CN106045967B - Substituted heterocyclic compounds and their use in medicine - Google Patents

Substituted heterocyclic compounds and their use in medicine Download PDF

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CN106045967B
CN106045967B CN201610211139.XA CN201610211139A CN106045967B CN 106045967 B CN106045967 B CN 106045967B CN 201610211139 A CN201610211139 A CN 201610211139A CN 106045967 B CN106045967 B CN 106045967B
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compound
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alkylene
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haloalkyl
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CN106045967A (en
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钟文和
金传飞
韦德活
张英俊
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Guangdong HEC Pharmaceutical
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Sunshine Lake Pharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

The invention relates to a substituted heterocyclic compound and application thereof in medicaments, and particularly provides a novel substituted heterocyclic compound or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and a preparation method thereof. The invention also relates to pharmaceutical compositions comprising the compounds of the invention, and the use of said compounds or pharmaceutical compositions in the treatment of 5-HT6Diseases associated with receptors, especiallyEspecially in Alzheimer's disease.

Description

Substituted heterocyclic compounds and their use in medicine
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a compound for treating Alzheimer's disease, a pharmaceutical composition containing the compound and application of the compound. In particular, the compounds of the present invention are useful as 5-HT6Substituted heterocyclic compounds of receptor antagonists.
Background
Various central nervous system disorders such as anxiety, depression, etc., are associated with disorders of the neurotransmitters 5-hydroxytryptamine (5-HT) or serotonin. The neurotransmitter 5-hydroxytryptamine (5-HT) functions as the primary regulatory neurotransmitter in the brain by being termed 5-HT1，5-HT2，5-HT3，5-HT4，5-HT5，5-HT6And 5-HT7Are mediated by a large family of receptors. Based on high levels of 5-HT in the brain6Receptor mRNA, 5-HT has been proposed6Receptors may play a role in the pathology and treatment of central nervous system disorders. In particular, 5-HT has been determined6Selective ligands have potential therapeutic utility in certain CNS (central nervous system) disorders, e.g. Parkinson's disease, Huntington's disease, anxiety, depression, manic depression, psychosis, epilepsy, obsessive-compulsive disorders, migraine, Alzheimer's disease (cognitive memory enhancement), sleep disorders, eating disorders such as anorexia and bulimia, panic attacks, ADHD (attention deficit hyperactivity disorder), attention deficit disorder, abuse of drugs such as cocaine, ethanol, nicotine and benzodiazepines
Figure BDA0000958341680000011
Cluster-induced desserts brain syndrome, schizophrenia, and conditions associated with spinal trauma or head injury such as hydrocephalus. It is contemplated that the compounds 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, 1403-14120(1994), Sibley, D.R. et al, Mol, Pharmacol.,43, 320-327(1993), A.J.Sleight et al, Neurotranssmision, 11, 1-5(1995) and Sleight, A.J. et al, Serotonin ID Research Alert, 1997, 2(3), 115-118).
It was found that known 5-HT6Receptor selective antagonists significantly increase glutamate and aspartate levels in the frontal cortex, but not norrennin, dopamine or 5-HT. This selective increase in specific neurochemicals noted during memory and cognition strongly suggests 5-HT6Role of ligands in cognition (Dawson, L.A.; Nguyen, H.Q.; Li, P., British Journal of Pharmacology, 2000, 130(1), 23-26). With known selectivity for 5-HT6Receptor antagonists have some positive effects on studies of memory and learning in animals (Rogers, D.C.; Hatcher, P.D.; Hagan, J.J., Society of Neuroscience, Abstract, 2000, 26, 680). 5-HT6A related potential therapeutic use of ligands is in the treatment of attention deficit disorders in children and adults. Because of 5-HT6Receptor antagonists appear to increase the activity of the nigrostriatal dopamine pathway and, because ADHD is associated with abnormalities in the caudate nucleus (Ernst, M; Zametkin, A.J.; Matochik, J.H.; Journal, P.A.; Cohen, R.M., Journal of neuroscience, 1998, 18(5), 5901-6Receptor antagonists may be useful in the treatment of attention deficit disorders. 5-HT has also been determined6Receptor antagonists are potentially useful compounds for the treatment of obesity. See, e.g., Bentley et al, br.j.pharmac.1999, supplement 126; bentley et al, j.psychopharmacol.1997, supplement a 64: 255; wooley et al, Neuropharmacology 2001, 41: 210-129 and WO 02098878.
The invention provides a compound with 5-HT6The new compound with receptor antagonistic activity has better clinical application prospect. Compared with the existing similar compounds, the compound of the invention has better drug effect, pharmacokinetic property and/or toxicological property.
Disclosure of Invention
The present invention relates to a substituted heterocyclic compoundThe disclosed compounds differ in that they have a good 5-HT6Receptor antagonistic activity. And, compared with the existing 5-HT6The receptor antagonist has the advantages of novel structure, stable property, low preparation cost, pharmacodynamics and pharmacokinetics advantages and good safety, thereby having better clinical application prospect.
The compounds of the present invention and pharmaceutical compositions comprising said compounds are directed to 5-HT6The receptor has good affinity effect, and can be used for treating 5-HT6The receptor-related diseases, especially Alzheimer's disease, have better treatment effect.
In one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of a compound of formula (I),
Figure BDA0000958341680000021
wherein the content of the first and second substances,
Figure BDA0000958341680000022
is a single bond or a double bond;
x is-O-, -NRx-、-S-、-C(＝O)-、-CH2-or-CHRy-；
n is 1,2,3 or 4;
m is 0, 1,2,3 or 4; and
each R1、R2、R3、R4、R5、R6、R7、R8、R9、RxAnd RyHave the meaning as described in the present invention.
In one embodiment, R1、R2、R3、R4And R5Each independently is H, D, F, Cl, Br, I, -CN, -NO2、-OH、-NRaRb、-C(＝O)Rc、-S(＝O)2Rc、-C(＝O)NRaRb、-S(＝O)2NRaRb、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Alkylthio group, (C)3-C8Cycloalkyl) - (C)0-C6Alkylene) -, (C)2-C10Heterocyclyl) - (C)0-C6Alkylene) -, (C)6-C10Aryl group) - (C0-C6Alkylene) -or (C)1-C9Heteroaryl) - (C)0-C6Alkylene) -, wherein said C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Alkylthio group, (C)3-C8Cycloalkyl) - (C)0-C6Alkylene) -, (C)2-C10Heterocyclyl) - (C)0-C6Alkylene) -, (C)6-C10Aryl group) - (C0-C6Alkylene) -and (C)1-C9Heteroaryl) - (C)0-C6Alkylene) -independently optionally substituted with one or more groups independently selected from D, F, Cl, Br, I, -CN, -NO2、-NH2-OH, -SH, -COOH, oxo (═ O), C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Alkylthio or C1-C6Substituted by alkylamino; and each Ra、RbAnd RcHave the meaning as described in the present invention.
In one embodiment, each R is6And R7Independently H, D, F, Cl, Br, I, -CN, -NH2、-OH、-COOH、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylamino radical, C1-C6Alkylthio group, (C)3-C8Cycloalkyl) - (C)0-C6Alkylene) -, (C)2-C10Heterocyclyl) - (C)0-C6Alkylene) -, (C)6-C10Aryl group) - (C0-C6Alkylene) -or (C)1-C9Heteroaryl) - (C)0-C6Alkylene) -.
In one embodiment, R8Is D, C2-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, (C)3-C8Cycloalkyl) - (C)0-C6Alkylene) -, (C)2-C10Heterocyclyl) - (C)0-C6Alkylene) -, (C)6-C10Aryl group) - (C0-C6Alkylene) -or (C)1-C9Heteroaryl) - (C)0-C6Alkylene) -, wherein said C2-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, (C)3-C8Cycloalkyl) - (C)0-C6Alkylene) -, (C)2-C10Heterocyclyl) - (C)0-C6Alkylene) -, (C)6-C10Aryl group) - (C0-C6Alkylene) -and (C)1-C9Heteroaryl) - (C)0-C6Alkylene) -is independently optionally substituted with one or more groups independently selected from D, -CN, -NO2-SH, -COOH, oxo (═ O), C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Haloalkoxy, C1-C6Alkylthio or C1-C6Substituted by alkylamino.
In one embodiment, each R is9Independently H, D, F, Cl, Br, I, -CN, -NO2、-OH、-NRaRb、-C(＝O)Rc、-S(＝O)2Rc、-C(＝O)NRaRb、-S(＝O)2NRaRb、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Aminoalkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylthio radical, C1-C6Haloalkylthio, (C)3-C8Cycloalkyl) - (C)0-C6Alkylene) -, (C)2-C10Heterocyclyl) - (C)0-C6Alkylene) -, (C)6-C10Aryl group) - (C0-C6Alkylene) -or (C)1-C9Heteroaryl) - (C)0-C6Alkylene) -; and each Ra、RbAnd RcHave the meaning as described in the present invention.
In one embodiment, RxAnd RyEach independently is D, F, Cl, Br, I, -CN, -NH2、-NO2、-OH、-COOH、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Aminoalkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylthio radical, C1-C6Haloalkylthio, (C)3-C8Cycloalkyl) - (C)0-C6Alkylene) -, (C)2-C10Heterocyclyl) - (C)0-C6Alkylene) -, (C)6-C10Aryl group) - (C0-C6Alkylene) -or (C)1-C9Heteroaryl) - (C)0-C6Alkylene) -.
In one embodiment, each R isa、RbAnd RcIndependently H, -OH, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, (C)3-C8Cycloalkyl) - (C)0-C6Alkylene) -, (C)2-C10Heterocyclyl) - (C)0-C6Alkylene) -, (C)6-C10Aryl group) - (C0-C6Alkylene) -or (C)1-C9Heteroaryl) - (C)0-C6Alkylene) -.
