CN106065018B - Substituted indole compounds and methods and uses thereof - Google Patents
Substituted indole compounds and methods and uses thereofDownload PDFInfo
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- CN106065018B CN106065018BCN201610219166.1ACN201610219166ACN106065018BCN 106065018 BCN106065018 BCN 106065018BCN 201610219166 ACN201610219166 ACN 201610219166ACN 106065018 BCN106065018 BCN 106065018B
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
Translated fromChineseDescription
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a compound and a composition for treating central nervous system dysfunction, and a using method and application thereof. In particular, indole compounds are described which are useful as 5-hydroxytryptamine reuptake inhibitors.
Background
5-hydroxytryptamine, a neurotransmitter that transmits signals in the brain and nervous system, plays an important role in Central Nervous System (CNS) dysfunction, especially anxiety, depression, aggression and impulsive mood. Antagonism or agonism of certain types of 5-hydroxytryptamine receptors can be effective in modulating central nervous system dysfunction. To date, at least 14 5-hydroxytryptamine receptors have been identified. These receptors can be divided into different families, which are designated as 5-HT1、5-HT2、5-HT3、5-HT4、5-HT5、5-HT6And 5-HT7And the different subtypes in each group are distinguished by a, b, c, etc.
Of all indications associated with 5-hydroxytryptamine dysfunction, depression is of prime importance, as it has been reported by the world health organization as the fourth most burdensome disease in humans. It is expected that disability from depression will jump to the second place in all diseases by the year 2020. (Bromet E, Andlade LH, Hwang I, et al, Cross-national epidemiology of DSM-IV major depression epsilon. BMC Med.2011,9: 90).
Historically, the treatment of mood disorders began in the 50's of the 20 th century and included tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) which were primarily therapeutic by blocking neurotransmitters (dopamine, norepinephrine and 5-hydroxytryptamine). However, non-selective and undesirable side effects on targets limit their use. By the 80's of the 20 th century, the appearance of selective 5-hydroxytryptamine reuptake inhibitors (SSRIs) changed this aspect. Such drugs are of comparable efficacy to TCAs, but have fewer side effects and less toxicity even when taken in excess (SarkoJ. Anddidepressant, old and new. A review of the same effects and toxin over. Emerg Med Clin North Am, 2000; 18(4): 637-54).
The invention provides novel compounds with 5-hydroxytryptamine reuptake inhibition activity, and the compounds have good clinical application prospects. Compared with the existing similar compounds, the compound of the invention has better drug effect, pharmacokinetic property and/or toxicological property.
Summary of the invention
The following is a summary of some aspects of the invention only and is not intended to be limiting. These aspects and others are described more fully below. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of the present specification differs from the cited documents, the disclosure of the present specification controls.
The invention provides a novel compound which has selective inhibition effect on reuptake of 5-hydroxytryptamine and can be used for preparing medicines for treating Central Nervous System (CNS) dysfunction, such as depression, anxiety and bipolar disorder.
The invention also provides processes for the preparation of such compounds and pharmaceutical compositions containing them.
In one aspect, the invention provides a compound that is a compound of formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (I),
wherein:
r is 1,2,3, 4, 5 or 6;
R8aand R8cEach independently is H, or R8aAnd R8cTogether forming a single bond, -CH2-、-CH2CH2-or-CH2CH2CH2-；
R8bAnd R8dEach independently is H, or R8bAnd R8dTogether forming a single bond, -CH2-、-CH2CH2-or-CH2CH2CH2-；
With the proviso that R8a、R8b、R8cAnd R8dNot H at the same time;
and each R1、R2、R3、R4、R5、R6、R7And Hy has the meaning as described in the present invention.
In one embodiment, r in formula (1) is 1,2,3, 4, 5 or 6;
R8aand R8cEach independently is H, and R8bAnd R8dTogether forming a single bond, -CH2-、-CH2CH2-or-CH2CH2CH2-; or R8aAnd R8cTogether forming a single bond, -CH2-、-CH2CH2-or-CH2CH2CH2-, and R8bAnd R8dEach independently is H;
and each R1、R2、R3、R4、R5、R6、R7And Hy has 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、-NRaRb、-ORc、-S(＝O)pRd、-C(＝O)Rd、-C(＝O)ORc、-C(＝O)NRaRb、-S(＝O)2NRaRb、-OC(＝O)Rd、-N(Ra)C(＝O)Rd、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C10Cycloalkyl) - (C)0-C6Alkylene) -, (3-10 membered heterocyclyl) - (C0-C6Alkylene) -, (C)6-C10Aryl group) - (C0-C6Alkylene) -or (5-10 membered heteroaryl) - (C)0-C6Alkylene) -, wherein said C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C10Cycloalkyl) - (C)0-C6Alkylene) -, (3-10 membered heterocyclyl) - (C0-C6Alkylene) -, (C)6-C10Aryl group) - (C0-C6Alkylene) -and (5-10 membered heteroaryl) - (C)0-C6Alkylene) -independently optionally substituted with one or more RxSubstituted by a group; and
each Ra、Rb、Rc、Rd、RxAnd p has the meaning as described in the present invention.
In one embodiment, each R is6And R7Independently H, D, F, Cl, Br, I, -CN, -NH2、-OH、-C(＝O)Rd、-C(＝O)ORc、-C(＝O)NRaRb、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Alkylamino, (C)3-C10Cycloalkyl) - (C)0-C6Alkylene) -, (3-10 membered heterocyclyl) - (C0-C6Alkylene) -, (C)6-C10Aryl group) - (C0-C6Alkylene) -or (5-10 membered heteroaryl) - (C)0-C6Alkylene) -, or R on the same carbon atom6And R7Can combine to form a carbonyl group, wherein said C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Alkylamino, (C)3-C10Cycloalkyl) - (C)0-C6Alkylene) -, (3-10 membered heterocyclyl) - (C0-C6Alkylene) -, (C)6-C10Aryl group) - (C0-C6Alkylene) -and (5-10 membered heteroaryl) - (C)0-C6Alkylene) -independently optionally substituted with one or more RxSubstituted by a group; and
each Ra、Rb、Rc、RdAnd RxHave the meaning as described in the present invention.
In one embodiment, Hy is 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with 1,2,3 or 4RySubstituted; and
each RyHave the meaning as described in the present invention.
In one embodiment, each R isyIndependently H, D, F, Cl, Br, I, -CN, -NO2、-NRaRb、-ORc、-S(＝O)pRd、-C(＝O)Rd、-C(＝O)ORc、-C(＝O)NRaRb、-S(＝O)2NRaRb、-OC(＝O)Rd、-N(Ra)C(＝O)Rd、C1-C6Alkyl radical, C1-C6Haloalkyl, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C10Cycloalkyl) - (C)0-C6Alkylene) -, (3-10 membered heterocyclyl) - (C0-C6Alkylene) -, (C)6-C10Aryl group) - (C0-C6Alkylene) -or (5-10 membered heteroaryl) - (C)0-C6Alkylene) -, wherein said C1-C6Alkyl radical, C1-C6Haloalkyl, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C10Cycloalkyl) - (C)0-C6Alkylene) -, (3-10 membered heterocyclyl) - (C0-C6Alkylene) -, (C)6-C10Aryl group) - (C0-C6Alkylene) -and (5-10 membered heteroaryl) - (C)0-C6Alkylene) -independently optionally substituted with one or more RxSubstituted by a group; and
each Ra、Rb、Rc、Rd、RxAnd p has the meaning as described in the present invention.
In one embodiment, each R isa、Rb、RcAnd RdIndependently H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, (C)3-C10Cycloalkyl) - (C)0-C6Alkylene) -, (3-10 membered heterocyclyl) - (C0-C6Alkylene) -, (C)6-C10Aryl group) - (C0-C6Alkylene) -or (5-10 membered heteroaryl) - (C)0-C6Alkylene) -, wherein said C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, (C)3-C10Cycloalkyl) - (C)0-C6Alkylene) -, (3-10 membered heterocyclyl) - (C0-C6Alkylene) -, (C)6-C10Aryl group) - (C0-C6Alkylene) -and (5-10 membered heteroaryl) - (C)0-C6Alkylene) -independently optionally substituted with one or more RxSubstituted by a group;
or RaAnd RbTogether with the nitrogen atom to which they are both attached form a 3-10 membered heterocyclyl, wherein said 3-10 membered heterocyclyl is optionally substituted with one or more RxSubstituted by a group; and
each RxHave the meaning as described in the present invention.
In one embodiment, each R isxIndependently H, F, Cl, Br, I, -CN, -NO2、-OH、-SH、-NH2、C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Alkylthio or C1-C6An alkylamino group.
In one embodiment, each p is independently 0, 1 or 2.
