Embodiment
definition and general terms
The present invention will list the document corresponding to the content specialized determined in detail, and embodiment is all attended by the diagram of structural formula and chemical formula.The present invention has expectedly contains all choices, variant and coordinator, and these may be included in existing invention field as defined by the following claims like that.Those skilled in the art is by many for identification similar or be equal to method described herein and material, and these can be applied in practice of the present invention and go.The present invention is limited to absolutely not the description of method and material.Have a lot of document distinguish with similar material and the present patent application or conflict, comprising but be never limited to the definition of term, the usage of term, the technology of description, or as the present patent application the scope that controls.
Unless other aspects of the following definition of application show by the present invention.According to object of the present invention, chemical element according to the periodic table of elements, CAS version and chemical physics handbook, 75 thed., 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 reference.
As described in the present invention, compound of the present invention can optionally replace by one or more substituting group, as general formula compound above, or as example special inside embodiment, subclass, and the compounds that the present invention comprises.Should be appreciated that " optional replacement " this term can exchange use with " substituted or unsubstituted " this term.Generally speaking, term " optionally " no matter before whether being positioned at term " replacement ", represent give the one or more hydrogen atoms in structure replace by concrete substituting group.Unless other aspects show, an optional substituted radical can have a substituting group to replace in each commutable position of group.Not only one or more substituting groups that position can be selected from concrete group in given structural formula replaced, and so substituting group can replace in each position identical or differently.Wherein said substituting group can be, but be not limited to, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkylamino, alkylthio, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, heteroaryloxy, oxo, carboxyl, the alkoxyl group that hydroxyl replaces, alkyl-the C (=O) that hydroxyl replaces, alkyl-C (=O), alkyl-S (=O), alkyl-S (=O) 2-, the alkyl-S (=O) that hydroxyl replaces, the alkyl-S (=O) that hydroxyl replaces 2, Carboxyalkoxy etc.
The term " alkyl " that the present invention uses represents the saturated straight chain of 1-20 carbon atom or the univalence hydrocarbyl of side chain.In certain embodiments, alkyl group comprises 1-6 carbon atom, and in further embodiments, alkyl group comprises 1-4 carbon atom.The example of alkyl comprises, but is not limited to, methyl (Me ,-CH 3), ethyl (Et ,-CH 2cH 3), n-propyl (n-Pr ,-CH 2cH 2cH 3), sec.-propyl (i-Pr ,-CH (CH 3) 2), normal-butyl (n-Bu ,-CH 2cH 2cH 2cH 3), isobutyl-(i-Bu ,-CH 2cH (CH 3) 2), sec-butyl (s-Bu ,-CH (CH 3) CH 2cH 3), the tertiary butyl (t-Bu ,-C (CH 3) 3), n-pentyl (-CH 2cH 2cH 2cH 2cH 3), 2-amyl group (-CH (CH 3) CH 2cH 2cH 3), 3-amyl group (-CH (CH 2cH 3) 2), 2-methyl-2-butyl (-C (CH 3) 2cH 2cH 3), 3-methyl-2-butyl (-CH (CH 3) CH (CH 3) 2), 3-methyl isophthalic acid-butyl (-CH 2cH 2cH (CH 3) 2), 2-methyl-1-butene base (-CH 2cH (CH 3) CH 2cH 3), n-hexyl (-CH 2cH 2cH 2cH 2cH 2cH 3), 2-hexyl (-CH (CH 3) CH 2cH 2cH 2cH 3), 3-hexyl (-CH (CH 2cH 3) (CH 2cH 2cH 3)), 2-methyl-2-amyl group (-C (CH 3) 2cH 2cH 2cH 3), 3-methyl-2-amyl group (-CH (CH 3) CH (CH 3) CH 2cH 3), 4-methyl-2-amyl group (-CH (CH 3) CH 2cH (CH 3) 2), 3-methyl-3-amyl group (-C (CH 3) (CH 2cH 3) 2), 2-methyl-3-amyl group (-CH (CH 2cH 3) CH (CH 3) 2), 2,3-dimethyl-2-butyl (-C (CH 3) 2cH (CH 3) 2), 3,3-dimethyl-2-butyl (-CH (CH 3) C (CH 3) 3), etc.Term " alkyl " and its prefix " alkane " use herein, all comprise the saturated carbon chains of straight chain and side chain.Term " alkylene " uses herein, and represent the saturated bivalent hydrocarbon radical obtained from straight or branched saturated carbon hydride cancellation two hydrogen atoms, such example comprises, but is not limited to, methylene radical, ethylidine, secondary sec.-propyl etc.
Term " thiazolinyl " represents the monovalent hydrocarbon of the straight or branched of 2-12 carbon atom, and wherein at least one position is undersaturated condition, and namely a C-C is sp 2double bond.In certain embodiments, alkenyl group comprises 2-6 carbon atom, and in further embodiments, alkenyl group comprises 2-4 carbon atom.Wherein alkenyl group can independently and optionally replace by one or more substituting group described in the invention, comprising group has negation, " suitable " or " E ", the location of " Z ", the example that wherein thiazolinyl is concrete comprises, but is not limited to, vinyl (-CH=CH 2), allyl group (-CH 2cH=CH 2), etc.
Term " alkynyl " represents the monovalent hydrocarbon of the straight or branched of 2-12 carbon atom, and wherein at least one position is undersaturated condition, and namely a C-C is sp triple bond.In certain embodiments, alkynyl group comprises 2-6 carbon atom, and in further embodiments, alkynyl group comprises 2-4 carbon atom.Wherein alkynyl group can independently and optionally replace by one or more substituting group described in the invention, the example that wherein alkynyl is concrete comprises, but is not limited to, ethynyl (-C â¡ CH), propargyl (-CH 2c â¡ CH), etc.
Term " assorted alkyl " represents in alkyl chain and can insert one or more heteroatoms, and wherein alkyl group and heteroatoms have implication as described in the present invention.Unless otherwise detailed instructions, assorted alkyl group contains 1-10 carbon atom, and some embodiments are, assorted alkyl group contains 1-5 carbon atom, and other embodiment is, assorted alkyl group contains 1-4 carbon atom, other embodiment is, assorted alkyl group contains 1-3 carbon atom.Such example comprises, but is not limited to, CH 3oCH 2-, CH 3cH 2oCH 2-, CH 3sCH 2-, (CH 3) 2nCH 2-, (CH 3) 2cH 2oCH 2-, CH 3oCH 2cH 2-, CH 3cH 2oCH 2cH 2-etc.
Term " heteroatoms " represents one or more O, S, N, P and Si atom, comprises N, the form of any oxidation state of S and P; The form of primary, secondary, tertiary amine and quaternary ammonium salt; Or the form that the hydrogen in heterocycle on nitrogen-atoms is substituted, such as, N (N in such as 3,4-dihydro-2 h-pyrrole bases), NH (NH in such as pyrrolidyl) or NR (NR in the pyrrolidyl that such as N-replaces).
Term " halogen " refers to F, Cl, Br or I.
Term " undersaturated " used in the present invention represents that structure division contains one or more degree of unsaturation.
Term " alkyl that hydroxyl replaces " represents that alkyl group is optionally substituted with one or more hydroxyl group and replaces, and wherein alkyl group has implication of the present invention.Such example comprises, but is not limited to methylol, hydroxyethyl, 1,2-dihydroxy ethyl etc.
The present invention use term " haloalkyl " represent alkyl group replace by one or more identical or different halogen atom, wherein alkyl group has implication as described in the present invention, halogen atom and fluorine, chlorine, bromine or iodine, such example comprises, but be not limited to trifluoromethyl, trifluoroethyl, chloromethyl, methyl fluoride etc.
Term " alkoxyl group " represents that alkyl group is connected with molecule rest part by Sauerstoffatom, and wherein alkyl group has implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-20 carbon atom, and some of them embodiment is, alkoxy base contains 1-6 carbon atom, and other embodiment is, alkoxy base contains 1-4 carbon atom.The example of alkoxy base comprises, but is not limited to, methoxyl group (MeO ,-OCH 3), oxyethyl group (EtO ,-OCH 2cH 3), 1-propoxy-(n-PrO, n-propoxy-,-OCH 2cH 2cH 3), 2-propoxy-(i-PrO, i-propoxy-,-OCH (CH 3) 2), 1-butoxy (n-BuO, n-butoxy ,-OCH 2cH 2cH 2cH 3), 2-methyl-l-propoxy-(i-BuO, i-butoxy ,-OCH 2cH (CH 3) 2), 2-butoxy (s-BuO, s-butoxy ,-OCH (CH 3) CH 2cH 3), 2-methyl-2-propoxy-(t-BuO, t-butoxy ,-OC (CH 3) 3) etc.And described alkoxyl group can be substituted or unsubstituted, and wherein substituting group can be, but is not limited to, hydroxyl, amino, halogen, cyano group, alkoxyl group, alkyl, thiazolinyl, alkynyl, sulfydryl, nitro etc.
Term " alkylthio " comprises C 1-6the alkyl of straight or branched is connected on the sulphur atom of divalence.Some of them embodiment is, alkylthio is more rudimentary C 1-4alkylthio, such example comprises, but is not limited to methylthio group (CH 3s-).
Term " alkylamino " comprises " N-alkylamino " and " N, N-dialkyl amido ", wherein amine groups separately replace by one or two alkyl group.Some of them embodiment is, alkylamino is one or two C 1-6alkyl is connected to the more rudimentary alkylamino group on nitrogen-atoms.Other embodiment is, alkylamino is C 1-4more rudimentary alkylamino group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example comprises, but is not limited to, N-methylamino-, N-ethylamino, N, N-dimethylamino, N, N-diethylin etc.
Term " cycloalkyl " or " carbocylic radical " refer to monovalence or multivalence, non-aromatic, the undersaturated ring of saturated or part, and do not comprise heteroatoms, comprising the monocycle of 3-6 carbon atom or two rings of 7-8 carbon atom.The bicyclic carbocyclic with 7-8 atom can be two rings [4,5] or [5,5] system.Suitable annular aliphatic base comprises, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of annular aliphatic base comprises, but is never limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-thiazolinyl, 1-cyclopentyl-2-thiazolinyl, 1-cyclopentyl-3-thiazolinyl, cyclohexyl, 1-cyclohexyl-1-thiazolinyl, 1-cyclohexyl-2-thiazolinyl, 1-cyclohexyl-3-thiazolinyl, cyclohexadienyl, suberyl, ring octyl group, ring nonyl etc.And described " annular aliphatic base " or " carbocyclic ring ", " carbocylic radical ", " cycloalkyl " can be substituted or unsubstituted, and wherein substituting group can be, but is not limited to, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, the alkoxyl group that hydroxyl replaces, the alkyl-C (=O) that hydroxyl replaces, alkyl-C (=O), alkyl-S (=O), alkyl-S (=O) 2-, the alkyl-S (=O) that hydroxyl replaces, the alkyl-S (=O) that hydroxyl replaces 2, Carboxyalkoxy etc.
Term " cycloalkyl oxy " comprises the optional cycloalkyl replaced, as defined herein, be connected on Sauerstoffatom, and be connected with all the other molecules by Sauerstoffatom, such example comprises, but is not limited to cyclopropyl oxygen base, cyclopentyloxy, cyclohexyl oxygen base, the cyclopropyl oxygen base etc. that hydroxyl replaces.
Term " cycloalkyl amino " represent the group of naphthene base that amino group is optionally replaced by one or two replace, wherein cycloalkyl has implication as described in the present invention, such example comprises, but be not limited to cyclopropylamino, clopentylamino, Cyclohexylamino, the cyclopropylamino that hydroxyl replaces, dicyclohexyl is amino, and Bicyclopropyl is amino.
Term " cycloalkyl fatty group " represent fatty group can replace by one or more group of naphthene base, wherein cycloalkyl and fatty group have implication as described in the present invention, such example comprises, but be not limited to Cvclopropvlmethvl, cyclopropylethyl, Cyclopropylpropyl, cyclopentyl-methyl, cyclohexyl-ethyl etc.
Term " cycloalkyl alkoxy " (" carbocyclylalkoxy ") represent alkoxy base replace by one or more cycloalkyl (" carbocylic radical ") group, wherein cycloalkyl (" carbocylic radical ") group and alkoxy base have implication as described in the present invention, such example comprises, but be not limited to cyclo propyl methoxy, cyclopropylethoxy, cyclopentyl oxyethyl group, cyclohexylethoxy radical, cyclohexyl methoxy, cyclopropyl propoxy-etc.
Term " heterocycle ", " heterocyclic radical ", " assorted alicyclic " or " heterocycle " commutative use herein, all refer to monocycle, dicyclo, or three-ring system, wherein on ring one or more carbon atom independent and optionally replace by heteroatoms, described heteroatoms has implication as described in the present invention, and ring can be completely saturated or comprise one or more degree of unsaturation, but be never the fragrant same clan, only have a tie point to be connected to other molecules and get on.One or more ring hydrogen atom independent and optionally replace by one or more substituting group described in the invention.Some of them embodiment is, " heterocycle ", " heterocyclic radical ", " assorted alicyclic " or " heterocycle " group be 3-7 ring monocycle (1-6 carbon atom be selected from N, O, P, 1-3 the heteroatoms of S, at this S or P optionally replace by one or more Sauerstoffatom and obtain such as SO, SO 2, PO, PO 2group, when described ring is triatomic ring, wherein only have a heteroatoms), or the dicyclo of 7-8 unit (4-7 carbon atom and be selected from N, O, P, 1-3 the heteroatoms of S, at this S or P optionally replace by one or more Sauerstoffatom and obtain such as SO, SO 2, PO, PO 2group).
Heterocyclic radical can be carbon back or heteroatoms base." heterocyclic radical " equally also comprises heterocyclic group and the saturated or unsaturated ring of part or heterocycle and closes the group formed.The example of heterocycle comprises, but is not limited to, pyrrolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl ï¼ thioxane base, thiazolidyl ï¼ oxazolidinyl, piperazinyl, homopiperazine base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl, epoxypropyl, azacycloheptyl, oxepane base, thia suberyl, 4-Methoxy-piperidin-1-base, 1,2,3,6-tetrahydropyridine-1-base, oxygen azepine base, diaza base, sulphur azepine base, pyrroline-1-base, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxy amyl group, pyrazolinyl, dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidyl imidazolinyl, imidazolidyl, 1, 2, 3, 4-tetrahydro isoquinolyl, 1, 2, 6-thiadiazine alkane 1, 1-dioxo-2-base, 4-hydroxyl-1, 4-azepine phosphine 4-oxide compound-1-base, 2-hydroxyl-1-(piperazine-1-base) ethyl ketone-4-base, 2-hydroxyl-1-(5, 6-dihydro-1, 2, 4-triazine-1 (4H)-Ji) ethyl ketone-4-base, 5, 6-dihydro-4H-1, 2, 4-oxadiazine-4-base, 2-hydroxyl-1-(5, 6-dihydropyridine-1 (2H)-Ji) 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-tetrahydrochysene-[1, 2, 4] triazole [1, 5-c] pyrimidine-6-base, 4, 5, 6, 7-tetrahydrochysene isoxazole [4, 3-c] pyridine-5-base, 3H-indyl 2-oxygen-5-azabicyclo [2.2.1] heptane-5-base, 2-oxygen-5-azabicyclo [2.2.2] octane-5-base, quinolizinyl and N-pyridyl urea.The example of heterocyclic group also comprises, 1,1-dioxothiomorpholinyl, and wherein on ring two carbon atoms replace by Sauerstoffatom as pyrimidine dione base.And described heterocyclic radical can be substituted or unsubstituted, and wherein substituting group can be, but is not limited to, oxo, hydroxyl, amino, halogen, cyano group, heteroaryl, alkoxyl group, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, the alkoxyl group that hydroxyl replaces, the alkyl-C (=O) that hydroxyl replaces, alkyl-C (=O), alkyl-S (=O), alkyl-S (=O) 2-, the alkyl-S (=O) that hydroxyl replaces, the alkyl-S (=O) that hydroxyl replaces 2, Carboxyalkoxy etc.
Term " heterocyclylalkoxy " comprises the alkoxyl group that heterocyclic radical replaces, and wherein Sauerstoffatom is connected with the rest part of molecule; Term " heterocyclic radical alkylamino " comprises the amino that heterocyclic radical replaces, and wherein nitrogen-atoms is connected with the rest part of molecule.Wherein heterocyclic radical, alkyl, alkoxyl group and alkylamino have implication as described in the present invention, and such example comprises, but are not limited to pyrroles-2-ylmethyl, morpholine-4-base ethyl, morpholine-4-base oxethyl, piperazine-4-base oxethyl, piperidin-4-yl ethylamino etc.
Term " heterocyclyloxy base " comprises the optional heterocyclic radical replaced, as defined herein, be connected on Sauerstoffatom, wherein Sauerstoffatom is connected with the rest part of molecule, and such example comprises, but be not limited to pyrroles-2-oxygen base, pyrroles-3-oxygen base, piperidines-2-oxygen base, piperidines-3-oxygen base, piperazine-2-oxygen base, piperidines-4-oxygen base etc.
Term " heterocyclylamino group " represent amino group replace by one or two heterocyclyl groups, wherein nitrogen-atoms is connected with the rest part of molecule, and heterocyclic radical has implication as described in the present invention, and such example comprises, but be not limited to, pyrroles-2-is amino, and pyrroles-3-is amino, and piperidines-2-is amino, piperidines-3-is amino, piperidines-4-is amino, and piperazine-2-is amino, and two pyrroles-2-are amino.
