CN101400674A

CN101400674A - Antibiotic compounds

Info

Publication number: CN101400674A
Application number: CNA2007800084306A
Authority: CN
Inventors: 吉恩-克里斯托福·高维恩; 克里斯蒂安·哈伯舒兰; 让-菲利普·斯维特; 科内丽亚·扎姆布朗恩·埃科林
Original assignee: Actelion Pharmaceuticals Ltd
Current assignee: Actelion Pharmaceuticals Ltd
Priority date: 2006-03-10
Filing date: 2007-03-09
Publication date: 2009-04-01
Also published as: CA2643962A1; EP1996579A2; WO2007105154A3; WO2007105154A2; JP2009529525A

Abstract

The invention relates to selected antibiotics of formula (Al) wherein R1 represents alkyl, alkoxy, haloalkoxy, halogen or cyano; one or two of U, V, W and X represent(s) N, the remaining represent CH, or, in case of U, V and/or W, may also represent CR<a> and, in the case of X, may also represent CR, R<a> representing halogen and R representing halogen or alkoxy; A<3> represents NHCO, CH2CH2, CH=CH, COCH2, CH(OH)CH2, CH2CH(OH), CH(OH)CH(OH) or OCH2; A<4> represents CH2, CO, CH2CH=CH, COCH=CH or CH2CONH; R<2> represents hydrogen, alkyl, hydroxyalkyl, alkylcarbonyloxyalkyl, carbamoyloxyalkyl, carboxyalkyl or carbamoylalkyl; R<3> and R<4> each independently represent hydrogen, hydroxy or alkylcarbonyloxy; or R<3> and R<4> together represent a bridged dimethylmethylenedioxy chain attached to the carbons bearing R<3> and R<4>; R<5> represents hydrogen, alkyl or hydroxyalkyl; and the dotted line represents a single bond or, when R<3> and R<4> represent hydrogen, also a double bond; and D represents alkyl, aryl or heteroaryl. An example of such an antibiotic is (E)-2-{(2R,3R,6R)-3-[3-(2,5-difluoro-phenyl)- allylamino]-6-[2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-2-yl}-ethanol.

Description

Antibiotique composition

The present invention relates to new microbiotic, comprise these new antibiotic antibacterial combinations and these compounds and be used for the treatment of purposes in the medicine of infection (for example infectation of bacteria) in preparation.These compounds comprise that to the various mankind and livestock pathogenic agent especially Gram-positive and Gram-negative aerobic and anerobe and mycobacterium are effective biocides.

Thereby antibiotic intensive use has forced microbial selective to be evolved produces the heredity mechanism of drug resistance.Modern medicine and social characteristic are the pathogenic micro-organism environment (for example in artificial joint) of having created slow growth and support secular pin main body (for example damaging patient's immunological competence), thereby aggravated chemical sproof development.

In hospital environment, streptococcus aureus (Staphylococcus aureus), streptococcus pneumoniae (Streptococcus pneumoniae), faecalis, Pseudomonas aeruginosa (Pseudomonas aeruginosa) number of series are increasing, main contagium develops into multidrug resistant, and therefore (if being not impossible) is difficult to treatment:

-streptococcus aureus has resistance to β-lactan and quinolone microbiotic, also has resistance now even to vancomycin;

-streptococcus pneumoniae has resistance to penicillin and quinolone microbiotic, even up-to-date macrolide is also had resistance;

-faecalis (Enteroccocci) has resistance to quinolone and vancomycin, and β-beta-lactam antibiotics also is invalid at these bacterial strains;

-enterobacteriaceae (Enterobacteriacea) has resistance to cynnematin and quinolone;

-Pseudomonas aeruginosa has resistance to β-lactan and quinolone.

The microorganism of other new generation (as acinetobacter or clostridium difficile (C.difficile)) (these microorganisms are selected in using existing antibiotic therapeutic process) is also just becoming the problem of a reality in hospital.

In addition, cause that the microorganism of persistent infection is considered to the pathogenic agent or the cofactor of severe chronic disease (for example stomach ulcer or heart trouble) gradually.

Therefore, reported a kind of novel quinoline with anti-microbial activity or 7-naphthyridine derivatives that is used for the treatment of the infection of Mammals (particularly human) in recent years.

WO 99/37635, WO 00/21948, WO 00/21952, WO 00/43383, WO 03/101138, WO 01/25227, WO 02/40474 and WO 2004/011454 disclose quinoline, naphthyridines and the quinazoline derivant that comprises 4-methyl piperidine base spacer groups.

WO 00/78748, WO 02/50040 and WO 02/50061 disclose quinoline and the 7-naphthyridine derivatives that comprises the piperazinyl spacer groups.

WO 01/07432, WO 01/07433, WO 02/08224, WO 02/056882, WO03/064421, WO 03/064431, WO 2004/002490 and WO 2004/058144 disclose quinoline, quinoxaline and the 7-naphthyridine derivatives that comprises 4-amino piperidine base spacer groups.

WO 04/035569 and WO 2006/014580 disclose quinoline and the 7-naphthyridine derivatives that comprises 3-aminomethyl piperidyl spacer groups.

WO 2004/002992, WO 03/087098, WO 2004/014361 and WO 2004/035569 disclose quinoline, quinoxaline and the 7-naphthyridine derivatives that comprises 4-aminocyclohexyl spacer groups.

In addition, PCT application No.PCT/EP2005/010154 (publication number WO 2006/032466) discloses some new bicyclic derivatives as the antimicrobial reagent that can effectively resist multiple bacterium with multi-drug resistant.Described bicyclic derivatives has formula (A1)

Wherein

R ¹Expression alkyl, alkoxyl group, halogenated alkoxy, halogen or cyano group;

One or two expression N among U, V, W and the X, remaining represents CH separately, or in the situation of U, V and/or W, also represents CR ^a, and in the situation of X, can also represent CR ^b

R ^aThe expression halogen;

R ^bExpression halogen or alkoxyl group;

D represents alkyl, aryl or heteroaryl;

M represents group M especially ²:

Wherein

A ³Expression NHCO, CH ₂CH ₂, CH=CH, COCH ₂, CH (OH) CH ₂, CH ₂CH (OH), CH (OH) CH (OH) or OCH ₂

A ⁴Expression CH ₂, CO, CH ₂CH=CH, COCH=CH or CH ₂CONH;

R ²Expression hydrogen, alkyl, hydroxyalkyl, alkyl carbonyl oxy alkyl, carbamoyloxy alkyl, carboxyalkyl or formamyl alkyl;

R ³And R ⁴Independent separately expression hydrogen, hydroxyl or alkyl carbonyl oxy; Perhaps R ³And R ⁴Common expression and be connected R ³And R ⁴The bridging dimethylated methylene dioxy base chain of carbon atom;

R ⁵Expression hydrogen, alkyl or hydroxyalkyl;

Dotted line is represented singly-bound, perhaps works as R ³And R ⁴During for hydrogen, also represent two keys.

The formula that the present invention relates to select as mentioned above (A1) compound and salt thereof.

Therefore compound of the present invention is selected from:

(E)-2-(2R, 3R, 6R)-(3-[3-(2,5-difluoro-phenyl)-allyl amino]-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-ethanol;

(2R, 3R, 6R)-3-[(E)-3-and (2,5-difluoro-phenyl)-acrylamide]-6-[2-(3-methoxyl group-quinoline-5-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-acetate;

(2R, 3R, 6R)-6-[2-(3-methoxyl group-quinoline-5-yl)-ethyl]-3-[(3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carbonyl)-ammonia]-tetrahydrochysene-pyrans-2-yl }-acetate;

(2R, 3R, 6R)-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-3-[(3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-ylmethyl)-ammonia]-tetrahydrochysene-pyrans-2-yl }-acetate;

(2R, 3R, 6R)-3-[(E)-3-and (2,5-difluoro-phenyl)-allyl amino]-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-acetate;

(2R, 3R, 6R)-3-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-6-[(1S)-1-hydroxyl-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-acetate;

(1R)-2-(2S, 5R, 6S)-5-and [anti--3-(2,5-difluoro-phenyl)-allyl amino]-6-hydroxymethyl-tetrahydrochysene-pyrans-2-yl }-1-(3-fluorine-6-methoxyl group-quinoline-4-yl)-ethanol;

(1S)-2-(2S, 5R, 6S)-5-and [anti--3-(2,5-difluoro-phenyl)-allyl amino]-6-hydroxymethyl-tetrahydrochysene-pyrans-2-yl }-1-(3-fluorine-6-methoxyl group-quinoline-4-yl)-ethanol;

2-(2R, 3R, 6R)-3-[(E)-3-and (2,5-difluoro-phenyl)-allyl amino]-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-ethanamide;

2-(2R, 3R, 6S)-3-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-6-[(1R, 2R)-1,2-dihydroxyl-2-(3-methoxyl group-quinoxaline-5-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-ethanamide;

(2R, 3R, 6R)-3-[(E)-3-and (2,5-difluoro-phenyl)-allyl amino]-6-[2-(6-methoxyl group-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-acetate;

2-(2R, 3R, 6R)-3-[(E)-3-and (2,5-difluoro-phenyl)-allyl amino]-6-[2-(6-methoxyl group-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-ethanamide;

2-(2R, 3R, 6S)-3-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-6-[(S)-1-hydroxyl-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-ethanamide;

3-(2,5-difluoro-phenyl)-N-(2S, 3R, 6S)-6-[(2R)-2-(3-fluorine-6-methoxyl group-quinoline-4-yl)-2-hydroxyl-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-(E)-acrylamide;

3-(2,5-difluoro-phenyl)-N-(2S, 3R, 6S)-6-[(2S)-2-(3-fluorine-6-methoxyl group-quinoline-4-yl)-2-hydroxyl-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-(E)-acrylamide;

3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid { (2S, 3R, 6S)-6-[(2R)-2-(3-fluorine-6-methoxyl group-quinoline-4-yl)-2-hydroxyl-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-acid amides;

3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid { (2S, 3R, 6S)-6-[(2S)-2-(3-fluorine-6-methoxyl group-quinoline-4-yl)-2-hydroxyl-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-acid amides;

3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid { (2S, 3R, 6S)-6-[(2R)-2-hydroxyl-2-(3-methoxyl group-quinoline-5-yl)-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-acid amides;

3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid { (2S, 3R, 6S)-6-[(2S)-2-hydroxyl-2-(3-methoxyl group-quinoline-5-yl)-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-acid amides;

3-(2,5-difluoro-phenyl)-N-(2S, 3R, 6S)-6-[(2R)-2-hydroxyl-2-(3-methoxyl group-quinoline-5-yl)-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-(E)-acrylamide;

3-(2,5-difluoro-phenyl)-N-(2S, 3R, 6S)-6-[(2S)-2-hydroxyl-2-(3-methoxyl group-quinoline-5-yl)-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-(E)-acrylamide;

2-(2R, 3R, 6S)-3-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-6-[(E)-2-(3-fluorine-6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-2-yl }-ethanamide;

(2S, 5R, 6R)-(5-[(E)-3-and (2,5-difluoro-phenyl)-allyl amino]-6-(2-hydroxyl-ethyl))-tetrahydrochysene-pyrans-2-carboxylic acid (6-methoxyl group-[1,5] naphthyridines-4-yl)-acid amides;

(2S, 5R)-5-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-tetrahydrochysene-pyrans-2-carboxylic acid (6-methoxyl group-[1,5] naphthyridines-4-yl)-acid amides;

(1S)-1-(2S, 5R)-5-[(E)-3-(3-fluorine-phenyl)-allyl amino]-tetrahydrochysene-pyrans-2-yl }-2-(6-methoxyl group-quinoline-4-yl)-ethanol;

7-fluorine-6-((3R, 6S)-6-[(1S)-1-hydroxyl-2-(6-methoxyl group-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-basic ammonia }-methyl)-4H-benzo [1,4] thiazine-3-ketone;

3-(2-fluorine-phenyl)-N-(3R, 6S)-6-[(1S)-1-hydroxyl-2-(6-methoxyl group-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-(E)-acrylamide;

3-(3-fluorine-phenyl)-N-(3R, 6S)-6-[(1S)-1-hydroxyl-2-(6-methoxyl group-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-(E)-acrylamide;

8-((1R, 2R)-2-(2S, 5R)-5-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-tetrahydrochysene-pyrans-2-yl }-1,2-dihydroxyl-ethyl)-quinoline-2-nitrile;

[(E)-3-(2,5-difluoro-phenyl)-allyl group]-3R, 6S)-6-[(E)-2-(3-fluorine-6-methoxyl group-quinoline-5-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-amine;

[(E)-3-(2,5-difluoro-phenyl)-allyl group]-(3R, 6S)-6-[2-(6-fluorine-3-methoxyl group-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-amine;

6-((3R, 6S)-6-[2-(6-fluorine-3-methoxyl group-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-basic ammonia }-methyl)-4H-pyrido [3,2-b] [1,4] thiazine-3-ketone;

(1R, 2R)-1-(2R, 5S)-5-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-tetrahydrochysene-pyrans-2-yl }-2-(6-fluorine-quinoline-4-yl)-ethane-1,2-glycol;

[(E)-3-(2,5-difluoro-phenyl)-allyl group]-(3S, 6R)-(E)-6-[2-(6-fluorine-quinoline-4-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-amine;

[(E)-3-(2,5-difluoro-phenyl)-allyl group]-(3S, 6R)-6-[2-(6-fluorine-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-amine;

6-(3S, 6R)-6-[2-(6-fluorine-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-basic ammonia }-methyl)-4H-pyrido [3,2-b] [1,4] thiazine-3-ketone;

3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid { (2R, 3R, 6S)-2-(2-hydroxyl-ethyl)-6-[(E)-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-acid amides;

2-(2R, 3R, 6S)-3-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-6-[(E)-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-2-yl }-ethanamide;

(2R, 3R, 6S)-3-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-6-[(E)-2-(3-fluorine-6-methoxyl group-quinoline-4-yl)-vinyl]-tetrahydrochysene-pyrans-2-yl }-acetate;

(2R, 3R, 6S)-3-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-6-[(E)-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-2-yl }-acetate;

[(2R, 3R, 6S)-3-[(E)-3-and (2,5-difluoro-phenyl)-allyl amino]-6-(6-methoxyl group-[1,5] naphthyridines-4-basic formamyl)-tetrahydrochysene-pyrans-2-yl]-acetate;

And salt.

The present invention be more particularly directed to following compound:

And salt.

Preferred following compound:

And salt.

According to first kind of specific embodiments, compound of the present invention is selected from:

And salt.

According to described-kind of specific embodiments, compound of the present invention is selected from especially:

And salt.

According to described-kind of specific embodiments, compound of the present invention can also be selected from:

And salt.

According to-kind of specific embodiments-individual version, compound of the present invention is selected from:

[(E)-3-(2,5-difluoro-phenyl)-allyl group]-(35,6R)-6-[2-(6-fluorine-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-amine;

And salt.

According to first kind of described version of specific embodiments, compound of the present invention is selected from especially:

And salt.

According to another version of first kind of specific embodiments, compound of the present invention is selected from:

And salt.

According to second specific examples, compound of the present invention is selected from:

And salt.

Formula I compound is applicable in human and livestock treatment as the chemotherapy active compound, and as the material of preserving inorganic and organic materials (particularly various organic materialss, for example polymkeric substance, lubricant, coating, fiber, leather, paper and timber).

The activity that has directed toward bacteria and bacterium sample biology according to compound of the present invention especially.Therefore, they are particularly suitable for preventing and treat local infection and the systemic infection that is caused by pathogenic agent in the mankind and the livestock treatment, and the illness relevant with infectation of bacteria, comprise, by streptococcus pneumoniae (Streptococcuspneumoniae), hemophilus influenzae (Haemophilus influenzae), moraxelle catarrhalis (Moraxellacatarrhalis), streptococcus aureus (Staphylococcus aureus), enterococcus faecalis, urine enterococcus (E.faecium), Enterococcus casseliflavus (E.casseliflavus), staphylococcus epidermidis (S.epidermidis), Streptococcus hemolyticus (S.haemolyticus), or Peptostreptococcus (Peptostreptococcus spp.) infects relevant pneumonia, otitis media, sinusitis, bronchitis, tonsillitis and mastoiditis; Infect relevant pharyngitis, rheumatic fever and glomerulonephritis by micrococcus scarlatinae (Streptococcus pyogenes), suis C and G group, diphtheria corynebacterium (Corynebacteriumdiphtheriae) or hemorrhagic coryneform bacteria (Actinobacillus haemolyticum); By mycoplasma pneumoniae (Mycoplasma pneumoniae), legionella pneumophilia (Legionella pneumophila), streptococcus pneumoniae (Streptococcus pneumoniae), hemophilus influenzae (Haemophilus influenzae) or the relevant respiratory tract infection of infection involving chlamydia pneumoniae; By streptococcus aureus, Streptococcus hemolyticus (S.haemolyticus), enterococcus faecalis (E.faecalis), faecium (E.faecium), enterococcus durans (E.durans), comprise blood or tissue infection that the bacterial classification of anti-known microbiotic (such as but not limited to β-lactan, vancomycin, aminoglycoside, quinolone, Mono Chloro Acetic Acid, tsiklomitsin and macrolide) causes, comprise endocarditis and osteomyelitis; Infect relevant simple skin and soft tissue infection and abscess by streptococcus aureus (Staphylococcus aureus), coagulase negative staphylococcus (being staphylococcus epidermidis, Streptococcus hemolyticus etc.), micrococcus scarlatinae, streptococcus agalactiae (Streptococcusag alactiae), suis group C-F (minute colony suis), viridans streptococci, Corynebacterium minutissimum (Corynebacteriumminutissimum), fusobacterium (Clostridium spp.) or Heng Senbaertong bacterium (Bartonella henselae), and lochiopyra; Infect relevant simplified acute urinary tract infections by streptococcus aureus, coagulase-negative staphylococcal species or faecalis; Urethritis and trachelitis; Infect relevant sexually transmitted disease (STD) by chlamydia trachomatis, Ducrey bacillus, treponema pallidum (Treponemapallidum), Ureaplasma urealyticum (Ureaplasma urealyticum) or Neiserria gonorrheae; Infect relevant toxin disease by streptococcus aureus (food poisoning and toxic shock syndrome) or suis A, B with the C group; Infect relevant ulcer by helicobacter pylori (Helicobacter pylori); Infect relevant whole body heating syndromes by Spirochaeta recurrentis (Borrelia recurrentis); Infect relevant Lyme disease by lime pathogenic bacteria (Borrelia burgdorferi); Infect relevant conjunctivitis, neuroparalytic keratitis and dacryocystitis by chlamydia trachomatis, gonococcus (Neisseria gonorrhoeae), streptococcus aureus, streptococcus pneumoniae, streptococcus pyogenes, Haemophilus influenzae (H.influenzae) or Li Site Pseudomonas (Listeria spp.); Infect multiple disease (MAC) disease of relevant propagation mycobacterium avium by mycobacterium avium (Mycobacterium avium) or Mycobacterium intracellulare (Mycobacterium intracellulare); The infection that causes by Mycobacterium tuberculosis (Mycobacterium tuberculosis), Mycobacterium leprae (M.Leprae), mycobacterium paratuberculosis (M paratuberculosis), mycobacterium kansasii (Mkansasii) or Mycobacterium chelonei (M chelonei); Infect relevant gastroenteritis by campylobacter jejuni (Campylobacterjejuni); Infect relevant intestinal protozoa by Cryptosporidium (Cryptosporidium spp.); Infect relevant odontogenic infection by Streptococcus viridans; Infect relevant persistent cough by bordetella pertussis (Bordetellapertussis); Infect relevant gas gangrene by clostridium perfringens (Clostridium perfringens) or Bacteroides (Bacteroides spp.); By helicobacter pylori or relevant atherosclerosis or the cardiovascular disorder of infection involving chlamydia pneumoniae.

Formula I compound according to the present invention also is used to prepare the medicine that treatment is infected, it is used to regulate bacterium, for example big enterobacteria, klebsiella pneumoniae (Klebsiella pneumoniae) and other enterobacteriaceae, acinetobacter, Stenothrophomonas maltophilia, Neisseria meningitidis, waxy Bacillus (Bacillus cereus), Bacillus anthracis (Bacillus anthracis), rod bacillus (Corynebacteriumspp.), propionibacterium acnes (Propionibacterium acnes) and Bacteroides (bacteroide spp).

Formula I compound according to the present invention also is used for the treatment of the protozoal infections that is caused by malaria plasmodium, plasmodium falciparum, toxoplasma gondii, Pneumocystis carinii, trypanosoma bocagei and leishmania.

The pathogenic agent of more than enumerating is used for explaining as just example, and is not to be to its restriction.

Except that the mankind, also can be used for the infectation of bacteria of others, as pig, ruminating animal, horse, dog, cat and poultry.

The present invention also relates separately to pharmacy acceptable salt, solvate and hydrate, and the composition of above-claimed cpd and preparation.

The example of basic cpd pharmacy acceptable salt of the present invention comprises, the salt of physiologically acceptable mineral acid, for example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid; Or organic acid salt, for example methylsulfonic acid, tosic acid, lactic acid, acetate, trifluoroacetic acid, citric acid, succsinic acid, fumaric acid, toxilic acid and Whitfield's ointment.In addition, acidic cpd of the present invention can form alkaline or alkaline-earth salts, for example sodium, potassium, lithium, calcium or magnesium salts; Ammonium salt; Organic alkali salt, for example methylamine, dimethylamine, Trimethylamine 99, triethylamine, quadrol, thanomin, choline hydroxide, meglumin, piperidines, morpholine, three (2-hydroxyethyl) amine, Methionin or arginic acid salt.Compound of the present invention can be solvate, especially hydrate.Can be in process of production, perhaps because the water absorbability of initial anhydrous compound of the present invention is carried out hydration reaction.

At least comprise a kind of above-mentioned compound of enumerating (or its pharmacy acceptable salt) as active ingredient and optional carrier and/or thinner and/or auxiliary according to pharmaceutical composition of the present invention, also may comprise other known microbiotic.

As mentioned above, treatment effectively comprises the reagent of compound of the present invention, solvate, its salt and preparation thereof equally within the scope of the present invention.Generally, compound of the present invention can combine separately or with other drug, by known in the art and acceptable manner administration.This treatment effective agents one of can be in the following manner administration: oral, for example tablet, dragee, sugar coated tablet, ball, semisolid, soft or hard capsule (for example soft with hard gelatin capsules), water or oil solution, emulsion, suspension or syrup; Administered parenterally comprises intravenous injection, muscle and subcutaneous injection, for example as injectable solution or suspension; As the suppository rectal administration, suck or injection as powder formulation, crystallite or sprays (for example liquid aerosol); Transdermal delivery system (TDS), the ointment that for example comprises activeconstituents be through percutaneous drug delivery, part or intranasal administration.Material of the present invention can also be used to infiltrate or be plated in the device that is used to transplant, as catheter or artificial joint.Pharmaceutically effective agents can also contain additive and be used for storage and stable purposes, for example salt of UV stabilizer, emulsifying agent, sweetener, spices, change seepage water pressure, buffer reagent, overlay film additive and antioxidant.

The present invention relates to the method for the treatment of disease on the other hand, comprises according to the pharmaceutical active amount using according to compound of the present invention (or its pharmacy acceptable salt) to the patient.

In addition, formula I compound can also be used for cleaning purpose, for example be used to remove pathogenic micro-organism and bacterium on the instruments, or make aseptic place and zone.When being used for this purposes, The compounds of this invention can be contained in solution or the spray agent.

Prepare compound of the present invention

Abbreviation:

Use following abbreviation:

AcOH acetate

AD-mix α 1,4-two (hydroquinine) phthalazines, K ₃Fe (CN) ₆, K ₂CO ₃And K ₂OsO ₄.2H ₂O

AD-mix β 1,4-two (dihydrochinidin) phthalazines, K ₃Fe (CN) ₆, K ₂CO ₃And K ₂OsO ₄.2H ₂O

AIBN 2,2 '-Diisopropyl azodicarboxylate

Aq. aqueous

BINAP 1,1 '-dinaphthalene-2,2 '-two diphenyl phosphines

BOC ₂O di-t-butyl sodium bicarbonate

The dba dibenzalacetone

DCC dicyclohexyl carbimide

1,2-DCE, 1,2-ethylene dichloride

The DCM methylene dichloride

(DHQ) ₂PHAL 1,4-two (hydroquinine) phthalazines

(DHQD) ₂PHAL 1,4-two (dihydrochinidin) phthalazines

The DIAD diisopropyl azodiformate

The DIBAH diisobutyl aluminium hydride

The DIPA Diisopropylamine

DIPEA N, N-diisopropylethylamine

DMAP 4-dimethyl aminopyridine

1,2-DME, 1,2-glycol dimethyl ether

DMF N, N-dimethyl formamide

The DMSO dimethyl sulfoxide (DMSO)

DMPU 1,3-dimethyl-3,4,5,6-tetrahydro--2 (1H)-pyrimidone

The EA ethyl acetate

The ESI electron spray(ES)

Ether or Et ₂The O ether

EtOH ethanol

H hour

HATU O-(7-azo benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester

The Hept heptane

The Hex hexane

The HV high vacuum condition

KHMDS hexamethyl silicon amine potassium

MeOH methyl alcohol

Min minute

The MCPBA metachloroperbenzoic acid

The MeCN acetonitrile

The MS mass spectroscopy

NBS N-bromo-succinimide

NHS N-N-Hydroxysuccinimide

N-BuLi n-Butyl Lithium

Org. organic

Pd/C is adsorbed on the palladium on the gac

PPh ₃Triphenylphosphine

The PTSA tosic acid

Quant. quantitative

The rac racemization

The Rf retention factors

Sat. saturated

SiO ₂Silica gel

The rt room temperature

The TBAF tetrabutyl ammonium fluoride

The TEA triethylamine

The TFA trifluoroacetic acid

The THF tetrahydrofuran (THF)

The TsCl Tosyl chloride

The wt% weight percent

The preparation method

Compound of the present invention can prepare according to the step that following examples are described, and it is used to illustrate the preparation of pharmaceutically active compound of the present invention, and unrestricted its scope.

When compound of the present invention uses the form of mixtures of enantiomorph to obtain, can use method well known in the art with Chiral Separation (for example, forming and the salt that separates diastereomer, perhaps chromatographic separation on chiral stationary phase).When compound of the present invention uses the form of mixtures of diastereomer to obtain, can separate by the appropriate combination of silica gel chromatography, high performance liquid chromatography (HPLC) and crystallization processes.

Embodiment

All temperature are ℃.The basic post of RP-C18 is used in all chirality facies analyses and preparation HPLC test.To analyze the HPLC test and on two different instruments, carry out, the cycle is respectively～and 2.5 minutes and～3.5 minutes.

Preparation A:3-methoxyl group-quinoline-5-formaldehyde

A.i.3,5-two bromoquinolines:

Under 0 ℃ temperature, (50g) dropwise joins vitriol oil H with 3-bromoquinoline ₂SO ₄Surpass 80 minutes (130ml), the speed control of adding is 0～10 ℃ at internal temperature.After adding fully, by part adding a NBS (48g), and stirred reaction mixture a whole night at room temperature.Pour on ice reaction mixture into (2L), and resulting solid is dissolved in DCM (600ml).With DCM (600m) aqueous layer extracted, the extract of merging washs through 1M NaOH (300ml), and concentrates in a vacuum.Resistates is adsorbed on SiO ₂On, the dispersive gains are positioned at the top of post, with DCM-Hex (1-1,3L) wash-out is used DCM (3L) then, use at last DCM-ether (1-1,2L) wash-out.The cut evaporation of last time obtains the title compound of 40g white solid.

