CN105085367B - Substituted heteroaryl compound and combinations thereof and purposes - Google Patents

Substituted heteroaryl compound and combinations thereof and purposes Download PDF

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CN105085367B
CN105085367B CN201510220454.4A CN201510220454A CN105085367B CN 105085367 B CN105085367 B CN 105085367B CN 201510220454 A CN201510220454 A CN 201510220454A CN 105085367 B CN105085367 B CN 105085367B
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methoxy
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CN105085367A (en
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张英俊
金传飞
高金恒
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a new class of heteroaryl compounds, and the pharmaceutical composition comprising the compound；The heteroaryl compound or pharmaceutical composition comprising the compound are used for exciting melatonin receptors.The invention further relates to the method for preparing this kind of compound and pharmaceutical composition and they treatment mammal, especially mankind's central nervous system dysfunction in purposes.

Description

Substituted heteroaryl compounds, compositions and uses thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to a novel compound for treating central nervous system dysfunction, a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound and the pharmaceutical composition in treating central nervous system dysfunction. More specifically, the invention relates to heteroaryl compounds which can be used as melatonin receptor agonists.
Background
Melatonin (melatonin) is a neuroendocrine hormone secreted by the pineal body, and its main physiological actions are: 1. the melatonin can inhibit the growth of various cancer cells such as breast cancer, melanoma, prostatic cancer, liver cancer and the like, and is an important physiological tumor inhibitor; 2. antioxidant effect, the body can generate free radicals such as oxygen free radicals, hydroxyl free radicals, etc. through enzymatic and non-enzymatic reactions, and melatonin can scavenge Reactive Oxygen Species (ROS) mainly by supplying electrons; 3. the melatonin is one of important factors for connecting a nervous system and an immune system of an organism and has an important function for maintaining the normal function of the organism; 4. anti-inflammatory and stress effects, melatonin can obviously promote the proliferative response of peripheral blood lymphocytes of patients with rheumatoid arthritis, and has resistance to low temperature, hypoxia, noise and light disturbance stress; 5. the glucolipid metabolism is regulated, and the melatonin can reduce blood sugar and blood fat and increase high-density lipoprotein; 6. antidepressant and anxiolytic effects; 7. the influence on sleep latency, and the function of melatonin in regulating the sleep-wake cycle through the mediation of specific melatonin receptorsUnique action (Malpaux B, Migaud M, et a1.biology of mam macromolecular photoperiod and the critical role in Japanese patent and memorandum. J Biol Rhythms, 2001, 16 (4): 336-. Melatonin is required to exert its biological effects by activating receptors, which belong to members of the G protein-coupled receptor superfamily and are widely present in SCN, hippocampus, cerebellar cortex, prefrontal lobe, basal ganglia, substantia nigra ventral tegmental area, nucleus accumbens, etc. of the nervous system, and in cell membranes and nuclei of other systems such as retina, blood vessels, mammary gland, liver, kidney, gastrointestinal tract and gonads. The human melatonin receptor has MT1、MT2And MT3Three subtypes. MT (multiple terminal)1The high concentration of the protein in SCN, thalamus nuclei and other parts can regulate sleep; MT (multiple terminal)2To circadian rhythms; MT (multiple terminal)3The effect is unclear. (Charlotte von Gal1, Jorg H, et al, Mammarian melatonin receptors: molecular biology and signal transmission. cell tissue RPs, 2002, 309 (1): 151-).
Among the melatonin receptor-related diseases, insomnia is a very important one. Insomnia is a sleep disorder syndrome in which the onset of sleep and maintenance of sleep are impaired, resulting in an inability to meet the individual's physiological needs for sleep quality and significant effects on the patient's daytime activities. Insomnia is a common disease, causes people to show depression and anxiety, can weaken an immune mechanism and prevent physical recovery, has an increasing trend along with the acceleration of modern life rhythm and insomnia, and also has many accidents caused by insufficient sleep in actual life. At present, people near 1/4 suffer from insomnia globally, the prevalence rate of sleep disorder in China reaches 42.7%, and about 3 hundred million middle-aged people suffer from sleep disorder. The global hypnotic market value in 2009 was $ 40 billion, with an annual growth rate of 11%.
At present, drug therapy is one of the main methods for treating insomnia, and clinically applied sedative hypnotic drugs include: barbiturates, benzodiazepinesQuasi-drugs, non-benzodiazepinesQuasi drugs, antidepressant drugs, melatonin, traditional Chinese medicines and the like. Barbiturates are derivatives of barbituric acid (malonylurea) that block the transmission of excitation to the cerebral cortex by selectively inhibiting the thalamus reticuloendothelial activation system. The medicines mainly comprise phenobarbital, amobarbital, secobarbital and the like. The medicine has large toxic and side effects, particularly serious liver and kidney toxicity, tolerance and dependence can be generated after long-term use, accumulated poisoning exists, and the medicine is less used for sedation and hypnosis in clinic at present. Dinitrogen benzeneThe quasi-drugs have the effects of sedation, muscle relaxation, antianxiety and anticonvulsant, and the drugs are frequently used clinically: mainly, midazolam (midazolam), triazolam (triazolam), alprazolam (alprazolam), estazolam (estazolam), diazepam (diazepam), flurazepam (flurazepam), clonazepam (clonazepam), and the like. Although these drugs can prolong total sleep time and shorten sleep latency, they reduce slow wave sleep and Rapid Eye Movement (REM) sleep, and do not really improve sleep quality. The adverse reaction and the complication are obvious, and the long-term application can cause the drug tolerance, the dependence and the withdrawal symptoms. (Krystal AD. the changing sexual on chloronic bacteria management. J Clin Psychiatry,2004, 65Suppl 8: 20-25). Non-benzodiazepinesSimilarly, the approved marketed drugs are zolpidem (zolpidem), zaleplon (zalepbn) and zopiclone (zopielone), which do not affect the normal sleep structure and do not generally produce insomnia rebound and withdrawal responses. Common adverse reactions are ataxia, headache, lethargy, memory difficulties, mental disorders, etc. (Rotht, Soubranec, Titeuxl, et al, efficiency and society of zolpidem-MR: a double-blind, plache-control in adults with primary insomniam. Sleep Med,2006,7 (5): 397-. Antidepressants do not have a specific hypnotic effect, but they have been modified by treatment of depression and anxietyGood insomnia symptoms are usually seen clinically in paroxetine (parooxetine), sertraline (sertraline), mirtazapine (mirtazapine), trazodone (trazodone) and amitriptyline, among others, and individual patients have no improvement or even worsen sleep when SSRIs are used (Uhlenhuth, EH, Balter MB, et al, Trends in sleep disorders for the pharmacotherapy of acute disorders by the entrance experience panel,1992-1997, Eur Neuropyhormatol, 1999.9Suppl 6: 393 and 398). Therefore, the development of sedative hypnotic drugs with high efficiency, high selectivity and small side effect becomes a research hotspot.
The melatonin medicine has good curative effect, small side effect and good application prospect. The melatonin receptor agonist ramelteon (ramelteon) which is firstly marketed in the united states in 2005 is used for treating insomnia, can shorten sleep latency, improve sleep efficiency and sleep maintenance, and does not damage cognitive activities of the next day and has no withdrawal symptom compared with the traditional medicine; however, this drug has mild side effects such as headache, fatigue, lethargy, etc. (Arendt J, Van Someren E J, Appleton R, et a1., Clinical update: melatonin and sleep disorders. Clin Med,2008, 8 (4): 381-383).
The invention provides novel compounds with melatonin receptor agonist activity, and the compounds have good clinical application prospect. 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 compound with melatonin receptor stimulant activity, which can be used for preparing medicaments for treating human central nervous system dysfunction, such as insomnia, stress reaction, seasonal affective disorder, insomnia caused by jet lag, fatigue and insomnia. The invention also provides processes for preparing these compounds, methods of using these compounds to treat the above-mentioned conditions in mammals, especially humans, and pharmaceutical compositions comprising these compounds.
Specifically, the method comprises the following steps:
in one aspect, the invention relates to a compound of formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula (I), or a prodrug thereof,
wherein, W, L, R1、R2、R3、R3a、R5、R6、R7、R8M, n and p have the meanings as described in the invention.
In one embodiment, each W is independently N or CH;
each L is independently CR4R4a；
R1Is C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C1-12Cycloalkyl radical, C6-10Aryl or heteroaryl of 5 to 12 atoms, wherein R1Optionally substituted by 1,2,3,4 or 5R9Substituted by a group;
R2is H, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C3-12Cycloalkyl or heterocyclyl of 3 to 12 atoms, wherein R2Optionally substituted by 1,2,3,4 or 5R9Substituted by a group;
R3、R3a、R4、R4a、R10and R10aEach independently of the others is H, D, F, Cl, Br, CN,C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C1-12Alkoxy radical, C1-12Alkylamino radical, C3-12Cycloalkyl, heterocyclic group consisting of 3 to 12 atoms, C6-10Aryl or heteroaryl of 5 to 12 atoms, or R3、R3aTogether with the carbon atom to which they are attached form C3-12Cycloalkyl or heterocyclyl of 3 to 12 atoms, wherein R3、R3a、R4、R4a、R10And R10aIndependently optionally substituted by 1,2,3,4 or 5R9Substituted by a group;
each R5And R6Independently D, F, Cl, Br, I, NO2、OH、CN、N3、C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C3-12Cycloalkyl, heterocyclic group consisting of 3 to 12 atoms, C6-10Aryl, 5-12-membered heteroaryl, - (CR)10R10a)qORc、-(CR10R10a)qNRaRb、-(CR10R10a)qS(＝O)tRc、-(CR10R10a)qS(＝O)2NRaRb、-(CR10R10a)qC(＝O)Rc、-(CR10R10a)qOC(＝O)Rc、-(CR10R10a)qC(＝O)ORc、-(CR10R10a)qN(Ra)C(＝O)Rc、-C(＝NRc)NRaRb、-N(Rc)C(＝O)NRaRb、-(CR10R10a)qN(Ra)S(＝O)tRcOr- (CR)10R10a)qC(＝O)NRaRbWherein each R is5And R6Independently optionally substituted by 1,2,3,4 or 5R9Substituted by a group;
R7is C3-12Cycloalkyl, 3-12 atomsHeterocyclic group, C6-12Aryl, 5-12-membered heteroaryl, - (C)1-4Alkylene group) - (C3-12Cycloalkyl) or- (C)1-4Alkylene) - (heterocyclic group consisting of 3-12 atoms) wherein R7Optionally substituted by 1,2,3,4 or 5R9Substituted by a group;
R8is H, F, Cl, Br, CN, C1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, C1-12Haloalkyl, C1-12Alkoxy radical, C3-12Cycloalkyl, heterocyclic group consisting of 3 to 12 atoms, - (C)1-4Alkylene group) - (C3-12Cycloalkyl) or- (C)1-4Alkylene) - (heterocyclic group consisting of 3-12 atoms) wherein R8Optionally substituted by 1,2,3,4 or 5R9Substituted by a group;
each R9Independently D, F, Cl, Br, I, CN, NO2、N3、NH2、OH、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Haloalkyl, C1-6Haloalkoxy or C1-6A haloalkylamino group;
each Ra、RbAnd RcIndependently H, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl, - (C)1-2Alkylene group) - (C3-6Cycloalkyl), 3-8 heterocyclic radical and- (C)1-2Alkylene) - (heterocyclic group consisting of 3-6 atoms), phenyl, - (C)1-2Alkylene group) - (C6-10Aryl), heteroaryl of 5 to 10 atoms or- (C)1-4Alkylene) - (heteroaryl of 5-10 atoms), or RaAnd RbAnd together with the nitrogen atom to which they are attached, form a heterocyclic group of 3 to 8 atoms in which each R isa、RbAnd RcIndependently optionally substituted by 1,2,3,4 or 5 groups independently selected from D, F, Cl, CN, N3、OH、NH2、C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy or C1-6Substituted with a substituent of alkylamino;
each m, n, p and q is independently 0, 1,2,3 or 4; and
each t is independently 1 or 2.
