CN101404989A - Antibacterial agents - Google Patents

Antibacterial agents Download PDF

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Publication number
CN101404989A
CN101404989A CNA200780009959XA CN200780009959A CN101404989A CN 101404989 A CN101404989 A CN 101404989A CN A200780009959X A CNA200780009959X A CN A200780009959XA CN 200780009959 A CN200780009959 A CN 200780009959A CN 101404989 A CN101404989 A CN 101404989A
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carboxylic acid
fluoro
group
acid amides
hydrogen
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CNA200780009959XA
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CN101404989B (en
Inventor
D·R·布朗
I·克林斯
L·G·洽普勒斯基
D·J·海登
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Biota Scientific Management Pty Ltd
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Prolysis Ltd
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Abstract

Compounds of formula (I) have antibacterial activity wherein R represents hydrogen or 1, 2 or 3 optional substituents; W is =C(R1)- or =N-; R1 is hydrogen or an optional substituent and R2 is hydrogen, methyl, or fluorine; or R1 and R2 taken together are -CH2-, -CH2CH2-, -O-, or, in either orientation, -O- CH2- Or -OCH2CH2-; R3 is a radical of formula -(Alk<1>)m-(Z)p-(Alk<2>)n-Q wherein m, p and n are independently 0 or 1, provided that at least one of m, p and n is 1, Z is -O-, -S-, -S(O)-, -S(O2)-, -NH-, -N(CH3)-, -N(CH2CH3)-, -C(=O)-, -O-(C=O)-, -C(=O)-O-, or an optionally substituted divalent monocyclic carbocyclic or heterocyclic radical having 3 to 6 ring atoms; or an optionally substituted divalent bicyclic heterocyclic radical having 5 to 10 ring atoms; Alk<1> and Alk<2> are optionally substituted C1C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene radicals, which may optionally terminate with or be interrupted by -O-, -S-, -S(O)-, -S(O2)-, -NH-, -N(CH3)-, or -N(CH2CH3)-; and Q is hydrogen, halogen, nitrile, or hydroxyl or an optionally substituted monocyclic carbocyclic or heterocyclic radical having 3 to 6 ring atoms; or an optionally substituted bicyclic heterocyclic radical having 5 to 10 ring atoms.

Description

Antibacterial
Invention field
Benzoylamide that the present invention relates to replace and picolinamide relate to the newcomer of this compounds as the application of antibacterial, and relate to the pharmaceutical composition that comprises these chemical compounds.
Background technology
Know many antibacterial types, comprised penicillin and cephalosporins, Tetracyclines, sulfonamides, monobactams, fluoroquinolones and quinolones, aminoglycoside, glycopeptide class, Macrolide, polymyxins, lincosamide class, trimethoprim and chloromycetin.The mechanism of action of these antibacterial has nothing in common with each other.
Antibacterial toleration at many known antimicrobial agents becomes more and more serious problem.Therefore, this area constantly needs alternate antibacterial, and especially mechanism of action is different from those materials of known antimicrobial agents type.
In the Gram-positive pathogen, the Resistant strain of in staphylococcus, streptococcus, mycobacteria and enterococcus, evolving/occurred makes that these antibacterials are difficult to eradicate especially.The example of these bacterial strains is methicillin toleration staphylococcus aureus (MRSA), methicillin toleration coagulase negative staphylococcus (MRCNS), penicillin toleration streptococcus pneumoniae and multidrug resistance enterococcus faecalis.Because the quick appearance of multidrug resistance bacterial strain, exploitation can effectively resist Resistant strain, especially the norvancomycin toleration enterococcus of more and more quantity and the antibacterial with novel binding mode of beta-lactam antibiotic toleration bacterial strain such as methicillin toleration staphylococcus aureus is most important.
Cell division is the very interested target spot of pharmaceutical industry, because this process comprises one group of target protein that conservative is higher, all these target proteins all are that various bacteria existence is necessary, and its activity is different from the protein of the fission process that participates in mammalian cell fully.Many chemical compound (Ohashi, Y. etc., J.Bacteriol.181 that act on each component of fission process have been described, 1348-1351 (1999), Jennings, L.D. etc., Bioorg Med Chem 12,5115-5131 (2004), Sutherland, A.G. etc., Org Biomol Chem 1,4138-4140 (2003), Margalit, D.N. etc., Proc.Natl.Acad.Sci.USA 101,11821-11826 (2004), Wang, J. etc., J.Biol.Chem.278,44424-44428 (2003), White, E.L. etc., J.Antimicrob.Chemother.50,111-114 (2002), Reynolds, R.C. etc., Bioorg Med Chem Lett14,3161-3164 (2004) and Stokes etc., J Biol Chem.280,39709-39715 (2005)).Up to now, great majority are attempted concentrating on FtsZ albumen, but because it has the chemical-biological activities of some analyzed in vitro.Unfortunately, the most compounds of having described up to now or render a service lowlyer or has undesirable pharmacological property or unknown specificity.
Summary of the invention
The present invention is based on following discovery: the Benzoylamide of replacement and picolinamide compounds have antibacterial activity, can prove by bacteria growing inhibiting as the member of this compounds.This chemical compound has resisting gram-positive bacteria, as staphylococcus, fusobacterium, listeria and Bacillus, as the activity of staphylococcus aureus, staphylococcus epidermidis, staphylococcus haemolyticus and staphylococcus saprophyticus, bacillus subtilis, anthrax bacillus and Bacillus cereus.Though the present invention is not subjected to the restriction of any concrete hypothesis on the mechanism of action of chemical compound, think that at present these activity are to mediate owing to suppressing cell division after chemical compound and the FtsZ protein binding.
Detailed Description Of The Invention
Aspect widely according to the present invention provides the Benzoylamide of replacement of formula (I) or picolinamide compound or its salt, hydrate or solvate to be used for the treatment of application in the medicine of bacterial infection in preparation:
Figure A20078000995900101
In the formula,
R represents hydrogen or 1,2 or 3 optional substituent group;
W is=C (R 1)-or=N-;
R 1Be hydrogen or optional substituent group, R 2Be methyl, hydrogen or fluorine; Or R 1And R 2Be together-CH 2-,-CH 2CH 2-,-O-, or arbitrary orientation-O-CH 2-,-OCH 2CH 2-;
R 3Be general formula-(Alk 1) m-(Z) p-(Alk 2) nThe group of-Q, wherein,
M, p and n are 0 or 1 independently, and prerequisite is that at least one is 1 among m, p and the n,
Z is-O-,-S-,-S (O)-,-S (O 2)-,-NH-,-N (CH 3)-,-N (CH 2CH 3)-,-C (=O)-,-O-,-(C=O)-,-C (=O)-O-or have the bivalence monocycle carbocyclic ring or the heterocyclic group of the optional replacement of 3-6 annular atoms; Or has a bivalence bicyclic heterocyclic group of the optional replacement of 5-10 annular atoms;
Alk 1And Alk 2Be the optional C that replaces 1-C 6Alkylidene, C 2-C 6Alkenylene or C 2-C 6Alkynylene, they can be randomly with-O-,-S-,-S (O)-,-S (O 2)-,-NH-,-N (CH 3)-or-N (CH 2CH 3)-be is terminal or by it at interval; With
Q be hydrogen, halogen, nitrile (CN) or hydroxyl or have the monocycle carbocyclic ring or the heterocyclic group of the optional replacement of 3-7 annular atoms; Or has a bicyclic heterocyclic group of the optional replacement of 5-10 annular atoms.
Other widely aspect, the present invention includes
(i) method of treatment target bacterial infection, this method comprise that the above-claimed cpd (I) that gives described object q.s is with bacteria growing inhibiting;
(ii) handle the method for base material germ contamination, this method comprises gdna contamination is applied the above-claimed cpd (I) of q.s with bacteria growing inhibiting;
The (iii) application of above-claimed cpd (I) in the human body therapy method;
The (iv) application of above-claimed cpd (I) in the treatment bacterial infection;
Think that some members in the type of compounds that general formula (I) limited are new, the present invention includes all these new members in the type.
Therefore, the present invention also comprises the Benzoylamide of replacement of general formula (IC) or noval chemical compound and salt, hydrate or the solvate of picolinamide:
Figure A20078000995900111
Wherein, W is=C (R 1)-or=N-; R 1Be hydrogen or optional substituent group, R 2Be hydrogen, methyl or fluorine; Or R 1And R 2Be together-CH 2-,-CH 2CH 2-,-O-or arbitrary orientation-O-CH 2-or-OCH 2CH 2-; R 4And R 5Be fluorine or chlorine independently, or R 4And R 5One of be hydrogen, and another is a fluorine or chlorine; And R 3Be the group that is selected from following general formula A-H, its medium ring take up an official post the meaning room can randomly be substituted:
Figure A20078000995900121
In the formula, Q is hydrogen, halogen, nitrile or hydroxyl; Or have the monocycle carbocyclic ring or a heterocyclic group of the optional replacement of 3-6 annular atoms; Or has a bicyclic heterocyclic group of the optional replacement of 5-10 annular atoms.
The present invention also comprises new pyridine amide compound and salt, hydrate or the solvate of general formula (ID):
Figure A20078000995900122
In the formula, R 2Be hydrogen, methyl or fluorine; R 3Such as in the general formula (IC) definition.
Term
Term " (C used herein a-C b) alkyl " (wherein, a and b are integers) expression has the straight or branched alkyl of a-b carbon atom.Therefore, when a is 1, b is 6 o'clock, and for example, this term comprises methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl and n-hexyl.
Term used herein " bivalence (C a-C b) " (wherein, a and b are integers) expression has a-b carbon atom and two unsaturated valent saturated hydrocarbon chains to alkylidene.This term for example comprises, methylene, ethylidene, positive propylidene and positive butylidene.
Term " (C used herein a-C b) thiazolinyl " (wherein, a and b are integers) expression has the straight or branched alkenyl part with a-b carbon atom of the two keys of at least one E or Z spatial chemistry (suitably time).This term for example comprises, vinyl, pi-allyl, 1-and crotyl and 2-methyl-2-acrylic.
Term used herein " bivalence (C a-C b) " expression has a-b carbon atom, at least one two keys and two unsaturated valent hydrocarbon chains to alkenylene.This term for example comprises ,-CH=CH-(ethenylidene) ,-CH=CH-CH 2-,-CH 2-CH=CH-,-CH=CH-CH 2-CH 2-,-CH=CH-CH 2-CH 2-CH 2-,-CH=CH-CH=CH-,-CH=CH-CH=CH-CH 2-,-CH=CH-CH=CH-CH 2-CH 2-,-CH=CH-CH 2-CH=CH-and-CH=CH-CH 2-CH 2-CH=CH-.
Term " C used herein a-C b" (wherein, a and b are integers) expression has a-b carbon atom and at least one triple-linked straight or branched alkyl to alkynyl.This term for example comprises, acetenyl, 1-propinyl, 1-and 2-butyne base, 2-methyl-2-propynyl, valerylene base, 3-pentynyl, 4-pentynyl, 2-hexin base, 3-hexin base, 4-hexin base and 5-hexin base.
Term used herein " bivalence (C a-C b) " (wherein, a and b are integers) expression has a-b carbon atom and at least one triple-linked bivalent hydrocarbon chain to alkynylene.This term for example comprises ,-C ≡ C-,-C ≡ C-CH 2-and-CH 2-C ≡ CH-.
Term used herein " cycloalkyl " expression has the monocycle or the bridge joint monocycle saturated carbon ring group of 3-8 carbon atom, for example comprise cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group and dicyclo [2.2.1] heptan-the 1-base.
Term used herein " aryl " expression list-or the bicyclic carbocyclic aromatic group.The example of this group is phenyl and naphthyl.
Term used herein " heteroaryl " expression contains heteroatomic monocycle or the bicyclic aromatic group of one or more S of being selected from, N and O, comprise the group that has two such monocycles or have a such monocycle and a monocyclic aromatic rings, described two rings condense or directly connect by covalent bond.The example of this group is thienyl, benzothienyl, furyl, benzofuranyl, pyrrole radicals, imidazole radicals, benzimidazolyl, thiazolyl, benzothiazolyl, thiazole and pyridine radicals, isothiazolyl, benzisothiazole base, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzoisoxazole base, isothiazolyl, triazolyl, benzotriazole base, thiadiazolyl group, oxadiazole base, pyridine radicals, pyridazinyl, pyrimidine radicals, pyridazinyl, triazine radical, indyl and indazolyl.
Term used herein " heterocyclic radical " or " heterocycle " comprise " heteroaryl " of above-mentioned definition, and also expression contains heteroatomic monocycle or the dicyclo non-aromatic group of one or more S of being selected from, N and O.The example of this group is a pyrrole radicals, furyl, thienyl, piperidyl, imidazole radicals ， oxazolyl ， isoxazolyl, thiazolyl, thiadiazolyl group, pyrazolyl, pyridine radicals, pyrrolidinyl, pyrimidine radicals, morpholinyl, piperazinyl, indyl, morpholinyl, benzofuranyl, pyranose ， isoxazolyl, benzimidazolyl, methylenedioxyphenyl, ethylidene dioxy phenyl, maleimide and butanimide group.
Except as otherwise noted, the term that uses in this paper arbitrary portion " replacement " expression is replaced by four compatible substituent groups at most, and each substituent group is (C for example independently 1-C 6) alkyl, (C 2-C 6) thiazolinyl, (C 2-C 6) alkynyl, (C 1-C 6) alkoxyl, hydroxyl, hydroxyl (C 1-C 6) alkyl, sulfydryl, sulfydryl (C 1-C 6) alkyl, (C 1-C 6) sulfane base, halogen (comprising fluorine, bromine and chlorine), fluorizated (C wholly or in part 1-C 3) alkyl, (C 1-C 3) alkoxyl or (C 1-C 3) sulfane base such as trifluoromethyl, trifluoromethoxy and trifluoromethylthio, nitro, nitrile (and CN), oxo (=O), the bicyclic heteroaryl of phenyl, phenoxy group, a 5-6 annular atoms or heteroaryloxy ,-COOR A,-COR A,-OCOR A,-SO 2R A,-CONR AR B,-SO 2NR AR B,-NR AR B, OCONR AR B,-NR BCOR A,-NR BCOOR A,-NR BSO 2OR AOr-NR ACONR AR B, R wherein AAnd R BBe hydrogen or (C independently 1-C 6) alkyl, perhaps at R AAnd R BUnder situation that same N atom links to each other, R AAnd R BForm the cyclic amino ring with this nitrogen-atoms.If substituent group is phenyl, phenoxy group or bicyclic heteroaryl or the heteroaryloxy with 5-6 annular atoms, then phenyl or hetero-aromatic ring itself can be replaced by any above-mentioned substituent group except that phenyl, phenoxy group, heteroaryl or heteroaryloxy." optional substituent group " or " substituent group " can be one of groups of above pointing out.
Term used herein " salt " comprises base addition salts, acid-addition salts and quaternary ammonium salt.Tart The compounds of this invention can form salt with alkali, comprises pharmaceutically acceptable salt, and described alkali comprises: alkali metal hydroxide, for example sodium hydroxide and potassium hydroxide; Alkaline earth metal hydroxide, for example hydroxide of calcium, barium, magnesium; Organic base such as N-methyl D-glucamine, choline three (methylol) amino-methane, L-arginine, L-lysine, N-ethylpiperidine, dibenzylamine etc.Alkali compounds (I) can form salt with acid, comprise pharmaceutically acceptable salt, described acid comprises: mineral acid such as halogen acids, example hydrochloric acid and hydrobromic acid, sulphuric acid, nitric acid or phosphoric acid etc., organic acid such as acetic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, benzoic acid, benzenesulfonic acid, glutamic acid, lactic acid and mandelic acid etc.To the summary of suitable salt referring to Stahl and Wermuth " pharmaceutical salts handbook: character, selection and use " ( Handbook of Pharmaceutical Salts: Properties, Selection, andUse) (Wiley-VCH, Weinheim, Germany, 2002).
Term ' solvate ' is used for describing the molecular complex that comprises The compounds of this invention and stoichiometric one or more pharmaceutically acceptable solvent molecules (for example ethanol).When being water, adopts by described solvent term " hydrate ".
Because the existence of asymmetric carbon atom, comprise the The compounds of this invention of one or more reality or potential chiral centre can various enantiomers or the form of diastereomer exist, each chiral centre is R or S spatial chemistry.The present invention includes all these enantiomers and diastereomer and composition thereof.
Aspect of the present invention
A kind of concrete chemical compound subclass that is used for antibacterial applications according to the present invention relates to the chemical compound of general formula (IA),
Figure A20078000995900151
In the formula, R 4And R 5Be fluorine or chlorine independently, or R 4And R 5One of be hydrogen and another is a fluorine or chlorine, R 1, R 2And R 3As mentioned defined in the general formula (I).
The another kind of concrete chemical compound subclass that is used for antibacterial applications according to the present invention relates to the chemical compound of general formula (IB):
Figure A20078000995900152
In the formula, R 2And R 3As mentioned defined in the general formula (I).
Be used for the more specific compound subclass of antibacterial applications according to the present invention, comprising the above chemical compound of general formula (IA), R 1And R 2Be hydrogen; In the chemical compound of general formula (IB) above, R 2Be hydrogen.
For radicals R 3, p can be 0, and m and/or n can be 1.Perhaps, p can be 1, Z can be have 3-6 annular atoms optional replacement carbocyclic ring or heteroaryl groups or have the bicyclic carbocyclic or the heteroaryl groups of the optional replacement of 5-10 annular atoms, be connected in R by ring carbon or nitrogen-atoms 3-(Alk 1) m-part and R 3-(Alk 2) n-Q part.The example of divalent group Z comprises the group of group under being selected from of taking arbitrary orientation in this embodiment:
Figure A20078000995900161
In another optional embodiment, p is 1, Z be have 3-6 annular atoms optional replacement monocycle non-aromatic carbocyclic ring or heterocyclic group or have the dicyclo non-aromatic carbocyclic ring or the heterocycle of the optional replacement of 5-10 annular atoms, they are connected in R by ring carbon or nitrogen-atoms 3-(Alk 1) m-part and R 3-(Alk 2) n-Q part.In this embodiment, the example of the optional Z group that replaces comprises the group of group under being selected from of taking arbitrary orientation:
Figure A20078000995900172
In any subclass or embodiment of the chemical compound that the present invention relates to and these chemical compounds mentioned above, Q can be a hydrogen.Yet Q also can be the group that is selected from above the concrete any bivalence Z group that limits, and one of them unsaturated chemical valence is saturated by hydrogen or optional substituent group.
In any subclass or embodiment of the chemical compound that the present invention relates to and these chemical compounds mentioned above, n and/or m can be 0.
In all chemical compounds that the present invention relates to and type of compounds, common radicals R 3If extend the length that also can not exceed the unbranched saturated hydrocarbon chain of 14 carbon atoms fully, promptly can not exceed about 16 dusts.For example, length can equal the length of the unbranched saturated hydrocarbon chain of 6-12 or 9-12 carbon atom, promptly is respectively about 6-14 dust and about 10-14 dust.
In the chemical compound that the present invention relates to, Alk 1And Alk 2If exist, for example can be, the optional straight chain C that replaces 1-C 6Alkylidene, C 2-C 6Alkenylene or C 2-C 6Alkynylene, separately can be randomly with-O-,-S-,-S (O)-,-S (O 2)-,-NH-,-N (CH 3)-or-N (CH 2CH 3)-,-C (=O)-,-O-(C=O)-,-C (=O)-O-is terminal or by it at interval.
Any optional substituent R and Alk 1, Alk 2, any optional substituent group that exists among Z and the Q for example can be selected from, methyl ,-OCH 3,-CF 3,-OCF 3, ethyl, cyclopropyl, oxo, hydroxyl ,-F ,-Cl ,-Br, cyano group, acetyl group, amino, methylamino, dimethylamino, acetyl-amino, carbamate ,-CONH 2, nitro ,-COOH and-CH 2OH.
Chemical compound and salt, hydrate or the solvate of general formula (IC) constitute unique aspect of the present invention:
Figure A20078000995900181
In the formula, W is=C (R 1)-or=N-;
R 1Be hydrogen or optional substituent group, R 2Be hydrogen, methyl or fluorine; Or R 1And R 2Be together-CH 2-,-CH 2CH 2-,-O-or arbitrary orientation-O-CH 2-or-OCH 2CH 2-;
R 4And R 5Be fluorine or chlorine independently, or R 4And R 5One of be hydrogen and another is a fluorine or chlorine;
R 3Be the group that is selected from following general formula A-H, wherein ring upward all can randomly be substituted in the room arbitrarily:
Figure A20078000995900182
In the formula, Q defines in the general formula (I) as mentioned, and any unsubstituted ring carbon can randomly be substituted.
In chemical compound (IC), at present preferred W is=CH-R 2Be hydrogen.
In chemical compound (IC), R 3In Q can be hydrogen or the optional phenyl that replaces.
In the concrete subclass of chemical compound (IC), R 3Be optional quinoline-2-base, benzothiazole-2-base, thiazol-2-yl, thiazole-4-base, thiazole-5-Ji, oxadiazole-3-Ji, oxadiazole-5-Ji, oxazole-2-Ji, oxazole-4-Ji, oxazole-5-base or thiazole and the pyridine-2-base that replaces.
According to aspects of the present invention can be at compound R 3The optional substituent group of last existence comprise methyl ,-OCH 3,-CF 3,-OCF 3, ethyl, cyclopropyl, oxo, hydroxyl ,-F ,-Cl ,-Br, cyano group, acetyl group, amino, methylamino, dimethylamino, acetyl-amino, carbamate ,-CONH 2, nitro ,-COOH and-CH 2OH.
Chemical compound and salt, hydrate or the solvate of general formula (ID) also constitute unique aspect of the present invention:
Figure A20078000995900191
In the formula, R 2Be hydrogen, methyl or fluorine; R 3Such as general formula (IC) definition.
The object lesson of chemical compound involved in the present invention comprises the chemical compound among this paper embodiment.
Have many synthetic schemes that are used for synthetic The compounds of this invention (I), but all schemes all depend on the known known chemical reaction of synthesis of organic scholar.Therefore, the chemical compound of general formula (I) can synthesize according to the method for describing in the normative document, and these methods are that those skilled in the art are well-known.Typical literature reference is " Advanced Organic Chemistry " (" Advanced Organic Chemistry "), the 4th edition (Wiley), J March, " organic transformation reaction summary " (" Comprehensive OrganicTransformation ", the 2nd edition (Wiley), R.C.Larock, " heterocyclic chemistry handbook (" Handbook of Heterocyclic Chemistry "), the 2nd edition (Pergamon), A.R.Katritzky), the summary document is referring to " Synthesis ", " Acc.Chem.Res. ", " Chem.Rev ", or primary document source or secondary that the normative document on-line search is identified are originated as " Chemical Abstracts " or " Beilstein ".
For example, chemical compound (I) can pass through group-(Alk 1) m-(Z) p-(Alk 2) nPrepare on the hydroxyl of-Q introducing chemical compound (II).
Figure A20078000995900201
The further details of the synthetic method of intermediate (II) and preparation scheme provides in an embodiment.
As mentioned above, chemical compound involved in the present invention is the antibacterial activity agent, because they can bacteria growing inhibiting.Therefore, these chemical compounds are applicable to the treatment people or the bacterial infection of other animals (for example other mammals, bird and fish) except that the people.This chemical compound comprises the chemical compound that suppresses gram-positive organism such as bacillus subtilis and staphylococcus aureus growth, and some chemical compounds also have the activity of some gram negative organism of antagonism.
Should understand, the concrete dosage level of any particular patient will depend on many factors, comprise activity, patient age, body weight, health status, sex, diet, administration time, route of administration, discharge rate, the drug regimen of the specific compound that is adopted and the seriousness of the disease specific for the treatment of.As pharmaceutical field is desired, determine safe acceptable dose by clinical trial, but daily dose can change in broad range, in each concrete case, regulate according to individual need.Yet usually, when chemical compound was grown up separately, every kind of used dosage of route of administration was 0.0001-150 milligram/kg body weight.But this dosage gives for example 1-5 time every day.For intravenous injection, suitable daily dose is 0.0001-150 milligram/kg body weight.Daily dose can give or give according to the divided dose scheme by single dose.
Can prepare chemical compound of the present invention be used for by with the corresponding to any administration of its pharmacokinetics character, for example oral, external, aseptic parenteral solution or suspensoid.Liquid preparations for oral administration can be the form of tablet, capsule, powder agent, granule, lozenge, liquid or gel preparation.The tablet of oral administration and capsule can be the unit dose appearance forms, can comprise conventional adjuvant such as binding agent, for example syrup, arabic gum, gelatin, Sorbitol, tragacanth or polyvinyl-ketopyrrolidine; Filler, for example lactose, sugar, corn-starch, calcium phosphate, Sorbitol or glycine; Tabletting lubricant, for example magnesium stearate, Pulvis Talci, Polyethylene Glycol or silicon dioxide; Disintegrating agent, potato starch for example, or acceptable wetting agent such as sodium lauryl sulphate.Tablet can carry out coating according to the known method of general pharmacy practice.Oral liquid can be the form of aqueous or oiliness suspensoid, solution, Emulsion, syrup or elixir for example, or the form of dried product, faces with preceding water or other suitable carriers and rebuilds.These liquid preparations can comprise conventional additives such as suspending agent, for example Sorbitol, syrup, methylcellulose, dextrose syrup, gelatin hydrogenation edible fat; Emulsifying agent, for example lecithin, sorbitan monooleate or arabic gum; Non-water transport carrier (can comprise edible oil), for example almond oil, fractionated Oleum Cocois, grease such as glycerol, propylene glycol or ethanol; Antiseptic, for example right-methyl hydroxybenzoate or propyl ester or sorbic acid also comprise conventional aromatic or coloring agent when needing.
When local skin was used, medicine can be made into emulsifiable paste, lotion or ointment.Being fit to medicinal emulsifiable paste or ointment formulation is conventional formulation well known in the art, for example described in the pharmacy canonical reference book, as British Pharmacopoeia.
During the eyes topical application, medicine can be made solution or suspensoid in suitable sterile aqueous or non-aqueous carrier.Also can comprise additive, for example buffer such as sodium metabisulfite or disodium edetate; Antiseptic comprises antibacterial and antifungal such as phenyl mercuric acetate or Mercury pernitrate., benzalkonium chloride or chlorhexidine, and thickening agent such as hydroxypropyl cellulose.
Activating agent also can give by parenteral in sterile media, no matter be subcutaneous, intravenous, or intramuscular or breastbone in or by infusion techniques, with the form of aseptic injection aqueous or oily suspensoid.According to used carrier and concentration, medicine can suspend or be dissolved in the carrier.Valuably, auxiliary reagent such as local anesthetic, antiseptic and buffer agent can be dissolved in the carrier.
Because The compounds of this invention is antibacterial activity agent and energy bacteria growing inhibiting, these chemical compounds also are applicable to the germ contamination of handling base material, for example hospital equipment or working surface.In order to handle contaminated base material, the described chemical compound of q.s can be applied to gdna contamination with bacteria growing inhibiting.
The following examples have been described the synthetic of The compounds of this invention.
Analytical method
The analytical method that is used for characterizing compounds comprise HPLC-MS and 1H NMR.
HPLC-MS condition-method 1
Mobile phase: A=acetonitrile
The B=10mM ammonium acetate aqueous solution
Gradient:
Time (minute) ％A ％B
0.00 20 80
0.30 20 80
4.00 90 10
5.00 90 10
5.03 20 80
Running time: 7 minutes
Flow velocity: 1 ml/min
Volume injected: variable, depend on sample concentration
Column temperature: 40 ℃
Post: 50 * 4.6mm Gemini C18; 5 μ m
PDA detector: analysis 220,240 and 254nm
HPLC-MS condition-method 2
Mobile phase: A=acetonitrile
The B=10mM ammonium acetate aqueous solution
Gradient:
Time (minute) ％A ％B
0.00 20 80
0.30 20 80
24.00 90 10
28.00 90 10
28.03 20 80
Running time: 30 minutes
Flow velocity: 1 ml/min
Volume injected: variable, depend on sample concentration
Column temperature: 40 ℃
Post: 50 * 4.6mm Gemini C18; 5 μ m
PDA detector: analysis 220,240 and 254nm
HPLC-MS condition-method 3
Mobile phase: A=acetonitrile+0.1% trifluoroacetic acid
B=water+0.1% trifluoroacetic acid
Gradient:
Time (minute) ％A ％B
0.0 0 100
1.8 95 5
2.1 95 5
2.3 0 100
2.4 0 100
Running time: 2.4 minutes
Flow velocity: 1 ml/min
Volume injected: 3 μ l
Column temperature: room temperature (20 ℃)
Post: 50 * 2.0mm Hypersil C18BDS; 5 μ m
The UV detector is set in the variable-wavelenght detector of 215nm
HPLC-MS condition-method 4
Mobile phase: A=acetonitrile+0.1% formic acid
B=water+0.1% formic acid
Gradient:
Time (minute) ％A ％B
0.0 0 100
2.5 100 0
2.7 100 0
2.71 0 100
3.0 0 100
Running time: 3.5 minutes
Flow velocity: 1 ml/min
Volume injected: 3 μ l
Column temperature: room temperature (20 ℃)
Post: 50 * 2.1mm Atlantis dC18; 5 μ m
The UV detector is set in the variable-wavelenght detector of 215nm
HPLC analysis condition-method 5
Figure A20078000995900231
Figure A20078000995900241
HPLC analysis condition-method 6
Figure A20078000995900242
HPLC analysis condition-method 7
Figure A20078000995900243
HPLC-MS condition-method 8
Mobile phase: A=acetonitrile+0.1% formic acid
B=water+0.1% formic acid
Gradient:
Time (minute) ％A ％B
0.0 10 90
7.0 10 90
15.0 90 10
18.0 90 10
25.0 10 90
30.0 10 90
Running time: 30.0 minutes
Flow velocity: 1 ml/min
Column temperature: room temperature (25 ℃)
Post: 250 * 4.6mm Xbridge dC18; 5 μ m
The UV detector is set in the variable-wavelenght detector of 215nm
HPLC-MS condition-method 9
Mobile phase: A=acetonitrile+0.1% formic acid
B=water+0.1% formic acid
Gradient:
Time (minute) ％A ％B
0.0 10 90
7.0 10 90
15.0 90 10
18.0 90 10
25.0 10 90
30.0 10 90
Running time: 30.0 minutes
Flow velocity: 1 ml/min
Column temperature: room temperature (25 ℃)
Post: 250 * 4.6mm Purospher Star dC18; 5 μ m
The UV detector is set in the variable-wavelenght detector of 262nm
NMR
1H NMR collection of illustrative plates is consistent with desired structure.
Fusing point is measured on Stuart Scientific SMP10 equipment and is proofreaied and correct.
Productive rate is not optimized.
Experimentation
Scheme 1:(a) SOCl 2, toluene refluxes; (b) aqueous NH 3
Carboxylic acid is converted into general process (method A) the .3-hydroxy benzenes carboxylic acid amides of carboxylic acid amides.
Figure A20078000995900261
3-hydroxy benzoic acid (110.5g, 0.8mol, 1 equivalent) is suspended in the toluene (500ml), slowly adds thionyl chloride (88.0ml, 1.2mol, 1.5 equivalents) under the room temperature.This solution is heated to backflow, kept 5 hours.Afterwards, make reactant liquor be cooled to room temperature and vacuum concentration.Residue is dissolved in the oxolane (300ml) and cools off in ice-methanol bath.Slowly dropwise drip concentrated ammonia solution (～300ml), make reaction mixture slowly be increased to room temperature, at room temperature stirred 16 hours.With the reaction mixture vacuum concentration, the gained solid suspension is also filtered in water.The solid of collecting washs with extra water (x3), and vacuum drying obtains fusing point 167-168 ℃ of the 3-hydroxybenzamide (79.9g, 72.8%) of pale solid form then.HPLC-MS (method 1): m/z 136[M-H] -.Rt=1.21 minute. 1H NMR(d 6-DMSO)δ＝9.53(s，1H)，7.78(s，1H)，7.30-7.15(m，4H)，6.88(d，J＝8Hz，1H)。
Scheme 2:(a) RX, K 2CO 3, NaI, DMF, 60 ℃.
