CN100384833C - Therapeutic chroman compounds - Google Patents

Therapeutic chroman compounds Download PDF

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CN100384833C
CN100384833C CNB02806562XA CN02806562A CN100384833C CN 100384833 C CN100384833 C CN 100384833C CN B02806562X A CNB02806562X A CN B02806562XA CN 02806562 A CN02806562 A CN 02806562A CN 100384833 C CN100384833 C CN 100384833C
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piperazine
methyl
reference example
oxo
compound
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CN1524077A (en
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M·查普德莱尼
T·达文波尔特
M·海伯莱因
C·霍尔希勒
J·麦克考利
E·皮尔森
D·索恩
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AstraZeneca AB
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    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

Provided herein is a compound represented by the Formula (I) wherein said compounds are useful for the treatment of migraine. Also provided are processes for the preparation of compounds of Formula (I) and intermediates.

Description

Therapeutic chroman compounds
Invention field
The present invention relates to new 8-aminoderivative, their preparation method, the medicinal compositions that contains them and their therepic use.
Background of invention
Serotonin (5-HT) relates to many psychiatric diseases, includes, but is not limited to depression, generalization anxiety, eating disorder, dementia, Panic-stricken and sleep disordered.In addition, serotonin relates to gastrointestinal illness, cardiovascular adjusting, dyskinesia, endocrinopathy, vasospasm and sexual dysfunction.5-hydroxytryptamine receptor has been subdivided at least 14 kinds of hypotypes, referring to Barnes and Sharp, and Neuropharmacology, 1999,38,1083-1152 is attached to herein by reference.These different hypotypes are responsible for the effect of serotonin in many physiopathology symptoms.5-HT 1Receptor family has high affinity to serotonin and is made up of 5 kinds of relevant acceptors.This family comprises 5-HT 1BAnd 5HT 1DReceptor subtype.Known and 5-HT 1The interactional compound of family has the treatment potentiality in above-mentioned disorder and disease.Specifically, be known as 5HT 1BAnd 5HT 1DThe compound of antagonist is thymoleptic and anxiolytic.Be 5HT 1BAnd 5HT 1DThe compound of agonist has been used to treat migraine.
Summary of the invention
Provide the have formula compound of (I) or the pharmacy acceptable salt of described compound at this:
Figure C0280656200051
Wherein
R 1On each position independent expression hydrogen, the optional alkyl that replaces, the optional cycloalkyl that replaces, sulfo-methoxyl group ,-NHA ,-NA 2,-NHC (=O) A, aminocarboxyl ,-C (=O) NHA ,-C (=O) NA 2, halogen, hydroxyl ,-OA, cyano group or aryl;
A is the optional alkyl that replaces, the optional cycloalkyl that replaces, the optional alkenyl that replaces or the optional alkynyl group that replaces;
R 2By following (i), (ii), (iii) or (iv) the expression:
Figure C0280656200061
R 3Independent expression-H, the optional C that replaces on each position 1-6Alkyl, the optional C that replaces 2-6Alkenyl, the optional C that replaces 2-6Alkynyl group, the optional C that replaces 3-6Cycloalkyl or AOH;
N is 2,3 or 4;
P is a heterocycle;
R 6For-H or methyl;
Y is-C (=O) NH-,-C (=O) NA-,-C (=O) N (A)-,-NHC (=O)-,-C (=S) NH-,-CH 2NH-,-C (=O)-,-C (=O) CH 2-,-CH 2C (=O)-,-C (=O)-piperazine-,-NAC (=O)-,-C (=S) N (A)-, CH 2NA, NACH 2Perhaps 5-unit heterocycle;
R 7For by one or more a plurality of R that is selected from 8-R 9And R 10Optional monocycle or bicyclic aromatic ring or heterocycle, the wherein R that replaces of substituting group 7Condense by singly-bound or by ring and to be connected in Y;
R 8For-CH 2-,-C (=O)-,-SO 2-,-SO 2NH-,-C (=O) NH-,-O-,-S-,-S (=O)-, connect (tether) R as joint 7To R 9Singly-bound, condense by singly-bound or by ring and to be connected in R 7Five-membered ring;
R 9For the optional heterocycle that replaces, the optional aryl that replaces, the optional piperazinyl-R11 that replaces, the optional morpholinyl-R11 that replaces or the optional thio-morpholinyl that replaces-or-C (=O) A;
R 10For the optional alkyl that replaces, the optional cycloalkyl that replaces, hydroxyl, aryl, cyano group, halogen ,-C (=O) NH 2-, methylthio group ,-NHA ,-NA 2,-NHC (=O) A, C (=O) NHA, C (=O) NA 2Or OA;
R 11For-H, alkyl, AOH ,-SO 2A ,-SO 2NH 2,-SO 2NHA ,-SO 2NA 2,-SO 2NHAR 9,-C (=O) R 9,-alkyl R 9, C (=O) A, C (=O) NH 2, C (=O) NHA, C (=O) NA 2Perhaps-C (=O) OA.
Term " alkyl " refers to contain any structure that has only carbon and hydrogen atom that can reach 14 carbon atoms at most.
Term " alkyl " uses separately or as suffix or prefix, refers to contain the straight or branched alkyl of about 12 carbon atoms of 1-.
Term " alkenyl " refers to have at least one carbon-to-carbon double bond and contains at least 2 to the straight or branched alkyl that can reach about 12 carbon atoms at most.
Term " alkynyl group " refers to have at least one carbon-to-carbon three key and contains at least 2 to the straight or branched alkyl that can reach about 12 carbon atoms at most.
Term " cycloalkyl " refers to contain at least 3 to the alkyl that comprises ring that can reach about 12 carbon atoms at most.
Term " cycloalkenyl group " refers to have at least one carbon-to-carbon double bond and contains at least 3 to the alkyl that comprises ring that can reach about 12 carbon atoms at most.
Term " cycloalkynyl radical " refers to have at least one carbon-to-carbon three key and contains about 7 to the alkyl that comprises ring that can reach about 12 carbon atoms at most.
Term " aromatics " refers to have (for example, the 4n+2 delocalized electron) of aromatic character and comprise 6 to the alkyl that can reach one or more many unsaturated carbocyclics of about 14 carbon atoms at most.
Term " aryl " refers to comprise the mono-cyclic aromatic group that contains 6 carbon atoms and contains the aromatic group of the polycyclic aromatic group that can reach about 14 carbon atoms at most.
Term " alkylidene group " refers to the divalent alkyl part, and wherein said part is used for two structures are linked together.
Term " heterocycle " or " heterocyclic " or " heterocyclic moiety " refer to contain ring have one or more a plurality of N, O and S of independently being selected from as the part of ring structure and on ring, contain at least 3 and can reach the heteroatomic unit price and the divalent group of about 20 atoms at most, preferred 5 and 6 yuan of rings.Heterocyclic moiety can be saturated or undersaturated, contain one or more a plurality of pairs of keys, and heterocyclic moiety can contain more than one ring.
Term " heteroaryl " refers to have the monovalent heterocyclic and the divalent group of aromatic character.
Heterocyclic moiety comprises for example monocycle part, for example: aziridine, oxyethane, thia propane, azetidine, trimethylene oxide, Thietane, tetramethyleneimine, pyrroline, imidazolidine, pyrazolidine, dioxolane, tetramethylene sulfone, 2, the 3-dihydrofuran, 2, the 5-dihydrofuran, tetrahydrofuran (THF), tetramethylene sulfide, piperidines, 1,2,3,6-tetrahydrochysene-pyridine, piperazine, morpholine, thiomorpholine, pyrans, thiapyran, 2, the 3-dihydropyrane, tetrahydropyrans, 1, the 4-dihydropyridine, 1, the 4-dioxane, 1, the 3-dioxane, dioxane, high piperidines, 2,3,4,7-tetrahydrochysene-1H-azepine High piperazine, 1,3-dioxepin (dioxepane), 4,7-dihydro-1,3-dioxepin English (dioxepin) and hexa-methylene oxide compound.Heterocyclic moiety comprises heteroaryl ring in addition, for example: pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, thienyl, furyl, pyrryl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazoles base, tetrazyl, 1,2,3-thiadiazolyl group, 1,2,3-oxadiazole base, 1,2,4-triazolyl, 1,2,4-thiadiazolyl group, 1,2,4-oxadiazole base, 1,3,4-triazolyl, 1,3,4-thiadiazolyl group and 1,3,4-oxadiazole base.In addition, heterocyclic moiety comprises many loop sections, for example: indoles, indoline, quinoline, tetrahydroquinoline, isoquinoline 99.9, tetrahydroisoquinoline, 1,4-benzodioxan, tonka bean camphor, melilotine, cumarone, 2,3-Dihydrobenzofuranes, 1,2-benzoisoxazole, thionaphthene, benzoxazole, benzothiazole, benzoglyoxaline, benzotriazole, Thioxanthine, carbazole, carboline, acridine, pyrazine alkane and quinolizine alkane.
Except that many ring heterocycles described above, heterocyclic moiety comprises many ring heterocyclic moieties, and wherein the ring between two or the more a plurality of ring condenses and comprises to the common more than one key of two rings and to two plural atoms that ring is common.Such bridging heterocyclic example comprises rubane, diazabicyclo [2.2.1] heptane and 7-oxabicyclo [2.2.1] heptane.
Term " halogeno-group " or " halogen " refer to fluorine, chlorine, bromine and iodine group.
Term " alkoxyl group " refers to the group of general formula-O-R, and wherein R is selected from alkyl.Alkoxyl group partly comprises methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, isobutoxy, cyclo propyl methoxy, allyloxy and alkynes propoxy-.
Term amine or amino refer to the group of general formula-NRR ', and wherein R and R ' independently are selected from hydrogen or alkyl.
Detailed description of the present invention
In the present invention on the other hand, A, R 1And R 3, as alkyl, alkenyl, alkynyl group with as cycloalkyl, they can be by halogen, nitro, cyano group, hydroxyl, trifluoromethyl, amino, carboxyl, formamido-, amidino groups, formamyl, sulfydryl, sulfamyl, C independently for each 1-4Alkyl, C 2-4Alkenyl, C 2-4Alkynyl group, C 3-6Cycloalkyl, C 3-6Cycloalkenyl group, C 1-4Alkoxyl group, C 1-4Alkyloyl, C 1-4Alkanoyloxy, N (C 1-4Alkyl), N (C 1-4Alkyl) 2, C 1-4Alkyl amido, (C 1-4Alkyloyl) 2Amino, N (C 1-4Alkyl) formamyl, N, N-(C 1-4Alkyl) 2Formamyl, (C 1-4) S, (C 1-4Alkyl) S (O), (C 1-4Alkyl) S (O) 2, (C 1-4) alkoxy carbonyl, N-(C 1-4Alkyl) sulfamyl, N, N-(C 1-4Alkyl) sulfamyl, C 1-4Alkyl sulfonyl is amino and heterocycle is optional replaces.
The optional substituent example of aryl and heterocyclic radical in the time must not defining in addition, is halogen, nitro, cyano group, hydroxyl, trifluoromethyl, amino, carboxyl, formamido-, amidino groups, formamyl, sulfydryl, sulfamyl, C 1-4Alkyl, C 2-4Alkenyl, C 2-4Alkynyl group, C 3-6Cycloalkyl, C 3-6Cycloalkenyl group, C 1-4Alkoxyl group, C 1-4Alkyloyl, C 1-4Alkanoyloxy, N (C 1-4Alkyl), N (C 1-4Alkyl) 2, C 1-4Alkanoylamino, (C 1-4Alkyloyl) 2Amino, N (C 1-4Alkyl) formamyl, N, N-(C 1-4Alkyl) 2Formamyl, (C 1-4) S, (C 1-4Alkyl) S (O), (C 1-4Alkyl) S (O) 2, (C 1-4) alkoxy carbonyl, N-(C 1-4Alkyl) sulfamyl, N, N-(C 1-4Alkyl) sulfamyl, C 1-4Alkyl sulfonyl amino and heterocycle.
A, R 1And R 3, each independently, as alkyl, alkenyl or alkynyl group, can be for straight chain or side chain, preferably have 1-6 carbon atom.When each independently is cycloalkyl, A, R 1And R 3Preferably has the 3-6 atom.When each is alkyl, A, R 1And R 3Other preferred meaning, comprise methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, cyclopentyl, neo-pentyl and cyclohexyl.Work as R 1During for halogen, R 1Preferred meaning be fluorine, chlorine and bromine.Work as R 1When being in 6 on the dicyclo, R 1Other preferred meaning be methyl, ethyl, oxyethyl group and methoxyl group.Work as R 1When being in 5 on the dicyclo, R 1Preferred meaning be-H, methyl, ethyl and methoxyl group.Work as R 1When being in 5 on the dicyclo, R 1More preferably-H.Work as R 1When being in the 7-position on the dicyclo, R 1Be preferably-H.
R 2Preferably represent by formula i.R 2Preferably represent that by formula i wherein n equals 2.R 2Most preferably by the N methyl piperazine basis representation.
R 3Preferably represent by hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-and the tertiary butyl.R 3Most preferably represent by methyl.
R 4Preferably by hydrogen, methyl, ethyl, n-propyl, sec.-propyl and TMS-oxyethyl group methoxy basis representation.R 4Most preferably represent by methyl.
R 6Preferably represent by H.
Y represents linking group.When Y be-C (=O) N (A)-time, Y is preferably-C (=O) N (CH 3)-.Y also can for-C (=O)-piperazine.When Y represented five-membered ring, Y can be by for example pyrroles, thiophene, furans, imidazoles, thiazole, oxazole, pyrazoles, isothiazole, isoxazole, 1,2,3-triazoles, 1,2,3-thiadiazoles, 1,2,3-oxadiazole, 1,2,4-triazole, 1,2,4-thiadiazoles, 1,2,4-oxadiazole, 1,3,4-triazole, 1,3,4-thiadiazoles or 1,3, the 4-oxadiazole is represented.
Y more preferably-C (=O) NH-.
Expression monocycle or bicyclic aromatic ring or heterocyclic R 7Example include, but is not limited to phenyl, 1-and 2-naphthyl, 2-, 3-and 4-pyridyl, 2-and 3-thienyl, 2-and 3-furyl, 1-, 2-and 3-pyrryl, imidazolyl, thiazolyl oxazolyl, pyrazolyl, isothiazolyl isoxazolyl, 1,2, the 3-triazolyl, 1,2, the 3-thiadiazolyl group, 1,2,3-oxadiazole base, 1,2, the 4-triazolyl, 1,2, the 4-thiadiazolyl group, 1,2,4-oxadiazole base, 1,3, the 4-triazolyl, 1,3, the 4-thiadiazolyl group, 1,3,4-oxadiazole base, quinolyl, isoquinolyl, indyl, benzothienyl, benzofuryl, benzimidazolyl-, benzothiazolyl benzoxazolyl or triazinyl.
R 7Also can by formula (v) the expression:
Figure C0280656200101
R 7Also can be in addition by formula (vi) expression:
Figure C0280656200111
Work as R 7Value when as above listing, R 8Can be as joint singly-bound ,-C (=O)-,-CH 2-,-C (=O)-,-SO 2-,-S (=O)-,-S-,-O-,-C (=O) NH-,-SO 2NH-perhaps condenses by singly-bound or ring and is connected in R 7Five-membered ring; And R 9Can represent aryl, heterocycle or heteroaryl, each is independent of the optional replacement of following group: halogen, nitro, cyano group, hydroxyl, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C 1-4Alkyl, C 2-4Alkenyl, C 2-4Alkynyl group, C 3-6Cycloalkyl, C 3-6Cycloalkenyl group, C 1-4Alkoxyl group, C 1-4Alkyloyl, C 1-4Alkanoyloxy, N-(C 1-4Alkyl), N (C 1-4Alkyl) 2, C 1-4Alkyl amido, (C 1-4Alkyloyl) 2Amino, N (C 1-4Alkyl) formamyl, N, N-(C 1-4) 2Formamyl, (C 1-4) S, C 1-4S (O), (C 1-4Alkyl) S (=O) 2, (C 1-4) alkoxy carbonyl, N-(C 1-4Alkyl) sulfamyl, N, N-(C 1-4Alkyl) sulfamyl, C 1-4Alkyl sulfonyl amino or heterocycle.R 9Be preferably the optional heterocyclic moiety that replaces.
R 9More preferably represent piperazine, thiomorpholine or morpholine, each independent optional replacement of substituting group that on carbon, is selected from A by at least one.Preferably work as R 7During for phenyl, R 8Can be five-membered ring, mix the heteroatoms that at least one is selected from N, O or S, and it can condense by ring and is connected in R 7Work as R 8When being the singly-bound as joint, R 9Be preferably methoxyl group, cyano group, be selected from A or R by at least one 11The optional five-membered ring that replaces of the substituting group of expression, for example by formula (vii), (viii) and (ix) compound of expression:
Figure C0280656200121
Work as R 8Represent and be connected in R when it condenses by ring in addition by the 5-unit heterocycle that contains N 7The time, R 9Be preferably be connected in nitrogen-atoms-C (=O) A, R 9Most preferably be-C (=O) CH 2CH 3
Work as R 7During for phenyl or 6-unit heterocycle, R 9Pass through R 8Chain is connected in phenyl or the heterocyclic 2-of 6-unit, 3-or 4-position.R 9Preferably pass through R 8Chain is connected in phenyl or 6-heterocyclic 3-of unit or 4-position.R 9More preferably pass through R 8Chain is connected in phenyl or 6-unit heterocyclic 4-position.
R 10Can represent that each is independently with halogen, nitro, cyano group, hydroxyl, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C by alkyl or cycloalkyl 1-4Alkyl, C 2-4Alkenyl, C 2-4Alkynyl group, C 3-6Cycloalkyl, C 3-6Cycloalkenyl group, C 1-4Alkoxyl group, C 1-4Alkyloyl, C 1-4Alkanoyloxy, N-(C 1-4Alkyl), N (C 1-4Alkyl) 2, C 1-4Alkyl amido, (C 1-4Alkyloyl) 2Amino, N (C 1-4Alkyl) formamyl, N, N-(C 1-4) 2Formamyl, (C 1-4) S, C 1-4S (O), (C 1-4Alkyl) S (O) 2, (C 1-4) alkoxy carbonyl, N-(C 1-4Alkyl) sulfamyl, N, N-(C 1-4Alkyl) sulfamyl, C 1-4Alkyl sulfonyl amino or heterocycle are optional to be replaced.R 10Be preferably halogen, be preferably chlorine or fluorine, cyano group or-OCH 3Work as R 10During for halogen, it is preferably chlorine or fluorine.Work as R 7During for phenyl or 6-unit hetero-aromatic ring, R 10Be connected in the heterocyclic 2-of phenyl or 6-unit, 3-or 4-position.Work as R 9Pass through R 8When chain is connected in phenyl or 6-unit heterocyclic 4-position, R 10Preferably be connected in phenyl or 6-heterocyclic 2-of unit or 3-position.Work as R 9Pass through R 8When chain is connected in phenyl or 6-unit heterocyclic 4-position, R 10More preferably be connected in phenyl or 6-unit heterocyclic 3-position.
Work as R 8When representing as the singly-bound of joint, R 9Preferably represent, replace and be connected in addition on the relative heteroatoms of the heteroatoms of joint in that the substituting group that is selected from A on the heterocyclic carbon by at least one is optional by R by the optional heterocycle that replaces 11The substituting group of expression replace (referring to for example, formula (vii), (viii) and (ix)).R 8Preferred heterogeneous ring compound be piperazine, morpholine or thiomorpholine.
Work as R 11Expression SO 2During A, it is preferably by the alkyl sulfonyl basis representation, more preferably-and SO 2CH 3,-SO 2CH 2CH 3, SO 2-n-C 3H 7, SO 2-i-C 3H 7, SO 2-n-C 4H 10,-SO 2-i-C 4H 10Or-SO 2-t-C 4H 10Work as R 11Expression C (=O) during A, preferably represent, more preferably by-C (=O) CH by alkyl-carbonyl 3,-C (=O) CH 2CH 3, C (=O)-n-C 4H 10,-C (=O)-i-C 4H 10,-C (=O)-t-C 4H 10Perhaps-C (=O) C 3H 7-expression.Work as R 11By C (=O) NHA or C (=O) NA 2During expression, it is preferably alkyl or dialkyl amido formyl radical, more preferably C (=O) NCH 2CH 3, C (=O) NH-ring C 6H 12Perhaps C (=O) NH-ring C 5H 10Work as R 11By C (=O) R 9During expression, it is preferably-C (=O)-tetramethyleneimine or-C (=O)-morpholine.Work as R 11By SO 2NA 2During expression, it is preferably SO 2N (CH 3) 2Work as R 11When being represented by AOH, it is preferably by CH 2CH 2OH or-C (=O) CH 2CH 2OH represents.R 11Also can be by-C (=O) OC 4H 10Expression.
In preferred embodiments, when Y by-C (=when O) NH represents:
(a) R 1On 6 of dicyclo is halogen or methoxyl group, most preferably is fluorine, and is hydrogen on 5 of dicyclo preferably, methyl, and ethyl or methoxyl group, and on 7 of dicyclo, be hydrogen.
(b) R 2Be methylpiperazine;
(c) R 6Be hydrogen;
(d) R 7Phenyl for the R8-R9 replacement;
(e) R 8It is singly-bound as joint;
(f) R 9Be heterocyclic moiety, be preferably by nitrogen and be connected in R 8Morpholine or piperazine and optional by R 11(to piperazine) replaces or works as R on other nitrogen 9During for morpholine by R 11Take up an official post at oxygen and to choose generation;
(g) R 11For AOH or-SO 2A, wherein A represents methyl or ethyl.
It is useful providing the compound as the form of free alkali at this, but also can be with the form of pharmacy acceptable salt, and/or provides with the form of pharmaceutically acceptable hydrate.For example the pharmacy acceptable salt of formula I compound comprises that those are derived from the mineral acid salt of hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, Hydrogen bromide, hydroiodic acid HI, nitrous acid and phosphorous acid for example.Pharmacy acceptable salt also can produce from organic acid, comprises aliphatic series single and dicarboxylate and aromatic acid.The pharmacy acceptable salt of other of The compounds of this invention comprises for example hydrochloride, vitriol, pyrosulphate, hydrosulfate, hydrosulphite, nitrate and phosphoric acid salt.
Provide the method for preparation I compound as additional features of the present invention.The known method of chemical field of the compound by producing similar can prepare chemical compound lot described here.Therefore, by adopting known method in the document,, can prepare compound of the present invention from known compound or the intermediate that is easy to prepare.For example, can prepare core dicyclo, heterocycle structure by at first preparing chromone, quinolone or quinoline.Connect the compound of the present invention of key to having Y as acid amides, the preferred logical method by the acid amides coupling is promptly by making amine and hydrochloride coupling prepare compound.If can not get on the market, can prepare the amine that uses among the present invention by known technology.For example, as the first step in the method for preparation I compound, nitro-compound can be reduced to amine.Nitro-compound can be the nitrophenyl compound.The amine that obtains can react with acid hydrochloride.
