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CN107235960B - Amide derivatives, preparation method and medical application thereof - Google Patents

Amide derivatives, preparation method and medical application thereof Download PDF

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Publication number
CN107235960B
CN107235960B CN201610187531.5A CN201610187531A CN107235960B CN 107235960 B CN107235960 B CN 107235960B CN 201610187531 A CN201610187531 A CN 201610187531A CN 107235960 B CN107235960 B CN 107235960B
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alkyl
pharmaceutically acceptable
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CN107235960A (en
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关东亮
白骅
盛首一
陈明孝
王中利
赵伟峰
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Zhejiang Hisun Pharmaceutical Co Ltd
Shanghai Aryl Pharmtech Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • C07D401/02—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
    • 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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Abstract

The invention relates to an amide derivative, a preparation method thereof and application thereof in medicines. Specifically, the invention relates to an amide derivative shown in a general formula (I), a preparation method thereof, a pharmaceutically acceptable salt thereof and application thereof as a therapeutic agent, particularly as a pancreatic hyperglycemia receptor antagonist, wherein the definition of each substituent in the general formula (I) is the same as that in the specification.

Description

Amide derivatives, preparation method and medical application thereof
Technical Field
The invention relates to a novel amide derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and application of the derivative as a therapeutic agent, in particular as a GCGR antagonist.
Background
Glucagon (Glucagon) is a linear polypeptide consisting of 29 amino acids secreted by pancreatic islet alpha cells, with a molecular weight of 3485; the concentration in serum is 50-100ng/L, and the half-life period in plasma is 5-10 minutes. Glucagon specifically binds to a B-type G protein-coupled receptor (glucagon receptor, GCGR) on the surface of a target cell such as liver or kidney, activates a downstream signal transduction pathway, and exerts a physiological effect. It is a hormone for promoting catabolism, and has strong effects of promoting glycogenolysis and gluconeogenesis, and can obviously raise blood sugar. 1mol/L of hormone can make 3X 106mol/L of glucose rapidly decomposes from glycogen (Johnson et al, J.biol.chem.1972, 247, 3229-3235).
Glucagon receptors are located on the cell surface, and G-protein coupled receptors with 7 transmembrane sequences are distributed mainly in the liver, and also in the kidney, heart, muscle, etc.
The major target organ for glucagon action is the liver. When combined with the receptor, the protein interacts with guanine nucleotide binding regulatory protein Gs, so that the subunit A of Gs releases and activates adenylate cyclase, and ATP is catalyzed to be converted into cAMP to play a biological effect. The pharmacological dose of glucagon can increase cAMP content in myocardial cells and enhance myocardial contraction. Glucagon receptor antagonists can compete with glucagon for the receptor, thereby blocking its action.
Diabetes is a disease characterized by high levels of plasma glucose. Uncontrolled hyperglycemia is associated with an increased risk of microvascular and macrovascular disease, including nephropathy, retinopathy, hypertension, stroke, and heart disease. Control of glucose homeostasis is the primary method of treating diabetes. Studies have been shown in animal models of healthy animals and type I and type II diabetes: removal of circulating glucagon with selective and specific antibodies results in a decrease in blood glucose levels. Thus one potential treatment for diabetes and other diseases involving dysglycemia is glucagon receptor antagonist blocking the glucagon receptor to increase insulin response, to reduce the rate of gluconeogenesis and/or to lower plasma glucose levels by reducing hepatic glucose output rate in the patient.
A series of GCGR antagonists have been disclosed, including WO2008042223, WO2010098994a1, WO2015066252, WO2012009226a1, WO2012009226a1, etc., and not all compounds that are GCGR antagonists have the property of being useful therapeutic drugs. Some of these properties include high affinity for the glucagon receptor, duration of receptor activation, oral bioavailability, and stability (e.g., ability to formulate or crystallize, shelf life). Such characteristics can lead to increased safety, tolerability, efficacy, therapeutic index, patient compliance, cost effectiveness, ease of preparation, and the like. It has been unexpectedly discovered that the particular stereochemistry and functional groups of the compounds of the present invention exhibit one or more of these desirable characteristics, including significantly improved receptor binding properties, oral bioavailability and/or other advantageous features that enhance their suitability for therapeutic use. GCGR antagonist drugs currently under investigation include: PF-06291874 (pyroxene) and LGD-6972(Ligand) in clinical phase II, while MK-3577 was developed by Merck. The invention provides a novel GCGR receptor antagonist, which is designed into a compound shown in a general formula (I), and the compound has larger structural difference compared with the compounds specifically disclosed in the prior art, and shows excellent anti-diabetic effect and action.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a novel amide derivative shown as a general formula (I), and a stereoisomer, a tautomer, an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof, a metabolite, a metabolic precursor or a prodrug thereof:
Figure BDA0000952278910000021
wherein:
A1、A2、A3and A4Each independently selected from CR5Or N, provided that A1、A2、A3And A4No more than two of N; wherein A is1、A2、A3And A4Each independently is preferably CR5；
B1、B2、B3And B4Each independently selected from CR6Or N, provided that B1、B2、B3And B4No more than two of N; wherein, B1、B2、B3And B4Each independently is preferably CR6；
L1Is selected from CH2O or NH, preferably O;
R1and R2Together with the attached N or C atom form a 4-to 8-membered heterocyclic group, preferably 5-to 7-membered heterocyclic group, wherein the heterocyclic group contains one or more N, O, S (O)mAn atom, and said heterocyclic group is optionally further substituted by one orA plurality of substituents selected from alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -NR7R8、-C(O)NR7R8、-C(O)R9、-C(O)OR9or-NR7C(O)R8Substituted with the substituent(s);
R3selected from alkyl, cycloalkyl or heterocyclyl, wherein said alkyl, cycloalkyl or heterocyclyl is optionally further substituted by one or more substituents selected from alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -NR7R8、-C(O)NR7R8、-C(O)R9、-C(O)OR9or-NR7C(O)R8Substituted with the substituent(s);
R4is selected from aryl or heteroaryl, wherein said aryl or heteroaryl is optionally further substituted by one or more groups selected from alkyl, halogen, hydroxy, cyano, nitro, alkoxy, -NR7R8、-C(O)NR7R8、-C(O)R9、-C(O)OR9or-NR7C(O)R8Wherein said alkyl or alkoxy is optionally further substituted with one or more halo;
R5each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, hydroxy, cyano, nitro, -NR7R8、-C(O)NR7R8、-C(O)R9、-C(O)OR9or-NR7C(O)R8Wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR7R8、-C(O)NR7R8、-C(O)R9、-C(O)OR9or-NR7C(O)R8Substituted with the substituent(s);
R6each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, hydroxy, cyano, nitro, -NR7R8、-C(O)NR7R8、-C(O)R9、-C(O)OR9or-NR7C(O)R8Which isSaid alkyl or alkoxy group in (1) is optionally further substituted with one or more groups selected from halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR7R8、-C(O)NR7R8、-C(O)R9、-C(O)OR9or-NR7C(O)R8Substituted with the substituent(s);
R7and R8Each independently selected from a hydrogen atom or an alkyl group, wherein the alkyl group is optionally further substituted by one or more groups selected from hydroxy, halogen, nitro, cyano, alkoxy, -NR10R11、-C(O)R10R11、-C(O)R12、-SO2R12、-C(O)OR12or-NR10C(O)R11Substituted with the substituent(s);
or, R7And R8Together with the linking N atom form a 4-to 8-membered heterocyclic group containing one or more N, O, S (O)mAnd said heterocyclyl is optionally further substituted with one or more groups selected from alkyl, halo, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR10R11、-C(O)R10R11、-C(O)R12、-SO2R12、-C(O)OR12or-NR10C(O)R11Substituted with the substituent(s);
R9selected from hydrogen atoms or alkyl groups, wherein the alkyl groups are optionally further substituted by one or more groups selected from hydroxy, halogen, nitro, cyano, alkoxy, -NR10R11、-C(O)R10R11、-C(O)R12、-SO2R12、-C(O)OR12or-NR10C(O)R11Substituted with the substituent(s);
R10、R11and R12Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, haloalkyl, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, nitro, cyano, alkoxy, heteroaryl, alkoxy, nitro, cyano, alkoxy,aryl, heteroaryl, carboxylic acid or carboxylic acid ester;
m is selected from 0, 1 or 2; and n is selected from 0, 1 or 2.