Make the general process (method B) of phenol generation alkylated reaction with alkyl halide.
Figure A20078000995900271
Embodiment 1:3-oxygen in ninth of the ten Heavenly Stems base-benzene carboxylic acid amides.
Figure A20078000995900272
In DMF (3ml) solution of 3-hydroxy benzenes carboxylic acid amides (200mg, 1.46mmol, 1 equivalent), add K 2CO 3(302mg, 2.19mmol, 1.5 equivalents) and NaI (43.5mg, 0.29mmol, 0.2 equivalent).N-nonyl chloride (0.32ml, 1.61mmol, 1.1 equivalents) is introduced in the suspension stirring after 5 minutes.The gained mixed liquor is heated to 60 ℃, kept 16 hours.Afterwards, make reactant liquor be cooled to room temperature and between EtOAc and water, distribute.Separate organic facies, (x2) washs with extra water, dry (MgSO 4), filter and vacuum concentration, obtain colorless solid.For 3-oxybenzamide in the positive ninth of the ten Heavenly Stems, with MeOH (～0.5ml) this colorless solid is stirred 5 minutes [NB:3-oxybenzamide in the positive ninth of the ten Heavenly Stems partly is dissolved among the MeOH], filter the required compound (116mg, 30%) that obtains the colorless solid form then.HPLC-MS (method 3): m/z 264[M+H] +, Rt=1.80 minute. 1HNMR (d 6-DMSO) δ=7.95 (s, 1H), 7.44-7.31 (m, 4H), 7.06 (ddd, J=8Hz, J=2Hz, J=1Hz, 1H), 3.99 (t, J=6.5Hz, 2H), 1.72 (quintet, J=6.5Hz, 2H), 1.42 (m, 2H), 1.34-1.26 (m, 10H), 0.86 (t, J=6.5Hz, 3H).
NB 1: final purification step depends on the character of R group.Other purification process that adopt in the building-up process of storehouse are:
1. recrystallization (for example, pure (neat) MeOH, EtOAc/ hexane, CH 3CN).
2. normal phase column chromatograph (silica gel).
3. preparation HPLC or preparation type TLC.
NB 2: for the water solublity target compound, the water vacuum concentration is washed with MeOH then.With methanol fraction vacuum concentration, and by preparation HPLC purification crude product.
Embodiment 2-44 (Table A)
Embodiment 2-44 is according to method B, and scheme 2 prepares
Figure A20078000995900281
Figure A20078000995900282
Figure A20078000995900283
Figure A20078000995900284
Figure A20078000995900291
Figure A20078000995900292
Figure A20078000995900293
Figure A20078000995900294
Figure A20078000995900295
Figure A20078000995900302
Figure A20078000995900311
The tabulation of product chemical compound title; Embodiment 2-44:
Embodiment The chemical compound title
2 3-propoxyl group benzene carboxylic acid amides
3 3-isopropoxy benzene carboxylic acid amides
4 3-(cyclo propyl methoxy) benzene carboxylic acid amides
5 3-(amoxy) benzene carboxylic acid amides
6 3-(allyloxy) benzene carboxylic acid amides
7 3-butyl phenyl ether carboxylic acid amides
8 3-(hexyloxy) benzene carboxylic acid amides
9 3-(2-methoxy ethoxy) benzene carboxylic acid amides
10 3-(4-phenoxy group butoxy) benzene carboxylic acid amides
11 3-[(2-methyl-2-acrylic) oxygen base (oxy)] the benzene carboxylic acid amides
12 3-(7-octene oxygen base) benzene carboxylic acid amides
13 3-(isoamoxy) benzene carboxylic acid amides
14 The 3-[(4-methyl amyl) oxygen base] the benzene carboxylic acid amides
15 3-(5-hexene oxygen base) benzene carboxylic acid amides
16 3-(2-propoxyl group ethyoxyl) benzene carboxylic acid amides
17 3-(6-heptene oxygen base) benzene carboxylic acid amides
18 5-[3-(amino carbonyl) phenoxy group] the amyl group acetas
19 3-(octyloxy) benzene carboxylic acid amides
20 3-(4-phenyl butoxy) benzene carboxylic acid amides
21 The 3-[(5-phenylpentyl) oxygen base] the benzene carboxylic acid amides
22 3-[(5-methyl hexyl) oxygen base] the benzene carboxylic acid amides
23 3-(2-quinolyl methoxyl group) benzene carboxylic acid amides
24 3-(oxygen base in heptan) benzene carboxylic acid amides
25 4-[3-(amino carbonyl) phenoxy group] ethyl n-butyrate.
26 4-[3-(amino carbonyl) phenoxy group] methyl butyrate
27 2-[3-(amino carbonyl) phenoxy group] cyclohexyl acetate
28 3-(2-suberyl ethyoxyl) benzene carboxylic acid amides
29 The 3-[(3-methyl-benzyl) oxygen base] the benzene carboxylic acid amides
30 The 3-[2-butenyloxy] the benzene carboxylic acid amides
31 3-(the hot alkynyloxy group of 2-) benzene carboxylic acid amides
32 3-(4-alkynyloxy group in the ninth of the ten Heavenly Stems) benzene carboxylic acid amides
33 2-[3-(amino carbonyl) phenoxy group] ethyl acetate
34 3-[(4-fluorobenzene ethyl) oxygen base] the benzene carboxylic acid amides
35 3-[(4-methoxybenzene ethyl) oxygen base] the benzene carboxylic acid amides
36 3-[(6-phenyl hexyl) oxygen base] the benzene carboxylic acid amides
37 6-[3-(amino carbonyl) phenoxy group] ethyl hexanoate
38 10-[3-(amino carbonyl) phenoxy group] methyl caprate
39 The 3-[(2-methyl amyl) oxygen base] the benzene carboxylic acid amides
40 3-[(E)-and 3-octene oxygen base] the benzene carboxylic acid amides
41 2-[3-(amino carbonyl) phenoxy group] butyl acetate
42 3-(4-hydroxyl butoxy) benzene carboxylic acid amides
43 4-[3-(amino carbonyl) phenoxy group] butyl butyrate
44 3-(4-cyclohexyl butoxy) benzene carboxylic acid amides
Scheme 3:(a) ROH, PPh 3-PS, DIAD, Et 3N, THF, room temperature
Make the general process (method C) of alkylation of phenol with alcohol by rice formula reaction (Mitsunobu reaction).
Embodiment 453-[(Z)-and 5-decene oxygen base] the benzene carboxylic acid amides
Figure A20078000995900322
Under the room temperature, at triphenyl phasphine (1.4g, the 3mmol of polymer support, based on load 2.15mmol/g[available from Ya Ergu company (Argonaut)], 1.5 equivalents) in THF (20ml) in the swollen suspension, add diisopropyl azodicarboxylate (0.47ml, 2.4mmol, 1.2 equivalents).Mixed liquor is jolted 5 minutes, add 3-hydroxybenzamide (274mg, 2mmol, 1 equivalent), triethylamine (0.28ml, 2mmol, 1 equivalent) and suitable-5-decenol (313mg, 2mmol, 1 equivalent) then.The gained suspension is at room temperature jolted 16 hours, filter then.With extra THF (x 3) washing resin,, obtain the crude product of colourless semi-solid form then with the filtrate and the cleaning mixture concentrating under reduced pressure that merge.On silicagel column, carry out the column chromatography purification,, obtain the required compound (390mg, 71%) of white solid form, fusing point 98-100 ℃ with EtOAc/ hexane (20%-40% gradient) eluting.HPLC-MS (method 1): m/z 276[M+H] +, Rt=5.00 minute. 1H NMR(CDCl 3)δ＝7.35(s，1H)，7.32-7.28(m，2H)，7.08-7.02(m，1H)，6.18(br，2H)，5.41-5.32(m，2H)，3.98(t，J＝6.4Hz，2H)，2.12-2.05(m，2H)，2.05-1.98(m，2H)，1.79(m，2H)，1.51(m，2H)，1.34-1.28(m，4H)，0.88(t，J＝7.0Hz，3H)。
NB 1: in some cases, use azoethane dicarboxylic ester (0.38ml, 2.4mmol, 1.2 equivalents) to replace the diisopropyl azodicarboxylate.
NB 2: in some cases, use unsupported triphenyl phasphine.In the phenol of contain fluorine atoms, detect less than product during the triphenyl phasphine of use polymer-support, so use triphenyl phasphine to react.
Embodiment 46-61 (table B)
Embodiment 46-61 is according to method C, and scheme 3 is synthetic
Figure A20078000995900341
Figure A20078000995900342
Figure A20078000995900344
Figure A20078000995900351
Figure A20078000995900352
The name list of product chemical compound; Embodiment 46-61:
Embodiment The chemical compound title
46 3-(10-undecyne oxygen base) benzene carboxylic acid amides
47 3-[(Z)-and 2-nonene oxygen base] the benzene carboxylic acid amides
48 3-(5-alkynyloxy group in the last of the ten Heavenly stems) benzene carboxylic acid amides
49 3-[(E)-and 2-nonene oxygen base] the benzene carboxylic acid amides
50 3-(2-alkynyloxy group in the ninth of the ten Heavenly Stems) benzene carboxylic acid amides
51 3-(3-alkynyloxy group in the ninth of the ten Heavenly Stems) benzene carboxylic acid amides
52 3-[(Z)-and 5-octene oxygen base] the benzene carboxylic acid amides
53 3-[2-(amoxy) ethyoxyl] the benzene carboxylic acid amides
54 3-[2-(hexyloxy) ethyoxyl] the benzene carboxylic acid amides
55 3-{[(5E)-2,6,10-trimethyl-5,9-hendecane dialkylene] the oxygen base } the benzene carboxylic acid amides
56 3-[(2E, 6Z)-2,6-nonane diene oxygen base] the benzene carboxylic acid amides
57 3-{3-[2-(tert-butyl group)-5-(trifluoromethyl)-1,3-oxazole-4-yl] propoxyl group } the benzene carboxylic acid amides
58 3-[(E)-and 5-decene oxygen base] the benzene carboxylic acid amides
59 3-(the hot alkynyloxy group of 3-) benzene carboxylic acid amides
60 The 3-[(3-methyl amyl) oxygen base] the benzene carboxylic acid amides
61 3-[(Z)-and 6-nonene oxygen base] the benzene carboxylic acid amides
Scheme 4:(a) Br (CH 2) 6Br, K 2CO 3, CH 3CN, 60 ℃; (b) PPh 3, CH 3CN refluxes; (c) (i) KHMDS, toluene, 0 ℃; (ii) RCHO ,-78 ℃ to room temperature; (d) H 2, 10%Pd/C, MeOH, room temperature.
Figure A20078000995900361
3-[(6-bromine hexyl) oxygen base] the benzene carboxylic acid amides
Figure A20078000995900362
(method D) is with K 2CO 3(1.38g, 10mmol, 1 equivalent) joins 3-hydroxybenzamide (1.37g, 10mmol, 1 equivalent) at CH 3In the suspension among the CN (100ml).This mixed liquor was at room temperature stirred 10 minutes, add 1 then, 6-two bromos-hexane (9.76g, 40mmol, 4 equivalents).The gained mixed liquor was stirred 16 hours down at 60 ℃.Afterwards, make reactant liquor be cooled to room temperature, any undissolved solid of elimination is also extremely dried with filtrate evaporated under reduced pressure.Residue is extracted in EtOAc and the water.Separate organic facies, use K continuously 2CO 3Solution, water and salt water washing.Use MgSO 4Dry also reduction vaporization is to smaller size smaller.Precipitated solid is filtered and wash, obtain the required compound (2.0g, 67%) of white solid form, fusing point 115-117 ℃ with the EtOAc/ pentane.HPLC-MS (method 1): m/z 300[M] +, 302[M+2H] +, Rt=4.08 minute.
6-[3-(amino carbonyl) phenoxy group] hexyl (triphenyl) phosphonium bromide.
Figure A20078000995900371
With 3-[(6-bromine hexyl) the oxygen base] benzene carboxylic acid amides (2.10g, 7mmol, 1 equivalent) and triphenyl phasphine (1.93g, 7.35mmol, 1.05 equivalents) be at CH 3Mixed-liquor return heating among the CN (30ml) 72 hours.Solvent evaporated under reduced pressure is used anhydrous Et 2O development residue is up to curing.With solid filtering and vacuum drying, obtain the required compound (4.0g, 100%) of white solid form.HPLC-MS (method 1): m/z 482[M-Br] +, Rt=3.65 minute.
Embodiment 62:3-{[(Z)-and 7-(3-thienyl)-6-heptenyl] the oxygen base } the benzene carboxylic acid amides.
Figure A20078000995900372
(method E) is at 0 ℃ and N 2Down, in 15 minutes time to 6-[3-(amino carbonyl) phenoxy group that stirs] hexyl (triphenyl) phosphonium bromide (2.0g, 3.55mmol, 1.2 equivalents) and in the suspension of dry toluene (28ml), dropwise drip two (trimethyl silyl) amide potassium (0.5M at leisure; 7.1ml, 3.55mmol, 1.2 equivalents) and solution in toluene.With this deep orange solution restir 20 minutes, be cooled to-78 ℃ under 0 ℃, add thiophene-3-carboxylic aldehyde (carboxaldehyde) immediately, allow temperature be increased to room temperature from-78 ℃.Should at room temperature stir 16 hours by faint yellow mixed liquor.Use saturated NH 4Cl aqueous solution (20ml) cancellation reactant mixture and with solvent removed under reduced pressure.Residue extracts CH 2Cl 2And H 2Among the O, separate organic facies, with salt water washing and dry (Na 2SO 4).Solvent evaporated under reduced pressure, and on silicagel column, pass through column chromatography purification residue, with EtOAc/ hexane (10%-50% gradient) eluting, obtain the required compound (300mg, 35%) of pale solid form, fusing point 71-73 ℃. 1H NMR analyzes, and is Z: the mixture of E (90: 10).HPLC-MS (method 1): m/z 316[M+H] +, Rt=4.62 minute.
Embodiment 63:3-{[7-(3-thienyl) heptyl] the oxygen base } the benzene carboxylic acid amides.
Figure A20078000995900373
3-{[(Z at embodiment 62)-and 7-(3-thienyl)-6-heptenyl] the oxygen base } (260mg in MeOH 0.82mmol) (8ml) solution, adds 10%Pd/C (30mg) to the benzene carboxylic acid amides.With this mixed liquor at H 2, stirred 3 days under the room temperature.Remove by filter catalyst by Celite pad, solvent evaporated under reduced pressure is to smaller size smaller.The solid of filtering-depositing is also used Et 2The O/ pentane washs, and obtains the required compound (130mg, 48%) of white solid form, fusing point 97-100 ℃.HPLC-MS (method 1): m/z 318[M+H] +, Rt=4.87 minute.
Embodiment 64:3-{[(Z)-and 7-(5-chloro-2-furyl)-6-heptenyl] the oxygen base } the benzene carboxylic acid amides.
Figure A20078000995900381
According to method E, by 6-[3-(amino carbonyl) phenoxy group] (triphenyl) phosphonium bromide is synthetic for hexyl.Productive rate 72%, fusing point 53-56 ℃. 1H NMR analyzes, and is Z: the mixture of E (81: 19).HPLC-MS (method 1): m/z 334[M+H] +, Rt=4.80 minute.
Scheme 5:(a) Br (CH 2) nBr (n=5,8) K 2CO 3, CH 3CN, 60 ℃; (b) ethinylation lithium ethylenediamine complex [LiC ≡ CH (H 2NCH 2CH 2NH 2)], DMSO, room temperature
Figure A20078000995900382
3-[(7-bromine heptyl) oxygen base] the benzene carboxylic acid amides.
Figure A20078000995900383
Synthetic according to method D.HPLC-MS (method 1): m/z 314[M] +, 316[M+2H] +, Rt=4.37 minute.
Embodiment 65:3-(8-alkynyloxy group in the ninth of the ten Heavenly Stems) benzene carboxylic acid amides.
Figure A20078000995900391
(method F) places three-neck flask with ethinylation lithium ethylenediamine complex (305mg, 3.3mmol, 1.1 equivalents), and the degassing blows N 2And be suspended among the DMSO (2ml).At N 2Under room temperature, in the suspension that stirs, dropwise drip 3-[(7-bromine heptyl at leisure) the oxygen base] DMSO (2ml) solution of benzene carboxylic acid amides (943mg, 3mmol, 1 equivalent).This reactant mixture was at room temperature stirred 16 hours.Afterwards, extract with 1N HCl solution dilution and with EtOAc (x3).With organic extract salt water washing, the drying (Na that merges 2SO 4), reduction vaporization is to doing.Crude product is passed through the column chromatography purification on silicagel column,, obtain the required compound (100mg, 13%) of white solid form, fusing point 82-83 ℃ with EtOAc/ hexane 20% eluting.HPLC-MS (method 1): m/z 260[M+H] +, Rt=4.26 minute.
3-[(7-bromine decyl) oxygen base] the benzene carboxylic acid amides.
Figure A20078000995900392
Synthetic according to method D.Productive rate 32%, fusing point 114-116 ℃, HPLC-MS (method 1): m/z 356[M] +, 358[M+2H] +, Rt=5.15 minute.
Embodiment 66:3-(11-dodecyne oxygen base) benzene carboxylic acid amides.
Figure A20078000995900393
According to method F, by 3-[(7-bromine decyl) the oxygen base] the benzene carboxylic acid amides is synthetic; Fusing point 106-108 ℃, HPLC-MS (method 1): m/z 302[M+H] +, Rt=5.02 minute.
Scheme 6:(a) ethinylation lithium ethylenediamine complex [LiC ≡ CH (H 2NCH 2CH 2NH 2)], DMSO, room temperature; (b) p-methyl benzenesulfonic acid, EtOH refluxes; (c) 3-hydroxy benzenes carboxylic acid amides, PPh 3-PS, DIAD, Et 3N, THF, room temperature
Figure A20078000995900401
10-undecyne-1-alcohol
(method G) is at room temperature and N 2Down, with commercially available 2-[(8-bromine octyl group) the oxygen base] DMSO (5ml) solution of tetrahydrochysene-2H-pyrans (1.0g, 3.4mmol, 1 equivalent) slowly dropwise is added drop-wise to the ethinylation lithium ethylenediamine complex (350mg of stirring, 3.8mmol, 1.1 equivalents) DMSO (5ml) suspension in.This reactant mixture was at room temperature stirred 18 hours and used pentane (50ml) dilution.With organic facies with 1NHCl solution (2 * 20ml) and water (2 * 20ml) washings, drying (Na 2SO 4), reduction vaporization is to doing.Residue (colourless liquid, 570mg, productive rate 70%) is dissolved in 95%EtOH (20ml) and the p-methyl benzenesulfonic acid (150mg), with mixed-liquor return heating 2.5 hours.After the cooling, solvent evaporated under reduced pressure.Residue by the column chromatography purification, with EtOAc/ hexane (10%-30% gradient) eluting, obtains the required compound (240mg, gross production rate 48%) of water white oil form on silicagel column.
Embodiment 67:3-(9-alkynyloxy group in the last of the ten Heavenly stems) benzene carboxylic acid amides.
Figure A20078000995900403
According to method C, scheme 3, synthetic by 3-hydroxy benzenes carboxylic acid amides and 10-undecyne-1-alcohol; Fusing point 111-112 ℃, HPLC-MS (method 1): m/z 274[M+H] +, Rt=4.61 minute.
Scheme 7:(a) SOCl 2, toluene refluxes; (b) aqueous NH 3(c) the n-ninth of the ten Heavenly Stems-Br, K 2CO 3, NaI, DMF, 60 ℃; (d) 10-undecyne alcohol, PPh 3-PS, DIAD, Et 3N, THF, room temperature
Figure A20078000995900411
2-chloro-5-hydroxy benzenes carboxylic acid amides.
Figure A20078000995900412
According to method A, scheme 1, synthetic by commercially available 2-chloro-5-hydroxy benzenes carboxylic acid.Productive rate 28%, fusing point 159-161 ℃, HPLC-MS (method 1): m/z 170[M-H] -, Rt=1.48 minute.
Embodiment 68:2-chloro-5-(oxygen base in the ninth of the ten Heavenly Stems) benzene carboxylic acid amides.
Figure A20078000995900413
According to method B, scheme 2, synthetic by 2-chloro-5-hydroxy benzenes carboxylic acid amides.Productive rate 80%, HPLC-MS (method 1): m/z 339[M+H+CH 3CN] +, Rt=5.29 minute.
Embodiment 69:2-chloro-5-(10-undecyne oxygen base) benzene carboxylic acid amides.
According to method C, scheme 3, synthetic by 2-chloro-5-hydroxy benzenes carboxylic acid amides.Productive rate 13%, HPLC-MS (method 1): m/z 322[M+H] +, Rt=4.94 minute.
Scheme 8:(a) BBr 3, CH 2Cl 2, room temperature; (b) R 1-Br, K 2CO 3, NaI, DMF, 60 ℃; (c) R 2-OH, PPh 3-PS, DIAD, Et 3N, THF, room temperature
2-fluoro-5-hydroxy benzenes carboxylic acid amides.
Figure A20078000995900422
(method H) is at room temperature and N 2Down, (1.0M is at CH with Boron tribromide solution 2Cl 2In, 23.6ml, 23.6mmol, 2 equivalents) the slow CH that dropwise is added drop-wise to the 2-fluoro-5-methoxybenzene carboxylic acid amides (2.0g, 11.8mmol, 1 equivalent) of stirring 2Cl 2(60ml) in the solution.This reactant mixture was at room temperature stirred 48 hours.Removal of solvent under reduced pressure is dissolved in the water (120ml) residue also with EtOAc (4 * 100ml) extractions.With organic extract water (2 * 100ml) washings, the dry (Na that merges 2SO 4), filter by silicagel pad.Filtrate evaporated under reduced pressure to doing, is obtained the required compound (1.50g, 82%) of gray solid form.
Embodiment 70-75 (table C)
According to method B, scheme 2, by the synthetic embodiment 70-72 of 2-fluoro-5-hydroxy benzenes carboxylic acid amides, according to method C, scheme 3 is by the synthetic embodiment 73-75 of 2-fluoro-5-hydroxy benzenes carboxylic acid amides.
Figure A20078000995900431
Figure A20078000995900432
Figure A20078000995900433
The name list of product chemical compound; Embodiment 70-75:
Embodiment The chemical compound title
70 2-fluoro-5-(oxygen base in the ninth of the ten Heavenly Stems) benzene carboxylic acid amides
71 2-fluoro-5-(oxygen base in the last of the ten Heavenly stems) benzene carboxylic acid amides
72 2-fluoro-5-(hendecane oxygen base) benzene carboxylic acid amides
73 2-fluoro-5-[(Z)-and 5-octene oxygen base] the benzene carboxylic acid amides
74 2-fluoro-5-[(E)-and 2-nonene oxygen base] the benzene carboxylic acid amides
75 2-fluoro-5-(10-undecyne oxygen base) benzene carboxylic acid amides
Scheme 9:(a) SOCl 2, toluene refluxes; (b) aqueous NH 3(c) BBr 3, CH 2Cl 2, room temperature; (d) the n-ninth of the ten Heavenly Stems-Br, K 2CO 3, NaI, DMF, 60 ℃.
Figure A20078000995900441
6-chloro-2-fluoro-3-methoxybenzene carboxylic acid amides.
Figure A20078000995900442
According to method A, scheme 1, synthetic by commercially available 6-chloro-2-fluoro-3-methoxybenzene carboxylic acid.Productive rate 85%, fusing point 154-156 ℃, HPLC-MS (method 1): m/z 245[M+H+CH 3CN] +, Rt=2.37 minute.
6-chloro-2-fluoro-3-hydroxy benzenes carboxylic acid amides.
Figure A20078000995900443
According to method H, synthetic by 6-chloro-2-fluoro-3-methoxybenzene carboxylic acid amides.Productive rate 90%.
Embodiment 76:6-chloro-2-fluoro-3-(oxygen base in the ninth of the ten Heavenly Stems) benzene carboxylic acid amides.
Figure A20078000995900444
According to method B, scheme 2, synthetic by 6-chloro-2-fluoro-3-hydroxy benzenes carboxylic acid amides.Productive rate 73%, fusing point 75-77 ℃, HPLC-MS (method 1): m/z 316[M+H] +, Rt=5.27 minute.
Scheme 10:(a) BBr 3, CH 2Cl 2, room temperature; (b) R-Br, K 2CO 3, NaI, DMF, 60 ℃.
Figure A20078000995900451
2-chloro-6-fluoro-3-hydroxy benzenes carboxylic acid amides.
Figure A20078000995900452
According to method H, synthetic by commercially available 2-chloro-6-fluoro-3-methoxybenzene carboxylic acid amides.Productive rate 78%.
Embodiment 77:2-chloro-6-fluoro-3-(hexyloxy) benzene carboxylic acid amides.
Figure A20078000995900453
According to method B, scheme 2, synthetic by 2-chloro-6-fluoro-3-hydroxy benzenes carboxylic acid amides.Productive rate 30%, fusing point 66-68 ℃, HPLC-MS (method 1): m/z 274[M+H] +, Rt=2.78 minute.
Embodiment 78:2-chloro-6-fluoro-3-(oxygen base in the ninth of the ten Heavenly Stems) benzene carboxylic acid amides.
Figure A20078000995900454
According to method B, scheme 2, synthetic by 2-chloro-6-fluoro-3-hydroxy benzenes carboxylic acid amides.Productive rate 15%, fusing point 64-66 ℃, HPLC-MS (method 1): m/z 316[M+H] +, Rt=5.13 minute.
Scheme 11:(a) SOCl 2, toluene refluxes; (b) aqueous NH 3(c) BBr 3, CH 2Cl 2, room temperature; (d) n-oneself-Br, K 2CO 3, NaI, DMF, 60 ℃.
2,4,6-three fluoro-3-methoxybenzene carboxylic acid amides.
Figure A20078000995900461
According to method A, scheme 1, by commercially available 2,4,6-three fluoro-3-methoxybenzene carboxylic acids are synthetic.Productive rate 85%, 102 ℃ of fusing points, HPLC-MS (method 1): m/z 206[M+H] +, Rt=2.40 minute.
2,4,6-three fluoro-3-hydroxy benzenes carboxylic acid amides.
According to method H, by 2,4,6-three fluoro-3-methoxybenzene carboxylic acid amides are synthetic.Productive rate 100%, HPLC-MS (method 1): m/z 190[M-H] -, Rt=1.07 minute.
Embodiment 79:2,4,6-three fluoro-3-(hexyloxy) benzene carboxylic acid amides.
Figure A20078000995900463
According to method B, scheme 2, by 2,4,6-three fluoro-3-hydroxy benzenes carboxylic acid amides are synthetic.Productive rate 54%, fusing point 89-90 ℃, HPLC-MS:m/z 276[M+H] +, Rt=4.36 minute.
Scheme 12:(a) BBr 3, CH 2Cl 2, room temperature; (b) n-oneself-Br, K 2CO 3, NaI, DMF, 60 ℃.
Figure A20078000995900464
2,4-two fluoro-3-hydroxy benzenes carboxylic acid amides.
Figure A20078000995900471
According to method H, by commercially available 2,4-two fluoro-3-methoxybenzene carboxylic acid amides is synthetic.Productive rate 98%, HPLC-MS (method 1): m/z 172[M-H] -, Rt=1.03 minute.
Embodiment 80:2,4-two fluoro-3-(hexyloxy) benzene carboxylic acid amides.
Figure A20078000995900472
According to method B, scheme 2, by 2,4-two fluoro-3-hydroxy benzenes carboxylic acid amides is synthetic.Productive rate 51%, fusing point 86-87 ℃.
Scheme 13:(a) SOCl 2, toluene refluxes; (b) aqueous NH 3(c) BBr 3, CH 2Cl 2, room temperature; (d) R 1-Br, K 2CO 3, NaI, DMF, 60 ℃; (e) R 2-OH, PPh 3-PS, DIAD, Et 3N, THF, room temperature
Figure A20078000995900473
2,6-two fluoro-3-methoxybenzene carboxylic acid amides.
Figure A20078000995900474
According to method A, scheme 1, by commercially available 2,6-two fluoro-3-methoxybenzene carboxylic acid is synthetic.Productive rate 84%, fusing point 167-169 ℃, HPLC-MS (method 1): m/z 188[M+H] +, Rt=2.00 minute.
2,6-two fluoro-3-hydroxy benzenes carboxylic acid amides.
According to method H, by 2,6-two fluoro-3-methoxybenzene carboxylic acid amides is synthetic.Productive rate 78%.HPLC-MS (method 1): m/z 172[M-H] -, Rt=1.25 minute
Embodiment 81-87 (table D)
According to method B, scheme 2, by 2,6-two fluoro-3-hydroxy benzenes carboxylic acid amides synthesizes embodiment 81-83.According to method C, scheme 3, by 2,6-two fluoro-3-hydroxy benzenes carboxylic acid amides synthesizes embodiment 84-88.
Figure A20078000995900482
The name list of product chemical compound; Embodiment 81-88:
Embodiment The chemical compound title
81 2,6-two fluoro-3-(hexyloxy) benzene carboxylic acid amides
82 2,6-two fluoro-3-(oxygen base in the ninth of the ten Heavenly Stems) benzene carboxylic acid amides
83 2-[3-(amino carbonyl)-2,4 difluorobenzene oxygen base] butyl acetate
84 2,6-two fluoro-3-[(E)-and 2-nonene oxygen base] the benzene carboxylic acid amides
85 2,6-two fluoro-3-[2-(hexyloxy) ethyoxyl] the benzene carboxylic acid amides
86 2,6-two fluoro-3-[(Z)-and 6-nonene oxygen base] the benzene carboxylic acid amides
87 2,6-two fluoro-3-[(Z)-and 5-decene oxygen base] the benzene carboxylic acid amides
88 2,6-two fluoro-3-(10-undecyne oxygen base) benzene carboxylic acid amides
Scheme 14:(a) K 2CO 3, DMF, room temperature; (b) NaOH, H 2O/IPA refluxes; (c) n-oneself-Br, K 2CO 3, DMF, 70 ℃.
Figure A20078000995900492
2-[3-(amino carbonyl)-2,4 difluorobenzene oxygen base] methyl acetate
Figure A20078000995900493
With 2,6-two fluoro-3-hydroxy benzenes carboxylic acid amides (1.2g, 7mmol, 1 equivalent), K 2CO 3DMF (30ml) mixed liquor of (2.87g, 21mmol, 3 equivalents) and methyl bromoacetate (.69ml, 7.35mmol, 1.05 equivalents) at room temperature stirred 18 hours.With the mixed liquor dilute with water, with EtOAc (4 * 80ml) extractions.With the organic extract drying (MgSO that merges 4) and reduction vaporization to doing.Product does not deal with and promptly is used for next step.HPLC-MS (method 1): m/z 246[M+H] +, Rt=2.08 minute.
2-[3-(amino carbonyl)-2,4 difluorobenzene oxygen base] acetic acid.
Figure A20078000995900501
With 2-[3-(amino carbonyl)-2,4 difluorobenzene oxygen base] methyl acetate (7mmol, 1 equivalent) adds in the water (20ml) and isopropyl alcohol (5ml) solution of NaOH (1g, 25mmol, 3.6 equivalents).This mixed-liquor return was stirred 1.5 hours, and water (40ml) dilutes and uses CH 2Cl 2(40ml) extraction.With concentrated hydrochloric acid solution with aqueous phase as acidified to pH 1.The solid of filtering-depositing, vacuum drying obtains required compound (130mg, 8%), fusing point 152-153 ℃ .HPLC-MS (method 1): m/z 312[M-H+2CH 3CN] -, Rt=0.91 minute.
Embodiment 89:2-[3-(amino carbonyl)-2,4 difluorobenzene oxygen base] Exceed 600.