Provide at this to prepare precursor compound or to be used to put into practice method aspect of the present invention, promptly by making formula (VIa) compound,
Figure C0280656200141
Halogen
VIa
(R 1, R 2, R 3And R 7As to formula I definition, unless otherwise indicated, and X is represented by O), with for example by
Figure C0280656200142
The compound reaction of expression, wherein R ' is represented by alkyl, is preferably low alkyl group (C for example 1-C 6), most preferably be methyl or ethyl, form the precursor of formula (VIb) compound:
Figure C0280656200151
R 1Be preferably fluorine, chlorine, methyl, methoxyl group, oxyethyl group or hydrogen.Halogen is preferably chlorine or bromine.For example in the presence of the tetrabutyl ammonium fluoride in THF, can carry out this reaction at catalyzer.For example can reaction stirred under room temperature and reflux.
Provide the method for preparing precursor compound in addition at this, this method comprises that the ester hydrolysis that makes compound (VIb) forms intermediate (VIc):
Figure C0280656200152
By making for example sodium hydroxide (aqueous solution) reaction of formula (VIb) compound and alkali, can carry out this reaction.Also provide by compound (VIc) cyclization to form the method that intermediate (VId) prepares intermediate at this.
Figure C0280656200153
By making formula (VIc) compound and strong acid (for example, H 2SO 4) reflux and further follow heating and with alkyl alcohol R for example " OH refluxes, R wherein " be C 1-4Alkyl, preferred ethyl can form midbody compound (VId).
In the present invention on the other hand, be provided in the presence of catalyzer and alkali, by making formula (VId) compound and R 2Amine reaction, form the method that intermediate formula (VIe) prepares intermediate:
In another embodiment of the invention, formula (VId) compound and the catalyst reaction that is selected from nickel and palladium.Preferably in phosphine part 2,2 '-two (diphenylphosphino)-1 for example, 1 '-dinaphthalene provides palladium under existing.Palladium can be used as three (dibenzalacetones), two palladiums and provides.Alkali is preferably selected from salt of wormwood, yellow soda ash, cesium carbonate and triethylamine and composition thereof.
The acid hydrochloride of formula (VIe) compound is provided at this in addition, and the latter is intermediate formula (VIf):
Figure C0280656200162
For example at acid and water (for example, HCL/H 2O) exist down, can form intermediate formula (VIf) by heating-type (VIe) compound.
The present invention provides intermediate formula (VIg) on the other hand:
Figure C0280656200171
Therefore, in the present invention on the other hand, leavings group is incorporated into the carboxylicesters of formula (VIf) compound.L is a leavings group.This intermediate is being acid activation useful to provide in the electrophilic reagent.L is represented by the chlorine in the intermediate formula (VIg) that preferably formula (VIg) is by making formula (VIf) compound and thionyl chloride (SOCl 2) reaction prepare.
Provide formula (VIh) compound at this:
Figure C0280656200172
The method of amine and acyl chloride reaction can be used for preparation I compound, for example formula (VIh) compound.For example, the method for preparation (VIh) can be included under the DIPEA existence and make formula (VIg) compound and H 2N-R 7Reaction.
Perhaps, at for example I-hydroxybenzotriazole (HOBT), O-(1H-benzotriazole-1-yl)-N, N, N ', N '-pentamethylene-urea a tetrafluoro borate (TBTU) and (dimethylamino) pyridine exist down, preferably by this order, by making formula (VIf) compound and H 2N-R 7Reaction also can preparation formula (VIh) compound
Formula (VIe), (VIf), (VIg) and compound (VIh) also can comprise the pharmacy acceptable salt of described compound.
By making the two keys (4H-chromene) on the dicyclic compound saturated, above Compounds and methods for also can be used for preparation formula (I) chroman derivatives.Decide according to reductive condition, can obtain or can not obtain the 4-oxo-derivative.
In following flow process 1, list the method that preparation is used for the acid hydrochloride of synthetic chromone:
Figure C0280656200181
Flow process 1: as the preparation of the chromone-2-carboxylic acid of the intermediate in The compounds of this invention synthetic.
Perhaps, as describing in following flow process 2, chromone-2-carboxylic acid can change acyl chlorides and rapid and suitable amine reaction into:
Figure C0280656200191
Flow process 2: the acid amides by the acyl chlorides intermediate is synthetic
The operation of other functional group includes, but is not limited to that O-takes off alkyl and N-takes off alkyl (flow process 3).
Figure C0280656200201
Flow process 3: include, but is not limited to N-and O-takes off alkyl with the operation of the functional group of compound of the present invention
Prepare quinoline of the present invention and quinolone compounds and synthesize the similar synthetic route generation of using of method by adopting with chromone-2-methane amide above and that in flow process 1-3, describe.These synthetic routes of quinoline of the present invention and quinolone compounds have been described in the flow process 4 hereinafter.
Therefore one of ordinary skill in the art would recognize that some compound of the present invention contains the carbon and/or the sulphur atom of for example asymmetric replacement, can exist with racemic form and separate with opticity.Therefore one of ordinary skill in the art would recognize that some compound of the present invention contains the carbon and/or the sulphur atom of for example asymmetric replacement, can exist with racemic form and separate with opticity.Some compound can present polymorph, therefore should understand to the present invention includes racemize, opticity, polymorph or stereoisomer form or their mixture, and latter's form has the character that is used for the treatment of the following disease of listing.How to prepare the opticity form (for example, by recrystallization technology resolution of racemic form, synthetic from the opticity raw material, chirality synthetic or by employing chiral stationary phase chromatographic separation) and how to measure the effectiveness that is used for the treatment of disease described above be well known in the art.
Discoverable type I compound is as 5-HT 1BAnd 5-HT 1DAgonist.Formula I compound and pharmacy acceptable salt thereof also can be used for the treatment of migrainous method.This treatment of diseases comprises needs the warm-blooded animal of treatment like this, preferred mammal, more preferably the formula I compound of people's significant quantity or the pharmacy acceptable salt of described compound.
In addition, provide formula I compound to be used for the such warm-blooded animal for the treatment of of needs, preferred mammal, the more preferably purposes in philtrum treatment disease such as the migrainous medicine in preparation.
The present invention provides the medicinal compositions that is suitable for treating disease described above in addition, comprises the formula I compound of the warm-blooded animal significant quantity of suffering from such disease or the medicinal compositions of pharmacy acceptable salt.
The present invention also provides and contains and the medicinal compositions of pharmaceutically acceptable carrier blended at the formula I of this definition compound or pharmacy acceptable salt.The preferred formula I compound that is used for the present composition is as above described.
All compounds described here have confirmed in test described below in conjunction with affinity (observed Ki value) less than about 10 μ M.In addition, by reversing 5HT 1BThe cavy low temperature of agonist induction, compound of the present invention has not only confirmed 5HT 1BAntagonistic activity, and these compounds be considered to oral effectively, therefore, they are preferred compounds.Embodiment 1,10,11,31,32,34,44,55,56,57,71 and 72 confirms to have 5HT hereinafter under 0.006-5.5mg/kg dosage 1BAntagonistic activity.In addition, compound described here confirms to have activity being used for the active study of antidepressant/anxiety helpless (learned helplessness) test.Embodiment 31,44,71 hereinafter and 72 confirms to have activity in the helpless test of study.In addition, compound is used to test maximum intrinsic activity (IA), and finds to have measured negative 50% IA to the positive 150% in the GTP γ S test described below, therefore confirms the scope that agonist (low percentage) is replied to antagonist (high percent).
Compound described here can be to be suitable for the form of oral use, for example provides with tablet, lozenge, form hard and soft capsule, the aqueous solution, oil solution, emulsion and suspensoid or transmit.This compound also can be provided for topical, for example, and as creme, flexible glue agent, gelifying agent, sprays or the aqueous solution, oil solution, emulsion and suspensoid.Compound described here also can provide with the form that is suitable for intranasal administration, for example as nasal spray, nasal drop or dried powder.Said composition also can give vagina or rectum with the form of suppository.Compound described here also can for example pass through the parenterai administration of vein, bladder, subcutaneous or intramuscularly or infusion.This compound can be by being blown into administration (for example as the powder that segments).The compounds of this invention also can be through skin or sublingual administration.
Therefore, adopt conventional pharmaceutical excipient well known in the art, composition of the present invention can obtain by ordinary method.Therefore, the composition that is intended for use oral use for example can comprise one or multiple tinting material, sweet taste, flavoring and/or sanitas.
The amount that produces the activeconstituents of single formulation with one or more mixed with excipients must be decided according to subject host and the concrete approach of administration.The dosage size of the treatment of the compound of formula I or prevention purpose should be naturally according to the character of symptom and seriousness, animal or patient's age and sex and route of administration, change according to the medical principle of knowing.Known various test and in vivo test are used for measuring compound in the purposes of above-mentioned disease and be particularly useful as 5HT 1BAnd 5HT 1DAgonist and antagonist.
Can show that by the helpless test of the study of cavy compound for example treats the purposes of dysthymia disorders, cavy owing to people's relevant being widely adopted of antidepressant activity.Learning helpless test can carry out according to following: 70 male Hartley cavys, the experiment of every about 350-425 gram of body weight is fed, and stable breeding under 12 hour daily cycle.This method was made up of following two phases: inductive phase and avoidance training phase.In inductive phase, research object is placed the standard cage (shuttlecages) (20 (length) * 16 (wide) * 21 (height) centimetre) that shuttles back and forth, described cage is fixed on the waffle slab.During the 1 hour every day training mission, electricity irritation (1.25mA is the duration of 10 seconds) was passed on the plate of cage in per 90 seconds.Research object has no chance to escape or avoid electric shock.Inducing sustained carrying out 2 days.
In avoidance training, test is also carried out in the cage that shuttles back and forth, unless research object is no longer returned in the identical chamber, wherein induces and takes place.In addition, cage central authorities are furnished with an arched door, and cavy can enter the left side or the right side of cage by arched door.The method that is adopted is the standard avoidance method that shuttles back and forth, and wherein compound conditioned stimulus (10sec sound and turn on the lamp of cavy place side cage) is used for indicating the electric current that bottom application adds to cage.Electricity irritation 5sec behind the beginning conditioned stimulus 5sec.Cavy enters the offside cage that shuttles back and forth by arched door before the electricity irritation, causes off-test (avoiding reaction).If apply electricity irritation, cavy enters the offside cage, then finishes electricity irritation and CS (escape) and ends.Reverse induces the helpless antidepressant activity with test-compound of cavy study relevant.
Avoidance training the duration of 45 minutes, carried out 2 days continuously, the beginnings in 48 hours after the last inductive education.70 research objects are divided into 6 groups, and every group of 11-12 only.These groups are as follows:
1) the non-group of inducing.Research object is positioned in the cage that shuttles back and forth but does not give inevitable electric shock, animal is accepted to avoid the training of step subsequently and gives solvent;
2) induce the solvent contrast;
3) imipramine 17.8mg/kg;
4) 0.3mg/kg compound;
5) 1mg/kg compound; With
6) 5mg/kg compound.
Giving the 2-6 group induces and the avoidance training task.Rapid injection in preceding 1 hour gives with the avoidance training task after inducing task.The injection back gave injection for the second time in 7-8 hour for the first time, gave 9 injections in 5 days altogether.No longer inject after the last avoidance training task.
Compound of the present invention can give with the volume of 1mL/kg bwt.Imipramine is dissolved in the DI water.Compound is dissolved in the DI water, adds several lactic acid (pH 5.5) to it.The solvent control group is that having with being subjected to treatment of lactic acid preparation organized the DI water of identical pH.
Main dependency variable is the escape failure during the avoidance training.Two factor variance analyses (ANOVA) are used for estimating the entire treatment effect, and DunnShi examines and determine (post hoc analysis) afterwards and is used for comparison vehicle treated group and drug treating group.Whether successfully the non-group of inducing is used for learning helpless by relatively weighing foundation with the vehicle treated group.
For example can be used to measure The compounds of this invention to 5HT 1BAnd 5HT 1DThe test of other of receptor affinity is at J.Med.Chem.41:1218-1235,1228 (1998) and J.Med.Chem.42:4981-5001 (1999) in description is arranged, they are attached to herein by reference.Can adopt some improved these test: the Chinese hamster ovary of stable transfection (CHO) expression of cell lines people 5-HT 1BAcceptor and 5-HT 1DThe frozen film of acceptor prepares liquid and thaws rapidly, and of short duration vortex is also containing 50mM Tris-HCl, 4mM MgCl 2, 4mM CaCl 2, 1mM EDTA test damping fluid (AB) in dilution, and transfer to pH 7.4 with NaOH.Final protein concentration is to 5-HT 1BFor about 0.185mg/ml with to 5-HT 1DFilm is 0.4mg/ml.Adopt [ 3H]-GR125743 (Amersham), in competition experiments, estimate test-compound.Ligand concentration in two tests to [ 3H]-GR125743 is 0.27nM.Kd, can in the 0.15nM-0.25nM scope, change.On one 96 hole test board (a kind of medicine/compound of every plate), carry out 5-HT simultaneously 1BAnd 5-HT 1DTest.The compound that in DMSO, prepares 10 serial dilutions (1 μ M-4pM, ultimate density) from the 10mM storing solution.Go up with quadruplicate preparation incubation mixture at 96 deep hole test boards (Matrix 1ml).The final every hole of test volume is 10 μ l compounds/non-specific; 100 μ l films, 100 μ l[ 3H]-GR125743 and 790 μ l AB.By adopting the combination of 10 μ M Methiothepins (Methiothepine) definition specificity.With test board jolting 5 minutes, incubation was other 55 minutes then.Adopt Packard Filtermate 196 by Beckman GF/B filter membrane (in PEI, soaking＞2 hours) filtration test plate then.With the ice-cold dcq buffer liquid of 1ml (5mM Tris-HCl-transfers to pH 7.4 with NaOH) filter membrane is washed 2 times.After the filter membrane drying, the Microscint 20 of 35 μ l is joined in every hole.On Packard TopCount, plate is counted to measure the CPM ' s in every hole then.Adopt figure and analysis software package GraphPad Prism, each test-compound is measured K iValue.Then by effectiveness with to 5-HT 1BWith respect to 5-HT 1DThe optionally series arrangement compound of acceptor.
A kind of can being used to measured compound to 5-HT 1BAnd 5HT 1DThe method of the affinity of acceptor is the Cortex of Guinea Pig test.This test is by Roberts etc., Br.J.Pharmacol., and 1996,117,384-388 describes in detail, and it is attached to herein by reference.Test is carried out according to following: cavy put to death and peels off cortex, weigh and in 50mM Tris-HCl (pH 7.7), use the Ultra-Turrax homogenization, and centrifugal 10 minutes in 48000xg and 5 ℃ subsequently.Pellet resuspended and centrifugal again.Last precipitation is suspended in the 0.32M sucrose damping fluid with the concentration that reaches the original weight in wet base of every ml 0.5g and in-70 ℃ of refrigerated storages.Radioligand is in conjunction with testing following carrying out: [ 3H] the saturated research of GR125743 5mL damping fluid (50mM Tris, 4mMCaCl 2, 4mM MgCl 2With 1mM EDTA, pH 7.7) in every pipe 3-4mg w.w., and the radioligand of 0.012-2nM (10-12 concentration) concentration range is tested in duplicate.In the presence of the 10mM Methiothepin, determine non-specific binding.In competition experiments, the radioligand concentration of every pipe 4-8mg w.w. and 0.2nM and the competition medicine of 10-12 concentration together use.Test in 30 ℃ and carry out also filtering termination fast in 2-4 hour, employing Brandel cell harvester by Whatman GF/B filter membrane (with 0.1% polymine (polyethyleneimine) pre-treatment).Bovine serum albumin (0.1%) is joined in the dcq buffer liquid to reduce non-specific binding.Adopt iteration non-linear curve fitting program LIGAND, can analyze the data that derive from experiment.By the LIGAND program, the K that adopts self-saturation research to obtain dThe value calculating K iValue.[ 3H] K of GR 125743 dValue can cause observed value and the B under 4.9 ± 0.2pmol/gw.w observed value of 46 ± 4pM Max
Whether GTP γ S can be used to measure compound in conjunction with test is 5HT 1BAnd 5HT IDAgonist or antagonist.A kind of test can be measured the GTP combination that agonist stimulates, for example by Lazareno, and the combination of S. (1999) Methods in Molecular Biology 106:231-245 general introduction.The people 5-HT that stable transfection Chinese hamster ovary celI system expresses 1BThe membrane prepare liquid of acceptor is available from for example Unisyn, Hopkinton, MA.Freezing film thaw, of short duration ultrasonic centrifugal and containing 20mM HEPES, 100mM NaCl, 1mM MgCl 2Be diluted to 167 μ g/ml albumen in the test damping fluid of 1 μ M GDP (pH being transferred to 7.4) with NaOH.With Polytron with the quick homogenization of film of dilution and face with before making it at room temperature balance at least 15 minutes.Containing or do not containing in the damping fluid of 100nM 5-HT (ultimate density), preparing test-compound serial dilution (10 μ M-1pM, ultimate density) from the 10mMDMSO storing solution.On the deep-well plates in 96 holes, make it contain the compound that contains or do not contain 5-HT by 180 μ L films (30 μ g albumen) and 40 μ L by quadruplicate preparation incubation mixture.Incubation is after 15 minutes under the room temperature, add 20 μ L [ 35S] GTP γ S (NEN; The 100pM ultimate density) to begin test.With mixture jolting 2 minutes, and under room temperature other 28 minutes of incubation.Adopt 96 hole Packard cell harvestors, filter termination reaction fast by Beckman GF/B glass fiber filter.Wash filter plate four times with the 1mL icy water.Normal dry filter plate also adds 30 μ L liquid scintillation cocktails (MicroScint 40, Packard) in every hole.Adopt TopCount Scintillation Counter (Packard) to measure the CPMs in every hole.Give a definition in 100nM 5-HT existence [ 35S] maximal stimulation of GTP γ S bonded.Independent definition basis in damping fluid [ 35S] GTP γ S.IC 50Value defined is compound concentrations under reacting at the 100nM 5-HT that obtains 50%.The maximum intrinsic activity of compound is defined as 5-HT and does not have the percentage of the maximum 5-HT inductive stimulation of 10 μ M compounds down.As the test internal standard substance, in each test, comprise the concentration response curve (1 μ M-1pM, final) of the 5-HT in the presence of compound is not and measure EC 50
Preferred compound of the present invention includes, but is not limited in the back to list in the page or leaf compound in the following table 1.
Table 1: compound
Figure C0280656200271
Figure C0280656200291
Figure C0280656200301
Figure C0280656200311
Figure C0280656200321
Figure C0280656200331
Figure C0280656200341
Figure C0280656200351
Figure C0280656200371
Figure C0280656200381
Figure C0280656200391
Figure C0280656200411
Figure C0280656200421
Figure C0280656200431
Figure C0280656200441
Also be provided at the pharmacy acceptable salt of the compound shown in the table 1 at this.
Illustrate the preparation of the intermediate in The compounds of this invention synthetic below with reference to embodiment, but do not plan to limit by any way the present invention.
Reference example 1
The preparation of reference example 1: 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride.
Reference example 1a:(E, Z)-2-(2-bromo-phenoxy group)-but-2-ene two diethyl phthalates.
With the acetylenedicarboxylic acid diethyl ester (20ml, 0.162mol) join 2-bromophenol in anhydrous 2-propyl alcohol (60ml) (28g, 0.162mol) in, add the tetrabutyl ammonium fluoride (0.5ml, 1.0M is in THF) of catalytic amount subsequently.At room temperature solution stirring also was heated to back flow reaction 1 hour in 4 hours then.Mixture is cooled to room temperature, and vacuum concentration is an oil (51g=91%) then.
Reference example 1b:(E, Z)-2-(2-bromo-phenoxy group)-but-2-ene diacid.
Will as in reference example 1a, prepare (E, Z)-(51g 148mmol) is suspended in the ethanol (95ml) and adds sodium hydroxide (12.9g, 0.323mol) solution in water (95ml) 2-(2-bromo-phenoxy group)-but-2-ene two diethyl phthalates.Solution was refluxed 1 hour, obtain clear and bright orange solution.Mixture is cooled to room temperature, with 6M HCl (50ml) acidifying.Vacuum concentrated mixture is also resistates and ethanol azeotropic (4x) then.Cross filter solid, wash with water, drying obtains being light orange solid (2Z)-2-(2-bromo-4-methoxyl group phenoxy group)-2-butylene diacid (24.3g, 88% yield).This crude product need not be further purified and can use.
Reference example 1c:8-bromo-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester.
With sulfuric acid (95mL) join as the crude product that in reference example 1b, prepares (E, Z)-2-(2-bromo-phenoxy group)-but-2-ene diacid in.After 45 minutes, obtain orange milky solution with air heating small of the stock mixture heating up.This solution is slowly joined in the dehydrated alcohol (500mL) of backflow.After the adding, reactant was refluxed 30 minutes, make it cooling then.Begin to form crystallization after 20 minutes, reactant is placed in refrigerator spent the night.Cross filter solid, with the washing in 9: 1 of cold ethanol/water, drying obtains the 8-bromo-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester (11.7g, 24% yield, mp 124-126 ℃) into pale solid.
Reference example 1d:8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester.
Will be as the 8-bromo-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester (Davies that in reference example 1c, prepares, Stephen etc., the 2597th page of J.Chem.Soc.Perkin Trans I, 1987) (3.0g, 10.1mmol) with the dry toluene azeotropic, be dissolved in white solid in the 100mL dry toluene then and be transferred in the reaction vessel.Make mixture through vacuum/argon gas (x2), be sequentially added into following reagent (positive argon pressure): N methyl piperazine (1.3ml, 11.1mmol), 2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene (0.75g, 1.2mmol), three (dibenzalacetones), two palladiums (0) (0.48g, 0.5mmol) and cesium carbonate (4.6g, 14.1mmol).Make mixture once more through vacuum/argon gas and 80 ℃ of following heated overnight.
Also toluene solution directly is filled in the 600ml filter funnel (silica gel 230-400 order ASTM is filled in the ethyl acetate) by diatomite filtration refrigerative reaction mixture, uses ethyl acetate (2L) washing then.With product 5-8% methyl alcohol/chloroform wash-out, the part of collection requirement obtains the impure a little orange/yellow solid of 2.5g (mp 120-123 ℃).With impure product chromatographyization on Waters Delta Prep 4000, use 1PrepPak post (Porasil 37-55 μ m 125
Figure C0280656200461
), with 3-5% methyl alcohol/chloroform wash-out.Collect product, drying obtains 8-(4-methyl isophthalic acid-piperazinyl)-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester (2.25g, 70% yield, mp 124-125 ℃) into yellow solid.GC/MS(EI，M+)m/z?316。
Reference example 1e:8-(4-methyl isophthalic acid-piperazinyl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride.
