CN104276993B - Indole derivatives and its application on drug - Google Patents

Indole derivatives and its application on drug Download PDF

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Publication number
CN104276993B
CN104276993B CN201410331513.0A CN201410331513A CN104276993B CN 104276993 B CN104276993 B CN 104276993B CN 201410331513 A CN201410331513 A CN 201410331513A CN 104276993 B CN104276993 B CN 104276993B
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base
alkyl
compound
group
title compound
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CN104276993A (en
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张英俊
金传飞
钟文和
陈康智
张
张时群
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Guangdong HEC Pharmaceutical
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Ruyuan Yongxing Technical Service Co Ltd
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

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

Abstract

The present invention provides some indole derivatives or its stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug, for treating Alzheimer's disease.The invention also discloses the pharmaceutical composition containing such compound and use the method for the compounds of this invention or its medicine composite for curing Alzheimer's disease.

Description

Indole derivatives and its application on drug
Technical field
The invention belongs to drug field and it is related to compound for treating Alzheimer's disease, comprising the compound Composition and application thereof and application method.Particularly, compound of the present invention is to can be used as 5-HT6The Yin of antagonist Diindyl derivative.
Background technique
A variety of central nervous system diseases such as anxiety, depression etc. with neurotransmitter serotonin (5-HT) or thrombocytin Disorder it is related.As modulability neurotransmitter main in brain, the function of neurotransmitter serotonin (5-HT) be pass through by Referred to as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6And 5-HT7A large amount of receptor families mediate.Based on Gao Shui in brain Flat 5-HT6Receptor mrna, it has been suggested that 5-HT6Receptor may play in the pathology of central nervous system disorders and treatment Effect.Specifically, it has been determined that 5-HT6Selective ligands have potential treatment effect, such as Parkinson to certain CNS illnesss Disease, Huntington's chorea, anxiety disorder, depression, manic-depressive psychosis, mental disease, epilepsy, obsessive-compulsive disorder, migraine, Alzheimer Disease (cognition and memory enhancing), sleep disturbance, eating disorder such as anorexia and bulimia nerovsa, panic attack, ADHD, attention lack Fall into obstacle, drug abuse such as cocaine, ethyl alcohol, nicotine and benzodiazepineRecessiveness brain syndrome, essence are taken off caused by class Refreshing Split disease and illness such as hydrocephalus related with spinal trauma or head injury.It is expected that the compound can also be used to treat Certain stomach intestinal disease such as functional bowel disorders.(see, for example, Roth, B.L. etc., J.Pharmacol.Exp.Ther., 268, 1403-14120 pages of (1994), Sibley, D.R. etc., Mol, Pharmacol., 43,320-327 (1993), A.J.Sleight Deng, Neurotransmission, 11,1-5 (1995) and Sleight, A.J. etc., Serotonin ID Research Alert, 1997,2 (3), 115-8).The study found that known 5-HT6Selective antagonist significantly improves in cortex of frontal lobe The level of glutamic acid and aspartic acid removes hormone, dopamine or 5-HT on first kidney without improving6Level.It is this memory and The selectivity raising for the specific neurochemical noticed in cognitive process has strongly suggested that 5-HT6Ligand is in cognition Act on (Dawson, L.A.；Nguyen, H.Q.；Li, P., British Journal of Pharmacology, 2000,130 (1), 23-26).With known selectivity 5-HT6Research that the memory of antagonists in animals and study carry out have it is some actively Effect (Rogers, D.C.；Hatcher, P.D.；Hagan, J.J., Society of Neuroscience, Abstracts, 2000,26,680).5-HT6The related potential treatment purposes of ligand is to treat the attention deficit disorder of children and adult.Because 5-HT6Antagonist seems to improve the activity of nigrostriatal dopamine approach, and because ADHD with it is different in caudate nucleus Chang Youguan (Ernst, M；Zametkin, A.J.；Matochik, J.H.；Jons, P.A.；Cohen, R.M., Journal of Neuroscience, 1998,18 (5), 5901-5907), so, 5-HT6Antagonist can treat attention deficit disorder.Also Through determining 5-HT6Antagonist is the potentially useful compound for treating obesity.See, for example, Bentley etc., Br.J.Pharmac.1999, supplementary issue 126；Bentley etc., J.Psychopharmacol.1997, supplementary issue A64:255；Wooley Deng Neuropharmacology2001,41:210-129 and WO02098878.
Summary of the invention
The present invention relates to the methods of new indole derivatives and treatment Alzheimer's disease.The compounds of this invention includes institute The pharmaceutical composition of compound is stated to 5-HT6There is preferable affinity interaction, especially has preferable treatment to Alzheimer's disease Effect.
On the one hand, the present invention relates to a kind of compounds, are the solid of structure shown in structure shown in formula (I) or formula (I) Isomers, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein:
K is 0,1,2,3 or 4；
M is 0,1,2,3 or 4；
N is 1,2 or 3；
Y is CH or N；
WhenWhen for singly-bound, X is CH or N, whenWhen for double bond, X C；
R1For H, D, C1-6Alkyl, C3-8Naphthenic base, halogenated C1-6Alkyl ,-C (=O) R7,-C (=O) OR7, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl or C1-9Heteroaryl C1-6Alkyl；
Each R2And R3It independently is H, D, F, Cl, Br, I, CN, NO2, OH, NH2, SO2Cl, R7aR7N- ,-C (=O) R7,-C (=O) NR7R7a,-OC (=O) NR7R7a,-OC (=O) OR7,-N (R7) C (=O) NR7R7a,-N (R7) C (=O) OR7a,-N (R7)C (=O)-R7a, R7S (=O)2, HO-C1-6Alkyl, R7aR7N-C1-6Alkyl, R7S (=O)-C1-6Alkyl, R7R7aN-C (=O)-C1-6 Alkyl, R7aR7N-C1-6Alkoxy, R7S (=O)-C1-6Alkoxy, R7R7aN-C (=O)-C1-6Alkoxy, C6-10Aryl, C1-9It is miscellaneous Aryl, C1-6Alkoxy, C1-6Alkylamino, C1-6Alkyl, halogenated C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C2-9Heterocycle, C3-8Ring Alkyl, C1-6Alkylthio group, C6-10Aryloxy group, C6-10Arylthio, C6-10Aryl C1-6Alkyl, C6-10Fragrant amino, C1-9Heteroaryl amino, C6-10Aryl C1-6Alkylamino, C1-9Heteroaryl C1-6Alkylamino, C1-9Heteroaryl oxygroup, C1-9Heteroaryl C1-6Alkyl, C6-10Aryl C1-6Alkoxy, C1-9Heteroaryl C1-6Alkoxy, C2-9Heterocycle oxygroup, C2-9Heterocycle C1-6Alkoxy, C2-9Heterocyclylamino group or C2-9Heterocycle alkylamino；
R4And R5It is each independently H, D, F, Cl, Br, I, CN, C1-6Alkyl, C3-8Naphthenic base, halogenated C1-6Alkyl, C1-6Alkane Oxygroup or halogenated C1-6Alkoxy；
R6For H, D, F, Cl, Br, I, CN, OH, NH2, SO2Cl, C1-6Alkyl, C3-8Naphthenic base, C1-6Alkoxy ,-C (=O) R7,-C (=O) OR7,-C (=O) NR7R7a, C6-10Aryl or C6-10Aryl C1-6Alkyl；With
Each R7And R7aIt independently is H, D, C1-6Alkyl, C1-6Miscellaneous alkyl, C1-6Halogenated alkyl, hydroxyl, amino, C1-6Alcoxyl Base, C6-10Aryl, C2-9Heterocycle, C3-8Naphthenic base, C6-10Aryloxy group, C2-9Heterocycle oxygroup, C3-8Cycloalkyl oxy, C6-10Virtue Amino, C2-9Heterocyclylamino group, C3-8Cycloalkyl amino, C1-9Heteroaryl or C3-8Carbocylic radical；Work as R7And R7aIt is former to be connected in the same nitrogen On son, R7, R7aThe former molecular ring of substituted or non-substituted 3-8 can be randomly formed with the nitrogen-atoms being attached thereto.
In some of these embodiments, R1For H, D, C1-4Alkyl, C3-6Naphthenic base or C6-10Aryl C1-4Alkyl.
In some of these embodiments, each R2And R3It independently is and stands alone as H, D, F, Cl, Br, I, OH, NH2, CN, C1-4 Alkyl, C3-6Naphthenic base, C1-4Alkoxy, C2-4Alkenyl, C2-4Alkynyl or C6-10Aryl.
In some of these embodiments, R4And R5Respectively stand alone as H, D, C1-4Alkyl, C3-6Naphthenic base, halogenated C1-4Alkyl Or C1-4Alkoxy.
In some of these embodiments, R6For H, D, F, Cl, Br, I ,-COOH, C1-4Alkyl, C3-6Naphthenic base, C6-10Virtue Base or C6-10Aryl C1-4Alkyl.
In some of these embodiments, the present invention has the vertical of structure shown in the structure as shown in formula (II) or formula (II) Body isomers, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein:
K is 0,1,2,3 or 4；
M is 0,1,2,3 or 4；
N is 1,2 or 3；
R1For H, D, C1-4Alkyl, C3-6Naphthenic base, halogenated C1-4Alkyl or C6-10Aryl C1-4Alkyl；
Each R2And R3Stand alone as H, D, F, Cl, Br, I, CN, OH, NH2, C1-4Alkyl, C3-6Naphthenic base, C1-4Alkoxy, C2-4 Alkenyl, C2-4Alkynyl or C6-10Aryl；
R4And R5Respectively stand alone as H, D, C1-4Alkyl, C3-6Naphthenic base, halogenated C1-4Alkyl or C1-4Alkoxy；With
R6For H, D, F, Cl, Br, I or C6-10Aryl C1-4Alkyl.
In some of these embodiments, R1For H, D, methyl, ethyl, propyl, butyl, cyclopropyl or cyclobutyl.
In other embodiments, each R2And R3Stand alone as H, D, F, Cl, Br, I, CN, OH, NH2, methyl, ethyl, Propyl, butyl, methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopropyl or cyclobutyl.
On the one hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition includes the compound of the present invention, and its Pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium or their combination.
In some of these embodiments, pharmaceutical composition of the present invention further includes treatment A Er The drug of Ci Haimo disease.
In other embodiments, pharmaceutical composition of the present invention, wherein the medicine for the treatment of Alzheimer's disease Object is donepezil, nalmefene, Risperidone, vitamin e, SAM-760, AVN-211, AVN-101, RP-5063, Tozadenant, PRX-3140, PRX-8066, SB-742457, naluzaton, Lu-AE58054, Tacrine, Rivastigmine, Galanthamine, Memantine, mitzapine, Venlafaxine, desipramine, nortriptyline, zolpidem, zopiclone, Nicergoline, pyrrole La Xitan, selegiline, pentoxifylline or their combination.
On the other hand, the present invention relates to the compounds of this invention or pharmaceutical composition in preparation for protecting or treating and 5- HT6Purposes in the drug of related disease.
On the other hand, the present invention relates to 5-HT6Related CNS illness includes: ADHD, and anxiety is related to stress Disease, schizophrenia, besetment and behavior disorder, manic-depressive psychosis, nervous disorders, memory disorders, attention deficit Obstacle, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's chorea.
On the other hand, the present invention relates to 5-HT6Related disease is disorder of gastrointestinal tract.
On the other hand, the present invention relates to 5-HT6Related disease is obesity.
Another aspect of the present invention is related to the method for preparation, separation and the purifying of formula (I) or formula (II) compound represented.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its Content in terms of him will make more specific complete description below.
Specific embodiment
Definition and general terms
The present invention will list in detail document corresponding to the content determining materialization, and embodiment is all accompanied by structure The diagram of formula and chemical formula.The present invention, which has, expectedly covers all choices, variant and coordinate, these may be such as right Existing invention field is included in defined in it is required that like that.Those skilled in the art will identify it is many similar or equivalent to This described method and substance, these can be applied to the practice of the present invention.The present invention is limited to absolutely not method and substance Description.There are many documents and similar substance to distinguish or contradict with the present patent application including but not limited to term Definition, the usage of term, the technology of description or range as controlled by the present invention.
The present invention will be using defined below unless other aspects show.Purpose according to the present invention, chemical element is according to member Plain periodic table, CAS version and Chemical Physics handbook, 75thEd., 1994 define.In addition, organic chemistry General Principle is shown in " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, and " March's Advanced Organic Chemistry ", Michael B.Smith and Jerry March, John Wiley& Sons, New York:2007, therefore all contents have all merged bibliography.
As described in the present invention, the compound of the present invention can be optionally replaced one or more substituent groups, such as General formula compound above, or such as example special inside embodiment, subclass, and a kind of compound that the present invention is included. It should be appreciated that this term can be used interchangeably " optionally replacing " this term with " substituted or unsubstituted ".In general, art Language " optionally " whether it is before the term " replaced ", indicates that one or more hydrogen atoms in given structure are specific Replaced substituent group.Unless otherwise indicated, an optional substituent group can have a substituent group group is each can Substituted position is replaced.When more than one position can be selected from the one or more of specific group in given structural formula Replaced substituent group, then substituent group can replace at various locations identical or differently.Wherein the substituent group can be, But it is not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio group, alkyl, alkenyl, alkynes Base, heterocycle, sulfydryl, nitro, aryloxy group, heteroaryloxy, oxo, carboxyl, the alkoxy that hydroxyl replaces, the alkane that hydroxyl replaces Base-C (=O), alkyl-C (=O), alkyl-S (=O), alkyl-S (=O)2, the alkyl-S (=O) that hydroxyl replaces, hydroxyl takes Alkyl-the S (=O) in generation2, Carboxyalkoxy etc..
Terminology used in the present invention " alkyl " indicates the saturated straight chain of 1-20 carbon atom or the univalence hydrocarbyl of branch.One In a little embodiments, alkyl group includes 1-6 carbon atom, and in further embodiments, alkyl group includes 1-4 carbon atom. The example of alkyl includes, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n-Pr ,- CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH (CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), tert-butyl (t-Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyl (- CH (CH3)CH2CH2CH3), 3- amyl (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl-1-butyl (- CH2CH2CH(CH3)2), 2- first Base -1- butyl (- CH2CH(CH3)CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 2- hexyl (- CH (CH3) CH2CH2CH2CH3), 3- hexyl (- CH (CH2CH3)(CH2CH2CH3)), 2- methyl -2- amyl (- C (CH3)2CH2CH2CH3), 3- first Base -2- amyl (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- amyl (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- penta Base (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)C(CH3)3), etc..Term " alkyl " and its prefix " alkane " It uses here, all includes the saturated carbon chains of straight chain and branch.Term " alkylene " uses here, indicates full from linear chain or branched chain The saturated divalent hydrocarbon radical that two hydrogen atoms obtain is eliminated with hydrocarbons, such example includes, but is not limited to, methylene, Ethylidine, secondary isopropyl etc..
Term " alkenyl " indicates the monovalent hydrocarbon of the linear chain or branched chain of 2-12 carbon atom, and wherein at least one position is not Saturation state, i.e. a C-C are sp2Double bond.In some embodiments, alkenyl group includes 2-6 carbon atom, in other realities It applies in example, alkenyl group includes 2-4 carbon atom.Wherein alkenyl group can be independently and optionally by one or more present invention Replaced described substituent group, including group has negation, " suitable " or " E ", the positioning of " Z ", wherein the specific example packet of alkenyl It includes, but is not limited to, vinyl (- CH=CH2), allyl (- CH2CH=CH2), etc..
Term " alkynyl " indicates the monovalent hydrocarbon of the linear chain or branched chain of 2-12 carbon atom, and wherein at least one position is not Saturation state, i.e. a C-C are tri- key of sp.In some embodiments, alkynyl group includes 2-6 carbon atom, in other realities It applies in example, alkynyl group includes 2-4 carbon atom.Wherein alkynyl group can be independently and optionally by one or more present invention Replaced described substituent group, wherein the specific example of alkynyl is included, but is not limited to, acetenyl (- C ≡ CH), propargyl (-CH2C ≡ CH), etc..
One or more hetero atoms can be inserted in term " miscellaneous alkyl " expression alkyl chain, wherein alkyl group and hetero atom With meaning as described in the present invention.Unless otherwise detailed instructions, miscellaneous alkyl group contains 1-10 carbon atom, some embodiment party Case is that miscellaneous alkyl group contains 1-5 carbon atom, and other embodiment is that miscellaneous alkyl group contains 1-4 carbon atom, Other embodiment is that miscellaneous alkyl group contains 1-3 carbon atom.Such example includes, but is not limited to, CH3OCH2, CH3CH2OCH2, CH3SCH2, (CH3)2NCH2, (CH3)2CH2OCH2, CH3OCH2CH2, CH3CH2OCH2CH2- Deng.
Term " hetero atom " indicates one or more O, S, N, P and Si atom, including the form of any oxidation state of N, S and P； The form of primary, secondary, tertiary amine and quaternary ammonium salt；Or the substituted form of hydrogen in heterocycle on nitrogen-atoms, for example, N (such as 3,4- bis- N in hydrogen -2H- pyrrole radicals), NH (such as NH in pyrrolidinyl) or NR (such as NR in the pyrrolidinyl of N- substitution).
Term " halogen " refers to F, Cl, Br or I.
" unsaturated " the expression structure division of term as used in the present invention contains one or more degrees of unsaturation.
Term " hydroxyl replace alkyl " indicate alkyl group replaced one or more hydroxyl groups, wherein alkyl base Group has meaning of the present invention.Such example includes, but is not limited to methylol, ethoxy, 1,2- dihydroxy ethyl Deng.
Terminology used in the present invention " halogenated alkyl " indicates alkyl group by one or more identical or different halogen atoms Replaced, wherein alkyl group has meaning as described in the present invention, halogen atom, that is, fluorine, chlorine, bromine or iodine, such example packet It includes, but is not limited to trifluoromethyl, trifluoroethyl, chloromethyl, methyl fluoride etc..
Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-20 carbon atom, some of real Applying example is, alkoxy base contains 1-6 carbon atom, and other embodiment is that alkoxy base contains 1-4 carbon atom. The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,-OCH2CH3), the third oxygen of 1- Base (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH3)2), 1- butoxy (n- BuO, n- butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, i- butoxy ,-OCH2CH(CH3)2), 2- fourth Oxygroup (s-BuO, s- butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t-BuO, t- butoxy,-OC (CH3)3) Etc..And the alkoxy can be substituted or unsubstituted, and wherein substituent group can be, but be not limited to, hydroxyl, ammonia Base, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, sulfydryl, nitro etc..
Term " alkylthio group " includes C1-6The alkyl of linear chain or branched chain is connected on the sulphur atom of divalent.Some of them are implemented Scheme is that alkylthio group is the C of lower level1-4Alkylthio group, such example include, but is not limited to methyl mercapto (CH3S-)。
Term " alkyl amino " includes " N- alkyl amino " and " N, N- dialkyl amido ", and wherein amine groups are separately Replaced one or two alkyl group.Some of embodiments are that alkyl amino is one or two C1-6Alkyl connection The alkylamino group of lower level on to nitrogen-atoms.Other embodiment is that alkyl amino is C1-4Lower level alkane Base amino group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example includes, but simultaneously It is not limited to, N- methylamino, N- ethylamino, N, N- dimethylamino, N, N- lignocaine etc..
Term " naphthenic base " or " carbocylic radical " refer to monovalence or multivalence, non-aromatic, saturation or the unsaturated ring in part, and Not comprising hetero atom, two rings of monocycle or 7-8 carbon atom including 3-6 carbon atom.It is bicyclic with 7-8 atom Carbocyclic ring can be two rings [4,5] or [5,5] system.Suitable annular aliphatic base includes, but is not limited to, naphthenic base, cyclenes Base and cycloalkynyl radical.The example of annular aliphatic base includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- Alkenyl, 1- cyclopenta -2- alkenyl, 1- cyclopenta -3- alkenyl, cyclohexyl, 1- cyclohexyl -1- alkenyl, 1- cyclohexyl -2- alkenyl, 1- cyclohexyl -3- alkenyl, cyclohexadienyl, suberyl, cyclooctyl, cyclononyl etc..And " annular aliphatic base " or " carbocyclic ring ", " carbocylic radical ", " naphthenic base " can be substituted or unsubstituted, and wherein substituent group can be, but be not limited to, hydroxyl Base, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocycle, sulfydryl, nitro, Aryloxy group, the alkoxy that hydroxyl replaces, the alkyl-C (=O), alkyl-C (=O), alkyl-S (=O), alkyl-S that hydroxyl replaces (=O)2, the alkyl-S (=O) that hydroxyl replaces, the alkyl-S (=O) that hydroxyl replaces2, Carboxyalkoxy etc..
