CN1292697A - Anti-viral compound - Google Patents
Anti-viral compound Download PDFInfo
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- CN1292697A CN1292697A CN988140519A CN98814051A CN1292697A CN 1292697 A CN1292697 A CN 1292697A CN 988140519 A CN988140519 A CN 988140519A CN 98814051 A CN98814051 A CN 98814051A CN 1292697 A CN1292697 A CN 1292697A
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- Prior art keywords
- pyridine
- product
- benzoyl
- imidazo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
Abstract
The present invention relates to compounds of Formula (I), which inhibit the growth of picornaviruses, Hepatitus viruses, enteroviruses, cardioviruses, polioviruses, coxsackieviruses of the A and B groups, echo virus and Mengo virus. In said Formula, A is phenyl, pyridyl, substituted phenyl, substituted pyridyl, or benzyl; R is hydrogen, COR4 or COCF; X is N-OH, O or CHR1 R1 is hydrogen, halo, CN, C -C alkyl -C≡ CH, CO(C -C alkyl), CO (C -C alkyl), or CONR2R3 R2 and R3 are independently hydrogen or C -C alkyl; A' is hydrogen, halo, C -C alkyl, benzyl, naphthyl, thienyl, furyl, pyridyl, pyrollyl, COR4 S(O)nR4 or a group of formula (II); R4 is C -C alkyl, phenyl, or substituted phenyl; n is 0,1, or 2; R5 is independently at each occurance hydrogen or halo; m is 1,2,3, or 4; and R6 is hydrogen, halo, CF, OH, CO H, NH, NO, CONHOCH, C -C alkyl, or CO (C -C alkyl), C -C alkoxy; or pharmaceutically acceptable salts thereof.
Description
Invention field
The present invention relates to antiviral compound and in pharmacy and pharmaceutical chemistry Application for Field.
Background of invention
The viral upper respiratory disease, promptly the flu sickness rate very high.According to estimates, only nearly 1,000,000,000 case just there is every year in the U.S..Rhinovirus is the main cause that causes human flu, and this virus is a member in the Picornaviridae family.At present identified the rhinovirus strains more than 110 kinds, therefore, it is unpractiaca developing comprehensive rhinovirus vaccine.So, the method that chemotherapy is seemingly better.Another member in the picornavirus family is an enterovirus, and it comprises about 80 kinds of human pathogens.Many enterovirus can cause the symptom of flu sample, and other then can cause even more serious disease, for example poliomyelitis, conjunctivitis, aseptic meningitis and myocarditis.
Can show rhinorrhea and nasal obstruction with the rhinovirus infection diseases associated.In addition, it is also relevant with otitis media, can bring out bronchitis, make the sinusitis aggravation and sharply show effect with asthma (precipitation) relevant.Although many people think that this disease is only horrible, its frequent generation and caused Economic Importance in healthy individual makes rhinovirus infection become the object of broad research.
Chemical compound can confirm with viral plaque inhibition test or cytopathy (CPE) test at an easy rate in the ability of vitro inhibition viral growth.Referring to Siminoff, " applied microbiology " (Applied Microbiology), 9 (1), 66 (1961).Although found the multiple chemical compound that can suppress picornavirus, much because 1) activity profile is limited, 2) disadvantageous side effect or 3) can not be in the animal or human prevention infection or disease but unacceptable.Referring to, " human virology's teaching material " (Textbook of Human Virology), Robert B.Belshe compiles, the 16th chapter, " rhinovirus ", Roland A.Levandowski, 391-405 (1985).Therefore, although exist treatment potentiality relevant of generally acknowledging and the research of being carried out up to now to attempt, do not have the therapeutic agent of effect yet with the rhinovirus inhibitor.For example, United States Patent (USP) 4,008,243,4,018,790,4,118,573,4,118,742 and 4,174,454 disclose antiviral benzimidazole compound.
Therefore, the invention provides new pyridine-imidazole chemical compound, this chemical compound can suppress for example rhinovirus (cattle and people's) etc. of picornavirus; Enterovirus is poliovirus etc. for example; The Coxsackie virus or the echo, enteric cytopathogenic human orphan virus of A and B group; Cardioviruses is encephalomyocarditis virus (EMC) etc. for example; Apthoviruses, for example foot and the virus of oral disease etc.; Hepatitis virus is the growth of hepatitis C virus etc. for example.
Summary of the invention
The invention provides the formula I compound or pharmaceutically acceptable salt thereof:
Wherein:
A is the phenyl of phenyl, pyridine radicals, replacement, the pyridine radicals or the benzyl of replacement;
R is hydrogen, COR
4Or COCF
3
X is N-OH, O or CHR
1
R
1Be hydrogen, halogen, CN, C
1-C
4Alkyl ,-C ≡ CH, CO (C
1-C
4Alkyl), CO
2(C
1-C
4Alkyl) or CONR
2R
3
R
2And R
3Be hydrogen or C independently of one another
1-C
4Alkyl;
A ' is hydrogen, halogen, C
1-C
6Alkyl, benzyl, naphthyl, thienyl, furyl, pyridine radicals, pyrrole radicals,
COR4, S (O)
nR
4Or the group of following formula
R
4Be C
1-C
6The phenyl of alkyl, phenyl or replacement;
N is 0,1 or 2;
R
5Be hydrogen or halogen independently of one another when occurring at every turn;
M is 1,2,3 or 4;
R
6Be hydrogen, halogen, CF
3, OH, CO
2H, NH
2, NO
2, CONHOCH
3, C
1-C
4Alkyl or CO
2(C
1-C
4Alkyl), C
1-C
4Alkoxyl.
The present invention also provides pharmaceutical preparation, and described pharmaceutical preparation contains The compounds of this invention or its officinal salt and pharmaceutically useful carrier, diluent or excipient.
The present invention also provides the method that suppresses picornavirus, and this method comprises, uses the formula I compound or pharmaceutically acceptable salt thereof of effective dose to the host of needs.
The present invention also provides the method that suppresses hepatitis C virus, and this method comprises, uses the formula I compound or pharmaceutically acceptable salt thereof of effective dose to the host of needs.
The present invention also provides the formula I chemical compound to be used to suppress the purposes of picornavirus, rhinovirus or hepatitis virus.
Detailed Description Of The Invention
The present invention relates to can be used as the above-mentioned formula I chemical compound of antiviral agent.
All temperature as herein described be degree centigrade (℃).All linear modules used herein are unit of weight, but are volume unit for liquid.
Term " C used herein
1-C
6Alkyl " expression contains the straight or branched alkyl of 1-6 carbon atom.Typical C
1-C
6Alkyl includes but are not limited to methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, neopentyl, hexyl etc.Term " C
1-C
6Alkyl " in the scope of its definition, comprise term " C
1-C
4Alkyl ", and comprise also that in the scope of its definition alkyl wherein forms the cycloalkyl of encircling.
Term " halogen " comprises chlorine, fluorine, bromine or iodine.
Term used herein " phenyl of replacement " expression is independently from each other halogen, C by 1,2 or 3
1-C
4Alkyl, C
1-C
6The phenyl ring that the substituent group of alkoxyl or trifluoromethyl replaces.
Term used herein " pyridine radicals of replacement " expression is independently from each other halogen, C by 1,2 or 3
1-C
4Alkyl, C
1-C
6The pyridine ring that the substituent group of alkoxyl or trifluoromethyl replaces.
As mentioned above, the present invention includes the officinal salt of the defined chemical compound of formula I.Although all be neutral usually, chemical compound of the present invention also can have enough acidity, enough alkalescence or have two kinds of functional groups simultaneously, therefore can form officinal salt with multiple inorganic base, mineral acid and organic acid reaction.
Term used herein " officinal salt " is meant the salt to the nontoxic substantially formula I chemical compound of organism alive.Typical officinal salt comprises by chemical compound of the present invention and inorganic or organic acid or inorganic base are reacted the salt that makes.Described salt is called acid-addition salts and base addition salts.
The acid that is used to form acid-addition salts includes but are not limited to, and mineral acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid etc. for example; Organic acid such as p-methyl benzenesulfonic acid, methanesulfonic acid, oxalic acid, to bromo-benzene sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid etc.
The example of described officinal salt includes but are not limited to: sulfate, pyrosulfate, disulfate, sulphite, bisulfites, phosphate, dibasic alkaliine, dihydric phosphate, sheet phosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprate, caprylate, acrylates, formates, isobutyrate, caproate, enanthate, propiolate, oxalates, malonate, succinate, suberate, sebacate, fumarate, maleate, butine-1, the 4-diacid salt, hexin-1, the 6-diacid salt, benzoate, chloro benzoate, ar-Toluic acid salt, dinitro-benzoate, hydroxy benzoate, methoxybenzoic acid salt, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenpropionate, phenylbutyric acid salt, citrate, lactate, gamma hydroxybutyrate, glycollate, tartrate, mesylate, propane sulfonic acid salt, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt, mandelate etc.Preferred pharmaceutically acceptable acid addition salts is and the salt of mineral acids formation such as hydrochloric acid and hydrobromic acid and the salt that forms with organic acid such as maleic acid and methanesulfonic acids.
Base addition salts includes but are not limited to, from deutero-salt such as inorganic base such as ammonium or alkali metal or alkaline earth metal hydroxide, carbonate, bicarbonates.Therefore, the alkali that can be used for preparing salt of the present invention comprises sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate etc.The form of preferred especially potassium salt and sodium salt.
The concrete counter ion counterionsl gegenions that should be appreciated that a part that constitutes the various salt of the present invention are unimportant, are pharmaceutically useful and counter ion counterionsl gegenions can not bring disadvantageous character to salt as long as salt is done as a whole.
Officinal salt of the present invention generally can pass through formula I chemical compound and equimolar amounts or excessive acid or alkali reaction formation.Usually reactant being mixed in neutral flux, for example, is ether, benzene etc. for acid-addition salts, is water, alcohol etc. for base addition salts.Salt was precipitated out from solution in about 1 hour to about 10 days usually, can separate by filtration or other conventional method then.
Chemical compound of the present invention can exist with cis or trans configuration, wherein, the substituent group that cis is meant the part of alkene wherein and the ring of being appointed as " A " are the chemical compound of cis, transly are meant that wherein the substituent group of alkene part is trans chemical compound with the ring of being appointed as " A ".Two kinds of isomers and composition thereof include within the scope of the invention.
The paragraph that below indicates letter is the preferred embodiments of the invention, but should be appreciated that the present invention is not limited in these embodiments, and other embodiment is also included within the scope of the present invention.Preferably the formula I chemical compound is, wherein:
A) A is the phenyl of phenyl, pyridine radicals, replacement or the pyridine radicals of replacement;
B) A is the phenyl of phenyl or replacement;
C) A is difluorophenyl or fluoro phenyl;
D) A is the phenyl of pyridine radicals, replacement or the pyridine radicals of replacement;
E) R is a hydrogen;
F) R is COCF
3
G) X is NOH;
H) X is CHR
1
I) R
1Be CONR
2R
3, CO
2(C
1-C
4Alkyl) or CN;
J) R
1Be CONR
2R
3
K) R
1Be CO
2(C
1-C
4Alkyl);
1) R
2And R
3Be methyl or hydrogen independently of one another;
M) A ' is C
1-C
6Alkyl, naphthyl, thienyl, COR
4, S (O)
nR
4Or the group of following formula
N) A ' is C
1-C
6Alkyl, COR
4, S (O)
nR
4Or the group of following formula
O) A ' is the group of following formula
P) A ' is C
1-C
6Alkyl, COR
4Or S (O)
nR
4
Q) A ' is COR
4Or S (O)
nR
4
R) R
5Be that fluorine and m are 5;
S) m is 1,2,3 or 5;
T) R
6Be CF
3, OH, CO
2H, NH
2, NO
2, CONHOCH
3, C
1-C
4Alkyl, C
1-C
4Alkoxyl;
U) R
6Be CF
3, OH, CONHOCH
3, C
1-C
4Alkyl, C
1-C
4Alkoxyl;
V) R
6Be CF
3, OH, C
1-C
4Alkyl, C
1-C
4Alkoxyl.
Reaction scheme
The formula I chemical compound can be by synthetic method known in the art and method disclosed herein preparation.Wherein A ' is hydrogen, C
1-C
6Alkyl, naphthyl, thienyl, furyl, pyridine radicals, pyrrole radicals or formula
The formula I chemical compound of group can be prepared shown in following reaction scheme I.
The reaction scheme I
L represents leaving group, shown in leaving group be selected from: halogen, O-trifluoromethanesulfonic acid root, O-methanesulfonate, O-tosylate etc.
Z represents hydrogen, C
1-C
6Alkyl, naphthyl, thienyl, furyl, pyridine radicals, pyrrole radicals or formula
Group.
Formula (A) chemical compound can be by synthetic method known in the art and method disclosed herein preparation.For example, formula (A) chemical compound can be prepared shown in following reaction scheme II.
The reaction scheme II
Using suitable anhydride, carboxylic acid or the acyl chlorides acidylate that replaces to form the chemical compound of formula (H) under the Friedel-Crafts condition, in the presence of Lewis acid the suitable aryl that replaces.(referring to, for example " Friedel-Crafts and relevant reaction " (Friedel-Crafts and RelatedReactions), editor G.A., Olah, J.Wiley﹠amp; Sons, N.Y., 31,32 chapters (1964)).Suitable Lewis acid catalyst includes but are not limited to trifluoroacetic anhydride/phosphoric acid, trifluoromethanesulfonic acid, iron chloride (III), zinc chloride, copper trifluoromethanesulfcomposite (CuOTf), phosphorus oxychloride, trifluoroacetic acid, aluminum chloride etc.Aluminum chloride is preferred Lewis acid.The suitable solvent includes but are not limited to dichloromethane, acetonitrile, 1,2-dichloroethanes, Nitrocarbol., lower alcohol, acetonitrile, dimethyl sulfoxine etc.Reaction is preferably carried out under the condition of " only ", with the preferred solvent of aryl conduct that replaces.The aryl that replaces uses with excessive greatly mole usually.For example, with respect to the 6-chloronicotinoyl chloride, adopt about 3-10 molar excess usually.General preferred about 3.8 molar excess.Reaction is preferably carried out under about 80 ℃.
Perhaps, formula (H) chemical compound can be by making formula (G) chemical compound and aryl anion according to method reaction well known in the art.The Weinreb amide of formula (G) can make by method well known in the art from corresponding 1-chloro-5-nicotinic acid.Equally, the acyl group anion that is used for preparation formula (H) chemical compound also is well known in the art, and can make by the method for putting down in writing in this area.For example, the bromine or iodine that suits to replace can be carried out metal-halogen exchange condition for aryl by method well known in the art and method disclosed herein and obtain metal aryl anion.General discussion about metal-halogen exchange condition can be referring to " organic reaction " (Organic Reactions), the 6th volume, 339 pages, (1951).The suitable solvent includes but are not limited to toluene, dimethyl formamide, dichloromethane, ether, acetonitrile, oxolane etc.Oxolane is preferred solvent.Suitable source metal includes but are not limited to molecule lithium, alkyl lithiumation thing etc., particularly tert-butyl lithium.N-BuLi is preferred source metal.Metal uses with excessive a little mole usually.For example, adopt about 1 to 1.1 molar excess usually.General preferred 1.03 molar excess.Reaction was preferably carried out about 15 minutes under about-78 ℃.
Formula (H) chemical compound can be obtained formula (J) chemical compound with ammonia amination under high pressure.Formula (H) chemical compound is dissolved in the The suitable solvent, adds liquefied ammonia, then reactant liquor is sealed in the high voltage bearing container.The suitable solvent includes but are not limited to toluene, lower alcohol, acetonitrile, ether, oxolane, dimethyl formamide, chloroform, dichloromethane etc.Ethanol is preferred solvent.Reaction was preferably carried out under about 145 ℃ about 16 hours.
Formula (A) chemical compound can be by method preparation well known in the art.For example, can be by adding alkali and toluene sulfochloride with formula (J) chemical compound toluenesulfonic acidization in atent solvent.The suitable solvent includes but are not limited to oxolane, lower alcohol, ethyl acetate, dichloromethane, acetonitrile, chloroform etc.Suitable alkali comprises triethylamine, sodium bicarbonate, sodium hydroxide, imidazoles etc.Pyridine is preferred alkali and solvent.Toluene sulfochloride uses with excessive a little mole usually.For example, with respect to formula (J) chemical compound, adopt about 1 to 2 molar excess usually.General preferred 1.1 molar excess.Reaction was preferably carried out 16 hours under about 90 ℃.
Formula (B) chemical compound can be prepared by synthetic method known in the art and method disclosed herein.For example, wherein L is that formula (B) chemical compound of bromine can be prepared shown in following reaction scheme III.
The reaction scheme III
Acetic acid bromination in The suitable solvent, in the presence of free-radical initiator of the suitable formula (K) that replaces is obtained formula (L) chemical compound.Suitable bromating agent includes but are not limited to molecular bromine, N-bromosuccinimide etc.N-bromosuccinimide is preferred bromating agent.The suitable solvent includes but are not limited to ether, oxolane, dichloromethane, chloroform, acetonitrile, benzene, dimethyl sulfoxine, carbon tetrachloride etc.Carbon tetrachloride is preferred solvent.Suitable free-radical initiator includes but are not limited to Phosphorous chloride., molecular phosphorus, benzoyl peroxide, UV radiation etc.Preferred initiator is benzoyl peroxide and UV radiation.Bromating agent uses with stoichiometry usually.For example, with respect to formula (K) chemical compound, use usually and preferred 1 equivalent.Initiator uses with catalytic amount usually.For example, with respect to formula (K) chemical compound, adopt about 0.1 to 1 molar percentage usually.General preferred 0.4 molar percentage.Reaction was preferably carried out under about 77 ℃ about 5 hours.
Formula (M) chemical compound can be by making formula (L) chemical compound by the methods known in the art amidatioon.For example, can then it be finished transformation with gasiform aminoacyl amination on the spot by with formula (L) compound dissolution or be suspended in the nucleophilicity source that adds chlorine in the The suitable solvent then and obtain corresponding acyl chlorides.The suitable solvent includes but are not limited to, alkane, dimethyl formamide, lower alcohol, ethyl acetate, dichloromethane, oxolane, ether, acetonitrile, chloroform etc.Dimethyl formamide, dichloromethane, hexane and toluene are preferred solvents.Suitable chlorinating agent includes but are not limited to thionyl chloride, phosphorus pentachloride, two (trichloromethyl) carbonic ester, allyl chlorocarbonate, Phosphorous chloride., triphosgene, oxalyl chloride etc.Oxalyl chloride is preferred chlorinating agent.Chlorinating agent uses with excessive a little mole usually.For example, with respect to formula (L) chemical compound, adopt about 1-2 molar excess usually.General 1.6 molar excess that adopt.The mole of ammonia is excessive greatly usually.For example, preferably in reactant mixture, feed the about ammonia that discharged uncertain amount in 1 hour of ammonia.Reaction is preferably carried out under about 0 ℃ when adding chlorinating agent, feeds ammonia about 1 hour then in about 3 hours of about 22 ℃ of reactions, and then in about 22 ℃.
In addition, wherein L is that formula (B) chemical compound of O-tosylate can be prepared shown in following reaction scheme IV.
The reaction scheme IV
Formula (O) chemical compound can prepare by methods known in the art from the suitable aldehyde that replaces.For example, formula (N) chemical compound is mixed with the acyl group anion equivalent such as the TMS cyanide of carboxylate, after hydrolysis, obtain the chemical compound of formula (O).The suitable solvent includes but are not limited to lower alcohol, ethyl acetate, dichloromethane, acetonitrile, chloroform etc.When aldehyde or acyl group anion equivalent were liquid, reaction was preferably carried out under the condition of " only ".Acyl group anion equivalent uses with stoichiometric proportion usually.For example, with respect to benzaldehyde, adopt usually and preferred 1 normal acyl group anion.After adding the acidylate equivalent, reaction was preferably carried out under about 25 ℃ about 72 hours, carried out obtaining in about 18 hours formula (O) chemical compound then under about 100 ℃.
Formula (P) chemical compound can methods known in the art prepare from formula (O) chemical compound.The acetylation of hydroxy acid is well known in the art.Referring to, Greene T.W. for example, " protecting group in the organic synthesis " (Protective Groups in Organic Synthesis), John Wiley﹠amp; Sons (1981).
Formula (Q) chemical compound can be by being prepared formula (P) chemical compound with method well known in the art and method amidatioon disclosed herein.Amidatioon is with similar substantially from the used method of formula (L) compound formula (M) chemical compound.
Formula (Q) chemical compound can be prepared by removing the deacetylate protecting group with method well known in the art from formula (P) chemical compound.Referring to, Greene T.W. for example, " protecting group in the organic synthesis " (Protective Groups in Organic Synthesis), John Wiley﹠Sons (1981).
Formula (R) chemical compound that alcohol moiety wherein has been transformed into leaving group can prepare by means commonly known in the art.For example, referring to Stang etc., " synthesizing " (Synthesis), 85-1266 page or leaf (1982).
Formula (C) chemical compound can be by means commonly known in the art and method disclosed herein preparation.For example, formula (A) chemical compound and formula (B) compound are obtained formula (C) chemical compound.The suitable solvent includes but are not limited to toluene, oxolane, dichloromethane, ether, acetonitrile etc.Dimethyl formamide is particularly preferred solvent.Suitable alkali includes but are not limited to cesium fluoride, cesium carbonate, the alkylamine etc. that is obstructed, particularly diisopropyl ethyl amine.Sodium hydride is particularly preferred alkali.Alkali uses with excessive a little mole usually.For example, with respect to formula (A) chemical compound, adopt about 1 to 1.25 molar excess usually.Formula (B) chemical compound uses with excessive a little mole.For example, with respect to formula (A) chemical compound, adopt about 1 to 1.1 molar excess usually.Preferred especially 1.05 molar excess.Deprotonation preferably at room temperature carried out about 1.5 hours.Behind adding formula (B) chemical compound, reaction was preferably at room temperature carried out about 7 days usually.
Formula (D) chemical compound can be by means commonly known in the art and method disclosed herein preparation.For example, can by with formula (C) compound dissolution in The suitable solvent and add trifluoroacetic anhydride and make formula (C) chemical compound cyclisation production (D) chemical compound.The suitable solvent includes but are not limited to toluene, dimethyl formamide, oxolane, ether, acetonitrile etc.Dichloromethane is particularly preferred solvent.Trifluoroacetic anhydride is used with excessive greatly mole usually.For example, with respect to formula (C) chemical compound, adopt about 5 to 20 molar excess usually.General preferred 12.4 molar excess.Carried out about 3 hours under the general preferred reflux temperature (40 ℃) of reaction at dichloromethane.
Formula (E) chemical compound can be by means commonly known in the art and method disclosed herein preparation.
Wherein X is CHR
1And R
1Be CONH
2, CO (C
1-C
4Alkyl), CONR
2R
3Or CO
2(C
1-C
4Alkyl) formula (E) chemical compound can be from formula (D) chemical compound by means commonly known in the art and method disclosed herein preparation.For example, with the suitable Horner-Emmons reagent that replaces (referring to, " organic reaction " (Organic Reactions), 1,977 25 volumes, 73 pages) add formula (D) chemical compound then with highly basic deprotonation in aprotic solvent and obtain formula (E) chemical compound.Suitable highly basic includes but are not limited to lithium alkylide, lithium diisopropylamine, two TMS Lithamide .s etc.Potassium tert-butoxide is preferred alkali.The suitable solvent includes but are not limited to ether, oxolane, dichloromethane, chloroform, dimethyl sulfoxine etc.Dimethyl formamide and oxolane are preferred solvents.Horner-Emmons reagent is suitable with excessive a little mole usually.For example, with respect to formula (D) chemical compound, be generally about 1 to 2 molar excess.General preferred l.1 molar excess.When adding formula (A) chemical compound, reaction is preferably carried out under about O ℃, carries out about 1 hour at about 25 ℃ then.
Wherein X is that formula (E) chemical compound of NOH can be prepared by methods known in the art and method disclosed herein.For example, can or be suspended in formula (D) compound dissolution and add azanol in the The suitable solvent then and obtain formula (E) chemical compound.The suitable solvent includes but are not limited to lower alcohol, ethyl acetate, dichloromethane, chloroform etc.Methanol or pyridine are preferred solvents.Azanol uses with excessive greatly mole usually.For example, with respect to formula (E) chemical compound, be generally about 3 to 10 molar excess.General preferred 5.0 molar excess.Reaction was preferably carried out under about 25 ℃ about 24 hours.
Wherein X is CHR
1And and R
1Formula (E) chemical compound that is H or CN can be prepared by methods known in the art and method disclosed herein from formula (D) chemical compound.For example, the Peterson alkene reagent (referring to " organic reaction " (OrganicReactions), 1990,38 volumes, 1 page) that suits to replace can be dissolved in The suitable solvent and use the highly basic deprotonation.Adding formula (D) chemical compound in product then.Suitable highly basic includes but are not limited to potassium tert-butoxide, lithium alkylide, lithium diisopropylamine, two TMS Lithamide .s etc.N-BuLi is preferred alkali.The suitable solvent includes but are not limited to ether, dichloromethane, chloroform, dimethyl formamide, dimethyl sulfoxine etc.Oxolane is preferred solvent.Peterson reagent uses with excessive greatly mole usually.For example, with respect to formula (D) chemical compound, be generally about 3 to 10 molar excess.General preferred 5.O molar excess.When Peterson reagent deprotonation and adding formula (D) chemical compound, reaction is preferably carried out under about-78 ℃, carries out about 24 hours in about 25 ℃ then.