Figure A20078000995900502
Positive bromo hexane (0.077ml, 0.55mmol, 1.05 equivalents) is added 2-[3-(amino carbonyl)-2,4 difluorobenzene oxygen base] acetic acid (120mg, 0.52mmol, 1 equivalent) and K 2CO 3(215mg, 1.56mmol, 3 equivalents) stir this mixed liquor 1.5 hours down at 70 ℃ in the suspension of DMF (3ml).After the cooling, mixed liquor is poured in the water (25ml) solid of filtering-depositing, water (2 * 20ml) washings under the room temperature.After the drying, develop this crude product solid, to filter and (3 * 10ml) wash, and obtain the required compound (99mg, 60%) of white solid form, 108 ℃ of fusing points with hexane by in hexane (10ml), stirring.HPLC-MS:m/z 316[M+H] +, Rt=4.09 minute.
Scheme 15:(a) ethinylation lithium ethylenediamine complex [LiC ≡ CH (H 2NCH 2CH 2NH 2)], DMSO, room temperature; (b) p-methyl benzenesulfonic acid, EtOH refluxes; (c) ClCH 2COCl, CH 2Cl 2, room temperature; (d) K 2CO 3, NaI, DMF, 60 ℃.
Figure A20078000995900511
7-octyne-1-alcohol.
According to method G, by commercially available 2-[(8-bromine hexyl) the oxygen base] tetrahydrochysene-2H-pyrans is synthetic.Gross production rate 55%, water white oil.
7-octyne base 2-chloracetate.
Figure A20078000995900513
Under 5 ℃, chloro-acetyl chloride (0.16ml, 2.0mmol, 1 equivalent) is added the CH of the 7-octyne-1-alcohol (300mg, 2.4mmol, 1.2 equivalents) that stirs 2Cl 2(6m-) in the solution.This reactant mixture is increased to room temperature, stirred 4 hours.Removal of solvent under reduced pressure, and with residue on silicagel column by the column chromatography purification, with EtOAc/ hexane (10%) eluting, obtain the required compound (450mg, 100%) of weak yellow liquid form.
Embodiment 90:7-octyne base 2-[3-(amino carbonyl)-2,4 difluorobenzene oxygen base] acetas.
According to method B, scheme 2, by 2,6-two fluoro-3-hydroxy benzenes carboxylic acid amides is synthetic.Productive rate 13%, fusing point 130-132 ℃, HPLC-MS (method 1): m/z 340[M+H] +, Rt=3.93 minute.
Scheme 16:(a) ZnEt 2, CH 2I 2, toluene, room temperature
Figure A20078000995900521
Embodiment 91:3-[4-(2-ethyl cyclopropyl) butoxy] the benzene carboxylic acid amides.
Figure A20078000995900522
At room temperature and N 2Diethyl zinc solution (1.1M in toluene, 1.84ml, 2.02mmol, 1 equivalent) is joined in dry toluene (1ml) solution of embodiment 52 (500mg, 2.02mmol, 1 equivalent) down.Slowly dropwise drip diiodo-acute pyogenic infection of nails alkane (0.244ml, 3.03mmol, 1.5 equivalents), and this reactant mixture was at room temperature stirred 5 days.With mixed liquor water (40ml) dilution, use CH 2Cl 2(4 * 40ml) extractions.With the organic extract drying (MgSO that merges 4), removal of solvent under reduced pressure.HPLC-MS analyzes, and the crude product residue comprises initial substance (80%) and required product (20%).Use diethyl zinc (1.1M in toluene, 6.1ml, 6.6mmol, 3.3 equivalents) and diiodo-acute pyogenic infection of nails alkane (0.244ml, 3.03mmol, 1.5 equivalents), in toluene (15ml), repeat this reaction in the same manner.Reactant mixture was stirred 5 days down at 50 ℃, and water (80ml) dilutes and uses CH 2Cl 2(4 * 50ml) extractions.With the organic extract drying (MgSO that merges 4), removal of solvent under reduced pressure.Develop residue by stirring in pentane (15ml), the solid of filtering-depositing with the pentane flushing, obtains 196mg whitening compound, fusing point 104-105 ℃.HPLC-MS analyzes, and it comprises initial substance (65%) and required product (35%).HPLC-MS (method 1): m/z 303[M+H+CH 3CN] +, Rt=4.83 minute.
Scheme 17:(a) Br (CH 2) 9OH, K 2CO 3, NaI, DMF, 60 ℃; (b) toluene sulfochloride, Et 3N, CH 2Cl 2, room temperature; (c) NaCN, H 2O/EtOH, 75 ℃.
Figure A20078000995900531
3-[(9-hydroxyl nonyl) oxygen base] the benzene carboxylic acid amides.
Figure A20078000995900532
According to method B, scheme 2 is synthetic.Productive rate 75%, fusing point 118-120 ℃, HPLC-MS (method 1): m/z 280[M+H] +, Rt=3.50 minute.
Embodiment 92:9-[3-(amino carbonyl) phenoxy group] nonyl 4-tosylate.
Figure A20078000995900533
Toluene sulfochloride (410mg, 2.15mmol, 1.5 equivalents) and triethylamine (0.40ml, 2.88mmol, 2 equivalents) are joined 3-[(9-hydroxyl nonyl) the oxygen base] CH of benzene carboxylic acid amides (400mg, 1.43mmol, 1 equivalent) 2Cl 2(4ml) in the solution, this reactant mixture was at room temperature stirred 6 days.Add saturated NaHCO 3Solution (40ml) is with mixed liquor CH 2Cl 2(3 * 30ml) extractions.With the organic extract drying (MgSO that merges 4), solvent evaporated under reduced pressure.Residue is passed through the column chromatography purification on silicagel column, use CH 3OH/CH 2Cl 2(2%) eluting obtains the required compound (428mg, 69%) of white solid form, fusing point 78-80 ℃.HPLC-MS (method 1): m/z 434[M+H] +, Rt=4.90 minute.
Embodiment 93:3-[(9-cyano group nonyl) oxygen base] the benzene carboxylic acid amides.
Figure A20078000995900541
With Cyanogran. (60mg, 1.22mmol, 1.3 equivalents) and adding 9-[3-(amino carbonyl) phenoxy group] nonyl 4-tosylate (407mg, 0.94mmol, 1 equivalent) in the solution of water (10ml) and 95%EtOH (8ml), this reactant mixture was stirred 2 days down at 75 ℃.After the cooling,, use CH under the room temperature with mixed liquor water (10ml) dilution 2Cl 2(3 * 10ml) extractions.With the organic extract drying (MgSO that merges 4), removal of solvent under reduced pressure.The crude product residue is passed through the column chromatography purification on silicagel column,, obtain the required compound (57mg, 21%) of white solid form, fusing point 96-97 ℃ with EtOAc/ hexane (50%) eluting.HPLC-MS (method 1): m/z 289[M+H] +, Rt=4.16 minute.
Scheme 18:(a) the n-ninth of the ten Heavenly Stems-Br, K 2CO 3, NaI, DMF, 60 ℃; (b) LiOH, NaOCH 3, MeOH refluxes.
The different cigarette nitrile of 2-(oxygen base in the ninth of the ten Heavenly Stems).
Figure A20078000995900543
According to method B, synthetic by the different cigarette nitrile of commercially available 2-hydroxyl.Productive rate 30%, semisolid, HPLC-MS (method 2): m/z 288[M+H+CH 3CN] +, Rt=21.46 minute.Reaction also produces by-product 1-nonyl-2-oxo-1,2-dihydro-4-pyridine nitrile, productive rate 39%, fusing point 46-48 ℃, HPLC-MS (method 1): m/z 288[M+H+CH 3CN] +, Rt=4.94 minute.
Embodiment 94:2-(oxygen base in the ninth of the ten Heavenly Stems) Pyrazinamide.
Figure A20078000995900551
Anhydrous CH with different cigarette nitrile of 2-(oxygen base in the ninth of the ten Heavenly Stems) (250mg, 1.0mmol, 1 equivalent) and Feldalat NM (10mg, 0.1mmol, 0.1 equivalent) 3OH (10ml) solution at room temperature stirred 2.5 hours.Water (1ml) solution that adds Lithium hydrate (24mg, 1.0mmol, 1 equivalent), and with this reaction mixture refluxed heating 3.5 hours.After the cooling, mixed liquor is poured in the water (40ml) under the room temperature.The solid of filtering-depositing, and, obtain the required compound (60mg, 23%) of white solid form, fusing point 108-110 ℃ at 50 ℃ of following vacuum dryings.HPLC-MS (method 1): m/z 265[M+H] +, Rt=5.08 minute.
Scheme 19:(a) Br 2, CCl 4, (b) K 2CO 3, CH 3CN, 60 ℃, 5 days, (c) dense H 2SO 4, H 2O, 40 ℃.
Figure A20078000995900552
1, the 2-dibromo-heptane
Figure A20078000995900553
At N 2Bromine (1.9ml, 37.28mmol, 1.05 equivalents) slowly dropwise is added drop-wise to the CCl of cooling at-10 ℃ 1-heptene (5ml, 35.5mmol, 1 equivalent) down, 4(7ml) in the solution.This reactant mixture was at room temperature stirred 16 hours.Solvent removed by evaporation at reduced pressure.With residue at CH 2Cl 2(200ml) and between 10% sodium metasulfite (sodium metabisulfate) aqueous solution (200ml) distribute.Separate organic facies, use the salt water washing, dry (Na 2SO 4).Reduction vaporization obtains the required compound (8.94g, 98%) of water white oil form to doing.
3-amyl group-2,3-dihydro-1,4-Ben Bing dioxine-6-nitrile and 2-amyl group-2,3-dihydro-1,4-Ben Bing dioxine-6-nitrile.
Figure A20078000995900561
With 1,2-dibromo-heptane (5.11g, 19.8mmol, 1.1 equivalents) adds two-hydroxy benzonitrile (2.43g, 18mmol, 1 equivalent) and K 2CO 3(12.4g, 90mmol, 5 equivalents) are at CH 3In the mixed liquor of CN (100ml).With this reaction mixture refluxed heating 4 days.After being cooled to room temperature, removal of solvent under reduced pressure; With residue water (200ml) dilution, with EtOAc (3 * 150ml) extractions.With the organic facies salt water washing that merges, dry (Na 2SO 4), reduction vaporization is to doing.Residue is passed through the column chromatography purification on silicagel column,, obtain the required compound (390mg, 9%) of water white oil form with EtOAc/ hexane (5%-10% gradient) eluting; The mixture of two kinds of regional isomers.HPLC-MS (method 1): m/z230[M-H] -, Rt=5.28 minute.
Embodiment 95:3-amyl group-2,3-dihydro-1,4-Ben Bing dioxine-6-carboxylic acid amides and 2-amyl group-2,3-dihydro-1,4-Ben Bing dioxine-6-carboxylic acid amides.
Figure A20078000995900562
With regional isomer 3-amyl group-2,3-dihydro-1,4-Ben Bing dioxine-6-nitrile and 2-amyl group-2,3-dihydro-1, (50mg is 0.22mmol) at dense H for the mixture of 4-Ben Bing dioxine-6-nitrile 2SO 4Vigorous stirring (0.5ml), and be warming up to 40 ℃.Dropwise add entry (82mg), this mixed liquor was stirred 45 minutes down at 40 ℃.Mixed liquor-5 ℃ of coolings down, is added ice (25ml) fast under the vigorous stirring.With mixed liquor restir 2 hours at room temperature.The solid of filtering-depositing washes with water, and at 40 ℃ of following vacuum dryings.Go up purification at preparation type TLC plate (Analtech, 2mm, 20 * 20), use the methyl tertiary butyl ether(MTBE) eluting, obtain the required compound (50mg, 93%) of white solid form, HPLC-MS (method 1): m/z 291[M+H+CH 3CN] +, Rt=4.14 minute.
Embodiment 96-99,101-116,117,119,122,124,128-134,137-139, 142,144-154,156-159 and 161-163 (table E)
According to following general process, synthetic embodiment 96-99,101-116,117,119,122,124,128-134,137-139,142,144-154, the chemical compound of 156-159 and 161-163: in dry DMF (B) solution of reactant (A), add 2,6-two fluoro-3-hydroxybenzamide (C) and potassium carbonate (D).Under the nitrogen environment, this reactant mixture is stirred down room temperature or 25 ℃.The reactant mixture reduction vaporization is extremely done, and residue is gone up by the column chromatography purification at silicagel column (230-400 μ), adopt ethyl acetate/hexane, obtain the product chemical compound as eluant.
Table E
Figure A20078000995900581
Figure A20078000995900591
Figure A20078000995900592
Figure A20078000995900601
Figure A20078000995900611
Figure A20078000995900612
Figure A20078000995900621
Figure A20078000995900622
Figure A20078000995900631
Figure A20078000995900632
Figure A20078000995900641
Figure A20078000995900642
Figure A20078000995900661
Figure A20078000995900662
Figure A20078000995900671
Figure A20078000995900681
Figure A20078000995900682
Figure A20078000995900691
Figure A20078000995900692
Figure A20078000995900701
Figure A20078000995900702
Figure A20078000995900711
Figure A20078000995900712
Embodiment 100:3-[4-(2-bromo-5-methoxyl group-phenyl)-thiazol-2-yl methoxyl group]-2,6-two fluoro-Benzoylamide
Figure A20078000995900721
At 3-[5-bromo-4-(2-bromo-5-methoxyl group-phenyl)-thiazol-2-yl methoxyl group]-2,6-two fluoro-Benzoylamide (0.06g, add in 6ml acetic acid solution .0001mol) zinc (0.06g .0001mol).With reaction mixture refluxed 30 minutes.Make reactant mixture arrive 25 ℃.This reactant mixture is filtered on the kieselguhr filter bed, in filtrate, add water and make the product precipitation.Filtration obtains white solid and dry (0.006g, 12%). 1H NMR (DMSO, 400MHz), 3.79 (s, 3H), 5.59 (s, 2H), 6.94 (dd, 1H, J=8.8Hz (o-coupling), J=4.0Hz), 7.09-7.15 (m, 1H), 7.27 (d, 1H, J-4.0Hz), and 7.40-7.43 (m, 1H), 7.63 (d, 1H, J=8.8Hz (o-coupling), 7.89 (wide s, 1H), 8.11 (s, 1H), 8.18 (s, 1H); MS ES+ (455.08 and 457.08) .HPLC (method 5) Rt=10.21 minute.
Embodiment 118:2,6-two fluoro-3-[4-(4-methoxyl group-phenyl)-5-propyl group-thiazol-2-yl methoxyl group]-Benzoylamide
Figure A20078000995900722
At 3-[5-pi-allyl-4-(4-methoxyl group-phenyl)-thiazol-2-yl methoxyl group]-2, (0.1g adds exsiccant 50mg and does Pd-C 6-two fluoro-Benzoylamide in 5ml absolute methanol solution 0.02mmol).Under the hydrogen environment, this reactant mixture was stirred 12 hours down at 25 ℃.Reactant mixture is filtered on the kieselguhr filter bed.Filtrate evaporated under reduced pressure to dry doubling is gone up by column chromatography purification residue at silicagel column (230-400 μ), with ethyl acetate/hexane (50: 50) eluting, obtains the title compound (0.02g, 2%) of white solid form. 1H NMR (DMSO-d 6, 400MHz); δ 0.92 (t, 3H, J=7.2Hz), 1.63-1.65 (m, 2H), 2.8 (t, 2H, J=7.6Hz (o-coupling), 3.79 (s, 3H), 5.47 (s, 2H), 7.02 (d, 2H, J=8.8Hz (o-coupling), 7.11 (m, 1H), 7.42 (m, 1H), 7.53 (d, 2H, J=8.8Hz (o-coupling), 7.88 (s, 1H), 8.16 (s, 1H), 8.38 (d, 1H, J=8.4Hz (o-coupling).MS ES+ (419.14), HPLC (method 5) Rt=16.58 minute.
Embodiment 120:3-[5-pi-allyl-4-(4-methoxyl group-phenyl)-thiazol-2-yl methoxyl group]-2,6-two fluoro-Benzoylamide
At 3-[5-bromo-4-(4-methoxyl group-phenyl)-thiazol-2-yl methoxyl group]-2,6-two fluoro-Benzoylamide (0.1g, 0.0002mol) the 5ml anhydrous DMF solution in add allyl tributyltin (0.072g 0.0002mol), and made the reactant mixture degassing 10 minutes.Then, and adding tetraphenylphosphonium palladium (0) (0.025g, 0.00002mol).Under the nitrogen environment, reactant mixture was heated 12 hours down at 120 ℃.Then reactant mixture is cooled to room temperature.To wherein adding 100ml water and use the ethyl acetate extraction chemical compound, with the organic layer of merging in anhydrous Na 2SO 4Last dry, reduction vaporization is to doing.Chemical compound is gone up by the column chromatography purification at silicagel column (230-400 μ),, obtained the title compound (0.120g, 60%) of brown solid form with methanol/DCM (2: 98) eluting. 1H NMR (DMSO-d 6, 400MHz): δ 3.79 (s, 3H), 5.11-5.14 (m, 1H), 5.16 (s, 1H), 5.48 (s, 2H), 5.57 (s, 1H), and 5.99-6.06 (m, 1H), 7.03 (d, 2H, J=8.4Hz (o-coupling), 7.11 (dt, 1H, J=9.2Hz (o-coupling), 7.36-7.42 (m, 1H), 7.56 (d, 2H, J=8.8Hz (o-coupling), 7.88 (wide s, 1H), 8.16 (wide s, 1H).MS ES+ (417.06), HPLC (method 5) Rt=16.96 minute.
Embodiment 121:2,6-two fluoro-3-[4-(4-methoxyl group-phenyl)-5-pyridin-3-yl-thiazol-2-yl methoxyl group]-Benzoylamide
Figure A20078000995900732
At 3-[5-bromo-4-(4-methoxyl group-phenyl)-thiazol-2-yl methoxyl group]-2,6-two fluoro-Benzoylamide (0.1g, DMF 0.02mmol): H 2In O (2: the 1) solution, and adding 3-pyridine boric acid (0.054g, 0.04mmol), potassium phosphate (0.056g, 0.025mmol).Make this reactant mixture degassing 10 minutes, adding dichloro-then, two [(0.023g's (triphenyl phasphine)-palladium (II) again 0.003mmol), outgased 10 minutes.Under the nitrogen environment, this reactant mixture was heated 12 hours down at 120 ℃.DMF is removed in distillation, be cooled to room temperature after, water is joined in the reactant mixture, use ethyl acetate extraction, with the organic layer of merging in anhydrous Na 2SO 4Last dry, reduction vaporization is to doing.Chemical compound is gone up by the column chromatography purification at silicagel column silicon dioxide (230-400 μ),, obtained the title compound (0.050g, 50%) of yellow solid form with ethyl acetate/hexane (50: 50) eluting. 1H NMR (DMSO-d 6, 400MHz): δ 3.75 (s, 3H), 5.59 (s, 2H), 6.92 (d, 2H, J=8.8Hz (o-coupling), 7.14 (dt, 1H, J=9.2Hz (o-coupling), 7.36 (d, 2H, J=8.4Hz (o-coupling), 7.45 (dt, 2H, J=9.2Hz (o-coupling) J=5.2Hz (o-coupling), 7.79 (m, 1H), 7.88 (wide s, 1H), 8.16 (wide s, 1H), 8.53 (d, 1H, J=2.0Hz (m-coupling), 8.57 (d, 1H, J=4.8Hz).MSES+ (454.10), HPLC (method 5) Rt=15.26 minute.
Embodiment 123:3-(5-bromo-benzothiazole-2-ylmethoxy)-2,6-two fluoro-Benzoylamide
Figure A20078000995900741
5-bromo-2-bromomethyl-benzothiazole (1.1g in 5ml anhydrous DMF solution 0.358mmol), adds 2,6-two fluoro-3-hydroxybenzamide (0.620g, 0.22mol) and potassium carbonate (1.73g, 1.25mmol).Under the nitrogen environment, this reactant mixture was stirred 24 hours down at 25 ℃.Water is joined in the reactant mixture, chemical compound is separated out, filter and wash, obtain the title compound (1.1g, 76%) of yellow solid form with ether. 1H NMR (DMSO-d 6, 400MHz): δ 5.71 (s, 2H), 7.11 (dt, 1H J=8.8Hz (o-coupling), 7.38-7.39 (m, 1H), 7.65 (d, 1H, J=8.8Hz (o-coupling), 7.90 (wide s, 1H), 8.13 (d, 1H, J=8.8Hz (o-coupling), 8.18 (s, 1H), 8.26 (wide s, 1H).MS ES+ (400.9), HPLC (method 5) Rt=16.57 minute.
Embodiment 125:2,6-two fluoro-3-[4-(4-methoxyl group-phenyl)-5-pyridine-2-base-thiazol-2-yl methoxyl group]-Benzoylamide
At 3-[5-bromo-4-(4-methoxyl group-phenyl)-thiazol-2-yl methoxyl group]-2, (0.1g, (0.081g's 6-two fluoro-Benzoylamide 0.02mmol), outgased 10 minutes to add 2-tributyl stannyl pyridine in 5ml anhydrous DMF solution 0.02mmol).(0.026g 0.002mmol) adds in the reactant mixture, outgases 10 minutes again, under nitrogen environment, heats 12 hours down at 120 ℃ then with four (triphenyl phasphine) palladium (0).Make reactant mixture be cooled to room temperature then, add entry, use ethyl acetate extraction, with the organic layer that merges in anhydrous Na 2SO 4Last dry, reduction vaporization is to doing.Chemical compound is gone up by the column chromatography purification at silicagel column (230-400 μ),, obtained the title compound (0.120g, 60%) of white solid form with ethyl acetate (40: 60) eluting. 1H NMR (DMSO-d 6, 400MHz): δ 3.80 (s, 3H), 5.55 (s, 2H), 6.99 (d, 2H, J=8.8Hz (o-coupling), 7.12 (dt, 1H, J=8.8Hz (o-coupling), 7.23 (d, 1H, J=8.0Hz (o-coupling), 7.29-7.32 (m, 1H), 7.44 (d, 2H, J=8.8Hz (o-coupling), 7.62 (m, 1H), 7.69 (dt, 1H, J=8.0Hz (o-coupling), 7.88 (wide s, 1H), 8.17 (wide s, 1H), 8.60 (d, 1H, J=4.0Hz), MSES+ (454.18), HPLC (method 5) Rt=15.6 minute.
Embodiment 126:3-(5-pi-allyl-benzothiazole-2-ylmethoxy)-2,6-two fluoro-Benzoylamide
Figure A20078000995900752
At 3-(5-bromo-benzothiazole-2-ylmethoxy)-2, (0.1g, in 5ml anhydrous DMF solution 0.025mol), (0.083g 0.025mol), makes the reactant mixture degassing 10 minutes to 6-two fluoro-Benzoylamide to add allyl tributyltin.(0.029g 0.0025mol), outgased 10 minutes again to add four (triphenyl phasphine) palladium (0).Under the nitrogen environment, compound of reaction 120 ℃ of down heating 1 hour, is cooled to room temperature then, water is added in the reactant mixture, use ethyl acetate extraction, with the organic layer of merging in anhydrous Na 2SO 4Last dry, reduction vaporization is to doing.With chemical compound ethyl acetate/hexane crystallization, produce the title compound (0.050g, 55%) of brown solid form. 1H NMR (DMSO-d 6, 400MHz): δ 3.52 (d, 2H, J=6.4Hz), 5.07-5.13 (m, 1H) 5.68 (s, 2H) 5.98-6.05 (m, 1H), 7.10 (dt, 1H, J=8.4Hz (o-coupling), 7.31 (d, 1H, J=8.4Hz (o-coupling), 7.38 (dt, 1H, J=9.2Hz (o-coupling), J=5.2Hz), 7.83 (s, 1H), 7.89 (wide s, 1H), 8.05 (d, 1H, J=8.4Hz (o-coupling), 8.17 (wide s, 1H) MS ES+ (361.05), HPLC (method 5) Rt=16.74 minute.
Embodiment 127:2,6-two fluoro-3-[4-(4-methoxyl group-phenyl)-5-pyridin-4-yl-thiazol-2-yl methoxyl group]-Benzoylamide
Figure A20078000995900761
At 3-[5-bromo-4-(4-methoxyl group-phenyl)-thiazol-2-yl methoxyl group]-2,6-two fluoro-Benzoylamide (0.2g, 5ml dry DMF 0.43mmol): H 2In O (2: the 1) solution, and adding 4-pyridine boric acid (0.108g, 0.87mmol), potassium phosphate (0.112g, 0.51mmol).Make the reactant mixture degassing 10 minutes then, the adding dichloro-is two, and [(0.046g's (triphenyl phasphine)-palladium (II) again 0.06mmol), outgased 10 minutes.Under the nitrogen environment, reactant mixture was heated 12 hours down at 120 ℃.DMF is removed in distillation, be cooled to room temperature after, water is joined in the reactant mixture, use ethyl acetate extraction, with the organic layer of merging in anhydrous Na 2SO 4Last dry, reduction vaporization is to doing.Chemical compound is gone up by the column chromatography purification at silicagel column (230-400 μ),, obtained the title compound (0.045g, 49%) of white solid form with ethyl acetate/hexane (50: 50) eluting. 1H NMR (DMSO-d 6, 400MHz): δ 3.80 (s, 3H), 5.59 (s, 2H), 6.94 (d, 2H, J=8.8Hz (o-coupling), 7.14 (dt, 1H), 7.34 (d, 1H, J=6.0Hz (o-coupling), 7.38 (d, 2H, J=8.8Hz (o-coupling), 7.41-7.45 (m, 1H), 7.89 (wide s, 1H), 8.17 (s, 1H), 8.60 (dd, 1H) MSES+ (454.12), HPLC (method 5) Rt=13.55 minute.
Embodiment 135:2,6-two fluoro-3-(5-propyl group-benzothiazole-2-ylmethoxy)-Benzoylamide
At 3-(5-pi-allyl-benzothiazole-2-ylmethoxy)-2, (0.1g in 5ml absolute methanol solution 0.27mmol), adds 20mg and does Pd-C 6-two fluoro-Benzoylamide.Under the hydrogen environment, this reactant mixture was stirred 12 hours down at 25 ℃.Reactant mixture is filtered on the kieselguhr filter bed.Filtrate evaporated under reduced pressure is extremely done chemical compound ethyl acetate/hexane crystallization, the title compound (0.014g, 14%) of generation faint yellow solid form. 1H NMR (DMSO-d 6, 400MHz): δ 0.92 (t, 3H, J=7.2Hz), 1.62-1.68 (m, 2H), 2.71,2H, J=7.2Hz), 5.67 (s, 2H), 7.12 (dt, 1H, J=8.8Hz (o-coupling) J=1.6Hz), 7.32 (d, 1H, J=8.4 (o-coupling), 7.38 (dt, 1H, J=9.2Hz (o-coupling), J=5.2Hz), 7.83 (s, 1H), 7.89 (wide s, 1H), 8.01 (d, 1H, J=8.4Hz (o-coupling) .8.17 (wide s, 1H).MS ES+ (363.08), HPLC (method 5) Rt=17.64 minute.
Embodiment 136:2,6-two fluoro-3-[5-(3-hydroxyl-phenyl)-benzothiazole-2-ylmethoxy]-Benzoylamide
Figure A20078000995900772
Under-78 ℃,, 6-two fluoro-3-[5-(3-methoxyl group-phenyl)-benzothiazole-2-ylmethoxy 2]-Benzoylamide (0.14g, in the anhydrous DCM suspension of 15ml 0.3mmol), dropwise add Boron tribromide (0.493g, 1.9mmol).Under the nitrogen environment, this reactant mixture was stirred 3 hours down at-78 ℃.Under 0 ℃, in reactant mixture, add 5ml water.The chemical compound ethyl acetate extraction.The organic layer that merges is in anhydrous Na 2SO 4Last dry, reduction vaporization is to doing.Chemical compound is gone up by the column chromatography purification at silicagel column (230-400 μ),, obtained the title compound (0.020g, 14%) of yellow solid form with ethyl acetate (40: 60) eluting. 1H NMR (DMSO-d 6, 400MHz): δ 5.71 (s, 2H), 6.80 (dd, 1H, J=9.6Hz (o-coupling), 7.11 (dt, 1H, J=8.0Hz (o-coupling), 7.17 (dt, 1H, J=8.0Hz (o-coupling), 7.29 (t, 1H, J=8.0Hz (o-coupling), 7.39-7.43 (m, 1H), 7.71 (dd, 1H, J=9.6Hz) 7.89 (wide s, 1H), and 8.18-8.22 (m, 2H).MS ES+ (413.01), HPLC (method 5) Rt=14.95 minute
Embodiment 140:2,6-two fluoro-3-[5-(4-hydroxyl-phenyl)-benzothiazole-2-ylmethoxy]-Benzoylamide
Figure A20078000995900781
With chemical compound 2,6-two fluoro-3-[5-(4-methoxyl group-phenyl)-benzothiazole-2-ylmethoxy]-(0.095g 0.223mmol) is dissolved among the 5ml DCM Benzoylamide, is cooled to-70 ℃.In this solution, dropwise add BBr 3(0.1ml 0.156mmol).After being added dropwise to complete, reactant mixture was at room temperature stirred 30 minutes.Reactant mixture MeOH cancellation.Concentrated reaction mixture is also used the column chromatography purification, obtains the chemical compound of (0.0025g, 3%) white solid form. 1H NMR (DMSO-d 6, 400MHz); δ 5.70 (s, 2H), 6.88 (d, 1H, J=8.4Hz (o-coupling), 7.10 (m, 1H), 7.41 (m, 2H), 7.60 (d, 2H, J=8.8Hz, (o-coupling), 7.71 (d, 2H), 7.89 (wide s, 1H), 8.13-8.17 (m, 2H), 9.62 (wide s, 1H); MS ES+ (413.0).
Embodiment 141:3-[5-(2-amino-phenyl)-benzothiazole-2-ylmethoxy]-2,6-two fluoro-Benzoylamide
Under nitrogen environment, the room temperature, in chemical compound 3-(5-bromo-benzothiazole-2-ylmethoxy)-2, the dry DMF of 6-two fluoro-Benzoylamide (0.3g 0.755mmol): H 2O (5mL: 2.5mL) in the solution, add phenyl amine-2-boric acid (0.260g, 1.5mmol) and K 2CO 3(0.125g, 0.9mmol).Then reactant mixture is outgased half an hour.With dichloro-two [(triphenyl phasphine)-palladium (II) add reactant mixture (0.080g, 0.113mmol) in, outgas half an hour again, under the nitrogen environment with reactant mixture 120 ℃ of heating 2 hours down.DMF is removed in distillation, be cooled to room temperature after, water is added in the reactant mixture, use ethyl acetate extraction, with the organic layer of merging in anhydrous Na 2SO 4Last dry, reduction vaporization is to doing.Chemical compound is gone up by the column chromatography purification at silicagel column (230-400 μ), with ethyl acetate/hexane (50: 50) eluting, obtains the title compound (0.025g, 8%) of yellow solid form. 1H NMR (DMSO-d 6, 400MHz); δ 4.86 (wide s, 2H), 5.71 (s, 2H), 6.66 (dt, 1H, J=8.4Hz (o-coupling), 6.78 (d, 1H, J=7.2Hz (o-coupling), and 7.04-7.13 (m, 3H), 7.37-7.44 (m, 1H), 7.51 (dd, 1H, J=8.4Hz (o-coupling), J=1.6Hz (m-coupling), 7.89 (wide s, 1H), 8.00 (wide s, 1H), 8.18 (d, 2H, J=4.0Hz); MS ES+ (412.16), HPLC (method 5) Rt=15.33 minute.