In one embodiment, R1、R2、R3、R4And R5Each independently is H, D, F, Cl, Br, I, -CN, -NO2、-OH、-NRaRb、-C(＝O)Rc、-S(＝O)2Rc、-C(＝O)NRaRb、-S(＝O)2NRaRb、C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Alkoxy radical, C1-C4Alkylthio group, (C)3-C6Cycloalkyl) - (C)0-C4Alkylene) -, (C)2-C6Heterocyclyl) - (C)0-C4Alkylene) -, (C)6-C10Aryl group) - (C0-C4Alkylene) -or (C)1-C5Heteroaryl) - (C)0-C4Alkylene) -, wherein said C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Alkoxy radical, C1-C4Alkylthio group, (C)3-C6Cycloalkyl) - (C)0-C4Alkylene) -, (C)2-C6Heterocyclyl) - (C)0-C4Alkylene) -, (C)6-C10Aryl group) - (C0-C4Alkylene) -and (C)1-C5Heteroaryl) - (C)0-C4Alkylene) -independently optionally substituted with one or more groups independently selected from D, F, Cl, Br, I, -CN, -NO2、-NH2-OH, -SH, -COOH, oxo (═ O), C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Alkylthio or C1-C4Substituted by alkylamino; and each Ra、RbAnd RcHave the meaning as described in the present invention.
In an implementation methodIn the scheme, R1、R2、R3、R4And R5Each independently is H, D, F, Cl, Br, I, -CN, -NO2、-OH、-NH2、-N(CH3)2、-C(＝O)CH3、-C(＝O)OH、-C(＝O)OCH3、-CONH2Methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, -CF3or-OCF3。
In one embodiment, each R is6And R7Independently H, D, F, Cl, Br, I, -CN, -NH2、-OH、-COOH、C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, C1-C4Alkylamino radical, C1-C4Alkylthio group, (C)3-C6Cycloalkyl) - (C)0-C4Alkylene) -, (C)2-C6Heterocyclyl) - (C)0-C4Alkylene) -, (C)6-C10Aryl group) - (C0-C4Alkylene) -or (C)1-C5Heteroaryl) - (C)0-C4Alkylene) -.
In one embodiment, each R is9Independently H, D, F, Cl, Br, I, -CN, -NO2、-OH、-NRaRb、-C(＝O)Rc、-S(＝O)2Rc、-C(＝O)NRaRb、-S(＝O)2NRaRb、C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Aminoalkyl radical, C1-C4Alkoxy radical, C1-C4Haloalkoxy, C1-C4Alkylthio radical, C1-C4Haloalkylthio, (C)3-C6Cycloalkyl) - (C)0-C4Alkylene) -, (C)2-C6Heterocyclyl) - (C)0-C4Alkylene) -, (C)6-C10Aryl group) - (C0-C4Alkylene) -or (C)1-C5Heteroaryl) - (C)0-C4Alkylene) -; and each Ra、RbAnd RcHave the meaning as described in the present invention.
In one embodiment, RxAnd RyEach independently is D, F, Cl, Br, I, -CN, -NH2、-NO2、-OH、-COOH、C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Aminoalkyl radical, C1-C4Alkoxy radical, C1-C4Haloalkoxy, C1-C4Alkylthio radical, C1-C4Haloalkylthio, (C)3-C6Cycloalkyl) - (C)0-C4Alkylene) -, (C)2-C6Heterocyclyl) - (C)0-C4Alkylene) -, (C)6-C10Aryl group) - (C0-C4Alkylene) -or (C)1-C5Heteroaryl) - (C)0-C6Alkylene) -; and each Ra、RbAnd RcHave the meaning as described in the present invention.
In one embodiment, each R isa、RbAnd RcIndependently H, -OH, C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, (C)3-C6Cycloalkyl) - (C)0-C4Alkylene) -, (C)2-C6Heterocyclyl) - (C)0-C4Alkylene) -, (C)6-C10Aryl group) - (C0-C4Alkylene) -or (C)1-C5Heteroaryl) - (C)0-C4Alkylene) -.
In one embodiment, each R is6And R7Independently H, D, F, Cl, Br, I, -CN、-NH2OH, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy or isopropoxy.
In one embodiment, each R is9Independently H, D, F, Cl, Br, I, -CN, -NO2、-OH、-NH2、-N(CH3)2、-C(＝O)CH3、-C(＝O)OH、-C(＝O)OCH3、-CONH2Methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, -CF3、-CH2CF3、-OCF3、-OCH2CF3or-OCH2CF2CHF2。
In one embodiment, RxAnd RyEach independently is D, F, Cl, Br, I, -CN, -NH2、-NO2OH, -COOH, methyl, ethyl, n-propyl or isopropyl.
In one embodiment, each R isa、RbAnd RcIndependently H, -OH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy or isopropoxy.
In one embodiment, R8Is D, C2-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, (C)3-C6Cycloalkyl) - (C)0-C4Alkylene) -, (C)2-C6Heterocyclyl) - (C)0-C4Alkylene) -, (C)6-C10Aryl group) - (C0-C4Alkylene) -or (C)1-C5Heteroaryl) - (C)0-C4Alkylene) -, wherein said C2-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, (C)3-C6Cycloalkyl) - (C)0-C4Alkylene) -, (C)2-C6Heterocyclyl) - (C)0-C4Alkylene) -, (C)6-C10Aryl group) - (C0-C4Alkylene) -and (C)1-C5Heteroaryl) - (C)0-C4Alkylene) -is independently optionally substituted with one or more groups independently selected from D, -CN, -NO2-SH, -COOH, oxo (═ O), C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Haloalkyl, C1-C4Haloalkoxy, C1-C4Alkylthio or C1-C4Substituted by alkylamino.
In one embodiment, R8Is D, ethyl, n-propyl, isopropyl or-CHF2、-CF3、-CH2CHF2、-CH2CF3、-CHFCF3、-CF2CF3、-CF2CH3、-CF2CHF2、-CF2CH2CH3、-CF2CH2CF3、-CF2CH2CHF2、-CH2CHFCH3、-CH2CHFCHF2、-CH2CHFCF3、-CH2CF2CH3、-CH2CF2CF3or-CH2CF2CHF2。
In one embodiment, the compound of the present invention is a compound having one of the following structures or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound having one of the following structures:
Figure BDA0000958341680000041
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 any combination thereof.
In one 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 one embodiment, the additional therapeutic agent described herein is donepezil (donepezil), nalmefene (nalmefene), risperidone (risperidone), vitamin E (vitamine E), AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, intepirine, idalopidine, tacrine (tacrine), rivastigmine (rivastigmine), galantamine (galantamine), memantine (memantine), Mirtazapine (Mirtazapine), venlafaxine (venlafaxine), despramine (desipramine), nortriptyline (nortriptyline), zolpidem (zolpidem), zopiclone (zopiclone), nicergoline (lacine), piracetam (pyridone), theobromine (theobromine), or any combination thereof.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament for the prevention, treatment or amelioration of 5-HT6A receptor associated disease.
In one embodiment, the invention relates to the treatment of 5-HT6The receptor associated disease is a CNS disorder.
In one embodiment, the invention relates to the treatment of 5-HT6The receptor associated disease is a CNS disorder, wherein said CNS disorder is ADHD, anxiety, a stress-related disease, schizophrenia, obsessive compulsive disorder, manic depression, a neurological disorder, a memory disorder, an attention deficit disorder, parkinson's disease, amyotrophic lateral sclerosis, alzheimer's disease or huntington's chorea.
In one embodiment, the invention relates to the treatment of 5-HT6The receptor-associated disease is a gastrointestinal disorder.
In one embodiment, the invention relates to the treatment of 5-HT6The receptor-related disease is obesity.
Another aspect of the invention relates to methods for the preparation, isolation and purification of compounds of formula (I).
Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict.
The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described 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 by the accompanying structural and chemical formulas. The invention is intended to cover 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 that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further 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 subcombination.
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, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be found in the descriptions of "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 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" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.
The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.
The term "stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
The term "chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.
The term "enantiomer" refers to two isomers of a compound that are not overlapping 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 "diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers 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 the general definitions of S.P. Parker, Ed., McGraw-Hilldictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; andEliel, E.and Wilen, S, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc, New York, 1994. Many organic compounds exist in an 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 denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A 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 may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.
Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as 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 exist as one of the possible isomers or as mixtures thereof, for example as racemates and mixtures of non-corresponding isomers (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 substituents 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.
Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (lowenergy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism 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 the description includes single, double, or triple bonds.
The term "unsaturated" or "unsaturated" means that the moiety contains one or more degrees of unsaturation.
The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention. It is understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted". In general, the terms "substituted" or "substituted" mean that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein the substituents can be, but are not limited to, D, F, Cl, Br, I, -CN, -NO2、-NH2OH, oxo (═ O), carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, haloalkyl, haloalkoxy, hydroxy-substituted alkyl, hydroxy-substituted haloalkyl, hydroxy-substituted alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, heteroaryloxy, hydroxy-substituted alkyl-C (═ O) -, alkyl-S (═ O)2-, hydroxy-substituted alkyl-S (═ O)2-, and the like.
In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other. For example, the formula "-NRaRb"and the formula" -C (═ O) NRaRb"between R and RaAnd RbAre not affected by each other.
In the description of the parts, the inventionSubstituents of the disclosed compounds are disclosed according to the group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1-C6Alkyl "means in particular independently disclosed methyl, ethyl, C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group.
In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain monovalent hydrocarbon radical 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 1-20 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 group (Et, -CH)2CH3) N-propyl (n-Pr, -CH)2CH2CH3) Isopropyl group (i-Pr, -CH (CH)3)2) N-butyl (n-Bu, -CH)2CH2CH2CH3) Isobutyl (i-Bu, -CH)2CH(CH3)2) Sec-butyl (s-Bu, -CH (CH)3)CH2CH3) Tert-butyl (t-Bu, -C (CH)3)3) N-pentyl (-CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH)3)CH2CH2CH3) 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) N-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH))3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2) 2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2)3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)3) N-heptyl, n-octyl, and the like.
