1;
Q1、R6、R7、R8、R9、R10、R11、R12and R13Each independently selected from: H. C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, which are unsubstituted or substituted by 1 to 5Q 4;
preferably, Q1, R6、R7、R8、R9、R10、R11、R12And R13Each independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C2-C6 haloalkenyloxy, C2-C6 haloalkynyloxy, -COOR ', -NR ' R ', -OR ', -COR ', -CONR ' R ', -O, -SR ', -SO ', and C2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; or the following groups substituted or unsubstituted with 1 to 5Q 4: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkylC3-C6 cycloalkyl- (C1-C6) alkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C2-C6 haloalkenyloxy, and C2-C6 haloalkynyloxy;
wherein R ', R' are independently selected from: H. phenyl substituted or unsubstituted with 1 to 3Q 4, benzyl substituted or unsubstituted with 1 to 3Q 4, C1-6 alkyl substituted or unsubstituted with 1 to 3Q 4, C1-6 haloalkyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkenyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkynyl substituted or unsubstituted with 1 to 3Q 4; alternatively, the groups R 'and R' are joined together to form a 4-7 membered ring;
wherein said substituent Q4 is selected from the group consisting of halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R′、-SO2NR′R″、-SOR′、-SO2R′、-NO2、-OCF3、-CF3、-C2F5、-C3F7or-CN.
In a preferred embodiment, the compounds of formula (I) according to the present invention have the structure shown in formula (VII) below:
Figure BDA0002378170860000171
R、X、Y、R6、R7、R8、R9、R10、R11、R12and R13As defined for general formula (VI).
In a preferred embodiment, the compounds of formula (I) according to the present invention have the structure shown in formula (VIII) below:
Figure BDA0002378170860000172
wherein:
r is selected from: H. c substituted or unsubstituted with 1-3Q 11-10An alkyl group;
x is selected from: o, NH or NQ 1;
y is selected from: o, NH or NQ 1;
r is 1,2,3 or 4;
s is 1,2 or 3;
t is 1 or 2;
ring A is a saturated, partially unsaturated, fully unsaturated 3-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, S or O, or a 3-10 membered saturated, partially unsaturated aliphatic ring; preferably a saturated, partially unsaturated, fully unsaturated 3-6 membered heterocyclyl or 3-6 membered saturated or partially unsaturated aliphatic ring containing 1-3 heteroatoms selected from N, S or O;
Q1、R14、R15and R16Each independently selected from: H. C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, which are unsubstituted or substituted by 1 to 5Q 4;
preferably, Q1, R14、R15And R16Independently selected from H, C1-C6 alkyl, alkenyl of C2-C6, alkynyl of C2-C6, halogen, cycloalkyl of C3-C6, cycloalkyl of C3-C6- (C1-C6) alkyl, alkoxy of C1-C6, alkenyloxy of C2-C6, alkynyloxy of C2-C6, haloalkyl of C1-C6, haloalkenyl of C2-C6, haloalkynyl of C2-C6, haloalkoxy of C1-C6, haloalkenyloxy of C2-C6, haloalkynyloxy of C2-C6, -COOR′、-NR′R″、-OR′、-COR′、-CONR′R″、＝O、-SR′、-SO2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; or the following groups substituted or unsubstituted with 1 to 5Q 4: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C2-C6 haloalkenyloxy, and C2-C6 haloalkynyloxy;
wherein R ', R' are independently selected from: H. phenyl substituted or unsubstituted with 1 to 3Q 4, benzyl substituted or unsubstituted with 1 to 3Q 4, C1-6 alkyl substituted or unsubstituted with 1 to 3Q 4, C1-6 haloalkyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkenyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkynyl substituted or unsubstituted with 1 to 3Q 4; alternatively, the groups R 'and R' are joined together to form a 4-7 membered ring;
wherein said substituent Q4 is selected from the group consisting of halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R′、-SO2NR′R″、-SOR′、-SO2R′、-NO2、-OCF3、-CF3、-C2F5、-C3F7or-CN;
preferably, the
Figure BDA0002378170860000181
The benzo A ring part of the derivative is 5,6,7, 8-tetrahydronaphthalene-1-yl, 2, 3-dihydro-1H-indene-4-yl, benzo [ d ]]Oxazol-7-yl, benzo [ d ]]Oxazol-4-yl, chroman-5-yl, chroman-7-yl, chroman-8-yl, 1,2,3, 4-tetrahydroquinolin-7-yl, 1,2,3, 4-tetrahydroquinolin-5-yl, 1H-indol-7-yl, 1H-indol-4-yl, or 2, 3-dihydro-1H-indol-4-yl.
In a preferred embodiment, the compounds of formula (I) according to the present invention have the structure shown in formula (IX) below:
Figure BDA0002378170860000191
wherein X, A, R, s, t, R14、R15And R16As defined for general formula (VIII).
In a preferred embodiment, the compounds of formula (I) according to the invention have the structure shown in formula (XX) below:
Figure BDA0002378170860000192
r is selected from: H. c substituted or unsubstituted with 1-3Q 11-10An alkyl group;
x is selected from: o, NH or NQ 1;
y is selected from: o, NH or NQ 1;
u is selected from 1,2,3 or 4;
p is selected from 1,2 or 3;
q is selected from 1,2,3 or 4;
-COYR is located on benzene ring with-X-CH2-ortho, meta or para to the attached carbon atom;
Q1、R4、R5、R17each independently selected from: H. C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C1 alkyl, unsubstituted or substituted with 1 to 5Q 40 haloalkenyloxy, C2-C10 haloalkynyloxy;
preferably, Q1, R4、R5、R17Independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C2-C6 haloalkenyloxy, C2-C6 haloalkynyloxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO ', C-6 haloalkynyloxy, -COOR', -NR 'R', -OR ', -COR', -CONR 'R', -O ', -SR', -SO ', C-S', C-2 haloalkoxy, C-C2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; or the following groups substituted or unsubstituted with 1 to 5Q 4: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C2-C6 haloalkenyloxy, and C2-C6 haloalkynyloxy;
wherein R ', R' are each independently selected from: H. phenyl substituted or unsubstituted with 1 to 3Q 4, benzyl substituted or unsubstituted with 1 to 3Q 4, C1-6 alkyl substituted or unsubstituted with 1 to 3Q 4, C1-6 haloalkyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkenyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkynyl substituted or unsubstituted with 1 to 3Q 4; alternatively, the groups R 'and R' are joined together to form a 4-7 membered ring;
wherein said substituent Q4 is selected from the group consisting of halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R′、-SO2NR′R″、-SOR′、-SO2R′、-NO2、-OCF3、-CF3、-C2F5、-C3F7or-CN.
In a preferred embodiment, the compounds of formula (I) according to the present invention have the structure represented by the following formula (XA):
Figure BDA0002378170860000201
wherein:
r is selected from: H. c substituted or unsubstituted with 1-3Q 11-10An alkyl group;
x is selected from: o, NH or NQ 1;
y is selected from: o, NH or NQ 1;
u is selected from 1,2,3 or 4;
-COYR is located on benzene ring with-X-CH2-ortho, meta or para to the attached carbon atom;
Q1、R6、R7、R8、R9、R10、R11and R17Each independently selected from: H. C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, which are unsubstituted or substituted by 1 to 5Q 4;
preferably, Q1, R6、R7、R8、R9、R10、R11And R17Each independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C2-C6 haloalkenyloxyC2-C6 haloalkynyloxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; or the following groups substituted or unsubstituted with 1 to 5Q 4: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C2-C6 haloalkenyloxy, and C2-C6 haloalkynyloxy;
wherein R ', R' are independently selected from: H. phenyl substituted or unsubstituted with 1 to 3Q 4, benzyl substituted or unsubstituted with 1 to 3Q 4, C1-6 alkyl substituted or unsubstituted with 1 to 3Q 4, C1-6 haloalkyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkenyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkynyl substituted or unsubstituted with 1 to 3Q 4; alternatively, the groups R 'and R' are joined together to form a 4-7 membered ring;
wherein said substituent Q4 is selected from the group consisting of halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R′、-SO2NR′R″、-SOR′、-SO2R′、-NO2、-OCF3、-CF3、-C2F5、-C3F7or-CN.
In a preferred embodiment, the compound of formula (I) according to the present invention has the structure represented by the following formula (XB):
Figure BDA0002378170860000211
wherein:
r is selected from: H. c substituted or unsubstituted with 1-3Q 11-10An alkyl group;
x is selected from: o, NH or NQ 1;
y is selected from: o, NH or NQ 1;
r is 1,2,3 or 4;
s is 1,2 or 3;
u is 1,2,3 or 4;
-COYR is located on benzene ring with-X-CH2-ortho, meta or para to the attached carbon atom;
ring A is a saturated, partially unsaturated, fully unsaturated 3-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, S or O, or a 3-10 membered saturated, partially unsaturated aliphatic ring; preferably a saturated, partially unsaturated, fully unsaturated 3-6 membered heterocyclyl or 3-6 membered saturated or partially unsaturated aliphatic ring containing 1-3 heteroatoms selected from N, S or O;
Q1、R14、R15and R17Each independently selected from: H. C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, which are unsubstituted or substituted by 1 to 5Q 4;
preferably, Q1, R14、R15And R17Independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C2-C6 haloalkenyloxy, C2-C6 haloalkynyloxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO ', C-6 haloalkynyloxy, -COOR', -NR 'R', -OR ', -COR', -CONR 'R', -O ', -SR', -SO ', C-S', C-2 haloalkoxy, C-C2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; or the following groups substituted or unsubstituted with 1 to 5Q 4: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C2-C6 haloalkenyloxy, and C2-C6 haloalkynyloxy;
wherein R ', R' are independently selected from: H. phenyl substituted or unsubstituted with 1 to 3Q 4, benzyl substituted or unsubstituted with 1 to 3Q 4, C1-6 alkyl substituted or unsubstituted with 1 to 3Q 4, C1-6 haloalkyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkenyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkynyl substituted or unsubstituted with 1 to 3Q 4; alternatively, the groups R 'and R' are joined together to form a 4-7 membered ring;
wherein said substituent Q4 is selected from the group consisting of halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R′、-SO2NR′R″、-SOR′、-SO2R′、-NO2、-OCF3、-CF3、-C2F5、-C3F7or-CN;
preferably, the
Figure BDA0002378170860000231
The benzo A ring part of the derivative is 5,6,7, 8-tetrahydronaphthalene-1-yl, 2, 3-dihydro-1H-indene-4-yl, benzo [ d ]]Oxazol-7-yl, benzo [ d ]]Oxazol-4-yl, chroman-5-yl, chroman-7-yl, chroman-8-yl, 1,2,3, 4-tetrahydroquinolin-7-yl, 1,2,3, 4-tetrahydroquinolin-5-yl, 1H-indol-7-yl, 1H-indol-4-yl, or 2, 3-dihydro-1H-indol-4-yl.
In all formulas containing Y-R of the present invention, such as formulas (I), (II), (IV), (VI), (VIII), (XX), (XA), (XB), etc., preferably Y-R is selected from-OH; -NH- (CH)aSO2OH，-NH-(CH)aCOOH, wherein a is 1,2,3,4 or 5; by 1-3 hydroxy, -N (C1-6 alkyl)2、-SO2C1-6 alkyl substituted or unsubstituted C1-6 alkyl.
Particularly preferred compounds of the invention are:
Figure BDA0002378170860000232
Figure BDA0002378170860000241
Figure BDA0002378170860000251
Figure BDA0002378170860000261
Figure BDA0002378170860000271
Figure BDA0002378170860000281
Figure BDA0002378170860000291
Figure BDA0002378170860000301
Figure BDA0002378170860000311
Figure BDA0002378170860000321
use of
Based on the new discovery of the present inventors, the present invention provides the use of the compound, its isomer, racemate, prodrug, solvate thereof, deutero-compound or pharmaceutically acceptable salt thereof, described herein, for the preparation of a medicament for preventing or treating diabetes or metabolic syndrome and diseases in mammals. The metabolic syndrome is selected from (but not limited to): diabetes, insulin resistance, hyperinsulinemia, impaired glucose tolerance, obesity and fatty liver. Common to these disorders is an abnormality in sugar, fat and protein metabolism.
Composition comprising a metal oxide and a metal oxide
As used herein, the term "composition of the invention" includes (but is not limited to): pharmaceutical compositions, dietary supplements, nutraceutical compositions, provided that they contain the ether compounds of the invention as an active ingredient for the prevention or treatment of urinary diseases or metabolic syndrome in mammals.
The present invention also provides a composition comprising: (a) an effective amount of a compound of formula (I), its isomers, racemates, its prodrugs, its solvates, deuterons or pharmaceutically acceptable salts thereof or mixtures thereof; and (b) a dietetic or pharmaceutically acceptable carrier or excipient.
In the present invention, the term "comprising" means that various ingredients can be used together in the mixture or composition of the present invention. Thus, the terms "consisting essentially of and" consisting of are encompassed by the term "comprising.
In the present invention, a "pharmaceutically acceptable" component is a substance that is suitable for use in humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
In the present invention, the "pharmaceutically acceptable carrier" or "dietetically acceptable carrier" is a pharmaceutically or dietetically acceptable solvent, suspending agent or excipient for delivering the compound of the present invention, its isomer, racemate, prodrug thereof, solvate thereof, deuteron or pharmaceutically acceptable salt thereof or a mixture thereof to animals or humans. The carrier may be a liquid or a solid.
In the present invention, the composition contains 1 to 200 parts by weight of the compound described herein, its isomer, racemate, prodrug thereof, solvate thereof, deuteride or pharmaceutically acceptable salt thereof; and 10-5000 parts by weight of pharmaceutically acceptable carriers or excipients. Preferably, the pharmaceutical composition comprises 5 to 150 parts by weight of the compound described herein, its isomer, racemate, prodrug thereof, solvate thereof, deutero-compound or pharmaceutically acceptable salt thereof; and 30-2000 parts by weight of a pharmaceutically acceptable carrier or excipient.
The dosage form of the pharmaceutical composition of the present invention may be various, and any dosage form may be used as long as it can allow the active ingredient to efficiently reach the body of a mammal. Such as may be selected from: tablets, capsules, powders, granules, syrups, solutions, suspensions, or aerosols. Wherein such ether compounds may be present in a suitable solid or liquid carrier or diluent.
Preferred pharmaceutical compositions are solid compositions, especially tablets and solid-filled or liquid-filled capsules, from the standpoint of ease of preparation and administration. Oral administration of the pharmaceutical composition is preferred.
The ether compounds or their compositions of the present invention may also be stored in sterile devices suitable for injection or instillation. In the pharmaceutical composition of the present invention, the active ingredient usually accounts for 1-50% (preferably 2-40%, more preferably 3-30%) of the total weight, and the balance is pharmaceutically acceptable carriers and other additives.
When the compounds or compositions thereof are used for the above-mentioned purposes, they may be mixed with one or more pharmaceutically acceptable carriers or excipients, such as solvents, diluents, etc., and may be orally administered in the form of: tablets, capsules, dispersible powders, granules, or suspensions (containing, for example, from about 0.05 to 5% suspending agent), syrups (containing, for example, from about 10 to 50% sugar), and elixirs (containing, for example, from about 20 to 50% ethanol), or may be administered parenterally in the form of sterile injectable solutions or suspensions (containing from about 0.05 to 5% suspending agent in an isotonic medium). For example, these pharmaceutical preparations may contain from about 1 to about 50% by weight, usually from about 2 to about 40% by weight, of the active ingredient in admixture with a carrier.