Embodiment 143:2,6-two fluoro-3-[5-(3-methoxyl group-phenyl)-benzothiazole-2-ylmethoxy]-Benzoylamide
Figure A20078000995900791
Under inert conditions, the room temperature, in chemical compound 3-(5-bromo-benzothiazole-2-ylmethoxy)-2,6-two fluoro-Benzoylamide (0.300g, dry DMF 0.755mmol): H 2O (5mL: 2.5mL) in the solution, add 3-methoxybenzene ylboronic acid (0.228g, 1.5mmol) and K 3PO 4(0.190g 0.9mmol), outgases half an hour.Adding dichloro-then in reactant mixture, two [(0.078g's (triphenyl phasphine)-palladium (II) again 0.075mmol), outgases half an hour.Under the nitrogen environment, reactant mixture was heated 2 hours down at 120 ℃.DMF is removed in distillation, is cooled to room temperature.Water is added in the reactant mixture, uses ethyl acetate extraction, with the organic layer that merges in anhydrous Na 2SO 4Last dry, reduction vaporization is to doing.Chemical compound is gone up by the column chromatography purification at silicagel column (230-400 μ), with ethyl acetate/hexane (50: 50) eluting, obtains the title compound (0.140g, 43%) of white solid form. 1H NMR (DMSO-d 6, 400MHz); δ 3.85 (s, 3H), 5.72 (s, 2H), 6.97 (t, 1H, J=6.8Hz (o-coupling), 7.11 (t, 1H, J=8.8Hz, (o-coupling), 7.30 (wide s, 1H), 7.34 (d, 1H, J=8.8Hz (o-coupling), 7.40 (dd, 2H, J=8.0Hz (o-coupling), 7.79 (d, 1H, J=8.0Hz (o-coupling), 7.90 (wide s, 1H), 8.18 (wide s, 1H), 8.21 (d, 1H, J=8.0Hz); MSES+ (427.14), HPLC (method 5) Rt=16.48 minute.
Embodiment 155:2,6-two fluoro-3-[4 '-(4-methoxyl group-phenyl)-[2,5 '] dithiazole base-2 '-ylmethoxy]-Benzoylamide
Figure A20078000995900801
At 3-[5-bromo-4-(4-methoxyl group-phenyl)-thiazol-2-yl methoxyl group]-2, (0.1g in 5ml anhydrous DMF solution 0.2mmol), adds 2-tributyl stannyl thiazole (0.071g to 6-two fluoro-Benzoylamide, 0.2mmol), make the reactant mixture degassing 10 minutes.Add then tetraphenyl phosphine palladium (0) (0.026g, 0.2mmol).Under the nitrogen environment, reactant mixture was heated 12 hours down at 120 ℃.Make reactant mixture be cooled to room temperature then.Add 100ml water, the chemical compound ethyl acetate extraction, with the organic layer of merging in anhydrous Na 2SO 4Last dry, reduction vaporization is to doing.Chemical compound is gone up by the column chromatography purification at silicagel column (230-400 μ), with ethyl acetate (40: 60) eluting, obtains the title compound (0.003g, 3%) of yellow solid form. 1H NMR (DMSO-d 6, 400MHz): δ 3.82 (s, 3H), 5.57 (s, 2H), 7.06 (d, 1H, J=8.4Hz (o-coupling), 7.13 (dt, 1H), 7.39-7.47 (m, 1H), 7.51 (d, 2H, J=8.4Hz (o-coupling), 7.52-7.58 (m, 1H), and 7.59-7.86 (m, 2H), 7.68 (d, 1H, J=3.2Hz), 7.84 (d, 1H, J=3.2Hz), 7.89 (wide s, 1H), 8.18 (wide s, 1H), 9.12 (s, 1H); MS ES+ (460.01), HPLC (method 5) Rt=15.64 minute.
Embodiment 160:2,6-two fluoro-3-[3-(5-methyl-2-phenyl-thiazole-4-yl)-propoxyl group]-Benzoylamide
Figure A20078000995900802
3-(5-methyl-2-phenyl-thiazole-4-yl)-third-1-alcohol
At 3-(5-methyl-2-phenyl-thiazole-4-yl)-third-1-alcohol (0.219g, 1.0mmol) the 5ml anhydrous DMF solution in, add 2,6-two fluoro-3-hydroxybenzamide (0.173g, 1.0mmol), PPh3 (0.262g, 1.0mmol) and the diisopropyl azodicarboxylate (0.202g, 1.0mmol).Under the nitrogen environment, reactant mixture stirring under 80 ℃ is spent the night.To doing, residue is gone up by the column chromatography purification at silicagel column (230-400 μ) with the reactant mixture reduction vaporization, with ethyl acetate/hexane (35: 65) eluting, obtains the title compound (0.050g, 13%) of white solid form. 1H NMR (DMSO-d 6, 400MHz): δ 2.44 (wide s, 3H), 3.14 (t, 2H, J=6.4Hz), 4.35 (t, 2H, J=6.4Hz), 7.04 (dt, 1H, J=9.2Hz (o-coupling), 7.22-7.28 (m, 1H), 7.43-7.49 (m, 3H), 7.83-7.86 (m, 3H), 8.10 (s, 1H); MS ES+ (375.15), HPLC (method 5) Rt=10.67 minute.
Embodiment 164:2,6-two fluoro-3-[4-(4-methoxyl group-phenyl)-[5,5 '] dithiazole base-2-ylmethoxy]-Benzoylamide
Figure A20078000995900811
2,6-two fluoro-3-[4-(4-methoxyl group-phenyl)-[5,5 '] dithiazole base-2-ylmethoxy]-Benzoylamide (0.100g, in 5ml anhydrous DMF solution 0.2mmol), adding 5-tributyl tin alkyl-thiazole-2-carboxylic acid (0.091g, 0.2mmol).Under the nitrogen environment, the stirring under 80 ℃ of this reactant mixture is spent the night.To doing, residue is gone up by the column chromatography purification at silicagel column (230-400 μ) with the reactant mixture reduction vaporization, with ethyl acetate/hexane (35: 65) eluting, obtains the title compound (0.025g, 25%) of white solid form. 1H NMR (DMSO-d 6, 400MHz): δ 3.78 (s, 3H), 5.57 (s, 2H), 6.97 (d, 2H, J=8.8Hz (o-coupling), 7.13 (t, 1H), 7.44 (d, J=8.8, (the o-coupling, 3H), 7.89 (wide s, 1H), 8.05 (s, 1H), 8.17 (wide s, 1H), 9.12 (s, 1H); MSES+ (459.94), HPLC (method 5) Rt=15.21 minute.
Embodiment 165:2-fluoro-3-hexyloxy-Benzoylamide
Figure A20078000995900812
2-fluoro-3-hydroxyl-Benzoylamide (0.12g, in 20mL DMF solution 0.774mmol), add 1-bromo hexane (0.13mL, 1.0mmol), potassium carbonate (0.213,1.4mmol).This reactant mixture was stirred 4 hours down at 90 ℃.DMF is removed in distillation, and with EtOAc extractive reaction mixture.Gained crude product chemical compound is gone up by the column chromatography purification at silicagel column (230-400 μ), with ethyl acetate/hexane (50: 50) eluting, obtains title compound.(0.05g，28％)。 1H NMR (DMSO-d 6, 400MHz D 2O): δ 0.82-0.99 (m, 3H), 1.10-1.33 (m, 6H), 1.67-1.71 (m, 2H), 3.99-4.15 (t, 2H, J=8.0Hz), 7.08-7.24 (m, 2H).MSES+ (214.33), HPLC (method 6) Rt=11.15 minute.
Embodiment 166:2-hydroxyl-3-hexyloxy-Benzoylamide
Figure A20078000995900821
With 2-fluoro-3-hexyloxy-Benzoylamide (0.30g, 1.2mmol), copper sulfate (0.10g, 0.4mol), copper (0.015g, 0.2mmol) and the mixed liquor of NaOH (2.5ml) stirred 14 hours down at 100 ℃.After reaction is finished, acidified reaction mixture, and extract with EtOAc.Gained crude product chemical compound is gone up by the column chromatography purification at silicagel column (230-400 μ), with ethyl acetate/hexane (50: 50) eluting, obtains yellow title compound (0.15g, 50%). 1H NMR (DMSO-d 6, 400MHz D 2O): δ 3.9 (s, 3H), 7.11-7.18 (m, 2H), 7.53-7.58 (m, 1H).MS ES+ (229.0M+2H adduct).HPLC (method 7) Rt=11.16 minute.
Embodiment 167:Synthetic 3-fluoro-5-hexyloxy Benzoylamide
Figure A20078000995900822
Under 0 ℃, (0.9g, in Tetrafluoroboric acid 3.8mmol) (20ml) solution, (0.315mg, water 4.6mmol) (5ml) solution stirred 1 hour to add sodium nitrite at 3-amino-5-hexyloxy Benzoylamide.Allow it arrive room temperature then, stirred 1 hour, heated 2 hours down at 60 ℃ again.Then, alkalize to pH=14, with dichloromethane (3 * 30ml) extractions with saturated NaOH solution.Evaporating solvent obtains crude product, goes up by the column chromatography purification at silicagel column (230-400 order), and dichloromethane is eluent (100mg, 11%). 1H NMR (DMSO-d 6, 400MHz D 2O): δ 0.88 (t, J=7.2Hz, 3H), 1.32 (m, 2H), 1.41 (m, 4H), 1.72 (m, 2H), 4.0 (t, J=7.2Hz, 2H), 6.97 (m, 1H), 7.22 (m, 1H), 7.28 (m, 1H), 7.52 (br s, 1H), 8.03 (br s, 1H).MS ES+ (238.0,239.0), HPLC (method 7) Rt=11.34 minute.
Embodiment 168:Synthetic 3-(pyrazol-1-yl methoxyl group)-Benzoylamide
Figure A20078000995900831
3-(pyrazol-1-yl methoxyl group)-essence of Niobe (250mg, 1.1 equivalents) and 5ml ammonia are placed pressurized canister, and 110 ℃ were heated 12 hours down.Then reactant is poured in the water (25ml), with dichloromethane (25ml * 4) extraction.Organic layer is dry on sodium sulfate, obtains crude product after concentrating.Product by the column chromatography purification, is used the 80%EtOAc-DCM eluting on 230-400 order silica gel.Obtain the pure product (50mg, 19%) of pressed powder form. 1H NMR (DMSO-d 6, 400MHz D 2O): δ 6.12 (s, 2H), 6.33 (m, 1H), 7.25 (m, 1H), 7.37 (m, 1H), 7.41 (m, 1H), 7.51 (m, 1H), 7.56 (m, 2H), 7.95 (br s, 1H), 7.99 (m, 1H).
MS ES+ (218.0,235.0-ammonium adduct), HPLC (method 7) Rt=9.08 minute.
Embodiment 169:3-[(2-methyl cyclopropyl) methoxyl group] the benzene carboxylic acid amides.
Figure A20078000995900832
According to method C, scheme 3 is synthetic.Productive rate 27%, fusing point 119-121 ℃, HPLC-MS (method 1): m/z 206[M+H] +, Rt=3.47 minute.
Embodiment 170:3-[(5-methyl-3-pyridine radicals) methoxyl group] the benzene carboxylic acid amides.
Figure A20078000995900841
(2.13g 12mmol), is α then, and (16mg 0.1mmol) adds 3,5-lutidines (1.14ml, CCl 10mmol) to α '-azo isobutyronitrile with N-bromine butanimide 4(40ml) in the solution.This reaction mixture refluxed was stirred 2 hours.After the cooling, remove by filter butanimide, and filtrate is evaporated to smaller size smaller (10ml).In this filtrate, add 3-hydroxy benzenes carboxylic acid amides (550mg, 4mmol) and K 2CO 3(830mg, the 6mmol) mixed liquor in DMF (5ml) stir newly-generated reactant mixture 24 hours down at 60 ℃.Use CH 2Cl 2(100ml) after the dilution, use Na 2CO 3Solution (40ml) and water (40ml) wash solution, dry (Na 2SO 4) and reduction vaporization to doing.Brown oil residue Et 2(2 * 10ml) development extractions are from Et for O 2The solid of O extract filtering-depositing and with pentane washing obtains the required product of 70mg (7.2% productive rate).Fusing point 152-154 ℃, HPLC-MS:m/z 243[M+H] +, Rt=2.28 minute.
Embodiment 171:The 3-[(3-benzyl bromide) oxygen base] the benzene carboxylic acid amides.
Figure A20078000995900842
According to method B, scheme 2 is synthetic.Productive rate 54%, fusing point 129-131 ℃, HPLC-MS (method 1): m/z 347[M+H+CH 3CN] +, Rt=3.99 minute.
Scheme 20:(a) KOH aqueous, (CH 3CO) 2O; (b) 3-hydroxy benzenes carboxylic acid amides, PPh 3, DIAD, Et 3N, THF, room temperature; (c) K 2CO 3, MeOH, H 2O.
Figure A20078000995900843
3-(methylol) phenylacetic acid ester
Figure A20078000995900851
Under the room temperature, in the 6.4N KOH solution (1.86ml, 12mmol, 1.5 equivalents) of the 3-hydroxy-benzyl alcohol (1.0g, 8mmol, 1 equivalent) that stirs, add ice (4g), add acetic anhydride (0.95ml, 10mmol, 1.25 equivalents) again.This reactant mixture was at room temperature stirred 3 hours.Add entry (50ml), mixed liquor was stirred 30 minutes, use CH then 2Cl 2(2 * 50ml) extractions.The organic extract that merges washs with saline (50ml), dry (Na 2SO 4) and reduction vaporization to doing.Clarifying oil residue by the column chromatography purification, with EtOAc/ hexane (1: 2) eluting, obtains the required product (714mg, 54% productive rate) of clarified oil form on silicagel column.HPLC-MS (method 1): m/z 165[M-H] -.Rt=2.52 minute.
Embodiment 172:3-[3-(amino carbonyl) phenoxy group] the aminomethyl phenyl acetas
Figure A20078000995900852
According to method C, scheme 3 is synthetic.Productive rate 32%, HPLC-MS (method 1): m/z 286[M+H] +Rt=3.44 minute.
Embodiment 173:The 3-[(3-hydroxybenzyl) oxygen base] the benzene carboxylic acid amides.
Figure A20078000995900853
With K 2CO 3Water (5ml) solution of (500mg, 3.62mmol, 5.75 equivalents) adds 3-[3-(amino carbonyl) phenoxy group] solution of aminomethyl phenyl acetas (180mg, 0.63mmol, 1 equivalent), N 2Down, with mixed liquor stirring at room 3 hours.Mixed liquor is acidified to pH 1 with 10%HCl solution, with EtOAc (2 * 30ml) extractions.With organic extract water (30ml) washing that merges, dry (Na 2SO 4) and reduction vaporization to doing, obtain the clarified oil residue, use Et 2The O development solidify to form white solid (70mg, 46% productive rate).Fusing point 122-123 ℃, HPLC-MS (method 1): m/z 244[M+H] +Rt=2.92 minute.
Scheme 21:(a) hexanol, 3 equivalent NaH, 100-120 ℃; (b) SOCl 2, toluene refluxes; (c) aqueous NH 3
Figure A20078000995900861
3-chloro-2-(hexyloxy) .gamma.-pyridinecarboxylic acid.
Figure A20078000995900862
Hexanol (10ml) solution of sodium hydride (60% in mineral oil, 600mg, 15.0mmol, 3 equivalents) was at room temperature stirred 2 hours.Add 2,3-two chloro-.gamma.-pyridinecarboxylic acid (960mg, 5.0mmol, 1 equivalent) also stirs reactant mixture 16 hours down at 100 ℃.With mixed liquor water (100ml) and pentane (300ml) dilution, separate biphase.Water is neutralized to pH 6.0 with 1N HCl solution, with EtOAc (3 * 80ml) extractions.With the EtOAc extract drying (MgSO that merges 4) and reduction vaporization to doing.Residue is developed with pentane, 0 ℃ of cooling down, and the solid of filtering-depositing obtains 410mg whitening compound (productive rate 32%). 1H-NMR analyzes, and comprises about 80% required product, need not to be further purified promptly to can be used for next step.HPLC-MS:m/z 256[M-H] -, Rt=2.94 minute.
Embodiment 174:3-chloro-2-(hexyloxy) Pyrazinamide.
Figure A20078000995900863
According to method A, synthetic from 3-chloro-2-(hexyloxy) .gamma.-pyridinecarboxylic acid.Productive rate 85% (crude product); TLC is further purified by the preparation type, and fusing point 75-77 ℃, HPLC-MS:m/z 298[M+H+CH 3CN] +, Rt=4.16 minute.
2-fluoro-3-hydroxy benzenes carboxylic acid amides.
According to method H, synthetic from commercially available 2-fluoro-3-methoxybenzene carboxylic acid amides.Productive rate 82%, fusing point 196-197 ℃, HPLC-MS (method 1): m/z 154[M-H] -, Rt=1.24 minute.
Embodiment 175-178 (table F)
Embodiment 175-178 is synthetic from 2-fluoro-3-hydroxy benzenes carboxylic acid amides.Embodiment 175,176 and 178 is according to method B, and scheme 2 is synthetic, and embodiment 177 is according to method C, and scheme 3 is synthetic.
Figure A20078000995900871
Figure A20078000995900872
The name list of product chemical compound; Embodiment 175-178:
Embodiment The chemical compound title
175 2-fluoro-3-(oxygen base in the ninth of the ten Heavenly Stems) benzene carboxylic acid amides
176 2-[3-(amino carbonyl)-2-fluorophenoxy] butyl acetate
177 2-fluoro-3-(10-undecyne oxygen base) benzene carboxylic acid amides
178 2,6-two fluoro-3-(4-hydroxyl butoxy) benzene carboxylic acid amides
Scheme 22:(a) 4-bromo M Cr, K 2CO 3, DMF, room temperature; (b) NaOH, IPA/H 2O refluxes; (c) n-BuBr, K 2CO 3, DMF, 50 ℃; (d) H 2, 5%Rh/C, BuOH, room temperature
Figure A20078000995900881
Embodiment 179:4-[3-(amino carbonyl)-2,4 difluorobenzene oxygen base]-2-butylene acid methyl ester
Figure A20078000995900882
According to method B, scheme 2, by 2,6-two fluoro-3-hydroxy benzenes carboxylic acid amides is synthetic.Productive rate 41%, fusing point 122-123 ℃, HPLC-MS (method 1): m/z 272[M+H] +, Rt=2.80 minute.
4-[3-(amino carbonyl)-2,4 difluorobenzene oxygen base]-2-butylene acid.
Figure A20078000995900883
With 4-[3-(amino carbonyl)-2,4 difluorobenzene oxygen base]-2-butylene acid methyl ester (1.25g, 4.61mmol, 1 equivalent) and NaOH (0.75g, 18.44mmol, 4 equivalents) be at isopropyl alcohol (10ml) and H 2Solution reflux among the O (20ml) 1 hour.After being cooled to room temperature, mixed liquor is acidified to pH1 with dense HCl.Filter the solid of white precipitate, use Et 2O (50ml) washing obtains 568mg, 48% productive rate, fusing point 187-188 ℃, HPLC-MS (method 1): m/z 258[M+H] +, Rt=0.98 minute. 1H-NMR analyzes, and is E: the isomer mixture of Z (3: 2).
Water Et 2(2 * 50ml) extractions are with the extract drying (Na that merges for O 2SO 4) and reduction vaporization to doing, obtain the light orange solid, 418mg, 35% productive rate, fusing point 127-128 ℃, HPLC-MS (method 1): m/z 258[M+H] +, Rt=0.99 minute. 1H-NMR analyzes, and is E: the isomer mixture of Z (3: 40).
Embodiment 180:4-[3-(amino carbonyl)-2,4 difluorobenzene oxygen base]-the 2-butylene acid butyl ester.
Figure A20078000995900891
With 4-[3-(amino carbonyl)-2,4 difluorobenzene oxygen base]-2-butylene acid (isomer mixture of E: Z (3: 2)) (526mg, 2mmol, 1 equivalent) is dissolved in the dry DMF (5ml).Add K 2CO 3(850mg, 6mmol, 3 equivalents) and n-butyl bromide (0.23ml, 2.1mmol, 1.05 equivalents) and with reactant mixture in 50 ℃ of down heating 70 hours, following 1.5 hours of room temperature.After cooling off under the room temperature, with mixture H 2O (50ml) dilution is with EtOAc (3 * 40ml) extractions.The organic extract H that merges 2O (6 * 30ml) washings, dry (MgSO 4) and reduction vaporization to doing.The oily residue by the column chromatography purification, is used CH on silicagel column 2Cl 2And MeOH/CH 2Cl 2(1%) eluting obtains 364mg, 57% productive rate, fusing point＜40 ℃.HPLC-MS (method 1): m/z 314[M+H] +, Rt=3.88 minute. 1H-NMR analyzes, and is E: the isomer mixture of Z (5: 7).E to acid: Z (3: 40) isomer mixture carries out identical reaction, and products therefrom is E: the isomer mixture of Z (1: 4).
Embodiment 181:4-[3-(amino carbonyl)-2,4 difluorobenzene oxygen base] butyl butyrate.
Figure A20078000995900892
At H 2, under the room temperature, with 4-[3-(amino carbonyl)-2,4 difluorobenzene oxygen base]-(100mg 0.32mmol) stirred 21 hours in butanols (5ml) with 5%Rh/C (5mg) in 2-butylene acid.Reactant mixture is filtered by the kieselguhr filter bed, use CH 2Cl 2(3 * 5ml) flushings.Filtrate evaporated under reduced pressure to doing, is obtained the required product of 88mg, productive rate 87%, fusing point 53-55 ℃.HPLC-MS (method 1): m/z316[M+H] +, Rt=3.49 minute.
Embodiment 182-197 (table G)
Embodiment 182-197 is by 2, and 6-two fluoro-3-hydroxy benzenes carboxylic acid amides is synthetic: embodiment 182,190, and 192,193 and 195 according to method B, and scheme 2 is synthetic, embodiment 183-189,191,194 and 196-197 according to method C, scheme 3 is synthetic.
Figure A20078000995900903
Figure A20078000995900911
Figure A20078000995900912
The name list of product chemical compound; Embodiment 182-197:
Embodiment The chemical compound title
182 2,6-two fluoro-3-[(5-methyl-3-isoxazolyl) methoxyl group] the benzene carboxylic acid amides
183 2,6-two fluoro-3-(2-furyl methoxyl group) benzene carboxylic acid amides
184 2,6-two fluoro-3-(3-furyl methoxyl group) benzene carboxylic acid amides
185 2,6-two fluoro-3-[(5-methyl-2-furyl) methoxyl group] the benzene carboxylic acid amides
186 2,6-two fluoro-3-(2-thienyl methoxyl group) benzene carboxylic acid amides
187 2,6-two fluoro-3-[(4-methyl-2-thienyl) methoxyl group] the benzene carboxylic acid amides
188 2,6-two fluoro-3-(3-thienyl methoxyl group) benzene carboxylic acid amides
189 2,6-two fluoro-3-(1,3-thiazoles-5-ylmethoxy) benzene carboxylic acid amides
190 2,6-two fluoro-3-[(2-methyl isophthalic acid, 3-thiazole-4-yl) methoxyl group] the benzene carboxylic acid amides
191 2,6-two fluoro-3-(1,3-thiazoles-2-ylmethoxy) benzene carboxylic acid amides
192 2,6-two fluoro-3-[(5-methyl isophthalic acid, 3-thiazol-2-yl) methoxyl group] the benzene carboxylic acid amides
193 2,6-two fluoro-3-[(4-methyl isophthalic acid, 3-thiazol-2-yl) methoxyl group] the benzene carboxylic acid amides
194 2,6-two fluoro-3-[(1-methyl isophthalic acid H-imidazoles-2-yl) methoxyl group] the benzene carboxylic acid amides
195 2,6-two fluoro-3-[(3-methyl-benzyl) the oxygen base] the benzene carboxylic acid amides
196 The 3-[(3-ethoxy benzyl) oxygen base]-2,6-two fluorobenzene carboxylic acid amides
197 2,6-two fluoro-3-[(6-methyl-2-pyridine radicals) methoxyl group] the benzene carboxylic acid amides
Scheme 23:(a) n-BuLi, Et 2NH, THF; (b) NaIO 4, MeOH; (c) NaBH4, MeOH; (d) PPh 3, DIAD, Et 3N, THF, room temperature
Figure A20078000995900921
Embodiment 198:2,6-two fluoro-3-[(2-methyl-4-pyridine radicals) methoxyl group] the benzene carboxylic acid amides.
Figure A20078000995900922
According to method C, scheme 3, by 2,6-two fluoro-3-hydroxy benzenes carboxylic acid amides is synthetic.Required structure block 4-methylol-2-picoline is then synthetic according to the described method of document, (Ragan, J.A., Jones, B.P., Meltz, C.N., Teixeira J.J.Jr. shown in scheme 23; Synthesis 2002,483-486. productive rate 34%, fusing point 185-186 ℃, HPLC-MS (method 1): m/z 279[M+H] +, Rt=2.50 minute.
Embodiment 199:2,6-two fluoro-3-([1,3] oxazole is [4,5-b] pyridine-2-ylmethoxy also) benzene carboxylic acid amides.
Figure A20078000995900923
According to method B, scheme 2, by 2,6-two fluoro-3-hydroxy benzenes carboxylic acid amides is synthetic.Productive rate 8%, fusing point 180-181 ℃, HPLC-MS (method 1): m/z 306[M+H] +, Rt=2.30 minute.
Embodiment 200:2,6-two fluoro-3-(2-quinolyl methoxyl group) benzene carboxylic acid amides.
Figure A20078000995900931
According to method B, scheme 2, by 2,6-two fluoro-3-hydroxy benzenes carboxylic acid amides is synthetic.Productive rate 48%, fusing point 216-218 ℃, HPLC-MS (method 1): m/z 315[M+H] +, Rt=3.43 minute.
Embodiment 201:3-(1-benzothiophene-5-ylmethoxy)-2,6-two fluorobenzene carboxylic acid amides.
Figure A20078000995900932
According to method B, scheme 2, by 2,6-two fluoro-3-hydroxy benzenes carboxylic acid amides is synthetic.Required structure block 5-(chloromethyl)-1-benzothiophene is then by synthesizing with the commercially available 1-benzothiophene of thionyl chloride chloridized-5-base methanol.Productive rate 10%, fusing point 146-148 ℃, HPLC-MS (method 1): m/z 320[M+H] +, Rt=3.95 minute.
Embodiment 202-207 (table H)
Embodiment 202-207 is according to method C, scheme 3, and by 2,6-two fluoro-3-hydroxy benzenes carboxylic acid amides is synthetic.
Figure A20078000995900933
The name list of product chemical compound; Embodiment 202-207:
Embodiment The chemical compound title
202 3-(1-benzothiophene-3-ylmethoxy)-2,6-two fluorobenzene carboxylic acid amides
203 2,6-two fluoro-3-(imidazo [1,2-a] pyridine-2-ylmethoxy) benzene carboxylic acid amides
204 3-(2,3-dihydro-1,4-benzene and dioxine-2-ylmethoxy)-2,6-two fluorobenzene carboxylic acid amides
205 2,6-two fluoro-3-[(5-methyl isophthalic acid-benzothiophene-2-yl) methoxyl group] the benzene carboxylic acid amides
206 3-(1-benzothiophene-2-ylmethoxy)-2,6-two fluorobenzene carboxylic acid amides
207 3-(1-benzofuran-2-ylmethoxy)-2,6-two fluorobenzene carboxylic acid amides
[5-(trifluoromethyl)-1-benzothiophene-2-yl] methanol.
Figure A20078000995900942
With pyridine (0.37ml, 4.72mmol, 1.5 equivalents), be that cyanuric fluoride (0.53ml, 6.3mmol, 2 equivalents) adds commercially available 5-(the trifluoromethyl)-1-benzothiophene-2-carboxylic acid (776mg, 3.15mmol, 1 equivalent) of stirring at CH then 2Cl 2In the solution (16ml), at N 2Preserve down to-10 ℃ ,-20.Generation cyanuric acid precipitation, and along with the carrying out of reaction increases gradually.Mixture adds frozen water and 100ml CH after stirring 2 hours under-20 to-10 ℃ 2Cl 2Remove by filter undissolved solid; Separate organic facies, water layer reuse CH from filtrate 2Cl 2(50ml) extraction once.The organic layer that merges washs with frozen water (50ml), dry (Na 2SO 4), be evaporated to smaller size smaller (15ml).Disposable adding NaBH 4(240mg, 6.3mmol, 2 equivalents) dropwise add MeOH (6.5ml) then at room temperature 15 minutes.Reactant mixture 1N H 2SO 4Neutralization, the reduction vaporization organic solvent.Residue extracts with EtOAc (80ml) and water (40ml); Separate organic layer, (2 * 60ml) extract water layer with EtOAc.The organic layer 1N H that merges 2SO 4With the salt water washing, dry (Na 2SO 4), solvent evaporated under reduced pressure.Residue by the column chromatography purification, with EtOAc/ hexane (10-20% gradient) eluting, obtains the required product (54.6% productive rate) of 400mg white solid form on silicagel column.HPLC-MS (method 1) provides a peak, and Rt=4.02 minute, but there is not ionization.
Embodiment 208:2,6-two fluoro-3-[5-(trifluoromethyl)-1-benzothiophene-2-yl] the methoxybenzene carboxylic acid amides.
Figure A20078000995900951
According to method C, scheme 3, by 2,6-two fluoro-3-hydroxy benzenes carboxylic acid amides and [5-(trifluoromethyl)-1-benzothiophene-2-yl] methanol are synthetic.Productive rate 3%, fusing point 150-152 ℃, HPLC-MS (method 1): m/z 386[M-H] -, Rt=4.39 minute.
Embodiment 209-217 (Table I)
Embodiment 209-217 is according to method B, scheme 2, and by 2,6-two fluoro-3-hydroxy benzenes carboxylic acid amides is synthetic.
Figure A20078000995900952
Figure A20078000995900961
Figure A20078000995900962
The name list of product chemical compound; Embodiment 209-217:
Embodiment The chemical compound title
209 3-(1,3-benzoxazole-2-ylmethoxy)-2,6-two fluorobenzene carboxylic acid amides
210 3-[(5-chloro-1,3-benzoxazole-2-yl) methoxyl group]-2,6-two fluorobenzene carboxylic acid amides
211 2,6-two fluoro-3-[(6-methyl isophthalic acid, 3-benzoxazole-2-yl) methoxyl group] the benzene carboxylic acid amides
212 2,6-two fluoro-3-[(5-methyl isophthalic acid, 3-benzoxazole-2-yl) methoxyl group] the benzene carboxylic acid amides
213 3-[5-(tert-butyl group)-1,3-benzoxazole-2-yl] methoxyl group-2,6-two fluorobenzene carboxylic acid amides
214 2,6-two fluoro-3-[(5-nitro-1,3-benzoxazole-2-yl) methoxyl group] the benzene carboxylic acid amides
215 3-(1,3-benzothiazole-2-ylmethoxy)-2,6-two fluorobenzene carboxylic acid amides
216 2,6-two fluoro-3-[(5-fluoro-1,3-benzothiazole-2-yl) methoxyl group] the benzene carboxylic acid amides
217 2,6-two fluoro-3-[5-(trifluoromethyl)-1,3-benzothiazole-2-yl] the methoxybenzene carboxylic acid amides
5-chloro-2-(chloromethyl)-1, the 3-benzothiazole.
Figure A20078000995900963
With 4-chloro-2-amino-benzo mercaptan (benzothiol) (4.05g, 25.4mmol, 1 equivalent) and 2-chloro-1,1,1-trimethoxy-ethane (5.0ml, 37mmol, 1.45 equivalents) was 60 ℃ of following agitating heating 2 hours.Reactant mixture is at room temperature cooled off, with ether (10ml) development.Filter undissolved solid and use Et 2O and pentane flushing obtain the required product of 1.54g (28% productive rate).Mother liquid evaporation to doing, is dissolved in Et with the orange solids residue 2Among the O (50ml), use 1N HCl (25ml), water (25ml), 5%NaHCO continuously 3Solution (25ml) and saline (25ml) flushing.With organic layer drying (MgSO 4) and reduction vaporization to smaller size smaller.Et is filtered and used to precipitated solid 2O and pentane wash, and obtain the required product 1.88g (34% productive rate) of second portion.Gross production rate 62%, fusing point 102-104 ℃, HPLC-MS (method 1): m/z 260[M+H+CH 3CN] +, Rt=4.52 minute.
