CN101384592A

CN101384592A - Anti-viral compounds

Info

Publication number: CN101384592A
Application number: CNA2006800532079A
Authority: CN
Inventors: T·W·罗克维; D·A·贝特本纳; A·C·克吕格尔; 岩崎仲彦; C·S·库珀; D·D·安德森; D·J·肯普夫; D·L·马迪根; C·E·莫特; J·P·尚利; M·D·图法诺; R·沃纳; R·张; A·莫拉; H·莫; T·皮洛-马蒂亚斯; S·Vl马斯; R·J·凯里克; W·何; L·卢
Original assignee: Abbott Laboratories
Current assignee: AbbVie Inc
Priority date: 2005-12-21
Filing date: 2006-12-20
Publication date: 2009-03-11
Also published as: ES2348557T3; JP2009521460A; CA2633752A1; CN101384591A; RU2441010C2; RU2008129782A; CN101443334A; ZA201107667B; ZA200805418B

Abstract

Compounds effective in inhibiting replication of Hepatitis C virus (''HCV'') or other viruses are disclosed. This invention is also directed to compositions comprising such compounds, co-formulation or co-administration of such compounds with other anti-viral or therapeutic agents, processes and intermediates for the syntheses of such compounds, and methods of using such compounds for the treatment of HCV or other viral infections.

Description

Antiviral compound

The application requires in the right of priority of the 60/752nd, No. 473 U.S. provisional application of submission on December 21st, 2005, and this application is incorporated herein by reference.

Invention field

The present invention relates to effectively to suppress the compound that hepatitis C virus (" HCV ") duplicates.The invention still further relates to the method for the described compound of preparation, comprise described compound compositions, be used for the intermediate of synthetic described compound, and use described compound to treat that HCV infects or the method for the illness/symptom relevant with it.In addition, the present invention relates to described compound and be used for the treatment of application in the medicine that HCV infects in preparation.

Background of invention

HCV, a kind of human pathogen is the RNA viruses that a kind of hepatovirus (Hepacivirus) that belongs to flaviviridae family belongs to.As the every other member of flaviviridae family, HCV has tunicary virion, and described virion contains the positive chain RNA genome, this genome single, be interrupted, all known virus-specific albumen of coding in the open reading frame.Comprise about 9500 Nucleotide in the open reading frame, about 3000 the amino acid whose single big polyproteins of described nucleotide coding.This polyprotein comprises core protein, envelope protein E1 and E2, embrane-associated protein p7, and Nonstructural Protein NS2, NS3, NS4A, NS4B, NS5A and NS5B.The cell protein enzymatic lysis is at the viral protein of NS2-NS3 contact, allows virus protease (NS3 proteolytic enzyme) mediation cracking subsequently.NS3 albumen also shows nucleoside triphosphate and RNA helicase activity.NS2 and NS4A also can participate in proteolytic activity.NS5A is the phosphoric acid albumen that participation is duplicated.NS5B is a RNA-RNA-dependent polysaccharase.The U.S. patent disclosure of announcing on December 30th, 2,004 2004/0265792 has mentioned that the above-mentioned Nonstructural Protein of inhibition can suppress HCV and duplicate.

HCV infects with to carry out the hepatopathy change relevant, comprises liver cirrhosis and hepatocellular carcinoma.The late period hepatopathy relevant with HCV is the most common indication of adult orthotopic liver transplantation.Chronic hepatitis C can come combination therapy with the ribavirin (ribavarin) that gives once every day with injecting a polyoxyethylene glycol interferon-' alpha ' (peginterferon-alpha) weekly.The polyoxyethylene glycol interferon-' alpha ' is to be connected on the polyoxyethylene glycol to slow down the interferon-' alpha ' that medicine is eliminated in the body.Injection of interferon-α compares with every day, and this has brought the raising of compliance and excellent clinically antiviral activity.But still have the restriction of significant effectiveness and tolerance, often insufficient because a lot of user is subjected to the influence and the virus of side effect from intravital elimination.

Carried out making great efforts to design the medicine that can suppress hepatitis C virus specifically.The U.S. patent 6,323,180 of Boehringer Ingelheim has been mentioned tripeptide compound, and described compound is to be suggested as the HCV serpin to be used for the treatment of the HCV infection.

Other method is ISIS-14803 (Isis Pharmaceuticals), a kind of conserved sequence complementary antisense inhibitor of and HCV RNA.This molecule is in conjunction with viral RNA, and suppresses the expression of duplicating desirable proteins.

By can be, and stop itself and the interactional yeast rna of viral internal ribosome entry site (BRES) to suppress the HCV translation to be described in people such as Das, J.VIROLOGY, 72 (7): among the 5638-5647 (1998) in conjunction with cell polypeptide.

The multiple life science related application of fused bicyclic heterogeneous ring compound has been proposed.The example of such heterogeneous ring compound comprise naphthyridine, Pyridopyrimidine, Mi Dingbing pyrimidine, pyrazolopyrimidine and thiazole also/Thienopyrimidine compound.

Assessed the application of naphthyridine type fused bicyclic compound in disease treatment.For example, the WO 93/13097 of the Boots that announces on July 8th, 1993 discloses [1,8] naphthyridine compounds, for example 4-(4-anisole amino)-6-oxyethyl group-7-methyl isophthalic acid, 8-naphthyridine-3-ethyl formate hydrochloride, it is suggested as rheumatism.The WO 95/00511 of the Boots that announces January 5 nineteen ninety-five discloses the ring condensed 4-aminopyridine compound that replaces, 3-oxyethyl group-5-(2-oxyethyl group-5-pyridinylamino)-2-methyl isophthalic acid for example, and the 8-naphthyridine, it is suggested as rheumatism.The WO 98/13350 of the Zeneca that announces on April 2nd, 1998 discloses [1,8] naphthyridine compounds, 2-acetylaminohydroxyphenylarsonic acid 5-(2-fluoro-5-hydroxy-4-methyl phenylamino)-1 for example, and 8-naphthyridine hydrochloride, it is suggested as anti-angiogenic agent.The WO 2004/055004 of the Neurogen that announces on July 1st, 2004 discloses the naphthyridine compounds as the capsicine receptor modulators, particular compound is 5-(4-trifluoromethyl-phenyl amino)-2-(3-trifluoromethyl-pyridine-2-yl)-[1,6] naphthyridine-7-formic acid and 2-methoxymethyl-4-(4-trifluoromethyl-phenyl amino)-7-(3-trifluoromethyl-pyridine-2-yl)-[1,8] naphthyridine-3-formic acid.

After deliberation the application of multiple treatment disease of Pyridopyrimidine type compound.For example, the WO 98/05661 of the Pfizer that announces on February 12nd, 1998 discloses the Pyridopyrimidine compound that replaces, [8-(1-ethyl-propyl group)-2-methyl-5 for example, 6,7,8-tetrahydrochysene-pyrido (2,3-d) pyrimidine-4-yl]-(2,4,6-trimethylammonium-phenyl)-amine, it is suggested as corticotropin releasing factor(CRF) (hormone) CKF (CRH) antagonist and is used for the treatment of alzheimer's disease and obesity.The WO 98/23613 of the Pfizer that announces on June 4th, 1998 discloses condensed bicyclic pyrimidine compound, comprise Pyridopyrimidine base-aminophenyl compound, (3-ethynyl-phenyl)-pyrido [3 for example, 4-d] pyrimidine-4-base-amine, it is suggested and is used for the treatment of for example cancer of high proliferation disease.The U.S. patent 6 of the Glaxo Wellcome that announces January 2 calendar year 2001,169,091 discloses bicyclic heteroaromatic compounds, 4-(4-benzyloxy phenylamino) pyrido [2 for example, 3-d]-pyrimidine, it is suggested as tyrosine kinase inhibitor and is used for the treatment of fibrosis, inflammation, central nervous system disease and cancer.The WO 01/32632 of the Eli Lilly that announces May 10 calendar year 2001 discloses the pyrimidine compound that 4-replaces, comprise 2-trifluoromethyl-4-[2-(2-(2-chloro-phenyl-) ethylamino] pyrido-[2,3-d] the pyrimidine hydrochloride, it is suggested as the mGluR1 antagonist and is used for the treatment of the nervous disorders relevant with the L-glutamic acid dysfunction, for example convulsions, migraine, psychosis, anxiety disorder and pain.The WO 01/57040 of the Abbott Laboratories that announces August 9 calendar year 2001 discloses 6,7-is dibasic-4-aminopyridine also [2,3-d] pyrimidine compound, 4-amino-6-(4-aminomethyl phenyl)-7-(4-bromophenyl) pyrido [2 for example, 3-d] pyrimidine, it is suggested as adenosine kinase inhibitors and is used for the treatment of pain and inflammation.The WO 2004/055004 of the Neurogen that announces on July 1st, 2004 discloses Pyridopyrimidine base-aminophenyl compound, 2-methyl-2-{4-[2-methyl-7-(3-methyl-pyridine-2-yl)-pyrido [2 for example, 3-d] pyrimidine-4-base amino]-phenyl }-propionic acid, it is as the capsicine receptor modulators.The U.S. patent 6,395,733 of the Pfizer that announces on May 28th, 2002 discloses heterocyclic fused pyrimidine compound, 3-chloro-phenyl-pyrido [2,3-d] pyrimidine-4-base-amine for example, and it is suggested and is used for the treatment of for example cancer of high proliferation disease.

After deliberation the application of Mi Dingbing pyrimidine Type fused bicyclic compound aspect insect control and disease treatment.For example, the U.S. patent 5,350,749 of the Dow Elanco that announces on September 27th, 1994 discloses Mi Dingbing [2, the 3-d] pyrimidine compound that 4-replaces, and it is suggested as mycocide, sterilant and miticide.The Warner-LambertWO 95/19774 that announces July 27 nineteen ninety-five discloses the Mi Dingbing pyrimidine compound, 4-benzylamino-7-methylamino Mi Dingbing [4 for example, 5-d] pyrimidine, it is suggested as tyrosine kinase inhibitor and is used for the treatment of cancer, vascular restenosis and psoriasis.

After deliberation Thienopyrimidine type fused bicyclic compound in the application of treatment in the multiple disease.For example, the WO 95/19774 of the Warner-Lambert that announces July 27 nineteen ninety-five discloses the annelated heterocycles pyrimidine compound, comprise 4-(3-bromobenzene amino) thieno-[2,3-d] pyrimidine, it is suggested as tyrosine kinase inhibitor and is used for the treatment of cancer, vascular restenosis and psoriasis.The U.S. patent 6 of the Glaxo Wellcome that announces January 2 calendar year 2001,169,091 discloses bicyclic heteroaromatic compounds, 5-methyl-4-(4-phenoxy group phenylamino) thieno-[2 for example, 3-d] the pyrimidine hydrochloride, it is suggested as tyrosine kinase inhibitor and is used for the treatment of fibrosis, inflammation, central nervous system disease and cancer.The WO01/32632 of the Eli Lilly that announces May 10 calendar year 2001 discloses the pyrimidine compound that 4-replaces, 6-methyl-4-[2 for example, 6-benzyl dichloride sulfenyl) ethylamino] thieno-[2,3-d] the pyrimidine hydrochloride, it is suggested as the mGluR1 antagonist and is used for the treatment of the nervous disorders relevant with the L-glutamic acid dysfunction, for example convulsions, migraine, psychosis, anxiety disorder and pain.

The WO 2004/014852 of the Bristol-Myers Squibb that announces on February 19th, 2004 discloses the imino-thiazolidinone compound, comprise 2-(4-aminophenyl)-5H-thiazole also [2,3-6] the fused bicyclic derivative of quinazoline-3-ketone, it is suggested as the NS5A-protein inhibitor and stops HCV to duplicate.

The WO 2004/014313 of the Bristol-Myers Squibb that announces on February 19th, 2004 discloses the combination therapy that is used for the treatment of virus disease, comprises imino-thiazolidone NS5A-albumen inhibition whose anti-HCV compound and the combination that can disturb other promoting agents of HCV function.

Summary of the invention

The present invention relates to have formula I (a), I (b), II (a) or the compound of II (b), the tautomer of these compounds and the pharmacologically acceptable salt of these compounds or tautomer.These compounds can use separately or unite to make with other medicines or material and be used for suppressing duplicating of HCV or other virus.These compounds, tautomer or salt can use separately or unite to make with other medicines or material and be used for disturbing HCV or other viral function.

The invention still further relates to the composition that comprises The compounds of this invention, tautomer or salt.The compounds of this invention can comprise one or more The compounds of this invention, tautomer or salt.The present composition also comprises one or more other antiviral or therapeutical agent.

In addition, the composition that the present invention relates to use The compounds of this invention, tautomer or salt or comprise described compound, tautomer or salt suppresses the method for HCV or other virus replication.These methods comprise with HCV or other virus or by the cell of HCV or described other virus infection and contacting with The compounds of this invention, tautomer or the salt of significant quantity, thus the duplicating of inhibition HCV or described other virus.

The invention still further relates to the composition that uses The compounds of this invention, tautomer or salt or comprise described compound, tautomer or salt and suppress the propagation or the infectious method of HCV or other virus.These methods comprise with HCV or other virus or by the cell of HCV or other virus infection and contacting with The compounds of this invention, tautomer or the salt of significant quantity, thus the propagation or the infection of inhibition HCV or other virus.

And, the present invention relates to the combination treatment HCV that uses The compounds of this invention, tautomer or salt or comprise described compound, tautomer or salt or the method for other virus infection.These methods comprise needs The compounds of this invention, tautomer or the salt of patient's effective dosage of treatment like this, thereby reduce HCV or other the viral blood among the described patient or organize level.

The invention still further relates to The compounds of this invention, tautomer or salt and be used for the treatment of application in HCV or other medicine for treating viral infections in preparation.

And, the invention still further relates to method for preparing The compounds of this invention, tautomer or salt and the intermediate that in these methods, uses.

Further feature of the present invention, target and advantage are conspicuous in the following detailed description.Yet although should be appreciated that and pointed out the preferred embodiment of the invention, providing of this detailed description only is illustrations, rather than restriction.

Detailed Description Of The Invention

Below being described in is exemplary in nature, but not intention the restriction disclosure, application or purposes.

Compound

The present invention relates to have the pharmacologically acceptable salt of compound, its tautomer and described compound or the tautomer of formula I (a) or I (b),

Wherein:

Z is-NR ⁴¹-;

A is carbocylic radical or heterocyclic radical, and optional by one or more R ¹⁸Replace, wherein R ¹⁸When occurring, be independently selected from every turn halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, azido-, alkyl, alkenyl, alkynyl ,-L _S-O-R _S,-L _S-S-R _S,-L _S-C (O) R _S,-L _S-OC (O) R _S,-L _S-C (O) OR _S,-L _S-N (R _SR _{S '}) ,-L _S-C (=NR _S) R _{S '},-L _S-S (O) R _S,-L _S-SO ₂R _S,-L _S-C (O) N (R _SR _{S '}) ,-L _S-N (R _S) C (O) R _{S '},-L _S-C (=NR _S) N (R _{S '}R _{S "}) ,-L _S-N (R _{S '}) C (=NR _S) R _{S "},-L _S-N (R _S) C (O) N (R _{S '}R _{S "}) ,-L _S-N (R _S) SO ₂R _{S '},-L _S-SO ₂N (R _SR _{S '}) and-L _S-N (R _S) SO ₂N (R _{S '}R _{S "});

R ¹⁰, R ¹⁷, R ³¹, R ³³, R ³⁵And R ⁴¹When occurring, be independently selected from respectively at every turn hydrogen, halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, azido-, alkyl, alkenyl, alkynyl, carbocylic radical, heterocyclic radical ,-L _S-O-R _S,-L _S-S-R _S,-L _S-C (O) R _S,-L _S-OC (O) R _S,-L _S-C (O) OR _S,-L _S-N (R _SR _{S '}) ,-L _S-C (=NR _S) R _{S '},-L _S-S (O) R _S,-L _S-SO ₂R _S,-L _S-C (O) N (R _SR _{S '}) ,-L _S-N (R _S) C (O) R _{S '},-L _S-C (=NR _S) N (R _{S '}R _{S "}) ,-L _S-N (R _{S '}) C (=NR _S) R _{S "},-L _S-N (R _S) C (O) N (R _{S '}R _{S "}) ,-L _S-N (R _S) SO ₂R _{S '},-L _S-SO ₂N (R _SR _{S '}) ,-L _S-N (R _S) SO ₂N (R _{S '}R _{S "}) ,-L _E-Q-L _{E '}-(C ₃-C ₁₈Carbocylic radical) and-L _E-Q-L _{E '}-(M ₃-M ₁₈Heterocyclic radical);

X be selected from a key ,-L _S-O-,-L _S-S-,-L _S-C (O)-,-L _S-N (R _S)-,-L _S-N (R _S) C (O)-,-L _S-C (O) N (R _S)-,-L _S-N (R _S) C (O) O-,-L _S-OC (O) N (R _S)-,-L _S-N (R _S) C (O) N (R _{S '})-,-L _S-C (=NR _S) N (R _{S '})-,-L _S-N (R _{S '}) C (=NR _S)-,-L _S-S (O)-,-L _S-SO ₂-,-L _S-C (O) O-and-L _S-OC (O)-;

R ²²Be carbocylic radical, heterocyclic radical, carbocylic radical alkyl or heterocyclic radical alkyl, and optional by one or more R ²⁶Replace, wherein R ²⁶When occurring, be independently selected from every turn halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, azido-, alkyl, alkenyl, alkynyl ,-L _S-O-R _S,-L _S-S-R _S,-L _S-C (O) R _S,-L _S-OC (O) R _S,-L _S-C (O) OR _S,-L _S-N (R _SR _{S '}) ,-L _S-C (=NR _S) R _{S '},-L _S-S (O) R _S,-L _S-SO ₂R _S,-L _S-OS (O) R _S,-L _S-OSO ₂R _S,-L _S-C (O) N (R _SR _{S '}) ,-L _S-N (R _S) C (O) R _{S '},-L _S-C (=NR _S) N (R _{S '}R _{S "}) ,-L _S-N (R _{S '}) C (=NR _S) R _{S "},-L _S-N (R _S) C (O) N (R _{S '}R _{S "}) ,-L _S-N=C (NR _SR _{S '}) (NR _SR _{S '}) ,-L _S-N (R _S) SO ₂R _{S '},-L _S-SO ₂N (R _SR _{S '}) ,-L _S-N (R _S) SO ₂N (R _{S '}R _{S "}) ,-L _E-Q-L _{E '}-(C ₃-C ₁₈Carbocylic radical) and-L _E-Q-L _{E '}-(M ₃-M ₁₈Heterocyclic radical); Perhaps R ²²Be alkyl, alkenyl or alkynyl, and optional by one or more R ²⁶Replace; Perhaps R ²²Be hydrogen;

Y be selected from a key ,-L _S-O-,-L _S-C (O)-,-L _S-S (O) ₂-,-L _S-S (O)-,-L _S-OS (O) ₂-,-L _S-OS (O)-,-L _S-C (O) O-,-L _S-OC (O)-,-L _S-OC (O) O-,-L _S-C (O) N (R ¹⁵)-,-L _S-N (R ¹⁵) C (O)-,-L _S-C (O) N (R ¹⁵) O-,-L _S-N (R ¹⁵) C (O) O-,-L _S-C (O) N (R ¹⁵) N (R ^{15 '})-,-L _S-S-,-L _S-C (S)-,-L _S-C (S) O-,-L _S-OC (S)-,-L _S-C (S) N (R ¹⁵)-,-L _S-N (R ¹⁵)-,-L _S-N (R ¹⁵) C (S)-,-L _S-N (R ¹⁵) S (O)-,-L _S-N (R ¹⁵) S (O) ₂-,-L _S-S (O) ₂N (R ¹⁵)-,-L _S-S (O) N (R ¹⁵)-,-L _S-C (S) N (R ¹⁵) O-and-L _S-C (S) N (R ¹⁵) N (R ^{15 '})-, be R wherein ¹⁵And R ^{15 '}When occurring, be independently selected from hydrogen, alkyl, alkenyl and alkynyl respectively at every turn;

R ⁵⁰Be-L ¹-A ¹, A wherein ¹Be selected from carbocylic radical, heterocyclic radical, alkyl, alkenyl and and alkynyl, and L ¹Be selected from key, alkylidene group, alkylene group and alkynylene, wherein an A ¹Optional by one or more R ³⁰Replace, and R ³⁰When occurring, be independently selected from every turn halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, azido-, alkyl, alkenyl, alkynyl ,-L _S-O-R _S,-L _S-S-R _S,-L _S-C (O) R _S,-L _S-OC (O) R _S,-L _S-C (O) OR _S,-L _S-N (R _SR _{S '}) ,-L _S-C (=NR _S) R _{S '}-,-L _S-S (O) R _S,-L _S-SO ₂R _S,-L _S-C (O) N (R _SR _{S '}) ,-L _S-N (R _S) C (O) R _{S '},-L _S-C (=NR _S) N (R _{S '}R _{S "}) ,-L _S-N (R _{S '}) C (=NR _S) R _{S "},-L _S-N (R _S) C (O) N (R _{S '}R _{S "}) ,-L _S-N (R _S) SO ₂R _{S '},-L _S-SO ₂N (R _SR _{S '}) ,-L _S-N (R _S) SO ₂N (R _{S '}R _{S "}) ,-L _E-Q-L _{E '}-(C ₃-C ₁₈Carbocylic radical) and-L _E-Q-L _{E '}-(M ₃-M ₁₈Heterocyclic radical), L and wherein ¹Optional by one or more R ³⁸Replace, and R ³⁸When occurring, be independently selected from every turn halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, azido-, alkoxyl group, thio alkoxy, alkyl-carbonyl, alkoxy carbonyl, alkyl-carbonyl oxygen base, alkylamino, alkoxycarbonyl amino ,-L _S-O-R _S,-L _S-S-R _S,-L _S-C (O) R _S,-L _S-OC (O) R _S,-L _S-C (O) OR _S,-L _S-N (R _SR _{S '}) ,-L _S-C (=NR _S) R _{S '},-L _S-S (O) R _S,-L _S-SO ₂R _S,-L _S-C (O) N (R _SR _{S '}) ,-L _S-N (R _S) C (O) R _{S '},-L _S-C (=NR _S) N (R _{S '}R _{S "}) ,-L _S-N (R _{S '}) C (=NR _S) R _{S "},-L _S-N (R _S) C (O) N (R _{S '}R _{S "}) ,-L _S-N (R _S) SO ₂R _{S '},-L _S-SO ₂N (R _SR _{S '}) ,-L _S-N (R _S) SO ₂N (R _{S '}R _{S "}), carbocylic radical, heterocyclic radical, carbocylic radical alkyl, heterocyclic radical alkyl ,-L _E-Q-L _{E '}-(C ₃-C ₁₈Carbocylic radical) and-L _E-Q-L _{E '}-(M ₃-M ₁₈Heterocyclic radical);

L _SWhen occurring, be independently selected from key, alkylidene group, alkylene group and an alkynylene at every turn;

R _S, R _{S '}And R _{S "}When occurring, be selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, thio alkoxy, alkoxyalkyl, alkoxy alkoxy alkyl, thio alkoxy alkyl, alkyl-carbonyl, alkyl-carbonyl alkyl, alkoxy carbonyl, alkoxy carbonyl alkyl, alkyl-carbonyl oxygen base, alkyl-carbonyl oxygen base alkyl, alkylamino, alkylamino alkyl, alkoxycarbonyl amino and alkoxycarbonyl amino alkyl independently of one another at every turn;

L _EAnd L _{E '}When occurring, be independently selected from respectively at every turn a key, alkylidene group, alkylene group, alkynylene ,-alkylidene group-O-alkylidene group-,-alkylidene group-S-alkylidene group-,-alkylidene group-NC (O)-alkylidene group-and-alkylidene group-C (O) N-alkylidene group-;

Q when occurring, be independently selected from every turn a key, alkylidene group, alkylene group, alkynylene ,-S-,-O-,-C (O)-,-N (R _S)-,-N (R _S) C (O)-,-C (O) N (R _S)-,-N (R _S) C (O) O-,-OC (O) N (R _S)-,-N (R _S) C (O) N (R _{S '})-,-C (=NR _S) N (R _{S '})-,-N (R _{S '}) C (=NR _S)-,-S (O)-,-SO ₂-,-O-SO ₂-,-SO ₂-O-,-O-S (O)-,-S (O)-O-,-C (O) O-and-OC (O)-;

R ¹⁰, R ¹⁵, R ^{15 '}, R ¹⁷, R ¹⁸, R ²⁶, R ³⁰, R ³¹, R ³³, R ³⁵, R ³⁸And R ⁴¹When occurring, choose wantonly independently respectively at every turn and be selected from following substituting group replacement: halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, alkoxyl group, alkylamino, alkoxy carbonyl and azido-by at least one; And

-L _E-Q-L _{E '}-(C ₃-C ₁₈Carbocylic radical) and L _E-Q-L _{E '}-(M ₃-M ₁₈Heterocyclic radical) each C in ₃-C ₁₈Carbocylic radical and M ₃-M ₁₈The heterocyclic radical part optional independently when occurring at every turn is selected from following substituting group replacement by at least one: hydrogen; halogen; the oxo base; thio group; hydroxyl; sulfydryl; nitro; cyano group; amino; carboxyl; formyl radical; phosphoric acid ester; azido-; alkyl; alkenyl; alkynyl; alkoxyl group; thio alkoxy; alkoxyalkyl; the thio alkoxy alkyl; alkyl-carbonyl; the alkyl-carbonyl alkyl; alkoxy carbonyl; alkoxy carbonyl alkyl; the alkyl-carbonyl oxygen base; alkyl-carbonyl oxygen base alkyl; alkylamino; the alkylamino alkyl; alkoxycarbonyl amino; carbocylic radical oxygen base; the heterocyclyloxy base; the carbocylic radical alkoxyl group; the heterocyclic radical alkoxyl group; the carbocylic radical alkoxy carbonyl; heterocyclic radical alkoxy carbonyl and alkoxycarbonyl amino alkyl.

In one embodiment, the present invention relates to have the pharmacologically acceptable salt of compound, its tautomer and described compound or the tautomer of formula I (a) or I (b), wherein:

Z is-NR ⁴¹-;

A is carbocylic radical or heterocyclic radical, and optional by one or more R ¹⁸Replace, wherein R ¹⁸When occurring, be independently selected from halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, azido-, C at every turn ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl ,-L _S-O-R _S,-L _S-S-R _S,-L _S-C (O) R _S,-L _S-OC (O) R _S,-L _S-C (O) OR _S,-L _S-N (R _SR _{S '}) ,-L _S-C (=NR _S) R _{S '},-L _S-S (O) R _S,-L _S-SO ₂R _S,-L _S-C (O) N (R _SR _{S '}) ,-L _S-N (R _S) C (O) R _{S '},-L _S-C (=NR _S) N (R _{S '}R _{S "}) ,-L _S-N (R _{S '}) C (=NR _S) R _{S "},-L _S-N (R _S) C (O) N (R _{S '}R _{S "}) ,-L _S-N (R _S) SO ₂R _{S '},-L _S-SO ₂N (R _SR _{S '}) and-L _S-N (R _S) SO ₂N (R _{S '}R _{S "});

R ¹⁰, R ¹⁷, R ³¹, R ³³, R ³⁵And R ⁴¹When occurring, be independently selected from hydrogen, halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, azido-, C respectively at every turn ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₃-C ₆Carbocylic radical, M ₃-M ₆Heterocyclic radical ,-L _S-O-R _S,-L _S-S-R _S,-L _S-C (O) R _S,-L _S-OC (O) R _S,-L _S-C (O) OR _S,-L _S-N (R _SR _{S '}) ,-L _S-C (=NR _S) R _{S '},-L _S-S (O) R _S,-L _S-SO ₂R _S,-L _S-C (O) N (R _SR _{S '}) ,-L _S-N (R _S) C (O) R _{S '},-L _S-C (=NR _S) N (R _{S '}R _{S "}) ,-L _S-N (R _{S '}) C (=NR _S) R _{S "},-L _S-N (R _S) C (O) N (R _{S '}R _{S "}) ,-L _S-N (R _S) SO ₂R _{S '},-L _S-SO ₂N (R _SR _{S '}) ,-L _S-N (R _S) SO ₂N (R _{S '}R _{S "}) ,-L _E-Q-L _{E '}-(C ₃-C ₁₈Carbocylic radical) and-L _E-Q-L _{E '}-(M ₃-M ₁₈Heterocyclic radical);

R ²²Be carbocylic radical, heterocyclic radical, carbocylic radical C ₁-C ₆Alkyl or heterocyclic radical C ₁-C ₆Alkyl, and optional by one or more R ²⁶Replace, wherein R ²⁶When occurring, be independently selected from halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, azido-, C at every turn ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl ,-L _S-O-R _S,-L _S-S-R _S,-L _S-C (O) R _S,-L _S-OC (O) R _S,-L _S-C (O) OR _S,-L _S-N (R _SR _{S '}) ,-L _S-C (=NR _S) R _{S '},-L _S-S (O) R _S,-L _S-SO ₂R _S,-L _S-OS (O) R _S,-L _S-OSO ₂R _S,-L _S-C (O) N (R _SR _{S '}) ,-L _S-N (R _S) C (O) R _{S '},-L _S-C (=NR _S) N (R _{S '}R _{S "}) ,-L _S-N (R _{S '}) C (=NR _S) R _{S "},-L _S-N (R _S) C (O) N (R _{S '}R _{S "}) ,-L _S-N=C (NR _SR _{S '}) (NR _SR _{S '}) ,-L _S-N (R _S) SO ₂R _{S '},-L _S-SO ₂N (R _SR _{S '}) ,-L _S-N (R _S) SO ₂N (R _{S '}R _{S "}) ,-L _E-Q-L _{E '}-(C ₃-C ₁₈Carbocylic radical) and-L _E-Q-L _{E '}-(M ₃-M ₁₈Heterocyclic radical); Perhaps R ²²Be C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl or C ₂-C ₆Alkynyl, and optional by one or more R ²⁶Replace; Perhaps R ²²Be hydrogen;

Y be selected from a key ,-L _S-O-,-L _S-C (O)-,-L _S-S (O) ₂-,-L _S-S (O)-,-L _S-OS (O) ₂-,-L _S-OS (O)-,-L _S-C (O) O-,-L _S-OC (O)-,-L _S-OC (O) O-,-L _S-C (O) N (R ¹⁵)-,-L _S-N (R ¹⁵) C (O)-,-L _S-C (O) N (R ¹⁵) O-,-L _S-N (R ¹⁵) C (O) O-,-L _S-C (O) N (R ¹⁵) N (R ^{15 '})-,-L _S-S-,-L _S-C (S)-,-L _S-C (S) O-,-L _S-OC (S)-,-L _S-C (S) N (R ¹⁵)-,-L _S-N (R ¹⁵)-,-L _S-N (R ¹⁵) C (S)-,-L _S-N (R ¹⁵) S (O)-,-L _S-N (R ¹⁵) S (O) ₂-,-L _S-S (O) ₂N (R ¹⁵)-,-L _S-S (O) N (R ¹⁵)-,-L _S-C (S) N (R ¹⁵) O-and-L _S-C (S) N (R ¹⁵) N (R ^{15 '})-, be R wherein ¹⁵And R ^{15 '}When occurring, be independently selected from hydrogen, C respectively at every turn ₁-C ₆Alkyl, C ₂-C ₆Alkenyl and C ₂-C ₆Alkynyl;

R ⁵⁰Be-L ¹-A ¹, A wherein ¹Be selected from carbocylic radical, heterocyclic radical, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl and C ₂-C ₆Alkynyl, and L ¹Be selected from a key, C ₁-C ₆Alkylidene group, C ₂-C ₆Alkylene group and C ₂-C ₆Alkynylene, wherein A ¹Optional by one or more R ³⁰Replace, and R ³⁰When occurring, be independently selected from halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, azido-, C at every turn ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl ,-L _S-O-R _S,-L _S-S-R _S,-L _S-C (O) R _S,-L _S-OC (O) R _S,-L _S-C (O) OR _S,-L _S-N (R _SR _{S '}) ,-L _S-C (=NR _S) R _{S '}-,-L _S-S (O) R _S,-L _S-SO ₂R _S,-L _S-C (O) N (R _SR _{S '}) ,-L _S-N (R _S) C (O) R _{S '},-L _S-C (=NR _S) N (R _{S '}R _{S "}) ,-L _S-N (R _{S '}) C (=NR _S) R _{S "},-L _S-N (R _S) C (O) N (R _{S '}R _{S "}) ,-L _S-N (R _S) SO ₂R _{S '},-L _S-SO ₂N (R _SR _{S '}) ,-L _S-N (R _S) SO ₂N (R _{S '}R _{S "}) ,-L _E-Q-L _{E '}-(C ₃-C ₁₈Carbocylic radical) and-L _E-Q-L _{E '}-(M ₃-M ₁₈Heterocyclic radical), L and wherein ¹Optional by one or more R ³⁸Replace, and R ³⁸When occurring, be independently selected from halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, azido-, C at every turn ₁-C ₆Alkoxyl group, C ₁-C ₆Thio alkoxy, C ₁-C ₆Alkyl-carbonyl, C ₁-C ₆Alkoxy carbonyl, C ₁-C ₆Alkyl-carbonyl oxygen base, C ₁-C ₆Alkylamino, C ₁-C ₆Alkoxycarbonyl amino ,-L _S-O-R _S,-L _S-S-R _S,-L _S-C (O) R _S,-L _S-OC (O) R _S,-L _S-C (O) OR _S,-L _S-N (R _SR _{S '}) ,-L _S-C (=NR _S) R _{S '},-L _S-S (O) R _S,-L _S-SO ₂R _S,-L _S-C (O) N (R _SR _{S '}) ,-L _S-N (R _S) C (O) R _{S '},-L _S-C (=NR _S) N (R _{S '}R _{S "}) ,-L _S-N (R _{S '}) C (=NR _S) R _{S "},-L _S-N (R _S) C (O) N (R _{S '}R _{S "}) ,-L _S-N (R _S) SO ₂R _{S '},-L _S-SO ₂N (R _SR _{S '}) ,-L _S-N (R _S) SO ₂N (R _{S '}R _{S "}), carbocylic radical, heterocyclic radical, carbocylic radical C ₁-C ₆Alkyl, heterocyclic radical C ₁-C ₆Alkyl ,-L _E-Q-L _{E '}-(C ₃-C ₁₈Carbocylic radical) and-L _E-Q-L _{E '}-(M ₃-M ₁₈Heterocyclic radical);

L _SWhen occurring, be independently selected from a key, C at every turn ₁-C ₆Alkylidene group, C ₂-C ₆Alkylene group and C ₂-C ₆Alkynylene;

R _S, R _{S '}And R _{S "}When occurring, be selected from hydrogen, C independently of one another at every turn ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Thio alkoxy, C ₁-C ₆Alkoxy C ₁-C ₆Alkyl, C ₁-C ₆Alkoxy C ₁-C ₆Alkoxy C ₁-C ₆Alkyl, C ₁-C ₆Thio alkoxy C ₁-C ₆Alkyl, C ₁-C ₆Alkyl-carbonyl, C ₁-C ₆Alkyl-carbonyl C ₁-C ₆Alkyl, C ₁-C ₆Alkoxy carbonyl, C ₁-C ₆Alkoxy carbonyl C ₁-C ₆Alkyl, C ₁-C ₆Alkyl-carbonyl oxygen base, C ₁-C ₆Alkyl-carbonyl oxygen base C ₁-C ₆Alkyl, C ₁-C ₆Alkylamino, C ₁-C ₆Alkylamino C ₁-C ₆Alkyl, C ₁-C ₆Alkoxycarbonyl amino and C ₁-C ₆Alkoxycarbonyl amino C ₁-C ₆Alkyl;

L _EAnd L _{E '}When occurring, be independently selected from a key, C respectively at every turn ₁-C ₆Alkylidene group, C ₂-C ₆Alkylene group, C ₂-C ₆Alkynylene ,-C ₁-C ₆Alkylidene group-O-C ₁-C ₆Alkylidene group-,-C ₁-C ₆Alkylidene group-S-C ₁-C ₆Alkylidene group-,-C ₁-C ₆Alkylidene group-NC (O)-C ₁-C ₆Alkylidene group-and-C ₁-C ₆Alkylidene group-C (O) N-C ₁-C ₆Alkylidene group-;

Q is independently selected from a key, C at every turn when occurring ₁-C ₆Alkylidene group, C ₂-C ₆Alkylene group, C ₂-C ₆Alkynylene ,-S-,-O-,-C (O)-,-N (R _S)-,-N (R _S) C (O)-,-C (O) N (R _S)-,-N (R _S) C (O) O-,-OC (O) N (R _S)-,-N (R _S) C (O) N (R _{S '})-,-C (=NR _S) N (R _{S '})-,-N (R _{S '}) C (=NR _S)-,-S (O)-,-SO ₂-,-O-SO ₂-,-SO ₂-O-,-O-S (O)-,-S (O)-O-,-C (O) O-and-OC (O)-;

R ¹⁰, R ¹⁵, R ^{15 '}, R ¹⁷, R ¹⁸, R ²⁶, R ³⁰, R ³¹, R ³³, R ³⁵, R ³⁸And R ⁴¹When occurring, choose wantonly independently respectively at every turn and be selected from following substituting group replacement: halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, C by at least one ₁-C ₆Alkoxyl group, C ₁-C ₆Alkylamino, C ₁-C ₆Alkoxy carbonyl and azido-; And

-L _E-Q-L _{E '}-(C ₃-C ₁₈Carbocylic radical) and-L _E-Q-L0 _E-(M ₃-M ₁₈Heterocyclic radical) each C in ₃-C ₁₈Carbocylic radical and M ₃-M ₁₈The heterocyclic radical part optional independently when occurring at every turn is selected from following substituting group replacement by at least one: hydrogen, halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, azido-, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Thio alkoxy, C ₁-C ₆Alkoxy C ₁-C ₆Alkyl, C ₁-C ₆Thio alkoxy C ₁-C ₆Alkyl, C ₁-C ₆Alkyl-carbonyl, C ₁-C ₆Alkyl-carbonyl C ₁-C ₆Alkyl, C ₁-C ₆Alkoxy carbonyl, C ₁-C ₆Alkoxy carbonyl C ₁-C ₆Alkyl, C ₁-C ₆Alkyl-carbonyl oxygen base, C ₁-C ₆Alkyl-carbonyl oxygen base C ₁-C ₆Alkyl, C ₁-C ₆Alkylamino, C ₁-C ₆Alkylamino C ₁-C ₆Alkyl, C ₁-C ₆Alkoxycarbonyl amino, C ₃-C ₇Carbocylic radical oxygen base, M ₃-M ₇Heterocyclyloxy base, C ₃-C ₇Carbocylic radical C ₁-C ₆Alkoxyl group, M ₃-M ₇Heterocyclic radical C ₁-C ₆Alkoxyl group, C ₃-C ₇Carbocylic radical C ₁-C ₆Alkoxy carbonyl, M ₃-M ₇Heterocyclic radical C ₁-C ₆Alkoxy carbonyl and C ₁-C ₆Alkoxycarbonyl amino C ₁-C ₆Alkyl.

In an example of the present embodiment, A is optional by one or more R ¹⁸The C that replaces ₅-C ₆Carbocylic radical.

In another example of the present embodiment, A is optional by one or more R ¹⁸The M that replaces ₅-M ₆Heterocyclic radical.

In also another example of the present embodiment, Y is-L _S-O-,-L _S-S-,-L _S-C (O) N (R ¹⁵)-or-L _S-N (R ¹⁵) C (O)-, R ¹⁵Be hydrogen, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl or C ₂-C ₆Alkynyl, and L ¹Be optional by one or more R ³⁸The C that replaces ₁-C ₆Alkylidene group.A wherein ¹Be C ₄-C ₆Carbocylic radical or M ₄-M ₆Heterocyclic radical, and optional by one or more R ³⁰Replace.

In also another example of the present embodiment, Y is-L _S-O-,-L _S-S-,-L _S-C (O) N (R ¹⁵)-or-L _S-N (R ¹⁵) C (O)-, R ¹⁵Be hydrogen, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl or C ₂-C ₆Alkynyl, and L ¹Be that a key (is R ⁵⁰Be-A ¹), A wherein ¹Be C ₄-C ₆Carbocylic radical or M ₄-M ₆Heterocyclic radical, and optional by one or more R ³⁰Replace.

In another example of the present embodiment, Y is-L _S-O-,-L _S-S-,-L _S-C (O) N (R ¹⁵)-or-L _S-N (R ¹⁵) C (O)-, R ¹⁵Be hydrogen, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl or C ₂-C ₆Alkynyl, and L ¹Be that a key (is R ⁵⁰Be-A ¹) or optional by one or more R ³⁸The C that replaces ₁-C ₆Alkylidene group, wherein A ¹Be dicyclo (for example condensed-bicyclic or bridging dicyclo), it has 6-14 annular atoms and optional by one or more R ³⁰Replace.

In another example of the present embodiment, X is-O-or-S-, and R ²²Be C ₅-C ₆Carbocylic radical or M ₅-M ₆Heterocyclic radical and optional by one or more R ²⁶Replace.

In also another example of the present embodiment, X is-S-or-O-, and R ²²Be

Or

R wherein ⁴⁸Be hydroxyl, amino, C ₁-C ₆Alkylamino, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkoxycarbonyl amino or C ₁-C ₆Alkyl-carbonyl oxygen base, and R ²²(R for example ⁴⁸Or R ²²In benzyl ring) optional by one or more R ²⁶Replace.

In another example of the present embodiment, A is C ₅-C ₆Carbocylic radical or M ₅-M ₆Heterocyclic radical and optional by one or more R ¹⁸Replace, wherein:

X is-O-or-S-;

R ²²Be

Or

R wherein ⁴⁸Be hydroxyl, amino, C ₁-C ₆Alkylamino, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkoxycarbonyl amino or C ₁-C ₆Alkyl-carbonyl oxygen base and R ²²(R for example ⁴⁸Or R ²²In benzyl ring) optional by one or more R ²⁶Replace;

Y is-L _S-O-,-L _S-S-,-L _S-C (O) N (R ¹⁵)-or-L _S-N (R ¹⁵) C (O)-, R wherein ¹⁵Be hydrogen, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl or C ₂-C ₆Alkynyl;

R ⁵⁰Be-L ¹-A ¹, wherein:

L ¹Be optional by one or more R ³⁸The C that replaces ₁-C ₆Alkylidene group, and A ¹Be C ₄-C ₆Carbocylic radical or M ₄-M ₆Heterocyclic radical and optional by one or more R ³⁰Replace; Perhaps

L ¹Be that a key (is R ⁵⁰Be-A ¹), A wherein ¹Be C ₄-C ₆Carbocylic radical or M ₄-M ₆Heterocyclic radical and optional by one or more R ³⁰Replace; Perhaps

L ¹Be that a key (is R ⁵⁰Be-A ¹) or optional by one or more R ³⁸The C that replaces ₁-C ₆Alkylidene group, wherein A ¹Be dicyclo (for example dicyclo of condensed dicyclo or bridging), it has 6-14 annular atoms and optional by one or more R ³⁰Replace.

Part

Or In annular atoms can be further replaced by S or other heteroatoms.

In another embodiment, the present invention relates to have the compound of formula II (a) or II (b), the tautomer of these compounds and the pharmacologically acceptable salt of these compounds or tautomer,

Wherein:

R ²And R ³Be independently selected from hydrogen, alkyl, alkoxy carbonyl and alkoxyalkyl aminocarboxyl;

R ⁴Be selected from hydrogen, alkoxy carbonyl and alkoxy carbonyl alkyl;

R ⁷Be selected from hydrogen, alkyl, haloalkyl, alkoxyl group, cycloalkyl, alkoxy carbonyl alkyl, alkoxy carbonyl alkyl amino, cyano alkoxy carbonylic alkyl, cyano group alkyl, hydroxyalkyl, morpholino, diazanyl, alkylamino alkoxyl group, alkoxyalkyl amino and aryl;

R ⁹Be selected from hydrogen, alkyl, alkoxyl group, haloalkyl, aryl-alkyl amino, hydroxyl, the alkoxycarbonyl amino alkyl, alkyl-carbonyl, amino, halogen, N-[alkyl aryl amino (artyl sulfo) arylalkyl]-the N-[(alkoxy carbonyl) alkyl] amino, the alkoxy aryl alkoxyl group, the halogenated aryl alkoxyl group, the nitro alkoxy aryl, the cyano-aryl alkoxyl group, aromatic yloxy yl alkyl, halogenated aryl oxygen base alkyl, cyano alkoxy, alkoxy aryl, the alkylaryl alkoxyl group, the haloalkyl aromatic yl aminocarbonyl, the alkylamino aromatic yl aminocarbonyl, alkoxy aryl, alkyl allyl group oxygen base and alkoxy carbonyl;

R ¹¹Be selected from hydrogen, hydroxyl, halogenated aryl oxygen base and alkyl;

R ¹²Be selected from hydrogen, artyl sulfo, aryl sulfonyl kia, aryloxy, sulfydryl, aromatic yl aminocarbonyl, aryl, alkoxy aryl, alkoxy aryl and alkyl-carbonyl-amino aryl; R wherein ¹²Optional by one or more R that are independently selected from ¹⁶Substituting group replace;

R ¹⁶Be selected from hydrogen, halogen, alkyl, alkoxyl group, hydroxyl, aminocarboxyl, alkyl amino-carbonyl, amino, alkyl-carbonyl-amino, the miscellaneous alkyl aryl carbonylamino, the heteroaryl carbonylamino, hydroxyl heteroaryl carbonylamino, hydroxyalkyl heteroaryl carbonylamino, heteroaryl carbonylamino alkyl-carbonyl-amino, the heteroarylalkyl carbonylamino, aryloxy aromatic yl alkyl carbonyl amino, the allyl amino carbonyl, alkoxy carbonyl, hydroxyalkyl, aromatic yl aminocarbonyl, the hydroxyaryl aminocarboxyl, alkoxyalkyl, the alkoxy aryl aminocarboxyl, the azido-alkyl, alkylamino aryl sulfonyl oxygen base, alkyl sulphonyl oxygen base, aryl alkylsulfonyl oxygen base, the alkoxy carbonyl alkoxyl group, the hydroxycarbonyl group alkoxyl group, cycloalkyl amino carbonyl, aryl-alkoxy carbonyl heterocyclic radical carbonylamino, aryloxy, imino alkyl, the alkyl thioketones, aromatic yl alkyl carbonyl amino, the alkylaryloxy alkyl-carbonyl-amino, the alkoxy aryl alkyl carbonylamino, heteroaryl carbonylamino alkyl-carbonyl-amino, the heteroarylalkyl carbonylamino, alkyl-carbonyl heterocyclic radical carbonylamino, amino, aminocarboxyl, alkyl amino-carbonyl, hydroxyalkyl, aminoalkyl group, the alkoxyalkyl aminocarboxyl, the oxyimino alkyl, the heteroaryl and the heteroaryl that are replaced by alkyl;

R ¹³Be selected from hydrogen, halogen, alkyl, alkyl-carbonyl-amino aryl sulfonyl, aminoaryl sulfenyl, alkoxy aryl, halogenated aryl alkoxyl group, alkyl-carbonyl-amino aryloxy, alkylamino aryloxy, hydroxyaryl oxygen base, alkyl amino-carbonyl alkoxy aryl and alkyl-carbonyl-amino alkoxy aryl.

In the family of subsets of the present embodiment in formula II (a) or II (b), R ¹²Be selected from

N is selected from 0 or 1 integer;

R ¹⁴Be selected from hydrogen, halogen, alkyl, alkoxyl group, hydroxyl, aminocarboxyl, alkyl amino-carbonyl, amino, alkyl-carbonyl-amino, the miscellaneous alkyl aryl carbonylamino, the heteroaryl carbonylamino, hydroxyl heteroaryl carbonylamino, hydroxyalkyl heteroaryl carbonylamino, heteroaryl carbonylamino alkyl-carbonyl-amino, the heteroarylalkyl carbonylamino, aryloxy aromatic yl alkyl carbonyl amino, the allyl amino carbonyl, alkoxy carbonyl, hydroxyalkyl, aromatic yl aminocarbonyl, the hydroxyaryl aminocarboxyl, alkoxyalkyl, alkoxy aryl aminocarboxyl and azido-alkyl;

RU is selected from hydrogen; halogen; alkyl; alkoxyl group; hydroxyl; aminocarboxyl; alkyl amino-carbonyl; amino; alkyl-carbonyl-amino; the miscellaneous alkyl aryl carbonylamino; the heteroaryl carbonylamino; hydroxyl heteroaryl carbonylamino; hydroxyalkyl heteroaryl carbonylamino; heteroaryl carbonylamino alkyl-carbonyl-amino; the heteroarylalkyl carbonylamino; aryloxy aromatic yl alkyl carbonyl amino; the allyl amino carbonyl; alkoxy carbonyl; hydroxyalkyl; aromatic yl aminocarbonyl; the hydroxyaryl aminocarboxyl; alkoxyalkyl; the alkoxy aryl aminocarboxyl; the azido-alkyl; alkylamino aryl sulfonyl oxygen base; alkyl sulphonyl oxygen base; aryl alkylsulfonyl oxygen base; the alkoxy carbonyl alkoxyl group; the hydroxycarbonyl group alkoxyl group; cycloalkyl amino carbonyl; aryl-alkoxy carbonyl heterocyclic radical carbonylamino; aryloxy; imino alkyl; the alkyl thioketones; aromatic yl alkyl carbonyl amino; the alkylaryloxy alkyl-carbonyl-amino; the alkoxy aryl alkyl carbonylamino; heteroaryl carbonylamino alkyl-carbonyl-amino; the heteroarylalkyl carbonylamino; alkyl-carbonyl heterocyclic radical carbonylamino; amino; aminocarboxyl; alkyl amino-carbonyl; hydroxyalkyl; aminoalkyl group; the alkoxyalkyl aminocarboxyl; the oxyimino alkyl; the heteroaryl and the heteroaryl that are replaced by alkyl.

In the family of subsets of the present embodiment in formula II (a) or II (b), R ²And R ³Be independently selected from hydrogen, ethoxy carbonyl, 3-N-methoxyl group-N-methylamino carbonyl and methyl;

R ⁴Be selected from hydrogen, tert-butoxycarbonyl and ethoxy carbonyl methyl;

R ⁷Be selected from hydrogen, methyl, ethyl, propyl group, butyl, sec.-propyl, isobutyl-, sec-butyl, trifluoromethyl, methoxyl group, oxyethyl group, cyclopentyl, hydroxyethyl, butyl, 1,1-two-(ethoxy carbonyl) methyl, ethoxy carbonyl methylamino, 1,1-two-(tert-butoxycarbonyl), cyano group-1-ethoxy carbonyl methyl, cyano group-1-tert.-butoxy-carbonyl methyl, cyano methyl, morpholinyl, ethoxy carbonyl ethyl, diazanyl, N, N-dimethylamino ethoxy, methoxy ethyl amino and cyano group-1-oxyethyl group-carbonyl methyl;

R ⁹Be selected from hydrogen, methyl, methoxyl group, phenyl, trifluoromethyl, phenyl methyl amino, hydroxyl, tert.-butoxy-carbonylamino methyl, carbonylamino, the methyl carbonyl, amino, bromine, chlorine, fluorine, methyl [1,8] naphthyridine-4-base amino-(2-phenyl sulfenyl benzene-5-ylmethyl) amino-(N-tert.-butoxy-carbonyl-N-methyl), the anisole ylmethoxy, the bromophenyl methoxyl group, the nitrophenyl methoxyl group, the cyano-phenyl methoxyl group, trifluoromethyl, phenoxymethyl, bromobenzene oxygen ylmethyl, the cyano group methoxyl group, the phenyl methoxyl group, methacrylic oxygen base, propoxy-, the aminomethyl phenyl methoxyl group, the aminomethyl phenyl methoxyl group, fluoro-3-aminomethyl phenyl aminocarboxyl, the trifluoromethyl aminocarboxyl, the trifluoromethyl aminocarboxyl, N, N-dimethylaminophenyl aminocarboxyl, fluorophenyl methoxyl group and chloro-phenyl-methoxyl group;

R ¹¹Be selected from hydrogen, hydroxyl, chlorophenoxy and methyl;

R ¹²As above about described in formula II (a) and the II (b);

R ¹³Be selected from hydrogen, chlorine, methyl, methyl carbonylamino phenyl sulfenyl, aminophenyl sulfenyl, phenyl methoxyl group, bromophenyl methoxyl group, methyl carbonylamino phenoxy group, N, N-dimethylamino phenoxyl, hydroxyphenoxy and methylamino carbonyl phenoxy group;

R ¹⁴Be selected from hydrogen, fluorine, methyl, methoxyl group, hydroxyl, aminocarboxyl, N-methylamino carbonyl, N, N-dimethylamino carbonyl, amino, tertiary butyl carbonylamino, 2,6-dimethyl furan base) carbonylamino, thienyl carbonyl amino, the hydroxy-pyridyl carbonylamino, (2-hydroxyl-6-picolyl) carbonylamino, (3-pyrazinyl) carbonylamino, furyl carbonyl amino methyl carbonylamino, (3-thienyl) propyl group carbonylamino, (3-phenoxy group) phenyl methyl carbonylamino, N-allyl amino carbonyl, ethoxy carbonyl, the 1-hydroxyethyl, aminocarboxyl, the ethylamino carbonyl, the phenyl amino carbonyl, the hydroxy phenyl aminocarboxyl, the propyl group aminocarboxyl, hydroxymethyl, hydroxyethyl, azido-ethyl and N, N-dimethylamino carbonyl;

R ¹⁶Be selected from hydrogen; hydroxyl; the methyl carbonylamino; methyl; sec.-propyl; fluorine; methoxyl group; oxyethyl group; propoxy-; isopropoxy; N; N-dimethylamino-naphthalene-1-base alkylsulfonyl oxygen base; ethylsulfonyl oxygen base; sec.-propyl alkylsulfonyl oxygen base; methyl sulphonyl oxygen base; benzyl alkylsulfonyl oxygen base; ethoxycarbonyl methoxy; the hydroxycarbonyl group methoxyl group; tertiary butyl carbonylamino; cyclopropyl carbonyl amino; benzyloxycarbonyl pyrrolidyl carbonylamino; phenoxy group; the methyl carbonylamino; the imino-ethyl; the thion ethyl; (S)-1-phenyl propyl carbonylamino; methylenedioxy phenoxy ylmethyl carbonylamino; (R)-1-phenyl-1-methoxymethyl carbonylamino; (S)-1-phenyl-1-methoxymethyl carbonylamino; furyl carbonyl amino methyl carbonylamino; thienyl propyl group carbonylamino; methyl carbonyl piperidyl carbonylamino; amino; aminocarboxyl; N-methylamino carbonyl; ethoxycarbonyl methoxy; sec.-propyl alkylsulfonyl oxygen base; methyl sulphonyl oxygen base; ethylsulfonyl oxygen base; phenyl methyl alkylsulfonyl oxygen base; the methyl carbonylamino; N-methylamino carbonyl; hydroxymethyl; amino-ethyl; the methoxy ethyl aminocarboxyl; the propyl group aminocarboxyl; N-methoxyl group-N-methylamino carbonyl; N; N-diethylamino carbonyl; N-(2-methoxy ethyl) aminocarboxyl; N-ethyl-N-methylamino carbonyl; N-hydroxyl-1-imino-ethyl; hydroxyethyl; amino methyl; N; N-dimethylamino-carbonyl; 2; 6-dimethyl furan base; 1H-[1; 2,4] triazolyl and pyridyl.

The salt of The compounds of this invention

The compounds of this invention or its tautomer can use with the form of salt.According to particular compound, the salt of compound can be owing to the physical properties of one or more salt but is favourable, for example medicine stability that improves under differing temps and humidity, or the required solubleness in water or oil.In some cases, the salt of compound can also be used as auxiliary agent in separation, purifying and/or the fractionation of compound.

When being intended to patient's administration of salt, this salt is preferably pharmaceutically useful.The salt that pharmacologically acceptable salt includes but not limited to be used to form an alkali metal salt and/or forms the additive salt of free acid or free alkali.These salt generally can be made by The compounds of this invention by ordinary method, for example by suitable acid or alkali and compound reaction are made.

The pharmaceutically acceptable acid additive salt of The compounds of this invention can be made by mineral acid or organic acid.Suitable representative examples of mineral pigments comprises hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, carbonic acid, sulfuric acid and phosphoric acid.Appropriate organic generally includes for example aliphatic series, cyclic aliphatic, aromatics, araliphatic, heterocyclic carboxylic acid and sulfonic acid class organic acid.The specific examples of appropriate organic salt comprises acetate, trifluoroacetate, formate, propionic salt, succinate, glycollate, gluconate, digluconate, lactic acid salt, malate, tartrate, Citrate trianion, ascorbate salt, glucuronate, maleate, fumarate, pyruvate salt, aspartate, glutaminate, benzoate, anthranilate, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetic acid salt, mandelate, embonate (pamoate), mesylate, esilate, benzene sulfonate, pantothenate, tosylate, the 2-isethionate, sufanilate, cyclohexyl-n-sulfonate, algenic acid, beta-hydroxy-butanoic acid salt, the galacturonic hydrochlorate, adipate, alginate, hydrosulfate, butyrates, camphorate, camsilate, cyclopentane propionate, dodecyl sulfate, glycoheptanoate, glycerophosphate, Hemisulphate, enanthate, hexanoate, nicotinate, the 2-naphthalenesulfonate, oxalate, palmitate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, thiocyanate-, tosylate and undecane hydrochlorate.

The pharmaceutically acceptable base addition salt of The compounds of this invention comprises for example metal-salt and organic salt.Preferred metal-salt includes but not limited to basic metal (Ia family) salt, alkaline-earth metal (IIa family) salt and the acceptable metal-salt of other physiology.Such salt can be made by aluminium, calcium, lithium, magnesium, potassium, sodium and zinc.The limiting examples of preferred organic salt can be made by tertiary amine and quaternary amine, for example tromethamine, diethylamine, N, N '-dibenzyl-ethylenediamin, chloroprocaine, choline, diethanolamine, quadrol, meglumine (N-methylglucosamine) and PROCAINE HCL, PHARMA GRADE.The alkalescence nitrogen-containing group can be quaternized with reagent, and described reagent has for example low alkyl group (C ₁-C ₆) halogenide (for example methyl, ethyl, propyl group and butyl muriate, bromide and iodide), dialkyl sulfate (for example Dimethylsulfate, diethyl sulfide hydrochlorate, dibutyl sulfide hydrochlorate and diamyl vitriol), long-chain halogenide (for example decyl, lauryl, myristyl and stearyl chlorination thing, bromide and iodide), aralkyl halide (for example benzyl and styroyl bromination thing) etc.

Solvate, prodrug and isomer

The compounds of this invention, its tautomer and salt thereof also can exist with solvate forms, described solvate forms with water, hydrate for example, or form with organic solvent, for example form methylate, ethylate or second nitrile compound respectively with methyl alcohol, ethanol or acetonitrile.The compounds of this invention can exist with the form of each solvate or its mixture.

In one aspect, The compounds of this invention, tautomer or salt can be prodrug forms.Some prodrug is derived from the aliphatic series of the acidic-group on the The compounds of this invention or aromatic ester.Other prodrugs are hydroxyl or amino aliphatic series or the aromatic esters on the The compounds of this invention.The invention still further relates to the phosphoric acid ester prodrug of the hydroxyl on the The compounds of this invention.

The compounds of this invention can comprise the carbon atom of the asymmetric replacement that is called chiral centre.According to the substituent configuration around the chiral carbon atom, these chiral centres are called " R " or " S ".Term used herein " R " and " S " they are as at Nomenclature of Organic Chemistry, Section E:Stereochemistry, and Recommendations 1974, PURE APPL.CHEM., defined configuration among the 45:11-30 (1976).The compounds of this invention can be used as but is not limited to single stereoisomers (for example single enantiomer or single diastereomer), stereoisomer mixture (for example any mixture of enantiomorph or diastereomer) or racemic mixture and exists.All such single stereoisomers, mixture and racemoid all are included in the scope of the present invention.The compound that is referred to herein as single stereoisomers is to describe the compound that exists with the form that is substantially devoid of other steric isomers (for example other enantiomorphs or diastereomer)." be substantially devoid of " and be meant, at least 80% compound is required steric isomer in the composition, at least 90% compound is required steric isomer in the preferred composition, and more preferably at least 95%, 96%, 97%, 98% or 99% compound is required steric isomer in the composition.When not specifying the stereochemistry of the chiral carbon that exists in the chemical structure, then chemical structure comprises the steric isomer that contains each chiral centre that is present in the chemical structure.

The single stereoisomers of The compounds of this invention can use several different methods known in the art to make.These methods include but not limited to that stereospecificity is synthetic, the chromatographic separation of diastereomer, and the chromatogram of enantiomorph splits, enantiomorph in the mixture of enantiomers is changed into diastereomer, isolate diastereomer by chromatography then, and independent enantiomorph and the enzyme of regeneration splits.

Stereospecificity is synthetic to be generally included and uses suitable optically-active pure (enantiomer-pure) or optically-active pure material and do not cause the stereochemistry generation racemization of chiral centre or the building-up reactions of conversion basically.The stereoisomer mixture of the compound that is generated by building-up reactions comprises racemic mixture, and the chromatographic technique that can for example be familiar with by those skilled in the art separates.The chromatographic separation of enantiomorph can be finished on the chiral chromatography resin, and a lot of chiral chromatography resins can be commercially available.In limiting examples, racemic modification is placed solution, and load on the post that contains chiral stationary phase.Can pass through the HPLC enantiomer separation then.

The fractionation of enantiomorph also can be carried out like this: by reacting with chiral auxiliary(reagent), the enantiomorph in the mixture is changed into diastereomer.The gained diastereomer can separate by column chromatography or crystallization/recrystallization.Contain when forming the carboxyl, amino of salt or covalent linkage or hydroxyl with chiral auxiliary(reagent) when desiring isolated compound, this technology is useful.The limiting examples of suitable chiral auxiliary(reagent) comprises amino acid, organic carboxyl acid or the organic sulfonic acid of chiral purity.In case isolate diastereomer by chromatography, promptly can regenerate single enantiomer.Usually, chiral auxiliary(reagent) can reclaim and reuse.

Enzyme for example esterase, Phosphoric acid esterase or lipase can be used for splitting enantiomorph derivative in the mixture of enantiomers.For example, can with the ester derivative of desiring the carboxyl in the isolated compound with can be optionally only in the hydrolysed mix a kind of enzyme of enantiomorph handle.The acid of gained enantiomer-pure can be separated from unhydrolysed ester then.

Perhaps, can use any method known in the art to prepare the salt of enantiomorph in the mixture, comprise with suitable optically pure alkali biological example alkali or phenylethylamine and handle carboxylic acid, the salt with enantiomer-pure precipitates or crystallization/recrystallization then.Be applicable to stereoisomer mixture, comprise racemic mixture fractionation/isolating method can referring to

(people such as Jacques, 1981, John Wiley and Sons, New York, NY).

The compounds of this invention can have one or more unsaturated carbon-to-carbon double bonds.Except as otherwise noted, otherwise all double bond isomers, for example cis (Z) and trans (E) isomer and composition thereof all are included in the scope of the compound of addressing.In addition, when compound existed with multiple different tautomeric forms, the compound of being addressed was not limited to any concrete tautomer, but comprised all tautomeric forms.

Some The compounds of this invention can be stablized the conformation form with separable difference and exist.Since restricted round asymmetric single bonded rotation, for example isolate different conformers owing to the asymmetric tolerable that reverses that hinders or the ring strain causes.The compounds of this invention comprises each conformer of these compounds and composition thereof.

Some The compounds of this invention can also exist as zwitterionic form, and the present invention includes each zwitterionic form of these compounds and composition thereof.

Definition

The compounds of this invention uses standardized denomination to describe in this article usually.The compound with asymmetric center for addressing should be appreciated that except as otherwise noted all steric isomers of compound and composition thereof all comprise in the present invention.The limiting examples of steric isomer comprises enantiomorph, diastereomer and cis-trans isomer.When the compound of addressing existed with multiple different tautomeric forms, compound comprised all tautomeric forms.This paper has used and has comprised variable (R for example ¹⁷, A ¹, L ¹, X, Y or Z) general formula some compounds are described.Except as otherwise noted, each variable in such general formula all is independent of any other variable and defines, and any variable more than occurring once in general formula defines when occurring at every turn independently.If substituting group is described to " being independently selected from " a group, then each substituting group is selected each other independently.Therefore, each substituting group and other substituting groups can be identical or different.

The number of carbon atom can pass through prefix " C in the hydrocarbyl substituent _x-C _y, " indication, wherein x is the minimal number of carbon atom in the substituting group, and y is a maximum number.Therefore, " C for example ₁-C ₆Alkyl " be meant the alkyl substituent that contains 1-6 carbon atom.Further illustrate C ₃-C ₆Cycloalkyl is meant the stable hydrocarbon basic ring that contains 3-6 carboatomic ring atom.The prefix that appends on the multicomponent substituting group only is applied to tight first composition after this prefix.Illustrate, term " alkylaryl " contains two compositions: alkyl and aryl.Therefore, C for example ₁-C ₆Alkylaryl is meant via aryl and is connected to C on the parent molecule part ₁-C ₆Alkyl.Equally, alkyl C ₆-C ₁₀Aryl is meant via C ₆-C ₁₀Aryl is connected to the alkyl on the parent molecule part.Similarly, the prefix on the halogenated alkoxy alkyl " halo " is meant that the alkoxyl group composition is replaced by one or more halogens, and the prefix on the halogenated alkoxy alkyl " halo " is meant that the alkyl composition is replaced by one or more halogens.

When the connection portion between two other parts of the chemical structure that is used to describe description, the composition that the leftmost side of connection portion is described be with the description structure in left part bonded composition.Illustrate, if chemical structure is X-L-Y, L is described to the methyl aryl ethyl, and then this chemical structure will be X-methyl-aryl-ethyl-Y.

If the connection portion is a key in the structure of describing, then the left part in institute's description scheme directly combines with saying the right side part of describing in the structure.For example, if chemical structure is described to X-L-Y, and L is selected from a key, and then this chemical structure will be X-Y.For another example, if chemical structure is described to-L-X, and L is selected from a key, and then this chemical structure will be-X.For another example, if chemical structure is described to X-L ₁-L ₂-Y, X-L ₁-L ₂-L ₃-Y or X-L ₁-L ₂-...-L _N-Y, and L ₁, L ₂, L ₃... L _NBe selected from a key, then this chemical structure will be X-Y.

When using chemical formula to describe substituting group, then the substituent part of free valency represented to have in the dash in chemical formula right side (or left side).

If substituting group is described as " substituted ", then non-hydrogen group has substituted the one or more hydrogen on this substituent carbon, nitrogen or the oxygen.Therefore, for example, the alkyl substituent of replacement is that wherein at least one non-hydrogen group has substituted the alkyl substituent of the hydrogen on this alkyl substituent.Illustrate the alkyl that single fluoroalkyl is replaced by a fluorine, the alkyl that fluoroalkyl is replaced by two fluorine.Will be appreciated that if two or more replacements are arranged, except as otherwise noted, each non-hydrogen group can be identical or different on substituting group.

If comprise carbon, nitrogen or the salt of at least one and one or more hydrogen atom bondings, then substituting group is " can be substituted ".

If substituting group is described to " optional substituted ", then this substituting group can be substituted or unsubstituted.If being described to the optional non-hydrogen group of given number that is up to, substituting group replaces, then but this substituting group can be unsubstituted or is up to the non-hydrogen group replacement that non-hydrogen group replacement of this given number or quilt are up to maximum the position of substitution number on the substituting group, and whichever is less.Therefore, for example, if substituting group is described to the optional heteroaryl that 3 non-hydrogen groups replace that is up to, but but then have any heteroaryl that is less than 3 the position of substitution will choose wantonly only be up to the position of substitution of having with this heteroaryl as many non-hydrogen group of number replace.Illustrate, tetrazyl (but only having a position of substitution) will be chosen wantonly and will be up to 1 non-hydrogen group replacement.Further illustrate, be up to 2 non-hydrogen groups replacements if amino nitrogen is described to choose wantonly, then primary amino nitrogen is chosen wantonly and is up to 2 non-hydrogen groups replacements, and the optional quilt of secondary amino nitrogen is up to 1 non-hydrogen group replacement.

Term " alkenyl " (separately or with other term combination) is meant and contains one or more pairs of keys and 2-20 carbon atom usually, 2-8 carbon atom more generally, even the straight or branched hydrocarbon substituent of 2-6 carbon atom more generally.In the alkenyl part, with respect to the group that replaces on the double key carbon, each carbon-to-carbon double bond can be cis or trans geometry.Substituent limiting examples like this comprises vinyl, 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butylene base, crotyl and 3-butenyl.

Term " alkylene group " (separately or with other term combination) is meant the divalence unsaturated alkyl, and it can be a straight or branched, and has at least one carbon-to-carbon double bond.Alkylene group contains 2-20 carbon atom usually, 2-8 carbon atom more generally, even 2-6 carbon atom more generally.The limiting examples of alkylene group comprises-C (H)=C (H)-,-C (H)=C (H)-CH ₂-,-C (H)=C (H)-CH ₂-CH ₂-,-CH ₂-C (H)=C (H)-CH ₂-,-C (H)=C (H)-CH (CH ₃)-and-CH ₂-C (H)=C (H)-CH (CH ₂CH ₃)-.

Term " alkoxyl group " (separately or with other term combination) is meant the alkyl that partly is connected via oxygen part and parent molecule (promptly-O-alkyl).Substituent limiting examples like this comprises methoxyl group (O-CH ₃), oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy.

Term " alkoxyalkyl " (separately or with other term combination) is meant the alkoxyl group that partly is connected via alkylidene group and parent molecule.The limiting examples of alkoxyalkyl comprises tert.-butoxy methyl, 2-ethoxyethyl group, 2-methoxy ethyl and methoxymethyl.

Term " alkoxy carbonyl " (separately or with other term combination) is meant the alkoxyl group that partly is connected via carbonyl and parent molecule (promptly-C (O)-O-alkyl).The representative example of alkoxy carbonyl includes but not limited to methoxycarbonyl, ethoxy carbonyl And tert-butoxycarbonyl.

Term " alkoxycarbonyl amino " (separately or with other term combination) is meant N (R _AR _B)-, be R wherein _ABe alkyl-O-C (O)-, and R _BBe alkyl-O-C (O)-or hydrogen.R _AAnd R _BCan be identical or different.

Term " alkoxycarbonyl amino alkyl " (separately or with other term combination) is meant N (R _AR _B)-alkylidene group-, R wherein _ABe alkyl-O-C (O)-, and R _BBe alkyl-O-C (O)-or hydrogen.R _AAnd R _BCan be identical or different.

Term " alkoxy carbonyl alkyl " (separately or with other term combination) is meant the alkoxy carbonyl that partly is connected via alkylidene group and parent molecule.The representative example of alkoxy carbonyl alkyl includes but not limited to 2-methoxyl group-2-oxoethyl, 2-oxyethyl group-2-oxoethyl, 3-methoxyl group-3-oxopropyl, 3-oxyethyl group-3-oxopropyl, 4-oxyethyl group-2-(ethoxy carbonyl)-4-oxo butyl, 5-methoxyl group-5-oxo amyl group and 6-methoxyl group-6-oxo-hexyl.