The effective administration dosage of the active ingredient employed will vary with the compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of about 0.1 to 1000mg/kg animal body weight, preferably 1 to 3 divided doses per day, or in sustained release form. For most large mammals, the total daily dose is about 5-6000mg, preferably about 10-1000 mg. Dosage forms suitable for oral administration contain about 1-200mg of the active compound in intimate admixture with a solid or liquid carrier. This dosage regimen may be adjusted to provide the best therapeutic response. For example, divided doses may be administered several times per day, or the dose may be proportionally reduced, as may be required by the urgency of the condition being treated.
The compound or the pharmaceutically acceptable salt thereof and the composition thereof can be administered by oral administration, intravenous, intramuscular or subcutaneous routes; oral administration is preferred. The solid support comprises: starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, and liquid carriers include: sterile water, polyethylene glycols, non-ionic surfactants and edible oils (such as corn, peanut and sesame oils) as are appropriate to the nature of the active ingredient and the particular mode of administration desired. Adjuvants commonly used in the preparation of pharmaceutical compositions may also advantageously be included, for example flavouring agents, colouring agents, preservatives and antioxidants such as vitamin E, vitamin C, BHT and BHA.
The active compounds or pharmaceutically acceptable salts thereof and compositions thereof may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds (as the free base or pharmaceutically acceptable salt) may also be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquids, polyethylene glycols and mixtures thereof in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injection include: sterile aqueous solutions or dispersions and sterile powders (for the extemporaneous preparation of sterile injectable solutions or dispersions). In all cases, these forms must be sterile and must be fluid to facilitate the syringe to expel the fluid. Must be stable under the conditions of manufacture and storage and must be resistant to the contaminating effects of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, alcohols (for example, glycerol, propylene glycol and liquid polyethylene glycols), suitable mixtures thereof and vegetable oils.
Synthetic routes to Compounds of the invention
The following shows a part of the synthetic routes for the compounds of the invention:
Figure BDA0002378170860000341
wherein Ar2 and Ar1 are as defined above, R1a is as defined for Q in formula I, and R2a is as defined for R in formula I. TAU refers to taurine and Gly to glycine.
The synthetic route for the substituted 7-hydroxyindole fragment is as follows (route A):
Figure BDA0002378170860000351
wherein R is1a、R3a、R4a、R5aIs defined as in formula VI with respect to R6、R7、R8、R9、R10、R11The same definition is applied.
When the compound is substituted by a substituent R1aIs Cl, F, R3a、R4aIs H, R5aIs CH3The synthetic route is as follows (route A-1):
Figure BDA0002378170860000352
when substituent R of the compound1a、R3a、R4aIs H, R5aIs CH3The synthetic route is as follows (route A-2):
Figure BDA0002378170860000353
the reduction of the indoline ring is according to the following synthetic route (scheme a-3):
Figure BDA0002378170860000354
according to the above synthetic route, the present invention synthesizes a series of compounds having indole ring, and the structural formula of the preferable compounds is shown in the following table:
Figure BDA0002378170860000361
when the general structure has the following structure:
Figure BDA0002378170860000362
wherein R is1、R2aAs defined for R2 in formula II, R3a、R4aAre as defined for R ', R' in formula II.
The synthetic route is referred to as follows:
Figure BDA0002378170860000371
(route B):
Figure BDA0002378170860000372
(route C):
Figure BDA0002378170860000373
according to the above synthetic route, the present invention synthesizes a series of benzo-heterocyclic compounds, the structural formula of the preferred compounds of which is shown in the following table:
Figure BDA0002378170860000374
Figure BDA0002378170860000381
intermediate fragment compounds, which are commercially available or prepared by the following synthetic route, are subsequently synthesized by the general synthetic route to the final product, as follows:
route D
Figure BDA0002378170860000382
The sodium salt of the compound of formula (xxxvi) was prepared as follows:
route E
Figure BDA0002378170860000383
Wherein Ar2 and Ar1 are as defined above, and R1a is as defined for Q in formula I.
According to the above synthetic route, the present invention synthesizes a series of benzo-heterocyclic compounds, the structural formula of the preferred compounds of which is shown in the following table:
Figure BDA0002378170860000391
the other left fragment heterocyclophenol was synthesized as follows:
route F:
Figure BDA0002378170860000401
route G:
Figure BDA0002378170860000402
route H:
Figure BDA0002378170860000403
route I:
Figure BDA0002378170860000404
route J:
Figure BDA0002378170860000405
wherein R is as defined for R6 in formula (VI).
Route K:
Figure BDA0002378170860000411
according to the above synthetic route, the present invention synthesizes a series of benzo-heterocyclic compounds, the structural formula of the preferred compounds of which is shown in the following table:
Figure BDA0002378170860000412
a series of compounds were obtained from the above synthetic route, wherein the structural formula of the preferred compounds is shown in the following table:
Figure BDA0002378170860000421
Figure BDA0002378170860000431
the general formula and the synthetic route of the nitrogen ether compound connected by the element N are referred as follows: route L:
Figure BDA0002378170860000432
a series of compounds were obtained from the above synthetic route, wherein the structural formula of the preferred compounds is shown in the following table:
Figure BDA0002378170860000433
the abbreviations involved in the foregoing synthetic schemes are as follows:
Figure BDA0002378170860000441
the main advantages of the invention are: the novel application of the compound shown in the formula (I) in the aspect of treating diabetes and metabolic syndrome is found for the first time, the pharmacological action is strong, the compound has the effects of reducing blood sugar and blood fat, reducing weight, obviously improving fatty liver and having excellent medicinal prospect.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers.
Example 15- (((5,6,7, 8-Tetrahydronaphthalen-1-yl) oxy) methyl) furan-2-carboxylic acid
Mixing 1.48 g of 5,6,7, 8-tetrahydronaphthol, 1.89 g of ethyl 5-chloromethyl-2-furancarboxylate and K2CO3About 1.8 g of DMF (N, N-dimethyl) solvent was addedFormamide) and reacting at 70 ℃ for about 3 hours (specific reaction time, monitoring by thin-layer chromatography or high performance liquid chromatography-mass spectrometry), adding saturated saline solution after the reaction is finished, extracting for 3 times by using ethyl acetate, washing for 3 times by using the saturated saline solution, drying an ethyl acetate layer by using anhydrous magnesium sulfate, mixing samples by using 200-300-mesh silica gel after filtering, and carrying out silica gel column chromatography to obtain 5- (((5,6,7, 8-tetrahydronaphthalene-1-yl) oxy) methyl) furan-2-carboxylic acid ethyl ester.
Dissolving the ester in tetrahydrofuran/methanol/water 3/3/1 solvent, adding 1.2 g NaOH aqueous solution, hydrolyzing at room temperature, finishing the reaction, adding water, evaporating the tetrahydrofuran and methanol solvent in vacuum, adjusting pH to 2 by using 1M hydrochloric acid solution, precipitating white solid, filtering, washing a filter cake for 3 times by using a small amount of water, and drying in vacuum to obtain the compound 5- (((5,6,7, 8-tetrahydronaphthalene-1-yl) oxy) methyl) furan-2-carboxylic acid.
1H NMR(500MHz,DMSO-d6)δ7.21(d,J＝3.4Hz,1H),7.05(t,J＝7.9Hz,1H),6.87(d,J＝8.1Hz,1H),6.73(d,J＝3.4Hz,1H),6.69(d,J＝7.6Hz,1H),5.10(s,2H),2.68(t,J＝5.9Hz,2H),2.54(t,J＝6.1Hz,2H),1.68(dtd,J＝11.5,5.8,5.1,2.9Hz,4H).
MS(ESI-):[M-H]-:271.10
Example 25- ((7-chloro-2, 3-dihydro-1H-inden-4-yl) oxy) methyl) furan-2-carboxylic acid
Synthesis procedure reference is made to example 1
1H NMR(400MHz,DMSO-d6)δ7.18(d,J＝3.4Hz,1H),7.15(d,J＝8.6Hz,1H),6.95(d,J＝8.7Hz,1H),6.72(d,J＝3.4Hz,1H),5.13(s,2H),2.84(dt,J＝14.9,7.5Hz,4H),2.01(p,J＝7.6Hz,2H).
MS(ESI-):[M-H]-:291.05
Example 35- ((2- (propyl-2-yn-1-oxy) -4-propylphenoxy) methyl) furan-2-carboxylic acid
The left fragment phenol synthesis route is referred to route B and the specific procedure is as follows: 1.362 g of 4-n-propylphenol was dissolved in dichloromethane, and 1.6 g of Br dissolved in dichloromethane was diluted at room temperature2Slowly dropping into phenol, reacting, using NaHCO3Washing with saturated aqueous solution of NaCl for 2 times, respectively, and anhydrous MgSO4Drying, mixing sample with 200-mesh and 300-mesh silica gel, passing through the column layerAnd (5) separating, separating and purifying.
Subsequent ligation of furan fragments the procedure for the synthesis of esters was referenced in example 1.
The resulting ester, 3.8 g pinacol diboron, 1.47 g potassium acetate, 0.82 g PdCl2(dppf) added to anhydrous 1, 4-dioxane with N2Gas protection, obtaining a furoic acid ethyl ester compound with Br substituted by boron ester through Suzuki coupling reaction at 100 ℃, directly mixing a sample with silica gel, separating and purifying through column chromatography to obtain 2.57 g of a compound, adding the compound into a tetrahydrofuran solution, and adding 2.4 g of H at 0 DEG C2O2Dropwise adding the mixture to react to obtain a furan ethyl formate compound with boron ester substituted by phenolic hydroxyl, subsequently extracting and washing the furan ethyl formate compound by using an ethyl acetate/sodium thiosulfate saturated aqueous solution, and carrying out anhydrous MgSO4Drying, mixing with 200-mesh and 300-mesh silica gel, and separating and purifying by column chromatography.
The resulting compound (1.92 g), 980 mg of 3-bromopropyne, 1.31 g of K2CO3Adding appropriate amount of DMF, reacting at 100 deg.C for 3-5 hr, monitoring by TLC, extracting with ethyl acetate/saturated NaCl aqueous solution system for 3-4 times, and washing with anhydrous MgSO4Drying, mixing with 200-mesh and 300-mesh silica gel, and separating and purifying by column chromatography.
The final hydrolysis step, according to the hydrolytic synthesis procedure in example 1, gave the compound 5- ((2- (propyl-2-yn-1-oxy) -4-propylphenoxy) methyl) furan-2-carboxylic acid
1H NMR(400MHz,DMSO-d6)δ7.20(d,J＝3.4Hz,1H),7.00(d,J＝8.2Hz,1H),6.91(d,J＝2.0Hz,1H),6.75(dd,J＝8.2,2.0Hz,1H),6.71(d,J＝3.4Hz,1H),5.07(s,2H),4.78(d,J＝2.4Hz,2H),3.53(t,J＝2.4Hz,1H),2.48(d,J＝7.6Hz,2H),1.57(h,J＝7.3Hz,2H),0.89(t,J＝7.3Hz,3H).
MS(ESI-):[M-H]-:313.12
Example 45- ((2- (methylamino) -4-propylphenoxy) methyl) furan-2-carboxylic acid
The left fragment phenol synthesis route is referred to route C and the specific procedure is as follows:
1.433 g of 4-n-propylphenol was dissolved in DCM and 1 g of 65% commercially available nitric acid was diluted in ten times the volume of DCM and added dropwise very slowly at room temperatureIn phenol, TLC monitoring, about half an hour can be finished, and then saturated NaHCO can be obtained3Washing with water solution for 2 times, washing with saturated NaCl water solution for 3 times, and washing with anhydrous MgSO4Drying, mixing with 200-mesh and 300-mesh silica gel, and separating and purifying by column chromatography.
The subsequent work up with the ethyl 5-chloromethyl-2-furancarboxylate fragment refers to the ester synthesis section of example 1.
Dissolving the obtained ethyl furoate in absolute methanol, adding 0.18 g of 10% Pd/C, reacting for about 3-5 hours under the environment of H2 to obtain a compound with nitro reduced into amino, filtering Pd/C, directly evaporating the solvent to dryness, directly carrying out the next reaction, adding 1.49 g of methyl iodide and 1.8 g of K2CO3Reacting in DMF solution at 70 deg.C for about 3 hr to obtain amino substituted compound, extracting with ethyl acetate/saturated NaCl water solution for 3 times, and washing with anhydrous MgSO4Drying, mixing with 200-mesh and 300-mesh silica gel, and separating and purifying by column chromatography.
Hydrolysis part referring to the synthetic procedure for hydrolysis in example 1, the compound 5- ((2- (methylamino) -4-propylphenoxy) methyl) furan-2-carboxylic acid was obtained
1H NMR(400MHz,DMSO-d6)δ7.21(d,J＝3.4Hz,1H),6.81(d,J＝7.7Hz,1H),6.77(d,J＝3.4Hz,1H),6.34(d,J＝7.6Hz,2H),5.05(s,2H),2.70(s,3H),2.43(t,J＝7.6Hz,2H),1.63–1.49(m,2H),0.88(t,J＝7.3Hz,3H).
MS(ESI-):[M-H]-:288.13
Example 55- ((2-methoxy-6-propylphenoxy) methyl) furan-2-carboxylic acid
Synthesis procedure reference is made to example 1
1H NMR(400MHz,DMSO-d6)δ7.16(d,J＝3.4Hz,1H),6.99(t,J＝7.9Hz,1H),6.90(dd,J＝8.2,1.6Hz,1H),6.74(dd,J＝7.6,1.6Hz,1H),6.57(d,J＝3.4Hz,1H),4.97(s,2H),3.82(s,3H),2.45–2.37(m,2H),1.43(h,J＝7.4Hz,2H),0.84(t,J＝7.3Hz,3H).
MS(ESI-):[M-H]-:289.12
Example 65- ((5-allyl-2-methoxyphenoxy) methyl) furan-2-carboxylic acid
Synthesis procedure reference is made to example 1
1H NMR(400MHz,DMSO-d6)δ7.20(d,J＝3.4Hz,1H),6.96–6.87(m,2H),6.75(dd,J＝8.2,2.0Hz,1H),6.71(d,J＝3.4Hz,1H),5.94(ddt,J＝16.9,10.1,6.7Hz,1H),5.10–4.98(m,4H),3.73(s,3H),3.29(d,J＝6.7Hz,2H).
MS(ESI-):[M-H]-:287.10
Example 75- ((2-methoxy-5-propylphenoxy) methyl) furan-2-carboxylic acid
Synthesis procedure reference is made to example 1
1H NMR(400MHz,DMSO-d6)δ7.20(d,J＝3.4Hz,1H),6.91(d,J＝2.0Hz,1H),6.88(d,J＝8.2Hz,1H),6.74(dd,J＝8.2,2.0Hz,1H),6.71(d,J＝3.4Hz,1H),5.08(s,2H),3.72(s,3H),2.47(t,J＝7.5Hz,2H),1.62–1.49(m,2H),0.87(t,J＝7.3Hz,3H).