Embodiment 218-221 (table J)
According to method B, scheme 2, by 2,6-two fluoro-3-hydroxy benzenes carboxylic acid amides and 5-chloro-2-(chloromethyl)-1, the 3-benzothiazole synthesizes embodiment 218-221.
Figure A20078000995900971
Figure A20078000995900972
The name list of product chemical compound; Embodiment 218-221:
Embodiment The chemical compound title
218 3-[(5-chloro-1,3-benzothiazole-2-yl) methoxyl group]-2,6-two fluorobenzene carboxylic acid amides
219 3-[(5-chloro-1,3-benzothiazole-2-yl) methoxyl group]-2-fluorobenzene carboxylic acid amides
220 6-chloro-3-[(5-chloro-1,3-benzothiazole-2-yl) methoxyl group]-2-fluorobenzene carboxylic acid amides
221 2-chloro-3-[(5-chloro-1,3-benzothiazole-2-yl) methoxyl group]-6-fluorobenzene carboxylic acid amides
Scheme 24:(a) K 2CO 3, NaI, DMF, 60 ℃; (b) dense H 2SO 4, H 2O, 40 ℃.
Figure A20078000995900981
2-[(5-chloro-1,3-benzothiazole-2-yl) methoxyl group] different cigarette nitrile.
Figure A20078000995900982
2-hydroxyl-4-cyano group-pyridine (240mg, 2mmol, 1 equivalent) is dissolved among the DMF (6ml), adds K 2CO 3(415mg, 3mmol, 1.5 equivalents) and NaI (60mg, 0.4mmol, 0.2 equivalent), mixed liquor at room temperature stirred 10 minutes.Add 5-chloro-2-(chloromethyl)-1,3-benzothiazole (436mg, 2mmol, 1 equivalent) stirs reactant mixture 3 hours down at 60 ℃, spends the night under the room temperature.Add H 2O is settled out brown solid, filters, and uses H 2The O flushing, drying is also used CH 3The CN recrystallization.Output 280mg (46%), fusing point 224-227 ℃, HPLC-MS (method 1): m/z 302[M+H] +, Rt=3.80 minute. 13The C-NMR Analysis and Identification is N-alkyl derivative (scheme 24).With DMF-H 2O mother solution reduction vaporization is to doing, and residue by the column chromatography purification, with EtOAc/ hexane (10%-100% gradient) eluting, obtains 45mg (7.5% productive rate) brown solid, HPLC-MS (method 1): m/z 302[M+H on silicagel column] +, Rt=4.86 minute. 13The C-NMR Analysis and Identification is required O-alkyl derivative (scheme 24).
Embodiment 222:2-[(5-chloro-1,3-benzothiazole-2-yl) methoxyl group] Pyrazinamide.
Figure A20078000995900991
With 2-[(5-chloro-1,3-benzothiazole-2-yl) methoxyl group] (40mg 0.13mmol) is dissolved in dense H to different cigarette nitrile 2SO 4(0.36ml) and under vigorous stirring this solution is heated down at 40 ℃.Dropwise add entry (50mg), mixed liquor stirred 3 hours down at 40 ℃.-5 ℃ down after the cooling, add trash ice (25ml) under the vigorous stirring fast, mixed liquor is restir 2 hours at room temperature.Add ammonia (pH 10), precipitated solid is filtered, use H 2The O flushing, drying.Brown solid is used the EtOAc eluting by preparation type TLC purification, obtains 20mg (47% productive rate), and fusing point 220-222 ℃, HPLC-MS (method 1): m/z 320[M+H] +, Rt=3.76 minute.
Scheme 25:(a) KOH, 2-methoxyl group-ethanol: H 2O (1: 1) refluxes; (b) ClCH 2C (OCH 3) 3(c) K 2CO 3, NaI, DMF, 60 ℃.
Figure A20078000995900992
2-(chloromethyl)-4-ethyl-1, the 3-benzothiazole.
Figure A20078000995900993
(method J) N 2Down, with 4-ethyl-1,3-benzothiazole-2-amine (1.0g, 5.6mmol, 1 equivalent) and KOH (7.4g, 112.2mmol, 20 equivalents) are at 2-methoxyl group-ethanol (9ml) and H 2Solution among the O (9ml) refluxes and stirred 20 hours.After the cooling, mixed liquor is poured in the water (150ml) under the room temperature, used CH 2Cl 2(2 * 40ml) extractions.Water neutralizes with dense HCl, uses CH 2Cl 2(3 * 70ml) extractions once more.The neutral extract water that merges (2 * 60ml) washings, dry (Na 2SO 4) and reduction vaporization to doing.With Huang-green semi-solid residue (790mg) and 2-chloro-1,1, the 1-trimethoxy-ethane (1.62g 10.4mmol) mixes, with mixture at N 2, 60 ℃ stirred 4 hours down.Evaporation under reduced pressure removed volatile material, brown liquid residue by the column chromatography purification, are used CH on silicagel column 2Cl 2/ hexane (10% and 50%) eluting obtains yellow liquid (406mg, the productive rate 34% in two steps).HPLC-MS (method 1): m/z 212[M+H] +, Rt=5.00 minute.
Embodiment 223:3-[(4-ethyl-1,3-benzothiazole-2-yl) methoxyl group]-2,6-two fluorobenzene carboxylic acid amides.
According to method B, scheme 2, by 2,6-two fluoro-3-hydroxy benzenes carboxylic acid amides and 2-(chloromethyl)-4-ethyl-1, the 3-benzothiazole is synthetic.Productive rate 17%, fusing point 184-186 ℃, HPLC-MS (method 1): m/z 349[M+H] +, Rt=4.16 minute.
2-(chloromethyl)-6-methoxyl group-1, the 3-benzothiazole
According to method J, scheme 25, by commercially available 6-methoxyl group-1,3-benzothiazole-2-amine is synthetic.Be directly used in next step.
Embodiment 224:2,6-two fluoro-3-[(6-methoxyl group-1,3-benzothiazole-2-yl) methoxyl group] the benzene carboxylic acid amides.
Figure A20078000995901011
According to method B, scheme 2, by 2,6-two fluoro-3-hydroxy benzenes carboxylic acid amides and 2-(chloromethyl)-6-methoxyl group-1, the 3-benzothiazole is synthetic.Productive rate 19%, fusing point 190-192 ℃, HPLC-MS (method 1): m/z 351[M+H] +, Rt=3.50 minute.
Scheme 26:(a) BrCH 2CN, K 2CO 3, NaI, DMF, 60 ℃; (b) KOH, 2-methoxyl group-ethanol: H 2O (1: 1) refluxes.
Figure A20078000995901012
Embodiment 225:3-(cyano group methoxyl group)-2,6-two fluorobenzene carboxylic acid amides.
Figure A20078000995901013
According to method B, scheme 2, by 2,6-two fluoro-3-hydroxy benzenes carboxylic acid amides is synthetic.Productive rate 86%, fusing point 122-123 ℃, HPLC-MS (method 1): m/z 213[M+H] +, Rt=1.97 minute.
Embodiment 226:3-[(4-chloro-1,3-benzothiazole-2-yl) methoxyl group]-2,6-two fluorobenzene carboxylic acid amides.
Figure A20078000995901014
(method K) is with the H of KOH (15.15g, 270mmol, 20 equivalents) 2O (25ml) solution joins 4-chloro-1, in 2-methoxyl group-ethanol (25ml) solution of 3-benzothiazole-2-amine (2.5g, 13.5mmol, 1 equivalent), with this reaction mixture refluxed heated overnight.After cooling off under the room temperature, with mixed liquor H 2O (200ml) dilution is acidified to pH 4 with 5N HCl solution, uses CH 2Cl 2(3 * 150ml) extractions.The organic extract that merges washs with saline (100ml), dry (Na 2SO 4) and be evaporated to driedly, obtain 1.5g (70% productive rate).With this crude product residue of 167mg (supposition 1.05mmol) and 3-(cyano group methoxyl group)-2,6-two fluorobenzene carboxylic acid amides (150mg 0.7mmol) mixes, mixed liquor in pre-heated oil bath, N 2Down, 120 ℃ were stirred 2 hours down.Add EtOH (2ml), with reactant mixture reheat 2 hours.After the cooling, cross filter solid under the room temperature,, with EtOAc/ pentane recrystallization, obtain the required product of faint yellow solid form, 62mg (productive rate 25% in second step) with the EtOH washing.HPLC-MS (method 1): m/z 355[M+H] +, Rt=3.75 minute.
Embodiment 227:3-[(6-chloro-1,3-benzothiazole-2-yl) methoxyl group]-2,6-two fluorobenzene carboxylic acid amides.
Figure A20078000995901021
According to method K, scheme 26, by 6-chloro-1,3-benzothiazole-2-amine and 3-(cyano group methoxyl group)-2,6-two fluorobenzene carboxylic acid amides are synthetic.Productive rate 38% (second step), fusing point 190-191 ℃, HPLC-MS (method 1): m/z 355[M+H] +, Rt=3.85 minute.
Embodiment 228:2,6-two fluoro-3-[(4-methyl isophthalic acid, 3-benzothiazole-2-yl) methoxyl group] the benzene carboxylic acid amides.
According to method K, scheme 26, by the 4-methyl isophthalic acid, 3-benzothiazole-2-amine and 3-(cyano group methoxyl group)-2,6-two fluorobenzene carboxylic acid amides are synthetic.Productive rate 36% (second step), fusing point 201-202 ℃, HPLC-MS (method 1): m/z 335[M+H] +, Rt=3.79 minute.
Embodiment 229:2,6-two fluoro-3-[(6-methyl isophthalic acid, 3-benzothiazole-2-yl) methoxyl group] the benzene carboxylic acid amides.
According to method K, scheme 26, by the 6-methyl isophthalic acid, 3-benzothiazole-2-amine and 3-(cyano group methoxyl group)-2,6-two fluorobenzene carboxylic acid amides are synthetic.Productive rate 17% (second step), HPLC-MS (method 1): m/z 335[M+H] +, Rt=3.70 minute.
Embodiment 230:2,6-two fluoro-3-[6-(trifluoromethoxy)-1,3-benzothiazole-2-yl] the methoxybenzene carboxylic acid amides.
Figure A20078000995901032
According to method K, scheme 26, by 6-(trifluoromethoxy)-1,3-benzothiazole-2-amine and 3-(cyano group methoxyl group)-2,6-two fluorobenzene carboxylic acid amides are synthetic.Productive rate 34% (second step), fusing point 174-175 ℃, HPLC-MS (method 1): m/z 405[M+H] +, Rt=4.14 minute.
6-propyl group-1,3-benzothiazole-2-amine.
Figure A20078000995901033
Under＜25 ℃, with Br 2Glacial acetic acid (18.5ml) solution of (3.8ml, 74mmol, 2 equivalents) dropwise joins in glacial acetic acid (110ml) solution of the 4-propyl group amine (5.0g, 37mmol, 1 equivalent) of stirring and ammonium thiocyanate (5.63g, 74mmol, 2 equivalents).The gained mixed liquor was at room temperature stirred 2 hours, use H 2O (700ml) dilution is with EtOAc (2 * 250ml) extractions.Water layer alkalizes to pH 10 with ammonia, with EtOAc (3 * 300ml) extractions.The alkaline extraction thing H that merges 2(reduction vaporization obtains the required product of white solid form, 2.34g (33% productive rate), fusing point 120-122 ℃ to doing to O for 2 * 200ml) washings, drying.HPLC-MS (method 1): m/z 193[M+H] +, Rt=3.92 minute.
Embodiment 231:2,6-two fluoro-3-[(6-propyl group-1,3-benzothiazole-2-yl) methoxyl group] the benzene carboxylic acid amides.
Figure A20078000995901041
According to method K, scheme 26, by 6-propyl group-1,3-benzothiazole-2-amine and 3-(cyano group methoxyl group)-2,6-two fluorobenzene carboxylic acid amides are synthetic.Productive rate 18% (second step), fusing point 173-175 ℃.HPLC-MS (method 1): m/z 363[M+H] +, Rt=4.35 minute.
Scheme 27:(a) NBS, α, α '-azo isobutyronitrile, CCl 4(b) K 2CO 3, DMF, 60 ℃; (c) 4-pyridine boric acid, Na 2CO 3, Pd (PPh 3) 4The ， diox.
Figure A20078000995901042
5-bromo-2-(bromomethyl)-1, the 3-benzothiazole.
Figure A20078000995901051
With N-bromine butanimide (4.45g, 25mmol, 1.4 equivalents), be α then, α '-azo isobutyronitrile (110mg, 0.7mmol, 0.04 equivalent) joins the CCl of 5-bromo-2-methyl-benzothiazole (4.07g, 17.85mmol, 1 equivalent) 4(110ml) in the solution.This reaction mixture refluxed was stirred 24 hours.After the cooling, remove by filter butanimide, and use CCl 4(100ml) flushing.To doing, the orange solids residue by the column chromatography purification, is used CH on silicagel column with filtrate evaporated under reduced pressure 2Cl 2/ hexane (20%-70% gradient) eluting obtains the required product (39% productive rate) of 2.15g white solid form.Fusing point 116-117, HPLC-MS (method 1): m/z 308[M+H] +, Rt=4.84 minute.Reaction also obtains 1.40g (20% productive rate) by-product 5-bromo-2-two bromomethyls-benzothiazole and unreacted initial substance of 0.89g (22%).
3-[(5-bromo-1,3-benzothiazole-2-yl) methoxyl group]-2,6-two fluorobenzene carboxylic acid amides.
Figure A20078000995901052
According to method B, scheme 2, by 2,6-two fluoro-3-hydroxy benzenes carboxylic acid amides and 5-bromo-2-(bromomethyl)-1, the 3-benzothiazole is synthetic.Productive rate 81%, fusing point 244-246 ℃, HPLC-MS (method 1): m/z 399,401[M+H] +, Rt=3.98 minute.
Embodiment 232:2,6-two fluoro-3-[5-(4-pyridine radicals)-1,3-benzothiazole-2-yl] the methoxybenzene carboxylic acid amides.
Figure A20078000995901053
With 3-[(5-bromo-1,3-benzothiazole-2-yl) methoxyl group]-2,6-two fluorobenzene carboxylic acid amides (168mg, 0.42mmol, 1 equivalent), 4-pyridine boric acid (98mg, 0.63mmol, 1.5 equivalents) and 2MNa 2CO 3The mixture of aqueous solution (0.42ml, 0.82mmol, 2 equivalents) is suspended in the diox (3.5ml), with the mixture degassing and use N 2Purge.Add four (triphenyl phasphine) palladium (0) catalyst (37mg, 0.031mmol, 0.075 equivalent), with reaction mixture refluxed heating 12 hours.After cooling off under the room temperature, with mixture H 2The O dilution, the solid of filtering-depositing is used H 2O, IMS, IMS/Et 2O and Et 2The O washing.Use CH 3The CN recrystallization obtains the required product (28% productive rate) of 47mg pale solid form, fusing point 255-258 ℃.HPLC-MS:m/z 398[M+H] +, Rt=3.28 minute.
Embodiment 233-241 (table K)
According to method B, scheme 2, by 2,6-two fluoro-3-hydroxy benzenes carboxylic acid amides synthesizes embodiment 233-241.
Figure A20078000995901061
Figure A20078000995901062
Figure A20078000995901071
The name list of product chemical compound; Embodiment 233-241:
Embodiment The chemical compound title
233 2,6-two fluoro-3-[(2-phenyl-1,3-thiazoles-4-yl) methoxyl group] the benzene carboxylic acid amides
234 3-[5-(4-chlorphenyl)-1,3,4-thiadiazoles-2-yl] methoxyl group-2,6-two fluorobenzene carboxylic acid amides
235 2,6-two fluoro-3-[(4-phenyl-1,3-thiazoles-2-yl) methoxyl group] the benzene carboxylic acid amides
236 2,6-two fluoro-3-[2-(4-aminomethyl phenyl)-1,3-thiazoles-4-yl] the methoxybenzene carboxylic acid amides
237 3-[(2-anilino--1,3-thiazoles-4-yl) methoxyl group]-2,6-two fluorobenzene carboxylic acid amides
238 2,6-two fluoro-3-[(5-phenyl-1,3,4-oxadiazole-2-yl) methoxyl group] the benzene carboxylic acid amides
239 2,6-two fluoro-3-[(5-phenyl-1,2,4-oxadiazole-3-yl) methoxyl group] the benzene carboxylic acid amides
240 2,6-two fluoro-3-[(3-phenyl-1,2,4-oxadiazole-5-yl) methoxyl group] the benzene carboxylic acid amides
241 2,6-two fluoro-3-[3-(4-methoxyphenyl)-1,2,4-oxadiazole-5-yl] the methoxybenzene carboxylic acid amides
Embodiment 242:2,6-two fluoro-3-[3-(4-hydroxy phenyl)-1,2,4-oxadiazole-5-yl] the methoxybenzene carboxylic acid amides.
Figure A20078000995901072
(method L) is at room temperature, N 2Down, (1.0M is at CH with Boron tribromide solution 2Cl 2In, 1.5ml, 1.5mmol, 2 equivalents) slowly be added drop-wise to 2 of stirring, 6-two fluoro-3-[3-(4-methoxyphenyl)-1,2,4-oxadiazole-5-yl] methoxybenzene carboxylic acid amides (272mg, 0.75mmol, 1 equivalent) is at CH 2Cl 2In the suspension (5ml).This reactant mixture was at room temperature stirred 4 hours, pour in the water (20ml).Add CH 2Cl 2(10ml), two-phase mixture was at room temperature stirred 30 minutes.Filter undissolved white solid, water and Et 2The O washing obtains 170mg (65% productive rate), and fusing point 209-210 ℃, HPLC-MS (method 1): m/z 348[M+H] +, Rt=3.00 minute.
Embodiment 243-250 (table L)
According to method B, scheme 2, by 2,6-two fluoro-3-hydroxy benzenes carboxylic acid amides synthesizes embodiment 243-250.
Figure A20078000995901081
Figure A20078000995901082
The name list of product chemical compound; Embodiment 243-250:
Embodiment The chemical compound title
243 2, and 6-two fluoro-3-(3-[4-(trifluoromethyl) phenyl]-1,2,4-oxadiazole-5-ylmethoxy) the benzene carboxylic acid amides
245 2,6-two fluoro-3-[3-(4-fluorophenyl)-1,2,4-oxadiazole-5-yl] the methoxybenzene carboxylic acid amides
246 3-[3-(4-chlorphenyl)-1,2,4-oxadiazole-5-yl] methoxyl group-2,6-two fluorobenzene carboxylic acid amides
247 2,6-two fluoro-3-[3-(4-aminomethyl phenyl)-1,2,4-oxadiazole-5-yl] the methoxybenzene carboxylic acid amides
248 2,6-two fluoro-3-[3-(4-isopropyl phenyl)-1,2,4-oxadiazole-5-yl] the methoxybenzene carboxylic acid amides
249 3-(3-[4-(tert-butyl group) phenyl]-1,2,4-oxadiazole-5-ylmethoxy)-2,6-two fluorobenzene carboxylic acid amides
250 3-[3-(4-ethylphenyl)-1,2,4-oxadiazole-5-yl] methoxyl group-2,6-two fluorobenzene carboxylic acid amides
Scheme 28:(a) (Boc) 2O, Et 3N, DMAP, THF; (b) K 2CO 3, NaI, DMF, room temperature; (c) 4N HCl ， diox, room temperature
Figure A20078000995901091
N-4-[5-(chloromethyl)-1,2,4-oxadiazole-3-yl] the phenylcarbamic acid tert-butyl ester.
Figure A20078000995901092
At 4-[5-(chloromethyl)-1,2,4-oxadiazole-3-yl] aniline (950mg, 4.53mmol, 1 equivalent), Et 3In the solution of N (0.20ml, 5.44mmol, 1.2 equivalents) and dimethyl aminopyridine (catalyst), add Boc acid anhydride (1.04g, 4.75mmol, 1.05 equivalents) in batches, this reactant mixture was at room temperature stirred 3 days.Solvent evaporated under reduced pressure, residue Et 2The O development, solids removed by filtration.To doing, residue by the column chromatography purification, with EtOAc/ hexane (20%) eluting, obtains emulsifiable paste shape solid, 780mg (55% productive rate) on silicagel column with filtrate evaporated under reduced pressure.The about 70%:m/z 308[M-H of HPLC-MS (method 1) purity assay] -, Rt=4.72 minute.Need not to be further purified and promptly can be used for next step.
N-[4-(5-[3-(amino carbonyl)-2,4 difluorobenzene oxygen base] methyl isophthalic acid, 2,4-oxadiazole-3-yl) phenyl] t-butyl carbamate.
Under the room temperature,, scheme 2,, 6-two fluoro-3-hydroxy benzenes carboxylic acid amides and N-4-[5-(chloromethyl)-1,2,4-oxadiazole-3-yl by 2 according to method B] the phenylcarbamic acid tert-butyl ester is synthetic.Productive rate 42%, fusing point 165-166 ℃, HPLC-MS (method 1): m/z 447[M+H] +, Rt=4.10 minute.
Embodiment 251:3-[3-(4-aminophenyl)-1,2,4-oxadiazole-5-yl] methoxyl group-2,6-two fluorobenzene carboxamide hydrochlorides.
Figure A20078000995901102
With N-[4-(5-[3-(amino carbonyl)-2,4-two fluorophenoxies] methyl isophthalic acid, 2,4-oxadiazole-3-yl) phenyl] t-butyl carbamate (300mg, 0.67mmol, 1 equivalent) and be dissolved in 4N HCl De diox (7ml, 28mmol, 42 equivalents) in, this reactant mixture at room temperature stirred spend the night.Volatile material, the anhydrous Et of residue are removed in decompression 2The O development is filtered the solid that forms and is used anhydrous Et 2The O flushing.Crude product (200mg) extracts among the EtOH (2ml), with the Et of 2N HCl 2O solution (0.3ml) and anhydrous Et 2The O development.Filter white solid and use anhydrous Et 2The O washing obtains the required product of 110mg (43% productive rate) .HPLC-MS (method 1): m/z 347[M+H-HCl] +, Rt=2.98 minute.
Embodiment 252-266 (table M)
According to method B, scheme 2, by 2,6-two fluoro-3-hydroxy benzenes carboxylic acid amides synthesizes embodiment 252,254-256 and 258-266.According to method L, by 2,6-two fluoro-3-[3-(2-methoxyphenyl)-1,2,4-oxadiazole-5-yl] the synthetic embodiment 253 and 257 of methoxybenzene carboxylic acid amides.
Figure A20078000995901111
Figure A20078000995901121
Figure A20078000995901122
The name list of product chemical compound; Embodiment 252-266:
Embodiment The chemical compound title
252 2,6-two fluoro-3-[3-(2-aminomethyl phenyl)-1,2,4-oxadiazole-5-yl] the methoxybenzene carboxylic acid amides
252a 2,6-two fluoro-3-[3-(2-methoxyphenyl)-1,2,4-oxadiazole-5-yl] the methoxybenzene carboxylic acid amides
253 2,6-two fluoro-3-[3-(2-hydroxy phenyl)-1,2,4-oxadiazole-5-yl] the methoxybenzene carboxylic acid amides
254 3-[3-(2-chlorphenyl)-1,2,4-oxadiazole-5-yl] methoxyl group-2,6-two fluorobenzene carboxylic acid amides
255 3-[3-(3-chlorphenyl)-1,2,4-oxadiazole-5-yl] methoxyl group-2,6-two fluorobenzene carboxylic acid amides
256 2,6-two fluoro-3-[3-(3-methoxyphenyl)-1,2,4-oxadiazole-5-yl] the methoxybenzene carboxylic acid amides
257 2,6-two fluoro-3-[3-(3-hydroxy phenyl)-1,2,4-oxadiazole-5-yl] the methoxybenzene carboxylic acid amides
258 2, and 6-two fluoro-3-(3-[3-(trifluoromethyl) phenyl]-1,2,4-oxadiazole-5-ylmethoxy) the benzene carboxylic acid amides
259 2,6-two fluoro-3-[3-(3-nitrobenzophenone)-1,2,4-oxadiazole-5-yl] the methoxybenzene carboxylic acid amides
260 3-[3-(2, the 6-Dichlorobenzene base)-1,2,4-oxadiazole-5-yl] methoxyl group-2,6-two fluorobenzene carboxylic acid amides
261 3-[3-(2, the 4-Dimethoxyphenyl)-1,2,4-oxadiazole-5-yl] methoxyl group-2,6-two fluorobenzene carboxylic acid amides
262 2,6-two fluoro-3-[3-(3-pyridine radicals)-1,2,4-oxadiazole-5-yl] the methoxybenzene carboxylic acid amides
263 2,6-two fluoro-3-(3-[(4-methylphenoxy) methyl]-1,2,4-oxadiazole-5-ylmethoxy) the benzene carboxylic acid amides
264 3-(3-[(2,6-dichlorophenoxy) methyl]-1,2,4-oxadiazole-5-ylmethoxy)-2,6-two fluorobenzene carboxylic acid amides
265 3-[3-(4-chloro benzyl)-1,2,4-oxadiazole-5-yl] methoxyl group-2,6-two fluorobenzene carboxylic acid amides
266 3-[(3-benzyl-1,2,4-oxadiazole-5-yl) methoxyl group]-2,6-two fluorobenzene carboxylic acid amides
Scheme 29:(a) NH 2OH.HCl, NaOH, EtOH; (b) bromoacetyl bromide, (c) K 2CO 3, DMF
Figure A20078000995901131
4-chloro-N-hydroxyl-Benzoylamide
Figure A20078000995901132
4-chloro benzonitrile (10.0g, add in EtOH 73.0mmol) (250mL) solution oxammonium hydrochloride. (5.03g, 73.0mmol) and NaOH (2.90g, 73.0mmol).With the reaction mixture refluxed that obtains 15 hours.After reaction is finished (TLC monitoring), concentrate mixed liquor, add EtOH, filter.With filtrate vacuum evaporation, be directly used in next step (crude product productive rate 12.0g, 66%).
5-bromomethyl-3-(4-chloro-phenyl)-[1,2,4] oxadiazoles
Figure A20078000995901141
With bromoacetyl bromide (1.50mL, 17.58mmol) add 4-chloro-N-hydroxyl-Benzoylamide (1.0g, 5.86mmol) and K 2CO 3(3.18g, 23.44mmol) in.This reactant mixture was heated 15 minutes down at 100 ℃.After reaction is finished (TLC monitoring), add entry (100mL), with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate.The crude product residue is gone up purification at silica gel (60-120M, 1%EtOAc-hexane), obtains the required product (0.44g, 28%) of white solid form.
Embodiment 267-270 (table N)
According to following universal method, the chemical compound of synthetic embodiment 267-270: at 5-bromomethyl-3-(4-chloro-phenyl)-[in the 2ml anhydrous DMF solution of 1,2,4] oxadiazoles (A), add reactant (B) and potassium carbonate (C).Under the nitrogen environment, this reactant mixture was stirred 24 hours down at 25 ℃.To doing, residue is gone up by the column chromatography purification at silica gel (230-400M), with ethyl acetate/hexane (45: 55) eluting, obtains the product chemical compound with the reactant mixture reduction vaporization.
Table N
Figure A20078000995901151
Scheme 30:(a) 2-benzyloxy-thioacetamide, DMF; (b) BBr 3, DCM, (c) PBr 3, the corresponding phenol of toluene (d)
Figure A20078000995901161
2-benzyloxymethyl-4-(4-chloro-phenyl)-thiazole
Figure A20078000995901162
2-benzyloxy-thioacetamide (3.0g, add in 3ml DMF solution 16.57mmol) 2-bromo-1-(4-chloro-phenyl)-ethyl ketone (3.0g, 12.87mmol).Under the nitrogen environment, this reactant mixture was heated 24 hours down at 130 ℃.After reaction is finished (TLC monitoring), add entry (25mL), with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate.The crude product residue is gone up purification at silica gel (230-400M, 2%EtOAc-hexane), obtain required product (2.0g, 49%).Also can prepare corresponding cyano derivative by identical universal method.
[4-(4-chloro-phenyl)-thiazol-2-yl]-methanol
Figure A20078000995901163
(2.0g, 6.34mmol) solution in 25ml DCM is cooled to-78 ℃, adds BBr then with 2-benzyloxymethyl-4-(4-chloro-phenyl)-thiazole 3(2.38ml, 25.3mmol).This reactant mixture was stirred 2 hours down at 25 ℃.After reaction is finished (TLC monitoring), 0 ℃ adds NaHCO down 3(20mL) solution is with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate.The crude product residue is gone up purification at silica gel (60-120M, 40%EtOAc-hexane), obtain required product (0.8g, 57%).Also can prepare corresponding cyano derivative by identical universal method.
2-bromomethyl-4-(4-chloro-phenyl)-thiazole
Figure A20078000995901171
In that [4-(4-chloro-phenyl)-thiazol-2-yl]-(0.80g adds PBr in 10ml toluene solution 3.55mmol) to methanol 3(0.51ml 5.33mmol), under the nitrogen environment, heats this reactant mixture 20 minutes down at 120 ℃.After reaction is finished (TLC monitoring), add entry (25mL), with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate, obtain required product (0.17g, 17%).Also can prepare corresponding cyano derivative by identical universal method.
Embodiment 271-276 (table O)
Chemical compound according to the synthetic embodiment 271-276 of following universal method: in the anhydrous DMF solution of reactant (A), add reactant (B) and potassium carbonate (C).Under the nitrogen environment, this reactant mixture was stirred 24 hours down at 25 ℃.To doing, residue is gone up by the column chromatography purification at silica gel (60-120M), uses the ethyl acetate/hexane eluting, obtains the product chemical compound with the reactant mixture reduction vaporization.
Table O
Figure A20078000995901182
Figure A20078000995901191
Figure A20078000995901192
Scheme 31:(a) thioacetamide, DMF; (b) NBS, CCl 4(c) 2,6-two fluoro-3-hydroxybenzamide, K 2CO 3, the corresponding boric acid of DMF (d), Su Shi (Suzuki) or Si Dier (Stille) condition (e) CuCN, pyridine.
Figure A20078000995901193
4-(4-methoxyl group-phenyl)-2-methyl-thiazole
Figure A20078000995901201
Under the nitrogen environment, (16.0g, 213mmol) (4.0g, mixture 17.5mmol) heated 24 hours down at 140 ℃ with 2-bromo-1-(4-methoxyl group-phenyl)-ethyl ketone with thioacetamide.After reaction is finished (TLC monitoring), add entry (100mL), with ethyl acetate extraction (3 * 100mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate.The crude product residue is gone up purification at silica gel (230-400M, 1%EtOAc-hexane), obtains required product (2.5g, 69%).
5-bromo-2-bromomethyl-4-(4-methoxyl group-phenyl)-thiazole
Figure A20078000995901202
4-(4-methoxyl group-phenyl)-2-methyl-thiazole (5.0, CCl 24.3mmol) 4(20mL) in the solution, (7.43g 41.74mmol), under the nitrogen environment, heats this reactant mixture 2 hours down at 100 ℃ to add NBS.After reaction is finished (TLC monitoring), to doing, residue is gone up by the column chromatography purification at silica gel (230-400M), with 1% ethyl acetate/hexane eluting, obtains required product (3.0g, 34%) with the reactant mixture reduction vaporization.
3-[5-bromo-4-(4-methoxyl group-phenyl)-thiazol-2-yl methoxyl group]-2,6-two fluoro-Benzoylamide
Figure A20078000995901203
5-bromo-2-bromomethyl-4-(4-methoxyl group-phenyl)-thiazole (0.50g in 5ml anhydrous DMF solution 1.37mmol), adds 2,6-two fluoro-3-hydroxyl-Benzoylamide (0.23g, 1.37mmol) and potassium carbonate (0.75g, 5.43mmol).Under the nitrogen environment, this reactant mixture was stirred 24 hours down at 25 ℃.To doing, residue is gone up by the column chromatography purification at silica gel (60-120M), with ethyl acetate/hexane (30: 70) eluting, obtains title compound (0.30g, 48%) with the reactant mixture reduction vaporization.