Term " cycloalkyl oxy " includes that the naphthenic base optionally replaced is connected on oxygen atom as defined herein, And it is connected by oxygen atom with remaining molecule, such example includes, but is not limited to cyclopropyl oxygroup, cyclopentyloxy, ring Hexyl oxygroup, the cyclopropyl oxygroup etc. that hydroxyl replaces.
Term " cycloalkyl amino " indicates replaced the group of naphthene base that amino group is optionally replaced by one or two, Middle naphthenic base has meaning as described in the present invention, and such example includes, but is not limited to cyclopropylamino, cyclopenta ammonia Base, Cyclohexylamino, the cyclopropylamino that hydroxyl replaces, dicyclohexyl amino, Bicyclopropyl amino etc..
Term " naphthenic base fatty group " indicates that fatty group can be replaced one or more groups of naphthene base, middle ring Alkyl and fatty group have meaning as described in the present invention, and such example includes, but is not limited to Cvclopropvlmethvl, cyclopropyl Base ethyl, Cyclopropylpropyl, cyclopentyl-methyl, cyclohexyl-ethyl etc..
Term " cycloalkyl alkoxy " (" carbocyclylalkoxy ") indicates alkoxy base by one or more naphthenic base Replaced (" carbocylic radical ") group, wherein naphthenic base (" carbocylic radical ") group and alkoxy base have contains as described in the present invention Justice, such example include, but is not limited to cyclo propyl methoxy, cyclopropylethoxy, cyclopenta ethyoxyl, cyclohexyl ethoxy Base, cyclohexyl methoxy, cyclopropyl propoxyl group etc..
Term " heterocycle ", " heterocycle ", " heteroalicyclic " or " heterocycle " are used interchangeably here, all refer to monocycle, Bicyclic or three-ring system, one or more carbon atoms are independently and optionally replaced hetero atom in middle ring, the hetero atom With meaning as described in the present invention, ring can be fully saturated or fragrant comprising one or more degrees of unsaturation, but definitely not The fragrant same clan, only one tie point are connected to other molecules up.Hydrogen atom on one or more rings independently and optionally by Replaced one or more substituent groups described in the invention.Some of embodiments are " heterocycles ", " heterocycle ", " heterolipid Ring race " or " heterocycle " group be 3-7 member ring monocycle (1-6 carbon atom and selected from N, O, P, the 1-3 hetero atom of S, herein S or P optionally obtains such as SO, SO replaced one or more oxygen atoms2, PO, PO2Group, when the ring be ternary When ring, only one of them hetero atom) or 7-8 member it is bicyclic (4-7 carbon atom and selected from N, O, P, the 1-3 hetero atom of S, Such as SO, SO are optionally obtained replaced one or more oxygen atoms in this S or P2, PO, PO2Group).
Heterocycle can be carbon-based or heteroatom group." heterocycle " equally also includes heterocyclic group and saturation or part insatiable hunger With ring or heterocycle and conjunction is formed by group.The example of heterocycle includes, but is not limited to, pyrrolidinyl, tetrahydrofuran base, dihydro Furyl, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, Thiophene oxane base, thiazolidinyl, oxazolidinyl, piperazinyl, high piperazine base, azelidinyl, oxetanylmethoxy, thietanyl, Homopiperidinyl, glycidyl, azacycloheptyl, oxetane, thiocycloheptyl, 4- Methoxy-piperidin -1- base, 1,2,3, 6- tetrahydropyridine -1- base, oxygen azepineBase, diazaBase, sulphur azepineBase, pyrrolin -1- base, 2- pyrrolinyl, 3- pyrrole Cough up quinoline base, indolinyl, 2H- pyranose, 4H- pyranose, dioxacyclohexyl, 1,3- dioxymyl, pyrazolinyl, two thiophenes Alkyl, dithienyl group, dihydrothiophene, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4- tetrahydro isoquinolyl, 1, 2,6- thiadiazine alkane 1,1- dioxo -2- base, 4- hydroxyl-Isosorbide-5-Nitrae-azepine phosphine 4- oxide -1- base, 2- hydroxyl -1- (piperazine - 1- yl) ethyl ketone -4- base, 2- hydroxyl -1- (5,6- dihydros -1,2,4- triazine -1 (4H)-yl) ethyl ketone -4- base, 5,6- dihydro -4H- 1,2,4- oxadiazines -4- base, 2- hydroxyl -1- (- 1 (2H)-yl of 5,6- dihydropyridine) ethyl ketone -4- base, 3- azabicyclo [3.1.0] Hexyl, 3- azabicyclo [4.1.0] heptyl, azabicyclo [2.2.2] hexyl, 2- methyl -5,6,7,8- tetrahydros-[1,2,4] three Azoles [1,5-c] pyrimidine -6- base, 4,5,6,7- tetrahydro isoxazole [4,3-c] pyridine -5- bases, 3H- indyl 2- oxygen -5- azepine are double Ring [2.2.1] heptane -5- base, 2- oxygen -5- azabicyclo [2.2.2] octane -5- base, quinazinyl and N- pyridyl urea.Heterocycle The example of group further includes that two carbon atoms are replaced oxygen atom as phonetic on 1,1- dioxothiomorpholinyl and its middle ring Pyridine diketo.And the heterocycle can be substituted or unsubstituted, and wherein substituent group can be, but be not limited to, oxo, Hydroxyl, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocycle, sulfydryl, nitro, fragrant oxygen Base, the alkoxy that hydroxyl replaces, alkyl-C (=O), the alkyl-C (=O) that hydroxyl replaces, alkyl-S (=O), alkyl-S (= O)2, the alkyl-S (=O) that hydroxyl replaces, the alkyl-S (=O) that hydroxyl replaces2, Carboxyalkoxy etc..
Term " heterocyclylalkoxy " includes the alkoxy that heterocycle replaces, wherein the rest part phase of oxygen atom and molecule Even；Term " heterocycle alkylamino " includes the amino that heterocycle replaces, and wherein nitrogen-atoms is connected with the rest part of molecule.Wherein Heterocycle, alkyl, alkoxy and alkylamino have meaning as described in the present invention, and such example includes, but is not limited to pyrrole Cough up -2- ylmethyl, morpholine -4- base ethyl, morpholine -4- base oxethyl, piperazine -4- base oxethyl, piperidin-4-yl ethylamino Deng.
Term " heterocycle oxygroup " includes that the heterocycle optionally replaced is connected on oxygen atom as defined herein, Wherein oxygen atom is connected with the rest part of molecule, and such example includes, but is not limited to pyrroles's -2- oxygroup, pyrroles's -3- oxygen Base, piperidines -2- oxygroup, piperidines -3- oxygroup, piperazine -2- oxygroup, piperidines -4- oxygroup etc..
Term " heterocyclylamino group " indicate amino group replaced one or two heterocyclyl groups, wherein nitrogen-atoms with The rest part of molecule is connected, and heterocycle has meaning as described in the present invention, and such example includes, but and unlimited In, pyrroles's -2- amino, pyrroles's -3- amino, piperidines -2- amino, piperidines -3- amino, piperidines -4- amino, piperazine -2- amino, two Pyrroles's -2- amino etc..
Term " aryl " can be used alone or as " aralkyl ", a big portion of " aralkoxy " or " aryloxy alkyl " Point, indicate the monocycle altogether containing 6-10 member ring, bicyclic and tricyclic carbocyclic ring system, wherein at least one ring system is aromatic series , wherein each ring system includes 3-7 member ring, and only one attachment point is connected with the rest part of molecule.Term " virtue Base " can be used interchangeably with term " aromatic rings ", if aromatic rings may include phenyl, naphthalene and anthryl.And the aryl can Be it is substituted or unsubstituted, wherein substituent group can be, but be not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl Base, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocycle, sulfydryl, nitro, aryloxy group, the alkoxy that hydroxyl replaces, hydroxyl Substituted alkyl-C (=O), alkyl-C (=O), alkyl-S (=O), alkyl-S (=O)2, hydroxyl replace alkyl-S (= O), the alkyl-S (=O) that hydroxyl replaces2, Carboxyalkoxy, etc..
Term " aralkyl " includes the alkyl group that aryl replaces.Some of embodiments are that aromatic alkyl group refers to " aralkyl of lower level " group, i.e. aryl group are connected to C1-6Alkyl group on.Other embodiment is aralkyl Base group refers to containing C1-4Alkyl " benzeme alkylene ".Wherein specific example includes benzyl, diphenyl methyl, phenethyl.Aralkyl On aryl can be further by halogen, alkyl, alkoxy, replaced halogenated alkyl and halogenated alkoxy.
Term " aryloxy group " includes that the aryl optionally replaced is connected on oxygen atom as defined herein, and by Oxygen atom is connected with molecule rest part, and wherein aryl group includes with meaning as described in the present invention, such example, but It is not limited to phenoxy group, toloxyl, ethylbenzene oxygroup etc..
Term " arylthio " includes that the aryl optionally replaced is connected on sulphur atom as defined herein, and by Sulphur atom is connected with molecule rest part, and wherein aryl group includes with meaning as described in the present invention, such example, but It is not limited to thiophenyl, Tolylsulfanvl, ethylbenzene sulfenyl etc..
Term " fragrant amino " indicates replaced the aryl group that amino group is optionally replaced by one or two, wherein aryl With meaning as described in the present invention, such example includes, but is not limited to phenyl amino, p-fluorophenyl amino, diphenyl Amino, xylyl amino, di-p-tolyl amino etc..
Term " aryl alkane amino " includes that the aromatic yl alkyl group containing nitrogen-atoms is connected to other groups by nitrogen-atoms On, wherein aryl alkyl has meaning as described in the present invention, and such example includes, but is not limited to phenyl methylamino, benzene Base ethylamino, naphthalene ethylamino etc..
Term " alkoxy aryl " includes that the aromatic yl alkyl group containing oxygen atom is connected to other groups by oxygen atom On, wherein aryl alkyl has meaning as described in the present invention, and such example includes, but is not limited to Phenylmethoxy, naphthalene Base oxethyl, phenyl-propoxy etc..
Term " heteroaryl " can be used alone or as most of " heteroaryl alkyl " or " heteroarylalkoxy ", Indicate the monocycle altogether containing 5-10 member ring, bicyclic and three-ring system, wherein at least one ring system is aromatic, and at least One ring system includes one or more hetero atoms, and wherein hetero atom has meaning of the present invention, wherein each ring body System includes 3-7 member ring, and only one attachment point is connected with molecule rest part.Term " heteroaryl " can " virtue be miscellaneous with term Ring " or " heteroaromatics " are used interchangeably.And the heteroaryl can be substituted or unsubstituted, and wherein substituent group can be with It is, but is not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl is miscellaneous Ring group, sulfydryl, nitro, aryloxy group, the alkoxy that hydroxyl replaces, the alkyl-C (=O) that hydroxyl replaces, alkyl-C (=O), alkane Base-S (=O), alkyl-S (=O)2, the alkyl-S (=O) that hydroxyl replaces, the alkyl-S (=O) that hydroxyl replaces2, carboxyl alcoxyl Base etc..
Other embodiment is that heteroaromatic includes monocycle below, but is not limited to these monocycles: 2- furyl, 3- furyl, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyl, 4- isoxazolyl, 5- isoxazole Base, 2- oxazolyl, 4- oxazolyl, 5- oxazolyl, 4- methylisoxazole -5- base, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- Pyridyl group, 3- pyridyl group, 4- pyridyl group, 2- pyrimidine radicals, 4- pyrimidine radicals, pyrimidine -5- base, pyridazinyl (such as 3- pyridazinyl), 2- thiophene Oxazolyl, 4- thiazolyl, 5- thiazolyl, tetrazole radical (such as 5- tetrazole radical), triazolyl (such as 2- triazolyl and 5- triazolyl), 2- thiophene Base, 3- thienyl, pyrazolyl (such as 2- pyrazolyl), isothiazolyl, 1,2,3-oxadiazoles base, 1,2,5- oxadiazoles base, 1,2,4- Oxadiazoles base, 1,2,3-triazoles base, 1,2,3- thio biphosphole base, 1,3,4- thio biphosphole base, 1,2,5- thio biphosphole base, 1,3, 4- thiadiazoles -2- base, pyrazinyl, pyrazine -2- base, 1,3,5-triazines base, benzo [d] thiazol-2-yl, imidazo [1,5-a] pyrrole Pyridine -6- base；It also include below bicyclic, but it is bicyclic to be not limited to these: benzimidazolyl, benzofuranyl, benzothienyl, Indyl (such as 2- indyl), purine radicals, quinolyl (such as 2- quinolyl, 3- quinolyl, 4- quinolyl) and isoquinolyl is (such as 1- isoquinolyl, 3- isoquinolyl or 4- isoquinolyl).
Term " heteroaryl amino " indicates replaced the heteroaryl groups that amino group is optionally replaced by one or two, Middle heteroaryl has meaning as described in the present invention, and such example includes, but is not limited to pyridin-4-yl amino, fluorine pyrrole Piperidinyl amino, bipyridyl amino etc..
Term " heteroaryloxy " includes that the heteroaryl optionally replaced is connected on oxygen atom as defined herein, and And be connected by oxygen atom with molecule rest part, wherein heteroaryl groups have meaning as described in the present invention, such example Include, but is not limited to pyridine oxygroup, 2-pyrimidinyl oxy etc..
Term " heteroaryl alkyl " indicate alkyl group replaced one or more heteroaryls, wherein heteroaryl and alkyl Group has meaning of the present invention, and such example includes, but is not limited to imidazoles -2- methyl, furans -2- ethyl, Yin Diindyl -3- methyl etc..
Term " heteroarylalkylamino " includes that the heteroarylalkyl group containing nitrogen-atoms is connected to other by nitrogen-atoms On group, wherein heteroaryl alkyl has meaning as described in the present invention, and such example includes, but is not limited to pyridine -2- Base methylamino, thiazol-2-yl ethylamino, imidazoles -2- base ethylamino, the third amino of pyrimidine -2-base, pyrimidine -2-base methylamino etc..
Term " aryloxy group " includes the aryl optionally replaced, as defined herein as be connected on oxygen atom, and And be connected by oxygen atom with molecule rest part, such example includes, but is not limited to phenoxy group etc..
Term " heteroarylalkoxy " includes that the heteroarylalkyl group containing oxygen atom is connected to other by oxygen atom On group, wherein heteroaryl alkyl has meaning as described in the present invention, and such example includes, but is not limited to pyridine -2- Ylmethoxy, thiazol-2-yl ethyoxyl, imidazoles -2- base oxethyl, pyrimidine -2-base propoxyl group, pyrimidine -2-base methoxyl group etc..
Unless otherwise indicated, structural formula described in the invention includes that (such as mapping is different for all isomeric forms Structure, diastereo-isomerism and geometrical isomerism (or conformational isomerism)): such as R, S configuration containing asymmetric center, (Z) of double bond, (E) isomers, and the conformer of (Z), (E).Therefore, the single three-dimensional chemical isomer of the compound of the present invention or its is right Reflect isomers, the mixture of diastereoisomer or geometric isomer (or conformer) belongs to the scope of the present invention.
Term " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo. Such conversion is hydrolyzed in blood by pro-drug or is that precursor structure is influenced through enzymatic conversion in blood or tissue.This hair Bright pro-drug compounds can be ester, and ester can be used as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, it can is acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are obtaining through the di on parent.It is completely begged for about pro-drug By following documents can be referred to: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press, 1987, J.Rautio et al, Prodrugs:Design and Clinical Applications, Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008,51,2328-2345.
Unless otherwise indicated, all tautomeric forms of the compound of the present invention are included in the scope of the present invention Within.In addition, unless otherwise indicated, the structural formula of compound described in the invention includes one or more different originals The enriched isotope of son.
" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change The metabolite for closing object can be identified that activity can be retouched by such as the present invention by technology well-known in the art It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, restoring, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.
The definition of neutral body chemistry of the present invention and the use of convention are typically referenced to following documents: S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994.The compound of the present invention may include asymmetric center or chiral centre, therefore There are different stereoisomers.All stereoisomeric forms in any ratio of the compound of the present invention, it is including but not limited to, diastereomeric Body, enantiomter, atropisomer and their mixture, such as racemic mixture constitute a part of the invention. Many organic compounds all exist with optical active forms, i.e. the plane of their capable Plane of rotation polarised lights.In description light When learning reactive compound, prefix D, L or R, S are used to indicate the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) use Come name compound linearly polarized light rotate symbol, (-) or l refer to compound be it is left-handed, prefix (+) or d refer to chemical combination Object is dextrorotation.The chemical structure of these stereoisomers is identical, but their stereochemical structure is different.It is specific vertical Body isomers can be enantiomer, and the mixture of isomers is commonly referred to as enantiomeric mixture.The enantiomer of 50:50 mixes Object is referred to as racemic mixture or racemic modification, this, which may cause in chemical reaction process, does not have stereoselectivity or three-dimensional fixed Tropism.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomters, lack light Learn activity.
Term " tautomer " or " tautomeric form " refer to that the isomer of the structure of different-energy can be with Pass through the mutual inversion of phases of low energy barrier.Such as proton tautomer (i.e. prototropic tautomer) includes passing through proton transfer Interconversion, such as the isomerization of keto-enol and imine-enamine.Valence (chemical valence) tautomer includes Recombinate the interconversion of bonding electrons.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document: S.M.Berge et al., Documented by J.Pharmaceutical Sciences, 66:1-19,1977.The salt that pharmaceutically acceptable nontoxic acid is formed It including, but is not limited to, inorganic acid salt formed by reacting with amino groups to form has a hydrochloride, hydrobromate, phosphate, sulfate, Perchlorate and acylate such as acetate, oxalates, maleate, tartrate, citrate, succinate, malonic acid Salt, or these salt are obtained by other methods described in the books or literature such as ion-exchange.Other are pharmaceutically acceptable Salt include adipate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, boric acid Salt, butyrate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonic acid Salt, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproic acid Salt, hydriodate, 2- hydroxy-ethanesulfonate salt, lactobionate, lactate, laruate, lauryl sulfate, malate, Malonate, mesylate, 2- naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, mistake Sulfate, 3- phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, Undecylate, valerate, etc..Salt obtained by an appropriate base includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4 Salt.The compound that the present invention is also intended to contemplate the group of any included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or Dispersion product can be obtained by quaternization.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmacy Upper acceptable salt further comprises appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halogenation Object, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8Sulphonic acid compound and aromatic sulphonic acid compound.
" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
When term " blocking group " refers to a substituent group and other reacted with functional groups, commonly used to block or protect Protect special functionality.For example, " blocking group of amino " refers to that a substituent group is connected to block or protect with amino group The functionality of amino in compound, suitable amido protecting group include acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC), Benzyloxycarbonyl group (CBZ) and 9- fluorenes methylene oxygen carbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to that the substituent group of hydroxyl is used to The functionality of hydroxyl is blocked or protects, suitable blocking group includes acetyl group and silicyl." carboxy protective group " refers to The substituent group of carboxyl is used to block or protect the functionality of carboxyl, and general carboxyl-protecting group includes-CH2CH2SO2Ph, cyano second Base, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxyl methyl, 2- (p-toluenesulfonyl) ethyl, 2- are (right Nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..Description general for blocking group can be joined Examine document: T.W.Greene, Protective Groups in Organic Synthesis, John Wiley&Sons, New York,1991；And P.J.Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
Term " ADHD " is the abbreviation of Attention-deficit hyperactivity disorder, means attention The mostly dynamic obstacle of defect, be it is a kind of childhood very common psychataxia.According to " the general disease in the world point of the World Health Organization Class handbook " the tenth edition (ICD-10, WHO, 1992) this disease be referred to as " hyperactivity disorder " (Hyperkinetic Disorder), point Class number is F90, general to be commonly called as again as " hyperactive children ".
Term " schizophrenia " refers to schizophrenia, schizophrenia-like disorder, schizoaffective disorder and spirit Characteristic of disease phrenoblabia, wherein term " mental disease " refers to vain hope, apparent illusion, amorphous language or unorganized behavior or deadlock Straightization behavior.Referring to Diagnostic and Statistical Manual of Mental Disorder, fourth edition, American Psychiatric Association, Washington, D.C..