In another embodiment, R1Is C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-6Cycloalkyl, phenyl or heteroaryl of 5 to 6 atoms, wherein R1Optionally substituted by 1,2,3,4 or 5R9Substituted by a group.
In another embodiment, R2Is H, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C3-6Cycloalkyl or C3-6Heterocyclic group, wherein R2Optionally substituted by 1,2 or 3R9Substituted by a group.
In another embodiment, R3、R3a、R4、R4a、R10And R10aAre respectively and independently H, D, F, Cl, Br, I, CN, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkoxy or C1-4Alkylamino, or R3、R3aTogether with the carbon atom to which they are attached form C3-6Cycloalkyl or heterocyclyl of 3 to 8 atoms, wherein R3、R3a、R4、R4a、R10And R10aEach independently optionally substituted by 1,2,3,4 or 5R9Substituted by a group.
In another embodiment, each R is5And R6Are respectively and independently D, F, Cl, Br, I, NO2、OH、CN、N3、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, phenyl, heteroaryl consisting of 5 to 6 atoms, - (CR)10R10a)qORc、-(CR10R10a)qNRaRb、-(CR10R10a)qS(＝O)tRc、-(CR10R10a)qS(＝O)2NRaRb、-(CR10R10a)qC(＝O)Rc、-(CR10R10a)qOC(＝O)Rc、-(CR10R10a)qC(＝O)ORc、-(CR10R10a)qN(Ra)C(＝O)RcOr- (CR)10R10a)qC(＝O)NRaRbWherein each R is5And R6Independently optionally substituted by 1,2,3,4 or 5R9Substituted by a group.
In another embodiment, R7Is C3-6Cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, phenyl, heteroaryl consisting of 5 to 10 atoms, - (C)1-2Alkylene group) - (C3-6Cycloalkyl) or- (C)1-2Alkylene) - (heterocyclic group consisting of 3-8 atoms) wherein R7Optionally substituted by 1,2,3,4 or 5R9Substituted by a group.
In another embodiment, R8Is H, F, Cl, Br, CN, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C3-6Cycloalkyl, 3-6 member heterocyclyl, - (C)1-2Alkylene group) - (C3-6Cycloalkyl) or- (C)1-2Alkylene) - (heterocyclic group consisting of 3-6 atoms) wherein R8Optionally substituted by 1,2,3,4 or 5R9Substituted by a group.
In another embodiment, each R is9Independently D, F, Cl, Br, I, CN, NO2、N3、NH2、OH、C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino or C1-4A haloalkyl group.
In another embodiment, each R isa、RbAnd RcIndependently H, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, heterocyclyl or phenyl of 3 to 6 atoms, or Ra、RbAnd the nitrogen atom to which they are attached, together form a heterocyclic group of 3 to 6 atoms, wherein each R isa、RbAnd RcIndependently optionally substituted by 1,2,3 or 4 groups independently selected from D, F, Cl, CN, N3、OH、NH2、C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy or C1-4Substituted by a substituent of alkylamino.
In another embodiment, R7Is piperazinyl, piperidinyl, morpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiomorpholinyl, dioxanyl, dithianyl or thiaxanyl, wherein R is7Optionally substituted by 1,2 or 3R9Substituted by a group.
In another embodiment, each R isa、RbAnd RcIndependently H, -CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH2CH2CH3、-CH(CH3)CH2CH3or-C (CH)3)3Wherein each R isa、RbAnd RcIndependently optionally substituted by 1,2,3 or 4 groups independently selected from D, F, Cl, CN, N3、OH、NH2、C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy or C1-4Substituted by a substituent of alkylamino.
In another embodiment, the present invention relates to a compound, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, of one of the following, but in no way limited to these compounds:
stereoisomers, tautomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of formula (I) are included within the scope of the present invention unless otherwise indicated.
In another aspect, the 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, vehicle or combination thereof.
In another embodiment, the pharmaceutical composition of the present invention further comprises other drugs for treating central nervous system dysfunction, wherein the other drugs for treating central nervous system dysfunction are sedative-hypnotic drugs, antipsychotic drugs, antiepileptic drugs, antidepressant drugs, antihistamine drugs, anti-Parkinson's disease drugs, GABA receptor agonists and/or GABA reuptake inhibitor drugs, drugs as iron ion channel blockers, drugs as monoamine oxidase inhibitors, adenosine A1/A2A drug that is a receptor agonist, a drug that is a melatonin receptor agonist, or any combination thereof.
In another embodiment, the additional agent for the treatment of central nervous system dysfunction is midazolam (midrazolam), triazolam (triazolam), alprazolam (alprazolam), estazolam (estazolam), diazepam (diazepam), flurazepam (flurazepam), nitrazepam (nitrazpam), clonazepam (clonazepam), temazepam (temazepam), flunitrazepam (flunitrazepam), oxazepam (oxazepam), zolpidem (zolpidem), zaleplon (zaleplon), zopiclone (zopiclone), eszopiclone (eszopiclone), indolon (tiagabine), gavage (gaboxadol), clopramine (doxolone), doxazone (chlorpromazine), chlorpromazine (chlorpromazine), doxazone (chlorpromazine), doxepin (chlorpromazine), doxepine), doxine (chlorpromazine), clopramine (doxine), clopramine (doxine), clopramine (doxine, aspirin (aspirin), diphenhydramine (diphenhydramine), chlorpheniramine (chlorphenamine), brotizolam (lentirmin), ramelteon (ramelteon), tesmeitong (tasimelteon), agomelatine (agomelatine), mianserin (mianserine), amitriptyline (amitriptyline), desipramine (desiprame), mirtazapine (mirtazapine), fluoxetine (fluxetine), trazodone (trazodone), duloxetine (duloxetine), fluvoxamine (fluvoxamine), vilazone (vilazodone), dapoxetine (dapoxetine), famoxadine (femoxetine), clomipramine (clomipramine), citalopram (citalopram), escitalopram (escitalopram), paroxetine (parooxetine), quetiapine (quetiapine), clozapine (clozapine), imipramine (imipramine), cannabirone (nabilone), doxepin (doxepin), gabapentin (gabapentin), pramipexole (pramipexole), melatonin (circadin), chlordiazepoxide (chloridizempoxide), perphenazine (perphenazine), suvorexant, Xuezang Guben or any combination thereof.
In another aspect, the invention relates to the use of a compound or composition disclosed herein for the preparation of a medicament for the prevention, treatment or alleviation of central nervous system dysfunction in a mammal, including a human.
In one embodiment, the central nervous system disorder is sleep disorder, stress response, depression, anxiety disorder, seasonal affective disorder, insomnia and fatigue due to jet lag, schizophrenia, convulsion, panic attack, melancholia, insomnia, psychotic disorder, epilepsy, parkinson's disease, senile dementia, various disorders associated with normal or pathological aging, migraine, memory loss or alzheimer's disease.
In another aspect, the invention relates to the use of a compound or composition disclosed herein for the preparation of a medicament for selectively agonizing a melatonin receptor in a biological specimen.
In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds encompassed by formula (I).
Biological test results show that the compound provided by the invention can be used as a better melatonin receptor agonist.
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
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 "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.
"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.
"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.
"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.
"diastereomer" refers to a stereoisomer that has two or more chiral neutrals and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hilldictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; andEliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.
Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.
Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
Depending on the choice of starting materials and processes, the compounds of the invention may exist in the form of one of the possible isomers or mixtures thereof, for example, the racemic and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.
Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
The 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. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemases and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2)nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tablesof Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of NotreDame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A PracticalApproach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (lowenergy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
"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 compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention.
In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, a substituted group may have one substituent substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently.
The term "unsubstituted" means that the specified group bears no substituents.
The term "optionally substituted with … …", is used interchangeably with the term "unsubstituted or substituted with …", i.e., the structure is unsubstitutedOr substituted with one or more substituents described herein, including, but not limited to, D, F, Cl, Br, I, N3、CN、NO2、OH、SH、NH2Alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like.
In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.
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 "C1-6Alkyl "means in particular independently disclosed methyl, ethyl, C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group.
In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)3) Ethyl group (Et, -CH)2CH3) N-propyl (n-Pr, -CH)2CH2CH3) Isopropyl group (i-Pr, -CH (CH)3)2) N-butyl (n-Bu, -CH)2CH2CH2CH3) Isobutyl (i-Bu, -CH)2CH(CH3)2) Sec-butyl (s-Bu, -CH (CH)3)CH2CH3) Tert-butyl (t-Bu, -C (CH)3)3) N-pentyl (-CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH)3)CH2CH2CH3) 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) N-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH))3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2)2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2) 3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)3) N-heptyl, n-octyl, and the like.
The term "alkylene" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon radical. Unless otherwise specified, the alkylene group contains 1 to 12 carbon atoms. In one embodiment, the alkylene group contains 1 to 6 carbon atoms; in another embodiment, the alkylene group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 3 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 2 carbon atoms. Examples of this include methylene (-CH)2-, ethylene (-CH)2CH2-, isopropylidene (-CH (CH)3)CH2-) and the like.
The 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 "tans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)2) Allyl (-CH)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 2-8 carbon atoms; in another embodiment, alkynyl groups contain 2-6 carbon atoms; in yet another embodiment of the present invention,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) 1-pentyloxy (n-pentyloxy, -OCH)2CH2CH2CH2CH3) 2-pentyloxy (-OCH (CH)3)CH2CH2CH3) 3-pentyloxy (-OCH (CH))2CH3)2) 2-methyl-2-butoxy (-OC (CH))3)2CH2CH3) 3-methyl-2-butoxy (-OCH (CH)3)CH(CH3)2) 3-methyl-l-butoxy (-OCH)2CH2CH(CH3)2) 2-methyl-l-butoxy (-OCH)2CH(CH3)CH2CH3) And so on.
The terms "haloalkyl", "haloalkenyl" or "haloalkoxy" denote alkyl, alkenyl or alkoxy groups substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, 2,3, 3-tetrafluoropropyl, trifluoromethoxy, and 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 12 carbon atoms; in another embodiment, cycloalkyl groups contain from 7 to 12 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein.
The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic, or tricyclic ring containing 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. 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, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepanyl, thiazepinyl, thiazepanyl, homopiperazinyl, homopiperidinyl, oxazepanyl, and the likeRadical, diazaRadical, S-N-azaRadicals, indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1, 3-benzodioxolyl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl. In heterocyclic radicals of-CH2Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl and pyrimidinedione. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group, 1-dioxothiomorpholinyl group. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.
In one embodiment, heterocyclyl is a 3-8 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 3-8 ring atoms in which at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 3 to 8 atoms may be carbon-based 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 heterocyclic groups consisting of 3 to 8 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxacycloheptanyl, oxazepanyl, thiazepanyl, thiazepanRadical, diazaRadical, S-N-azaAnd (4) a base. In heterocyclic radicals of-CH2Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl and pyrimidinedione. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group, 1-dioxothiomorpholinyl group. Said heterocyclyl group of 3 to 8 atoms may be optionally substituted by one or more substituents as described herein.