¹HNMR(CDCl ₃)δ：8.94(d，J＝2.2Hz，1H)；8.73(d，J＝2.2Hz，1H)；8.08(d，J＝8.5Hz，1H)；7.88(d，J＝7.5Hz，1H)；7.62(dd，J＝7.5，8.5Hz，1H)。

A.ii.5-bromine-3-methoxy quinoline:

With the mixture heating up to 125 of sodium methylate (14.5g) and DMPU (350ml) ℃, and to wherein adding a part of intermediate A .i (34.5g).Reacting by heating is 1 hour under uniform temp.Reaction mixture is to room temperature then, and pours to (300g) on ice.Behind the ice-out, leach solid and dry in a vacuum.With ether (4 * 150ml) extraction filtrates.The extract salt water washing that merges, and at Na ₂SO ₄Last dry.Filter the back evaporating solvent, resistates is through SiO ₂(hexane-ethyl acetate 4-1) purifying obtains and solid blended material.This material is dissolved in DCM, and at Na ₂SO ₄Last dry.Filter, evaporate, the further in a vacuum drying of solid obtains the title compound (24.5g) of beige solid shape.

¹H?NMR(CDCl ₃)δ：8.68(d，J＝2.8Hz，1H)；8.03(d，J＝8.3Hz，1H)；7.80(d，J＝7.5Hz，1H)；7.72(d，J＝2.8Hz，1H)；7.42(dd，J＝7.5，8.3Hz，1H)；4.02(s，3H)。

MS(ESI，m/z)：239.7[M+H ⁺]。

A.iii.3-methoxyl group-quinoline-5-formaldehyde:

THF (250ml) solution of intermediate A .ii (10g) is cooled to-78 ℃, adds n-BuLi (22ml).After 15 minutes, add ether (20ml) solution of DMF (10ml) rapidly.Stirred solution 15 minutes adds EtOH (5ml), adds 1M NaHSO then ₄(40ml).Be warming up to room temperature, with EA (100ml) dilution organic layer.Two separate is used EA (100ml) aqueous layer extracted 1 time.The organic layer salt water washing that merges, and evaporate to dryness.Resistates is through SiO ₂(EA-Hex1-2, then 1-1) chromatography purification obtains the title compound (4.75g) of little yellow solid shape.

¹HNMR(CDCl ₃)δ：10.32(s，1H)；9.02(d，J＝2.9Hz，1H)；8.75(d，J＝2.9Hz，1H)；8.31(d，J＝8.3Hz，1H)；8.02(d，J＝7.1Hz，1H)；7.72(dd，J＝7.1，8.3Hz，1H)；4.02(s，3H)。

MS(ESI，m/z)：187.9[M+H ⁺]。

Preparation B:6-methoxyl group-[1,5] naphthyridines-4-formaldehyde

B.i.2-methoxyl group-8-styryl-[1,5] naphthyridines:

With 6-methoxyl group-[1,5] naphthyridines-4-basic trifluoromethayl sulfonic acid ester (1.5g, 4.86mmol), trans styryl boric acid (0.8g, 5.35mmol) and K ₂CO ₃(0.9g, 6.32mmol) double-neck flask of packing into.Use the nitrogen flush environment.Add dioxane (20ml) and water (5ml).At room temperature stirred the mixture 5 minutes, and added Pd (PPh ₃) ₄(0.28g, 0.24mmol).Mixture added 5 hours under refluxing.Cooling back EA (10ml) and water (50ml) diluted reaction mixture.With EA (2 * 100ml) aqueous layer extracted.The extract that evaporate to dryness merges.Resistates is through SiO ₂(hexane-ethyl acetate 1-1) chromatography purification obtain leaving standstill crystalline buttery title alkene (1.26g, 4.8mmol).

¹H?NMR(d6—DMSO)δ：8.77(d，J＝4.7Hz，1H)；8.28(d，J＝9.0Hz，1H)；8.19(d，J＝16.7Hz，1H)；8.01(d，J＝4.7Hz，1H)；7.91(d，J＝16.7Hz，1H)；7.74(m，2H)；7.40—7.34(m，3H)；7.30(d，J＝9.0Hz，1H)；4.12(s，3H)。

B.ii.1-(6-methoxyl group-[1,5] naphthyridines-4-yl)-2-phenyl-ethane-1,2-glycol

(1.26g adds amsacrine (0.52g) and AD in the mixture of 2-methyl 4.8mmol)-2-propyl alcohol (24ml) and water (24ml) to intermediate B .i

(7g).At room temperature stirred the mixture 12 hours.The careful sodium bisulfite (7.5g) that adds also continues to stir 20 minutes.Two-layer decant is come out, and (2 * 100ml) extract water layer with EA.The organic layer that merges is at Na ₂SO ₄Last drying, filtration and evaporate to dryness.Resistates hexane-ethyl acetate (1-3, grind in 30ml), leach the gained solid, and the dry in a vacuum title glycol (1.3g) that obtains white solid.

MS(ESI，m/z)：297.1[M+H ⁺]。

B.iii.6-methoxyl group-[1,5] naphthyridines-4-formaldehyde:

(1.3g adds NaIO in acetone 4.4mmol) (15ml) solution to intermediate B .ii ₄(2.35g, water 10.96mmol) (5ml) solution.At room temperature stirred reaction mixture is 30 minutes.Compound of reaction leaches solid through THF (100ml) dilution.Evaporate to dryness filtrate, with the resistates resuspending in water (100ml), ether (10ml) and Hex (100ml).At room temperature stirred slurries 15 minutes and filtration.Solid water and Hex washing.Obtain the title aldehyde (0.42g) of white solid after the drying.

¹HNMR(d6—DMSO)δ：11.25(s，1H)；9.02(d，J＝4.4Hz，1H)；8.42(d，J＝9.1Hz，1H)；7.92(d，J＝4.4Hz，1H)；7.40(d，J＝9.1Hz，1H)；4.11(s，3H)。

Preparation C:(E)-3-(2,5-difluoro-phenyl)-propenal:

C.i. (E)-3-(2,5-difluoro-phenyl)-vinylformic acid ethyl ester:

To the NaH of ice-cooled mistake (1.13g, 60% is suspended in oil, add in THF 28.2mmol) (32ml) suspension triethyl phosphine acetic ester (5.6ml, 28.2mmol).At room temperature stirred reaction mixture is 20 minutes.Dropwise add 2,5-difluoro-phenyl aldehyde (3.34g, 23.5mmol).After 30 minutes, add 10%NaHSO ₄(100ml) aqueous solution, mixture dilutes with EA (150ml).Separate two-phase, with EA (2 * 100ml) aqueous layer extracted 2 times.The organic layer that merges is with salt water washing (100ml), at Na ₂SO ₄Last drying, filtration and evaporate to dryness.Resistates is at SiO ₂(hexane-ethyl acetate 19-1) goes up the title unsaturated ester (5.0g, 100%) that chromatography purification obtains colorless oil.

¹H?NMR(CDCl ₃)：7.76(dd，J＝1，16.1Hz，1H)；7.26—7.21(m，1H)；7.13—7.03(m，2H)；16.1Hz，1H)；4.29(q，J＝7.1Hz，2H)；1.36(t，J＝7.1Hz，3H)。

C.ii. (E)-3-(2,5-difluoro-phenyl)-the third-2-alkene-1-alcohol:

With intermediate C.i (5.0g, ether 23.5mmol) (100ml) solution cool off at 0 ℃, add DIBAH solution (1M is dissolved in Hex, 60ml, 60mmol).Under uniform temp, stirred the mixture 40 minutes.Add entry (6ml), stirred the mixture 30 minutes.Solid leaches the back and thoroughly washs with ether.Filtrate concentrates the title alcohol (4.0g, productive rate 98%) that evaporate to dryness obtains colorless oil.

¹H?NMR(CDCl ₃)：7.15(ddd，J＝3.1，5.9，9.0Hz，1H)；7.00(td，J＝4.6，9.0Hz，1H)；6.95—6.87(m，1H)；6.75(dd，J＝1.3，16.1Hz，1H)；6.45(td，J＝5.3，16.1Hz，1H)；4.38(br?d，J＝5.3Hz，2H)；1.63(s，1H)。

C.iii. (E)-3-(2,5-difluoro-phenyl)-propenal

At room temperature, (1.70g adds in DCM 10mmol) (20ml) solution that Dess-(15wt% is dissolved in DCM to the Martin oxidizing agent solution, 20ml) to intermediate C.ii.At room temperature stirred the mixture 3 hours.Be concentrated into anhydrous after, resistates is at SiO ₂(hexane-ethyl acetate 9-1) goes up the title aldehyde (1.06g, productive rate 63%) that chromatography purification obtains white solid.

¹H NMR (d6-DMSO): 9.74 (d, J=7.6Hz, 1H); 7.88-7.81 (m, 1H); 7.79 (overlapping, dd, J=1.4,16.0Hz, 1H); 7.46-7.37 (m, 2H); 6.67 (dd, J=7.6,16.0Hz, 1H).

Preparation D:3-methoxyl group-quinoxaline-5-formaldehyde:

D.i.2-cyano group-N-(2-methyl-6-nitro-phenyl)-ethanamide:

To 2-methyl-6-N-methyl-p-nitroaniline (25g, add in benzene 164.3mmol) (200ml) solution cyanoacetic acid (14.5g, 170.46mmol) and PCl ₅(35g, 168mmol).In 60 ℃ of following reacting by heating mixtures 7 hours.After being cooled to room temperature, filter reaction mixture, solid benzene and water washing.The solid drying under reduced pressure obtain the yellow solid shape the title ethanamide (24g, 109mmol).

¹H?NMR(d6—DMSO)δ：10.2(s，1H)；7.78(d，J＝8.3Hz，1H)；7.65(d，J＝8.3Hz，1H)；7.43(t，J＝8.3Hz，1H)；3.95(s，2H)；2.30(s，3H)。

D.ii.3-hydroxyl-5-methyl-1-oxygen base-quinoxaline-2-formonitrile HCN:

(24g adds pyridine (100ml) in 1Maq.NaOH 109.5mmol) (100ml) mixing solutions to intermediate D.i.Reaction mixture at room temperature stirred 4 hours.Adding 1Maq.HCl adjusting pH is 6.Leach solid and wash with water.Solid grinds with EtOH.Dry in a vacuum then, obtain the yellow solid shape the title nitrile (17.7g, 87.9mmol).

MS(ESI，m/z)：202.1[M+H] ⁺。

D.iii.8-methyl-quinoxaline-2-alcohol:

To intermediate D.ii (17.7g, add in water 87.9mmol) (300ml) and EtOH (24ml) solution V-Brite B (35.4g, 203.9mmol).Reaction mixture heated 1 hour down at 60 ℃.Reaction mixture filters when warm, adds 1Maq.HCl and regulates filtrate pH to 2.Add solid NaOH (10g) then, pH value of solution becomes alkalescence.Add EA (150ml).(2 * 150ml) extract 2 times water layer with EA.The organic extract liquid that merges is at Na ₂SO ₄Last drying, filtration and concentrated evaporate to dryness.Resistates is dry in a vacuum obtain the yellow solid shape the title intermediate (11.1g, 69mmol).

¹H?NMR(d6—DMSO)δ：11.75(br?s，1H)；8.17(s，1H)；7.62(d，J＝8.4Hz，1H)；7.40(d，J＝8.4Hz，1H)；7.21(t，J＝8.4Hz，1H)；2.42(s，3H)。

MS(ESI，m/z)：161.1[M+H] ⁺。

D.iv.2-chlorine-8-methyl-quinoxaline:

(11.1g, phosphoryl chloride 69.5mmol) (80ml) solution heated 2 hours down at 110 ℃ intermediate D.iii.After being cooled to room temperature, reaction mixture is poured on the ice (200g).(2 * 200ml) extract water layer with EA.The extraction liquid that merges is with salt solution (100ml) washing, at Na ₂SO ₄Last drying, filtration and concentrated evaporate to dryness.Resistates through silica gel (Hex-EA1-1) chromatogram purification obtain the red solid shape the title intermediate (12.5g, 69.5mmol).

¹HNMR(d6—DMSO)δ：8.99(s，1H)；7.97(m，1H)；7.80(m，2H)；2.68(s，3H)。

MS(ESI，m/z)：179.2[M+H] ⁺。

D.v.2-methoxyl group-8-methyl-quinoxaline:

To intermediate D.iv (12.5g, add in DMF 69.5mmol) (80ml) solution sodium methylate (9g, 166mmol).Reaction mixture heated 4 hours down at 45 ℃.After being cooled to room temperature, reaction mixture separates and water (10ml) and EA (200ml).Organic layer water (100ml) washs once, at Na ₂SO ₄Last drying, filtration and concentrated evaporate to dryness.Resistates through silica gel (Hex-EA 1-4) chromatogram purification obtain the yellow solid shape the title intermediate (10.2g, 58.55mmol).

¹HNMR(CDCl ₃)δ：8.48(s，1H)；7.88(d，J＝7.9Hz，1H)；7.55(d，J＝7.9Hz，1H)；7.47(t，J＝7.9Hz，1H)；4.12(s，3H)；2.69(s，3H)。

MS(ESI，m/z)：175.4[M+H] ⁺。

D.vi.8-two brooethyl-2-methoxyl group-quinoxaline:

CCl to intermediate D.v (10.2g) ₄(560ml) add in the solution AIBN (0.96g) and NBS (25.9g, 145.5mmol).Reaction mixture heated 3 hours down at 80 ℃.After being cooled to room temperature, water (200ml) washing reaction mixture, organic layer is at Na ₂SO ₄Last dry, filtration and concentrated in a vacuum.Resistates grinds with MeOH, after drying in a vacuum, obtain micron look solid state the title dibromide (14.4g, 43.3mmol).

¹H?NMR(d6—DMSO)δ：8.69(s，1H)；8.25(dd，J＝1.3，7.5Hz，1H)；8.07(dd，J＝1.3，8.3Hz，1H)；8.02(s，1H)；7.74(dd，J＝7.5，8.3Hz，1H)；4.14(s，3H)。

MS(ESI，m/z)：332.8[M+H] ⁺。

D.vii.3-methoxyl group-quinoxaline-5-formaldehyde:

At room temperature, (10.7g adds water (70ml) solution of Silver Nitrate (15g) in EtOH 32.2mmol) (330ml) solution to intermediate D.vi.At room temperature stirring reaction is 1 hour.With MeCN (200ml) diluted reaction mixture, leach solid, filtrate concentrates in a vacuum.Resistates through silicagel pad (elutriant: EA) filter the title aldehyde obtain little yellow solid shape (6.2g, 32.2mmol).

¹H?NMR(d6—DMSO)δ：11.15(s，1H)；8.74(s，1H)；8.36(dd，J＝1.3，8.1Hz，1H)；8.21(dd，J＝1.3，7.9Hz，1H)；7.80(dd，J＝7.9，8.1Hz，1H)；4.14(s，3H)。

MS(ESI，m/z)：189.2[M+H] ⁺。

Preparation E:3-fluorine-6-methoxyl group-[1,5] naphthyridines-4-formaldehyde

E.i. instead-7-fluorine-2-methoxyl group-8-styryl-[1,5] naphthyridines:

8-bromine-7-fluorine-2-methoxyl group-[1,5] naphthyridines (is prepared according to WO 2004/058144; 7g, 27.2mmol), anti--phenyl vinyl boric acid (4.23g, 1.05eq) and K ₂CO ₃(4.9g) double-neck flask of packing into.Use the nitrogen flush environment, add dioxane (40ml) and water (10ml).At room temperature stirred the mixture 5 minutes, and added Pd (PPh ₃) ₄(1.56g, 5mol%).Mixture heats a whole night under refluxing.After the cooling, evaporating solvent in a vacuum, resistates is with EA (2 * 150ml) extractions.The extract salt water washing that merges is at Na ₂SO ₄Last drying, filtration and evaporate to dryness.Resistates obtains the title compound (7.2g, productive rate 94%) of white solid through chromatography purification (heptane-ethyl acetate 2-1).

MS(ESI，m/z)：281.0[M+H ⁺]。

E.ii.1-(3-fluorine-6-methoxyl group-[1,5] naphthyridines-4-yl)-2-phenyl-ethane-1,2-glycol:

(7.2g 8.9mmol) is starting raw material, uses the 2.iv step of embodiment 2, makes the title glycol (7.6g, productive rate 94%) of white foam shape with intermediate E .i.Compound use EA as elutriant through chromatogram purification.

¹H?NMR(CDCl ₃)δ：8.42(d，J＝0.7Hz，1H)；8.28(d，J＝9.1Hz，1H)；7.24—7.15(m，4H)；7.08(m，2H)；6.70(br?s，1H)；5.28(br?s，1H)；5.10(d，J＝7.9Hz，1H)；4.11(s，3H)；3.85(br?s，1H)。

E.iii.3-fluorine-6-methoxyl group-[1,5] naphthyridines-4-formaldehyde:

(7.6g adds NaIO in acetone 23.95mmol) (150ml) solution to intermediate E .ii ₄Water (12.8g) (30ml) solution.At room temperature stirred the mixture 1 hour.Remove in a vacuum and desolvate, resistates water (500ml) dilution.Leach the gained solid, water thoroughly washs, and collects and the dry in a vacuum title aldehyde (4.0g) that obtains light beige solid shape.

¹H?NMR(d6—DMSO)δ：11.08(s，1H)；9.01(d，J＝1.3Hz，1H)；8.41(d，J＝9.1Hz，1H)；7.37(d，J＝9.1Hz，1H)；4.09(s，3H)。

MS(ESI，m/z)：206.9[M+H ⁺]。

Preparation F:3-fluorine-6-methoxyl group-quinoline-5-formaldehyde

F.i.5-bromine-3-fluorine-6-methoxyl group-quinoline:

MeCN (9ml) solution of 3-fluorine-6-methoxyl group-quinoline (0.89g) is cooled to 0 ℃, adds NBS (1g).Mixture stirred 2 hours under this temperature.Reaction mixture is risen to room temperature and react a whole night.Add 10%aq.NaHSO ₃(20ml).Mixture dilute with water (100ml) leaches the gained solid, washes with water, the dry in a vacuum title compound (1.03g, productive rate 80%) that obtains white solid.

¹HNMR(d ₆—DMSO)δ：8.85(d，J＝2.7Hz，1H)；8.18(dd，J＝2.7，10.2Hz，1H)；8.14(d，J＝9.0Hz，1H)；7.77(d，J＝9.0Hz，1H)；4.04(s，3H)。

MS(ESI，m/z)：255.7[M—H ⁺]。

F.ii.3-fluorine-6-methoxyl group-quinoline-5-formaldehyde:

With intermediate F.i (1.0g 3.9mmol) is starting raw material, uses E.i, E.ii and the E.iii step of preparation E, make white solid title aldehyde (0.68g, 3.31mmol).

¹H?NMR(d ₆—DMSO)δ：10.69(s，1H)；9.16(dd，J＝2.9，11.7Hz，1H)；8.88(d，J＝2.9Hz，1H)；8.38(d，J＝9.0Hz，1H)；7.83(d，J＝9.0Hz，1H)；4.12(s，3H)。

Preparation G:(3R, 6S)-[6-(1-phenyl-1H-tetrazolium-5-sulfonymethyl)-tetrahydrochysene-pyrans-3-yl]-t-butyl carbamate:

G.i. (2S, 5R)-5-tert-butoxycarbonyl ammonia-tetrahydrochysene-pyrans-2-toluene-4-sulfonic group methyl esters:

To ice-cooled mistake (3R, 6S)-(6-hydroxymethyl-tetrahydrochysene-pyrans-3-yl)-t-butyl carbamate (makes according to the described method of Eur.J.Org.Chem. (2003); 25g adds TEA (30ml), DMAP (1.8g) and TsCl (22.6g) in DCM 108mmol) (650ml) solution.Reaction was at room temperature stirred 4 hours.Add saturated NaHCO ₃(100ml).Under reduced pressure remove volatile matter, resistates is dissolved in EA (400ml).Organic layer is with saturated CuSO ₄(2 * 150ml), water (3 * 150ml) and salt solution (100ml) washing.Organic layer is at Na ₂SO ₄Last drying, filtration and concentrated evaporate to dryness, after drying obtains white solid (41.8g), and it need not purifying and can use.

G.ii. (3R, 6S)-(6-iodomethyl-tetrahydrochysene-pyrans-3-yl)-t-butyl carbamate:

(18g adds NaI (20g) in acetone 46.7mmol) (200ml) solution to intermediate G.i.Reaction mixture refluxed heating 24 hours.Be cooled to room temperature, add entry (200ml), remove volatile matter in a vacuum.Filtration residue, and water and Hex thoroughly wash, and obtains the iodide (12.2g, productive rate 76%) of beige solid in the high vacuum condition drying.

MS(ESI，m/z)：342.2[M+H ⁺]。

G.iii. (3R, 6S)-[6-(1-phenyl-1H-tetrazolium-5-basic sulfenyl methyl)-tetrahydrochysene-pyrans-3-yl]-t-butyl carbamate:

(7g adds KOH (3.0g) in EtOH 39mmol) (100ml) solution to 1-phenyl-1H-tetrazolium-5-mercaptan.Reaction mixture refluxed 1 hour, and adding intermediate G.ii (11.6g, 34mmol).Mixture refluxes a whole night.Add entry (150ml), under reduced pressure remove volatile matter.Leach solid, water thoroughly washs, the dry sulfide (13.3g, quantitative) that obtains white solid in high vacuum.

MS(ESI，m/z)：392.5[M+H ⁺]。

G.iv. (3R, 6S)-[6-(1-phenyl-1H-tetrazolium-5-sulfonymethyl)-tetrahydrochysene-pyrans-3-yl]-t-butyl carbamate:

(13.3g, ((11g 8.9mmol), adds 30% H to EtOH 34mmol) then to add the ammonium molybdate tetrahydrate in the solution of 150ml and THF (150ml) to intermediate G.iii ₂O ₂(50ml).Mixture heats a whole night down at 60 ℃.Reaction mixture is cooled to room temperature, and volatile matter is under reduced pressure removed in water (200ml) dilution.Resistates is located away from EA (300ml) and water (100ml), and (2 * 300ml) extract water layer with EA.The extract that merges concentrates evaporate to dryness.With the resistates resuspending in ether.Leach solid, water and Hex washing obtain the title sulfone (11.8g, productive rate 81%) of white solid.

¹H?NMR(CDCl ₃)δ：7.69—7.60(m，5H)；4.23(m，1H)；3.95—3.80(m，2H)；3.68—3.52(m，2H)；2.86(t，J＝10.7Hz，1H)；2.11(m，1H)；1.79(m，1H)；1.60—45(m，2H)；1.43(s，9H)；1.37(m，1H)。

MS(ESI，m/z)：424.5[M+H ⁺]。

Preparation H:6-fluorine-quinoline-4-formaldehyde

(prepare with 4-bromine-6-fluorine-quinoline with reference to WO 2004/014361; 6g 26.5mmol) is starting raw material, uses E.i, E.ii and the E.iii step of preparation E, make the beige solid shape title aldehyde (4.3g, 24.5mmo1).

¹H?NMR(d6—DMSO)δ：10.50(s，1H)；9.23(d，J＝4.2Hz，1H)；8.68(dd，J＝2.9，10.8Hz，1H)；8.25(dd，J＝5.8，9.3Hz，1H)；8.11(d，J＝4.2Hz，1H)；7.83(ddd，J＝2.9，9.3，10.8Hz，1H)。

Preparation I:(3S, 6R)-[6-(1-phenyl-1H-tetrazolium-5-sulfonymethyl)-tetrahydrochysene-pyrans-3-yl]-carboxylamine tertiary butyl ester

I.i. (S)-(1-hydroxymethyl-penta-4-thiazolinyl)-t-butyl carbamate:

At room temperature, (1.15g adds the olefin(e) acid methyl esters (12.9g of (S)-2-tert-butoxycarbonyl ammonia-5-in THF 53mmol) (300ml) suspension to LiBH4,53mmol, according to J.Org.Chem. (1995), 60,2210 the preparation) THF (100ml) solution.At room temperature stirred the mixture 4 hours, and poured water into, and extract with EA.Organic layer salt water washing is at MgSO ₄Last dry, concentrate the title alcohol (11.4g, productive rate 99%) that obtains colorless oil.

¹H?NMR(CDCl ₃)δ：5.75—5.65(m，1H)，5.00—4.90(m，2H)，4.5(br，1H，OH)，3.70—3.45(m，3H)，2.10—2.00(m，2H)，1.60—1.35(m，2H)，1.38(s，9H)。

I.ii. (1S, 3RS, 4RS)-(1-hydroxymethyl-3-oxyethane-propyl group)-t-butyl carbamate

(11.4g 53mmol) is dissolved in 1,2-DCE (300ml) and water (250ml), adds 1M phosphoric acid buffer agent pH8 (150ml) with intermediate compound I .i.Add MCPBA (14.3g, 1.1eq, 70%), mixture firmly stirs a whole night.Separate phase, water extracts once more with DCM.The organic layer that merges is with saturated NaHCO ₃Solution washing is at MgSO ₄Last dry, filter and concentrated evaporate to dryness.Resistates is through SiO ₂(Hex:EA1:1 is EA then) chromatogram purification obtains the title epoxide (7.74g, productive rate 63%, the mixture of diastereomer) of colorless oil.

¹H?NMR(CDCl ₃)δ：4.90—4.85(m，1H)，3.75—3.50(m，3H)，3.00—2.90(m，1H)，2.80—2.51(m，1H)，2.6(br，1H，OH)，2.55—2.50(m，1H)，1.80—1.40(m，4H)，1.42(s，9H)。

I.iii. (3S, 6R)-(6-hydroxymethyl-tetrahydrochysene-pyrans-3-yl)-t-butyl carbamate

Intermediate compound I .ii (2.3g, solution and the D of DCM 10mmol) (50ml), L-10 camphorsulfonic acid (0.1eq) reaction.Reaction is heating slightly.Mixture at room temperature stirred 3 hours, concentrated and through SiO ₂(EA) chromatogram purification obtains the title tetrahydropyran derivatives (0.874g, productive rate 37%) of colorless solid shape.

¹HNMR(CDCl ₃)δ：4.28(br，1H)，4.20—10(m，1H)，3.70—3.30(m，5H)，3.04(t，1H，J＝10.6Hz)，2.20—2.00(m，2H，1.75—1.20(m，11H)。

I.iv. (3R, 6S)-[6-(1-phenyl-1H-tetrazolium-5-sulfonymethyl)-tetrahydrochysene-pyrans-3-yl]-t-butyl carbamate:

With intermediate compound I .iii (8.2g 35.4mmol) is starting raw material, uses the step of preparation G, make white solid the title sulfone (5.9g, 13.9mmol).