In one embodiment, R1、R2、R3、R4And R5Each independently is H, D, F, Cl, Br, I, -CN, -NO2、-NRaRb、-ORc、-S(＝O)pRd、-C(＝O)Rd、-C(＝O)ORc、-C(＝O)NRaRb、-S(＝O)2NRaRb、-OC(＝O)Rd、-N(Ra)C(＝O)Rd、C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, (C)3-C6Cycloalkyl) - (C)0-C4Alkylene) -, (3-6 membered heterocyclyl) - (C0-C4Alkylene) -, (phenyl) - (C)0-C4Alkylene) -or (5-6 membered heteroaryl) - (C)0-C4Alkylene) -, wherein said C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, (C)3-C6Cycloalkyl) - (C)0-C4Alkylene) -, (3-6 membered heterocyclyl) - (C0-C4Alkylene) -, (phenyl) - (C)0-C4Alkylene) -and (5-6 membered heteroaryl) - (C)0-C4Alkylene) -independently optionally substituted with one or more RxSubstituted by a group; and
each Ra、Rb、Rc、Rd、RxAnd p has the meaning as described in the present invention.
In one embodiment, each R is6And R7Independently H, D, F, Cl, Br, I, -CN, -NH2、-OH、-C(＝O)Rd、-C(＝O)ORc、-C(＝O)NRaRb、C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Alkoxy radical, C1-C4Alkylamino, (C)3-C6Cycloalkyl) - (C)0-C4Alkylene) -, (3-6 membered heterocyclyl) - (C0-C4Alkylene) -, (phenyl) - (C)0-C4Alkylene) -or (5-6 membered heteroaryl) - (C)0-C4Alkylene) -, or R on the same carbon atom6And R7Can combine to form a carbonyl group, wherein said C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Alkoxy radical, C1-C4Alkylamino, (C)3-C6Cycloalkyl) - (C)0-C4Alkylene) -, (3-6 membered heterocyclyl) - (C0-C4Alkylene) -, (phenyl) - (C)0-C4Alkylene) -and (5-6 membered heteroaryl) - (C)0-C4Alkylene) -independently optionally substituted with one or more RxSubstituted by a group; and
each Ra、Rb、Rc、RdAnd RxHave the meaning as described in the present invention.
In one embodiment, each R isa、Rb、RcAnd RdIndependently H, C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, (C)3-C6Cycloalkyl) - (C)0-C4Alkylene) -, (3-6 membered heterocyclyl) - (C0-C4Alkylene) -, (phenyl) - (C)0-C4Alkylene) -or (5-6 membered heteroaryl)-(C0-C4Alkylene) -, wherein said C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, (C)3-C6Cycloalkyl) - (C)0-C4Alkylene) -, (3-6 membered heterocyclyl) - (C0-C4Alkylene) -, (phenyl) - (C)0-C4Alkylene) -and (5-6 membered heteroaryl) - (C)0-C4Alkylene) -independently optionally substituted with one or more RxSubstituted by a group;
or RaAnd RbTogether with the nitrogen atom to which they are both attached form a 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl is optionally substituted with one or more RxSubstituted by a group; and
each RxHave 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、-NH2、-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、-C(＝O)CH3、-COOH、-CONH2Methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy or isopropoxy.
In one embodiment, each R isa、Rb、RcAnd RdIndependently H, methyl, ethyl, n-propyl, isopropyl, -CF3、-CH2CF3or-CH2CF2CHF2。
In one embodiment, Hy is the following sub-structural formula:
wherein W is-O-, -S-or-NH-;
each n is independently 0, 1,2,3 or 4; and
each RyHave the meaning as described in the present invention.
In one embodiment, each R isyIndependently H, D, F, Cl, Br, I, -CN, -NO2、-NRaRb、-ORc、-S(＝O)pRd、-C(＝O)Rd、-C(＝O)ORc、-C(＝O)NRaRb、-S(＝O)2NRaRb、-OC(＝O)Rd、-N(Ra)C(＝O)Rd、C1-C4Alkyl radical, C1-C4Haloalkyl, C2-C4Alkenyl radical, C2-C4Alkynyl, (C)3-C6Cycloalkyl) - (C)0-C4Alkylene) -, (3-6 membered heterocyclyl) - (C0-C4Alkylene) -, (phenyl) - (C)0-C4Alkylene) -or (5-6 membered heteroaryl) - (C)0-C4Alkylene) -, wherein said C1-C4Alkyl radical, C1-C4Haloalkyl, C2-C4Alkenyl radical, C2-C4Alkynyl, (C)3-C6Cycloalkyl) - (C)0-C4Alkylene) -, (3-6 membered heterocyclyl) - (C0-C4Alkylene) -, (phenyl) - (C)0-C4Alkylene) -and (5-6 membered heteroaryl) - (C)0-C4Alkylene) -independently optionally substituted with one or more RxSubstituted by a group; and
each Ra、Rb、Rc、Rd、RxAnd p has the meaning as described in the present invention.
In one embodiment, each R isyIndependently H, D, F, Cl, Br, I, -CN, -NO2、-OH、-NH2、-N(CH3)2、-C(＝O)CH3、-C(＝O)OH、-C(＝O)OCH3、-CONH2A, AAlkyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, -CF3、-CH2CF3、-OCF3、-OCH2CF3or-OCH2CF2CHF2。
In one embodiment, the compound of the present invention is a compound having one of the following structures or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound having one of the following structures:
in another aspect, the present invention relates to a pharmaceutical composition comprising a compound disclosed herein.
In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
In one embodiment, the pharmaceutical composition of the present invention further comprises a drug for treating central nervous system dysfunction, wherein the drug for treating central nervous system dysfunction is an antidepressant, an anxiolytic, a lithium salt drug as an affective stabilizer, an atypical antipsychotic, an antiepileptic, an antiparkinsonian, a drug as a selective 5-hydroxytryptamine reuptake inhibitor, a central nervous stimulant, a nicotine antagonist, or any combination thereof.
In another embodiment, the drug for treating central nervous system dysfunction of the present invention is amitriptyline (amitriptyline), desipramine (desipramine), mirtazapine (mirtazapine), bupropion (bupropion), reboxetine (reboxetine), fluoxetine (fluoxetine), trazodone (trazodone), sertraline (sertraline), duloxetine (duloxetine), fluvoxamine (fluvoxamine), milnacipran (milnacipran), levomilnacipran (levomilnacipran), desvenlafaxine (desvenlafaxine), vilazodone (vilazodone), venlafaxine (venlafaxine), dapoxetine (dapoxetine), nefazodone (nefazodone), femoxetine (femoxetine), chlorpropazine (chlorpromazine), ziprasidone (sulbactam), ziprasidone (sulipratropizide), sulipratropizide (sulbactam), sulipratropium (sulipratropium), sulbactam (sulbactam), ziprasidone (sulbactam), sulbactam (sulbactam), sulbact, Piperacillin (peroospirone), clozapine (clozapine), modafinil (modafinil), mecamylamine (mecamylamine), cabergoline (cabergoline), adamantane (amantane), imipramine (imipramine), pramipexole (pramipexole), thyroxine (thyroxine), dextromethorphan (dextromethorphan), quinidine (quinidine), naltrexone (naltrexone), samindorfanin, buprenorphine (buprenorphine), melatonin (melatonin), alprazolam (alprazolam), pipamperone (pipamerone), vetepitant (vestipitant), chlordiazepoxide (chlorpropoxide), perphenazine (perphenazine), or any combination thereof.
In another aspect, the invention relates to the use of a compound or composition disclosed herein for the manufacture of a medicament for the prevention, treatment or alleviation of central nervous system dysfunction. For example, in one embodiment, the medicament is for preventing, treating or reducing central nervous system dysfunction in a mammal, and in another embodiment, the medicament is for preventing, treating or reducing central nervous system dysfunction in a human.
In one embodiment, the central nervous system disorder is depression, anxiety, mania, schizophrenia, bipolar disorder, sleep disorder, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, movement disorder, sexual dysfunction, musculoskeletal pain disorder, cognitive disorder, memory disorder, parkinson's disease, huntington's disease, phobias, substance abuse or addiction, withdrawal symptoms from drug addiction, or premenstrual tension syndrome.
In another aspect, the invention relates to the use of a compound or composition disclosed herein for the manufacture of a medicament for inhibiting 5-hydroxytryptamine reuptake.
In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula (I).
Biological test results show that the compound provided by the invention can be used as a better selective 5-hydroxytryptamine reuptake inhibitor.
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.
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 "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 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.
The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent.
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.
"pharmaceutically acceptable" refers to those 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.
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 compounds of the invention may be optionally substituted with one or more substituents, as described herein, such as compounds of the general formula above, or as specifically exemplified, sub-classified and encompassed within the examples.
The term "optionally substituted", is used interchangeably with the term "unsubstituted or substituted with …., i.e., the structure is unsubstituted or substituted with one or more substituents described herein, including, but not limited to, D, F, Cl, N3，-CN，-OH，-SH，-NH2Alkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl and the like.
In addition, unless otherwise expressly indicated, the description of the invention wherein "… is independently" and "… is independently" and "… is independently" is to be understood in a broad sense means that the particular items expressed between the same symbols do not affect each other in the different groups, or that the particular items expressed between the same symbols do not affect each other in the same groups.