In one embodiment, heterocyclyl is a 3-6 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 3-6 ring atoms in which at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 3 to 6 atoms may be carbon-based 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. Said heterocyclyl group of 3 to 6 atoms may be optionally substituted by one or more substituents as described herein.
In another embodiment, heterocyclyl is a 5-6 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 5-6 ring atoms in which at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 5 to 6 atoms may be carbon-based 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 heterocyclic groups consisting of 5 to 6 atoms include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinylPyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxocyclopentyl, dithiocyclopentyl, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, sulfolane, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, 2-piperidonyl, 3, 5-dioxopiperidinyl and pyrimidinedionyl, 1-dioxothiomorpholinyl. Said heterocyclyl group of 5 to 6 atoms may be optionally substituted by one or more substituents as described herein.
The terms "fused bicyclic ring," "fused bicyclic group," and "fused ring group" are used interchangeably herein and all refer to monovalent or multivalent saturated or partially unsaturated fused ring systems, which refer to non-aromatic bicyclic ring systems. Such systems may contain independent or conjugated unsaturated systems, but the core structure does not contain aromatic or heteroaromatic rings (although aromatic groups may be substituted thereon).
The terms "spirocyclic", "spiro", "spirobicyclic" or "spirobicyclic" are used interchangeably herein to refer to a monovalent or multivalent saturated or partially unsaturated ring system in which one ring is derived from a specific ring carbon atom on another ring. For example, as described below, one saturated fused ring system (rings B and B') is referred to as a "fused bicyclic ring", while ring a and ring B share a carbon atom in two saturated ring systems, referred to as a "spiro ring" or a "spirobicyclic ring". Each ring in the fused bicyclic and spirobicyclic groups may be a carbocyclic or heterocyclic group, and each ring is optionally substituted with one or more substituents described herein.
The term "heterocycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, or oxygen atoms.
The term "n-atomic" where n is an integer typically describes the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is n. For example, piperidinyl is a heterocycloalkyl group of 6 atoms, while 1,2,3, 4-tetrahydronaphthalene is a cycloalkyl group of 10 atoms.
The term "unsaturated" as used herein means that the group contains one or more unsaturations.
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 "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
The term "azido" or "N3"represents an azide structure. Such groups may be linked to other groups, e.g. to a methyl group to form azidomethane (Men)3) Or linked to a phenyl group to form azidobenzene (PhN)3)。
The term "aryl" denotes a monocyclic, bicyclic and tricyclic carbon ring system containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring is aromatic, wherein each ring comprises 3 to 7 atoms in the ring and has one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include phenyl, naphthyl and anthracenyl. The aryl group may independently 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, wherein at least one ring is aromatic and at least one aromatic ring contains one or more heteroatoms, wherein each ring contains a ring of 5 to 7 atoms with one or more attachment points to the rest of the molecule. 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, a heteroaryl group of 5-10 atoms contains 1,2,3, or 4 heteroatoms independently selected from O, S, and N.
Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 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; 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 "alkylamino" includes "N-alkylamino" and "N, N-dialkylaminoAnd (iv) a group "wherein the amino groups are each independently substituted with one or two alkyl groups. In some of these embodiments, the alkylamino group is one or two C1-6Lower alkylamino groups in which the alkyl group is attached to the nitrogen atom. In other embodiments, the alkylamino group is C1-3Lower alkylamino groups of (a). 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 term "aminoalkyl" includes C substituted with one or more amino groups1-10A straight or branched alkyl group. In some of these embodiments, aminoalkyl is C substituted with one or more amino groups1-6"lower aminoalkyl" and other examples are aminoalkyl which is C substituted with one or more amino groups1-4Examples of "lower aminoalkyl" radicals include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.
As described herein, a ring system formed by a substituent on a ring having a bond to the center (as shown below) represents that the substituent may be substituted at any substitutable position on the ring. For example, formula B represents any possible substituted position on the B ring as shown in formulas c, d, e, f, g, h, i.
The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)1-C24) Esters, acyloxymethyl esters, carbonates, ammoniaCarbamates 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: T.Higuchi and V.Stella, Pro-drugs as Novel delivery systems, Vol.14of the A.C.S.Symphosium Series, Edward B.Roche, ed., Bioredeployers in Drug designs, American Pharmaceutical Association and PergammonPress, 1987, J.Rautio et al, Prodrug: Design and Clinical Applications, Nature review delivery, 2008,7,255 and 270, S.J.Hecker et al, Prodrugs of pharmaceuticals and phosphates, Journal of chemical Chemistry,2008,51,2328 and 2345.
"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 such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, etc. formed by reaction with amino groupsAcid salts, or they can be obtained by other methods described in the literature, for example by 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, lauryl sulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained by reaction with a suitable base include alkali metals, alkaline earth metals, ammonium and N+(C1-C4Alkyl radical)4A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8Sulfonates 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, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.
When the solvent is water, the term "hydrate" may be used. In some embodiments, a molecule of a compound of the present invention may be associated with a molecule of water, such as a monohydrate; in other embodiments, 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 still other embodiments, 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.
Pharmaceutical compositions, formulations and administration of the compounds of the invention
The present invention provides a pharmaceutical composition comprising a compound disclosed herein, or a compound listed in table 1; and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof. The amount of compound in the pharmaceutical compositions disclosed herein is that amount which is effective to detect agonism of the receptor in the biological sample or patient.
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.
Coloring and flavoring agents may be used in all of the above dosage forms.
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 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.
Use of the Compounds and compositions of the invention
The present invention provides medicaments for treating, preventing, or alleviating central nervous system dysfunction in mammals, including humans, using the disclosed compounds and pharmaceutical compositions, and may also be used in the preparation of medicaments for agonizing melatonin receptors.
In particular, the amount of the compound in the composition of the present invention is effective to detectably and selectively agonize melatonin receptors, and the compound of the present invention may be useful as a drug for treating Central Nervous System (CNS) dysfunction such as sleep disorders, stress, seasonal affective disorder, insomnia and fatigue due to jet lag, insomnia, depression, anxiety, psychotic disorders, epilepsy, parkinson's disease, senile dementia, various disorders associated with normal or pathological aging, migraine, memory loss or alzheimer's disease 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 diseases in mammals, including humans, by administering to a patient an effective amount of a compound or composition of the present invention. The human central nervous system dysfunctional diseases further include, but are not limited to, sleep disorders, stress reactions, depression, anxiety disorders, seasonal affective disorders, insomnia and fatigue due to jet lag, schizophrenia, convulsions, panic attacks, melancholia, insomnia, psychotic disorders, epilepsy, Parkinson's disease, senile dementia, various disorders associated with normal or pathological aging, migraine, memory loss or Alzheimer's disease, etc.
In addition to being beneficial for human therapy, the compounds and pharmaceutical compositions of the present invention may also find application in veterinary therapy for pets, animals of the introduced species and mammals in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.
General 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. 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 0.6 mL/min. mobile phase: 5% -95% ((CH with 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:
CD3OD deuterated methanol
CDC13Deuterated chloroform
DMF N, N-dimethylformamide
DMSO-d6Deuterated dimethyl sulfoxide
g
h hours
mL, mL
RT, RT, r.t. Room temperature
Typical synthetic procedures for preparing the disclosed compounds of the present invention are shown in synthetic schemes 1 and 2 below. Each W, R unless otherwise stated3、R3a、R5、RcAnd m has the definition as described in the present invention.
Synthesis scheme 1:
has the formula (A)5) And the formula (A)6) The disclosed compounds of the present invention of the structure shown can be prepared by the general synthetic methods described in scheme 1, with reference to the examples for specific procedures. In FIG. 1, heteroaryl Compounds: (1) With acetic anhydride in the presence of a base such as triethylamine to give an amide compound (2). Amide compounds (a)2) With sulfuryl chloride (C) in DMF as solvent under the action of alkali such as sodium hydride3) Reaction to give a sulfonamide compound (4). Compound (A) to (B)4) Removal of trichloroacetyl groups under the action of a base, such as potassium hydroxide, to give compounds which are agonists of melatonin receptors (5) Compound (A) to (B)5) Further reacting with formaldehyde to obtain another compound which can be used as melatonin receptor agonist (6)。
Synthesis scheme 2:
has the formula (A)13) And the formula (A)14) The disclosed compounds of the present invention of the structure shown can be prepared by the general synthetic methods described in FIG. 2The concrete steps can be obtained by referring to the examples. In FIG. 2, heteroaryl Compounds: (7) With Boc in the presence of a base, e.g. triethylamine2O reaction to obtain the compound (A)8). Compound (A) to (B)8) With an alkylating agent, such as 1, 2-dibromoethane or methyl iodide, in the presence of a base to give a compound (A)9). Compound (A) to (B)9) Sequentially reducing with borane-tetrahydrofuran, and reacting with acetic anhydride under alkaline condition to obtain amide compound10). Compound (A) to (B)10) Heating in water to remove the protecting group to obtain a compound (A)11). Compound (A) to (B)11) With sulfonyl chlorides (c)3) Under the action of alkali, the sulphonamide is obtained through sulphonylation reaction12). Compound (A) to (B)12) Removal of trichloroacetyl groups by the action of a base, e.g. potassium hydroxide, to give compounds which are agonists of melatonin receptors (13) Compound (A) to (B)13) Can further react with formaldehyde to obtain another compound which can be used as a melatonin receptor agonist (14). The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in connection with the examples.
Examples
Example 1N- (2- (5-methoxy-1- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole- 3-yl) ethyl) acetamide
Step 1) N- (2- (5-methoxy-1H-indol-3-yl) ethyl) acetamide
2- (5-methoxy-1H-indol-3-yl) ethylamine hydrochloride (454mg,2.00mmol) and triethylamine (0.56mL,4.00mmol) were added to dichloromethane (10mL), acetic anhydride (0.19mL,2.00mmol) was slowly added dropwise at 0 deg.C, and after addition, the reaction was transferred to 25 deg.C for 3 hours. To the resulting reaction mixture was added dichloromethane (60mL), followed by washing with saturated aqueous sodium bicarbonate solution (60mL), separating the organic phase, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying the resulting residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/5 to 1/10) to give the title compound as a white solid (419mg, 90%).
MS(ESI,pos.ion)m/z:233.2[M+H]+；
1H NMR(400MHz,DMSO-d6):δ10.65(s,1H),7.95(t,J＝5.3Hz,1H),7.22(d,J＝8.7Hz,1H),7.10(d,J＝2.0Hz,1H),7.02(d,J＝2.3Hz,1H),6.71(dd,J＝8.7,2.4Hz,1H),3.76(s,3H),3.30(dd,J＝13.4,7.2Hz,2H),2.77(t,J＝7.4Hz,2H),1.81(s,3H)。
Step 2)2,2, 2-trichloro-1- (4- (2-methoxyphenyl) piperazin-1-yl) acetyl
1- (2-methoxyphenyl) piperazine hydrochloride (1.0g,4.39mmol) and triethylamine (2.5mL,17.70mmol) were suspended in dichloromethane (15mL), trichloroacetyl chloride (1.0mL,8.96mmol) was slowly added dropwise at 0 ℃, after completion of the dropwise addition, the reaction mixture was transferred to 25 ℃ for 24 hours to stop the reaction, dichloromethane (50mL) was added to the resulting reaction mixture, washed with a saturated aqueous sodium bicarbonate solution (40mL), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give the title compound as a pale yellow solid (763mg, 52%).