In a preferred embodiment of the present invention, the compound of formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof is a compound of formula (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,
Figure BDA0000952278910000031
wherein: a. the1～A4、B1～B4、L1、R1～R4And n is as defined in formula (I).
In a preferred embodiment of the present invention, the compound of formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof is a compound of formula (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,
Figure BDA0000952278910000032
wherein: a. the1～A4、B1～B4、L1、R3And R4And n is as defined in formula (I).
In a preferred embodiment of the present invention, the compound of formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof is a compound of formula (IV) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,
Figure BDA0000952278910000041
wherein: a. the1～A4、B1～B4、L1、R3And R4And n is as defined in formula (I)。
In a preferred embodiment of the present invention, the compound of any one of the general formulae (I) to (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R is3Is selected from C3-6Alkyl, preferably n-propyl.
In a preferred embodiment of the present invention, the compound of any one of the general formulae (I) to (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R is4Selected from 5-6 membered heteroaryl, wherein said heteroaryl is optionally further substituted with one or more substituents of halogen, alkyl or alkoxy, wherein said alkyl or alkoxy is optionally further substituted with one or more halogens; as a further preferred embodiment, wherein R4Selected from pyrazolyl, wherein said pyrazolyl is optionally further substituted with trifluoromethyl or trifluoromethoxy.
In a preferred embodiment of the present invention, the compound of any one of the general formulae (I) to (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R is5Each independently selected from a hydrogen atom, an alkyl group or a halogen, wherein the halogen is preferably F, Cl or Br.
In a preferred embodiment of the present invention, the compound of any one of the general formulae (I) to (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R is6Each independently selected from a hydrogen atom, an alkyl group or a halogen, wherein the halogen is preferably F, Cl or Br.
In a preferred embodiment of the present invention, a compound represented by any one of the general formulae (I) to (IV) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
A1、A2、A3and A4Each independently selected from CR5；
B1、B2、B3And B4Each independently selected from CR6；
L1Is selected from O;
R1and R2Together with the linking N or C atom, form a 4-to 8-membered heterocyclic group, preferably 5-to 7-membered; whereinThe heterocyclic radical contains one or more N, O, S (O)mAn atom, and said heterocyclyl is optionally further substituted with one or more halogens; preferably F, Cl or Br, more preferably F;
R3is selected from alkyl, wherein said alkyl is optionally further substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl or-NR7R8Substituted with the substituent(s);
R4is selected from aryl or heteroaryl, wherein said aryl or heteroaryl is optionally further substituted by one or more groups selected from alkyl, halogen, hydroxy, cyano, nitro, alkoxy, -NR7R8、-C(O)NR7R8、-C(O)R9、-C(O)OR9or-NR7C(O)R8Wherein said alkyl or alkoxy is optionally further substituted with one or more halo;
R5each independently selected from a hydrogen atom, an alkyl group, or a halogen, wherein said alkyl group is optionally further substituted with one or more halogens;
R6each independently selected from a hydrogen atom, an alkyl group, or a halogen, wherein said alkyl group is optionally further substituted with one or more halogens; and is
R7～R9And n is as defined in formula (I).
Preferred compounds of the invention include, but are not limited to:
Figure BDA0000952278910000051
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
Further, the present invention provides a method for preparing a compound of the general formula (I) or a salt thereof, comprising the steps of:
Figure BDA0000952278910000061
hydrolyzing the compound of the general formula (Ia) under alkaline conditions to obtain a compound of a general formula (Ib); carrying out a condensation reaction of a compound of formula (Ib) or a salt thereof with a compound of formula (Ic) or a salt thereof in the presence of a condensation reagent, preferably bis (2-oxo-3-oxazolidinyl) phosphoryl chloride and N, N-diisopropylethylamine to give a compound of formula (Id); carrying out Mistunobu reaction on the compound with the general formula (Id) and the compound with the general formula (Ie) in the presence of a dehydrating reagent and a phosphine ligand, preferably in the presence of diisopropyl azodicarboxylate and triphenylphosphine to obtain a compound with a general formula (IA); the compound of formula (IA) is hydrolyzed under basic conditions to give the compound of formula (I).
Wherein:
Raand RbEach independently is alkyl, wherein said alkyl is optionally further substituted with one or more halogens;
L1is O; and is
A1～A4、B1～B4、R1～R4And n is as defined in formula (I).
The invention provides a preparation method of a compound or a salt thereof shown in a general formula (II), which comprises the following steps:
Figure BDA0000952278910000062
hydrolyzing the compound of formula (IIa) under basic conditions to obtain a compound of formula (IIb); carrying out a condensation reaction of the compound of the general formula (IIb) or a salt thereof and the compound of the general formula (Ic) or a salt thereof in the presence of a condensation reagent, preferably bis (2-oxo-3-oxazolidinyl) phosphoryl chloride and N, N-diisopropylethylamine to obtain a compound of the general formula (IIc); carrying out Mistunobu reaction on the compound with the general formula (IIc) and the compound with the general formula (Ie) in the presence of a dehydrating reagent and a phosphine ligand, preferably in the presence of diisopropyl azodicarboxylate and triphenylphosphine to obtain a compound with a general formula (IIA); hydrolyzing the compound of the general formula (IIA) under alkaline conditions to obtain a compound of a general formula (II).