Term " aryl " can be used alone or conduct " aralkyl ", most of " aralkoxy " or " aryloxy alkyl ", represent the monocycle altogether containing 6-10 ring, dicyclo, with the carbocyclic ring system of three rings, wherein, at least one member ring systems is aromatic, wherein each member ring systems comprises 3-7 ring, and only has an attachment point to be connected with the rest part of molecule.Term " aryl " can exchange with term " aromatic nucleus " and use, as aromatic nucleus can comprise phenyl, and naphthyl and anthryl.And described aryl can be substituted or unsubstituted, and wherein substituting group can be, but is not limited to, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, the alkoxyl group that hydroxyl replaces, the alkyl-C (=O) that hydroxyl replaces, alkyl-C (=O), alkyl-S (=O), alkyl-S (=O) 2-, the alkyl-S (=O) that hydroxyl replaces, the alkyl-S (=O) that hydroxyl replaces 2, Carboxyalkoxy, etc.
Term " aralkyl " comprises the alkyl group that aryl replaces.Some of them embodiment is, aromatic alkyl group refers to " more rudimentary aralkyl " group, and namely aromatic yl group is connected to C 1-6alkyl group on.Other embodiment is that aromatic alkyl group refers to containing C 1-4" the benzene alkylene " of alkyl.Wherein specific examples comprises benzyl, diphenyl methyl, styroyl.Aryl on aralkyl can further by halogen, alkyl, alkoxyl group, and haloalkyl and halogenated alkoxy replaced.
Term " aryloxy " comprises the optional aryl replaced, as defined herein, be connected on Sauerstoffatom, and be connected with molecule rest part by Sauerstoffatom, wherein aromatic yl group has implication as described in the present invention, and such example comprises, but is not limited to phenoxy group, tolyloxy, second phenoxy group etc.
Term " arylthio " comprises the optional aryl replaced, as defined herein, be connected on sulphur atom, and be connected with molecule rest part by sulphur atom, wherein aromatic yl group has implication as described in the present invention, and such example comprises, but is not limited to thiophenyl, Tolylsulfanvl, ethylbenzene sulfenyl etc.
Term " virtue amino " represent the aromatic yl group that amino group is optionally replaced by one or two replace, wherein aryl has implication as described in the present invention, such example comprises, but be not limited to phenyl amino, to Fluorophenylamino, diphenyl amino, xylyl is amino, and di-p-tolyl is amino.
The aromatic yl alkyl group that term " aryl alkane amino " comprises containing nitrogen-atoms is connected on other groups by nitrogen-atoms, wherein arylalkyl has implication as described in the present invention, and such example comprises, but is not limited to phenyl methylamino-, phenylethylamino, naphthyl ethylamino etc.
The aromatic yl alkyl group that term " alkoxy aryl " comprises containing Sauerstoffatom is connected on other groups by Sauerstoffatom, wherein arylalkyl has implication as described in the present invention, and such example comprises, but is not limited to Phenylmethoxy, naphthyl oxyethyl group, phenyl-propoxy etc.
Term " heteroaryl " can be used alone or as most of " heteroarylalkyl " or " heteroarylalkoxy ", represent the monocycle altogether containing 5-10 ring, dicyclo, and three-ring system, wherein at least one member ring systems is aromatic, and at least one member ring systems comprises one or more heteroatoms, and wherein heteroatoms has implication of the present invention, wherein each member ring systems comprises 3-7 ring, and only has an attachment point to be connected with molecule rest part.Term " heteroaryl " can exchange with term " fragrant heterocycle " or " heteroaromatics " and use.And described heteroaryl can be substituted or unsubstituted, and wherein substituting group can be, but is not limited to, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, the alkoxyl group that hydroxyl replaces, the alkyl-C (=O) that hydroxyl replaces, alkyl-C (=O), alkyl-S (=O), alkyl-S (=O) 2-, the alkyl-S (=O) that hydroxyl replaces, the alkyl-S (=O) that hydroxyl replaces 2, Carboxyalkoxy etc.
Other embodiment is, virtue heterocycle comprises following monocycle, but be not limited to these monocycles: 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methyl-isoxazole-5-base, N-pyrryl, 2-pyrryl, 3-pyrryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, pyrimidine-5-base, pyridazinyl (as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazyl (as 5-tetrazyl), triazolyl (as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (as 2-pyrazolyl), isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 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-triazinyl, benzo [d] thiazol-2-yl, imidazo [1, 5-a] pyridine-6-base, also following dicyclo is comprised, but be never limited to these dicyclos: benzimidazolyl-, benzofuryl, benzothienyl, indyl (as 2-indyl), purine radicals, quinolyl (as 2-quinolyl, 3-quinolyl, 4-quinolyl), with isoquinolyl (as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl).
Term " heteroaryl amino " represent the heteroaryl groups that amino group is optionally replaced by one or two replace, wherein heteroaryl has implication as described in the present invention, and such example comprises, but is not limited to pyridin-4-yl amino, between fluorine pyridinylamino, bipyridyl is amino.
Term " heteroaryloxy " comprises the optional heteroaryl replaced, as defined herein, be connected on Sauerstoffatom, and be connected with molecule rest part by Sauerstoffatom, wherein heteroaryl groups has implication as described in the present invention, such example comprises, but is not limited to pyridyloxy, 2-pyrimidinyl oxy etc.
Term " heteroarylalkyl " represent alkyl group replace by one or more heteroaryl, wherein heteroaryl and alkyl group have implication of the present invention, and such example comprises, but are not limited to imidazoles-2-methyl, furans-2-ethyl, indoles-3-methyl etc.
The heteroarylalkyl group that term " heteroarylalkylamino " comprises containing nitrogen-atoms is connected on other groups by nitrogen-atoms, wherein heteroarylalkyl has implication as described in the present invention, such example comprises, but be not limited to pyridine-2-base methylamino-, thiazol-2-yl ethylamino, imidazoles-2-base ethylamino, pyrimidine-2-base third is amino, pyrimidine-2-base methylamino-etc.
Term " aryloxy " comprises the optional aryl replaced, being connected on Sauerstoffatom like that as defined herein, and is connected with molecule rest part by Sauerstoffatom, and such example comprises, but is not limited to phenoxy group etc.
The heteroarylalkyl group that term " heteroarylalkoxy " comprises containing Sauerstoffatom is connected on other groups by Sauerstoffatom, wherein heteroarylalkyl has implication as described in the present invention, such example comprises, but be not limited to pyridine-2-ylmethoxy, thiazol-2-yl oxyethyl group, imidazoles-2-base oxethyl, pyrimidine-2-base propoxy-, pyrimidine-2-base methoxyl group etc.
Unless other aspects show, structural formula described in the invention comprises all isomeric forms (as enantiomerism, diastereo-isomerism, with rotamerism (or conformational isomerism)): R, S configuration such as containing asymmetric center, (Z), (E) isomer of double bond, and (Z), (E) conformer.Therefore, the single three-dimensional chemical isomer of compound of the present invention or its enantiomer, diastereomer, or the mixture of geometrical isomer (or conformer) all belongs to scope of the present invention.
Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo.Such conversion by prodrug be hydrolyzed in blood or blood or tissue in through enzymatic conversion be the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, aliphatics (C as prodrug 1-24) ester class, acyloxymethyl ester class, carbonic ether, amino formate and amino acid esters.Such as, a compound in the present invention comprises hydroxyl, namely its acidylate can be obtained the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that di on parent obtains.Can with reference to Publication about Document about the complete discussion of prodrug: 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 other aspects show, all tautomeric forms of compound of the present invention are included within scope of the present invention.In addition, unless other aspects show, the structural formula of compound described in the invention comprises the enriched isotope of one or more different atom.
" meta-bolites " refers to concrete compound or its salt in vivo by product that metabolism obtains.The meta-bolites of a compound can be identified by the known technology in affiliated field, and its activity can be characterized by such method of test that adopts as described in the present invention.Such product can be by passing through oxidation to drug compound, and reduction, hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the meta-bolites of compound, comprise and compound of the present invention and Mammals fully contacted the meta-bolites that for some time produces.
The definition of neutral body chemistry of the present invention and the usual reference of the use of convention are with Publication about Document: 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.Compound of the present invention can comprise asymmetric center or chiral centre, therefore there is different steric isomers.The stereoisomeric forms in any ratio that compound of the present invention is all, include, but not limited to, diastereomer, enantiomer, atropisomer, and their mixture, as racemic mixture, constitutes a part of the present invention.A lot of organic compound all exists with optical active forms, i.e. the plane of their capable Plane of rotation polarized light.When describing optically active compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) are used for the symbol naming compound plane polarized light to rotate, and (-) or l refer to that compound is left-handed, and prefix (+) or d refer to that compound is dextrorotation.The chemical structure of these steric isomers is identical, but their three-dimensional arrangement is different.Specific steric isomer can be enantiomorph, and the mixture of isomer is commonly referred to enantiomeric mixture.The mixture of enantiomers of 50:50 is called as racemic mixture or racemic modification, and this may cause not having stereoselectivity or stereospecificity in chemical reaction process.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack optical activity.
Term " tautomer " or " tautomeric form " refer to that the isomers of the structure of different-energy can be transformed mutually by low energy barrier.Such as proton tautomer (i.e. prototropic tautomer) comprises the change by proton shifting, as the isomerization of keto-enol and imine-enamine.Valence (valency) tautomer comprises the change reassembling into bonding electron.
" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of compound of the present invention.Pharmacy acceptable salt in affiliated field known by us, as document: S.M.Berge et al., J.Pharmaceutical Sciences, 66:1-19, described in 1977.The salt that pharmaceutically acceptable nontoxic acid is formed comprises, but is not limited to, and reacting with amino group the inorganic acid salt formed has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate, and organic acid salt is as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate, or obtain these salt by additive method such as ion exchange method described on books document.Other pharmacy acceptable salts comprise adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate, etc..The salt obtained by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N +(C 1-4alkyl) 4salt.The quaternary ammonium salt that the compound that the present invention also intends the group contemplating any comprised N is formed.Water-soluble or oil soluble or dispersion product can be obtained by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium, etc.Pharmacy acceptable salt comprises suitable, nontoxic ammonium further, the amine positively charged ion that quaternary ammonium salt and gegenions are formed, as halogenide, and oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C 1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the associated complex that one or more solvent molecule and compound of the present invention are formed.The solvent forming solvate comprises, but is not limited to, water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid, monoethanolamine.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.
Time term " blocking group " refers to a substituting group and other reacted with functional groups, be commonly used to block or protect special functional.Such as; " amino blocking group " refer to a substituting group be connected with amino group block or protect in compound amino functional; suitable amido protecting group comprises ethanoyl; trifluoroacetyl group; tertbutyloxycarbonyl (BOC), carbobenzoxy-(Cbz) (CBZ) and the sub-methoxycarbonyl (Fmoc) of 9-fluorenes.Similarly, " hydroxy-protective group " refers to that the substituting group of hydroxyl is used for blocking or protecting the functional of hydroxyl, and suitable blocking group comprises ethanoyl and silyl." carboxy protective group " refers to that the substituting group of carboxyl is used for blocking or protecting the functional of carboxyl, and general carboxyl-protecting group comprises-CH 2cH 2sO 2ph; cyano ethyl; 2-(TMS) ethyl; 2-(TMS) ethoxyl methyl; 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl alkylsulfonyl) ethyl, 2-(diphenylphosphino) ethyl; nitro-ethyl, etc.Can reference for the general description of blocking group: 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 deficit hyperactivity disorder, be a kind of Childhood very common psychataxia.According to " Global Access classification of diseases handbook " the tenth edition (ICD-10 of the World Health Organization, WHO, 1992) claim this disease for " hyperactivity disorder " (Hyperkinetic Disorder), classifying and numbering is F90, is generally commonly called as again as " crossing dynamic youngster ".
Term " schizophrenia " refers to schizophrenia, schizophrenia-like disorder, schizoaffective disorder and psychotic disorder, and wherein term " psychosis " refers to vain hope, significantly illusion, amorphous language or unorganized behavior or stiffization behavior.See Diagnostic and Statistical Manual of Mental Disorder, the 4th edition, American Psychiatric Association, Washington, D.C..
the description of the compounds of this invention
The indole derivatives that the present invention relates to, its pharmacy acceptable salt, and pharmaceutical preparation, have antagonism 5-HT 6, especially have potential purposes to the treatment of Alzheimer's disease.
On the one hand, the present invention relates to a kind of compound, it is the steric isomer of structure shown in the structure shown in formula I or formula I, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy 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;
When during for singly-bound, X is CH or N, when during for double bond, X is C;
R 1for H, D, C 1-6alkyl, C 3-8cycloalkyl, halo C 1-6alkyl ,-C (=O) R 7,-C (=O) OR 7, C 6-10aryl, C 1-9heteroaryl, C 6-10aryl C 1-6alkyl or C 1-9heteroaryl C 1-6alkyl;
Each R 2and R 3be H, D, F, Cl, Br, I, CN, NO independently 2, OH, NH 2, SO 2cl, R 7ar 7n-,-C (=O) R 7,-C (=O) NR 7r 7a,-OC (=O) NR 7r 7a,-OC (=O) OR 7,-N (R 7) C (=O) NR 7r 7a,-N (R 7) C (=O) OR 7a,-N (R 7) C (=O)-R 7a, R 7s (=O) 2-, HO-C 1-6alkyl, R 7ar 7n-C 1-6alkyl, R 7s (=O)-C 1-6alkyl, R 7r 7an-C (=O)-C 1-6alkyl, R 7ar 7n-C 1-6alkoxyl group, R 7s (=O)-C 1-6alkoxyl group, R 7r 7an-C (=O)-C 1-6alkoxyl group, C 6-10aryl, C 1-9heteroaryl, C 1-6alkoxyl group, C 1-6alkylamino, C 1-6alkyl, halo C 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 2-9heterocyclic radical, C 3-8cycloalkyl, C 1-6alkylthio, C 6-10aryloxy, C 6-10arylthio, C 6-10aryl C 1-6alkyl, C 6-10virtue is amino, C 1-9heteroaryl amino, C 6-10aryl C 1-6alkylamino, C 1-9heteroaryl C 1-6alkylamino, C 1-9heteroaryl oxygen base, C 1-9heteroaryl C 1-6alkyl, C 6-10aryl C 1-6alkoxyl group, C 1-9heteroaryl C 1-6alkoxyl group, C 2-9heterocyclyloxy base, C 2-9heterocyclic radical C 1-6alkoxyl group, C 2-9heterocyclylamino group or C 2-9heterocyclic radical alkylamino;
R 4and R 5be H, D, F, Cl, Br, I, CN, C independently of one another 1-6alkyl, C 3-8cycloalkyl, halo C 1-6alkyl, C 1-6alkoxyl group or halo C 1-6alkoxyl group;
R 6for H, D, F, Cl, Br, I, CN, OH, NH 2, SO 2cl, C 1-6alkyl, C 3-8cycloalkyl, C 1-6alkoxyl group ,-C (=O) R 7,-C (=O) OR 7,-C (=O) NR 7r 7a, C 6-10aryl or C 6-10aryl C 1-6alkyl; With
Each R 7and R 7abe H, D, C independently 1-6alkyl, C 1-6assorted alkyl, C 1-6haloalkyl, hydroxyl, amino, C 1-6alkoxyl group, C 6-10aryl, C 2-9heterocyclic radical, C 3-8cycloalkyl, C 6-10aryloxy, C 2-9heterocyclyloxy base, C 3-8cycloalkyl oxy, C 6-10virtue is amino, C 2-9heterocyclylamino group, C 3-8cycloalkyl amino, C 1-9heteroaryl or C 3-8carbocylic radical; Work as R 7and R 7abe connected on same nitrogen-atoms, R 7, R 7asubstituted or non-substituted 3-8 former molecular ring at random can be formed with the nitrogen-atoms be attached thereto.
Wherein in some embodiments, R 1for H, D, C 1-4alkyl, C 3-6cycloalkyl or C 6-10aryl C 1-4alkyl.
Wherein in some embodiments, each R 2and R 3be be independently H, D, F, Cl, Br, I, OH, NH independently 2, CN, C 1-4alkyl, C 3-6cycloalkyl, C 1-4alkoxyl group, C 2-4thiazolinyl, C 2-4alkynyl or C 6-10aryl.
Wherein in some embodiments, R 4and R 5respective is independently H, D, C 1-4alkyl, C 3-6cycloalkyl, halo C 1-4alkyl or C 1-4alkoxyl group.
Wherein in some embodiments, R 6for H, D, F, Cl, Br, I ,-COOH, C 1-4alkyl, C 3-6cycloalkyl, C 6-10aryl or C 6-10aryl C 1-4alkyl.
Wherein in some embodiments, the present invention has the steric isomer of structure shown in structure as shown in formula II or formula II, tautomer, oxynitride, solvate, meta-bolites, pharmacy 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;
R 1for H, D, C 1-4alkyl, C 3-6cycloalkyl, halo C 1-4alkyl or C 6-10aryl C 1-4alkyl;
Each R 2and R 3independent is H, D, F, Cl, Br, I, CN, OH, NH 2, C 1-4alkyl, C 3-6cycloalkyl, C 1-4alkoxyl group, C 2-4thiazolinyl, C 2-4alkynyl or C 6-10aryl;
R 4and R 5respective is independently H, D, C 1-4alkyl, C 3-6cycloalkyl, halo C 1-4alkyl or C 1-4alkoxyl group; With
R 6for H, D, F, Cl, Br, I or C 6-10aryl C 1-4alkyl.
