CN101384591A

CN101384591A - Anti-viral compounds

Info

Publication number: CN101384591A
Application number: CNA2006800531964A
Authority: CN
Inventors: D·A·贝特本纳; D·A·德格; C·J·马林; A·C·克吕格尔; 岩崎仲彦; T·W·罗克维; C·S·库珀; D·D·安德森; P·L·唐纳; B·E·格林; D·J·肯普夫; D·刘; K·F·麦丹尼; D·L·马迪根; C·E·莫特; J·K·普拉特; J·P·尚利; M·D·图法诺; R·沃纳; R·张
Original assignee: Abbott Laboratories
Current assignee: Abbott Laboratories
Priority date: 2005-12-21
Filing date: 2006-12-20
Publication date: 2009-03-11
Also published as: CA2633752A1; JP2009521460A; RU2008129782A; ZA201107667B; CN101443334A; ES2348557T3; ZA200805418B; RU2441010C2; CN101384592A

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 Pfizer WO 98/23613 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 WO01/57040 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 WO 95/19774 of the Wamer-Lambert 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 WO 01/32632 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 WO2004/014852 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 WO2004/014313 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, I (a), the compound of I (b), I (c), I (d), I (e), I (f), I (g) or I (h), the tautomer of these compounds, and the pharmacologically acceptable salt of these compounds or tautomer.These compounds, tautomer or salt can use separately or unite use with other drug or promoting agent, to suppress HCV or other virus replications.These compounds, tautomer or salt can also use separately or unite use with other drug or promoting agent, to interrupt HCV or other viral functions.

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

In addition, the invention still further relates to the method that the composition that uses The compounds of this invention, tautomer or salt or comprise The compounds of this invention, tautomer or salt suppresses HCV or other virus replications.These methods comprise HCV or another kind of virus or have infected HCV or the cell of described another kind of virus contact with The compounds of this invention, tautomer or the salt of significant quantity, to suppress HCV or viral the duplicating of described another kind thus.

The invention still further relates to the composition that uses The compounds of this invention, tautomer or salt or comprise The compounds of this invention, tautomer or salt and suppress the method for HCV or other virus multiplications or propagation.These methods comprise HCV or another kind of virus or have infected HCV or the cell of another kind of virus contact with The compounds of this invention, tautomer or the salt of significant quantity, to suppress HCV or viral propagation or the propagation of described another kind thus.

In addition, the invention still further relates to the method that the composition that uses The compounds of this invention, tautomer or salt or comprise The compounds of this invention, tautomer or salt is treated HCV or other virus infectiones.These methods comprise that the patient to this treatment of needs uses the The compounds of this invention of significant quantity, tautomer or salt, to reduce among the patient HCV or other viral blood thus or to 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.

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

Other features of the present invention, purpose and advantage are conspicuous in the following detailed description.Yet though should be appreciated that and pointed out the preferred embodiments of the invention, the detailed Description Of The Invention that provides is explanation for example just, rather than restriction.To those skilled in the art, by detailed Description Of The Invention, within the scope of the present invention a plurality of different changes and modification all will be conspicuous.

Detailed Description Of The Invention

Following description is exemplary, and is not in order to limit the disclosure of invention, application or purposes.

Compound

The present invention relates to have the compound of formula I, its tautomer, and the pharmacologically acceptable salt of compound or tautomer,

Wherein:

W ₁, W ₂, W ₃And W ₄Be independently selected from N or C (R respectively ³³);

Z be a key ,-CR ⁴¹R ^{41 '}-or-NR ⁴¹-, R wherein ⁴¹And R ^{41 '}Be independently selected from hydrogen, alkyl, alkenyl and alkynyl respectively;

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 ³³And R ³⁵When 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 or heterocyclic radical, 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 (RSR _{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=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 quilt-individual or a plurality of R ²⁶Replace; Perhaps R ²²Be hydrogen;

Y be selected from a key ,-O-,-C (O)-,-S (O) ₂-,-S (O)-,-OS (O) ₂-,-OS (O)-,-C (O) O-,-OC (O)-,-OC (O) O-,-C (O) N (R ¹⁵)-,-N (R ¹⁵) C (O)-,-C (O) N (R ¹⁵) O-,-N (R ¹⁵) C (O) O-,-C (O) N (R ¹⁵) N (R ¹⁵)-,-S-,-C (S)-,-C (S) O-,-OC (S)-,-C (S) N (R ¹⁵)-,-N (R ¹⁵)-,-N (R ¹⁵) C (S)-,-N (R ¹⁵) S (O)-,-N (R ¹⁵) S (O) ₂-,-S (O) ₂N (R ¹⁵)-,-S (O) N (R ¹⁵)-,-C (S) N (R ¹⁵) O-and-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);

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 independently 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 respectively at every turn;

L _EAnd L _{E '}When occurring, be independently selected from key, alkylidene group, alkylene group and an alkynylene respectively at every turn;

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 ³³, R ³⁵, R ³⁸, R ⁴¹And R ^{41 '}When 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 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 and alkoxycarbonyl amino alkyl.

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

Z be a key ,-CR ⁴¹R ^{41 '}-or-NR ⁴¹-, R wherein ⁴¹And R ^{41 "}Be independently selected from hydrogen, C respectively ₁-C ₆Alkyl, C ₂-C ₆Alkenyl and C ₂-C ₆Alkynyl;

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 ³³And R ³⁵When 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 or heterocyclic radical 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-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 _SR _{S "},-L _S-N=C (NR _SR _{S '}) (NR _SR _{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); 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 ,-O-,-C (O)-,-S (O) ₂-,-S (O)-,-OS (O) ₂-,-OS (O)-,-C (O) O-,-OC (O)-,-OC (O) O-,-C (O) N (R ¹⁵)-,-N (R ¹⁵) C (O)-,-C (O) N (R ¹⁵) O-,-N (R ¹⁵) C (O) O-,-C (O) N (R ¹⁵) N (R ^{15 '})-,-S-,-C (S)-,-C (S) O-,-C (S) N (R ¹⁵)-,-N (R ¹⁵)-,-N (R ¹⁵) C (S)-,-N (R ¹⁵) S (O)-,-N (R ¹⁵) S (O) ₂-,-S (O) ₂N (R ¹⁵)-,-S (O) N (R ¹⁵)-,-C (S) N (R ¹⁵) O-and-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 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 _SAnd R _{S "}When occurring, be independently selected from hydrogen, C respectively 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 and C ₂-C ₆Alkynylene;

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)-;

-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: 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 and C ₁-C ₆Alkoxycarbonyl amino C ₁-C ₆Alkyl.

In an example of this embodiment, W ₁, W ₂And W ₃Be N.W ₄Be C (R ³³), and Z is-NR ⁴¹-.

In another example of this embodiment, A is C ₅-C ₆Carbocylic radical, described carbocylic radical is optional by one or more R ¹⁸Replace.

In another example of this embodiment, A is M ₅-M ₆Heterocyclic radical, described heterocyclic radical is optional by one or more R ¹⁸Replace.

In another example of this embodiment, Y is-C (O) N (R ¹⁵)-or-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, wherein A ¹Be C ₄-C ₆Carbocylic radical or M ₄-M ₆Heterocyclic radical, and optional by one or more R ³⁰Replace.

In another example of this embodiment, Y is-C (O) N (R ¹⁵)-or-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 this embodiment, Y is-C (O) N (R ¹⁵)-or-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 two rings (being fused bicyclic or bridged bicyclic), described two rings have 6-14 annular atoms, and optional by one or more R ³⁰Replace.

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

In another example of this embodiment, R ¹⁰, R ³³, R ³⁵, R ⁴¹And R ^{41 '}When occurring, be independently selected from hydrogen, halogen or C respectively at every turn ₁-C ₆Alkyl, and R ¹⁷Be C ₁-C ₆Alkyl.

In another example of this embodiment, R ¹⁰Be hydrogen, and R ¹⁷Be C ₁-C ₆Alkyl.

In another example of this embodiment, W ₁, W ₂And W ₃Be N, W ₄Be C (R ³³), and Z is-NR ⁴¹-, wherein:

R ³³And R ³⁵Be independently selected from hydrogen, halogen or C respectively ₁-C ₆Alkyl;

R ⁴¹Be selected from hydrogen or C ₁-C ₆Alkyl;

R ¹⁰Be hydrogen;

R ¹⁷Be C ₁-C ₆Alkyl or C ₃-C ₆Cycloalkyl;

A is C ₅-C ₆Carbocylic radical or M ₅-M ₆Heterocyclic radical, and optional by one or more R ¹⁸Replace;

X is-S-or-O-;

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 ²²In R ⁴⁸Or benzyl ring) optional by one or more R ²⁶Replace;

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

R ⁵⁰Be-L ¹-A ¹, wherein:

L ¹Be C ₁-C ₆Alkylidene group, and optional by one or more R ³⁸Replace A ¹Be C ₄-C ₁₂Carbocylic radical or M ₄-M ₁₂Heterocyclic radical, and optional by one or more R ³⁰Replace; Perhaps

L ¹Be that a key (is R ⁵⁰Be-A ¹), A ¹Be C ₄-C ₁₂Carbocylic radical or M ₄-M ₁₂Heterocyclic radical, and optional by one or more R ³⁰Replace; Perhaps

L ¹Be that a key (is R ⁵⁰Be-A ¹), and A ¹Be two rings (for example fused bicyclic or bridged bicyclic), described two rings have 6-12 annular atoms, and optional by one or more R ³⁰Replace.

R ⁴¹Be selected from hydrogen or C ₁-C ₆Alkyl;

R ¹⁰Be hydrogen;

R ¹⁷Be C ₁-C ₆Alkyl or C ₃-C ₆Cycloalkyl;

X is-S-or-O-;

R ²²Be

Or

Y is-C (O) O-or-OC (O)-; And

R ⁵⁰Be-L ¹-A ¹, wherein:

L ¹Be that a key (is R ⁵⁰Be-A ¹), and A ¹Be hydrogen; Perhaps

Part

In annular atoms can substitute with S or other heteroatomss.

In another embodiment, the present invention relates to have the compound of the structural formula that is selected from formula I (a), I (b), I (c) and I (d), the tautomer of these compounds, and the pharmacologically acceptable salt of these compounds or tautomer:

Wherein:

R ¹⁷, R ³³And R ³⁵Be independently selected from hydrogen, halogen, C respectively ₁-C ₆Alkyl or C ₃-C ₆Cycloalkyl;

R ⁴¹Be selected from hydrogen or C ₁-C ₆Alkyl;

X is-S-or-O-;

R ²²Be

Or

Y is-C (O) N (R ¹⁵)-or-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 that a key (is R ⁵⁰Be-A ¹), and A ¹Be two rings (for example fused bicyclic or bridged bicyclic), described two rings have 6-12 annular atoms, and optional by one or more R ³⁰Replace; Perhaps

L ¹Be optional by one or more R ³⁸The C that replaces ₁-C ₆Alkyl, and A ¹Be hydrogen or optional by one or more R ³⁰The C that replaces ₁-C ₆Alkyl;

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, C ₁-C ₆Haloalkyl ,-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 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, C ₁-C ₆Haloalkyl ,-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=C (NR _SR _{S '}) (NR _SR _{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 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, C ₁-C ₆Haloalkyl ,-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 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);

R _S, R _{S '}And R _{S "}When occurring, be independently selected from hydrogen, C respectively at every turn ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Haloalkyl, 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, amino C ₁-C ₆Alkyl, C ₁-C ₆Alkylamino C ₁-C ₆Alkyl, C ₁-C ₆Alkoxycarbonyl amino and C ₁-C ₆Alkoxycarbonyl amino C ₁-C ₆Alkyl;

R ¹⁵, R ¹⁷, R ¹⁸, R ²⁶, R ³⁰, 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 and azido-by at least one;-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: 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 ₆Haloalkyl, 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 and C ₁-C ₆Alkoxycarbonyl amino C ₁-C ₆Alkyl;

M is 0,1,2 or 3;

N is 0 or 1;

P is 0,1,2 or 3; And

U is-CH ₂-or-CH ₂-CH ₂-, and optional by one or more R ¹⁸Replace.

In another embodiment, the present invention relates to have the compound of the structural formula that is selected from formula I (a), I (b), I (c) and I (d), the tautomer of these compounds, and the pharmacologically acceptable salt of these compounds or tautomer, wherein:

R ¹⁷, R ³³And R ³⁵Be independently selected from hydrogen, halogen or C respectively ₁-C ₆Alkyl;

R ⁴¹Be selected from hydrogen or C ₁-C ₆Alkyl;

X is-S-or-O-;

R ²²Be C ₄-C ₁₂Carbocylic radical or M ₄-M ₁₂Heterocyclic radical (for example indoles or imidazoles), and optional quilt-individual or a plurality of R ²⁶Replace;

R ⁵⁰Be-L ¹-A ¹, wherein:

L ¹Be C ₁-C ₆Alkylidene group, and optional by one or more R ³⁸Replace, and A ¹Be C ₄-C ₁₂Carbocylic radical or M ₄-M ₁₂Heterocyclic radical, and optional by one or more R ³⁰Replace; Perhaps

L ¹Be that a key (is R ⁵⁰Be-A ¹), and A ¹Be C ₄-C ₁₂Carbocylic radical or M ₄-M ₁₂Heterocyclic radical, and optional by one or more R ³⁰Replace; Perhaps

L ¹Be that a key (is R ⁵⁰Be-A ¹), and A ¹Be two rings (for example fused bicyclic or bridged bicyclic), described two rings have 6-12 annular atoms, and optional by one or more R ³⁰Replace; Perhaps L ¹Be optional by one or more R ³⁸The C that replaces ₁-C ₆Alkyl, and A ¹Be hydrogen or optional by one or more R ³⁰The C that replaces ₁-C ₆Alkyl;

R ¹⁸, R ²⁶, R ³⁰, R ³⁸, m, n, p and U in the top embodiment definition; And R ¹⁵, R ¹⁷, R ¹⁸, R ²⁶, R ³⁰, 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 and azido-by at least one.

In an example of this embodiment, L ¹Be C ₁-C ₆Alkylidene group, and replaced by at least one phosphoric acid ester, and A ¹Be hydrogen.

In another example of this embodiment, L ¹Be C ₁-C ₆Alkylidene group, and replaced A by at least one phosphoric acid ester ¹Be hydrogen, X is-S-or-O-, R ²²Be

R ⁴⁸Be amino, and optional by one or more R ²⁶Replace R ¹⁷Be C ₁-C ₆Alkyl (for example methyl, sec.-propyl or butyl), and R ⁴¹, R ³³And R ³⁵Be hydrogen or halogen independently.In a lot of examples, Y is-C (O) N (R ¹⁵)-, and R ¹⁵Be hydrogen.In a lot of other examples, Y is-C (O) N (R ¹⁵)-, and R ¹⁵Be C ₁-C ₆Alkyl or C ₂-C ₆Alkenyl (for example-CH ₃Or-CH ₃-CH ₂=CH ₂).In a lot of other examples, R ⁴⁸By at least one R ²⁶Replace.Suitable R ²⁶Limiting examples comprise-C (O)-O-C ₁-C ₆Alkyl ,-SO ₂-C ₁-C ₆Alkyl ,-C (O)-C ₁-C ₆Alkylidene group-C ₃-C ₁₈Carbocylic radical (for example-C (O)-C ₁-C ₆Alkylidene group-phenyl) or-C (O)-C ₁-C ₆Alkylidene group-M ₃-M ₁₈Heterocyclic radical, C wherein ₃-C ₁₈Carbocylic radical and M ₃-M ₁₈Heterocyclic radical can further be chosen wantonly by one or more groups for example halogen, C ₁-C ₆Alkyl or C ₁-C ₆Haloalkyl replaces.

In another example of this embodiment, L ¹Be C ₁-C ₆Alkylidene group, and by at least one R ³⁸Replace, and A ¹Be hydrogen.Suitable R ³⁸Limiting examples comprise halogen, oxo base, thio group, hydroxyl, sulfydryl, amino, C ₅-C ₆Carbocylic radical-O-or M ₅-M ₆Heterocyclic radical-O-.

R ⁴¹Be selected from hydrogen or C ₁-C ₆Alkyl;

X is-S-or-O-;

R ²²Be

And it is optional by one or more R ²⁶Replace, wherein R ⁴⁸Be hydroxyl, amino, C ₁-C ₆Alkylamino, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkoxycarbonyl amino or C ₁-C ₆The alkyl-carbonyl oxygen base;

R ⁵⁰Be-L ¹-A ¹, L wherein ¹Be C ₁-C ₆Alkylidene group, and optional by one or more R ³⁸Replace A ¹Be C ₄-C ₁₂Carbocylic radical or M ₄-M ₁₂Heterocyclic radical, and optional by one or more R ³⁰Replace;

In an example of this embodiment, X is-O-.

In another example of this embodiment, X is-S-.

In another example of this embodiment, R ⁴⁸Be amino, and optional by one or more R ²⁶Replace.

In another example of this embodiment, R ¹⁷Be C ₁-C ₆Alkyl (for example methyl, sec.-propyl or butyl), and R ⁴¹, R ³³And R ³⁵Be hydrogen or halogen independently.

In another example of this embodiment, A ¹Be C ₅-C ₆Carbocylic radical (for example phenyl) or M ₅-M ₆Heterocyclic radical (for example pyridyl or thienyl), and optional by one or more R ³⁰Replace (for example-F ,-Br ,-CH ₃Or-CF ₃).

In another example of this embodiment, R ⁴⁸Be amino, and optional by at least one R ²⁶Replace.Suitable R ²⁶Limiting examples comprise-C (O)-O-C ₁-C ₆Alkyl ,-SO ₂-C ₁-C ₆Alkyl ,-C (O)-C ₁-C ₆Alkylidene group-C ₃-C ₁₈Carbocylic radical (for example-C (O)-C ₁-C ₆Alkylidene group-phenyl) or-C (O)-C ₁-C ₆Alkylidene group-M ₃-M ₁₈Heterocyclic radical, wherein C ₃-C ₁₈Carbocylic radical and M ₃-M ₁₈Heterocyclic radical can further be replaced by at least one phosphoric acid ester, and optional by one or more other parts for example halogen, C ₁-C ₆Alkyl or C ₁-C ₆Haloalkyl replaces.

In another example of this embodiment, L ¹Be C ₁-C ₆Alkylidene group (for example-CH ₂-,-CH (CH ₃)-,-CH ₂-CH ₂-,-C (CH ₃) ₂-,-CH (CH ₂CH ₃)-,-C (CH ₃) (CH ₂CH ₃)-,-C (CH ₂CH ₃) (CH ₂CH ₃)-or-CH ₂-CH (CH ₃)-), and optional by one or more R ³⁸(for example phosphoric acid ester, halogen, hydroxyl ,-CO ₂-C ₁-C ₆Alkyl or-CO ₂-O-C ₁-C ₆Alkyl) replace, X is-S-R ⁴⁸Be amino, and optional by one or more R ²⁶Replace R ¹⁷Be C ₁-C ₆Alkyl (for example methyl, sec.-propyl or butyl), R ⁴¹, R ³³And R ³⁵Be hydrogen or halogen independently, and A ¹Be C ₅-C ₆Carbocylic radical (for example phenyl) or M ₅-M ₆Heterocyclic radical (for example pyridyl or thienyl), and optional by one or more R ³⁰(for example-F ,-Br ,-CH ₃Or-CF ₃) replace.In a lot of examples, Y is-C (O) N (R ¹⁵)-, and R ¹⁵Be hydrogen.In a lot of other examples, Y is-C (O) N (R ¹⁵)-, and R ¹⁵Be C ₁-C ₆Alkyl or C ₂-C ₆Alkenyl (for example-CH ₃Or-CH ₃-CH ₂=CH ₂).In a lot of other examples, R ⁴⁸Optional by at least one R ²⁶Replace.Suitable R ²⁶Limiting examples comprise-C (O)-O-C ₁-C ₆Alkyl ,-SO ₂-C ₁-C ₆Alkyl ,-C (O)-C ₁-C ₆Alkylidene group-C ₃-C ₁₈Carbocylic radical (for example-C (O)-C ₁-C ₆Alkylidene group-phenyl) or-C (O)-C ₁-C ₆Alkylidene group-M ₃-M ₁₈Heterocyclic radical, wherein C ₃-C ₁₈Carbocylic radical and M ₃-M ₁₈Heterocyclic radical can further be replaced by at least one phosphoric acid ester, and optional by one or more other parts for example halogen, C ₁-C ₆Alkyl or C ₁-C ₆Haloalkyl replaces.

In another example of this embodiment, L ¹Be C ₁-C ₆Alkylidene group (for example-CH ₂-,-CH (CH ₃)-,-CH ₂-CH ₂-,-C (CH ₃) ₂-,-CH (CH ₂CH ₃)-,-C (CH ₃) (CH ₂CH ₃)-,-C (CH ₂CH ₃) (CH ₂CH ₃)-or-CH ₂-CH (CH ₃)-), and optional by one or more R ³⁸(for example phosphoric acid ester, halogen, hydroxyl ,-CO ₂-C ₁-C ₆Alkyl or-CO ₂-O-C ₁-C ₆Alkyl) replace, X is-O-R ⁴⁸Be amino, and optional by one or more R ²⁶Replace R ¹⁷Be C ₁-C ₆Alkyl (for example methyl, sec.-propyl or butyl), R ⁴¹, R ³³And R ³⁵Be hydrogen or halogen independently, and A ¹Be C ₅-C ₆Carbocylic radical (for example phenyl) or M ₅-M ₆Heterocyclic radical (for example pyridyl or thienyl), and optional by one or more R ³⁰(for example-F ,-Br ,-CH ₃Or-CF ₃) replace.In a lot of examples, Y is-C (O) N (R ¹⁵)-and R ¹⁵Be hydrogen.In a lot of other examples, Y is-C (O) N (R ¹⁵)-, and R ¹⁵Be C ₁-C ₆Alkyl or C ₂-C ₆Alkenyl (for example-CH ₃Or-CH ₃-CH ₂=CH ₂).In a lot of examples, R ⁴⁸Optional by at least one R ²⁶Replace.Suitable R ²⁶Limiting examples comprise-C (O)-O-C ₁-C ₆Alkyl ,-SO ₂-C ₁-C ₆Alkyl ,-C (O)-C ₁-C ₆Alkylidene group-C ₃-C ₁₈Carbocylic radical (for example-C (O)-C ₁-C ₆Alkylidene group-phenyl) or-C (O)-C ₁-C ₆Alkylidene group-M ₃-M ₁₈Heterocyclic radical, wherein C ₃-C ₁₈Carbocylic radical and M ₃-M ₁₈Heterocyclic radical can further be replaced by at least one phosphoric acid ester, and optional by one or more other parts for example halogen, C ₁-C ₆Alkyl or C ₁-C ₆Haloalkyl replaces.

R ⁴¹Be selected from hydrogen or C ₁-C ₆Alkyl;

X is-S-or-O-;

R ²²Be

R ⁵⁰Be-A ¹, A wherein ¹Be two rings (for example fused bicyclic or bridged bicyclic), described two rings have 6-12 annular atoms, and optional by one or more R ³⁰Replace;

R ¹⁸, R ²⁶, R ³⁰, m, n, p and U in the top embodiment definition; And

R ¹⁵, R ¹⁷, R ¹⁸, R ²⁶, R ³⁰, R ³³, R ³⁵And 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 and azido-by at least one.

In an example of this embodiment, A ¹Be two rings (for example 2,3-dihydro-1H-indenyl) with 9-11 annular atoms, and optional by one or more R ³⁰(hydroxyl C for example ₁-C ₆Alkyl) replace, X is-S-R ⁴⁸Be amino, and optional by one or more R ²⁶Replace R ¹⁷Be C ₁-C ₆Alkyl (for example methyl, sec.-propyl or butyl), and R ⁴¹, R ³³And R ³⁵Be hydrogen or halogen independently.In a lot of examples, Y is-C (O) N (R ¹⁵)-, and R ¹⁵Be hydrogen.In a lot of other examples, Y is-C (O) N (R ¹⁵)-, and R ¹⁵Be C ₁-C ₆Alkyl or C ₂-C ₆Alkenyl (for example-CH ₃Or-CH ₃-CH ₂=CH ₂).In a lot of other examples, R ⁴⁸Optional by at least one R ²⁶Replace.Suitable R ²⁶Limiting examples comprise-C (O)-O-C ₁-C ₆Alkyl ,-SO ₂-C ₁-C ₆Alkyl ,-C (O)-C ₁-C ₆Alkylidene group-C ₃-C ₁₈Carbocylic radical (for example-C (O)-C ₁-C ₆Alkylidene group-phenyl) or-C (O)-C ₁-C ₆Alkylidene group-M ₃-M ₁₈Heterocyclic radical, wherein C ₃-C ₁₈Carbocylic radical and M ₃-M ₁₈Heterocyclic radical can further be replaced by at least one phosphoric acid ester, and optional by one or more other parts for example halogen, C ₁-C ₆Alkyl or C ₁-C ₆Haloalkyl replaces.

In another example of this embodiment, A ¹Be two rings (for example 2,3-dihydro-1H-indenyl) with 9-11 annular atoms, and optional by one or more R ³⁰(hydroxyl C for example ₁-C ₆Alkyl) replace, X is-O-R ⁴⁸Be amino, and optional by one or more R ²⁶Replace R ¹⁷Be C ₁-C ₆Alkyl (for example methyl, sec.-propyl or butyl), and R ⁴¹, R ³³And R ³⁵Be hydrogen or halogen independently.In a lot of examples, Y is-C (O) N (R ¹⁵)-, and R ¹⁵Be hydrogen.In a lot of other examples, Y is-C (O) N (R ¹⁵)-, and R ¹⁵Be C ₁-C ₆Alkyl or C ₂-C ₆Alkenyl (for example-CH ₃Or-CH ₃-CH ₂=CH ₂).In a lot of other examples, R ⁴⁸Optional by at least one R ²⁶Replace.Suitable R ²⁶Limiting examples comprise-C (O)-O-C ₁-C ₆Alkyl ,-SO ₂-C ₁-C ₆Alkyl ,-C (O)-C ₁-C ₆Alkylidene group-C ₃-C ₁₈Carbocylic radical (for example-C (O)-C ₁-C ₆Alkylidene group-phenyl) or-C (O)-C ₁-C ₆Alkylidene group-M ₃-M ₁₈Heterocyclic radical, wherein C ₃-C ₁₈Carbocylic radical and M ₃-M ₁₈Heterocyclic radical can by at least-individual phosphoric acid ester further replaces, and is and optional by one or more other parts for example halogen, C ₁-C ₆Alkyl or C ₁-C ₆Haloalkyl replaces.

R ⁴¹Be selected from hydrogen or C ₁-C ₆Alkyl;

X is-S-or-O-;

R ²²Be C ₄-C ₁₂Carbocylic radical or M ₄-M ₁₂Heterocyclic radical (for example

R wherein ⁴⁸Be hydroxyl, amino, C ₁-C ₆Alkylamino, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkoxycarbonyl amino or C ₁-C ₆And optional the alkyl-carbonyl oxygen base), by one or more R ²⁶Replace;

Y is-C (O) N (R ¹⁵) N (R ^{15 '})-,-N (R ¹⁵) C (O) O-,-C (O) O-,-O-,-C (O)-,-OC (O) O-,-OS (O) ₂-or-N (R ¹⁵) S (O) ₂-, R wherein ¹⁵And R ^{15 '}Be independently selected from hydrogen, C respectively 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 hydrogen or optional by one or more R ³⁰The C that replaces ₁-C ₆Alkyl;

R ¹⁸, R ²⁶, R ³⁰, R ³⁸, m, n, p and U in the top embodiment definition; And R ¹⁵, R ^{15 '}, R ¹⁷, R ¹⁸, R ²⁶, R ³⁰, 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 and azido-by at least one.

R ⁴¹Be selected from hydrogen or C ₁-C ₆Alkyl;

X is a key;

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 is-C (O) N (R ¹⁵)-,-N (R ¹⁵) C (O)-,-C (O) O-,-O-,-C (O)-,-OC (O) O-,-N (R ¹⁵) S (O) ₂-,-N (R ¹⁵) C (O) O-,-OS (O) ₂-or-C (O) N (R ¹⁵) N (R ^{15 '})-, be R wherein ¹⁵And R ^{15 '}Be independently selected from hydrogen, C respectively ₁-C ₆Alkyl, C ₂-C ₆Alkenyl or C ₂-C ₆Alkynyl;

R ⁵⁰Be-L ¹-A ¹, wherein:

In another embodiment, the present invention relates to have the compound of formula I (e), its tautomer, and the pharmacologically acceptable salt of described compound or tautomer,

Wherein:

W ₁, W ₂, W ₃And W ₄Be independently selected from N or C (R respectively ³³) (W for example ₁, W ₂And W ₃Be N, W ₄Be C (R ³³));

R ¹⁷, R ³³And R ³⁵When occurring, be independently selected from hydrogen, halogen, C respectively at every turn ₁-C ₆Alkyl or C ₃-C ₆Cycloalkyl;

R ⁴¹Be selected from hydrogen or C ₁-C ₆Alkyl;

A is C ₅-C ₁₂Carbocylic radical or M ₅-M ₁₂Heterocyclic radical (for example benzoxazolyl or phenyl), and optional by one or more R ¹⁸Replace;

X is-S-or-O-;

R ²²Be C ₄-C ₁₂Carbocylic radical or M ₄-M ₁₂Heterocyclic radical (for example phenyl or

R wherein ⁴⁸Be hydroxyl, amino, C ₁-C ₆Alkylamino, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkoxycarbonyl amino or C ₁-C ₆And R the alkyl-carbonyl oxygen base), ²²Optional by one or more R ²⁶Replace;

Y be a key ,-C (O) N (R ¹⁵)-or-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 a key, and A ¹Be C ₄-C ₁₂Carbocylic radical or M ₄-M ₁₂Heterocyclic radical, and optional by one or more R ³⁰Replace; Perhaps

L ¹Be a key, and A ¹Be two rings (for example fused bicyclic or bridged bicyclic), described two rings have 6-12 annular atoms, and optional by one or more R ³⁰Replace; Perhaps

R ¹⁸, R ²⁶, R ³⁰And R ³⁸Such as in the top embodiment definition; And

R ¹⁵, R ¹⁷, R ¹⁸, R ²⁶, R ³⁰, 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 and azido-by at least one.

In an example of this embodiment, W ₁, W ₂And W ₃Be N, W ₄Be C (R ³³), A is C ₇-C ₁₀Carbocylic radical or M ₇-M ₁₀Heterocyclic radical (for example two rings are as benzoxazolyl), and Y is a key.

In example described herein and embodiment, only such as but not limited to, A ¹Can be selected from: phenyl, pyridyl, thiazolyl, thienyl, furyl, tetrahydrofuran base, pyrryl, pyrazinyl, cyclobutyl, cyclohexyl, naphthyl, indolinyl, indenyl, 2,3-dihydro-1H-indenyl, chromanyl, benzo [d] [1,3] dioxa cyclopentenyl, 2,3-dihydrobenzo [b] [1,4] dioxane base, 3,4-dihydro-2H-benzo [b] [1,4] Dioxepane base, 1,2,3,4-tetralyl, 2,3-dihydro benzo furyl, 4,5,6,7-tetrahydrochysene benzfuran base, norborneol alkyl and adamantyl.Equally, only such as but not limited to, R ¹⁸, R ²⁶And R ³⁰When occurring, can be independently selected from 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 ₁-C ₆Haloalkyl, C ₁-C ₆Hydroxyalkyl, 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 and C ₁-C ₆Alkoxycarbonyl amino C ₁-C ₆Alkyl, and R ³⁸When occurring, can 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, C ₁-C ₆Haloalkyl, C ₁-C ₆Hydroxyalkyl, 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 ₁-C ₆Alkoxycarbonyl amino C ₁-C ₆Alkyl, C ₃-C ₅Cycloalkyl and C ₃-C ₅Cycloalkyl C ₁-C ₆Alkyl.

In another embodiment, the present invention relates to have formula I (a), the compound of I (b), I (c), I (d) or I (e), the tautomer of these compounds, and the pharmacologically acceptable salt of these compounds or tautomer, wherein:

R ¹⁷Be hydrogen, C ₁-C ₆Alkyl (R for example ¹⁷Be C ₁-C ₆Alkyl, for example sec.-propyl or methyl) or C ₃-C ₆Cycloalkyl;

R ⁴¹Be selected from hydrogen or C ₁-C ₆Alkyl (R for example ⁴¹Be hydrogen);

A is C ₅-C ₆Carbocylic radical or M ₅-M ₆Heterocyclic radical, and optional by one or more R ¹⁸Replace, and W ₁, W ₂, W ₃And W ₄Be independently selected from N or C (R respectively ³³) (W for example ₁, W ₂And W ₃Be N, W ₄Be C (R ³³));

R ³³And R ³⁵Be independently selected from hydrogen, halogen or C respectively ₁-C ₆Alkyl (R for example ³³And R ³⁵Be hydrogen);

X is-S-or-O-(for example X be-S-);

R ²²Be

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 (R for example ⁴⁸Be amino), and R ²²Optional by one or more R ²⁶Replace;

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

R ⁵⁰Be-L ¹-A ¹, wherein:

L ¹Be C ₁-C ₆Alkylidene group (L for example ¹Be-CH ₂-or-CH (CH ₃)-), and optional by one or more R ³⁸Replace A ¹Be C ₄-C ₁₂Carbocylic radical or M ₄-M ₁₂Heterocyclic radical (for example phenyl, pyridyl, thiazolyl, thienyl, furyl, tetrahydrofuran base, pyrryl, pyrazinyl, cyclobutyl, cyclohexyl or naphthyl), wherein A ¹Optional by one or more R ³⁰Replace, perhaps L ¹Be a key, and A ¹Be two ring (for example naphthyl, indolinyl, indenyl, 2,3-dihydro-1H-indenyl, chromanyl, benzo [d] [1,3] dioxa cyclopentenyls, 2 with 6-12 annular atoms, 3-dihydrobenzo [b] [1,4] dioxane base, 3,4-dihydro-2H-benzo [b] [1,4] Dioxepane base, 1,2,3,4-tetralyl, 2,3-dihydro benzo furyl, 4,5,6,7-tetrahydrochysene benzfuran base, norborneol alkyl or adamantyl), A wherein ¹Optional by one or more R ³⁰Replace; R ¹⁸, R ²⁶And 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 respectively at every turn ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Haloalkyl, C ₁-C ₆Hydroxyalkyl, 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 and C ₁-C ₆Alkoxycarbonyl amino C ₁-C ₆Alkyl; 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 ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Haloalkyl, C ₁-C ₆Hydroxyalkyl, 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 ₁-C ₆Alkoxycarbonyl amino C ₁-C ₆Alkyl, C ₃-C ₅Cycloalkyl and C ₃-C ₅Cycloalkyl C ₁-C ₆Alkyl;

M is 0,1,2 or 3;

N is 0 or 1;

P is 0,1,2 or 3; And

U is-CH ₂-or-CH ₂-CH ₂-, and optional by one or more R ¹⁸Replace.

R ¹⁷Be C ₁-C ₆Alkyl (for example sec.-propyl) or C ₃-C ₆Cycloalkyl;

R ³³And R ³⁵Be hydrogen;

R ⁴¹Be hydrogen;

W ₁, W ₂And W ₃Be N, W ₄Be C (H), and A is C ₅-C ₆Carbocylic radical or M ₅-M ₆Heterocyclic radical, and optional by one or more R ¹⁸Replace,

X is-S-;

R ²²Be

R wherein ⁴⁸Be amino, and R ²²Optional by one or more R ²⁶Replace;

Y is-C (O) N (R ¹⁵)-, be 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 C ₁-C ₆Alkylidene group (for example-CH ₂-or-CH (CH ₃)-), and optional by one or more R ³⁸Replace, and A ¹Be C ₄-C ₁₂Carbocylic radical or M ₄-M ₁₂Heterocyclic radical (for example phenyl, pyridyl, thiazolyl, thienyl, furyl, tetrahydrofuran base, pyrryl, pyrazinyl, cyclobutyl, cyclohexyl or naphthyl), and optional by one or more R ³⁰Replace, perhaps

L ¹Be a key, and A ¹Be two ring (for example naphthyl, indolinyl, indenyl, 2,3-dihydro-1H-indenyl, chromanyl, benzo [d] [1,3] dioxa cyclopentenyls, 2 with 6-12 annular atoms, 3-dihydrobenzo [b] [1,4] dioxane base, 3,4-dihydro-2H-benzo [b] [1,4] Dioxepane base, 1,2,3,4-tetralyl, 2,3-dihydro benzo furyl, 4,5,6,7-tetrahydrochysene benzfuran base, norborneol alkyl or adamantyl), and optional by one or more R ³⁰Replace;

R ¹⁸, R ²⁶And 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 respectively at every turn ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Haloalkyl, C ₁-C ₆Hydroxyalkyl, 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 and C ₁-C ₆Alkoxycarbonyl amino C ₁-C ₆Alkyl;

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 ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Haloalkyl, C ₁-C ₆Hydroxyalkyl, 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 ₁-C ₆Alkoxycarbonyl amino C ₁-C ₆Alkyl, C ₃-C ₅Cycloalkyl and C ₃-C ₅Cycloalkyl C ₁-C ₆Alkyl;

M is 0,1,2 or 3;

N is 0 or 1;

P is 0,1,2 or 3; And

U is-CH ₂-or-CH ₂-CH ₂-and optional by one or more R ¹⁸Replace.

As the limiting examples of above-mentioned embodiment, the pharmacologically acceptable salt of compound, its tautomer, compound or tautomer characterizes by at least one following feature or its any suitable combination:

(a) W ₁, W ₂And W ₃Be N, W ₄Be C (R ³³), and Z is-NR ⁴¹-;

(b) A is optional by one or more R ¹⁸The C that replaces ₅-C ₆Carbocylic radical;

(c) A is optional by one or more R ¹⁸The M that replaces ₅-M ₆Heterocyclic radical;

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

(e) Y is-C (O) N (R ¹⁵)-or-N (R ¹⁵) C (O)-, R ¹⁵Be hydrogen, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl or C ₂-C ₆Alkynyl, L ¹It is a key or optional by one or more R ³⁸The C that replaces ₁-C ₆Alkylidene group, and A ¹Be two rings with 6-14 annular atoms, and optional by one or more R ³⁰Replace;

(f) X be-O-or-S-, R ²²Be C ₅-C ₆Carbocylic radical or M ₅-M ₆Heterocyclic radical, and optional by one or more R ²⁶Replace;

(g) R ¹⁰, R ³³, R ³⁵, R ⁴¹And R ^{41 '}Be independently selected from hydrogen or C respectively ₁-C ₆Alkyl, and R ¹⁷Be C ₁-C ₆Alkyl;

(h) R ¹⁰Be hydrogen, and R ¹⁷Be C ₁-C ₆Alkyl;

(i) A ¹Be selected from phenyl, pyridyl, thiazolyl, thienyl, furyl, tetrahydrofuran base, pyrryl, pyrazinyl, cyclobutyl, cyclohexyl, naphthyl, indolinyl, indenyl, 2,3-dihydro-1H-indenyl, chromanyl, benzo [d] [1,3] dioxa cyclopentenyl, 2,3-dihydrobenzo [b] [1,4] dioxane base, 3,4-dihydro-2H-benzo [b] [1,4] Dioxepane base, 1,2,3,4-tetralyl, 2,3-dihydro benzo furyl, 4,5,6,7-tetrahydrochysene benzfuran base, norborneol alkyl and adamantyl;

(j) R ¹⁸, R ²⁶And 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 respectively at every turn ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Haloalkyl, C ₁-C ₆Hydroxyalkyl, 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 and C ₁-C ₆Alkoxycarbonyl amino C ₁-C ₆Alkyl;

(k) 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 ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Haloalkyl, C ₁-C ₆Hydroxyalkyl, 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 ₁-C ₆Alkoxycarbonyl amino C ₁-C ₆Alkyl, C ₃-C ₅Cycloalkyl and C ₃-C ₅Cycloalkyl C ₁-C ₆Alkyl; And/or

(l) has the compound of the formula that is selected from I (a), I (b), I (c), I (d) or I (e).

In another embodiment, the present invention relates to Pyridopyrimidine base-aminophenyl amide compound, the tautomer of described compound, and the pharmacologically acceptable salt of described compound or tautomer, wherein said compound is equivalent to the compound of formula I (f):

Wherein:

X is selected from O and S;

R ⁵⁰Be selected from

With

Wherein HET is optional by R ³⁰The heterocyclic radical that replaces;

R ³⁰Be one or more following substituting groups that are independently selected from: hydrogen, halogen, alkyl, haloalkyl, alkoxyl group, hydroxyl, Alkoximino alkyl, cyano group, alkylamino, haloalkyl cycloalkyl and aminocarboxyl;

R ²⁰Be selected from hydrogen and alkyl;

M is selected from 0 and 1 integer;

Perhaps R ⁵⁰And R ¹⁵Form the first monocyclic heterocycles of the heteroatomic 5-12 that contains one or more O of being selected from, N and S with their institute's bonded nitrogen; Wherein said heterocycle is optional to be replaced by at least one alkyl; Perhaps R ¹⁵Be selected from hydrogen and alkyl;

R ¹⁷Be selected from hydrogen and alkyl;

R ²²Be selected from aryl and heterocycle; R wherein ²²Optional by one or more R that are independently selected from ²⁶Substituting group replace;

R ²⁶Be selected from hydrogen; hydroxyl; heteroaryl; alkoxycarbonyl amino; amino; alkyl; the heterocyclic radical carbonylamino; miscellaneous alkyl aryl amino; amino carbonyl amino; alkoxycarbonyl amino; halogen; alkyl-carbonyl-amino; the aminoalkyl group carbonylamino; alkyl sulfonyl-amino; halo alkoxy carbonyl amino; miscellaneous alkyl aryl amino; alkylamino; alkyl amino-carbonyl; the alkylamino alkoxy carbonyl; the morpholino alkoxycarbonyl amino; the miscellaneous alkyl aryl alkoxycarbonyl amino; the alkylamino alkoxycarbonyl amino; alkylamino hydroxy alkoxy base carbonylamino; dialkyl amido; alkyl monosubstituted amino; the alkoxycarbonyl amino imino-; amino imino; [2-(miscellaneous alkyl aryl amino)-4-(halo heteroaryl amino carbonyl)]-(artyl sulfo) aryl-ureido; the heteroaryl carbonylamino; the aryl-alkyl amino carbonylamino; the cycloalkyl amino carbonylamino; the heteroarylalkyl amino carbonyl amino; the alkoxyalkyl amino carbonyl amino; aryl-alkoxy carbonyl amino; the heteroaryl alkoxycarbonyl amino; the heterocyclic radical alkoxycarbonyl amino; alkoxycarbonyl amino propyl group amino; aryl-amino-carbonyl; the alkoxyalkyl carbonylamino; the alkoxy aryl alkyl-carbonyl-amino; hydroxyalkyl aromatic yl alkyl carbonyl amino;

Azido-, alkylamino alkyl, morpholino carbonyl amino, alkyl amino-carbonyl amino, aryl-alkyl amino carbonylamino and cycloalkyl alkyl amino.

In an example of this embodiment, R ²²Be selected from

With

R ²⁴Be selected from hydrogen, hydroxyl, heteroaryl, alkoxycarbonyl amino, amino, alkyl, heterocyclic radical carbonylamino, miscellaneous alkyl aryl amino, amino carbonyl amino, alkoxycarbonyl amino and halogen;

Azido-, alkylamino alkyl, morpholino carbonyl amino, alkyl amino-carbonyl amino, aryl-alkyl amino carbonylamino and cycloalkyl alkyl amino;

R ²⁸Be selected from hydrogen, halogen and alkyl.

In another example of this embodiment, HET is selected from pyridyl, thiazolyl, thiadiazolyl group, isothiazolyl and morpholinyl; Perhaps R ⁵⁰With R ¹⁵Form optional together by one or more methyl substituted morpholinyls;

R ¹⁵Be selected from hydrogen, methyl and sec.-propyl;

R ¹⁷Be selected from hydrogen, methyl, sec.-propyl and the tertiary butyl;

R ²⁰Be selected from hydrogen and methyl;

R ²²As mentioned about described in the formula I (f);

R ²⁴Be selected from hydrogen, hydroxyl, 1H-indyl, tert-butoxycarbonyl amino, amino, pyrrolidyl carbonylamino, isopropyl pyridine also [2,3-d] pyrimidinyl-amino, amino carbonyl amino, fluorine and methyl;

R ²⁶Be selected from hydrogen, amino, hydroxyl, tert-butoxycarbonyl amino, the propyl group carbonylamino, the pyrrolidyl carbonylamino, the amino-ethyl carbonylamino, methyl sulfenyl amino, trichlorine ethoxy carbonyl amino, isopropyl pyridine also [2,3-d] pyrimidinyl-amino, N, N-dimethylamino carbonyl, methoxyl group, N, N-dimethylamino-ethoxy carbonyl, morpholinyl ethoxy carbonyl amino, 1-methylpyrrole alkyl-ethoxy carbonyl amino, 1-methyl-piperidyl-methoxycarbonyl amino, N, N-dimethylamino-propoxycarbonyl amino, three chloroethoxies-carbonylamino, N, N-dimethylamino-2-hydroxyl propoxycarbonyl amino, amino propoxycarbonyl amino, propyl group amino, N-methyl-N-propyl group amino, N-ethyl-N-propyl group amino, N, the N-dimethylamino, pyrryl, two-tert-butoxycarbonyl amino imino, the diamino imino-, [2-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base amino)-4-(5-bromopyridine-2-base aminocarboxyl)-phenyl sulfenyl] the phenyl amino carbonylamino, piperidino carbonyl amino, the phenyl methyl amino carbonyl amino, the amyl group amino carbonyl amino, the phenylethyl amino carbonyl amino, the thienyl methyl amino carbonyl amino, the furyl methyl amino carbonyl amino, the methoxy ethyl amino carbonyl amino, phenyl methoxycarbonyl amino, thienyl methoxycarbonyl amino, butoxy carbonyl amino, tetrahydrofuran base methoxycarbonyl amino, methoxy ethoxy-2-ethoxy carbonyl amino, phenylcarbonyl group amino, the ethoxyl methyl carbonylamino, dimethoxy benzene ylmethyl carbonylamino, hydroxymethyl phenyl methyl carbonylamino, azido-, methyl sulfenyl amino, N, N-dipropyl amino, 7-isopropyl pyridine also [2,3-d] pyrimidine-4-base amino, morpholinyl carbonyl amino, the methylamino carbonylamino, N, N-dimethylamino carbonylamino, the ethylamino carbonylamino, piperidino carbonyl amino, the cyclopentyl amino carbonyl amino, the cyclopropyl amino carbonyl amino, N-butyl-N-methylamino carbonylamino, the amyl group amino carbonyl amino, the ethoxyethyl group amino carbonyl amino, N-phenyl methyl-N-methylamino carbonylamino, N, N-diisopropylaminoethyl carbonylamino, N, the N-diethylamino, 2,2-dimethyl propyl amino, the cyclopropyl methylamino, piperidyl and piperidino carbonyl amino;

R ²⁸Be selected from hydrogen, chlorine and methyl;

R ³⁰Be one or more following substituting groups that are selected from: hydrogen, bromine, fluorine, methyl, hydroxyl, methoxyl group, methoxyimino ethyl, cyano group, trifluoromethyl, N, N-dimethylamino, trifluoromethyl cyclohexyl and aminocarboxyl.

A limiting examples of formula I (f) compound is 4-(4-amino-phenyl sulfenyl)-N-(5-bromo-pyridine-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide.

In another embodiment, the present invention relates to the reverse amide compound of Pyridopyrimidine base-aminophenyl, the tautomer of described compound, or the pharmacologically acceptable salt of described compound or tautomer, wherein the compound of this embodiment is structurally corresponding to formula I (g):

Wherein:

R ²⁷Be selected from hydrogen and alkyl;

R ³²Be selected from artyl sulfo and aryloxy; R wherein ³²Optional by one or more R that are independently selected from ³⁶Substituting group replace;

R ³⁶Be selected from hydrogen, hydroxyl, amino, dialkyl amido, halo alkoxy carbonyl amino, alkyl and alkoxy aryl;

R ⁶⁰Be selected from aryl and heterocyclic radical; R wherein ⁶⁰Optional by R ⁴⁰Replace;

R ⁴⁰Be selected from hydrogen, halogen, haloalkyl, alkoxyl group, halogenated alkoxy, dialkyl amido, alkyl monosubstituted amino, hydroxyl, alkyl-carbonyl-amino and alkyl.

In the subgroup of the embodiment in formula I (g), R ³²Be selected from

With

R ³⁴Be selected from hydrogen and hydroxyl;

R ³⁶Be selected from hydrogen, hydroxyl, amino, dialkyl amido, halo alkoxy carbonyl amino, alkyl and alkoxy aryl.

In another subgroup of embodiment in formula I (g), R ²⁷Be selected from hydrogen, methyl, ethyl and sec.-propyl;

R ³²Such as top about formula I (g) description;

R ³⁴Be selected from hydrogen and hydroxyl;

R ³⁶Be selected from hydrogen, hydroxyl, amino, N, N-dimethylamino, dichloro ethoxy carbonyl amino, the tertiary butyl, methyl and phenyl methoxyl group;

R ⁴⁰Be one or more following substituting groups that are selected from: hydrogen, trifluoromethyl, bromine, chlorine, fluorine, methoxyl group, trifluoromethoxy, N, N-dimethylamino, hydroxyl, methyl carbonylamino and methyl;

R ⁶⁰Be selected from phenyl, furyl, pyrazinyl, pyridyl, thienyl and pyrryl.

In another embodiment, the present invention relates to Pyridopyrimidine base-aminoheteroaryl compounds, the tautomer of described compound, or the pharmacologically acceptable salt of described compound or tautomer, wherein the compound of this embodiment is structurally corresponding to formula I (h):

Wherein:

R ⁵⁷Be selected from alkyl and hydroxyalkyl;

R ⁷⁴Be selected from hydrogen and hydroxyl;

R ⁸⁶Be selected from hydrogen, hydroxyl, halo alkoxy carbonyl amino and amino;

R ⁹⁰Be selected from halogenated aryl and aryl.

In the subgroup of the embodiment in formula I (h), R ⁵⁷Be selected from methyl, sec.-propyl and hydroxymethyl ethyl;

R ⁷⁴Be selected from hydrogen and hydroxyl;

R ⁸⁶Be selected from hydrogen, hydroxyl, amino and trichlorine ethoxy carbonyl amino;

R ⁹⁰Be selected from phenyl and bromophenyl.

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 phosphoric acid ester prodrug of the hydroxyl on the The compounds of this invention is preferred prodrug.

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, SectionE:Stereochemistry, and Recommendations 1974,

., 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 substituting group 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 straight chain or straight chain, 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 include 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 include 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 substituting group 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 straight chain or straight chain, 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.

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) be 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 o-Yi oxazinyl and p-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 ﹠ 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

Shown the exemplary process for preparing these [1,8] naphthyridine type compounds in the following reaction scheme 1,2,3 and 4.

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: the method for preparing 6-replacement-2-aminopyridine

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 pH10, 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: the method for 4-chloro-[1, the 8] naphthyridine that preparation replaces

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 pH12, 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 pH12, 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: preparation aminophenyl coupling agent

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: the coupling of 4-chloro-[1, the 8] naphthyridine of replacement and the amino-benzene base of replacement

R ⁹As defined above;

X as defined above;

R as defined above

Preparation 7-substituted-4-amino phenyl-replacement-pyrido [2,3-d] pyrimidine compound

Typical case's preparation (reaction scheme 8) of 7-substituted-4-amino phenyl-replacement-pyrido [2,3-d] pyrimidine compound comprises the aminophenyl coupling agent (being described in reaction scheme 3,5 and 6) and 6-replacement-2-amidino groups-3-cyanopyridine compound of replacement 9Linked reaction (reaction scheme 7).

Preparation acid amides coupling agent

Described in reaction scheme 3, multiple different aminophenyl coupling agent is possible.In reaction scheme 5, the aminophenyl compound that has the acid amides replacement in 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: preparation acid amides coupling agent

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 pH5 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: prepare reverse acid amides coupling agent

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

R as defined above.

Preparation N, N-dimethyl carbonamidine coupling agent 9:

The preparation of 7-substituted-4-amino phenyl-replacement-pyrido [2,3-d] pyrimidine can be passed through N, and N-dimethyl methyl amidino compounds 9 is finished with multiple coupling agent coupling, and some coupling agent is described in reaction scheme 3,5 and 6.

N, the preparation of N-dimethyl methyl amidine compound 9 can be finished described in reaction scheme 7.Be added in the diethyl ether solution of sodium hydride (or sodium Metal 99.5) at about 0 ℃ of alkyl methyl ketone and ethyl formate, carried out 2 hours replacement.After the adding, allow this be reflected at stirred overnight at room temperature.After adding ether again, go out precipitation, vacuum-drying in vacuum drier by the vacuum filtration sharp separation.With this material dissolves in the water that contains the 2-malonamide nitrile.Add the Piperidineacetic acid salts solution, and with about 2 hours of gained vlil.This mixture is cooled to room temperature, is adjusted to pH4 with Glacial acetic acid.Go out the gained solid by isolated by vacuum filtration, wash with water, and dry, and product is accredited as 6-replacement-2-oxo-1,2-dihydropyridine-3-formonitrile HCN 24.Available phosphoryl chloride changes into compound 24 2-chloro-pyridine (described in reaction scheme 7) or changes into the 2-bromopyridine.The 2-bromopyridine makes like this: prepare the toluene solution of compound 24, and under refluxad reacted about 5 hours with bromination Tetrabutyl amonium bromide and five phosphorus oxide.With the cooling of this reaction mixture, add entry, and with this mixture in stirring at room about 2 hours.With this reaction mixture dilution with toluene, isolate organic layer, use the salt water washing, and use dried over mgso, filter and vacuum concentration, obtained the 2-bromopyridine.The ethanolic soln and the liquefied ammonia of 2-chloropyridine or 2-bromopyridine were reacted about 20 hours in about 130 ℃ in the high pressure vessel of sealing.With this reaction mixture vacuum concentration, wash resistates with water, drying has obtained 6-replacement-2-amino-cigarette nitrile 25.With compound 25 and N, the dinethylformamide dimethyl acetal is dissolved in the toluene, and about 3 hours of reflux.Gained solution is cooled to room temperature, and vacuum concentration, 6-replacement-3-cyano group-pyridine-2-base-N obtained, N-dimethyl carbonamidine 9.