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.
The term "unsaturated" or "unsaturated" means that the moiety contains one or more degrees of unsaturation.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of 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 terms "halogen" and "halo" are used interchangeably herein to refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain, monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. In one embodiment, the alkyl group contains 1 to 6 carbon atoms; in 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) And so on.
The term "alkylene" denotes a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon. Unless otherwise specified, the alkylene group contains 1 to 12 carbon atoms. Examples of this include methylene (-CH)2-, ethylene (-CH)2CH2-, isopropylidene (-CH (CH)3)CH2-) and the like.
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 may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 6 carbon atoms; in another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)2) Allyl (-CH)2CH＝CH2) And so on.
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. a carbon-carbon sp triple bond, wherein said alkynyl radical may optionally be substituted with one or more substituents as described herein. In one embodiment, alkynyl groups contain 2-6 carbon atoms; in another embodiment, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)2C.ident.CH), 1-propynyl (-C.ident.C-CH)3) And so on.
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 may be 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) And so on.
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. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like. The alkylamino group is optionally substituted with one or more substituents described herein.
The term "haloalkyl" denotes an alkyl group substituted with one or more halogen atoms, wherein the alkyl group has the meaning as described herein, examples of which include, but are not limited to, -CF3、-CH2CF3、-CH2CF2CHF2And the like.
The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. In one embodiment, the cycloalkyl group contains 3 to 10 carbon atoms; in another embodiment, cycloalkyl contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group may be optionally substituted with one or more substituents described herein.
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 at least one ring atom is selected from nitrogen, sulfur, and oxygen, and which may be fully saturated or contain one or more degrees of unsaturation, but not one aromatic ring. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH2-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thietanyl, oxazepanyl, oxazepinyl, and oxazepinyl
Radical, diaza
Radical, S-N-aza
Aryl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl, and the like. In heterocyclic radicals of-CH2Examples of-groups substituted with-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl, pyrimidinedione, and the like. Examples of sulfur atoms in heterocyclic groups that are oxidized include, but are not limited to, ringsButyl sulfone, thiomorpholinyl 1, 1-dioxide, and the like. The heterocyclyl group is optionally substituted with one or more substituents described herein.
The term "x-membered", wherein x is an integer, typically describes the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is x. For example, pyrimidinyl and pyridinyl are 6-membered heteroaryl and thienyl is 5-membered heteroaryl.
The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state form of P; 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 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 aryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the aryl group. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring". Examples of aryl groups can include phenyl, naphthyl, anthracene, and the like. The aryl group may be optionally substituted with one or more substituents described herein.
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 (i.e., 5 to 6 membered), wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms. The heteroaryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the heteroaryl group. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the 5-10 membered heteroaryl group comprises 1,2,3, or 4 heteroatoms independently selected from O, S and N; in another embodiment, the heteroaryl group is a lower 5-6 membered heteroaryl.
Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), and the like, 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl, and the like; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridyl, and the like.
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, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-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) 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 "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)1-24) 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, primers: Design and Clinical Applications, Nature Reviews Drug Discovery,2008,7,255-.
"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism 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: berge et al, descriptive acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. 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, malates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanates, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N+(C1-4Alkyl 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. The alkali metal or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etcAnd 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, ethanolamine, or mixtures thereof. 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 "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 "therapeutically effective amount" means an amount of a compound that, when administered to a subject to treat a disease, is sufficient to effect treatment of the disease. The "therapeutically effective amount" may vary with the compound, the disease and the severity, as well as the condition, age, weight, sex, etc., of the subject to be treated.
The indole compound, the pharmaceutically acceptable salt, the pharmaceutical preparation and the composition thereof can be used as a selective 5-hydroxytryptamine reuptake inhibitor and have potential application in treatment of central nervous system dysfunction, such as depression, anxiety and bipolar disorder in human.
Unless otherwise indicated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are encompassed 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.
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.
The compounds of formula (I) may exist in different tautomeric forms and all such tautomers are included within the scope of the invention.
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.
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).
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.
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 invention relates to intermediates for the preparation of compounds of formula (I).
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.
Pharmaceutical compositions, formulations and administration of the compounds of the invention
The invention provides a pharmaceutical composition, which comprises a compound shown as a formula (I) or an individual stereoisomer, a 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.
It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, if appropriate, in the form of a pharmaceutically acceptable derivative thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adduct or derivative that upon administration to a patient in need thereof provides, directly or indirectly, a compound of the present invention or a metabolite or residue thereof.
The pharmaceutical compositions disclosed herein can be prepared and packaged in bulk (bulk) form, wherein a safe and effective amount of a compound of the invention can be extracted and then administered to a patient in the form of a powder or syrup. Alternatively, the pharmaceutical compositions disclosed herein may be prepared and packaged in unit dosage forms, wherein each physically discrete unit contains a safe and effective amount of a compound of the invention. When prepared in unit dosage form, the disclosed pharmaceutical compositions can generally contain, for example, from 0.5mg to 1g, or from 1mg to 700mg, or from 5mg to 100mg of the disclosed compounds.
As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle, which is compatible with the dosage form or pharmaceutical composition to be administered. Each excipient, when mixed, must be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that would substantially reduce the efficacy of the disclosed compounds and which would result in a pharmaceutical composition that is not pharmaceutically acceptable when administered to a patient. Furthermore, each excipient must be pharmaceutically acceptable, e.g., of sufficiently high purity.
Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific function in the composition. For example, certain pharmaceutically acceptable excipients may be selected to aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected to aid in the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be selected to facilitate carrying or transporting the disclosed compounds from one organ or portion of the body to another organ or portion of the body when administered to a patient. Certain pharmaceutically acceptable excipients may be selected that enhance patient compliance.
Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and provide alternative functions, depending on how many such excipients are present in the formulation and which other excipients are present in the formulation.
The skilled person is knowledgeable and skilled in the art to enable them to select suitable amounts of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there is a large amount of resources available to the skilled person, who describes pharmaceutically acceptable excipients and is used to select suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (The American Pharmaceutical Association and The Pharmaceutical Press).
Various carriers for formulating pharmaceutically acceptable compositions, and well known techniques for their preparation, are disclosed in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. sup. 1999, Marcel Dekker, New York, The contents of each of which are incorporated herein by reference. Except insofar as any conventional carrier is incompatible with the disclosed compounds, such as by producing any undesirable biological effect or interacting in a deleterious manner with any other ingredient in a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention.
The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack publishing company).
Thus, in another aspect, the invention relates to a process for preparing a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, which process comprises admixing the ingredients. Pharmaceutical compositions comprising the disclosed compounds may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.
The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, e.g., suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.
In one embodiment, the compounds disclosed herein may be formulated in oral dosage forms. In another embodiment, the compounds disclosed herein may be formulated in an inhalation dosage form. In another embodiment, the compounds disclosed herein can be formulated for nasal administration. In yet another embodiment, the compounds disclosed herein can be formulated for transdermal administration. In yet another embodiment, the compounds disclosed herein may be formulated for topical administration.
The pharmaceutical compositions provided by the present invention may be provided as compressed tablets, milled tablets, chewable lozenges, fast-dissolving tablets, double-compressed tablets, or enteric-coated, sugar-coated or film-coated tablets.
The pharmaceutical composition provided by the present invention may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch or calcium alginate.
The pharmaceutical compositions provided herein may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups.
Dosage unit formulations for oral administration may be microencapsulated, where appropriate. They may also be prepared as extended or sustained release compositions, for example by coating or embedding the particulate material in a polymer, wax or the like.
The oral pharmaceutical composition provided by the invention can also be provided in the form of liposome, micelle, microsphere or nano system. Micellar dosage forms can be prepared using the methods described in U.S. Pat. No.6,350,458.
The pharmaceutical compositions provided herein can be provided as non-effervescent or effervescent granules and powders for reconstitution into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and sources of carbon dioxide.
Coloring and flavoring agents may be used in all of the above dosage forms.
The disclosed compounds may also be conjugated to soluble polymers as targeted drug carriers.
The pharmaceutical compositions provided by the present invention may be formulated into immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms.
The pharmaceutical compositions provided by the present invention may be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.
The pharmaceutical compositions provided by the present invention may be administered parenterally by injection, infusion or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.
The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for solution or suspension in a liquid prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in The art of pharmaceutical Science (see Remington: The Science and Practice of Pharmacy, supra).
The pharmaceutical compositions provided herein may be formulated for single or multiple dose administration. The single dose formulations are packaged in ampoules, vials or syringes. The multi-dose parenteral formulation must contain a bacteriostatic or fungistatic concentration of the antimicrobial agent. All parenteral formulations must be sterile, as is known and practiced in the art.
In another aspect, the disclosed pharmaceutical compositions may be formulated in any dosage form suitable for administration to a patient by inhalation, such as a dry powder, aerosol, suspension, or solution composition.
Pharmaceutical compositions suitable for transdermal administration may be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient may be delivered from a patch agent by iontophoresis, as generally described in Pharmaceutical Research,3(6),318 (1986).
Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
Use of the Compounds and compositions of the invention
The compound and the pharmaceutical composition provided by the invention can be used for preparing medicines for preventing, treating or relieving central nervous system dysfunction of mammals including human beings, and can also be used for preparing medicines for inhibiting reuptake of 5-hydroxytryptamine.
In particular, the amount of the compound in the composition of the present invention is effective to detectably and selectively inhibit the reuptake of 5-hydroxytryptamine, and the compound of the present invention is useful as a medicament for the treatment of Central Nervous System (CNS) disorders such as depression and anxiety in humans.
The compounds of the present invention may be used in, but are in no way limited to, the prevention, treatment, or alleviation of central nervous system dysfunctional disorders by administering to a patient an effective amount of a compound or composition of the present invention. The dysfunctional central nervous system diseases further include, but are not limited to, depression, anxiety, mania, schizophrenia, sleep disorders, bipolar disorders, obsessive-compulsive disorders, panic disorders, post-traumatic stress disorders, movement disorders, sexual dysfunction, musculoskeletal pain disorders, cognitive disorders, memory disorders, Parkinson's disease, Huntington's disease, phobias, substance abuse or addiction, withdrawal symptoms from drug addiction, premenstrual tension syndrome, and the like.
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.
In one embodiment, the presently disclosed methods of treatment comprise administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention. Various embodiments of the present disclosure include methods of treating the above-mentioned diseases by administering to a patient in need thereof a safe and effective amount of a disclosed compound or a pharmaceutical composition comprising a disclosed compound.
In one embodiment, the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds may be administered by any suitable route of administration, including systemic and topical administration.
In one embodiment, a disclosed compound or a pharmaceutical composition comprising a disclosed compound may be administered once or several times at different time intervals over a specified period of time according to a dosing regimen. For example, once, twice, three times or four times daily. The administration may be carried out until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds depend on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, which can be determined by the skilled person. In addition, suitable dosing regimens for the compounds or pharmaceutical compositions comprising the disclosed compounds, including the duration of the regimen, will depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the desired therapeutic effect, and other factors within the knowledge and experience of the skilled artisan. Such a skilled artisan will also appreciate that adjustments to the subject's response to the dosage regimen, or the need for changes in the subject's patient over time, may be required.
The compounds disclosed herein may be administered simultaneously, or before or after, one or more other therapeutic agents. The compounds of the invention may be administered separately from the other therapeutic agents, by the same or different routes of administration, or together with them in pharmaceutical compositions.
For an individual of about 50-70kg, the disclosed pharmaceutical compositions and combinations may be in unit dosage form containing from about 1-1000mg, or from about 1-500mg, or from about 1-250mg, or from about 1-150mg, or from about 0.5-100mg, or from about 1-50mg of the active ingredient. The therapeutically effective amount of the compound, pharmaceutical composition or combination thereof will depend on the species, weight, age and condition of the individual, the disease (disorder) or illness (disease) being treated, or the severity thereof. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient to prevent, treat or inhibit the progression of the disease (disorder) or condition (disease).
The above cited dose profiles have been demonstrated in vitro and in vivo tests using beneficial mammals (e.g., mice, rats, dogs, monkeys) or isolated organs, tissues and specimens thereof. The compounds disclosed herein are used in vitro in the form of solutions, e.g. aqueous solutions, and also enterally, parenterally, especially intravenously, in vivo, e.g. in the form of suspensions or aqueous solutions.
General synthetic procedure
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. The reagents were purchased from commercial suppliers such as Aldrich Chemical Company, 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 Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.
The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.
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.
1H NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer.1H NMR Spectrum in CDC13、DMSO-d6、CD3OD or acetone-d6TMS (0ppm) or chloroform (7.26ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in hertz (Hz).
The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-M (column model: Zorbax SB-C18,2.1X 30mm,3.5 micron, 6min, flow rate of 0.6 mL/min). Mobile phase: 5% -95% (CH containing 0.1% formic acid)3CN) in (H containing 0.1% formic acid)2O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.
Pure compounds were detected by UV at 210nm/254nm using Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (column model: NOVASEP 50/80mm DAC).
The following acronyms are used throughout the invention:
AcOH、HOAc、CH3COOH acetic acid
BOC, Boc tert-butoxycarbonyl
CH2Cl2DCM dichloromethane
CDC13Deuterated chloroform
CD3OD deuterated methanol
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
EDTA ethylene diamine tetraacetic acid
Et3N, TEA Triethylamine
EtOAc, EA ethyl acetate
g
h hours
HCl hydrogen chloride
MeCN、CH3CN acetonitrile
mL, mL
PE Petroleum ether (60-90 deg.C)
RT, RT, r.t. Room temperature
Rt Retention time
TFA trifluoroacetic acid
Tris-HCl Tris (hydroxymethyl) aminomethane-hydrochloric acid
The following synthetic schemes describe the steps for preparing the compounds disclosed herein, wherein each R is, unless otherwise indicatedyAnd n has the definitions set forth herein; each m is independently 0, 1,2,3 or 4; x and Y are each independently CH or N, and at least one of X and Y is N.
Synthesis scheme 1:
formula (A), (B) and5) The compounds shown can be prepared by the method described in scheme 1: first, a compound (A)1) And a compound of (A)2) Under the action of alkali to obtain a compound (A)3) Then the compound (A), (B), (C), (3) Removing Boc protecting group in dichloromethane solution of trifluoroacetic acid or ethyl acetate solution of hydrogen chloride, and reacting with compound (A), (B), (C) and (C) in the presence of base such as potassium carbonate or sodium carbonate4) Carrying out nucleophilic substitution reaction to obtain a target compound (A)5)。
Synthesis scheme 2:
formula (A), (B) and7) The compounds shown can be prepared by the method described in scheme 2: first, a compound (A)4) And a compound of (A)2) Under the action of alkali to obtain a compound (A)6) Then the compound (A), (B), (C), (6) After removing Boc protecting group in dichloromethane solution of trifluoroacetic acid or ethyl acetate solution of hydrogen chloride, under the assistance of alkali such as potassium carbonate or sodium carbonate,and a compound of (A)1) Carrying out nucleophilic substitution reaction to obtain a target compound (A)7)。
Synthesis scheme 3:
formula (A), (B) and9) The compounds shown can be prepared by the method described in scheme 3: compound (A) to (B)6) Removing Boc protecting group in dichloromethane solution of trifluoroacetic acid or ethyl acetate solution of hydrogen chloride, and reacting with compound (A), (B), (C) and (C) in the presence of base such as potassium carbonate or sodium carbonate8) Carrying out nucleophilic substitution reaction to obtain a target compound (A)9)。
The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in connection with the examples.
Example 12- (3- (3- (5-cyano-1H-indol-3-yl) propyl) -3, 8-diazabicyclo [3.2.1]Octane-8-yl) pyrimidine-4-carboxamides
Step 1)3- (3- (5-cyano-1H-indol-3-yl) propyl) -3, 8-diazabicyclo [3.2.1]Octane-8-methylSynthesis of tert-butyl ester
3- (3-chloropropyl) -1H-indole-5-carbonitrile (2.80g,12.80mmol), tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (2.72g,12.80mmol), sodium carbonate (2.04g,19.21mmol) and potassium iodide (213mg,1.28mmol) were added in this order to acetonitrile (30mL), and the reaction solution was heated and refluxed overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE/EA (v/v) ═ 3/2) to give the title compound as a white solid (3.54g, 70.1%).
MS(ESI,pos.ion)m/z:395.3(M+1)；
1H NMR(CDCl3,600MHz)δ(ppm):8.44(brs,1H),7.98(s,1H),7.43-7.42(m,2H),7.11(s,1H),4.23-4.16(m,2H),2.81(t,J＝7.2Hz,2H),2.67(d,J＝9.6Hz,2H),2.37(t,J＝6.6Hz,2H),2.26-2.21(m,2H),1.90-1.84(m,6H),1.49(s,9H).
Step 2)2- (3- (3- (5-cyano-1H-indol-3-yl) propyl) -3, 8-diazabicyclo [3.2.1]Octane-8-Yl) Synthesis of pyrimidine-4-carboxamides
Tert-butyl 3- (3- (5-cyano-1H-indol-3-yl) propyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (330mg,0.84mmol) was dissolved in dichloromethane (10mL), trifluoroacetic acid (1.5mL) was added, and the solution was left to react at room temperature for 1 hour and then dried under reduced pressure. The resulting solid was dissolved in acetonitrile (15mL), and 2-chloropyrimidine-4-carboxamide (132mg,0.84mmol), sodium carbonate (266mg,2.51mmol) and potassium iodide (13mg,0.08mmol) were added in this order, and then the reaction solution was raised in temperature and refluxed overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a pale yellow solid (275mg, 79.1%).