Will (1.01g 3.19mmol) be suspended among the 6M HCl (60ml) and reflux 1.5 hours (obtaining clear and bright solution after 20 minutes) as 8-(4-methyl isophthalic acid-piperazinyl)-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester of preparing in reference example 1d.Make the reactant cooling.Vacuum concentrated solution adds dry toluene (x3), solution vacuum concentration once more, obtains 8-(4-methyl isophthalic acid-piperazinyl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (1.02g, quantitative yield) into yellow powder.LC/MS(M+1)m/z?289。
Reference example 2
Figure C0280656200462
The preparation of 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride.
Reference example 2a:(2Z)-2-(2-bromo-4-methoxyl group phenoxy group)-2-butylene two diethyl phthalates.
Acetylenedicarboxylic acid ethyl ester (17.8ml, 0.145mol) join 2-bromo-4-methoxyphenol (the 1241st page of Synlett, 1997) in anhydrous 2-propyl alcohol (55ml) (27.3g, 0.134mol) in, the tetrabutyl ammonium fluoride (0.4ml, 1.0M is in THF) that adds catalytic amount subsequently.At room temperature, solution stirring is spent the night, be heated to back flow reaction then 30 minutes.Cooling forms precipitation down.Solution cooling and filtration, obtain (2Z)-2-(2-bromo-4-methoxyl group phenoxy group)-2-butylene two diethyl phthalates (29.9g, 62% yield) into yellow solid.Attention: solid contains (2E)-2-(2-bromo-4-methoxyl group phenoxy group)-2-butylene two diethyl phthalates of 10%.GC/MS (EI, M+) m/z 344 and 346.
Reference example 2b:(2Z)-2-(2-bromo-4-methoxyl group phenoxy group)-2-butylene diacid.
Will be as (2Z)-2-(2-bromo-4-methoxyl group the phenoxy group)-2-butylene two diethyl phthalate (29.9g that in reference example 2a, prepare, 86.6mmol) be suspended in the ethanol (55ml) and add sodium hydroxide (7.0g, 0.175mol) solution in water (55ml).Solution was refluxed 1 hour, obtain clear and bright orange solution.Vacuum is removed most of ethanol, adds 6M HCl (50ml) then.Cross filter solid, wash with water and drying, obtain being light orange solid (2Z)-2-(2-bromo-4-methoxyl group phenoxy group)-2-butylene diacid (24.3g, 88% yield).
Reference example 2c:6-methoxyl group-8-bromo-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester.
Sulfuric acid (50ml) is joined (2Z)-2-(2-bromo-4-methoxyl group phenoxy group)-2-butylene diacid (24.3g, 86.6mmol; As in above reference example 2b, preparing) in.After 5-10 minute, obtain clear and bright dark-brown solution with air heating small of the stock mixture heating up.This solution is slowly joined in the dehydrated alcohol (250ml) of backflow.After the adding, reactant was refluxed 30 minutes, make it cooling then.Begin to form crystallization after 20 minutes, reactant is placed in refrigerator spent the night.Cross filter solid,, obtain 8-bromo-6-methoxyl group-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester (12.3g, 50% yield, mp 159-161 ℃) into pale solid with cold ethanol/water washing in 9: 1 and dry.
Reference example 2d:6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester.
Will (9.2g 28.1mmol) with the dry toluene azeotropic, be dissolved in white solid in the 300ml dry toluene in the single neck round-bottomed flask of 500mL then as 8-bromo-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester of preparing in above embodiment 2c.By argon cleaning and vacuum (3x) are hocketed mixture is outgased, be sequentially added into following reagent: N methyl piperazine (4.0ml, 35.1mmol), 2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene (1.05g, 1.69mmol), three (dibenzalacetones), two palladiums (0) (0.50g, 0.56mmol) and cesium carbonate (12.8g, 39.3mmol).By argon gas purge and vacuum are hocketed mixture is outgased once more, and heated 17 hours down at 80 ℃.(0.10g, 0.11mmol) with 2,2 '-two (diphenylphosphino)-1, (0.20g 0.32mmol) and reactant stirred other 55 hours down at 80 ℃ 1 '-dinaphthalene, and this moment, conversion was complete substantially to add other three (dibenzalacetones), two palladiums (0).
The refrigerative reaction mixture with tetrahydrofuran (THF) (250mL) dilution, is filtered vacuum concentration.Chromatography purification resistates on silica gel, with the part of 2-5% methyl alcohol/chloroform wash-out and collection requirement, vacuum concentration is used the methylene dichloride grinding residues, obtains the yellow powder of 7.4g (76%).
Reference example 2e:6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid.
Will (1.0g 2.89mmol) be suspended in 6M HCl (60ml) and the methyl alcohol (10mL) and be warmed to back flow reaction 3.0 hours as 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester of preparing in above reference example 2d.Make the reactant cooling.Vacuum concentrated solution also adds dry toluene (x3), solution vacuum concentration once more.Vacuum-drying resistates (17h) obtains 6-methoxyl group-8-(4-methyl isophthalic acid-piperazinyl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (1.0g, quantitative yield) into yellow powder.
Reference example 3
Figure C0280656200481
6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride.
Reference example 3a:(EZ)-2-(2-bromo-4-fluorophenoxy)-2-butylene two diethyl phthalates.
Use and identical synthetic method that in above reference example 1a, illustrates and identical stoichiometry, from 2-bromo-4-fluorophenol and synthetic this compound of acetylenedicarboxylic acid diethyl ester.
Reference example 3b:(EZ)-2-(2-bromo-4-fluorophenoxy)-2-butylene diacid.
Use and identical synthetic method that in above reference example 1b, illustrates and identical stoichiometry, from synthesizing this compound as (EZ)-2-(2-bromo-4-fluorophenoxy)-2-butylene two diethyl phthalates that among above reference example 3a, prepare.
Reference example 3c:6-fluoro-8-bromo-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester.
Use and identical synthetic method that in above reference example 1c, illustrates and identical stoichiometry, from synthesizing this compound as (EZ)-2-(2-bromo-4-the fluorophenoxy)-2-butylene diacid that among above reference example 3b, prepares.
Reference example 3d:6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester.
Use and identical synthetic method that in above reference example 1d, illustrates and identical stoichiometry, from synthesizing this compound as the 6-fluoro-8-bromo-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester that among above reference example 3c, prepares.
Reference example 3e:6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride.
Use and identical synthetic method that in above reference example 1e, illustrates and identical stoichiometry, from begin synthetic this compound as 6-methoxyl group-8-(4-methyl-piperazine-1-the yl)-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester that among embodiment 3d, prepares.
Reference example 4
Figure C0280656200501
The preparation of 6-methyl-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride.
Reference example 4a:(E, Z)-2-(2-bromo-4-methylphenoxy)-2-butylene two diethyl phthalates.
(10mL 83mmol) is dissolved in the ether (90mL) with 2-bromo-4-methylphenol.To wherein drip triethylamine (13.7mL, 98mmol), add subsequently dimethyl acetylenedicarbexylate (11.2mL, 91mmol).At room temperature, the mixture stirring that generates is spent the night.By adding ether (200mL) and tetrahydrofuran (THF) (50mL) processing reaction thing, with the mixture of 1N HCl (200mL), water (200mL) and salt solution (100mL) washing generation.Dry then (Na 2SO 4) organic phase, filtering and simmer down to reddish-brown oil, it need not be further purified and can use.
With reference to 4b:(2E, Z)-2-(2-bromo-4-fluorophenoxy)-2-butylene diacid.
Use and identical synthetic method that in above embodiment 1b, illustrates and identical stoichiometry, from as among above reference example 4a, prepare (E, Z)-2-(2-bromo-4-methylphenoxy)-2-butylene two diethyl phthalates synthesize this compound.
Reference example 4c:6-methyl-8-bromo-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester.
Use and identical synthetic method that in above reference example 1c, illustrates and identical stoichiometry, from synthesizing this compound as (2Z)-2-(2-bromo-4-the methylphenoxy)-2-butylene diacid that among above reference example 4b, prepares.
Reference example 4d:6-methyl-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester.
Use and identical synthetic method that in above reference example 1d, illustrates and identical stoichiometry, from synthesizing this compound as the 6-methyl-8-bromo-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester that among above reference example 4c, prepares.
Reference example 4e:6-methyl-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride.
Use and identical synthetic method that in above reference example 1e, illustrates and identical stoichiometry, from begin synthetic this compound as 6-methyl-8-(4-methyl-piperazine-1-the yl)-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester that among reference example 4d, prepares.
Reference example 5
Figure C0280656200511
The preparation of 6-chloro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride.
Reference example 5a:(E, Z)-2-(2-bromo-4-chlorophenoxy)-2-butylene two diethyl phthalates.
By the synthetic method identical with identical stoichiometry, prepare this compound from 2-bromo-4-chlorophenol and dimethyl acetylenedicarbexylate with the preparation of in reference example 4a, describing.
Reference example 5b:(2E, Z)-2-(2-bromo-4-fluorophenoxy)-2-butylene diacid.
Use and identical synthetic method that in above reference example 1b, illustrates and identical stoichiometry, from as among above reference example 5a, prepare (E, Z)-2-(2-bromo-4-chlorophenoxy)-2-butylene two diethyl phthalates synthesize this compound.
Reference example 5c:6-chloro-8-bromo-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester.
Use and identical synthetic method that in above embodiment 1c, illustrates and identical stoichiometry, from as among above reference example 5b, prepare (2E, Z)-2-(2-bromo-4-chlorophenoxy)-2-butylene diacid synthesizes this compound.
Reference example 5d:6-chloro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester.
The identical synthetic method and identical stoichiometry using as illustrate in above embodiment 1d are from synthesizing this compound as the 6-chloro-8-bromo-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester for preparing among above reference example 5c.
Reference example 5e:6-chloro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride.
Use and identical synthetic method that in above reference example 1e, illustrates and identical stoichiometry, from begin synthetic this compound as 6-chloro-8-(4-methyl-piperazine-1-the yl)-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester that among above reference example 5d, prepares.
Reference example 6
Figure C0280656200521
The preparation of 5-methyl-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride.
Reference example 6a:(E, Z)-2-(2-chloro-5-methylphenoxy)-2-butylene two diethyl phthalates.
By the synthetic method identical with identical stoichiometry, prepare this compound from 2-chloro-5-methylphenol and dimethyl acetylenedicarbexylate with the preparation of in reference example 1a, describing.
Reference example 6b:(2E, Z)-2-(2-chloro-5-methylphenoxy)-2-butylene diacid.
Use and identical synthetic method that in above reference example 1b, illustrates and identical stoichiometry, from as among above reference example 6a, prepare (E, Z)-2-(2-chloro-5-methylphenoxy)-2-butylene two diethyl phthalates synthesize this compound.
Reference example 6c:5-methyl-8-chloro-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester.
Use and identical synthetic method that in above reference example 1c, illustrates and identical stoichiometry, from synthesizing this compound as (2Z)-2-(2-chloro-5-the methylphenoxy)-2-butylene diacid that among reference example 6b, prepares.
Reference example 6d:5-methyl-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester.
Will (1.0g 3.6mmol) uses the dry toluene azeotropic, then white solid is dissolved in the 100ml dry toluene in the single neck round-bottomed flask of 250mL as 5-methyl-8-chloro-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester of preparing in above reference example 6c.By argon cleaning and vacuum (3x) are hocketed mixture is outgased, be sequentially added into following reagent: N methyl piperazine (0.6ml, 5.37mmol), (2 '-dicyclohexyl phosphanyl-biphenyl-2-yl)-(JACS 1998 for dimethyl-amine, 120, the 9722nd page) (40mg, 0.1mmol), three (dibenzalacetones), two palladiums (0) (66mg, 0.072mmol) and cesium carbonate (1.6g, 5.37mmol).Argon cleaning and vacuum are hocketed mixture is outgased once more, and heated 17 hours down at 80 ℃.Add other three (dibenzalacetones), two palladiums (0) (66mg, 0.072mmol) and (2 '-two cyclopentyl phosphanyl-biphenyl-2-yls)-dimethyl-amine (40g, 0.1mmol) also reactant was stirred other 4 days down at 80 ℃, transform by HPLC and still only finish about 50% this moment.Add tetrahydrofuran (THF) (100mL), filter the mixture that merges, vacuum concentration and the chromatography purification on silica gel are used in 2.5% methanol-eluted fractions in the chloroform.The part that vacuum concentration requires obtains yellow powder (250mg=21%).
Reference example 6e:5-methyl-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride.
Use and identical synthetic method that in above embodiment 1e, illustrates and identical stoichiometry, from begin synthetic this compound as 5-methyl-8-(4-methyl-piperazine-1-the yl)-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester that among reference example 6d, prepares.
Reference example 7
Figure C0280656200541
The preparation of 5-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride.
Reference example 7a:(E, Z)-2-(2-bromo-5-methoxyl group phenoxy group)-2-butylene two acid esters.
By with identical synthetic method of the preparation of in reference example 1a, describing and identical stoichiometry, prepare this compound from 2-bromo-5-methoxyphenol and dimethyl acetylenedicarbexylate.
Reference example 7b:(E, Z)-2-(2-bromo-5-methoxyl group phenoxy group)-2-butylene diacid.
Use and identical synthetic method that in above reference example 1b, illustrates and identical stoichiometry, from as among reference example 7a, prepare (E, Z)-2-(2-bromo-5-methoxyl group phenoxy group)-2-butylene two diethyl phthalates synthesize this compound.
Reference example 7c:5-methoxyl group-8-bromo-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester.
Use and identical synthetic method that in above reference example 1c, illustrates and identical stoichiometry, from as among above reference example 7b, prepare (E, Z)-2-(2-bromo-5-methoxyl group phenoxy group)-2-butylene diacid synthesizes this compound.
Reference example 7d:5-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester.
Use and identical synthetic method that in above reference example 1d, illustrates and identical stoichiometry, from synthesizing this compound as the 5-methoxyl group-8-bromo-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester that among above reference example 7c, prepares.
Reference example 7e:5-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride.
Use the method identical, from preparing this compound as 5-methoxyl group-8-(4-methyl-piperazine-1-the yl)-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester that among above reference example 7d, prepares with the preparation in 1e.
Reference example 8
Figure C0280656200551
The preparation of 1-(6-piperazine-1-base-2,3-dihydro-indoles-1-yl)-ethyl ketone.
Reference example 8a:1-[5-(4-benzyl-piperazine-1-yl)-2,3-dihydro-indoles-1-yl]-ethyl ketone.
(3.0g 12.5mmol) is dissolved in the toluene (60mL) with 1-ethanoyl-5-bromine indoline.To wherein add sodium tert-butoxide (1.68g, 17.5mmol), the N-benzyl diethylenediamine (2.4mL, 13.8mmol), S-BINAP (0.93g, 1.5mmol) and Pd 2(dba) 3(0.46g, 0.5mmol).By three round-robin vacuum and nitrogen wash mixture is outgased, stir down up to GC analysis confirmation reaction at 95 ℃ then and finish (1h).With ethyl acetate (150mL) diluted mixture thing, wash with water and wash with 2N HCl (2x 100mL).The aqueous extract that contains that merges is alkalized with dense ammonium hydroxide, extract with ethyl acetate (2x 100mL).Dry (MgSO 4) organic extracting solution of merging and concentrating, obtain solid (2.7g), it through chromatography purification, is obtained white solid (1.81g, 43%).Mp＝150.5-152.8℃。
Reference example 8b:1-(6-piperazine-1-base-2,3-dihydro-indoles-1-yl)-ethyl ketone.
Will be as the 1-[5-(4-benzyl-piperazine-1-yl)-2 that in above reference example 8a, prepares, 3-dihydro-indoles-1-yl]-(0.37g 1.1mmol) is dissolved in the methyl alcohol (5mL) ethyl ketone.(0.9g is 14mmol) also the mixture heating up to 65 that generates ℃ reaction 2 hours to add Pd/C (90mg, 10%) and ammonium formiate.Filtering mixt is also used the hot methanol washing leaching cake.Concentrate the filtrate that merges, obtain required product (0.26g, 90%).
Reference example 9
Figure C0280656200561
The preparation of 2-chloro-5-piperazine-1-base benzonitrile.
Reference example 9a:3-cyano group-4-chloroaniline.
(25g 137mmol) is dissolved in the ethanol (275mL) with 2-chloro-5-nitrobenzonitrile.(154.5g .685M) and under 70 ℃ stirs mixture 30 minutes to add stannous chloride dihydrate.Then mixture is cooled to room temperature and is poured in the trash ice.Make mixture be alkalescence with solid sodium hydroxide.(3x 100mL) extracts this mixture with ethyl acetate.United extraction liquid is used the salt water washing, dry (MgSO 4), concentrating and the vacuum-drying resistates, recrystallization from ethanol obtains light brown needle (10.6g, 51%).
Reference example 9b:2-chloro-5-piperazine-1-base benzonitrile.
Will as 3-cyano group-4-chloroaniline of in reference example 9a, preparing (10.1g 66mmol) is dissolved in the propyl carbinol (300mL), add two-(2-chloroethyl) amine hydrochlorate (23.2g, 130mmol) and potassiumiodide (50mg, catalytic amount).Under refluxing,, but spend the night in refrigerator and cooled then mixture heating up 3 days.Collect solid precipitation after filtration, with cold propyl carbinol washing and dry.Crude product is distributed between methylene dichloride and 2N ammonium hydroxide.Separate organic layer, dry (Na 2SO 4) and concentrate, obtain light yellow solid (9.1g, 59%), obtain unimodal through GC and TLC analysis.
Reference example 10
Figure C0280656200562
4-[1,2,3] preparation of thiadiazoles-5-base-aniline.
With SnCl 2H 2O (3.21g, 5 equivalents) join (5-(4-nitrophenyl)-1,2,3-thiadiazoles (Lancaster Synthesis) (0.59g, 2.8mmol) in the soup compound in anhydrous EtOH (50mL) and reactant be heated to 70 ℃ the reaction 2 hours.Make reactant be cooled to room temperature and be poured into saturated NaHCO 3In ice.Product is extracted dry (MgSO with EtOAc (2X) 4) solution, vacuum-evaporation is to doing, and obtains 126-128 ℃ of the light yellow solid mp of 0.47g.
Reference example 11
Figure C0280656200571
1-[4-(4-amino-phenyl)-piperazine-1-yl]-preparation of ethyl ketone.
Reference example 11a:4-(4-nitrophenyl)-1-ethanoyl piperazine.
(2.5g 12.1mmol) is dissolved in the methylene dichloride (100ml) with 1-(4-nitrophenyl) piperazine.(2.0ml 14.5mmol) and reactant is cooled to 0 ℃ to add triethylamine.(1.25ml 13.3mmol) and under 0 ℃ stirs reactant 1 hour to drip diacetyl oxide.Add saturated sodium bicarbonate, with dichloromethane extraction reactant (x3), dry (MgSO 4), filter and vacuum concentration, obtain 4-(4-nitrophenyl)-1-ethanoyl piperazine (3.01g) into yellow solid.GC/MS(EI，M+)m/z＝249。
Reference example 11b:1-[4-(4-amino-phenyl)-piperazine-1-yl]-ethyl ketone.
Will (3.0g 12.0mmol) mixes in methyl alcohol (100ml) and is added in 2M ammonia and 10% palladium carbon (300mg) in the methyl alcohol (50ml) as 4-(4-nitrophenyl)-1-ethanoyl piperazine of preparing in above reference example 11a.With mixture hydrogenation in the Parr device (50 pounds/square inch) 1.5 hours.
Make the reactant cooling, filtering catalyst and vacuum concentrated solution.With crude product solid recrystallization from ethyl acetate, obtain being pale red purple solid 4-(4-ethanoyl-1-piperazinyl) aniline (1.86g, 70% yield, mp 149.5-150.5 ℃).GC/MS(EI，M+)m/z＝219。
Reference example 12
Figure C0280656200581
The preparation of 4-(4-methylsulfonyl-piperazine-1-yl)-aniline.
Reference example 12a:4-(4-nitrophenyl)-1-methylsulfonyl piperazine.
(2.79g 13.5mmol) is dissolved in the methylene dichloride (100ml) with 1-(4-nitrophenyl) piperazine.(2.25ml 16.2mmol) and reactant is cooled to 0 ℃ to add triethylamine.(1.15ml 14.9mmol) and reactant stirred 1 hour down at 0 ℃ to drip methylsulfonyl chloride.Add saturated sodium bicarbonate and use dichloromethane extraction reactant (x3), dry (MgSO 4), filtering, vacuum concentration obtains 4-(4-the nitrophenyl)-1-methylsulfonyl piperazine (3.83g, quantitative yield) into yellow solid.GC/MS(EI，M+)m/z＝285。
Reference example 12b:4-(4-methylsulfonyl-piperazine-1-yl)-aniline.
Will (3.83g 13.4mmol) mixes in methyl alcohol (100ml) and is added in 2M ammonia and 10% palladium carbon (400mg) in the methyl alcohol (50ml) as 4-(4-nitrophenyl)-1-methylsulfonyl piperazine of preparing in above reference example 12a.With mixture hydrogenation in the Parr device (50 pounds/square inch) 3 hours.
Make the reactant cooling, filtering catalyst is used methanol wash, washs with chloroform then.Chloroform partly contain require in a small amount but look more single product.Vacuum concentration chloroform part, recrystallization from ethyl acetate obtains 4-[4-(the methylsulfonyl)-1-piperazinyl into glossiness brown solid] aniline (0.94g, 27% yield, mp 192-193 ℃).GC/MS(EI，M+)m/z＝255。
Reference example 13
Figure C0280656200582
The preparation of 4-thiomorpholine-4-base-aniline:
Reference example 13a:4-(4-nitro-phenyl)-thiomorpholine.
(3.0g 21.3mmol) is dissolved in the toluene (25mL) with the 4-fluoronitrobenzene.(2.4mL 23.4mmol) and under 100 ℃ spends the night the mixture stirring to add thiomorpholine.In the time of 17 hours, mixture is distributed between ethyl acetate (100mL) and saturated sodium bicarbonate (50mL).Separate organic layer, dry (Na 2SO 4), filter vacuum concentration.Use the hexane grinding residues, obtain the glassy yellow solid.
Reference example 13b:4-thiomorpholine-4-base-aniline.
Will (3.0g 13.4mmol) be dissolved in the ethanol (250mL) and adds 10% palladium carbon (250mg) as 4-(4-nitro-phenyl)-thiomorpholine of preparing in above reference example 13a.With the jolting 3 hours in the Parr hydrogenator of this mixture.Pass through diatomite filtration reaction mixture, vacuum concentration then.Use the hexane grinding residues, obtain gray solid (2.1g).
Reference example 14
The preparation of 1-(4-amino-phenyl)-1-morpholine-4-base-ketone.
Reference example 14a:1-morpholine-4-base-1-(4-nitro-phenyl)-ketone.