MS(ESI-):[M-H]-:289.12
Example 85- ((3-methoxy-4-propylphenoxy) methyl) furan-2-carboxylic acid
The synthesis operation is as in example 3, replacing liquid bromine with NBS, replacing the bromination reaction solvent dichloromethane with acetonitrile, operating the subsequent reaction conditions the same, replacing pinacol ester diboron with n-propylboronic acid in suzuki coupling, operating the subsequent reaction conditions the same, obtaining a coupled compound of ethyl furoate, directly performing hydrolysis reaction, and hydrolyzing in example 1 to obtain the compound of 5- ((3-methoxy-4-propylphenoxy) methyl) furan-2-carboxylic acid.
1H NMR(400MHz,DMSO-d6)δ7.16(d,J＝3.4Hz,1H),6.99(d,J＝8.2Hz,1H),6.72(d,J＝3.4Hz,1H),6.59(d,J＝2Hz,1H),6.52(dd,J＝8.2Hz,2HZ,1H),5.07(s,2H),3.73(s,3H),2.41(t,J＝7.6Hz,2H),1.46(h,J＝7.4Hz,2H),0.84(t,J＝7.3Hz,3H).
MS(ESI-):[M-H]-:289.12
Example 95- ((2-acetylamino-6-methoxy-4-propylphenoxy) methyl) furan-2-carboxylic acid
Synthesis procedure referring to example 4, following substitution of the amine group, methyl iodide was replaced with acetyl chloride and the reaction temperature was room temperature.
1H NMR(400MHz,DMSO-d6)δ8.84(s,1H),7.41–7.30(m,1H),7.15(d,J＝3.4Hz,1H),6.64(d,J＝2.0Hz,1H),6.56(d,J＝3.4Hz,1H),4.95(s,2H),3.81(s,3H),2.46(t,J＝7.6Hz,2H),2.01(s,3H),1.56(h,J＝7.4Hz,2H),0.89(t,J＝7.3Hz,3H).
MS(ESI-):[M-H]-:346.14
Example 105- ((2, 3-dihydro-1H-inden-4-yl) oxy) methyl) furan-2-carboxylic acid
Synthesis procedure reference is made to example 1
1H NMR(400MHz,DMSO-d6)δ7.20(d,J＝3.4Hz,1H),7.10(t,J＝7.8Hz,1H),6.87(dd,J＝11.5,7.7Hz,2H),6.73(d,J＝3.4Hz,1H),5.13(s,2H),2.84(t,J＝7.5Hz,2H),2.75(t,J＝7.4Hz,2H),1.98(p,J＝7.4Hz,2H).
MS(ESI-):[M-H]-:257.09
Example 115- ((2-acetylamino-4-propylphenoxy) methyl) furan-2-carboxylic acid
Synthesis procedure referring to example 4, following substitution of the amine group, methyl iodide was replaced with acetyl chloride and the reaction temperature was room temperature.
1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),7.72(d,J＝2.2Hz,1H),7.21(d,J＝3.5Hz,1H),7.08(d,J＝8.3Hz,1H),6.87(dd,J＝8.3,2.2Hz,1H),6.76(d,J＝3.5Hz,1H),5.16(s,2H),2.46(t,J＝7.6Hz,2H),2.06(s,3H),1.53(q,J＝7.4Hz,2H),0.87(t,J＝7.3Hz,3H).
MS(ESI-):[M-H]-:316.13
Example 125- ((2- (dimethylamino) -6-methoxy-4-propylphenoxy) methyl) furan-2-carboxylic acid synthesis procedure reference example 4.
1H NMR(400MHz,DMSO-d6)δ7.17(d,J＝3.4Hz,1H),6.63(d,J＝3.4Hz,1H),6.17(d,J＝1.8Hz,1H),6.08(d,J＝1.8Hz,1H),4.99(s,2H),3.77(s,3H),2.84(s,6H),2.48(t,J＝7.7Hz,2H),1.58(h,J＝7.4Hz,2H),0.90(t,J＝7.3Hz,3H).
MS(ESI-):[M-H]-:332.16
Example 135- ((2-methoxy-6- (methylamino) -4-propylphenoxy) methyl) furan-2-carboxylic acid
Synthesis procedure reference is made to example 4
1H NMR(400MHz,DMSO-d6)δ7.17(d,J＝3.4Hz,1H),6.62(d,J＝3.4Hz,1H),6.15(d,J＝1.8Hz,1H),6.04(d,J＝1.8Hz,1H),4.83(s,2H),3.72(s,3H),2.66(s,3H),2.42(t,J＝7.7Hz,2H),1.57(q,J＝7.5Hz,2H),0.90(t,J＝7.3Hz,3H).
MS(ESI-):[M-H]-:318.14
Example 145- ((2-methyl-4-propylphenoxy) methyl) furan-2-carboxylic acid
Synthesis procedure reference is made to example 8
1H NMR(400MHz,DMSO-d6)δ7.19(d,J＝3.4Hz,1H),6.97(m,3H),6.71(d,J＝3.5Hz,1H),5.09(s,2H),2.45(t,J＝7.5Hz,2H),2.11(s,3H),1.54(h,J＝7.4Hz,2H),0.87(t,J＝7.3Hz,3H).
MS(ESI-):[M-H]-:273.12
Example 155- (((7-methyl-2, 3-dihydro-1H-inden-4-yl) oxy) methyl) furan-2-carboxylic acid
Synthesis procedure reference is made to example 1
1H NMR(400MHz,DMSO-d6)δ7.19(d,J＝3.4Hz,1H),6.90(d,J＝8.2Hz,1H),6.80(d,J＝8.1Hz,1H),6.71(d,J＝3.4Hz,1H),5.08(s,2H),2.77(t,J＝7.5Hz,4H),2.14(s,3H),1.98(p,J＝7.5Hz,2H).
MS(ESI-):[M-H]-:271.10
Example 165- ((4-allyl-3-methoxyphenoxy) methyl) furan-2-carboxylic acid
Synthetic procedure in accordance with example 8, in the suzuki coupling, n-propylboronic acid was replaced with allylboronic acid pinacol ester and the rest of the synthetic procedure was the same.
1H NMR(400MHz,DMSO-d6)δ7.21(d,J＝3.4Hz,1H),7.01(d,J＝8.3Hz,1H),6.75(d,J＝3.4Hz,1H),6.65(d,J＝2.4Hz,1H),6.57(dd,J＝8.2,2.4Hz,1H),5.91(ddt,J＝17.1,10.5,6.5Hz,1H),5.11(s,2H),5.00(dq,J＝7.5,1.7Hz,1H),4.98–4.93(m,1H),3.77(s,3H),3.23(d,J＝6.6Hz,2H).
MS(ESI-):[M-H]-:287.10
Example 175- (((4-propyl-5, 6,7, 8-tetrahydronaphthalen-1-yl) oxy) methyl) furan-2-carboxylic acid
Synthesis procedure reference is made to example 8
1H NMR(400MHz,DMSO-d6)δ7.19(d,J＝3.4Hz,1H),6.91(d,J＝8.3Hz,1H),6.82(d,J＝8.4Hz,1H),6.70(d,J＝3.4Hz,1H),5.06(s,2H),2.61(t,J＝5.9Hz,2H),2.56(t,J＝6.0Hz,2H),2.46–2.39(m,2H),1.74–1.60(m,4H),1.49(h,J＝7.4Hz,2H),0.92(t,J＝7.3Hz,3H).
MS(ESI-):[M-H]-:313.15
Example 185- (((2,3,6, 7-tetrahydro-1H, 5H-pyrido [3,2,1-ij ] quinolin-8-yl) oxy) methyl) furan-2-carboxylic acid
Synthesis procedure reference is made to example 1
1H NMR(400MHz,DMSO-d6)δ7.18(d,J＝3.4Hz,1H),6.70–6.61(m,2H),6.26(d,J＝8.2Hz,1H),5.00(s,2H),3.03(dt,J＝11.1,5.6Hz,4H),2.61(t,J＝6.5Hz,2H),2.53(t,J＝6.0Hz,2H),1.90–1.76(m,4H).
MS(ESI-):[M-H]-:313.13
Example 195- ((4-propyl-2- (trifluoromethoxy) phenoxy) methyl) furan-2-carboxylic acid Synthesis procedure reference example 3, replacement of iodomethane with trifluoroiodomethane
1H NMR(400MHz,DMSO-d6)δ7.30(d,J＝8.6Hz,1H),7.21–7.14(m,3H),6.72(d,J＝3.4Hz,1H),5.22(s,2H),2.56–2.51(m,2H),1.56(h,J＝7.4Hz,2H),0.87(t,J＝7.3Hz,3H).
MS(ESI-):[M-H]-:343.09
Example 205- ((4-allyl-2- (trifluoromethoxy) phenoxy) methyl) furan-2-carboxylic acid
Synthesis procedure reference example 19
1H NMR(400MHz,DMSO-d6)δ7.34(d,J＝8.2Hz,1H),7.21–7.16(m,2H),7.13(d,J＝3.4Hz,1H),6.70(d,J＝3.4Hz,1H),5.94(ddt,J＝16.8,10.0,6.7Hz,1H),5.22(s,2H),5.12–5.02(m,2H),3.35(d,J＝6.7Hz,2H).
MS(ESI-):[M-H]-:341.07
Example 216- ((4-allyl-2-methoxyphenoxy) methyl) pyridine acid
Synthesis procedure Ethyl 5-chloromethyl-2-furancarboxylate was replaced with methyl 2-bromomethyl-6-pyridinecarboxylate in reference example 1
1H NMR(400MHz,DMSO-d6)δ8.02(p,J＝7.4Hz,2H),7.73(dd,J＝7.1,1.6Hz,1H),6.94(d,J＝8.2Hz,1H),6.84(d,J＝2.0Hz,1H),6.68(d,J＝8.0Hz,1H),5.94(ddt,J＝16.8,10.0,6.8Hz,1H),5.20(s,2H),5.12–4.99(m,2H),3.78(s,3H),3.30(d,J＝6.7Hz,2H).
MS(ESI-):[M-H]-:298.12
Example 226- ((2-methoxy-4-propylphenoxy) methyl) pyridine acid
Synthesis procedure reference is made to example 21
1H NMR(500MHz,DMSO-d6)δ8.06(t,J＝7.7Hz,1H),8.01(dd,J＝7.8,1.3Hz,1H),7.77(dd,J＝7.6,1.3Hz,1H),6.92(d,J＝8.2Hz,1H),6.85(d,J＝2.0Hz,1H),6.67(dd,J＝8.2,2.0Hz,1H),5.19(s,2H),3.79(s,3H),2.50–2.45(m,2H),1.61–1.52(m,2H),0.88(t,J＝7.3Hz,3H).
MS(ESI-):[M-H]-:300.13
Example 235- ((benzo [ d ] oxazol-4-oxy) methyl) furan-2-carboxylic acid
Chemical synthetic route referring to scheme J, the specific procedure is as follows:
2-Nitro resorcinol 1.56 g dissolved in MeOH, 0.15 g 10% Pd/C, H added2Reducing under environment, monitoring by TLC, completing the reaction for about 3-5 hours, filtering Pd/C, evaporating the solvent to dryness, directly putting into the next step, dissolving in trimethyl orthoformate, N2Protecting, adding 2-3 drops of 98% concentrated sulfuric acid to catalyze, reacting at about 130 deg.C, extracting and washing with ethyl acetate/saturated NaCl water solution for 3 times, anhydrous MgSO4Drying, mixing with 200-mesh and 300-mesh silica gel, and separating and purifying by column chromatography.
Subsequent operation referring to example 1
1H NMR(400MHz,DMSO-d6)δ8.67(s,1H),7.43–7.33(m,2H),7.22(d,J＝3.4Hz,1H),7.10(dd,J＝5.8,3.2Hz,1H),6.80(d,J＝3.4Hz,1H),5.43(s,2H).
MS(ESI-):[M-H]-:258.05
Example 245- ((benzo [ d ] oxazol-7-oxy) methyl) furan-2-carboxylic acid
Synthetic reference example 23, 2-Nitroresorcinol was replaced by 3-Nitro-1, 2-benzenediol
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),7.40(dd,J＝8.0,1.0Hz,1H),7.33(t,J＝8.0Hz,1H),7.24–7.18(m,1H),7.14(d,J＝3.4Hz,1H),6.78(d,J＝3.4Hz,1H),5.74(s,2H).
MS(ESI-):[M-H]-:258.05
Example 255- ((chroman-7-oxy) methyl) furan-2-carboxylic acid
Scheme F was synthesized by the following procedure:
1.62 g of 7-hydroxy-chromen-4-one in absolute ethanol/tetrahydrofuran ═ 3: 1, adding0.32 g of 10% Pd/C, a few drops of concentrated hydrochloric acid are added dropwise in H2Catalytic reduction is carried out under the environment to obtain the left fragment phenol.
For further working, see example 1
1H NMR(400MHz,DMSO-d6)δ7.19(d,J＝3.4Hz,1H),6.95(d,J＝8.2Hz,1H),6.72(d,J＝3.5Hz,1H),6.50(dd,J＝8.4,2.6Hz,1H),6.41(d,J＝2.6Hz,1H),5.05(s,2H),4.13–4.07(m,2H),2.65(t,J＝6.4Hz,2H),1.94–1.82(m,2H).
MS(ESI-):[M-H]-:273.08
Example 265- (((1-methyl-1, 2,3, 4-tetrahydroquinolin-7-yl) oxy) methyl) furan-2-carboxylic acid
Scheme G was synthesized as follows:
1.63 g of 3, 4-dihydro-7-hydroxy-2 (1H) -quinolinone are dissolved in 1-fold molar equivalent in DMF, 1.02 g of imidazole are added and the mixture is stirred under N2Under protection, 1.81 g of tert-butyldimethylsilyl chloride dissolved in DMF was added dropwise, the reaction was carried out at room temperature for about 3 to 5 hours, monitored by TLC, extracted and washed 3 times with ethyl acetate/saturated aqueous NaCl solution, anhydrous MgSO4Drying, mixing with 200-mesh and 300-mesh silica gel, and separating and purifying by column chromatography.
2.63 g of the product of the previous step are dissolved in DMF and 1.97 g of K are added2CO3And 1.62 g of methyl iodide, at room temperature for about 5-8 hours, followed by TLC monitoring and work-up as above.
2.62 g of the product obtained are dissolved in anhydrous tetrahydrofuran, N2Protecting, adding 1.35 ml of 1mol/l 9-BBN dropwise at 65 ℃, reacting for about 2-3 hours, monitoring by TLC, quenching by saturated NaCl aqueous solution, and carrying out the post-treatment in the same way.
The reduced benzopiperidine was dissolved in tetrahydrofuran, 10.8 ml of 1mol/l tetrabutylammonium fluoride tetrahydrofuran solution was added dropwise, the reaction was carried out for about 2-3h, TLC monitoring was carried out, quenching was carried out with saturated NaCl aqueous solution, and the post-treatment was the same as above.