Embodiment 1:(E)-2-(2R, 3R, 6R)-(3-[3-(2,5-difluoro-phenyl)-allyl amino]-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-ethanol

1.i.[(2R, 3R, 6S)-6-(tertiary butyl-dimethyl-silanyloxy ylmethyl)-2-((2RS)-2,3-dihydroxyl-propyl group)-3,6-dihydro-2H-pyrans-3-yl]-t-butyl carbamate:

To (2R, 3R, 6S)-[2-allyl group-6-(tertiary butyl-dimethyl-silanyloxy ylmethyl)-3,6-dihydro-2H-pyrans-3-yl]-(according to Eur.J.Org.Chem. (2003), 2418-2427 described methods make t-butyl carbamate; 60.7g, add in the mixture of 2-methyl 158.2mmol)-2-propyl alcohol (750ml) and water (750ml) red prussiate of potash (182.4g, 553.8mmol), salt of wormwood (65.8g, 476.0mmol), (DHQ) ₂(1.12g is 1.4mmol) with potassium perosmate dihydrate (0.118g) for PHAL.Reaction mixture is mechanical stirring 24 hours at room temperature.Slowly add sodium bisulfite (316g).Two-layer decant, water layer extracts once more with EA (500ml).The organic extract liquid salt water washing that merges is at MgSO ₄Last drying, filtration and concentrated evaporate to dryness.Resistates is through SiO ₂(Hex-EA1-4) pad filters the title glycol that obtains yellow oily, and (61.0g, 146.0mmol), this compound is 2-1 epimer mixture.

MS(ESI，m/z)：418.0[M+H ⁺]。

1.ii.[(2R, 3R, 6S)-2-((4RS)-2,2-dimethyl-[1,3] dioxolane-4-ylmethyl)-6-hydroxymethyl-tetrahydrochysene-pyrans-3-yl]-t-butyl carbamate:

To intermediate 1.i (61g, add in THF 146.0mmol) (710ml) mixture PTSA (1.38g, 7.3mmol) and 2,2-Propanal dimethyl acetal (54.0ml, 439.1mmol).Reaction mixture at room temperature stirred 90 minutes.(1M is dissolved in THF, 230ml) to add TBAF.Reacted 90 minutes.Reaction mixture concentrates evaporate to dryness, and resistates is through SiO ₂(Hex-EA1-4) chromatogram purification obtain thickness buttery title compound (44.7g, 130.1mmol).This compound is 2-1 epimer mixture.

MS(ESI，m/z)：344.2[M+H ⁺]。

1.iii.[(2R, 3R, 6S)-2-((4RS)-2,2-dimethyl-[1,3] dioxolane-4-ylmethyl)-6-hydroxymethyl-tetrahydrochysene-pyrans-3-yl]-t-butyl carbamate

(19.7g adds platinum oxide (0.7g) in EA 57.3mmol) (230ml) solution to intermediate 1.ii.Gained suspension stirred in hydrogen 5 hours.Remove catalyzer through diatomite filtration, the filtrate decompression distillation.Resistates is through SiO ₂(EA-Hex4-1～1-0) column chromatography purifying obtains the title compound (19.43g) of white solid.This compound is 2-1 epimer mixture.

MS(ESI，m/z)：346.1[M+H ⁺]。

1.iv.[(2R, 3R, 6S)-2-((4R)-2,2-dimethyl-[1,3] dioxolane-4-ylmethyl)-6-(1-phenyl-1H-tetrazolium-5-basic sulfenyl methyl)-tetrahydrochysene-pyrans-3-yl]-t-butyl carbamate

(19.4g dropwise adds PPh3 (29g), phenyltetrazole mercaptan (14g) and DIAD (16.7ml) in THF 56.1mmol) (500ml) solution to the intermediate 1.iii of ice-cooled mistake.Gained solution at room temperature stirs a whole night.Reaction mixture concentrates evaporate to dryness, and resistates is through SiO ₂(EA-Hex1-3～1-0) column chromatography purifying obtains the title sulfide (28.85g, productive rate 99%) of colorless solid shape.This compound is 2-1 epimer mixture.

MS(ESI，m/z)：506.0[M+H ⁺]

1.v.[(2R, 3R, 6S)-2-((4RS)-2,2-dimethyl-[1,3] dioxolane-4-ylmethyl)-6-(1-phenyl-1H-tetrazolium-5-sulfonymethyl)-tetrahydrochysene-pyrans-3-yl]-t-butyl carbamate

In the EtOH of intermediate 1.iv (28.4g) (240ml) and THF (240ml) solution, add ammonium molybdate heptahydrate (17.73g) and 50% aq.H ₂O ₂(82.5ml).Mixture heats a whole night down at 60 ℃.Be cooled to room temperature, reaction mixture dilute with water (250ml) is under reduced pressure removed volatile matter.In aqueous resistates, add EA (150ml), separate phase.Water layer extracts three times with EA.The organic layer that merges is at MgSO ₄Last dry, filtration, and underpressure distillation.Resistates is through SiO ₂(DCM-MeOH 19-1～9-1) column chromatography purifying at first obtains the required sulfone of colorless viscous oil, obtain the [(2R of white foam then, 3R, 6S)-2-((2RS)-2,3-dihydroxyl-propyl group)-6-(1-phenyl-1H-tetrazolium-5-sulfonymethyl)-tetrahydrochysene-pyrans-3-yl]-t-butyl carbamate (9.4g).The latter is dissolved in THF (90ml), and reacts with PTSA (0.187g) and 2,2-Propanal dimethyl acetal (6.95ml).Reaction mixture at room temperature stirred 2.5 hours.Add entry (8ml) and aq.NaHCO ₃, concentrate evaporate to dryness then.Resistates is located away from water and EA, separates phase.Organic layer salt water washing is at MgSO ₄Last dry, also underpressure distillation of filtration.Resistates is after drying in high vacuum, obtains more title sulfone (9.94g).

MS(ESI，m/z)：538.0[M+H ⁺]。

1.vi.{ (2R, 3R, 6S)-2-((4RS)-2,2-dimethyl-[1,3] dioxolane-4-ylmethyl)-6-anti--[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate

With 6-methoxyl group-[1,5] naphthyridines-4-formaldehyde (reference preparation B; 1.7g, 9.03mmol) and intermediate 1.v (4g, 1,2-DME 7.45mmol) (40ml) solution is cooled to-78 ℃, (0.5M is dissolved in toluene, 24ml) above 10 minutes dropwise to add KHMDS.Under this temperature, stirred the mixture 30 minutes.Reaction is risen to room temperature surpass 30 minutes, add entry (50ml).Two-layer decant, water layer EA (2 * 150ml) extracting twice.The organic layer salt water washing that merges is at Na ₂SO ₄Last dry, filter and concentrated evaporate to dryness.Resistates is through SiO ₂(Hex-EA 1-1 then 1-4) chromatogram purification obtains the title alkene (2.8g, productive rate 62%) of colourless foam shape.

MS(ESI，m/z)：500.4[M+H ⁺]

1.vii.a.{ (2R, 3R, 6S)-2-(2-hydroxyl-ethyl)-6-anti--[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

With

1.vii.b.{ (2R, 3R, 6R)-2-(2-hydroxyl-ethyl)-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate

Intermediate 1.vi (2.8g, 5.6mmol) be dissolved in THF-AcOH-water mixture (1-3-1,50ml) and 60 ℃ the heating 6 hours.Reaction mixture is concentrated evaporate to dryness, and resistates is cut apart in EA and saturated NaHCO ₃Between, add NaHCO ₃Solid is regulated pH to 7.Water layer extracts once with EA, and the salt water washing of the organic layer of merging is through Na ₂SO ₄Drying, filtration and concentrated evaporate to dryness.Resistates is dissolved in acetone (100ml), adds warm NaIO ₄Water (3g) (10ml) solution.Stirred the mixture 1 hour.Reaction mixture filters by Celite pad, removes in a vacuum and desolvates.Resistates EA extracting twice.The organic layer that merges is through Na ₂SO ₄Dry, filtration and concentrated in a vacuum.Resistates is dissolved in MeOH (30ml), adds NaBH ₄(0.7g).Reacted 15 minutes.Add 10%aq.NaHSO ₄(100ml).Remove volatile matter in a vacuum, (3 * 100ml) extract three times aqueous resistates with EA.The organic layer salt water washing that merges is through Na ₂SO ₄Drying, filtration and concentrated evaporate to dryness.Resistates is through SiO ₂(DCM-MeOH 19-1) chromatogram purification obtains colourless foam (1.76g), it is characterized in that the mixture of two kinds of title compounds.

MS(ESI，m/z)：430.1[M+H ⁺]。

1.viii.a.{ (2R, 3R, 6R)-2-(2-hydroxyl-ethyl)-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

With

1.viii.b.[(2R, 3R, 6S)-6-[(1R, 2R)-1,2-dihydroxyl-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-2-(2-hydroxyl-ethyl)-tetrahydrochysene-pyrans-3-yl]-t-butyl carbamate:

In the solution of intermediate 1.vii (1.76g, the mixture of compound), add red prussiate of potash (4.04g), K ₂CO ₃(1.7g) amsacrine (0.47g), (DHDQ) ₂PHAL (0.035g) and potassium perosmate dihydrate (0.005g).Mixture at room temperature stirred 40 hours.Add sodium bisulfite (6g).Two-layer decant, (2 * 150ml) extract 2 times water layer with EA.The organic layer salt water washing that merges is through Na ₂SO ₄Drying, filtration and concentrated evaporate to dryness.Resistates is through SiO ₂(DCM-MeOH 19-1) chromatogram purification, obtain colourless foam the first title alkane 1.viii.a (1.34g, 3.1mmol).

MS(ESI，m/z)：432.0[M+H ⁺]

With DCM-MeOH 6-1 wash-out purifying obtain the colourless foam shape title glycol 1.viii.b (0.4g, 0.86mmol).

MS(ESI，m/z)：464.3[M+H ⁺]。

1.ix. (2R, 3R, 6R)-2-{ 3-ammonia-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-ethanol:

At room temperature, stir intermediate 1.viii.a (1.34g, TFA 3.1mmol) (10ml) solution 15 minutes.Be evaporated to do after, with resistates water-soluble (50ml), once with EA (50ml) extraction.The pH that adds 3Maq.NaOH adjusting water layer is 12, and (4 * 100ml) extract 4 times water layer with DCM-MeOH 9-1 mixture.The organic layer that merges is with the salt water washing, through Na ₂SO ₄Drying, filtration and concentrated evaporate to dryness.Dry in high vacuum, resistates is through SiO ₂(DCM-MeOH 6-1 contains 1%aq.NH ₄OH) chromatogram purification obtains the title amine (0.65g, productive rate 63%) of colourless foam shape.

MS(ESI，m/z)：332.3[M+H ⁺]。

1.x. (E)-2-(2R, 3R, 6R)-3-[3-(2,5-difluoro-phenyl)-allyl amino]-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-ethanol:

(0.1g, the solution of 1,2-DCE 0.3mmol) (4.5ml) and MeOH (1.5ml) add (E)-3-(2,5-difluoro-phenyl)-propenal, and (with reference to preparation C, 0.055g is 1.1eq.) with 3 to intermediate 1.ix

Molecular sieve (1g).Mixture heats a whole night down at 50 ℃.Add NaBH after being cooled to room temperature ₄(0.1g).Reacted 2 hours, and passed through then

Pad filters (with saturated aq.NaHCO ₃Handle).Filtrate is concentrated evaporate to dryness.Resistates is through SiO ₂(DCM-MeOH 19-1 contains 0.5% aq.NH ₄OH) chromatogram purification obtains water white oil (0.09g, productive rate 61%).

MS(ESI，m/z)：484.1[M+H ⁺]。

Embodiment 2:{ (2R, 3R, 6R)-3-[(E)-3-and (2,5-difluoro-phenyl)-acrylamide]-6-[2-(3-methoxyl group-quinoline-5-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-acetate

2.i.{ (2R, 3R, 6S)-2-((4RS)-2,2-dimethyl-[1,3] dioxolane-4-ylmethyl)-6-[(E)-2-(3-methoxyl group-quinoline-5-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate

Use the 1.vi step of embodiment 1, (1.99g is 3.7mmol) with 3-methoxyl group-quinoline-5-formaldehyde (reference preparation A with intermediate 1.v; 0.67g) be starting raw material, carry out the Julia coupling obtain the white foam shape title compound (1.07g, 2.14mmol).Compound is through SiO ₂(EA-Hex 1-1) chromatogram purification.This compound is 2-1 epimer mixture.

MS(ESI，m/z)：499.2[M+H ⁺]。

2.ii.{ (2R, 3R, 6R)-2-((4RS)-2,2-dimethyl-[1,3] dioxolane-4-ylmethyl)-6-[2-(3-methoxyl group-quinoline-5-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

(1.07g adds 10%Pd/C (0.23g) in EA 2.14mmol) (35ml) solution to intermediate 2.i.Gained suspension stirred 1 hour under hydrogen.Remove by filter catalyzer.Filtrate decompression distillation, and in high vacuum the dry title compound that obtains the white foam shape (1.03g, 2.05mmol).This compound is 2-1 epimer mixture.

MS(ESI，m/z)：501.1[M+H ⁺]。

2.iii.3-(2RS)-(2R, 3R, 6R)-3-ammonia-6-[2-(3-methoxyl group-quinoline-5-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-propane-1,2-glycol:

With TFA (21ml) solution stirring of intermediate 2.ii (1.03g) 10 minutes.Add entry (7ml).Stirred the gained mixture 1 hour and concentrate drying.Resistates adds the 1Maq.NaOH alkalization.Add DCM-MeOH9-1 and separate phase.Water layer extracts 6 times with DCM-MeOH9-1, and the extract of merging is through MgSO ₄Dry, also underpressure distillation of filtration.Obtain the white foam shape title compound (0.69g, 1.91mmol).This compound is 2-1 epimer mixture.

¹HNMR (CDCl ₃) master signal δ: 8.65 (d, J=2.8Hz, 1H); 7.89 (d, J=8.4Hz, 1H); 7.56 (m, 1H); 7.45 (m, 1H); 7.31 (m, 1H); 4.03 (m, 1H); 3.94 (s, 3H); 3.79 (m, 1H); 3.63 (m, 2H); 3.47 (m, 1H); 3.14 (m, 2H); 2.95 (m, 1H); 2.25-2.05 (m, 5H); 2.03-1.87 (m, 3H); 1.85-1.67 (m, 3H); 1.59 (m, 1H); 1.23 (m, 1H).

MS(ESI，m/z)：361.1[M+H ⁺]。

2.iv. (E)-3-(2,5-difluoro-phenyl)-N-(2R, 3R, 6R)-2-((2RS)-2,3-dihydroxyl-propyl group)-6-[2-(3-methoxyl group-quinoline-5-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-acrylamide:

To intermediate 2.iii (0.360g, 1mmol) and 3-(2,5-difluoro-phenyl)-vinylformic acid (0.203g, add in DMF 1.1mmol) (15ml) solution DIPEA (0.514ml, 3mmol) and HATU (0.456g, 1.2mmol).Reaction mixture at room temperature stirred 90 minutes and concentrated evaporate to dryness.Resistates is dissolved in DCM-MeOH9-1 (50ml), and with saturated NaHCO ₃(20ml) washing.(2 * 20ml) extractions 2 times, the organic layer of merging is through MgSO with DCM-MeOH 9-1 for water layer ₄Dry, also underpressure distillation of filtration.Resistates is through SiO ₂(DCM-MeOH 19-1 contains 1% aq.NH ₄OH～DCM-MeOH 9-1 contains 1% aq.NH ₄OH) column chromatography purifying obtains the title amide (0.331g, productive rate 62%) of orange solids shape.

¹H NMR (d ₆-DMSO) master signal δ: 8.69 (d, J=2.7Hz, 1H); 8.30 (d, J=8.6Hz, 1H); 7.87-7.79 (m, 2H); 7.56-7.50 (m, 4H); 7.40-7.27 (m, 2H); 7.02 (dd, J=5.1,15.9Hz, 1H); 4.58 (m, 2H); 4.23 (m, 1H); 4.06 (overlapping, m, 2H); 4.02 (overlapping, s, 3H); 3.86-3.76 (m, 2H); 3.45-3.24 (overlapping, m, 2H); 3.09-2.99 (m, 1H); 2.16 (m, 1H); 2.00 (m, 3H); 1.67 (m, 2H); 1.37 (m, 1H); 1.21 (m, 1H).

MS(ESI，m/z)：527.0[M+H ⁺]。

2.v. (E)-3-(2,5-difluoro-phenyl)-1-(2RS, 5R)-2-hydroxyl-5-[2-(3-methoxyl group-quinoline-5-yl)-ethyl]-six hydrogen-pyrans [3,2-b] pyrroles-1-yl }-acrylketone:

At room temperature, in acetone (1.7ml) solution of intermediate 2.iv (0.153g), add NaIO ₄Water (0.156g) (0.5ml) solution.Reaction mixture stirred 30 minutes and concentrated evaporate to dryness.Resistates is through SiO ₂(EA-Hex 2-1) purifying obtains not having coloring agent (0.118g, productive rate 82%).

MS(ESI，m/z)：495.1[M+H ⁺]。

2.vi.{ (2R, 3R, 6R)-3-[(E)-3-and (2,5-difluoro-phenyl)-acrylamide]-6-[2-(3-methoxyl group-quinoline-5-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-acetate:

(0.114g dropwise adds water (2ml) solution of Textone (0.193g) and SODIUM PHOSPHATE, MONOBASIC (0.193g) in 2-methyl 0.23mmol)-2-propyl alcohol (5ml) and 2-methyl-2-butylene (1.2ml) solution to intermediate 2.v.Gained solution at room temperature stirs a whole night, and removes volatile matter in high vacuum.Resistates water and Hex dilution.Separate phase, organic layer extracts 1 time with Hex.It is 3 that water layer is acidified to pH, and extracts 3 times with EA.The extract that merges is with cold water washing and underpressure distillation.The no coloring agent of gained grinds in ether, filters and drying under reduced pressure, obtains the title compound (0.069g, productive rate 58%) of white solid.

¹H NMR (d ₆-DMSO) δ: 12.32 (br.s, 1H); 8.82 (m, 1H); 8.58 (m, 1H); 8.05 (m, 2H); 7.51 (m, 4H); 7.37 (m, 2H); 7.03 (m, 1H); 4.36 (m, 1H); 4.02 (overlapping, s, 3H); 4.01 (overlapping, m, 1H); 3.86 (m, 1H); 3.39 (m, 1H); 3.10 (m, 1H); 2.44 (overlapping, m, 2H); 2.25 (m, 1H); 1.92 (m, 2H); 1.65 (m, 2H); 1.37 (m, 1H).

MS(ESI，m/z)：511.0[M+H ⁺]。

Embodiment 3:{ (2R, 3R, 6R)-6-[2-(3-methoxyl group-quinoline-5-yl)-ethyl]-3-[(3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carbonyl)-ammonia]-tetrahydrochysene-pyrans-2-yl }-acetate

3.i.3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid { (2R, 3R, 6R)-2-((2RS)-2,3-dihydroxyl-propyl group)-6-[2-(3-methoxyl group-quinoline-5-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-acid amides:

With intermediate 2.iii (0.270g, 0.75mmol) and 3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] (0.174g 1.1eq) is starting raw material to thiazine-6-carboxylic acid, uses the 2.iv step of embodiment 2, obtain light brown orange foamed title compound (0.187g, 0.32mmol).This compound is 2-1 epimer mixture.

¹H NMR (d ₆-DMSO) master signal δ: 11.29 (s, 1H); 8.69 (dd, J=1.7,2.7Hz, 1H); 8.36 (d, J=9.3Hz, 1H); 8.01 (d, J=7.9Hz, 1H); 7.88-7.79 (m, 2H); 7.66 (dd, J=1.3,7.9Hz, 1H); 7.51 (m, 1H); 4.64 (d, J=5.2Hz, 2H); 4.58 (m, 1H); 4.25 (m, 1H); 4.08 (overlapping, m, 1H); 4.03 (overlapping, s, 3H); 3.95 (m, 1H); 3.77 (m, 1H); 3.69 (d, J=5.1Hz, 2H); 3.39-3.25 (overlapping, m, 4H); 3.07 (m, 1H); 2.28 (m, 1H); 1.98 (m, 2H); 1.83-1.58 (m, 3H); 1.27 (m, 1H); 1.20 (m, 1H).

3.ii.3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid [(2R, 3R, 6R)-6-[2-(3-methoxyl group-quinoline-5-yl)-ethyl]-2-(2-oxygen-ethyl)-tetrahydrochysene-pyrans-3-yl]-acid amides:

(0.148g 0.27mmol) is starting raw material, uses the 2.v step of embodiment 2, obtains the title aldehyde (0.078g, productive rate 56%) of colourless foam shape with intermediate 3.i.

MS(ESI，m/z)：521.1[M+H ⁺]。

3.iii.{ (2R, 3R, 6R)-6-[2-(3-methoxyl group-quinoline-5-yl)-ethyl]-3-[(3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carbonyl)-ammonia]-tetrahydrochysene-pyrans-2-yl }-acetate:

(0.073g 0.14mmol) is starting raw material, uses the 2.vi step of embodiment 2, obtains the title acid (0.032g, productive rate 42%) of pale solid shape with intermediate 3.ii.Compound grinds purifying in ether.

¹H NMR (d ₆-DMSO) δ: 11.29 (s, 1H); 8.76 (m, 1H); 8.55 (m, 1H); 8.12-7.87 (m, 3H); 7.67-7.47 (m, 3H); 4.45 (m, 1H); 4.14 (overlapping, m, 1H); 4.04 (overlapping, s, 3H); 3.96 (overlapping, m, 1H); 3.76 (m, 1H); 3.46-3.25 (m, 2H); 3.04 (m, 1H); 2.53-2.20 (m, 4H); 2.01 (m, 2H); 1.69 (m, 2H); 1.30 (m, 1H).

MS(ESI，m/z)：537.0[M+H ⁺]。

Embodiment 4:{ (2R, 3R, 6R)-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-and ethyl]-3-[(3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-ylmethyl)-ammonia]-tetrahydrochysene-pyrans-2-yl }-the acetate tri hydrochloride:

4.i. (2RS)-3-(2R, 3R, 6R)-3-ammonia-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-propane-1,2-glycol:

(1.98g 3.98mmol) is starting raw material, uses 2.ii and the 2.iii step of embodiment 2, obtains the title compound (1.30g, productive rate 94%) of white solid with intermediate 1.vi.

MS(ESI，m/z)：362.1[M+H ⁺]。

4.ii.6-((2R, 3R, 6R)-2-((2RS)-2,3-dihydroxyl-propyl group)-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-basic ammonia }-methyl)-4H-pyrido [3,2-b] [1,4] thiazine-3-ketone:

(0.644g is 1.78mmol) with 3-oxygen-3,4-dihydro-2H-pyrido [3 with intermediate 4.i, 2-b] (0.380g 1.1eq.) is starting raw material to [1,4] thiazine-6-formaldehyde, use the 1.x step of embodiment 1, obtain the title compound (0.583g, productive rate 60%) of white foam shape.

¹H NMR (d ₆-DMSO) δ: 10.93 (s, 1H); 8.69 (dd, J=1.1,4.4Hz, 1H); 8.27 (d, J=9.0Hz, 1H); 7.78 (dd, J=1.3,7.9Hz, 1H); 7.56 (t, J=4.4Hz, 1H); 7.28 (d, J=9.0Hz, 1H); 7.12 (d, J=7.9Hz, 1H); 4.65-4.46 (m, 2H); 4.20-4.05 (overlapping, m, 1H); 4.05 (overlapping, s, 3H); 3.70 (overlapping, s, 2H); 3.70-3.56 (overlapping, m, 2H); 3.56 (overlapping, s, 2H); 3.41-3.19 (overlapping, m, 3H); 3.17-3.07 (m, 1H); 2.74 (m, 1H); 2.09 (m, 1H); 1.92-1.70 (m, 5H); 1.51 (m, 1H); 1.37 (m, 1H); 1.25 (m, 1H).

MS(ESI，m/z)：540.0[M+H ⁺]。

4.iii.{ (2R, 3R, 6R)-2-((2RS)-2,3-dihydroxyl-propyl group)-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-(3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-ylmethyl)-t-butyl carbamate:

(0.5g adds 1M aq.NaOH (1ml) in dioxane 0.92mmol) (4.5ml) and water (0.6ml) solution to intermediate 4.ii.Solution is cooled to 0 ℃ and add Boc ₂O (0.303g).After stirring a whole night, add 1M aq.NaOH (0.5ml) and Boc ₂O (0.3g).After 4 hours, add 1M aq.NaOH (1ml) and Boc once more ₂O (0.3g), reaction mixture stirred 16 hours.Add EA, separate phase.Water layer extracts 2 times with EA, and the organic layer of merging is with the salt water washing, through MgSO ₄Dry, also underpressure distillation of filtration.Resistates is through SiO ₂(DCM-MeOH 19-1 contains 1% aq.NH ₄OH DCM-MeOH 9-1 then contains 1% aq.NH ₄OH) the column chromatography purifying obtains light yellow foamed title compound (0.449g, productive rate 76%).

¹H NMR (CDCl ₃) master signal δ: 9.27 (br.s, 1H); 8.64 (dd, J=1.3,4.5Hz, 1H); 8.19 (dd, J=1.2,9.0Hz, 1H); 7.56 (m, 1H); 7.36 (m, 1H); 7.10 (dd, J=1.8,9.0Hz, 1H); 6.84 (br.d, J=5.4Hz, 1H); 4.66-4.53 (m, 2H); 4.39-4.09 (m, 2H); 4.04 (overlapping, s, 3H); 4.00 (overlapping, m, 1H); 3.73-3.51 (m, 3H); 3.47 (d, J=5.4Hz, 2H); 3.23-3.09 (m, 2H); 2.12-1.13 (m, 19H).

MS(ESI，m/z)：640.0[M+H ⁺]。

4.iv.[(2R, 3R, 6R)-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-and ethyl]-2-(2-oxygen-ethyl)-tetrahydrochysene-pyrans-3-yl]-(3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-ylmethyl)-t-butyl carbamate:

(0.444g 0.69mmol) is starting raw material, uses the 2.v step of embodiment 2, obtains colourless thickness buttery title aldehyde (0.372g, productive rate 88%) with intermediate 4.iii.Compound is through SiO ₂Use DCM-MeOH 19-1 as elutriant column chromatography purifying.

¹H?NMR(CDCl ₃)δ：9.77(br.s，1H)；8.65(d，J＝4.5Hz，1H)；8.37(br.s，1H)；8.19(d，J＝9.0Hz，1H)；7.57(d，J＝8.0Hz，1H)；7.36(d，J＝4.5Hz，1H)；7.10(d，J＝9.0Hz，1H)；6.84(d，J＝7.7Hz，1H)；4.83(m，1H)；4.20—4.13(m，2H)；4.06(s，3H)；3.60(m，1H)；3.48(d，J＝2.3Hz，2H)；3.23(m，1H)；3.07(m，1H)；2.90(m，1H)；2.59(m，1H)；1.90(m，2H)；1.75(m，3H)；1.34(m，11H)。

MS(ESI，m/z)：608.0[M+H ⁺]。

4.v.{ (2R, 3R, 6R)-3-[tert-butoxycarbonyl-(3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-ylmethyl)-ammonia]-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-acetate:

(0.365g 0.6mmol) is starting raw material, uses the 2.vi step of embodiment 2, obtains the title acid (0.258g, productive rate 69%) of yellow solid shape with intermediate 4.iv.Compound grinds purifying in ether.