Wherein X is CHR
1And R
1Formula (E) chemical compound that is halogen can be CH from X wherein
2Formula (E) chemical compound by the preparation of methods known in the art and method disclosed herein.For example, can be CH with X wherein
2Formula (E) chemical compound be dissolved in the The suitable solvent and add suitable halogenating agent to form product.The suitable solvent includes but are not limited to dichloromethane, oxolane, chloroform, acetonitrile, acetic acid etc.Oxolane and carbon tetrachloride are preferred solvents.Suitable halogenating agent includes but are not limited to benzene seleniyl chlorine/aluminum chloride, thionyl chloride, molecular bromine, CsSO
4F, NFTh etc.Halogenating agent uses with excessive a little mole usually.For example, with respect to raw material, be generally about 1 to 2 molar excess.General preferred 1.1 molar excess.When adding halogenating agent, reaction is preferably carried out under about-10 ℃, carries out about 1 hour at about 22 ℃ then.
It will be appreciated by those skilled in the art that, by reaction scheme disclosed herein isolating suitable/ratio of anti-product can have very big variation, can be from cis completely or trans completely to equal proportion separately, this depends on used raw material and the reaction condition that is adopted.
Wherein A ' is COR
5The formula I chemical compound can be prepared according to the method shown in the following reaction scheme V.
The reaction scheme V
Formula (S) chemical compound can be prepared by methods known in the art and method disclosed herein, for example, can be according to formula (H) chemical compound being changed an accepted way of doing sth (S) chemical compound with the basic similarly mode of an accepted way of doing sth (E) chemical compound that formula (D) chemical compound is changed described in the literary composition.
Formula (T) chemical compound can be prepared by methods known in the art and method disclosed herein.For example, can be with formula (S) chemical compound and formula BrCH
2COR
5Chemical compound in the presence of iodine is anionic, be dissolved in the chemical compound of the formula that obtains in the The suitable solvent (T).The suitable solvent includes but are not limited to toluene, dimethyl formamide, dichloromethane, oxolane, ether, acetonitrile etc.Acetonitrile is preferred solvent.Suitable iodine negative ion source includes but are not limited to, and iodine salt is sodium iodide, potassium iodide and ammonium iodide etc. for example.Sodium iodide is preferred iodine negative ion source.Formula BrCH
2COR
5Chemical compound uses with excessive greatly mole usually.For example, with respect to formula (S) chemical compound, adopt about 2 to 10 molar excess usually.General preferred about 3.7 molar excess.The iodine anion is used with excessive greatly mole usually.For example, with respect to formula (S) chemical compound, adopt about 2 to 10 molar excess usually.General preferred about 3.8 molar excess.Reaction was preferably carried out under the reflux temperature of solvent about 40 hours.
Formula (U) chemical compound can be prepared by methods known in the art and method disclosed herein.For example, can be with formula (T) chemical compound, amino nitrile and alkali mixing also are dissolved in the formula that obtains in the The suitable solvent (U) chemical compound.The suitable solvent includes but are not limited to toluene, dimethyl formamide, dichloromethane, oxolane, ether, acetonitrile etc.Acetonitrile is preferred solvent.Suitable alkali includes but are not limited to carbonate, hydroxide etc.Potassium carbonate is preferred alkali.Amino nitrile uses with excessive a little mole usually.For example, with respect to formula (T) chemical compound, adopt general preferred 1.02 molar excess of about 1 to 1.05 molar excess usually.Alkali uses with excessive greatly mole usually.For example, with respect to formula (T) chemical compound, adopt about 2 to 5 molar excess usually.General preferred 3.05 molar excess.General preferred under the reflux temperature of about solvent, the carrying out about 14 hours of reaction.
Wherein A ' is S (O)
nR
5The formula I chemical compound can be prepared according to the method shown in the following reaction scheme VI.
The reaction scheme VI
Formula (W) chemical compound can be prepared by methods known in the art and method disclosed herein.For example, can be with the formula V chemical compound according to the described similar mode of formula (D) chemical compound transformation accepted way of doing sth (E) chemical compound being changed an accepted way of doing sth (W) chemical compound with above.
Formula (X) chemical compound can be prepared by methods known in the art and method disclosed herein.For example, can be in The suitable solvent and add iodination reagent and form formula (X) chemical compound with formula (W) compound dissolution.The suitable solvent includes but are not limited to toluene, dimethyl formamide, dichloromethane, oxolane, ether, acetonitrile etc.Acetonitrile is preferred solvent.Suitable iodating agent includes but are not limited to molecular iodine, N-iodosuccinimide etc.N-iodosuccinimide is preferred iodating agent.Iodating agent also preferably uses with stoichiometry or with formula (W) chemical compound equimolar amounts usually.Reaction was preferably carried out under about 0 ℃ about 15 minutes.
Formula (Y) chemical compound can be prepared by methods known in the art and method disclosed herein.For example, the sulfide that suits to replace and imidazopyridyl anion or anion equivalent can be reacted by means commonly known in the art.Suitable sulfide includes but are not limited to symmetric sulfide, asymmetric sulfide and mercaptan sulphonic acid ester.The mercaptan sulphonic acid ester can be from the disulphide that generally can buy by means commonly known in the art and " JACS " (J.Am.Chem.Soc.) instruction preparation in 1977,4405.
Formula (Y) chemical compound can be prepared by methods known in the art and method disclosed herein from formula (X) chemical compound.For example, carry out metal-halogen exchange reaction according to the description in above preparation formula (H) chemical compound with formula (X) chemical compound substantially, add the suitable sulfide that replaces then.It will be appreciated by those skilled in the art that, opposite with the preparation of the phenyl anion that is used to form formula (H) chemical compound (wherein not containing acid proton), the analog of formula (X) contains an acid proton, therefore used alkali and take off proton before carrying out metal-halogen exchange reaction.Suitable alkali includes but are not limited to molecule lithium, lithium alkylide, Lithamide. such as lithium diisopropylamine, lithium hydride etc.Phenyl lithium is preferred alkali.Tert-butyl lithium is preferred source metal.The suitable solvent includes but are not limited to toluene, dimethyl formamide, dichloromethane, acetonitrile, ether, oxolane etc.Oxolane is preferred solvent.Alkali uses with excessive a little extremely excessive greatly mole usually.For example, with respect to formula (X) chemical compound, adopt about 1.5 to 3 molar excess usually.General preferred 2.2 molar excess.Metal uses with excessive a little extremely excessive greatly mole usually.For example, with respect to formula (X) chemical compound, adopt about 1.5 to 3 molar excess usually.General preferred 2.5 molar excess.Reaction is preferably carried out under about-78 ℃, carries out about 3 minutes after adding alkali, carries out about 10 minutes after adding source metal then, carries out about 30 minutes after adding sulfide then.
Perhaps, formula (Y) chemical compound can be prepared from the imidazopyridyl anion equivalent that is made under the Ullmann coupling condition by formula (X) chemical compound.About the summary of Ullmann reaction referring to " synthesizing " (Synthesis), 9-21, (1974).For example, formula (X) chemical compound can be dissolved in the The suitable solvent, add the copper source, add the suitable sulfide that replaces then.The suitable solvent includes but are not limited to toluene, dimethyl formamide, dichloromethane, acetonitrile, ether, oxolane, pyridine etc.Pyridine is preferred solvent.Suitable copper source includes but are not limited to molecule copper, Red copper oxide (I) etc.Bronze or copper powder are preferred copper sources.Copper uses with excessive a little extremely excessive greatly mole usually.For example, with respect to formula (X) chemical compound, adopt about 1.2 to 3 molar excess usually.General preferred 1.5 molar excess.Sulfide uses with insufficient a little mole usually.For example, with respect to formula (X) chemical compound, adopt about 50 to 90 molar percentages usually.General preferred 78 molar percentages.Reaction was preferably carried out under about 100 ℃ about 80 hours.
Perhaps, formula (Y) chemical compound can utilize the catalytic formula of palladium (X) chemical compound and the suitable trimethyl-mercaptan-Xi that replaces, be R
4S-Sn (alkyl)
3Between cross-coupling reaction be prepared.Referring to, for example " synthesising communication " (Synth.Commun), 22, (5), p 683, (1992).
Formula (Z) chemical compound can be by being prepared formula (Y) chemical compound according to method well known in the art and method oxidation disclosed herein.Become the general description of sulfone can be sulfide oxidation, the 7th volume, 6.2 chapters, 762 pages, Pergamon Press, Inc.New York, (1991) referring to " organic synthesis complete works " (Comprehenive Organic Synthesis).
It will be understood by those skilled in the art that best (but be not must) each point in The compounds of this invention is synthetic removes the trifluoroacetyl group protecting group in the above reaction scheme.This protecting group remove can be by means commonly known in the art and method disclosed herein finish.For example, can remove the product that trifluoroacetyl group obtains corresponding deprotection by formula (D), (E), (V), (W), (X), (Y) or compound dissolution (Z) are added alkali then in The suitable solvent.Suitable alkali includes but are not limited to hydroxide, carbonate, amine etc.Preferred alkali is diisopropyl ethyl amine.Perhaps, can be with protecting group hydrolysis on silica-gel carrier.Referring to Greene T.W., " protecting group in the organic synthesis " (Protective Groups in OrganicSynthesis), John Wiley﹠amp; Sons (1981).
Usually, when when reacting to the reflux temperature of reactant mixture for about-78 ℃, the reaction of reaction scheme I-VI can be finished in about 15 minutes to 72 hours basically.It will be understood by those skilled in the art that reaction rate increases along with the rising of temperature usually.But best (but be not must) reacts the kind and the amount of the by-product that is produced with control better with lower speed.The selection of reaction dissolvent is also not really crucial, as long as used solvent is inert to the reaction carried out and reactant can dissolve fully to finish required reaction.Reaction just can be passed through methods known in the art separation of intermediates chemical compound after finishing as required.For example, compound crystal can be collected by filtering then, perhaps, can be removed reaction dissolvent by extraction, evaporation or decantation.As needs, also can with intermediate by routine techniques for example recrystallization or solid carrier for example the chromatographic isolation on silica gel or the aluminium oxide be further purified.Before being used for subsequent reaction, preferably the chemical compound with formula A-Z separates.
Preparation example and embodiment
Following preparation example and embodiment further illustrate special aspects of the present invention.But, should be appreciated that these embodiment only for the purpose of description, be not intended in office where face limits scope of the present invention.
The chemical compound that is used as raw material in synthetic chemical compound of the present invention is known in the art, and those chemical compounds that can not buy can be synthetic by this area conventional method commonly used easily.
It will be appreciated by those skilled in the art that when carrying out said method, may on reactant, introduce the chemoproection base to prevent the generation of side reaction.For example, any amine, alcohol, alkylamine or the carboxyl that may exist on the reactant can be protected with any ability that can not react in a desired manner the remainder of molecule conventional protecting group that has a negative impact.Can or remove various protecting groups in turn with the methods known in the art while then.
The cis of The compounds of this invention and trans forms can be used column chromatography, and for example reversed-phase HPLC separates.Can be with chemical compound with suitable proportion acetonitrile and water or first alcohol and water eluting from the pillar.
In following preparation example and embodiment, the term fusing point, NMR (Nuclear Magnetic Resonance) spectrum, the electron collision mass spectrum, field absorption mass spectrum, fast atom bombardment mass spectroscopy, high resolution mass spectrum, infrared spectrum, ultraviolet spectra, elementary analysis, high performance liquid chromatography, thin layer chromatography, nitrogen, water, ethyl acetate, ether, dichloromethane, dimethyl formamide, chloroform, methanol, ethanol, acetonitrile, oxolane, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sulphuric acid, hydrobromic acid, hydrochloric acid, ammonium hydroxide, sodium sulfite, sodium sulfite, sodium nitrite, sodium sulfate, saturated sodium-chloride, sodium bromide, ammonium chloride, magnesium sulfate, sodium acetate and room temperature are abbreviated as " m.p. " respectively, " NMR ", " EIMS ", " MS (FD) ", " MS (FAB) ", " MS (HR) ", " IR ", " UV ", " analysis ", " HPLC ", " TLC ", " N
2", " H
2O ", " EtOAc ", " Et
2O ", " CH
2Cl
2", " DMF ", " CHCl
3", " MeOH ", " EtOH ", " CH
3CN ", " THF ", " NaOH ", " KOH ", " NHCO
3", " H
2SO
4", " HBr ", " HCl ", " NH
4OH ", " Na
2SO
3", " NaHSO
3", " NaNO
2", " Na
2SO
4", " saline ", " NaBr ", " NH
4Cl ", " MgSO
4", " NaOAc " and " RT ".If not otherwise stated, MS (FD) values reported is corresponding to mass number.In addition, absworption peak listed in the IR spectrum only is interested peak, is not viewed all peak values.
The NMR wave spectrum records on Br ü ker Corp.270MHz instrument or General Electric QE-300300MHz instrument.Chemical shift with δZhi (to tetramethylsilane low move white ten thousand/) expression.MS (FD) wave spectrum records with carbon dendrite emitter stage on Varian-MAT 731 spectrometers.The EIMS wave spectrum records on the CEC 21-110 of Consolidated Electrodynamics company instrument.IR spectrum records on Perkin-Elmer 281 instruments.UV spectrum records on Cary 118 instruments.TLC carries out on the E.Merck silica gel plate.Fusing point is not proofreaied and correct.
In the NMR wave spectrum, it is unimodal having used following abbreviation " s ", " d " is doublet, " dd " is double doublet, " t " is triplet, and " q " is quartet, and " m " is multiplet, " dm " is two multiplets, and " br.s ", " br.d ", " br.t " and " br.m " are respectively wide unimodal, doublet, triplet and multiplet." J " is coupling constant, and unit is hertz (Hz).If not otherwise stated, the NMR data are data of chemical compound free alkali.
Used term " MS " in the preparation example, " analysis ", " IR ", " UV " and " NMR " represent the consistent of corresponding mass spectrum, elementary analysis, infrared spectrum, ultraviolet spectra and NMR (Nuclear Magnetic Resonance) spectrum and required product.
Preparation example 1
2-chloro-5-benzoyl pyridine
With aluminum chloride (100g, 0.730mol) at the blanket of nitrogen low suspension in 200ml benzene.(53g, 100ml benzole soln 0.30mol) reflux then and spend the night to add the 6-chloronicotinoyl chloride in the suspension of rapid stirring.Reactant liquor is cooled to room temperature, adds the 1L ethyl acetate, use the 5N sodium hydroxide pH to 8.5.The aluminum salt precipitation that filtering forms.With the filtrate water washing, use dried over sodium sulfate, then vacuum concentration.With the yellowish-brown solid that obtains with 3: 2 ether: the hexane recrystallization obtains 54.6g (83%) yellowish-brown crystalloid product.EA，MS(FD)。
Preparation example 2
2-chloro-5-(4-fluoro benzoyl) pyridine
(150ml, 1.60mmol) (17.7g 100mmol) obtains the 15.2g product according to being transformed into product with preparation example 1 basic similarly mode with the 6-chloronicotinoyl chloride with fluorobenzene.(66．1％)。EA，MS(FD)，NMR。
Preparation example 3
2-amino-5-benzoyl pyridine
(100g 0.460mol) is dissolved in 500ml 3A ethanol and 400ml anhydrous ammonia, places in the high-pressure gas tank, then in 145 ℃ of heating 16 hours with 2-chloro-5-benzoyl pyridine.Vacuum is steamed and is desolventized, and remaining yellowish-brown solid is obtained 77.4g (85%) yellowish-brown solid, shaped product with the ethanol/water recrystallization.EA，MS(FD)。
Preparation example 4
2-amino-5-(4-fluoro benzoyl) pyridine
(59.1g 251mmol) obtains the 35.4g product according to being transformed into product with preparation example 3 basic similarly modes with 2-chloro-5-(4-fluoro benzoyl) pyridine.(65．3％)。EA，MS(FD)。
Preparation example 5
1,2-dihydro-2-tosyl imino group-5-benzoyl pyridine
With 2-amino-5-benzoyl pyridine (77.44g, 0.390mol) and paratoluensulfonyl chloride (82.03g 0.43mol) mixes in the 300ml pyridine then under blanket of nitrogen in 90 ℃ of heating 16 hours.The vacuum steaming removes pyrido solid was stirred 1 hour in 1.5L water.Leach solid and obtain 118.7g (86%) rice white crystalloid product with re-crystallizing in ethyl acetate.EA，MS(FD)。
Preparation example 6
1,2-dihydro-2-tosyl imino group-5-(4-fluoro benzoyl) pyridine
(35.0g 162mmol) obtains the 47.7g product according to being transformed into product with preparation example 5 basic similarly modes with 2-amino-5-(4-fluoro benzoyl) pyridine.(79．6％)。MS(FD)，NMR。
Preparation example 7
α-bromo-(4-fluorophenyl) acetic acid
With 4-fluorophenylacetic acid (20g, 0.13mol), benzoyl peroxide (130mg, 0.540mmol) and N-bromosuccinimide (23.1g 0.130mol) in mixing in the 500ml carbon tetrachloride under the blanket of nitrogen, refluxed 5 hours down in UV irradiation (GE cold quartz mercury vapor lamp) then.Reactant liquor is cooled to room temperature, the filtering butanimide.Vacuum steam to be removed carbon tetrachloride and the oil of remnants is obtained 26.2g (87%) light yellow solid shape product with the hexane recrystallization.EA，MS(FD)。
Preparation example 8
α-bromo-(4-methoxyphenyl) acetic acid
(25.0g 150mmol) obtains the 36.6g product according to being transformed into product with preparation example 7 basic similarly modes with the 4-methoxyphenylacetic acid.(100％)。MS(FD)，NMR。
Preparation example 9
α-bromo-(naphthalene-2-yl) acetic acid
(37.2g 200mmol) obtains the 34.5g product according to being transformed into product with preparation example 7 basic similarly modes with (naphthalene-2-yl) acetic acid.(65％)．MS(FD)，NMR。
Preparation example 10
α-bromo-naphthalene acetic acid
(37.2g 200mol) obtains the 32.4g product according to being transformed into product with preparation example 7 basic similarly modes with naphthalene acetic acid.(60．8％)。MS(FD)，NMR。
Preparation example 11
α-bromo-(2-fluorophenyl) acetic acid
(19.9g 129mmol) obtains the 24.0g product according to being transformed into product with preparation example 7 basic similarly modes with (2-fluorophenyl) acetic acid.(79．9％)。
Preparation example 12
α-bromo-(3-fluorophenyl) acetic acid
(20.0g 130mmol) obtains the 24.3g product according to being transformed into product with preparation example 7 basic similarly modes with (3-fluorophenyl) acetic acid.(80．0％)。
Preparation example 13
α-bromo-(2,4 difluorobenzene base) acetic acid
(21.3g 124mmol) obtains the 24.8g product according to being transformed into product with preparation example 7 basic similarly modes with 2,4 difluorobenzene acetic acid.(79．5％)。NMR。
Preparation example 14
α-bromo-(3, the 5-difluorophenyl) acetic acid
(20.4g 118mmol) obtains the 21.0g product according to being transformed into product with preparation example 7 basic similarly modes with (3, the 5-difluorophenyl) acetic acid.(70．9％)。NMR。
Preparation example 15
α-bromo-(2, the 5-difluorophenyl) acetic acid
(20.5g 119mmol) obtains the 27.3g product according to being transformed into product with preparation example 7 basic similarly modes with (2, the 5-difluorophenyl) acetic acid.(91．0％)。NMR。
Preparation example 16
α-bromo-(3-trifluoromethyl) acetic acid
(20g 90mmnol) obtains the 27.7g product according to being transformed into product with preparation example 7 basic similarly modes with (3-trifluoromethyl) acetic acid.(100％)。NMR。
Preparation example 17
α-bromo-(4-bromophenyl) acetic acid
(25.8g 120mmol) obtains the 30.2g product according to being transformed into product with preparation example 7 basic similarly modes with (4-bromophenyl) acetic acid.(85．7％)。NMR。
Preparation example 18
α-bromo-(2,3, the 4-trifluorophenyl) acetic acid
(9.55g 50.3mmol) obtains the 13.5g product according to being transformed into product with preparation example 7 basic similarly modes with (2,3, the 4-trifluorophenyl) acetic acid.(100％)。NMR。
Preparation example 19
α-bromo-(3, the 4-difluorophenyl) acetic acid
(15.2g 88.2mmol) obtains the 22.2g product according to being transformed into product with preparation example 7 basic similarly modes with (3, the 4-difluorophenyl) acetic acid.(100％)。NMR。
Preparation example 20
α-bromo-(3, the 4-Dichlorobenzene base) acetic acid
(25.0g 122mmol) obtains the 34.6g product according to being transformed into product with preparation example 7 basic similarly modes with (3, the 4-Dichlorobenzene base) acetic acid.(100％)。NMR。
Preparation example 21
α-bromo-(2,4, the 5-trifluorophenyl) acetic acid
(9.56g 50.3mmol) obtains the 13.6g product according to being transformed into product with preparation example 7 basic similarly modes with (2,4, the 5-trifluorophenyl) acetic acid.(100％)。NMR。
Preparation example 22
α-bromo-(2-chlorphenyl) acetic acid
(25.3g 148mmol) obtains the 22.8g product according to being transformed into product with preparation example 7 basic similarly modes with (2-chlorphenyl) acetic acid.(62．0％)。MS(FD)，NMR。
Preparation example 23
α-bromo-(3-chlorphenyl) acetic acid
(20.9g 123mmol) obtains the 30.5g product according to being transformed into product with preparation example 7 basic similarly modes with (3-chlorphenyl) acetic acid.(100％)。NMR。
Preparation example 24
α-bromo-(4-chlorphenyl) acetic acid
(25.0g 147mmol) obtains the 21.7g product according to being transformed into product with preparation example 7 basic similarly modes with (4-chlorphenyl) acetic acid.(60．0％)。NMR。
Preparation example 25
α-bromo-(4-Trifluoromethoxyphen-l) acetic acid
(9.91g 45.1mmol) obtains the 13.5g product according to being transformed into product with preparation example 7 basic similarly modes with (4-Trifluoromethoxyphen-l) acetic acid.(100％)。NMR。
Preparation example 26
α-bromo-(3-Trifluoromethoxyphen-l) acetic acid
(9.75g 44.3mmol) obtains the 13.3g product according to being transformed into product with preparation example 7 basic similarly modes with (3-Trifluoromethoxyphen-l) acetic acid.(100％)。NMR。
Preparation example 27
α-bromo-(2-fluoro-4-trifluoromethyl) acetic acid
(9.56g 43.1mmol) obtains the 13.0g product according to being transformed into product with preparation example 7 basic similarly modes with (2-fluoro-4-trifluoromethyl) acetic acid.(100％)。NMR。
Preparation example 28
α-bromo-(2-methoxyphenyl) acetic acid
(25.0g 150mmol) obtains the 26.5g product according to being transformed into product with preparation example 7 basic similarly modes with (2-methoxyphenyl) acetic acid.(72％)。MS(FD)，NMR。
Preparation example 29
α-bromo-(4-nitrobenzophenone) acetic acid