The subsequent chemistry, with reference to example 1, finally yielded 5- (((1-methyl-1, 2,3, 4-tetrahydroquinolin-7-yl) oxy) methyl) furan-2-carboxylic acid
1H NMR(400MHz,DMSO-d6)δ7.19(d,J＝3.4Hz,1H),6.78(d,J＝8.0Hz,1H),6.71(d,J＝3.4Hz,1H),6.23–6.15(m,2H),5.03(s,2H),3.18–3.13(m,2H),2.80(s,3H),2.61(t,J＝6.4Hz,2H),1.89–1.80(m,2H).
MS(ESI-):[M-H]-:286.12
Example 275- (((4-propylnaphthalen-1-yl) oxy) methyl) furan-2-carboxylic acid
Synthetic reference example 8
1H NMR(400MHz,DMSO-d6)δ8.16(dd,J＝8.4,1.4Hz,1H),8.01(d,J＝8.4Hz,1H),7.57(ddd,J＝8.4,6.8,1.5Hz,1H),7.50(ddd,J＝8.1,6.7,1.3Hz,1H),7.27(d,J＝7.8Hz,1H),7.24(d,J＝3.4Hz,1H),7.07(d,J＝7.8Hz,1H),6.84(d,J＝3.4Hz,1H),5.31(s,2H),2.98–2.91(m,2H),1.67(h,J＝7.4Hz,2H),0.96(t,J＝7.3Hz,3H).
MS(ESI-):[M-H]-:309.12
Example 285- ((chroman-8-oxy) methyl) furan-2-carboxylic acid Synthesis reference example 25
1H NMR(400MHz,DMSO-d6)δ7.20(d,J＝3.5Hz,1H),6.87(d,J＝7.7Hz,1H),6.77–6.65(m,3H),5.04(s,2H),4.15–4.08(m,2H),2.72(t,J＝6.4Hz,2H),1.97–1.84(m,2H).
MS(ESI-):[M-H]-:273.1
Example 295- ((chroman-5-oxy) methyl) furan-2-carboxylic acid
Synthetic reference example 25
1H NMR(400MHz,DMSO-d6)δ7.21(d,J＝3.4Hz,1H),7.02(t,J＝8.2Hz,1H),6.74(d,J＝3.5Hz,1H),6.63(d,J＝8.1Hz,1H),6.41(d,J＝8.2Hz,1H),5.11(s,2H),4.06(dd,J＝5.8,4.3Hz,2H),2.55(t,J＝6.6Hz,2H),1.86(dq,J＝6.3,2.2Hz,2H).
MS(ESI-):[M-H]-:273.1
Example 305- ((1-methyl-1, 2,3, 4-tetrahydroquinolin-5-yl) oxy) methyl) furan-2-carboxylic acid Synthesis reference example 26
1H NMR(400MHz,DMSO-d6)δ7.19(d,J＝3.4Hz,1H),6.95(t,J＝8.2Hz,1H),6.69(d,J＝3.4Hz,1H),6.40(d,J＝8.1Hz,1H),6.29(d,J＝8.3Hz,1H),5.05(s,2H),3.14–3.07(m,2H),2.81(s,3H),1.89–1.78(m,2H).
MS(ESI-):[M-H]-:286.1
Example 315- ((1-methyl-1H-indol-4-yl) oxy) methyl) furan-2-carboxylic acid Synthesis reference example 1
1H NMR(400MHz,DMSO-d6)δ7.22(d,J＝1.4Hz,1H),7.21(d,J＝1.1Hz,1H),7.10–7.06(m,2H),6.78(d,J＝3.4Hz,1H),6.70(q,J＝4.5Hz,1H),6.41(d,J＝3.1Hz,1H),5.24(s,2H),3.76(s,3H).
MS(ESI-):[M-H]-:270.1
Example 325- ((1-Methylindolin-4-yl) oxy) methyl) furan-2-carboxylic acid
Scheme K was synthesized as follows:
1.47 g 1-methylindole-4-alcohol is dissolved in acetic acid, 3.15 g sodium cyanoborohydride is added for reaction overnight, the mixture is put into water and extracted by ethyl acetate, anhydrous MgSO4Drying, mixing with 200-mesh and 300-mesh silica gel, and separating and purifying by column chromatography.
Reference compound for subsequent reaction example 1
1H NMR(400MHz,DMSO-d6)δ7.20(d,J＝3.4Hz,1H),6.99(t,J＝8.0Hz,1H),6.71(d,J＝3.4Hz,1H),6.43(d,J＝8.2Hz,1H),6.21(d,J＝7.8Hz,1H),5.10(s,2H),3.23(t,J＝8.2Hz,2H),2.77(t,J＝8.2Hz,2H),2.67(s,3H).
MS(ESI-):[M-H]-:273.1
Example 335- ((1-methyl-1H-indol-7-yl) oxy) methyl) furan-2-carboxylic acid
Scheme A-2 was synthesized as follows:
2.24 g of 7-benzyloxyindole was dissolved in DMF, 0.52 g of NaH was added portionwise at room temperature, stirring was continued for half an hour, 1.56 g of methyl iodide was added, the reaction was allowed to proceed for about 3 to 5 hours at room temperature, monitored by TLC, quenched by addition of saturated aqueous NaCl, extracted with ethyl acetate, and dried over MgSO 44Drying, mixing with 200-mesh and 300-mesh silica gel, and separating and purifying by column chromatography.
The resulting compound was dissolved in methanol, 0.23 g of 10% Pd/C, 3.2 g of ammonium formate were added, the reaction was refluxed at 80 ℃ for about 2-3 hours, and the desired phenol fragment was obtained by TLC monitoring.
The subsequent chemistry was referenced to compound example 1.
1H NMR(500MHz,DMSO-d6)δ7.22(d,J＝3.4Hz,1H),7.18(d,J＝3.1Hz,1H),7.14(dd,J＝7.8,0.9Hz,1H),6.90(t,J＝7.8Hz,1H),6.80(dd,J＝7.7,0.9Hz,1H),6.78(d,J＝3.4Hz,1H),6.35(d,J＝3.0Hz,1H),5.25(s,2H),3.96(s,3H).
MS(ESI-):[M-H]-:270.1
Example 345- (2-methoxy-4-propylphenethyl) furan-2-carboxylic acid was synthesized specifically as follows:
1.89 g of ethyl 5-chloromethyl-2-furancarboxylate and 3.93 g of triphenylphosphine were added with a catalytic amount of DMF and refluxed in toluene for about 5 hours, then cooled, and the precipitated solid was filtered off and washed once with dry ether to give ({5- [ ethoxycarbonyl ] furan-2-yl } methyl) triphenylphosphine chloride which was directly fed to the next step.
4.51 g ({5- [ ethoxycarbonyl ]]Furan-2-yl } methyl) triphenylphosphine chloride and 2.15 g 4-bromo-2-methoxybenzaldehyde, 1.66 g K2CO3In anhydrous THF, N2Refluxing for 2-3 hr under protection to obtain product, extracting with ethyl acetate/saturated NaCl solution and washing for 3 times, anhydrous MgSO4Drying, filtering, mixing with 200-mesh silica gel of 300 meshes, and separating and purifying by column chromatography.
The product of the previous step was dissolved in MeOH and 0.35 g of 10% Pd/C, H was added2Reducing to obtain 5- (2-methoxy-4-propyl phenethyl) furan-2-carboxylic acid under the environment.
1H NMR(400MHz,DMSO-d6)δ7.10(d,J＝3.4Hz,1H),7.02(d,J＝7.6Hz,1H),6.79(d,J＝1.6Hz,1H),6.67(dd,J＝7.5,1.6Hz,1H),6.28(d,J＝3.4Hz,1H),3.78(s,3H),2.88(tt,J＝6.3,4.0Hz,4H),2.55–2.51(m,2H),1.58(dt,J＝8.9,7.4Hz,2H),0.89(t,J＝7.3Hz,3H).
MS(ESI-):[M-H]-:287.14
Example 352-hydroxyethyl 5- ((4-allyl-2-methoxyphenoxy) methyl) furan-2-carboxylate
Synthetic reference general scheme
Wherein the synthesis of furancarboxylic acid is referred to compound example 1, the ester-forming reaction synthesis procedure is as follows:
2.88 g of furoic acid in DMF, 2.07 g of K2CO3And 1.875 g of 2-bromoethyl acetateAlcohol, 50 ℃ for about 2-3 hours, TLC monitoring, post-treatment extraction with ethyl acetate/saturated aqueous NaCl and washing 3 times, anhydrous MgSO4Drying, filtering, mixing with 200-mesh silica gel of 300 meshes, and separating and purifying by column chromatography.
1H NMR(400MHz,DMSO-d6)δ7.30(d,J＝3.5Hz,1H),6.99(d,J＝8.1Hz,1H),6.81(d,J＝1.9Hz,1H),6.74(d,J＝3.5Hz,1H),6.69(dd,J＝8.2,2.0Hz,1H),5.94(td,J＝16.8,6.8Hz,1H),5.11–5.00(m,4H),4.94(t,J＝5.6Hz,1H),4.26(t,J＝5.0Hz,2H),3.74(s,3H),3.67(q,J＝5.2Hz,2H),3.30(d,J＝6.8Hz,2H).
MS(ESI+):[M-H]+:333.13
Example 365- ((4-chloronaphthalen-1-yl) oxy) methyl) -3-methylfuran-2-carboxylic acid
For synthesis see example 1
1H NMR(400MHz,DMSO-d6)δ8.21(d,J＝8.3Hz,1H),8.13(d,J＝8.4Hz,1H),7.77–7.69(m,1H),7.67–7.58(m,2H),7.16(d,J＝8.3Hz,1H),6.74(s,1H),5.32(s,2H),2.30(s,3H).
MS(ESI-):[M-H]-:315.05
Example 375- ((4-allyl-2-methoxyphenoxy) methyl) -3-methylfuran-2-carboxylic acid
For synthesis see example 1
1H NMR(400MHz,DMSO-d6)δ6.98(d,J＝8.1Hz,1H),6.81(d,J＝2.0Hz,1H),6.69(dd,J＝8.1,2.0Hz,1H),6.59(s,1H),5.95(td,J＝16.8,6.7Hz,1H),5.13–5.01(m,2H),4.99(s,2H),3.74(s,3H),3.30(d,J＝6.7Hz,2H),2.27(s,3H).
MS(ESI-):[M-H]-:301.12
Example 385- ((2, 4-Dichloronaphthalen-1-yl) oxy) methyl) furan-2-carboxylic acid Synthesis see example 1
1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝8.3Hz,1H),8.06(d,J＝8.3Hz,1H),7.89(s,1H),7.72(dt,J＝23.6,7.2Hz,2H),7.16(d,J＝3.4Hz,1H),6.70(d,J＝3.4Hz,1H),5.22(s,2H)
MS(ESI-):[M-H]-:335.0
Example 395- ((4-Methoxynaphthalen-1-yl) oxy) methyl) furan-2-carboxylic acid Synthesis see example 1
1H NMR(400MHz,DMSO-d6)δ8.16–8.04(m,2H),7.54(dt,J＝6.4,3.4Hz,2H),7.23(d,J＝3.4Hz,1H),7.05(d,J＝8.4Hz,1H),6.87(d,J＝8.4Hz,1H),6.81(d,J＝3.5Hz,1H),5.27(s,2H),3.93(s,3H).
MS(ESI-):[M-H]-:297.08
Example 405- ((4-chloro-1-methyl-1H-indol-7-yl) oxy) methyl) furan-2-carboxylic acid
The left fragment phenol synthesis is shown in scheme A-1, and the specific procedure is as follows:
4.73 g of 2-bromo-5-chloronitrobenzene in anhydrous tetrahydrofuran, N2Protection, 60 ml of 1mol/L vinyl magnesium bromide tetrahydrofuran solution is added dropwise at-78 ℃, the reaction is carried out for about 3 to 5 hours, and saturated NH is monitored by TLC4Quenching with Cl aqueous solution, extracting with ethyl acetate/saturated NaCl aqueous solution, washing, anhydrous MgSO4Drying, filtering, mixing with 200-mesh silica gel of 300 meshes, and separating and purifying by column chromatography.
The next Suzuki coupling and conversion of the boron ester to the phenolic hydroxyl group, see example 3, gives the left fragment phenol.
Subsequent syntheses referred to example 1.
1H NMR(400MHz,DMSO-d6)δ7.32(d,J＝3.1Hz,1H),7.22(d,J＝3.4Hz,1H),6.98(d,J＝8.2Hz,1H),6.83(d,J＝8.3Hz,1H),6.78(d,J＝3.4Hz,1H),6.38(d,J＝3.1Hz,1H),5.27(s,2H),3.97(s,3H).
MS(ESI-):[M-H]-:304.1
Example 415- ((4-fluoro-1-methyl-1H-indol-7-yl) oxy) methyl) furan-2-carboxylic acid
Please refer to example 40 for synthesis.
1H NMR(400MHz,DMSO-d6)δ7.26(d,J＝3.1Hz,1H),7.21(d,J＝3.4Hz,1H),6.77(d,J＝3.4Hz,1H),6.76–6.72(m,1H),6.68(dd,J＝9.8,8.4Hz,1H),6.41(d,J＝3.1Hz,1H),5.24(s,2H),3.97(s,3H).
MS(ESI-):[M-H]-:288.1
Example 425- ((1, 4-dimethyl-1H-indol-7-yl) oxy) methyl) furan-2-carboxylic acid
For synthesis see example 40
1H NMR(400MHz,DMSO-d6)δ7.21(d,J＝3.4Hz,1H),7.17(d,J＝3.1Hz,1H),6.75(d,J＝3.5Hz,1H),6.69(d,J＝1.8Hz,2H),6.35(d,J＝3.1Hz,1H),5.21(s,2H),3.95(s,3H),2.36(s,3H).
MS(ESI-):[M-H]-:284.1
Example 435- ((1H-indol-7-yl) oxy) methyl) furan-2-carboxylic acid
2.23 g of 7-benzyloxyindole was dissolved in methanol, and 0.15 g of 10% Pd/C, H was added2Reduction under the environment, TLC about 3 hours, reaction is finished, solvent is filtered and evaporated, and the next step is directly carried out, referring to the operation of ester formation and hydrolysis after example 1.
1H NMR(400MHz,DMSO-d6)δ11.19(s,1H),7.23(dd,J＝4.6,3.0Hz,2H),7.17(d,J＝7.8Hz,1H),6.91(t,J＝7.8Hz,1H),6.86(d,J＝3.4Hz,1H),6.80(d,J＝7.7Hz,1H),6.41(t,J＝2.4Hz,1H),5.28(s,2H).
MS(ESI-):[M-H]-:256.07
Example 444- (((5,6,7, 8-tetrahydronaphthalen-1-yl) oxy) methyl) benzoic acid
For synthesis see example 1
1H NMR(500MHz,DMSO-d6)δ8.02–7.95(m,2H),7.56(d,J＝8.1Hz,2H),7.02(t,J＝7.9Hz,1H),6.78(d,J＝8.1Hz,1H),6.67(d,J＝7.6Hz,1H),5.17(s,2H),2.67(dt,J＝18.0,6.4Hz,4H),1.71(dddd,J＝20.3,11.0,5.9,2.9Hz,4H).