Reaction scheme 7: preparation N, N-dimethyl carbonamidine coupling agent

R ⁷As defined above

Preparation 7-substituted-4-amino phenyl-replacement-pyrido [2,3-d] pyrimidine

As mentioned above, 7-substituted-4-amino phenyl-replacement-pyrido [2,3-d] preparation of pyrimidine can be by will be as shown in reaction scheme 7 the 6-replacement-3-cyano group-pyridine-2-base-N of replacement, N-dimethyl carbonamidine 9 is finished with multiple coupling agent coupling, and some coupling agent is described in reaction scheme 3,5 and 6.This linked reaction has been described in the reaction scheme 8.

In typical preparation, answer the aminophenyl coupling agent described in scheme 3,5 and 6 to be dissolved in the acetate with being similar to compound, and about 130 ℃ of stir abouts 15 minutes.This mixture is cooled to room temperature, and vacuum is removed acetate, by reverse-phase chromatography purifying gained resistates.At this moment can by currently known methods remove any protective group base for example Boc, Troc etc. to generate end product.

The pyrido of reaction scheme 8:7-substituted-4-amino phenyl-replacement [2,3-d] pyrimidine

Reaction scheme 8: continuous

R ⁷, R ⁹, X and R as defined above

Preparation formula I, I (a), I (b), I (c), I (d) and I (e) compound

Synthetic being usually directed to of formula I, I (a), I (b), I (c), I (d) or I (e) compound

With

Reaction, W wherein ₁, W ₂, W ₃, W ₄, A, X, Y, R ¹⁰, R ¹⁷, R ²², R ³⁵And R ⁵⁰Have the implication that provides as in superincumbent embodiment or the example, and K is Cl or other halogen.Synthetic as formula I, I (a), I (b), I (c), I (d) or I (e) compound described in superincumbent embodiment or the example also in reaction scheme 9-12 illustrated.

The representative compounds of formula I, I (a), I (b), I (c), I (d) or I (e), wherein W ₄Be CH, W ₁, W ₂And W ₃Be N, and Z is NR ⁴¹, can use method to make as in reaction scheme 9, describing.

Reaction scheme 9

Can be in acid such as but not limited in the presence of the acetate, in the following wherein R of high temperature (for example about 80 ℃ to about 150 ℃) ⁴¹The amine of formula (2) that is hydrogen is with the N of formula (1), and N-dimethyl methyl amidine compound is handled, thus the compound of production (3).Acetate can play the function of solvent.Other suitable solvents also can be used for this reaction.

R wherein ⁴¹The N-alkylation that is formula (2) compound of hydrogen generates wherein R ⁴¹Be formula (2) and (3) compound of alkyl.This method can be used formula R ⁴¹X ¹Alkylating agent promote X wherein ¹Be halogen, tosylate, triflate or methanesulfonates, at alkali, such as but not limited to organic bases for example triethylamine or diisopropylamine, or mineral alkali for example yellow soda ash, cesium carbonate or salt of wormwood exist down, in suitable solvent, and carry out under in about room temperature to about 100 ℃ of temperature.

Reaction scheme 10

The N of formula (1), the preparation of N-dimethyl methyl amidine compound can make described in reaction scheme 10.With the ketone of formula (4) and the ester of formula (5), alkali such as but not limited to sodium hydride or potassium hydride KH (or sodium Metal 99.5) in the presence of, in about 0 ℃, react in such as but not limited to ether at suitable solvent, the salt of acquisition formula (6), wherein M is potassium or sodium.In the presence of Piperidineacetic acid salt, under about reflux conditions, with formula (6) salt handle production (7a) and nitrile (7b) with the 2-malonamide nitrile.Can be at this moment or in the later stage of route of synthesis, use purification technique well known by persons skilled in the art to come separated region isomer (7a) and (7b).By handling, formula (7a) compound can be changed into wherein X with phosphoryl chloride ²Be formula (8) compound of Cl, perhaps,, formula (7a) compound can be changed into wherein X by in suitable solvent, under reflux conditions, handling with Tetrabutylammonium bromide and five phosphorus oxide ²It is formula (8) compound of Br.To wherein X ²Be the solution of formula (8) compound of Cl or Br and liquefied ammonia in the high pressure vessel of sealing under high temperature, for example in about 130 ℃ of reactions, acquisition formula (9) compound.Formula (9) compound and N, the dinethylformamide dimethyl acetal reacts the N of production (1), N-dimethyl methyl amidine compound at solvent in such as but not limited to toluene under reflux state.

Reaction scheme 11

R wherein ⁴¹Be hydrogen, and X be formula (2) compound of O or S can be according to reaction scheme 11 by formula (10) compound via synthetic making of two steps, wherein R ₁₀₁Be leavings group such as but not limited to halogen, triflate or methanesulfonates (fluorine methanesulfonates or methanesulfonates can use method known to those skilled in the art to be made by corresponding alcohol), described two steps are synthetic to be that the reduction of nitro is R then ₁₀₁Displacement, perhaps R ₁₀₁Displacement, be the reduction of nitro then.

R ₁₀₁With X wherein is the R of O or S ²²The displacement of XH can suitable alkali such as but not limited to salt of wormwood, saleratus, cesium carbonate, cesium bicarbonate, yellow soda ash, sodium bicarbonate, sodium hydride or potassium hydride KH in the presence of, and choose wantonly in the presence of 18-hat-6, in the high temperature promotion of getting off.This reaction usually at solvent such as but not limited to N, extremely carry out under about 180 ℃ of temperature in about room temperature in dinethylformamide or the methyl-sulphoxide.This reaction usually at solvent such as but not limited to N, extremely carry out under about 180 ℃ of temperature in about room temperature in dinethylformamide or the methyl-sulphoxide.This reaction can also be carried out in microwave oven.Should be appreciated that formula (11) compound can also pass through wherein R ₁₀₁Be-formula (10) compound of X-H and X wherein ³Be the formula R of leavings group such as but not limited to halogen, triflate or methanesulfonates ²²X ³The reaction of compound uses the reaction conditions of having a try to obtain.This replacement(metathesis)reaction can also be carried out in the presence of metal catalyst, described metal catalyst is such as but not limited to metallic copper, CuI or acid chloride, choose wantonly at part such as but not limited to 2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene or tri-butyl phosphine exist down, and choose wantonly alkali such as but not limited to pyridine, triethylamine, sodium tert-butoxide, cesium carbonate or sodium hydride in the presence of.This reaction generally,, is carried out in the dinethylformamide such as but not limited to toluene or N at solvent extremely under about 180 ℃ of temperature in about room temperature.

The reduction of nitro can be finished by handling nitro-compound with reductive agent such as but not limited to iron powder/ammonium chloride or tin chloride (II) in suitable solvent.

It is also understood that also and can by the following method formula (10) compound be transformed an accepted way of doing sth (2) compound: use aforesaid reaction conditions, at first, carry out replacement(metathesis)reaction then the nitro functions reduction.

Reaction scheme 12

Reaction scheme 12 has been described the preparation of formula I compound, wherein W ₄Be CH, W ₁, W ₂And W ₃Be N, Z is NR ⁴¹, and Y is C (O) N (R ¹⁵) or C (S) N (R ¹⁵).

Can be with wherein X by alkyl or benzyl ester hydrolysis or hydrogenation is accordingly obtained ⁴Be oxygen, and R ₁₀₂The acid that is the formula (13) of hydrogen transforms an accepted way of doing sth (13a) compound.This can be by finishing with suitable amine coupling.Standard linked reaction condition is well known by persons skilled in the art.A kind of such condition is, at first this acid is changed into Acibenzolar, for example use N-hydroxyl 1 succinimide, N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride or TBTU, with alkali such as but not limited to N-methylmorpholine or diisopropylethylamine, handle this acid at solvent in such as but not limited to methylene dichloride or methyl-sulphoxide, do not separate, use formula N (H) (R then ^w) (R ³) or formula NR ¹⁵R ⁵⁰The amine of H is handled this activatory ester.In reaction scheme 9, such operation can also be applied to formula (2) compound before at formula (2) compound and the reaction of formula (1) compound.

X wherein ⁴Be the formula (13) of O or (13a) compound to X wherein ⁴It is the formula (13) of S or (13a) conversion of compounds can be by realizing with the Lawesson agent treated.

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 in a 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

N-(4-fluoro-3-methyl-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-methoxyl group-phenyl sulfenyl)-benzamide

According to the method for embodiment 137C, substitute 5-amino-ortho-cresol with 4-fluoro-3-monomethylaniline, will derive from product and the reaction of 4-fluoro-3-monomethylaniline of embodiment 137B, after reaction product developed from methyl alcohol, obtained this title compound, be pale solid (61mg, 68%).1H?NMR(300MHz，DMSO-D6)δ?ppm10.21(s，1H)，10.19(s，1H)，8.86(d，J＝8.46Hz，1H)，8.59(s，1H)，7.98(s，1H)，7.80(dd，J＝8.46，1.47Hz，1H)，7.62-7.68(m，2H)，7.52-7.59(m，1H)，7.40(d，J＝8.82Hz，2H)，7.11(t，J＝9.19Hz，1H)，6.96-7.04(m，J＝8.82Hz，3H)，3.77(s，3H)，3.17-3.29(m，1H)，2.22(d，J＝1.47Hz，3H)，1.34(d，J＝6.99Hz，6H)；MS(ESI ⁺)m/z?554.2(M+H) ⁺，(ESI ^-)m/z?552.2(M-H) ^-。

Embodiment 2

N-(4-fluoro-3-methyl-phenyl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

According to the method for embodiment 150,, the product of embodiment 1 is reacted with the product of the product alternate embodiment 138 of embodiment 1, obtained resistates, come purifying, obtained this title compound by development from methyl alcohol, be pale solid (9.6mg, 20%).1H?NMR(300MHz，DMSO-D6)δ?

10.20(s，1H)，10.15(s，1H)，9.95(s，1H)，8.84(s，1H)，8.57(s，1H)，7.95(s，1H)，7.71-7.87(m，1H)，7.65(dd，J＝7.17，2.39Hz，1H)，7.61(s，1H)，7.52-7.59(m，1H)，7.31(d，J＝8.46Hz，2H)，7.10(t，J＝9.19Hz，1H)，6.91(s，1H)，6.85(d，J＝8.82Hz，2H)，3.19-3.27(m，J＝0.74Hz，1H)，2.22(s，3H)，1.33(d，J＝6.99Hz，6H)；MS(ESI ⁺)m/z?540.2(M+H) ⁺，(ESI ^-)m/z?538.2(M-H) ^-。

Embodiment 3

3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-methoxyl group-phenyl sulfenyl)-N-(3-trifluoromethyl-phenyl)-benzamide

According to the method for embodiment 137C, replace 5-amino-ortho-cresol with 3-(trifluoromethyl) aniline, will derive from product and 3-(trifluoromethyl) aniline reaction of embodiment 137B, after reaction product developed from methyl alcohol, obtained this title compound, be pale solid (73mg, 77%).1H?NMR(300MHz，DMSO-D6)δ?ppm：10.54(s，1H)，8.93(d，J＝8.46Hz，1H)，8.67(s，1H)，8.22(s，1H)，8.04(d，J＝8.09Hz，1H)，7.99(s，1H)，7.85(d，J＝7.72Hz，1H)，7.74(d，J＝8.46Hz，1H)，7.59(t，J＝8.09Hz，1H)，7.45(d，J＝8.46Hz，1H)，7.41(d，J＝8.82Hz，2H)，6.92-7.11(m，4H)，3.77(s，3H)，3.20-3.31(m，1H)，1.35(d，J＝6.62Hz，6H)；MS(ESI ⁺)m/z?590.3(M+H) ⁺，(ESI ^-)m/z?588.1(M-H) ^-。

Embodiment 4

4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(3-trifluoromethyl-phenyl)-benzamide

According to the method for embodiment 150,, the product of embodiment 3 is reacted with the product of the product alternate embodiment 138 of embodiment 3, obtained resistates, come purifying, obtained this title compound by development from methyl alcohol, be pale solid (16.7mg, 28%).1H?NMR(300MHz，DMSO-D6)δ?ppm：10.48(s，1H)，10.21(s，1H)，9.97(s，1H)，8.88(d，J＝9.19Hz，1H)，8.59(s，1H)，8.21(s，1H)，7.95-8.10(m，2H)，7.83(d，J＝8.46Hz，1H)，7.62-7.69(m，J＝6.80，2.39Hz，1H)，7.59(t，J＝8.09Hz，1H)，7.44(d，J＝7.35Hz，1H)，7.32(d，J＝8.46Hz，2H)，6.90-6.99(m，1H)，6.86(d，J＝8.46Hz，2H)，3.20-3.29(m，1H)，1.34(d，J＝6.99Hz，6H)；MS(ESI ⁺)m/z?576.2(M+H) ⁺，(ESI ^-)m/z?574.2(M-H) ^-。

Embodiment 5

3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-methoxyl group-phenyl sulfenyl)-N-(4-trifluoromethyl-phenyl)-benzamide

Method according to embodiment 137C, substitute 5-amino-ortho-cresol with 4-(trifluoromethyl) aniline, product and 4-(trifluoromethyl) aniline reaction of embodiment 137B will be derived from, after reaction product developed from methyl alcohol, obtained the reaction of this title compound, be pale solid (62mg, 65%).1H?NMR(300MHz，DMSO-D6)δ?ppm：10.86(s，1H)，10.56(s，1H)，8.92(d，J＝6.99Hz，1H)，8.66(s，1H)，7.99(d，J＝8.46Hz，2H)，7.84(d，J＝7.72Hz，1H)，7.58-7.78(m，3H)，7.36-7.50(m，2H)，7.23-7.36(m，1H)，6.86-7.14(m，3H)，3.77(s，3H)，3.20-3.29(m，1H)，1.35(d，J＝6.62Hz，6H)；MS(ESI ⁺)m/z?590.6(M+H) ⁺，(ESI ^-)m/z?588.2(M-H) ^-。

Embodiment 6

4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(4-trifluoromethyl-phenyl)-benzamide

According to the method for embodiment 150,, the product of embodiment 5 is reacted with the product of the product alternate embodiment 138 of embodiment 5, obtained resistates, come purifying, obtained this title compound by development from methyl alcohol, be pale solid (7.7mg, 16%).1H NMR (300MHz, DMSO-D6) δ ppm9.15 (d, J=8.82Hz, 1H), 9.01 (s, 1H), 7.93-8.10 (m, 5H), 7.71 (d, J=8.82Hz, 2H), 7.34 (d, J=8.46Hz, 2H), 7.10 (d, J=8.46Hz, 1H), and 6.82-6.90 (m, 2H), 3.27-3.44 (m, 1H), 1.40 (d, J=6.99Hz, 6H) [with a TFA be added in the NMR pipe with accelerate to split-therefore without any NH or OH peak]; MS (ESI ⁺) m/z 576.2 (M+H) ⁺, (ESI ^-) m/z 574.2 (M-H) ^-

Embodiment 7

N-(3-dimethylamino-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-methoxyl group-phenyl sulfenyl)-benzamide

Method according to embodiment 137C, use N, N-dimethyl-1, the 3-phenylenediamine substitutes 5-amino-ortho-cresol, will derive from product and the N of embodiment 137B, N-dimethyl-1, the 3-phenylenediamine reacts, and after reaction product is developed from methyl alcohol, has obtained this title compound, be pale solid (53mg, 58%).1H?NMR(300MHz，DMSO-D6)δ?ppm10.33(s，1H)，9.99(s，1H)，8.87(s，1H)，8.61(s，1H)，7.98(s，1H)，7.80(s，1H)，7.65(d，J＝6.62Hz，1H)，7.40(d，J＝8.82Hz，2H)，7.09-7.19(m，3H)，6.94-7.05(m，3H)，6.41-6.53(m，1H)，3.77(s，3H)，3.18-3.30(m，1H)，2.88(s，6H)，1.34(d，J＝6.99Hz，6H)；MS(ESI ⁺)m/z565.3(M+H) ⁺，(ESI ^-)m/z?563.3(M-H) ^-。

Embodiment 8

3-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxymethyl]-benzonitrile

Embodiment 8A

4-methyl-3-oxo-valeral, sodium salt

To be equipped with the flame-dried 100-mL flask nitrogen purging of 25-mL addition funnel, and to wherein adding anhydrous diethyl ether (40mL), add then the sodium thin slice (1.65g, 0.0725mol).This reaction mixture is cooled to ice/bath temperature, and 0 ℃ via added lentamente in 1.5 hours methyl isopropyl Ketone (6.244g, 0.0725mol) and ethyl formate (5.481g, 0.0725mol) solution in anhydrous diethyl ether (5mL).Add finish after, remove cooling bath, and with this reaction mixture in stirred overnight at room temperature.And then add ether (10mL) breaking the gained precipitation, and go out solid by the vacuum filtration sharp separation.Solid is washed with a small amount of ether, in vacuum drier dry 1 hour then, obtained this title product, be pale solid (5.35g, 54% productive rate).This product need not be further purified and be used for next step.

Embodiment 8B

6-sec.-propyl-2-oxo-1,2-dihydro-pyridine-3-formonitrile HCN

To the product of embodiment 8A (5.35g, 0.0393mol) and the 2-malonamide nitrile (3.47g, 0.0413mol) solution in water (35mL) was in stirring at room 10 minutes.The stock solution (making) that in this mixture, adds 2.5mL Piperidineacetic acid salt by 9.8mL piperidines, 6mL acetate and 10mL water, and with this vlil 2 hours.Then this mixture is cooled to room temperature, is adjusted to pH4 by adding Glacial acetic acid.Isolate the gained light yellow solid by vacuum filtration, (2 * 30mL) washings, and vacuum-drying have obtained this title product (4.36g, 68%) to water.

Embodiment 8C

2-bromo-6-sec.-propyl-cigarette nitrile

With the product of embodiment 8B (4.35g, 0.0269mol), (10.4g, 0.0323mol) (8.01g, 1.05mol) vlil in toluene (80mL) is 5 hours with five phosphorus oxide for Tetrabutylammonium bromide.Then this reaction mixture is cooled to room temperature, adds entry (80mL), and with this mixture stirring at room 2 hours.This reaction mixture is diluted with toluene (20mL), and isolate organic layer.Water layer is washed with toluene (50mL), and the organic layer that merges is washed with salt solution (50mL), use anhydrous magnesium sulfate drying, filter, and vacuum concentration, obtained this title product, be yellow oil (5.64g, 93%).

Embodiment 8D

2-amino-6-sec.-propyl-cigarette nitrile

With embodiment 8C (21g, 0.093mol) and the solution of liquefied ammonia (250mL) in 500mL ethanol in sealed high-pressure vessel in 130 ℃ the reaction 20 hours.With this reaction mixture vacuum concentration, and resistates is ground to fine powder, (2 * 50mL) washings, and in vacuum drying oven dry 24 hours have obtained this title compound to water, are beige solid (14g, 93%) then.

Embodiment 8E

N '-(3-cyano group-6-sec.-propyl-pyridine-2-yl)-N-N-dimethyl-carbonamidine

(7.1g, 0.044mol) and N, (6.44mL, 0.0484mol) vlil in toluene (100mL) is 3 hours for the dinethylformamide dimethyl acetal with the product of embodiment 8D.Gained solution is cooled to room temperature, and vacuum concentration, obtained this title compound (9.5g, 100%), be dense brown oil, it can solidify when leaving standstill.Though show that by NMR this product is pure, it contains a small amount of high foreign pigment.It can be carried out silica gel chromatography purifying (ethyl acetate/hexane gradient), obtain light yellow oil, it can solidify (having reclaimed about 70% from chromatogram purification) when leaving standstill.

Embodiment 8F

3-(4-chloro-3-nitro-phenoxymethyl)-benzonitrile

According to the method for embodiment 9C, substitute 1-chloromethyl-4-methoxyl group-benzene with 3-brooethyl-benzonitrile, made this title compound (0.813g, 98%).

Embodiment 8G

3-[4-(4-hydroxyl-phenyl sulfenyl)-3-nitro-phenoxymethyl]-benzonitrile

According to the method for embodiment 9D, substitute 1-chloro-4-(4-methoxyl group-benzyloxy)-2-nitro-benzene with 3-(4-chloro-3-nitro-phenoxymethyl)-benzonitrile, made this title compound (1.07g, 100%).

Embodiment 8H

3-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenoxymethyl]-benzonitrile

According to the method for embodiment 9D, foretell benzonitrile with 3-[4-(4-hydroxyl-phenyl sulfenyl)-3-nitro-phenoxymethyl and substitute 4-[4-(4-methoxyl group-benzyloxy)-2-nitro-phenyl sulfenyl]-phenol, made this title compound (0.97g, 98%).

Embodiment 8I

With the product of embodiment 8E (47.4mg, 0.219mmol) and the product of embodiment 8H (76.3mg, 0.219mmol) solution in acetate (1mL) is being preheated in 130 ℃ the oil bath and was stirring 15 minutes.Then this mixture is cooled to room temperature, vacuum is removed acetate, and pass through at Waters Symmetry C8 post (25mm * 100mm, 7 μ m particle diameters) the anti-phase preparation HPLC purifying gained resistates that carries out on, use 10% to the 100% acetonitrile/solution gradient of 0.1% trifluoroacetic acid in water with 8 minutes (10 minute runtime) of speed wash-out of 40mL/ minute, obtained this title compound, be trifluoroacetate (14mg, 10%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：10.94(s，1H)，9.69(s，1H)，8.88(d，J＝8.46Hz，1H)，8.70(s，1H)，7.92(s，1H)，7.72-7.87(m，3H)，7.62(t，J＝7.72Hz，1H)，7.15-7.28(m，J＝8.82Hz，2H)，7.08-7.15(m，2H)，6.99-7.06(m，1H)，6.61-6.72(m，2H)，5.18(s，2H)，3.19-3.30(m，1H)，1.34(d，J＝6.99Hz，6H)；MS(ESI)m/z?520.3(M+H)+，(ESI-)m/z?518.3(M-H)-。

Embodiment 9

4-[4-(4-methoxyl group-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol

Embodiment 9A

2-amino-6-methyl-cigarette nitrile

With 2-chloro-6-methyl-cigarette nitrile (25g, 0.164mol) and liquefied ammonia (250mL) in 500mL ethanol in sealed high-pressure vessel in 130 ℃ the reaction 20 hours.With this reaction mixture vacuum concentration, and with the resistates water (2 * 50mL) washings, in vacuum drying oven dry 24 hours then, obtained this title compound, be light yellow solid (18g, 82%). ¹H?NMR(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 9B

N '-(3-cyano group-6-methyl-pyridine-2-yl)-N, N-dimethyl-carbonamidine

(10g, 75.19mmol) and N, (11mL, 82.71mmol) vlil in toluene (100mL) is 6 hours for the dinethylformamide dimethyl acetal with the product of embodiment 9A.After being cooled to room temperature,, obtained this title compound, be yellow solid (13.78g, 98%) this solution for vacuum concentration. 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 9C

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, the solution in the dinethylformamide (5ml) was in stirring at room 16 hours.Then frozen water (10mL) is added in this solution, collects the gained solid by filtering, and dry in vacuum drying oven, obtained this title compound (0.812g, 96%).

Embodiment 9D

4-[4-(4-methoxyl group-benzyloxy)-2-nitro-phenyl sulfenyl]-phenol

With the product of embodiment 9C (0.812g, 2.76mmol), the 4-hydroxythiophenol (0.419,3.32mmol) and cesium carbonate (2.16g, 6.64mmol) at N, the solution in the dinethylformamide (5mL) was in 100 ℃ of heating 16 hours.After being cooled to room temperature, this mixture is poured in the frozen water (20mL), gained solution 1N hcl acidifying.(3 * 10mL) extractions with the extraction liquid dried over mgso that merges, are filtered and vacuum concentration, have obtained this title compound (1.06g, 100%) with ethyl acetate with this solution then.

Embodiment 9E

4-[2-amino-4-(4-methoxyl group-benzyloxy)-phenyl sulfenyl]-phenol

With the product of embodiment 9D (1.06g, 2.76mmol), iron powder (0.63g, 11.04mmol) and ammonium chloride (0.18g, 3.31mmol) vlil in methyl alcohol (18mL), tetrahydrofuran (THF) (18mL) and water (6mL) solution is 3 hours.The gained mixture is diluted with methyl alcohol (50mL), and filter via Celite pad.The filtrate vacuum concentration to 10mL, is diluted this solution with water (50mL), and (2 * 50mL) extract with ethyl acetate.With the extraction liquid dried over mgso that merges, filter and vacuum concentration, obtained this title compound (0.99g, 100%).

Embodiment 9F

With the product of embodiment 9B (28.4mg, 0.151mmol) and the product of embodiment 9E (53.3mg, 0.151mmol) solution in acetate (1mL) is being preheated in 130 ℃ the oil bath and was stirring 20 minutes.Then this mixture is cooled to room temperature, vacuum is removed acetate, and the gained resistates is developed with methyl alcohol, has obtained this title compound, is tawny 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)-。

Embodiment 10

4-(4-amino-phenoxy group)-N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 10A

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

With the mixture of 4-bromaniline (2.58g 14.99mmol) in anhydrous methylene chloride (100mL) 4-chloro-3-nitrobenzoyl chloride (3.60g, 17.99mmol) and N, the N-diisopropylethylamine (3.14mL 17.99mmol) handles, and with the gained mixture stirring at room 17 hours.Remove by rotary evaporation in vacuo and to desolvate, resistates is placed ethyl acetate (100mL), and water (2 * 50mL) and the salt water washing., filter the organic extract liquid drying with anhydrous sodium sulphate, and vacuum concentration, obtained product, be tawny solid (5.132g, 14.45mmol, 96%).

Embodiment 10B

4-[4-(4-bromo-phenyl amino formyl radical)-2-nitro-phenoxy group] phenyl }-t-butyl carbamate

At the product (5.132g of room temperature with embodiment 10A, 14.45mmol) at anhydrous N, solution in the dinethylformamide (50mL) N-Boc-4-hydroxyanilines (3.024g, 14.45mmol) and salt of wormwood (3.994g, 28.90mmol) handle, heated 4.5 hours under nitrogen atmosphere at 80 ° then.This reaction is cooled to room temperature, and removes by rotary evaporation in vacuo and to desolvate.Resistates is placed ethyl acetate (200mL), and water (4x50mL) and salt solution (50mL) washing.With the organic layer anhydrous sodium sulfate drying, filter, and concentrate by rotary evaporation, obtained product, be dark yellow solid (7.38g, 13.97mmol, 97%).

Embodiment 10C

4-[2-amino-4-(4-bromo-phenyl amino formyl radical)-phenoxy group]-phenyl }-t-butyl carbamate

With the product of embodiment 10B (7.383g, 13.97mmol), iron powder (4.80g, 85.94mmol) and ammonium chloride (4.896g, 91.53mmol) solution in ethanol (60mL), tetrahydrofuran (THF) (60mL) and water (30mL) was 80 ° of heating 1.5 hours.After being cooled to room temperature, with this mixture with ethyl acetate (300mL) dilution, and water (4 * 100mL) and salt solution (50mL) wash., filter and vacuum concentration the organic phase drying with sodium sulfate, obtained this title compound, be light tan solid (6.658g, 13.36mmol, 96%).

Embodiment 10D

4-[4-(4-bromo-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-phenyl }-t-butyl carbamate

With the product of embodiment 8E (2.89g, 13.36mmol) and the product of embodiment 10C (6.658g, 13.36mmol) solution in acetate (50mL) is being preheated in 140 ℃ the oil bath and was stirring 20 minutes.This reaction is cooled to room temperature,, concentrates by rotary evaporation with hexane (250mL) dilution, and with dichloromethane/hexane coevaporation (4 *).Resistates is dry under high vacuum.By fast silica gel chromatogram purifying resistates, with 30% ethyl acetate/dichloromethane wash-out, use the ethanol/methylene wash-out then, obtained this title compound, be brown solid (6.48g, 72%).

Embodiment 10E

In room temperature, (2.78g 4.152mmol) handled 30 minutes in methylene dichloride (25mL) with trifluoroacetic acid (25mL) with the product of embodiment 10D.Remove by rotary evaporation in vacuo and to desolvate, and resistates is placed in the ethyl acetate (400mL), and with saturated sodium bicarbonate aqueous solution (2 * 100mL), water (2 * 100mL) and salt solution (100mL) wash.With the organic phase anhydrous sodium sulfate drying, filter, and vacuum concentration.The gained solid is developed with 3% ethanol/methylene, and vacuum-drying, obtained this title compound, be oldlace solid (1.77g, 75%). ¹HNMR(300MHz，DMSO-D6)δ?ppm?1.32(d，J＝6.99Hz，6H)3.09-3.31(m，1H)5.03(s，2H)6.57(d，J＝8.82Hz，2H)6.78(d，J＝8.82Hz，2H)6.83(d，J＝8.82Hz，1H)7.53(d，J＝8.82Hz，2H)7.60(d，J＝8.82Hz，1H)7.75(d，J＝9.19Hz，2H)7.85(dd，J＝8.46，2.21Hz，1H)8.16(d，J＝2.21Hz，1H)8.62(s，1H)8.84(d，J＝8.46Hz，1H)10.00(s，1H)10.29(s，1H)；MS(ESI+)m/z?569/571(M+H) ⁺，MS(ESI-)m/z?567/569(M-H) ^-。

Embodiment 11

4-(4-amino-phenoxy group)-N-(5-bromo-pyridine-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 11A

4-[2-amino-4-(5-bromo-pyridine-2-base formamyl)-phenoxy group]-phenyl }-t-butyl carbamate

Method according to embodiment 10A is reacted 4-chloro-3-nitrobenzoyl chloride and 5-bromo-pyridine-2-base amine, generated N-(4-bromo-phenyl)-4-chloro-3-nitro-benzamide, use the method for embodiment 10B and 10C that it is handled successively, obtained this title product.

Embodiment 11B

Use the method for embodiment 10D; product with the product alternate embodiment 10C of embodiment 11A; the product of embodiment 11A and the product of embodiment 8E are reacted; obtained { 4-[4-(5-bromo-pyridine-2-base formamyl)-2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-phenoxy group]-phenyl }-t-butyl carbamate; use the method for embodiment 10E to react it; obtained the crude product of this title compound; pass through silica gel chromatography; use ethanol/methylene as eluent; obtained this title compound (74mg, 53%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm?1.32(d，J＝6.99Hz，6H)3.13-3.30(m，1H)5.04(s，2H)6.57(d，J＝8.82Hz，2H)6.80(d，J＝8.83Hz，2H)6.78(d，J＝8.45Hz，1H)7.60(d，J＝8.46Hz，1H)7.95(dd，J＝8.64，2.39Hz，1H)8.06(dd，J＝8.82，2.57Hz，1H)8.18(d，J＝8.82Hz，1H)8.25(d，J＝1.84Hz，1H)8.50(d，J＝2.57Hz，1H)8.62(s，1H)8.85(d，J＝8.46Hz，1H)9.97(s，1H)10.90(s，1H)；MS(ESI+)m/z?570/572(M+H)+，(ESI-)m/z?568/570(M-H)-。

Embodiment 12

4-(4-amino-phenoxy group)-N-(5-bromo-thiazol-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 12A

4-[2-amino-4-(5-bromo-thiazol-2-yl formamyl)-phenoxy group]-phenyl }-t-butyl carbamate

Method according to embodiment 10A, mixture and the reaction of 5-bromo-thiazol-2-yl amine with 4-chloro-3-nitrobenzoyl chloride, make N-(5-bromo-thiazol-2-yl)-4-chloro-3-nitro-benzamide, used the method for embodiment 10B and 10C that it is handled successively, obtained this title product.

Embodiment 12B

Embodiment 8E uses the method for embodiment 10D; product with the product alternate embodiment 10C of embodiment 12A; the product of embodiment 12A and the product of embodiment 8E are reacted; obtained { 4-[4-(5-bromo-thiazol-2-yl formamyl)-2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-phenoxy group]-phenyl }-t-butyl carbamate; use the method for embodiment 10E to react it; obtained the crude product of this title compound; it is passed through silica gel chromatography; use methyl alcohol/methylene fluoride as eluent; obtained this title compound (110mg, 72%).1H?NMR(300MHz，DMSO-D6)δ?ppm?1.32(d，J＝6.99Hz，6H)3.13-3.28(m，1H)5.06(s，2H)6.58(d，J＝8.82Hz，2H)6.79(d，J＝8.82Hz，2H)6.80(d，J＝8.45Hz，1H)7.61(d，J＝8.46Hz，1H)7.64(s，1H)8.01(dd，J＝8.82，2.21Hz，1H)8.34(d，J＝2.21Hz，1H)8.64(s，1H)8.85(d，J＝8.46Hz，1H)9.98(s，1H)12.83(s，1H)；MS(ESI+)m/z?576/578(M+H)+。

Embodiment 13

4-(4-amino-phenyl sulfenyl)-N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 13A

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

With the product of embodiment 10A (1.00g, 2.816mmol), the 4-aminothiophenol (529mg, 4.224mmol) and anhydrous sodium acetate (1.155g, 14.08mmol) reflux 19 hours under nitrogen atmosphere of the mixture in dehydrated alcohol (30mL).This reaction is cooled to room temperature, and removes ethanol by rotary evaporation.Resistates is placed in the water (50mL), and (2 * 100mL) extract with ethyl acetate.The organic extract liquid that merges is washed with salt solution (50mL), use anhydrous sodium sulfate drying, filter, and vacuum concentration.Solid with 4% ethyl acetate/dichloromethane (25mL) development, has been obtained this title compound, be yellow solid (1.091g, 87%).

Embodiment 13B

4-[4-(4-bromo-phenyl amino formyl radical)-2-nitro-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Product (1.091g with embodiment 13A, 2.456mmol) and tert-Butyl dicarbonate (804mg, 3.683mmol) 1, mixture in the 4-dioxane (16mL) reflux 5.5 hours under nitrogen atmosphere, at this moment add other Boc acid anhydrides (750mg) again, and allow this reaction reflux again 15 hours.This reaction is cooled to room temperature, and removes by rotary evaporation in vacuo and to desolvate.The gained solid is developed with 2.5% ethyl acetate/dichloromethane, obtained this title compound, be orange solids (1.198g, 90%).

Embodiment 13C

4-[2-amino-4-(4-bromo-phenyl amino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

With the product of embodiment 13B (1.198g, 2.20mmol), iron powder (756mg, 13.53mmol) and ammonium chloride (771mg, 14.41mmol) suspension in water (15mL) and ethanol (30mL) was in 90 ° of heating 1 hour.This reaction is cooled to room temperature.With this mixture with ethyl acetate (200mL) dilution, and water (2 * 50mL) and salt solution (50mL) wash., filter the organic phase drying with sodium sulfate, and vacuum concentration, obtained this title compound, be light yellow solid (1.08g, 95%).

Embodiment 13D

4-[4-(4-bromo-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

With the product of embodiment 8E (109mg, 0.504mmol) and the product of embodiment 13C (200mg, 0.389mmol) solution had been preheated in 140 ℃ the oil bath stirring 15 minutes in acetate (10mL).This reaction is cooled to room temperature,, concentrates by rotary evaporation with hexane (100mL) dilution, and with dichloromethane/hexane co-evaporated (4 *).Resistates is dry under high vacuum.By fast silica gel chromatogram purifying resistates,,, obtained this title compound (108mg, 40%) with 4% ethanol/methylene wash-out with 20% ethyl acetate/dichloromethane wash-out.

Embodiment 13E

(106mg 0.1546mmol) handled 30 minutes in methylene dichloride (3mL) with trifluoroacetic acid (3mL) with the product of embodiment 13D in room temperature.Remove by rotary evaporation and to desolvate, and resistates is placed ethyl acetate (75mL), with saturated sodium bicarbonate aqueous solution (50mL), water and salt water washing.With the organic phase anhydrous sodium sulfate drying, filter, and vacuum concentration.By the fast silica gel chromatogram purifying, with 5% ethanol/methylene wash-out, obtained this title compound, be light yellow solid (55mg, 61%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)3.13-3.31(m，1H)5.60(s，2H)6.63(d，J＝8.82Hz，2H)6.88(d，J＝8.46Hz，1H)7.14(d，J＝8.46Hz，2H)7.52(d，J＝8.82Hz，2H)7.64(d，J＝8.46Hz，1H)7.73(d，J＝8.82Hz，2H)7.78(dd，J＝8.27，1.65Hz，1H)7.94(d，J＝1.47Hz，1H)8.59(s，1H)8.88(d，J＝8.82Hz，1H)10.16(s，1H)10.28(s，1H)；MS(ESI+)m/z?585/587(M+H) ⁺，MS(ESI-)m/z?583/585(M-H) ^-。

Embodiment 14

4-(4-amino-phenyl sulfenyl)-N-(4-bromo-phenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 13D; product with the product alternate embodiment 8E of embodiment 9B; the product of embodiment 13C and the product of embodiment 9B are reacted; obtained { 4-[4-(4-bromo-phenyl amino formyl radical)-2-(7-methyl-pyrido [2; 3-d] pyrimidine-4-base amino)-the phenyl sulfenyl]-phenyl }-t-butyl carbamate; use the method for embodiment 13E that it is reacted; obtained the crude product of this title compound; by the HPLC purifying; use the ammonium acetate wash-out; obtained this title product (22mg, 36%).1H?NMR(300MHz，DMSO-D6)δ?ppm：2.68(s，3H)5.59(s，2H)6.63(d，J＝8.82Hz，2H)6.87(d，J＝6.62Hz，1H)7.14(br?d，J＝8.46Hz，2H)7.46-7.61(br?m，1H)7.52(d，J＝8.82Hz，2H)7.69-7.86(br?m，1H)7.73(d，J＝9.19Hz，2H)7.94(br?m，1H)8.58(brs，1H)8.82(br?s，1H)10.15(br?s，1H)10.26(br?s，1H)。

Embodiment 15

4-[4-(5-bromo-thiazol-2-yl formamyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Embodiment 15A

4-[2-amino-4-(5-bromo-thiazol-2-yl formamyl)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 10A, mixture and the reaction of 5-bromo-thiazol-2-yl amine with 4-chloro-3-nitrobenzoyl chloride, obtain N-(5-bromo-thiazol-2-yl)-4-chloro-3-nitro-benzamide, used the method for embodiment 13A, 13B and 13C that it is handled successively, obtained this title product.

Embodiment 15B

Use the method for embodiment 13D, product with the product alternate embodiment 13C of embodiment 15A, the product of embodiment 15A and the product of embodiment 8E are reacted, obtained the crude product of this title compound, it is passed through silica gel chromatography, use ethanol/methylene as eluent, obtained this title compound (50mg, 25%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.62Hz，6H)1.49(s，9H)3.16-3.30(m，1H)6.93(d，J＝8.46Hz，1H)7.40(m，3H)7.56(d，J＝8.46Hz，2H)7.61-7.71(m，1H)7.93(dd，J＝8.46，1.84Hz，1H)8.14(d，J＝1.47Hz，1H)8.59(s，1H)8.87(d，J＝8.82Hz，1H)9.64(s，1H)10.21(s，1H)12.89(s，1H)；MS(ESI+)m/z?692/694(M+H)+。

Embodiment 16

4-(4-amino-phenyl sulfenyl)-N-(5-bromo-thiazol-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 13E,, obtained the crude product of this title compound product and the trifluoroacetic acid reaction of embodiment 15B, it is passed through silica gel chromatography, use ethanol/methylene as eluent, obtained this title compound (120mg, 76%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)3.15-3.30(m，1H)5.64(s，2H)6.65(d，J＝8.46Hz，2H)6.84(d，J＝8.46Hz，1H)7.15(d，J＝8.46Hz，2H)7.65(d，J＝8.46Hz，1H)7.64(s，1H)7.92(dd，J＝8.46，1.84Hz，1H)8.10(d，J＝1.47Hz，1H)8.59(s，1H)8.89(d，J＝8.46Hz，1H)10.14(s，1H)12.85(s，1H)；MS(ESI+)m/z?592/594(M+H)+。

Embodiment 17

-(4-amino-phenyl sulfenyl)-N-(5-bromo-pyridine-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 17A

N-(5-bromo-pyridine-2-yl)-4-chloro-3-nitro-benzamide

(22.0g, 0.1mol) (17.3g, 0.1mol) mixture in toluene (250mL) refluxed 4 hours, allowed HCl gas overflow via the water-cooled condenser of opening with 2-amino-5-bromopyridine with 4-chloro-3-nitrobenzoyl chloride.This reaction mixture is cooled to room temperature,, has obtained this title compound (33.9g, 95%) with hexane (200mL) dilution and filtration.

Embodiment 17B

4-(4-amino-phenyl sulfenyl)-N-(5-bromo-pyridine-2-yl)-3-nitro-benzamide

With the product of embodiment 17A (24.2g, 0.0678mol), 4-amino-thiophenol (12.7g, 0.102mol, 1.5eq) and sodium acetate trihydrate (46.1g, 0.339mol, 5.0eq) mixture in 500mL ethanol under nitrogen under reflux conditions reflux 2 hours.Then this reaction mixture is cooled to room temperature, and adds 200mL water.This mixture was stirred 30 minutes, filter, and vacuum-drying, this title compound (29.8g, 99%) obtained.

Embodiment 17C

4-[4-(5-bromo-pyridine-2-base formamyl)-2-nitro-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

With the product of embodiment 17B (68.2g, 0.15mol) and pyridine (23.7g, 24mL, 0.3mol, 2eq) mixture in methylene dichloride (1.2L) is in stirring at room.With 1 hour in this mixture with on a small quantity repeatedly mode add 9-fluorenyl methoxy carbonyl chlorine (42.7g, 0.165mol, 1.1eq).With this reaction mixture stirring at room 3.5 hours, during be settled out product, be yellow solid.This mixture is filtered, and with the filter cake washed with dichloromethane, and vacuum-drying, obtained this title compound (98.6g, 98%), be yellow solid.

Embodiment 17D

4-[2-amino-4-(5-bromo-pyridine-2-base formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

In the 5 liter of three neck round-bottomed flask that is equipped with water condenser, heating jacket and overhead stirrer, enter Glacial acetic acid (0.75L) and 200proof ethanol (0.75L), add then embodiment 17C product (40.0g, 60mmol) and iron powder (13.3g, 240mmol).Then this mixture heating up was refluxed 6 hours, be cooled to room temperature, and, stirred 10-15 minute, and dilute with 1.0L water with 1.0-1.5L EtOAc dilution.With this two-phase mixture vigorous stirring 5-0 minute, and separate each layer.Remove red water layer, and discard.The residue EtOAc layer that will have suspended solids is finally removed all redness with 6 * 1.0L water washing.Filter the EtOAc layer then to collect the lacteous solid, it is washed with 300mL EtOAc, and in vacuum drying oven, be dried to constant weight (40 ℃, chamber vacuum, 24 hours), obtained this title compound (37g, 97%).

Embodiment 17E

4-[4-(5-bromo-pyridine-2-base formamyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

Product (23.9g with embodiment 17D, 37.4mmol) and N '-(3-cyano group-6-sec.-propyl-pyridine-2-yl)-N, N-dimethyl-carbonamidine (9.71g, 44.9mmol, 1.2eq) mixture in the 450mL Glacial acetic acid heated 2 hours in 150 ℃ oil bath, was cooled to room temperature then.With this reaction mixture vacuum-evaporation, and resistates is dissolved in about 70mL methylene dichloride.Use Biotage Flash 75M tube, come this material of purifying, at first use 1:4 ethyl acetate/dichloromethane wash-out, use 98:2 methylene chloride wash-out then by silica gel chromatography.Products therefrom is developed with methylene dichloride, and filtered, obtained this title compound, be white solid (17.6g, 58%).

Embodiment 17F

4-(4-amino-phenyl sulfenyl)-N-(5-bromo-pyridine-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

To under nitrogen and be equipped with the product that adds embodiment 17E in 3 liter of three neck round-bottomed flask of addition funnel and overhead stirrer (32.35g, 40.0mmol) and anhydrous tetrahydro furan (0.5L).In this yellow solution with very fast rate of addition add tetrabutylammonium (solution of 1.0M in THF, 32.0mL, 32mmol).After adding is finished, should stir 3 hours by the redness clear solution,, and stirred 5 minutes with 1.0L water and 400mL EtOAc dilution.Separate each layer, take out water layer and discard.Organic layer is washed with 1 premium on currency again, and remove 1 premium on currency again.Again with the dilution of 1L water and 400mL EtOAc water, and vigorous stirring 5 minutes has obtained emulsion with this mixture.Break emulsion by adding the 50-100mL saturated brine, and gentle agitation.Organic layer with 4 * 1L water washing, and is used salt solution as required, to break emulsion.After the final water washing, add 400mL EtOAc, and suspension was stirred 1 hour, collect solid by filtering, wash with 400mL EtOAc, use the 500mL water washing, and in vacuum drying oven, be dried to constant weight (60 ℃, the chamber vacuum, 24 hours), obtain this title compound (22.6g, 96%), be the lacteous powder.

Embodiment 18

4-(4-amino-phenyl sulfenyl)-N-(4-bromo-3-fluoro-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 18A

4-[2-amino-4-(4-bromo-3-fluoro-phenyl amino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 10A, mixture and the reaction of 4-bromo-3-fluoro-phenyl amine with 4-fluoro-3-nitrobenzoyl chloride, generated N-(4-bromo-3-fluoro-phenyl)-4-chloro-3-nitro-benzamide, according to the method for embodiment 13A, 13B and 13C it is handled successively, obtained this title product.

Embodiment 18B

Use the method for embodiment 13D; product with the product alternate embodiment 13C of embodiment 18A; product and embodiment 8E reaction with embodiment 18A; obtained { 4-[4-(4-bromo-3-fluoro-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-the phenyl sulfenyl]-phenyl }-t-butyl carbamate; use the method for embodiment 13E to react it; obtained the crude product of this title compound; by the HPLC purifying; use the ammonium acetate wash-out; obtained this title product (8mg, 7%).

Embodiment 19

4-(4-amino-phenyl sulfenyl)-N-(5-chloro-pyridine-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 19A

4-(4-amino-phenyl sulfenyl)-3-nitro-phenylformic acid

A solution of 4-chloro-3-nitrobenzoic acid (2.00g, 10.0mmol), 4-aminothiophenol (10.0mmol) and cesium carbonate (6.52g, 20.0mmol) at anhydrous N, 90 ℃ of under a of dinethylformamide (10mL) was heated at nitrogen atmosphere for 2 hours.This reaction is cooled to room temperature and poured into 50 mL of ice water and ethyl acetate (100mL).With this mixture stirred while adjusting the pH to 2 with concentratedhydrochloric acid, separate each layer and with organic phase with washing water (2 * 50mL) and salt solution (50mL), use anhydrous sodium sulfate drying, filter, and concentrate by rotary evaporation in vacuo.With resistates and dichloromethane/hexane coevaporation and the residue triturated with methylene dichloride, obtained this title compound, be dark yellow solid (2.115g, 73%).

Embodiment 19B

4-[4-(9H-fluorenes-9-ylmethoxy carbonylamino)-phenyl sulfenyl]-3-nitro-phenylformic acid

Product (1.00g with embodiment 19A, 3.445mmol) N of dropping of the suspension in anhydrous methylene chloride (40mL), (1.77mL 7.234mmol) handles O-two (trimethyl silyl) ethanamide, and the gained orange solution was stirred 30 minutes under nitrogen atmosphere in room temperature.Add then anhydrous pyridine (0.557mL, 6.89mmol), add in three batches afterwards solid 9-fluorenyl methoxy carbonyl chlorine (1.114g, 4.306mmol).Should react and stir 30 minutes, pour into then in the water (75mL), and with 1N hydrochloric acid pH regulator to 1., after 15 minutes this mixture is transferred in the separating funnel in stirring at room, and (500mL is 2 * 150mL) then with ethyl acetate extraction.With the organic extract liquid water that merges (2 * 50mL) and salt solution (50mL) washing, use anhydrous sodium sulfate drying, filtration, and concentrate by rotary evaporation in vacuo.With the methylene dichloride development, obtained this title compound, be yellow solid (1.29g, 73%).

Embodiment 19C

[4-(4-chloroformyl-2-nitro-phenyl sulfenyl)-phenyl]-carboxylamine 9H-fluorenes-9-ylmethyl ester

Product (500mg with embodiment 19B, 0.976mmol) suspension in anhydrous methylene chloride (10mL) and tetrahydrofuran (THF) (5mL) is with the oxalyl chloride (solution of 2M in methylene dichloride, 0.976mL, 1.951mmol) and N, dinethylformamide (3) handle and with gained solution under nitrogen atmosphere in stirring at room 2 hours.Remove by rotary evaporation in vacuo and to desolvate, and resistates is dry under high vacuum, obtained this title compound, be yellow solid (0.571g).

Embodiment 19D

4-[4-(5-chloro-pyridine-2-base formamyl)-2-nitro-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

Product (471mg with embodiment 19C, 0.861mmol) solution in anhydrous tetrahydro furan (8mL) is with 5-chloro-2-aminopyridine (125mg, 0.972mmol) and diisopropylethylamine (0.232mL 1.332mmol) handles, and stirs 18 hours under nitrogen atmosphere in room temperature.Remove by rotary evaporation in vacuo and to desolvate, resistates is placed ethyl acetate (250mL), and with saturated sodium bicarbonate aqueous solution (50mL), water (2 * 50mL) and salt solution (50mL) wash.With the organic phase anhydrous sodium sulfate drying, filter, and vacuum concentration.With the methylene dichloride development, obtained this title compound, be yellow solid (373mg, 61%).

Embodiment 19E

4-[2-amino-4-(5-chloro-pyridine-2-base formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

Product (371mg with embodiment 19D, 0.5954mmol), ammonium chloride (208.6mg, 3.900mmol) and iron powder (204.5mg, 3.662mmol) in the mixture of water (6mL), ethanol (12mL) and tetrahydrofuran (THF) (12mL) under nitrogen atmosphere 90 ° the heating 3 hours.This reaction is cooled to room temperature, with ethyl acetate (200mL) dilution, and water (2 * 50mL) and salt solution (50mL) wash.With the organic phase anhydrous sodium sulfate drying, filter, and concentrate by rotary evaporation in vacuo, obtained product, be pale solid (321mg, 91%).

Embodiment 19F

4-[4-(5-chloro-pyridine-2-base formamyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

With the product of embodiment 8E (88mg, 0.4063mmol) and the product of embodiment 19E (241mg, 0.4063mmol) solution in acetate (10mL) is being preheated in 140 ℃ the oil bath and was stirring 1.5 hours.This reaction is cooled to room temperature,, concentrates by rotary evaporation with hexane (100mL) dilution, and with dichloromethane/hexane coevaporation (4 *).Resistates is dry under high vacuum, by the fast silica gel chromatogram purifying, use 2% ethanol/methylene then, obtained this title compound, be yellow solid (168mg, 54%).

Embodiment 19G

(167mg, 0.2185mmol) 1, (18.3mg, the 0.437mmol) solution-treated in water (2mL) is then 60 ℃ of heating 40 minutes with lithium hydroxide monohydrate for the solution in the 4-dioxane (4mL) with the product of embodiment 19F in room temperature.This reaction is cooled to room temperature,, uses 1N hydrochloric acid with water pH regulator to 6, and separate each layer with ethyl acetate (100mL) and water (30mL) dilution.With the organic phase water (2 * 25mL) and salt solution (25mL) washing, use anhydrous sodium sulfate drying, filter, and concentrated by rotary evaporation in vacuo.By fast silica gel chromatogram purifying resistates, with 5% ethanol/methylene wash-out, obtained this title compound, be yellow solid (84mg, 71%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)3.15-3.30(m，1H)5.62(s，2H)6.65(d，J＝8.46Hz，2H)6.77-6.89(m，1H)7.15(d，J＝8.46Hz，2H)7.64(d，J＝8.09Hz，1H)7.87(d，J＝8.46Hz，1H)7.95(dd，J＝8.82，2.57Hz，1H)8.04(s，1H)8.21(d，J＝9.19Hz，1H)8.42(d，J＝2.57Hz，1H)8.58(s，1H)8.89(d，J＝8.46Hz，1H)10.13(s，1H)10.92(s，1H)；MS(ESI+)m/z?542/544(M+H) ⁺。

Embodiment 20

4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(4-trifluoromethyl-thiazol-2-yl)-benzamide

Embodiment 20A

4-[2-amino-4-(4-trifluoromethyl-thiazol-2-yl formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

Use the method for embodiment 19D, replace 5-chloro-2-aminopyridine with 4-trifluoromethyl-thiazol-2-yl amine, with the mixture of products of embodiment 19C and 4-trifluoromethyl-thiazol-2-yl amine reaction, then according to the method for embodiment 19E with nitroreduction, obtained this title product.

