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CN110117264B - Phenyl sulfone derivative and application thereof in medicines - Google Patents

Phenyl sulfone derivative and application thereof in medicines Download PDF

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CN110117264B
CN110117264B CN201810487243.0A CN201810487243A CN110117264B CN 110117264 B CN110117264 B CN 110117264B CN 201810487243 A CN201810487243 A CN 201810487243A CN 110117264 B CN110117264 B CN 110117264B
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phenyl
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CN110117264A (en
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钟文和
金传飞
陈康智
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Guangdong HEC Pharmaceutical
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    • A—HUMAN NECESSITIES
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    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

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Abstract

The invention discloses phenyl sulfone derivatives and application thereof in medicines, in particular to novel phenyl sulfone derivatives and a medicine composition containing the same. The invention also relates to methods for preparing such compounds and pharmaceutical compositions, and their use in the preparation of therapeutic and 5-HT 6 Use in medicine of receptor-related diseases, in particular Alzheimer's disease.

Description

Phenyl sulfone derivative and application thereof in medicines
Technical Field
The invention belongs to the field of medicines, and particularly relates to a compound for treating Alzheimer's disease, a pharmaceutical composition containing the compound, and application and a using method thereof. In particular, the compounds of the invention are useful as 5-HT 6 Phenylsulfone derivatives of receptor antagonists.
Background
Various Central Nervous System (CNS) disorders such as anxiety, depression, etc. and nervesThe transmitter 5-hydroxytryptamine (5-HT) is involved in disorders. 5-hydroxytryptamine (5-HT) acts as the major regulatory neurotransmitter in the brain, whose function is mediated through a large number of receptor families, including 5-HT 1 ，5-HT 2 ，5-HT 3 ，5-HT 4 ，5-HT 5 ，5-HT 6 And 5-HT 7 . Based on high levels of 5-HT in the brain 6 Receptors and studies thereof have been proposed to provide 5-HT 6 Receptors may play a role in the pathology and treatment of central nervous system disorders. In particular, 5-HT has been identified 6 Selective ligands have potential therapeutic effects on certain Central Nervous System (CNS) disorders, such as Parkinson's disease, huntington's disease, anxiety, depression, manic depression, psychosis, epilepsy, obsessive-compulsive disorders, migraine, alzheimer's disease, sleep disorders, eating disorders such as anorexia and bulimia, panic attacks, attention Deficit Hyperactivity Disorder (ADHD), attention Deficit Disorder (ADD), abuse of drugs such as cocaine, ethanol, nicotine and benzodiazepines
Figure BDA0001666881410000011
Class) and conditions associated with spinal trauma or head injury (e.g., hydrocephalus). Predicting said 5-HT 6 The selective ligands may also be useful in the treatment of certain gastrointestinal disorders (such as functional bowel disorders) (see, e.g., roth, B.L. et al, J.Pharmacol. Exp. Ther, 268, pages 1403-14120 (1994), sibley, D.R. et al, mol, pharmacol.,43, 320-327 (1993), A.J.Slight et al, neurotransmission,11,1-5 (1995) and Slight, A.J. et al, serotonin ID Research Alert,1997,2 (3), 115-8).
Research has found that 5-HT is involved in the processes of memory and cognition 6 The selective antagonist can significantly increase the level of glutamate and aspartate in the frontal cortex without increasing nor-nephrohormone, dopamine or 5-HT 6 Is a level of (c). This increased selectivity of specific neurochemicals strongly suggests 5-HT 6 The role of the ligand in cognition (Dawson, l.a.; nguyen, h.q.; li, p.; british Journal of Pharmacology,2000, 130 (1),23-26). Furthermore, people use selective 5-HT 6 Antagonists have studied animals' memory and learning and produced positive effects (Rogers, d.c.; latch, p.d.; hagan, j., society of Neuroscience, abstracts,2000, 26, 680). In addition, 5-HT 6 Antagonists increase the activity of the nigrostriatal dopamine pathway (Ernst, M; zametkin, a.j.; matochik, j.h.; jons, p.a.; cohen, r.m.; journal of Neuroscience,1998, 18 (5), 5901-5907), and thus 5-HT 6 The ligands have potential therapeutic uses for attention deficit disorders in children and adults. In addition, 5-HT 6 Antagonists may also be useful as potential compounds for the treatment of obesity (see, e.g., bentley et al, br. J. Pharmac.1999, journal 126; bentley et al, J. Psychopharmacol.1997, journal A64:255; wooley et al, neuropharmacology 2001, 41:210-129 and WO 02098878).
Disclosure of Invention
The present invention provides a class of compounds having 5-HT 6 The phenyl sulfone derivative with receptor antagonistic activity has better clinical application prospect. Compared with the existing similar compounds, the compound of the invention has the advantages of 5-HT 6 The receptor has a high affinity and exhibits high selectivity and antagonistic properties for this receptor, while having better potency, pharmacokinetic properties and/or toxicological properties, such as a good brain/plasma ratio (brain plasma ratio), good bioavailability, good metabolic stability or reduced inhibition of mitochondrial respiration.
The excellent properties of certain parameters of the compounds of the present invention, such as half-life, clearance, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, solubility, etc., can contribute to a reduction in side effects, an expansion of therapeutic index, or an improvement in tolerability, etc.
The present invention relates to novel phenylsulfone derivatives for the treatment of Alzheimer's disease and methods of treating Alzheimer's disease. The compounds of the present invention and pharmaceutical compositions comprising said compounds are useful for treating 5-HT 6 The receptor has better affinity effect, and particularly has better therapeutic effect on Alzheimer's disease.
In one aspect, the present invention relates to a compound which is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I),
Figure BDA0001666881410000021
Wherein each R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R m Q and M have the meanings as described in the present invention.
In one embodiment, Q is CH or N.
In one embodiment, M is-NR m -、-CH 2 -or-O-.
In one embodiment, R 1 Is C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkyl or halo C 1-6 An alkoxy group.
In one embodiment, R m H, D, C of a shape of H, D, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, C 3-8 Cycloalkyl or C 2-10 A heterocyclic group.
In one embodiment, R 2 、R 3 And R is 4 Each independently is H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 2-10 Heterocyclyl, C 6-10 Aryl or C 1-9 Heteroaryl groups.
In one embodiment, R 5 、R 6 、R 7 、R 8 And R is 9 Each independently is H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 2-10 Heterocyclyl, C 6-10 Aryl or C 1-9 Heteroaryl groups.
In one embodiment, R 1 Is C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-4 Alkyl or halo C 1-4 An alkoxy group.
In one embodiment, R m H, D, C of a shape of H, D, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl or C 3-8 A heterocyclic group.
In one embodiment, R 2 、R 3 And R is 4 Each independently is H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-8 Heterocyclyl, C 6-10 Aryl or C 1-9 Heteroaryl groups.
In one embodiment, R 5 、R 6 、R 7 、R 8 And R is 9 Each independently is H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-8 Heterocyclyl, C 6-10 Aryl or C 1-9 Heteroaryl groups.
In one embodiment, R 1 Is methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, -CHF 2 、-CF 3 、-CH 2 CF 3 、-CF 2 CHF 2 、-CHFCF 3 、-CF 2 CF 3 、-CH 2 CF 2 CF 3 、-CH 2 CF 2 CHF 2 、-OCHF 2 、-OCF 3 、-OCH 2 CF 3 、-OCF 2 CHF 2 、-OCHFCF 3 、-OCF 2 CF 3 、-OCH 2 CF 2 CF 3 、-OCH 2 CF 2 CHF 2 、-OCF 2 CH 2 CH 3 、-OCF 2 CH 2 CF 3 、-OCF 2 CH 2 CHF 2 、-OCH 2 CHFCH 3 or-OCH 2 CF 2 CH 3 。
In one embodiment, R m H, D is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl or tetrahydrofuranyl.
In one embodiment, R 2 、R 3 And R is 4 Each independently is H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NH 2 Methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, -CHF 2 、-CF 3 、-CH 2 CF 3 、-CF 2 CHF 2 、-CHFCF 3 、-CF 2 CF 3 、-CH 2 CF 2 CF 3 or-CH 2 CF 2 CHF 2 。
In one embodiment, R 5 、R 6 、R 7 、R 8 And R is 9 Each independently is H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NH 2 Methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, -CHF 2 、-CF 3 、-CH 2 CF 3 、-CF 2 CHF 2 、-CHFCF 3 、-CF 2 CF 3 、-CH 2 CF 2 CF 3 、-CH 2 CF 2 CHF 2 、-OCHF 2 、-OCF 3 、-OCH 2 CF 3 、-OCF 2 CHF 2 、-OCHFCF 3 、-OCF 2 CF 3 、-OCH 2 CF 2 CF 3 、-OCH 2 CF 2 CHF 2 、-OCF 2 CH 2 CH 3 、-OCF 2 CH 2 CF 3 、-OCF 2 CH 2 CHF 2 、-OCH 2 CHFCH 3 or-OCH 2 CF 2 CH 3 。
In one embodiment, the invention relates to a compound which is a stereoisomer, a geometric isomer, a tautomer, a nitroxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the structure of formula (II) or of the structure of formula (II),
Figure BDA0001666881410000031
each R is 1 、R 5 、R 6 、R 7 、R 8 And R is 9 Has the meaning as described in the present invention.
In one embodiment, the compounds of the invention are stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of a compound having one of the following structures:
Figure BDA0001666881410000032
Figure BDA0001666881410000041
Figure BDA0001666881410000051
in another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention.
In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.
In another embodiment, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent that is a drug for treating alzheimer's disease, a drug for treating a neurological disorder, or a combination thereof.
In yet another embodiment, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent which is donepezil (donepezil), nalmefene (nalmefene), risperidone (risperidone), vitamin E (Vitamin E), SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX-8066, SB-742457, naluzaton, lu-AE58054, tacrine (tacrine), rivastigmine (rivastigmine), galantamine (memantine), mirtazapine (Mirtazapine), venlafaxine (venlafaxine), desmoprene (desipramine), nortriptyline (nortriptyline), zolpidem (zolpidem), zopiclone (zoclone), nique (gehline), pyrine (granisethionine), or a combination thereof.
In a further aspect, the present invention relates to the use of a compound or a pharmaceutical composition according to the invention for the preparation of a medicament for the prevention, treatment or alleviation of 5-HT 6 Receptor-related diseases.
In one embodiment, the invention relates to a method of treating 5-HT 6 The receptor-related disease is a CNS disorder.
In one embodiment, the invention relates to a method of treating 5-HT 6 The receptor-associated CNS disorder is attention deficit hyperactivity disorder, anxiety, stress-related disorders, schizophrenia, obsessive-compulsive disorder, manic-depressive disorders, neurological disorders, memory disorders, attention deficit disorder, parkinson's disease, amyotrophic lateral sclerosis, alzheimer's disease or huntington's disease.
In another embodiment, the invention relates to a method of treating 5-HT 6 The receptor-related disease is gastrointestinal disorder。
In another embodiment, the invention relates to a method of treating 5-HT 6 The receptor-related disease is obesity.
The invention also encompasses the use of the compounds of the invention and pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical product for the treatment of Alzheimer's disease, as well as those conditions described herein. The compounds of the invention are also useful in the manufacture of a medicament for alleviating, preventing, controlling or treating 5-HT mediated disorders, particularly Alzheimer's disease. The present invention comprises pharmaceutical compositions comprising a therapeutically effective amount of a compound represented by formula (I) or (II) in combination with at least one pharmaceutically acceptable carrier, adjuvant or diluent.
Unless otherwise indicated, all suitable isotopic variations, stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are intended to be within the scope of the invention.
Unless otherwise indicated, the structural formulae described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R, S configuration containing asymmetric centers, the (Z), (E) isomers of double bonds, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the invention, or enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers) thereof, are all within the scope of the invention.
All tautomeric forms of the compounds of the invention are included within the scope of the invention unless otherwise indicated. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.
The disclosed compounds may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention is intended to encompass all stereoisomeric forms of the compounds of formula (I) or (II), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, as well as mixtures thereof, such as racemic mixtures, as part of the present invention.
In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers of that structure are contemplated as being within the present invention and are included as presently disclosed compounds. When stereochemistry is indicated by the solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of that structure are so defined and defined.
Nitrogen oxides of the compounds of the present invention are also included within the scope of the present invention. The nitrogen oxides of the compounds of the invention may be prepared by oxidizing the corresponding nitrogen-containing basic species at elevated temperatures using customary oxidizing agents, such as hydrogen peroxide, in the presence of an acid such as acetic acid, or by reaction with peracetic acid in a suitable solvent, such as dichloromethane, ethyl acetate or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.
In another aspect, the present invention relates to intermediates for preparing compounds of formula (I) or formula (II).
In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I) or formula (II).
The compounds of formula (I) or (II) may be present in the form of salts. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith.
If the compounds of the present invention are basic, the desired salts may be prepared by any suitable method provided in the literature, for example, using mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Or organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; pyranose acids, such as glucuronic acid and galacturonic acid; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, ethanesulfonic acid, and the like.
If the compounds of the invention are acidic, the desired salts can be prepared by suitable methods, for example, using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali or alkaline earth metal hydroxides, and the like. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary, and cyclic ammonia such as piperidine, morpholine and piperazine, and the like, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
Any of the embodiments of any of the aspects of the invention may be combined with other embodiments, provided that they do not contradict. Furthermore, in any of the embodiments of any of the aspects of the present invention, any technical feature may be applied to the technical feature in other embodiments as long as they do not contradict.
The foregoing merely outlines certain aspects of the invention and is not limited in this regard. These and other aspects are described more fully below. All references in this specification are incorporated herein by reference in their entirety.
Detailed description of the invention
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event of one or more of the incorporated references, patents and similar materials differing from or contradictory to the present application (including but not limited to defined terms, term application, described techniques, etc.), the present application controls.
It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, chemical elements are in accordance with CAS version of the periodic Table of the elements, and handbook of chemistry and physics, 75 th edition, 1994. In addition, general principles of organic chemistry may be referenced to the descriptions in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato:1999, and "March's Advanced Organic Chemistry" by Michael b.smith and Jerry March, john Wiley & Sons, new york:2007, the entire contents of which are incorporated herein by reference.
The articles "a," "an," and "the" are intended to include "at least one" or "one or more" unless the context clearly dictates otherwise or otherwise. Thus, as used herein, these articles refer to one or to more than one (i.e., to at least one) object. For example, "a component" refers to one or more components, i.e., more than one component is contemplated as being employed or used in embodiments of the described embodiments.
The term "subject" as used herein refers to an animal. Typically the animal is a mammal. The subject, for example, also refers to a primate (e.g., human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
The term "patient" as used herein refers to a human (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects.
The term "stereoisomer" refers to a compound having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
The term "chiral" is a molecule that has properties that do not overlap with its mirror image; and "achiral" refers to a molecule that may overlap with its mirror image.
The term "enantiomer" refers to two isomers of a compound that do not overlap but are in mirror image relationship to each other.
The term "racemate" or "racemic mixture" refers to an equimolar mixture of two enantiomers lacking optical activity.
The term "diastereoisomer" refers to a stereoisomer that has two or more chiralities and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. The diastereomeric mixture may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
The stereochemical definitions and rules used in the present invention generally follow S.P. Parker, ed., mcGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, new York; and Eliel, E.and Wilen, S, "Stereochemistry of Organic Compounds", john Wiley & Sons, inc., new York,1994. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to represent the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light by a compound, where (-) or l indicates that the compound is left-handed. The compound prefixed with (+) or d is dextrorotatory. One particular stereoisomer is an enantiomer, and a mixture of such isomers is referred to as an enantiomeric mixture. A50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
Any asymmetric atom (e.g., carbon, etc.) of the disclosed compounds may exist in racemic or enantiomerically enriched form, such as in the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
Depending on the choice of starting materials and methods, the compounds of the invention may be present in the form of one of the possible isomers or mixtures thereof, for example racemates and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.
The resulting mixture of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, e.g., by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.
Any of the resulting racemates of the end products or intermediates can be resolved into the optical enantiomers by methods familiar to those skilled in the art, e.g., by separation of the diastereoisomeric salts thereof obtained, using known methods. The racemic product can also be separated by chiral chromatography, e.g., using chiral adsorbentsHigh Performance Liquid Chromatography (HPLC). In particular, enantiomers may be prepared by asymmetric synthesis, for example, reference may be made to Jacques, et al, encomers, racemates and Resolutions (Wiley Interscience, new York, 1981); principles of Asymmetric Synthesis (2) nd Ed.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be interconverted by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers (prototropic tautomer)) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers (valance tautomers) include interconversions by recombination of some of the bond-forming electrons. Specific examples of keto-enol tautomerism are tautomerism of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
The term "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optional bond" means that the bond may or may not be present, and that the description includes single, double, or triple bonds.
The term "unsaturated" or "unsaturated" means that the moiety contains one or more unsaturations.
The compounds of the invention may be optionally substituted with one or more substituents, as described in the present invention, such as the compounds of the general formula above, or as specific examples within the examples, subclasses, and classes of compounds encompassed by the invention. It is to be understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a specific substituent. An optional substituent group may be substituted at each substitutable position of the group unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position. Wherein the substituents may be, but are not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, azido, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo (=o), carboxyl, haloalkyl, haloalkoxy, hydroxyl-substituted alkyl, hydroxyl-substituted haloalkyl, hydroxyl-substituted alkoxy, and the like.
In addition, unless explicitly indicated otherwise, the descriptions used in this disclosure of the manner in which each … is independently "and" … is independently "and" … is independently "are to be construed broadly as meaning that particular items expressed between the same symbols in different groups do not affect each other, or that particular items expressed between the same symbols in the same groups do not affect each other.
In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C 1-6 Alkyl "means in particular methyl, ethyl, C independently disclosed 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 An alkyl group.
In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" or "aryl" group, it will be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.
The term "alkyl" or "alkyl group" as used herein means a saturated, straight or branched, monovalent hydrocarbon group containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1 to 20 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ) Ethyl (Et, -CH) 2 CH 3 ) N-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Isopropyl (i-Pr, -CH (CH) 3 ) 2 ) N-butyl (n-Bu, -CH) 2 CH 2 CH 2 CH 3 ) Isobutyl (i-Bu, -CH) 2 CH(CH 3 ) 2 ) Sec-butyl (s-Bu, -CH (CH) 3 )CH 2 CH 3 ) Tert-butyl (t-Bu, -C (CH) 3 ) 3 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) N-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 ) N-heptyl, n-octyl, and the like.
The term "alkylene" means a saturated divalent hydrocarbon group resulting from the removal of two hydrogen atoms from a saturated straight or branched hydrocarbon group. Unless otherwise specified, alkylene groups contain 1 to 12 carbon atoms. In one embodiment, the alkylene group contains 1 to 6 carbon atoms; in another embodiment, the alkylene group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 3 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 2 carbon atoms. Examples of this include methylene (-CH) 2 (-), ethylene (-CH) 2 CH 2 (-), isopropylidene (-CH (CH) 3 )CH 2 (-), etc. The alkylene group is optionally substituted with one or more substituents described herein.
The term "alkenyl" denotes a straight-chain or branched monovalent hydrocarbon radical containing 2 to 12 carbon atoms, in which there is at least one site of unsaturation, i.e. one carbon-carbon sp 2 Double bonds, wherein the alkenyl groups are optionally substituted with one or more substituents described herein, including "cis" and "tans" Or "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group comprises 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-ch=ch) 2 ) Allyl (-CH) 2 CH＝CH 2 ) And so on.
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing from 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp triple bond, wherein the alkynyl group is optionally substituted with one or more substituents as described herein. In one embodiment, the alkynyl group contains 2 to 8 carbon atoms; in another embodiment, the alkynyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH) 2 C.ident.CH), 1-propynyl (-C.ident.C-CH) 3 ) And so on.
The term "H" denotes a single hydrogen atom. Such radicals may be attached to other groups, such as to an oxygen atom, to form a hydroxyl group.
The term "heteroatom" means one or more of oxygen (O), sulfur (S), nitrogen (N), phosphorus (P) or silicon (Si), including any oxidation state forms of nitrogen (N), sulfur (S) and phosphorus (P); primary, secondary, tertiary and quaternary ammonium salt forms; or a form in which the hydrogen on the nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).
The terms "halogen" and "halo" refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
The term "haloalkyl", "haloalkenyl" or "haloalkoxy" means an alkyl, alkenyl or alkoxy group substituted with one or more halogen atoms, wherein the alkyl, alkenyl or alkoxy group has the meaning described herein, examples of which include, but are not limited to, difluoromethyl, trifluoromethyl, trifluoromethoxy, 2-trifluoroethoxy, 2, 3-tetrafluoropropoxy, and the like. The haloalkyl, haloalkenyl or haloalkoxy groups are optionally substituted with one or more substituents described herein.
The term "alkoxy" means that the alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy groups are optionally substituted with one or more substituents described herein.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) 3 ) Ethoxy (EtO, -OCH) 2 CH 3 ) 1-propoxy (n-PrO, n-propoxy, -OCH) 2 CH 2 CH 3 ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) 3 ) 2 ) 1-butoxy (n-BuO, n-butoxy, -OCH) 2 CH 2 CH 2 CH 3 ) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH) 2 CH(CH 3 ) 2 ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ) 1-pentoxy (n-pentoxy, -OCH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentoxy (-OCH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentoxy (-OCH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butoxy (-OC (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butoxy (-OCH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-l-butoxy (-OCH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-l-butoxy (-OCH) 2 CH(CH 3 )CH 2 CH 3 ) And so on.
The term "n atoms" where n is an integer, typically describes the number of ring-forming atoms in a molecule where the number of ring-forming atoms is n. For example, piperidinyl is a 6-atom-composed heterocyclyl group, while 1,2,3, 4-tetrahydronaphthalene is a 10-atom-composed cycloalkyl group.
The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. Bicyclic or tricyclic ring systems may include fused rings, bridged rings, and spiro rings. In one embodiment, cycloalkyl groups contain 3 to 10 carbon atoms; in another embodiment, cycloalkyl groups contain 3 to 8 carbon atoms; in yet another embodiment, cycloalkyl groups contain 3 to 6 carbon atoms. The cycloalkyl group is optionally substituted with one or more substituents described herein.
The term "heterocyclyl" or "heterocycle" is used interchangeably herein to refer to a monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms in which one or more atoms in the ring are independently replaced by heteroatoms having the meaning as described herein, which rings may be fully saturated or contain one or more unsaturations, but none of the aromatic rings. In one embodiment, the heterocyclyl group is a monocyclic ring of 3-8 membered rings (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give a ring like SO, SO 2 ，PO，PO 2 Where the ring is a three-membered ring, in which there is only one heteroatom), or a 7-to 12-membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give a ring of formula SO, SO 2 ，PO，PO 2 Is a group of (2). The heterocyclyl group is optionally substituted with one or more substituents described herein.
The ring atoms of the heterocyclic groups may be carbon groups or heteroatom groups. Wherein, is a ring-CH 2 The group is optionally replaced by-C (=o) -the sulphur atom of the ring is optionally oxidized to S-oxide and the nitrogen atom of the ring is optionally oxidized to N-oxide. Examples of heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazole A group selected from the group consisting of a pyrazolyl group, an imidazolinyl group, an imidazolidinyl group, a tetrahydrofuranyl group, a dihydrofuranyl group, a tetrahydrothienyl group, a dihydrothienyl group, a 1, 3-dioxacyclopentyl group, a dithiocyclopentyl group, a tetrahydropyranyl group, a dihydropyranyl group, a 2H-pyranyl group, a 4H-pyranyl group, a tetrahydrothiopyranyl group, a piperidinyl group, a morpholinyl group, a thiomorpholinyl group, a piperazinyl group, a dioxanyl group, a dithianyl group, a thiazanyl group, a homopiperazinyl group, a homopiperidinyl group, an oxepinyl group, a thiepinyl group, and an oxazanyl group
Figure BDA0001666881410000111
Radical, diaza->
Figure BDA0001666881410000112
Radical, thiazal->
Figure BDA0001666881410000113
Radical, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl, and the like. In heterocyclic groups-CH 2 Examples of the substitution of the-group by-C (=o) -include, but are not limited to, 2-oxo-pyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidonyl, 3, 5-dioxopiperidyl, pyrimidinedionyl, and the like. Examples of sulfur atoms in the heterocyclyl group that are oxidized include, but are not limited to, sulfolane, thiomorpholino 1, 1-dioxide, and the like. The heterocyclyl group is optionally substituted with one or more substituents described herein.
The term "aryl" or "aromatic ring" means a monocyclic, bicyclic, and tricyclic carbocyclic ring system containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 atoms of a ring. The aryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the aryl group. The term "aryl" may be used interchangeably with the term "aromatic ring" or "aromatic ring". Examples of aryl groups may include phenyl, naphthyl, and anthracene. The aryl group is optionally substituted with one or more substituents described herein.
The term "heteroaryl" or "heteroaromatic ring" means monocyclic, bicyclic, and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms. Heteroaryl groups are typically, but not necessarily, attached to the parent molecule through an aromatic ring of the heteroaryl group. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "aromatic heterocycle" or "heteroaromatic. The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the heteroaryl group of 5 to 10 atoms comprises 1,2,3 or 4 heteroatoms independently selected from O, S and N.
Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1, 3-dithiotriazinyl, 1, 3-dithio, 3-triazolyl, 1, 3-triazolyl; the following bicyclic rings are also included, but are in no way limited to: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), imidazo [1,2-a ] pyridinyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridinyl, and the like.
The term "prodrug" as used herein, means a compound that is converted in vivo intoA compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue. The prodrug of the invention can be ester, and in the prior invention, the ester can be phenyl ester, aliphatic (C 1-24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, one compound of the invention may contain a hydroxyl group, i.e., it may be acylated to provide the compound in a prodrug form. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following documents: higuchi et al, pro-drugs as Novel Delivery Systems, vol.14, A.C.S. symposium Series; roche et al ed., bioreversible Carriers in Drug Design, american Pharmaceutical Association and Pergamon Press,1987; rautio et al, prodrugs Design and Clinical Applications, nature Reviews Drug Discovery,2008,7,255-270,and Hecker et al,Prodrugs of Phosphates and Phosphonates,J.Med.Chem, 2008,51,2328-2345, each of which is incorporated herein by reference.