MS(ESI-):[M-H]-:281.13
Example 454- (((4-chloronaphthalen-1-yl) oxy) methyl) benzoic acid
For synthesis see example 1
1H NMR(500MHz,DMSO-d6)δ8.38–8.30(m,1H),8.17–8.11(m,1H),8.06–7.99(m,2H),7.74(ddd,J＝8.3,6.8,1.3Hz,1H),7.71–7.65(m,3H),7.62(d,J＝8.3Hz,1H),7.08(d,J＝8.4Hz,1H),5.43(s,2H).
MS(ESI-):[M-H]-:311.06
Example 463- (((4-chloronaphthalen-1-yl) oxy) methyl) benzoic acid
For synthesis see example 1
1H NMR(500MHz,DMSO-d6)δ8.30(dd,J＝8.4,1.2Hz,1H),8.15–8.11(m,2H),7.95(dt,J＝7.8,1.5Hz,1H),7.82(dt,J＝7.7,1.6Hz,1H),7.74(ddd,J＝8.3,6.7,1.3Hz,1H),7.66(ddd,J＝8.2,6.8,1.3Hz,1H),7.63(d,J＝8.3Hz,1H),7.58(t,J＝7.7Hz,1H),7.10(d,J＝8.4Hz,1H),5.42(s,2H).
MS(ESI-):[M-H]-:311.06
Example 475- (((1-methyl-4-propyl-1H-indol-7-yl) oxy) methyl) furan-2-carboxylic acid ethyl ester
For synthesis see scheme A-1
For a detailed operation, refer to example 40.
1H NMR(500MHz,DMSO-d6)δ7.30(d,J＝3.4Hz,1H),7.16(d,J＝3.1Hz,1H),6.79(d,J＝3.4Hz,1H),6.70(q,J＝7.9Hz,2H),6.38(d,J＝3.0Hz,1H),5.23(s,2H),4.28(q,J＝7.1Hz,2H),3.95(s,3H),2.69(dd,J＝8.4,6.7Hz,2H),1.68–1.57(m,2H),1.29(t,J＝7.1Hz,3H).
MS(ESI+):[M-H]+:342.16
Example 485- ((1-methyl-4-propyl-1H-indol-7-yl) oxy) methyl) furan-2-carboxylic acid
Prepared by hydrolysis of the compound of example 47, 3.41 g of the compound of example 47 are dissolved in THF/MeOH/H2To a solvent of O-3/3/1, 1.2 g NaOH was added, TLC monitoring was performed, the reaction was completed, a large amount of water was added to the solvent, the organic solvent was evaporated, then PH 1 was adjusted with 1mol/L hydrochloric acid solution, there was a large amount of white precipitate, filtration was performed and washing was performed with pure water several times until PH 7 of the filtered water, and the solid was dried to obtain compound 48.
1H NMR(400MHz,DMSO-d6)δ7.22(d,J＝3.4Hz,1H),7.16(d,J＝3.1Hz,1H),6.76(d,J＝3.4Hz,1H),6.74–6.64(m,2H),6.38(d,J＝3.1Hz,1H),5.21(s,2H),3.95(s,3H),2.69(t,J＝7.5Hz,2H),1.63(h,J＝7.3Hz,2H),0.90(t,J＝7.3Hz,3H).
MS(ESI-):[M-H]-:312.13
Example 495- ((methyl (5,6,7, 8-tetrahydronaphthalen-1-yl) amino) methyl) furan-2-carboxylic acid
For synthesis see scheme L
The specific operation is as follows: 1.77 g of 5,6,7, 8-tetrahydronitronaphthalene dissolved in methanol, 0.17 g of 10% Pd/C, H2Reducing under the environment, monitoring by TLC,after the reaction, the solvent was evaporated by filtration, dissolved in DMF and 1.8 g of K was added2CO3And 1.89 g of ethyl 5-chloromethyl-2-furancarboxylate, reacting at room temperature, monitoring by TLC, filtering after the reaction is finished, extracting by EA for three times, washing for 4 and 5 times by saturated NaCl aqueous solution, and MgSO4Drying, filtering and evaporating the solution to dryness, directly dissolving in MeCN, adding 37% formaldehyde aqueous solution 10ml and NaBH at 0 deg.C3CN 1.26 g, 1ml of 10% acetic acid aqueous solution was added thereto to react, the temperature was slowly raised to room temperature, after completion of the reaction, a saturated NaCl aqueous solution was added thereto, EA was extracted, the organic phase was dried, and the mixture was applied to a column to obtain an ester, followed by hydrolysis according to the procedure of example 1 to obtain Compound 49.
1H NMR(500MHz,DMSO-d6)δ7.03(t,J＝7.6Hz,2H),6.90(d,J＝7.9Hz,1H),6.79(d,J＝7.5Hz,1H),6.37(d,J＝3.2Hz,1H),4.00(s,2H),2.76–2.70(m,4H),2.58(s,3H),1.70(q,J＝7.1Hz,4H).
MS(ESI-):[M-H]-:284.14
Example 505- ((methyl (naphthalen-1-yl) amino) methyl) furan-2-carboxylic acid Synthesis see example 49
1H NMR(500MHz,DMSO-d6)δ8.33(d,J＝8.0Hz,1H),7.99–7.92(m,1H),7.66(d,J＝8.1Hz,1H),7.62–7.54(m,2H),7.47(t,J＝7.8Hz,1H),7.23(d,J＝7.4Hz,1H),7.17(d,J＝3.3Hz,1H),6.51(d,J＝3.3Hz,1H),4.31(s,2H),2.85(s,3H).
MS(ESI-):[M-H]-:280.11
Example 516- ((1-methyl-1H-indol-7-yl) oxy) methyl) pyridine acid
For the left phenol fragment synthesis see example 33 and for the subsequent syntheses see example 1
1H NMR(400MHz,DMSO-d6)δ8.03(d,J＝8.0Hz,2H),7.83(d,J＝7.1Hz,1H),7.22(s,1H),7.13(d,J＝7.9Hz,1H),6.88(t,J＝7.8Hz,1H),6.71(d,J＝7.8Hz,1H),6.37(s,1H),5.36(s,2H),4.07(s,3H).
MS(ESI-):[M-H]-:281.1
Example 523- ((1-methyl-1H-indol-7-yl) oxy) methyl) benzoic acid Synthesis see example 51
1H NMR(400MHz,DMSO-d6)δ8.13(s,1H),7.93(d,J＝7.7Hz,1H),7.78(d,J＝7.6Hz,1H),7.55(t,J＝7.7Hz,1H),7.20(d,J＝3.0Hz,1H),7.12(d,J＝7.8Hz,1H),6.89(t,J＝7.8Hz,1H),6.74(d,J＝7.7Hz,1H),6.36(d,J＝3.0Hz,1H),5.30(s,2H),4.02(s,3H).
MS(ESI-):[M-H]-:280.11
Example 534- ((1-methyl-1H-indol-7-yl) oxy) methyl) benzoic acid
For synthesis see example 51
1H NMR(400MHz,DMSO-d6)δ8.00(d,J＝7.8Hz,2H),7.65(d,J＝7.9Hz,2H),7.20(d,J＝3.0Hz,1H),7.12(d,J＝7.9Hz,1H),6.88(t,J＝7.8Hz,1H),6.72(d,J＝7.7Hz,1H),6.36(d,J＝3.0Hz,1H),5.30(s,2H),4.03(s,3H).
MS(ESI-):[M-H]-:280.11
EXAMPLE 544- (((7-chloro-2, 3-dihydro-1H-inden-4-yl) oxy) methyl) benzoic acid Synthesis see example 1
1H NMR(500MHz,DMSO-d6)δ7.99–7.93(m,2H),7.57–7.52(m,2H),7.14(d,J＝8.6Hz,1H),6.84(d,J＝8.6Hz,1H),5.22(s,2H),2.91(dt,J＝17.3,7.5Hz,4H),2.06(p,J＝7.6Hz,2H).
MS(ESI-):[M-H]-:301.07
Example 553- (((7-chloro-2, 3-dihydro-1H-inden-4-yl) oxy) methyl) benzoic acid
For synthesis see example 1
1H NMR(500MHz,DMSO-d6)δ8.02(d,J＝1.8Hz,1H),7.90(dt,J＝7.7,1.5Hz,1H),7.68(dt,J＝7.7,1.6Hz,1H),7.53(t,J＝7.7Hz,1H),7.15(d,J＝8.6Hz,1H),6.87(d,J＝8.6Hz,1H),5.21(s,2H),2.90(dt,J＝10.5,7.5Hz,4H),2.05(p,J＝7.6Hz,2H).
MS(ESI-):[M-H]-:301.07
Example 563- (((5,6,7, 8-tetrahydronaphthalen-1-yl) oxy) methyl) sodium benzoate
Synthesis of 3- (((5,6,7, 8-tetrahydronaphthalen-1-yl) oxy) methyl) benzoic acid referring to example 1, 2.82 g of the obtained carboxylic acid was dissolved in methanol, 0.54 g of sodium methoxide was added, stirred at room temperature for 2-3 hours, and evaporated to dryness to give compound 56.
1H NMR(500MHz,DMSO-d6)δ7.96(d,J＝1.9Hz,1H),7.85–7.79(m,1H),7.41(dt,J＝7.6,1.7Hz,1H),7.31(t,J＝7.6Hz,1H),7.02(t,J＝7.9Hz,1H),6.80(d,J＝8.0Hz,1H),6.65(d,J＝7.6Hz,1H),5.08(s,2H),2.68(t,J＝6.0Hz,2H),2.62(t,J＝6.3Hz,2H),1.78–1.64(m,4H).
MS(ESI-):[M-H]-:281.13
EXAMPLE 574- (((5,6,7, 8-tetrahydronaphthalen-1-yl) oxy) methyl) sodium benzoate Synthesis see example 56.
1H NMR(500MHz,DMSO-d6)δ7.88(d,J＝7.9Hz,2H),7.35(d,J＝7.8Hz,2H),7.01(t,J＝7.8Hz,1H),6.79(d,J＝8.1Hz,1H),6.65(d,J＝7.6Hz,1H),5.07(s,2H),2.68(t,J＝6.0Hz,2H),2.62(t,J＝6.3Hz,2H),1.78–1.63(m,4H).
MS(ESI-):[M-H]-:281.13
Example 583- (((1-methyl-1H-indol-7-yl) oxy) methyl) sodium benzoate
See example 56 for synthesis.
1H NMR(500MHz,DMSO-d6)δ8.05(s,1H),7.85(d,J＝7.6Hz,1H),7.48(d,J＝7.6Hz,1H),7.33(t,J＝7.5Hz,1H),7.18(d,J＝3.0Hz,1H),7.10(d,J＝7.9Hz,1H),6.88(t,J＝7.8Hz,1H),6.74(d,J＝7.7Hz,1H),6.34(d,J＝3.0Hz,1H),5.21(s,2H),4.01(s,3H).
MS(ESI-):[M-H]-:280.11
EXAMPLE 593- (((7-chloro-2, 3-dihydro-1H-inden-4-yl) oxy) methyl) sodium benzoate
See example 56 for synthesis.
1H NMR(500MHz,DMSO-d6)δ7.96(s,1H),7.84(d,J＝7.5Hz,1H),7.39(d,J＝7.5Hz,1H),7.31(t,J＝7.5Hz,1H),7.13(d,J＝8.6Hz,1H),6.86(d,J＝8.6Hz,1H),5.12(s,2H),2.89(q,J＝7.3Hz,4H),2.04(p,J＝7.5Hz,2H).
MS(ESI-):[M-H]-:301.06
Example 603- ((methyl (5,6,7, 8-tetrahydronaphthalen-1-yl) amino) methyl) benzoic acid synthesis see example 49.
1H NMR(500MHz,DMSO-d6)δ7.96(s,1H),7.83(d,J＝7.6Hz,1H),7.55(d,J＝7.6Hz,1H),7.42(t,J＝7.6Hz,1H),7.03(t,J＝7.7Hz,1H),6.93(d,J＝7.8Hz,1H),6.77(d,J＝7.5Hz,1H),4.01(s,2H),2.74(dd,J＝34.6,5.7Hz,4H),2.48(s,3H),1.70(p,J＝3.0Hz,4H).
MS(ESI-):[M-H]-:294.16
Example 612-hydroxyethyl-5- (((1-methyl-1H-indol-7-yl) oxy) methyl) furan-2-carboxylate
2.71 g of the compound prepared in example 33 are dissolved in DMF, 1.5g of potassium carbonate and 1.25 g of bromoethanol are added, the reaction is carried out at room temperature, the reaction is completely detected by TLC, the mixture is poured into ice water, extracted by ethyl acetate, added with silica gel and subjected to rotary evaporation through a column to obtain the required product.
1H-NMR(DMSO-d6,400MHz):δ7.33-7.34(d,J＝3.2Hz,1H),7.18-7.19(d,J＝3.2Hz,1H),7.14-7.16(d,J＝7.6Hz,1H),6.89-6.93(t,J＝7.6Hz,1H),6.79-6.82(m,2H),6.35-6.36(d,J＝3.2Hz,1H),4.91(s,1H),5.28(s,2H),4.25-4.28(t,J＝4.8Hz,2H),3.66-3.69(t,J＝4.8Hz,2H).
MS(ESI-):[M-H]-:314.1
EXAMPLE 622- (dimethylamino) ethyl-5- (((1-methyl-1H-indol-7-yl) oxy) methyl) furan-2-carboxylic acid the desired compound was synthesized according to the procedure of example 61.
1H-NMR(DMSO-d6,400MHz):δ7.30-7.30(d,J＝3.5Hz,1H),7.18-7.19(d,J＝3.0Hz,1H),7.13-7.15(d,J＝8.0Hz,1H),6.88-6.91(t,J＝8.0Hz,1H),6.79-6.81(m,2H),6.35-6.35(d,J＝3.5Hz,1H)，5.27(s,2H),4.31-4.33(t,J＝5.5Hz,2H),2.55-2.57(t,J＝5.5Hz,2H),2.18(s,6H).
MS(ESI-):[M-H]-:341.2
Example 632- (methylsulfonyl) propyl-5- (((1-methyl-1H-indol-7-yl) oxy) methyl) furan-2-carboxylate
The desired compound was synthesized by the method of example 61.
1H-NMR(DMSO-d6,400MHz):δ7.37-7.38(d,J＝4.0Hz,1H),7.18-7.18(d,J＝3.0Hz,1H),7.13-7.15(d,J＝8.0Hz,1H),6.88-6.91(t,J＝8.0Hz,1H),6.82-6.83(d,J＝4.0Hz,1H),6.80-6.81(d,J＝8.0Hz,2H),6.34-6.35(d,J＝3.0Hz,1H)，5.28(s,2H),4.33-4.35(t,J＝6.0Hz,2H),3.96(s,3H),3.24-3.27(t,J＝7.5Hz,2H),3.01(s,3H),2.08-2.14(m,2H).
MS(ESI-):[M-H]-:376.1
Example 645- ((1, 2-dimethyl-1H-indol-7-yl) oxy) methyl) furan-2-carboxylic acid
1H NMR(400MHz,DMSO-d6)δ7.22(d,J＝3.5Hz,1H),7.04(d,J＝7.7Hz,1H),6.85(t,J＝7.8Hz,1H),6.76(t,J＝6.2Hz,2H),6.17(s,1H),5.24(s,2H),3.86(s,3H),2.33(s,3H).