Wherein in some embodiments, R 1for H, D, methyl, ethyl, propyl group, butyl, cyclopropyl or cyclobutyl.
In other embodiments, each R 2and R 3independent is H, D, F, Cl, Br, I, CN, OH, NH 2, methyl, ethyl, propyl group, butyl, methoxyl group, oxyethyl group, propoxy-, butoxy, cyclopropyl or cyclobutyl.
Wherein in some embodiments, the present invention comprises one of them structure following:
or its steric isomer, tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or prodrug.ã
The present invention also comprises the application of compound of the present invention and pharmacy acceptable salt thereof, for the production of pharmaceutical prod treatment Alzheimer's disease, comprises that those are described in the invention.Compound of the present invention is used for alleviating for the production of a kind of pharmaceuticals equally, stops, and controls or treatment 5-HT 6the illness mediated, particularly Alzheimer's disease.The present invention comprises pharmaceutical composition, and this pharmaceutical composition comprises compound representated by formula formula I or formula II and the pharmaceutically acceptable carrier of at least one, the effective treatment consumption needed for the combination of assistant agent or thinner.
Unless other aspects show, the steric isomer that compound of the present invention is all, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, salt and pharmaceutically acceptable prodrug all belong to scope of the present invention.
Specifically, salt is pharmacy acceptable salt.It must be applicable to chemistry or toxicologically that term " pharmaceutically acceptable " comprises material or composition, relevant with other components of composition preparation and the Mammals that is used for the treatment of.
The salt of compound of the present invention also comprise for the preparation of or purifying formula I or formula II shown in the salt of enantiomer of compound separation shown in the intermediate of compound or formula I or formula II, but not necessarily pharmacy acceptable salt.
If compound of the present invention is alkaline, then conceivable salt can be prepared by any suitable method that document provides, and such as, uses mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid etc.Or use organic acid, as acetic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxalic acid, hydroxyethanoic acid and Whitfield's ointment; Pyrans saccharic acid, as glucuronic acid and galacturonic acid; Alpha-hydroxy acid, as citric acid and tartrate; Amino acid, as aspartic acid and L-glutamic acid; Aromatic acid, as phenylformic acid and styracin; Sulfonic acid, as tosic acid, ethyl sulfonic acid, etc.
If compound of the present invention is acid, then conceivable salt can be prepared by suitable method, e.g., uses mineral alkali or organic bases, as ammonia (uncle's ammonia, parahelium, tertiary ammonia), and alkali metal hydroxide or alkaline earth metal hydroxides, etc.Suitable salt comprises, but is not limited to, from the organic salt that amino acid obtains, as glycine and arginine, and ammonia, as uncle ammonia, parahelium and tertiary ammonia, and ring-type ammonia, as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salt.
the compounds of this invention and pharmaceutical composition, preparation and administration
When can be used for treatment, (formula I or formula II compound and pharmacy acceptable salt thereof can be used as unprocessed pharmaceutical chemicals and give the formula for the treatment of significant quantity, and the activeconstituents that also can be used as pharmaceutical composition provides.Therefore, present disclosure also provides pharmaceutical composition, and this pharmaceutical composition comprises the formula formula I or formula II compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carrier, thinner or vehicle for the treatment of significant quantity.
Comprise the methods for the treatment of of the compounds of this invention or pharmaceutical composition administration, comprise administration patient being carried out to other anti-Alzheimer disease drugs (combination therapy) further, wherein the medicine of other anti-Alzheimer diseases is selected from E2020, Nalmefene, risperidone, vitamin E, SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX-8066, SB-742457, naluzaton, Lu-AE58054, tacrine, rivastigmine, lycoremine, memantine, meter Ta Zhaping, Venlafaxine, desipramine, nortriptyline, zolpidem, Zopiclone, nicergoline, piracetam, selegiline, pentoxifylline or their combination.
Term as used herein " treatment significant quantity " refers to the total amount of each active ingredient being enough to demonstrate significant patient benefit.When using independent activeconstituents individually dosed, this term only refers to this composition.When Combination application, and though this term then refer to combination, successively or simultaneously administration time, all cause the combined amount of the activeconstituents of result for the treatment of.Formula formula I or formula II compound and pharmacy acceptable salt described above.From compatible with other compositions of preparation and harmless to its recipient meaning, carrier, thinner or vehicle must be acceptable.According to the another aspect of present disclosure, also be provided for the method for useful in preparing drug formulations, the method comprises and formula I or formula II compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carrier, thinner or vehicle being mixed.Term used in the present invention " pharmaceutically acceptable " refers to such compound, raw material, composition and/or formulation, they are in the scope that rational medicine judges, to be applicable to patient tissue contacts and without excessive toxicity, pungency, transformation reactions or the other problems symmetrical with rational interests/Hazard ratio and complication, and to be effective to given application.
Usually, compound of the present invention is applied to treat significant quantity by any conventional method of application of the material for playing similar effectiveness.Suitable dosage range typically is 1-500mg every day, preferred every day 1-100mg, most preferably every day 1-30mg, this depends on many factors, such as the seriousness of institute's disease therapy, the age of subject and relative health, the effect of compound used therefor, the approach used and form, use for indication and the preference of relevant medical practitioner and experience.Treat the those of ordinary skill of described disease areas without the need to too much testing the treatment significant quantity relying on the disclosure of personal knowledge and the application can determine the compounds of this invention of given disease.
Usually, compound of the present invention is used with pharmaceutical dosage forms, described pharmaceutical preparation comprise those be suitable for oral (comprise oral cavity and sublingual), rectum, nose, locally, pharmaceutical preparation that lung, vagina or parenteral (comprise intramuscular, intra-arterial, sheath interior, subcutaneous and intravenously) are used or the pharmaceutical preparation that is suitable for sucking or being blown into administration form.Preferred method of application is generally oral, uses suitable per daily dose scheme, can adjust according to disease degree to it.
One or more compounds of the present invention can be placed in pharmaceutical composition and unit dosage form together with one or more conventional adjuvant, carrying agent or thinner.Pharmaceutical composition and unit dosage form can comprise the conventional ingredient of conventional ratio, contain or do not contain other active compound or composition, and unit dosage form can contain the activeconstituents of any suitable significant quantity matched with applied plan per daily dose scope.The filling capsule that the application form of pharmaceutical composition can be solid such as tablet or filling capsule, semisolid, powder, sustained release preparation or liquid such as solution, suspensoid, emulsion, elixir or orally use; Or for the suppository form of rectum or vaginal application; Or for parenteral use sterile injectable solutions form.Therefore, in every sheet containing having an appointment 1mg activeconstituents or more broadly, the preparation containing 0.01 to about 100mg activeconstituents of having an appointment is suitable representational unit dosage form.
Compound of the present invention can be mixed with various Orally administered dosage form.Pharmaceutical composition and dosage form can comprise one or more compound or pharmaceutically acceptable salt thereofs of the present invention as activeconstituents.Pharmaceutically useful carrying agent can be solid or liquid.The preparation bag ^ of solid form: agent, tablet, pill, capsule, cachet, suppository and dispersible granule.Solid carrier can be one or more materials, and it also can be used as thinner, correctives, solubilizing agent, lubricant, suspension agent, tackiness agent, sanitas, tablet disintegrant or coating material.In powder, carrier is generally the solid of porphyrize, and the activeconstituents of itself and porphyrize forms mixture.In tablets, activeconstituents usually mixes with the carrying agent with required adhesive capacity mutually with suitable ratio and is pressed into required shape and size.Powder and tablet are preferably containing the active compound of 1% to about 70% of having an appointment.Suitable carrying agent includes but not limited to carbonic acid money, Magnesium Stearate, talcum powder, sugar, lactose, pectin, dextrin, starch, gelatin, tragakanta, methylcellulose gum, Xylo-Mucine, low melt wax, theobroma oil etc.Terms " formulation " is intended to comprise house has coating material as carrying agent to provide the preparation of the active compound of capsule, in described capsule the activeconstituents of with or without carrier surround by this carrying agent of combining with it.Similarly, cachet and lozenge is also comprised.Tablet, powder, capsule, pill, cachet and lozenge are all be suitable for Orally administered solid form.
Other is suitable for Orally administered form and comprises the preparation that the preparation (comprising emulsion, syrup, elixir, aqueous solution agent, aqueous suspension) of liquid form or purport change the solid form of liquid form preparation before use at once into.Emulsion can be prepared in solution such as aqueous solution of propylene glycol maybe can contain emulsifying agent such as Yelkin TTS, polyoxyethylene-sorbitan mono-oleate or gum arabic.Aqueous solution agent is by adding suitable tinting material, correctives, stablizer and thickening material to prepare in water by solubilize active ingredients.The activeconstituents of porphyrize to be dispersed in water by the glue with viscous substance such as natural or synthesis, resin, methylcellulose gum, Xylo-Mucine and other known suspension agent by aqueous suspension to be prepared.The preparation of liquid form comprises solution, suspensoid and emulsion, and except activeconstituents, it can also contain tinting material, correctives, stablizer, buffer reagent, artificial with natural sweeting agent, dispersion agent, thickening material, solubilizing agent etc.
Compound of the present invention can be formulated for parenteral use (such as, being used as bolus injection or continuous infusion by injection) and ampoule can be present in a unit, syringe filling in advance, low capacity infuse in or be present in and with the addition of in the multi-dose container of sanitas.The adoptable form of composition has suspensoid, solution or emulsion such as in oiliness or aqueous vehicle, such as, solution in Aqueous Solutions of Polyethylene Glycol.The example of oiliness or non-aqueous carrying agent, thinner, solvent or vehicle comprises propylene glycol, polyoxyethylene glycol, vegetables oil (such as sweet oil) and injection organic ester (such as ethyl oleate), and can containing formulating substances as sanitas, wetting agent, emulsifying agent or suspension agent, stablizer and/or dispersion agent.Or activeconstituents can be powder type, its preparation method be sterile solid is carried out without mattress packing or by by solution freeze-drying to build with suitable excipients such as aseptic, pyrogen-free water before use.
Compound of the present invention can be formulated for and be locally applied to epidermis with ointment, ointment or lotion form or with transdermal patch form.Ointment and ointment can such as be prepared by the water-based or oleaginous base that with the addition of suitable thickening material and/or jelling agent.Lotion can use or oleaginous base preparation and usually also containing one or more emulsifying agents, stablizer, dispersion agent, suspension agent, thickening material or tinting material.Be suitable for the preparation of topical application in mouth and comprise the lozenge comprising and be in flavored base, be generally the activeconstituents in sucrose and gum arabic or tragakanta; Comprise and be in the lozenge of inert base as the activeconstituents in gelatin and glycerine or sucrose and gum arabic; And comprise the mouth wash shua of the activeconstituents be in appropriate liquid carrying agent.
Compound of the present invention can be formulated for and use with suppository form.Can first by low melt wax as fatty glyceride mixt or theobroma oil fusing, and by activeconstituents such as by the dispersion that stirs.Then the uniform mixture of melting is poured in the mould of suitable size, make it cool and solidify.
Compound of the present invention can be formulated for vaginal application.Vaginal suppository in addition to the active ingredient (s also containing carrying agent known in this field, tampon, newborn blue or green agent, gelifying agent, paste, foaming agent or sprays are suitable.
Compound of the present invention can be formulated for nasal administration.Can by solution or suspensoid by ordinary method, such as directly apply to nasal cavity with dropper, suction pipe or atomizer.Preparation can be single dose or multiple doses form.For the multiple doses form of dropper or suction pipe, this can by being used solution that is suitable, pre-determined volume or suspensoid realizes by patient.For atomizer, this can such as be realized by metering atomising atomizing pump.
Compound of the present invention can be formulated for aerosol and use, and is particularly applied to respiratory tract and comprises intranasal administration.Compound has little granularity usually, the granularity of such as 5 microns or more decimal magnitude.Described granularity is by method well known in the art, such as obtain by micronization.Activeconstituents is to provide containing the suitable pressurized package of propellent as chlorofluorocarbon (CFC) such as Refrigerant 12, trichlorofluoromethane or dichloro tetrafluoro ethane or carbonic acid gas or other suitable gas.Aerosol also can contain tensio-active agent as Yelkin TTS suitably.Drug dose controls by metering valve.Or, activeconstituents can with dry powdered form, such as at suitable powder base as lactose, starch, the powdered mixture form of starch derivative as the compound in Vltra tears and polyvinylpyrrolidone provide.Powder carrying agent will form gel in nasal cavity.Powder composition can such as exist with gelatine capsule agent or cartridge case or bubble Army packaged form in a unit ' by sucker by wherein using powder.
When needing, preparation can be prepared with the enteric coating being suitable for slowly-releasing or controlled release and using activeconstituents.Such as, compound of the present invention can be formulated into transdermal or subcutaneous drug delivery device.When necessary slow release compounds and when the compliance of patient for treatment's scheme is most important, these delivery systems are favourable.Compound in transdermal delivery system is often attached on skin-adhesive solid carrying agent.The compound paid close attention to also can with penetration enhancer, such as laurocapram " 1-12 pit foundation nitrogen heterocyclic-2-in heptan ketone) combinationally use.Subcutaneous layer is inserted into by subcutaneous for Sustained release delivery systems by operation or injection.Compound is encapsulated in lipid soluble membrane, such as silicon rubber or Biodegradable polymeric such as poly(lactic acid) by hypodermic implant.
Pharmaceutical preparation is preferably unit dosage form.In this form, preparation is subdivided into the unitary dose containing sufficient quantity activeconstituents.Unit dosage form can be the preparation of packaging kit, containing the preparation of discrete magnitude in packaging, and the tablet of such as packaging kit, capsule and powder in the vial or ampulla agent.In addition, unit dosage form can be capsule, tablet, cachet or lozenge itself, or it can be any one in these forms of suitable number in packaging kit form.
Other suitable medicinal carrying agent and their preparation are at Remington:The Science and Practice of Pharmacy1995Martin, and E.W edits, Mack Publishing Company, the 19th edition, has description in Easton, Pennsylvania.
the purposes of the compounds of this invention and pharmaceutical composition
The feature of pharmaceutical composition of the present invention comprises the compound listed by the compound shown in formula formula I or formula II or the present invention, and pharmaceutically acceptable carrier, assistant agent or vehicle.In composition of the present invention, the amount of compound can detectably antagonism 5-HT effectively 6with treatment of obesity, gastrointestinal tract disease, CNS illness, wherein said CNS illness comprises: ADHD, anxiety, the disease relevant to stress, schizophrenia, obsessional idea and behavior disorder, manic depressive illness, nervous disorders, dysmnesia, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington Chorea etc.
" significant quantity " or " effective dose " of compound of the present invention or pharmaceutically acceptable composition refer to process or alleviate one or more the present invention mention the significant quantity of the severity of illness.According to method of the present invention, compound and composition can be any dosage and any route of administration come effectively for the treatment of or the severity that palliates a disease.Situation according to patient changes by required measuring accurately, and this depends on race, the age, the general condition of patient, the severity of infection, special factor, administering mode, etc.Compound or composition can with one or more other treatment agent Combined Preparation, as discussed in the present invention.
the general synthetic method of the compounds of this invention
Usually, compound of the present invention can be prepared by method described in the invention, and unless there are further instruction, wherein substituent definition is as shown in formula I or formula II.Reaction scheme below and embodiment are used for illustrating content of the present invention further.
Those skilled in the art will realize that: chemical reaction described in the invention can be used for preparing many other compounds of the present invention suitably, and is all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.Such as; synthesis according to the compound of those non-illustrations of the present invention can successfully be completed by modifying method by those skilled in the art; as suitable protection interference group, by the reagent that utilizes other known except described in the invention, or reaction conditions is made the amendment of some routines.In addition, reaction disclosed in this invention or known reaction conditions are also applicable to the preparation of other compounds of the present invention admittedly.
The embodiments described below, to be decided to be degree Celsius unless other aspects show all temperature.Reagent is bought in goods providers as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, all not through being further purified, unless other aspects show during use.General reagent from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao buy obtain.
Anhydrous tetrahydro furan is through sodium Metal 99.5 backflow drying and obtains.Anhydrous methylene chloride and chloroform are through hydrolith backflow drying and obtain.Ethyl acetate, sherwood oil, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.
Below reacting is generally under nitrogen or argon gas positive pressure or on anhydrous solvent, overlap a drying tube (unless showing in other), the soft rubber ball that reaction flask is suitable all beyond the Great Wall, and substrate is squeezed into by syringe.Glassware is all dried.
Chromatographic column uses silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDC1 3, d 6-DMSO, CD 3oD or d 6-acetone is solvent (reporting in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) as reference standard.In time there is multiplet, abbreviation below will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, quartet), dt (doublet of triplets, two triplet).Coupling constant, represents with hertz (Hz).