MS(ESI,pos.ion)m/z:416.2(M+1)；
1H NMR(CDCl3,600MHz)δ(ppm):9.01(brs,1H),8.52(d,J＝4.8Hz,1H),7.97(s,1H),7.71(s,1H),7.43-7.39(m,2H),7.25(d,J＝4.8Hz,1H),7.12(s,1H),6.24(brs,1H),4.77(brs,2H),2.80(t,J＝7.2Hz,2H),2.75(d,J＝10.2Hz,2H),2.36-2.32(m,4H),2.08-2.07(m,2H),1.99-1.96(m,2H),1.84-1.82(m,2H).
Example 22- (3- (4- (5-cyano-1H-indol-3-yl) butyl) -3, 8-diazabicyclo [3.2.1]Octane-8-yl) pyrimidine-4-carboxamides
Step 1)3- (4- (5-cyano-1H-indol-3-yl) butyl) -3, 8-diazabicyclo [3.2.1]Octane-8-methylSynthesis of tert-butyl ester
The title compound was prepared according to the procedure for example 1, step 1, by reacting 3- (4-chlorobutyl) -1H-indole-5-carbonitrile (2.80g,12.03mmol), 3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (2.55g,12.03mmol), sodium carbonate (1.91g,18.05mmol) and potassium iodide (200mg,1.20mmol) in acetonitrile (30mL) to give a crude product which was purified by silica gel column chromatography (PE/EA (v/v) ═ 3/2) to give the title compound as a white solid (3.98g, 80.9%).
MS(ESI,pos.ion)m/z:409.2(M+1)；
1H NMR(CDCl3,600MHz)δ(ppm):8.56(brs,1H),7.97(s,1H),7.42(s,2H),7.11(s,1H),4.20-4.10(m,2H),2.77(t,J＝7.2Hz,2H),2.62(d,J＝10.2Hz,2H),2.35(t,J＝7.2Hz,2H),2.22-2.19(m,2H),1.83(brs,4H),1.77-1.73(m,2H),1.56-1.52(m,2H),1.49(s,9H).
Step 2)2- (3- (4- (5-cyano-1H-indol-3-yl) butyl) -3, 8-diazabicyclo [3.2.1]Octane-8-Yl) Synthesis of pyrimidine-4-carboxamides
The title compound of this step was prepared according to the method of example 1, step 2, by reacting a solid obtained by reacting 3- (4- (5-cyano-1H-indol-3-yl) butyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (330mg,0.81mmol) and trifluoroacetic acid (1.5mL) in dichloromethane (10mL) with 2-chloropyrimidine-4-carboxamide (127mg,0.81mmol), sodium carbonate (257mg,2.43mmol) and potassium iodide (13mg,0.08mmol) in acetonitrile (15mL) to give a crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a light yellow solid (160mg, 46.1%).
MS(ESI,pos.ion)m/z:430.2(M+1)；
1H NMR(CDCl3,600MHz)δ(ppm):8.94(brs,1H),8.51(d,J＝4.8Hz,1H),7.95(s,1H),7.70(s,1H),7.43-7.39(m,2H),7.24(d,J＝4.2Hz,1H),7.11(s,1H),6.20(br s,1H),4.74(brs,2H),2.76(t,J＝7.2Hz,2H),2.71(d,J＝10.2Hz,2H),2.34-2.29(m,4H),2.01-2.00(m,2H),1.93-1.92(m,2H),1.75-1.72(m,2H),1.54-1.52(m,2H).
Example 33- (3- (8- (4, 6-dimethylpyrimidin-2-yl) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl)Propyl) -1H-indole-5-carbonitrile
The title compound was prepared according to the method of example 1, step 2, by reacting 3- (3- (5-cyano-1H-indol-3-yl) propyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (330mg,0.84mmol) and trifluoroacetic acid (1.5mL) in dichloromethane (10mL) with 2-chloro-4, 6-dimethylpyrimidine (119mg,0.84mmol), sodium carbonate (266mg,2.51mmol) and potassium iodide (14mg,0.08mmol) in acetonitrile (15mL) to give a crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a pale yellow solid (263mg, 78.5%).
MS(ESI,pos.ion)m/z:401.2(M+1)；
1H NMR(CDCl3,600MHz)δ(ppm):8.89(brs,1H),7.98(s,1H),7.43-7.39(m,2H),7.12(s,1H),6.22(s,1H),4.74(brs,2H),2.81(t,J＝7.2Hz,2H),2.77-7.74(m,2H),2.36-2.32(m,4H),2.27(s,6H),2.07-2.02(m,2H),1.97-1.91(m,2H),1.84-1.82(m,2H).
Example 43- (4- (8- (4, 6-dimethylpyrimidin-2-yl) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl)Butyl) -1H-indole-5-carbonitrile
The title compound of this step was prepared according to the method of example 1, step 2, by reacting a solid obtained by reacting 3- (4- (5-cyano-1H-indol-3-yl) butyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (330mg,0.81mmol) and trifluoroacetic acid (1.5mL) in dichloromethane (10mL) with 2-chloro-4, 6-dimethylpyrimidine (115mg,0.81mmol), sodium carbonate (257mg,2.43mmol) and potassium iodide (13mg,0.08mmol) in acetonitrile (15mL) to give a crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a pale yellow solid (235mg, 70.1%).
MS(ESI,pos.ion)m/z:415.2(M+1)；
1H NMR(CDCl3,600MHz)δ(ppm):8.76(brs,1H),7.95(s,1H),7.43-7.37(m,2H),7.10(s,1H),6.26(s,1H),4.72(brs,2H),2.81(t,J＝7.2Hz,2H),2.73-2.71(m,2H),2.40-2.32(m,4H),2.28(s,6H),2.07-2.02(m,2H),1.94-1.91(m,2H),1.74-1.71(m,2H),1.66-1.63(m,2H).
Example 52- (8- (3- (5-cyano)-1H-indol-3-yl) propyl) -3, 8-diazabicyclo [3.2.1]Octane-3-yl) pyrimidine-4-carboxamides
Step 1)3- (4-carbamoylpyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl esterSynthesis of (2)
2-chloropyrimidine-4-carboxamide (0.74g,4.70mmol), tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (1.00g,4.71mmol) and sodium carbonate (0.75g,7.05mmol) were added to acetonitrile (15mL), and the reaction was allowed to warm and reflux overnight. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a red solid (1.30g, 82.8%).
MS(ESI,pos.ion)m/z:334.2(M+1)；
1H NMR(CDCl3,600MHz)δ(ppm):8.54(d,J＝4.7Hz,1H),7.61(s,1H),7.32(d,J＝4.7Hz,1H),6.15(s,1H),4.40-4.30(m,4H),3.20(brs,2H),1.96-1.94(m,2H),1.74-1.68(m,2H),1.50(s,9H).
Step 2)2- (8- (3- (5-cyano-1H-indol-3-yl) propyl) -3, 8-diazabicyclo [3.2.1]Octane-3-Yl) Synthesis of pyrimidine-4-carboxamides
Tert-butyl 3- (4-carbamoylpyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (300mg,0.90mmol) was dissolved in dichloromethane (10mL), trifluoroacetic acid (1.5mL) was added, and the solution was left to react at room temperature for 1 hour and then dried under reduced pressure. The resulting solid was dissolved in acetonitrile (15mL), and 3- (3-chloropropyl) -1H-indole-5-carbonitrile (197mg,0.90mmol), potassium iodide (15mg,0.09mmol) and sodium carbonate (286mg,2.70mmol) were added in this order, and then the reaction liquid was raised to temperature and refluxed overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a pale yellow solid (200mg, 53.5%).
MS(ESI,pos.ion)m/z:416.2(M+1)；
1H NMR(DMSO-d6,600MHz)δ(ppm):11.44(s,1H),8.53(d,J＝4.0Hz,1H),8.11(s,2H),7.73(s,1H),7.51(d,J＝8.2Hz,1H),7.40(d,J＝8.0Hz,1H),7.37(s,1H),7.10(d,J＝3.8Hz,1H),3.13-3.07(m,2H),2.79(t,J＝6.8Hz,2H),2.49-2.41(m,2H),1.89-1.83(m,4H),1.52-1.46(s,2H),1.26-1.21(m,4H).
Example 62- (8- (4- (5-cyano-1H-indol-3-yl) butyl) -3, 8-diazabicyclo [3.2.1]Octane-3-yl) pyrimidine-4-carboxamides
The title compound was prepared according to the procedure for example 5, step 2, by reacting 3- (4-carbamoylpyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (300mg,0.90mmol) and trifluoroacetic acid (1.5mL) in dichloromethane (10mL) with 3- (4-chlorobutyl) -1H-indole-5-carbonitrile (209mg,0.90mmol), potassium iodide (15mg,0.09mmol) and sodium carbonate (286mg,2.70mmol) in acetonitrile (15mL) to give a crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a light yellow solid (300mg, 77.6%).