The term "metabolite" as used herein refers to a product obtained by metabolizing a specific compound or salt thereof in vivo. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.
As used herein, "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as in the literature: s.m. berge et al, j.pharmaceutical Sciences,66:1-19,1977. Pharmaceutically acceptable salts includeSalts of the compounds with acids, including, but not limited to, inorganic acid salts (e.g., hydrochloride, hydrobromide, phosphate, sulfate, nitrate, perchlorate) and organic acid salts (e.g., acetate, glycolate, oxalate, maleate, tartrate, citrate, succinate, fumarate, mandelate, sulfosalicylate), or by other methods described in the literature such as ion exchange. Further pharmaceutically acceptable salts include adipic acid salts, alginates, ascorbates, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoronate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodidate, 2-hydroxy-ethanesulfonate, lactobionic aldehyde, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts also include salts of the compounds with bases including, but not limited to, inorganic base salts (e.g., alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4 Alkyl group 4 Salts), alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. The water-soluble or oil-soluble or dispersible product may be obtained by quaternization. The pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and counter-ion forming amine cations, such as halides, hydroxides, carboxylates, sulphates, phosphates, nitrates, C 1-8 Sulfonate and aromatic sulfonate. Organic base salts (e.g., primary, secondary and tertiary amine salts, substituted amines (including naturally occurring substituted amines, cyclic amines, basic ion exchange resins) salts), some of which areThe organic amine salts include, for example, isopropylamine salt, benzathine (benzathine) salt, choline salt (choline), diethanolamine salt, diethylamine salt, lysine salt, meglumine (meglumine) salt, piperazine salt and tromethamine salt.
"solvate" according to the present invention refers to an association of one or more solvent molecules with a compound according to the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules that are water.
When the solvent is water, the term "hydrate" may be used. In one embodiment, a molecule of a compound of the invention may be associated with a water molecule, such as a monohydrate; in another embodiment, one molecule of the present compounds may be bound to more than one water molecule, such as a dihydrate, and in yet another embodiment, one molecule of the present compounds may be bound to less than one water molecule, such as a hemihydrate. It should be noted that the hydrates described in the present invention retain the biological effectiveness of the compounds in a non-hydrated form.
The term "protecting group" or "PG" refers to a substituent that is commonly used to block or protect a particular functionality when reacted with other functional groups. For example, by "protecting group for an amino group" is meant a substituent attached to the amino group to block or protect the functionality of the amino group in the compound, suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality that a substituent of a hydroxy group serves to block or protect the hydroxy group, and suitable protecting groups include trialkylsilyl, acetyl, benzoyl and benzyl. "carboxyl protecting group" refers to the functionality of a substituent of a carboxyl group to block or protect the carboxyl group, and typically the carboxyl protecting group includes-CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2-P-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General description of protecting groups can be found in the literature: greene et al Protective Groups in Organic Synthesis, john Wiley&Sons,New York,1991and Kocienski et al.,Protecting Groups,Thieme,Stuttgart,2005。
The term "treating" as used herein refers in some embodiments to ameliorating a disease or disorder (i.e., slowing or preventing or alleviating the progression of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or disorder physically (e.g., stabilizing a perceived symptom) or physiologically (e.g., stabilizing a parameter of the body) or both. In other embodiments, "treating" refers to preventing or delaying the onset, or exacerbation of a disease or disorder.
The term "preventing" or "prevention" refers to a reduction in the risk of acquiring a disease or disorder (i.e., stopping the progression of at least one clinical symptom of a disease in a subject who may or may not have been predisposed to facing such a disease, but who has not yet experienced or exhibited symptoms of the disease).
The term "CNS" is an abbreviation for Central nervous system, meaning the central nervous system. CNS disorders refer to disorders of the central nervous system. The central nervous system is composed of the brain and spinal cord (brain and spinal cord are central parts of various reflex arcs) and is the most main part of the human nervous system.
The term "ADHD" is an abbreviation for Attention-deficit-deficit hyperactivity disorder, meaning Attention-deficit hyperactivity disorder, a mental disorder that is very common in childhood. According to the tenth edition of the world general disease Classification handbook (ICD-10, WHO, 1992) of the world health organization, this disorder is called "hyperactive disorder" (Hyperkinetic Disorder), and the classification number is F90, which is commonly known as "overactive child".
The term "schizophrenia" refers to schizophrenia, schizophreniform disorders, schizoaffective disorders, and psychotic disorders, wherein the term "psychosis" refers to delusions, overt hallucinations, unorganized language or unorganized behavior, or rigidity behavior. See Diagnostic and Statistical Manual of Mental Disorder, fourth edition, american Psychiatric Association, washington, d.c.
Pharmaceutically acceptable acid addition salts may be formed by the reaction of a compound of the invention with an inorganic or organic acid and pharmaceutically acceptable base addition salts may be formed by the reaction of a compound of the invention with an inorganic or organic base. Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound, basic or acidic moiety using conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g., na, ca, mg or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or an organic solvent or a mixture of both. Generally, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile where appropriate. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, mack Publishing Company, easton, pa., (1985); and "manual of pharmaceutically acceptable salts: a list of further suitable salts can be found in Properties, selection and application (Handbook of Pharmaceutical Salts: properties, selection, and Use) ", stahl and Wermuth (Wiley-VCH, weinheim, germany, 2002).
In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents (e.g., ethanol, DMSO, etc.) containing them, for their crystallization. The disclosed compounds may form solvates inherently or by design with pharmaceutically acceptable solvents (including water); accordingly, the present invention is intended to include solvated and unsolvated forms.
Any formulae given herein are also intended to represent non-isotopically enriched forms as well as isotopically enriched forms of such compounds. Isotopically enriched compounds have structures depicted by the general formulae given herein except that one or more atoms areAtomic substitutions having a selected atomic weight or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H， 3 H， 11 C， 13 C， 14 C， 15 N， 17 O， 18 O， 18 F， 31 P， 32 P， 35 S， 36 Cl and Cl 125 I。
In another aspect, the compounds of the invention include isotopically enriched compounds defined in the invention, e.g., wherein a radioisotope, such as 3 H， 14 C and C 18 F, or in which non-radioactive isotopes are present, e.g 2 H and 13 C. such isotopically enriched compounds are useful in metabolic studies (using 14 C) Reaction kinetics studies (using, for example 2 H or 3 H) Detection or imaging techniques, such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution assays, or may be used in radiation therapy of a patient. 18 F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) or (II) can be prepared by conventional techniques familiar to those skilled in the art or by describing the examples and processes of preparation in the present invention using a suitable isotopically labeling reagent in place of the originally used unlabeled reagent.
In addition, heavier isotopes are in particular deuterium (i.e., 2 substitution of H or D) may provide certain therapeutic advantages, which are brought about by a higher metabolic stability. For example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is to be understood that deuterium in the context of the present invention is considered as a substituent for the compounds of formula (I) or (II). The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. The term "isotopically enriched factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent of a compound of the present invention is designated as deuterium, the compound is substituted for each designated deuterium atom Having an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation at each named deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those wherein the crystallization solvent may be isotopically substituted, e.g. D 2 O, acetone-d 6 、DMSO-d 6 Those solvates of (a).
Compounds of the invention and pharmaceutical compositions, formulations and administration
When useful in therapy, a therapeutically effective amount of the compounds of formulas (I) through (II) and pharmaceutically acceptable salts thereof may be administered as raw chemicals, as well as the active ingredient of a pharmaceutical composition. Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of formulae (I) to (II) or individual stereoisomers, racemic or non-racemic mixtures of isomers or pharmaceutically acceptable salts or solvates thereof. In one embodiment of the invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant, or vehicle, and optionally, other therapeutic and/or prophylactic ingredients.
Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail in, for example, ansel h.c. et al, ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, williams & Wilkins, philiadelphia; gennaro a.r.et al, remington: the Science and Practice of Pharmacy (2000) Lippincott, williams & Wilkins, philadelphia; and Rowe R.C., handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, chicago.
Methods of treatment comprising the administration of a compound or pharmaceutical composition of the invention further comprise administering to the patient an additional anti-Alzheimer's agent (combination therapy), wherein the additional anti-Alzheimer's agent is donepezil, nalmefene, risperidone, vitamin E, SAM-760, AVN-211, AVN-101, RP-5063, tozadant, PRX-3140, PRX-8066, SB-742457, naluzaton, lu-AE58054, tacrine, cabazitaxel, galantamine, memantine, mirtazapine, venlafaxine, desipramine, zolpidem, zopiclone, nicergoline, piracetam, selegiline, hexanone, or a combination thereof.
The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to exhibit a meaningful patient benefit. When separate active ingredients are used for separate administration, the term refers only to the ingredient. When applied in combination, the term refers to the combined amounts of the active ingredients that result in a therapeutic effect, whether administered in combination, sequentially or simultaneously. The compounds of formulae (I) to (II) and their pharmaceutically acceptable salts are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. According to another aspect of the present disclosure, there is also provided a process for preparing a pharmaceutical formulation, which comprises mixing a compound of formulae (I) to (II), or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for use in the intended use.
In general, the compounds of the present invention are administered in therapeutically effective amounts by any conventional manner of administration for substances that exert similar effects. Suitable dosage ranges are typically 1-500mg per day, preferably 1-100mg per day, most preferably 1-30mg per day, depending on a variety of factors, such as the severity of the disease being treated, the age and relative health of the subject being administered, the potency of the compound used, the route and form of administration, the indication for which administration is aimed, and the preferences and experience of the relevant medical practitioner. One of ordinary skill in the art of treating such diseases will be able to determine, without undue experimentation and by virtue of personal knowledge and the disclosure of this application, a therapeutically effective amount of a compound of the present invention for a given disease.
Typically, the compounds of the invention are administered in the form of pharmaceutical preparations, including those suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or for inhalation or insufflation administration. The preferred mode of administration is generally oral, which can be adjusted according to the degree of pain using a suitable daily dosage regimen.
One or more compounds of the present invention may be placed in pharmaceutical compositions and unit dosage forms together with one or more conventional adjuvants, carriers or diluents. The pharmaceutical compositions and unit dosage forms may contain conventional ingredients in conventional proportions, with or without additional active compounds or ingredients, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range for which it is to be used. The pharmaceutical compositions may be in the form of a solid such as a tablet or filled capsule, a semi-solid, a powder, a slow release formulation, or a liquid such as a solution, suspension, emulsion, elixir, or filled capsule for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of a sterile injectable solution for parenteral use. Thus, formulations containing about 1mg of active ingredient per tablet or more broadly, containing about 0.01 to about 100mg of active ingredient are suitable representative unit dosage forms.
The compounds of the present invention may be formulated in a variety of dosage forms for oral administration. Pharmaceutical compositions and dosage forms may comprise one or more compounds of the invention or pharmaceutically acceptable salts thereof as active ingredient. The pharmaceutically acceptable carrier may be a solid or a liquid. The solid form formulation comprises: powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier may be one or more substances which may also be used as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is typically a finely divided solid which forms a mixture with the finely divided active ingredient. In tablets, the active ingredient is usually mixed with a carrier having the necessary binding capacity in the appropriate proportions and compacted in the shape and size desired. Powders and tablets preferably contain from about 1% to about 70% of the active compound. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "formulation" is intended to include formulations of the active compound which contain the encapsulating material as a carrier to provide a capsule in which the active ingredient, with or without the carrier, is surrounded by the carrier in association therewith. Similarly, cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges are all solid forms suitable for oral administration.
Other forms suitable for oral administration include liquid form preparations (including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions) or solid form preparations intended to be converted to liquid form preparations immediately prior to use. The emulsion may be prepared in a solution such as an aqueous propylene glycol solution or may contain an emulsifier such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickeners. Aqueous suspensions can be prepared by dispersing the finely divided active ingredient in water with viscous substances such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well known suspending agents. Formulations in liquid form include solutions, suspensions and emulsions which may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The compounds of the invention may be formulated for parenteral administration (e.g., by injection such as bolus injection or continuous infusion) and may be presented in unit dosage form in ampoules, pre-filled syringes, small volume infusion solutions or in multi-dose containers with added preservative. The compositions may take the form of suspensions, solutions or emulsions, for example in oily or aqueous vehicles, such as solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g. olive oil) and injectable organic esters (e.g. ethyl oleate), and may contain formulatory substances such as preserving, wetting, emulsifying or suspending agents, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form obtained by sterile packaging of sterile solid or by lyophilizing the solution for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
The compounds of the invention may be formulated for topical application to the epidermis in the form of ointments, creams or lotions or in the form of transdermal patches. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, typically sucrose and acacia or tragacanth; lozenges comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
The compounds of the present invention may be formulated for administration in the form of suppositories. The low melting wax, such as a fatty acid glyceride mixture or cocoa butter, may first be melted and the active ingredient dispersed uniformly, for example by stirring. The molten homogeneous mixture is then poured into a mold of suitable size, allowed to cool and solidify.
The compounds of the invention may be formulated for vaginal administration. Pessaries, tampons, creamers, gels, pastes, foams or sprays containing in addition to the active ingredient a carrier known in the art are suitable.
The compounds of the invention may be formulated for nasal administration. Solutions or suspensions may be applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or nebulizer. The formulation may be in single or multiple dose form. For multi-dose forms of droppers or pipettes, this may be achieved by administering a suitable, predetermined volume of solution or suspension to the patient. For a nebulizer this may be achieved, for example, by a metered atomizing spray pump.
The compounds of the invention may be formulated for aerosol administration, particularly for administration to the respiratory tract and include intranasal administration. The compounds typically have a small particle size, for example on the order of 5 microns or less. The particle size may be obtained by methods known in the art, for example by micronization. The active ingredient is provided in a pressurized package containing a suitable propellant such as a chlorofluorocarbon (CFC) such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane or carbon dioxide or other suitable gas. The aerosol may also suitably contain a surfactant such as lecithin. The dosage of the drug may be controlled by a metering valve. Alternatively, the active ingredient may be provided in the form of a dry powder, for example as a powder mixture of the compounds in a suitable powder matrix such as lactose, starch derivatives such as hydroxypropyl methylcellulose and polyvinylpyrrolidone. The powder carrier will form a gel in the nasal cavity. The powder composition may be present in unit dosage form, for example in the form of a gelatin capsule or cartridge or blister pack from which the powder may be administered by an inhaler.
If desired, the formulations may be prepared with enteric coatings suitable for slow or controlled release administration of the active ingredient. For example, the compounds of the invention may be formulated as transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when it is necessary to slow the release of the compound and when patient compliance with the treatment regimen is critical. Compounds in transdermal delivery systems are often attached to a skin adherent solid carrier. The compounds of interest may also be used in combination with permeation enhancers, such as laurocapram (1-dodecylazepan-2-one). The sustained release delivery system may be inserted subcutaneously into the subcutaneous layer by surgery or injection. Subcutaneous implants encapsulate the compound in a liquid soluble film, such as silicone rubber, or a biodegradable polymer, such as polylactic acid.
The pharmaceutical formulation is preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form may be a packaged formulation containing discrete amounts of the formulation, such as packaged tablets, capsules and powders in vials or ampoules. In addition, the unit dosage form may be a capsule, tablet, cachet, or lozenge itself, or it may be the appropriate number of any of these forms in a packaged unit form.
Other suitable pharmaceutically acceptable carriers and their formulations are described in Remington: the Science and Practice of Pharmacy 1995Martin, E.W. edit Mack Publishing Company, 19 th edition, easton, pennsylvania.
Use of the compounds and pharmaceutical compositions of the invention
The compound and the pharmaceutical composition provided by the invention can be used for preparing medicines for preventing, treating or relieving Alzheimer's disease, and also can be used for preparing medicines for preventing, treating or relieving Alzheimer's disease and 5-HT 6 Medicines for receptor-related diseases.
The pharmaceutical compositions of the present invention are characterized by comprising a compound represented by the formulae (I) to (II) or a compound listed in the present invention, and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of compound in the pharmaceutical compositions of the invention is effective to detectably antagonize 5-HT 6 Receptors are used to treat obesity, gastrointestinal disorders, CNS disorders, wherein the CNS disorders are ADHD, anxiety, stress-related disorders, schizophrenia, obsessive-compulsive disorders, manic-depressive disorders, neurological disorders, memory disorders, attention deficit disorders, parkinson's disease, amyotrophic lateral sclerosis, alzheimer's disease and huntington's disease, and the like.
An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the invention refers to an amount effective to treat or reduce the severity of one or more of the conditions referred to herein. The compounds and compositions according to the methods of the invention can be in any amount and by any route effective for treating or lessening the severity of the disease. The exact amount necessary will vary depending on the patient's condition, depending on the race, age, general condition of the patient, severity of the infection, particular factors, mode of administration, and the like. The compound or composition may be administered in combination with one or more other therapeutic agents, as discussed herein.
The compounds and pharmaceutical compositions of the present invention are useful for veterinary treatment of mammals, in addition to human therapy, in pets, in animals of introduced species and in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.
General methods for the Synthesis of Compounds of the invention
For the purpose of illustrating the invention, examples are set forth below. It is to be understood that the invention is not limited to these examples but provides a method of practicing the invention.
In general, the compounds of the invention may be prepared by the methods described herein, wherein the substituents are as defined in formulas (I) to (II), unless otherwise indicated. The following reaction schemes and examples are provided to further illustrate the present invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare many other compounds of the present invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of those non-exemplified compounds according to the invention can be successfully accomplished by modification methods by those skilled in the art, such as appropriate protection of interfering groups, by use of other known reagents than those described herein, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also well-known to be applicable to the preparation of other compounds of the present invention.
The examples described below are given unless otherwise indicated that all temperatures are given in degrees celsius. Reagents were purchased from commercial suppliers such as Ling Kai medicine, aldrich Chemical Company, inc., arco Chemical Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated. The general reagents were purchased from Shandong Chemicals, guangdong Chemicals, guangzhou Chemicals, tianjin Chemie, inc., qingdao Tenglong chemical Co., ltd., and Qingdao ocean chemical works.
The anhydrous tetrahydrofuran is obtained by reflux drying of metallic sodium. The anhydrous methylene chloride and chloroform are obtained by reflux drying of calcium hydride. Ethyl acetate, N-dimethylacetamide and petroleum ether were dried over anhydrous sodium sulfate in advance for use.
The following reaction is typically carried out under nitrogen or argon pressure or with a dry tube (unless otherwise indicated) over anhydrous solvent, the reaction flask is capped with a suitable rubber stopper and the substrate is injected through a syringe. The glassware was all dried.
The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao ocean chemical plant. Nuclear magnetic resonance spectroscopy with CDC1 3 、DMSO-d 6 、CD 3 OD or acetone-d 6 TMS (0 ppm) or chloroform (7.25 ppm) was used as a reference standard for the solvent (reported in ppm). When multiple peaks occur, the following abbreviations will be used: s (single, singlet), d (doublet ), t (triplet, quartet), q (quartet), m (multiplet ), br (broadened, broad), brs (broadened singlet, broad singlet), dd (doublet of doublets, doublet), ddd (doublet of doublet of doublets, doublet), dt (doublet of triplets, doublet), td (triplet of doublets, triplet), tt (triplet of triplets, triplet). Coupling constant J, expressed in hertz (Hz).
Low resolution Mass Spectrometry (MS) data were determined by a spectrometer of the Agilent 6320 series LC-MS equipped with a G1312A binary pump and a G1316A TCC (column temperature kept at 30 ℃), a G1329A autosampler and a G1315B DAD detector were applied for analysis, and an ESI source was applied to the LC-MS spectrometer.
Low resolution Mass Spectrometry (MS) data were determined by a spectrometer of the Agilent6120 series LC-MS equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315D DAD detector were applied for analysis, and an ESI source was applied to the LC-MS spectrometer.
Both spectrometers were equipped with a Agilent Zorbax SB-C18 column, 2.1X130 mm,5 μm format. The injection volume is determined by the sample concentration; the flow rate is 0.6mL/min; the peak of the HPLC was read by recording the UV-Vis wavelengths at 210nm and 254 nm. The mobile phase was a 0.1% acetonitrile formate solution (phase a) and a 0.1% ultrapure formate solution (phase B). Gradient elution conditions are shown in table 1:
TABLE 1
Time (min) Phase A (CH) 3 CN，0.1％HCOOH) Phase B (H) 2 O，0.1％HCOOH)
0-3 5-100 95-0
3-6 100 0
6-6.1 100-5 0-95
6.1-8 5 95
Compound purification was assessed by Agilent 1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm on a Zorbax SB-C18 column, 2.1X130 mm,4 μm,10 min, flow rate of 0.6mL/min,5-95% (0.1% aqueous formic acid in acetonitrile) and column temperature maintained at 40 ℃.
The following abbreviations are used throughout the present invention:
Figure BDA0001666881410000191
the following synthetic schemes describe the steps for preparing the disclosed compounds. Unless otherwise indicated, each R 5 、R 6 、R 7 、R 8 And R is 9 With the definition according to the invention.
Synthesis scheme 1
Figure BDA0001666881410000201
The [ (x) ray ]9) The compounds shown can be prepared by the following procedure: the [ (x) ray ]1) The compound shown reacts with glycol to obtain the compound shown in the formula2) A compound shown; then [ ]2) The compound is reacted with thiophenol containing different substituent groups to obtain the compound shown in the formula3) The compounds shown. The [ (x) ray ]3) The compounds shown are oxidized to obtain the formula [ ]4) A compound shown; then [ ]4) Deprotection of the compounds shown gives the formula [ ]5) The compounds shown. The [ (x) ray ]5) The compound shown reacts with piperazine to obtain the formula6) The compounds shown. The [ (x) ray ]6) The protecting group on the compound is shown to obtain the formula [ ]7) A compound shown; the [ (x) ray ]7) The shown compound is fluorinated to obtain the formula [ ]8) The compounds shown. The [ (x) ray ]8) The compound is shown to remove protecting group to obtain the formula [ ]9) The target compounds shown.
Synthesis scheme 2
Figure BDA0001666881410000211
The [ (x) ray ]9) The compounds shown can be prepared by the following procedure: the [ (x) ray ]1) The compound shown reacts with piperazine to obtain the compound shown in the formula10) A compound shown; then [ ]10) The protecting group on the compound is shown to obtain the formula [ ] 11) The compounds shown. The [ (x) ray ]11) The compound shown reacts with thiophenol containing different substituent groups to obtain the formula12) A compound shown; the [ (x) ray ]12) The shown compound is fluorinated to obtain the formula [ ]13) A compound shown; the [ (x) ray ]13) The compounds shown are oxidized to obtain the formula [ ]8) The compounds shown. The [ (x) ray ]8) The compound is shown to remove protecting group to obtain the formula [ ]9) The target compounds shown.
Synthesis scheme 3
Figure BDA0001666881410000212
The [ (x) ray ]17) The compounds shown can be prepared by the following procedure: the [ (x) ray ]14) The compound shown reacts with thiophenol containing different substituent groups to obtain the formula15) A compound shown; the [ (x) ray ]15) The compounds shown are oxidized to obtain the formula [ ]16) The compounds shown. The [ (x) ray ]16) The compound shown reacts with piperazine to obtain the formula17) The target compounds shown.
Synthesis scheme 4
Figure BDA0001666881410000221
The [ (x) ray ]17) The compounds shown can be prepared by the following procedure: the [ (x) ray ]14) The compound shown reacts with piperazine to obtain the formula18) A compound shown; the [ (x) ray ]18) The protecting group on the compound is shown to obtain the formula [ ]19) A compound shown; the [ (x) ray ]19) The compound shown reacts with thiophenol containing different substituent groups to obtain the formula20) A compound shown; the [ (x) ray ]20) The compounds shown are oxidized to obtain the formula [ ]21) A compound shown; the [ (x) ray ] 21) The compound is shown to remove protecting group to obtain the formula [ ]17) The target compounds shown.
The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further described below in conjunction with the examples.
Examples
Example 1 1 Synthesis of- (2- (difluoromethyl) -3- (phenylsulfonyl) phenyl) piperazine
Figure BDA0001666881410000222
Step 1) Synthesis of 2- (2-bromo-6-fluorophenyl) -1, 3-dioxolane
2-bromo-6-fluoro-benzaldehyde (1.00 g,4.92 mmol), 4-methylbenzenesulfonic acid (88 mg,0.49 mmol), ethylene glycol (5 mL,89.4 mmol) and toluene (8 mL) were added to a 100mL single-neck round-bottom flask and reacted at 90℃for 22 hours in an oil bath; most of the solvent was removed by spin-drying under reduced pressure, water (30 mL) was added, followed by extraction with ethyl acetate (30 mL); the organic phase was dried over anhydrous sodium sulfate (3 g), filtered, and the filtrate was dried under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) to give the title compound as a colorless oil (1.08 g, 88.7%).
MS(ESI,pos.ion)m/z:246.9[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.37(d,J＝8.0Hz,1H),7.19(td,J＝8.0,5.4Hz,1H),7.08–7.00(m,1H),6.33(d,J＝0.4Hz,1H),4.25(t,J＝6.8Hz,2H),4.05(t,J＝6.8Hz,2H).
Step 2) Synthesis of 2- (2-fluoro-6- (phenylthio) phenyl) -1, 3-dioxolane
2- (2-bromo-6-fluorophenyl) -1, 3-dioxolane (1.5 g,6.07 mmol), thiophenol (0.77 g,6.94 mmol), potassium t-butoxide (0.82 g,7.26 mmol), tris (dibenzylideneacetone) dipalladium (0.29 g,0.31 mmol), bis (2-diphenylphosphine) phenyl ether (0.34 g,0.61 mmol) and toluene (15 mL) were added to a 100mL single port round bottom flask and reacted for 15 hours at 100deg.C under nitrogen blanket; the reaction was stopped, dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) =20/1) to give the title compound as a white solid (1.55 g, 92.4%).