Wherein:
Raand RbEach independently is alkyl, wherein said alkyl is optionally further substituted with one or more halogens;
L1is O; and is
A1～A4、B1～B4、R1～R4And n is as defined in formula (I).
The invention provides a preparation method of a compound or a salt thereof shown in a general formula (III), which comprises the following steps:
Figure BDA0000952278910000071
carrying out a condensation reaction between the compound of the general formula (Ib) or a salt thereof and the compound of the general formula (IIIa) or a salt thereof in the presence of a condensation reagent, preferably bis (2-oxo-3-oxazolidinyl) phosphoryl chloride and N, N-diisopropylethylamine to obtain a compound of the general formula (IIIb); carrying out Mistunobu reaction on the compound with the general formula (IIIb) and the compound with the general formula (Ie) in the presence of a dehydration reagent and a phosphine ligand, preferably in the presence of diisopropyl azodicarboxylate and triphenylphosphine to obtain a compound with a general formula (IIIA); and (3) hydrolyzing the compound of the general formula (IIIA) under alkaline conditions to obtain a compound of a general formula (III).
Wherein:
Rbis alkyl, wherein said alkyl is optionally further substituted with one or more halogens;
L1is O; and is
A1～A4、B1～B4、R1～R4And n is as defined in formula (I).
The invention provides a preparation method of a compound or a salt thereof shown in a general formula (IV), which comprises the following steps:
Figure BDA0000952278910000072
carrying out a condensation reaction of the compound of the general formula (IIb) or a salt thereof and the compound of the general formula (IIIa) or a salt thereof in the presence of a condensation reagent, preferably bis (2-oxo-3-oxazolidinyl) phosphoryl chloride and N, N-diisopropylethylamine to obtain a compound of the general formula (IVa); carrying out a Mistunobu reaction on the compound of the general formula (IVa) and the compound of the general formula (Ie) in the presence of a dehydration reagent and a phosphine ligand, preferably in the presence of diisopropyl azodicarboxylate and triphenylphosphine to obtain a compound of the general formula (IVA); the compound of the general formula (IVA) is hydrolyzed under alkaline conditions to give the compound of the general formula (IV).
Wherein:
Rbis alkyl, wherein said alkyl is optionally further substituted with one or more halogens;
L1is O; and is
A1～A4、B1～B4、R1～R4And n is as defined in formula (I).
In the above preparation method, the basic condition is provided by an organic base or an inorganic base, the organic base is preferably selected from diisopropylethylamine, diisopropylamine, pyridine, triethylamine, piperidine, N-methylpiperazine, 4-dimethylaminopyridine, more preferably diisopropylamine and triethylamine; the inorganic base is preferably selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and more preferably lithium hydroxide.
Further, the present invention provides a compound represented by general formulae (IA) to (IVA) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:
Figure BDA0000952278910000081
wherein:
Rbis alkyl, wherein said alkyl is optionally further substituted with one or more halogens;
A1～A4、B1～B4、L1、R1～R4and n is as defined in formula (I).
Preferred compounds of formulae (IA) to (IA) include, but are not limited to:
Figure BDA0000952278910000082
Figure BDA0000952278910000091
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
Furthermore, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formulae (I) to (IV) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or a combination thereof.
The invention provides a method for inhibiting a glucagon receptor in vitro, which comprises the step of contacting the glucagon receptor with any one of general formulas (I) to (IV) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the stereoisomer, the tautomer or the pharmaceutically acceptable salt thereof.
The invention provides an application of a compound of any one of general formulas (I) to (IV) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing medicaments for treating type I diabetes, type II diabetes, hyperglycemia, obesity or insulin resistance.
The invention provides an application of a compound of any one of general formulas (I) to (IV) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing a glucagon receptor antagonist or inverse agonist.
The invention provides an application of a compound of any one of general formulas (I) to (IV) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing medicaments for treating hyperlipidemia, dyslipidemia, hypercholesterolemia, atherosclerosis and metabolic syndrome.
The compounds of any one of the general formulae (I) to (IV) of the present invention or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, can inhibit the glucagon receptor in vitro and thus can be used for the preparation of glucagon receptor antagonists or inverse agonists, while the present invention further provides methods for the treatment of type I diabetes, type II diabetes, hyperglycemia, obesity, insulin resistance, hyperlipidemia, dyslipidemia, hypercholesterolemia, atherosclerosis or metabolic syndrome comprising the step of administering to an animal a therapeutically effective amount of a compound of any one of the general formulae (I) to (IV) of the present invention or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.
Detailed description of the invention
Unless stated to the contrary, some of the terms used in the specification and claims of the present invention are defined as follows:
"alkyl" when taken as a group or part of a group means including C1-C20Straight-chain or branched aliphatic hydrocarbon groups. Preferably C1-C10Alkyl, more preferably C1-C6An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be optionally substituted or unsubstituted.
"alkynyl" as a group or part of a group refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, and can be straight or branched. Preferably selected is C2-C10Alkynyl of (2), more preferably C2-C6Alkynyl, most preferably C2-C4Alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. Alkynyl may be optionalSubstituted or unsubstituted.
"cycloalkyl" refers to saturated or partially saturated monocyclic, fused ring, bridged ring, and spiro carbocyclic rings, i.e., including monocyclic cycloalkyl, fused ring alkyl, bridged cycloalkyl, and spirocycloalkyl. Preferably C3-C12Cycloalkyl, more preferably C3-C8Cycloalkyl, most preferably C3-C6A cycloalkyl group. Examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cyclopropyl, cyclohexenyl being preferred.
"spirocycloalkyl" refers to a 5 to 18 membered polycyclic group having two or more cyclic structures with single rings sharing a single carbon atom (called the spiro atom) with each other, containing 1 or more double bonds within the ring, but no ring has a completely conjugated pi-electron aromatic system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified according to the number of spiro atoms shared between rings into mono-spiro, di-spiro, or multi-spiro cycloalkyl groups, preferably mono-spiro and di-spiro cycloalkyl groups, preferably 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro [4.5] decyl, spiro [4.4] nonyl, spiro [3.5] nonyl, spiro [2.4] heptyl.
"fused cycloalkyl" refers to a 5 to 18 membered all carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of "fused ring alkyl" include, but are not limited to: bicyclo [3.1.0] hexyl, bicyclo [3.2.0] hept-1-enyl, bicyclo [3.2.0] heptyl, decalinyl or tetradecaphenanthryl.