MS(ESI,pos.ion)m/z:337.0[M+H]+；
1H NMR(400MHz,CDCl3):δ7.09-7.06(m,1H),6.96-6.91(m,3H),4.03(brs,4H),3.91(s,3H),3.18(t,J＝4.4Hz,4H)。
Step 3) 4-methoxy-3- (4- (2,2, 2-trichloroacetyl) piperazin-1-yl) benzene-1-sulfonyl chloride
2,2, 2-trichloro-1- (4- (2-methoxyphenyl) piperazin-1-yl) acetyl (550mg,1.63mmol) was dissolved in dichloromethane (5mL), and then the above solution was dropwise added to chlorosulfonic acid (3mL) at 0 ℃ and, after 1 hour of reaction, the reaction solution was poured into a mixture of ice water (30mL) and dichloromethane (50mL) and vigorously stirred. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (548mg, 78.5%).
MS(ESI,pos.ion)m/z:435.0[M+H]+；
1H NMR(400MHz,CDCl3):δ7.75(dd,J＝8.8,2.4Hz,1H),7.47(d,J＝2.4Hz,1H),7.01(d,J＝8.8Hz,1H),4.00(brs,7H),3.21(t,J＝4.8Hz,4H)。
Step 4) N- (2- (5-methoxy-1- ((4-methoxy-3- (4- (2,2, 2-trichloroacetyl) piperazin-1-yl) benzene Yl) sulfonyl) -1H-indol-3-yl) ethyl) acetamide
N- (2- (5-methoxy-1H-indol-3-yl) ethyl) acetamide (100mg,0.43mmol) and sodium hydride (60% in mineral oil, 17mg,0.43mmol) were added to DMF (6mL) at 0 deg.C, then 4-methoxy-3- (4- (2,2, 2-trichloroacetyl) piperazin-1-yl) benzene-1-sulfonyl chloride (225mg,0.52mmol) was slowly added to the system. After 10 minutes of reaction, the temperature was raised to 25 ℃ and the reaction was continued for 2 hours. Ethyl acetate (50mL) was added, followed by washing with a saturated aqueous solution of sodium chloride (30mL × 3), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/2) to give the title compound as a white solid (239mg, 88%).
MS(ESI,pos.ion)m/z:631.2[M+H]+；
1H NMR(400MHz,DMSO-d6):δ7.99(t,J＝5.7Hz,1H),7.79(d,J＝9.0Hz,1H),7.55(s,1H),7.55-7.51(m,1H),7.27(d,J＝2.3Hz,1H),7.07(t,J＝5.2Hz,2H),6.93(dd,J＝9.0,2.5Hz,1H),3.88(m,6H),3.77(s,4H),3.32-3.26(m,2H),3.04(m,4H),2.72(t,J＝6.9Hz,2H),1.77(s,3H)。
Step 5) N- (2- (5-methoxy-1- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole- 3-yl) ethyl) acetamide
N- (2- (5-methoxy-1- ((4-methoxy-3- (4- (2,2, 2-trichloroacetyl) piperazin-1-yl) phenyl) sulfonyl) -1H-indol-3-yl) ethyl) acetamide (0.2g,0.32mmol) was dissolved in tetrahydrofuran (20mL) at 25 ℃ and potassium hydroxide (50mg,0.94mmol, 1mmol/mL in water) was slowly added. After the reaction solution was stirred for 48 hours, methylene chloride (50mL) was added thereto, the organic phase was separated, washed with a saturated aqueous solution of sodium chloride (30mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol (v/v) ═ 30/1) to give the title compound as a white solid (129mg, 84%).
MS(ESI,pos.ion)m/z:487.2[M+H]+；
1H NMR(600MHz,DMSO-d6):δ8.00(t,J＝5.5Hz,1H),7.78(d,J＝9.0Hz,1H),7.56(s,1H),7.49(dd,J＝8.7,2.3Hz,1H),7.19(d,J＝2.2Hz,1H),7.09(d,J＝2.5Hz,1H),7.02(d,J＝8.8Hz,1H),6.94(dd,J＝9.0,2.5Hz,1H),3.78(s,3H),3.76(s,3H),3.31(dd,J＝12.9,7.0Hz,2H),2.83(s,4H),2.82(s,4H),2.74(t,J＝7.0Hz,2H),1.79(s,3H)；
13C NMR(150MHz,DMSO-d6):δ169.7,156.7,156.5,142.3,132.4,129.6,129.0,125.0,122.2,121.1,115.8,114.7,113.9,112.2,102.8,56.4,55.9,51.1,45.8,38.6,25.1,23.1。
Example 2N- (2- (5-methoxy-1- ((4-methoxy-3- (4-methylpiperazin-1-yl) phenyl) sulfonyl) - 1H-indol-3-yl) ethyl) acetamide
N- (2- (5-methoxy-1- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indol-3-yl) ethyl) acetamide (100mg,0.21mmol) was dissolved in methanol (15mL) at 25 ℃ and three drops of acetic acid were added. Sodium cyanoborohydride (32mg,0.51mmol) and formaldehyde (40% aqueous solution, 41. mu.L, 0.63mmol) were slowly added to the above reaction solution at 0 ℃. After 10 minutes of the reaction, the temperature was raised to 25 ℃ and stirring was continued, and after overnight, water (10mL) and sodium carbonate (74mg,0.7mmol) were added to the system, followed by extraction with methylene chloride (30 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (86mg, 84%).
MS(ESI,pos.ion)m/z:501.3[M+H]+；
1H NMR(600MHz,DMSO-d6):δ7.98(s,1H),7.78(d,J＝9.0Hz,1H),7.55(s,1H),7.49(dd,J＝8.6,2.0Hz,1H),7.20(d,J＝1.9Hz,1H),7.09(d,J＝2.1Hz,1H),7.03(d,J＝8.7Hz,1H),6.94(dd,J＝8.9,2.2Hz,1H),3.79(s,3H),3.76(s,3H),3.30(t,J＝6.6Hz,2H),2.91(s,4H),2.73(t,J＝6.8Hz,2H),2.42(s,4H),2.20(s,3H),1.78(s,3H)；
13C NMR(150MHz,DMSO-d6):δ169.6,156.6,156.5,141.8,132.4,129.6,129.0,124.9,122.2,121.0,115.8,114.7,113.9,112.2,102.8,56.4,55.9,55.0,49.9,46.2,38.5,25.1,23.1。
Example 3N- (2- (5-methoxy-1- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole- 3-yl) -2-methylpropyl) acetamide
Step 1) tert-butyl 3- (cyanomethyl) -5-methoxy-1H-indole-1-carboxylate
2- (5-methoxy-1H-indol-3-yl) acetonitrile (1g,5.37mmol) and 4-dimethylaminopyridine (catalytic amount) were dissolved in dichloromethane (10 mL). Di-tert-butyl dicarbonate (1.5mL,6.44mmol) was slowly added to the above reaction mixture at 25 ℃ and, after the addition was completed, the resulting reaction system was stirred at room temperature for 5 hours. The resulting reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a white solid (1.48g, 96%).
MS(ESI,pos.ion)m/z:287.3[M+H]+；
1H NMR(400MHz,CDCl3):δ8.04(d,J＝8.2Hz,1H),7.60(s,1H),6.98(dd,J＝9.0,2.4Hz,1H),6.93(d,J＝2.4Hz,1H),3.87(s,3H),3.73(d,J＝1.1Hz,2H),1.66(s,9H)。
Step 2) tert-butyl 3- (2-cyanopropan-2-yl) -5-methoxy-1H-indole-1-carboxylate
Tert-butyl 3- (cyanomethyl) -5-methoxy-1H-indole-1-carboxylate (1.72g,5.99mmol) and sodium hydride (60% in mineral oil, 431mg,10.78mmol) were added to DMF (20mL) at 0 deg.C followed by slow addition of methyl iodide (1.87mL,29.97 mmol). After 10 minutes of reaction, the temperature was raised to 25 ℃ and stirring was continued for 12 hours. Ethyl acetate (80mL) was added, followed by water washing (50mL × 3), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 50/1) to give the title compound as a brown oily liquid (865mg, 46%).
MS(ESI,pos.ion)m/z:315.3[M+H]+；
1H NMR(400MHz,CDCl3):δ8.04(d,J＝8.6Hz,1H),7.48(s,1H),7.25(d,J＝2.4Hz,1H),6.98(dd,J＝9.1,2.5Hz,1H),3.89(s,3H),1.83(s,6H),1.67(s,9H)。
Step 3) tert-butyl 3- (1-amino-2-methylpropan-2-yl) -5-methoxy-1H-indole-1-carboxylate
Tert-butyl 3- (2-cyanopropan-2-yl) -5-methoxy-1H-indole-1-carboxylate (470mg,1.50mmol) was dissolved in tetrahydrofuran (10mL) under nitrogen, followed by slow addition of borane-tetrahydrofuran solution (3mL,3.00mmol) and the resulting reaction was warmed to 80 ℃ and stirred for 12 hours. Then, methanol (5mL) was added thereto, spin-dried under reduced pressure, and the resulting residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a brown oily liquid (362mg, 76%).
Step 4) tert-butyl 3- (1-acetylamino-2-methylpropan-2-yl) -5-methoxy-1H-indole-1-carboxylate
The title compound was prepared as described in example 1, step 1 by reacting tert-butyl 3- (1-amino-2-methylpropan-2-yl) -5-methoxy-1H-indole-1-carboxylate (362mg,1.14mmol), triethylamine (303 μ L,2.27mmol) and acetic anhydride (130 μ L,1.36mmol) in dichloromethane (10mL) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/5) to give the title compound as a white solid (385mg, 94%).
MS(ESI,pos.ion)m/z:361.3[M+H]+；
1H NMR(600MHz,CDCl3):δ8.05(s,1H),7.35(s,1H),7.17(d,J＝2.4Hz,1H),6.94(dd,J＝9.1,2.3Hz,1H),3.86(s,3H),3.64(d,J＝5.9Hz,2H),1.90(s,3H),1.67(s,9H),1.40(s,6H)。
Step 5) N- (2- (5-methoxy-1H-indol-3-yl) -2-methylpropyl) acetamide
Tert-butyl 3- (1-acetylamino-2-methylpropan-2-yl) -5-methoxy-1H-indole-1-carboxylate (385mg,1.07mmol) was added to water (10mL), the reaction was warmed to 100 ℃ and stirred under reflux for 12 hours. Then, dichloromethane (40mL) was added to the above reaction mixture, and washed with a saturated aqueous solution of sodium chloride (30mL × 2), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 30/1) to give the title compound as a white solid (250mg, 90%).
MS(ESI,pos.ion)m/z:261.3[M+H]+；
1H NMR(600MHz,DMSO-d6):δ10.65(s,1H),7.63(t,J＝6.0Hz,1H),7.24(d,J＝8.7Hz,1H),7.21(d,J＝2.1Hz,1H),7.02(d,J＝2.4Hz,1H),6.72(dd,J＝8.7,2.2Hz,1H),3.76(s,3H),3.40(d,J＝6.2Hz,2H),1.83(s,3H),1.30(s,6H)。
Step 6) N- (2- (5-methoxy-1- ((4-methoxy-3- (4- (2,2, 2-trichloroacetyl) piperazin-1-yl) benzene Yl) sulfonyl) -1H-indol-3-yl) -2-methylpropyl) acetamide
The title compound was prepared as described in example 1, step 4 by reacting N- (2- (5-methoxy-1H-indol-3-yl) -2-methylpropyl) acetamide (122mg,0.47mmol), sodium hydride (60% mixed in mineral oil, 18mg,0.47mmol) and 4-methoxy-3- (4- (2,2, 2-trichloroacetyl) piperazin-1-yl) benzene-1-sulfonyl chloride (245mg,0.56mmol) in DMF (10mL) and purifying the crude by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a white solid (241mg, 78%).