MS(ESI,pos.ion)m/z:277.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.42–7.30(m,6H),7.14(dd,J＝10.8,8.8Hz,1H),6.91(d,J＝8.0Hz,1H),6.27(s,1H),4.13(t,J＝6.8Hz,2H),3.94(t,J＝6.8Hz,2H).
Step 3) Synthesis of 2- (2-fluoro-6- (phenylsulfonyl) phenyl) -1, 3-dioxolane
2- (2-fluoro-6- (phenylthio) phenyl) -1, 3-dioxolane (1.5 g,5.43 mmol) and dichloromethane (15 mL) were added to a 100mL single port round bottom flask at 25℃and m-chloroperoxybenzoic acid (2.87 g,13.3 mmol) was added and the reaction stirred for a further 12 hours; the reaction was stopped, water (20 mL) was added, the solution was separated, and the organic phase was dried under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) to give the title compound as a white solid (1.57 g, 93.8%).
MS(ESI,pos.ion)m/z:308.9[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.99(d,J＝7.6Hz,1H),7.88(d,J＝7.2Hz,2H),7.82–7.73(m,2H),7.66–7.34(m,3H),6.56(d,J＝1.6Hz,1H),4.05(t,J＝6.8Hz,2H),3.89(t,J＝6.8Hz,2H).
Step 4) Synthesis of 2-fluoro-6- (phenylsulfonyl) benzaldehyde
2- (2-fluoro-6- (phenylsulfonyl) phenyl) -1, 3-dioxolane (1.57 g,5.09 mmol), trifluoroacetic acid (2.18 mL,29.3 mmol) and dichloromethane (15 mL) were added to a 100mL single neck round bottom flask at 25℃and the reaction stirred for a further 12 hours; water (20 mL) was added, the solution was separated, and the organic phase was dried under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) to give the title compound as a white solid (1.3 g, 96.6%).
MS(ESI,pos.ion)m/z:265.0[M+H] + ；
1 HNMR(400MHz,DMSO-d 6 )δ(ppm)10.49(s,1H),8.01–7.95(m,3H),7.88(td,J＝8.8,5.2Hz,1H),7.79–7.71(m,2H),7.67(t,J＝8.0Hz,2H).
Step 5) Synthesis of 2- (phenylsulfonyl) -6- (piperazin-1-yl) benzaldehyde
2-fluoro-6- (phenylsulfonyl) benzaldehyde (1.3 g,4.92 mmol), potassium carbonate (1.38 g,9.98 mmol), piperazine (1.08 g,12.5 mmol) and acetonitrile (15 mL) were added to a 100mL single neck round bottom flask and reacted for 16 hours at 90℃in an oil bath; the reaction was stopped, most of the solvent was removed by spin-drying under reduced pressure, water (20 mL) and dichloromethane (30 mL) were added, the organic phase was separated, and the spin-dried under pressure and purified by column chromatography (dichloromethane/methanol (v/v) =15/1) to give the title compound as a yellowish green solid (1.28 g, 78.8%).
MS(ESI,pos.ion)m/z:330.9[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.38(s,1H),7.89(d,J＝7.6Hz,2H),7.79(d,J＝7.6Hz,1H),7.74–7.68(m,2H),7.64(t,J＝8.0Hz,2H),7.58(d,J＝8.0Hz,1H),2.81(t,J＝4.4Hz,4H),2.74(t,J＝4.4Hz,4H).
Step 6) Synthesis of 2- (phenylsulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde
2- (phenylsulfonyl) -6- (piperazin-1-yl) benzaldehyde (1.28 g,3.88 mmol), triethylamine (1.08 mL,7.8 mmol) and dichloromethane (20 mL) were added to a 100mL single neck round bottom flask at 0deg.C followed by dropwise addition of trifluoroacetic anhydride (0.83 mL,5.89 mmol); after the dripping is finished, transferring to 25 ℃ for reaction for 2.5 hours; water (30 mL) was added, the solution was separated, the organic phase was dried over anhydrous sodium sulfate (3 g), filtered, and the filtrate was dried under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate (v/v) =2/1) to give the title compound as a yellow solid (1.28 g, 77.5%).
MS(ESI,pos.ion)m/z:427.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.49(s,1H),7.91(d,J＝7.6Hz,2H),7.86(d,J＝7.6Hz,1H),7.77–7.70(m,2H),7.67–7.63(m,3H),3.65(brs,4H),3.00(brs,4H)。
Step 7) 1- (4- (2- (difluoromethyl) -3- (phenylsulfonyl) phenyl) piperazin-1-yl) -2, 2-trifluoroacetyl Is synthesized by (a)
2- (phenylsulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde (1.28 g,3 mmol) and diethylaminosulfur trifluoride (1.4 mL,11 mmol) were added to a 100mL single neck round bottom flask at 25℃and the reaction stirred for a further 12 hours; dichloromethane (20 mL) was added, then added portionwise to saturated sodium bicarbonate solution (30 mL), the solution separated, the organic phase dried over anhydrous sodium sulfate (4 g), filtered, the filtrate dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) to give the title compound as a white solid (0.78 g, 57.9%).
MS(ESI,pos.ion)m/z:449.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.13(t,J＝4.4Hz,1H),7.90(d,J＝7.6Hz,2H),7.86(d,J＝4.8Hz,2H),7.72(t,J＝7.6Hz,1H),7.65(d,J＝8.0Hz,2H),7.51(t,J＝54.8Hz,1H),3.72(t,J＝4.8Hz,4H),2.97(brs,4H).
Step 8) Synthesis of 1- (2- (difluoromethyl) -3- (phenylsulfonyl) phenyl) piperazine
1- (4- (2- (difluoromethyl) -3- (phenylsulfonyl) phenyl) piperazin-1-yl) -2, 2-trifluoroacetyl (0.78 g,1.74 mmol), tetrahydrofuran (5 mL), ethanol (5 mL) and water (5 mL) were added to a 100mL single port round bottom flask at 25℃and potassium carbonate (0.69 g,4.99 mmol) was added and the reaction stirred for a further 12 hours; the reaction was stopped, most of the solvent was removed by spin-drying under reduced pressure, water (20 mL) was added, then dichloromethane (30 mL) was added for extraction, the organic phase was separated, and the organic phase was spin-dried under reduced pressure and purified by column chromatography (dichloromethane/methanol (v/v) =20/1) to give the title compound as a white solid (0.46 g, 75.0%).
MS(ESI,pos.ion)m/z:353.2[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.10(d,J＝7.8Hz,1H),7.89(d,J＝7.8Hz,2H),7.85(t,J＝8.4Hz,1H),7.76(d,J＝8.4Hz,1H),7.72(t,J＝7.8Hz,1H),7.64(t,J＝8.4Hz,2H),7.39(t,J＝53.4Hz,1H),2.86(brs,4H),2.83(t,J＝6.6Hz,4H)；
13 C NMR(150MHz,DMSO-d 6 )δ(ppm)155.6,142.0,141.3,134.0,133.0,129.9,128.9,127.6,127.3,126.7(t,J＝22.35Hz),117.8(t,J＝237.9Hz),54.8,46.2.
Example 2 1 Synthesis of- (2- (difluoromethyl) -3- ((2-fluorophenyl) sulfonyl) phenyl) piperazine
Figure BDA0001666881410000241
Step 1) Synthesis of 2-bromo-6- (piperazin-1-yl) benzaldehyde
2-bromo-6-fluoro-benzaldehyde (5.00 g,24.6 mmol), piperazine (7.0 g,81 mmol), potassium carbonate (7.0 g,51 mmol) and acetonitrile (30 mL) were added to a 100mL single-neck round bottom flask, and reacted at 90℃in an oil bath for 12 hours; the reaction was stopped, most of the solvent was removed by spin-drying under reduced pressure, dichloromethane (50 mL) was added, followed by washing with water (30 mL. Times.2); separating, and drying the organic phase by using anhydrous sodium sulfate (3 g); filtration, spin-drying of the filtrate under reduced pressure, and column chromatography purification (dichloromethane/methanol (v/v) =20/1) gave the title compound as a yellowish green solid (5.9 g, 89%).
MS(ESI,pos.ion)m/z:268.9[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)10.07(s,1H),7.44(t,J＝7.8Hz,1H),7.34(d,J＝7.8Hz,1H),7.23(d,J＝8.4Hz,1H),2.94-2.92(m,4H),2.86–2.84(m,4H).
Step 2) Synthesis of 2-bromo-6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde
2-bromo-6- (piperazin-1-yl) benzaldehyde (5.90 g,21.9 mmol) and dichloromethane (20 mL) were added to a 100mL single neck round bottom flask at 25℃and triethylamine (6.2 mL,45 mmol) was added followed by dropwise addition of trifluoroacetic anhydride (4.5 mL,32 mmol) and the reaction was continued with stirring for 2.5 hours; the reaction was stopped, the reaction solution was washed with water (30 ml×2), the organic phase was dried over anhydrous sodium sulfate (3 g), filtered, and the filtrate was dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) to give the title compound as a yellow solid (2.8 g, 35%).
MS(ESI,pos.ion)m/z:364.8[M+H] + ；
1 HNMR(600MHz,DMSO-d 6 )δ(ppm)10.21(s,1H),7.49(t,J＝7.8Hz,1H),7.44(d,J＝7.8Hz,1H),7.28(d,J＝7.8Hz,1H),3.78(t,J＝4.8Hz,2H),3.80(t,J＝4.8Hz,2H),3.13(t,J＝7.8Hz,4H).
Step 3) 2- ((2-fluorophenyl) thio) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde Finished products
2-bromo-6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde (1.4 g,3.83 mmol), 2-fluorobenzylthiophenol (0.64 g,4.98 mmol), potassium tert-butoxide (0.58 g,5.2 mmol), tris (dibenzylideneacetone) dipalladium (0.18 g,0.19 mmol), bis (2-diphenylphosphino) phenyl ether (0.22 g,0.40 mmol) and toluene (15 mL) were added to a 50mL single neck round bottom flask and reacted for 15 hours in an oil bath at 100℃under nitrogen protection; the reaction was stopped, dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) =4/1) to give the title compound as a yellow oil (1.03 g, 65.1%).
MS(ESI,pos.ion)m/z:412.9[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.43(s,1H),7.69–7.58(m,2H),7.42(td,J＝8.4,5.6Hz,2H),7.37(t,J＝7.6Hz,1H),7.06(d,J＝8.0Hz,1H),6.37(d,J＝8.0Hz,1H),3.80(t,J＝4.8Hz,4H),3.14(t,J＝4.8Hz,4H).
Step 4) 1- (4- (2- (difluoromethyl) -3- ((2-fluorophenyl) thio) phenyl) piperazin-1-yl) -2, 2-trifluoro Synthesis of acetyl
The title compound was prepared as described in example 1, step 7 by reacting 2- ((2-fluorophenyl) thio) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde (1.03 g,2.50 mmol) in diethylaminosulfur trifluoride (5.00 ml,38.2 mmol) and subjecting the crude product to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) and concentrated to dryness to give the title compound as a white solid (0.73 g, 67.3%).
MS(ESI,pos.ion)m/z:434.8[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.55(t,J＝49.2Hz,1H),7.55–7.50(m,1H),7.46(td,J＝7.6,1.6Hz,1H),7.42–7.35(m,2H),7.30(t,J＝7.6Hz,1H),7.26(d,J＝8.0Hz,1H),6.79(d,J＝8.0Hz,1H),3.80–3.79(m,4H),3.00–2.96(m,4H).
Step 5) 1- (4- (2- (difluoromethyl) -3- ((2-fluorophenyl) sulfonyl) phenyl) piperazin-1-yl) -2, 2-tris Synthesis of fluoroacetyl
The title compound was prepared as described in example 1, step 3 by reacting 1- (4- (2- (difluoromethyl) -3- ((2-fluorophenyl) thio) phenyl) piperazin-1-yl) -2, 2-trifluoroacetyl (0.73 g,1.68 mmol), m-chloroperoxybenzoic acid (1.3 g,6.03 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) to give the title compound as a yellow-green solid (0.45 g, 57.4%).
MS(ESI,pos.ion)m/z:466.8[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.20–8.13(m,1H),8.07(t,J＝7.2Hz,1H),7.90–7.87(m,2H),7.85–7.78(m,1H),7.52(t,J＝7.2Hz,1H),7.46(t,J＝53.2Hz,1H),7.42(dd,J＝10.8,9.2Hz,1H),3.72(brs,4H),3.00–2.96(m,4H).
Step 6) Synthesis of 1- (2- (difluoromethyl) -3- ((2-fluorophenyl) sulfonyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 8 by reacting 1- (4- (2- (difluoromethyl) -3- ((2-fluorophenyl) sulfonyl) phenyl) piperazin-1-yl) -2, 2-trifluoroacetyl (0.45 g,0.96 mmol), potassium carbonate (0.4 g,2.89 mmol) in tetrahydrofuran (5 mL), ethanol (5 mL), water (5 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =20/1) and concentrating and drying to give the title compound as a white solid (0.12 g, 33.6%).
MS(ESI,pos.ion)m/z:371.2[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.14(d,J＝8.4Hz,1H),8.07(t,J＝7.2Hz,1H),7.91(t,J＝7.8Hz,1H),7.85–7.82(m,2H),7.54(t,J＝8.4Hz,1H),7.44(t,J＝9.6Hz,1H),7.27(t,J＝54.0Hz,1H),2.86(s,4H),2.85(s,4H)；
13 C NMR(150MHz,DMSO-d 6 )δ(ppm)158.5(d,J＝252.5Hz),155.5,141.0,137.3(d,J＝8.7Hz),132.9,129.9,129.7(d,J＝13.1Hz),129.2,127.6,126.8(t,J＝22.4Hz),125.6(d,J＝3.6Hz),117.7(d,J＝20.7Hz),111.9(t,J＝237.5Hz),54.9,46.1.
Example 3 1 Synthesis of- (2- (difluoromethyl) -3- ((2-chlorophenyl) sulfonyl) phenyl) piperazine
Figure BDA0001666881410000261
Step 1) Synthesis of 2- (2- ((2-chlorophenyl) thio) -6-fluorophenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 2 by reacting 2- (2-bromo-6-fluorophenyl) -1, 3-dioxolane (2.4 g,9.71 mmol), 2-chlorophenylthiol (1.7 g,11.8 mmol), potassium tert-butoxide (1.4 g,12.5 mmol), tris (dibenzylideneacetone) dipalladium (0.45 g,0.49 mmol) and bis (2-diphenylphosphine) phenyl ether (0.55 g,1.0 mmol) in toluene (15 mL) and concentrating and drying to give the title compound as a yellow solid (2.5 g, 82.8%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =20/1).
MS(ESI,pos.ion)m/z:311.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)7.60–7.57(m,1H),7.46(td,J＝8.4,6.0Hz,1H),7.38–7.32(m,2H),7.28(ddd,J＝10.8,8.4,1.2Hz,1H),7.12–7.08(m,1H),7.02(d,J＝8.4Hz,1H),6.26(s,1H),4.16–4.13(m,2H),3.97–3.95(m,2H).
Step 2) Synthesis of 2- (2- ((2-chlorophenyl) sulfonyl) -6-fluorophenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 3 by reacting 2- (2- ((2-chlorophenyl) thio) -6-fluorophenyl) -1, 3-dioxolane (2.5 g,8.04 mmol), m-chloroperoxybenzoic acid (3.5 g,20.3 mmol) in dichloromethane (20 mL) and concentrating and drying to give the title compound as a white solid by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1)(2.65g,96.1％)。MS(ESI,pos.ion)m/z:342.8[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.31(dd,J＝7.8,1.8Hz,1H),8.07(d,J＝7.8Hz,1H),7.83–7.78(m,2H),7.74–7.67(m,3H),6.30(d,J＝1.8Hz,1H),4.01–3.97(m,2H),3.77(t,J＝6.6Hz,2H).
Step 3) Synthesis of 2- ((2-chlorophenyl) sulfonyl) -6-fluorobenzaldehyde
The title compound was prepared as described in example 1, step 4 by reacting 2- (2- ((2-chlorophenyl) sulfonyl) -6-fluorophenyl) -1, 3-dioxolane (2.65 g,7.73 mmol), trifluoroacetic acid (4.0 mL,54 mmol) in dichloromethane (20 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) to give the title compound as a white solid (2.28 g, 98.7%).
MS(ESI,pos.ion)m/z:298.9[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)10.36(s,1H),8.29(dd,J＝7.8,1.8Hz,1H),8.01(d,J＝7.2Hz,1H),7.93(td,J＝7.8,4.8Hz,1H),7.84–7.79(m,2H),7.73(td,J＝7.8,1.2Hz,1H),7.70(dd,J＝7.8,1.2Hz,1H).
Step 4) Synthesis of 2- ((2-chlorophenyl) sulfonyl) -6- (piperazin-1-yl) benzaldehyde
The title compound was prepared as described in example 1, step 5 by reacting 2- ((2-chlorophenyl) sulfonyl) -6-fluorobenzaldehyde (2.28 g,7.63 mmol), piperazine (1.98 g,23.0 mmol), potassium carbonate (2.11 g,15.3 mmol) in acetonitrile (20 mL) and drying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =15/1) to give the title compound as a yellow solid (2.7 g, 97%).
MS(ESI,pos.ion)m/z:365.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)10.18(s,1H),8.13(dd,J＝7.8,1.2Hz,1H),7.89(d,J＝7.8Hz,1H),7.79(t,J＝7.8Hz,1H),7.74(td,J＝7.8,1.8Hz,1H),7.68(td,J＝7.8,1.2Hz,1H),7.65–7.62(m,2H),2.86(t,J＝4.8Hz,4H),2.77(t,J＝4.8Hz,4H).
Step 5) 2- ((2-chlorophenyl) sulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde Synthesis
The title compound was prepared as described in example 1, step 6 by reacting 2- ((2-chlorophenyl) sulfonyl) -6- (piperazin-1-yl) benzaldehyde (2.7 g,7.4 mmol), trifluoroacetic anhydride (1.6 mL,11 mmol), triethylamine (3.2 mL,23 mmol) in dichloromethane (20 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =2/1) to give the title compound as a yellow solid (1.6 g, 46.9%).
MS(ESI,pos.ion)m/z:461.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.31(s,1H),8.14(dd,J＝7.6,1.6Hz,1H),7.94(d,J＝7.6Hz,1H),7.81(t,J＝8.0Hz,1H),7.78–7.66(m,3H),7.64(d,J＝7.6Hz,1H),3.67(brs,4H),3.09–2.99(m,4H).
Step 6) 1- (4- (3- ((2-chlorophenyl) sulfonyl) -2- (difluoromethyl) phenyl) piperazin-1-yl) -2, 2-tris Synthesis of fluoroacetyl
The title compound was prepared as described in example 1, step 7 by reacting 2- ((2-chlorophenyl) sulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde (1.6 g,3.5 mmol) in diethylaminosulfur trifluoride (8.0 mL,61.0 mmol) and subjecting the crude product to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) and concentrated to dryness to give the title compound as a white solid (0.4 g, 23.9%).
MS(ESI,pos.ion)m/z:482.7[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.23(dd,J＝7..9,1.2Hz,1H),8.12(dd,J＝7.8,1.2Hz,1H),7.90–7.82(m,2H),7.75(td,J＝7.8,1.8Hz,1H),7.68(td,J＝7.8,1.2Hz,1H),7.64(dd,J＝7.8,1.2Hz,1H),7.41(t,J＝53.8Hz,1H),3.70(t,J＝4.8Hz,4H),2.96(t,J＝4.8Hz,4H)。
Step 7) Synthesis of 1- (3- ((2-chlorophenyl) sulfonyl) -2- (difluoromethyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 8 by reacting 1- (4- (3- ((2-chlorophenyl) sulfonyl) -2- (difluoromethyl) phenyl) piperazin-1-yl) -2, 2-trifluoroacetyl (0.4 g,0.83 mmol), potassium carbonate (0.34 g,2.46 mmol) in tetrahydrofuran (5 mL), ethanol (5 mL), water (5 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =20/1) and concentrating and drying to give the title compound as a white solid (0.27 g, 84.3%).
MS(ESI,pos.ion)m/z:387.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.22(d,J＝7.8Hz,1H),8.10(d,J＝7.8Hz,1H),7.85(t,J＝8.0Hz,1H),7.81(d,J＝7.8Hz,1H),7.74(td,J＝7.8,1.8Hz,1H),7.67(t,J＝7.8Hz,1H),7.63(d,J＝7.8Hz,1H),7.36(t,J＝53.4Hz,1H),3.10(brs,4H),3.00(brs,4H)；
13 C NMR(150MHz,DMSO-d 6 )δ(ppm)153.9,140.5,139.0,136.1,132.9,132.4,131.4,131.0,129.7,128.6,128.5,127.3(t,J＝22.7Hz),111.7(t,J＝239.1Hz),50.8,43.9.
Example 4 1 Synthesis of- (2- (difluoromethyl) -3- ((2-bromophenyl) sulfonyl) phenyl) piperazine
Figure BDA0001666881410000281
Step 1) Synthesis of 2- ((2-bromophenyl) thio) -6-fluorobenzaldehyde
2, 6-difluorobenzaldehyde (2.60 g,18.3 mmol), 2-bromothiophenol (1.30 mL,10.8 mmol), potassium carbonate (2.90 g,21.0 mmol) and N, N-dimethylformamide (20 mL) were added to a 100mL single-neck round-bottom flask and reacted at 80℃in an oil bath for 12 hours; the reaction was stopped, ethyl acetate (30 mL) was added, washed with water (30 ml×2), the organic phase was dried over anhydrous sodium sulfate (5 g), filtered, and the filtrate was dried under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =50/1), concentrated and dried to give the title compound as a yellowish green solid (4.02 g, 83.6%).
MS(ESI,pos.ion)m/z:310.8[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.42(s,1H),7.88(dd,J＝8.0,1.2Hz,1H),7.71(dd,J＝7.6,2.0Hz,1H),7.58–7.51(m,2H),7.48(td,J＝7.6,2.0Hz,1H),7.21(dd,J＝10.8,8.4Hz,1H),6.46(d,J＝8.4Hz,1H).
Step 2) Synthesis of 2- (2- ((2-bromophenyl) thio) -6-fluorophenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 1 by reacting 2- ((2-bromophenyl) thio) -6-fluorobenzaldehyde (4.02 g,12.9 mmol), 4-methylbenzenesulfonic acid (0.25 g,1.5 mmol) and ethylene glycol (8 mL,143 mmol) in toluene (20 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) to give the title compound as a yellow solid (3.8 g, 82.8%).
MS(ESI,pos.ion)m/z:354.7[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.58(dd,J＝7.6,1.2Hz,1H),7.27(td,J＝8.4,5.6Hz,1H),7.19(dd,J＝7.6,0.8Hz,1H),7.10–7.03(m,3H),7.00(dd,J＝8.0,1.2Hz,1H),6.41(s,1H),4.26(t,J＝6.8Hz,2H),4.01(t,J＝6.8Hz,2H).
Step 3) Synthesis of 2- (2- ((2-bromophenyl) sulfonyl) -6-fluorophenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 3 by reacting 2- (2- ((2-bromophenyl) thio) -6-fluorophenyl) -1, 3-dioxolane (3.8 g,10.7 mmol), m-chloroperoxybenzoic acid (5.88 g,27.3 mmol) in dichloromethane (20 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) to give the title compound as a white solid (2.33 g, 56.2%).
MS(ESI,pos.ion)m/z:387.0[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.30(dd,J＝8.0,1.6Hz,1H),8.05(d,J＝8.0Hz,1H),7.84(dd,J＝7.6,1.2Hz,1H),7.77(td,J＝8.0,5.2Hz,1H),7.74(dd,J＝7.6,1.2Hz,1H),7.70–7.64(m,2H),6.26(d,J＝1.6Hz,1H),3.97(t,J＝6.8Hz,2H),3.74(t,J＝6.8Hz,2H).
Step 4) Synthesis of 2- ((2-bromophenyl) sulfonyl) -6-fluorobenzaldehyde
The title compound was prepared as described in example 1, step 4 by reacting 2- (2- ((2-bromophenyl) sulfonyl) -6-fluorophenyl) -1, 3-dioxolane (2.33 g,6.02 mmol), trifluoroacetic acid (5.0 mL,67.1 mmol) in dichloromethane (15 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) to give the title compound as a white solid (1.9 g, 92%).
MS(ESI,pos.ion)m/z:342.7[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.36(s,1H),8.29(dd,J＝8.0,1.6Hz,1H),7.96–7.94(m,1H),7.89(td,J＝8.0,4.8Hz,1H),7.86(dd,J＝8.0,0.8Hz,1H),7.80(t,J＝9.6Hz,1H),7.74(dd,J＝8.0,0.8Hz,1H),7.68(td,J＝7.6,1.6Hz,1H).
Step 5) Synthesis of 2- ((2-bromophenyl) sulfonyl) -6- (piperazin-1-yl) benzaldehyde
The title compound was prepared as described in example 1, step 5 by reacting 2- ((2-bromophenyl) sulfonyl) -6-fluorobenzaldehyde (1.9 g,5.54 mmol), piperazine (1.45 g,16.8 mmol), potassium carbonate (1.5 g,10.9 mmol) in acetonitrile (20 mL) and drying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =15/1) to give the title compound as a yellow solid (1.98 g, 87.4%).
MS(ESI,pos.ion)m/z:409.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.19(s,1H),8.16(dd,J＝8.0,1.6Hz,1H),7.87(d,J＝7.6Hz,1H),7.83–7.75(m,2H),7.76–7.70(m,1H),7.67–7.60(m,2H),2.87(t,J＝4.8Hz,4H),2.78(t,J＝4.8Hz,4H).
Step 6) 2- ((2-bromophenyl) sulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde Synthesis
The title compound was prepared as described in example 1, step 6 by reacting 2- ((2-bromophenyl) sulfonyl) -6- (piperazin-1-yl) benzaldehyde (1.98 g,4.84 mmol), trifluoroacetic anhydride (1.0 mL,7.1 mmol), triethylamine (2.0 mL,14 mmol) in dichloromethane (20 mL) and drying to give the title compound as a yellow solid (1.7 g, 69.5%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =2/1).