Term " alkyl " (separately or with other term combination) is meant and contains 1-20 carbon atom usually, 1-8 carbon atom more generally, even the straight or branched saturated hydrocarbyl substituting group of 1-6 carbon atom more generally.Substituent limiting examples like this comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, hexyl and octyl group.

Term " alkylamino " (separately or with other term combination) is meant-NR _AR _B, R wherein _ABe alkyl, and R _BIt is hydrogen or alkyl.R _AAnd R _BCan be identical or different.For example, C ₁-C ₆Alkylamino is meant-NR _AR _B, R wherein _ABe C ₁-C ₆Alkyl, and R _BBe hydrogen or C ₁-C ₆Alkyl.

Term " alkylamino alkyl " (separately or with other term combination) is meant N (R _AR _B)-alkylidene group-, R wherein _ABe alkyl, and R _BIt is hydrogen or alkyl.R _AAnd R _BCan be identical or different.Therefore, C ₁-C ₆Alkylamino C ₁-C ₆Alkyl is meant N (R _AR _B)-C ₁-C ₆Alkylidene group-, R wherein _ABe C ₁-C ₆Alkyl, and R _BBe hydrogen or C ₁-C ₆Alkyl.

Term " alkyl-carbonyl " (separately or with other term combination) is meant the alkyl that partly is connected via carbonyl and parent molecule (promptly-C (O)-alkyl).The representative example of alkyl-carbonyl includes but not limited to ethanoyl, ethyl carbonyl

1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxo butyl and 1-oxo amyl group.

Term " alkyl-carbonyl alkyl " (separately or with other term combination) is meant the alkyl-carbonyl that partly is connected via alkylidene group and parent molecule.The representative example of alkyl-carbonyl alkyl includes but not limited to 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxo butyl and 3-oxo amyl group.

Term " alkyl-carbonyl oxygen base " (separately or with other term combination) is meant the alkyl-carbonyl that partly is connected via oxygen base section and parent molecule.The representative example of alkyl-carbonyl oxygen base includes but not limited to acetoxyl group, ethyl ketonic oxygen base and tertiary butyl ketonic oxygen base.

Term " alkyl-carbonyl oxygen base alkyl " (separately or with other term combination) is meant the alkyl-carbonyl oxygen base that partly is connected via alkylidene group and parent molecule.The representative example of alkyl-carbonyl oxygen base alkyl includes but not limited to 2-(acetoxyl group) ethyl, 3-(acetoxyl group) propyl group and 3-(propionyloxy) propyl group.

Term " alkylidene group " or " alkylidene group " (separately or with other term combination) be meant by containing 1-20 carbon atom usually, 1-8 carbon atom more generally, even the straight or branched saturated hydrocarbon chain deutero-divalent group of 1-6 carbon atom more generally.The representative example of alkylidene group includes but not limited to-CH ₂-,-CH ₂CH ₂-,-CH ₂CH ₂CH ₂-,-CH ₂CH ₂CH ₂CH ₂-and-CH ₂CH (CH ₃) CH ₂-.

Term " alkynyl " (separately or with other term combination) is meant and contains one or more triple bonds and 2-20 carbon atom usually, 2-8 carbon atom more generally, even the straight or branched hydrocarbon substituent of 2-6 carbon atom more generally.Substituent limiting examples like this comprises ethynyl, 1-proyl, 2-propynyl, 3-proyl, decynyl, ethyl acetylene base, 2-butyne base and 3-butynyl.

Term " alkynylene " (separately or with other term combination) is meant the divalence unsaturated alkyl, and it can be a straight or branched, and has at least one carbon-to-carbon triple bond.Representative alkynylene for example comprises-C ≡ C-.-C≡C-CH ₂-。-C≡C-CH ₂-CH ₂-。-CH ₂-C≡C-CH ₂-。-C ≡ C-CH (CH ₃)-and-CH ₂-C ≡ C-CH (CH ₂CH ₃)-.

Term " amino " (separately or with other term combination) is meant-NH ₂Term " mono-substituted amino " (separately or with other term combination) is meant amino substituting group, and one of them hydrogen atom is substituted by non-hydrogen substituting group.Term " dibasic amino " (separately or with other term combination) is meant amino substituting group, and wherein two hydrogen atoms are substituted by non-hydrogen substituting group that can be identical or different.

Term " aminocarboxyl " (separately or with other term combination) is meant-C (O)-NH ₂, it can also be described to:

Term " aminoalkyl group " (separately or with other term combination) is meant-alkylidene group-NH ₂

Term " aminoalkyl group carbonyl " (separately or with other term combination) is meant-C (O)-alkylidene group-NH ₂For example, " amino methyl carbonyl " can be described to:

Term " amino-sulfonyl " (separately or with other term combination) is meant-S (O) ₂-NH ₂, it can also be described to:

Term " aryl " (separately or with other term combination) is meant the aromatic carbocyclyl groups that contains 6-14 carbon atom.The limiting examples of aryl comprises phenyl, naphthyl, anthryl and indenyl.Aryl can partly be connected with parent molecule via any commutable carbon atom of this group.

Term " arylalkyl " (separately or with other term combination) is meant the aryl that partly is connected via alkylidene group and parent molecule.The representative example of substituted/unsubstituted arylalkyl includes but not limited to benzyl, 4-(benzyloxy) benzyl, the 4-methoxy-benzyl, the 4-hydroxybenzyl, 3-(1,3-benzodioxole-5-yl)-the 2-methyl-propyl, 3-(phenoxy group) benzyl, 3-(1,3-benzodioxole-5-yl) propyl group, the 2-phenylethyl, the 3-phenyl propyl, the 2-naphthyl methyl, 3,5-di-t-butyl-2-hydroxybenzyl, the 3-methoxy-benzyl, 3, the 4-dimethoxy-benzyl, 4-(dimethylamino) benzyl, 4-[3-(dimethylamino) propoxy-] benzyl, (6-methoxyl group-2-naphthyl) methyl and 2-naphthalene-2-base ethyl.

Term " aromatic yl alkyl carbonyl " (separately or with other term combination) is meant the arylalkyl that partly is connected via carbonyl and parent molecule (be arylalkyl-C (O)-).The representative example of aromatic yl alkyl carbonyl includes but not limited to 2-naphthyl ethanoyl and phenyl acetyl.

Term " alkoxy aryl " (separately or with other term combination) is meant that the arylalkyl that partly is connected via oxygen base section and parent molecule (is an arylalkyl-O-).The representative example of alkoxy aryl includes but not limited to 2-phenyl ethoxy, 3-naphthalene-2-base propoxy-and 5-phenyl pentyloxy.

Term " alkoxy aryl alkyl " (separately or with other term combination) is meant the alkoxy aryl that partly is connected via alkylidene group and parent molecule.The representative example of alkoxy aryl alkyl includes but not limited to benzyloxymethyl, 2-(benzyloxy) ethyl and (2-phenyl ethoxy) methyl.

Term " aryl-alkoxy carbonyl " (separately or with other term combination) is meant the alkoxy aryl that partly is connected via carbonyl and parent molecule.The representative example of aryl-alkoxy carbonyl includes but not limited to benzyloxycarbonyl and naphthalene-2-ylmethoxy carbonyl.

Term " aryl carbonyl " (separately or with other term combination) is meant the aryl that partly is connected via carbonyl and parent molecule.The representative example of aryl carbonyl includes but not limited to benzoyl and naphthoyl.

Term " aryloxy " (separately or with other term combination) is meant the aryl that partly is connected via oxygen base section and parent molecule.The representative example of substituted/unsubstituted aryloxy includes but not limited to phenoxy group, naphthyloxy, 3-bromine phenoxy group, 4-chlorophenoxy, 4-methylphenoxy and 3,5-dimethoxy phenoxy group.

Term " aryloxy alkyl " (separately or with other term combination) is meant the aryloxy that partly is connected via alkylidene group and parent molecule.The representative example of aryloxy alkyl includes but not limited to 2-phenoxy group ethyl, 3-naphthalene-2-base oxygen base propyl group and phenoxymethyl.

Term " aryloxycarbonyl " (separately or with other term combination) is meant the aryloxy that partly is connected via carbonyl and parent molecule.

Term " artyl sulfo " (separately or with other term combination) is meant that the aryl that partly is connected via sulphur atom and parent molecule (is an aryl-S-).The representative example of artyl sulfo includes but not limited to thiophenyl, naphthalene-1-base sulfenyl and naphthalene-2-base sulfenyl.

Term " artyl sulfo alkyl " (separately or with other term combination) be meant aryl-S-alkylidene group-.The representative example of artyl sulfo alkyl includes but not limited to (thiophenyl) methyl, 2-(thiophenyl) ethyl and 3-(thiophenyl) propyl group.

Term " aryl thio alkoxy " (separately or with other term combination) is meant the artyl sulfo alkyl that partly is connected via oxygen base and parent molecule.

Term " aryl thio alkoxy alkyl " (separately or with other term combination) is meant the aryl thio alkoxy that partly is connected via alkylidene group and parent molecule.

Term " carbocyclic ring " or " carbon ring group " or " carbocylic radical " (separately or with other term combination) are meant saturated (for example " cycloalkyl "), fractional saturation (for example " cycloalkenyl group " or " cycloalkynyl radical ") or unsaturated entirely (for example " aryl ") ring system, wherein contain 0 heteroatomic ring atom and 3-18 carboatomic ring atom usually." annular atoms " or " ring element " is the atom that is combined together to form the ring of cyclic substituents.Carbocylic radical can be but be not limited to monocycle or two or more fused rings or bridge joint ring or volution.It (is C that carbocylic radical can contain 3-14 ring element ₃-C ₁₄Carbocylic radical is C for example ₃-C ₁₄Cycloalkyl), 3-10 ring element (is C ₃-C ₁₀Carbocylic radical is C for example ₃-C ₁₀Cycloalkyl), 3-8 ring element (is C ₃-C ₈Carbocylic radical is C for example ₃-C ₈Cycloalkyl), 3-6 ring element (is C ₃-C ₆Carbocylic radical is C for example ₃-C ₆Cycloalkyl), 4-10 ring element (is C ₄-C ₁₀Carbocylic radical is C for example ₄-C ₁₀Cycloalkyl and C ₄-C ₁₀Cycloalkenyl group), 4-8 ring element (is C ₄-C ₈Carbocylic radical is C for example ₄-C ₈Cycloalkyl and C ₄-C ₈Cycloalkenyl group) or 5-7 ring element (be C ₅-C ₇Carbocylic radical is C for example ₅-C ₇Cycloalkyl, C ₅-C ₇Cycloalkenyl group and phenyl).Substituted carbocylic radical can have cis or trans geometry.The representative example of carbocylic radical includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, cyclopentenyl, cyclopentadienyl, cyclohexadienyl, adamantyl, decahydro naphthyl, octahydro indenyl, cyclohexenyl, phenyl, naphthyl, fluorenyl, indanyl, 1,2,3,4-tetrahydrochysene-naphthyl, indenyl, different indenyl, two ring decyls, anthryl, phenanthrene, benzo naphthyl (also being called " phenalenyl "), naphthane base and norpinanyl.Carbocylic radical can be connected via any commutable carbon atom of this group on the parent molecule part.

Term " carbocylic radical alkyl " (separately or with other term combination) is meant the carbocylic radical that partly is connected via alkylidene group and parent molecule.For example, C ₃-C ₁₀Carbocylic radical C ₁-C ₆Alkyl is meant via C ₁-C ₆The C that alkylidene group and parent molecule partly are connected ₃-C ₁₀Carbocylic radical.Equally, C ₅-C ₇Carbocylic radical C ₁-C ₆Alkyl is meant via C ₁-C ₆The C that alkylidene group and parent molecule partly are connected ₅-C ₇Carbocylic radical.

0 term " carbocylic radical alkoxyl group " (separately or with other term combination) is meant that the carbocylic radical alkyl that partly is connected via oxygen base and parent molecule (is carbocylic radical-alkylidene group-O-).For example, C ₃-C ₁₀Carbocylic radical C ₁-C ₆Alkoxyl group is meant the C that partly is connected via oxygen base and parent molecule ₃-C ₁₀Carbocylic radical C ₁-C ₆Alkyl.Equally, C ₅-C ₇Carbocylic radical C ₁-C ₆Alkoxyl group is meant the C that partly is connected via oxygen base and parent molecule ₅-C ₇Carbocylic radical C ₁-C ₆Alkyl.

Term " carbocylic radical alkoxyalkyl " (separately or with other term combination) is meant the carbocylic radical alkoxyl group that partly is connected via alkylidene group and parent molecule (be carbocylic radical-alkylidene group-O-alkylidene group-).For example, C ₃-C ₁₀Carbocylic radical C ₁-C ₆Alkoxy C ₁-C ₆Alkyl is meant via C ₁-C ₆The C that alkylidene group and parent molecule partly are connected ₃-C ₁₀Carbocylic radical C ₁-C ₆Alkoxyl group.

Term " carbocylic radical alkoxy carbonyl " (separately or with other term combination) is meant the carbocylic radical alkoxyl group that partly is connected via carbonyl and parent molecule (promptly-C (O)-O-alkylidene group-carbocylic radical).For example, C ₃-C ₁₀Carbocylic radical C ₁-C ₆Alkoxy carbonyl is meant the C that partly is connected via carbonyl and parent molecule ₃-C ₁₀Carbocylic radical C ₁-C ₆Alkoxyl group.As limiting examples, " phenyl ethoxy carbonyl " can be described to:

Term " carbocylic radical alkyl-carbonyl " (separately or with other term combination) is meant the carbocylic radical alkyl that partly is connected via carbonyl and parent molecule (promptly-C (O)-alkylidene group-carbocylic radical).For example, " phenylethyl carbonyl " can be described to:

Term " carbocylic radical carbonyl " (separately or with other term combination) is meant the carbocylic radical that partly is connected via carbonyl and parent molecule (be carbocylic radical-C (O)-).For example, " phenylcarbonyl group " can be described to:

Term " carbocylic radical oxygen base " (separately or with other term combination) is meant that the carbocylic radical that partly is connected via oxygen base section and parent molecule (is a carbocylic radical-O-).

Term " carbocylic radical oxygen base alkyl " (separately or with other term combination) is meant the carbocylic radical oxygen base that partly is connected via alkylidene group and parent molecule (be carbocylic radical-O-alkylidene group-).

Term " carbocylic radical oxygen base carbonyl " (separately or with other term combination) is meant the carbocylic radical oxygen base that partly is connected via carbonyl and parent molecule (promptly-C (O)-O-carbocylic radical).For example, " phenyl oxygen base carbonyl " can be described to:

Term " carbocylic radical sulfenyl " (separately or with other term combination) is meant that the carbocylic radical that partly is connected via sulphur atom and parent molecule (is a carbocylic radical-S-).

Term " carbocylic radical thio alkoxy " (separately or with other term combination) is meant carbocylic radical-alkylidene group-S-.

Term " carbocylic radical thio alkoxy alkyl " (separately or with other term combination) be meant carbocylic radical-alkylidene group-S-alkylidene group-.

Term " carbocylic radical sulfenyl alkyl " (separately or with other term combination) is meant the carbocylic radical sulfenyl that partly is connected via alkylidene group and parent molecule (be carbocylic radical-S-alkylidene group-).

Term " carbocylic radical carbocylic radical " (separately or with other term combination) is meant the carbocylic radical that partly is connected via another carbocylic radical and parent molecule (be carbocylic radical-carbocylic radical-).For example, C ₃-C ₁₀Carbocylic radical C ₅-C ₇Carbocylic radical is meant via C ₅-C ₇The C that carbocylic radical and parent molecule partly are connected ₃-C ₁₀Carbocylic radical (is C ₃-C ₁₀Carbocylic radical-C ₅-C ₇Carbocylic radical-).

Term " carbocylic radical carbocylic radical alkyl " (separately or with other term combination) is meant the carbocylic radical carbocylic radical that partly is connected via alkylidene group and parent molecule.

Term " carbocylic radical alkoxyl group carbocylic radical alkyl " (separately or with other term combination) be meant carbocylic radical-alkylidene group-O-carbocylic radical-alkylidene group-.For example, C ₃-C ₁₀Carbocylic radical C ₁-C ₆Alkoxy C ₅-C ₇Carbocylic radical C ₃-C ₄Alkyl is meant C ₃-C ₁₀Carbocylic radical-C ₁-C ₆Alkylidene group-O-C ₅-C ₇Carbocylic radical-C ₃-C ₄Alkylidene group-.

Term " (carbocylic radical alkyl) carbocylic radical alkyl " (separately or with other term combination) be meant carbocylic radical-alkylidene group-carbocylic radical-alkylidene group-.For example, C ₃-C ₁₀Carbocylic radical C ₁-C ₆Alkyl C ₅-C ₇Carbocylic radical C ₃-C ₄Alkyl is meant C ₃-C ₁₀Carbocylic radical-C ₁-C ₆Alkylidene group-C ₅-C ₇Carbocylic radical-C ₃-C ₄Alkylidene group-.

Term " carbocylic radical alkoxyl group heterocyclic radical alkyl " (separately or with other term combination) be meant carbocylic radical-alkylidene group-O-heterocyclic radical-alkylidene group-.

Term " carbocylic radical carbonyl heterocyclic radical alkyl " (separately or with other term combination) be meant carbocylic radical-C (O)-heterocyclic radical-alkylidene group-.

Term " carbocylic radical heterocyclic radical alkyl " (separately or with other term combination) be meant carbocylic radical-heterocyclic radical-alkylidene group-.

Term " carbocylic radical carbonyl carbon cyclic group alkyl " (separately or with other term combination) be meant carbocylic radical-C (O)-carbocylic radical-alkylidene group-.For example, C ₃-C ₁₀Carbocylic radical carbonyl C ₄-C ₈Carbocylic radical C ₁-C ₆Alkyl is meant C ₃-C ₁₀Carbocylic radical-C (O)-C ₄-C ₈Carbocylic radical-C ₁-C ₆Alkylidene group-.

Term " (carbocylic radical alkyl) heterocyclic radical alkyl " (separately or with other term combination) is meant carbocylic radical-alkylidenyl-heterocyclic base-alkylidene group.

Term " carbonyl " (separately or with other term combination) be meant-C (O)-, it can also be described to:

Term " carboxyl " (separately or with other term combination) is meant-C (O)-OH, and it can also be described to:

Term " carboxyalkyl " (separately or with other term combination) is meant the carboxyl that partly is connected via alkylidene group and parent molecule.The representative example of carboxyalkyl includes but not limited to carboxyl methyl, 2-carboxy ethyl and 3-carboxyl propyl group.

Term " ring amino " (separately or with other term combination) is meant the heterocyclic radical part, wherein comprises at least one azo-cycle atom, and all the other annular atomses are carbon and optional nitrogen or sulphur.The limiting examples of such part comprises piperidyl, piperazinyl and thiazine group.

Term " cycloalkenyl group " (separately or with other term combination) be meant non-aromatics, the undersaturated carbocylic radical substituting group of part, it has 0 heteroatomic ring unit, and 4-18 carbocyclic ring unit usually.The representative example of cycloalkenyl group includes but not limited to cyclobutene base, cyclopentenyl, cyclohexenyl and octahydro naphthyl.

Term " cycloalkyl " (separately or with other term combination) is meant the saturated carbon cyclic group, and it has 0 heteroatomic ring unit, and 3-18 carbocyclic ring unit usually.The limiting examples of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, decahydro naphthyl and norpinanyl.

Term " naphthene base carbonyl " (separately or with other term combination) is meant the cycloalkyl that partly is connected via carbonyl and parent molecule.

Term " cyano group " (separately or with other term combination) is meant-CN that it can also be described to

Term " dialkyl amido " (separately or with other term combination) is meant-NR _AR _B, R wherein _AAnd R _BBe independently selected from alkyl.

Term " dialkyl amino carbonyl " (separately or with other term combination) is meant that the dialkyl amido that partly is connected via carbonyl and parent molecule (is N (R _AR _B)-C (O)-, R wherein _AAnd R _BBe independently selected from alkyl).

Term " formyl radical " (separately or with other term combination) is meant-C (O) H.

Term " halogen " or " halo " (separately or with other term combination) be meant fluorine (it can be described to-F), chlorine (it can be described to-Cl), bromine (it can be described to-Br) or iodine (it can be described to-I).

Prefix " halo " is meant that the substituting group that this prefix connects is replaced by one or more halogens of selecting independently.For example, " haloalkyl " (separately or with other term combination) is meant alkyl substituent, and wherein at least one hydrogen is substituted by halogen.The limiting examples of haloalkyl comprises chloromethyl, 1-bromotrifluoromethane, methyl fluoride, difluoromethyl, trifluoromethyl and 1,1,1-trifluoroethyl.Further illustrate, " halogenated alkoxy " (separately or with other term combination) is meant alkoxy substituent, and wherein at least one hydrogen is substituted by halogen.The limiting examples of halo-alkoxy substituent comprises chlorine methoxyl group, 1-bromine oxethyl, fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy (also being called " perfluoro-methyl oxygen base ") and 1,1,1 ,-trifluoro ethoxy.Will be appreciated that if substituting group is replaced by more than one halogen, then halogen can be identical or different (except as otherwise noted).

Prefix " perhalogeno " is meant that the halogen that each hydrogen on the substituting group that this prefix connects is all selected independently replaces, and promptly each hydrogen on this substituting group is all replaced by halogen.If all halogens all are identical, then prefix is determined halogen usually.Therefore, for example, term " perfluor " is meant that each hydrogen on the substituting group that this prefix connects is all replaced by fluorine.Illustrate, term " perfluoroalkyl " is meant alkyl substituent, and wherein fluorine has substituted each hydrogen.The substituent limiting examples of perfluoroalkyl comprises trifluoromethyl (CF ₃), full sec.-propyl, perfluoro butyl, perfluor decyl and perfluor osmanthus base.Further illustrate, term " perfluoro alkoxy " is meant alkoxy substituent, and wherein each hydrogen is substituted by fluorine.The substituent limiting examples of perfluoro alkoxy comprises trifluoromethoxy (O-CF ₃), perfluor isopropoxy, perfluor butoxy, perfluor oxygen in last of the ten Heavenly stems base and perfluor bay oxygen base.

Term " heterocycle " or " heterocyclic radical " or " heterocyclic radical " (separately or with other term combination) are meant saturated (for example " heterocyclic radical alkyl "), unsaturated (for example " heterocycloalkenyl " or " heterocycle alkynyl ") of part or unsaturated entirely (for example " heteroaryl ") ring system, it contains 3-18 annular atoms usually, wherein at least one annular atoms is heteroatoms (being nitrogen, oxygen or sulphur), and all the other annular atomses are independently selected from carbon, nitrogen, oxygen and sulphur.Heterocyclic radical can be connected with parent molecule via any commutable carbon or nitrogen-atoms in this group, and condition is to obtain stable molecule.

Heterocyclic radical can be but be not limited to monocycle that it (is M that described monocycle contains 3-14 annular atoms usually ₃-M ₁₄Heterocyclic radical), 3-8 annular atoms (is M ₃-M ₈Heterocyclic radical), 3-6 annular atoms (is M ₃-M ₆Heterocyclic radical) or 5-6 annular atoms (be M ₅-M ₆Heterocyclic radical).The limiting examples of monocyclic heterocycles base comprises furyl, the dihydrofuran base, tetrahydrofuran base, pyrryl, different pyrryl, pyrrolinyl, pyrrolidyl, imidazolyl, different imidazolyl, imidazolinyl, imidazolidyl, pyrazolyl, pyrazolinyl, pyrazolidyl, triazolyl, tetrazyl, the dithiole base, oxygen thia cyclopentenyl oxazolyl isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, the isothiazoline base, thiazolidyl, the isothiazole alkyl, thiadiazolyl group Evil thiazolyl oxadiazole base (comprises 1,2,3-oxadiazole base, 1,2,4-oxadiazole base (also being called " azoximyl "), 1,2,5-oxadiazole base (also being called " furazan base ") and 1,3,4-oxadiazole base) oxatriazole base (comprises 1,2,3,4-oxatriazole base and 1,2,3,5-oxatriazole base) Er oxazolyl (comprises 1,2,3-Er oxazolyl, 1,2,4-Er oxazolyl, 1,3,2-Er oxazolyl and 1,3,4-Er oxazolyl), the oxathiolane base, pyranyl (comprises 1,2-pyranyl and 1, the 4-pyranyl), dihydro pyranyl, pyridyl, piperidyl, diazine (comprises pyridazinyl (also being called " 1; the 2-diazine "), pyrimidyl (also being called " 1; the 3-diazine ") and pyrazinyl (also being called " 1; the 4-diazine ")), piperazinyl, triazinyl (comprises s-triazinyl (also being called " 1; 3; the 5-triazinyl "), the as-triazinyl (also is called 1,2, the 4-triazinyl) and v-triazinyl (also being called " 1; 2; the 3-triazinyl ") oxazinyl (comprise 1,2, the 3-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl (also being called " pentoxazolyl "), 1,2,6-oxazinyl and 1, the 4-oxazinyl) oxazinyl (comprising Lin Yi oxazinyl and Dui Yi oxazinyl) oxazolidinyl isoxazole alkyl Evil thiazinyl (comprises 1,2,5-Evil thiazinyl or 1,2,6-Evil thiazinyl) oxadiazine base (comprises 1,4,2-oxadiazine base and 1,3,5,2-oxadiazine base), morpholinyl, azepine

Base, oxa-

Base, thia Base and diaza

Base.

Heterocyclic radical can also include but not limited to condense two or more rings together, for example, phthalazinyl (comprises [1,8] phthalazinyl and [1,6] phthalazinyl), thiazole and pyrimidyl, the Thienopyrimidine base, the Mi Dingbing pyrimidyl, the Pyridopyrimidine base, the pyrazolopyrimidine base, the indolizine base, pyrindine base (pyrindinyl), pyrans and pyrryl, the 4H-quinolizinyl, purine radicals, the pyridopyridine base (comprises pyrido [3,4-b]-pyridyl, pyrido [3,2-b]-pyridyl and pyrido [4,3-b]-pyridyl), Pyridopyrimidine and pteridyl.Other limiting examples of fused rings heterocyclic radical comprise the benzo-fused heterocycle base, indyl for example, pseudoindoyl, pseudoindolyl (also being called " pseudoindolyl "), iso indazolyl (also being called " benzopyrazoles base "), benzo azine group (comprising quinolyl (also being called " 1-benzo azine group ") and isoquinolyl (also being called " 2-benzo azine group ")), phthalazinyl, quinoxalinyl, benzodiazine base (comprising cinnolines base (also being called " 1; 2-benzodiazine base ") and quinazolyl (also being called " 1; 3-benzodiazine base ")), benzopyranyl (comprising " chromenyl " and " heterochromatic thiazolinyl "), benzo thiapyran base (also being called " benzothiopyran base ") benzoxazolyl Yin oxazinyl (indoxazinyl) (also being called " benzoisoxazole base "), the adjacent first lactam group (anthranilyl) of benzene, the benzodioxole base, benzo dioxane base Ben Bing oxadiazole base, benzofuryl (also being called " tonka-bean ketone group "), isobenzofuran-base, benzothienyl (also is called " benzothienyl ", " thianaphthenyl " and " benzothienyl "), isobenzo-thienyl (also is called " isobenzo-thienyl ", " isothianaphthene base " and " isobenzo-thienyl "), benzothiazolyl, the diazosulfide base, benzimidazolyl-, benzotriazole base benzoxazinyl (comprises 1,3, the 2-benzoxazinyl, 1,4, the 2-benzoxazinyl, 2,3,1-benzoxazinyl and 3,1, the 4-benzoxazinyl), Ben Bing Yi oxazinyl (comprises 1,2-Ben Bing Yi oxazinyl and 1,4-Ben Bing Yi oxazinyl), tetrahydro isoquinolyl, carbazyl, xanthenyl and acridyl.

Term " two fused rings " heterocyclic radical (separately or with other term combination) is meant that containing two condenses ring filling, fractional saturation or aromatic heterocyclic radical.The limiting examples of two fused rings heterocyclic radicals comprises that phthalazinyl (comprises [1,8] phthalazinyl and [1,6] phthalazinyl), thiazole and pyrimidyl, the Thienopyrimidine base, the Mi Dingbing pyrimidyl, the Pyridopyrimidine base, the pyrazolopyrimidine base, the indolizine base, pyrindine base (pyrindinyl), pyrans and pyrryl, the 4H-quinolizinyl, purine radicals, the pyridopyridine base, pteridyl, indyl, pseudoindoyl, pseudoindolyl, iso indazolyl, the benzo azine group, phthalazinyl, quinoxalinyl, quinazolyl, the benzodiazine base, benzopyranyl, benzo thiapyran base benzoxazolyl Yin oxazinyl (indoxazinyl), the adjacent first lactam group (anthranilyl) of benzene, the benzodioxole base, benzo dioxane base Ben Bing oxadiazole base, benzofuryl, isobenzofuran-base, benzothienyl, isobenzo-thienyl, benzothiazolyl, the diazosulfide base, benzimidazolyl-, benzotriazole base benzoxazinyl, Ben Bing Yi oxazinyl and tetrahydro isoquinolyl.

Heterocyclic radical can comprise one or more sulphur atoms as ring element; In some cases, sulphur atom is oxidized to SO or SO ₂Nitrogen heteroatom in the heterocyclic radical can or cannot be by quaternized, and can maybe cannot be oxidized to the N-oxide compound.In addition, nitrogen heteroatom can maybe cannot be a N-protected.

As used in this article, the number of annular atoms can pass through prefix " M in the heterocyclic radical part _x-M _y, " expression, wherein x is the minimal number of annular atoms in the heterocyclic radical part, y is a maximum number.

Term " heterocyclic radical alkoxyl group " (separately or with other term combination) is meant the heterocyclic radical alkyl that partly is connected via oxygen base and parent molecule.

Term " heterocyclic radical alkoxyalkyl " (separately or with other term combination) is meant the heterocyclic radical alkoxyl group that partly is connected via alkylidene group and parent molecule (be heterocyclic radical-alkylidene group-O-alkylidene group-).

Term " heterocyclic radical alkoxy carbonyl " (separately or with other term combination) is meant the heterocyclic radical alkoxyl group that partly is connected via carbonyl and parent molecule (be heterocyclic radical-alkylidene group-O-C (O)-).

Term " heterocyclic radical alkyl " (separately or with other term combination) is meant the heterocyclic radical that partly is connected via alkylidene group and parent molecule (heterocyclic radical C for example ₁-C ₆Alkyl).

Term " heterocyclic radical alkyl-carbonyl " (separately or with other term combination) is meant the heterocyclic radical alkyl that partly is connected via carbonyl and parent molecule (promptly-C (O)-alkylidenyl-heterocyclic base).

Term " heterocyclic radical carbonyl " (separately or with other term combination) is meant the heterocyclic radical that partly is connected via carbonyl and parent molecule (promptly-C (O)-heterocyclic radical).

Term " heterocyclyloxy base " or " (heterocyclic radical) oxygen base " (separately or with other term combination) are meant the heterocyclic radical that partly is connected via oxygen base and parent molecule.

Term " (heterocyclic radical) oxygen base alkyl " (separately or with other term combination) is meant the heterocyclyloxy base that partly is connected via alkylidene group and parent molecule (be heterocyclic radical-O-alkylidene group-).

Term " (heterocyclic radical) oxygen base carbonyl " (separately or with other term combination) is meant (heterocyclic radical) oxygen base of partly being connected via carbonyl and parent molecule (be heterocyclic radical-O-C (O)-).

Term " heterocyclic radical sulfenyl " (separately or with other term combination) is meant the heterocyclic radical that partly is connected via-S-and parent molecule.

Term " heterocyclic radical thio alkoxy " (separately or with other term combination) is meant heterocyclic radical-alkylidene group-S-.

Term " heterocyclic radical thio alkoxy alkyl " (separately or with other term combination) be meant heterocyclic radical-alkylidene group-S-alkylidene group-.

Term " heterocyclic radical sulfenyl alkyl " (separately or with other term combination) is meant the heterocyclic radical sulfenyl that partly is connected via alkylidene group and parent molecule (be heterocyclic radical-S-alkylidene group-).

Term " heterocyclic radical carbocylic radical " (separately or with other term combination) is meant the heterocyclic radical that partly is connected via carbocylic radical and parent molecule (be heterocyclic radical-carbocylic radical-).

Term " heterocyclic radical carbocylic radical alkyl " (separately or with other term combination) is meant the heterocyclic radical carbocylic radical that partly is connected via alkylidene group and parent molecule (be heterocyclic radical-carbocylic radical-alkylidene group-).

Term " (heterocyclic radical) alkoxyl group carbocylic radical alkyl " (separately or with other term combination) be meant heterocyclic radical-alkylidene group-O-carbocylic radical-alkylidene group-.

Term " (heterocyclic radical) carbonyl carbon cyclic group alkyl " (separately or with other term combination) be meant heterocyclic radical-C (O)-carbocylic radical-alkylidene group-.

Term " (heterocyclic radical) heterocyclic radical alkyl " (separately or with other term combination) be meant heterocyclic radical-heterocyclic radical-alkylidene group-.

Term " (heterocyclic radical) alkoxyl group heterocyclic radical alkyl " (separately or with other term combination) be meant heterocyclic radical-alkylidene group-O-heterocyclic radical-alkylidene group-.

Term " (heterocyclic radical) carbonyl heterocyclic radical alkyl " (separately or with other term combination) be meant heterocyclic radical-C (O)-heterocyclic radical-alkylidene group-.

Term " (heterocyclic radical alkyl) carbocylic radical alkyl " (separately or with other term combination) be meant heterocyclic radical-alkylidene group-carbocylic radical-alkylidene group-.

Term " (heterocyclic radical alkyl) heterocyclic radical alkyl " (separately or with other term combination) be meant heterocyclic radical-alkylidenyl-heterocyclic base-alkylidene group-.Therefore, for example, (M ₃-M ₁₀Heterocyclic radical C ₁-C ₆Alkyl) M ₅-M ₆Heterocyclic radical C ₁-C ₃Alkyl is meant M ₃-M ₁₀Heterocyclic radical-C ₁-C ₆Alkylidene group-M ₅-M ₆Heterocyclic radical-C ₁-C ₃Alkylidene group-.

Term " heteroaryl " (separately or with other term combination) is meant the aromatic heterocyclic radical that contains 5-18 annular atoms usually.Heteroaryl can be a monocycle, or two or more fused rings.The limiting examples of 5 yuan of heteroaryls comprises imidazolyl; Furyl; Thienyl (or thienyl or thienyl); Pyrazolyl; Oxazolyl; Isoxazolyl; Thiazolyl; 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,2,5-oxadiazole base and 1,3,4-oxadiazole base; And isothiazolyl.The limiting examples of 6 yuan of heteroaryls comprises pyridyl; Pyrazinyl; Pyrimidyl; Pyridazinyl and 1,3,5-triazines base, 1,2,4-triazinyl and 1,2,3-triazinyl.The limiting examples of 6/5-unit fused ring heteroaryl comprises the adjacent first lactam group (anthranilyl) of benzothienyl, isobenzo-thienyl, benzoisoxazole base, benzoxazolyl, purine radicals and benzene.The limiting examples of 6/6-unit fused ring heteroaryl comprises quinolyl; Isoquinolyl; And benzoxazinyl (comprising cinnolines base and quinazolyl).

Term " heteroaryl alkoxyl group " (separately or with other term combination) is meant that the heteroarylalkyl that partly is connected via oxygen base and parent molecule (is heteroaryl-alkylidene group-O-).The representative example of heteroaryl alkoxyl group includes but not limited to 2-pyridin-3-yl oxyethyl group, 1,3-thiazoles-5-ylmethoxy, 3-quinoline-3-base propoxy-and 5-pyridin-4-yl amyl group oxygen base.

Term " heteroaryl alkoxyalkyl " (separately or with other term combination) is meant the heteroaryl alkoxyl group that partly is connected via alkylidene group and parent molecule (be heteroaryl-alkylidene group-O-alkylidene group-).The representative example of heteroaryl alkoxyalkyl includes but not limited to (2-pyridin-3-yl oxyethyl group) methyl, (3-quinoline-3-base propoxy-) methyl, (1,3-thiazoles-5-ylmethoxy) methyl and 2-(5-pyridin-4-yl amyl group oxygen base) ethyl.

Term " heteroaryl alkoxy carbonyl " (separately or with other term combination) is meant the heteroaryl alkoxyl group that partly is connected via carbonyl and parent molecule (be heteroaryl-alkylidene group-O-C (O)-).The representative example of heteroaryl alkoxy carbonyl includes but not limited to (2-pyridin-3-yl oxyethyl group) carbonyl, (3-quinoline-3-base propoxy-) carbonyl, 2-(1,3-thiazoles-5-ylmethoxy) carbonyl and (5-pyridin-4-yl amyl group oxygen base) carbonyl.

Term " heteroarylalkyl " (separately or with other term combination) is meant the heteroaryl that partly is connected via alkylidene group and parent molecule.The representative example of heteroarylalkyl includes but not limited to 3-quinolyl methyl, 3-pyridylmethyl, 4-pyridylmethyl, 1H-imidazol-4 yl methyl, 1H-pyrroles-2-ylmethyl, pyridin-3-yl methyl and 2-pyrimidine-2-base propyl group.

Term " heteroarylalkyl carbonyl " (separately or with other term combination) is meant the heteroarylalkyl that partly is connected via carbonyl and parent molecule (be heteroaryl-alkylidene group-C (O)-).

Term " heteroaryl carbonyl " (separately or with other term combination) is meant the heteroaryl that partly is connected via carbonyl and parent molecule.The representative example of heteroaryl carbonyl includes but not limited to pyridin-3-yl carbonyl, (1,3-thiazoles-5-yl) carbonyl and quinoline-3-base carbonyl.

Term " heteroaryloxy " (separately or with other term combination) is meant the heteroaryl that partly is connected via oxygen base and parent molecule.The representative example of heteroaryloxy includes but not limited to pyridin-3-yl oxygen base and quinoline-3-base oxygen base.

Term " heteroaryloxy alkyl " (separately or with other term combination) is meant the heteroaryloxy that partly is connected via alkylidene group and parent molecule (be heteroaryl-O-alkylidene group-).

Term " heteroaryloxy carbonyl " (separately or with other term combination) is meant the heteroaryloxy that partly is connected via carbonyl and parent molecule (be heteroaryl-O-C (O)-).

Term " heteroaryl sulfenyl " (separately or with other term combination) is meant the heteroaryl that partly is connected via-S-and parent molecule.

Term " heteroaryl thio alkoxy " (separately or with other term combination) is meant heteroaryl-alkylidene group-S-.

Term " heteroaryl thio alkoxy alkyl " (separately or with other term combination) be meant heteroaryl-alkylidene group-S-alkylidene group-.

Term " heteroaryl sulfenyl alkyl " (separately or with other term combination) is meant the heteroaryl sulfenyl that partly is connected via alkylidene group and parent molecule (be heteroaryl-S-alkylidene group-).

Term " hydrogen " (separately or with other term combination) is meant hydrogen group, and can be described as-H.

Term " hydroxyl " (separately or with other term combination) is meant-OH.

Term " hydroxyalkyl " (separately or with other term combination) is meant alkyl substituent, and wherein one or more hydrogen quilt-OH are alternative.The representative example of hydroxyalkyl includes but not limited to hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and 2-ethyl-4-hydroxyl heptyl.

Term " ketone group " (separately or with other term combination) is meant the oxo base, and can be described to=O.

Term " imino alkyl " (separately or with other term combination) is meant the group of following formula:

Wherein H can choose wantonly by alkyl or hydroxyl and replace, and in this case, substituting group will be alkyl imino alkyl or oxyimino alkyl respectively.

Term " nitro " (separately or with other term combination) is meant-NO ₂

Term " oxo base " (separately or with other term combination) is meant=the O part is (promptly ).

Term " oxygen base " (separately or with other term combination) is meant-O-.

Term " propargyl " (separately or with other term combination) is meant and is described to-CH ₂The monoradical of-CH ≡ CH.

Term " alkylsulfonyl " (separately or with other term combination) is meant-S (O) ₂-, it can also be described to:

Term " sulfinyl " (separately or with other term combination) be meant-S (O)-, it can also be described to:

Term " sulfenyl " or " thia " (separately or with other term combination) are meant-S-.

Term " mercaptan ", " sulfydryl " or " sulfydryl " (separately or with other term combination) are meant the sulfydryl substituting group (promptly-SH).Therefore, for example, mercaptoalkyl is meant alkyl substituent, and wherein one or more hydrogen quilt-SH substitute, and the alkyl sulfenyl is meant alkyl-S-.

Term " thio alkoxy " (separately or with other term combination) is meant the alkyl that partly is connected via-S-and parent molecule.The representative example of thio alkoxy includes but not limited to methyl sulfenyl, ethyl sulfenyl and butyl sulfenyl.

Term " thio alkoxy alkyl " (separately or with other term combination) is meant the thio alkoxy that partly is connected via alkylidene group and parent molecule (be alkyl-S-alkylidene group-).

Term " thiocarbonyl " (separately or with other term combination) is meant carbonyl, and wherein Sauerstoffatom is substituted by sulphur.Such substituting group can be described to-C (S)-, and can be described to:

Term " pharmaceutically acceptable " uses as adjective and is meant that the noun of modification is suitable for use as the part of medicament production or medicament production.

Term " treatment significant quantity " is meant and is enough to show significant patient's benefit, for example the total amount of each active substance of descending of virus load.

Term " prodrug " is meant the derivative of The compounds of this invention, and it has can chemistry or metabolism cracked group, and is transformed into the The compounds of this invention that has pharmacologically active in vivo by solvolysis or under physiological condition.The prodrug of compound be the functional group (for example amino, hydroxyl or carboxyl) by compound reaction and with the ordinary method preparation.The prodrug derivant form often provides following advantage: solvability, histocompatibility or delay release in mammalian organism (referring to, Bungard, H.,

, pp.7-9,21-24, Elsevier, Amsterdam1985).Prodrug comprises the well-known acid derivative of those skilled in the art, for example, and by ester with female acidic cpd and suitable pure prepared in reaction, or the acid amides by female acidic cpd and suitable amine reaction are made.The example of prodrug includes but not limited to the alcohol in the The compounds of this invention or acetic ester or salt, manthanoate or salt, benzoic ether or salt or other acylated derivatives of amine functional group.

Term " solvate " is meant the physics association body of The compounds of this invention and one or more organic or inorganic solvent molecules.This physics associates and often comprises hydrogen bond.In some cases, solvate can be separated, for example, and when one or more solvent molecules are incorporated in the lattice of solid crystal." solvate " comprises solution phase and separable solvate.The exemplary solvent thing includes but not limited to hydrate, ethylate and methylate.

Term " chirality " be meant do not have symmetrical plane and therefore can not with its mirror image eclipsed molecule.Chiral molecules can exist with two kinds of forms, and a kind of is right-hand lay, a kind of be left-hand to.

Term " steric isomer " is meant to have with identical sequence and connects, but the isomer with different three-dimensional arrangement.The term steric isomer comprises for example enantiomorph and diastereomer.

Term " cis-trans isomer " is meant the different steric isomer of stereochemistry around two keys or ring.The cis-trans isomer is also referred to as geometrical isomer.

Term " enantiomorph " is meant the steric isomer of the chiral material with mirror.

Term " diastereomer " is meant the steric isomer that is not enantiomorph or mirror images of each other.

Term " racemic mixture " is meant the mixture by (+) and (-) enantiomorph of the chiral material of equal portions.Though independent molecule is a chirality, racemic mixture does not have optically-active.

Term " tautomer " is meant the isomer that can transform mutually.For example, enol and ketone are tautomers, because by using acid or alkaline purification, they can transform mutually.

Term " positional isomers " is meant two or more composition isomer that the position of specified substituent or group is different.Functional group connects on can be in the structure of the carbon skeleton different position.For example, [1,3] imidazoles is described as [1,4] imidazoles is described as

It is positional isomers.

Term " N-protected base " or " N-protected " are meant can protect the amino group that undesirable reaction does not take place.N-protected base commonly used is described in Greene and Wuts,

(3 ^RdEd., John Wiley ﹠amp; Sons, among the NY (1999), it is incorporated herein by reference.The limiting examples of N-protected base comprises acyl group for example formyl radical, ethanoyl, propionyl, valeryl, tertiary butyl ethanoyl, 2-chloracetyl, 2-acetyl bromide, trifluoroacetyl group, tribromo-acetyl base, phthaloyl, ortho-nitrophenyl oxygen base ethanoyl, benzoyl, 4-chlorobenzene formacyl, 4-benzoyl bromide or 4-nitro benzoyl; Alkylsulfonyl is benzenesulfonyl or p-toluenesulfonyl for example; Sulfenyl is phenyl sulfenyl (phenyl-S-) or trityl group sulfenyl (trityl-S-) for example; Sulfinyl is p-methylphenyl sulfinyl (p-methylphenyl-S (O)-) or tertiary butyl sulfinyl (t-Bu-S (O)-) for example; Carbamate forms for example benzyloxycarbonyl of group, to the chlorine benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl, to the nitro benzyloxycarbonyl, 2-nitro benzyloxycarbonyl, to the bromo-benzyloxy-carbonyl, 3,4-dimethoxy benzyloxycarbonyl, 3,5-dimethoxy benzyloxycarbonyl, 2,4-dimethoxy benzyloxycarbonyl, 4-methoxyl group benzyloxy base carbonyl, 2-nitro-4,5-dimethoxy benzyloxycarbonyl, 3,4,5-trimethoxy benzyloxycarbonyl, 1-(to biphenyl)-1-methyl ethoxy carbonyl, dimethyl-3,5-dimethoxy benzyloxycarbonyl, diphenyl-methyl oxygen base carbonyl, tertiary butyl oxygen base carbonyl, the di-isopropyl methoxycarbonyl, sec.-propyl oxygen base carbonyl, ethoxy carbonyl, methoxycarbonyl, allyloxy carbonyl, 2,2,2-three chloro-oxyethyl group-carbonyls, phenyloxycarbonyl, 4-nitro-phenyloxycarbonyl, fluorenyl-9-methoxycarbonyl, the cyclopentyloxy carbonyl, adamantyl oxygen base carbonyl, cyclohexyl oxygen base carbonyl or thiophenyl carbonyl; Alkyl for example benzyl, to methoxy-benzyl, trityl group or benzyloxymethyl; P-methoxyphenyl; With silyl trimethyl silyl for example.Preferred N-protected base comprises formyl radical, ethanoyl, benzoyl, valeryl, tertiary butyl ethanoyl, phenyl sulfonyl, benzyl, tertiary butyl oxygen base carbonyl (Boc) and benzyloxycarbonyl (Cbz).

Use following abbreviation among general synthetic method that is described below and the embodiment:

AcOH=acetate

The atm=normal atmosphere

Boc=N-tert-butoxycarbonyl (protecting group)

CDI=1,1 '-carbonyl dimidazoles

CH ₂Cl ₂=methylene dichloride (dichloro-methane)

The inferior ketone [cupric iodide (I)] of CuI=iodate

DCE=1, the 2-ethylene dichloride

The DEAD=diethyl azodiformate

The DMA=N-N-N,N-DIMETHYLACETAMIDE

The DMAP=4-dimethyl aminopyridine

DMF=N, dinethylformamide

The DMSO=methyl-sulphoxide

EDCI=(N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide hydrochloride

EMME=2-oxyethyl group methylene radical-diethyl malonate

Et ₃The N=triethylamine

The Ether=ether

The EtI=iodoethane

The EtOAc=ethyl acetate

EtOH=ethanol

Fe=iron

Fe (AcAc) 3=Acetyl Acetone iron (III)

Fmoc muriate=chloroformic acid 9-fluorenyl methyl ester

The HOBt=N-hydroxybenzotriazole

Hunig ' s alkali=N, the N-diisopropylethylamine

The IPA=Virahol

K ₂CO ₃=salt of wormwood

KOH=potassium hydroxide

The LDA=diisopropylamine lithium

MeOH=methyl alcohol

The MsCl=methylsulfonyl chloride

The NaH=sodium hydride

NH ₂The OHHCl=hydroxy amine hydrochloric acid salt

The NMP=1-N-methyl-2-2-pyrrolidone N-

Mg ₂SO ₄=sal epsom

Na ₂SO ₄=sodium sulfate

NH ₃=ammonia

NH ₄Cl=ammonium chloride

NH ₄OH=ammonium hydroxide

The PG=protecting group is Boc-or Troc-for example

POCl ₃=phosphoryl chloride

The R-MgCl=grignard reagent

The alkyl iodide of R-I=alkyl iodide or replacement

SnCl2=tin protochloride (tin chloride (II))

The TFA=trifluoroacetic acid

The THF=tetrahydrofuran (THF)

The TLC=thin-layer chromatography

Trifluoromethanesulfanhydride anhydride=Trifluoromethanesulfonic anhydride

Troc=2,2,2-trichlorine ethoxy carbonyl-(protecting group)

General synthetic method and embodiment

Following synthetic method and reaction scheme are for example understood the general method that can prepare The compounds of this invention.Raw material can or use the well-known method of those skilled in the art to make by the commercial source acquisition.For example, can use to be similar to route of synthesis given below, and the known synthetic method in synthetic organic chemistry field, or its modification, this is that those skilled in the art understand.

The present invention includes the compound that comprises by synthetic method or metabolic process preparation.Metabolic process comprise be included in take place in the human or animal body (body in) those or ectogenetic those.

If substituting group described herein is incompatible with synthetic method of the present invention, can be stable under the reaction conditions that described substituting group uses in these methods with substituting group with suitable protecting group protection.Can in reaction sequence, proper time point remove protecting group so that required intermediate or target compound to be provided.Suitable protecting group is well-known in the art with being used for protection or the substituent method of deprotection, and the example can be referring to Greene and Wuts above.

Preparation 7-replacement-4-replacement-[1,8] naphthyridine compounds

Can pass through will

Or With

Reaction comes synthesis type I (a) or I (b) compound, wherein A, X, Y, R ¹⁰, R ¹⁷, R ²², R ³¹, R ³³, R ³⁸And R ⁵⁰Have the implication that provides in top embodiment or the example, and K is Cl or another kind of halogen.Equally, formula II (a) or II (b) compound synthetic comprise with

Or

With

Reaction, wherein R ², R ³, R ⁷, R ⁹, R ¹¹, R ¹²And R ¹³Have the implication that provides in top embodiment or the example, and K is Cl or another kind of halogen.It shown in the following reaction scheme 1,2,3 and 4 exemplary process of these [1,8] naphthyridine-compounds of preparation.

7-replacement-4-replacement-[1,8] naphthyridine compounds generally is by with 7-replacement-4-chloro-[1,8] naphthyridine compounds 8 and coupling compound for example 10,11 and 12 (reaction scheme 3) couplings and synthetic (reaction scheme 4).Other 4-replace [1,8] naphthyridine compounds and can use suitable coupling compound to make by similar approach.

Preparation 6-replacement-2-aminopyridine

In typical case's preparation of describing in reaction scheme 1, in the metallic reactors of sealing, with 2, the solution of 6-dichloropyridine was handled about 40 hours at about 180 ℃ with ammonium hydroxide.After being cooled to room temperature, product is filtered, obtained 6-chloro-2-aminopyridine.With this product and hexane-2, the solution of 5-diketone in benzene about 20 hours, heating under refluxad, azeotropic removal of water with acetic acid treatment.This reaction mixture is cooled to room temperature, with the ether dilution, with dilute hydrochloric acid and water washing.With the organic layer dried over mgso, filter and vacuum concentration, obtained 6-chloro-2-(2,5-dimethyl-pyrroles-1-base-pyridine.Compound 1 usefulness grignard reagent (R-MgX) is handled under room temperature and nitrogen atmosphere in anhydrous tetrahydro furan (THF) and 1-Methyl-2-Pyrrolidone (NMP), added acetopyruvic acid iron (III) [Fe (AcAc) ₃], and with this mixture in stirring at room about 18 hours.During reaction, add grignard reagent twice, and add iron catalyst.Come stopped reaction by pouring in 5% acetate, and use extracted with diethyl ether.With the ether layer dried over sodium sulfate, filter and vacuum concentration, obtained 6-replacement-2-(2,5-dimethyl-pyrroles-1-yl)-pyridine 2.Compound 2 can be directly changed into 6-replacement-2-aminopyridine 4, perhaps can be by the following method that it is further functionalized: in the presence of lithium diisopropylamine (LDA), with the alkyl iodide reaction of itself and alkyl iodide or replacement.In this case, at-30 ℃, the drips of solution of compound 2 in anhydrous tetrahydro furan is added in the solution that is stirring of lithium diisopropylamine in anhydrous tetrahydro furan with 30 minutes.With the solution of alkyl iodide (R-I) in tetrahydrofuran (THF) that dripped alkyl iodide or replacement in about 30 minutes, be warmed to room temperature afterwards then.After 2 hours, come stopped reaction in the saturated nacl aqueous solution by pouring into, and use extracted with diethyl ether.With this diethyl ether solution dried over mgso, filter and vacuum concentration, obtained 6-replacement-2-(2,5-dimethyl-pyrroles-1-yl) pyridine 3.With compound 2 or 3 and the solution of hydroxy amine hydrochloric acid salt in the second alcohol and water in about 100 ℃ the heating about 16 hours, be cooled to room temperature, and use dichloromethane extraction, use dried over mgso, filter and vacuum concentration, obtained 6-replacement-aminopyridine 4, it is used for reaction scheme 2.6-substituting group in the reaction scheme 1 is aforesaid R ⁷

Reaction scheme 1

Preparation 7-replacement-4-chloro-[1,8] naphthyridine

Typical case's preparation of describing in the reaction scheme 2 comprises the 2-aminopyridine 4 of 6-replacement is mixed with 2-oxyethyl group methylene radical-diethyl malonate (EMME), and under agitation heated about 2.5 hours in about 100 ℃.This reaction mixture is cooled to room temperature, with the hexane dilution, with the gained solid filtering, and vacuum-drying, obtained aminomethylene malonic ester 5.Then compound 5 is dissolved in the diphenyl ether, gained solution was heated about 30 minutes at 250 ℃.After being cooled to room temperature,, filter out the gained solid with the hexane dilution, and vacuum-drying, the 7-replacement-4-oxo-1 that replaces obtained, 4-dihydro-[1,8] naphthyridine-3-ethyl formate " E ".With the solution of compound 6 and potassium hydroxide (KOH) in the metallic reactors of sealing in about 16 hours of 180 ℃ of heating, be cooled to room temperature, and be adjusted to pH6 with 1N hydrochloric acid.Filter out the gained precipitation, and dry, obtained 7-replacement [1,8] naphthyridine-4-alcohol 7.Mixture and phosphoryl chloride (POCl with compound 7 ₃) mix, and, carry out cooling process in the ice by pouring under agitation in about 50 ℃ of heating 6 hours.After the cooling, use dense ammonium hydroxide to be adjusted to pH 10, and use dichloromethane extraction, use anhydrous sodium sulfate drying, filter and vacuum concentration, obtained 7-replacement-4-chloro-[1,8] naphthyridine 8.The substituting group of compound 8 R that conduct has been described in the above in reaction scheme 2 ⁷Show.

Reaction scheme 2

Preparation aminophenyl coupling agent (10,11 and 12)

Multiple different aminophenyl coupling agent is possible.Coupling agent in the reaction scheme 3 is the example of these multiple coupling agents.

In typical preparation, at about 50 ℃, the 2-chloro-nitrobenzene compound that replaces was handled about 2 hours with thiophenol sodium in dimethyl formamide (DMF), cooling, and with the methylene dichloride dilution, wash with water, use dried over sodium sulfate, filter and vacuum concentration, obtained the 2-phenyl sulfenyl-nitrobenzene compound that replaces.Then with this nitro-compound tin protochloride (SnCl ₂) or iron (Fe) in ethanol, reduce.With 1N sodium hydroxide this reaction mixture is adjusted to pH 12, uses ethyl acetate extraction, use dried over sodium sulfate, filter and vacuum concentration, obtained the 2-phenyl sulfenyl-amino-benzene compound 10 that replaces.

Similarly, the 2-hydroxyl-nitrobenzene compound that replaces accordingly is dissolved in the dimethyl formamide,, stirs and about 5 days of 100 ℃ of heating with the sodium phenylate solution reaction.With this compound of reaction cooling, and, wash with water, use dried over sodium sulfate, filter and vacuum concentration, obtained the 2-phenoxy group-nitrobenzene compound that replaces with the methylene dichloride dilution.Then with this nitro-compound tin protochloride (SnCl ₂) and iron (Fe) in ethanol, reduce.Use 1N sodium hydroxide that this reaction mixture is adjusted to pH 12, use ethyl acetate extraction, use dried over sodium sulfate, filter and vacuum concentration, obtained the 2-phenoxy group-amino-benzene compound 12 that replaces.

Similarly, can be by the bromotoluene that use to replace with hydroxy alkylated with R wherein ⁹The compound 10 that is the hydroxyl of hydroxyl or protection is further modified, to generate corresponding 5-replacement-phenoxy group-2-substituted 4-phenyl sulfenyl-amino-benzene compound 11.

Reaction scheme 3

R ⁹As defined above;

X is OH, NH ₂, NHR, halogen, alkyl or alkoxyl group

R is alkyl, alkoxyl group, bromine, fluorine, chlorine or cyano group

Preparation 7-substituted-4-amino phenyl-[1,8] naphthyridine

As shown in reaction scheme 4, the coupling agent (compound 10,11,12 etc.) that will be suitable for synthetic required 7-substituted-4-amino phenyl-[1,8] naphthyridine is dissolved in the ethanol, and reacts about 7 hours in 80 ℃ in ethanol with compound 8.With this reaction mixture vacuum concentration, and from the tetrahydrofuran (THF) that contains several methyl alcohol recrystallization.Filter, obtained required 7-substituted-4-amino phenyl-[1,8] naphthyridine 13,14 or 15.

Reaction scheme 4

R ⁹As defined above;

X as defined above;

R as defined above

Preparation acid amides coupling agent

Described in reaction scheme 3, multiple different aminophenyl coupling agent is possible.Method according to describing in the reaction scheme 4 can be used to these aminophenyl coupling agents prepare required 7-substituted-4-amino phenyl-[1,8] naphthyridine.

In reaction scheme 5, the aminophenyl compound that has the acid amides replacement on 3-phenyl position has been described.

With 4-chloro-3-nitrobenzoyl chloride and N, the N-diisopropylamine is handled with the aniline of the replacement in the methylene dichloride, and in stirring at room about 17 hours.Solvent removed in vacuo is dissolved in resistates in the ethyl acetate, and dried over sodium sulfate is used in water and salt water washing, filters and vacuum concentration, has obtained N-substituted-phenyl-4-chloro-3-nitrobenzamide 16.

Can come further modified compound 16 by displacement 4-cl radical, to generate 3-amino-4-substituted benzene oxygen yl-benzamide 17 and 3-amino-4-substituted-phenyl sulfenyl benzamide 18.

Compound 17 generally can make like this: with benzamide 16 at anhydrous N, in the dinethylformamide with 4-(N-tert-butoxycarbonyl) amino-phenol (N-Boc-4-hydroxyanilines) and salt of wormwood in room temperature reaction, then about 5 hours of about 80 ℃ of heating.This reaction is cooled to room temperature, and solvent removed in vacuo places ethyl acetate to resistates, water and salt water washing.With the organic layer dried over sodium sulfate, filter and vacuum concentration, obtained 4-N-tert-butoxycarbonyl amino-substituted compounds 17.Can remove the compound of Boc protecting group by several different methods with production 17.

In a similar manner, compound 16 and 4-aminothiophenol and anhydrous sodium acetate can be reacted in dehydrated alcohol, heating is about 19 hours under reflux state.After being cooled to room temperature, vacuum is removed ethanol, and resistates is placed water, and uses ethyl acetate extraction.With organic extract liquid salt water washing, use dried over sodium sulfate, filter and vacuum concentration.With ethyl acetate-methylene dichloride development, obtained compound 18.

Reaction scheme 5

Acid amides benzyl ring, phenoxy group ring and phenyl sulfenyl ring can be substituted as mentioned above.Some example will need to use protecting group, and remove protecting group in the suitable time subsequently.

R as defined above.

Prepare reverse acid amides coupling agent

Shown the preparation of reverse acid amides coupling agent in the reaction scheme 6.In typical case preparation, with the Benzoyl chloride of 4-fluoro-3-N-methyl-p-nitroaniline and replacement, Hunig ' s alkali (N, N-diisopropylethylamine) in tetrahydrofuran (THF) under stirring about 1 hour at room temperature reaction.In this solution, add entry, and collect gained solid (compound 19) by filtering, dry in vacuum drying oven.

At N, the solution in the dinethylformamide was in about 2 hours of about 80 ℃ of heating with compound 19,4-hydroxythiophenol and salt of wormwood.After being cooled to room temperature, this mixture is poured in the frozen water, used ethyl acetate extraction,, filter and vacuum concentration, obtained 4-hydroxy phenyl sulfenyl intermediate the extraction liquid dried over mgso.With about 3 hours of this intermediate, iron powder and the ammonium chloride vlil in tetrahydrofuran (THF) and water.With the cooling of gained mixture, with methyl alcohol dilution and filtration.With the filtrate water dilution, and use dichloromethane extraction.With dichloromethane extraction liquid dried over mgso, filter and vacuum concentration, obtained the 4-hydroxy analogs of compound 23.

Similarly, can be with compound 19 and 4-aminothiophenol and cesium carbonate at N, in the dinethylformamide in about 4 hours of about 90 ℃ of reactions.After being cooled to room temperature, this mixture is poured in the frozen water, and it is acidified to pH 5 with 1N hydrochloric acid.With this solution of ethyl acetate extraction, the extraction liquid dried over sodium sulfate, filter and vacuum concentration, obtained corresponding 4-aminophenyl sulfenyl-3-p-nitroanilide.With the dichloromethane solution and the chloroformic acid 2,2 of this anilide, 2-trichloro ethyl ester and pyridine reacted about 16 hours then.With this solution water successively and salt water washing,, filter and vacuum concentration then the extraction liquid dried over sodium sulfate.Resistates is developed with hexane and ethyl acetate, obtained the compound 22 of corresponding Troc-amino-protection.Aminocompound with this Troc-protection is dissolved in ethanol and the tetrahydrofuran (THF) then, and under refluxad reacts about 6 hours with iron powder and ammonium chloride.With the cooling of gained mixture, with alcohol dilution and filtration.With the filtrate vacuum concentration, obtained the compound 23 of Troc-amido protecting.

Similarly, can also be with compound 19 at anhydrous N, solution in the dinethylformamide and 4-tert-butoxycarbonyl amino-phenol (N-Boc-4-hydroxyanilines) and salt of wormwood is in room temperature reaction, and about 5 hours of about 80 ℃ of heating.This reaction is cooled to room temperature, and solvent removed in vacuo places ethyl acetate to resistates.Dried over sodium sulfate is used in water and salt water washing, filters and vacuum concentration, has obtained the compound 20 of N-Boc protection.Then compound 20 is dissolved in ethanol, tetrahydrofuran (THF) and the water,, this mixture was heated about 2 hours at about 90 ℃ with iron powder and ammonium chloride reaction.After being cooled to room temperature, this mixture is diluted with ethyl acetate, filter, and with filtrate water and salt water washing.With the organic phase dried over sodium sulfate, filter and vacuum concentration, obtained coupling agent compound 22.

Reaction scheme 6

The PG=protecting group is Boc-, Troc-etc. for example

R as defined above.

For each independent step, optimum reaction condition and reaction times can change according to the substituting group under existing in used concrete reactant and the used reactant.Except as otherwise noted, otherwise solvent, temperature and other reaction conditionss can easily select by those skilled in the art.Can carry out aftertreatment to reaction with usual manner, for example from resistates, remove and desolvate, and be further purified, such as but not limited to crystallization, distillation, extraction, development and chromatography according to the common known method in this area.

Should be appreciated that providing above-mentioned embodiment and reaction scheme and the following examples only is to illustrate for example, rather than restriction.By this specification sheets, within the scope of the present invention various changes and modification it will be apparent to those skilled in the art that.

Embodiment 1

(7-methyl-[1,8] naphthyridine-4-yl)-(5-methyl-2-phenyl sulfenyl-phenyl)-amine

Embodiment 1a

2-[(6-methyl-pyridine-2-base is amino)-methylene radical]-diethyl malonate

(12.48g, 115mmol) (7.46mL, mixture 89.2mmol) are under agitation in 100 ℃ of heating 2.5 hours with 2-oxyethyl group methylene radical-diethyl malonate with 2-methyl-5-aminopyridine.Be cooled to room temperature and dilute with hexane.Filtration is also dry under vacuum, obtains this title compound (21.05g, 85%).

Embodiment 1b

7-methyl-4-oxo-1,4-dihydro-[1,8] naphthyridine-3-ethyl formate

Diphenyl ether is heated to 250 ℃, and with several small portions with about 5 minutes clock times add example I a product (2.50g, 9.0mmol), then 250 ℃ of heating 30 minutes.After being cooled to room temperature, dilute with hexane.With gained solid filtering and dry under vacuum, obtain this title compound, be brown solid (1.47g, 71%).

Embodiment 1c

7-methyl-[1,8] naphthyridine-4-alcohol

With the product of example I b (1.30g, 5.59mmol) and NaOH (233mg, 5.82mmol) solution in 20mL water in the metallic reactors of sealing in 180 ℃ of heating 16 hours.Be cooled to room temperature, and be adjusted to pH 6 with 1N HCl.Filtration gained throw out is also dry under vacuum, obtains this title compound, is black solid (743mg, 82%).

Embodiment 1d

5-chloro-2-methyl-[1,8] naphthyridine

(320mg is 2.0mmol) at 6mL POCl with the product of embodiment 1c ₃In mixture under agitation in 50 ℃ the heating 6 hours.Be cooled to room temperature and by pouring stopped reaction in the ice into.Use NH ₄OH is adjusted to pH 10, and uses CH ₂Cl ₂Extraction.Use Na ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound, is brown solid (322mg, 90%).

Embodiment 1e

4-methyl-2-nitro-1-phenyl sulfenyl-benzene

(3.96g, 30mmol) (2.65mL is 20mmol) under agitation in 50 ℃ of heating 2 days for solution in 60mL DMF and 4-chloro-3-nitrotoluene with thiophenol sodium.Be cooled to room temperature and use CH ₂Cl ₂Dilution.Wash with water, and with organic layer Na ₂SO ₄Dry.Filter and under vacuum, concentrate, obtain this title compound (4.29g, 87%).

¹HNMR(300?MHz，CDCl ₃)δ?ppm:2.36(s，3H)6.76(d，J＝8.09Hz，1H)7.16(d，J＝8.46Hz，1H)7.45(m，3H)7.58(m，2H)8.03(s，1H).

Embodiment 1f

5-methyl-2-phenyl sulfenyl-phenyl amine

Product (1.17g, 7.0mmol) solution and the SnCl in the anhydrous EtOH of 25mL with embodiment 1e ₂(3.58g is 29.8mmol) in stirring at room 16 hours.Be adjusted to pH12 with 1N NaOH, and extract with EtOAc.Use Na ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound (835mg, 82%).

¹H?NMR(300MHz，CDCl ₃)δ?ppm:2.30(2，3H)6.62(d，J＝8.83Hz，1H)6.69(s，1H)7.10(m，3H)7.21(m，2H)7.54(d，J＝7.72Hz，2H).

Embodiment 1g

(7-methyl-[1,8] naphthyridine-4-yl)-(5-methyl-2-phenyl sulfenyl-phenyl)-amine

With the product of embodiment 1d (65mg, 0.36mmol) and the product of embodiment 1f (77mg, 0.36mmol) solution that is stirring in 3mL EtOH was in 80 ℃ of heating 7 hours.Under vacuum, concentrate.Recrystallize from the THF that contains several MeOH.Filter, obtain this title compound, be the hydrochloride (62mg, 43%) of white solid.

¹H?NMR(300MHz，CDCl ₃)δppm:1.62(brs，1H)2.43(s，3H)2.52(s，3H)6.02(d，J＝7.0Hz，1H)7.05-7.35(m，8H)7.70(brs，1H)8.00(d，J＝7.0Hz，1H)8.85(d，J＝8.5Hz，1H)10.80(brs，1H)；MS(ESI+)m/z358(M-Cl)+；(ESI-)m/z356(M-HCl)-.

Embodiment 2

(5-methyl-2-phenyl sulfenyl-phenyl)-(7-propyl group-[1,8] naphthyridine-4-yl)-amine

Embodiment 2a

2-(2,5-dimethyl-pyrroles-1-yl)-6-methyl-pyridine

(5.0g, 46mmol) and hexane-2, (5.4mL, 46mmol) (0.5mL 7.9mmol) handles the solution in 60mL benzene the 5-diketone with HOAc with 2-methyl-5-aminopyridine.Solution was heated azeotropic removal of water 20 hours with solution under refluxing.Be cooled to room temperature and dilute with ether.With rare HCl and water washing.With organic layer MgSO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound (4.7g, 55%).

Embodiment 2b

2-(2,5-dimethyl-pyrroles-1-yl)-6-propyl group-pyridine

(7.53g, 40.0mmol) solution in the anhydrous THF of 30mL under agitation is added drop-wise in the solution of LDA (42.4mmol) in the anhydrous THF of 30mL in-30 ℃ the product of embodiment 2a.Stirred 30 minutes in-30 ℃.Under agitation with the 30 minutes EtI (3.42mLs of dropping in the anhydrous THF of 20mL ₅42.0mmol) in, be heated to room temperature then.After 2 hours, come stopped reaction by pouring in the saturated NaCl solution, and use extracted with diethyl ether.Use MgSO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound.This product with EtOAc/ hexane wash-out, obtains this title compound (5.21g, 60%) by the silica gel column chromatography purifying.

Embodiment 2c

6-propyl group-pyridine-2-base amine

With the product of embodiment 2b (348mg, 1.52mmol) and NH ₂(530mg, 7.62mmol) solution in 4mL EtOH/1.5mL water is cooled to room temperature, and uses CH in 100 ℃ of heating 16h OH HCl ₂Cl ₂Extraction.Use MgSO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound, is amber oily thing (223mg, 100%).

Embodiment 2d

2-[(6-propyl group-pyridine-2-base is amino)-methylene radical]-diethyl malonate

According to the method among the example I a, product (223mg with embodiment 2c, 1.52mmol) and 2-oxyethyl group methylene radical-diethyl malonate (0.350mL, 1.75mmol) reaction, carry out after the silica gel column chromatography purifying purifying with EtOAc/ hexane wash-out, obtain this title compound (386mg, 80%).

Embodiment 2e

4-oxo-7-propyl group-1,4-dihydro-[1,8] naphthyridine-3-ethyl formate

According to the method for example I b, (6.87g 22.4mmol) heats in diphenyl ether, obtains this title compound, is brown solid (4.73g, 81%) with the product of embodiment 2d.

Embodiment 2f

7-propyl group-[1,8] naphthyridine-4-alcohol

According to the method for embodiment 1c, (4.73g, 18.1mmol) (756mg, 18.9mmol) reaction obtains this title compound, is solid (3.42g, 100%) with NaOH with the product of embodiment 2e.

Embodiment 2g

5-chloro-2-propyl group-[1,8] naphthyridine

According to the method for example I d, with the product of embodiment 2f (145mg, 0.76mmol) and POCl ₃The 4mL reaction obtains this title compound, is solid (135mg, 86%).