(25.5g 141mmol) obtains the 36.6g product according to being transformed into product with preparation example 7 basic similarly modes with (4-nitrobenzophenone) acetic acid.(100％)。NMR。
Preparation example 30
α-bromo-(3-thienyl) acetic acid
(8.60g 54.4mmol) is dissolved in the acetic acid solution of 100ml 30%HBr with (thiene-3-yl-) mandelic acid.With solution stirring at room 18 hours.Transparent dark solution is poured in the 2.5L frozen water and is used immediately into extracted with diethyl ether (4 * 400ml).Ether is handled with dried over sodium sulfate and with decolorizing carbon.Steam and remove ether and residue and methylbenzene azeotropic are removed residual acetic acid.Solid crude product is obtained the 9.07g product with the hexane recrystallization.(75．％)．EA，MS(FD)。
Preparation example 31
α-bromo-benzylacetic acid
With the L-phenylalanine (55.0g, 330mmol) and sodium bromide (130g 1.09mol) is dissolved in the 3N sulphuric acid that 550ml is cooled to 0 ℃, and (32.0g, 469mmol), the temperature that keeps reactant liquor is between 0 to 5 ℃ slowly to add sodium nitrite then in this solution.Continue at 0 ℃ and stirred 1 hour, stirring at room is 1.5 hours then.With mixture extracted with diethyl ether (4 * 300ml).With ether with the salt water washing (2 * 500ml), use dried over mgso, then vacuum concentration.Residue is obtained crystalloid phenylalanine raw material with 50ml cyclohexane extraction recrystallization.The filtering solid also obtains the 64g crude product, the not purified direct use of this crude product with the filtrate vacuum concentration.(84．7％)。
Preparation example 32
α-bromo-(4-fluorophenyl) acetamide
(26.1g, 112mmol) solution in 175ml dry methylene chloride and 3 DMF cools off with ice bath under blanket of nitrogen with α-bromo-(4-fluorophenyl) acetic acid.In 25 minutes, drip the 25ml dry methylene chloride solution of oxalyl chloride (25.0g, 224 mmol).Remove ice bath and reactant liquor was stirred 3 hours.Vacuum is steamed and is desolventized, then with methylbenzene azeotropic (3 * 25ml).The oil of remnants is dissolved in 300ml toluene and 300ml hexane, uses the mechanical agitator vigorous stirring then.Be blown into ammonia 1 hour by the gas dispersion pipe at the top of this solution then.Solid that filtering forms and vacuum are steamed and are desolventized.Solid is dissolved in ethyl acetate/water and with organic layer 1N hydrochloric acid, saturated sodium bicarbonate and salt water washing, uses dried over sodium sulfate then.Filtering sodium sulfate vacuum then steams except that ethyl acetate.Remaining solid is obtained the required product of 19.6g (75%) with the ethyl acetate/hexane recrystallization.MS(FD)，NMR。
Preparation example 33
α-bromo-(4-methoxyphenyl) acetamide
(36.6g 150mmol) obtains the 13.5g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-(4-methoxyphenyl) acetic acid.(37％)。MS(FD)，NMR。
Preparation example 34
α-bromo-(naphthalene-2-yl) phenyl-acetamides
(34.5g 130mmol) obtains the 11.5g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-(naphthalene-2-yl) acetic acid.(33．5％)。EA，MS(FD)。
Preparation example 35
α-bromo-naphthyl acetamide
(32.4g 122mmol) obtains the 14.6g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-naphthalene acetic acid.(46％)。MS(FD)，NMR。
Preparation example 36
α-bromo-(2-fluorophenyl) acetamide
(24.0g 103mmol) obtains the 14.0g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-(2-fluorophenyl) acetic acid.(60％)。MS(FD)，NMR。
Preparation example 37
α-bromo-(3-fluorophenyl) acetamide
(24.3g 104mmol) obtains the 16.3g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-(3-fluorophenyl) acetic acid.(67．0％)。MS(FD)，NMR。
Preparation example 38
α-bromo-(2,4 difluorobenzene base) acetamide
(23.3g 93.0mmol) obtains the 7.88g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-(2,4 difluorobenzene base) acetic acid.(34．3％)。NMR。
Preparation example 39
α-bromo-(3, the 5-difluorophenyl) acetamide
(21.0g 83.8mmol) obtains the 14.4g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-(3, the 5-difluorophenyl) acetic acid.(68．7％)。NMR。
Preparation example 40
α-bromo-(2, the 5-difluorophenyl) acetamide
(27.3g 109mmol) obtains the 18.5g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-(2, the 5-difluorophenyl) acetic acid.(68．0％)。MS(FD)，NMR。
Preparation example 41
α-bromo-(3-trifluoromethyl) acetamide
(27.7g 98.0mmol) obtains the 14.2g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-(3-trifluoromethyl) acetic acid.(51．4％)。MS(FD)，NMR。
Preparation example 42
α-bromo-(4-bromophenyl) acetamide
(30.2g 103mmol) obtains the 23.5g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-(4-bromophenyl) acetic acid.(78．1％)。MS(FD)，NMR。
Preparation example 43
α-bromo-(2,3, the 4-trifluorophenyl) acetamide
(13.5g 50.3mmol) obtains the 10.2g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-(2,3, the 4-trifluorophenyl) acetic acid.(75．7％)。MS(FD)，NMR。
Preparation example 44
α-bromo-(3, the 4-difluorophenyl) acetamide
(22.2g 88.0mmol) obtains the 7.88g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-(3, the 4-difluorophenyl) acetic acid.(35．7％)。MS(FD)，NMR。
Preparation example 45
α-bromo-(3, the 4-Dichlorobenzene base) acetamide
(34.6g 122mmol) obtains the 11.8g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-(3, the 4-Dichlorobenzene base) acetic acid.(34．2％)。MS(FD)，NMR。
Preparation example 46
α-bromo-(2,4, the 5-trifluorophenyl) acetamide
(13.6g 50.3mmol) obtains the 7.34g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-(2,4, the 5-trifluorophenyl) acetic acid.(54．4％)。NMR。
Preparation example 47
α-bromo-(2-chlorphenyl) acetamide
(22.8g 91.7mmol) obtains the 17.5g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-(2-chlorphenyl) acetic acid.(77％)。MS(FD)，NMR。
Preparation example 48
α-bromo-(3-chlorphenyl) acetamide
(30.5g 123mmol) obtains the 17.8g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-(2-chlorphenyl) acetic acid.(59％)。MS(FD)，NMR。
Preparation example 49
α-bromo-(4-chlorphenyl) acetamide
(21.7g 86.9mmol) obtains the 15.7g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-(4-chlorphenyl) acetic acid.(73％)。MS(FD)，NMR。
Preparation example 50
α-bromo-(4-Trifluoromethoxyphen-l) acetamide
(13.5g 45.1mmol) obtains the 11.1g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-(4 Trifluoromethoxyphen-l) acetic acid.(83％)。MS(FD)，NMR。
Preparation example 51
α-bromo-(3-Trifluoromethoxyphen-l) acetamide
(13.3g 44.3mmol) obtains the 9.43g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-(3-Trifluoromethoxyphen-l) acetic acid.(71％)。MS(FD)，NMR。
Preparation example 52
α-bromo-(2-fluoro-4-trifluoromethyl) acetamide
(13.0g 43.1mmol) obtains 11.1g according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-(2-fluoro-4-trifluoromethyl) acetic acid.(86％)。MS(FD)，NMR。
Preparation example 53
α-bromo-phenyl-acetamides
(21.5g 100mmol) obtains the 16.8g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-phenylacetic acid.(78％)。NMR。
Preparation example 54
α-bromo-(thiene-3-yl-) acetamide
(9.07g 41.0mmol) obtains the 6.50g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromine (thiene-3-yl-) acetic acid.(72．0％)。MS，MP。
Preparation example 55
α-bromo-(2-methoxyphenyl) acetamide
(26.5g 108mmol) obtains the 21.6g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-(2-methoxyphenyl) acetic acid.(82．0％)。NMR。
Preparation example 56
α-bromo-isobutyl group acetamide
(35.0g 179mmol) obtains the 20.9g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-(4-methyl) valeric acid.(60．1％)。EA，MS(EI)。
Preparation example 57
α-bromo-benzyl acetamide
(64.0g 279mmol) obtains the 22.5g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-benzylacetic acid.(35．4％)。EA，MS(FD)。
Preparation example 58
α-bromo-(4-nitrobenzophenone) acetamide
(36.6g 141mmol) obtains the 19.3g product according to being transformed into product with preparation example 32 basic similarly modes with α-bromo-(4-nitrobenzophenone) acetic acid.(52．9％)。NMR。
Preparation example 59
2,6-difluoro mandelic acid
With 2, the 6-difluorobenzaldehyde (25.0g, 176mmol) and zinc iodide (5.0mg 0.02mmol) places under blanket of nitrogen with flame-dried 250ml three neck round-bottomed flasks.(17.45g 176.0mmol), stirs reactant liquor 72 hours then to drip the TMS cyanide in 20 minutes.Add 9N HCl (200ml), solution is refluxed spend the night then.Reactant liquor is cooled to room temperature and uses extracted with diethyl ether.Ether is extracted with saturated sodium bicarbonate, then with 5N HCl be acidified to pH1. should tart solution with extracted with diethyl ether and with the organic layer dried over sodium sulfate.Filtering sodium sulfate vacuum steaming then obtains white solid except that ether, and it is obtained 23.6g (71%) white solid product with the chloroform recrystallization.NMR，MS，IR，EA。
Preparation example 60
2,3,4,5,6-five fluorine mandelic acid
With 2,3,4,5, (49.4g 252mmol) obtains the 52.3g product according to being transformed into product with preparation example 59 basic similarly modes to 6-phenyl-pentafluoride formaldehyde.(86．0％)。EA，MS(FD)。
Preparation example 61
2-trifluoromethyl mandelic acid
(43.9g 252mmol) obtains the 39.1g product according to being transformed into product with preparation example 59 basic similarly modes with the 2-trifluoromethylated benzaldehyde.(70．5％)。EA，MS(FD)。
Preparation example 62
The thiene-3-yl-mandelic acid
(28.3g 252mmol) obtains the 13.4g product according to being transformed into product with preparation example 59 basic similarly modes with thiene-3-yl-formaldehyde.(33．8％)。EA，MS(FD)。
Preparation example 63
2-trifluoromethyl-4-fluorine mandelic acid
(48.4g 252mmol) obtains the 50.1g product according to being transformed into product with preparation example 59 basic similarly modes with 2-trifluoromethyl-4-fluorobenzaldehyde.(84％)。EA，MS(FD)。
Preparation example 64
2-fluoro-6-trifluoromethyl mandelic acid
(48.4g 252mmol) obtains the 49.7g product according to being transformed into product with preparation example 59 basic similarly modes with 2-fluoro-6-trifluoromethylated benzaldehyde.(84％)。EA，MS(FD)。
Preparation example 65
4-carboxyl mandelic acid
(33.0g 252mmol) obtains the 27.0g product according to being transformed into product with preparation example 59 basic similarly modes with the 4-cyanobenzaldehyde.(54．6％)。MS(FD)，NMR。
Preparation example 66
α-0-acetyl group-(2, the 6-difluorophenyl) acetic acid
The acetic acid solution (150ml) of 30%HBr is joined 2, and 6-difluoro mandelic acid (16.9g stirs then in 50ml acetic acid solution 89.9mmol) and spends the night. and pour into reactant liquor in the 1.5L frozen water and stirred 1 hour.With aqueous solution with extracted with diethyl ether and with the organic layer dried over sodium sulfate.Filtering sodium sulfate and vacuum steaming remove ether and obtain white solid, and it is obtained 18.54 (90%) white solid products with the ether/hexane recrystallization.EA，MS(FD)。
Preparation example 67
α-0-acetyl group-(2,3,4,5, the 6-pentafluorophenyl group) acetic acid
With 2,3,4,5, (70.5g 291mmol) obtains the 82.8g product according to being transformed into product with preparation example 66 basic similarly modes to 6-five fluorine mandelic acid.(100％)。EA，MS(FD)。
Preparation example 68
α-O-acetyl group-(2-trifluoromethyl) acetic acid
(19.8g 90.0mmol) obtains the 20.8g product according to being transformed into product with preparation example 66 basic similarly modes with 2-trifluoromethyl mandelic acid.(88．0％)。EA，MS(FD)。
Preparation example 69
α-O-acetyl group-(2-trifluoromethyl-4-fluorophenyl) acetic acid
(49.4g 208mmol) obtains the 58.1g product according to being transformed into product with preparation example 66 basic similarly modes with 2-trifluoromethyl-4-fluorine mandelic acid.(100％)。EA，MS(FD)。
Preparation example 70
α-O-acetyl group-(2-fluoro-6-trifluoromethyl) acetic acid
(48.4g 252mmol) obtains the 50.1g product according to being transformed into product with preparation example 66 basic similarly modes with 2-fluoro-6-trifluoromethyl mandelic acid.(84％)。EA，MS(FD)。
Preparation example 71
α-O-acetyl group-(4-trifluoromethyl) acetic acid
(19.8g 89.9mmol) obtains the 20.3g product according to being transformed into product with preparation example 66 basic similarly modes with 4-trifluoromethyl mandelic acid.(86％)。MS(FD)，NMR。
Preparation example 72
α-O-acetyl group-(4-carboxyl phenyl) acetic acid
(27.0g 138mmol) obtains the 27.5g product according to being transformed into product with preparation example 66 basic similarly modes with 4-carboxyl mandelic acid.(83．9％)。MS(FD)，NMR。
Preparation example 73
α-O-acetyl group-(2, the 6-difluorophenyl) acetamide
(18.5g, 80.4mmol) solution in 200ml dry methylene chloride and 3 DMF cools off with ice bath under blanket of nitrogen with α-O-acetyl group-(2, the 6-difluorophenyl) acetic acid.In 25 minutes, drip the 50ml dry methylene chloride solution of oxalyl chloride (50.0g, 448 mmol).Remove ice bath and reactant liquor was stirred 3 hours.Vacuum is steamed and is desolventized, then with methylbenzene azeotropic (3 * 25ml).The oil of remnants is dissolved in 100ml toluene and 700ml hexane, uses the mechanical agitator vigorous stirring then.Be blown into ammonia 1 hour by the gas dispersion pipe at the top of this solution then.Solid that filtering forms and vacuum are steamed and are desolventized.Solid is dissolved in ethyl acetate/water and with organic layer 1N hydrochloric acid, saturated sodium bicarbonate and salt water washing, uses dried over sodium sulfate then.Filtering sodium sulfate vacuum then steams except that ethyl acetate.Remaining solid is obtained the required product of 16.7g (90%) with the ethyl acetate/hexane recrystallization.
Preparation example 74
α-O-acetyl group-(2,3,4,5, the 6-pentafluorophenyl group) acetamide
(106g 373mmol) obtains the 94.0g product according to being transformed into product with preparation example 73 basic similarly modes with α-0-acetyl group-(2,3,4,5, the 6-pentafluorophenyl group) acetic acid.(89％)。EA，MS(FD)。
Preparation example 75
α-O-acetyl group-(2-trifluoromethyl) acetamide
(20.8g 79.4mmol) obtains the 18.8g product according to being transformed into product with preparation example 73 basic similarly modes with α-O-acetyl group-(2-trifluoromethyl) acetic acid.(90．7％)。EA，MS(FD)。
Preparation example 76
α-O-acetyl group-(2-trifluoromethyl-4-fluorophenyl) acetamide
(58.1g 208mmol) obtains the 52.4g product according to being transformed into product with preparation example 73 basic similarly modes with α-O-acetyl group-(2-trifluoromethyl-4-fluorophenyl) acetic acid.(90．0％)。EA，MS(FD)。
Preparation example 77
α-0-acetyl group-(2-fluoro-6-trifluoromethyl) acetamide
(53.4g 191mmol) obtains the 47.9g product according to being transformed into product with preparation example 73 basic similarly modes with α-O-acetyl group-(2-fluoro-4-trifluoromethyl) acetic acid.(90％)。EA，MS(FD)。
Preparation example 78
α-O-acetyl group-(4-trifluoromethyl) acetamide
(20.3g 77.3mmol) obtains the 18.8g product according to being transformed into product with preparation example 73 basic similarly modes with α-O-acetyl group-(4-trifluoromethyl) acetic acid.(93％)。
Preparation example 79
Methyl-(Alpha-hydroxy-4-methoxycarbonyl group benzyl) acetas
(23.2g 97.3mmol) is suspended in the 300ml dichloromethane, and reactant liquor is also added 3 DMF simultaneously in stirring under the blanket of nitrogen in ice bath with α-O-acetyl group-(4-carboxyl phenyl) acetic acid.In 20 minutes, drip oxalyl chloride (50.0g, 50ml dry methylene chloride solution 448mmol).Remove ice bath and with about 5 hours of reactant liquor stirring at room (until all solid dissolvings).Steaming desolventizes and places addition funnel to stir then residue and 200ml methanol spends the night.Steaming desolventizes and residue is added in the ethyl acetate.With ethyl acetate with sodium bicarbonate (3 * 100ml) and the salt water washing, use dried over sodium sulfate then.The vacuum steaming removes ethyl acetate and obtains 22g oil.(100％)。EA，MS(FD)。
Preparation example 80
Alpha-hydroxy-(2, the 6-difluorophenyl) acetamide
(16.7g 73.0mmol) is dissolved in 125ml methanol and 35ml diisopropyl ethyl amine, refluxes then 3 hours with α-O-acetyl group-(2, the 6-difluorophenyl) acetamide.The vacuum steaming desolventizes and remaining solid is obtained 11.42g (84%) white solid product with the ethyl acetate/hexane recrystallization.EA，MS(FD)。
Preparation example 81
Alpha-hydroxy-(2,3,4,5, the 6-pentafluorophenyl group) acetamide
(83.0g 293mmol) obtains the 66.6g product according to being transformed into product with preparation example 80 basic similarly modes with α-O-acetyl group-(2,3,4,5, the 6-pentafluorophenyl group) acetamide.(94％)。EA，MS(FD)。
Preparation example 82
Alpha-hydroxy-(2-trifluoromethyl) acetamide
(18.4g 70.6mmol) obtains the 14.3g product according to being transformed into product with preparation example 80 basic similarly modes with α-O-acetyl group-(2-trifluoromethyl) acetamide.(92．4％)。MS(FD)，NMR。
Preparation example 83
Alpha-hydroxy-(2-trifluoromethyl-4-fluorophenyl) acetamide
(50.4g 181mmol) obtains the 40.9g product according to being transformed into product with preparation example 80 basic similarly modes with α-O-acetyl group-(2-trifluoromethyl-4-fluorophenyl) acetamide.(95％)。EA，MS(FD)。
Preparation example 84
Alpha-hydroxy-(2-fluoro-6-trifluoromethyl) acetamide
(44.6g 160mmol) obtains the 32.1g product according to being transformed into product with preparation example 80 basic similarly modes with α-O-acetyl group-(2-methyl fluoride-6-trifluoromethyl) acetamide.(85％)。EA，MS(FD)。
Preparation example 85
Alpha-hydroxy-(4-trifluoromethyl) acetamide
(18.8g 65.3mmol) obtains the 13.8g product according to being transformed into product with preparation example 80 basic similarly modes with α-O-acetyl group-(4-trifluoromethyl) acetamide.(96．1％)。EA，MS(FD)。
Preparation example 86
Alpha-hydroxy-(4-methoxycarbonyl group phenyl) acetamide joins methyl-(Alpha-hydroxy-4-methoxycarbonyl group benzyl) acetas with freshly prepd methanol ammonia solution (300ml), and (21.8g, 97.3mmol) stirring is spent the night then.The vacuum steaming desolventizes and residue is obtained the 17.5g product with the dichloromethane recrystallization.(85．7％)。EA，MS(FD)。
Preparation example 87
α-O-tosyl imino group-(2, the 6-difluorophenyl) acetamide
With Alpha-hydroxy-(2, the 6-difluorophenyl) acetamide (9.80g, 52.4mmol), 4-dimethylaminopyridine (500mg, 4.10mmol) and diisopropyl ethyl amine (10.04ml 57.6mmol) mixes in the 300ml dry methylene chloride under blanket of nitrogen.(11.0g 57.6mmol) and with the reactant liquor stirring spends the night to add paratoluensulfonyl chloride.Vacuum is steamed and to be desolventized and the solid of remnants is dissolved in ethyl acetate.Ethyl acetate with 1N HCl, saturated sodium bicarbonate and salt water washing, is used dried over sodium sulfate then.Filtering sodium sulfate and vacuum steaming remove ethyl acetate and obtain white solid.This solid is obtained the required product of 15.8g (88%) white powder with the ethyl acetate/hexane recrystallization.EA，MS(FD)。
Preparation example 88
(12.1g 50.0mmol) obtains the 18.3g product according to being transformed into product with preparation example 87 basic similarly modes to α-O-tosyl imino group-(2,3,4,5, the 6-pentafluorophenyl group) acetamide with Alpha-hydroxy-(2,3,4,5, the 6-pentafluorophenyl group) acetamide.(92％)。EA，MS(FD)。
Preparation example 89
α-O-tosyl imino group-(2-trifluoromethyl) acetamide
(14.3g 65.2mmol) obtains the 21.0g product according to being transformed into product with preparation example 87 basic similarly modes with Alpha-hydroxy-(2-trifluoromethyl) acetamide.(86％)。EA，MS(FD)。
Preparation example 90
α-O-tosyl imino group-(2-trifluoromethyl-4-fluorophenyl) acetamide
(11.9g 50.0mmol) obtains the 17.0g product according to being transformed into product with preparation example 87 basic similarly modes with Alpha-hydroxy-(2-trifluoromethyl-4-fluorophenyl) acetamide.(87％)。EA，MS(FD)。
Preparation example 91
α-O-tosyl imino group-(2-fluoro-6-trifluoromethyl) acetamide
(11.9g 50.0mmol) obtains the 17.8g product according to being transformed into product with preparation example 87 basic similarly modes with Alpha-hydroxy-(2-fluoro-4-trifluoromethyl) acetamide.(91％)。EA，MS(FD)。
Preparation example 92
α-O-tosyl imino group-(4-trifluoromethyl) acetamide
(9.35g 42.7mmol) obtains the 12.7g product according to being transformed into product with preparation example 87 basic similarly modes with Alpha-hydroxy-(4-trifluoromethyl) acetamide.(80％)。EA，MS(FD)。
Preparation example 93
α-O-tosyl imino group-(4-methoxycarbonyl group phenyl) acetamide
(10.5g 50.0mmol) obtains the 14.6g product according to being transformed into product with preparation example 87 basic similarly modes with Alpha-hydroxy-(4-methoxycarbonyl group phenyl) acetamide.(80．2％)。EA，MS(FD)。
Preparation example 941,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[2,4-difluorophenyl]-the carbamyl ylmethyl)-pyridine
With 1, (10.6g 30.0mmol) is dissolved in 75ml DMF and stirring to 2-dihydro-2-tosyl imino group-5-benzoyl pyridine under blanket of nitrogen in flame-dried flask.(1.32g is 33.0mmol) and with solution stirring 1.5 hours to add sodium hydride.(7.88g is 31.5mmol) and with solution stirring at room 7 days to add α-bromo-(2,4 difluorobenzene base) acetamide then.Pour into reactant liquor in the 2.5L water and stirred 1 hour.Filter and collect the precipitation of separating out.Filter cake is obtained the 13.2g product with the ethyl acetate/hexane recrystallization.(84％)。EA，MS(FD)。
Preparation example 951,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[4-fluorophenyl]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (27.1g; 77.0mmol) and α-bromo-(4-fluorophenyl) acetamide (19.6g 84.5mmol) obtains the 35.0g product according to being transformed into product with the basic similarly modes of preparation example 94.(90．4％)。EA，MS(FD)。
Preparation example 961,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[4-methoxyphenyl]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (10.6g; 30.0mmol) and α-bromo-(4-methoxyphenyl) acetamide (8.05g; 33.0mmol) according to being transformed into product with preparation example 94 basic similarly modes; different is to replace sodium hydride and add sodium iodide (4.50g with cesium fluoride; 30.0mmol), obtain the 6.32g product.(41．0％)。EA，MS(FD)。
Preparation example 971,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[naphthalene-2-yl]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (18.5g; 52.7mmol) and α-bromo-(naphthalene-2-yl) acetamide (14.6g 55.3mmol) obtains the 15.0g product according to being transformed into product with the basic similarly modes of preparation example 94.(53．3％)。EA，MS(FD)。
Preparation example 981,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-naphthyl-carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (14.6g; 41.5mmol) and α-bromo-(naphthalene-1-yl) acetamide (11.5g 43.6mmol) obtains the 14.3g product according to being transformed into product with the basic similarly modes of preparation example 94.(64％)。EA，MS(FD)。
Preparation example 991,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[2-fluorophenyl]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (12.3g; 35.1mmol) and α-bromo-(2-fluorophenyl) acetamide (8.54g 36.8mmol) obtains the 16.5g product according to being transformed into product with the basic similarly modes of preparation example 94.(93．6％)。EA，MS(FD)。
Preparation example 1001,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[3-fluorophenyl]-the carbamyl ylmethyl)-pyridine
With 1, (16.3g 70.3mmol) obtains the 29.8g product according to being transformed into product with preparation example 94 basic similarly modes to 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (23.6g, 66.9mmol) and α-bromo-3-fluorophenyl) acetamide.(88．5％)。EA，MS(FD)。
Preparation example 1011,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[3,5-difluorophenyl]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (10.6g; 30.0mmol) and α-bromo-(3, the 5-difluorophenyl) acetamide (7.88g 31.5mmol) obtains the 14.2g product according to being transformed into product with the basic similarly modes of preparation example 94.(91．0％)。EA，MS(FD)。