¹HNMR(d ₆—DMSO)δ：12.28(s，1H)；10.92(s，1H)；8.68(d，J＝4.4Hz，1H)；8.26(d，J＝9.0Hz，1H)；7.76(d，J＝8.0Hz，1H)；7.56(d，J＝4.4Hz，1H)；7.27(d，J＝9.0Hz，1H)；6.82(d，J＝8.0Hz，1H)；4.50(m，2H)；4.19(m，2H)；4.05(s，3H)；3.64(m，1H)；3.56(d，J＝3.4Hz，2H)；3.22(m，1H)；3.07(m，1H)；2.79(m，1H)；2.37(m，1H)；1.93(m，1H)；1.87—1.73(m，4H)；1.46—1.37(m，6H)；1.26(m，4H)。

MS(ESI，m/z)：624.0[M+H ⁺]。

4.vi.{ (2R, 3R, 6R)-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-and ethyl]-3-[(3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-ylmethyl)-ammonia]-tetrahydrochysene-pyrans-2-yl }-the acetate tri hydrochloride:

To intermediate 4.v (0.256g, add in dioxane 0.41mmol) (1ml) suspension dioxane contain anhydrous HCl (5N, 0.86ml).Gained solution at room temperature stirred 3 hours.Mixture concentrates evaporate to dryness.Residual solid is diluted with ether, and underpressure distillation.The gained solid grinds in ether and filters.Dry in high vacuum, obtain three salt acidify salts (0.260g) of white solid.

¹HNMR (d ₆-DMSO) δ: 11.16 (s, 1H); 9.53 (br.s, 1H); 9.18 (br.s, 1H); 8.95 (d, J=5.1Hz, 1H); 8.56 (d, J=9.0Hz, 1H); 7.92 (m, 2H); 7.53 (d, J=9.2Hz, 1H); 7.30 (d, J=7.9Hz, 1H); 4.65 (m, 1H); 4.28 (br.s, 2H); 4.11 (s, 3H); 3.82 (m, 1H); 3.64 (overlapping, s, 2H); 3.60 (overlapping, m, 1H); 3.26 (m, 2H); 2.86-2.66 (m, 2H); 2.09 (m, 1H); 1.96 (m, 4H); 1.34 (m, 1H).

MS(ESI，m/z)：524.7[M+H ⁺]。

Embodiment 5:{ (2R, 3R, 6R)-3-[(E)-3-and (2,5-difluoro-phenyl)-allyl amino]-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-the acetate dihydrochloride:

5.i. (2RS)-3-(2R, 3R, 6R)-3-[(E)-3-and (2,5-difluoro-phenyl)-allyl amino]-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-propane-1,2-glycol:

With intermediate 4.i (0.470g, 1.3mmol) and (E)-3-(2,5-difluoro-phenyl)-propenal (0.240g; 1.1eq.) be starting raw material, use the 1.x step of embodiment 1, obtain the title compound (0.450g, productive rate 67%) of white foam shape.

¹H NMR (d ₆-DMSO) δ: 8.69 (dd, J=1.1,4.4Hz, 1H); 8.27 (d, J=9.0Hz, 1H); 7.58-7.48 (m, 2H); 7.31-7.22 (m, 2H); 7.18-7.10 (m, 1H); 6.62 (t, J=16.1Hz, 1H); 6.52 (m, 1H); 4.73 (br.s, 1H); 4.55-4.44 (m, 2H); 4.17 (m, 1H); 4.05 (s, 3H); 3.69-3.58 (m, 2H); 3.38 (overlapping, m, 2H); 3.28 (overlapping, m, 2H); 3.12 (m, 1H); 2.77 (m, 1H); 1.99-1.72 (m, 6H); 1.54-1.23 (m, 3H).

MS(ESI，m/z)：514.0[M+H ⁺]。

5.ii.[(E)-3-(2,5-difluoro-phenyl)-allyl group]-(2R, 3R, 6R)-2-((2RS)-2,3-dihydroxyl-propyl group)-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

(0.73g 1.42mmol) is starting raw material, uses the 4.iii step of embodiment 4, obtains the title compound (0.65g, productive rate 74%) of white foam shape with intermediate 5.i.Compound is through SiO ₂(DCM-MeOH 19-1 is 9-1 column chromatography purifying then.This compound is 2-1 epimer mixture.

¹HNMR (CDCl ₃) master signal δ: 8.66 (d, J=3.7Hz, 1H); 8.30 (dd, J=6.3,9.0Hz, 1H); 7.42 (m, 1H); 7.14 (overlapping, d, J=9.1Hz, 1H); 7.09 (overlapping, m, 1H); 7.01-6.93 (m, 1H); 6.90-6.84 (m, 1H); 6.52 (d, J=16.0Hz, 1H); 6.24 (m, 1H); 4.35-4.20 (m, 3H); 4.06 (s, 3H); 3.96-3.89 (m, 1H); 3.83 (dd, J=5.2,16.9Hz, 1H); 3.66 (m, 2H); 3.50 (m, 1H); 3.26-3.14 (m, 3H); 2.27-2.20 (br.m, 2H); 2.10-1.84 (m, 6H); 1.47 (overlapping, s, 9H); 1.46 (overlapping, m, 1H).

MS(ESI，m/z)：614.1[M+H ⁺]。

5.iii.[(E)-3-(2,5-difluoro-phenyl)-allyl group]-[(2R, 3R, 6R)-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-2-(2-oxygen-ethyl)-tetrahydrochysene-pyrans-3-yl]-t-butyl carbamate:

(0.645g 1.05mmol) is starting raw material, uses the 2.v step of embodiment 2, obtains the title aldehyde (0.557g, productive rate 91%) of white foam shape with intermediate 5.ii.Resistates is through SiO ₂(DCM-MeOH 97-3～19-1) column chromatography purifying.

¹H NMR (CDCl ₃) δ: 9.75 (m, 1H); 8.65 (d, J=4.6Hz, 1H); 8.29 (d, J=9.1Hz, 1H); 7.43 (d, J=4.6Hz, 1H); 7.14 (overlapping, d, J=9.1Hz, 1H); 7.08 (overlapping, m, 1H); 7.02-6.95 (m, 1H); 6.92-6.85 (m, 1H); 6.52 (d, J=16.1Hz, 1H); 6.22 (td, J=5.2,15.8Hz, 1H); 4.79 (m, 1H); 4.24 (m, 1H); 4.08 (s, 3H); 3.76 (dd, J=4.5,16.8Hz, 1H); 3.66-3.58 (m, 1H); 3.31-3.21 (m, 1H); 3.14-3.04 (m, 1H); 2.89-2.80 (m, 1H); 2.54 (dd, J=4.7,15.3Hz, 1H); 1.93-1.89 (m, 4H); 1.86-1.79 (m, 1H); 1.48 (overlapping, s, 9H); 1.47 (overlapping, m, 2H).

MS(ESI，m/z)：582.0[M+H ⁺]

5.iv.{ (2R, 3R, 6R)-3-tert-butoxycarbonyl-[(E)-3-(2,5-difluoro-phenyl)-allyl group]-ammonia }-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-acetate:

(0.557g 0.96mmol) is starting raw material, uses the 2.vi step of embodiment 2, obtains the title acid (0.58g, productive rate 99%) of colourless foam shape with intermediate 5.iii.Compound grinds purifying in ether.

¹H NMR (CDCl ₃) δ: 8.52 (d, J=4.6Hz, 1H); 8.36 (d, J=9.1Hz, 1H); 7.27 (overlapping, m, 1H); 7.12-6.86 (m, 4H); 6.53 (d, J=15.8Hz, 1H); 6.27 (m, 1H); 4.60 (m, 1H); 4.30-4.07 (m, 2H); 3.99 (s, 3H); 3.85-3.70 (m, 2H); 3.02 (m, 2H); 2.79 (m, 1H); 2.49 (dd, J=3.7,14.2Hz, 1H); 1.94-1.90 (m, 3H); 1.84-1.77 (m, 3H); 1.52-1.40 (overlapping, m, 3H); 1.27 (s, 9H).

MS(ESI，m/z)：598.1[M+H ⁺]。

5.v.{ (2R, 3R, 6R)-3-[(E)-3-and (2,5-difluoro-phenyl)-allyl amino]-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-the acetate dihydrochloride:

(0.100g 0.167mml) is starting raw material, uses the 4.vi step of embodiment 4, obtains the title compound (0.074g, productive rate 78%) of white solid with intermediate 5.iv.

¹H NMR (D ₂O) δ: 8.80 (d, J=9.2Hz, 1H); 8.36 (d, J=9.2Hz, 1H); 8.03 (d, J=6.0Hz, 1H); 7.51 (d, J=9.3Hz, 1H); 7.31 (m, 1H); 7.15 (m, 2H); 6.97 (d, J=16.3Hz, 1H); 6.35 (m, 1H); 4.79 (overlapping, s, 1H); 4.61 (m, 1H); 4.14 (s, 3H); 4.06-3.84 (m, 3H); 3.58 (m, 1H); 3.45 (m, 2H); 2.90-2.79 (m, 1H); 2.59 (dd, J=3.6,15.0Hz, 1H); 2.25-2.00 (m, 3H); 1.96-1.79 (m, 3H); 1.54-1.40 (m, 1H).

MS(ESI，m/z)：498.0[M+H ⁺]。

Embodiment 6:{ (2R, 3R, 6R)-3-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-6-[(1S)-1-hydroxyl-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-the acetate dihydrochloride:

6.i.[(2R, 3R, 6S)-6-[(1R, 2R)-and 1,2-dihydroxyl-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-2-((4RS)-2,2-dimethyl-[1,3] dioxolane-4-ylmethyl)-tetrahydrochysene-pyrans-3-yl]-t-butyl carbamate:

Intermediate 1.vi (1.274g, 2.55mmol) and amsacrine (0.291g 3.06mmol) is suspended in 2-methyl-2-propyl alcohol (13ml), water (13ml) and EA (4ml), to wherein adding AD-mix (4.5g).Reaction mixture at room temperature stirred 24 hours.Add Sodium Pyrosulfite and (10g) and EA (50ml).Two-layer decant, water layer extracts 2 times with EA.The organic layer that merges is through Na ₂SO ₄Dry, filtration and concentrated in a vacuum.Resistates is through SiO ₂(DCM-MeOH 9-1) chromatogram purification obtains the glycol (1.2g) of required white foam.This compound is 2-1 epimer mixture.

MS(ESI，m/z)：534.0[M+H ⁺]。

6.ii.{ (2R, 3R, 6S)-2-((4RS)-2,2-dimethyl-[1,3]-6-[(4R dioxolane-4-ylmethyl), 5R)-5-(6-methoxyl group-[1,5] naphthyridines-4-yl)-2-oxygen-[1,3] dioxolane-4-yl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

To the intermediate 6.i of ice-cooled mistake (1.22g, add in DCM 2.30mmol) (12ml) solution pyridine (1.12ml, 13.80mmol) and triphosgene (0.341g, 1.15mmol).Be reflected at 0 ℃ and stirred 30 minutes down, at room temperature stirred then 1 hour.Reaction mixture is with saturated NaHCO ₃Dilution, two-layer decant.The organic layer that merges is through Na ₂SO ₄Dry, filter and at concentrated evaporate to dryness.Resistates is through SiO ₂(DCM-MeOH19-1) chromatogram purification obtains the title cyclic carbonate (1.18g, productive rate 92%) of white foam shape.This compound is 2-1 epimer mixture.

MS(ESI，m/z)：560.0[M+H ⁺]。

6.iii.{ (2R, 3R, 6S)-2-((4RS)-2,2-dimethyl-[1, dioxolane-4-ylmethyl)-6 3]-[(1S)-1-hydroxyl-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

(1.178g adds 20% and is adsorbed in Pd on the carbon (OH) in EA 2.11mmol) (80ml) solution to intermediate 6.ii ₂(moisturize, 0.443g), suspension stirred 2 hours under hydrogen.Leach catalyzer, filtrate concentrates evaporate to dryness.Resistates is through SiO ₂(DCM-MeOH9-1) chromatogram purification obtains the title compound (0.973g, productive rate 89%) of white foam shape.

MS(ESI，m/z)：518.0[M+H ⁺]。

6.iv. (2RS)-3-(2R, 3R, 6S)-3-ammonia-6-[(1S)-1-hydroxyl-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-propane-1,2-glycol:

(0.97g 1.87mmol) is raw material in fact, uses the 2.iii step of embodiment 2, makes brown foamed title amine (0.57g, productive rate 80%) with intermediate 6.iii.This compound is 2-1 epimer mixture.

¹HNMR (the master signal δ of d6-DMSO): 8.69 (d, J=4.4Hz, 1H); 8.27 (d, J=9.0Hz, 1H); 7.59 (d, J=4.5Hz, 1H); 7.27 (d, J=9.0Hz, 1H); 4.57-4.42 (m, 2H); 4.06 (overlapping, s, 3H); 4.05-3.89 (overlapping, m, 2H); 3.68 (m, 1H); 3.59-3.45 (m, 2H); 3.28 (m, 3H); 2.93-2.82 (m, 2H); 1.87-1.69 (m, 1H); 1.62-1.57 (m, 3H); 1.54-1.27 (m, 4H).

MS(ESI，m/z)：378.2[M+H ⁺]。

6.v. (2RS)-3-{ (2R, 3R, 6S)-3-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-6-[(1S)-1-hydroxyl-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-propane-1,2-glycol:

With intermediate 6.iv (0.570g, 1.51mmol) and (E)-3-(0.279g 1.1eq) is starting raw material to (2,5-difluoro-phenyl)-propenal, use the 1.x step of embodiment 1, make the title compound (0.420g. productive rate 52%) of white solid.

¹H NMR (d ₆-DMSO) master signal δ: 8.69 (d, J=4.4Hz, 1H); 8.27 (d, J=9.0Hz, 1H); 7.59 (d, J=4.5Hz, 1H); 7.52 (m, 2H); 7.32-7.23 (m, 2H); 7.22-7.10 (m, 1H); 6.62 (overlapping, t, J=16.3Hz, 1H); 6.53 (overlapping, m, 1H); 4.58 (m, 1H); 4.48 (d, J=6.5Hz, 1H); 4.26-4.09 (m, 1H); 4.04 (s, 3H); 3.91 (m, 1H); 3.72 (m, 1H); 3.53 (m, 2H); 3.40-3.29 (m, 4H); 2.92 (m, 1H); 2.76 (m, 1H); 1.96 (m, 1H); 1.82-1.68 (m, 4H); 1.62-1.37 (m, 3H).

(DCM-MeOH 9-1 contains 1% aq.NH to Rf=0.38 ₄OH).

MS(ESI，m/z)：529.8.

6.vi.[(E)-3-(2,5-difluoro-phenyl)-allyl group]-{ (2R, 3R, 6S)-2-((2RS)-2,3-dihydroxyl-propyl group)-6-[(1S)-1-hydroxyl-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

(0.363g 0.69mmol) is starting raw material, uses the 4.iii step of embodiment 4, obtains the N-protection amine (0.279g, productive rate 64%) of white foam with intermediate 6.v.This compound is 2-1 epimer mixture.

MS(ESI，m/z)：629.9[M+H ⁺]。

6.vii.{ (2R, 3R, 6S)-3-tert-butoxycarbonyl-[(E)-3-(2,5-difluoro-phenyl)-allyl group]-ammonia }-6-[(1S)-1-hydroxyl-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-acetate:

(0.275g 0.43mmol) is starting raw material, uses 2.v and the vi step of embodiment 2, makes the title acid (0.257g, productive rate 99%) of colourless foam shape with intermediate 6.vi.

MS(ESI，m/z)：614.0[M ⁺]。

6.viii.{ (2R, 3R, 6R)-3-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-6-[(1S)-1-hydroxyl-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-the acetate dihydrochloride:

(0.252g 0.41mmol) is starting raw material, uses the 4.vi step of embodiment 4, makes the title acid (0.24g, productive rate 99%) of little yellow solid shape with intermediate 6.vii.This compound grinds in ether.

¹H NMR (d ₆-DMSO) δ: 8.69 (d, J=4.4Hz, 1H); 8.27 (d, J=9.0Hz, 1H); 7.59 (d, J=4.5Hz, 1H); 7.52 (m, 2H); 7.32-7.23 (m, 2H); 7.22-7.10 (m, 1H); 6.62 (overlapping, t, J=16.3Hz, 1H); 6.53 (overlapping, m, 1H); 4.58 (m, 1H); 4.48 (d, J=6.5Hz, 1H); 4.26-4.09 (m, 1H); 4.04 (s, 3H); 3.91 (m, 1H); 3.72 (m, 1H); 3.53 (m, 2H); 3.40-3.29 (m, 4H); 2.92 (m, 1H); 2.76 (m, 1H); 1.96 (m, 1H); 1.82-1.68 (m, 4H); 1.62-1.37 (m, 3H).

MS(ESI，m/z)：514.0[M+H ⁺]。

Embodiment 7:(1RS)-2-(2S, 5R, 6S)-5-and [anti--3-(2,5-difluoro-phenyl)-allyl amino]-6-hydroxymethyl-tetrahydrochysene-pyrans-2-yl }-1-(3-fluorine-6-methoxyl group-quinoline-4-yl)-ethanol:

7.i. (2R, 3S, 6R)-6-allyl group-2-(tertiary butyl-phenylbenzene-silanyloxy ylmethyl)-3,6-dihydro-2H-pyrans-3-alcohol:

To ice-cooled mistake (2R, 3S, 6R)-6-allyl group-2-hydroxymethyl-3,6-dihydro-2H-pyrans-3-alcohol (describes preparation, 2418-2427 according to Eur.J.org.Chem. (2003); 31.55g, add in DCM 185.4mmol) (650ml) solution imidazoles (24.96g, 2eq.).(50.45g, DCM 210.7mmol) (130ml) solution was above 90 minutes dropwise to add tert-butyl diphenyl chlorosilane.After 2 hours, add saturated NaHCO ₃The aqueous solution (250ml).Two separate, organic layer salt solution washed twice is through MgSO ₄Drying, filtration and concentrated evaporate to dryness.Resistates is through SiO ₂(Hex-EA 5-1) chromatogram purification obtains the title compound (51.52g, productive rate 68%) of yellow oily.

¹H?NMR(CDCl ₃)δ：7.74—7.68(m，4H)；7.47—7.38(6H)；5.87—5.76(m，3H)；5.10—5.04(m，2H)；4.19—4.15(m，2H)；3.89(dd，J＝5.3，10.0Hz，1H)；3.79(dd，J＝7.3，10.0Hz，1H)；3.68(m，1H)；2.70(br?s，1H)；2.38(m，1H)；2.28(m，1H)；1.09(s，9H)。

7.ii. (2RS)-3-[(2R, 5S, 6R)-6-(tertiary butyl-phenylbenzene-silanyloxy ylmethyl)-5-hydroxyl-5,6-dihydro-2H-pyrans-2-yl]-propane-1,2-glycol:

To intermediate 7.i (51.52g, in the solution of 2-methyl 126.1mmol)-2-propyl alcohol (560ml), EA (15ml) and water (560ml), add red prussiate of potash (189.48g, 3eq.), K ₂CO ₃(67.10g, 3eq.), (DHQD) ₂PHAL (1.5121g, 0.015eq.) and the potassium perosmate dihydrate (0.1907g, 0.004eq.).Reaction mixture stirred 2 days, added sodium bisulfite (150.92g).Two-layer decant, (2 * 350ml) extract 2 times water layer with EA.The organic layer that merges is with salt solution (500ml) washing, through MgSO ₄Drying, filtration and concentrated evaporate to dryness.Resistates is through SiO ₂(Hex-EA1-1, EA then) filters, and obtains the title product (36.33g, productive rate 65%) of yellow oily.This compound is 2-1 epimer mixture.

¹H?NMR(d ₆—DMSO)δ：7.71—7.65(m，4H)；7.47—7.40(m，6H)；5.80—5.65(m，2H)；4.95(m，1H)；4.50—4.35(m，3H)；3.92—3.28(m，7H)；1.80—1.65(m，1.33H)；1.17(m，0.67H)；0.99(s，9H)。

7.iii. (2R, 3S, 6R)-2-(tertiary butyl-phenylbenzene-silanyloxy ylmethyl)-6-((4RS)-2,2-dimethyl-[1,3] dioxolane-4-ylmethyl)-3,6-dihydro-2H-pyrans-3-alcohol:

At room temperature, to intermediate 7.ii (34.83g, add in DCM 78.7mmol) (575ml) solution PTSA (0.90g, 4.7mmol) and 2,2-Propanal dimethyl acetal (24ml, 195.2mmol).After 2 hours, add entry (100mL) and saturated NaHCO ₃(200ml), two be separated.Water layer extracts through DCM (260ml).The organic layer that merges is with the salt water washing, through MgSO ₄Drying, filtration and concentrated evaporate to dryness.Resistates is through SiO ₂(Hex-EA1-1) chromatogram purification obtain yellow oily title compound (36.19g, 74.9mmol).This compound is 2-1 epimer mixture.

¹H?NMR(CDCl ₃)δ：7.72—7.67(m，4H)；7.50—7.39(m，6H)；5.85—5.77(m，2H)；4.23—3.41(m，8H)；2.80(br?s，1H)；2.06(m，0.33H)；1.80—1.65(1.67H)；1.40(s，3H)；1.33(s，3H)；1.09(s，9H)。

7.iv. (2R, 3S, 6R)-2-(tertiary butyl-phenylbenzene-silanyloxy ylmethyl)-6-((4RS)-2,2-dimethyl-[1,3] dioxolane-4-ylmethyl)-tetrahydrochysene-pyrans-3-alcohol:

To intermediate 7.iii (36.16g, add in EA 74.9mmol) (600ml) solution platinum oxide hydrate (1.1g, 4.8mmol).Reaction mixture stirred 2 hours under hydrogen.Remove by filter catalyzer, filtrate concentrates evaporate to dryness and obtains thickness buttery title alcohol (36.18g, productive rate 99%).This compound is 2-1 epimer mixture.

MS(ESI，m/z)：485.2[M+H ⁺]。

7.v. (2R, 6S)-2-(tertiary butyl-phenylbenzene-silanyloxy ylmethyl)-6-((4RS)-2,2-dimethyl-[1,3] dioxolane-4-ylmethyl)-dihydro-pyrans-3-ketone:

(12g, DCM 24.75mmol) (100ml) solution add Dai Si-Martin's reagent (Dess-Martin periodinane), and (15wt% is dissolved in DCM, 50ml) to intermediate 7.iv.Mixture at room temperature stirred 4 hours.Reaction mixture is with DCM (30ml) dilution, and with saturated NaHCO ₃(30ml) washing.Organic layer is through Na ₂SO ₄Drying, filtration and concentrated evaporate to dryness.Resistates chromatogram purification (Hex-EA3-1) obtains the title compound (10.9g, productive rate 91%) of colorless oil.This compound is 2-1 epimer mixture.

¹H?NMR(CDCl ₃)δ：7.72—7.61(m，4H)；7.46—7.38(m，6H)；4.55(m，1H)；4.32(m，1H)；4.13—3.90(m，7H)；3.59(m，1H)；2.65—2.59(m，2H)；2.2—2.05(m，1.33H)；1.91—1.71(m，2.66H)；1.42(s，3H)；1.38(s，2H)；1.36(s，1H)；1.05(s，9H)。

7.vi. (2S, 3RS, 6S)-phenmethyl-[2-(tertiary butyl-phenylbenzene-silanyloxy ylmethyl)-6-((4RS) 2,2-dimethyl-[1,3] dioxolane-4-ylmethyl)-tetrahydrochysene-pyrans-3-yl]-amine:

To intermediate 7.v (10.9g, add in 1,2-DCE 22.58mmol) (60ml) solution phenmethyl amine (2.5ml, 1eq.) and sodium triacetoxy borohydride (6.7g, 1.4eq.).Mixture at room temperature stirs-whole night.Add saturated NaHCO ₃(200ml).Two-layer decant, organic layer is through Na2SO ₄Drying, filtration and concentrated evaporate to dryness.Resistates is through SiO ₂(Hex-EA3-1) chromatogram purification obtains the title compound (9.7g, productive rate 74%) of little yellow oily.This compound is four isomer mixtures.

MS(ESI，m/z)：574.8[M+H ⁺]。

7.vii. (2S, 3RS, 6S)-2-(tertiary butyl-phenylbenzene-silanyloxy ylmethyl)-6-((4RS) 2,2-dimethyl-[1,3] dioxolane-4-ylmethyl)-tetrahydrochysene-pyrans-3-basic amine:

(9.7g adds AcOH (1.1ml) and 10% Pd/C (4g) in EtOH 16.9mmol) (190ml) solution to intermediate 7.vi.Compound of reaction stirred 8 hours under hydrogen.Filtering mixt, catalyzer EtOH and water washing.After the inspissation, resistates is with saturated NaHCO ₃EA (2 * 250mL) extractions are used in (100ml) dilution then.The organic extract that merges is with the salt water washing, through Na ₂SO ₄Drying, filtration and concentrated evaporate to dryness.Resistates is through SiO ₂(DCM-MeOH 97-3 contains 1% aq.NH ₄OH) chromatogram purification obtains the title amine (5.5g, productive rate 67%) of colorless oil.

MS(ESI，m/z)：484.1[M+H ⁺]。

7.viii. (2S, 3R, 6S)-[2-(tertiary butyl-phenylbenzene-silanyloxy ylmethyl)-6-((4RS)-2,2-dimethyl-[1,3] dioxolane-4-ylmethyl)-tetrahydrochysene-pyrans-3-yl]-t-butyl carbamate:

To intermediate 7.vii (5.5g, add in DCM 11.37mmol) (65ml) solution Boc2O (3.0g, 1.2eq.) and TEA (3.2mL, 2.0eq.).Reaction mixture at room temperature stirs a whole night.After concentrating evaporate to dryness, resistates is through SiO ₂(Hex-toluene-DCM-EA 13-3-1-3) chromatogram purification at first obtains mixture (2S, the 3S of 2-1 epimer, 6S)-isomer (1.98g, productive rate 29%), obtain the mixture (4.0g, productive rate 60%) of 2-1 required epimer then.

¹HNMR(CDCl ₃)δ：7.71—7.67(m，4H)；7.48—7.38(m，6H)；5.39(d，J＝7.5Hz，1H)；4.18—3.43(m，8H)；2.12(m，0.33H)；1.89—1.49(m，5.67H)；1.43(s，9H)；1.37(s，3H)；1.31(s，1H)；1.28(s，2H)；1.07(s，9H)。

7.ix.[(2S, 3R, 6S)-2-(tertiary butyl-phenylbenzene-silanyloxy ylmethyl)-6-((2RS)-2,3-dihydroxyl-propyl group)-tetrahydrochysene-pyrans-3-yl]-t-butyl carbamate:

(4.0g 6.85mmol) is dissolved in AcOH (30ml), water (10ml) and THF (10ml), adds solution 3 hours at 50 ℃ with intermediate 7.viii.Reaction mixture concentrates evaporate to dryness, and resistates is located away from saturated NaHCO ₃(40ml) and EA (100ml).Organic layer is through Na ₂SO ₄Dry.Filter and concentrated evaporate to dryness.Resistates is through SiO ₂(Hex-EA1-3) chromatogram purification obtains the title glycol (3.38g, productive rate 90%) of colorless oil.

MS(ESI，m/z)：544.2[M+H ⁺]。

7.x.[(2S, 3R, 6S)-2-(tertiary butyl-phenylbenzene-silanyloxy ylmethyl)-6-(2-oxygen-ethyl)-tetrahydrochysene-pyrans-3-yl]-t-butyl carbamate:

At room temperature, (1.5g adds NaIO in acetone 2.75mmol) (30ml) solution to intermediate 7.ix ₄(1.5g, water 2.5eq.) (10ml) solution.Stirring reaction 40 minutes leaches solid, and filtrate concentrates in a vacuum.Resistates is located away from water (50ml) and EA (100ml).Water layer EA (100ml) extraction-inferior, the extract of merging is with the salt water washing, through Na ₂SO ₄Drying, filtration and concentrated evaporate to dryness.Resistates is through SiO ₂(Hex-EA 2-1) chromatogram purification obtains the title aldehyde (1.3g) of colourless foam shape.