MS(ESI,pos.ion)m/z:504.8[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.33(s,1H),8.18(dd,J＝8.0,1.6Hz,1H),7.91(d,J＝7.6Hz,1H),7.84–7.78(m,2H),7.76–7.70(m,2H),7.65(td,J＝7.6,1.6Hz,1H),3.69(brs,4H),3.06(brs,4H).
Step 7) 1- (4- (3- ((2-bromophenyl) sulfonyl) -2- (difluoromethyl) phenyl) piperazin-1-yl) -2, 2-tris Synthesis of fluoroacetyl
The title compound was prepared as described in example 1, step 7 by reacting 2- ((2-bromophenyl) sulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde (1.7 g,3.36 mmol) in diethylaminosulfur trifluoride (5.0 mL,38.2 mmol) and subjecting the crude product to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) and concentrated to dryness to give the title compound as a white solid (0.61 g, 34.1%).
MS(ESI,pos.ion)m/z:527.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.25(d,J＝7.6Hz,1H),8.09(d,J＝7.6Hz,1H),7.90–7.81(m,3H),7.73(t,J＝7.2Hz,1H),7.65(td,J＝7.6,1.6Hz,1H),7.42(t,J＝53.2Hz,1H),3.71(t,J＝4.8Hz,4H),2.97(t,J＝4.8Hz,4H).
Step 8) Synthesis of 1- (2- (difluoromethyl) -3- ((2-bromophenyl) sulfonyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 8 by reacting 1- (4- (3- ((2-bromophenyl) sulfonyl) -2- (difluoromethyl) phenyl) piperazin-1-yl) -2, 2-trifluoroacetyl (0.6 g,1.14 mmol), potassium carbonate (0.5 g,3.62 mmol) in tetrahydrofuran (5 mL), ethanol (5 mL), water (5 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =20/1) and concentrating and drying to give the title compound as a white solid (0.43 g, 87.6%).
MS(ESI,pos.ion)m/z:431.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.21(dd,J＝7.8,12Hz,1H),8.01(dd,J＝7.8,0.6Hz,1H),7.82(dd,J＝7.8,1.2Hz,1H),7.81(t,J＝8.4Hz,1H),7.76(d,J＝7.8Hz,1H),7.71(td,J＝7.2,1.2Hz,1H),7.64(td,J＝7.6,1.8Hz,1H),7.29(t,J＝53.6Hz,1H),2.83(brs,4H),2.81(brs,4H)；
13 C NMR(150MHz,DMSO-d 6 )δ(ppm)155.4(t,J＝4.2Hz),140.7,140.5,135.9,135.8,132.7,131.3,128.8,127.5,126.6(t,J＝23.0Hz),120.2,111.9(t,J＝237.9Hz),54.8,46.0.
Example 5 1 Synthesis of- (2- (difluoromethyl) -3- (m-toluenesulfonyl) phenyl) piperazine
Figure BDA0001666881410000301
Step 1) Synthesis of 2- (2-fluoro-6- (m-tolylthio) phenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 2 by reacting 2- (2-bromo-6-fluorophenyl) -1, 3-dioxolane (1.0 g,4.05 mmol), m-tolylthiophenol (608 mg,4.90 mmol), potassium tert-butoxide (681 mg,6.07 mmol), tris (dibenzylideneacetone) dipalladium (185 mg,0.19 mmol) and bis (2-diphenylphosphino) phenyl ether (0.218 g,0.40 mmol) in toluene (10 mL) and concentrating and drying to give the title compound as a colorless oil (1.01 g, 85.9%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =50/1).
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.28–7.21(m,3H),7.18(td,J＝8.1,5.6Hz,1H),7.14(d,J＝7.3Hz,1H),6.94–6.89(m,2H),6.49(s,1H),4.32–4.28(m,2H),4.06–4.02(m,2H),2.35(s,3H).
Step 2) Synthesis of 2- (2-fluoro-6- (m-toluenesulfonyl) phenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 3 by reacting 2- (2-fluoro-6- (m-tolylthio) phenyl) -1, 3-dioxolane (0.97 g,3.3 mmol), m-chloroperoxybenzoic acid (2.1 g,9.7 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) to give the title compound as a pale yellow solid (0.73 g, 68%).
MS(ESI,pos.ion)m/z:322.9[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.96(d,J＝8.0Hz,1H),7.67–7.63(m,2H),7.52(td,J＝8.1,4.9Hz,1H),7.41–7.37(m,2H),7.30–7.28(m,1H),6.76(d,J＝1.6Hz,1H),4.17(t,J＝6.8Hz,2H),3.97(t,J＝6.6Hz,2H),2.40(s,3H).
Step 3) Synthesis of 2-fluoro-6- (m-toluenesulfonyl) benzaldehyde
The title compound was prepared as described in example 1, step 4 by reacting 2- (2-fluoro-6- (m-toluenesulfonyl) phenyl) -1, 3-dioxolane (0.67 g,2.08 mmol), trifluoroacetic acid (1.4 g,12.5 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) to give the title compound as a white solid (0.45 g, 77.8%).
MS(ESI,pos.ion)m/z:279.1[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)10.66(s,1H),7.99(d,J＝7.9Hz,1H),7.76–7.62(m,3H),7.51–7.37(m,3H),2.44(s,3H).
Step 4) Synthesis of 2- (piperazin-1-yl) -6- (m-toluenesulfonyl) benzaldehyde
The title compound was prepared as described in example 1, step 5 by reacting 2-fluoro-6- (m-toluenesulfonyl) benzaldehyde (423 mg,1.52 mmol), piperazine (390 mg,4.57 mmol), potassium carbonate (425 mg,3.04 mmol) in acetonitrile (10 mL) and drying to give the title compound as a pale yellow oil (420 mg, 80.2%) by silica gel column chromatography (dichloromethane/methanol (v/v) =15/1).
MS(ESI,pos.ion)m/z:345.2[M+H] + ；
1 HNMR(600MHz,CDCl 3 )δ(ppm)10.47(s,1H),7.85(d,J＝7.5Hz,1H),7.72(d,J＝8.1Hz,2H),7.58(t,J＝8.0Hz,1H),7.39–7.30(m,3H),2.98–2.95(m,4H),2.93–2.89(m,4H),2.42(s,3H).
Step 5) Synthesis of 2- (m-toluenesulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde
The title compound was prepared as described in example 1, step 6 by reacting 2- (piperazin-1-yl) -6- (m-toluenesulfonyl) benzaldehyde (380 mg,1.1 mmol), trifluoroacetic anhydride (350 mg,1.67 mmol), triethylamine (0.47 mL,3.36 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =2/1) to give the title compound as a yellow oil (200 mg, 41%).
MS(ESI,pos.ion)m/z:440.8[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)10.59(s,1H),7.89(d,J＝7.9Hz,1H),7.73–7.70(m,2H),7.62(t,J＝8.0Hz,1H),7.43–7.41(m,2H),7.38(d,J＝8.1Hz,1H),3.82–3.80(m,2H),3.74–3.72(m,2H),3.09(brs,4H),2.44(s,3H).
Step 6) 1- (4- (2- (difluoromethyl) -3- (m-toluenesulfonyl) phenyl) piperazin-1-yl) -2, 2-trifluoroethyl Synthesis of acyl groups
The title compound was prepared as described in example 1, step 7 by reacting 2- (m-toluenesulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde (460 mg,1.05 mmol) in diethylaminosulfur trifluoride (2.0 mL,15.2 mmol) and subjecting the crude product to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) followed by concentration and drying to give the title compound as a yellow solid (0.37 g, 76.3%).
MS(ESI,pos.ion)m/z:463.2[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.07(d,J＝7.9Hz,1H),7.69–7.65(m,3H),7.61(t,J＝53.2Hz,1H),7.55(d,J＝8.0Hz,1H),7.44(s,1H),7.43(d,J＝5.1Hz,1H),3.83(brs,2H),3.76–3.74(m,2H),3.01–2.98(m,4H),2.43(s,3H).
Step 7) Synthesis of 1- (2- (difluoromethyl) -3- (m-toluenesulfonyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 8 by reacting 1- (4- (2- (difluoromethyl) -3- (m-toluenesulfonyl) phenyl) piperazin-1-yl) -2, 2-trifluoroacetyl (0.3 g,0.65 mmol), potassium carbonate (0.27 g,1.95 mmol) in tetrahydrofuran (3 mL), ethanol (3 mL), water (3 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =20/1), concentrating and drying to give the title compound as a yellow solid (215 mg, 90.4%).
MS(ESI,pos.ion)m/z:367.2[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.05(s,1H),7.71–7.45(m,5H),7.41(brs,2H),3.21(brs,4H),3.10(brs,4H),2.41(s,3H).
Example 6 1 Synthesis of- (2- (difluoromethyl) -3- ((3-methoxyphenyl) sulfonyl) phenyl) piperazine
Figure BDA0001666881410000321
Step 1) Synthesis of 2- (2-fluoro-6- ((3-methoxyphenyl) thio) phenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 2 by reacting 2- (2-bromo-6-fluorophenyl) -1, 3-dioxolane (1.0 g,4.05 mmol), 3-methoxyphenylthiophenol (680 mg,4.85 mmol), potassium tert-butoxide (704 mg,6.28 mmol), tris (dibenzylideneacetone) dipalladium (200 mg,0.21 mmol) and bis (2-diphenylphosphinophenone) ether (0.23 g,0.42 mmol) in toluene (10 mL) and concentrating and drying to give the title compound as a yellow oil (1.0 g, 81%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =50/1).
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.26(dd,J＝13.3,5.3Hz,1H),7.20(td,J＝8.2,5.7Hz,1H),7.02–6.90(m,4H),6.85(dd,J＝8.3,2.4Hz,1H),4.37–4.23(m,2H),4.09–3.99(m,2H),3.78(s,3H).
Step 2) Synthesis of 2- (2-fluoro-6- ((3-methoxyphenyl) sulfonyl) phenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 3 by reacting 2- (2-fluoro-6- ((3-methoxyphenyl) thio) phenyl) -1, 3-dioxolane (0.99 g,3.2 mmol), m-chloroperoxybenzoic acid (2.7 g,13 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) to give the title compound as a pale yellow oil (0.95 g, 87%).
MS(ESI,pos.ion)m/z:338.8[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.94(d,J＝8.0Hz,1H),7.52(td,J＝8.2,4.9Hz,1H),7.48–7.25(m,5H),7.12(dt,J＝5.9,2.7Hz,1H),6.79(d,J＝1.7Hz,1H),4.30–4.11(m,2H),4.09–3.92(m,2H),3.83(s,3H).
Step 3) Synthesis of 2-fluoro-6- ((3-methoxyphenyl) sulfonyl) benzaldehyde
The title compound was prepared as described in example 1, step 4 by reacting 2- (2-fluoro-6- ((3-methoxyphenyl) sulfonyl) phenyl) -1, 3-dioxolane (0.89 g,2.63 mmol), trifluoroacetic acid (1.8 g,16.1 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) to give the title compound as a yellow oil (0.7 g, 90.4%).
MS(ESI,pos.ion)m/z:295.1[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)10.66(s,1H),7.96(d,J＝7.9Hz,1H),7.69(td,J＝8.2,5.0Hz,1H),7.46–7.39(m,4H),7.16–7.12(m,1H),3.87(s,3H).
Step 4) Synthesis of 2- ((3-methoxyphenyl) sulfonyl) -6- (piperazin-1-yl) benzaldehyde
The title compound was prepared as described in example 1, step 5 by reacting 2-fluoro-6- ((3-methoxyphenyl) sulfonyl) benzaldehyde (700 mg,2.38 mmol), piperazine (620 mg,7.2 mmol), potassium carbonate (640 mg,4.8 mmol) in acetonitrile (10 mL) and drying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =15/1) to give the title compound as a pale yellow oil (470 mg, 55.4%).
MS(ESI,pos.ion)m/z:360.9[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)10.49(s,1H),7.85(d,J＝7.5Hz,1H),7.59(t,J＝8.0Hz,1H),7.53–7.47(m,2H),7.46–7.36(m,2H),7.11(ddd,J＝8.3,2.5,0.8Hz,1H),3.90(s,3H),2.99–2.97(m,4H),2.96–2.94(m,4H).
Step 5) 2- ((3-methoxyphenyl) sulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzyl Synthesis of aldehydes
The title compound was prepared as described in example 1, step 6 by reacting 2- ((3-methoxyphenyl) sulfonyl) -6- (piperazin-1-yl) benzaldehyde (445 mg,1.23 mmol), trifluoroacetic anhydride (531 mg,2.53 mmol), triethylamine (0.52 mL,3.75 mmol) in dichloromethane (10 mL) and drying to give the title compound as a yellow oil (390 mg, 69.2%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =2/1).
MS(ESI,pos.ion)m/z:456.8[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)10.49(s,1H),7.85(d,J＝7.5Hz,1H),7.59(t,J＝8.0Hz,1H),7.53–7.47(m,2H),7.46–7.36(m,2H),7.11(ddd,J＝8.3,2.5,0.8Hz,1H),3.90(s,3H),2.98(dd,J＝5.1,3.4Hz,4H),2.95(dd,J＝5.0,3.3Hz,4H).
Step 6) 1- (4- (2- (difluoromethyl) -3- ((3-methoxyphenyl) sulfonyl) phenyl) piperazin-1-yl) -2, synthesis of 2-trifluoroacetyl
The title compound was prepared as described in example 1, step 7 by reacting 2- ((3-methoxyphenyl) sulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde (310 mg,0.68 mmol) in diethylaminosulfur trifluoride (2.0 ml,15.2 mmol) and subjecting the crude product to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) and concentrated to dryness to give the title compound as a yellow solid (0.21 g, 64.6%).
MS(ESI,pos.ion)m/z:479.2[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.07(d,J＝7.9Hz,1H),7.67(t,J＝8.0Hz,1H),7.62(t,J＝53.2Hz,1H),7.56(d,J＝8.0Hz,1H),7.45(t,J＝7.9Hz,1H),7.42(dt,J＝7.8,1.3Hz,1H),7.39–7.37(m,1H),7.14(ddd,J＝8.0,2.5,1.2Hz,1H),3.86(s,3H),3.83(brs,2H),3.76–3.73(m,2H),3.01(t,J＝4.9Hz,4H).
Step 7) Synthesis of 1- (2- (difluoromethyl) -3- ((3-methoxyphenyl) sulfonyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 8 by reacting 1- (4- (2- (difluoromethyl) -3- ((3-methoxyphenyl) sulfonyl) phenyl) piperazin-1-yl) -2, 2-trifluoroacetyl (0.2 g,0.42 mmol), potassium carbonate (0.165 g,1.18 mmol) in tetrahydrofuran (3 mL), ethanol (3 mL), water (3 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =20/1) and concentrating and drying to give the title compound as a yellow solid (152 mg, 95.1%).
MS(ESI,pos.ion)m/z:382.9[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.09(d,J＝7.9Hz,1H),7.65(t,J＝8.0Hz,1H),7.61–7.29(m,5H),7.11(dt,J＝7.0,2.2Hz,1H),3.86(s,3H),3.10–2.98(m,4H),2.98–2.87(m,4H).
Example 7 1 Synthesis of- (2- (difluoromethyl) -3- ((3-fluorophenyl) sulfonyl) phenyl) piperazine
Figure BDA0001666881410000341
Step 1) 2- ((3-fluorophenyl) thio) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde Finished products
The title compound was prepared as described in example 2, step 3 by reacting 2-bromo-6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde (1.1 g,3.0 mmol), 3-fluorobenzylthiophenol (0.48 g,3.7 mmol), potassium tert-butoxide (0.50 g,4.45 mmol), tris (dibenzylideneacetone) dipalladium (0.14 g,0.15 mmol) and bis (2-diphenylphosphino) phenyl ether (0.16 g,0.30 mmol) in toluene (15 mL) and concentrating and drying to give the title compound as a yellow oil (320 mg, 26%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =20/1). MS (ESI, pos.ion) m/z 413.2[ M+H ]] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)10.55(s,1H),7.41–7.39(m,1H),7.33–7.28(m,2H),7.24(d,J＝8.6Hz,1H),7.14–7.12(m,1H),6.92(d,J＝8.0Hz,1H),6.68(d,J＝8.1Hz,1H),3.98–3.89(m,2H),3.89–3.78(m,2H),3.25–3.07(m,4H).
Step 2) 1- (4- (2- (difluoromethyl) -3- ((3-fluorophenyl) thio) phenyl) piperazin-1-yl) -2, 2-trifluoro Synthesis of acetyl
The title compound was prepared as described in example 1, step 7 by reacting 2- ((3-fluorophenyl) thio) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde (310 mg,0.75 mmol) in diethylaminosulfur trifluoride (3.0 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) to give the title compound as a yellow solid (0.3 g, 91.8%).
MS(ESI,pos.ion)m/z:434.8[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.39(t,J＝54.4Hz,1H),7.42–7.29(m,2H),7.18–7.10(m,3H),7.07–6.93(m,2H),3.89(s,2H),3.84–3.76(m,2H),3.09–2.99(m,4H).
Step 3) 1- (4- (2- (difluoromethyl) -3- ((3-fluorophenyl) sulfonyl) phenyl) piperazin-1-yl) -2, 2-tris Synthesis of fluoroacetyl
The title compound was prepared as described in example 1, step 3 by reacting 1- (4- (2- (difluoromethyl) -3- ((3-fluorophenyl) thio) phenyl) piperazin-1-yl) -2, 2-trifluoroacetyl (0.3 g,0.69 mmol), m-chloroperoxybenzoic acid (450 mg,2.08 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) to give the title compound as a pale yellow oil (0.215 g, 66.7%).
MS(ESI,pos.ion)m/z:467.2[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.14(d,J＝7.9Hz,1H),7.69–7.65(m,2H),7.58(t,J＝65.8Hz,1H),7.60–7.52(m,3H),7.33(td,J＝8.2,2.1Hz,1H),3.84(s,2H),3.76–3.73(m,2H),3.02–2.98(m,4H).
Step 4) Synthesis of 1- (2- (difluoromethyl) -3- ((3-fluorophenyl) sulfonyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 8 by reacting 1- (4- (2- (difluoromethyl) -3- ((3-fluorophenyl) sulfonyl) phenyl) piperazin-1-yl) -2, 2-trifluoroacetyl (0.15 g,0.32 mmol), potassium carbonate (0.175 g,1.25 mmol) in tetrahydrofuran (2 mL), ethanol (2 mL), water (2 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =20/1) and concentrating and drying to give the title compound as a yellow solid (70 mg, 58.8%).
MS(ESI,pos.ion)m/z:370.9[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.14(d,J＝7.9Hz,1H),7.68(t,J＝7.9Hz,2H),7.62–7.54(m,2H),7.50(td,J＝8.1,5.3Hz,1H),7.47–7.23(m,2H),3.05–2.97(m,4H),2.96–2.87(m,4H).
Example 8 1 Synthesis of- (2- (difluoromethyl) -3- ((3-chlorophenyl) sulfonyl) phenyl) piperazine
Figure BDA0001666881410000351
Step 1) Synthesis of 2- (2-fluoro-6- ((3-chlorophenyl) thio) phenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 2 by reacting 2- (2-bromo-6-fluorophenyl) -1, 3-dioxolane (2.0 g,8.09 mmol), 3-chlorophenylthiol (1.4 g,9.75 mmol), potassium tert-butoxide (1.37 g,12.2 mmol), tris (dibenzylideneacetone) dipalladium (385 mg,0.41 mmol) and bis (2-diphenylphosphino) phenyl ether (0.48 g,0.87 mmol) in toluene (15 mL) and concentrating and drying to give the title compound as a colorless oil (1.35 g, 53.7%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =50/1).
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.36–7.34(m,1H),7.27–7.20(m,4H),7.04–6.99(m,2H),6.44(s,1H),4.29(td,J＝6.3,4.2Hz,2H),4.05(td,J＝6.7,4.4Hz,2H).
Step 2) Synthesis of 2- (2-fluoro-6- ((3-chlorophenyl) sulfonyl) phenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 3 by reacting 2- (2-fluoro-6- ((3-chlorophenyl) thio) phenyl) -1, 3-dioxolane (1.3 g,4.2 mmol), m-chloroperoxybenzoic acid (2.3 g,11 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) to give the title compound as a pale yellow oil (1.1 g, 70%).
MS(ESI,pos.ion)m/z:343.8[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.95(d,J＝8.1Hz,1H),7.53(td,J＝8.0,4.9Hz,1H),7.48–7.26(m,5H),7.14–7.12(m,1H),6.80(d,J＝1.7Hz,1H),4.31–4.11(m,2H),4.09–3.91(m,2H).
Step 3) Synthesis of 2-fluoro-6- ((3-chlorophenyl) sulfonyl) benzaldehyde
The title compound was prepared as described in example 1, step 4 by reacting 2- (2-fluoro-6- ((3-chlorophenyl) sulfonyl) phenyl) -1, 3-dioxolane (0.91 g,2.65 mmol), trifluoroacetic acid (1.8 g,16.1 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) to give the title compound as a white solid (0.66 g, 83.2%).
MS(ESI,pos.ion)m/z:298.9[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)10.57(s,1H),8.00(d,J＝7.9Hz,1H),7.86(d,J＝1.7Hz,1H),7.80(d,J＝7.8Hz,1H),7.73(td,J＝8.2,5.0Hz,1H),7.57(d,J＝8.2Hz,1H),7.53–7.41(m,2H).
Step 4) Synthesis of 2- ((3-chlorophenyl) sulfonyl) -6- (piperazin-1-yl) benzaldehyde
The title compound was prepared as described in example 1, step 5 by reacting 2-fluoro-6- ((3-chlorophenyl) sulfonyl) benzaldehyde (630 mg,2.11 mmol), piperazine (550 mg,6.38 mmol), potassium carbonate (600 mg,4.30 mmol) in acetonitrile (10 mL) and drying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =15/1) to give the title compound as a pale yellow oil (680 mg, 88.1%).
MS(ESI,pos.ion)m/z:365.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)10.43(s,1H),7.92(dd,J＝4.7,2.8Hz,2H),7.87(d,J＝7.8Hz,1H),7.64(t,J＝8.0Hz,1H),7.56(d,J＝8.2Hz,1H),7.47(dd,J＝16.1,8.1Hz,2H),2.97–2.96(m,8H).
Step 5) 2- ((3-chlorophenyl) sulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde Synthesis
The title compound was prepared as described in example 1, step 6 by reacting 2- ((3-chlorophenyl) sulfonyl) -6- (piperazin-1-yl) benzaldehyde (660 mg,1.81 mmol), trifluoroacetic anhydride (570 mg,2.71 mmol), triethylamine (0.75 mL,5.44 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =2/1) to give the title compound as a yellow oil (560 mg, 67.2%).
MS(ESI,pos.ion)m/z:461.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)10.55(s,1H),7.91(dd,J＝6.8,5.0Hz,2H),7.84(d,J＝7.8Hz,1H),7.66(t,J＝8.0Hz,1H),7.59(d,J＝8.6Hz,1H),7.50(t,J＝7.9Hz,1H),7.43(d,J＝8.1Hz,1H),3.85–3.78(m,2H),3.76–3.68(m,2H),3.04(dd,J＝7.8,4.6Hz,4H).
Step 6) 1- (4- (2- (difluoromethyl) -3- ((3-chlorophenyl) sulfonyl) phenyl) piperazin-1-yl) -2, 2-tri Synthesis of fluoroacetyl
The title compound was prepared as described in example 1, step 7 by reacting 2- ((3-chlorophenyl) sulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde (500 mg,1.08 mmol) in diethylaminosulfur trifluoride (4.0 mL,30.4 mmol) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) to give the title compound as a yellow solid (0.316 g, 60.3%).
MS(ESI,pos.ion)m/z:483.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.15(d,J＝7.9Hz,1H),7.84(d,J＝1.7Hz,1H),7.79(d,J＝7.8Hz,1H),7.72(t,J＝8.0Hz,1H),7.59(t,J＝8.1Hz,2H),7.54(t,J＝53.6Hz,1H),7.51(t,J＝7.9Hz,1H),3.85(brs,2H),3.80–3.73(m,2H),3.02(d,J＝4.3Hz,4H).
Step 7) Synthesis of 1- (2- (difluoromethyl) -3- ((3-chlorophenyl) sulfonyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 8 by reacting 1- (4- (2- (difluoromethyl) -3- ((3-chlorophenyl) sulfonyl) phenyl) piperazin-1-yl) -2, 2-trifluoroacetyl (0.312 g,0.65 mmol), potassium carbonate (0.3 g,2.15 mmol) in tetrahydrofuran (3 mL), ethanol (3 mL), water (3 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =20/1) and concentrating and drying to give the title compound as a yellow solid (220 mg, 88%).
MS(ESI,pos.ion)m/z:386.8[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.12(d,J＝7.9Hz,1H),7.83(s,1H),7.77(d,J＝7.8Hz,1H),7.67(t,J＝8.0Hz,1H),7.56(d,J＝8.2Hz,1H),7.53(d,J＝8.2Hz,1H),7.44(t,J＝7.9Hz,1H),7.37(t,J＝54.0Hz,1H),3.28(s,1H),3.02(d,J＝3.9Hz,4H),2.95(d,J＝3.9Hz,4H).
Example 9 1 Synthesis of- (2- (difluoromethyl) -3- ((4-fluorophenyl) sulfonyl) phenyl) piperazine
Figure BDA0001666881410000371
Step 1) 2- ((4-fluorophenyl) thio) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde Finished products
The title compound was prepared as described in example 2, step 3 by reacting 2-bromo-6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde (1.4 g,3.83 mmol), 4-fluorobenzylthiophenol (0.64 g,4.98 mmol), potassium tert-butoxide (0.58 g,5.2 mmol), tris (dibenzylideneacetone) dipalladium (0.18 g,0.19 mmol) and bis (2-diphenylphosphino) phenyl ether (0.22 g,0.40 mmol) in toluene (15 mL) and concentrating and drying to give the title compound as a yellow oil (1.28 g, 80.9%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =20/1). MS (ESI, pos.ion) m/z 412.8[ M+H ]] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.41(s,1H),7.59(dd,J＝8.8,5.6Hz,2H),7.37–7.31(m,3H),7.02(d,J＝8.0Hz,1H),6.37(d,J＝8.4Hz,1H),3.80–3.77(m,4H),3.13–3.09(m,4H).