MS(ESI,pos.ion)m/z:430.2(M+1)；
1H NMR(DMSO-d6,600MHz)δ(ppm):11.39(s,1H),8.54(d,J＝4.6Hz,1H),8.14(s,1H),8.09(s,1H),7.74(s,1H),7.51(d,J＝8.4Hz,1H),7.40(d,J＝8.3Hz,1H),7.35(s,1H),7.11(d,J＝4.4Hz,1H),3.53-3.45(m,2H),3.21-3.13(m,2H),3.12-3.05(m,2H),2.76(t,J＝7.3Hz,2H),2.57-2.51(m,2H),1.94-1.86(m,2H),1.72(dt,J＝14.7,7.3Hz,2H),1.61-1.55(m,2H),1.54-1.48(m,2H).
Example 73- (3- (3- (4, 6-dimethoxypyrimidin-2-yl) -3, 8-diazabicyclo [ 3.2.1%]Octane-8-Yl) propyl) -1H-indole-5-carbonitrile
Step 1)3- (4, 6-dimethoxypyrimidine-2-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl esterSynthesis of esters
The title compound was prepared according to the procedure for example 5, step 1, by reacting 2-chloro-4, 6-dimethoxypyrimidine (1.00g,5.73mmol), 3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (1.22g,5.73mmol) and sodium carbonate (911mg,8.59mmol) in acetonitrile (15mL) to give a crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a red solid (1.41g, 70.1%).
MS(ESI,pos.ion)m/z:351.2(M+1)；
1H NMR(CDCl3,600MHz)δ(ppm):5.39(s,1H),4.40-4.28(m,4H),3.85(s,6H),3.22-3.20(m,2H),1.95-1.94(m,2H),1.75-1.68(m,2H),1.49(s,9H).
Step 2)3- (3- (3- (4, 6-dimethoxypyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-yl)Synthesis of propyl) -1H-indole-5-carbonitrile
The title compound was prepared according to the procedure for example 5, step 2, by reacting tert-butyl 3- (4, 6-dimethoxypyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (310mg,0.88mmol) and trifluoroacetic acid (1.5mL) in dichloromethane (10mL) with 3- (3-chloropropyl) -1H-indole-5-carbonitrile (193mg,0.88mmol), potassium iodide (15mg,0.09mmol) and sodium carbonate (281mg,2.65mmol) in acetonitrile (15mL) to give a crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a light yellow solid (250mg, 65.5%).
MS(ESI,pos.ion)m/z:433.2(M+1)；
1H NMR(DMSO-d6,600MHz)δ(ppm):11.38(brs,1H),8.03(s,1H),7.49(d,J＝8.4Hz,1H),7.40(dd,J＝8.4,1.1Hz,1H),7.29(d,J＝1.0Hz,1H),5.36(s,1H),3.85(s,6H),3.17-3.13(m,2H),2.74(t,J＝7.4Hz,2H),2.57-2.51(m,2H),1.94-1.86(m,4H),1.53-1.45(m,2H),1.25-1.20(m,4H).
Example 83- (4- (3- (4, 6-dimethoxypyrimidin-2-yl) -3, 8-diazabicyclo [ 3.2.1)]Octane-8-Yl) butyl) -1H-indole-5-carbonitrile
The title compound was prepared according to the procedure for example 5, step 2, by reacting tert-butyl 3- (4, 6-dimethoxypyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (310mg,0.88mmol) and trifluoroacetic acid (1.5mL) in dichloromethane (10mL) with 3- (4-chlorobutyl) -1H-indole-5-carbonitrile (206mg,0.88mmol), potassium iodide (15mg,0.09mmol) and sodium carbonate (281mg,2.65mmol) in acetonitrile (15mL) to give a crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a pale yellow solid (265mg, 67.1%).
MS(ESI,pos.ion)m/z:447.2(M+1)；
1H NMR(DMSO-d6,600MHz)δ(ppm):11.39(s,1H),8.09(s,1H),7.74(s,1H),7.34(s,1H),7.18(d,J＝4.4Hz,1H),5.36(s,1H),3.85(s,6H),3.55-3.50(m,2H),3.24-3.11(m,2H),3.12-3.05(m,2H),2.78(t,J＝7.4Hz,2H),2.56-2.51(m,2H),1.95-1.87(m,2H),1.74–7.72(m,2H),1.62-1.56(m,2H),1.53-1.48(m,2H).
Example 93- (3- (3- (pyridin-2-yl) -3, 8-diazabicyclo [ 3.2.1)]Octane-8-yl) propyl) -1H-Indole-5-carbonitriles
Step 1)3- (pyridin-2-yl) -3, 8-diazabicyclo [3.2.1]Synthesis of octane-8-carboxylic acid tert-butyl ester
The title compound of this step was prepared according to the procedure of example 5, step 1, by reacting 2-chloropyridine (0.80g,7.05mmol), 3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (1.50g,7.05mmol) and sodium carbonate (1.12g,10.57mmol) in acetonitrile (15mL) to prepare a crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to afford the title compound as a pale yellow solid (1.45g, 71.1%).
MS(ESI,pos.ion)m/z:290.2(M+1)；
1H NMR(CDCl3,400MHz)δ(ppm):8.16(d,J＝4.0Hz,1H),7.43(td,J＝8.8,2.0Hz,1H),6.54-6.50(m,2H),4.38-4.35(m,2H),4.30-4.28(m,2H),3.20-3.15(m,2H),1.95-1.93(m,2H),1.74-1.67(m,2H),1.50(s,9H).
Step 2)3- (3- (3- (pyridin-2-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-yl) propyl) -1H-indoleSynthesis of indole-5-carbonitriles
The title compound was prepared according to the procedure for example 5, step 2, by reacting tert-butyl 3- (pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (300mg,1.04mmol) and trifluoroacetic acid (1.5mL) in dichloromethane (10mL) with 3- (3-chloropropyl) -1H-indole-5-carbonitrile (227mg,1.04mmol), potassium iodide (17mg,0.10mmol) and sodium carbonate (330mg,3.11mmol) in acetonitrile (15mL) to give a crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a pale yellow solid (280mg, 72.7%).
MS(ESI,pos.ion)m/z:372.2(M+1)；
1H NMR(CDCl3,400MHz)δ(ppm):8.02(d,J＝4.4Hz,1H),7.88(s,1H),7.60-7.55(m,1H),7.48(d,J＝8.4Hz,1H),7.37(d,J＝8.4Hz,1H),7.21(s,1H),6.69(dd,J＝6.8,5.2Hz,1H),6.63(d,J＝8.8Hz,1H),3.15-3.06(m,2H),2.77(t,J＝10.2Hz,2H),2.48-2.41(m,2H),1.94-1.75(m,4H),1.52-1.46(m,2H),1.27-1.22(m,4H).
Example 103- (4- (3- (pyridin-2-yl) -3, 8-diazabicyclo [ 3.2.1)]Octane-8-yl) butyl) -1H-Indole-5-carbonitriles
The title compound was prepared according to the procedure for example 5, step 2, by reacting tert-butyl 3- (pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (300mg,1.04mmol) and trifluoroacetic acid (1.5mL) in dichloromethane (10mL) with 3- (4-chlorobutyl) -1H-indole-5-carbonitrile (241mg,1.04mmol), potassium iodide (17mg,0.10mmol) and sodium carbonate (330mg,3.11mmol) in acetonitrile (15mL) to give a crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a light yellow solid (280mg, 70.0%).
MS(ESI,pos.ion)m/z:386.2(M+1)；
1H NMR(CDCl3,400MHz)δ(ppm):8.09(dd,J＝4.8,1.2Hz,1H),7.89(s,1H),7.46-7.42(m,1H),7.40(d,J＝8.4Hz,1H),7.34(dd,J＝8.4,1.2Hz,1H),7.06(s,1H),6.55(dd,J＝6.8,5.2Hz,1H),6.48(d,J＝8.8Hz,1H),3.55-3.45(m,2H),3.20-3.15(m,2H),3.12-3.03(m,2H),3.01-2.94(m,2H),2.77(t,J＝7.2Hz,2H),2.46-2.42(m,2H),1.93-1.91(m,2H),1.66-1.63(m,2H),1.54-1.52(m,2H).
Example 113- (3- (8- (3-cyanopyridin-2-yl) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) propanes1H-indole-5-carbonitrile
The title compound was prepared according to the method of example 1, step 2, by reacting 3- (3- (5-cyano-1H-indol-3-yl) propyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (330mg,0.84mmol) and trifluoroacetic acid (1.5mL) in dichloromethane (10mL) with 2-chloronicotinonitrile (116mg,0.84mmol), sodium carbonate (266mg,2.51mmol) and potassium iodide (14mg,0.08mmol) in acetonitrile (15mL) to give a crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a light yellow solid (170mg, 51.3%).
MS(ESI,pos.ion)m/z:397.2(M+1)；
1H NMR(CDCl3,600MHz)δ(ppm):9.02(brs,1H),8.25(dd,J＝4.8,2.0Hz,1H),7.93(s,1H),7.70(dd,J＝7.6,2.0Hz,1H),7.41(d,J＝8.4Hz,1H),7.38(dd,J＝8.4,1.2Hz,1H),7.11-7.09(m,1H),6.61-6.59(m,1H),4.75(brs,2H),2.78(t,J＝7.2Hz,2H),2.74(t,J＝10.2Hz,2H),2.36-2.30(m,4H),2.08-2.05(m,2H),1.95-1.93(m,2H),1.85-1.83(m,2H).