The description of the compounds of this invention
Indole derivatives of the present invention, pharmaceutically acceptable salt and its pharmaceutical preparation have antagonism 5-HT6, Especially there is potential purposes to the treatment of Alzheimer's disease.
On the one hand, the present invention relates to a kind of compounds, are the solid of structure shown in structure shown in formula (I) or formula (I) Isomers, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite are pharmaceutically acceptable Salt or prodrug,
Wherein:
K is 0,1,2,3 or 4；
M is 0,1,2,3 or 4；
N is 1,2 or 3；
Y is CH or N；
WhenWhen for singly-bound, X is CH or N, whenWhen for double bond, X C；
R1For H, D, C1-6Alkyl, C3-8Naphthenic base, halogenated C1-6Alkyl ,-C (=O) R7,-C (=O) OR7, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl or C1-9Heteroaryl C1-6Alkyl；
Each R2And R3It independently is H, D, F, Cl, Br, I, CN, NO2, OH, NH2, SO2Cl, R7aR7N- ,-C (=O) R7,-C (=O) NR7R7a,-OC (=O) NR7R7a,-OC (=O) OR7,-N (R7) C (=O) NR7R7a,-N (R7) C (=O) OR7a,-N (R7)C (=O)-R7a, R7S (=O)2, HO-C1-6Alkyl, R7aR7N-C1-6Alkyl, R7S (=O)-C1-6Alkyl, R7R7aN-C (=O)-C1-6 Alkyl, R7aR7N-C1-6Alkoxy, R7S (=O)-C1-6Alkoxy, R7R7aN-C (=O)-C1-6Alkoxy, C6-10Aryl, C1-9It is miscellaneous Aryl, C1-6Alkoxy, C1-6Alkylamino, C1-6Alkyl, halogenated C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C2-9Heterocycle, C3-8Ring Alkyl, C1-6Alkylthio group, C6-10Aryloxy group, C6-10Arylthio, C6-10Aryl C1-6Alkyl, C6-10Fragrant amino, C1-9Heteroaryl amino, C6-10Aryl C1-6Alkylamino, C1-9Heteroaryl C1-6Alkylamino, C1-9Heteroaryl oxygroup, C1-9Heteroaryl C1-6Alkyl, C6-10Aryl C1-6Alkoxy, C1-9Heteroaryl C1-6Alkoxy, C2-9Heterocycle oxygroup, C2-9Heterocycle C1-6Alkoxy, C2-9Heterocyclylamino group or C2-9Heterocycle alkylamino；
R4And R5It is each independently H, D, F, Cl, Br, I, CN, C1-6Alkyl, C3-8Naphthenic base, halogenated C1-6Alkyl, C1-6Alkane Oxygroup or halogenated C1-6Alkoxy；
R6For H, D, F, Cl, Br, I, CN, OH, NH2, SO2Cl, C1-6Alkyl, C3-8Naphthenic base, C1-6Alkoxy ,-C (=O) R7,-C (=O) OR7,-C (=O) NR7R7a, C6-10Aryl or C6-10Aryl C1-6Alkyl；With
Each R7And R7aIt independently is H, D, C1-6Alkyl, C1-6Miscellaneous alkyl, C1-6Halogenated alkyl, hydroxyl, amino, C1-6Alcoxyl Base, C6-10Aryl, C2-9Heterocycle, C3-8Naphthenic base, C6-10Aryloxy group, C2-9Heterocycle oxygroup, C3-8Cycloalkyl oxy, C6-10Virtue Amino, C2-9Heterocyclylamino group, C3-8Cycloalkyl amino, C1-9Heteroaryl or C3-8Carbocylic radical；Work as R7And R7aIt is former to be connected in the same nitrogen On son, R7, R7aThe former molecular ring of substituted or non-substituted 3-8 can be randomly formed with the nitrogen-atoms being attached thereto.
In some of these embodiments, R1For H, D, C1-4Alkyl, C3-6Naphthenic base or C6-10Aryl C1-4Alkyl.
In some of these embodiments, each R2And R3It independently is and stands alone as H, D, F, Cl, Br, I, OH, NH2, CN, C1-4 Alkyl, C3-6Naphthenic base, C1-4Alkoxy, C2-4Alkenyl, C2-4Alkynyl or C6-10Aryl.
In some of these embodiments, R4And R5Respectively stand alone as H, D, C1-4Alkyl, C3-6Naphthenic base, halogenated C1-4Alkyl Or C1-4Alkoxy.
In some of these embodiments, R6For H, D, F, Cl, Br, I ,-COOH, C1-4Alkyl, C3-6Naphthenic base, C6-10Virtue Base or C6-10Aryl C1-4Alkyl.
In some of these embodiments, the present invention has the vertical of structure shown in the structure as shown in formula (II) or formula (II) Body isomers, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein:
K is 0,1,2,3 or 4；
M is 0,1,2,3 or 4；
N is 1,2 or 3；
R1For H, D, C1-4Alkyl, C3-6Naphthenic base, halogenated C1-4Alkyl or C6-10Aryl C1-4Alkyl；
Each R2And R3Stand alone as H, D, F, Cl, Br, I, CN, OH, NH2, C1-4Alkyl, C3-6Naphthenic base, C1-4Alkoxy, C2-4 Alkenyl, C2-4Alkynyl or C6-10Aryl；
R4And R5Respectively stand alone as H, D, C1-4Alkyl, C3-6Naphthenic base, halogenated C1-4Alkyl or C1-4Alkoxy；With
R6For H, D, F, Cl, Br, I or C6-10Aryl C1-4Alkyl.
In some of these embodiments, R1For H, D, methyl, ethyl, propyl, butyl, cyclopropyl or cyclobutyl.
In other embodiments, each R2And R3Stand alone as H, D, F, Cl, Br, I, CN, OH, NH2, methyl, ethyl, Propyl, butyl, methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopropyl or cyclobutyl.
In some of these embodiments, the present invention includes the structure of one of:
Or its stereoisomer, mutually Tautomeric, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug.
The present invention also includes the application of the compound of the present invention and its pharmaceutically acceptable salt, for producing medical product Alzheimer's disease is treated, it is described in the invention including those.The compound of the present invention is equally used for producing a kind of pharmaceuticals For mitigating, prevent, control or treatment 5-HT6The illness mediated, especially Alzheimer's disease.The present invention includes medicine group Object is closed, which includes compound representated by formula formula (I) or formula (II) and at least one pharmaceutically acceptable load Effective treatment dosage needed for the combination of body, adjuvant or diluent.
Unless otherwise indicated, the stereoisomer that the compound of the present invention is all, geometric isomer, tautomerism Body, nitrogen oxides, hydrate, solvate, metabolite, salt and pharmaceutically acceptable prodrug belong to model of the invention It encloses.
Specifically, salt is pharmaceutically acceptable salt.Term " pharmaceutically acceptable " includes substance or composition must Must be suitble to chemistry or toxicologically, it is related with the other components of composition preparation and mammal for treatment.
The salt of the compound of the present invention further includes the intermediate for being used to prepare or purifying compound shown in formula (I) or formula (II) Or the salt of the enantiomter of the separation of compound shown in formula (I) or formula (II), but it is not necessarily pharmaceutically acceptable salt.
If the compound of the present invention be it is alkaline, conceivable salt can be by provided in the literature any suitable Method is prepared, for example, using inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid etc..Or using organic Acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid；Pyrans Saccharic acid, such as glucuronic acid and galacturonic acid；Alpha-hydroxy acid, such as citric acid and tartaric acid；Amino acid, such as asparatate and paddy Propylhomoserin；Aromatic acid, such as benzoic acid and cinnamic acid；Sulfonic acid, such as p-methyl benzenesulfonic acid, ethanesulfonic acid, etc..
If the compound of the present invention be it is acid, conceivable salt can be prepared by suitable method, e.g., Using inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide or alkaline earth metal hydroxide, etc. Deng.Suitable salt includes, but is not limited to, organic salt obtained from amino acids, such as glycine and arginine, ammonia, and such as primaquine, secondary Ammonia and tertiary ammonia and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium Inorganic salts.
The compounds of this invention and pharmaceutical composition, preparation and administration
When available for treatment, formula (formula (I) or formula (II) compound and its pharmaceutically acceptable salt of therapeutically effective amount It can be used as unprocessed chemicals to give, the active constituent for being alternatively arranged as pharmaceutical composition provides.Therefore, present disclosure is also There is provided pharmaceutical composition, the pharmaceutical composition include therapeutically effective amount formula formula (I) formula (II) compound or its pharmaceutically may be used The salt of receiving and one or more pharmaceutically acceptable carriers, diluent or excipient.
It further comprise carrying out other to patient to resist comprising the treatment method that the compounds of this invention or pharmaceutical composition are administered The administration of Alzheimer disease drug (combination therapy), wherein the drug of other anti-Alzheimer diseases is selected from donepezil, receives Mei Fen, Risperidone, vitamin e, SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX- 8066, SB-742457, naluzaton, Lu-AE58054, Tacrine, Rivastigmine, galanthamine, Memantine, mitzapine, Venlafaxine, desipramine, nortriptyline, zolpidem, zopiclone, Nicergoline, Piracetam, selegiline, pentoxifylline Alkali or their combination.
Term as used herein " therapeutically effective amount " refers to each active group for being enough to show significant patient benefit The total amount divided.When using separate active ingredients for separate administration, which only refers to the ingredient.When combining applications, the term Then refer to the combined amount for regardless of combination, sequential or simultaneous administration all causing the active constituent of therapeutic effect.Formula formula (I) or formula (II) compound and its pharmaceutically acceptable salt are as described above.From it is compatible with preparation other compositions and to its recipient it is harmless In the sense that for, carrier, diluent or excipient must be acceptable.According to another aspect of the present disclosure, it also mentions For method for preparing pharmaceutical preparations, this method includes by formula (I) or formula (II) compound or its pharmaceutically acceptable salt It is mixed with one or more pharmaceutically acceptable carriers, diluent or excipient.Term used in the present invention " pharmaceutically may be used Receive " refer to such compound, raw material, composition and/or dosage form, they are applicable within the scope of reasonable medical judgment In contacted with patient tissue and without excessive toxicity, irritation, allergy or it is relative to a reasonable benefit/risk ratio other Problem and complication, and effective for given application.
In general, the compound of the present invention is by any conventional application method of the substance for playing similar effectiveness to treat Effective quantity is administered.Suitable dosage range is typically daily 1-500mg, preferably daily 1-100mg, most preferably daily 1- 30mg, this depends on many factors, such as age and the relative health, institute of the seriousness of treated disease, subject With the effect of compound, the approach of application and form, the preference of the targeted indication and related medical practitioner of application and Experience.The those of ordinary skill for treating the disease areas relies on personal knowledge and disclosure of this application without excessive experiment It can determine that the therapeutically effective amount of the compounds of this invention for giving disease.
In general, the compound of the present invention is applied with pharmaceutical preparation form, the pharmaceutical preparation includes that those are suitable for taking orally (including oral cavity and sublingual), rectum, nose, part, lung, vagina or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous and vein It is interior) application pharmaceutical preparation or the pharmaceutical preparation suitable for sucking or being blown into administration form.Preferred method of application is usually to take orally, Using suitable daily dose plan, it can be adjusted according to illness degree.
One or more compounds of the invention can be placed in together with one or more conventional adjuvants, carrying agent or diluent In pharmaceutical composition and unit dosage form.Pharmaceutical composition and unit dosage form may include the conventional ingredient of conventional ratio, With or without other reactive compound or ingredient, unit dosage form can contain and applied planned daily dose range phase Any suitable a effective amount of active constituent claimed.The application form of pharmaceutical composition can be solid such as tablet or filling glue Wafer, semisolid, powder, sustained release preparation or liquid such as solution, suspension, emulsion, elixir or the filling glue being administered orally Wafer；Or for rectum or the suppository form of vaginal application；Or the sterile injectable solutions form for parenterally using. Therefore, in every containing about 1mg active constituent or more broadly, the preparation containing about 0.01 to about 100mg active constituent is suitable Representative unit dosage form.
The compound of the present invention can be configured to the dosage form of various oral administrations.Pharmaceutical composition and dosage form can Using comprising one or more compound or pharmaceutically acceptable salt thereofs of the invention as active constituent.Pharmaceutical carrying agent can be solid Or liquid.The preparation packet ^: agent, tablet, pill, capsule, cachet, suppository and dispersible granule of solid form.Solid Carrier can be one or more substances, be also used as diluent, corrigent, solubilizer, lubricant, suspending agent, bonding Agent, preservative, tablet disintegrant or coating material.In powder, carrier is usually finely ground solid, with finely ground activity at Divide and forms mixture.In tablets, active constituent is usually mixed with having the carrying agent of required adhesive force with the ratio for being suitable for And it is pressed into required shapes and sizes.Powder and tablet preferably comprise from about the reactive compound of 1% to about 70%.Suitable cultivation Body includes but is not limited to carbonate, magnesium stearate, talcum powder, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, first Base cellulose, sodium carboxymethylcellulose, low melt wax, cocoa butter etc..Terms " formulation ", which is intended to include house, coating material conduct Carrying agent is to provide the preparation of the reactive compound of capsule, and the active constituent of with or without carrier is by therewith in the capsule In conjunction with the carrying agent surrounded.It similarly, further include cachet and pastille.Tablet, powder, capsule, pill, cachet and ingot Agent is adapted for the solid form being administered orally.
Other forms for being suitable for being administered orally include preparation (including emulsion, syrup, elixir, the aqueous solution of liquid form Agent, aqueous suspension) or it is intended to preparation using the preceding solid form for being changed into liquid form preparation at once.Emulsion can be molten Emulsifier such as lecithin, Sorbitan Monooleate or Arab are prepared or can contained in liquid such as aqueous solution of propylene glycol Glue.Active constituent can be by being dissolved in water and suitable colorant, corrigent, stabilizer and thickening being added by aqueous solution agent It is prepared by agent.Aqueous suspension can be by with for example natural or synthetic glue of stickum, resin, methylcellulose, carboxymethyl Finely ground active constituent is dispersed in water to prepare by sodium cellulosate and other well known suspending agent.The preparation of liquid form includes Solution, suspension and emulsion, it can also contain colorant, corrigent, stabilizer, buffer, people other than active constituent Sweetener make and natural, dispersing agent, thickener, solubilizer etc..
The compound of the present invention can be prepared for parenteral administration (for example, passing through injection such as bolus injection or continuous defeated Note application) and can be present in a unit ampoule, in advance filling syringe, in low capacity infusion or be present in It is added in the multi-dose container of preservative.The adoptable form of composition has suspension for example in oily or aqueous excipients Agent, solution or emulsion, such as solution in polyethylene glycol solution.Oiliness or non-aqueous carrying agent, diluent, solvent or The example of excipient includes propylene glycol, polyethylene glycol, vegetable oil (such as olive oil) and organic esters for injection (such as oleic acid second Ester), and formulating substances such as preservative, wetting agent, emulsifier or suspending agent, stabilizer and/or dispersing agent can be contained.Alternatively, Active constituent can be powder type, preparation method be by sterile solid carry out without mattress dispense or by by solution be lyophilized so as to Using preceding with suitable excipient is for example sterile, pyrogen-free water is constructed.
The compound of the present invention can be prepared in the form of ointment, cream or lotion or in a form of transdermal patch office Portion is applied to epidermis.Ointment and cream can be for example with being added to the aqueous or oily of suitable thickener and/or gelling agent Property matrix is prepared.Lotion can be prepared with water or oily matrix and usually also contain one or more emulsifying agents, steady Determine agent, dispersing agent, suspending agent, thickener or colorant.Preparation suitable for topical application in the mouth includes comprising in flavoring base The pastille of matter, usually sucrose and the active constituent in Arabic gum or tragacanth；Comprising in inert base such as gelatin and The pastille of active constituent in glycerol or sucrose and Arabic gum；And comprising being in a suitable liquid carrier active constituent Collutory.
The compound of the present invention can be prepared for applying with suppository form.It can be first by low melt wax such as fatty acid glycerine Ester admixture or cocoa butter fusing, and active constituent is for example dispersed evenly by stirring.Then by the homogeneous mixture of melting It pours into the mold of suitable size, be allowed to cool and solidify.
The compound of the present invention can be prepared for vaginal application.Also contain carrying agent known in this field in addition to the active ingredient (s Vaginal plug, tampon, milk agent, gelling agent, paste, foaming agent or spray are suitable.
The compound of the present invention can be prepared for nasal administration.Can by solution or suspension by conventional method, example Such as nasal cavity is directly applied to dropper, suction pipe or sprayer.Preparation can be single dose or multiple dose form.For dropper or suction The multiple dose form of pipe, this can be realized by solution that be suitable for by patient's application, predetermined volume or suspension.For Sprayer, this can for example be realized by metering atomizing pump.
The compound of the present invention can be prepared for aerosol application, especially be applied to respiratory tract and including intranasally applying With.Compound usually has a small granularity, such as the granularity of 5 microns or more decimal magnitude.The granularity can pass through this field Well known method for example passes through micronization acquisition.Active constituent is to contain suitable propellant such as chlorofluorocarbon (CFC) such as dichloro The pressurized package of difluoromethane, trichlorofluoromethane or dichlorotetra-fluoroethane or carbon dioxide or other suitable gas provides.Gas Mist agent can also suitably contain surfactant such as lecithin.Drug dose can be controlled by metering valve.Alternatively, active constituent can With with dry powdered form, for example in suitable powder base such as lactose, starch, starch derivatives such as hydroxypropyl methyl cellulose and The mixture of powders form of compound in polyvinylpyrrolidone provides.Powder carrier will form gel in nasal cavity.Powder Composition can be in a unit for example with gelatine capsule agent or cylindrantherae or bubble army's packaged form presence ' inhalator can be passed through By wherein applying powder.
When needing, preparation can be prepared with the enteric coating for being suitable for sustained release or controlled release application active constituent.For example, this The compound of invention can be formulated into transdermal or subcutaneous drug delivery device.When it is necessary to release the compound and work as patient for treatment When the compliance of scheme is most important, these delivery systems are advantageous.Compound in transdermal delivery system is often attached to In skin adhesive solid carrying agent.Compound of interest can also be with penetration enhancer, such as laurocapram " hole 1- 12 Base azacyclo- hept- 2- ketone) it is applied in combination.It can be inserted subcutaneously into a sustained release delivery system by surgery or injection hypodermic layer.Subcutaneously Compound is encapsulated in liquid soluble membrane, such as silicon rubber or Biodegradable polymeric such as polylactic acid for implantation material.
Pharmaceutical preparation is preferably unit dosage form.In the form, preparation is subdivided into containing appropriate amount active constituent Unit dose.Unit dosage form can be the preparation of packaging kit, the preparation containing discrete magnitude in packaging, such as complete packet The tablet of dress, capsule and powder or ampulla agent in the vial.In addition, unit dosage form can be capsule, tablet, flat Wafer or pastille itself or its any one of these form that can be suitable number in package form.
Other suitable medicinal carriers and their preparation are in Remington:The Science and Practice of Pharmacy1995Martin, E.W are edited, Mack Publishing Company, and the 19th edition, Easton, Pennsylvania In be described.
The purposes of the compounds of this invention and pharmaceutical composition
The feature of pharmaceutical composition of the invention includes listed by formula formula (I) or formula (II) compound represented or the present invention Compound and pharmaceutically acceptable carrier, adjuvant or excipient.Can there is the amount of compound in composition of the invention Imitate ground detectably antagonism 5-HT6To treat obesity, enterogastric diseases, CNS illness, wherein the CNS illness includes: ADHD, anxiety, disease relating to mental stress, schizophrenia, besetment and behavior disorder, manic-depressive psychosis, nerve Illness, memory disorders, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntingdon dance Step disease etc..
" effective quantity " or " effective dose " of the compound of the present invention or pharmaceutically acceptable composition refer to processing or Mitigate the effective quantity that one or more present invention are previously mentioned the severity of illness.According to the method for the present invention, compound and combination Object can be any dosage and any administration route to be efficiently used for handling or mitigate the severity of disease.Required standard True amount will change according to the case where patient, this is depending on ethnic, the age, the general condition of patient, the severity of infection, Special factor, administration mode, etc..Compound or composition can be administered in combination with one or more other therapeutic agents, such as What the present invention was discussed.