The term "alkylene" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon radical. Unless otherwise specified, the alkylene group contains 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)2CH2-, isopropylidene (-CH (CH)3)CH2-) and the like. The alkylene group is optionally substituted with one or more substituents described herein.
The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp2A double bond, wherein the alkenyl group is optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z".
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp triple bond, wherein said alkynyl radical is optionally substituted with one or more substituents as described herein.
The term "heteroatom" denotes one or more of oxygen (O), sulfur (S), nitrogen (N), phosphorus (P) or silicon (Si), including nitrogen (N), sulfur (S) and phosphorus (P) in any oxidation state; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a 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 terms "haloalkyl", "haloalkoxy" or "haloalkylthio" mean that the alkyl, alkoxy or alkylthio group is substituted with one or more halogen atoms, wherein the alkyl, alkoxy and alkylthio groups have the meaning described herein, examples of which include, but are not limited to, difluoromethyl, trifluoromethyl, trifluoromethoxy, 2,2, 2-trifluoroethyl, 2,2, 2-trifluoroethoxy, 2,2,3, 3-tetrafluoropropyl, 2,2,3, 3-tetrafluoropropoxy, and the like. The haloalkyl, haloalkoxy or haloalkylthio group is optionally substituted with one or more substituents described herein.
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 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 group is 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)2CH3) 1-propoxy (n-PrO, n-propoxy, -OCH)2CH2CH3) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)3)2) 1-butoxy (n-BuO, n-butoxy, -OCH)2CH2CH2CH3) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)2CH(CH3)2) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)3)CH2CH3) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)3)3) 1-pentyloxy (n-pentyloxy, -OCH)2CH2CH2CH2CH3) 2-pentyloxy (-OCH (CH)3)CH2CH2CH3) 3-pentyloxy (-OCH (CH))2CH3)2) 2-methyl-2-butoxy (-OC (CH))3)2CH2CH3) 3-methyl-2-butoxy (-OCH (CH)3)CH(CH3)2) 3-methyl-l-butoxy (-OCH)2CH2CH(CH3)2) 2-methyl-l-butoxy (-OCH)2CH(CH3)CH2CH3) And so on.
The term "alkylthio" refers to C1-C6The linear or branched alkyl group is attached to the rest of the molecule through a sulfur atom.
The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" wherein the amino groups are each independently substituted with one or two alkyl groups, wherein the alkyl groups have the meaning as described herein.
The term "aminoalkyl" includes C substituted with one or more amino groups1-C10Straight chain orA branched alkyl group.
The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms.
The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and 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 a heteroatom having the meaning described herein, which ring may be fully saturated or contain one or more unsaturations, but not one aromatic ring.
The term "aryl" denotes monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring is aromatic.
The term "heteroaryl" denotes 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 is aromatic and at least one ring contains one or more heteroatoms.
The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)1-C24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, 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: higuchi et al, Pro-drugs as Novel Delivery Systems, vol.14, a.c.s.symposium Series; roche et al, ed., Bioreversible Cariers in drug design, American Pharmaceutical Association and Pergamon Press, 1987; rautio et al, Prodrugs Design and Clinical applicationNature Reviews Drug Discovery,2008,7, 255-.
The term "metabolite" as used herein refers to a product obtained by the metabolism of a particular compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: s.m.berge et al, j.pharmaceutical Sciences, 66: 1-19,1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, laurylsulfates, malates, methanesulfonates, 2-hydroxyethanesulfonates, bisulfatesNaphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, embonates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanates, p-toluenesulfonate, undecanoates, valeriates, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N+(C1-C4Alkyl radical)4A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-C8Sulfonates and aromatic sulfonates.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.
When the solvent is water, the term "hydrate" may be used. In one embodiment, a molecule of a compound of the present invention may be associated with a molecule of water, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be associated with more than one molecule of water, such as a dihydrate, and in yet another embodiment, one molecule of the compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the compound in its non-hydrated form.
The term "protecting group" or "PG" refers to a substituent that, when reacted with other functional groups, is generally used to block or protect a particular functionality. For example, "protecting group for amino group" means a substituent withThe amino group is linked to block or protect the functionality of the amino group in the compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality of a substituent of a hydroxy group to block or protect the hydroxy group, and suitable protecting groups include trialkylsilyl, acetyl, benzoyl and benzyl. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH2CH2SO2Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions 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" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" 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" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.
The term "prevent" or "prevention" refers to a reduction in the risk of acquiring a disease or disorder (i.e., arresting the development of at least one clinical symptom of a disease in a subject that may be facing or predisposed to facing such a disease, but who has not yet experienced or exhibited symptoms of the disease).
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate 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 the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of pharmaceutical salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany,2002) may find some additional lists of suitable salts.
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 containing them (e.g., ethanol, DMSO, etc.), for their crystallization. The compounds disclosed herein may form solvates with pharmaceutically acceptable solvents (including water), either inherently or by design; thus, the present invention is intended to include both solvated and unsolvated forms.
Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass 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 as2H，3H，11C，13C，14C，15N，17O，18O，18F，31P，32P，35S，36Cl and125I。
in another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, e.g. wherein a radioisotope, e.g. is present3H，14C and18those compounds of F, or in which a non-radioactive isotope is present, e.g.2H and13C. the isotopically enriched compounds can be used for metabolic studies (use)14C) Reaction kinetics study (using, for example2H or3H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiotherapy of a patient.18F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques known to those skilled in the art or by the procedures and examples described in the present specification using a suitable isotopically labelled reagent in place of the original used unlabelled reagent.
In addition, heavier isotopes are, in particular, deuterium (i.e.,2substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is to be understood that deuterium in the present invention is considered as a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic and natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated 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 in which the crystallization solvent may be isotopically substituted, e.g. D2O, acetone-d6、DMSO-d6Those solvates of (a).
Unless otherwise indicated, all suitable isotopic variations, stereoisomers, tautomers, nitroxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are within the scope of the present invention.
The compounds of the present disclosure may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention contemplates that all stereoisomeric forms of the compounds of formula (I), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, and mixtures thereof, such as racemic mixtures, are integral to the invention.
Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms.
In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.
Nitroxides of the compounds of the present invention are also included within the scope of the present invention. The nitroxides of the compounds of the present invention may be prepared by oxidation of the corresponding nitrogen-containing basic species using a common oxidizing agent (e.g. hydrogen peroxide) in the presence of an acid such as acetic acid at elevated temperature, or by reaction with a peracid in a suitable solvent, for example peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or 3-chloroperoxybenzoic acid in chloroform or dichloromethane.
In another aspect, the invention relates to intermediates for the preparation of compounds of formula (I).
In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula (I).
The compounds of formula (I) 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. In another embodiment, the salts need not be pharmaceutically acceptable salts and may be intermediates useful in the preparation and/or purification of compounds of formula (I) and/or in the isolation of enantiomers of compounds of formula (I).
If the compounds of the invention are basic, the desired salts may be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids and the like, or using organic acids such as acetic, maleic, succinic, mandelic, fumaric, malonic, pyruvic, oxalic, glycolic and salicylic acids, pyranonic acids such as glucuronic and galacturonic acids, α -hydroxy acids such as citric and tartaric acids, amino acids such as aspartic and glutamic acids, aromatic acids such as benzoic and cinnamic acids, sulfonic acids such as p-toluenesulfonic, ethanesulfonic, and the like.
If the compounds of the invention are acidic, the desired salts can be prepared by suitable methods, e.g., 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 amines, and cyclic amines such as piperidine, morpholine, piperazine and the like, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention. In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or combination thereof. In another embodiment, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel, or spray dosage form.
Compounds of the invention and pharmaceutical compositions, formulations and administrations thereof
When useful in therapy, a therapeutically effective amount of a compound of formula (I) and pharmaceutically acceptable salts thereof may be administered as the raw chemical or as an active ingredient in a pharmaceutical composition. Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of formula (I) or an individual stereoisomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate 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 excipient agents are well known to those skilled in the art and are described in detail, for example, in Ansel h.c.et al, Ansel's Pharmaceutical Dosage Forms and Drug delivery systems (2004) Lippincott, Williams & Wilkins, philidelphia; 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.
A method of treatment comprising administering a compound or pharmaceutical composition of the invention, further comprising administering to the patient an additional anti-Alzheimer's disease agent (combination therapy), wherein the additional anti-Alzheimer's disease agent is donepezil, nalmefene, risperidone, vitamins E, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, intepirdine, idalopidine, tacrine, rivastigmine, galantamine, memantine, mirtazapine, venlafaxine, descumulan, nortriptyline, zolpidem, zopiclone, nicergoline, piracetam, selegiline, pentoxifylline, or any combination thereof.
The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to show meaningful patient benefit. When the active ingredient alone is used for separate administration, the term refers only to that ingredient. When used in combination, the term refers to the combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, sequentially or simultaneously. The compounds of formula (I) and pharmaceutically acceptable salts thereof 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 the preparation of a pharmaceutical formulation, which process comprises bringing into intimate admixture a compound of formula (I), 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 which are effective for their intended use.
In general, the compounds of the present invention are administered in therapeutically effective amounts by any conventional means of administration for substances that exert similar effects. Suitable dosage ranges are typically from 1 to 500mg per day, preferably from 1 to 100mg per day, most preferably from 1 to 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 being made, 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 relying on 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 formulations 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 administration by inhalation or insufflation. The preferred mode of administration is generally oral, and may be adjusted to the level of pain using a suitable daily dosage regimen.