Preparation example 1021,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[2,5-difluorophenyl]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (10.6g; 30.0mmol) and α-bromo-(2, the 5-difluorophenyl) acetamide (7.88g 31.5mmol) obtains the 15.3g product according to being transformed into product with the basic similarly modes of preparation example 94.(98％)。EA，MS(FD)。
Preparation example 1031,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[3-trifluoromethyl]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (10.6g; 30.0mmol) and α-bromo-(3-trifluoromethyl) acetamide (8.88g 31.5mmol) obtains the 12.7g product according to being transformed into product with the basic similarly modes of preparation example 94.(76％)。EA，MS(FD)。
Preparation example 1041,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[4-bromophenyl]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (10.6g; 30.0mmol) and α-bromo-(4-bromophenyl) acetamide (9.23g 31.5mmol) obtains the 13.7g product according to being transformed into product with the basic similarly modes of preparation example 94.(81％)。EA，MS(FD)。
Preparation example 1051,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[2,3,4-trifluorophenyl]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (10.6g, 30.0mml) and α-bromo-(2,3; the 4-trifluorophenyl) (8.44g 31.5mmol) obtains 11.3g according to being transformed into product with preparation example 94 basic similarly modes to acetamide.(70％)。
Preparation example 1061,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[3,4-difluorophenyl]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (10.6g; 30.0mmol) and α-bromo-(3, the 4-difluorophenyl) acetamide (7.88g 31.5mmol) obtains the 9.53g product according to being transformed into product with the basic similarly modes of preparation example 94.(61％)。EA，MS(FD)。
Preparation example 1071,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[3,4-Dichlorobenzene base]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (10.6g; 30.0mmol) and α-bromo-(3, the 4-Dichlorobenzene base) acetamide (9.00g 31.5mmol) obtains the 13.8g product according to being transformed into product with the basic similarly modes of preparation example 94.(83％)。EA，MS(FD)。
Preparation example 1081,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[2,4,5-trifluorophenyl]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (9.18g, 26.1mmol) and α-bromo-(2,4; the 5-trifluorophenyl) (7.34g 27.4mmol) obtains 11.6g according to being transformed into product with preparation example 94 basic similarly modes to acetamide.(83％)。MS(FAB)，NMR。
Preparation example 1091,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[2-chlorphenyl]-the carbamyl ylmethyl)-pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl pyridine (10.6g, 30.0mmol) and α-bromo-2-chlorphenyl acetamide (7.83g 31.5mmol) obtains the 10.4g product according to being transformed into product with the basic similarly modes of preparation example 94.(69％)。EA，MS(FD)。
Preparation example 1101,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[3-chlorphenyl]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (10.6g; 30.0mmol) and α-bromo-(3-chlorphenyl) acetamide (7.83g 31.5mmol) obtains the 13.4g product according to being transformed into product with the basic similarly modes of preparation example 94.(77％)。EA，MS(FD)。
Preparation example 1111,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[4-chlorphenyl]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (10.6g; 30.0mmol) and α-bromo-(4-chlorphenyl) acetamide (7.81g 31.5mmol) obtains the 13.8g product according to being transformed into product with the basic similarly modes of preparation example 94.(88％)。EA，MS(FD)。
Preparation example 1121,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[4-Trifluoromethoxyphen-l]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (10.6g; 30.0mmol) and α-bromo-(4-Trifluoromethoxyphen-l) acetamide (9.83g; 33.0mmol) according to being transformed into product with preparation example 94 basic similarly modes; different is to replace sodium hydride with cesium fluoride, obtains the 13.2g product.(77％)。EA，MS(FD)。
Preparation example 1131,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[3-Trifluoromethoxyphen-l]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (10.6g; 30.0mmol) and α-bromo-(3-Trifluoromethoxyphen-l) acetamide (9.43g 31.6mmol) obtains the 12.5g product according to being transformed into product with the basic similarly modes of preparation example 94.(73％)。EA，MS(FD)。
Preparation example 1141,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[2-fluoro-4-trifluoromethyl]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (7.04g; 20.0mmol) and α-bromo-(2-fluoro-4-trifluoromethyl) acetamide (6.50g 21.7mmol) obtains the 10.1g product according to being transformed into product with the basic similarly modes of preparation example 94.(88％)。EA，MS(FD)。
Preparation example 1151,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-phenyl-carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (10.6g; 30.0mmol) and α-bromo-phenyl-acetamides (6.74g; 31.5mmol) according to being transformed into product with preparation example 94 basic similarly modes; different is to replace sodium hydride with cesium fluoride, obtains the l3.3g product.(91％)。EA，MS(FD)。
Preparation example 1161,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[4-trifluoromethyl]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (10.0g; 28.5mmol) and α-O-tosyl imino group-(4-trifluoromethyl) acetamide (11.1g 29.9mmol) obtains the 13.9g product according to being transformed into product with the basic similarly modes of preparation example 94.(88％)。EA，MS(FD)。
Preparation example 1171,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[2-fluoro-6-trifluoromethyl]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (10.6g; 30.0mmol) and α-O-tosyl imino group-(2-trifluoromethyl-6-fluorophenyl) acetamide (12.9g; 33.0mmol) according to being transformed into product with preparation example 94 basic similarly modes; different is with diisopropyl ethyl amine replacement sodium hydride and reacts between 90 to 100 ℃, obtain the 2.90g product.(16．9％)。MS(FD)，NMR。
Preparation example 1181,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[2,3,4,5,6-pentafluorophenyl group]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (5.28g; 15.0mmol) and α-O-tosyl imino group-(2; 3,4,5; the 6-pentafluorophenyl group) acetamide (5.93g; 15.0mmol) according to being transformed into product with preparation example 94 basic similarly modes, different is with cesium carbonate replacement sodium hydride and reacts under 60 ℃, obtain the 5.07g product.(59％)。EA，MS(FD)。
Preparation example 1191,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[2,6-difluorophenyl]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (10.6g; 30.0mmol) and α-O-tosyl imino group-(2; the 6-difluorophenyl) acetamide (10.7g; 31.5mmol) according to being transformed into product with preparation example 94 basic similarly modes; different is to be reflected under 60 ℃ to carry out, and obtains the 7.44g product.(48％)。EA，MS(FD)。
Preparation example 1201,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[2-trifluoromethyl]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (10.6g; 30.0mmol) and α-O-tosyl imino group-(2-trifluoromethyl) acetamide (11.8g; 31.5mmol) according to being transformed into product with preparation example 94 basic similarly modes; different is to be reflected under 70 ℃ to carry out, and obtains the 7.37g product.(44．4％)。EA，MS(FD)。
Preparation example 1211,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[thiene-3-yl-]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (9.90g; 28.1mmol) and α-O-tosyl imino group-(thiene-3-yl-) acetamide (6.50g 29.6mmol) obtains the 11.3g product according to being transformed into product with the basic similarly modes of preparation example 94.(81．7％)。EA，MS(FD)。
Preparation example 1221,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[2-trifluoromethyl-4-fluorophenyl]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (10.6g; 30.0mmol) and α-O-tosyl imino group-(2-trifluoromethyl-6-fluorophenyl) acetamide (12.9g; 33.0mmol) according to being transformed into product with preparation example 94 basic similarly modes; different is with diisopropyl ethyl amine replacement sodium hydride and reacts between 50 to 60 ℃, obtain the 14.5g product.(84％)。EA，MS(FD)。
Preparation example 123
1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-benzyl-carbamyl ylmethyl)-pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl pyridine (10.6g, 30.0mmol) and α-bromo-benzyl acetamide (7.52g 33.0mmol) obtains the 802mg product according to being transformed into product with the basic similarly modes of preparation example 94.(5．36％)。MS(FD)，NMR。
Preparation example 124
1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-isobutyl group-carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (7.04g; 20.0mmol) and α-bromo-isobutyl group acetamide (8.54g; 44.0mmol) according to being transformed into product with preparation example 94 basic similarly modes; different is to replace sodium hydride with cesium carbonate, obtains the 3.35g product.(36．0％)。EA，MS(FD)。
Preparation example 125
1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[2-methoxyphenyl]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (10.6g; 30.0mmol) and α-O-tosyl imino group-(2-methoxyphenyl) acetamide (7.69g 31.5mmol) obtains the 10.4g product according to being transformed into product with the basic similarly modes of preparation example 94.(68％)。EA，MS(FD)。
Preparation example 126
1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[4-methoxycarbonyl group phenyl]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (12.0g; 34.2mmol) and α-O-tosyl imino group-(4-methoxycarbonyl group phenyl) acetamide (13.0g 35.9mmol) obtains the 15.5g product according to being transformed into product with the basic similarly modes of preparation example 94.(83％)。EA，MS(FD)。
Preparation example 1271,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[4-nitrobenzophenone]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (10.6g; 30.0mmol) and α-bromo-(4-nitrobenzophenone) acetamide (8.55g 33.0mmol) obtains the 15.3g product according to being transformed into product with the basic similarly modes of preparation example 94.(96．2％)。MS(FD)，NMR。
Preparation example 1281,2-dihydro-2-tosyl imino group-5-(4-fluoro benzoyl)-N-(the 1-[4-fluorophenyl]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-(4-fluoro benzoyl) pyridine (7.40g; 20.0mmol) and α-bromo-(4-fluorophenyl) acetamide (5.10g 22.0mmol) obtains the 9.15g product according to being transformed into product with the basic similarly modes of preparation example 94.(88％)。EA，MS(FD)。
Preparation example 1291,2-dihydro-2-tosyl imino group-5-(4-fluoro benzoyl)-N-(1-[2-fluoro-4-trifluoromethyl]-the carbamyl ylmethyl)-pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl pyridine (7.40g; 20.0mmol) and α-bromo-(2-fluoro-4-trifluoromethyl) acetamide (8.60g; 22.0mmol) according to being transformed into product with preparation example 94 basic similarly modes; different is to replace sodium hydride with diisopropyl ethyl amine, obtains the 8.95g product.(76％)。EA，MS(FD)。
Preparation example 130
2-amino-5-methoxycarbonyl group-pyridine
(50.0g 0.362mol) is dissolved in 3.5L methanol and is cooled to 0 ℃ then under blanket of nitrogen with the 6-amino-nicotinic acid.Fed hydrogen chloride gas 45 minutes in solution, the temperature that keeps solution simultaneously is between 0-15 ℃.Then reactant liquor was heated 4 hours in 65 ℃.Vacuum is steamed except that methanol and with residue and is added in the 400ml water.With saturated sodium bicarbonate pH is transferred to about 6.3 and separate out precipitation.Leach the precipitation and wash with water.Filter cake is obtained the 48.9g product in 80 ℃ of vacuum dryings.(88．7％)。EA，MS(FD)。
Preparation example 131
2-tosyl imino group-5-methoxycarbonyl group pyridine
(48.9g 0.321mol) is dissolved in the 400ml pyridine under blanket of nitrogen with 2-amino-5-methoxycarbonyl group-pyridine.(73.5g 0.386mol) and with solution heated 16 hours in about 77.5 ℃ to add p-methyl benzenesulfonic acid.Vacuum concentration makes volume reduce 3/4, adds 3.5L water then.Leach the precipitation of formation, wash with water to dry then and obtain the 78.4g product.(79．7％)。MS(FD)，NMR。
Preparation example 1321,2-dihydro-2-tosyl imino group-5-methoxycarbonyl group-(1-phenyl-carbamyl ylmethyl)-pyridine
With 2-tosyl imino group-5-methoxycarbonyl group pyridine (73.4g, 0.240mol) at the blanket of nitrogen low suspension in 465ml DMF.Add at twice sodium hydride (60%, 10.1g, 0.253mol).After reactant all dissolves (about 45 minutes), (53.8g is 0.252mol) and with solution toluene 64 hours to add α-bromophenyl acetamide.Vacuum concentration reduces 2/3 with volume, then mixture is poured in the 3L water and with mixture and is stirred 2 hours.Filter cake is obtained the 103.4g product in 60 ℃ of vacuum dryings.(98．2％)。MS(FD)，NMR。
Preparation example 1332-trifluoroacetamido-3-phenyl-6-(methoxycarbonyl group) imidazo [1,2-a] pyridine
With 1; 2-dihydro-2-tosyl imino group-5-methoxycarbonyl group-N-(1-phenyl-carbamyl ylmethyl) pyridine (103.3g; 0.235mol), trifluoroacetic anhydride (286ml, 2.03mol) and the 573ml dichloromethane under blanket of nitrogen, mix and be heated to backflow.Solution was refluxed 6 hours, then vacuum concentration.With residue be dissolved in the 1.5L dichloromethane and with saturated sodium bicarbonate (3 * 500ml) and saline (2 * 500ml) wash, and filter then with dried over sodium sulfate.With the mother solution vacuum concentration, residue is added in the ethyl acetate of 250ml heat, make product separate out precipitation with the 700ml hexane then.To separate out sedimentary mixture and place refrigerator 18 hours, filter then, use hexane wash, obtain the 75.3g product in 40 ℃ of following vacuum dryings.(quantitative yield).NMR。
Preparation example 134
2-amino-3-phenyl-6-(methoxycarbonyl group) imidazo [1,2-a] pyridine
With the 2-trifluoroacetamido-(136g 0.440mol) is dissolved in 845ml methanol to 3-phenyl-6-(methoxycarbonyl group) imidazo [1,2-a] pyridine.In 15 minutes, add diisopropyl ethyl amine (280ml, 1.61mol).Reactant liquor slowly is heated to backflow to be stirred 68 hours then.Reactant liquor is cooled to 0 ℃ leaches precipitation then.Filter cake dried then with cold methanol wash obtain the 84.0g product.(71．4％)。EA，MS(FD)。
Preparation example 135
2-amino-3-phenyl-6-(carboxyl) imidazo [1,2-a] pyridine
With 2-amino-3-phenyl-6-(methoxycarbonyl group) imidazo [1,2-a] pyridine (83.9g, 0.314mol), lithium hydroxide monohydrate (65.9g, 1.57mol), 1113ml THF and 371ml water mixed then stirring at room 18 hours.Add in the 5L water with the reactant liquor vacuum concentration and with residue.With 5N HCl pH is transferred to 5.The precipitation that leaches formation is dried then and was obtained the 80.5g product in 72 hours.(quantitative yield).NMR，MS(FD)。
Preparation example 136
2-amino-3-phenyl-6-(N-methyl-N-methoxyl group carbamoyl) imidazo [1,2-a] pyridine
(80.4g, 0.317mol) and N, (92.8g 0.951mol) is dissolved in 500ml DMF to O-dimethyl hydroxyl amine hydrochlorate under blanket of nitrogen with 2-amino-3-phenyl-6-(carboxyl) imidazo [1,2-a]-pyridine.(123g is 0.951mol) and with mixture stirring at room 30 minutes to add diisopropyl ethyl amine.Add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (122g, 0.634mol) stirring at room 19 hours then.Vacuum is steamed except that DMF and with residue and is poured in the 4L water.With water layer with dichloromethane extraction (3 * 500ml) and with organic extract liquid salt water washing, use dried over sodium sulfate, filter vacuum concentration then.Residue is added in the 400ml ethyl acetate then stirring at room 1 hour to form precipitation.Leach precipitation and wash with cold ethyl acetate.Filter cake is obtained the 55.5g product in 40 ℃ of vacuum dryings.(59．2％)。MS(FD)，NMR。
Preparation example 137
The 2-iodine pyridine
With the 2-bromopyridine (48.0g, 303mmol) and the hydroiodic acid solution of the 240ml 47% 8 hours stirring at room 3.5 days then that reflux.Pour reactant mixture in the sodium hydrate aqueous solution (240ml40%NaOH and 250g ice).With mixture with extracted with diethyl ether (3 * 200ml), then with ether with the water washing of 100ml salt, use dried over sodium sulfate, filter vacuum concentration then.With residue vacuum distilling twice, the fraction between collecting 83 and 88 ℃ obtains the 18.6g product.(30％)。EA，MS(FD)。
Preparation example 138
The 4-iodine pyridine
(50.0g 257mmol) obtains 32.9g according to being transformed into product with preparation example 137 basic similarly modes with the 4-bromopyridine hydrochloride.(62．4％)。MS(FD)，NMR。
Preparation example 139N-(3-phenyl-6-[N-methyl-N-carbamoyl] imidazo [1,2-a] pyridine-2-yl)-2,
2,5,5-tetramethyl-1-azepine-2,5-two sila cycloalkanes alkane
(0.592g 2.00mmol) is suspended in the 20ml dimethylbenzene with 2-amino-3-phenyl-6-(N-methyl-N-methoxyl group carbamoyl) imidazo [1,2-a] pyridine.Add 1,1 ' ethylene (N, N, 1,1-tetramethylsilane alkanamine) (1.227g, 5.28mmol) and zinc iodide (10mg is 0.031mmol) and with mixture heated backflow 4 hours.Vacuum is steamed and is desolventized, and crude product is directly used in subsequent reaction without being further purified.
Preparation example 140
1-carbamoyl methyl isophthalic acid, 2-dihydro-2-tosyl imino group-6-benzoyl pyridine
To stir 1,2-dihydro-2-tosyl imino group-5-benzoyl pyridine (11.65g, add in the dry DMF solution of 100ml 32.10mmol) diisopropyl ethyl amine (6.34ml, 34.2mmol).After 15 minutes, solution becomes clarification.Add then iodoacetamide (6.74g, 34.2mmol).Mixture was stirred 24 hours, pour in the water (2L) then and continue and stirred 1 hour.The collection solid dries then and obtains 13.15g (97%) white solid.EIMS，NMR。
Preparation example 141
Diethyl-(N-methyl-carbamyl ylmethyl) phosphonate ester
(aqueous solution, 8.3ml methanol solution 47mmol) are cooled to-78 ℃ with 4.12ml 40% methylamine.In 10 minutes, drip phosphine acyl acetic acid three ethyl (8.85ml, 44.2mmol).Reactant mixture is warming up to room temperature, under this temperature, stirs 29 hours (TLC: ethanol/methylene: 1/9) then.Desolventize in 35 ℃ of vacuum steamings, the colourless liquid that obtains is carried out purification (0.5mmHg/130 ℃) by distillation.(87％)。NMR。
Preparation example 142
Isopropyl mercaptan-sulfonic acid isopropyl ester
iPr-S(O)
2-S-(iPr)
In 30 minutes to diisopropyl propanethiol sulphonic acid ester (10.0g, in 55ml acetic acid solution 66.5mmol) in 0 ℃ drip down 33% hydrogen peroxide (14.4g, 140mmol).After the stirring at room 24 hours, evaporating solvent to dry doubling obtains 8.5g colorless oil product with crude product oil by column chromatography purification (ethyl acetate/hexane).(70％)。
1H-NMR，
13C-NMR。
Preparation example 1431-carbamoyl methyl isophthalic acid, 2-dihydro-2-tosyl imino group-6-(methoxycarbonyl group) pyridine
With 1, (20g 65.3mmol) is suspended among the exsiccant DMF (120ml) and under nitrogen atmosphere and stirs 2-dihydro-2-tosyl imino group-5-methoxycarbonyl group pyridine.Add diisopropyl ethyl amine (125.2ml, 71.82mmol) and the 2-iodoacetamide (13.28g is 71.82mmol) and with reactant mixture stirring at room 24 hours.Pour into reactant liquor in the water (60ml) and stirred 90 minutes.Solid collected by filtration, water (1L) and ether (200ml) washing, vacuum drying obtains the required product of 21.8g (91.7%) white solid then.MS(FAB)，NMR。
Preparation example 144
2-trifluoroacetamido-6-methoxycarbonyl group-imidazo [1,2-a] pyridine
Under the argon atmospher, to 1-carbamoyl methyl isophthalic acid, 2-dihydro-2-tosyl imino group-6-(methoxycarbonyl group) pyridine (5.00g, add in dry methylene chloride 13.8mmol) (75ml) solution trifluoroacetic anhydride (60ml, 425mmol).The solution that forms was refluxed 3 hours.Vacuum is steamed and is desolventized.Residue is added in the ethyl acetate (150ml) also with this suspension stirring 30 minutes.Collect solid, pour in the water (50ml) and stirred 30 minutes.Collection solid vacuum drying then obtains 1.92g (49%) white solid product.MS(FAB)，NMR。
Preparation example 1452-trifluoroacetamido-6-(N-methoxyl group N-methyl acylamino-)-imidazo [1,2-a] pyridine
In 20 minutes, to cold (20 ℃) 2-trifluoroacetamido-6-methoxycarbonyl group-imidazo [1,2-a] pyridine (1.50g, 5.23mmol) and N, O-dimethylamino hydrochlorate (893mg, 9.15mmol) 30ml THF solution in drip isopropylmagnesium chloride (12.0ml, 24.1mmol).Reactant mixture was stirred 1 hour in-20 ℃.Steaming desolventizes, and residue is dissolved in ethyl acetate and washs with saturated ammonium chloride.With the organic extract liquid drying (sodium sulfate) that merges then vacuum steam to desolventize and obtain 1.23g white solid (75%).HRMS value of calculation C
12H
11N
4O
3F
3: 316.0783.Measured value: 316.0782, NMR.
Preparation example 1462-trifluoroacetamido-3-phenyl-6-(N-methyl-N-methoxyl group carbamoyl)-imidazo [1,2-a] pyridine
(12.0g 33mol) obtains the 8.0g product according to being transformed into product with preparation example 189 basic similarly modes with 2-trifluoroacetamido-3-phenyl-6-methoxycarbonyl group-imidazo [1,2-a] pyridine.(68％)。MS(FAB)，NMR。
Preparation example 147
2-chloro-5-(N-methyl-N-methoxyl group carbamoyl) pyridine
To 2,6-dichloro nicotine (880mg, add in 20ml acetone soln 5mmol) N-methoxyl group-N-methylamino hydrochlorate (500mg, 5.13mmol) diisopropyl ethyl amine (1.33g, 10.2mmol).Reactant mixture was stirred 10 minutes.The vacuum steaming desolventizes and the residue that obtains is obtained 950mg oily product by the column chromatography purification.(95％)。
Preparation example 148
2-chloro-5-(1-phenyl-2-N-methylamino formoxyl vinyl) pyridine
Under 0 ℃ and the argon atmospher, (9.2g adds (N-methylamino formoxyl methyl) diethyl phosphonate (4.81g, the dry DMF solution of 50ml 23.0mmol) in the dry DMF solution of 25ml 46mmol) to hexamethyldisilane base potassium azide.With reactant mixture in 0 ℃ of stir about 2 hours.Add 2-chloro-5-benzoyl pyridine (2.5g, the dry DMF solution of 25ml 11.5mmol) by sleeve pipe.Remove ice bath, the brown solution that forms is warming up to room temperature and stirred 16 hours.Ethyl acetate extraction is handled and used to mixture with saturated ammonium chloride (30ml).Merge organic layer and, use the salt water washing then with the saturated ammonium chloride washing.After dried over sodium sulfate, the vacuum steaming desolventizes and the residue that obtains is obtained 1.5g (50%) E by chromatographic column (hexane/ethyl acetate 1: 1): the mixture of Z isomer (1: 1.5).Crystallization Separation is passed through in isomer.The Z-isomer, IR, NMR, E-isomer, IR, NMR.
Preparation example 149
2-chloro-5-(2, the 3-difluoro benzoyl) pyridine
Under-78 ℃, to 1-bromo-2,3-two fluorobenzene (0.114g, add in 3ml dry THF solution 0.746mmol) n-BuLi (hexane solution of 1.6M, 0.47ml, 0.749mmol).Reactant mixture was stirred 1 hour under this temperature.(0.13g, 5ml THF solution 0.68mmol) are warming up to room temperature with reactant mixture and stirred 6 hours to add 6-chloro-N-methoxyl group-N-methyl-nicotiamide.Add saturated ammonium chloride and with mixture with dichloromethane extraction (3 * 10ml).Merge organic layer, use dried over sodium sulfate then with the salt water washing.The vacuum steaming desolventizes and residue is obtained 130mg (77%) oily product by column chromatography purification (hexane/ethyl acetate 9: 1).IR，NMR。
Preparation example 1502-chloro-5-(1-(2, the 3-difluorophenyl)-2-N-methylamino formoxyl vinyl) pyridine
2-chloro-5-(2, the 3-difluoro benzoyl) pyridine is obtained two kinds of mixture of isomers according to being transformed into product with preparation example 203 basic similarly modes.After re-crystallizing in ethyl acetate, isolate Z isomer with 35% yield, IR, NMR, E isomer then reclaim with 17% yield from filtrate and obtain IR, NMR.