The general synthetic method of the compounds of this invention
Generally, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein the definition of substituent group is as shown in formula (i) or formula (ii).Following reaction scheme and embodiment is for further lifting Example illustrates the contents of the present invention.
Those skilled in the art will realize that: chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent purchase is in quotient Product supplier such as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Imperial chemistry examination is risen in factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Qingdao Agent Co., Ltd and Haiyang Chemical Plant, Qingdao are commercially available.
Anhydrous tetrahydro furan is dried to obtain by sodium metal reflux.Anhydrous methylene chloride and chloroform are returned by calcium hydride Stream is dried to obtain.Ethyl acetate, petroleum ether, n,N-dimethylacetamide and n,N-Dimethylformamide are through anhydrous sodium sulfate thing It is first dry to use.
Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below Show), reaction flask all squeezed by syringe beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is using silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR spectrum with CDC13,d6-DMSO,CD3OD or d6Acetone is solvent (report is as unit of ppm), with TMS (0ppm) or chloroform (7.25ppm) As reference standard.When there is multiplet, following abbreviation will be used: s (singlet, unimodal), d (doublet, it is double Peak), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, quartet), dt (doublet of triplets, double triplets).Coupling constant is indicated with hertz (Hz).
By outfit G1312A binary pump and a G1316A TCC, (column temperature is maintained at 30 to low resolution mass spectrometry (MS) data DEG C) the spectrometer of Agilent6320 series LC-MS measure, G1329A automatic sampler and G1315B DAD detector Applied to analysis, the source ESI is applied to LC-MS spectrometer.
Low resolution mass spectrometry (MS) data are by being equipped with G1311A quaternary pump and G1316A TCC (column temperature is maintained at 30 DEG C) The spectrometer of Agilent6120 series LC-MS measure, G1329A automatic sampler and G1315D DAD detector application In analysis, the source ESI is applied to LC-MS spectrometer.
Both the above spectrometer is provided with Agilent Zorbax SB-C18 column, and specification is 2.1 × 30mm, and 5 μm.Note Beam product is determined by sample concentration；Flow velocity is 0.6mL/min；The peak value of HPLC is by 210nm and 254nm UV-Vis wavelength records reading.Mobile phase is that 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid are ultrapure water-soluble Liquid (phase B).Condition of gradient elution is as shown in table 1:
Table 1
Time (min) A(CH3CN, 0.1%HCOOH) B(H2O, 0.1%HCOOH)
0-3 5-100 95-0
3-6 100 0
6-6.1 100-5 0-95
6.1-8 5 95
Compound purifying is by Agilent1100 series of high efficiency liquid chromatogram (HPLC) come what is evaluated, and wherein UV is detected At 210nm and 254nm, Zorbax SB-C18 column, specification be 2.1 × 30mm, 4 μm, 10 minutes, flow velocity 0.6mL/min, (0.1% aqueous formic acid) of (0.1% formic acid acetonitrile solution) of 5-95%, column temperature is maintained at 40 DEG C.
The use of logogram word below is through the present invention:
H2SO4Sulfuric acid
HOAc acetic acid
NaOAc sodium acetate
MeCN,CH3CN acetonitrile
Cl3C2OCl trichloro-acetic chloride
CHCl3Chloroform
CDC13Deuterated chloroform
ClSO2OH chlorosulfonic acid
DMF N,N-dimethylformamide
DMAC DMAC N,N' dimethyl acetamide
DMSO dimethyl sulfoxide
EtOAc ethyl acetate
EA ethyl acetate
HCl hydrochloric acid
MgSO4Magnesium sulfate
MeOH,CH3OH methanol
HCHO formaldehyde
CH2Cl2, DCM methylene chloride
ML, ml milliliters
PE petroleum ether (60-90 DEG C)
Na2CO3 Sodium carbonate
NaHCO3Sodium bicarbonate
KOH potassium hydroxide
RT, rt room temperature
Rt retention time
NaBH3CN sodium cyanoborohydride
NaCl sodium chloride
NaH sodium hydride
Na2SO4Sodium sulphate
THF tetrahydrofuran
C5H8O 1,4- dihydropyran
C2H7NHCl dimethylamine hydrochloride
Et3N, TEA triethylamine
H2O water
DME glycol dimethyl ether
TsCl paratoluensulfonyl chloride
5- flutamine 2- (the fluoro- 1H- indol-3-yl of 5-) ethamine
6- flutamine 2- (the fluoro- 1H- indol-3-yl of 6-) ethamine
EDTA ethylenediamine tetra-acetic acid
PEI polyethyleneimine
Pargyline Pargyline
Tris-HCl tri- (methylol) aminomethane-hydrochloric acid
Following synthetic schemes describes the step of preparation disclosed compound of present invention.Unless otherwise stated, each m and R3Have Definition as described in the present invention.
Synthetic method 1
Compound (4) and (5) can be prepared by following process:
Difference replace tryptamines compound (1) reacted with formaldehyde, under the conditions of existing for the reducing agent sodium cyanoborohydride To double methylated compounds (2).Compound (2) with sulfonic acid chloride obtain in the presence of alkali compound (3).Compound (3) in alkali Obtained under the action of (potassium hydroxide) removing tribromo-acetyl based compound (4), compound (4) further with formaldehyde reaction Conjunction object (5)。
Synthetic method 2
Compound (11) and (12) can be prepared by following process:
Different substituted phenylhydrazines hydrochloride compounds (6) react to obtain with 3,4-2H- dihydropyran Benzazole compounds (7)。 Formula (7) compound represented catalytic amount DMAP (4-dimethylaminopyridine) effect under react to obtain chemical combination with paratoluensulfonyl chloride Object (8).Compound (8) react to obtain with dimethylamine compound (9).Then, compound (9) reacted under alkali effect with sulfonic acid chloride Obtain compound (10)；Compound (10) potassium hydroxide effect under removing trichloroacetyl obtain compound (11).Finally, formula Compound (11) react to obtain with formaldehyde formula compound (12)。
Compound provided by the invention, pharmaceutical composition and its application are further described with reference to embodiments.
Embodiment
Embodiment 1:2- (the fluoro- 1- of 6- (4- methoxy -3- (piperazine -1- base) benzenesulfonyl) -1H- indol-3-yl)-N, N- bis- The synthesis of methyl ethyl-amine
Step 1) 2- (the fluoro- 1H- indol-3-yl of 6-)-N, the synthesis of N- dimethyl amine
6- fluorochrome hydrochloride (1g, 4.66mmol) and sodium acetate (382mg, 4.66mmol) are added to methanol (15mL) In, then NaBH is successively slowly added at 0 DEG C3CN (881mg, 13.98mmol) and formaldehyde (40%, 0.975mL, 13.98mmol).Reaction is warming up to 25 DEG C after ten minutes, and the reaction was continued 5 hours.Stop reaction, sequentially adds water (10mL) and carbon Sour sodium (988mg, 9.32mmol) quenching reaction.It is extracted with methylene chloride (50mL x3), merges organic phase, use anhydrous sodium sulfate It is dry.Filtering, filtrate decompression are spin-dried for, and column chromatographic purifying (methylene chloride/methanol (v/v)=20/1) obtains title compound as palm fibre Color solid (824.6mg, 85.9%).
MS(ESI,pos.ion)m/z:207.1[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 8.12 (brs, 1H), 7.50 (dd, J=8.4,5.2Hz, 1H), 7.02 (d, J=2.2Hz, 1H), 7.00-6.98 (m, 1H), 6.90-6.85 (m, 1H), 2.95-2.91 (m, 2H), 2.67-2.63 (m, 2H),2.35(s,6H)。
The synthesis of the chloro- 1- of step 2) 2,2,2- tri- (4- (2- anisyl) piperazine -1- base) ethyl ketone
1- (2- methoxyphenyl) piperazine hydrochloride (1.0g, 4.39mmol) and triethylamine (2.5mL, 17.70mmol) are added Enter into 15mL methylene chloride, trichloro-acetic chloride (1.0mL, 8.96mmol) is slowly added dropwise under 0 DEG C of low temperature bath, after dripping, turns It moves at 25 DEG C and reacts 24 hours, stop reaction, 50mL methylene chloride is added, is washed with saturated sodium bicarbonate solution (40mL), point Organic phase is dry with anhydrous sodium sulfate after liquid.Filtering, filtrate decompression are spin-dried for, column chromatographic purifying (petrol ether/ethyl acetate (v/v) =10/1) obtaining title compound is faint yellow solid (763mg, 52%).
MS(ESI,pos.ion)m/z:337.0[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.09-7.06(m,1H),6.96-6.91(m,3H),4.03(brs, 4H), 3.91 (s, 3H), 3.18 (t, J=4.4Hz, 4H)；
The synthesis of step 3) 4- methoxy -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene -1- sulfonic acid chloride
The chloro- 1- of 2,2,2- tri- (4- (2- anisyl) piperazine -1- base) ethyl ketone (550mg, 1.63mmol) is dissolved in 5mL bis- It in chloromethanes, is then added drop-wise in 3mL chlorosulfonic acid in the case where 0 DEG C of low temperature is bathed, after reaction one hour, introduces the reaction solution to ice water In the mixed liquor of (30mL) and methylene chloride (50mL), it is vigorously stirred rear liquid separation, organic phase is dry with anhydrous magnesium sulfate.Filtering, Filtrate decompression is spin-dried for obtaining title compound being faint yellow solid (548mg, 78.5%).
MS(ESI,pos.ion)m/z:435.0[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 7.75 (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)；
The chloro- 1- of step 4) 2,2,2- tri- (4- (5- (the fluoro- 1H- indoles -1- sulphonyl of 3- (2- (dimethylamino) ethyl) -6- Base) -2- anisyl) piperazine -1- base) and ethyl ketone synthesis
By 2- (the fluoro- 1H- indol-3-yl of 6-)-N, N- dimethyl amine (487.6mg, 2.367mmol) and hydrogen at 0 DEG C Change sodium (94.7mg, 2.4mmol) to be added in DMF (3mL), is then slowly added into 4- methoxy -3- (4- (2,2,2- tribromo-acetyls Base) piperazine -1- base) benzene -1- sulfonic acid chloride (860mg, 1.97mmol).Reaction ten minutes later, is warming up to 25 DEG C, and it is 2 small that the reaction was continued When.100mL ethyl acetate is added, then washes (30mL x3) with saturated sodium chloride solution, organic phase anhydrous sodium sulfate after liquid separation It is dry.Filtering, filtrate decompression are spin-dried for, and it is light that column chromatographic purifying (methylene chloride/methanol (v/v)=50/), which obtains title compound, Brown solid (386mg, 32.4%).
MS(ESI,pos.ion)m/z:605.2[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 7.68 (dd, J=9.8,2.2Hz, 1H), 7.56 (dd, J=8.6, 2.3Hz, 1H), 7.42 (dd, J=8.7,5.2Hz, 1H), 7.33 (s, 1H), 7.28 (d, J=2.3Hz, 1H), 6.99 (td, J= 9.0,2.3Hz, 1H), 6.86 (d, J=8.7Hz, 1H), 3.93 (brs, 4H), 3.88 (s, 3H), 3.08 (t, J=4.9Hz, 4H), 2.85 (t, J=7.4Hz, 2H), 2.63 (t, J=8.5Hz, 2H), 2.35 (s, 6H)；
Step 5) 2- (the fluoro- 1- of 6- (4- methoxy -3- (piperazine -1- base) benzenesulfonyl) -1H- indol-3-yl)-N, N- diformazan The synthesis of base ethamine
At 25 DEG C, by 2,2,2- tri- chloro- 1- (4- (5- (the fluoro- 1H- indoles -1- sulphurs of 3- (2- (dimethylamino) ethyl) -6- Acyl group) -2- anisyl) piperazine -1- base) secondKetone(359mg, 0.594mmol) is dissolved in tetrahydrofuran (20mL), then slowly It is added potassium hydroxide (100mg, 1.783mmol are made into 1mmol/ml aqueous solution).After reaction solution is stirred to react 24 hours, it is added 60ml methylene chloride；Organic phase washes (30mL x3) with saturated sodium chloride solution, and organic phase is dry with anhydrous sodium sulfate after liquid separation. Filtering, filtrate is depressurized and spin-dried, and it is yellowish that column chromatographic purifying (methylene chloride/methanol (v/v)=10/1), which obtains title compound, Color solid (248mg, 90.8%).
MS(ESI,pos.ion)m/z:231.1[M+2H]2+/2；
1H NMR(400MHz,CDCl3): δ (ppm) 7.68 (dd, J=9.6,2.4Hz, 1H), 7.51 (dd, J=8.8, 2.3Hz, 1H), 7.39 (dd, J=8.7,2.4Hz, 1H), 7.32 (s, 1H), 7.28 (d, J=2.3Hz, 1H), 6.97 (td, J= 9.0,2.3Hz, 1H), 6.81 (d, J=8.6Hz, 1H), 3.85 (s, 3H), 3.01 (d, J=5.0Hz, 4H), 2.95 (d, J= 4.8Hz, 4H), 2.80 (t, J=7.4Hz, 2H), 2.57 (t, J=7.2Hz, 2H), 2.31 (s, 6H)；
13C NMR(100MHz,CDCl3): δ (ppm) 161.1 (d, J=240.0Hz), 156.7,142.4,135.7 (d, J =12.0Hz), 129.9,127.5,123.4 (d, J=4.0Hz), 122.6,120.9,120.3 (d, J=10.0Hz), 116.5, 111.5 (d, J=24.0Hz), 111.0,101.3 (d, J=28.0Hz), 59.2,56.1,51.6,46.2,45.5,23.6.
Embodiment 2:2- (the fluoro- 1- of 6- ((4- methoxy -3- (4- methylpiperazine-1-yl) phenyl) sulfonyl) -1H- indoles -3- Base)-N, the synthesis of N- dimethyl amine
By 2- (the fluoro- 1- of 6- (4- methoxy -3- (piperazine -1- base) benzenesulfonyl) -1H- indol-3-yl)-N, N- dimethyl second Amine (248mg, 0.539mmol) is dissolved in methanol (10mL), and two drop acetic acid are added.At 0 DEG C, by sodium cyanoborohydride (85mg, 1.35mmol) it is slowly added into reaction solution with formaldehyde (40%, 0.112mL, 1.617mmol).Reaction ten minutes later, is warming up to 25℃；After the reaction was continued 5 hours, 10mL water is added and sodium carbonate (370mg, 3.5mmol) is quenched, is then extracted with dichloromethane (50mL x3).Merge organic phase, anhydrous sodium sulfate is dry；Filtering, filtrate decompression are spin-dried for, column chromatographic purifying (methylene chloride/first Alcohol (v/v)=15/1) title compound is obtained as white solid (160.6mg, 62.9%).
HPLC analysis:96.8%.
MS(ESI,pos.ion)m/z:238.3[M+2]+/2；
1H NMR(400MHz,CDCl3): δ (ppm) 7.68 (dd, J=9.8,2.3Hz, 1H), 7.50 (dd, J=8.6, 2.3Hz, 1H), 7.39 (dd, J=8.6,5.2Hz, 1H), 7.33 (s, 1H), 7.28 (d, J=2.3Hz, 1H), 6.96 (td, J= 9.0,2.4Hz, 1H), 6.80 (d, J=8.6Hz, 1H), 3.84 (s, 3H), 3.02 (s, 4H), 2.80 (t, J=7.4Hz, 2H), 2.60-2.56(m,6H),2.33(s,3H),2.31(s,6H)；
13C NMR(100MHz,CDCl3): δ (ppm) 161.1 (d, J=241.0Hz), 156.7,142.0,135.6 (d, J =12.0Hz), 129.9,127.5,123.4 (d, J=4.0Hz), 122.5,120.9,120.3 (d, J=10.0Hz), 116.4, 111.5 (d, J=24.0Hz), 111.0,101.3 (d, J=28.0Hz), 59.2,56.1,55.2,50.3,46.2,45.5, 23.5。
Embodiment 3:2- (5- methoxy -1- (4- methoxy -3- (piperazine -1- base) benzenesulfonyl) -1H- indol-3-yl)-N, N- The synthesis of dimethyl amine
Step 1) 2- (5- methoxy -1H- indol-3-yl)-N, the synthesis of N- dimethyl amine
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e., by 5-MT 5-methoxytryptamine salt Hydrochlorate (801mg, 3.53mmol), sodium acetate (382mg, 4.66mmol), NaBH3CN (881mg, 13.98mmol) and formaldehyde (40%, 0.975mL, 13.98mmol) reaction preparation in methanol (15mL), crude product is through silica gel column chromatography (methylene chloride/first Alcohol (v/v)=10/1), it is yellow oil (691mg, 89.8%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:219.10[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 8.03 (s, 1H), 7.24 (d, J=8.8Hz, 1H), 7.05 (d, J= 2.3Hz, 1H), 7.00 (d, J=1.7Hz, 1H), 6.85 (dd, J=8.8,2.4Hz, 1H), 3.87 (s, 3H), 2.94 (t, J= 8.4Hz,2H),2.70-2.66(m,2H),2.38(s,6H)；
The chloro- 1- of step 2) 2,2,2- tri- (4- (5- (3- (2- (dimethylamino) ethyl) -5- methoxy -1H- indoles -1- sulphonyl Base) -2- anisyl) piperazine -1- base) and ethyl ketone synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (5- methoxy- 1H- indol-3-yl)-N, N- dimethyl amine (409mg, 1.88mmol), sodium hydride (90mg, 2.25mmol), 4- methoxy -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene -1- sulfonic acid chloride (981mg, 2.25mmol) reaction system in DMF (3mL) Standby, for crude product through silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is light brown that concentrate drying, which obtains title compound, Color solid (290mg, 25%).
MS(ESI,pos.ion)m/z:617.2[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 7.85 (d, J=9.0Hz, 1H), 7.52 (dd, J=8.6,2.3Hz, 1H), 7.31 (s, 1H), 7.26-7.25 (m, 1H), 6.95 (d, J=2.3Hz, 1H), 6.92 (dd, J=8.9,2.5Hz, 1H), 6.82 (d, J=8.7Hz, 1H), 3.96 (brs, 4H), 3.86 (s, 3H), 3.83 (s, 3H), 3.05 (t, J=4.9Hz, 4H), 2.86 (t, J=7.4Hz, 2H), 2.66 (t, J=8.5Hz, 2H), 2.39 (s, 6H)；
Step 3) 2- (5- methoxy -1- (4- methoxy -3- (piperazine -1- base) benzenesulfonyl) -1H- indol-3-yl)-N, N- bis- The synthesis of methyl ethyl-amine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., chloro- by 2,2,2- tri- 1- (4- (5- (3- (2- (dimethylamino) ethyl) -5- methoxy -1H- indoles -1- sulfonyl) -2- anisyl) piperazine -1- base) Ethyl ketone (290mg, 0.47mmol), potassium hydroxide (79mg, 1.41mmol are made into 1mmol/ml aqueous solution) are in tetrahydrofuran Reaction preparation in (20mL), crude product are marked through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), concentrate drying Topic compound is white solid (110mg, 49.6%).
MS(ESI,pos.ion)m/z:237.3[M+2H]2+/2；
1H NMR(400MHz,CDCl3): δ (ppm) 7.86-7.84 (m, 1H), 7.47 (dd, J=8.6,2.3Hz, 1H), 7.30 (s, 1H), 7.26 (s, 1H), 6.90-6.88 (m, 2H), 6.77 (d, J=8.6Hz, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 2.99 (d, J=4.3Hz, 4H), 2.93 (d, J=2.6Hz, 4H), 2.78 (t, J=7.4Hz, 2H), 2.57 (t, J= 8.5Hz,2H),2.31(s,6H)。
Embodiment 4:2- (5- methoxy -1- ((4- methoxy -3- (4- methylpiperazine-1-yl) phenyl) sulfonyl) -1H- indoles - 3- yl)-N, the synthesis of N- dimethyl amine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., by 2- (5- methoxy -1- (4- methoxy -3- (piperazine -1- base) benzenesulfonyl) -1H- indol-3-yl)-N, N- dimethyl amine (101mg, 0.21mmol), Sodium cyanoborohydride (40mg, 0.63mmol) and formaldehyde (40%, 0.044mL, 0.63mmol) the reaction system in methanol (10mL) Standby, for crude product through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), concentrate drying obtains title compound as white Solid (55.7mg, 53.6%).