One or more compounds of the present invention may be presented in pharmaceutical compositions and unit dosage forms together with one or more conventional adjuvants, carriers or diluents. The pharmaceutical compositions and unit dosage forms can contain conventional ingredients in conventional proportions, with or without additional active compounds or ingredients, and the unit dosage forms can contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be applied in the form of solids such as tablets or filled capsules, semisolids, powders, sustained release formulations or liquids such as solutions, suspensions, emulsions, elixirs or filled capsules 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, from 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 orally administered dosage forms. Pharmaceutical compositions and dosage forms may comprise one or more compounds of the invention or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutically acceptable carrier may be a solid or a liquid. Solid form formulation package: powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act 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 is in admixture with the finely divided active ingredient. In tablets, the active ingredient is usually mixed with a carrier having the necessary binding capacity in suitable 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, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like.
The term "formulation" is intended to include preparations of the active compound that contain the encapsulating material as a carrier to provide a capsule in which the active ingredient, with or without a carrier, is surrounded by the carrier in association therewith. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges are 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 which are intended to be converted into a liquid form preparation immediately before use. Emulsions may be prepared in solutions such as aqueous propylene glycol or may contain emulsifying agents 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 thickening agents. Aqueous suspensions may be formulated by dispersing the finely divided active ingredient in water with viscous material, for example, natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents. Liquid form preparations 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 or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or non-aqueous 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 agents such as preservatives, wetting agents, emulsifying or suspending agents, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic packaging of a sterile solid or by lyophilisation of a solution for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
The compounds of the present invention may be formulated for topical application to the epidermis in the form of an ointment, cream or lotion, or in the form of a transdermal patch. 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 flavoured base, usually 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, can be melted first and the active ingredient dispersed homogeneously, for example by stirring. The molten homogeneous mixture is then poured into a suitably sized mold, allowed to cool and solidify.
The compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
The compounds of the present invention may be formulated for nasal administration. The solutions or suspensions can be applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or nebulizer. The formulations may be in single or multiple dose form. For a dropper or pipette multi-dose form, this may be achieved by the patient administering an appropriate, predetermined volume of solution or suspension. For a nebulizer, this can be achieved, for example, by a metered atomizing spray pump.
The compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compounds typically have small particle sizes, for example, on the order of 5 microns or less. The particle size may be obtained by methods well known in the art, for example by micronization. The active ingredient is provided in pressurized packs containing a suitable propellant, such as a chlorofluorocarbon (CFC) for example 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 medicament may be controlled by a metering valve. Alternatively, the active ingredient may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone. The powder carrier will form a gel in the nasal cavity. The powder compositions may be presented in unit dosage form, for example in gelatin capsules or cartridges or blister packs from which the powder may be administered by means of an inhaler.
If desired, the formulations may be prepared with enteric coatings suitable for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention may be formulated as transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with the treatment regimen is critical. The 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 a penetration enhancer, such as laurocapram (1-dodecyl azepan-2-one). The sustained release delivery system may be inserted subcutaneously into the subcutaneous layer by surgery or injection. Subcutaneous implants encapsulate compounds in a liquid soluble film, such as silicone rubber, or a biodegradable polymer, such as polylactic acid.
The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as tablets, capsules, and powders or ampoules in vials. In addition, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in a packaged form.
Other suitable pharmaceutical carriers and their formulations are described in Remington: the Science and Practice of pharmacy 1995Martin, edited by E.W, 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 reducing Alzheimer's disease, and can also be used for preparing medicines for preventing, treating or reducing 5-HT6A pharmaceutical product for a disease associated with a receptor.
The pharmaceutical composition of the present invention is characterized by comprising a compound represented by formula (I) or a compound listed in the present invention, and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of compound in the compositions of the invention is effective to detectably antagonize 5-HT6The receptors are useful for the treatment of CNS disorders, including ADHD, anxiety, stress-related disorders, schizophrenia, obsessive-compulsive disorders, manic depression, neurological disorders, memory disorders, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's chorea, and obesity.
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 mentioned herein. The compounds and compositions according to the methods of the present invention can be administered in any amount and by any route effective to treat or reduce the severity of the disease. The exact amount necessary will vary depending on the patient, depending on the race, age, general condition of the patient, severity of 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.
In addition to being beneficial for human therapy, the compounds and pharmaceutical compositions of the present invention may also find application in veterinary therapy for pets, animals of the introduced species and mammals in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.
General Synthesis of Compounds of the invention
To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.
In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Lingkai medicine, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin HaoLiyu Chemicals Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaseiki chemical plant.
The anhydrous tetrahydrofuran is obtained by refluxing and drying the metallic sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, N, N-dimethylacetamide and petroleum ether were used dried over anhydrous sodium sulfate in advance.
The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.
The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants. Nuclear magnetic resonance spectroscopy with CDC13、DMSO-d6、CD3OD or acetone-d6As solvent (reported in ppm) TMS (0ppm) or chloroform (7.25ppm) was used as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet ), m (multiplet, multiplet), br (broad ), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in hertz (Hz).
Low resolution Mass Spectral (MS) data were measured by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained 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 Spectral (MS) data were determined by Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was used for the LC-MS spectrometer.
Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1X 30mm, 5 μm. The injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; peaks of HPLC were recorded by UV-Vis wavelength at 210nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase a) and 0.1% formic acid in ultrapure water (phase B).
Compound purification was assessed by Agilent 1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm, a Zorbax SB-C18 column, 2.1X 30mm, 4 μm, 10 min, flow rate 0.6mL/min, 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), the column temperature was maintained at 40 ℃.
The following acronyms are used throughout the invention:
Pd/C palladium carbon catalyst
AcOH acetic acid
MeCN,CH3CN acetonitrile
CHCl3Chloroform
CDC13Deuterated chloroform
DMSO dimethyl sulfoxide
DMSO-d6Deuterated dimethyl sulfoxide
DMF N, N-dimethylformamide
EtOAc, EA ethyl acetate
HCl hydrochloric acid
MgSO4Magnesium sulfate
MgCl2Magnesium chloride
MeOH,CH3OH methanol
HCHO Formaldehyde
CH2Cl2DCM dichloromethane
mL, mL
PE Petroleum ether (60-90 deg.C)
Na2CO3Sodium carbonate
NaHCO3Sodium bicarbonate
M, mol/L mol/liter
K2CO3Potassium carbonate
KOH potassium hydroxide
RT Room temperature
Rt Retention time
h, hr
NaBH3CN Cyanoborohydride sodium salt
NaCl sodium chloride
KCl potassium chloride
Na2SO4Sodium sulfate
THF tetrahydrofuran
EDTA ethylene diamine tetraacetic acid
PEI polyethyleneimine
Pargyline Pargyline
Tris-HCl Tris (hydroxymethyl) aminomethane-hydrochloric acid
NADPH reduced coenzyme II
The following synthetic schemes describe the steps for preparing the compounds disclosed herein. Unless otherwise stated in the context of the present invention,
Figure BDA0000958341680000161
is a single or double bond, each R1、R2、R3、R4、R5、R8、R9M and X have the definitions as described in the present invention.
Synthesis scheme 1
Figure BDA0000958341680000162
Formula (A), (B) and5) The compounds shown can be prepared by the methods described in scheme 1. First, formula (A)1) The compound reacts with piperidone derivative under the action of alkali to obtain a compound shown as a formula (I)2) The product shown; then formula (A), (B), (C), (2) Removing the protecting group of the compound to obtain a compound of the formula (I)3) A compound shown in the specification; formula (A), (B) and3) A compound of the formula4) The compound shown in the formula (A) is obtained after the reaction and the reductive amination5) The target compound shown.
The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in connection with the examples.
Examples
Example 13 Synthesis of- (1- (3- (2,2, 2-trifluoroethoxy) benzyl) piperidin-4-yl) -1H-indole
Figure BDA0000958341680000171
Step 1) Synthesis of 4- (1H-indol-3-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
Indole (5.0g,42.7mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (10.1g,51.2mmol) were added to methanol (50mL), followed by KOH (4.78g,85.4mmol), the reaction was stopped after 8 hours at oil bath 70 deg.C, quenched by addition of water (150mL), a large amount of yellow solid precipitated, filtered, and the residue was dried under vacuum to give the title compound as a tan solid (10.9g, 86.2%).
MS(ESI,pos.ion)m/z:299.2[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.43(s,1H),7.74(d,J＝8.2Hz,1H),7.31(d,J＝8.2Hz,1H),7.18–7.15(m,1H),7.08–7.05(m,1H),6.94(d,J＝2.4Hz,1H),6.08(brs,1H),4.12(d,J＝2.0Hz,2H),3.65(t,J＝5.6Hz,2H),2.53(brs,2H),1.49(s,9H).
Step 2) Synthesis of 4- (1H-indol-3-yl) piperidine-1-carboxylic acid tert-butyl ester
4- (1H-indol-3-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (10.0g,33.5mmol) was added to a mixed solvent of methanol (30mL) and tetrahydrofuran (30mL), followed by addition of Pd/C (3.0g, 10%). 1atmH at 25 ℃2The reaction was carried out under pressure for 15 hours. The reaction was stopped, filtered, the filtrate was spin-dried under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give the title compound as a white solid (9.14g, 91%).
MS(ESI,pos.ion)m/z:201.1[M+H-100]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.24(s,1H),7.82(d,J＝8.4Hz,1H),7.35(d,J＝7.8Hz,1H),7.24–7.21(m,1H),7.19–7.16(m,1H),7.09(d,J＝3.0Hz,1H),4.22(t,J＝9.2Hz,2H),2.95–2.84(m,3H),2.03–1.98(m,2H),1.68–1.54(m,2H),1.47(s,9H).
Step 3) Synthesis of 3- (piperidin-4-yl) -1H-indole
Tert-butyl 4- (1H-indol-3-yl) piperidine-1-carboxylate (9.0g,30mmol) was added to dichloromethane (50mL) at 25 deg.C, followed by a solution of hydrogen chloride in ethyl acetate (20mL,2mmol/mL), the reaction was stopped after stirring for 3 hours, quenched by addition of saturated sodium bicarbonate solution (50mL), and the organic phase was dried over anhydrous sodium sulfate after separation. Filtration, spin-drying of the filtrate under reduced pressure, and column chromatography purification (dichloromethane/methanol (v/v) ═ 10/1) gave the title compound as a light yellow oil (5.46g, 91%).