Algorithm (MS) data are measured by the spectrograph of the Agilent6320 series LC-MS being equipped with G1312A binary pump and a G1316A TCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315B DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Algorithm (MS) data are measured by the spectrograph of the Agilent6120 series LC-MS being equipped with G1311A quaternary pump and G1316A TCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315D DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Above two kinds of spectrographs are provided with Agilent Zorbax SB-C18 post, and specification is 2.1 à 30mm, 5 μm.Volume injected is determined by sample concentration; Flow velocity is 0.6mL/min; The peak value of HPLC records reading by the UV-Vis wavelength at 210nm and 254nm place.Moving phase is the formic acid acetonitrile solution (phase A) of 0.1% and the formic acid ultrapure water solution (phase B) of 0.1%.Condition of gradient elution is as shown in table 1:
Table 1
Time (min) A(CH 3CNï¼0.1ï¼ HCOOH) B(H 2Oï¼0.1ï¼ HCOOH) 0-3 5-100 95-0 3-6 100 0 6-6.1 100-5 0-95 6.1-8 5 95Compound purifying is evaluated by Agilent1100 series of high efficiency liquid chromatography (HPLC), wherein UV detects at 210nm and 254nm place, Zorbax SB-C18 post, specification is 2.1 à 30mm, 4 μm, 10 minutes, flow velocity was 0.6mL/min, (0.1% aqueous formic acid) of (the 0.1% formic acid acetonitrile solution) of 5-95%, column temperature remains on 40 DEG C.
The use of brief word below runs through the present invention:
H 2sO 4sulfuric acid
HOAc acetic acid
NaOAc sodium-acetate
MeCN, CH 3cN acetonitrile
Cl 3c 2oCl trichoroacetic chloride
CHCl 3chloroform
CDC1 3deuterochloroform
ClSO 2oH chlorsulfonic acid
DMF DMF
DMAC N,N-dimethylacetamide
DMSO dimethyl sulfoxide (DMSO)
EtOAc ethyl acetate
EA ethyl acetate
HCl hydrochloric acid
MgSO 4magnesium sulfate
MeOH, CH 3oH methyl alcohol
HCHO formaldehyde
CH 2cl 2, DCM methylene dichloride
ML, ml milliliter
PE sherwood oil (60-90 DEG C)
Na 2cO 3sodium carbonate
NaHCO 3sodium bicarbonate
KOH potassium hydroxide
RT, rt room temperature
Rt retention time
NaBH 3cN sodium cyanoborohydride
NaCl sodium-chlor
NaH sodium hydride
Na 2sO 4sodium sulfate
THF tetrahydrofuran (THF)
C 5h 8o Isosorbide-5-Nitrae-dihydropyrane
C 2h 7nHCl dimethylamine hydrochloride
Et 3n, TEA triethylamine
H 2o water
DME glycol dimethyl ether
TsCl Tosyl chloride
5-fluorine tryptamines 2-(the fluoro-1H-indol-3-yl of 5-) ethamine
6-fluorine tryptamines 2-(the fluoro-1H-indol-3-yl of 6-) ethamine
EDTA ethylenediamine tetraacetic acid (EDTA)
PEI polymine
Pargyline Pargyline
Tris-HCl tri-(methylol) aminomethane-hydrochloric acid
Following synthetic schemes describes preparation the present invention and to come into the open the step of compound.Unless otherwise indicated, each m and R 3there is definition as described in the present invention.
Synthetic method 1
Compound ( 4) and ( 5) can be prepared by following process:
Different replace tryptamines compound ( 1) and formaldehyde reaction, obtain under reductive agent sodium cyanoborohydride existent condition two methylated compounds ( 2).Compound ( 2) with SULPHURYL CHLORIDE obtain under the effect of alkali compound ( 3).Compound ( 3) obtain removing under the effect of alkali (potassium hydroxide) tribromo-acetyl based compound ( 4), compound ( 4) obtain with formaldehyde reaction further compound ( 5).
Synthetic method 2
Compound ( 11) and ( 12) can be prepared by following process:
Different substituted phenylhydrazines hydrochloride compound ( 6) with 3,4-2H-dihydropyrane be obtained by reacting Benzazole compounds ( 7).Formula ( 7) shown in compound in catalytic amount DMAP (DMAP) effect lower and Tosyl chloride be obtained by reacting compound ( 8).Compound ( 8) with dimethylamine be obtained by reacting compound ( 9).Then, compound ( 9) be obtained by reacting with SULPHURYL CHLORIDE under alkali effect compound ( 10); Compound ( 10) remove under potassium hydroxide effect tribromo-acetyl base obtain compound ( 11).Finally, formula compound ( 11) with formaldehyde reaction obtain formula compound ( 12).
Below in conjunction with embodiment, compound provided by the invention, pharmaceutical composition and application thereof are further described.
Embodiment
the synthesis of embodiment 1:2-(the fluoro-1-of 6-(4-methoxy-3-(piperazine-1-base) benzenesulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine
step 1) synthesis of 2-(the fluoro-1H-indol-3-yl of 6-)-N, N-dimethyl amine
6-fluorine tryptamine hydrochloride (1g, 4.66mmol) and sodium-acetate (382mg, 4.66mmol) are joined in methyl alcohol (15mL), then at 0 DEG C, slowly adds NaBH successively 3cN (881mg, 13.98mmol) and formaldehyde (40%, 0.975mL, 13.98mmol).React and be warming up to 25 DEG C after 10 minutes, continue reaction 5 hours.Stopped reaction, adds water (10mL) and sodium carbonate (988mg, 9.32mmol) cancellation reaction successively.With methylene dichloride (50mL x3) extraction, merge organic phase, use anhydrous sodium sulfate drying.Filter, filtrate decompression is spin-dried for, and it is brown solid (824.6mg, 85.9%) that column chromatography purification (methylene chloride/methanol (v/v)=20/1) obtains title compound.
MS(ESI,pos.ion)m/z:207.1[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)8.12(brs,1H),7.50(dd,Jï¼8.4,5.2Hz,1H),7.02(d,Jï¼2.2Hz,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)ã
step 2) synthesis of 2,2,2-tri-chloro-1-(4-(2-methoxyphenyl) piperazine-1-base) ethyl ketone
By 1-(2-p-methoxy-phenyl) piperazine hydrochloric acid (1.0g, 4.39mmol) with triethylamine (2.5mL, 17.70mmol) join in 15mL methylene dichloride, under 0 DEG C of low temperature bath, slowly drip trichoroacetic chloride (1.0mL, 8.96mmol), after dripping, react 24 hours at being transferred to 25 DEG C, stopped reaction, adds 50mL methylene dichloride, wash with saturated sodium bicarbonate solution (40mL), organic phase anhydrous sodium sulfate drying after separatory.Filter, filtrate decompression is spin-dried for, and it is faint yellow solid (763mg, 52%) that column chromatography purification (petrol ether/ethyl acetate (v/v)=10/1) obtains title compound.
MS(ESI,pos.ion)m/z:337.0[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):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,Jï¼4.4Hz,4H)ï¼
step 3) synthesis of 4-methoxy-3-(4-(2,2,2-tribromo-acetyl base) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE
By 2,2, the chloro-1-of 2-tri-(4-(2-methoxyphenyl) piperazine-1-base) ethyl ketone (550mg, 1.63mmol) be dissolved in 5mL methylene dichloride, then be added drop-wise in 3mL chlorsulfonic acid under 0 DEG C of low temperature bath, react after one hour, reaction solution is imported in the mixed solution of frozen water (30mL) and methylene dichloride (50mL), separatory after vigorous stirring, organic phase anhydrous magnesium sulfate drying.Filter, filtrate decompression is spin-dried for and namely obtains title compound is faint yellow solid (548mg, 78.5%).
MS(ESI,pos.ion)m/z:435.0[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.75(dd,Jï¼8.8,2.4Hz,1H),7.47(d,Jï¼2.4Hz,1H),7.01(d,Jï¼8.8Hz,1H),4.00(brs,7H),3.21(t,Jï¼4.8Hz,4H)ï¼
step 4) synthesis of 2,2,2-tri-chloro-1-(4-(5-(3-(2-(dimethylamino) ethyl) the fluoro-1H-indoles of-6--1-alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone
By 2-(the fluoro-1H-indol-3-yl of 6-)-N at 0 DEG C; N-dimethyl amine (487.6mg; 2.367mmol) with sodium hydride (94.7mg; 2.4mmol) join in DMF (3mL); then 4-methoxy-3-(4-(2 is slowly added; 2,2-tribromo-acetyl base) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (860mg, 1.97mmol).React after ten minutes, be warming up to 25 DEG C, continue reaction 2 hours.Add 100mL ethyl acetate, then wash (30mL x3) with saturated nacl aqueous solution, organic phase anhydrous sodium sulfate drying after separatory.Filter, filtrate decompression is spin-dried for, and it is Light brown solid (386mg, 32.4%) that column chromatography purification (methylene chloride/methanol (v/v)=50/) obtains title compound.
MS(ESI,pos.ion)m/z:605.2[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.68(dd,Jï¼9.8,2.2Hz,1H),7.56(dd,Jï¼8.6,2.3Hz,1H),7.42(dd,Jï¼8.7,5.2Hz,1H),7.33(s,1H),7.28(d,Jï¼2.3Hz,1H),6.99(td,Jï¼9.0,2.3Hz,1H),6.86(d,Jï¼8.7Hz,1H),3.93(brs,4H),3.88(s,3H),3.08(t,Jï¼4.9Hz,4H),2.85(t,Jï¼7.4Hz,2H),2.63(t,Jï¼8.5Hz,2H),2.35(s,6H)ï¼
step 5) synthesis of 2-(the fluoro-1-of 6-(4-methoxy-3-(piperazine-1-base) benzenesulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine
At 25 DEG C, by chloro-for 2,2,2-tri-1-(4-(5-(3-(2-(dimethylamino) ethyl) the fluoro-1H-indoles of-6--1-alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) second ketone(359mg, 0.594mmol) is dissolved in tetrahydrofuran (THF) (20mL), then slowly adds potassium hydroxide (100mg, 1.783mmol are made into the 1mmol/ml aqueous solution).Reaction solution stirring reaction, after 24 hours, adds 60ml methylene dichloride; Organic phase saturated nacl aqueous solution is washed (30mL x3), organic phase anhydrous sodium sulfate drying after separatory.Filter, filtrate decompression be spin-dried for, it is faint yellow solid (248mg, 90.8%) that column chromatography purification (methylene chloride/methanol (v/v)=10/1) obtains title compound.
MS(ESI,pos.ion)m/z:231.1[M+2H] 2+/2ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.68(dd,Jï¼9.6,2.4Hz,1H),7.51(dd,Jï¼8.8,2.3Hz,1H),7.39(dd,Jï¼8.7,2.4Hz,1H),7.32(s,1H),7.28(d,Jï¼2.3Hz,1H),6.97(td,Jï¼9.0,2.3Hz,1H),6.81(d,Jï¼8.6Hz,1H),3.85(s,3H),3.01(d,Jï¼5.0Hz,4H),2.95(d,Jï¼4.8Hz,4H),2.80(t,Jï¼7.4Hz,2H),2.57(t,Jï¼7.2Hz,2H),2.31(s,6H)ï¼
13C?NMR(100MHz,CDCl 3):δ(ppm)161.1(d,Jï¼240.0Hz),156.7,142.4,135.7(d,Jï¼12.0Hz),129.9,127.5,123.4(d,Jï¼4.0Hz),122.6,120.9,120.3(d,Jï¼10.0Hz),116.5,111.5(d,Jï¼24.0Hz),111.0,101.3(d,Jï¼28.0Hz),59.2,56.1,51.6,46.2,45.5,23.6ã
the synthesis of embodiment 2:2-(the fluoro-1-of 6-((4-methoxy-3-(4-methylpiperazine-1-yl) phenyl) alkylsulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine
By 2-(the fluoro-1-of 6-(4-methoxy-3-(piperazine-1-base) benzenesulfonyl)-1H-indol-3-yl)-N; N-dimethyl amine (248mg; 0.539mmol) be dissolved in methyl alcohol (10mL), add two acetic acid.At 0 DEG C, sodium cyanoborohydride (85mg, 1.35mmol) and formaldehyde (40%, 0.112mL, 1.617mmol) are slowly joined in reaction solution.React after ten minutes, be warming up to 25 DEG C; Continue reaction after 5 hours, add 10mL water and sodium carbonate (370mg, 3.5mmol) cancellation, then use dichloromethane extraction (50mL x3).Merge organic phase, anhydrous sodium sulfate drying; Filter, filtrate decompression is spin-dried for, and it is white solid (160.6mg, 62.9%) that column chromatography purification (methylene chloride/methanol (v/v)=15/1) obtains title compound.
HPLC?analysis:96.8ï¼ ã
MS(ESI,pos.ion)m/z:238.3[M+2]+/2ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.68(dd,Jï¼9.8,2.3Hz,1H),7.50(dd,Jï¼8.6,2.3Hz,1H),7.39(dd,Jï¼8.6,5.2Hz,1H),7.33(s,1H),7.28(d,Jï¼2.3Hz,1H),6.96(td,Jï¼9.0,2.4Hz,1H),6.80(d,Jï¼8.6Hz,1H),3.84(s,3H),3.02(s,4H),2.80(t,Jï¼7.4Hz,2H),2.60-2.56(m,6H),2.33(s,3H),2.31(s,6H)ï¼
13C?NMR(100MHz,CDCl 3):δ(ppm)161.1(d,Jï¼241.0Hz),156.7,142.0,135.6(d,Jï¼12.0Hz),129.9,127.5,123.4(d,Jï¼4.0Hz),122.5,120.9,120.3(d,Jï¼10.0Hz),116.4,111.5(d,Jï¼24.0Hz),111.0,101.3(d,Jï¼28.0Hz),59.2,56.1,55.2,50.3,46.2,45.5,23.5ã
the synthesis of embodiment 3:2-(5-methoxy-1-(4-methoxy-3-(piperazine-1-base) benzenesulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine
step 1) synthesis of 2-(5-methoxy-1H-indol-3-yl)-N, N-dimethyl amine
This step title compound prepares, by 5-MT 5-methoxytryptamine hydrochloride (801mg, 3.53mmol), sodium-acetate (382mg, 4.66mmol), NaBH with reference to the method described by embodiment 1 step 1 3cN (881mg, 13.98mmol) with formaldehyde (40%, 0.975mL, 13.98mmol) reaction preparation in methyl alcohol (15mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is yellow oil (691mg, 89.8%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:219.10[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)8.03(s,1H),7.24(d,Jï¼8.8Hz,1H),7.05(d,Jï¼2.3Hz,1H),7.00(d,Jï¼1.7Hz,1H),6.85(dd,Jï¼8.8,2.4Hz,1H),3.87(s,3H),2.94(t,Jï¼8.4Hz,2H),2.70-2.66(m,2H),2.38(s,6H)ï¼
step 2) conjunction of 2,2,2-tri-chloro-1-(4-(5-(3-(2-(dimethylamino) ethyl)-5-methoxy-1H-indoles-1-alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone become
This step title compound prepares with reference to the method described by embodiment 1 step 4, 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-tribromo-acetyl base) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (981mg, 2.25mmol) reaction preparation in DMF (3mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is Light brown solid (290mg that concentrate drying obtains title compound, 25%).
MS(ESI,pos.ion)m/z:617.2[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.85(d,Jï¼9.0Hz,1H),7.52(dd,Jï¼8.6,2.3Hz,1H),7.31(s,1H),7.26-7.25(m,1H),6.95(d,Jï¼2.3Hz,1H),6.92(dd,Jï¼8.9,2.5Hz,1H),6.82(d,Jï¼8.7Hz,1H),3.96(brs,4H),3.86(s,3H),3.83(s,3H),3.05(t,Jï¼4.9Hz,4H),2.86(t,Jï¼7.4Hz,2H),2.66(t,Jï¼8.5Hz,2H),2.39(s,6H)ï¼
step 3) synthesis of 2-(5-methoxy-1-(4-methoxy-3-(piperazine-1-base) benzenesulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine
This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2, 2, the chloro-1-of 2-tri-(4-(5-(3-(2-(dimethylamino) ethyl)-5-methoxy-1H-indoles-1-alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone (290mg, 0.47mmol), potassium hydroxide (79mg, 1.41mmol, be made into the 1mmol/ml aqueous solution) reaction preparation in tetrahydrofuran (THF) (20mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is white solid (110mg that concentrate drying obtains title compound, 49.6%).
MS(ESI,pos.ion)m/z:237.3[M+2H] 2+/2ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.86-7.84(m,1H),7.47(dd,Jï¼8.6,2.3Hz,1H),7.30(s,1H),7.26(s,1H),6.90-6.88(m,2H),6.77(d,Jï¼8.6Hz,1H),3.83(s,3H),3.81(s,3H),2.99(d,Jï¼4.3Hz,4H),2.93(d,Jï¼2.6Hz,4H),2.78(t,Jï¼7.4Hz,2H),2.57(t,Jï¼8.5Hz,2H),2.31(s,6H)ã
the synthesis of embodiment 4:2-(5-methoxy-1-((4-methoxy-3-(4-methylpiperazine-1-yl) phenyl) alkylsulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine
This step title compound prepares with reference to the method described by embodiment 1 step 5, 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) with formaldehyde (40%, 0.044mL, 0.63mmol) reaction preparation in methyl alcohol (10mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is white solid (55.7mg that concentrate drying obtains title compound, 53.6%).