Embodiment 2h

According to the method for embodiment 1g, (65mg is 0.31mmol) with the product (68mg of embodiment 1f with the product of embodiment 2g, 0.31mmol) reacted 24 hours, obtain this title compound, be the solid hydrochloride, it is developed with ether, obtain (110mg, 84%).

¹HNMR(300?MHz，DMSO-d ₆)δ?ppm:0.97(t，J＝7.35Hz，3H)2.38(qnt，J＝7.35Hz，2H)2.99(dd，J＝7.35Hz，J＝7.72Hz，2H)6.31(d，J＝7.35Hz，1H)7.23(s，5H)7.35(m，4H)7.79(d，J＝8.46Hz，1H)8.38(d，J＝6.98Hz，1H)9.01(d，J＝8.46Hz，1H)11.10(s，1H)14.35(brs，1H)；MS(ESI+)m/z386(M-Cl)+；(ESI-)m/z?384(M-HCl)-.

Embodiment 3

(7-ethyl-[1,8] naphthyridine-4-yl)-(5-methyl-2-phenyl sulfenyl-phenyl)-amine

Embodiment 3a

2-(2,5-dimethyl-pyrroles-1-yl)-6-ethyl-pyridine

Under nitrogen to the product that is cooled to-40 ℃ embodiment 2a (6.82g, 36.6mmol) solution in the anhydrous THF of 75mL drip n-BuLi (solution of 2.5M in hexane) (16mL, 40mmol).Gained solution stirred 30 minutes at low temperatures, used CH then ₃(2.4mL 38.6mmol) handles I.After adding was finished, to-30 ℃, post-heating was to room temperature in 20 minutes with mixture heating up.Subsequently by pouring in the salt brine solution, and with product with the stopping of reaction by separating with the EtOAc extraction.Use MgSO ₄Drying is filtered and is concentrated under vacuum.By silica gel column chromatography purifying purifying,, obtain this title compound (4.42g, 60%) with EtOAc/ hexane wash-out.

Embodiment 3b

6-ethyl-pyridine-2-base amine

(4.93g 0.025mol) is dissolved in the mixture of EtOH (80mL) and water (30mL) the product of example I a.In this mixture, add hydroxy amine hydrochloric acid salt (8.6g, 0.123mol), and with gained mixture heating up to 100 ℃ 8 hours.Reaction mixture is poured in the diluted sodium hydroxide solution, by using CH ₂Cl ₂Extraction separates crude product, uses MgSO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound.This material is used with isolating state.

Embodiment 3c

2-[(6-ethyl-pyridine-2-base is amino)-methylene radical]-diethyl malonate

With the crude product of embodiment 3b and 2-oxyethyl group methylene radical-diethyl malonate (6.6mL 0.032mol) mixes, and with this mixture under nitrogen in oil bath in 100 ℃ of heating 2 hours.By the silicagel column purified by flash chromatography,, obtain this title compound (7.16g, 98%) with EtOAc/ hexane wash-out.

Embodiment 3d

7-ethyl-4-oxo-1,4-dihydro-[1,8] naphthyridine-3-ethyl formate

According to the method for example I b, (7.16g 0.024mol) heats in diphenyl ether, obtains this title compound (4.73g, 79%), is brown solid with the product of embodiment 3c.

Embodiment 3e

7-ethyl-[1,8] naphthyridine-4-alcohol

According to the method for embodiment 1c, (4.70g, 19.1mmol) (0.808g, 20.2mmol) reaction obtains this title compound, is light green solid (2.43g, 73%) with NaOH with the product of embodiment 3d.

Embodiment 3f

5-chloro-2-ethyl-[1,8] naphthyridine

According to the method for example I d, (200mg 1.14mmol) uses POCl with the product of embodiment 3e ₃Handle, obtain this title compound, be brown solid (183mg, 83%).

Embodiment 3g

(7-ethyl-[1,8] naphthyridine-4-yl)-(5-methyl-2-phenyl sulfenyl-phenyl)-amine

According to the method for embodiment, (88mg, 0.46mmol) (100mg, 0.46mmol) reaction is 24 hours, obtains this title compound, is hydrochloride, and it is developed with ether, obtains (134mg, 70%) with the product of embodiment 1f with the product of embodiment 3f.

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.34(t，J＝7.35Hz，3H)3.02(q，J＝7.35Hz，2H)6.69(d，J＝6.99Hz，1H)6.97(d，J＝8.82Hz，2H)7.10(dd，J＝7.35Hz，1H)7.15(d，J＝8.82Hz，2H)7.30(dd，J＝8.09Hz，J＝7.72Hz，2.H)7.56(dd，J＝2.94Hz，J＝9.19Hz，1H)7.71(d，J＝2.57Hz，1H)7.88(d，J＝8.82Hz，1H)8.52(d，J＝6.99Hz，1H)9.02(d，J＝8.45Hz，1H)11.16(br?s，1H)14.56(br?s，1H)；MS(ESI+)m/z376(M-Cl)+；(ESI-)m/z?374(M-HCl)-.

Embodiment 4

4-[2-(7-ethyl-[1,8] naphthyridine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenol

Embodiment 4a

Three fluoro-methylsulfonic acid 4-methyl-2-nitro-phenylesters

With 4-methyl-2-nitrophenols (6.0g, 39.1mmol) and Et ₃(16.38mL is 117.5mmol) at 100mL CH for N ₂Cl ₂In solution (7.25mL 43.1mmol) handles 30 minutes with trifluoromethanesulfanhydride anhydride in 0 ℃ under nitrogen.By adding the MeOH stopped reaction.Use 10% citric acid, 0.5m KOH and water washing successively.Use MgSO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound, and it by silica gel column chromatography purifying purifying, is used CH ₂Cl ₂Wash-out obtains amber oily thing (11.22g, 100%).

Embodiment 4b

4-(4-methyl-2-nitro-phenyl sulfenyl)-phenol

With the product of embodiment 4a (11.22g, 39.3mmol) and 4-mercapto-phenol (4.96g ₅39.3mmol) in 100mL EtOH, use Na ₂CO ₃Handle, and under refluxing heated overnight.Be cooled to room temperature, and the water stopped reaction.Extract with EtOAc.Use MgSO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound, and it by silica gel column chromatography purifying purifying, with 25%EtOAc/ hexane wash-out, is obtained red oil (8.65g, 85%).

Embodiment 4c

4-(2-amino-4-methyl-phenyl sulfenyl)-phenol

According to the method for embodiment 1f, (8.65g 31.3mmol) uses SnCl with the product of embodiment 4b ₂Reduction obtains this title compound, is white solid (8.51g, 100%).

Embodiment 4d

According to the method for embodiment 1g, (131mg is 0.530mmol) with the product (97mg of embodiment 3f with the product of embodiment 4c, 0.503mmol) reacted 21 hours, obtain this title compound, be hydrochloride, it with 5:1 ether/THF development, is obtained (210mg, 98%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.37(t，J＝7.35Hz，3H)2.33(s，3H)3.05(q，J＝7.35Hz，2H)6.29(d，J＝6.99Hz，1H)6.74(d，J＝8.46Hz，2H)7.00(m，1H)7.17-7.29(m，4H)7.84(d，J＝8.83Hz，1H)8.43(d，J＝6.98Hz，1H)9.09(d，J＝8.83Hz，1H)9.90(s，1H)11.12(br?s，1H)14.38(br?s，1H)；MS(ESI+)m/z?388(M-Cl)+；(ESI-)m/z?386(M-HCl)-.

Embodiment 5

4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

By the method for embodiment 1g, (277mg is 0.156mmol) with the product (361mg of embodiment 4c with the product of embodiment 1d, 0.156mmol) reacted 5 hours, in that crude product is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetate (231mg, 30%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.33(s，3H)2.77(s，3H)6.29(d，J＝6.99Hz，1H)6.73(d，J＝8.82Hz，2H)7.01(d，J＝7.72Hz，1H)7.19(d，J＝8.46Hz，2H)7.24(s，1H)7.27(s，1H)7.81(d，J＝8.82Hz，1H)8.44(d，J＝6.99Hz，1H)9.01(d，J＝8.82Hz，1H)9.91(s，1H)11.03(s，1H)14.38(br.s，1H)；MS(ESI+)m/z?374(M+H)+.

Embodiment 6

4-[4-methyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

According to the method for embodiment 1g, (275mg is 0.133mmol) with the product (231mg of embodiment 4c with the product of embodiment 2g, 0.133mol) reacted 5 hours, crude product by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate (288mg, 42%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.98(t，J＝7.35Hz，2H)1.85(m，2H)2.33(s，3H)3.00(t，J＝7.35Hz2H)6.29(d，J＝6.99Hz，1H)6.73(d，J＝8.46Hz，2H)7.00(m，2H)7.19(d，J＝8.46?Hz，2H)7.27(s，1H)7.83(d，J＝8.82?Hz，1H)8.43(d，J＝7.35?Hz，1H)9.04(d，J＝8.46Hz，1H)9.90(s，1H)11.04(s，1H)14.40(br.s，1H)；MS(ESI+)m/z?402(M+H)+.

Embodiment 7

(5-methyl-2-phenyl sulfenyl-phenyl)-(7-trifluoromethyl-[1,8] naphthyridine-4-yl)-amine

Embodiment 7a

2,6-two bromo-nicotinic acid

With 2, (2.50g 13.0mmol) reacted 2 hours in 110 ℃ under 177psi pressure in the metallic reactors of sealing with 25mL 30%HBr/HOAc the sample of 6-two chloro-nicotinic acid.Be cooled to room temperature and, wash with water with EtOAc extraction.Use MgSO ₄Dry filter also concentrates under vacuum, obtains this title compound, obtains this title compound, is solid (3,22g, 88%).

Embodiment 7b

The 7-bromo-1-tertiary butyl-4-oxo-1,4-dihydro-[1,8] naphthyridine-3-ethyl formate

The product of embodiment 7a is carried out reaction sequence among the patent US 6,818,654, obtain this title compound.

Embodiment 7c

The 1-tertiary butyl-4-oxo-7-Trifluoromethyl-1,4-dihydro-[1,8] naphthyridine-3-ethyl formate

Under nitrogen in 75 ℃ of products with embodiment 7b (101mg, 0.28mmol) with two fluoro-fluorosulfonyl-methyl acetates (0.132mL, 1.43mmol) in 2mL DMF with CuI (71mg; 0.37mmol) reacted 15 hours; obtain this title compound, be solid (57mg, 59%).

Embodiment 7d

5-chloro-2-trifluoromethyl-[1,8] naphthyridine

, handle with the method for example I b-Id successively then the product of embodiment 7c trifluoroacetic acid deprotection according to the method for embodiment 16b, obtain this title compound, be solid (142mg, 87%).Productive rate is final step in proper order.

Embodiment 7e

According to the method for embodiment 1g, (65mg, 0.28mmol) (61.5mg, 0.28mmol) reaction is 28 hours, obtains this title compound, is hydrochloride, after the ether development, obtains (131mg, 99%) with the product of embodiment 1f with the product of embodiment 7d.

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:6.43(d，J＝6.99Hz，1H)7.23(m，4H)7.35(m，4H)8.39(d，J＝8.82Hz，1H)8.55(d，J＝6.99Hz，1H)9.48(d，J＝8.46Hz，1H)11.55(brs，1H)；MS(ESI+)m/z?412(M-Cl)+；(ESI-)m/z?410(M-HCl)-.

Embodiment 8

(7-sec.-propyl-[1,8] naphthyridine-4-yl)-(5-methyl-2-phenyl sulfenyl-phenyl)-amine

Embodiment 8a

2-(2,5-dimethyl-pyrroles-1-yl)-6-sec.-propyl-pyridine

According to the method for embodiment 12c, (1.5g, 7.26mmol) (4.35mL, 8.7mmol) reaction after 1 hour, adds Grignard reagent and iron catalyst again, obtains this title compound with the bromination isopropyl-magnesium with the product of embodiment 12b.This product is by the silica gel column chromatography purifying, and 2%EtOAc/ hexane wash-out obtains (880mg, 56%).

Embodiment 8b

5-chloro-2-sec.-propyl-[1,8] naphthyridine

The product of embodiment 8a is handled with the method for 2c-2g successively, obtained this title compound.

Embodiment 8c

According to the method for embodiment 1g, (0.098g, 0.475mmol) (0.102g, 0.475mmol) reaction is 18 hours, obtains this title compound, and it by the HPLC purifying, is used the TFA wash-out with the product of embodiment 1f with the product of embodiment 8b.Be converted into hydrochloride by the 4N HCl processing that is used in room temperature in the diox, obtain hydrochloride form (0.076g, 38%).

¹HNMR(300MHz，DMSO-d ₆)δ?ppm1.37(d，J＝6.99Hz，6H)2.38(s，3H)3.30(m，1H)6.32(d，J＝6.99Hz，1H)7.24(s，5H)7.34(m，3H)7.86(d，J＝8.82Hz，1H)8.39(d，J＝7.35Hz，1H)9.08(d，J＝8.46Hz，1H)11.16(s，1H)14.36(m，1H)；MS(ESI+)m/z?386.0(M+H)+.

Embodiment 9

(5-methoxyl group-2-phenyl sulfenyl-phenyl)-(7-methyl-[1,8] naphthyridine-4-yl)-amine

Embodiment 9a

4-methoxyl group-2-nitro-1-phenyl sulfenyl-benzene

Method according to embodiment 1e, with 1-chloro-4-methoxyl group-2-nitro-benzene (3.75g, 20.0mmol) and thiophenol sodium (3.96g, 30.0mmol) in 70 ℃ of reactions 48 hours, obtain this title compound, with 25% EtOAc/ hexane (2.70g, 54%) afterwards by silica gel column chromatography purifying purifying, obtain this title compound, be yellow oil.

Embodiment 9b

5-methoxyl group-2-phenyl sulfenyl-phenyl amine

According to the method for embodiment 1f, with the product of embodiment 9a (2.70g, 10.2mmol) and SnCl ₂(9.40g, 50.0mmol) reaction is 22 hours, obtains this title compound, is white solid (2.28g, 96%).

Embodiment 9c

According to the method for embodiment 1g, (69mg, 0.30mmol) (53mg, 0.30mmol) reaction after the solid development, obtain this title compound, are hydrochloride (119mg, 96%) with the product of embodiment 1d with the product of embodiment 9b.

¹H?NMR(300MHz，DMSO-d ₆)δppm:2.75(s，3H)3.83(s，3H)6.34(d，J＝6.99Hz，1H)7.07(m，7H)7.57(d，J＝8.46Hz，1H)7.76(d，J＝8.46Hz，1H)8.85(d，J＝6.99Hz，1H)8.99(d，J＝8.46Hz，1H)11.16(br?s，1H)14.43(brs，1H)；MS(ESI+)m/z?374(M-Cl)+；(ESI-)m/z?372(M-HCl)-.

Embodiment 10

7-methyl-4-(5-methyl-2-phenyl sulfenyl-phenyl amino)-[1,8] naphthyridine-3-ethyl formate

Embodiment 10a

4-chloro-7-methyl-[1,8] naphthyridine-3-ethyl formate

According to the method for example I d, (1.0g is 4.30mmol) with 12mL POCl with the product of example I b ₃Reacted 4 hours, and obtained this title compound, be brown-pink solid (619mg, 57%).

Embodiment 10b

According to the method for embodiment 1g, (438mg, 2.03mmol) (510mg, 2.03mmol) reaction is 10 minutes, obtains this title compound, and it by silica gel column chromatography purifying purifying, is used 4% MeOH/CH with the product of embodiment 1f with the product of embodiment 10a ₂Cl ₂Wash-out is solid (114mg, 57%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.33(t，J＝6.99Hz，3H)2.16(s，3H)2.62(s，3H)4.29(q，J＝7.11Hz，2H)6.86(s，1H)7.04(d，J＝8.09Hz，1H)7.15-7.34(m，6H)7.39(d，J＝7.72Hz，1H)7.69(d，J＝8.82Hz，1H)9.17(s，1H)10.13(s，1H)；MS(ESI+)m/z?430(M+H)+，(ESI-)m/z?428(M-H)-.

Embodiment 11

7-methyl-4-(5-methyl-2-phenyl sulfenyl-phenyl amino)-[1,8] naphthyridine-3-formic acid methoxyl group-methyl-acid amides

Embodiment 11a

7-methyl-4-(5-methyl-2-phenyl sulfenyl-phenyl amino)-[1,8] naphthyridine-3-formic acid

With the product of embodiment 10 (250mg, 0.58mmol) with 2mL 1N NaOH in the 4mL diox in 65 ℃ of reactions 30 minutes.Be cooled to room temperature and dilute with water, be adjusted to pH3 with 1N HCl, and by vacuum filtration with the gained solids constituent from, obtain this title compound (215mg, 92%).

Embodiment 11b

With the product of embodiment 11a (50,5mg, 0.125mmol) with 1,1 '-carbonyl dimidazoles (40.8mg, 0.215mmol) reaction 30 minutes under nitrogen in 2mL DMF.Add N, O-dimethyl hydroxyl amine hydrochlorate (25mg, 0.215mmol), and in stirring at room 24 hours.Solvent is concentrated under vacuum, obtain this title compound.With crude product by the HPLC purifying with behind the AA wash-out, be separated into free alkali (12mg, 21%).

¹H?NMR(300MHz，DMSO-D6)δ?ppm:2.23(s，3H)2.67(s，3H)2.89(s，3H)3.39(s，3H)6.86(s，1H)6.91-7.04(m，1H)7.15-7.35(m，7H)7.44(d，J＝8.46Hz，1H)8.34(d，J＝8.09Hz，1H)8.67(s，1H)；MS(ESI+)m/z?445(M+H) ⁺，467(M+Na) ⁺，MS(ESI-)m/z?443(M-H) ^-.

Embodiment 12

4-[2-(7-isobutyl--[1,8] naphthyridine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenol

Embodiment 12a

6-chloro-pyridine-2-base amine

With 2, (500g 3.37mol) uses NH in 180 ℃ to the 6-dichloropyridine in the metallic reactors of sealing ₄OH handled 40 hours.After being cooled to room temperature, product is separated by suction strainer, obtain this title compound, be solid (400g, 92%).

Embodiment 12b

2-chloro-6-(2,5-dimethyl-pyrroles-1-yl)-pyridine

According to the method for embodiment 2a, (20g, 156mmol) with hexane-2, (18.3mL 156mmol) handled 2 hours the 5-diketone, obtained this title compound (17.7g, 55%) with the product of embodiment 12a.

Embodiment 12c

2-(2,5-dimethyl-pyrroles-1-yl)-6-isobutyl--pyridine

(1.0g, (2.90mL 5.81mmol) handles 4.84mmol) to be used in 2.0M magnesium chloride among 30mLTHF and the 3mL NMP with the product of embodiment 12b under nitrogen in room temperature.Add Fe (acac) ₃(85mg is 0.242mmol) and in stirring at room 18 hours.In reaction process, add Grignard reagent and catalyzer again.By pouring in 5% acetate, and use extracted with diethyl ether with the stopping of reaction.Use Na ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound, and by silica gel column chromatography purifying purifying, 10% EtOAc/ hexane wash-out obtains (620mg, 56%) with it.

Embodiment 12d

5-chloro-2-isobutyl--[1,8] naphthyridine

The product of embodiment 12c is handled with the method for 2c-2g successively, obtained this title compound.

Embodiment 12e

According to the method for embodiment 1g, (100mg is 45.3mmol) with the product (105mg of embodiment 4c with the product of embodiment 12d, 45.3mmol) reacted 18 hours, after using TFA as wash-out by the HPLC purifying crude product, obtain this title compound, be trifluoroacetate (90mg, 47%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm0.97(d，J＝6.62Hz，6H)，2.13-2.30(m，1H)，2.33(s，3H)，2.89(d，J＝6.99Hz，2H)，6.29(d，J＝6.99Hz，1H)，6.73(d，J＝8.46Hz，2H)，7.00(d，J＝8.09Hz，1H)，7.13-7.34(m，4H)，7.81(d，J＝8.46Hz，1H)，8.43(d，J＝6.99Hz，1H)，9.03(d，J＝8.46Hz，1H)，10.99(br.s.，1H)，14.36(br.s.，1H)；MS(ESI+)m/z?416(M+H)+；(ESI-)m/z?414(M-H)-.

Embodiment 13

4-[2-(7-oxyethyl group-[1,8] naphthyridine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenol

Embodiment 13a

The 1-tertiary butyl-7-chloro-4-oxo-1,4-dihydro-[1,8] naphthyridine-3-ethyl formate

This title compound is with 2 of description among the patent US 6,818,654, the preparation of 6-two chloro-nicotinic acid.

Embodiment 13b

7-chloro-4-oxo-1,4-dihydro-[1,8] naphthyridine-3-ethyl formate

With the product of embodiment 13a (0.282gm, 0.91mmol) in room temperature with contain two vitriolic 2mL TFA and mix.The gained mixture was in 70 ℃ of heating 16.5 hours.Remove volatile matter under the vacuum, and resistates is suspended in the water.Product is collected by vacuum filtration, washed with water, and dry under vacuum, obtain this title compound, be cream-colored solid (0.214gm, 93%).

Embodiment 13c

[1,8] naphthyridine-2, the 5-glycol

(0.208gm 0.82mmol) reacts as described in embodiment 1c, obtains this title compound, is chocolate solid (0.196gm, 97%) with the product of embodiment 13b.

Embodiment 13d

2,5-two chloro-[1,8] naphthyridine

(0.111gm 0.68mmol) reacts as described in example I d, obtains this title compound, is faint yellow solid (0.124gm, 91%) with the product of embodiment 13c.

Embodiment 13e

4-[2-(7-chloro-[1,8] naphthyridine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenol

With the product of embodiment 13d (0.67g, 3.36mmol) and the product of embodiment 4c (0.78g, 3.36mmol) heating 5.5 hours under refluxing in 10mL ethanol.Reaction mixture is cooled to room temperature, and under vacuum, concentrates, obtain yellow solid, it is used (1.43g, 100%) under situation about not being further purified except that desolvating.

Embodiment 13f

(0.025g .063mmol) the 2mL 21% weight NaOEt that is used among the EtOH handles with the product of embodiment 13e.The gained mixture heated 4 hours under refluxing.Solvent is concentrated under vacuum, obtain brown oily resistates.This thick oily matter is used the TFA wash-out by the HPLC purifying.This title compound is separated into the trifluoroacetic acid salt form, obtains light brown powder (20mg, 78%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.44(t，J＝6.99Hz，3H)2.32(s，3H)4.56(q，J＝6.99Hz，2H)6.24(d，J＝6.99Hz，1H)6.68-6.81(m，2H)6.98(d，J＝8.09Hz，1H)7.05-7.34(m，3H)7.34(d，J＝9.19Hz，1H)8.30(d，J＝6.99Hz，1H)8.92(d，J＝9.19Hz，1H)10.81(s，1H)14.17(s，1H)；MS(ESI+)m/z?404(M+H)+；(ESI-)m/z?402(M+H)-.

Embodiment 14

4-[2-(2,7-dimethyl-[1,8] naphthyridine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenol

Embodiment 14a

2,7-dimethyl-1H-[1,8] naphthyridine-4-ketone

To contain 2-methyl-5-aminopyridine (5.0g, 46.2mmol) and methyl aceto acetate (6.54mL, 552.3mmol) and the flask of 5mL Tripyrophosphoric acid in 120 ℃ of heating 2 hours.Be cooled to room temperature and pour in the water usefulness 1N NaOH neutralization into.Use CH ₂Cl ₂MgSO is used in extraction ₄Drying is filtered and is concentrated under vacuum, obtains yellow oil, and it was heated 1 hour in 250 ℃ in diphenyl ether.Be cooled to room temperature,, and product separated by suction strainer, obtain this title compound, it is used under the situation of purifying not with hexane dilution.

Embodiment 14b

4-chloro-2,7-dimethyl-[1,8] naphthyridine

According to the method for embodiment 1d, (500mg is 2.87mmol) with 10mL POCl with the product of embodiment 14a ₃Reacted 2 hours, and obtained this title compound, it is used under the situation of purifying not.

Embodiment 14c

Method according to embodiment 1g, product (60mg with embodiment 14b, 0.31mmol) with the product (72mg of embodiment 4c, 0.31mmol) reacted 12 hours, obtain this title compound, be rough solid, it is passed through the HPLC purifying with it, use the TFA wash-out, obtaining as product is trifluoroacetate (45mg, 37%).

¹HNMR(300MHz，DMSO-d ₆)δ?ppm:2.23(s，3H)2.75(s，3H)3.43(s，3H)6.10(s，1H)6.68(d，J＝8.82Hz，2H)6.99-7.20(m，3H)7.20-7.38(m，2H)7.75(d，J＝8.82Hz，1H)8.96(d，J＝8.82Hz，1H)9.86(s，1H)10.78(s，1H)14.21(s，1H)；MS(APCI)m/z?386(M-H)-.

Embodiment 15

4-[2-(7-methoxyl group-[1,8] naphthyridine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenol

Embodiment 15a

4-[2-(7-chloro-[1,8] naphthyridine-4-base is amino)-4-methyl-phenyl sulfenyl 3-phenol

(670mg, 3.36mmol) with product (780mg3.36mmol) reaction of embodiment 4c 5.5 hours, the method according to embodiment 1g obtained this title compound, is hydrochloride (1.43g, 100%) with the product of embodiment 13e.

Embodiment 15b

(0.100g, 0.254mmol) (95%, 0.27g 5mmol) handles with 5mL methyl alcohol and Powdered NaOMe with the product of embodiment 15a.The gained mixture heated 18 hours under refluxing.Solvent is concentrated under vacuum, obtain orange oily resistates.This rough oily matter is by HPLC purifying (gradient 0-95% CH ₃CN/0.1% TFA), obtains this title compound, be trifluoroacetate, it is separated, be yellow powder (75mg, 76%)

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.32(s，3H)4.10(s，3H)6.25(d，J＝7.35Hz，1H)6.65-6.81(m，3H)6.99(d，J＝8.09Hz，1H)7.13-7.29(m，3H)7.38(d，J＝9.19Hz，1H)8.30(d，J＝7.35Hz，1H)8.94(d，J＝9.19Hz，1H)9.89(s，1H)10.81(s，1H)14.21(s，1H)；MS(ESI+)m/z?390(M+H)+；(ESI-)m/z?388(M+H)-.

Embodiment 16

4-[4-methyl-2-([1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

Embodiment 16a

The 1-tertiary butyl-4-oxo-1,4-dihydro-[1,8] naphthyridine-3-ethyl formate

Reaction sequence with 2-chloro-nicotinic acid sample carries out description among the patent US 6,818,654 obtains this title compound.

Embodiment 16b

4-hydroxyl-[1,8] naphthyridine-3-ethyl formate

(6.36g is 23.1mmol) with 50mL trifluoroacetic acid and 1mLH with the product of embodiment 16a ₂SO ₄In room temperature reaction 1 hour.Solvent is concentrated under vacuum, obtain this title compound, be solid (5.05g, 99%).

Embodiment 16c

4-chloro-[1,8] naphthyridine

The product of embodiment 16b is reacted according to the method for embodiment 1c and example I d, obtain this title compound, be solid (106mg, 96%).

Embodiment 16d

4-[4-methyl-2-([1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

Method according to embodiment 1g, with the product of 0.9M embodiment 16c at methyl alcohol (0.080mL, 0.07mmol) solution and the product of 0.7M embodiment 4c at ethanol (0.100mL, 0.07mmol) solution reaction 18 hours, obtain crude product, with it by the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetate (0.017g, 51%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.33(s，3H)6.33(d，J＝6.99Hz，1H)6.69-6.78(m，2H)7.02(d，J＝8.09Hz，1H)7.16-7.20(m，2H)7.23-7.29(m，2H)7.92(dd，J＝8.46，4.41Hz，1H)8.51(d，J＝6.99Hz，1H)9.10-9.23(m，2H)11.14(s，1H)；MS(ESI+)m/z?360.0(M+H)+，(ESI-)m/z?358.1(M-H)-.

Embodiment 17

4-[2-(7-sec.-propyl-[1,8] naphthyridine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenol

According to the method for embodiment 1g, (100mg is 0.435mmol) with the product (105mg of embodiment 4c with the product of embodiment 8b, 0.435mmol) reacted 18 hours, produce this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain trifluoroacetate (90mg, 47%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.97(d，J＝6.62Hz，6H)，2.13-2.30(m，1H)，2.33(s，3H)，2.89(d，J＝6.99Hz，2H)，6.29(d，J＝6.99Hz，1H)，6.73(d，J＝8.46Hz，2H)，7.00(d，J＝8.09Hz，1H)，7.13-7.34(m，4H)，7.81(d，J＝8.46Hz，1H)，8.43(d，J＝6.99Hz，1H)，9.03(d，J＝8.46Hz，1H)，10.99(br.s.，1H)，14.36(br.s.，1H)；MS?ESI+m/z?416(M+H)+；ESI-m/z?414(M-H)-.

Embodiment 18

N-{4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 18a

N-[4-(4-methyl-2-nitro-phenyl sulfenyl)-phenyl]-ethanamide

According to the method for embodiment 4b, (1g, 3.51mmol) (0.65g, 351mmol) reaction is 18 hours, obtains this title compound (1.04g, 98%) with N-(4-sulfydryl-phenyl)-ethanamide with the product of embodiment 4a.

Embodiment 18b

N-[4-(2-amino-4-methyl-phenyl sulfenyl)-phenyl]-ethanamide

Described in embodiment 1f, with the product of embodiment 18a (0.30gm, 1mmol) and SnCl ₂Reaction obtains this title compound (0.27gm, 100%), is succsinic acid oily matter, and it is used under situation about not being further purified.

Embodiment 18c

Product (0.27gm with embodiment 18c, 1mmol) (0.178gm 1mmole) mixes, and according to the method reaction of describing among the embodiment 1g with the product of embodiment 1d, obtain raw product, be brown solid, it by the HPLC purifying, is used the TFA wash-out, obtain trifluoroacetate, it is converted into hydrochloride by the 4N HCl processing that is used in room temperature in the diox, obtains this title compound (40.0mg, 7.5%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.04(s，3H)2.35(s，3H)2.76(s，3H)6.29(d，J＝6.99Hz，1H)7.24(m，5H)7.50(d，J＝8.82Hz，2H)7.78(d，J＝8.82Hz，1H)8.40(d，J＝6.99Hz，1H)9.02(m，1H)10.08(s，1H)11.09(s，1H)14.37(s，1H)；MS(ESI+)m/z?415.1(M+H)+，(ESI-)m/z?413.1(M-H)-.

Embodiment 19

N-{4-[2-(7-ethyl-[1,8] naphthyridine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenyl }-ethanamide

Method according to embodiment 1g, product (92mg with embodiment 3f, 0.47mmol) with the product (130mg of embodiment 18b, 0.47mmol) reacted 22 hours, obtain this title compound, be solid, after crude product is used the TFA wash-out by the HPLC purifying, be trifluoroacetate (68mg, 26%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.37(t，J＝7.72Hz，1H)2.04(s，3H)2.35(s，3H)3，05(q，J＝7.72Hz，2H)6.31(d，J＝6.98Hz，1H)7.15(d，J＝8.83Hz，1H)7.20-7.35(m，3H)7.49(d，J＝8.83Hz，2H)7.82(d，J＝8.82Hz，1H)8.41(d，J＝6.99Hz，1H)8.99(d，J＝8.82Hz，1H)10.04(s，1H)11.01(br?s，1H)14.39(br?s，1H).MS(ESI+)m/z?429(M+H-Cl)+；(ESI-)m/z?427(M-H-Cl)-.

Embodiment 20

N-{4-[4-methyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

According to the method for embodiment 1g, (93mg is 0.44mmol) with the product (123mg of embodiment 18b with the product of embodiment 2g, 0.44mmol) reacted 23 hours, obtain this title compound, after crude product is used the TFA wash-out by the HPLC purifying, be trifluoroacetate solid (72mg, 29%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.98(t，J＝7.35Hz，3H)，1.84(dq，J＝14.75，7.46Hz，2H)，2.04(s，3H)，2.35(s，3H)，2.99(t，J＝7.35Hz，2H)，6.31(d，J＝6.99Hz，1H)，7.15(d，J＝8.09Hz，1H)，7.20-7.33(m，4H)，7.50(d，J＝8.46Hz，2H)，7.81(d，J＝8.46Hz，1H)，8.41(d，J＝6.99Hz，1H)，9.00(d，J＝8.46Hz，1H)，10.05(s，1H)，11.02(s，1H)；MS(ESI+)m/z?443(M+H)+；(ESI-)m/z?441(M-H)-.

Embodiment 21

N-{4-[4-methyl-2-(7-trifluoromethyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

With the product of embodiment 7d (50.0mg, 0.215mmol) and the product of embodiment 18b (59.0mg, 0.215mmol) solution in ethanol (2mL) is preheating to 80 ℃ oil bath and was stirring 16 hours.Then mixture is cooled to room temperature, under vacuum, removes ethanol, and the thick resistates of gained is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetate (22.0mg, 22%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.03(s，3H)，2.32(s，3H)，6.33(d，J＝5，52Hz，1H)，7.01(d，J＝8.09Hz，1H)，7.15(d，J＝8.46Hz，1.H)，7.21-7.27(m，3H)，7.54(d，J＝8.82Hz，2H)，8.01(d，J＝8.46Hz，1H)，8.65(d，J＝5.51Hz，1H)，9.17(d，J＝8.46Hz，1H)，9.42(s，1H)，10.04(s，1H)；MS(ESI+)m/z?469(M+H-TFA)+，(ESI-)m/z?467(M-H-TFA)-.

Embodiment 22

N-{4-[2-(7-sec-butyl-[1,8] naphthyridine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 22a

2-sec-butyl-5-chloro-[1,8] naphthyridine

Embodiment 22b

Method according to embodiment 1g, product (50mg with embodiment 22a, 0.226mmol) with the product (62mg of embodiment 18b, 0.226mmol) reacted 16 hours, obtain this rough title compound, by HPLC purifying TFA wash-out, the acquisition product is trifluoroacetate (33mg, 32%) with it.

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.85(t，J＝7.35Hz，3H)，1.35(d，J＝6.99Hz，3H)，1.73(dd，J＝13.60，6.99Hz，1H)，1.79-1.90(m，1H)，2.03(s，3H)，2.35(s，3H)，3.01-3.13(m，1H)，6.32(d，J＝7.35Hz，1H)，7.14(d，J＝7.72Hz，1H)，7.22-7.32(m，4H)，7.51(d，J＝8.82Hz，2H)，7.84(d，J＝8.46Hz，1H)，8.41(d，J＝6.99Hz，1H)，9.02(d，J＝8.46Hz，1H)，10.05(s，1H)，11.02(s，1H)；MS(ESI+)m/z?457(M+H)+，(ESI-)m/z?455(M-H)-.

Embodiment 23

N-{4-[2-(7-cycloalkyl-[1,8] naphthyridine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 23a

5-chloro-2-cycloalkyl-[1,8] naphthyridine

Embodiment 23b

Method according to embodiment 1g, product (50mg with embodiment 23a, 0.215mmol) with the product (58mg of embodiment 18b, 0.215mmol) reacted 16 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (29rng, 29%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.71-1.76(m，3H)，1.79-1.93(m，4H)，2.04(s，3H)，2.14(d，J＝7.72Hz，2H)，2.35(s，3H)，6.31(d，J＝6.99Hz，1H)，7.14(d，J＝8.09Hz，1H)，7.21-7.32(m，4H)，7.51(d，J＝8.82Hz，2H)，7.84(d，J＝8.82Hz，1H)，8.40(d，J＝6.99Hz，1H)，8.99(d，J＝8.46Hz，1H)，10.05(s,1H)，11.00(s，1H)；MS(ESI+)m/z469(M+H)+，(ESI-)m/z?467(M-H)-.

Embodiment 24

N-(4-{2-[7-(2-hydroxyl-ethyl)-[1,8] naphthyridine-4-base is amino]-4-methyl-phenyl sulfenyl }-phenyl)-ethanamide

Embodiment 24a

N-{4-t2-(7-chloro-[1,8] naphthyridine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenyl }-ethanamide

According to the method for embodiment 1g, the product of embodiment 13d (200mg, 1.0mmol) and the product of embodiment 18b (215mg, 1.0mmol) reaction obtains rough solid, and it by the HPLC purifying, is used the TFA wash-out, obtains this title compound (200mg, 48%).

Embodiment 24b

2-{5-[2-(4-acetylamino-phenyl sulfenyl)-5-methyl-phenyl amino]-[1,8] naphthyridine-2-yl }-diethyl malonate

To sodium hydride (95%, 0.045g, 1.8mmol) in the slurries in the anhydrous THF of 10mL in 0 ℃ under nitrogen, drip diethyl malonate (0.32g, 2.0mmol).In stirring at room 30 minutes, (0.141g 0.3mmol) handled, and in 110 ℃ of heating 2 hours, cooling also distributed between EtOAc and water with the product of embodiment 24a with mixture.Ethyl acetate layer is washed with saturated brine, use dried over sodium sulfate, filter and concentrate, obtain this title compound, be yellow glass shape thing (0.14g, 84% productive rate).

Embodiment 24c

With the product of embodiment 24b (56mg, 0.10mmol) and NaBH ₄(40mg 1.00mmol) reacted 24 hours in 5mL EtOH.Use NH ₄The Cl stopped reaction, and be adjusted to pH 7 with rare HCl.With the EtOAc extraction, use Na ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains this rough title compound, and it by the HPLC purifying, is used the TFA wash-out, obtains trifluoroacetate (15mg, 25%).

¹HNMR(300MHz，DMSO-d ₆)δ?ppm:2.04(s，3H)2.35(s，3H)3.16(t，J＝6.43Hz，2H)3.91(t，J＝6.25Hz，2H)6.31(d，J＝6.99Hz，1H)7.14(d，J＝8.09Hz，1H)7.22-7.33(m，4H)7.51(d，J＝8.82Hz，2H)7.83(d，J＝8.82Hz，1H)8.42(d，J＝6.99Hz，1H)8.94-9.05(m，1H)10.04(s，1H)11.03(s，1H)14.40(s，1H)；MS(ESI+)m/z?445(M+H-TFA)+.

Embodiment 25

N-{4-[2-(7-butyl-[1,8] naphthyridine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 25a

2-butyl-6-(2,5-dimethyl-pyrroles-1-yl)-pyridine

According to the method for embodiment 2b, (1.0g, 5.37mmol) (0.55mL, 5.64mmol) reaction obtains this title compound (790mg, 64%) with the propyl iodide of alternative iodoethane with the product of embodiment 2a.

Embodiment 25b

2-butyl-5-chloro-[1,8] naphthyridine

The product of embodiment 2a carries out the synthetic order among the embodiment 2b-2g, obtains this title compound.

Embodiment 25c

Method according to embodiment 1g, product (170mg with embodiment 25b, 0.77mmol) with the product (209mg of embodiment 18b, 0.77mmol) reacted 19 hours, obtain this title compound, after crude product is used the TFA wash-out by the HPLC purifying, be the trifluoroacetate (130mg, 30%) of solid form.

¹H NMR (300MHz, DMSO-d ₆) δ ppm:0.95 (t, J=7.72Hz, 3H) 1.39 (sextets, 2H), J=7.72Hz) 1.80 (qnt, J=7.72Hz, 2H) 2.04 (s, 3H) 2.35 (s, 3H) 3.01 (dd, J=7.36Hz, 2H) 6.81 (d, J=6.99Hz, 1H) 7.15 (d, J=8.09Hz, 1H) 7.22-7.32 (m, 4H) 7.50 (d, J=8.82Hz, 2H) 7.82 (d, J=8.46Hz, 1H) 8.41 (d, J=6.99Hz, 1H) 9.00 (d, J=8.82Hz, 1H) 10.06 (br s, 1H) 11.02 (br s, 1H) 14,41 (br s, 1H); MS (ESI+) m/z 457 (M+H); (ESI-) m/z 455 (M-H)-.

Embodiment 26

N-{4-[4-methyl-2-([1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

According to the method for embodiment 1g, (50mg is 0.304mmol) with the product (83mg of embodiment 18b with the product of embodiment 16c, 0.304mmol) reacted 16 hours, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain trifluoroacetate (29mg, 24%).

¹HNMR(300MHz，DMSO-d ₆)δ?ppm:2.04(s，3H)，2.35(s，3H)，6.34(d，J＝6.99Hz，1H)，7.17(d，J＝7.72Hz，1H)，7.23(d，J＝8.46Hz，2H)，7.28-7.34(m，2H)，7.49(d，J＝8.82Hz，2H)，7.90(dd，J＝8.46，4.41Hz，1H)，8.48(d，J＝6.99Hz，1H)，9.11(dd，J＝8.46，1.47Hz，1H)，9.17(dd，J＝4.41，1.47Hz，1H)，10.04(s，1H)，11.12(s，1H)；MS(ESI+)m/z?401(M+H)+，(ESI-)m/z399(M-H)-.

Embodiment 27

The crude product of embodiment 24b is passed through silica gel column chromatography purifying purifying, 3% MeOH/CH ₂Cl ₂Wash-out by the HPLC purifying, is used the TFA wash-out then, obtains this title compound, trifluoroacetate (70mg, 42%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.22(t，J＝7.17Hz，6H)2.04(s，3H)2.35(s，3H)4.24(q，J＝6.99Hz，4H)5.55(s，1H)6.36(d，J＝6.99Hz，1H)7.12(d，J＝8.09Hz，1H)7.22-7.33(m，4H)7.54(d，J＝8.82Hz，2H)7.96(d，J＝8.46Hz，1H)8.46(d，J＝6.99Hz，1H)9.16(d，J＝8.46Hz，1H)10.06(s，1H)11.20(s，1H)14.53(s，1H)；MS(ESI+)m/z?559(M+H＝TFA)+.

Embodiment 28

5-[2-(4-acetylamino-phenyl sulfenyl)-5-methyl-phenyl amino]-[1,8] naphthyridine-2-base is amino }-ethyl acetate

In sealed tube with the product of embodiment 24a (47mg, 0.10mmol) with glycine ethyl ester hydrochloride (84mg, 0.10mmol) in 2mL EtOH in 150 ℃ of reactions 1 hour.Be cooled to room temperature and concentrated.Be adjusted to pH 7 and, use Na with 1M HCl with the EtOAc extraction ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains this rough title compound, and it by the HPLC purifying, is used the TFA wash-out, and obtaining product is trifluoroacetic acid solid (12.mg, 19%).

¹HNMR(300MHz，DMSO-d ₆)δ?ppm:1.22(t，J＝6.99Hz，3H)2.04(s，3H)2.33(s，3H)4.15(q，J＝7.23Hz，2H)4.27(d，J＝6.25Hz，2H)6.08(d，J＝6.99Hz，1H)7.04(d，J＝5.52Hz，1H)7.07(d，J＝6.62Hz，1H)7.19-7.30(m，4H)7.57(d，J＝8.46Hz，2H)8.04(t，J＝6.62Hz，1H)8.53(d，J＝9.19Hz，1H)8.72(t，J＝5.88Hz，1H)10.08(s，1H)10.43(s，1H)13.43(d，J＝5.88Hz，1H)；MS(ESI+)m/z?502(M+H-TFA)+.

Embodiment 29

2-{5-[2-(4-acetylamino-phenyl sulfenyl)-5-methyl-phenyl amino]-[1,8] naphthyridine-2-yl }-propanedioic acid tert-butyl ester ethyl ester

In 0 ℃ under nitrogen to sodium hydride (95%, 0.025g, 1.0mmol) drip in the slurries in the anhydrous THF of 5mL propanedioic acid tertiary butyl ester ethyl ester (0.188g, 1.0mmol).This mixture is in stirring at room 30 minutes, and (0.47g 0.1mmol) handled, in 110 ℃ of heating 2 hours with the product of embodiment 46a.The cooling of this solution and be added in the water, be adjusted to pH 4 with 1M HCl, extract with EtOAc, and wash with saturated brine.Use Na ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains this rough title compound, by chromatography purification on silicon-dioxide, uses l% MeOH at CH it ₂Cl ₂In the mixture wash-out, obtain this title compound, be hydrochloride (0.040g, 64% productive rate).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.26(t，J＝7.11Hz，3H)1.49(s，9H)2.04(s，3H)2.30(s，3H)4.16(q，J＝7.11Hz，2H)5.76(s，1H)6.07(d，J＝5.88Hz，1H)6.98(d，J＝7.72Hz，1H)7.11(d，J＝8.09Hz，1H)7.26(m，4H)7.56(d，J＝8.82Hz，2H)8.03(d，J＝5.88Hz，1H)8.25(d，J＝9.93Hz，1H)9.07(s，1H)10.05(s，1H)13.18(s，1H)；MS(ESI+)m/z587(M+H)+

Embodiment 30

5-[2-(4-acetylamino-phenyl sulfenyl)-5-methyl-phenyl amino]-[1,8] naphthyridine-2-yl }-cyano group-ethyl acetate

According to the method for embodiment 27, (0.240mg 2.1mmol) substitutes diethyl malonate, makes this title compound with ethyl cyanacetate.Crude product by chromatography purification on silicon-dioxide, with the eluant solution of 2% methyl alcohol in methylene dichloride, is obtained yellow powder (0.092g, 55% productive rate).

¹HNMR(300MHz，DMSO-d ₆)δ?ppm:1.28(t，J＝6.99Hz，3H)03(s，3H)2.31(s，3H)4.24(q，J＝6.99Hz，2H)6.15(d，J＝5.88Hz，1H)7.01(d，J＝8.09Hz，1H)7.12(d，J＝1.47Hz，1H)7.17(d，J＝9.56Hz，2H)7.23(d，J＝8.46Hz，2H)7.53(d，J＝8.82Hz，2H)8.13(d，J＝5.88Hz，1H)8.60(d，J＝9.56Hz，1H)9.37(s，1H)10.03(s，1H)13.09(s，1H)；MS(ESI+)m/z512(M+H)+.

Embodiment 31

5-[2-(4-acetylamino-phenyl sulfenyl)-5-methyl-phenyl amino]-[1,8] naphthyridine-2-yl }-cyano group-tert.-butyl acetate

According to the method for embodiment 27, (0.282mg 2.0mmol) substitutes diethyl malonate, makes this title compound with the cyanoacetic acid tert-butyl ester.Crude product by chromatography purification on silicon-dioxide, with the eluant solution of 2% methyl alcohol in methylene dichloride, is obtained yellow solid (0.067 g ₅37% productive rate).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.52(s，9H)2.03(s，3H)2.30(s，3H)6.14(d，J＝5.88Hz，1H)6.98-7.27(m，6H)7.53(d，J＝8.82Hz，2H)8.11(d，J＝5.88Hz，1H)8.55(d，J＝9.56Hz，1H)9.33(s，1H)10.03(s，1H)13.12(s，1H)；MS(ESI+)m/z?540(MM+H)+.

Embodiment 32

N-{4-[2-(7-cyano methyl-[1,8] naphthyridine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenyl }-ethanamide

(0.101g 0.19mmol) is added to 5mL trifluoroacetic acid and 5mLCH the product of embodiment 31 ₂Cl ₂In.Mixture in stirring at room 2 hours, and is concentrated under vacuum, obtain rough title compound.Resistates by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate (0.083g, 80%).

¹H?NMR(300MHz，DMSO-d ₆)δppm:2.04(s，3H)2.35(s，3H)4.64(s，2H)6.35(d，J＝6.99Hz，1H)7.18(d，J＝8.46Hz，1H)7.23(d，J＝8.82Hz，2H)7.30(m，2H)7.48(d，J＝8.46Hz，2H)7.85(d，J＝8.82Hz，1H)8.44(d，J＝6.99Hz，1H)9.09(d，J＝8.82Hz，1H)10.04(s，1H)11.14(s，1H)14.58(s，1H)；MS(ESI+)m/z?440(M+H)+.

Embodiment 33

N-{4-[3-(7-methyl-[1,8] naphthyridine-4-base is amino)-xenyl-4-base sulfenyl]-phenyl }-ethanamide

Product (53mg with embodiment 106c, 0.11mmol) mixture in saturated sodium bicarbonate solution (0.5mL) and toluene (1mL) is with phenyl-boron dihydroxide (14mg, 0.11mmol) and tetrakis triphenylphosphine palladium (8mg, 0.0074mmol) processing, and under refluxing, heated 4 hours.With the reaction mixture cooling, and between ethyl acetate and water, distribute.Layer is separated, and with organic layer salt water washing, with dried over sodium sulfate and filtration.Organic layer is concentrated under vacuum, obtain rough title compound, be orange, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (15mg, 30%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.06(s，3H)，2.77(s，3H)，6.44(d，J＝6.99Hz，1)，7.21(d，J＝8.09Hz，1H)，7.36(d，J＝8.46Hz，2H)7.41-7.52(m，3H)，7.58(d，J＝8.82Hz，2H)，7.71(d，J＝7.35Hz，2H)，7.75-7.87(m，3H)，8.44(d，J＝6.62Hz，1H)，9.02(d，J＝8.82Hz，1H)，10.10(s，1H)11.12(s，1H)，14.41(s，1H)；MS(ESI+)m/z?477(M+H)+.

Embodiment 34

N-{4-[5-hydroxy-4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 34A

N-[4-(5-hydroxy-4-methyl-2-nitro-phenyl sulfenyl)-phenyl]-ethanamide

With 2-methyl-4-nitro-5-chlorophenol (1.5g, 8.0mmol), 4-acetamido thiophenol (1.6g, 8.8mmol) and cesium carbonate (5.74g, 17.6mmol) mixture in DMF (10mL) in 100 ℃ the heating 2.5 hours.With the mixture cooling,, and, use anhydrous sodium sulfate drying then with organic layer water and the washing of 10% sodium chloride aqueous solution with ethyl acetate (100mL) dilution.Siccative is filtered, and under vacuum, remove and desolvate, obtain this title compound, be solid (2.5g, 81%).

Embodiment 34b

N-[4-(2-amino-5-hydroxy-4-methyl-phenyl sulfenyl)-phenyl]-ethanamide

With the product of embodiment 34a (2.5g, 6.45mmol), iron powder (1.79g, 32mmol) and ammonium chloride (0.514g, 9.6mmol) solution in methyl alcohol (10mL), tetrahydrofuran (THF) (10mL) and water (5mL) is heated to and refluxed 1.5 hours.The gained mixture dilutes with methyl alcohol (50mL), and filters by Celite pad.Filtrate is concentrated into the volume of 10mL under vacuum, and, extracts with ethyl acetate (2 x 50mL) with this solution with water (50mL) dilution.The extract that merges washs with 10% sodium-chlor, uses dried over mgso then, filters and concentrates under vacuum, obtains this title compound (1.7g, 91%).

Embodiment 34c

Method according to embodiment 1g, product (102mg with embodiment 1d, 0.570mmol) in ethanol (2mL) with the product (161mg of embodiment 34b, 0.560mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (50mg, 21%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.05(s，3H)2.12(s，3H)2.75(s，3H)6.31(d，J＝6.99Hz，1H)6.61(s，1H)7.15(s，1H)7.29(d，J＝8.46Hz，2H)7.56(d，J＝8.82Hz，2H)7.77(d，J＝8.82Hz，1H)8.39(d，J＝5.52Hz，1H)8.96(d，J＝8.82Hz，1H)9.90(s，1H)10.08(s，1H)10.84(s，1H)14.24(br?s，1H)；MS(ESI+)m/z?431(M+H)+.

Embodiment 35

N-{4-[2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-4-trifluoromethyl-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 35a

N-[4-(2-amino-4-trifluoromethyl-phenyl sulfenyl)-phenyl]-ethanamide

According to the method for embodiment 1e with 2-chloro-5-trifluoromethyl-phenyl amine (250mg, 1.11mmol) solution in DMF and N-(4-sulfydryl-phenyl)-ethanamide (185mg, 1.11mmol) reaction is 16 hours, obtains product (350mg, 88%), with its method SnCl according to embodiment 1f ₂Reduction obtains this title compound, is solid (260mg, 80%).

Embodiment 35b

Method according to embodiment 1g, product (50mg with embodiment 2g, 0.242mmol) with the product (79.0mg of embodiment 35a, 0.242mmol) reacted 16 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain two-trifluoroacetate (10.5mg, 10%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.98(t，J＝7.35Hz，3H)，1.81-1.92(m，J＝7.35Hz，2H)，2.07(s，3H)，3.01(t，J＝7.54Hz，2H)，6.44(d，J＝6.99Hz，1H)，7.11(d，J＝8.46Hz，1H)，7.42-7.49(m，J＝8.46Hz，2H)，7.69(d，J＝8.82Hz，2H)，7.78(dd，J＝8.82，1.47Hz，1H)，7.87(d，J＝8.82Hz，1H)，7.91(d，J＝1.10Hz，1H)，8.52(d，J＝6.99Hz，1H)，9.03(d，J＝8.46Hz，1H)，11.14(s，1H)；MS(ESI+)m/z?497(M+H)+，ESI-m/z?495(M-H)-.

Embodiment 36

N-{4-[2-(7-methyl-[1,8] naphthyridine-4-base is amino)-4-trifluoromethyl-phenyl sulfenyl]-phenyl }-ethanamide

According to the method for embodiment 1g, (50mg is 0.280mmol) with the product (91mg of embodiment 35a with the product of embodiment 1d, 0.280mmol) reacted 16 hours, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain trifluoroacetate (21.5mg, 20%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.07(s，3H)，2.78(s，3H)，6.43(d，J＝6.99Hz，1H)，7.09-7.15(m，1H)，7.44(d，J＝8.46Hz，2H)，7.68(d，J＝8.46Hz，2H)，7.78(dd，J＝8.64，1.65Hz，1H)，7.84(d，J＝8.82Hz，1H)，7.92(d，J＝1.84Hz，1H)，8.52(d，J＝7.35Hz，1H)，9.00(d，J＝8.46Hz，1H)，10.19(s，1H)，11.12(s，1H)；MS(ESI+)m/z?469(M+H-TFA)+，(ESI-)m/z?467(M-H-TFA)-.

Embodiment 37

[2-(4-acetylamino-phenyl sulfenyl)-5-methyl-phenyl]-[7-(2-hydroxyl-ethyl)-[1,8] naphthyridine-4-yl]-t-butyl carbamate

(22mg, 0.05mmol) (16mg 0.07mmol) reacts in the anhydrous THF of 2mL with tert-Butyl dicarbonate with the product of embodiment 24.Add Et3N (8.0mg, 0.08mmol) and the N of catalytic amount, N-4-dimethyl aminopyridine, and stirring 2 hours.Pour in the water, and neutralize with 1M HCl.With the EtOAc extraction, use Na ₂SO ₄Dry also filtration also concentrates under vacuum, obtains this rough title compound, and it is passed through silica gel column chromatography purifying purifying, 1% MeOH/CH ₂Cl ₂Wash-out, obtaining product is free alkali solid (7.0mg, 26%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.59(s，9H)2.03(s，3H)2.25(s，3H)2.96(t，J＝6.62Hz，2H)3.81(m，2H)4.74(t，J＝5.33Hz，1H)5.76(d，J＝6.90Hz，1H)6.63(s，1H)6.85(m，2H)7.22(d，J＝8.82Hz，2H)7.36(d，J＝8.09Hz，1H)7，52(d，J＝8.82Hz，2H)7.70(d，J＝8.46Hz，1H)8.50(d，J＝8.09Hz，1H)10.00(s，1H)；MS(ESI-)m/z?545(M+H)+，

Embodiment 38

N-{4-[2-(7-butyl-[1,8] naphthyridine-4-base is amino)-4-methyl-benzenesulfonyl]-phenyl }-ethanamide

(100mg 0.226mmol) is dissolved among the HOAc (1mL), and is cooled to 0 ℃ the product of embodiment 20.(56mg 0.113mmol), and is heated to room temperature with reaction mixture to add two (monoperphthalic acid) magnesium hexahydrate in this solution.This rough title compound used the TFA wash-out by the HPLC purifying, and the acquisition product is trifluoroacetic acid (34mg, 32%).

¹HNMR(500MHz，DMSO-d ₆)δ?ppm:1.07(t，J＝7.32Hz，3H)，1.91-1.98(m，4H)，2.11(s，3H)，2.49(s，3H)，3.05-3.10(m，2H)，6.03(d，J＝6.84Hz，1H)，7.31(d，J＝8.79Hz，2H)，7.35(s，1H)，7.48(d，J＝8.79Hz，2H)，7.67(d，J＝7.81Hz，1H)，7.83(d，J＝8.79Hz，1H)，8.10(d，J＝7.81Hz，1H)，8.19(d，J＝6.84Hz，1H)，9.05(d，J＝8.79Hz，1H)；MS(ESI+)m/z?459(M+H-TFA)+；(ESI-)m/z?457(M-H-TFA)-.

Embodiment 39

N-{3-fluoro-4-[4-methyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 39a

2-fluoro-1-methyl sulfenyl-4-nitro-benzene

To 1, (1.50g, (4.44mL 10.3mmol), also evaporated mixture in 1 hour in stirring at room 2-two fluoro-4-oil of mirbane then 9.3mmol) to drip the 15% NaSMe aqueous solution in 5 ℃ in the solution in MeOH (15mL).The solid that obtains is dissolved among the 150mL EtOAc, uses H ₂MgSO is used in O (twice) and salt water washing ₄Dry also evaporation obtains crude product, and it by carrying out purifying with cold normal hexane washing, is obtained required product, is yellow crystals (1.58g, 90%).

Embodiment 39b

3-fluoro-4-methyl sulfenyl-phenyl amine

Will the product of the embodiment 39a in the mixture of EtOH (7.5mL) and HOAc (7.5mL) (1.57g, 8.4mmol) and iron powder (1.41g 25.2mmol) is heated to 80 ℃ gradually, and this uniform temp heating 1 hour.Reaction mixture is evaporated.Resistates at CHCl ₃And 10%NaHCO ₃Between distribute, pass through diatomite filtration then.With organic layer H ₂MgSO is used in the O washing ₄Dry also evaporation obtains crude product, and it by carrying out purifying with the normal hexane washing, is obtained required product, is light brown crystal (1.08g, 82%).

Embodiment 39c

N-(3-fluoro-4-methyl sulfenyl-phenyl)-ethanamide

Will the product of the embodiment 39c in the pyridine (10mL) (1.08g, 6.9mmol) and Ac ₂(0.97mL is 10.3mmol) in 50 ℃ of heating 2 hours, evaporation then for O.With resistates H ₂The O dilution is acidified to pH 3 with 10% HCl, extracts with EtOAc then.Organic layer H ₂MgSO is used in O and salt water washing ₄Dry also evaporation obtains crude product, and it by carrying out purifying with the normal hexane washing, is obtained this title compound, is clear crystal (1.26g, 92%).

Embodiment 39d

N-[3-fluoro-4-(4-methyl-2-nitro-phenyl sulfenyl)-phenyl]-ethanamide

With the product of embodiment 39c (1.00g, 5.0mmol) and t-BuSNa (1.88g, 15.1mmol) in dry DMF (10mL) under the nitrogen gas stream in 160 ℃ of heating 4 hours, be cooled to room temperature then.(2.36mL 17.6mmol), heats mixture 4 hours in 80 ℃ under nitrogen gas stream then to add 1-chloro-4-methyl-2-oil of mirbane in room temperature in reaction mixture.With mixture H ₂The O dilution extracts with EtOAc then.With extract H ₂MgSO is used in O and salt water washing ₄Dry also evaporation.Resistates with 2:1 EtOAc/ hexane wash-out, obtains this title compound by the silica gel column chromatography purifying, is yellow crystals (1.04g, 65%).

Embodiment 39e

N-[4-(2-amino-4-methyl-phenyl sulfenyl)-3-fluoro-phenyl]-ethanamide

According to the method for embodiment 237E, with product Fe and the NH of embodiment 39d ₄The Cl reduction obtains this title compound.

Embodiment 39f

According to the method for embodiment 1g, (100mg, 0.48mmol) (140mg 0.48mmol) in 120 ℃ of reactions 22 hours, obtains this title compound, is solid (120mg, 54%) in the product of embodiment 39e with the product of embodiment 2g.

¹HNMR (300MHz, DMSO-d ₆) δ ppm:0.99 (t, J=7.3Hz, 3H), 1.86 (sextet, J=7.3Hz, 2H), 2.06 (s, 3H), 2.36 (s, 3H), 3.01 (t, J=7.3Hz, 2H), 6.28 (d, J=6.9Hz, 1H), 7.12-7.35 (m, 5H), 7.55 (dd, J=12.1,2.2Hz, 1H), 7.82 (d, J=8.8Hz, 1H), 8.42 (d, J=6.9Hz, 1H), 9.04 (d, J=8.8Hz, 1H); MS (ESI+) m/z 461 (M+H)+, ESI-m/z 459 (M-H)-

Embodiment 40

N-{3,5-two fluoro-4-[4-methyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 40a

N-[3,5-two fluoro-4-(4-methyl-2-nitro-phenyl sulfenyl)-phenyl]-ethanamide

Use the method for embodiment 39a, with 1,2,3-three fluoro-5-oil of mirbane substitute 1, and 2-two fluoro-4-oil of mirbane make this title compound.With product 2,6-two fluoro-1-methyl sulfenyl-4-oil of mirbane carry out the method for embodiment 39b, 39c and 39d, obtain this title compound then.

Embodiment 40b

N-[4-(2-amino-4-methyl-phenyl sulfenyl)-3,5-two fluoro-phenyl]-ethanamide

According to the method for embodiment 237E, with product Fe and the NH of embodiment 40a ₄The Cl reduction obtains this title compound.

Embodiment 40c

According to the method for embodiment 1g, (100mg, 0.48mmol) (140mg 0.48mmol) in 120 ℃ of reactions 16 hours, obtains this title compound (120mg, 52%) of salt form with the product of embodiment 2g with the product of embodiment 40c.

¹H NMR (300MHz, DMSO-d ₆) δ ppm:0.99 (t, J=7.3Hz, 3H), 1.86 (sextet, J=7.3Hz, 2H), 2.06 (s, 3H), 2.36 (s, 3H), 3.01 (t, J=7.3Hz, 2H), 6.28 (d, J=6.9Hz, 1H), 7.12-7.35 (m, 5H), 7.55 (dd, J=12.1,2.2Hz, 1H), 7.82 (d, J=8.8Hz, 1H), 8.42 (d, J=6.9Hz, 1H), 9.04 (d, J=8.8Hz, 1H); MS (ESI+) m/z 461 (M+H)+, (ESI-) m/z 459 (M-H)-.

Embodiment 41

(7-methyl-[1,8] naphthyridine-4-yl)-(5-methyl-2-phenoxy group-phenyl)-amine

Embodiment 41a

4-methyl-2-nitro-1-phenoxy group-benzene

According to the method for embodiment 1c, (5.0g, 30mmol) (2.65mL, 30mmol) solution in 60mL DMF is under agitation in 100 ℃ of heating 5 days with 4-chloro-3-nitrotoluene with the sodium phenylate trihydrate.This product is used CH by the silica gel column chromatography purifying ₂Cl ₂Wash-out obtains this title compound, is orange solids (1.36g, 30%).

Embodiment 41b

5-methyl-2-phenoxy group-phenyl amine

According to the method for embodiment 1f, (884mg 3.86mmol) uses SnCl with the product of embodiment 41a ₂(3.5g 19.0mmol) handled 24 hours, obtained this title compound, was yellow oil (710mg, 93%).

Embodiment 41c

(7-methyl-[1,8] naphthyridine-4-yl)-(5-methyl-2-phenoxy group-phenyl)-amine

According to the method for embodiment 1g, (65mg 0.36mmol) with the product reaction of embodiment 1d, obtains this title compound, and it is developed with ether, and the acquisition product is hydrochloride (12mg, 8.8%) with the product of embodiment 41b.

¹HNMR(300MHz，DMSO-d ₆)δppm:0.95(t，J＝7.73Hz，3H)1.82(q，J＝7.72Hz，2H)2.97(dd，J＝7.73Hz，2H)6.68(d，J＝6.99Hz，1H)6.99(d，J＝7.72Hz，2H)7.12(dd，J＝8.82Hz，2H)7.30(dd，J＝8.09Hz，2H)7.66(dd，J＝8.82Hz，J＝2.58Hz，1H)7.71(d，J＝2.2Hz，1H)7.77(d，J＝8.82Hz，1H)8.52(d，J＝6.98Hz，1H)9.07(d，J＝8.82Hz，1H)11.26(br?s，1H)14.45(brs，1H)；MS(ESI+)m/z?390(M-Cl)+；(ESI-)m/z388(M-HCl)-.

Embodiment 42

(5-chloro-2-phenoxy group-phenyl)-(7-ethyl-[1,8] naphthyridine-4-yl)-amine

Embodiment 42a

4-chloro-2-nitro-1-phenoxy group-benzene

In the solution (50mL) of DMF, add 1-bromo-2-nitro-4-chloro-benzene (5.0g, 21.1mmol), phenol (1.9g, 21.1mmol) and Na ₂CO ₃(2.3g, 21.1mmol).This solution is heated to 85 ℃ and stir and to spend the night.This reaction is poured in the water, and extract with EtOAc.Wash with water, and use Na ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains yellow oil, and by silica gel column chromatography purifying purifying, hexane: ethyl acetate (90:10) wash-out obtains this title compound (3.8g, 74%) with it.

Embodiment 42b

5-chloro-2-phenoxy group-phenyl amine

With embodiment 42a product (13g, 52.1mmol) and SnCl ₂(method according to embodiment 1f obtains this title compound, is white solid (9.0g, 79%) for 49.3g, 260mmol) reaction

Embodiment 42c

(5-chloro-2-phenoxy group-phenyl)-(7-ethyl-[1,8] naphthyridine-4-yl)-amine

(100mg, 0.46mmol) (88mg 0.46mmol) according to the method reaction of embodiment 1g, obtains this title compound, and with 2:1 ether/THF development, the acquisition product is hydrochloride (134mg, 70%) with it with the product of embodiment 3f with the product of embodiment 42b.

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.34(t，J＝7.35Hz，3H)3.02(q，J＝7.35Hz，2H)6.69(d，J＝6.99Hz，1H)6.97(d，J＝8.82Hz，2H)7.10(dd，J＝7.35Hz，1H)7.15(d，J＝8.82Hz， ²H)7.30(dd，J＝8.09Hz，J＝7.72Hz，2H)7.56(dd，J＝2.94Hz，J＝9.19Hz，1H)7.71(d，J＝2.57Hz，1H)7.88(d，J＝8.82Hz，1H)8.52(d，J＝6.99Hz，1H)9.02(d，J＝8.45Hz，1H)11.16(br?s，1H)14.56(br?s，1H)；MS(ESI+)m/z?376(M-Cl)+；(ESI-)m/z?374(M-HCl)-.

Embodiment 43

(5-chloro-2-phenoxy group-phenyl)-(7-trifluoromethyl-[1,8] naphthyridine-4-yl)-amine

Product (60mg with embodiment 42b, 0.27mmol) with the product (63mg of embodiment 7d, 0.27mmol) reacted 24 hours according to the method for embodiment 1g, obtain this title compound of rough solid form, it is developed with 4:1 ether/THF, the acquisition product is hydrochloride (112mg, 91%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:6.82(d，J＝6.99Hz，1H)6.98(d，J＝7.72Hz，2H)7.13(m，2H)7.32(dd，J＝7.73Hz，J＝8.82Hz，2H)7.57(dd，J＝2.57Hz，J＝8.82Hz，1H)7.71(d，J＝2.57Hz，1H)8.36(d，J＝8.82Hz，1H)8.69(d，J＝6.99Hz，1H)9.42(d，J＝8.82Hz，1H)11.47(br?s，1H)14.40(br?s，1H)；MS(ESI+)m/z?416(M-Cl)+；(ESI-)m/z?414(M-HCl)-.

Embodiment 44

4-[4-benzylamino-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

Embodiment 44a

4-(4-amino-2-nitro-phenyl sulfenyl)-phenol

With 4-chloro-3-N-methyl-p-nitroaniline (1.0g, 5.79mmol), the 4-hydroxythiophenol (0.75g, 6.00mmol), cesium carbonate (3.9g, 12mmol) solution in DMSO (10mL) in 100 ℃ the heating 16 hours.Then frozen water (50mL) is added in this solution, and the gained slurries are handled with ethyl acetate (100mL), layer is separated, and organic layer is used anhydrous sodium sulfate drying then with 10% sodium bicarbonate and the washing of 10% sodium-chlor.Siccative is filtered and under vacuum, concentrate, obtain this title compound, be red solid (1.45g, 92%).

Embodiment 44b

4-(4-benzylamino-2-nitro-phenyl sulfenyl)-phenol

With embodiment a product (0.63g, 2.4mmol), phenyl aldehyde (0.24g, 2.3mmol) and sodium cyanoborohydride (0.15g, 2.4mmol) solution in the methyl alcohol that contains 1% acetate (10mL) was in stirring at room 16 hours.Reaction mixture water (20mL) is ended, and gained solution simmer down to yellow solid in a vacuum.This solid is dissolved in the ethyl acetate (50mL), and water, 10% sodium bicarbonate and the washing of 10% sodium-chlor.With the organic layer anhydrous sodium sulfate drying, filter and remove in a vacuum and desolvate, obtain light yellow oil.This oily matter is loaded on silicagel column, and use CBbCl ₂Use 1% methyl alcohol at CH then ₂Cl ₂In eluant solution.The product fraction that obtains is merged, and be evaporated to driedly, obtain this title compound, be yellow solid (0.63g, 77%).

Embodiment 44c

4-(2-4-benzylamino-4-phenyl sulfenyl)-phenol

According to the method for embodiment 237E, with product Fe and the NH of embodiment 44b ₄The Cl reduction obtains this title compound.

Embodiment 44d

According to the method for embodiment 1g, (105mg is 0.50mmol) with the product (161mg of embodiment 44c with the product of embodiment 2g, 0.50mmol) reacted 18 hours, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain trifluoroacetate (68mg, 22%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.97(t，J＝7.35Hz，3H)1.83(sext，J＝7.35Hz，2H)2.97(dd，J＝7.35Hz，2H)4.29(m，2H)6.15(d，J＝6.99Hz，1H)6.51(d，J＝8.46Hz，2H)6.93(d，J＝8.46Hz，2H)7.22-7.38(m，8H)7.78(d，J＝8.83Hz，1H)8.95(d，J＝8.46Hz，1H)9.66(s，1H)10.90(br?s，1H)14.21(br?s，1H)；MS(ESI+)m/z?493(M+H-TFA)+.

Embodiment 45

4-[4-benzylamino-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

According to the method for embodiment 1g, (57mg is 0.319mmol) with the product (102mg of embodiment 44c with the product of embodiment 1d, 0.319mmol) reacted 72 hours, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain trifluoroacetate (169mg, 91%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.74(s，3H)4.30(s，2H)6.15(d，J＝6.99Hz，1H)6.52(d，J＝8.46Hz，1H)6.56-7.39(m，11H)7.75(d，J＝8.46Hz，1H)8.28(d，J＝7.36Hz，1H)9.50(br?s，1H)10.85(br?s，1H)14.25(br?s，1H)；MS(ESI+)m/z?465(M+H-TFA)+；(ESI-)m/z463(M-H-TFA)-.

Embodiment 46

N-{4-[4-methyl-2-(7-morpholine-4-base-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 46a

N-{4-[2-(7-chloro-[1,8] naphthyridine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenyl }-ethanamide

According to the method for embodiment 1g, (200mg is 1.0mmol) with the product (215mg of embodiment 18b with the product of embodiment 13d, 1.0mmol) reacted 24 hours, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain trifluoroacetate (200mg, 45%).