MS(ESI,pos.ion)m/z:201.1[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):8.47(s,1H),7.75(d,J＝8.4Hz,1H),7.32(d,J＝8.4Hz,1H),7.17–7.14(m,1H),7.09–7.04(m,1H),6.93(d,J＝2.4Hz,1H),3.37(brs,2H),3.07–2.99(m,3H),2.06–2.04(m,2H),2.02–1.90(m,2H).
Step 4) Synthesis of 3- (1- (3- (2,2, 2-trifluoroethoxy) benzyl) piperidin-4-yl) -1H-indole
3- (piperidin-4-yl) -1H-indole (300mg,1.5mmol), 3- (2,2, 2-trifluoroethoxy) benzaldehyde (408mg,2.0mmol) and AcOH (0.2mL) were added to MeOH (10mL) at 25 deg.C, followed by NaBH3CN (284mg,4.5mmol), and after 5 hours of reaction, the reaction was stopped, and quenched by the addition of water (10mL) and sodium carbonate (318mg,3.0mmol) in that order. Extract with dichloromethane (50mL x 3), combine the organic phases and dry over anhydrous sodium sulfate. Filtration, spin-drying of the filtrate under reduced pressure, and column chromatography purification (dichloromethane/methanol (v/v) ═ 50/1) gave the title compound as a light yellow oil (326mg, 56%).
MS(ESI,pos.ion)m/z:389.1[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.05(s,1H),7.67(d,J＝7.6Hz,1H),7.33(d,J＝8.2Hz,1H),7.17(t,J＝7.8Hz,2H),7.04(t,J＝8.0Hz,1H),6.98(d,J＝2.4Hz,1H),6.83(d,J＝7.8Hz,1H),6.76(dd,J＝8.2,2.4Hz,1H),6.68(s,1H),4.34(q,J＝8.4Hz,2H),3.56(s,2H),2.98(t,J＝11.4Hz,2H),2.81–2.75(m,1H),2.17(t,J＝11.4Hz,2H),2.06–2.01(m,2H),1.85–1.78(m,2H).
Example Synthesis of 23- (1- (3- (2,2,3, 3-tetrafluoropropoxy) benzyl) piperidin-4-yl) -1H-indole
Figure BDA0000958341680000181
The title compound was prepared as described in example 1, step 4, i.e., 3- (piperidin-4-yl) -1H-indole (300mg,1.5mmol), 3- (2,2,3, 3-tetrafluoropropoxy) benzaldehyde (472mg,2.0mmol) and NaBH3CN (284mg,4.5mmol) was prepared by reaction in MeOH (10mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1), concentrated and dried to give the title compound as a light yellow oil (322mg, 51.0%).
MS(ESI,pos.ion)m/z:421.1[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.04(s,1H),7.69(d,J＝8.4Hz,1H),7.34(d,J＝8.4Hz,1H),7.17(td,J＝7.4,3.6Hz,2H),7.05–7.02(m,1H),6.98(d,J＝2.4Hz,1H),6.82(d,J＝7.2Hz,1H),6.74(dd,J＝8.4,2.4Hz,1H),6.68(s,1H),6.06(tt,J＝52.8,4.8Hz,1H),4.36(t,J＝12.0Hz,2H),3.55(s,2H),3.00(t,J＝11.4Hz,2H),2.83–2.74(m,1H),2.17(t,J＝11.4Hz,2H),2.06–2.02(m,2H),1.89–1.74(m,2H).
Example of 35-methoxy-3- (1- (3- (2,2, 2-trifluoroethoxy) benzyl) piperidin-4-yl) -1H-indole Synthesis of
Figure BDA0000958341680000182
Step 1) Synthesis of 4- (5-methoxy-1H-indol-3-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
This step was performed as described in example 1, step 1, using 5-methoxyindole (5.0g,34.0mmol), 4-oxopiperidine-1-carboxylic acid tert-butyl ester (8.1g,41.0mmol) and potassium hydroxide (3.8g,68.0mmol) in methanol (50mL) and filtered to dryness to give the title compound as a brown solid (10.3g, 92.3%).
MS(ESI,pos.ion)m/z:329.1[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.27(s,1H),7.29(d,J＝2.4Hz,1H),7.24(d,J＝8.8Hz,1H),7.12(d,J＝2.4Hz,1H),6.86(dd,J＝8.8,2.4Hz,1H),6.08(s,1H),4.12(d,J＝2.0Hz,2H),3.85(s,3H),3.65(t,J＝5.6Hz,2H),2.53(brs,2H),1.49(s,9H).
Step 2) Synthesis of 4- (5-methoxy-1H-indol-3-yl) piperidine-1-carboxylic acid tert-butyl ester
The title compound of this step was prepared as described in example 1, step 2, by reacting 4- (5-methoxy-1H-indol-3-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (10.0g,30.5mmol) and Pd/C (3.0g, 10%) in a mixed solvent of THF (30mL) and MeOH (20mL), purifying the crude by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1), concentrating and drying to give the title compound as a white solid (8.6g, 85.0%).
MS(ESI,pos.ion)m/z:231.3[M+H-100]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.95(s,1H),7.23(d,J＝8.8Hz,1H),7.03(d,J＝2.0Hz,1H),6.91(d,J＝2.0Hz,1H),6.84(dd,J＝8.8,2.4Hz,1H),4.22(t,J＝9.2Hz,2H),3.85(s,3H),2.95–2.84(m,3H),2.03–2.00(m,2H),1.68–1.54(m,2H),1.47(s,9H).
Step 3) Synthesis of 5-methoxy-3- (piperidin-4-yl) -1H-indole
The title compound was prepared as described in example 1, step 3 by reacting tert-butyl 4- (5-methoxy-1H-indol-3-yl) piperidine-1-carboxylate (8.6g,26.0mmol) with a solution of hydrogen chloride in ethyl acetate (20mL,2mmol/mL) in dichloromethane (50mL), purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1), concentrating and drying to give the title compound as a pale yellow solid (4.86g, 81.0%).
MS(ESI,pos.ion)m/z:231.1[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):10.72(s,1H),7.23(d,J＝8.8Hz,1H),7.13(d,J＝2.4Hz,1H),7.07(d,J＝2.0Hz,1H),6.72(dd,J＝8.8,2.4Hz,1H),3.77(s,3H),3.35(brs,2H),3.06–2.99(m,3H),2.05–2.02(m,2H),2.01–1.90(m,2H).
Step 4) Synthesis of 5-methoxy-3- (1- (3- (2,2, 2-trifluoroethoxy) benzyl) piperidin-4-yl) -1H-indole Become into
The title compound was prepared as described in example 1, step 4, i.e. 5-methoxy-3- (piperidin-4-yl) -1H-indole (310mg,1.35mmol), 3- (2,2, 2-trifluoroethoxy) benzaldehyde (450mg,2.20mmol) and NaBH3CN (180mg,1.70mmol) was prepared by reaction in MeOH (10mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1), concentrated and dried to give the title compound as a light yellow oil (138mg, 24.5%).
MS(ESI,pos.ion)m/z:419.3[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.86(s,1H),7.26(d,J＝7.8Hz,1H),7.22(d,J＝9.0Hz,1H),7.05(d,J＝1.8Hz,1H),7.02(d,J＝7.2Hz,1H),6.99(s,1H),6.94(d,J＝1.8Hz,1H),6.85–6.79(m,2H),4.34(q,J＝8.4Hz,2H),3.85(s,3H),3.54(s,2H),2.99(t,J＝11.4Hz,2H),2.81–2.73(m,1H),2.17(t,J＝11.4Hz,2H),2.04–2.01(m,2H),1.84–1.75(m,2H)；
13C NMR(150MHz,CDCl3)δ(ppm):157.7,154.0,141.0,131.8,129.6,127.3,124.6(q,J＝276.5Hz),123.5,121.5,120.7,115.7,113.7,112.2,112.0,101.4,66.0(q,J＝35.4Hz),63.5,56.3,54.6,33.6,33.1.
Example 45-methoxy-3- (1- (3- (2,2,3, 3-tetrafluoropropoxy) benzyl) piperidin-4-yl) -1H-indole Synthesis of (2)
Figure BDA0000958341680000191
The title compound was prepared as described in example 1, step 4, i.e., 5-methoxy-3- (piperidin-4-yl) -1H-indole (300mg,1.30mmol), 3- (2,2,3, 3-tetrafluoropropoxy) benzaldehyde (472mg,2.0mmol) and NaBH3CN (246mg,3.9mmol) was prepared by reaction in MeOH (10mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1), concentrated and dried to give the title compound as a light yellow oil (235mg, 38.8%).
MS(ESI,pos.ion)m/z:451.3[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.86(s,1H),7.26(d,J＝7.8Hz,1H),7.23(d,J＝9.0Hz,1H),7.04(d,J＝1.8Hz,1H),7.02(d,J＝7.2Hz,1H),6.97(s,1H),6.94(d,J＝1.8Hz,1H),6.83(dd,J＝9.0,2.4Hz,1H),6.81(dd,J＝8.4,2.4Hz,1H),6.07(tt,J＝52.8,4.8Hz,2H),4.34(t,J＝12.0Hz,3H),3.85(s,3H),3.55(s,2H),3.00(t,J＝11.4Hz,2H),2.82–2.73(m,1H),2.17(t,J＝11.4Hz,2H),2.04–2.01(m,2H),1.88–1.75(m,2H)；
13C NMR(150MHz,CDCl3)δ(ppm):157.6,154.0,131.8,130.1,129.6,127.3,123.5,121.4,120.8,115.5,114.8(tt,J＝248.4,26.4Hz),113.4,112.2,112.1,109.2(tt,J＝248.4,33.9Hz),101.4,65.4(q,J＝29.9Hz),63.5,56.3,54.6,33.6,33.1.