¹H?NMR(CDCl ₃)δ：9.74(t，J＝1.9Hz，1H)；7.69—7.66(m，4H)；7.49—7.39(m，6H)；5.45(d，J＝6.75Hz，1H)；4.26(m，1H)；3.96—3.61(m，4H)；2.68(m，1H)；2.44(ddd，J＝1.8，5.4，16.3Hz，1H)；1.92—1.78(m，3H)；1.44(s，9H)；1.43(m，1H)；1.07(s，9H)。

7.xi.{ (2S, 3R, 6S)-2-(tertiary butyl-phenylbenzene-silanyloxy ylmethyl)-6-[(2RS)-2-(3-fluorine-6-methoxyl group-quinoline-4-yl)-2-hydroxyl-ethyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

Under-78 ℃, (0.9ml, (2.5N is dissolved in hexane, 2.5ml) to add n-BuLi in THF 2.5eq.) (17ml) solution to DIPA.Under this temperature, stirred the mixture 5 minutes, and rose to 0 ℃ then.After 15 minutes, solution is cooled to-78 ℃, adds 3-fluorine-6-methoxyl group-quinoline and (describe preparation according to WO 2005/049575; 1.12g, THF 2.5eq.) (5ml) solution.Reacted 4 hours.(1.3g, THF 2.54mmol) (5ml) solution reacted 10 minutes, rose to room temperature then rapidly dropwise to add intermediate 7.x.Stirring reaction is 20 minutes once more, uses 10% aq.NaHSO ₄(30ml) quench.Organic layer dilutes with EA (100ml).Two-layer decant, water layer extracts 2 times with EA.The organic layer that merges is with the salt water washing, through Na ₂SO ₄Drying, filtration and concentrated evaporate to dryness.Resistates is through SiO ₂(Hex-EA 2-then 1-1) chromatogram purification obtains colourless foam title compound (0.98g, productive rate 56%).This compound is 1-1 epimer mixture.

MS(ESI，m/z)：689.0[M+H ⁺]。

7.xii.{ (2S, 3R, 6S)-6-[(2RS)-2-(3-fluorine-6-methoxyl group-quinoline-4-yl)-2-hydroxyl-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

(0.98g, (1M is dissolved in THF, 2.2ml) to add TBAF in THF 1.42mmol) (5ml) solution to intermediate 7.xi.At room temperature reacted 1 hour.After concentrating evaporate to dryness, resistates is through SiO ₂(EA-Hex 3-1) chromatogram purification obtains the title compound (0.57g, productive rate 89%) of colourless foam shape.This compound is 1-1 epimer mixture.

MS(ESI，m/z)：451.0[M+H ⁺]。

7.xiii. (1RS)-2-((2S, 5R, 6S)-and 5-ammonia-6-hydroxymethyl-tetrahydrochysene-pyrans-2-yl)-1-(3-fluorine-6-methoxyl group-quinoline-4-yl)-ethanol:

To 7.xii (0.57g, add in dioxane 1.26mmol) (3ml) solution dioxane contain HCl (5N, 3ml).Mixture at room temperature stirred 3 hours.Remove in a vacuum and desolvate, with resistates water-soluble (5ml).Add K ₂CO ₃Regulating pH is 7.Vaporize water, resistates is through SiO ₂(DCM-MeOH6-11%aq.NH ₄OH) chromatogram purification obtains the title amine (0.4g, productive rate 90%) of colourless foam shape.This compound is 1-1 epimer mixture.

MS(ESI，m/z)：351.0[M+H ⁺]。

7.xiv. (1RS)-2-(2S, 5R, 6S)-5-and [anti--3-(2,5-difluoro-phenyl)-allyl amino]-6-hydroxymethyl-tetrahydrochysene-pyrans-2-yl }-1-(3-fluorine-6-methoxyl group-quinoline-4-yl)-ethanol:

With intermediate 7.xiii (0.1g, 0.285mmol) and (E)-3-(2,5-difluoro-phenyl)-propenal (0.053g, 1.1eq) be starting raw material, use the 1.x step of embodiment 1, obtain the title compound (0.135g, productive rate 94%) of colourless foam shape.Compound is through SiO ₂(DCM-MeOH93-7 contains 1%aq.NH ₄OH) chromatogram purification.This compound is 1-1 epimer mixture.

MS(ESI，m/z)：503.2[M+H ⁺]。

Embodiment 8:2-(2R, 3R, 6R)-3-[(E)-3-and (2,5-difluoro-phenyl)-allyl amino]-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-the ethanamide dihydrochloride:

8.i.[(E)-3-(2; 5-difluoro-phenyl)-allyl group]-{ (2R; 3R; 6R)-2-hydroxyl amino formyl radical methyl-6-[2-(6-methoxyl group-[1; 5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate and { (2R; 3R; 6R)-2-carbamyl ylmethyl-6-[2-(6-methoxyl group-[1; 5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-[(E)-3-(2,5-difluoro-phenyl)-allyl group]-t-butyl carbamate:

To intermediate 5.v (0.11g, add in DMF 0.19mmol) (2.3ml) solution DIPEA (0.16ml, 0.93mmol) and HATU (0.11g, 0.28mmol).Gained solution at room temperature stirred 30 minutes.The adding oxammonium hydrochloride (0.019g, 0.28mmol).After at room temperature stirring a whole night, (0.019g 0.28mmol), at room temperature stirred 24 hours once more to add oxammonium hydrochloride.Reaction mixture concentrates evaporate to dryness.Resistates is located away from water and DCM-MeOH9-1, separates phase.Water layer extracts 5 times with DCM-MeOH.The organic layer that merges is through Na ₂SO ₄Drying, filtration and vapourisation under reduced pressure filtrate.Resistates is through SiO ₂(DCM-MeOH 9-1 contains 1% aq.NH ₄OH) the column chromatography purifying obtains the title amide (0.032g, productive rate 29%) of yellow oily, obtains title hydroxamic acid (0.045g, productive rate 40%) then.

Acid amides: MS (ESI, m/z): 597.0[M+H ⁺].

Hydroxamic acid: MS (ESI, m/z): 613.0[M+H ⁺].

8.ii.2-(2R, 3R, 6R)-3-[(E)-3-and (2,5-difluoro-phenyl)-allyl amino]-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-the ethanamide dihydrochloride:

With { (2R; 3R; 6R)-2-carbamyl ylmethyl-6-[2-(6-methoxyl group-[1; 5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-[(E)-3-(2; 5-difluoro-phenyl)-allyl group]-(0.030g 0.049mmol) is starting raw material to t-butyl carbamate, uses the 4.vi step of embodiment 4; obtain the title compound (0.017g, productive rate 60%) of yellow solid shape.Compound grinds purifying in ether.

MS(ESI，m/z)：497.0[M+H ⁺]。

Embodiment 9:2-{ (2R, 3R, 6S)-3-[(E)-3-and (2,5-difluoro-phenyl)-allyl amino]-6-[(1R, 2R)-1,2-dihydroxyl-2-(3-methoxyl group-quinoxaline-5-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-ethanamide:

9.i.{ (2R, 3R, 6S)-2-((4RS)-2,2-dimethyl-[1,3] dioxolane-4-ylmethyl)-6-[2-(3-methoxyl group-quinoxaline-5-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

(9.67g is 18mmol) with 3-methoxyl group-quinoxaline-5-formaldehyde (reference preparation D with intermediate 1.v; 3.38g) be starting raw material, use the 1.vi step of embodiment 1, carry out the Julia coupling and obtain little yellow foam title compound (3.72g, productive rate 41%).Compound is through SiO ₂(EA-Hex 1-1) column chromatography purifying.This compound is 2-1 epimer mixture.

MS(ESI，m/z)：500.1[M+H ⁺]。

9.ii.{ (2R, 3R, 6S)-2-((2RS)-2,3-dihydroxyl-propyl group)-6-[(E)-2-(3-methoxyl group-quinoxaline-5-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

Intermediate 9.i (3.72g) is dissolved in AcOH (60ml), water (20ml) and THF (20ml), and solution was 60 ℃ of heating 5 hours.Reaction mixture concentrates evaporate to dryness, and resistates is located away from EA (200ml) and saturated NaHCO ₃(200ml).Adding 1Maq.NaOH adjusting water layer pH is 8.(2 * 150ml) extract 2 times throw out with EA.The extract that merges is with the salt water washing, through Na2SO ₄Drying, filtration and concentrated evaporate to dryness.Resistates is through SiO ₂(EA-Hept4-1) chromatogram purification obtains the title compound (2.45g) of colourless foam shape.This compound is 2-1 epimer mixture.

MS(ESI，m/z)：460.1.1[M+H ⁺]。

9.iii.{ (2R, 3R, 6S)-3-tert-butoxycarbonyl ammonia-6-[(E)-2-(3-methoxyl group-quinoxaline-5-yl)-vinyl]-tetrahydrochysene-pyrans-2-yl }-acetate:

With intermediate 9.ii (2.45g 5.3mmol) is starting raw material, uses 2.v and the 2.vi step of embodiment 2, obtain the colourless foam shape title acid (0.65g, 1.46mmol).Compound use EA-Hex1-2 as elutriant through SiO ₂Chromatogram purification.

MS(ESI，m/z)：443.8[M+H ⁺]。

9.iv.{ (2R, 3R, 6S)-2-carbamyl ylmethyl-6-[(E)-2-(3-methoxyl group-quinoxaline-5-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

Under 0 ℃, (0.65g adds TEA (0.265ml) and isobutyl chlorocarbonate (0.24g) in THF 1.46mmol) (10ml) solution to intermediate 9.iii.Stirring reaction is 1 hour under this temperature, adds NH ₄OH (3ml) aqueous solution.Firmly stirring reaction is 30 minutes.Add EA (50ml).Two-layer decant, water layer EA (50ml) extraction-inferior.The organic layer that merges is with the salt water washing, through Na ₂SO ₄Drying, filtration and concentrated evaporate to dryness.Resistates grinds the title amide (0.47g) that (Hex) obtains the bright beige solid shape of 75% purity.

MS(ESI，m/z)：442.8[M+H ⁺]。

9.v.{2R, 3R, 6S)-2-carbamyl ylmethyl-6-[(1R, 2R)-1,2-dihydroxyl-2-(3-methoxyl group-quinoxaline-5-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

(0.47g 1.05mmol) is starting raw material, uses the 6.i step of embodiment 6, and asymmetric dihydroxy reaction obtains the title glycol (0.19g, productive rate 38%) of colourless foam shape with intermediate 9.iv.Compound use DCM-MeOH 9-1 as elutriant through SiO ₂Chromatogram purification.

¹H NMR (d ₆-DMSO) δ: 8.60 (s, 1H); 7.91-7.87 (m, 2H); 7.63 (dd, J=7.3,8.2Hz, 1H); 7.39 (br s, 1H); 6.89 (br s, 1H); 6.82 (d, J=8.8Hz, 1H); 5.62 (d, J=7.2Hz, 1H); 5.11 (d, J=7.2Hz, 1H); 4.35 (d, J=3.7Hz, 1H); 4.06 (m, 1H); 4.03 (overlapping, s, 3H); 4.02-3.92 (m, 2H); 3.57 (m, 1H); 2.39 (dd, J=10.4,15.9Hz, 1H); 2.10-2.04 (m, 2H); 1.85 (m, 1H); 1.68-1.57 (m, 2H); 1.40 (s, 9H).

MS(ESI，m/z)：477.0[M+H ⁺]。

9.vi.2-2R, 3R, 6S)-3-ammonia-6-[(1R, 2R)-1,2-dihydroxyl-2-(3-methoxyl group-quinoxaline-5-yl)-ethyl] tetrahydrochysene-pyrans-2-yl }-ethanamide:

(0.19g 0.4mmol) is starting raw material, uses the 1.ix step of embodiment 1, obtains the title amine (0.071g, productive rate 47%) of colourless foam shape with intermediate 9.v.

MS(ESI，m/z)：377.2[M+H ⁺]。

9.vii.2-{ (2R, 3R, 6S)-3-[(E)-3-and (2,5-difluoro-phenyl)-allyl amino]-6-[(1R, 2R)-1,2-dihydroxyl-2-(3-methoxyl group-quinoxaline-5-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-ethanamide:

With intermediate 9.vi (0.071g, 0.285mmol) and (E)-3-(2,5-difluoro-phenyl)-propenal (0.031g, 1.1eq) be starting raw material, use the 1.x step of embodiment 1, obtain the title compound (0.020g of colourless foam shape, productive rate 20%, purity 75%).Compound is through SiO ₂(DCM-MeOH 9-1 contains 1%aq.NH ₄OH) chromatogram purification.

MS(ESI，m/z)：528.7[M+H ⁺]。

Embodiment 10:{ (2R, 3R, 6R)-3-[(E)-3-and (2,5-difluoro-phenyl)-allyl amino]-6-[2-(6-methoxyl group-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-the acetate dihydrochloride:

10.i.{ (2R, 3R, 6R)-3-tert-butoxycarbonyl-[(E)-3-(2,5-difluoro-phenyl)-allyl group]-ammonia }-6-[2-(6-methoxyl group-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-acetate:

With intermediate 1.v (5.68g; 10.57mmol) and 6-methoxyl group-quinoline-4-formaldehyde (1.8g; 9.6mmol) be starting raw material; use 1.vi step (the Julia coupling of embodiment 1 continuously; productive rate 46%); the 2.ii of embodiment 2 (hydrogenation, productive rate 96%) and 2.iii (acetonization and Boc deprotection, productive rate 99%); 1.x (the reduction amination of embodiment 1; productive rate 78%), 2.v (the circulation division of the 4.iii of embodiment 4 (generating Boc, productive rate 68%) and embodiment 2; productive rate 95%) and 2.vi (generate acid; productive rate 99%), obtain the colourless foam shape title compound (1.48g, 2.41mmol).

MS(ESI，m/z)：581.1[M+H ⁺]。

10.ii.{ (2R, 3R, 6R)-3-[(E)-3-and (2,5-difluoro-phenyl)-allyl amino]-6-[2-(6-methoxyl group-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-the acetate dihydrochloride:

(0.283g 0.475mmol) is starting raw material, uses the 4.vi step of embodiment 4, obtains the title acid (0.267g, productive rate 96%) of beige solid shape with intermediate 10.i.Compound grinds purifying in ether.

MS(ESI，m/z)：497.0[M+H ⁺]。

Embodiment 11:2-(2R, 3R, 6R)-3-[(E)-3-and (2,5-difluoro-phenyl)-allyl amino]-6-[2-(6-methoxyl group-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-the ethanamide dihydrochloride:

11.i.{ (2R, 3R, 6R)-2-carbamyl ylmethyl-6-[2-(6-methoxyl group-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-[(E)-3-(2,5-difluoro-phenyl)-allyl group]-t-butyl carbamate:

(1.15g 1.93mmol) is starting raw material, uses the 9.iv step of embodiment 9, obtains the foamed title ethanamide of canescence (0.506g, productive rate 44%) with intermediate 10.i.Compound uses DCM-MeOH 19-1 to contain 0.5% aq.NH ₄OH is as elutriant, through SiO ₂Chromatogram purification.

MS(ESI，m/z)：596.0[M+H ⁺]。

11.ii.2-(2R, 3R, 6R)-3-[(E)-3-and (2,5-difluoro-phenyl)-allyl amino]-6-[2-(6-methoxyl group-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-ethanamide:

(0.045g 0.076mmol) is starting raw material, uses the 4.vi step of embodiment 4, obtains the title compound (0.034g, productive rate 80%) of little yellow solid shape with intermediate 11.i.Compound grinds purifying in ether.

MS(ESI，m/z)：496.0[M+H ⁺]。

Embodiment 12:2-{ (2R, 3R, 6S)-3-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-6-[(S)-1-hydroxyl-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-ethanamide:

12.i.{ (2R; 3R; 6S)-2-carbamyl ylmethyl-6-[(S)-1-hydroxyl-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-[(E)-3-(2,5-difluoro-phenyl)-allyl group]-t-butyl carbamate:

Under 0 ℃, in the THF of intermediate 6.vii (0.724g) (8ml) solution, add TEA (0.427ml) and isobutyl chlorocarbonate (0.367ml).Stirring reaction is 1 hour under this temperature, adds ammoniacal liquor (2.5ml).Firmly stirring reaction is 45 minutes.Add EA (20ml).Two-layer decant, water layer are with EA (10ml) extraction once.The organic layer that merges is with the salt water washing, through Na ₂SO ₄Drying, filtration and concentrated evaporate to dryness.Resistates is through SiO ₂(DCM-MeOH19-1 contains 0.5% aq.NH ₄OH, 9-1 contains 1% aq.NH then ₄OH) the column chromatography purifying obtains the foamed title amide of canescence (0.485g).

MS(ESI，m/z)：613.0[M+H ⁺]。

12.ii.2-(2R, 3R, 6S)-3-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-6-[(S)-1-hydroxyl-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-ethanamide:

In dioxane (0.311ml) solution of intermediate 12.i (0.1g), add the dioxane (0.346ml) that contains 5NHCl.Be evaporated to do after, resistates is through SiO ₂(DCM-MeOH 19-1 contains 1%aq.NH ₄OH, 9-1 contains 1% aq.NH then ₄OH) column chromatography purifying obtains the foamed title compound of canescence (0.032g).

Rf=0.33, DCM-MeOH9-1 contains 1% aq.NH ₄OH.

MS(ESI，m/z)：513.0[M+H ⁺]。

Embodiment 13:3-(2,5-difluoro-phenyl)-N-{ (2S, 3R, 6S)-6-[(2RS) 2-(3-fluorine-6-methoxyl group-quinoline-4-yl)-2-hydroxyl-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-(E)-acrylamide:

With intermediate 7.xiii (0.100g, 0.29mmol) and (E)-3-(2,5-difluoro-phenyl)-vinylformic acid (0.058g, 0.31mmol) be starting raw material, use the 2.iv step of embodiment 2, obtain yellow foamed title amide (0.123g, productive rate 83%).Compound is through SiO ₂(DCM-MeOH19-1 contains 1% aq.NH ₄OH) chromatogram purification, this compound are 1-1 epimer mixture.

(DCM-MeOH 9-1 contains 1% aq.NH to Rf=0.41 ₄OH).

MS(ESI，m/z)：517.2[M+H ⁺]。

Embodiment 14:3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid { (2S, 3R, 6S)-6-[(2RS) 2-(3-fluorine-6-methoxyl group-quinoline-4-yl)-2-hydroxyl-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-acid amides:

(0.100g is 0.29mmol) with 3-oxygen-3,4-dihydro-2H-pyrido [3 with intermediate 7.xiii, 2-b] (0.06g 1eq.) is starting raw material to [1,4] thiazine-6-carboxylic acid, use the 2.iv step of embodiment 2, obtain the title amide (0.072g, productive rate 46%) of beige solid shape.Compound is through SiO ₂(DCM-MeOH19-1 contains 1%aq.NH ₄OH) chromatogram purification, this compound are 1-1 epimer mixture.

(DCM-MeOH 9-1 contains 1% aq.NH to Rf=0.41 ₄OH).

¹HNMR (d ₆-DMSO) δ: 11.24 (s, 0.5H); 11.16 (s, 0.5H); 8.69 (d, J=1.8Hz, 0.5H); 8.68 (d, J=1.8Hz, 0.5H); 8.32 (d, J=8.9Hz, 0.5H); 8.27 (d, J=8.9Hz, 0.5H); 7.98-7.90 (m, 3H); 7.62 (d, J=4.4Hz, 0.5H); 7.59 (d, J=4.4Hz, 0.5H); 7.40 (d, J=2.2Hz, 0.5H); 7.37 (d, J=2.2Hz, 0.5H); 5.79 (m, 1H); 5.62-5.50 (two is overlapping, m, 2 * 0.5H); 4.66 (t, J=5.0Hz, 0.5H); 4.61 (t, J=5.5Hz, 0.5H); 4.27 (m, 0.5H); 4.12-4.02 (m, 1H); 3.91 (s, 3H); 3.91 (overlapping, m, 0.5H); 3.80 (m, 0.5H); 3.70-3.60 (m, 2.5H); 3.45-3.34 (m, 2H); 2.61 (m, 0.5H); 2.27 (m, 0.5H); 2.11 (m, 1H); 2.15-2.06 (m, 0.5H); 1.99-1.64 (m, 2.5H); 1.45-1.33 (m, 1H).

MS(ESI，m/z)：542.8[M ⁺]。

Embodiment 15:3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid { (2S, 3R, 6S)-6-[(2RS)-2-hydroxyl-2-(3-methoxyl group-quinoline-5-yl)-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-acid amides:

15.i.2-(tertiary butyl-phenylbenzene-silanyloxy ylmethyl)-6-[(2RS)-2-hydroxyl-2-(3-methoxyl group-quinoline-5-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

THF (70ml) solution of 5-bromine-3-methoxy quinoline (3.12g) is cooled to-78 ℃, and adding n-BuLi (2.5N, 5.2ml).Mixture stirred 15 minutes under identical temperature, added intermediate 7.x (1.6g, THF 3.12mmol) (5ml) solution rapidly.Reacted 5 minutes, and rose to room temperature then.After 15 minutes, add 10% aq.NaHSO ₄(100ml).Two-layer decant, water layer extracts with EA (100ml).The organic layer thing that merges is with the salt water washing, through Na ₂SO ₄Drying, filtration and concentrated evaporate to dryness.Resistates is through SiO ₂(Hept-EA 3-1 then 1-1) chromatogram purification obtains the title compound (0.46g) of colourless foam shape.This compound is 2-1 isomer mixture.

MS(ESI，m/z)：671.0[M+H ⁺]。

15.ii.{ (2S, 3R, 6S)-6-[(2RS)-2-hydroxyl-2-(3-methoxyl group-quinoline-5-yl)-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

(0.46g 0.68mmol) is starting raw material, uses the 7.xii step of embodiment 7, obtains the title alcohol (0.26g, productive rate 86%) of colourless foam shape with intermediate 15.i.Compound uses EA as elutriant, through SiO ₂Chromatogram purification, this compound are 2-1 isomer mixture.

MS(ESI，m/z)：432.9[M ⁺]。

15.iii. (2RS)-2-[(2S, 5R, 6S)-and 5-ammonia-6-hydroxymethyl-tetrahydrochysene-pyrans-2-yl]-1-(3-methoxyl group-quinoline-5-yl)-ethanol:

(0.23g 0.53mmol) is starting raw material, uses the 1.ix step of embodiment 1, obtains the title amine (0.15g, productive rate 84%) of colourless foam shape with intermediate 15.ii.

MS(ESI，m/z)：333.1[M+H ⁺]。

15.iv.3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid { (2S, 3R, 6S)-6-[(2RS)-2-hydroxyl-2-(3-methoxyl group-quinoline-5-yl)-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-acid amides:

With intermediate 15.iii (0.05g, 0.15mmol) and 3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] (0.032g 1eq.) is starting raw material to thiazine-6-carboxylic acid, uses the 2.iv step of embodiment 2, obtain the title amide (0.030g, productive rate 38%) of pale solid shape.Compound is through SiO ₂(DCM-MeOH 9-1 contains 1%aq.NH ₄OH) chromatogram purification, this compound are 2-1 epimer mixture.

¹HNMR (d ₆-DMSO) δ: 11.24 (s, 0.34H); 11.18 (s, 0.66H); 8.66 (m, 1H); 8.34 (d, J=9.0Hz, 0.34H); 8.26 (d, J=9.0Hz, 0.66H); 7.99-7.94 (m, 1.66H); 7.74-7.69 (m, 1.34H); 7.71 (m, 1H); 7.63-7.55 (m, 2H); 5.48-5.35 (m, 2H); 4.75 (t, J=5.5Hz, 0.34H); 4.67 (t, J=5.1Hz, 0.66H); 4.33 (m, 0.34H); 4.09 (m, 0.66H); 3.97 (s, 3 * 0.34H); 3.95 (s, 3 * 0.66H); 3.96 (overlapping, m, 1H); 3.80 (m, 0.66H); 3.66-3.60 (m, 2H); 3.52 (m, 0.34H); 3.41 (t, J=5.6Hz, 1H); 2.43-2.27 (two is overlapping, m, 1H); 2.03-1.83 (m, 3H); 1.69-1.59 (m, 2H); 1.51-1.41 (m, 1H).

MS(ESI，m/z)：525.6[M+H ⁺]。

Embodiment 16:3-(2,5-difluoro-phenyl)-N-(2S, 3R, 6S)-6-[(2RS)-2-hydroxyl-2-(3-methoxyl group-quinoline-5-yl)-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-(E)-acrylamide:

With intermediate 15.iii (0.1g, 0.3mmol) and (E)-3-(0.055g 1eq.) be starting raw material to (2,5-difluoro-phenyl)-vinylformic acid, and the 2.iv step of use embodiment 2 obtains the title amide (0.095g, productive rate 63%) of colorless oil.Compound is through SiO ₂(DCM-MeOH 9-1 contains 1% aq.NH ₄OH) chromatogram purification, this compound are 2-1 epimer mixture.

MS(ESI，m/z)：498.9[M+H ⁺]。

Embodiment 17:2-{ (2R, 3R, 6S)-3-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-6-[(E)-2-(3-fluorine-6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-2-yl }-ethanamide:

17.i.{ (2R, 3R, 6S)-2-((4RS)-2,2-dimethyl-[1, dioxolane-4-ylmethyl)-6 3]-[(E)-2-(3-fluorine-6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

With 3-fluorine-6-methoxyl group-[1,5] naphthyridines-4-formaldehyde (reference preparation E; 3.17g 15.37mmol) (8.98g 16.71mmol) is starting raw material, uses the 1.vi step of embodiment 1, obtains light yellow foamed title alkene (4.02g, productive rate 50%) with intermediate 1.v.Compound uses Hept-EA 1-2 as elutriant, through SiO ₂Chromatogram purification.This compound is 2-1 epimer mixture.

MS(ESI，m/z)：500.4[M+H ⁺]。

17.ii.{2-carbamyl ylmethyl-6-[2-(3-fluorine-6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

With intermediate 17.i (3.85g; 7.44mmol) be starting raw material; use the 9.ii step (deprotection of embodiment 9; productive rate 80%), 9.iii (generate aldehyde oxidation then, productive rate is respectively 93% and 62%); 9.iv (generate acid amides; productive rate 51%), obtain the pale solid shape title amide (0.759g, 1.65mmol).

¹H?NMR(d ₆—DMSO)δ：8.81(d，J＝3.8Hz，1H)；8.29(d，J＝9.0Hz，1H)；7.35(br?s，1H)；7.28—7.20(m，3H)；6.88(br?d，J＝8.4Hz，1H)；6.82(br?s，1H)；4.52(m，1H)；4.33(m，1H)；4.05(s，3H)；3.66(m，1H)；2.58(dd，J＝10.3，14.8Hz，1H)；2.13—1.98(m，2H)；1.72—1.53(m，3H)；1.40(s，9H)。

MS(ESI，m/z)：460.7[M+H ⁺]。

17.iii.2-(2R, 3R, 6S)-3-ammonia-6-[2-(3-fluorine-6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-2-yl }-ethanamide:

(0.258g 0.56mmol) is starting raw material, uses the 1.ix step of embodiment 1, obtains the title amine (0.132g, productive rate 65%) of beige solid shape with intermediate 17.ii.