"bridged cycloalkyl" means a 5 to 18 membered all carbon polycyclic group containing two or more cyclic structures sharing two non-directly attached carbon atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12, more preferably 7 to 10. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of "bridged cycloalkyl" groups include, but are not limited to: (1s,4s) -bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, (1s,5s) -bicyclo [3.3.1] nonyl, bicyclo [2.2.2] octyl, and (1r,5r) -bicyclo [3.3.2] decyl.
The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted.
"Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably herein and all refer to non-aromatic heterocyclic groups in which one or more of the ring-forming atoms is a heteroatom, such as oxygen, nitrogen, sulfur, and the like, including monocyclic, fused, bridged, and spiro rings, i.e., including monocyclic heterocyclic groups, fused heterocyclic groups, bridged heterocyclic groups, and spiro heterocyclic groups. Preferably having a 5 to 7 membered monocyclic ring or a 7 to 10 membered bi-or tricyclic ring, which may contain 1,2 or 3 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, thiomorpholinyl, tetrahydropyranyl, 1, 1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo [3.2.1] octyl, and piperazinyl. The heterocyclic group may be optionally substituted or unsubstituted.
"spiroheterocyclyl" refers to a 5-to 18-membered polycyclic group having two or more cyclic structures wherein the individual rings share an atom with one another and which contains 1 or more double bonds within the ring, but none of the rings have a fully conjugated pi-electron aromatic system wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably, it is6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1, 7-dioxaspiro [4.5]]Decyl, 2-oxa-7-azaspiro [4.4]Nonyl, 7-oxaspiro [3.5]]Nonyl and 5-oxaspiro [2.4]]A heptyl group.
"fused heterocyclyl" refers to an all-carbon polycyclic group containing two or more ring structures sharing a pair of atoms with each other, one or more of the rings may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron aromatic system, wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to: octahydropyrrolo [3,4-c]Pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo [3.1.0]Hexyl, octahydrobenzo [ b ]][1,4]Dioxins (dioxines).
"bridged heterocyclyl" means a 5-to 14-membered, 5-to 18-membered polycyclic group containing two or more cyclic structures sharing two atoms not directly attached to each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen, or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to: 2-azabicyclo [2.2.1]Heptyl, 2-azabicyclo [2.2.2]Octyl and 2-azabicyclo [3.3.2]A decyl group.
The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl. The heterocyclic group may be optionally substituted or unsubstituted.
"aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion. The term "aryl" includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferably aryl is C6-C10Aryl, more preferably aryl is phenyl and naphthyl, most preferably phenyl. The aryl group may be optionally substituted or unsubstituted. The "aryl" may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples include, but are not limited to:
Figure BDA0000952278910000121
"heteroaryl" refers to an aromatic 5-to 6-membered monocyclic or 9-to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1, 2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, benzodioxolyl, benzimidazolyl, indolyl, isoindolyl, 1, 3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, and benzisoxazolyl. Heteroaryl groups may be optionally substituted or unsubstituted. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples include, but are not limited to:
Figure BDA0000952278910000122
"alkoxy" refers to a radical of (alkyl-O-). Wherein alkyl is as defined herein. C1-C6Alkoxy groups of (4) are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
"hydroxy" refers to an-OH group.
"halogen" means fluorine, chlorine, bromine and iodine, preferably chlorine, bromine and iodine.
"amino" means-NH2。
"cyano" means-CN.
"nitro" means-NO2。
"benzyl" means-CH2-phenyl.
"carboxy" refers to-C (O) OH.
"carboxylate" refers to-C (O) O (alkyl) or (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
As used herein, "substituted" or "substituted," unless otherwise specified, means that the group may be substituted with one or more groups selected from: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate-O, -NR7R8、-C(O)NR7R8、-C(O)R9、-C(O)OR9or-NR7C(O)R8Wherein R is7、R8And R9The definition of (A) is described in the general formula (I).
"pharmaceutically acceptable salts" refers to certain salts of the above compounds which retain their biological activity and are suitable for pharmaceutical use. The pharmaceutically acceptable salts of the compounds of formula (I) may be metal salts, amine salts with suitable acids. The metal salt is preferably alkali metal or alkaline earth metal salt; suitable acids include inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, malic, maleic, mandelic, methanesulfonic, nitric, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like, with hydrochloric, hydrobromic, phosphoric and sulfuric acids being particularly preferred, and the hydrochloride salt being most preferred.
"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, in admixture with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
Detailed Description
The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.
Examples
The examples show the preparation of representative compounds represented by formula (I) and the associated structural identification data. It must be noted that the following examples are intended to illustrate the invention and are not intended to limit the invention.
1The H NMR spectrum was obtained using a Bruker instrument (400MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00ppm) was used.1Method for H NMR expression: s is singlet, d is doublet, t is triplet, m is multiplet, br is broadened, dd is doublet of doublet, dt is doublet of triplet. If a coupling constant is provided, it is in Hz. The mass spectrum is measured by an LC/MS instrument,the ionization mode can be ESI or APCI.
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier. In the following examples, all temperatures are in degrees Celsius unless otherwise indicated, and unless otherwise indicated, the various starting materials and reagents are commercially available or synthesized according to known methods, and none of the commercially available materials and reagents are used without further purification, and unless otherwise indicated, commercially available manufacturers include, but are not limited to, Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Prov Chemical science Inc. and Sci Chemical science Inc., among others.
CD3OD: deuterated methanol.
CDCl3: deuterated chloroform.
DMSO-d6: deuterated dimethyl sulfoxide.
In the examples, the reaction was carried out under an argon atmosphere unless otherwise specified.
In the examples, the solution in the reaction is an aqueous solution unless otherwise specified.