MS(ESI-):[M-H]-:284.1
Example 65 (5- ((1-methyl-1H-indol-7-yl) oxy) methyl) furan-2-carbonyl) glycine
2.71 g of the compound of example 33 was dissolved in a mixed solvent of DCM/DMF-10/1, 5.7 g of HATU and 2.48 ml of DIPEA were added, and after half an hour of reaction, 1.875 g of taurine and 1.59 g of na2co31 were added, and then several drops of water were added dropwise, overnight reaction was performed, the precipitate was filtered, DCM was washed 2 times, the precipitate was dissolved in MeOH, and the mixture was applied to a column to obtain compound 65.
1H NMR(500MHz,DMSO-d6)δ8.68(t,J＝6.0Hz,1H),7.18(d,J＝3.1Hz,1H),7.17–7.11(m,2H),6.91(t,J＝7.8Hz,1H),6.81(d,J＝7.7Hz,1H),6.77(d,J＝3.5Hz,1H),6.35(d,J＝3.0Hz,1H),5.23(s,2H),3.95(s,3H),3.88(d,J＝6.0Hz,2H).
MS(ESI-):[M-H]-:327.11
Example 662- (5- (((1-methyl-1H-indol-7-yl) oxy) methyl) furan-2-carboxamide) ethane-1-sulfonic acid
Synthesis of example 65
1H NMR(500MHz,DMSO-d6)δ8.41(t,J＝5.5Hz,1H),7.18(d,J＝3.0Hz,1H),7.14(d,J＝7.8Hz,1H),7.05(d,J＝3.4Hz,1H),6.90(t,J＝7.8Hz,1H),6.80(d,J＝7.7Hz,1H),6.74(d,J＝3.4Hz,1H),6.34(d,J＝3.1Hz,1H),5.20(s,2H),3.50(q,J＝6.5Hz,2H),2.66(t,J＝7.0Hz,2H).
MS(ESI-):[M-H]-:377.09
Example 672- (5- ((4-chloronaphthalen-1-yl) oxy) methyl) furan-2-carboxamide) ethane-1-sulfonic acid
Synthesis of example 65
1H NMR(500MHz,DMSO-d6)δ8.51(t,J＝5.5Hz,1H),8.28(d,J＝8.4Hz,1H),8.18(d,J＝8.4Hz,1H),7.78(ddd,J＝8.4,6.8,1.3Hz,1H),7.73–7.64(m,2H),7.26(d,J＝8.4Hz,1H),7.13(d,J＝3.4Hz,1H),6.88(d,J＝3.5Hz,1H),5.38(s,2H),3.56(q,J＝6.6Hz,2H),2.71(t,J＝7.0Hz,2H).
MS(ESI-):[M-H]-:408.04
Example 682- (5- ((7-chloro-2, 3-dihydro-1H-inden-4-yl) oxy) methyl) furan-2-carboxamide) ethane-1-sulfonic acid
Synthesis of example 65
1H NMR(500MHz,DMSO-d6)δ8.40(t,J＝5.5Hz,1H),7.17(d,J＝8.6Hz,1H),7.03(d,J＝3.4Hz,1H),6.98(d,J＝8.7Hz,1H),6.70(d,J＝3.4Hz,1H),5.10(s,2H),3.49(q,J＝6.5Hz,2H),2.86(dt,J＝14.8,7.5Hz,4H),2.65(t,J＝6.9Hz,2H),2.02(p,J＝7.5Hz,2H).
MS(ESI-):[M-H]-:398.05
Example 692- (5- ((3-methoxy-4-propylphenoxy) methyl) furan-2-carboxamide) ethane-1-sulfonic acid
Synthesis of example 65
1H NMR(500MHz,DMSO-d6)δ8.39(t,J＝5.6Hz,1H),7.02(dd,J＝12.4,5.8Hz,2H),6.78–6.66(m,1H),6.61(s,1H),6.55(d,J＝8.3Hz,1H),5.06(s,2H),3.75(s,3H),3.50(q,J＝6.6Hz,2H),2.66(t,J＝7.2Hz,2H),2.43(t,J＝7.7Hz,2H),1.48(q,J＝7.5Hz,2H),0.86(t,J＝7.4Hz,3H).
MS(ESI-):[M-H]-:396.12
Example 702- (5- ((4-chloro-2-methylphenoxy) methyl) furan-2-carboxamide) ethane-1-sulfonic acid Synthesis please refer to example 65
1H NMR(500MHz,DMSO-d6)δ8.41(t,J＝5.5Hz,1H),7.26–7.18(m,2H),7.13(d,J＝8.4Hz,1H),7.04(d,J＝3.4Hz,1H),6.71(d,J＝3.4Hz,1H),5.11(s,2H),3.50(q,J＝6.6Hz,2H),2.66(t,J＝7.0Hz,2H),2.13(s,3H).
MS(ESI-):[M-H]-:372.04
Example 712- (4-fluoro-3- ((5,6,7, 8-tetrahydronaphthalen-1-yl) oxy) methyl) benzamide) ethane-1-sulfonic acid
Synthesis of example 65
1H NMR(500MHz,DMSO-d6)δ8.58(t,J＝5.4Hz,1H),8.04(dd,J＝7.1,2.3Hz,1H),7.84(ddd,J＝8.0,5.0,2.2Hz,1H),7.36(t,J＝9.2Hz,1H),7.05(t,J＝7.9Hz,1H),6.86(d,J＝8.1Hz,1H),6.69(d,J＝7.6Hz,1H),5.13(s,2H),3.53(q,J＝6.6Hz,2H),2.69(q,J＝6.2,5.1Hz,4H),2.58(t,J＝6.2Hz,2H),1.70(dq,J＝12.2,6.6,5.7Hz,4H).
MS(ESI-):[M-H]-:406.12
Example 722- (5- ((4-bromo-5, 6,7, 8-tetrahydronaphthalen-1-yl) oxy) methyl) furan-2-carboxamide) ethane-1-sulfonic acid
Synthesis of example 65
1H NMR(500MHz,DMSO-d6)δ8.40(t,J＝5.5Hz,1H),7.38(d,J＝8.7Hz,1H),7.03(d,J＝3.4Hz,1H),6.93(d,J＝8.8Hz,1H),6.70(d,J＝3.4Hz,1H),5.09(s,2H),3.49(q,J＝6.5Hz,2H),2.66(t,J＝7.0Hz,2H),2.61(t,J＝6.2Hz,2H),2.56(t,J＝6.2Hz,2H),1.78–1.58(m,4H).
MS(ESI-):[M-H]-:456.02
Example 732- (5- ((4-methylnaphthalen-1-yl) oxy) methyl) furan-2-carboxamide) ethane-1-sulfonic acid
Synthesis of example 65
1H NMR(500MHz,DMSO-d6)δ8.45(t,J＝5.5Hz,1H),8.17(d,J＝8.3Hz,1H),7.94(d,J＝8.3Hz,1H),7.62–7.55(m,1H),7.52(t,J＝7.8Hz,1H),7.28(d,J＝7.8Hz,1H),7.10–7.00(m,2H),6.79(d,J＝3.4Hz,1H),5.26(s,2H),3.52(q,J＝6.6Hz,2H),2.69(t,J＝7.1Hz,2H),2.56(s,3H).
MS(ESI-):[M-H]-:388.09
Example 742- (5- ((4-allyl-3-methoxyphenoxy) methyl) furan-2-carboxamide) ethane-1-sulfonic acid
Synthesis of example 65
1H NMR(500MHz,DMSO-d6)δ8.45(t,J＝5.6Hz,1H),7.09(d,J＝3.4Hz,1H),7.05(d,J＝8.2Hz,1H),6.76(d,J＝3.4Hz,1H),6.69(d,J＝2.4Hz,1H),6.63(dd,J＝8.3,2.5Hz,1H),6.03–5.85(m,1H),5.12(s,2H),5.08–4.98(m,2H),3.81(s,3H),3.56(q,J＝6.6Hz,2H),3.28(d,J＝6.5Hz,2H),2.73(t,J＝7.1Hz,2H).
MS(ESI-):[M-H]-:394.10
Example 752- (3- ((7-chloro-2, 3-dihydro-1H-inden-4-yl) oxy) methyl) benzamide) ethane-1-sulfonic acid
Synthesis of example 65
1H NMR(500MHz,DMSO-d6)δ8.56(t,J＝5.4Hz,1H),7.88(d,J＝1.9Hz,1H),7.73(dt,J＝7.8,1.5Hz,1H),7.58(dt,J＝7.7,1.5Hz,1H),7.48(t,J＝7.6Hz,1H),7.14(d,J＝8.6Hz,1H),6.87(d,J＝8.6Hz,1H),5.17(s,2H),3.59–3.49(m,2H),2.90(dt,J＝15.0,7.5Hz,4H),2.70(dd,J＝7.8,6.5Hz,2H),2.05(p,J＝7.6Hz,2H).
MS(ESI-):[M-H]-:408.08
Example 762- (3- ((5,6,7, 8-tetrahydronaphthalen-1-yl) oxy) methyl) benzamide) ethane-1-sulfonic acid
Synthesis of example 65
1H NMR(500MHz,DMSO-d6)δ8.56(t,J＝5.4Hz,1H),7.89(s,1H),7.73(d,J＝7.7Hz,1H),7.60(d,J＝7.6Hz,1H),7.49(t,J＝7.7Hz,1H),7.02(t,J＝7.9Hz,1H),6.80(d,J＝8.1Hz,1H),6.66(d,J＝7.6Hz,1H),5.13(s,2H),3.57–3.50(m,2H),2.69(t,J＝6.9Hz,4H),2.64(t,J＝6.3Hz,2H),1.78–1.64(m,4H).
MS(ESI-):[M-H]-:388.13
Example 772- (5- ((naphthalene-1-oxy) methyl) furan-2-carboxamide) ethane-1-sulfonic acid
Synthesis of example 65
1H NMR(500MHz,DMSO-d6)δ8.46(t,J＝5.5Hz,1H),8.14(d,J＝8.1Hz,1H),7.92–7.83(m,1H),7.56–7.41(m,4H),7.18(d,J＝7.6Hz,1H),7.08(d,J＝3.4Hz,1H),6.81(d,J＝3.4Hz,1H),5.30(s,2H),3.55–3.48(m,2H),2.67(t,J＝7.1Hz,2H).
MS(ESI-):[M-H]-:374.08
Example 782- (5- ((5,6,7, 8-tetrahydronaphthalen-1-yl) oxy) methyl) furan-2-carboxamide) ethane-1-sulfonic acid
Synthesis of example 65
1H NMR(500MHz,DMSO-d6)δ8.39(t,J＝5.5Hz,1H),7.09–6.99(m,2H),6.88(d,J＝8.1Hz,1H),6.71–6.65(m,2H),5.06(s,2H),3.49(q,J＝6.6Hz,2H),2.66(dt,J＝17.2,6.6Hz,4H),2.54(t,J＝6.2Hz,2H),1.68(qd,J＝9.3,7.1,3.6Hz,4H).
MS(ESI-):[M-H]-:378.11
Example 792- (3- ((1-methyl-1H-indol-7-yl) oxy) methyl) benzamide) ethane-1-sulfonic acid
Synthesis of example 65
1H NMR(500MHz,DMSO-d6)δ8.58(t,J＝5.4Hz,1H),7.99(d,J＝1.8Hz,1H),7.81–7.73(m,1H),7.69(d,J＝7.5Hz,1H),7.52(t,J＝7.7Hz,1H),7.19(d,J＝3.0Hz,1H),7.12(d,J＝7.8Hz,1H),6.89(t,J＝7.8Hz,1H),6.74(d,J＝7.7Hz,1H),6.35(d,J＝3.0Hz,1H),5.27(s,2H),4.02(s,3H),3.60–3.50(m,2H),2.71(t,J＝7.1Hz,2H).
MS(ESI-):[M-H]-:387.11
Example 802- (4-methoxy-3- ((5,6,7, 8-tetrahydronaphthalen-1-yl) oxy) methyl) benzamide) ethane-1-sulfonic acid
Synthesis of example 65
1H NMR(500MHz,DMSO-d6)δ8.43(t,J＝5.4Hz,1H),7.91(d,J＝2.4Hz,1H),7.78(dd,J＝8.6,2.4Hz,1H),7.13(d,J＝8.6Hz,1H),7.03(t,J＝7.9Hz,1H),6.77(d,J＝8.1Hz,1H),6.66(d,J＝7.6Hz,1H),5.04(s,2H),3.89(s,3H),3.51(q,J＝6.6Hz,2H),2.68(t,J＝7.0Hz,4H),2.62(t,J＝6.4Hz,2H),1.71(qt,J＝10.0,4.9Hz,4H).
MS(ESI-):[M-H]-:418.14
Example 812- (5- ((2, 3-dihydro-1H-inden-4-yl) oxy) methyl) furan-2-carboxamide) ethane-1-sulfonic acid
Synthesis of example 65
1H NMR(500MHz,DMSO-d6)δ8.40(s,1H),7.10(d,J＝7.8Hz,1H),7.03(d,J＝3.4Hz,1H),6.90(d,J＝8.1Hz,1H),6.85(d,J＝7.4Hz,1H),6.70(d,J＝3.4Hz,1H),5.09(s,2H),3.50(q,J＝6.6Hz,2H),2.84(t,J＝7.4Hz,2H),2.76(t,J＝7.4Hz,2H),2.66(t,J＝7.1Hz,2H),2.05–1.89(m,2H).
MS(ESI-):[M-H]-:364.09
Example 822- (3- ((4-chloronaphthalen-1-yl) oxy) methyl) benzamide) ethane-1-sulfonic acid
Synthesis of example 65
1H NMR(500MHz,DMSO-d6)δ8.62(t,J＝5.3Hz,1H),8.33(d,J＝8.3Hz,1H),8.13(d,J＝8.4Hz,1H),8.01(s,1H),7.78(d,J＝7.7Hz,1H),7.76–7.69(m,2H),7.66(t,J＝7.6Hz,1H),7.62(d,J＝8.3Hz,1H),7.53(t,J＝7.7Hz,1H),7.10(d,J＝8.3Hz,1H),5.38(s,2H),3.56(t,J＝6.5Hz,2H),2.73(s,2H).
MS(ESI-):[M-H]-:418.06
Example 832- (5- ((7-methyl-2, 3-dihydro-1H-inden-4-yl) oxy) methyl) furan-2-carboxamide) ethane-1-sulfonic acid
Synthesis of example 65
1H NMR(500MHz,DMSO-d6)δ8.39(t,J＝5.6Hz,1H),7.08–6.96(m,1H),6.90(d,J＝8.2Hz,1H),6.80(d,J＝8.2Hz,1H),6.71–6.61(m,1H),5.04(s,2H),3.50(q,J＝6.7Hz,2H),3.18(s,3H),2.76(t,J＝7.7Hz,4H),2.66(t,J＝7.2Hz,2H),1.98(p,J＝7.3Hz,2H).