MS(ESI，m/z)：361.0[M+H ⁺]。

17.iv.2-(2R, 3R, 6S)-3-[(E)-3-and (2,5-difluoro-phenyl)-allyl amino]-6-[(E) 2-(3-fluorine-6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-2-yl }-ethanamide:

With intermediate 17.iii (0.126g, 0.35mmol) and (E)-3-(2,5-difluoro-phenyl)-propenal (0.065g, 1.1eq.) be starting raw material, use the 1.x step of embodiment 1, obtain the title compound (0.060g, productive rate 33%) of white solid.

¹H?NMR(d ₆—DMSO)δ：8.82(d，J＝2.1Hz，1H)；8.28(d，J＝9.0Hz，1H)；7.49(m，1H)；7.35(br?s，1H)；7.31—7.20(m，4H)；7.13(m，1H)；6.81(br?s，1H)；6.62(d，J＝16.0Hz，1H)；6.51(td，J＝5.3，16.0Hz，1H)；4.51—4.41(m，2H)；4.05(s，3H)；3.42—3.34(m，2H)；2.80(m，1H)；2.62(dd，J＝9.7，14.4Hz，1H)；2.35(dd，J＝3.8，14.4Hz，1H)；1.95—1.74(m，3H)；1.61—1.43(m，2H)。

MS(ESI，m/z)：512.9[M+H ⁺]。

Embodiment 18:(2S, 5R, 6R)-(5-[(E)-3-and (2,5-difluoro-phenyl)-allyl amino]-6-(2-hydroxyl-ethyl))-tetrahydrochysene-pyrans-2-carboxylic acid (6-methoxyl group-[1,5] naphthyridines-4-yl)-acid amides:

18.i. (2S, 5R, 6R)-5-tert-butoxycarbonyl ammonia-6-[(4RS) 2,2-dimethyl-[1,3] dioxolane-4-ylmethyl]-tetrahydrochysene-pyrans-2-carboxylic acid:

(5g adds NaIO in the solution of DCM 14.48mmol) (32ml), MeCN (32ml) and water (46ml) to the intermediate 1.ii of ice-cooled mistake ₄(14.6g, 68.17mmol) and RuCl ₃(0.030g, 0.15mmol).Reaction mixture stirred 5 hours under this temperature.Reaction mixture dilutes with EA (150ml), solids removed by filtration.Add MeOH (30ml), filter gained suspension.Filtrate is used 10% NaHSO ₃(60ml) aqueous solution is handled.Separate phase, water layer extracts 3 times with EA.The organic layer that merges is with the salt water washing, through Na ₂SO ₄Drying, filtration and vapourisation under reduced pressure obtain brown foam (quantitative).This compound is 2-1 epimer mixture.

MS(ESI，m/z)：360.1[M+H ⁺]。

18.ii.{ (2S, 5R, 6R)-6-formamyl-2-[(4RS)-2,2-dimethyl-[1,3] dioxolane-4-ylmethyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

(5.27g 14.6mmol) is starting raw material, uses the 12.i step of embodiment 12, obtains the title amide (3.16g, productive rate 60%) of colourless foam shape with intermediate 18.i.Compound uses EA-hexanaphthene 4-1 as elutriant, through SiO ₂Chromatogram purification.This compound is 2-1 epimer mixture.

MS(ESI，m/z)：359.1[M+H ⁺]。

18.iii.{ (2S, 5R, 6R)-2-[(4RS)-and 2,2-dimethyl-[1,3] dioxolane-4-ylmethyl)-6-(6-methoxyl group-[1,5] naphthyridines-4-basic formamyl)-tetrahydrochysene-pyrans-3-yl]-t-butyl carbamate:

To intermediate 18.ii (2.3g, 6.42mmol), rac-BINAP (0.288g, 0.46mmol), (dba) ₃Pd ₂.CHCl ₃(0.120g, 0.12mmol) and cesium carbonate (2.56g adds dioxane (82ml) in mixture 7.86mmol).Mixture ultrasonication 10 minutes adds a 6-methoxyl group-[1,5] naphthyridines-4-basic trifluoro-methane sulfonate then and (describes preparation according to WO03/064431; 2.10g, 6.81mmol).The gained mixture was 100 ℃ of heating 4 hours.Reaction mixture is through diatomite filtration, and filtrate concentrates in a vacuum.Resistates is through SiO ₂(DCM-MeOH 19-1) purifying obtain the foamed title amide of blush (3.27g, 6.32mmol).This compound is 2-1 epimer mixture.

MS(ESI，m/z)：477.0[M+H ⁺]。

18.iv. (2S, 5R, 6S)-5-ammonia-6-[(2RS)-2,3-dihydroxyl-propyl group]-tetrahydrochysene-pyrans-2-carboxylic acid (6-methoxyl group-[1,5] naphthyridines-4-yl)-acid amides:

(2.72g 2.06mmol) is starting raw material, uses the 1.ix step of embodiment 1, obtains the title amine (1.27g, productive rate 64%) of blush solid state with intermediate 18.iii.Compound uses DCM-MeOH 6-1 to contain 1% aq.NH ₄OH is as elutriant, through SiO ₂Chromatogram purification.This compound is 2-1 epimer mixture.

¹HNMR(d ₆—DMSO)δ：10.59(s，0.66H)；10.51(s，0.34H)；8.70(d，J＝5.0Hz，1H)；8.45(d，J＝5.0Hz，0.34H)；8.39(d，J＝5.0Hz，0.66H)；8.28(d，J＝9.0Hz，1H)；7.33(d，J＝9.0Hz，1H)；4.50(br?s，1H)；4.47(dd，J＝4.3，7.0Hz，0.34H)；4.31(dd，J＝3.5，9.0Hz，0.66H)；4.11(m，0.66H)；4.09(s，3×0.34H)；4.08(s，3×0.66H)；3.96(m，0.34H)；3.63(m，1H)；3.37—3.21(m，5H)，2.97(m，0.66H)；2.91(m，0.34H)；2.08(m，1H)；1.96(m，0.66H)；1.82—1.42(m，4.34H)。

MS(ESI，m/z)：377.0[M+H ⁺]。

18.v. (2S, 5R, 6R)-5-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-6-[(2RS)-2,3-dihydroxyl-propyl group]-tetrahydrochysene-pyrans-2-carboxylic acid (6-methoxyl group-[1,5] naphthyridines-4-yl)-acid amides:

With intermediate 18.iv (0.58g, 1.55mmol) and (E)-3-(2,5-difluoro-phenyl)-propenal (0.286g, 1.1eq.) be starting raw material, use the 1.x step of embodiment 1, obtain the title compound (0.393g, productive rate 48%) of white solid.Compound uses DCM-MeOH9-1 to contain 1% aq.NH ₄OH is as elutriant, through SiO ₂Chromatogram purification.This compound is 2-1 epimer mixture.

¹HNMR(d ₆—DMSO)δ：10.64(s，0.66H)；10.56(s，0.34H)；8.69(d.J＝5.0Hz，1H)；8.42(d，J＝5.0Hz，0.34H)；8.37(d，J＝5.0Hz，0.66H)；8.28(d，J＝9.0Hz，1H)；7.49(m，1H)；7.32(d，J＝9.0Hz，1H)；7.27(m，1H)；7.12(m，1H)；6.63(d，J＝16.2Hz，1H)；6.49(m，1H)；4.52—4.42(m，3H)；4.26(m，1H)；4.06(s，3×0.34H)；4.04(s，3×0.66H)；3.65(m，1H)；3.44—3.24(m，4H)；2.81(m，1H)；2.12—1.41(m，7H)。

MS(ESI，m/z)：529.0[M+H ⁺]。

18.vi.[(E)-3-(2; 5-difluoro-phenyl)-allyl group]-(2R, 3R, 6S)-2-[(2RS)-2; 3-dihydroxyl-propyl group]-6-(6-methoxyl group-[1,5] naphthyridines-4-basic formamyl)-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

(0.351g 0.66mmol) is starting raw material, uses the 4.iii step of embodiment 4, obtains the title glycol (0.307g, productive rate 73%) of colourless foam shape with intermediate 18.v.Compound uses DCM to contain 7.5% MeOH through SiO ₂Chromatogram purification, this compound are 2-1 epimer mixture.

MS(ESI，m/z)：629.0[M+H ⁺]。

18.vii.[(E)-3-(2; 5-difluoro-phenyl)-allyl group]-[(2R; 3R, 6S)-2-(2-hydroxyl-ethyl)-6-(6-methoxyl group-[1,5] naphthyridines-4-basic formamyl)-tetrahydrochysene-pyrans-3-yl]-t-butyl carbamate:

(0.294g adds NaIO in acetone 0.47mmol) (4ml) solution to intermediate 18.vi ₄(0.25g, (0.9ml) aqueous solution 1.17mmol).Reacted 1 hour.Leach solid, filtrate concentrates evaporate to dryness.White foam is dissolved in MeOH (3ml), by a part adding NaBH ₄(0.042g, 1.12mmol).Reaction was at room temperature stirred 1 hour.Add entry, depress the evaporation volatile matter adding.Add DCM-MeOH, separate phase.Water layer extracts 2 times with DCM-MeOH 9-1, and the organic layer of merging is through Na ₂SO ₄Drying is depressed evaporation adding.Dry in high vacuum, obtain yellow foamed title compound (0.272g, productive rate 97%).

Rf＝0.30，DCM—MeOH?19—1.

MS(ESI，m/z)：599.1[M+H ⁺]。

18.viii. (2S, 5R, 6R)-(5-[(E)-3-and (2,5-difluoro-phenyl)-allyl amino]-6-(2-hydroxyl-ethyl)-tetrahydrochysene-pyrans-2-carboxylic acid (6-methoxyl group-[1,5] naphthyridines-4-yl)-acid amides:

(0.268g 0.45mmol) is starting raw material, uses the 2.iii step of embodiment 2, obtains the foamed title compound of canescence (0.271g, productive rate 96%) with intermediate 18.vii..

¹H?NMR(d ₆—DMSO)δ：10.56(s，1H)；8.70(d，J＝5.0Hz，1H)；8.39(d，J＝5.0Hz，1H)；8.28(d，J＝9.0Hz，1H)；7.48(m，1H)；7.32(d，J＝9.0Hz，1H)；7.24(m，1H)；7.13(m1H)；6.65(d，J＝16.1Hz，1H)；6.51(td，J＝5.6，16.1Hz，1H)；4.40(br?s，1H)；4.36(m，1H)；4.26(m，1H)；4.04(s，3H)；3.65—3.54(m，2H)；3.51—3.35(m，2H)；2.85(m，1H)；2.14(m，1H)；1.97(m，1H)；1.80—1.70(m，2H)；1.68—1.54(m，3H)。

Embodiment 19:(2S, 5R)-5-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-tetrahydrochysene-pyrans-2-carboxylic acid (6-methoxyl group-[1,5] naphthyridines-4-yl)-acid amides:

19.i. (3R, 6S)-(6-formamyl-tetrahydrochysene-pyrans-3-yl)-t-butyl carbamate:

To (2S, 5R)-(description prepares 2418-2427 to 5-tert-butoxycarbonyl ammonia-tetrahydrochysene-pyrans-2-carboxylic acid according to Eur.J.Org.Chem. (2003); Add NHS (1.5g) and DCC (2.7g) in EA 3g) (50ml) solution.Stirring reaction-whole night at room temperature.The filtering solid.Filtrate concentrates in a vacuum, and resistates is dissolved in THF (180ml).NH ₃Gas passed through solution 10 minutes, and the muddy mixture of gained at room temperature stirred 1 hour.In mixture, add SiO ₂(20g), remove volatile matter by circulating and evaporating.Raw material is through SiO ₂The title compound that obtains white solid (1.3g) of (DCM-MeOH19-1) chromatogram purification.

MS(ESI，m/z)：245.3[M+H ⁺]。

19.ii.[(3R, 6S)-6-(6-methoxyl group-[1,5] naphthyridines-4-basic formamyl)-tetrahydrochysene-pyrans-3-yl]-t-butyl carbamate:

To intermediate 19.i (0.8g), cesium carbonate (1.3g), rac-BINAP (0.145g) and (dba) ₃Pd ₂.CHCl ₃Add dioxane (41ml) in the mixture (0.057g).Mixture ultrasonication 15 minutes adds 6-methoxyl group-[1,5] naphthyridines-4-basic trifluoro-methane sulfonate (1.0g).Mixture heats a whole night at 100 ℃.Filter, filtrate concentrates evaporate to dryness, and resistates is through SiO ₂(DCM-MeOH19-1) purifying obtains foam title amide (1.3g).

¹HNMR (CDCl ₃) δ: 10.57 (s, 1H); 8.70 (d, J=5.2Hz, 1H); 8.51 (d, J=5.2Hz, 1H); 8.22 (d, J=9.0Hz, 1H); 7.16 (d, J=9.0Hz, 1H); 4.32 (m, 2H); 4.12 (s, 3H); 4.01 (dd, J=2.5,11.4Hz, 1H); 3.72 (m, 1H); 3.23 (t, J=10.6Hz, 1H); 2.39 (qd, J=2.8,10.2Hz, 1H); 2.22 (m.1H); 1.76 (m, 1H); 1.47 (overlapping, m, 1H); 1.47 (s, 9H).

MS(ESI，m/z)：403.6[M+H ⁺]。

19.iii. (2S, 5R)-5-ammonia-tetrahydrochysene-pyrans-2-carboxylic acid (6-methoxyl group-[1,5] naphthyridines-4-yl)-acid amides:

With intermediate 19.ii (1.3g) is starting raw material, uses the 1.ix step of embodiment 1, obtains the title amine (0.5g) of white solid.Compound is through SiO ₂(DCM-MeOH19-1 contains 1% spissated aq.NH ₄OH) chromatogram purification.

MS(ESI，m/z)：303.2[M+H ⁺]。

19.iv. (2S, 5R)-5-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-tetrahydrochysene-pyrans-2-carboxylic acid (6-methoxyl group-[1,5] naphthyridines-4-yl)-acid amides:

With intermediate 19.iii (0.254g, 0.84mmol) and (E)-3-(2,5-difluoro-phenyl)-propenal (0.141g, 1.0eq.) be starting raw material, use the 1.x step of embodiment 1, obtain the title compound (0.12g, productive rate 31%) of white solid.Compound uses DCM-MeOH 97-3 to contain 0.5% aq.NH ₄OH is as elutriant, through SiO ₂Chromatogram purification.

¹H?NMR(d ₆—DMSO)δ：10.52(s，1H)；8.71(d，J＝5.0Hz，1H)；8.38(d，J＝5.0Hz，1H)；8.27(d，J＝9.0Hz，1H)；7.48(m，1H)；7.32(d，J＝9.0Hz，1H)；7.25(m，1H)；7.11(m，1H)；6.63(d，J＝16.2Hz，1H)；6.50(td，J＝5.3，16.2Hz，1H)；4.21(dd，J＝3.2，10.7Hz，1H)；4.08(dd，J＝2.1，10.7Hz，1H)；4.02(s，3H)；3.48—3.35(m，2H)；3.25(t，J＝10.5Hz，1H)；2.69(m，1H)；2.18—2.14(m，2H)；1.99(br?s，1H)；1.55(m，1H)；1.35(m，1H)。

MS(ESI，m/z)：454.9[M+H ⁺]。

Embodiment 20:(1S)-1-(2S, 5R)-5-[(E)-3-(3-fluorine-phenyl)-allyl amino]-tetrahydrochysene-pyrans-2-yl }-2-(6-methoxyl group-quinoline-4-yl)-ethanol:

20.i.{ (3R, 6S)-6-[2-(3-methoxyl group-quinoline-5-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

With (3R, 6S)-[6-(1-phenyl-1H-tetrazolium-5-sulfonymethyl)-tetrahydrochysene-pyrans-3-yl]-t-butyl carbamate (reference preparation G; 15g is 35.4mmol) with 3-methoxyl group-quinoline-5-formaldehyde (reference preparation F; 6.3g, 33.7mmol) be starting raw material, use the 1.vi step of embodiment 1, obtain the title alkene (9.9g, productive rate 76%) of colorless solid shape.Compound grinds purifying in Hex-ether mixture.

¹H NMR (CDCl ₃) δ: 8.72 (d, J=4.5Hz, 1H); 8.02 (d, J=9.2Hz, 1H); 7.36-7.25 (m, 3H); 7.26 (d, J=15.8Hz, 1H); 6.42 (dd, J=5.2,15.8Hz, 1H); 4.27 (m, 1H); 4.08 (m, 1H); 3.98 (s, 3H); 3.74 (br s, 1H); 3.18 (t, J=10.6Hz, 1H); 2.22 (m, 1H); 1.98 (m, 1H); 1.75-1.60 (m, 2H); 1.48 (s, 9H), 1.47 (overlapping, m, 1H).

MS(ESI，m/z)：385.3[M+H ⁺]。

20.ii.{ (3R, 6S)-6-[(1S, 2S)-1,2-dihydroxyl-2-(6-methoxyl group-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

(9.9g 25.7mmol) is starting raw material, uses the 6.i step of embodiment 6, obtains the title glycol (10.5g, productive rate 97%) of colourless foam shape with intermediate 20.i.Compound uses DCM-MeOH9-1 as elutriant, through SiO ₂Chromatogram purification.

¹H?NMR(d ₆—DMSO)δ：8.71(d，J＝4.5Hz，1H)；7.93(d，J＝9.0Hz，1H)；7.54(d，J＝4.5Hz，1H)；7.44—7.38(m，2H)；6.851(br?s，1H)；6.65(d，J＝8.2Hz，1H)；5.43(d，J＝5.4Hz，1H)；5.36(m，1H)；4.83(d，J＝6.3Hz，1H)；3.89(s，3H)；3.79(m，1H)；3.56(m，1H)；3.37(br?s，1H)；2.72(t，J＝10.6Hz，1H)；1.85(m，1H)；1.71—1.65(m，2H)；1.36(s，9H)；1.21(m，1H)。

20.iii. (3R, 6S)-6-[(4R, 5R)-5-(6-methoxyl group-quinoline-4-yl)-2-oxygen-[1,3] dioxolane-4-yl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

In the DCM of the intermediate 20.ii of ice-cooled mistake (10.2g) (130ml) solution, add pyridine (12ml) and triphosgene (3.62g).Be reflected under this temperature and stirred 30 minutes, at room temperature stirred then 90 minutes.Reaction mixture NaHCO ₃Aqueous solution dilution, two-layer decant.Organic layer is through Na ₂SO ₄Drying, filtration and concentrated evaporate to dryness.Resistates is through SiO ₂(DCM-MeOH 19-1) chromatogram purification obtains the title cyclic carbonate (10.5g) of colourless foam shape.

¹H NMR (CDCl ₃) δ: 8.82 (d, J=4.5Hz, 1H); 8.10 (d, J=9.3Hz, 1H); 7.49-7.43 (m, 2H); 7.21 (br.s, 1H); 6.27 (d, J=4.2Hz, 1H); 4.61 (m, 1H); 4.28 (ddd, J=2.0,4.7,10.6Hz, 2H); 3.95 (s, 3H); 3.70 (m, 2H); 3.18 (t, J=10.7Hz, 1H); 2.27 (m, 1H); 1.84 (m, 2H); 1.46 (s, 9H); 1.45 (m is overlapping, 1H).

MS(ESI，m/z)：445.0[M+H ⁺]。

20.iv. (3R, 6S)-6-[(1S)-1-hydroxyl-2-(6-methoxyl group-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

In argon gas, in the EA of intermediate 20.iii (2.75g) (250ml) solution, add Pd/C (1.32g).Gained suspension stirs in hydrogen.2.5 after hour, add Pd/C (0.66g) once more, be reflected in the hydrogen and stir a whole night.Filtration catalizer, filtrate concentrate in a vacuum.Resistates is through SiO ₂(DCM-MeOH 19-1 contains 1% aq.NH ₄OH) column chromatography purifying obtains the title compound (1.23g) of white foam shape.

¹H NMR (d ₆-DMSO) δ: 8.62 (d, J=4.4Hz, 1H); 7.92 (d, J=9.0Hz, 1H); 7.42 (d, J=2.5Hz, 1H); 7.40 (dd, J=2.7,9.0Hz, 1H); 7.33 (d, J=4.4Hz, 1H); 6.76 (br d, J=8.0Hz, 1H); 4.83 (d, J=6.4Hz, 1H); 3.91 (s, 3H); 3.90 (overlapping, m, 1H); 3.74 (m, 1H); 3.38 (br.s, 1H); 3.29 (overlapping, dd, visible J=3.8Hz, 1H); 3.12 (d, J=10.4Hz, 1H); 2.98 (t, J=10.3Hz, 1H); 2.97 (m is overlapping, 1H); 1.90 (d, J=9.2Hz, 1H); 1.60 (m, 2H); 1.39 (s, 9H); 1.38 (m is overlapping, 1H).

MS(ESI，m/z)：403.0[M+H ⁺]。

20.v. (1S)-1-((2S, 5R)-(5-ammonia-tetrahydrochysene-pyrans-2-yl)-2-(6-methoxyl group-quinoline-4-yl)-ethanol:

With TFA (15ml) solution stirring of intermediate 20.iv (1.23g) 10 minutes.The solution concentration evaporate to dryness uses the alkalization of 2Maq.NaOH solution, with DCM-MeOH 9-1 dilution, separates phase.Water layer extracts 6 times with DCM-MeOH 9-1.The organic layer that merges is through Na ₂SO ₄Drying, filtration and concentrated evaporate to dryness obtain white solid (0.768g).

¹H NMR (DMSO) δ: 8.62 (d, J=4.4Hz, 1H); 7.92 (d, J=9.1Hz, 1H); 7.44 (d, J=2.7Hz, 1H); 7.39 (dd, J=2.8,9.1Hz, 1H); 7.32 (d, J=4.4Hz, 1H); 4.79 (d, J=6.3Hz, 1H); 3.91 (s, 3H); 3.88 (ddd, J=1.8,4.4,10.5Hz, 1H); 3.73 (m, 1H); 3.31 (dd, J=4.0,13.6Hz, 1H); 3.10 (dt, J=3.4,10.4Hz, 1H); 2.93 (m is overlapping, 1H); 2.87 (t is overlapping, J=10.5Hz, 1H); 2.61 (m, 1H); 1.92 (m, 1H); 1.56 (m, 2H); 1.39 (br s, and 2H) 1.13 (m, 1H).

MS(ESI，m/z)：303.2[M+H ⁺]。

20.vi. (1S)-1-(2S, 5R)-5-[(E)-3-(3-fluorine-phenyl)-allyl amino]-tetrahydrochysene-pyrans-2-yl }-2-(6-methoxyl group-quinoline-4-yl)-ethanol:

With intermediate 20.v (0.1g, 0.33mmol) and (E)-3-(0.050g 1.0eq.) be starting raw material to (3-fluorine-phenyl)-propenal, and the 1.x step of use embodiment 1 obtains the title compound (0.063g, productive rate 43%) of white solid.Compound uses DCM-MeOH97-3 to contain 0.5% aq.NH ₄OH is as elutriant, through SiO ₂Chromatogram purification.

MS(ESI，m/z)：437.0[M+H ⁺]。

Embodiment 21:7-fluorine-6-((3R, 6S)-6-[(1S)-1-hydroxyl-2-(6-methoxyl group-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-basic ammonia }-methyl)-4H-benzo [1,4] thiazine-3-ketone:

With intermediate 20.v (0.051g, 0.17mmol) and 7-fluorine-3-oxygen-3,4-dihydro-2H-benzo [1,4] thiazine-6-formaldehyde (is described preparation according to WO 02/056882,0.036g, 1.0eq.) be starting raw material, use the 1.x step of embodiment 1, obtain the title compound (0.020g, productive rate 23%) of white solid.Compound uses DCM-MeOH 19-1 to contain 0.5% aq.NH ₄OH is as elutriant, through SiO ₂Chromatogram purification.

¹HNMR (d ₆-DMSO) δ: 10.55 (s, 1H); 8.62 (d, J=4.4Hz, 1H); 7.91 (d, J=9.0Hz, 1H); 7.42-7.40 (m, 2H); 7.32 (d, J=4.4Hz, 1H); 7.20 (d, J=9.0Hz, 1H); 7.09 (d, J=6.8Hz, 1H); 4.79 (d, J=6.3Hz, 1H); 4.04 (m, 1H); 3.90 (s, 3H); 3.77-3.71 (m, 3H); 3.46 (s, 2H); 3.30 (dd, J=3.8,13.1Hz, 1H); 3.15 (m, 1H); 3.00-2.90 (m, 2H); 2.50 (overlapping, m, 1H); 2.09-1.99 (m, 2H); 1.66-1.51 (m, 2H); 1.18 (m, 1H).

MS(ESI，m/z)：498.1[M+H ⁺]。

Embodiment 22:3-(2-fluorine-phenyl)-N-(3R, 6S)-6-[(1S)-1-hydroxyl-2-(6-methoxyl group-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-(E)-acrylamide:

With intermediate 20.v (0.1g, 0.33mmol) and (E)-3-(0.055g 1.0eq.) be starting raw material to (2-fluorine-phenyl)-vinylformic acid, and the 2.iv step of use embodiment 2 obtains the title compound (0.085g, productive rate 57%) of white solid.Compound uses DCM-MeOH 97-3 to contain 0.5% aq.NH ₄OH is as elutriant, through SiO ₂Chromatogram purification.

¹H?NMR(d ₆—DMSO)δ：8.63(d，J＝4.2Hz，1H)；8.13(d，J＝7.2Hz，1H)；7.95(d，J＝9.0Hz，1H)；7.64(t，J＝7.2Hz，1H)；7.62—7.19(m，7H)；6.70(d，J＝15.8Hz，1H)；4.87(d，J＝6.4Hz，1H)；4.02(m，1H)；3.92(s，3H)；3.92—3.78(m，2H)；3.35(m，1H)；3.21(m，1H)；3.08—2.93(m，2H)；1.98(m，1H)；1.80—1.60(m，2H)；1.43(m，1H)。

Embodiment 23:3-(3-fluorine-phenyl)-N-(3R, 6S)-6-[(1S)-1-hydroxyl-2-(6-methoxyl group-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-(E)-acrylamide:

With intermediate 20.v (0.1g, 0.33mmol) and (E)-3-(0.055g 1.0eq.) be starting raw material to (3-fluorine-phenyl)-vinylformic acid, and the 2.iv step of use embodiment 2 obtains the title compound (0.030g, productive rate 20%) of white solid.Compound uses DCM-MeOH 97-3 to contain 0.5% aq.NH ₄OH is as elutriant, through SiO ₂Chromatogram purification.

¹H?NMR(d ₆—DMSO)δ：8.63(d，J＝4.2Hz，1H)；8.05(d，J＝7.8Hz，1H)；7.92(d，J＝9.0Hz，1H)；7.56—7.25(m，7H)；7.19(m，1H)；6.62(d，J＝15.8Hz，1H)；4.87(d，J＝6.5Hz，1H)；4.02(m，1H)；3.92(s，3H)；3.92—3.78(m，2H)；3.35(m，1H)；3.21(m，1H)；3.08—2.93(m，2H)；2.01(m，1H)；1.80—1.60(m，2H)；1.43(m，1H)。

Embodiment 24:8-((1R, 2R)-2-(2S, 5R)-5-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-tetrahydrochysene-pyrans-2-yl }-1,2-dihydroxyl-ethyl)-quinoline-2-nitrile:

6-formyl radical-tetrahydrochysene-pyrrole 24.i. (3R, 6S)-(muttering-3-yl)-t-butyl carbamate:

DCM (25ml) solution of oxalyl chloride (3.5ml) is cooled to-78 ℃, dropwise adds DCM (25ml) solution of DMSO (3.5ml).Stir after 15 minutes, dropwise add (3R, 6S)-DCM (25ml) solution of (6-hydroxymethyl-tetrahydrochysene-pyrans-3-yl)-t-butyl carbamate (describing preparation, 2418-2427) according to Eur.J.org.Chem. (2003).Reaction mixture stirred 1 hour, dropwise added DCM (15ml) solution of TEA (15ml).Rise to 0 ℃ and reacted 1 hour.Add saturated NaHCO ₃(50ml).Separate organic layer, through Na ₂SO ₄Dry, filtration and concentrated in a vacuum.Resistates is through SiO ₂(Hex-EA 1-2) chromatogram purification obtains the title aldehyde (2.5g) of colorless solid shape.