Example 1
(R) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) benzoyl) piperidine-3-carboxylic acid
Figure BDA0000952278910000141
First step of
4- (1-hydroxybutyl) benzoic acid methyl ester
Methyl p-formylbenzoate 1a (10.0g, 60.92mmol) was dissolved in 100mL of tetrahydrofuran, and propylmagnesium bromide (33.5mL, 67.0mmol) was added thereto at-78 ℃ to conduct a reaction at room temperature for 3 hours. 300mL of ethyl acetate was added, and the mixture was washed with a saturated ammonium chloride solution (200mL) and a saturated sodium chloride solution (200mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate system) to give methyl 4- (1-hydroxybutyl) benzoate 1b (8.66g, colorless liquid) in yield: 68.0 percent
MS m/z(ESI)：209.0[M+1]
Second step of
4-Butylbenzoic acid methyl ester
Methyl 4- (1-hydroxybutyl) benzoate 1b (6.58g, 31.6mmol) was dissolved in 100mL of dichloromethane, and pyridine chlorochromate (8.17g, 37.9mmol) was added thereto at 0 ℃ to react at room temperature for 18 hours. After diluting with 200mL of dichloromethane, anhydrous magnesium sulfate was added and the mixture was stirred for 10 minutes, the mixture was filtered and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate system) to obtain methyl 4-butyrylbenzoate 1c (6.20g, white solid) in yield: 95.2 percent
MS m/z(ESI)：207.0[M+1]
The third step
(R) -4- (1-hydroxybutyl) benzoic acid methyl ester
borane-N, N-diethylaniline (5.53mL, 30.0mmol) was dissolved in 100mL of tetrahydrofuran, and (S) -2-methyl-CBS-oxazolylborane (1.5mL, 1.50mmol) was added, followed by dropwise addition of a solution of methyl 4-butyrylbenzoate 1c (6.20g, 30.0mmol) in tetrahydrofuran (50mL) and reaction at room temperature for 0.5 hour. The reaction was quenched by dropwise addition of 10mL of methanol to the reaction solution, followed by addition of 1M hydrochloric acid (130mL) and petroleum ether (300mL), and the organic phase was washed with 1M hydrochloric acid (120mL) and saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl (R) -4- (1-hydroxybutyl) benzoate 1d (6.07g, colorless liquid), yield: 97.0 percent
MS m/z(ESI)：209.0[M+1]
The fourth step
(R) -4- (1-hydroxybutyl) benzoic acid
Methyl (R) -4- (1-hydroxybutyl) benzoate 1d (600mg, 2.88mmol) was dissolved in 10mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1/1), and 1mL of lithium hydroxide monohydrate (104mg, 14.4mmol) was added to react at room temperature for 18 hours. The reaction solution was concentrated, adjusted to pH 5 with 1M hydrochloric acid, extracted with ethyl acetate (50mL), and the organic phase was washed with a saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (R) -4- (1-hydroxybutyl) benzoic acid 1e (560mg, white solid) in yield: 100 percent.
MS m/z(ESI)：194.9[M+1]
The fifth step
(R) -1- (4- (R) -1-hydroxybutyl) benzoylpiperidinyl) -3-carboxylic acid ethyl ester
(R) -4- (1-hydroxybutyl) benzoic acid 1e (194mg, 1.00mmol), (R) -piperidine-3-carboxylic acid ethyl ester 1f (157mg, 1.00mmol) and bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (254mg, 1.00mmol) were dissolved in 10mL of dichloromethane, N-diisopropylethylamine (0.89mL, 5.00mmol) was added, and the reaction mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate system) to give 1g (250mg, colorless oil) of (R) -1- (4- (R) -1-hydroxybutyl) benzoylpiperidinyl) -3-carboxylic acid ethyl ester, yield: 75.0 percent.
MS m/z(ESI)：334.0[M+1]
The sixth step
(R) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) benzoyl) piperidine-3-carboxylic acid ethyl ester
1g (200mg, 0.60mmol) of ethyl (R) -1- (4- (R) -1-hydroxybutyl) benzoylpiperidinyl) -3-carboxylate was dissolved in 10mL of tetrahydrofuran, diisopropyl azodicarboxylate (243mg, 1.20mmol) and triphenylphosphine (315mg, 1.20mmol) were added, then a solution of 3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenol in tetrahydrofuran was added for 1H (154mg, 0.60mmol), and the reaction solution was reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (elution machine: petroleum ether: ethyl acetate system) to give ethyl (R) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) benzoyl) piperidine-3-carboxylate 1i (320mg, colorless liquid), yield: 93.3 percent.
MS m/z(ESI)：571.9[M+1]
Seventh step
(R) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) benzoyl) piperidine-3-carboxylic acid
Ethyl (R) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) benzoyl) piperidine-3-carboxylate 1i (320mg, 0.56mmol) was dissolved in 10mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1/1), and 1mL of an aqueous solution of lithium hydroxide monohydrate (235mg, 5.60mmol) was added and reacted at room temperature for 18 hours. The reaction solution was concentrated, adjusted to pH 5 with 0.5M hydrochloric acid, extracted with ethyl acetate (100mL), and the organic phase was washed with a saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (R) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) benzoyl) piperidine-3-carboxylic acid 1(100mg, white solid) in yield: 32.9 percent
MS m/z(ESI)：543.9[M+1]
1H NMR(400MHz,CHLOROFORM-d)):δ8.03(s,1H),7.91(br.s.,1H),7.69(s,1H),7.42-7.28(m,4H),6.58(s,1H),5.17(br.s.,1H),4.57(br.s.,1H),2.97(s,3H),2.89(s,3H),2.76-2.61(m,1H),2.16-2.02(m,2H),1.86(br.s.,6H),1.56(br.s.,2H),1.47-1.38(m,1H),1.05-0.90(m,3H)
Example 2
(R) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) -2-fluorobenzoyl) piperidine-3-carboxylic acid
Figure BDA0000952278910000161
First step of
2-fluoro-4- (1-hydroxybutyl) benzoic acid methyl ester
Methyl 2-fluoro-4-formylbenzoate 2a (3.0g, 16.5mmol) was dissolved in 60mL tetrahydrofuran, and propylmagnesium bromide (8.6mL, 17.3mmol) was added slowly with stirring under nitrogen at-78 ℃ and allowed to react at room temperature for 2 hours. The reaction solution was cooled to 0 ℃, saturated ammonium chloride solution (30mL) was slowly added, extraction was performed with ethyl acetate (20mL × 3), the organic phase was dried over anhydrous sodium sulfate, and concentration was performed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate system) to obtain methyl 2-fluoro-4- (1-hydroxybutyl) benzoate 2b (850mg, colorless liquid), yield: 23.0 percent
1H NMR(400MHz,CDCl3):δ7.86(dd,J＝6.9,2.1Hz,1H),7.53–7.44(m,1H),7.09(dd,J＝10.3,8.7Hz,1H),4.74-4.63(m,1H),3.91(s,3H),2.18(s,1H),1.81-1.69(m,1H),1.64(ddd,J＝15.4,12.5,5.8Hz,1H),1.47-1.34(m,1H),1.33-1.22(m,1H),0.91(t,J＝7.4Hz,3H).