EXAMPLE 55 Synthesis of fluoro-3- (1- (3- (2,2, 2-trifluoroethoxy) benzyl) piperidin-4-yl) -1H-indole
Figure BDA0000958341680000201
Step 1) Synthesis of 4- (5-fluoro-1H-indol-3-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
This step was performed as described in example 1, step 1, using 5-fluoroindole (5.0g,37.0mmol), 4-oxopiperidine-1-carboxylic acid tert-butyl ester (8.1g,41.0mmol) and potassium hydroxide (4.14g,74.0mmol) in methanol (50mL) and filtered to dryness to give the title compound as a yellow solid (9.47g, 81%).
MS(ESI,pos.ion)m/z:317.1[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.17(s,1H),7.26–7.21(m,2H),7.08(d,J＝2.4Hz,1H),6.93(td,J＝8.6,2.4Hz,1H),6.12(brs,1H),4.11(d,J＝2.0Hz,2H),3.66(t,J＝5.6Hz,2H),2.54(brs,2H),1.49(s,9H).
Step 2) Synthesis of 4- (5-fluoro-1H-indol-3-yl) piperidine-1-carboxylic acid tert-butyl ester
The title compound was prepared as described in example 1, step 2 by reacting 4- (5-fluoro-1H-indol-3-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (9.0g,28.5mmol) and Pd/C (3.0g, 10%) in a mixed solvent of THF (30mL) and MeOH (20mL), purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1), concentrating and drying to give the title compound as a white solid (7.9g, 87.2%).
1H NMR(400MHz,CDCl3)δ(ppm):8.15(s,1H),7.26–7.22(m,2H),7.09(d,J＝2.4Hz,1H),6.94–6.92(m,1H),4.09–4.02(m,2H),2.99–2.88(m,2H),2.86(brs,1H),1.94-1.91(m,2H),1.53–1.46(m,2H),1.41(s,9H).
Step 3) Synthesis of 5-fluoro-3- (piperidin-4-yl) -1H-indole
The title compound was prepared as described in example 1, step 3 by reacting tert-butyl 4- (5-fluoro-1H-indol-3-yl) piperidine-1-carboxylate (7.0g,22.0mmol) with a solution of hydrogen chloride in ethyl acetate (20mL,2mmol/mL) in dichloromethane (50mL), purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1), concentrating and drying to give the title compound as a pale yellow oil (4.56g, 95%).
MS(ESI,pos.ion)m/z:219.1[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.19(s,1H),7.26–7.22(m,2H),7.09(d,J＝2.4Hz,1H),6.93(td,J＝8.4,2.4Hz,1H),3.04–3.02(m,2H),2.80(tt,J＝12.0,3.0Hz,1H),2.65–2.59(m,2H),1.86–1.80(m,2H),1.53(qd,J＝12.0,3.6Hz,2H).
Step 4) Synthesis of 5-fluoro-3- (1- (3- (2,2, 2-trifluoroethoxy) benzyl) piperidin-4-yl) -1H-indole
The title compound was prepared as described in example 1, step 4, i.e. 5-fluoro-3- (piperidin-4-yl) -1H-indole (300mg,1.37mmol), 3- (2,2, 2-trifluoroethoxy) benzaldehyde (450mg,2.20mmol) and NaBH3CN (180mg,2.86mmol) was prepared by reaction in MeOH (10mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1), concentrated and dried to give the title compound as a light yellow oil (251mg, 45%).
MS(ESI,pos.ion)m/z:407.1[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.07(s,1H),7.51(dd,J＝8.2,5.4Hz,1H),7.28–7.25(m,1H),7.03–6.98(m,3H),6.92(d,J＝1.8Hz,1H),6.86–6.82(m,2H),4.33(q,J＝8.4Hz,2H),3.56(s,2H),3.03(t,J＝11.4Hz,2H),2.82(tt,J＝11.4,3.6Hz,1H),2.19(t,J＝12.0Hz,2H),2.01–1.98(m,2H),1.82(qd,J＝12.6,3.6Hz,2H).
Example 65 Synthesis of-fluoro-3- (1- (3- (2,2,3, 3-tetrafluoropropoxy) benzyl) piperidin-4-yl) -1H-indole Become into
Figure BDA0000958341680000211
The title compound of this step was prepared as described in example 1, step 4Is prepared from 5-fluoro-3- (piperidin-4-yl) -1H-indole (300mg,1.37mmol), 3- (2,2,3, 3-tetrafluoropropoxy) benzaldehyde (472mg,2.0mmol) and NaBH3CN (250mg,3.97mmol) was prepared by reaction in MeOH (10mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1), concentrated and dried to give the title compound as a light yellow oil (282mg, 47%).
MS(ESI,pos.ion)m/z:439.2[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.07(s,1H),7.51(dd,J＝9.0,5.4Hz,1H),7.28–7.26(m,1H),7.02(d,J＝7.2Hz,1H),7.01–6.98(m,2H),6.93(d,J＝2.0Hz,1H),6.87–6.81(m,2H),6.07(tt,J＝52.8,5.4Hz,1H),4.38(t,J＝11.9Hz,2H),3.62(s,2H),3.08–3.06(m,2H),2.85(tt,J＝11.9,3.5Hz,1H),2.25(t,J＝11.9,2H),2.07–2.04(m,2H),1.87(qd,J＝12.7,3.5Hz,2H).
EXAMPLE 75 Synthesis of chloro-3- (1- (3- (2,2, 2-trifluoroethoxy) benzyl) piperidin-4-yl) -1H-indole
Figure BDA0000958341680000212
Step 1) Synthesis of 4- (5-chloro-1H-indol-3-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
This step was performed as described in example 1, step 1, using 5-chloroindole (5.0g,33.1mmol), 4-oxopiperidine-1-carboxylic acid tert-butyl ester (8.0g,40.2mmol) and potassium hydroxide (3.70g,66.0mmol) in methanol (50mL) and filtered to dryness to give the title compound as a yellow solid (9.12g, 83%).
MS(ESI,pos.ion)m/z:333.1[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.31(s,1H),7.56(d,J＝2.0Hz,1H),7.22(d,J＝8.4Hz,1H),7.13(dd,J＝8.6,2.0Hz,1H),7.02(d,J＝2.0Hz,1H),6.09(s,1H),4.13(d,J＝2.0Hz,2H),3.67(t,J＝5.6Hz,2H),2.54(brs,2H),1.48(s,9H).
Step 2) Synthesis of 4- (5-chloro-1H-indol-3-yl) piperidine-1-carboxylic acid tert-butyl ester
The title compound was prepared as described in example 1, step 2, by reacting 4- (5-chloro-1H-indol-3-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (9.0g,27.1mmol) and Pd/C (3.0g, 10%) in a mixed solvent of THF (30mL) and MeOH (20mL), purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1), concentrating and drying to give the title compound as a white solid (7.15g, 79%).
1H NMR(400MHz,CDCl3)δ(ppm):8.30(s,1H),7.57(d,J＝2.0Hz,1H),7.22(d,J＝8.6Hz,1H),7.12(dd,J＝8.6,2.0Hz,1H),7.01(d,J＝2.0Hz,1H),4.09–4.03(m,2H),2.98–2.88(m,2H),2.87(brs,1H),1.95–1.91(m,2H),1.53–1.47(m,2H),1.43(s,9H).
Step 3) Synthesis of 5-chloro-3- (piperidin-4-yl) -1H-indole
The title compound was prepared as described in example 1, step 3 by reacting tert-butyl 4- (5-chloro-1H-indol-3-yl) piperidine-1-carboxylate (7.0g,20.9mmol) with a solution of hydrogen chloride in ethyl acetate (20mL,2mmol/mL) in dichloromethane (50mL), purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1), concentrating and drying to give the title compound as a pale yellow oil (4.55g, 93%).
MS(ESI,pos.ion)m/z:235.1[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.27(s,1H),7.58(d,J＝2.0Hz,1H),7.22(d,J＝8.4Hz,1H),7.14–7.11(m,1H),7.02(d,J＝2.0Hz,1H),3.05–3.02(m,2H),2.81(tt,J＝12.0,3.0Hz,1H),2.65–2.60(m,2H),1.86–1.81(m,2H),1.54(qd,J＝12.0,3.6Hz,2H).
Step 4) Synthesis of 5-chloro-3- (1- (3- (2,2, 2-trifluoroethoxy) benzyl) piperidin-4-yl) -1H-indole
The title compound was prepared as described in example 1, step 4, i.e. 5-chloro-3- (piperidin-4-yl) -1H-indole (300mg,1.28mmol), 3- (2,2, 2-trifluoroethoxy) benzaldehyde (450mg,2.20mmol) and NaBH3CN (158mg,2.5mmol) in MeOH (10mL) was prepared and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1), concentrated and dried to give the title compound as a light yellow oilAs (276mg, 51%).
MS(ESI,pos.ion)m/z:423.1[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.07(s,1H),7.52(d,J＝8.4Hz,1H),7.32(d,J＝1.2Hz,1H),7.28–7.26(m,1H),7.07–7.04(m,1H),7.01(d,J＝7.8Hz,1H),6.99(s,1H),6.91(d,J＝1.8Hz,1H),6.85(dd,J＝7.8,1.8Hz,1H),4.35(q,J＝8.4Hz,2H),3.57(s,2H),3.02(t,J＝11.4Hz,2H),2.83–2.75(m,1H),2.19(t,J＝12.0Hz,2H),2.03–1.98(m,2H),1.86–1.77(m,2H).
Example 85 Synthesis of chloro-3- (1- (3- (2,2,3, 3-tetrafluoropropoxy) benzyl) piperidin-4-yl) -1H-indole Become into
Figure BDA0000958341680000221
The title compound was prepared as described in example 1, step 4, i.e., 5-chloro-3- (piperidin-4-yl) -1H-indole (300mg,1.28mmol), 3- (2,2,3, 3-tetrafluoropropoxy) benzaldehyde (472mg,2.0mmol) and NaBH3CN (158mg,2.5mmol) was prepared by reaction in MeOH (10mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1), concentrated and dried to give the title compound as a light yellow oil (331mg, 57%).