Embodiment 46b

In sealed tube with the product of embodiment 46a (0.047g, 0.1mmol) and morpholine (0.087g, 1.0mmol) in ethanol (0.5mL) in 110 ℃ of heating 1 hour, be cooled to room temperature and concentrate.This thick resistates is used the TFA wash-out by the HPLC purifying, obtains this title compound, is trifluoroacetate (0.030g, 50%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.04(s，3H)，2.33(s，3H)，3.56-3.93(m，8H)，6.07(d，J＝6.99Hz，1H)，7.09(d，J＝8.09Hz，1H)，7.20-7.32(m，4H)，7.54(d，J＝8.82Hz，2H)，8.07(t，J＝6.80Hz，1H)，8.64(d，J＝9.56Hz，1H)，10.06(s，1H)，10.45(s，1H)，13.42(d，J＝5.88Hz，1H)；MS(ESI+)m/z?486(M+H) ⁺.

Embodiment 47

(7-methyl-[1,8] naphthyridine-4-yl)-(5-methyl-2-p-methylphenyl sulfenyl-phenyl)-amine

Embodiment 47a

4-methyl-2-nitro-1-p-methylphenyl sulfenyl-benzene

Method according to embodiment 1e, product (5.00g with embodiment 4a, 17.53mmol) with the 4-methylbenzene thiophenol (2.17g of alternative thiophenol, 17.53mmol) reacted 18 hours, obtain this rough title compound, it by silica gel column chromatography purifying purifying, is used 5%EtOAc/ hexane wash-out, obtain solid (3.53g, 78%).

Embodiment 47b

5-methyl-2-p-methylphenyl sulfenyl-phenyl amine

According to the method for embodiment 1f, with the product SnCl of embodiment 47a ₂Reduction obtains this title compound.

Embodiment 47c

According to the method for embodiment 1g, (267mg is 1.56mmol) with the product (358mg of embodiment 47b with the product of embodiment 1d, 1.56mmol) reacted 48 hours, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain trifluoroacetate (347mg, 46%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.22(s，3H)2.37(s，3H)2.77(s，3H)6.27(d，J＝7.35Hz，1H)7.04(d，J＝7.72Hz，2H)7.14(m，2H)7.29(m，3H)7.79(d，J＝8.82Hz，1H)8.39(d，J＝6.99Hz，1H)8.95(d，J＝8.46Hz，1H)11.25(br.s.，1H)14.39(br.s.，1H)；MS(ESI+)m/z?372(M+H)+.

Embodiment 48

(7-methyl-[1, S] naphthyridine-4-yl)-(tolyl sulfenyl-phenyl between 5-methyl-2-)-amine

Embodiment 48a

Tolyl sulfenyl-benzene between 4-methyl-2-nitro-1-

Method according to embodiment 1e, product (9.46g with embodiment 4a, 33.17mmol) with the 3-methylbenzene thiophenol (4.12g of alternative thiophenol, 33.17mmol) reacted 18 hours, obtain this rough title compound, it by silica gel column chromatography purifying purifying, is used 5%EtOAc/ hexane wash-out, obtain solid (7.50g, 87%).

Embodiment 48b

Tolyl sulfenyl-phenyl amine between 5-methyl-2-

According to the method for embodiment 1f, with the product SnCl of embodiment 48a ₂Reduction obtains this title compound.

Embodiment 48c

(7-methyl-[1,8] naphthyridine-4-yl)-(tolyl sulfenyl-phenyl between 5-methyl-2-)-amine

According to the method for embodiment 1g, (267mg is 1.56mmol) with the product (358mg of embodiment 48b with the product of embodiment 1d, 1.56mmol) reacted 48 hours, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain trifluoroacetate (116mg, 15%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.10(s，3H)2.38(s，3H)2.76(s，3H)6.27(d，J＝7.35Hz，1H)7.00(m，3H)7.40(m，3H)7.78(d，J＝8.82Hz，1H)8.37(d，J＝6.99Hz，1H)8.92(d，J＝8.82Hz，1H)11.08(br.s.，1.H)14.45(br.s.，1H)；MS(ESI+)m/z?372(M+H)+.

Embodiment 49

[2-(4-fluoro-phenyl sulfenyl)-5-methyl-phenyl]-(7-methyl-[1,8] naphthyridine-4-yl)-amine

Embodiment 49a

1-(4-fluoro-phenyl sulfenyl)-4-methyl-2-nitro-benzene

Method according to embodiment 1e, product (5.00g with embodiment 4a, 17.53mmol) with the 4-fluoro thiophenol (2.24g of alternative thiophenol, 17.53mmol) reacted 18 hours, obtain this rough title compound, it is passed through silica gel column chromatography purifying purifying, with 5% EtOAc/ hexane wash-out, obtain solid (3.39g, 74%).

Embodiment 49b

2-(4-fluoro-phenyl sulfenyl)-5-methyl-phenyl amine

Product SnC with embodiment 49a ₂Reduction obtains this title compound according to the method for embodiment 1f.

Embodiment 49c

According to the method for embodiment 1g, (167mg is 0.94mmol) with the product (218mg of embodiment 49b with the product of embodiment 1d, 0.94mmol) reacted 48 hours, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain trifluoroacetate (224mg, 49%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.37(m，3H)2.77(m，3H)6.29(d，J＝6.99Hz，1H)7.10(m，2H)7.32(m，5H)7.80(d，J＝8.46Hz，1H)8.41(d，J＝6.99Hz，1H)8.95(d，J＝8.46Hz，1H)11.04(br.s.，1H)14.43(br.s.，1H)；MS(ESI+)m/z?376(M+H)+.

Embodiment 50

[2-(4-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl]-(7-methyl-[1,8] naphthyridine-4-yl)-amine

Embodiment 50a

1-(4-methoxyl group-phenyl sulfenyl)-4-methyl-2-nitro-benzene

According to the method for embodiment 4b, (5.0g, 175mmol) (2.45g, 175mmol) reaction is 18 hours, obtains solid product (3.76g, 78%) with 4-methoxyl group-benzenethiol with the product of embodiment 4a.

Embodiment 50b

2-(4-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl amine

According to the method for embodiment 1f, the product SnCl of routine 50a will be executed ₂Reduction obtains this title compound.

Embodiment 50c

According to the method for embodiment 1g, (167mg is 0.94mmol) with the product (245mg of embodiment 50b with the product of embodiment 1d, 0.94mmol) reacted 48 hours, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain trifluoroacetate (325mg, 70%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.35(s，3H)2.77(s，3H)3.73(s，3H)6.26(d，J＝6.99Hz，1H)6.85(d，J＝8.82Hz，2H)7.11(d，J＝7.72Hz，1H)7.26(d，J＝8.82Hz，2H)7.31(s，1H)7.80(d，J＝8.46Hz，1H)8.41(d，J＝6.99Hz，1H)8.99(d，J＝8.82Hz，1H)11.04(br.s.，1H)14.32(br.s.，1H)；MS?ESI+m/z?388(M+H)+.

Embodiment 51

[2-(3,4-dimethoxy-phenyl sulfenyl)-5-methyl-phenyl]-(7-methyl-[1,8] naphthyridine-4-yl)-amine

Embodiment 51a

2-(3,4-dimethoxy-phenyl sulfenyl)-5-methyl-phenyl amine

According to the method for embodiment 4b, (11.25g, 39.5mmol) with 3, (6.71g, 39.5mmol) reaction is 18 hours, obtains solid product (7.75g, 64%) for 4-dimethoxy-benzenethiol with the product of embodiment 4a.

Embodiment 51b

2-(3,4-dimethoxy-phenyl sulfenyl)-5-methyl-phenyl amine

According to the method for embodiment 1f, with the product SnCl of embodiment 51a ₂Reduction obtains this title compound.

Embodiment 51c

According to the method for embodiment 1g, (277mg is 1.56mmol) with the product (430mg of embodiment 51b with the product of embodiment 1d, 1.56mmol) reacted 5 hours, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain trifluoroacetate (628mg, 79%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.35(s，3H)2.76(s，3H)3.56(s，3H)3.68(s，3H)6.24(d，J＝6.99Hz，1H)6.82(m，3H)7.29(m，3H)7.79(d，J＝8.46Hz，1H)838(d，J＝6.99Hz，1H)8.97(d，J＝8.46Hz，1H)10.97(s，1H)14.35(s，1H)；MS(ESI+)m/z?418(M+H)+.

Embodiment 52

3-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

Embodiment 52a

3-(4-methyl-2-nitro-phenyl sulfenyl)-phenol

According to the method for embodiment 4b, (10.14g, 35.6mmol) (4.48g, 35.6mmol) reaction is 18 hours, obtains solid product (7.88g, 85%) with 3-(4-methyl-2-nitro-phenyl sulfenyl)-phenol with the product of embodiment 4a.

Embodiment 52b

3-(2-amino-4-methyl-phenyl sulfenyl)-phenol

According to the method for embodiment 1f, with the product SnCl of embodiment 52a ₂Reduction obtains this title compound.

Embodiment 52c

According to the method for embodiment 1g, (277mg is 1.56mmol) with the product (245mg of embodiment 52b with the product of embodiment 1d, 1.56mmol) reacted 5 hours, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain trifluoroacetate (399mg, 52%).

¹HNMR(300MHz，DMSO-d ₆)δ?ppm:2.38(s，3H)2.75(s，3H)6.30(d，J＝6.99Hz，1H)6.53-6.58(m，2H)6.61(d，J＝8.09Hz，1H)6.90-7.08(m，1H)7.27-7.47(m，3H)7.77(d，J＝8.46Hz，1H)8.39(d，J＝6.99Hz，1H)8.94(d，J＝8.82Hz，1H)9.58(s，1H)10.96(s，1H)14.34(s，1H)；MS(ESI+)m/z?374(M+H)+.

Embodiment 53

[3-(7-methyl-[1,8] naphthyridine-4-base is amino)-4-phenyl sulfenyl-phenyl]-methyl alcohol

Embodiment 53a

4-hydroxyl-3-nitro-ethyl benzoate

According to the method for embodiment 4a, (15.0g is 76.1mmol) with Trifluoromethanesulfonic anhydride (14.0mL with the solution of 4-hydroxyl-3-nitro-ethyl benzoate, 83.7mmol) reacted 15 minutes, obtain this title compound, be succsinic acid oily matter (22.26g, 89%).

Embodiment 53b

3-nitro-4-phenyl sulfenyl-ethyl benzoate

According to the method for embodiment 1e, (22.6g, 676mmol) (7.54g, 67.6mmol) reaction is 24 hours, obtains this title compound, is solid (13.2g, 67%) with thiophenol sodium with the product of embodiment 53a.

Embodiment 53c

3-amino-4-phenyl sulfenyl-ethyl benzoate

According to the method for embodiment 1f, product and SnCl2 reaction with embodiment 53b obtain this title compound, are solid.

Embodiment 53c

3-(7-methyl-[1,8] naphthyridine-4-base is amino)-4-phenyl sulfenyl-ethyl benzoate

According to the method for embodiment 1g, (2.06g is 1.16mmol) with the product (3.18g of embodiment 53b with the product of embodiment 1d, 1.16mmol) reacted 5 hours, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain trifluoroacetate (3.61g, 59%).

Embodiment 53d

Will the product of the embodiment 53c among the 60mL THF (2.30g, 5.54mmol) and LiAlH ₄(420mg, 11.0mmol) reaction is 18 hours, uses rare HCl stopped reaction then.Use NH ₄OH is adjusted to pH 10.Use CH ₂Cl ₂MgSO is used in extraction ₄Drying is filtered and is concentrated under vacuum, obtains this rough title compound, and it by the HPLC purifying, is used the TFA wash-out, obtains trifluoroacetate (325mg, 70%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.76(s，3H)3.99(br.s，1H)4.58(s，2H)6.31(d，J＝7.35Hz，1H)7.25(s，5H)7.40(m，2H)7.46(s，1H)7.78(d，J＝8.82Hz，1H)8.42(d，J＝6.99Hz，1H)8.95(d，J＝8.46Hz，1H)11.06(br.s.，1H)14.44(br.s.，1H)；MS(ESI+)m/z374(M+H)+.

Embodiment 54

[2-(4-oxyethyl group-phenyl sulfenyl)-5-methyl-phenyl]-(7-methyl-[1,8] naphthyridine-4-yl)-amine

Embodiment 54a

1-(4-oxyethyl group-phenyl sulfenyl)-4-methyl-2-nitro-benzene

With the product of embodiment 4b (500mg, 1.91mmol) with NaH (0.048g, 2.01mmol) in 10mL THF in 0 ℃ of reaction 2 hours.Be heated to room temperature, and slowly add EtI (0.232mL, 2.87mmol), then in stirring at room 4 days.Water is ended, and layer is separated, and use MgSO ₄Drying is filtered and is concentrated under vacuum, obtains product, is solid (510mg, 92%).Method SnCl according to embodiment 1f ₂Reduction obtains this title compound.

Embodiment 54b

According to the method for embodiment 1g, (250mg is 1.56mmol) in the product (259mg of embodiment 54a with the product of embodiment 1d, 1.56mmol) reacted 5 hours, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain trifluoroacetate (241mg, 30%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.31(t，J＝6.99Hz，3H)2.34(s，3H)2.76(s，3H)3.97(q，J＝6.99Hz，2H)6.26(d，J＝7.35Hz，1H)6.83(d，J＝8.82Hz，2H)7.11(d，J＝7.72Hz，1H)7.24(d，J＝8.82Hz，2H)7.27(s，1H)7.30(s，1H)7.80(d，J＝8.82Hz，1H)8.41(d，J＝6.99Hz，1H)8.99(d，J＝8.82Hz，1H)11.01(s，1H)14.38(s，1H)；MS(ESI+)m/z?402(M+H)+.

Embodiment 55

(7-methyl-[1,8] naphthyridine-4-yl)-[5-methyl-2-(4-propoxy--phenyl sulfenyl)-phenyl]-amine

Embodiment 55a

4-methyl-2-nitro-1-(4-propoxy--phenyl sulfenyl)-benzene

(600mg, 2.30mmol) (0.83g 2.30mmol) reacted 2 hours in 0 ℃ in 10mL THF the product of embodiment 4b with NaH.(0.232mL 2.87mmol), stirred 7 days in 50 ℃ then to be heated to room temperature and the slow EtI of adding.Water is ended, and layer is separated, and uses MgSO ₄Drying is filtered and is concentrated under vacuum, obtains product, is solid (700mg, 100%).Method SnCl according to embodiment 1f ₂Reduction obtains this title compound.

Embodiment 55b

According to the method for embodiment 1g, (250mg is 1.56mmol) in the product (273mg of embodiment 55a with the product of embodiment 1d, 1.56mmol) reacted 5 hours, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain trifluoroacetate (187mg, 23%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.97(t，J＝7.35Hz，3H)1.62-1.79(m，2H)2.34(s，3H)2.76(s，3H)3.86(t，J＝6.43Hz，2H)6.27(d，J＝6.99Hz，1H)6.84(d，J＝8.82Hz，2H)7.11(d，J＝7.72Hz，1H)7.24(d，J＝8.46Hz，2H)7.29(s，1H)7.80(d，J＝8.46Hz，1H)8.42(d，J＝6.99Hz，1H)8.99(d，J＝8.46Hz，1H)11.01(s，1H)14.39(s，1H)；MS(ESI+)m/z416(M+H)+.

Embodiment 56

[2-(4-isopropoxy-phenyl sulfenyl)-5-methyl-phenyl]-(7-methyl-[1,8] naphthyridine-4-yl)-amine

Embodiment 56a

2-(4-isopropoxy-phenyl sulfenyl)-5-methyl-phenyl amine

With the product of embodiment 4b (600mg, 2.30mmol) with NaH (0.83g, 2.44mmol) in 10mL THF in 0 ℃ of reaction 2 hours.Be heated to room temperature, and (0.574mL 5.74mmol), stirred 10 days in 50 ℃ then slowly to add i-Pr-I.Water is ended, and layer is separated, and uses MgSO ₄Drying is filtered and is concentrated under vacuum, obtains product, is solid (730mg, 100%).Method SnCl according to embodiment 1f ₂Reduction obtains this title compound.

Embodiment 56b

According to the method for embodiment 1g, (250mg is 1.56mmol) with the product (427mg of embodiment 56a with the product of embodiment 1d, 1.56mmol) reacted 5 hours, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain trifluoroacetate (185mg, 23%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.23(d，J＝6.25Hz，6H)2.34(s，3H)2.76(s，3H)4.48-4.58(m，1H)6.27(d，J＝6.99Hz，1H)6.81(d，J＝8.82Hz，2H)7.14(d，J＝8.09Hz，1H)7.22(d，J＝8.82Hz，2H)7.27(s，1H)7.30(s，1H)7.79(d，J＝8.82Hz，1H)8.41(d，J＝6.99Hz，1H)8.99(d，J＝8.46Hz，1H)10.99(s，1H)14.36(s，1H)；MS(ESI+)m/z?416(M+H)+.

Embodiment 57

N-(4-bromo-phenyl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(7-propyl group-[1,8] naphthyridine-4-base is amino)-benzamide

Embodiment 57a

N-(4-bromo-phenyl)-4-chloro-3-nitro-benzamide

With 4-bromaniline (2.58g 14.99mmol) at anhydrous CH ₂Cl ₂Mixture (100mL) with 4-chloro-3-nitrobenzoyl chloride (3.60g, 17.99mmol) and N, N-di-isopropyl-ethylamine (3.14mL 17.99mmol) handles, and with the gained mixture in stirring at room 17 hours.Solvent is concentrated under vacuum, obtain this title compound, resistates is dissolved in the ethyl acetate (100mL), and water and salt water washing.Organic extract Na ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound, is brown solid (5.132g, 14.45mmol, 96%).

Embodiment 57b

N-(4-bromo-phenyl)-4-(4-hydroxyl-phenyl sulfenyl)-3-nitro-benzamide

With the product of embodiment 57a (553mg, 1.557mmol) solution in dry DMF (15mL) in room temperature with the 4-mercapto-phenol (196mg, 1.557mmol) and cesium carbonate (1.015g 3.114mmol) handles, and heats 3 hours in 100 ℃ under nitrogen then.Reaction is cooled to room temperature, and solvent is concentrated under vacuum, obtain this title compound.Resistates is dissolved in H ₂Among the O (30mL), and regulate pH to 3 with the 1N HCl aqueous solution.Use the ethyl acetate extraction water then, and the organic extract that merges is washed with salt solution (25mL).Organic layer Na ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound.Resistates is developed with methylene dichloride, and by silica gel column chromatography purifying purifying, with 6%-30% ethyl acetate/dichloromethane gradient elution, obtains this title product, is blackyellow solid (517mg, 1.16mmol, 75%).

Embodiment 57c

3-amino-N-(4-bromo-phenyl)-4-(4-hydroxyl-phenyl sulfenyl)-benzamide

According to the method for embodiment 237E, with product Fe and the NH of embodiment 57b ₄The Cl reduction obtains this title compound.

Embodiment 57d

According to the method for embodiment 1g, (138mg is 0.154mmol) with the product (64mg of embodiment 57C with the product of embodiment 2g, 0.154mmol) reacted 40 hours, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain trifluoroacetate (30mg, 20%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.99(t，J＝7.35Hz，3H)1.69-1.96(m，2H)3.02(t，J＝7.35Hz，2H)6.42(d，J＝6.99Hz，1H)6.87(d，J＝8.46Hz，2H)7.02(d，J＝8.46Hz，1H)7.33(d，J＝8.46Hz，2H)7.54(d，J＝9.19Hz，2H)7.72(d，J＝8.82Hz，2H)7.87(d，J＝8.82Hz，1H)7.98(dd，J＝8.46，1.84Hz，1H)8.02(d，J＝1.84Hz，1H)8.52(d，J＝6.62Hz，1H)9.09(d，J＝8.46Hz，1H)10.09(s，1H)10.37(s，1H)11.14(s，1H)14.54(s，1H)；MS(ESI+)m/z?585/587(M+H)+.

Embodiment 58

5-dimethylamino-naphthalene-1-sulfonic acid 4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenylester

(167mg, 0.94mmol) (245mg is 0.94mmol) at 10mL CH with 5-dimethylamino-naphthalene-1-alkylsulfonyl chlorine with the product of embodiment 5 ₂Cl ₂In with N, the N-diisopropyl ethyl amine (0.530mL, 410mmol) reaction 22 hours.Wash with water, and use Na ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains this rough title compound, and it by the HPLC purifying, is used the TFA wash-out, obtains trifluoroacetate (35mg, 40%).

¹H?NMR(300MHz，DMSO-d ₆)δppm:2.75(s，3H)2.86(s，6H)6.65(d，J＝6.99Hz，1H)6.76(d，J＝9.19Hz，2H)6.87(d，2H)7.16(d，J＝8.82Hz，1H)7.34(d，J＝7.72Hz，1H)7.53-7.62(m，2H)7.69-7.79(m，3H)7.97(d，J＝7.35Hz，1H)8.22(d，J＝8.82Hz，1H)8.50(d，J＝6.99Hz，1H)8.60(d，J＝8.46Hz，1H)8.82(d，J＝8.82Hz，1H)；MS1H)8.50(d，J＝6.99Hz，1H)8.60(d，J＝8.46Hz，1H)8.82(d，J＝8.82Hz，1H)；MS(DCI?NH3+)m/z?611(M+H)+.

Embodiment 59

Ethyl sulfonic acid 4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenylester

According to the method for embodiment 58, (100mg is 0.24mmol) with ethylsulfonyl chlorine (31.0mg with the product of embodiment 5; 0.24mmol) reacted 18 hours, obtain this rough title compound, it is passed through the HPLC purifying; use the TFA wash-out, obtain trifluoroacetate (20mg, 14%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:10.98(s，1H)8.89(d，J＝8.46Hz，1H)8.39(d，J＝6.99Hz，1H)7.76(d，J＝8.82Hz，1H)7.45-7.50(m，1H)7.36-7.42(m，2H)7.25(d，2H)7.17(d，2H)6.33(d，J＝6.99Hz，1H)3.47(q，J＝7.35Hz，2H)2.75(s，3H)2.40(s，3H)1.34(t，J＝7.35Hz，3H)；MS(DCI?NH3+)m/z?466(M+H)+.

Embodiment 60

Third-2-sulfonic acid 4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenylester

According to the method for embodiment 58, (80.0mg is 0.195mmol) with second-2-alkylsulfonyl chlorine (27.8mg with the product of embodiment 5; 0.195mmol) reacted 18 hours, obtain this rough title compound, it is passed through the HPLC purifying; use the TFA wash-out, obtain trifluoroacetate (20mg, 21%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:8.90(d，J＝8.46Hz，1H)8.39(d，J＝6.99Hz，1H)7.76(d，J＝8.82Hz，1H)7.43-7.49(m，1H)7.35-7.42(m，2H)7.24·7.29(m，2H)7.12-7.19(m，2H)6.33(d，J＝6.99Hz，1H)2.75(s，3H)3.66(m，1)2.39(s，3H)1.40(d，J＝6.99Hz，6H)；MS(DCINH3+)m/z?480(M+H)+.

Embodiment 61

Methylsulfonic acid 4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenylester

According to the method for embodiment 58, (80mg is 0.195mmol) with methane sulfonyl chloride (22.3mg with the product of embodiment 5,0.195mxnol) reacted 18 hours, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain trifluoroacetate (36mg, 32%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:8.88(d，J＝8.46Hz，1H)8.39(d，J＝6.99Hz，1H)7.76(d，J＝8.46Hz，1H)7.45-7.51(m，1H)7.35-7.42(m，2H)7.26(d，2H)7.19(d，2H)6.33(d，J＝6.99Hz，1H)3.34(s，3H)2.75(s，3H)2.40(s，3H)；MS(DCINH3+)m/z?452(M+H)+.

Embodiment 62

Ethyl sulfonic acid 4-[2-(7-ethyl-[1,8] naphthyridine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenylester

According to the method for embodiment 58, (20mg is 0.47mmol) with SULPHURYL CHLORIDE (72mg with the product of embodiment 4,0.56mmol) reacted 22 hours, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain trifluoroacetate (70mg, 25%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:8.31(d，1H)7.73(d，1H)7.11(d，1H)6.85(d，1H)6.74(s，2H)6.64(d，2H)6.53(d，2H)5.75(d，1H)2.81(q，2H)2.42(q，2H)1.78(s，3H)0.76(m，6H)；MS(ESI+)m/z?484(M+H)+.

Embodiment 63

Phenyl-methylsulfonic acid 4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenylester

According to the method for embodiment 58, (120mg is 0.294mmol) with phenyl-methane sulfonyl chloride (55mg with the product of embodiment 5,0.294mmol) reacted 22 hours, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain trifluoroacetate (15mg, 9%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:8.31(d，1H)7.73(d，1H)7.11(d，1H)6.85(d，1H)6.74(s，2H)6.64(d，2H)6.53(d，2H)5.75(d，1H)2.81(q，2H)2.42(q，2H)1.78(s，3H)0.76(m，6H)；MS(ESI+)m/z?484(M+H) ⁺.

Embodiment 64

4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenoxy group }-ethyl acetate

(0.20Og 0.536mmol) is suspended in the acetone, and adds K the material of embodiment 5 ₂CO ₃(0.089g 0.536mmol) handles, and reaction mixture is heated to refluxed 4 hours during this period with bromo-ethyl-acetic ester with it.Reaction mixture is cooled to room temperature, concentrates with solid filtering and under vacuum, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (24mg, 10%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.22(t，J＝6.99Hz，3H)，2.34(s，3H)，2.74(s，3H)，4.20(q，J＝6.99Hz，2H)，5.47(s，2H)，6.49(d，J＝7.72Hz，1H)，6.75(d，.J＝8.82Hz，2H)，7.00(d，J＝8.09Hz，1H)，7.20(d，J＝8.46Hz，2H)，7.25-7.40(m，2H)，7.87(d，J＝8.82Hz，1H)，8.63(d，J＝7.72Hz，1H)，9.06(d，J＝8.46Hz，1H)，9.89(s，1H)；MS(ESI)m/z?460(M+H)+，(ESI-)m/z?458(M-H)-.

Embodiment 65

4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenoxy group }-acetate

The product of embodiment 64 (0.246g.535mmol) is dissolved among 10mL 5%NaOH and the 10mL EtOH, and be heated to 100 ℃ 2 hours, then in stirring at room 10 hours.Remove all solvents under the vacuum this moment, and brown oil is dissolved in the water, 2mL HCl added wherein, and form yellow mercury oxide.Filter the collecting precipitation thing, and with solid dried overnight (150mg, 64%) under vacuum.

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.33(s，3H)，2.75(s，3H)，5.42(s，2H)，6.46(d，J＝7.35Hz，1H)，6.52(s，1H)，6.75(d，J＝8.46Hz，2H)，6.99(d，J＝8.46Hz，1H)，7.15-7.40(m，J＝8.46Hz，4H)，7.85(s，1H)，8.62(s，1H)，9.08(d，J＝8.09Hz，1H)，9.90(s，1H)；MS(ESI)m/z?432(M+H)+，(ESI-)m/z?430(M-H)-.

Embodiment 66

2,2-dimethyl-N-{4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-propionic acid amide

The product of embodiment 83 (0.50g 0.134mmol) is dissolved among the DMF, with 2,2-dimethyl-propionyl chloride (0.016g, 0.134mmol), and in stirring at room 1 hour.Under nitrogen gas stream, remove DMF, and thick resistates is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetate (40.0mg, 65%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.22(s，9H)，2.35(s，3H)，2.76(s，3H)，6.33(d，J＝6.99Hz，1H)，7.15(s，1HI)，7.24(d，J＝8.46Hz，3H)，7.31(s，1H)，7.61(d，J＝8.82Hz，2H)，7.80(s，1H)，8.42(s，1H)，8.96(s，1H)，9.27(s，1H)，10.99(s，1H)MS(ESI+)m/z?457(M+H)+，(ESI-)m/z?455(M-H)-.

Embodiment 67

N-{4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-butyramide

(0.50g 0.134mmol) is dissolved among the DMF, and (0.016g 0.134mmol) handles, and in stirring at room 1 hour with butyryl chloride the product of embodiment 83.Under nitrogen gas stream, remove DMF, and thick resistates is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetate (41.0mg, 65%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.91(t，J＝7.35Hz，3H)，1.54-1.65(m，2H)，2.27(t，J＝7.35Hz，2H)，2.35(s，3H)，2.76(s，3H)，6.31(d，J＝6.99Hz，1H)，7.15(d，J＝8.09Hz，1H)，7.21-7.32(m，4H)，7.53(d，J＝8.82Hz，2H)，7.78(d，J＝8.82Hz，1H)，8.41(d，J＝6.99Hz，1H)，8.96(d，J＝8.46Hz，1H)，9.98(s，1H)，11.00(s，1H)；MS(ESI+)m/z443(M+H)+，(ESI-)m/z?441(M-H)-.

Embodiment 68

Ethylene-acetic acid 4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-acid amides

(0.50g 0.134mmol) is dissolved among the DMF, and (0.016g 0.134mmol) handles, and in stirring at room 1 hour with the cyclopropanecarbonyl-acyl chlorides the product of embodiment 83.Under nitrogen gas stream, remove DMF, and thick resistates is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetate (25.mg, 40%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.80(d，J＝6.25Hz，4H)，1.71-1.79(m，1H)，2.35(s，3H)，2.76(s，3H)，6.31(d，J＝7.35Hz，1H)，7.16(d，J＝7.72Hz，1H)，7.21-7.32(m，4H)，7.51(d，J＝8.82Hz，2H)，7.78(d，J＝8.82Hz，1H)，8.41(d，J＝7.35Hz，1H)，8.96(d，J＝8.82Hz，1H)，10.29(s，1H)，10.99(s，1H)；MS(ESI+)m/z?441(M+H)+，(ESI-)m/z?439(M-H)-.

Embodiment 69

2-{4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-the phenyl amino formyl radical }-tetramethyleneimine-1-benzyl formate

Carbobenzoxy-proline(Pro) (0.110g 0.443mmol) is dissolved among the THF, in wherein add N-methylmorpholine (0.133g, 0.443mmol).Add then the different propylene ester of anhydrous chloroformic acid (0.053g, o.443mmol), and with reaction mixture in stirring at room 30 minutes.(0.150g, the 0.402mmol) solution in THF was in stirring at room 1 hour to add the product of embodiment 83 this moment.This reaction mixture dilute with water is used CH ₂Cl ₂Na is used in extraction ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains this rough title compound, and it by the HPLC purifying, is used the TFA wash-out, obtains this title compound, is trifluoroacetate (118mg, 48%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.82-1.98(m，3H)，2.22(s，2H)，2.35(s，3H)，2.75(s，3H)，4.27-4.40(m，1H)，4.89-4.98(m，1H)，5.00-5.13(m，2H)，6.35(t，J＝6.80Hz，1H)，7.06-7.22(m，3H)，7.24-7.39(m，6H)，7.55(d，J＝8.46Hz，2H)，7.78(d，J＝8.82Hz，1H)，8.44(d，J＝6.99Hz，1H)，8.96(dd，J＝11.95，8.64Hz，1H)，10.20(s，1H)，11.04(s，1H)，14.39(s，1H)；MS(ESI+)m/z?604(M+H)+，(ESI-)m/z?602(M-H)-.

Embodiment 70

(7-methyl-[1,8] naphthyridine-4-yl)-[5-methyl-2-(4-phenoxy group-phenyl sulfenyl)-phenyl]-amine

Embodiment 70a

5-methyl-2-(4-phenoxy group-phenyl sulfenyl)-phenyl amine

The product of embodiment 4c (0.500g, 1.91mmol) with phenyl-boron dihydroxide (0.701g, 5.74mmol), venus crystals (II) (0.659g, 3.83mmol) and triethylamine (0.387g 3.83mmol) is dissolved in CH together ₂Cl ₂In.In stirring at room 48 hours, add 2 normal each reagent this moment again.In stirring at room 16 hours, add each reagent of 2eq this moment more again.Again in stirring at room 16 hours.To react dilute with water, use ethyl acetate extraction, use Na ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains crude product, with its silica gel column chromatography purifying purifying, with 20%EtOAc/ hexane wash-out (0.100g, 15%).Method according to embodiment 1f is reduced this product, obtains this title compound (90mg, 98%).

Embodiment 70b

According to the method for embodiment 1g, (50mg is 0.28mmol) with the product (86mg of embodiment 70a with the product of embodiment 1d, 0.28mmol) reacted 24 hours, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetate (64mg, 50%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.37(s，3H)，2.73·2.79(m，3H)，6.30(d，J＝6.99Hz，1H)，6.78-6.87(m，2H)，6.97(d，J＝7.72Hz，2H)，7.17-7.24(m，1H)，7.24-7.28(m，2H)，7.32-7.36(m，3H)，7.37·7.46(m，2H)，7.79(d，J＝8.82Hz，1H)，8.42(d，J＝7.35Hz，1H)，8.96(d，J＝8.46Hz，1H)，11.00(s，1H)；MS(ESI+)m/z?450(M+H)+，(ESI-)m/z?448(M-H)-.

Embodiment 71

N-{3-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 71a

3-(4-methyl-2-nitro-phenyl sulfenyl)-phenyl amine

(1.00g, 3.51mmol) (658mg 5.26mmol) is dissolved among the DMF, in wherein adding K with 3-amino-benzenethiol the product of embodiment 4a ₂CO ₃(848mg, 6.14mmol).Then reaction mixture be heated to 100 ℃ 16 hours.Then reaction mixture is cooled to room temperature, dilute with water, and use ethyl acetate extraction, obtain this title compound (650mg, 71%).

Embodiment 71b

N-[3-(4-methyl-2-nitro-phenyl sulfenyl)-phenyl]-ethanamide

The product of embodiment 71a (650mg 2.50mmol) is dissolved among the DCM, and add Acetyl Chloride 98Min. (196mg, 2.50mmol).In stirring at room 1 hour, obtained this title compound (690mg, 61%) by solid collected by filtration this moment.

Embodiment 71c

N-[3-(2-amino-4-methyl-phenyl sulfenyl)-phenyl]-ethanamide

According to the method for embodiment 1f, with the product SnCl of embodiment 71b ₂Reduction obtains this title compound (120mg, 20%).

Embodiment 71d

Method according to embodiment 1g, product (100mg with embodiment 1d, 0.559mmol) with the product (152mg of embodiment 71c, 0.559mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetic acid (45mg, 18%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.97(s，3H)，2.38(s，3H)，2.74(s，3H)，6.26(d，J＝6.99Hz，1H)，6，84(d，J＝8.46Hz，1H)，7.06(t，J＝8.09Hz，1H)，7.25(d，J＝8.09Hz，1H)，7.33-7.41(m，2H)，7.41-7.54(m，2H)，7.74(d，J＝8.82Hz，1H)，8.33(d，J＝6.99Hz，1H)，8.89(d，J＝8.82Hz，1H)，9.81(s，1H)，10.91(s，1H)；MS(ESI+)m/z?415(M+H)+，(ESI-)m/z?413(M-H)-.

Embodiment 72

2-[4-(1-imino--ethyl)-phenyl sulfenyl]-5-methyl-phenyl }-(7-methyl-[1,8] naphthyridine-4-yl)-amine

Embodiment 72a

Thioacetyl imido acid naphthalene-2-ylmethyl ester; HBr salt

(2.00g, 9.05mmol) (680mg 9.05mmol) is dissolved in CH with the thioacetyl imines 2-brooethyl-naphthalene ₃Among the Cl, and in stirring at room 1 hour.Product is filtered collection, obtain this title compound (1.500g, 77%).

Embodiment 72b

The product of embodiment 72a (239mg, 0.805mmol) and embodiment 83 (150mg, product 0.403mmol) is dissolved among the EtOH, and in stirring at room 1 hour.Solvent is concentrated under vacuum, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate (118mg, 70%).

¹HNMR(300MHz，DMSO-d ₆)δ?ppm:2.32(s，3H)，2.36·2.43(m，3H)，2.76(s，3H)，6.38(d，J＝6.99Hz，1H)，7.19-7.27(m，2H)，7.32-7.45(m，5H)，7.79(d，J＝8.82Hz，1H)，8.44(d，J＝6.99Hz，1H)，8.57(s，1H)，8.89-9.00(m，1H)，9.55(s，1H)，11.10(s，1H)；MS(ESI+)m/z?414(M+H)+，(ESI-)m/z?412(M-H)-.

Embodiment 73

1-{4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-the second thioketones

The product of embodiment 18 (265mg .639mmol) and Lawesson reagent (517mg 1.28mmol) is dissolved in the 3mL toluene, and be heated to 80 ℃ 16 hours.Reaction mixture is cooled to room temperature, washes with water, and extract with EtOAc.Use Na ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains this rough title compound, and it by the HPLC purifying, is used the TFA wash-out, obtains trifluoroacetate (14mg, 5%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.33(s，3H)，2.59(s，3H)，2.63(s，3H)，3.75(s，1H)，6.17(s，1H)，6.88(d，J＝10.30Hz，1H)，7.06-7.21(m，3H)，7.21-7.27(m，2H)，7.39(d，J＝8.46Hz，1H)，7.78(d，J＝8.46Hz，2H)，8.63(d，J＝8.82Hz，1H)，11.59(s，1H)；MS(ESI+)m/z?431(M+H)+，(ESI-)m/z?429(M-H)-.

Embodiment 74

N-{4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-2-phenyl-butyramide

(has the N that polymkeric substance connects to containing 3 equivalent PS-DCC resins, N, '-dicyclohexylcarbodiimide) in the flask, add the 2-phenyl-butyric acid (27mg that is dissolved among the 3mL DMA, 0.16mmol), add then HOBt (22mg, 0.16mmol), the product (50mg of embodiment 83,0.134mmol) and the diethyl isopropylamine (52mg, 0.402mmol).Reaction is heated to 55 ℃ spends the night, filter and transfer in the phial that contains 3 equivalent MP-Carbonate (macropore carbonic ether) resin.Reactor and PS-DCC resin are washed with MeOH, and the filtrate that merges was being shaken on the MP-carbonate resin 2 hours in room temperature.Remove by filter the MP-Carbonate resin, and reaction is concentrated into dried.By the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (2mg, 40%).

¹H?NMR(500MHz，DMSO-D ₂O)δ?ppm:0.83-0.89(m，3H)，1.66-1.74(m，J＝7.17，6.90，6.90，6.90，6.90Hz，1H)，2.00-2.08(m，1H)，2.32-2.38(m，3H)，2.72-2.75(m，3H)，3.53-3.57(m，1H)，6.37(d，J＝7.02Hz，1H)，7.14-7.19(m，1H)，7.21(d，J＝8.85Hz，2H)，7.24·7.31(m，3H)，7.32-7.39(m，4H)，7.50(dd，J＝8.85，1.53Hz，2H)，7.69(d，J＝8.85Hz，1H)，8.39(d，J＝7.02Hz，1H)，8.84-8.88(m，1H)，10.28(s，1H)；MS(ESI+)m/z519；(ESI-)m/z?517，631(M+TFA-H)-.

Embodiment 75

N-{4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-4-phenyl-butyramide

This title compound be with 4-phenyl-butyric acid (27mg, 0.16mmol) as acid, (1mg, 2%) that makes according to the method for embodiment 74.

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.85-1.92(m，J＝7.55，7.55，7.55，7.55Hz，2H)，2.32(t，J＝7.32Hz，2H)，2.36(s，3H)，2.59-2.64(m，J＝7.63Hz，2H)，2.74(s，3H)，6.34(d，J＝7.02Hz，1H)，7.17-7.23(m，6H)，7.29-7.35(m，4H)，7.45(d，J＝8.85Hz，2H)，7.73(d，J＝8.54Hz，1H)，8.36(d，J＝7.32Hz，1H)，8.89(d，J＝8.54Hz，1H)；MS(ESI+)m/z?519；(ESI-)m/z?517，631(M+TFA-H)-.

Embodiment 76

N-{4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-2-o-tolyl oxygen base-ethanamide

This title compound be with o-tolyl oxygen base-acetate (26mg, 0.16mmol) as acid, (3mg, 5%) that makes according to the method for embodiment 74.

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.25(s，3H)，2.36(s，3H)，2.75(s，3H)，4.70(s，2H)，6.34(d，J＝7.32Hz，1H)，6.86(d，J＝7.93Hz，1H)，6.90(t，J＝7.32Hz，1H)，7.14-7.20(m，2H)，7.21-7.26(m，3H)，7.30-7.33(m，2H)，7.48(d，J＝8.54Hz，2H)，7.73(d，J＝8.85Hz，1H)，8.36(d，J＝7.02Hz，1H)，8.88(d，J＝8.85Hz，1H)；MS(ESI+)m/z?521；(ESI-)m/z?519，633(M+TFA-H)-.

Embodiment 77

N-{4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-2-p-methylphenyl oxygen base-ethanamide

This title compound be to use p-methylphenyl oxygen base-acetate (26mg, 0.16mmol) as acid, (3mg, 5%) that makes according to the method for embodiment 74.

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.24(s，3H)，2.36(s，3H)，2.75(s，3H)，4.64(s，2H)，6.33(d，J＝7.32Hz，1H)，6.89(d，J＝8.54Hz，2H)，7.13(d，J＝8.24Hz，2H)，7.21(d，J＝8.85Hz，2H)，7.25-7.29(m，1H)，7.31-7.33(m，2H)，7.48(d，J＝8.54Hz，2H)，7.72(d，J＝8.54Hz，1H)，8.35(d，J＝7.02Hz，1H)，8.87(d，J＝8.85Hz，1H)；MS(ESI+)m/z?521；(ESI-)m/z?19，633(M+TFA-H)-.

Embodiment 78

2-methoxyl group-N-{4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-2-phenyl-ethanamide

This title compound be with R-methoxyl group-phenyl-acetic acid (26mg, 0.16mmol) as acid, (3mg, 5%) that makes according to the method for embodiment 74.

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.35(s，3H)，2.73(s，3H)，3.36(s，3H)，4.82(s，1H)，6.36(d，J＝7.02Hz，1H)，7.21(d，J＝8.54Hz，3H)，7.28-7.33(m，2H)，7.37(d，J＝7.02Hz，1H)，7.41(t，J＝7.32Hz，2H)，7.47(d，J＝7.02Hz，2H)，7.53-7.58(m，2H)，7.69(d，J＝8.85Hz，1H)，8.38(d，J＝7.02Hz，1H)，8.86(d，J＝8.54Hz，1H)；MS(ESI+)m/z?521；(ESI-)m/z?519，633(M+TFA-H)-.

Embodiment 79

This title compound be with S-methoxyl group-phenyl-acetic acid (26mg, 0.16mmol) as acid, (3mg, 5%) that makes according to the method for embodiment 74.

¹H?NMR(300MHz，DMSO-d ₆)δppm:2.35(s，3H)，2.73(s，3H)，3.36(s，3H)，4.82(s，1H)，6.36(d，J＝7.32Hz，1H)，7.21(d，J＝8.54Hz，3H)，7.29-7.32(m，2H)，7.35-7.38(m，1H)，7.41(t，J＝7.17Hz，2H)，7.46-7.49(m，2H)，7.54-7.57(m，2H)，7.69(d，J＝8.54Hz，1H)，8.38(d，J＝7.02Hz，1H)，8.86(d，.J＝8.54Hz，1H)；MS(ESI+)m/z?521；(ESI-)m/z?519，633(M+TFA-H)-.

Embodiment 80

Furans-3-formic acid (4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-the phenyl amino formyl radical }-methyl)-acid amides

This title compound be with [(furans-2-carbonyl)-amino]-acetate (27mg, 0.16mmol) as acid, (1mg, 2%) that makes according to the method for embodiment 74.

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.36(s，3H)，2.75(s，3H)，4.02(s，2H)，6.34(d，J＝7.02Hz，1H)，6.67(dd，J＝3.66，1.83Hz，2H)，7.16(d，J＝3.05Hz，1H)，7.22(t，J＝8.85Hz，3H)，7.29-7.33(m，2H)，7.46(d，J＝8.85Hz，2H)，7.74(d，J＝8.54Hz，1H)，7.85(s，1H)，8.37(d，J＝7.32Hz，1H)，8.87(d，J＝8.85Hz，1H)；MS(ESI+)m/z?524；(ESI-)m/z?521

Embodiment 81

N-{4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-4-thiene-3-yl--butyramide

This title compound be with 4-thiophene-2-base-butyric acid (27mg, 0.16mmol) as acid, (0.7mg, 1%) that makes according to the method for embodiment 74.

¹H?NMR(300MHz，DMSO-d ₆)δppm:1.89-1.96(m，2H)，2.34-2.39(m，5H)，2.75(s，3H)，2.85(t，J＝7.63Hz，2H)，6.34(d，J＝7.32Hz，1H)，6.88(d，J＝2.44Hz，1H)，6.96(dd，J＝5.19，3.36Hz，1H)，7.18-7.25(m，3H)，7.29-7.33(m，3H)，7.45(d，J＝8.85Hz，2H)，7.73(d，J＝8.54Hz，1H)，8.36(d，J＝7.32Hz，1H)，8.89(d，J＝8.54Hz，1H)；MS(ESI+)m/z?525；(ESI-)m/z?523，637(M+TFA-H)-.

Embodiment 82

1-ethanoyl-piperidine-1-carboxylic acid 4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-acid amides

This title compound be with 1-ethanoyl-piperidine-1-carboxylic acid (27mg, 0.16mmol) as acid, (0.7mg, 1%) that makes according to the method for embodiment 74.

¹HNMR(300MHz，DMSO-d ₆)δ?ppm:1.77-1.84(m，2H)，2.03(s，3H)，2.36(s，4H)，2.56-2.64(m，2H)，2.75(s，3H)，3.05-3.12(m，1H)，3.83-3.91(m，1H)，4.37-4.43(m，1H)，6.30-6.36(m，1H)，7.18-7.25(m，4H)，7.29-7.34(m，2H)，7.41-7.48(m，2H)，7.72-7.77(m，1H)，8.34-8.38(m，1H)，8.87-8.91(m，1H)；MS(ESI+)m/z?526；(ESI-)m/z?524，638(M+TFA-H)-.

Embodiment 83

[2-(4-amino-phenyl sulfenyl)-5-methyl-phenyl]-(7-methyl-[1,8] naphthyridine-4-yl)-amine

The product of embodiment 18 (200mg 0.48mmol) is suspended among the 6N HCl (10mL), and in air, be heated to 100 ℃ 1 hour.Then solution is cooled off in ice bath, and alkalize with solid NaOH (2.64gm).Crude product is passed through to separate with dichloromethane extraction, and, use the TFA wash-out, obtain this title compound, be trifluoroacetate (96.1mg, 37%) by the HPLC purifying.

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm；2.31(s，3H)2.77(s，3H)6.30(d，J＝6.99Hz，1H)6.57(d，J＝8.46Hz，2H)6.90(d，J＝7.72Hz，1H)7.07(d，J＝8.46Hz，2H)7.23(m，J＝7.72Hz，2H)7.81(d，J＝8.82Hz，1H)8.46(d，J＝7.35Hz，1H)9.04(d，J＝8.46Hz，1H)11.05(s，1H).MS(ESI+)m/z?373.1(M+H)+；(ESI-)m/z?371.1(M-H)-.

Embodiment 84

4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-benzamide

Embodiment 84a

4-(4-methyl-2-nitro-phenyl sulfenyl)-phenylformic acid

(0.94g, 3.31mmol) (0.51g 3.31mmol) reacts under nitrogen with 80 ℃ in aqueous ethanolic solution with 4-sulfydryl-phenylformic acid with the product of embodiment 4a.Reaction mixture is poured in the water, and used the Glacial acetic acid acidifying.The solid collected by filtration product washes with water, and dry in a vacuum, obtains this title compound (0.877g, 91%), and the isolating product of institute is enough pure for use.

Embodiment 84b

4-(4-methyl-2-nitro-phenyl sulfenyl)-benzamide

The product of embodiment 84a (0.3g 1.04mmol) is dissolved among the THF (ISmL), and with N-methylmorpholine (0.131mL 1.19mmol) handles, in ice bath, cool off then, and add isobutyl chlorocarbonate (0.148mL, 1.14mmol).Under agitation the gained mixture heating up to room temperature 30 minutes.In ice bath, cool off, add ammonia then and be heated to room temperature.By adding entry and collecting solid by vacuum filtration this title compound is separated, it is used (0.289g, 96%) under situation about not being further purified.

Embodiment 84c

According to the method for embodiment 1f, (0.289g, 1.0mmol) (0.95g, 5mmol) reaction obtains this title compound, is pale solid (0.226g, 88%) with tin protochloride with the product of embodiment 84c.

Embodiment 84d

Method according to embodiment 1g, product (0.156g with embodiment 1d, 0.875mmol) with the product (0.226g of embodiment 84d, 0.875mmol) reacted 24 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (0.185g, 38%).

¹HNMR(300MHz，DMSO-d ₆)δ?ppm:2.37-2.46(m，3H)2.74(s，3H)6.36(d，J＝6.99Hz，1H)7.19(d，J＝8.46Hz，2H)7.31-7.46(m，3H)7.47-7.57(m，1H)7.68(d，J＝8.46Hz，2H)7.75(d，J＝8.46Hz，1H)7.90(s，1H)8.39(d，J＝7.35Hz，1H)8.90(d，J＝8.46Hz，1H)11.02(s，1H)；MS(ESI+)m/z?401.0(M+H)+；(ESI-)m/z?399.0(M-H-).

Embodiment 85

N-methyl-4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-benzamide

Embodiment 85a

N-methyl-4-(4-nitro-phenyl sulfenyl)-benzamide

Described in embodiment 84c, substitute ammonia with the N-methylamine in the methyl alcohol, (0.32g 1.11mmol) reacts, and obtains this title compound (0.32g, 94%) with the product of embodiment 84b.

Embodiment 85b

4-(2-amino-4-methyl-phenyl sulfenyl)-N-methyl-benzamide

The product of embodiment 85a is reacted as describing among the embodiment 84d, obtain this title compound (0.28g, 97%).

Embodiment 85c

Method according to embodiment 1g, product (0.277g with embodiment 85b, 1.05mmol) with the product (0.09g of embodiment 1d, 0.504mmol) reacted 41 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (0.078g, 28%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.41(s，3H)2.70-2.82(m，6H)6.36(d，J＝6.99Hz，1H)7.20(d，J＝8.46Hz，2H)7.35-7.45(m，2H)7.51(d，1H)7.64(d，J＝8.46Hz，2H)7.75(d，J＝8.82Hz，1H)8.33-8.45(m，2H)8.90(d，J＝8.82Hz，1H)11.03(s，1H)；MS(ESI+)m/z?415.0(M+H)+；(ESI-)m/z?413.1(M-H)-.

Embodiment 86

3-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-benzamide

Embodiment 86a

3-(4-methyl-2-nitro-phenyl sulfenyl)-phenylformic acid

As describing among the embodiment 84b, (0.94g, 3.29mmol) (0.51g 3.31mmol) reacts, and obtains this title compound (0.77g, 80%) with 3-sulfydryl-phenylformic acid with the product of embodiment 84a.

Embodiment 86b

3-(4-methyl-2-nitrophenyl sulfenyl)-benzamide

(0.25g 0.86mmol) reacts as describing among the embodiment 84c, obtains this title compound (0.238g, 95%) with the product of embodiment 86a.

Embodiment 86c

3-(4-methyl-2-amino-phenyl sulfenyl)-benzamide

The product of embodiment 86b is reacted as describing among the embodiment 84d, obtain this title compound (0.204g, 96%).

Embodiment 86d

Product (0.204g with embodiment 86c, 0.79mmol) with the product (0.144g of embodiment 1d, 0.79mmol) reacted 24 hours, method according to embodiment 1g, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (0.159gm, 38%).

¹HNMR(300MHz，DMSO-d ₆)δ?ppm2.39(s，3H)2.74(s，3H)6.31(d，J＝6.99Hz，1H)7.18-7.55(m，6H)7.61-7.79(m，3H)7.90(s，1H)8.37(d，J＝6.99Hz，1H)8.88(d，J＝8.82Hz，1H)；MS(ESI+)m/z?401.0(M+H)+；(ESI-)m/z?399.0(M-H)-.

Embodiment 87

N-methyl-3-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-benzamide

Embodiment 87a

N-methyl-3-(4-methyl-2-nitro-phenyl sulfenyl)-benzamide

As describing among the embodiment 84c, substitute ammonia with the N-methylamine in the methyl alcohol, (0.25g 0.86mmol) reacts, and obtains this title compound (0.25g, 96%) with the product of embodiment 86a.

Embodiment 87b

N-methyl-3-(4-methyl-2-amino-phenyl sulfenyl)-benzamide

The product of embodiment 87a is reacted as describing among the embodiment 84d, obtain this title compound (0.208g, 92%).

Embodiment 87c

Method according to embodiment 1g, product (0.208g with embodiment 87b, 0.76mmol) with the product (0.136g of embodiment 1d, 0.76mmol) reacted 24 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (0.204,49%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.39(s，3H)2.65-2.81(m，6H)6.27(d，J＝7.35Hz，1H)7.20-7.82(m，8H)8.35(d，J＝6.99Hz，2H)8.87(d，J＝8.46Hz，1H)10.97(s，1H)；MS(ESI+)m/z?415.0(M+H)+；(ESI-)m/z?413.0(M-H)-.

Embodiment 88

N, N-dimethyl-3-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-benzamide

Embodiment 88a

N, N-dimethyl-3-(4-methyl-2-nitro-phenyl sulfenyl)-benzamide

As describing among the embodiment 84c, be used in the N in the methyl alcohol, the N-dimethyl amine substitutes ammonia, and (0.25g 0.86mmol) reacts, and obtains this title compound (0.26g, 100%) with the product of embodiment 86a.

Embodiment 88b

3-(2-amino-4-methyl-phenyl sulfenyl)-N, N-dimethyl-benzamide

The product of embodiment 88a is reacted as describing among the embodiment 84d, obtain this title compound (0.175g, 71%).

Embodiment 88c

Method according to embodiment 1g, product (0.175g with embodiment 88b, 0.610mmol) with the product (0.109g of embodiment 1d, 0.61mmol) reacted 24 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (0.1552g, 45%).

¹HNMR(300MHz，DMSO-d ₆)δ?ppm:2.40(s，3H)2.75(s，6H)2.92(s，3H)6.34(d，J＝6.99Hz，1H)7.11-7.53(m，7H)7.76(d，J＝8.82Hz，1H)8.39(d，J＝6.99Hz，1H)8.94(d，J＝8.82Hz，1H)；MS(ESI+)m/z?429.0(M+H)+；(ESI-)m/z?427.0(M-H)-

Embodiment 89

[2-(2-fluoro-phenyl sulfenyl)-5-methyl-phenyl]-(7-methyl-[1,8] naphthyridine-4-yl)-amine

Embodiment 89a

1-(2-fluoro-phenyl sulfenyl)-4-methyl-2-nitro-benzene

(1.50g, 5.3mmol) (0.56mL 5.3mmol) is added drop-wise to Na in room temperature with 2-fluorobenzene mercaptan the product of the embodiment 4a in EtOH (15mL) ₂CO ₃The aqueous solution (0.563g, 5.3mmol) in.Mixture heating up to refluxing 1 hour, is evaporated then.Resistates is diluted with EtOAc, use H ₂MgSO is used in O, 5% KOH and salt water washing ₄Drying is filtered and is concentrated under vacuum, obtains this title compound, is yellow crystals, and it by carrying out purifying with cold normal hexane washing, is obtained this title compound, is yellow crystals (1.15g, 83%).

Embodiment 89b

2-(2-fluoro-phenyl sulfenyl)-5-methyl-phenyl amine

According to the method for embodiment 237E, with product Fe and the NH of embodiment 89a ₄The Cl reduction obtains this title compound.

Embodiment 89c

According to the method for embodiment 1g, (200mg is 1.12mmol) with the product (260mg of embodiment 89b with the product of embodiment 1d, 1.12mmol) reacted 72 hours, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain product trifluoroacetic acid (180mg, 43%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.32(s，3H)，2.62(s，3H)，6.11(br-s，1H)，6.95-7.45(m，8H)，8.26(br-s，1H)，8.55-8.70(m，1H)，9.08(br-s，1H)；MS(ESI+)m/z376(M+H)+，(ESI-)m/z?374(M-H)-.

Embodiment 90

[3-(7-methyl-[1,8] naphthyridine-4-base is amino)-4-phenyl sulfenyl-benzyl]-t-butyl carbamate

Embodiment 90a

3-nitro-4-(phenyl sulfenyl) benzonitrile

(16.29g, 123.3mmol) (15.0g is 82.2mmol) under agitation in 100 ℃ of heating 24 hours for solution in 150mL DMF and 4-chloro-3-nitrobenzonitrile with thiophenol sodium.Be cooled to room temperature and dilute with EtOAc.Wash with water, and with organic layer MgSO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound, and it by silica gel column chromatography purifying purifying, with 5%EtOAc/ hexane wash-out, is obtained yellow solid (4.0g, 19%).

Embodiment 90b

3-amino-(thiophenyl) benzylamino t-butyl formate

With the product of embodiment 90a (4.0g, 15.6mmol) and tert-Butyl dicarbonate (1.70g, solution 7.79mmol) is with Ra-Ni H at 60psi in MeOH ₂Following catalytic reduction.Remove catalyzer, and under vacuum, concentrate, obtain this title compound, it by silica gel column chromatography purifying purifying, with 10%EtOAc/ hexane wash-out, is obtained the mixture of two embodiment, be limpid oily matter (2.41g, 46%).

Embodiment 90d

(3-(7-methyl isophthalic acid, 8-naphthyridine-4-base is amino)-4-(thiophenyl) phenyl) methyl carbamic acid tert-butyl ester

Method according to embodiment 1g, product (557mg with embodiment 1d, 3.12mmol) with the product (1.032mg of embodiment 90b, 3.12mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetic acid (310mg, 17%).

¹HNMR(300MHz，DMSO-d ₆)δ?ppm:1.37(s，9H)2.76(s，3H)4.19(d，J＝6.25Hz，2H)6.29(d，J＝6.99Hz，1H)7.25(s，5H)7.31(s，1H)7.37(d，J＝3.31Hz，2H)7.44-7.56(m，1H)7.79(d，J＝8.82Hz，1H)8.42(d，J＝6.99Hz，1H)8.94(d，J＝8.46Hz，1H)11.05(s，1H)14.43(s，1H)；MS(ESI+)m/z?473(M+H)+.

Embodiment 91

[2-(2,5-dimethyl-furans-3-base sulfenyl)-5-methyl-phenyl]-(7-methyl-[1,8] naphthyridine-4-yl)-amine

Embodiment 91A

2,5-dimethyl-3-(4-methyl-2-nitro-phenyl sulfenyl)-furans

This title compound is prepared as follows: by with 1-chloro-4-methyl-2-nitro-benzene (2.00g, 11.7mmol), 2,5-dimethyl-furans-3-mercaptan (1.50g, 11.7mmol) and K ₂CO ₃(3.233g 23.4mmol) heated 4 hours in 100 ℃ in DMF.Then reaction mixture is cooled to room temperature, and dilute with water, and use ethyl acetate extraction, use Na ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound (3.5g, 85%).

Embodiment 91b

2-(2,5-dimethyl-furans-3-base sulfenyl)-5-methyl-phenyl amine

According to the method for embodiment 1f, with the product SnCl of embodiment 91a ₂Reduction obtains this title compound.

Embodiment 91c

According to the method for embodiment 1g, (50mg is 0.217mmol) with the product (51mg of embodiment 91b with the product of example I d, 0.217mmol) reacted 18 hours, obtain rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (2.6mg, 3.2%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm2.15(d，J＝15.08Hz，6H)，2.33(s，3H)，2.77(s，3H)，5.98(s，1H)，6.29(d，J＝6.99Hz，1H)，7.08(d，J＝8.09Hz，1H)，7.24-7.39(m，2H)，7.83(d，J＝8.46Hz，1H)，8.47(d，J＝6.62Hz，1H)，9.03(d，J＝8.46Hz，1H)，11.04(s，1H)；MS(ESI+)m/z?378(M+H-TFA)+；(ESI+)m/z?399(M+Na-TFA)-；(ESI+)m/z?773(2M+Na-TFA)-.

Embodiment 92

(4-{2-[ethoxy carbonyl methyl-(7-methyl-[1,8] naphthyridine-4-yl)-amino]-4-methyl-phenyl sulfenyl }-phenoxy group)-ethyl acetate

(200mg 0.536mmol) is suspended in the acetone, in wherein adding K the product of embodiment 5 ₂CO ₃(81mg, 0.589mmol) and ethyl bromoacetate (89mg, 0.536mmol).Then reaction mixture is heated to and refluxed 4 hours, reaction mixture is cooled to room temperature, and under vacuum, removes and desolvate.By the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (15mg, 6%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm1.21(td，J＝7.08，2.39Hz，6H)，2.35(s，3H)，2.73(s，3H)，4.18(ddd，J＝14.16，10.66，7.17Hz，4H)，4.76(s，2H)，5.46(s，2H)，6.47(d，J＝7.35Hz，1H)，6.87(d，J＝8.82Hz，2H)，7.14(d，J＝8.09Hz，1H)，7.21-7.42(m，4H)，7.86(d，J＝8.46Hz，1H)，8.61(d，J＝7.72Hz，1H)，9.03(d，J＝8.46Hz，1H)；MS(ESI+)m/z?546(M+H-TFA)+.

Embodiment 93

[3-chloro-4-(4-chloro-phenoxy group)-phenyl]-(7-methyl-[1,8] naphthyridine-4-yl)-amine

Embodiment 93A

2-chloro-1-(4-chloro-phenoxy group)-4-nitro-benzene

With 1,2-two chloro-4-nitro-benzene (9.2g, 48mmol), 4-chloro-phenol (6.2g, 48mmol) and salt of wormwood (19.9g, 144mmol) solution in DMF (80mL) be heated to 90 ℃ 16 hours.After being cooled to room temperature, mixture being poured in the water (600mL), and used ethyl acetate extraction.Dried over mgso is used in the extract salt water washing that merges, and filters and concentrates under vacuum, obtains this title compound (13.5g, 99%).

Embodiment 93B

3-chloro-4-(4-chloro-phenoxy group)-phenyl amine

With the product solution of embodiment 93A (8.49g, 30mmol), iron powder (8.4g, 150mmol) and ammonium chloride (2.4g 45mmol) is heated at ethanol (180mL), THF (210mL) and water (60mL) solution and refluxed 16 hours.The gained mixture is cooled off, and filter by Celite pad.Filtrate water and ethyl acetate are distributed.Use the ethyl acetate extraction water.Dried over sodium sulfate is used in the extract salt water washing that merges, and filters and concentrates.With the resistates silica gel purification,, obtain this title compound (6.5g, 86%) with hexane-hexane/ethyl acetate (8:2) wash-out.

Embodiment 93C

Will the embodiment 93B in the ethanol (10mL) (254mg, 1.0mmol) and example I d (179mg 1.0mrnol) refluxed 16 hours.Mixture is cooled to room temperature and filtration, solid is washed with ethyl acetate, drying obtains this title compound, is hydrochloride (411mg, 95%).

¹H?NMR(300MHz，DMSO-D ₆)δ?ppm2.76(s，3H)6.94(d，J＝7.35Hz，1H)7.10(m，2H)7.33(d，J＝8.46Hz，1H)7.49(m，3H)7.80(m，2H)8.53(d，J＝6.99Hz，1H)9.18(d，J＝8.82Hz，1H)11.34(s，1H)14.49(s，1H)；(ESI-)m/z?394(M-H)-.

Embodiment 94

[2-(4-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl]-(7-trifluoromethyl-[1,8] naphthyridine-4-yl)-amine

Method according to embodiment 1g, product (50mg with embodiment 7d, 0.215mmol) with the product (53mg of embodiment 50b, 0.215mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (28mg, 30%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.35(s，3H)，3.71(s，3H)，6.38(d，J＝6.99Hz，1H)，6.78-6.89(m，2H)，7.11-7.19(m，1H)，7.23-7.32(m，4H)，8.41(d，J＝8.46Hz，1H)，8.58(d，J＝6.99Hz，1H)，9.43(d，J＝8.46Hz，1H)；MS(ESI+)m/z?442(M+H-TFA)+；(ESI-)m/z?440(M-H-TFA)-.

Embodiment 95

4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-N-phenyl-benzamide

Embodiment 95a

4-methyl-2-nitro-phenylformic acid

(5.00g is 30.8mmol) with 50% H with 4-methyl-2-nitrobenzonitrile ₂SO ₄(25mL) suspension in HOAc (25mL) is heated to and refluxed 22 hours.Under agitation reaction mixture is poured in the frozen water (150g), and stirred 30 minutes in 5 ℃.Filter the crystal of collecting precipitation, use H ₂The washing of O and normal hexane, and in 40 ℃ dry in a vacuum, obtain this title compound, be light brown crystal (4.85g, 87%).

Embodiment 95b

4-methyl-2-nitro-N-phenyl-benzamide

With the product of embodiment 95a (1.00g, 5.5mmol) and SOCl ₂(4.03mL 55.0mmol) refluxed 2 hours.Excessive SOCl is removed in decompression ₂, obtain corresponding chloride of acid, be light yellow oil.Upward in the solution of the chloride of acid of Huo Deing in THF (15mL) in 5 ℃ drip aniline (0.53mL, 5.8mmol) and Et ₃N (1.17mL, 8.3mmol), and with mixture in stirring at room 3.5 days.Reaction mixture is evaporated.With resistates H ₂The O dilution is acidified to pH3 with 10%HCl, extracts with EtOAc then.With extract 10% NaHCO ₃MgSO is used in washing ₄Drying is filtered and is concentrated under vacuum, obtains this title compound, is light brown crystal, and it by carrying out purifying with the normal hexane washing, is obtained required product, is light brown crystal (0.80g, 57%).

Embodiment 95c

2-amino-4-methyl-N-phenyl-benzamide

According to the method for embodiment 237E, with product Fe and the NH of embodiment 95b ₄The Cl reduction obtains this title compound.

Embodiment 95d

4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-N-phenyl-benzamide

According to the method for embodiment 1g, (150mg, 0.84mmol) (190mg, 0.84mmol) reaction is 6 hours, obtains this rough title compound, and it is passed through silica gel column chromatography purifying purifying, uses 50:1 CH in the product of embodiment 95c with the product of embodiment 1d ₂Cl ₂/ MeOH wash-out obtains this title compound (210mg, 68%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.40(s，3H)，2.68(s，3H)，6.62(d，J＝6.9Hz，1H)，6.98(t，J＝7.3Hz，1H)，7.19(t，J＝7.3Hz，2H)，7.36(s，1H)，7.38(d，J＝8.3Hz，1H)，7.52(d，J＝7.3Hz，2H)，7.67(d，J＝8.8Hz，1H)，7.78(d，J＝8.3Hz，1H)，8.40(d，J＝6.9Hz，1H)，8.94(d，J＝8.8Hz，1H)；MS(ESI+)m/z?369(M+H)，ESI-m/z367(M-H).

Embodiment 96

N-[3-(7-methyl-[1,8] naphthyridine-4-base is amino)-4-phenyl sulfenyl-phenyl]-ethanamide

Embodiment 96a

3-nitro-4-phenyl sulfenyl-phenyl amine

With 2-nitro-4-chloroaniline (1.0g, 5.79mmol), thiophenol sodium (0.84g, 6.4mmol) mixture in DMF (10mL) in 100 ℃ the heating 2.5 hours.Mixture is cooled off,, and, use anhydrous sodium sulfate drying then organic layer water, 20% potassium hydroxide aqueous solution and the washing of 10% sodium chloride aqueous solution with ethyl acetate (100mL) dilution.Siccative is filtered, and solvent is concentrated under vacuum, obtain this title compound, be red solid (0.98g, 69%).

Embodiment 96b

N-(3-nitro-4-phenyl sulfenyl-phenyl)-ethanamide

(0.98g, 3.97mmol) (0.38g 3.74mmol) handles, and in 80 ℃ of heating 2 hours with diacetyl oxide in pyridine (10mL) with the product of embodiment 96a.Solvent is concentrated under vacuum, obtain this title compound, be red oil, it is used (0.96g, 98%) under situation about not being further purified.

Embodiment 96c

N-(3-amino-4-phenyl sulfenyl-phenyl)-ethanamide

According to the method for embodiment 237E, with the solution of the product of embodiment 96b with Fe and NH ₄The Cl reduction obtains this title compound.

Embodiment 96d

Method according to embodiment 1g, product (100mg with example I d, 0.560mmol) with the product (140mg of embodiment 96c, 0.560mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (77mg, 27%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.08(s，3H)2.75(s，3H)6.33(d，J＝7.35Hz，1H)7.06·7.26(m，4H)7.43-7.61(m，2H)7.77(d，J＝8.46Hz，1H)7.97(d，J＝1.84Hz，1H)8.39(d，J＝6.99Hz，1H)8.89(d，J＝8.82Hz，1H)10.36(s，1H)11.02(s，1H)14.36(s，1H)；MS(ESI+)m/z?401(M+H)+，(ESI-)m/z?399(M+H)-.

Embodiment 97

[2-(4-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl]-(7-propyl group-[1,8] naphthyridine-4-yl)-amine

Method according to embodiment 1g, product (275mg with embodiment 2g, 1.33mmol) with the product (326mg of embodiment 50b, 1.33mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (392mg, 56%)

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.98(t，J＝7.35Hz，3H)1.85(m，2H)2.34(s，3H)3.00(t，J＝7.54Hz，2H)3.72(s，3H)6.27(d，J＝6.99Hz，1H)6.84(d，J＝8.82Hz，2H)7.11(d，J＝7.72Hz，1H)7.27(m，4H)7.83(d，J＝8.82Hz，1H)8.41(d，J＝6.99Hz，1H)9.02(d，J＝8.46Hz，1H)11.06(br.s.，1H)14.37(br.s.，1H)；MS(ESI+)m/z?416(M+H)+.

Embodiment 98

3-[4-methyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

According to the method for embodiment 1g, with product (275mg, 1.33mmol) product (307mg of embodiment 52b of embodiment 2g, 1.33mmol) reacted 18 hours, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtaining product is trifluoroacetate (305mg ₅45%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.97(t，J＝7.35Hz，3H)1.75-1.94(m，2H)2.38(s，3H)2.98(t，J＝7.35Hz，2H)6.30(d，J＝6.99Hz，1H)6.49-6.66(m，3H)6.91-7.04(m，1H)7.29·7.44(m，3H)7.79(d，J＝8.82Hz，1H)8.39(d，.J＝7.35Hz，1H)8.96(d，J＝8.46Hz，1H)9.57(s，1H)10.95(s，1H)14.34(s，1H)；MS(ESI+)m/z?402(M+H-TFA)+.

Embodiment 99

Third-2-sulfonic acid 4-[4-methyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenylester

With the product of embodiment 6 (120mg, 0.274mmol) with the sec.-propyl SULPHURYL CHLORIDE (43mg, 0.30mmol), N, the N-diisopropyl ethyl amine (43mg, 0.33mmol) and catalytic DMAP at CH ₂Cl ₂Middle reaction 18 hours obtains this rough title compound, and it by the HPLC purifying, is used the TFA wash-out, and the acquisition product is trifluoroacetic acid (40mg, 23%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:8.75(d，J＝8.54Hz，1H)8.20(d，J＝6.71Hz，1H)7.58(d，J＝8.54Hz，1H)7.26(d，J＝7.93Hz，1H)7.17-7.21(m，2H)7.08(d，J＝9.16Hz，2H)6.95(d，J＝8.54Hz，2H)6.15(d，J＝6.71Hz，1H)3.43-3.51(m，J＝13.43，1H)2.79(t，J＝7.63，7.63Hz，2H)2.20(s，3H)1.61-1.67(m，2H)1.21(d，J＝6.71Hz，6H)0.78(t，J＝7.32Hz，3H)；MS(ESI+)m/z?508(M+H)+.