Second step of
2-fluoro-4-butyrylbenzoic acid methyl ester
Methyl 2-fluoro-4- (1-hydroxybutyl) benzoate 2b (850mg, 3.76mmol) was dissolved in 20mL of dichloromethane, and pyridine chlorochromate (970mg, 4.51mmol) was added thereto under an argon atmosphere at 0 ℃ to react at room temperature for 18 hours. After diluting with 200mL of dichloromethane, anhydrous sodium sulfate was added and the mixture was stirred for 10 minutes, the mixture was filtered and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate system) to obtain methyl 2-fluoro-4-butyrylbenzoate 2c (670mg, white solid) in yield: 80.0 percent
MS m/z(ESI)：224.9[M+1]
The third step
(R) -2-fluoro-4- (1-hydroxybutyl) benzoic acid methyl ester
borane-N, N-diethylaniline (0.88mL, 4.95mmol) was dissolved in 100mL tetrahydrofuran, and (S) -2-methyl-CBS-oxazaborolidine (0.25mL, 0.25mmol) was added and stirred at 0 ℃ for 3 minutes under argon protection, followed by dropwise addition of a solution of methyl 2-fluoro-4-butyrylbenzoate 2c (1.11g, 4.95mmol) in tetrahydrofuran (8mL) for 10 minutes, after which the reaction was continued for 20 minutes. After the reaction solution was cooled to 0 ℃, 0.6mL of methanol was slowly added to quench the reaction, and during the dropwise addition, bubbles were generated, 1M hydrochloric acid (6mL) was added, extraction was performed with petroleum ether (10mL × 4), the combined organic phases were washed with 1M hydrochloric acid (10mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (R) -2-fluoro-4- (1-hydroxybutyl) benzoic acid methyl 2d (1.12g, colorless liquid), yield: 100 percent
1H NMR(400MHz,CDCl3):δ7.86(dd,J＝6.9,2.1Hz,1H),7.53–7.44(m,1H),7.09(dd,J＝10.3,8.7Hz,1H),4.74–4.63(m,1H),3.91(s,3H),2.18(s,1H),1.81-1.69(m,1H),1.64(ddd,J＝15.4,12.5,5.8Hz,1H),1.47-1.34(m,1H),1.33-1.22(m,1H),0.91(t,J＝7.4Hz,3H).
The fourth step
(R) -2-fluoro-4- (1-hydroxybutyl) benzoic acid
Methyl (R) -2-fluoro-4- (1-hydroxybutyl) benzoate 2d (600mg, 2.65mmol) was dissolved in 10mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1/4), and 2.7mL of lithium hydroxide monohydrate (557mg, 13.25mmol) was added to the solution, followed by reaction at room temperature for 2 hours. The reaction was concentrated, adjusted to pH 2-3 with 1M hydrochloric acid, extracted with ethyl acetate (10mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (R) -2-fluoro-4- (1-hydroxybutyl) benzoic acid 2e (560mg, colorless liquid), yield: 99 percent
MS m/z(ESI)：212.9[M+1]
The fifth step
(R) -1- (2-fluoro-4- (R) -1-hydroxybutyl) benzoylpiperidinyl) -3-carboxylic acid ethyl ester
(R) -2-fluoro-4- (1-hydroxybutyl) benzoic acid 2e (150mg, 0.71mmol), (R) -piperidine-3-carboxylic acid ethyl ester 1f (142uL, 0.92mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (270mg, 1.06mmol) and N, N-diisopropylethylamine (0.50mL, 2.82mmol) were dissolved in 5mL of tetrahydrofuran, and the reaction mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate system) to give 2g (240mg, colorless liquid) of (R) -1- (2-fluoro-4- (R) -1-hydroxybutyl) benzoylpiperidinyl) -3-carboxylic acid ethyl ester, yield: 96.0 percent.
MS m/z(ESI)：352.0[M+1]
The sixth step
(R) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) -2-fluorobenzoyl) piperidine-3-carboxylic acid ethyl ester
2g (151mg, 0.43mmol) of ethyl (R) -1- (2-fluoro-4- (R) -1-hydroxybutyl) benzoylpiperidinyl) -3-carboxylate, 1H (100mg, 0.39mmol) of 3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenol and triphenylphosphine (204mg, 0.78mmol) were dissolved in 6mL of tetrahydrofuran, stirred for 3 minutes, diisopropyl azodicarboxylate (154uL, 0.78mmol) was added, and the reaction mixture was reacted at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate system) to give ethyl (R) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) -2-fluorobenzoyl) piperidine-3-carboxylate 2H (150mg, yellow liquid), yield: 65.0 percent.
MS m/z(ESI)：589.9[M+1]
Seventh step
(R) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) -2-fluorobenzoyl) piperidine-3-carboxylic acid
Ethyl (R) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) -2-fluorobenzoyl) piperidine-3-carboxylate 2H (150mg, 0.26mmol) and 0.26mL of an aqueous solution of lithium hydroxide monohydrate (55mg, 1.30mmol) were dissolved in 7mL of a mixed solvent of tetrahydrofuran and methanol (V/V. multidot. 2/5) and reacted at room temperature for 18 hours. The reaction solution was concentrated, adjusted pH 2-3 with 1M hydrochloric acid, extracted with ethyl acetate (8mL × 4), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (developing solvent: petroleum ether: ethyl acetate 1:2.5) to give (R) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) -2-fluorobenzoyl) piperidine-3-carboxylic acid 2(8mg, yellow solid) in yield: 6.0 percent
MS m/z(ESI)：561.9[M+1]
1H NMR(400MHz,DMSO):δ12.41(s,1H),8.55(s,1H),8.11(s,1H),7.47(d,J＝31.3Hz,2H),7.28(t,J＝8.7Hz,1H),6.78(s,2H),5.44(d,J＝5.3Hz,1H),3.26-3.09(m,2H),3.10-2.85(m,2H),1.96(ddd,J＝23.9,15.8,7.1Hz,3H),1.83(s,6H),1.65(ddd,J＝30.8,15.4,6.5Hz,3H),1.50–1.32(m,3H),0.91(dd,J＝12.4,6.9Hz,3H).
Example 3
(S) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) -2-fluorobenzoyl) piperidine-3-carboxylic acid
Figure BDA0000952278910000191
First step of
(S) -1- (2-fluoro-4- (R) -1-hydroxybutyl) benzoylpiperidinyl) -3-carboxylic acid ethyl ester
(R) -2-fluoro-4- (1-hydroxybutyl) benzoic acid 2e (150mg, 0.71mmol), (S) -piperidine-3-carboxylic acid ethyl ester 3a (142uL, 0.92mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (270mg, 1.06mmol) and N, N-diisopropylethylamine (0.50mL, 2.82mmol) were dissolved in 5mL of tetrahydrofuran, and the reaction mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developer: petroleum ether: ethyl acetate system) to give (S) -ethyl 1- (2-fluoro-4- (R) -1-hydroxybutyl) benzoylpiperidinyl) -3-carboxylate 3b (250mg, colorless liquid), yield: 99.0 percent.