Will the 4-nitrobenzoyl chloride in the tetrahydrofuran (THF) (10mL) (5g, 27mmol) slowly join morpholine (5g, 88mmol) and triethylamine (2.7g is 27mmol) in the solution in tetrahydrofuran (THF) (50mL) and at room temperature stirred 4 hours.In mixture, add ethyl acetate (200mL), the mixture that water (25mL), 1N HCl (25mL), water (25mL), saturated sodium bicarbonate (25mL), water (25mL) and salt solution (25mL) washing merge.Dry (Na 2SO 4) mixture, filtering, vacuum concentration, resistates need not be further purified and can use.
Reference example 14b:1-(4-amino-phenyl)-1-morpholine-4-base-ketone.
As among the reference example 13b, preparing, prepare this compound from 1-morpholine-4-base-1-(4-nitro-phenyl)-ketone.
Reference example 15
Figure C0280656200601
The preparation of 5-amino-2-morpholine-4-base-benzonitrile.
Reference example 15a:2-morpholine-4-base-5-nitro-benzonitrile.
(3.3g 19.9mmol) is dissolved in the ethyl acetate (10mL) with 3-cyano group-4-fluoronitrobenzene.(2.2mL, 25mmol) and N, (3.5mL 20mmol) and at room temperature stirs mixture and spends the night the N-diisopropylethylamine to add morpholine.In the time of 17 hours, add other ethyl acetate (150mL), the mixture that water (50mL) and salt solution (50mL) washing merge, dry (Na 2SO 4), filter vacuum concentration.Resistates need not be further purified and can use.
Reference example 15b:5-amino-2-morpholine-4-base-benzonitrile.
As among the reference example 13b, preparing, from 2-morpholine-4-base-5-nitro-benzonitrile (as among above reference example 15a, preparing) this compound of preparation.
Reference example 16
Figure C0280656200602
The preparation of 3-fluoro-4-morpholine-4-base-aniline.
Reference example 16a:4-(2-fluoro-4-nitro-phenyl)-morpholine.
With 3, (3.7g 23.2mmol) is dissolved in the ethyl acetate (10mL) the 4-difluoro nitrobenzene.(2.2mL, 25mmol) and N, (4mL 23mmol) and at room temperature stirs mixture and spends the night the N-diisopropylethylamine to add morpholine.In the time of 17 hours, add other ethyl acetate (150mL), the mixture that water (50mL) and salt solution (50mL) washing merge, dry (Na 2SO 4), filter vacuum concentration.Resistates need not be further purified and can use.
Reference example 16b:3-fluoro-4-morpholine-4-base-aniline.
As among the reference example 13b, preparing, from 4-(2-fluoro-4-nitro-phenyl)-morpholine (as among above reference example 16a, preparing) this compound of preparation.
Reference example 17
Figure C0280656200611
The preparation of 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester:
Reference example 17a:4-(4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester.
(4.8g 34mmol) is dissolved in the ethyl acetate (25mL) with the 4-fluoronitrobenzene.(6.7g, 36mmol) and N, (6.3mL 36mmol) and under 65 ℃ stirs mixture 5 days the N-diisopropylethylamine, is cooled to room temperature to add piperazine-1-carboxylic acid tert-butyl ester.Add ether (100mL), the mixture that water (25mL) and salt solution (25mL) washing merge, dry (Na 2SO 4), filter vacuum concentration.Use the hexane grinding residues, obtain glassy yellow solid (8g, 77%).
Reference example 17b:4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester.
As among the reference example 13b, preparing, from 4-(4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (as among reference example 17a, preparing) preparation 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester.
Reference example 18
Figure C0280656200612
The preparation of 3-morpholine-4-base-aniline
Reference example 18a:4-(3-nitro-phenyl)-morpholine.
(10g 71mmol) is dissolved in the acetonitrile (100mL) with the 3-fluoronitrobenzene.(30mL 350mmol) and under 150 ℃/80 pounds/square inch, made mixture reaction 18 hours in pressure reactor to add morpholine.Reactant is cooled to room temperature, vacuum concentration, the mixture of the column chromatography purification total amount 5g on silica gel is used CH 2Cl 2Wash-out.Be separated into the product (3.6g) of glassy yellow oil.
Reference example 18b:3-morpholine-4-base-aniline.
As among the reference example 13b, preparing, from 4-(3-nitro-phenyl)-morpholine (as among reference example 18a, preparing) preparation 3-morpholine-4-base-aniline.
Reference example 19
2-[4-(4-amino-phenyl)-piperazine-1-yl]-the alcoholic acid preparation.
Reference example 19a:2[4-(4-nitrophenyl) piperazine-1-yl]-ethanol.
By with the identical method of in above reference example 13a, describing, available from the market 4-fluoronitrobenzene (Aldrich) and N-available on the market (2-hydroxyethyl) piperazine (Aldrich) preparation 2[4-(4-nitrophenyl) piperazine-1-yl]-ethanol.
Reference example 19b:2-[4-(4-amino-phenyl)-piperazine-1-yl]-ethanol.
As described at reference example 13b, by catalytic hydrogenation 2[4-(4-nitrophenyl) piperazine-1-yl]-ethanol (as in reference example 19a, preparing) preparation 2-[4-(4-amino-phenyl)-piperazine-1-yl]-ethanol.
Reference example 20
Figure C0280656200622
The preparation of 4-morpholine-4-base-aniline.
With 4-(4-nitrophenyl) morpholine (10.3g, 49.5mmol; ) (Lancaster Synthesis) be suspended in the methyl alcohol (130ml) and be added in 2M ammonia and 5% palladium carbon (100mg) in the methyl alcohol (70mL).Mixture hydrogenation in the Parr device (50 pounds/square inch) 1 hour.Make the reactant cooling, filtering catalyst, vacuum concentrated solution.With crude product solid recrystallization from ethyl acetate/hexane, obtain being pale red purple solid 4-(4-morpholinyl) aniline (6.2g, 70% yield, mp 132-133 ℃).GC/MS(EI，M+)m/z＝178。
Reference example 21
Figure C0280656200631
The preparation of 4-amino-3-hydroxy base morpholine.
Under 30 ℃, with the 4-nitro-(3.34g 14.9mmol) is dissolved in the 59ml ethanol 3-hydroxy phenyl morpholine (Maybridge Chemical).Stirring the mixture under 25 ℃ and following under the stirring with tin chloride (II) dihydrate (16.8 grams, 74.5mmol) processing.During 30 minutes yellow suspension is heated to backflow.TLC shows the reaction progress in several hours.Mixture was refluxed 18 hours, be cooled to room temperature and concentrated, obtain yellow soup compound to remove most of ethanol.With the saturated sodium bicarbonate aqueous solution treating mixture up to be alkalescence.Use the ethyl acetate extraction mixture, filter, separate organic layer.With ethyl acetate water layer is extracted twice in addition.United extraction liquid through dried over mgso, filters, and concentrates, and obtains the red-violet colour solid of 1.02 grams.Proton N MR consistent with the CI mass spectroscopy (through positivity ion CI m/z=195 base peak with through negativity ion CI m/z=193 base peak) with required product.
Reference example 22
Figure C0280656200632
The preparation of 6-methoxyl group-8-(4-methyl-[1,4] Diazesuberane-1-yl)-4-oxo-4H-chromene-2-carboxylic acid.
Reference example 22a:6-methoxyl group-8-(4-methyl-[1,4] Diazesuberane-1-yl)-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester.
In the 250mL 3 neck round-bottomed flasks that are equipped with reflux exchanger, nitrogen inlet and magnetic stirring apparatus, add 1.5g (4.59mmol, 1.0 8-bromo-6-methoxyl group-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester (reference example 2c) equivalent), 84mg (0.092mmol, 0.02 three (dibenzalacetones), two palladiums equivalent), 342mg (0.55mmol, 0.12 racemize 2 equivalent), 2 '-two (diphenylphosphino)-1, the 4A molecular sieve of 1 '-dinaphthalene and 2g.In this suspension, add the 150mL dry toluene.In the suspension that is stirring, add 628mg then, 684 μ L, the high piperazine of 1-methyl of (5.50mmol, 1.2 equivalents) adds the cesium carbonate of 2.05g (6.3mmol, 1.4 equivalents) subsequently.Then mixture heating up to 80 ℃ 3 days.When finishing, this time analyzes the monitoring performance by aliquot LC/MS.When reaction is defined as finishing, be cooled to room temperature, filter by Celite pad then, use toluene wash, to remove solid by-product.Through the flash chromatography purifying, the gradient of using the 5-20% methyl alcohol in methylene dichloride obtains the required product of 1.0g (60%) as eluent.
Mass spectrum: to [C 19H 24N 2O 5+ H] +Calculated value m/z=361; Obs.=361
Reference example 22b:6-methoxyl group-8-(4-methyl-[1,4] Diazesuberane-1-yl)-4-oxo-4H-chromene-2-carboxylic acid.
6-methoxyl group-8-(4-methyl-[1,4] Diazesuberane-1-yl)-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester that in the 125mL Erlenmeyer flask that is equipped with magnetic stirring apparatus, adds 319mg (0.89mmol, 1.0 equivalents).This material is dissolved among the THF of 30mL, adds the methyl alcohol of 30mL then.The water that contains 41mg (0.97mmol, 1.1 equivalents) lithium hydroxide that in the solution that this is stirring, adds 30mL.At room temperature, this mixture was stirred 2 hours.By LC/MS monitoring reaction performance, add the 2N HCl of 10mL then.Concentrate this mixture then, drying is ground with ether, and obtaining with quantitative yield is the product of hydrochloride.
Mass spectrum: to [C 17H 20N 2O 5+ H] +Calculated value m/z=333; Obs.=333
Reference example 23
Figure C0280656200651
The preparation of 6-oxyethyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carbonyl chloride.
Reference example 23a:8-bromo-6-hydroxyl-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester:
Oxy-compound, 8-bromo-6-hydroxyl-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester forms as the by product during synthetic 8-bromo-6-methoxyl group-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester.By flash chromatography, use 20% ethyl acetate in methylene dichloride to the same solvent that contains 2% methyl alcohol gradient eluent progressively, it can be separated from crude product methoxylation compound.The oxy-compound of last wash-out is concentrated, obtain pure compound.Mass spectrum: to [C 12H 9BrO 5+ H] +Calculated value m/z=313,315; Obs.=313,315.
Reference example 23b:8-bromo-6-oxyethyl group-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester:
The 8-bromo-6-hydroxyl-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester (reference example 23a) that in the 100mL 3 neck round-bottomed flasks that are equipped with reflux exchanger, nitrogen inlet and magnetic stirring apparatus, adds 700mg (2.24mg, 1.0 equivalents).This material is dissolved in the 50mL toluene, adds 689mg then, the K of the ethyl sulfate of 586 μ L (4.47mmol, 2.0 equivalents) and 309mg (2.24mmol, 1.0 equivalents) 2CO 3Then reactant was heated to back flow reaction 24 hours.When this finishes time, by the LC/MS monitoring show reaction finish＞95%.Cool off reactant then, add the ethyl acetate of 100mL and use 0.5N HCl solution washing organic layer, through Na 2SO 4Drying is filtered, and concentrates.Make resistates be subjected to flash chromatography, 40% ethyl acetate of use in hexane is as eluent.Concentrated and purified part obtains the colorless solid of 500mg (65%).
Mass spectrum: to [C 14H 13BrO 5+ H] +Calculated value m/z=341,343; Obs.=341,343
Reference example 23c:6-oxyethyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester:
In the 100mL 3 neck round-bottomed flasks that are equipped with reflux exchanger, magnetic stirring apparatus and nitrogen inlet, add 350mg (1.03mmol, 1.0 8-bromo-6-oxyethyl group-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester (reference example 23b) equivalent), 18.9mg (0.02mmol, 0.02 three (dibenzalacetones), two palladiums equivalent), 77mg (0.123mmol, 0.12 racemize 2 equivalent), 2 '-two (diphenylphosphino)-1, the 4A molecular sieve of 1 '-dinaphthalene and 1g and 60mL dry toluene.In the suspension that is stirring, add 113mg then, 1255 μ L, the 1-methylpiperazine of (1.13mmol, 1.1 equivalents) adds the cesium carbonate of 470mg (1.44mmol, 1.4 equivalents) subsequently.Then mixture heating up to 80 ℃ 3 days.When this time finishes, analyze the monitoring performance by aliquot LC/MS.When reaction is defined as finishing, be cooled to room temperature, filter by Celite pad then, use toluene wash, to remove solid by-product.Through the flash chromatography purifying, the gradient liquid that uses the 5-40% methyl alcohol in methylene dichloride is as eluent, and what obtain that 350mg (75%) requires is the product of yellow solid.Mass spectrum: to [C 19H 24N 2O 5+ H] +Calculated value m/z=361; Obs.=361.
Reference example 23d:6-oxyethyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid:
6-oxyethyl group-8-(4-methyl-piperazine-1-the yl)-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester (reference example 23c) that in the 125mL Erlenmeyer flask that is equipped with magnetic stirring apparatus, adds 500mg (1.39mmol, 1.0 equivalents).This material is dissolved among the THF of 30mL, adds the methyl alcohol of 30mL then.The water that contains 64.2mg (1.53mmol, 1.1 equivalents) lithium hydroxide that in the solution that this is stirring, adds 30mL.At room temperature, this mixture was stirred 2 hours.By LC/MS monitoring reaction performance, add the 2N HCl of 10mL then.Concentrate this mixture then, drying is ground with ether, and obtaining with quantitative yield is the product of hydrochloride.
Mass spectrum: to [C 17H 20N 2O 5+ H] +Calculated value m/z=333; Obs.=333.
Reference example 23e:6-oxyethyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carbonyl chloride:
In the 100mL round-bottomed flask that is equipped with reflux exchanger, nitrogen inlet and magnetic stirring apparatus, add 6-oxyethyl group-8-(4-methyl-piperazine-1-the yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 23d) of 250mg (0.68mmol, 1.0 equivalents) and the methylene dichloride of 20mL.Add 129.5mg then in the suspension that is stirring, the oxalyl chloride of 164L (1.02mmol, 1.5 equivalents) adds 1 DMF that works as catalyzer from 50 microliter syringes subsequently.Mixture was stirred 2 hours, under nitrogen atmosphere, on rotatory evaporator, be concentrated into dried, dry under the high vacuum subsequently then.Analyze the performance of determining reaction by aliquot LC/MS, with its THF solution quencher with methylamine.The crude product material that obtains is used for amidate action subsequently.
Reference example 24
Figure C0280656200671
The preparation of 8-bromo-6-methoxyl group-4-(2-TMS-oxyethyl group methoxy base)-quinaldic acid's methyl esters.
Reference example 24a:2-(2-bromo-4-methoxyl group-phenyl amino)-but-2-ene two dimethyl phthalates.
With 2-bromo-4-anisidine (6.02g, 29.8mmol) solution in the 125mL anhydrous methanol with dimethyl acetylenedicarbexylate (3.70mL 30.2mmol) handles and under nitrogen, with solution in the heating down 8 hours that refluxes.Reaction mixture concentrates, and is dissolved in the hot ethanol once more.Obtain yellow crystal (6.93g, 68%) after filtration.From ethanol, obtain the crystallization (0.942g, 9%) of after-crop.Merging filtrate, through the flash chromatography on silica gel purifying, use 4: 1 hexanes: eluent ethyl acetate, obtain other 1.63g, total recovery is 93% (16%).
1H?NMR(300MHz，DMSO，d 6)δ9.60(s，1H，N H)，7.26(d，1H，J m＝2.7Hz，Ar H 3)，6.93(dd，1H，J 0＝8.7，J m＝2.7Hz，Ar H 5)，6.87(d，1H，J o＝8.7Hz，Ar H 6)，5.34(s，1H，C＝C H)，3.76(s，3H，OC H 3)，3.68(s，3H，CHCO 2C H 3)，3.66(s，3H，CNCO 2C H 3)；
Mass spectrum: to [C 13H 14BrNO 5+ H] +Calculated value m/z=344,346; Obs.=344,346.
Reference example 24b:8-bromo-6-methoxyl group-4-oxo-1,4-dihydro-quinaldic acid's methyl esters.
Dowtherm (Dow-Therm) (175mL) is heated to 244 ℃ and added as solid 2-(2-bromo-4-methoxyl group-phenyl amino)-but-2-ene two dimethyl phthalate (9.50g in batches in 7 minutes, 27.6mmol), holding temperature is 230-240 ℃ simultaneously.Under 240-245 ℃,, be cooled to room temperature then brown reaction mixture heating 45 minutes.Cooling forms yellow mercury oxide down.The hexane that adds about 100mL in mixture, separate solid is dry under high vacuum with other hexane wash after filtration, obtains the product (6.73g, 78%) into yellow solid.
1H NMR (300MHz, DMSO, d 6) δ 12.01 (s, 1H, N H), 7.86 (d, 1H, J m=2.7Hz, Ar H 5), 7.52 (s, 1H, C=C H), 7.48 (d, 1H, J m=2.7Hz, Ar H 7), 3.93 (s, 6H, OC H 3And CO 2C H 3);
Mass spectrum: to [C 12H 10BrNO 4+ H] +Calculated value m/z=312,314; Obs.312,314.
Reference example 24c:8-bromo-6-methoxyl group-4-(2-TMS-oxyethyl group methoxy base)-quinaldic acid's methyl esters.
With 8-bromo-6-methoxyl group-4-oxo-1, (6.73g, 21.6mmol) (60% suspension in oil, 1.028g 25.7mmol) handle the brown solution in the 100mL N-Methyl pyrrolidone 4-dihydro-quinaldic acid's methyl esters with sodium hydride.Gas produces and observes heating.Under nitrogen, reactant was stirred under room temperature 10 minutes.(5.00mL 28.3mmol) causes muddy a little light brown solution to add 2-(trimethyl silyl) ethoxyl methyl chlorine.In room temperature after following 2.5 hours, be poured into reaction mixture in the 800mL water and stirred 15 minutes.Separate the milky white precipitate that generates after filtration, wash with water, dry under high vacuum, obtain product (9.70g, quantitative yield) into Off-white solid.
1H NMR (300MHz, DMSO, d 6) δ 7.976 (d, 1H, J m=2.7Hz, Ar H 7), 7.79 (s, 1H, C=C H), 7.53 (d, 1H, J m=2.7Hz, Ar H 5), 5.70 (s, 2H, OC H 2O), 339 (s, 6H, OC H 3And CO 2C H 3), 3.88 (t, 2H, J=8.0Hz, OC H 2CH 2Si), 0.97 (t, 2H, J=8.0Hz, OCH 2 H 2Si)) ,-0.04 (s, 9H, Si (C H 3) 3
Mass spectrum: to [C 18H 24BrNO 5Si+H] +Calculated value m/z=442,444; Obs.442,444.
Reference example 25
Figure C0280656200691
6-methoxyl group-8-(4-methyl-[1,4] Diazesuberane-1-yl)-4-oxo-1,4-dihydro-quinaldic acid's preparation.
Reference example 25a:6-methoxyl group-8-(4-methyl-[1,4] Diazesuberane-1-yl)-4-(2-TMS-oxyethyl group methoxy base)-quinaldic acid's methyl esters.
To 2-bromo-6-methoxyl group-4-(2-TMS--oxyethyl group methoxy base)-quinaldic acid's methyl esters (1.01g, 2.28mmol), the high piperazine of N-methyl (0.32mL, 2.57mmol) and 4
Figure C0280656200692
Add Pd in the clear and bright light brown solution of molecular sieve in the 30mL dry toluene 2(dba) 2(43.8mg, 0.048mmol) and BINAP (169.8mg, 0.27mmol).(1.124g 3.45mmol) handles the amaranth solution that generates with cesium carbonate.Under nitrogen, reaction mixture was heated 21 hours under refluxing.The peak green reaction mixture is cooled to room temperature and concentrated.Through flash chromatography on silica gel purifying crude mixture, use 95: 5-40: 60 methylene dichloride: the gradient liquid wash-out of methyl alcohol obtains being the required product of yellow foamy (1.004g, 92%).
1H?NMR(300MHz，DMSO，d 6)δ7.67(s，1H，Ar H 3)，6.94(d，1H，J m＝2.4Hz，Ar H 5)，6.66(d，1H，J m＝2.4Hz，Ar H 7)，5.60(s，2H，OC H 2O)，3.94(s，3H，CO 2C H 3)，3.88(s，3H，OC H 3)，3.82(t，2H，J＝8.0Hz，OC H 2CH 2Si)，3.75(bs，4H，ArNC H 2CH 2CH 2NCH 3&ArNC H 2CH 2N-CH 3)，3.45(bs，2H，ArNCH 2C H 2NCH 3)，3.31(bs，2H，ArNCH 2CH 2C H 2NCH 3)，2.83(s，3H，NC H 3)，2.28(bs，2H?ArNCH 2C H 2?CH 2NCH 3)，0.92(t，2H，J＝8.0Hz，OCH 2C H 2Si)，-0.04(s，9H，Si(C H 3) 3；
Mass spectrum: to [C 24H 37N 3O 5Si+H] +Calculated value m/z=476; Obs.476.Reference example 25b:6-methoxyl group-8-(4-methyl-[1,4] Diazesuberane-1-yl)-4-oxo-1,4-dihydro-quinaldic acid.
To 6-methoxyl group-8-(4-methyl-[1,4] Diazesuberane-1-yl)-4-(2-TMS-oxyethyl group methoxy base)-quinaldic acid's methyl esters (1.00g, 2.10mmol) at 3: 1: 1 tetrahydrofuran (THF)s of 18mL: methyl alcohol: add in the light brown solution in the water lithium hydroxide monohydrate (0.267g, 6.35mmol).At room temperature, reaction mixture was stirred 5 hours, be acidified to pH 4 and stirred other 20 minutes with 1N HCl.Concentrated reaction mixture, dry under high vacuum, obtain orange foam.
1H?NMR(300MHz，DMSO，d 6)δ11.06(s，1H，N H)，7.53(s，1H,C＝C H)，7.00(d，1H，J m＝2.4Hz，Ar H 5)，6.70(d，1H，J m＝2.4Hz，Ar H 7)，4.05-3.99(m，2H，ArNC H 2CH 2CH 2NCH 3)，3.87(s，3H，OC H 3)，3.68-3.60(m，2H，ArNC H 2CH 2NCH 3)，3.54-3.47(m，2H，ArNCH 2C H 2NCH 3)，3.41-3.26(m，2H，ArNCH 2CH 2C H 2NCH 3)，2.82(d，3H，J＝4.8Hz，NC H 3)，2.46-2.41(m，1H?ArNCH 2C H 2CH 2NCH 3)，2.30-2.25(m，1H?ArNCH 2C H 2CH 2NCH 3)；
Mass spectrum: to [C 17H 21N 3O 4+ H] +Calculated value m/z=332; Obs.332.
Reference example 26
Figure C0280656200711
6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-1,4-dihydro-quinaldic acid's preparation.
By preparing this compound with the identical method that the preparation of reference example 25 is described.