Embodiment 100

Methylsulfonic acid 4-[4-methyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenylester

With the product of embodiment 6 (100mg, 0.228mmol) with methylsulfonyl chloride (28mg, 0.251mmol), N, the N-diisopropyl ethyl amine (88.4mg, 0.684mmol) and catalytic DMAP at CH ₂Cl ₂Middle reaction 18 hours obtains this rough title compound, and it by the HPLC purifying, is used the TFA wash-out, and the acquisition product is trifluoroacetic acid (20mg, 15%).

¹H?NMR(300MHz，DMSO-d ₆)δppm:0.97(t，J＝7.35Hz，3H)1.77-1.90(m，2H)2.40(s，3H)2.98(t，J＝7.54Hz，2H)3.43(s，3H)6.34(d，J＝6.99Hz，1H)7.19(d，2H)7.27(d，2H)7.36-7.40(m，2H)7.48(d，1H)7.78(d，J＝8.82Hz，1H)8.39(d，J＝6.99Hz，1H)8.91(d，J＝8.46Hz，1H)；MS(DCI?NH3+)480?m/z(M+H)+.

Embodiment 101

Ethyl sulfonic acid 4-[4-methyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenylester

Product (100mg with embodiment 6,0.228mmol) and ethyl sulfonyl chloride (28mg, 0.228mmol), N, (88.5mg 0.685mmol) reacted in methylene dichloride 18 hours with catalytic DMAP the N-diisopropyl ethyl amine, obtained this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (30mg, 22%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.97(t，J＝7.35Hz，3H)1.34(t，J＝7.17Hz，3H)1.79-1.87(m，2H)2.40(s，3H)2.98(t，J＝7.54Hz，2H)3.47(q，J＝7.35Hz，2H)6.34(d，J＝7.35Hz，1H)7.14-7.19(m，2H)7.27(d，2H)7.39(s，2H)7.46(d，1H)7.78(d，J＝8.46Hz，1H)8.39(d，J＝6.99Hz，1H)8.92(d，J＝8.82Hz，1H)；MS(ESI+)m/z?494(M+H)+.

Embodiment 102

Third-2-sulfonic acid 4-[2-(7-ethyl-[1,8] naphthyridine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenylester

Product (100mg with embodiment 4,0.233mmol) and sec.-propyl SULPHURYL CHLORIDE (40mg, 0.280mmol), N, (90mg 0.70mmol) reacted 18 hours at methylene dichloride with catalytic DMAP the N-diisopropyl ethyl amine, obtained this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (12mg, 12%).

1H?NMR(300MHz，DMSO-d ₆)δppm:8.93(d，J＝8.46Hz，1H)8.40(d，J＝7.35Hz，1H)7.79(d，J＝8.82Hz，1H)7.46(d，1H)7.37(s，2H)7.27(d，2H)7.15(d，J＝8.82Hz，2H)6.35(d，J＝6.99Hz，1H)3.66(m，J＝7.72Hz，1H)3.03(q，J＝7.72Hz，2H)2.40(s，3H)1.40(d，6H)1.36(t，3H)；MS(ESI+)m/z?494(M+H)+.

Embodiment 103

Phenyl-methylsulfonic acid 4-[2-(7-ethyl-[1,8] naphthyridine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenylester

Product (98mg with embodiment 4,0.228mmol) and benzyl SULPHURYL CHLORIDE (43mg, 0.228mmol), N, (88mg 0.686mmol) reacted in methylene dichloride 18 hours with catalytic DMAP the N-diisopropyl ethyl amine, obtained this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (35mg, 23%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.35(t，J＝7.54Hz，3H)2.39(s，3H)3.03(q，J＝7.72Hz，2H)4.94(s，2H)6.33(d，J＝6.99Hz，1H)7.07(d，J＝8.82Hz，2H)7.25(d，J＝8.82Hz，2H)7.38·7.49(m，8H)7.79(d，J＝8.82Hz，1H)8.39(d，J＝6.99Hz，1H)8.91(d，J＝8.82Hz，1H)；MS(ESI+)m/z?542(M+H)+.

Embodiment 104

N-{4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenoxymethyl]-phenyl }-ethanamide

Embodiment 104A

4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenol

With the product of embodiment 1d (893mg, 5mmol) and 2-amino-4-methyl-phenol (616mg, 5mmol) backflow 4 hours in ethanol (20mL).Mixture is cooled to room temperature and evaporation.Resistates with hexane/ethyl acetate (3:1) development, is obtained this title compound with quantitative yield.

Embodiment 104B

(2-hydroxy-5-methyl base-phenyl)-(7-methyl-[1,8] naphthyridine-4-yl)-t-butyl carbamate

To embodiment 104A (1.51g, 5mmol) and tert-Butyl dicarbonate (2.4g, 11mmol) add in the mixture in the anhydrous THF of 20mL NaOH (40mL, IN, 40mmol).To pour in the water in stirring at room 40 hours, use the citric acid acidifying, and use ethyl acetate extraction.With the organic layer dried over mgso, filter and concentrate.Resistates by chromatography purification on silicon-dioxide, with the eluant solution of 2% methyl alcohol in methylene dichloride, is obtained this title compound (1.70g, 93%).

Embodiment 104C

N-{4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-Ji amino)-phenoxymethyl]-phenyl }-ethanamide

With embodiment 104B (37mg, 0.1inmol), N-(4-chloromethyl-phenyl)-ethanamide (22mg, 0.12mmol), cesium carbonate (130mg, 0.4mmol) and the solution in the mixture of iodate tertiary butyl ammonium (0.001g) in DMF (1mL) in stirring at room 16 hours.Mixture is poured in the water, and used ethyl acetate extraction.With the organic layer dried over mgso, filter and under vacuum, concentrate, obtain this title compound.In resistates, add methylene dichloride (2mL) and trifluoroacetic acid (2mL), and in stirring at room 2 hours.With solvent evaporation, and resistates by on silicon-dioxide chromatography purification, with solution-5% methyl alcohol the eluant solution in methylene dichloride of 2% methyl alcohol in methylene dichloride, obtain this title compound, be trifluoroacetate (11mg, 21%).

¹HNMR(300MHz，DMSO-d ₆)δ?ppm2.00(s，3H)2.31(s，3H)2.74(s，3H)5.05(s，2H)6.36(d，J＝6.99Hz，1H)7.12(d，J＝8.46Hz，2H)7.25(m，3H)7.40(d，J＝8.46Hz，2H)7.73(d，J＝8.46Hz，1H)8.43(d，J＝6.99Hz，1H)8.98(d，J＝8.46Hz，1H)9.89(s，1H)10.65(s，1H)14.25(s，1H)；MS(ESI+)m/z?413(M+H)+.

Embodiment 105

2-{5-[2-(4-acetylamino-phenyl sulfenyl)-5-methyl-phenyl amino]-[1,8] naphthyridine-2-yl }-ethyl propionate

To sodium hydride (95%, 0.025g, 1.0mmol) in the slurries in the anhydrous THF of 5mL in 0 ℃ under nitrogen, drip 2-methyl-diethyl malonate (0.174g, 1.0mmol).This mixture is in stirring at room 30 minutes, handles with the product of embodiment 24a that (0.047g, 1.0mmol), in 120 ℃ of microwave heatings 1 hour, cooling distributed between ethyl acetate and water, and neutralizes with 1M HCl.With the resistates ethyl acetate extraction, and with the organic layer Na that merges ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains rough title compound.Resistates by chromatography purification on silicon-dioxide, with the eluant solution of 1% methyl alcohol in methylene dichloride, is obtained this title compound (0.031g, 62%).

1H?NMR(300MHz，DMSO-D6)δ?ppm1.14(t，J＝7.17Hz，3H)1.52(d，J＝7.35Hz，3H)2.04(s，3H)2.30(s，3H)4.10(m，3H)6.17(s，br，1H)7.04(m，3H)7.26(d，J＝8.82Hz，2H)7.48(d，J＝7.35Hz，1H)7.57(d，J＝8.46Hz，2H)8.45(d，J＝8.46Hz，1H)8.78(d，J＝8.82Hz，1H)9.11(s，1H)10.05(s，1H)；(ESI+)m/z?501(M+H)+.

Embodiment 106

N-{4-[4-bromo-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 106a

N-[4-(4-bromo-2-nitro-phenyl sulfenyl)-phenyl]-ethanamide

With 2-fluoro-4-bromo nitrobenzene (0.875g, 3.9mmol), 4-acetamido thiophenol (0.797g, 4.29mmol) and cesium carbonate (1.4g, 4.29mmol) mixture in DMF (8mL) in 100 ℃ the heating 2.5 hours.With the mixture cooling, be poured on ice, the gained solid by filtration is collected, and dry under vacuum, obtain this title compound, be yellow solid (1.4g, 100%).

Embodiment 106b

N-[4-(2-amino-4-bromo-phenyl sulfenyl)-phenyl]-ethanamide

With the product of embodiment 106a (1.4g, 3.9mmol), iron powder (0.874g, 15.6mmol) and ammonium chloride (0.253g, 4.68mmol) solution in methyl alcohol (6mL), THF (6mL) and water (2mL) is heated to and refluxed 1.5 hours.The gained mixture dilutes with methyl alcohol (50mL), and filters by Celite pad.Filtrate is concentrated into the volume of 10mL under vacuum,, (50mL), and uses ethyl acetate extraction the solution with water dilution.The extract that merges washs with 10% sodium-chlor, uses dried over mgso then, filters and concentrates under vacuum, obtains this title compound (1.2g, 92%).

Embodiment 106c

Product (106mg with embodiment 1d, 0.59mmol) with the product (200mg of embodiment 106b, 0.59mmol) in ethanol (2mL), reacted 18 hours, method according to embodiment 1g, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (53mg, 19%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.05(s，3H)2.77(s，3H)，6.41(d，J＝6.99Hz，1H)，7.02(d，J＝8.82Hz，1H)，7.33(d，J＝8.46Hz，2H)，7.58(d，J＝8.82Hz，2H)，7.65(dd，J＝8.46，2.21Hz，1H)7.77(d，J＝2.21Hz，1H)，7.81(d，J＝8.82Hz，1H)，8.48(d，J＝6.99Hz，1H)，8.96(d，J＝8.82Hz，1H)，10.11(s，1H)，11.06(s，1H)，14.53(s，1H)；MS(DCI/NH3)m/z479(M+H)+.

Embodiment 107

N-{4-[2-(7-diazanyl-[1,8] naphthyridine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenyl }-ethanamide

According to the method for embodiment 47, (0.050g 1.0mmol) substitutes morpholine, makes this title compound with hydrazine hydrate.Crude product is used the HPLC purifying by HTP, use the TFA wash-out, obtaining this title compound is trifluoroacetate (0.0125g, 19%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.04(s，3H)，2.33(s，3H)，6.13(d，J＝7.35Hz，1H，7.06(d，J＝8.09Hz，1H)，7.09-7.19(m，1H)，7.19-7.32(m，4H)，7.57(d，J＝8.82Hz，2H)，8.10(d，J＝6.99Hz，1H)，8.62(d，J＝9.56Hz，1H)，10.09(s，1H)，10.53(s，1H)，13.64(s，1H)；MS(ESI+)m/z?431(M+H)+；

Embodiment 108

N-(4-{2-[7-(2-dimethylamino-oxyethyl group)-[1,8] naphthyridine-4-base is amino]-4-methyl-phenyl sulfenyl }-phenyl)-ethanamide

According to the method for embodiment 27, use N, (0.044g 0.5mmol) substitutes diethyl malonate to the N-dimethylethanolamine, makes this title compound.Crude product by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate (0.05g, 70%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.04(s，3H)，2.35(s，3H)，2.92(s，6H)，3.64-3.68(m，2H)，4.73-4.86(m，2H)，6.31(d，J＝6.99Hz，1H)，7.14(d，J＝8.82Hz，1H)，7.24(d，J＝8.46Hz，2H)，7.27-7.32(m，2H)，7.36(d，J＝8.82Hz，1H)，7.51(d，J＝8.46Hz，2H)，8.33(d，J＝6.99Hz，1H)，8.95(d，J＝9.19Hz，1H)，9.87(s，1H)，10.07(s，1H)，10.88(s，1H)，14.23(s，1H)；MS(ESI+)m/z?488(M+H) ⁺；

Embodiment 109

N-(4-{2-[7-(2-methoxyl group-ethylamino)-[1,8] naphthyridine-4-base is amino]-4-methyl-phenyl sulfenyl }-phenyl)-ethanamide

According to the method for embodiment 47, (75mg 1.0mmol) substitutes morpholine, makes this title compound with 2-methoxy ethyl amine.Crude product by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate (10mg, 17%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.04(s，3H)，2.33(s，3H)，3.31(s，3H)，3.56(t，J＝4.96Hz，2H)，3.60-3.67(m，2H)，6.05(d，J＝6.99Hz，1H)，6.95(d，J＝9.19Hz，1H)，7.05(d，J＝8.09Hz，1H)，7.20·7.31(m，J＝7.91，7.91Hz，4H)，7.56(d，J＝8.46Hz，2H)，7.96-8.11(m，1H)，8.33-8.49(m，2H)，10.07(s，1H)，10.32(s，1H)，13.42(d，J＝5.88Hz，1H)；MS(ESI+)m/z?474(M+H) ⁺.

Embodiment 110

(7-isobutyl--[1,8] naphthyridine-4-yl)-[2-(4-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl]-amine

According to the method for embodiment 1g, (60mg is 0.271mmol) with the product (66mg of embodiment 50b with the product of embodiment 12d, 0.271mmol) reacted 25 hours, obtain this title compound, it is developed with 3:1 ether/THF, obtain this title compound, be hydrochloride (121mg, 96%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.97(d，J＝6.62Hz，6H)2.24(m，J＝6.62Hz，1H)2.34(s，3H)2.89(d，J＝7.35Hz，2H)3.72(s，3H)6.27(d，J＝6.99Hz，1H)6.84(d，J＝8.46Hz，2H)7.10(d，J＝8.09Hz，1H)7.23-7.32(m，4H)7.81(d，J＝8.46Hz，1H)8.41(d，J＝6.99Hz，1H)9.07(d，J＝8.46Hz，1H)11.09(br?s，1H)14.40(br?s，1H)；MS(ESI+)m/z?430(M-Cl)+；(ESI-)m/z?428(M-HCl)-.

Embodiment 111

5-[2-(4-amino-phenyl sulfenyl)-5-methyl-phenyl amino]-[1,8] naphthyridine-2-yl }-cyano group-ethyl acetate

(19mg, 0.037mmol), 2mL ethanol and 1M hydrochloric acid (1.5mL) mixes, and in 90 ℃ of heating 3 hours, cooling also concentrated under vacuum, obtains this title compound with the product of embodiment 30.Crude product by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate (10mg, 46%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.28(t，J＝6.99Hz，3H)，2.28(s，3H)，4.25(q，J＝7.11Hz，2H)，6.14(d，J＝5.88Hz，1H)，6.67(d，J＝8.46Hz，2H)，6.86(d，J＝7.72Hz，1H)，6.98-7.28(m，5H)，8.15(d，J＝5.88Hz，1H)，8.65(d，J＝9.56Hz，1H)，9.49(s，1H)，13.14(s，1H)；MS(ESI+)m/z?470(M+H) ⁺.

Embodiment 112

N-{4-[2-(7-isobutyl--[1,8] naphthyridine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenyl }-ethanamide

Product (50mg with embodiment 12d, 0.226mmol) in the product (62mg of embodiment 18b, 0.226mmol) reacted 18 hours, method according to embodiment 1g, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (35mg, 33%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.97(d，J＝6.62Hz，7H)，2.03(s，3H)，2.23(s，1H)，2.35(s，3H)，2.89(d，J＝7.35Hz，2H)，6.31(d，J＝7.35Hz，1H)，7.14(d，J＝8.09Hz，1H)，7.21-7.33(m，4H)，7.50(d，J＝8.46Hz，2H)，7.80(d，J＝8.82Hz，1H)，8.41(d，J＝6.99Hz，1H)，8.99(d，J＝8.82Hz，1H)，10.04(s，1H)；MS(ESI+)m/z?457(M+H-TFA)+；(ESI-)m/z?455(M-H-TFA)-.

Embodiment 113

N-methyl-4-[4-methyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-benzamide

Method according to embodiment 1g, product (0.155g with embodiment 85b, 0.57mmol) with the product 3.15M of embodiment 2g at ethanol (0.18mL, 0.57mmol) in solution reaction 24 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (0.180g, 56%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.97(t，J＝7.35Hz，3H)1.72-1.91(m，2H)2.41(s，3H)2.75(d，J＝4.41Hz，3H)2.97(t，J＝7.35Hz，2H)6.36(d，J＝6.99Hz，1H)7.20(d，J＝8.46Hz，2H)7.33-7.47(m，2H)7.50(d，1H)7.63(d，J＝8.46Hz，2H)7.77(d，J＝8.82Hz，1H)8.30-8.44(m，J＝6.62，6.62Hz，2H)8.91(d，J＝8.82Hz，1H)10.86-11.09(s，1H)；MS(ESI+)m/z?443.2(M+H)+；(ESI-)m/z?441.2(M-H)-.

Embodiment 114

N-methyl-3-[4-methyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-benzamide

Method according to embodiment 1g, product (0.155g with embodiment 87b, 0.57mmol) with the product 3.15M of embodiment 2g at ethanol (0.18mL, 0.57mmol) in solution reaction 24 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (0.042g, 13%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.98(t，J＝7.35Hz，3H)1.76-1.91(m，2H)2.39(s，3H)2.70(d，J＝4.41Hz，3H)2.91-3.04(m，2H)6.27(d，J＝6.99Hz，1H)7.18-7.42(m，4H)7.42-7.51(m，1H)7.55-7.63(m，2H)7.76(d，J＝8.82Hz，1H)8.28-8.41(m，J＝6.99Hz，2H)8.88(d，J＝8.46Hz，1H)10.95(s，1H)；MS(ESI+)m/z443.2(M+H)+；(ESI-)m/z?441.2(MM-H)-.

Embodiment 115

4-[4-methyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-methyl alcohol

Embodiment 115a

[4-(4-methyl-2-nitro-phenyl sulfenyl)-phenyl]-methyl alcohol

(0.5g 1.73mmol) is dissolved among the THF (15r π L), and cools off in ice bath the product of embodiment 84b.(3.6mL, the 3.6mmol) solution in spend the night gained mixture heating up to room temperature and stirring at THF to add diborane 1.0M under nitrogen in cold solution.Crude product is separated by extraction aftertreatment (ether/water), and use MgSO ₄Drying is filtered and is concentrated under vacuum, obtains rough title compound.By flash chromatography on silica gel method purifying, obtain as aureus solid alcohol (0.392g, 82%).

Embodiment 115b

[4-(2-amino-4-methyl-phenyl sulfenyl)-phenyl]-methyl alcohol

As describing among the embodiment 1f, (0.389g, 1.41mmol) (1.4g 7.05mmol) reacts, and obtains this title compound with quantitative yield, is orange with tin protochloride with the product of embodiment 115a.

Embodiment 115c

According to embodiment 1g to method, with the product 3.15M of embodiment 2g at ethanol (0.08mL, 0.25mmol) in solution and the product (0.061g of embodiment 115b, 0.25mmol) reacted 18.5 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (0.0195g, 14%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.98(t，J＝7.35Hz，3H)1.75·1.93(m，2H)2.31-2.42(s，3H)2.91-3.08(m，2H)4.42(s，2H)6.30(d，J＝6.99Hz，1H)7.11-7.42(m，7H)7.81(d，J＝8.46Hz，1H)8.39(d，J＝6.99Hz，1H)8.98(d，J＝8.82Hz，1H)11.01(s，1H)；MS(ESI+)m/z?416.2(M+H)+，(ESI-)m/z?414.3(M-H)-.

Embodiment 116

4-[4-(4-bromo-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol

Embodiment 116A

4-[2-amino-4-(4-bromo-benzyloxy)-phenyl sulfenyl]-phenol

Use the condition of describing among the embodiment 237C, solution and 1-bromo-4-brooethyl-benzene reaction with 4-chloro-3-nitro-phenol, obtain 4-(4-bromo-benzyloxy)-1-chloro-2-nitro-benzene, it is handled with the method for embodiment 237D and 237E successively, obtain this title compound.

Embodiment 116B

Use the method for embodiment 237F, product with the product alternate embodiment 237E of embodiment 116A, the product of embodiment 116A and the product of embodiment 237B are reacted, obtain rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate (19mg, 17%).

¹H?NMR(300MHz，DMSO-D ₆)δ?ppm:2.72(s，3H)5.13(s，2H)6.63(m，2H)7.03(dd，J＝8.82，2.57Hz，1H)7.10(m，2H)7.21(d，J＝8.46Hz，2H)7.40(m，2H)7.54(d，J＝8.09Hz，1H)7.66(s，1H)7.73(d，J＝8.46Hz，1H)8.72(s，1H)8.84(d，J＝8.46Hz，1H)9.69(s，1H)11.08(m，1H)；MS(ESI+)m/z?545，547(M+H)+.

Embodiment 117

N-{4-[4-hydroxyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Method according to embodiment 1g, product (35mg with embodiment 2g, 0.17mmol) with the product (46mg of embodiment 232B, 0.17mmol) in ethanol (1mL), reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (15mg, 20%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.97(t，J＝7.35Hz，3H)1.72-1.92(m，2H)2.01(s，3H)2.98(t，J＝7.35Hz，2H)6.30(d，J＝7.35Hz，1H)6.89(d，J＝2.57Hz，1H)6.91-6.98(m，1H)7.04(s，2H)7.38(d，J＝8.82Hz，3H)7.78(d，J＝8.82Hz，1H)8.34(d，J＝6.99Hz，1H)8.93(d，J＝8.82Hz，1H)9.94(s，1H)10.28(s，1H)10.94(s，1H)14.30(s，1H)；MS(ESI+)m/z?445(M+H)+.

Embodiment 118

[2-(2,5-dimethyl-furans-3-base sulfenyl)-5-methyl-phenyl]-(7-isobutyl--[1,8] naphthyridine-4-yl)-amine

Method according to embodiment 1g, product (80mg with embodiment 12d, 0.362mmol) with the product (85mg of embodiment 91b, 0.362mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (28mg, 19%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.97(d，J＝6.62Hz，6H)，2.14(d，J＝13.97Hz，6H)，2.19-2.30(m，1H)，2.33(s，3H)，2.90(d，J＝7.35Hz，2H)，5.97(s，1H)，6.28(d，J＝7.35Hz，1H)，7.08(d，J＝8.09Hz，1H)，7.21-7.35(m，2H)，7.83(d，J＝8.82Hz，1H)，8.46(d，J＝6.99Hz，1H)，9.05(d，J＝8.82Hz，1H)，11.02(br.S.，1H)；MS(ESI+)m/z?418(M+H-TFA)+.

Embodiment 119

N-{4-[4-(2-methyl-benzyloxy)-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 119a

N-{4-[2-amino-4-(2-methyl-benzyloxy)-phenyl sulfenyl]-phenyl }-ethanamide

With the product of embodiment 232b (28mg, 0.085mmol), 2-methyl benzyl bromine (13mg, 0.096mmol) and salt of wormwood (13mg, 0.09mmol) mixture in the mixture in DMF (1mL) was in stirring at room 15 hours.Be poured on reaction mixture on ice next day, and via solid collected by filtration, obtain this title compound (32mg, 100%).

Embodiment 119b

N-{4-[4-(2-methyl-benzyloxy)-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Method according to embodiment 1g, product (18mg with embodiment 1d, 0.085mmol) with the product (32mg of embodiment 119a, 0.085mmol) ethanol (1mL) reaction 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (23mg, 42%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.97(t，J＝7.35Hz，3H)1.69-1.94(m，2H)2.02(s，3H)2.32(s，3H)2.99(t，J＝7.35Hz，2H)5.14(s，2H)6.32(d，J＝6.99Hz，1H)6.98-7.30(m，7H)7.41(dd，J＝11.40，8.82Hz，4H)7.80(d，J＝8.82Hz，1H)8.38(d，J＝6.99Hz，1H)8.97(d，J＝8.46Hz，1H)9.98(s，1H)11.02(s，1H)14.37(s，1H)；MS(ESI+)m/z?549(M+H)+.

Embodiment 120

N-{4-[4-(3-methyl-benzyloxy)-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 120a

N-{4-[2-amino-4-(3-methyl-benzyloxy)-phenyl sulfenyl]-phenyl }-ethanamide

With the product of embodiment 232b (28mg, 0.085mmol), 3-methyl benzyl bromine (13mg, 0.096mmol) and salt of wormwood (13mg, 0.09mmol) mixture in the mixture in DMF (1mL) was in stirring at room 15 hours.Be poured on reaction mixture on ice next day, and solid filtering is collected, and obtains this title compound (32mg, 100%).

Embodiment 120b

N-{4-[4-(3-methyl-benzyloxy)-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Method according to embodiment 1g, product (18mg with embodiment 1d, 0.085mmol) with the product (32mg of embodiment 120a, 0.085mmol) ethanol (1mL) reaction 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (14mg, 26%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.97(t，J＝7.35Hz，3H)1.62-1.93(m，2H)2.02(s，3H)2.31(s，3H)2.99(t，J＝7.35Hz，2H)5.11(s，2H)6.30(d，J＝6.99Hz，1H)6.97·7.33(m，8H)7.34-7.50(m，3H)7.80(d，J＝8.82Hz，1H)8.36(d，J＝6.99Hz，1H)8.97(d，J＝8.82Hz，1H)9.97(s，1H)11.01(s，1H)14.36(s，1H)；MS(ESI+)m/z?549(M+H)+.

Embodiment 121

(5-bromo-2-phenyl sulfenyl-phenyl)-(7-methyl-[1,8] naphthyridine-4-yl)-amine

Embodiment 121a

5-bromo-2-phenyl sulfenyl-phenyl amine

With 4-bromo-2-nitrophenols (10.0g, 45.9mmol) and Et ₃(14.0mL is 137.6mmol) at 100mL CH for N ₂Cl ₂In mixture (8.5mL 50.5mmol) handled 30 minutes in 0 ℃ with Trifluoromethanesulfonic anhydride under nitrogen.By adding the MeOH stopped reaction.Use 10% citric acid, 0.5m KOH and water washing successively.Use MgSO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound, and it by silica gel column chromatography purifying purifying, is used CH ₂Cl ₂Wash-out obtains succsinic acid oily matter (15.2g, 95%).

Embodiment 121b

(4-bromo-2-nitrophenyl) (phenyl) sulfane

With the product of embodiment 121a (15.2g, 43.4mmol) and benzenethiol (4.4mL 43.4mmol) uses Na in 100mL EtOH ₂CO ₃Handle, and under refluxing heated overnight.Be cooled to room temperature, and the water stopped reaction.Extract with EtOAc.Use MgSO ₄Dry filter also concentrates under vacuum, obtains this title compound, and it by silica gel column chromatography purifying purifying, with 5%EtOAc/ hexane wash-out, is obtained yellow oil (13.3g, 99%).

Embodiment 121c

5-bromo-2-(thiophenyl) aniline

According to the method for embodiment 1f, (2.0g 6.45mmol) uses SnCl with the product of embodiment 121b ₂Reduction obtains this title compound, is limpid oily matter (1.8g, 100%).

Embodiment 121d

(5-bromo-2-phenyl sulfenyl-phenyl)-(7-methyl-[1,8] naphthyridine-4-yl)-amine

Method according to embodiment 1g, product (278mg with embodiment 1d, 1.56mmol) with the product (437mg of embodiment 121c, 1.56mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (129mg, 15%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.77(s，3H)6.43(d，J＝6.99Hz，1H)7.20(d，J＝8.46Hz，1H)7.34(s，5H)7.69(dd，J＝8.82，2.21Hz，1H)7.81(m，2H)8.47(d，J＝6.99Hz,1H)8.95(d，J＝8.46Hz，1H)；MS(ESI+)m/z?422(M+H-TFA)+.

Embodiment 122

4-[4-methyl-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenoxy group]-phenol

Embodiment 122a

4-(4-methyl-2-nitro-phenoxy) phenol

With Resorcinol (3.2g, 29.0mmol) and K ₂CO ₃(8.0g, 54.0mmol) (3.0g is 19.3mmol) together under agitation in 100 ℃ of heating 24 hours for the solution in 40mLDMF and 1-fluoro-4-methyl-2-oil of mirbane.Be cooled to room temperature and dilute with EtOAc.Wash with water, and with organic layer MgSO ₄Dry.Filter and under vacuum, concentrate, obtain this title compound, it by silica gel column chromatography purifying purifying, with 5%EtOAc/ hexane wash-out, is obtained orange (1.89g, 40%).

Embodiment 122b

4-(2-amino-4-methylphenoxy) phenol

According to the method for embodiment 1f, (1.89g 7.71mmol) uses SnCl with the product of embodiment 122a ₂Reduction obtains this title compound, is white solid (1.42g, 86%).

Embodiment 122c

4-(4-methyl-2-(7-methyl isophthalic acid, 8-naphthyridine-4-base is amino) phenoxy group) phenol

Method according to embodiment 1g, product (278mg with embodiment 1d, 1.56mmol) in the product (336mg of embodiment 122b, 1.56mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (226mg, 31%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.34(s，3H)2.74(s，3H)6.56(d，J＝6.99Hz，1H)6.64-6.71(m，2H)6.75-6.81(m，2H)6.89(d，J＝8.46Hz，1H)7.26(dd，J＝8.46，1.84Hz，1H)7.31(s，1H)7.76(d，J＝8.82Hz，1H)8.48(d，J＝6.99Hz，1H)8.95(d，J＝8.46Hz，1H)9.34(s，1H)10.91(s，1H)14.36(s，1H)；MS(ESI+)m/z?358(M+H-TFA)+.

Embodiment 123

Two-[3-(7-methyl-[1,8] naphthyridine-4-base is amino)-4-phenyl sulfenyl-benzyl]-t-butyl carbamate

Product (556mg with embodiment 1d, 3.12mmol) with the product (1.032g of embodiment 90c, 3.12mmol) reacted 18 hours, method according to embodiment 1g, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (228mg, 31%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.35(s，9H)2.76(s，6H)4.45(s，4H)6.28(d，J＝6.99Hz，2H)7.20-7.31(m，12H)7.34(s，4H)7.77(d，J＝8.82Hz，2H)8.40(d，J＝6.99Hz，2H)8.90(d，J＝8.82Hz，2H)11.00(s，2H)14.40(s，2H)；MS(ESI+)m/z829(M+H-TFA)+.

Embodiment 124

(5-bromo-2-phenoxy group-phenyl)-(7-propyl group-[1,8] naphthyridine-4-yl)-amine

Embodiment 124a

4-bromo-2-nitro-1-phenoxy group benzene

With phenol (2.35g, 25.0mmol) and K ₂CO ₃(9.4g, 68.1mmol) (5.0g is 22.7mmol) together under agitation in 100 ℃ of heating 24 hours for solution in 40mL DMF and 4-bromo-1-fluoro-2-oil of mirbane.Be cooled to room temperature and dilute with EtOAc.Wash with water, and with organic layer MgSO ₄Dry.Filter and under vacuum, concentrate, obtain this title compound, it by silica gel column chromatography purifying purifying, with 15% EtOAc/ hexane wash-out, is obtained yellow oil (6.6g, 99%).

Embodiment 124b

5-bromo-2-phenoxybenzamine

According to the method for embodiment 1f, (6.6g 22.5mmol) uses SnCl with the product of embodiment 124a ₂Reduction obtains this title compound, is brown oil (5.9g, 100%).

Embodiment 124c

N-(5-bromo-2-Phenoxyphenyl)-7-propyl group-1,8-naphthyridine-4-amine

Method according to embodiment 1g, product (275mg with embodiment 2g, 1.33mmol) with the product (351mg of embodiment 124b, 1.33mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (470mg, 65%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.95(t，J＝7.35Hz，3H)1.72-1.93(m，2H)2.91-3.02(m，2H)6.70(d，J＝6.99Hz，1H)6.97(d，J＝7.72Hz，2H)7.10(t，J＝8.27Hz，2H)7.27-7.36(m，2H)7.68(dd，J＝8.82，2.57Hz，1H)7.78(d，J＝8.46Hz，1H)7.82(d，J＝2.57Hz，1H)8.52(d，J＝6.99Hz，1H)8.89(d，J＝8.82Hz，1H)10.90(s，1H)14.49(s，1H)；MS(ESI+)m/z?436(M+H-TFA)+.

Embodiment 125

(5-bromo-2-phenoxy group-phenyl)-(7-methyl-[1,8] naphthyridine-4-yl)-amine

Method according to embodiment 1g, product (278mg with embodiment 1d, 1.56mmol) with the product (412mg of embodiment 124b, 1.56mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (206mg, 25%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.73(s，3H)6.69(d，J＝7.35Hz，2H)6.96(d，J＝7.72Hz，2H)7.05-7.15(m，3H)7.24-7.36(m，2H)7.68(dd，J＝8.82，2.57Hz，1H)7.75(d，J＝8.46Hz，1H)7.82(d，J＝2.21Hz，1H)8.52(d，J＝6.99Hz，1H)8.86(d，J＝8.82Hz，1H)10.93(s，1H)14.49(s，1H)；MS(ESI+)m/z?408(M+H-TFA)+.

Embodiment 126

4-[4-chloro-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenoxy group]-N-(2-methoxyl group-ethyl)-benzamide

Embodiment 126a

4-(4-chloro-2-nitro-phenoxy) methyl benzoate

With 1, (20.0g is 104.2mmol) with A-methyl hydroxybenzoate (15.85g, 104.2mmol) the mixture Na in 150mL EtOH for 4-two chloro-2-oil of mirbane ₂CO ₃Handle, and under refluxing heated overnight.Be cooled to room temperature and water stopped reaction.Extract with EtOAc.Use MgSO ₄Dry filter also concentrates under vacuum, obtains this title compound, with it

By silica gel column chromatography purifying purifying, 10% EtOAc/ hexane wash-out obtains this title compound, is yellow solid (29.6g, 92%).

Embodiment 126b

4-(4-chloro-2-nitro-phenoxy) phenylformic acid

Will (29.6g 96.2mmol) handles with the LiOH aqueous solution (1M), and heating 1 hour under refluxing at the product of the embodiment 126a among the 200mL MeOH.Be cooled to room temperature, and with the HCl aqueous solution (1M) acidifying.Throw out is filtered, use H ₂O washing, and dry air obtain this title compound, are yellow solid (28.2g, 100%).

Embodiment 126c

4-(4-chloro-2-nitro-phenoxy) Benzoyl chloride

(4.0g is 13.6mmol) at 40mL CH with the product of embodiment 126b ₂Cl ₂In with oxalyl chloride (3.5g, 27.2mmol) and DMF (catalytic amount) processing.Mixture was stirred 12 hours.Mixture is concentrated under vacuum, obtain this title compound, be yellow oil (4.2g, 100%).

Embodiment 126d

4-(4-chloro-2-nitro-phenoxy)-N-(2-methoxy ethyl) benzamide

At CH ₂Cl ₂In the product of embodiment 126c (1.0g, (722mg is 9.61mmol) at CH 3.2mmol) to be added to the 2-methoxyethyl amine ₂Cl ₂In mixture in.Mixture was stirred 12 hours.Mixture is concentrated this title compound of acquisition under vacuum, it by silica gel column chromatography purifying purifying, with 50% EtOAc/ hexane wash-out, is obtained this title compound, be yellow oil (1.1g, 100%).

Embodiment 126e

4-(2-amino-4-chlorophenoxy)-N-(2-methoxy ethyl) benzamide

According to the method for embodiment 1f, with the product (1.0g of embodiment 126d ₅2.85mmol) use SnCl ₂Reduction obtains this title compound, is limpid oily matter (900mg, 100%).

Embodiment 126f

4-(4-chloro-2-(7-methyl isophthalic acid, 8-naphthyridine-4-base is amino) phenoxy group)-N-(2-methoxy ethyl) benzamide

Method according to embodiment 1g, product (111mg with embodiment 1d, 0.62mmol) with the product (200mg of embodiment 126e, 0.62mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (89.4mg, 25%).

¹H?NMR(300MHz，DMSO-D ₆)δ?ppm:2.73(s，3H)3.25(s，3H)3.32-3.50(m，4H)6.72(d，J＝6.99Hz，1H)6.97(d，J＝8.82Hz，2H)7.30(d，J＝8.82Hz，1H)7.61(dd，J＝8.82，2.57Hz，1H)7.70-7.80(m，4H)8.42(t，J＝5.15Hz，1H)8.53(d，J＝6.99Hz，1H)8.82(d，J＝8.82Hz，1H)10.90(s，1H)14.54(s，1H)；MS(ESI+)m/z?463(M+H-TFA)+.

Embodiment 127

4-[4-chloro-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenoxy group]-N-propyl group-benzamide

Embodiment 127a

4-(4-chloro-2-nitro-phenoxy)-N-propyl benzamide

To method, (1.0g, 3.2mmol) (568mg, 9.61mmol) reaction is 12 hours, obtains this title compound (1.02g, 100%) with third-1-amine with the product of embodiment 126c according to embodiment 126d.

Embodiment 127b

4-(2-amino-4-chlorophenoxy)-N-propyl benzamide

(1.0g 2.99mmol) uses SnCl with the product of embodiment 127a ₂Reduction, the method according to embodiment 1f obtains this title compound, is limpid oily matter (834mg, 92%).

Embodiment 127c

4-(4-chloro-2-(7-methyl isophthalic acid, 8-naphthyridine-4-base is amino) phenoxy group)-N-propyl benzamide

Method according to embodiment 1g, product (111mg with embodiment 1d, 0.62mmol) with the product (190mg of embodiment 127b, 0.62mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (45.9mg, 13%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.86(t，J＝7.54Hz，3H)1.39-1.60(m，2H)2.72(s，3H)3.08-3.26(m，2H)6.72(d，J＝6.99Hz，1H)6.96(d，J＝8.82Hz，2H)7.29(d，J＝8.82Hz，1H)7.61(dd，J＝8.82，2.57Hz，1H)7.69-7.80(m，4H)8.34(t，J＝5.52Hz，1H)8.53(d，J＝6.99Hz，1H)8.82(d，J＝8.46Hz，1H)10.91(s，1H)14.55(s，1H)；MS(ESI+)m/z447(M+H-TFA)+.

Embodiment 128

4-[4-chloro-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenoxy group]-N-methoxyl group-N-methyl-benzamide

Embodiment 128a

4-(4-chloro-2-nitro-phenoxy)-N-methoxyl group-N-methyl-benzamide

According to the method for embodiment 126d, with the product (1.0g of embodiment 126c _s3.20mmol) (391mg, 6.41mmol) reaction is 12 hours, obtains this title compound (1.03g, 100%) with the N-methoxyethyl amine.

Embodiment 128b

4-(2-amino-4-chlorophenoxy)-N-methoxyl group-N-methyl-benzamide

Obtain this title compound, (1.0g 2.97mmol) uses SnCl with the product of embodiment 128a ₂Reduction according to the method for embodiment 1f, is limpid oily matter (911mg, 100%).

Embodiment 128c

4-(4-chloro-2-(7-methyl isophthalic acid, 8-naphthyridine-Ji amino) phenoxy group)-N-methoxyl group-N-methyl-benzamide

Method according to embodiment 1g, product (111mg with embodiment 1d, 0.62mmol) with the product (192mg of embodiment 128b, 0.62mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetic acid (50.9mg, 15%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.72(s，3H)3.19(s，3H)3.42(s，3H)6.71(d，J＝6.99Hz，1H)6.94(d，J＝8.82Hz，2H)7.36(d，J＝8.82Hz，1H)7.50(d，J＝8.82Hz，2H)7.63(dd，J＝8.82，2.57Hz，1H)7.72(d，J＝8.82Hz，1H)7.75(d，J＝2.57Hz，1H)8.53(d，J＝6.99Hz，1H)8.81(d，J＝8.46Hz，1H)10.88(s，1H)14.46(s，1H)；MS(ESI+)m/z?449(M+H-TFA)+.

Embodiment 129

4-[4-chloro-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenoxy group]-N, N-diethyl-benzamide

Embodiment 129a

4-(4-chloro-2-nitro-phenoxy)-N, N-diethylbenzene methane amide

At CH ₂Cl ₂In the product of embodiment 126c (1.0g, (469mg is 6.41mmol) at CH 3.2mmol) to be added to diethylamide ₂Cl ₂In mixture in.To mix and stir 12 hours.Mixture is concentrated this title compound of acquisition under vacuum, it by silica gel column chromatography purifying purifying, with 50% EtOAc/ hexane wash-out, is obtained yellow oil (1.1g, 100%).

Embodiment 129b

4-(2-amino-4-chlorophenoxy)-N, N-diethylbenzene methane amide

According to the method for embodiment 1f, (1.0g 2.87mmol) uses SnCl with the product of embodiment 129a ₂Reduction obtains this title compound, is limpid oily matter (772mg, 85%).

Embodiment 129c

4-(4-chloro-2-(7-methyl isophthalic acid, 8-naphthyridine-4-base is amino) phenoxy group)-N, N-diethylbenzene methane amide

Method according to embodiment 1g, product (II1mg with embodiment 1d, 0.62mmol) with the product (199mg of embodiment 129b, 0.62mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetic acid (49.2mg, 14%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.01(s，6H)2.73(s，3H)3.35(s，1H)3.53-3.81(m，4H)6.70(d，J＝7.35Hz，1H)6.93(d，J＝8.46Hz，2H)7.22(d，J＝8.82Hz，2H)7.34(d，J＝8.82Hz，1H)7.62(dd，J＝8.82，2.57Hz，1H)7.73(d，J＝6.25Hz，1H)7.75(s，1H)8.53(d，J＝6.99Hz，1H)8.82(d，J＝8.82Hz，1H)10.92(s，1H)14.55(s，1H)；MS(ESI+)m/z?461(M+H-TFA)+.

Embodiment 130

4-[4-chloro-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenoxy group]-N-propyl group-benzamide

Product (75mg with embodiment 2g, 0.36mmol) with the product (111mg of embodiment 127b, 0.36mmol) reacted 18 hours, method according to embodiment 1g, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (25.8mg, 12%).

¹HNMR(300MHz，DMSO-d ₆)δ?ppm:0.86(t，J＝7.35Hz，3H)0.95(t，J＝7.35Hz，3H)1.37-1.56(m，2H)1.72-1.88(m，2H)2.96(t，J＝7.54Hz，2H)3.08-3.22(m，2H)6.72(d，J＝6.99Hz，1H)6.97(d，J＝8.82Hz，2H)7.29(d，J＝8.82Hz，1H)7.61(dd，J＝8.82，2.57Hz，1H)7.75(d，J＝8.82Hz，4H)8.34(t，J＝5.70Hz，1H)8.52(d，J＝6.99Hz，1H)8.85(d，J＝8.82Hz，1H)10.90(s，1H)14.55(s，1H)；MS(ESI+)m/z?475(M+H-TFA)+.

Embodiment 131

4-[4-chloro-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenoxy group]-N-(2-methoxyl group-ethyl)-benzamide

Method according to embodiment 1g, product (75mg with embodiment 2g, 0.36mmol) product (116mg of embodiment 126e, 0.36mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (101.7mg, 46%).

¹HNMR(300MHz，DMSO-d ₆)δ?ppm:0.95(t，J＝7.35Hz，3H)1.70-1.90(m，2H)2.90-3.01(m，2H)3.24(s，3H)3.32-3.47(m，4H)6.73(d，J＝6.99Hz，1H)6.98(d，J＝8.82Hz，2H)7.29(d，J＝8.82Hz，1H)7.61(dd，J＝8.82，2.57Hz，1H)7.71-7.81(m，4H)8.42(t，J＝4.78Hz，1H)8.53(d，J＝6.99Hz，1H)8.85(d，J＝8.82Hz，1H)10.92(s，1H)14.57(s，1H)；MS(ESI+)m/z?491(M+H-TFA)+.

Embodiment 132

4-[4-chloro-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenoxy group]-N-methoxyl group-N-methyl-benzamide

Method according to embodiment 1g, product (75mg with embodiment 2g, 0.36mmol) with the product (111mg of embodiment 128b, 0.36mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (76.3mg, 36%).

¹HNMR(300MHz，DMSO-d ₆)δ?ppm:0.88-1.03(m，3H)1.70-1.91(m，2H)2.88-3.00(m，2H)3.18(s，3H)3.42(s，3H)6.71(d，J＝7.35Hz，1H)6.94(d，J＝8.82Hz，2H)7.36(d，J＝8.82Hz，1H)7.50(d，J＝8.82Hz，2H)7.59-7.66(m，1H)7.71-7.79(m，2H)8.53(d，J＝6.99Hz，1H)8.84(d，J＝8.82Hz，1H)10.89(s，1H)14.54(s，1H)；MS(ESI+)m/z477(M+H-TFA)+.

Embodiment 133

4-[4-chloro-2-([1,8] naphthyridine-4-base is amino)-phenoxy group]-N-ethyl-N-methyl-benzamide

Embodiment 133a

4-(4-chloro-2-nitro-phenoxy)-N-ethyl-N-methyl-benzamide

At CH ₂Cl ₂In the product of embodiment 126c (1.0g, (379mg is 6.41mmol) at CH 3.2mmol) to be added to the N-methyl ethyl-amine ₂Cl ₂In mixture in.Mixture was stirred 12 hours.Mixture is concentrated under vacuum, obtain this title compound, it by silica gel column chromatography purifying purifying, with 50% EtOAc/ hexane wash-out, is obtained yellow oil (1.03g, 100%).

Embodiment 133b

4-(2-amino-4-chlorophenoxy)-N-ethyl-N-methyl-benzamide

According to the method for embodiment 1f, (1.0g 2.99mmol) uses SnCl with the product of embodiment 133a ₂Reduction obtains this title compound, is limpid oily matter (751mg, 83%).

Embodiment 133c

4-(2-(1,8-naphthyridine-4-base is amino)-4-chlorophenoxy)-N-ethyl-N-methyl-benzamide

Method according to embodiment 1g, product (1OOmg with embodiment 16c, 0.61mmol) with the product (185mg of embodiment 133b, 0.61mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (141mg, 42%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.86-1.18(m，3H)2.62-2.92(m，5H)6.76(d，J＝7.35Hz，1H)6.94(d，J＝8.82Hz，2H)7.25(d，J＝8.09Hz，2H)7.34(d，J＝8.82Hz，1H)7.63(dd，J＝8.82，2.57Hz，1H)7.75(d，J＝2.57Hz，1H)7.85(dd，J＝8.46，4.41Hz，1H)8.61(d，J＝6.99Hz，1H)8.96(dd，J＝8.64，1.29Hz，1H)9.14(dd，J＝4.23，1.29Hz，1H)11.06(s，1H)14.74(s，1H)；MS(ESI+)m/z?433(M+H-TFA)+.

Embodiment 134

4-[4-(4-bromo-benzyloxy)-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

Method according to embodiment 1g, product (100mg with embodiment 1d, 0.559mmol) with the product (224mg of embodiment 116A, 0.559mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetic acid (129mg, 61%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.76(s，3H)5.12(s，2H)6.26(d，J＝6.99Hz，1H)6.65(d，J＝8.45HZ，2H)7.07-7.25(m，5H)7.39(d，J＝8.45Hz，2H)7.60(d，J＝8.45Hz，2H)7.81(d，J＝8.45Hz，1H)8.39(d，.J＝7.35Hz，1H)8.99(d，J＝8.45Hz，1H)9.78(s，1H)11.05(br?s，1H)14.40(br?s，1H)；MS(ESI+)m/z?544，546(M+H-TFA)+；(ESI-)m/z?542，544(M-H-TFA)-.

Embodiment 135

4-[4-(3-bromo-benzyloxy)-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

With the condition of describing among the embodiment 237C, solution and 1-bromo-3-brooethyl-benzene reaction with 4-chloro-3-nitro-phenol, obtain 4-(3-bromo-benzyloxy)-1-chloro-2-nitro-benzene, it is handled with the method for 237D and 237E successively, obtains 4-[2-amino-4-(3-bromo-benzyloxy)-phenyl sulfenyl]-phenol.

Method according to embodiment 1g, product (57mg with embodiment 1d, 0.319mmol) and 4-[2-amino-4-(3-bromo-benzyloxy)-phenyl sulfenyl]-phenol (128mg, 0.319mmol) reacted 28 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (118mg, 56%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.76(3H)5.15(s，2H)6.25(d，J＝6.99Hz，1H)6.65(d，J＝8.46Hz，2H)7.06-7.68(m，8H)7.80(d，J＝8.46Hz，1H)8.39(d，J＝6.99Hz，1H)8.99(d，J＝8.45Hz，1H)9.78(s，1H)11.02(br?s，1H)14.39(br?s，1H)；MS(ESI+)m/z?544，546(M+H-TFA)+；(ESI-)m/z?542，544(M-H-TFA)-.

Embodiment 136

4-[4-(3-bromo-benzyloxy)-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

Method according to embodiment 1g, product (62mg with embodiment 2g, 0.30mmol) and 4-[2-amino-4-(3-bromo-benzyloxy)-phenyl sulfenyl]-phenol (120mg, 0.30mmol) reacted 48 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (86mg, 41%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.98(t，J＝7.73Hz，3H)1.85(dt，J＝7.73Hz，2H)3.00(dd，J＝7.72Hz，2H)5.15(s，2H)6.27(d，J＝7.35Hz，1H)6.66(d，J＝8.82Hz，2H)7.07-7.69(m，7H)7.65(s，1H)7.83(d，J＝8.82Hz，1H)8.41(d，J＝6.99Hz，1H)9.03(d，J＝8.82Hz，1H)9.81(s，1H)11.05(br?s，1H)14.43(br?s，1H)；MS(ESI+)m/z572，574(M+H-TFA)+；(ESI-)m/z?570-572(M-H-TFA)-.

Embodiment 137

4-[4-(4-bromo-benzyloxy)-2-([1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

Method according to embodiment 1g, product (50mg with embodiment 16c, 0.30mmol) with the product (120mg of embodiment 116A, 0.30mmol) reacted 26 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (95mg, 49%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:5.12(s，2H)6.30(d，J＝7.35Hz，1H)6.64(d，J＝8.82Hz，2H)7.08-7.25(m，3H)7.39(d，J＝8.09Hz，2H)7.60(d，J＝8.09Hz，2H)7.91(dd，J＝4.42Hz，1H)8.46(d，J＝6.98Hz，1H)9.12(d，J＝8.46Hz，2H)9.17(d，J＝4.42Hz，1H)9.78(s，1H)11.10(br?s，1H)14.49(br?s，1H)；(ESI+)m/z?529，531(M+H-TFA)+；(ESI-)m/z528，530(M-H-TFA)-.

Embodiment 138

4-[4-(3-bromo-benzyloxy)-2-([1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

Method according to embodiment 1g, product (50mg with [0522] embodiment 16c, 0.30mmol) and 4-[2-amino-4-(3-bromo-benzyloxy)-phenyl sulfenyl]-phenol (120mg, 0.30mmol) reacted 40 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (87mg, 45%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:5.15(s，2H)6.30(d，J＝6.99Hz，1H)6.66(d，J＝8.83Hz，2H)7.08-7.47(m，6H)7.56(d，J＝7.72Hz，1H)7.65(m，1H)7.92(dd，J＝4.41Hz，J＝8.46Hz，1H)8.18(d，J＝6.99Hz，1H)9.14(dd，J＝8.83Hz，1H)9.17(dd，J＝5.88Hz，J＝1.84Hz，1H)9.80(s，1H)11.16(br?s，1H)14.53(br?s，1H)；MS(ESI+)m/z529，531(M+H-TFA)＝；(ESI-)m/z?528，530(M-H-TFA)-.

Embodiment 139

4-[4-(3-fluoro-benzyloxy)-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

Use the condition of describing among the embodiment 231C, solution and 1-brooethyl-3-fluoro-benzene reaction with 4-chloro-3-nitro-phenol, obtain 1-chloro-4-(3-fluoro-benzyloxy)-2-nitro-benzene, it is handled with the 237E method of embodiment 237D successively, obtains 4-[2-amino-4-(3-fluoro-benzyloxy)-phenyl sulfenyl]-phenol.

Method according to embodiment 1g, product (53mg with embodiment 1d, 0.30mmol) and 4-[2-amino-4-(3-fluoro-benzyloxy)-phenyl sulfenyl]-phenol (102mg, 0.30mmol) reacted 20 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (60mg, 33%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.76(s，3H)5.16(s，2H)6.27(d，J＝6.99Hz，1H)6.64(d，J＝8.46Hz，2H)7.03-7.36(m，7H)7.45(m，J＝6.26Hz，1H)7.80(d，J＝8.82Hz，1H)8.39(d，J＝6.98Hz，1H)8.99(d，J＝8.82Hz，1H)9.78(s，1H)11.02(br?s，1H)14.39(br?s，1H)；MS(ESI+)m/z，484(M+H-TFA)+；(ESI-)m/z，482(M-H-TFA)-.

Embodiment 140

4-[4-(4-fluoro-benzyloxy)-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

Solution and 1-brooethyl-4-fluoro-benzene reaction with 4-chloro-3-nitro-phenol, use the condition of describing among the embodiment 237C, obtain 1-chloro-4-(4-fluoro-benzyloxy)-2-oil of mirbane, it is handled with the method for 237D and 237E successively, obtains 4-[2-amino-4-(4-fluoro-benzyloxy)-phenyl sulfenyl]-phenol.

Method according to embodiment 1g, product (53mg with embodiment 1d, 0.30mmol) and 4-[2-amino-4-(4-fluoro-benzyloxy)-phenyl sulfenyl]-phenol (102mg, 0.30mmo1) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (115mg, 64%)

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.76(s，3H)5.11(s，2H)6.26(d，J＝6.99Hz，1H)6.65(d，J＝8.46Hz，2H)7.10(d，J＝8.82Hz，2H)7.15-7.27(m，4H)7.49(m，J＝5.88Hz，2H)7.81(d，J＝8.46Hz，1H)8.40(d，J＝6.98Hz，1H)8.98(d，J＝8.46Hz，1H)9.78(s，1H)11.03(br?s，1H)14.36(br?s，1H)；MS(ESI+)m/z，484(M+H-TFA)+；(ESI-)m/z，482(M-H-TFA)-.

Embodiment 141

4-[4-(4-fluoro-benzyloxy)-2-([1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

Method according to embodiment 1g, product (50mg with embodiment 16c, 0.30mmol) and 4-[2-amino-4-(4-fluoro-benzyloxy)-phenyl sulfenyl]-phenol (102mg, 0.30mmol) reacted 20 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (99mg, 56%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:5.11(s，2H)6.31(d，J＝6.99Hz，1H)6.64(d，J＝8.45Hz，2H)7.08-7.27(m，6H)7.50(m，J＝5.51Hz，2H)7.91(d，J＝4.41Hz，1H)8.47(d，J＝6.98Hz，1H)9.13(dd，J＝1.47Hz，J＝8.45Hz，1H)9.17(dd，J＝1.47Hz，J＝4.05Hz，1H)9.79(s，1H)11.14(br?s，1H)14.50(br?s，1H)；MS(ESI+)m/z，470(M+H-TFA)+；(ESI-)m/z，468(M-H-TFA)-.

Embodiment 142

4-[4-(3-fluoro-benzyloxy)-2-([1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

Method according to embodiment 1g, product (50mg with embodiment 16c, 0.30mmol) and 4-[2-amino-4-(3-fluoro-benzyloxy)-phenyl sulfenyl]-phenol (102mg, 0.30mmol) reacted 22 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (75mg, 43%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:5.16(s，2H)6.31(d，J＝736Hz，1H)6.64(d，J＝8.82Hz，2H)7.09-7.28(m，6H)7.29(2，1H)7.44(m，J＝6.61Hz，1H)7.93(dd，J＝4.41Hz，1H)8.47(d，J＝6.98Hz，1H)9.14(dd，J＝1.47Hz，J＝8.46Hz，1H)9.18((dd，J＝1.47Hz，J＝4.41Hz，1H)9.79(s，1H)11.16(br?s，1H)14.52(br?s，1H)；MS(ESI+)m/z，470(M+H-TFA)+；(ESI-)m/z，468(M-H-TFA)-.

Embodiment 143

4-[4-(4-chloro-benzyloxy)-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

Embodiment 143a

4-[2-amino-4-(4-chloro-benzyloxy)-phenyl sulfenyl]-phenol

Use the condition of describing among the embodiment 237C, solution and the reaction of 1-chloro-4-brooethyl benzene with 4-chloro-3-nitro-phenol obtain 4-(4-chloro-benzyloxy)-1-chloro-2-nitro-benzene, and it is handled with the method for 237D and 237E successively, obtain this title compound.

Embodiment 143b

Method according to embodiment 1g, product (85mg with embodiment 2g, 0.41mmol) with the product (146mg of embodiment 143a, 0.41mmol) reacted 26 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (89mg, 68%).

¹H NMR (300MHz, DMSO-d ₆) δ ppm:0.98 (t, J=7.35Hz, 3H) 1.83 (sextet, J=7.35Hz, 2H) 3.00 (dd, J=7.35Hz, 2H) 5.13 (s, 2H) 6.27 (d, J=6.99Hz, 1H) 6.64 (d, J=8.82Hz, 2H) 7.05-7.25 (m, J=8.45Hz, 4H) 7.48 (m, 4H) 7.83 (d, J=8.45Hz, 1H) 8.40 (d, J=6.99Hz, 1H) 9.00 (d, J=8.46Hz, 1H) 9.78 (s, 1H) 11.03 (br s, and 1H) 14.40 (br s, 1H); MS (ESI+) m/z, 528,530 (M+H-TFA)+; (ESI-) m/z, 526,528 (M-H-TFA)-.

Embodiment 144

4-[4-(3-chloro-benzyloxy)-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

Embodiment 144a

4-[2-amino-4-(3-chloro-benzyloxy)-phenyl sulfenyl]-phenol

Use the condition of describing among the embodiment 237C, solution and the reaction of 1-chloro-3-brooethyl benzene with 4-chloro-3-nitro-phenol obtain 4-(3-chloro-benzyloxy)-1-chloro-2-nitro-benzene, and it is handled with the method for 237D and 237E successively, obtain this title compound.

Embodiment 144b

4-[2-amino-4-(3-chloro-benzyloxy)-phenyl sulfenyl]-phenol

Method according to embodiment 1g, product (85mg with embodiment 2g, 0.41mmol) with the product (146mg of embodiment 144a, 0.41mmol) reacted 24 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (85mg, 65%).

¹H NMR (300MHz, DMSO-d ₆) δ ppm:0.98 (t, J=7.32Hz, 3H) 1.85 (sextet, J=7.35Hz, 2H) 3.00 (dd, J=7.72Hz, 2H) 5.15 (s, 2H) 6.26 (d, J=6.99Hz, 1H) 6.65 (d, J=8.83Hz, 2H) 7.07-7.25 (m, 5H) 7.35-7.54 (m, 3H) 7.83 (d, J=8.46Hz, 1H) 8.40 (d, J=7.36Hz, 1H) 9.02 (d, J=8.46Hz, 1H) 9.79 (s, 1H) 11.02 (br s, and 1H) 14.39 (br s, 1H); MS (ESI+) m/z, 528,530 (M+H-TFA)+; (ESI-) m/z, 526,528 (M-H-TFA)-.

Embodiment 145

4-[4-(3-fluoro-benzyloxy)-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

Method according to embodiment 1g, product (85mg with embodiment 2g, 0.41mmol) and 4-[2-amino-4-(3-fluoro-benzyloxy)-phenyl sulfenyl]-phenol (141mg, 0.41mmol) reacted 24 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (95mg, 37%).

¹H NMR (300MHz, DMSO-d ₆) δ ppm:0.98 (t, J=7.36Hz, 3H) 1.85 (sextet, J=7.72Hz, 2H) 3.00 (dd, J=7.36Hz, 2H) 5.16 (s, 2H) 6.27 (d, J=7.35Hz, 1H) 6.66 (d, J=8.83Hz, 2H) 7.09-7.34 (m, 7H) 7.43 (m, J=6.25Hz, 1H) 7.83 (d, J=8.83Hz, 1H) 8.40 (d, J=6.99Hz, 1H) 9.03 (d, J=8.83Hz, 1H) 9.80 (s, 1H) 11.04 (br s, and 1H) 14.45 (br s, 1H); MS (ESI+) m/z, 512 (M+H-TFA)+; (ESI-) m/z, 510 (M-H-TFA)-.

Embodiment 146

4-[4-(3-chloro-benzyloxy)-2-([1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

Method according to embodiment 1g, product (50mg with embodiment 16c, 0.30mmol) product (107mg of embodiment 144a, 0.30mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (109mg, 60%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.77(s，3H)5.16(s，2H)6.25(d，J＝6.98Hz，1H)6.66(d，J＝8.83Hz，2H)7.07-7.25(m，J＝8.46Hz，5H)7.38-7.53(m，3H)7.80(d，J＝8.45Hz，1H)8.40(d，J＝6.99Hz，1H)8.99(d，J＝8.83HZ，1H)9.79(s，1H)11.02(brs，1H)14.38(brs，1H)；MS(ESI+)m/z?500(M+H-TFA)+；(ESI-)m/z?498(M-H-TFA)-.

Embodiment 147

4-[4-(4-chloro-phenoxy group)-2-([1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

Method according to embodiment 1g, product (50mg with embodiment 16c, 0.30mmol) with the product (107mg of embodiment 143a, 0.30mmol) reacted 24 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (50mg, 27%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:5.14(s，2H)6.31(d，J＝7.36Hz，1H)6.64(d，J＝8.82Hz，2H)7.05-7.40(m，J＝8.46Hz，4H)7.46(m，J＝5.52Hz，3H)7.93(m，J＝4.41Hz，1H)8.48(d，J＝6.98Hz，1H)9.17(m，J＝1.47Hz，J＝5.88Hz，3H)9.79(s，1H)11.15(br?s，1H)14.54(br?s，1H)；MS(ESI+)m/z，486(M+H-TFA)+；(ESI-)m/z，484(M-H-TFA)-.

Embodiment 148

4-[4-(3-chloro-benzyloxy)-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

Method according to embodiment 1g, product (71mg with embodiment 1d, 0.40mmol) with the product (143mg of embodiment 144a, 0.41mmol) reacted 24 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (122mg, 49%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.77(s，3H)5.16(s，2H)6.25(d，J＝6.98Hz，1H)6.66(d，J＝8.83Hz，2H)7.07-7.25(m，J＝8.46Hz，5H).7.38-7.53(m，3H)7.80(d，J＝8.45Hz，1H)8.40(d，J＝6.99Hz，1H)8.99(d，J＝8.83HZ，1H)9.79(s，1H)11.02(br?s，1H)14.38(br?s，1H)；MS(ESI+)m/z?500(M+H-TFA)+；(ESI-)m/z?498(M-H-TFA)-.

Embodiment 149

4-[4-benzyloxy-2-([1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

Use the condition of describing among the embodiment 237C, solution and brooethyl-benzene reaction with 4-chloro-3-nitro-phenol, obtain 4-benzyloxy-1-chloro-2-nitro-benzene, it is handled with the method for 237D and 237E successively, obtain 4-(2-amino-4-benzyloxy-phenyl sulfenyl)-phenol.

Method according to embodiment 1g, product (100mg with embodiment 16c, 0.559mmol) and 4-(2-amino-4-benzyloxy-phenyl sulfenyl)-phenol (224mg, 0.559mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product be trifluoroacetate (mg, %).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:5.14(s，2H)，6.31(d，J＝6.99Hz，1H)，6.61-6.69(m，2H)，7.08-7.23(m，5H)，7.32-7.46(m，5H)，7.92(dd，J＝8.46，4.41Hz，1H)，8.47(d，J＝6.99Hz，1H)，9.10-9.21(m，2H)，9.77(s，1H)，11.14(s，1H)；MS(ESI+)m/z?452(M+H-TFA)+；(ESI-)m/z?450(M-H-TFA)-.

Embodiment 150

4-[4-(4-chloro-benzyloxy)-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

Method according to embodiment 1g, product (100mg with embodiment 1d, 0.559mmol) with the product (224mg of embodiment 143a, 0.559mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product be trifluoroacetate (mg, %).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.77(s，3H)，5.16(s，2H)，6.26(d，J＝6.99Hz，1H)，6.65(d，J＝8.46Hz，2H)，7.09-7.24(m，5H)，7.37-7.44(m，3H)，7.51(s，1H)，7.81(d，J＝8.82Hz，1H)，8.40(d，J＝6.99Hz，1H)，8.99(d，J＝8.82Hz，1H)，9.80(s，1H)，11.04(s，1H)；MS(ESI+)m/z?500(M+H-TFA)+；(ESI-)m/z?498(M-H-TFA)-.

Embodiment 151

4-[4-benzyloxy-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

Method according to embodiment 1g, product (50mg with embodiment 1d, 0.280mmol) and 4-(2-amino-4-benzyloxy-phenyl sulfenyl)-phenol (91mg, 0.280mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (22mg, 17%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.76(s，3H)，5.13(s，2H)，6.26(d，J＝6.99Hz，1H)，6.65(d，J＝8.46Hz，2H)，7.08-7.22(m，5H)，7.32-7.46(m，5H)，7.80(d，J＝8.46Hz，1H)，8.39(d，J＝6.99Hz，1H)，8.99(d，J＝8.46Hz，1H)，9.78(s，1H)，11.01(s，1H)；MS(ESI+)m/z?466(M+H-TFA)+；(ESI-)m/z?464(M-H-TFA)-.

Embodiment 152

4-[4-benzyloxy-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

Method according to embodiment 1g, product (50mg with embodiment 2g, 0.241mmol) and 4-(2-amino-4-benzyloxy-phenyl sulfenyl)-phenol (78mg, 0.241mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (2mg, 2%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.98(t，J＝7.35Hz，3H)，1.78-1.91(m，J＝7.43，7.43，7.43，7.43，7.43Hz，2H)，3.00(t，J＝7.54Hz，2H)，5.13(s，2H)，6.27(d，J＝6.99Hz，1H)，6.65(d，J＝8.82Hz，2H)，7.09-7.23(m，5H)，7.32-7.46(m，5H)，7.82(d，J＝8.82Hz，1H)，8.39(d，J＝6.99Hz，1H)，9.02(d，J＝8.82Hz，1H)，9.78(s，1H)，11.00(s，1H)；MS(ESI+)m/z?494(M+H-TFA)+；(ESI-)m/z?492(M-H-TFA)-.

Embodiment 153

N-{4-[4-(3-methoxyl group-benzyloxy)-2-(7-propyl group-[1,8] naphthyridine-Ji amino)-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 153a

N-{4-[2-amino-4-(3-methoxyl group-benzyloxy)-phenyl sulfenyl]-phenyl }-ethanamide

With the product of embodiment 232B (28mg, 0.085mmol), 3-methoxy-benzyl bromine (19mg, 0.096mmol) and salt of wormwood (13mg, 0.09mmol) mixture in the mixture in DMF (1mL) was in stirring at room 15 hours.Be poured on reaction mixture on ice next day, and solid filtering is collected, and obtains this title compound (33mg, 100%).

Embodiment 153b

N-{4-[4-(3-methoxyl group-benzyloxy)-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Method according to embodiment 1g, product (18mg with embodiment 1d, 0.085mmol) with the product (33mg of embodiment 153a, 0.085mmol) in ethanol (1mL), reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (14mg, 30%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.97(t，J＝7.35Hz，3H)1.69-1.93(m，2H)2.02(s，3H)2.99(t，J＝6.99Hz，2H)3.75(s，3H)5.13(s，2H)6.29(d，J＝7.35Hz，1H)6.91(dd，J＝8.09，2.57Hz，1H)6.95-7.05(m，2H)7.13(d，J＝8.82Hz，2H)7.16-7.24(m，2H)7.31(t，J＝8.09Hz，1H)7.38(d，J＝8.46Hz，1H)7.42(d，J＝8.82Hz，2H)7.80(d，J＝8.82Hz，1H)8.35(d，J＝6.99Hz，1H)8.97(d，J＝8.82Hz，1H)9.97(s，1H)11.00(s，1H)14.36(s，1H)；MS(ESI+)m/z?565(M+H)+.

Embodiment 154

N-{4-[4-(3-bromo-benzyloxy)-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 154a

N-{4-[2-amino-4-(3-bromo-benzyloxy)-phenyl sulfenyl]-phenyl }-ethanamide

With the product of embodiment 232B (28mg, 0.085mmol), the 3-bromo benzyl bromo (24mg, 0.096mmol) and salt of wormwood (13mg, 0.09mmol) mixture in DMF (1mL) was in stirring at room 15 hours.Be poured on reaction mixture on ice next day, and solid filtering is collected, and obtains this title compound (37mg, 100%).

Embodiment 154b

N-{4-[4-(3-bromo-benzyloxy)-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Method according to embodiment 1g, product (18mg with embodiment 1d, 0.085mmol) and embodiment 154a (37mg, 0.085mmol) product in ethanol (1mL), reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (15mg, 30%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.97(t，J＝7.35Hz，3H)1.65-1.90(m，2H)2.02(s，3H)2.99(t，J＝7.54Hz，2H)5.17(s，2H)6.29(d，J＝6.99Hz，1H)7.14(d，J＝8.82Hz，2H)7.17-7.27(m，2H)7.28-7.40(m，3H)7.42(d，J＝8.46Hz，2H)7.55(d，J＝7.72Hz，1H)7.66(s，1H)7.80(d，J＝8.46Hz，1H)8.37(d，J＝6.99Hz，1H)8.97(d，J＝8.82Hz，1H)9.98(s，1H)11.00(s，1H)14.37(s，1H)；MS(ESI+)m/z?613(M+H)+.

Embodiment 155

N-{4-[4-(3-nitro-benzyloxy)-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 155a

N-{4-[2-amino-4-(3-nitro-benzyloxy)-phenyl sulfenyl]-phenyl }-ethanamide

With the product of embodiment 232B (28tng, 0.085mmol), 3-nitrobenzyl bromine (21mg, 0.096mmol) and salt of wormwood (13mg, 0.09mmol) mixture in DMF (1mL) stirred 15 hours.Be poured on reaction mixture on ice next day, and solid filtering is collected, and obtains this title compound (34mg, 100%).

Embodiment 155b

N-{4-[2-(7-methyl-[1,8] naphthyridine-4-base is amino)-4-(3-nitro-benzyloxy)-phenyl sulfenyl]-phenyl }-ethanamide

Method according to embodiment 1g, product (18mg with embodiment 1d, 0.085mmol) with the product (34mg of embodiment 155a, 0.085mmol) in ethanol (1mL), reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (13mg, 29%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.98(t，J＝7.35Hz，3H)1.72-1.92(m，2H)2.02(s，3H)2.99(t，J＝7.54Hz，2H)5.32(s，2H)6.30(d，J＝6.99Hz，1H)7.15(d，J＝8.46Hz，2H)7.19-7.25(m，1H)7.27(d，J＝2.57Hz，1H)7.38(d，J＝8.82Hz，1H)7.43(d，J＝8.46Hz，2H)7.72(t，J＝7.91Hz，1H)7.81(d，J＝8.82Hz，1H)7.91(d，J＝7.72Hz，1H)8.22(d，J＝8.82Hz，1H)8.32(s，1H)8.37(d，J＝7.35Hz，1H)8.97(d，J＝8.82Hz，1H)9.98(s，1H)11.01(s，1H)14.37(s，1H)；MS(ESI+)m/z?580(M+H)+.