Example 123- (4- (8- (3-cyanopyridin-2-yl) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) butanes1H-indole-5-carbonitrile
The title compound of this step was prepared according to the method of example 1, step 2, by reacting a solid obtained by reacting 3- (4- (5-cyano-1H-indol-3-yl) butyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (330mg,0.81mmol) and trifluoroacetic acid (1.5mL) in dichloromethane (10mL) with 2-chloronicotinonitrile (112mg,0.81mmol), sodium carbonate (257mg,2.43mmol) and potassium iodide (13mg,0.08mmol) in acetonitrile (15mL) to give a crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a pale yellow solid (183mg, 55.2%).
MS(ESI,pos.ion)m/z:411.2(M+1)；
1H NMR(CDCl3,400MHz)δ(ppm):8.26(dd,J＝4.8,2.0Hz,1H),7.92(s,1H),7.69(dd,J＝7.6,2.0Hz,1H),7.41(d,J＝8.4Hz,1H),7.37(dd,J＝8.4,1.2Hz,1H),7.10-7.09(m,1H),6.60(dd,J＝7.6,4.8Hz,1H),4.74(brs,2H),2.74(t,J＝7.6Hz,2H),2.69(t,J＝10.2Hz,2H),2.35-2.29(m,4H),2.02-2.00(m,2H),1.94-1.93(m,2H),1.75-1.73(m,2H),1.55-1.52(m,2H).
Example 133- (3- (8- (3-methoxypyridin-2-yl) -3, 8-diazabicyclo [3.2.1]Octane-3-yl)Propyl) -1H-indole-5-carbonitrile
The title compound was prepared according to the method of example 1, step 2, by reacting a solid obtained by reaction of tert-butyl 3- (3- (5-cyano-1H-indol-3-yl) propyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (330mg,0.84mmol) and trifluoroacetic acid (1.5mL) in dichloromethane (10mL) with 2-chloro-3-methoxypyridine (120mg,0.84mmol), sodium carbonate (266mg,2.51mmol) and potassium iodide (14mg,0.08mmol) in acetonitrile (15mL) to give a crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a pale yellow solid (200mg, 59.6%).
MS(ESI,pos.ion)m/z:402.2(M+1)；
H NMR(CDCl3,400MHz)δ(ppm):8.50(d,J＝4.8,1H),7.92(s,1H),7.53(dd,J＝7.6,1.6Hz,1H),7.39(d,J＝8.4Hz,1H),7.36(dd,J＝8.4,1.2Hz,1H),7.08(s,1H),6.74(dd,J＝7.6,4.8Hz,1H),4.77(brs,2H),3.83(s,3H),2.81(t,J＝7.2Hz,2H),2.76-2.72(m,2H),2.37-2.33(m,4H),2.12-2.10(m,2H),2.01-1.98(m,2H),1.89-1.86(m,2H).
Example 143- (4- (8- (3-methoxypyridin-2-yl) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl)Butyl) -1H-indole-5-carbonitrile
The title compound of this step was prepared according to the method of example 1, step 2, by reacting a solid obtained by reacting 3- (4- (5-cyano-1H-indol-3-yl) butyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (330mg,0.81mmol) and trifluoroacetic acid (1.5mL) in dichloromethane (10mL) with 2-chloro-3-methoxypyridine (116mg,0.81mmol), sodium carbonate (257mg,2.43mmol) and potassium iodide (13mg,0.08mmol) in acetonitrile (15mL) to give a crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a light yellow solid (190mg, 56.3%).
MS(ESI,pos.ion)m/z:416.2(M+1)；
1H NMR(CDCl3,600MHz)δ(ppm):8.50(d,J＝4.8,1H),7.93(s,1H),7.51(dd,J＝8.0,1.6Hz,1H),7.37(d,J＝8.4Hz,1H),7.34(dd,J＝8.8,1.2Hz,1H),7.05(s,1H),6.71(dd,J＝7.6,4.8Hz,1H),4.70(brs,2H),3.83(s,3H),2.75-2.69(m,4H),2.36-2.28(m,4H),2.02-2.00(m,2H),1.95-1.94(m,2H),1.69-1.67(m,2H),1.58-1.56(m,2H).
Example 152- (3- (3- (5-cyano-1H-indol-3-yl) propyl) -3, 8-diazabicyclo [3.2.1]Pungent foodAlk-8-yl) nicotinamide
The title compound was prepared according to the method of example 1, step 2, by reacting 3- (3- (5-cyano-1H-indol-3-yl) propyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (300mg,0.76mmol) and trifluoroacetic acid (1.5mL) in dichloromethane (10mL) with 2-chloronicotinamide (120mg,0.76mmol), sodium carbonate (242mg,2.28mmol) and potassium iodide (13mg,0.08mmol) in acetonitrile (15mL) to give a crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a light yellow solid (158mg, 50.1%).
MS(ESI,pos.ion)m/z:415.2(M+1)；
1H NMR(DMSO-d6,600MHz)δ(ppm):11.41(brs,1H),8.14-8.10(m,1H),8.04(s,1H),7.91(s,1H),7.62(dd,J＝7.2,1.8Hz,1H),7.49(d,J＝8.4Hz,1H),7.45(s,1H),7.40(dd,J＝8.3,1.0Hz,1H),7.32(s,1H),6.71(dd,J＝6.9,4.9Hz,1H),4.74(brs,2H),2.81(t,J＝7.2Hz,2H),2.76-2.74(m,2H),2.38-2.32(m,4H),2.09-2.07(m,2H),1.99-1.97(m,2H),1.83-1.75(m,2H).
Example 162- (3- (4- (5-cyano-1H-indol-3-yl) butyl) -3, 8-diazabicyclo [3.2.1]Pungent foodAlk-8-yl) nicotinamide
The title compound was prepared according to the procedure for example 1, step 2, by reacting 3- (4- (5-cyano-1H-indol-3-yl) butyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (300mg,0.73mmol) and trifluoroacetic acid (1.5mL) in dichloromethane (10mL) with 2-chloronicotinamide (115mg,0.73mmol), sodium carbonate (233mg,2.20mmol) and potassium iodide (12mg,0.07mmol) in acetonitrile (15mL) to give a crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a light yellow solid (185mg, 58.8%).
MS(ESI,pos.ion)m/z:429.2(M+1)；
1H NMR(DMSO-d6,600MHz)δ(ppm):11.35(brs,1H),8.09(dd,J＝4.7,1.9Hz,1H),8.04(s,1H),7.88(s,1H),7.59(dd,J＝7.4,1.9Hz,1H),7.49(d,J＝8.4Hz,1H),7.39(dd,J＝8.4,1.4Hz,2H),7.28(d,J＝1.7Hz,1H),6.67(dd,J＝7.4,4.7Hz,1H),4.73(brs,2H),2.80(t,J＝7.2Hz,2H),2.75(d,J＝10.2Hz,2H),2.35-2.31(m,4H),2.02-2.00(m,2H),1.85-1.82(m,2H),1.58-1.53(m,2H),1.42-1.37(m,2H).
Example 173- (3- (8- (4- (trifluoromethyl) pyridin-2-yl) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-Yl) propyl) -1H-indole-5-carbonitrile
The title compound was prepared according to the method of example 1, step 2, by reacting a solid obtained by reaction of 3- (3- (5-cyano-1H-indol-3-yl) propyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (300mg,0.76mmol) and trifluoroacetic acid (1.5mL) in dichloromethane (10mL) with 2-chloro-4-trifluoromethylpyridine (138mg,0.76mmol), sodium carbonate (242mg,2.28mmol) and potassium iodide (13mg,0.08mmol) in acetonitrile (15mL) to give a crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a light yellow solid (200mg, 59.9%).
MS(ESI,pos.ion)m/z:440.2(M+1)；
1H NMR(CDCl3,600MHz)δ(ppm):9.02(brs,1H),8.18(d,J＝5.2Hz,1H),7.94(s,1H),7.47(d,J＝8.4Hz,1H),7.35(d,J＝8.4Hz,1H),7.24(s,1H),6.80(d,J＝5.2Hz,1H),6.74(s,1H),4.75(brs,2H),2.88-2.86(m,2H),2.76(t,J＝10.2Hz,2H),2.36-2.34(m,4H),2.14-2.13(m,2H),2.01-1.96(m,2H),1.83-1.80(m,2H).
Example 183- (4- (8- (4- (trifluoromethyl) pyridin-2-yl) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-Yl) butyl) -1H-indole-5-carbonitrile
The title compound of this step was prepared according to the method of example 1, step 2, by reacting a solid obtained by reacting 3- (4- (5-cyano-1H-indol-3-yl) butyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (300mg,0.73mmol) and trifluoroacetic acid (1.5mL) in dichloromethane (10mL) with 2-chloro-4-trifluoromethylpyridine (133mg,0.73mmol), sodium carbonate (233mg,2.20mmol) and potassium iodide (12mg,0.07mmol) in acetonitrile (15mL) to give a crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a light yellow solid (190mg, 57.1%).