Reference example 27
Figure C0280656200712
The preparation of 6-methoxyl group-8-(4-methyl-[1,4] Diazesuberane-1-yl)-4-(2-TMS-oxyethyl group methoxy base)-quinaldic acid's (4-morpholine-4-base-phenyl)-acid amides.
Reference example 27a:8-bromo-6-methoxyl group-4-oxo-1,4-dihydro-quinaldic acid.
To 8-bromo-6-methoxyl group-4-(2-TMS-oxyethyl group methoxy base)-quinaldic acid's methyl esters (reference example 24c) (4.98g, 11.3mmol) at 3: 1: 1 tetrahydrofuran (THF)s of 75mL: methyl alcohol: add in the light brown solution in the water lithium hydroxide monohydrate (1.367g, 32.6mmol).At room temperature, reactant was stirred 5 hours.Concentrated reaction mixture also is poured in the water then.With 1N HCl solution is acidified to pH 2, separates the solid that generates after filtration.Then solid suspension in methyl alcohol, filter, obtain required product (2.6732g, 80%).From methyl alcohol filtrate, obtain the product of other 0.5768g (17%).
1H?NMR(300MHz，DMSO，d 6，TFA?Shake)δ7.86(d，1H，J m＝2.7Hz，Ar H 5)，7.55(d，1H，J m＝2.7Hz，Ar H 7)，7.32(s，1H，C＝C H)，3.94(s，3H，OC H 3)；
Mass spectrum: to [C 11H 8BrNO 4+ H] +Calculated value m/z=298,300; Obs.=298,300.
Reference example 27b:8-bromo-6-methoxyl group-4-oxo-1,4-dihydro-quinaldic acid (4-morpholine-4-base-phenyl)-acid amides.
To 8-bromo-6-methoxyl group-4-oxo-1,4-dihydro-quinaldic acid (reference example 27a) (3.446g, 11.56mmol), TBTU (9.039g, 28.15mmol) and HOBt (3.757g, 27.8mmol) add 4-morpholino aniline (2.733g in the yellow suspension in the 100mL dimethyl formamide, 15.3mmol) and diisopropylethylamine (8.2mL, 50.2mmol).Under nitrogen, the marroon solution that generates was stirred under room temperature 16 hours, during reactant become brown-green and form in a large number and precipitate.Filter reaction mixture is with dimethyl formamide, water and methanol wash solid.Dry under high vacuum, obtain required product (3.09g, 58%) into yellow solid.
1H?NMR(300MHz，DMSO，d 6)δ12.13(s，1H，N H)，10.18(s，1H，C(O)N H)，7.90(d，1H，J m＝2.7Hz，Ar H 5)，7.68(d，2H，J o＝9.0Hz，Ar H 2’& H 6’)，7.63(s，1H，C＝C H)，7.51(d，1H，J m＝2.7Hz，Ar H 7)，7.00(d，2H，J o＝9.0Hz，Ar H 3’& H 5’)，3.94(s，3H，OC H 3)，3.75(t，4H，J＝4.8Hz，OCH H 2CH 2N)，3.10(t，4H，J＝4.8Hz，OCH 2C H 2N)；
Mass spectrum: to [C 21H 20BrN 3O 4+ H] +Calculated value m/z=458,460; Obs.=458,460.
Reference example 27c:8-bromo-6-methoxyl group-4-(2-TMS-oxyethyl group methoxy base)-quinaldic acid's (4-morpholine-4-base-phenyl)-acid amides.
With 8-bromo-6-methoxyl group-4-oxo-1,4-dihydro-quinaldic acid (4-morpholine-4-base-phenyl)-acid amides (reference example 27b) (3.092g, 6.75mmol) (60% suspension is in oil with sodium hydride for yellow suspension in the 40mL N-Methyl pyrrolidone, 0.410g, 10.24mmol) handle.Gas sends and observes heating, and suspension becomes light brown and almost clear and bright.Under nitrogen, reactant was stirred under room temperature 10 minutes.(1.6mL 9.1mmol) causes the solution of the light brown of muddiness a little to add 2-(trimethyl silyl) ethoxymethyl chloride.Reaction mixture is poured in the 300mL water after 4.5 hours in reaction under the room temperature, stirred 15 minutes, store down at 0 ℃ then and spend the night.Separate solid is suspended in the methyl alcohol after filtration, filters once more, and is dry under high vacuum, obtains the product (3.190g, 80%) into yellow solid.
1H?NMR(300MHz，DMSO，d 6)δ10.18(s，1H，C(O)N H)，7.95(d，1H，J m＝2.4Hz，Ar H 7)，7.83(s，1H，Ar H 3)，7.69(d，2H，J o＝9.0Hz，Ar H 2’& H 6’)，7.51(d，1H，J m＝2.7Hz，Ar H 5)，7.00(d，2H，J o＝9.0Hz，Ar H 3’& H 5’)，5.69(s，2H，OCH 2O)，3.95(s，3H，OC H 3)，3.85(t，2H，J＝8.0Hz，OC H 2CH 2Si)，3.75(t，4H，J＝4.7Hz，OC H 2CH 2N)，3.10(t，4H，J＝4.7Hz，OCH 2C H 2N)，0.94(t，2H，J＝8.0Hz，OCH 2C H 2Si)，-0.04(s，9H，Si(C H 3) 3；
Mass spectrum: to [C 27H 34BrN 3O 5Si+H] +Calculated value m/z=588,590; Obs.=588,590.
Reference example 27d:6-methoxyl group-8-(4-methyl-[1,4] Diazesuberane-1-yl)-4-(2-TMS-oxyethyl group methoxy base)-quinaldic acid's (4-morpholine-4-base-phenyl)-acid amides.
To 8-bromo-6-methoxyl group-4-(2-TMS-oxyethyl group methoxy base)-quinaldic acid (reference example 27c) (4-morpholine-4-base-phenyl)-acid amides (1.155g, 1.96mmol), the high piperazine of N-methyl (0.39mL, 3.14mmol) and 4
Figure C0280656200731
Add Pd in the yellow-green colour suspension of molecular sieve in the 30mL dry toluene 2(dba) 2(90.0mg, 0.098mmol) and BINAP (0.358g, 0.58mmol).(2.544g 7.81mmol) handles, and the reddish-brown mixture of the generation color that becomes is more shallow with cesium carbonate.Heating is 17 hours under the following reaction mixture of nitrogen is refluxing.Clear and bright brown solution is cooled to room temperature, concentrates, then through the flash chromatography on silica gel purifying, use 95: 5-50: 50 methylene dichloride: the slow gradient elution of methyl alcohol obtains required product (0.989g, 81%).
1H?NMR(300MHz，DMSO，d 6)δ9.88(s，1H，N H)，7.73(s，1H，Ar H 3)，7.68(d，2H，J o＝8.9Hz，Ar H 2’& H 6’)，7.00(d，2H，J o＝8.9Hz，Ar H 3’& H 5’)，6.94(d，1H，J m＝2.7Hz，Ar H 5)，6.66(d，1H，J m＝2.7Hz，Ar H 7)，5.62(s，2H，OCH 2O)，3.87(s，3H，OC H 3)，3.80(t，2H，J＝8.0Hz，OC H 2CH 2Si)，3.73(t，4H，J＝4.7Hz，OC H 2CH 2N)，3.63(t，2H，J＝5.9Hz，ArNC H 2CH 2CH 2NCH 3)，3.33(bs，2H，ArNC H 2CH 2NCH 3)，3.09(t，4H，J＝4.7Hz，OCH 2C H 2N)，2.97(bs，2H，ArNCH 2C H 2NCH 3)，2.69(bs，2H，ArNCH 2CH 2C H 2NCH 3)，2.35(s，3H，NC H 3)，2.09(bs，2H?ArNCH 2C H 2CH 2NCH 3)，0.94(t，2H，J＝8.0Hz，OCH 2C H 2Si)，-0.03(s，9H，Si(C H 3) 3；
Mass spectrum: to [C 33H 47N 5O 5Si+H] +Calculated value m/z=622; Obs.=622.
Reference example 28
Figure C0280656200741
The preparation of 8-bromo-4-dimethylamino-6-methoxyl group-quinaldic acid (4-morpholine-4-base-phenyl)-acid amides.
Reference example 28a:8-bromo-4-chloro-6-methoxyl group-quinaldic acid (4-morpholine-4-base-phenyl)-acid amides.
With 8-bromo-6-methoxyl group-4-oxo-1,4-dihydro-quinaldic acid (reference example 27b) (1.75mmol) suspension in the 20mL methylene dichloride with oxalyl chloride (1.5mL, 17.2mmol) and catalytic dimethyl formamide (3) handle.Make the violent bubbling of reaction mixture and become more clear and bright.Under refluxing,, be cooled to room temperature, simmer down to light yellow solid (remaining under the nitrogen) reactant heating 2 hours.
In the yellow solution of acyl chlorides in the 20mL methylene dichloride, add 4-morpholino aniline (0.347g, 1.94mmol) and diisopropylethylamine (1.0mL, 6.1mmol).Solution becomes orange and observes gas and send.In 30 minutes, solid begins to precipitate from solution.At room temperature, reactant was stirred 1 hour.Separate solid is dry under high vacuum after filtration, obtains required product (0.406g, 49%).
1H?NMR(300MHz，DMSO，d 6)δ10.15(s，1H，C(O)N H)，8.33(s，1H，Ar H 3)，8.10(d，1H，J m＝2.7Hz，Ar H 7)，7.70(d，2H，J o＝9.0Hz，Ar H 2’& H 6’)，7.56(d，1H，J m＝2.7Hz，Ar H 5)，7.01(d，2H，J o＝9.0Hz，Ar H 3’& H 5’)，4.06(s，3H，OC H 3)，3.75(t，4H，J＝4.8Hz，OC H 2CH 2N)，3.11(t，4H，J＝4.8Hz，OCH 2C H 2N)；
Mass spectrum: to [C 21H 19BrClN 3O 3+ H] +Calculated value m/z=476,478; Obs.=476,478.
Reference example 28b:8-bromo-4-dimethylamino-6-methoxyl group-quinaldic acid (4-morpholine-4-base-phenyl)-acid amides.
Under 100 ℃, in the Parr bomb, with 8-bromo-4-chloro-6-methoxyl group-quinaldic acid (4-morpholine-4-base-phenyl)-acid amides (reference example 28a) (0.1512g, the 0.317mmol) heating of the solution in the 2.0M dimethylamine of 100mL in tetrahydrofuran (THF).Initial pressure is 75-80 pound/square inch, maintains about 60 pounds/square inch then.After 18 hours, reactant is cooled to room temperature, concentrates, drying obtains the crude product into brown solid.Purifying on silica gel, use 100: 0-95: 5 methylene dichloride: the gradient elution of methyl alcohol obtains purified product (0.142g, 92%).
1H?NMR(300MHz，DMSO，d 6)δ10.20(s，1H，C(O)N H)，7.90(d，1H，J m＝2.7Hz，Ar H 5)，7.69(d，2H，J o＝9.0Hz，Ar H 2’& H 6’)，7.60(s，1H，Ar H 3)，7.41(d，1H，J m＝2.7Hz，Ar H 7)，7.01(d，2H，J o＝9.0Hz，Ar H 3’& H 5’)，3.96(s，3H，OC H 3)，3.75(t，4H，J＝4.8Hz，OC H 2CH 2N)，3.10(t，4H，J＝4.8Hz，OCH 2C H 2N)，3.08(s，6H，N(C H 3) 2)；
Mass spectrum: to [C 21H 19BrClN 3O 3+ H] +Calculated value m/z=485,487; Obs.=485,487.
Reference example 29
Figure C0280656200761
6-fluoro-4-methoxyl group-8-(4-methyl-piperazine-1-yl)-quinaldic acid's preparation.
Reference example 29a:8-bromo-6-fluoro-4-methoxyl group-quinaldic acid's methyl esters.
The 8-bromo-6-fluoro-4-oxo-1 that in the 150mL 3 neck round-bottomed flasks that are equipped with reflux exchanger, magnetic stirring apparatus and nitrogen inlet, adds 2.0g (6.76mmol, 1.0 equivalents), 4-dihydro-quinaldic acid's methyl esters.Then this material is dissolved among the NMP of 50mL.At room temperature in solution, carefully add 60% suspension of 300mg (7.44mmol, 1.1 equivalents) sodium hydride in oil then in batches.Occur yellow then, show to have formed negatively charged ion, follow and send hydrogen.Anion solutions is continued to stir 1 hour, add 1.14g, the methyl iodide of 500 μ L (8.04mmol, 1.2 equivalents) by syringe then.Make mixture reaction other 2 hours, and used the careful quencher of 20mL water then.Collect solid after filtration, wash with water then, obtain pure O for 2.1g (98%) the colorless solid material that methylates with 1L water dilution postprecipitation.
Mass spectrum: to [C 12H 9BrFNO 3+ H] +Calculated value m/z=314,316; Obs.=314,316.
Perhaps, in the 100mL 3 neck round-bottomed flasks that are equipped with reflux exchanger, nitrogen inlet and magnetic stirring apparatus, add 350mg (1.17mmol, 1.0 8-bromo-6-fluoro-4-oxo-1 equivalent), the K of 4-dihydro-quinaldic acid's methyl esters and 242mg (1.75mmol, 1.5 equivalents) 2CO 3This material is suspended among the DMSO of 20mL, is heated to 70 ℃ of reactions 1 hour then.Anionic negatively charged ion forms obviously when mixture becomes muddy.Make mixture be cooled to 35 ℃, add 331mg then, the methyl iodide of 145 μ L (2.33mmol, 2.0 equivalents) also continues to stir 2 hours.When this time finishes, determine through LC/MS whether reaction is finished.When finishing, mixture is poured in the 200mL water, collects the solid that forms after filtration, wash with water, after the drying, obtain the O-methylate of 340mg (93%).
Reference example 29b:6-fluoro-4-methoxyl group-8-(4-methyl-piperazine-1-yl)-quinaldic acid's methyl esters.
In the 250mL 3 neck round-bottomed flasks that are equipped with reflux exchanger, magnetic stirring apparatus and nitrogen inlet, add 2.1g (6.68mmol, 1.0 8-bromo-6-fluoro-4-methoxyl group-quinaldic acid's methyl esters (reference example 29a) (122mg equivalent), 0.134mmol, 0.02 three (dibenzalacetones), two palladiums equivalent), 499mg (0.802mmol, 0.12 racemize 2 equivalent), 2 '-two (diphenylphosphino)-1, the 4A molecular sieve of 1 '-dinaphthalene and 1g and 80mL dry toluene.In the suspension that is stirring, add 736mg then, 815 μ L, the 1-methylpiperazine of (7.35mmol, 1.1 equivalents) adds the cesium carbonate of 3.05g (9.35mmol, 1.4 equivalents) subsequently.Then mixture heating up to 80 ℃ reaction 36 hours.When finishing, this time analyzes the monitoring performance by aliquot LC/MS.When reaction is defined as finishing, be cooled to room temperature, filter by Celite pad then, use toluene wash, to remove solid by-product.Through the flash chromatography purifying, the gradient liquid that uses the 5-20% methyl alcohol in methylene dichloride obtains the required product of 2.0g (90%) as eluent.Mass spectrum: to [C 17H 20FN 3O 3+ H] +Calculated value m/z=334; Obs.=334.
Reference example 29c:6-fluoro-4-methoxyl group-8-(4-methyl-piperazine-1-yl)-quinaldic acid.
6-fluoro-4-methoxyl group-8-(4-methyl-piperazine-1-the yl)-quinaldic acid's methyl esters (reference example 29b) that in the 125mL Erlenmeyer flask that contains 30mL THF and 30mL methyl alcohol, adds 2.1g (6.3mmol).Follow to stir in this solution, to add 30mL water down, wherein be dissolved with 291mg (6.9mmol, 1.1 equivalents) lithium hydroxide monohydrate.Make this solution reaction 1 hour, use the quencher of 10mL 2N HCl solution then.Filtering solution then is with the 0.5N HCl solution washing solid of 10mL.Concentrate the filtrate that merges then, obtain 2.15g (95%) solid yellow product into hydrochloride.Mass spectrum: to [C 16H 18FN 3O 3+ H] +Calculated value m/z=320; Obs.=320.
Embodiment 1
Figure C0280656200781
8-(4-methyl isophthalic acid-piperazinyl)-N-[4-(4-morpholinyl) phenyl]-4-oxo-4H-chromene-2-methane amide.
With 8-(4-methyl isophthalic acid-piperazinyl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) (400mg, 1.23mmol) be suspended in anhydrous N, in the dinethylformamide (20ml) and add triethylamine (0.69ml 4.92mmol), obtains clear and bright solution.Be sequentially added into following reagent: I-hydroxybenzotriazole (HOBt (205mg, mol)), O-(1H-benzotriazole-1-yl)-N, N, N ', (TBTU (435mg, 3.1mmol)) adds 4-(dimethylamino) pyridine (25mg) to N '-pentylidene-urea a tetrafluoro borate then.After at room temperature stirring 5 minutes, and 4-(4-morpholinyl) aniline (reference example 21) (220mg, mmol).At room temperature reactant is stirred and spend the night.Vacuum concentrated solution distributes residuum between chloroform/saturated sodium bicarbonate, with chloroform extraction (x3), and dry (MgSO 4), vacuum concentration obtains crude product.
Chromatographyization on silica gel (230-400 order ASTM) and successively with ethyl acetate and 2.5-5% methyl alcohol/chloroform wash-out, what obtain 190mg (% yield) be the 8-of yellow solid (4-methyl isophthalic acid-piperazinyl)-N-[4-(4-morpholinyl) phenyl]-4-oxo-4H-chromene-2-methane amide (mp 217-218 ℃ decomposition and 244-247 ℃ of fusing).LC/MS(M+1)m/z＝449。
Embodiment 2
Figure C0280656200791
2-{1-[4-(2-methoxyl group-phenyl)-piperazine-1-yl]-methanoyl }-8-(4-methyl-piperazine-1-yl)-chromene-4-ketone.
By the identical method of in embodiment 1, using, prepare this compound, obtain yellow solid from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and 1-available on the market (2-methoxyl group-phenyl)-piperazine (Aldrich).MS(M+H)m/z＝463。
Embodiment 3
Figure C0280656200792
2-{1-[4-(1-ethanoyl-2,3-dihydro-1H-indoles-6-yl)-piperazine-1-yl]-methanoyl }-8-(4-methyl-piperazine-1-yl)-chromene-4-ketone.
As preparation among the embodiment 1, from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and 1-(6-piperazine-1-base-2,3-dihydro-indoles-1-yl)-ethyl ketone (reference example 8) prepares this compound, obtains yellow solid.MS(M+H)m/z＝516。
Embodiment 4
Figure C0280656200801
2-chloro-5-(4-{1-[8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-yl]-methanoyl }-piperazine-1-yl)-benzonitrile.
As preparation among the embodiment 1, prepare this compound, obtain yellow solid from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and 2-chloro-5-piperazine-1-base benzonitrile (reference example 9).MS(M+H)m/z＝493。
Embodiment 5
Figure C0280656200802
2-{1-[4-(4-methoxyl group-phenyl)-piperazine-1-yl]-methanoyl }-8-(4-methyl-piperazine-1-yl)-chromene-4-ketone.
As preparation among the embodiment 1, prepare this compound, obtain yellow solid from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and 1-available on the market (4-methoxyl group-phenyl)-piperazine (Aldrich).MS(M+H)m/z＝463。
Embodiment 6
8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (5-furans-2-base-1H-pyrazole-3-yl)-acid amides.
As preparation among the embodiment 1, prepare this compound, obtain yellow solid from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and 5-available on the market furans-2-base-1H-pyrazole-3-yl amine (Maybridge).MS(M+H)m/z＝420。
Embodiment 7
Figure C0280656200812
8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-imidazoles-1-base-phenyl)-acid amides.
As preparation among the embodiment 1, prepare this compound, obtain yellow solid from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and 4-available on the market imidazoles-1-base-aniline (Aldrich).MS(M+H)m/z＝430。
Embodiment 8
Figure C0280656200821
8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-[1,2,3] thiadiazoles-5-base-phenyl)-acid amides.
As preparation among the embodiment 1, from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and 4-[1,2,3] thiadiazoles-5-base-aniline (reference example 10) prepares this compound, obtains yellow solid.MS(M+H)m/z＝448。
Embodiment 9
8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid 4-[1,2,3] thiadiazoles-5-base-benzyl acid amides.
As preparation among the embodiment 1, from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and (Maybridge) available on the market 4-[1,2,3] thiadiazoles-5-base-benzylamine prepares this compound, obtains yellow solid.MS(M+H)m/z＝462。
Embodiment 10
Figure C0280656200831
8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-ethanoyl-piperazine-1-yl)-phenyl]-acid amides.
As preparation among the embodiment 1, from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and 1-[4-(4-amino-phenyl)-piperazine-1-yl]-ethyl ketone (reference example 11) prepares this compound, obtains yellow solid.MS(M+H)m/z＝499。
Embodiment 11
Figure C0280656200832
8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-methylsulfonyl-piperazine-1-yl)-phenyl]-acid amides.
As preparation among the embodiment 1; prepare this compound, obtain yellow solid from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and 4-(4-methylsulfonyl-piperazine-1-yl)-aniline (reference example 12).MS(M+H)m/z＝526。
Embodiment 12
Figure C0280656200841
8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (2-methoxyl group-4-morpholine-4-base-phenyl)-acid amides.
With 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) (0.10g, 0.35mmol), HOBt (0.10g, 0.7mmol), TBTU (0.225g, 0.7mmol), 4-(dimethylamino) pyridine (0.01g, catalytic amount), triethylamine (0.15mL, 1.04mmol) and 2-available on the market methoxyl group-4-morpholine-4-base-aniline (SALOR) (0.08g 0.38mmol) is dissolved in the dimethyl formamide (2.5mL) and at room temperature stirs and spend the night.Add ethyl acetate (150mL), the mixture that water (3x 50mL) washing generates, dry (Na 2SO 4), filtering, vacuum concentration grinds with ether, obtains yellow solid (85mg, 54%).LCMS：m/z＝480.3。
Embodiment 13
Figure C0280656200842
8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (3-chloro-4-morpholine-4-base-phenyl)-acid amides.
As preparation among the embodiment 12, prepare this compound, obtain yellow solid from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and 3-chloro-4-morpholine available on the market-4-base-aniline (Maybridge).(110mg＝73％)，LCMS-m/z＝483.5。
Embodiment 14
Figure C0280656200851
8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-thiomorpholine-4-base-phenyl)-acid amides.
As preparation among the embodiment 12, prepare this compound from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and 4-thiomorpholine-4-base-aniline (reference example 13), obtain yellow solid.(55mg＝38％)，LCMS-m/z＝465.5。
Embodiment 15
Figure C0280656200852
8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (2,5-diethoxy-4-morpholine-4-base-phenyl)-acid amides.