Embodiment 156

N-{4-[4-(4-cyano group-benzyloxy)-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 156a

N-{4-[2-amino-4-(4-cyano group-benzyloxy)-phenyl sulfenyl]-phenyl }-ethanamide

With the product of embodiment 232B (28mg, 0.085mmol), the 4-cyano-benzyl bromide (19mg, 0.096mmol) and salt of wormwood (13mg, 0.09mmol) mixture in DMF (1mL) was in stirring at room 15 hours.Be poured on reaction mixture on ice next day, and solid filtering is collected, and obtains this title compound (33mg, 100%).

Embodiment 156b

N-{4-[4-(4-cyano group-benzyloxy)-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Method according to embodiment 1g, product (18mg with embodiment 1d, 0.085mmol) with the product (33mg of embodiment 156a, 0.085mmol) in ethanol (1ml), reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (12mg, 21%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.97(t，J＝7.35Hz，3H)1.69-1.92(m，2H)2.02(s，3H)2.99(t，J＝7.54Hz，2H)5.27(s，2H)6.30(d，J＝6.99Hz，1H)7.14(d，J＝8.82Hz，2H)7.17-7.27(m，2H)7.37(d，J＝8.46Hz，1H)7.42(d，J＝8.82Hz，2H)7.64(d，J＝8.09Hz，2H)7.81(d，J＝8.82Hz，1H)7.89(d，J＝8.46Hz，2H)8.38(d，J＝6.99Hz，1H)8.97(d，J＝8.82Hz，1H)9.98(s，1H)11.01(s，1H)14.38(s，1H)；MS(ESI+)m/z?560(M+H)+.

Embodiment 157

N-{4-[4-(2-bromo-benzyloxy)-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 157a

N-{4-[2-amino-4-(2-bromo-benzyloxy)-phenyl sulfenyl]-phenyl }-ethanamide

With the product of embodiment 232B (56mg, 0.17mmol), the 2-bromo benzyl bromo (26 D1,0.17mmol) and salt of wormwood (26mg, 0.19mmol) mixture in DMF (1mL) was in stirring at room 15 hours.Be poured on reaction mixture on ice next day, and solid filtering is collected, and obtains this title compound (75mg, 100%).

Embodiment 157b

N-{4-[4-(2-bromo-benzyloxy)-2-(7-propyl group-[1,8] naphthyridine-4-base is amino))-the phenyl sulfenyl]-phenyl }-ethanamide

Product (35mg with embodiment 2g, 0.17mmol) with the product (75mg of embodiment 157a, 0.17mmol) in ethanol (1mL), reacted 18 hours, method according to embodiment 1g, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (18mg, 29%).

¹H?NMR(300MHz，DMSO-d ₆)，δ?ppm:0.97(t，J＝7.35Hz，3H)，1.72-1.92(m，2H)2.02(s，3H)，2.99(t，J＝7.35Hz，2H)，5.17(s，2H)，6.33(d，J＝6.99Hz，1H)，7.16(d，J＝8.46Hz，2H)，7.18-7.28(m，2H)，7.28-7.51(m，5H)，7.60(dd，J＝7.54，1.65Hz，1H)，7.69(d，J＝6.99Hz，1H)，7.81(d，J＝8.82Hz，1H)，8.39(d，J＝6.99Hz，1H)，8.97(d，J＝8.82Hz，1H)，9.99(s，1H)，11.02(s，1H)，14.37(s，1H):MS(ESI+)m/z?613M+H)+.

Embodiment 158

N-{4-[4-(4-bromo-benzyloxy)-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 158a

N-{4-[2-amino-4-(4-bromo-benzyloxy)-phenyl sulfenyl]-phenyl }-ethanamide

With the product of embodiment 232B (28mg, 0.085mmol), the 4-bromo benzyl bromo (24mg, 0.096mmol) and salt of wormwood (13mg, 0.09mmol) mixture in DMF (1mL) was in stirring at room 15 hours.Be poured on reaction mixture on ice next day, and solid filtering is collected, and obtains this title compound (37mg, 100%).

Embodiment 158b

N-{4-[4-(4-bromo-benzyloxy)-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Method according to embodiment 1g, product (18mg with embodiment 1d, 0.085mmol) with the product (37mg of embodiment 158a, 0.085mmol) in ethanol (1mL), reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (26mg, 42%)

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.97(t，J＝7.35Hz，3H)1.67-1.92(m，2H)2.02(s，3H)2.99(t，J＝7.54Hz，2H)5.14(s，2H)6.30(d，J＝6.99Hz，1H)7.14(d，J＝8.46Hz，2H)7.16-7.26(m，2H)7.31-7.49(m，5H)7.53-7.66(m，2H)7.80(d，J＝8.46Hz，1H)8.37(d，J＝6.99Hz，1H)8.97(d，J＝8.82Hz，1H)9.97(s，1H)11.00(s，1H)14.37(s，1H)；MS(ESI+)m/z?615(M+H)+.

Embodiment 159

N-{4-[4-chloro-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenoxy group]-phenyl }-ethanamide

Embodiment 159A

N-[4-(4-chloro-2-nitro-phenoxy group)-phenyl]-ethanamide

With 2-fluoro-5-chloronitrobenzene (0.5g, 2.85mmol), the 4-acetaminophenol (0.45g, 3.00mmol) and cesium carbonate (0.98g, 3.00mmol) mixture in DMSO (5mL) in 90 ℃ the heating 6 hours.Mixture is cooled off,, and, use anhydrous sodium sulfate drying then organic layer water, 20% aqueous sodium hydroxide solution and the washing of 10% sodium chloride aqueous solution with ethyl acetate (100mL) dilution.Siccative is filtered, and solvent is concentrated this title compound of acquisition under vacuum, be brown solid (0.71g, 81%).

Embodiment 159B

N-[4-(2-amino-4-chloro-phenoxy group)-phenyl]-ethanamide

According to the method for embodiment 237E, with product Fe and the NH of embodiment 159A ₄The Cl reduction obtains this title compound.

Embodiment 159C

Method according to embodiment 1g, product (50mg with embodiment 1d, 0.280mmol) with the product (77mg of embodiment 159B, 0.280mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (25mg, 17%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.92-2.11(m，3H)2.74(s，3H)6.69(d，J＝6.99Hz，1H)6.87-6.99(m，2H)7.07(d，J＝9.19Hz，1H)7.45-7.57(m，3H)7.69(d，J＝2.57Hz，1H)7.77(d，J＝8.82Hz，1H)8.52(d，J＝6.99Hz，1H)8.91(d，J＝8.46Hz，1H)9.93(s，1H)10.92(s，1H)14.50(s，1H)；MS(ESI+)m/z?419(M+H)+，(ESI-)m/z?417(M-H)-.

Embodiment 160

[2-(3,4-dimethyl-phenyl sulfenyl)-5-methyl-phenyl]-(7-propyl group-[1,8] naphthyridine-4-yl)-amine

With 3, the 4-thiophenol dimethyl benzene substitutes the 4-mercapto-phenol, method according to embodiment 1g, (70mg 0.338mmol) with the product reaction of embodiment 4c 20 hours, obtains this rough title compound with the product of embodiment 2g, it is developed with 4:1 ether/THF, obtain this title compound, be hydrochloride (135mg, 88%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.99(t，J＝7.35Hz，3H)1.82(m，J＝7.35HZ，2H)1.93(s，3H)2.05(s，3H)2.36(s，3H)2.99(q，J＝7.35Hz，2H)6.20(d，J＝6.99Hz，1H)6.94(m，3H)7.32(m，2H)7.34(s，1H)7.80(d，J＝8.82Hz，1H)8.33(d，J＝7.35Hz，1H)8.97(d，J＝8.82Hz，1H)10.96(brs，1H)14.29(brs，1H)；MS(ESI+)m/z?414(M-Cl)+；(ESI-)m/z?412(M-HCl)-.

Embodiment 161

(7-ethyl-[1,8] naphthyridine-4-yl)-[2-(4-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl]-amine

With the product of embodiment 3f (79mg, 0.41mmol) product of embodiment 50b (88mg, 0.41mmol) reaction is 23 hours, according to the method for embodiment 1g, obtain this rough title compound, it is developed with 3:1 ether/THF, obtain this title compound (162mg, 90%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.37(t，J＝7.35Hz，3H)2.34(s，3H)3.05(q，J＝7.35Hz，2H)3.72(s，3H)6.27(d，J＝6.98Hz，1H)6.85(m，J＝8.82Hz，J＝2.20Hz，2H)7.10(d，J＝8.09Hz，1H)7.23-7.32(m，4H)7.83(d，J＝8.83Hz，1H)8.41(d，J＝6.98Hz，1H)9.11(d，J＝8.83Hz，1H)11.16(br?s，1H)14.39(br?s，1H)；MS(ESI+)m/z?402(M-Cl)+；(ESI-)m/z?400(M-HCl)-.

Embodiment 162

4-[4-chloro-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenoxy group]-N-methyl-benzamide

Embodiment 162a

4-(4-chloro-2-nitro-phenoxy group)-N-methyl-benzamide

With the product of embodiment 126c (225mg, 0.72mmol) with methylamine (1.0mL, 2.0mmol) in THF (20mL) in room temperature reaction.THF is removed in decompression.Thick resistates by purified by flash chromatography, with hexane/ethyl acetate (30:70) wash-out, is obtained this title compound (110mg, 50%).

Embodiment 162b

4-(2-amino-4-chloro-phenoxy group)-N-methyl-benzamide

As describing among the embodiment 1f, (200mg 0.65mmol) uses SnCl with the product of embodiment 162a ₂Reduction obtains this title compound (100mg, 55%).

Embodiment 162c

Product (64mg with embodiment 2g, 0.31mmol) and embodiment 162b (85.0mg, 0.31mmol) in ethanol (5mL), in sealed tube, reacted 18 hours in 85 ℃, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (25mg, 31%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:8.85(d，J＝8.82Hz，1H)8.53(d，J＝7.35Hz，1H)8.33(d，J＝4.17Hz，1H)7.71-7.78(m，4H)7.61(dd，J＝8.82，2.57Hz，1H)7.29(d，1H)6.97(d，J＝8.82Hz，2H)6.73(d，J＝6.99Hz，1H)2.93-3.00(t，2H)2.71(d，3H)1.76-1.87(m，2H)0.95(t，J＝7.35Hz，3H)；MS(ESI+)m/z?561(M+H)+.

Embodiment 163

1-{4-[4-chloro-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenoxy group]-phenyl }-the ethyl ketone oxime

Embodiment 163a

1-[4-(2-amino-4-chloro-phenoxy group)-phenyl]-ethyl ketone

As describing among the embodiment 1f, with the product of embodiment 164a (1.0g, 3.4mmol) and SnCl ₂Reaction obtains this title compound (0.70g, 78%).

Embodiment 163b

1-[4-(2-amino-4-chloro-phenoxy group)-phenyl]-the ethyl ketone oxime

To the product of the embodiment 163a in ethanol (15mL) (150mg, add in 0.57mmol) hydroxy amine hydrochloric acid salt (41.8mg, 0.60mmol) and diisopropyl ethyl amine (82mg, 0.63mmol).To react on 60 ℃ of heating 3 hours.The reaction cooling, and pour in the water.With the solution extracted with diethyl ether.With organic layer water, salt water washing, and use dried over sodium sulfate, filter and under vacuum, concentrate, obtain this title compound (65mg, 42%).

Embodiment 163c

Product (45mg with embodiment 2g, 0.217mmol) with the product (60.0mg of embodiment 163b, 0.217mmol) in ethanol (10mL), in sealed tube, reacted 18 hours in 85 ℃, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (25mg, 31%).

¹H?NMR(500MHz，DMSO-d ₆)δ?ppm:0.98(t，J＝7.32，2.44Hz，3H)1.81-1.88(m，2H)2.09(s，3H)2.99(t，2H)6.74(d，J＝7.32Hz，1H)6.97(d，J＝9.28Hz，2H)7.26(d，J＝9.28Hz，1H)7.56(d，J＝8.79Hz，2H)7.61(dd，J＝9.03，2.69Hz，1H)7.75(d，J＝2.44Hz，1H)7.77·7.79(m，1H)8.57(d，J＝6.84Hz，1H)8.93(d，J＝8.30Hz，1H)；MS(ESI+)m/z?447(M+H)+.

Embodiment 164

1-{4-[4-chloro-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenoxy group]-phenyl }-ethanol

Embodiment 164a

1-[4-(4-chloro-2-nitro-phenoxy group)-phenyl]-ethyl ketone

1-bromo-4-chloro-2-oil of mirbane (5g, 21.2mmol) be added to the 4-hydroxy acetophenone (2.87g, 21.1mmol) and K ₂CO ₃(7.28g is 0.052mol) in the solution in DMF (50mL).Mixture was heated 15 hours in 80 ℃.Reaction is poured in the water.With ethyl acetate (2x) aqueous phase extracted, and the phase water that will merge, salt water washing, use dried over sodium sulfate, filter also and under vacuum, concentrate, obtain this title compound.To urge resistates by purified by flash chromatography,, obtain this title compound (4.8g, 77.8%) with (hexane/ethyl acetate 70:30) wash-out.

Embodiment 164b

1-[4-(4-chloro-2-nitro-phenoxy group)-phenyl]-ethanol

The product of embodiment 164a (0.7g 2.4mmol) is added in the ethanol (30mL), and drip sodium borohydride (115g, 3.11mmol).To react and stir 1 hour, destroy excessive sodium borohydride by dripping acetate then.Reaction is poured on ice/waterborne, and uses ethyl acetate extraction.With organic phase water, salt water washing, and use dried over sodium sulfate, filter and under vacuum, concentrate, obtain this title compound (0.634g, 90%).

Embodiment 164c

1-[4-(2-amino-4-chloro-phenoxy group)-phenyl]-ethanol

As described in embodiment 1f, (0.58g 1.9mmol) uses SnCl with the product of embodiment 164b ₂Reduction obtains this title compound (0.36g, 70%).

Embodiment 164d

Product (125mg with embodiment 2g, 0.60mmol) with the product (160mg of embodiment 164c, 0.60mmol) in ethanol (10mL), in sealed tube, reacted 18 hours in 85 ℃, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (40mg, 12%)

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:8.91(d，J＝8.82Hz，1H)8.52(d，J＝6·99Hz，1H)7.78(d，J＝8.82Hz，1H)7.70(d，J＝2.57Hz，1H)7.56(dd，J＝8.82，2.57Hz，1H)7.23(d，J＝8.46Hz，2H)7.12(d，J＝8.82Hz，1H)6.87-6.94(m，2H)6.69(d，J＝6.99Hz，1H)4.63(q，J＝6.25Hz，1H)2.97(t，J＝7.54Hz，2H)1.75-1.88(m，J＝7.35，7.35，7.35，7.35Hz，2H)1.19(d，J＝6.25Hz，3H)0.95(t，J＝7.35Hz，3H)；)；MS(ESI-)m/z?432(M-H)-.

Embodiment 165

Third-2-sulfonic acid 4-[4-chloro-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenoxy group]-phenylester

Embodiment 165a

4-chloro-1-(4-methoxyl group-phenoxy group)-2-nitro-benzene

1-bromo-4-chloro-2-oil of mirbane (10g, 42.2mmol) be added to the 4-methoxyphenol (5.3g, 42.2mmol) and K ₂CO ₃(14.5g is 105mmol) in the solution in DMF (50mL).Mixture was heated 16 hours in 80 ℃.Reaction mixture is poured on waterborne.Use the ethyl acetate extraction water layer, and the phase water that will merge, salt water washing, use dried over sodium sulfate, filter also and under vacuum, concentrate, obtain this title compound.Crude product by silica gel column chromatography purifying purifying, with (hexane/ethyl acetate 90:10) wash-out, is obtained this title compound (8.0g, 67%).

Embodiment 165b

4-(4-chloro-2-nitro-phenoxy group)-phenol

To at CH ₂Cl ₂The product of embodiment 165a (20mL) (0.98g, add in 3.5mmol) boron tribromide (0.95g, 3.90mmol).To react and stir 18 hours.Add methyl alcohol to destroy excessive boron tribromide.Reaction is poured in the water, and use dichloromethane extraction.To be separated.With organic phase water, salt water washing, use dried over sodium sulfate, filter and under vacuum, concentrate, obtain this title compound.Crude product by silica gel column chromatography purifying purifying, is obtained this title compound (0.57,60%) with (hexane/ethyl acetate 90:10).

Embodiment 165c

4-(2-amino-4-chloro-phenoxy group)-phenol

As describing among the embodiment 1f, with the product of embodiment 165b (1.0g, 3.7mmol) and SnCl ₂Reaction obtains this title compound (0.7g, 78%).

Embodiment 165d

4-[4-chloro-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenoxy group]-phenol

Product (80mg with embodiment 1d, 4.5mmol) with the product (106mg of embodiment 165c, 4.5mmol) reacted 18 hours in 85 ℃ in sealed tube at ethanol (15mL), obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (40mg, 18%).

Embodiment 165e

With the product of embodiment 165d (43mg, 0.085mmol) with the sec.-propyl SULPHURYL CHLORIDE (14.5rag, 0.102mmol), N, the N-diisopropyl ethyl amine (33mg, 0.255mmol) and catalytic DMAP at CH ₂Cl ₂Middle reaction 18 hours obtains this rough title compound, and it by the HPLC purifying, is used the TFA wash-out, and the acquisition product is trifluoroacetic acid (16mg, 31%).

¹H?NMR(300MHz，DMSO-d ₆)δppm:1.38(d，J＝6.99Hz，6H)2.73(s，3H)3.54-3.65(m，1H)6.69(d，J＝6.99Hz，1H)7.01(d，J＝9.19Hz，2H)7.20(d，J＝9.19Hz，2H)7.27(d，J＝8.82Hz，1H)7.60(dd，J＝8.82，2.57Hz，1H)7.70-7.75(m，2H)8.51(d，J＝6.99Hz，1H)8.81(d，J＝8.82Hz，1H)；MS(ESI+)m/z?484(M+H)+.

Embodiment 166

4-[4-chloro-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenoxy group]-N-methyl-benzamide

Product (100mg with embodiment 1d, 0.562mmol) with the product (155.0mg of embodiment 162b, 0.562mmol) in ethanol (5mL), in sealed tube, reacted 18 hours in 85 ℃, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (40mg, 13%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:8.82(d，J＝8.46Hz，1H)8.53(d，J＝6.99Hz，1H)8.33(d，J＝4.41Hz，1H)7.71-7.78(m，4H)7.61(dd，J＝8.82，2.57Hz，1H)7.30(d，J＝8.82Hz，1H)6.96(d，J＝8.82Hz，2H)6.72(d，J＝6.99Hz，1H)2.71-2.77(m，6H)；MS(ESI+)m/z?419(M+H)+.

Embodiment 167

[2-(4-amino methyl-phenoxy group)-5-chloro-phenyl]-(7-methyl-[1,8] naphthyridine-4-yl)-amine

Embodiment 167a

4-(4-chloro-2-nitro-phenoxy group)-benzonitrile

1-bromo-4-chloro-2-oil of mirbane (10g, 42.3mmol) be added to the 4-cyanophenol (5.0g, 42.3mmol) and K ₂CO ₃(14.6g is 0.10tnol) in the solution in DMF (50mL).Mixture was heated to 15 hours at 80 ℃.Reaction is poured in the water.Use the ethyl acetate extraction water layer, and, use dried over sodium sulfate the organic phase water, the salt water washing that merge.Organic phase is filtered and under vacuum, concentrate.Resistates by purified by flash chromatography, with (hexane/ethyl acetate 4:1) wash-out, is obtained product (9.0g, 77.8%).

Embodiment 167b

4-(2-amino-4-chloro-phenoxy group)-benzonitrile

Product (0.5g, 1.8mmol) the interior BiCl that adds to the embodiment 116a in dehydrated alcohol (20mL) ₃(0.86g, 27.3mmol) and NaBH ₄(0.55g 14.6mmol), cools off in ice/water-bath simultaneously.This mixture stirred 20 hours.To react by diatomite filtration to remove bismuth.To react concentrating under reduced pressure.Resistates was handled 15 hours with 5%HCl, then with ammonium hydroxide alkalization (pH=10).With the solution ethyl acetate extraction.With ethyl acetate layer water, salt water washing, use dried over sodium sulfate, filter and under vacuum, concentrate, obtain this title compound, be solid (0.34g, 77%).

Embodiment 167c

4-[4-chloro-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenoxy group]-benzonitrile

Product (100mg with embodiment 1d, 0.408mmol) bathe the product (100mg of embodiment 167b, 0.408mmol) in ethanol (10mL), in sealed tube, reacted 18 hours in 85 ℃, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (125mg, 44%).

Embodiment 167d

With the product of embodiment 167c (88mg, 0.175mmol) in lithium aluminum hydride (13.3mg, 0.351mmol) in THF (5mL) in 60 ℃ of reactions 15 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetic acid (15mg, 14%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:11.04(s，1H)8.92(d，J＝8.82Hz，1H)8.54(d，J＝6.99Hz，1H)8.18(s，2H)7.72-7.80(m，2H)7.59(dd，J＝9.01，2.76Hz，1H)7.40(d，J＝8.82Hz，2H)6.99-7.12(m，3H)6.74(d，J＝6.99Hz，1H)3.97(q，J＝5.52Hz，2H)2.74(s，3H)；MS(ESI+)m/z391(M+H)+.

Embodiment 168

3-[4-chloro-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenoxy group]-N, N-dimethyl-benzamide

Embodiment 168a

3-(4-chloro-2-nitro-phenoxy group)-phenylformic acid

In the solution of DMF (50mL), add 1-bromo-2-nitro-4-chloro-benzene (10.0g, 42.2mmol), the 3-hydroxy-benzoic acid (5.8g, 42.0mmol) and K ₂CO ₃(17.5g, 0.13mol).Solution is heated to 85 ℃, and stirs and spend the night.Reaction is poured in the distilled water, and use ethyl acetate extraction.With organic layer distilled water, the salt water washing that merges, use Na ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains thick oily matter.This oily matter is used CH by by silica gel column chromatography purifying purifying ₂Cl ₂/ MeOH (90:10) wash-out obtains this title compound (7.4gm, 60%).

Embodiment 168b

3-(4-chloro-2-nitro-phenoxy group)-Benzoyl chloride

With the product (2.0g.6.8mmol) of embodiment 168a with oxalyl chloride (9.0g, 13.6mmol) and catalytic DMF handled 5 hours in 60 ℃.Remove excessive oxalul chloride under the vacuum.Resistates is handled (chased) with benzene, obtain required product (2.2g, 94%).

Embodiment 168c

3-(4-chloro-2-nitro-phenoxy group)-N, N-dimethyl-benzamide

(2.0g, (0.6g 13.3mmol), and will react stirring 16 hours to add dimethyl amine in 6.4mmol) to the product of the embodiment 168b in THF (25mL).Reaction is poured in the water, and use ethyl acetate extraction.Organic layer with 5% HCl, water, salt water washing, is used dried over sodium sulfate, filter and under vacuum, concentrate, obtain this title compound (1.9g, 87%).

Embodiment 168d

3-(2-amino-4-chloro-phenoxy group)-N, N-dimethyl-benzamide

As describing among the embodiment 1f, with the product of embodiment 168c (1.5g, 4.6mmol) and SnCl ₂Reaction obtains this title compound (0.91g, 68%).

Embodiment 168e

Product (177mg with embodiment 2g, 0.86mmol) with the product (249mg of embodiment 168d, 0.86mmol) in ethanol (5mL), in sealed tube, reacted 18 hours in 85 ℃, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (100mg, 20.2%).

1H?NMR(500MHz，DMSO-D6)δ?ppm:8.86(d，J＝8.79Hz，1H)8.52(d，J＝6.84Hz，1H)7.74(d，1H)7.72(d，1H)7.60(dd，J＝8.79，2.93Hz，1H)7.28-7.33(m，1H)7.27(d，2H)7.06(d，J＝7.81Hz，1H)6.99(dd，J＝8.06，2.69Hz，1H)6.71(d，J＝6.84Hz，1H)2.96(t，2H)2.91(s，3H)2.70(s，3H)1.79-1.86(m，2H)0.96(t，J＝7.49Hz，3H)；MS(ESI+)m/z461(M+H)+.

Embodiment 169

3-[4-chloro-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenoxy group]-the phenylformic acid ethyl ester

Embodiment 169a

3-(4-chloro-2-nitro-phenoxy group)-ethyl benzoate

(2.0g fed HCl gas 10 hours in 6.8mmol) to the product of the embodiment 168a in ethanol (5OmL) under cooling.Under vacuum, remove excess ethyl alcohol.Solid is dissolved in the ethyl acetate.With the saturated NaHCO of organic layer ₃, water, salt water washing, use dried over sodium sulfate, filter also and under vacuum, concentrate, obtain this title compound (2.Og, 91%).

Embodiment 169b

3-(2-amino-4-chloro-phenoxy group)-ethyl benzoate

As describing among the embodiment 1f, with the product of embodiment 169a (1.5g, 4.7mmol) and SnCl ₂Reaction obtains this title compound (1.0g, 73%).

Embodiment 169c

3-[4-chloro-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenoxy group]-ethyl benzoate

Product (113mg with embodiment 2g, 0.55mmol) with the product (160mg of embodiment 169b, 0.55mmol) in ethanol (5mL), in sealed tube, reacted 18 hours in 85 ℃, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (200mg, 63%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:8.76(d，J＝8.46Hz，1H)8.54(d，J＝6.99Hz，1H)7.74(dd，J＝5.70，3.13Hz，2H)7.58-7.65(m，J＝5.70，5.70，2.57Hz，2H)7.29-7.43(m，3H)7.20(dd，J＝7.72，2.21Hz，1H)6.68(d，J＝6.99Hz，1H)4.23(q，J＝6.99Hz，2H)2.96(t，J＝7.54Hz，2H)1.77-1.85(m，2H)1.29(t，3H)0.95(t，J＝7.35Hz，3H)；MS(ESI+)m/z?461(M+H)+.

Embodiment 170

1-{3-[4-chloro-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenoxy group]-phenyl }-ethanol

Embodiment 170a

1-[3-(4-chloro-2-nitro-phenoxy group)-phenyl]-ethyl ketone

1-bromo-4-chloro-2-oil of mirbane (10g, 42.2mmol) be added to the 3-hydroxy acetophenone (5.5g, 42.2mmol) and K ₂CO ₃(11.7g is 84.6mmol) in the solution in DMF (50mL).Will be in 80 ℃ of heating 16 hours.Reaction is poured in the water.With ethyl acetate (2x) aqueous phase extracted, and the phase water that will merge, salt water washing, use dried over sodium sulfate, filter also and under vacuum, concentrate, obtain this title compound.Thick resistates with (hexane/ethyl acetate 70:30) wash-out, obtains this title compound (8.6g, 70%) by purified by flash chromatography.

Embodiment 170b

1-[3-(4-chloro-2-nitro-phenoxy group)-phenyl]-ethanol

To the product of the embodiment 170a in ethanol (50mL) (1.8g, add in 6.2mmol) in batches sodium borohydride (0.32g, 8.64mmol).To react on stirring at room 16 hours.Destroy excessive sodium borohydride by adding acetate.Reaction is poured on ice/waterborne, and uses ethyl acetate extraction.With organic phase water, salt water washing, use dried over sodium sulfate, filter and under vacuum, concentrate, obtain this title compound.Crude product is passed through silica gel column chromatography purifying purifying, with (hexane/ethyl acetate/methyl alcohol (75:15:5) wash-out obtains required product (0.98g, 54%).

Embodiment 170c

1-[3-(2-amino-4-chloro-phenoxy group)-phenyl]-ethanol

As describing among the embodiment 1f, (0.98g 3.3mmol) uses SnCl with the product of embodiment 170b ₂Reduction obtains this title compound (0.61g, 70%).

Embodiment 170d

Product (140mg with embodiment 2g, 0.68mmol) with the product (178mg of embodiment 170c, 0.68mmol) in ethanol (5mL), in sealed tube, reacted 18 hours in 85 ℃, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (110mg, 30%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:8.86(d，J＝8.46Hz，1H)8.53(d，J＝7.35Hz，1H)7.77(d，J＝8.82Hz，1H)7.71(d，J＝2.57Hz，1H)7.58(dd，J＝8.82，2.57Hz，1H)7.17-7.22(d，2H)7.01(d，J＝7.72Hz，1H)6.87(s，1H)6.78(dd，J＝7.54，2.02Hz，1H)6.68(d，J＝6.99Hz，1H)4.55-4.62(q，J＝6.62Hz，1H)2.96(t，J＝7.54Hz，2H)1.76-1.86(m，2H)1.12(d，J＝6.62Hz，3H)0.95(t，J＝7.35Hz，3H)；MS(ESI+)m/z?434(M+H)+.

Embodiment 171

3-[4-chloro-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenoxy group]-benzamide

Embodiment 171a

3-(4-chloro-2-nitro-phenoxy group)-benzamide

(1.8g 6.13mmol) is added to cold NH the product of embodiment 168b ₄Among the OH (15mL), and stirred 1 hour.Reaction is poured in the water, and use ethyl acetate extraction.With organic layer water, salt water washing, use dried over sodium sulfate, filter and under vacuum, concentrate, obtain this title compound (1.66g, 92%).

Embodiment 171b

3-(2-amino-4-chloro-phenoxy group)-benzamide

According to the method for describing among the embodiment 1f, with the product of embodiment 171a (0.56g, 1.9mmol) and SnCl ₂Reaction obtains this title compound (0.60g, 83%).

Embodiment 171c

3-[4-chloro-2-(7-propyl group-[1,8] naphthyridine-Ji amino)-phenoxy group]-benzamide

Product (140mg with embodiment 2g, 0.68mmol) with the product (178mg of embodiment 171b, 0.68mmol) in ethanol (5mL), in sealed tube, reacted 18 hours in 85 ℃, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (110mg, 30%).

¹H?NMR(500MHz，DMSO-d ₆)δ?ppm:8.81(d，J＝8.54Hz，1H)8.45(d，J＝7.32Hz，1H)6.76-6.79(m，2H)6.64(d，J＝8.54Hz，2H)6.44(s，1H)6.37(t，J＝7.93Hz，1H)6.31(d，J＝8.54Hz，1H)7.16(dd，J＝7.93，2.44Hz，1H)6.84(d，J＝7.32Hz，1H)2.95(t，J＝7.32Hz，2H)1.80(m，2H)0.95(t，J＝7.32Hz，3H)；MS(ESI+)m/z?433(M+H)+.

Embodiment 172

3-[4-chloro-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenoxy group]-N-ethyl-benzamide

Embodiment 172a

(1.6g, 5.1mmol) (0.4g 8.0mmol), and will react and stir 16 hours interior adding ethylamine to the embodiment 168b in THF (25mL).Reaction is poured in the water, and use ethyl acetate extraction.Organic layer with 5% HCl, water and salt water washing, is used dried over sodium sulfate, filter and under vacuum, concentrate, obtain this title compound (1.4g, 85%).

Embodiment 172b

3-(2-amino-4-chloro-phenoxy group)-N-ethyl-benzamide

As describing among the embodiment 1f, with the product of embodiment 172a (0.90g, 2.8mmol) and SnCl ₂Reaction obtains this title compound (0.65g, 81%).

Embodiment 172c

Product (128mg with embodiment 2g, 0.62mmol) and embodiment 172b (180mg, 0.62mmol) in ethanol (10mL), in sealed tube, reacted 18 hours in 85 ℃, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (70mg, 20%).

¹H?NMR(500MHz，DMSO-d ₆)δ?ppm:8.84(d，J＝8.82Hz，1H)8.53(d，J＝7.26Hz，1H)8.39(t，J＝5.45Hz，1H)7.72-7.76(m，2H)7.60(dd，J＝8.82，2.59Hz，1H)7.54(d，J＝7.78Hz，1H)7.32-7.36(m，2H)7.25(d，J＝8.82Hz，1H)7.09(dd，J＝7.78，2.59Hz，1H)6.70(d，J＝7.26Hz，1H)3.19-3.25(m，2H)2.96(t，J＝7.52Hz，2H)1.79-1.84(m，2H)1.08(t，J＝7.00Hz，3H)0.95(t，J＝7.52Hz，3H)；MS(ESI+)m/z?461(M+H)+.

Embodiment 173

3-[4-chloro-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenoxy group]-N-phenyl-benzamide

Embodiment 173a

To the product of the embodiment 168b in THF (25mL) (0.81g, add in 2.6mmol) benzyl amine (0.25g, 2.6mmol) and N, the N-diisopropyl ethyl amine (0.67g, 5,2mmol).To react and stir 16 hours.Reaction is poured in the water, and use ethyl acetate extraction.Organic layer with 5%HCl, water, salt water washing, is used dried over sodium sulfate, filter and under vacuum, concentrate, obtain this title compound (0.8g, 85%).

Embodiment 173b

3-(2-amino-4-chloro-phenoxy group)-N-phenyl-benzamide

As describing among the embodiment 1f, with the product of embodiment 173a (0.84g, 2.3mmol) and SnCl ₂Reaction obtains required product (0.60g, 77%).

Embodiment 173c

Product (131mg with embodiment 2g, 0.63mmol) with the product (214mg of embodiment 173b, 0.63mmol) in ethanol (10mL), in sealed tube, reacted 18 hours in 85 ℃, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (125mg, 31%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:10.11(s，1H)8.80(d，J＝8.82Hz，1H)8.53(d，J＝6.99Hz，1H)7.67-7.75(m，4H)7.58-7.67(m，2H)7.40-7.46(m，2H)7.30-7.37(m，3H)7.08-7.18(m，2H)6.70(d，J＝7.35Hz，1H)2.92(t，2H)1.73-1.82(m，2H)0.92(t，J＝7.35Hz，3H)；MS(ESI+)m/z?509(M+H)+.

Embodiment 174

3-[4-chloro-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenoxy group]-N-(3-hydroxyl-phenyl)-benzamide

Embodiment 174a

N-[3-(tertiary butyl-dimethyl-silyl oxygen base)-phenyl]-3-(4-chloro-2-nitro-phenoxy group)-benzamide

To the product of the embodiment 168b in THF (25mL) (1.3g, add in 4.2mmol) 3-(tertiary butyl-dimethyl-silyl oxygen base)-phenyl amine (1.0g, 4.2mmol) and N ₅The N-diisopropyl ethyl amine (0.67g, 5.2mmol).To react and stir 16 hours.Reaction is poured in the water, and use ethyl acetate extraction.Organic layer with 5% HCl, water, salt water washing, is used dried over sodium sulfate, filter and under vacuum, concentrate, obtain this title compound (1.3g, 85%).

Embodiment 174b

3-(4-chloro-2-nitro-phenoxy group)-N-(3-hydroxyl-phenyl)-benzamide

To the product of the embodiment 174a in THF (25mL) (1.5g, add in 3.0mmol) tetrabutylammonium (0.94g, 3.6mmol).To react and stir 16 hours.Reaction is poured in the water, and use ethyl acetate extraction.With organic layer water, salt water washing, use dried over sodium sulfate, filter and under vacuum, concentrate, obtain this title compound (1.0g, 86%).

Embodiment 174c

3-(2-amino-4-chloro-phenoxy group)-N-(3-hydroxyl-phenyl)-benzamide

As describing among the embodiment 1f, with the product of embodiment 174b (1.0g, 2.6mmol) and SnCl ₂Reaction obtains this title compound (0.71g, 84%).

Embodiment 174d

Product (144mg with embodiment 2g, 0.70mmol) with the product (247mg of embodiment 174c, 0.70mmol) in ethanol (10mL), in sealed tube, reacted 18 hours in 85 ℃, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (123mg, 27%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:10.02(s，1H)9.45(s，1H)8.81(d，J＝8.82Hz，1H)8.53(d，J＝7.35Hz，1H)7.74(m，2H)7.69(d，2H)7.61(dd，1H)7.43(s，2H)7.33(s，2H)7.17(m，1H)7.12(s，2H)6.71(d，J＝6.99Hz，1H)6.52(m，1H)2.93(t，J＝7.54Hz，2H)1.72-1.86(m，2H)0.93(t，J＝7.35Hz，3H)；MS(ESI+)m/z?525(M+H)+.

Embodiment 175

3-[4-chloro-2-(7-propyl group-[1,8] naphthyridine-Ji amino)-phenoxy group]-N-propyl group-benzamide

Embodiment 175a

3-(4-chloro-2-nitro-phenoxy group)-N-propyl group-benzamide

(1.0g, 3.2mmol) (0.38g 6.4mmol), and will react and stir 16 hours interior adding n-propyl amine to the embodiment 168b in THF (25mL).Pour into reaction in the water and use ethyl acetate extraction.Organic layer with 5% HCl, water, salt water washing, is used dried over sodium sulfate, filter and under vacuum, concentrate, obtain this title compound (0.88g, 82%).

Embodiment 175b

3-(2-amino-4-chloro-phenoxy group)-N-propyl group-benzamide

As describing among the embodiment 1f, with embodiment 175a (0.88g, product 2.6mmol) and SnCl ₂Reaction obtains this title compound (0.61g, 76%).

Embodiment 175c

3-[4-chloro-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenoxy group]-N-propyl group-benzamide

Product (110mg with embodiment 2g, 0.53mmol) with the product (162mg of embodiment 175b, 0.53mmol) in ethanol (10mL), in sealed tube, reacted 18 hours in 85 ℃, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (50mg, 16%).

¹HNMR(300MHz，DMSO-d ₆)δ?ppm:0.85(t，J＝7.54Hz，3H)0.95(t，J＝7.35Hz，3H)1.42-1.54(m，2H)1.75-1.88(m，2H)2.96(t，J＝7.54Hz，2H)3.15(q，2H)6.69(d，J＝6.99Hz，1H)7.09(dd，J＝7.54，2.39Hz，1H)7.26(d，J＝8.82Hz，1H)7.32-7.36(m，2H)7.54(d，J＝8.09Hz，1H)7.60(dd，J＝8.82，2.57Hz，1H)7.72-7.77(m，2H)8.39(t，J＝5.70Hz，1H)8.52(d，J＝7.35Hz，1H)8.82(d，J＝8.82Hz，1H)；MS(ESI+)m/z?475(M+H)+.

Embodiment 176

3-[4-chloro-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenoxy group]-phenyl }-methyl alcohol

Embodiment 176a

3-(4-chloro-2-nitro-phenoxy group)-phenyl aldehyde

In the solution of DMF (50mL), add 1-bromo-2-nitro-4-chloro-benzene (10.0g, 42.2mmol), the 3-hydroxy benzaldehyde (5.2g, 42.2mmol) and K ₂CO ₃(11.5g, 84.6mmol).Solution is heated to 85 ℃, and stirs and spend the night.Reaction is poured in the distilled water, and use ethyl acetate extraction.The organic layer that merges is used Na with distilled water, salt water washing ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound.This solid with hexane/ethyl acetate (4:1) washing, obtains this title compound (4.4gm, 41%) by silica gel column chromatography purifying purifying.

Embodiment 176b

[3-(4-chloro-2-nitro-phenoxy group)-phenyl]-methyl alcohol

To the product (2.0g.7.2mmol) of the embodiment 176a in ethanol (25mL) add sodium borohydride (0.32g, 8.6mmol).To react and stir 4 hours.Destroy excessive sodium borohydride by adding acetate.Pour into reaction in the water and use ethyl acetate extraction.Organic layer is separated, and water, salt water washing, use dried over sodium sulfate, filter also concentratedly under vacuum, obtain this title compound (1.9g, 94%).

Embodiment 176c

[3-(2-amino-4-chloro-phenoxy group)-phenyl]-methyl alcohol

With the product of embodiment 176b (1.9g, 6.8mmol) and SnCl ₂Reaction as describing among the embodiment 1f, obtains this title compound (1.4g, 83%).

Embodiment 176d

Product (110mg with embodiment 1d, 0.62mmol) and embodiment 176c (153mg, 0.62mmol) in ethanol (10mL), in sealed tube, reacted 18 hours in 85 ℃, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (50mg, 16%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:8.96-9.00(m，1H)8.52(d，J＝6.99Hz，1H)7.70-7.74(m，2H)7.57(dd，J＝9.01，2.39Hz，1H)7.15·7.25(m，2H)7.00(d，J＝7.72Hz，1H)6.88(s，1H)6.82(dd，1H)6.68(d，J＝6.99Hz，1H)4.37(s，2H)2.74(s，3H)；MS(ESI+)m/z?392(M+H)+.

Embodiment 177

1-{3-[4-chloro-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenoxy group]-phenyl }-ethanol

Product (125mg with embodiment 1d, 0.70mmol) with the product (184mg of embodiment 170c, 0.70mmol) in ethanol (10mL), in sealed tube, reacted 18 hours in 85 ℃, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (59mg, 16%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.15(d，J＝6.25Hz，，3H)2.62(s，3H)4.60(q，J＝6.37Hz，1H)6.64(d，J＝7.35Hz，1H)6.73-6.79(m，1H)6.89(s，1H)7.01(d，J＝7.72Hz，1H)7.16(t，J＝8.09Hz，2H)7.56(dd，J＝8.82，2.57Hz，1H)7.68-7.72(m，2H)8.53(d，J＝6.99Hz，1H)9.18(d，J＝8.46Hz，1H)；MS(ESI+)m/z?406(M+H)+.

Embodiment 178

3-[4-chloro-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenoxy group]-N-(3-hydroxyl-phenyl)-benzamide

Product (125mg with embodiment 1d, 0.70mmol) with the product (237mg of embodiment 174c, 0.70mmol) in ethanol (10mL), in sealed tube, reacted 18 hours in 85 ℃, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (120mg, 28%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:10.00(s，1H)8.81(d，J＝8.46Hz，1H)8.55(d，J＝6.99Hz，1H)7.72-7.75(m，2H)7.65-7.71(m，1H)7.62(dd，J＝9.01，2.76Hz，1H)7.42(s，2H)7.30(d，J＝8.82Hz，1H)7.26(s，1H)7.16(dd，J＝7.35，2.57Hz，1H)7.10(d，J＝5.52Hz，2H)6.71(d，J＝6.99Hz，1H)6.48-6.55(m，1H)2.69(s，3H)；MS(ESI-)m/z?495(M-H)-.

Embodiment 179

[5-chloro-2-(4-sec.-propyl-phenoxy group)-phenyl]-(7-methyl-[1,8] naphthyridine-4-yl)-amine

Embodiment 179a

4-chloro-1-(4-sec.-propyl-phenoxy group)-2-nitro-benzene

1-bromo-4-chloro-2-oil of mirbane (12g, 50.7mmol) be added to the 4-isopropyl-phenol (8.3g, 60.8mmol) and K ₂CO ₃(14.0g is 101mmol) in the solution in DMF (70mL).Mixture was heated 16 hours in 80 ℃.Reaction is poured in the water.Use the ethyl acetate extraction water, and the phase water that will merge, salt water washing, use dried over sodium sulfate, filter also and under vacuum, concentrate, obtain this title compound.Crude product by silica gel column chromatography purifying purifying, is obtained this title compound (13.5g, 92%) with (hexane/ethyl acetate 90:10).

Embodiment 179b

5-chloro-2-(4-sec.-propyl-phenoxy group)-phenyl amine

With the product of embodiment 179a (13.7g, 46.8mmol) and SnCl ₂Reaction as describing among the embodiment 1f, obtains this title compound (10.3g, 84.4%).

Embodiment 179

Product (120mg with embodiment 1d, 0.67mmol) with the product (175mg of embodiment 179b, 0.67mmol) in ethanol (10mL), in sealed tube, reacted 18 hours in 85 ℃, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (60mg, 17%).

¹HNMR(300MHz，DMSO-d ₆)δ?ppm:8.86(d，J＝8.46Hz，1H)8.51(d，J＝7.35Hz，1H)7.75(d，1H)7.70(d，1H)7.55(dd，J＝7.87，1H)7.14(m，3H)6.89(d，J＝8.64，2.76Hz，2H)6.67(d，J＝6.98Hz，1H)2.79(m，1H)2.73(s，3H)1.09(d，J＝6.99Hz，6H)；MS(ESI+)m/z404(M+H)+.

Embodiment 180

2-[3-(1-azido--ethyl)-phenoxy group]-5-chloro-phenyl }-(7-propyl group-[1,8] naphthyridine-4-yl)-amine

Embodiment 180a

2-[3-(1-azido--ethyl)-phenoxy group]-5-chloro-phenyl amine

Adding phenylbenzene phosphide nitrine in the product of the embodiment 170c in toluene (25mL) (1.72g 6.23mmol), adds 1 then, and 8-diazabicyclo [4.3.0] 11-7-alkene (0.95g, 6.2mmol).Mixture was stirred 18 hours at 25 ℃.Reaction is poured in the water, and use ethyl acetate extraction.With organic layer water, the salt water washing that merges, use dried over sodium sulfate, filter and under vacuum, concentrate, obtain this title compound.With crude product purifying on silica gel,, obtain this title compound (700mg, 50%) with hexane/ethyl acetate/methyl alcohol (85:17:3) wash-out.

Embodiment 180b

2-[3-(1-azido--ethyl)-phenoxy group]-5-chloro-phenyl }-(7-and general-[1,8] naphthyridine-4-yl)-amine

Product (130mg with embodiment 2g, 0.63mmol) with the product (181mg of embodiment 180a, 0.63mmol) in ethanol (10mL), in sealed tube, reacted 18 hours in 85 ℃, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (11mg, 11%).

¹H?NMR(500MHz，DMSO-d ₆)δ?ppm:0.91(t，J＝7.42Hz，3H)1.23(d，J＝6.59Hz，3H)1.74-1.81(m，2H)2.91(t，J＝7.69Hz，2H)4.61(q，J＝6.59Hz，1H)6.67(d，J＝7.14Hz，1H)6.82(s，2H)6.99(d，J＝7.14Hz，1H)7.21(d，J＝8.79Hz，2H)7.52(dd，J＝8.79Hz，1H)7.64(d，J＝2.75Hz，1H)7.65(d，J＝8.79Hz，1H)8.48(d，J＝6.04Hz，1H)8.81(d，J＝8.79Hz，1H)；MS(ESI+)m/z?459(M+H)+.

Embodiment 181

3-[4-fluoro-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenoxy group]-N, N-dimethyl-benzamide

Embodiment 181a

3-(4-fluoro-2-nitro-phenoxy group)-phenylformic acid ethyl ester

2, the 5-difluoro nitrobenzene (5.0g, 31.4mmol), the 3-nipagin A (5.2g, 31.4mmol) and K ₂CO ₃(8.7g 62.8mmol) is added among the DMF (50mL).Solution is heated to 85 ℃ and stirred 16 hours.The reaction cooling.Reaction is fallen as in the distilled water, and use ethyl acetate extraction.The organic layer that merges is used dried over sodium sulfate with distilled water, salt water washing, filters and concentrates under vacuum, obtains this title compound.Thick resistates by silica gel column chromatography purifying purifying, with hexane/ethyl acetate (90:10) wash-out, is obtained this title compound (7.0g, 73%).

Embodiment 181b

3-(4-fluoro-2-nitro-phenoxy group)-phenylformic acid

(3.0g 9.8mmol) is added to THF/H the product of embodiment 181a ₂In the O solution (5:1).Disposable adding lithium hydroxide monohydrate (0.82g, 19.5mmol).With solution be heated to 60 ℃ 2 hours.To react cooling.Add distilled water.With 10% HCl with pH regulator to 4.0.With the mixture ethyl acetate extraction.The organic phase water, the saturated NaHCO that merge ₃, water, salt water washing, use dried over sodium sulfate, filter also and under vacuum, concentrate, obtain this title compound (2.65g, 97%).

Embodiment 181c

3-(4-fluoro-2-nitro-phenoxy group)-Benzoyl chloride

With the product of embodiment 181b (1.6g, 5.6mmol) with oxalyl chloride (0.86g, 6.7mmol) and catalytic DMF in room temperature treatment 6 hours.Under vacuum, remove oxalyl chloride.Resistates is handled (chased) with benzene, obtain this title compound (1.66g, 94%).

Embodiment 181d

3-(4-fluoro-2-nitro-phenoxy group)-N, N-dimethyl-benzamide

The product of embodiment 181c (1.0g 3.4mmol) is added among the THF (25mL), and add dimethyl amine (0.31g, g, 6.8mmol).To react on stirring at room 16 hours.Reaction is poured on ice/waterborne, and uses ethyl acetate extraction.Organic layer with 5% HCl, water, salt water washing, is used dried over sodium sulfate, filter and under vacuum, concentrate, obtain this title compound (0.90g, 87%).

Embodiment 181e

3-(2-amino-4-fluoro-phenoxy group)-N, N-dimethyl-benzamide

As describing among the embodiment 1f, (1.1g 3.4mmol) uses SnCl with the product of embodiment 181d ₂Reduction obtains this title compound (0.88g, 88%).

Embodiment 181f

Product (110mg with embodiment 2g, 0.53mmol) in the product (154rng of embodiment 181e, 0.53mmol) reacted 18 hours in 85 ℃ in sealed tube at ethanol (10mL), obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetic acid (65mg, 20%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.95(t，J＝7.35Hz，3H)1.74-1.87(m，2H)2.66(s，3H)2.90(s，3H)2.96(t，2H)6.71(d，J＝6.99Hz，1H)6.82(s，1H)6.91(dd，J＝8.27，1.65Hz，1H)7.01(d，J＝7.72Hz，1H)7.27(t，J＝7.91Hz，1H)7.36-7.45(m，2H)7.56(dd，J＝8.82，2.94Hz，1H)7.75(d，J＝8.46Hz，1H)8.52(d，J＝6.99Hz，1H)8.83(d，J＝8.46Hz，1H)；MS(ESI+)m/z?445(M+H)+.

Embodiment 182

2-[4-(1-amino-ethyl)-phenoxy group]-5-chloro-phenyl }-(7-methyl-[1,8] naphthyridine-4-yl)-amine

Embodiment 182a

1-[4-(1-azido--ethyl)-phenoxy group]-4-chloro-2-nitro-benzene

To the product of the embodiment 164b in toluene (20mL) (0.30g adds phenylbenzene phosphide nitrine (036g 6.26mmol) in 1.0mmol), adds 1 then, 8-diazabicyclo [4.3.0] 11-7-alkene (0.19g, 1.3mmol).Mixture was stirred 18 hours in 25 ℃.Pour into reaction in the water and use ethyl acetate extraction.The organic layer that merges is used dried over sodium sulfate with 5% HCl, saturated NaCl (IX) washing, filters and concentrates under vacuum, obtains this title compound.Crude product by silica gel column chromatography purifying purifying, with hexane/ethyl acetate/methyl alcohol (85:15:5) wash-out, is obtained this title compound (300mg, 94%).

Embodiment 182b

1-[4-(4-chloro-2-nitro-phenoxy group)-phenyl]-ethyl }-benzyl carbamate

Adding trimethyl-phosphine in the product (1.3g 4.1mmol) of the embodiment 182a in THF (20mL) (4.7g, 5.4mmol).After 30 minutes, (0.85g 5.0mmol) handles, and stirred 18 hours this mixture with chloroformic acid benzyl ester with reaction mixture in stirring at room.Reaction is poured in the 0.1M potassium phosphate buffer (pH=7.0), and use dichloromethane extraction.With organic layer water, salt water washing, use dried over sodium sulfate, filter and under vacuum, concentrate, obtain this title compound.Resistates is handled with cold ethyl acetate.Collect the gained white depositions, obtain this title compound (1.9g, 74%).

Embodiment 182c

1-[4-(2-amino-4-chloro-phenoxy group)-phenyl]-ethyl }-benzyl carbamate

As described in embodiment 237E, with the product of embodiment 182b (1.0g, 2.34mmol) and SnCl ₂Reaction obtains this title compound (0.75g, 80%).

Embodiment 182d

With the product of embodiment 1d (120mg, 0.67mmol) with the product of embodiment 182b (266mg, 0.67mmol) in ethanol (10mL) in sealed tube in 85 ℃ of reactions 18 hours.Under vacuum, remove ethanol then.Then thick resistates was handled 10 hours with excessive 48% HBr.Under vacuum, remove excessive HBr, and, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid (15mg, 17%) resistates ketone HPLC purifying.

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.38(d，J＝6.62Hz，3H)2.74(s，3H)4.36(q，1H)6.72(d，J＝6.99Hz，1H)7.03(d，J＝8.82Hz，2H)7.13(d，J＝8.82Hz，1H)7.39(d，J＝8.82Hz，2H)7.59(dd，J＝8.82，2.57Hz，1H)7.72-7.78(m，2H)8.24(s，2H)8.53(d，J＝7.35Hz，1H)8.88(d，J＝8.82Hz，1H)；MS(ESI-)m/z?403(M-H)-.

Embodiment 183

Embodiment 183a

N-[4-(2-nitro-4-trifluoromethyl-phenyl sulfenyl)-phenyl]-ethanamide

With 1-chloro-2-nitro-4-trifluoromethyl-benzene (250mg, 1.10mmol), N-(4-sulfydryl-phenyl)-ethanamide (185mg, 1.10mmol) and K ₂CO ₃(268mg 1.94mmol) heated 16 hours in 100 ℃ in DMF.Then reaction mixture is cooled to room temperature, dilute with water, and extract with ethyl acetate (350mg, 88%).

Embodiment 183B

N-[4-(2-amino-4-trifluoromethyl-phenyl sulfenyl)-phenyl]-ethanamide

The product of embodiment 183a (350mg, 0.985mmol) and Pt (IV) O ₂(4mg 0.2mmol) places the 50ml round-bottomed flask, and is dissolved among 1ml EtOH and the 1ml THF.Reaction mixture is placed under the vacuum, and with air bag backfill H ₂Leading to air bag and spending the night, purge and use N with reaction mixture next day ₂Backfill.Filter and under vacuum, concentrate, obtain this title compound (260mg, 80%).

Embodiment 183c

Method according to embodiment 1g, product (50mg with embodiment 1d, 0.280mmol) with the product (91mg of embodiment 183b, 0.280mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (18mg, 16%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.07(s，3H)，2.78(s，3H)，6.43(d，J＝6.99Hz，1H)，7.09-7.15(m，1H)，7.44(d，J＝8.46Hz，2H)，7.68(d，J＝8.46Hz，2H)，7.78(dd，J＝8.64，1.65Hz，1H)，7.84(d，J＝8.82Hz，1H)，7.92(d，J＝1.84Hz，1H)，8.52(d，J＝7.35Hz，1H)，9.00(d，J＝8.46Hz，1H)，10.19(s，1H)，11.12(s，1H)；MS(ESI+)m/z?469(M+H-TFA)+；(ESI-)m/z?467(M-H-TFA)-.

Embodiment 184

[5-methyl-2-(1H-[1,2,4] triazole-3-base sulfenyl)-phenyl 3-(7-propyl group-[1,8] naphthyridine-4-yl)-amine

Embodiment 184A

5-methyl-2-(1H-[1,2,4] triazole-3-base sulfenyl)-phenyl amine

With 1-chloro-4-methyl-2-nitro-benzene (3.00g, 17.5mmol), 1H-[1,2,4] triazole-3-mercaptan (1.94g, 19.2mmol) and K ₂CO ₃(4.22g, 30.6mmol) in DMF in 100 ℃ the heating 16 hours, make this title compound.Then reaction mixture is cooled to room temperature, dilute with water, and use ethyl acetate extraction.Use Na ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound (1.1g, 26%).

Embodiment 184b

5-methyl-2-(1H-[1,2,4] triazole-3-base sulfenyl)-phenyl amine

According to the method for embodiment 1f, with the product SnCl of embodiment 184a ₂Reduction obtains this title compound.

Embodiment 184c

[5-methyl-2-(1H-[1,2,4] triazole-3-base sulfenyl)-phenyl]-(7-propyl group-[1,8] naphthyridine-4-yl)-amine

Method according to embodiment 1g, product (60mg with embodiment 2g, 0.290mmol) with the product (60mg of embodiment 184b, 0.290mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (17mg, 16%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.98(t，J＝7.35Hz，3H)，1.78-1.91(m，2H)，2.38(s，3H)，2.99(t，2H)，6.33(d，J＝6.99Hz，1H)，7.29-7.39(m，2H)，7.46(d，J＝8.09Hz，1H)，7.83(d，J＝8.82Hz，1H)，8.44(d，J＝6.99Hz，1H)，9.00(d，J＝8.46Hz，1H)，11.07(s，1H)，14.16-14.55(m，2H)；MS(ESI+)m/z?377(M+H-TFA)+；(ESI-)m/z?375(M-H-TFA)-.

Embodiment 185

[2-(2-amino-phenyl sulfenyl)-5-methyl-phenyl]-(7-propyl group-[1,8] naphthyridine-4-yl)-amine

Embodiment 185A

2-(4-methyl-2-nitro-phenyl sulfenyl)-phenyl amine

With 1-chloro-4-methyl-2-nitro-benzene (3.00g, 17.5mmol), 2-amino-benzenethiol (2.41g, 19.23mmol) and K ₂CO ₃(4.22g, 30.6mmol) in DMF in 100 ℃ the heating 16 hours, make this title compound.Then reaction mixture is cooled to room temperature, dilute with water, and with ethyl acetate extraction (0.990g, 21%).

Embodiment 185b

N-[2-(4-methyl-2-nitro-phenyl sulfenyl)-phenyl]-ethanamide

(0.9903.80mmol) is dissolved in CH the product of embodiment 185a ₂Cl ₂In, and the adding Acetyl Chloride 98Min. (0.328g, 4.183mmol).In stirring at room 1 hour, collected (910mg, 79%) with this title compound by filtering this moment with reaction mixture.

Embodiment 185c

N-[2-(2-amino-4-methyl-phenyl sulfenyl)-phenyl]-ethanamide

Product SnCl with embodiment 185b ₂Reduction, the method according to embodiment 1f obtains this title compound.

Embodiment 185d

N-{2-[4-methyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Method according to embodiment 1g, product (150mg with embodiment 2g, 0.726mmol) with the product (198mg of embodiment 185c, 0.726mmol) reacted 42 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (150mg, 46%).

Embodiment 185e

Embodiment 185d is dissolved in 50% HCl:H ₂Among the O, and be heated to 100 ℃ 1 hour.Then reaction mixture is cooled to room temperature,, uses CH with 2N NaOH alkalization ₂Cl ₂Na is used in extraction ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound.By the HPLC purifying, use the TFA wash-out, the acquisition product is trifluoroacetate (87mg, 64%).

¹HNMR(300MHz，DMSO-d ₆)δ?ppm:0.98(t，J＝7.35Hz，3H)，1.79-1.92(m，J＝7.43，7.43，7.43，7.43，7.43Hz，2H)，2.32(s，3H)，3.00(t，J＝7.54Hz，2H)，6.34(d，J＝6.99Hz，1H)，6.49(t，J＝7.54Hz，1H)，6.68(d，J＝6.99Hz，1H)，6.92(d，J＝8.09Hz，1H)，7.05-7.13(m，1H)，7.15-7.20(m，1H)，7.24(d，J＝8.46Hz，1H)，7.28(s，1H)，7.84(d，J＝8.82Hz，1H)，8.42(d，J＝6.99Hz，1H)，9.06(d，J＝8.82Hz，1H)；MS(ESI+)m/z?401(M+H-TFA)+；(ESI-)m/z?399(M-H-TFA)-.

Embodiment 186

N-{3-[3-methyl-5-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl 3-phenyl }-ethanamide

Embodiment 186A

3-amino-benzenethiol copper

According to the method for describing among the embodiment 187a, (2.00g 15.98mmol) handles, and obtains this title compound (3.67g, 100%) with 3-amino-benzenethiol.

Embodiment 186b

3-(3-methyl-5-nitro-phenyl sulfenyl)-phenyl amine

According to the method for embodiment 187d, (400mg, 1.85mmol) (348mg 1.85mmol) prepares this title compound, obtains this title compound (300mg, 62%) with embodiment 186a with embodiment 187c.

Embodiment 186c

N-[3-(3-methyl-5-nitro-phenyl sulfenyl)-phenyl]-ethanamide

This title compound is the method according to embodiment 185b, use embodiment 186b (115mg, 0.442mmol) and Acetyl Chloride 98Min. (52mg, 0.663mmol) preparation, acquisition (130mg, 97%).

Embodiment 186d

N-[3-(3-amino-5-methyl-phenyl sulfenyl)-phenyl]-ethanamide

This title compound is the method according to embodiment 183b, use embodiment 186c product (130mg, 0.430mrnol) and PtO ₂(2mg 0.009mmol) prepares, and obtains (73mg, 62%).

Embodiment 186f

N-{3-[3-methyl-5-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Method according to embodiment 1g, product (70mg with embodiment 2g, 0.338mmol) with the product (73mg of embodiment 186d, 0.338mmol) reacted 16 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (14mg, 10%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.96(t，J＝7.35Hz，3H)，1.75-1.89(m，2H)，2.03(s，3H)，2.36(s，3H)，2.98(t，J＝7.54Hz，2H)，6.85(d，J＝7.35Hz，1H)，7.06-7.14(m，2H)，7.22(s，2H)，7.35(t，J＝7.91Hz，1H)，7.47(d，1H)，7.76-7.82(m，2H)，8.45(d，J＝7.35Hz，1H)，8.98(d，J＝8.82Hz，1H)，10.07(s，1H)，10.97(s，1H)；MS(ESI+)m/z?443(M+H-TFA)+；(ESI-)m/z?441(M-H-TFA)-.

Embodiment 187

N-{4-[3-methyl-5-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 187a

N-(4-sulfydryl-phenyl)-ethanamide copper

N-(4-sulfydryl-phenyl)-ethanamide (1.00g, 5.98mmol) and Cu ₂(385mg 27.0mmol) is dissolved among the EtOH O, and is heated to backflow 24 hours.Be cooled to room temperature with reaction mixture this moment, and this title compound is collected (1.374g, 100%) by filtering.

Embodiment 187b

2-bromo-4-methyl-6-nitro-phenyl amine

This title compound is prepared as follows: (20.0g 131mmol) is dissolved in 200mL HOAc 4-methyl-2-nitro-phenyl amine.Then reaction mixture is heated to 100 ℃ till mixture evenly.This moment reaction mixture is cooled to room temperature, and with 10 minutes the dropping Br ₂(25.21g, 157mmol).Orange solids forms, and after adding is finished with the reaction mixture dilute with water, and collect this title compound (29g, 96%) by filtering.

Embodiment 187c

1-bromo-3-methyl-5-nitro-benzene

This title compound is prepared as follows: (10.0g 43.2mmol) is dissolved in 60mL MeOH and 8mL H the product of embodiment 187b ₂SO ₄In (dense).With mixture heating up to 85 ℃, add NaNO this moment in batches ₂(7.466g, 108.2mmol), so that reaction mixture can not bubble over.After adding is finished, again reaction mixture was stirred 30 minutes in 85 ℃.Then reaction mixture is cooled to room temperature, dilute with water, and use CH ₂Cl ₂Extraction.Use Na ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound (8.00g, 85%).

Embodiment 187d

N-[4-(3-methyl-5-nitro-phenyl sulfenyl)-phenyl]-ethanamide

This title compound is prepared as follows: with the product of embodiment 187c (400mg, 1.85mmol), embodiment 187a (425mg, 1.852mmol), 10mL quinoline and 2mL pyridine be heated to 170 ℃ 22 hours.Be cooled to room temperature with reaction mixture this moment, with 30% HCl stopped reaction, uses extracted with diethyl ether, uses Na ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound.By the silica gel column chromatography purifying, with solution (280mg, the 50%) wash-out of 30% ethyl acetate in hexane.

Embodiment 187E

N-[4-(3-amino-5-methyl-phenyl sulfenyl)-phenyl]-ethanamide

Use the method for embodiment 183b, with the product of embodiment 187d (280mg, 0.926mmol) and PtO ₂(2mg 0.009mmol), obtains this title compound (240mg, 95%).

Embodiment 187f

Method according to embodiment 1g, product (70mg with embodiment 2g, 0.338mmol) with the product (198mg of embodiment 187e, 0.726mmol) reacted 16 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (5mg, 4%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.96(t，J＝7.35Hz，3H)，1.76-1.89(m，2H)，2.05(s，3H)，2.33(s，3H)，2.97(t，J＝7.54Hz，2H)，6.80(d，J＝7.35Hz，1H)，6.95(s，1H)，7.10(d，J＝15.44Hz，2H)，7.46(d，J＝8.82Hz，2H)，7.67(d，J＝8.82Hz，2H)，7.78(d，J＝8.82Hz，1H)，8.46(d，J＝6.99Hz，1H)，8.96(d，J＝8.46Hz，1H)，10.14(s，1H)，10.90(s，1H)；MS(ESI+)m/z?443(M+H-TFA)+；(ESI-)m/z?441(M-H-TFA)-.

Embodiment 188

[3-(4-amino-phenyl sulfenyl)-5-methyl-phenyl]-(7-propyl group-[1,8] naphthyridine-4-yl)-amine

(60mg 0.136mmol) handles according to the condition of embodiment 185, obtains this title compound (10mg, 18%) with the product of embodiment 187.

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.96(t，J＝7.35Hz，3H)，1.76-1.89(m，2H)，2.30(s，3H)，2.97(t，J＝7.54Hz，2H)，6.65(d，J＝8.46Hz，2H)，6.74-6.83(m，2H)，6.94(s，1H)，7.03(s，1H)，7.23(d，J＝8.46Hz，2H)，7.78(d，J＝8.82HH)1H)，8.45(d，J＝6.99Hz，1H)，8.96(d，J＝8.46Hz，1H)，10.90(s，1H)；MS(ESI+)m/z?401(M+H-TFA)+.

Embodiment 189

(3-benzyloxy-phenyl)-(7-propyl group-[1,8] naphthyridine-4-yl)-amine

Embodiment 189a

1-benzyloxy-3-nitro-benzene

With 3-nitro-phenol (1.00g, 7.189mmol) with bromotoluene (1.352g, 7.91mmol) and K ₂CO ₃(1.242g 8.986mmol) handles at DMF.With reaction mixture be heated to 100 ℃ 1 hour, be cooled to room temperature with reaction mixture this moment, dilute with water, and use ethyl acetate extraction.Use Na ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound (1.6g, 97%).

Embodiment 189b

3-benzyloxy-phenyl amine

According to the method for embodiment 183b, with the product of embodiment 189a (1.600g, 6.98mmol) and PtO ₂(15mg 0.070mmol), obtains this title compound (1.00g, 72%).

Embodiment 189c

(3-benzyloxy-phenyl)-(7-propyl group-[1,8] naphthyridine-4-yl)-amine

Method according to embodiment 1g, product (30mg with embodiment 2g, 0.145mmol) with the product (29mg of embodiment 189b, 0.145mmol) reacted 16 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (27mg, 50%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.97(t，J＝7.35Hz，3H)，1.77-1.90(m，J＝7.35Hz，2H)，2.99(t，J＝7.35Hz，2H)，5.17(s，2H)，6.80(d，J＝6.99Hz，1H)，7.06(dd，J＝8.46，1.10Hz，1H)，7.09-7.15(m，J＝3.68Hz，2H)，7.37-7.51(m，5H)，7.82(d，J＝8.82Hz，1H)，8.46(d，J＝7.35Hz，1H)，9.03(d，J＝8.82Hz，1H)，11.00(s，1H)；MS(ESI+)m/z?370(M+H-TFA)+；(ESI-)m/z?368(M-H-TFA)-.

Embodiment 190

[3-(4-bromo-benzyloxy)-phenyl]-(7-methyl-[1,8] naphthyridine-4-yl)-amine

Embodiment 190A

1-(4-bromo-benzyloxy)-3-nitro-benzene

According to the method for 189a, (1.00g, 7.189mmol) (1.976g 7.90mmol) handles, and obtains this title compound (2.1g, 97%) with 4-bromo-bromotoluene with 3-nitro-phenol.

Embodiment 190B

3-(4-bromo-benzyloxy)-phenyl amine

According to embodiment 1f method, with the product SnCl of embodiment 190a ₂Reduction makes this title compound.

Embodiment 190c

[3-(4-bromo-benzyloxy)-phenyl]-(7-methyl-[1,8] naphthyridine-4-yl)-amine

Method according to embodiment 1g, product (50mg with embodiment 1d, 0.316mmol) with the product (88mg of embodiment 190b, 0.316mmol) reacted 16 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (80mg, 60%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.75(s，3H)，5.16(s，2H)，6.81(d，J＝7.35Hz，1H)，7.04-7.14(m，3H)，7.43(d，J＝8.46Hz，2H)，7.51(t，J＝8.09Hz，1H)，7.62(d，J＝8.46Hz，2H)，7.79(d，J＝8.82Hz，1H)，8.47(d，J＝6.99Hz，1H)，9.00(d，J＝8.46Hz，1H)，10.98(s，1H)；MS(ESI+)m/z?422(M+H-TFA)+；(ESI-)m/z?419(M-H-TFA)-.

Embodiment 191

N-{4-[3-fluoro-5-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenoxy group]-phenyl }-ethanamide

Embodiment 191a

N-[4-(3-fluoro-5-nitro-phenoxy group)-phenyl]-ethanamide

To N-(4-hydroxy phenyl) ethanamide (1.00g, 6.5mmol) in the solution in DMSO (12ml) in room temperature drip 1M t-BuOK/THF solution (7.13ml, 7.13mmol), and with mixture under nitrogen gas stream in stirring at room 30 minutes.Add 1 in room temperature, 3-two fluoro-5-oil of mirbane (0.89ml, 7.8mmol), then under nitrogen gas stream with mixture in stirring at room 2 hours, stirred 2 hours at 50 ℃ then.Reaction mixture is cooled to room temperature, uses H ₂The O dilution extracts with EtOAc then.With extract H ₂MgSO is used in O and salt water washing ₄Dry filter also concentrates under vacuum, obtains this title compound, is light brown solid, with it by using i-Pr ₂Purifying is carried out in the O washing, obtains required product, is light brown crystal (1.73g, 92%).

Embodiment 191b

N-[4-(3-amino-5-fluoro-phenoxy group)-phenyl]-ethanamide

According to the method for embodiment 237E, with product Fe and the NH of embodiment 191a ₄The Cl reduction obtains this title compound.

Embodiment 191c

According to the method for embodiment 1g, (150mg, 0.84mmol) (190mg, 0.84mmol) reaction is 6 hours, obtains this rough title compound, and it is passed through silica gel column chromatography purifying purifying, uses 50:1 CH with the product of embodiment 191b with the product of embodiment 3f ₂Cl ₂/ MeOH wash-out obtains this title compound (210mg, 68%).

¹H?NMR(300MHz，DMSO-d ₆)δppm:2.40(s，3H)，2.68(s，3H)，6.62(d，J＝6.9Hz，1H)，6.98(t，J＝7.3Hz，1H)，7.19(t，J＝7.3Hz，2H)，7.36(s，1H)，7.38(d，J＝8.3Hz，1H)，7.52(d，J＝7.3Hz，2H)，7.67(d，J＝8.8Hz，1H)，7.78(d，J＝8.3Hz，1H)，8.40(d，J＝6.9Hz，1H)，8.94(d，J＝8.8Hz，1H)；MS(ESI+)m/z?369(M+H)+，(ESI-)m/z?367(M-H)-.