HPLC analysis:96.10%；
MS(ESI,pos.ion)m/z:244.2[M+2H]2+/2；
1H NMR(400MHz,CDCl3): δ (ppm) 7.85 (d, J=9.0Hz, 1H), 7.47 (dd, J=8.6,2.3Hz, 1H), 7.31 (s, 1H), 7.27 (d, J=2.3Hz, 1H), 6.93-6.90 (m, 1H), 6.88 (d, J=2.4Hz, 1H), 6.78 (d, J=8.7Hz, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 3.01 (brs, 4H), 2.84-2.80 (m, 2H), 2.64-2.60 (m,2H),2.56(brs,4H),2.36(s,6H),2.34(s,3H)；
13C NMR(100MHz,CDCl3):δ(ppm)156.6,156.5,141.8,132.2,130.2,130.1,124.2, 122.4,120.9,116.5,114.9,113.6,110.9,102.2,59.1,56.1,56.0,55.2,50.3,46.3,45.4, 23.5。
Embodiment 5:2- (5- methyl-1-(4- methoxy-3- (piperazine-1- base) benzenesulfonyl)-1H- indol-3-yl)-N, N- The synthesis of dimethyl amine
Step 1) 2- (5- Methyl-1H-indole -3- base)-N, the synthesis of N- dimethyl amine
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e., by 5-methyltryptamine salt Hydrochlorate (996mg, 4.74mmol), sodium acetate (389mg, 4.74mmol), NaBH3CN (881mg, 13.98mmol) and formaldehyde (40%, 0.975mL, 13.98mmol) reaction preparation in methanol (15mL), crude product is through silica gel column chromatography (methylene chloride/first Alcohol (v/v)=10/1), it is yellow oil (887.5mg, 92.6%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:203.15[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 7.95 (s, 1H), 7.38 (s, 1H), 7.24 (d, J=8.4Hz, 1H), 7.02-6.98 (m, 2H), 2.96 (t, J=8.4Hz, 2H), 2.71 (t, J=8.4Hz, 2H), 2.46 (s, 3H), 2.39 (s, 6H)；
The chloro- 1- of step 2) 2,2,2- tri- (4- (5- (3- (2- (dimethylamino) ethyl) -5- Methyl-1H-indole -1- sulphonyl Base) -2- anisyl) piperazine -1- base) and ethyl ketone synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (5- methyl- 1H- indol-3-yl)-N, N- dimethyl amine (448mg, 2.22mmol), sodium hydride (107mg, 2.66mmol), 4- methoxy -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene -1- sulfonic acid chloride (1.16g, 2.66mmol) reaction system in DMF (5mL) Standby, for crude product through silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is light brown that concentrate drying, which obtains title compound, Color solid (308mg, 23%).
MS(ESI,pos.ion)m/z:601.0[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 7.83 (d, J=8.4Hz, 1H), 7.53 (dd, J=8.6,2.3Hz, 1H), 7.30 (s, 1H), 7.28-7.26 (m, 2H), 7.12 (dd, J=8.4,1.2Hz, 1H), 6.82 (d, J=8.7Hz, 1H), 3.96 (brs, 4H), 3.86 (s, 3H), 3.05 (t, J=4.9Hz, 4H), 2.84 (t, J=7.4Hz, 2H), 2.63 (t, J= 8.6Hz,2H),2.42(s,3H),2.36(s,6H)；
Step 3) 2- (5- methyl-1-(4- methoxy-3- (piperazine-1- base) benzenesulfonyl)-1H- indol-3-yl)-N, N- bis- The synthesis of methyl ethyl-amine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., chloro- by 2,2,2- tri- 1- (4- (5- (3- (2- (dimethylamino) ethyl) -5- Methyl-1H-indole -1- sulfonyl) -2- anisyl) piperazine -1- base) Ethyl ketone (301mg, 0.50mmol), potassium hydroxide (84mg, 1.5mmol are made into 1mmol/ml aqueous solution) are in tetrahydrofuran Reaction preparation in (20mL), crude product are marked through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), concentrate drying Topic compound is white solid (220mg, 96.5%).
MS(ESI,pos.ion)m/z:229.1[M+2H]2+/2；
1H NMR(400MHz,CDCl3): δ (ppm) 7.83 (d, J=8.4Hz, 1H), 7.52 (dd, J=8.6,2.2Hz, 1H), 7.35 (s, 1H), 7.29-7.27 (m, 2H), 7.12 (d, J=7.7Hz, 1H), 6.79 (d, J=8.8Hz, 1H), 3.83 (s, 3H), 3.15 (d, J=3.3Hz, 4H), 3.08 (d, J=3.1Hz, 4H), 2.94-2.90 (m, 2H), 2.79-2.75 (m, 2H),2.47(s,6H),2.41(s,3H)。
Embodiment 6:2- (1- ((4- methoxy -3- (4- methylpiperazine-1-yl) phenyl) sulfonyl) -5- Methyl-1H-indole - 3- yl)-N, the synthesis of N- dimethyl amine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., by 2- (5- methyl-1- (4- methoxy -3- (piperazine -1- base) benzenesulfonyl) -1H- indol-3-yl)-N, N- dimethyl amine (100mg, 0.22mmol), Sodium cyanoborohydride (42mg, 0.66mmol) and formaldehyde (40%, 0.046mL, 0.66mmol) the reaction system in methanol (10mL) Standby, for crude product through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), concentrate drying obtains title compound as white Solid (70mg, 68%).
HPLC analysis:97.96%；
MS(ESI,pos.ion)m/z:236.25[M+2H]2+/2；
1H NMR(400MHz,CDCl3): δ (ppm) 7.82 (d, J=8.4Hz, 1H), 7.48 (dd, J=8.6,2.3Hz, 1H), 7.30 (s, 1H), 7.28 (d, J=2.3Hz, 1H), 7.24 (s, 1H), 7.09 (dd, J=8.5,1.1Hz, 1H), 6.76 (d, J=8.7Hz, 1H), 3.82 (s, 3H), 3.00 (s, 4H), 2.81 (t, J=7.4Hz, 2H), 2.62-2.58 (m, 2H), 2.55(s,4H),2.39(s,3H),2.33(s,6H),2.33(s,3H)；
13C NMR(100MHz,CDCl3):δ(ppm)156.4,141.8,133.8,132.8,131.4,130.2,126.1, 123.4,122.4,120.8,119.4,116.5,113.7,110.9,59.2,56.0,55.2,50.3,46.2,45.5,23.5, 21.5。
Embodiment 7:2- (1- (4- methoxy -3- (piperazine -1- base) benzenesulfonyl) -1H- indol-3-yl)-N, N- dimethyl The synthesis of ethamine
Step 1) 2- (1H- indol-3-yl)-N, the synthesis of N- dimethyl amine
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e., by tryptamine hydrochloride (588mg, 3.0mmol), sodium acetate (246mg, 3.0mmol), NaBH3CN (881mg, 13.98mmol) and formaldehyde (40%, 0.975mL, 13.98mmol) the reaction preparation in methanol (15mL), crude product is through silica gel column chromatography (methylene chloride/methanol (v/ V)=10/1), being concentrated and dried and obtaining title compound is Light brown solid (563mg, 99.8%).
MS(ESI,pos.ion)m/z:189.1[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 8.08 (s, 1H), 7.62 (d, J=8.0Hz, 1H), 7.35 (d, J= 8.0Hz, 1H), 7.21-7.17 (m, 1H), 7.14-7.10 (m, 1H), 7.02 (d, J=1.2Hz, 1H), 2.98 (t, J= 8.0Hz,2H),2.71-2.67(m,2H),2.37(s,6H)；
The chloro- 1- of step 2) 2,2,2- tri- (4- (5- (3- (2- (dimethylamino) ethyl) -1H- indoles -1- sulfonyl) -2- first Oxygen phenyl) piperazine -1- base) ethyl ketone synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (1H- indoles- 3- yl)-N, N- dimethyl amine (282mg, 1.5mmol), sodium hydride (72mg, 1.8mmol), 4- methoxy -3- (4- (2,2,2- Trichloroacetyl) piperazine -1- base) benzene -1- sulfonic acid chloride (785mg, 1.8mmol) reaction preparation in DMF (5mL), crude product warp Silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is faint yellow solid that concentrate drying, which obtains title compound, (486mg, 55.3%).
MS(ESI,pos.ion)m/z:587.0[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 7.97 (d, J=8.2Hz, 1H), 7.56 (dd, J=8.72.3Hz, 1H), 7.51 (d, J=7.7Hz, 1H), 7.36 (s, 1H), 7.34-7.29 (m, 2H), 7.24-7.22 (m, 1H), 6.84 (d, J= 8.7Hz, 1H), 3.96-3.90 (m, 4H), 3.86 (s, 3H), 3.06 (t, J=4.9Hz, 4H), 2.92 (t, J=7.4Hz, 2H), 2.70 (t, J=8.5Hz, 2H), 2.41 (s, 6H)；
Step 3) 2- (1- (4- methoxy -3- (piperazine -1- base) benzenesulfonyl) -1H- indol-3-yl)-N, N- dimethyl second The synthesis of amine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., chloro- by 2,2,2- tri- 1- (4- (5- (3- (2- (dimethylamino) ethyl) -1H- indoles -1- sulfonyl) -2- anisyl) piperazine -1- base) ethyl ketone (529mg, 0.90mmol), potassium hydroxide (151mg, 2.7mmol are made into 1mmol/ml aqueous solution) are in tetrahydrofuran (20mL) Reaction preparation, crude product obtain title compound through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), concentrate drying For white solid (374mg, 94%).
MS(ESI,pos.ion)m/z:222.2[M+2H]2+/2；
1H NMR(400MHz,CDCl3): δ (ppm) 7.96 (d, J=8.2Hz, 1H), 7.51 (d, J=2.3Hz, 1H), 7.49-7.47 (m, 1H), 7.35 (s, 1H), 7.31-7.27 (m, 2H), 7.23-7.19 (m, 1H), 6.78 (d, J=8.7Hz, 1H),3.83(s,3H),3.02-3.00(m,4H),2.95-2.94(m,4H),2.85-2.81(m,2H),2.61-2.57(m, 2H),2.32(s,6H)。
Embodiment 8:2- (1- ((4- methoxy -3- (4- methylpiperazine-1-yl) phenyl) sulfonyl) -1H- indol-3-yl) - The synthesis of N, N- dimethyl amine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., by 2- (1- (4- first Oxygen -3- (piperazine -1- base) benzenesulfonyl) -1H- indol-3-yl)-N, N- dimethyl amine (349mg, 0.79mmol), cyano boron The reaction preparation in methanol (10mL) of sodium hydride (151mg, 2.4mmol) and formaldehyde (40%, 0.166mL, 2.4mmol), it is thick to produce For object through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is white solid that concentrate drying, which obtains title compound, (210mg, 58.3%).
HPLC analysis:97.67%；
MS(ESI,pos.ion)m/z:457.20[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 7.98 (d, J=8.2Hz, 1H), 7.54-7.49 (m, 2H), 7.37 (s, 1H), 7.33-7.31 (m, 1H), 7.29-7.28 (m, 1H), 7.25-7.22 (m, 1H), 6.80 (d, J=8.7Hz, 1H), 3.85 (s,3H),3.02(s,4H),2.89-2.85(m,2H),2.67-2.63(m,2H),2.58(s,4H),2.36(s,6H),2.35 (s,3H)；
13C NMR(100MHz,CDCl3):δ(ppm)156.5,141.8,135.5,131.1,130.2,124.8,123.3, 123.2,122.5,120.9,119.5,116.5,114.0,110.9,59.1,56.0,55.1,50.2,46.2,45.3,23.4。
Embodiment 9:2- (the chloro- 1- of 5- (4- methoxy -3- (piperazine -1- base) benzenesulfonyl) -1H- indol-3-yl)-N, N- bis- The synthesis of methyl ethyl-amine
Step 1) 2- (the chloro- 1H- indol-3-yl of 5-)-N, the synthesis of N- dimethyl amine
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e., by 5- chloramine (427mg,2.2mmol)、NaBH3CN (416mg, 6.6mmol) and formaldehyde (40%, 0.477mL, 6.6mmol) are in methanol Reaction preparation in (15mL), crude product are marked through silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), concentrate drying Topic compound is brown solid (478mg, 97.8%).
MS(ESI,pos.ion)m/z:223.1[M+1]+；
1H NMR(400MHz,CDCl3): δ (ppm) 8.32 (s, 1H), 7.55 (d, J=2.0Hz, 1H), 7.23 (d, J= 8.8Hz, 1H), 7.11 (dd, J=8.8,2.0Hz, 1H), 7.02 (d, J=2.0Hz, 1H), 2.93-2.89 (m, 2H), 2.67- 2.64(m,2H),2.36(s,6H)；
The chloro- 1- of step 2) 2,2,2- tri- (4- (5- (the chloro- 1H- indoles -1- sulphonyl of 3- (2- (dimethylamino) ethyl) -5- Base) -2- anisyl) piperazine -1- base) and ethyl ketone synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (the chloro- 1H- of 5- Indol-3-yl)-N, N- dimethyl amine (383mg, 1.72mmol), sodium hydride (76mg, 1.90mmol), 4- methoxy -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene -1- sulfonic acid chloride (828mg, 1.90mmol) reaction preparation in DMF (5mL), For crude product through silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is solid for light brown that concentrate drying obtains title compound Body (356mg, 33.2%).
MS(ESI,pos.ion)m/z:621.2[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 7.88 (d, J=8.8Hz, 1H), 7.53 (dd, J=8.8,2.4Hz, 1H), 7.47 (d, J=2.0Hz, 1H), 7.39 (s, 1H), 7.28-7.25 (m, 2H), 6.85 (d, J=8.8Hz, 1H), 3.96 (brs, 4H), 3.88 (s, 3H), 3.07 (t, J=5.2Hz, 4H), 2.88-2.84 (m, 2H), 2.68 (t, J=8.4Hz, 2H), 2.40(s,6H)；
Step 3) 2- (the chloro- 1- of 5- (4- methoxy -3- (piperazine -1- base) benzenesulfonyl) -1H- indol-3-yl)-N, N- diformazan The synthesis of base ethamine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., chloro- by 2,2,2- tri- 1- (4- (5- (3- (2- (dimethylamino) ethyl) the chloro- 1H- indoles -1- sulfonyl of -5-) -2- anisyl) piperazine -1- base) second Ketone (346mg, 0.56mmol), potassium hydroxide (94mg, 1.68mmol are made into 1mmol/ml aqueous solution) are at tetrahydrofuran (20mL) Middle reaction preparation, crude product obtain title compound through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), concentrate drying Object is white solid (140mg, 52.7%).
MS(ESI,pos.ion)m/z:477.25[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 7.88 (d, J=8.8Hz, 1H), 7.48 (dd, J=8.8,2.4Hz, 1H), 7.43 (d, J=2.0Hz, 1H), 7.38 (s, 1H), 7.27-7.23 (m, 2H), 6.79 (d, J=8.8Hz, 1H), 3.84 (s,3H),3.05-2.96(m,8H),2.80–2.76(m,2H),2.59-2.55(m,2H),2.31(s,6H)；
13C NMR(100MHz,CDCl3):δ(ppm)156.5,142.0,133.6,132.3,129.7,128.9,124.7, 124.5,122.4,120.4,119.1,116.3,114.8,110.8,58.9,55.9,51.2,45.8,45.3,23.2。
It is realApply a 10:2- (the chloro- 1- of 5- ((4- methoxy -3- (4- methylpiperazine-1-yl) phenyl) sulfonyl) -1H- indoles - 3- yl)-N, the synthesis of N- dimethyl amine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., by 2- (the chloro- 1- of 5- (4- methoxy -3- (piperazine -1- base) benzenesulfonyl) -1H- indol-3-yl)-N, N- dimethyl amine (110mg, 0.23mmol), Sodium cyanoborohydride (43mg, 0.69mmol) and formaldehyde (40%, 0.048mL, 0.69mmol) the reaction system in methanol (10mL) Standby, for crude product through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), concentrate drying obtains title compound as white Solid (106mg, 93.6%).
HPLC analysis:95.68%；
MS(ESI,pos.ion)m/z:246.2[M+2H]2+/2；
1H NMR(400MHz,CDCl3): δ (ppm) 7.87 (d, J=8.8Hz, 1H), 7.47 (dd, J=8.8,2.4Hz, 1H), 7.43 (d, J=1.6Hz, 1H), 7.37 (s, 1H), 7.26 (d, J=2.4Hz, 1H), 7.23 (dd, J=8.8,2.0Hz, 1H), 6.79 (d, J=8.4Hz, 1H), 3.84 (s, 3H), 3.01 (s, 4H), 2.80-2.76 (m, 2H), 2.60-2.56 (m, 6H),2.33(s,3H),2.32(s,6H)；
13C NMR(100MHz,CDCl3):δ(ppm)156.4,141.7,133.6,132.2,129.6,128.9,124.7, 124.5,122.2,120.3,119.1,116.2,114.8,110.7,58.8,55.8,54.9,50.0,46.0,45.2,23.1。
Embodiment 11:2- (the bromo- 1- of 5- (4- methoxy -3- (piperazine -1- base) benzenesulfonyl) -1H- indol-3-yl)-N, N- The synthesis of dimethyl amine
Step 1) 2- (the bromo- 1H- indol-3-yl of 5-)-N, the synthesis of N- dimethyl amine
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e., by 5- bromoamine (896mg,3.8mmol)、NaBH3CN (718mg, 11.4mmol) and formaldehyde (40%, 0.823mL, 11.4mmol) are in methanol Reaction preparation in (15mL), crude product are marked through silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), concentrate drying Topic compound is brown solid (705mg, 70.4%).
MS(ESI,pos.ion)m/z:267.0[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 8.41 (s, 1H), 7.71 (d, J=1.6Hz, 1H), 7.24 (dd, J= 8.4,1.6Hz, 1H), 7.16 (d, J=8.4Hz, 1H), 6.98 (d, J=2.0Hz, 1H), 2.91-2.87 (m, 2H), 2.65- 2.61(m,2H),2.35(s,6H)；
The chloro- 1- of step 2) 2,2,2- tri- (4- (5- (the bromo- 1H- indoles -1- sulphonyl of 3- (2- (dimethylamino) ethyl) -5- Base) -2- anisyl) piperazine -1- base) and ethyl ketone synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (the bromo- 1H- of 5- Indol-3-yl)-N, N- dimethyl amine (400mg, 1.50mmol), sodium hydride (72mg, 1.8mmol), 4- methoxy -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene -1- sulfonic acid chloride (785mg, 1.8mmol) reaction preparation in DMF (5mL), slightly For product through silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is Light brown solid that concentrate drying, which obtains title compound, (334mg, 33.5%).
MS(ESI,pos.ion)m/z:665.0[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 7.83 (d, J=8.8Hz, 1H), 7.62 (d, J=1.6Hz, 1H), 7.53 (dd, J=8.8,2.4Hz, 1H), 7.41-7.38 (m, 2H), 7.27 (s, 1H), 6.85 (d, J=8.8Hz, 1H), 3.96 (s,4H),3.88(s,3H),3.09-3.06(m,4H),2.85-2.82(m,2H),2.66-2.62(m,2H),2.37(s,6H)；
Step 3) 2- (the bromo- 1- of 5- (4- methoxy -3- (piperazine -1- base) benzenesulfonyl) -1H- indol-3-yl)-N, N- diformazan The synthesis of base ethamine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., chloro- by 2,2,2- tri- 1- (4- (5- (3- (2- (dimethylamino) ethyl) the bromo- 1H- indoles -1- sulfonyl of -5-) -2- anisyl) piperazine -1- base) second Ketone (539mg, 0.81mmol), potassium hydroxide (134mg, 2.4mmol are made into 1mmol/ml aqueous solution) are at tetrahydrofuran (20mL) Middle reaction preparation, crude product obtain title compound through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), concentrate drying Object is white solid (211mg, 50.1%).