As preparation among the embodiment 12, from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and available on the market 2,5-diethoxy-4-morpholine-4-base-aniline (Aldrich) prepares this compound, obtains yellow solid.(80mg＝50％)，LCMS-m/z＝537.6。
Embodiment 16
Figure C0280656200861
8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-cyano methyl-phenyl)-acid amides.
As preparation among the embodiment 12, prepare this compound from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and (4-amino-phenyl)-acetonitrile available on the market (Aldrich), obtain yellow solid.(65mg＝54％)，LCMS-m/z＝403.5。
Embodiment 17
Figure C0280656200862
8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (1H-indoles-5-yl)-acid amides.
As preparation among the embodiment 12, prepare this compound, obtain yellow solid from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and 1H-available on the market indoles-5-base amine (Aldrich).(35mg＝29％)，LCMS-m/z＝401.6。
Embodiment 18
Figure C0280656200871
8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(1-morpholine-4-base-methanoyl)-phenyl]-acid amides.
As preparation among the embodiment 12, prepare this compound, obtain yellow solid from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and 1-(4-amino-phenyl)-1-morpholine-4-base-ketone (reference example 14).(21mg＝15％)，LCMS-m/z＝477.6。
Embodiment 19
Figure C0280656200872
8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(2,6--dimethyl-morpholine-4-yl)-phenyl]-acid amides.
As preparation among the embodiment 12, from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and 4-available on the market (2,6-dimethyl-morpholine-4-yl)-aniline (Maybridge) prepares this compound, obtains yellow solid.(60mg＝42％)，LCMS-m/z＝477.6。
Embodiment 20
Figure C0280656200881
8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-fluoro-phenoxy group)-phenyl]-acid amides.
As preparation among the embodiment 12, prepare this compound, obtain yellow solid from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and 4-available on the market (4-fluoro-phenoxy group)-aniline (Maybridge).(110mg＝77％)，LCMS-m/z＝475.6。
Embodiment 21
Figure C0280656200882
8-(4-methyl-piperazine-1-yl)-2-(6-morpholine-4-base-benzoxazoles-2-yl)-chromene-4-ketone.
Under nitrogen, (0.532g 1.85mmol) places 25mL 3 neck flasks also to handle with PPA (6g) with 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1).Use prepared intermediate 4-amino-3-hydroxy base morpholine (0.43g (～85% is pure) ,～2mmol) treating mixture then.Mixture is stirred and in oil bath, be heated to 205 ℃ and reacted 3 hours, obtain adopting dark liquid.Mixture is cooled to room temperature and uses the 10mL water treatment, obtain dark solution.With the 1N aqueous sodium hydroxide solution solution slowly is neutralized to pH～7, forms solid.Collect solid, wash with water several times, dry air and vacuum-drying at room temperature obtains the black solid of 0.65g.(10%MeOH is at CHCl for TLC 3In in SiO 2On) at R f～0.5 shows 2 main components and several low R fMinor constituent.At room temperature, use the saturated sodium bicarbonate aqueous solution abrasive solid.Leach, wash with water several times, dry air obtains the Dark grey solid of 0.65g.TLC shows and the previous identical component of finding.Mass spectroscopy shows m/e=447 and shows m/e=446 through negativity ion CI through positivity ion CI.Be dissolved in solid in 2% methyl alcohol in chloroform and with it at the Megabond Elute silicagel column (SiO of 10g 2) go up chromatographyization, use 2% methanol-eluted fractions in chloroform.Fast slightly R fYellow color component concentrate, obtain the yellow solid of 0.0188g.The CI mass spectroscopy is shown as the m/e=447 of base peak through positive ion CI.Solid recrystallization in methyl alcohol, obtain the yellow solid of 0.0178g, fusing point is 158.1-158.8 ℃.Proton N MR (CHCl 3) consistent with required product with the CI mass spectroscopy (through positive ion CI base peak m/z=447 with through negative ion CI base peak m/z=446).
Embodiment 22
8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (2-hydroxyl-4-morpholine-4-base-phenyl)-acid amides.
Under nitrogen, (0.3768g 1.16mmol) places 100mL 3 neck flasks and it is dissolved in 20mL DMF with 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1).Successively with triethylamine (0.49mL, 3.5mmol), the HOBT hydrate (0.36g, 2.3mmol), TBTU (0.74g, 2.3mmol) and DMAP (0.020g) treatment soln.Mixture was stirred 10 minutes, and (0.228g 1.17mmol) handles to use 4-amino-3-hydroxy base morpholine (reference example 21) then.Mixture was stirred 15 minutes, and (0.17mL 1.2mmol) handles to use triethylamine then.Mixture was at room temperature stirred 42 hours, it is joined in the solution of 50mL saturated sodium bicarbonate aqueous solution and 50mL water then.Mixture ethyl acetate extraction 4 times, through dried over mgso, filter, concentrate, obtain the purpureal oil of 0.834 gram.Be dissolved in oil in 2% methyl alcohol in chloroform and add on the silicagel column (diameter 5.5cm, length 10.5cm), successively be used in 2% methyl alcohol in the chloroform and 5% methanol-eluted fractions in chloroform.Concentrate yl moiety, obtain the orange/yellow solid of 0.2031 gram.Solid is dissolved in the methyl alcohol, filters by the intermediate sintering glass funnel, a few ml volumes of simmer down to form solid.Leach solid, use methanol wash, dry air obtains 0.1613 brown solid that restrains, MP 248.4-249.6 ℃.Proton COSY NMR consistent with the CI mass spectroscopy (through positive ion CI m/z=465 with through negative ion CI m/z=463) with required product.
Embodiment 23
8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (5-oxyethyl group-benzothiazole-2-yl)-acid amides.
As preparation among the embodiment 12, prepare this compound, obtain yellow solid from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and 5-oxyethyl group-benzothiazole available on the market-2-base amine (SALOR).(55mg＝39％)，LCMS-m/z＝465.3。
Embodiment 24
Figure C0280656200911
8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-bromo-phenyl)-acid amides.
As preparation among the embodiment 12, prepare this compound from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and 4-bromo-aniline available on the market (Aldrich), obtain yellow solid.(1.0g＝75％)，LCMS-m/z＝442.4。
Embodiment 25
8-(4-methylpiperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid methyl-(4-morpholine-4-base-phenyl) acid amides.
Under nitrogen, (0.1046g 0.2332mmol) places the single neck round-bottomed flask of 10mL with 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides (embodiment 1).Solid is dissolved in the 2.8mL dry DMF.Also (95% of 0.011g 0.44mmol) handles with a sodium hydride at room temperature to stir yellow solution.Mixture sends gas and becomes red solution.Under nitrogen, it was stirred 20 minutes, (0.015mL, 0.033g 0.233mmol) handle to use methyl iodide then.The mixture sealing was also at room temperature stirred 18 hours.
Concentrated reaction mixture obtains dark semi-solid to remove most DMF (35C bathes @0.5mm).It is successively dripped and the processing of 10mL ethyl acetate with several.Through the dried over mgso mixture, filter, concentrate, obtain the yellow glass shape material of 0.0564 gram.With ether abrading glass shape material, leach, dry under high vacuum, obtain the brown solid of 0.0302g, MP 245.0-246.8 ℃.Proton N MR consistent with the CI mass spectroscopy (through positive ion CI m/z=463) with required product.
Embodiment 26
Figure C0280656200921
8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (3-morpholine-4-base-phenyl)-acid amides.
As preparation among the embodiment 12, prepare this compound from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and 3-morpholine-4-base-aniline (reference example 18), obtain yellow solid.(120mg＝86％)，LCMS-m/z＝449.5。
Embodiment 27
Figure C0280656200922
8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (3-cyano group-4-morpholine-4-base-phenyl)-acid amides.
As preparation among the embodiment 12, prepare this compound, obtain yellow solid from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and 5-amino-2-morpholine-4-base-benzonitrile (reference example 15).(120mg＝82％)，LCMS-m/z＝474.5。
Embodiment 28
Figure C0280656200931
8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (3-fluoro-4-morpholine-4-base-phenyl)-acid amides.
As preparation among the embodiment 12, prepare this compound, obtain yellow solid from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and 3-fluoro-4-morpholine-4-base-aniline (reference example 16).(120mg＝83％)，LCMS-m/z＝467.6。
Embodiment 29
Figure C0280656200932
4-[4-(1-[8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-yl]-methanoyl }-amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester.
As preparation among the embodiment 12, prepare this compound, obtain yellow solid from 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 1) and 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (reference example 17).(260mg＝53％)，LCMS-m/z＝548.6。
Embodiment 30
8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazine-1-base-phenyl)-acid amides.
With 4-[4-({ 1-[8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-yl]-methanoyl }-amino)-phenyl]-(160mg 0.3mmol) is dissolved in the ethyl acetate (20mL) and is cooled to 0 ℃ piperazine-1-carboxylic acid tert-butyl ester (embodiment 29).With the slow bubbling of HCl gas 2 minutes.Solid begins precipitation.Add methyl alcohol (3-4mL) to dissolve this solid and other 2 minutes of HCl gas bell.The concentrating under reduced pressure mixture grinds with ether, and vacuum-drying obtains brown solid (100mg, 76%).LCMS/m/z＝448.6。
Embodiment 31
Figure C0280656200942
6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides:
With 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 2) (3.0g, 8.5mmol), TBTU (5.5g, 17mmol), I-hydroxybenzotriazole (2.6g, 17mmol), 4-dimethylaminopyridine (0.05g, catalytic) and 4-available on the market morpholine-4-base-aniline (1.66g 9.3mmol) is dissolved in the dimethyl formamide (100mL).(3.5mL 25mmol) and at room temperature stirs this mixture 17 hours to add triethylamine.The vacuum concentration reaction mixture distributes resistates between chloroform (400mL) and saturated sodium bicarbonate aqueous solution (50mL).Separate organic layer, dry (Na 2SO 4), vacuum filtration and vacuum concentration.Chromatography purification resistates on silica gel is used in the 2-5% methanol-eluted fractions in the chloroform, grinds with ether then, obtains yellow powder.(1.6g＝39％)LCMS-m/z＝479.5mp＝234-236℃。
Embodiment 32
Figure C0280656200951
6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-methylsulfonyl-piperazine-1-yl)-phenyl]-acid amides.
As preparation among the embodiment 1; prepare this compound, obtain yellow solid from 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 2) and 4-(4-methylsulfonyl-piperazine-1-yl)-aniline (reference example 12).GC/MS(EI，M+)m/z＝556。
Embodiment 33
Figure C0280656200961
6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (3-chloro-4-morpholine-4-base-phenyl)-acid amides.
As preparation among the embodiment 12, prepare this compound, obtain yellow solid from 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 2) and 3-chloro-4-morpholine available on the market-4-base-aniline (Maybridge).(45mg＝31％)LCMS-m/z＝513.5。
Embodiment 34
Figure C0280656200962
6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (3-fluoro-4-morpholine-4-base-phenyl)-acid amides.
As preparation among the embodiment 12, prepare this compound, obtain yellow solid from 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 2) and 3-fluoro-4-morpholine-4-base-aniline (reference example 16).(55mg＝61％)，LCMS-m/z＝497.5。
Embodiment 35
Figure C0280656200971
6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (2-methoxyl group-4-morpholine-4-base-phenyl)-acid amides.
As preparation among the embodiment 12, prepare this compound, obtain yellow solid from 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 2) and 2-available on the market methoxyl group-4-morpholine-4-base-aniline (SALOR).(55mg＝38％)，LCMS-m/z＝510.5。
Embodiment 36
Figure C0280656200972
6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-thiomorpholine-4-base-phenyl)-acid amides.
As preparation among the embodiment 12, prepare this compound from 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 2) and 4-thiomorpholine-4-base-aniline (reference example 13), obtain yellow solid.(99mg＝71％)，LCMS-m/z＝495.5。
Embodiment 37
Figure C0280656200981
6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(2,6-dimethyl-morpholine-4-yl)-phenyl]-acid amides.
As preparation among the embodiment 12, from 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 2) and 4-available on the market (2,6-dimethyl-morpholine-4-yl)-aniline (Maybridge) prepares this compound, obtains yellow solid.(70mg＝49％)，LCMS-m/z＝507.5。
Embodiment 38
Figure C0280656200982
6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (3-morpholine-4-base-phenyl)-acid amides.
As preparation among the embodiment 12, prepare this compound from 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 2) and 3-morpholine-4-base-aniline (reference example 18), obtain yellow solid.(80mg＝60％)，LCMS-m/z＝479.5。
Embodiment 39
Figure C0280656200991
6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid 4-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-phenyl }-acid amides.
As preparation among the embodiment 12, from 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 2) and 2-[4-(4-amino-phenyl)-piperazine-1-yl]-ethanol (reference example 19) prepares this compound, obtains yellow solid.(80mg＝60％)。Mp=211.5-212.2 ℃ (decomposition), through positive ion MS-base peak m/z=492 and through negative ion CI at m/z=490.
Embodiment 40
Figure C0280656200992
6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(1-morpholine-4-base-methanoyl)-phenyl]-acid amides.
As preparation among the embodiment 12, prepare this compound, obtain yellow solid from 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 2) and 1-(4-amino-phenyl)-1-morpholine-4-base-ketone (reference example 14).(170mg＝80％)，LCMS-m/z＝507.5。
Embodiment 41
6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (3-cyano group-4-morpholine-4-base-phenyl)-acid amides.
As preparation among the embodiment 12, prepare this compound, obtain yellow solid from 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 2) and 5-amino-2-morpholine-4-base-benzonitrile (reference example 15).(120mg＝57％)，LCMS-m/z＝504.5。
Embodiment 42
Figure C0280656201002
4-[4-(1-[6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-yl]-methanoyl }-amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester.
Under nitrogen, (1.04g 2.93mmol) places 250ml three-necked flask and it is dissolved in 50ml DMF with 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 2).Solution successively use triethylamine (1.22mL, 8.79mmol), the HOBT hydrate (0.90g, 5.9mmol), TBTU (1.88g, 5.9mmol) and DMAP (0.056g 0.46mmol) handles.This mixture was stirred 10 minutes, and (0.81g 2.9mmol) handles with 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (reference example 17) with it then.Mixture was stirred 15 minutes, and (0.41mL 2.9mmol) handles to use triethylamine then.At room temperature mixture was stirred 18 hours, concentrate (1mm Hg pressure, 45C bathes) then, obtain adopting dark liquid.Handle concentrated solution with the 80mL saturated sodium bicarbonate aqueous solution, use ethyl acetate extraction, in organic layer, form the yellow solid that suspends.Leach solid, with the ether washing, wash with water, vacuum-drying (0.1mm Hg Ya Li @25C) obtains 0.36 yellow solid that restrains, M.P.=232.3-232.8C.
Proton N MR consistent with the CI mass spectroscopy (through positive ion CI m/e 578 with through negative ion CI m/e 576) with required product.
Water layer with ethyl acetate extraction twice, through dried over mgso, is filtered, concentrate, obtain the dark semi-solid of 1.35 grams.It is ground and make it at room temperature to place with ether, form solid.Leach solid,, obtain the yellow solid of 0.4816 gram with ether washing, vacuum-drying at room temperature.CI mass spectroscopy consistent with required product (through positive ion CI M/Z=578 with through negative ion CI and M/Z=576).
Embodiment 43
Figure C0280656201011
6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazine-1-base-phenyl)-acid amides.
Under nitrogen, with 4-[4-({ 1-[6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-yl]-methanoyl }-amino)-phenyl]-(0.792 gram 1.37mmol) places 50ml round-bottomed flask and it is dissolved in the 15ml methylene dichloride to piperazine-1-carboxylic acid tert-butyl ester (embodiment 42).With 15ml trifluoroacetic acid (195mmol) treatment soln, obtain dark solution and it was at room temperature stirred 18 hours.It is concentrated, obtain brown foam.Handle foam and at room temperature stir the formation yellow solid with the 30ml saturated sodium bicarbonate aqueous solution.Leach solid, wash with water several times, dry air and under high vacuum (0.1mm Hg pressure) drying, obtain 0.493 the gram yellow solid, M.P.=203.6-204.7C.
Proton N MR and CI mass spectroscopy and required product consistent (through positive ion CI m/z=478 with through negative ion CI m/z=476).
Embodiment 44-54
In Argonaut Quest synthesizer, by parallel acidylate 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazine-1-base-phenyl)-acid amides (embodiment 43), preparation following examples.
Use 11 kinds of different acidylate available on the market and sulfonylation agents, derive the piperazine side chain in a parallel manner.The resin that uses is Argonaut Tech polystyrene polyimide resin.Every 5ml Quest pipe adds the initial N-H piperazine and the 3ml methylene dichloride of 0.010 gram (0.021mmol), adds the PS-DIEA resin (di-isopropyl benzylamine PS resin) of 4 equivalents (0.08mmol) subsequently, to remove HCl.Use acyl chlorides, SULPHURYL CHLORIDE or isocyanic ester (every kind 2 equivalent) then, handle each pipe with some other methylene dichloride subsequently.Tube sealing also at room temperature stirred 3 hours under nitrogen.Open mixture then and also handle, to remove any excessive acidylate or sulfonylation agent with the triple polyimide resins of PS-(primary amine PS resin) of about 4 equivalents (0.08mmol).Mixture is sealed and stirred 1.5 hours, and direct filtration enters phial then, concentrates, and obtains product.Identify product and find that through HPLC purity is greater than 90% by the HPLC mass spectroscopy.Make compound be used for the 5-HTlb experiment to be used to measure 5-HT receptor binding affinity and selectivity.
Embodiment 44
Figure C0280656201031
6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazine-1-yl)-phenyl]-acid amides.
By described above parallel synthetic, prepare this compound from 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazine-1-base-phenyl)-acid amides (embodiment 43) and propionyl chloride available on the market (Aldrich).Through positive ion CI MS-base peak at m/z=534.
Embodiment 45
Figure C0280656201032
6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-ethylsulfonyl-piperazine-1-yl)-phenyl]-acid amides.Through positive ion CI MS-base peak at m/z=570
By described above parallel synthetic, prepare this compound from 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazine-1-base-phenyl)-acid amides (embodiment 43) and ethyl sulfonyl chloride available on the market (Aldrich).
Embodiment 46
Figure C0280656201041
6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-dimethylamino alkylsulfonyl-piperazine-1-yl)-phenyl]-acid amides.
By described above parallel synthetic, prepare this compound from 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazine-1-base-phenyl)-acid amides (embodiment 43) and dimethylamino SULPHURYL CHLORIDE available on the market (Aldrich).Through positive ion CI MS-base peak at m/z=585.
Embodiment 47
Figure C0280656201042
4-[4-(1-[6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-yl]-methanoyl }-amino)-phenyl]-piperazine-1-carboxylic acid dimethylformamide.
By described above parallel synthetic, prepare this compound from 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazine-1-base-phenyl)-acid amides (embodiment 43) and dimethylcarbamyl chloride available on the market (Aldrich).Through positive ion CIMS-base peak at m/z=549.
Embodiment 48
Figure C0280656201051
4-[4-(1-[6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-yl]-methanoyl }-amino)-phenyl]-piperazine-1-carboxylic acid ethanamide.
By described above parallel synthetic, prepare this compound from 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazine-1-base-phenyl)-acid amides (embodiment 43) and ethyl isocyanate available on the market (Aldrich).Through positive ion CI MS-base peak at m/z=549.
Embodiment 49
Figure C0280656201052
4-[4-(1-[6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-yl]-methanoyl }-amino)-phenyl]-piperazine-1-carboxylic acid cyclohexyl amide.
By described above parallel synthetic, prepare this compound from 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazine-1-base-phenyl)-acid amides (embodiment 43) and cyclic isocyanate polyhexamethylene available on the market (Aldrich).Through positivity ion CIMS-base peak at m/z=603.
Embodiment 50
Figure C0280656201061
4-[4-(1-[6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-yl]-methanoyl }-amino)-phenyl]-piperazine-1-carboxylic acid cyclopentyl amide.
By described above parallel synthetic, prepare this compound from 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazine-1-base-phenyl)-acid amides (embodiment 43) and cyclopentyl carbonyl chloride available on the market (Aldrich).Through positivity ion CI MS-base peak at m/z=574.
Embodiment 51
Figure C0280656201062
6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid 4-[4-(1-tetramethyleneimine-1-base-methanoyl)-piperazine-1-yl]-phenyl }-acid amides.
By described above parallel synthetic, prepare this compound from 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazine-1-base-phenyl)-acid amides (embodiment 43) and 1-tetramethyleneimine carbonyl chloride available on the market (Aldrich).Through positivity ion CIMS-base peak at m/z=575.
Embodiment 52
Figure C0280656201071
6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid 4-[4-(propane-2-alkylsulfonyl)-piperazine-1-yl]-phenyl }-acid amides.
By described above parallel synthetic, prepare this compound from 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazine-1-base-phenyl)-acid amides (embodiment 43) and sec.-propyl SULPHURYL CHLORIDE available on the market (Aldrich).Through positivity ion CI MS-base peak at m/z=584.
Embodiment 53
Figure C0280656201072
6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid 4-[4-(2-methyl-propionyl)-piperazine-1-yl]-phenyl }-acid amides.
By described above parallel synthetic, prepare this compound from 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazine-1-base-phenyl)-acid amides (embodiment 43) and isobutyryl chloride available on the market (Aldrch).Through positivity ion CI MS-base peak at m/z=548.
Embodiment 54
Figure C0280656201081
6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid 4-[4-(1-morpholine-4-base-methanoyl)-piperazine-1-yl]-phenyl }-acid amides.
By described above parallel synthetic, prepare this compound from 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazine-1-base-phenyl)-acid amides (embodiment 43) and morpholine available on the market-4-carbonyl chloride (Aldrich).Through positivity ion CI MS-base peak at m/z=591.
Embodiment 55
Figure C0280656201082
6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides.
As preparation in embodiment 1, prepare this compound from 6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 3) and 4-morpholine-4-base-aniline (reference example 20), obtain yellow solid.MS(M+H)m/z＝467。
Embodiment 56
Figure C0280656201091
6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-methylsulfonyl-piperazine-1-yl)-phenyl]-acid amides.
As preparation in embodiment 1; prepare this compound, obtain yellow solid from 6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 3) and 4-(4-methylsulfonyl-piperazine-1-yl)-aniline (reference example 12).MS(M+H)m/z＝544。
Embodiment 57
Figure C0280656201092
6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-ethanoyl-piperazine-1-yl)-phenyl]-acid amides.
As preparation in embodiment 1, from 6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 3) and 1-[4-(4-amino-phenyl)-piperazine-1-yl]-ethyl ketone (reference example 11) prepares this compound, obtains yellow solid.MS(M+H)m/z＝508。
Embodiment 58
Figure C0280656201101
6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (3-chloro-4-morpholine-4-base-phenyl)-acid amides.