Embodiment 192

4-[3-fluoro-5-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenoxy group]-N, N-dimethyl-benzamide

Embodiment 192a

4-(3-fluoro-5-nitro-phenoxy group)-methyl benzoate

To the 4-methyl hydroxybenzoate (3.00g, 19.5mmol) in the solution in DMSO (30ml) in room temperature add t-BuOK (2.56g, 21.5mmol), and with mixture under nitrogen gas stream in stirring at room 30 minutes.Drip 1 in room temperature, 3-two fluoro-5-oil of mirbane (2.34ml.20.5mmol).Mixture was heated 2 hours in 90 ℃ under nitrogen gas stream.Reaction mixture is cooled to room temperature, uses H ₂The O dilution extracts with EtOAc then.With extract H ₂MgSO is used in O and salt water washing ₄Drying is filtered and is concentrated under vacuum, obtains this title compound, is brown oil, and it is used i-Pr ₂The O crystallization.Crystal is filtered collection, obtain required product, be light brown crystal (1.92g, 40%).Filtrate by silica gel column chromatography purifying purifying, with 4:1 EtOAc/ hexane wash-out, is obtained other product (1.46g, 30%), be light brown crystal.

Embodiment 192b

4-(3-fluoro-5-nitro-phenoxy group)-phenylformic acid

With the product of embodiment 192a (3.30g, 11.3mmol) and 2N NaOH (11.3ml 22.7mmol) refluxed 30 minutes among MeOH (33ml), evaporated then.Resistates is dissolved in H ₂Among the O, and under agitation be acidified to pH 2 with 10% HCl.Throw out is collected by filtering, used H ₂O washing, and dried overnight in a vacuum obtain this title compound, are pale yellow crystals (3.03g, 96%).

Embodiment 192c

4-(3-fluoro-5-nitro-phenoxy group)-N, N-dimethyl-benzamide

With the product of embodiment 192b (1.00g, 3.6mmol) and SOCl ₂(3.97ml 54.1mmol) refluxed 1 hour.Excessive SOCl is removed in decompression ₂, obtain corresponding chloride of acid, be light brown oily matter.To 2N Me ₂NH/THF solution (18.0ml, 36.1mmol) interior in 5 ℃ of chloride of acid solution in THF (10ml) that obtain with dropping in 15 minutes.To be mixed in 5 ℃ and stir 1 hour, then evaporation.With resistates H ₂O handles, and filters and collect the gained solid.With solid H ₂The O washing, and dry in a vacuum, obtain this title compound, be pale yellow crystals (1.09g, 99%).

Embodiment 192d

4-(3-amino-5-fluoro-phenoxy group)-benzoic acid methyl ester

According to the method for embodiment 237E, with product Fe and the NH of embodiment 192c ₄The Cl reduction obtains this title compound.

Embodiment 192e

According to the method for embodiment 1g, (80mg is 0.45mmol) with the product (130mg of embodiment 192d with the product of embodiment 1d, 0.45mmol) reaction 20 hours, obtains this rough title compound, it is carried out purifying by developing with EtOAc, obtain product (150mg, 79%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.77(s，3H)，2.98(br-s，6H)，6.97-7.08(m，2H)，7.12(d，J＝7.0Hz，1H)，7.18-7.25(m，1H)，7.23(d，J＝8.8Hz，2H)，7.53(d，J＝8.8Hz，2H)，7.79(d，J＝8.5Hz，1H)，8.59(d，J＝7.0Hz，1H)，9.00(d，J＝8.5Hz，1H)；MS(ESI+)m/z?417(M+H)+，(ESI-)m/z415(M-H)-.

Embodiment 193

4-[3-chloro-5-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenoxy group]-phenol

Embodiment 193a

1-chloro-3,5-dinitrobenzene-benzene

To t-BuONO (5.41ml, 41.0mmol) and CuCl ₂(4.41g is 32.8mmol) at CH ₃Slowly add 3 in 58-60 ℃ in the mixture among the CN (100ml), and the 5-dinitraniline (5.00g, 27.3mmol).After the adding, mixture in 65 ℃ of heating 30 minutes, is evaporated then.Resistates is diluted with EtOAc 200ml, with 20% HCl, 10% NaHCO ₃With the salt water washing.With organic layer MgSO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound, and it by silica gel column chromatography purifying purifying, with 10:1 EtOAc/ hexane wash-out, is obtained this title compound, is pale yellow crystals (4.60g, 83%).

Embodiment 193b

4-(3-chloro-5-nitro-phenoxy group)-phenol

With the product of embodiment 193a (1.00g, 5.0mmol), Resorcinol (0.50g, 4.5mmol) and K ₂CO ₃(0.78g 5.6mmol) heated 3.5 hours in 110 ℃ in DMF (10ml).Reaction mixture is cooled to room temperature, uses H ₂The O washing extracts with EtOAc then.With extract H ₂MgSO is used in O and salt water washing ₄Drying is filtered and is concentrated under vacuum, obtains this title compound.With resistates i-Pr ₂O handles, and crosses the elimination insoluble substance.With the filtrate evaporation, by silica gel column chromatography purifying purifying,, obtain this title product with 5:2 EtOAc/ hexane wash-out, be light yellow oil (0.51g, 43%).

Embodiment 193c

4-(3-amino-5-chloro-phenoxy group)-phenol

Embodiment 193d

Method according to embodiment 1g, product (100mg with embodiment 2g, 0.48mmol) with the product (140mg of embodiment 134c, 0.48mmol) reacted 17 hours, obtain this rough title compound, it by carrying out purifying with the EtOAc development, is obtained this title compound (140mg, 71%).

¹H NMR (300MHz, DMSO-d ₆) δ ppm:0.98 (t, J=7.4Hz, 3H), 1.86 (sextet, J=7.4Hz, 2H), 3.00 (t, J=7.4Hz, 2H), 6.87 (d, J=8.8Hz, 2H), 6.95 (d, J=1.8Hz, 1H), 6.99-7.07 (m, 2H), 7.04 (d, J=8.8Hz, 2H), 7.28 (d, J=1.8Hz, 1H), 7.81 (d, J=8.8Hz, 1H), 8.57 (d, J=7.0Hz, 1H), 9.02 (d, J=8.8Hz, 1H); MS (ESI+) m/z 406,408 (M+H)+, (ESI-) m/z 404,406 (M-H)-.

Embodiment 194

N-{4-[3-chloro-5-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenoxy group]-phenyl }-ethanamide

Embodiment 194a

N-[4-(3-chloro-5-nitro-phenoxy group)-phenyl]-ethanamide

With the product of embodiment 193a (1.06g, 5.2mmol), N-(4-hydroxy phenyl) ethanamide

(0.70g, 4.5mmol) and K ₂CO ₃(0.79g 5.7mmol) heated 6 hours in 110 ℃ in DMF (14ml).Reaction mixture is cooled to room temperature, uses H ₂The O dilution extracts with EtOAc then.With extract H ₂MgSO is used in O and salt water washing ₄Dry filter also concentrates under vacuum, obtains this rough title compound, is pale yellow crystals, with it by using i-Pr ₂Purifying is carried out in the O washing, obtains required product, is light brown crystal (1.28g, 92%).

Embodiment 194b

N-[4-(3-amino-5-chloro-phenoxy group)-phenyl]-ethanamide

Embodiment 194c

According to the method for embodiment 1g, (100mg is 0.48mmol) with the product (130mg of embodiment 194bc with the product of embodiment 2g, 0.48mmol) reaction 22 hours, obtains this rough title compound, it is carried out purifying by developing with EtOAc, obtain product (110mg, 51%).

¹H NMR (300MHz, DMSO-d ₆) δ ppm:1.00 (t, J=7.0Hz, 3H), 1.87 (sextet, J=7.0Hz, 2H), 2.08 (s, 3H), 3.01 (t, J=7.0Hz, 2H), 7.01 (s, 1H), 7.07 (d, J=7.0Hz, 1H), 7.07 (s, 1H), 7.14 (d, J=7.2Hz, 2H), 7.30 (s, 1H), 7.72 (d, J=7.2Hz, 2H), 7.76 (d, J=8.7Hz, 1H), 8.55 (d, J=7.0Hz, 1H), 9.03 (d, J=8.7Hz, 1H); MS (ESI+) m/z447,449 (M+H)+, (ESI-) m/z445,447 (M-H)-.

Embodiment 195

4-[3-chloro-5-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenoxymethyl]-N-methyl-benzamide

Embodiment 195a

4-(3-chloro-5-nitro-phenoxymethyl)-methyl benzoate

With the product of embodiment 13a (2.50g, 12.3mmol), 4-hydroxymethyl methyl benzoate (2.30g, 13.6mmol) and K ₂CO ₃(2.14g 15.4mmol) heated 16 hours in 110 ℃ at DMF (50mL).Reaction mixture is cooled to room temperature, and uses H ₂The O dilution.Filter the collecting precipitation thing, and use H ₂O and/-Pr ₂The O wash-out obtains this title compound, is light brown crystal (2.54g).

Embodiment 195b

4-(3-chloro-5-nitro-phenoxymethyl)-phenylformic acid

With the product of embodiment 195a (2.50g, 13.5mmol) and 2N NaOH (7.77ml 15.5mmol) refluxed 1 hour among MeOH (25mL), evaporated then.Resistates is dissolved in H ₂Among the O, under agitation also be acidified to pH 2 with 10% HCl.Filter the collecting precipitation thing, use H ₂O washing, dried overnight in a vacuum, obtaining this title compound is light brown crystal (2.30g, 62%).

Embodiment 195c

4-(3-chloro-5-nitro-phenoxymethyl)-N-methyl-benzamide

With the product of embodiment 195b (0.70g, 2.3mmol) and SOCl ₂(2.50ml 34.1mmol) refluxed 1 hour.Excessive SOCl is removed in decompression ₂, obtain corresponding chloride of acid, be light brown solid.To 2N MeNH ₂/ THF solution (11.4mL, 22.8mmol) in the solution of 5 ℃ of chloride of acid that obtain above the dropping in THF (7mL).Mixture was stirred evaporation then 1 hour in 5 ℃.With resistates H ₂O handles, and is acidified to pH 2 with 10% HCl, filters then and collects the gained solid.With solid H ₂O and i-Pr ₂The O washing, dry in a vacuum, obtain this title compound, be light brown crystal (0.69g, 95%).

Embodiment 195d

4-(3-amino-5-chloro-phenoxymethyl)-N-methyl-benzamide

According to the method for embodiment 237E, with product Fe and the NH of embodiment 195c ₄The Cl reduction obtains this title compound.

Embodiment 195e

According to the method for embodiment 1g, (100mg is 0.56mmol) in the product (160mg of embodiment 195d with the product of embodiment 1d, 0.56mmol) reaction 15 hours, obtains this rough title compound, it is carried out purifying by developing with EtOAc, obtain product (240mg, 99%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.75(s，3H)，2.79(d，J＝4.4Hz，3H)，5.26(s，2H)，6.90(d，J＝7.0Hz，1H)，7.14(br-t，J＝1.9Hz，1H)，7.18(br-t，J＝1.9Hz，1H)，7.20(br-t，J＝1.9Hz，1H)，7.53(d，J＝8.5Hz，2H)，7.77(d，J＝8.8Hz，1H)，7.87(d，J＝8.5Hz，2H)，8.47(br-s，1H)，8.50(d，J＝7.0Hz，1H)，9.08(d，J＝8.8Hz，1H)，11.08(br-s，1H)；MS(ESI+)m/z?433，435(M+H)+，(ESI-)m/z?431，433(M-H)-.

Embodiment 196

[3-(4-bromo-benzyloxy)-5-chloro-phenyl]-(7-propyl group-[1,8] naphthyridine-4-yl)-amine

Embodiment 196a

1-(4-bromo-benzyloxy)-3-chloro-5-nitro-benzene

With the product of embodiment 193a (0.75g, 3.7mmol), 4-bromobenzyl alcohol (0.77g, 4.1mmol) and K ₂CO ₃(0.64g 4.6mmol) heated 23 hours in 110 ℃ in DMF (15ml).Reaction mixture is cooled to room temperature, uses H ₂The O dilution is acidified to pH2 with 10%HCl, extracts with EtOAc then.With extract H ₂MgSO is used in O and salt water washing ₄Drying is filtered and is concentrated under vacuum, obtains this title compound.With the mixture process of resistates with 50mL normal hexane and EtOAc (3:1) and silica gel.After 30 minutes, mixture is passed through diatomite filtration in stirring at room.With the filtrate evaporation, and with gained solid i-Pr ₂The O washing obtains this title compound, is pale yellow crystals (0.70g).

Embodiment 196b

3-(4-bromo-benzyloxy)-5-chloro-phenyl amine

According to the method for embodiment 237E, with product Fe and the NH of embodiment 196a ₄The Cl reduction obtains this title compound.

Embodiment 196c

[3-(4-bromo-benzyloxy)-S-chloro-phenyl]-(7-propyl group-[1,8] naphthyridine-4-yl)-amine

Method according to embodiment 1g, product (100mg with embodiment 2g, 0.39mmol) with the product (120mg of embodiment 196b, 0.39mmol) reacted 22 hours, obtain this rough title compound, it by carrying out purifying with the EtOAc development, is obtained this title compound (1990mg, 100%).

¹H NMR (300MHz, DMSO-d ₆) δ ppm:0.96 (t, J=7.4Hz, 3H), 1.83 (sextet, J=7.4Hz, 2H), 2.97 (t, J=7.4Hz, 2H), 5.18 (s, 2H), 6.91 (d, J=6.7Hz, 1H), 7.05-7.17 (m, 3H), 7.43 (d, J=8.4Hz, 2H), 7.63 (d, J=8.4Hz, 2H), 7.73 (d, J=8.5Hz, 1H), 8.51 (d, J=6.7Hz, 1H), 9.05 (d, J=8.5Hz, 1H); MS (ESI+) m/z 482,484,486 (M+H)+, (ESI-) m/z 480,482,484 (M-H)-.

Embodiment 197

N-{4-[3-chloro-5-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenoxymethyl]-phenyl }-ethanamide

Embodiment 197a

Acetate 4-acetylamino-benzyl ester

To 4-hydroxymethyl aniline (2.00g, 15.9mmol) in the solution in pyridine (20ml) in room temperature with dripping Ac in 5 minutes ₂O (3.76mL, 39.8mmol), and with mixture stirring 1 hour, evaporation then.Resistates H ₂O (20mL) dilution, and under agitation be acidified to pH 3 with dense HCl.The gained crystal is collected by filtering, with a small amount of cold H ₂O washing, and, obtain this title compound in room temperature dried overnight in a vacuum, be light brown crystal (2.90g, 88%).

Embodiment 197b

N-(4-hydroxymethyl-phenyl)-ethanamide

To the product of the embodiment 197a in THF (40mL) (4.00g, 19.3mmol) in room temperature with 10 minutes dropping LiOH aqueous solution (0.91g, 21.2mmol).With mixture in stirring at room 27 hours, evaporation then.With aqueous residue H ₂The O dilution is adjusted to pH4 with 10% HCl, extracts with EtOAc then.With extract salt water washing, use MgSO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound, and purifying is carried out in its logical supercooled EtOAc washing, obtains this title compound, is clear crystal (2.92g, 92%).

Embodiment 197c

N-[4-(3-chloro-5-nitro-phenoxymethyl)-phenyl]-ethanamide

With the product of embodiment 193a (1.00g, 4.9mmol), the product of embodiment 197b (0.90g, 5.4mmol) and K ₂CO ₃(0.86g 6.2mmol) heated 10 hours in 100 ℃ in DMF (20mL).Reaction mixture is cooled to room temperature, uses H ₂The O dilution.Filter and collect the gained solid, use H ₂The O washing, dry in a vacuum, obtain the brown crystal, it by silica gel column chromatography purifying purifying, with 5:2EtOAc/ hexane wash-out, is obtained this title compound, be black orange crystal (0.47g, 30%).

Embodiment 197d

N-[4-(3-amino-5-chloro-phenoxymethyl)-phenyl]-ethanamide

According to the method for embodiment 237E, with product Fe and the NH of embodiment 196c ₄The Cl reduction obtains this title compound.

Embodiment 197e

N-{4-[3-chloro-5-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenoxymethyl]-phenyl }-acetyl

Amine

According to the method for embodiment 1g, with product (70mg, 0.39mtnol) product (110mg of usefulness embodiment 197d of embodiment 1d, 0.39mmol) reacted 23 hours, obtain this rough title compound, it is developed with EtOAc, obtain this title compound (140mg, 82%).

¹H?NMR(300MHz，DMSO-d6)δppm:2.05(s，3H)，2.75(s，3H)，5.11(s，2H)，6.90(d，J＝7.0Hz，1H)，7.12(br-s，1H)，7.17(br-s，2H)，7.38(d，J＝8.5Hz，2H)，7.61(d，J＝8.5Hz，2H)，7.78(d，J＝8.9Hz，1H)，8.50(d，J＝7.0Hz，1H)，9.12(d，J＝8.9Hz，1H)，10.06(s，1H)，11.17(br-s，1H)；MS(ESI+)m/z433，435(M+H)+，(ESI-)m/z431，433(M-H)-.

Embodiment 198

(5-methyl-2-phenoxy group-phenyl)-(7-propyl group-[1,8] naphthyridine-4-yl)-amine

Method according to embodiment 1g, product (82mg with embodiment 2g, 0.40mmol) and embodiment 42b (88mg, 0.40mmol) product reaction 24 hours, obtain this rough title compound, it with 3:1 ether/THF development, is obtained this title compound, be hydrochloride (159mg, 93%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.95(t，J＝7.73Hz，3H)1.82(q，J＝7.72Hz，2H)2.97(dd，J＝7.73Hz，2H)6.68(d，J＝6.99Hz，1H)6.99(d，J＝7.72Hz，2H)7.12(dd，J＝8.82Hz，2H)7.30(dd，J＝8.09Hz，2H)7.66(dd，J＝8.82Hz，J＝2.58Hz，1H)7.71(d，J＝2.2Hz，1H)7.77(d，J＝8.82Hz，1H)8.52(d，J＝6.98Hz，1H)9.07(d，J＝8.82Hz，1H)11.26(br?s，1H)14.45(brs，1H)；MS(ESI+)m/z?390(M-Cl)+；(ESI-)m/z?388(M-HCl)-.

Embodiment 199

2,2-dimethyl-N-{3-[4-methyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-propionic acid amide

Embodiment 199a

3-(4-methyl-2-nitro-phenyl sulfenyl)-phenyl amine

This title compound is prepared as follows: with 3-amino-benzenethiol (5.034g, 40.21mmol), 1-chloro-4-methyl-2-nitro-benzene (4.600g, 26.81mmol) and K ₂CO ₃(6.484g 46.92mmol) is dissolved among the DMF, and be heated to 100 ℃ 16 hours.At this moment, reaction mixture is cooled to room temperature, and dilute with water, use ethyl acetate extraction, use Na ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound (2.3g, 32%).

Embodiment 199b

N-[3-(4-methyl-2-nitro-phenyl sulfenyl)-phenyl]-ethanamide

This title compound is prepared as follows: (8.20g, 31.50mmol) (2.72g 34.65mmol) is dissolved in CH with ethanoyl chlorine 3-(4-methyl-2-nitro-phenyl sulfenyl)-phenyl amine ₂Cl ₂In.It in stirring at room 2 hours, is filtered and collect this title compound (8.78g, 92%) this moment.

Embodiment 199c

N-[3-(2-amino-4-methyl-phenyl sulfenyl)-phenyl]-ethanamide

According to 14 pairs of methods of embodiment, with the product SnCl of embodiment 199b ₂Reduction obtains this title compound.

Embodiment 199d

N-{3-[4-methyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

This title compound is prepared as follows: with the product of embodiment 2g (750mg, 3.63mmol) and the product of embodiment 199c (988mg 3.63mmol) mixes in 10mL EtOH, and be heated to 80 ℃ 40 hours.After being cooled to room temperature, under vacuum, removing and desolvate, obtain this title compound (1.2g, 74%).

Embodiment 199e

[2-(3-amino-phenyl sulfenyl)-5-methyl-phenyl]-(7-propyl group-[1,8] naphthyridine-4-yl)-amine

This title compound is prepared as follows: with product (1.20g, 2.71mmol) the usefulness 10mL 50% HCI aqueous solution processing of embodiment 199d.With this reaction mixture be heated to 100 ℃ 1 hour.Be cooled to room temperature with reaction mixture this moment, and alkalize with 2N NaOH.Use CH then ₂Cl ₂Na is used in extraction ₂The SO drying is filtered and is concentrated under vacuum, obtains this title compound (720mg, 66%).

Embodiment 199f

This title compound is prepared as follows: in the method for embodiment 74, with 2, (26mg 0.16mmol) as acid, obtains this title compound (3mg, 5%) to 2-dimethyl-propionic acid.

¹H?NMR(500MHz，DMSO-D ₂O)δ?ppm:0.97(t，J＝7.48Hz，3H)，1.16(s，9H)，1.79-1.86(m，2H)，2.39(s，3H)，2.94-3.00(m，2H)，6.31(d，J＝7.02Hz，1H)，6.87(d，J＝8.24Hz，1H)，7.07(t，J＝7.93Hz，1H)，7.33-7.38(m，3H)，7.43-7.49(m，1H)，7.57-7.61(m，1H)，7.72(d，J＝8.85Hz，1H)，8.28(d，J＝7.02Hz，1H)，8.86(d，J＝8.85Hz，1H)，9.10(s，1H)；MS(ESI+)m/z?485(M+TFA+H)+；(ESI-)m/z?483(M+TFA-H).

Embodiment 200

2,5-dimethyl-furans-3-formic acid 3-[4-methyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-acid amides

This title compound is prepared as follows: in the method for embodiment 74, with 2, (26mg 0.16mmol) as acid, obtains this title compound (3mg, 5%) to 5-dimethyl-furans-3-formic acid.

¹HNMR(500MHz，DMSO-D ₂O)δ?ppm:0.93(t，J＝7.32Hz，3H)，1.70-1.77(m，2H)，2.26(s，3H)，2.39(s，3H)，2.47(s，3H)，2.82-2.86(m，2H)，6.27(d，J＝7.02Hz，1H)，6.53(s，1H)，6.86(d，J＝8.24Hz，1H)，7.08(t，J＝7.93Hz，1H)，7.35(s，1H)，7.38(dt，J＝7.63，2.14Hz，2H)，7.54(d，J＝7.93Hz，1H)，7.61(t，J＝2.14Hz，1H)，7.66(d，J＝8.54Hz，1H)，8.26(d，J＝7.02Hz，1H)，8.82(d，J＝8.85Hz，1H)；MS(ESI+)m/z?523(M+TFA+H)+；(ESI-)m/z?521(M+TFA-H)-.

Embodiment 201

Thiophene-2-carboxylic acid 3-[4-methyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-acid amides

This title compound is prepared as follows: in the method for embodiment 74, (26mg 0.16mmol) as acid, obtains this title compound (3mg, 5%) with thiophene-2-carboxylic acid.

¹HNMR(500MHz，DMSO-D ₂O)δ?ppm:0.90(t，J＝7.32Hz，3H)，1.67-1.75(m，2H)，2.40(s，3H)，2.76-2.82(m，2H)，6.27(d，J＝7.32Hz，1H)，6.88(d，J＝7.93Hz，1H)，7.10(t，J＝7.93Hz，1H)，7.22-7.26(m，1H)，7.36(s，1H)，7.38-7.42(m，2H)，7.57·7.60(m，2H)，7.65(d，J＝8.54Hz，1H)，7.86(dd，J＝5.03，1.07Hz，1H)，7.90(dd，J＝3.81，1.07Hz，1H)，8.25(d，J＝7.02Hz，1H)，8.81(d，J＝8.54Hz，1H)MS.(ESI+)m/z511(M+TFA+H)+.

Embodiment 202

The 6-hydroxy-n-3-[4-methyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-niacinamide

This title compound is prepared as follows: in the method for embodiment 74, (26mg 0.16mmol) as acid, obtains this title compound (3mg, 5%) with 6-hydroxyl-nicotinic acid.

¹H?NMR(500MHz，DMSO-D ₂O)δ?ppm:0.92(t，J＝7.32Hz，3H)，1.69·1.77(m，2H)，2.37-2.42(m，3H)，2.82-2.88(m，2H)，6.24(d，J＝7.02Hz，1H)，6.46(d，J＝9.46Hz，1H)，6.87(d，J＝8.54Hz，1H)，7.09(t，J＝8.09Hz，1H)，7.32-7.37(m，2H)，7.39(d，J＝7.93Hz，1H)，7.55-7.60(m，2H)，7.67(d，J＝8.85Hz，1H)，7.91(dd，J＝9.76，2.75Hz，1H)，8.09(d，J＝2.44Hz，1H)，8.24(d，J＝7.02Hz，1H)，8.82(d，J＝8.54Hz，1H)；MS(ESI+)m/z?522(M+TFA+H)+；(ESI-)m/z?520(M+TFA-H).

Embodiment 203

2-hydroxyl-6-methyl-N-{3-[4-methyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-niacinamide

This title compound is prepared as follows: in the method for embodiment 74, (26mg 0.16mmol) as acid, obtains this title compound (3mg, 5%) with 2-hydroxyl-6-methyl-nicotinic acid.

¹HNMR(500MHz，DMSO-D ₂O)δ?ppm:0.89(t，J＝7.48Hz，3H)，1.64-1.71(m，J＝7.48，7.48，7.48，7.48Hz，2H)，2.36(s，3H)，2.40(s，3H)，2.76-2.81(m，3H)，6.22(d，J＝7.02Hz，1H)，6.46(d，J＝7.32Hz，1H)，6.86(d，J＝8.24Hz，I?H)，7.10(t，J＝7.93Hz，1H)，7.14-7.18(m，1H)，7.35(s，1H)，7.39(d，J＝8.24Hz，1H)，7.57-7.59(m，1H)，7.62(d，J＝8.54Hz，2H)，8.21(d，J＝7.32Hz，1H)，8.27(d，J＝7.32Hz，1H)，8.82(d，J＝8.85Hz，1H)；MS(ESI+)m/z?536(M+TFA+H)+.

Embodiment 204

Pyrazine-2-formic acid 3-[4-methyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-acid amides

This title compound is prepared as follows: in the method for embodiment 74, (26mg 0.16mrnol) as acid, obtains this title compound (3mg, 5%) with pyrazine-2-formic acid.

¹HNMR(500MHz，DMSO-D ₂O)δ?ppm:0.87(t，J＝7.48Hz，3H)，1.63-1.70(m，2H)，2.40(s，3H)，2.74-2.78(m，2H)，6.28(d，J＝7.02Hz，1H)，6.94(d，J＝8.54Hz，1H)，7.13(t，J＝7.93Hz，1H)，7.36(d，J＝1.22Hz，1H)，7.40(d，J＝7.93Hz，1H)，7.53(dd，J＝7.63，1.53Hz，1H)，7.61(d，J＝7.93Hz，1H)，7.65(d，J＝8.54Hz，1H)，7.76(t，J＝1.83Hz，1H)，8.25(d，J＝7.02Hz，1H)，8.78-8.84(m，2H)，8.94(d，J＝2.44Hz，1H)；MS(ESI+)m/z507(M+TFA+H)+.

Embodiment 205

Furans-2-formic acid (3-[4-methyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-the phenyl amino formyl radical }-methyl)-acid amides

This title compound is prepared as follows: in the method for embodiment 74, (26mg 0.16mmol) as acid, obtains this title compound (3mg, 5%) with [(furans-2-carbonyl)-amino]-acetate.

¹HNMR(500MHz，DMSO-D ₂O)δ?ppm:0.96(t，J＝7.32Hz，3H)，1.78-1.86(m，2H)，2.39(s，3H)，2.94-3.01(m，2H)，6.34(d，J＝7.02Hz，1H)，6.62-6.68(m，1H)，6.87(d，J＝7.63Hz，1H)，7.02-7.12(m，2H)，7.14-7.22(m，2H)，7.37(d，J＝5.49Hz，2H)，7.48(d，J＝8.54Hz，1H)，7.51(s，1H)，7.72(d，J＝8.85Hz，1H)，7.81-7.87(m，2H)，8.33(d，J＝7.02Hz，1H)，8.86(d，J＝8.54Hz，1H)；MS(ESI+)m/z?552(M+TFA+H)+.

Embodiment 206

N-{3-[4-methyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-4-thiophene-2-base-butyramide

This title compound is prepared as follows: in the method for embodiment 74, (26mg 0.16mmol) as acid, obtains this title compound (3mg, 5%) with 4-thiophene-2-base-butyric acid.

¹H?NMR(500MHz，DMSO-D ₂O)δ?ppm:0.96(t，J＝7.32Hz，3H)，1.79-1.84(m，2H)，1.85-1.89(m，2H)，2.28(t，J＝7.48Hz，2H)，2.39(s，3H)，2.79-2.84(m，2H)，2.92-2.98(m，2H)，6.29(d，J＝7.02Hz，1H)，6.82-6.88(m，2H)，6.96(dd，J＝4.88，3.36Hz，1H)，7.05(t，J＝7.93Hz，1H)，7.22(dd，J＝8.24，1.22Hz，1H)，7.31(dd，J＝5.03，1.07Hz，1H)，7.35-7.38(m，2H)，7.45-7.51(m，2H)，7.70(d，J＝8.54Hz，1H)，8.27(d，J＝7.32Hz，1H)，8.84(d，J＝8.54Hz，1H)；MS(ESI+)m/z?553(M+TFA+H)+.

Embodiment 207

N-{3-[4-methyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-2-(3-phenoxy group-phenyl)-ethanamide

This title compound is prepared as follows: in the method for embodiment 74, (26mg 0.16mmol) as acid, obtains this title compound (3mg, 5%) with (3-phenoxy group-phenyl)-acetate.

¹HNMR(500MHz，DMSO-D ₂O)δ?ppm:0.96(t，J＝7.32Hz，3H)，1.77-1.85(m，2H)，2.39(s，3H)，2.92-2.99(m，2H)，3.55(s，2H)，6.32(d，J＝7.32Hz，1H)，6.84-6.90(m，2H)，6.96(s，1H)，7.00(d，J＝7.63Hz，2H)，7.07(ddd，J＝7.78，4.12，3.97Hz，2H)，7.16(t，J＝7.48Hz，1H)，7.23(d，J＝9.15Hz，1H)，7.33-7.42(m，5H)，7.44-7.47(m，1H)，7.49(s，1H)，7.69(d，J＝8.85Hz，1H)，8.27(d，J＝7.02Hz，1H)，8.85(d，J＝8.54Hz，1H)；MS(ESI+)m/z?611(M+TFA+H)+.

Embodiment 208

N-allyl group-3-[4-chloro-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenoxy group]-benzamide

Embodiment 208a

3-(4-chloro-2-nitro-phenoxy group)-methyl benzoate

(7.00g 29.60mmol) is dissolved among the DMF, adds K 1-bromo-4-chloro-2-nitro-benzene ₂CO ₃(5.11g, 37.01mmol) and 3-hydroxy-benzoic acid methyl esters (4.95g, 32.57mmol).Then reaction mixture is heated to 100 ℃ 2 hours, reaction mixture is cooled to room temperature, water dilution, and use ethyl acetate extraction.With solvent Na ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound (7.2g, 79%).

Embodiment 208b

3-(2-amino-4-chloro-phenoxy group)-methyl benzoate

According to the method for embodiment 1f, (7.20g 23.40mmol) uses SnCl with the product of embodiment 208a ₂(13.310g, 70.20mmol) reduction obtains this title compound (6.2g, 95%).

Embodiment 208c

3-[4-chloro-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenoxy group]-methyl benzoate

The product of embodiment 1d (175mg, 0.979mmol) and the product of embodiment 208b (272mg 0.979mmol) is dissolved among the anhydrous EtOH of 2mL, and be heated to 80 ℃ 16 hours.Cool off reaction mixture this moment, and remove and desolvate, and obtains this title compound, is the brown foam, it is not further purified be used for next step (410mg, 93%).

Embodiment 208d

3-[4-chloro-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenoxy group]-phenylformic acid

(447mg 1.065mmol) is dissolved in 5ml1:1 (THF: water) in the solution the product of embodiment 208c.In wherein add LiOH (51mg, 2.129mmol), and with reaction mixture be heated to 60 ℃ 2 hours, then reaction mixture is cooled to room temperature, and is adjusted to neutrality with HOAc.With the product ethyl acetate extraction.Use Na ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound (180mg, 42%).

Embodiment 208e

The product of embodiment 208d (60mg 0.147mmol) is dissolved among the THOF, in wherein add N-methylmorpholine (49mg, 0.162mmol) and the different propylene ester of chloroformic acid (36mg, 0.295mmol).With it in stirring at room 1 hour, add this moment allyl amine (42mg, 0.739mmol), and with reaction mixture in room temperature restir 1 hour.Remove THF then under nitrogen gas stream, thick oily matter by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetic acid (8.0mg, 9.5%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.92(s，3H)，2.74(s，2H)，3.86(d，J＝5.15Hz，2H)，5.04-5.16(m，2H)，5.73-5.98(m，1H)，6.73(d，J＝6.99Hz，1H)，7.10(dd，J＝7.72，2.21Hz，1H)，7.27-7.43(m，3H)，7.51-7.65(m，2H)，7.69-7.82(m，2H)，8.54(d，J＝7.35Hz，1H)，8.82(d，J＝8.46Hz，1H)；MS(ESI+)m/z?445(M+TFA+H)+；(ESI-)m/z443(M+TFA-H)-.

Embodiment 211

(5-chloro-2-phenoxy group-phenyl)-(7-phenyl-[1,8] naphthyridine-4-yl)-amine

Embodiment 211a

2-(2,5-dimethyl-pyrroles-1-yl)-6-phenyl-pyridine

Will be according to the 2-chloro-6-(2 that makes described in the embodiment 8a, 5-dimethyl-pyrroles-1-yl)-pyridine (0.097g, 0.47mmol) (0.185mL 0.564mmol) reacted 24 hours in 75 ℃ under nitrogen in the presence of 2mole% tetrakis triphenylphosphine palladium (0) with tributyl-phenyl-stannane.Volatile matter is removed in decompression then, obtains crude product, and it by flash chromatography on silica gel method purifying, is obtained this title compound (0.103g.88%).

Embodiment 211b

6-phenyl-pyridine-2-base amine

With the replacement described among the embodiment 211a pyridine (0.289g 1.7mmol) reacts as describing among the embodiment 2c, obtains this title compound with quantitative yield.

Embodiment 211c

5-chloro-2-phenyl-[1,8] naphthyridine

The product of embodiment 211b is reacted according to the method for embodiment 2d, 2e, 2f and 2g, obtain this title compound.

Embodiment 211d

(5-chloro-2-phenoxy group-phenyl)-(7-phenyl-[1,8] naphthyridine-4-yl)-amine

Method according to embodiment 1g, product (0.108g with embodiment 211f, 0.45mmol) with the product (0.100g of embodiment 42b, 0.46mmol) reacted 28 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (0.144g, 57%).

¹H?NMR(300MHz，DMSO-d ₆)

?ppm:6.75(d，J＝6.99Hz，1H)6.99(d，J＝7.72Hz，2H)7.11(t，J＝7.35Hz，1H)7.18(d，J＝8.82Hz，1H)7.32(t，J＝7.91Hz，2H)7.59(dd，J＝8.82，2.57Hz，1H)7.64(m，3H)7.75(d，J＝2.57Hz，1H)8.36(dd，J＝6.62，2.94Hz，2H)8.51(d，J＝9.19Hz，1H)8.61(d，J＝6.99Hz，1H)9.10(d，J＝8.82Hz，1H)；MS(ESI+)m/z?423，9(M+H)+；(ESI-)-m/z?422.0(M-H)-.

Embodiment 212

2-(7-methyl-[1,8] naphthyridine-4-base is amino)-xenyl-4-methyl-formiate

Embodiment 212a

4-bromo-3-nitro-methyl benzoate

(1.17g 4.76mmol) is dissolved in the methyl alcohol (5mL) that contains 5 vitriol oils commercially available 4-bromo-3-nitro-phenylformic acid.With mixture in air in 90 ℃ of heating 6 hours, and add MeOH (7mL) again, add the vitriol oil (0.6mL) then.Reheat 24 hours.Extraction aftertreatment (ethyl acetate-water), use MgSO then ₄Drying is filtered and is concentrated under vacuum, obtains this title compound with quantitative yield.

Embodiment 212b

2-nitro-xenyl-4-methyl-formiate

With the product of embodiment 212a (0.100g, 0.384mmol) with iodobenzene (0.375mL, 3.35mmol) and copper powder (0.188g, 2.96mmol) mixing, and with mixture in sealed tube, be heated to 218 ℃ 90 minutes.Then reaction mixture is diluted with methylene dichloride, and pass through diatomite filtration.To obtain this title compound (0.0847g, 86%) by under vacuum, concentrating the crude product flash chromatography on silica gel method purifying (ethyl acetate-hexane) that obtains.

Embodiment 212c

2-amino-xenyl-4-methyl-formiate

(0.0795g 0.309mmol) is dissolved in the ethanol (2mL), adds oxidation Pt (IV) (5.2mg) in this solution the product of embodiment 212b.With the reaction mixture vacuum outgas, be exposed under the atmospheric hydrogen 3 hours in room temperature then.Remove catalyzer by diatomite filtration, and filtrate is concentrated under vacuum, obtain this title compound with quantitative yield.

Embodiment 212d

2-(7-methyl-[1,8] naphthyridine-4-base is amino)-xenyl-4-methyl-formiate

According to the method for embodiment 1g, (0.0552g, 0.309mmol) (0.070g, 0.309mmol) reaction is 92 hours, obtains this title compound, and it by the HPLC purifying, is used the AA wash-out with the product of embodiment 212c with the product of embodiment 1d.The 4N HCl that the gained solid is used in the diox develops, and produces hydrochloride, and it is collected (0.0747g, 55%) by vacuum filtration.

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.72(s，3H)3.91(s，3H)6.27(d，J＝6.99Hz，1H)7.30(m，J＝6.99Hz，3H)7.52(m，2H)7.74(d，，J＝8.82Hz，1H)7.79(d，J＝8.09Hz，1H)8.09(d，J＝1.47Hz，1H)8.16(dd，J＝7.91，1.65Hz，1H)8.30(d，J＝6.99Hz，1H)9.15(d，J＝8.82Hz，1H)11.54(s，1H)；MS(ESI+)m/z369.9(M+H)+.

Embodiment 213

(4-methyl-xenyl-2-yl)-(7-propyl group-[1,8] naphthyridine-4-yl)-amine

Embodiment 213a

4-methyl-2-nitro-xenyl

(0.107g 0.49mmol) adds CsCO in the solution in dry toluene (3mL) to commercially available l-bromo-4-methyl-2-nitro-benzene ₃(0.305g, 0.94mmol), add then phenyl-boron dihydroxide (0.062g, 0.49mmol) and 2,8,9-triisobutyl-2,5,8, (0.1M is at toluene (0.200mL, 4mole%) solution in) for 9-four azepines-1-phospha dicyclo [3.3.3.] undecane.Nitrogen was fed in the gained suspension 3 minutes, add then acid chloride (0.0043g, 4mole%), with the reactor sealing and immerse in 80 ℃ of oil baths and heated 22 hours.By diatomite filtration and removing volatiles under vacuum, obtain crude product (0.105g, 100%) then, the isolating product of institute is enough pure for use.

Embodiment 213b

4-methyl-xenyl-2-base amine

The product of embodiment 213a is reacted as describing among the embodiment 212c, obtain this title amine (0.088g, 100%).

Embodiment 213c

(4-methyl-xenyl-2-yl)-(7-propyl group-[1,8] naphthyridine-4-yl)-amine

Method according to embodiment 1g, product (0.106g with embodiment 2g, 0.49mmol) with the product (0.088g of embodiment 213b, 0.49mmol) reacted 65 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (0.122g, 52%).

¹H?NMR(300MHz，DMSO-d ₆)

?ppm:0.96(t，J＝7.35Hz，3H)1.81(d，J＝7.72Hz，2H)2.43(s，3H)2.89-3.02(m，2H)6.31(d，J＝6.99Hz，1H)7.14-7.58(m，8H)7.77(d，J＝8.46Hz，1H)8.32(d，J＝7.35Hz，1H)8.91(d，J＝8.46Hz，1H)10.91-11.08(m，1H)；MS(ESI+)m/z354.0(M+H)+；(ESI-)m/z?351.9(M-H)-.

Embodiment 214

(4-methyl-xenyl-2-yl)-(7-propyl group-[1,8] naphthyridine-4-yl)-amine

Embodiment 214a

4 '-methoxyl group-4-methyl-2-nitro-xenyl

Describe as embodiment 213a, (0.074g 0.49mmol) substitutes boric acid with 4-anisole ylboronic acid, with 1-bromo-4-methyl-2-oil of mirbane (0.107g, 0.49mmol) reaction, obtaining xenyl with quantitative yield, isolating product purity enough is used for next step.

Embodiment 214b

4 '-methoxyl group-4-methyl-xenyl-2-base amine

The product of embodiment 214a is reacted as describing among the 212c, obtain this title amine (0.107g, 100%).

Embodiment 214

(4 '-methoxyl group-4-methyl-xenyl-2-yl)-(7-methyl-[1,8] naphthyridine-4-yl)-amine

Method according to embodiment 1g, product (0.088g with embodiment 1d, 0.49mmol) with the product (107mg of embodiment 214b, 0.49mmol) reacted 65 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (0.106g, 45%).

¹HNMR(300MHz，DMSO-d ₆)δ?ppm:2.41(s，3H)2.72(s，3H)3.66(s，3H)6.29(d，J＝6.99Hz，1H)6.84(d，J＝8.82Hz，2H)7.27-7.53(m，5H)7.75(d，J＝8.46Hz，1H)8.32(d，J＝6.99Hz，1H)8.90(d，J＝8.46Hz，1H)10.88·11.05(m，1H)；MS(ESI+)m/z?356.0(M+H)+；(ESI-)m/z?354.1(M-H)-.

Embodiment 215

N-[4 '-methyl-2 '-(7-methyl-[1,8] naphthyridine-4-base is amino)-xenyl-4-yl]-ethanamide

Embodiment 215a

N-(4 '-methyl-2 '-nitro-xenyl-4-yl)-ethanamide

With 1-bromo-4-methyl-2-nitro-benzene (0.102g, 0.49mmol) react as describing among the embodiment 213a, with N-[4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-s pentaborane-2-yl)-phenyl]-ethanamide (0.130g 0.49mmol) substitutes phenyl-boron dihydroxide, and in 100 ℃ of heating 18 hours.To react by diatomite filtration, volatile matter is removed in decompression, and crude product is passed through the silicagel column purified by flash chromatography, with EtOAc-hexane wash-out, obtains this title xenyl (0.051mg, 38%).

Embodiment 215b

N-(2 '-amino-4 '-methyl-xenyl-4-yl)-ethanamide

(0.062g 0.23mmol) reacts as describing among the embodiment 212c, obtains this title amine with quantitative yield with the product of embodiment 215a.

Embodiment 215

Method according to embodiment 1g, product (0.041g with embodiment 1d, 0.23mmol) with the product (0.062g of embodiment 215b, 0.23mmol) in 100 ℃ of reactions 46 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (0.073g, 60%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.98(s，3H)2.42(s，3H)2.72(s，3H)6.28(d，J＝6.99Hz，1H)7.27-7.56(m，7H)7.74(d，J＝8.46Hz，1H)8.33(d，J＝7.35Hz，1H)8.94(d，J＝8.82Hz，1H)9.95(s，1H)11.06(s，1H)；MS(ESI+)m/z?383.1(M+H)+，(ESI-)m/z?381.1(M-H)-.

Embodiment 216

N-[4 '-methyl-2 '-(7-methyl-[1,8] naphthyridine-4-base is amino)-xenyl-3-yl]-ethanamide

Embodiment 216a

N-(4 '-methyl-2 '-nitro-xenyl-3-yl)-ethanamide

(0.107g 0.49mmol) reacts as describing among the embodiment 215a, with 3-acetamido phenyl-boron dihydroxide (0.086g with 1-bromo-4-methyl-2-nitro-benzene, 0.49mmol) alternative phenyl-boron dihydroxide, substitute 2,8 with dicyclohexylamine (4mole%), 9-triisobutyl-2,5,8,9-four azepines-1-phospha dicyclo [3.3.3.] undecane, and the Yong diox substitutes toluene, obtain this title xenyl (0.0552g, 42%).

Embodiment 216b

N-(2 '-amino-4 '-methyl-xenyl-3-yl)-ethanamide

(0.070g 0.26mmol) reacts as describing among the embodiment 212c, obtains this title amine with quantitative yield with the product of embodiment 216a.

Embodiment 216

According to the method for embodiment 1g, (0.046g is 0.26mmol) with the product (0.063g of embodiment 216b with the product of embodiment 1g, 0.26mmol) in 100 ℃ of reactions 47 hours, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (0.085g, 64%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:1.93(s，3H)2.43(s，3H)2.71(s，3H)6.34(d，J＝6.99Hz，1H)7.04(d，J＝7.35Hz，1H)7.17(t，J＝7.72Hz，1H)7.22-7.31(m，1H)7.36(s，1H)7.40-7.54(m，2H)7.72(d，J＝8.46Hz，1H)7.77(s，1H)8.36(s，1H)8.88(d，J＝8.82Hz，1H)9.88(s，1H)10.99(s，1H)；MS(ESI+)m/z?383.0(M+H)+；(ESI-)m/z?381.1(M-H)-.

Embodiment 217

(3 '-methoxyl group-4-methyl-xenyl-2-yl)-(7-methyl-[1,8] naphthyridine-4-yl)-amine

Embodiment 217a

3 '-methoxyl group-4-methyl-2-nitro-xenyl

With 1-bromo-4-methyl-2-nitro-benzene (0.107g, 0.49mmol) react as describing among the embodiment 216a, (0.074g 0.45mmol) substitutes 3-acetamido phenyl-boron dihydroxide with 3-anisole ylboronic acid, obtain this title xenyl (0.083g, 76%).

Embodiment 217b

3 '-methoxyl group-4-methyl-xenyl-2-base amine

(0.083g 0.34mmol) reacts as describing among the embodiment 212c, obtains this title amine with quantitative yield with the product of embodiment 217b.

Embodiment 217c

In method according to embodiment 1g, product (0.065g with embodiment 1d, 0.36mmol) with the product (0.072g of embodiment 217b, 0.34mmol) 100 ℃ of reactions 96 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain trifluoroacetate (0.102gm, 64%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.43(s，3H)2.72(s，3H)3.62(s，3H)6.29(d，J＝7.35Hz，1H)6.77(dd，J＝7.91，2.02Hz，1H)6.87-7.00(m，2H)7.17(t，J＝7.91Hz，1H)7.36(s，1H)7.41-7.46(m，1H)7.51-7.56(m，1H)7.75(d，J＝8.46Hz，1H)8.32(d，J＝7.35Hz，1H)8.91(d，J＝8.82Hz，1H)11.99·12.22(s，1H)；MS(ESI+)m/z?356.0(M+H)+；(ESI-)m/z354.0(M-H)-.

Embodiment 218

(7-propyl group-[1,8] naphthyridine-4-yl)-(4-trifluoromethyl-xenyl-2-yl)-amine

Embodiment 218a

2-nitro-4-trifluoromethyl-xenyl

As describing among the embodiment 213a with commercially available 1-bromo-2-nitro-4-trifluoromethyl-benzene (0.130g, 0.48mmol) and phenyl-boron dihydroxide (0.072g, 0.59mmol) reaction, the Yong diox substitutes toluene, substitutes acid chloride with two (triphenylphosphine) Palladous chloride (II), and omit 2,8,9-triisobutyl-2,5,8,9-four azepines-1-phospha dicyclo [3.3.3.] undecane.Originally react completely after three hours, and obtain this title xenyl with quantitative yield, isolating product be enough pure for use.

Embodiment 218b

4-trifluoromethyl-xenyl-2-base amine

The product of embodiment 218a is reacted as describing among the embodiment 212c,, obtain this title amine with quantitative yield with 3:1THF/EtOH (4mL) instead of ethanol.

Embodiment 218c

(7-propyl group-[1,8] naphthyridine-4-yl)-(4-trifluoromethyl-xenyl-2-yl)-amine

According to the method for embodiment 1g, ((0.057g is 0.24mmol) in 100 ℃ of reactions 64 hours at the product of ethanol (0.078mL, 0.24mmol) solution in) and embodiment 218b for 3.15M with the product of embodiment 2g.(0.103mL 0.32mmol), and continues heating (70 hours) in 100 ℃ to the product that the consumption of parent material needs regularly to add embodiment 2g altogether.This rough title compound by the HPLC purifying, is used the TFA wash-out, and the acquisition product is trifluoroacetate (0.0058g, 5%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.96(t，J＝7.35Hz，3H)1.73-1.92(m，2H)2.90-3.02(m，2H)6.37(d，J＝6.99Hz，1H)7.32(d，J＝7.72Hz，3H)7.48(dd，J＝7.91，1.65Hz，2H)7.80(d，J＝8.82Hz，1H)7.86(d，J＝8.09Hz，1H)7.94-8.03(m，2H)8.35(d，J＝6.99Hz，1H)8.91(d，J＝8.82Hz，1H)；MS(ESI+)m/z?408.1(M+H)+；(ESI-)m/z?406.2(M-H)-.

Embodiment 219

(5-methyl-xenyl-2-yl)-(7-propyl group-[1,8] naphthyridine-4-yl)-amine

Embodiment 219a

2-bromo-4-methyl isophthalic acid-nitro-benzene

In 70 ℃ under nitrogen, to containing at CH ₃90% nitrite tert-butyl among the CN (40mL) (1.47mL, 11.2mmol) and cupric bromide (II) (2.0g, (1.13g is 7.46mmol) at CH to drip commercially available 5-methyl-2-nitro-phenyl amine in flask 8.95mmol) ₃Solution among the CN (8mL).After 20 minutes, by pouring among rare HCl, and, use MgSO by crude product being separated with extracted with diethyl ether with the stopping of reaction ₄Drying, and under vacuum, concentrate.The silicagel column purified by flash chromatography obtains this title compound (0.811g, 50%).

Embodiment 219b

5-methyl-2-nitro-xenyl

As describing among the embodiment 218a, (0.20g, 0.93mmol) (0.135g 1.11mmol) reacted 19.5 hours in 80 ℃ with phenyl-boron dihydroxide with the product of embodiment 219a.With the reaction mixture cooling, and, filtrate is concentrated under vacuum, obtain crude product, it by the silicagel column purified by flash chromatography, is obtained this title xenyl (0.187g, 94%), be yellow oil by diatomite filtration.

Embodiment 219c

5-methyl-xenyl-2-base amine

(0.0885g 0.41mmol) according to the method reaction of embodiment 212c, obtains this title amine (0.0724g, 96%) with the product of embodiment 219b.

Embodiment 219c

(5-methyl-xenyl-2-yl)-(7-propyl group-[1,8] naphthyridine-4-yl)-amine

According to the method for embodiment 1g, ((0.0724g is 0.40mmol) in 100 ℃ of reactions 66 hours for the product of 4.1MZ ethanol (0.10mL, 0.40mmol) solution in) and embodiment 219c with the product of embodiment 2g.The consumption of parent material need add the product of embodiment 2g again, and (0.03mL 0.12mmol), and continue to stir (19h) in 100 ℃.This rough title compound by the HPLC purifying, is used the TFA wash-out, and the acquisition product is trifluoroacetate (0.060g, 32%).

¹H?NMR.(300MHz，DMSO-d ₆)δ?ppm:0.95(t，J＝7.35Hz，3H)1.70-1.89(m，2H)2.46(s，3H)2.88-3.00(m，2H)6.28(d，J＝6.99Hz，1H)7.11-7.53(m，8H)7.76(d，J＝8.82Hz，1H)8.30(d，J＝6.99Hz，1H)8.91(d，J＝8.82Hz，1H)10.98(s，1H)；MS(ESI+)m/z?354.2(M+H)+.

Embodiment 220

[2-(4-amino-phenyl sulfenyl)-5-methyl-phenyl]-(7-propyl group-[1,8] naphthyridine-4-yl)-amine

(0.197g 0.445mmol) reacts as describing among the embodiment 83, obtains this rough title compound, and it is passed through the HPLC purifying, uses the TFA wash-out, and the acquisition product is a trifluoroacetate with the product of embodiment 20.

¹H?NMR(500MHz，DMSO-d ₆)δ?ppm:0.98(t，J＝7.25Hz，3H)1.80-1.91(m，2H)2.31(s，3H)2.96-3.04(m，2H)6.31(d，J＝6.96Hz，1H)6.57(d，J＝8.69Hz，2H)6.91(d，J＝8.11Hz，1H)7.07(d，J＝8.69Hz，2H)7.18-7.29(m，2H)7.83(d，J＝8.69Hz，1H)8.45(d，J＝6.96Hz，1H)9.06(d，J＝8.69Hz，1H)11.03(s，1H)；MS(ESI+)m/z?401.1(M+H)+；(ESI-)m/z?399.1(M-H)-

Embodiment 221

4-[4-phenoxymethyl-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

Embodiment 221a

(4-bromo-3-nitro-phenyl)-methyl alcohol

With commercially available 4-bromo-3-nitro-phenylformic acid (5.95g 0.024mole) reacts as described in embodiment 115a, obtains this title compound with quantitative yield, isolating product be enough pure for use.

Embodiment 221b

1-bromo-2-nitro-4-phenoxymethyl-benzene

With the product of embodiment 221a (0.5g, 2.15mmol) with phenol (0.203g, 2.15mmol) and triphenyl phosphine (0.735g 2.80mmol) mixes under nitrogen in anhydrous THF (7mL), and gained solution is cooled off in ice bath.In this cold solution, drip diisopropyl azodiformate (0.467mL, 2.37mmol).Continue to stir 15 minutes in 0 ℃, remove cooling bath then, reaction mixture is heated to room temperature, carry out aftertreatment among rare HCl by pouring into, and use extracted with diethyl ether.The extract MgSO that merges ₄Drying is filtered and is concentrated under vacuum, obtains this rough title compound, and it by the silicagel column purified by flash chromatography, with EtOAc-hexane wash-out, is obtained this title compound (0.162g, 25%).

Embodiment 221c

4-(2-nitro-4-phenoxymethyl-phenyl sulfenyl)-phenol

Under 80 ℃ of nitrogen, (0.16g, 0.52mmol) (0.073g, 0.52mmol) (0.91mmol) there is reaction down in 0.126g at salt of wormwood in DMF with 90%4-sulfydryl-phenol with the product of embodiment 221b.By pouring among the HCl, and use extracted with diethyl ether after 18 hours with the stopping of reaction.The extract MgSO that merges ₄Drying is filtered and is concentrated under vacuum, obtains this title compound.Crude product by the silicagel column purified by flash chromatography, with EtOAc-hexane wash-out, is obtained this title compound (0.155g, 84%).

Embodiment 221d

4-(2-amino-4-phenoxymethyl-phenyl sulfenyl)-phenol

As describing among the embodiment 1f, (0.154g, 0.43mmol) (0.41g 2.17mmol) reacts, and obtains this title compound (0.132g, 100%) with tin protochloride with the product of embodiment 221c.

Embodiment 221

According to the method for embodiment 1g, ((0.066g, 0.205mmol) reaction is 16.5 hours at the product of ethanol (0.05OmL, 0.205mmol) solution in) and embodiment 221d for 4.1M with the product of embodiment 2g.The consumption of parent material need add again embodiment 2g product (0.025mL, 0.102mmol), and in 80 ℃ of acute heating (12 hours).This rough title compound by the HPLC purifying, is used the TFA wash-out, and the acquisition product is trifluoroacetate (0.0269g, 21.5%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.98(t，J＝7.54Hz，3H)1.76-1.99(m，2H)3.00(t，J＝7.35Hz，2H)5.12(s，2H)6.31(d，J＝6.99Hz，1H)6.79(d，J＝8.82Hz，2H)6.91-7.07(m，4H)7.17-7.37(m，4H)7.43-7.55(m，2H)7.84(d，J＝8.82Hz，1H)8.47(d，J＝7.35Hz，1H)9.04(d，J＝8.46Hz，1H)9.97(s，1H)；MS(ESI+)m/z?494.2(M+H)+；(ESI-)m/z?492.2(M-H)-.

Embodiment 222

4-[2-(7-methyl-[1,8] naphthyridine-4-base is amino)-4-phenoxymethyl-phenyl sulfenyl]-phenol

Method according to embodiment 1g, product (0.037g with embodiment 1d, 0.205mmol) with the product (0.066g of embodiment 221d, 0.205mmol) reacted 16.5 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (0.041g, 34%).

¹HNMR(300MHz，DMSO-d ₆)δ?ppm:2.77(s，3H)5.13(s，2H)6.31(d，J＝6.99Hz，1H)6.79(d，J＝8.46Hz，2H)6.88·7.12(m，4H)7.20-7.36(m，4H)7.46-7.56(m，2H)7.81(d，J＝8.82Hz，1H)8.48(d，J＝6.99Hz，1H)9.02(d，J＝8.46Hz，1H)10.01(s，1H)；MS(ESI+)m/z?466.3(M+H)+；(ESI-)m/z?464.2(M-H)-.

Embodiment 223

Embodiment 223a

1-bromo-4-(4-bromo-phenoxymethyl)-2-nitro-benzene

(0.372g 2.15mmol) substitutes phenol, and (0.5g 2.15mmol) describes as embodiment 221b and reacts, and obtains this title compound, is white solid (0.238g, 29%) with the product of embodiment 221a with 4-bromo-phenol.

Embodiment 223b

4-[4-(4-bromo-phenoxymethyl)-2-nitro-phenyl sulfenyl]-phenol

(0.236g 0.61mmol) reacts as describing among the embodiment 221c, obtains this title compound (0.188g, 71%) with the product of embodiment 223a.

Embodiment 223c

4-[2-amino-4-(4-bromo-phenoxymethyl)-phenyl sulfenyl]-phenol

(0.186g 0.43mmol) reacts as describing among the embodiment 221d, obtains this title compound (0.121g, 70%) with the product of embodiment 223b.

Embodiment 223

4-[4-(4-bromo-phenoxymethyl)-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

According to the method for embodiment 1g, (0.03g, 0.167mmol) (0.060g, 0.15mmol) reaction is 17.5 hours with the product of embodiment 223c with the product of embodiment 1d.The consumption of parent material need add the product of embodiment 1d again, and (0.016g 0.09mmol), and continues heating (18 hours) in 80 ℃.This rough title compound by the HPLC purifying, is used the TFA wash-out, and the acquisition product is trifluoroacetate (0.056g, 55%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.77(s，3H)5.12(s，2H)6.30(d，J＝6.99Hz，1H)6.79(d，J＝8.82Hz，2H)6.92-7.08(m，3H)7.25(d，J＝8.82Hz，2H)7.42-7.54(m，4H)7.81(d，J＝8.82Hz，1H)8.47(d，J＝6.99Hz，1H)9.01(d，J＝8.46Hz，1H)9.98(s，1H)；MS(ESI+)m/z?546.0(M+H)+.

Embodiment 224

4-[4-(4-bromo-benzyloxy)-2-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

According to the method for embodiment 1g, (4.1M is in product (0.060g, 0.15mmol) reaction 17.5 of ethanol (0.055rnL, 0.225mmol) solution in) with embodiment 223c with the product of embodiment 2g.The consumption of parent material need add the product of embodiment 2g again, and (0.028mL 0.114mmol), and continues heating (18 hours) in 80 ℃.This rough title compound by the HPLC purifying, is used the TFA wash-out, and the acquisition product is trifluoroacetate (0.044g, 41%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0:98(t，J＝7.35Hz，3H)1.77-1.96(m，2H)3.00(t，J＝7.54Hz，2H)5.13(s，2H)6.31(d，J＝6.99Hz，1H)6.79(d，J＝8.82Hz，2H)6.91-7.07(m，3H)7.26(d，J＝8.46Hz，2H)7.40-7.56(m，4H)7.84(d，J＝8.82Hz，1H)8.47(d，J＝6.99Hz，1H)9.04(d，J＝8.82Hz，1H)9.98(s，1H)；MS(ESI+)m/z?573.9(M+H)+；(ESI-)m/z?572.1(M-H)-

Embodiment 225

Embodiment 225a

1-bromo-4-(3-bromo-phenoxymethyl)-2-nitro-benzene

(0.372g 2.15mmol) substitutes phenol, and (0.5g 2.15mmol) reacts as describing among the embodiment 221b, obtains this title compound (0.832g, 56%) with the product of embodiment 221a with 3-bromo-phenol.

Embodiment 225b

4-[4-(3-bromo-phenoxymethyl)-2-nitro-phenyl sulfenyl]-phenol

(0.462g 1.19mmol) reacts as describing among the embodiment 221c, obtains this title compound (0.412g, 80%) with the product of embodiment 225a.

Embodiment 225c

4-[2-amino-4-(3-bromo-phenoxymethyl)-phenyl sulfenyl]-phenol

(0.412g 0.95mmol) reacts as describing among the embodiment 221d, obtains this title compound (0.310g, 81%) with embodiment 225b.

Embodiment 225

4-[4-(3-bromo-phenoxymethyl)-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenol

According to the method for embodiment 1g, (0.034g, 0.193mmol) (0.078g, 0.193mmol) reaction is 15 hours with the product of embodiment 225c with the product of embodiment 1d.The consumption of parent material need add the product of embodiment 1d again, and (0.019g 0.109mmol), and continues heating (18 hours) in 80 ℃.This rough title compound by the HPLC purifying, is used the TFA wash-out, and the acquisition product is trifluoroacetate (0.041g, 32%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.77(s，3H)5.15(s，2H)6.30(d，J＝7.35Hz，1H)6.79(d，J＝8.46Hz，2H)6.95-7.08(m，2H)7.16(d，1H)7.20-7.30(m，4H)7.45-7.55(m，2H)7.81(d，J＝8.82Hz，1H)8.47(d，J＝7.35Hz，1H)9.01(d，J＝8.46Hz，1H)9.98(s，1H)；Ms(ESI+)m/z?546.0(M+H)+；(ESI-)m/z542.0.

Embodiment 226

According to the method for embodiment 1g, ((0.078g, 0.193mmol) reaction is 15 hours at the product of ethanol (0.075mL, 0.308mmol) solution in) and embodiment 225c for 4.1M with the product of embodiment 2g.The consumption of parent material need add the product of embodiment 2g again, and (0.028mL 0.114mmol), and continues heating (18 hours) in 80 ℃.This rough title compound by the HPLC purifying, is used the TFA wash-out, and the acquisition product is trifluoroacetate (0.038g, 28%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.98(t，J＝7.35Hz，3H)1.85(d，J＝7.35Hz，2H)3.00(t，J＝7.54Hz，2H)5.16(s，2H)6.31(d，J＝7.35Hz，1H)6.79(d，J＝8.46Hz，2H)6.95-7.09(m，2H)7.16(d，1H)7.18-7.34(m，4H)7.42-7.58(m，2H)7.84(d，J＝8.46Hz，1H)8.48(d，J＝6.99Hz，1H)9.04(d，J＝8.46Hz，1H)9.98(s，1H)10.99-11.19(m，1H)；MS(ESI+)m/z?573.9(M+H)+；(ESI-)m/z?572.3(M-H)-.

Embodiment 227

(7-methyl-[1,8] naphthyridine-4-yl)-[5-methyl-2-(pyridine-2-base sulfenyl)-phenyl]-amine

Embodiment 227a

2-(4-methyl-2-nitro-phenyl sulfenyl)-pyridine

This title compound is prepared as follows: with three fluoro-methanesulfonics and 4-methyl-2-nitro-phenylester (3.50g, 12.27mmol) with pyridine-2-mercaptan (2.046g, 18.41mmol) and K ₂CO ₃(2.968g, 21.48mmol) in DMF in 100 ℃ of reactions 16 hours, then reaction mixture is cooled to room temperature, and dilute with water, with the EtOAc extraction, use Na ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains this title compound (2.52g, 78%).

Embodiment 227b

5-methyl-2-(pyridine-2-base sulfenyl)-phenyl amine

According to the method for embodiment 1f, (2.250g 10.23mmol) uses SnCl with the product of embodiment 277a ₂(5.820g 30.70mmol) in 80 ℃ of reductase 12s hour, obtains this title compound, with it by silica gel column chromatography purifying purifying, with 30% EtOAc/ hexane (1.52g, 70%) wash-out.

Embodiment 227c

(7-methyl-[1,8] naphthyridine-yl)-[5-methyl-2-(pyridine-2-base sulfenyl)-phenyl]-amine

Method according to embodiment 1g, product (60mg with embodiment 227b, 0.278mmol) with the product (50mg of embodiment 1d, 0.278mmol) reacted 16 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (24mg, 28%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.44(s，3H)，2.73(s，3H)，6.45(d，J＝6.99Hz，1H)，7.02-7.12(m，J＝7.72，1.10Hz，2H)，7.40-7.49(m，2H)，7.50-7.58(m，J＝1.84Hz，1H)，7.72(dd，J＝8.46，3.31Hz，2H)，8.21-8.27(m，J＝2.94，0.74Hz，1H)，8.38(d，J＝6.99Hz，1H)，8.85(d，J＝8.82Hz，1H)，10.99(s，1H)；MS(ESI+)m/z?359(M+H-TFA)+；(ESI-)m/z?357(M-H-TFA)-.

Embodiment 228

(5-chloro-2-phenoxy group-phenyl)-[1,6] naphthyridine-5-base-amine

Embodiment 228a

2-trimethyl silyl ethynyl-cigarette nitrile

In the pressurized vessel of suitable size, with commercially available 2-chloro-cigarette nitrile (1.5g, 10.8mmol) with triphenyl phosphine (0.228g, 8mole%) and acid chloride (II) (0.083g, 3.5mol%) mixing in triethylamine (2OmL).Nitrogen was fed in the gained suspension 5 minutes in room temperature, (8.5mL 60.1mmol), with the reactor sealing, and immerses in 80 ℃ of oil baths to add trimethyl silyl acetylene then.18.5 after hour, pressure tube cools to room temperature, and is filtered content.Filtrate is concentrated under vacuum, and crude product with EtOAc/ hexane wash-out, obtains this title compound (1.62g, 75%) by the silicagel column purified by flash chromatography, be brown solid.

Embodiment 228b

2-(2,2-dimethoxy-ethyl)-cigarette nitrile

(1.62g, 8.09mmol) (25wt% (8.74g, 40.4mmol) solution in methyl alcohol (5mL)) is in 80 ℃ of reactions hour with sodium methylate with the product of embodiment 228a.By crude product being separated, use MgSO with extracted with diethyl ether ₄Drying is filtered also and is concentrated under vacuum, obtains this title compound (1.46g, 94%), isolating product be enough pure for use.

Embodiment 228c

2-(2,2-dimethoxy-ethyl)-niacinamide

(1.46g 7.6mmol) is dissolved in the methyl alcohol (2OmL), in wherein at room temperature adding 3N sodium carbonate solution (35mL), adds 15% superoxol (35mL) then the product of embodiment 228b.To react and stir 4.5 hours, distribute by adding ethyl acetate and solid sodium chloride then.With water several times, and the organic phase that merges stirred with the solid sodium bisulfite, use MgSO then with ethyl acetate extraction ₄Drying is filtered also and is concentrated under vacuum, obtains this title compound (1.36g, 85%), isolating product be enough pure for use.

Embodiment 228d

[1,6] naphthyridine-5-alcohol

The product of embodiment 228c (1.36g 6.47mmol) is dissolved in the benzene (35ml), and in this solution, add the tosic acid pyridine (0.20g, 0.8mmol).Mixture heating up to refluxing 23 hours, is concentrated under vacuum then, obtains this title compound with quantitative yield, isolating product be enough pure for use.

Embodiment 228e

5-chloro-[1,6] naphthyridine

With the product of embodiment 228d (0.250g 1.71mmol) mixes with phosphorus oxychloride (4mL), and under nitrogen in 80 ℃ of heating 18.5 hours, remove volatile matter by vacuum distilling then.Resistates is become slurries with ice, and with dense ammonium hydroxide alkalize (pH 7-8).This title compound is collected by vacuum filtration, is washed with water, and dry under vacuum, obtain gray solid (0.245g, 87%), isolating product be enough pure for use.

Embodiment 228f

(5-chloro-2-phenoxy group-phenyl)-[1,6] naphthyridine-5-base-amine

Method according to embodiment 1g, product (0.040g with embodiment 228e, 0.24mmol) with the product (0.048g of embodiment 42b, 0.24mmol) in 100 ℃ of reactions 48 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (0.046g, 40%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:6.96(d，J＝7.35Hz，2H)7.00-7.10(m，2H)7.22-7.39(m，4H)7.66(dd，J＝8.46，4.41Hz，1H)7.91(d，J＝1.84Hz，1H)8.07(d，J＝6.25Hz，1H)8.76(d，J＝8.46Hz，1H)9.07(d，J＝3.31Hz，1H)；MS(ESI+)m/z?348.0(M+H)+；(ESI-)m/z?346.1(M-H)-.

Embodiment 229

N-{4-[4-methyl-2-([1,6] naphthyridine-5-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

According to the method for embodiment 1g, (0.040g, 0.24mmol) (0.162mL, 0.24mmol) solution in was in 100 ℃ of reactions 17.5 hours at ethanol with the product of 1.5M embodiment 18b with the product of embodiment 228e.The consumption of parent material need add the product of embodiment 228e again, and (0.027g 0.16mmol), and continues heating (24 hours) in 100 ℃, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (0.038g, 27%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.02(s，3H)2.36(s，3H)7.12-7.37(m，5H)7.38-7.53(m，3H)7.73·7.92(m，J＝8.64，4.60Hz，2H)8.94(d，J＝8.46Hz，1H)9.18(d，J＝4.04Hz，1H)9.99(s，1H)；MS(ESI+)m/z?401.3(M+H)+；(ESI-)m/z399.0(M-H)-.

Embodiment 230

(5-methyl-2-phenyl sulfenyl-phenyl)-[1,8] naphthyridine-Ji-amine

According to the method for embodiment 1g, (0.051g, 0.31mmol) (0.066g, 0.31mmol) reaction is 22.5 hours with the product of embodiment 1f with the product of embodiment 16c.The consumption of parent material need add the product (0.018g of embodiment 16c again, 0.113mmol), and in 80 ℃ of continuation heating (22 hours), obtain this rough title compound, it by the HPLC purifying, is used the ammonium acetate wash-out, the acquisition product is a free alkali, then it is handled with trifluoroacetic acid, obtain corresponding trifluoroacetate (0.062g, 43%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.38(s，3H)6.36(d，J＝6.99Hz，1H)7.23(s，5H)7.30-7.42(m，3H)7.89(dd，J＝8.46，4.41Hz，1H)8.46(d，J＝6.99Hz，1H)9.03-9.10(m，1H)9.15(dd，J＝4.41，1.47Hz，1H)MS(ESI+)m/z?344.0(M+H)+；(ESI-)m/z?342.0(M-H)-.