MS(ESI-):[M-H]-:378.11
Example 842- (5- (((1, 2-dimethyl-1H-indol-7-yl) oxy) methyl) furan-2-carboxamide) ethane-1-sulfonic acid
Synthesis of example 65
1H NMR(600MHz,DMSO-d6)δ8.41(t,J＝5.5Hz,1H),7.07–7.01(m,2H),6.85(t,J＝7.8Hz,1H),6.77–6.71(m,2H),6.15(d,J＝1.1Hz,1H),5.19(s,2H),3.86(s,3H),3.50(td,J＝7.0,5.4Hz,2H),2.66(t,J＝7.0Hz,2H),2.33(s,3H).MS(ESI-):[M-H]-:391.10
Example 852- (5- (((1,2, 3-trimethyl-1H-indol-7-yl) oxy) methyl) furan-2-carboxamide) ethane-1-sulfonic acid
Synthesis of example 65
MS(ESI-):[M-H]-:405.12
The beneficial effects of the compounds of the present invention are further illustrated below by activity experiments, but this should not be understood as the only beneficial effects of the compounds of the present invention.
EXAMPLE 86 in vitro Activity of Compounds of the invention to inhibit gluconeogenesis
Because abnormal enhancement of hepatic gluconeogenesis is the main reason for the increase of fasting blood glucose of diabetics, the abnormal enhancement of hepatic gluconeogenesis effectively inhibits excessive hepatic gluconeogenesis and reduces endogenous glucose generation, and is one of important means for treating type 2 diabetes. Thus, the inhibitory effect of the compounds disclosed in this application on mouse primary hepatocyte gluconeogenesis is its main mechanism of action against diabetes. Thus, the inventors used a mouse primary hepatocyte gluconeogenesis model to evaluate the anti-diabetic activity of each compound of the present application.
And (3) testing the sample:
the chemical names and preparation methods of the compounds of the invention are shown in the preparation examples of the compounds.
The experimental method comprises the following steps:
after overnight fasting, mice were anesthetized by intraperitoneal injection with 500mg/kg chloral hydrate and were sequentially administered with EGTA-containing buffer and collagenase-containing buffer via the portal vein by Seglen two-step perfusionLiver perfusion is performed. After perfusion, the whole liver was removed, washed with MEM medium and placed in a petri dish containing the same medium, the liver was shredded, filtered using a 100 mesh screen, the filtrate was transferred to a 50ml centrifuge tube, centrifuged at 4 ℃ at low speed and the hepatocytes were separated with 40% Percoll solution, the supernatant was discarded, the cells were resuspended in MEM medium containing 10% FBS, 10nM insulin and 10nM DEX, a small amount of trypan blue staining was performed to detect cell activity and counted, and the cell activity was measured at 1.3 × 105The cells/well were seeded in 48-well plates plated with gelatin and placed at 37 ℃ in 5% CO2Culturing in an incubator. After adherent culture of mouse primary hepatocytes for 4h, the cells were experimentally cultured in sugar-free DMEM medium containing different concentrations of compound, 0.1% DMSO (solvent control) or 500 μ M Metformin (positive control), 0.1% BSA, pretreated for 1.5h, and then replaced in 0.1% BSA sugar-free DMEM solution with or without gluconeogenic substrate (20mM sodium lactate, 2mM sodium pyruvate) and different concentrations of compound, 0.1% DMSO (solvent control) or 500 μ M Metformin (positive control). After incubation for 4h at 37 ℃, the culture solution was collected and its glucose concentration was measured using a glucose kit. Meanwhile, the cells were washed 3 times with PBS and lysed by adding 0.5M NaOH, and the protein concentration was determined to correct the glucose content. The data without gluconeogenic substrate was subtracted from the data with gluconeogenic substrate to obtain results representing the gluconeogenic level and the ratio of gluconeogenic level of each compound group to the solvent control group was calculated.
Experimental results and conclusions:
we chose the compound metformin as a positive control compound which significantly inhibited gluconeogenesis in mouse primary hepatocytes at 500 μ M at levels reduced by about 50% compared to the control group. Therefore, we set at compound evaluation: a compound is considered to have significant anti-diabetic activity when its gluconeogenic level in mouse primary hepatocytes is reduced by 30% or more compared to a control group.
The table below discloses fold-over gluconeogenesis levels of the compounds of the present application, as well as the corresponding concentrations administered, the lower the number, the better the activity.
Figure BDA0002378170860000681
Figure BDA0002378170860000691
Experimental results show that the test compound has good inhibitory activity on gluconeogenesis. The compound has better clinical application potential in the related treatment field.
Example 87 In vitro Activity of Compounds of the invention to inhibit fat Synthesis in HepG2 cells
And (3) testing the sample:
the chemical names and preparation methods of the compounds of the invention are shown in the preparation examples of the compounds.
The experimental method comprises the following steps:
when HepG2 cells cultured in 12-well plates were 85% confluent, they were starved overnight in serum-free MEM medium (containing 0.1% B SA), and the medium was replaced with MEM containing a different concentration of the target compound, 500. mu.M AICAR or 0.1% D MSO according to the experimental design, and after preincubation for 21 hours, the medium was replaced with MEM containing 0.02. mu. Ci/ml of 14C-acetate sodiu M, and target compound, AICAR and solvent control DMSO were added at the same concentration as that in preincubation, and the cells were incubated at 37 ℃ and 5% CO overnight2Incubate in incubator for 3 h. At the end of the experiment, cells were washed 3 times with ice PBS, 300. mu.l of 0.5MKOH was added to each well, lysed for 1h at room temperature with shaking, 250. mu.l of cell lysate was added to 320. mu.l of 20% KOH (dissolved in methanol), mixed well and saponified for 3h at 90 ℃. After the sample is cooled, 400 mul of petroleum ether is added to extract unsaponifiable lipid, namely sterol lipid, the mixture is centrifuged for 5min at the room temperature of 2500rpm, the upper solution is collected in a glass test tube, the extraction is repeated once, 1ml of scintillation fluid is added into the upper collection fluid after the vacuum pumping, and the mixture is shaken and uniformly mixed, and then the liquid scintillation instrument reads the number. Mu.l of distilled water was added to dilute the crude saponified sample, and 320. mu.l of 5N H was added2SO4And (3) carrying out acidification reaction on the saponified product. Adding 400 μ l petroleum ether to extract fatty acid, centrifuging at room temperature 2500rpm for 5min, collecting the upper layer solution, and weighingAnd (4) performing secondary extraction once, vacuum-pumping, adding 1ml of scintillation fluid, shaking, uniformly mixing, and reading by using a liquid scintillation instrument. The remaining cell lysates were assayed for protein content by the Bradford method, CPM values were corrected for protein amount, adipogenesis rate of primary hepatocytes was calculated, and the synthesis levels of the various compounds, sterol lipids and fatty acid, were calculated as ratios to the solvent control group, respectively.
Experimental results and conclusions:
we chose the compound AICAR as a positive control compound that significantly inhibited sterol lipid synthesis and fatty acid synthesis in HepG2 cells. Experimental results show that the compound has an obvious inhibition effect on sterol lipid synthesis of HepG2 cells, has a certain reduction effect on fatty acid synthesis, and has the potential of regulating lipid metabolism and improving fatty liver.
The table below discloses the fold of sterol lipid synthesis and fatty acid synthesis of the compounds of the present application on HepG2 cells, and the corresponding dosing concentrations.
TABLE 2 Effect of the compounds of the invention on the synthesis of sterol lipids and fatty acids from HepG2 cells
Figure BDA0002378170860000701
aSterol lipid synthesis at 500 μ M for the positive control AICAR was 0.650;
bfatty acid synthesis was 0.815 at 500 μ M for the positive control AICAR.
EXAMPLE 88 Effect of Compounds on pyruvate tolerance in CD1 mice and idiopathic type 2 diabetes ob/ob mice
8-week-old CD1 mice were purchased from Rick laboratory animals, Inc., Shanghai, and were divided into groups of 6 mice each having a compound content of 50mg/kg and a solvent control group according to their fasting blood glucose and body weight. Compound 50mg/kg of each compound was orally administered to each group of mice, and 0.5% CMC was orally administered to the solvent control group of mice. After 1 hour of administration, all mice were injected with 2.0g/kg of sodium pyruvate intraperitoneally, and blood glucose values at 0, 15, 30, 60, and 120min were measured. The genetic spontaneous ob/ob mice were introduced into Jackson, USA and bred in SPF-class animal houses. After gene identification, 3-4 weeks old ob/ob mice begin high-fat feed feeding, after 8 weeks old, the ill mice are grouped according to fasting blood glucose and body weight of the mice, and each group comprises 8 mice, namely a compound 100mg/kg group and a solvent control group. Compound groups ob/ob mice were orally administered with 100mg/kg of each compound, and solvent control groups were orally administered with 0.5% CMC. After 1 hour of administration, all ob/o b mice were injected with 1.5g/kg of sodium pyruvate intraperitoneally and blood glucose values were measured at 0, 15, 30, 60 and 120 min. The result shows that the blood sugar of the mice in the compound group is reduced compared with the blood sugar of the solvent control group, and the larger the reduction value is, the better the activity is shown:
table effect of single administration of compound on pyruvate tolerance in CD1 and ob/ob mice (rate of decline, n-6/8).
Figure BDA0002378170860000711
P <0.05, p <0.01 compared to solvent control mice.
EXAMPLE 89 study of the antidiabetic Effect of the Compounds of the present invention on the spontaneous type 2 diabetic ob/ob mice
The genetic spontaneous ob/ob mice were introduced into Jackson, USA and bred in SPF-class animal houses. Ob/ob mice 3-4 weeks old were genetically identified and then fed with high-fat diet, and at 7 weeks old, random blood glucose and fasting blood glucose were measured, and the mice with the disease were divided into 3 groups of 8 mice each, based on fasting, random blood glucose and body weight, which were the compound-15 mg/kg group, the compound-50 mg/kg group and the model control group of example 33, respectively. Examples groups of mice were orally administered either 15mg/kg or 50mg/kg of the compound of example 33, model control groups of mice were orally administered 0.5% CMC, each group of mice were administered 2 times a day for 26 consecutive days, random, fasting blood glucose was measured periodically during the administration period, glucose tolerance test was performed on day 22 of administration, improvement of insulin resistance state was observed in ob/ob mice, blood was taken at the end of the test, blood lipid level was measured, and liver was isolated to determine triglyceride level in liver. The results are as follows:
1. EXAMPLE 33 Effect of Compounds on blood glucose in ob/ob mice
The results show that the compound of example 33 can produce obvious blood sugar reducing effect after single administration of 50mg/kg for 4 hours, the blood sugar reducing rate of mice in the administration group is significantly lower than that of a model control group (P <0.01), the blood sugar reducing rate is 15.7%, and the blood sugar reducing rate after administration for 10 hours is 29.2% (Table 3). The compound of example 33 significantly reduced random and fasting blood glucose in ob/ob mice upon chronic continuous administration (tables 4, 5). Example 33 compound-15 mg/kg group mice had significantly lower random blood glucose than the model control group (P <0.05) from day 12 of administration and remained until the end of the experiment; example 33 Compound-50 mg/kg group mice had significantly lower random blood glucose than the model control group (P <0.05) by day 4 of dosing, with a mean blood glucose reduction of 39.1%. Example 33 Compound-15 mg/kg mice had significantly lower fasting plasma glucose than the model control group (P <0.05) from day 8 of dosing, with a mean blood glucose reduction of 19.8%; example 33 Compound-50 mg/kg mice had significantly lower fasting plasma glucose than the model control group (P <0.05) from day 4 of dosing, with a mean hypoglycemic rate of 34.4%. Therefore, the compound of example 33 has a significant hypoglycemic effect on type 2 diabetic ob/ob mice, and is dose-dependent.
Table 3 hypoglycemic effects of the compound of example 33 on ob/ob mice given in a single dose (blood glucose, mM, Mean ± SE, n ═ 8).
Figure BDA0002378170860000721
P <0.05, p <0.01 compared to model control.
TABLE 4 Effect of example 33 Compounds on ob/ob mouse randomized blood glucose after chronic administration (blood glucose, mM, Mean + -SE, n-8)
Figure BDA0002378170860000722
P <0.05, p <0.01 compared to model control.
TABLE 5 Effect of example 33 Compound on fasting plasma glucose in ob/ob mice after chronic administration (blood glucose, mM, Mean + -SE, n-8)
Figure BDA0002378170860000731
P <0.05, p <0.01 compared to model control group
2. EXAMPLE 33 Effect of Compounds on ob/ob mouse glucose tolerance
Oral glucose tolerance experiments were performed on day 22 post-dose, with each group of mice orally taking 1.5g/kg glucose, and blood glucose and serum insulin levels were measured before and 10, 15, 30 and 60min post-dose. The results show that the blood glucose values of 15mg/kg and 50mg/kg group mice of the compound of example 16 before and 10, 15, 30 and 60min after sugar administration are significantly lower than those of the model control group, and the glucose tolerance of ob/ob mice can be improved dose-dependently (Table 6); example 33 serum insulin levels at 10, 15, 30 and 60min after saccharide administration were significantly higher in both the compound 15mg/kg and 50mg/kg group mice than in the model control group, which dose-dependently promoted glucose-stimulated insulin release from ob/ob mice (Table 7). Therefore, it is suggested that the compound of example 33 has a significant effect of improving glucose tolerance and pancreatic islet responsiveness to glucose in ob/ob mice.
TABLE 6 influence of the compound of example 33 on ob/ob mouse oral glucose tolerance (mmol/L, Mean. + -. SE, n ═ 8)
Figure BDA0002378170860000732
P <0.05, p <0.01 compared to model control group
TABLE 7 influence of the compound of example 33 on ob/ob mouse glucose-stimulated insulin release (mmol/L, Mean + -SE, n-8)
Figure BDA0002378170860000741
P <0.05, p <0.01 compared to model control group
3. EXAMPLE 33 Effect of Compounds on glycated hemoglobin in ob/ob mice
After 15mg/kg and 50mg/kg of the compound in example 33 were continuously administered to ob/ob mice for 26 days, the glycosylated hemoglobin level of the ob/ob mice was significantly reduced (Table 8), thereby indicating that the compound in example 16 can significantly improve the carbohydrate metabolism of type 2 diabetic ob/ob mice after long-term administration.
TABLE 8 influence of the compound of example 33 on glycated hemoglobin in ob/ob mice (HbA1 c%, Mean. + -. SE, n ═ 8)
Figure BDA0002378170860000742
P <0.01 in comparison to model control group
4. EXAMPLE 33 Effect of Long-term administration of Compounds on the serum triglyceride levels of ob/ob mice
Significant reductions in serum triglyceride levels occurred in ob/ob mice following administration of 15mg/kg and 50mg/kg of the compound of example 33 for 26 consecutive days (Table 9). This suggests that the compound of example 33 has a certain ameliorating effect on the blood lipid disorders of ob/ob type 2 diabetic mice after long-term administration.
TABLE 9 Effect of the compound of example 33 on ob/ob mouse serum triglycerides (mmol/L, Mean. + -. SE, n ═ 8)
Figure BDA0002378170860000743
P <0.05, compared to model control group
5. EXAMPLE 33 Effect of Long-term administration of Compounds on liver triglyceride levels in ob/ob mice
After 15mg/kg and 50mg/kg of the compound of example 33 for 26 days, ob/ob mice showed a significant decrease in hepatic triglyceride levels, both significantly lower than the model control group (Table 10). Thus, the compound of example 33 has a significant improvement effect on hepatic lipid changes of ob/ob mice with type 2 diabetes after long-term administration.