24.ii. (3R, 6S)-(6-ethynyl-tetrahydrochysene-pyrans-3-yl)-t-butyl carbamate:

In the MeCN of p-toluene sulfonyt azide (3.08g) (200ml) solution, add K ₂CO ₃(5.38g) with 2-phosphine oxide dimethyl phthalate (2.13ml).Mixture at room temperature stirred 2 hours, added MeOH (30ml) solution of intermediate 24.i (2.5g).Mixture at room temperature stirs a whole night.After concentrating evaporate to dryness, resistates is located away from water (50ml) and EA (100ml).(2 * 100ml) extract water layer with EA.The organic layer that merges is with the salt water washing, through Na ₂SO ₄Drying, filtration and concentrated evaporate to dryness.Resistates is through SiO ₂(EA-Hex1-3) filters the title alkynes (1.9g) that obtains white solid.

¹HNMR(CDCl ₃)δ：4.78(m，1H)；4.39(m，1H)；4.14(dd，J＝3.0，11.4Hz，1H)；3.71(m，1H)；3.34(m，1H)；2.50(d，J＝2.2Hz，1H)；2.11—1.99(m，2H)；1.73(m，1H)；1.60(m，1H)；1.46(s，9H)。

MS(ESI，m/z)：226.2[M+H ⁺]。

24.iii. suitable, anti--[(3R, 6S)-6-(2-tributyl tin alkyl-vinyl)-tetrahydrochysene-pyrans-3-yl]-t-butyl carbamate:

To intermediate 24.ii (1.95g, add in THF 8.65mmol) (26ml) solution bi triphenyl phosphorus palladium chloride (0.12g, 0.17mmol), add then tributyltin chloride (2.75ml, 10.38mmol).Mixture at room temperature stirred 20 minutes.Reaction mixture concentrates evaporate to dryness, and resistates is through SiO ₂The title stannic hydride that (Hex is Hex-EA9-1 then) chromatogram purification obtains (3.4g, the mixture such as mol such as grade of cis-trans-isomer).

24.iv. anti--(3R, 6S)-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

Dioxane (new distillatory to intermediate 24.iii (5g), 50ml) add 2-cyano group-quinoline-8-basic triflate (2.0g in the solution, 6.6mmol), LiCl (0.936g), 2,6-di-t-butyl-4-methylphenol (small amount of crystalline), (PPh ₃) ₄Pd (0.153g).Mixture heats a whole night at 100 ℃.After the cooling, the filtering solid, filtrate concentrates evaporate to dryness.Resistates is through SiO ₂(Hex-EA1-1) chromatogram purification obtains the title alkene (1.80g, productive rate 71%) of white solid.

¹H NMR (d ₆-DMSO) δ: 8.72 (d, J=4.7Hz, 1H); 8.25 (d, J=9.0Hz, 1H); 7.84 (d, J=4.7Hz, 1H); 7.55 (d, J=16.5Hz, 1H); 7.28 (d, J=9.0Hz, 1H); 6.93 (dd, J=5.3Hz, 16.5Hz, 1H); 6.85 (d, J=7.7Hz, 1H); 4.04 (s, 3H); 4.01 (overlap, m, 1H); 3.90 (m, 1H); 3.39 (brs, 1H); 3.10 (t, J=10.6Hz, 1H); 1.89 (m, 2H); 1.50 (m, 2H); 1.39 (s, 9H).

MS(ESI，m/z)：386.1[M+H ⁺]。

24.v. (3R, 6S)-6-[(1R, 2R)-2-(cyano group-quinoline-8-yl)-1,2-dihydroxyl-ethyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

(1.80g 4.74mmol) is starting raw material, uses the 6.i step of embodiment 6, obtains the title glycol (1.60g, productive rate 81%) of white solid with intermediate 24.iv.

MS(ESI，m/z)：419.2[M+H ⁺]。

24.vi.8-[(1R, 2R)-2-((2S, 5R)-5-ammonia-tetrahydrochysene-pyrans-2-yl)-1,2-dihydroxyl-ethyl]-quinoline-2-nitrile:

(1.1g 2.61mmol) is starting raw material, uses the 1.ix step of embodiment 1, obtains the title amine (0.62g, productive rate 74%) of colorless solid shape with intermediate 24.v.

MS(ESI，m/z)：314.2[M+H ⁺]。

24.vii.8-((1R, 2R)-2-(2S, 5R)-5-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-tetrahydrochysene-pyrans-2-yl }-1,2-dihydroxyl-ethyl)--quinoline-2-nitrile:

With intermediate 24.vi (0.158g, 0.5mmol) and (E)-3-(2,5-difluoro-phenyl)-propenal (0.084g, 1.0eq.) be starting raw material, use the 1.x step of embodiment 1, obtain the title compound (0.04g, productive rate 17%) of white solid.Compound uses DCM-MeOH 19-1 to contain 0.5% aq.NH ₄OH is as elutriant, through SiO ₂Chromatogram purification.

¹H NMR (d ₆-DMSO) δ: 8.65 (d, J=8.5Hz, 1H); 8.07-7.99 (m, 3H); 7.80 (dd, J=7.2,8.3Hz, 1H); 7.49 (m, 1H); 7.25 (m, 1H); 7.13 (m, 1H); 6.61 (d, J=16.4Hz, 1H); 6.48 (td, J=5.4,16.4Hz, 1H); 5.77 (dd, J=2.9,6.3Hz, 1H); 5.16 (d, J=7.6Hz, 1H); 4.35 (d, J=6.3Hz, 1H); 3.91 (m, 1H); 3.60 (m, 1H); 3.42-3.32 (m, 2H), 3.24 (m, 1H); 2.81 (t, J=10.3Hz, 1H); 2.56 (overlapping, m, 1H); 2.11 (m, 1H); 1.90 (m, 1H); 1.76 (br s, 1H); 1.56 (m, 1H); 1.24 (m, 1H).

MS(ESI，m/z)：465.6[M+H ⁺]。

Embodiment 25:[(E)-3-(2,5-difluoro-phenyl)-allyl group]-3R, 6S)-6-[(E)-2-(3-fluorine-6-methoxyl group-quinoline-5-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-amine:

25.i.{ (3R, 6S)-6-[(E)-2-(3-fluorine-6-methoxyl group-quinoline-5-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

With (3R, 6S)-[6-(1-phenyl-1H-tetrazolium-5-sulfonymethyl)-tetrahydrochysene-pyrans-3-yl]-t-butyl carbamate (reference preparation G; 1.43g 3.4mmol) (0.462g 2.25mmol) is starting raw material, uses the 1.vi step of embodiment 1, obtains the title alkene (0.85g, productive rate 62%) of white solid with 3-fluorine-6-methoxyl group-quinoline-5-formaldehyde.Compound uses EA-Hex1-1 as elutriant, through SiO ₂Chromatogram purification.

¹HNMR(d ₆—DMSO)δ：8.90(d，J＝2.7Hz，1H)；8.32(dd，J＝3.0，11.4Hz，1H)；8.12(d，J＝9.3Hz，1H)；7.78(d，J＝9.3Hz，1H)；7.99(d，J＝16.2Hz，1H)；6.93(d，J＝8.1Hz，1H)；6.35(dd，J＝5.7，16.2Hz，1H)；4.12—3.99(m，2H)；4.10(s，3H)；3.50(br?s，1H)；3.21(t，J＝10.5Hz，1H)；2.03—2.00(m，2H)；1.62(m，1H)；1.49(m，1H)；1.49(s，9H)。

25.ii.6-[(3R, 6S)-(E)-2-(3-fluorine-6-methoxyl group-quinoline-5-yl)-vinyl]-tetrahydrochysene-pyrans-3-basic amine:

(0.3g 0.745mmol) is starting raw material, uses the 1.ix step of embodiment 1, obtains the title amine (0.16g, productive rate 71%) of white solid with intermediate 25.i.Compound uses DCM-MeOH9-1 to contain 1% aq.NH ₄OH is as elutriant, through SiO ₂Chromatogram purification.

MS(ESI，m/z)：465.6[M+H ⁺]。

25.iii.[(E)-3-(2,5-difluoro-phenyl)-allyl group]-3R, 6S)-6-[(E)-2-(3-fluorine-6-methoxyl group-quinoline-5-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-amine:

With intermediate 25.ii (0.1g, 0.33mmol) and (E)-3-(0.055g 1.0eq.) be starting raw material to (2,5-difluoro-phenyl)-propenal, and the 1.x step of use embodiment 1 obtains the title compound (0.034g, productive rate 22%) of colorless oil.Compound uses DCM-MeOH 19-1 to contain 0.5% aq.NH ₄OH is as elutriant, through SiO ₂Chromatogram purification.

MS(ESI，m/z)：455.0[M+H ⁺]。

Embodiment 26:[(E)-3-(2,5-difluoro-phenyl)-allyl group]-(3R, 6S)-6-[2-(6-fluorine-3-methoxyl group-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-amine:

26.i.{ (3R, 6S)-6-[2-(6-fluorine-3-methoxyl group-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

(0.55g adds 10% Pd/C (0.25g) in EA 1.36mmol) (6ml) and MeOH (20ml) solution to intermediate 25.i.Be reflected under the hydrogen and stirred 2 hours.Leach catalyzer, filtrate concentrates the title compound (0.55g) that evaporate to dryness obtains white solid.

MS(ESI，m/z)：405.0[M+H ⁺]。

26.ii. (3R, 6S)-6-[2-(6-fluorine-3-methoxyl group-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-basic amine:

(0.55g 1.36mmol) is starting raw material, uses the 1.ix step of embodiment 1, obtains the title amine (0.3g, productive rate 72%) of colorless oil with intermediate 26.i.Compound uses DCM-MeOH9-1 to contain 1% aq.NH ₄OH is as elutriant, through SiO ₂Chromatogram purification.

MS(ESI，m/z)：305.1[M+H ⁺]。

26.iii.[(E)-3-(2,5-difluoro-phenyl)-allyl group]-(3R, 6S)-6-[2-(6-fluorine-3-methoxyl group-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-amine:

With intermediate 26.ii (0.15g, 0.49mmol) and (E)-3-(0.082g 1.0eq.) be starting raw material to (2,5-difluoro-phenyl)-propenal, and the 1.x step of use embodiment 1 obtains the title compound (0.17g, productive rate 75%) of colorless oil.Compound uses DCM-MeOH 19-1 to contain 0.5% aq.NH ₄OH is as elutriant, through SiO ₂Chromatogram purification.

¹HNMR(d6—DMSO)δ：8.77(d，J＝2.7Hz，1H)；8.12(dd，J＝3.2，11.2Hz，1H)；7.97(d，J＝9.2Hz，1H)，7.63(d，J＝9.2Hz，1H)；7.48(m，1H)；7.24(m，1H)；7.11(m，1H)6.59(d，J＝16.1Hz，1H)；6.48(td，J＝5.2，16.2Hz，1H)；4.02(m1H)；3.95(s，3H)；3.37(m，2H)，3.13—2.92(m，3H)；2.88(t，J＝10.5Hz，1H)；2.55(m，1H)；1.96(m，1H)；1.75(br?s，1H)；1.66—1.55(m，3H)；1.26—1.10(m，2H)。

MS(ESI，m/z)：456.9[M+H ⁺]。

Embodiment 27:6-((3R, 6S)-6-[2-(6-fluorine-3-methoxyl group-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-basic ammonia }-methyl)-4H-pyrido [3,2-b] [1,4] thiazine-3-ketone:

With intermediate 26.ii (0.15g, 0.49mmol) and 3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] (0.095g 1.0eq.) is starting raw material to thiazine-6-formaldehyde, uses the 1.x step of embodiment 1, obtain the title compound (0.035g, productive rate 17%) of pale solid shape.Compound uses DCM-MeOH9-1 to contain 1%aq.NH ₄OH is as elutriant, through SiO ₂Chromatogram purification.

MS(ESI，m/z)：482.8[M+H ⁺]。

Embodiment 28:(1R, 2R)-1-(2R, 5S)-5-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-tetrahydrochysene-pyrans-2-yl }-2-(6-fluorine-quinoline-4-yl)-ethane-1,2-glycol:

28.i.{ (3S, 6R)-6-[(E)-2-(6-fluorine-quinoline-4-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

With (3S, 6R)-[6-(1-phenyl-1H-tetrazolium-5-sulfonymethyl)-tetrahydrochysene-pyrans-3-yl]-t-butyl carbamate (reference preparation I, 1.69g, 4mmol) with 3-methoxyl group-quinoline-5-formaldehyde (reference preparation D, 0.7g, 4mmol) be starting raw material, use the 1.vi step of embodiment 1, obtain the title alkene (1.03g, productive rate 69%) of white solid.Compound uses Hept-EA1-1 then 1-4 as elutriant, through SiO ₂Chromatogram purification.

MS(ESI，m/z)：373.1[M+H ⁺]。

28.ii.{ (3S, 6R)-6-[(1R, 2R)-2-(6-fluorine-quinoline-4-yl)-1,2-dihydroxyl-ethyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

(0.497g 1.33mmol) is starting raw material, uses the 6.i step of embodiment 6, obtains the title glycol (0.54g, productive rate 99%) of white solid with intermediate 28.i.Compound uses DCM-MeOH 9-1 as elutriant, through SiO ₂Chromatogram purification.

MS(ESI，m/z)：407.0[M+H ⁺]。

28.iii. (1R, 2R)-1-[(2R, 5S)-5-ammonia-tetrahydrochysene-pyrans-2-yl]-2-(6-fluorine-quinoline-4-yl)-ethane-1,2-glycol:

(0.54g 1.32mmol) is starting raw material, uses the 1.ix step of embodiment 1, obtains the title amine (0.21g, productive rate 51%) of colourless foam shape with intermediate 28.ii.

MS(ESI，m/z)：307.1[M+H ⁺]。

28.iv. (1R, 2R)-1-(2R, 5S)-5-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-tetrahydrochysene-pyrans-2-yl }-2-(6-fluorine-quinoline-4-yl)-ethane-1,2-glycol:

With intermediate 28.iii (0.21g, 0.68mmol) and (E)-3-(2,5-difluoro-phenyl)-propenal (0.115g, 1.0eq.) be starting raw material, use the 1.x step of embodiment 1, obtain the title compound (0.095g, productive rate 31%) of white foam shape.Compound uses DCM-MeOH 9-1 to contain 1% aq.NH ₄OH is as elutriant, through SiO ₂Chromatogram purification.

MS(ESI，m/z)：458.9[M+H ⁺]。

Embodiment 29:[(E)-3-(2,5-difluoro-phenyl)-allyl group]-(3S, 6R)-(E)-6-[2-(6-fluorine-quinoline-4-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-amine:

29.i. (3S, 6R)-6-[(E)-2-(6-fluorine-quinoline-4-yl)-vinyl]-tetrahydrochysene-pyrans-3-basic amine:

(0.226g 0.6mmol) is starting raw material, uses the 1.ix step of embodiment 1, obtains the title amine (0.135g, productive rate 82%) of colourless foam shape with intermediate 28.i.Compound uses DCM-MeOH9-1 to contain 1% aq.NH ₄OH is as elutriant, through SiO ₂Chromatogram purification.

MS(ESI，m/z)：273.2[M+H ⁺]。

29.ii.[(E)-3-(2,5-difluoro-phenyl)-allyl group]-(3S, 6R)-(E)-6-[2-(6-fluorine-quinoline-4-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-amine:

With intermediate 29.i (0.131g, 0.48mmol) and (E)-3-(0.089g 1.1eq.) be starting raw material to (2,5-difluoro-phenyl)-propenal, and the 1.x step of use embodiment 1 obtains the title compound (0.112g, productive rate 54%) of colorless oil.Compound uses DCM-MeOH 97-3 to contain 0.3% aq.NH ₄OH is as elutriant, through SiO ₂Chromatogram purification.

¹H?NMR(d ₆—DMSO)δ：8.82(d，J＝4.6Hz，1H)；8.09(dd，J＝5.7，9.2Hz，1H)；7.97(dd，J＝2.7，10.6Hz，1H)；7.72—7.65(M，2H)；7.48(m，1H)；7.31(d，J＝15.8Hz，1H)；7.24(m，1H)；7.11(m，1H)；6.63(d，J＝15.8Hz，1H)；6.62(d，J＝15.8Hz，1H)；6.51(td，J＝5.5，15.8Hz，1H)；4.11—4.03(m，2H)；3.48—3.35(m，2H)；3.10(t，J＝10.5Hz，1H)；2.60(m，1H)；2.10(m，1H)；1.90—1.88(m，2H)；1.54—1.23(m，2H)。

MS(ESI，m/z)：425.0[M+H ⁺]。

Embodiment 30:[(E)-3-(2,5-difluoro-phenyl)-allyl group]-(3S, 6R)-6-[2-(6-fluorine-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-amine:

30.i.{ (3S, 6R)-6-[2-(6-fluorine-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

(0.277g 0.74mmol) is starting raw material, uses the 2.ii step of embodiment 2, obtains the title alkane (0.267g, productive rate 95%) of colourless foam shape with intermediate 28.i.Compound uses DCM-MeOH 9-1 to contain 1% aq.NH ₄OH is as elutriant, through SiO ₂Chromatogram purification.

MS(ESI，m/z)：375.1[M+H ⁺]。

30.ii. (3S, 6R)-6-[2-(6-fluorine-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-basic amine:

(0.261g 0.7mmol) is starting raw material, uses the 1.ix step of embodiment 1, obtains the title amine (0.155g, productive rate 81%) of little yellow oily with intermediate 30.i.Compound uses DCM-MeOH9-1 to contain 1% aq.NH ₄OH is as elutriant, through SiO ₂Chromatogram purification.

MS(ESI，m/z)：275.1[M+H ⁺]。

30.iii.[(E)-3-(2,5-difluoro-phenyl)-allyl group]-(3S, 6R)-6-[2-(6-fluorine-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-yl }-amine:

With intermediate 30.ii (0.08g, 0.29mmol) and (E)-3-(0.054g 1.1eq.) be starting raw material to (2,5-difluoro-phenyl)-propenal, and the 1.x step of use embodiment 1 obtains the title compound (0.106g, productive rate 85%) of colorless oil.Compound uses DCM-MeOH 19-1 to contain 0.5% aq.NH ₄OH is as elutriant, through SiO ₂Chromatogram purification.

MS(ESI，m/z)：426.7[M+H ⁺]。

Embodiment 31:6-(3S, 6R)-6-[2-(6-fluorine-quinoline-4-yl)-ethyl]-tetrahydrochysene-pyrans-3-basic ammonia }-methyl)-4H-pyrido [3,2-b] [1,4] thiazine-3-ketone:

With intermediate 30.ii (0.064g, 0.24mmol) and 3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] (0.050g 1.0eq.) is starting raw material to thiazine-6-formaldehyde, uses the 1.x step of embodiment 1, obtain the title compound (0.063g, productive rate 60%) of white foam shape.Compound uses DCM-MeOH 9-1 to contain 1% aq.NH ₄OH is as elutriant, through SiO ₂Chromatogram purification.

¹H?NMR(d ₆—DMSO)δ：10.87(s，1H)；8.77(d，J＝4.4Hz，1H)；8.08(dd，J＝5.7，9.2Hz，1H)；7.85(dd，J＝2.8，10.7Hz，1H)；7.73(d，J＝7.8Hz，1H)；7.66(m，1H)；7.39(d，J＝4.4Hz，1H)；7.09(d，J＝7.8Hz，1H)；4.00(m，1H)；3.78—3.68(m，2H)；3.53(s，2H)；3.17(m，1H)；3.10—3.00(m，2H)；2.94(t，J＝10.5Hz，1H)；2.50(m，1H)；2.11(m，1H)；1.99(m，1H)；1.79—1.65(m，3H)；1.32—1.11(m，2H)。

MS(ESI，m/z)：452.8[M+H ⁺]。

Embodiment 32:3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid { (2R, 3R, 6S)-2-(2-hydroxyl-ethyl)-6-[(E)-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-acid amides:

32.i.3-3-ammonia-6-[(E)-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-2-yl }-propane-1,2-glycol:

(2.19g 4.39mmol) is starting raw material, uses the 2.iii step of embodiment 2, obtains the title compound (1.35g, productive rate 85%) of pale solid shape with intermediate 1.vi.This compound is 2-1 epimer mixture.

MS(ESI，m/z)：360.3[M+H ⁺]。

32.ii.3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid { (2R, 3R, 6S)-2-((2R)-2,3-dihydroxyl-propyl group)-6-[(E)-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-acid amides and 3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid (2R, 3R, 6S)-2-((2S)-2,3-dihydroxyl-propyl group)-6-[(E)-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-acid amides:

(0.2g is 0.55mmol) with 3-oxygen-3,4-dihydro-2H-pyrido [3 with intermediate 32.i, 2-b] (0.116g 1.1eq.) is starting raw material to [1,4] thiazine-6-carboxylic acid, use the 1.x step of embodiment 1, obtain the title compound of white solid.This isomer is through SiO ₂(DCM-MeOH93-7 contains 0.7%aq.NH ₄OH) chromatography is partly separated, and obtains the first wash-out isomer (0.019g, productive rate 6%), comprises the cut (0.12g, productive rate 39%) and the second wash-out isomer (0.055g, productive rate 18%) of two kinds of isomer.

MS (ESI, m/z): 551.9[M+H ⁺] (isomer mixture).

32.iii.3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid [6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-2-(2-oxygen-ethyl)-tetrahydrochysene-pyrans-3-yl]-acid amides:

(0.12g 0.21mmol) is starting raw material, uses the 2.v step of embodiment 2, obtains the title aldehyde (0.09g, productive rate 72%) of white solid with intermediate 32.ii.

¹HNMR(d ₆—DMSO)δ：11.24(s，1H)；9.72(s，1H)；8.77(d，J＝4.5Hz，1H)；8.34(d，J＝9.0Hz，1H)；8.28(d，J＝9.0Hz，1H)；8.02—7.94(m，2H)；7.68—7.57(m，2H)；7.30(d，J＝9.0Hz，1H)；7.11(dd，J＝4.0，16.8Hz，1H)；4.76(m，1H)；4.65(m，1H)；4.05(m，1H)；4.03(s，3H)；3.72(s，2H)；2.57(m，2H)；2.18—1.90(m，2H)；1.94—1.89(m，2H)。

MS(ESI，m/z)：520.1[M+H ⁺]。

32.iv.3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid { (2R, 3R, 6S)-2-(2-hydroxyl-ethyl)-6-[(E)-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-acid amides:

Under 0 ℃, (0.07g adds NaBH in MeOH 0.13mmol) (3ml) and THF (1ml) solution to intermediate 32.iii. ₄(0.02g).Be reflected under this temperature and stirred 1 hour.Add entry (2ml).Remove volatile matter in a vacuum, (DCM-MeOH 19-1 contains 0.5%aq.NH to the resistates chromatogram purification ₄OH) obtain solid matter, in ether, grind then, filter, and dry in high vacuum.Obtain the title alcohol (0.025g, productive rate 35%) of white solid.

MS(ESI，m/z)：521.8[M+H ⁺]。

Embodiment 33:2-(2R, 3R, 6S)-3-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-6-[(E)-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-2-yl }-ethanamide:

33.i.{ (2R, 3R, 6S)-2-carbamyl ylmethyl-6-[(E)-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

With intermediate 1.vi (5.5g; 11mmol) be starting raw material; use the 9.ii (deprotection, productive rate 89%) of embodiment 9 respectively; the 2.v of embodiment 2 (generates aldehyde; productive rate 99%) and 2.vi (generate acid; productive rate 76%) and the 9.iv of embodiment 9 (productive rate 30%) obtain little yellow solid shape title amide (0.602g, 1.36mmol).

MS(ESI，m/z)：521.8[M+H ⁺]。

33.ii.2-3-ammonia-6-[(E)-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-2-yl }-ethanamide:

(0.6g 1.36mmol) is starting raw material, uses the 1.ix step of embodiment 1, obtains the title amine (0.33g, productive rate 71%) of brown solid shape with intermediate 33.i.

MS(ESI，m/z)：343.0[M+H ⁺]。

33.iii.2-(2R, 3R, 6S)-3-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-6-[(E)-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-2-yl }-ethanamide:

With intermediate 33.ii (0.110g, 0.32mmol) and (E)-3-(2,5-difluoro-phenyl)-propenal (0.059g, 1.1eq) be starting raw material, use the 1.x step of embodiment 1, obtain the title compound (0.054g, productive rate 34%) of white solid.Compound is through SiO ₂(DCM-MeOH 19-1 contains 0.5% aq.NH ₄OH) chromatogram purification.

MS(ESI，m/z)：495.0[M+H ⁺]。

Embodiment 34:(2R, 3R, 6S)-3-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-6-[(E)-2-(3-fluorine-6-methoxyl group-quinoline-4-yl)-vinyl]-tetrahydrochysene-pyrans-2-yl }-acetate:

34.i.3-fluorine-6-methoxyl group-quinoline-4-formaldehyde:

THF (100ml) solution of DIPA (3.5ml) is cooled to-78 ℃, and (2.5N is dissolved in hexane, 10ml) to add n-BuLi.Stirred reaction mixture is 5 minutes under this temperature, rises to 0 ℃ then.Stirred reaction mixture 15 minutes is cooled to-78 ℃ then.(4.38g 24.7mmol), stirred the mixture under-78 ℃ temperature 3 hours to add the 3-fluorine-6-methoxyl group-quinoline that is dissolved in THF (20ml+5ml rinsing).Dropwise add DMF (3ml).After 15 minutes, it is room temperature that reaction mixture is risen to.Add 10%NaHSO ₄The aqueous solution (10ml).Remove volatile matter in a vacuum, add saturated sodium bicarbonate in the resistates and form alkalescence.(2 * 200ml) extract 2 times water layer with EA.The organic layer that merges is with the salt water washing, at Na ₂SO ₄Last drying, filtration and evaporate to dryness.Resistates obtains the title aldehyde (3.05g, productive rate 60%) of little yellow solid shape through chromatogram purification (hexane-ethyl acetate 1-1).This compound contains 20% starting material.

¹H?NMR(CDCl ₃)δ?10.86(s，1H)；8.81(d，J＝1.8Hz，1H)；8.50(d，J＝2.8Hz，1H)；8.03(d，J＝9.2Hz，1H)；7.40(dd，J＝2.8，9.2Hz，1H)；4.01(s，3H)。

34.ii.{ (2R, 3R, 6S)-2-[(4RS)-2,2-dimethyl-[1,3] dioxolane-4-ylmethyl]-6-[(E)-2-(3-fluorine-6-methoxyl group-quinoline-4-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-the carboxylamine tertiary butyl ester:

(3.05g, 11.9mmol) (6.95g 12.9mmol) is starting raw material, uses the 1.vi step of embodiment 1, obtains light yellow foamed title alkene (5.38g, productive rate 80%) with intermediate 1.v with intermediate 34.i.This compound uses Hept-EA1-2 as the elutriant chromatogram purification.This compound comprises 2-1 epimer mixture and 3-1E-Z mixture.