MS m/z(ESI)：352.0[M+1]
Second step of
(S) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) -2-fluorobenzoyl) piperidine-3-carboxylic acid ethyl ester
Ethyl (S) -1- (2-fluoro-4- (R) -1-hydroxybutyl) benzoylpiperidinyl) -3-carboxylate 3b (83mg, 0.24mmol), 3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenol 1H (55mg, 0.21mmol) and triphenylphosphine (110mg, 0.42mmol) were dissolved in 5mL of tetrahydrofuran, stirred under argon for 3 minutes, diisopropyl azodicarboxylate (83uL, 0.42mmol) was added, and the reaction mixture was reacted at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developer: petroleum ether: ethyl acetate system) to give ethyl (S) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) -2-fluorobenzoyl) piperidine-3-carboxylate 3c (100mg, yellow liquid), yield: 81.0 percent.
MS m/z(ESI)：589.9[M+1]
The third step
(S) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) -2-fluorobenzoyl) piperidine-3-carboxylic acid
Ethyl (S) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) -2-fluorobenzoyl) piperidine-3-carboxylate 3c (100mg, 0.17mmol) and 0.17mL of an aqueous solution of lithium hydroxide monohydrate (37mg, 0.87mmol) were dissolved in 5.5mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 3/8) and reacted at room temperature for 18 hours. The reaction solution was concentrated, adjusted pH 2-3 with 1M hydrochloric acid, extracted with ethyl acetate (8mL × 4), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (developing solvent: petroleum ether: ethyl acetate 1:2.5) to give (S) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) -2-fluorobenzoyl) piperidine-3-carboxylic acid 3(8mg, yellow solid), yield: 10.0 percent
MS m/z(ESI)：561.9[M+1]
1H NMR(400MHz,DMSO):δ12.41(s,1H),8.55(s,1H),8.11(s,1H),7.51(s,2H),7.28(t,J＝8.7Hz,1H),6.78(s,2H),5.44(dd,J＝11.6,6.3Hz,1H),3.28-3.16(m,2H),3.15-2.92(m,2H),1.96(ddd,J＝23.1,14.6,6.1Hz,3H),1.83(s,6H),1.69(ddd,J＝43.4,23.9,10.5Hz,3H),1.51-1.34(m,3H),0.95-0.87(m,3H).
Example 4
2- ((R) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) benzoyl) -3-piperidinyl) acetic acid
Figure BDA0000952278910000201
First step of
(R) -1- (4- (R) -1-hydroxybutyl) benzoylpiperidinyl) -3-carboxylic acid ethyl ester
(R) -4- (1-hydroxybutyl) benzoic acid 1e (250mg, 1.29mmol), (R) -piperidine-3-acetic acid ethyl ester hydrochloride 4a (267mg, 1.29mmol) and bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (392mg, 1.54mmol) were dissolved in 15mL of dichloromethane, N-diisopropylethylamine (1.12mL, 6.44mmol) was added, and the reaction mixture was reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate system) to give (R) -1- (4- (R) -1-hydroxybutyl) benzoylpiperidinyl) -3-acetic acid ethyl ester 4b (300mg, colorless oil), yield: 67.1 percent.
MS m/z(ESI)：348.0[M+1]
Second step of
2- ((R) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) benzoyl) -3-piperidinyl) acetic acid ethyl ester
Ethyl (R) -1- (4- (R) -1-hydroxybutyl) benzoylpiperidinyl) -3-acetate 4b (300mg, 0.86mmol), 3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenol 1H (221mg, 0.86mmol) and triphenylphosphine (451mg, 1.72mmol) were dissolved in 30mL of tetrahydrofuran, diisopropyl azodicarboxylate (0.34mL, 1.72mmol) was added, and the reaction solution was reacted at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate system) to give ethyl 2- ((R) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) benzoyl) -3-piperidinyl) acetate 4c (276mg, white solid) in yield: 54.6 percent.
MS m/z(ESI)：586.0[M+1]
The third step
2- ((R) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) benzoyl) -3-piperidinyl) acetic acid
Ethyl 2- ((R) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) benzoyl) -3-piperidinyl) acetate 4c (276mg, 0.47mmol) was dissolved in 20mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1/1), and 1mL of an aqueous solution of lithium hydroxide monohydrate (196mg, 4.70mmol) was added and reacted at room temperature for 6 hours. Extraction with ethyl acetate (120mL) was added and the organic phase was washed with saturated ammonium chloride solution (100mL x2) and saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- ((R) -1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) benzoyl) -3-piperidinyl) acetic acid 4(220mg, white solid) yield: 84.0 percent
MS m/z(ESI)：558.0[M+1]
1H NMR(400MHz,CHLOROFORM-d):δ7.85(s,1H),7.70(br.s.,1H),7.32(br.s.,4H),6.75-6.41(m,2H),5.33-5.16(m,1H),4.71-4.52(m,1H),3.82-3.70(m,1H),2.75-2.40(m,1H),2.33-2.28(m,1H),2.01-1.70(m,11H),1.56-1.38(m,4H),1.31-1.18(m,2H),0.97-0.82(m,3H).
Example 5
1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) benzoyl) -5, 5-difluoropiperidine-3-carboxylic acid
Figure BDA0000952278910000221
First step of
(R) -Ethyl-5, 5-difluoro-1- (4- ((R) -1-hydroxyethyl) benzoyl) piperidine-3-carboxylic acid methyl ester
(R) -4- (1-hydroxybutyl) benzoic acid 1e (306mg, 1.57mmol), (R) -ethyl-5, 5-difluoropiperidine-3-carboxylic acid methyl ester 5a (282mg, 1.57mmol) and bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (798mg, 3.14mmol) were dissolved in 20mL of dichloromethane, N-diisopropylethylamine (2.73mL, 15.7mmol) was added, and the reaction mixture was reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate system) to give (R) -ethyl-5, 5-difluoro-1- (4- ((R) -1-hydroxyethyl) benzoyl) piperidine-3-carboxylic acid methyl ester 5b (500mg, colorless oil), yield: 89.2 percent.
MS m/z(ESI)：356.0[M+1]
Second step of
1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) benzoyl) -5, 5-difluoropiperidine-3-carboxylic acid methyl ester
Methyl (R) -ethyl-5, 5-difluoro-1- (4- ((R) -1-hydroxyethyl) benzoyl) piperidine-3-carboxylate 5b (250mg, 0.70mmol), 3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenol 1H (180mg, 0.70mmol) were dissolved in 15mL tetrahydrofuran, tri-n-butylphosphine (0.26mL, 1.05mmol) was added under argon protection, then a solution of diisopropyl azodicarboxylate (265mg, 1.05mmol) in 10mL tetrahydrofuran was slowly added, and the reaction was reacted at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (elution machine: petroleum ether: ethyl acetate system) to give methyl 1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) benzoyl) -5, 5-difluoropiperidine-3-carboxylate 5c (300mg, white solid) in yield: 71.8 percent.