Step 2) 1- (4- (2- (difluoromethyl) -3- ((4-fluorophenyl) thio) phenyl) piperazin-1-yl) -2, 2-trifluoro Synthesis of acetyl
The title compound was prepared as described in example 1, step 7 by reacting 2- ((4-fluorophenyl) thio) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde (1.28 g,3.1 mmol) in diethylaminosulfur trifluoride (5.0 mL,38.2 mmol) and subjecting the crude product to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) and concentrated to dryness to give the title compound as a white solid (1.0 g, 74.2%).
MS(ESI,pos.ion)m/z:435.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.45(dd,J＝8.8,5.2Hz,2H),7.39(d,J＝54.4Hz,1H),7.28–7.22(m,1H),7.07(t,J＝8.8Hz,2H),7.00(d,J＝8.0Hz,1H),6.86(d,J＝8.0Hz,1H),3.86(brs,2H),3.77(brs,2H),3.01(t,J＝4.8Hz,4H).
Step 3) 1- (4- (2- (difluoromethyl) -3- ((4-fluorophenyl) sulfonyl) phenyl) piperazin-1-yl) -2, 2-tris Synthesis of fluoroacetyl
The title compound was prepared as described in example 1, step 3 by reacting 1- (4- (2- (difluoromethyl) -3- ((4-fluorophenyl) thio) phenyl) piperazin-1-yl) -2, 2-trifluoroacetyl (1.0 g,2.3 mmol), m-chloroperoxybenzoic acid (1.8 g,8.34 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) to give the title compound as a pale yellow solid (0.73 g, 68.0%).
MS(ESI,pos.ion)m/z:466.7[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.09(d,J＝8.0Hz,1H),7.92–7.86(m,2H),7.68(d,J＝8.4Hz,1H),7.55(d,J＝5.2Hz,1H),7.52(t,J＝50.4Hz,1H),7.21(t,J＝8.4Hz,2H),3.82(brs,2H),3.74(t,J＝4.4Hz,2H),2.99(t,J＝4.4Hz,4H).
Step 4) Synthesis of 1- (2- (difluoromethyl) -3- ((4-fluorophenyl) sulfonyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 8 by reacting 1- (4- (2- (difluoromethyl) -3- ((4-fluorophenyl) sulfonyl) phenyl) piperazin-1-yl) -2, 2-trifluoroacetyl (0.73 g,1.57 mmol), potassium carbonate (0.65 g,4.7 mmol) in tetrahydrofuran (3 mL), ethanol (3 mL), water (3 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =20/1) and concentrating and drying to give the title compound as a yellow solid (330 mg, 56.9%).
MS(ESI,pos.ion)m/z:371.0[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.12(d,J＝7.8Hz,1H),8.02–7.97(m,2H),7.87(t,J＝7.8Hz,1H),7.77(d,J＝8.4Hz,1H),7.50(t,J＝9.0Hz,2H),7.40(t,J＝54.0Hz,1H),2.87(t,J＝4.8Hz,4H),2.85(t,J＝4.8Hz,4H).
Example 10 Synthesis of 1- (2- (difluoromethyl) -3- ((4-chlorophenyl) sulfonyl) phenyl) piperazine
Figure BDA0001666881410000381
Step 1) Synthesis of 2- (2-fluoro-6- ((4-chlorophenyl) thio) phenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 2 by reacting 2- (2-bromo-6-fluorophenyl) -1, 3-dioxolane (1.2 g,4.86 mmol), 4-chlorophenylthiol (0.77 g,5.29 mmol), potassium tert-butoxide (0.71 g,6.28 mmol), tris (dibenzylideneacetone) dipalladium (0.23 g,0.24 mmol) and bis (2-diphenylphosphino) phenyl ether (0.28 g,0.5 mmol) in toluene (15 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =50/1) to give the title compound as a colorless oil (0.62 g, 41.1%).
MS(ESI,pos.ion)m/z:310.9[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.49–7.44(m,2H),7.41(td,J＝8.0,5.6Hz,1H),7.35–7.30(m,2H),7.20(ddd,J＝10.8,2.4,0.8Hz,1H),6.99(d,J＝8.0Hz,1H),6.27(s,1H),4.14(t,J＝6.8Hz,2H),3.95(t,J＝6.8Hz,2H).
Step 2) Synthesis of 2- (2-fluoro-6- ((4-chlorophenyl) sulfonyl) phenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 3 by reacting 2- (2-fluoro-6- ((4-chlorophenyl) thio) phenyl) -1, 3-dioxolane (1.2 g,3.86 mmol), m-chloroperoxybenzoic acid (2.08 g,9.64 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) to give the title compound as a pale yellow oil (1.23 g, 92.9%).
MS(ESI,pos.ion)m/z:343.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)7.99(d,J＝7.8Hz,1H),7.91–7.86(m,2H),7.78(td,J＝7.8,4.8Hz,1H),7.74–7.70(m,2H),7.66(dd,J＝10.8,8.4Hz,1H),6.50(d,J＝1.2Hz,1H),4.09–4.02(m,2H),3.88(t,J＝6.8Hz,2H).
Step 3) Synthesis of 2-fluoro-6- ((4-chlorophenyl) sulfonyl) benzaldehyde
The title compound was prepared as described in example 1, step 4 by reacting 2- (2-fluoro-6- ((4-chlorophenyl) sulfonyl) phenyl) -1, 3-dioxolane (1.19 g,3.47 mmol), trifluoroacetic acid (1.8 g,16.1 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) to give the title compound as a white solid (1.03 g, 99.3%).
MS(ESI,pos.ion)m/z:299.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)10.43(s,1H),8.00–7.94(m,3H),7.87(td,J＝8.4,5.4Hz,1H),7.76–7.70(m,3H).
Step 4) Synthesis of 2- ((4-chlorophenyl) sulfonyl) -6- (piperazin-1-yl) benzaldehyde
The title compound was prepared as described in example 1, step 5 by reacting 2-fluoro-6- ((4-chlorophenyl) sulfonyl) benzaldehyde (1.03 g,3.45 mmol), piperazine (480 mg,10.0 mmol), potassium carbonate (480 mg,7.1 mmol) in acetonitrile (10 mL) and drying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =15/1) to give the title compound as a pale yellow solid (950 mg, 75.4%). MS (ESI, pos.ion) m/z 365.1[ M+H ]] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)10.34(s,1H),7.89(d,J＝8.4Hz,2H),7.82(d,J＝7.6Hz,1H),7.74(t,J＝8.4Hz,1H),7.72(d,J＝8.4Hz,2H),7.61(d,J＝7.8Hz,1H),2.82(t,J＝4.8Hz,4H),2.75(t,J＝4.8Hz,4H).
Step 5) 2- ((4-chlorophenyl) sulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde Synthesis
The title compound was prepared as described in example 1, step 6 by reacting 2- ((4-chlorophenyl) sulfonyl) -6- (piperazin-1-yl) benzaldehyde (940 mg,2.58 mmol), trifluoroacetic anhydride (0.55 mL,3.90 mmol), triethylamine (0.72 mL,5.2 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =2/1) to give the title compound as a yellow solid (870 mg, 73.3%).
MS(ESI,pos.ion)m/z:461.0[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)10.39(s,1H),7.86–7.82(m,3H),7.71(t,J＝7.8Hz,1H),7.68–7.65(m,2H),7.62(d,J＝7.8Hz,1H),3.62–3.56(m,4H),2.96(t,J＝4.8Hz,2H),2.94(t,J＝4.8Hz,2H).
Step 6) 1- (4- (2- (difluoromethyl) -3- ((4-chlorophenyl) sulfonyl) phenyl) piperazin-1-yl) -2, 2-tris Synthesis of fluoroacetyl
The title compound was prepared as described in example 1, step 7 by reacting 2- ((4-chlorophenyl) sulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde (870 mg,1.89 mmol) in diethylaminosulfur trifluoride (4.0 ml,30.4 mmol) and subjecting the crude product to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) and concentrated to dryness to give the title compound as a yellow solid (0.75 g, 82.3%).
MS(ESI,pos.ion)m/z:483.0[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.17(t,J＝4.8Hz,1H),7.91(d,J＝8.4Hz,2H),7.88(d,J＝4.8Hz,2H),7.72(d,J＝8.4Hz,2H),7.50(t,J＝53.8Hz,1H),3.79–3.70(m,4H),3.00–2.97(m,4H).
Step 7) Synthesis of 1- (2- (difluoromethyl) -3- ((4-chlorophenyl) sulfonyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 8 by reacting 1- (4- (2- (difluoromethyl) -3- ((4-chlorophenyl) sulfonyl) phenyl) piperazin-1-yl) -2, 2-trifluoroacetyl (0.75 g,1.55 mmol), potassium carbonate (0.66 g,4.78 mmol) in tetrahydrofuran (3 mL), ethanol (3 mL), water (3 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =20/1) and concentrating and drying to give the title compound as a yellow solid (490 mg, 81.5%).
MS(ESI,pos.ion)m/z:386.8[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.10–8.06(m,1H),7.86(d,J＝9.0Hz,2H),7.82(t,J＝7.8Hz,1H),7.73(d,J＝7.8Hz,1H),7.70–7.66(m,2H),7.33(t,J＝53.8Hz,1H),2.84–2.80(m,4H),2.80–2.79(m,4H).
EXAMPLE 11 Synthesis of 1- (2- (difluoromethyl) -3- ((4-bromophenyl) sulfonyl) phenyl) piperazine
Figure BDA0001666881410000401
Step 1) Synthesis of 2- ((4-bromophenyl) thio) -6-fluorobenzaldehyde
2, 6-difluorobenzaldehyde (0.76 g,5.35 mmol), 4-bromothiophenol (0.50 g,2.64 mmol), potassium carbonate (0.78 g,5.6 mmol) and N, N-dimethylformamide (10 mL) were added to a 100mL single-neck round-bottom flask and reacted at 80℃in an oil bath for 12 hours; the reaction was stopped, ethyl acetate (30 mL) was added, washed with water (30 ml×2), the organic phase was dried over anhydrous sodium sulfate (5 g), filtered, and the filtrate was dried under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =50/1), and concentrated and dried to give the title compound as a yellowish green solid (0.82 g, 65.8%).
MS(ESI,pos.ion)m/z:310.8[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)10.39(s,1H),7.71(d,J＝8.4Hz,2H),7.49(d,J＝8.4Hz,2H),7.24(t,J＝9.0Hz,1H),7.17(dd,J＝10.2,7.8Hz,1H),6.59(d,J＝8.4Hz,1H).
Step 2) Synthesis of 2- (2- ((4-bromophenyl) thio) -6-fluorophenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 1 by reacting 2- ((4-bromophenyl) thio) -6-fluorobenzaldehyde (4.02 g,12.9 mmol), 4-methylbenzenesulfonic acid (0.25 g,1.5 mmol) and ethylene glycol (8 mL,143 mmol) in toluene (20 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) to give the title compound as a yellow solid (3.0 g, 65.7%).
MS(ESI,pos.ion)m/z:354.8[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)7.60–7.57(m,2H),7.42(td,J＝8.4,6.0Hz,1H),7.27–7.23(m,2H),7.23–7.19(m,1H),7.01(d,J＝7.8Hz,1H),6.27(s,1H),4.16–4.13(m,2H),3.98–3.94(m,2H).
Step 3) Synthesis of 2- (2- ((4-bromophenyl) sulfonyl) -6-fluorophenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 3 by reacting 2- (2- ((4-bromophenyl) thio) -6-fluorophenyl) -1, 3-dioxolane (3.0 g,8.45 mmol), m-chloroperoxybenzoic acid (3.68 g,21.3 mmol) in dichloromethane (20 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) to give the title compound as a white solid (1.80 g, 55.0%).
MS(ESI,pos.ion)m/z:387.0[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.00(d,J＝7.8Hz,1H),7.90–7.86(m,2H),7.83–7.77(m,3H),7.67(dd,J＝10.8,8.4Hz,1H),6.51(d,J＝1.2Hz,1H),4.05(t,J＝6.8Hz,2H),3.90(t,J＝6.8Hz,2H).
Step 4) Synthesis of 2- ((4-bromophenyl) sulfonyl) -6-fluorobenzaldehyde
The title compound was prepared as described in example 1, step 4 by reacting 2- (2- ((4-bromophenyl) sulfonyl) -6-fluorophenyl) -1, 3-dioxolane (1.80 g,4.65 mmol), trifluoroacetic acid (5.0 mL,67.1 mmol) in dichloromethane (15 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) to give the title compound as a white solid (1.2 g, 75.2%).
MS(ESI,pos.ion)m/z:343.0[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.45(s,1H),8.01(d,J＝7.6Hz,1H),7.94–7.85(m,5H),7.76(t,J＝8.8Hz,1H).
Step 5) Synthesis of 2- ((4-bromophenyl) sulfonyl) -6- (piperazin-1-yl) benzaldehyde
The title compound was prepared as described in example 1, step 5 by reacting 2- ((4-bromophenyl) sulfonyl) -6-fluorobenzaldehyde (1.2 g,3.5 mmol), piperazine (0.89 g,10.0 mmol), potassium carbonate (0.98 g,7.1 mmol) in acetonitrile (20 mL) and drying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =15/1) to give the title compound as a yellow solid (1.05 g, 73.4%).
MS(ESI,pos.ion)m/z:409.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)10.32(s,1H),7.87–7.84(m,2H),7.83–7.79(m,3H),7.74(t,J＝7.8Hz,1H),7.60(dd,J＝8.4,1.2Hz,1H),2.81(t,J＝4.8Hz,4H),2.74(t,J＝4.8Hz,4H).
Step 6) 2- ((4-bromophenyl) sulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde Synthesis
The title compound was prepared as described in example 1, step 6 by reacting 2- ((4-bromophenyl) sulfonyl) -6- (piperazin-1-yl) benzaldehyde (1.05 g,2.57 mmol), trifluoroacetic anhydride (0.55 mL,3.9 mmol), triethylamine (1.0 mL,7.2 mmol) in dichloromethane (20 mL) and drying to give the title compound as a yellow solid (1.15 g, 88.7%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =2/1).
MS(ESI,pos.ion)m/z:504.6[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)10.45(s,1H),7.89(d,J＝7.8Hz,1H),7.88–7.86(m,2H),7.84–7.80(m,2H),7.77(t,J＝7.8Hz,1H),7.69(d,J＝7.8Hz,1H),3.68–3.62(m,4H),3.02(t,J＝4.8Hz,2H),3.00(t,J＝4.8Hz,2H).
Step 7) 1- (4- (3- ((4-bromophenyl) sulfonyl) -2- (difluoromethyl) phenyl) piperazin-1-yl) -2, 2-tris Synthesis of fluoroacetyl
The title compound was prepared as described in example 1, step 7 by reacting 2- ((4-bromophenyl) sulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde (1.15 g,2.28 mmol) in diethylaminosulfur trifluoride (5.0 mL,38.2 mmol) and subjecting the crude product to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) and concentrated to dryness to give the title compound as a white solid (0.60 g, 50.2%).
MS(ESI,pos.ion)m/z:527.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.14(t,J＝4.4Hz,1H),7.88–7.79(m,6H),7.47(t,J＝53.4Hz,1H),3.72(brs,4H),2.99–2.95(m,4H).
Step 8) Synthesis of 1- (2- (difluoromethyl) -3- ((4-bromophenyl) sulfonyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 8 by reacting 1- (4- (3- ((4-bromophenyl) sulfonyl) -2- (difluoromethyl) phenyl) piperazin-1-yl) -2, 2-trifluoroacetyl (0.6 g,1.14 mmol), potassium carbonate (0.47 g,3.4 mmol) in tetrahydrofuran (5 mL), ethanol (5 mL), water (5 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =20/1) and concentrating and drying to give the title compound as a white solid (0.45 g, 91.7%).
MS(ESI,pos.ion)m/z:430.7[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.10(dd,J＝7.8,0.6Hz,1H),7.86–7.84(m,3H),7.81–7.79(m,2H),7.76(d,J＝7.8Hz,1H),7.35(t,J＝53.8Hz,1H),2.84(t,J＝4.8Hz,4H),2.81(t,J＝4.8Hz,4H).
EXAMPLE 12 Synthesis of 1- (2- (difluoromethyl) -3-p-toluenesulfonyl) piperazine
Figure BDA0001666881410000421
Step 1) Synthesis of 2- (2-fluoro-6- (p-toluenesulfonio) phenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 2 by reacting 2- (2-bromo-6-fluorophenyl) -1, 3-dioxolane (1.5 g,7.26 mmol), p-toluene thiophenol (840 mg,6.72 mmol), potassium tert-butoxide (720 mg,7.26 mmol), tris (dibenzylideneacetone) dipalladium (280 mg,0.31 mmol) and bis (2-diphenylphosphino) phenyl ether (0.34 g,0.61 mmol) in toluene (10 mL) and concentrating and drying to give the title compound as a white solid (1.29 g, 73.2%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =50/1).
MS(ESI,pos.ion)m/z:291.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.36–7.23(m,5H),7.09(dd,J＝10.4,8.8Hz,1H),6.79(d,J＝8.0Hz,1H),6.28(s,1H),4.16(t,J＝6.8Hz,2H),3.97(t,J＝6.8Hz,2H),2.32(s,3H).
Step 2) Synthesis of 2- (2-fluoro-6- (p-toluenesulfonyl) phenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 3 by reacting 2- (2-fluoro-6- (p-toluenesulfonic) phenyl) -1, 3-dioxolane (1.05 g,3.62 mmol), m-chloroperoxybenzoic acid (1.95 g,9.04 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) to give the title compound as a pale yellow solid (1.11 g, 95.2%).
MS(ESI,pos.ion)m/z:322.9[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.92(d,J＝8.0Hz,1H),7.77–7.70(m,3H),7.60(dd,J＝10.8,8.8Hz,1H),7.44(d,J＝8.0Hz,2H),6.56(d,J＝1.6Hz,1H),4.03(t,J＝6.8Hz,2H),3.87(t,J＝6.8Hz,2H),2.38(s,3H).
Step 3) Synthesis of 2-fluoro-6- (p-toluenesulfonyl) benzaldehyde
The title compound was prepared as described in example 1, step 4 by reacting 2- (2-fluoro-6- (p-toluenesulfonyl) phenyl) -1, 3-dioxolane (1.11 g,3.44 mmol), trifluoroacetic acid (1.6 mL,21.5 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) to give the title compound as a white solid (0.84 g, 98.2%).
MS(ESI,pos.ion)m/z:279.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.50(s,1H),7.95(d,J＝7.6Hz,1H),7.90–7.83(m,3H),7.73(t,J＝9.2Hz,1H),7.48(d,J＝8.0Hz,2H),2.40(s,3H).
Step 4) Synthesis of 2- (piperazin-1-yl) -6- (p-toluenesulfonyl) benzaldehyde
The title compound was prepared as described in example 1, step 5 by reacting 2-fluoro-6- (p-toluenesulfonyl) benzaldehyde (940 mg,3.38 mmol), piperazine (730 mg,8.45 mmol), potassium carbonate (950 mg,6.87 mmol) in acetonitrile (10 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =15/1) and concentrating and drying to give the title compound as a pale yellow solid (910 mg, 78.1%). MS (ESI, pos.ion) m/z 344.9[ M+H ] ] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.39(s,1H),7.77(t,J＝8.4Hz,3H),7.70(t,J＝7.6Hz,1H),7.56(d,J＝7.6Hz,1H),7.44(d,J＝8.4Hz,2H),2.81(brs,4H),2.75(brs,4H),2.39(s,3H).
Step 5) Synthesis of 2- (p-toluenesulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde
The title compound was prepared as described in example 1, step 6 by reacting 2- (piperazin-1-yl) -6- (p-toluenesulfonyl) benzaldehyde (480 mg,2.85 mmol), trifluoroacetic anhydride (0.6 mL,4.3 mmol), triethylamine (0.98 mL,7.1 mmol) in dichloromethane (10 mL) and drying to give the title compound as a yellow solid (960 mg, 76.8%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =2/1).
MS(ESI,pos.ion)m/z:441.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.49(s,1H),7.82(d,J＝7.6Hz,1H),7.79(d,J＝8.0Hz,2H),7.73(t,J＝8.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.45(d,J＝8.4Hz,2H),3.65(brs,4H),3.00(brs,4H),2.39(s,3H).
Step 6) 1- (4- (2- (difluoromethyl) -3- (p-toluenesulfonyl) phenyl) piperazin-1-yl) -2, 2-trifluoroethyl Synthesis of acyl groups
The title compound was prepared as described in example 1, step 7 by reacting 2- (p-toluenesulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde (960 mg,2.18 mmol) in diethylaminosulfur trifluoride (2.0 ml,15.2 mmol) and subjecting the crude product to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) followed by concentration and drying to give the title compound as a white solid (0.53 g, 52.5%).
MS(ESI,pos.ion)m/z:462.8[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.05(dd,J＝6.0,2.0Hz,1H),7.85–7.79(m,2H),7.76(d,J＝8.4Hz,2H),7.50(t,J＝54.8Hz,1H),7.42(d,J＝8.4Hz,2H),3.68(brs,4H),2.93(brs,4H),2.37(s,3H).
Step 7) Synthesis of 1- (2- (difluoromethyl) -3- (p-toluenesulfonyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 8 by reacting 1- (4- (2- (difluoromethyl) -3- (p-toluenesulfonyl) phenyl) piperazin-1-yl) -2, 2-trifluoroacetyl (0.53 g,1.15 mmol), potassium carbonate (0.5 g,3.62 mmol) in tetrahydrofuran (3 mL), ethanol (3 mL), water (3 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =20/1), concentrating and drying to give the title compound as a yellow solid (300 mg, 71.4%).
MS(ESI,pos.ion)m/z:366.9[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.07(d,J＝7.8Hz,1H),7.85(t,J＝8.4Hz,1H),7.80(d,J＝8.4Hz,2H),7.77(d,J＝7.8Hz,1H),7.47(d,J＝7.8Hz,2H),7.43(t,J＝53.4Hz,1H),2.87(t,J＝6.6Hz,4H),2.84(t,J＝6.6Hz,4H),2.43(s,3H).
Example 13 Synthesis of 1- (2- (difluoromethyl) -3- ((4-methoxyphenyl) sulfonyl) phenyl) piperazine
Figure BDA0001666881410000441
Step 1) Synthesis of 2- (2-fluoro-6- ((4-methoxyphenyl) thio) phenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 2 by reacting 2- (2-bromo-6-fluorophenyl) -1, 3-dioxolane (1.2 g,4.86 mmol), 4-methoxyphenylthiophenol (770 mg,5.46 mmol), potassium tert-butoxide (704 mg,6.28 mmol), tris (dibenzylideneacetone) dipalladium (230 mg,0.24 mmol) and bis (2-diphenylphosphinophenone) ether (0.28 g,0.50 mmol) in toluene (10 mL) and concentrating and drying to give the title compound as a white solid (1.05 g, 70.6%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =50/1). MS (ESI, pos.ion) m/z 307.2[ M+H ]] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.42(d,J＝8.8Hz,2H),7.29(td,J＝8.0,6.0 Hz,1H),7.03–6.98(m,3H),6.65(d,J＝8.0Hz,1H),6.27(s,1H),4.18(t,J＝6.8Hz,2H),3.99(t,J＝6.8Hz,2H),3.80(s,3H).
Step 2) Synthesis of 2- (2-fluoro-6- ((4-methoxyphenyl) sulfonyl) phenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 3 by reacting 2- (2-fluoro-6- ((4-methoxyphenyl) thio) phenyl) -1, 3-dioxolane (1.05 g,3.43 mmol), m-chloroperoxybenzoic acid (1.88 g,8.72 mmol) in dichloromethane (10 mL) and drying to give the title compound as a white solid (1.04 g, 89.7%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1).
MS(ESI,pos.ion)m/z:339.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)7.90(d,J＝8.4Hz,1H),7.84–7.80(m,2H),7.75(td,J＝8.4,4.8Hz,1H),7.61(dd,J＝10.8,8.4Hz,1H),7.20–7.15(m,2H),6.62(d,J＝1.2Hz,1H),4.07(t,J＝6.6Hz,1H),3.92(t,J＝6.6Hz,1H),3.87(s,3H).
Step 3) Synthesis of 2-fluoro-6- ((4-methoxyphenyl) sulfonyl) benzaldehyde
The title compound was prepared as described in example 1, step 4 by reacting 2- (2-fluoro-6- ((4-methoxyphenyl) sulfonyl) phenyl) -1, 3-dioxolane (1.04 g,3.10 mmol), trifluoroacetic acid (1.4 mL,18.8 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) to give the title compound as a white solid (0.91 g, 99.7%).
MS(ESI,pos.ion)m/z:295.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)10.52(s,1H),7.93–7.90(m,3H),7.85(td,J＝8.0,4.8Hz,1H),7.71(t,J＝9.6Hz,1H),7.20–7.17(m,2H),3.86(s,3H).
Step 4) Synthesis of 2- ((4-methoxyphenyl) sulfonyl) -6- (piperazin-1-yl) benzaldehyde
The title compound was prepared as described in example 1, step 5 by reacting 2-fluoro-6- ((4-methoxyphenyl) sulfonyl) benzaldehyde (910 mg,3.09 mmol), piperazine (680 mg,10 mmol), potassium carbonate (880 mg,6.4 mmol) in acetonitrile (10 mL) and drying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =15/1) to give the title compound as a pale yellow oil (520 mg, 46.7%).