With 6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 3) (150mg, 0.43mmol), I-hydroxybenzotriazole (140mg, 0.9mmol), O-(1H-benzotriazole-1-yl)-N, N, N ', N '-pentamethylene-urea a tetrafluoro borate (290mg, 0.9mmol), 4-(dimethylamino) pyridine (10mg, catalytic), (0.2mL 1.5mmol) is dissolved in the dimethyl formamide (2.5mL) with 3-chloro-4-morpholine available on the market-4-base-aniline (Maybridge) triethylamine and stirring is at room temperature spent the night.In the time of 17 hours, add an entry (20mL) and a mixture that generates stirring 15-30 minute.The vacuum filtration mixture washes resistates with water, and dry air obtains yellow powder (220mg=quantitative yield).LC/MS-m/z＝501.5。
Embodiment 59
Figure C0280656201102
6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (3-fluoro-4-morpholine-4-base-phenyl)-acid amides.
As preparation in embodiment 58, prepare this compound, obtain yellow solid (210mg=99%) from 6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 3) and 3-fluoro-4-morpholine-4-base-aniline (reference example 16).LC/MS-m/z＝485.5。
Embodiment 60
Figure C0280656201111
6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (3-cyano group-4-morpholine-4-base-phenyl)-acid amides.
As preparation in embodiment 58, prepare this compound, obtain yellow solid (210mg=99%) from 6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 3) and 5-amino-2-morpholine-4-base-benzonitrile (reference example 15).LC/MS-m/z＝492.5。
Embodiment 61
Figure C0280656201112
6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(1-morpholine-4-base-methanoyl)-phenyl]-acid amides.
As preparation in embodiment 58, prepare this compound from 6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 3) and 1-(4-amino-phenyl)-1-morpholine-4-base-ketone (reference example 14), obtain yellow solid (220mg=quantitative yield).LC/MS-m/z＝495.5。
Embodiment 62
Figure C0280656201121
6-methyl-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides.
As preparation in embodiment 1, prepare this compound from 6-methyl-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 4) and 4-morpholine-4-base-aniline (reference example 20), obtain yellow solid.LC/MS-m/z＝463.6。
Embodiment 63
Figure C0280656201122
6-methyl-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(1-morpholine-4-base-methanoyl)-phenyl]-acid amides.
As preparation in embodiment 1, prepare this compound, obtain yellow solid from 6-methyl-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 4) and 1-(4-amino-phenyl)-1-morpholine-4-base-ketone (reference example 14).LC/MS-m/z＝491.6。
Embodiment 64
Figure C0280656201131
6-methyl-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (3-fluoro-4-morpholine-4-base-phenyl)-acid amides.
As preparation in embodiment 1, prepare this compound, obtain yellow solid from 6-methyl-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 4) and 3-fluoro-4-morpholine-4-base-aniline (reference example 16).LC/MS-m/z＝504.5。
Embodiment 65
Figure C0280656201132
6-chloro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides.
As preparation in embodiment 1, prepare this compound from 6-chloro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 5) and 4-morpholine-4-base-aniline (reference example 20), obtain yellow solid.LC/MS-m/z＝483.3。
Embodiment 66
Figure C0280656201141
5-methyl-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides.
As preparation in embodiment 1, prepare this compound from 5-methyl-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 6) and 4-morpholine-4-base-aniline (reference example 20), obtain yellow solid.(116mg＝84％)LCMS-m/z＝463.5。
Embodiment 67
Figure C0280656201142
5-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides.
As preparation in embodiment 1, prepare this compound from 5-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 7) and 4-morpholine-4-base-aniline (reference example 20), obtain yellow solid (149mg=50%) LCMS-m/z=479.4.
Piperazine-1-base-phenyl amide that following additional embodiments replaces in conjunction with structurally similar to embodiment 44-54 4-.
Embodiment 68
Figure C0280656201151
6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid 4-[4-(3-hydroxyl-propionyl)-piperazine-1-yl]-phenyl }-acid amides.
(1.5 grams 2.12mmol) place the CH that contains 50mL with 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazine-1-base-phenyl)-acid amides (embodiment 43) 2Cl 2The 100mL flask in.With triethylamine (4 equivalents, 1.2mL, 8.5mmol) and β-propionyl lactone (0.2mL 3.2mmol) handles this suspension and reactant was at room temperature stirred 2 hours, is heated to 50 ℃ then and reacts 2 hours.Add the other b-propionyl lactone of 0.8mL then and reactant was heated other 4 hours.Make reactant be cooled to room temperature, concentrate then (1mm Hg pressure).Handle concentrated solution with saturated sodium bicarbonate aqueous solution, collect the solid that generates through vacuum filtration.Chromatography purification resistates on silica gel is used in 2% methanol-eluted fractions in the chloroform, concentrates then (1mm Hg pressure).Grind with ether then, follow, obtain yellow powder (100mg) LCMS-m/z 550, mp=195-197 ℃ 50 ℃ of following high vacuum dry 48 hours.
Embodiment 69
Figure C0280656201152
4-[4-(1-[6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-yl]-methanoyl }-amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester.
Method according to embodiment 42, prepare this compound from 6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 3) and 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (reference example 17), obtain the yellow powder LCMS-m/z=556 of (1.65 grams, 64%); Mp=219-220 ℃.
Embodiment 70
Figure C0280656201161
4-[4-({ 1-[6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazine-1-base-phenyl)-acid amides.
Use the method for embodiment 43, from as 4-[4-({ 1-[6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-yl]-methanoyl }-amino)-phenyl of preparation among embodiment 69]-piperazine-1-carboxylic acid tert-butyl ester prepares this compound, obtains yellow solid LCMS-m/z=466.
Embodiment 71
6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-ethylsulfonyl-piperazine-1-yl)-phenyl]-acid amides.
({ (4.0 grams 5.77mmol) place the CH that contains 50mL to 1-[6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazine-1-base-phenyl)-acid amides two (trifluoroacetate) (as the free acid of the compound of preparation in embodiment 70) with 4-[4- 2Cl 2And in the flask of triethylamine (3.2mL and 23mmol) and in 15 minutes, add ethyl sulfonyl chloride in batches (0.6mL, 6.35mmol) (each 0.1mL) made it at room temperature to stir 20 hours.Concentrate (1mm Hg pressure) reactant, add saturated sodium bicarbonate aqueous solution then and use CHCl 3Extract.Merge organic moiety, with the saturated sodium-chloride washing, dry (MgSO 4), concentrate (1mm Hg pressure), obtain yellow solid, with its recrystallization from methyl alcohol, obtain the product LCMS-m/z=558 of 1.33 grams; Mp=233-234 ℃.
Embodiment 72
Figure C0280656201171
6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazine-1-yl)-phenyl]-acid amides.
({ (0.69 gram 1.00mmol) places the CH that contains 25mL to 1-[6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazine-1-base-phenyl)-acid amides two (trifluoroacetate) (as the free acid of the compound of preparation in embodiment 70) with 4-[4- 2Cl 2And in the flask of triethylamine (0.56mL and 4mmol) and add propionyl chloride (0.95mL 1.1mmol), at room temperature stirred reactant 20 hours.Chromatography purification resistates on silica gel is used in 2% methanol-eluted fractions in the chloroform, concentrates then (1mm Hg pressure).Use the ether grinding residues, use CHCl then 3Dissolving and concentrated CHCl 3,, obtain yellow powder (260mg) LCMS-m/z 522 45 ℃ of following high vacuum dry 48 hours.
Embodiment 73
Figure C0280656201181
6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid 4-[4-(3-hydroxyl-propionyl)-piperazine-1-yl]-phenyl }-acid amides.
Use the above method of in embodiment 68, describing; prepare this compound from 6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazine-1-base-phenyl)-acid amides and β-propionyl lactone; obtain the yellow powder LCMS-m/z=538 of 65mg, mp=195-199 ℃.
Below illustrate the chromene-2-" contrary acid amides (reverse amide) " (or the chromene-2-base-benzamide that replaces) of replacement.
Embodiment 74
Figure C0280656201182
N-[8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-yl]-4-morpholine-4-base-benzamide.
Under 65 ℃; with 8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride reference example 1 (227mg; 0.69mmol), triethylamine (2 equivalents; 1.389mmol; 0.193mL) and diphenyl phosphoryl azide (0.69mmol 0.15mL) stirred in toluene (10mL) 30 minutes.Make reactant be cooled to 22 ℃ and add 4-morpholino phenylformic acid (0.7mmol, 145mg), other triethylamine (0.051mL, 0.7mmol) and CH 3CN (5mL) and reactant is heated to refluxed 1 hour.Concentration response thing (1mm Hg pressure) also distributes resistates between 1N methylsulfonic acid and ether.Use solid K then 2CO 3Alkalization acid layer also extracts CHCl to product 3In.Dry (MgSO 4) organic layer, concentrating under reduced pressure, remaining yellow solid is further purified it with silica gel column chromatography, use CHCl 3-at CHCl 3In 4%CH 3The OH wash-out.Concentrate the part that contains product, obtain the product LC/MS-m/z=449 of 13mg.
The enantiomorph of 8-(4-methyl-piperazine-1-yl)-chromene-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides.
Embodiment 75
Figure C0280656201191
Racemize-8-(4-methyl-piperazine-1-yl)-chroman-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides.
Racemize-8-(4-methyl isophthalic acid-piperazine-1-yl)-chroman-2-carboxylic acid hydrochloride (embodiment 75a) (1.04mmol) is dissolved in anhydrous N, in the dinethylformamide (40ml) and be sequentially added into following reagent: HOBt (0.17g, 1.14mmol), TBTU (0.37g, 1.14mmol) and triethylamine (0.6ml, 4.2mmol).After at room temperature stirring 5 minutes, (0.185g at room temperature stirs 1.14mmol) and with reactant and to spend the night to add 4-(4-morpholinyl) aniline (reference example 20).
Vacuum concentrated solution distributes residuum between chloroform/saturated sodium bicarbonate, with chloroform extraction (x3), and dry (MgSO 4) and vacuum concentration, obtain crude product.
With crude product chromatographyization on Waters Delta Prep 4000, use 1PrepPak post (Porasil 37-55 μ m 125
Figure C0280656201192
), with 2.5% methyl alcohol/chloroform wash-out.Collect product, obtain yellow oil.In oil, add ethyl acetate.Solution is refluxed, and yellow solid is filtered in cooling then, obtains racemize-8-(4-methyl-piperazine-1-yl)-chroman-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides (mp 215-216 ℃) of 55mg (12% yield).Mother liquor contains 76mg, and it is directly used in chiral separation described below.LC/MS(M+1)m/z＝437。
Embodiment 75a
Racemize-8-(4-methyl isophthalic acid-piperazine-1-yl)-chroman-2-carboxylic acid hydrochloride.
(0.74g 2.3mmol) is dissolved in the glacial acetic acid (50ml) and adds 10% palladium carbon (80mg) with 8-(4-methyl isophthalic acid-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid, ethyl ester (reference example 1).Under 70 ℃, in Parr device (50 pounds/square inch), with mixture hydrogenation 3 hours.Then, add dense HCl and 10% palladium carbon (100mg) and make mixture under 70 ℃ once more through hydrogenation (50 pounds/square inch) 1 hour.Make the reactant cooling, filtering catalyst and vacuum concentrated solution.Add toluene and concentrated solution repeatedly, obtain being foamy racemize-8-(4-methyl isophthalic acid-piperazine-1-yl)-chroman-2-carboxylic acid hydrochloride, it need not be further purified and promptly can be used for next step reaction.LC/MS(M+1)m/z＝277。
Embodiment 76
(+)-8-(4-methyl-piperazine-1-yl)-chroman-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides.
By using chiral column (ChiralPak AD, 5cm * 50cm, 20 μ), separation of racemic-8-(4-methyl-piperazine-1-yl)-chroman-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides (embodiment 75) (0.52g, enantiomorph 1.19mmol).With fast (+) isomer of 45% isopropanol/hexane wash-out (embodiment 76) and with slow (-) isomer of 75% isopropanol/hexane wash-out (embodiment 77).
Obtain fast (+) isomer (embodiment 76) (250mg, mp 206-207 ℃, α for white solid D+ 92.66 in methylene dichloride).LC/MS(M+1)m/z＝437。
Embodiment 77
Figure C0280656201211
(-)-8-(4-methyl-piperazine-1-yl)-chroman-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides.
By using chiral column (ChiralPak AD, 5cm * 50cm, 20 μ), separation of racemic-8-(4-methyl-piperazine-1-yl)-chroman-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides (embodiment 75) (0.52g, enantiomorph 1.19mmol).With fast (+) isomer of 45% isopropanol/hexane wash-out (embodiment 76) and with slow (-) isomer of 75% isopropanol/hexane wash-out (embodiment 77).
Obtain being slow (-) isomer of pale red purple solid (embodiment 77) (260mg, mp205.5-207 ℃, α D-91.08 in methylene dichloride).LC/MS(M+1)m/z＝437。
The enantiomorph of 8-(4-methyl-piperazine-1-yl)-4-oxo-chroman-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides.
Embodiment 78
Figure C0280656201212
Racemize-8-(4-methyl-piperazine-1-yl)-4-oxo-chroman-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides.
Racemize-8-(4-methyl isophthalic acid-piperazine-1-yl)-4-oxo-chroman-2-carboxylic acid hydrochloride (embodiment 78a) (1.04mmol) is dissolved in anhydrous N, in the dinethylformamide (40ml) and be sequentially added into following reagent: HOBt (0.17g, 1.14mmol), TBTU (0.37g, 1.14mmol) and triethylamine (0.6ml, 4.2mmol).After at room temperature stirring 5 minutes, (0.185g at room temperature stirs 1.14mmol) and with reactant and to spend the night to add 4-(4-morpholinyl) aniline (reference example 20).
Vacuum concentrated solution distributes residuum between chloroform/saturated sodium bicarbonate, with chloroform extraction (x3), and dry (MgSO 4), vacuum concentration obtains crude product.
With crude product chromatographyization on Waters Delta Prep 4000, use 1PrepPak post (Porasil 37-55 μ m 125 ), with 2.5% methyl alcohol/chloroform wash-out.Collect product, obtain yellow oil.In oil, add ethyl acetate.Solution is refluxed, filter the refrigerative yellow solid then, obtain racemize-8-(4-methyl-piperazine-1-yl)-4-oxo-chroman-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides (mp 215-216 ℃) of 55mg (12% yield).Mother liquor contains 76mg, and it is directly used in chiral separation described below.LC/MS(M+1)m/z＝451。
Embodiment 78a
Racemize-8-(4-methyl isophthalic acid-piperazine-1-yl)-4-oxo-chroman-2-carboxylic acid hydrochloride.
(0.33g 1.04mmol) is dissolved among the 6M HCl (20ml) and is heated to 100 ℃ and reacted 1.5 hours with racemize-8-(4-methyl isophthalic acid-piperazinyl)-4-oxo-chroman-2-carboxylic acid, ethyl ester (embodiment 78b).The cooling reactant.Vacuum concentrated solution also adds dry toluene (x3), solution vacuum concentration once more, obtain being yellow foamy racemize-8-(4-methyl isophthalic acid-piperazine-1-yl)-4-oxo-chroman-2-carboxylic acid hydrochloride (0.44g, quantitative yield), it is directly used in next step reaction.LC/MS(M+1)m/z＝291。
Embodiment 78b
Racemize-8-(4-methyl isophthalic acid-piperazine-1-yl)-4-oxo-chroman-2-carboxylic acid, ethyl ester.
With racemize-8-(4-methyl isophthalic acid-piperazine-1-yl)-4-hydroxyl-chroman-2-carboxylic acid, ethyl ester (embodiment 78c) (0.43g, 1.3mmol) be dissolved in the anhydrous methylene chloride (35ml) and add Manganse Dioxide (1.2g, 13mmol).Reactant at room temperature stirred spend the night.
By diatomite filtration reactant and solvent removed in vacuo, obtain racemize-8-(4-methyl isophthalic acid-piperazine-1-yl)-4-oxo-chroman-2-carboxylic acid, ethyl ester (0.37g, 86% yield) into white solid, it is directly used in next step reaction.GC/MS(EI，M+)m/z＝318。
Embodiment 78c
Racemize-8-(4-methyl isophthalic acid-piperazine-1-yl)-4-hydroxyl-chroman-2-carboxylic acid, ethyl ester.
(0.48g 1.5mmol) is dissolved in the glacial acetic acid (50ml) and adds 10% palladium carbon (100mg) with 8-(4-methyl isophthalic acid-piperazine-1-yl)-4-oxo-4H-chroman-2-carboxylic acid, ethyl ester (reference example 1).With mixture in the Parr device (50 pounds/square inch) in 70 ℃ of following hydrogenations 3 hours.
Make the reactant cooling, filtering catalyst and vacuum concentrated solution.In residuum, add ethyl acetate/saturated sodium bicarbonate, with ethyl acetate extraction mixture (x3), dry (MgSO 4) and desorb, obtain racemize-8-(4-methyl isophthalic acid-piperazine-1-yl)-4-hydroxyl-chroman-2-carboxylic acid, ethyl ester (0.43g, 90% yield) into yellow oil.GC/MS(EI，M+)m/z＝320。
Embodiment 79
Figure C0280656201231
8-(4-methyl-piperazine-1-yl)-4-oxo-chroman-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides (isomer of rapid movement).
By using chiral column (ChiralPak AD, 5cm * 50cm, 20 μ), separation of racemic-8-(4-methyl-piperazine-1-yl)-4-oxo-chroman-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides (embodiment 78) (100mg, enantiomorph 0.22mmol).Gradient liquid wash-out isomer with the 35-55% isopropanol/hexane.Obtain fast isomer (40mg, 216 ℃ of decomposition of mp) for light yellow solid.LC/MS(M+1)m/z＝451。
Embodiment 80
Figure C0280656201241
8-(4-methyl-piperazine-1-yl)-4-oxo-chroman-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides (isomer of microinching).
By using chiral column (ChiralPak AD, 5cm * 50cm, 20 μ), separation of racemic-8-(4-methyl-piperazine-1-yl)-4-oxo-chroman-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides (100mg, enantiomorph 0.22mmol).Gradient liquid wash-out isomer with the 35-55% isopropanol/hexane.Obtain slow isomer (32mg, 215 ℃ of decomposition of mp) for pale solid.LC/MS(M+1)m/z＝451。
Embodiment 81
Figure C0280656201242
4-[4-(1-[6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-yl]-methanoyl }-amino)-phenyl]-piperazine-1-carboxylic acid buserelin:
With 6-fluoro-8-(4-methyl-piperazine-1-yl)-(150mg 0.216mmol) places the CH that contains 10mL to 4-oxo-4H-chromene-2-carboxylic acid (4-piperazine-1-base-phenyl)-acid amides (embodiment 71) 2Cl 2The 50mL flask in.With triethylamine (0.1mL, 0.67mmol) and ethyl isocyanate (0.21mL, 18.7mg 0.26mmol) handle this suspension and at room temperature reactant being stirred 18 hours.Concentration response thing (1mm Hg pressure) and the chromatography purification concentrated solution on silica gel.Be used in 1% methanol-eluted fractions in the chloroform, concentrate then (1mm Hg pressure).Grind with ether then, follow, obtain yellow powder (79mg) LCMS-AP+537.4, mp=236-238 ℃ 50 ℃ of following high vacuum dry 48 hours.
Embodiment 82
Figure C0280656201251
6-methoxyl group-8-(4-methyl-[1,4] Diazesuberane-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides:
In being equipped with the 100mL round-bottomed flask of nitrogen inlet and magnetic stirring apparatus, add 327mg (0.89mmol, 1.0 6-methoxyl group-8-equivalent) (4-methyl-[1,4] Diazesuberane-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (reference example 23).This material is dissolved among the DMF of 20mL, adds the 4-morpholino aniline of 189mg (1.06mmol, 1.2 equivalents) then.In the solution that is stirring, add the TBTU of 568mg (1.77mmol, 2.0 equivalents) and the HOBT of 239mg (1.77mmol, 2.0 equivalents) simultaneously rapidly.At this moment,, in 5 minutes, add 457mg, 577 μ L (25.2mmol, 4.0 equivalents) by syringe.Reactant was at room temperature stirred 18 hours, under high vacuum, on rotatory evaporator, concentrate then, to remove DMF.Use the methyl alcohol grinding residues, reclaim the crude product solid after filtration.Through these resistatess of flash chromatography purifying, the gradient liquid that uses the 5-10% methyl alcohol in methylene dichloride is as eluent then.Concentrate the material of the wash-out that obtains from chromatography, dry under high vacuum, be suspended in the methylene dichloride, through K 2CO 3Drying concentrates, and crystallization from methyl alcohol then obtains the free alkali into the pure products of the yellow solid of 345mg (79%).Mass spectrum: to [C 27H 32FN 4O 5+ H] +Calculated value m/z=393; Obs.=393.
Embodiment 83
Figure C0280656201261
6-oxyethyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides:
In being equipped with the 100mL flask of nitrogen inlet and magnetic stirring apparatus, add the 4-morpholino aniline of 133mg (.748mmol, 1.1 equivalents), it is dissolved in the methylene dichloride of 20mL then.In this mixture, add 290mg then, 367 μ L (2.24mmol, 3.3 ethyl diisopropyl amine equivalent), the solution that adds 6-oxyethyl group-8-(4-methyl-piperazine-1-the yl)-4-oxo-4H-chromene-2-carbonyl chloride (reference example 23) of the 250mg (0.68mmol, 1.0 equivalents) in the methylene dichloride that has been dissolved in 10ml subsequently.Reactant was stirred 4 hours, do not see having product further to form through LC/MS afterwards.On rotatory evaporator, concentrate the crude product reactant, grind with 10mL methyl alcohol then.Collect the crude product solid after filtration,, use the gradient liquid wash-out of the 2-20% methyl alcohol in methylene dichloride then through flash chromatography.Recrystallization from methylene dichloride and hexane obtains 55mg (16%) and is the pure product of yellow solid.Mass spectrum: to [C 27H 32N 4O 5+ H] +Calculated value m/z=493; Obs.=493.
Embodiment 84
6-oxyethyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazine-1-yl)-phenyl]-acid amides:
By the similar method of using with preparation 4-morpholino anils, from 250mg (0.68mmol, 1.0 6-oxyethyl group-8-equivalent) (4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carbonyl chloride (reference example 23) and 175mg (0.748mmol, 1.1 1-[4-equivalent) (4-amino-phenyl)-piperazine-1-yl]-third-1-ketone prepares this compound, obtains 45mg (12%) and be the required product of yellow solid.
Mass spectrum: to [C 30H 37N 5O 5+ H] +Calculated value m/z=548; Obs.=548.