Embodiment 20B

Use the method for embodiment 19F; product with the product alternate embodiment 19E of embodiment 20A; the product of embodiment 20A and the product of embodiment 8E are reacted; obtained { 4-[2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-4-(4-trifluoromethyl-thiazol-2-yl formamyl)-phenyl sulfenyl ］-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester; use the method for embodiment 19G that it is reacted; obtained the crude product of this title compound; by developing purifying with 3% ethanol/methylene; obtained this title compound (73mg, 68%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)3.17-3.32(m，1H)5.65(s，2H)6.66(d，J＝8.46Hz，2H)6.84(d，J＝8.46Hz，1H)7.16(d，J＝8.46Hz，2H)7.65(d，J＝8.46Hz，1H)7.96(dd，J＝8.46，1.84Hz，1H)8.01(s，1H)8.13(d，J＝1.47Hz，1H)8.59(s，1H)8.90(d，J＝8.46Hz，1H)10.14(s，1H)13.02(s，1H)；MS(ESI+)m/z?582(M+H)+。

Embodiment 21

4-(4-amino-phenyl sulfenyl)-N-(3-fluoro-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 21A

4-[2-amino-4-(3-fluoro-phenyl amino formyl radical)-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

Use the method for embodiment 19D, substitute 5-chloro-2-aminopyridine, mixture of products and the 3-fluoro-phenyl amine of embodiment 19C are reacted with 3-fluoro-phenyl amine, then according to the method for embodiment 19E with nitroreduction, obtained this title product.

Embodiment 21B

Use the method for embodiment 19F; product with the product alternate embodiment 19E of embodiment 21A; the product of embodiment 21A and the product of embodiment 8E are reacted; obtained { 4-[4-(3-fluoro-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-the phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester; use the method for embodiment 19G to react it; obtained the crude product of this title compound; pass through silica gel chromatography; use ethanol/methylene as eluent; obtained this title product (9mg, 55%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.62Hz，6H)3.13-3.35(m，1H)5.60(s，2H)6.64(d，J＝8.46Hz，2H)6.84-6.98(m，2H)7.15(d，J＝8.46Hz，2H)7.37(q，J＝7.97Hz，1H)7.53(d，J＝8.09Hz，1H)7.64(dd，J＝8.09，0.74Hz，1H)7.68-7.83(m，2H)7.95(s，1H)8.59(s，1H)8.89(d，J＝8.82Hz，1H)10.16(s，1H)10.34(s，1H)；MS(ESI+)m/z?525(M+H)+。

Embodiment 22

N-(4-bromo-phenyl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 22A

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

At the product (553mg of room temperature with embodiment 10A, 1.557mmol) at anhydrous N, solution in the dinethylformamide (15mL) with the 4-mercapto-phenol (196mg, 1.557mmol) and cesium carbonate (1.015g, 3.114mmol) handle, heated 3 hours under nitrogen atmosphere at 100 ℃ then.This reaction is cooled to room temperature, and removes by rotary evaporation in vacuo and to desolvate.Resistates is placed H ₂Among the O (30mL), use 1N hydrochloric acid with pH regulator to 3.(2 * 50mL) extract, and the organic extract liquid that merges is washed with salt solution (25mL) with ethyl acetate with water.With the organic layer anhydrous sodium sulfate drying, filter, and concentrate by rotary evaporation.Purifying resistates as described below: with the methylene dichloride development, and carry out the fast silica gel chromatogram purifying, use the 6%-30% ethyl acetate/dichloromethane to carry out gradient elution, obtained product, be dark yellow solid (517mg, 75%).

Embodiment 22B

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

With the product of embodiment 22A (409.9mg, 0.9205mmol) and iron powder (206mg, 3.682mmol) reflux 1 hour under nitrogen atmosphere of the suspension in acetate (7mL) and ethanol (7mL).This reaction is cooled to room temperature.With this mixture water (30mL) dilution, with pH regulator to 6, (2 * 50mL) extract with ethyl acetate with water with solid sodium carbonate.The organic extract liquid that merges is washed with salt solution (25mL), use dried over sodium sulfate, filter, and vacuum concentration, obtained this title compound, be tawny solid (290mg, 0.6983mmol, 76%).

Embodiment 22C

With the product of embodiment 8E (21mg, 0.0963mmol) and the product of embodiment 22B (40mg, 0.0963mmol) solution in acetate (1mL) is being preheated in 140 ℃ the oil bath and was stirring 1 hour.This reaction is cooled to room temperature,, concentrates by rotary evaporation with hexane (100mL) dilution, and with dichloromethane/hexane coevaporation (4 *).With resistates reconcentration under high vacuum.By fast silica gel chromatogram purifying resistates, with 4% ethanol/methylene wash-out, obtained this title compound, be yellow solid (29mg, 0.0494mmol, 51%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)3.18-3.29(m，1H)6.85(d，J＝8.82Hz，2H)6.89-6.97(m，1H)7.31(d，J＝8.46Hz，2H)7.52(d，J＝9.19Hz，2H)7.58-7.69(m，1H)7.73(d，J＝9.19Hz，2H)7.76-7.84(m，1H)7.86-8.07(m，1H)8.59(s，1H)8.76-9.01(m，1H)9.96(s，1H)10.20(s，1H)10.31(s，1H)；MS(ESI+)m/z?586/588(M+H) ⁺，MS(ESI-)m/z?584/586(M-H) ^-。

Embodiment 23

N-(5-bromo-pyridine-2-yl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 23A

3-amino-N-(5-bromo-pyridine-2-yl)-4-(4-hydroxyl-phenyl sulfenyl)-benzamide

Method according to embodiment 10A, mixture and 5-bromo-pyridine-2-base amine reaction with 4-chloro-3-nitrobenzoyl chloride, generate N-(4-bromo-phenyl)-4-chloro-3-nitro-benzamide, used the method for embodiment 22A and 22B that it is handled successively, obtained this title product.

Embodiment 23B

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 23A, the product of embodiment 23A and the product of embodiment 8E are reacted, obtained the crude product of this title compound, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (42mg, 43%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.99Hz，6H)3.17-3.36(m，1H)6.84-6.88(m，2H)6.90(d，J＝8.46Hz，1H)7.33(d，J＝8.46Hz，2H)7.81(d，J＝8.09Hz，1H)7.86-7.97(m，1H)8.04(s，1H)8.06(dd，J＝8.82，2.57Hz，1H)8.16(d，J＝8.83Hz，1H)8.50(d，J＝2.57Hz，1H)8.75(brs，1H)8.96(d，J＝8.82Hz，1H)10.02(s，1H)10.96(s，1H)；MS(ESI+)m/z?587/589(M+H)+。

Embodiment 24

N-(5-bromo-pyrimidine-2-base)-4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 24A

3-amino-N-(5-bromo-pyrimidine-2-base)-4-(4-hydroxyl-phenyl sulfenyl)-benzamide

Method according to embodiment 10A, mixture and the reaction of 5-bromo-pyrimidine-2-base amine with 4-chloro-3-nitrobenzoyl chloride, generate N-(5-bromo-pyrimidine-2-base)-4-chloro-3-nitro-benzamide, used the method for embodiment 22A and 22B that it is handled successively, obtained this title product.

Embodiment 24B

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 24A, the product of embodiment 24A and the product of embodiment 8E are reacted, obtained the crude product of this title compound, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (34mg, 33%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.99Hz，6H)3.07-3.50(m，1H)6.86(d，J＝8.46Hz，2H)6.92(d，J＝8.09Hz，1H)7.33(d，J＝8.46Hz，2H)7.86(d，J＝8.09Hz，2H)7.96(s，1H)8.81(s，1H)8.88(s，2H)8.99(d，J＝9.19Hz，1H)10.03(s，1H)11.18(s，1H)；MS(ESI+)m/z?588/590(M+H)+。

Embodiment 25

N-(5-bromo-pyridine-2-yl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 23A, and product with the product alternate embodiment 8E of embodiment 9B, the product of embodiment 23A and the product of embodiment 9B are reacted, obtained the crude product of this title compound,, obtained this title compound by using the HPLC purifying of TFA, be trifluoroacetate (41mg, 43%).1H?NMR(300MHz，DMSO-D6)δ?ppm：2.77(s，3H)6.85(d，J＝8.46Hz，2H)6.95(d，J＝8.46Hz，1H)7.32(d，J＝8.82Hz，2H)7.86(d，J＝8.46Hz，1H)7.97(dd，J＝8.46，1.84Hz，1H)8.02-8.11(m，2H)8.19(d，J＝9.19Hz，1H)8.51(d，J＝1.84Hz，1H)8.89(s，1H)9.00(d，J＝8.82Hz，1H)10.05(brs，1H)10.99(s，1H)11.73(br?s，1H)；MS(ESI+)m/z?559/561(M+H)+。

Embodiment 26

N-(3-bromo-phenyl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 26A

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

Method according to embodiment 10A, mixture and the reaction of 3-bromo-phenyl amine with 4-chloro-3-nitrobenzoyl chloride, generate N-(3-bromo-phenyl)-4-chloro-3-nitro-benzamide, used the method for embodiment 22A and 22B that it is handled successively, obtained this title product.

Embodiment 26B

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 26A, the product of embodiment 26A and the product of embodiment 8E are reacted, obtained the crude product of this title compound, pass through silica gel chromatography, use ethanol/methylene as eluent, obtained this title product (24mg, 42%).MS(ESI+)m/z?586/588(M+H)+。

Embodiment 27

N-(3-bromo-phenyl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 26A, and product with the product alternate embodiment 8E of embodiment 9B, the product of embodiment 26A and the product of embodiment 9B are reacted, obtained the crude product of this title compound,, used ethanol/methylene as eluent by silica gel chromatography, obtained this title product (22mg, 47%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm：2.68(s，3H)6.81-6.89(m，2H)6.89-7.01(m，1H)7.22-7.38(m，4H)7.49-7.64(m，1H)7.67-7.89(m，2H)7.92-8.03(m，1H)8.04-8.17(m，1H)8.58(s，1H)8.70-8.91(m，1H)9.96(s，1H)10.20(s，1H)10.31(s，1H)；MS(ESI+)m/z?558/560(M+H)+。

Embodiment 28

N-(4-bromo-phenyl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 28A

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

Use the solution of product of the method Processing Example 10A of embodiment 22A and 22B successively, obtained this title product.

Embodiment 28B

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 28A, and product with the product alternate embodiment 8E of embodiment 9B, the product of embodiment 28A and the product of embodiment 9B are reacted, obtained the crude product of this title compound,, used ethanol/methylene as eluent by silica gel chromatography, obtained this title product (24mg, 51%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm：2.68(s，3H)6.85(d，J＝8.46Hz，2H)6.89-7.00(m，1H)7.31(d，J＝8.82Hz，2H)7.45-7.64(m，3H)7.67-7.88(m，3H)7.97(s，1H)8.58(s，1H)8.70-8.92(m，1H)9.96(s，1H)10.19(s，1H)10.29(s，1H)；MS(ESI+)m/z558/560(M+H)+。

Embodiment 29

4-[4-(3-fluoro-benzyloxy)-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol embodiment 29A

N '-(3-cyano group-pyridine-2-yl)-N, N-dimethyl-carbonamidine

(5g, 42mmol) and N, (6.13mL, 46.2mmol) vlil in toluene (20mL) is 3 hours for the dinethylformamide dimethyl acetal with 2-amino-cigarette nitrile.After being cooled to room temperature,, obtained this title compound (7.3g, 100%) with this solution for vacuum concentration.

Embodiment 29B

1-chloro-4-(3-fluoro-benzyloxy)-2-nitro-benzene

According to the method for embodiment 9C, substitute 1-chloromethyl-4-methoxyl group-benzene with 1-brooethyl-3-fluoro-benzene, made this title compound (0.56g, 100%).

Embodiment 29C

4-[4-(3-fluoro-benzyloxy)-2-nitro-phenyl sulfenyl ］-phenol

According to the method for embodiment 9D, substitute 1-chloro-4-(4-methoxyl group-benzyloxy)-2-nitro-benzene with 1-chloro-4-(3-fluoro-benzyloxy)-2-nitro-benzene, made this title compound (0.57g, 77%).

Embodiment 29D

4-[2-amino-4-(3-fluoro-benzyloxy)-phenyl sulfenyl]-phenol

According to the method for embodiment 9E, with 4-[4-(3-fluoro-benzyloxy)-2-nitro-phenyl sulfenyl]-the alternative 4-[4-(4-methoxyl group-benzyloxy) of phenol-2-nitro-phenyl sulfenyl]-phenol, made this title compound (0.501g, 96%).

Embodiment 29E

4-[4-(3-fluoro-benzyloxy)-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol

With the product of embodiment 29A (35mg, 0.2mmol) and the product of embodiment 29D (68mg, 0.2mmol) solution in acetate (1mL) was heated to 130 ℃ via 15 minutes from room temperature gradually in oil bath, then 130 ℃ of heating 1.5 hours.This mixture is cooled to room temperature, vacuum concentration, obtained the crude product of this title compound, on Waters Symmetry C8 post, pass through anti-phase preparation HPLC purifying (25mm * 100mm, 7 μ m particle diameters), use the aqueous solution of 10%-100% acetonitrile/0.1% trifluoroacetic acid to carry out gradient elution (10 minute working time) via 8 minutes, obtained this title compound with 40mL/ minute speed, be trifluoroacetate (28mg, 30%).1H?NMR(300MHz，DMSO-d ₆)δ?ppm：5.14(s，2H)6.65(m，2H)7.14(m，8H)7.49(m，1H)7.66(m，1H)8.61(s，1H)8.88(d，J＝7.47Hz，1H)9.07(s，1H)9.65(s，1H)10.34(s，1H)；MS(ESI)m/z?471(M+H)+。

Embodiment 30

N-(4-bromo-phenyl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 28A, and product with the product alternate embodiment 8E of embodiment 29A, the product of embodiment 28A and the product of embodiment 29A are reacted, obtained the crude product of this title compound,, used ethanol/methylene as eluent by silica gel chromatography, obtained this title product (11mg, 24%).1H?NMR(300MHz，DMSO-D6)δ?ppm：6.85(d，J＝8.82Hz，2H)6.88-7.01(brm，1H)7.31(d，J＝8.46Hz，2H)7.52(d，J＝8.82Hz，2H)7.61-7.87(brm，2H)7.73(d，J＝9.19Hz，2H)7.92-8.09(brm，1H)8.54-8.72(br?m，1H)8.87-9.04(br?m，1H)9.03-9.19(br?m，1H)9.96(brs，1H)10.31(br?d，J＝9.56Hz，2H)；MS(ESI+)m/z?544/546(M+H)+。

Embodiment 31

N-(2-bromo-benzyl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 31A

3-amino-N-(2-bromo-benzyl)-4-(4-hydroxyl-phenyl sulfenyl)-benzamide

Method according to embodiment 10A, mixture and the reaction of 2-bromo-benzyl amine with 4-chloro-3-nitrobenzoyl chloride, generate N-(2-bromo-benzyl)-4-chloro-3-nitro-benzamide, used the method for embodiment 22A and 22B that it is handled successively, obtained this title product.

Embodiment 31B

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 31A, and product with the product alternate embodiment 8E of embodiment 9B, the product of embodiment 31A and the product of embodiment 9B are reacted, obtained the crude product of this title compound,, used ethanol/methylene as eluent by silica gel chromatography, obtained this title product (60mg, 71%).1H?NMR(300MHz，DMSO-D6)δ?ppm：2.68(s，3H)4.48(d，J＝5.52Hz，2H)6.84(d，J＝8.82Hz，2H)6.87-6.96(m，1H)7.16-7.25(m，1H)7.25-7.40(m，4H)7.56(d，J＝8.09Hz，1H)7.61(d，J＝8.82Hz，1H)7.76(d，J＝8.82Hz，1H)7.93(s，1H)8.58(s，1H)8.74-8.85(m，1H)8.94-9.21(m，1H)9.94(s，1H)10.16(s，1H)；MS(ESI+)m/z?572/574(M+H)+。

Embodiment 32

N-(2-bromo-benzyl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 31A, and product with the product alternate embodiment 8E of embodiment 29A, the product of embodiment 31A and the product of embodiment 29A are reacted, obtained the crude product of this title compound,, used ethanol/methylene as eluent by silica gel chromatography, obtained this title product (58 mg, 60%).1H?NMR(300MHz，DMSO-D6)δ?ppm：4.48(d，J＝5.88Hz，2H)6.84(d，J＝8.46Hz，2H)6.87-7.02(m，1H)7.13-7.44(m，5H)7.58-7.64(m，1H)7.64-7.84(m，2H)7.93(s，1H)8.62(d，J＝1.84Hz，1H)8.82-9.20(m，3H)9.94(s，1H)10.30(s，1H)；MS(ESI+)m/z558/560(M+H)+。

Embodiment 33

N-(4-bromo-benzyl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 33A

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

Method according to embodiment 10A, mixture and the reaction of 4-bromo-benzyl amine with 4-chloro-3-nitrobenzoyl chloride, generate N-(4-bromo-benzyl)-4-chloro-3-nitro-benzamide, used the method for embodiment 22A and 22B that it is handled successively, obtained this title product.

Embodiment 33B

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 33A, and product with the product alternate embodiment 8E of embodiment 9B, the product of embodiment 33A and the product of embodiment 9B are reacted, obtained the crude product of this title compound,, used ethanol/methylene as eluent by silica gel chromatography, obtained this title product (40mg, 40%).1H?NMR(500MHz，DMSO-D6)δ?ppm：2.67(s，3H)4.41(d，J＝6.22Hz，2H)6.83(d，J＝8.82Hz，2H)6.86-6.95(m，1H)7.25(d，J＝8.30Hz，2H)7.28(d，J＝8.82Hz，2H)7.50(d，J＝8.30Hz，2H)7.52-7.59(m，1H)7.65-7.80(m，1H)7.81-7.98(m，1H)8.49-8.63(m，1H)8.69-8.84(m，1H)8.93-9.07(m，1H)9.83-9.97(m，1H)10.11(s，1H)；MS(ESI+)m/z?572/574(M+H)+。

Embodiment 34

N-(4-bromo-benzyl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 33A, and product with the product alternate embodiment 8E of embodiment 29A, the product of embodiment 33A and the product of embodiment 29A are reacted, obtained the crude product of this title compound,, used ethanol/methylene as eluent by silica gel chromatography, obtained this title product (26mg, 26%).1H?NMR(300MHz，DMSO-D6)δ?ppm：4.41(d，J＝5.88Hz，2H)6.76-6.96(m，1H)6.83(d，J＝8.46Hz，2H)7.20-7.33(m，4H)7.51(d，J＝8.46Hz，2H)7.58-7.80(m，2H)7.82-7.97(m，1H)8.52-8.69(m，1H)8.86-9.18(m，3H)9.94(s，1H)10.28(s，1H)；MS(ESI+)m/z?558/560(M+H)+。

Embodiment 35

N-benzyl-4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 35A

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

According to mixture and the reaction of benzyl amine of the method for embodiment 10A with 4-chloro-3-nitrobenzoyl chloride, generated N-benzyl-4-chloro-3-nitro-benzamide, use the method for embodiment 22A and 22B that it is handled successively, obtained this title product.

Embodiment 35B

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 35A, and product with the product alternate embodiment 8E of embodiment 9B, the product of embodiment 35A and the product of embodiment 9B are reacted, obtained the crude product of this title compound,, used ethanol/methylene as eluent by silica gel chromatography, obtained this title product (50mg, 54%).1H?NMR(300MHz，DMSO-D6)δ?ppm：2.67(s，3H)4.45(d，J＝5.88Hz，2H)6.78-6.96(m，1H)6.83(d，J＝8.46Hz，2H)7.15-7.40(m，7H)7.55(d，J＝7.35Hz，1H)7.73(d，J＝5.88Hz，1H)7.90(s，1H)8.56(s，1H)8.80(d，J＝8.09Hz，1H)9.01(s，1H)9.94(s，1H)10.14(s，1H)；MS(ESI+)m/z?494(M+H)+，(ESI-)m/z?492(M-H)-。

Embodiment 36

N-benzyl-4-(4-hydroxyl-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 35A, and product with the product alternate embodiment 8E of embodiment 29A, the product of embodiment 35A and the product of embodiment 29A are reacted, obtained the crude product of this title compound,, used ethanol/methylene as eluent by silica gel chromatography, obtained this title product (39mg, 55%).1H?NMR(300MHz，DMSO-D6)δ?ppm：4.45(d，J＝5.88Hz，2H)6.83(d，J＝8.82Hz，2H)6.82-6.93(m，1H)7.16-7.44(m，7H)7.56-7.81(m，2H)7.90(brs，1H)8.61(brs，1H)8.79-9.22(brm，3H)9.94(br?s，1H)10.28(br?s，1H)；MS(ESI+)m/z?480(M+H)+。

Embodiment 37

N-(4-bromo-phenyl)-4-(4-hydroxyl-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 37A

4-(4-hydroxyl-phenoxy group)-3-nitro-phenylformic acid

With quinhydrones (3.00g, 0.0272mol) and potassium hydroxide (2.293g, 0.0409mol) solution in anhydrous dimethyl sulfoxide (20mL) 120 ℃ under nitrogen atmosphere the heating 30 minutes.(5.49g, the 0.0272mol) solution in methyl-sulphoxide (25mL) were reflected at this under uniform temp restir 2 hours then with dripping 4-chloro-3-nitrobenzoic acid in 30 minutes at 120 ℃.Then this is reflected in the ice bath and cools off, pour in the 100mL frozen water.With dense HCl this mixture is acidified to pH3, and (3 * 100mL) extract with ether.(anhydrous sodium sulfate drying is used in 3 * 150mU washing, filters, and concentrates by rotary evaporation in vacuo the ether extraction liquid water that merges.By fast silica gel chromatogram purifying resistates, with the 2%-3% ethanol/methylene gradient elution that contains 0.5% acetate, behind the dichloromethane/hexane coevaporation, obtained product, be orange solids (2.432g, 32%).

Embodiment 37B

N-(4-bromo-phenyl)-4-(4-hydroxyl-phenoxy group)-3-nitro-benzamide

Product (200mg with embodiment 37A, 0.7267mmol) and 4-bromaniline (193.3mg, 1.090mmol) (0.052mL 0.5814mmol) handles, and reflux is 2 hours then with phosphorus trichlorides under nitrogen atmosphere at 50 ℃ for mixture in dry toluene (6mL).This reaction is cooled to room temperature, adds entry (30mL).(3 * 25mL) extract this mixture, with the organic extract liquid salt water washing that merges, use anhydrous sodium sulfate drying then, filter, and concentrate by rotary evaporation in vacuo with ethyl acetate.By the fast silica gel chromatogram purifying, with 10% ethyl acetate/dichloromethane wash-out, obtained product, be light orange solid (124mg, 40%).

Embodiment 37C

3-amino-N-(4-bromo-phenyl)-4-(4-hydroxyl-phenoxy group)-benzamide

With the product of embodiment 37B (116.6mg, 0.2717mmol) and iron powder (60.7mg, 1.087mmol) reflux 1 hour under nitrogen atmosphere of the solution in acetate (2mL) and ethanol (2mL).Then this reaction is cooled to room temperature.This mixture water (20mL) dilution, with pH regulator to 6, use ethyl acetate (2 * 50mL) aqueous phase extracted with solid sodium carbonate.The organic extract liquid that merges is washed with salt solution (25mL), use dried over sodium sulfate, filter, and vacuum concentration, obtained this title compound, be beige solid (100mg, 92%).

Embodiment 37D

With the product of embodiment 8E (15.4mg, 0.0714mmol) and the product of embodiment 37C (28.5mg, 0.0714mmol) solution in acetate (1mL) is being preheated in 140 ℃ the oil bath and was stirring 1 hour.This reaction is cooled to room temperature,, concentrates by rotary evaporation with hexane (100mL) dilution, and with dichloromethane/hexane coevaporation (4 *).Under high vacuum, after the drying,,, obtained this title product (24mg, 59%) with 5% ethanol/methylene wash-out by fast silica gel chromatogram purifying resistates. ¹H?NMR(300MHz，DMSO-D6)δ?ppm：1.32(d，J＝6.62Hz，6H)3.14-3.29(m，1H)6.75(d，J＝8.82Hz，2H)6.83-6.98(m，3H)7.53(d，J＝8.82Hz，2H)7.60(d，J＝8.46Hz，1H)7.76(d，J＝8.82Hz，2H)7.87(dd，J＝8.82，1.84Hz，1H)8.17(d，J＝1.47Hz，1H)8.61(s，1H)8.82(d，J＝8.82Hz，1H)9.39(s，1H)10.02(s，1H)10.31(s，1H)；MS(ESI+)m/z?570/572(M+H) ⁺，MS(ESI-)m/z?568/570(M-H) ^-。

Embodiment 38

N-(4-bromo-phenyl)-4-(4-hydroxyl-phenoxy group)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 37D, product with the product alternate embodiment 8E of embodiment 9B, the product of embodiment 37C and the product of embodiment 9B are reacted, obtained the crude product of this title compound, pass through silica gel chromatography, use ethanol/methylene as eluent, obtained this title product (42mg, 49%).1H?NMR(300MHz，DMSO-D6)δppm：2.66(s，3H)6.75(d，J＝8.82Hz，2H)6.89(t，J＝8.27Hz，3H)7.53(d，J＝8.82Hz，3H)7.75(d，J＝9.19Hz，2H)7.86(dd，J＝8.64，1.65Hz，1H)8.18(d，J＝1.47Hz，1H)8.61(s，1H)8.77(d，J＝8.46Hz，1H)9.39(s，1H)10.00(s，1H)10.30(s，1H)；MS(ESI+)m/z?542/544(M+H)+。

Embodiment 39

N-(3-bromo-phenyl)-4-(4-hydroxyl-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 39A

3-amino-N-(3-bromo-phenyl)-4-(4-hydroxyl-phenoxy group)-benzamide

Use the method for embodiment 37A, mixture and reacted with hydroquinone with 4-chloro-3-nitrobenzoic acid, generated 4-(4-hydroxyl-phenoxy group)-3-nitro-phenylformic acid, method according to embodiment 37B is handled it with 3-bromo-phenyl amine, according to the method reduction of embodiment 37C, obtained this title product then.

Embodiment 39B

Use the method for embodiment 37D, product with the product alternate embodiment 37C of embodiment 39A, product reaction with embodiment 39A and embodiment 8E, obtained the crude product of this title compound, pass through silica gel chromatography, use ethanol/methylene as eluent, obtained this title product (27mg, 62%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.32(d，J＝6.99Hz，6H)3.14-3.29(m，1H)6.75(d，J＝8.82Hz，2H)6.82-6.96(m，3H)7.23-7.41(m，2H)7.60(d，J＝8.46Hz，1H)7.70-7.81(m，1H)7.87(d，J＝8.82Hz，1H)8.10(s，1H)8.17(s，1H)8.61(s，1H)8.82(d，J＝8.46Hz，1H)9.39(s，1H)10.02(s，1H)10.33(s，1H)；MS(ESI+)m/z?570/572(M+H)+。

Embodiment 40

N-(3-bromo-phenyl)-4-(4-hydroxyl-phenoxy group)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 37D, product with the product alternate embodiment 37C of embodiment 39A, and use the product of the product alternate embodiment 8E of embodiment 9B, the product of embodiment 39A and the product of embodiment 9B are reacted, obtained the crude product of this title compound,, used ethanol/methylene as eluent by silica gel chromatography, obtained this title product (32mg, 75%).1H?NMR(300MHz，DMSO-D6)δ?ppm：2.67(s，3H)6.75(d，J＝8.82Hz，2H)6.82-6.98(m，3H)7.20-7.38(m，2H)7.54(d，J＝8.46Hz，1H)7.69-7.81(m，1H)7.87(dd，J＝8.64，2.02Hz，1H)8.10(s，1H)8.19(d，J＝1.84Hz，1H)8.61(s，1H)8.78(d，J＝8.46Hz，1H)9.39(s，1H)10.01(s，1H)10.32(s，1H)；MS(ESI+)m/z?542/544(M+H)+。

Embodiment 41

4-(4-hydroxyl-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-phenyl-benzamide

Embodiment 41A

3-amino-4-(4-hydroxyl-phenoxy group)-N-phenyl-benzamide

Method according to embodiment 37A, with the mixture and the reacted with hydroquinone of 4-chloro-3-nitrobenzoic acid, generated 4-(4-hydroxyl-phenoxy group)-3-nitro-phenylformic acid, according to the method for embodiment 37B it is handled with phenyl amine, according to the method reduction of embodiment 37C, obtained this title product then.

Embodiment 41B

Use the method for embodiment 37D, product with the product alternate embodiment 37C of embodiment 41A, the product of embodiment 41A and the product of embodiment 8E are reacted the crude product that has obtained this title compound, pass through silica gel chromatography, use ethanol/methylene as eluent, obtained this title product (16mg, 42%).1H?NMR(300MHz，DMSO-D6)δppm：1.32(d，J＝6.62Hz，6H)3.12-3.30(m，1H)6.74(d，J＝8.82Hz，2H)6.89(t，J＝8.09Hz，3H)7.09(t，J＝7.35Hz，1H)7.35(t，J＝7.91Hz，2H)7.60(d，J＝8.82Hz，1H)7.76(d，J＝7.72Hz，2H)7.88(dd，J＝8.64，2.02Hz，1H)8.17(d，J＝2.21Hz，1H)8.61(s，1H)8.82(d，J＝8.46Hz，1H)9.38(s，1H)10.02(s，1H)10.19(s，1H)；MS(DCI/NH3)m/z?492(M+H)+。

Embodiment 42

N-benzyl-4-(4-hydroxyl-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-methyl-benzamide

Embodiment 42A

3-amino-N-benzyl-4-(4-hydroxyl-phenoxy group)-N-methyl-benzamide

Method according to embodiment 37A, mixture and reacted with hydroquinone with 4-chloro-3-nitrobenzoic acid, generated 4-(4-hydroxyl-phenoxy group)-3-nitro-phenylformic acid, method according to embodiment 37B is handled it with benzyl-methyl-amine, according to the method reduction of embodiment 37C, obtained this title product then.

Embodiment 42B

Use the method for embodiment 37D, product with the product alternate embodiment 37C of embodiment 42A, the product of embodiment 42A and the product of embodiment 8E are reacted, obtained the crude product of this title compound, pass through silica gel chromatography, use ethanol/methylene as eluent, obtained this title product (37mg, 45%).

Embodiment 43

N-(2-fluoro-phenyl)-4-(4-hydroxyl-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 43A

4-(4-benzyloxy-phenoxy group)-3-nitro-phenylformic acid

With 4-benzyloxy-phenol (2.00g, 0.01mol) and potassium hydroxide (1.12g, 0.02mol) solution in anhydrous dimethyl sulfoxide (20mL) stirred 10 minutes under nitrogen atmosphere in room temperature.Enter 4-chloro-3-nitrobenzoic acid (2.01g, the 0.01mol) solution in methyl-sulphoxide (5mL), and with this mixture 120 ℃ the heating 1 hour.Then this is reflected in the ice bath and cools off, and pour in the 100mL frozen water.With dense HCl this mixture is acidified to pH3, collects the gained solid by vacuum filtration then, wash with water, and dry in vacuum drying oven, obtained this title product (3.5g, 96%).

Embodiment 43B

3-amino-4-(4-benzyloxy-phenoxy group)-phenylformic acid

With the product of embodiment 43A (0.73g, 2.0mmol), iron powder (1.12g, 20mmol) and ammonium chloride (1.08g, 20mmol) methyl alcohol (20mL), tetrahydrofuran (THF) (20mL) and water (10mL) in solution in 80 ℃ of heating 48 hours.After being cooled to room temperature, this mixture is diluted with methyl alcohol (50mL), and filter via Celite pad.With the filtrate vacuum concentration, then by silica gel chromatography, use ethanol/methylene as eluent, obtained this title product (670mg, 100%).

Embodiment 43C

4-(4-benzyloxy-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid

Product (432mg with embodiment 8E, 2.0mmol) and the product (670mg of embodiment 43B, 2.0mmol) solution in acetate (5mL) is being preheated in 140 ℃ the oil bath and stirring 30 minutes, this reaction is cooled to room temperature, concentrate by rotary evaporation, and with dichloromethane/hexane coevaporation (4 *).Under high vacuum, after the drying,, use the ethanol/methylene wash-out, obtained this title product (560mg, 55%) by fast silica gel chromatogram purifying resistates.

Embodiment 43D

4-(4-benzyloxy-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-Benzoyl chloride

(224mg, 0.443mmol) solution in thionyl chloride (2mL) refluxed 1 hour with the product of embodiment 43C.This mixture is cooled to room temperature, adds toluene (5mL), and, obtained this title product, be solid this mixture vacuum concentration.

Embodiment 43E

4-(4-benzyloxy-phenoxy group)-N-(2-fluoro-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

With the product of embodiment 43D (53mg, 0.1mmol), N, N-diisopropylethylamine (0.052mL, 0.3mmol), 2-fluoro-phenyl amine (0.014mL, 0.15mmol) solution in methylene dichloride (2mL) was in stirring at room 1 hour, vacuum concentration has obtained this title product then.

Embodiment 43F

(72mg, 0.5mmol) solution in trifluoroacetic acid (5mL) was in stirring at room 1 hour with the product of embodiment 43E and pentamethylbenzene.Remove by rotary evaporation in vacuo and to desolvate, and with dichloromethane/hexane coevaporation (2 *), obtained the crude product of this title compound, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (11mg, 22%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.62Hz，6H)3.28(m，1H)6.77(m，2H)6.93(m，3H)7.26(m，3H)7.58(m，1H)7.88(d，J＝8.82Hz，1H)8.00(dd，J＝8.64，2.02Hz，1H)8.14(d，J＝2.21Hz，1H)8.91(s，1H)9.00(d，J＝8.09Hz，1H)9.47(s，1H)10.13(s，1H)11.48(s，1H)；MS(ESI+)m/z?510(M+H)+。

Embodiment 44

4-(4-hydroxyl-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(3-methoxyl group-phenyl)-benzamide

Use the method for embodiment 43E, with the product of embodiment 43D and the solution reaction of 3-methoxyl group-phenyl amine, obtained 4-(4-benzyloxy-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(3-methoxyl group-phenyl)-benzamide.The method of using embodiment 43F has then obtained the crude product of this title compound with this product deprotection, by silica gel chromatography, uses ethanol/methylene as eluent, has obtained this title product (12mg, 40%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.32(d，J＝6.99Hz，6H)3.11-3.29(m，1H)3.75(s，3H)6.68(dd，J＝8.09，1.84Hz，1H)6.75(d，J＝8.82Hz，2H)6.89(t，J＝8.64Hz，3H)7.24(t，J＝8.09Hz，1H)7.37(d，J＝8.09Hz，1H)7.45(t，J＝2.21Hz，1H)7.60(d，J＝8.46Hz，1H)7.86(dd，J＝8.64，1.65Hz，1H)8.17(s，1H)8.61(s，1H)8.82(d，J＝8.46Hz，1H)9.38(s，1H)10.01(s，1H)10.15(s，1H)；MS(ESI+)m/z?522(M+H)+。

Embodiment 45

N-(3-formamyl-phenyl)-4-(4-hydroxyl-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 43E; with the product of embodiment 43D and the solution reaction of 3-amino-benzamide; obtained 4-(4-benzyloxy-phenoxy group)-N-(3-formamyl-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide.The method of using embodiment 43F has then obtained the crude product of this title compound with this product deprotection, by using the HPLC purifying of TFA, has obtained this title compound, is trifluoroacetate (30mg, 56%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.62Hz，6H)3.28(m，1H)6.78(m，2H)6.94(m，3H)7.40(m，2H)7.60(d，J＝7.72Hz，1H)7.91(m，3H)8.02(dd，J＝8.82，2.21Hz，1H)8.17(d，J＝2.21Hz，1H)8.22(m，1H)8.91(s，1H)9.00(d，J＝8.46Hz，1H)9.48(s，1H)10.37(s，1H)11.50(s，1H)；MS(ESI+)m/z?535(M+H)+。

Embodiment 46

4-(4-hydroxyl-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-pyridin-3-yl-benzamide

Use the method for embodiment 43E,, obtained 4-(4-benzyloxy-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-pyridin-3-yl-benzamide the product of embodiment 43D and the solution reaction of pyridin-3-yl amine.The method of using embodiment 43F has then obtained the crude product of this title compound with this product deprotection, by using the HPLC purifying of TFA, has obtained this title compound, is trifluoroacetate (23mg, 47%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.99Hz，6H)3.29(m，1H)6.78(m，2H)6.95(m，3H)7.54(dd，J＝8.27，4.96Hz，1H)7.90(d，J＝8.82Hz，1H)8.02(dd，J＝8.82，2.21Hz，1H)8.16(d，J＝2.21Hz，1H)8.29(m，1H)8.39(dd，J＝4.78，1.47Hz，1H)8.94(s，1H)9.04(m，2H)9.48(s，1H)10.59(s，1H)11.59(s，1H)；MS(ESI+)m/z?493(M+H)+。

Embodiment 47

4-(4-hydroxyl-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-pyridin-4-yl-benzamide

Use the method for embodiment 43E,, obtained 4-(4-benzyloxy-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-pyridin-4-yl-benzamide the product of embodiment 43D and the solution reaction of pyridin-4-yl amine.The method of using embodiment 43F has then obtained the crude product of this title compound with this product deprotection, by using the HPLC purifying of TFA, has obtained this title compound, is trifluoroacetate (30mg, 61%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.62Hz，6H)3.27(m，1H)6.78(m，2H)6.94(m，3H)7.81(d，J＝8.46Hz，1H)8.01(dd，J＝8.64，2.02Hz，1H)8.22(m，3H)8.72(d，J＝6.99Hz，2H)8.83(s，1H)8.96(d，J＝8.46Hz，1H)9.50(s，1H)11.10(s，1H)11.35(s，1H)；MS(ESI+)m/z?493(M+H)+。

Embodiment 48

4-(4-hydroxyl-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-pyridine-2-base-benzamide

Use the method for embodiment 43E,, obtained 4-(4-benzyloxy-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-pyridine-2-base-benzamide the product of embodiment 43D and the solution reaction of pyridine-2-base amine.The method of using embodiment 43F has then obtained the crude product of this title compound with this product deprotection, by using the HPLC purifying of TFA, has obtained this title compound, is trifluoroacetate (5mg, 10%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.99Hz，6H)3.28(m，1H)6.78(m，2H)6.87(d，J＝8.82Hz，1H)6.94(m，2H)7.18(dd，J＝7.35，4.78Hz，1H)7.88(m，2H)8.09(dd，J＝8.46，2.21Hz，1H)8.17(d，J＝8.46Hz，1H)8.22(d，J＝2.21Hz，1H)8.38(d，J＝2.94Hz，1H)8.94(s，1H)9.03(d，J＝8.82Hz，1H)9.48(s，1H)10.80(s，1H)11.61(s，1H)；MS(ESI+)m/z?493(M+H)+。

Embodiment 49

N-(2-formamyl-phenyl)-4-(4-hydroxyl-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 43E; with the product of embodiment 43D and the solution reaction of 2-amino-benzamide; obtained 4-(4-benzyloxy-phenoxy group)-N-(2-formamyl-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide.The method of using embodiment 43F has then obtained the crude product of this title compound with this product deprotection, by using the HPLC purifying of TFA, has obtained this title compound, is trifluoroacetate (18mg, 34%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.99Hz，6H)3.28(m，1H)6.76(m，2H)6.96(m，3H)7.18(m，1H)7.57(m，1H)7.85(m，4H)8.10(d，J＝2.21Hz，1H)8.43(s，1H)8.68(d，J＝8.46Hz，1H)8.91(s，1H)9.00(d，J＝8.82Hz，1H)9.48(s，1H)″.50(s，1H)12.99(s，1H)；MS(ESI+)m/z?535(M+H)+。

Embodiment 50

N-(3-fluoro-phenyl)-4-(4-hydroxyl-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 43E,, obtained 4-(4-benzyloxy-phenoxy group)-N-(3-fluoro-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide the product of embodiment 43D and the solution reaction of 3-fluoro-phenyl amine.The method of using embodiment 43F has then obtained the crude product of this title compound with this product deprotection, by using the HPLC purifying of TFA, has obtained this title compound, is trifluoroacetate (7mg, 14%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)3.28(m，1H)6.78(m，2H)6.93(m，4H)7.39(m，1H)7.55(m，1H)7.74(m，1H)7.85(d，J＝8.46Hz，1H)7.97(dd，J＝8.82，2.21Hz，1H)8.13(d，J＝1.84Hz，1H)8.88(s，1H)8.98(d，J＝8.46Hz，1H)9.46(s，1H)10.42(s，1H)11.34(s，1H)；MS(ESI+)m/z?510(M+H)+。

Embodiment 51

N-(4-fluoro-phenyl)-4-(4-hydroxyl-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 43E,, obtained 4-(4-benzyloxy-phenoxy group)-N-(4-fluoro-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide the product of embodiment 43D and the solution reaction of 4-fluoro-phenyl amine.The method of using embodiment 43F has then obtained the crude product of this title compound with this product deprotection, by using the HPLC purifying of TFA, has obtained this title compound, is trifluoroacetate (27mg, 53%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.62Hz，6H)3.28(m，1H)6.76(m，2H)6.92(m，3H)7.20(m，2H)7.76(m，2H)7.85(d，J＝8.82Hz，1H)7.96(dd，J＝8.64，2.39Hz，1H)8.13(d，J＝2.21Hz，1H)8.88(s，1H)8.98(d，J＝8.46Hz，1H)9.46(s，1H)10.30(s，1H)11.35(s，1H)；

MS(ESI+)m/z?510(M+H)+。

Embodiment 52

N-(2-bromo-phenyl)-4-(4-hydroxyl-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 43E,, obtained 4-(4-benzyloxy-phenoxy group)-N-(2-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide the product of embodiment 43D and the solution reaction of 2-bromo-phenyl amine.The method of using embodiment 43F has then obtained the crude product of this title compound with this product deprotection, by using the HPLC purifying of TFA, has obtained this title compound, is trifluoroacetate (8mg, 14%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)3.28(m，1H)6.77(m，2H)6.94(m，3H)7.24(m，1H)7.44(m，1H)7.54(dd，J＝7.74，1.84Hz，1H)7.73(dd，J＝8.09，1.50Hz，1H)7.86(d，J＝8.46Hz，1H)8.01(dd，J＝8.64，2.02Hz，1H)8.15(d，J＝2.21Hz，1H)8.89(s，1H)8.98(d，J＝8.46Hz，1H)9.46(s，1H)10.06(s，1H)11.37(s，1H)；MS(ESI+)m/z?570，572(M+H)+。

Embodiment 53

N-(2-hydroxy-5-methyl base-phenyl)-4-(4-hydroxyl-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 43E, with the product of embodiment 43D and the solution reaction of 2-amino-4-methyl-phenol, obtained 4-(4-benzyloxy-phenoxy group)-N-(2-hydroxy-5-methyl base-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide.The method of using embodiment 43F has then obtained the crude product of this title compound with this product deprotection, by using the HPLC purifying of TFA, has obtained this title compound, is trifluoroacetate (15mg, 29%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)2.22(s，3H)3.29(m，1H)6.79(m，4H)6.92(m，3H)7.47(d，J＝1.32Hz，1H)7.87(d，J＝8.82Hz，1H)7.97(dd，J＝8.46，2.21Hz，1H)8.13(d，J＝2.21Hz，1H)8.91(s，1H)9.00(d，J＝8.46Hz，1H)9.45(m，3H)11.46(s，1H)；MS(ESI+)m/z?522(M+H)+。

Embodiment 54

4-(4-hydroxyl-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(4-methoxyl group-phenyl)-benzamide

Use the method for embodiment 43E, with the product of embodiment 43D and the solution reaction of 4-methoxyl group-phenyl amine, obtained 4-(4-benzyloxy-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(4-methoxyl group-phenyl)-benzamide.The method of using embodiment 43F has then obtained the crude product of this title compound with this product deprotection, by using the HPLC purifying of TFA, has obtained this title compound, is trifluoroacetate (27mg, 52%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)3.28(m，1H)3.74(s，3H)6.77(m，2H)6.92(m，5H)7.64(m，2H)7.87(d，J＝8.82Hz，1H)7.96(dd，J＝8.64，2.02Hz，1H)8.12(d，J＝2.21Hz，1H)8.89(s，1H)8.99(d，J＝8.46Hz，1H)9.46(s，1H)10.12(s，1H)11.41(s，1H)；MS(ESI+)m/z?522(M+H)+。

Embodiment 55

N-(4-fluoro-phenyl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 55A

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

Method according to embodiment 10A, mixture and the reaction of 4-fluoro-phenyl amine with 4-chloro-3-nitrobenzoyl chloride, generate 4-chloro-N-(4-fluoro-phenyl)-3-nitro-benzamide, used the method for embodiment 22A and 22B that it is handled successively, obtained this title product.

Embodiment 55B

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 55A, the product of embodiment 55A and the product of embodiment 8E are reacted, obtained the crude product of this title compound, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (47mg, 45%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.99Hz，6H)3.27(m，1H)6.84(m，2H)6.97(d，J＝8.46Hz，1H)7.18(m，2H)7.31(m，2H)7.80(m，4H)7.95(s，1H)8.75(s，1H)8.96(d，J＝8.46Hz，1H)10.00(s，1H)10.28(s，1H)11.28(s，1H)；MS(ESI+)m/z?526(M+H)+。

Embodiment 56

N-(4-fluoro-phenyl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 55A, and product with the product alternate embodiment 8E of embodiment 9B, the product of embodiment 55A and the product of embodiment 9B are reacted, obtained the crude product of this title compound,, obtained this title compound by using the HPLC purifying of TFA, be trifluoroacetate (24mg, 24%).1H?NMR(300MHz，DMSO-D6)δ?ppm：2.75(s，3H)6.83(m，2H)7.00(d，J＝8.46Hz，1H)7.18(m，2H)7.31(m，2H)7.76(m，3H)7.86(d，J＝8.09Hz，1H)7.96(s，1H)8.81(s，1H)8.95(d，J＝8.09Hz，1H)10.00(s，1H)10.28(s，1H)11.38(s，1H)；(ESI+)m/z?498(M+H)+。

Embodiment 57

N-(4-fluoro-phenyl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 55A, and product with the product alternate embodiment 8E of embodiment 29A, the product of embodiment 55A and the product of embodiment 29A are reacted, obtained the crude product of this title compound,, obtained this title compound by using the HPLC purifying of TFA, be trifluoroacetate (24mg, 24%).1H?NMR(300MHz，DMSO-D6)δ?ppm：6.84(m，2H)6.97(d，J＝8.46Hz，1H)7.18(m，2H)7.32(m，2H)7.79(m，4H)7.95(s，1H)8.74(s，1H)9.02(d，J＝8.09Hz，1H)9.12(d，J＝2.82Hz，1H)9.99(s，1H)10.27(s，1H)11.21(s，1H)；MS(ESI+)m/z?484(M+H)+。

Embodiment 58

N-(2-fluoro-phenyl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 58A

3-amino-N-(2-fluoro-phenyl)-4-(4-hydroxyl-phenyl sulfenyl)-benzamide

Method according to embodiment 10A, mixture and the reaction of 2-fluoro-phenyl amine with 4-chloro-3-nitrobenzoyl chloride, generate 4-chloro-N-(2-fluoro-phenyl)-3-nitro-benzamide, used the method for embodiment 22A and 22B that it is handled successively, obtained this title product.

Embodiment 58B

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 58A, the product of embodiment 58A and the product of embodiment 8E are reacted, obtained the crude product of this title compound, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (43mg, 41%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.99Hz，6H)3.28(m，1H)6.84(m，2H)6.99(d，J＝8.46Hz，1H)7.26(m，5H)7.57(t，J＝7.35Hz，1H)7.87(t，J＝8.09Hz，2H)7.97(s，1H)8.81(s，1H)8.99(d，J＝8.82Hz，1H)10.01(s，1H)10.12(s，1H)11.38(s，1H)；MS(ESI+)m/z?526(M+H)+。

Embodiment 59

N-(2-fluoro-phenyl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 58A, and product with the product alternate embodiment 8E of embodiment 9B, the product of embodiment 58A and the product of embodiment 9B are reacted, obtained the crude product of this title compound,, obtained this title compound by using the HPLC purifying of TFA, be trifluoroacetate (45mg, 45%).1H?NMR(300MHz，DMSO-D6)δ?ppm：2.75(s，3H)6.84(m，2H)7.00(d，J＝8.46Hz，1H)7.28(m，5H)7.56(m，1H)7.80(d，J＝8.09Hz，1H)7.89(d，J＝8.46Hz，1H)7.98(s，1H)8.83(s，1H)8.95(d，J＝8.46Hz，1H)10.01(s，1H)10.12(s，1H)11.49(s，1H)；MS(ESI+)m/z?498(M+H)+。

Embodiment 60

N-(2-fluoro-phenyl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 58A, and product with the product alternate embodiment 8E of embodiment 29A, the product of embodiment 58A and the product of embodiment 29A are reacted, obtained the crude product of this title compound,, obtained this title compound by using the HPLC purifying of TFA, be trifluoroacetate (55mg, 57%).1H?NMR(300MHz，DMSO-D6)δ?ppm：6.84(m，2H)7.00(d，J＝8.09Hz，1H) 7.26(m，5H)7.57(m，1H)7.89(m，2H)7.98(s，1H)8.85(s，1H)9.08(d，J＝7.72Hz，1H)9.17(d，J＝2.94Hz，1H)10.02(s，1H)10.13(s，1H)11.58(s，1H)；MS(ESI+)m/z?484(M+H)+。

Embodiment 61

N-(3-fluoro-phenyl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 61A

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

Method according to embodiment 10A, mixture and the reaction of 3-fluoro-phenyl amine with 4-chloro-3-nitrobenzoyl chloride, generate 4-chloro-N-(3-fluoro-phenyl)-3-nitro-benzamide, used the method for embodiment 22A and 22B that it is handled successively, obtained this title product.

Embodiment 61B

Product with the product alternate embodiment 22B of embodiment 61A, obtained the crude product of this title compound, the product of embodiment 61A and the product of embodiment 8E are reacted, use the method for embodiment 22C, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (44mg, 42%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.99Hz，6H)3.28(m，1H)6.90(m，4H)7.36(m，3H)7.52(m，1H)7.73(m，1H)7.84(d，J＝8.46Hz，2H)7.95(s，1H)8.78(s，1H)8.98(d，J＝8.46Hz，1H)10.01(s，1H)10.41(s，1H)11.38(s， 1H)；MS(ESI+)m/z?526(M+H)+。

Embodiment 62

N-(3-fluoro-phenyl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 61A, and product with the product alternate embodiment 8E of embodiment 9B, the product of embodiment 61A and the product of embodiment 9B are reacted, obtained the crude product of this title compound,, obtained this title compound by using the HPLC purifying of TFA, be trifluoroacetate (56mg, 56%).1H?NMR(300MHz，DMSO-D6)δ?ppm：2.74(s，3H)6.90(m，4H)7.35(m，3H)7.52(d，J＝9.19Hz，1H)7.73(m，2H)7.85(d，J＝8.46Hz，1H)7.96(s，1H)8.78(s，1H)8.93(d，J＝8.46Hz，1H)10.01(s，1H)10.40(s，1H)11.34(s，1H)；MS(ESI+)m/z?498(M+H)+。

Embodiment 63

N-(3-fluoro-phenyl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 61A, and product with the product alternate embodiment 8E of embodiment 29A, the product of embodiment 61A and the product of embodiment 29A are reacted, obtained the crude product of this title compound,, obtained this title compound by using the HPLC purifying of TFA, be trifluoroacetate (54mg, 56%).1H?NMR(300MHz，DMSO-D6)δ?ppm：6.90(m，4H)7.35(m，3H)7.53(d，J＝9.19Hz，1H)7.72(m，1H)7.84(m，2H)7.96(s，1H)8.76(s，1H)9.03(d，J＝8.09Hz，1H)9.14(d，J＝3.31Hz，1H)10.00(s，1H)10.40(s，1H)11.26(s，1H)；MS(ESI+)m/z?484(M+H)+。

Embodiment 64

4-[4-(3-bromo-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl)-t-butyl carbamate

Embodiment 64A

4-[2-amino-4-(3-bromo-phenyl amino formyl radical)-phenyl sulfenyl]-phenyl)-t-butyl carbamate

Method according to embodiment 10A is reacted the mixture and the 3-bromo-phenyl amine of 4-chloro-3-nitrobenzoyl chloride, generated N-(3-bromo-phenyl)-4-chloro-3-nitro-benzamide, use the method for embodiment 13A, 13B and 13C that it is handled successively, obtained this title product.