HPLC?analysis:96.10ï¼ ï¼
MS(ESI,pos.ion)m/z:244.2[M+2H] 2+/2ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.85(d,Jï¼9.0Hz,1H),7.47(dd,Jï¼8.6,2.3Hz,1H),7.31(s,1H),7.27(d,Jï¼2.3Hz,1H),6.93-6.90(m,1H),6.88(d,Jï¼2.4Hz,1H),6.78(d,Jï¼8.7Hz,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)ï¼
13C?NMR(100MHz,CDCl 3):δ(ppm)156.6,156.5,141.8,132.2,130.2,130.1,124.2,122.4,120.9,116.5,114.9,113.6,110.9,102.2,59.1,56.1,56.0,55.2,50.3,46.3,45.4,23.5ã
the synthesis of embodiment 5:2-(5-methyl isophthalic acid-(4-methoxy-3-(piperazine-1-base) benzenesulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine
step 1) synthesis of 2-(5-Methyl-1H-indole-3-base)-N, N-dimethyl amine
This step title compound prepares, by 5-methyltryptamine hydrochloride (996mg, 4.74mmol), sodium-acetate (389mg, 4.74mmol), NaBH with reference to the method described by embodiment 1 step 1 3cN (881mg, 13.98mmol) with formaldehyde (40%, 0.975mL, 13.98mmol) reaction preparation in methyl alcohol (15mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is yellow oil (887.5mg, 92.6%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:203.15[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.95(s,1H),7.38(s,1H),7.24(d,Jï¼8.4Hz,1H),7.02-6.98(m,2H),2.96(t,Jï¼8.4Hz,2H),2.71(t,Jï¼8.4Hz,2H),2.46(s,3H),2.39(s,6H)ï¼
step 2) 2,2,2-tri-chloro-1-(4-(5-(3-(2-(dimethylamino) ethyl)-5-Methyl-1H-indole-1-alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone synthesis
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 2-(5-Methyl-1H-indole-3-base)-N, N-dimethyl amine (448mg, 2.22mmol), sodium hydride (107mg, 2.66mmol), 4-methoxy-3-(4-(2, 2, 2-tribromo-acetyl base) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (1.16g, 2.66mmol) reaction preparation in DMF (5mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is Light brown solid (308mg that concentrate drying obtains title compound, 23%).
MS(ESI,pos.ion)m/z:601.0[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.83(d,Jï¼8.4Hz,1H),7.53(dd,Jï¼8.6,2.3Hz,1H),7.30(s,1H),7.28-7.26(m,2H),7.12(dd,Jï¼8.4,1.2Hz,1H),6.82(d,Jï¼8.7Hz,1H),3.96(brs,4H),3.86(s,3H),3.05(t,Jï¼4.9Hz,4H),2.84(t,Jï¼7.4Hz,2H),2.63(t,Jï¼8.6Hz,2H),2.42(s,3H),2.36(s,6H)ï¼
step 3) synthesis of 2-(5-methyl isophthalic acid-(4-methoxy-3-(piperazine-1-base) benzenesulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine
This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2, 2, the chloro-1-of 2-tri-(4-(5-(3-(2-(dimethylamino) ethyl)-5-Methyl-1H-indole-1-alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone (301mg, 0.50mmol), potassium hydroxide (84mg, 1.5mmol, be made into the 1mmol/ml aqueous solution) reaction preparation in tetrahydrofuran (THF) (20mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is white solid (220mg that concentrate drying obtains title compound, 96.5%).
MS(ESI,pos.ion)m/z:229.1[M+2H] 2+/2ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.83(d,Jï¼8.4Hz,1H),7.52(dd,Jï¼8.6,2.2Hz,1H),7.35(s,1H),7.29-7.27(m,2H),7.12(d,Jï¼7.7Hz,1H),6.79(d,Jï¼8.8Hz,1H),3.83(s,3H),3.15(d,Jï¼3.3Hz,4H),3.08(d,Jï¼3.1Hz,4H),2.94-2.90(m,2H),2.79-2.75(m,2H),2.47(s,6H),2.41(s,3H)ã
the synthesis of embodiment 6:2-(1-((4-methoxy-3-(4-methylpiperazine-1-yl) phenyl) alkylsulfonyl)-5-Methyl-1H-indole-3-base)-N, N-dimethyl amine
This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2-(5-methyl isophthalic acid-(4-methoxy-3-(piperazine-1-base) benzenesulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine (100mg, 0.22mmol), sodium cyanoborohydride (42mg, 0.66mmol) with formaldehyde (40%, 0.046mL, 0.66mmol) reaction preparation in methyl alcohol (10mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is white solid (70mg that concentrate drying obtains title compound, 68%).
HPLC?analysis:97.96ï¼ ï¼
MS(ESI,pos.ion)m/z:236.25[M+2H] 2+/2ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.82(d,Jï¼8.4Hz,1H),7.48(dd,Jï¼8.6,2.3Hz,1H),7.30(s,1H),7.28(d,Jï¼2.3Hz,1H),7.24(s,1H),7.09(dd,Jï¼8.5,1.1Hz,1H),6.76(d,Jï¼8.7Hz,1H),3.82(s,3H),3.00(s,4H),2.81(t,Jï¼7.4Hz,2H),2.62-2.58(m,2H),2.55(s,4H),2.39(s,3H),2.33(s,6H),2.33(s,3H)ï¼
13C?NMR(100MHz,CDCl 3):δ(ppm)156.4,141.8,133.8,132.8,131.4,130.2,126.1,123.4,122.4,120.8,119.4,116.5,113.7,110.9,59.2,56.0,55.2,50.3,46.2,45.5,23.5,21.5ã
the synthesis of embodiment 7:2-(1-(4-methoxy-3-(piperazine-1-base) benzenesulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine
step 1) synthesis of 2-(1H-indol-3-yl)-N, N-dimethyl amine
This step title compound prepares, by tryptamine hydrochloride (588mg, 3.0mmol), sodium-acetate (246mg, 3.0mmol), NaBH with reference to the method described by embodiment 1 step 1 3cN (881mg, 13.98mmol) with formaldehyde (40%, 0.975mL, 13.98mmol) reaction preparation in methyl alcohol (15mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is Light brown solid (563mg, 99.8%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:189.1[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)8.08(s,1H),7.62(d,Jï¼8.0Hz,1H),7.35(d,Jï¼8.0Hz,1H),7.21-7.17(m,1H),7.14-7.10(m,1H),7.02(d,Jï¼1.2Hz,1H),2.98(t,Jï¼8.0Hz,2H),2.71-2.67(m,2H),2.37(s,6H)ï¼
step 2) synthesis of 2,2,2-tri-chloro-1-(4-(5-(3-(2-(dimethylamino) ethyl)-1H-indoles-1-alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 2-(1H-indol-3-yl)-N, N-dimethyl amine (282mg, 1.5mmol), sodium hydride (72mg, 1.8mmol), 4-methoxy-3-(4-(2, 2, 2-tribromo-acetyl base) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (785mg, 1.8mmol) reaction preparation in DMF (5mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is faint yellow solid (486mg that concentrate drying obtains title compound, 55.3%).
MS(ESI,pos.ion)m/z:587.0[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.97(d,Jï¼8.2Hz,1H),7.56(dd,Jï¼8.72.3Hz,1H),7.51(d,Jï¼7.7Hz,1H),7.36(s,1H),7.34-7.29(m,2H),7.24-7.22(m,1H),6.84(d,Jï¼8.7Hz,1H),3.96-3.90(m,4H),3.86(s,3H),3.06(t,Jï¼4.9Hz,4H),2.92(t,Jï¼7.4Hz,2H),2.70(t,Jï¼8.5Hz,2H),2.41(s,6H)ï¼
step 3) synthesis of 2-(1-(4-methoxy-3-(piperazine-1-base) benzenesulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine
This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2, 2, the chloro-1-of 2-tri-(4-(5-(3-(2-(dimethylamino) ethyl)-1H-indoles-1-alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone (529mg, 0.90mmol), potassium hydroxide (151mg, 2.7mmol, be made into the 1mmol/ml aqueous solution) reaction preparation in tetrahydrofuran (THF) (20mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is white solid (374mg that concentrate drying obtains title compound, 94%).
MS(ESI,pos.ion)m/z:222.2[M+2H] 2+/2ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.96(d,Jï¼8.2Hz,1H),7.51(d,Jï¼2.3Hz,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,Jï¼8.7Hz,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)ã
the synthesis of embodiment 8:2-(1-((4-methoxy-3-(4-methylpiperazine-1-yl) phenyl) alkylsulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine
This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2-(1-(4-methoxy-3-(piperazine-1-base) benzenesulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine (349mg, 0.79mmol), sodium cyanoborohydride (151mg, 2.4mmol) with formaldehyde (40%, 0.166mL, 2.4mmol) reaction preparation in methyl alcohol (10mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is white solid (210mg that concentrate drying obtains title compound, 58.3%).
HPLC?analysis:97.67ï¼ ï¼
MS(ESI,pos.ion)m/z:457.20[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.98(d,Jï¼8.2Hz,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,Jï¼8.7Hz,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)ï¼
13C?NMR(100MHz,CDCl 3):δ(ppm)156.5,141.8,135.5,131.1,130.2,124.8,123.3,123.2,122.5,120.9,119.5,116.5,114.0,110.9,59.1,56.0,55.1,50.2,46.2,45.3,23.4ã
the synthesis of embodiment 9:2-(the chloro-1-of 5-(4-methoxy-3-(piperazine-1-base) benzenesulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine
step 1) synthesis of 2-(the chloro-1H-indol-3-yl of 5-)-N, N-dimethyl amine
This step title compound prepares, by 5-chlorine tryptamines (427mg, 2.2mmol), NaBH with reference to the method described by embodiment 1 step 1 3cN (416mg, 6.6mmol) with formaldehyde (40%, 0.477mL, 6.6mmol) reaction preparation in methyl alcohol (15mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), it is brown solid (478mg, 97.8%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:223.1[M+1] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)8.32(s,1H),7.55(d,Jï¼2.0Hz,1H),7.23(d,Jï¼8.8Hz,1H),7.11(dd,Jï¼8.8,2.0Hz,1H),7.02(d,Jï¼2.0Hz,1H),2.93â2.89(m,2H),2.67â2.64(m,2H),2.36(s,6H)ï¼
step 2) synthesis of 2,2,2-tri-chloro-1-(4-(5-(3-(2-(dimethylamino) ethyl) the chloro-1H-indoles of-5--1-alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 2-(the chloro-1H-indol-3-yl of 5-)-N, N-dimethyl amine (383mg, 1.72mmol), sodium hydride (76mg, 1.90mmol), 4-methoxy-3-(4-(2, 2, 2-tribromo-acetyl base) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (828mg, 1.90mmol) reaction preparation in DMF (5mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is Light brown solid (356mg that concentrate drying obtains title compound, 33.2%).
MS(ESI,pos.ion)m/z:621.2[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.88(d,Jï¼8.8Hz,1H),7.53(dd,Jï¼8.8,2.4Hz,1H),7.47(d,Jï¼2.0Hz,1H),7.39(s,1H),7.28â7.25(m,2H),6.85(d,Jï¼8.8Hz,1H),3.96(brs,4H),3.88(s,3H),3.07(t,Jï¼5.2Hz,4H),2.88â2.84(m,2H),2.68(t,Jï¼8.4Hz,2H),2.40(s,6H)ï¼
step 3) synthesis of 2-(the chloro-1-of 5-(4-methoxy-3-(piperazine-1-base) benzenesulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine
This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2, 2, the chloro-1-of 2-tri-(4-(5-(3-(2-(dimethylamino) ethyl) the chloro-1H-indoles of-5--1-alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone (346mg, 0.56mmol), potassium hydroxide (94mg, 1.68mmol, be made into the 1mmol/ml aqueous solution) reaction preparation in tetrahydrofuran (THF) (20mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is white solid (140mg that concentrate drying obtains title compound, 52.7%).
MS(ESI,pos.ion)m/z:477.25[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.88(d,Jï¼8.8Hz,1H),7.48(dd,Jï¼8.8,2.4Hz,1H),7.43(d,Jï¼2.0Hz,1H),7.38(s,1H),7.27-7.23(m,2H),6.79(d,Jï¼8.8Hz,1H),3.84(s,3H),3.05-2.96(m,8H),2.80â2.76(m,2H),2.59-2.55(m,2H),2.31(s,6H)ï¼
13C?NMR(100MHz,CDCl 3):δ(ppm)156.5,142.0,133.6,132.3,129.7,128.9,124.7,124.5,122.4,120.4,119.1,116.3,114.8,110.8,58.9,55.9,51.2,45.8,45.3,23.2ã
Real execute the synthesis of routine 10:2-(the chloro-1-of 5-((4-methoxy-3-(4-methylpiperazine-1-yl) phenyl) alkylsulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine
This step title compound prepares with reference to the method described by embodiment 1 step 5, 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) with formaldehyde (40%, 0.048mL, 0.69mmol) reaction preparation in methyl alcohol (10mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is white solid (106mg that concentrate drying obtains title compound, 93.6%).
HPLC?analysis:95.68ï¼ ï¼
MS(ESI,pos.ion)m/z:246.2[M+2H] 2+/2ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.87(d,Jï¼8.8Hz,1H),7.47(dd,Jï¼8.8,2.4Hz,1H),7.43(d,Jï¼1.6Hz,1H),7.37(s,1H),7.26(d,Jï¼2.4Hz,1H),7.23(dd,Jï¼8.8,2.0Hz,1H),6.79(d,Jï¼8.4Hz,1H),3.84(s,3H),3.01(s,4H),2.80â2.76(m,2H),2.60â2.56(m,6H),2.33(s,3H),2.32(s,6H)ï¼
13C?NMR(100MHz,CDCl 3):δ(ppm)156.4,141.7,133.6,132.2,129.6,128.9,124.7,124.5,122.2,120.3,119.1,116.2,114.8,110.7,58.8,55.8,54.9,50.0,46.0,45.2,23.1ã
the synthesis of embodiment 11:2-(the bromo-1-of 5-(4-methoxy-3-(piperazine-1-base) benzenesulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine
step 1) synthesis of 2-(the bromo-1H-indol-3-yl of 5-)-N, N-dimethyl amine
This step title compound prepares, by 5-bromine tryptamines (896mg, 3.8mmol), NaBH with reference to the method described by embodiment 1 step 1 3cN (718mg, 11.4mmol) with formaldehyde (40%, 0.823mL, 11.4mmol) reaction preparation in methyl alcohol (15mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), it is brown solid (705mg, 70.4%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:267.0[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)8.41(s,1H),7.71(d,Jï¼1.6Hz,1H),7.24(dd,Jï¼8.4,1.6Hz,1H),7.16(d,Jï¼8.4Hz,1H),6.98(d,Jï¼2.0Hz,1H),2.91â2.87(m,2H),2.65â2.61(m,2H),2.35(s,6H)ï¼
step 2) synthesis of 2,2,2-tri-chloro-1-(4-(5-(3-(2-(dimethylamino) ethyl) the bromo-1H-indoles of-5--1-alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 2-(the bromo-1H-indol-3-yl of 5-)-N, N-dimethyl amine (400mg, 1.50mmol), sodium hydride (72mg, 1.8mmol), 4-methoxy-3-(4-(2, 2, 2-tribromo-acetyl base) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (785mg, 1.8mmol) reaction preparation in DMF (5mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is Light brown solid (334mg that concentrate drying obtains title compound, 33.5%).
MS(ESI,pos.ion)m/z:665.0[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.83(d,Jï¼8.8Hz,1H),7.62(d,Jï¼1.6Hz,1H),7.53(dd,Jï¼8.8,2.4Hz,1H),7.41-7.38(m,2H),7.27(s,1H),6.85(d,Jï¼8.8Hz,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)ï¼
step 3) synthesis of 2-(the bromo-1-of 5-(4-methoxy-3-(piperazine-1-base) benzenesulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine
This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2, 2, the chloro-1-of 2-tri-(4-(5-(3-(2-(dimethylamino) ethyl) the bromo-1H-indoles of-5--1-alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone (539mg, 0.81mmol), potassium hydroxide (134mg, 2.4mmol, be made into the 1mmol/ml aqueous solution) reaction preparation in tetrahydrofuran (THF) (20mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is white solid (211mg that concentrate drying obtains title compound, 50.1%).
MS(ESI,pos.ion)m/z:261.10[M+2H] 2+/2ï¼
1H?NMR(400MHz,DMSO-d 6):δ(ppm)7.87(d,Jï¼8.8Hz,1H),7.82(d,Jï¼1.6Hz,1H),7.72(s,1H),7.57(dd,Jï¼8.8,2.4Hz,1H),7.48(dd,Jï¼8.8,2.0Hz,1H),7.24(d,Jï¼2.4Hz,1H),7.07(d,Jï¼8.8Hz,1H),3.81(s,3H),2.98(s,8H),2.79(t,Jï¼7.2Hz,2H),2.57(t,Jï¼7.2Hz,2H),2.24(s,6H)ï¼
13C?NMR(100MHz,DMSO-d 6):δ(ppm)156.9,141.8,133.7,133.2,128.7,127.6,125.7,122.9,122.7,121.0,116.4,115.9,115.6,112.4,58.5,56.5,49.4,45.2,44.7,22.4ã
the synthesis of embodiment 12:2-(the bromo-1-of 5-((4-methoxy-3-(4-methylpiperazine-1-yl) phenyl) alkylsulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine
This step title compound prepares with reference to the method described by embodiment 1 step 5, 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) with formaldehyde (40%, 0.075mL, 1.08mmol) reaction preparation in methyl alcohol (10mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is white solid (175mg that concentrate drying obtains title compound, 92.1%).