MS(ESI,pos.ion)m/z:659.2[M+H]+；
1H NMR(600MHz,DMSO-d6):δ7.79(t,J＝9.1Hz,1H),7.77(t,J＝6.3Hz,1H),7.58(dd,J＝8.7,2.2Hz,1H),7.42(s,1H),7.25(t,J＝3.0Hz,2H),7.08(d,J＝8.8Hz,1H),6.94(dd,J＝9.1,2.3Hz,1H),3.96–3.76(m,10H),3.34(d,J＝3.9Hz,2H),3.03(s,4H),1.80(s,3H),1.28(s,6H)。
Step 7) N- (2- (5-methoxy-1- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole- 3-yl) -2-methylpropyl) acetamide
The title compound was prepared as described in example 1, step 5 by reacting N- (2- (5-methoxy-1- ((4-methoxy-3- (4- (2,2, 2-trichloroacetyl) piperazin-1-yl) phenyl) sulfonyl) -1H-indol-3-yl) -2-methylpropyl) acetamide (445mg,0.67mmol), potassium hydroxide (113mg,2.02mmol, 1mmol/mL aq.) in tetrahydrofuran (20mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (229mg, 66%).
MS(ESI,pos.ion)m/z:515.3[M+H]+；
1H NMR(600MHz,DMSO-d6):δ7.79-7.78(m,2H),7.53(dd,J＝8.7,2.4Hz,1H),7.42(s,1H),7.26(d,J＝2.4Hz,1H),7.15(d,J＝2.4Hz,1H),7.03(d,J＝8.8Hz,1H),6.94(dd,J＝9.1,2.4Hz,1H),3.79(s,3H),3.77(s,3H),3.38(d,J＝6.3Hz,2H),2.81-2.78(dd,J＝14.6,4.1Hz,8H),1.81(s,3H),1.28(s,6H)；
13C NMR(151MHz,DMSO):δ170.1,156.7,155.9,142.5,130.5,130.5,129.7,128.8,124.1,122.2,115.7,114.8,113.1,112.0,105.3,56.4,55.9,51.5,47.8,46.0,36.5,26.0,23.0。
Example 4N- (2- (5-methoxy-1- ((4-methoxy-3- (4-methylpiperazin-1-yl) phenyl) sulfonyl) - 1H-indol-3-yl) -2-methylpropyl) acetamide
The title compound of this step was prepared by the method described in example 2 by reacting N- (2- (5-methoxy-1- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indol-3-yl) -2-methylpropyl) acetamide (120mg,0.23mmol), three drops of acetic acid, sodium cyanoborohydride (37mg,0.58mmol) and formaldehyde (40% in water, 53 μ L,0.70mmol) in methanol (15 mL). The resulting reaction mixture was basified with sodium carbonate (106mg,0.8mmol), extracted with dichloromethane (30mL × 3), the organic phase was dried over anhydrous sodium sulfate after washing with water, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (111mg, 90%).
MS(ESI,pos.ion)m/z:515.0[M+H]+；
1H NMR(600MHz,DMSO-d6):δ7.78(d,J＝9.1Hz,2H),7.52(dd,J＝8.6,1.9Hz,1H),7.41(s,1H),7.26(s,1H),7.16(s,1H),7.03(d,J＝8.7Hz,1H),6.93(dd,J＝9.0,2.0Hz,1H),3.79(s,3H),3.76(s,3H),3.37(d,J＝6.2Hz,2H),2.90(s,4H),2.40(s,4H),2.19(s,3H),1.80(s,3H),1.28(s,6H)；
13C NMR(150MHz,DMSO-d6):δ170.1,156.6,155.9,141.9,130.5,130.5,129.7,128.8,124.1,122.4,115.7,114.8,113.1,112.1,105.4,56.4,55.9,55.0,50.0,47.8,46.2,36.5,26.0,23.0。
Example 5N- ((1- (5-methoxy-1- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole Indol-3-yl) cyclopropyl) methyl) acetamide
Step 1) tert-butyl 3- (1-cyanocyclopropyl) -5-methoxy-1H-indole-1-carboxylate
Tert-butyl 3- (cyanomethyl) -5-methoxy-1H-indole-1-carboxylate (864mg,3.02mmol) and sodium hydride (60% in mineral oil, 217mg,5.43mmol) were added to DMSO (20mL) at 0 deg.C, then 1, 2-dibromoethane (0.29mL,3.32mmol) was added slowly to the system, and after stirring for 10 min, the temperature was raised to 25 deg.C and stirring was continued for 3H. To the resulting reaction mixture was added ethyl acetate (80mL), followed by washing with water (50mL × 3), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 50/1) to give the title compound as a brown oily liquid (302mg, 32%).
MS(ESI,pos.ion)m/z:313.1[M+H]+；
1H NMR(400MHz,CDCl3):δ8.03(d,J＝7.9Hz,1H),7.48(s,1H),7.25(d,J＝2.4Hz,1H),7.01(dd,J＝9.1,2.5Hz,1H),3.93(s,3H),1.68(s,9H),1.40-1.35(m,2H),1.31-1.28(m,2H)。
Step 2) tert-butyl 3- (1- (aminomethyl) cyclopropyl) -5-methoxy-1H-indole-1-carboxylate
Prepared as described in example 3, step 3 by reacting tert-butyl 3- (1-cyanocyclopropyl) -5-methoxy-1H-indole-1-carboxylate (780mg,2.50mmol) with borane-tetrahydrofuran solution (1mmol/mL,5mL,5.00mmol) in tetrahydrofuran (10mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a brown oily liquid (569mg, 72%).
Step 3) tert-butyl 3- (1- (acetylaminomethyl) cyclopropyl) -5-methoxy-1H indole-1-carboxylate
The title compound was prepared as described in example 1, step 1 by reacting tert-butyl 3- (1- (aminomethyl) cyclopropyl) -5-methoxy-1H-indole-1-carboxylate (560mg,1.77mmol), triethylamine (471 μ L,3.54mmol) and acetic anhydride (201 μ L,2.12mmol) prepared above in dichloromethane (10mL) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/5) to give the title compound as a white solid (552mg, 87%).
MS(ESI,pos.ion)m/z:359.1[M+H]+；
1H NMR(600MHz,CDCl3):δ7.98(s,1H),7.41(s,1H),7.12(d,J＝2.2Hz,1H),6.94(dd,J＝9.0,2.3Hz,1H),3.87(s,3H),3.46(d,J＝4.9Hz,2H),1.93(s,3H),1.66(s,9H),0.92(t,J＝4.8Hz,2H),0.84(t,J＝4.6Hz,2H)。
Step 4) N- ((1- (5-methoxy-1H-indol-3-yl) cyclopropyl) methyl) acetamide
The title compound was prepared as described in example 3, step 4 by refluxing tert-butyl 3- (1- (acetamidomethyl) cyclopropyl) -5-methoxy-1H indole-1-carboxylate (445mg,1.24mmol) in water (10 mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 30/1) to give the title compound as a white solid (295mg, 92%).
MS(ESI,pos.ion)m/z:259.2[M+H]+；
1H NMR(600MHz,DMSO-d6):δ10.61(s,1H),7.77(t,J＝5.7Hz,1H),7.21(d,J＝8.7Hz,1H),7.11(t,J＝2.3Hz,2H),6.71(dd,J＝8.7,2.4Hz,1H),3.76(s,3H),3.30(d,J＝5.8Hz,2H),1.76(s,3H),0.79(q,J＝4.2Hz,2H),0.66(q,J＝4.2Hz,2H)。
Step 5) N- ((1- (5-methoxy-1- ((4-methoxy-3- (4- (2,2, 2-trichloroacetyl) piperazin-1-yl) Phenyl) sulfonyl) -1H-indol-3-yl) cyclopropyl) methyl) acetamide
The title compound was prepared as described in example 1, step 4 by reacting N- ((1- (5-methoxy-1H-indol-3-yl) cyclopropyl) methyl) acetamide (160mg,0.62mmol), sodium hydride (60% mixed in mineral oil, 25mg,0.62mmol) and 4-methoxy-3- (4- (2,2, 2-trichloroacetyl) piperazin-1-yl) benzene-1-sulfonyl chloride (324mg,0.74mmol) in DMF (10mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a white solid (245mg, 60%).
MS(ESI,pos.ion)m/z:657.1[M+H]+；
1H NMR(600MHz,DMSO-d6):δ7.83(t,J＝5.6Hz,1H),7.75(d,J＝9.0Hz,1H),7.58(s,1H),7.56(dd,J＝8.7,2.1Hz,1H),7.23(d,J＝1.9Hz,1H),7.14(d,J＝2.2Hz,1H),7.07(d,J＝8.8Hz,1H),6.92(dd,J＝9.0,2.3Hz,1H),3.82-3.77(m,10H),3.27-3.25(m,2H),3.03(s,4H),1.72(s,3H),0.83(s,2H),0.70(s,2H)。
Step 6) N- ((1- (5-methoxy-1- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole- 3-yl) cyclopropyl) methyl) acetamide
The title compound was prepared as described in example 1, step 5 by reacting N- ((1- (5-methoxy-1- ((4-methoxy-3- (4- (2,2, 2-trichloroacetyl) piperazin-1-yl) phenyl) sulfonyl) -1H-indol-3-yl) cyclopropyl) methyl) acetamide (235mg,0.36mmol), potassium hydroxide (60mg,1.07mmol, as a 1mmol/mL aqueous solution) in tetrahydrofuran (20mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (150mg, 82%).
MS(ESI,pos.ion)m/z:513.0[M+H]+；
1H NMR(600MHz,DMSO-d6):δ7.86(t,J＝5.7Hz,1H),7.75(d,J＝9.0Hz,1H),7.58(s,1H),7.51(dd,J＝8.7,2.2Hz,1H),7.15(t,J＝2.7Hz,2H),7.02(d,J＝8.8Hz,1H),6.93(dd,J＝9.0,2.5Hz,1H),3.79(s,3H),3.77(s,3H),3.27(d,J＝5.7Hz,2H),2.80(s,4H),2.79(s,4H),1.74(s,3H),0.84(t,J＝5.2Hz,2H),0.70(t,J＝5.2Hz,2H)；
13C NMR(150MHz,DMSO-d6):δ169.7,156.7,156.4,142.5,131.9,129.8,128.9,126.7,125.5,122.2,115.7,114.7,113.6,112.1,103.3,56.4,55.9,51.4,45.9,45.6,23.0,17.6,10.5。
Example 6N- ((1- (5-methoxy-1- ((4-methoxy-3- (4-methylpiperazin-1-yl) phenyl) sulfonyl) - 1H-indol-3-yl) cyclopropyl) methyl) acetamide
The title compound was prepared by the method described in example 2 by reacting N- ((1- (5-methoxy-1- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indol-3-yl) cyclopropyl) methyl) acetamide (100mg,0.20mmol), three drops of acetic acid, sodium cyanoborohydride (31mg,0.49mmol) and formaldehyde (40% in water, 40 μ L,0.59mmol) in methanol (15 mL). The reaction mixture was basified with sodium carbonate (74mg,0.7mmol), extracted with dichloromethane (30mL × 3), the washed organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (94mg, 92%).