Embodiment 85
Figure C0280656201271
6-methoxyl group-4-oxo-8-piperazine-1-base-4H-chromene-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides:
In the 50mL round-bottomed flask that is equipped with reflux exchanger, nitrogen inlet and magnetic stirring apparatus, add 50mg (0.115mmol, 1.0 1 of 6-methoxyl group-8-equivalent) (4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides (embodiment 31) and 10mL, the 2-ethylene dichloride.In this solution, add 49mg by syringe then, the chloroformic acid 1-chloro-ethyl ester of 37 μ L (0.345mmol, 3.0 equivalents).Form precipitation, show the formation intermediate.Reactant is heated to refluxed 3 days, carry out aliquot analysis through LC/MS and only show and formed micro-product.At this moment, the sodium iodide that in the reactant that refluxes, adds 52mg (0.345mmol, 3.0 equivalents).LC/MS analyzes and shows formation demethylation product in other 5 days gradually then.Cool off reactant then, concentrate on rotatory evaporator, the suspension of conduct in containing the methylene dichloride of methyl alcohol is through K then 2CO 3Drying is removed solid after filtration, subsequently the solution flash chromatographyization, uses the gradient liquid wash-out of the 5-20% methyl alcohol in methylene dichloride, and obtaining 34mg (64%) is reddish solid pure products.
Mass spectrum: to [C 25H 28N 4O 5+ H] +Calculated value m/z=465; Obs.=465.
Embodiment 86
Figure C0280656201281
6-hydroxyl-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides:
In the 50mL round-bottomed flask that is equipped with reflux exchanger, nitrogen inlet and magnetic stirring apparatus, add 6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides (embodiment 31) of 50mg (0.115mmol, 1.0 equivalents) and the methylene dichloride of 20mL.The 1N solution of boron tribromide in methylene dichloride that in this solution, adds 1mL.Reactant was at room temperature stirred 2.5 days, show through LC/MS this moment and finish.Concentration response thing on rotatory evaporator adds methyl alcohol then.Concentrated methyl alcohol also repeats 5 times, up to BBr 3Be removed as HBr and boric acid trimethylammonium ester.The solid hydrogen bromate resistates that obtains is shown as＞85% pure products through LC/MS.Mass spectrum: to [C 25H 28N 4O 5+ H] +Calculated value m/z=465; Obs.=465.
Embodiment 87 (method 1)
Figure C0280656201282
6-methoxyl group-8-(4-methyl-[1,4] Diazesuberane-1-yl)-4-oxo-1,4-dihydro-quinaldic acid (4-morpholine-4-base-phenyl)-acid amides.
To 6-methoxyl group-8-(4-methyl-[1,4] Diazesuberane-1-yl)-4-oxo-1,4-dihydro-quinaldic acid (2.10mmol) (reference example 25b) and diisopropylethylamine (1.4mL, 8.6mmol) add TBTU (1.40g in the solution in the 34mL dimethyl formamide, 4.36mmol) and HOBt (0.588g, 4.35mmol), add subsequently 4-morpholino aniline (0.463g, 2.60mmol).Under nitrogen, the dark-brown solution that generates was stirred under room temperature 19 hours.Vacuum concentration reactant and the crude product that generates with the methylene chloride dissolving.Filter the mixture that generates, obtain some and be the product of yellow solid.Concentrated filtrate also distributes between methylene dichloride and saturated sodium bicarbonate aqueous solution.Wash organic layer with saturated sodium bicarbonate, dry (Mg 2SO 4), vacuum concentration obtains brown solid.It is suspended in the methyl alcohol, filters, obtain required product (0.714g, 69%) into yellow solid.
1H?NMR(300MHz，DMSO，d 6)δ9.97(bs，1H，N H)，7.67(d，2H，J o＝8.8Hz，Ar H 2’& H 6’)，7.47(bs，1H，Ar H 5)，7.00(s，1H，C＝C H)，6.99(d，2H，J o＝8.8Hz，Ar H 3’& H 5’)，6.71(bs，1H，Ar H 7)，3.85(s，3H，OC H 3)，3.75(t，4H，J＝4.6Hz，OC H 2CH 2N)，3.70(bs，2H，ArNC H 2CH 2CH 2NCH 3)，3.55(bs，2H，ArNC H 2CH 2NCH 3)，3.09(t，4H，J＝4.6Hz，OCH 2C H 2N)，2.95(bs，2H，ArNCH 2C H 2NCH 3)，2.73(bs，2H，ArNCH 2CH 2C H 2NCH 3)，2.36(s，3H，NC H 3)，2.07(bs，2H?ArNCH 2C H 2CH 2NCH 3)；
Mass spectrum: to [C 27H 33N 5O 4+ H] +Calculated value m/z=492; Obs.=492.
Embodiment 87 (method 2)
Figure C0280656201291
6-methoxyl group-8-(4-methyl-[1,4] Diazesuberane-1-yl)-4-oxo-1,4-dihydro-quinaldic acid (4-morpholine-4-base-phenyl)-acid amides.
With 6-methoxyl group-8-(4-methyl-[1,4] Diazesuberane-1-yl)-4-(2-TMS-oxyethyl group methoxy base)-(0.989g, 1.59mmol) solution in 20mL methyl alcohol is poured in the 300mL 0.05N hydrochloric acid quinaldic acid's (4-morpholine-4-base-phenyl)-acid amides (reference example 27d).Deep yellow solution clear and bright in 5 minutes becomes muddiness.Mixture was at room temperature stirred 45 minutes, be adjusted to pH 7 with 10% sodium hydroxide then.The yellow mercury oxide that separate to generate after filtration washes with water and dry under high vacuum, obtains the required product (0.629g, 80%) into yellow solid.
1H?NMR(300MHz，DMSO，d 6)δ9.97(bs，1H，C(O)N H)，7.67(d，2H，J o＝8.8Hz，Ar H 2’& H 6’)，7.47(bs，1H，Ar H 5)，7.00(s，1H，C＝C H)，6.99(d，2H，J o＝8.8Hz，Ar H 3’& H 5’)，6.71(bs，1H，Ar H 7)，3.85(s，3H，OC H 3)，3.75(t，4H，J＝4.6Hz，OC H 2H 2N)，3.70(bs，2H，ArNC H 2CH 2CH 2NCH 3)，3.55(bs，2H，ArNC H 2CH 2NCH 3)，3.09(t，4H，J＝4.6Hz，OCH 2C H 2N，2.95(bs，2H，ArNCH 2C H 2NCH 3)，2.73(bs，2H，ArNCH 2CH 2C H 2NCH 3)，2.36(s，3H，NC H 3)，2.07(bs，2H?ArNCH 2C H 2CH 2NCH 3)；
Mass spectrum: to [C 27H 33N 5O 4+ H] +Calculated value m/z=492; Obs.=492.To C 27H 33N 5O 4.1.0 equivalent HCl.0.3 equivalent H 2O analysis theories calculated value C 60.79H 6.54N13.13.Measured value C 60.82H 6.53N 13.17.
Embodiment 88
6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-1,4-dihydro-quinaldic acid (4-morpholine-4-base-phenyl)-acid amides.
According to method, from 8-bromo-6-methoxyl group-4-(2-TMS-oxyethyl group methoxy base)-quinaldic acid's methyl esters (reference example 24c) preparation title compound in reference example 25a and description in embodiment 87 (method 1).Obtain yellow solid.Mass spectrum: to [C 26H 31N 5O 4+ H] +Calculated value m/z=478; Obs.478.
Embodiment 89
6-methoxyl group-8-(4-methyl-piperazine-1-yl)-4-oxo-1,4-dihydro-quinaldic acid [4-(4-propionyl-piperazine-1-yl)-phenyl]-acid amides.
Except from 1-[4-(4-amino-phenyl)-piperazine-1-yl]-third-1-ketone forms acid amides, according to method, from 8-bromo-6-methoxyl group-4-(2-TMS-oxyethyl group methoxy base)-quinaldic acid's methyl esters (reference example 24c) preparation title compound in reference example 25a and description in embodiment 87 (method 1).Obtain yellow solid.Mass spectrum: to [C 29H 36N 6O 4+ H] +Calculated value m/z=533; Obs.533.
Embodiment 90
Figure C0280656201312
6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-1,4-dihydro-quinaldic acid (4-morpholine-4-base-phenyl)-acid amides.
The method that use is described in embodiment 87 (method 1), from 6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-1,4-dihydro-quinaldic acid's hydrochloride (reference example 26) preparation title compound.After the chromatographyization, crystallization from methyl alcohol then obtains the pure product into 150mg (55%) yellow solid.Mass spectrum: to [C 25H 28FN 5O 3+ H] +Calculated value m/z=466; Obs.=466.
Embodiment 91
Figure C0280656201321
6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-1,4-dihydro-quinaldic acid [4-(4-propionyl-piperazine-1-yl)-phenyl]-acid amides.
The method that use is described in embodiment 87 (method 1), from 6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-1,4-dihydro-quinaldic acid's hydrochloride (200mg, 0.59mmol) (reference example 26) preparation title compound.31% yield.Mass spectrum: to [C 28H 33FN 6O 3+ H] +Calculated value m/z=521; Obs.=521.
Embodiment 92
8-[(2-dimethylamino-ethyl)-methyl-amino]-6-methoxyl group-4-oxo-1,4-dihydro-quinaldic acid (4-morpholine-4-base-phenyl)-acid amides.
According to method in reference example 25a and description in embodiment 87 (method 2), use N, N, N '-trimethylammonium quadrol is used for the Pd catalyzed coupling, from 8-bromo-6-methoxyl group-4-(2-TMS-oxyethyl group methoxy base)-quinaldic acid's methyl esters (reference example 24c) preparation title compound.Obtain yellow solid.Mass spectrum: to [C 26H 33N 5O 4+ H] +Calculated value m/z=480; Obs.=480.
Embodiment 93
Figure C0280656201331
8-[(3-dimethylamino-propyl group)-methyl-amino]-6-methoxyl group-4-oxo-1,4-dihydro-quinaldic acid (4-morpholine-4-base-phenyl)-acid amides.
According to method in reference example 25a and description in embodiment 87 (method 2), use N, N, N '-trimethylammonium-1, the 3-propylene diamine is used for the Pd catalyzed coupling, from 8-bromo-6-methoxyl group-4-(2-TMS-oxyethyl group methoxy base)-quinaldic acid's methyl esters (reference example 24c) preparation title compound.Obtain yellow solid.Mass spectrum: to [C 27H 35N 5O 4+ H] +Calculated value m/z=494; Obs.=494.
Embodiment 94
Figure C0280656201332
8-((3R)-(+)-3-dimethylamino-tetramethyleneimine-1-yl)-6-methoxyl group-4-oxo-1,4-dihydro-quinaldic acid (4-morpholine-4-base-phenyl)-acid amides.
According to method in reference example 25a and description in embodiment 87 (method 2), use (3R)-(+)-3-(dimethylamino) tetramethyleneimine to be used for the Pd catalyzed coupling, from 8-bromo-6-methoxyl group-4-(2-TMS-oxyethyl group methoxy base)-quinaldic acid's methyl esters (reference example 24c) preparation title compound.Obtain yellow solid.Mass spectrum: to [C 27H 33N 5O 4+ H] +Calculated value m/z=492; Obs.=492.
Embodiment 95
Figure C0280656201341
8-((3S)-(-)-3-dimethylamino-tetramethyleneimine-1-yl)-6-methoxyl group-4-oxo-1,4-dihydro-quinaldic acid (4-morpholine-4-base-phenyl)-acid amides.
According to method in reference example 25a and description in embodiment 87 (method 2), use (3S)-(-)-3-(dimethylamino) tetramethyleneimine to be used for the Pd catalyzed coupling, from 8-bromo-6-methoxyl group-4-(2-TMS-oxyethyl group methoxy base)-quinaldic acid's methyl esters (reference example 24c) preparation title compound.Obtain yellow solid.Mass spectrum: to [C 27H 33N 5O 4+ H] +Calculated value m/z=492; Obs.=492.
Embodiment 96
Figure C0280656201342
6-methoxyl group-8-[methyl-(1-methyl-tetramethyleneimine-3-yl)-amino]-4-oxo-1,4-dihydro-quinaldic acid (4-morpholine-4-base-phenyl)-acid amides.
According to method in reference example 25a and description in embodiment 87 (method 2), use N, N '-dimethyl-3-amino-pyrrolidine is used for the Pd catalyzed coupling, from 8-bromo-6-methoxyl group-4-(2-TMS-oxyethyl group methoxy base)-quinaldic acid's methyl esters (reference example 24c) preparation title compound.Obtain yellow solid.Mass spectrum: to [C 27H 33N 5O 4+ H] +Calculated value m/z=492; Obs.=492.
Embodiment 97
Figure C0280656201351
8-[ethyl-(1-ethyl-tetramethyleneimine-3-yl)-amino]-6-methoxyl group-4-oxo-1,4-dihydro-quinaldic acid (4-morpholine-4-base-phenyl)-acid amides.
According to method in reference example 25a and description in embodiment 87 (method 2), use 3-diethylamino tetramethyleneimine to be used for the Pd catalyzed coupling, from 8-bromo-6-methoxyl group-4-(2-TMS-oxyethyl group methoxy base)-quinaldic acid's methyl esters (reference example 24c) preparation title compound.Obtain yellow solid.Mass spectrum: to [C 29H 37N 5O 4+ H] +Calculated value m/z=520; Obs.=520.
Embodiment 98
Figure C0280656201361
4-dimethylamino-6-methoxyl group-8-(4-methyl-piperazine-1-yl)-quinaldic acid's (4-morpholine-4-base-phenyl)-acid amides.
To 8-bromo-4-dimethylamino-6-methoxyl group-quinaldic acid (4-morpholine-4-base-phenyl)-acid amides (reference example 28b) (139.9mg, 0.288mmol), N methyl piperazine (48 μ L, 0.43mmol) and 4
Figure C0280656201362
Add Pd in the suspension of molecular sieve in the 15mL dry toluene 2(dba) 2(15.3mg, 16.7 μ mol), BINAP (63.0mg, 0.101mmol) and cesium carbonate (0.436g, 1.345mmol).Under nitrogen, the amaranth mixture that generates was heated 20 hours under refluxing.Reaction mixture is cooled to room temperature and concentrated.Through flash chromatography on silica gel purifying crude mixture, use 100: 0-95: 5 methylene dichloride: the gradient elution of methyl alcohol obtains the required product (96.9mg, 67%) into yellow solid.
1H NMR (300MHz, DMSO, d 6) δ 10.06 (s, 1H, C (O) N H), 7.69 (d, 2H, J o=9.0Hz, Ar H 2 '﹠amp; H 6 '), 7.58 (s, 1H, Ar H 3), 7.58 (d, 2H, J o=9.0Hz, Ar H 3 '﹠amp; H 5 '), 6.95 (d, 1H, J m=2.7Hz, Ar H 5), 6.76 (d, 1H, J m=2.7Hz, Ar H 7), 3.90 (s, 3H, OC H 3), 3.75 (t, 4H, J=4.8Hz, OC H 2CH 2N), 3.37 (bs, 4H, ArNC H 2CH 2N), 3.10 (t, 4H, J=4.8Hz, OCH 2C H 2N), 3.01 (s, 6H, N (C H 3) 2), 2.71 (bs, 4H, ArNCH 2C H 2N), 2.35 (s, 3H, R 2NC H 3); Mass spectrum: to [C 28H 36N 6O 3+ H] +Calculated value m/z=505; Obs.=505.5.
Embodiment 99
6-methoxyl group-4-methylamino-8-(4-methyl-piperazine-1-yl)-quinaldic acid's (4-morpholine-4-base-phenyl)-acid amides.
According to the method that embodiment 98 is described, use the N-methylamine, from 8-bromo-6-methoxyl group-4-oxo-1,4-dihydro-quinaldic acid (reference example 27b) prepares title compound, with preparation 8-bromo-4-methylamino-6-methoxyl group-quinaldic acid (4-morpholine-4-base-phenyl)-acid amides.Obtain glassy orange solids.Mass spectrum: to [C 27H 34N 6O 3+ H] +Calculated value m/z=491; Obs.=491.5.
Embodiment 100
6-fluoro-4-methoxyl group-8-(4-methyl-piperazine-1-yl)-quinaldic acid's (4-morpholine-4-base-phenyl)-acid amides.
6-fluoro-4-methoxyl group-8-(4-methyl-piperazine-1-the yl)-quinaldic acid's hydrochloride that in the 250mL round-bottomed flask that is equipped with nitrogen inlet and magnetic stirring apparatus, adds 2.01g (6.3mmol, 1.0 equivalents).This material is dissolved among the DMF of 20mL, adds the 4-morpholino aniline of 1.35g (7.56mmol, 1.2 equivalents) then.In the solution that is stirring, add 4.05g (12.6mmol rapidly simultaneously, 2.0 (the 2-(1H-benzotriazole-1-yl)-1,1,3 of TBTU equivalent), 3-tetramethyl-urea a tetrafluoro borate) and the HOBT (I-hydroxybenzotriazole hydrate) of 1.7g (12.6mmol, 2.0 equivalents).At this moment,, in 5 minutes, add 3.25g, 4.11mL (25.2mmol, 4.0 equivalents) by syringe.At room temperature, reactant was stirred 18 hours, under high vacuum, on rotatory evaporator, concentrate, then to remove DMF.Also reclaim the crude product solid after filtration with the methyl alcohol grinding residues.Then material is dissolved in the methylene dichloride and also extracts with 10% sodium hydrogen carbonate solution.Dry organic layer concentrates then.Through these resistatess of flash chromatography purifying, the gradient liquid that uses the 5-10% methyl alcohol in methylene dichloride is as eluent then.The material that obtains from chromatography crystallization from methyl alcohol, obtain pure product then into the yellow solid of 2.83g (93%).Mass spectrum: to [C 26H 30FN 5O 3+ H] +Calculated value m/z=480; Obs.=480.
Embodiment 101
6-fluoro-4-oxo-8-piperazine-1-base-4H-chromene-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides: according to .Tetrahedron such as Howarth, 1998,54, the logical method preparation of 10899-10914.
At N 2Under atmosphere and the magnetic agitation; with exsiccant 6-fluoro-8-(4-methyl-piperazine-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazine-1-yl)-phenyl]-acid amides (embodiment 72) (1g; 1.9mmol) join the strict exsiccant 1 of 100mL in flask, in the 2-ethylene dichloride.Mixture is cooled to 0 ℃ and drip fresh distillatory chloroformic acid 1-chloro-ethyl ester (650ul, 858mg, 6mmol, 3 equivalents).Then reactant was heated 5 hours under refluxing, at this moment, LC/MS shows that initial substance consumption is complete.Add NaI (1g, 1 equivalent) and continue other 2 days of heating.Make reactant cooling and reduction vaporization to doing then.Add MeOH (100mL) and be heated to back flow reaction 4 hours, heat filtering also is evaporated to dried.Through the chromatographic separation product, use silica gel and CHCl 3/ 5%MeOH is as eluent.Obtaining 700mg is the product HCl salt of yellow solid.LCMS-m/z＝508。

Claims (6)

1. one kind by the compound of formula (I) expression or the pharmacy acceptable salt of described compound:
Figure C028065620002C1
Wherein
R 1On each position, independently represent hydrogen, be not substituted or substituted C 1-6Alkyl, be not substituted or substituted C 3-6Cycloalkyl, sulfo-methoxyl group ,-NHA ,-NA 2,-NHC (=O) A, aminocarboxyl ,-C (=O) NHA ,-C (=O) NA 2, halogen, hydroxyl ,-OA, cyano group or monocycle or encircle C more 6-14Aryl;
A is not for being substituted or substituted C 1-6Alkyl, be not substituted or substituted C 3-6Cycloalkyl, be not substituted or substituted C 2-6Alkenyl or be not substituted or substituted C 2-6Alkynyl group;
R 2By following (i), (ii), (iii) or (iv) the expression:
Figure C028065620002C2
R 3On each position independent expression-H, be not substituted or substituted C 1-6Alkyl, be not substituted or substituted C 2-6Alkenyl, be not substituted or substituted C 2-6Alkynyl group, be not substituted or substituted C 3-6Cycloalkyl or AOH;
N is 2,3 or 4;
P is a pyrrolidyl;
R 6For-H or methyl;
Y is-C (=O) NH-,-C (=O) NA-,-C (=O)-,-C (=O)-piperazine-;
R 7For not being substituted or by one or more R of being selected from 8-R 9And R 10The substituting group phenyl ring or 5-6 unit heterocycle, the wherein R that replace 7Be connected in Y by singly-bound;
R 8For-O-, connect R as joint 7To R 9Singly-bound;
R 9For not being substituted or substituted piperazinyl-R 11, be not substituted or substituted morpholinyl-R 11
R 10For not being substituted or substituted C 1-6Alkyl, be not substituted or substituted C 3-6Cycloalkyl, hydroxyl, monocycle or encircle C more 6-14Aryl, cyano group, halogen ,-C (=O) NH 2-, methylthio group ,-NHA ,-NA 2,-NHC (=O) A, C (=O) NHA, C (=O) NA 2Or OA;
R 11For-H, C 1-6Alkyl, AOH ,-SO 2A ,-SO 2NH 2,-SO 2NHA ,-SO 2NA 2,-SO 2NHAR 9,-C (=O) R 9,-C 1-6Alkyl R 9, C (=O) A, C (=O) NH 2, C (=O) NHA, C (=O) NA 2Perhaps-C (=O) OA;
The group of above-mentioned substituted group for being replaced: halogen, nitro, cyano group, hydroxyl, trifluoromethyl, amino, carboxyl, formamido-, amidino groups, formamyl, sulfydryl, sulfamyl, C by following group 1-4Alkyl, C 2-4Alkenyl, C 2-4Alkynyl group, C 3-6Cycloalkyl, C 3-6Cycloalkenyl group, C 1-4Alkoxyl group, C 1-4Alkyloyl, C 1-4Alkanoyloxy, N (C 1-4Alkyl), N (C 1-4Alkyl) 2, C 1-4Alkyl amido, (C 1-4Alkyloyl) 2Amino, N-(C 1-4Alkyl) formamyl, N, N-(C 1-4Alkyl) 2Formamyl, (C 1-4Alkyl) S, (C 1-4Alkyl) S (O), (C 1-4Alkyl) S (=O) 2, (C 1-4) alkoxy carbonyl, N-(C 1-4Alkyl) sulfamyl, N, N-(C 1-4Alkyl) 2Sulfamyl, C 1-4Alkyl sulfonyl amino;
The first heterocycle of above-mentioned 5-6 is to have one or more heteroatomic saturated or unsaturated unit price or divalent groups that independently are selected from N, O and S.
2. the compound of claim 1, wherein said compound is racemize 8-(4-methyl-piperazine-1-yl)-chroman-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides or its pharmacy acceptable salt.
3. the compound of claim 2, wherein said compound is (+)-8-(4-methyl-piperazine-1-yl)-chroman-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides or its pharmacy acceptable salt.
4. the compound of claim 2, wherein said compound is (-)-8-(4-methyl-piperazine-1-yl)-chroman-2-carboxylic acid (4-morpholine-4-base-phenyl)-acid amides or its pharmacy acceptable salt.
5. each compound or its pharmacy acceptable salt of claim 1-4 is used for the treatment of application in the migrainous medicine in preparation.
6. medicinal compositions, it comprises each compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier of claim 1-4.
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