Embodiment 64B

Use the method for embodiment 13D, product with the product alternate embodiment 13C of embodiment 64A, the product of embodiment 64A and the product of embodiment 8E are reacted, obtained the crude product of this title compound, it is passed through the fast silica gel chromatogram purifying, use the ethanol/methylene wash-out, obtained this title compound (32mg, 23%).1H?NMR(300MHz，DMSO-D6)δppm：1.34(d，J＝6.99Hz，6H)1.48(s，9H)3.22(m，1H)7.01(d，J＝8.09Hz，1H)7.30(m，2H)7.36(d，J＝8.46Hz，2H)7.54(d，J＝8.82Hz，2H)7.64(d，J＝8.46Hz，1H)7.73(m，1H)7.81(d，J＝8.09Hz，1H)8.00(s，1H)8.08(s，1H)8.60(s，1H)8.86(d，J＝8.46Hz，1H)9.60(s，1H)10.23(s，1H)10.35(s，1H)；MS(ESI+)m/z?685，687(M+H)+。

Embodiment 65

4-(4-amino-phenyl sulfenyl)-N-(3-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

In room temperature the product of embodiment 64B was handled 30 minutes in methylene dichloride (3mL) with trifluoroacetic acid (3mL), solvent removed in vacuo has obtained this title compound, is trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.37(d，J＝6.99Hz，6H)3.30(m，1H)6.65(d，J＝8.46Hz，2H)6.97(d，J＝8.46Hz，1H)7.16(d，J＝8.46Hz，2H)7.30(m，2H)7.72(m，1H)7.88(dd，J＝8.46，1.84Hz，1H)7.96(m，2H)8.05(s，1H)8.92(s，1H)9.07(d，J＝8.46Hz，1H)10.37(s，1H)11.82(s，1H)；MS(ESI+)m/z?585，587(M+H)+。

Embodiment 66

4-[4-(3-bromo-phenyl amino formyl radical)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Use the method for embodiment 13D, product with the product alternate embodiment 13C of embodiment 64A, and product with the product alternate embodiment 8E of embodiment 9B, the product of embodiment 64A and the product of embodiment 9B are reacted, obtained the crude product of this title compound,, used ethanol/methylene as eluent by silica gel chromatography, obtained this title compound (27mg, 21%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.48(s，9H)2.69(s，3H)7.00(d，J＝8.09Hz，1H)7.34(m，4H)7.54(m，3H)7.72(m，1H)7.81(d，J＝8.09Hz，1H)8.01(s，1H)8.07(s，1H)8.60(s，1H)8.82(d，J＝8.46Hz，1H)9.60(s，1H)10.22(s，1H)10.34(s，1H)；MS(ESI+)m/z?657，659(M+H)+。

Embodiment 67

4-(4-amino-phenyl sulfenyl)-N-(3-bromo-phenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

In room temperature the product of embodiment 66 was handled 30 minutes in methylene dichloride (3mL) with trifluoroacetic acid (3mL), solvent removed in vacuo has obtained this title compound, is trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：2.77(s，3H)6.65(d，J＝8.46Hz，2H)6.97(d，J＝8.46Hz，1H)7.16(d，J＝8.46Hz，2H)7.30(m，2H)7.72(m，1H)7.90(m，3H)8.05(s，1H)8.92(s，1H)9.01(d，J＝8.46Hz，1H)10.36(s，1H)11.78(s，1H)；MS(ESI+)m/z?557，559(M+H)+。

Embodiment 68

4-[4-(3-bromo-phenyl amino formyl radical)-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Use the method for embodiment 13D, product with the product alternate embodiment 13C of embodiment 64A, and product with the product alternate embodiment 8E of embodiment 29A, the product of embodiment 64A and the product of embodiment 29A are reacted, obtained the crude product of this title compound,, used ethanol/methylene as eluent by silica gel chromatography, obtained this title compound (31mg, 24%).1H?NMR(300?MHz，DMSO-D6)δ?ppm：1.48(s，9H)7.01(d，J＝8.46Hz，1H)7.32(m，4H)7.54(d，J＝8.46Hz，2H)7.71(m，2H)7.82(d，J＝7.72Hz，1H)8.01(s，1H)8.08(s，1H)8.64(s，1H)8.96(d，J＝8.09Hz，1H)9.11(d，J＝2.94Hz，1H)9.61(s，1H)10.35(s，1H)10.36(s，1H)；MS(ESI+)m/z?643/645(M+H)+。

Embodiment 69

4-(4-amino-phenyl sulfenyl)-N-(3-bromo-phenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

In room temperature the product of embodiment 68 was handled 30 minutes in methylene dichloride (3mL) with trifluoroacetic acid (3mL), solvent removed in vacuo has obtained this title compound, is trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：6.65(d，J＝8.82Hz，2H)6.97(d，J＝8.46Hz，1H)7.17(d，J＝8.46Hz，2H)7.30(m，2H)7.72(m，1H)7.91(m，3H)8.05(s，1H)8.91(s，1H)9.12(d，J＝8.46Hz，1H)9.19(d，J＝3.68Hz，1H)10.36(s，1H)11.72(s，1H)；MS(ESI+)m/z543/545(M+H)+。

Embodiment 70

4-[4-(2-amino-butyryl radicals amino)-phenyl sulfenyl]-N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

To the product of embodiment 13E (59mg, 0.1mmol) and Boc-Abu-OH (22mg 0.11mmol) adds 3-(diethoxy phosphoryl oxy)-1 in the solution in tetrahydrofuran (THF) (5ml), 2,3-phentriazine-4 (3H)-ketone (36mg, 0.11mmol) and triethylamine (0.07ml, 0.5mmol).Mixture stirring at room 16 hours, is poured in the saturated sodium carbonate solution then, and used ethyl acetate extraction.With the organic layer dried over mgso, filter and evaporation.In resistates, add methylene dichloride (2ml) and trifluoroacetic acid (2ml), then stirring at room 1 hour.With solvent evaporation, and come the purifying resistates, obtained this title compound (62mg, 85%) by the HPLC that uses NH4OH.1H?NMR(300MHz，DMSO-D6)δ?ppm：0.90(t，J＝7.54Hz，3H)1.33(d，J＝6.99Hz，6H)1.48(m，1H)1.66(m，1H)1.90(s，3H)3.22(m，2H)7.02(m，2H)7.40(d，J＝8.46Hz，2H)7.52(d，J＝8.46Hz，2H)7.61(d，J＝8.46Hz，1H)7.72(m，5H)7.94(s，1H)8.52(s，1H)8.79(s，1H)10.33(s，1H)；MS(ESI+)m/z?670，672(M+H)+。

Embodiment 71

Tetramethyleneimine-2-formic acid 4-[4-(4-bromo-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-acid amides

Use the method for embodiment 70, with (S)-tetramethyleneimine-1, the 2-dioctyl phthalate 1-tert-butyl ester substitutes Boc-Abu-OH, with the product of embodiment 13E with (S)-tetramethyleneimine-1,2-dioctyl phthalate 1-tert-butyl ester reaction has obtained the crude product of this title compound, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (48mg, 53%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.99Hz，6H)1.95(m，3H)2.37(m，1H)3.28(m，3H)4.32(m，1H)7.14(s，1H)7.45(d，J＝8.82Hz，2H)7.54(d，J＝8.82Hz，2H)7.63(d，J＝8.82Hz，2H)7.73(d，J＝8.82Hz，2H)7.85(s，2H)8.02(s，1H)8.70(s，2H)8.92(s，1H)9.23(s，1H)10.38(s，1H)10.67(s，1H)11.10(s，1H)；MS(ESI+)m/z?682/684(M+H)+。

Embodiment 72

4-[4-(3-amino-propionyl amino)-phenyl sulfenyl]-N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 70, substitute Boc-Abu-OH with 3-tert-butoxycarbonyl amino-propionic acid, product and 3-tert-butoxycarbonyl amino-propionic acid reaction with embodiment 13E, obtained the crude product of this title compound, by using the HPLC purifying of TFA, with the aqueous sodium carbonate neutralization, obtained this title compound (15mg, 23%) then.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.33(d，J＝6.62Hz，6H)2.41(t，J＝6.25Hz，2H)2.83(t，J＝6.25Hz，2H)3.20(m，1H)6.97(d，J＝8.46Hz，1H)7.39(d，J＝8.46Hz，2H)7.54(m，3H)7.70(m，5H)7.95(s，1H)8.47(s，1H)8.79(d，J＝8.09Hz，1H)10.32(s，1H)；MS(ESI+)m/z?656/658(M+H)+。

Embodiment 73

4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-phenyl-benzamide

Embodiment 73A

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

According to the method for embodiment 10A, mixture and phenyl amine reaction with 4-chloro-3-nitrobenzoyl chloride have generated 4-chloro-3-nitro-N-phenyl-benzamide, use the method for embodiment 22A and 22B that it is handled successively, have obtained this title product.

Embodiment 73B

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 73A, the product of embodiment 73A and the product of embodiment 8E are reacted the crude product that has obtained this title compound, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (42mg, 34%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.62Hz，6H)，3.23-3.35(m，1H)，6.84(d，J＝8.82Hz，2H)，6.98(d，J＝8.46Hz，1H)，7.10(t，J＝7.54Hz，1H)，7.25-7.39(m，4H)，7.73(d，J＝7.72Hz，2H)，7.85(s，2H)，7.96(s，1H)，8.79(s，1H)，8.98(d，J＝6.62Hz，1H)，10.00(s，1H)，10.22(s，1H)，11.28(s，1H)；MS(ESI+)m/z?508(M+H)+。

Embodiment 74

4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-phenyl-benzamide

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 73A, and product with the product alternate embodiment 8E of embodiment 9B, the product of embodiment 73A and the product of embodiment 9B are reacted, obtained the crude product of this title compound,, obtained this title compound by using the HPLC purifying of TFA, be trifluoroacetate (44mg, 37%).1H?NMR(300MHz，DMSO-D6)δ?ppm：2.75(s，3H)，6.78-6.89(m，2H)，7.00(d，J＝8.09Hz，1H)，7.10(t，J＝7.35Hz，1H)，7.25-7.41(m，4H)，7.73(d，J＝7.72Hz，2H)，7.78(d，J＝8.82Hz，1H)，7.87(d，J＝8.46Hz，1H)，7.97(s，1H)，8.81(s，1H)，8.94(d，J＝9.19Hz，1H)，10.00(s，1H)，10.22(s，1H)，11.38(s，1H)；MS(ESI+)m/z?480(M+H)+。

Embodiment 75

4-(4-hydroxyl-phenyl sulfenyl)-N-phenyl-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide uses the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 73A, and,, obtained the crude product of this title compound with the product reaction of product and the embodiment 29A of embodiment 73A with the product of the product alternate embodiment 8E of embodiment 29A, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (45mg, 39%).1H?NMR(300MHz，DMSO-D6)δ?6.84ppm：(d，J＝8.82?Hz，2H)，6.99(d，J＝8.82Hz，1H)，7.10(t，J＝7.35Hz，1H)，7.26-7.42(m，4H)，7.73(d，J＝7.35Hz，2H)，7.84(s，2H)，7.97(s，1H)，8.81(s，1H)，9.06(s，1H)，9.15(s，1H)，9.98(s，1H)，10.21(s，1H)，11.29(s，1H)；MS(ESI+)mz?466(M+H)+。

Embodiment 76

4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-thiazol-2-yl-benzamide

Embodiment 76A

3-amino-4-(4-hydroxyl-phenyl sulfenyl)-N-thiazol-2-yl-benzamide

Method according to embodiment 10A, mixture and the reaction of thiazol-2-yl amine with 4-chloro-3-nitrobenzoyl chloride, generate 4-chloro-3-nitro-N-thiazol-2-yl-benzamide, used the method for embodiment 22A and 22B that it is handled successively, obtained this title product.

Embodiment 76B

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 76A, the product of embodiment 76A and the product of embodiment 8E are reacted, obtained the crude product of this title compound, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (38mg, 30%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.37(d，J＝6.62Hz，6H)，3.23-3.39(m，1H)，6.87(d，J＝8.46Hz，2H)，6.95(d，J＝8.46Hz，1H)，7.28(d，J＝3.31Hz，1H)，7.31-7.38(m，2H)，7.55(d，J＝3.68Hz，1H)，7.91(d，J＝8.46Hz，1H)，8.02(d，J＝8.46Hz，1H)，8.10(d，J＝1.84Hz，1H)，8.85(s，1H)，9.03(d，J＝8.46Hz，1H)，10.07(s，1H)，12.65(s，1H)；MS(ESI+)m/z?515(M+H)+。

Embodiment 77

4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-thiazol-2-yl-benzamide

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 76A, and product with the product alternate embodiment 8E of embodiment 9B, the product of embodiment 76A and the product of embodiment 9B are reacted, obtained the crude product of this title compound,, obtained this title compound by using the HPLC purifying of TFA, be trifluoroacetate (28mg, 23%).1H?NMR(300MHz，DMSO-D6)δ?ppm：2.77(s，3H)，6.87(d，J＝8.82Hz，2H)，6.96(d，J＝8.46Hz，1H)，7.28(d，J＝3.31Hz，1H)，7.34(d，J＝8.82Hz，2H)，7.55(d，J＝3.68Hz，1H)，7.85(d，J＝8.82Hz，1H)，8.02(dd，J＝8.46，1.84Hz，1H)，8.12(d，J＝1.84Hz，1H)，8.89(s，1H)，9.00(d，J＝8.46Hz，1H)，10.09(s，1H)，12.69(s，1H)；MS(ESI+)m/z?487(M+H)+。

Embodiment 78

4-(4-hydroxyl-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-N-thiazol-2-yl-benzamide

Use the method for embodiment 22C, product with the product alternate embodiment 22B of embodiment 76A, and product with the product alternate embodiment 8E of embodiment 29A, the product of embodiment 76A and the product of embodiment 29A are reacted, obtained the crude product of this title compound,, obtained this title compound by using the HPLC purifying of TFA, be trifluoroacetate (45mg, 39%).1H?NMR(300MHz，DMSO-D6)δ?ppm：6.86(d，J＝8.46Hz，2H)，6.97(d，J＝8.46Hz，1H)，7.28(d，J＝3.31Hz，1H)，7.34(d，J＝8.82Hz，2H)，7.55(d，J＝3.68Hz，1H)，7.96(dd，J＝8.27，4.60Hz，1H)，8.03(dd，J＝8.46，1.84Hz，1H)，8.13(d，J＝1.84Hz，1H)，8.92(s，1H)，9.13(d，J＝8.09Hz，1H)，9.18-9.23(m，1H)，10.06(s，1H)，11.85(s，1H)，12.64(s，1H)；MS(ESI+)m/z?473(M+H)+。

Embodiment 79

N-(3-bromo-phenyl)-4-(3-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 79A

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

With N-(3-bromo-phenyl)-4-chloro-3-nitro-benzamide (from embodiment 26A) (0.356g, 1.0mmol), 3-hydroxythiophenol (0.126g, 1.0mmol) and cesium carbonate (0.65g, 2.0mmol) at N, the solution in the dinethylformamide (5mL) in 95 ℃ the heating 3 hours.After being cooled to room temperature, this mixture is poured in the frozen water (20mL), gained solution 1N hcl acidifying.(3 * 10mL) extractions with the extraction liquid dried over mgso that merges, are filtered and vacuum concentration, have obtained this title compound (0.430g, 97%) with ethyl acetate with this solution then.

Embodiment 79B

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

With the product of embodiment 79A (0.43g, 0.97mmol), iron powder (0.28g, 5.0mmol) and ammonium chloride (0.08g, 1.5mmol) vlil in ethanol (18mL), tetrahydrofuran (THF) (18mL) and water (6mL) solution is 3 hours.The gained mixture is diluted with ethanol (50mL), and filter via Celite pad.With filtrate vacuum concentration to volume is 10mL, this solution with water (50mL) is diluted, and (2 * 50mL) extracts with ethyl acetate.With the extraction liquid dried over sodium sulfate that merges, filter and vacuum concentration, obtained this title compound (0.41g, 98%).

Embodiment 79C

With the product of embodiment 79B (62.0mg, 0.15mmol) and the product of embodiment 8E (32.0mg, 0.15mmol) solution in acetate (1mL) is being preheated in 140 ℃ the oil bath and was stirring 20 minutes, with this mixture cooling and vacuum concentration.Come purifying gained resistates by the HPLC that uses TFA, obtained this title compound, be trifluoroacetate (32mg, 30%).1HNMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.99Hz，6H)，3.19-3.34(m，1H)，6.70(dd，J＝7.72，1.84Hz，1H)，6.75(t，J＝2.02Hz，1H)，6.80(d，J＝7.72Hz，1H)，7.14(t，J＝7.91Hz，1H)，7.24-7.38(m，3H)，7.71-7.77(m，1H)，7.80(d，J＝8.46Hz，1H)，7.91(d，J＝8.09Hz，1H)，8.01(s，1H)，8.08(s，1H)，8.73(s，1H)，8.91(d，J＝8.46Hz，1H)，9.72(s，1H)，10.44(s，1H)，11.26(s，1H)；MS(ESI+)m/z?586/588(M+H)+。

Embodiment 80

N-(3-bromo-phenyl)-4-(3-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 79C, product with the product alternate embodiment 8E of embodiment 9B, the product of embodiment 79B and the product of embodiment 9B are reacted, obtained the crude product of this title compound, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (35mg, 35%).1H?NMR(300MHz，DMSO-D6)δ?ppm：2.72(s，3H)，6.71(dd，J＝7.72，1.84Hz，1H)，6.75(t，J＝2.02Hz，1H)，6.81(d，J＝8.09Hz，1H)，7.14(t，J＝7.91Hz，1H)，7.27-7.37(m，3H)，7.68-7.79(m，2H)，7.90(d，J＝7.72Hz，1H)，8.02(s，1H)，8.08(s，1H)，8.72(s，1H)，8.85(d，J＝8.09Hz，1H)，9.72(s，1H)，10.42(s，1H)，11.17(s，1H)；MS(ESI+)m/z?558/560(M+H)+。

Embodiment 81

N-(3-bromo-phenyl)-4-(3-hydroxyl-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 79C, product with the product alternate embodiment 8E of embodiment 29A, the product of embodiment 79B and the product of embodiment 29A are reacted, obtained the crude product of this title compound, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (44mg, 45%).1H?NMR(300MHz，DMSO-D6)δ?ppm：6.70(dd，J＝8.09，1.84Hz，1H)，6.75(s，1H)，6.81(d，J＝7.72Hz，1H)，7.14(t，J＝7.91Hz，1H)，7.26-7.38(m，3H)，7.72-7.77(m，1H)，7.79(d，J＝6.62Hz，1H)，7.88(d，J＝6.25Hz，1H)，8.01(s，1H)，8.08(s，1H)，8.71(s，1H)，8.94(s，1H)，9.10(s，1H)，9.71(s，1H)，10.41(s，1H)，11.08(s，1H)：MS(ESI+)m/z?544/546(M+H)+。

Embodiment 82

4-(3-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-phenyl-benzamide

Embodiment 82A

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

Use the method for embodiment 81A and 81B,, obtained this title product deriving from 4-chloro-3-nitro-N-phenyl-benzamide reaction of embodiment 73A.

Embodiment 82B

Use the method for embodiment 79C, product with the product alternate embodiment 79B of embodiment 82A, the product of embodiment 82A and the product of embodiment 8E are reacted, obtained the crude product of this title compound, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (52mg, 45%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.62Hz，6H)，3.21-3.34(m，1H)，6.69(dd，J＝7.54，2.02Hz，1H)，6.74(t，J＝1.84Hz，1H)，6.80(d，J＝8.09Hz，1H)，7.12(q，J＝7.60Hz，2H)，7.28-7.39(m，3H)，7.71-7.83(m，3H)，7.91(d，J＝7.72Hz，1H)，8.02(s，1H)，8.72(s，1H)，8.91(d，J＝8.46Hz，1H)，9.71(s，1H)，10.30(s，1H)，11.18(s，1H)；MS(ESI+)m/z?508(M+H)+。

Embodiment 83

4-(3-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-phenyl-benzamide

Use the method for embodiment 79C, product with the product alternate embodiment 79B of embodiment 82B, and product with the product alternate embodiment 8E of embodiment 9B, the product of embodiment 82B and the product of embodiment 9B are reacted, obtained the crude product of this title compound,, obtained this title compound by using the HPLC purifying of TFA, be trifluoroacetate (25mg, 21%).1H?NMR(300MHz，DMSO-D6)δ?ppm：2.74(s，3H)，6.69(dd，J＝7.91，2.02Hz，1H)，6.74(t，J＝2.02Hz，1H)，6.79(d，J＝7.72Hz，1H)，7.07-7.17(m，2H)，7.33(d，J＝3.31Hz，1H)，7.36(s，1H)，7.37(d，J＝4.04Hz，1H)，7.76(t，J＝8.27Hz，3H)，7.94(d，J＝8.09Hz，1H)，8.03(s，1H)，8.79(s，1H)，8.90(d，J＝8.46Hz，1H)，9.72(s，1H)，10.31(s，1H)，11.44(s，1H)；MS(ESI+)m/z?480(M+H)+。

Embodiment 84

N-(4-bromo-phenyl)-4-(3-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 84A

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

Use the method for embodiment 81A and 81B,, obtained this title product deriving from the product reaction of embodiment 10A.

Embodiment 84B

Use the method for embodiment 79C, product with the product alternate embodiment 79B of embodiment 84A, the product of embodiment 84A and the product of embodiment 8E are reacted, obtained the crude product of this title compound, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (33mg, 31%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.62Hz，6H)，3.22-3.34(m，1H)，6.69(dd，J＝7.91，2.02Hz，1H)，6.74(t，J＝2.02Hz，1H)，6.80(d，J＝8.09Hz，1H)，7.12(t，J＝7.91Hz，1H)，7.34(d，J＝8.09Hz，1H)，7.48-7.58(m，2H)，7.70-7.79(m，2H)，7.84(d，J＝8.46Hz，1H)，7.93(d，J＝8.46Hz，1H)，8.01(s，1H)，8.78(s，1H)，8.94(d，J＝8.46Hz，1H)，9.72(s，1H)，10.43(s，1H)，11.43(s，1H)；MS(ESI+)m/z?586/588(M+H)+。

Embodiment 85

N-(4-bromo-phenyl)-4-(3-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 79C, product with the product alternate embodiment 79B of embodiment 84A, and product with the product alternate embodiment 8E of embodiment 9B, the product of embodiment 84A and the product of embodiment 9B are reacted, obtained the crude product of this title compound,, obtained this title compound by using the HPLC purifying of TFA, be trifluoroacetate (28mg, 28%).1H?NMR(300MHz，DMSO-D6)δ?ppm：2.73(s，3H)，6.70(dd，J＝7.72，2.21Hz，1H)，6.74(t，J＝1.84Hz，1H)，6.80(d，J＝7.72Hz，1H)，7.13(t，J＝7.91Hz，1H)，7.33(d，J＝8.09Hz，1H)，7.51-7.58(m，2H)，7.70-7.78(m，3H)，7.91(d，J＝8.09Hz，1H)，8.02(s，1H)，8.75(s，1H)，8.88(d，J＝8.09Hz，1H)，9.72(s，1H)，10.42(s，1H)，11.31(s，1H)；MS(ESI+)m/z?558/560(M+H)+。

Embodiment 86

4-(4-amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-p-methylphenyl-benzamide

Embodiment 86A

4-fluoro-3-nitro-Benzoyl chloride

(1.00g 5.40mmol) is dissolved in 1, adds SOCl in the solution in the 2-ethylene dichloride (30mL) to 4-fluoro-3-nitro-phenylformic acid ₂(6.42g, 54.0mmol).Then this reaction mixture was heated 16 hours at 80 ℃.At this moment this reaction mixture is cooled to room temperature, and solvent removed in vacuo, this title product obtained.

Embodiment 86B

4-fluoro-3-nitro-N-p-methylphenyl-benzamide

To p-methylphenyl amine (626mg, 5.89mmol) and Hunig ' s alkali (2.054ml, 11.8mmol) in the solution in tetrahydrofuran (THF) (20mL) via the product that dripped the embodiment 86A in tetrahydrofuran (THF) (10mL) in 10 minutes (1.20g, 5.89mmol).This solution stirring at room 1 hour, with this reaction mixture dilute with water, and is collected this title compound (1.77g, 100%) by filtering.

Embodiment 86C

[4-(2-nitro-4-p-methylphenyl formamyl-phenoxy group)-phenyl]-t-butyl carbamate

With the product of embodiment 86B (1.77g, 5.45mmol), KOH (736mg, 12.9mmol) and (4-hydroxyl-phenyl)-t-butyl carbamate (1.35g 6.45mmol) is dissolved among the DMSO, and 80 ℃ of heating 2 hours.At this moment this reaction mixture is cooled to room temperature, and dilute with water.Collect this title compound (380mg, 12.7%) by filtering then.

Embodiment 86D

[4-(2-amino-4-p-methylphenyl formamyl-phenoxy group)-phenyl]-t-butyl carbamate

(380mg, 0.819mmol) reduction has obtained this title product (321mg, 90%) with the product of embodiment 86C according to the method for embodiment 10C.

Embodiment 86E

4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-p-methylphenyl formamyl-phenoxy group]-phenyl }-t-butyl carbamate

Product (160.0mg with embodiment 8E, 0.739mmol) and the product (321.0mg of embodiment 86D, 0.739mmol) solution in acetate (1mL) is being preheated in 130 ℃ the oil bath and stirring 10 minutes, then this mixture is cooled to room temperature, and vacuum is removed acetate, obtained this title product (305mg, 64%).

Embodiment 86F

(305mg 0.504mmol) is dissolved in methylene dichloride (5mL) and the trifluoroacetic acid (2mL) with the product of embodiment 86E.With this solution in stirring at room 1 hour, solvent removed in vacuo then. come purifying gained resistates by the HPLC that uses TFA, obtained this title compound, be trifluoroacetate (35mg, 14%). ¹H?NMR(300MHz，DMSO-D ₆)δ?ppm：1.34(d，J＝6.99Hz，6H)，2.28(s，3H)，3.28(qt，J＝13.70，6.94Hz，1H)，6.82-6.88(m，2H)，6.91-6.99(m，3H)，7.16(d，J＝8.46Hz，2H)，7.63(d，J＝8.46Hz，2H)，7.86(d，J＝8.46Hz，1H)，7.98(dd，J＝8.46，2.21Hz，1H)，8.13(d，J＝2.21Hz，1H)，8.87(s，1H)，8.98(d，J＝8.46Hz，1H)，10.17(s，1H)；MS(ESI+)m/z?505(M+H-TFA)+；(ESI-)m/z503(M-H-TFA)-。

Embodiment 87

4-(4-amino-phenoxy group)-N-(4-fluoro-3-methyl-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 87A

4-[2-amino-4-(4-fluoro-3-methyl-phenyl amino formyl radical)-phenoxy group]-phenyl }-t-butyl carbamate

Method according to embodiment 86B, mixture of products and 4-fluoro-3-methyl-phenyl amine reaction with embodiment 86A, generate 4-fluoro-N-(4-fluoro-3-methyl-phenyl)-3-nitro-benzamide, used the method for embodiment 86C and 395D that it is handled successively successively, obtained this title product.

Embodiment 87B

Use the method for embodiment 86E; product with the product alternate embodiment 86D of embodiment 87A; the product of embodiment 87A and the product of embodiment 8E are reacted; obtained { 4-[4-(4-fluoro-3-methyl-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-phenoxy group]-phenyl }-t-butyl carbamate; use the method for embodiment 86F to react it; obtained resistates; by using the HPLC purifying of TFA; obtained this title compound; be trifluoroacetate (20mg, 11%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.62Hz，6H)，2.24(s，3H)，3.21-3.37(m，J＝13.79，7.17，6.99Hz，1H)，6.84-7.00(m，5H)，7.12(t，J＝9.19Hz，1H)，7.54-7.59(m，1H)，7.66(dd，J＝6.80，2.39Hz，1H)，7.86(d，J＝8.46Hz，1H)，7.98(dd，J＝8.82，2.21Hz，1H)，8.13(d，J＝2.21Hz，1H)，8.88(s，1H)，8.98(d，J＝8.46Hz，1H)，10.23(s，1H)；MS(ESI+)m/z?523(M+H-TFA)+；(ESI-)m/z?521(M-H-TFA)-。

Embodiment 88

4-(4-amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(3-trifluoromethyl-phenyl)-benzamide

Embodiment 88A

4-[2-amino-4-(3-trifluoromethyl-phenyl amino formyl radical)-phenoxy group]-phenyl }-t-butyl carbamate

Method according to embodiment 86B, mixture of products and 3-trifluoromethyl-phenyl amine reaction with embodiment 86A, generate 4-fluoro-3-nitro-N-(3-trifluoromethyl-phenyl)-benzamide, used the method for embodiment 86C and 86D that it is handled successively, obtained this title product.

Embodiment 88B

Use the method for embodiment 86E; product with the product alternate embodiment 86D of embodiment 88A; the product of embodiment 88A and the product of embodiment 8E are reacted; obtained { 4-[2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-4-(3-trifluoromethyl-phenyl amino formyl radical)-phenoxy group]-phenyl }-t-butyl carbamate; use the method for embodiment 86F to react it; obtained resistates; by using the HPLC purifying of TFA; obtained this title compound; be trifluoroacetate (55mg, 23%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)，3.22-3.35(m，1H)，6.79-7.11(m，6H)，7.47(d，J＝7.72Hz，1H)，7.61(t，J＝8.09Hz，1H)，7.87(d，J＝8.82Hz，1H)，7.99-8.10(m，2H)，8.17(d，J＝2.21Hz，1H)，8.23(s，1H)，8.88(s，1H)，8.99(d，J＝8.82Hz，1H)，10.57(s，1H)；MS(ESI+)m/z559(M+H-TFA)+；(ESI-)m/z?557(M-H-TFA)-。

Embodiment 89

N-(4-bromo-phenyl)-4-(1H-indoles-5-base sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 89A

5-iodo-indoles-1-t-butyl formate

In room temperature with 5-iodine indoles (2.00g, 8.229mmol) solution in anhydrous methylene chloride (40mL) is with tert-Butyl dicarbonate (2.155g, 9.875mmol) and 4-dimethylaminopyridine (201mg 1.646mmol) handles, and with this solution stirring at room 16 hours.Remove by rotary evaporation in vacuo and to desolvate, and with resistates by the fast silica gel chromatogram purifying, with 1:1 hexanes/ch wash-out, obtained this title compound, be lightpink oily matter (2.57g, 91%).

Embodiment 89B

5-triisopropyl silyl sulfenyl-indoles-1-t-butyl formate

Under nitrogen atmosphere with the product (200mg of embodiment 89A, 0.583mmol) solution in anhydrous tetrahydro furan (4mL) is with [1,1 '-two (diphenylphosphino) ferrocene] palladium chloride methylene dichloride complex compound (5mg) processing, and with this solution nitrogen purging several minutes, adding is according to the triisopropyl silicomethane mercaptan potassium (146.5mg of Tetrahedron Lettrs 35 (20) 3,221 1994 preparations, 0.6411mmol), and should react reflux 15 minutes, this reaction is cooled to room temperature, and remove by rotary evaporation in vacuo and to desolvate, obtained this title compound, be colorless oil (210mg, 89%).

Embodiment 89C

5-sulfydryl-indoles-1-t-butyl formate

At-20 ℃ under nitrogen atmosphere, product (203.7mg with embodiment 89B, 0.502mmol) solution in anhydrous tetrahydro furan (4mL) is with the solution (0.552mL of 1M tetrabutylammonium in tetrahydrofuran (THF), 0.552mmol) handle, and this being reflected at-20 ℃ stirred 15 minutes, should react with ethyl acetate (50mL) dilution, and water (2 * 25mL) and salt solution (25mL) wash.With the organic phase anhydrous magnesium sulfate drying, filter, and concentrate by rotary evaporation in vacuo, obtained yellow oil.By the fast silica gel chromatogram purifying, use 5% ethyl acetate/hexane as eluent, obtained this title compound (42mg, 33%).

Embodiment 89D

5-[4-(4-bromo-phenyl amino formyl radical)-2-nitro-phenyl sulfenyl]-indoles-1-t-butyl formate

At room temperature product (39.9mg with embodiment 89C under nitrogen atmosphere, 0.160mmol) product (56.8mg of embodiment 10A of the solution in dehydrated alcohol (2mL), 0.160mmol) and anhydrous sodium acetate (66mg 0.800mmol) handles, and reflux is 2 hours then.This reaction is cooled to room temperature, and removes by rotary evaporation in vacuo and to desolvate.Resistates is placed ethyl acetate (50mL), and water (2 * 25mL) and salt solution (25mL) washing.With the organic phase anhydrous sodium sulfate drying, filter, and vacuum concentration.By the fast silica gel chromatogram purifying, use methylene dichloride as eluent, obtained this title compound, be yellow solid (77mg, 85%).

Embodiment 89E

5-[2-amino-4-(4-bromo-phenyl amino formyl radical)-phenyl sulfenyl]-indoles-1-t-butyl formate

Product (75mg with embodiment 89D, 0.132mmol), iron powder (45.3mg, 0.811mmol) and ammonium chloride (46mg, 0.864mmol) suspension in water (1mL) and ethanol (2mL) is 95 ℃ of heating 30 minutes, this reaction is cooled to room temperature, with ethyl acetate (50mL) dilution, and water (2 * 25mL) and salt solution (25mL) wash.With the organic phase anhydrous sodium sulfate drying, filter, and concentrate by rotary evaporation in vacuo, obtained this title compound, be yellow solid (65mg, 92%).

Embodiment 89F

With the product of embodiment 8E (25mg, 0.116mmol) and the product of embodiment 89E (62.6mg, 0.116mmol) solution in acetate (2mL) is being preheated in 140 ℃ the oil bath and was stirring 1 hour.This reaction is cooled to room temperature,, concentrates by rotary evaporation with hexane (50mL) dilution, and with dichloromethane/hexane coevaporation (4 *).With resistates vacuum-drying, by the fast silica gel chromatogram purifying, use 4% ethanol/methylene wash-out then, obtained this title compound (11mg, 16%). ¹H NMR (300MHz, DMSO-D6) δ ppm:1.35 (d, family 6.62Hz, 6H) 3.16-3.30 (m, 1H) 6.44-6.53 (m, 1H) 6.89 (d, J=8.46Hz, 1H) 7.15 (dd, J=8.46,1.47Hz, 1H) 7.42-7.46 (m, 1H) 7.46-7.55 (m, 3H) 7.65 (d, J=8.46Hz, 1H) 7.69-7.78 (m, 4H) 7.98 (d, J=1.47Hz, 1H) 8.61 (s, 1H) 8.90 (d, J=8.82Hz, 1H) 10.22 (s, 1H) 10.29 (s, and 1H) 11.38 (s, 1H); MS (ESI+) m/z 609/611 (M+H) ⁺

Embodiment 90

4-(4-azido--phenyl sulfenyl)-N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

(62.4mg, 0.1066mmol) solution in concentrated hydrochloric acid (2mL) is by dripping Sodium Nitrite (14.7mg, 0.2131mmol) solution-treated in water (1mL) with the product that is cooled to 0 °-5 ℃ embodiment 13E.After 0 ℃ is stirred 1 hour, 0 ℃ drip sodiumazide (13.8mg, 0.2131mmol) and sodium acetate (72.6mg, the 0.885mmol) solution in water (2mL), and this is reflected at 0 ℃ of stirring 1 hour.Should react the dilution of water (25mL) and ethyl acetate (50mL) then, use 6N aqueous sodium hydroxide solution to 7-8, separates each layer to the water layer pH regulator, and with organic phase washing salt solution (25mL).With the organic phase anhydrous sodium sulfate drying, filter, and concentrate by rotary evaporation in vacuo.By the fast silica gel chromatogram purifying, use 30% ethyl acetate/dichloromethane the gained resistates, obtained this title compound, be yellow solid (21mg, 32%) as eluent. ¹H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.62Hz，6H)3.11-3.32(m，1H)7.10(d，J＝8.46Hz，2H)7.21(d，J＝8.46Hz，1H)7.41(d，J＝8.46Hz，2H)7.53(d，J＝8.82Hz，2H)7.63(d，J＝8.46Hz，1H)7.74(d，J＝9.19Hz，2H)7.81-7.91(m，1H)8.03(d，J＝1.10Hz，1H)8.58(s，1H)8.82(d，J＝8.46Hz，1H)10.23(s，1H)10.39(s，1H)；MS(ESI+)m/z?611/613(M+H) ⁺。

Embodiment 91

N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-methylsulfonyl amino-phenoxy group)-benzamide

Embodiment 91A

4-(4-amino-phenoxy group)-N-(4-bromo-phenyl)-3-nitro-benzamide

(250mg, 0.4732mmol) solution in methylene dichloride (5mL) was handled 30 minutes with trifluoroacetic acid (5mL) with the product of embodiment 10B in room temperature.Remove by rotary evaporation in vacuo and to desolvate, resistates is placed ethyl acetate (100mL), and with saturated sodium bicarbonate aqueous solution (2 * 50mL), water (50mL) and salt solution (50mL) washs.With the organic phase anhydrous sodium sulfate drying, filter, and vacuum concentration, obtained this title compound, be light orange solid (197mg, 97%).

Embodiment 91B

N-(4-bromo-phenyl)-4-(4-methylsulfonyl amino-phenoxy group)-3-nitro-benzamide

(195mg 0.4554mmol) is dissolved in the anhydrous pyridine (5mL), and (0.106mL 1.366mmol) handles, and stirring at room 19 hours with methylsulfonyl chloride with the product of embodiment 91A under nitrogen atmosphere.Remove by rotary evaporation in vacuo and to desolvate, and resistates is dissolved in the ethyl acetate (100mL), with 1N hydrochloric acid (2 * 50mL), water (50mL) and salt solution (50mL) washs.With the organic phase anhydrous sodium sulfate drying, filter, and vacuum concentration, obtained this title compound, be light orange solid (225mg, 98%).

Embodiment 91C

3-amino-N-(4-bromo-phenyl)-4-(4-methylsulfonyl amino-phenoxy group)-benzamide

Product (223mg with embodiment 91B, 0.4404mmol) and iron powder (98mg, 1.762mmol) suspension in acetate (5mL) and ethanol (5mL) reflux 30 minutes under nitrogen atmosphere, this reaction is cooled to room temperature, water (50mL) dilution, and to handle until pH with solid sodium carbonate be 6.With ethyl acetate (100mL) extraction, organic phase with salt solution (50mL) washing, is used anhydrous sodium sulfate drying, filter, and concentrate by rotary evaporation in vacuo.With gained oily matter and dichloromethane/hexane coevaporation, obtained this title compound, be light tan solid (195mg, 93%).

Embodiment 91D

Product (22.7mg with embodiment 8E, 0.105mmol) and the product (50mg of embodiment 91C, 0.105mmol) solution in acetate (2mL) is being preheated in 140 ℃ the oil bath and stirring 40 minutes, this reaction is cooled to room temperature, dilute with hexane (50mL), concentrate by rotary evaporation in vacuo, and with dichloromethane/hexane coevaporation (4 *).With resistates vacuum-drying, by the fast silica gel chromatogram purifying, use 5% ethanol/methylene then as eluent, obtained this title compound, be white solid (42mg, 62%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm：1.31(d，J＝6.62Hz，6H)2.88(s，3H)3.12-3.28(m，1H)7.00(d，J＝8.82Hz，2H)7.06(d，J＝8.46Hz，1H)7.16(d，J＝8.82Hz，2H)7.48-7.61(m，3H)7.76(d，J＝8.82Hz，2H)7.91(dd，J＝8.82，1.10Hz，1H)8.18(s，1H)8.59(s，1H)8.75(d，J＝8.46Hz，1H)9.62(s，1H)10.03(s，1H)10.36(s，1H)；MS(ESI+)m/z?647/649(M+H) ⁺。

Embodiment 92

4-(1H-benzoglyoxaline-5-base oxygen base)-N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 92A

1H-benzoglyoxaline-5-alcohol

(500mg, 3.374mmol) solution in 48% Hydrogen bromide (10mL) refluxed 2 hours with 5-methoxyl group benzo imidazoles.This reaction is cooled to room temperature, removes by rotary evaporation in vacuo and desolvate, and, obtained this title compound, be tawny solid (701mg, 96%) resistates and toluene (50mL) azeotropic.

Embodiment 92B

5-hydroxyl-benzoglyoxaline-1-t-butyl formate

At room temperature product (200mg with embodiment 92A under nitrogen atmosphere, 0.930mmol) anhydrous 1, suspension in the 4-dioxane (6mL) diisopropylethylamine (0.179mL, 1.023mmol) and tert-Butyl dicarbonate (223mg, 1.023mmol) handle, then this is reflected at 80 ℃ of heating 1 hour.This reaction is cooled to room temperature, and removes by rotary evaporation in vacuo and to desolvate.By fast silica gel chromatogram purifying resistates, use 3% ethanol/methylene as eluent, obtained 6-hydroxyl isomer (79mg, 36%) and 5-hydroxyl title compound (79mg, 36%).

Embodiment 92C

5-[4-(4-bromo-phenyl amino formyl radical)-2-nitro-phenoxy group]-benzoglyoxaline-1-t-butyl formate

Product (117.5mg with embodiment 10A, 0.331mmol) and the product (77.5mg of embodiment 92B, 0.331mmol) be dissolved in anhydrous N, in the dinethylformamide (3mL), (91.5mg 0.662mmol) handles, and heats 30 minutes under nitrogen atmosphere at 80 ° with salt of wormwood, this reaction is cooled to room temperature, and removes by rotary evaporation in vacuo and to desolvate.By the silica gel chromatography purifying, use ethanol/methylene as eluent, obtained this title compound, be light yellow foam (85mg, 46%).

Embodiment 92D

The method of 5-[2-amino-4-(4-bromo-phenyl amino formyl radical)-phenoxy group fore-telling benzoglyoxaline-1-t-butyl formate use embodiment 89E is reacted the product of embodiment 92C, has obtained this title product (24mg, 30%).

Embodiment 92E

Product (9.3mg with embodiment 8E, 0.043mmol) and the product (22.6mg of embodiment 92D, 0.043mmol) solution in acetate (1mL) is being preheated in 140 ℃ the oil bath and stirring 30 minutes, this reaction is cooled to room temperature, dilute with hexane (50mL), concentrate by rotary evaporation, and with dichloromethane/hexane coevaporation (4 *).With resistates vacuum-drying, and, obtained this title compound, be trifluoroacetate (17mg, 48%) by using the HPLC purifying of TFA. ¹H?NMR(300MHz，DMSO-D6)δ?ppm：1.31(d，J＝6.99Hz，6H)3.11-3.30(m，1H)7.03(d，J＝8.46Hz，2H)7.28(d，J＝2.21Hz，1H)7.54(d，J＝8.82Hz，2H)7.61(d，J＝8.82Hz，1H)7.65(d，J＝8.46Hz，1H)7.76(d，J＝8.82Hz，2H)7.92(dd，J＝8.64，2.02Hz，1H)8.17(d，J＝1.10Hz，1H)8.47(s，1H)8.69(s，1H)8.81(d，J＝8.46Hz，1H)10.36(s，1H)10.55(brs，1H)；MS(ESI+)m/z?594/596(M+H) ⁺。

Embodiment 93

N-(4-bromo-phenyl)-4-(1H-indoles-5-base oxygen base)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 93A

5-benzyloxy-indoles-1-t-butyl formate

With 5-benzyloxy indole (500mg, 2.24mmol) solution in anhydrous methylene chloride is with tert-Butyl dicarbonate (586.5mg, 2.69mmol) and 4-dimethylaminopyridine (55mg 0.448mmol) handles, and this is reflected at room temperature stirs under nitrogen atmosphere 15 hours.Remove by rotary evaporation and to desolvate, and with resistates by the fast silica gel chromatogram purifying, use methylene dichloride as eluent, obtained this title compound, be colorless oil (682mg, 94%).

Embodiment 93B

5-hydroxyl-indoles-1-t-butyl formate

(680mg, 2.103mmol) (265mg 4.205mmol) handles the solution in ethanol (20mL), and stirs 1 hour under nitrogen atmosphere in room temperature with 10% palladium on carbon (68mg) and ammonium formiate with the product of embodiment 93A.Should react via 0.45 μ PTFE membrane filtration, and use the methanol wash catalyzer.Filtrate is concentrated by rotary evaporation in vacuo, and just resistates places ethyl acetate (50mL), water (2 * 25mL) and salt solution (25mL) wash, use anhydrous sodium sulfate drying, filter, and vacuum concentration, obtained this title compound, be white solid (475mg, 96%).

Embodiment 93C

5-[4-(4-bromo-phenyl amino formyl radical)-2-nitro-phenoxy group]-indoles-1-t-butyl formate

With the product of embodiment 10A (406.5mg, 1.145mmol) (267mg 1.145mmol) is dissolved in anhydrous N with embodiment 93B, in the dinethylformamide (8mL), (316mg 2.289mmol) handles, and heats 3 hours under nitrogen atmosphere at 80 ° with salt of wormwood.This reaction is cooled to room temperature, and removes by rotary evaporation in vacuo and to desolvate.Resistates is placed water (50mL), and (2 * 50mL) extract with ethyl acetate.The organic extract liquid that merges is washed with salt solution (25mL), use anhydrous sodium sulfate drying, filter, and concentrate by rotary evaporation in vacuo.By the fast silica gel chromatogram purifying, use 1% ethyl acetate/dichloromethane as eluent, obtained this title compound, be yellow foam (519mg, 82%).

Embodiment 93D

5-[2-amino-4-(4-bromo-phenyl amino formyl radical)-phenoxy group]-indoles-1-t-butyl formate

Product (517mg with embodiment 93C, 0.936mmol), iron powder (322mg, 5.76mmol) and ammonium chloride (328mg, 6.13mmol) in water (3mL) and ethanol (6mL), heated 30 minutes in 90 ℃, the reaction mixture vacuum filtration that this is hot, and with resistates methyl alcohol and ethyl acetate washing.Filtrate is concentrated by rotary evaporation in vacuo, resistates water (50mL) and ethyl acetate (100mL) is distributed, and with the organic phase water (2 * 50mL) and salt solution (50mL) wash.With the organic phase anhydrous sodium sulfate drying, filter, and concentrate by rotary evaporation in vacuo, obtained this title compound, be canescence foam (325mg, 66%).

Embodiment 93E

Product (20.7mg with embodiment 8E, 0.0957mmol) and the product (50mg of embodiment 93D, 0.0957mmol) solution in acetate (2mL) is being preheated in 140 ℃ the oil bath and stirring 30 minutes, this reaction is cooled to room temperature, dilute with hexane (50mL), concentrate by rotary evaporation, and with dichloromethane/hexane coevaporation (4 *).With resistates vacuum-drying, by the fast silica gel chromatogram purifying, use 2% ethanol/methylene then as eluent, obtained this title compound, be pale solid (29mg, 51%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm：1.31(d，J＝6.99Hz，6H)3.11-3.29(m，1H)6.34-6.45(m，1H)6.81-6.90(m，2H)7.24(d，J＝2.21Hz，1H)7.35-7.44(m，2H)7.53(d，J＝8.82Hz，2H)7.58(d，J＝8.46Hz，1H)7.76(d，J＝8.82Hz，2H)7.84(dd，J＝8.46，1.47Hz，1H)8.19(d，J＝1.47Hz，1H)8.65(s，1H)8.83(d，J＝8.46Hz，1H)10.05(s，1H)10.30(s，1H)11.16(s，1H)；MS(APCI+)m/z?593/595(M+H) ⁺。

Embodiment 94

N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-methylsulfonyl amino-phenyl sulfenyl)-benzamide

Embodiment 94A

N-(4-bromo-phenyl)-4-(4-methylsulfonyl amino-phenyl sulfenyl)-3-nitro-benzamide

(200mg 0.4501mmol) is dissolved in the anhydrous pyridine (4mL), and (0.084mL 1.080mmol) handles, and stirring at room 19 hours with methylsulfonyl chloride with the product of embodiment 13A under nitrogen atmosphere.Remove by rotary evaporation in vacuo and to desolvate, and resistates is dissolved in the methylene dichloride (100mL), with (2 * 50mL) washings of 1N hydrochloric acid.With the organic phase anhydrous sodium sulfate drying, filter, and vacuum concentration, obtained this title compound, be yellow solid (233mg, 99%).

Embodiment 94B

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

Use of the suspension reaction of the method for embodiment 89E, obtained this title product (201mg, 92%) the product of embodiment 94A.

Embodiment 94C

To execute the product 1mg of routine 8E, 0.098mmol) and the product 8.1mg of embodiment 94B, 0.098mmol) stirring 1 hour in the oil bath of 140 ℃ of solution in acetate (2mL).This reaction is cooled to room temperature,, concentrates by rotary evaporation with hexane (50mL) dilution, and with dichloromethane/hexane coevaporation (4 *).With resistates vacuum-drying, by the fast silica gel chromatogram purifying, use 3% ethanol/methylene then as eluent, obtained this title compound, be light yellow solid (24mg, 37%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.62Hz，6H)3.04(s，3H)3.15-3.30(m，1H)7.11(d，J＝8.09Hz，1H)7.22(d，J＝8.82Hz，2H)7.40(d，J＝8.46Hz，2H)7.53(d，J＝8.82Hz，2H)7.64(d，J＝8.46Hz，1H)7.74(d，J＝9.19Hz，2H)7.83(dd，J＝9.01，0.92Hz，1H)8.00(s，1H)8.59(s，1H)8.85(d，J＝8.46Hz，1H)10.03(s，1H)10.23(s，1H)10.35(s，1H)；MS(APCI+)m/z?663/665(M+H) ⁺。

Embodiment 95

3-[4-(3-bromo-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Embodiment 95A

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

With N-(3-bromo-phenyl)-4-chloro-3-nitro-benzamide (deriving from embodiment 26A) (2.13g, 6.0mmol), 3-aminothiophenol (0.75g, 6.0mmol) and cesium carbonate (4.0g, 12.0mmol) at N, the solution in the dinethylformamide (20mL) in 95 ℃ the heating 3 hours.After being cooled to room temperature, this mixture is poured in the frozen water (100mL), gained solution is adjusted to pH6 with 1N hydrochloric acid.(3 * 50mL) extractions with the extraction liquid dried over sodium sulfate that merges, are filtered and vacuum concentration, have obtained this title compound (2.87g, 99%) with ethyl acetate with this solution then.

Embodiment 95B

{ 3-[4-(3-bromo-phenyl amino formyl radical)-2-nitro-phenyl sulfenyl]-phenyl }-t-butyl carbamate is with the product (2.8g of embodiment 95A; 6.0mmol) and tert-Butyl dicarbonate (2.8g; 12.6mmol) 1; solution in the 4-dioxane (75mL) is in 100 ℃ of heating 16 hours, cooling and vacuum concentration.Resistates by the silica gel chromatography purifying, with 3:1 hexane/ethyl acetate wash-out, has been obtained this title compound, be yellow foam (2.87g, 84%).

Embodiment 95C

{ 3-[2-amino-4-(3-bromo-phenyl amino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate is with the product (2.87g of embodiment 95B; 5.28mmol), iron powder (1.5g; 26.4mmol) and ammonium chloride (0.43g, 8.0mmol) vlil in ethanol (75mL), tetrahydrofuran (THF) (75mL) and water (25mL) solution is 6 hours.The gained mixture is diluted with ethanol (50mL), and filter via Celite pad.With filtrate vacuum concentration to volume is 10mL, with this solution with water dilution (50mL) with ethyl acetate extraction (2 * 50mL).With the extraction liquid dried over sodium sulfate that merges, filter and vacuum concentration, obtained this title compound, be yellow powder (2.47g, 91%).

Embodiment 95D

With the product of embodiment 95C (1.03g, 2.0mmol) and the product of embodiment 8E (0.43mg, 2.0mmol) solution in acetate (10mL) is being preheated in 140 ℃ the oil bath and was stirring 20 minutes, with this mixture cooling, and vacuum concentration.The gained resistates by the silica gel chromatography purifying, with 96:4 methylene chloride wash-out, has been obtained this title compound (0.67g, 49%).

Embodiment 96

4-(3-amino-phenyl sulfenyl)-N-(3-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

(0.67g 0.98mmol) drips trifluoroacetic acid (5mL) in the slurries in methylene dichloride (10mL) to the product of embodiment 95D.With this solution stirring 30 minutes, and vacuum concentration.Come purifying gained resistates by the HPLC that uses TFA, obtained this title compound, be trifluoroacetate (15mg, 35%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.62Hz，6H)，3.22-3.33(m，1H)，6.31-6.64(m，3H)，6.97(t，J＝7.91Hz，1H)，7.23-7.41(m，3H)，7.69-7.79(m，1H)，7.83(d，J＝9.56Hz，1H)，7.91(d，J＝11.03Hz，1H)，7.99(s，1H)，8.07(s，1H)，8.79(s，1H)，8.95(d，J＝7.35Hz，1H)，10.41(s，1H)，11.40(s，1H)。

Embodiment 97

Tetramethyleneimine-2-formic acid 3-[4-(3-bromo-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-acid amides

Embodiment 97A

2-{3-[4-(3-bromo-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-the phenyl amino formyl radical }-tetramethyleneimine-1-t-butyl formate

Product (0.080g with embodiment 96,0.1mmol), L-Boc-proline(Pro) (0.028g, 0.13mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (0.025g, 0.13mmol), the I-hydroxybenzotriazole hydrate (0.018g, 0.13mmol) and N, N-diisopropylethylamine (0.039g, 0.3mmol) at N, mixture in the dinethylformamide (2mL) stirred 16 hours, pours in the water, and with ethyl acetate extraction (3 * 15mL).With the extraction liquid dried over sodium sulfate that merges, filter and vacuum concentration, obtained this title compound, it directly uses without purifying.