Embodiment 277-287 (table P)
Chemical compound according to the synthetic embodiment 277-287 of following universal method: at 3-[5-bromo-4-(4-methoxyl group-phenyl)-thiazol-2-yl methoxyl group]-2, in the 5ml dry DMF of 6-two fluoro-Benzoylamide (A) and water (2.5ml) solution, add reactant (B) and potassium phosphate (C).Make the reactant mixture degassing 10 minutes, add two (triphenyl phasphine) palladiums (II) of dichloro-then (D).Under the nitrogen environment, this reactant mixture was heated 12 hours down at 120 ℃.After reaction is finished (TLC monitoring), add entry (25mL), with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate.The crude product residue is gone up purification at silica gel (45%EtOAc-hexane), obtains required product chemical compound.
Table P
Figure A20078000995901211
Figure A20078000995901221
Figure A20078000995901222
Figure A20078000995901231
Figure A20078000995901232
Figure A20078000995901241
Embodiment 288:2,6-two fluoro-3-[4 '-(4-methoxyl group-phenyl)-[4,5 '] dithiazole base-2 '-ylmethoxy]-Benzoylamide
Figure A20078000995901242
At 3-[5-bromo-4-(4-methoxyl group-phenyl)-thiazol-2-yl methoxyl group]-2, (0.20g in 5ml anhydrous DMF solution 0.043mmol), adds 4-tributyl stannyl thiazole (0.16g to 6-two fluoro-Benzoylamide, 0.43mmol), make this reactant mixture degassing 10 minutes.(0.05g 0.043mmol), under the nitrogen environment, heats this reactant mixture 12 hours down at 120 ℃ to add four (triphenyl phasphine) palladium (0) then.Make reactant mixture be cooled to room temperature then, add entry (25mL), with ethyl acetate (3 * 50mL) extraction mixture.With the organic layer that merges in anhydrous Na 2SO 4Last dry, reduction vaporization is to doing.Chemical compound is gone up by the column chromatography purification at silica gel (230-400M), with ethyl acetate/hexane (40: 60) eluting, obtains the title compound (0.072g, 36%) of white solid form. 1H NMR (DMSO-d 6, 400MHz): δ 3.80 (s, 3H), 5.56 (s, 2H), 7.01 (d, J=8.80Hz, 2H), 7.13 (m, 1H), 7.41-7.50 (m, 4H), 7.90 (br s, 1H), 8.18 (br s, 1H) and 9.18 (s, 1H).MS ES+ (460.32), HPLC (method II) Rt=16.37 minute.
Embodiment 289:3-[5-cyano group-4-(4-methoxyl group-phenyl)-thiazol-2-yl methoxyl group]-2,6-two fluoro-Benzoylamide
At 3-[5-bromo-4-(4-methoxyl group-phenyl)-thiazol-2-yl methoxyl group]-2,6-two fluoro-Benzoylamide (0.20g, add in pyridine 0.43mmol) (4.0mL) solution CuCN (0.19g, 2.19mmol).With this reactant mixture 150 ℃ of following microwave heatings 2 hours.After reaction was finished, usefulness 1N HCl solution to 3-4, was used ethyl acetate extraction (3 * 50mL) with pH regulator.The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate.The crude product residue is gone up purification at silica gel (60-120M, 45%EtOAc-hexane), obtains the required product (0.02g, 11%) of brown solid form. 1HNMR (DMSO-d 6, 400MHz): δ 3.79 (s, 3H), 5.67 (s, 2H), 7.16 (m, 3H), 7.42 (m, 1H), 7.88 (br s, 1H), 8.03 (d, J=8.80Hz, 2H) and 8.19 (br s, 1H) .MS ES+ (402.07), HPLC (method I) Rt=16.60 minute.
Scheme 32:(a) Zn/ acetic acid; (b) BBr 3/ DCM
Figure A20078000995901252
2,6-two fluoro-3-[4-(4-methoxyl group-phenyl)-thiazol-2-yl methoxyl group]-Benzoylamide
Figure A20078000995901253
At 3-[5-bromo-4-(4-methoxyl group-phenyl)-thiazol-2-yl methoxyl group]-2, (2.0g in 50ml acetic acid solution 4.37mmol), adds Zn powder (2.0g) to 6-two fluoro-Benzoylamide.This reactant mixture was heated 1 hour down at 120 ℃.After reaction is finished (TLC monitoring), add entry (100mL), usefulness NaOH solution to 8-9, is used ethyl acetate extraction (3 * 150mL) with pH regulator.The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate, obtain the required product (0.8g, 50%) of white solid form.
Embodiment 290:2,6-two fluoro-3-[4-(4-hydroxyl-phenyl)-thiazol-2-yl methoxyl group]-Benzoylamide
Figure A20078000995901261
With 2,6-two fluoro-3-[4-(4-methoxyl group-phenyl)-thiazol-2-yl methoxyl group]-(0.20g, 15ml DCM solution 0.53mmol) is cooled to-78 ℃ to Benzoylamide, adds BBr then 3(0.2ml, 2.14mmol).This reactant mixture was stirred 2 hours down at 25 ℃.After reaction is finished (TLC monitoring), 0 ℃ adds NaHCO down 3(20mL) solution is with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filtering and concentrate, residue is gone up by the column chromatography purification at silica gel (60-120M), with ethyl acetate/hexane (50: 50) eluting, obtains the title compound (0.06g, 31%) of light yellow solid form. 1H NMR (DMSO-d 6, 400MHz): δ 5.55 (s, 2H), 6.83 (d, J=8.40Hz, 2H), 7.13 (m, 1H), 7.40 (m, 1H), 7.78 (d, J=8.80Hz, 2H), 7.88 (br s, 1H), 7.91 (s, 1H), 8.17 (br s, 1H) and 9.64 (br s, 1H).MS ES+ (363.25), HPLC (method I) Rt=14.57 minute.
Scheme 33:(a) thioacetamide; (b) NBS; (c) 2,6-two fluoro-3-hydroxybenzamide, K 2CO 3, DMF.
Figure A20078000995901262
4-(2-methyl-thiazole-4-yl)-benzonitrile
This chemical compound is prepared according to the universal method described in the preparation of 4-(4-methoxyl group-phenyl)-2-methyl-thiazole (scheme 31).
4-(5-bromo-2-bromomethyl-thiazole-4-yl)-benzonitrile
Figure A20078000995901271
This chemical compound is prepared according to the universal method described in the preparation of 5-bromo-2-bromomethyl-4-(4-methoxyl group-phenyl)-thiazole (scheme 31).
Embodiment 291:3-[5-bromo-4-(4-cyano group-phenyl)-thiazol-2-yl methoxyl group]-2,6-two fluoro-Benzoylamide
4-(5-bromo-2-bromomethyl-thiazole-4-yl)-benzonitrile (0.43g in 5ml anhydrous DMF solution 1.20mmol), adds 2,6-two fluoro-3-hydroxyl-Benzoylamide (0.20g, 1.20mmol) and potassium carbonate (0.58g, 4.20mmol).Under the nitrogen environment, this reactant mixture was stirred 24 hours down at 25 ℃.The reactant mixture reduction vaporization is to doing, and residue is gone up by the column chromatography purification at silica gel (60-120M), with ethyl acetate/hexane (30: 70) eluting, obtains the title compound (0.35g, 66%) of white solid form. 1H NMR (DMSO-d 6, 400MHz): δ 5.57 (s, 2H), 7.13 (m, 1H), 7.44 (m, 1H), 7.89 (br s, 1H), 8.0 (d, J=8.40Hz, 2H), 8.10 (d, J=8.40Hz, 2H) and 8.17 (br s, 1H).MS ES+ (450.09), HPLC (method I) Rt=16.127 minute.
Scheme 34:(a) NH 2OH.HCl, NaOH, EtOH; (b) bromoacetyl bromide, (c) K 2CO 3, DMF.
Figure A20078000995901281
Trifluoromethoxyphen-l-N-hydroxyl-Benzoylamide
Figure A20078000995901282
4-trifluoromethoxy benzonitrile (1.0g, in EtOH 5.0mmol) (20mL) solution, add oxammonium hydrochloride. (0.365g, 5.0mmol) and NaOH (0.212g, 5.0mmol).With the reaction mixture refluxed that obtains 15 hours.After reaction is finished (TLC monitoring), enriched mixture adds EtOH, filters.With filtrate vacuum evaporation, be directly used in next step (crude product productive rate 12.0g, 66%).
5-bromomethyl-3-(Trifluoromethoxyphen-l)-[1,2,4] oxadiazoles
With bromoacetyl bromide (2.0mL, 23.12mmol) add trifluoromethoxy-N-hydroxyl-Benzoylamide (0.40g, 5.86mmol) and K 2CO 3(0.87g, 6.0mmol) in.This reactant mixture was heated 15 minutes down at 100 ℃.After reaction is finished (TLC monitoring), add entry (100mL), with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate.The crude product residue is gone up purification at silica gel (60-120M, 3%EtOAc-hexane), obtains the required product (0.25g, 43%) of white solid form.
Embodiment 292:3-[3-(4-trifluoromethoxy-phenyl)-[1,2,4] oxadiazole-5-ylmethoxy]-2-fluoro-Benzoylamide
5-bromomethyl-3-(Trifluoromethoxyphen-l)-[1,2,4] oxadiazole (0.24g in 2.5ml anhydrous DMF solution 1.0mmol), adds 2,6-two fluoro-3-hydroxybenzamide (0.18g, 1.0mmol) and potassium carbonate (0.516g, 3.7mmol).Under the nitrogen environment, this reactant mixture was stirred 24 hours down at 25 ℃.To doing, residue is gone up by the column chromatography purification at silica gel (60-120M) with this reactant mixture reduction vaporization, with ethyl acetate/hexane (50: 50) eluting, obtains the title compound (0.090g, 20%) of white solid form. 1H NMR (DMSO-d 6, 400MHz): δ 5.71 (s, 2H), 7.15 (t, J=7.60Hz, 1H), 7.40 (m, 1H), 7.60 (d, J=8.0Hz, 2H), 7.91 (brs, 1H), 8.15 (d, J=8.40Hz, 2H) and 8.18 (br s, 1H).MS ES+ (416.28), HPLC (method I) Rt=16.79 minute.
Scheme 35:
Figure A20078000995901292
4-chloromethyl-2-(4-methoxyl group-phenyl)-oxazoles (universal method)
Figure A20078000995901293
1,3 acetone dichloride (0.504g, in toluene 3.90mmol) (5ml) solution, add the 4-methoxy benzamide (0.30g, 1.90mmol).This reactant mixture was heated 1 hour down at 120 ℃.After reaction is finished (TLC monitoring), to doing, residue is gone up purification at silica gel (230-400M, 15%EtOAc-hexane), obtains required product (0.37g, 83%) with the reactant mixture reduction vaporization.
Embodiment 293:2,6-two fluoro-3-[2-(4-methoxyl group-phenyl)-oxazole-4-ylmethoxy]-Benzoylamide
Figure A20078000995901301
4-chloromethyl-2-(4-methoxyl group-phenyl)-oxazole (0.100g in 2ml anhydrous DMF solution 0.4mmol), adds 2,6-two fluoro-3-hydroxyl-Benzoylamide (0.077g, 0.40mmol) and potassium carbonate (0.216g, 1.50mmol).Under the nitrogen environment, this reactant mixture was stirred 24 hours down at 25 ℃.The reactant mixture reduction vaporization is to doing, and residue is gone up by the column chromatography purification at silica gel (60-120M), with ethyl acetate/hexane (50: 50) eluting, obtains the title compound (0.044g, 27%) of white solid form. 1H NMR (DMSO-d 6, 400MHz): δ 4.01 (s, 3H), 5.12 (s, 2H), 7.10 (m, 3H), 7.40 (m, 1H), 7.85 (br s, 1H), 7.93 (d, J=8.80Hz, 2H), 8.13 (br s, 1H) and 8.25 (s, 1H).MS ES+ (361.16), HPLC (method I) Rt=15.47 minute.
Embodiment 294:3-[2-(4-chloro-phenyl)-oxazole-4-ylmethoxy]-2,6-two fluoro-Benzoylamide
4-chloromethyl-2-(4-chloro-phenyl)-oxazole (0.20g in 2ml anhydrous DMF solution 0.87mmol), adds 2,6-two fluoro-3-hydroxyl-Benzoylamide (0.15g, 0.78mmol) and potassium carbonate (0.363g, 2.60mmol).Under the nitrogen environment, this reactant mixture was stirred 24 hours down at 25 ℃.The reactant mixture reduction vaporization is to doing, and residue is gone up by the column chromatography purification at silica gel (60-120M), with ethyl acetate/hexane (50: 50) eluting, obtains the title compound (0.10g, 31%) of white solid form. 1H NMR (DMSO-d 6, 400MHz): δ 5.149s, 2H), 7.12 (t, J=9.20Hz, 1H), 7.40 (m, 1H), 7.63 (d, J=8.40,2H), 7.85 (br s, 1H), 8.0 (d, J=8.40Hz, 2H), 8.13 (br s, 1H) and 8.36 (s, 1H).MS ES+ (365.13), HPLC (method I) Rt=16.36 minute.
Embodiment 295:2,6-two fluoro-3-(2-p-methylphenyl-oxazole-4-ylmethoxy)-Benzoylamide
4-chloromethyl-2-p-methylphenyl-oxazole (0.10g in 2ml anhydrous DMF solution 0.50mmol), adds 2,6-two fluoro-3-hydroxyl-Benzoylamide (0.08g, 0.50mmol) and potassium carbonate (0.233g, 1.50mmol).Under the nitrogen environment, this reactant mixture was stirred 24 hours down at 25 ℃.The reactant mixture reduction vaporization is to doing, and residue is gone up by the column chromatography purification at silica gel (60-120M), with ethyl acetate/hexane (50: 50) eluting, obtains the title compound (0.03g, 18%) of white solid form. 1H NMR (DMSO-d 6, 400MHz): δ 2.37 (s, 3H), 5.13 (s, 2H), 7.11 (m, 1H), 7.36 (d, J=8.0Hz, 2H), 7.41 (m, 1H), 7.88 (m, 3H), 8.12 (br s, 1H) and 8.29 (s, 1H).MS ES+ (345.24), HPLC (method I) Rt=16.07 minute.
Scheme 36:
Figure A20078000995901312
2-(4-methoxyl group-phenyl)-4,5-dimethyl-oxazoles (universal method)
Under the nitrogen environment, (2.1g, 10.0mmol) (0.30g, mixture 1.0mmol) heated 15 hours down at 115 ℃ with the 4-methoxy benzamide with 3-chloro-2-butanone.After reaction is finished (TLC monitoring), to doing, residue is gone up purification at silica gel (230-400M, 20%EtOAc-hexane) with the reactant mixture reduction vaporization, obtains the required product (0.17g, 42%) of white solid form.Also can prepare corresponding chlorinated derivative by this universal method.
4-bromomethyl-2-(4-methoxyl group-phenyl)-5-methyl-oxazoles
Figure A20078000995901321
4-bromomethyl-2-(4-methoxyl group-phenyl)-5-methyl-oxazoles (0.17g, in acetonitrile 0.80mmol) (4.0mL) solution, add NBS (7.43g, 41.74mmol).Under the nitrogen environment, this reactant mixture was stirred 1 hour down at 25 ℃.After reaction is finished (TLC monitoring), reactant mixture is cooled to 0 ℃, adds 2ml water.Filtration gained precipitation obtains required product (0.11g, 46%) after the drying.Also can prepare corresponding chlorinated derivative by identical universal method.
Embodiment 296:2,6-two fluoro-3-[2-(4-methoxyl group-phenyl)-5-methyl-oxazole-4-ylmethoxy]-Benzoylamide
Figure A20078000995901322
4-bromomethyl-2-(4-methoxyl group-phenyl)-5-methyl-oxazole (0.10g in 2ml anhydrous DMF solution 0.35mmol), adds 2,6-two fluoro-3-hydroxyl-Benzoylamide (0.061g, 0.35mmol) and potassium carbonate (0.171g, 1.05mmol).Under the nitrogen environment, this reactant mixture was stirred 24 hours down at 25 ℃.The reactant mixture reduction vaporization is to doing, and residue is gone up by the column chromatography purification at silica gel (60-120M), with ethyl acetate/hexane (50: 50) eluting, obtains the title compound (0.117g, 87%) of white solid form. 1H NMR (DMSO-d 6, 400MHz): δ 2.42 (s, 3H), 3.82 (s, 3H), 5.06 (s, 2H), 7.10 (m, 3H), 7.37 (m, 1H), 7.86 (m, 3H) and 8.13 (br s, 1H).MS ES+ (375.12), HPLC (method I) Rt=15.78 minute.
Embodiment 297:3-[2-(4-chloro-phenyl)-5-methyl-oxazole-4-ylmethoxy]-2,6-two fluoro-Benzoylamide
Figure A20078000995901331
4-bromomethyl-2-(4-chloro-phenyl)-5-methyl-oxazole (0.12g in 2ml anhydrous DMF solution 0.42mmol), adds 2,6-two fluoro-3-hydroxyl-Benzoylamide (0.072g, 0.42mmol) and potassium carbonate (0.203g, 1.20mmol).Under the nitrogen environment, this reactant mixture was stirred 24 hours down at 25 ℃.The reactant mixture reduction vaporization is to doing, and residue (60-120M) on silica gel with ethyl acetate/hexane (50: 50) eluting, obtains the title compound (0.01g, 6%) of white solid form by the column chromatography purification. 1H NMR (DMSO-d 6, 400MHz): δ 2.49 (s, 3H), 5.09 (s, 2H), 7.11 (m, 1H), 7.38 (m, 1H), 7.60 (d, J=8.40Hz, 2H), 7.85 (br s, 1H), 7.95 (d, J=8.40Hz, 2H) and 8.13 (br s, 1H).MS ES+ (379.25), HPLC (method I) Rt=16.71 minute.
Scheme 37:(a) PBr 3(b) SnCl 2.2H 2O; (c) 2-benzoyloxy chloroacetic chloride; (d) lawesson reagent (Lawesson ' s reagent); (e) BBr 3(f) 2,6-two fluoro-3-hydroxybenzamide, K 2CO 3, DMF; (g) Su Shi (Suzuki) or stannyl condition.
Figure A20078000995901332
2,5-two bromos-3-nitro-pyridine
Figure A20078000995901333
(10.0g in 45.66mmol) the 70ml toluene and 7mlDMF solution, adds PBr at 5-bromo-3-nitro-pyridine-2-alcohol 3(6.60ml 68.49mmol), under the nitrogen environment, heats this reactant mixture 20 minutes down at 120 ℃.After reaction is finished (TLC monitoring), add entry (100mL), with ethyl acetate extraction (3 * 200mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate, obtain required product (10.30g, 80.03%).
2,5-two bromos-pyridin-3-yl amine
Figure A20078000995901341
2, (10.30g in 100ml alcoholic solution 35.47mmol), slowly adds SnCl to 5-two bromos-3-nitro-pyridine 2(24.0g, 106.42mmol).This reactant mixture was heated 2 hours down at 80 ℃.After reaction is finished (TLC monitoring), the reactant mixture reduction vaporization is extremely done.Add entry (250mL), isolate white solid, use NaOH solution quaternization mixture then.In this mixed liquor, add the 250ml ethyl acetate.Filter, residue washs with ethyl acetate, layering, dry (Na 2SO 4), filter, concentrate, obtain required product (6.20g, 67.39%).
2-benzyloxy-N-(2,5-two bromos-pyridin-3-yl)-acetamide
Figure A20078000995901342
2, and 5-two bromos-pyridin-3-yl amine (8.6g, in 50ml DCM solution 34.12mmol), the adding triethylamine (5.3ml, 37.53mmol).This reactant mixture is cooled to 0 ℃.In this mixed liquor, add 2-benzyloxy chloroacetic chloride (7.45g, 35ml DCM solution 40.95mmol).This reactant mixture was stirred 12 hours down at 25 ℃.After reaction is finished (TLC monitoring), the reactant mixture reduction vaporization is extremely done.Residue is gone up by the column chromatography purification at silica gel (60-120M), with ethyl acetate/hexane (10: 90) eluting, obtains title compound (3.2g, 24.17%).
2-benzyloxymethyl-5-bromo-thiazole is [5,4-b] pyridine also
Figure A20078000995901343
2-benzyloxy-N-(2,5-two bromos-pyridin-3-yl)-acetamide (2.5g, in 30ml toluene solution 6.248mmol), add lawesson reagent (Lawesson ' s reagent) (1.51g, 3.74mmol).This reactant mixture was heated 2 hours down at 120 ℃.After reaction is finished (TLC monitoring), the reactant mixture reduction vaporization is extremely done.Residue is gone up by the column chromatography purification at silica gel (60-120M), with ethyl acetate/hexane (5: 95) eluting, obtains title compound (1.60g, 76.5%).
5-bromo-2-bromomethyl-thiazole is [5,4-b] pyridine also
Figure A20078000995901351
With 2-benzyloxymethyl-5-bromo-thiazole also [5,4-b] pyridine (1.60g, DCM 4.77mmol) (15mL) solution is cooled to-78 ℃, adds BBr then 3(2.27ml, 23.86mmol).This reactant mixture was stirred 2 hours down at 25 ℃.After reaction is finished (TLC monitoring), 0 ℃ adds NaHCO down 3Solution (20mL) is with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate, obtain required product (2.0g, crude product productive rate).
Embodiment 298:3-(5-bromo-thiazole is [5,4-b] pyridine-2-ylmethoxy also)-2,6-two fluoro-Benzoylamide
Figure A20078000995901352
5-bromo-2-bromomethyl-thiazole also [5,4-b] pyridine (2.0g in 10ml anhydrous DMF solution 6.493mmol), adds 2,6-two fluoro-3-hydroxyl-Benzoylamide (1.01g, 5.84mmol) and potassium carbonate (3.09g, 22.72mmol).Under the nitrogen environment, this reactant mixture was stirred 24 hours down at 25 ℃.The reactant mixture reduction vaporization is to doing, and residue (60-120M) on silica gel with ethyl acetate/hexane (50: 50) eluting, obtains title compound (1.80g, 69%) by the column chromatography purification. 1HNMR (DMSO-d 6, 400MHz): δ 5.72 (s, 2H), 7.12 (t, J=7.60Hz, 1H), 7.39 (m, 1H), 7.90 (br s, 1H), 8.18 (br s, 1H) and 8.80 (m, 2H).MSES+ (402.08), HPLC (method I) Rt=15.50 minute.
3-(5-pi-allyl-thiazole is [5,4-b] pyridine-2-ylmethoxy also)-2,6-two fluoro-Benzoylamide
Figure A20078000995901353
At 3-(5-bromo-thiazole is [5,4-b] pyridine-2-ylmethoxy also)-2,6-two fluoro-Benzoylamide (0.15g, 0.37mmol) the 5ml anhydrous DMF solution in, (0.26ml 0.86mmol), makes this reactant mixture degassing 10 minutes to add allyl tributyltin.(0.007g 0.0056mmol), under the nitrogen environment, heats this reactant mixture 1 hour down at 120 ℃ to add four (triphenyl phasphine) palladium (0) then.Make reactant mixture be cooled to room temperature then, add entry (25mL), use the ethyl acetate extraction chemical compound.With the organic layer that merges in anhydrous Na 2SO 4Last dry, reduction vaporization is to doing.Chemical compound is gone up by the column chromatography purification at silica gel (100-200M), with ethyl acetate/hexane (60: 40) eluting, obtains title compound (0.10g, 75%).
Embodiment 299:2,6-two fluoro-3-(5-propyl group-thiazole is [5,4-b] pyridine-2-ylmethoxy also)-Benzoylamide
Figure A20078000995901361
At 3-(5-pi-allyl-thiazole is [5,4-b] pyridine-2-ylmethoxy also)-2,6-two fluoro-Benzoylamide (0.018g, 0.049mmol) the 5ml absolute methanol solution in, add Pd-C (10%, 5mg), under the hydrogen environment, this reactant mixture was stirred 12 hours down at 25 ℃.Reactant mixture is filtered on the kieselguhr filter bed, and filtrate evaporated under reduced pressure produces the title compound (0.0078g, 43%) of white solid form to doing. 1H NMR (DMSO-d 6, 400MHz); δ 0.91 (m, 3H), 1.65 (m, 2H), 2.74 (m, 2H), 5.69 (s, 2H), 7.12 (m, 1H), 7.39 (m, 1H), 7.90 (br s, 1H), 8.18 (br s, 1H), 8.27 (br s, 1H) and 8.52 (br s, 1H).MSES+ (364.11), HPLC (method I) Rt=15.85 minute.
Embodiment 300:2,6-two fluoro-3-[5-(1-methyl isophthalic acid H-imidazoles-2-yl)-thiazole is [5,4-b] pyridine-2-ylmethoxy also]-Benzoylamide
Figure A20078000995901362
At 3-(5-bromo-thiazole is [5,4-b] pyridine-2-ylmethoxy also)-2,6-two fluoro-Benzoylamide (0.10g, 0.24mmol) the 5ml anhydrous DMF solution in, (0.120g 0.32mmol), makes the reactant mixture degassing 10 minutes to add 1-methyl-2-tributyl tin alkyl-1H-imidazoles.(0.004g 0.0037mmol), under the nitrogen environment, heats reactant mixture 12 hours down at 120 ℃ to add four (triphenyl phasphine) palladium (0) then.Make reactant mixture be cooled to room temperature then, add entry (25mL), use the ethyl acetate extraction chemical compound.With the organic layer that merges in anhydrous Na 2SO 4Last dry, reduction vaporization is to doing.Chemical compound is gone up by the column chromatography purification at silica gel (230-400M), with ethyl acetate/hexane (40: 60) eluting, obtains the title compound (0.020g, 20%) of brick-red solid form. 1H NMR (DMSO-d 6, 400MHz): δ 3.14 (s, 3H), 5.67 (s, 2H), 7.07 (m, 1H), 7.28-7.37 (m, 2H), 7.87 (m, 2H), 8.28 (s, 1H), 8.53 (s, 1H) and 8.75 (br s, 1H).MSES+ (402.22), HPLC (method I) Rt=12.05 minute.
Embodiment 301:2,6-two fluoro-3-[5-(1-methyl isophthalic acid H-pyrroles-2-yl)-thiazole is [5,4-b] pyridine-2-ylmethoxy also]-Benzoylamide
At 3-(5-bromo-thiazole is [5,4-b] pyridine-2-ylmethoxy also)-2,6-two fluoro-Benzoylamide (0.10g, 0.24mmol) the 5ml anhydrous DMF solution in, (0.120g 0.32mmol), makes this reactant mixture degassing 10 minutes to add 1-methyl-2-tributyl tin alkyl-1H-pyrroles.(0.004g 0.0037mmol), under the nitrogen environment, heats this reactant mixture 12 hours down at 120 ℃ to add four (triphenyl phasphine) palladium (0) then.Make reactant mixture be cooled to room temperature then, add entry (25mL), use the ethyl acetate extraction chemical compound.With the organic layer that merges in anhydrous Na 2SO 4Last dry, reduction vaporization is to doing.Chemical compound is gone up by the column chromatography purification at silica gel (230-400M), with ethyl acetate/hexane (40: 60) eluting, obtains the title compound (0.032g, 32%) of yellow solid form. 1H NMR (DMSO-d 6, 400MHz): δ 3.73 (s, 3H), 5.72 (s, 2H), 6.13 (br s, 1H), 6.40 (br s, 1H), 6.97 (s, 1H), 7.12 (m, 1H), 7.42 (m, 1H), 7.90 (br s, 1H), 8.18 (brs, 1H), 8.48 (s, 1H) and 8.75 (s, 1H).MS ES+ (401.26), HPLC (method I) Rt=15.61 minute.
Embodiment 302:2,6-two fluoro-3-(5-phenyl-thiazole is [5,4-b] pyridine-2-ylmethoxy also)-Benzoylamide
Figure A20078000995901381
At 3-(5-bromo-thiazole is [5,4-b] pyridine-2-ylmethoxy also)-2,6-two fluoro-Benzoylamide (0.20g, 0.49mmol) 4ml DMF and the solution of water (2.0ml) in, add phenylboric acid (0.12g, 0.99mmol) and potassium phosphate (0.13g, 0.59mmol).Make this reactant mixture degassing 10 minutes, add then two (triphenyl phasphine) palladiums (II) of dichloro-(0.070g, 0.099mmol).Under the nitrogen environment, this reactant mixture was heated 2 hours down at 120 ℃.After reaction is finished (TLC monitoring), add entry (25mL), with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate.The crude product residue is gone up purification at silica gel (100-200M, 60%EtOAc-hexane), obtains the required product (0.080g, 41%) of beige solid form. 1H NMR (DMSO-d 6, 400MHz): δ 5.74 (s, 2H), 7.10 (m, 1H), 7.41-7.56 (m, 4H), 7.85 (m, 3H), 8.19 (m, 1H), 8.71 (br s, 1H) and 8.98 (br s, 1H).MS ES+ (398.09), HPLC (method I) Rt=16.07 minute.
Scheme 38:
4-chloromethyl-2-p-methylphenyl-thiazole (representative embodiment)
Figure A20078000995901383
(0.84g, in toluene 6.62mmol) (5ml) solution, (0.50g 3.31mmol), heats this reactant mixture 1 hour down at 120 ℃ to add 4-methylthio phenyl Methanamide at 1,3 dichloroacetone.After reaction is finished (TLC monitoring), to doing, residue is gone up purification at silica gel (230-400M, 15%EtOAc-hexane), obtains required product (0.49g, 67%) with the reactant mixture reduction vaporization.Also can prepare other derivants by identical universal method.
3-(4-chloromethyl-thiazol-2-yl)-phenol
Figure A20078000995901391
(0.42g, in toluene 3.26mmol) (5mL) solution, (0.25g 1.63mmol), heats this reactant mixture 1 hour down at 120 ℃ to add 3-hydroxyl Aminothiocarbonylbenzene at 1,3 dichloroacetone.Back (TLC monitoring) is finished in reaction, reactant mixture is evaporated to dried, adds entry, extracts (x 3) with EtOAc.The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate.The crude product residue is gone up purification at silica gel (230-400M, 10%EtOAc-hexane), obtains required product (0.14g, 38%).
Scheme 39:(a) 2-benzyloxy acetamide, DMF; (b) BBr 3, DCM; (c) 2,6-two fluoro-3-hydroxybenzamide, K 2CO 3, DMF.
Figure A20078000995901392
2-benzyloxymethyl-4-(4-chloro-phenyl)-oxazoles (exemplary process)
(1.40g, in 4ml DMF solution 8.56mmol), (2.0g 8.56mmol), under the nitrogen environment, heats this reactant mixture 6 hours down at 130 ℃ to add 2-bromo-1-(4-chloro-phenyl)-ethyl ketone at 2-benzyloxy-acetamide.After reaction is finished (TLC monitoring), add entry (25mL), with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate.The crude product residue is gone up purification at silica gel (230-400M, 10%EtOAc-hexane), obtains required product (1.1g, 44%).
2-bromomethyl-4-(4-chloro-phenyl)-oxazoles (exemplary process)
Figure A20078000995901401
(1.10g, 10ml DCM solution 3.6mmol) is cooled to-78 ℃, adds BBr then with 2-benzyloxymethyl-4-(4-chloro-phenyl)-oxazoles 3(1.76ml, 18.0mmol).This reactant mixture was stirred 2 hours down at 25 ℃.After reaction is finished (TLC monitoring), 0 ℃ adds NaHCO down 3Solution (20mL) is with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate, obtain required product (0.5g, 49%, crude product).
Embodiment 303-310 (table Q)
Chemical compound according to the synthetic embodiment 303-310 of following universal method: in the 2ml anhydrous DMF solution of reactant (A), add 2,6-two fluoro-3-hydroxyl-Benzoylamide (B) and potassium carbonate (C).Under the nitrogen environment, this reactant mixture was stirred 24 hours down at 25 ℃.To doing, residue (60-120M) on silica gel with ethyl acetate/hexane (50: 50) eluting, obtains the product chemical compound by the column chromatography purification with the reactant mixture reduction vaporization.