Preparation example 1511-(2-oxo-2-phenylethyl)-2-chloro-5-[(E)-and 1-phenyl-2-methylamino formoxyl vinyl] the pyridine iodide
To 2-chloro-5-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl] pyridine (100mg, 0.367mmol) and bromoacetophenone (0.270g, 1.35mmol) add in the mixture in the 5ml acetonitrile NaI (0.21g, 1.4mmol).With reaction mixture refluxed 40 hours.Vacuum is steamed the ethanol (40-45 ℃) that removes acetonitrile and the residue that obtains is dissolved in heat.After filtering fast, wash with the 100ml ether, obtain solid, shaped product, yield 85% with cold ethyl acetate washing then with the filtrate vacuum concentration and with the solid that obtains.IR，NMR。
Preparation example 1521-[2-oxo-2-(4-fluorophenyl) ethyl]-2-chloro-5-[(E)-1-phenyl-2-methylamino formoxyl vinyl] the pyridine iodide
With 2-chloro-5-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl] (300mg 1.10mmol) obtains the 395mg product with 4-bromofluorobenzene ethyl ketone according to being transformed into product with preparation example 151 basic similarly modes to pyridine.(67％)IR，NMR。
Preparation example 1531-[2-oxopropyl]-2-chloro-5-[(E)-1-phenyl-2-methylamino formoxyl vinyl] the pyridine iodide
With 2-chloro-5-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl] (300mg 1.10mmol) obtains 297 mg products with chlroacetone according to being transformed into product with preparation example 151 basic similarly modes to pyridine.(60％)。NMR。
Preparation example 1541-[2-oxo-3, the 3-dimethylbutyl]-2-chloro-5-[(E)-1-phenyl-2-methylamino formoxyl vinyl] the pyridine iodide
With 2-chloro-5-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl] (300mg 1.10mmol) obtains the 141mg product with the chlorine pinacoline according to being transformed into product with preparation example 151 basic similarly modes to pyridine.(26％)。IR。
Preparation example 1551-(N, N-diethyl acetylamino)-2-chloro-5-[(E)-and 1-phenyl-2-methylamino formoxyl vinyl] the pyridine iodide
With 2-chloro-5-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl] (140mg, 0.514mmol) with 2-chloro-N, the N-diethyl acetamide obtains the 75.9mg product according to being transformed into product with preparation example 151 basic similarly modes to pyridine.(29％)。NMR。
Preparation example 1561-[2-oxo-3, the 3-dimethylbutyl]-2-chloro-5-[(E)-1-(2, the 3-difluorophenyl)-2-methylamino formoxyl vinyl] the pyridine iodide
With 2-chloro-5-[(E)-1-(2, the 3-difluorophenyl)-2-N-methylamino formoxyl vinyl] pyridine (250mg, 0.810mmol) and the chlorine pinacoline according to being transformed into product with the basic similarly modes of preparation example 151, obtain the 199mg product.(46％)。IR。
Embodiment 12-trifluoroacetamido-3-(2, the 5-difluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[2,5-difluorophenyl]-carbamyl ylmethyl)-pyridine (14.9 g, 28.6mmol) be dissolved in the 400ml dichloromethane and add trifluoroacetic anhydride (50ml, 354mmol).Solution is heated to backflow (using dry-ice condenser to keep the backflow of volatile matter) and stirred 3 hours.The vacuum steaming desolventizes and residue is added in the 700ml ethyl acetate.With solution with saturated sodium bicarbonate (3 * 100ml) and saline (3 * 100ml) wash, and use dried over sodium sulfate, filter vacuum concentration then.Crude product is obtained the 12.1g product with the ethyl acetate/hexane recrystallization.(94．6％)。EA，MS(FD)。
Embodiment 22-trifluoroacetamido-3-(4-methoxyphenyl)-6-benzoyl-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[4-methoxyphenyl]-the carbamyl ylmethyl)-(13.2g 23.3mmol) obtains the 10.6g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(92％)。EA，MS(FD)。
Embodiment 32-trifluoroacetamido-3-(naphthalene-2-yl)-6-benzoyl-imidazo [1.2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[naphthalene-2-yl]-the carbamyl ylmethyl)-(14.7g 27.4mmol) obtains the 10.4g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(82．4％)。EA，MS(FD)。
Embodiment 4
2-trifluoroacetamido-3-naphthyl-6 benzoyls-imidazo [1,2-a] pyridine
With 1, (11.3g 22.0mmol) obtains the 8.25g product according to being transformed into product with embodiment 1 basic similarly mode to 2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-naphthyl-carbamyl ylmethyl)-pyridine.(82％)。EA，MS(FD)。
Embodiment 5
2-trifluoroacetamido-3-(2-fluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[2-fluorophenyl]-the carbamyl ylmethyl)-(12.3g 24.5mmol) obtains the 10.2g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(97％)．EA，MS(FD)。
Embodiment 62-trifluoroacetamido-3-(3-fluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[3-fluorophenyl]-the carbamyl ylmethyl)-(26.6g 52.8mmol) obtains the 21.6g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(95．8％)。EA，MS(FD)。
Embodiment 72-trifluoroacetamido-3-(2,4 difluorobenzene base)-6-benzoyl-imidazo [1,2-a] pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[2; the 4-difluorophenyl]-the carbamyl ylmethyl)-pyridine (11.0g, 21.1mmol) according to implement 1 basic similarly mode and be transformed into product and obtain the 9.24g product. (98.5%).EA，MS(FD)。
Embodiment 82-trifluoroacetamido-3-(3, the 5-difluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[3,5-difluorophenyl]-the carbamyl ylmethyl)-(13.3g 25.6mmol) obtains the 10.2g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(90．1％)。EA，MS(FD)。
Embodiment 9 2-trifluoroacetamido-3-(4-fluorophenyl)-6-benzoyl imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[4-fluorophenyl]-the carbamyl ylmethyl)-(35.0g 69.6mmol) obtains the 18.6g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(62．7％)。EA，MS(FD)。
Embodiment 102-trifluoroacetamido-3-(3-trifluoromethyl)-6-benzoyl-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[3-trifluoromethyl]-the carbamyl ylmethyl)-(13.3g 24.1mmol) obtains the 9.08g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(80％)。EA，MS(FD)。
Embodiment 11 2-trifluoroacetamido-3-(4-bromophenyl)-6-benzoyl-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[4-bromophenyl]-the carbamyl ylmethyl)-(12.7g 22.5mmol) obtains the 10.5g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(95．4％)。EA，MS(FD)。
Embodiment 122-trifluoroacetamido-3-(2,3, the 4-trifluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[2,3,4-trifluorophenyl]-the carbamyl ylmethyl)-(11.3g 20.9mmol) obtains the 8.43g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(87％)。EA，MS(FD)。
Embodiment 132-trifluoroacetamido-3-(3, the 4-difluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[3,4-fluorophenyl]-the carbamyl ylmethyl)-(9.53g 18.3mmol) obtains the 7.44g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(91％)。EA，MS(FD)。
Embodiment 142-trifluoroacetamido-3-(3, the 4-Dichlorobenzene base)-6-benzoyl-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[3,4-Dichlorobenzene base]-the carbamyl ylmethyl)-(13.8g 24.9mmol) obtains the 9.91g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(83％)。EA，MS(FAB)。
Embodiment 152-trifluoroacetamido-3-(2,4, the 5-trifluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[2,4,5-trifluorophenyl]-the carbamyl ylmethyl)-(11.6g 21.5mmol) obtains the 9.28g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(93％)。EA，MS(FD)。
Embodiment 162-trifluoroacetamido-3-(2-chlorphenyl)-6-benzoyl-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[2-chlorphenyl]-the carbamyl ylmethyl)-(14.2g 27.3mmol) obtains the 10.8g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(88％)。EA，MS(FD)。
Embodiment 17 2-trifluoroacetamido-3-(3-chlorphenyl)-6-benzoyl-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[3-chlorphenyl]-the carbamyl ylmethyl)-(12.0g 23.1mmol) obtains the 8.97g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(88％)。EA，MS(FD)。
Embodiment 18 2-trifluoroacetamido-3-(4-chlorphenyl)-6-benzoyl-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[4-chlorphenyl]-the carbamyl ylmethyl)-(13.8g 26.5mmol) obtains the 10.7g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(91％)。EA，MS(FD)。
Embodiment 192-trifluoroacetamido-3-(4-Trifluoromethoxyphen-l)-6-benzoyl-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[4-Trifluoromethoxyphen-l]-the carbamyl ylmethyl)-(13.2g 23.3mmol) obtains the 10.6g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(92％)。EA，MS(FD)。
Embodiment 202-trifluoroacetamido-3-(3-Trifluoromethoxyphen-l)-6-benzoyl-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[3-Trifluoromethoxyphen-l]-the carbamyl ylmethyl)-(12.5g 22.0mmol) obtains the 10.4g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(96％)。EA，MS(FD)。
Embodiment 212-trifluoroacetamido-3-(2-fluoro-4-trifluoromethyl)-6-benzoyl-imidazo [1,2-a] pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[2-fluoro-4-trifluoromethyl]-the carbamyl ylmethyl)-(10.1g 17.7mmol) obtains the 8.03g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(92％)。EA，MS(FD)。
Embodiment 22
2-trifluoroacetamido-3-phenyl-6-benzoyl-imidazo [1,2-a] pyridine
With 1, (13.3g 27.3mmol) obtains the 10.0g product according to being transformed into product with embodiment 1 basic similarly mode to 2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-phenyl-carbamyl ylmethyl)-pyridine.(90％)。EA，MS(FD)。
Embodiment 232-trifluoroacetamido-3-(2, the 6-difluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[2,6-difluorophenyl]-the carbamyl ylmethyl)-(7.44g 14.3mmol) obtains the 5.26g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(82．8％)。EA，MS(FD)。
Embodiment 242-trifluoroacetamido-3-(2,3,4,5, the 6-pentafluorophenyl group)-6-benzoyl-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[2,3; 4; 5, the 6-pentafluorophenyl group]-the carbamyl ylmethyl)-(3.00g 5.22mmol) obtains the 1.58g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(60．8％)。EA，MS(FD)。
Embodiment 252-trifluoroacetamido-3-(2-trifluoromethyl)-6-benzoyl-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[2-trifluoromethyl]-the carbamyl ylmethyl)-(7.37g 13.3mmol) is transformed into product according to mode similar to Example 1 substantially and obtains the 6.22g product pyridine.(98％)。EA，MS(FD)。
Embodiment 26 2-trifluoroacetamido-3-(thiene-3-yl-)-6-benzoyl imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[thiene-3-yl-]-the carbamyl ylmethyl)-(11.4g 23.1mmol) obtains the 8.88g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(92．6％)。EA，MS(FD)。
Embodiment 272-trifluoroacetamido-3-(2-trifluoromethyl-4-fluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[2-trifluoromethyl-4-fluorophenyl]-the carbamyl ylmethyl)-(14.5g 25.3mmol) obtains the 11.0g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(88％)。EA，MS(FD)。
Embodiment 282-trifluoroacetamido-3-(2-fluoro-6-trifluoromethyl)-6-benzoyl-imidazo [1,2-a] pyridine
With 1; 2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-[2-fluoro-6-trifluoromethyl]-the carbamyl ylmethyl)-(2.90g 5.08mmol) obtains the 2.37g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(94％)。EA，MS(FD)。
Embodiment 292-trifluoroacetamido-3-(4-trifluoromethyl)-6-benzoyl-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[4-trifluoromethyl]-the carbamyl ylmethyl)-(13.3g 24.1mmol) obtains the 10.1g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(88．1％)。EA，MS(FD)。
Embodiment 302-trifluoroacetamido-3-(2-methoxyphenyl)-6-benzoyl-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[2-methoxyphenyl]-the carbamyl ylmethyl)-(10.4g 20.3mmol) obtains the 7.40g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(83％)。EA，MS(FD)。
Embodiment 312-trifluoroacetamido-3-(4-methoxycarbonyl group phenyl)-6-benzoyl-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[2-methoxyphenyl]-the carbamyl ylmethyl)-(15.5g 28.5mmol) obtains the 12.6g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(94．5％)。EA，MS(FD)。
Embodiment 322-trifluoroacetamido-3-(4-nitrobenzophenone)-6-benzoyl-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-benzoyl-N-(the 1-[2-methoxyphenyl]-the carbamyl ylmethyl)-(15.3g 28.9mmol) obtains the 11.2g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(85．1％)。EA，MS(FD)。
Embodiment 33
2-trifluoroacetamido-3-benzyl-6-benzoyl-imidazo [1,2-a] pyridine
With 1, (3.44g 6.89mmol) obtains the 2.19g product according to being transformed into product with embodiment 1 basic similarly mode to 2-dihydro-2-tosyl imino group-5-benzoyl-N-(1-benzyl-carbamyl ylmethyl)-pyridine.(74．0％)。EA，MS(FD)。
Embodiment 34
2-trifluoroacetamido-3-isobutyl group-6-benzoyl-imidazo [1,2-a] pyridine
With 1, (3.30g 7.09mmol) obtains the 2.37g product according to being transformed into product with embodiment 1 basic similarly mode to 2-two-hydrogen-2-tosyl imino group-5-benzoyl-N-(1-isobutyl group-carbamyl ylmethyl)-pyridine.(85．9％)。EA，MS(FD)。
Embodiment 352-trifluoroacetamido-3-(4-fluorophenyl)-6-(4-fluoro benzoyl)-imidazo [1,2-a] pyridine
With 1,2-dihydro-2-tosyl imino group-5-(4-fluoro benzoyl)-N-(the 1-[4-fluorophenyl]-the carbamyl ylmethyl)-(9.15g 17.6mmol) obtains the 7.11g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(91％)。EA，MS(FD)。
Embodiment 362-trifluoroacetamido-3-(2-fluoro-4-trifluoromethyl)-6-(4-fluoro benzoyl)-imidazo [1,2-a] pyridine
With 1; 2-dihydro-2-tosyl imino group-5-(4-fluoro benzoyl)-N-(1-[2-fluoro-4-trifluoromethyl]-the carbamyl ylmethyl)-(8.95g 15.2mmol) obtains the 6.75g product according to being transformed into product with embodiment 1 basic similarly mode to pyridine.(87％)。EA，MS(FD)。
Embodiment 37
2-trifluoroacetamido-6-benzoyl-imidazo [1,2-a] pyridine
To 1-carbamoyl methyl isophthalic acid, 2-dihydro-2-tosyl imino group-6-benzoyl pyridine (7.15g, add in 85ml dry methylene chloride suspension 17.46mmol) trifluoroacetic anhydride (62ml, 439mmol).Mixture was stirred 2.5 hours in 30 ℃ under argon atmospher.Vacuum is steamed and to be desolventized and foam is added ethyl acetate (600ml), use then sodium bicarbonate (2 * 250ml) and saline (1 * 250ml) washs.With organic layer drying (sodium sulfate) then vacuum steam to desolventize and obtain 5.5g (92%) white solid product.EIMS，NMR。
Embodiment 38
2-trifluoroacetamido-3-iodo-6-benzoyl-imidazo [1,2-a] pyridine
To be cooled to 0 ℃ 2-trifluoroacetamido-6-benzoyl-imidazo [1,2-a] pyridine (2.0g, add in the dry acetonitrile solution of 6.0mmol) 50ml in batches N-iodosuccinimide (1.35g, 6.0mmol).Mixture was stirred 10 minutes. vacuum is steamed and is removed acetonitrile and residue is dissolved in ethyl acetate (250ml), uses NaHSO
3(40%p/v, 2 * 200ml) and NaHCO
3(2 * 200ml) washings.With organic layer drying (sodium sulfate) then vacuum steam to remove ethyl acetate and obtain 2.60g (95%) yellow solid shape product.EIMS，NMR。
Embodiment 39
2-trifluoroacetamido-3-methyl mercapto-6-benzoyl-imidazo [1,2-a] pyridine
(1.00g 2.17mmol) is dissolved in the 20ml pyridine and (uses the KOH drying in advance, use the 3A molecular sieve drying then, 0.04%H under argon atmospher with 2-trifluoroacetamido-3-iodo-6-benzoyl-imidazo [1,2-a] pyridine
2O).The adding bronze (207mg, 3.25mol).By syringe in the brown solution of golden float, add methyl disulfide (160 μ l, 2.17mmnol).Reactant mixture in 104 ℃ of heating 1 hour, was heated 68 hours in 100 ℃ then.Progress by the NMR monitoring reaction (is taken out sample, hydrolysis and usefulness ammonia/NH
4Cl (1: 9) washing detects by NMR then).When reaction finishes, reactant mixture diluted in the 3L ethyl acetate stirred then 15 minutes.Add 2L NH
4OH/NH
4Cl (1: 9) is then with mixture vigorous stirring 30 minutes in the funnel of 10L.Separatory adds 2L NH in organic layer
4OH/NH
4Cl (1: 9).Mixture was stirred 30 minutes once more static then 5 to 10 minutes.Separatory is with organic layer salt water washing.With organic layer vacuum evaporation, the brown solid of residue is carried out extremely fast column chromatography (MeOH/CH
2Cl
2, 2: 98) and obtain 670mg (81%) brown solid.NMR。
Embodiment 40
2-trifluoroacetamido-3-methyl sulphonyl-6-benzoyl-imidazo [1,2-a] pyridine
With 2-trifluoroacetamido-3-methyl mercapto-6-benzoyl-imidazo [1,2-a] pyridine (500mg, 1.37mmol) and mCPBA (563mg 2.62mmol) mixes in the 20ml dry methylene chloride.Reactant mixture in 0 ℃ of stirring 3 hours, is washed with the 1ml saturated sodium bicarbonate then.Mixture is washed with diatomite filtration and with ethyl acetate.Obtain the white yellow solid of 385mg (67%) with the filtrate vacuum concentration and with residue by the column chromatography purification.NMR。
Embodiment 41
2-trifluoroacetamido-3-iprotiazem base-6-benzoyl-imidazo [1,2-a] pyridine
(100mg 0.22mmol) is dissolved in exsiccant pyridine (10ml) under room temperature and argon atmospher with 2-trifluoroacetamido-3-iodo-6-benzoyl-imidazo [1,2-a] pyridine.Add bronze (21mg, 0.33mmol), add then diisopropyl disulfide (35 μ l, 0.22mmol).With mixture in 100-102 ℃ of agitating heating 83 hours.Reactant liquor is cooled to room temperature, pours in the 1L ethyl acetate and stirred 1 hour.The NN that adds 9: 1 then
4Cl/NH
4OH solution (750ml) also stirs mixture 15 minutes with mechanical agitator.Water layer becomes light blue, and organic extract liquid is used 9: 1 NH of 750ml once more
4Cl/NH
4OH solution washing (15 minutes) is used salt water washing (750ml) then.Vacuum is steamed and is removed ethyl acetate and residue is passed through purification by flash chromatography (ethyl acetate: hexane 1: 1).Yield with 20% (18mg) obtains brown oily product.
1H-NMR，
13C-NMR。
Embodiment 422-trifluoroacetamido-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
(1.88g 9.00mmol) places under argon atmospher with flame-dried flask with the exsiccant THF of 250ml with diethyl-(N-methylamino formoxyl methyl) phosphate ester.Solution is cooled to-78 ℃, drips two TMS potassamide (30ml, 22.5mmol then; 0.5M toluene solution).Mixture was stirred 2 hours in-78 ℃.Drip 2-trifluoroacetamido-6-benzoyl-imidazo [1,2-a] pyridine (2.00g, 100ml dry THF solution 6.00mmol).Reactant mixture in-78 ℃ of stirrings 2 hours, is warming up to room temperature then.With the brown solution stirring at room that forms 60 hours.Vacuum is steamed and is removed THF, and residue is added in the 400ml ethyl acetate, uses saturated NH
4(2 * 100ml) washings are used the salt water washing once to Cl then.After dried over mgso, vacuum is steamed to desolventize and is obtained brown solid.NMR to crude product only the analysis showed that " E " isomer and some other are arranged without the by-product of identifying.With crude product by column chromatography purification (acetonitrile: dichloromethane (2: 1)) obtain 920mg (40%) product.EIMS，NMR。
Embodiment 432-trifluoroacetamido-3-iodo-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
To 2-trifluoroacetamido-the 6-[(E)-2-N-5-methylamino formoxyl-1-phenyl vinyl that is cooled to 0 ℃]-imidazo [1; 2-a] pyridine (423mg; 1.22mmol) the dry acetonitrile solution of 20ml in add N-iodosuccinimide (1.34mmol in batches; 302mg), then mixture was stirred 10 minutes.Required product is separated out white solid precipitation, leaches precipitation and dries then and obtain the 375mg crude product.Vacuum is steamed and is removed acetonitrile and residue is dissolved in ethyl acetate (50ml).With ethyl acetate with sodium bisulfate (40%p/v) (2 * 50ml) and sodium bicarbonate (2 * 50ml) wash.With organic layer drying (sodium sulfate) then vacuum steam to remove ethyl acetate and obtain 240mg (98% total recovery) white solid product.EIMS，NMR。
Embodiment 442-trifluoroacetamido-3-isopropyl sulfonyl base-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
Under the argon atmospher; to the 2-trifluoroacetamido-3-iodo-6-[(E that is cooled to 0 ℃)-2-N-methylamino formoxyl-1-phenyl vinyl]-imidazo [1; 2-a] pyridine (70mg, and adding phenyl reason in 5ml THF solution 0.15mmol) (230 μ l, 0.33mmol).Reactant mixture was stirred 3 minutes, inject then tert-butyl lithium (310 μ l, 0.38mmol).Stir after 10 minutes, add isopropyl mercaptan sulfonic acid isopropyl ester (109mg, 5ml THF solution 0.60mmol).Reactant mixture in-78 ℃ of stirrings 30 minutes, is dripped and 10ml THF cessation reaction with 2 then.Add ethyl acetate (15ml) and make mixture be warming up to room temperature.With the solution diatomite filtration, vacuum is steamed and is desolventized then.Residue is dissolved in exsiccant dichloromethane (10ml) and is cooled to 0 ℃.Dichloromethane (40ml) solution that drips pre-dry mCPBA (208mg, 5 equivalents are excessive, with the 100% theoretical yield calculating of sulfide coupled product) then changes into sulfone (TLC monitoring) fully until raw material.Then solution is used (2 * 50ml) washings of sodium sulfite (50ml) and sodium bicarbonate.With organic layer drying (sodium sulfate) then vacuum steam and to desolventize.With residue by fast silica gel chromatogram purification (acetonitrile: dichloromethane 1: 1) obtain 47mg white solid product.(63％)。NMR。
Embodiment 45
2-trifluoroacetamido-6-(2, the 3-difluoro benzoyl)-imidazo [1,2-a] pyridine
Under-78 ℃ and the argon atmospher, to 1-bromo-2, (480ml adds n-BuLi (2.05ml, 10ml dry THF solution 4.42mmol) to 3-two fluorobenzene in THF solution 4.32mmol).Stir after l0 minute, drip 2-trifluoroacetamido-6-(N-methoxyl group-N-methyl nitrosourea base)-imidazo [1,2-a] pyridine (513mg, THF 1.88mmol) (15ml) solution.Reactant mixture was stirred 1 hour in-78 ℃.Add ammonium chloride then and, use ammonium chloride (2 * 20ml) washings then reactant liquor ethyl acetate (25ml) extraction.Vacuum is steamed and to be desolventized, with residue by fast silica gel chromatogram purification (dichloromethane: acetonitrile 2.5: 1) obtain 395mg white solid product.(57％)。EIMS，NMR。
Embodiment 462-trifluoroacetamido-6-[(E)-1-(2, the 3-difluorophenyl)-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
(0.454g 1.27mmol) obtains the 120mg product according to being transformed into product with preparation example 183 basic similarly modes with 2-trifluoroacetamido-6-(2, the 3-difluoro benzoyl)-imidazo [1,2-a] pyridine.(23％)。
1H-NMR，
13C-NMR。
Embodiment 472-trifluoroacetamido-3-iodo-6-[(E)-1-(2, the 3-difluorophenyl)-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
To 2-trifluoroacetamido-the 6-[(E)-1-(2 that is cooled to 0 ℃; the 3-difluorophenyl)-2-N-methylamino formoxyl vinyl]-imidazo [1; 2-a] pyridine (116mg, add in the dry acetonitrile solution of 0.27mmol) 10ml in batches N-iodosuccinimide (67mg, 0.30mmol).Reactant mixture was stirred 15 minutes.Vacuum is steamed and is desolventized, and residue is dissolved in ethyl acetate (25ml), and (sodium bicarbonate (2 * 25ml) washings are used in 40%p/v, 2 * 25ml) washings then with hydrogen phosphite sodium.With organic layer drying (sodium sulfate) then vacuum steam to remove ethyl acetate, obtain 130mg (86%) product.