Embodiment 231

N-{4-[4-chloro-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 231a

N-[4-(5-chloro-2-nitro-phenyl sulfenyl)-phenyl]-ethanamide

With 2, the 4-dichloronitrobenzene (0.25g, 1.3mmol), 4-acetamido thiophenol (0.26g, 1.43mmol) and cesium carbonate (0.466g, 1.43mmol) mixture in DMF (3mL) in 100 ℃ the heating 2.5 hours.With the mixture cooling,,, use anhydrous sodium sulfate drying then with organic layer water and the washing of 10% sodium chloride solution with ethyl acetate (100mL) dilution.Siccative is filtered, and under vacuum, remove and desolvate.Resistates by silica gel column chromatography purifying purifying, is used CH ₂Cl ₂/ methanol-eluted fractions obtains this title compound, is yellow solid (0.25g, 63%).

Embodiment 231b

N-(4-(5-chloro-2-nitrophenylsulfenyl) phenyl) ethanamide

With the product of embodiment 231A (0.25g, solution 0.77mmol), iron powder (0.29g, 5.2mmol) and ammonium chloride (0.084g 1.6mmol) is heated in methyl alcohol (2mL), tetrahydrofuran (THF) (2mL) and water (0.7mL) solution and refluxed 1.5 hours.The gained mixture is diluted with methyl alcohol (50mL), and filter by Celite pad.Filtrate is concentrated into the volume of 10mL under vacuum,, and extracts with ethyl acetate (2 x 50mL) with this solution with water (50mL) dilution.The extract that merges washs with 10% sodium-chlor, uses dried over mgso then, filters and concentrates under vacuum, obtains this title compound (0.20g, 87%).

Embodiment 231c

N-{4-[5-chloro-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Product (48mg with embodiment 1d, 0.27mmol) with the product (78mg of embodiment 231b, 0.27mmol) in ethanol (2ml), reacted 18 hours, method according to embodiment 1g, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (12mg, 28%).

^1HNMR(300MHz，DMSO-d ₆)δ?ppm:2.06(s，3H)2.77(s，3H)，6.39(d，J＝7.35Hz，1H)，6.96(d，J＝1.84Hz，1H)，7.38(d，J＝8.82Hz，2H)7.51(s，2H)，7.62(d，J＝8.82Hz，2H)，7.81(d，J＝8.82Hz，1H)，8.47(d，J＝7.35Hz，1H)8.97(d，J＝8.82Hz，1H)，10.15(s，1H)，11.01(s，1H)，14.48(s，1H)；MS(DCI/NH3)m/z?435(M+H)+.

Embodiment 232

N-{4-[4-cyano group methoxyl group-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 232a

N-[4-(4-hydroxyl-2-nitro-phenyl sulfenyl)-phenyl]-ethanamide

With 3-nitro-4-chlorophenol (1.59g, 8.97mmol), 4-acetamido thiophenol (2g, 10.76mmol) and cesium carbonate (7.0g, 21.53mmol) mixture in DMF (20mL) in 100 ℃ the heating 2.5 hours.Mixture is cooled off, be poured on ice, filter and collect the gained solid, and dry under vacuum, obtain this title compound, be yellow solid (2.7g, 100%).

Embodiment 232b

N-[4-(2-amino-4-hydroxy-phenyl sulfenyl)-phenyl]-ethanamide

With the solution of embodiment 232A (2.7g, 8.97mmol), iron powder (2.0g, 35.9mmol) and ammonium chloride (0.58g 10.76mmol) is heated in methyl alcohol (6mL), THF (6mL) water (2mL) solution and refluxed 1.5 hours.The gained mixture dilutes with methyl alcohol (50mL), and filters by Celite pad.Filtrate is concentrated into the volume of 10mL under vacuum,, and extracts with ethyl acetate (2 x 50mL) with this solution with water (50mL) dilution.The extract that merges washs with 10% sodium-chlor, uses dried over mgso then, filters and concentrates under vacuum, obtains this title compound (2.46g, 77%).

Embodiment 232c

N-[4-(2-amino-4-cyano group methoxyl group-phenyl sulfenyl)-phenyl]-ethanamide

With the product of embodiment 232B (56mg, 0.17mmol), the 2-bromoacetonitrile (20mg, 0.17mmol) and salt of wormwood (26mg, 0.19mmol) mixture in DMF (1mL) was in stirring at room 15 hours.Be poured on reaction mixture on ice next day, and solid filtering is collected, and obtains this title compound (53mg, 100%).

Embodiment 232d

Method according to embodiment 1g, product (30mg with embodiment 1d, 0.17mmol) in ethanol (1mL) with the product (53mg of embodiment 232c, 0.17mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (9mg, 19%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.03(s，3H)2.76(s，3H)，5.23(s，2H)，6.32(d，J＝6.99Hz，1H)，7.18(d，J＝8.46Hz，2H)7.23(dd，J＝8.82，2.57Hz，1H)，7.31(d，J＝2.57Hz，1H)，7.38(d，J＝8.82Hz，1H)7.45(d，J＝8.82Hz，2H)，7.80(d，J＝8.46Hz，1H)，8.41(d，J＝6.99Hz，1H)8.96(d，J＝8.46Hz，1H)，10.01(s，1H)，11.04(s，1H)，14.42(s，1H)；MS(ESI+)m/z?456(M+H)+.

Embodiment 233

N-{4-[4-benzyloxy-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 233a

N-[4-(2-amino-4-benzyloxy-phenyl sulfenyl)-phenyl]-ethanamide

With the product of embodiment 232B (56mg, 0.17mmol), bromotoluene (21mg, 0.17mmol) and salt of wormwood (26mg, 0.19mmol) mixture in DMF (1mL) was in stirring at room 15 hours.Be poured on reaction mixture on ice next day, and solid filtering is collected, and obtains this title compound (62mg, 100%).

Embodiment 233b

Method according to embodiment 1g, product (30mg with embodiment 1d, 0.17mmol) in ethanol (1mL) with the product (62mg of embodiment 233a, 0.17mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (24mg, 47%).

^1HNMR(300MHz，DMSO-d ₆)δ?ppm:2.02(s，3H)2.75(s，3H)5.15(s，2H)6.29(d，J＝7.35Hz，1H)7.12(d，J＝8.82Hz，2H)7.16-7.27(m，2H)7.29·7.52(m，8H)7.78(d，J＝8.82Hz，1H)8.36(d，J＝6.99Hz，1H)8.94(d，J＝8.82Hz，1H)9.97(s，1H)11.00(s，1H)14.34(s，1H)；MS(ESI+)m/z?507(M+H)+.

Embodiment 234

N-{4-[4-(2-methyl-allyl group oxygen base)-2-(7-methyl-[1,8] naphthyridine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 234a

N-{4-[2-amino-4-(2-methyl-allyl group oxygen base)-phenyl sulfenyl]-phenyl }-ethanamide

With the product of embodiment 232B (56mg, 0.17mmol), 2-methyl-3-bromopropylene (20mg, 0.17mmol) and salt of wormwood (26mg, 0.19mmol) mixture in DMF (1mL) was in stirring at room 15 hours.Be poured on reaction mixture on ice next day, and solid filtering is collected, and obtains this title compound (55mg, 100%).

Embodiment 234b

Method according to embodiment 1g, product (30mg with embodiment 1d, 0.17mmol) with the product (55mg of embodiment 234a, 0.17mmol) in ethanol (1mL), reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (12mg, 25%).

¹HNMR(300MHz，DMSO-d ₆)δ?ppm:1.76(s，3H)2.02(s，3H)，2.75(s，3H)，4.52(s，2H)，4.98(s，1H)，5.05(s，1H)，6.30(d，J＝7.35Hz，1H)，7.04-7.19(m，4H)，7.36(s，1H)，7.41(d，J＝8.46Hz，2H)7.78(d，J＝8.82Hz，1H)，8.37(d，J＝6.99Hz，1H)，8.94(d，J＝8.46Hz，1H)9.97(s，1H，)10.99(s，1H)，14.33(s，1H)；MS(ESI+)m/z?471(M+H)+.

Embodiment 235

N-{4-[2-(7-methyl-[1,8] naphthyridine-4-base is amino)-4-propoxy--phenyl sulfenyl]-phenyl }-ethanamide

Embodiment 235a

N-[4-(2-amino-4-propoxy--phenyl sulfenyl)-phenyl]-ethanamide

With the product of embodiment 232B (56mg, 0.17mmol), 2-methyl-3-bromopropylene (20mg, 0.17mmcS) and salt of wormwood (26mg, 0.19mmole) mixture in DMF (1mL) was in stirring at room 15 hours.Be poured on reaction mixture on ice next day, and solid filtering is collected, and obtains this title compound (55mg, 100%).

Embodiment 235b

Method according to embodiment 1g, product (30mg with embodiment 1d, 0.17mmol) at the product (55mg of ethanol (1mL) with embodiment 235a, 0.17mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (14mg, 30%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.97(t，J＝7.35Hz，3H)1.59-1.83(m，2H)2.02(s，3H)2.75(s，3H)3.97(t，J＝6.43Hz，2H)6.31(d，J＝7.35Hz，1H)7.04-7.18(m，4H)7.25-7.45(m，J＝8.64，3.86Hz，3H)7.77(d，J＝8.46Hz，1H)8.35(d，J＝7.35Hz，1H)8.94(d，J＝8.82Hz，1H)9.96(s，1H)10.99(s，1H)14.31(s，1H)；MS(ESI+)m/z?459(M+H)+.

Embodiment 236

4-[4-(4-acetylamino-phenyl sulfenyl)-3-(7-propyl group-[1,8] naphthyridine-4-base is amino)-phenoxymethyl]-methyl benzoate

Embodiment 236a

4-[4-(4-acetylamino-phenyl sulfenyl)-3-amino-phenoxymethyl]-methyl benzoate

With the product of embodiment 232B (28mg, 0.085mmol), 4-methoxycarbonyl bromotoluene (22mg, 0.096mmol) and salt of wormwood (13mg, 0.09mmol) mixture in DMF (1mL) was in stirring at room 15 hours.Be poured on reaction mixture on ice next day, and solid filtering is collected, and obtains this title compound (35mg, 100%).

Embodiment 236b

Method according to embodiment 1g, product (18mg with embodiment 1d, 0.085mmol) in ethanol (1mL) with the product (35mg of embodiment 236a, 0.085mmol) reacted 18 hours, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, the acquisition product is trifluoroacetate (22mg, 37%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:0.97(t，J＝7.35Hz，3H)1.75-1.93(m，2H)，2.02(s，3H)，2.99(t，J＝7.54Hz，2H)，3.86(s，3H)5.26(s，2H)6.30(d，J＝6.99Hz，1H)7.14(d，J＝8.82Hz，2H)，7.17-7.27(m，2H)，7.37(d，J＝8.46Hz，1H)，7.42(d，J＝8.82Hz，2H)，7.59(d，J＝8.46Hz，2H)，7.80(d，J＝8.46Hz，1H)7.99(d，J＝8.09Hz，2H)，8.36(d，J＝7.35Hz，1H)，8.97(d，J＝8.46Hz，1H)9.98(s，1H)，11.01(s，1H)，14.38(s，1H)；MS(ESI+)m/z?593(M+H)+.

Embodiment 237

4-[4-(4-methoxyl group-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol

Embodiment 237A

2-amino-6-methyl-cigarette nitrile

With 2-chloro-6-methyl-cigarette nitrile (25g, 0.164mol) and liquefied ammonia (250mL) in 500mL ethanol the sealing high pressure vessel in 130 ℃ the reaction 20 hours.Reaction mixture is concentrated under vacuum, and with resistates with (2 x 50mL) washing, in vacuum chamber dry 24 hours then, obtain this title compound, be light yellow solid (18g, 82%).

¹HNMR(300MHz，DMSO-d ₆)δ?ppm:2.30(s，3H)，6.52(d，J＝7.7Hz，1H)，6.78(s，2H)，7.73(d，J＝7.7Hz，1H).

Embodiment 237B

N '-(3-amino-6-methyl-pyridine-2-yl)-N, N-dimethyl-carbonamidine

With the product of embodiment 237A (10g, 75.19mmol) and N, dinethylformamide dimethyl acetal (11mL, the 82.71mmol) heating 6 hours under refluxing of the solution in toluene (100mL).After being cooled to room temperature, solution is concentrated under vacuum, obtain this title compound, be yellow solid (13.78g, 98%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:2.41(s，3H)，3.06(s，3H)，3.14(s，3H)，6.87(d，J＝7.7Hz，1H)，7.89(d，J＝8.1Hz，1H)，8.59(s，1H).

Embodiment 237C

1-chloro-4-(4-methoxyl group-benzyloxy)-2-nitro-benzene

With 4-chloro-3-nitro-phenol (0.5g, 2.88mmol), 1-chloromethyl-4-methoxyl group-benzene (0.496g, 3.17mmol), salt of wormwood (1.19g, 8.64mmol) and tetrabutylammonium iodide (0.005g, 0.0135mmol) at N, dinethylformamide (5ml) was in stirring at room 16 hours.Then frozen water (10mL) is added in this solution, filters and collect the gained solid, and dry in vacuum chamber, obtain this title compound (0.812g, 96%).

Embodiment 237D

4-[4-(4-methoxyl group-benzyloxy)-2-nitro-phenyl sulfenyl]-phenol

With the product of embodiment 237C (0.812g, 2.76mmol), the 4-hydroxythiophenol (0.419,3.32mmol) and cesium carbonate (2.16g is 6.64mmol) at N ₁Solution in the dinethylformamide (5mL) be heated to 100 ℃ 16 hours.After being cooled to room temperature, mixture is poured in the frozen water (20mL), gained solution 1N hcl acidifying.(3 x 10mL) extracts this solution with ethyl acetate, and the extract dried over mgso of merging is filtered and concentrated under vacuum, obtains this title compound (1.06g, 100%).

Embodiment 237E

4-[2-amino-4-(4-methoxyl group-benzyloxy)-phenyl sulfenyl]-phenol

With the solution of the product of embodiment 237D (1.06g, 2.76mmol), iron powder (0.63g, 11.04mmol) and ammonium chloride (0.18g 3.31mmol) is heated in methyl alcohol (18mL), tetrahydrofuran (THF) (18mL) and water (6mL) solution and refluxed 3 hours.The gained mixture dilutes with methyl alcohol (50mL), and filters by Celite pad.Filtrate is concentrated into the volume of 10mL under vacuum, with this solution with water (50mL) dilution, with ethyl acetate (2 x 50mL) extraction.The extract dried over mgso that merges is filtered and is concentrated under vacuum, obtains this title compound (0.99g, 100%).

Embodiment 237F

With the product of embodiment 237B (28.4mg, 0.151mmol) and the product of embodiment 237E (53.3mg, 0.151mmol) solution was preheating to 130 ℃ the oil bath stirring 20 minutes in acetate (1mL).Then mixture is cooled to room temperature, under vacuum, removes acetate, and the gained resistates is developed with methyl alcohol, obtain this title compound, be brown solid (26.5mg, 35%).

¹H?NMR(300MHz，DMSO-d ₆)δ?ppm:9.92(s，1H)，9.63(s，1H)，8.70(d，J＝8.09Hz，1H)，8.55(s，1H)，7.52(d，J＝8.46Hz，1H)，7.38(d，J＝8.82Hz，2H)，7.27(s，1H)，7.06-7.18(m，3H)，6.94(d，J＝8.46Hz，3H)，6.61-6.72(m，2H)，5.02(s，2H)，3.75(s，3H)，2.66(s，3H)；MS(ESI+)m/z?497.2(M+H)+，(ESI-)m/z?495.3(M-H)-.

Biological evaluation

Analyze representative compounds of the present invention according to the measuring method that describes below.

Use following initial abbreviation:

IC ₅₀50% inhibition concentration

TC ₅₀50% poisoning concentration

The improved dulbecco minimum essential medium Dulbecco of DMEM Dulbecco ^TM

RNA Yeast Nucleic Acid

The RT-PCR reverse transcriptase-polymerase chain reaction

SEAP excretory alkaline phosphatase

The polyprotein that the hepatitis c virus gene group coding is big, after processing, polyprotein produces synthon for the necessary functional component of RNA.The optional cell that produces the subgene group HCV RNA (replicon) of high and lasting level is a derived from human hepatoma cells (Huh7), as people such as Ikeda, and J.

, 76 (6): people such as 2997-3006 (2002) and Blight,

, described in the 290:1972-1974 (2000).In the clone mechanism of rna replicon be considered to the liver cell that infects in total length HCV duplicate identical.The compounds of this invention is the HCV rna replicon inhibitor in the following replicon mensuration system.

The assessment of HCV inhibitor in the HCV replicon

Assess the restraining effect of representative compounds of the present invention for HCV genotype 1a and 1b replicon.Also measure and assessed the cytotoxicity of representative compounds of the present invention for host cell by MTT.By people such as Yi, , 304 (2): the method for describing among the 197-210 (2002) keeps clone.

A.RNA measures and SEAP measures

The purpose of these mensuration is the effectiveness that the assessment compound duplicates at vitro inhibition HCV genotype 1a and 1b.

With genotype 1a and/or 1b replicon cell in containing the DMEM substratum of 5% foetal calf serum with 3-5 * 10 ³Individual cells/well is layered in the flat board of 96-hole.Second day, take out substratum, and replace with the fresh culture of the compound that contains 8 serial dilutions.Untreated control cultures is handled in the same manner, but in substratum, do not added inhibitor.With flat board at CO ₂In the incubator in 37 ℃ of cultivations.At the 4th day, behind the taking-up substratum, in each hole, add 100 μ l lysis buffers (RTL) (Qiagen).Introduction (Qiagen RNAeasy) according to the manufacturer comes purifying RNA, and in 200 μ l water wash-out.By the real-time RT-PCR method, come quantitative assay HCV rna level from a part (5 μ l in the middle of the 200 μ l) purifying RNA.Primer and the source probe specific sequence in 5 '-untranslated zone (5 ' UTR).RT-PCR is reflected at 48 ℃ to carry out 30 minutes, carried out 40 following cycles then and set: 95 ℃, and 15s; 54 ℃, 30s; With 72 ℃, 40s.Perhaps, cultivate 4 days with compound after, measure the activity of SEAP in each culture supernatants according to manufacturer's specification sheets.Calculate HCV RNA or the minimizing per-cent of SEAP in the presence of compound, (San Diego CA), calculates 50% inhibition concentration (IC by nonlinear regression analysis for 4.0 versions, GraphPad software to use Prism program ₅₀).

When using aforesaid method to measure, representative compounds of the present invention is with the IC of about 30nM to about 100 μ M ₅₀Value suppresses duplicating of HCV replicon.

B. cytotoxic assay

The purpose of this mensuration is to determine that compound is in external toxicity for the virus host cell.

In the replicon cell, use the cytotoxicity of measuring compound based on the cell proliferation/viability of cyclophorase.In brief, with HCV replicon cell in containing the DMEM substratum of 5% FCS with 3-5 * 10 ³Individual cells/well is layered in the flat board of 96-hole.At the 1st day, take out substratum, and replace with the fresh culture of the compound that contains 8 serial dilutions.Untreated control cultures is handled in the same manner, but in substratum, do not added inhibitor.With flat board at CO ₂In the incubator in 37 ℃ of cultivations.At the 4th day, in each hole, add the stock solution (solution of 4mg/ml in PBS, Sigma cat.# M 2128) of tetrazolium salts MTT with 25 μ l/ holes.Flat board was further cultivated 4 hours, added 0.02 N HCl with 20% SDS and handle with lysing cell with 50 μ l/ holes.After the overnight incubation, measure optical density(OD) by reading flat board at the 570/650nm wavelength.Calculate the first that forms

Blue reduction per-cent with respect to contrast, and (San Diego CA), calculates 50% toxic concentration (TC by nonlinear regression analysis for 4.0 versions, GraphPad software to use Prism program ₅₀).

When using aforesaid method to measure, the TC50 value of representative compounds of the present invention is greater than the corresponding IC of these compounds ₅₀Value.

Pharmaceutical composition and application

The present invention relates to comprise the pharmaceutical composition of The compounds of this invention.As limiting examples, pharmaceutical composition of the present invention comprises one or more The compounds of this invention, and wherein each compound is independently selected from formula I (a), I (b), II (a) or II (b) compound.Preferably, each compound is independently selected from the compound of embodiment 1-237.

The invention still further relates to the pharmaceutical composition of the pharmacologically acceptable salt, solvate or the prodrug that comprise The compounds of this invention.Pharmacologically acceptable salt can be a zwitter-ion or can be derived from pharmaceutically acceptable inorganic or organic acid or alkali.Preferably, the pharmacologically acceptable salt of The compounds of this invention keeps the biological effectiveness of the compound of free acid or alkali form, there are not unsuitable toxicity, pungency or anaphylaxis simultaneously, have rational profit/danger than, using for its purpose is effectively, and does not have disadvantageous biotic influence or other undesirable influences.The limiting examples of pharmacologically acceptable salt includes but not limited to following: acetate, adipate, alginate, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulphite, butyrates, camphorate, camsilate, digluconate, cyclopentane propionate, dodecyl sulfate, esilate, gluceptate, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, 2-isethionate (isethionate), lactic acid salt, maleate, mesylate, nicotinate, the 2-naphthalenesulfonate, oxalate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, thiocyanate-, tosilate and hendecoic acid salt.The alkalescence nitrogen-containing group can also be with for example following reagent is quaternized: elementary alkyl halide (for example methyl, ethyl, propyl group or butyl muriate, bromide or iodide), dialkyl sulfate (for example dimethyl, diethyl, dibutyl or diamyl vitriol), long-chain halogenide (for example decyl, lauryl, myristyl or stearyl chlorination thing, bromide or iodide), aralkyl halide (for example benzyl or styroyl bromination thing).Can be used for other salt of the present invention and comprise and basic metal or the alkaline-earth metal salt that forms of sodium, potassium, calcium or magnesium for example, perhaps the salt that forms with organic bases.The example that can be used for forming the acid of pharmaceutically acceptable acid additive salt includes but not limited to hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, succsinic acid, citric acid or other suitable inorganic or organic acids.

The invention still further relates to the pharmaceutical composition that comprises The compounds of this invention (or its salt, solvate or prodrug) and another therapeutical agent.In limiting examples, pharmaceutical composition of the present invention comprises a kind of, two kinds, three kinds or more kinds of The compounds of this invention (or its salt, solvate or prodrug) and a kind of, two kinds, three kinds or more kinds of other treatment agent.Such as but not limited to, these other treatment agent can be selected from antiviral agent (for example anti-HIV agent or other whose anti-HCV agent), immunomodulator, carcinostatic agent or chemotherapeutics or anti-inflammatory agent.The specific examples of these other treatment agent includes but not limited to ribavirin; Interferon, rabbit (for example IFN α 2a or 2b); Proteinase inhibitor; Immunosuppressor; Antibody (for example therapeutic monoclonal antibodies or chimeric antibody); Antisense or siRNA; Hiv inhibitor; Hepatitis B (HBV) inhibitor; The medicine that is used for the treatment of liver cirrhosis and liver inflammation; Omega IFN (BioMedicines Inc., Emeryville, CA); The BILN-2061 serpin (Boehringer Ingelheim Pharma KG, Ingelheim, Germany); The Summetrel antiviral agent (Endo Pharmaceuticals Holdings Inc., Chadds Ford, PA); Roferon AIFN-α 2a (F.Hoffmann-La Roche LTD, Basel, Switzerland); PegasysPEGylated IFN-α 2a (F.Hoffmann-La Roche LTD, Basel, Switzerland); Pegasys and ribavirin PEGylated IFN-α 2a/ ribavirin (F.Hoffmann-La RocheLTD, Basel, Switzerland); CellCept HCV IgG immunosuppressor (F.Hoffmann-LaRoche LTD, Basel, Switzerland); Wellferon lymphoblastoid IFN-α n1 (GlaxoSmithKline plc, Uxbridge, UK); Albuferon-α albumin IFN-α 2b (Human Genome Sciences Inc., Rockville, MD); The Levovirin ribavirin (ICNPharmaceuticals, Costa Mesa, CA); IDN-6556 caspase inhibitor (IdunPharmaceuticals Inc., San Diego, CA); The agent of IP-501 fibrosis (IndevusPharmaceuticals Inc., Lexington, MA); Actimmune INF-γ (InterMune Inc., Brisbane, CA); Infergen A IFN alfacon-1 (InterMune Pharmaceuticals Inc., Brisbane, CA); ISIS 14803 antisenses (ISIS Pharmaceuticals Inc., Carlsbad, CA/Elan Pharmaceuticals Inc., New York, NY); JTK-003 RdRp inhibitor (Japan Tobacco Inc., Tokyo, Japan); Pegasys and Ceplene PEGylated IFN-α 2a/ immunomodulator (Maxim Pharmaceuticals inc., San Diego, CA); The Ceplene immunomodulator (Maxim Pharmaceuticals Inc., San Diego, CA); Civacir HCV IgG immunosuppressor (Nabi Biopharmaceuticals Inc., Boca Raton, FL); Intron A and Zadaxin IFN-α 2b/ α 1-thymosin (RegeneRx Biopharmiceuticals Inc., Bethesda, MD/SciClone Pharmaceuticals Inc., San Mateo, CA); Levovirin IMPDH inhibitor (Ribapharm Inc., Costa Mesa, CA); Viramidine IMPDH inhibitor (Ribapharm Inc., Costa Mesa, CA); The Heptazyme ribozyme (RibozymePharmaceuticals Inc., Boulder, CO); Intron A IFN-α 2b (Schering-PloughCorporation, Kenilworth, NJ); PEG-Intron PEGylated IFN-α 2b (Schering-Plough Corporation, Kenilworth, NJ); Rebetron IFN-α 2b/ ribavirin (Schering-Plough Corporation, Kenilworth, NJ); Ribavirin (Schering-Plough Corporation, Kenilworth, NJ); PEG-Intron/ ribavirin PEGylated IFN-α 2b/ ribavirin (Schering-Plough Corporation, Kenilworth, NJ); The Zadazim immunomodulator (SciClone Pharmaceuticals Inc., San Mateo, CA); Rebif IFN-β 1a (Serono, Geneva, Switzerland); IFN-β and EMZ701 IFN-β and EMZ701 (Transition Therapeutics Inc., Ontario, Canada); T67 'beta '-tubulin inhibitor (Tularik Inc., South San Francisco, CA); VX-497 IMPDH inhibitor (Vertex Pharmaceuticals Inc., Cambridge, MA); The VX-950/LY-570310 serpin (Vertex Pharmaceuticals Inc., Cambridge, MA/Eli Lillyand Co., Inc., Indianapolis, IN); The natural IFN-α of Omniferon (Viragen Inc., Plantation, FL); XTL-002 monoclonal antibody (XTL Biopharmaceuticals); (compound VX-950 hereinafter, VertexPharmaceuticals Inc.);

(compound S CH503034 hereinafter, Schering-Plough Co.); With

(compound GS9137 hereinafter, Gilead Sciences, Inc., Foster City, CA).Can also comprise any other required therapeutical agent in the pharmaceutical composition of the present invention.

In one embodiment, pharmaceutical composition of the present invention comprises one or more The compounds of this invention (or its salt, solvate or prodrug) and one or more other antiviral agents.

In another embodiment, pharmaceutical composition of the present invention comprises one or more The compounds of this invention (or its salt, solvate or prodrug) and one or more other whose anti-HCV agent.In an example, each The compounds of this invention is independently selected from the compound of formula I (a), I (b), II (a) or II (b) compound or embodiment 1-237, and each other whose anti-HCV agent is independently selected from HCVRNA RNA-dependent AG14361 (for example ucleosides or non-nucleosides type AG14361), HCV proteinase inhibitor or HCV helicase inhibitor.

In another embodiment, pharmaceutical composition of the present invention comprises one or more The compounds of this invention (or its salt, solvate or prodrug) and two or more other whose anti-HCV agent.Preferably, each The compounds of this invention is independently selected from the compound of formula I (a), I (b), II (a) or II (b) compound or embodiment 1-237.Other whose anti-HCV inhibitor can be selected from identical inhibitor classification (for example all they be selected from HCV RNA RNA-dependent AG14361 or be selected from the HCV proteinase inhibitor) or be selected from different inhibitor classification (for example one or more are selected from HCVRNA RNA-dependent AG14361, other be selected from the HCV proteinase inhibitor).

In another embodiment, pharmaceutical composition of the present invention comprises at least a The compounds of this invention (or its salt, solvate or prodrug) and at least a HCV RNA RNA-dependent AG14361.Preferably, each The compounds of this invention is independently selected from the compound of formula I (a), I (b), II (a) or II (b) compound or embodiment 1-237.

In another embodiment, pharmaceutical composition of the present invention comprises at least a The compounds of this invention (or its salt, solvate or prodrug) and at least a HCV proteinase inhibitor.Preferably, each The compounds of this invention is selected from the compound of formula I (a), I (b), II (a) or II (b) compound or embodiment 1-237.

In another embodiment, pharmaceutical composition of the present invention comprises at least a The compounds of this invention (or its salt, solvate or prodrug), at least a HCV RNA RNA-dependent AG14361 and at least a HCV proteinase inhibitor.Preferably, The compounds of this invention is selected from the compound of formula I (a), I (b), II (a) or II (b) compound or embodiment 1-237.

In another embodiment, pharmaceutical composition of the present invention comprises at least a The compounds of this invention (or its salt, solvate or prodrug) and two or more whose anti-HCV agent, and each described whose anti-HCV agent is independently selected from HCV RNA RNA-dependent AG14361 or HCV proteinase inhibitor.Preferably, The compounds of this invention is selected from the compound of formula I (a), I (b), II (a) or II (b) compound or embodiment 1-237.

In another embodiment, pharmaceutical composition of the present invention comprises at least a The compounds of this invention (or its salt, solvate or prodrug) and three kinds or multiple other whose anti-HCV agent, and each described other whose anti-HCV agent is independently selected from HCV RNA RNA-dependent AG14361 or HCV proteinase inhibitor.Preferably, The compounds of this invention is selected from the compound of formula I (a), I (b), II (a) or II (b) compound or embodiment 1-237.

The limiting examples of HCV RNA RNA-dependent AG14361 is included in those that describe among WO0190121 (A2), US6348587B1, WO0160315, WO0132153, EP1162196A1 and the WO0204425.The limiting examples of HCV proteinase inhibitor comprises BILN-2061, VX-950 and SCH503034.

In another embodiment, pharmaceutical composition of the present invention comprises at least a The compounds of this invention (or its salt, solvate or prodrug) and for example anti--HBV or the anti-HIV agent of one or more other antiviral agents.The limiting examples of anti--HBV agent comprises Adefovir, lamivudine and tenofovir.The limiting examples of anti-HIV medicine comprise ritonavir, lopinavir, that Wei of indoles, viracept see nelfinaivr, Saquinavir, amprenavir, atazanavir, for Pune's Wei, TMC-114, fosamprenavir, zidovudine, lamivudine, Didanosine, stavudine, tenofovir, zalcitabine, A Bokawei, Yi Feiweilun, nevirapine, La Weiding, TMC-125, L-870812, S-1360, enfuvirtide, T-1249, and other hiv proteases, reversed transcriptive enzyme, intergrase or fusion inhibitor.As skilled in the art to understand, can also comprise other required antiviral agents in the pharmaceutical composition of the present invention.

In one embodiment, pharmaceutical composition of the present invention comprises at least a The compounds of this invention or its salt, solvate or prodrug and at least a the resisting-the HBV agent that is selected from formula I (a), I (b), II (a) or II (b) compound or embodiment 1-237 compound.In another embodiment, pharmaceutical composition of the present invention comprises at least a The compounds of this invention or its salt, solvate or prodrug and at least a anti-HIV agent that is selected from formula I (a), I (b), II (a) or II (b) compound or embodiment 1-237 compound.In another embodiment, pharmaceutical composition of the present invention comprises at least a The compounds of this invention or its salt, solvate or prodrug and at least a anti-hepatitis A (hepatitis A) agent, fight against press-ganging type hepatitis (hepatitis D) agent, (hepatitis E) agent of anti-hepatitis E or anti-hepatitis G (hepatitis G) agent that is selected from formula I (a), I (b), II (a) or II (b) compound or embodiment 1-237 compound.

In another embodiment, pharmaceutical composition of the present invention comprises at least a The compounds of this invention or its salt, solvate or prodrug and at least a medicine that is suitable for treating the liver inflammation that is selected from formula I (a), I (b), II (a) or II (b) compound or embodiment 1-237 compound.

Pharmaceutical composition of the present invention comprises pharmaceutically acceptable carrier or vehicle usually.The limiting examples of suitable pharmaceutically acceptable carrier/vehicle comprises sugar (lactose for example, glucose or sucrose), starch (for example W-Gum or yam starch), Mierocrystalline cellulose or derivatives thereof (Xylo-Mucine for example, ethyl cellulose or cellulose acetate), oils (peanut oil for example, Oleum Gossypii semen, Thistle oil, sesame oil, sweet oil, Semen Maydis oil or soybean oil), glycols (for example propylene glycol), buffer reagent (for example magnesium hydroxide or aluminium hydroxide), agar, alginic acid, tragacanth gum powder, Fructus Hordei Germinatus, gelatin, talcum powder, theobroma oil, the water that does not contain pyrogen, isotonic saline solution, Ringer's solution, ethanol or phosphate buffered saline buffer.As skilled in the art to understand, pharmaceutical composition of the present invention can also comprise lubricant, tinting material, releasing agent, Drug coating, sweeting agent, correctives or spices, sanitas or antioxidant.

Pharmaceutical composition of the present invention can be via number of ways, for example oral, parenteral, hypogloeeis, rectum, part or introduce spraying and come patient's administration to there being this to need.Topical can comprise that the use percutaneous dosing is for example through skin patch or Iontophoretic device.That parenteral admin includes but not limited to is subcutaneous, intravenously, intramuscular or breastbone inner injection, and infusion techniques.

Pharmaceutical composition of the present invention can use method well-known in the art to prepare based on its route of administration.For example, can use suitable dispersion agent or wetting agent and suspension agent aseptic injection preparation to be made the form of sterile injectable water or oil suspension.The suppository that is used for rectal administration can make like this: for example theobroma oil or polyoxyethylene glycol mix with medicine and suitable non-irritating excipient, described vehicle is solid at normal temperatures, but in rectal temperature is liquid, will and discharge medicine in the internal rectum fusing thus.The solid dosage that is used for oral administration can be capsule, tablet, pill, pulvis or granula.I in such solid dosage can for example sucrose, lactose or starch mix with at least a inert diluent with active compound.Handle beyond the inert diluent, solid dosage can also comprise for example lubricant of other materials.For capsule, tablet and pill, formulation can also comprise buffer reagent.Tablet and pill also can be used the enteric coating dressing.The liquid dosage form that is used for oral administration can comprise pharmaceutical acceptable emulsion, solution, suspension, syrup or elixir, and it contains this area inert diluent commonly used.Liquid dosage form can also comprise wetting agent, emulsifying agent, suspension agent, sweeting agent, correctives or fragrance material.Pharmaceutical composition of the present invention can also be with the liposome form administration as describing in U.S. patent 6,703,403.Be applied to pharmaceutical preparation of the present invention generally at for example Hoover, John E.,

(Mack Publishing Co., Easton, PA:1975), and and Lachman, L, eds.,

Discuss in (Marcel Decker, New York, N.Y., 1980).

The invention still further relates to and use The compounds of this invention (or its salt, solvate or prodrug) to suppress the method that HCV duplicates.In one embodiment, the inventive method comprises HCV virus is contacted with the The compounds of this invention (or its salt, solvate or prodrug) of significant quantity, suppresses duplicating of HCV virus thus.In another embodiment, the inventive method comprises and contacting with the The compounds of this invention of significant quantity (or its salt, solvate or prodrug) having infected the cell of HCV virus, suppresses HCV virus duplicating in cell thus.In another embodiment, the inventive method comprises that the cell with HCV virus or infection contacts with two or more The compounds of this invention (or its salt, solvate or prodrug) of significant quantity, suppresses duplicating of HCV virus thus." inhibition " used herein is meant remarkable reduction or eliminates repressed activity (for example virus replication).Under many circumstances, representative compounds of the present invention can reduce at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more with duplicate (for example in aforesaid HCV replicon is measured) of HCV virus.

The compounds of this invention can suppress all HCV hypotypes.The example of the HCV hypotype that can suppress by the present invention includes but not limited to HCV hypotype 1,2,3,4,5 and 6, comprises HCV genotype 1a, 1b, 2a, 2b, 2c or 3a.In one embodiment, use The compounds of this invention (or its salt, solvate or prodrug) to suppress duplicating of HCV genotype 1a.In another embodiment, use The compounds of this invention (or its salt, solvate or prodrug) to suppress duplicating of HCV genotype 1b.In another embodiment, use The compounds of this invention (or its salt, solvate or prodrug) to suppress duplicating of HCV genotype 1a and 1b.

The invention still further relates to and use The compounds of this invention (or its salt, solvate or prodrug) to treat the method that HCV infects.These methods generally include to the The compounds of this invention of HCV patient's administering therapeutic significant quantity (or its salt, solvate or prodrug), to reduce the HCV virus levels in blood samples of patients or the liver thus.Term used herein " treatment " is meant reverse, alleviate, suppress this term at disease or one or more symptoms of illness or disease or illness, the progress that suppresses one or more symptoms of disease or illness or disease or illness, perhaps one or more symptoms of preventing disease or illness or disease or illness.Term " treatment " is meant therapeutic action.In one embodiment, in one embodiment, these methods comprise to two or more The compounds of this invention of HCV patient's administering therapeutic significant quantity (or its salt, solvate or prodrug), to reduce the HCV virus levels in blood samples of patients or the liver thus.Preferably, the compound that uses in these methods is selected from the compound of formula I (a), I (b), II (a) or II (b) compound or embodiment 1-237, or its salt, solvate or prodrug.

In yet another aspect, the present invention relates to use pharmaceutical composition of the present invention to treat the method that HCV infects.Any pharmaceutical composition of Miao Shuing can use at this purpose herein.These methods generally include the pharmaceutical composition of the present invention to HCV patient's administering therapeutic significant quantity, to reduce the HCV virus levels in blood samples of patients or the liver thus.When pharmaceutical composition comprised the other treatment agent, it can also treat other diseases, obstacle or illness among the patient.

In one embodiment, the pharmaceutical composition of using comprises at least a The compounds of this invention or its salt, solvate or the prodrug that is selected from formula I (a), I (b), II (a) or II (b) compound or embodiment 1-237 compound, with at least a other whose anti-HCV agent, described other whose anti-HCV agent are selected from HCV RNA RNA-dependent AG14361, HCV proteinase inhibitor or HCV helicase inhibitor.In another embodiment, the pharmaceutical composition of using comprises at least a The compounds of this invention or its salt, solvate or the prodrug that is selected from formula I (a), I (b), II (a) or II (b) compound or embodiment 1-237 compound, with a kind of, two or more HCV RNA RNA-dependent AG14361 (for example those that describe among WO0190121 (A2), US6348587B1, WO0160315, WO0132153, EP1162196A1 and the WO0204425).In another embodiment, the pharmaceutical composition of using comprises at least a The compounds of this invention or its salt, solvate or the prodrug that is selected from formula I (a), I (b), II (a) or II (b) compound or embodiment 1-237 compound, with a kind of, two or more HCV proteinase inhibitor (for example BILN-2061, VX-950 and SCH503034).

In another embodiment, the pharmaceutical composition of using comprises at least a The compounds of this invention that is selected from formula I (a), I (b), II (a) or II (b) compound or embodiment 1-237 compound or its salt, solvate or prodrug and at least aly is selected from following antiviral agent: anti-HIV agent, anti--the HBV agent, anti-hepatitis A agent, the agent of fight against press-ganging type hepatitis, anti-hepatitis E agent or anti-hepatitis G agent.

In yet another aspect, the invention provides use The compounds of this invention and other therapeutical agent and treat the method that HCV infects.These methods comprise to the The compounds of this invention of HCV patient's administering therapeutic significant quantity and other therapeutical agent, to reduce the HCV virus levels in blood samples of patients or the liver thus.Each The compounds of this invention (or its salt, solvate or prodrug) can merge in unitary agent with the other treatment agent, and to patient's administration simultaneously.They can also administration simultaneously in different preparations.In addition, they can the order administration.

In one embodiment, the The compounds of this invention of using comprises that one or more are selected from compound or its salt, solvate or the prodrug of formula I (a), I (b), II (a) or II (b) compound or embodiment 1-237 compound, and the other treatment agent of using comprises that one or more are selected from the promoting agent of HCVRNA RNA-dependent AG14361, HCV proteinase inhibitor or HCV helicase inhibitor.In another embodiment, the The compounds of this invention of using comprises that one or more are selected from compound or its salt, solvate or the prodrug of formula I (a), I (b), II (a) or II (b) compound or embodiment 1-237 compound, and the other treatment agent of using comprises that two or more are selected from the promoting agent of HCV RNA RNA-dependent AG14361, HCV proteinase inhibitor or HCV helicase inhibitor.In another embodiment, the The compounds of this invention of using comprises that one or more are selected from compound or its salt, solvate or the prodrug of formula I (a), I (b), II (a) or II (b) compound or embodiment 1-237 compound, and the other treatment agent of using comprises a kind of, two or more HCV RNA RNA-dependent AG14361 (for example those that describe among WO0190121 (A2), US6348587B1, WO0160315, WO0132153, EP1162196A1 and the WO0204425).In another embodiment, the The compounds of this invention of using comprises that one or more are selected from compound or its salt, solvate or the prodrug of formula I (a), I (b), II (a) or II (b) compound or embodiment 1-237 compound, and the other treatment agent of using comprises a kind of, two or more HCV proteinase inhibitor (for example BILN-2061, VX-950 and SCH503034).

The compounds of this invention (or its salt, solvate or prodrug) can also with other for example anti-HIV agent of required medicine, anti--the HBV agent, anti-hepatitis A agent, the agent of fight against press-ganging type hepatitis, anti-hepatitis E agent or anti-hepatitis G agent or other antiviral Combined Preparation.

The compounds of this invention (or its salt, solvate or prodrug) can be with single dose or the dosage that separates to patient's administration.Typical per daily dose can for but be not limited to the 0.1-200mg/kg body weight, 0.25-100mg/kg body weight for example.Unit-dose composition can contain this tittle or its a plurality of inferior amounts constitute per daily dose.Preferably, each dosage contains the The compounds of this invention that can effectively reduce the capacity of HCV viral load in blood samples of patients or the liver.The amount of the active ingredient of preparation one-pack type or the active ingredient of merging can become according to host who is treated and t specific administration approach.Be to be understood that, for any concrete patient, concrete dosage level will depend on multiple factor, comprise activity, age, body weight, general health situation, sex, diet, administration time, route of administration, secretion speed, the drug regimen of used particular compound and the severity of the specified disease for the treatment of.

In yet another aspect, formula I (a), I (b), II (a) or II (b) compound or pharmaceutically acceptable salt thereof, steric isomer or tautomer can be used as independent pharmaceutically active agents administration, perhaps unite use, with treatment and relevant infection or the symptom of other viruses that contains RNA with one or more other promoting agents.

The infection that treatment or prevention are caused by the virus that contains RNA can provide by combination therapy, what first antiviral agent that is provided by one or more formulas I (a), I (b), II (a) or II (b) compound or its salt of treatment significant quantity and treatment significant quantity be provided in described combination therapy is selected from second promoting agent that following compound provides by one or more: other antiviral agent; The host immune conditioning agent; Interferon derivative, for example interferon-' alpha ', Pegylation (pegylated)-interferon-' alpha ', interferon-beta and interferon-; Cytokine; Vaccine; Nucleoside analog; The inhibitor that causes the handicapped key enzyme of HCV, the example of such enzyme are HCV metalloprotease, HCV serine protease, inosine list phosphate dehydrogenase (IMPDH) and HCV helicase; Virion albumen is HCV NS4B albumen and the proteic inhibitor of HCV NS5a for example; With the inhibition HCV function promoting agent that for example HCV enters, HCV assembles and HCV goes out.Also comprise vaccine, described vaccine comprises the antigen adjuvant combination of HCV antigen or anti-HCV.Also comprise with the host cell interaction between component with blocking virus albumen synthetic promoting agent, described promoting agent works by the translation steps of the HCV virus replication that inhibition internal ribosome entry site (IRES) starts, perhaps blocking virus particle maturation, and with the viroporin family of target membranin family for example the material of HCV P7 discharge.

In one embodiment, the present invention relates to the method for the infection treating or prevent to be caused by the virus that contains RNA, described method comprises to the formula I (a) of patient's administering therapeutic significant quantity of this treatment of needs, I (b), II (a) or II (b) compound or pharmaceutically acceptable salt thereof.

In another embodiment, the present invention relates to the method for the infection treating or prevent to be caused by the virus that contains RNA, described method comprises to co-administered one or more of the patient of this treatment of needs and is selected from the therapeutical agent of host immune conditioning agent and second antiviral agent or its combination and formula I (a), I (b), II (a) or II (b) compound or pharmaceutically acceptable salt thereof of treatment significant quantity.

In another embodiment, the present invention relates to the method for the infection treating or prevent to cause by the virus that contains RNA, described method comprises to co-administered one or more of the patient of this treatment of needs and is selected from interferon-' alpha ', Pegylation (pegylated)-interferon-' alpha ', interferon-beta, interferon-, cytokine, vaccine and comprises antigen and the therapeutical agent of the vaccine of adjuvant and second antiviral agent or its combination, with formula I (a), I (b), II (a) or II (b) compound or pharmaceutically acceptable salt thereof of treatment significant quantity.

In another embodiment, the present invention relates to the method for the infection treating or prevent to be caused by the virus that contains RNA, described method comprises to co-administered one or more of the patient of this treatment of needs and is selected from the host immune conditioning agent and suppresses second antiviral agent that HCV duplicates or the therapeutical agent and formula I (a), I (b), II (a) or II (b) compound or pharmaceutically acceptable salt thereof for the treatment of significant quantity of its combination by suppressing the host cell function relevant with virus replication.

In another embodiment, the present invention relates to the method for the infection treating or prevent to cause by the virus that contains RNA, described method comprises to the patient of this treatment of needs is co-administered can treat or alleviate the symptom that HCV infects, comprise the therapeutical agent or the therapeutical agent combination of liver cirrhosis and liver inflammation, with formula I (a), I (b), II (a) or II (b) compound or pharmaceutically acceptable salt thereof of treatment significant quantity.

In another embodiment, the present invention relates to the method for the infection treating or prevent to cause by the virus that contains RNA, described method comprises to co-administered one or more of the patient of this treatment of needs can treat the treatment of diseases agent that is caused by hepatitis B virus (HBV) infection among the patient, with formula I (a), I (b), II (a) or II (b) compound or pharmaceutically acceptable salt thereof of treatment significant quantity.

In another embodiment, the present invention relates to the method for the infection treating or prevent to cause by the virus that contains RNA, described method comprises to co-administered one or more of the patient of this treatment of needs can treat the treatment of diseases agent that is caused by human immunodeficiency virus (HIV) infection among the patient, with formula I (a), I (b), II (a) or II (b) compound or pharmaceutically acceptable salt thereof of treatment significant quantity.

Term " combination therapy " (or " combined therapy ") is intended to be included in uses each therapeutical agent in a sequential manner in the treatment plan, so that the beneficial effect of drug regimen to be provided, comprise also that with simultaneously co-administered these therapeutical agents of mode basically for example orally ingestible has the capsule of the separation of the single capsule of these therapeutical agents of fixed proportion or each therapeutical agent." combination therapy " also comprises by oral, intravenously, intramuscular or other parenteral approach and being administered to simultaneously or sequentially in the body, comprise as directly absorbing via mucosal tissue of existing in Dou Tongdao.The order administration also comprises drug regimen, wherein each therapeutical agent can come administration at different time and/or by different approaches, but combined action is to provide beneficial effect, for example is effective by the pharmacokinetics of each therapeutical agent or the combined action of pharmacokinetics effect.

The invention still further relates to The compounds of this invention or its pharmacologically acceptable salt, solvate or prodrug and be used for the treatment of application in HCV or other medicine for treating viral infections in preparation.In one embodiment, the The compounds of this invention that the present invention relates to be selected from formula I (a), I (b), II (a) or II (b) compound or its salt, solvate or prodrug is used for the treatment of application in the medicine that HCV infects in preparation.In another embodiment, the present invention relates to two or more The compounds of this invention (or its salt, solvate or prodrug) and be used for the treatment of application in the medicine that HCV infects in preparation, each of wherein said two or more compounds all is independently selected from formula I (a), I (b), II (a) or II (b) compound.

In another embodiment, the present invention relates at least a The compounds of this invention (or its salt, solvate or prodrug) and at least a other therapeutical agent and be used for the treatment of application in the medicine that HCV infects in preparation.Preferably, The compounds of this invention is selected from formula I (a), I (b), II (a) or II (b) compound, and other therapeutical agent can be selected from but is not limited to antiviral agent (for example anti-HIV agent or other whose anti-HCV agent), immunomodulator, carcinostatic agent or chemotherapeutics and anti-inflammatory agent.The specific examples of other therapeutical agent includes but not limited to ribavirin; Interferon, rabbit (for example IFN α 2a or 2b); Proteinase inhibitor; Immunosuppressor; Antibody antibody (for example therapeutic monoclonal antibodies or chimeric antibody); Antisense or siRNA; Hiv inhibitor; Hepatitis B (HBV) inhibitor; The medicine that is used for the treatment of liver cirrhosis and liver inflammation; Omega IFN (BioMedicines Inc., Emeryville, CA); The BILN-2061 serpin (Boehringer Ingelheim Pharma KG, Ingelheim, Germany); The Summetrel antiviral agent (Endo PharmaceuticalsHoldings Inc., Chadds Ford, PA); Roferon A IFN-α 2a (F.Hoffmann-LaRoche LTD, Basel, Switzerland); Pegasys PEGylated IFN-α 2a (F.Hoffmann-La Roche LTD, Basel, Switzerland); Pegasys and ribavirin PEGylated IFN-α 2a/ ribavirin (F.Hoffmann-La Roche LTD, Basel, Switzerland); CellCept HCV IgG immunosuppressor (F.Hoffmann-La Roche LTD, Basel, Switzerland); Wellferon lymphoblastoid IFN-α n1 (GlaxoSmithKlineplc, Uxbridge, UK); Albuferon-α albumin IFN-α 2b (Human GenomeSciences Inc., Rockville, MD); The Levovirin ribavirin (ICN Pharmaceuticals, Costa Mesa, CA); IDN-6556 caspase inhibitor (Idun Pharmaceuticals Inc., SanDiego, CA); The agent of IP-501 fibrosis (Indevus Pharmaceuticals Inc., Lexington, MA); Actimmune INF-γ (InterMune Inc., Brisbane, CA); Infergen A IFNalfacon-1 (InterMune Pharmaceuticals Inc., Brisbane, CA); ISIS 14803 antisenses (ISIS Pharmaceuticals Inc., Carlsbad, CA/Elan Pharmaceuticals Inc., NewYork, NY); JTK-003 RdRp inhibitor (Japan Tobacco Inc., Tokyo, Japan); Pegasys and Ceplene PEGylated IFN-α 2a/ immunomodulator (MaximPharmaceuticals inc., San Diego, CA); The Ceplene immunomodulator (MaximPharmaceuticals Inc., San Diego, CA); Civacir HCV IgG immunosuppressor (NabiBiopharmaceuticals Inc., Boca Raton, FL); Intron A and Zadaxin IFN-α 2b/ α 1-thymosin (RegeneRx Biopharmiceuticals Inc., Bethesda, MD/SciClonePharmaceuticals Inc., San Mateo, CA); Levovirin IMPDH inhibitor (Ribapharm Inc., Costa Mesa, CA); Viramidine IMPDH inhibitor (RibapharmInc., Costa Mesa, CA); The Heptazyme ribozyme (Ribozyme Pharmaceuticals Inc., Boulder, CO); Intron A IFN-α 2b (Schering-Plough Corporation, Kenilworth, NJ); PEG-Intron PEGylated IFN-α 2b (Schering-Plough Corporation, Kenilworth, NJ); Rebetron IFN-α 2b/ ribavirin (Schering-PloughCorporation, Keni lworth, NJ); Ribavirin (Schering-Plough Corporation, Kenilworth, NJ); PEG-Intron/ ribavirin PEGylated IFN-α 2b/ ribavirin (Schering-Plough Corporation, Kenilworth, NJ); The Zadazim immunomodulator (SciClone Pharmaceuticals Inc., San Mateo, CA); Rebif IFN-β 1a (Serono, Geneva, Switzerland); IFN-β and EMZ701 IFN-β and EMZ701 (TransitionTherapeutics Inc., Ontario, Canada); T67 'beta '-tubulin inhibitor (Tularik Inc., South San Francisco, CA); VX-497 IMPDH inhibitor (Vertex PharmaceuticalsInc., Cambridge, MA); The VX-950/LY-570310 serpin (VertexPharmaceuticals Inc., Cambridge, MA/Eli Lilly and Co., Inc., Indianapolis, IN); The natural IFN-α of Omniferon (Viragen Inc., Plantation, FL); XTL-002 monoclonal antibody (XTL Biopharmaceuticals); Compound VX-950 (VertexPharmaceuticals Inc.); Compound S CH503034 (Schering-Plough Co.); With compound GS9137 (Gilead Sciences, Inc., Foster City, CA).

In another embodiment, the present invention relates at least a The compounds of this invention (or its salt, solvate or prodrug) and at least a other antiviral agent and be used for the treatment of application in the medicine for treating viral infections in preparation.Preferably, The compounds of this invention is selected from formula I (a), I (b), II (a) or II (b) compound, and described other antiviral agent can be selected from but is not limited to whose anti-HCV or anti-HIV agent.In an example, the present invention relates at least a The compounds of this invention that is selected from formula I (a), I (b), II (a) or II (b) compound (or its salt, solvate or prodrug) and at least a other whose anti-HCV agent and be used for the treatment of application in the medicine that HCV infects in preparation.The limiting examples of whose anti-HCV agent comprises HCV RNA RNA-dependent AG14361 (for example nucleosides or non-nucleosides type AG14361) or HCV proteinase inhibitor.In another example, relate at least a be selected from the The compounds of this invention of formula I (a), I (b), II (a) or II (b) compound (or its salt, solvate or prodrug) and at least two or more other whose anti-HCV agent be used for the treatment of application in the medicine that HCV infects in preparation.Each described other whose anti-HCV agent can be independently selected from HCVRNA RNA-dependent AG14361 or HCV proteinase inhibitor.

In another embodiment, the present invention relates at least a The compounds of this invention that is selected from formula I (a), I (b), II (a) or II (b) compound (or its salt, solvate or prodrug) and at least a anti-HIV agent and be used for the treatment of application in the medicine that HIV or HCV infect in preparation.In another embodiment, the present invention relates at least a The compounds of this invention that is selected from formula I (a), I (b), II (a) or II (b) compound (or its salt, solvate or prodrug) and at least a anti-hepatitis A agent, resistance of hepatitis B agent, the agent of fight against press-ganging type hepatitis, anti-hepatitis E agent or anti-hepatitis G agent and be used for the treatment of application in the medicine of viral hepatitis in preparation.In another embodiment, the present invention relates at least a The compounds of this invention that is selected from formula I (a), I (b), II (a) or II (b) compound (or its salt, solvate or prodrug) and the agent of at least a liver inflammation treatment and be used for the treatment of application in the medicine of hepatitis C in preparation.

Describe to provide illustrating and describing above of the present invention, but be not exhaustive or limit the invention to disclosed content.According to top instruction, change and modification are possible, perhaps can obtain from enforcement of the present invention.Therefore, it is noted that scope of the present invention is limited by claims and equivalents thereof.

Claims

1. the pharmacologically acceptable salt of the tautomer of compound, described compound or described compound or tautomer, wherein said compound has formula I (a) or I (b),

Wherein:

Z is-NR ⁴¹-;

Y be selected from a key ,-L _S-O-,-L _S-C (O)-,-L _S-S (O) ₂-,-L _S-S (O)-,-L _S-OS (O) ₂-,-L _S-OS (O)-,-L _S-C (O) O-,-L _S-OC (O)-,-L _S-OC (O) O-,-L _S-C (O) N (R ¹⁵)-,-L _S-N (R ¹⁵) C (O)-,-L _S-C (O) N (R ¹⁵) O-,-L _S-N (R ¹⁵) C (O) O-,-L _S-C (O) N (R ¹⁵) N (R ¹⁵)-,-L _S-S-,-L _S-C (S)-,-L _S-C (S) O-,-L _S-OC (S)-,-L _S-C (S) N (R ¹⁵)-,-L _S-N (R ¹⁵)-,-L _S-N (R ¹⁵) C (S)-,-L _S-N (R ¹⁵) S (O)-,-L _S-N (R ¹⁵) S (O) ₂-,-L _S-S (O) ₂N (R ¹⁵)-,-L _S-S (O) N (R ¹⁵)-,-L _S-C (S) N (R ¹⁵) O-and-L _S-C (S) N (R ¹⁵) N (R ^{15 '})-, be R wherein ¹⁵And R ^{15 '}When occurring, be independently selected from hydrogen, alkyl, alkenyl and alkynyl respectively at every turn;

R ⁵⁰Be-L ¹-A ¹, A wherein ¹Be selected from carbocylic radical, heterocyclic radical, alkyl, alkenyl and alkynyl, and L ¹Be selected from key, alkylidene group, alkylene group and alkynylene, wherein an A ¹Optional by one or more R ³⁰Replace, and R ³⁰When occurring, be independently selected from every turn halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, azido-, alkyl, alkenyl, alkynyl ,-L _S-O-R _S,-L _S-S-R _S,-L _S-C (O) R _S,-L _S-OC (O) R _S,-L _S-C (O) OR _S,-L _S-N (R _SR _{S '}) ,-L _S-C (=NR _S) R _{S '}-,-L _S-S (O) R _S,-L _S-SO ₂R _S,-L _S-C (O) N (R _SR _{S '}) ,-L _S-N (R _S) C (O) R _{S '},-L _S-C (=NR _S) N (R _{S '}R _{S "}) ,-L _S-N (R _{S '}) C (=NR _S) R _{S "},-L _S-N (R _S) C (O) N (R _{S '}R _{S "}) ,-L _S-N (R _S) SO ₂R _{S '},-L _S-SO ₂N (R _SR _{S '}) ,-L _S-N (R _S) SO ₂N (R _{S '}R _{S "}) ,-L _E-Q-L _{E '}-(C ₃-C ₁₈Carbocylic radical) and-L _E-Q-L _{E '}-(M ₃-M ₁₈Heterocyclic radical), L and wherein ¹Optional by one or more R ³⁸Replace, and R ³⁸When occurring, be independently selected from every turn halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, azido-, alkoxyl group, thio alkoxy, alkyl-carbonyl, alkoxy carbonyl, alkyl-carbonyl oxygen base, alkylamino, alkoxycarbonyl amino ,-L _S-O-R _S,-L _S-S-R _S,-L _S-C (O) R _S,-L _S-OC (O) R _S,-L _S-C (O) OR _S,-L _S-N (R _SR _{S '}) ,-L _S-C (=NR _S) R _{S '},-L _S-S (O) R _S,-L _S-SO ₂R _S,-L _S-C (O) N (R _SR _{S '}) ,-L _S-N (R _S) C (O) R _{S '},-L _S-C (=NR _S) N (R _{S '}R _{S "}) ,-L _S-N (R _{S '}) C (=NR _S) R _{S "},-L _S-N (R _S) C (O) N (R _{S '}R _{S "}) ,-L _S-N (R _S) SO ₂R _{S '},-L _S-SO ₂N (R _SR _{S '}) ,-L _S-N (R _S) SO ₂N (R _{S '}R _{S "}), carbocylic radical, heterocyclic radical, carbocylic radical alkyl, heterocyclic radical alkyl ,-L _E-Q-L _{E '}-(C ₃-C ₁₈Carbocylic radical) and-L _E-Q-L _{E '}-(M ₃-M ₁₈Heterocyclic radical);

2. the compound of claim 1, tautomer or salt, wherein:

Z is-NR ⁴¹-;

R ²²Be carbocylic radical, heterocyclic radical, carbocylic radical C ₁-C ₆Alkyl or heterocyclic radical C ₁-C ₆Alkyl, and optional by one or more R ²⁶Replace, wherein R ²⁶When occurring, be independently selected from halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphorus 4 acid esters, azido-, C at every turn ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl ,-L _S-O-R _S,-L _S-S-R _S,-L _S-C (O) R _S,-L _S-OC (O) R _S,-L _S-C (O) OR _S,-L _S-N (R _SR _{S '}) ,-L _S-C (=NR _S) R _{S '},-L _S-S (O) R _S,-L _S-SO ₂R _S,-L _S-OS (O) R _S,-L _S-OSO ₂R _S,-L _S-C (O) N (R _SR _{S '}) ,-L _S-N (R _S) C (O) R _{S '},-L _S-C (=NR _S) N (R _{S '}R _{S "}) ,-L _S-N (R _{S '}) C (=NR _S) R _{S "},-L _S-N (R _S) C (O) N (R _{S '}R _{S "}) ,-L _S-N=C (NR _SR _{S '}) (NR _SR _{S '}) ,-L _S-N (R _S) SO ₂R _{S '},-L _S-SO ₂N (R _SR _{S '}) ,-L _S-N (R _S) SO ₂N (R _{S '}R _{S "}) ,-L _E-Q-L _{E '}-(C ₃-C ₁₈Carbocylic radical) and-L _E-Q-L _{E '}-(M ₃-M ₁₈Heterocyclic radical); Perhaps R ²²Be C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl or C ₂-C ₆Alkynyl, and optional by one or more R ²⁶Replace; Perhaps R ²²Be hydrogen;

Y be selected from a key ,-L _S-O-,-L _S-C (O)-,-L _S-S (O) ₂-,-L _S-S (O)-,-L _S-OS (O) ₂-,-L _S-OS (O)-,-L _S-C (O) O-,-L _S-OC (O)-,-L _S-OC (O) O-,-L _S-C (O) N (R ¹⁵)-,-L _S-N (R ¹⁵) C (O)-,-L _S-C (O) N (R ¹⁵) O-,-L _S-N (R ¹⁵) C (O) O-,-L _S-C (O) N (R ¹⁵) N (R ¹⁵)-,-L _S-S-,-L _S-C (S)-,-L _S-C (S) O-,-L _S-OC (S)-,-L _S-C (S) N (R ¹⁵)-,-L _S-N (R ¹⁵)-,-L _S-N (R ¹⁵) C (S)-,-L _S-N (R ¹⁵) S (O)-,-L _S-N (R ¹⁵) S (O) ₂-,-L _S-S (O) ₂N (R ¹⁵)-,-L _S-S (O) N (R ¹⁵)-,-L _S-C (S) N (R ¹⁵) O-and-L _S-C (S) N (R ¹⁵) N (R ^{15 '})-, be R wherein ¹⁵And R ^{15 '}When occurring, be independently selected from hydrogen, C respectively at every turn ₁-C ₆Alkyl, C ₂-C ₆Alkenyl and C ₂-C ₆Alkynyl;

-L _E-Q-L _{E '}-(C ₃-C ₁₈Carbocylic radical) and-L _E-Q-L _E-(M ₃-M ₁₈Heterocyclic radical) each C in ₃-C ₁₈Carbocylic radical and M ₃-M ₁₈The heterocyclic radical part optional independently when occurring at every turn is selected from following substituting group replacement by at least one: hydrogen, halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, azido-, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Thio alkoxy, C ₁-C ₆Alkoxy C ₁-C ₆Alkyl, C ₁-C ₆Thio alkoxy C ₁-C ₆Alkyl, C ₁-C ₆Alkyl-carbonyl, C ₁-C ₆Alkyl-carbonyl C ₁-C ₆Alkyl, C ₁-C ₆Alkoxy carbonyl, C ₁-C ₆Alkoxy carbonyl C ₁-C ₆Alkyl, C ₁-C ₆Alkyl-carbonyl oxygen base, C ₁-C ₆Alkyl-carbonyl oxygen base C ₁-C ₆Alkyl, C ₁-C ₆Alkylamino, C ₁-C ₆Alkylamino C ₁-C ₆Alkyl, C ₁-C ₆Alkoxycarbonyl amino, C ₃-C ₇Carbocylic radical oxygen base, M ₃-M ₇Heterocyclyloxy base, C ₃-C ₇Carbocylic radical C ₁-C ₆Alkoxyl group, M ₃-M ₇Heterocyclic radical C ₁-C ₆Alkoxyl group, C ₃-C ₇Carbocylic radical C ₁-C ₆Alkoxy carbonyl, M ₃-M ₇Heterocyclic radical C ₁-C ₆Alkoxy carbonyl and C ₁-C ₆Alkoxycarbonyl amino C ₁-C ₆Alkyl.

3. compound, tautomer or the salt of each claim among the claim 1-2, wherein A is C ₅-C ₆Carbocylic radical or M ₅-M ₆Heterocyclic radical, and optional by one or more R ¹⁸Replace.

4. compound, tautomer or the salt of each claim among the claim 1-3, wherein Y is-L _S-O-,-L _S-S-,-L _S-C (O) N (R ¹⁵)-or-L _S-N (R ¹⁵) C (O)-, R ¹⁵Be hydrogen, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl or C ₂-C ₆Alkynyl, and L ¹Be optional by one or more R ³⁸The C that replaces ₁-C ₆Alkylidene group, and A wherein ¹Be C ₄-C ₆Carbocylic radical or M ₄-M ₆Heterocyclic radical, and optional by one or more R ³⁰Replace.

5. compound, tautomer or the salt of each claim among the claim 1-3, wherein Y is-L _S-O-,-L _S-S-,-L _S-C (O) N (R ¹⁵)-or-L _S-N (R ¹⁵) C (O)-, R ¹⁵Be hydrogen, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl or C ₂-C ₆Alkynyl, and L ¹Be key, wherein an A ¹Be C ₄-C ₆Carbocylic radical or M ₄-M ₆Heterocyclic radical, and optional by one or more R ³⁰Replace.

6. compound, tautomer or the salt of each claim among the claim 1-3, wherein Y is-L _S-O-,-L _S-S-,-L _S-C (O) N (R ¹⁵)-or-L _S-N (R ¹⁵) C (O)-, R ¹⁵Be hydrogen, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl or C ₂-C ₆Alkynyl, and L ¹It is a key or optional by one or more R ³⁸The C that replaces ₁-C ₆Alkylidene group, wherein A ¹Be dicyclo (for example condensed-bicyclic or bridging dicyclo), it has 6-14 annular atoms and optional by one or more R ³⁰Replace.

7. compound, tautomer or the salt of each claim among the claim 1-6, wherein X be-O-or-S-, and R ²²Be C ₅-C ₆Carbocylic radical or M ₅-M ₆Heterocyclic radical, and optional by one or more R ²⁶Replace.

8. compound, tautomer or the salt of each claim among the claim 1-6, wherein X be-S-or-O-, and R ²²Be

Or

R wherein ⁴⁸Be hydroxyl, amino, C ₁-C ₆Alkylamino, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkoxycarbonyl amino or C ₁-C ₆Alkyl-carbonyl oxygen base, and R wherein ²²Optional by one or more R ²⁶Replace.

9. the pharmacologically acceptable salt of the tautomer of compound, described compound or described compound or tautomer, wherein said compound has formula II (a) or II (b),

Or

Wherein:

R ⁴Be selected from hydrogen, alkoxy carbonyl and alkoxy carbonyl alkyl;

10. the compound of claim 9, tautomer or salt, wherein:

R ¹²Be selected from

With

N is the integer that is selected from O and 1;

R ¹⁶Be selected from hydrogen; halogen; alkyl; alkoxyl group; hydroxyl; aminocarboxyl; alkyl amino-carbonyl; amino; alkyl-carbonyl-amino; the miscellaneous alkyl aryl carbonylamino; the heteroaryl carbonylamino; hydroxyl heteroaryl carbonylamino; hydroxyalkyl heteroaryl carbonylamino; heteroaryl carbonylamino alkyl-carbonyl-amino; the heteroarylalkyl carbonylamino; aryloxy aromatic yl alkyl carbonyl amino; the allyl amino carbonyl; alkoxy carbonyl; hydroxyalkyl; aromatic yl aminocarbonyl; the hydroxyaryl aminocarboxyl; alkoxyalkyl; the alkoxy aryl aminocarboxyl; the azido-alkyl; alkylamino aryl sulfonyl oxygen base; alkyl sulphonyl oxygen base; aryl alkylsulfonyl oxygen base; the alkoxy carbonyl alkoxyl group; the hydroxycarbonyl group alkoxyl group; cycloalkyl amino carbonyl; aryl-alkoxy carbonyl heterocyclic radical carbonylamino; aryloxy; imino alkyl; the alkyl thioketones; aromatic yl alkyl carbonyl amino; the alkylaryloxy alkyl-carbonyl-amino; the alkoxy aryl alkyl carbonylamino; heteroaryl carbonylamino alkyl-carbonyl-amino; the heteroarylalkyl carbonylamino; alkyl-carbonyl heterocyclic radical carbonylamino; amino; aminocarboxyl; alkyl amino-carbonyl; hydroxyalkyl; aminoalkyl group; the alkoxyalkyl aminocarboxyl; the oxyimino alkyl; the heteroaryl and the heteroaryl that are replaced by alkyl.

11. the compound of claim 9, tautomer or salt, wherein R ²And R ³Be independently selected from hydrogen, ethoxy carbonyl, 3-N-methoxyl group-N-methylamino carbonyl and methyl;

R ⁴Be selected from hydrogen, tert-butoxycarbonyl and ethoxy carbonyl methyl;

R ⁹Be selected from hydrogen, methyl, methoxyl group, phenyl, trifluoromethyl, phenmethyl amino, hydroxyl, tert.-butoxy-carbonylamino methyl, carbonylamino, the methyl carbonyl, amino, bromine, chlorine, fluorine, methyl [1,8] naphthyridine-4-base amino-(2-phenyl sulfenyl benzene-5-ylmethyl) amino-(N-tert.-butoxy-carbonyl-N-methyl), the anisole ylmethoxy, the bromophenyl methoxyl group, the nitrophenyl methoxyl group, the cyano-phenyl methoxyl group, trifluoromethyl, phenoxymethyl, bromobenzene oxygen ylmethyl, the cyano group methoxyl group, the phenyl methoxyl group, methacrylic oxygen base, propoxy-, the aminomethyl phenyl methoxyl group, the aminomethyl phenyl methoxyl group, fluoro-3-aminomethyl phenyl aminocarboxyl, the trifluoromethyl aminocarboxyl, the trifluoromethyl aminocarboxyl, N, N-dimethylaminophenyl aminocarboxyl, fluorophenyl methoxyl group and chloro-phenyl-methoxyl group;

R ¹¹Be selected from hydrogen, hydroxyl, chlorophenoxy and methyl;

R ¹²As above about described in formula II (a) and the II (b);

12. contain the pharmaceutical composition of compound, tautomer or the salt of each claim among the claim 1-11.

13. the compound of each claim, tautomer or salt are used for suppressing the application of the medicine of HCV virus replication among the claim 1-11 in preparation.

14. the compound of each claim, tautomer or salt are used for the treatment of application in the medicine that HCV infects in preparation among the claim 1-11.

15. suppress the method for HCV virus replication, described method comprises that compound, tautomer or the salt with each claim among the claim 1-11 of HCV virus and significant quantity contacts, thereby suppresses duplicating of described virus.

16. the method that treatment HCV infects, described method comprises compound, tautomer or the salt of each claim in the claim 1-11 of HCV patient's effective dosage, thereby reduces the HCV virus levels in blood samples of patients or the liver.

17. the method for the compound of each claim among the preparation claim 1-11, described method comprises a described step of reaction scheme among the reaction scheme 1-6.