Table Q
Figure A20078000995901411
Figure A20078000995901412
Figure A20078000995901421
Figure A20078000995901422
Scheme 40:(a) acetamide; (b) NBS, AIBN, CCl 4(c) 2,6-two fluoro-3-hydroxybenzamide, K 2CO 3, DMF; (d) Zn/ acetic acid; (e) BBr 3, DCM.
Figure A20078000995901431
4-(4-methoxyl group-phenyl)-2-methyl-oxazoles
Figure A20078000995901432
According to scheme 31 described method preparations.
5-bromo-2-bromomethyl-4-(4-methoxyl group-phenyl)-oxazoles
Figure A20078000995901433
According to scheme 31 described method preparations.
3-[5-bromo-4-(4-methoxyl group-phenyl)-oxazole-2-ylmethoxy]-2,6-two fluoro-Benzoylamide
Figure A20078000995901434
According to scheme 31 described method preparations.
Embodiment 311:2,6-two fluoro-3-[4-(4-methoxyl group-phenyl)-oxazole-2-ylmethoxy]-Benzoylamide
Figure A20078000995901441
At 3-[5-bromo-4-(4-methoxyl group-phenyl)-oxazole-2-ylmethoxy]-2, (0.06g in 5ml acetic acid solution 0.13mmol), adds 50mg Zn powder to 6-two fluoro-Benzoylamide.This reactant mixture was heated 1 hour down at 120 ℃.After reaction is finished (TLC monitoring), add entry (25mL), usefulness NaOH solution to 8-9, is used ethyl acetate extraction (3 * 50mL) with pH regulator.The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate, obtain the required product (0.02g, 40%) of white solid form. 1H NMR (DMSO-d 6, 400MHz): δ 3.77 (s, 3H), 5.36 (s, 2H), 6.99 (d, J=8.40Hz, 2H), 7.12 (m, 1H), 7.37 (m, 1H), 7.71 (d, J=8.40Hz, 2H), 7.87 (br s, 1H), 8.15 (br s, 1H) and 8.56 (s, 1H).MS ES+ (361.24), HPLC (method I) Rt=15.41 minute.
Embodiment 312:2,6-two fluoro-3-[4-(4-hydroxyl-phenyl)-oxazole-2-ylmethoxy]-Benzoylamide
Figure A20078000995901442
With 2,6-two fluoro-3-[4-(4-methoxyl group-phenyl)-oxazole-2-ylmethoxy]-(0.20g, 10ml DCM solution 0.55mmol) is cooled to-78 ℃ to Benzoylamide, adds BBr then 3(0.10ml, 2.20mmol).This reactant mixture was stirred 2 hours down at 25 ℃.After reaction is finished (TLC monitoring), 0 ℃ adds NaHCO down 3(20mL) solution is with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate.Residue is gone up by the column chromatography purification at silica gel (60-120M), with ethyl acetate/hexane (50: 50) eluting, obtains the title compound (0.012g, 6%) of white solid form. 1H NMR (DMSO-d 6, 400MHz): δ 5.35 (s, 2H), 6.82 (d, J=8.40Hz, 2H), 7.14 (m, 1H), 7.38 (m, 1H), 7.58 (d, J=8.40Hz, 2H), 7.87 (br s, 1H), 8.15 (br s, 1H), 8.47 (s, 1H) and 9.63 (s, 1H).MS ES+ (347.22), HPLC (method I) Rt=14.00 minute.
Scheme 41:(a) thioacetamide; (b) NBS, AIBN, CCl 4(c) CuCN, pyridine; (d) MeOH, dry (dry) HCl; (e) NBS, AIBN, CCl 4(f) 2,6-two fluoro-3-hydroxybenzamide, K 2CO 3, DMF.
Figure A20078000995901451
4-(4-methoxyl group-phenyl)-2-methyl-thiazole
Figure A20078000995901452
Under the nitrogen environment, (16.0g, 213mmol) (4.0g, mixed liquor 17.5mmol) heated 24 hours down at 140 ℃ with 2-bromo-1-(4-methoxyl group-phenyl)-ethyl ketone with thioacetamide.After reaction is finished (TLC monitoring), add entry (25mL), with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate.The crude product residue is gone up purification at silica gel (230-400M, 1%EtOAc-hexane), obtains required product (2.5g, 69%).
5-bromo-4-(4-methoxyl group-phenyl)-2-methyl-thiazole
At 5-bromo-2-bromomethyl-4-(4-methoxyl group-phenyl)-thiazole (5.0g, 20mlCCl 24.3mmol) 4In the solution, add NBS (4.32g, 24.3mmol) and AIBN (0.4g, 2.43mmol).Under the nitrogen environment, this reactant mixture was heated 2 hours down at 100 ℃.After reaction is finished (TLC monitoring), to doing, residue is gone up by the column chromatography purification at silica gel (230-400M), with 1% ethyl acetate/hexane eluting, obtains required product (4.0g, 58%) with the reactant mixture reduction vaporization.
4-(4-methoxyl group-phenyl)-2-methyl-thiazole-5-nitrile
Figure A20078000995901461
5-bromo-4-(4-methoxyl group-phenyl)-2-methyl-thiazole (2.0g, in 15ml pyridine solution 7.0mmol), add CuCN (3.10g, 35.2mmol), with this reactant mixture 150 ℃ of following microwave heatings 2 hours.After reaction was finished, usefulness 1N HCl solution to 3-4, was used ethyl acetate extraction (3 * 50mL) with pH regulator.The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate.The crude product residue is gone up purification at silica gel (60-120M, 12%EtOAc-hexane), obtains the required product (1.5g, 92%) of white solid form.
4-(4-methoxyl group-phenyl)-2-methyl-thiazole-5-carboxylate methyl ester
Figure A20078000995901462
Under 0 ℃, (0.50g in 15ml methanol solution 2.1mmol), fed dry HCl gas 1 hour at 4-(4-methoxyl group-phenyl)-2-methyl-thiazole-5-nitrile.This reactant mixture was stirred 24 hours down at 25 ℃.After reaction is finished (TLC monitoring), the reactant mixture reduction vaporization is extremely done.Add entry (50ml), use NaHCO 3Solution to 7-8, is used ethyl acetate extraction (3 * 50mL) with pH regulator.The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate, obtain the required product (0.25g, 44%) of white solid form.
2-bromomethyl-4-(4-methoxyl group-phenyl)-thiazole-5-carboxylic acid methyl ester
Figure A20078000995901463
At 4-(4-methoxyl group-phenyl)-2-methyl-thiazole-5-carboxylate methyl ester (0.25g, 20ml CCl 0.94mmol) 4In the solution, add NBS (0.16g, 0.94mmol) and AIBN (0.015g, 0.094mmol).Under the nitrogen environment, this reactant mixture was heated 2 hours down at 100 ℃.After reaction is finished (TLC monitoring), to doing, residue is gone up by the column chromatography purification at silica gel (230-400M), with 10% ethyl acetate/hexane eluting, obtains required product (0.078g, 24%) with the reactant mixture reduction vaporization.
Embodiment 313:2-(3-carbamoyl-2,4-two fluoro-phenoxymethyl)-4-(4-methoxyl group-phenyl)-thiazole-5-carboxylic acid methyl ester
2-bromomethyl-4-(4-methoxyl group-phenyl)-thiazole-5-carboxylic acid methyl ester (0.05g in 2ml anhydrous DMF solution 0.14mmol), adds 2,6-two fluoro-3-hydroxyl-Benzoylamide (0.025g, 0.14mmol) and potassium carbonate (0.07g, 0.50mmol).Under the nitrogen environment, this reactant mixture was stirred 24 hours down at 25 ℃.To doing, residue (60-120M) on silica gel with ethyl acetate/hexane (50: 50) eluting, obtains the title compound (0.025g, 40%) of white solid form by the column chromatography purification with the reactant mixture reduction vaporization. 1H NMR (DMSO-d 6, 400MHz): δ 3.76 (s, 3H), 3.81 (s, 3H), 5.60 (s, 2H), 7.01 (d, J=8.40Hz, 2H), 7.12 (m, 1H), 7.41 (m, 1H), 7.74 (d, J=8.40Hz, 2H), 7.90 (br s, 1H) and 8.18 (br s, 1H).MS ES+ (435.06), HPLC (method I) Rt=15.86 minute.
Scheme 42:(a) trifluoromethanesulfanhydride anhydride (triflic anhydride), pyridine, DCM; (b) 2,6-two fluoro-3-[5-(4,4,5,5-tetramethyl-[1,3,2] two assorted oxygen pentaborane-2-bases (dioxaborolan-2-yl))-1H-indenes-2-ylmethoxy]-Benzoylamide, Pd catalyst, potassium phosphate; (c) H 2, Pd-C.
Figure A20078000995901481
Trifluoromethanesulfonic acid hexamethylene-1-alkenyl esters
(5.0g, in 80ml DCM solution 51mmol), (4.48ml 56.0mmol), is cooled to-78 ℃ with the reactant mixture that obtains to add pyridine at Ketohexamethylene.In this reactant mixture, add trifluoromethanesulfanhydride anhydride (7.40ml, 30ml DCM solution 56.0mmol) in 1 hour.This reactant mixture was stirred 24 hours down at 25 ℃.After reaction is finished (TLC monitoring), the reactant mixture reduction vaporization is extremely done.Residue is developed with pentane, topples over organic layer, dry (Na 2SO 4), filter and concentrate, obtain required product (5.0g, 42%).
Embodiment 314:3-(5-hexamethylene-1-thiazolinyl-1H-indenes-2-ylmethoxy)-2,6-two fluoro-Benzoylamide
Figure A20078000995901483
2,6-two fluoro-3-[5-(4,4,5,5-tetramethyl-[1,3,2] two assorted oxygen pentaborane-2-yls)-1H-indenes-2-ylmethoxy]-(0.10g in the solution of 3ml dry DMF 0.20mmol) and water (1.5ml), adds trifluoromethanesulfonic acid hexamethylene-1-alkenyl esters (0.15g to Benzoylamide, 0.60mmol) and potassium phosphate (0.057g, 0.20mmol).With this reactant mixture degassing 10 minutes, add then two (triphenyl phasphine) palladiums (II) of dichloro-(0.02g, 0.03mmol).Under the nitrogen environment, this reactant mixture was heated 1 hour down at 80 ℃.After reaction is finished (TLC monitoring), add entry (25mL), with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate.The crude product residue is gone up purification at silica gel (230-400M, 45%EtOAc-hexane), obtains the required product (0.017g, 19) of white solid form. 1H NMR (DMSO-d 6, 400MHz): δ 1.63 (m, 4H), 2.20 (m, 2H), 2.45 (m, 2H), 5.67 (s, 2H), 6.29 (m, 1H), 7.12 (m, 1H), 7.37 (m, 1H), 7.57 (m, 2H), 7.90 (br s, 1H), 8.03 (d, J=8.40Hz, 1H) and 8.18 (br s, 1H).MS ES+ (401.16), HPLC (method II) Rt=14.13 minute.
Embodiment 315:3-(5-cyclohexyl-1H-indenes-2-ylmethoxy)-2,6-two fluoro-Benzoylamide
At 3-(5-hexamethylene-1-thiazolinyl-1H-indenes-2-ylmethoxy)-2, and 6-two fluoro-Benzoylamide (0.01g, in 5ml absolute methanol solution 0.25mmol), adding Pd-C (10%, 100mg).Under the hydrogen environment, this reactant mixture was stirred 48 hours down at 25 ℃.Reactant mixture is filtered on the kieselguhr filter bed, and reduction vaporization produces the title compound (0.01g, 10%) of white solid form to doing. 1H NMR (DMSO-d 6, 400MHz); δ 1.40 (m, 6H), 1.72 (m, 4H), 2.63 (m, 1H), 5.66 (s, 2H), 7.09 (m, 1H), 7.35 (m, 2H), 7.83 (br s, 1H), 7.89 (d, J=8.40Hz, 1H), 7.99 (d, J=8.40Hz, 1H) and 8.18 (br s, 1H).MSES+ (403.33), HPLC (method II) Rt=18.76 minute.
Scheme 43:(a) trifluoromethanesulfanhydride anhydride, pyridine, DCM; (b) 2,6-two fluoro-3-[5-(4,4,5,5-tetramethyl-[1,3,2] two assorted oxygen pentaborane-2-yls)-1H-indenes-2-ylmethoxy]-Benzoylamide, Pd catalyst, potassium phosphate; (c) H 2, Pd-C.
Figure A20078000995901492
Three fluoro-methanesulfonic acid rings, penta-1-alkenyl esters
Figure A20078000995901493
(5.0g, in 80ml DCM solution 59mmol), (5.2ml 65.0mmol), is cooled to-78 ℃ with the reactant mixture that obtains to add pyridine at Ketocyclopentane.In this reactant mixture, add trifluoromethanesulfanhydride anhydride (9.2ml, the solution of 30ml DCM 65.0mmol) in 1 hour.Reactant mixture was stirred 24 hours down at 25 ℃.After reaction is finished (TLC monitoring), the reactant mixture reduction vaporization is extremely done.Residue is developed with pentane, topples over organic layer, dry (Na 2SO 4), filter and concentrate, obtain required product (2.4g, 22%).
Embodiment 316:3-(5-ring penta-2-thiazolinyl-1H-indenes-2-ylmethoxy)-2,6-two fluoro-Benzoylamide
Figure A20078000995901501
2,6-two fluoro-3-[5-(4,4,5,5-tetramethyl-[1,3,2] two assorted oxygen pentaborane-2-yls)-1H-indenes-2-ylmethoxy]-(0.25g in the solution of 7ml dry DMF 0.56mmol) and water (3.5ml), adds trifluoromethanesulfonic acid ring penta-1-alkenyl esters (0.37g to Benzoylamide, 1.70mmol) and potassium phosphate (0.14g, 0.60mmol).Made the reactant mixture degassing 10 minutes, add then two (triphenyl phasphine) palladiums (II) of dichloro-(0.05g, 0.08mmol).Under the nitrogen environment, this reactant mixture was heated 1 hour down at 80 ℃.After reaction is finished (TLC monitoring), add entry (25mL), with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate.The crude product residue is gone up purification at silica gel (230-400M, 45%EtOAc-hexane), obtains the required product (0.14g, 65%) of white solid form. 1H NMR (DMSO-d 6, 400MHz): δ 1.22 (m, 2H), 2.01 (m, 2H), 2.88 (m, 2H), 5.68 (s, 2H), 6.43 (s, 1H), 7.01 (t, J=9.20Hz, 1H), 7.37 (m, 1H), 7.67 (d, J=8.40Hz, 1H), 7.89 (br s, 1H), 7.94 (s, 1H), 8.07 (d, J=8.40Hz, 1H) and 8.18 (br s, 1H).MSES+ (387.15), HPLC (method II) Rt=13.74 minute.
Embodiment 317:3-(5-cyclopenta-1H-indenes-2-ylmethoxy)-2,6-two fluoro-Benzoylamide
Figure A20078000995901502
At 3-(5-ring penta-1-thiazolinyl-1H-indenes-2-ylmethoxy)-2, and 6-two fluoro-Benzoylamide (0.05g, in 5ml absolute methanol solution 0.10mmol), adding Pd-C (10%, 100mg).Under the hydrogen environment, this reactant mixture was stirred 48 hours down at 25 ℃.Reactant mixture filters on the kieselguhr filter bed, and reduction vaporization produces the title compound (0.005g, 10%) of white solid form to doing. 1HNMR (DMSO-d 6, 400MHz); δ 1.22 (m, 2H), 1.67 (m, 4H), 1.80 (m, 2H), 2.07 (m, 2H), 3.20 (m, 1H), 5.67 (s, 2H), 7.09 (m, 1H), 7.37 (m, 2H), 7.87 (m, 2H), 8.0 (m, 1H) and 8.18 (br s, 1H).MS ES+ (389.12), HPLC (method II) Rt=18.19 minute.
Embodiment 318-333
Scheme 44 (embodiment 318-320): (a) lawesson reagent; (b) bromoacetophenone of Qu Daiing; (c) LAH, THF; (d) PBr 3, toluene; (e) 2,6-two fluoro-3-hydroxybenzamide, K 2CO 3, DMF.
Figure A20078000995901511
The sulfo-ethyl oxalate
Figure A20078000995901512
(10.0g, in 120ml toluene solution 85.30mmol), (24.15g 59.7mmol), heats this reactant mixture 12 hours down at 120 ℃ to add lawesson reagent at ethyl oxalate.After reaction is finished (TLC monitoring), the reactant mixture reduction vaporization is extremely done.Residue is gone up by the column chromatography purification at silica gel (230-400M), with ethyl acetate/hexane (5: 95) eluting, obtains title compound (1.8g, 16%).
4-(4-trifluoromethyl-phenyl)-thiazole-2-carboxylic acid, ethyl ester (representative embodiment)
Figure A20078000995901521
2-bromo-1-(4-trifluoromethyl-phenyl)-ethyl ketone (0.50g, in 7ml alcoholic solution 0.80mmol), add the sulfo-ethyl oxalate (0.15g, 1.14mmol).Under the nitrogen environment, this reactant mixture was heated 2 hours down at 80 ℃.After reaction is finished (TLC monitoring), the concentrating under reduced pressure reactant mixture adds entry (25mL), with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate.The crude product residue is gone up purification at silica gel (230-400M, 2%EtOAc-hexane), obtains required product (0.21g, 76%).By identical universal method, also can prepare other derivants.
[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-methanol
Figure A20078000995901522
(0.056g 1.40mmol) in the suspension of the anhydrous THF of 8ml, dropwise adds 4-(4-trifluoromethyl-phenyl)-thiazole-2-carboxylic acid ethyl ester (0.21g, solution of 5mlTHF 0.71mmol) at ice-cold LAH.This reactant mixture was stirred 1 hour down at 25 ℃.After reaction is finished (TLC monitoring), reactant mixture is cooled to 0 ℃, goes out, add 15%NaOH solution (2mL) then, last 4ml water with the 2.5ml shrend.Gained solution is passed through kieselguhr depth filtration, deep bed filtration, concentrating under reduced pressure filter liquor.Add entry (50mL), with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate, obtain required product (0.13g, 70%).Also can prepare other derivants by identical universal method.
2-bromomethyl-4-(4-trifluoromethyl-phenyl)-thiazole
Figure A20078000995901523
(0.13g in 2ml toluene solution 0.50mmol), adds PBr at [4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-methanol 3(0.072ml 0.752mmol), under the nitrogen environment, heats this reactant mixture 20 minutes down at 120 ℃.After reaction is finished (TLC monitoring), add entry (25mL), with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate.The crude product residue is gone up purification at silica gel (230-400M, 1%EtOAc-hexane), obtains required product (0.04g, 25%).Also can prepare other derivants by identical universal method.
Scheme 45 (embodiment 321): (a) MeOH, H 2SO 4(b) SnCl 2.2H 2O, EtOH; (c) 2-benzyloxy chloroacetic chloride; (d) lawesson reagent; (e) BBr 3, DCM; (f) PBr 3, toluene-DMF; (g) 2,6-two fluoro-3-hydroxybenzamide, K 2CO 3, DMF.
Figure A20078000995901531
4-chloro-3-nitro-essence of Niobe
(5.0g in 50ml methanol solution 24.81mmol), adds H at 4-chloro-3-nitrobenzoic acid 2SO 4(2ml 37.02mmol), heats this reactant mixture 5 hours down at 70 ℃.After reaction is finished (TLC monitoring), the reactant mixture reduction vaporization is extremely done.Add entry (50mL), with ethyl acetate extraction (3 * 50mL).With the organic facies drying (Na that merges 2SO 4), filter and concentrate, obtain required product (5.04g, 94%).
3-amino-4-chloro-essence of Niobe
Figure A20078000995901541
(5.0g in 100ml alcoholic solution 23.19mmol), adds SnCl at 4-chloro-3-nitro-essence of Niobe 2.2H 2(26.0g 115.96mmol), heats this reactant mixture 2 hours down at 80 ℃ O.After reaction is finished (TLC monitoring), the reactant mixture reduction vaporization is extremely done.Add entry (100mL), with NaOH solution quaternization mixture, with EtOAc (3 * 250mL) extractions of heat.The organic facies that merges is at Na 2SO 4Last dry, filter and concentrate, obtain required product (3.0g, 69%).
3-(2-benzyloxy-acetyl-amino)-4-chloro-essence of Niobe
Figure A20078000995901542
With carbonic acid one benzyl ester (3.50g, 50ml DCM 21.0mmol) and the solution of 0.50ml DMF are cooled to-78 ℃, add then oxalyl chloride (11.79ml, 105mmol).The reactant mixture that stirring at room temperature obtains 1 hour.After reaction is finished (TLC monitoring), concentrate and obtain 2-benzyloxy chloroacetic chloride (3.0g, 96%).In the ice-cold solution that 3-amino-4-chloro-essence of Niobe forms in 10ml DMC, add triethylamine (2.47ml, 17.78mmol), be added in then 2-benzyloxy chloroacetic chloride among the 10ml DCM (3.0g, 17.78mmol).This reactant mixture was stirred 12 hours at 25 ℃.After reaction is finished (TLC monitoring), the reactant mixture reduction vaporization is to doing.Residue is gone up by the column chromatography purification at silica gel (60-120M), with ethyl acetate/hexane (5: 95) eluting, obtains title compound (1.70g, 31%).
3-(2-benzyloxy-ethanethioyl amino)-4-chloro-essence of Niobe
Figure A20078000995901543
(1.70g, in 20ml toluene solution 5.10mmol), (1.03g 2.50mmol), heats this reactant mixture 2 hours down at 120 ℃ to add lawesson reagent at 3-(2-benzyloxy-acetyl-amino)-4-chloro-essence of Niobe.After reaction is finished (TLC monitoring), the reactant mixture reduction vaporization is extremely done.Residue is gone up by the column chromatography purification at silica gel (60-120M), with ethyl acetate/hexane (5: 95) eluting, obtains title compound (1.20g, 67%).
2-benzyloxymethyl-benzothiazole-6-carboxylate methyl ester
Figure A20078000995901551
3-(2-benzyloxy-ethanethioyl amino)-4-chloro-essence of Niobe (1.20g, in the solution of 8ml NMP 3.40mmol), add in batches NaH (0.12g, 5.10mmol).This reactant mixture was heated 3 hours down at 160 ℃.After reaction is finished (TLC monitoring), reactant mixture is poured in the 150ml frozen water, with ethyl acetate extraction (3 * 150mL).With the organic facies drying (Na that merges 2SO 4), filter and concentrate, obtain required product (1.07g, 56%).
2-methylol-benzothiazole-6-carboxylate methyl ester
Figure A20078000995901552
(0.10g, 2mlDCM 0.32mmol) are cooled to-78 ℃, add BBr then with 2-benzyloxymethyl-benzothiazole-6-carboxylate methyl ester 3(0.06ml, 0.64mmol).This reactant mixture was stirred 2 hours down at 25 ℃.After reaction is finished (TLC monitoring), 0 ℃ adds NaHCO down 3(20mL) solution is with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate, obtain required product (0.08g, crude product productive rate).
2-bromomethyl-benzothiazole-6-carboxylate methyl ester
Figure A20078000995901553
(0.08g in 5ml toluene 0.40mmol) and the solution of 1ml DMF, adds PBr at 2-methylol-benzothiazole-6-carboxylate methyl ester 3(0.06ml, 0.60mmol).Under the nitrogen environment, this reactant mixture was heated 20 minutes down at 120 ℃.After reaction is finished (TLC monitoring), add entry (25mL), with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate, obtain required product (0.044g, 36%).
Scheme 46 (embodiment 322):
Figure A20078000995901561
Benzo [1,3] dioxole-5-nitrile
3,4 dihydroxy benzonitriles (5.0g, in 20ml DMF solution 37.0mmol), add methylene bromide (19.25g, 110.0mmol) and potassium carbonate (25.50g, 184.90mmol).Under the nitrogen environment, this reactant mixture was heated 2 hours down at 120 ℃.After reaction is finished (TLC monitoring), reactant mixture is cooled to room temperature.(50ml) joins in the reactant mixture with water, with ethyl acetate (3 * 100mL) extract compounds.With the organic layer that merges in anhydrous Na 2SO 4Last dry, reduction vaporization produces the title compound (5.16g, 94.8%) of yellow solid form to doing.
N-hydroxyl-benzo [1,3] dioxole-5-carbonamidine (carboxamidine)
To benzo [1,3] dioxole-5-nitrile (5.0g, add in EtOH 33.9mmol) (100mL) solution oxammonium hydrochloride. (4.68g, 67.90mmol) and NaOH (2.71g, 67.9mmol).With the reaction mixture refluxed that obtains 12 hours.After reaction is finished (TLC monitoring), enriched mixture adds EtOH, filters.With filtrate evaporated under reduced pressure, be directly used in next step (crude product productive rate 4.8g, 78.68%).
3-benzo [1,3] dioxole-5-base-5-bromomethyl-[1,2,4] oxadiazoles
Figure A20078000995901571
With bromoacetyl bromide (0.22g, 1.10mmol) join N-hydroxyl-benzo [1,3] dioxole-5-carbonamidine (0.40g, 0.55mmol) and K 2CO 3(0.38g, 0.78mmol) in.This reactant mixture was heated 15 minutes down at 100 ℃.After reaction is finished (TLC monitoring), add entry (25mL), with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate.The crude product residue is gone up purification at silica gel (60-120M, 5%EtOAc-hexane), obtains required product (0.05g, 31%).
Scheme 47 (embodiment 323): (a) ethyl bromide acetone, EtOH; (b) LAH, THF; (c) PBr 3, toluene; (d) 2,6-two fluoro-3-hydroxybenzamide, K 2CO 3, DMF.
Figure A20078000995901572
2-(4-methoxyl group-phenyl)-thiazole-4-carboxylic acid ethyl ester
Figure A20078000995901573
Ice-cold 4-methoxyl group-Aminothiocarbonylbenzene (0.50g, in ethanol 2.98mmol) (25ml) solution, add triethylamine (0.41ml, 2.98mmol), dropwise add then ethyl bromide acetone (0.56ml, 4.40mmol).This reactant mixture was heated 12 hours down at 65 ℃.After reaction is finished (TLC monitoring), the reactant mixture reduction vaporization to doing, is added entry (25mL), with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate.The crude product residue is gone up purification at silica gel (60-120M, 10%EtOAc-hexane), obtains required product (0.38g, 48%).
[2-(4-methoxyl group-phenyl)-thiazole-4-yl]-methanol
Figure A20078000995901581
(0.08g in the suspension of the anhydrous THF of 10ml 2.07mmol), adds 2-(4-methoxyl group-phenyl)-thiazole-4-carboxylic acid ethyl ester (0.26g, 5ml THF solution 0.98mmol) at ice-cold LAH.This reactant mixture is heated to 60 ℃, continues 1 hour.After reaction is finished (TLC monitoring), reactant mixture is cooled to 0 ℃, adds entry (2.0ml), add 15%NaOH solution (2mL) again, add 4ml water at last.Make gained solution by kieselguhr depth filtration, deep bed filtration, concentrating under reduced pressure; Add entry (25mL), with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate, obtain required product (0.14g, 64%).
4-bromomethyl-2-(4-methoxyl group-phenyl)-thiazole
Figure A20078000995901582
(0.12g in 3ml toluene solution 0.50mmol), adds PBr at [2-(4-methoxyl group-phenyl)-thiazole-4-yl]-methanol 3(0.078ml 0.813mmol), under the nitrogen environment, heats this reactant mixture 20 minutes down at 120 ℃.After reaction is finished (TLC monitoring), add entry (25mL), with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate, obtain required product (0.13g, 84%).
Scheme 48 (embodiment 324): (a) propionic andydride, K 2CO 3(b) NBS, AIBN, CCl 4(c) 2,6-two fluoro-3-hydroxybenzamide, K 2CO 3, DMF.
Figure A20078000995901583
3-(4-chloro-phenyl)-5-ethyl-[1,2,4] oxadiazoles
With propionic andydride (0.75mL, 5.79mmol) join 4-chloro-N-hydroxyl-Benzoylamide (0.50g, 2.89mmol) and K 2CO 3(2.0g, 14.48mmol) in.This reactant mixture was heated 30 minutes down at 100 ℃.After reaction is finished (TLC monitoring), reactant mixture is cooled to 0 ℃, adds entry (25mL), with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate.The crude product residue is gone up purification at silica gel (60-120M, 5%EtOAc-hexane), obtains required product (0.29g, 48%).
5-(1-bromo-ethyl)-3-(4-chloro-phenyl)-[1,2,4] oxadiazoles
Figure A20078000995901591
At 3-(4-chloro-phenyl)-5-ethyl-[1,2,4] oxadiazoles (0.29g, CCl 1.38mmol) 4(10mL) in the solution, add NBS (0.24g, 1.38mmol) and AIBN (0.02g, 0.0001mmol).Under the nitrogen environment, this reactant mixture was heated 2 hours down at 100 ℃.After reaction is finished (TLC monitoring), to doing, residue is gone up by the column chromatography purification at silica gel (230-400M), with 1% ethyl acetate/hexane eluting, obtains required product (0.12g, 30%) with the reactant mixture reduction vaporization.
Scheme 49 (embodiment 325): (a) PBr 3, toluene; (b) 2,6-two fluoro-3-hydroxybenzamide, K 2CO 3, DMF.
Figure A20078000995901592
4-bromomethyl-5-methyl-2-phenyl-2H-[1,2,3] triazole
Figure A20078000995901593
(5-methyl-2-phenyl-2H-[1,2,3] triazole-4-yl)-(0.25g in 10ml toluene solution 1.30mmol), adds PBr to methanol 3(0.53g 1.90mmol), under the nitrogen environment, heats this reactant mixture 20 minutes down at 120 ℃.After reaction is finished (TLC monitoring), add entry (25mL), with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate, obtain the required product (0.30g, 90%) of yellow solid form.
Scheme 50 (embodiment 326): (a) CuCN, pyridine; (b) oxammonium hydrochloride., ethanol; (c) chloracetyl chloride, K 2CO 3(d) 2,6-two fluoro-3-hydroxybenzamide, K 2CO 3, DMF.
Figure A20078000995901601
Thiazole-2-nitrile
Figure A20078000995901602
The 2-bromethiazole (1.0g, in 4ml pyridine solution 6.09mmol), add CuCN (1.09g, 12.19mmol).This reactant mixture was heated 3 hours down at 150 ℃.After reaction was finished, usefulness 1N HCl solution to 3-4, was used ethyl acetate extraction (3 * 50mL) with pH regulator.The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate, obtain required product (0.42g, 63%).
N-hydroxyl-thiazole-2-carbonamidine
Figure A20078000995901603
Thiazole-2-nitrile (0.42g, in EtOH 3.80mmol) (20mL) solution, add oxammonium hydrochloride. (0.53g, 7.60mmol) and pyridine (0.27g, 3.40mmol).With the reaction mixture refluxed that obtains 15 hours.After reaction is finished (TLC monitoring), enriched mixture adds EtOH, filters.With filtrate evaporated under reduced pressure, be directly used in next step (crude product output 0.50g, 91% crude product productive rate).
5-chloromethyl-3-thiazol-2-yl-[1,2,4] oxadiazoles
With chloracetyl chloride (5.0mL, 44.5mmol) join N-hydroxyl-thiazole-2-carbonamidine (0.50g, 3.49mmol) and K 2CO 3(1.0g, 7.20mmol) in.This reactant mixture was heated 15 minutes down at 100 ℃.After reaction is finished (TLC monitoring), add entry (25mL), with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate.The crude product residue is gone up purification at silica gel (230-400M, 10%EtOAc-hexane), obtains the required product (0.18g, 25%) of white solid form.