HPLC?analysis:97.67ï¼ ï¼
MS(ESI,pos.ion)m/z:268.2[M+2H] 2+/2ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.82(d,Jï¼8.8Hz,1H),7.59(d,Jï¼1.6Hz,1H),7.47(dd,Jï¼8.8,2.4Hz,1H),7.37-7.35(m,2H),7.26(d,Jï¼2.4Hz,1H),6.78(d,Jï¼8.8Hz,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).ï¼
13C?NMR(100MHz,CDCl 3):δ(ppm)156.4,141.7,133.9,132.7,129.5,127.3,124.3,122.2,122.1,120.1,116.5,116.1,115.1,110.7,58.7,55.8,54.9,50.0,46.0,45.2,23.1ã
the synthesis of embodiment 13:2-(the fluoro-1-of 5-(4-methoxy-3-(piperazine-1-base) benzenesulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine
step 1) synthesis of 2-(the fluoro-1H-indol-3-yl of 5-)-N, N-dimethyl amine
This step title compound prepares, by 5-fluorine tryptamines (560mg, 3.14mmol), NaBH with reference to the method described by embodiment 1 step 1 3cN (593mg, 9.42mmol) with formaldehyde (40%, 0.680mL, 9.42mmol) reaction preparation in methyl alcohol (15mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), it is brown oil (630mg, 97.3%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:207.1[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)8.15(s,1H),7.26-7.22(m,2H),7.07(d,Jï¼2.4Hz,1H),6.92(td,Jï¼8.8,2.4Hz,1H),2.94â2.91(m,2H),2.67â2.65(m,2H),2.38(s,6H)ï¼
step 2) synthesis of 2,2,2-tri-chloro-1-(4-(5-(3-(2-(dimethylamino) ethyl) the fluoro-1H-indoles of-5--1-alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 2-(the fluoro-1H-indol-3-yl of 5-)-N, N-dimethyl amine (308mg, 1.50mmol), sodium hydride (72mg, 1.8mmol), 4-methoxy-3-(4-(2, 2, 2-tribromo-acetyl base) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (785mg, 1.8mmol) reaction preparation in DMF (3mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is Light brown solid (270mg that concentrate drying obtains title compound, 29.8%).
MS(ESI,pos.ion)m/z:605.0[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.91(dd,Jï¼9.2,4.4Hz,1H),7.53(dd,Jï¼8.4,2.0Hz,1H),7.41(s,1H),7.27(d,Jï¼2.4Hz,1H),7.17(dd,Jï¼8.4,2.4Hz,1H),7.04(td,Jï¼8.8,2.4Hz,1H),6.85(d,Jï¼8.8Hz,1H),3.96(brs,4H),3.88(s,3H),3.07(t,Jï¼5.2Hz,4H),2.93(t,Jï¼11.2Hz,2H),2.82-2.78(m,2H),2.51(s,6H)ï¼
step 3) synthesis of 2-(the fluoro-1-of 5-(4-methoxy-3-(piperazine-1-base) benzenesulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine
This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2, 2, the chloro-1-of 2-tri-(4-(5-(3-(2-(dimethylamino) ethyl) the fluoro-1H-indoles of-5--1-alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone (366mg, 0.6mmol), potassium hydroxide (101mg, 1.8mmol, be made into the 1mmol/ml aqueous solution) reaction preparation in tetrahydrofuran (THF) (20mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is faint yellow solid (100mg that concentrate drying obtains title compound, 36%).
MS(ESI,pos.ion)m/z:461.1[M+1] +ï¼
1H?NMR(400MHz,DMSO-d 6):δ(ppm)7.91(dd,Jï¼8.8,4.4Hz,1H),7.72(s,1H),7.56(dd,Jï¼8.8,2.4Hz,1H),7.42(dd,Jï¼9.2,2.4Hz,1H),7.23(d,Jï¼2.4Hz,1H),7.18(td,Jï¼9.2,2.4Hz,1H),7.06(d,Jï¼8.8Hz,1H),3.81(s,3H),2.95(brs,8H),2.77(t,Jï¼7.6Hz,2H),2.55(t,Jï¼7.6Hz,2H),2.22(s,6H)ï¼
13C?NMR(100MHz,DMSO-d 6):δ(ppm)159.4(d,Jï¼236.6Hz),156.8,141.9,132.5(d,Jï¼9.7Hz),131.4,128.8,126.2,122.6,121.6(d,Jï¼4.0Hz),115.9,115.1(d,Jï¼9.5Hz),112.8(d,Jï¼25.5Hz),112.3,106.0(d,Jï¼23.5Hz),58.6,56.5,49.7,45.3,44.9,22.6ã
the synthesis of embodiment 14:2-(the fluoro-1-of 5-((4-methoxy-3-(4-methylpiperazine-1-yl) phenyl) alkylsulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine
This step title compound prepares with reference to the method described by embodiment 1 step 5, 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), sodium cyanoborohydride (40mg, 0.63mmol) with formaldehyde (40%, 0.044mL, 0.63mmol) reaction preparation in methyl alcohol (10mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is faint yellow solid (70mg that concentrate drying obtains title compound, 70.3%).
HPLC?analysis:97.07ï¼ ï¼
MS(ESI,pos.ion)m/z:238.1[M+2H] 2+/2ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.89(dd,Jï¼8.8,4.4Hz,1H),7.48(dd,Jï¼8.8,2.4Hz,1H),7.38(s,1H),7.26(d,Jï¼2.0Hz,1H),7.12(dd,Jï¼8.8,2.4Hz,1H),7.00(td,Jï¼9.2,2.8Hz,1H),6.79(d,Jï¼8.4Hz,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)ï¼
13C?NMR(100MHz,CDCl 3):δ(ppm)159.5(d,Jï¼238.9Hz),156.4,141.7,132.0(d,Jï¼9.2Hz),131.6,129.7,124.8,122.2,120.7(d,Jï¼4.0Hz),116.2,114.8(d,Jï¼9.2Hz),112.4(d,Jï¼25.3Hz),110.7,105.0(d,Jï¼23.8Hz),58.7,55.8,54.9,50.0,46.0,45.2,23.2ã
the synthesis of embodiment 15:3-(1-((4-methoxy-3-(piperazine-1-base) phenyl) alkylsulfonyl)-1H-indol-3-yl)-N, N-dimethylpropane-1-amine
step 1) synthesis of 3-(1H-indol-3-yl) propyl group-1-alcohol
Phenylhydrazine (2.25g, 20.8mmol) is dissolved in 4%H 2sO 4 (aq)(50mL) with in the mixed solvent of N,N-dimethylacetamide (10mL), be warming up to 100 DEG C, then drip Isosorbide-5-Nitrae-dihydropyrane (1.9mL, 20.8mmol).Be warming up to 100 DEG C, reaction 20h, then reaction mixture is cooled to room temperature, add extraction into ethyl acetate (50mL Ã 3), then wash (50mL Ã 3). organic phase anhydrous sodium sulfate drying, filters, concentrated filtrate, silica column purification (petrol ether/ethyl acetate (v/v)=2/1), concentrates and obtains white solid (2.29g, 63.0%).
MS(ESI,pos.ion)m/z:176.3[M+H]+ï¼
1H?NMR(400MHz,CDCl 3),δ(ppm):8.02(brs,1H),7.60(d,Jï¼7.8Hz,1H),7.32(d,Jï¼8.1Hz,1H),7.20-7.16(m,1H),7.13-7.09(m,1H),6.95(t,Jï¼1.0Hz,1H),3.71(t,Jï¼6.4Hz,2H),2.84(t,Jï¼7.4Hz,2H),2.00-1.94(m,2H)ï¼
step 2) synthesis of 3-(1H-indol-3-yl) propyl group 4-toluene sulfonic acide ester
By 3-(1H-indol-3-yl) propyl group-1-alcohol (0.88g, 5.0mmol) be dissolved in methylene dichloride (20mL), add triethylamine (0.8mL successively, 6.0mmol) with Tosyl chloride (1.14g, 6.0mmol), add rear room temperature reaction 4h, add methylene dichloride (50mL), then add water (100mL), after separatory, organic phase is with dry without ability aqueous sodium persulfate, filter, concentrated filtrate, silica column purification (petrol ether/ethyl acetate (v/v)=4/1), concentrated, it is white solid white solid (1.04g that drying obtains title compound, 63.0%).
MS(ESI,pos.ion)m/z:330.2[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.98(brs,1H),7.77(d,Jï¼8.3Hz,2H),7.48(d,Jï¼7.9Hz,1H),7.35-7.30(m,3H),7.18(td,Jï¼7.1,1.0Hz,1H),7.10-7.06(m,1H),6.9(d,Jï¼2.0Hz,1H),4.08(t,Jï¼6.2Hz,2H),2.81(t,Jï¼7.2Hz,2H),2.43(s,3H),2.07-2.00(m,2H)ï¼
step 3) synthesis of 3-(1H-indol-3-yl)-N, N-dimethylpropane-1-amine
By 3-(1H-indol-3-yl) propyl group 4-toluene sulfonic acide ester (1.2g, 3.65mmol) with dimethylamine hydrochloric acid (1.2g, 14.6mmol) be dissolved in 10mL acetonitrile, then triethylamine (1.95mL is added, 14.6mmol), react 15 hours at oil bath 60 DEG C, stopped reaction, ethyl acetate (50mL) is added after being cooled to room temperature, then wash (60mL) with saturated sodium bicarbonate solution, organic phase anhydrous sodium sulfate drying after separatory, filter, concentrated filtrate, silica column purification (methylene chloride/methanol (v/v)=20/1), concentrated, it is yellow liquid (383mg that drying obtains title compound, 52%).
MS(ESI,pos.ion)m/z:203.2[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)8.40(s,1H),7.61(d,Jï¼7.8Hz,1H),7.34(d,Jï¼8.0Hz,1H),7.19(td,Jï¼7.2,1.0Hz,1H),7.13-7.09(m,1H),6.96(t,Jï¼0.9Hz,1H),2.79(t,Jï¼7.6Hz,2H),2.45-2.41(m,2H),2.29(s,6H),1.97-1.86(m,2H)ï¼
step 4) synthesis of 2,2,2-tri-chloro-1-(4-(5-((3-(3-(dimethylamino) propyl group)-1H-indoles-1-base) alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 3-(1H-indol-3-yl)-N, N-dimethylpropane-1-amine (375mg, 1.86mmol), sodium hydride (80mg, 2.0mmol), 4-methoxy-3-(4-(2, 2, 2-tribromo-acetyl base) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (892mg, 2.1mmol) reaction preparation in DMF (5mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is Light brown solid (251mg that concentrate drying obtains title compound, 22.5%).
MS(ESI,pos.ion)m/z:601.2[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.98(d,Jï¼8.3Hz,1H),7.55(dd,Jï¼8.6,2.3Hz,1H),7.48(d,Jï¼7.6Hz,1H),7.33-7.21(m,4H),6.84(d,Jï¼8.7Hz,1H),3.96(brs,4H),3.86(s,3H),3.05(t,Jï¼4.9Hz,4H),2.71(t,Jï¼7.5Hz,2H),2.47(t,Jï¼7.4Hz,2H),2.35(s,6H),1.95-1.91(m,2H)ï¼
step 5) 3-(1-((4-methoxy-3-(piperazine-1-base) phenyl) alkylsulfonyl)-1H-indol-3-yl)-N, N-dimethylpropane-1-amine
This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2, 2, the chloro-1-of 2-tri-(4-(5-((3-(3-(dimethylamino) propyl group)-1H-indoles-1-base) alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone (251mg, 0.42mmol), potassium hydroxide (70mg, 1.25mmol, be made into the 1mmol/ml aqueous solution) reaction preparation in tetrahydrofuran (THF) (10mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is pale yellow oil (174mg that concentrate drying obtains title compound, 90.6%).
HPLC?analysis:95.81ï¼ ï¼
MS(ESI,pos.ion)m/z:229.2[M+2H] 2+/2ï¼
1H?NMR(400MHz,CD 3OD):δ(ppm)8.01(d,Jï¼8.0Hz,1H),7.66(dd,Jï¼8.0,4.0Hz,1H),7.60(d,Jï¼8.0Hz,1H),7.57(s,1H),7.43(d,Jï¼4.0Hz,1H),7.38-7.34(m,1H),7.30-7.26(m,1H),7.08(d,Jï¼8.0Hz,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,Jï¼8.0Hz,2H),2.18-2.10(m,2H)ï¼
13C?NMR(100MHz,CD 3OD):δ(ppm)158.3,141.5,136.9,132.0,131.0,125.9,124.9,124.8,124.4,122.7,120.5,117.9,114.9,112.8,58.6,56.7,45.0,43.5,25.3,22.6ã
the synthesis of embodiment 16:3-(1-((4-methoxy-3-(4-methylpiperazine-1-yl) phenyl) alkylsulfonyl)-1H-indol-3-yl)-N, N-dimethylpropane-1-amine
This step title compound prepares with reference to the method described by embodiment 1 step 5, by 3-(1-((4-methoxy-3-(piperazine-1-base) phenyl) alkylsulfonyl)-1H-indol-3-yl)-N, N-dimethylpropane-1-amine (71mg, 0.16mmol), sodium cyanoborohydride (30mg, 0.48mmol) with formaldehyde (40%, 0.034mL, 0.48mmol) reaction preparation in methyl alcohol (10mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is white solid (60.6mg that concentrate drying obtains title compound, 80.8%).
HPLC?analysis:95.27ï¼ ï¼
MS(ESI,pos.ion)m/z:236.2[M+2H] 2+/2ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)8.00(d,Jï¼8.4Hz,1H),7.55(dd,Jï¼8.4,2.4Hz,1H),7.49(d,Jï¼8.0Hz,1H),7.37(s,1H),7.34-7.31(m,2H),7.27-7.23(m,1H),6.84(d,Jï¼8.4Hz,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)ï¼
13C?NMR(100MHz,CDCl 3):δ(ppm)156.4,141.5,135.5,130.6,129.9,124.8,123.1,123.0,122.5,121.4,119.3,116.4,113.9,110.9,58.2,55.9,54.9,49.8,45.7,44.0,25.1,22.4ã
the synthesis of embodiment 17:3-(the fluoro-1-of 5-((4-methoxy-3-(piperazine-1-base) phenyl) alkylsulfonyl)-1H-indol-3-yl)-N, N-dimethylpropane-1-amine
step 1) synthesis of 3-(the fluoro-1H-indol-3-yl of 5-) propyl group-1-alcohol
This step title compound prepares with reference to the method described by embodiment 15 step 1, is dissolved in 4%H by 4-fluorophenyl hydrazine hydrochloride (3.37g, 20.8mmol) and Isosorbide-5-Nitrae-dihydropyrane (1.9mL, 20.8mmol) 2sO 4(aq) (50mL) and N, reaction preparation in the mixed solvent of N-N,N-DIMETHYLACETAMIDE (10mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying, it is white solid (3.53g, 88%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:194.2[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)8.05(brs,1H),7.27-7.23(m,1H),7.03(d,Jï¼2.0Hz,1H),6.96-6.91(m,1H),3.72(t,Jï¼6.4Hz,2H),2.81(t,Jï¼7.5Hz,2H),2.00-1.93(m,2H)ï¼
step 2) synthesis of 3-(the fluoro-1H-indol-3-yl of 5-) propyl group 4-toluene sulfonic acide ester
This step title compound prepares with reference to the method described by embodiment 15 step 2, by 3-(the fluoro-1H-indol-3-yl of 5-) propyl group-1-alcohol (0.97g, 5.0mmol), triethylamine (0.8mL, 6.0mmol) and and Tosyl chloride (1.14g, 6.0mmol) be dissolved in reaction preparation in methylene dichloride (20mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purifying, it is white solid (1.28g, 74.0%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:348.1[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):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,Jï¼9.6,2.4Hz,1H),6.96(d,Jï¼2.1Hz,1H),6.92(dd,Jï¼9.1,2.5Hz,1H),4.07(t,Jï¼6.2Hz,2H),2.75(t,Jï¼7.3Hz,2H),2.44(s,3H),2.05-1.97(m,2H)ï¼
step 3) synthesis of 3-(the fluoro-1H-indol-3-yl of 5-)-N, N-dimethylpropane-1-amine
This step title compound prepares with reference to the method described by embodiment 15 step 3, by 3-(5-fluorine 1H-indol-3-yl) propyl group 4-toluene sulfonic acide ester (1.27g, 3.65mmol), dimethylamine hydrochloric acid (1.2g, 14.6mmol) with triethylamine (1.95mL, 14.6mmol) be dissolved in reaction preparation in 10mL acetonitrile, crude on silica gel column chromatography (methylene chloride/methanol (v/v)=20/1) purifying, it is yellow oil (0.79g, 98.6%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:221.2[M+H] +ï¼
1H?NMR(CDCl 3,400MHz),δ(ppm)8.14(s,1H),7.20-7.16(m,1H),7.14(d,Jï¼2.4Hz,1H),6.96(s,1H),6.84(td,Jï¼9.0,2.5Hz,1H),2.66(t,Jï¼7.6Hz,2H),2.35(t,Jï¼7.4,2H),2.22(s,6H),1.87-1.79(m,2H)ï¼
step 4) 2,2,2-tri-chloro-1-(4-(5-((3-(3-(dimethylamino) propyl group) the fluoro-1H-indoles of-5--1-base) alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone synthesis
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 3-(the fluoro-1H-indol-3-yl of 5-)-N, N-dimethylpropane-1-amine (125mg, 0.57mmol), sodium hydride (27mg, 0.68mmol), 4-methoxy-3-(4-(2, 2, 2-tribromo-acetyl base) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (298mg, 0.68mmol) reaction preparation in DMF (3mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is Light brown solid (131mg that concentrate drying obtains title compound, 37%).