1H-NMR，
13C-NMR。
Embodiment 482-trifluoroacetamido-3-phenyl-6-(2, the 3-difluoro benzoyl)-imidazo [1,2-a] pyridine
Under-78 ℃ to 2, the 3-difluoro bromobenzene (471ml, add in dry THF 4.206mmol) (20ml) solution n-butyllithium solution (hexane solution of 1.6M, 2.63ml).The yellow solution that forms was stirred 70 minutes under identical temperature; drip 2-trifluoroacetamido-3-phenyl-6-(N-methyl-N-methoxyl group carbamoyl) imidazo [1 by conduit then; 2-a] pyridine (0.500g, dry THF 1.28mmol) (20ml) solution.Reddish orange solution was heated up in 60 minutes.Add saturated ammonium chloride and, use ethyl acetate extraction then mixture stirring 25 minutes.With organic layer salt water washing, dry (sodium sulfate), vacuum concentration obtains the 390mg orange solids by column chromatography purification (dichloromethane/acetonitrile 4/1) then.(69％)。MS(FAB)，NMR。
Embodiment 492-trifluoroacetamido-3-phenyl-6-[(E)-1-(2, the 3-difluorophenyl)-2-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
With diethyl-(217mg, 250ml dry THF solution 1.04mmol) places under argon atmospher with in the flame-dried flask (N-methylamino formoxyl methyl) phosphonate ester.Solution is cooled to-78 ℃, drips two TMS potassamide solution (5.13ml, 2.56mmol then; 0.5M toluene solution).Mixture was stirred 2 hours in-78 ℃.Drip 2-trifluoroacetamido-3-phenyl-6-(2, the 3-difluoro benzoyl)-imidazo [1,2-a] pyridine (300mg, 100ml dry THF solution 0.693mmol).Reactant mixture in-78 ℃ of stirrings 2 hours, is warming up to room temperature then.With 48 hours (the needing a large amount of solvents) of brown solution stirring at room that forms to prevent reactant the being mixed heterogenetic solvent of back formation.Vacuum steam to remove THF and with mixture with the dilution of 400ml ethyl acetate, with the saturated ammonium chloride washing (2 * 100ml), use the salt water washing then once.After dried over mgso, vacuum is steamed to desolventize and is obtained brown solid.Residue is obtained the 57.6mg product by column chromatography purification (acetonitrile: dichloromethane, 2: 1).(22％)。
1HNMR，
13C?NMR。
Embodiment 502-trifluoroacetamido-3-phenyl-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
(618mg 1.27mmol) obtains the 526mg product according to being transformed into product with embodiment 49 basic similarly modes with 2-trifluoroacetamido-3-phenyl-6-benzoyl-imidazo [1,2-a] pyridine.(75％)。EIMS，NMR。
Embodiment 512-trifluoroacetamido-3-(2, the 5-difluorophenyl)-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
(500rng 1.15mmol) obtains the 483mg product according to being transformed into product with embodiment 49 basic similarly modes with 2-trifluoroacetamido-3-(2, the 5-difluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(86％)。EIMS，NMR。
Embodiment 522-trifluoroacetamido-3-(2-trifluoromethyl-4-fluorophenyl)-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
(500mg 1.04mmol) obtains the 439mg product according to being transformed into product with embodiment 49 basic similarly modes with 2-trifluoroacetamido-3-(2-trifluoromethyl-4-fluoro-phenyl)-6-benzoyl imidazo [1,2-a] pyridine.(79％)。EIMS，NMR。
Embodiment 532-trifluoroacetamido-3-(2,3, the 4-trifluorophenyl)-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
(303mg 0.672mmol) obtains the 168mg product according to being transformed into product with embodiment 49 basic similarly modes with 2-trifluoroacetamido-3-(2,3, the 4-trifluorophenyl)-6-benzoyl imidazo [1,2-a] pyridine.(50％)。NMR。
Embodiment 54
2-trifluoroacetamido-3-(3, the 5-difluorophenyl)-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
(240mg, 0.554mmol) to obtain the 161mg ratio be two kinds of isomer E: Z of 1: 1 according to being transformed into product with the basic similarly modes of embodiment 49 with 2-trifluoroacetamido-3-(3, the 5-difluorophenyl)-6-benzoyl imidazo [1,2-a] pyridine.Yield 60%.EIMS，NMR。
Embodiment 552-trifluoroacetamido-3-(3-trifluoromethyl)-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
(228mg 0.491mmol) obtains the 228mg product according to being transformed into product with embodiment 49 basic similarly modes with 2-trifluoroacetamido-3-(3-trifluoromethyl)-6-benzoyl imidazo [1,2-a] pyridine.(57％)。EIMS，NMR。
Embodiment 56
2-amino-3-(2,4 difluorobenzene base)-6-benzoyl-imidazo [1,2-a] pyridine
(9.24g 20.8mmol) is dissolved in 250ml MeOH and 170ml 1N NaOH with 2-trifluoroacetamido-3-(2,4 difluorobenzene base)-6-benzoyl-imidazo [1,2-a] pyridine.With solution 2 weeks of stirring at room under blanket of nitrogen.Leach precipitation and filter cake is dissolved in the 900ml ethyl acetate.With solution with the salt water washing (3 * 50ml), use dried over sodium sulfate, filter vacuum concentration then.Residue is obtained two batches of products, yield 5.57g with the ethyl acetate/hexane recrystallization.(76．8％)。EA，MS(FD)。
Embodiment 57
2-amino-3-(3, the 5-difluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine
(10.2g 22.9mmol) obtains the 4.93g product according to being transformed into product with embodiment 56 basic similarly modes with 2-trifluoroacetamido-3-(3, the 5-difluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(61．6％)。EA，MS(FD)。
Embodiment 58
2-amino-3-(naphthalene-2-yl)-6-benzoyl-imidazo [1,2-a] pyridine
(6.05g 13.7mmol) obtains the 3.50g product according to being transformed into product with embodiment 56 basic similarly modes with 2-trifluoroacetamido-3-(naphthalene-2-yl)-6-benzoyl-imidazo [1,2-a] pyridine.(70．4％)。MS(FD)，NMR。
Embodiment 59
2-amino-3-naphthyl-6-benzoyl-imidazo [1,2-a] pyridine
(8.25g 18.0mmol) obtains the 4.73g product according to being transformed into product with embodiment 56 basic similarly modes with 2-trifluoroacetamido-3-naphthyl-6-benzoyl-imidazo [1,2-a] pyridine.(73％)。EA，MS(FD)。
Embodiment 60
2-amino-3-(2, the 5-difluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine
(12.1g 27.1mmol) obtains the 6.10g product according to being transformed into product with embodiment 56 basic similarly modes with 2-trifluoroacetamido-3-(2, the 5-difluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(64．6％)。EA，MS(FD)。
Embodiment 61
2-amino-3-(2, the 6-difluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine
(6.01g 13.5mmol) obtains the 3.42g product according to being transformed into product with embodiment 56 basic similarly modes with 2-trifluoroacetamido-3-(2, the 6-difluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(72．6％)。EA，MS(FD)。
Embodiment 62
2-amino-3-(4-trifluoromethyl)-6-benzoyl-imidazo [1,2-a] pyridine
(10.1g 21.2mmol) obtains the 4.43g product according to being transformed into product with embodiment 56 basic similarly modes with 2-trifluoroacetamido-3-(4-trifluoromethyl)-6-benzoyl-imidazo [1,2-a] pyridine.(54．8％)。EA，MS(FD)。
Embodiment 63
2-amino-3-(2-fluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine
(9.46g 22.2mmol) obtains the 6.70g product according to being transformed into product with embodiment 56 basic similarly modes with 2-trifluoroacetamido-3-(2-fluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(91．4％)。EA，MS(FD)。
Embodiment 64
2-amino-3-(3-fluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine
(14.3g 33.6mmol) obtains the 8.30g product according to being transformed into product with embodiment 56 basic similarly modes with 2-trifluoroacetamido-3-(3-fluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(74．7％)。EA，MS(FD)。
Embodiment 65
2-amino-3-(4-fluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine
(18.6g 43.7mmol) obtains the 11.2g product according to being transformed into product with embodiment 56 basic similarly modes with 2-trifluoroacetamido-3-(4-fluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(77．2％)。EA，MS(FD)。
Embodiment 66
2-amino-3-benzyl-6-benzoyl-imidazo [1,2-a] pyridine
(2.14g 5.06mmol) obtains the 1.29g product according to being transformed into product with embodiment 56 basic similarly modes with 2-trifluoroacetamido-3-benzyl-6-benzoyl-imidazo [1,2-a] pyridine.(78．2％)。EA，MS(FD)。
Embodiment 67 2-amino-3-(3-trifluoromethyl)-6-benzoyl-imidazo [1,2-a] pyridine
With 2-trifluoroacetamido-3-(3-trifluoromethyl)-6-benzoyl-imidazo [1,2-a] pyridine (9.39g, 19.7mmol) be dissolved in 200ml MeOH and add diisopropyl ethyl amine (100ml, 574mmol).Solution is heated to backflow, under blanket of nitrogen, refluxes then and stirred 2 days.Obtain the 6.59g product with solution for vacuum concentration and with residue with the ethyl acetate/hexane recrystallization.(87．9％)。EA，MS(FD)。
Embodiment 68
2-amino-3-(4-methoxyphenyl)-6-benzoyl-imidazo [1,2-a] pyridine
(4.89g 11.1mmol) obtains the 3.08g product according to being transformed into product with embodiment 67 basic similarly modes with 2-trifluoroacetamido-3-(4-methoxyphenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(80％)。EA，MS(FD)。
Embodiment 69
2-amino-3-(4-bromophenyl)-6-benzoyl-imidazo [1,2-a] pyridine
(3.00g 6.15mmol) obtains the 1.80g product according to being transformed into product with embodiment 67 basic similarly modes with 2-trifluoroacetamido-3-(4-bromophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(75％)。EA，MS(FD)。
Embodiment 70 2-amino-3-(2,3, the 4-trifluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine
(8.43g 18.2mmol) obtains the 5.82g product according to being transformed into product with embodiment 67 basic similarly modes with 2-trifluoroacetamido-3-(2,3, the 4-trifluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(87％)。EA，MS(FD)。
Embodiment 71
2-amino-3-(3, the 4-difluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine
(7.44g 16.7mmol) obtains the 5.09g product according to being transformed into product with embodiment 67 basic similarly modes with 2-trifluoroacetamido-3-(3, the 4-difluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(87．2％)。EA，MS(FD)。
Embodiment 72 2-amino-3-(3, the 4-Dichlorobenzene base)-6-benzoyl-imidazo [1,2-a] pyridine
(9.91g 20.8mmol) obtains the 7.17g product according to being transformed into product with embodiment 67 basic similarly modes with 2-trifluoroacetamido-3-(3, the 4-Dichlorobenzene base)-6-benzoyl-imidazo [1,2-a] pyridine.(90．4％)。EA，MS(FD)。
Embodiment 73 2-amino-3-(2,4, the 5-trifluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine
(9.28g 20.0mmol) obtains the 7.28g product according to being transformed into product with embodiment 67 basic similarly modes with 2-trifluoroacetamido-3-(2,4, the 5-trifluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(98．9％)。EA，MS(FD)。
Embodiment 74
2-amino-3-(2-chlorphenyl)-6-benzoyl-imidazo [1,2-a] pyridine
(10.8g 24.2mmol) obtains the 7.45g product according to being transformed into product with embodiment 67 basic similarly modes with 2-trifluoroacetamido-3-(2-chlorphenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(88．5％)。EA，MS(FD)。
Embodiment 75
2-amino-3-(3-chlorphenyl)-6-benzoyl-imidazo [1,2-a] pyridine
(8.97g 20.2mmol) obtains the 6.05g product according to being transformed into product with embodiment 67 basic similarly modes with 2-trifluoroacetamido-3-(3-chlorphenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(86．1％)。EA，MS(FD)。
Embodiment 76
2-amino-3-(4-chlorphenyl)-6-benzoyl-imidazo [1,2-a] pyridine
(10.8g 24.2mmol) obtains the 7.17g product according to being transformed into product with embodiment 67 basic similarly modes with 2-trifluoroacetamido-3-(4-chlorphenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(85．2％)。EA，MS(FD)。
Embodiment 77 2-amino-3-(4-Trifluoromethoxyphen-l)-6-benzoyl-imidazo [1,2-a] pyridine
(10.6g 21.5mmol) obtains the 8.24g product according to being transformed into product with embodiment 67 basic similarly modes with 2-trifluoroacetamido-3-(4-Trifluoromethoxyphen-l)-6-benzoyl-imidazo [1,2-a] pyridine.(96．7％)。EA，MS(FD)。
Embodiment 78 2-amino-3-(3-Trifluoromethoxyphen-l)-6-benzoyl-imidazo [1,2-a] pyridine
(10.4g 21.1mmol) obtains the 7.89g product according to being transformed into product with embodiment 67 basic similarly modes with 2-trifluoroacetamido-3-(3-Trifluoromethoxyphen-l)-6-benzoyl-imidazo [1,2-a] pyridine.(94．4％)。MS(FD)，NMR。
Embodiment 792-amino-3-(2-fluoro-4-trifluoromethyl)-6-benzoyl-imidazo [1,2-a] pyridine
(8.03g 16.2mmol) obtains the 6.00g product according to being transformed into product with embodiment 67 basic similarly modes with 2-trifluoroacetamido-3-(2-fluoro-4-trifluoromethyl)-6-benzoyl-imidazo [1,2-a] pyridine.(92．8％)。EA，MS(FD)。
Embodiment 802-amino-3-(2,3,4,5, the 6-pentafluorophenyl group)-6-benzoyl-imidazo [1,2-a] pyridine
(5.03g 10.1mmol) obtains the 3.79g product according to being transformed into product with embodiment 67 basic similarly modes with 2-trifluoroacetamido-3-(2,3,4,5, the 6-pentafluorophenyl group)-6-benzoyl-imidazo [1,2-a] pyridine.(93．3％)。EA，MS(FD)。
Embodiment 81 2-amino-3-(2-trifluoromethyl)-6-benzoyl-imidazo [1,2-a] pyridine
(6.22g 13.0mmol) obtains the 4.25g product according to being transformed into product with embodiment 67 basic similarly modes with 2-trifluoroacetamido-3-(2-trifluoromethyl)-6-benzoyl-imidazo [1,2-a] pyridine.(85．5％)。EA，MS(FD)。
Embodiment 82
2-amino-3-(thiene-3-yl-)-6-benzoyl-imidazo [1,2-a] pyridine
(8.88g 21.4mmol) obtains the 5.51g product according to being transformed into product with embodiment 67 basic similarly modes with 2-trifluoroacetamido-3-(thiene-3-yl-)-6-benzoyl-imidazo [1,2-a] pyridine.(80．7％)。EA，MS(FD)。
Embodiment 832-amino-3-(2-trifluoromethyl-4-fluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine
(11.0g 22.2mmol) obtains the 8.60g product according to being transformed into product with embodiment 67 basic similarly modes with 2-trifluoroacetamido-3-(2-trifluoromethyl-4-fluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(97．2％)。MS(FD)。
Embodiment 842-amino-3-(2-fluoro-6-trifluoromethyl)-6-benzoyl-imidazo [1,2-a] pyridine
With 2-trifluoroacetamido-3-(2-fluoro-6-trifluoromethyl)-6-benzoyl-imidazo [1; 2-a] pyridine 2-trifluoroacetamido-3-(2; 3; 4; 5; the 6-pentafluorophenyl group)-(1.80g 3.64mmol) obtains the 1.28g product according to being transformed into product with embodiment 67 basic similarly modes to 6-benzoyl-imidazo [1,2-a] pyridine.(88．3％)。EA，MS(FD)。
Embodiment 85 2-amino-3-(2-methoxyphenyl)-6-benzoyl-imidazo [1,2-a] pyridine
(7.40g 16.8mmol) obtains the 5.0g product according to being transformed into product with embodiment 67 basic similarly modes with 2-trifluoroacetamido-3-(2-methoxyphenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(87％)。EA，MS(FD)。
Embodiment 86 2-amino-3-(4-methoxycarbonyl group phenyl)-6-benzoyl-imidazo [1,2-a] pyridine
(2.13g 16.8mmol) obtains the 1.44g product according to being transformed into product with embodiment 67 basic similarly modes with 2-trifluoroacetamido-3-(4-methoxycarbonyl group phenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(85％)。EA，MS(FD)。
Embodiment 87
2-amino-3-(4-nitrobenzophenone)-6-benzoyl-imidazo [1,2-a] pyridine
(8.59g 18.9mmol) obtains the 5.04g product according to being transformed into product with embodiment 67 basic similarly modes with 2-trifluoroacetamido-3-(4-nitrobenzophenone)-6-benzoyl-imidazo [1,2-a] pyridine.(74．4％)。EA，MS(FD)。
Embodiment 88 2-amino-3-isobutyl group-6-benzoyl-imidazo [1,2-a] pyridine
(2.37g 6.09mmol) obtains the 1.49g product according to being transformed into product with embodiment 67 basic similarly modes with 2-trifluoroacetamido-3-isobutyl group-6-benzoyl-imidazo [1,2-a] pyridine.(83．5％)。EA，MS(FD)。
Embodiment 89
2-amino-3-(4-carboxyl phenyl)-6-benzoyl-imidazo [1,2-a] pyridine
(3.00g 8.09mmol) is dissolved in 25ml THF and 8ml water and stirring at room with 2-amino-3-(4-methoxycarbonyl group phenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(968mg 40.4mmol) and with the reactant liquor stirring spends the night to add Lithium hydrate.Remove and to desolvate, in solid, add entry, then with solid filtering and wash with water.Solid is obtained the 2.62g product with recrystallizing methanol.(91％)。EA，MS(FD)。
Embodiment 90 2-amino-3-(4-N-methoxyl group acylamino-)-6-benzoyl-imidazo [1,2-a] pyridine
With 2-amino-3-(4-carboxyl phenyl)-6-benzoyl-imidazo [1; 2-a] pyridine (714mg; 2.00mmol), methoxy amine hydrochlorate (1.34g, 16.0mmol) and diisopropyl ethyl amine (2.93ml, 16.0mmol) at the blanket of nitrogen low suspension in the dry DMF of 20ml.Solution became yellowish orange by clarification in 20 minutes.With the reactant liquor stirred overnight at room temperature.Vacuum is steamed and is removed DMF, residue is poured into stirred then in the water 1 hour.Leach solid then and dry.Crude product is obtained the 317mg product with re-crystallizing in ethyl acetate.(41．0％)。EA，MS(FD)。
Embodiment 91 2-amino-3-(4-fluorophenyl)-6-(4-fluoro benzoyl)-imidazo [1,2-a] pyridine
(7.11g 16.0mmol) obtains the 4.80g product according to being transformed into product with embodiment 67 basic similarly modes with 2-trifluoroacetamido-3-(4-fluorophenyl)-6-(4-fluoro benzoyl)-imidazo [1,2-a] pyridine.(86．2％)。MS(FD)，NMR。
Embodiment 922-amino-3-(2-fluoro-4-trifluoromethyl)-6-(4-fluoro benzoyl)-imidazo [1,2-a] pyridine
(6.75g 13.2mmol) obtains the 4.66g product according to being transformed into product with embodiment 67 basic similarly modes with 2-trifluoroacetamido-3-(2-fluoro-4-trifluoromethyl)-6-(4-fluoro benzoyl)-imidazo [1,2-a] pyridine.(85％)。EA，MS(FD)。
Embodiment 93
2-amino-3-phenyl-6-(α-phenethyl)-imidazo [1,2-a] pyridine
With N-(3-phenyl-6-[N-methyl-N-methoxyl group carbamoyl] imidazo [1; 2-a] pyridine-2-yl)-2; 2; 5; 5-tetramethyl-1-azepine-2, (812mg 4mmol) is dissolved in 30ml THF and add benzylmagnesium chloride (the THF solution of 2M to 5-two sila Pentamethylene. under blanket of nitrogen; 6ml, 12.0mmol).With mixture stirring at room 18 hours, add 15ml MeOH and 3ml acetic acid then.With mixture stirring at room 1 hour.Vacuum is steamed and is desolventized, and residue is added 400ml ethyl acetate and 60ml NaHCO
3In.Tell ethyl acetate and with the salt water washing (2 * 75ml), with dried over sodium sulfate vacuum concentration then.Residue is passed through positive flash chromatography (ethyl acetate) purification.Product is obtained the 398mg product with re-crystallizing in ethyl acetate.(31．6％)。MS(FD)，NMR。
Embodiment 94
2-amino-3-phenyl-6-(pyridine formoxyl)-imidazo [1,2-a] pyridine
With the 2-iodine pyridine (1.23g, 6.00mmol) under blanket of nitrogen, be dissolved in 40ml THF and add ethylmagnesium bromide (2ml, 3M, 6mmol).With mixture stirring at room 30 minutes, add N-(3-phenyl-6-[carboxyl] imidazo [1,2-a] pyridine-2-yl)-2,2,5,5-tetramethyl-1-azepine-2,5-two sila Pentamethylene. (820mg, 25ml THF solution 2mmol) by sleeve pipe then.With the mixture stirring at room that forms 18 hours.Add methanol (4ml) and 2ml acetic acid, then with mixture stirring at room 1 hour.The vacuum steaming desolventizes and residue is passed through the normal-phase chromatography purification.Product is obtained the 205mg product with re-crystallizing in ethyl acetate.(10．9％)。MS(FD)，NMR。
Embodiment 95
2-amino-3-phenyl-6-(nicotinoyl)-imidazo [1,2-a] pyridine
With N-(3-phenyl-6-[carboxyl] imidazo [1,2-a] pyridine-2-yl)-2,2,5,5-tetramethyl-1-azepine-2, (820mg 2.00mmol) obtains the 271mg product according to being transformed into product with embodiment 94 basic similarly modes with the 3-iodine pyridine to 5-two sila Pentamethylene..(14．4％)。EA，MS(FD)。
Embodiment 96
2-amino-3-phenyl-6-(different nicotinoyl)-imidazo [1,2-a] pyridine
With N-(3-phenyl-6-[carboxyl] imidazo [1,2-a] pyridine-2-yl)-2,2,5,5-tetramethyl-1-azepine-2, (3.28g 8.00rnmol) obtains the 1.74g product according to being transformed into product with embodiment 94 basic similarly modes with the 4-iodine pyridine to 5-two sila Pentamethylene..(69．3％)。EA，MS(FD)。
Embodiment 972-amino-3-(2,4 difluorobenzene base)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
With 2-amino-3-(2,4 difluorobenzene base)-(1.00g 2.87mmol) is dissolved in 40ml 80%EtOH/H to 6-benzoyl-imidazo [1,2-a] pyridine
2O.Add oxammonium hydrochloride. (2.39g, 34.4mrnol) and NaOAc (2.82g, 34.4mmol), then with this mixture heated backflow 4 hours.Process by the HPLC monitoring reaction.Vacuum is steamed and is desolventized, and residue is added in the 900ml ethyl acetate.With solution with saturated sodium bicarbonate (3 * 100ml) and saline (3 * 100ml) wash, and use dried over sodium sulfate, filter vacuum concentration then.With the residue ethyl acetate, further obtain 130mg E-isomer then by the HPLC purification.(17．2％)。MS(FD)，UV。
Embodiment 982-amino-3-(4-methoxyphenyl)-6-(benzyl oxime-α-yl)-imidazo [1,2-a] pyridine
(2.00g 5.83mmol) obtains 490mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(4-methoxyphenyl)-6-benzoyl-imidazo [1,2-a] pyridine; (24.0%); EA, MS (FD), and not true on a small quantity quantitative Z-product.EA，MS(FD)。
Embodiment 992-amino-3-(naphthalene-2-yl)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(2.00g 5.51mmol) obtains 115mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(naphthalene-2-yl)-6-benzoyl-imidazo [1,2-a] pyridine.(5．52％)。EA，MS(FD)。
Embodiment 100
2-amino-3-naphthyl-6-(benzyl oxime-α-yl)-imidazo [1,2-a] pyridine
[1, (2.00g 5.51mmol) obtains 470mg E-product, (22.6%), EA, MS (FD), and 810mg Z-product according to being transformed into product with embodiment 97 basic similarly modes to the 2-al pyridine with 2-amino-3-naphthyl-6-benzoyl-imidazo.(38．9％)。NMR。
Embodiment 1012-amino-3-(2-fluorophenyl)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(2.62g 7.92mmol) obtains 1.08g E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(2-fluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(39．3％)。MS(FD)，NMR。
Embodiment 1022-amino-3-(3-fluorophenyl)-6-[(E)-1-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(2.00g 6.04mmol) obtains 463mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(3-fluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(22．2％)，EA，MS(FD)。
Embodiment 1032-amino-3-(4-fluorophenyl)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(3.00g 9.06mmol) obtains 2.78g E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(4-fluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(88．8％)。EA，MS(FD)。