Scheme 51 (embodiment 327): (a) chloroacetic chloride, Et 3N; (b) lawesson reagent; (c) Br 2, DCM; (d) NBS, AIBN, CCl 4(e) 2,6-two fluoro-3-hydroxybenzamide, K 2CO 3, DMF.
Figure A20078000995901611
N-(4-phenoxy group-phenyl)-acetamide
Figure A20078000995901612
Ice-cold 4-phenoxy group-phenyl amine (1.0g, in 10ml DCM solution 5.39mmol), add triethylamine (0.90ml, 5.93mmol), add again chloroacetic chloride (0.50g, 6.47mmol).This reactant mixture was stirred 2 hours down at 25 ℃.After reaction is finished (TLC monitoring), add entry, with DCM (3 * 50mL) extractions.With the organic facies drying (Na that merges 2SO 4), filter and concentrate, obtain required product (1.20g, crude product productive rate).
N-(4-phenoxy group-phenyl)-thioacetamide
Figure A20078000995901613
N-(4-phenoxy group-phenyl)-acetamide (1.20g, in 10ml toluene solution 5.28mmol), add lawesson reagent (1.50g, 3.70mmol).This reactant mixture was heated 2 hours down at 120 ℃.After reaction is finished (TLC monitoring), to doing, residue is gone up by the column chromatography purification at silica gel (60-120M), with ethyl acetate/hexane (5: 95) eluting, obtains title compound (0.78g, 60.7%) with the reactant mixture reduction vaporization.
2-methyl-6-phenoxy group-benzothiazole
(0.78g in 10mlDCM solution 3.20mmol), dropwise adds Br at ice-cold N-(4-phenoxy group-phenyl)-thioacetamide 2(0.32ml, 6.40mmol).This reactant mixture was heated 2 hours down at 45 ℃.After reaction is finished (TLC monitoring), the reduction vaporization reactant mixture.Use NH 4OH solution alkalization residue is used ethyl acetate extraction.With the organic facies drying (Na that merges 2SO 4), filter and concentrate.Residue is gone up by the column chromatography purification at silica gel (230-400M), with ethyl acetate/hexane (3: 97) eluting, obtains title compound (0.08g, 10.3%).
2-bromomethyl-6-phenoxy group-benzothiazole
Figure A20078000995901622
At 2-methyl-6-phenoxy group-benzothiazole (0.06g, 5ml CCl 0.24mmol) 4In the solution, add NBS (0.039g, 0.22mmol) and AIBN (0.004g, 0.024mmol).Under the nitrogen environment, this reactant mixture was heated 2 hours down at 100 ℃.After reaction is finished (TLC monitoring), to doing, residue is gone up by the column chromatography purification at silica gel (230-400M), with 1% ethyl acetate/hexane eluting, obtains required product (0.005g, 6.3%) with the reactant mixture reduction vaporization.
Scheme 52 (embodiment 330): (a) NBS, AIBN, CCl 4(b) 2,6-two fluoro-3-hydroxybenzamide, K 2CO 3, DMF.
7-bromomethyl-quinoline
At 7-methylquinoline (0.10g, 5ml CCl 0.70mmol) 4In the solution, add NBS (0.14g, 0.77mmol) and AIBN (0.025g, 0.15mmol).Under the nitrogen environment, this reactant mixture was heated 2 hours down at 100 ℃.After reaction is finished (TLC monitoring), to doing, residue is gone up by the column chromatography purification at silica gel (230-400M), with 1% ethyl acetate/hexane eluting, obtains required product (0.090g, 58%) with the reactant mixture reduction vaporization.
Embodiment 318-333 (table R)
Chemical compound according to the synthetic embodiment 318-333 of following universal method: in the anhydrous DMF solution of reactant (A), add 2,6-two fluoro-3-hydroxyl-Benzoylamide (B) and potassium carbonate (C).Under the nitrogen environment, reactant mixture was stirred 24 hours down at 25 ℃.To doing, residue by the column chromatography purification, is used the ethyl acetate/hexane eluting on silica gel, obtain the product chemical compound with the reactant mixture reduction vaporization.
Table R
Figure A20078000995901641
Figure A20078000995901642
Figure A20078000995901651
Figure A20078000995901652
Figure A20078000995901661
Figure A20078000995901671
Figure A20078000995901672
Scheme 53:(a) thioacetamide, DMF; (b) NBS, AIBN, CCl 4, (c) 2,6-two fluoro-3-hydroxybenzamide, K 2CO 3, DMF (d) Zn, AcOH (e) BBr 3.DCM.
Figure A20078000995901681
4-(3-methoxyl group-phenyl)-2-methyl-thiazole
Figure A20078000995901682
Under the nitrogen environment, (8.0g, 106.0mmol) (2.0g, mixture 8.81mmol) heated 6 hours down at 140 ℃ with 2-bromo-1-(3-methoxyl group-phenyl)-ethyl ketone with thioacetamide.After reaction is finished (TLC monitoring), add entry (50mL), with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate.The crude product residue is gone up purification at silica gel (230-400M, 2%EtOAc-hexane), obtains required product (1.5g, 83%).
5-bromo-2-bromomethyl-4-(3-methoxyl group-phenyl)-thiazole
Figure A20078000995901683
4-(3-methoxyl group-phenyl)-2-methyl-thiazole (1.50,20ml CCl 7.30mmol) 4In the solution, add NBS (2.60g, 14.60mmol) and AIBN (0.12g, 0.73mmol).Under the nitrogen environment, this reactant mixture was heated 2 hours down at 100 ℃.After reaction is finished (TLC monitoring), to doing, residue is gone up by the column chromatography purification at silica gel (230-400M), with 2% ethyl acetate/hexane eluting, obtains required product (1.20g, 45%) with the reactant mixture reduction vaporization.
3-[5-bromo-4-(3-methoxyl group-phenyl)-thiazol-2-yl methoxyl group]-2,6-two fluoro-Benzoylamide
Figure A20078000995901691
5-bromo-2-bromomethyl-4-(3-methoxyl group-phenyl)-thiazole (0.80g in 5ml anhydrous DMF solution 2.20mmol), adds 2,6-two fluoro-3-hydroxyl-Benzoylamide (0.38g, 2.20mmol) and potassium carbonate (1.06g, 7.70mmol).Under the nitrogen environment, this reactant mixture was stirred 24 hours down at 25 ℃.To doing, residue (60-120M) on silica gel with ethyl acetate/hexane (50: 50) eluting, obtains the title compound (0.50g, 49%) of white solid form by the column chromatography purification with the reactant mixture reduction vaporization.
2,6-two fluoro-3-[4-(3-methoxyl group-phenyl)-thiazol-2-yl methoxyl group]-Benzoylamide
Figure A20078000995901692
At 3-[5-bromo-4-(3-methoxyl group-phenyl)-thiazol-2-yl methoxyl group]-2,6-two fluoro-Benzoylamide (0.50g, in 10ml acetic acid solution 1.10mmol), adding Zn powder (0.50g, w/w).This reactant mixture was heated 1 hour down at 120 ℃.After reaction is finished (TLC monitoring), add entry (50mL), usefulness NaOH solution to 8-9, is used ethyl acetate extraction (3 * 100mL) with pH regulator.The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate, obtain required product (0.22g, 53%).
Embodiment 334:2,6-two fluoro-3-[4-(3-hydroxyl-phenyl)-thiazol-2-yl methoxyl group]-Benzoylamide
Figure A20078000995901701
With 2,6-two fluoro-3-[4-(3-methoxyl group-phenyl)-thiazol-2-yl methoxyl group]-(0.20g, 15ml DCM solution 0.53mmol) is cooled to-78 ℃ to Benzoylamide, adds BBr then 3(0.20ml, 2.14mmol).This reactant mixture was stirred 2 hours down at 25 ℃.After reaction is finished (TLC monitoring), 0 ℃ adds NaHCO down 3(20mL) solution is with ethyl acetate extraction (3 * 50mL).The organic facies water, the salt water washing that merge, dry (Na 2SO 4), filter and concentrate.Residue is gone up by the column chromatography purification at silica gel (60-120M), with ethyl acetate/hexane (50: 50) eluting, obtains the title compound (0.065g, 33%) of white solid form. 1H NMR (DMSO-d 6, 400MHz): δ 5.60 (s, 2H), 6.74 (m, 1H), 7.10 (m, 1H), 7.24 (m, 1H), 7.37-7.45 (m, 3H), 7.90 (br s, 1H), 8.10 (s, 1H), 8.17 (br s, 1H) and 9.55 (s, 1H).MSES+ (362.99), HPLC (method II) Rt=14.95 minute.
Minimal inhibitory concentration (MIC) test
Antimicrobial acivity by the susceptibility test determination The compounds of this invention in liquid medium.Regulation (National Committee for ClinicalLaboratory Standards (NCCLS) (the antimicrobial susceptibility dilution process-Di of NCCLS.2000. aerobe five editions according to standardization committee of U.S. clinical laboratory, Recognized Standards M7-A5.NCCLS, Wayne, Pa.), adopt the meat soup microdilution to measure the MIC of chemical compound to every kind of bacterial strain.
In brief, in porous plate, add the solution of test compound in 100 μ l 1.6%DMSO.To transfer to suitable enriching on the meat soup from some antibacterial colonies of fresh cut plate, as MuellerHinton.Cell suspending liquid is adjusted to optical density 0.09, and further diluted with 1: 100 with 2 warm * meat soup.This cell suspending liquid is assigned in each hole of the solution that contains chemical compound, and making final volume is 200 μ l.Plate in 37 ℃ of following overnight incubation (16-20 hour), is write down turbidity by naked eyes and quantitative spectrophotometer.MIC is defined as the least concentration that suppresses visible growth.
Find that chemical compound of the present invention has antimicrobial acivity in above-mentioned MIC test.
The result
Table 1 has shown that each embodiment resists bacillus subtilis 168 CAMinimal inhibitory concentration (MIC).If MIC≤8 mcg/ml then activity is designated as ' A ' are if MIC is a 16-64 mcg/ml then activity is designated as ' B ', if MIC is greater than 64 mcg/ml then activity is designated as ' C '.
Table 1 bacillus subtilis MIC
Embodiment Active Embodiment Active Embodiment Active
1 A 33 C 65 A
2 C 34 B 66 A
3 C 35 B 67 A
4 C 36 A 68 A
5 B 37 C 69 A
6 C 38 A 70 A
7 C 39 B 71 A
8 B 40 A 72 B
9 C 41 B 73 A
10 A 42 B 74 A
11 C 43 B 75 A
12 B 44 A 76 A
13 B 45 A 77 B
14 B 46 A 78 A
15 B 47 A 79 B
16 C 48 A 80 B
17 B 49 A 81 A
18 C 50 A 82 A
19 A 51 A 83 A
20 A 52 A 84 A
21 B 53 C 85 A
22 B 54 B 86 A
23 B 55 A 87 A
24 A 56 A 88 A
25 C 57 A 89 A
26 C 58 A 90 A
27 C 59 A 91 A
28 A 60 B 92 A
29 B 61 A 93 A
30 C 62 A 94 A
31 B 63 A 95 B
32 A 64 A
Table 1 (continuing) bacillus subtilis MIC
Embodiment Active Embodiment Active Embodiment Active
96 B 153 A 210 A
97 A 154 A 211 A
98 A 155 A 212 A
99 A 156 A 213 A
100 A 157 A 214 B
101 B 158 A 215 A
102 A 159 A 216 A
103 A 160 A 217 A
104 A 161 A 218 A
105 A 162 A 219 A
106 A 163 A 220 A
107 A 164 A 221 A
108 B 165 A 222 A
109 A 166 C 223 A
110 A 167 B 224 B
111 A 168 C 225 C
112 A 169 C 226 B
113 A 170 C 227 A
114 A 171 B 228 A
115 B 172 C 229 A
116 B 173 C 230 A
117 A 174 B 231 A
118 A 175 A 232 B
119 A 176 A 233 A
120 A 177 A 234 A
121 A 178 B 235 A
122 A 179 C 236 A
123 A 180 A 237 B
124 A 181 A 238 B
125 A 182 C 239 B
126 A 183 B 240 A
127 A 184 B 241 A
128 A 185 C 242 A
129 C 186 A 243 A
130 A 187 B 244
131 B 188 B 245 A
132 A 189 C 246 A
133 A 190 B 247 A
134 B 191 B 248 A
135 A 192 C 249 A
136 A 193 B 250 A
137 B 194 C 251 B
138 C 195 A 252 A
139 A 196 A 253 B
140 C 197 B 254 A
141 A 198 B 255 A
142 A 199 C 256 A
143 C 200 A 257 A
144 C 201 A 258 A
145 B 202 A 259 A
146 A 203 C 260 A
147 B 204 B 261 B
148 A 205 A 262 B
149 A 206 A 263 A
150 A 207 A 264 B
151 A 208 A 265 A
152 B 209 B 266 B
Table 1 (continuing) bacillus subtilis MIC
Embodiment Active Embodiment Active Embodiment Active
267 A 290 A 314 A
268 A 291 A 315 A
269 A 292 A 316 A
270 A 293 A 317 A
271 A 294 A 318 A
272 A 295 A 319 A
273 A 296 A 320 A
274 A 297 A 321 A
275 B 298 A 322 A
276 A 299 A 323 A
277 A 301 A 324 A
278 A 302 A 325 A
279 A 303 A 326 B
280 A 304 A 327 A
281 A 305 A 328 A
282 A 306 A 329 A
283 A 307 A 330 B
284 A 308 A 331 A
285 A 309 A 332 B
286 A 310 A 333 A
287 A 311 A 334 B
288 A 312 B
289 A 313 A
Also tested the activity of some embodiment chemical compound antagonism pathogenic organisms body staphylococcus aureus ATCC29213.Table 2 has shown that these embodiment resist the MIC of staphylococcus aureus.If same MIC≤8 mcg/ml then activity is designated as ' A ' are if MIC is a 16-64 mcg/ml then activity is designated as ' B ', if MIC is greater than 64 mcg/ml then activity is designated as ' C '.
Table 2 staphylococcus aureus MIC
Embodiment Active Embodiment Active Embodiment Active
1 A 46 A 72 B
5 B 47 B 73 A
8 B 49 A 74 A
12 A 51 B 75 A
15 B 52 A 76 A
17 B 53 C 77 B
18 C 54 B 78 A
19 A 55 A 79 B
24 A 56 A 80 B
26 C 57 B 81 A
27 C 58 A 82 A
28 C 59 B 83 B
29 B 60 B 84 A
30 C 61 A 85 A
31 B 62 A 86 A
32 B 64 A 87 A
36 C 65 A 88 A
39 B 66 A 89 A
40 A 67 A 90 A
41 B 68 A 91 A
42 B 69 A 93 B
43 B 70 A 94 A
45 A 71 A 95 C
Table 2 (continuing) staphylococcus aureus MIC
Embodiment Active Embodiment Active Embodiment Active
98 A 153 A 208 A
99 A 155 A 209 C
100 A 156 A 210 A
101 B 157 A 211 B
102 A 158 A 212 B
103 A 159 A 213 B
104 A 161 A 214 B
105 A 162 A 215 A
106 A 163 A 216 A
107 A 164 A 217 A
108 B 165 A 218 A
109 B 166 C 219 A
111 A 167 B 220 A
114 A 168 C 221 A
115 A 169 C 222 A
116 B 170 C 223 A
117 A 171 B 224 C
118 A 172 C 225 C
119 A 173 C 226 B
120 A 174 B 227 A
121 A 175 A 228 B
122 A 176 B 229 A
123 A 177 A 230 A
124 A 178 B 231 A
125 A 179 C 232 A
126 A 180 B 233 A
127 A 181 B 235 A
128 B 182 C 236 A
129 B 183 B 237 B
130 A 184 B 239 B
132 A 185 C 240 A
133 A 186 B 241 A
134 B 187 B 242 A
135 A 188 B 243 A
136 A 189 C 245 A
137 B 190 B 246 A
138 C 191 B 247 A
139 A 192 C 248 A
140 A 193 B 249 A
141 A 194 C 250 A
143 A 195 B 251 B
144 C 196 B 252 A
145 C 197 B 256 B
146 B 200 B 257 A
147 B 201 B 260 A
148 A 202 B 262 B
149 B 204 B 263 B
150 B 205 A 265 B
151 B 206 C 266 B
152 B 207 B
Table 2 (continuing) staphylococcus aureus MIC
Embodiment Active Embodiment Active Embodiment Active
267 A 289 A 311 A
268 B 290 A 312 A
269 A 291 A 313 A
270 A 292 A 314 B
271 A 293 A 315 A
272 A 294 A 316 A
273 A 295 A 317 A
274 A 296 A 318 A
275 B 297 A 319 A
276 A 298 A 320 A
277 A 299 A 321 A
278 A 300 B 322 A
279 A 301 B 323 A
280 A 302 A 324 A
281 A 303 A 325 B
282 A 304 A 326 B
283 A 305 A 327 A
284 A 306 A 331 B
285 A 307 A 333 A
286 A 308 B 334 A
287 A 309 A
288 A 310 B
Also test some embodiment and resisted the activity of other bacteria types.Table 3 has shown that these embodiment resist the MIC of various bacteria types.If same MIC≤8 mcg/ml then activity is designated as ' A ' are if MIC is a 16-64 mcg/ml then activity is designated as ' B ', if MIC is greater than 64 mcg/ml then activity is designated as ' C '.
The MIC of the anti-various antibacterials of table 3
Figure A20078000995901761
Figure A20078000995901771
Also tested the activity of the clinical isolatess of some embodiment staphylococcuss.Table 4 has shown that these embodiment resist the MIC of various clinical isolatess.If same MIC≤8 mcg/ml then activity is designated as ' A ' are if MIC is a 16-64 mcg/ml then activity is designated as ' B ', if MIC is greater than 64 mcg/ml then activity is designated as ' C '.
The MIC of the anti-clinical isolates of table 4
Figure A20078000995901781
1S, susceptible; I is general; R, drug resistance
2Van, vancomycin; LZD, Linezolid; Tet, tetracycline; MI, minocycline; CC, clindamycin, SXT, trimethoprim/Sulfamethoxazole; Doxy, doxycycline; IMLS, inductive macrolide-Lincoln's amide-Streptogramin B drug resistance; TMP, trimethoprim; Rif, rifampicin
Also tested the activity of each embodiment in mouse infection staphylococcus aureus septicemia model.Table 5 showed the staphylococcus aureus of intraperitoneal inoculation fatal dose after 1 hour, the single intraperitoneal gives each embodiment of 100mg/kg treat after, infecting mouse was the 7th day survival rate.
Table 5 Mus survival rate
Embodiment Survival rate
The carrier contrast 0
218 100
106 100
241 100
247 100
246 100

Claims (42)

1. the Benzoylamide of the replacement of general formula (I) or picolinamide compound or its salt, hydrate or solvate are used for the treatment of application in the medicine of bacterial infection in preparation:
Figure A2007800099590002C1
In the formula, R represents hydrogen or 1,2 or 3 optional substituent group;
W is=C (R 1)-or=N-;
R 1Be hydrogen or optional substituent group, R 2Be hydrogen, methyl or fluorine; Or R 1And R 2Be together-CH 2-,-CH 2CH 2-,-O-, or arbitrary orientation-O-CH 2-or-OCH 2CH 2-;
R 3Be general formula-(Alk 1) m-(Z) p-(Alk 2) nThe group of-Q, wherein,
M, p and n are 0 or 1 independently, and prerequisite is that at least one is 1 among m, p and the n,
Z is-O-,-S-,-S (O)-,-S (O 2)-,-NH-,-N (CH 3)-,-N (CH 2CH 3)-,-C (=O)-,-O-(C=O)-,-C (=O)-O-or have the bivalence monocycle carbocyclic ring or the heterocyclic radical of the optional replacement of 3-6 annular atoms; Or has a bivalence bicyclic heterocyclic radical of the optional replacement of 5-10 annular atoms;
Alk 1And Alk 2Be the optional C that replaces 1-C 6Alkylidene, C 2-C 6Alkenylene or C 2-C 6Alkynylene, they can be randomly with-O-,-S-,-S (O)-,-S (O 2)-,-NH-,-N (CH 3)-or-N (CH 2CH 3)-be is terminal or by it at interval; With
Q is hydrogen, halogen, nitrile or hydroxyl or optional monocycle carbocyclic ring or the heterocyclic radical that replaces with 3-6 annular atoms; Or has a bicyclic heterocyclic radical of the optional replacement of 5-10 annular atoms.
2. application as claimed in claim 1 is characterized in that, described chemical compound has general formula (IA)
Figure A2007800099590002C2
In the formula, R 4And R 5Be fluorine or chlorine independently, or R 4And R 5One of be hydrogen and another is a fluorine or chlorine, R 1, R 2And R 3Defined in claim 1.
3. application as claimed in claim 1 is characterized in that, described chemical compound has general formula (IB)
Figure A2007800099590003C1
In the formula, R 2Be hydrogen, methyl or fluorine; R 3Defined in claim 1.
4. as each described application among the claim 1-3, it is characterized in that R 1And R 2Be hydrogen.
5. each described application in the claim as described above is characterized in that p is 0, and m and/or n are 1.
6. as each described application among the claim 1-4, it is characterized in that p is 1, Z be have 3-6 annular atoms optional replacement heteroaryl or have the bicyclic heteroaryl of the optional replacement of 5-10 annular atoms, they are connected in R by ring carbon or nitrogen-atoms 3-(Alk 1) m-part and R 3-(Alk 2) n-Q part.
7. application as claimed in claim 6 is characterized in that, described divalent group Z is selected from following group, and these groups can randomly be substituted, and take arbitrary orientation:
Figure A2007800099590003C2
8. application as claimed in claim 6 is characterized in that, described divalent group Z is selected from following group, and these groups can randomly be substituted, and take arbitrary orientation:
Figure A2007800099590004C1
9. application as claimed in claim 6 is characterized in that, described divalent group Z is selected from following group, and these groups can randomly be substituted, and take arbitrary orientation:
Figure A2007800099590004C2
10. as each described application among the claim 1-4, it is characterized in that, p is 1, Z be have 3-6 annular atoms optional replacement non-armaticity carbocyclic ring of monocycle or heterocyclic radical or have the non-armaticity carbocyclic ring of dicyclo or the heterocyclic radical of the optional replacement of 5-10 annular atoms, they are connected in R by ring carbon or nitrogen-atoms 3-(Alk 1) m-part and R 3-(Alk 2) n-Q part.
11. application as claimed in claim 10 is characterized in that, described divalent group Z is selected from following group, and these groups can randomly be substituted, and take arbitrary orientation:
Figure A2007800099590004C3
12., it is characterized in that Q is a hydrogen as each described application among the claim 6-11.
13., it is characterized in that Q is the group that is selected from any bilvalent radical that each limited among the claim 6-9 as each described application among the claim 1-11, one of them unsaturated chemical valence is saturated by hydrogen or optional substituent group.
14., it is characterized in that n is 0 as each described application among the claim 6-13.
15., it is characterized in that m is 0 as each described application among the claim 6-14.
16. each described application in the claim as described above is characterized in that radicals R 3Length be no more than the length of unbranched saturated hydrocarbon chain with 14 carbon atoms.
17., it is characterized in that radicals R as each described application among the claim 1-15 3Length be equivalent to have the length of the unbranched saturated hydrocarbon chain of 6-12 or 9-12 carbon atom.
18. each described application in the claim as described above is characterized in that Alk 1And Alk 2If exist, then be the optional straight chain C that replaces 1-C 6Alkylidene, C 2-C 6Alkenylene or C 2-C 6Alkynylene, separately can be randomly with-O-,-S-,-S (O)-,-S (O 2)-,-NH-,-N (CH 3)-or-N (CH 2CH 3)-,-C (=O)-,-O-(C=O)-,-C (=O)-O-is terminal or by it at interval.
19. each described application in the claim as described above is characterized in that, any optional substituent R and Alk 1, A1k 2, any optional substituent group that exists among Z and the Q is selected from methyl, ethyl, cyclopropyl, oxo, hydroxyl, halogen, cyano group, acetyl group, amino, methylamino, dimethylamino, acetyl-amino, carbamate and CH 2OH.
20. application as claimed in claim 2 is characterized in that, R 2Be hydrogen, R 3Be the group that is selected from general formula A-H:
In the formula, Q such as claim 1 qualification, any unsubstituted ring carbon can randomly be substituted.
21. application as claimed in claim 20 is characterized in that, Q is hydrogen or the optional phenyl that replaces.
22. application as claimed in claim 2 is characterized in that, R 2Be hydrogen, R 3Be optional quinoline-2-base, benzothiazole-2-base, thiazole and pyridine-2-base, thiazol-2-yl, thiazole-4-base, the thiazole-5-Ji, oxazole-2-Ji, oxazole-4-Ji, oxadiazole-3-Ji Huo oxadiazole-5-base that replaces.
23. application as claimed in claim 22 is characterized in that, R 3The phenyl that is optionally substituted replaces.
24., it is characterized in that R as each described application among the claim 20-22 3In any optional substituent group be selected from methyl ,-OCH 3,-CF 3,-OCF 3, ethyl, cyclopropyl, oxo, hydroxyl ,-F ,-Cl ,-Br, cyano group, acetyl group, amino, methylamino, dimethylamino, acetyl-amino, carbamate ,-CONH 2, nitro ,-COOH and-CH 2OH.
25. the Benzoylamide of the replacement of a general formula (IC) or picolinamide compound or its salt, hydrate or solvate:
Figure A2007800099590006C1
In the formula, W is=C (R 1)-or=N-;
R 1Be hydrogen or optional substituent group, R 2Be hydrogen, methyl or fluorine; Or R 1And R 2Be together-CH 2-,-CH 2CH 2-,-O-or arbitrary orientation-O-CH 2-or-OCH 2CH 2-;
R 4And R 5Be fluorine or chlorine independently, or R 4And R 5One of be hydrogen and another is a fluorine or chlorine;
R 3Be the group that is selected from following general formula A-H, its medium ring take up an official post the meaning room all can randomly be substituted:
Figure A2007800099590007C1
In the formula, Q is hydrogen, halogen, nitrile or hydroxyl; Or have the monocycle carbocyclic ring or a heterocyclic radical of the optional replacement of 3-6 annular atoms; Or has a bicyclic heterocyclic radical of the optional replacement of 5-10 annular atoms.
26. chemical compound as claimed in claim 25 is characterized in that, W is=CH-R 2Be hydrogen.
27., it is characterized in that radicals R as claim 25 or 26 described chemical compounds 3In Q be hydrogen or the optional phenyl that replaces.
28., it is characterized in that R as claim 25 or 26 described chemical compounds 3Be optional quinoline-2-base, benzothiazole-2-base, thiazol-2-yl, thiazole-4-base, thiazole-5-Ji, oxadiazole-3-Ji, oxadiazole-5-Ji, oxazole-2-Ji, oxazole-4-Ji, oxazole-5-base or thiazole and the pyridine-2-base that replaces.
29. chemical compound as claimed in claim 28 is characterized in that, R 3The phenyl that is optionally substituted replaces.
30., it is characterized in that R as each described chemical compound among the claim 25-29 3In any optional substituent group be selected from: methyl ,-OCH 3,-CF 3,-OCF 3, ethyl, cyclopropyl, oxo, hydroxyl ,-F ,-Cl ,-Br, cyano group, acetyl group, amino, methylamino, dimethylamino, acetyl-amino, carbamate ,-CONH 2, nitro ,-COOH and-CH 2OH.
31. picolinamide compound or its salt, hydrate or the solvate of a general formula (ID):
Figure A2007800099590007C2
In the formula, R 2Be hydrogen, methyl or fluorine; R 3Such as claim 25 qualification.
32. chemical compound as claimed in claim 31 is characterized in that, R 2Be hydrogen.
33., it is characterized in that radicals R as claim 31 or 32 described chemical compounds 3In Q be hydrogen or the optional phenyl that replaces.
34., it is characterized in that R as claim 31 or 32 described chemical compounds 3Be optional quinoline-2-base, benzothiazole-2-base, thiazol-2-yl, thiazole-4-base, thiazole-5-Ji, oxadiazole-3-Ji, oxadiazole-5-Ji, oxazole-2-Ji, oxazole-4-Ji, oxazole-5-base or thiazole and the pyridine-2-base that replaces.
35. chemical compound as claimed in claim 34 is characterized in that, R 3The phenyl that is optionally substituted replaces.
36., it is characterized in that R as each described chemical compound among the claim 31-25 3In any optional substituent group be selected from: methyl ,-OCH 3,-CF 3,-OCF 3, ethyl, cyclopropyl, oxo, hydroxyl ,-F ,-Cl ,-Br, cyano group, acetyl group, amino, methylamino, dimethylamino, acetyl-amino, carbamate ,-CONH 2, nitro ,-COOH and-CH 2OH.
37. a pharmaceutical composition, it comprises as each described chemical compound and pharmaceutically acceptable carrier among the claim 25-36.
38. a bactericidal composition, its comprise a certain amount of effectively bacteria growing inhibiting as each described chemical compound and pharmaceutically acceptable carrier among the claim 25-36.
39. as the application of each described chemical compound among the claim 1-36 in the method for treatment human body or animal body.
40. as the application of each described chemical compound among the claim 1-36 in the treatment bacterial infection.
41. a method for the treatment of the bacterial infection that suffer to infect object, described method comprise give described object a certain amount of be enough to bacteria growing inhibiting as each described chemical compound among the claim 1-36.
42. a method of handling base material germ contamination, described method comprise with a certain amount of be enough to bacteria growing inhibiting as gdna contamination as described in each described chemical compound is applied among the claim 1-36.
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CN102531946A (en) * 2012-01-05 2012-07-04 山东大学 3-methoxybenzamide (MBA) derivant as well as preparation method and application thereof
CN103635466A (en) * 2011-04-20 2014-03-12 生物科学管理有限责任公司 Aromatic amides and uses thereof
CN104981469A (en) * 2012-11-08 2015-10-14 罗格斯新泽西州立大学 Antimicrobial agents
CN105461585A (en) * 2014-09-09 2016-04-06 香港理工大学 3-aminobenzamide derivatives as beta-lactam auxiliary antibiotics, and preparation method and application thereof
US10071082B2 (en) 2013-11-08 2018-09-11 Rutgers, The State University Of New Jersey Antimicrobial agents
US10513528B2 (en) 2016-02-25 2019-12-24 Taxis Pharmaceuticals, Inc. Synthetic processes and intermediates
US10774093B2 (en) 2017-03-30 2020-09-15 Taxis Pharmaceuticals, Inc. Synthetic processes and synthetic intermediates
CN112479984A (en) * 2020-11-27 2021-03-12 湖北航天化学技术研究所 Method for synthesizing enol trifluoromethanesulfonate

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103635466A (en) * 2011-04-20 2014-03-12 生物科学管理有限责任公司 Aromatic amides and uses thereof
CN102531946A (en) * 2012-01-05 2012-07-04 山东大学 3-methoxybenzamide (MBA) derivant as well as preparation method and application thereof
CN104981469A (en) * 2012-11-08 2015-10-14 罗格斯新泽西州立大学 Antimicrobial agents
US10071082B2 (en) 2013-11-08 2018-09-11 Rutgers, The State University Of New Jersey Antimicrobial agents
US11129814B2 (en) 2013-11-08 2021-09-28 Taxis Pharmaceuticals, Inc. Antimicrobial agents
CN105461585A (en) * 2014-09-09 2016-04-06 香港理工大学 3-aminobenzamide derivatives as beta-lactam auxiliary antibiotics, and preparation method and application thereof
US10513528B2 (en) 2016-02-25 2019-12-24 Taxis Pharmaceuticals, Inc. Synthetic processes and intermediates
US10774093B2 (en) 2017-03-30 2020-09-15 Taxis Pharmaceuticals, Inc. Synthetic processes and synthetic intermediates
CN112479984A (en) * 2020-11-27 2021-03-12 湖北航天化学技术研究所 Method for synthesizing enol trifluoromethanesulfonate
CN112479984B (en) * 2020-11-27 2022-12-13 湖北航天化学技术研究所 Method for synthesizing enol trifluoromethanesulfonate

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