MS(ESI,pos.ion)m/z:361.2[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)10.40(s,1H),7.83(d,J＝9.0Hz,2H),7.72(d,J＝7.2Hz,1H),7.68(t,J＝8.4Hz,1H),7.54(d,J＝7.8Hz,1H),7.15(d,J＝9.0Hz,2H),3.84(s,3H),2.81–2.80(m,4H),2.75–2.73(m,4H).
Step 5) 2- ((4-methoxyphenyl) sulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzyl Synthesis of aldehydes
The title compound was prepared as described in example 1, step 6 by reacting 2- ((4-methoxyphenyl) sulfonyl) -6- (piperazin-1-yl) benzaldehyde (520 mg,1.44 mmol), trifluoroacetic anhydride (0.38 mL,2.70 mmol), triethylamine (0.54 mL,3.9 mmol) in dichloromethane (10 mL) and drying to give the title compound as a yellow solid (400 mg, 60.7%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =2/1).
MS(ESI,pos.ion)m/z:457.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)10.49(s,1H),7.82(d,J＝8.4Hz,2H),7.77(d,J＝7.8Hz,1H),7.70(t,J＝8.4Hz,1H),7.61(d,J＝7.8Hz,1H),7.14(d,J＝9.0Hz,2H),3.83(s,3H),3.67–3.59(m,4H),2.99(t,J＝4.8Hz,2H),2.97(t,J＝4.8Hz,2H).
Step 6) 1- (4- (2- (difluoromethyl) -3- ((4-methoxyphenyl) sulfonyl) phenyl) piperazin-1-yl) -2, synthesis of 2-trifluoroacetyl
The title compound was prepared as described in example 1, step 7 by reacting 2- ((4-methoxyphenyl) sulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde (400 mg,0.87 mmol) in diethylaminosulfur trifluoride (2.0 ml,15.2 mmol) and subjecting the crude product to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) and concentrated to dryness to give the title compound as a white solid (0.25 g, 59.6%).
MS(ESI,pos.ion)m/z:478.8[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)7.98(dd,J＝6.6,1.8Hz,1H),7.81–7.74(m,4H),7.50(t,J＝53.8Hz,1H),7.12–7.08(m,2H),3.80(s,3H),3.71–3.62(m,4H),2.94–2.87(m,4H).
Step 7) Synthesis of 1- (2- (difluoromethyl) -3- ((4-methoxyphenyl) sulfonyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 8 by reacting 1- (4- (2- (difluoromethyl) -3- ((4-methoxyphenyl) sulfonyl) phenyl) piperazin-1-yl) -2, 2-trifluoroacetyl (0.37 g,0.77 mmol), potassium carbonate (0.32 g,2.31 mmol) in tetrahydrofuran (3 mL), ethanol (3 mL), water (3 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =20/1) and concentrating and drying to give the title compound as a white solid (240 mg, 81.1%).
MS(ESI,pos.ion)m/z:383.0[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.01(d,J＝7.8Hz,1H),7.85(d,J＝9.0Hz,2H),7.81(t,J＝7.8Hz,1H),7.73(d,J＝7.8Hz,1H),7.45(t,J＝53.8Hz,1H),7.17(d,J＝9.0Hz,2H),3.87(s,3H),2.86(t,J＝4.8Hz,4H),2.82(t,J＝4.8Hz,4H).
EXAMPLE 14 Synthesis of 1- (2- (difluoromethyl) -3- ((4-trifluoromethylphenyl) sulfonyl) phenyl) piperazine
Figure BDA0001666881410000461
Step 1) Synthesis of 2- (2-fluoro-6- ((4-trifluoromethylphenyl) thio) phenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 2 by reacting 2- (2-bromo-6-fluorophenyl) -1, 3-dioxolane (1.0 g,4.05 mmol), 4-trifluoromethylphenyl thiophenol (920 mg,5.16 mmol), potassium tert-butoxide (610 mg,5.39 mmol), tris (dibenzylideneacetone) dipalladium (190 mg,0.20 mmol) and bis (2-diphenylphosphino) phenyl ether (0.24 g,0.43 mmol) in toluene (10 mL) and concentrating and drying to give the title compound as a yellow oil (1.16 g, 83.2%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =50/1).
MS(ESI,pos.ion)m/z:345.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)7.71(d,J＝8.4Hz,2H),7.52(td,J＝8.4,6.0Hz,1H),7.39–7.32(m,3H),7.26(d,J＝7.6Hz,1H),6.29(s,1H),4.14(t,J＝6.8Hz,2H),3.95(t,J＝6.8Hz,2H).
Step 2) Synthesis of 2- (2-fluoro-6- ((4-trifluoromethylphenyl) sulfonyl) phenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 3 by reacting 2- (2-fluoro-6- ((4-trifluoromethylphenyl) thio) phenyl) -1, 3-dioxolane (1.16 g,3.37 mmol), m-chloroperoxybenzoic acid (1.78 g,8.25 mmol) in dichloromethane (10 mL) and drying to give the title compound as a white solid (0.96 g, 75.7%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1).
MS(ESI,pos.ion)m/z:377.1[M+H] + ；
1 H NMR(600MHz,CDCl3)δ(ppm)8.11(d,J＝7.8Hz,2H),8.07(d,J＝7.8Hz,1H),8.04(d,J＝8.4Hz,2H),7.83(td,J＝8.4,4.8Hz,1H),7.70(dd,J＝10.8,8.0Hz,1H),6.49(d,J＝1.2Hz,1H),4.04(t,J＝6.8Hz,2H),3.88(t,J＝6.8Hz,2H).
Step 3) Synthesis of 2-fluoro-6- ((4-trifluoromethylphenyl) sulfonyl) benzaldehyde
The title compound was prepared as described in example 1, step 4 by reacting 2- (2-fluoro-6- ((4-trifluoromethylphenyl) sulfonyl) phenyl) -1, 3-dioxolane (0.96 g,2.55 mmol), trifluoroacetic acid (1.1 mL,14.8 mmol) in dichloromethane (10 mL) and drying to give the title compound as a white solid (0.81 g, 95.5%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1).
MS(ESI,pos.ion)m/z:333.0[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)10.44(s,1H),8.20(d,J＝8.4Hz,2H),8.09(d,J＝7.8Hz,1H),8.05(d,J＝8.4Hz,2H),7.93(td,J＝8.4,5.4Hz,1H),7.80(t,J＝9.0Hz,1H).
Step 4) Synthesis of 2- ((4-trifluoromethylphenyl) sulfonyl) -6- (piperazin-1-yl) benzaldehyde
The title compound was prepared as described in example 1, step 5 by reacting 2-fluoro-6- ((4-trifluoromethylphenyl) sulfonyl) benzaldehyde (720 mg,2.44 mmol), piperazine (680 mg,7.9 mmol) and potassium carbonate (680 mg,4.9 mmol) in acetonitrile (10 mL) and drying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =15/1) to give the title compound as a pale yellow solid (460 mg, 50.5%).
MS(ESI,pos.ion)m/z:398.8[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)10.29(s,1H),8.07(d,J＝8.4Hz,2H),8.01(d,J＝8.4Hz,2H),7.89(d,J＝7.2Hz,1H),7.77(t,J＝8.4Hz,1H),7.63(d,J＝7.8Hz,1H),2.82(t,J＝5.4Hz,4H),2.74(t,J＝5.4Hz,4H).
Step 5) 2- ((4-trifluoromethylphenyl) sulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzene Synthesis of formaldehyde
The title compound was prepared as described in example 1, step 6 by reacting 2- ((4-trifluoromethylphenyl) sulfonyl) -6- (piperazin-1-yl) benzaldehyde (490 mg,1.23 mmol), trifluoroacetic anhydride (0.35 mL,2.48 mmol), triethylamine (0.45 mL,3.2 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =2/1) to give the title compound as a yellow solid (350 mg, 57.6%).
MS(ESI,pos.ion)m/z:495.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)10.41(s,1H),8.08(d,J＝7.8Hz,2H),8.01(d,J＝8.4Hz,2H),7.95(d,J＝7.8Hz,1H),7.79(t,J＝7.8Hz,1H),7.70(d,J＝7.8Hz,1H),3.67–3.61(m,4H),3.01(t,J＝4.8Hz,2H),2.99(t,J＝4.8Hz,2H).
Step 6) 1- (4- (2- (difluoromethyl) -3- ((4-trifluoromethylphenyl) sulfonyl) phenyl) piperazin-1-yl) -2, synthesis of 2, 2-trifluoroacetyl
The title compound was prepared as described in example 1, step 7 by reacting 2- ((4-trifluoromethylphenyl) sulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde (320 mg,0.65 mmol) in diethylaminosulfur trifluoride (2.0 mL,15.2 mmol) and subjecting the crude product to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) and concentrated to dryness to give the title compound as a white solid (0.27 g, 80.8%).
MS(ESI,pos.ion)m/z:517.0[M+H] + ；
1 HNMR(600MHz,DMSO-d 6 )δ(ppm)8.16(dd,J＝7.2,1.2Hz,1H),8.02(d,J＝8.4Hz,2H),7.94(d,J＝8.4Hz,2H),7.86–7.80(m,2H),7.39(t,J＝53.8Hz,1H),3.72–3.63(m,4H),2.93–2.90(m,4H).
Step 7) Synthesis of 1- (2- (difluoromethyl) -3- ((4-trifluoromethylphenyl) sulfonyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 8 by reacting 1- (4- (2- (difluoromethyl) -3- ((4-trifluoromethylphenyl) sulfonyl) phenyl) piperazin-1-yl) -2, 2-trifluoroacetyl (0.26 g,0.50 mmol), potassium carbonate (0.21 g,1.52 mmol) in tetrahydrofuran (3 mL), ethanol (3 mL), water (3 mL) and drying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =20/1) to give the title compound as a white solid (150 mg, 69.0%).
MS(ESI,pos.ion)m/z:420.8[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.21(d,J＝7.8Hz,1H),8.11(d,J＝8.4Hz,2H),8.04(d,J＝8.4Hz,2H),7.92(t,J＝7.8Hz,1H),7.82(d,J＝8.4Hz,1H),7.35(t,J＝53.8Hz,1H),2.87(brs,4H),2.86(brs,4H).
EXAMPLE 15 Synthesis of 1- (2- (difluoromethyl) -3- ((2, 4-dimethylphenyl) sulfonyl) phenyl) piperazine
Figure BDA0001666881410000481
Step 1) Synthesis of 2- (2-fluoro-6- ((2, 4-dimethylphenyl) thio) phenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 2 by reacting 2- (2-bromo-6-fluorophenyl) -1, 3-dioxolane (1.0 g,4.05 mmol), 2, 4-dimethylbenzene thiophenol (670 mg,4.86 mmol), potassium tert-butoxide (681 mg,5.71 mmol), tris (dibenzylideneacetone) dipalladium (190 mg,0.20 mmol) and bis (2-diphenylphosphinophenone) ether (0.24 g,0.43 mmol) in toluene (10 mL) and concentrating and drying to give the title compound as a yellow oil (1.24 g, 99%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =50/1).
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.35(d,J＝7.8Hz,1H),7.14(s,1H),7.11–7.07(m,1H),7.04(d,J＝7.8Hz,1H),6.87–6.83(m,1H),6.58(d,J＝8.0Hz,1H),6.46(s,1H),4.35–4.33(m,2H),4.10–4.07(m,2H),2.37(s,3H),2.34(s,3H).
Step 2) Synthesis of 2- (2-fluoro-6- ((2, 4-dimethylphenyl) sulfonyl) phenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 3 by reacting 2- (2-fluoro-6- ((2, 4-dimethylphenyl) thio) phenyl) -1, 3-dioxolane (1.19 g,3.94 mmol), m-chloroperoxybenzoic acid (2.12 g,10.45 mmol) in dichloromethane (10 mL) and drying to give the title compound as a white solid (1.15 g, 87.3%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1).
MS(ESI,pos.ion)m/z:336.9[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.99(d,J＝8.1Hz,1H),7.91(d,J＝8.0Hz,1H),7.55–7.50(m,1H),7.34(t,J＝8.0Hz,1H),7.21(d,J＝8.1Hz,1H),7.09(s,1H),6.59(d,J＝1.7Hz,1H),4.15(t,J＝6.8Hz,2H),3.92(t,J＝6.7Hz,2H),2.40(s,3H),2.34(s,3H).
Step 3) Synthesis of 2-fluoro-6- ((2, 4-dimethylphenyl) sulfonyl) benzaldehyde
The title compound was prepared as described in example 1, step 4 by reacting 2- (2-fluoro-6- ((2, 4-dimethylphenyl) sulfonyl) phenyl) -1, 3-dioxolane (1.14 g,3.41 mmol), trifluoroacetic acid (2.3 g,20.3 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) to give the title compound as a white solid (0.99 g, 99.4%).
MS(ESI,pos.ion)m/z:293.1[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)10.57(s,1H),8.01(d,J＝8.2Hz,1H),7.94(d,J＝7.9Hz,1H),7.72–7.68(m,1H),7.43(t,J＝9.0Hz,1H),7.24(d,J＝7.8Hz,1H),7.09(s,1H),2.40(s,3H),2.37(s,3H).
Step 4) Synthesis of 2- ((2, 4-dimethylphenyl) sulfonyl) -6- (piperazin-1-yl) benzaldehyde
The title compound was prepared as described in example 1, step 5 by reacting 2-fluoro-6- ((2, 4-dimethylphenyl) sulfonyl) benzaldehyde (990 mg,3.39 mmol), piperazine (875 mg,10.16 mmol), potassium carbonate (936 mg,6.7 mmol) in acetonitrile (10 mL) and drying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =15/1) to give the title compound as a pale yellow solid (906 mg, 74.3%).
MS(ESI,pos.ion)m/z:359.2[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)10.37(s,1H),7.95(d,J＝8.2Hz,1H),7.88(d,J＝7.7Hz,1H),7.61(t,J＝8.0Hz,1H),7.40(d,J＝8.1Hz,1H),7.22(d,J＝8.0Hz,1H),7.05(s,1H),2.98(br,8H),2.42(s,3H),2.39(s,3H).
Step 5) 2- ((2, 4-dimethylphenyl) sulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzene Synthesis of formaldehyde
The title compound was prepared as described in example 1, step 6 by reacting 2- ((2, 4-dimethylphenyl) sulfonyl) -6- (piperazin-1-yl) benzaldehyde (890 mg,2.48 mmol), trifluoroacetic anhydride (0.78 g,3.69 mmol), triethylamine (0.7 mL,5.0 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =2/1) to give the title compound as a yellow solid (882 mg, 78.1%).
MS(ESI,pos.ion)m/z:454.8[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)10.51(s,1H),7.94(d,J＝8.2Hz,1H),7.87–7.85(m,1H),7.63(t,J＝8.0Hz,1H),7.38(d,J＝8.1Hz,1H),7.23(d,J＝8.0Hz,1H),7.08(s,1H),3.83–3.80(m,2H),3.75–3.73(m,2H),3.07–3.05(m,4H),2.41(s,3H),2.40(s,3H).
Step 6) 1- (4- (2- (difluoromethyl) -3- ((2, 4-dimethylphenyl) sulfonyl) phenyl) piperazine-1-yl) -2-one of the groups, synthesis of 2, 2-trifluoroacetyl
The title compound was prepared as described in example 1, step 7 by reacting 2- ((2, 4-dimethylphenyl) sulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde (870 mg,1.91 mmol) in diethylaminosulfur trifluoride (2.0 ml,15.2 mmol) and subjecting the crude product to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) and concentrated to dryness to give the title compound as a pale yellow solid (554 mg, 60.7%).
MS(ESI,pos.ion)m/z:477.2[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.99(d,J＝8.1Hz,1H),7.96(d,J＝7.9Hz,1H),7.64(t,J＝8.0Hz,1H),7.55(d,J＝8.0Hz,1H),7.52(t,J＝54.0Hz,1H),7.25(d,J＝8.1Hz,1H),7.10(s,1H),3.83(s,2H),3.74(s,2H),3.01(t,J＝4.2Hz,4H),2.42(s,3H),2.34(s,3H).
Step 7) Synthesis of 1- (2- (difluoromethyl) -3- ((2, 4-dimethylphenyl) sulfonyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 8 by reacting 1- (4- (2- (difluoromethyl) -3- ((2, 4-dimethylphenyl) sulfonyl) phenyl) piperazin-1-yl) -2, 2-trifluoroacetyl (0.55 g,1.15 mmol), potassium carbonate (319 mg,2.29 mmol) in tetrahydrofuran (3 mL), ethanol (3 mL), water (3 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =20/1) and concentrating and drying to give the title compound as a pale yellow solid (404 mg, 92.0%).
MS(ESI,pos.ion)m/z:381.0[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.97(d,J＝8.1Hz,1H),7.95(d,J＝7.9Hz,1H),7.61(t,J＝8.0Hz,1H),7.56(d,J＝8.0Hz,1H),7.41(t,J＝54.0Hz,1H),7.21(d,J＝7.9Hz,1H),7.07(s,1H),3.06–3.01(m,4H),2.98–2.94(m,4H),2.39(s,3H),2.34(s,3H).
EXAMPLE 16 Synthesis of 1- (3- ((5-chloro-2-methylphenyl) sulfonyl) -2- (difluoromethyl) phenyl) piperazine
Figure BDA0001666881410000501
Step 1) Synthesis of 2- (2- ((5-chloro-2-methylphenyl) thio) -6-fluorophenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 2 by reacting 2- (2-bromo-6-fluorophenyl) -1, 3-dioxolane (2.0 g,8.1 mmol), 5-chloro-2-methylbenzothiool (1.54 g,9.8 mmol), potassium tert-butoxide (1.36 g,11.4 mmol), tris (dibenzylideneacetone) dipalladium (370 mg,0.40 mmol) and bis (2-diphenylphosphino) phenyl ether (0.43 g,0.79 mmol) in toluene (10 mL) and concentrating and drying the crude product to give the title compound as a yellow oil (2.23 g, 84.5%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =50/1). MS (ESI, pos.ion) m/z 325.1[ M+H ]] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.32(d,J＝1.8Hz,1H),7.22–7.21(m,2H),7.19–7.16(m,1H),6.97–6.93(m,1H),6.74(d,J＝8.0Hz,1H),6.42(s,1H),4.34–4.30(m,2H),4.09–4.05(m,2H),2.33(s,3H).
Step 2) Synthesis of 2- (2- ((5-chloro-2-methylphenyl) sulfonyl) -6-fluorophenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 3 by reacting 2- (2- ((5-chloro-2-methylphenyl) thio) -6-fluorophenyl) -1, 3-dioxolane (2.23 g,6.8 mmol), m-chloroperoxybenzoic acid (2.94 g,10.2 mmol) in dichloromethane (10 mL) and drying to give the title compound as a white solid (900 mg, 36.7%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1).
MS(ESI,pos.ion)m/z:357.1[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.14(d,J＝2.2Hz,1H),7.97(d,J＝8.0Hz,1H),7.59–7.56(m,1H),7.51–7.49(m,1H),7.40–7.37(m,1H),7.22(d,J＝8.1Hz,1H),6.51(d,J＝1.7Hz,1H),4.15–4.13(m,2H),3.93–3.91(m,2H),2.31(s,3H).
Step 3) Synthesis of 2- ((5-chloro-2-methylphenyl) sulfonyl) -6-fluorobenzaldehyde
The title compound was prepared as described in example 1, step 4 by reacting 2- (2- ((5-chloro-2-methylphenyl) sulfonyl) -6-fluorophenyl) -1, 3-dioxolane (900 mg,2.5 mmol), trifluoroacetic acid (1.67 g,14.6 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) to give the title compound as a white solid (0.71 g, 93.1%).
MS(ESI,pos.ion)m/z:313.1[M+H] + ；
H NMR(400MHz,CDCl 3 )δ(ppm)10.54(s,1H),8.10(d,J＝2.2Hz,1H),7.98(d,J＝7.9Hz,1H),7.78–7.72(m,1H),7.52–7.49(m,2H),7.24–7.22(m,1H),2.39(s,3H).
Step 4) Synthesis of 2- ((5-chloro-2-methylphenyl) sulfonyl) -6- (piperazin-1-yl) benzaldehyde
The title compound was prepared as described in example 1, step 5 by reacting 2- ((5-chloro-2-methylphenyl) sulfonyl) -6-fluorobenzaldehyde (710 mg,2.30 mmol), piperazine (580 mg,6.7 mmol), potassium carbonate (620 mg,4.4 mmol) in acetonitrile (10 mL) and drying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =15/1) to give the title compound as a pale yellow solid (560 mg, 66.0%).
MS(ESI,pos.ion)m/z:378.8[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)10.32(s,1H),8.04(d,J＝2.2Hz,1H),7.94(d,J＝7.8Hz,1H),7.66(t,J＝8.0Hz,1H),7.46(d,J＝8.1Hz,2H),7.18(d,J＝8.1Hz,1H),2.99(s,8H),2.43(s,3H).
Step 5) 2- ((5-chloro-2-methylphenyl) sulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzene Synthesis of formaldehyde
The title compound was prepared as described in example 1, step 6 by reacting 2- ((5-chloro-2-methylphenyl) sulfonyl) -6- (piperazin-1-yl) benzaldehyde (550 mg,1.45 mmol), trifluoroacetic anhydride (0.46 g,2.15 mmol), triethylamine (0.41 mL,2.9 mmol) in dichloromethane (10 mL) and subjecting the crude product to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =2/1) and concentrated to dryness to give the title compound as a yellow solid (530 mg, 76.9%).
MS(ESI,pos.ion)m/z:475.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)10.47(s,1H),8.03(d,J＝2.1Hz,1H),7.90(d,J＝7.8Hz,1H),7.68(t,J＝8.0Hz,1H),7.50–7.48(m,1H),7.43(d,J＝8.1Hz,1H),7.21(d,J＝8.2Hz,1H),3.83–3.81(m,2H),3.75–3.73(m,2H),3.09–3.05(m,4H),2.44(s,3H).
Step 6) 1- (4- (3- ((5-chloro-2-methylphenyl) sulfonyl) -2- (difluoromethyl) phenyl) piperazin-1-yl) Synthesis of 2, 2-trifluoroacetyl
The title compound was prepared as described in example 1, step 7 by reacting 2- ((5-chloro-2-methylphenyl) sulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde (520 mg,1.10 mmol) in diethylaminosulfur trifluoride (2.0 ml,15.2 mmol) and subjecting the crude product to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) and concentrated to dryness to give the title compound as a pale yellow solid (348 mg, 63.9%).
MS(ESI,pos.ion)m/z:496.7[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.07(d,J＝2.1Hz,1H),8.00(d,J＝7.9Hz,1H),7.69(t,J＝8.0Hz,1H),7.59(s,1H),7.53–7.50(m,1H),7.46(t,J＝44.0Hz,1H),7.24(d,J＝8.2Hz,1H),3.85(s,2H),3.76(d,J＝4.3Hz,2H),3.04–3.02(m,4H),2.35(s,3H).
Step 7) Synthesis of 1- (3- ((5-chloro-2-methylphenyl) sulfonyl) -2- (difluoromethyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 8 by reacting 1- (4- (3- ((5-chloro-2-methylphenyl) sulfonyl) -2- (difluoromethyl) phenyl) piperazin-1-yl) -2, 2-trifluoroacetyl (0.34 g,0.68 mmol), potassium carbonate (190 mg,1.38 mmol) in tetrahydrofuran (3 mL), ethanol (3 mL), water (3 mL) and drying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =20/1) to give the title compound as a pale yellow solid (229 mg, 83.5%).
MS(ESI,pos.ion)m/z:401.2[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.05(d,J＝1.9Hz,1H),8.01(d,J＝7.9Hz,1H),7.66(t,J＝8.1Hz,1H),7.57(d,J＝8.1Hz,1H),7.47–7.46(m,1H),7.34(t,J＝54.0Hz,1H),7.20(d,J＝8.1Hz,1H),3.04–3.02(m,4H),2.96–2.95(m,4H),2.35(s,3H).
EXAMPLE 17 Synthesis of 1- (2- (difluoromethyl) -3- ((2, 4-dichlorophenyl) sulfonyl) phenyl) piperazine
Figure BDA0001666881410000521
Step 1) Synthesis of 2- (2-fluoro-6- ((2, 4-dichlorophenyl) thio) phenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 2 by reacting 2- (2-bromo-6-fluorophenyl) -1, 3-dioxolane (1.0 g,4.05 mmol), 2, 4-dichlorobenzothiool (640 mg,4.86 mmol), potassium tert-butoxide (681 mg,5.71 mmol), tris (dibenzylideneacetone) dipalladium (190 mg,0.20 mmol) and bis (2-diphenylphosphino) phenyl ether (0.24 g,0.43 mmol) in toluene (10 mL) and concentrating and drying to give the title compound as a white solid (812 mg, 58.1%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =50/1).
MS(ESI,pos.ion)m/z:345.0[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.45(d,J＝2.2Hz,1H),7.33–7.30(m,1H),7.17–7.14(m,1H),7.12–7.08(m,1H),7.05(d,J＝7.9Hz,1H),6.97(d,J＝8.5Hz,1H),6.41(s,1H),4.29–4.26(m,2H),4.05–4.01(m,2H).
Step 2) Synthesis of 2- (2-fluoro-6- ((2, 4-dichlorophenyl) sulfonyl) phenyl) -1, 3-dioxolane
The title compound was prepared as described in example 1, step 3 by reacting 2- (2-fluoro-6- ((2, 4-dichlorophenyl) thio) phenyl) -1, 3-dioxolane (800 mg,2.32 mmol), m-chloroperoxybenzoic acid (1.25 g,6.16 mmol) in dichloromethane (10 mL) and drying to give the title compound as a white solid (254 mg, 86.2%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1).
MS(ESI,pos.ion)m/z:377.1[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.24(d,J＝8.6Hz,1H),8.13(d,J＝8.0Hz,1H),7.60–7.57(m,1H),7.51(dd,J＝8.6,2.0Hz,1H),7.48(d,J＝2.0Hz,1H),7.41–7.37(m,1H),6.46(d,J＝1.6Hz,1H),4.15–4.13(m,2H),3.90–3.87(m,2H).