Embodiment 97B

Use the method for embodiment 96, the product of embodiment 97A is handled with trifluoroacetic acid.Remaining crude product by using the HPLC purifying of TFA, has been obtained this title compound, be trifluoroacetate (21mg, 23%, two step).1H?NMR(300MHz，DMSO-D6)δppm：1.35(d，J＝6.99Hz，6H)，1.90-2.04(m，3H)，2.30-2.42(m，1H)，3.19-3.35(m，3H)，4.20-4.35(m，1H)，7.16(d，J＝8.09Hz，1H)，7.29-7.37(m，4H)，7.49(d，J＝9.19Hz，1H)，7.68-7.81(m，3H)，7.90(d，J＝8.46Hz，1H)，8.04(s，1H)，8.08(s，1H)，8.69(d，J＝22.06Hz，2H)，8.90(d，J＝7.35Hz，1H)，9.32(s，1H)，10.45(s，1H)，10.63(s，1H)。

Embodiment 98

N-(3-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-[3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-benzamide

With the product of embodiment 96 (0.029g, 0.05mmol) and the product of embodiment 8E (0.011mg, 0.05mmol) solution in acetate (1.0mL) is being preheated in 140 ℃ the oil bath and was stirring 20 minutes, with this mixture cooling and vacuum concentration.Come purifying gained resistates by the HPLC that uses TFA, obtained this title compound, be trifluoroacetate (22mg, 45%).

Embodiment 99

4-[3-(2-amino-acetylamino)-phenyl sulfenyl]-N-(3-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

According to the method for using among the embodiment 97A, substitute L-Boc-proline(Pro) and embodiment 97B with tert-butoxycarbonyl amino-acetate, made this title compound by the product of embodiment 96.Crude product by using the HPLC purifying of TFA, has been obtained this title compound, be trifluoroacetate (9mg, 10%, 2 step).1H?NMR(300MHz，DMSO-D6)δppm：1.35(d，J＝6.99Hz，6H)，3.19-3.35(m，J＝23.16Hz，1H)，3.75(d，J＝5.52Hz，2H)，7.14(d，J＝7.35Hz，1H)，7.29-7.38(m，4H)，7.46(d，J＝7.72Hz，1H)，7.70(s，1H)，7.72-7.84(m，2H)，7.90(s，1H)，8.01-8.12(m，5H)，8.75(s，1H)，8.91(s，1H)，10.44(s，1H)，10.50(s，1H)。

Embodiment 100

4-[4-(4-bromo-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

Embodiment 100A

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

With the product of embodiment 10A (3.0g, 8.44mmol), the 4-aminothiophenol (1.06g, 8.44mmol) and cesium carbonate (5.5g, 17.0mmol) at N, the solution in the dinethylformamide (15mL) was 90 ℃ of heating 4 hours.After being cooled to room temperature, this mixture is poured in the frozen water (100mL), gained solution is acidified to pH5 with 1N hydrochloric acid.(3 * 50mL) extractions with the extraction liquid dried over sodium sulfate that merges, are filtered and vacuum concentration, have obtained this title compound, are orange solids (3.6g, 96%) with ethyl acetate with this solution then.

Embodiment 100B

4-[4-(4-bromo-phenyl amino formyl radical)-2-nitro-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

To the product of embodiment 100A (3.6g, 8.1mmol) methylene dichloride (100mL) and pyridine (1.3g 16.2mmol) adds chloroformic acid 2,2 in Nei the slurries, the 2-trichloro ethyl ester (2.16g, 10.2mmol).With this solution stirring 16 hours, water, salt water washing were with dried over sodium sulfate and vacuum concentration.The gained resistates was developed in the hexane/ethyl acetate at 9: 1, obtained this title compound, be orange powder (4.15g, 83%).

Embodiment 100C

4-[2-amino-4-(4-bromo-phenyl amino formyl radical)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

With the product of embodiment 100B (1.23g, 2.0mmol), iron powder (0.56g, 10.0mmol) and the vlil of ammonium chloride (0.16g, 3.0) in ethanol (30mL), tetrahydrofuran (THF) (30mL) and water (10mL) solution 6 hours.The gained mixture is diluted with ethanol (50mL), and filter via Celite pad.With filtrate vacuum concentration to volume is 10mL, this solution with water (50mL) is diluted, and (2 * 50mL) extracts with ethyl acetate.With the extraction liquid dried over sodium sulfate that merges, filter and vacuum concentration, obtained this title compound, be yellow powder (1.12g, 95%).

Embodiment 100D

With the product of embodiment 100C (1.12g, 1.9mmol) and the product of embodiment 8E (0.41mg, 1.9mmol) solution in acetate (10mL) is being preheated in 140 ℃ the oil bath and was stirring 40 minutes, with this mixture cooling and vacuum concentration.The gained resistates is developed in the methyl alcohol of minimum volume, and collected, obtained this title compound (0.98g, 68%) by filtering.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)，3.19-3.27(m，1H)，4.96(s，2H)，7.07(d，J＝8.46Hz，1H)，7.41(d，J＝8.46Hz，2H)，7.50-7.69(m，5H)，7.74(d，J＝8.82Hz，2H)，7.81(d，J＝8.46Hz，1H)，8.00(s，1H)，8.59(s，1H)，8.85(d，J＝8.46Hz，1H)，10.24(s，1H)，10.35(s，1H)，10.38(s，1H)；MS(ESI+)m/z?761(M+H)+。

Embodiment 101

N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-[4-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-benzamide

With the product of embodiment 13E (0.029g, 0.05mmol) and the product of embodiment 8E (0.011mg, 0.05mmol) solution in acetate (1.0mL) is being preheated in 140 ℃ the oil bath and was stirring 20 minutes, with this mixture cooling and vacuum concentration.Come purifying gained resistates by the HPLC that uses TFA, obtained this title compound, be trifluoroacetate (24mg, 55%).1HNMR(300MHz，DMSO-D6)δ?ppm：1.33(t，J＝7.35Hz，12H)，3.19-3.34(m，2H)，7.30(d，J＝8.09Hz，1H)，7.49(d，J＝8.82Hz，2H)，7.54(d，J＝8.82Hz，2H)，7.68-7.88(m，7H)，7.91(d，J＝8.46Hz，1H)，8.02(s，1H)，8.74(s，1H)，8.87(s，1H)，8.93(d，J＝7.72Hz，1H)，8.99(d，J＝8.82Hz，1H)，10.42(s，1H)，10.71(s，1H)；MS(ESI+)m/z?756/758(M+H)+。

Embodiment 102

4-(4-acetylamino-phenyl sulfenyl)-N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

With the product of embodiment 13E (0.029g, 0.05mmol) and diacetyl oxide (0.0068g, 0.066mmol) solution in acetate (0.3mL) stirred 20 minutes in 130 ℃, with this mixture cooling, and vacuum concentration.Come purifying gained resistates by the HPLC that uses TFA, obtained this title compound, be trifluoroacetate (20mg, 54%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.99Hz，6H)，2.06(s，3H)，3.16-3.32(m，1H)，7.09(d，J＝8.09Hz，1H)，7.38(d，J＝8.82Hz，2H)，7.53(d，J＝8.82Hz，2H)，7.62(d，J＝8.46Hz，2H)，7.73(d，J＝8.82Hz，2H)，7.77(d，J＝9.93Hz，1H)，7.84(d，J＝8.09Hz，1H)，7.96(s，1H)，8.72(s，1H)，8.91(d，J＝7.72Hz，1H)，10.12(s，1H)，10.37(s，1H)，11.07(s，1H)；MS(ESI+)m/z?627/629(M+H)+。

Embodiment 103

N-(4-bromo-phenyl)-4-(4-dimethylamino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

With the product of embodiment 13E (0.058g, 0.1mmol) and 37% formalin (0.080mL, 1.0mmol) solution in formic acid (0.038mL) stirred 15 minutes in 105 ℃, with this mixture cooling and vacuum concentration.The gained resistates by using the HPLC purifying of NH4OH, has been obtained this title compound, be yellow powder (12mg, 20%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)，2.94(s，6H)，3.14-3.27(m，1H)，6.75(d，J＝8.82Hz，2H)，6.89(s，1H)，7.28(d，J＝8.82Hz，2H)，7.52(d，J＝8.82Hz，2H)，7.62(s，1H)，7.73(d，J＝9.19Hz，2H)，7.78(s，1H)，7.95(s，1H)，8.58(s，1H)，8.86(s，1H)，10.17(s，1H)，10.28(s，1H)；MS(ESI+)m/z?613/615(M+H)+。

Embodiment 104

4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-p-methylphenyl-benzamide

Embodiment 104A

[4-(2-amino-4-p-methylphenyl formamyl-phenyl sulfenyl)-phenyl]-t-butyl carbamate

Use the method for embodiment 10A, mixture and the reaction of 4-chloro-3-nitrobenzoyl chloride with the 4-bromaniline, obtained 4-chloro-3-nitro-N-p-methylphenyl-benzamide, it has been reacted, obtained this title product according to the condition of describing among embodiment 13A, 13B and the 13C.

Embodiment 104B

Method according to embodiment 95D; product with the product alternate embodiment 404C of embodiment 104A; the product of embodiment 104A and the product of embodiment 8E are reacted; obtained { 4-[2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-4-p-methylphenyl formamyl-phenyl sulfenyl]-phenyl }-t-butyl carbamate; the condition of using embodiment 96 is with its deprotection; obtained crude product; by using the HPLC purifying of TFA; obtained this title product; be trifluoroacetate (36mg, 23%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.37(d，J＝6.99Hz，6H)，2.27(s，3H)，3.17-3.39(m，1H)，6.64(d，J＝8.46Hz，2H)，6.94(d，J＝8.46Hz，1H)，7.15(dd，J＝8.46，2.94Hz，4H)，7.60(d，J＝8.46Hz，2H)，7.86(dd，J＝8.27，1.65Hz，1H)，7.90-7.96(m，2H)，8.88(s，1H)，9.04(d，J＝8.82Hz，1H)，10.14(s，1H)，11.64(s，1H)；MS(ESI+)m/z?521(M+H)+。

Embodiment 105

4-(4-amino-phenyl sulfenyl)-N-(3-fluoro-4-methyl-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 105A

4-[2-amino-4-(3-fluoro-4-methyl-phenyl amino formyl radical)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

Use the method for embodiment 10A, mixture and the reaction of 4-chloro-3-nitrobenzoyl chloride with 3-fluoro-4-methyl-phenyl amine, obtained 4-chloro-N-(3-fluoro-4-methyl-phenyl)-3-nitro-benzamide, use the condition of describing among embodiment 100A, 100B and the 100C that it is reacted, obtained this title product.

Embodiment 105B

4-[4-(3-fluoro-4-methyl-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

Use the method for embodiment 100D, product with the product alternate embodiment 100C of embodiment 105A, the product of embodiment 105A and the product of embodiment 8E are reacted, obtained crude product, by being developed, it comes purifying in methylene dichloride, obtained the viscosity yellow solid, it directly uses (0.108g, 30%) without purifying.

Embodiment 105C

To the product of embodiment 105B (0.108g, 0.15mmol) add in the solution in tetrahydrofuran (THF) (3mL) and water (3mL) 1M NaOH (0.5mL, 0.5mmol).60 ℃ of heating 40 minutes, cooling was adjusted to pH6 with 1N hydrochloric acid with this solution, and (3 * 20mL) extract with ethyl acetate.With the extraction liquid dried over sodium sulfate that merges, filter and vacuum concentration.The gained resistates by using the HPLC purifying of TFA, has been obtained this title compound, be trifluoroacetate (20mg, 20%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.37(d，J＝6.99Hz，6H)，2.19(s，3H)，3.06-3.42(m，1H)，6.64(d，J＝8.82Hz，2H)，6.96(d，J＝8.46Hz，1H)，7.16(d，J＝8.82Hz，2H)，7.24(t，J＝8.82Hz，1H)，7.41(dd，J＝8.46，1.84Hz，1H)，7.65(dd，J＝12.32，2.02Hz，1H)，7.86(dd，J＝8.27，1.65Hz，1H)，7.89-7.97(m，2H)，8.90(s，1H)，9.06(d，J＝8.46Hz，1H)，10.32(s，1H)，11.73(s，1H)；MS(ESI+)m/z?539(M+H)+。

Embodiment 106

4-[4-(3,3-dimethyl-urea groups)-phenyl sulfenyl]-N-(3-fluoro-4-methyl-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Will the product of the embodiment 105B in the tetrahydrofuran (THF) (3mL) (0.108g, 0.15mmol) with DBU (0.023g, 0.15mmol) and the dimethyl amine (solution of 2.0M in THF, 0.75mL, 1.5mmol) handle, and in the pipe of sealing, heated 20 minutes in 60 ℃, cooling, and vacuum concentration.The gained resistates by the silica gel chromatography purifying, with 97:3 methylene chloride wash-out, has been obtained this title compound (0.08g, 88%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)，2.19(s，3H)，2.93(s，6H)，3.15-3.29(m，1H)，7.01(d，J＝8.46Hz，1H)，7.23(t，J＝8.64Hz，1H)，7.33(d，J＝8.46Hz，2H)，7.43(dd，J＝8.27，1.65Hz，1H)，7.57(d，J＝8.82Hz，2H)，7.62-7.71(m，2H)，7.80(dd，J＝8.27，1.65Hz，1H)，7.99(s，1H)，8.50(s，1H)，8.60(s，1H)，8.87(d，J＝8.46Hz，1H)，10.22(s，1H)，10.30(s，1H)；MS(ESI+)m/z?610(M+H)+。

Embodiment 107

3-[4-(3-bromo-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-phenyl }-t-butyl carbamate

Embodiment 107A

4-(3-amino-phenoxy group)-N-(3-bromo-phenyl)-3-nitro-benzamide

With N-(3-bromo-phenyl)-4-chloro-3-nitro-benzamide (deriving from embodiment 16A) (0.71g, 2.0mmol), 3-amino-phenol (0.22g, 2.0mmol) and potassium hydroxide powder (0.23g, 4.0mmol) solution in methyl-sulphoxide (5mL) is in 100 ℃ of heating 30 minutes, after being cooled to room temperature, this mixture is poured in the frozen water (100mL), and gained solution is adjusted to pH5 with 1N hydrochloric acid.(3 * 50mL) extractions with the extraction liquid dried over sodium sulfate that merges, are filtered and vacuum concentration, have obtained this title compound (0.8g, 93%) with ethyl acetate with this solution then.

Embodiment 107B

3-[2-amino-4-(3-bromo-phenyl amino formyl radical)-phenoxy group]-phenyl }-t-butyl carbamate

According to the method for embodiment 13B and 13C, the product reaction with embodiment 107A has obtained this title compound.

Embodiment 107C

Use the method for embodiment 95D, product with the product alternate embodiment 95C of embodiment 107B, the product of embodiment 107B and the product of embodiment 8E are reacted, obtained crude product, it by the silica gel chromatography purifying, with 97:3 methylene chloride wash-out, has been obtained this title compound, be tawny foam (350mg, 40%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.32(d，J＝6.99Hz，6H)，1.45(s，9H)，3.13-3.25(m，1H)，6.60(d，J＝7.35Hz，1H)，7.05(d，J＝8.46Hz，1H)，7.11-7.24(m，2H)，7.27-7.38(m，3H)，7.57(d，J＝8.46Hz，1H)，7.74-7.81(m，1H)，7.92(dd，J＝8.64，2.02Hz，1H)，8.11(s，1H)，8.19(d，J＝2.21Hz，1H)，8.60(s，1H)，8.77(d，J＝8.46Hz，1H)，9.44(s，1H)，10.03(s，1H)，10.38(s，1H)；MS(ESI+)m/z?669/671(M+H)+。

Embodiment 108

3-[4-(3-bromo-phenyl amino formyl radical)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-phenyl }-t-butyl carbamate

Use the method for embodiment 95D, product with the product alternate embodiment 95C of embodiment 107B, and product with the product alternate embodiment 8E of embodiment 9B, the product of embodiment 107B and the product of embodiment 9B are reacted, obtained crude product, it by using the HPLC purifying of NH4OH, has been obtained this title compound (28mg, 44%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.45(s，9H)，2.66(s，3H)，6.61(d，J＝8.09Hz，1H)，7.04(d，J＝8.46Hz，1H)，7.11-7.23(m，2H)，7.25-7.39(m，3H)，7.51(d，J＝8.46Hz，1H)，7.71-7.80(m，1H)，7.91(dd，J＝8.46，2.21Hz，1H)，8.09-8.12(m，1H)，8.20(d，J＝1.84Hz，1H)，8.60(s，1H)，8.73(d，J＝8.46Hz，1H)，9.44(s，1H)，10.02(s，1H)，10.36(s，1H)；MS(ESI+)m/z?641/643(M+H)+。

Embodiment 109

4-(3-amino-phenoxy group)-N-(3-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

The method that the product of embodiment 107C is applied embodiment 96 is handled, and the product with the product alternate embodiment 404D of embodiment 107C has obtained resistates, comes purifying by development in methylene dichloride, has obtained this title compound.1H?NMR(300MHz，DMSO-D6)δppm：1.35(d，J＝6.62Hz，6H)，3.16-3.41(m，1H)，6.29(d，J＝8.09Hz，1H)，6.33(s，1H)，6.42(d，J＝8.09Hz，1H)，7.03(t，J＝8.09Hz，1H)，7.13(d，J＝8.46Hz，1H)，7.27-7.39(m，2H)，7.72-7.79(m，1H)，7.91(d，J＝8.46Hz，1H)，8.04(dd，J＝8.64，2.39Hz，1H)，8.08-8.11(m，1H)，8.14(d，J＝2.21Hz，1H)，8.93(s，1H)，9.00(d，J＝8.82Hz，1H)，10.43(s，1H)，11.72(s，1H)；MS(ESI+)m/z?569/571(M+H)+。

Embodiment 110

(3-[4-(3-bromo-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-the phenyl amino formyl radical }-methyl)-t-butyl carbamate

Product (0.068g with embodiment 109,0.1mmol), tert-butoxycarbonyl amino-acetate (0.023g, 0.13mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (0.025g, 0.13mmol), the I-hydroxybenzotriazole hydrate (0.015g, 0.11mmol) and N, N-diisopropylethylamine (0.029g, 0.22mmol) at N, mixture in the dinethylformamide (2mL) stirred 16 hours, pour in the water, and (3 * 15mL) extracted with ethyl acetate.With the extraction liquid dried over sodium sulfate that merges, filter and vacuum concentration, obtained resistates, by the silica gel chromatography purifying,, obtained this title compound (50mg, 69%) with 96:4 methylene chloride wash-out.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.31(d，J＝6.62Hz，6H)，1.38(s，9H)，3.13-3.27(m，1H)，3.68(d，J＝5.88Hz，2H)，6.63-6.71(m，1H)，7.04(t，J＝6.43Hz，1H)，7.08(d，J＝8.46Hz，1H)，7.24(d，J＝4.78Hz，2H)，7.26-7.37(m，2H)，7.49(s，1H)，7.58(d，J＝8.46Hz，1H)，7.72-7.79(m，1H)，7.92(dd，J＝8.64，2.02Hz，1H)，8.11(s，1H)，8.19(d，J＝1.47Hz，1H)，8.59(s，1H)，8.76(d，J＝8.46Hz，1H)，10.00(s，1H)，10.05(s，1H)，10.39(s，1H)。

Embodiment 111

4-[3-(2-amino-acetylamino)-phenoxy group]-N-(3-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

According to the method for embodiment 96, (0.04g 0.055mmol) handles with trifluoroacetic acid with the product of embodiment 110.Crude product is come purifying by development in methylene dichloride, obtained this title compound, be trifluoroacetate (0.046g, 98%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.33(d，J＝6.99Hz，6H)，3.21-3.32(m，1H)，3.75(d，J＝5.52Hz，2H)，6.81(d，J＝9.19Hz，1H)，7.14(d，J＝8.82Hz，1H)，7.24-7.38(m，3H)，7.45(s，1H)，7.72-7.78(m，1H)，7.81(d，J＝8.46Hz，1H)，8.02(dd，J＝8.82，2.21Hz，1H)，8.10(s，3H)，8.18(d，J＝1.84Hz，1H)，8.80(s，1H)，8.92(d，J＝8.46Hz，1H)，10.45(s，1H)，11.26(s，1H)。

Embodiment 112

4-(3-amino-phenoxy group)-N-(3-bromo-phenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

According to the method for embodiment 96, (0.028g 0.044mmol) handles with trifluoroacetic acid with the product of embodiment 108.Crude product is come purifying by development in methylene dichloride, obtained this title compound, be trifluoroacetate (0.025g, 87%).1H?NMR(300MHz，DMSO-D6)δ?ppm：2.75(s，3H)，6.24(d，J＝8.09Hz，1H)，6.30(s，1H)，6.39(d，J＝7.72Hz，1H)，7.01(t，J＝7.91Hz，1H)，7.12(d，J＝8.82Hz，1H)，7.25-7.40(m，2H)，7.69-7.78(m，1H)，7.82(d，J＝8.82Hz，1H)，8.03(dd，J＝8.64，2.39Hz，1H)，8.12(dd，J＝17.46，2.02Hz，2H)，8.88-9.00(m，2H)，10.41(s，1H)，11.60(s，1H)；MS(ESI+)m/z?541/543(M+H)+。

Embodiment 113

4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid N '-(4-bromo-phenyl)-hydrazides

Embodiment 113A

(4-{2-amino-4-[N '-(4-bromo-phenyl)-diazanyl carbonyl]-the phenyl sulfenyl }-phenyl)-carboxylamine 2,2,2-three chloro-ethyl esters

Method according to embodiment 10A, mixture and (4-bromo-phenyl)-hydrazine reaction with 4-chloro-3-nitrobenzoyl chloride, generated 4-chloro-3-nitro-phenylformic acid N '-(4-bromo-phenyl)-hydrazides, use the method for embodiment 100A, 100B and 100C that it is handled successively, obtained this title product.

Embodiment 113B

Method according to EXAMPLE Example 100D; product with the product alternate embodiment 409C of embodiment 113A; the product of embodiment 113A and the product of embodiment 8E are reacted; obtained 4-[4-[N '-(4-bromo-phenyl)-diazanyl carbonyl]-2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-the phenyl sulfenyl]-phenyl }-carboxylamine 2; 2; 2-three chloro-ethyl esters; the condition of using embodiment 105C is with its deprotection; obtained crude product; it by using the HPLC purifying of NH4OH, has been obtained this title compound (10mg, 13%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.33(d，J＝6.62Hz，6H)，3.14-3.27(m，1H)，5.60(s，2H)，6.63(d，J＝8.82Hz，2H)，6.70(d，J＝8.82Hz，2H)，6.84(d，J＝7.35Hz，1H)，7.14(d，J＝8.46Hz，2H)，7.29(d，J＝8.82Hz，2H)，7.64(d，J＝7.72Hz，1H)，7.74(d，J＝8.46Hz，1H)，7.85(s，1H)，8.11(s，1H)，8.58(s，1H)，8.87(d，J＝9.56Hz，1H)，10.13(s，1H)，10.36(s，1H)；MS(ESI+)m/z?600/602(M+H)+。

Embodiment 114

N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-trifluoromethyl-benzamide

Embodiment 114A

N-(4-fluoro-3-nitro-phenyl)-3-trifluoromethyl-benzamide

With 4-fluoro-3-nitro-aniline (2.00g, 12.8mmol), 3-trifluoromethyl-Benzoyl chloride (1.895mL, 12.8mmol), (4.463mL, 25.6mmol) solution in tetrahydrofuran (THF) (50ml) was in stirring at room 1 hour for Hunig ' s alkali.Then water (450mL) is added in this solution, and collects the gained solid by filtering, and dry in vacuum drying oven, obtained this title compound (3.311g, 97%).

Embodiment 114B

N-[4-(4-hydroxyl-phenyl sulfenyl)-3-nitro-phenyl]-3-trifluoromethyl-benzamide

With the product of embodiment 114A (2.00g, 5.80mmol), the 4-hydroxythiophenol (0.732g, 5.80mmol) and salt of wormwood (1.604g, 11.6mmol) at N, the solution in the dinethylformamide (40mL) was in 80 ℃ of heating 2 hours.After being cooled to room temperature, this mixture is poured in the frozen water (100mL).(3 * 150mL) extractions with the extraction liquid dried over mgso that merges, are filtered and vacuum concentration, have obtained this title compound (2.52g, 100%) with ethyl acetate with this solution then.

Embodiment 114C

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-3-trifluoromethyl-benzamide

With the product of embodiment 114B (0.660g, 1.52mmol), iron powder (0.339g, 6.07mmol) and ammonium chloride (0.099g, 1.82mmol), the vlil of tetrahydrofuran (THF) (18mL) and water (6mL) solution 3 hours.The gained mixture is diluted with methyl alcohol (50mL), and filter via Celite pad.Filtrate water (50mL) is diluted, and (2 * 100mL) extract with methylene dichloride.With the extraction liquid dried over mgso that merges, filter and vacuum concentration, obtained this title compound (0.60g, 97%).

Embodiment 114D

Product (40.0mg with embodiment 9B, 0.212mmol) and the product (86.0mg of embodiment 114C, 0.212mmol) solution in acetate (1mL) is being preheated in 130 ℃ the oil bath and stirring 20 minutes, then this mixture is cooled to room temperature, vacuum is removed acetate, and by using the HPLC purifying gained resistates of TFA, has obtained this title compound, be trifluoroacetate (11mg, 10%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm：2.74(s，3H)，6.70(d，J＝8.82Hz，2H)，7.18(d，J＝8.46Hz，3H)，7.64(dd，J＝8.46，2.21Hz，1H)，7.79(t，J＝7.72Hz，2H)，7.93-8.07(m，J＝6.62Hz，2H)，8.21-8.30(m，2H)，8.78(s， 1H)，8.92(d，J＝7.72Hz，1H)，9.79(s，1H)，10.67(s，1H)，11.17-11.50(m，1H)MS(ESI+)m/z548.2(M+H)+，(ESI-)m/z?546.2(M-H)-。

Embodiment 115

N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-trifluoromethyl-benzamide

Product (40.0mg with embodiment 8E, 0.212mmol) and the product (75.0mg of embodiment 114C, 0.185mmol) solution in acetate (1mL) is being preheated in 130 ℃ the oil bath and stirring 20 minutes, then this mixture is cooled to room temperature, vacuum is removed acetate, and by using the HPLC purifying gained resistates of TFA, has obtained this title compound, be trifluoroacetate (3.2mg, 4%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.99Hz，6H)，6.71(d，J＝8.82Hz，2H)，7.19(d，J＝8.82Hz，3H)，7.65(d，J＝9.19Hz，1H)，7.75-7.89(m，2H)，7.98(d，J＝7.72Hz，2H)，8.23-8.33(m，3H)，8.76(s，1H)，8.95(d，J＝8.09Hz，1H)，9.78(s，1H)，10.66(s，1H)MS(ESI+)m/z?576.2(M+H)+，(ESI-)m/z574.3(M-H)-。

Embodiment 116

4-bromo-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 116A

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

This title compound is the method according to embodiment 114A, substitutes with 4-bromo-Benzoyl chloride that 3-trifluoromethyl-Benzoyl chloride makes, and has obtained this title compound (1.125g, 90%).

Embodiment 116B

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

This title compound is the method according to embodiment 114B, makes with the product of the product alternate embodiment 114A of embodiment 116A, has obtained this title compound (0.75g, 50%).

Embodiment 116C

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

This title compound is the method according to embodiment 114C, makes with the product of the product alternate embodiment 114B of embodiment 116B, has obtained this title compound (0.5g, 80%).

Embodiment 116D

Product (40.0mg with embodiment 29A, 0.212mmo1) and the product (87.0mg of embodiment 116C, 0.212mmol) solution in acetate (1mL) is being preheated in 130 ℃ the oil bath and stirring 20 minutes, then this mixture is cooled to room temperature, vacuum is removed acetate, and by using the HPLC purifying gained resistates of TFA, has obtained this title compound, be trifluoroacetate (37.2mg, 25%).1H?NMR(300MHz，DMSO-D6)δ?ppm：6.70(d，J＝8.82Hz，2H)，7.10-7.22(m，3H)，7.62(dd，J＝8.64，2.02Hz，1H)，7.73-7.83(m，3H)，7.85-7.93(m，2H)，8.00(s，1H)，8.73(s，1H)，9.00(d，J＝8.09Hz，1H)，9.13(d，J＝3.31Hz，1H)，9.77(s，1H)，10.50(s，1H)；MS(ESI+)m/z?544(M+H)+，(ESI-)m/z?542(M-H)-。

Embodiment 117

4-bromo-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 117A

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

This title compound is the method according to embodiment 114A, substitutes 4-fluoro-3-nitro-aniline with 3-nitro-phenyl amine, and makes with 4-bromo-Benzoyl chloride alternative 3-trifluoromethyl-Benzoyl chloride, has obtained this title product (3.373g, 90%).

Embodiment 117B

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

This title compound is the method according to embodiment 114B, makes with the product of the product alternate embodiment 114A of embodiment 117A, has obtained this title product (1.8g, 80%).

Embodiment 117C

4-bromo-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Product (40.0mg with embodiment 29A, 0.212mmol) and the product (61.0mg of embodiment 117B, 0.212mmol) solution in acetate (1mL) is being preheated in 130 ℃ the oil bath and stirring 20 minutes, then this mixture is cooled to room temperature, vacuum is removed acetate, and by using the HPLC purifying gained resistates of TFA, has obtained this title compound, be trifluoroacetate (25.0mg, 30%).1H?NMR(300MHz，DMSO-D6)δ?ppm：7.45(t，J＝8.09Hz，1H)，7.52-7.61(m，2H)，7.74-7.86(m，3H)，7.94(d，J＝8.82Hz，2H)，8.33(t，J＝1.84Hz，1H)，8.88(s，1H)，9.09-9.17(m，2H)，10.48(s，1H)，10.94(s，1H)；MS(ESI+)m/z?420(M+H)+，(ESI-)m/z?417(M-H)-。

Embodiment 118

4-chloro-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 118A

N-(3-amino-phenyl)-4-chloro-benzamide

This title compound makes like this: according to the method for embodiment 117A, substitute 4-bromo-benzoyl fluoride with 4-chloro-Benzoyl chloride, the method for using embodiment 114B has then obtained this title product with nitroreduction.

Embodiment 118B

4-chloro-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Use the method for embodiment 117C, product with the product alternate embodiment 117B of embodiment 118A, the product of embodiment 118A and the product of embodiment 29A are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (21mg, 26%).1H?NMR(300MHz，DMSO-D6)δ?ppm：7.43-7.50(m，J＝8.09，8.09Hz，1H)，7.52-7.61(m，J＝12.69，8.27Hz，2H)，7.63(d，J＝8.82Hz，2H)，7.81-7.90(m，1H)，8.01(d，J＝8.46Hz，2H)，8.32(t，J＝1.84Hz，1H)，8.91(s，1H)，9.10-9.19(m，2H)，10.49(s，1H)，11.15(s，1H)；MS?ESI+m/z?376(M+H)+，ESI-m/z?374(M-H)-。

Embodiment 119

4-methoxyl group-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 119A

N-(3-amino-phenyl)-4-methoxyl group-benzamide

This title compound makes like this: according to the method for embodiment 117A, substitute 4-bromo-Benzoyl chloride with 4-methoxyl group-Benzoyl chloride, the method for using embodiment 114B has then obtained this title product with nitroreduction.

Embodiment 119B

Use the method for embodiment 117C, product with the product alternate embodiment 117B of embodiment 119A, the product of embodiment 119A and the product of embodiment 29A are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (15mg, 19%).1H?NMR(300MHz，DMSO-D6)δ?ppm：3.85(s，3H)，7.08(d，J＝8.82Hz，2H)，7.44(t，J＝7.91Hz，1H)，7.50-7.61(m，2H)，7.81-7.88(m，1H)，7.98(d，J＝9.19Hz，2H)，8.32(t，J＝1.84Hz，1H)，8.91(s，1H)，9.14(d，J＝5.88Hz，2H)，10.26(s，1H)，11.11(s，1H)；MS?ESI+m/z?372(M+H)+，ESI-m/z?370(M-H)-。

Embodiment 120

3-chloro-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 120A

N-(3-amino-phenyl)-3-chloro-benzamide

This title compound makes like this: according to the method for embodiment 117A, substitute 4-bromo-Benzoyl chloride with 3-chloro-Benzoyl chloride, the method for using embodiment 114B has then obtained this title product with nitroreduction.

Embodiment 120B

3-chloro-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Use the method for embodiment 117C, product with the product alternate embodiment 117B of embodiment 120A, the product of embodiment 120A and the product of embodiment 29A are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (29mg, 35%).1H?NMR(300MHz，DMSO-D6)δ?ppm：7.46(t，J＝7.91Hz，1H)，7.54-7.62(m，3H)，7.65-7.72(m，1H)，7.84(dt，J＝5.52，3.68Hz，1H)，7.91-7.96(m，J＝7.72Hz，1H)，8.03(t，J＝1.84Hz，1H)，8.33(t，J＝1.84Hz，1H)，8.91(s，1H)，9.11-9.18(m，2H)，10.52(s，1H)，11.09(s，1H)；ESI+m/z?376(M+H)+，ESI-m/z?373(M-H)-。

Embodiment 121

3-bromo-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 121A

N-(3-amino-phenyl)-3-bromo-benzamide

This title compound makes like this: according to the method for embodiment 117A, substitute 4-bromo-Benzoyl chloride with 3-bromo-Benzoyl chloride, the method for using embodiment 114B has then obtained this title product with nitroreduction.

Embodiment 121B

3-bromo-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Use the method for embodiment 117C, use the product of the product alternate embodiment 117B of embodiment 121A, the product of embodiment 121A and the product reaction of embodiment 29A have been obtained crude product, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (24mg, 27%).1H?NMR(300?MHz，DMSO-D6)δ?ppm：7.47-7.62(m，4H)，7.80-7.91(m，2H)，7.98(d，J＝7.72Hz，1H)，8.16(t，J＝1.65Hz，1H)，8.32(t，J＝1.84Hz，1H)，8.95(s，1H)，9.12-9.20(m，2H)，10.54(s，1H)，11.33(s，1H)；MS?ESI+m/z?420(M+H)+，ESI-m/z?418(M-H)-。

Embodiment 122

2-chloro-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 122A

N-(3-amino-phenyl)-2-chloro-benzamide

This title compound makes like this: according to the method for embodiment 117A, substitute 4-bromo-Benzoyl chloride with 2-chloro-Benzoyl chloride, the method for using embodiment 114B has then obtained this title product with nitroreduction.

Embodiment 122B

2-chloro-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Use the method for embodiment 117C, product with the product alternate embodiment 117B of embodiment 122A, the product of embodiment 122A and the product of embodiment 29A are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (18mg, 22%).1H?NMR(300MHz，DMSO-D6)δ?ppm：7.45-7.54(m，4H)，7.56-7.62(m，3H)，7.83-7.90(m，1H)，8.25-8.29(m，1H)，8.93(s，1H)，9.12-9.18(m，2H)，10.70(s，1H)，11.23(s，1H)；MS?ESI+m/z?376(M+H)+，ESI-m/z?374(M-H)-。

Embodiment 123

2-bromo-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 123A

N-(3-amino-phenyl)-2-bromo-benzamide

This title compound makes like this: according to the method for embodiment 117A, substitute 4-bromo-Benzoyl chloride with 2-bromo-Benzoyl chloride, the method for using embodiment 114B has then obtained this title product with nitroreduction.

Embodiment 123B

2-bromo-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Use the method for embodiment 117C, product with the product alternate embodiment 117B of embodiment 123A, the product of embodiment 123A and the product of embodiment 29A are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (18mg, 22%).1H?NMR(300MHz，DMSO-D6)δ?ppm：7.44-7.54(m，4H)，7.56-7.60(m，2H)，7.74(dd，J＝7.91，0.92Hz，1H)，7.82-7.89(m，1H)，8.27(s，1H)，8.92(s，1H)，9.11-9.19(m，2H)，10.68(s，1H)，11.20(s，1H)；MS?ESI+m/z?420(M+H)+，ESI-m/z?418(M-H)-。

Embodiment 124

2-methoxyl group-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 124A

N-(3-amino-phenyl)-2-methoxyl group-benzamide

This title compound makes like this: according to the method for embodiment 117A, substitute 4-bromo-Benzoyl chloride with 2-methoxyl group-Benzoyl chloride, the method for using embodiment 114B has then obtained this title product with nitroreduction.

Embodiment 124B

Use the method for embodiment 117C, product with the product alternate embodiment 117B of embodiment 124A, the product of embodiment 124A and the product of embodiment 29A are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (26mg, 33%).1H?NMR(300MHz，DMSO-D6)δ?ppm：3.90(s，3H)，7.08(t，J＝6.99Hz，1H)，7.20(d，J＝8.46Hz，1H)，7.41-7.56(m，4H)，7.62(dd，J＝7.54，1.65Hz，1H)，7.88(dt，1H)，8.28(s，1H)，8.94(s，1H)，9.12-9.19(m，2H)，10.30(s，1H)，11.30(s，1H)；MS?ESI+m/z?372(M+H)+，ESI-m/z?370(M-H)-。

Embodiment 125

3-methoxyl group-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 125A

N-(3-amino-phenyl)-3-methoxyl group-benzamide

This title compound makes like this: according to the method for embodiment 117A, substitute 4-bromo-Benzoyl chloride with 3-methoxyl group-Benzoyl chloride, the method for using embodiment 114B has then obtained this title product with nitroreduction.

Embodiment 125B

Use the method for embodiment 117C, product with the product alternate embodiment 117B of embodiment 125A, the product of embodiment 125A and the product of embodiment 29A are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (35mg, 45%).1H?NMR(300MHz，DMSO-D6)δ?ppm：3.85(s，3H)，7.18(dd，J＝7.54，2.02Hz，1H)，7.42-7.51(m，3H)，7.53-7.61(m，3H)，7.82(dd，J＝7.72，5.15Hz，1H)，8.32(t，J＝1.84Hz，1H)，8.89(s，1H)，9.09-9.17(m，2H)，10.38(s，1H)，10.99(s，1H)；MS?ESI+m/z?372(M+H)+，ESI-m/z?370(M+H)-。

Embodiment 126

3-fluoro-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 126A

N-(3-amino-phenyl)-3-fluoro-benzamide

This title compound makes like this: according to the method for embodiment 117A, substitute 4-bromo-Benzoyl chloride with 3-fluoro-Benzoyl chloride, the method for using embodiment 114B has then obtained this title product with nitroreduction.

Embodiment 126B

3-fluoro-N-[3-(pyrido [2,3-d] pyrimidine-4-base the is amino)-great benzamide of phenyl

Use the method for embodiment 117C, product with the product alternate embodiment 117B of embodiment 126A, the product of embodiment 126A and the product of embodiment 29A are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (21mg, 28%).1H?NMR(300MHz，DMSO-D6)δ?ppm：7.41-7.53(m，2H)，7.54-7.65(m，3H)，7.77-7.86(m，3H)，8.33(s，1H)，8.89(s，1H)，9.10-9.16(m，2H)，10.48(s，1H)，10.97(s，1H)；MS?ESI+m/z?360(M+H)+，ESI-m/z?358(M-H)-。

Embodiment 127

3-bromo-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 127A

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

This title compound makes like this: according to the method for embodiment 114A, substitute 3-trifluoromethyl-Benzoyl chloride with 3-bromo-Benzoyl chloride, then product is reacted according to the method for embodiment 114B and 114C, obtained this title product.

Embodiment 127B

Use the method for embodiment 117C, use the product of the product alternate embodiment 117B of embodiment 127A, the product of embodiment 127A and the product reaction of embodiment 29A have been obtained crude product, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (41mg, 27%).1H?NMR(300MHz，DMSO-D6)δ?ppm：6.70(d，J＝8.46Hz，2H)，7.13-7.21(m，3H)，7.51(t，J＝7.91Hz，1H)，7.63(dd，J＝8.46，2.21Hz，1H)，7.78-7.88(m，2H)，7.94(d，J＝8.09Hz，1H)，8.01(s，1H)，8.13(s，1H)，8.78(s，1H)，9.03(d，J＝8.09Hz，1H)，9.15(d，J＝3.31Hz，1H)，9.79(s，1H)，10.55(s，1H)；MS?ESI+m/z549(M+H)+，ESI+m/z?470(M-73)+，ESI-m/z?544(M-H)-。

Embodiment 128

4-chloro-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 128A

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-4-chloro-benzamide

This title compound makes like this: according to the method for embodiment 114A, substitute 3-trifluoromethyl-Benzoyl chloride with 4-chloro-Benzoyl chloride, then product is reacted according to the method for embodiment 114B and 114C, obtained this title product.

Embodiment 128B

Use the method for embodiment 117C, product with the product alternate embodiment 117B of embodiment 128A, the product of embodiment 128A and the product of embodiment 29A are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (24mg, 17%).1H?NMR(300MHz，DMSO-D6)δ?ppm：6.70(d，J＝8.82Hz，2H)，7.12-7.23(m，3H)，7.56-7.68(m，3H)，7.85(dd，J＝8.27，4.60Hz，1H)，7.93-8.05(m，3H)，8.78(s，1H)，9.03(d，J＝7.72Hz，1H)，9.15(d，J＝2.94Hz，1H)，9.79(s，1H)，10.53(s，1H)；MS?ESI+m/z?500(M+H)+，ESI+m/z?426(M-73)+，ESI-m/z?498(M-H)-。

Embodiment 129

N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-4-methoxyl group-benzamide

Embodiment 129A

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-4-methoxyl group-benzamide

This title compound makes like this: according to the method for embodiment 114A, substitute 3-trifluoromethyl-Benzoyl chloride with 4-methoxyl group-Benzoyl chloride, then product is reacted according to the method for embodiment 114B and 114C, obtained this title product.

Embodiment 129B

Use the method for embodiment 117C, use the product of the product alternate embodiment 117B of embodiment 129A, the product of embodiment 129A and the product of embodiment 29A are reacted, obtained crude product,, obtained this title compound by using the HPLC purifying of TFA, be trifluoroacetate (1mg, 2%).1H?NMR(300?MHz，DMSO-D6)δ?ppm：3.83(s，3H)，6.65-6.73(m，2H)，7.00-7.10(m，2H)，7.12-7.22(m，3H)，7.64(dd，J＝8.82，2.21Hz，1H)，7.87(dd，J＝8.64，3.86Hz，1H)，7.93(t，J＝8.09Hz，2H)，8.03(d，J＝1.47Hz，1H)，8.79(s，1H)，9.04(d，J＝7.72Hz，1H)，9.15(d，J＝2.94Hz，1H)，9.76(s，1H)，10.30(s，1H)，11.42(s，1H)；MS?ESI+m/z?496(M+H)+，ESI-m/z?494(M-H)-。

Embodiment 130

N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

With 2-chloro-5-N-methyl-p-nitroaniline (3g, 17.4mmole), the 4-hydroxythiophenol (2.4g, 19.0mmol), cesium carbonate (12.35g, 38mmol) solution in dimethyl formamide (35ml) in 100 ℃ the heating 16 hours.Then frozen water (200mL) is added in this solution, and in the gained slurries, adds ethyl acetate (200ml).Separate each layer, and organic layer is washed 10% with 10% sodium bicarbonate and 10% sodium-chlor, use anhydrous sodium sulfate drying.Filter out siccative, and solvent removed in vacuo, yellow oil obtained.By this oily matter of silica gel chromatography purifying,, obtained yellow solid (4-(2-amino-4-nitro-phenyl sulfenyl)-phenol) (2.1g, 46%) with methylene chloride (97:3) wash-out.

Product (340mg with embodiment 9B, 1.80mmol) and 4-(2-amino-4-nitro-phenyl sulfenyl)-phenol (480mg, 1.80mmol) solution in acetate (10mL) is being preheated in 130 ℃ the oil bath and stirring 30 minutes, then this mixture is cooled to room temperature, vacuum is removed acetate, obtained brown oil (4-[2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base amino)-4-nitro-phenyl sulfenyl]-phenol) (0.65g, 89%).

With 4-[2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base amino)-4-nitro-phenyl sulfenyl]-phenol (0.19g, 0.469mmol) and the slurries of 10% Pd/C (0.025g) in acetate (3ml) place under the nitrogen atmosphere, stirring at room 2 hours.With this dope filtration, and solvent removed in vacuo, obtained brown oil, be 4-[4-amino-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-acetate (0.21g, 91%) of phenol.

To in the 1ml pyridine, contain 4-[4-amino-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenyl sulfenyl]-phenol (50mg, 0.133mmole), (40mg, solution 0.284mmole) was stirring at room 18 hours for Benzoyl chloride.With solvent vacuum-evaporation, and resistates stirred 18 hours with 2N NaOH (1ml).With this reaction mixture vacuum concentration, and, obtained this title compound, be trifluoroacetate (27mg, 42%) by using the HPLC purifying gained resistates of TFA.1H?NMR(300MHz，DMSO-D6)δ?ppm：2.72(s，3H)，6.65-6.76(m，2H)，7.07-7.24(m，3H)，7.44-7.76(m，6H)，7.94(d，J＝6.62Hz，2H)，8.02(s，1H)，8.69(s，1H)，8.86(d，J＝8.46Hz，1H)，9.76(s，1H)，10.43(s，1H)。

Embodiment 131

Furans-2-formic acid [4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-acid amides

Method according to embodiment 130, substitute Benzoyl chloride with 2 furoyl chloride, with 4-[4-amino-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-the phenyl sulfenyl]-solution reaction of phenol and 2 furoyl chloride reaction, obtained crude product,, obtained this title compound by using the HPLC purifying of TFA, be trifluoroacetate (17mg, 28%).1H?NMR(300MHz，DMSO-D6)δ?ppm：2.75(s，3H)，6.59-6.83(m，3H)，7.16(d，J＝8.46Hz，3H)，7.26-7.36(m，1H)，7.63(dd，J＝8.64，2.39Hz，1H)，7.81(d，J＝8.82Hz，1H)，7.91-8.04(m，2H)，8.81(s，1H)，8.93(d，J＝8.46Hz，1H)，9.78(s，1H)，10.42(s，1H)，11.52(s，1H)。

Embodiment 132

N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzsulfamide

Product (340mg with embodiment 9B, 2.31mmol) and 4-(2-amino-4-nitro-phenyl sulfenyl)-phenol (610mg, 2.30mmol) solution in acetate (10mL) is being preheated in 130 ℃ the oil bath and stirring 10 minutes, then this mixture is cooled to room temperature, vacuum is removed acetate, obtained brown oil (4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-4-nitro-phenyl sulfenyl]-phenol) (0.92g, 92%).

With 4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-4-nitro-phenyl sulfenyl]-phenol (0.7g, 1.73mmol) and the slurries of 10% Pd/C (100mg) in acetate (10ml) and methyl alcohol (10mL) place under the hydrogen capsule atmosphere, stirring at room 20 hours.With this dope filtration, and solvent removed in vacuo, obtained 4-[4-amino-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol, be acetate.

To in the 1ml pyridine, contain 4-[4-amino-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenyl sulfenyl]-phenol (100mg, 0.200mmol), (43mg, solution 0.250mmol) was stirring at room 18 hours for benzene sulfonyl chloride.With solvent vacuum-evaporation, and, obtained this title compound, be trifluoroacetate (23mg, 18%) by using the HPLC purifying gained resistates of TFA.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.99Hz，6H)，3.21-3.37(m，1H)，6.57-6.77(m，2H)，6.94-7.06(m，2H)，7.04-7.21(m，2H)，7.21(d，J＝1.47Hz，1H)，7.51-7.71(m，3H)，7.80(d，J＝6.99Hz，2H)，7.88(d，J＝8.46Hz，1H)，8.79(s，1H)，8.92(d，J＝8.46Hz，1H)，9.80(s，1H)，10.59(s，1H)，11.50(s，1H)。

Embodiment 133

[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-Urethylane

To in the 1ml pyridine, contain 4-[4-amino-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenyl sulfenyl]-phenol (100mg, 0.200mmol), (25mg, solution 0.250mmol) was stirring at room 18 hours for methoxycarbonyl chlorine.With solvent vacuum-evaporation, and come purifying gained resistates, obtained this title compound, be trifluoroacetate (15mg, 13%) by the HPLC that uses TFA.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.99Hz，6H)，3.23-3.32(m，1H)，3.66(s，3H)，6.54-6.74(m，2H)，7.01-7.24(m，3H)，7.37(dd，J＝8.82，2.21Hz，1H)，7.61(s，1H)，7.86(d，J＝8.46Hz，1H)，8.78(s，1H)，8.95(s，1H)，9.72(s，1H)，9.92(s，1H)，11.41(bs，1H)。

Embodiment 134

[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzyl carbamate

Method according to embodiment 133, substitute methoxycarbonyl chlorine with benzyloxycarbonyl chlorine, to contain 4-[4-amino-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-the phenyl sulfenyl]-solution reaction of phenol and benzyloxycarbonyl chlorine, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (27mg, 21%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.62Hz，6H)，3.18-3.40(m，1H)，5.15(s，2H)，6.47-6.74(m，2H)，7.10(d，J＝8.46Hz，2H)，7.18(d，J＝8.46Hz，1H)，7.30-7.47(m，6H)，7.65(d，J＝1.84Hz，1H)，7.91(d，J＝8.46Hz，1H)，8.82(s，1H)，8.97(d，J＝8.46Hz，1H)，9.73(s，1H)，10.07(s，1H)，11.68(s，1H)。

Embodiment 135

4-(4-amino-phenyl sulfenyl)-N-(4-bromo-phenyl)-3-(the 7-tertiary butyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

With 3,3-dimethyl-2-butanone reacts according to the method for describing among the embodiment 8A-8E, has obtained N '-(the 6-tertiary butyl-3-cyano group-pyridine-2-yl)-N, N-dimethyl-carbonamidine.

Use the method for embodiment 13D; with N '-(the 6-tertiary butyl-3-cyano group-pyridine-2-yl)-N; the product of the product alternate embodiment 8E of N-dimethyl-carbonamidine; product and N '-(the 6-tertiary butyl-3-cyano group-pyridine-2-yl)-N with embodiment 13C; N-dimethyl-carbonamidine reaction; obtained { 4-[4-(4-bromo-phenyl amino formyl radical)-2-(the 7-tertiary butyl-pyrido [2; 3-d] pyrimidine-4-base amino)-the phenyl sulfenyl]-phenyl }-t-butyl carbamate; use the method for embodiment 13E to react it, obtained the crude product of this title compound, by using the HPLC purifying of TFA; obtained this title product, be trifluoroacetate (15mg, 7%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.45(s，9H)，6.64(d，J＝8.5Hz，2H)，6.95(d，J＝8.5Hz，1H)，7.16(d，J＝8.8Hz，2H)，7.54(d，J＝9.2Hz，2H)，7.72(d，J＝8.8Hz，2H)，7.86(m，1H)，7.93(s，1H)，8.09(m，1H)，8.86(m，1H)，9.05(m，1H)，10.34(s，1H)，11.61(bs，1H)；MS(ESI)+m/z?598/600(M+H)+。

Embodiment 136

3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-methoxyl group-phenyl sulfenyl)-methyl benzoate

Embodiment 136A

4-(4-methoxyl group-phenyl sulfenyl)-3-nitro-methyl benzoate

(5mL, 40.7mmol) (10.52g 48.8mmol) adds CsCO in the solution in DMF (40mL) with 3-nitro-4-chloro benzoic ether to the 4-methoxybenzenethiol ₃(26.5g, 81.4mmol), and with this reaction mixture 80 ℃ the heating 3 hours.After the cooling, this solution is poured in the water, and with ethyl acetate extraction (3 * 100mL).With the organic layer MgSO that merges ₄Drying is filtered, and vacuum concentration, by the silica gel chromatography purifying, uses ethyl acetate/hexane as eluent, has obtained this title compound (10.93g, 80%).

Embodiment 136B

3-amino-4-(4-methoxyl group-phenyl sulfenyl)-methyl benzoate

Be heated to backflow in product, iron powder and the ammonium chloride solution in methyl alcohol, tetrahydrofuran (THF) and the aqueous solution with embodiment 136A.The gained mixture is filtered, and filtrate is concentrated.Add ethyl acetate then, stir, filter and vacuum concentration, obtained this title compound (7.16g, 90%).

Embodiment 136C

With the product of embodiment 136B (1.58g, 5.5mmol) and the product of embodiment 8E (1.18g, 5.5mmol) solution in acetate (10mL) was 140 ℃ of heating 1 hour.Then this reaction mixture is cooled to room temperature, vacuum concentration.By the silica gel chromatography purifying, use the mixture of 4% methyl alcohol in methylene dichloride resistates, obtained this title compound, be white solid (1.16g, 46%) as eluent.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.33(d，J＝6.99Hz，6H)，3.13-3.29(m，1H)，3.79(s，3H)，3.83(s，3H)，6.89-6.98(m，1H)，7.02(d，J＝8.46Hz，2H)，7.42(d，J＝8.82Hz，2H)，7.57-7.67(m，1H)，7.72-7.82(m，1H)，7.85-7.98(m，1H)，8.58(s，1H)，8.84(s，1H)，10.17(s，1H)；MS(ESI)+m/z?461(M+H)+。

Embodiment 137

N-(3-hydroxy-4-methyl-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-methoxyl group-phenyl sulfenyl)-benzamide

Embodiment 137A

3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-methoxyl group-phenyl sulfenyl)-phenylformic acid

To the product of the embodiment 136C in tetrahydrofuran (THF) (20mL) (1.56g, add in 3.4mmol) the 1N aqueous sodium hydroxide solution (10mL, 10mmol), and with this reaction mixture 50 ℃ of heating 3 hours.After this reaction mixture was cooled to room temperature, being adjusted to pH with 1N hydrochloric acid was 6.5, removes formed precipitation by vacuum filtration.Product is dry under high vacuum, obtained this title compound, be pale solid (643mg, 42%).