MS(ESI,pos.ion)m/z:619.2[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.68(dd,Jï¼9.8,2.2Hz,1H),7.56(dd,Jï¼8.6,2.3Hz,1H),7.42(dd,Jï¼8.7,5.2Hz,1H),7.33(s,1H),7.28(d,Jï¼2.3Hz,1H),6.99(td,Jï¼9.0,2.3Hz,1H),6.86(d,Jï¼8.7Hz,1H),3.93(brs,4H),3.88(s,3H),3.08(t,Jï¼4.9Hz,4H),2.85(t,Jï¼7.4Hz,2H),2.63(t,Jï¼8.5Hz,2H),2.35(s,6H)ï¼
step 5) synthesis of 3-(1-((4-methoxy-3-(piperazine-1-base) phenyl) alkylsulfonyl) the fluoro-1H-indol-3-yl of-5-)-N, N-dimethylpropane-1-amine
This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2, 2, the chloro-1-of 2-tri-(4-(5-((3-(3-(dimethylamino) propyl group) the fluoro-1H-indoles of-5--1-base) alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone (514mg, 0.83mmol), potassium hydroxide (116mg, 2.07mmol, be made into the 1mmol/ml aqueous solution) reaction preparation in tetrahydrofuran (THF) (15mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is pale yellow oil (223mg that concentrate drying obtains title compound, 57%).
HPLC?annalysis:96.03ï¼ ï¼
MS(ESI,pos.ion)m/z:238.3[M+2H] 2+/2ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.93(dd,Jï¼8.0,4.0Hz,1H),7.51(dd,Jï¼8.0,4.0Hz,1H),7.36(s,1H),7.29(s,1H),7.14(dd,Jï¼8.0,4.0Hz,1H),7.04(td,Jï¼8.0,2.0Hz,1H),6.82(d,Jï¼8.0Hz,1H),3.86(s,3H),3.06-3.05(m,4H),2.99(brs,4H),2.65(t,Jï¼8.0Hz,2H),2.39(t,Jï¼8.0Hz,2H),2.29(s,6H),1.90-1.82(m,2H)ï¼
13C?NMR(100MHz,CDCl 3):δ(ppm)159.5(d,Jï¼239.0Hz),156.5,142.1,132.2(d,Jï¼10.0Hz),131.8,129.7,124.5,122.8(d,Jï¼4.0Hz),122.3,116.3,114.8(d,Jï¼9.0Hz),112.4(d,Jï¼25.0Hz),110.8,105.2(d,Jï¼24.0Hz),59.0,55.9,51.3,45.9,45.3,26.7,22.5ã
the conjunction of embodiment 18:3-(1-((4-methoxy-3-(4-methylpiperazine-1-yl) phenyl) alkylsulfonyl) the fluoro-1H-indol-3-yl of-5-)-N, N-dimethylpropane-1-amine become
This step title compound prepares with reference to the method described by embodiment 1 step 5, by 3-(1-((4-methoxy-3-(piperazine-1-base) phenyl) alkylsulfonyl) the fluoro-1H-indol-3-yl of-5-)-N, N-dimethylpropane-1-amine (71mg, 0.15mmol), sodium cyanoborohydride (28mg, 0.45mmol) with formaldehyde (40%, 0.034mL, 0.48mmol) reaction preparation in methyl alcohol (10mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is white solid (41mg that concentrate drying obtains title compound, 44%).
HPLC?analysis:96.26ï¼ ï¼
MS(ESI,pos.ion)m/z:245.2[M+2H] 2+/2ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.94(dd,Jï¼8.8,4.4Hz,1H),7.50(dd,Jï¼8.8,2.4Hz,1H),7.37(s,1H),7.30(d,Jï¼2.0Hz,1H),7.13(dd,Jï¼8.8,2.4Hz,1H),7.04(td,Jï¼9.6,2.4Hz,1H),6.83(d,Jï¼8.8Hz,1H),3.87(s,3H),3.03(brs,4H),2.67(t,Jï¼7.6,2H),2.59(brs,4H),2.47(t,Jï¼7.2,2H),2.37(s,9H),1.95-1.88(m,2H)ï¼
13C?NMR(100MHz,CDCl 3):δ(ppm)159.5(d,Jï¼239.1Hz),.156.4,141.7,131.9(d,Jï¼18.0Hz),129.8,124.6,122.2,116.3,114.9(d,Jï¼9.3Hz),112.5(d,Jï¼25.3Hz),110.8,105.1(d,Jï¼23.8Hz),58.7,55.9,55.0,50.1,46.0,44.9,26.2,22.5ã
the synthesis of embodiment 19:3-(the chloro-1-of 5-((4-methoxy-3-(piperazine-1-base) phenyl) alkylsulfonyl)-1H-indol-3-yl)-N, N-dimethylpropane-1-amine
step 1) synthesis of 3-(the chloro-1H-indol-3-yl of 5-) propyl group-1-alcohol
This step title compound prepares with reference to the method described by embodiment 15 step 1, is dissolved in 4%H2SO4 (a by p-hydrochloride (3.72g, 20.8mmol) and Isosorbide-5-Nitrae-dihydropyrane (1.9mL, 20.8mmol) q) (50mL) and N, reaction preparation in the mixed solvent of N-N,N-DIMETHYLACETAMIDE (10mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying, it is white solid (2.35g, 54%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:210.2[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)8.10(brs,1H),7.56(d,Jï¼1.8Hz,1H),7.26-7.24(m,2H),7.11(dd,Jï¼8.6,1.9Hz,1H),6.99(s,1H),3.71(t,Jï¼6.4Hz,2H),2.80(t,Jï¼7.5Hz,2H),1.99-1.92(m,2H)ï¼
step 2) synthesis of 3-(the chloro-1H-indol-3-yl of 5-) propyl group 4-toluene sulfonic acide ester
This step title compound prepares with reference to the method described by embodiment 15 step 2, by 3-(the chloro-1H-indol-3-yl of 5-) propyl group-1-alcohol (1.05g, 5.0mmol), triethylamine (0.8mL, 6.0mmol) and and Tosyl chloride (1.14g, 6.0mmol) be dissolved in reaction preparation in methylene dichloride (20mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purifying, it is white solid (1.09g, 60.0%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:364.1[M+H] +ï¼
1H?NMR(CDCl 3,400MHz):δ(ppm)8.03(brs,1H),7.76(d,Jï¼8.3Hz,2H),7.44(d,Jï¼2.0Hz,1H),7.31(d,Jï¼8.0Hz,2H),7.26-7.24(m1H),7.11(dd,Jï¼8.6,2.0Hz,1H),6.95(d,Jï¼2.2Hz,1H),4.07(t,Jï¼6.2Hz,2H),2.75(t,Jï¼7.3Hz,2H),2.44(s,3H),2.04-1.97(m,2H)ï¼
step 3) synthesis of 3-(the chloro-1H-indol-3-yl of 5-)-N, N-dimethylpropane-1-amine
This step title compound prepares with reference to the method described by embodiment 15 step 3, by 3-(the chloro-1H-indol-3-yl of 5-) propyl group 4-toluene sulfonic acide ester (1.33g, 3.65mmol), dimethylamine hydrochloric acid (1.2g, 14.6mmol) with triethylamine (1.95mL, 14.6mmol) be dissolved in reaction preparation in 10mL acetonitrile, crude on silica gel column chromatography (methylene chloride/methanol (v/v)=20/1) purifying, it is yellow oil (0.68g, 78%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:237.1[M+H] +ï¼
1H?NMR(CDCl 3,400MHz):δ8.20(s,1H),7.55(d,Jï¼1.9Hz,1H),7.27-7.25(m,1H),7.12(dd,Jï¼8.6,2.0Hz,1H),7.01(s,1H),2.74(t,Jï¼7.6Hz,2H),2.42(t,Jï¼7.5Hz,2H),2.29(s,6H),1.94-1.86(m,2H)ï¼
step 4) 2,2,2-tri-chloro-1-(4-(5-((3-(3-(dimethylamino) propyl group) the chloro-1H-indoles of-5--1-base) alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone synthesis
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 3-(the chloro-1H-indol-3-yl of 5-)-N, N-dimethylpropane-1-amine (245mg, 1.03mmol), sodium hydride (50mg, 1.22mmol), 4-methoxy-3-(4-(2, 2, 2-tribromo-acetyl base) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (543mg, 1.25mmol) reaction preparation in DMF (5mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is pale yellow oil (192mg that concentrate drying obtains title compound, 29%).
MS(ESI,pos.ion)m/z:635.1[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.89(d,Jï¼8.8Hz,1H),7.52(dd,Jï¼8.8,2.3Hz,1H),7.45(d,Jï¼1.9Hz,1H),7.33(s,1H),7.27-7.24(m,2H),6.84(d,Jï¼8.7Hz,1H),3.96(brs,4H),3.87(s,3H),3.07(t,Jï¼5.0Hz,4H),2.65(t,Jï¼7.4Hz,2H),2.38(t,Jï¼7.4Hz,2H),2.40(s,6H),1.87-1.84(m,2H)ï¼
step 5) synthesis of 3-(1-((4-methoxy-3-(piperazine-1-base) phenyl) alkylsulfonyl) the chloro-1H-indol-3-yl of-5-)-N, N-dimethylpropane-1-amine
This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2, 2, the chloro-1-of 2-tri-(4-(5-((3-(3-(dimethylamino) propyl group) the chloro-1H-indoles of-5--1-base) alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone (837mg, 1.32mmol), potassium hydroxide (221mg, 3.95mmol, be made into the 1mmol/ml aqueous solution) reaction preparation in tetrahydrofuran (THF) (30mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is pale yellow oil (385mg that concentrate drying obtains title compound, 59%).
HPLC?analysis:96.32ï¼ ï¼
MS(ESI,pos.ion)m/z:246.2[M+2H] 2+/2ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.90(d,Jï¼8.8Hz,1H),7.50(dd,Jï¼8.8,2.4Hz,1H),7.46(d,Jï¼2.0Hz,1H),7.35(s,1H),7.29(d,Jï¼2.8Hz,1H),7.26(dd,Jï¼8.8,2.0Hz,1H),6.81(d,Jï¼8.8Hz,1H),3.86(s,3H),3.06-2.99(m,8H),2.65(t,Jï¼7.2Hz,2H),2.38(t,Jï¼7.2Hz,2H),2.29(s,6H),1.89-1.83(m,2H)ï¼
13C?NMR(100MHz,CDCl 3):δ(ppm)156.5,142.0,133.8,132.3,129.7,128.9,124.7,124.2,122.4,122.3,119.3,116.3,114.8,110.8,58.9,55.9,51.1,45.8,45.3,26.8,22.4ã
the conjunction of embodiment 20:3-(1-((4-methoxy-3-(4-methylpiperazine-1-yl) phenyl) alkylsulfonyl) the chloro-1H-indol-3-yl of-5-)-N, N-dimethylpropane-1-amine become
This step title compound prepares with reference to the method described by embodiment 1 step 5, by 3-(1-((4-methoxy-3-(piperazine-1-base) phenyl) alkylsulfonyl) the chloro-1H-indol-3-yl of-5-)-N, N-dimethylpropane-1-amine (231mg, 0.47mmol), sodium cyanoborohydride (89mg, 1.41mmol) with formaldehyde (40%, 0.099mL, 1.41mmol) reaction preparation in methyl alcohol (10mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is pale yellow oil (121mg that concentrate drying obtains title compound, 51%).
HPLC?analysis:97.32ï¼ ï¼
MS(ESI,pos.ion)m/z:253.1[M+2H] 2+/2ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.91(d,Jï¼8.8Hz,1H),7.50(dd,Jï¼8.8,2.4Hz,1H),7.46(d,Jï¼2.0Hz,1H),7.35(s,1H),7.30(d,Jï¼2.0Hz,1H),7.26(dd,Jï¼8.8,2.0Hz,1H),6.82(d,Jï¼8.0Hz,1H),3.87(s,3H),3.03(brs,4H),2.67(t,Jï¼7.2Hz,2H),2.37(s,3H),2.33(s,6H),1.93-1.85(m,2H)ï¼
13C?NMR(100MHz,CDCl 3):δ(ppm)156.5,141.8,133.8,132.2,129.7,128.9,124.7,124.2,122.2,119.2,116.2,114.8,110.8,110.0,58.7,55.9,54.9,50.1,46.0,45.0,26.4,22.4ã
the synthesis of embodiment 21:3-(the bromo-1-of 5-((4-methoxy-3-(piperazine-1-base) phenyl) alkylsulfonyl)-1H-indol-3-yl)-N, N-dimethylpropane-1-amine
step 1) synthesis of 3-(the bromo-1H-indol-3-yl of 5-) propyl group-1-alcohol
This step title compound prepares with reference to the method described by embodiment 15 step 1, is dissolved in 4%H by 4-bromophenyl-hydrazine hydrochloride (4.64g, 20.8mmol) and Isosorbide-5-Nitrae-dihydropyrane (1.9mL, 20.8mmol) 2sO 4 (aq)(50mL) and N, reaction preparation in the mixed solvent of N-N,N-DIMETHYLACETAMIDE (10mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying, it is white solid (1.59g, 30%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:256.0[M+H] +ï¼
1H?NMR(CDCl 3,400MHz),δ(ppm)8.34(brs,1H),7.74(d,Jï¼1.6Hz,1H),7.27(dd,Jï¼8.4,1.6Hz,1H),7.19(d,Jï¼8.4Hz,1H),6.92-6.93(m,1H),3.71(t,Jï¼6.4Hz,2H),2.79(t,Jï¼7.2Hz,2H),1.92-1.99(m,2H)ï¼
step 2) synthesis of 3-(the bromo-1H-indol-3-yl of 5-) propyl group 4-toluene sulfonic acide ester
This step title compound prepares with reference to the method described by embodiment 15 step 2, by 3-(the bromo-1H-indol-3-yl of 5-) propyl group-1-alcohol (1.28g, 5.0mmol), triethylamine (0.8mL, 6.0mmol) with Tosyl chloride (1.14g, 6.0mmol) be dissolved in reaction preparation in methylene dichloride (20mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purifying, it is white solid (1.32g, 63.0%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:408.0[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)8.26(brs,1H),7.80(d,Jï¼8.0Hz,2H),7.62(d,Jï¼0.8Hz,1H),7.34(d,Jï¼8.0Hz,2H),7.2-7.28(m,2H),6.91(d,Jï¼1.6Hz,1H),4.09(t,Jï¼6.0Hz,2H),2.75(t,Jï¼7.2Hz,2H),2.46(s,3H),1.99-2.02(m,2H)ï¼
step 3) synthesis of 3-(the bromo-1H-indol-3-yl of 5-)-N, N-dimethylpropane-1-amine
This step title compound prepares with reference to the method described by embodiment 15 step 3, by 3-(the bromo-1H-indol-3-yl of 5-) propyl group 4-toluene sulfonic acide ester (1.49g, 3.65mmol), dimethylamine hydrochloric acid (1.2g, 14.6mmol) with triethylamine (1.95mL, 14.6mmol) be dissolved in reaction preparation in 10mL acetonitrile, crude on silica gel column chromatography (methylene chloride/methanol (v/v)=20/1) purifying, it is yellow oil (0.96g, 94%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:281.1[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)8.15(s,1H),7.74(d,Jï¼1.7Hz,1H),7.29-7.23(m,2H),7.03(t,Jï¼1.2Hz,1H),2.76(t,Jï¼7.5Hz,2H),2.45(t,Jï¼8.0Hz,2H),2.34(s,6H),1.97-1.89(m,2H)ï¼
step 4) 2,2,2-tri-chloro-1-(4-(5-((3-(3-(dimethylamino) propyl group) the bromo-1H-indoles of-5--1-base) alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone synthesis
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 3-(the bromo-1H-indol-3-yl of 5-)-N, N-dimethylpropane-1-amine (425mg, 1.51mmol), sodium hydride (66mg, 1.65mmol), 4-methoxy-3-(4-(2, 2, 2-tribromo-acetyl base) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (725mg, 1.66mmol) reaction preparation in DMF (5mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is pale yellow oil (312mg that concentrate drying obtains title compound, 30%).
MS(ESI,pos.ion)m/z:679.1[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.84(d,Jï¼8.8Hz,1H),7.62(d,Jï¼1.8Hz,1H),7.52(dd,Jï¼8.6,2.3Hz,1H),7.40(dd,Jï¼8.8,1.9Hz,1H),7.31(s,1H),7.27(s,1H),6.84(d,Jï¼8.7Hz,1H),3.96(s,4H),3.87(s,3H),3.07(t,Jï¼5.0Hz,4H),2.65(t,Jï¼7.4Hz,2H),2.38(t,Jï¼7.1Hz,2H),2.29(s,6H),1.87-1.84(m,2H)ï¼
step 5) synthesis of 3-(1-((4-methoxy-3-(piperazine-1-base) phenyl) alkylsulfonyl) the bromo-1H-indol-3-yl of-5-)-N, N-dimethylpropane-1-amine
This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2, 2, the chloro-1-of 2-tri-(4-(5-((3-(3-(dimethylamino) propyl group) the bromo-1H-indoles of-5--1-base) alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone (312mg, 0.46mmol), potassium hydroxide (77mg, 1.38mmol, be made into the 1mmol/ml aqueous solution) reaction preparation in tetrahydrofuran (THF) (15mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is pale yellow oil (158mg that concentrate drying obtains title compound, 64%).