Step 3) Synthesis of 2-fluoro-6- ((2, 4-dichlorophenyl) sulfonyl) benzaldehyde
The title compound was prepared as described in example 1, step 4 by reacting 2- (2-fluoro-6- ((2, 4-dichlorophenyl) sulfonyl) phenyl) -1, 3-dioxolane (744 mg,1.97 mmol), trifluoroacetic acid (1.35 g,11.8 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) to give the title compound as a white solid (575 mg, 87.5%).
MS(ESI,pos.ion)m/z:333.1[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)10.46(s,1H),8.30(d,J＝8.6Hz,1H),8.22(d,J＝8.0Hz,1H),7.79–7.76(m,1H),7.56–7.55(m,1H),7.53–7.49(m,1H),7.47(d,J＝2.0Hz,1H),1.62(s,3H),1.28(s,3H).
Step 4) Synthesis of 2- ((2, 4-dichlorophenyl) sulfonyl) -6- (piperazin-1-yl) benzaldehyde
The title compound was prepared as described in example 1, step 5 by reacting 2-fluoro-6- ((2, 4-dichlorophenyl) sulfonyl) benzaldehyde (560 mg,1.68 mmol), piperazine (434 mg,5.04 mmol), potassium carbonate (460 mg,3.33 mmol) in acetonitrile (10 mL) and drying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =15/1) to give the title compound as a pale yellow solid (327 mg, 48.7%).
MS(ESI,pos.ion)m/z:399.1[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)10.26(s,1H),8.23(d,J＝8.6Hz,1H),8.16(d,J＝7.9Hz,1H),7.68(t,J＝8.1Hz,1H),7.53–7.51(m,1H),7.49–7.47(m,1H),7.43(d,J＝2.0Hz,1H),2.98(br,8H).
Step 5) 2- ((2, 4-dichlorophenyl) sulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzyl Synthesis of aldehydes
The title compound was prepared as described in example 1, step 6 by reacting 2- ((2, 4-dichlorophenyl) sulfonyl) -6- (piperazin-1-yl) benzaldehyde (319 mg,0.8 mmol), trifluoroacetic anhydride (252 mg,1.19 mmol), triethylamine (0.22 mL,1.58 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =2/1) to give the title compound as a yellow solid (280 mg, 70.7%).
MS(ESI,pos.ion)m/z:494.7[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)10.40(s,1H),8.18(d,J＝8.6Hz,1H),8.15(d,J＝7.9Hz,1H),7.70(t,J＝8.1Hz,1H),7.54–7.52(m,1H),7.47–7.45(m,2H),3.81(s,2H),3.74–3.71(m,2H),3.06–3.04(m,4H).
Step 6) 1- (4- (2- (difluoromethyl) -3- ((2, 4-dichlorophenyl) sulfonyl) phenyl) piperazin-1-yl) -2, synthesis of 2-trifluoroacetyl
The title compound was prepared as described in example 1, step 7 by reacting 2- ((2, 4-dichlorophenyl) sulfonyl) -6- (4- (2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde (270 mg,0.55 mmol) in diethylaminosulfur trifluoride (2.0 mL,15.2 mmol) and subjecting the crude product to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) and concentrated to dryness to give the title compound as a pale yellow solid (238 mg, 84.4%).
MS(ESI,pos.ion)m/z:517.1[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.29(d,J＝8.6Hz,1H),8.25(d,J＝8.0Hz,1H),7.71(t,J＝8.1Hz,1H),7.59(d,J＝8.0Hz,1H),7.55–7.53(m,1H),7.48(d,J＝2.0Hz,1H),7.40(t,J＝54.0Hz,1H),3.84(s,2H),3.76(s,2H),3.03–3.01(m,1H).
Step 7) Synthesis of 1- (2- (difluoromethyl) -3- ((2, 4-dichlorophenyl) sulfonyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 8 by reacting 1- (4- (2- (difluoromethyl) -3- ((2, 4-dichlorophenyl) sulfonyl) phenyl) piperazin-1-yl) -2, 2-trifluoroacetyl (228 mg,0.44 mmol), potassium carbonate (122 mg,0.87 mmol) in tetrahydrofuran (3 mL), ethanol (3 mL), water (3 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =20/1) and concentrating and drying to give the title compound as a pale yellow solid (180 mg, 96.9%).
MS(ESI,pos.ion)m/z:420.8[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.28(t,J＝9.3Hz,2H),7.69(t,J＝8.0Hz,1H),7.59(d,J＝8.0Hz,1H),7.50–7.49(m,1H),7.44(d,J＝1.6Hz,1H),7.30(t,J＝54.0Hz,1H),3.04–3.02(m,4H),2.95–2.94(m,4H).
EXAMPLE 18 Synthesis of 1- (3- (phenylsulfonyl) -2- (trifluoromethyl) phenyl) piperazine
Figure BDA0001666881410000541
Step 1) (Synthesis of 3-fluoro-2-trifluoromethylphenyl) phenylsulfide
The title compound was prepared as described in example 11, step 1 by reacting 1, 3-difluoro-2-trifluoromethylbenzene (1.0 g,5.49 mmol), thiophenol (0.35 mL,3.40 mmol), potassium carbonate (0.92 g,6.7 mmol) in N, N-dimethylformamide (8 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =100/1) to give the title compound as a colorless oil (900 mg, 97.2%).
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.60–7.53(m,1H),7.50(s,5H),7.31(dd,J＝11.6,8.4Hz,1H),6.85(d,J＝7.6Hz,1H).
Step 2) Synthesis of 1-fluoro-3- (benzenesulfonyl) -2- (trifluoromethyl) benzene
The title compound was prepared as described in example 1, step 3 by reacting (3-fluoro-2-trifluoromethylphenyl) sulfide (600 mg,2.2 mmol), m-chloroperoxybenzoic acid (1.5 g,7.0 mmol) in dichloromethane (10 mL) and subjecting the crude product to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) and concentrated drying to give the title compound as a pale yellow solid (602 mg, 89.5%).
MS(ESI,pos.ion)m/z:304.9[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.33(d,J＝8.4Hz,1H),7.82(d,J＝7.8Hz,2H),7.78(td,J＝8.4,4.8Hz,1H),7.64–7.60(m,1H),7.52(t,J＝8.4Hz,2H),7.49(t,J＝8.4Hz,1H).
Step 3) Synthesis of 1- (3- (phenylsulfonyl) -2- (trifluoromethyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 5 by reacting 1-fluoro-3- (benzenesulfonyl) -2- (trifluoromethyl) benzene (600 mg,1.97 mmol), piperazine (520 mg,6.01 mmol), potassium carbonate (540 mg,3.9 mmol) in N, N-dimethylformamide (5 mL) and drying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =30/1) to give the title compound as a pale yellow solid (250 mg, 34.2%).
MS(ESI,pos.ion)m/z:370.9[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.14(d,J＝7.2Hz,1H),7.90(t,J＝7.8Hz,1H),7.85(d,J＝8.4Hz,1H),7.82(d,J＝7.2Hz,2H),7.72(t,J＝7.8Hz,1H),7.65–7.62(m,2H),2.87–2.83(m,4H),2.80–2.78(m,4H).
Example 19 Synthesis of 1- (3- ((2-fluorophenyl) sulfonyl) -2- (trifluoromethyl) phenyl) piperazine
Figure BDA0001666881410000551
Step 1) Synthesis of 1- (3-fluoro-2- (trifluoromethyl) phenyl) piperazine
1, 3-difluoro-2- (trifluoromethyl) benzene (1.3 g,4.92 mmol) and piperazine (5.0 g,58.05 mmol) were placed in a 100mL flask and reacted at 90℃in an oil bath for 16 hours; the reaction was stopped, water (20 mL) and dichloromethane (30 mL) were added, the organic phase was separated, dried under pressure, and purified by column chromatography (dichloromethane/methanol (v/v) =15/1) to give the title compound as a yellowish green solid (3.5 g, 73.4%).
MS(ESI,pos.ion)m/z:249.0[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.41(dd,J＝14.4,8.4Hz,1H),6.98(d,J＝8.0Hz,1H),6.87(dd,J＝14.8,9.2Hz,1H),3.03–2.97(m,4H),2.96–2.90(m,4H).
Step 2) Synthesis of t-butyl 4- (3-fluoro-2- (trifluoromethyl) phenyl) piperazine-1-carboxylate
1- (3-fluoro-2- (trifluoromethyl) phenyl) piperazine (2.1 g,8.46 mmol) and triethylamine (2.2 mL,16 mmol) were added to dichloromethane (20 mL) at 25℃followed by the dropwise addition of di-tert-butyl dicarbonate (2.2 mL,10 mmol); after the dripping is finished, continuing to react for 16 hours; water (30 mL) was added, the solution was separated, the organic phase was dried over anhydrous sodium sulfate (3.0 g), filtered, and the filtrate was dried under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate (v/v) =5:1) to give the title compound as a white solid (2.43 g, 82.5%).
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.66(dd,J＝15.2,8.4Hz,1H),7.23(d,J＝8.4Hz,1H),7.17(dd,J＝11.2,8.4Hz,1H),3.45(brs,4H),2.88(t,J＝4.8Hz,4H),1.43(s,9H).
Step 3) Synthesis of tert-butyl 4- (3- ((2-fluorophenyl) thio) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate
Tert-butyl 4- (3-fluoro-2- (trifluoromethyl) phenyl) piperazine-1-carboxylate (1.2 g,3.45 mmol), 2-fluorobenzenesulfide (0.45 mL,4.2 mmol), potassium carbonate (0.55 g,4.0 mmol) and N, N-dimethylformamide (10 mL) were added to a 100mL single-neck round-bottom flask and reacted at 120℃in an oil bath for 12 hours; the reaction was stopped, ethyl acetate (30 mL) was added, washed with water (30 ml×2), the organic phase was dried over anhydrous sodium sulfate (5 g), filtered, and the filtrate was dried under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =50/1), and concentrated and dried to give the title compound as a white solid (0.85 g, 54.0%).
MS(ESI,pos.ion)m/z:456.8[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.47–7.37(m,2H),7.22(t,J＝8.0Hz,1H),7.19–7.13(m,2H),7.05(d,J＝8.0Hz,1H),6.76(d,J＝8.0Hz,1H),3.57(brs,4H),2.87(brs,4H),1.48(s,9H).
Step 4) Synthesis of tert-butyl 4- (3- ((2-fluorophenyl) sulfonyl) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate Finished products
The title compound was prepared according to the procedure described in example 1, step 3 by reacting tert-butyl 4- (3- ((2-fluorophenyl) thio) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate (850 mg,1.86 mmol), m-chloroperoxybenzoic acid (1.35 g,6.26 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) to give the title compound as a white solid (0.25 g, 27.5%).
MS(ESI,pos.ion)m/z:433.2[M+H-56] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.43(d,J＝8.4Hz,1H),8.08(t,J＝7.6Hz,1H),7.75(t,J＝8.4Hz,1H),7.61(d,J＝8.4Hz,2H),7.35(t,J＝7.6Hz,1H),7.11(t,J＝9.2Hz,1H),3.53(brs,4H),2.89(brs,4H),1.47(s,9H).
Step 5) Synthesis of 1- (3- ((2-fluorophenyl) sulfonyl) -2- (trifluoromethyl) phenyl) piperazine
Tert-butyl 4- (3- ((2-fluorophenyl) sulfonyl) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate (250 mg,0.51 mmol) and dichloromethane (50 mL) were added to a 100mL single neck round bottom flask at 25 ℃ and ethyl hydrogen chloride solution (2 m,2 mL) was added and the reaction stirred for 2 hours; stopping the reaction, spin-drying under reduced pressure, adding saturated sodium bicarbonate solution (20 mL), and then adding ethyl acetate (20 mL) for extraction; separating, and drying the organic phase with anhydrous sodium sulfate (3.5 g); filtration, spin-drying of the filtrate under reduced pressure, and column chromatography purification (dichloromethane/methanol (v/v) =20/1) gave the title compound as a pale yellow solid (120 mg, 60.4%).
MS(ESI,pos.ion)m/z:389.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.19(d,J＝7.6Hz,1H),8.01–7.89(m,3H),7.86–7.78(m,1H),7.52(t,J＝7.6Hz,1H),7.44(dd,J＝10.4,8.8Hz,1H),2.87(brs,4H),2.85(brs,4H).
EXAMPLE 20 Synthesis of 1- (3- ((2-chlorophenyl) sulfonyl) -2- (trifluoromethyl) phenyl) piperazine
Figure BDA0001666881410000561
Step 1) (2-chlorophenyl) (3-fluoro-2- (trifluoromethyl) phenyl) sulfide Synthesis
The title compound was prepared as described in example 11, step 1 by reacting 1, 3-difluoro-2-trifluoromethylbenzene (1.0 g,5.49 mmol), 2-chlorophenylthiol (0.36 mL,3.1 mmol), potassium carbonate (0.88 g,6.4 mmol) in N, N-dimethylformamide (8 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =100/1) to give the title compound as a colorless oil (900 mg, 94.7%).
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.67(d,J＝8.0Hz,1H),7.65–7.59(m,1H),7.53–7.37(m,4H),6.89(d,J＝8.0Hz,1H).
Step 2) Synthesis of 1- ((2-chlorophenyl) sulfonyl) -3-fluoro-2- (trifluoromethyl) benzene
The title compound was prepared as described in example 1, step 3 by reacting (2-chlorophenyl) (3-fluoro-2- (trifluoromethyl) phenyl) sulfide (900 mg,2.93 mmol), m-chloroperoxybenzoic acid (2.11 g,9.78 mmol) in dichloromethane (10 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) and concentrating and drying to give the title compound as a pale yellow solid (480 mg, 80.6%). MS (ESI, pos.ion) m/z:339.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.31(d,J＝8.0Hz,1H),8.18(d,J＝8.0Hz,1H),8.10(td,J＝8.4,5.2Hz,1H),8.02–7.94(m,1H),7.80(td,J＝8.0,1.6Hz,1H),7.74–7.68(m,2H).
step 3) Synthesis of 1- (3- ((2-chlorophenyl) sulfonyl) -2- (trifluoromethyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 5 by reacting 1- ((2-chlorophenyl) sulfonyl) -3-fluoro-2- (trifluoromethyl) benzene (400 mg,1.18 mmol), piperazine (320 mg,3.7 mmol), potassium carbonate (350 mg,2.5 mmol) in N, N-dimethylformamide (5 mL) and drying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =30/1) to give the title compound as a pale yellow solid (120 mg, 25.1%).
MS(ESI,pos.ion)m/z:404.8[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.33(d,J＝8.2Hz,1H),8.12(td,J＝8.4,5.2Hz,1H),8.07(d,J＝8.2Hz,1H),7.93–7.90(m,1H),7.78(td,J＝8.2,1.8Hz,1H),7.60(d,J＝7.6Hz,1H),7.56–7.51(m,1H),2.54(t,J＝4.8Hz,4H),2.28(brs,4H).
Example 21 Synthesis of 1- (3- ((2-bromophenyl) sulfonyl) -2- (trifluoromethyl) phenyl) piperazine
Figure BDA0001666881410000571
Step 1) (2-bromophenyl) (3-fluoro-2- (trifluoromethyl) phenyl) sulfide Synthesis
The title compound was prepared as described in example 11, step 1 by reacting 1, 3-difluoro-2-trifluoromethylbenzene (0.8 g,4.39 mmol), 2-bromophenylthiol (0.35 mL,2.91 mmol), potassium carbonate (0.8 g,5.8 mmol) in N, N-dimethylformamide (8 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =100/1) to give the title compound as a colorless oil (0.91 g, 88.0%).
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.83(dd,J＝8.0,0.8Hz,1H),7.65(dd,J＝14.0,8.0Hz,1H),7.48(td,J＝6.8,1.2Hz,1H),7.46-7.38(m,3H),6.91(d,J＝8.0Hz,1H).
Step 2) Synthesis of 1- ((2-bromophenyl) sulfonyl) -3-fluoro-2- (trifluoromethyl) benzene
The title compound was prepared as described in example 1, step 3 by reacting (2-bromophenyl) (3-fluoro-2- (trifluoromethyl) phenyl) sulfide (900 mg,2.56 mmol), m-chloroperoxybenzoic acid (1.4 g,6.49 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) to give the title compound as a pale yellow solid (700 mg, 71.3%).
MS(ESI,pos.ion)m/z:382.7[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.28(d,J＝8.0Hz,1H),8.20(d,J＝7.6Hz,1H),8.09(td,J＝8.4,5.6Hz,1H),8.03–7.96(m,1H),7.89(dd,J＝7.6,1.2Hz,1H),7.75(td,J＝7.6,1.2Hz,1H),7.70(td,J＝7.6,1.6Hz,1H).
Step 3) Synthesis of 1- (3- ((2-bromophenyl) sulfonyl) -2- (trifluoromethyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 5 by reacting 1- ((2-bromophenyl) sulfonyl) -3-fluoro-2- (trifluoromethyl) benzene (1.0 g,2.61 mmol), piperazine (460 mg,10 mmol), potassium carbonate (700 mg,5.0 mmol) in N, N-dimethylformamide (5 mL) and drying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =30/1) to give the title compound as a pale yellow solid (300 mg, 25.6%).
MS(ESI,pos.ion)m/z:449.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.35(d,J＝8.4Hz,1H),8.10(td,J＝8.4,5.4Hz,1H),8.05(d,J＝8.4Hz,1H),7.91(dd,J＝9.0,10.8Hz,1H),7.78(td,J＝8.4,1.8Hz,1H),7.58(d,J＝7.6Hz,1H),7.55–7.51(m,1H),2.53(t,J＝4.8Hz,4H),2.29(brs,4H).
EXAMPLE 22 Synthesis of 1- (3- (m-toluenesulfonyl) -2- (trifluoromethyl) phenyl) piperazine
Figure BDA0001666881410000581
Step 1) (Synthesis of 3-fluoro-2- (trifluoromethyl) phenyl) m-toluene sulfide
The title compound was prepared as described in example 11, step 1 by reacting 1, 3-difluoro-2-trifluoromethylbenzene (1.2 g,6.59 mmol), m-tolylthiophenol (0.41 g,3.3 mmol), potassium carbonate (0.7 g,5.0 mmol) in N, N-dimethylformamide (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =100/1) to give the title compound as a colorless oil (0.85 g, 90%).
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.40–7.28(m,3H),7.30–7.19(m,2H),6.95(dd,J＝10.7,8.6Hz,1H),6.79(d,J＝8.2Hz,1H),2.40(s,3H).
Step 2) Synthesis of 1-fluoro-3- (m-toluenesulfonyl) -2- (trifluoromethyl) benzene
The title compound was prepared as described in example 1, step 3 by reacting (3-fluoro-2- (trifluoromethyl) phenyl) m-toluene sulfide (850 mg,2.97 mmol), m-chloroperoxybenzoic acid (2.5 g,12 mmol) in dichloromethane (10 mL) and subjecting the crude product to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) and drying to give the title compound as a white solid (930 mg, 98.4%).
MS(ESI,pos.ion)m/z:318.9[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.32(d,J＝8.0Hz,1H),7.79(td,J＝8.2,4.9Hz,1H),7.62–7.58(m,2H),7.51–7.49(m,1H),7.43–7.40(m,2H),2.43(s,3H).
Step 3) Synthesis of 1- (3- (m-toluenesulfonyl) -2- (trifluoromethyl) phenyl) piperazine
The title compound was prepared according to the method described in example 1, step 5 by reacting 1-fluoro-3- (m-toluenesulfonyl) -2- (trifluoromethyl) benzene (0.9 g,2.83 mmol), piperazine (480 mg,11.4 mmol), potassium carbonate (800 mg,5.7 mmol) in N, N-dimethylformamide (10 mL) and drying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =30/1) to give the title compound as a pale yellow oil (120 mg, 11%).
MS(ESI,pos.ion)m/z:385.2[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.27(d,J＝7.9Hz,1H),7.72(t,J＝8.0Hz,1H),7.65–7.59(m,3H),7.40(d,J＝4.8Hz,2H),3.07–3.01(m,4H),3.00–2.94(m,4H),2.43(s,3H).
EXAMPLE 23 Synthesis of 1- (3- (m-methoxyphenylsulphonyl) -2- (trifluoromethyl) phenyl) piperazine
Figure BDA0001666881410000591
Step 1) (Synthesis of 3-fluoro-2- (trifluoromethyl) phenyl) m-methoxyphenylsulfide
The title compound was prepared as described in example 11, step 1 by reacting 1, 3-difluoro-2-trifluoromethylbenzene (1.2 g,6.59 mmol), m-methoxyphenylthiol (0.46 g,3.3 mmol), potassium carbonate (0.7 g,5.0 mmol) in N, N-dimethylformamide (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =100/1) to give the title compound as a pale yellow oil (0.78 g, 79%).
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.34(t,J＝8.0Hz,1H),7.27–7.25(m,1H),7.09(d,J＝7.7Hz,1H),7.04–7.02(m,1H),6.97–6.95(m,2H),6.84(d,J＝8.1Hz,1H),3.83(s,3H).
Step 2) Synthesis of 1-fluoro-3- (m-methoxybenzenesulfonyl) -2- (trifluoromethyl) benzene
The title compound was prepared as described in example 1, step 3 by reacting (3-fluoro-2- (trifluoromethyl) phenyl) m-methoxyphenylsulfide (760 mg,2.51 mmol), m-chloroperoxybenzoic acid (1.35 g,6.28 mmol) in dichloromethane (10 mL) and subjecting the crude product to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) and concentrating and drying to give the title compound as a white solid (800 mg, 95.2%).
MS(ESI,pos.ion)m/z:334.8[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.30(d,J＝8.1Hz,1H),7.79(td,J＝8.2,4.9Hz,1H),7.52–7.50(m,1H),7.44(t,J＝8.0Hz,1H),7.36–7.31(m,2H),7.15(dd,J＝8.2,2.1Hz,1H),3.87(s,3H).
Step 3) Synthesis of 1- (3- (m-methoxyphenylsulfonyl) -2- (trifluoromethyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 5 by reacting 1-fluoro-3- (m-methoxybenzenesulfonyl) -2- (trifluoromethyl) benzene (0.8 g,2.39 mmol), piperazine (630 mg,7.31 mmol), potassium carbonate (675 mg,4.83 mmol) in N, N-dimethylformamide (10 mL) and drying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =30/1) to give the title compound as a pale yellow oil (570 mg, 73%).
MS(ESI,pos.ion)m/z:401.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.20(d,J＝7.8Hz,1H),7.69(t,J＝8.0Hz,1H),7.62(d,J＝8.1Hz,1H),7.45–7.30(m,3H),7.10(dd,J＝8.0,1.4Hz,1H),3.85(s,1H),3.00(brs,4H),2.67(brs,4H).
EXAMPLE 24 Synthesis of 1- (3- (3-fluorobenzenesulfonyl) -2- (trifluoromethyl) phenyl) piperazine
Figure BDA0001666881410000601
Step 1) Synthesis of tert-butyl 4- (3- ((3-fluorophenyl) thio) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate
Tert-butyl 4- (3-fluoro-2- (trifluoromethyl) phenyl) piperazine-1-carboxylate (2.0 g,5.74 mmol), 3-fluorobenzene thiophenol (1.1 g,8.6 mmol), potassium carbonate (1.5 g,11 mmol) and N, N-dimethylformamide (15 mL) were added to a 100mL single-neck round bottom flask and reacted at 120℃in an oil bath for 12 hours; the reaction was stopped, ethyl acetate (30 mL) was added, washed with water (30 ml×2), the organic phase was dried over anhydrous sodium sulfate (5 g), filtered, and the filtrate was dried under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =40/1), concentrated and dried to give the title compound as a white solid (1.0 g, 38.1%).
MS(ESI,pos.ion)m/z:456.9[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.44(td,J＝8.2,6.3Hz,1H),7.38–7.29(m,1H),7.22–6.88(m,5H),3.57(s,4H),2.91(s,4H),1.50(s,9H).
Step 2) Synthesis of tert-butyl 4- (3- ((3-fluorophenyl) sulfonyl) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate Finished products
The title compound was prepared according to the procedure described in example 1, step 3 by reacting tert-butyl 4- (3- ((3-fluorophenyl) thio) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate (1.0 g,2.19 mmol), m-chloroperoxybenzoic acid (2.0 g,11.6 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) to give the title compound as a yellow oil (0.55 g, 51.4%).
MS(ESI,pos.ion)m/z:433.2[M+H-56] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.27(d,J＝7.9Hz,1H),7.73(t,J＝8.1Hz,1H),7.64–7.54(m,2H),7.52–7.40(m,2H),7.29–7.22(m,1H),3.52(s,4H),2.88(t,J＝4.5Hz,4H),1.45(s,9H).
Step 3) Synthesis of 1- (3- ((3-fluorophenyl) sulfonyl) -2- (trifluoromethyl) phenyl) piperazine
Tert-butyl 4- (3- ((3-fluorophenyl) sulfonyl) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate (350 mg,0.71 mmol) and dichloromethane (5 mL) were added to a 50mL single neck round bottom flask at 25 ℃ and ethyl hydrogen chloride solution (2 m,2 mL) was added and the reaction stirred for 2 hours; stopping the reaction, spin-drying under reduced pressure, adding saturated sodium bicarbonate solution (20 mL), and then adding ethyl acetate (20 mL) for extraction; separating, and drying the organic phase by using anhydrous sodium sulfate (3 g); filtration, spin-drying of the filtrate under reduced pressure, and column chromatography purification (dichloromethane/methanol (v/v) =20/1) gave the title compound as a pale yellow solid (150 mg, 54.4%).
MS(ESI,pos.ion)m/z:388.8[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.28(d,J＝7.9Hz,1H),7.74(t,J＝8.1Hz,1H),7.66(d,J＝8.1Hz,1H),7.63(d,J＝7.9Hz,1H),7.56–7.46(m,2H),7.33–7.26(m,1H),3.04–2.99(m,4H),2.99–2.93(m,4H).