MS(ESI,pos.ion)m/z:455.2[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.03(s,1H),7.51(d,J＝8.4Hz,1H),7.31(d,J＝1.8Hz,1H),7.25(d,J＝7.8Hz,1H),7.07–7.04(m,1H),7.01(d,J＝7.8Hz,1H),6.96(s,1H),6.94(d,J＝1.8Hz,1H),6.84–6.82(m,1H),6.07(tt,J＝53.4,5.4Hz,1H),4.34(t,J＝12.0Hz,2H),3.53(s,2H),2.99(t,J＝11.4Hz,2H),2.79(tt,J＝12.0,3.6Hz,1H),2.17–2.14(m,2H),2.01–1.98(m,2H),1.82–1.77(m,2H).
EXAMPLE 96 Synthesis of fluoro-3- (1- (3- (2,2, 2-trifluoroethoxy) benzyl) piperidin-4-yl) -1H-indole
Figure BDA0000958341680000222
Step 1) Synthesis of 4- (6-fluoro-1H-indol-3-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
This step was performed as described in example 1, step 1, using 6-fluoroindole (3.0g,22.2mmol), 4-oxopiperidine-1-carboxylic acid tert-butyl ester (5.3g,26.6mmol) and potassium hydroxide (1.78g,31.8mmol) in methanol (50mL) and filtered to dryness to give the title compound as a yellow solid (6.87g, 98%).
MS(ESI,pos.ion)m/z:317.3[M+H]+；
1H NMR(600MHz,DMSO-d6)δ(ppm):11.23(s,1H),7.80(dd,J＝9.0,5.4Hz,1H),7.42(s,1H),7.15(dd,J＝10.2,2.4Hz,1H),6.89(td,J＝11.4,2.4Hz,1H),6.12(s,1H),4.03(brs,2H),3.55(d,J＝5.4Hz,2H),2.48(brs,2H),1.43(s,9H).
Step 2) Synthesis of 4- (6-fluoro-1H-indol-3-yl) piperidine-1-carboxylic acid tert-butyl ester
The title compound was prepared as described in example 1, step 2 by reacting 4- (6-fluoro-1H-indol-3-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (3.5g,11.0mmol) and Pd/C (310mg, 10%) in a mixed solvent of THF (15mL) and MeOH (10mL), purifying the crude by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1), concentrating and drying to give the title compound as a white solid (3.16g, 90.0%).
MS(ESI,pos.ion)m/z:219.3[M+H-100]+；
1H NMR(600MHz,DMSO-d6)δ(ppm):10.87(s,1H),7.53(dd,J＝9.0,5.4Hz,1H),7.09(dd,J＝9.6,2.4Hz,2H),6.81(td,J＝9.6,2.4Hz,1H),4.04(t,J＝7.2Hz,2H),2.97–2.77(m,3H),1.94–1.91(m,2H),1.50–1.47(m,2H),1.41(s,9H).
Step 3) Synthesis of 6-fluoro-3- (piperidin-4-yl) -1H-indole
The title compound was prepared as described in example 1, step 3 by reacting tert-butyl 4- (6-fluoro-1H-indol-3-yl) piperidine-1-carboxylate (3.1g,9.7mmol) with a solution of hydrogen chloride in ethyl acetate (10mL,2mmol/mL) in dichloromethane (30mL), purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1), concentrating and drying to give the title compound as a pale yellow oil (1.75g, 83%).
MS(ESI,pos.ion)m/z:219.1[M+H]+；
1H NMR(600MHz,DMSO-d6)δ(ppm):10.83(s,1H),7.53(dd,J＝9.0,5.4Hz,1H),7.09(dd,J＝10.2,2.4Hz,1H),7.05(d,J＝1.8Hz,1H),6.80(ddd,J＝9.6,8.4,2.4Hz,1H),3.00(t,J＝12.0Hz,2H),2.80(tt,J＝11.4,3.0Hz,1H),2.63(td,J＝12.0,1.8Hz,2H),1.86–1.82(m,2H),1.53(qd,J＝12.0,3.6Hz,2H).
Step 4) Synthesis of 6-fluoro-3- (1- (3- (2,2, 2-trifluoroethoxy) benzyl) piperidin-4-yl) -1H-indole
The title compound was prepared as described in example 1, step 4, i.e. 6-fluoro-3- (piperidin-4-yl) -1H-indole (300mg,1.37mmol), 3- (2,2, 2-trifluoroethoxy) benzaldehyde (420mg,2.06mmol) and NaBH3CN (173mg,2.06mmol) was prepared by reaction in MeOH (10mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1), concentrated and dried to give the title compound as a light yellow oil (260mg, 46.6%).
MS(ESI,pos.ion)m/z:407.2[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.05(s,1H),7.50(dd,J＝8.4,5.4Hz,1H),7.26(t,J＝7.8Hz,1H),7.03–6.98(m,3H),6.92(d,J＝1.8Hz,1H),6.86–6.82(m,2H),4.34(q,J＝8.4Hz,2H),3.57(s,2H),3.02(t,J＝11.4Hz,2H),2.80(tt,J＝11.4,3.6Hz,1H),2.19(t,J＝12.0Hz,2H),2.01–1.98(m,2H),1.82(qd,J＝12.6,3.6Hz,2H).
Example 106 Synthesis of fluoro-3- (1- (3- (2,2,3, 3-tetrafluoropropoxy) benzyl) piperidin-4-yl) -1H-indole Become into
Figure BDA0000958341680000231
This step was performed by the method described in example 1, step 4, i.e., 6-fluoro-3- (piperidin-4-yl) -1H-indole (300mg,1.37mmol), 3- (2,2,3, 3-tetrafluoropropoxy) benzaldehyde (487mg,2.06mmol) and NaBH3CN(130mg,2.06mmol)Prepared by reaction in MeOH (10mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1), concentrated and dried to give the title compound as a light yellow oil (386mg, 64.1%).
MS(ESI,pos.ion)m/z:439.2[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.07(s,1H),7.51(dd,J＝9.0,5.4Hz,1H),7.27(t,J＝7.8Hz,1H),7.02(d,J＝7.2Hz,1H),7.00(dd,J＝9.6,2.4Hz,1H),6.98(s,1H),6.92(d,J＝1.8Hz,1H),6.87–6.81(m,2H),6.06(tt,J＝52.8,5.4Hz,1H),4.33(t,J＝12.0Hz,2H),3.56(s,2H),3.03(t,J＝12.0Hz,2H),2.80(tt,J＝12.0,3.0Hz,1H),2.24–2.14(m,2H),2.03–2.00(m,2H),1.83(qd,J＝12.6,3.6Hz,2H).
Example 116 Synthesis of chloro-3- (1- (3- (2,2, 2-trifluoroethoxy) benzyl) piperidin-4-yl) -1H-indole
Figure BDA0000958341680000241
Step 1) Synthesis of 4- (6-chloro-1H-indol-3-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
This step was performed as described in example 1, step 1, using 6-chloroindole (3.0g,19.8mmol), 4-oxopiperidine-1-carboxylic acid tert-butyl ester (4.7g,24.0mmol) and potassium hydroxide (1.58g,28.2mmol) in methanol (50mL) and filtered to dryness to give the title compound as a yellow solid (6.1g, 92.8%).
MS(ESI,pos.ion)m/z:333.2[M+H]+；
1H NMR(600MHz,DMSO-d6)δ(ppm):11.31(s,1H),7.83(d,J＝8.4Hz,1H),7.48(s,1H),7.44(d,J＝1.8Hz,1H),7.06(dd,J＝8.4,1.8Hz,1H),6.13(s,1H),4.05(brs,2H),3.57(t,J＝4.8Hz,2H),3.37(brs,2H),1.45(s,9H).
Step 2) Synthesis of 4- (6-chloro-1H-indol-3-yl) piperidine-1-carboxylic acid tert-butyl ester
The title compound was prepared as described in example 1, step 2 by reacting 4- (6-chloro-1H-indol-3-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (3.5g,10.5mmol) and Pd/C (310mg, 10%) in a mixed solvent of THF (15mL) and MeOH (10mL), purifying the crude by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1), concentrating and drying to give the title compound as a white solid (2.52g, 72.0%).
MS(ESI,pos.ion)m/z:235.1[M+H-100]+；
1H NMR(600MHz,DMSO-d6)δ(ppm):10.95(s,1H),7.55(d,J＝8.4Hz,1H),7.37(d,J＝1.8Hz,1H),7.15(d,J＝1.8Hz,1H),6.97(dd,J＝8.4,1.8Hz,1H),4.09–4.01(m,2H),2.97–2.88(m,2H),2.87(brs,1H),1.94–1.90(m,2H),1.53–1.45(m,2H),1.41(s,9H).
Step 3) Synthesis of 6-chloro-3- (piperidin-4-yl) -1H-indole
The title compound was prepared as described in example 1, step 3 by reacting tert-butyl 4- (6-chloro-1H-indol-3-yl) piperidine-1-carboxylate (2.5g,7.5mmol) with a solution of hydrogen chloride in ethyl acetate (10mL,2mmol/mL) in dichloromethane (30mL), purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1), concentrating and drying to give the title compound as a pale yellow oil (1.58g, 90.0%).
MS(ESI,pos.ion)m/z:235.1[M+H]+；
1H NMR(600MHz,DMSO-d6)δ(ppm):10.92(s,1H),7.55(d,J＝8.4Hz,1H),7.37(d,J＝1.8Hz,1H),7.10(s,1H),6.95(dd,J＝8.4,1.8Hz,1H),3.02–2.99(m,2H),2.80(tt,J＝12.0,3.0Hz,1H),2.65–2.59(m,2H),1.86–1.80(m,2H),1.53(qd,J＝12.0,3.6Hz,2H).