MS m/z(ESI)：593.9[M+1]
The third step
1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) benzoyl) -5, 5-difluoropiperidine-3-carboxylic acid
Methyl 1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) benzoyl) -5, 5-difluoropiperidine-3-carboxylate 5c (418mg, 0.70mmol) was dissolved in 20mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 1/1), and 2mL of an aqueous solution of lithium hydroxide monohydrate (295mg, 7.00mmol) was added and reacted at room temperature for 3 hours. The reaction was added 120mL of ethyl acetate, washed successively with saturated ammonium chloride solution (100mL × 2) and saturated sodium chloride solution (100mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1- (4- ((S) -1- (3, 5-dimethyl-4- (4- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) butyl) benzoyl) -5, 5-difluoropiperidine-3-carboxylic acid 5(260mg, white solid) in yield: 63.7 percent
MS m/z(ESI)：579.9[M+1]
1H NMR(400MHz,DMSO-d6):δ12.84(s,1H),8.57(s,1H),8.12(s,1H),7.52(d,J＝7.78Hz,2H),7.41(d,J＝7.03Hz,2H),6.79(s,2H),5.47(t,J＝6.02Hz,1H),4.48(br.s.,1H),3.33(m,2H),2.77(br.s.,1H),2.89(s,1H),2.40(br.s.,1H),2.12-2.34(m,1H),1.88-2.02(m,1H),1.70-1.88(m,7H),1.28-1.54(m,2H),0.87-1.00(m,3H)
Biological evaluation
Test example 1 pharmacokinetic testing of preferred Compounds of the invention
1. Purpose of experiment
SD rats are used as test animals, and after the compounds in the example 1 are subjected to gastric lavage and are measured by an LC/MS/MS method, the drug concentrations in blood plasma of the rats at different moments are measured, and the pharmacokinetic characteristics of the compounds in the rats are researched.
2. Experimental protocol
2.1 Experimental drugs and animals
A compound of example 1;
healthy adult SD male rats 3 purchased from viton laboratory animal technology ltd, production license number: 11400700109943.
2.2 drug formulation and administration
Weighing a proper amount of experimental medicine, adding 1mL of ethanol, performing ultrasonic treatment to obtain a solution, adding 1.5mL of PEG400 and 2.5mL of water, and simultaneously performing vortex mixing to prepare 0.6 mg/mL;
healthy adult SD male rats 3 were individually gavaged after overnight fasting at a dose of 3 mg/kg.
2.3 sample Collection
The throat vein blood was collected at 0.15mL before and 15 min, 30 min, 1 hr, 2 hr, 4 hr, 8 hr, 12 hr and 24 hr after administration, placed in heparinized tubes, 5500 rpm, centrifuged for 10 min, stored at-30 deg.C, and fed 4 hr after administration.
2.4 sample treatment
Plasma sample processing (For plasma samples):
a20. mu.L sample was taken and IS (containing verapamil 5 ng. mL) was added-1And glibenclamide 50 ng/mL-1) And then 70. mu.L of the supernatant was added to 70. mu.L of water, and the mixture was vortex-mixed for 10 minutes, and 10. mu.L of the supernatant of the mixture was transferred to an LC-MS/MS system for analysis.
Dosing sample treatment (For dose sample):
the administration sample was diluted with a mixed solvent of methanol and water (1:1, v/v) to a concentration of 100 ng/mL-1100. mu.L of the diluted sample and 100. mu.L of an internal standard solution (100 ng. mL) were taken-1) Add 500. mu.L of IS solution and 600. mu.L of water, vortex mix and take the supernatant of 10. mu.L of the mixture to the LC-MS/MS system for analysis.
3. Pharmacokinetic parameter results
The pharmacokinetic parameters of preferred compounds of the invention are shown in table 1.
TABLE 1 pharmacokinetic data table for the compound of example 1
Figure BDA0000952278910000241
And (4) conclusion: the compound of the embodiment 1 of the invention has better pharmacokinetic advantage.
Test example 2 Effect of a Single oral administration of the Compound of the present invention on random blood glucose in db/db mice
1. Purpose of experiment
Observing the influence of the preferred compound of the invention on the random blood sugar of db/db mice with type II diabetes after single oral administration, adopting a tail blood sampling method, and measuring the blood sugar value by a portable glucometer so as to evaluate the in-vivo blood sugar reduction effect of the tested compound.
2. Experimental protocol
2.1 test animals
Male db/db mice, 100, 9-10 weeks, were provided by the university of Nanjing model animal institute, license number: SCXK (Su) 2010-0001, and a positive control group and a solvent control group are set.
2.2 test substances
Example 1, with ethanol: PEG 400: 20 parts of water: 30: 50 the required concentration is prepared.
2.3 modes of administration
Oral gavage was given, and the placebo group was filled with the same volume of ethanol: PEG 400: 20 parts of water: 30: 50, the administration volume is 10ml/kg, and the administration dose is 30 mg/kg.
2.4 test methods
Male db/db mice, grouped by non-fasting blood glucose and body weight, were 6 mice per group, solvent control and different compound dosing groups. The animals in each group are respectively orally administered with the tested drug and the solvent once, the tail blood sugar value detection is carried out respectively at 1h, 2h, 4h, 6h, 8h, 12h and 24h before and after the administration, the blood sugar reducing effect and the maintaining time of the tested object are observed, and a 24-hour blood sugar curve is drawn. The blood glucose modulating effect of the compounds was determined by comparison with blood glucose in db/db mice given vehicle control alone.
3. Results of the experiment
The blood glucose lowering rates of preferred compounds of the invention are shown in table 2.
TABLE 2 blood glucose drop rate Table of example 1
Figure BDA0000952278910000251
And (4) conclusion: the compound of the example 1 of the invention shows better hypoglycemic effect in 2 hours, 4 hours and 6 hours.
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 (5)

1. A compound, or a pharmaceutically acceptable salt thereof, wherein said compound is:
Figure FDA0002785998460000011
2. a pharmaceutical composition comprising an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
3. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 2 in the manufacture of a medicament for the treatment of type I diabetes, type II diabetes, obesity.
4. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 2, in the preparation of a glucagon receptor antagonist.
5. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 2 for the manufacture of a medicament for the treatment of hyperlipidemia, hypercholesterolemia, atherosclerosis.
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