MS(ESI,pos.ion)m/z:527.1[M+H]+；
1H NMR(600MHz,CDCl3):δ7.87(d,J＝9.0Hz,1H),7.48(dd,J＝8.6,2.0Hz,1H),7.38(s,1H),7.28(s,1H),7.07(d,J＝2.2Hz,1H),6.94(dd,J＝9.0,2.2Hz,1H),6.81(d,J＝8.7Hz,1H),3.86(s,3H),3.85(s,3H),3.42(d,J＝5.6Hz,2H),3.02(s,4H),2.58(s,4H),2.36(s,3H),1.91(s,3H),0.94(t,J＝4.9Hz,2H),0.78(t,J＝4.8Hz,2H)；
13C NMR(150MHz,CDCl3):δ170.0,156.4,156.4,141.7,131.4,130.2,129.7,125.9,124.3,122.2,116.2,114.8,113.7,110.7,102.5,55.9,55.7,54.9,50.0,46.6,45.9,23.3,17.6,10.8。
Example 7N- (2- (5-methoxy-1- ((3- (piperazin-1-yl) -4- (2,2,3, 3-tetrafluoropropoxy) phenyl) sulfone Acyl) -1H-indol-3-yl) ethyl) acetamide
Step 1) N- (2- (5-methoxy-1- ((4- (2,2,3, 3-tetrafluoropropoxy) -3- (4- (2,2, 2-trichloroacetyl) Yl) piperazin-1-yl) phenyl) sulphonylYl) -1H-indol-3-yl) ethyl) acetamide
The title compound was prepared as described in example 1, step 4, i.e., N- (2- (5-methoxy-1H-indol-3-yl) ethyl) acetamide (200mg,0.86mmol), sodium hydride (60% in mineral oil, 34mg,0.86mmol) and 4- (2,2,3, 3-tetrafluoropropoxy) -3- (4- (2,2, 2-trichloroacetyl) piperazin-1-yl) benzene-1-sulfonyl chloride (560mg,1.03mmol) in DMF (10 mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/2) to give the title compound as a white solid (422mg, 67%).
MS(ESI,pos.ion)m/z:731.2[M+H]+；
1H NMR(400MHz,DMSO-d6):δ7.98(t,J＝5.7Hz,1H),7.80(d,J＝9.0Hz,1H),7.57(s,1H),7.54(dd,J＝8.7,2.3Hz,1H),7.34(d,J＝2.3Hz,1H),7.19(d,J＝8.8Hz,1H),7.09(d,J＝2.4Hz,1H),6.94(dd,J＝9.0,2.5Hz, 1H),6.60(tt,J＝51.9,5.3Hz,1H),4.67(t,J＝13.1Hz,2H),3.76(m,7H),3.32-3.27(m,2H),3.05(s,4H),2.73(t,J＝7.0Hz,2H),1.78(s,3H)。
Step 2) N- (2- (5-methoxy-1- ((3- (piperazin-1-yl) -4- (2,2,3, 3-tetrafluoropropoxy) phenyl) sulfone Acyl) -1H-indol-3-yl) ethyl) acetamide
The title compound was prepared as described in example 1, step 5 by reacting N- (2- (5-methoxy-1- ((4- (2,2,3, 3-tetrafluoropropoxy) -3- (4- (2,2, 2-trichloroacetyl) piperazin-1-yl) phenyl) sulfonyl) -1H-indol-3-yl) ethyl) acetamide (424mg,0.58mmol), potassium hydroxide (100mg,1.74mmol, prepared as a 1mmol/mL aqueous solution) in tetrahydrofuran (20 mL). The crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (272mg, 80%).
MS(ESI,pos.ion)m/z:587.1[M+H]+；
1H NMR(600MHz,DMSO-d6):δ8.01(t,J＝5.3Hz,1H),7.80(d,J＝9.0Hz,1H),7.57(s,1H),7.49(dd,J＝8.6,1.6Hz,1H),7.25(s,1H),7.14(d,J＝8.7Hz,1H),7.09(d,J＝2.0Hz,1H),6.94(dd,J＝9.0,2.0Hz,1H),6.54(tt,J＝51.9,4.4Hz,1H),4.63(t,J＝13.3Hz,2H),3.76(s,3H),3.31(d,J＝6.2Hz,2H),2.85(s,4H),2.81(s,4H),2.74(t,J＝6.9Hz,2H),1.79(s,3H)；
13C NMR(150MHz,DMSO-d6):δ169.7,156.6,154.2,142.7,132.4,130.7,129.6,124.9,121.7,121.3,116.3,114.7,114.1,114.0,102.8,65.3(t,J＝27.5Hz),55.9,51.3,45.8,38.5,25.1,23.1。
Example 8N- (2- (5-methoxy-1- ((3- (4-methylpiperazin-1-yl) -4- (2,2,3, 3-tetrafluoropropoxy) Phenyl) sulfonyl) -1H-indol-3-yl) ethyl) acetamide
The title compound of this step was prepared by the method described in example 2 by reacting N- (2- (5-methoxy-1- ((3- (piperazin-1-yl) -4- (2,2,3, 3-tetrafluoropropoxy) phenyl) sulfonyl) -1H-indol-3-yl) ethyl) acetamide (320mg,0.55mmol), three drops of acetic acid, sodium cyanoborohydride (86mg,1.36mmol) and formaldehyde (40% in water, 113. mu.L, 1.65mmol) in methanol (15 mL). The reaction mixture was basified with sodium carbonate (204mg,1.9mmol), extracted with dichloromethane (30mL × 3), the washed organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (94mg, 92%).
MS(ESI,pos.ion)m/z:601.1[M+H]+；
1H NMR(400MHz,DMSO-d6):δ7.99(t,J＝5.3Hz,1H),7.81(d,J＝9.0Hz,1H),7.57(s,1H),7.50(d,J＝7.3Hz,1H),7.27(s,1H),7.15(d,J＝8.7Hz,1H),7.10(d,J＝1.5Hz,1H),6.95(d,J＝8.9Hz,1H),6.54(tt,J＝52.0,4.6Hz,1H),4.64(t,J＝13.3Hz,2H),3.77(s,3H),3.32(dd,J＝12.6,6.5Hz,2H),2.93(s,4H),2.75(t,J＝6.7Hz,2H),2.41(s,4H),2.19(s,3H),1.80(s,3H)；
13C NMR(100MHz,DMSO-d6):δ169.6,156.6,154.1,142.2,132.4,130.8,129.6,124.9,121.7,121.2,116.3,114.7,114.1,113.9,102.8,65.3(t,J＝27.5Hz),55.9,55.0,50.0,46.1,38.5,25.1,23.1。
Example 9N- (2- (5-methoxy-1- ((3- (piperazin-1-yl) -4- (2,2,3, 3-tetrafluoropropoxy) phenyl) sulfone Acyl) -1H-indol-3-yl) -2-methylpropyl) acetamide
Step 1) N- (2- (5-methoxy-1- ((4- (2,2,3, 3-tetrafluoropropoxy) -3- (4- (2,2, 2-trichloroacetyl) Yl) piperazin-1-yl) phenyl) sulfonyl) -1H-indol-3-yl) -2-methylpropyl) acetamide
The title compound was prepared by reacting N- (2- (5-methoxy-1H-indol-3-yl) -2-methylpropyl) acetamide (170mg,0.65mmol), sodium hydride (60% in mineral oil, 26mg,0.65mmol) and 4- (2,2,3, 3-tetrafluoropropoxy) -3- (4- (2,2, 2-trichloroacetyl) piperazin-1-yl) benzene-1-sulfonyl chloride (420mg,0.78mmol) in DMF (10mL) as described in step 4of example 1. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/2) to give the title compound as a white solid (447mg, 90%). MS (ESI, pos.ion) M/z 759.0[ M + H ]]+；
1H NMR(600MHz,DMSO-d6):δ7.80(d,J＝9.1Hz,1H),7.75(t,J＝6.2Hz,1H),7.58(dd,J＝8.7,2.2Hz,1H),7.43(s,1H),7.32(d,J＝2.2Hz,1H),7.25(d,J＝2.3Hz,1H),7.20(d,J＝8.8Hz,1H),6.93(dd,J＝9.1,2.3Hz,1H),6.60(tt,J＝51.7,4.9Hz,1H),4.68(t,J＝13.1Hz,2H),3.93-3.72(m,7H),3.37(d,J＝6.2Hz,2H),3.04(s,4H),1.79(s,3H),1.28(s,6H)。
Step 2) N- (2- (5-methoxy-1- ((3- (piperazin-1-yl) -4- (2,2,3, 3-tetrafluoropropoxy) phenyl) sulfone Acyl) -1H-indol-3-yl) -2-methylpropyl) acetamide
The title compound was prepared as described in example 1, step 5 by reacting N- (2- (5-methoxy-1- ((4- (2,2,3, 3-tetrafluoropropoxy) -3- (4- (2,2, 2-trichloroacetyl) piperazin-1-yl) phenyl) sulfonyl) -1H-indol-3-yl) -2-methylpropyl) acetamide (230mg,0.30mmol), potassium hydroxide (51mg,0.90mmol, prepared as a 1mmol/mL aqueous solution) in tetrahydrofuran (20 mL). The crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (151mg, 81%).
MS(ESI,pos.ion)m/z:615.2[M+H]+；
1H NMR(600MHz,DMSO-d6):δ7.81-7.78(m,2H),7.53(dd,J＝8.7,2.2Hz,1H),7.44(s,1H),7.27(d,J＝2.4Hz,1H),7.21(d,J＝2.2Hz,1H),7.15(d,J＝8.7Hz,1H),6.95(dd,J＝9.1,2.4Hz,1H),6.55(tt,J＝52.0,4.9Hz,1H),4.65(t,J＝13.3Hz,2H),3.78(s,3H),3.39(d,J＝6.2Hz,2H),2.83-2.82(m,4H),2.79-2.78(m,4H),1.81(s,3H),1.29(s,6H)；
13C NMR(100MHz,DMSO-d6):δ170.0,155.9,154.1,142.8,130.6,130.5,130.5,129.9,124.0,121.7,116.2,114.7,114.0,113.1,105.4,65.2(t,J＝28.0Hz),55.9,51.5,47.8,45.9,36.5,25.9,23.0。
Example 10N- (2- (5-methoxy-1- ((3- (4-methylpiperazin-1-yl) -4- (2,2,3, 3-tetrafluoropropoxy) Phenyl) sulfonyl) -1H-indol-3-yl) -2-methylpropyl) acetamide
The title compound of this step was prepared as described in example 2, i.e. N- (2- (5-methoxy-1- ((3- (piperazin-1-yl) -4- (2,2,3, 3-tetrafluoropropoxy) phenyl) sulfonyl) -1H-indol-3-yl) -2-methylpropyl) acetamide (100mg,0.16mmol), three drops of acetic acid, sodium cyanoborohydride (26mg,0.41mmol) and formaldehyde (40% in water, 37. mu.L, 0.48mmol) in methanol (15 mL). The reaction mixture was basified with sodium carbonate (59mg,0.56mmol), extracted with dichloromethane (30mL × 3), the washed organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (92mg, 90%).