EXAMPLE 25 Synthesis of 1- (3- (m-chlorobenzenesulfonyl) -2- (trifluoromethyl) phenyl) piperazine
Figure BDA0001666881410000611
Step 1) (Synthesis of 3-fluoro-2- (trifluoromethyl) phenyl) m-chlorophenyl sulfide
The title compound was prepared as described in example 11, step 1 by reacting 1, 3-difluoro-2-trifluoromethylbenzene (1.25 g,6.84 mmol), m-chlorophenylthiol (0.5 g,3.5 mmol), potassium carbonate (0.95 g,6.8 mmol) in N, N-dimethylformamide (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =100/1) to give the title compound as a pale yellow oil (0.9 g, 95%).
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.45(s,1H),7.41–7.30(m,4H),7.04–7.01(m,1H),6.91(d,J＝8.1Hz,1H).
Step 2) Synthesis of 1-fluoro-3- (m-chlorobenzenesulfonyl) -2- (trifluoromethyl) benzene
The title compound was prepared as described in example 1, step 3 by reacting (3-fluoro-2- (trifluoromethyl) phenyl) m-chlorobenzenesulfide (900 mg,2.93 mmol), m-chloroperoxybenzoic acid (2.0 g,11.6 mmol) in dichloromethane (10 mL) and subjecting the crude product to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) followed by concentration and drying to give the title compound as a white solid (950 mg, 95.6%).
MS(ESI,pos.ion)m/z:339.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.34(d,J＝8.0Hz,1H),7.91–7.74(m,2H),7.72(d,J＝7.7Hz,1H),7.65–7.43(m,3H).
Step 3) Synthesis of 1- (3- (m-chlorobenzenesulfonyl) -2- (trifluoromethyl) phenyl) piperazine
The title compound was prepared according to the method described in example 1, step 5 by reacting 1-fluoro-3- (m-chlorobenzenesulfonyl) -2- (trifluoromethyl) benzene (0.3 g,0.89 mmol), piperazine (600 mg,6.96 mmol), potassium carbonate (650 mg,4.71 mmol) in N, N-dimethylformamide (10 mL) and drying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =30/1) to give the title compound as a pale yellow oil (170 mg, 47.4%).
MS(ESI,pos.ion)m/z:404.8[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.27(d,J＝7.8Hz,1H),7.79(s,1H),7.77–7.69(m,2H),7.65(d,J＝8.0Hz,1H),7.55(d,J＝7.8Hz,1H),7.46(t,J＝7.9Hz,1H),3.01(brs,4H),2.97(brs,4H).
EXAMPLE 26 Synthesis of 1- (3-p-toluenesulfonyl-2- (trifluoromethyl) phenyl) piperazine
Figure BDA0001666881410000621
Step 1) (Synthesis of 3-fluoro-2- (trifluoromethyl) phenyl) p-toluene sulfide
The title compound was prepared as described in example 11, step 1 by reacting 1, 3-difluoro-2-trifluoromethylbenzene (1.5 g,8.2 mmol), p-tolylthiophenol (0.5 mL,4.59 mmol), potassium carbonate (1.4 g,10.1 mmol) in N, N-dimethylformamide (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =100/1) to give the title compound as a pale yellow oil (1.2 g, 91.3%).
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.52(td,J＝8.4,6.0Hz,1H),7.43(d,J＝8.0Hz,2H),7.33(d,J＝8.0Hz,2H),7.26(dd,J＝11.6,8.4Hz,1H),6.74(d,J＝8.0Hz,1H),2.36(s,3H).
Step 2) Synthesis of 1-fluoro-3-p-toluenesulfonyl-2- (trifluoromethyl) benzene
The title compound was prepared as described in example 1, step 3 by reacting (3-fluoro-2- (trifluoromethyl) phenyl) p-toluene sulfide (1.2 g,4.19 mmol), m-chloroperoxybenzoic acid (2.8 g,13.0 mmol) in dichloromethane (10 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) and concentrating and drying to give the title compound as a pale yellow solid (1.1 g, 82.5%).
MS(ESI,pos.ion)m/z:318.5[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.26(d,J＝8.0Hz,1H),7.73(td,J＝8.0,4.8Hz,1H),7.68(d,J＝8.0Hz,2H),7.46(t,J＝9.6Hz,1H),7.30(d,J＝8.4Hz,2H),2.41(s,3H).
Step 3) Synthesis of 1- (3-p-toluenesulfonyl-2- (trifluoromethyl) phenyl) piperazine
The title compound was prepared by the method described in example 1, step 5 by reacting 1-fluoro-3-p-toluenesulfonyl-2- (trifluoromethyl) benzene (1.1 g,3.46 mmol), piperazine (460 mg,10 mmol) and potassium carbonate (550 mg,4.0 mmol) in N, N-dimethylformamide (10 mL) and concentrating and drying the crude product to give the title compound as a pale yellow oil (300 mg, 22.8%) by silica gel column chromatography (dichloromethane/methanol (v/v) =30/1).
MS(ESI,pos.ion)m/z:385.2[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.12(d,J＝7.6Hz,1H),7.91(t,J＝7.6Hz,1H),7.86(d,J＝7.6Hz,1H),7.74(d,J＝8.4Hz,2H),7.47(d,J＝8.4Hz,2H),2.89–2.84(m,4H),2.82–2.81(m,4H),2.43(s,3H).
EXAMPLE 27 Synthesis of 1- (3- ((4-methoxyphenyl) sulfonyl) -2- (trifluoromethyl) phenyl) piperazine
Figure BDA0001666881410000631
Step 1) (Synthesis of 3-fluoro-2- (trifluoromethyl) phenyl) (4-methoxyphenyl) sulfide
The title compound was prepared as described in example 11, step 1 by reacting 1, 3-difluoro-2-trifluoromethylbenzene (1.5 g,8.2 mmol), p-methoxyphenylthiophenol (0.6 g,4.28 mmol), potassium carbonate (1.2 g,8.7 mmol) in N, N-dimethylformamide (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =100/1) to give the title compound as a pale yellow oil (1.1 g, 85.0%).
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.55–7.47(m,3H),7.22(dd,J＝11.6,8.4Hz,1H),7.12–7.09(m,2H),6.65(d,J＝8.4Hz,1H),3.83(s,3H).
Step 2) Synthesis of 1-fluoro-3- ((4-methoxyphenyl) sulfonyl) -2- (trifluoromethyl) benzene
The title compound was prepared as described in example 1, step 3 by reacting (3-fluoro-2- (trifluoromethyl) phenyl) (4-methoxyphenyl) sulfide (1.1 g,3.64 mmol), m-chloroperoxybenzoic acid (2.5 g,12.0 mmol) in dichloromethane (10 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) and concentrating and drying to give the title compound as a pale yellow solid (0.77 g, 63.3%). MS (ESI, pos.ion) m/z 334.9[ M+H ]] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.22(d,J＝8.0Hz,1H),7.75(d,J＝8.8Hz,2H),7.71(td,J＝8.4,5.2Hz,1H),7.44(t,J＝9.6Hz,1H),6.96(d,J＝9.0Hz,2H),3.85(s,3H).
Step 3) Synthesis of 1- (3- ((4-methoxyphenyl) sulfonyl) -2- (trifluoromethyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 5 by reacting 1-fluoro-3- ((4-methoxyphenyl) sulfonyl) -2- (trifluoromethyl) benzene (0.75 g,2.24 mmol), piperazine (600 mg,7.0 mmol), potassium carbonate (500 mg,3.6 mmol) in N, N-dimethylformamide (10 mL) and drying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =30/1) to give the title compound as a pale yellow solid (200 mg, 22.3%).
MS(ESI,pos.ion)m/z:401.2[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)7.98(d,J＝7.6Hz,1H),7.80(t,J＝7.6Hz,1H),7.76(d,J＝8.4Hz,1H),7.73(d,J＝9.0Hz,2H),7.12–7.08(m,2H),3.81(s,3H),2.80(t,J＝4.8Hz,4H),2.78–2.73(m,4H).
EXAMPLE 28 Synthesis of 1- (3- (4-fluorobenzenesulfonyl) -2- (trifluoromethyl) phenyl) piperazine
Figure BDA0001666881410000641
Step 1) Synthesis of tert-butyl 4- (3- ((4-fluorophenyl) thio) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate
Tert-butyl 4- (3-fluoro-2- (trifluoromethyl) phenyl) piperazine-1-carboxylate (3.0 g,8.61 mmol), 4-fluorobenzenesulfide (1.5 mL,14.0 mmol), potassium carbonate (1.8 g,13 mmol) and N, N-dimethylformamide (15 mL) were added to a 100mL single-neck round-bottom flask and reacted at 120℃in an oil bath for 12 hours; the reaction was stopped, ethyl acetate (30 mL) was added, washed with water (30 ml×2), the organic phase was dried over anhydrous sodium sulfate (5 g), filtered, and the filtrate was dried under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =40/1), and concentrated and dried to give the title compound as a pale yellow oil (2.6 g, 33.1%).
MS(ESI,pos.ion)m/z:457.1[M+H] + ；
Step 2) Synthesis of tert-butyl 4- (3- ((4-fluorophenyl) sulfonyl) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate Finished products
The title compound was prepared as described in example 1 step 3 by reacting tert-butyl 4- (3- ((4-fluorophenyl) thio) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate (1.3 g,2.85 mmol), m-chloroperoxybenzoic acid (2.0 g,11.6 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) to give the title compound as a white solid (0.45 g, 32.3%).
MS(ESI,pos.ion)m/z:432.8[M+H-56] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.12(d,J＝8.0Hz,1H),7.95(t,J＝8.0Hz,1H),7.78(d,J＝8.0Hz,1H),7.61(dd,J＝8.8,5.2Hz,2H),7.35(t,J＝8.8Hz,2H),3.34(brs,4H),2.82–2.69(m,4H),1.39(s,9H).
Step 3) Synthesis of 1- (3- ((4-fluorophenyl) sulfonyl) -2- (trifluoromethyl) phenyl) piperazine
Tert-butyl 4- (3- ((4-fluorophenyl) sulfonyl) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate (450 mg,0.92 mmol) was dissolved in dichloromethane (5 mL) at 25 ℃, ethyl hydrogen chloride solution (2 m,2 mL) was added and the reaction was continued with stirring for 2 hours; stopping the reaction, spin-drying under reduced pressure, adding saturated sodium bicarbonate solution (20 mL), and then adding ethyl acetate (20 mL) for extraction; separating, and drying the organic phase with anhydrous sodium sulfate (2.0 g); filtration, spin-drying of the filtrate under reduced pressure, and column chromatography purification (dichloromethane/methanol (v/v) =20/1) gave the title compound as a white solid (120 mg, 33.5%).
MS(ESI,pos.ion)m/z:388.9[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.13(d,J＝7.8Hz,1H),7.94–7.87(m,3H),7.84(d,J＝7.8Hz,1H),7.50–7.45(m,2H),2.88–2.83(m,4H),2.81–2.80(m,4H).
EXAMPLE 29 Synthesis of 1- (3- ((4-chlorophenyl) sulfonyl) -2- (trifluoromethyl) phenyl) piperazine
Figure BDA0001666881410000651
Step 1) (Synthesis of 3-fluoro-2- (trifluoromethyl) phenyl) (4-chlorophenyl) sulfide
The title compound was prepared as described in example 11, step 1 by reacting 1, 3-difluoro-2-trifluoromethylbenzene (2.8 g,15.0 mmol), p-chlorophenylthiol (1.5 g,10.4 mmol), potassium carbonate (2.5 g,18.1 mmol) in N, N-dimethylformamide (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =100/1) to give the title compound as a pale yellow oil (2.55 g, 80.2%).
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.64–7.57(m,1H),7.58–7.54(m,2H),7.53–7.48(m,2H),7.36(dd,J＝11.6,8.4Hz,1H),6.94(d,J＝8.0Hz,1H).
Step 2) Synthesis of 1-fluoro-3- ((4-chlorophenyl) sulfonyl) -2- (trifluoromethyl) benzene
The title compound was prepared as described in example 1, step 3 by reacting (3-fluoro-2- (trifluoromethyl) phenyl) (4-chlorophenyl) sulfide (2.55 g,8.31 mmol), m-chloroperoxybenzoic acid (6.0 g,28.0 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) to give the title compound as a white solid (2.3 g, 81.7%).
MS(ESI,pos.ion)m/z:339.0[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.27(d,J＝8.0Hz,1H),8.09(td,J＝8.4,5.2Hz,1H),8.01–7.93(m,1H),7.88(d,J＝8.4Hz,2H),7.78–7.72(m,2H).
Step 3) Synthesis of 1- (3- ((4-chlorophenyl) sulfonyl) -2- (trifluoromethyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 5 by reacting 1-fluoro-3- ((4-chlorophenyl) sulfonyl) -2- (trifluoromethyl) benzene (2.0 g,5.90 mmol), piperazine (1.55 g,18.0 mmol), potassium carbonate (1.22 g,8.85 mmol) in N, N-dimethylformamide (10 mL) and drying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =30/1) to give the title compound as a pale yellow solid (620 mg, 26.2%).
MS(ESI,pos.ion)m/z:405.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.40(d,J＝8.8Hz,2H),8.32(d,J＝8.0Hz,1H),8.11(td,J＝8.4,5.2Hz,1H),8.01–7.96(m,3H),3.92–3.89(m,2H),3.59–3.52(m 2H),2.87–2.85(m,4H).
Example 30 Synthesis of 1- (3- ((2, 4-dimethylphenyl) sulfonyl) -2- (trifluoromethyl) phenyl) piperazine
Figure BDA0001666881410000661
Step 1) (2, 4-dimethylphenyl) (3-fluoro-2- (trifluoromethyl) phenyl) sulfide Synthesis
The title compound was prepared as described in example 11, step 1 by reacting 1, 3-difluoro-2-trifluoromethylbenzene (2.0 g,11 mmol), 2, 4-dimethylbenzene (1.0 g,7.23 mmol), potassium carbonate (1.5 g,11 mmol) in N, N-dimethylformamide (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =100/1) to give the title compound as a pale yellow oil (2.07 g, 95.3%).
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.45(d,J＝7.8Hz,1H),7.21–7.16(m,2H),7.10(d,J＝7.8Hz,1H),6.91–6.87(m,1H),6.50(d,J＝8.1Hz,1H),2.40(s,3H),2.32(s,3H).
Step 2) Synthesis of 1- ((2, 4-dimethylphenyl) sulfonyl) -3-fluoro-2- (trifluoromethyl) benzene
The title compound was prepared as described in example 1, step 3 by reacting (2, 4-dimethylphenyl) (3-fluoro-2- (trifluoromethyl) phenyl) sulfide (2.07 g,6.89 mmol), m-chloroperoxybenzoic acid (2.97 g,14.6 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) to give the title compound as a pale yellow solid (2.18 g, 95.2%).
MS(ESI,pos.ion)m/z:332.9[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.23(d,J＝8.1Hz,1H),7.89(d,J＝8.1Hz,1H),7.76(td,J＝8.2,5.0Hz,1H),7.52–7.48(m,1H),7.20(d,J＝8.1Hz,1H),7.09(s,1H),2.41(s,3H),2.34(s,3H).
Step 3) 1- (3- ((2, 4-dimethylphenyl) sulfonyl)) Synthesis of 2- (trifluoromethyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 5 by reacting 1- ((2, 4-dimethylphenyl) sulfonyl) -3-fluoro-2- (trifluoromethyl) benzene (2.17 g,6.53 mmol), piperazine (1.7 g,19.8 mmol), potassium carbonate (1.8 g,13 mmol) in N, N-dimethylformamide (10 mL) and drying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) =30/1) to give the title compound as a light yellow oil (1.53 g, 58.8%).
MS(ESI,pos.ion)m/z:399.0[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.14(d,J＝7.8Hz,1H),7.85(d,J＝8.1Hz,1H),7.68(t,J＝8.0Hz,1H),7.63(d,J＝8.0Hz,1H),7.16(d,J＝8.1Hz,1H),7.07(s,1H),3.01–3.00(m,4H),2.94–2.92(m,4H),2.39(s,3H),2.33(s,3H).
Example 31 Synthesis of 1- (3- ((5-chloro-2-methylphenyl) sulfonyl) -2- (trifluoromethyl) phenyl) piperazine
Figure BDA0001666881410000671
Step 1) (synthesis of 5-chloro-2-methylphenyl) (3-fluoro-2- (trifluoromethyl) phenyl) sulfide
The title compound was prepared as described in example 11, step 1 by reacting 1, 3-difluoro-2-trifluoromethylbenzene (0.86 g,4.7 mmol), 5-chloro-2-methylbenzothiool (0.5 g,3.15 mmol), potassium carbonate (0.65 g,4.7 mmol) in N, N-dimethylformamide (10 mL) and concentrating and drying to give the title compound as a pale yellow oil (1.0 g, 98.9%) by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =100/1).
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.48(d,J＝2.1Hz,1H),7.35–7.33(m,1H),7.29(s,1H),7.27–7.25(m,1H),7.01–6.96(m,1H),6.63(d,J＝8.1Hz,1H),2.32(s,3H).
Step 2) Synthesis of 1- ((5-chloro-2-methylphenyl) sulfonyl) -3-fluoro-2- (trifluoromethyl) benzene
The title compound was prepared as described in example 1, step 3 by reacting (5-chloro-2-methylphenyl) (3-fluoro-2- (trifluoromethyl) phenyl) sulfide (1.0 g,3.12 mmol), m-chloroperoxybenzoic acid (1.35 g,7.74 mmol) in dichloromethane (10 mL) and drying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) to give the title compound as a pale yellow solid (0.9 g, 81.8%).
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.29(d,J＝8.1Hz,1H),7.98(s,1H),7.84–7.79(m,1H),7.58–7.49(m,2H),7.24(d,J＝8.2Hz,1H),2.35(s,3H).
Step 3) Synthesis of 1- (3- ((5-chloro-2-methylphenyl) sulfonyl) -2- (trifluoromethyl) phenyl) piperazine
The title compound was prepared as described in example 1, step 5 by reacting 1- ((5-chloro-2-methylphenyl) sulfonyl) -3-fluoro-2- (trifluoromethyl) benzene (0.9 g,2.55 mmol), piperazine (0.66 g,7.66 mmol), potassium carbonate (0.71 g,5.1 mmol) in N, N-dimethylformamide (10 mL) and concentrating and drying to give the title compound as a pale yellow oil (375 mg, 35.1%) by silica gel column chromatography (dichloromethane/methanol (v/v) =30/1).
MS(ESI,pos.ion)m/z:418.8[M+H] + ；
1 H NMR(600MHz,CDCl 3 ) Delta (ppm) 8.19 (d, j=7.9 hz, 1H), 7.93 (s, 1H), 7.73 (t, j=8.0 hz, 1H), 7.68 (d, j=8.0 hz, 1H), 7.46-7.45 (m, 1H), 7.21 (d, j=8.2 hz, 1H), 3.04-3.02 (m, 4H), 2.97-2.96 (m, 4H), 2.35 (s, 3H). Biological assay
The following experimental methods were used to carry out biological assays on the compounds of the invention:
EXAMPLE A evaluation of the compounds of the invention for human 5-HT expressed on CHO cells by radioligand binding assays 6 Affinity of receptors
32 μg of the prepared expressed human 5-HT 6 CHO cell membrane protein of receptor, 2nM radiolabel [3H ]]LSD, different test concentrations of compound, and test buffer are mixed well, and then mixedIncubating the solution at 37 ℃ for 120min; wherein, the test buffer comprises the following components: 50mM Tris-HCl (pH 7.4), 10mM MgCl 2 0.5mM EDTA, 10. Mu.M pargyline and 20mg/l protease inhibitor.
The non-specific binding sites were removed by addition of 100. Mu.M 5-HT. After incubation, the mixture was filtered under vacuum through a glass filter (GF/B, packard) with a membrane pre-impregnated with 0.3% PEI prior to filtration. After filtration, the filters were rinsed several times with 50mM Tris-HCl. After the filters were dried, the radioactivity of the filters was counted in a scintillation counter (Topcount, packard) using scintillation cocktail. Wherein the standard reference compound is 5-HT, and multiple concentrations are tested in each experiment to obtain competition inhibition curve, nonlinear regression analysis is performed by Hill equation curve to obtain IC 50 The value is calculated by the ChengPrusoff equation to obtain the Ki value.
The inventive compound pairs human 5-HT expressed on CHO cells 6 The results of the affinity assays for the receptors are shown in table a.
Table a affinity assay results for compounds of the invention
Example number Ki(nM) Example number Ki(nM)
Example 1 4.5 Example 17 3.4
Example 2 2.2 Example 19 2.9
Example 3 1.8 Example 24 4.2
Example 7 3.1 Example 25 3.1
Example 8 2.5 Example 29 6.7
As can be seen from Table A, the compounds of the present invention are found in 5-HT 6 Higher activity is commonly demonstrated in affinity assays for receptors.
EXAMPLE B pharmacokinetic evaluation of dogs and monkeys after intravenous injection or gavage of the Compounds of the invention
1) Test animal
The test animals are dogs and monkeys, and specific information is shown in table 2:
TABLE 2 subject animal information Table of the invention
Germ line Grade Sex (sex) Weight of body Age of Source
Beagle dog Cleaning stage Male male 8～10kg For 6-7 weeks Hunan Stick laboratory animal Co Ltd
Macaca fascicularis monkey SPF Male male 3～5kg Age 4 GUANGDONG LANDAU BIOTECHNOLOGY Co.,Ltd.
2) Analysis method
The LC/MS/MS system for analysis comprises an Agilent 1200 series vacuum degasser, a binary pump, an orifice plate automatic sampler, a constant temperature column incubator and an Agilent G6430A triple quadrupole mass spectrometer of an Electrified Spray Ionization (ESI) source. Quantitative analysis was performed in MRM mode, where the parameters of the MRM transitions are shown in table 3:
TABLE 3 Table 3
Fracture voltage 30V
Capillary voltage 140V
Dryer temperature 350℃
Atomizer 40psi
Dryer flow rate 9L/min
Analysis was performed using waters XBridge C18 (2.1 x 50mm,3.5 μm column, 5 μl sample injected) under the following conditions: the mobile phases were water+2 mM ammonium formate+0.1% formic acid (mobile phase A) and methanol+2 mM ammonium formate+0.1% formic acid (mobile phase B), the flow rates were 0.4mL/min, and the mobile phase gradients are shown in Table 4:
TABLE 4 Table 4
Time Gradient of mobile phase B
1.1min 5％
1.6min 95％
2.6min 95％
2.7min 5％
3.7min Termination of
3) Experimental method
Pharmacokinetic evaluations in dogs and monkeys were performed on the compounds of the invention, as follows:
the experiments were divided into two groups, one group administered by intravenous injection and one group by intragastric administration. The compounds of the present invention were administered to the test animals as 5%DMSO+5%Kolliphor HS 15+2% (2% hcl) +88% saline in saline or 10%DMSO+10%Kolliphor HS 15+80% physiological saline. For the intravenous administration group, the administration dose was 1mg/kg, and then blood (0.3 mL) was intravenously taken at time points of 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours after administration, and centrifuged at 3,000 or 4,000rpm for 10 minutes, and the plasma solution was collected and stored at-20℃or-70 ℃. For the gavage administration group, the administration dose was 2.5mg/kg or 5mg/kg, and then blood (0.3 mL) was intravenously taken at the time points 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours after administration, and centrifuged at 3,000 or 4,000rpm for 10 minutes, and the plasma solution was collected and stored at-20℃or-70 ℃.
The plasma solutions obtained by collecting the groups are subjected to LC/MS/MS analysis, and analysis results show that the compound has better pharmacokinetic properties in dogs and monkeys.
In the description of the present specification, reference to the terms "one example," "some examples," "an implementation," "an example," "a particular example," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the example, implementation, or example is included in at least one example, implementation, or example of the present invention. In this specification, the schematic representations of the above terms are not necessarily for the same examples, implementations or illustrations. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments, implementations, or examples. Furthermore, the features of the different embodiments, implementations or examples and the different embodiments, implementations or examples described in this specification may be combined and combined by persons skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims (4)

1. A compound having the structure of one of:
Figure FDF0000024242650000011
Figure FDF0000024242650000012
or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising a compound of claim 1; and
the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.
3. The pharmaceutical composition of claim 2, further comprising an additional therapeutic agent that is a drug for treating alzheimer's disease, a drug for treating a neurological disorder, or a combination thereof; wherein the additional therapeutic agent is donepezil, nalmefene, risperidone, vitamins E, SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX-8066, SB-742457, naluzaton, lu-AE58054, tacrine, cabazitaxel, galanthamine, memantine, mirtazapine, venlafaxine, desipramine, nortriptyline, zolpidem, zopiclone, nicergoline, piracetam, selegiline, pentoxifylline, or a combination thereof.
4. Use of a compound according to claim 1 or a pharmaceutical composition according to any one of claims 2-3 for the manufacture of a medicament for the prevention, treatment or alleviation of 5-HT 6 Receptor-related diseases; wherein said and 5-HT 6 The receptor-related disease is a CNS disorder, gastrointestinal disorder or obesity; wherein the CNS disorder is attention deficit hyperactivity disorder, anxiety, stress-related disorders, schizophrenia, obsessive-compulsive disorder, manic-depressive disorders, neurological disorders, memory disorders, attention deficit disorder, parkinson's disease, amyotrophic lateral sclerosis, alzheimer's disease or huntington's disease.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1433407A (en) * 2000-06-20 2003-07-30 法玛西雅厄普约翰美国公司 Bis-arylsulfones
WO2004080986A1 (en) * 2003-03-11 2004-09-23 Glaxo Group Limited Phenyl sulfone derivatives and their use in the treatment of cns disorders

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1433407A (en) * 2000-06-20 2003-07-30 法玛西雅厄普约翰美国公司 Bis-arylsulfones
WO2004080986A1 (en) * 2003-03-11 2004-09-23 Glaxo Group Limited Phenyl sulfone derivatives and their use in the treatment of cns disorders

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