TABLE 10 Effect of the compound of example 33 on ob/ob mouse liver triglycerides (μmol/g, Mean. + -. SE)
Figure BDA0002378170860000751
P <0.01 in comparison to model control group
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (20)

1. A compound of formula (I), its isomer, racemate, prodrug, solvate, deuteride or pharmaceutically acceptable salt thereof:
Figure FDA0002378170850000011
r is selected from: H. c substituted or unsubstituted with 1-3Q 11-10An alkyl group;
x is selected from: o, NH, NQ1, CH2Or CHQ 1;
y is selected from: o, NH or NQ 1;
ar1, Ar2 are independently selected from heteroaryl, aryl, benzoheterocyclyl or benzoalicyclic groups substituted or unsubstituted with 1-10Q 1;
wherein said substituent Q1 is selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R′、-NHC(＝O)R′Amino, mercapto, cyano, nitro, hydroxy; C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, which are unsubstituted or substituted by 1 to 5Q 4; the following groups substituted or unsubstituted with 1 to 5Q 2: heteroaryl containing one to two oxygen or nitrogen atoms, heteroaryl (C1-C6) alkyl containing one to two oxygen or nitrogen atoms, (C6-C12) fused heterocyclyl (C1-C6) alkyl containing one to two oxygen or nitrogen atoms, C5-C12 aryl (C1-C6) alkyl, phenoxy, benzyloxycarbonyl,
wherein the substituent Q2 is selected from halogen, oxo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, amino, mercapto, cyano, nitro, hydroxy, phenyl or phenoxy which is substituted or unsubstituted by 1-3Q 3,
wherein the substituent Q3 is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, amino, mercapto, cyano and hydroxyl,
wherein R ', R' are each independently selected from: H. phenyl substituted or unsubstituted with 1 to 3Q 4, benzyl substituted or unsubstituted with 1 to 3Q 4, C1-10 alkyl substituted or unsubstituted with 1 to 3Q 4, C1-10 haloalkyl substituted or unsubstituted with 1 to 3Q 4, C2-10 alkenyl substituted or unsubstituted with 1 to 3Q 4, C2-10 alkynyl substituted or unsubstituted with 1 to 3Q 4; alternatively, the radicals R 'and R' are joined together to form a 4-to 7-membered ring,
wherein said substituent Q4 is selected from the group consisting of halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R′、-SO2NR′R″、-SOR′、-SO2R′、-NO2、-OCF3、-CF3、-C2F5、-C3F7or-CN.
2. The compound of claim 1, wherein Ar1 and Ar2 are each independently selected from 5-14 membered heteroaryl, 6-14 membered aryl, benzo 3-10 membered heterocyclyl, or benzo 3-10 membered alicyclic ring, substituted or unsubstituted with 1-5Q 1.
3. The compound of claim 1, wherein Ar2 and Ar1 are each independently selected from phenyl, naphthyl, tetrahydronaphthyl, indanyl, benzoxazolyl, chromanyl, tetrahydroquinolinyl, indolyl, indolinyl, tetrahydropyridoquinolinyl, indenyl, benzopyranyl or quinolinyl, substituted or unsubstituted with 1-5Q 1.
4. The compound of claim 1, wherein said Ar2 is selected from phenyl, naphthyl, tetrahydronaphthyl, indanyl, benzoxazolyl, chromanyl, tetrahydroquinolinyl, indolyl, indolinyl, tetrahydropyridoquinolinyl, indenyl, benzopyranyl, quinolinyl, substituted or unsubstituted with 1-5Q 1; ar1 is preferably phenyl, pyridyl or furyl substituted or unsubstituted with 1 to 5 of Q1.
5. A compound according to claim 1, wherein substituent Q1 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C2-C6 haloalkenyloxy, C2-C6 haloalkynyloxy, -COOR ', -NR ' R ', -OR ', -COR ', -CONR ' R ', -O, -SR ', -SO ', -2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C2-C6 haloalkenyloxy, C2-C6 haloalkynyloxy which are unsubstituted or substituted by 1 to 5Q 4.
6. As claimed in claim 1The compound is characterized in that Y-R is selected from-OH; -NH- (CH)aSO2OH，-NH-(CH)aCOOH, wherein a is 1,2,3,4 or 5; substituted by 1-3 substituents selected from hydroxy, -N (C1-6 alkyl)2and-SO2C1-6 alkyl or unsubstituted C1-6 alkyl.
7. The compound of claim 1, having the structure of formula (II):
Figure FDA0002378170850000021
r is selected from: H. c substituted or unsubstituted with 1-3Q 11-10An alkyl group;
x is selected from: o, NH, NQ1, CH2Or CHQ 1;
y is selected from: o, NH or NQ 1;
n is selected from 1,2,3,4, or 5;
m is selected from 1 or 2;
Q1、R1、R2each independently selected from: H. C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, which are unsubstituted or substituted by 1 to 5Q 4;
wherein R ', R' are each independently selected from: H. phenyl substituted or unsubstituted with 1 to 3Q 4, benzyl substituted or unsubstituted with 1 to 3Q 4, C1-6 alkyl substituted or unsubstituted with 1 to 3Q 4, C1-6 haloalkyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkenyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkynyl substituted or unsubstituted with 1 to 3Q 4; alternatively, the groups R 'and R' are joined together to form a 4-7 membered ring;
wherein said substituent Q4 is selected from the group consisting of halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R′、-SO2NR′R″、-SOR′、-SO2R′、-NO2、-OCF3、-CF3、-C2F5、-C3F7or-CN.
8. The compound of claim 1, having the structure of formula (IV):
Figure FDA0002378170850000031
r is selected from: H. c substituted or unsubstituted with 1-3Q 11-10An alkyl group;
x is selected from: o, NH or NQ 1;
y is selected from: o, NH or NQ 1;
o is selected from 1 or 2;
p is selected from 1,2 or 3;
q is selected from 1,2,3 or 4;
Q1、R3、R4、R5each independently selected from: H. C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; is covered with 1-5Q4 substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy;
wherein R ', R' are each independently selected from: H. phenyl substituted or unsubstituted with 1 to 3Q 4, benzyl substituted or unsubstituted with 1 to 3Q 4, C1-6 alkyl substituted or unsubstituted with 1 to 3Q 4, C1-6 haloalkyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkenyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkynyl substituted or unsubstituted with 1 to 3Q 4; alternatively, the groups R 'and R' are joined together to form a 4-7 membered ring;
wherein said substituent Q4 is selected from the group consisting of halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R′、-SO2NR′R″、-SOR′、-SO2R′、-NO2、-OCF3、-CF3、-C2F5、-C3F7or-CN.
9. The compound of claim 1, having the structure of formula (VI):
Figure FDA0002378170850000041
wherein:
r is selected from: H. c substituted or unsubstituted with 1-3Q 11-10An alkyl group;
x is selected from: o, NH or NQ 1;
y is selected from: o, NH or NQ 1;
Q1、R6、R7、R8、R9、R10、R11、R12and R13Each independently selected from: H. C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halogen, C3-C6 cycloalkyl,C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, which are unsubstituted or substituted by 1 to 5Q 4;
wherein R ', R' are independently selected from: H. phenyl substituted or unsubstituted with 1 to 3Q 4, benzyl substituted or unsubstituted with 1 to 3Q 4, C1-6 alkyl substituted or unsubstituted with 1 to 3Q 4, C1-6 haloalkyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkenyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkynyl substituted or unsubstituted with 1 to 3Q 4; alternatively, the groups R 'and R' are joined together to form a 4-7 membered ring;
wherein said substituent Q4 is selected from the group consisting of halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R′、-SO2NR′R″、-SOR′、-SO2R′、-NO2、-OCF3、-CF3、-C2F5、-C3F7or-CN.
10. The compound of claim 1, having the structure of formula (VIII):
Figure FDA0002378170850000051
wherein:
r is selected from: H. substituted or not with 1-3Q 1Substituted C1-10An alkyl group;
x is selected from: o, NH or NQ 1;
y is selected from: o, NH or NQ 1;
r is 1,2,3 or 4;
s is 1,2 or 3;
t is 1 or 2;
ring A is a saturated, partially unsaturated, fully unsaturated 3-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, S or O, or a 3-10 membered saturated, partially unsaturated aliphatic ring;
Q1、R14、R15and R16Each independently selected from: H. C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, which are unsubstituted or substituted by 1 to 5Q 4;
wherein R ', R' are independently selected from: H. phenyl substituted or unsubstituted with 1 to 3Q 4, benzyl substituted or unsubstituted with 1 to 3Q 4, C1-6 alkyl substituted or unsubstituted with 1 to 3Q 4, C1-6 haloalkyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkenyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkynyl substituted or unsubstituted with 1 to 3Q 4; alternatively, the groups R 'and R' are joined together to form a 4-7 membered ring;
wherein said substituent Q4 is selected from the group consisting of halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R′、-SO2NR′R″、-SOR′、-SO2R′、-NO2、-OCF3、-CF3、-C2F5、-C3F7or-CN.
11. The compound of claim 1, having the structure of formula (XX):
Figure FDA0002378170850000061
r is selected from: H. c substituted or unsubstituted with 1-3Q 11-10An alkyl group;
x is selected from: o, NH or NQ 1;
y is selected from: o, NH or NQ 1;
u is selected from 1,2,3 or 4;
p is selected from 1,2 or 3;
q is selected from 1,2,3 or 4;
-COYR is located on benzene ring with-X-CH2-ortho, meta or para to the attached carbon atom;
Q1、R4、R5、R17each independently selected from: H. C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, which are unsubstituted or substituted by 1 to 5Q 4;
wherein R ', R' are each independently selected from: H. phenyl substituted or unsubstituted with 1 to 3Q 4, benzyl substituted or unsubstituted with 1 to 3Q 4, C1-6 alkyl substituted or unsubstituted with 1 to 3Q 4, C1-6 haloalkyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkenyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkynyl substituted or unsubstituted with 1 to 3Q 4; alternatively, the groups R 'and R' are joined together to form a 4-7 membered ring;
wherein said substituent Q4 is selected from the group consisting of halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R′、-SO2NR′R″、-SOR′、-SO2R′、-NO2、-OCF3、-CF3、-C2F5、-C3F7or-CN.
12. The compound of claim 1, having a structure represented by the following general formula (XA):
Figure FDA0002378170850000071
wherein:
r is selected from: H. c substituted or unsubstituted with 1-3Q 11-10An alkyl group;
x is selected from: o, NH or NQ 1;
y is selected from: o, NH or NQ 1;
u is selected from 1,2,3 or 4;
-COYR is located on benzene ring with-X-CH2-ortho, meta or para to the attached carbon atom;
Q1、R6、R7、R8、R9、R10、R11and R17Each independently selected from: H. C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxyC2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, which are unsubstituted or substituted by 1 to 5Q 4;
wherein R ', R' are independently selected from: H. phenyl substituted or unsubstituted with 1 to 3Q 4, benzyl substituted or unsubstituted with 1 to 3Q 4, C1-6 alkyl substituted or unsubstituted with 1 to 3Q 4, C1-6 haloalkyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkenyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkynyl substituted or unsubstituted with 1 to 3Q 4; alternatively, the groups R 'and R' are joined together to form a 4-7 membered ring;
wherein said substituent Q4 is selected from the group consisting of halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R′、-SO2NR′R″、-SOR′、-SO2R′、-NO2、-OCF3、-CF3、-C2F5、-C3F7or-CN.
13. The compound of claim 1, having the structure of formula (XB):
Figure FDA0002378170850000081
wherein:
r is selected from: H. c substituted or unsubstituted with 1-3Q 11-10An alkyl group;
x is selected from: o, NH or NQ 1;
y is selected from: o, NH or NQ 1;
r is 1,2,3 or 4;
s is 1,2 or 3;
u is 1,2,3 or 4;
-COYR is located on benzene ring with-X-CH2-ortho, meta or para to the attached carbon atom;
ring A is a saturated, partially unsaturated, fully unsaturated 3-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, S or O, or a 3-10 membered saturated, partially unsaturated aliphatic ring;
Q1、R14、R15and R17Each independently selected from: H. C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halogen, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R ', -NHC (═ O) R', amino, mercapto, cyano, nitro, hydroxy; C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl- (C1-C6) alkyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, C1-C10 haloalkyl, C2-C10 haloalkenyl, C2-C10 haloalkynyl, C1-C10 haloalkoxy, C2-C10 haloalkenyloxy, C2-C10 haloalkynyloxy, which are unsubstituted or substituted by 1 to 5Q 4;
wherein R ', R' are independently selected from: H. phenyl substituted or unsubstituted with 1 to 3Q 4, benzyl substituted or unsubstituted with 1 to 3Q 4, C1-6 alkyl substituted or unsubstituted with 1 to 3Q 4, C1-6 haloalkyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkenyl substituted or unsubstituted with 1 to 3Q 4, C2-6 alkynyl substituted or unsubstituted with 1 to 3Q 4; alternatively, the groups R 'and R' are joined together to form a 4-7 membered ring;
wherein said substituent Q4 is selected from the group consisting of halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO2R′、-SO3R′、-SO2NR′R″、-SOR′、-SO2R′、-NO2、-OCF3、-CF3、-C2F5、-C3F7or-CN.
14. The compound of claim 1, having the structure:
Figure FDA0002378170850000091
Figure FDA0002378170850000101
Figure FDA0002378170850000111
Figure FDA0002378170850000121
Figure FDA0002378170850000131
Figure FDA0002378170850000141
Figure FDA0002378170850000151
Figure FDA0002378170850000161
Figure FDA0002378170850000171
Figure FDA0002378170850000181
15. a composition, comprising:
(a) an effective amount of a compound of any one of claims 1-14, isomers, racemates thereof, prodrugs thereof, solvates thereof, deuterides or pharmaceutically acceptable salts thereof: and
(b) a dietetic or pharmaceutically acceptable carrier or excipient.
16. Use of the compound of any one of claims 1 to 14, its isomer, racemate, prodrug, solvate, deuteron or pharmaceutically acceptable salt thereof, or the composition of claim 15 for the prevention and treatment of diabetes and metabolic syndrome.
17. The use of claim 16, wherein the metabolic syndrome is selected from the group consisting of: diabetes, insulin resistance, hyperinsulinemia, impaired glucose tolerance, obesity and fatty liver.
18. A method for preventing or treating diabetes or metabolic syndrome in a mammal comprising the steps of: administering to a mammalian subject in need thereof an effective amount of a compound, isomer, racemate, prodrug thereof, solvate thereof, deuteron or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 or a composition according to claim 15.
19. The method of claim 18, wherein the metabolic syndrome is selected from the group consisting of: diabetes, insulin resistance, hyperinsulinemia, impaired glucose tolerance, obesity and fatty liver.
20. The method of claim 18, wherein the mammal is a human.
CN202010074613.5A 2020-01-22 2020-01-22 Ether compound and pharmaceutical application thereof in preventing and treating diabetes and metabolic syndrome Pending CN113149941A (en)

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