Step 4) Synthesis of 6-chloro-3- (1- (3- (2,2, 2-trifluoroethoxy) benzyl) piperidin-4-yl) -1H-indole
The title compound was prepared as described in example 1, step 4, i.e. 6-chloro-3- (piperidin-4-yl) -1H-indole (300mg,1.28mmol), 3- (2,2, 2-trifluoroethoxy) benzaldehyde (530mg,2.6mmol) and NaBH3CN (164mg,2.6mmol) was prepared by reaction in MeOH (10mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1), concentrated and dried to give the title compound as a light yellow oil (208mg, 38.5%).
MS(ESI,pos.ion)m/z:423.1[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.07(s,1H),7.51(d,J＝8.4Hz,1H),7.31(d,J＝1.2Hz,1H),7.26(t,J＝7.8Hz,1H),7.04(dd,J＝8.4,1.2Hz,1H),7.02(d,J＝7.8Hz,1H),6.99(s,1H),6.93(d,J＝1.8Hz,1H),6.84(dd,J＝7.8,1.8Hz,1H),4.34(q,J＝8.4Hz,2H),3.56(s,2H),3.01(t,J＝11.4Hz,2H),2.83–2.74(m,1H),2.19(t,J＝12.0Hz,2H),2.02–1.98(m,2H),1.85–1.77(m,2H).
Example 126 Synthesis of chloro-3- (1- (3- (2,2,3, 3-tetrafluoropropoxy) benzyl) piperidin-4-yl) -1H-indole Become into
Figure BDA0000958341680000251
The title compound was prepared as described in example 1, step 4, i.e., 6-chloro-3- (piperidin-4-yl) -1H-indole (300mg,1.28mmol), 3- (2,2,3, 3-tetrafluoropropoxy) benzaldehyde (453mg,1.92mmol) and NaBH3CN (120mg,1.92mmol) was prepared by reaction in MeOH (10mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1), concentrated and dried to give the title compound as a light yellow oil (265mg, 45.6%).
MS(ESI,pos.ion)m/z:455.1[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.00(s,1H),7.51(d,J＝8.4Hz,1H),7.31(d,J＝1.8Hz,1H),7.26(d,J＝7.8Hz,1H),7.05(dd,J＝8.4,1.8Hz,1H),7.02(d,J＝7.8Hz,1H),6.96(s,1H),6.94(d,J＝1.8Hz,1H),6.81(dd,J＝8.4,2.4Hz,1H),6.06(tt,J＝53.4,5.4Hz,1H),4.34(t,J＝12.0Hz,2H),3.53(s,2H),3.02–2.98(m,2H),2.79(tt,J＝12.0,3.6Hz,1H),2.15(td,J＝12.0,2.4Hz,2H),2.02–1.98(m,2H),1.79(qd,J＝12.6,3.6Hz,2H).
Example 136-chloro-3- (1- (3- (2,2,3, 3-tetrafluoropropoxy) benzyl) -1,2,3, 6-tetrahydropyridine-4- Synthesis of 1H-indoles
Figure BDA0000958341680000252
Step 1) Synthesis of 6-chloro-3- (1,2,3, 6-tetrahydropyridin-4-yl) -1H-indole
The title compound was prepared as described in example 1, step 3 by reacting 4- (6-chloro-1H-indol-3-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (1.0g,3.0mmol) and hydrogen chloride in ethyl acetate (10mL,2mmol/mL) in dichloromethane (20mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) and concentrated to dryness to give the title compound as a pale yellow oil (370mg, 53%).
MS(ESI,pos.ion)m/z:233.1[M+H]+；
1H NMR(600MHz,DMSO-d6)δ(ppm):11.35(s,1H),7.80(d,J＝8.4Hz,1H),7.45(s,1H),7.43(d,J＝1.8Hz,1H),7.04(dd,J＝8.4,1.8Hz,1H),6.14(brs,1H),3.52(d,J＝2.4Hz,2H),3.06(t,J＝6.0Hz,2H),1.81(brs,2H).
Step 2) 6-chloro-3- (1- (3- (2,2,3, 3-tetrafluoropropoxy) benzyl) -1,2,3, 6-tetrahydropyridin-4-yl) -one-step Synthesis of 1H-indoles
The title compound was prepared as described in example 1, step 4, i.e. 6-chloro-3- (1,2,3, 6-tetrahydropyridin-4-yl) -1H-indole (130mg,0.56mmol), 3- (2,2,3, 3-tetrafluoropropoxy) benzaldehyde (264mg,1.12mmol) and NaBH3CN (70mg,1.12mmol) was prepared by reaction in MeOH (10mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1), concentrated and dried to give the title compound as a light yellow oil (170mg, 67.2%).
MS(ESI,pos.ion)m/z:453.1[M+H]+；
1H NMR(600MHz,DMSO-d6)δ(ppm):11.38(s,1H),7.82(d,J＝9.0Hz,1H),7.53(s,1H),7.45(s,1H),7.43(t,J＝7.8Hz,1H),7.21(s,1H),7.17(d,J＝7.2Hz,1H),7.13(d,J＝7.8Hz,1H),7.06(d,J＝8.4Hz,1H),6.68(tt,J＝52.0,4.8Hz,1H),6.14(brs,1H),4.61(t,J＝13.2Hz,2H),4.19(brs,2H),3.64(brs,2H),2.73(brs,2H),2.08(brs,2H).
Biological assay
EXAMPLE A radioligand binding assay to evaluate the expression of pairs of compounds of the invention on CHO cells5-HT of human origin6Affinity of receptor
32 mu g of the prepared expression active human 5-HT6CHO cell membrane protein of receptor, 2nM radiolabel [3H]LSD, compounds of different test concentrations, 100. mu.M 5-HT (5-HT for removal of non-specific binding sites) and test buffer were mixed well and the mixture was incubated at 37 ℃ for 120 min; wherein, the components of the test buffer are as follows: 50mM Tris-HCl (pH 7.4), 10mM MgCl20.5mM EDTA, 10. mu.M pargyline and 20mg/L protease inhibitor.
After incubation, the mixture was filtered under vacuum using a glass fiber filter (GF/B, Packard), the filter membrane of which was pre-soaked with 0.3% PEI prior to filtration. After filtration, 50mM Tri was usedsHCl washes the filter membrane several times. After the filters are dried, the radioactivity of the filters is counted in a scintillation counter (Topcount, Packard) using scintillation cocktail. The standard reference compound was 5-HT, and multiple concentrations were tested in each experiment to obtain the competitive inhibition curve, which was analyzed by non-linear regression using the Hill equation curve to obtain IC50The value is calculated by the ChengPrusoff equation to obtain the Ki value.
Pairing of human 5-HT expressed on CHO cells with the Compounds of the invention according to the method described above6Affinity test of receptor, the result shows that the compound of the invention is 5-HT of human origin6The receptor has better affinity. In a specific example, the compounds of the invention are directed against 5-HT of human origin expressed on CHO cells6The Ki value of receptor binding is less than 0.1 μ M; preferably, the Ki value is less than 0.05. mu.M. More specifically, the compounds prepared in example 9, example 11 and example 12 had Ki values of less than 0.1 μ M; the compound prepared in example 10 had a Ki value of less than 0.05. mu.M.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an embodiment," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment, or example is included in at least one embodiment, or example of the invention. In this specification, a schematic representation of the above terms does not necessarily refer to the same embodiment, implementation, or example. 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 various examples, embodiments, or examples described in this specification, as well as features of various examples, embodiments, or examples, may be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (7)

1. A compound which is a compound represented by formula (I) or a stereoisomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt of the compound represented by formula (I),
Figure FDA0002340625380000011
wherein:
Figure FDA0002340625380000012
is a single bond;
x is-O-or-S-;
R1、R4and R5Each independently is H or D;
R2and R3Each independently is H, D, F, Cl, Br or I;
each R6And R7Independently is H or D;
R8is C1-C6Haloalkyl, wherein said C1-C6Haloalkyl is independently optionally substituted with one or more substituents independently selected from D, C1-C6Alkyl or C1-C6Substituted with a substituent of haloalkyl;
each R9Independently is H or D;
n is 1,2,3 or 4; and
m is 0, 1,2,3 or 4.
2. The compound of claim 1, wherein R8Is C1-C4Haloalkyl, wherein said C1-C4Haloalkyl is independently optionally substituted with one or more substituents independently selected from D, C1-C4Alkyl or C1-C4Substituted by a substituent of a haloalkyl group.
3. The compound of claim 1, wherein R8is-CHF2、-CF3、-CH2CHF2、-CH2CF3、-CHFCF3、-CF2CF3、-CF2CH3、-CF2CHF2、-CF2CH2CH3、-CF2CH2CF3、-CF2CH2CHF2、-CH2CHFCH3、-CH2CHFCHF2、-CH2CHFCF3、-CH2CF2CH3、-CH2CF2CF3or-CH2CF2CHF2。
4. The compound of claim 1, which is a compound having one of the following structures or a stereoisomer, tautomer, hydrate, solvate, or pharmaceutically acceptable salt of a compound having one of the following structures:
Figure FDA0002340625380000013
Figure FDA0002340625380000021
5. a pharmaceutical composition comprising a compound of any one of claims 1-4, and further optionally a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or any combination thereof.
6. The pharmaceutical composition of claim 5, further comprising an additional therapeutic agent, wherein the additional therapeutic agent is donepezil, nalmefene, risperidone, vitamins E, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, intepirdine, idalopidine, tacrine, rivastigmine, galantamine, memantine, mirtazapine, venlafaxine, descumidine, nortriptyline, zolpidem, zopiclone, nicergoline, piracetazone, selegiline, pentoxifylline, or any combination thereof.
7. Use of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to any one of claims 5 to 6 for the manufacture of a medicament for the prevention, treatment or alleviation of 5-HT6A receptor associated disease.
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