MS(ESI，m/z)：517.1[M+H ⁺]。

34.iii. (2RS)-3-{ (2R, 3R, 6S)-3-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-6-[(E)-2-(3-fluorine-6-methoxyl group-quinoline-4-yl)-vinyl]-tetrahydrochysene-pyrans-2-yl }-propane-1,2-glycol:

(2.63g 5.1mmol) is starting raw material, uses the 2.iii step (deprotection, productive rate 67%) of embodiment 2 and the 1.x step (reduction amination, productive rate 91%) of embodiment 1, obtains the foamed title compound of little yellow (1.62g) with intermediate 34.ii.After per step finished, rough reaction mixture passed through SiO ₂Use DCM-MeOH 6-1 to contain 1%NH respectively ₄The OH aqueous solution and DCM-MeOH 9-1 contain 1%NH ₄The OH aqueous solution is as the elutriant chromatogram purification.This compound comprises 2-1 epimer mixture and 3-1E-Z mixture.

MS(ESI，m/z)：567.7[M+H ⁺]。

34.iv. (2R, 3R, 6S)-3-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-6-[(E)-2-(3-fluorine-6-methoxyl group-quinoline-4-yl)-vinyl]-tetrahydrochysene-pyrans-2-yl }-acetate:

With intermediate 34.iii (1.58g, 3mmol) be starting raw material, use the 4.iii step of embodiment 4 (to generate Boc, productive rate 74%), the 2.v of embodiment 2 (generates aldehyde, productive rate 82%) and the step of the 4.vi (productive rate 52%) of 2.vi (generate acid, productive rate 98%) and embodiment 4 obtain the title compound (0.037g) of pale solid shape.After finishing final step, compound uses DCM-MeOH 6-1 to contain 1%aq.NH ₄OH is as elutriant, through SiO ₂Chromatogram purification.This compound comprises 2-1 E-Z mixture.

MS(ESI，m/z)：513.0[M+H ⁺]。

Embodiment 35:{ (2R, 3R, 6S)-3-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-6-[(E)-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-2-yl }-acetate:

35.i. (2RS)-3-{ (2R, 3R, 6S)-3-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-6-[(E)-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-2-yl }-propane-1,2-glycol:

With intermediate 32.i (1.43g, 4mmol) and (E)-3-(0.672g 1.0eq) be starting raw material to (2,5-difluoro-phenyl)-propenal, and the 1.x step of use embodiment 1 obtains the title compound (1.34g, productive rate 65%) of colourless foam shape.Compound is through SiO ₂(DCM-MeOH 9-1 contains 1% aq.NH ₄OH) behind the chromatogram purification, this compound is 2-1 epimer mixture.

¹H?NMR(d6—DMSO)δ：8.71(d，J＝4.6Hz，1H)；8.24(d，J＝9.0Hz，1H)；7.84(d，J＝4.5Hz，0.33H)；7.82(d，J＝4.5Hz，0.67H)；7.58—7.45(m，2H)；7.27(d，J＝9.0Hz，1H)；7.25(m，1H)；7.12(m，1H)；7.01—6.92(m，1H)，6.63(d，J＝16.1Hz，1H)；6.51(td，J＝5.1，16.1Hz，1H)；4.68(br?s，0.67H)；4.51—4.35(m，2.33H)；4.21(m，0.67H)；4.11(m，0.33H)；4.04(s，3×0.33H)；4.02(s，3×0.67H)；3.62(m，1H)；3.39—3.25(m，4H)；2.75(m，1H)；2.05—1.37(m，7H)。

MS(ESI，m/z)：512.0[M+H ⁺]。

35.ii.[(E)-3-(2,5-difluoro-phenyl)-allyl group]-(2R, 3R, 6S)-2-[(2RS)-2,3-dihydroxyl-propyl group]-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-t-butyl carbamate:

(1.34g adds di-t-butyl two carbonate (0.9g) and TEA (0.75ml) in DCM 2.62mmol) (13ml) solution to intermediate 35.i.Mixture at room temperature stirred 24 hours.Adding di-t-butyl two carbonate (0.5g) reacted 24 hours again.Reaction mixture concentrates evaporate to dryness, and resistates is through SiO ₂(DCM-MeOH 19-1 then 9-1) chromatogram purification obtains the title compound (0.77g, productive rate 48%) of colourless foam shape.

¹H?NMR(CDCl ₃)δ：8.71(d，J＝4.7Hz，1H)；8.23(d，J＝9.0Hz，0.67H)；8.22(d，J＝9.0Hz，0.33H)；7.68—7.61(m，2H)；7.14(d，J＝9.0Hz，1H)；7.13(m，1H)；7.01(m，1H)；6.94(m，1H)；6.77(dd，J＝5.6，16.5Hz，1H)，6.57(d，J＝16.1Hz，1H)；6.29(td，J＝5.1，16.1Hz，1H)；4.64(m，0.33H)；4.48—4.24(m，3.67H)；4.12(s，3×0.33H)；4.11(s，3×0.67H)；4.10—3.92(m，2H)；3.71(app?td，J＝3.4，11.0Hz，1H)；3.58(m，1H)；2.31—1.71(m，8H)；1.50(s，9H)。

35.iii.{ (2R, 3R, 6S)-3-tert-butoxycarbonyl-[(E)-3-(2,5-difluoro-phenyl)-allyl group]-ammonia }-6-[(E)-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-2-yl }-acetate:

(0.77g 1.25mmol) is starting raw material, uses the step of 2.v (generating aldehyde, productive rate 82%) and the 2.vi (generating acid, productive rate 98%) of embodiment 2, obtains the title acid (0.48g) of colourless foam shape with intermediate 35.ii.After final step was finished, the compound compound used DCM-MeOH93-7 as elutriant, through SiO ₂Chromatogram purification.

¹H?NMR(d6—DMSO)δ：12.19(br?s，1H)；8.72(d，J＝4.8Hz，1H)；8.25(d，J＝9.0Hz，1H)；7.85(d，J＝4.8Hz，1H)；7.57—7.47(m，2H)；7.27(d，J＝9.0Hz，1H)；7，24(m，1H)；7.13(m，1H)；6.91(dd，J＝16.1，5.3Hz，1H)；6.52(d，J＝16.1Hz，1H)；6.43(td，J＝5.0，16.1Hz，1H)；4.55—4.45(m，2H)；4.27—4.04(m，2H)；4.04(s，3H)；3.85(dd，J＝4.8，16.9Hz，1H)；2.88(dd，J＝9.8，14.7Hz，1H)；2.38(dd，J＝4.6，14.7Hz，1H)；2.17(m，1H)；2.02—1.85(m，2H)；1.61(m，1H)；1.40(s，9H)。

35.iv.{ (2R, 3R, 6S)-3-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-6-[(E)-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-2-yl }-acetate:

(0.1g, TFA 0.17mmol) (2ml) solution at room temperature stirred 15 minutes intermediate 35.iii..Remove in a vacuum and desolvate, with resistates water-soluble (10ml) and DCM-MeOH (9-1,30ml) in.Regulating water layer pH is 7, separates organic layer.Water layer DCM-MeOH (9-1,30ml) extraction once more, the organic layer of merging is with the salt water washing, through Na ₂SO ₄Drying, filtration and concentrated evaporate to dryness.Resistates grinds in ether, leaches solid, and in high vacuum the dry title compound (0.045g, productive rate 54%) that obtains the colorless solid shape.

MS(ESI，m/z)：496.4[M+H ⁺]。

Embodiment 36:[(2R, 3R, 6S)-3-[(E)-3-and (2,5-difluoro-phenyl)-allyl amino]-6-(6-methoxyl group-[1,5] naphthyridines-4-basic formamyl)-tetrahydrochysene-pyrans-2-yl]-acetate:

36.i. (2S, 5R, 6R)-5-tert-butoxycarbonyl ammonia-6-[(4RS) 2,2-dimethyl-[1,3] dioxolane-4-ylmethyl]-tetrahydrochysene-pyrans-2-carboxylic acid:

(5g adds NaIO in the solution of DCM 14.48mmol) (32ml), MeCN (32ml) and water (46ml) to the intermediate 1.ii of ice-cooled mistake ₄(14.6g, 68.17mmol) and RuCl ₃(0.030g, 0.15mmol).Stirred reaction mixture is 5 hours under uniform temp.This reaction mixture dilutes with EA (150ml), solids removed by filtration.Add MeOH (30ml), filter gained suspension.Filtrate is through 10%NaHSO ₃(60ml) aqueous solution is handled.Separate phase, water layer extracts 3 times with EA.The organic layer that merges is with the salt water washing, at Na ₂SO ₄Last drying, filtration and vapourisation under reduced pressure obtain brown foam (quantitative).This compound is 2-1 epimer mixture.

MS(ESI，m/z)：360.1[M+H ⁺]。

36..ii.{ (2S, 5R, 6R)-6-formamyl-2-[(4RS)-2,2-dimethyl-[1,3] dioxolane-4-ylmethyl]-tetrahydrochysene-pyrans-3-yl }-the carboxylamine tertiary butyl ester:

(5.27g 14.6mmol) is starting raw material, uses the 10.ii step of embodiment 10, obtains the title amide (3.16g, productive rate 60%) of colourless foam shape with intermediate 36.i.This compound uses EA-hexanaphthene 4-1 as elutriant, through chromatography purification.This compound is 2-1 epimer mixture.

MS(ESI，m/z)：359.1[M+H ⁺]。

36.iii.{ (2S, 5R, 6R)-2-[(4RS)-and 2,2-dimethyl-[1,3] dioxolane-4-ylmethyl)-6-(6-methoxyl group-[1,5] naphthyridines-4-basic formamyl)-tetrahydrochysene-pyrans-3-yl]-the carboxylamine tertiary butyl ester:

To intermediate 36.ii (2.3g, 6.42mmol), rac-BINAP (0.288g, 0.46mmol), (dba) ₃Pd ₂.CHCl ₃(0.120g, 0.12mmol) and cesium carbonate (2.56g adds dioxane (82ml) in mixture 7.86mmol).Mixture ultrasonication 10 minutes, and a then adding 6-methoxyl group-[1,5] naphthyridines-4-basic trifluoro-methane sulfonate (according to WO03/064431 preparation is described, 2.10g, 6.81mmol).This mixture was 100 ℃ of heating 4 hours.Reaction mixture filters by silicon-dioxide (hexane-ethyl acetate 1-4) cushion plate, and filtrate concentrates in a vacuum.Resistates passes through SiO ₂(DCM-MeOH 19-1) purifying obtain little red foamed title amide (3.27g, 6.32mmol).This compound is 2-1 epimer mixture.

MS(ESI，m/z)：477.0[M+H ⁺]。

36.iv. (2S, 5R, 6S)-5-ammonia-6-[(2RS)-2,3-dihydroxyl-propyl group]-tetrahydrochysene-pyrans-2-carboxylic acid (6-methoxyl group-[1,5] naphthyridines-4-yl)-acid amides:

(2.72g 2.06mmol) is starting raw material, uses the 1.viii step of embodiment 1, obtains the title amine (1.27g, productive rate 64%) of little red solid state with intermediate 36.iii.This compound uses DCM-MeOH 6-1 to contain 1%NH ₄The OH aqueous solution is as elutriant, through chromatogram purification.This compound is 2-1 epimer mixture.

¹H?NMR(d6—DMSO)δ：10.59(s，0.66H)；10.51(s，0.34H)；8.70(d，J＝5.0Hz，1H)；8.45(d，J＝5.0Hz，0.34H)；8.39(d，J＝5.0Hz，0.66H)；8.28(d，J＝9.0Hz，1H)；7.33(d，J＝9.0Hz，1H)；4.50(br?s，1H)；4.47(dd，J＝4.3，7.0Hz，0.34H)；4.31(dd，J＝3.5，9.0Hz，0.66H)；4.11(m，0.66H)；4.09(s，3×0.34H)；4.08(s，3×0.66H)；3.96(m，0.34H)；3.63(m，1H)；3.37—3.21(m，5H)，2.97(m，0.66H)；2.91(m，0.34H)；2.08(m，1H)；1.96(m，0.66H)；1.82—1.42(m，4.34H)。

MS(ESI，m/z)：377.0[M+H ⁺]。

36.v. (2S, 5R, 6R)-5-[(E)-3-(2,5-difluoro-phenyl)-allyl amino]-6-[(2RS)-2,3-dihydroxyl-propyl group]-tetrahydrochysene-pyrans-2-carboxylic acid (6-methoxyl group-[1,5] naphthyridines-4-yl)-acid amides:

(1.0g adds 3 in 1,2-DCE 2.65mmol) (30ml) and MeOH (10ml) solution to intermediate 36.iv

Molecular sieve (10g) and (E)-3-(2,5-difluoro-phenyl)-propenal (0.49g, 1.1eq).Mixture was 50 ℃ of heating 18 hours.Be cooled to 0 ℃, add NaBH ₄(1g) reaction was carried out 45 minutes.Filter reaction mixture, and solid DCM-MeOH (9-1,200ml) washing.Filtrate is with salt solution (50ml) washing, through Na ₂SO ₄Drying, filtration and concentrated evaporate to dryness.(DCM-MeOH 93-7 contains 0.7% aq.NH to the resistates chromatogram purification ₄OH) obtain the title glycol (1.1g, productive rate 78%) of colourless foam shape.This compound is 2-1 epimer mixture.

¹HNMR(d6—DMSO)δ：10.64(s，0.66H)；10.56(s，0.34H)；8.69(d.J＝5.0Hz，1H)；8.42(d，J＝5.0Hz，0.34H)；8.37(d，J＝5.0Hz，0.66H)；8.28(d，J＝9.0Hz，1H)；7.49(m，1H)；7.32(d，J＝9.0Hz，1H)；7.27(m，1H)；7.12(m，1H)；6.63(d，J＝16.2Hz，1H)；6.49(m，1H)；4.52—4.42(m，3H)；4.26(m，1H)；4.06(s，3×0.34H)；4.04(s，3×0.66H)；3.65(m，1H)；3.44—3.24(m，4H)；2.81(m，1H)；2.12—1.41(m，7H)。

MS(ESI，m/z)：529.0[M+H ⁺]。

36.vi.[(2R, 3R, 6S)-3-[(E)-3-and (2,5-difluoro-phenyl)-allyl amino]-6-(6-methoxyl group-[1,5] naphthyridines-4-basic formamyl)-tetrahydrochysene-pyrans-2-yl]-acetate:

With intermediate 36.v (1.1g; 2.1mmol) be starting raw material; use the 4.iii (generating Boc, productive rate 68%) of embodiment 4; the 2.v of embodiment 2 (generation aldehyde) and 2.vi (generate acid; productive rate 30%) and the 35.vi (deprotection of embodiment 35; productive rate 54%) step obtains the title compound (0.080g) of white solid.After finishing final step, compound uses DCM-MeOH 6-1 to contain 1%aq.NH ₄OH is through SiO ₂Chromatogram purification.

MS(ESI，m/z)：513.4[M+H ⁺]。

The pharmacological characteristic of The compounds of this invention

In vitro tests

Laboratory method:

These tests are according to " Methods for dilution Antimicrobial Susceptibility Tests forBacteria that Grow Aerobically (the antimicrobial susceptibility test method of dilution grow aerobically bacterium), the 4th edition; Approval standard: NCCLS file M7-A4; National Committee for ClinicalLaboratory St and ards (the stdn council of national clinical labororatory): Villanova, PA, USA, 1997 " implement.Regulate mensuration minimal inhibitory concentration (MICs among Mueller-Hinton Broth (BBL) by microdilution at positively charged ion; Mg/l), and according to NCCLS standard (the stdn council of national clinical labororatory, the method for dilution antimicrobial susceptibility) implement.The pH of test media is 7.2-7.3.

The result:

All embodiment compounds have been tested at multiple Gram-positive and gram negative bacterium.

General antiseptic-germicide test-results is presented in hereinafter the form (mg/l of MIC unit).

The embodiment sequence number	Streptococcus aureus A798	Streptococcus pneumoniae 49619	Moraxelle catarrhalis A894
The embodiment sequence number	Streptococcus aureus A798	Streptococcus pneumoniae 49619	Moraxelle catarrhalis A894	1	<＝.031	<＝.031	<＝.031
9	<＝.031	<＝.031	<＝.031	1	<＝.031	<＝.031	<＝.031
9	<＝.031	<＝.031	<＝.031	16	0.063	1	0.25
21	0.125	0.5	<＝.031	16	0.063	1	0.25

Claims

1, be selected from following compound:

(E)-2-{ (2R, 3R, 6R)-(3-[3-(2,5-two fluoro-phenyl)-allyl amino]-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-ethanol;

(2R, 3R, 6R)-3-[(E)-3-(2,5-two fluoro-phenyl)-acrylamide]-6-[2-(3-methoxy yl-quinoline-5-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-acetate;

(2R, 3R, 6R)-6-[2-(3-methoxy yl-quinoline-5-yl)-ethyl]-3-[(3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carbonyl)-ammonia]-tetrahydrochysene-pyrans-2-yl }-acetate;

(2R, 3R, 6R)-3-[(E)-3-(2,5-two fluoro-phenyl)-allyl amino]-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-acetate;

(2R, 3R, 6R)-3-[(E)-3-(2,5-two fluoro-phenyl)-allyl amino]-6-[(1S)-1-hydroxyl-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-acetate;

(1R)-2-{ (2S, 5R, 6S)-and 5-[is anti--3-(2,5-two fluoro-phenyl)-allyl amino]-6-hydroxymethyl-tetrahydrochysene-pyrans-2-yl }-1-(3-fluoro-6-methoxyl group-quinolyl-4)-ethanol;

(1S)-2-{ (2S, 5R, 6S)-and 5-[is anti--3-(2,5-two fluoro-phenyl)-allyl amino]-6-hydroxymethyl-tetrahydrochysene-pyrans-2-yl }-1-(3-fluoro-6-methoxyl group-quinolyl-4)-ethanol;

2-{ (2R, 3R, 6R)-3-[(E)-3-(2,5-two fluoro-phenyl)-allyl amino]-6-[2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-ethanamide;

2-{ (2R, 3R, 6S)-3-[(E)-3-(2,5-two fluoro-phenyl)-allyl amino]-6-[(1R, 2R)-1,2-dihydroxyl-2-(3-methoxyl group-quinoxaline-5-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-ethanamide;

(2R, 3R, 6R)-3-[(E)-3-(2,5-two fluoro-phenyl)-allyl amino]-6-[2-(6-methoxyl group-quinolyl-4)-ethyl]-tetrahydrochysene-pyrans-2-yl }-acetate;

2-{ (2R, 3R, 6R)-3-[(E)-3-(2,5-two fluoro-phenyl)-allyl amino]-6-[2-(6-methoxyl group-quinolyl-4)-ethyl]-tetrahydrochysene-pyrans-2-yl }-ethanamide;

2-{ (2R, 3R, 6S)-3-[(E)-3-(2,5-two fluoro-phenyl)-allyl amino]-6-[(S)-1-hydroxyl-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-ethyl]-tetrahydrochysene-pyrans-2-yl }-ethanamide;

3-(2,5-two fluoro-phenyl)-N-{ (2S, 3R, 6S)-6-[(2R)-2-(3-fluoro-6-methoxyl group-quinolyl-4)-2-hydroxyl-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-(E)-acrylamide;

3-(2,5-two fluoro-phenyl)-N-{ (2S, 3R, 6S)-6-[(2S)-2-(3-fluoro-6-methoxyl group-quinolyl-4)-2-hydroxyl-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-(E)-acrylamide;

3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid (2S, 3R, 6S)-6-[(2R)-2-(3-fluoro-6-methoxyl group-quinolyl-4)-2-hydroxyl-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-acid amides;

3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid (2S, 3R, 6S)-6-[(2S)-2-(3-fluoro-6-methoxyl group-quinolyl-4)-2-hydroxyl-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-acid amides;

3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid (2S, 3R, 6S)-6-[(2R)-2-hydroxyl-2-(3-methoxy yl-quinoline-5-yl)-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-acid amides;

3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid (2S, 3R, 6S)-6-[(2S)-2-hydroxyl-2-(3-methoxy yl-quinoline-5-yl)-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-acid amides;

3-(2,5-two fluoro-phenyl)-N-{ (2S, 3R, 6S)-6-[(2R)-2-hydroxyl-2-(3-methoxy yl-quinoline-5-yl)-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-(E)-acrylamide;

3-(2,5-two fluoro-phenyl)-N-{ (2S, 3R, 6S)-6-[(2S)-2-hydroxyl-2-(3-methoxy yl-quinoline-5-yl)-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-(E)-acrylamide;

2-{ (2R, 3R, 6S)-3-[(E)-3-(2,5-two fluoro-phenyl)-allyl amino]-6-[(E)-2-(3-fluoro-6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-2-yl }-ethanamide;

(2S, 5R, 6R)-(5-[(E)-3-(2,5-two fluoro-phenyl)-allyl amino]-6-(2-hydroxyl-ethyl))-tetrahydrochysene-pyrans-2-carboxylic acid (6-methoxyl group-[1,5] naphthyridines-4-yl)-acid amides;

(2S, 5R)-5-[(E)-3-(2,5-two fluoro-phenyl)-allyl amino]-tetrahydrochysene-pyrans-2-carboxylic acid (6-methoxyl group-[1,5] naphthyridines-4-yl)-acid amides;

(1S)-1-{ (2S, 5R)-5-[(E)-3-(3-fluoro-phenyl)-allyl amino]-tetrahydrochysene-pyrans-2-yl }-2-(6-methoxyl group-quinolyl-4)-ethanol;

7-fluoro-6-((3R, 6S)-6-[(1S)-1-hydroxyl-2-(6-methoxyl group-quinolyl-4)-ethyl]-tetrahydrochysene-pyrans-3-base ammonia }-methyl)-4H-benzo [1,4] thiazine-3-ketone;

3-(2-fluoro-phenyl)-N-{ (3R, 6S)-6-[(1S)-1-hydroxyl-2-(6-methoxyl group-quinolyl-4)-ethyl]-tetrahydrochysene-pyrans-3-yl }-(E)-acrylamide;

3-(3-fluoro-phenyl)-N-{ (3R, 6S)-6-[(1S)-1-hydroxyl-2-(6-methoxyl group-quinolyl-4)-ethyl]-tetrahydrochysene-pyrans-3-yl }-(E)-acrylamide;

8-((1R, 2R)-2-{ (2S, 5R)-5-[(E)-3-(2,5-two fluoro-phenyl)-allyl amino]-tetrahydrochysene-pyrans-2-yl }-1,2-dihydroxyl-ethyl)-quinoline-2-nitrile;

[(E)-3-(2,5-two fluoro-phenyl)-allyl group]-3R, 6S)-6-[(E)-2-(3-fluoro-6-methoxy yl-quinoline-5-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-amine;

[(E)-3-(2,5-two fluoro-phenyl)-allyl group]-(3R, 6S)-6-[2-(6-fluoro-3-methoxyl group-quinolyl-4)-ethyl]-tetrahydrochysene-pyrans-3-yl }-amine;

6-((3R, 6S)-6-[2-(6-fluoro-3-methoxyl group-quinolyl-4)-ethyl]-tetrahydrochysene-pyrans-3-base ammonia }-methyl)-4H-pyrido [3,2-b] [1,4] thiazine-3-ketone;

(1R, 2R)-1-{ (2R, 5S)-5-[(E)-3-(2,5-two fluoro-phenyl)-allyl amino]-tetrahydrochysene-pyrans-2-yl }-2-(6-fluoro-quinolyl-4)-ethane-1, the 2-glycol;

[(E)-3-(2,5-two fluoro-phenyl)-allyl group]-(3S, 6R)-(E)-6-[2-(6-fluoro-quinolyl-4)-vinyl]-tetrahydrochysene-pyrans-3-yl }-amine;

[(E)-3-(2,5-two fluoro-phenyl)-allyl group]-(3S, 6R)-6-[2-(6-fluoro-quinolyl-4)-ethyl]-tetrahydrochysene-pyrans-3-yl }-amine; With

6-(3S, 6R)-6-[2-(6-fluoro-quinolyl-4)-ethyl]-tetrahydrochysene-pyrans-3-base ammonia }-methyl)-4H-pyrido [3,2-b] [1,4] thiazine-3-ketone;

3-oxygen-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxylic acid (2R, 3R, 6S)-2-(2-hydroxyl-ethyl)-6-[(E)-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-3-yl }-acid amides;

2-{ (2R, 3R, 6S)-3-[(E)-3-(2,5-two fluoro-phenyl)-allyl amino]-6-[(E)-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-2-yl }-ethanamide;

(2R, 3R, 6S)-3-[(E)-3-(2,5-two fluoro-phenyl)-allyl amino]-6-[(E)-2-(3-fluoro-6-methoxyl group-quinolyl-4)-vinyl]-tetrahydrochysene-pyrans-2-yl }-acetate;

(2R, 3R, 6S)-3-[(E)-3-(2,5-two fluoro-phenyl)-allyl amino]-6-[(E)-2-(6-methoxyl group-[1,5] naphthyridines-4-yl)-vinyl]-tetrahydrochysene-pyrans-2-yl }-acetate;

[(2R, 3R, 6S)-3-[(E)-3-(2,5-two fluoro-phenyl)-allyl amino]-6-(6-methoxyl group-[1,5] naphthyridines-4-base formamyl)-tetrahydrochysene-pyrans-2-yl]-acetate;

And the salt of one of these compounds.

2, according to the compound of claim 1, it is selected from following compound:

3-(2,5-two fluoro-phenyl)-N-{ (2S, 3R, 6S)-6-[(2R) 2-(3-fluoro-6-methoxyl group-quinolyl-4)-2-hydroxyl-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-(E)-acrylamide;

3-(2,5-two fluoro-phenyl)-N-{ (2S, 3R, 6S)-6-[(2S) 2-(3-fluoro-6-methoxyl group-quinolyl-4)-2-hydroxyl-ethyl]-2-hydroxymethyl-tetrahydrochysene-pyrans-3-yl }-(E)-acrylamide;

And the salt of one of these compounds.

3, according to the compound of claim 1, it is selected from following compound:

[(E)-3-(2,5-two fluoro-phenyl)-allyl group]-(3S, 6R)-6-[2-(6-fluoro-quinolyl-4)-ethyl]-tetrahydrochysene-pyrans-3-yl }-amine;

And these compounds it-salt.

4, according to the compound of claim 3, it is selected from following compound:

And the salt of one of these compounds.

5, according to the compound of claim 4, it is selected from following compound:

And the salt of one of these compounds.

6, according to the compound of claim 1, it is selected from following compound:

6-((3S, 6R)-6-[2-(6-fluoro-quinolyl-4)-ethyl]-tetrahydrochysene-pyrans-3-base ammonia }-methyl)-4H-pyrido [3,2-b] [1,4] thiazine-3-ketone;

And the salt of one of these compounds.

7, as compound or its pharmacy acceptable salt according to one of claim 1～6 definition of medicine.

8, a kind of pharmaceutical composition comprises according to the compound of one of claim 1～6 definition or its pharmacy acceptable salt as effective constituent and at least a pharmaceutically inert excipients.

9, compound or its pharmacy acceptable salt according to the definition of one of claim 1～6 is used to prepare the purposes of preventing or treating the medicine that infects.