Embodiment 137B

3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-methoxyl group-phenyl sulfenyl)-Benzoyl chloride

With the product of embodiment 137A (500mg, 1.120mmol) in methylene dichloride (10mL) with oxalyl chloride (0.115mL, 1.344mmol) and 1 DMF handle.Stirring at room 1 hour, vacuum concentration obtained this title compound then, is brown solid with the gained reaction mixture, and it need not further be handled and directly use.

Embodiment 137C

(20.4mg, 0.1655mmol) (70mg, 0.1655mmol) (0.025mL 0.1806mmol) handles the solution in methylene dichloride (4mL) with triethylamine with the product that derives from embodiment 137B with 5-amino-ortho-cresol in room temperature.With gained solution stirring 18 hours.Then with this reaction mixture water and salt water washing, and with the organic layer MgSO that merges ₄Drying, vacuum concentration has obtained resistates, by the silica gel chromatography purifying, uses methyl alcohol and methylene dichloride as eluent it, has obtained this title compound (55mg, 65%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)，2.07(s，3H)，3.17-3.28(m，1H)，3.77(s，3H)，6.86-7.10(m，5H)，7.30-7.46(m，3H)，7.64(d，J＝7.35Hz，1H)，7.72-7.86(m，1H)，7.95(s，1H)，8.43-8.68(m，1H)，8.77-8.97(m，1H)，9.27-9.46(m，1H)，10.02(s，1H)，10.21-10.40(m，1H)；MS(APCI)m/z?552(M+H)+。

Embodiment 138

3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-methoxyl group-phenyl sulfenyl)-N-p-methylphenyl-benzamide

Method according to embodiment 137C, product (the 70mg of embodiment 137B will be derived from, 0.1505mmol) usefulness para-totuidine (16mg, 0.1505mmol), triethylamine (0.025mL, 0.1806mmol) and methylene dichloride (4mL) processing, behind the chromatogram purification, obtained this title compound, be pale solid (64mg, 80%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.62Hz，6H)2.27(s，3H)3.17-3.30(m，1H)3.78(s，3H)7.00(d，J＝8.82Hz，2H)7.14(d，J＝8.09Hz，2H)7.40(d，J＝8.82Hz，2H)7.62(d，J＝8.46Hz，1H)7.80(d，J＝8.09Hz，1H)7.99(s，1H)8.59(s，1H)8.86(d，J＝8.46Hz，1H)10.13(s，1H)10.20(s，1H)；MS(APCI)m/z?536(M+H)+。

Embodiment 139

N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-methoxyl group-phenyl sulfenyl)-benzamide

According to the method for embodiment 137C, substitute 5-amino-ortho-cresol with the 4-bromaniline, with deriving from product and the reaction of 4-bromaniline of embodiment 137B, behind the silica gel chromatography purifying, obtained this title compound, be pale solid (109mg, 85%).

Embodiment 140

N-(3-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-methoxyl group-phenyl sulfenyl)-benzamide

According to the method for embodiment 137C, substitute 5-amino-ortho-cresol with the 3-bromaniline, with deriving from product and the reaction of 3-bromaniline of embodiment 137B, behind the silica gel chromatography, obtained this title compound, be pale solid (50mg, 38%).1H?NMR(300MHz，DMSO-D6)δppm：1.34(d，J＝6.99Hz，6H)，3.16-3.30(m，1H)，3.77(s，3H)，7.00(d，J＝8.82Hz，2H)，7.40(d，J＝8.82Hz，2H)，7.53(d，J＝8.82Hz，2H)，7.64(d，J＝8.82Hz，1H)，7.74(d，J＝8.82Hz，2H)，7.81(dd，J＝8.46，1.84Hz，1H)，7.99(d，J＝1.47Hz，1H)，8.59(s，1H)，8.86(d，J＝8.82Hz，1H)，10.21(s，1H)，10.33(s，1H)；MS(APCI)m/z?602(M+H)+。

Embodiment 141

Tolyl-benzamide between 3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-methoxyl group-phenyl sulfenyl)-N-

According to the method for embodiment 137C, substitute 5-amino-ortho-cresol with meta-aminotoluene, with deriving from product and the meta-aminotoluene reaction of embodiment 137B, behind the silica gel chromatography purifying, obtained this title compound, be pale solid (56mg, 70%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)，2.21(s，3H)，3.15-3.29(m，1H)，3.78(s，3H)，7.00(d，J＝8.82Hz，2H)，7.12-7.37(m，4H)，7.40(d，J＝8.82Hz，2H)，7.64(d，J＝8.46Hz，1H)，7.84(d，J＝11.40Hz，1H)，7.99(s，1H)，8.59(s，1H)，8.86(d，J＝8.46Hz，1H)，9.87(s，1H)，10.21(s，1H)；MS(APCI)m/z?536(M+H)+。

Embodiment 142

3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(3-methoxyl group-phenyl)-4-(4-methoxyl group-phenyl sulfenyl)-benzamide

According to the method for embodiment 137C, substitute 5-amino-ortho-cresol with m-anisidine, with deriving from product and the m-anisidine reaction of embodiment 137B, behind the silica gel chromatography purifying, obtained this title compound, be pale solid (60mg, 85%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)，3.17-3.29(m，1H)，3.74(s，3H)，3.77(s，3H)，6.68(dd，J＝8.09，1.84Hz，1H)，6.92-6.98(m，1H)，6.99(d，J＝8.82Hz，2H)，7.24(t，J＝8.09Hz，1H)，7.31-7.50(m，5H)，7.68(d，J＝8.09Hz，1H)，7.79(d，J＝7.35Hz，1H)，7.96(s，1H)，8.61(s，1H)，8.89(d，J＝8.09Hz，1H)，10.18(s，1H)；MS(APCI)m/z552(M+H)+。

Embodiment 143

3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(2-methoxyl group-phenyl)-4-(4-methoxyl group-phenyl sulfenyl)-benzamide

According to the method for embodiment 137C, substitute 5-amino-ortho-cresol with ORTHO ANISIDINE, with deriving from product and the ORTHO ANISIDINE reaction of embodiment 137B, behind the silica gel chromatography purifying, obtained this title compound, be pale solid (120mg, 67%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)，3.12-3.28(m，1H)，3.78(s，3H)，3.81(s，3H)，6.92-7.05(m，4H)，7.05-7.12(m，1H)，7.13-7.23(m，1H)，7.40(d，J＝8.82Hz，2H)，7.64(d，J＝8.46Hz，1H)，7.71(d，J＝7.72Hz，1H)，7.81(d，J＝8.82Hz，1H)，7.99(s，1H)，8.59(s，1H)，8.86(d，J＝8.46Hz，1H)，9.44(s，1H)，9.44(s，1H)；MS(APCI)m/z?553(M+H)+。

Embodiment 144

3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-methoxyl group-phenyl sulfenyl)-N-o-tolyl-benzamide

According to the method for embodiment 137C, substitute 5-amino-ortho-cresol with Ortho Toluidine, with deriving from product and the Ortho Toluidine reaction of embodiment 137B, behind the silica gel chromatography purifying, obtained this title compound, be pale solid (74mg, 92%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)，2.34(s，3H)，3.18-3.29(m，1H)，3.78(s，3H)，6.91(d，J＝7.35Hz，1H)，7.00(d，J＝8.09Hz，2H)，7.22(t，J＝7.72Hz，1H)，7.40(d，J＝8.46Hz，2H)，7.50-7.72(m，4H)，7.81(d，J＝8.09Hz，1H)，8.00(s，1H)，8.59(s，1H)，8.87(d，J＝8.46Hz，1H)，10.13(s，1H)，10.21(s，1H)；MS(APCI)m/z?536(M+H)+。

Embodiment 145

Tolyl-benzamide between 3-(7-ethyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-hydroxyl-phenyl sulfenyl)-N-

According to the method for embodiment 150, use the product of the product alternate embodiment 138 of embodiment 141, the product reaction with embodiment 141 has obtained resistates, by using the HPLC purifying of TFA, has obtained this title compound, is trifluoroacetate (24mg, 50%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.99Hz，6H)，2.21(s，3H)，3.22-3.41(m，1H)，6.84(d，J＝8.46Hz，2H)，7.00(d，J＝8.09Hz，1H)，7.11-7.28(m，2H)，7.31(d，J＝8.46Hz，2H)，7.88(t，J＝9.01Hz，2H)，7.96(s，1H)，8.82(s，1H)，8.99(d，J＝8.09Hz，1H)，9.89(s，1H)，10.00(s，1H)；MS(APCI)m/z?522(M+H)+。

Embodiment 146

N-(2-hydroxyl-phenyl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

According to the method for embodiment 150, use the product of the product alternate embodiment 138 of embodiment 143, the product reaction with embodiment 143 has obtained resistates, comes purifying by development in methyl alcohol and ether, has obtained this title compound (26mg, 55%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.37(d，J＝6.99Hz，6H)，3.21-3.43(m，1H)，6.83(s，1H)，6.84(d，J＝8.82Hz，2H)，6.92(d，J＝8.09Hz，1H)，7.02(d，J＝8.09Hz，2H)，7.32(d，J＝8.46Hz，2H)，7.63(d，J＝8.09Hz，1H)，7.93(dd，J＝8.46，1.84Hz，1H)，7.99(s，1H)，8.94(s，1H)，9.08(d，J＝8.46Hz，1H)，9.51(s，1H)，9.74(s，1H)，10.02(s，1H)；MS(APCI)m/z?524(M+H)+。

Embodiment 147

4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-o-tolyl-benzamide

According to the method for embodiment 150, use the product of the product alternate embodiment 138 of embodiment 144, the product reaction with embodiment 144 has obtained resistates, by using the HPLC purifying of TFA, has obtained this title compound, is trifluoroacetate (24mg, 50%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.62Hz，6H)，2.11(s，3H)，3.21-3.43(m，1H)，6.72(d，J＝7.72Hz，1H)，6.79-6.92(m，3H)，7.00(d，J＝8.09Hz，1H)，7.24(d，J＝8.46Hz，2H)，7.34(d，J＝6.62Hz，1H)，7.52(d，J＝7.72Hz，1H)，7.63(d，J＝7.72Hz，1H)，7.81(d，J＝8.46Hz，1H)，7.92(s，1H)，8.66(s，1H)，8.91(d，J＝8.09Hz，1H)，10.04(s，1H)；MS(APCI)m/z?522(M+H)+。

Embodiment 148

4-(4-methoxyl group-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-o-tolyl-benzamide

Embodiment 148A

4-(4-methoxyl group-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-methyl benzoate

Method according to embodiment 136C, product with the product alternate embodiment 8E of embodiment 9B, with the product of embodiment 136B (2.67g, 9.23mmol) and the product of embodiment 9B (1.72g, 9.23mmol) reaction, obtained resistates, by the silica gel chromatography purifying, use the mixture of 4% methyl alcohol in methylene dichloride it, obtained this title compound as eluent, be white solid (1.79g, 45%).

Embodiment 148B

(0.208mL 1.94mmol) adds AlMe in the solution in toluene (10mL) to Ortho Toluidine ₃(0.97mL, 1.94mmol), and with this reaction mixture stirring at room 30 minutes.The product of disposable then adding embodiment 148A (140mg, 0.324mmol), and with this reaction mixture refluxed 3 hours.This reaction mixture is cooled to room temperature, pours in the quick solution that is stirring of Rochelle ' s salt.In solution, after stirred overnight at room temperature, should react with ethyl acetate extraction (3 * 50mL).With the organic layer MgSO that merges ₄Drying, and vacuum concentration is to resistates, by the silica gel chromatography purifying, uses the mixture of methyl alcohol in methylene dichloride as eluent it, obtained this title compound (106mg, 65%).1H?NMR(300MHz，DMSO-D6)δ?ppm：2.21(s，3H)，2.69(s，3H)，3.78(s，3H)，7.00(d，J＝8.82Hz，2H)，7.11-7.35(m，5H)，7.40(d，J＝8.82Hz，2H)，7.57(d，J＝8.46Hz，1H)，7.84(d，J＝6.99Hz，1H)，8.00(s，1H)，8.59(s，1H)，8.81(d，J＝8.09Hz，1H)，9.87(s，1H)，10.20(s，1H)；MS(APCI)m/z?508(M+H)+。

Embodiment 149

4-(4-methoxyl group-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-N-o-tolyl-benzamide

According to the method for embodiment 150, use the product of the product alternate embodiment 138 of embodiment 148B, with the product reaction of embodiment 148B, obtained resistates,, obtained this title compound by using the HPLC purifying of TFA, be trifluoroacetate (26mg, 55%).1H?NMR(300MHz，DMSO-D6)δ?ppm：2.21(s，3H)，2.69(s，3H)，6.85(d，J＝8.46Hz，2H)，6.94(d，J＝8.09Hz，1H)，7.07-7.26(m，4H)，7.31(d，J＝8.82Hz，2H)，7.57(d，J＝8.46Hz，1H)，7.83(d，J＝8.46Hz，1H)，7.98(s，1H)，8.59(s，1H)，8.82(d，J＝8.46Hz，1H)，9.85(s，1H)，9.96(s，1H)，10.19(s，1H)；MS(APCI)m/z?494(M+H)+。

Embodiment 150

4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-p-methylphenyl-benzamide

With derive from embodiment 138 compound (50mg, 0.0933mmol) and BBr ₃(0.4mL, 0.4mmol) and methylene dichloride (4mL) merge 30 minutes in room temperature.Should react by adding methyl alcohol (5mL) and handle, vacuum concentration has obtained oily matter then.Come purifying gained resistates by the HPLC that uses TFA, obtained this title compound, be trifluoroacetate (20mg, 41%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.62Hz，6H)，2.27(s，3H)，3.17-3.30(m，1H)，3.78(s，3H)，7.00(d，J＝8.82Hz，2H)，7.14(d，J＝8.09Hz，2H)，7.40(d，J＝8.82Hz，2H)，7.62(d，J＝8.46Hz，1H)，7.80(d，J＝8.09Hz，1H)，7.99(s，1H)，8.59(s，1H)，8.86(d，J＝8.46Hz，1H)，10.13(s，1H)，10.20(s，1H)；MS(APCI)m/z?536(M+H)+。

Embodiment 151

4-(4-amino-phenyl sulfenyl)-N-(4-bromo-phenyl)-3-(7-sec.-propyl-1-methyl isophthalic acid H-pyrido [2,3-d] pyrimidine-4-subunit amino)-benzamide

With the product of embodiment 100 (114mg, 0.15mmol), methyl-iodide (9 μ L, 0.15mmol) and cesium carbonate (48mg, 0.15mmol) in DMF (3mL) in stirring at room 16 hours.This mixture is added in the water, comes pH regulator to 3 is used ethyl acetate extraction, use dried over mgso, filter and evaporation by adding 1M HCl.Resistates is added in tetrahydrofuran (THF) (5mL) and the water (5mL), and (0.6mL 1N) adds in this solution with sodium hydroxide then.60 ℃ of heating 1 hour, cooling pH regulator to 3, was used ethyl acetate extraction by 1M HCl, uses dried over mgso with this mixture, filtered and evaporation.Resistates by silica gel purification, with the mixture wash-out of mixture to 2% methyl alcohol of 1% methyl alcohol in methylene dichloride in methylene dichloride, has been obtained this title compound (50mg, 56%). ¹H?NMR(500MHz，DMSO-d ₆)δ?ppm：1.31(d，J＝6.84Hz，6H)3.14(m，1H)3.64(s，3H)5.49(s，2H)6.64(m，3H)7.15(d，J＝8.30Hz，2H)7.39(dd，J＝8.30，1.95Hz，1H)7.44(d，J＝8.30Hz，1H)7.50(m，2H)7.60(d，J＝1.95Hz，1H)7.73(m，2H)8.15(s，1H)8.56(d，J＝7.81Hz，1H)10.12(s，1H)；MS(ESI+)m/z?599?601(M+H)+。

Embodiment 152

Phenylsulfonic acid 4-[4-phenyl sulfonyl oxygen base-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-hexamethylene-butadienyl sulfenyl]-phenylester

With the product of embodiment 153C (65mg, 0.180mmol) with benzene sulfonyl chloride (0.046mL, 0.36mmol) and triethylamine (0.066mL, 0.468mmol) at N, in the dinethylformamide (1mL) in room temperature reaction 2 hours.This mixture is poured in the water (10mL) then, and (3 * 10mL) extract with ethyl acetate with gained solution, with the extraction liquid dried over mgso that merges, filter and vacuum concentration, and by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate (19mg, 14%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：6.92(m，4H)，7.19(m，4H)，7.62(m，6H)，7.81(m，5H)，7.92(m，2H)，9.01(bs，1H)；MS(ESI+)m/z?643(M+H)+。

Embodiment 153

Carbonic acid 4-(4-tert-butoxycarbonyl oxygen base-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base the is amino)-phenylester tert-butyl ester

Embodiment 153A

4-(4-hydroxyl-phenyl sulfenyl)-3-nitro-phenol

With 4-chloro-3-nitro-phenol (2.0g, 11.52mmol), the 4-hydroxythiophenol (1.45g, 11.52mmol) and cesium carbonate (11.26g, 34.56mmol) at N, the solution in the dinethylformamide (25mL) in 100 ℃ the heating 4 hours.After being cooled to room temperature, add 1N hydrochloric acid (150mL), (2 * 100mL) extractions with the extraction liquid dried over mgso that merges, are filtered and vacuum concentration with ethyl acetate with gained solution, obtained the crude product of this title compound, by the silica gel chromatography purifying, use hexane/ethyl acetate as eluent, obtained this title product, be bright orange solid (1.35g, 45%).

Embodiment 153B

3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenol

According to the method for embodiment 9E, (1.34g is 5.09mmol) with iron (1.42g with the product of embodiment 153A, 25.48mmol) and ammonium chloride (409mg, 1.5mmol) in 20mL EtOH/20mL THF/6mL water, react, obtained this title compound (1.168g, 97%).

Embodiment 153C

4-(4-hydroxyl-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenol

Use the method for embodiment 29E, product with the product alternate embodiment 29D of embodiment 153B, product (380mg with embodiment 153B, 1.63mmol) product and the product (284mg of embodiment 29A, 1.63mmol) reaction, obtained solid, it is developed with methyl alcohol, obtained this title compound (209mg, 35%).

Embodiment 153D

Product (195mg with embodiment 153C, 0.539mmol) and tert-Butyl dicarbonate (234mg, 1.078mmol), triethylamine (0.165mL, 1.19mmol) and 4-dimethylaminopyridine (2mg) in methylene dichloride (5mL), tetrahydrofuran (THF) (3mL) and dimethyl formamide (1mL) in room temperature reaction 16 hours.Then this mixture is poured in the water (10mL), and (3 * 10mL) extractions with the extraction liquid dried over mgso that merges, are filtered and vacuum concentration, have obtained this title compound (256mg, 84%) with ethyl acetate with gained solution. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.47(s，9H)，1.49(s，9H)，7.13(d，J＝8.8Hz，2H)，7.20(m，1H)，7.29(d，J＝8.8Hz，2H)，7.35(m，1H)，7.46(m，1H)，7.63(m，1H)，8.61(m，1H)，8.82(m，1H)，9.08(m，1H)，10.27(s，1H)；MS(ESI+)m/z?563(M+H)+。

Embodiment 154

4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(5-trifluoromethyl-[1,3,4] thiadiazoles-2-yl)-benzamide

Embodiment 154A

4-[2-nitro-4-(5-trifluoromethyl-[1,3,4] thiadiazoles-2-base formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

Product (290mg with embodiment 19C, 0.546mmol) solution in anhydrous tetrahydro furan (5mL) is with 2-amino-5-Trifluoromethyl-1,3,4-thiadiazoles (102mg, 0.601mmol) and diisopropylethylamine (0.143mL, 0.819mmol) handle, stirred 16 hours under nitrogen atmosphere in room temperature.Should react with ethyl acetate (100mL) dilution, and with saturated sodium bicarbonate aqueous solution (25mL), water (2 * 25mL) and salt solution (25mL) wash.With the organic phase anhydrous sodium sulfate drying, filter, and vacuum concentration.With the methylene dichloride development, obtained this title compound (308mg, 85%).

Embodiment 154B

4-[2-amino-4-(5-trifluoromethyl-[1,3,4] thiadiazoles-2-base formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

Product (307mg with embodiment 154A, 0.463mmol), ammonium chloride (162mg, 3.03mmol) and iron powder (159mg, 2.845mmol) solution in the mixture of water (3mL), ethanol (6mL) and tetrahydrofuran (THF) (6mL) 90 ℃ under nitrogen atmosphere the heating 1 hour.This reaction is cooled to room temperature, with ethyl acetate (100mL) dilution, and water (3 * 50mL) and salt solution (50mL) wash.With the organic phase anhydrous sodium sulfate drying, filter, and concentrate by rotary evaporation in vacuo, obtained product, be light yellow solid (224mg, 76%).

Embodiment 154C

4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(5-trifluoromethyl-[1,3,4] thiadiazoles-2-base formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

With the product of embodiment 8E (75.8mg, 0.3503mmol) and the product of embodiment 154B (222mg, 0.3503mmol) solution in acetate (8mL) is being preheated in 140 ℃ the oil bath and was stirring 1.5 hours.This reaction is cooled to room temperature,, concentrates by rotary evaporation with hexane (100mL) dilution, and with dichloromethane/hexane coevaporation (4 times).Resistates is dry under high vacuum, by the fast silica gel chromatogram purifying,, use 3% ethanol/methylene wash-out then then with 30% ethyl acetate/dichloromethane wash-out, obtained this title compound, be yellow solid (" 6mg, 41%).

Embodiment 154D

Product (114mg with embodiment 154C, 0.1416mmol) 1, solution in the 4-dioxane (4mL) lithium hydroxide monohydrate (11.9mg, 0.2833mmol) solution in water (2mL) is in room temperature treatment, 65 ℃ of heating 30 minutes, this reaction is cooled to room temperature then, with ethyl acetate (100mL) and water (50mL) dilution, with 1N hydrochloric acid water being adjusted to pH is 5-6, and separates each layer.With the organic phase water (2 * 25mL) and salt solution (25mL) washing, use anhydrous sodium sulfate drying, filter, and concentrated by rotary evaporation in vacuo.With the development of 3% ethanol/methylene, obtained this title compound, be light yellow solid (57mg, 69%). ¹HNMR(300MHz，DMSO-d ₆/TFA)δ?ppm：1.35(d，J＝6.62Hz，6H)3.08-3.51(m，1H)7.25(d，J＝8.46Hz，1H)7.39(d，J＝8.46Hz，2H)7.55(d，J＝8.82Hz，2H)7.94(d，J＝8.82Hz，1H)8.18(dd，J＝8.46，2.21Hz，1H)8.27(d，J＝1.84Hz，1H)8.99(s，1H)9.10(d，J＝8.82Hz，1H)；MS(ESI+)m/z?583(M+H) ⁺，(ESI-)m/z?581(M-H) ^-。

Embodiment 155

Embodiment 155A

4-[4-cyclopentyl formamyl-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2, the 2-trichloro ethyl ester

Under nitrogen atmosphere, product (50mg with embodiment 162b, 0.0824mmol) be dissolved in anhydrous N, in the dinethylformamide (1mL), and with cyclopentyl amine (8.4mg, 0.0989mmol), 3-(diethoxy phosphoryl oxy)-1,2,3-phentriazine-4 (3H)-ketone (49.3mg, 0.1648mmol) and triethylamine (0.034mL 0.2472mmol) handles.This was reflected at stirring at room 16 hours, and removes by rotary evaporation in vacuo and to desolvate.By fast silica gel chromatogram purifying resistates, with 4% ethanol/methylene wash-out, obtained this title compound, be light yellow solid (41mg, 74%).

Embodiment 155B

4-(4-amino-phenyl sulfenyl)-N-cyclopentyl-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

(39.9mg, 0.0592mmol) 1, (5.9mg, the 0.148mmol) solution-treated in water (1mL) is then 60 ℃ of heating 1 hour with sodium hydroxide for the solution in the 4-dioxane (2mL) with the product of embodiment 155A.This reaction is cooled to room temperature, and dilutes with ethyl acetate (50mL) and water (25mL).With water layer pH regulator to 5, separate each layer with 1N hydrochloric acid, and with organic phase water (2 * 25mL) and salt solution (25mL) washing.With the organic extract liquid anhydrous sodium sulfate drying, filter, and concentrate by rotary evaporation in vacuo.By fast silica gel chromatogram purifying resistates, with 4% methyl alcohol/methylene fluoride wash-out, obtained this title compound, be white solid (19mg, 64%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.34(d，J＝6.62Hz，6H)1.43-1.58(m，4H)1.59-1.75(m，2H)1.78-1.96(m，2H)3.12-3.32(m，1H)4.11-4.26(m，1H)5.57(s，2H)6.61(d，J＝8.46Hz，2H)6.81(d，J＝8.82Hz，1H)7.11(d，J＝8.46Hz，2H)7.64(t，J＝9.01Hz，1H)7.83(s，1H)8.21(d，J＝6.62Hz，1H)8.56(s，1H)8.86(d，J＝8.82Hz，1H)10.10(s，1H)；MS(ESI+)m/z?499(M+H) ⁺，(ESI-)m/z497(M-H) ^-。

Embodiment 156

4-[4-(4-bromo-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 2-dimethylamino-ethyl ester

With the product of embodiment 100 (76mg, 0.1mmol), 2-dimethylamino-ethanol (50 μ L, 0.5mmol) and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (15 μ L, 0.1mmol) in tetrahydrofuran (THF) (5mL) in 60 ℃ of heating 1 hour.In this mixture, add saturated sodium carbonate, use ethyl acetate extraction, use dried over mgso, filter and evaporation.Resistates by using the anti-phase preparation HPLC method purifying of TFA, has been obtained this title compound, be trifluoroacetate (48mg, 52%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.36(d，J＝6.99Hz，6H)2.88(s，6H)3.28(m，1H)3.43(m，2H)4.43(t，J＝4.95Hz，2H)7.08(d，J＝8.09Hz，1H)7.40(d，J＝8.82Hz，2H)7.53(m，4H)7.73(d，J＝8.82Hz，2H)7.84(m，2H)7.98(s，1H)8.78(s，1H)8.95(s，1H)9.62(s，1H)9.99(s，1H)10.38(s，1H)11.28(s，1H)；MS(ESI+)m/z?700702(M+H)+。

Embodiment 157

4-[4-(4-bromo-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 2-morpholine-4-base-ethyl ester

With the product of embodiment 100 (76mg, 0.1mmol), 2-morpholine-4-base-ethanol (60 μ L, 0.5mmol) and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (15 μ L, 0.1mmol) in tetrahydrofuran (THF) (5mL) in 60 ℃ of heating 1 hour.In this mixture, add saturated sodium carbonate, use ethyl acetate extraction, use dried over mgso, filter and evaporation.Resistates by using the anti-phase preparation HPLC method purifying of TFA, has been obtained this title compound, be trifluoroacetate (30mg, 35%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.35(d，J＝6.62Hz，6H)3.46(m，11H)4.45(t，J＝4.95Hz，2H)7.07(d，J＝8.46Hz，1H)7.41(d，J＝8.82Hz，2H)7.54(m，4H)7.73(d，J＝8.82Hz，2H)7.83(m，2H)7.98(s，1H)8.78(s，1H)8.97(d，J＝8.46Hz，1H)10.02(s，1H)10.38(s，1H)11.34(s，1H)；MS(ESI+)m/z?742?744(M+H)+。

Embodiment 158

4-[4-(4-bromo-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 2-(1-methyl-tetramethyleneimine-2-yl)-ethyl ester

Product (76mg with embodiment 100,0.1mmol), 2-(1-methyl-tetramethyleneimine-2-yl)-ethanol (68 μ L, 0.5mmol) and 1, (15 μ L 0.1mmol) heated 1 hour in 60 ℃ in tetrahydrofuran (THF) (5mL) 8-diazabicylo [5.4.0] 11 carbon-7-alkene.In this mixture, add saturated sodium carbonate, use ethyl acetate extraction, use dried over mgso, filter and evaporation.Resistates by using the anti-phase preparation HPLC method purifying of TFA, has been obtained this title compound, be trifluoroacetate (26mg, 27%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.36(d，J＝6.99Hz，6H)1.70(m，1H)1.90(m，3H)2.28(m，2H)2.86(d，J＝4.41Hz，3H)3.10(m，1H)3.30(m，2H)3.56(m，1H)4.19(t，J＝6.43Hz，2H)7.07(d，J＝8.09Hz，1H)7.40(d，J＝8.82Hz，2H)7.54(m，4H)7.73(d，J＝8.82Hz，2H)7.86(m，2H)7.98(s，1H)8.81(s，1H)8.96(d，J＝8.46Hz，1H)9.55(s，1H)9.93(s，1H)10.39(s，1H)11.45(s，1H)；MS(ESI+)m/z?740?742(M+H)+。

Embodiment 159

4-[4-(4-bromo-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 1-methyl-piperidines-3-ylmethyl ester

With the product of embodiment 100 (76mg, 0.1mmol), (1-methyl-piperidines-3-yl)-methyl alcohol (65mg, 0.5mmol) and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (15 μ L, 0.1mmol) in tetrahydrofuran (THF) (5mL) in 60 ℃ of heating 1 hour.In this mixture, add saturated sodium carbonate, use ethyl acetate extraction, use dried over mgso, filter and evaporation.Resistates by using the anti-phase preparation HPLC method purifying of TFA, has been obtained this title compound, be trifluoroacetate (36mg, 37%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：.1.20(m，1H)1.36(d，J＝6.99Hz，6H)1.78(m，3H)2.14(m，1H)2.79(d，J＝4.04Hz，3H)3.28(m，1H)3.44(m，4H)4.02(m，2H)7.07(d，J＝8.09Hz，1H)7.40(d，J＝8.82Hz，2H)7.54(m，4H)7.73(d，J＝8.82Hz，2H)7.85(m，2H)7.98(s，1H)8.79(s，1H)8.95(d，J＝8.46Hz，1H)9.46(s，1H)9.96(s，1H)10.38(s，1H)11.38(s，1H)；MS(ESI+)m/z?740?742(M+H)+。

Embodiment 160

4-[4-(4-bromo-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 3-dimethylamino-propyl diester

With the product of embodiment 100 (76mg, 0.1mmol), 3-dimethylamino-third-1-alcohol (59 μ L, 0.5mmol) and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (15 μ L, 0.1mmol) in tetrahydrofuran (THF) (5mL) in 60 ℃ of heating 1 hour.In this mixture, add saturated sodium carbonate, use ethyl acetate extraction, use dried over mgso, filter and evaporation.Resistates by using the anti-phase preparation HPLC method purifying of TFA, has been obtained this title compound, be trifluoroacetate (31mg, 33%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.35(d，J＝6.99Hz，6H)2.01(m，2H)2.81(d，J＝4.41Hz，6H)3.16(m，2H)3.28(m，1H)4.16(t，J＝6.25Hz，2H)7.06(d，J＝8.46Hz，1H)7.40(d，J＝8.82Hz，2H)7.52(m，4H)7.73(d，J＝8.82Hz，2H)7.84(m，2H)7.98(s，1H)8.77(s，1H)8.94(d，J＝8.46Hz，1H)9.47(s，1H)9.93(s，1H)10.38(s，1H)11.30(s，1H)；MS(ESI+)m/z?714?716(M+H)+。

Embodiment 161

4-(4-amino-phenyl sulfenyl)-N-(the 5-tertiary butyl-thiazol-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 161A

N-(5-tertiary butyl thiazole-2-yl)-4-chloro-3-nitro-benzamide

(1.336g, 6.681mmol) (1.044g 6.681mmol) handles the solution in anhydrous pyridine (30mL), this is reflected at room temperature stirs under nitrogen atmosphere with 2-amino-5-tertiary butyl thiazole with 4-chloro-3-nitrobenzoyl chloride.Remove by rotary evaporation in vacuo and to desolvate, and with resistates dried on a vacuum pump.Resistates is placed ethyl acetate (100mL) and washedwith water (4 * 50mL) and salt solution (50mL).With the organic phase anhydrous sodium sulfate drying, filter, and vacuum concentration. by silica gel chromatography purifying eluting with 5% ethyl acetate/dichloromethane, obtained this title compound (1.76g, 78%).

Embodiment 161B

4-(4-aminophenyl sulfenyl)-N-(5-tertiary butyl thiazole-2-yl)-3-nitro-benzamide

With the product of embodiment 161A (500mg, 1.472mmol), the 4-aminothiophenol (350mg, 2.796mmol) and anhydrous sodium acetate (604mg, 7.36mmol) reflux 3 hours under nitrogen atmosphere of the mixture in dehydrated alcohol (15mL).This reaction is cooled to room temperature, and removes ethanol by rotary evaporation.Resistates water (50mL) and ethyl acetate (100mL) are distributed, and with the organic phase water (2 * 50mL) and salt solution (50mL) wash.With the organic extract liquid anhydrous sodium sulfate drying, filter, and vacuum concentration.Solid with 4% ethyl acetate/dichloromethane (25mL) development, has been obtained this title compound (452mg, 72%).

Embodiment 161C

4-[4-(the 5-tertiary butyl-thiazol-2-yl formamyl)-2-nitro-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

Product (226mg with embodiment 161B, 0.5274mmol) suspension in anhydrous methylene chloride (5mL) is with 9-fluorenyl methoxy carbonyl chlorine (164mg, 0.6329mmol) and anhydrous pyridine (0.085mL, 1.055mmol) handle, and with the gained yellow solution under nitrogen atmosphere in stirring at room 3 hours.Should react with ethyl acetate (100mL) dilution, and water (2 * 50mL) and salt solution (50mL) wash.With the organic phase anhydrous sodium sulfate drying, filter, and concentrate by rotary evaporation in vacuo, obtained this title compound, be yellow solid (338mg, 98%).

Embodiment 161D

4-[2-amino-4-(the 5-tertiary butyl-thiazol-2-yl formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

Product (336mg with embodiment 161C, 0.516mmol), ammonium chloride (181mg, 3.382mmol) and iron powder (177mg, 3.175mmol) in the mixture of water (3mL), ethanol (6mL) and tetrahydrofuran (THF) (6mL) 90 ℃ under nitrogen atmosphere the heating 1 hour.This reaction is cooled to room temperature, with ethyl acetate (100mL) dilution, and water (3 * 50mL) and salt solution (50mL) wash.With the organic phase anhydrous sodium sulfate drying, filter, and concentrate by rotary evaporation in vacuo, obtained product, be light yellow solid (290mg, 90%).

Embodiment 161E

4-[4-(the 5-tertiary butyl-thiazol-2-yl formamyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

With the product of embodiment 8E (100.4mg, 0.4643mmol) and the product of embodiment 161D (288.2mg, 0.4643mmol) solution in acetate (6mL) is being preheated in 140 ℃ the oil bath and was stirring 1 hour.This reaction is cooled to room temperature,, concentrates by rotary evaporation with hexane (100mL) dilution, and with dichloromethane/hexane coevaporation (4 times).Resistates is dry under high vacuum, by the fast silica gel chromatogram purifying,, use 50% ethyl acetate/dichloromethane wash-out then then with 20% ethyl acetate/dichloromethane wash-out, obtained this title compound (125mg, 34%).

Embodiment 161F

(123.4mg, 0.1558mmol) 1, (13mg, the 0.3116mmol) solution-treated in water (2mL) is then 65 ℃ of heating 1 hour with lithium hydroxide monohydrate for the solution in the 4-dioxane (4mL) with the product of embodiment 161E in room temperature.This reaction is cooled to room temperature,, uses 1N hydrochloric acid with water pH regulator to 6, and separate each layer with ethyl acetate (100mL) and water (30mL) dilution.With the organic phase water (2 * 25mL) and salt solution (25mL) washing, use anhydrous sodium sulfate drying, filter, and concentrated by rotary evaporation in vacuo.By fast silica gel chromatogram purifying resistates,, obtained this title compound (58mg, 65%) with 4% ethanol/methylene wash-out. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.28(s，9H)1.34(d，J＝6.99Hz，6H)3.17-3.34(m，1H)5.64(s，2H)6.65(d，J＝8.46Hz，2H)6.80(s，1H)6.82(d，J＝8.46Hz，1H)7.16(d，J＝8.46Hz，2H)7.65(d，J＝8.46Hz，1H)7.88-7.98(dd，1H)8.11(s，1H)8.58(s，1H)8.89(d，J＝8.46Hz，1H)10.13(s，1H)12.47(s，1H)；MS(ESI+)m/z570(M+H) ⁺，(ESI-)m/z?568(M-H) ^-。

Embodiment 162

4-(4-amino-phenyl sulfenyl)-N-(3-fluoro-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-methyl-benzamide

Embodiment 162a

3-nitro-4-[4-(2,2,2-three chloro-ethoxy carbonyl amino)-phenyl sulfenyl]-phenylformic acid

(4.0g is 13.8mmol) at 75mL CH to 4-(4-amino-phenyl sulfenyl)-3-nitro-phenylformic acid in room temperature ₂Cl ₂In solution in via dripped in 10 minutes two (trimethyl silyl) ethanamide (6.73mL, 27.6mmol), with this reaction mixture stirring at room 1 hour.With pyridine (2.23mL 27.6mmol) is added in this reaction mixture, drip then the TROC-chloro-formic ester (2.04mL, 15.2mmol).Stir after 2 hours,,, use 1N HCl pH regulator to 3.0 with the dilution of 200mL water with this reaction mixture vacuum concentration.Decant goes out the aqueous solution, and resistates is placed CH ₂Cl ₂In, the gained yellow mercury oxide is filtered, obtained this title compound (5.14g, 80%).

Embodiment 162b

[4-(4-chloroformyl-2-nitro-phenyl sulfenyl)-phenyl]-carboxylamine 2,2,2-three chloro-ethyl esters

With the product of embodiment 162a (2.0g, 42.9mmol) reflux 3 hours in the thionyl chloride that contains 1 dimethyl formamide (10mL).Cooling and vacuum concentration, dried overnight under high vacuum.This title compound need not be further purified and directly use.

Embodiment 162c

(4-{4-[(3-fluoro-phenyl)-methyl-formamyl]-2-nitro-phenyl sulfenyl }-phenyl)-carboxylamine 2,2,2-three chloro-ethyl esters

With the product of embodiment 162b (0.25g, 0.516mmol) and (4-fluoro-phenyl)-methyl-amine (71mg, 0.568mmol) reflux 3 hours in toluene (20mL).After this solution cooling, with this reaction mixture vacuum concentration, obtained this title compound (295mg, 99% productive rate), be light yellow solid.

Embodiment 162d

(4-{2-amino-4-[(4-fluoro-phenyl)-methyl-formamyl]-the phenyl sulfenyl }-phenyl)-carboxylamine 2,2,2-three chloro-ethyl esters

According to the method for embodiment 9E, with product (295mg, 0.516mmol) usefulness Fe and the NH of embodiment 162c ₄This title compound that is obtained is isolated in the Cl reduction, is white solid (205mg, 73% productive rate).

Embodiment 162e

4-[4-[(4-fluoro-phenyl)-methyl-formamyl]-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

With the product of embodiment 162d (205.2mg, 0.3780mmol) and the product of embodiment 8E (81.8mg, 0.3780mmol) in 10mL acetate in 140 ℃ of heating 1 hour.This reaction mixture is cooled to room temperature, and vacuum concentration has then obtained the crude product of this title compound, it by the silica gel chromatography purifying, with the mixture wash-out of 4% methyl alcohol in methylene dichloride, is isolated this title compound that is obtained, be white solid (175mg, 65% productive rate).

Embodiment 162f

4-(4-amino-phenyl sulfenyl)-N-(4-fluoro-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-methyl-benzamide

With the product of embodiment 162d (70mg, 0.0980mmol) in THF (10mL) with 1N NaOH (1mL, 1.00mmol) reaction, and with this reaction mixture 55 ℃ of heating 1 hour.With this reaction mixture cooling, and vacuum concentration is to remove THF.With pH regulator to 6.0, remove formed precipitation with 1N HCl by vacuum filtration, and dry under high vacuum, obtained this title compound, be light yellow solid (45mg, 85% productive rate). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.32(d，J＝6.99Hz，6H)3.12-3.25(m，1H)3.34(s，3H)6.52-6.67(m，3H)6.94-7.11(m，5H)7.10-7.20(m，2H)7.20-7.41(m，2H)7.61(d，J＝8.46Hz，1H)8.51(s，1H)8.80(d，J＝8.09Hz，1H)10.10(s，1H)；MS(ESI)m/z?539(M+H)+。

Embodiment 163

4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(5-methyl-thiazol-2-yl)-benzamide

This title compound is the method according to embodiment 162, substitutes (4-fluoro-phenyl)-methyl-amine with 2-amino-5-methyl-thiazole and make in embodiment 162c.

Embodiment 164

4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(4-methyl-thiazol-2-yl)-benzamide

This title compound is the method according to embodiment 162, substitutes (4-fluoro-phenyl)-methyl-amine with 2-amino-4-methyl-thiazole and make in embodiment 162c.

Embodiment 165

Embodiment 165A

(4-{4-[(4-fluoro-phenyl)-methyl-formamyl]-2-nitro-phenyl sulfenyl }-phenyl)-carboxylamine 2,2,2-three chloro-ethyl esters

According to the method for embodiment 162c with the compound of embodiment 162b (250mg, 0.516mmol) with 4-fluoro-phenyl amine (71mg, 0.568mmol) reaction has obtained this title compound, it need not further be handled and directly use.

Embodiment 165B

With the product of embodiment 165A (295mg, 0.516mmol) according to the method for embodiment 9E with Fe and NH ₄The Cl reduction has obtained this title compound (205mg, 73% productive rate).

Embodiment 165C

With the product of embodiment 8E (48mg, 0.221mmol) and the product of embodiment 165B (120mg, 0.221mmol) merging in acetate (6mL), and method is reacted described in 614E, obtained this title compound, be light yellow solid (83mg, 54%).

Embodiment 165D

(83mg 0.1162mmol) reacts with method described in NaOH such as the embodiment 162f, has obtained this title compound 617D (46mg, 74%), is yellow solid with the product of embodiment 165C.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.32(d，J＝6.99Hz，6H)3.12-3.25(m，1H)3.34(s，3H)6.52-6.67(m，3H)6.94-7.11(m，5H)7.10-7.20(m，2H)7.20-7.41(m，2H)7.61(d，J＝8.46Hz，1H)8.51(s，1H)8.80(d，J＝8.09Hz，1H)10.10(s，1H)；MS(ESI)m/z?539(m+H)+。

Embodiment 166

4-[2-amino-4-([1,3,4] thiadiazoles-2-base formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

Embodiment 166A

4-[2-nitro-4-([1,3,4] thiadiazoles-2-base formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

(300mg is 0.6197mmol) with [1,3,4] thiadiazoles-(62mg 0.6197mmol) reacts in toluene (10mL) method described in embodiment 162c 2-base amine, has obtained this title compound (340mg, 100% productive rate) with the product of embodiment 162b.

Embodiment 166B

With the product of embodiment 166A (340mg, 0.6197mmol) according to the method for embodiment 9E with Fe and NH ₄The Cl reduction has obtained this title compound (231mg, 72% productive rate), is white solid.1H?NMR(300MHz，DMSO-D6)δ?ppm：4.94(s，2H)5.59(s，2H)7.14-7.35(m，4H)7.42(s，1H)7.50(d，J＝8.46Hz，2H)9.22(s，1H)10.26(s，1H)；MS(ESI)m/z?520(M+H)+。

Embodiment 167

4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(3-methyl-isothiazole-5-yl)-benzamide

Embodiment 167A

4-[4-(3-methyl-isothiazole-5-base formamyl)-2-nitro-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

Product (290mg with embodiment 19C, 0.546mmol) solution in anhydrous tetrahydro furan (5mL) is with 5-amino-3-methyl isoniazthiolane hydrochlorate (90.5mg, 0.6008mmol) and diisopropylethylamine (0.238mL, 1.365mmol) handle, and stirred 18 hours under nitrogen atmosphere in room temperature.Should react with ethyl acetate (100mL) dilution, with saturated sodium bicarbonate aqueous solution (25mL), water (2 * 25mL) and salt solution (25mL) washing.With the organic phase anhydrous sodium sulfate drying, filter, and vacuum concentration, obtained this title compound (202mg, 61%).

Embodiment 167B

4-[2-amino-4-(3-methyl-isothiazole-5-base formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

Product (200mg with embodiment 167A, 0.328mmol), ammonium chloride (115mg, 2.152mmol) and iron powder (113mg, 2.021mmol) in the mixture of water (2mL), ethanol (4mL) and tetrahydrofuran (THF) (4mL) 90 ℃ under nitrogen atmosphere the heating 1 hour.This reaction is cooled to room temperature, with ethyl acetate (50mL) dilution, and water (3 * 50mL) and salt solution (50mL) wash.With the organic phase anhydrous sodium sulfate drying, filter, and concentrate by rotary evaporation in vacuo.By the silica gel chromatography purifying, with 5% ethanol/methylene wash-out, obtained product, be golden solid (114mg, 60%).

Embodiment 167C

4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(3-methyl-isothiazole-5-base formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

With the product of embodiment 8E (42mg, 0.1939mmol) and the product of embodiment 167B (112.2mg, 0.1939mmol) solution in acetate (4mL) is being preheated in 140 ℃ the oil bath and was stirring 1 hour.This reaction is cooled to room temperature,, concentrates by rotary evaporation with hexane (100mL) dilution, and with dichloromethane/hexane coevaporation (4 times).Resistates is dry under high vacuum, by the silica gel chromatography purifying,, use 4% ethanol/methylene wash-out then then with 30% ethyl acetate/dichloromethane wash-out, obtained this title compound (119mg, 82%).

Embodiment 167D

(117mg, 0.156mmol) 1, (13.1mg, the 0.312mmol) solution-treated in water (2mL) is then 70 ℃ of heating 1 hour with lithium hydroxide monohydrate for the solution in the 4-dioxane (4mL) with the product of embodiment 167C in room temperature.This reaction is cooled to room temperature, and with ethyl acetate (50mL) and water (25mL) dilution, with 1N hydrochloric acid water layer being adjusted to pH is 5, and separates each layer.With organic phase with washing water (2 * 25mL) and salt solution (25mL), use anhydrous sodium sulfate drying, filtration, and concentrated by rotary evaporation in vacuo.By silica gel chromatography purifying resistates, with 5% ethanol/methylene wash-out, obtained this title compound, be light yellow solid (58.5mg, 71%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.34(d，J＝6.99Hz，6H)2.33(s，3H)3.14-3.30(m，1H)5.63(s，2H)6.65(d，J＝8.46Hz，2H)6.87(s，1H)6.91(d，J＝8.82Hz，1H)7.15(d，J＝8.46Hz，2H)7.65(d，J＝8.09Hz，1H)7.86(d，J＝7.72Hz，1H)8.03(s，1H)8.59(s，1H)8.89(d，J＝8.09Hz，1H)10.19(s，1H)12.17(s，1H)；MS(ESI+)m/z528(M+H) ⁺，(ESI-)m/z?526(M-H) ^-。

Embodiment 168

4-[4-[1-(3-bromo-phenyl)-oxyethyl group]-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol

Embodiment 168a

1-(1-bromo-ethyl)-4-fluoro-benzene

To 1-(3-bromo-phenyl)-ethanol (7.0g, 34.0mmol) drip in the solution in methylene dichloride (40mL) phosphorus tribromide (77g, 34.0mmol).With mixture stirring at room 16 hours.Pour this reaction into ice/waterborne.With sodium bicarbonate water is alkalized.With the water dichloromethane extraction.With organic phase water, salt water washing, and use dried over sodium sulfate, filter and vacuum concentration, obtained this title compound (7.8g, 80%).

Embodiment 168b

4-[1-(3-bromo-phenyl)-oxyethyl group]-1-chloro-2-nitro-benzene

To the product of the embodiment 168a in DMF (50mL) (7.8g, add in 30mmol) 4-chloro-3-nitro-phenol (5.14g, 30.0mmol) and K ₂CO ₃(8.18g, 60mmol).This mixture was heated 16 hours at 80 ℃.Should react the cooling and pour in the water.Water with ethyl acetate extraction (2 *), with phase water, the salt water washing that merges, and is used dried over sodium sulfate. with the organic phase concentrating under reduced pressure.Resistates by silica gel chromatography purifying (with hexane/ethyl acetate 90:10 wash-out), has been obtained this title compound (7.0g, 66%).

Embodiment 168c

4-{4-[1-(3-bromo-phenyl)-oxyethyl group]-2-nitro-phenyl sulfenyl }-phenol

To the product of the embodiment 168b in DMF (50mL) (5.0g, add in 14.0mmol) the 4-mercapto-phenol (1.7g, 14.0mmol) and K ₂CO ₃(3.8g, 28mmol).This mixture was heated 16 hours at 80 ℃.Should react the cooling and pour in the water.With ethyl acetate extraction (2 *), and the phase water that will merge, salt water washing are used dried over sodium sulfate with water.With the organic phase concentrating under reduced pressure.Resistates by silica gel chromatography purifying (with hexane/ethyl acetate/methyl alcohol 75:15:5 wash-out), has been obtained this title compound (5.2g, 83%).

Embodiment 168d

4-{2-amino-4-[1-(3-bromo-phenyl)-oxyethyl group]-the phenyl sulfenyl }-phenol

(5.4g is 12.2mmol) with Fe and NH with the product of embodiment 168c according to the method for embodiment 9E ₄Cl handles, and has obtained this title compound (3.6g, 76%).

Embodiment 168e

In sealed tube with the product (125mg of embodiment 29A, 0.72mmol) with the product (298mg of embodiment 168d, 0.72mmol) in acetate (10mL), reacted 5 minutes in 125 ℃, obtained the crude product of this title compound, by using the HPLC purifying of TFA, obtained product, be trifluoroacetic acid (120mg, 31%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.54(d，J＝6.25Hz，3H)5.52(q，J＝6.25Hz，1H)6.66(d，J＝8.82Hz，2H)6.85(s，1H)7.07-7.12(m，3H)7.19(s，1H)7.32(t，J＝7.72Hz，1H)7.39-7.49(m，2H)7.61(s，2H)8.57(s，1H)8.80(s，1H) 9.06(s，1H)9.65(s，1H)；MS(ESI-)m/z?545(M-H)-。

Embodiment 169

4-[4-(5-fluoro-pyridine-2-base formamyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

Use the method for embodiment 100D, product with the product alternate embodiment 100C of embodiment 174A, the product of embodiment 174A and the product of embodiment 8E are reacted, obtained crude product, it is passed through the silica gel chromatography purifying, with the mixture wash-out of 2% methyl alcohol in methylene dichloride, obtained this title compound (127mg, 55%). ¹H?NMR(300MHz，DMS0-d ₆)δppm：1.34(d，J＝6.99Hz，6H)3.13-3.28(m，1H)4.97(s，2H)7.00(d，J＝8.09Hz，1H)7.43(d，J＝8.82Hz，2H)7.63(d，J＝8.82Hz，1H)7.60(d，J＝8.46Hz，2H)7.79(dt，J＝8.73，3.13Hz，1H)7.89(d，J＝8.82Hz，1H)8.10(s，1H)8.20(dd，J＝8.82，3.68Hz，1H)8.39(d，J＝2.94Hz，1H)8.59(s，1H)8.86(d，J＝8.46Hz，1H)10.21(s，1H)10.40(s，1H)10.91(s，1H)。

Embodiment 170

4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(5-trifluoromethyl-pyridine-2-base formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

Use the method for embodiment 100D, product with the product alternate embodiment 100C of embodiment 175A, the product of embodiment 175A and the product of embodiment 8E are reacted, obtained crude product, by the silica gel chromatography purifying, with the mixture wash-out of 2% methyl alcohol in methylene dichloride, obtained this title compound. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.34(d，J＝6.62Hz，6H)3.08-3.29(m，1H)4.97(s，2H)7.00(d，J＝8.46Hz，1H)7.44(d，J＝8.82Hz，2H)7.51-7.70(m，3H)7.92(d，J＝9.56Hz，1H)8.12(s，1H)8.23(dd，J＝9.01，2.02Hz，1H)8.39(d，J＝9.19Hz，1H)8.59(s，1H)8.77(s，1H)8.86(d，J＝8.46Hz，1H)10.22(s，1H)10.41(s，1H)11.26(s，1H)。

Embodiment 171

4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(5-methyl-pyridine-2-base formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

Use the method for embodiment 100D, product with the product alternate embodiment 100C of embodiment 173A, the product of embodiment 173A and the product of embodiment 8E are reacted, obtained crude product, by the silica gel chromatography purifying, with the mixture wash-out of 2% methyl alcohol in methylene dichloride, obtained this title compound. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.34(d，J＝6.99Hz，6H)2.27(s，3H)3.14-3.29(m，J＝9.19Hz，1H)4.97(s，2H)6.99(d，J＝8.46Hz，1H)7.43(d，J＝8.46Hz，2H)7.53-7.78(m，J＝8.09，2.21Hz，2H)7.59(d，J＝8.46Hz，2H)7.90(d，J＝7.72Hz，1H)8.06(d，J＝8.46Hz，1H)8.10(s，1H)8.20(d，J＝2.21Hz，1H)8.59(s，1H)8.86(d，J＝8.46Hz，1H)10.20(s，1H)10.40(s，1H)10.69(s，1H)。

Embodiment 172

4-(4-amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(4-trifluoromethyl-phenyl)-benzamide

Embodiment 172a

4-fluoro-3-nitro-Benzoyl chloride

This title compound makes like this: (1.00g 5.40mmol) is dissolved in the ethylene dichloride (25mL), adds SOCl with 4-fluoro-3-nitro-phenylformic acid ₂(6.427g, 54.02mmol).80 ℃ of heating 12 hours, vacuum was removed all solvents then with this mixture, and described oily crude product directly carries out later use (1.10g, 100%) without purifying.