MS(ESI,pos.ion)m/z:454.2(M+1)；
1H NMR(CDCl3,600MHz)δ(ppm):8.94(brs,1H),8.11(d,J＝4.8Hz,1H),7.90(s,1H),7.44(d,J＝8.4Hz,1H),7.33(d,J＝8.4Hz,1H),7.16(s,1H),6.76(d,J＝5.2Hz,1H),6.74(s,1H),4.77(brs,2H),2.76(t,J＝7.2Hz,2H),2.75-2.71(m,2H),2.34-2.30(m,4H),2.01-2.00(m,2H),1.93-1.91(m,2H),1.76-1.74(m,2H),1.57-1.53(m,2H).
Example 192- (3- (3- (5-cyano-1H-indol-3-yl) propyl) -3, 8-diazabicyclo [3.2.1]Pungent foodAlk-8-yl) -4-methylthiazole-5-carboxamides
The title compound of this step was prepared according to the method of example 1, step 2, by reacting tert-butyl 3- (3- (5-cyano-1H-indol-3-yl) propyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (300mg,0.76mmol) and trifluoroacetic acid (1.5mL) in dichloromethane (10mL) to give a solid which was reacted with 2-bromo-4-methylthiazole-5-carboxamide (168mg,0.76mmol), sodium carbonate (242mg,2.28mmol) and potassium iodide (13mg,0.07mmol) were reacted in acetonitrile (15mL) to prepare a crude product, which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a light yellow solid (210mg, 63.5%).
MS(ESI,pos.ion)m/z:435.2(M+1)；
1H NMR(CDCl3,600MHz)δ(ppm):9.02(brs,1H),7.89(s,1H),7.40(d,J＝8.4Hz,1H),7.32(dd,J＝8.4,0.8Hz,1H),7.11(s,1H),4.77(brs,2H),2.79-2.77(m,2H),2.73(t,J＝10.2Hz,2H),2.41(s,3H),2.36-2.33(m,4H),2.08-2.06(m,2H),1.98-1.95(m,2H),1.84-1.80(m,2H).
Example 202- (3- (4- (5-cyano-1H-indol-3-yl) butyl) -3, 8-diazabicyclo [3.2.1]Pungent foodAlk-8-yl) -4-methylthiazole-5-carboxamides
The title compound of this step was prepared according to the method of example 1, step 2, by reacting tert-butyl 3- (4- (5-cyano-1H-indol-3-yl) butyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (300mg,0.73mmol) and trifluoroacetic acid (1.5mL) in dichloromethane (10mL) to give a solid which was reacted with 2-bromo-4-methylthiazole-5-carboxamide (162mg,0.73mmol), sodium carbonate (233mg,2.20mmol) and potassium iodide (12mg,0.07mmol) were reacted in acetonitrile (15mL) to prepare a crude product, which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a pale yellow solid (200mg, 60.7%).
MS(ESI,pos.ion)m/z:449.2(M+1)；
1H NMR(CDCl3,600MHz)δ(ppm):9.01(brs,1H),7.90(s,1H),7.41(d,J＝8.4Hz,1H),7.31(dd,J＝8.4,0.8Hz,1H),7.12(s,1H),4.76(brs,2H),2.77(t,J＝7.2Hz,2H),2.73-2.71(m,2H),2.40(s,3H),2.34-2.30(m,4H),2.03-2.01(m,2H),1.94-1.92(m,2H),1.74-1.70(m,2H),1.57-1.54(m,2H).
Biological assay
3Example A: compound p [ H ] in rat synaptosomes]Assay for inhibition of 5-HT uptake
Test method
Buffer (106.2mM NaCl,4.5mM KCl,2.25mM MgSO 2) at 37 deg.C4,1.08mMNaH2PO4,22.5mM NaHCO39.9mM glucose, 9. mu.M EGTA and 45. mu.M ascorbic acid (pH 7.4)), synaptosome (150. mu.g) with 0.1. mu. Ci [ sic ], [ solution of3H]5-hydroxytryptamine, test compound or positive drug or negative control is added, and incubation is carried out for 15 minutes.
Imipramine as a standard positive compound for inhibiting the uptake of 5-hydroxytryptamine, 10 μ M imipramine was added to the same mixed system to block the uptake of 5-hydroxytryptamine, and the mixture was incubated at 4 ℃ for 15 minutes to determine the basal control activity value. Through experiments, the intake inhibition values of imipramine with different concentrations on rat brain synaptosomes are tested, and inhibition curves are prepared.
The incubated sample was rapidly filtered through a glass fiber filter (GF/B, Packard) under vacuum using a 96-sample cell harvester (Unifilter, Packard) and washed twice in ice-cold incubation buffer to eliminate free [ alpha ], [ beta ] -form3H]5-hydroxytryptamine. The filters were dried and the residual radioactivity was counted in scintillation cocktail (Microscint 0, Packard) in a scintillation counter (Topcount, Packard). The results of the experiment were measured with respect to the control group [2 ]3H]Percent inhibition of 5-hydroxytryptamine uptake is expressed.
Data analysis
The SERT transporter inhibitory effect of rat synaptosome consists of3H]5-HT concentration. The tested compound is tested at least twice under the condition that the concentration exceeds 6 logs, and the data is subjected to nonlinear regression analysis by a Hill equation curve to obtain IC50The value is obtained.
In a specific embodiment, the compound of the present invention is para3H]IC for 5-HT reuptake inhibition50Values less than 20 nM; preferably, IC50A value of less than 10nM, more preferably, IC50Values were less than 5 nM. In particular, IC of the compound prepared in example 1 of the invention50Value 15nM, IC of the compound prepared in example 250The value was 7.6nM, IC of the compound prepared in example 550Value 1.5nM, IC of the compound prepared in example 1550Value of 2.1nM, IC of the compound prepared in example 1650The value was 7.6nM, IC of the compound prepared in example 1950Value 7.5nM, IC of the compound prepared in example 2050The value was 9 nM.
The experimental result shows that the compound of the invention is para [2 ]3H]The reuptake of 5-HT has better inhibitory activity.
In the description herein, references to the description of the term "one embodiment," "an embodiment," "some embodiments," "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 (9)
1. A compound which is a compound represented by formula (I) or a pharmaceutically acceptable salt of the compound represented by formula (I),
wherein:
r is 2,3 or 4;
R8aand R8cEach independently is H, R8bAnd R8dTogether form-CH2CH2-; or,
R8aand R8cTogether form-CH2CH2-，R8bAnd R8dEach independently is H;
R2is-CN;
R1、R3、R4and R5Each independently is H or D;
each R6And R7Independently is H or D;
hy is the following sub-structure:
wherein W is-O-or-S-; each n is independently 0, 1 or 2;
each RyIndependently H, D, -CN, -ORc、-C(＝O)NRaRb、C1-C4Alkyl or C1-C4A haloalkyl group;
each RaAnd RbIndependently is H;
each RcIndependently is C1-C4An alkyl group.
2. The compound of claim 1, wherein each RaAnd RbIndependently is H;
each RcIndependently methyl, ethyl, n-propyl or isopropyl.
3. The compound of claim 1, wherein each RyIndependently H, D, -CN, -CONH2Methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, -CF3or-CH2CF3。
4. The compound of claim 1, which is a compound having one of the following structures or a pharmaceutically acceptable salt of a compound having one of the following structures:
5. a pharmaceutical composition comprising a compound of any one of claims 1-4; and
the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
6. The pharmaceutical composition according to claim 5, further comprising a drug for treating central nervous system dysfunction, which is an antidepressant, an anxiolytic, a lithium salt as an affective stabilizer, an atypical antipsychotic, an antiepileptic, an anti-parkinson drug, a nicotinic antagonist or any combination thereof.
7. The pharmaceutical composition of claim 5, further comprising a drug for treating central nervous system dysfunction, wherein the drug for treating central nervous system dysfunction is amitriptyline, desipramine, mirtazapine, bupropion, reboxetine, fluoxetine, trazodone, sertraline, duloxetine, fluvoxamine, milnacipran, levomilnacipran, desvenlafaxine, vilazone, venlafaxine, dapoxetine, nefazodone, fementine, clomipramine, citalopram, escitalopram, paroxetine, lithium carbonate, buspirone, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, clozapine, modafinil, mecamylamine, cabergoline, adamantane, imipramipexole, thyroxine, dextromethorphan, quinidine, naltrexone, and, samidorphan, buprenorphine, melatonin, alprazolam, pipamperone, vertetipitan, chlordiazepoxide, perphenazine, or any combination thereof.
8. 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 7 in the manufacture of a medicament for the prevention, treatment or alleviation of central nervous system dysfunction.
9. 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 7 in the manufacture of a medicament for inhibiting 5-hydroxytryptamine reuptake.
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