MS(ESI,pos.ion)m/z:261.10[M+2H]2+/2；
1H NMR(400MHz,DMSO-d6): δ (ppm) 7.87 (d, J=8.8Hz, 1H), 7.82 (d, J=1.6Hz, 1H), 7.72 (s, 1H), 7.57 (dd, J=8.8,2.4Hz, 1H), 7.48 (dd, J=8.8,2.0Hz, 1H), 7.24 (d, J=2.4Hz, 1H), 7.07 (d, J=8.8Hz, 1H), 3.81 (s, 3H), 2.98 (s, 8H), 2.79 (t, J=7.2Hz, 2H), 2.57 (t, J= 7.2Hz,2H),2.24(s,6H)；
13C NMR(100MHz,DMSO-d6):δ(ppm)156.9,141.8,133.7,133.2,128.7,127.6, 125.7,122.9,122.7,121.0,116.4,115.9,115.6,112.4,58.5,56.5,49.4,45.2,44.7, 22.4。
Embodiment 12:2- (the bromo- 1- of 5- ((4- methoxy -3- (4- methylpiperazine-1-yl) phenyl) sulfonyl) -1H- indoles - 3- yl)-N, the synthesis of N- dimethyl amine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., by 2- (the bromo- 1- of 5- (4- methoxy -3- (piperazine -1- base) benzenesulfonyl) -1H- indol-3-yl)-N, N- dimethyl amine (185mg, 0.36mmol), Sodium cyanoborohydride (68mg, 1.08mmol) and formaldehyde (40%, 0.075mL, 1.08mmol) the reaction system in methanol (10mL) Standby, for crude product through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), concentrate drying obtains title compound as white Solid (175mg, 92.1%).
HPLC analysis:97.67%；
MS(ESI,pos.ion)m/z:268.2[M+2H]2+/2；
1H NMR(400MHz,CDCl3): δ (ppm) 7.82 (d, J=8.8Hz, 1H), 7.59 (d, J=1.6Hz, 1H), 7.47 (dd, J=8.8,2.4Hz, 1H), 7.37-7.35 (m, 2H), 7.26 (d, J=2.4Hz, 1H), 6.78 (d, J=8.8Hz, 1H),3.83(s,3H),3.00(s,4H),2.80-2.76(m,2H),2.60-2.56(m,6H),2.33(s,3H),2.31(s, 6H).；
13C NMR(100MHz,CDCl3):δ(ppm)156.4,141.7,133.9,132.7,129.5,127.3,124.3, 122.2,122.1,120.1,116.5,116.1,115.1,110.7,58.7,55.8,54.9,50.0,46.0,45.2,23.1。
Embodiment 13:2- (the fluoro- 1- of 5- (4- methoxy -3- (piperazine -1- base) benzenesulfonyl) -1H- indol-3-yl)-N, N- The synthesis of dimethyl amine
Step 1) 2- (the fluoro- 1H- indol-3-yl of 5-)-N, the synthesis of N- dimethyl amine
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e., by 5- flutamine (560mg,3.14mmol)、NaBH3CN (593mg, 9.42mmol) and formaldehyde (40%, 0.680mL, 9.42mmol) are in methanol Reaction preparation in (15mL), crude product are marked through silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), concentrate drying Topic compound is brown oil (630mg, 97.3%).
MS(ESI,pos.ion)m/z:207.1[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 8.15 (s, 1H), 7.26-7.22 (m, 2H), 7.07 (d, J=2.4Hz, 1H), 6.92 (td, J=8.8,2.4Hz, 1H), 2.94-2.91 (m, 2H), 2.67-2.65 (m, 2H), 2.38 (s, 6H)；
The chloro- 1- of step 2) 2,2,2- tri- (4- (5- (the fluoro- 1H- indoles -1- sulphonyl of 3- (2- (dimethylamino) ethyl) -5- Base) -2- anisyl) piperazine -1- base) and ethyl ketone synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (the fluoro- 1H- of 5- Indol-3-yl)-N, N- dimethyl amine (308mg, 1.50mmol), sodium hydride (72mg, 1.8mmol), 4- methoxy -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene -1- sulfonic acid chloride (785mg, 1.8mmol) reaction preparation in DMF (3mL), slightly For product through silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is Light brown solid that concentrate drying, which obtains title compound, (270mg, 29.8%).
MS(ESI,pos.ion)m/z:605.0[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 7.91 (dd, J=9.2,4.4Hz, 1H), 7.53 (dd, J=8.4, 2.0Hz, 1H), 7.41 (s, 1H), 7.27 (d, J=2.4Hz, 1H), 7.17 (dd, J=8.4,2.4Hz, 1H), 7.04 (td, J= 8.8,2.4Hz, 1H), 6.85 (d, J=8.8Hz, 1H), 3.96 (brs, 4H), 3.88 (s, 3H), 3.07 (t, J=5.2Hz, 4H), 2.93 (t, J=11.2Hz, 2H), 2.82-2.78 (m, 2H), 2.51 (s, 6H)；
Step 3) 2- (the fluoro- 1- of 5- (4- methoxy -3- (piperazine -1- base) benzenesulfonyl) -1H- indol-3-yl)-N, N- diformazan The synthesis of base ethamine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., chloro- by 2,2,2- tri- 1- (4- (5- (3- (2- (dimethylamino) ethyl) the fluoro- 1H- indoles -1- sulfonyl of -5-) -2- anisyl) piperazine -1- base) second Ketone (366mg, 0.6mmol), potassium hydroxide (101mg, 1.8mmol are made into 1mmol/ml aqueous solution) are at tetrahydrofuran (20mL) Middle reaction preparation, crude product obtain title compound through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), concentrate drying Object is faint yellow solid (100mg, 36%).
MS(ESI,pos.ion)m/z:461.1[M+1]+；
1H NMR(400MHz,DMSO-d6): δ (ppm) 7.91 (dd, J=8.8,4.4Hz, 1H), 7.72 (s, 1H), 7.56 (dd, J=8.8,2.4Hz, 1H), 7.42 (dd, J=9.2,2.4Hz, 1H), 7.23 (d, J=2.4Hz, 1H), 7.18 (td, J= 9.2,2.4Hz, 1H), 7.06 (d, J=8.8Hz, 1H), 3.81 (s, 3H), 2.95 (brs, 8H), 2.77 (t, J=7.6Hz, 2H), 2.55 (t, J=7.6Hz, 2H), 2.22 (s, 6H)；
13C NMR(100MHz,DMSO-d6): δ (ppm) 159.4 (d, J=236.6Hz), 156.8,141.9,132.5 (d, ), J=9.7Hz 131.4,128.8,126.2,122.6,121.6 (d, J=4.0Hz), 115.9,115.1 (d, J=9.5Hz), 112.8 (d, J=25.5Hz), 112.3,106.0 (d, J=23.5Hz), 58.6,56.5,49.7,45.3,44.9,22.6.
Embodiment 14:2- (the fluoro- 1- of 5- ((4- methoxy -3- (4- methylpiperazine-1-yl) phenyl) sulfonyl) -1H- indoles - 3- yl)-N, the synthesis of N- dimethyl amine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., by 2- (the fluoro- 1- of 5- (4- methoxy -3- (piperazine -1- base) benzenesulfonyl) -1H- indol-3-yl)-N, N- dimethyl amine (97mg, 0.21mmol), cyanogen The reaction preparation in methanol (10mL) of base sodium borohydride (40mg, 0.63mmol) and formaldehyde (40%, 0.044mL, 0.63mmol), For crude product through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is pale yellow colored solid that concentrate drying, which obtains title compound, Body (70mg, 70.3%).
HPLC analysis:97.07%；
MS(ESI,pos.ion)m/z:238.1[M+2H]2+/2；
1H NMR(400MHz,CDCl3): δ (ppm) 7.89 (dd, J=8.8,4.4Hz, 1H), 7.48 (dd, J=8.8, 2.4Hz, 1H), 7.38 (s, 1H), 7.26 (d, J=2.0Hz, 1H), 7.12 (dd, J=8.8,2.4Hz, 1H), 7.00 (td, J= 9.2,2.8Hz, 1H), 6.79 (d, J=8.4Hz, 1H), 3.84c (s, 3H), 3.00 (s, 4H), 2.80-2.76 (m, 2H), 2.60-2.57(m,6H),2.33(s,3H),2.32(s,6H)；
13C NMR(100MHz,CDCl3): δ (ppm) 159.5 (d, J=238.9Hz), 156.4,141.7,132.0 (d, J =9.2Hz), 131.6,129.7,124.8,122.2,120.7 (d, J=4.0Hz), 116.2,114.8 (d, J=9.2Hz), 112.4 (d, J=25.3Hz), 110.7,105.0 (d, J=23.8Hz), 58.7,55.8,54.9,50.0,46.0,45.2, 23.2。
Embodiment 15:3- (1- ((4- methoxy -3- (piperazine -1- base) phenyl) sulfonyl) -1H- indol-3-yl)-N, N- bis- The synthesis of methylpropane -1- amine
The synthesis of step 1) 3- (1H- indol-3-yl) propyl -1- alcohol
Phenylhydrazine (2.25g, 20.8mmol) is dissolved in 4%H2SO4(aq)(50mL) and DMAC N,N' dimethyl acetamide (10mL) In the mixed solvent is warming up to 100 DEG C, and Isosorbide-5-Nitrae-dihydropyran (1.9mL, 20.8mmol) then is added dropwise.100 DEG C are warming up to, reaction Then reaction mixture is cooled to room temperature by 20h, ethyl acetate extraction (50mL × 3) is added, and then washing (50mL × 3) has Machine is mutually dried, filtered with anhydrous sodium sulfate, and filtrate, silica gel column purification (petrol ether/ethyl acetate (v/v)=2/1), concentration is concentrated Obtain white solid (2.29g, 63.0%).
MS(ESI,pos.ion)m/z:176.3[M+H]+；
1H NMR(400MHz,CDCl3), δ (ppm): 8.02 (brs, 1H), 7.60 (d, J=7.8Hz, 1H), 7.32 (d, J =8.1Hz, 1H), 7.20-7.16 (m, 1H), 7.13-7.09 (m, 1H), 6.95 (t, J=1.0Hz, 1H), 3.71 (t, J= 6.4Hz, 2H), 2.84 (t, J=7.4Hz, 2H), 2.00-1.94 (m, 2H)；
The synthesis of step 2) 3- (1H- indol-3-yl) propyl 4- oluene sulfonic acides ester
3- (1H- indol-3-yl) propyl -1- alcohol (0.88g, 5.0mmol) is dissolved in methylene chloride (20mL), successively plus Enter triethylamine (0.8mL, 6.0mmol) and paratoluensulfonyl chloride (1.14g, 6.0mmol), 4h is reacted at room temperature after adding, is added two Then plus water (100mL) chloromethanes (50mL), organic phase is dried, filtered with no ability aqueous sodium persulfate after liquid separation, and filtrate, silicon is concentrated Rubber column gel column purifies (petrol ether/ethyl acetate (v/v)=4/1), concentration, and being dried to obtain title compound is white solid white solid (1.04g, 63.0%).
MS(ESI,pos.ion)m/z:330.2[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 7.98 (brs, 1H), 7.77 (d, J=8.3Hz, 2H), 7.48 (d, J= 7.9Hz, 1H), 7.35-7.30 (m, 3H), 7.18 (td, J=7.1,1.0Hz, 1H), 7.10-7.06 (m, 1H), 6.9 (d, J= 2.0Hz, 1H), 4.08 (t, J=6.2Hz, 2H), 2.81 (t, J=7.2Hz, 2H), 2.43 (s, 3H), 2.07-2.00 (m, 2H)；
The synthesis of step 3) 3- (1H- indol-3-yl)-N, N- dimethylpropane -1- amine
By 3- (1H- indol-3-yl) propyl 4- oluene sulfonic acides ester (1.2g, 3.65mmol) and dimethylamine hydrochloric acid (1.2g, It 14.6mmol) is dissolved in 10mL acetonitrile, triethylamine (1.95mL, 14.6mmol) then is added, reacted 15 hours at 60 DEG C of oil bath, Stop reaction, ethyl acetate (50mL) is added after being cooled to room temperature, then (60mL) is washed with saturated sodium bicarbonate solution, after liquid separation Organic phase is dried, filtered with anhydrous sodium sulfate, and filtrate is concentrated, and silica gel column purification (methylene chloride/methanol (v/v)=20/1) is dense Contracting, being dried to obtain title compound is yellow liquid (383mg, 52%).
MS(ESI,pos.ion)m/z:203.2[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 8.40 (s, 1H), 7.61 (d, J=7.8Hz, 1H), 7.34 (d, J= 8.0Hz, 1H), 7.19 (td, J=7.2,1.0Hz, 1H), 7.13-7.09 (m, 1H), 6.96 (t, J=0.9Hz, 1H), 2.79 (t, J=7.6Hz, 2H), 2.45-2.41 (m, 2H), 2.29 (s, 6H), 1.97-1.86 (m, 2H)；
The chloro- 1- of step 4) 2,2,2- tri- (4- (5- ((3- (3- (dimethylamino) propyl) -1H- indoles -1- base) sulfonyl) - 2- anisyl) piperazine -1- base) ethyl ketone synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 3- (1H- indoles- 3- yl)-N, N- dimethylpropane -1- amine (375mg, 1.86mmol), sodium hydride (80mg, 2.0mmol), 4- methoxy -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene -1- sulfonic acid chloride (892mg, 2.1mmol) reaction preparation in DMF (5mL), slightly For product through silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is Light brown solid that concentrate drying, which obtains title compound, (251mg, 22.5%).
MS(ESI,pos.ion)m/z:601.2[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 7.98 (d, J=8.3Hz, 1H), 7.55 (dd, J=8.6,2.3Hz, 1H), 7.48 (d, J=7.6Hz, 1H), 7.33-7.21 (m, 4H), 6.84 (d, J=8.7Hz, 1H), 3.96 (brs, 4H), 3.86 (s, 3H), 3.05 (t, J=4.9Hz, 4H), 2.71 (t, J=7.5Hz, 2H), 2.47 (t, J=7.4Hz, 2H), 2.35 (s, 6H),1.95-1.91(m,2H)；
Step 5) 3- (1- ((4- methoxy -3- (piperazine -1- base) phenyl) sulfonyl) -1H- indol-3-yl)-N, N- diformazan Base propane -1- amine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., chloro- by 2,2,2- tri- 1- (4- (5- ((3- (3- (dimethylamino) propyl) -1H- indoles -1- base) sulfonyl) -2- anisyl) piperazine -1- base) ethyl ketone (251mg, 0.42mmol), potassium hydroxide (70mg, 1.25mmol are made into 1mmol/ml aqueous solution) are in tetrahydrofuran (10mL) Reaction preparation, crude product obtain title compound through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), concentrate drying For light yellow oil (174mg, 90.6%).
HPLC analysis:95.81%；
MS(ESI,pos.ion)m/z:229.2[M+2H]2+/2；
1H NMR(400MHz,CD3OD): δ (ppm) 8.01 (d, J=8.0Hz, 1H), 7.66 (dd, J=8.0,4.0Hz, 1H), 7.60 (d, J=8.0Hz, 1H), 7.57 (s, 1H), 7.43 (d, J=4.0Hz, 1H), 7.38-7.34 (m, 1H), 7.30- 7.26 (m, 1H), 7.08 (d, J=8.0Hz, 1H), 3.89 (s, 3H), 3.37-3.35 (m, 4H), 3.25-3.22 (m, 4H), (3.21-3.18 m, 2H), 2.90 (s, 6H), 2.82 (t, J=8.0Hz, 2H), 2.18-2.10 (m, 2H)；
13C NMR(100MHz,CD3OD):δ(ppm)158.3,141.5,136.9,132.0,131.0,125.9,124.9, 124.8,124.4,122.7,120.5,117.9,114.9,112.8,58.6,56.7,45.0,43.5,25.3,22.6。
Embodiment 16:3- (1- ((4- methoxy -3- (4- methylpiperazine-1-yl) phenyl) sulfonyl) -1H- indol-3-yl) - The synthesis of N, N- dimethylpropane -1- amine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., by 3- (1- ((4- first Oxygen -3- (piperazine -1- base) phenyl) sulfonyl) -1H- indol-3-yl)-N, N- dimethylpropane -1- amine (71mg, 0.16mmol), sodium cyanoborohydride (30mg, 0.48mmol) and formaldehyde (40%, 0.034mL, 0.48mmol) are in methanol Reaction preparation in (10mL), crude product are marked through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), concentrate drying Topic compound is white solid (60.6mg, 80.8%).
HPLC analysis:95.27%；
MS(ESI,pos.ion)m/z:236.2[M+2H]2+/2；
1H NMR(400MHz,CDCl3): δ (ppm) 8.00 (d, J=8.4Hz, 1H), 7.55 (dd, J=8.4,2.4Hz, 1H), 7.49 (d, J=8.0Hz, 1H), 7.37 (s, 1H), 7.34-7.31 (m, 2H), 7.27-7.23 (m, 1H), 6.84 (d, J= 8.4Hz,1H),3.86(s,3H),3.07(brs,4H),2.79-2.73(m,4H),2.66(brs,4H),2.57(s,6H), 2.41(s,3H),2.15-2.07(m,2H)；
13C NMR(100MHz,CDCl3):δ(ppm)156.4,141.5,135.5,130.6,129.9,124.8,123.1, 123.0,122.5,121.4,119.3,116.4,113.9,110.9,58.2,55.9,54.9,49.8,45.7,44.0,25.1, 22.4。
Embodiment 17:3- (the fluoro- 1- of 5- ((4- methoxy -3- (piperazine -1- base) phenyl) sulfonyl) -1H- indol-3-yl) - The synthesis of N, N- dimethylpropane -1- amine
The synthesis of step 1) 3- (the fluoro- 1H- indol-3-yl of 5-) propyl -1- alcohol
This step title compound method referring to described in 15 step 1 of embodiment is prepared, i.e., by 4- fluorobenzene hydrazonium salt Hydrochlorate (3.37g, 20.8mmol) and 1,4- dihydropyran (1.9mL, 20.8mmol) are dissolved in 4%H2SO4(aq) (50mL) and N, N- The in the mixed solvent of dimethyl acetamide (10mL) reacts preparation, and crude product is through silica gel column chromatography (petrol ether/ethyl acetate (v/ V) it=2/1) purifies, it is white solid (3.53g, 88%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:194.2[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 8.05 (brs, 1H), 7.27-7.23 (m, 1H), 7.03 (d, J= 2.0Hz, 1H), 6.96-6.91 (m, 1H), 3.72 (t, J=6.4Hz, 2H), 2.81 (t, J=7.5Hz, 2H), 2.00-1.93 (m,2H)；
The synthesis of step 2) 3- (the fluoro- 1H- indol-3-yl of 5-) propyl 4- oluene sulfonic acides ester
This step title compound method referring to described in 15 step 2 of embodiment is prepared, i.e., by 3- (the fluoro- 1H- of 5- Indol-3-yl) propyl -1- alcohol (0.97g, 5.0mmol), triethylamine (0.8mL, 6.0mmol) and and paratoluensulfonyl chloride (1.14g, 6.0mmol) is dissolved in reaction preparation in methylene chloride (20mL), and crude product is through silica gel column chromatography (petroleum ether/acetic acid second Ester (v/v)=4/1) purifying, it is white solid (1.28g, 74.0%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:348.1[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)8.00(brs,1H),7.79(s,1H),7.77(s,1H),7.33(s, 1H), 7.31 (s, 1H), 7.27-7.24 (m, 1H), 7.09 (dd, J=9.6,2.4Hz, 1H), 6.96 (d, J=2.1Hz, 1H), 6.92 (dd, J=9.1,2.5Hz, 1H), 4.07 (t, J=6.2Hz, 2H), 2.75 (t, J=7.3Hz, 2H), 2.44 (s, 3H), 2.05-1.97(m,2H)；
Step 3) 3- (the fluoro- 1H- indol-3-yl of 5-)-N, the synthesis of N- dimethylpropane -1- amine
This step title compound method referring to described in 15 step 3 of embodiment is prepared, i.e., by 3- (5- fluorine 1H- Indol-3-yl) propyl 4- oluene sulfonic acides ester (1.27g, 3.65mmol), dimethylamine hydrochloric acid (1.2g, 14.6mmol) He Sanyi Amine (1.95mL, 14.6mmol), which is dissolved in 10mL acetonitrile, reacts preparation, and crude product is through silica gel column chromatography (methylene chloride/methanol (v/ V) it=20/1) purifies, it is yellow oil (0.79g, 98.6%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:221.2[M+H]+；
1H NMR(CDCl3, 400MHz), δ (ppm) 8.14 (s, 1H), 7.20-7.16 (m, 1H), 7.14 (d, J=2.4Hz, 1H), 6.96 (s, 1H), 6.84 (td, J=9.0,2.5Hz, 1H), 2.66 (t, J=7.6Hz, 2H), 2.35 (t, J=7.4, 2H),2.22(s,6H),1.87-1.79(m,2H)；
The chloro- 1- of step 4) 2,2,2- tri- (4- (5- ((3- (3- (dimethylamino) propyl) the fluoro- 1H- indoles -1- base of -5-) sulphur Acyl group) -2- anisyl) piperazine -1- base) and ethyl ketone synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 3- (the fluoro- 1H- of 5- Indol-3-yl)-N, N- dimethylpropane -1- amine (125mg, 0.57mmol), sodium hydride (27mg, 0.68mmol), 4- methoxy - The reaction in DMF (3mL) of 3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene -1- sulfonic acid chloride (298mg, 0.68mmol) Preparation, for crude product through silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is light that concentrate drying, which obtains title compound, Brown solid (131mg, 37%).