Embodiment 172b

4-fluoro-3-nitro-N-(4-trifluoromethyl-phenyl)-benzamide

This title compound makes like this: (475mg 2.95mmol) is dissolved among the THF (20ml) with 4-trifluoromethyl-phenyl amine in room temperature.In this solution, add Hunig ' s alkali (762mg, 5.86mmol), then via the product (600mg, 2.95mmol) solution in THF (10mL) that dripped embodiment 172a in 5 minutes.Add finish after, this reaction mixture stirring at room 1 hour, and is poured in the water, collect this title compound (900mg, 93%) by filtering.

Embodiment 172c

4-[2-nitro-4-(4-trifluoromethyl-phenyl amino formyl radical)-phenoxy group]-phenyl }-t-butyl carbamate

With the product of embodiment 172b (215mg 0.655mmol) is dissolved among the DMSO (30ml), to wherein add KOH (75mg, 1.31mmol) and (4-hydroxyl-phenyl)-t-butyl carbamate (137mg, 0.655mmol).Then this reaction mixture was heated 2 hours at 80 ℃, this reaction mixture is cooled to room temperature, dilute with water, and by filtering collection this title compound (240mg, 78%).

Embodiment 172d

4-[2-amino-4-(4-trifluoromethyl-phenyl amino formyl radical)-phenoxy group]-phenyl }-t-butyl carbamate

According to the method for embodiment 9E product and Fe and NH with embodiment 172c ₄The Cl reaction has obtained this title compound (204mg, 90%).

Embodiment 172e

4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-trifluoromethyl-phenyl amino formyl radical)-phenoxy group]-phenyl }-t-butyl carbamate

With the product of embodiment 8E (100mg, 0.462mmol) and the product of embodiment 172d (204mg 0.462mmol) is dissolved among the HOAc, places 10 minutes in the oil bath of 120 ℃ of preheatings.Remove under nitrogen gas stream and desolvate, gained oily crude product directly carries out use subsequently without purifying.

Embodiment 172f

The product of embodiment 172e is dissolved in the 1:1 mixture of TFA in DCM, and stirring at room 2 hours.Solvent removed in vacuo by using the HPLC purifying of TFA, has obtained product with the oily crude product, is trifluoroacetate (85mg, 36%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.75(d，J＝6.99Hz，6H)，7.21(d，J＝8.09Hz，2H)，7.29-7.35(m，2H)，7.38(d，J＝8.82Hz，1H)，8.14(d，J＝8.82Hz，2H)，8.25(d，J＝8.46Hz，1H)，8.40(d，J＝8.46Hz，3H)，8.56(d，J＝1.84Hz，1H)，9.26(s，1H)，9.37(d，J＝8.82Hz，1H)，10.98(s，1H)；MS(ESI+)m/z?559(M+TFA+H)+；(ESI-)m/z?557(M+TFA-H)-。

Embodiment 173

4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(5-methyl-pyridine-2-yl)-benzamide

Embodiment 173A

4-[2-amino-4-(5-methyl-pyridine-2-base formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

Use the method for embodiment 10A; the product of 2-amino-5-picoline and the product of embodiment 162e are reacted; obtained 4-[4-(5-methyl-pyridine-2-base formamyl)-2-nitro-phenyl sulfenyl]-phenyl }-carboxylamine 2; 2; 2-three chloro-ethyl esters; it is reacted according to the condition of describing among the embodiment 100C, obtained this title product.

Embodiment 173B

Use the method for embodiment 100D, product with the product alternate embodiment 100C of embodiment 173A, the product of embodiment 173A and the product of embodiment 8E are reacted, obtained crude product, by the silica gel chromatography purifying, with the mixture wash-out of 2% methyl alcohol in methylene dichloride, obtained this title compound.

Embodiment 173C

In the solution of product in tetrahydrofuran (THF) and water (1:1) of embodiment 173B., add 1MNaOH (5 equivalent).60 ℃ of heating 40 minutes, cooling was adjusted to pH6 with 1N hydrochloric acid, and uses ethyl acetate extraction with this solution.With the extraction liquid dried over mgso that merges, filter and vacuum concentration.Crude product by the silica gel chromatography purifying, with the mixture wash-out of 4% methyl alcohol in methylene dichloride, has been obtained this title compound. ¹H?NMR(300MHz，DMSO-d ₆)δppm：1.34(d，J＝6.99Hz，6H)2.27(s，3H)3.14-3.29(m，1H)5.62(s，2H)6.64(d，J＝8.09Hz，2H)6.82(d，J＝8.46Hz，1H)7.15(d，J＝8.09Hz，2H)7.64(d，J＝8.46Hz，2H)7.87(dd，J＝8.27，1.29Hz，1H)7.97-8.11(m，2H)8.19(s，1H)8.32(s，1H)8.50-8.61(m，1H)8.89(d，J＝8.82Hz，1H)10.12(s，1H)10.63(s，1H)。

Embodiment 174

4-(4-amino-phenyl sulfenyl)-N-(5-fluoro-pyridine-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 174A

4-[2-amino-4-(5-fluoro-pyridine-2-base formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

Use the method for embodiment 10A; 2-amino-mixture of 5-fluorine pyridine and the product of embodiment 162e is convenient; obtained 4-[4-(5-fluoro-pyridine-2-base formamyl)-2-nitro-phenyl sulfenyl]-phenyl }-carboxylamine 2; 2; 2-three chloro-ethyl esters; it is reacted according to the condition of describing among the embodiment 100C, obtained this title product.

Embodiment 174B

The product of embodiment 174A and the product of embodiment 8E are reacted, use the method for embodiment 100D, product with the product alternate embodiment 100C of embodiment 174A, obtained crude product, it is passed through the silica gel chromatography purifying, with the mixture wash-out of 2% methyl alcohol in methylene dichloride, obtained this title compound (127mg, 55%).

Embodiment 174C

In the solution of product in tetrahydrofuran (THF) and water (1:1) of embodiment 174B, add 1MNaOH (5 equivalent).60 ℃ of heating 40 minutes, cooling was adjusted to pH6 with 1N hydrochloric acid, and uses ethyl acetate extraction with this solution.With the extraction liquid dried over mgso that merges, filter and vacuum concentration.The gained resistates by the silica gel chromatography purifying, with the mixture wash-out of 2% methyl alcohol in methylene dichloride, has been obtained this title compound. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.34(d，J＝6.99Hz，6H)3.15-3，29(m，J＝6.89，6.89，6.89，6.89Hz，1H)5.62(s，2H)6.65(d，J＝8.46Hz，2H)6.83(d，J＝8.46Hz，1H)7.15(d，J＝8.46Hz，2H)7.64(d，J＝8.46Hz，1H)7.79(dt，J＝8.64，2.94Hz，1H)7.87(dd，J＝8.46，1.84Hz，1H)8.04(d，J＝1.84Hz，1H)8.20(dd，J＝9.19，4.04Hz，1H)8.38(d，J＝2.94Hz，1H)8.58(s，1H)8.89(d，J＝8.46Hz，1H)10.13(s，1H)10.85(s，1H)。

Embodiment 175

4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(5-trifluoromethyl-pyridine-2-yl)-benzamide

Embodiment 175A

4-[2-amino-4-(5-trifluoromethyl-pyridine-2-base formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

Use the method for embodiment 10A; the mixture of 2-amino-5-5-flumethiazine and the product of embodiment 162e are reacted; obtained 4-[2-nitro-4-(5-trifluoromethyl-pyridine-2-base formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 2; 2; 2-three chloro-ethyl esters; it is reacted according to the condition of describing among the embodiment 100C, obtained this title product.

Embodiment 175B

Use the method for embodiment 100D, product with the product alternate embodiment 100C of embodiment 175A, the product of embodiment 175A and the product of embodiment 8E are reacted, obtained crude product, by the silica gel chromatography purifying, with the mixture wash-out of 2% methyl alcohol in methylene dichloride, obtained this title compound.

Embodiment 175C

In the solution of product in tetrahydrofuran (THF) and water (1:1) of embodiment 175B, add 1MNaOH (5 equivalent).60 ℃ of heating 40 minutes, cooling was adjusted to pH6 with 1N hydrochloric acid, and uses ethyl acetate extraction with this solution.With the extraction liquid dried over mgso that merges, filter and vacuum concentration.Crude product by the silica gel chromatography purifying, with the mixture wash-out of 2% methyl alcohol in methylene dichloride, has been obtained this title compound. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.34(d，J＝6.62Hz，6H)3.15-3.29(m，1H)5.63(s，2H)6.65(d，J＝8.46Hz，2H)6.84(d，J＝8.46Hz，1H)7.16(d，J＝8.46Hz，2H)7.64(d，J＝8.46Hz，1H)7.90(d，J＝6.99Hz，1H)8.06(s，1H)8.23(dd，J＝8.82，1.47Hz，1H)8.39(d，J＝8.82Hz，1H)8.59(s，1H)8.76(s，1H)8.89(d，J＝8.46Hz，1H)10.14(s，1H)11.20(s，1H)。

Embodiment 176

4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(4-methoxyl group-phenyl)-benzamide

This title compound is the method according to embodiment 174, substitutes 2-amino-5-fluorine pyridine with the 4-anisidine and make in embodiment 174a.

Embodiment 177

4-(4-amino-phenyl sulfenyl)-N-cyclohexyl-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 177A

4-[4-cyclohexyl carboxyamide base-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl] phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

Under nitrogen atmosphere with the product (50mg of embodiment 162b, 0.0824mmol) be dissolved in anhydrous N, in the dinethylformamide (1.5mL), and with cyclo-hexylamine (8.2mg, 0.0824mmol), 3-(diethoxy phosphoryl oxy)-1,2,3-phentriazine-4 (3H)-ketone (49.3mg, 0.1648mmol) and triethylamine (0.034mL, 0.2472mmol) processing.This was reflected at stirring at room 16 hours, and removes by rotary evaporation in vacuo and to desolvate.Should react with ethyl acetate (50mL) dilution, and with 10% aqueous sodium carbonate (2 * 25mL), water (25mL) and salt solution (25mL) washs.With the organic layer anhydrous sodium sulfate drying, filter, and concentrate by rotary evaporation in vacuo.By silica gel chromatography purifying resistates,, obtained this title compound (45mg, 79%) with 4% ethanol/methylene wash-out.

Embodiment 177B

Product (43mg with embodiment 177A, 0.0625mmol) 1, solution in the 4-dioxane (2mL) sodium hydroxide (6.2mg, 0.156mmol) solution-treated in water (1mL), and 60 ℃ of heating 30 minutes, then this reaction is cooled to room temperature, and dilutes with ethyl acetate (50mL) and water (25mL).With the pH regulator to 5 of 1N hydrochloric acid with water layer, separate each layer, and with organic phase water (2 * 25mL) and salt solution (25mL) washing.With the organic extract liquid anhydrous sodium sulfate drying, filter, and concentrate by rotary evaporation in vacuo.With 4% ethanol/methylene wash-out, obtained this title compound by silica gel chromatography purifying resistates, be white solid (16mg, 50%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.00-1.37(m，5H)1.34(d，J＝6.99Hz，6H)1.50-1.65(m，1H)1.65-1.89(m，4H)3.15-3.31(m，1H)3.64-3.81(m，1H)5.57(s，2H)6.61(d，J＝8.46Hz，2H)6.82(d，J＝8.46Hz，1H)7.11(d，J＝8.46Hz，2H)7.59-7.71(m，2H)7.82(d，J＝1.84Hz，1H)8.13(d，J＝7.72Hz，1H)8.56(s，1H)8.86(d，J＝8.46Hz，1H)10.11(s，1H)；MS(ESI+)m/z513(M+H) ⁺，(ESI-)m/z?511(M-H) ^-。

Embodiment 178

4-(4-amino-3-fluoro-phenoxy group)-N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

This title compound is according to the Troc method among embodiment 100 A-C, substitutes the 4-amino-phenol with 4-amino-3-fluorophenol and makes.Crude product by silica gel chromatography purifying (mixture of 3% methyl alcohol in methylene dichloride), has been obtained this title compound (0.11g, 65%). ¹H?NMR(300?MHz，DMSO-d ₆)δ?ppm：1.32(d，J＝6.62Hz，6H)，3.14-3.27(m，1H)，5.04(s，2H)，6.45-6.86(m，3H)，6.94(d，J＝8.82Hz，1H)，7.53(d，J＝8.82Hz，2H)，7.60(d，J＝8.46Hz，1H)，7.76(d，J＝8.82Hz，2H)，7.88(dd，J＝8.64，2.02Hz，1H)，8.16(d，J＝1.84Hz，1H)，8.61(s，1H)，8.81(d，J＝8.46Hz，1H)，10.01(s，1H)，10.32(s，1H)；MS(ESI+)m/z?587(M+H) ⁺。

Embodiment 179

[4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-(2,6-dimethyl-morpholine-4-yl)-ketone

Embodiment 179A

4-[4-(2,6-dimethyl-morpholine-4-carbonyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl] phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

Under nitrogen atmosphere with the product (75mg of embodiment 162b, 0.1236mmol) be dissolved in anhydrous N, in the dinethylformamide (2mL), and with cis-2, and the 6-thebaine (16.1mg, 0.1359mmol), 3-(diethoxy phosphoryl oxy)-1,2,3-phentriazine-4 (3H)-ketone (74mg, 0.2472mmol) and triethylamine (0.052mL 0.3707mmol) handles.This was reflected at stirring at room 16 hours, uses ethyl acetate (50mL) dilution then, and with 10% aqueous sodium carbonate (2 * 25mL), water (25mL) and salt solution (25mL) washs.With the organic phase anhydrous sodium sulfate drying, filter, and concentrate by rotary evaporation in vacuo.By silica gel chromatography purifying resistates, with 3% ethanol/methylene wash-out, obtained this title compound, be light yellow solid (58mg, 67%).

Embodiment 179B

(56mg, 0.0795mmol) 1, the solution in the 4-dioxane (2mL) is with sodium hydroxide (8mg, the 0.1988mmol) solution-treated in water (1mL), and 60 ℃ of heating 30 minutes with the product of embodiment 179A.Then this reaction is cooled to room temperature, and dilutes with ethyl acetate (50mL) and water (25mL).With the pH regulator to 5 of 1N hydrochloric acid with water layer, separate each layer, and with organic phase water (2 * 25mL) and salt solution (25mL) washing.With the organic extract liquid anhydrous sodium sulfate drying, filter, and concentrate by rotary evaporation in vacuo.By fast silica gel chromatogram purifying resistates, use 5% ethanol/methylene, obtained this title compound, be pale solid (18mg, 43%). ¹H?NMR(300MHz，DMSO-d ₆/TFA)δ?ppm：0.91-1.25(m，6H)1.37(d，J＝6.99Hz，6H)2.70-2.97(m，1H)3.25-3.40(m，1H)3.45-3.64(m，4H)4.20-4.52(m，1H)5.72(s，2H)7.29(d，J＝8.09Hz，1H)7.35(d，J＝8.46Hz，2H)7.48(dd，J＝7.91，2.02Hz，1H)7.50(d，J＝8.45Hz，2H)7.60(d，J＝1.84Hz，1H)7.96(d，J＝8.82Hz，1H)8.97(s，1H)9.07(d，J＝8.82Hz，1H)；MS(ESI+)m/z?529(M+H) ⁺，(ESI-)m/z?527(M-H) ^-。

Embodiment 180

4-[4-(the 5-tertiary butyl-[1,3,4] thiadiazoles-2-base formamyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

Use the method for embodiment 100D, product with the product alternate embodiment 100C of embodiment 181A, the product of embodiment 181A and the product of embodiment 8E are reacted, obtained crude product, it is passed through the silica gel chromatography purifying, with the mixture wash-out of 2% methyl alcohol in methylene dichloride, obtained this title compound (160mg, 50%). ¹H?NMR(300MHz，DMSO-d ₆)δppm：1.34(d，J＝6.99Hz，6H)1.41(s，9H)4.97(s，2H)7.00(d，J＝8.46Hz，1H)7.44(d，J＝8.46Hz，2H)7.55-7.71(m，J＝11.40，8.46Hz，3H)7.96(dd，J＝8.09，2.21Hz，1H)8.15(d，J＝1.10Hz，1H)8.59(s，1H)8.86(d，J＝8.46Hz，1H)10.23(s，1H)10.42(s，1H)12.89(s，1H)。

Embodiment 181

4-(4-amino-phenyl sulfenyl)-N-(the 5-tertiary butyl-[1,3,4] thiadiazoles-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 181A

4-[2-amino-4-(the 5-tertiary butyl-[1,3,4] thiadiazoles-2-base formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

Use the method for embodiment 10A; with the 5-tertiary butyl-[1; 3,4] thiadiazoles-mixture of 2-base amine and the product reaction of embodiment 162e have obtained { 4-[4-(the 5-tertiary butyl-[1; 3; 4] thiadiazoles-2-base formamyl)-2-nitro-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters; it is reacted according to the condition of describing among the embodiment 100C, obtained this title product.

Embodiment 181B

Use the method for embodiment 100D, product with the product alternate embodiment 100C of embodiment 181A, the product of embodiment 181A and the product of embodiment 8E are reacted, obtained crude product, it is passed through the silica gel chromatography purifying, with the mixture wash-out of 2% methyl alcohol in methylene dichloride, obtained this title compound (160mg, 50%).

Embodiment 181C

In the solution of product in tetrahydrofuran (THF) and water (1:1) of embodiment 181B, add 1MNaOH (5 equivalent).60 ℃ of heating 40 minutes, cooling was adjusted to pH6 with 1N hydrochloric acid, and uses ethyl acetate extraction with this solution.With the extraction liquid dried over mgso that merges, filter and vacuum concentration. the gained resistates by the silica gel chromatography purifying, with the mixture wash-out of 4% methyl alcohol in methylene dichloride, has been obtained this title compound. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.34(d，J＝6.62Hz，6H)1.41(s，9H)3.16-3.30(m，1H)5.64(s，1H)6.65(d，J＝8.46Hz，2H)6.85(d，J＝8.46Hz，1H)7.15(d，J＝8.46Hz，2H)7.65(d，J＝8.46Hz，1H)7.94(dd，J＝8.46，1.84Hz，1H)8.10(d，J＝1.47Hz，1H)8.59(s，1H)8.89(d，J＝8.82Hz，1H)10.15(s，1H)12.85(s，1H)。

Embodiment 182

4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-styroyl formamyl-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

Product (60mg to the embodiment 162a in the 3mL dry DMF, 0.1mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (19mg, 0.1mmol), I-hydroxybenzotriazole hydrate (13.5mg, 0.1mmol) and 4-dimethylaminopyridine (12mg, 0.1mmol) middle adding phenylethylamine (36mg, 0.3mmol).After 18 hours, should react dilute with water in room temperature,, and be extracted in the ethyl acetate with 1N HCl neutralization.Ethyl acetate is used MgSO mutually ₄Drying is filtered and vacuum concentration.Crude product by the silica gel chromatography purifying, with the mixture wash-out of 4% methyl alcohol in methylene dichloride, has been obtained this title compound. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.33(d，J＝6.99Hz，6H)2.82(t，J＝7.35Hz，2H)3.15-3.28(m，1H)3.41-3.53(m，2H)4.96(s，2H)7.01(d，J＝8.46Hz，1H)7.15-7.33(m，6H)7.38(d，J＝8.46Hz，2H)7.56(d，J＝8.46Hz，2H)7.65(dd，J＝15.81，8.82Hz，1H)7.86(s，1H)8.58(s，2H)8.83(d，J＝8.46Hz，1H)10.18(s，1H)10.37(s，1H)。

Embodiment 183

4-[4-(4-bromo-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 3-dimethylamino-2-hydroxyl-propyl diester

With the product of embodiment 100 (76mg, 0.1mmol), 3-dimethylamino-the third-1, the 2-glycol (59 μ L, 0.5mmol) and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (15 μ L, 0.1mmol) in tetrahydrofuran (THF) (5mL) in 60 ℃ of heating 1 hour.In this mixture, add saturated sodium carbonate, use ethyl acetate extraction, use dried over mgso, filter and evaporation.Resistates by using the anti-phase preparation HPLC method purifying of TFA, has been obtained this title compound, be trifluoroacetate (42mg, 43%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.36(d，J＝6.99Hz，6H)2.80(d，J＝4.41Hz，3H)2.84(d，J＝4.41Hz，3H)3.15(m，2H)3.28(m，1H)4.10(m，3H)7.08(d，J＝8.09Hz，1H)7.41(d，J＝8.82Hz，2H)7.54(m，4H)7.72(d，J＝8.82Hz，2H)7.89(m，2H)7.99(s，1H)8.87(s，1H)9.00(d，J＝8.46Hz，1H)9.33(s，1H)10.01(s，1H)10.40(s，1H)11.70(s，1H)；MS(ESI+)m/z?730?732(M+H)+。

Embodiment 184

4-[4-(4-bromo-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 3-amino-propyl diester

Product (76mg with embodiment 100,0.1mmol), (3-hydroxyl-propyl group)-t-butyl carbamate (85 μ L, 0.5mmol) and 1, (15 μ L 0.1mmol) heated 1 hour in 60 ℃ in tetrahydrofuran (THF) (5mL) 8-diazabicylo [5.4.0] 11 carbon-7-alkene.In this mixture, add saturated sodium carbonate, use ethyl acetate extraction, use dried over mgso, filter and evaporation.Resistates is added in methylene dichloride (2mL) and the trifluoroacetic acid (2mL), and stirring at room 1 hour.With solvent evaporation, and, obtained this title compound, be trifluoroacetate (56mg, 61%) the anti-phase preparation HPLC method purifying of resistates by use TFA. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.35(d，J＝6.99Hz，6H)1.90(m，2H)2.91(m，2H)3.27(m，1H)4.16(t，J＝6.43Hz，2H)7.06(d，J＝8.46Hz，1H)7.40(d，J＝8.82Hz，2H)7.52(m，4H)7.77(m，7H)7.98(s，1H)8.76(s，1H)8.93(d，J＝8.46Hz，1H)9.90(s，1H)10.38(s，1H)11.28(s，1H)；MS(ESI+)m/z?686?688(M+H)+。

Embodiment 185

4-(4-amino-phenyl sulfenyl)-N-(4-chloro-2,6-dimethyl-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 185A

4-[4-(4-chloro-2,6-dimethyl-phenyl amino formyl radical)-2-nitro-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

With the product of embodiment 162b (300mg, 0.6197mmol) and 4-chloro-2,6-dimethyl-phenyl amine (119mg, 0.6197mmol) in toluene (10mL), merge, and react described in embodiment 162c, obtained this title compound, it need not further be handled and directly use.

Embodiment 185B

4-[2-amino-4-(4-chloro-2,6-dimethyl-phenyl amino formyl radical)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

According to the method for embodiment 9E with the product among the embodiment 185A with Fe and NH ₄The Cl reduction has obtained this title compound (253mg, the productive rate of process step 640A and 640B is 71%), is pale solid.

Embodiment 185C

4-[4-(4-chloro-2,6-dimethyl-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

Product (67mg with embodiment 8E, 0.3097mmol) and the product of embodiment 185B (166mg 0.3097mmol) merges in acetate (10mL), and as described in embodiment 162e, react, obtained this title compound (126mg, 55% productive rate).

Embodiment 185D

(126mg 0.309mmol) uses the NaOH deprotection, has obtained this title compound (119mg, 68%), is pale solid with the product of embodiment 185C according to the method for describing among the embodiment 162f. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.34(d，J＝6.99Hz，6H)2.15(s，6H)3.09-3.32(m，1H)6.63(d，J＝8.82Hz，2H)6.89(d，J＝8.46Hz，1H)7.14(d，J＝8.82Hz，2H)7.18-7.34(m，3H)7.57-7.76(m，1H)7.84(d，J＝7.35Hz，1H)7.92(s，1H)8.51-8.75(m，1H)8.91(d，J＝7.72Hz，1H)9.77(s，1H)10.62(s，1H)；MS(ESI)m/z?570(M+H)+。

Embodiment 186

4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(5-methyl-[1,3,4] thiadiazoles-2-yl)-benzamide

Embodiment] 86A

4-[4-(5-methyl-[1,3,4] thiadiazoles-2-base formamyl)-2-nitro-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

With the product of embodiment 162b (300mg, 0.6197mmol) and 5-methyl-[1,3,4] thiadiazoles-2-base amine (71mg, 0.6197mmol) solution in toluene (10mL) is as reacting described in embodiment 162c, obtained this title compound, is yellow powder.

Embodiment 186B

4-[2-amino-4-(5-methyl-[1,3,4] thiadiazoles-2-base formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

According to the method for embodiment 9E with the product among the embodiment 186A (0.6197mmol) with Fe and NH ₄The Cl reduction has obtained this title compound (254mg, 77%), is solid.

Embodiment 186C

4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino) 4-(5-methyl-[1,3,4] thiadiazoles-2-base formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

With the product of embodiment 8E (67mg, 0.3097mmol) and the product of embodiment 186B (150mg 0.2815mmol) merges in acetate (5mL), and as reacting described in embodiment 162e, has obtained this title compound (134mg, 68%).

Embodiment 187

4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-[1,3,4] thiadiazoles-2-base-benzamide

Embodiment 187A

4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-([1,3,4] thiadiazoles-2-base formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

With the product of embodiment 8E (68mg, 0.3180mmol) and the product of embodiment 166B (150mg 0.2891mmol) merges in acetate (10mL), and as reacting described in embodiment 162e, has obtained this title compound (52mg, 26%).

Embodiment 187B

(52mg 0.0750mmol) uses the NaOH deprotection, has obtained this title compound (28mg, 72% productive rate), is pale solid with the product among the embodiment 187A according to the method for describing among the embodiment 162f.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.62Hz，6H)3.17-3.30(m，1H)5.66(s，1H)6.66(d，J＝8.46?Hz，2H)6.86(d，J＝8.82Hz，1H)7.16(d，J＝8.46Hz，2H)7.65(d，J＝7.72Hz，1H)7.96(d，J＝6.99Hz，1H)8.08-8.20(m，1H)8.48-8.69(m，1H)8.80-9.01(m，1H)9.21(s，1H)10.05-10.30(m，1H)12.92-13.12(m，1H)；MS(ESI)m/z?515(M+H)+。

Embodiment 188

With the product of embodiment 8E (68mg, 0.3180mmol) and the product of embodiment 166B (150mg 0.2891mmol) merges in acetate (10mL), and as reacting described in embodiment 162e, has obtained this title compound (52mg, 26%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.34(d，J＝6.99Hz，6H)3.09-3.29(m，1H)4.97(s，2H)7.01(d，J＝8.46Hz，1H)7.45(d，J＝8.46Hz，2H)7.55-7.77(m，3H)7.99(d，J＝8.46Hz，1H)8.19(s，1H)8.60(s，1H)8.87(d，J＝8.46Hz，1H)9.21(s，1H)10.24(s，1H)10.43(s，1H)12.88-13.25(m，1H)；MS(ESI)m/z?691(M+H)+。

Embodiment 189

4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(5-methyl-[1,3,4] thiadiazoles-2-base formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

With the product of embodiment 8E (67mg, 0.3097mmol) and the product of embodiment 186B (150mg 0.2815mmol) merges in acetate (5mL), and as reacting described in embodiment 162e, has obtained this title compound (134mg, 68%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.33(d，J＝6.62Hz，6H)2.61(s，3H)3.15-3.29(m，1H)4.97(s，2H)6.88-7.10(m，1H)7.44(d，J＝8.46Hz，2H)7.60(d，J＝8.46Hz，2H)7.88-8.05(m，1H)8.10-8.23(m，1H)8.52-8.64(m，1H)8.79-8.93(m，1H)10.15-10.29(m，1H)10.41(s，1H)；MS(ESI)m/z?705，703(M+H)+。

Embodiment 190

N-[4-(4-amino-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-trifluoromethyl-benzamide

This title compound is the Troc method according to embodiment 100 A-C, and reacts with the methyl amidine that derives from embodiment 9B, substitutes the 4-bromo-benzoyl chloride with the 3-trifluoromethyl benzoyl chloride and makes.Crude product is come purifying by development in the 1:1 ethyl acetate/hexane, obtained this title compound (0.12g, 69%), be the tawny solid. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：2.68(s，3H)，5.47(s，2H)，6.56(d，J＝8.46Hz，2H)，6.95(d，J＝8.46Hz，1H)，7.08(d，J＝8.46Hz，2H)，7.48-7.68(m，2H)，7.78(t，J＝7.54Hz，1H)，7.91(s，1H)，7.97(d，J＝7.35Hz，1H)，8.21-8.37(m，2H)，8.57(s，1H)，8.81(d，J＝8.46Hz，1H)，10.06(s，1H)，10.56(s，1H)；MS(ESI+)m/z?547(M+H) ⁺。

Embodiment 191

N-[4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-trifluoromethyl-benzamide

This title compound is the Troc method according to embodiment 100 A-C, and reacts with the methyl amidine that derives from embodiment 9B, substitutes the 4-bromo-benzoyl chloride with the 3-trifluoromethyl benzoyl chloride and makes.Crude product is come purifying by development in the 1:1 ethyl acetate/hexane, obtained this title compound (0.15g, 79%), be the tawny solid. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.34(d，J＝6.99Hz，6H)，3.15-3.28(m，1H)，5.46(s，2H)，6.56(d，J＝8.46Hz，2H)，6.95(d，J＝8.82Hz，1H)，7.09(d，J＝8.46Hz，2H)，7.56-7.67(m，2H)，7.78(t，J＝7.72Hz，1H)，7.90(d，J＝2.21Hz，1H)，7.97(d，J＝7.72Hz，1H)，8.22-8.32(m，2H)，8.57(s，1H)，8.86(d，J＝8.82Hz，1H)，10.07(s，1H)，10.56(s，1H)；MS(ESI+)m/z?575(M+H) ⁺。

Embodiment 192

4-(4-amino-2-chloro-phenoxy group)-N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

This title compound is the Troc method according to embodiment 100 A-C, and reacts with the methyl amidine that derives from embodiment 9B, substitutes the 4-amino-phenol with 4-amino-2-chlorophenol and makes.Crude product by silica gel chromatography purifying (mixture of 3% methyl alcohol in methylene dichloride), has been obtained this title compound (0.09g, 51%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.32(d，J＝6.99Hz，6H)，3.16-3.28(m，1H)，5.37(s，2H)，6.55(dd，J＝8.82，2.57Hz，1H)，6.68(d，J＝2.21Hz，1H)，6.72(d，J＝8.82Hz，1H)，6.94(d，J＝8.82Hz，1H)，7.53(d，J＝8.82Hz，2H)，7.61(d，J＝8.46Hz，1H)，7.75(d，J＝9.19Hz，2H)，7.85(dd，J＝8.64，2.02Hz，1H)，8.16(d，J＝1.84Hz，1H)，8.63(s，1H)，8.86(d，J＝8.46Hz，1H)，10.03(s，1H)，10.31(s，1H)；MS(ESI+)m/z?603(M+H) ⁺。

Embodiment 193

3-fluoro-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 193a

3-fluoro-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-nitro-phenyl]-benzamide

This title compound is the method according to embodiment 115, substitutes the 3-trifluoromethyl benzoyl chloride with the 3-fluorobenzoyl chloride, has obtained this title compound (0.48g, 57%).

Embodiment 193b

With the product of embodiment 8E (60.6mg, 0.28mmol) and the product of embodiment 193a (99mg, 0.28mmol) solution in acetate (1mL) is being preheated in 130 ℃ the oil bath and was stirring 10 minutes.Then this mixture is cooled to room temperature, vacuum is removed acetate, and by using the HPLC purifying gained resistates of TFA, has obtained this title compound, is trifluoroacetate (35mg, 24%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.36(d，J＝6.62Hz，6H)3.17-3.34(m，1H)6.69(t，J＝9.19Hz，2H)7.08-7.26(m，3H)7.39-7.51(m，1H)7.54-7.69(m，2H)7.70-7.91(m，3H)8.01(s，1H)8，78(s，1H)8.96(d，J＝8.46Hz，1H)9.78(s，1H)10.52(s，1H)11.35(s，1H)；MS(ESI+)m/z?526(M+H)+，(ES1-)m/z?524(M-H)-。

Embodiment 194

3-bromo-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 194a

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

This title compound is the method for describing according among the embodiment 115, substitutes (0.34g, 65%) that the 3-trifluoromethyl benzoyl chloride makes with the 3-bromo-benzoyl chloride.

Embodiment 194b

With the product of embodiment 8E (54.4mg, 0.25mmol) and the product of embodiment 194a (100mg, 0.25mmol) solution in acetate (1mL) is being preheated in 130 ℃ the oil bath and was stirring 10 minutes.Then this mixture is cooled to room temperature, vacuum is removed acetate, and by using the HPLC purifying gained resistates of TFA, has obtained this title compound, is trifluoroacetate (32mg, 22%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.25-1.40(m，6H)3，23-3.35(m，1H)6.70(d，J＝8.82Hz，2H)7.09-7.25(m，3H)7.41-7.59(m，1H)7.56-7.69(m，1H)7.73-7.87(m，2H)7.88-8.06(m，2H)8.08-8.17(m，1H)8.77(s，1H)8.96(d，J＝8.82Hz，1H)9.78(s，1H)10.49-10.60(m，1H)11.34(s，1H)；MS(ESI+)m/z?586(M+H)+，(ESI-)m/z?584(M-H)-。

Embodiment 195

N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-4-trifluoromethyl-benzamide

Embodiment 195a

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-4-trifluoromethyl-benzamide

This title compound is the method for describing according among the embodiment 115, substitutes the 3-trifluoromethyl benzoyl chloride with the 4-trifluoromethyl benzoyl chloride and makes, and has obtained this title compound (0.48g, 53%).

Embodiment 195b

With the product of embodiment 8E (45mg, 0.208mmol) and the product of embodiment 195a (84.1mg, 0.208mmol) solution in acetate (1mL) is being preheated in 130 ℃ the oil bath and was stirring 10 minutes.Then this mixture is cooled to room temperature, vacuum is removed acetate, and the gained resistates is passed through the silica gel chromatography purifying, from 99:1 CH ₂Cl ₂/ MeOH begins to 97:3CH ₂Cl ₂/ MeOH carries out gradient elution.To contain the level part merging of product, vacuum concentration has obtained the tawny solid, is this title compound (39mg, 32%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.24-1.41(m，6H)3.23(dd，J＝12.50，5.88Hz，1H)6.74(d，J＝8.82Hz，2H)7.08(d，J＝8.82Hz，1H)7.19(d，J＝8.82Hz，2H)7.53-7.66(m，2H)7.84-8.01(m，3H)8.14(d，J＝8.46Hz，2H)8.56(s，1H)8.83(d，J＝8.09Hz，1H)9.75(s，1H)10.10(s，1H)10.60(s，1H)；MS(ESI+)m/z?576(M+H)+，(ESI-)m/z?574(M-H)-。

Embodiment 196

4-bromo-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 196a

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

This title compound is the method for describing according among the embodiment 115, substitutes the 3-trifluoromethyl benzoyl chloride with the 4-bromo-benzoyl chloride and makes, and has obtained this title compound (0.32g, 56%).

Embodiment 196b

With the product of embodiment 8E (41mg, 0.187mmol) and the product of embodiment 196a (77.8mg, 0.187mmol) solution in acetate (1mL) is being preheated in 130 ℃ the oil bath and was stirring 10 minutes.Then this mixture is cooled to room temperature, vacuum is removed acetate, and the gained resistates is passed through the silica gel chromatography purifying, from 99:1 CH ₂Cl ₂/ MeOH begins to 97:3CH ₂Cl ₂/ MeOH carries out gradient elution.To contain the level part merging of product, vacuum concentration has obtained the tawny solid, is this title compound (56mg, 51%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.24-1.38(m，6H)3.26(s，1H)6.74(t，J=8.27Hz，2H)7.05(s，1H)7.18(d，J＝8.46Hz，2H)7.61(d，J＝8.82Hz，2H)7.75(d，J＝8.46Hz，2H)7.90(d，J＝8.46Hz，3H)8.56(s，1H)8.83(d，J＝7.72Hz，1H)9.74(s，1H)10.09(s，1H)10.45(s，1H)；MS(ESI+)m/z?588(M+H)+，(ESI-)m/z?586(M-H)-。

Embodiment 197

4-fluoro-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 197a

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-4-fluoro-benzamide

This title compound is the method for describing according among the embodiment 115, substitutes the 3-trifluoromethyl benzoyl chloride with the 4-fluorobenzoyl chloride and makes, and has obtained this title compound (0.43g, 59%).

Embodiment 197b

Product (79mg with embodiment 8E, 0.367mmol) and the product (130mg of embodiment 197a, 0.367mmol) solution in acetate (1mL) is being preheated in 130 ℃ the oil bath and stirring 10 minutes. then this mixture is cooled to room temperature, vacuum is removed acetate, and the gained resistates is passed through the silica gel chromatography purifying, from 99:1 CH ₂Cl ₂/ MeOH begins to 97:3CH ₂Cl ₂/ MeOH carries out gradient elution.To contain the level part merging of product, vacuum concentration has obtained the tawny solid, is this title compound (69mg, 36%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.32(t，J＝7.54Hz，6H)3.16-3.30(m，1H)6.73(d，J＝8.46Hz，2H)7，07(d，J＝8.46Hz，1H)7.18(d，J＝8.46Hz，2H)7.37(t，J＝8.82Hz，2H)7.61(d，J＝8.46Hz，2H)7.89-8.09(m，3H)8.56(s，1H)8.83(d，J＝8.46Hz，1H)9.73(s，1H)10.08(s，1H)10.40(s，1H)；MS(ESI+)m/z?526(M+H)+，(ESI-)m/z?524(M-H)-。

Embodiment 198

3-chloro-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 198a

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-3-chloro-benzamide

This title compound is the method for describing according among the embodiment 115, substitutes the 3-trifluoromethyl benzoyl chloride with the 3-chloro-benzoyl chloride and makes, and has obtained this title compound (0.49g, 45%).

Embodiment 198b

With the product of embodiment 8E (65mg, 0.302mmol) and the product of embodiment 198a (112mg, 0.302mmol) solution in acetate (1mL) is being preheated in 130 ℃ the oil bath and was stirring 10 minutes.Then this mixture is cooled to room temperature, vacuum is removed acetate, and the gained resistates is passed through the silica gel chromatography purifying, from 99:1 CH ₂Cl ₂/ MeOH begins to 97:3CH ₂Cl ₂/ MeOH carries out gradient elution.To contain the level part merging of product, vacuum concentration has obtained the tawny solid, is this title compound (45mg, 28%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.28-1.38(m，6H)3.16-3.28(m，1H)6.73(d，J＝8.46Hz，2H)7.07(d，J＝8.82Hz，1H)7.19(d，J＝8.82Hz，2H)7.52-7.75(m，4H)7.85-8.07(m，3H)8.56(s，1H)8.83(d，J＝8.09Hz，1H)9.74(s，1H)10.09(s，1H)10.48(s，1H)；MS(ESI+)m/z?542(M+H)+，(ESI-)m/z?540(M-H)-。

Embodiment 199

4-(4-amino-phenoxy group)-N-(5-chloro-pyridine-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 199A

4-chloro-N-(5-chloro-pyridine-2-yl)-3-nitro-benzamide

Under nitrogen atmosphere, with 4-chloro-3-nitrobenzoyl chloride (1.00g, 4.99mmol) solution in anhydrous methylene chloride (20mL) is with 2-amino-5-chloropyridine (643mg, 4.99mmol) and N, N-diisopropylethylamine (1.05mL, 6.00mmol) handle, and with the gained mixture stirring at room 18 hours., except that desolvating resistates is placed in the ethyl acetate (100mL) by rotary evaporation in vacuo, and wash with saturated sodium bicarbonate aqueous solution (50mL), water (2 x 50mL) and salt solution (50mL).With the organic extract liquid anhydrous sodium sulfate drying, filter, and vacuum concentration.With the development of 5% ethyl acetate/dichloromethane, obtained this title compound, be dark yellow solid (660mg, 42%).

Embodiment 199B

4-[4-(5-chloro-pyridine-2-base formamyl)-2-nitro-phenoxy group]-phenyl }-t-butyl carbamate

At the product (300mg of room temperature with embodiment 199A, 0.9612mmol) at anhydrous N, solution in the dinethylformamide (5mL) with the N-Boc-4-hydroxyanilines (201mg, 0.9612mmol) and salt of wormwood (266mg, 1.922mmol) handle, under nitrogen atmosphere, heated 5 hours then in 80 ℃.This reaction is cooled to room temperature, and removes by rotary evaporation in vacuo and to desolvate.Resistates is placed in the ethyl acetate (100mL), and water (4 * 50mL) and salt solution (50mL) washing.With the organic layer anhydrous sodium sulfate drying, filter, and concentrate by rotary evaporation in vacuo.With the development of 5% ethyl acetate, obtained this title compound (284mg, 61%).

Embodiment 199C

4-[2-amino-4-(5-chloro-pyridine-2-base formamyl)-phenoxy group]-phenyl }-t-butyl carbamate

Product (282mg with embodiment 199B, 0.5816mmol), iron powder (200mg, 3.577mmol) and ammonium chloride (204mg, 3.809mmol) suspension in ethanol (8mL) and water (4mL) is in 80 ℃ of heating 45 minutes, after being cooled to room temperature, with this mixture with ethyl acetate (100mL) dilution, and water (2 * 50mL) and salt solution (50mL) wash., filter and vacuum concentration the organic phase drying with sodium sulfate, obtained this title compound, be beige solid (250mg, 94%).

Embodiment 199D

4-[4-(5-chloro-pyridine-2-base formamyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-phenyl }-t-butyl carbamate

Product (118mg with embodiment 8E, 0.5452mmol) and the product (248mg of embodiment 199C, 0.5452mmol) solution in acetate (5mL) is being preheated in 140 ℃ the oil bath and stirring 20 minutes, this reaction is cooled to room temperature, dilute with hexane (100mL), concentrate by rotary evaporation, and with dichloromethane/hexane coevaporation (4 times).Resistates is dry under high vacuum, then by the fast silica gel chromatogram purifying,, obtained this title compound with 2%MeOH/ methylene dichloride wash-out, be yellow solid (164mg, 48%).

Embodiment 199E

(162.2g is 0.2591mmol) with the solution-treated of trifluoroacetic acid (2mL) in methylene dichloride (2mL) 30 minutes with the product of embodiment 199D in room temperature.Remove by rotary evaporation and to desolvate, and resistates is placed in the ethyl acetate (75mL), and with saturated sodium bicarbonate aqueous solution (30mL), water (2 * 30mL) and salt solution (30mL) wash.With the organic phase anhydrous sodium sulfate drying, filter, and vacuum concentration.By the silica gel chromatography purifying,, obtained this title compound (104mg, 76%) with 4% ethanol/methylene wash-out. ¹H?NMR(300MHz，DMSO-d ₆)δppm：1.32(d，J＝6.99Hz，6H)3.09-3.30(m，1H)5.04(s，2H)6.57(d，J＝8.82Hz，2H)6.78(d，J＝8.83Hz，1H)6.79(d，J＝8.82Hz，2H)7.60(d，J＝8.46Hz，1H)7.94-7.98(m，2H)8.20-8.27(m，2H)8.43(d，J＝2.94Hz，1H)8.62(s，1H)8.85(d，J＝8.46Hz，1H)9.97(s，1H)10.91(s，1H)；MS(ESI+)m/z?526/528(M+H) ⁺。

Embodiment 200

This title compound is that the method according to embodiment 10A-C makes.Then with the product coupling of product and embodiment 8E. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.32(d，6.99Hz，6H)1.46(s，9H)3.12-3.29(m，1H)6.94(d，J=8.45Hz，1H)6.96(d，J＝8.82Hz，2H)7.43(d，J＝8.82Hz，2H)7.53(d，J＝8.82Hz，2H)7.58(d，J＝8.82Hz，1H)7.76(d，J＝8.82Hz，2H)7.89(dd，J＝8.64，2.02Hz，1H)8.17(d，J＝2.21Hz，1H)8.60(s，1H)8.79(d，J＝8.46Hz，1H)9.35(s，1H)10.03(s，1H)10.34(s，1H)；MS(ESI+)m/z?669/671(M+H) ⁺。

Embodiment 201

4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(6-methoxyl group-pyridin-3-yl)-benzamide

Embodiment 201A

4-[4-(6-methoxyl group-pyridin-3-yl formamyl)-2-nitro-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

Product (290mg with embodiment 19C, 0.546mmol) solution in anhydrous tetrahydro furan (5mL) is with 5-amino-2-methoxypyridine (78.5mg, 0.601mmol) and diisopropylethylamine (0.143mL 0.819mmol) handles, and stirs 18 hours under nitrogen atmosphere in room temperature.Should react with ethyl acetate (100mL) dilution, and with saturated sodium bicarbonate aqueous solution (25mL), water (2 * 25mL) and salt solution (25mL) wash.With the organic phase anhydrous sodium sulfate drying, filter, and vacuum concentration.With the development of 3% ethanol/methylene, obtained this title compound, be dark yellow solid (202mg, 60%).

Embodiment 201B

4-[2-amino-4-(6-methoxyl group-pyridin-3-yl formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

Product (200mg with embodiment 201A, 0.3233mmol), ammonium chloride (113mg, 2.118mmol) and iron powder (111mg, 1.988mmol) in the mixture of water (3mL), ethanol (6mL) and tetrahydrofuran (THF) (6mL), under nitrogen atmosphere, heated 75 minutes in 80 ℃, this reaction is cooled to room temperature, with ethyl acetate (100mL) dilution, and water (2 * 0mL) and salt solution (50mL) wash.With the organic phase anhydrous sodium sulfate drying, filter, and concentrate by rotary evaporation in vacuo, obtained product, be oldlace solid (175mg, 92%).

Embodiment 201C

4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(6-methoxyl group-pyridin-3-yl formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

With the product of embodiment 8E (64mg, 0.2934mmol) and the product of embodiment 201B (173mg, 0.294mmol) solution in acetate (4mL) is being preheated in 140 ℃ the oil bath and was stirring 1 hour.This reaction is cooled to room temperature,, concentrates by rotary evaporation with hexane (100mL) dilution, and with dichloromethane/hexane coevaporation (4 times).Resistates is dry under high vacuum, by the fast silica gel chromatogram purifying, use 4% ethanol/methylene then, obtained this title compound, be light yellow solid (123mg, 55%).

Embodiment 201D

At the product (121.8mg of room temperature with embodiment 201C, 0.1603mmol) 1, solution in the 4-dioxane (3mL) lithium hydroxide monohydrate (13.5mg, 0.3206mmol) solution-treated in water (1.5mL), 70 ℃ of heating 30 minutes, this reaction is cooled to room temperature then, with ethyl acetate (75mL) and water (30mL) dilution, with water pH regulator to 6, and separate each layer with 1N hydrochloric acid.With the organic phase water (2 * 25mL) and salt solution (25mL) washing, use anhydrous sodium sulfate drying, filter, and concentrated by rotary evaporation in vacuo.By fast silica gel chromatogram purifying resistates, use 6% ethanol/methylene, obtained this title compound, be light yellow solid (66mg, 77%). ¹H?NMR(300MHz，DMSO-d ₆)δppm：1.34(d，J＝6.99Hz，6H)3.05-3.39(m，1H)3.83(s，3H)5.59(s，2H)6.64(d，J＝8.46Hz，2H)6.82(d，J＝8.82Hz，1H)6.88(dd，J＝7.35，1.84Hz，1H)7.14(d，J＝8.46Hz，2H)7.57-7.69(m，1H)7.73-7.85(m，1H)7.89-7.99(m，1H)8.01(dd，J＝9.01，2.76Hz，1H)8.48(d，J＝2.57Hz，1H)8.52-8.66(m，1H)8.83-8.98(m，1H)10.16(s，1H)10.20(s，1H)；MS(ESI+)m/z?538(M+H) ⁺，560(M+Na) ⁺，(ESI-)m/z?536(M-H) ^-。

Embodiment 202

N-(5-bromo-thiazol-2-yl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 202A

N-(5-bromo-thiazol-2-yl)-4-chloro-3-nitro-benzamide

(1.539g, 7.694mmol) (2.00g 7.694mmol) handles the solution in anhydrous pyridine (40mL), and this is reflected at room temperature stirs under nitrogen atmosphere 18 hours with 2-amino-5-bromo thiazole list hydrobromate with 4-chloro-3-nitrobenzoyl chloride.Remove by rotary evaporation in vacuo and to desolvate, and oily matter is dry under high vacuum.Resistates is placed in the ethyl acetate (150mL), and water (4 * 50mL) and salt solution (50mL) washing, then with the organic phase anhydrous sodium sulfate drying, filtration, and vacuum concentration.With the development of 6% ethyl acetate/dichloromethane, obtained this title compound, be rose pink-brown solid (1.92g, 69%).

Embodiment 202B

N-(5-bromo-thiazol-2-yl)-4-(4-hydroxyl-phenyl sulfenyl)-3-nitrobenzamide

Product (300mg at room temperature embodiment 202A, 0.8274mmol) at anhydrous N, solution in the dinethylformamide (8mL) with the 4-mercapto-phenol (104.4mg, 0.8274mmol) and cesium carbonate (539mg, 1.655mmol) handle, under nitrogen atmosphere, heated 2 hours then in 100 ℃.This reaction is cooled to room temperature and removes and desolvate by rotary evaporation in vacuo.Resistates is placed water (50mL), use 1N hydrochloric acid pH regulator to 3.With water layer with ethyl acetate (100mL) extraction, and with the organic extract liquid water (2 * 25mL) and salt solution (25mL) wash.With the organic layer anhydrous sodium sulfate drying, filter, and concentrate by rotary evaporation, obtained product, be golden brown solid (416mg, 111%).

Embodiment 202C

3-amino-N-(5-bromo-thiazol-2-yl)-4-(4-hydroxyl-phenyl sulfenyl)-benzamide

With the product of embodiment 202B (414mg, 0.9153mmol) and iron powder (204.5mg, 3.66mmol) reflux 1 hour under nitrogen atmosphere of the suspension in acetate (7mL) and ethanol (7mL).This reaction is cooled to room temperature, and with this mixture water (50mL) and ethyl acetate (100mL) dilution.With water layer pH regulator to 5, separate each layer with solid sodium carbonate, and with organic phase water (2 * 50mL) and salt solution (50mL) washing.With the organic extract liquid dried over sodium sulfate, filter, and vacuum concentration, obtained this title compound, be yellow solid (315mg, 90%).

Embodiment 202D

The product of A solution of the product of embodiment 8E (92mg, 0.4262mmol) and the product of embodiment 202C (180mg, 0.4262mmol) solution in acetate (4mL) is being preheated in 140 ℃ the oil bath and was stirring 1 hour.This reaction is cooled to room temperature,, concentrates by rotary evaporation with hexane (100mL) dilution, and with dichloromethane/hexane coevaporation (4 times).Resistates is dry under high vacuum, by the silica gel chromatography purifying,, obtained this title compound then with 5% ethanol/methylene wash-out, be light yellow solid (151mg, 60%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.34(d，J＝6.99Hz，6H)3.14-3.32(m，1H)6.82-6.93(m，3H)7.33(d，J＝8.46Hz，2H)7.60-7.70(m，2H)7.93(dd，J＝8.46，1.84Hz，1H)8.13(d，J＝1.47Hz，1H)8.59(s，1H)8.88(d，J＝8.82Hz，1H)10.02(s，1H)10.19(s，1H)12.87(s，1H)；MS(ESI+)m/z?593/595(M+H) ⁺。

Embodiment 203

N-[4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-4-bromo-benzamide

The product of embodiment 13A is reacted according to the Troc method of embodiment 100b.Product reaction with reaction product and embodiment 8E.Crude product by using the anti-phase preparation HPLC method purifying of TFA, has been obtained this title compound, be trifluoroacetate (81mg, 23%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.37(d，J＝6.62Hz，6H)3.32(m，1H)6.56(d，J＝8.82Hz，2H)7.06(m，3H)7.60(dd，J＝8.64，2.21Hz，1H)7.76(m，2H)7.90(m，3H)8.00(d，J＝2.21Hz，1H)8.88(s，1H)9.03(d，J＝8.46Hz，1H)10.52(s，1H)11.77(s，1H)；MS(ESI+)m/z585?587(M+H)+。

Embodiment 204

N-[4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-bromo-benzamide

The product of embodiment 66 is reacted according to the Troc method of embodiment 100b.Substitute the 4-bromo-benzoyl chloride with the 3-bromo-benzoyl chloride, with reaction product and the reaction of embodiment 8 ear products.Crude product by using the anti-phase preparation HPLC method purifying of TFA, has been obtained this title compound, be trifluoroacetate (57mg, 18%). ¹H?NMR(300?MHz，DMSO-d ₆)δppm：1.37(d，J＝6.99Hz，6H)3.30(m，1H)6.57(d，J＝8.46Hz，2H)7.08(m，3H)7.51(m，1H)7.61(dd，J＝8.64，2.21Hz，1H)7.81(d，J＝6.99Hz，1H)7.93(m，2H)8.00(d，J＝2.21Hz，1H)8.12(m，1H)8.88(s，1H)9.03(d，J＝8.46Hz，1H)10.55(s，1H)11.76(s，1H)；MS(ESI+)m/z?585?587(M+H)+。

Embodiment 205

N-[4-(4-amino-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-4-bromo-benzamide

The product of embodiment 13 is reacted according to the Troc method of embodiment 100.Product reaction with reaction product and embodiment 9B.Crude product is come purifying by development in the 1:1 ethyl acetate/hexane, obtained this title compound (86 mg, 39%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：2.68(s，3H)5.45(s，2H)6.55(d，J＝8.46Hz，2H)6.94(d，J＝8.46Hz，1H)7.07(d，J＝8.46Hz，2H)7.56(m，2H)7.74(d，J＝8.46Hz，2H)7.90(m，3H)8.56(s，1H)8.80(d，J＝8.46Hz，1H)10.04(s，1H)10.40(s，1H)；MS(ESI+)m/z?557?559(M+H)+。

Embodiment 206

N-[4-(4-amino-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-bromo-benzamide

The product of embodiment 66 is reacted according to the Troc method of embodiment 100.Substitute the 4-bromo-benzoyl chloride with the 3-bromo-benzoyl chloride, with the product reaction of reaction product and embodiment 9B.Crude product is come purifying by development in the 1:1 ethyl acetate/hexane, obtained this title compound (71mg, 33%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：2.68(s，3H)5.45(s，2H)6.55(d，J＝8.46Hz，2H)6.94(d，J＝8.46Hz，1H)7.07(d，J＝8.46Hz，2H)7.53(m，3H)7.80(m，1H)7.93(m，2H)8.13(m， 1H)8.56(s，1H)8.80(d，J＝8.46Hz，1H)10.04(s，1H)10.43(s，1H)；MS(ESI+)m/z?557?559(M+H)+。

Embodiment 207

4-(4-amino-phenyl sulfenyl)-N-(4-bromo-2,6-dimethyl-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 207A

4-[4-(4-bromo-2,6-dimethyl-phenyl amino formyl radical)-2-nitro-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

Product (300mg with embodiment 162b, 0.6197mmol) and 4-bromo-2, (123mg 0.6197mmol) heats described in solution in toluene (10mL) such as the embodiment 162c 6-dimethyl-phenyl amine, obtained this title compound, it need not further be handled and directly use.