MS(ESI,pos.ion)m/z:628.9[M+H]+；
1H NMR(600MHz,DMSO-d6):δ7.80-7.76(m,2H),7.53(dd,J＝8.6,2.1Hz,1H),7.43(s,1H),7.26(d,J＝2.1Hz,1H),7.23(d,J＝2.1Hz,1H),7.15(d,J＝8.7Hz,1H),6.94(dd,J＝9.0,2.2Hz,1H),6.53(tt,J＝52.0,4.4Hz,1H),4.64(t,J＝13.3Hz,2H),3.77(s,3H),3.38(d,J＝6.2Hz,2H),2.92(s,4H),2.40(s,4H),2.19(s,3H),1.80(s,3H),1.28(s,6H)；
13C NMR(150MHz,DMSO-d6):δ170.1,156.0,154.1,142.2,130.6,130.5,130.4,129.9,124.1,121.9,116.3,115.3(tt,J＝247.4,22.9Hz),114.8,113.9,113.2,109.8(tt,J＝246.7,33.8Hz),105.4,65.2(tt,J＝27.2Hz),55.9,55.0,50.1,47.8,46.1,36.6,26.0,23.0。
Example 11N- ((1- (5-methoxy-1- ((3- (piperazin-1-yl) -4- (2,2,3, 3-tetrafluoropropoxy) phenyl) Sulfonyl) -1H-indol-3-yl) cyclopropyl) methyl) acetamide
Step 1) N- ((1- (5-methoxy-1- ((4- (2,2,3, 3-tetrafluoropropoxy) -3- (4- (2,2, 2-trichloroacetyl) Yl) piperazin-1-yl) phenyl) sulfonyl) -1H-indol-3-yl) cyclopropyl) methyl) acetamide
The title compound was prepared by the method described in example 1, step 4, i.e. reacting N- ((1- (5-methoxy-1H-indol-3-yl) cyclopropyl) methyl) acetamide (133mg,0.51mmol), sodium hydride (60% in mineral oil, 21mg,0.51mmol) and 4- (2,2,3, 3-tetrafluoropropoxy) -3- (4- (2,2, 2-trichloroacetyl) piperazin-1-yl) benzene-1-sulfonyl chloride (331mg,0.62mmol) in DMF (10 mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/2) to give the title compound as a white solid (269mg, 69%).
MS(ESI,pos.ion)m/z:756.7[M+H]+；
1H NMR(600MHz,DMSO-d6):δ7.84(t,J＝5.7Hz,1H),7.76(d,J＝9.0Hz,1H),7.59(s,1H),7.57(dd,J＝8.7,2.1Hz,1H),7.30(d,J＝2.1Hz,1H),7.19(d,J＝8.8Hz,1H),7.14(d,J＝2.3Hz,1H),6.92(dd,J＝9.0,2.4Hz,1H),6.60(tt,J＝51.8,4.9Hz,1H),4.67(t,J＝13.1Hz,2H),3.77(s,7H),3.27-3.25(m,2H),3.04(s,4H),1.72(s,3H),0.83(t,J＝4.9Hz,2H),0.70(t,J＝4.8Hz,2H).
Step 2) N- ((1- (5-methoxy-1- ((3- (piperazin-1-yl) -4- (2,2,3, 3-tetrafluoropropoxy) phenyl) sulfone) Acyl) -1H-indol-3-yl) cyclopropyl) methyl) acetamide
The title compound was prepared as described in example 1, step 5 by reacting N- ((1- (5-methoxy-1- ((4- (2,2,3, 3-tetrafluoropropoxy) -3- (4- (2,2, 2-trichloroacetyl) piperazin-1-yl) phenyl) sulfonyl) -1H-indol-3-yl) cyclopropyl) methyl) acetamide (265mg,0.35mmol), potassium hydroxide (59mg,1.05mmol, prepared as a 1mmol/mL aqueous solution) in tetrahydrofuran (20 mL). The crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (201mg, 94%).
MS(ESI,pos.ion)m/z:612.9[M+H]+；
1H NMR(600MHz,DMSO-d6):δ7.86(t,J＝5.8Hz,1H),7.76(d,J＝9.0Hz,1H),7.60(s,1H),7.51(dd,J＝8.6,2.3Hz,1H),7.20(d,J＝2.3Hz,1H),7.15-7.13(m,2H),6.93(dd,J＝9.0,2.5Hz,1H),6.54(tt,J＝52.0,4.9Hz,1H),4.64(t,J＝13.3Hz,2H),3.78(s,3H),3.28(d,J＝5.8Hz,2H),2.83-2.82(m,4H),2.79-2.78(m,4H),1.74(s,3H),0.84(q,J＝4.4Hz,2H),0.71(q,J＝4.4Hz,2H)；
13C NMR(150MHz,DMSO-d6):δ169.7,156.4,154.2,142.8,132.0,130.7,129.7,126.7,125.7,121.8,116.2,114.7,114.0,113.7,109.8(tt,J＝247.5,33.0Hz).103.4,65.2(t,J＝27.0Hz),55.9,51.5,45.9,45.5,23.0,17.7,10.5。
Example 12N- ((1- (5-methoxy-1- ((3- (4-methylpiperazin-1-yl) -4- (2,2,3, 3-tetrafluoropropoxy) Yl) phenyl) sulfonyl) -1H-indol-3-yl) cyclopropyl) methyl) acetamide
The title compound of this step was prepared by the method described in example 2 by reacting N- ((1- (5-methoxy-1- ((3- (piperazin-1-yl) -4- (2,2,3, 3-tetrafluoropropoxy) phenyl) sulfonyl) -1H-indol-3-yl) cyclopropyl) methyl) acetamide (120mg,0.16mmol), three drops of acetic acid, sodium cyanoborohydride (31mg,0.49mmol) and formaldehyde (40% in water, 44. mu.L, 0.59mmol) in methanol (15 mL). The reaction mixture was basified with sodium carbonate (59mg,0.56mmol), extracted with dichloromethane (30mL × 3), the washed organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (110mg, 90%).
MS(ESI,pos.ion)m/z:626.9[M+H]+；
1H NMR(600MHz,CDCl3):δ7.84(d,J＝9.0Hz,1H),7.46(dd,J＝8.6,2.1Hz,1H),7.35(s,1H),7.31(d,J＝2.1Hz,1H),7.07(d,J＝2.3Hz,1H),6.93(dd,J＝9.0,2.4Hz,1H),6.80(d,J＝8.6Hz,1H),6.00(tt,J＝53.2,3.24Hz,1H),4.35(t,J＝11.9Hz,2H),3.84(s,3H),3.41(d,J＝5.7Hz,2H),3.12(s,4H),2.71(s,4H),2.46(s,3H),1.89(s,3H),0.92(t,J＝5.1Hz,2H),0.77(t,J＝5.1Hz,2H)；
13C NMR(150MHz,CDCl3):δ170.1,156.5,153.8,141.9,132.2,131.5,130.1,125.7,124.9,122.0,117.1,114.7,113.8,112.9,102.6,65.1(t,J＝29.0Hz),55.8,54.6,49.2,46.5,45.3,23.3,17.6,10.7。
Example 13N- (2- (5-methoxy-1- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole Indol-3-yl) propyl) acetamide
Step 1) tert-butyl 3- (1-cyanoethyl) -5-methoxy-1H-indole-1-carboxylate
The title compound was prepared as described in example 3, step 2 by reacting tert-butyl 3- (cyanomethyl) -5-methoxy-1H-indole-1-carboxylate (1.72g,5.99mmol), sodium hydride (60% in mineral oil, 719mg,17.98mmol) and iodomethane (1.87mL,29.97mmol) in DMF (20mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 50/1) to give the title compound as a brown oily liquid (540mg, 30%).
MS(ESI,pos.ion)m/z:301.2[M+H]+；
1H NMR(400MHz,CDCl3):δ8.05(d,J＝8.2Hz,1H),7.57(s,1H),7.02(d,J＝2.3Hz,1H),6.98(dd,J＝9.0,2.5Hz,1H),4.05(dd,J＝7.2,0.8Hz,1H),3.87(s,3H),1.75(d,J＝7.2Hz,3H),1.67(s,9H)。
Step 2) tert-butyl 3- (1-aminopropan-2-yl) -5-methoxy-1H-indole-1-carboxylate
Prepared as described in example 3, step 3 by reacting tert-butyl 3- (1-cyanoethyl) -5-methoxy-1H-indole-1-carboxylate (540mg,1.80mmol) with borane-tetrahydrofuran solution (1mmol/mL,3.6mL,3.60mmol) in tetrahydrofuran (10mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a brown oily liquid (487mg, 89%).
Step 3) tert-butyl 3- (1-acetamidopropan-2-yl) -5-methoxy-1H-indole-1-carboxylate
The title compound was prepared as described in example 1, step 1 by reacting tert-butyl 3- (1-acetamidopropan-2-yl) -5-methoxy-1H-indole-1-carboxylate (487mg,1.60mmol), triethylamine (324 μ L,3.2mmol) and acetic anhydride (181 μ L,1.92mmol) in dichloromethane (10mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/5) to give the title compound as a white solid (399mg, 72%).
MS(ESI,pos.ion)m/z:347.2[M+H]+；
1H NMR(600MHz,CDCl3):δ7.99(s,1H),7.37(s,1H),7.08(d,J＝2.4Hz,1H),6.93(dd,J＝9.0,2.5Hz,1H),3.86(s,3H),3.55-3.46(m,2H),3.20(dd,J＝13.8,6.9Hz,1H),1.93(s,3H),1.66(s,9H),1.34(d,J＝7.0Hz,3H).
Step 4) N- (2- (5-methoxy-1H-indol-3-yl) propyl) acetamide
The title compound was prepared as described in example 3, step 4 by reacting tert-butyl 3- (1- (acetamidomethyl) cyclopropyl) -5-methoxy-1H indole-1-carboxylate (388mg,1.12mmol) in water (10mL) at reflux. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 30/1) to give the title compound as a white solid (253mg, 92%).
MS(ESI,pos.ion)m/z:247.10[M+H]+；
1H NMR(600MHz,CDCl3):δ8.28(s,1H),7.27-7.26(m,1H),7.09(d,J＝2.3Hz,1H),7.00(s,1H),6.87(dd,J＝8.8,2.4Hz,1H),3.86(s,3H),3.63-3.33(m,3H),1.90(s,3H),1.36(d,J＝7.0Hz,3H)。
Step 5) N- (2- (5-methoxy-1- ((4-methoxy-3- (4- (2,2, 2-trichloroacetyl) piperazin-1-yl) benzene Yl) sulfonyl) -1H-indol-3-yl) propyl) acetamide
The title compound was prepared as described in example 1, step 4 by reacting N- (2- (5-methoxy-1H-indol-3-yl) propyl) acetamide (250mg,1.02mmol), sodium hydride (60% in mineral oil, 41mg,1.02mmol) and 2,2, 2-trichloro-1- (4- (2-methoxyphenyl) piperazin-1-yl) acetyl (531mg,1.22mmol) in DMF (10 mL). The crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/2) to give the title compound as a white solid (472mg, 72%).