MS(ESI,pos.ion)m/z:619.2[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 7.68 (dd, J=9.8,2.2Hz, 1H), 7.56 (dd, J=8.6, 2.3Hz, 1H), 7.42 (dd, J=8.7,5.2Hz, 1H), 7.33 (s, 1H), 7.28 (d, J=2.3Hz, 1H), 6.99 (td, J= 9.0,2.3Hz, 1H), 6.86 (d, J=8.7Hz, 1H), 3.93 (brs, 4H), 3.88 (s, 3H), 3.08 (t, J=4.9Hz, 4H), 2.85 (t, J=7.4Hz, 2H), 2.63 (t, J=8.5Hz, 2H), 2.35 (s, 6H)；
Step 5) 3- (1- ((4- methoxy -3- (piperazine -1- base) phenyl) sulfonyl) the fluoro- 1H- indol-3-yl of -5-)-N, N- The synthesis of dimethylpropane -1- amine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., chloro- by 2,2,2- tri- 1- (4- (5- ((3- (3- (dimethylamino) propyl) the fluoro- 1H- indoles -1- base of -5-) sulfonyl) -2- anisyl) piperazine -1- Base) ethyl ketone (514mg, 0.83mmol), potassium hydroxide (116mg, 2.07mmol are made into 1mmol/ml aqueous solution) is in tetrahydrofuran Reaction preparation in (15mL), crude product are marked through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), concentrate drying Topic compound is light yellow oil (223mg, 57%).
HPLC annalysis:96.03%；
MS(ESI,pos.ion)m/z:238.3[M+2H]2+/2；
1H NMR(400MHz,CDCl3): δ (ppm) 7.93 (dd, J=8.0,4.0Hz, 1H), 7.51 (dd, J=8.0, 4.0Hz, 1H), 7.36 (s, 1H), 7.29 (s, 1H), 7.14 (dd, J=8.0,4.0Hz, 1H), 7.04 (td, J=8.0, 2.0Hz, 1H), 6.82 (d, J=8.0Hz, 1H), 3.86 (s, 3H), 3.06-3.05 (m, 4H), 2.99 (brs, 4H), 2.65 (t, J=8.0Hz, 2H), 2.39 (t, J=8.0Hz, 2H), 2.29 (s, 6H), 1.90-1.82 (m, 2H)；
13C NMR(100MHz,CDCl3): δ (ppm) 159.5 (d, J=239.0Hz), 156.5,142.1,132.2 (d, J =10.0Hz), 131.8,129.7,124.5,122.8 (d, J=4.0Hz), 122.3,116.3,114.8 (d, J=9.0Hz), 112.4 (d, J=25.0Hz), 110.8,105.2 (d, J=24.0Hz), 59.0,55.9,51.3,45.9,45.3,26.7, 22.5。
Embodiment 18:3- (1- ((4- methoxy -3- (4- methylpiperazine-1-yl) phenyl) sulfonyl) fluoro- 1H- indoles-of -5- 3- yl)-N, the synthesis of N- dimethylpropane -1- amine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., by 3- (1- ((4- first Oxygen -3- (piperazine -1- base) phenyl) sulfonyl) the fluoro- 1H- indol-3-yl of -5-)-N, N- dimethylpropane -1- amine (71mg, 0.15mmol), sodium cyanoborohydride (28mg, 0.45mmol) and formaldehyde (40%, 0.034mL, 0.48mmol) are in methanol Reaction preparation in (10mL), crude product are marked through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), concentrate drying Topic compound is white solid (41mg, 44%).
HPLC analysis:96.26%；
MS(ESI,pos.ion)m/z:245.2[M+2H]2+/2；
1H NMR(400MHz,CDCl3): δ (ppm) 7.94 (dd, J=8.8,4.4Hz, 1H), 7.50 (dd, J=8.8, 2.4Hz, 1H), 7.37 (s, 1H), 7.30 (d, J=2.0Hz, 1H), 7.13 (dd, J=8.8,2.4Hz, 1H), 7.04 (td, J= 9.6,2.4Hz, 1H), 6.83 (d, J=8.8Hz, 1H), 3.87 (s, 3H), 3.03 (brs, 4H), 2.67 (t, J=7.6,2H), 2.59 (brs, 4H), 2.47 (t, J=7.2,2H), 2.37 (s, 9H), 1.95-1.88 (m, 2H)；
13C NMR(100MHz,CDCl3): δ (ppm) 159.5 (d, J=239.1Hz) .156.4,141.7,131.9 (d, J =18.0Hz), 129.8,124.6,122.2,116.3,114.9 (d, J=9.3Hz), 112.5 (d, J=25.3Hz), 110.8, 105.1 (d, J=23.8Hz), 58.7,55.9,55.0,50.1,46.0,44.9,26.2,22.5.
Embodiment 19:3- (the chloro- 1- of 5- ((4- methoxy -3- (piperazine -1- base) phenyl) sulfonyl) -1H- indol-3-yl) - The synthesis of N, N- dimethylpropane -1- amine
The synthesis of step 1) 3- (the chloro- 1H- indol-3-yl of 5-) propyl -1- alcohol
This step title compound method referring to described in 15 step 1 of embodiment is prepared, i.e., will be to chlorobenzene hydrazonium salt Hydrochlorate (3.72g, 20.8mmol) and 1,4- dihydropyran (1.9mL, 20.8mmol) are dissolved in 4%H2SO4 (aq) (50mL) and N, The in the mixed solvent of N- dimethyl acetamide (10mL) reacts preparation, and crude product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1 it) purifies, it is white solid (2.35g, 54%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:210.2[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 8.10 (brs, 1H), 7.56 (d, J=1.8Hz, 1H), 7.26-7.24 (m, 2H), 7.11 (dd, J=8.6,1.9Hz, 1H), 6.99 (s, 1H), 3.71 (t, J=6.4Hz, 2H), 2.80 (t, J= 7.5Hz,2H),1.99-1.92(m,2H)；
The synthesis of step 2) 3- (the chloro- 1H- indol-3-yl of 5-) propyl 4- oluene sulfonic acides ester
This step title compound method referring to described in 15 step 2 of embodiment is prepared, i.e., by 3- (the chloro- 1H- of 5- Indol-3-yl) propyl -1- alcohol (1.05g, 5.0mmol), triethylamine (0.8mL, 6.0mmol) and and paratoluensulfonyl chloride (1.14g, 6.0mmol) is dissolved in middle reaction preparation in methylene chloride (20mL), and crude product is through silica gel column chromatography (petroleum ether/acetic acid Ethyl ester (v/v)=4/1) purifying, it is white solid (1.09g, 60.0%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:364.1[M+H]+；
1H NMR(CDCl3, 400MHz): δ (ppm) 8.03 (brs, 1H), 7.76 (d, J=8.3Hz, 2H), 7.44 (d, J= 2.0Hz, 1H), 7.31 (d, J=8.0Hz, 2H), 7.26-7.24 (m1H), 7.11 (dd, J=8.6,2.0Hz, 1H), 6.95 (d, J=2.2Hz, 1H), 4.07 (t, J=6.2Hz, 2H), 2.75 (t, J=7.3Hz, 2H), 2.44 (s, 3H), 2.04-1.97 (m, 2H)；
Step 3) 3- (the chloro- 1H- indol-3-yl of 5-)-N, the synthesis of N- dimethylpropane -1- amine
This step title compound method referring to described in 15 step 3 of embodiment is prepared, i.e., by 3- (the chloro- 1H- of 5- Indol-3-yl) propyl 4- oluene sulfonic acides ester (1.33g, 3.65mmol), dimethylamine hydrochloric acid (1.2g, 14.6mmol) He Sanyi Amine (1.95mL, 14.6mmol), which is dissolved in 10mL acetonitrile, reacts preparation, and crude product is through silica gel column chromatography (methylene chloride/methanol (v/ V) it=20/1) purifies, it is yellow oil (0.68g, 78%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:237.1[M+H]+；
1H NMR(CDCl3, 400MHz): δ 8.20 (s, 1H), 7.55 (d, J=1.9Hz, 1H), 7.27-7.25 (m, 1H), 7.12 (dd, J=8.6,2.0Hz, 1H), 7.01 (s, 1H), 2.74 (t, J=7.6Hz, 2H), 2.42 (t, J=7.5Hz, 2H), 2.29(s,6H),1.94-1.86(m,2H)；
The chloro- 1- of step 4) 2,2,2- tri- (4- (5- ((3- (3- (dimethylamino) propyl) the chloro- 1H- indoles -1- base of -5-) sulphur Acyl group) -2- anisyl) piperazine -1- base) and ethyl ketone synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 3- (the chloro- 1H- of 5- Indol-3-yl)-N, N- dimethylpropane -1- amine (245mg, 1.03mmol), sodium hydride (50mg, 1.22mmol), 4- methoxy - The reaction in DMF (5mL) of 3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene -1- sulfonic acid chloride (543mg, 1.25mmol) Preparation, for crude product through silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is light that concentrate drying, which obtains title compound, Yellow oil (192mg, 29%).
MS(ESI,pos.ion)m/z:635.1[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 7.89 (d, J=8.8Hz, 1H), 7.52 (dd, J=8.8,2.3Hz, 1H), 7.45 (d, J=1.9Hz, 1H), 7.33 (s, 1H), 7.27-7.24 (m, 2H), 6.84 (d, J=8.7Hz, 1H), 3.96 (brs, 4H), 3.87 (s, 3H), 3.07 (t, J=5.0Hz, 4H), 2.65 (t, J=7.4Hz, 2H), 2.38 (t, J=7.4Hz, 2H),2.40(s,6H),1.87-1.84(m,2H)；
Step 5) 3- (1- ((4- methoxy -3- (piperazine -1- base) phenyl) sulfonyl) the chloro- 1H- indol-3-yl of -5-)-N, N- The synthesis of dimethylpropane -1- amine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., chloro- by 2,2,2- tri- 1- (4- (5- ((3- (3- (dimethylamino) propyl) the chloro- 1H- indoles -1- base of -5-) sulfonyl) -2- anisyl) piperazine -1- Base) ethyl ketone (837mg, 1.32mmol), potassium hydroxide (221mg, 3.95mmol are made into 1mmol/ml aqueous solution) is in tetrahydrofuran Reaction preparation in (30mL), crude product are marked through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), concentrate drying Topic compound is light yellow oil (385mg, 59%).
HPLC analysis:96.32%；
MS(ESI,pos.ion)m/z:246.2[M+2H]2+/2；
1H NMR(400MHz,CDCl3): δ (ppm) 7.90 (d, J=8.8Hz, 1H), 7.50 (dd, J=8.8,2.4Hz, 1H), 7.46 (d, J=2.0Hz, 1H), 7.35 (s, 1H), 7.29 (d, J=2.8Hz, 1H), 7.26 (dd, J=8.8,2.0Hz, 1H), 6.81 (d, J=8.8Hz, 1H), 3.86 (s, 3H), 3.06-2.99 (m, 8H), 2.65 (t, J=7.2Hz, 2H), 2.38 (t, J=7.2Hz, 2H), 2.29 (s, 6H), 1.89-1.83 (m, 2H)；
13C NMR(100MHz,CDCl3):δ(ppm)156.5,142.0,133.8,132.3,129.7,128.9,124.7, 124.2,122.4,122.3,119.3,116.3,114.8,110.8,58.9,55.9,51.1,45.8,45.3,26.8,22.4。
Embodiment 20:3- (1- ((4- methoxy -3- (4- methylpiperazine-1-yl) phenyl) sulfonyl) chloro- 1H- indoles-of -5- 3- yl)-N, the synthesis of N- dimethylpropane -1- amine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., by 3- (1- ((4- first Oxygen -3- (piperazine -1- base) phenyl) sulfonyl) the chloro- 1H- indol-3-yl of -5-)-N, N- dimethylpropane -1- amine (231mg, 0.47mmol), sodium cyanoborohydride (89mg, 1.41mmol) and formaldehyde (40%, 0.099mL, 1.41mmol) are in methanol Reaction preparation in (10mL), crude product are marked through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), concentrate drying Topic compound is light yellow oil (121mg, 51%).
HPLC analysis:97.32%；
MS(ESI,pos.ion)m/z:253.1[M+2H]2+/2；
1H NMR(400MHz,CDCl3): δ (ppm) 7.91 (d, J=8.8Hz, 1H), 7.50 (dd, J=8.8,2.4Hz, 1H), 7.46 (d, J=2.0Hz, 1H), 7.35 (s, 1H), 7.30 (d, J=2.0Hz, 1H), 7.26 (dd, J=8.8,2.0Hz, 1H), 6.82 (d, J=8.0Hz, 1H), 3.87 (s, 3H), 3.03 (brs, 4H), 2.67 (t, J=7.2Hz, 2H), 2.37 (s, 3H),2.33(s,6H),1.93-1.85(m,2H)；
13C NMR(100MHz,CDCl3):δ(ppm)156.5,141.8,133.8,132.2,129.7,128.9,124.7, 124.2,122.2,119.2,116.2,114.8,110.8,110.0,58.7,55.9,54.9,50.1,46.0,45.0,26.4, 22.4。
Embodiment 21:3- (the bromo- 1- of 5- ((4- methoxy -3- (piperazine -1- base) phenyl) sulfonyl) -1H- indol-3-yl) - The synthesis of N, N- dimethylpropane -1- amine
The synthesis of step 1) 3- (the bromo- 1H- indol-3-yl of 5-) propyl -1- alcohol
This step title compound method referring to described in 15 step 1 of embodiment is prepared, i.e., by 4- bromobenzene hydrazonium salt Hydrochlorate (4.64g, 20.8mmol) and 1,4- dihydropyran (1.9mL, 20.8mmol) are dissolved in 4%H2SO4(aq)(50mL) and N, N- The in the mixed solvent of dimethyl acetamide (10mL) reacts preparation, and crude product is through silica gel column chromatography (petrol ether/ethyl acetate (v/ V) it=2/1) purifies, it is white solid (1.59g, 30%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:256.0[M+H]+；
1H NMR(CDCl3, 400MHz), δ (ppm) 8.34 (brs, 1H), 7.74 (d, J=1.6Hz, 1H), 7.27 (dd, J =8.4,1.6Hz, 1H), 7.19 (d, J=8.4Hz, 1H), 6.92-6.93 (m, 1H), 3.71 (t, J=6.4Hz, 2H), 2.79 (t, J=7.2Hz, 2H), 1.92-1.99 (m, 2H)；
The synthesis of step 2) 3- (the bromo- 1H- indol-3-yl of 5-) propyl 4- oluene sulfonic acides ester
This step title compound method referring to described in 15 step 2 of embodiment is prepared, i.e., by 3- (the bromo- 1H- of 5- Indol-3-yl) propyl -1- alcohol (1.28g, 5.0mmol), triethylamine (0.8mL, 6.0mmol) and paratoluensulfonyl chloride (1.14g, It 6.0mmol) is dissolved in middle reaction preparation in methylene chloride (20mL), crude product is through silica gel column chromatography (petrol ether/ethyl acetate (v/ V) it=4/1) purifies, it is white solid (1.32g, 63.0%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:408.0[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 8.26 (brs, 1H), 7.80 (d, J=8.0Hz, 2H), 7.62 (d, J= 0.8Hz, 1H), 7.34 (d, J=8.0Hz, 2H), 7.2-7.28 (m, 2H), 6.91 (d, J=1.6Hz, 1H), 4.09 (t, J= 6.0Hz, 2H), 2.75 (t, J=7.2Hz, 2H), 2.46 (s, 3H), 1.99-2.02 (m, 2H)；
Step 3) 3- (the bromo- 1H- indol-3-yl of 5-)-N, the synthesis of N- dimethylpropane -1- amine
This step title compound method referring to described in 15 step 3 of embodiment is prepared, i.e., by 3- (the bromo- 1H- of 5- Indol-3-yl) propyl 4- oluene sulfonic acides ester (1.49g, 3.65mmol), dimethylamine hydrochloric acid (1.2g, 14.6mmol) He Sanyi Amine (1.95mL, 14.6mmol), which is dissolved in 10mL acetonitrile, reacts preparation, and crude product is through silica gel column chromatography (methylene chloride/methanol (v/ V) it=20/1) purifies, it is yellow oil (0.96g, 94%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:281.1[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 8.15 (s, 1H), 7.74 (d, J=1.7Hz, 1H), 7.29-7.23 (m, 2H), 7.03 (t, J=1.2Hz, 1H), 2.76 (t, J=7.5Hz, 2H), 2.45 (t, J=8.0Hz, 2H), 2.34 (s, 6H), 1.97-1.89(m,2H)；
The chloro- 1- of step 4) 2,2,2- tri- (4- (5- ((3- (3- (dimethylamino) propyl) the bromo- 1H- indoles -1- base of -5-) sulphur Acyl group) -2- anisyl) piperazine -1- base) and ethyl ketone synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 3- (the bromo- 1H- of 5- Indol-3-yl)-N, N- dimethylpropane -1- amine (425mg, 1.51mmol), sodium hydride (66mg, 1.65mmol), 4- methoxy - The reaction in DMF (5mL) of 3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene -1- sulfonic acid chloride (725mg, 1.66mmol) Preparation, for crude product through silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is light that concentrate drying, which obtains title compound, Yellow oil (312mg, 30%).
MS(ESI,pos.ion)m/z:679.1[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 7.84 (d, J=8.8Hz, 1H), 7.62 (d, J=1.8Hz, 1H), 7.52 (dd, J=8.6,2.3Hz, 1H), 7.40 (dd, J=8.8,1.9Hz, 1H), 7.31 (s, 1H), 7.27 (s, 1H), 6.84 (d, J=8.7Hz, 1H), 3.96 (s, 4H), 3.87 (s, 3H), 3.07 (t, J=5.0Hz, 4H), 2.65 (t, J=7.4Hz, 2H), 2.38 (t, J=7.1Hz, 2H), 2.29 (s, 6H), 1.87-1.84 (m, 2H)；
Step 5) 3- (1- ((4- methoxy -3- (piperazine -1- base) phenyl) sulfonyl) the bromo- 1H- indol-3-yl of -5-)-N, N- The synthesis of dimethylpropane -1- amine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., chloro- by 2,2,2- tri- 1- (4- (5- ((3- (3- (dimethylamino) propyl) the bromo- 1H- indoles -1- base of -5-) sulfonyl) -2- anisyl) piperazine -1- Base) ethyl ketone (312mg, 0.46mmol), potassium hydroxide (77mg, 1.38mmol are made into 1mmol/ml aqueous solution) is in tetrahydrofuran Reaction preparation in (15mL), crude product are marked through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), concentrate drying Topic compound is light yellow oil (158mg, 64%).