HPLC?analysis:97.79ï¼ ï¼
MS(ESI,pos.ion)m/z:268.0[M+2H] 2+/2ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.81(d,Jï¼8.8Hz,1H),7.57(d,Jï¼1.6Hz,1H),7.47(dd,Jï¼8.4,2.0Hz,1H),7.36(dd,Jï¼8.8,2.0Hz,1H),7.31-7.25(m,2H),6.80(d,Jï¼8.8Hz,1H),3.82(s,3H),3.03-2.98(m,8H),2.61(t,Jï¼7.2Hz,2H),2.41(t,Jï¼7.6Hz,2H),2.29(s,6H),1.88-1.80(m,2H)ï¼
13C?NMR(100MHz,CDCl 3):δ(ppm)156.6,141.7,134.0,132.7,129.5,127.4,124.0,122.6,122.2,121.9,116.5,116.3,115.1,110.9,58.8,55.9,50.5,45.2,44.8,26.2,22.4ã
the conjunction of embodiment 22:3-(1-((4-methoxy-3-(4-methylpiperazine-1-yl) phenyl) alkylsulfonyl) the bromo-1H-indol-3-yl of-5-)-N, N-dimethylpropane-1-amine become
This step title compound prepares with reference to the method described by embodiment 1 step 5, by 3-(1-((4-methoxy-3-(piperazine-1-base) phenyl) alkylsulfonyl) the bromo-1H-indol-3-yl of-5-)-N, N-dimethylpropane-1-amine (71mg, 0.13mmol), sodium cyanoborohydride (25mg, 0.39mmol) with formaldehyde (40%, 0.027mL, 0.39mmol) reaction preparation in methyl alcohol (10mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is pale yellow oil (40mg that concentrate drying obtains title compound, 56%).
HPLC?analysis:95.72ï¼ ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)7.86(d,Jï¼8.8Hz,1H),7.62(d,Jï¼2.0Hz,1H),7.49(dd,Jï¼8.8,2.4Hz,1H),7.39(dd,Jï¼8.8,2.0Hz,1H),7.33(s,1H),7.29(d,Jï¼2.4Hz,1H),6.82(d,Jï¼8.4Hz,1H),3.86(s,3H),3.03(brs,4H),2.66(t,Jï¼7.2Hz,2H),2.58(brs,4H),2.44(t,Jï¼7.2Hz,2H),2.36(s,3H),2.34(s,6H),1.93-1.86(m,2H)ï¼
13C?NMR(100MHz,CDCl 3):δ(ppm)156.5,141.8,134.1,132.7,129.6,127.4,124.1,122.3,122.2,121.9,116.5,116.2,115.2,110.8,58.7,55.9,54.9,50.1,46.0,45.0,26.4,22.3ã
the synthesis of embodiment 23:3-(3-(dimethylamino) propyl group)-1-((4-methoxy-3-(piperazine-1-base) phenyl) alkylsulfonyl)-1H-indoles-5-formonitrile HCN
step 1) synthesis of 3-(3-hydroxypropyl)-1H-indoles-5-formonitrile HCN
This step title compound prepares with reference to the method described by embodiment 15 step 1, is dissolved in 4%H by 4-cyanophenylhydrazine hydrochloride (3.52g, 20.8mmol) and Isosorbide-5-Nitrae-dihydropyrane (1.9mL, 20.8mmol) 2sO 4 (aq)(50mL) and N, reaction preparation in the mixed solvent of N-N,N-DIMETHYLACETAMIDE (10mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying, it is white solid (1.46g, 35%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:201.1[M+H] +ï¼
1H?NMR(400MHz,DMSO-d 6):δ(ppm):11.36(s,1H),7.50-7.48(m,1H),7.38(dd,Jï¼8.4,1.5Hz,1H),7.31(d,Jï¼2.0Hz,1H),4.46(t,Jï¼5.1,1H),3.47-3.43(m,2H),2.74(d,Jï¼7.6Hz,2H),1.81-1.74(m,2H)ï¼
step 2) 3-(5-cyano-1 H-indol--3-base) propyl group-4-toluene sulfonic acide ester
This step title compound prepares with reference to the method described by embodiment 15 step 2, by 3-(3-hydroxypropyl)-1H-indoles-5-first cyanogen (1.00g, 5.0mmol), triethylamine (0.8mL, 6.0mmol) and and Tosyl chloride (1.14g, 6.0mmol) be dissolved in reaction preparation in methylene dichloride (20mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purifying, it is white solid (1.33g, 7.0%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:355.1[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)8.51(br?s,1H),7.83(s,1H),7.77(d,Jï¼8.3Hz,2H),7.40(s,2H),7.33(d,Jï¼8.1Hz,2H),7.08(d,Jï¼2.2Hz,1H),4.08(t,Jï¼6.1Hz,2H),2.81(t,Jï¼7.3Hz,2H),2.45(s,3H),2.06-1.99(m,2H)ï¼
step 3) synthesis of 3-(3-(dimethylamino) propyl group)-1H-indoles-5-formonitrile HCN
This step title compound prepares with reference to the method described by embodiment 15 step 3, by 3-(5-cyano-1 H-indol--3-base) propyl group 4-toluene sulfonic acide ester (1.29g, 3.65mmol), dimethylamine hydrochloric acid (1.2g, 14.6mmol) with triethylamine (1.95mL, 14.6mmol) be dissolved in reaction preparation in 10mL acetonitrile, crude on silica gel column chromatography (methylene chloride/methanol (v/v)=20/1) purifying, it is yellow oil (795mg, 96%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:228.1[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)8.95(s,1H),7.92(s,1H),7.39(d,Jï¼1.2Hz,2H),7.1(s,1H),2.78(t,Jï¼7.4Hz,2H),2.48(t,Jï¼7.4Hz,2H),2.34(s,6H),1.97-1.89(m,2H)ï¼
step 4) conjunction of 3-(3-(dimethylamino) propyl group)-1-((4-methoxy-3-(4-(2,2,2-tribromo-acetyl) piperazine-1-base) phenyl) alkylsulfonyl)-1H-indoles-5-formonitrile HCN become
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 3-(3-(dimethylamino) propyl group)-1H-indoles-5-formonitrile HCN (375mg, 1.65mmol), sodium hydride (80mg, 2.0mmol), 4-methoxy-3-(4-(2, 2, 2-tribromo-acetyl base) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (872mg, 2.0mmol) reaction preparation in DMF (5mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is pale yellow oil (395mg that concentrate drying obtains title compound, 38%).
MS(ESI,pos.ion)m/z:626.2[M+H] +ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)8.05(d,Jï¼8.6Hz,1H),7.84(d,Jï¼1.0Hz,1H),7.58-7.47(m,2H),7.47(s,1H),7.31(d,Jï¼2.3Hz,1H),6.88(d,Jï¼8.8Hz,1H),4.11(s,4H),3.88(s,3H),3.09(t,Jï¼4.9Hz,4H),2.72(t,Jï¼7.6Hz,2H),2.47(t,Jï¼7.2Hz,2H),2.35(s,6H),1.95-1.89(m,2H)ï¼
step 5) synthesis of 3-(3-(dimethylamino) propyl group)-1-((4-methoxy-3-(piperazine-1-base) phenyl) alkylsulfonyl)-1H-indoles-5-formonitrile HCN
This step title compound prepares with reference to the method described by embodiment 1 step 5, by 3-(3-(dimethylamino) propyl group)-1-((4-methoxy-3-(4-(2, 2, 2-tribromo-acetyl) piperazine-1-base) phenyl) alkylsulfonyl)-1H-indoles-5-formonitrile HCN (382mg, 0.61mmol), potassium hydroxide (102mg, 1.82mmol, be made into the 1mmol/ml aqueous solution) reaction preparation in tetrahydrofuran (THF) (15mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is pale yellow oil (130mg that concentrate drying obtains title compound, 44%).
HPLC?analysis:96.19ï¼ ï¼
MS(ESI,pos.ion)m/z:241.7[M+2H] 2+/2ï¼
1H?NMR(600MHz,CDCl 3):δ(ppm)8.05(d,Jï¼9.0Hz,1H),7.83(s,1H),7.55-7.53(m,2H),7.48(s,1H),7.30-7.28(m,1H),6.84(d,Jï¼9.0Hz,1H),3.85(s,3H),3.04-2.99(m,8H),2.68(t,Jï¼7.8Hz,2H),2.43(t,Jï¼7.8Hz,2H),2.30(s,6H),1.90-1.85(m,2H)ï¼
13C?NMR(100MHz,CDCl 3):δ(ppm)156.8,142.4,137.0,131.0,129.4,127.4,124.8,124.6,122.5,122.4,119.4,116.2,114.4,110.9,106.4,58.8,55.9,51.4,45.9,45.4,27.0,22.2ã
the synthesis of embodiment 24:3-(3-(dimethylamino) propyl group)-1-((4-methoxy-3-(4-methylpiperazine-1-yl) phenyl) alkylsulfonyl)-1H-indoles-5-formonitrile HCN
This step title compound prepares with reference to the method described by embodiment 1 step 5, by 3-(3-(dimethylamino) propyl group)-1-((4-methoxy-3-(piperazine-1-base) phenyl) alkylsulfonyl)-1H-indoles-5-formonitrile HCN (89mg, 0.19mmol), sodium cyanoborohydride (36mg, 0.57mmol) with formaldehyde (40%, 0.039mL, 0.57mmol) reaction preparation in methyl alcohol (10mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is pale yellow oil (35mg that concentrate drying obtains title compound, 39%).
HPLC?analysis:95.06ï¼ ï¼
MS(ESI,pos.ion)m/z:248.6[M+2H] 2+/2ï¼
1H?NMR(400MHz,CDCl 3):δ(ppm)8.08(d,Jï¼8.8Hz,1H),7.85(s,1H),7.58-7.55(m,2H),7.50(s,1H),7.33(d,Jï¼2.4Hz,1H),6.87(d,Jï¼8.8Hz,1H),3.89(s,3H),3.07(brs,4H),2.75(t,Jï¼7.2Hz,2H),2.63(brs,4H),2.44(brs,8H),2.39(s,3H),1.99(brs,2H)ï¼
13C?NMR(100MHz,CDCl 3):δ(ppm)156.8,141.9,137.0,130.8,129.4,127.5,124.9,124.5,122.5,121.7,119.3,116.2,114.5,111.0,106.5,58.4,55.9,54.9,49.9,45.9,44.7,26.1,22.1ã
the synthesis of embodiment 252-(the chloro-1-of 6-(4-methoxy-3-(piperazine-1-base) benzenesulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine
step 1) synthesis of 2-(the chloro-1H-indol-3-yl of 6-)-N, N-dimethyl amine
This step title compound prepares with reference to the method described by embodiment 1 step 1, by 6-chlorine tryptamines (840mg, 4.3mmol), NaBH3CN (416mg, 6.6mmol) with formaldehyde (40%, 0.477mL, 6.6mmol) reaction preparation in methyl alcohol (15mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), it is brown oil (806mg, 83.8%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:223.2[M+H]+ï¼
1H?NMR(400MHz,CDCl3):δ(ppm)8.46(s,1H),7.49(d,Jï¼8.4Hz,1H),7.26(d,Jï¼1.6Hz,1H),7.07(dd,Jï¼8.4,1.6Hz,1H),6.95(t,Jï¼1.2Hz,1H),2.94-2.91(m,2H),2.68-2.64(m,2H),2.36(s,6H)ã
step 2) 2,2,2-tri-chloro-1-(4-(5-(3-(2-(dimethylamino) ethyl) the chloro-1H-indoles of-6--1-alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone synthesis
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 2-(the chloro-1H-indol-3-yl of 6-)-N, N-dimethyl amine (585mg, 2.6mmol), sodium hydride (208mg, 5.2mmol), 4-methoxy-3-(4-(2, 2, 2-tribromo-acetyl base) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (1.7g, 3.9mmol) reaction preparation in DMF (3mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is Light brown solid (537mg that concentrate drying obtains title compound, 32.8%).
MS(ESI,pos.ion)m/z:621.2[M+H]+ï¼
1H?NMR(400MHz,CDCl3):δ(ppm)7.99(d,Jï¼2.0Hz,1H),7.54(dd,Jï¼8.4,2.0Hz,1H),7.41(d,Jï¼8.4Hz,1H),7.34(s,1H),7.31(d,Jï¼2.4Hz,1H),7.21(dd,Jï¼8.4,1.6Hz,1H),6.86(d,Jï¼8.8Hz,1H),4.06-3.90(m,4H),3.88(s,3H),3.08(t,Jï¼5.2Hz,,4H),2.88-2.84(m,2H),2.66-2.62(m,2H),2.37(s,6H)ã
step 3) synthesis of 2-(the chloro-1-of 6-(4-methoxy-3-(piperazine-1-base) benzenesulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine
This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2, 2, the chloro-1-of 2-tri-(4-(5-(3-(2-(dimethylamino) ethyl) the chloro-1H-indoles of-6--1-alkylsulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone (530mg, 0.85mmol), potassium hydroxide (143mg, 2.55mmol, be made into the 1mmol/ml aqueous solution) reaction preparation in tetrahydrofuran (THF) (20mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is faint yellow solid (350mg that concentrate drying obtains title compound, 86.5%).
MS(ESI,pos.ion)m/z:477.1[M+H]+ï¼
1H?NMR(400MHz,CDCl3):δ(ppm)7.98(d,Jï¼1.6Hz,1H),7.49(dd,Jï¼8.4,2.4Hz,1H),7.37(d,Jï¼8.4Hz,1H),7.33(s,1H),7.30(d,Jï¼2.0Hz,1H),7.18(dd,Jï¼8.4,2.0Hz,1H),6.80(d,Jï¼8.4Hz,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)ï¼
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,,58.9,55.8,51.4,45.9,45.3,23.3ã
the synthesis of embodiment 262-(the chloro-1-of 6-(4-methoxy-3-(piperazine-1-base) benzenesulfonyl)-1H-indol-3-yl)-N, N-dimethyl amine
This step title compound prepares with reference to the method described by embodiment 1 step 6, 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) with formaldehyde (40%, 0.112mL, 1.617mmol) reaction preparation in methyl alcohol (10mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is faint yellow solid (169mg that concentrate drying obtains title compound, 71.8%).
MS(ESI,pos.ion)m/z:246.2[M+2H] 2+/2ï¼
1H?NMR(400MHz,CDCl3):δ(ppm)7.98(d,Jï¼1.6Hz,1H),7.48(dd,Jï¼8.8,2.4Hz,1H),7.36(d,Jï¼8.4Hz,1H),7.32(s,1H),7.29(d,Jï¼2.4Hz,1H),7.17(dd,Jï¼8.4,1.6Hz,1H),6.80(d,Jï¼8.4Hz,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)ï¼
13C?NMR(100MHz,CDCl3):δ(ppm)156.4,141.7,135.5,130.5,129.4,123.5,122.2,120.6,120.1,116.2,113.9,110.7,58.9,55.8,54.9,50.0,46.0,45.3,23.2ã
Biological test
The present invention adopts following methods to carry out biological test to the compound shown in formula I or formula II:
1. use radio ligand binding assay assessing compound to expressing the people source 5-HT on Chinese hamster ovary celI 6the avidity of acceptor
The expression that 32 μ g prepare there is people source 5-HT 6compound and the assay buffer of the Chinese hamster ovary celI membranin of acceptor, 2nM radioactively labelled substance [3H] LSD, different test concentrations mix, and hatch 120min for 37 DEG C; Assay buffer composition is: 50mMTris-HCl (pH7.4), 10mM MgCl 2, 0.5mM EDTA, 10 μMs of Pargylines and 20mg/l proteinase inhibitor.
Add 100 μMs of 5-HT and remove nonspecific binding site.After hatching, above-mentioned mixed solution is used glass filter under vacuum, filter first uses 0.3%PEI preimpregnation before filtration.Rinse several times with 50mM Tris-HCl again after filtration.After filter drying, with scintillation mixed solution counting radioactivity on scintiloscope.Standard reference compounds is 5-HT, all tests several concentration and obtain its Competitive assays curve and calculate IC in each experiment 50.
The compound provided the embodiment of the present invention according to the method described above carries out radio ligand binding assay assessing compound to expressing the people source 5-HT on Chinese hamster ovary celI 6the avidity of acceptor measures, result see table 1, the avidity measurement result that table 1 provides for the embodiment of the present invention.
The avidity measurement result of the compound that table 1 embodiment of the present invention provides
Embodiment number IC 50(nM) Embodiment number IC 50(nM) Embodiment number IC 50(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 23As shown in Table 1, compound of the present invention at radio ligand binding assay assessing compound to expressing people source 5-HT on Chinese hamster ovary celI 6higher activity is generally demonstrated in the avidity test of acceptor.
In the description of this specification sheets, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term not must for be identical embodiment or example.And the specific features of description, structure, material or feature can combine in one or more embodiment in office or example in an appropriate manner.In addition, when not conflicting, the feature of the different embodiment described in this specification sheets or example and different embodiment or example can carry out combining and combining by those skilled in the art.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, and those of ordinary skill in the art can change above-described embodiment within the scope of the invention, revises, replace and modification.
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