1H NMR(600MHz,DMSO-d6):δ8.03(t,J＝5.7Hz,1H),7.78(d,J＝9.0Hz,1H),7.55(dd,J＝8.7,2.2Hz,1H),7.53(s,1H),7.26(d,J＝2.2Hz,1H),7.19(d,J＝2.3Hz,1H),7.07(d,J＝8.8Hz,1H),6.93(dd,J＝9.0,2.4Hz,1H),3.93-3.75(m,10H),3.46-3.42(m,2H),3.03-3.02(m,4H),3.00-2.97(m,1H),1.78(s,3H),1.23(d,J＝6.5Hz,3H)。
Step 6) N- (2- (5-methoxy-1- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole- 3-yl) propyl) acetamide
The title compound was prepared by the method described in example 1, step 5, i.e. reacting N- (2- (5-methoxy-1- ((4-methoxy-3- (4- (2,2, 2-trichloroacetyl) piperazin-1-yl) phenyl) sulfonyl) -1H-indol-3-yl) propyl) acetamide (445mg,0.69mmol), potassium hydroxide (116mg,2.07mmol, 1mmol/mL in water) in tetrahydrofuran (20 mL). The crude product was subjected to silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (321mg, 93%).
MS(ESI,pos.ion)m/z:501.3[M+H]+；
1H NMR(600MHz,DMSO-d6):δ8.05(t,J＝5.7Hz,1H),7.77(d,J＝9.0Hz,1H),7.52(s,1H),7.50(dd,J＝8.7,2.2Hz,1H),7.19(dd,J＝12.2,2.3Hz,2H),7.02(d,J＝8.8Hz,1H),6.93(dd,J＝9.0,2.4Hz,1H),3.78(s,3H),3.76(s,3H),3.46-3.42(m,1H),3.06-2.97(m,2H),2.81-2.80(m,8H),1.79(s,3H),1.24(d,J＝6.7Hz,3H)；
13C NMR(100MHz,DMSO-d6):δ169.8,156.6,156.4,142.4,131.8,129.8,129.0,126.7,123.8,122.1,115.7,114.7,113.8,112.1,103.1,56.3,55.9,51.3,45.9,44.8,30.9,23.0,18.3。
Example 14N- (2- (5-methoxy-1- ((4-methoxy-3- (4-methylpiperazin-1-yl) phenyl) sulfonyl) - 1H-indol-3-yl) propyl) acetamide
The title compound of this step was prepared by the method described in example 2 by reacting N- (2- (5-methoxy-1- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indol-3-yl) propyl) acetamide (200mg,0.40mmol), three drops of acetic acid, sodium cyanoborohydride (63mg,1.00mmol) and formaldehyde (40% in water, 90 μ L,1.20mmol) in methanol (15 mL). The reaction mixture was adjusted to pH 7.0 to 8.0 with saturated aqueous sodium carbonate solution, extracted with dichloromethane (30 mL. times.3), washed with saturated aqueous sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (195mg, 95%).
MS(ESI,pos.ion)m/z:515.0[M+H]+；
1H NMR(600MHz,DMSO-d6):δ8.03(t,J＝5.7Hz,1H),7.77(d,J＝9.0Hz,1H),7.52(s,1H),7.50(dd,J＝8.7,2.3Hz,1H),7.19(t,J＝2.8Hz,2H),7.02(d,J＝8.8Hz,1H),6.93(dd,J＝9.0,2.4Hz,1H),3.79(s,3H),3.76(s,3H),3.46-3.42(m,1H),3.05-2.96(m,2H),2.90(s,4H),2.40(s,4H),2.19(s,3H),1.78(s,3H),1.23(d,J＝6.7Hz,3H)；
13C NMR(150MHz,DMSO-d6):δ169.8,156.6,156.4,141.9,131.9,129.8,128.9,126.8,123.9,122.2,115.8,114.8,113.8,112.1,103.0,56.4,55.9,55.0,50.0,46.2,44.9,30.9,23.1,18.4。
Biological assay
Example A melatonin MT1Receptor binding affinity assay
Test method
The affinity of the compounds for the humanized MT1 receptor transfected by CHO cells was evaluated using the radioligand binding method. Homogenizing protein (64. mu.g) at 22 ℃ to a cell membrane of 0.01nM [ mu.g ]125I]iodomelatonin and buffer (50mM Tris-HCl (pH 7.4), 5mM MgCl2And 1% BSA), with or without test compound, and incubated for 60 minutes. The standard reference compound was melatonin, and 1. mu.M melatonin was added to the mixed system under the above conditions to measure the non-specific binding value.
The incubated samples were passed through a glass fiber filter (GF/B, Packard) pre-soaked with 0.3% PEI under vacuum using a 96-sample cell harvester (Unifilter, Packard) and washed repeatedly several times with ice-cold 50mM Tris-HCl. 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 are expressed as the percentage inhibition of the specific binding of the radioligand relative to the control.
The standard reference compound was melatonin, and the competitive curve was obtained from experimental data for melatonin at a series of concentrations.
Data analysis
Evaluation of humanized MT of Compounds transfected into CHO cells Using radioligand binding method1The affinity of the receptor. The test compound is tested at least three times, and the data is subjected to a Hill equation curve fitting method to determine IC through competition curve nonlinear regression analysis50Values and Hill coefficients, calculated from the ChengPrusoff equation, and Ki values calculated.
The experimental results show that the compound of the invention is used for MT1The receptor shows a strong binding affinity.
TABLE 1 humanized MT transfected by CHO cells with the compounds provided in the examples of the invention1Results of receptor binding affinity experiments
Example No. 2 Ki(nM) Example No. 2 Ki(nM)
Example 1 35 Example 8 30
Example 2 30 Example 9 19
Example 3 49 Example 10 22
Example 4 42 Example 11 120
Example 5 190 Example 12 86
Example 6 190 Example 13 13
Example 7 36 Example 14 20
Finally, it should be noted that there are other ways of implementing the invention. Accordingly, the embodiments of the present invention will be described by way of illustration, but not limitation to the description of the present invention, and modifications made within the scope of the present invention or equivalents added to the claims are possible. All publications or patents cited herein are incorporated by reference.

Claims (9)

1. A compound which is a compound represented by formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt of a compound represented by formula (I),
wherein,
each W is independently N or CH;
each L is independently CR4R4a；
R1Is C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl or C3-6Cycloalkyl, wherein R1Optionally substituted by 1,2,3,4 or 5R9Substituted by a group;
R2is H or C1-4Alkyl radical, wherein R2Optionally substituted by 1,2,3,4 or 5R9Substituted by a group;
R3、R3a、R4、R4a、R10and R10aEach independently is H, D, F, Cl, Br, CN, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkoxy or C1-4Alkylamino, or R3、R3aTogether with the carbon atom to which they are attached form C3-6Cycloalkyl or heterocyclyl of 3 to 8 atoms, wherein R3、R3a、R4、R4a、R10And R10aEach independently optionally substituted by 1,2,3,4 or 5R9Substituted by a group;
each R5And R6Independently D, F, Cl, Br, I, NO2、OH、CN、N3、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl or- (CR)10R10a)qORcWherein each R is5And R6Independently optionally substituted by 1,2,3,4 or 5R9Substituted by a group;
R7is C3-6Cycloalkyl, a heterocyclic group consisting of 5 to 6 atoms, - (C)1-2Alkylene group) - (C3-6Cycloalkyl) or- (C)1-2Alkylene) - (heterocyclic group consisting of 3-8 atoms) wherein R7Optionally substituted by 1,2,3,4 or 5R9Substituted by a group;
R8is H or C1-4Alkyl radical, wherein R8Optionally substituted by 1,2,3,4 or 5R9Substituted by a group;
each R9Independently D, F, Cl, Br, I, CN, NO2、N3、NH2、OH、C1-4Alkyl radical、C1-4Alkoxy radical, C1-4Alkylamino or C1-4A haloalkyl group;
Rcindependently H, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl or C3-6Cycloalkyl, wherein RcIndependently optionally substituted by 1,2,3 or 4 groups independently selected from D, F, Cl, CN, N3、OH、NH2、C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy or C1-4Substituted with a substituent of alkylamino; and
each m, n, p and q is independently 0, 1,2,3 or 4.
2. The compound of claim 1, wherein R7Is piperazinyl, piperidinyl, morpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiomorpholinyl, dioxanyl, dithianyl or thiaxanyl, wherein R is7Optionally substituted by 1,2 or 3R9Substituted by a group.
3. The compound of claim 1, wherein RcIndependently H, -CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH2CH2CH3、-CH(CH3)CH2CH3or-C (CH)3)3Wherein R iscIndependently optionally substituted by 1,2,3 or 4 groups independently selected from D, F, Cl, CN, N3、OH、NH2、C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy or C1-4Substituted by a substituent of alkylamino.
4. The compound of claim 1, having the structure of one of:
5. a pharmaceutical composition comprising a compound of any one of claims 1-4; further comprising a pharmaceutically acceptable excipient, carrier, or combination thereof.
6. The pharmaceutical composition according to claim 5, further comprising an additional agent for the treatment of CNS dysfunction, wherein the additional agent for the treatment of CNS dysfunction is a sedative hypnotic agent, an antipsychotic agent, an antiepileptic agent, an antidepressant agent, an antihistamine agent, an anti-Parkinson's disease agent, a GABA receptor agonist and/or GABA reuptake inhibitor agent, an agent that is an iron channel blocker, an agent that is a monoamine oxidase inhibitor, an adenosine A inhibitor1/A2A drug that is a receptor agonist, a drug that is a melatonin receptor agonist, or any combination thereof.
7. The pharmaceutical composition according to claim 5, further comprising an additional agent for the treatment of central nervous system dysfunction, said additional agent for the treatment of central nervous system dysfunction being midazolam (midazolam), triazolam (triazolam), alprazolam (alprazolam), estazolam (estazolam), diazepam (diazepam), fluazepam (flurazepam), nitrazepam (nitrazepam), clonazepam (clonazepam), temazepam (temazepam), flunitrazepam (fluratizepam), oxazepam (oxazepam), zolpidem (zolpidem), zaleplon (zaleplon), zopiclone (zopiclone), dexzopiclone (zoiclone), diazepam (indolone (indoxacillin), tiagabine (zadoxine), clozapine (clozapine), clozapine (clopyram), clozapine (clozapine), clo, Carbamazepine (carbamazepine), promethazine (promethazine), lorazepam (lorazepam), hydroxyzine (hydroxyzine), aspirin (aspirin), diphenhydramine (diphenhydramine), chlorphenamine (chlorphenamine), brotizolam (lentirmin), ramelteon (ramelteon), temethamine (tasimelteon), agomelatine (agomelatine), mianserin (mianserine), amitriptyline (amitriptyline), desipramine (desipramine), mirtazapine (mirtazapine), fluoxetine (fluoxetine), trazodone (trazodone), duloxetine (duloxetine), fluvoxamine (fluvoxamine), vilazone (vilazone), dapoxetine (doxazone), pramipeline (pramipeline), pramipeline (pramipexole), pramipexole (pramipexole), pramipeline (pramipeline), pramipeline (pramipexole (pramipeline), pramipeline (pramipexole), pramipeline (pramipeline), pramipexole (pramipeline), pramipeline (pramipeline), pramipexole (pramipeline), pramipeline (pramipeline), pramipexole (pramipeline (pramipexole (pramipexo, Melatonin (circarin), chlordiazepoxide (chlorphenamide), perphenazine (perphenazine), suvorexant, Xuezang Guben, 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 in a mammal, including a human;
the central nervous system dysfunction is sleep disorder, stress response, depression, anxiety disorder, seasonal affective disorder, insomnia and fatigue caused by jet lag, schizophrenia, convulsion, panic attack, melancholia, psychotic disorder, epilepsy, Parkinson's disease, senile dementia, various disorders related to normal or pathological aging, migraine, memory loss or Alzheimer's disease.
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 for the manufacture of a medicament for selectively agonizing a melatonin receptor in a biological sample.
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