HPLC analysis:97.79%；
MS(ESI,pos.ion)m/z:268.0[M+2H]2+/2；
1H NMR(400MHz,CDCl3): δ (ppm) 7.81 (d, J=8.8Hz, 1H), 7.57 (d, J=1.6Hz, 1H), 7.47 (dd, J=8.4,2.0Hz, 1H), 7.36 (dd, J=8.8,2.0Hz, 1H), 7.31-7.25 (m, 2H), 6.80 (d, J= 8.8Hz, 1H), 3.82 (s, 3H), 3.03-2.98 (m, 8H), 2.61 (t, J=7.2Hz, 2H), 2.41 (t, J=7.6Hz, 2H), 2.29(s,6H),1.88-1.80(m,2H)；
13C NMR(100MHz,CDCl3):δ(ppm)156.6,141.7,134.0,132.7,129.5,127.4,124.0, 122.6,122.2,121.9,116.5,116.3,115.1,110.9,58.8,55.9,50.5,45.2,44.8,26.2,22.4。
Embodiment 22:3- (1- ((4- methoxy -3- (4- methylpiperazine-1-yl) phenyl) sulfonyl) bromo- 1H- indoles-of -5- 3- yl)-N, the synthesis of N- dimethylpropane -1- amine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., by 3- (1- ((4- first Oxygen -3- (piperazine -1- base) phenyl) sulfonyl) the bromo- 1H- indol-3-yl of -5-)-N, N- dimethylpropane -1- amine (71mg, 0.13mmol), sodium cyanoborohydride (25mg, 0.39mmol) and formaldehyde (40%, 0.027mL, 0.39mmol) are in methanol Reaction preparation in (10mL), crude product are marked through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), concentrate drying Topic compound is light yellow oil (40mg, 56%).
HPLC analysis:95.72%；
1H NMR(400MHz,CDCl3): δ (ppm) 7.86 (d, J=8.8Hz, 1H), 7.62 (d, J=2.0Hz, 1H), 7.49 (dd, J=8.8,2.4Hz, 1H), 7.39 (dd, J=8.8,2.0Hz, 1H), 7.33 (s, 1H), 7.29 (d, J=2.4Hz, 1H), 6.82 (d, J=8.4Hz, 1H), 3.86 (s, 3H), 3.03 (brs, 4H), 2.66 (t, J=7.2Hz, 2H), 2.58 (brs, 4H), 2.44 (t, J=7.2Hz, 2H), 2.36 (s, 3H), 2.34 (s, 6H), 1.93-1.86 (m, 2H)；
13C NMR(100MHz,CDCl3):δ(ppm)156.5,141.8,134.1,132.7,129.6,127.4,124.1, 122.3,122.2,121.9,116.5,116.2,115.2,110.8,58.7,55.9,54.9,50.1,46.0,45.0,26.4, 22.3。
Embodiment 23:3- (3- (dimethylamino) propyl) -1- ((4- methoxy -3- (piperazine -1- base) phenyl) sulfonyl) - The synthesis of 1H- indoles -5- formonitrile HCN
The synthesis of step 1) 3- (3- hydroxypropyl) -1H- indoles -5- formonitrile HCN
This step title compound method referring to described in 15 step 1 of embodiment is prepared, i.e., by 4- cyanophenylhydrazine Hydrochloride (3.52g, 20.8mmol) and 1,4- dihydropyran (1.9mL, 20.8mmol) are dissolved in 4%H2SO4(aq)(50mL) and N, The in the mixed solvent of N- dimethyl acetamide (10mL) reacts preparation, and crude product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1 it) purifies, it is white solid (1.46g, 35%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:201.1[M+H]+；
1H NMR(400MHz,DMSO-d6): δ (ppm): 11.36 (s, 1H), 7.50-7.48 (m, 1H), 7.38 (dd, J= 8.4,1.5Hz, 1H), 7.31 (d, J=2.0Hz, 1H), 4.46 (t, J=5.1,1H), 3.47-3.43 (m, 2H), 2.74 (d, J =7.6Hz, 2H), 1.81-1.74 (m, 2H)；
Step 2) 3- (5- cyano-1 H-indol -3- base) propyl -4- oluene sulfonic acides ester
This step title compound method referring to described in 15 step 2 of embodiment is prepared, i.e., by 3- (3- hydroxyl third Base) -1H- indoles -5- first cyanogen (1.00g, 5.0mmol), triethylamine (0.8mL, 6.0mmol) and and paratoluensulfonyl chloride (1.14g, 6.0mmol) is dissolved in middle reaction preparation in methylene chloride (20mL), and crude product is through silica gel column chromatography (petroleum ether/acetic acid Ethyl ester (v/v)=4/1) purifying, it is white solid (1.33g, 7.0%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:355.1[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 8.51 (br s, 1H), 7.83 (s, 1H), 7.77 (d, J=8.3Hz, 2H), 7.40 (s, 2H), 7.33 (d, J=8.1Hz, 2H), 7.08 (d, J=2.2Hz, 1H), 4.08 (t, J=6.1Hz, 2H), 2.81 (t, J=7.3Hz, 2H), 2.45 (s, 3H), 2.06-1.99 (m, 2H)；
The synthesis of step 3) 3- (3- (dimethylamino) propyl) -1H- indoles -5- formonitrile HCN
This step title compound method referring to described in 15 step 3 of embodiment is prepared, i.e., by 3- (5- cyano- 1H- indol-3-yl) propyl 4- oluene sulfonic acides ester (1.29g, 3.65mmol), dimethylamine hydrochloric acid (1.2g, 14.6mmol) and three Ethamine (1.95mL, 14.6mmol), which is dissolved in 10mL acetonitrile, reacts preparation, and crude product is through silica gel column chromatography (methylene chloride/methanol (v/v)=20/1 it) purifies, it is yellow oil (795mg, 96%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:228.1[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 8.95 (s, 1H), 7.92 (s, 1H), 7.39 (d, J=1.2Hz, 2H), (7.1 s, 1H), 2.78 (t, J=7.4Hz, 2H), 2.48 (t, J=7.4Hz, 2H), 2.34 (s, 6H), 1.97-1.89 (m, 2H)；
Step 4) 3- (3- (dimethylamino) propyl) -1- ((4- methoxy -3- (4- (2,2,2- tribromo-acetyl) piperazine -1- base) Phenyl) sulfonyl) -1H- indoles -5- formonitrile HCN synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 3- (3- (diformazan ammonia Base) propyl) -1H- indoles -5- formonitrile HCN (375mg, 1.65mmol), sodium hydride (80mg, 2.0mmol), 4- methoxy -3- (4- (2, 2,2- trichloroacetyls) piperazine -1- base) benzene -1- sulfonic acid chloride (872mg, 2.0mmol) reaction preparation in DMF (5mL), it is thick to produce For object through silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is light yellow oil that concentrate drying, which obtains title compound, (395mg, 38%).
MS(ESI,pos.ion)m/z:626.2[M+H]+；
1H NMR(400MHz,CDCl3): δ (ppm) 8.05 (d, J=8.6Hz, 1H), 7.84 (d, J=1.0Hz, 1H), 7.58-7.47 (m, 2H), 7.47 (s, 1H), 7.31 (d, J=2.3Hz, 1H), 6.88 (d, J=8.8Hz, 1H), 4.11 (s, 4H), 3.88 (s, 3H), 3.09 (t, J=4.9Hz, 4H), 2.72 (t, J=7.6Hz, 2H), 2.47 (t, J=7.2Hz, 2H), 2.35(s,6H),1.95-1.89(m,2H)；
Step 5) 3- (3- (dimethylamino) propyl) -1- ((4- methoxy -3- (piperazine -1- base) phenyl) sulfonyl) -1H- Yin The synthesis of diindyl -5- formonitrile HCN
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., by 3- (3- (diformazan ammonia Base) propyl) -1- ((4- methoxy -3- (4- (2,2,2- tribromo-acetyl) piperazine -1- base) phenyl) sulfonyl) -1H- indoles -5- first Nitrile (382mg, 0.61mmol), potassium hydroxide (102mg, 1.82mmol are made into 1mmol/ml aqueous solution) are in tetrahydrofuran Reaction preparation in (15mL), crude product are marked through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), concentrate drying Topic compound is light yellow oil (130mg, 44%).
HPLC analysis:96.19%；
MS(ESI,pos.ion)m/z:241.7[M+2H]2+/2；
1H NMR(600MHz,CDCl3): δ (ppm) 8.05 (d, J=9.0Hz, 1H), 7.83 (s, 1H), 7.55-7.53 (m, 2H), 7.48 (s, 1H), 7.30-7.28 (m, 1H), 6.84 (d, J=9.0Hz, 1H), 3.85 (s, 3H), 3.04-2.99 (m, 8H), 2.68 (t, J=7.8Hz, 2H), 2.43 (t, J=7.8Hz, 2H), 2.30 (s, 6H), 1.90-1.85 (m, 2H)；
13C NMR(100MHz,CDCl3):δ(ppm)156.8,142.4,137.0,131.0,129.4,127.4,124.8, 124.6,122.5,122.4,119.4,116.2,114.4,110.9,106.4,58.8,55.9,51.4,45.9,45.4, 27.0,22.2。
Embodiment 24:3- (3- (dimethylamino) propyl) -1- ((4- methoxy -3- (4- methylpiperazine-1-yl) phenyl) sulphonyl Base) -1H- indoles -5- formonitrile HCN synthesis
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., by 3- (3- (diformazan ammonia Base) propyl) -1- ((4- methoxy -3- (piperazine -1- base) phenyl) sulfonyl) -1H- indoles -5- formonitrile HCN (89mg, 0.19mmol), Sodium cyanoborohydride (36mg, 0.57mmol) and formaldehyde (40%, 0.039mL, 0.57mmol) the reaction system in methanol (10mL) Standby, for crude product through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is yellowish that concentrate drying, which obtains title compound, Color grease (35mg, 39%).
HPLC analysis:95.06%；
MS(ESI,pos.ion)m/z:248.6[M+2H]2+/2；
1H NMR(400MHz,CDCl3): δ (ppm) 8.08 (d, J=8.8Hz, 1H), 7.85 (s, 1H), 7.58-7.55 (m, 2H), 7.50 (s, 1H), 7.33 (d, J=2.4Hz, 1H), 6.87 (d, J=8.8Hz, 1H), 3.89 (s, 3H), 3.07 (brs, 4H), 2.75 (t, J=7.2Hz, 2H), 2.63 (brs, 4H), 2.44 (brs, 8H), 2.39 (s, 3H), 1.99 (brs, 2H)；
13C NMR(100MHz,CDCl3):δ(ppm)156.8,141.9,137.0,130.8,129.4,127.5,124.9, 124.5,122.5,121.7,119.3,116.2,114.5,111.0,106.5,58.4,55.9,54.9,49.9,45.9, 44.7,26.1,22.1。
Embodiment 252- (the chloro- 1- of 6- (4- methoxy -3- (piperazine -1- base) benzenesulfonyl) -1H- indol-3-yl)-N, N- bis- The synthesis of methyl ethyl-amine
Step 1) 2- (the chloro- 1H- indol-3-yl of 6-)-N, the synthesis of N- dimethyl amine
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e., by 6- chloramine (840mg, 4.3mmol), NaBH3CN (416mg, 6.6mmol) and formaldehyde (40%, 0.477mL, 6.6mmol) are in methanol Reaction preparation in (15mL), crude product are marked through silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), concentrate drying Topic compound is brown oil (806mg, 83.8%).
MS(ESI,pos.ion)m/z:223.2[M+H]+；
1H NMR (400MHz, CDCl3): δ (ppm) 8.46 (s, 1H), 7.49 (d, J=8.4Hz, 1H), 7.26 (d, J= 1.6Hz, 1H), 7.07 (dd, J=8.4,1.6Hz, 1H), 6.95 (t, J=1.2Hz, 1H), 2.94-2.91 (m, 2H), 2.68- 2.64(m,2H),2.36(s,6H)。
The chloro- 1- of step 2) 2,2,2- tri- (4- (5- (the chloro- 1H- indoles -1- sulphonyl of 3- (2- (dimethylamino) ethyl) -6- Base) -2- anisyl) piperazine -1- base) and ethyl ketone synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 2- (the chloro- 1H- of 6- Indol-3-yl)-N, N- dimethyl amine (585mg, 2.6mmol), sodium hydride (208mg, 5.2mmol), 4- methoxy -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene -1- sulfonic acid chloride (1.7g, 3.9mmol) reaction preparation in DMF (3mL), slightly For product through silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is Light brown solid that concentrate drying, which obtains title compound, (537mg, 32.8%).
MS(ESI,pos.ion)m/z:621.2[M+H]+；
1H NMR (400MHz, CDCl3): δ (ppm) 7.99 (d, J=2.0Hz, 1H), 7.54 (dd, J=8.4,2.0Hz, 1H), 7.41 (d, J=8.4Hz, 1H), 7.34 (s, 1H), 7.31 (d, J=2.4Hz, 1H), 7.21 (dd, J=8.4,1.6Hz, 1H), 6.86 (d, J=8.8Hz, 1H), 4.06-3.90 (m, 4H), 3.88 (s, 3H), 3.08 (t, J=5.2Hz, 4H), 2.88- 2.84(m,2H),2.66-2.62(m,2H),2.37(s,6H)。
Step 3) 2- (the chloro- 1- of 6- (4- methoxy -3- (piperazine -1- base) benzenesulfonyl) -1H- indol-3-yl)-N, N- diformazan The synthesis of base ethamine
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., chloro- by 2,2,2- tri- 1- (4- (5- (3- (2- (dimethylamino) ethyl) the chloro- 1H- indoles -1- sulfonyl of -6-) -2- anisyl) piperazine -1- base) second Ketone (530mg, 0.85mmol), potassium hydroxide (143mg, 2.55mmol are made into 1mmol/ml aqueous solution) are in tetrahydrofuran Reaction preparation in (20mL), crude product are marked through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), concentrate drying Topic compound is faint yellow solid (350mg, 86.5%).
MS(ESI,pos.ion)m/z:477.1[M+H]+；
1H NMR (400MHz, CDCl3): δ (ppm) 7.98 (d, J=1.6Hz, 1H), 7.49 (dd, J=8.4,2.4Hz, 1H), 7.37 (d, J=8.4Hz, 1H), 7.33 (s, 1H), 7.30 (d, J=2.0Hz, 1H), 7.18 (dd, J=8.4,2.0Hz, 1H), 6.80 (d, J=8.4Hz, 1H), 3.84 (s, 3H), 3.02-3.00 (m, 4H), 2.96-2.95 (m, 4H), 2.80-2.76 (m,2H),2.57-2.53(m,2H),2.29(s,6H)；
13C NMR(100MHz,CDCl3):δ(ppm)156.5,142.1,135.5,130.4,129.5,129.4,123.5, 123.5,122.3,120.7,120.1,116.3,114.0,110.8,,58.9,55.8,51.4,45.9,45.3,23.3。
Embodiment 262- (the chloro- 1- of 6- (4- methoxy -3- (piperazine -1- base) benzenesulfonyl) -1H- indol-3-yl)-N, N- bis- The synthesis of methyl ethyl-amine
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by 2- (the chloro- 1- of 6- (4- methoxy -3- (piperazine -1- base) benzenesulfonyl) -1H- indol-3-yl)-N, N- dimethyl amine (228mg, 0.47mmol), Sodium cyanoborohydride (89mg, 1.41mmol) and formaldehyde (40%, 0.112mL, 1.617mmol) the reaction system in methanol (10mL) Standby, for crude product through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is yellowish that concentrate drying, which obtains title compound, Color solid (169mg, 71.8%).
MS(ESI,pos.ion)m/z:246.2[M+2H]2+/2；
1H NMR (400MHz, CDCl3): δ (ppm) 7.98 (d, J=1.6Hz, 1H), 7.48 (dd, J=8.8,2.4Hz, 1H), 7.36 (d, J=8.4Hz, 1H), 7.32 (s, 1H), 7.29 (d, J=2.4Hz, 1H), 7.17 (dd, J=8.4,1.6Hz, 1H), 6.80 (d, J=8.4Hz, 1H), 3.83 (s, 3H), 3.02 (s, 4H), 2.80-2.76 (m, 2H), 2.57-2.53 (m, 6H),2.32(s,3H),2.29(s,6H)；
13C NMR(100MHz,CDCl3):δ(ppm)156.4,141.7,135.5,130.5,129.4,123.5,122.2, 120.6,120.1,116.2,113.9,110.7,58.9,55.8,54.9,50.0,46.0,45.3,23.2。
Biologic test
The present invention carries out biologic test to formula (I) or formula (II) compound represented using following methods:
1. with radio ligand binding assay evaluation compound to the source of people 5-HT being expressed on CHO cells6The parent of receptor And power
The 32 μ g expression prepared there is into source of people 5-HT6The CHO cell membrane protein of receptor, 2nM radioactively labelled substance [3H] LSD, the compound of different test concentrations and test buffer are uniformly mixed, 37 DEG C of incubation 120min；Test buffer ingredient Are as follows: 50mMTris-HCl (pH7.4), 10mM MgCl2, 0.5mM EDTA, 10 μM of Pargylines and 20mg/l protease inhibitors.
100 μM of 5-HT removal nonspecific binding sites are added.After incubation, above-mentioned mixed liquor is used into glass under vacuum conditions The filtering of glass filter, filter are first presoaked with 0.3%PEI before filtration.It is rinsed several times with 50mM Tris-HCl again after filtering.To After filter is dry, radioactivity is counted on the scintillometer with scintillation mixed solution.Standard reference compounds are 5-HT, are being tested every time In test several concentration and obtain its competition inhibition curve and calculate IC50。
Radio ligand binding assay is carried out to compound provided in an embodiment of the present invention according to the method described above and evaluates chemical combination Object is to the source of people 5-HT being expressed on CHO cells6The affinity determination of receptor, as a result referring to table 1, table 1 is the embodiment of the present invention The affinity measurement result of offer.
The affinity measurement result of the compound provided in an embodiment of the present invention of table 1
Example No. IC50(nM) Example No. IC50(nM) Example No. IC50(nM)
Embodiment 2 22 Embodiment 8 15 Embodiment 17 28
Embodiment 3 99 Embodiment 10 9.7 Embodiment 18 32
Embodiment 4 18 Embodiment 12 4.7 Embodiment 19 5.1
Embodiment 5 19 Embodiment 14 7.5 Embodiment 20 18
Embodiment 6 16 Embodiment 15 48 Embodiment 21 8.1
Embodiment 7 32 Embodiment 16 21 Embodiment 22 23
As shown in Table 1, compound of the present invention is thin in CHO to expressing in radio ligand binding assay evaluation compound Source of people 5-HT on born of the same parents6Higher activity is generally shown in the affinity test of receptor.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means particular features, structures, materials, or characteristics described in conjunction with this embodiment or example It is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms need not It must be directed to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be any It can be combined in any suitable manner in a or multiple embodiment or examples.In addition, without conflicting with each other, the technology of this field The feature of different embodiments or examples described in this specification and different embodiments or examples can be combined by personnel And combination.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example Property, it is not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned Embodiment is changed, modifies, replacement and variant.

Claims (9)

1. a kind of compound, the structure with one of:
Or its pharmaceutically acceptable salt.
2. a kind of pharmaceutical composition includes compound described in claim 1 and pharmaceutically acceptable carrier, excipient is dilute Release agent, adjuvant, medium or their combination.
3. pharmaceutical composition according to claim 2, wherein further including additional therapeutic agent, these additional treatments Agent is the drug for treating nervous disorders.
4. pharmaceutical composition according to claim 3, wherein the additional therapeutic agent is: donepezil (donepezil), nalmefene (nalmefene), Risperidone (risperidone), vitamin e (Vitamin E), SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX-8066, SB-742457, naluzaton, Lu- AE58054, Tacrine (tacrinE), Rivastigmine (rivastigmine), galanthamine (galantamine), Memantine (memantine), mitzapine (Mirtazapine), Venlafaxine (venlafaxine), desipramine (desipramine), Nortriptyline (nortriptyline), zolpidem (zolpidem), zopiclone (zopiclone), Nicergoline (nicergoline), Piracetam (piracetam), selegiline (selegiline), pentoxifylline (pentoxifylline) or their combination.
5. pharmaceutical composition described in compound described in claim 1 or claim 2-4 any one is in medicine preparation Purposes, the drug is for treatment or prevention and 5-HT6Related disease.
6. purposes according to claim 5, wherein described and 5-HT6Related disease is CNS illness.
7. purposes according to claim 6, wherein the CNS illness includes: ADHD, anxiety is related to stress Disease, schizophrenia, besetment and behavior disorder, manic-depressive psychosis, memory disorders, attention deficit disorder, pa gold Gloomy disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's chorea.
8. purposes according to claim 5, wherein described and 5-HT6Related disease is disorder of gastrointestinal tract.
9. purposes according to claim 5, wherein described and 5-HT6Related disease is obesity.
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