Embodiment 1042-amino-3-(3, the 5-difluorophenyl)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(1.00g 2.87mmol) obtains the 65mgE-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(3, the 5-difluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(6．22％)。EA，MS(FD)。
Embodiment 1052-amino-3-(2, the 5-difluorophenyl)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(1.00g 2.87mmol) obtains 315mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(2, the 5-difluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(30．2％)。EA，MS(FD)。
Embodiment 1062-amino-3-(3-trifluoromethyl)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(2.00g 5.24mmol) obtains 579mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(3-trifluoromethyl)-6-benzoyl-imidazo [1,2-a] pyridine.(27．9％)。EA，MS(FD)。
Embodiment 107 2-amino-3-(4-bromophenyl)-6-(benzyl oxime-α-yl)-imidazo [1,2-a] pyridine
(1.80g 4.59mmol) obtains 1: 1 E of 1.20g and Z isomer mixture of products according to being transformed into product with the basic similarly modes of embodiment 97 with 2-amino-3-(4-bromophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(64．2％)。EA，MS(FD)。
Embodiment 1082-amino-3-(2,3, the 4-trifluorophenyl)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(2.00g 5.45mmol) obtains 508mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(2,3, the 4-trifluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(24．1％)。EA，MS(FD)。
Embodiment 1092-amino-3-(3, the 4-difluorophenyl)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(2.00g 5.73mmol) obtains 507mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(3, the 4-difluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(24．2％)。EA，MS(FD)。
Embodiment 1102-amino-3-(3, the 4-Dichlorobenzene base)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(2.00g 5.25mmol) obtains 643mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(3, the 4-Dichlorobenzene base)-6-benzoyl-imidazo [1,2-a] pyridine.(31．1％)。EA，MS(FD)。
Embodiment 1112-amino-3-(2,4, the 5-trifluorophenyl)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(2.00g 5.45mmol) obtains 344mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(2,4, the 5-trifluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(16．6％)。EA，MS(FD)。
Embodiment 1122-amino-3-(2-chlorphenyl)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(2.00g 5.76mmol) obtains 180mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(2-chlorphenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(8．61％)。EA，MS(FD)。
Embodiment 1132-amino-3-(3-chlorphenyl)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(2.00g 5.75mmol) obtains 551mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(3-chlorphenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(26．4％)。EA，MS(FD)。
Embodiment 1142-amino-3-(4-chlorphenyl)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(2.00g 5.75mmol) obtains 180mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(4-chlorphenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(8．61％)。EA，MS(FD)。
Embodiment 1152-amino-3-(4-Trifluoromethoxyphen-l)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(2.00g 5.04mmol) obtains 383mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(4-Trifluoromethoxyphen-l)-6-benzoyl-imidazo [1,2-a] pyridine.(18．4％)。EA，MS(FD)。
Embodiment 1162-amino-3-(3-Trifluoromethoxyphen-l)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(2.00g 5.04mmol) obtains 224mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(3-Trifluoromethoxyphen-l)-6-benzoyl-imidazo [1,2-a] pyridine.(10．8％)。EA，MS(FD)。
Embodiment 1172-amino-3-(2-fluoro-4-trifluoromethyl)-6-(benzyl oxime-α-yl)-imidazo [1,2-a] pyridine
(2.00g 5.01mmol) obtains 742mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(2-fluoro-4-trifluoromethyl)-6-benzoyl-imidazo [1,2-a] pyridine.(35．7％)。EA，MS(FD)。
Embodiment 118
2-amino-3-phenyl-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
With 2-amino-3-phenyl-6-benzoyl-imidazo [1,2-a] pyridine (133mg, 0.426mmol) with oxammonium hydrochloride. (500mg, 7.20mmo1), 2.5ml pyridine and 7.5ml dehydrated alcohol handle.Reflux after 2.5 hours, add the 200ml ethyl acetate and the saturated NaHSO of solution
3Washed twice.With organic layer with dried over mgso then vacuum steam and to desolventize.Product crystallization in ethyl acetate is obtained 64mg E-product, (45.7%), MS (FD) and 68mg Z isomer.(48．6％)。MS(FD)。
Embodiment 1192-amino-3-(2, the 6-difluorophenyl)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(2.00g 5.73mmol) obtains 383mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(2, the 6-difluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(18．4％)。EA，MS(FD)。
Embodiment 1202-amino-3-(2,3,4,5, the 6-pentafluorophenyl group)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(4.52g 11.2mmol) obtains 940mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(2, the 6-difluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(20％)。EA，MS(FD)。
Embodiment 1212-amino-3-(2-trifluoromethyl)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(2.00g 5.25mmol) obtains 146mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(2-trifluoromethyl)-6-benzoyl imidazo [1,2-a] pyridine.(7．02％)。EA，MS(FD)。
Embodiment 1222-amino-3-(thiene-3-yl-)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(2.00g 6.27mmol) obtains 497mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(thiene-3-yl-)-6-benzoyl-imidazo [1,2-a] pyridine.(23．8％)。EA，MS(FD)。
Embodiment 1232-amino-3-(2-trifluoromethyl-4-fluorophenyl)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(2.00g 5.01mmol) obtains 288mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(2-trifluoromethyl-4-fluorophenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(13．8％)。EA，MS(FD)。
Embodiment 1242-amino-3-(2-fluoro-6-trifluoromethyl)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
With 2-amino-3-(2-fluoro-6-trifluoromethyl)-6-benzoyl-imidazo [1; 2-a] (1.28g 3.21mmol) obtains 75.0mg E-product, (5.64%) according to being transformed into product with embodiment 97 basic similarly modes to pyridine; EA, MS (FD) and 395mg Z-product.(29．7％)。MS(FD)，NMR。
Embodiment 1252-amino-3-(4-trifluoromethyl)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(2.00g 5.25mmol) obtains 512mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(4-trifluoromethyl)-6-benzoyl-imidazo [1,2-a] pyridine.(24．6％)。EA，MS(FD)。
Embodiment 1262-amino-3-(4-methoxycarbonyl group phenyl)-6-[(E)-benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(1.00g 2.70mmol) obtains 437mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(4-methoxycarbonyl group phenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(43．5％)。EA，MS(FD)。
Embodiment 127 2-amino-3-(4-carboxyl phenyl)-6-[benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(2.00g 5.60mmol) obtains 990mg E and Z isomer mixture according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(4-carboxyl phenyl)-6-benzoyl-imidazo [1,2-a] pyridine.(46.6% total recovery).NMR。
Embodiment 128
2-amino-3-benzyl-6-[benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(2.00g 5.60mmol) obtains 210mg E isomer product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-benzyl-6-benzoyl-imidazo [1,2-a] pyridine.(16．5％)。EA，MS(FAB)。
Embodiment 129
2-amino-3-isobutyl group-6-[benzyl oxime-α-yl]-imidazo [1,2-a] pyridine
(820mg 2.80mmol) obtains 120mg E isomer product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-isobutyl group-6-benzoyl-imidazo [1,2-a] pyridine.(13．9％)。EA，MS(FAB)。
Embodiment 1302-amino-3-(4-fluorophenyl)-6-[(E)-1-(4-luorobenzyl) oxime-α-yl]-imidazo [1,2-a] pyridine
With 2-amino-3-(4-fluorophenyl)-6-(4-fluoro benzoyl)-imidazo [1; 2-a] (2.00g 5.73mmnol) obtains 572mg E-product, (27.4%) according to being transformed into product with embodiment 97 basic similarly modes to pyridine; EA, MS (FD) and 198mg Z-product.(9．47％)。EA，MS(FD)。
Embodiment 1312-amino-3-(2-fluoro-4-trifluoromethyl)-6-[(E)-1-(4-luorobenzyl) oxime-α-yl]-imidazo [1,2-a] pyridine
(2.00g 4.80mmol) obtains 310mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-(2-fluoro-4-trifluoromethyl)-6-(4-fluoro benzoyl)-imidazo [1,2-a] pyridine.(15％)。EA，MS(FD)。
Embodiment 132 2-amino-3-phenyl-6-[(E)-phenylacetone oxime-α-yl]-imidazo [1,2-a] pyridine
(732mg 2.24mmol) obtains 485mg E-product according to being transformed into product with embodiment 97 basic similarly modes with 2-amino-3-phenyl-6-(α-phenyl acetyl)-imidazo [1,2-a] pyridine.(63．3％)。EA，MS(FD)。
Embodiment 133
2-amino-3-phenyl-6-(picolinyl oxime-α-yl)-imidazo [1,2-a] pyridine
To 2-amino-3-phenyl-6-(pyridine formoxyl)-imidazo [1,2-a] pyridine (1.57g, add in the suspension of 100ml 80% aquiferous ethanol 5.00mmol) oxammonium hydrochloride. (4.17g, 60.0mmol) and NaOAc (4.92g, 60.0mmol).Mixture was refluxed 6 hours, and vacuum is steamed and is desolventized then.Residue is distributed between 900ml ethyl acetate and 100ml saturated sodium bicarbonate.Tell ethyl acetate and use the salt water washing, use dried over sodium sulfate, filter vacuum concentration then.Residue is obtained two kinds of product mixture of isomers with re-crystallizing in ethyl acetate.Mixture is developed then with solid filtering with dichloromethane.Filtrate chromatographic isolation (positive) is obtained the 75.8mg cis-product.(4．6％)。EA，MS(FD)。Solid is obtained the trans product of 134mg for twice with recrystallizing methanol.(8．1％)。EA，MS(FD)。
Embodiment 134
2-amino-3-phenyl-6-(picolyl oxime-α-yl)-imidazo [1,2-a] pyridine
With 2-amino-3-phenyl-6-(nicotinoyl)-imidazo [1; 2-a] (1.18g 3.75mmol) obtains the 127mg cis-product, (10.3%) according to being transformed into product with embodiment 78 basic similarly modes to pyridine; MS (FD), NMR and 20.5mg 80% trans product.(1.3% correction value).MS(FD)，NMR。
Embodiment 135 2-amino-3-phenyl-6-(suitable-different cigarette base oxime-α-yl)-imidazo [1,2-a] pyridine
(1.57g 5.00mmol) obtains the 466mg cis-product according to being transformed into product with embodiment 78 basic similarly modes with 2-amino-3-phenyl-6-(different nicotinoyl)-imidazo [1,2-a] pyridine; (28.3%); EA, MS (FD), the trans product of NMR and 230mg.(14％)。EA，MS(FD)。
Embodiment 136 2-amino-3-phenyl-6-(1-phenyl-2-cyano group vinyl)-imidazo [1,2-a] pyridine
With 2-amino-(1.57g 5.00mmol) is dissolved in 30ml THF to 3-phenyl-6-benzoyl-imidazo [1,2-a] pyridine; add diethyl phosphorocyanidate (1.63g then successively; 10.0mmol) and two TMS potassamides (toluene solution of 0.5M, 5ml, 10mmol).Reactant liquor was stirred 5 days.Vacuum is steamed and is removed THF and residue is dissolved in the 500ml ethyl acetate.Ethyl acetate is used 50ml water and saline, and (2 * 50ml) washings are used dried over sodium sulfate, then vacuum concentration.Residue is obtained the 250mg product by positive flash chromatography (ethyl acetate) purification, it is obtained 98mg Z-product with re-crystallizing in ethyl acetate, (5.82%), EA, MS (FD) and 128mg E-product.(7．60％)。EA，MS(FD)。
Embodiment 137
2-amino-3-isobutyl group-6-(1-phenyl-2-cyano group vinyl)-imidazo [1,2-a] pyridine
(1.46g 5.00mmol) obtains 200mg Z-product, (12.7%), MS (FD), NMR and 130mg E-product according to being transformed into product with embodiment 136 basic similarly modes with 2-amino-3-isobutyl group-6-benzoyl-imidazo [1,2-a] pyridine.(8．23％)。EA，MS(FD)。
Embodiment 138
2-amino-3-methyl mercapto-6-benzoyl-imidazo [1,2-a] pyridine
(100mg 263mmol) is dissolved in the mixture of 20ml ethanol/methylene (1: 1), adds 5g silica gel then with 2-trifluoroacetamido-3-methyl mercapto-6-benzoyl-imidazo [1,2-a] pyridine.With mixture stirring at room 2 days.Residue is filtered and use washed with dichloromethane, then the filtrate vacuum concentration is obtained 63mg (85%) yellow solid.
1H-NMR(200MHz，CDCl
3)d2．12(s，3H，SMe)，4．40(bs，2H，NH
2)7．46-7．80(m，7H，ArH+H
7+H
8)，8．68(d，J
57=1．7，H
5)。
13C-NMR(50MHz，CDCl
3)d18．0(SMe)，95．0，122．7，125．8，127．7，128．5，129．6，132．6，137．4，145．3，156．1，193．5。
Embodiment 139
2-amino-3-methyl sulphonyl-6-benzoyl-imidazo [1,2-a] pyridine
(160mg 0.438mmol) obtains the 92mg product according to being transformed into product with embodiment 138 basic similarly modes with 2-trifluoroacetamido-3-methyl sulphonyl-6-benzoyl-imidazo [1,2-a] pyridine.(78％)。
1H-NMR(200MHz，CDCl
3)d3．06(s，3H，SO
2Me)，4．82(bs，2H，NH
2)，7．53-7．82(m，6H，ArH+H
7+H
8)，8．78(d，J
57=1．6，H
5)。
Embodiment 140
2-amino-3-iprotiazem base-6-benzoyl-imidazo [1,2-a] pyridine
(16mg 0.0393mmol) obtains the 11mg product according to being transformed into product with embodiment 138 basic similarly modes with 2-trifluoroacetamido-3-isopropyl sulfonyl-6-benzoyl-imidazo [1,2-a] pyridine.(88％)。EIMS m/z311M
+(28), 268 (100), 224 (27), 105 (41), 77 (29),
1H-NMR (CDCl
3) d8.75 (s, 1H, H
5), 7.79-7.47 (m, 7H, Ar), 4.62 (bs, 2H, NH
2), 3.09 (septet, 1H, J=6.4Hz, CH (CH
3)
2, 1.22 (d, 6H, J=6.7Hz, (CH
3)
2-CH),
13C-NMR (CDCl
3) d199.3,157.1,145.2,137.3,132.6,129.5,128.4,127.9,126.0,122.8,113.6,40.8,23.4.
Embodiment 141
2-amino-3-phenyl-6-(2-fluoro benzoyl)-imidazo [1,2-a] pyridine
Under the argon atmospher, (191ml drips tert-butyl lithium in dry THF 1.75mmol) (2ml) solution to 1-bromo-2-fluorobenzene.After stirring 50 minutes under-78 ℃, add 2-amino-3-phenyl-6-(N-methyl-N-methoxyl group carbamoyl) imidazo [1,2-a] pyridine (148mg, dry THF 0.5mmol) (3ml) solution.With the reddish orange solution that forms restir 50 minutes under same temperature, be warming up to room temperature then.Solution poured in the water (20ml) use ethyl acetate extraction (2 * 20ml) then.Organic layer is washed with water, dry (sodium sulfate), vacuum is steamed to desolventize and is obtained brown solid then.The crude product solid is obtained 84.0mg (50.6%) yellow solid shape product by column chromatography purification (dichloromethane/acetonitrile 2.5/1).MS(FAB)m／z?332．2(M++1，51．99)，NMR(200MHz，CDCl
3)d4．27(bs，2H，NH)，7．12-7．58(m，11H，ArH+H
7+H
8)，8．7l(s，H
5)。
Embodiment 142
2-amino-3-phenyl-6-(3-fluoro benzoyl)-imidazo [1,2-a] pyridine
(148mg 0.500mmol) obtains the 37mg product with 1-bromo-3-fluorobenzene according to being transformed into product with embodiment 141 basic similarly modes with 2-amino-3-phenyl-6-(N-methyl-N-methoxyl group carbamoyl) imidazo [1,2-a] pyridine.(37％)。MS(FAB
+)m／z?332．2(M
++1，86．6)，NMR(200MHz，CDCl
3)d4．22(bs，2H，NH)，7．21-7．55(m，11H，ArH+H
7+H
8x)，8．69(d，J
57=1．1，H
5)。
Embodiment 143
2-amino-3-phenyl-6-(4-fluoro benzoyl)-imidazo [1,2-a] pyridine
(584mg 1.97mmol) obtains the 205mg product with 1-bromo-4-fluorobenzene according to being transformed into product with embodiment 141 basic similarly modes with 2-amino-3-phenyl-6-(N-methyl-N-methoxyl group carbamoyl) imidazo [1,2-a] pyridine.(52％)。NMR(200MHz，CDCl
3)d4．31(bs，2H，NH)，7．15(m，2H，F-ArH)，7．25-7．56(m，7H，ArH+H
7+H
8)，7．78(m，2H，F-ArH)，8．69(s，H
5)。
Embodiment 144 2-amino-3-phenyl-6-(2, the 3-difluoro benzoyl)-imidazo [1,2-a] pyridine
Under-78 ℃ to 2, the 3-difluoro bromobenzene (0.945g, add in dry THF 8.44mmol) (20ml) solution n-BuLi (hexane solution of 1.6M, 5.27ml).The yellow solution that forms was stirred 70 minutes under same temperature; under argon atmospher, drip 2-amino-3-phenyl-6-(N-methyl-N-methoxyl group carbamoyl) imidazo [1 by sleeve pipe then; 2-a] pyridine (500mg, dry THF 1.69mmol) (20ml) solution.The orange solution that forms was warming up to room temperature very lentamente in 2.5 hours.Add saturated ammonium chloride, mixture is stirred used ethyl acetate extraction in 25 minutes then.With organic layer salt water washing, dry (sodium sulfate).Steaming desolventizes and residue is obtained 440mg (74.7%) yellow solid shape product by column chromatography purification (dichloromethane/acetonitrile, 4/1) purification.MS(FAB)m／z?350．1(M
++1，100．0)，NMR(200MHz，DMSO?d
6)d?5．71(bs，2H，NH)，7．27-7．70(m，11H，F-ArH+ArH+H
7+H
8)，8．58(dd，J
57=1．8，J
58=0．9，H
5)。
Embodiment 1452-amino-3-methyl mercapto-6-(1-phenyl-2-cyano group vinyl)-imidazo [1,2-a] pyridine
Under-78 ℃ to 2-amino-3-methyl mercapto-6-benzoyl-imidazo [1,2-a] pyridine (40mg, drip in 4ml dry THF solution 0.14mmol) diethyl phosphonyl nitrile (phospononitrile) (265mg, 1.5mmol).Form orange solids.Add 2ml THF and reactant mixture was stirred 2 hours in-78 ℃.Reactant mixture was warming up to room temperature in 3 hours.Solution becomes green.With 1 hydrolysis of dripping, vacuum is steamed and is desolventized with mixture, and residue is carried out column chromatography (ethyl acetate) obtain 23mg (51%) E-isomer,
1H-NMR (200MHz, CDCl
3) d2.22 (s, 3H, SMe), 4.43 (bs, 2H, NH
2), 5.75 (s, 1H, H
Ethylene), 7.04 (dd, 1H, J
57=2.0, J
78=9.1, H
7), 7.32-7.50 (m, 6H, ArH+H
8), 8.54 (dd, J
58=0.9, J
57=2.0, H
5) and 14mg (32%) Z-isomer,
1H-NMR (200MHz, CDCl
3) d2.10 (s, 3H, SMe), 4.40 (bs, 2H, NH
2), 5.79 (s, 1H, H
Ethylene), 7.13 (dd, 1H, J
57=1.9, J
78=9.2, H
7), 7.32 (dd, J
58=0.8, J
78=9.2, H
8), 7.47-7.53 (m, 5H, ArH), 8.07 (dd
1J
58=0.8, J
57=1.9, H
5).
Embodiment 1462-amino-3-methyl sulphonyl-6-(1-phenyl-2-cyano group vinyl) imidazo [1,2-a] pyridine
2-amino-6-benzoyl-3-(methyl sulphonyl) imidazo [1,2-a] pyridine is obtained the vinyl nitrile mixture that ratio is two kinds of isomer E: Z of 1: 2 according to being transformed into product with embodiment 145 basic similarly modes, and total recovery is 77%.The Z-isomer is separated (isopropyl alcohol: ethyl acetate/3: 7) by column chromatography.
1H-NMR (200MHz, CDCl
3) d3.17 (s, 3H, SO
2Me), 4.66 (bs, 2H, NH
2), 5.77 (s, 1H, H
Ethylene), 7.10 (dd, 1H, J
57=1.8, J
78=9.3, H
7), 7.30-7.46 (m, 6H, ArH+H
8), 8.82 (dd, J
56x=0.8, J
57=1.8, H
5).
Embodiment 1472-amino-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
With 2-trifluoroacetamido-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine (300mg, 0.77mmol) stirring at room 5 hours in the presence of 0.5N NaOH (17ml).Solution is neutralized to pH=7 with HCl (5% aqueous solution), uses CHCl then
3(3 * 50ml) extractions.With the organic extract liquid drying (sodium sulfate) that merges then vacuum steam to desolventize and obtain 130mg (58%) light brown solid, shaped product.M.P.97-99 ℃, NMR (CDCl
3) d7.61 (d, 1H, J=1.4Hz, H
5), 7.47-7.41 (m, 3H, Ar), 7.33-7.27 (m, 3H, Ar), 7.12 (dd, 1H, J=9.3,1.8Hz, H7 ó H
8), 6.77 (s, 1H, H
3), 6.36 (s, 1H, H
Vinyl), 5.13 (wide d, 1H, J=4.9Hz, NHMe), 3.90 (wide s, 2H, NH
2), 2.62 (d, 3H, J=4.9Hz, CH
3NH), EIMS m/z 292M
+(100), 262 (32), 234 (20), 223 (15), 215 (13), 178 (8), 160 (10), 117 (6), 105 (9), 77 (9).
Embodiment 1482-amino-3-iprotiazem base-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
Under argon atmospher to the 2-trifluoroacetamido-3-iodo-6-[(E that is cooled to-78 ℃)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1; 2-a] pyridine (72mg; 0.15mmol) 5ml THF solution in add phenyl lithium (230 μ l, 0.33mmol).Reactant mixture was stirred 3 hours, inject then tert-butyl lithium (310 μ l, 0.38mmol).Stir after 10 minutes, add isopropyl mercaptan-sulfonic acid isopropyl ester (109mg, 5ml THF solution 0.600mmol).Reactant mixture in-78 ℃ of stirrings 30 minutes, is dripped and 10ml THF cessation reaction with 2 then.Add ethyl acetate (15ml) and mixture is warming up to room temperature.With solution with diatomite filtration then vacuum steam and to desolventize.Obtained removing the isopropyl sulfide of trifluoroacetyl group through radial chromatography, this intermediate is purified form.The ratio of intermediate/product depends on the speed of radial chromatography.The trifluoroacetyl based raw material is mixed in ethanol/methylene with silica gel and the stirring 2 days of will luming.Total recovery with 73% after filtering obtains product.EIMS m/z 366M
+(33), 323 (100), 293 (18), 237 (15), 196 (10), 178 (7), 102 (6),
1H-NMR (CDCl
3) d8.01 (d, 1H, J=1.5Hz, H
5), 7.47-7.20 (m, 7H, Ar), 6.40 (s, 1H, H
Vinyl), 5.20 (wide s, 1H, J=4.9Hz, NHMe), 4.26 (wide s, 2H, NH
2), 2.97 (septet, 1H, J=6.8Hz, CH (CH
3)
2), 2.65 (d, 3H, J=4.9Hz, CH
3NH), 1.13 (d, 6H, J=6.8Hz, (CH
3)
2CH).
Embodiment 1492-amino-3-isopropyl sulfonyl-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
With 2-trifluoroacetamido-3-isopropyl sulfonyl-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1; 2-a] (45mg 0.09mmol) is dissolved in 1: 1 methanol to pyridine: in the mixture of dichloromethane and add silica gel until forming caking.The vigorous stirring of will luming 2 days.Behind diatomite filtration, obtain the white solid product.(33mg，89％)。EIMS m/z 398M
+(44), 292 (100), 262 (27), 233 (15), 215 (9) 205 (8), 178 (7), 77 (6), 58 (8), NMR (CDCl
3) d8.46 (s, 1H, H
5), 7.53-7.30 (m, 7H, Ar), 6.41 (s, 1H, H
Vinyl), 5.30 (d, 1H, J=4.8Hz, NHMe), 5.17 (wide s, 2H, NH
2), 3.26 (septet, 1H, J=7.0Hz, CH (CH
3)
2), 2.12 (d, 3H, J=4.8Hz, CH
3NH), 1.34 (d, 6H, J=7.0Hz, (CH
3)
2CH).
Embodiment 1502-amino-3-phenyl-6-(1-(2, the 3-difluorophenyl) oxime)-imidazo [1,2-a] pyridine
With 2-amino-3-phenyl-6-(2; the 3-difluoro benzoyl)-(0.15g is 0.43mmol) with oxammonium hydrochloride. (0.357g for imidazo [1,2-a] pyridine; 5.16mmol) and sodium acetate (0.424g, 5.16mmol) mixing in 80% alcoholic solution (9ml).Reactant mixture was refluxed 20 hours under argon atmospher.Vacuum is steamed to desolventize residue is added in ethyl acetate-water.With organic layer with saturated sodium bicarbonate (2 * 20ml) and saline (2 * 25ml) washings dry then (sodium sulfate) obtain yellow solid shape product with quantitative yield after the evaporation.Record E by NMR: the ratio of Z is 2/1.NMR(200MHz，DMSO-d
6)d5．34(bs，NH
2?E)，5．38(NH
2?Z)，8．04(s，H
5?E)，8．91(H
5?Z)，11．77(s，OH?E)，12．14(s，OH?Z)。
Embodiment 1512-amino-3-phenyl-6-(1-(2, the 3-difluorophenyl)-2-N-methylamino formoxyl vinyl)-imidazo [1,2-a] pyridine
With 2-trifluoroacetamido-3-phenyl-6-[(E)-1-(2; the 3-difluorophenyl)-2-methylamino formoxyl vinyl]-imidazo [1; 2-a] (0.13g 0.26mmol) is dissolved in methanol/diisopropyl ethyl amine (4ml 1/1 v/v) and refluxed 4 days under argon atmospher then pyridine.The vacuum steaming desolventizes and mixture is obtained 27mg (32.5%) product by column chromatography purification (dichloromethane/acetonitrile/methanol 55/40/5) recovery.
1H NMR (200MHz, CDCl
3) d3.86 (d, J=9.0,3H, CONHCH
3), 4.15 (bs, 2H, NH), 6.64 (s, H
Ethylene), 7.02-7.45 (m, 10H, F-ArH+ArH+H
7+ H
8), 8.14 (d, J
57=1.5, H
5),
13C NMR (50MHz, CDCl
3) d33.7,114.6,118.0,118.4,121.0,121.6,122.4,122.6,123.2,124.2,127.7,127.7,128.9,129.7,147.0,148.7,161.9.
Embodiment 1522-amino-3-phenyl-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
With 2-trifluoroacetamido-3-phenyl-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-(190mg 0.420mmol) obtains the 127-135mg product according to being transformed into product with embodiment 151 basic similarly modes to imidazo [1,2-a] pyridine.(85-90％)。NMR (200MHz, CD
3OD): d2.60 (s, 3H, NHCH
3), 6.44 (s, 1H, H
Ethylene), 7.20-7.42 (m, 12H, ArH+H
7+ H
8), 7.91 (bs, 1H, H
5).
Embodiment 1532-amino-3-(2, the 5-difluorophenyl)-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
With 2-trifluoroacetamido-3-(2; the 5-difluorophenyl)-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1; 2-a] (333mg 0.682mmol) obtains the 227-241mg product according to being transformed into product with embodiment 151 basic similarly modes to pyridine.(85-90％)。EIMS m/z 404M
+(100), 374 (17), 345 (12), 207 (9), 152 (7), 140 (7), 105 (7), 77 (11), NMR (CDCl
3) d7.62 (dd, 1H, J=2.1,1.2Hz, H
5), 7.45-6.99 (m, 10H, Ar), 6.35 (s, 1H, H
Vinyl), 5.19 (d, 1H, J=4.9Hz, NH), 4.18 (wide s, 2H, NH
2), 2.63 (d, 3H, J=5.0Hz, CH
3).
Embodiment 1542-amino-3-(2-trifluoromethyl-4-fluorophenyl)-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
With 2-trifluoroacetamido-3-(2-trifluoromethyl-4-fluorophenyl)-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1; 2-a] (310mg 0.576mmol) obtains the 216-229mg product according to being transformed into product with embodiment 151 basic similarly modes to pyridine.(85-90％)。MS (FD) (EI
+) m/z 454M
+(100), 424 (19), 395 (12), 356 (7), 279 (10), 209 (11), 77 (9), NMR (CDCl
3) d7.52 (dd, 1H, J=8.4Hz, H
7ó H
8), 7.47-7.16 (m, 9H, Ar), 6.94 (d, 1H, J=8.9Hz, H
7ó H
8), 6.16 (s, 1H, H
Vinyl), 5.39 (wide d, 1H, J=4.6Hz, NHMe), 3.92 (wide s, 2H, NH
2), 2.55 (d, 3H, J=4.7 Hz, CH
3).
Embodiment 1552-amino-3-(2,3, the 4-trifluorophenyl)-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
With 2-trifluoroacetamido-3-(2; 3; the 4-trifluorophenyl)-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-(134mg 0.265mmol) obtains the 92.3-97.7mg product according to being transformed into product with embodiment 151 basic similarly modes to imidazo [1,2-a] pyridine.(85-90％)。EIMS m/z 423M
+(6), 422 (25), 392 (6), 353 (14), 259 (14), 105 (16), 84 (100), NMR (CDCl
3) d7.70 (s, 1H, C7H
3N
2), 7.44-7.00 (m, 9H, Ar), 6.63 (s, 1H, CH=C), 5.20 (wide s, 1H, NH-CH
3), 4.13 (wide s, 2H, NH
2), 2.62 (d, J=4.9Hz, 3H, NH-CH
3
Embodiment 1562-amino-3-(3, the 5-difluorophenyl)-6-(1-phenyl-2-N-methylamino formoxyl vinyl)-imidazo [1,2-a] pyridine
With 2-trifluoroacetamido-3-(3; the 5-difluorophenyl)-6-(1-phenyl-2-N-methylamino formoxyl vinyl)-imidazo [1; 2-a] (113mg 0.232mmol) obtains the 77.3-81.8mg product according to being transformed into product with embodiment 151 basic similarly modes to pyridine.(85-90％)。EIMS m/z 405M
+(34), 404 (100), 374 (22), 345 (17), 84 (14), NMR (CDCl
3) d8.28 and 7.92 (s, 1H, C7H
3N
2), 7.5-6.7 (m, 10H, Ar), 6.36 and 6.28 (s, 1H, CH=C), 5.71 y 5.24 (wide s, 1H, NH-CH
3), 4.22 (wide s, 2H, NH
2), 2.82 and 2.65 (d, J=4.9 and 4.9Hz, 3H, NH-CH
3).
Embodiment 1572-amino-3-(3-trifluoromethyl)-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
With 2-trifluoroacetamido-3-(3-trifluoromethyl)-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1; 2-a] (142mg 0.273mmol) obtains the 98.4-104mg product according to being transformed into product with embodiment 151 basic similarly modes to pyridine.(85-90％)。EIMS m/z 437M
+(36), 436 (100), 406 (18), 377 (16), 279 (10), 77 (6), NMR (CDCl
3) d7.83 (s, 1H, C
7H
3N
2), 7.64 (m, 11H, Ar), 6.42 and 6.38 (s, 1H, CH=C), 5.13 (s, wide, 1H, NH-CH
3), 4.11 (s is wide, 2H, NH
2), 2.62 (d, J=4.9Hz, 3H, NH-CH
3).
Embodiment 1582-amino-3-benzoyl-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
With 1-(2-oxo-2-phenylethyl)-2-chloro-5-[(E)-1-phenyl-2-methylamino formoxyl vinyl] pyridine iodide (0.250g; 0.482mmol) and amino nitrile (220mg; 0.49mmol) and potassium carbonate (200mg 1.47mmol) mixes in the 10ml acetonitrile.With reaction mixture refluxed 14 hours.After being cooled to room temperature, mixture being filtered and filter cake is washed with acetonitrile.Obtain the solid, shaped product of 62.8mg light color, yield 39% with mother liquid evaporation and with residue by column chromatography purification (acetone/ethyl acetate 1: 1).MS(HR)，NMR。
Embodiment 1592-amino-3-(4-fluoro benzoyl)-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
With 1-[2-oxo-2-(4-fluorophenyl) ethyl]-2-chloro-5-[(E)-1-phenyl-2-methylamino formoxyl vinyl] (400mg 0.740mmol) obtains the 118mg product according to being transformed into product with embodiment 158 basic similarly modes to the pyridine iodide.(38％)。IR (KBr) u (cm
-1) 3676,3457,3283,3102,1735,1640,1640,1448,1352,1154,849,700, NMR (300MHz, DMSO-d
6) d8.56 (s, 1H); 7.86 (d, 1H, J=5.12); 7.56-7.49 (m, 2H); 7.36 (d, 1H, J=8.79); 7.3-7.2 (m, 5H); 7.15 (m, 2H); 6.44 (s, 1H); 6 (s, 2H); 2.48 (s, 3H), MS (HR): value of calculation C
24H
19N
4O
2414.1492, measured value 414.1498.
Embodiment 1602-amino-3-acetyl group-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
With the 1-[2-oxopropyl]-2-chloro-5-[(E)-1-phenyl-2-methylamino formoxyl vinyl] (400mg 0.870mmol) obtains the 118mg product according to being transformed into product with embodiment 158 basic similarly modes to the pyridine iodide.(40％)。MS (HR): m/z value of calculation C
19H
18N
4O
2334.1430.Measured value 334.1430, IR (KBr) u (cm
-1) 3440,1614,1530,1458,1348,820.
Embodiment 1612-amino-3-tert-butyl group acetyl group-6-[(E)-1-phenyl-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
With 1-[2-oxo-3, the 3-dimethylbutyl]-2-chloro-5-[(E)-1-phenyl-2-methylamino formoxyl vinyl] (140mg 0.280mmol) obtains the 31.9mg product according to being transformed into product with embodiment 158 basic similarly modes to the pyridine iodide.(30％)。MS (HR): value of calculation C
22H
24N
4O
2376.1899, measured value 376.1900, NMR (300MHz, DMSO-d
6) d9.22 (s, 1H); 7.8 (d, 1H, J=4.4); 7.4-7.3 (m, 4H); 7.18 (d, 1H, J=4); (7.16 d, 1H, J=2,5); 6.43 (s, 1H); 6.35 (sa, 2H); 2.52 (d, 3H, J=4.4); 1.17 (s, 9H).
Embodiment 1622-amino-3-tert-butyl group acetyl group-6-[(E)-1-(2, the 3-difluorophenyl)-2-N-methylamino formoxyl vinyl]-imidazo [1,2-a] pyridine
With 1-[2-oxo-3; the 3-dimethylbutyl]-2-chloro-5-[(E)-1-(2; the 3-difluorophenyl)-and 2-methylamino formoxyl vinyl] (120mg 0.220mmol) obtains the 11.2mg product according to being transformed into product with embodiment 158 basic similarly modes to the pyridine iodide.(12％)。MS (HR): value of calculation C
22H
22N
4O
2F
2412.1711, measured value 412.1713, NMR (300MHz, CDCl
3) d9.4 (s, 1H); 7.28 (d, 1H, J=1.1); 7.21-7.14 (m, 3H); 6.98 (m, 1H); 6.49 (s, 1H); 5.62 (sa, 1H); 5.35 (s, 2H); 2.78 (d, 3H, J=4.76); 1.32 (s, 9H).
As mentioned above, chemical compound of the present invention can be used as antiviral agent.They have the activity of inhibition to various enterovirus and rhinovirus.One embodiment of the invention are methods that treatment or prevention picornavirus infect, and this method comprises, uses formula (I) compound or pharmaceutically acceptable salt thereof of effective dose to the host of the described treatment of needs.
Term used herein " effective dose " is meant the amount of the formula I chemical compound that can suppress virus replication.Comprise therapeutic or preventative treatment by the inhibition that method of the present invention realized to picornavirus.Certainly, should determine according to the concrete condition of case, comprise the chemical compound of for example using, route of administration, the disease of being treated and the individuality of being treated for the concrete dosage that obtains the The compounds of this invention that treatment or preventive effect use.Typically every day, dosage was that about 0.01mg/kg is to about 50 mg/kg body weight reactive compound of the present invention.Preferably every day, dosage was about O.05mg/kg to about 20mg/kg, and optimal dose is extremely about 10mg/kg of about 0.1mg/kg.
Chemical compound can carry out administration by all means, comprises oral, rectum, percutaneous, subcutaneous, intravenous, intramuscular and intranasal.Preferably before administration, chemical compound of the present invention is made preparation.Therefore, another embodiment of the invention is the pharmaceutical preparation that contains effective dose formula I compound or pharmaceutically acceptable salt thereof and pharmaceutically suitable carrier, diluent or excipient.
Active component content in the described preparation is 0.1% to 99.9% of a weight of formulation." pharmaceutically useful " is meant that carrier, diluent or excipient can be compatible with other composition of preparation and harmless to its user.
Pharmaceutical preparation of the present invention can prepare with composition known and that be easy to get by known method.When preparation compositions of the present invention, usually active component is mixed with carrier, or dilute with carrier, perhaps being encapsulated in can be in the carrier of capsule, sachet, paper capsule or other vessel form.When carrier during as diluent, it can be solid, semisolid or the fluent material of carrier, excipient or solvent as active component.Therefore, compositions can be tablet, pill, powder, lozenge, sachet, cachet, elixir, suspensoid, Emulsion, solution, syrup, aerosol (solid form or in liquid vehicle), contain the powder of the ointment of for example maximum 10% (weight) reactive compound, soft hard gelatin capsule, suppository, sterile injectable solution, aseptic packaging etc.
Following example of formulations only is illustrative, is not to want to limit by any way scope of the present invention.
Formulation example 1
Prepare hard gelatin capsule with following composition:
Amount
(mg/ capsule)
Active component 250
Exsiccant starch 200
Magnesium stearate 10
Total amount 460mg
Test method
Make African green monkey kidney cell (BSC-1) or Hela cell (5-3) in 25 milliliters of Falcon flasks in containing 5% inactivated fetal bovine serum (FBS), penicillin (150 units/ml) and in 199 culture medium of streptomycin (150 mcg/ml (μ g/ml)) grow under 37 ℃.When forming the monolayer that merges, remove the grown cultures liquid on upper strata and in each flask, add the suitable viral dilution liquid (for example echo, enteric cytopathogenic human orphan virus, Mengo virus, Coxsackie virus, poliovirus or rhinovirus) of 0.3ml.After at room temperature adsorbing 1 hour, the cell thin of viral infection is covered with 199 culture fluid that contain FBS, penicillin and streptomycin that contain 1 part of 1%Ionagar No.2 and 1 part of double strength, contain the medicine that concentration is 100,50,25,12,6,3 and 0 μ g/ml in the culture fluid.The contrast of the flask of medicine as test will do not contained.It is 10 that the storing solution of chemical compound is diluted to concentration with dimethyl sulfoxine
4μ g/ml.Then with the flask insulation, for poliovirus, Coxsackie virus, echo, enteric cytopathogenic human orphan virus and Mengo virus, in 37 ℃ of insulations 72 hours, for rhinovirus, in 32 ℃ of insulations 120 hours.Viral infection is being arranged and can see viral plaque in time multiplexed cell system zone.The sodium acetate that adds 10% formalin and 2% in each flask is with inactivation of viruses and make cell thin be fixed on the flask surface.With crystal violet with pericellular zone dyeing after, to plaque count, do not consider the size of plaque.Under each drug level, the counting and the contrast of plaque compared.The activity of test compound can be represented with percent or inhibition percent that plaque reduces.Perhaps, can weigh activity with the drug level that suppresses plaque formation 50%.50% inhibiting value is called " IC
50".Chemical compound of the present invention can demonstrate at least 30% under the single dose of 50 μ mol, preferred 50%, first-selected plaque formation inhibitory action 85% or more.Dose response titration to The compounds of this invention demonstrates IV
50Value＜10 μ M.
Claims (9)
1. formula I compound or pharmaceutically acceptable salt thereof:
Wherein:
A is the phenyl of phenyl, pyridine radicals, replacement, the pyridine radicals or the benzyl of replacement;
R is hydrogen, COR
4Or COCF
3
X is N-OH, O or CHR
1
R
1Be hydrogen, halogen, CN, C
1-C
4Alkyl ,-C ≡ CH, CO (C
1-C
4Alkyl), CO
2(C
1-C
4Alkyl) or CONR
2R
3
R
2And R
3Be hydrogen or C independently of one another
1-C
4Alkyl;
A ' is hydrogen, halogen, C
1-C
6Alkyl, benzyl, naphthyl, thienyl, furyl, pyridine radicals, pyrrole radicals, COR
4, S (O)
nR
4Or the group of following formula
R
4Be C
1-C
6The phenyl of alkyl, phenyl or replacement;
N is 0,1 or 2;
R
5Be hydrogen or halogen independently of one another when occurring at every turn;
M is 1,2,3 or 4;
R
6Be hydrogen, halogen, CF
3, OH, CO
2H, NH
2, NO
2, CONHOCH
3, C
1-C
4Alkyl or CO
2(C
1-C
4Alkyl), C
1-C
4Alkoxyl.
2. the chemical compound of claim 1, wherein R is a hydrogen.
3. the chemical compound of claim 2, wherein:
A is the phenyl of phenyl or replacement;
A ' is C
1-C
6Alkyl, COR
4, S (O)
nR
4Or the group of following formula
4. the chemical compound of claim 1, wherein X is NOH or CHR
1
5. the chemical compound of claim 3, wherein X is NOH or CHR
1
6. the chemical compound of claim 5, wherein:
X is CHR
1
R
1Be CN, CO (C
1-C
4Alkyl) or CONR
2R
3
A is fluoro phenyl or difluorophenyl;
A ' is the group of following formula
R
5It is halogen.
7. the method that suppresses hepatitis C virus, this method comprise, uses any described chemical compound in the claim 1 to 6 of effective dose to the host of needs.
8. the method that suppresses picornavirus, this method comprise, uses any described chemical compound in the claim 1 to 6 of effective dose to the host of needs.
9. pharmaceutical preparation, described preparation contain as any described chemical compound and one or more pharmaceutically useful carriers, excipient or diluent in the claim 1 to 6 of active component.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US1998/010299 WO1999059587A1 (en) | 1998-05-20 | 1998-05-20 | Anti-viral compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1292697A true CN1292697A (en) | 2001-04-25 |
Family
ID=22267098
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN988140519A Pending CN1292697A (en) | 1998-05-20 | 1998-05-20 | Anti-viral compound |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP1077701A4 (en) |
| JP (1) | JP2002515433A (en) |
| KR (1) | KR20010025055A (en) |
| CN (1) | CN1292697A (en) |
| AU (1) | AU7583098A (en) |
| BR (1) | BR9815899A (en) |
| CA (1) | CA2332403A1 (en) |
| CZ (1) | CZ289425B6 (en) |
| EA (1) | EA200001208A1 (en) |
| HU (1) | HUP0102117A2 (en) |
| IL (1) | IL139166A0 (en) |
| NO (1) | NO20005795L (en) |
| SK (1) | SK17482000A3 (en) |
| TR (1) | TR200003414T2 (en) |
| WO (1) | WO1999059587A1 (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102046621A (en) * | 2008-05-27 | 2011-05-04 | 生物区科学管理控股有限公司 | Antiviral salts |
| CN101218238B (en) * | 2005-03-21 | 2011-10-26 | S*Bio私人有限公司 | Imidazo[1,2-a]pyridine derivatives: preparation and pharmaceutical applications |
| CN102459165A (en) * | 2009-04-15 | 2012-05-16 | 雅培制药有限公司 | Anti-viral compounds |
| US8541424B2 (en) | 2008-12-23 | 2013-09-24 | Abbott Laboratories | Anti-viral compounds |
| US8546405B2 (en) | 2008-12-23 | 2013-10-01 | Abbott Laboratories | Anti-viral compounds |
| CN109535405A (en) * | 2017-09-21 | 2019-03-29 | 宁波聚嘉新材料科技有限公司 | The preparation method of polyarylate of the one kind based on 2- (4- carboxyl phenyl) -5- pyridone and imidazoles |
| CN109810085A (en) * | 2019-04-19 | 2019-05-28 | 上海皓元生物医药科技有限公司 | The preparation method of ACC inhibitor and its intermediate |
| CN110746450A (en) * | 2019-09-17 | 2020-02-04 | 济南康和医药科技有限公司 | Synthetic method of beraprost sodium key intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AUPR213700A0 (en) | 2000-12-18 | 2001-01-25 | Biota Scientific Management Pty Ltd | Antiviral agents |
| AR048650A1 (en) * | 2004-05-04 | 2006-05-10 | Tibotec Pharm Ltd | DERIVATIVES OF (1,10B-DIHIDRO-2- (AMINOCARBONIL-PHENYL) -5H-PIRAZOLO [1,5 C] [1,3] BENZOXAZIN-5-IL) METHANONE PHENYL AS INHIBITORS OF HIV VIRAL REPLICATION |
| DE602005020313D1 (en) | 2004-08-12 | 2010-05-12 | Amgen Inc | Bis-aryl SULPHONAMIDES |
| US7666880B2 (en) | 2005-03-21 | 2010-02-23 | S*Bio Pte Ltd. | Imidazo[1,2-A]pyridine derivatives: preparation and pharmaceutical applications |
| WO2007076035A2 (en) | 2005-12-21 | 2007-07-05 | Abbott Laboratories | Anti-viral compounds |
| ES2378473T3 (en) | 2005-12-21 | 2012-04-12 | Abbott Laboratories | Antiviral compounds |
| ES2395386T3 (en) | 2005-12-21 | 2013-02-12 | Abbott Laboratories | Antiviral compounds |
| WO2008133753A2 (en) | 2006-12-20 | 2008-11-06 | Abbott Laboratories | Anti-viral compounds |
| WO2014060381A1 (en) | 2012-10-18 | 2014-04-24 | Bayer Cropscience Ag | Heterocyclic compounds as pesticides |
| WO2014067962A1 (en) | 2012-10-31 | 2014-05-08 | Bayer Cropscience Ag | Novel heterocyclic compounds as pest control agents |
| CN104370732B (en) * | 2014-01-26 | 2015-08-19 | 山东信立泰药业有限公司 | The preparation method of a kind of clopidogrel and intermediate thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4096264A (en) * | 1975-12-09 | 1978-06-20 | Merck & Co., Inc. | Certain substituted imidazo [1,2-a] pyridines |
| US4250174A (en) * | 1979-05-02 | 1981-02-10 | Merck & Co., Inc. | 3-Substituted imidazo [1,2-A] pyridines |
| US5693661A (en) * | 1995-06-07 | 1997-12-02 | Eli Lilly And Company | Anti-viral compounds |
| US5891874A (en) * | 1996-06-05 | 1999-04-06 | Eli Lilly And Company | Anti-viral compound |
| CA2257296A1 (en) * | 1996-06-05 | 1997-12-11 | Mark Joseph Tebbe | Anti-viral compounds |
| US5821242A (en) * | 1996-06-06 | 1998-10-13 | Eli Lilly And Company | Anti-viral compounds |
-
1998
- 1998-05-20 AU AU75830/98A patent/AU7583098A/en not_active Abandoned
- 1998-05-20 IL IL13916698A patent/IL139166A0/en unknown
- 1998-05-20 JP JP2000549252A patent/JP2002515433A/en not_active Withdrawn
- 1998-05-20 CZ CZ20004278A patent/CZ289425B6/en unknown
- 1998-05-20 CN CN988140519A patent/CN1292697A/en active Pending
- 1998-05-20 HU HU0102117A patent/HUP0102117A2/en unknown
- 1998-05-20 WO PCT/US1998/010299 patent/WO1999059587A1/en not_active Application Discontinuation
- 1998-05-20 EP EP98923565A patent/EP1077701A4/en not_active Withdrawn
- 1998-05-20 TR TR2000/03414T patent/TR200003414T2/en unknown
- 1998-05-20 EA EA200001208A patent/EA200001208A1/en unknown
- 1998-05-20 SK SK1748-2000A patent/SK17482000A3/en unknown
- 1998-05-20 CA CA002332403A patent/CA2332403A1/en not_active Abandoned
- 1998-05-20 KR KR1020007012999A patent/KR20010025055A/en not_active Application Discontinuation
- 1998-05-20 BR BR9815899-6A patent/BR9815899A/en not_active IP Right Cessation
-
2000
- 2000-11-16 NO NO20005795A patent/NO20005795L/en not_active Application Discontinuation
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| CN101218238B (en) * | 2005-03-21 | 2011-10-26 | S*Bio私人有限公司 | Imidazo[1,2-a]pyridine derivatives: preparation and pharmaceutical applications |
| CN102046621B (en) * | 2008-05-27 | 2014-11-12 | 生物区科学管理控股有限公司 | Antiviral salts |
| CN102046621A (en) * | 2008-05-27 | 2011-05-04 | 生物区科学管理控股有限公司 | Antiviral salts |
| US9163017B2 (en) | 2008-12-23 | 2015-10-20 | Abbvie Inc. | Anti-viral compounds |
| US9249138B2 (en) | 2008-12-23 | 2016-02-02 | Abbvie Inc. | Anti-viral compounds |
| US8541424B2 (en) | 2008-12-23 | 2013-09-24 | Abbott Laboratories | Anti-viral compounds |
| US8546405B2 (en) | 2008-12-23 | 2013-10-01 | Abbott Laboratories | Anti-viral compounds |
| CN102459165B (en) * | 2009-04-15 | 2015-09-02 | Abbvie公司 | Antiviral compound |
| CN102459165A (en) * | 2009-04-15 | 2012-05-16 | 雅培制药有限公司 | Anti-viral compounds |
| US9278922B2 (en) | 2009-04-15 | 2016-03-08 | Abbvie Inc. | Anti-viral compounds |
| CN109535405A (en) * | 2017-09-21 | 2019-03-29 | 宁波聚嘉新材料科技有限公司 | The preparation method of polyarylate of the one kind based on 2- (4- carboxyl phenyl) -5- pyridone and imidazoles |
| CN109810085A (en) * | 2019-04-19 | 2019-05-28 | 上海皓元生物医药科技有限公司 | The preparation method of ACC inhibitor and its intermediate |
| CN110746450A (en) * | 2019-09-17 | 2020-02-04 | 济南康和医药科技有限公司 | Synthetic method of beraprost sodium key intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| NO20005795L (en) | 2001-01-18 |
| KR20010025055A (en) | 2001-03-26 |
| SK17482000A3 (en) | 2005-03-04 |
| TR200003414T2 (en) | 2001-03-21 |
| EA200001208A1 (en) | 2001-06-25 |
| CA2332403A1 (en) | 1999-11-25 |
| NO20005795D0 (en) | 2000-11-16 |
| HUP0102117A2 (en) | 2001-12-28 |
| IL139166A0 (en) | 2001-11-25 |
| WO1999059587A1 (en) | 1999-11-25 |
| EP1077701A4 (en) | 2002-03-20 |
| CZ289425B6 (en) | 2002-01-16 |
| EP1077701A1 (en) | 2001-02-28 |
| BR9815899A (en) | 2001-02-20 |
| AU7583098A (en) | 1999-12-06 |
| JP2002515433A (en) | 2002-05-28 |
| CZ20004278A3 (en) | 2001-05-16 |
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