Embodiment 207B

4-[2-amino-4-(4-bromo-2,6-dimethyl-phenyl amino formyl radical)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

With the product (0.6197mmol) of embodiment 207A according to the method for embodiment 9E with Fe and NH ₄The Cl reduction has obtained this title compound (239mg, 62% productive rate), is white solid.

Embodiment 207C

4-[4-(4-bromo-2,6-dimethyl-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

With the product of embodiment 8E (62mg, 0.2881mmol) and the product of embodiment 207B (178mg, 0.2881mmol) merging in acetate (10mL), and described in 614E, react, obtain this title compound (146mg, 65% productive rate), be light solid.

Embodiment 207D

With the product of embodiment 207C (120mg, 0.1521mmol) described in embodiment 162f with the NaOH reaction, obtained this title compound (65mg, 70%), be pale solid. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.34(d，J＝6.99Hz，6H)2.15(s，6H)3.09-3.32(m，1H)6.63(d，J＝8.82Hz，2H)6.89(d，J＝8.46Hz，1H)7.14(d，J＝8.82Hz，2H)7.18-7.34(m，3H)7.57-7.76(m，1H)7.84(d，J＝7.35Hz，1H)7.92(s，1H)8.51-8.75(m，1H)8.91(d，J＝7.72Hz，1H)9.77(s，1H)10.62(s，1H)；MS(ESI)m/z?613，615(M+H)+。

Embodiment 208

4-(4-amino-phenyl sulfenyl)-N-(4-bromo-phenyl)-N-sec.-propyl-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 208A

(4-{4-[(4-bromo-phenyl)-sec.-propyl-formamyl]-2-nitro-phenyl sulfenyl }-phenyl)-carboxylamine 2,2,2-three chloro-ethyl esters

Product (311mg with embodiment 162b, 0.6428mmol) and (4-bromo-phenyl)-sec.-propyl-amine (137mg, 0.6428mmol) heat described in solution in toluene (10mL) such as the embodiment 162c, having obtained this title compound, it need not further be handled and directly use.

Embodiment 208B

(4-{2-amino-4-[(4-bromo-phenyl)-sec.-propyl-formamyl]-the phenyl sulfenyl }-phenyl)-carboxylamine 2,2,2-three chloro-ethyl esters

With the product (0.6428mmol) of embodiment 208A according to the method for embodiment 9E with Fe and NH ₄The Cl reduction has obtained this title compound (218mg, 53% productive rate), is pale solid.

Embodiment 208C

4-[4-[(4-bromo-phenyl)-sec.-propyl-formamyl]-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

With the product of embodiment 8E (53mg, 0.2469mmol) and the product of embodiment 208B (156mg, 0.2881mmol) merging in acetate (10mL), and described in 614E, react, obtain this title compound (68mg, 34% productive rate), be light solid.

Embodiment 208D

With the product of embodiment 208C (68mg, 0.0847mmol) described in embodiment 162f with the NaOH reaction, obtained this title compound (65mg, 79%), be pale solid. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.07(d，J＝6.62Hz，6H)1.33(dd，J＝6.99Hz，6H)3.10-3.29(m，1H)4.70-4.92(m，1H)5.55(s，1H)6.59(d，J＝8.46Hz，2H)6.50-6.57(m，1H)6.99-7.05(m，1H)7.08(dd，J＝16.73，8.64Hz，4H)7.16-7.24(m，1H)7.49(d，J＝8.46Hz，2H)7.56(d，J＝8.09Hz，1H)8.48(s，1H)8.77(d，J＝8.46Hz，1H)9.80-10.05(m，1H)；MS(ESI)m/z?629(M+H)+。

Embodiment 209

This compound is that the method according to embodiment 100A, 100B and 100C makes, and has obtained this title compound.

Embodiment 210

4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(1-phenyl-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

Use the method for embodiment 182, (60mg, (36mg 0.33mmol) reacts, and has obtained this title product for mixture 0.1mmol) and methyl-benzyl amine with the product of embodiment 162a. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.33(d，J＝6.99Hz，6H)1.45(d，J＝6.99Hz，3H)3.15-3.28(m，1H)4.95(s，2H)5.08-5.25(m，1H)7.04(d，J＝846Hz，1H)7.22(d，J＝6.99Hz，1H)7.26-7.41(m，6H)7.55(d，J＝8.82Hz，2H)7.62(d，J＝8.46Hz，1H)7.75(dd，J＝8.27，1.65Hz，1H)7.94(d，J＝1.84Hz，1H)8.57(s，1H)8.82(dd，J＝8.46，3.68Hz，2H)10.20(s，1H)10.36(s，1H)。

Embodiment 211

4-[4-[1-(4-bromo-phenyl)-ethylamino formyl radical]-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

Use the method for embodiment 182, (60mg, (60mg 0.33mmol) reacts mixture 0.1mmol) and methyl-4-bromo-benzyl amine, has obtained this title product with the product of embodiment 162a. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.33(d，J＝6.99Hz，6H)1.44(d，J＝6.99Hz，3H)3.16-3.27(m，1H)4.95(s，2H)5.06-5.17(m，1H)7.04(d，J＝8.46Hz，1H)7.22-7.41(m，4H)7.45-7.58(m，3H)7.63(d，J＝8.46Hz，1H)7.74(dd，J＝8.64，1.29Hz，1H)7.93(d，J＝1.10Hz，1H)8.02(s，1H)8.58(s，1H)8.82(d，J＝2.21Hz，1H)8.84(s，1H)10.21(s，1H)10.36(s，1H)。

Embodiment 212

N-[4-(4-amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-trifluoromethyl-benzamide

This title compound is the Boc method according to embodiment 10A-C, with the product coupling of embodiment 8E after make.Crude product by using the HPLC purifying of TFA, has been obtained this title compound, be trifluoroacetate (0.18g, 53%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.33(d，J=6.99Hz，6H)，3.14-3.37(m，1H)，6.92(s，4H)，7.03(d，J＝9.19Hz，1H)，7.69(dd，J＝9.19，2.57Hz，1H)，7.81(t，J＝8.64Hz，2H)，7.99(d，J＝7.72Hz，1H)，8.09(d，J＝2.57Hz，1H)，8.23-8.33(m，2H)，8.83(s，1H)，8.92(d，J＝8.46Hz，1H)，10.65(s，1H)，11.32(s，1H)；MS(ESI+)m/z?559(M+H) ⁺。

Embodiment 213

N-[4-(4-amino-phenoxy group)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-trifluoromethyl-benzamide

This title compound makes like this: according to the Boc method of embodiment 10A-C, use the 3-5-trifluoromethylaniline to substitute the 4-bromaniline in a first step, then with the product coupling of product and embodiment 9B.Crude product by using the HPLC purifying of TFA, has been obtained this title compound, be trifluoroacetate (0.191g, 59%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：2.72(s，3H)，6.90(s，4H)，7.04(d，J＝8.82?Hz，1H)，7.68(dd，J＝8.82，2.57Hz，1H)，7.74(d，J＝8.46Hz，1H)，7.81(t，J＝7.91Hz，2H)，7.99(d，J＝7.72Hz，1H)，8.10(d，J＝2.57Hz，1H)，8.23-8.33(m，2H)，8.83(s，1H)，8.86(d，J＝8.46Hz，1H)，10.64(s，1H)，11.26-11.34(m，1H)；MS(ESI+)m/z?531(M+H) ⁺。

Embodiment 214

N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-trifluoromethoxy-benzamide

Embodiment 214a

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-3-trifluoromethoxy-benzamide

This title compound is according to the method for describing among the embodiment 115, makes with 3-trifluoromethoxy Benzoyl chloride alternative 3-trifluoromethyl benzoyl chloride, has obtained this title compound (0.35g, 41%).

Embodiment 214b

With the product of embodiment 8E (64mg, 0.294mmol) and the product of embodiment 214a (124mg, 0.294mmol) solution in acetate (1mL) is being preheated in 130 ℃ the oil bath and was stirring 10 minutes.Then this mixture is cooled to room temperature, vacuum is removed acetate, and the gained resistates is passed through the silica gel chromatography purifying, from 99:1 CH ₂Cl ₂/ MeOH begins to 97:3CH ₂Cl ₂/ MeOH carries out gradient elution.Merge level part of containing product, vacuum concentration is this title compound (28mg, 16%) to the tawny solid. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.34(d，J＝6.62Hz，6H)3.14-3.29(m，1H)6.74(d，J＝8.82Hz，1H)7.07(d，J＝8.82Hz，1H)7.19(d，J＝8.82Hz，2H)7.56-7.70(m，4H)7.62-7.73(m，2H)7.83-8.00(m，1H)8.01(d，J＝7.72Hz，1H)8.56(s，1H)8.83(d，J＝8.46Hz，1H)9.75(s，1H)10.09(s，1H)10.51(s，1H)；MS(ESI+)m/z?592(M+H)+，(ESI-)m/z?590(M-H)-。

Embodiment 215

N-[4-(4-amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-4-bromo-benzamide

This title compound is the method according to embodiment 252, makes with 4-bromo-N-(4-fluoro-3-nitrophenyl) benzamide gradient N-(4-fluoro-3-nitrophenyl) benzamide in embodiment 252a.The crude product of final deprotection by using the anti-phase preparation HPLC method purifying of TFA, is obtained this title compound (126mg, 32%), be trifluoroacetate. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.33(d，J＝6.99Hz，6H)3.26(m，1H)6.92(m，4H)7.02(d，J＝8.82Hz，1H)7.68(dd，J=9.19，2.57Hz，1H)7.77(d，J＝8.46Hz，2H)7.82(d，J＝8.82Hz，1H)7.92(d，J＝8.46Hz，2H)8.08(d，J＝2.57Hz，1H)8.82(s，1H)8.91(d，J＝8.82Hz，1H)10.50(s，1H)11.32(s，1H)；MS(ESI+)m/z?569，571(M+H)+。

Embodiment 216

N-[4-(4-amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-bromo-benzamide

This title compound is the method according to embodiment 252, substitutes N-(4-fluoro-3-nitrophenyl) benzamide with 3-bromo-N-(4-fluoro-3-nitrophenyl) benzamide and make in embodiment 252a.The crude product of final deprotection by using the anti-phase preparation HPLC method purifying of TFA, has been obtained this title compound, be trifluoroacetate (90mg, 23%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.33(d，J＝6.62Hz，6H)3.26(m，1H)6.90(m，4H)7.03(d，J＝8.82Hz，1H)7.52(t，J＝7.91Hz，1H)7.68(dd，J＝9.19，2.57Hz，1H)7.82(d，J＝8.82Hz，2H)7.96(d，J＝8.46Hz，1H)8.08(d，J＝2.57Hz，1H)8.15(m，1H)8.83(s，1H)8.92(d，J＝8.46Hz，1H)10.53(s，1H)11.38(s，1H)；MS(ESI+)m/z?569?571(M+H)+。

Embodiment 217

N-[4-(4-amino-phenoxy group)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-4-bromo-benzamide

This title compound is the method according to embodiment 252, in embodiment 252a, substitute N-(4-fluoro-3-nitrophenyl) benzamide, and the product with the product alternate embodiment 8E of embodiment 9B makes in embodiment 252c with 4-bromo-N-(4-fluoro-3-nitrophenyl) benzamide.The crude product of final deprotection by using the anti-phase preparation HPLC method purifying of TFA, has been obtained this title compound, be trifluoroacetate (137mg, 36%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：2.72(s，3H)6.94(m，4H)7.06(d，J＝8.82Hz，1H)7.69(dd，J＝8.82，2.57Hz，1H)7.78(m，3H)7.92(d，J＝8.46Hz，2H)8.11(d，J＝2.57Hz，1H)8.84(m，2H)10.32(s，1H)11.46(s，1H)；MS(ESI+)m/z?541?543(M+H)+。

Embodiment 218

N-[4-(4-amino-phenoxy group)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-bromo-benzamide

This title compound is the method according to embodiment 252, in embodiment 252a, substitute N-(4-fluoro-3-nitrophenyl) benzamide, and the product with the product alternate embodiment 8E of embodiment 9B makes in embodiment 252c with 3-bromo-N-(4-fluoro-3-nitrophenyl) benzamide.Crude product by using the anti-phase preparation HPLC method purifying of TFA, has been obtained this title compound, be trifluoroacetate (103mg, 27%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：2.73(s，3H)6.96(m，4H)7.06(d，J＝8.82Hz，1H)7.52(t，J＝7.91Hz，1H)7.68(dd，J＝8.82，2.57Hz，1H)7.76(d，J＝8.46Hz，1H)7.82(m，1H)7.96(d，J＝7.72Hz，1H)8.11(d，J＝2.21Hz，1H)8.14(m，1H)8.82(m，2H)10.54(s，1H)11.42(s，1H)；MS(ESI+)m/z?541543(M+H)+。

Embodiment 219

4-(4-amino-phenyl sulfenyl)-N-(5-bromo-pyridine-2-yl)-3-(7-ethyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

(0.942g, 5.0mmol) solution in anhydrous tetrahydro furan (50mL) is cooled to-78 ℃ with the product of embodiment 9B under nitrogen atmosphere.In this solution, drip to add lentamente lithium diisopropylamine solution (solution of 3.0mL 2.0M in toluene/hexane/heptane, 6.0mmol, 1.2eq).After adding is finished, this reaction mixture was stirred 1 hour at-78 ℃.Drip then methyl-iodide (1.42g, 10.0mmol, 2.0eq).With this reaction mixture-78 ℃ of restir 1.5 hours, during all solids dissolving.Then reaction flask is taken out from cooling bath, add saturated aqueous ammonium chloride (25mL) and water (25mL).(3 * 100mL) extract, and with the organic layer salt water washing that merges, use anhydrous magnesium sulfate drying, filtration, and vacuum-evaporation with ethyl acetate with this reaction mixture.Resistates is passed through the silica gel chromatography purifying, use 3/2 hexane: eluent ethyl acetate, obtained N '-(3-cyano group-6-ethyl-pyridine-2-yl)-N, N-dimethyl-carbonamidine (0.87g, 86% productive rate), with its method reaction according to embodiment 17E, with N '-(3-cyano group-6-ethyl-pyridine-2-yl)-N, the product of N-dimethyl-carbonamidine alternate embodiment 8E.

Embodiment 220

N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 220a

N-(4-fluoro-3-nitrophenyl) benzamide

5 ℃ to 4-fluoro-3-N-methyl-p-nitroaniline (2.00g, 12.8mmol) and Et ₃N (1.98mL, 14.1mmol) drip to add in the solution in THF (40mL) Benzoyl chloride (1.58ml, 13.5mmol).This mixture was stirred 1 hour at 5 ℃, be warmed to room temperature, then evaporation.Resistates is suspended in H ₂Among the O (100ml), be adjusted to pH2, extract with EtOAc then.With extraction liquid H ₂O, 10% NaHCO ₃With the salt water washing, use MgSO ₄Drying, and vacuum concentration have obtained crude product, with it by using i-Pr ₂O washs purifying, has obtained this title compound, is light brown crystal (2.70g, 81%).

Embodiment 220b

N-[4-(4-hydroxy phenyl sulfenyl)-3-nitrophenyl] benzamide

With the product of embodiment 220a (0.50g, 1.9mmol), the 4-mercapto-phenol (0.28g, 2.0mmol) and K ₂CO ₃(0.32g, 2.3mmol) mixture in DMF (10mL) under agitation adds H then in 90 ℃ of heating 1 hour ₂O (100ml).Gained oiliness crystal is extracted with EtOAc.With extraction liquid H ₂MgSO is used in O (3 times) and salt water washing ₄Drying is filtered and vacuum concentration, has obtained the crude product of this title compound, with it by using i-Pr ₂O washs purifying, has obtained required product, is yellow crystals (0.68g, 96%).

Embodiment 220c

N-[3-amino-4-(4-hydroxy phenyl sulfenyl) phenyl] benzamide

Product (0.67g with embodiment 220b, 1.8mmol) and Fe powder (0.31g, 5.5mmol) suspension in the mixture of EtOH (6.7mL) and HOAc (6.7mL) is heated to 80 ℃ gradually, and 80 ℃ of heating 3 hours. with this reaction mixture evaporation. with resistates at EtOAc and 10% NaHCO ₃Between distribute, filter then in (via diatomite).With organic layer salt water washing, use MgSO ₄Drying is filtered and vacuum concentration, has obtained the crude product of this title compound, with it by using i-Pr ₂O washs purifying, has obtained required compound, is light brown crystal (0.53g, 86%).

Embodiment 220d

(75mg is 0.35mmol) with the product of embodiment 220C (117mg, 0.35mmol) reaction 5 minutes in the 2mL Glacial acetic acid with the product of embodiment 8E.Be cooled to room temperature, and the acetate vacuum is removed, obtained, it is come purifying by development in EtOAc, obtained this title compound, be solid (70mg, 40%) crude product. ¹H NMR (300MHz, DMSO-d ₆) δ ppm:1.34 (d, J=7.0Hz, 6H), 3.22 (septet, J=7.0Hz, 1H), 6.73 (d, J=8.5Hz, 2H), 7.08 (d, J=8.5Hz, 1H), 7.18 (d, J=8.5Hz, 2H), 7.48-7.60 (m, 3H), 7.62 (d, J=8.5Hz, 1H), 7.64 (dd, J=8.5,2.2Hz, 1H), 7.90-7.99 (m, 2H), 7.98 (d, J=2.2Hz, 1H), 8.56 (s, 1H), 8.84 (d, J=8.5Hz, 1H), 9.73 (s, 1H), 10.09 (s, 1H), 10.39 (s, 1H); MS (ESI+) m/z 508 (M+H)+, (ESI-) m/z 506 (M-H)-.

Embodiment 221

Pyrazine-2-formic acid [4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-acid amides

Embodiment 221a

Pyrazine-2-formic acid (4-fluoro-3-nitrophenyl) acid amides

5 ℃ to pyrazine-2-formic acid (2.00g, 16.1mmol) and Et ₃(2.50ml, (1.74mL 17.7mmol), and stirs this mixture 1 hour at 5 ℃ N 17.7mmol) to drip Vinyl chloroformate in the solution in THF (40mL).5 ℃ in this mixture, add 4-fluoro-3-N-methyl-p-nitroanilines (2.80g, 17.7mmol).This mixture is warmed to room temperature, stirring at room 4 hours, evaporation then.Resistates is suspended in H ₂O (100ml) and i-Pr ₂In the mixture of O (100ml), and stirring at room 30 minutes.Collect the gained crystal by filtering, and use H ₂O and i-Pr ₂The O washing has obtained required product, is light brown crystal (2.91g, 69%).

Embodiment 221b

Pyrazine-2-formic acid [4-(4-hydroxyl-phenyl sulfenyl)-3-nitrophenyl] acid amides

Embodiment 221a obtains according to the method among the embodiment 220, has obtained this title compound, is yellow crystals (83%).

Embodiment 221c

Pyrazine-2-formic acid [3-amino-4-(4-hydroxyl-phenyl sulfenyl) phenyl] acid amides

The product of embodiment 221b is reacted according to the method for embodiment 220c, obtained this title compound, be light brown crystal (65%).

Embodiment 221d

(75mg is 0.35mmol) with the product of embodiment 221c (117mg, 0.35mmol) reaction 6 minutes in the 2mL Glacial acetic acid with the product of embodiment 8E.Be cooled to room temperature, and the acetate vacuum is removed, obtained, it is come purifying by development in EtOAc, obtained this title compound, be solid (83mg, 47%) crude product. ¹H NMR (300MHz, DMSO-d ₆) δ ppm:1.34 (d, J=7.0Hz, 6H), 3.23 (septet, J=7.0Hz, 1H), 6.75 (d, J=8.5Hz, 2H), 7.04 (d, J=8.4Hz, 1H), 7.21 (d, J=8.5Hz, 2H), 7.62 (d, J=8.1Hz, 1H), 7.74 (br-d, J=8.4Hz, 1H), 8.10 (d, J=1.1Hz, 1H), 8.56 (s, 1H), 8.82 (dd, J=2.2,1.1Hz, 1H), 8.85 (d, J=8.1Hz, 1H), 8.93 (d, J=2.2Hz, 1H), 9.28 (d, J=1.1Hz, 1H), 9.77 (s, 1H), 10.11 (s, 1H), 10.89 (s, 1H); MS (ESI+) m/z 510 (M+H)+, (ESI-) m/z 508 (M-H)-.

Embodiment 222

Pyridine-2-formic acid [4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-acid amides

Embodiment 222a

Pyridine-2-formic acid (4-fluoro-3-nitrophenyl) acid amides

This title compound is the method according to embodiment 221, substitutes pyrazine-2-formic acid with pyridine-2-formic acid and makes, and has obtained this title compound, is light brown crystal (88%).

Embodiment 222b

Pyridine-2-formic acid [4-(4-hydroxyl-phenyl sulfenyl)-3-nitrophenyl] acid amides

The product of embodiment 222a is to obtain according to the method for embodiment 220, has obtained this title compound, is yellow crystals (95%).

Embodiment 222c

Pyridine-2-formic acid [3-amino-4-(4-hydroxyl-phenyl sulfenyl) phenyl] acid amides

Use the product of embodiment 222b to prepare this title compound, be light brown crystal (84%).

Embodiment 222d

(75mg is 0.35mmol) with the product of embodiment 222c (117mg, 0.35mmol) reaction 5 minutes in the 2mL Glacial acetic acid with the product of embodiment 8E.Be cooled to room temperature, and the acetate vacuum is removed, obtained, it is come purifying by development in EtOAc, obtained this title compound, be solid (110mg, 60%) crude product. ¹H NMR (300MHz, DMSO-d ₆) δ ppm:1.34 (d, J=7.0Hz, 6H), 3.23 (septet, J=7.0Hz, 1H), 6.75 (d, J=8.4Hz, 2H), 7.04 (d, J=8.4Hz, 1H), 7.20 (d, J=8.4Hz, 2H), 7.62 (d, J=8.4Hz, 1H), 7.69 (ddd, J=7.7,4.8,1.5Hz, 1H), 7.74 (dd, J=8.4,2.2Hz, 1H), 8.07 (td, J=7.7,1.5Hz, 1H), 8.12-8.18 (m, 2H), 8.56 (s, 1H), 8.73 (br-d, J=4.8Hz, 1H), 8.85 (d, J=8.4Hz, 1H), 9.76 (s, 1H), 10.11 (s, 1H), 10.79 (s, 1H); MS (ESI+) m/z 509 (M+H)+, (ESI-) m/z 507 (M-H)-.

Embodiment 223

4-[4-(2-amino-acetylamino)-phenoxy group]-N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 223A

(4-[4-(4-bromo-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-the phenyl amino formyl radical }-methyl)-t-butyl carbamate

Product (50mg with embodiment 100,0.0878mmol) solution in anhydrous tetrahydro furan (2mL) with N-(tert-butoxycarbonyl) glycine (18.5mg, 0.1054mmol) and N, N '-dicyclohexylcarbodiimide (21.7mg, 0.1054mmol) handle, and stirring at room 2.5 days.Remove by rotary evaporation in vacuo and to desolvate, and with resistates by the silica gel chromatography purifying, with 7% ethanol/methylene wash-out, obtained this title compound (49.5mg, 78%).

Embodiment 223B

At the product (48.5mg of room temperature with embodiment 223A, 0.668mmol) trifluoroacetic acid (1mL) that is used in the methylene dichloride (1mL) handled 40 minutes, remove by rotary evaporation and to desolvate, resistates is placed in the ethyl acetate (60mL), and with saturated sodium bicarbonate aqueous solution (50mL), water (2 * 50mL) and salt solution (50mL) washing.With the organic phase anhydrous sodium sulfate drying, filter, and vacuum concentration.By using the HPLC purifying of AA, obtained this title compound, be white solid (12mg, 29%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.31(d，J＝6.99Hz，6H)3.12-3.28(m，1H)3.25(s，2H)6.98(d，J＝8.83Hz，1H)7.00(d，J＝9.19Hz，2H)7.54(d，J＝8.82Hz，2H)7.58(d，J＝8.82Hz，1H)7.62(d，J＝9.19Hz，2H)7.76(d，J＝8.82Hz，2H)7.89(dd，J＝8.82，1.10Hz，1H)8.17(s，1H)8.58(s，1H)8.71-8.83(m，1H)10.35(s，1H)；MS(ESI+)m/z?626/628(M+H) ⁺。

Embodiment 224

4-(4-amino-phenyl sulfenyl)-N-(5-fluoro-pyridin-3-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 224A

5-fluoro-nicotinic acid

With 2,6-two chloro-5-fluoro-3-pyridine carboxylic acids (3.00g, 0.0143mol), anhydrous sodium acetate (3.516g, 0.0429mol) and the mixture of 10% palladium on carbon (0.300g) in methyl alcohol (50mL) in the down hydrogenation 18 hours of 1 atmospheric pressure hydrogen pressure (air bag).Should react via 0.45 μ PTFE film vacuum filtration, and with methyl alcohol (25mL) thorough washing.Filtrate is concentrated by rotary evaporation in vacuo.Resistates is placed ethyl acetate (100mL) and water (30mL), use 6N hydrochloric acid water layer pH regulator to 3, and separate each layer.With the organic phase water (2 * 30mL), salt solution (30mL) washing, use anhydrous sodium sulfate drying then, filter, and vacuum concentration.Obtained this title compound, be white solid (1.293g, 64%).

Embodiment 224B

(5-fluoro-pyridin-3-yl)-benzyl carbamate

With the product of embodiment 224A (1.00g, 7.087mmol) and N-methylmorpholine (0.86mL, 7.796mmol) anhydrous 1, in the 2-ethylene dichloride (30mL) under nitrogen atmosphere in stirring at room 10 minutes.(1.68mL 7.796mmol), and is reflected at this under uniform temp and stirred 30 minutes to drip the diphenylphosphine acylazide then.Should react then via 20 minutes and be heated to 75 ℃ lentamente, and under this temperature, keep 1 hour.(1.10mL 10.63mmol) and cuprous iodide (20mg), and should react and reflux 3 hours to enter benzyl alcohol.Then this reaction is cooled to room temperature, and removes by rotary evaporation in vacuo and to desolvate.By the silica gel chromatography purifying, with 20% ethyl acetate/dichloromethane wash-out, obtained this title compound, be pale solid (718mg, 41%).

Embodiment 224C

5-fluoro-pyridin-3-yl amine

Product (716mg with embodiment 224B, 2.908mmol) solution in methyl alcohol (17mL) by very/empty nitrogen purging outgas in proper order (repeating 3 times), with 10% palladium on carbon (72mg) and ammonium formiate (917mg 14.54mmol) handles, and under nitrogen atmosphere reflux 1.5 hours.This reaction is cooled to room temperature,, on the fritted glass disk funnel, filters, with ethyl acetate (75mL) washing via 50mL silica gel bed (230-400 order) with ethyl acetate (80mL) dilution.By rotary evaporation in vacuo filtrate is concentrated, obtained this title compound, be white crystalline solid (283mg, 87%).

Embodiment 224D

4-[4-(5-fluoro-pyridin-3-yl formamyl)-2-nitro-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

Product (259mg with embodiment 19C, 0.488mmol) product (60.2mg of embodiment 224C of the solution in anhydrous tetrahydro furan (5mL), 0.537mmol) and diisopropylethylamine (0.128mL 0.732mmol) handles, and stirs 15 hours under nitrogen atmosphere in room temperature.Remove by rotary evaporation in vacuo and to desolvate, and resistates is placed ethyl acetate (100mL), with saturated sodium bicarbonate aqueous solution (25mL), water (2 * 25mL) and salt solution (25mL) wash.With the organic phase anhydrous sodium sulfate drying, filter, and vacuum concentration.With the development of 3% ethanol/methylene, obtained this title compound, be yellow solid (176mg, 60%).

Embodiment 224E

4-[2-amino-4-(5-fluoro-pyridin-3-yl formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

Product (174mg with embodiment 224D, 0.2868mmol), ammonium chloride (100.5mg, 1.879mmol) and iron powder (98.5mg, 1.764mmol) in the mixture of water (3mL), ethanol (6mL) and tetrahydrofuran (THF) (6mL) under nitrogen atmosphere in 80 ℃ the heating 1 hour.This reaction is cooled to room temperature, with ethyl acetate (100mL) dilution, and water (2 * 25mL) and salt solution (25mL) wash.With the organic phase anhydrous sodium sulfate drying, filter, and concentrate by rotary evaporation in vacuo, obtained product, be yellow solid (160mg, 97%).

Embodiment 224F

4-[4-(5-fluoro-pyridin-3-yl formamyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

Just the product of embodiment 8E (60mg, 0.2743mmol) and the product of embodiment 224E (158.2mg, 0.2743mmol) solution in acetate (4mL) is being preheated in 140 ℃ the oil bath and was stirring 1 hour.Be cooled to room temperature, with hexane (100mL) dilution, and vacuum concentration is reflected under the high vacuum this dry, by the silica gel chromatography purifying, carry out the gradient performance then, obtained this title compound with the 2%-4% ethanol/methylene, be pale solid (120mg, 59%).

Embodiment 224G

At the product (118.9mg of room temperature with embodiment 224F, 0.159mmol) 1, solution in the 4-dioxane (3mL) lithium hydroxide monohydrate (13.3mg, 0.318mmol) solution-treated in water (1.5mL), 70 ℃ of heating 45 minutes, this reaction is cooled to room temperature then, with ethyl acetate (100mL) and water (30mL) dilution, with water pH regulator to 6, and separate each layer with 1N hydrochloric acid.With the organic phase water (2 * 25mL) and salt solution (25mL) washing, use anhydrous sodium sulfate drying, filter, and concentrated by rotary evaporation in vacuo.By silica gel chromatography purifying resistates, with 5% ethanol/methylene wash-out, obtained this title compound, be yellow solid (51mg, 61%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.34(d，J＝6.99Hz，6H)3.10-3.34(m，1H)5.61(s，2H)6.64(d，J＝8.46Hz，2H)6.90(d，J＝8.09Hz，1H)7.15(d，J＝8.46Hz，2H)7.65(d，J＝8.09Hz，1H)7.81(dd，J＝7.17，1.65Hz，1H)7.97(s，1H)8.13-8.23(m，1H)8.32(d，J＝2.57Hz，1H)8.59(s，1H)8.76(d，J＝1.47Hz，1H)8.89(d，J＝8.09Hz，1H)10.18(s，1H)10.59(s，1H)；MS(ESI+)m/z?526(M+H) ⁺，(ESI-)m/z?524(M-H) ^-。

Embodiment 225

4-(4-amino-phenoxy group)-N-(the 5-tertiary butyl-[1,3,4] thiadiazoles-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 225a

N-(the 5-tertiary butyl-[1,3,4] thiadiazoles-2-yl)-4-fluoro-3-nitro-benzamide

This title compound is with the 5-tertiary butyl-[1,3,4] thiadiazoles-(232mg, 1.474mmol), the method synthetic according to embodiment 172b has obtained this title compound to 2-base amine, is solid (400mg, 84%).

Embodiment 225b

4-[4-(the 5-tertiary butyl-[1,3,4] thiadiazoles-2-base formamyl)-2-nitro-phenoxy group]-phenyl }-t-butyl carbamate

This title compound is that the product by Processing Example 225a under the condition of embodiment 172c makes, and has obtained this title compound (600mg, 72%).

Embodiment 225c

4-[2-amino-4-(the 5-tertiary butyl-[1,3,4] thiadiazoles-2-base formamyl)-phenoxy group]-phenyl }-t-butyl carbamate

The condition that this title compound is to use embodiment 9E is made by the product of embodiment 225b, has obtained this title compound (157mg, 33%).

Embodiment 225d

4-[4-(the 5-tertiary butyl-[t, 3,4] thiadiazoles-2-base formamyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-phenyl }-t-butyl carbamate

With the product of embodiment 225c (157mg, 0.323mmol) and the product of embodiment 8E (70mg 0.323mmol) is dissolved among the HOAc, and places 10 minutes in 120 ℃ of oil baths of preheating.Solvent removed in vacuo, this oily crude product are directly used (212mg, 99%) without purifying.

Embodiment 225e

(212mg 0.323mmol) is dissolved in TFA at CH with the product of embodiment 225d ₂Cl ₂In the 1:1 mixture in, and stirring at room 2 hours.Solvent removed in vacuo, and, obtained product with the HPLC purifying of oily crude product by use TFA, be trifluoroacetate (9mg, 5%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.34(d，J＝6.99Hz，6H)，1.42(s，9H)，3.21-3.36(m，1H)，6.79-6.87(m，2H)，6.94(d，J＝8.82Hz，3H)，7.86(d，J＝8.46Hz，1H)，8.15(dd，J＝8.82，2.21Hz，1H)，8.28(d，J＝2.21Hz，1H)，8.88(s，1H)，8.99(d，J＝8.46Hz，1H)；MS(ESI+)m/z?555(M+TFA+H)+；(ESI-)m/z?553(M+TFA-H)-。

Embodiment 226

4-(4-amino-phenoxy group)-N-(5-fluoro-pyridine-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 226a

4-fluoro-N-(5-fluoro-pyridine-2-yl)-3-nitro-benzamide

According to the method for embodiment 172a, with the product of embodiment 172a and 5-fluoro-pyridine-(165mg, 1.474mmol) reaction has obtained this title compound (404mg, 98%) to 2-base amine.

Embodiment 226b

4-[4-(5-fluoro-pyridine-2-base formamyl)-2-nitro-phenoxy group]-phenyl }-t-butyl carbamate

This title compound is that the product by Processing Example 226a under the condition of embodiment 172c makes, and has obtained this title compound (568mg, 83%).

Embodiment 226c

4-[2-amino-4-(5-fluoro-pyridine-2-base formamyl)-phenoxy group]-phenyl }-t-butyl carbamate

The condition that this title compound is to use embodiment 9E is made by the product of embodiment 226b, has obtained this title compound (203mg, 38%).

Embodiment 226d

4-[4-(5-fluoro-pyridine-2-base formamyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-phenyl }-t-butyl carbamate

With the product of embodiment 8E (100mg, 0.462mmol) and the product of embodiment 226c (203mg 0.462mmol) is dissolved among the HOAc, and places 10 minutes in 120 ℃ of oil baths of preheating.Then this reaction mixture is cooled to room temperature, and solvent removed in vacuo, this title compound (282mg, 100%) obtained.

Embodiment 226e

(282mg 0.462mmol) is dissolved in TFA at CH with the product of embodiment 226d ₂Cl ₂In the 1:1 mixture in, and stirring at room 2 hours.Solvent removed in vacuo, and, obtained product with the HPLC purifying of oily crude product by use TFA, be trifluoroacetate. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.33(t，J＝6.99Hz，6H)，3.22-3.36(m，1H)，6.84-7.00(m，6H)，7.76-7.91(m，2H)，8.09(dd，J＝8.82，2.21Hz，1H)，8.14-8.27(m，2H)，8.40(d，J＝2.94Hz，1H)，8.90(s，1H)，9.00(d，J＝8.82Hz，1H)，10.93(s，1H)；MS(ESI+)m/z?510(M+TFA+H)+；(ESI-)m/z?508(M+TFA-H)-。

Embodiment 227

4-(4-amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(5-trifluoromethyl-pyridine-2-yl)-benzamide

Embodiment 227a

4-fluoro-3-nitro-N-(5-trifluoromethyl-pyridine-2-yl)-benzamide

According to the method for embodiment 172b, with the product of embodiment 172a and 5-trifluoromethyl-pyridine-(239mg, 1.474mmol) reaction has obtained this title compound (485mg, 100%) to 2-base amine.

Embodiment 227b

4-[2-nitro-4-(5-trifluoromethyl-pyridine-2-base formamyl)-phenoxy group]-phenyl }-t-butyl carbamate

The product of embodiment 227a is that the method according to embodiment 172c makes, and has obtained this title compound (333mg, 44%).

Embodiment 227c

4-[2-amino-4-(5-trifluoromethyl-pyridine-2-base formamyl)-phenoxy group]-phenyl }-t-butyl carbamate

With the product of embodiment 227b according to the method for embodiment 9E with Fe and NH ₄The Cl reduction has obtained this title compound (271mg, 86%).

Embodiment 227d

4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(5-trifluoromethyl-pyridine-2-base formamyl)-phenoxy group]-phenyl }-t-butyl carbamate

With the product of embodiment 8E (120mg, 0.555mmol) and the product of embodiment 227c (271mg 0.555mmol) is dissolved among the HOAc, and places 10 minutes in 120 ℃ of oil baths of preheating.Then this reaction mixture is cooled to room temperature, and solvent removed in vacuo, this title compound (366mg, 100%) obtained.

Embodiment 227e

(366mg 0.555mmol) is dissolved in TFA at CH with the product of embodiment 227d ₂Cl ₂In the 1:1 mixture in, and stirring at room 2 hours.Solvent removed in vacuo, and, obtained product with the HPLC purifying of oily crude product by use TFA, be trifluoroacetate (47mg, 15%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.35(d，J＝6.99Hz，6H)，3.29(dt，J＝13.70，6.94Hz，1H)，6.86-7.00(m，5H)，7.88(d，J＝8.46Hz，1H)，8.11(dd，J＝8.64，2.39Hz，1H)，8.21-8.30(m，2H)，8.40(d，J＝8.82Hz，1H)，8.79(s，1H)，8.90(s，1H)，9.00(d，J＝8.46Hz，1H)，11.28(s，1H)；

MS(ESI+)m/z?560(M+TFA+H)+；(ESI-)m/z?558(M+TFA-H)-。

Embodiment 228

4-(4-amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-[1,3,4] thiadiazoles-2-base-benzamide

Embodiment 228a

4-fluoro-3-nitro-N-[1,3,4] thiadiazoles-2-base-benzamide

According to the method for embodiment 172b, (149mg, 1.474mmol) reaction has obtained this title compound (272mg, 67%) with the basic amine of product and [1,3,4] thiadiazoles-2-of embodiment 172a.

Embodiment 228b

4-[2-nitro-4-([1,3,4] thiadiazoles-2-base formamyl)-phenoxy group]-phenyl }-t-butyl carbamate

The product of embodiment 228a is handled (272mg, 59%) by the method for embodiment 172c.

Embodiment 228c

4-[2-amino-4-([1,3,4] thiadiazoles-2-base formamyl)-phenoxy group]-phenyl }-t-butyl carbamate

The product of embodiment 228b is used condition Fe and the NH of embodiment 9E ₄The Cl reduction has obtained this title compound (217mg, 82%).

Embodiment 228d

4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-([1,3,4] thiadiazoles-2-base formamyl)-phenoxy group]-phenyl }-t-butyl carbamate

With the product of embodiment 8E (110mg, 0.509mmol) and the product of embodiment 228c (217mg 0.509mmol) is dissolved among the HOAc, and places 10 minutes in 120 ℃ of oil baths of preheating.Then this reaction mixture is cooled to room temperature, and solvent removed in vacuo, this title compound (304mg, 100%) obtained.

Embodiment 228e

(304mg 0.509mmol) is dissolved in TFA at CH with the product of embodiment 227d ₂Cl ₂In the 1:1 mixture in, and stirring at room 2 hours.Solvent removed in vacuo, and, obtained product with the HPLC purifying of oily crude product by use TFA, be trifluoroacetate (47mg, 15%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.35(d，J＝6.99Hz，6H)，3.29(dt，J＝13.70，6.94Hz，1H)，6.82-6.98(m，5H)，7.87(d，J＝8.82Hz，1H)，8.18(dd，J＝8.82，2.21Hz，1H)，8.31(d，J＝2.21Hz，1H)，8.89(s，1H)，9.00(d，J＝8.46Hz，1H)，9.23(s，1H)，13.09(s，1H)；MS(ESI+)m/z?499(M+TFA+H)+；(ESI-)m/z?497(M+TFA-H)-。

Embodiment 229

N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-2-trifluoromethyl-benzamide

Embodiment 229a

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-2-trifluoromethyl-benzamide

This title compound is according to the method for describing among the embodiment 115, makes with 2-trifluoromethyl benzoyl chloride alternative 3-trifluoromethyl benzoyl chloride, has obtained this title compound (0.63g, 74%).

Embodiment 229b

With the product of embodiment 8E (79mg, 0.367mmol) and the product of embodiment 229a (148mg, 0.367mmol) solution in acetate (1mL) is being preheated in 130 ℃ the oil bath and was stirring 10 minutes.Then this mixture is cooled to room temperature, vacuum is removed acetate, and the gained resistates is passed through the silica gel chromatography purifying, from 99:1 CH ₂Cl ₂/ MeOH begins to 97:3CH ₂Cl ₂/ MeOH carries out gradient elution.Merge level part of containing product, vacuum concentration is this title compound (50mg, 24%) to the tawny solid. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.24-1.37(m，6H)3.16-3.29(m，1H)6.63-6.78(m，2H)7.08(d，J＝8.46Hz，1H)7.17(d，J＝8.46Hz，2H)7.42-7.52(m，1H)7.61(d，J＝8.46Hz，1H)7.71(t，J＝6.62Hz，2H)7.82(dd，J＝18.02，7.35Hz，2H)7.81-7.96(m，1H)8.56(s，1H)8.81(d，J＝8.46Hz，1H)9.73(s，1H)10.12(s，1H)10.72(s，1H)；MS(ESI+)m/z?576(M+H)+，(ESI-)m/z?574(M-H)-。

Embodiment 230

4-chloro-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 230a

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-4-chloro-benzamide

This title compound is the method according to embodiment 115, substitutes the 3-trifluoromethyl benzoyl chloride with the 4-chloro-benzoyl chloride and makes.Obtained this title compound (0.19g, 100%).

Embodiment 230b

With the product of embodiment 8E (54mg, 0.248mmol) and the product of embodiment 230a (91.9mg, 0.248mmol) solution in acetate (1mL) is being preheated in 130 ℃ the oil bath and was stirring 10 minutes.Then this mixture is cooled to room temperature, vacuum is removed acetate, and the gained resistates is passed through the silica gel chromatography purifying, from 99:1 CH ₂Cl ₂/ MeOH begins to 97:3CH ₂Cl ₂/ MeOH carries out gradient elution.Merge level part of containing product, vacuum concentration is this title compound (120mg, 89%) to the tawny solid. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.33(d，J＝6.99Hz，6H)3.13-3.28(m，1H)6.73(d，J＝8.46Hz，2H)7.07(d，J＝8.82Hz，1H)7.18(d，J＝8.46Hz，2H)7.53-7.66(m，3H)7.90-8.02(m，4H)8.56(s，1H)8.83(d，J＝8.46Hz，1H)9.74(s，1H)10.09(s，1H)10.45(s，1H)；MS(ESI+)m/z?542(M+H)+，(ESI-)m/z?540(M-H)-。

Embodiment 231

4-(4-amino-phenyl sulfenyl)-N-(5-bromo-pyridin-3-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 231A

(5-bromo-pyridin-3-yl)-benzyl carbamate

With the 5-bromo-nicotinic acid (1.00g, 4.95mmol) and N-methylmorpholine (0.60mL, 5.445mmol) anhydrous 1, the mixture in the 2-ethylene dichloride (20mL) under nitrogen atmosphere in stirring at room 10 minutes.(1.17mL 5.445mmol), and is reflected at this under uniform temp and stirred 30 minutes to drip the diphenylphosphine acylazide then.Then via 20 minutes with this sluggish be heated to 75 ℃, and under this temperature, kept 1 hour.(0.77mL 7.434mmol) and cuprous iodide (15mg), and should react backflow 3 hours to add benzyl alcohol.Then this reaction is cooled to room temperature, and removes by rotary evaporation in vacuo and to desolvate.By the silica gel chromatography purifying, carry out gradient elution with 12% to 20% ethyl acetate/dichloromethane, obtained this title compound, be white solid (524mg, 34%).

Embodiment 231B

5-bromo-pyridin-3-yl amine two hydrobromates

(200mg, 0.6512mmol) (solution of 33 weight %HBr in acetate, 3mL) suspension in was stirring at room 4 hours at hydrogen bromide solution with the product of embodiment 231A.Remove by rotary evaporation in vacuo and to desolvate, and, obtained this title compound, be pinkish solid (205mg, 94%) resistates and dry toluene (10mL) azeotropic.

Embodiment 231C

4-[4-(5-bromo-pyridin-3-yl formamyl)-2-nitro-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

Product (259mg with embodiment 19C, 0.488mmol) product (180mg of embodiment 231B of the solution in anhydrous tetrahydro furan (5mL), 0.5366mmol) and diisopropylethylamine (0.34mL 1.951mmol) handles, and stirs 16 hours under nitrogen atmosphere in room temperature.Should react with ethyl acetate (150mL) dilution, and with saturated sodium bicarbonate aqueous solution (25mL), water (2 * 25mL) and salt solution (25mL) wash.With the organic phase anhydrous sodium sulfate drying, filter, and vacuum concentration.With the development of 2% ethanol/methylene, obtained this title compound, be yellow solid (148mg, 45%).

Embodiment 231D

4-[2-amino-4-(5-bromo-pyridin-3-yl formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

Product (146.5mg with embodiment 231C, 0.2195mmol), ammonium chloride (77mg, 1.438mmol) and iron powder (75.4mg, 1.35mmol) in the mixture of water (3mL), ethanol (6mL) and tetrahydrofuran (THF) (6mL) under nitrogen atmosphere in 80 ℃ the heating 1 hour.This reaction is cooled to room temperature, with ethyl acetate (100mL) dilution, and water (3 * 50mL) and salt solution (50mL) wash.With the organic phase anhydrous sodium sulfate drying, filter, and concentrate by rotary evaporation in vacuo.With 4% ethanol/methylene wash-out, obtained this title compound by the silica gel chromatography purifying, be yellow solid (103mg, 74%).

Embodiment 231E

4-[4-(5-bromo-pyridin-3-yl formamyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

With the product of embodiment 8E (34.4mg, 0.1592mmol) and the product of embodiment 231D (101.5mg, 0.1592mmol) solution in acetate (5mL) is being preheated in 140 ℃ the oil bath and was stirring 1 hour.This reaction is cooled to room temperature,, concentrates by rotary evaporation with hexane (100mL) dilution, and with dichloromethane/hexane coevaporation (4 times).Resistates is dry under high vacuum, by the silica gel chromatography purifying, carry out gradient elution then with 2% to 4% ethanol/methylene, obtained this title compound (98mg, 76%).

Embodiment 231F

(96mg, 0.1187mmol) 1, (10.0mg, the 0.2374mmol) solution-treated in water (1mL) is then 70 ℃ of heating 30 minutes with lithium hydroxide monohydrate for the solution in the 4-dioxane (2mL) with the product of embodiment 231E in room temperature.This reaction is cooled to room temperature,, uses 1N hydrochloric acid with water layer pH regulator to 5, and separate each layer with ethyl acetate (50mL) and water (30mL) dilution.With the organic phase water (2 * 25mL) and salt solution (25mL) washing, use anhydrous sodium sulfate drying, filter, and concentrated by rotary evaporation in vacuo.By silica gel chromatography purifying resistates, with 5% ethanol/methylene wash-out, obtained this title compound, be light yellow solid (36mg, 2%). ¹H?NM[R(300MHz，DMSO-d ₆)δ?ppm：1.34(d，J＝6.62Hz，6H)3.12-3.30(m，1H)5.61(s，2H)6.64(d，J＝8.09Hz，2H)6.90(dd，J＝6.43，1.29Hz，1H)7.15(d，J＝8.46Hz，2H)7.65(dd，J＝8.09，1.84Hz，1H)7.81(dd，J＝7.91，2.39Hz，1H)7.97(s，1H)8.43(d，J＝1.84Hz，1H)8.48-8.51(m，2H)8.59(s，1H)8.88(d，J＝1.84Hz，1H)10.18(s，1H)10.51(s，1H)；MS(ESI+)m/z?586/588(M+H) ⁺。

Embodiment 232

4-(4-amino-phenyl sulfenyl)-N-(4-bromo-phenyl)-3-(7-ethyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 233

3-dimethylamino-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 233a

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-3-dimethylamino-benzamide

This title compound is according to the method for embodiment 115, uses 3-N, and N-dimethyl benzoyl chloride hydrochloride substitutes the 3-trifluoromethyl benzoyl chloride and makes, and has obtained this title compound (0.35g, 40%).

Embodiment 233b

With the product of embodiment 8E (64mg, 0.295mmol) and the product of embodiment 233a (112mg, 0.295mmol) solution in acetate (1mL) is being preheated in 130 ℃ the oil bath and was stirring 10 minutes.Then this mixture is cooled to room temperature, vacuum is removed acetate, and the gained resistates is passed through the silica gel chromatography purifying, from 99:1 CH ₂Cl ₂/ MeOH begins to 97:3CH ₂Cl ₂/ MeOH carries out gradient elution.Merge level part of containing product, vacuum concentration is this title compound (18mg, 12%) to the tawny solid. ¹HNMR(300MHz，DMSO-d ₆)δ?ppm：1.28-1.39(m，6H)2.95(s，6H)3.19-3.28(m，1H)6.72(d，J＝8.46Hz，2H)6.88-6.97(m，1H)7.07(d，J＝8.82Hz，1H)7.19(t，J＝8.82Hz，4H)7.31(t，J＝8.09Hz，1H)7.57-7.72(m，2H)7.94(d，J＝1.84Hz，1H)8.56(s，1H)8.83(d，J＝8.46Hz，1H)9.72(s，1H)10.08(s，1H)10.26(s，1H)；MS(ESI+)m/z?551(M+H)+，(ESI-)m/z?549(M-H)-。

Embodiment 234

4-(4-amino-2,3-dimethyl-phenoxy group)-N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

This title compound makes like this: according to the Boc method of embodiment 10A-C, with 4-amino-2, the 3-xylenol substitutes the 4-amino-phenol in step 320C.Product with this product and embodiment 8E reacts then.Crude product by using the HPLC purifying of TFA, has been obtained this title compound, be trifluoroacetate (0.06g, 50%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.35(d，J＝6.62Hz，6H)，2.00(s，3H)，2.08(s，3H)，3.13-3.36(m，1H)，6.72(d，J＝8.46Hz，1H)，6.79(d，J＝8.46Hz，1H)，6.89(d，J＝8.46Hz，1H)，7.55(d，J＝8.82Hz，2H)，7.74(d，J＝9.19Hz，2H)，7.87(d，J＝8.46Hz，1H)，7.94(dd，J＝8.64，2.39Hz，1H)，8.12(d，J＝2.21Hz，1H)，8.89(s，1H)，8.99(d，J＝8.46Hz，1H)，10.36(s，1H)，11.44(s，1H)；MS(ESI+)m/z?597(M+H) ⁺。

Embodiment 235

N-[4-(4-amino-phenyl sulfenyl)-3-(7-ethyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-4-bromo-benzamide

Make the product of embodiment 100 according to the Troc method of describing among the embodiment 100, and with product and N '-(3-cyano group-6-ethyl-pyridine-2-yl)-N, N-dimethyl-carbonamidine coupling.Crude product is come purifying by development in the 1:1 ethyl acetate/hexane, obtained this title compound (30mg, 78%). ¹H?NMR(300MHz，DMSO-d6)δ?ppm：1.33(t，J＝7.54Hz，3H)2.96(q，J＝7.35Hz，2H)5.45(s，2H)6.55(m，2H)6.94(d，J＝8.46Hz，1H)7.06(m，2H)7.57(m，2H)7.74(m，2H)7.90(m，3H)8.57(s，1H)8.83(d，J＝8.82Hz，1H)10.05(s，1H)10.41(s，1H)；MS(ESI+)m/z?571?573(M+H)+。

Embodiment 236

4-bromo-N-[4-(4-dimethylamino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

With the product of embodiment 203 (200mg, 0.34mmol), formaldehyde (1mL, 37%) and formic acid mixes, and 110 ℃ of heating 15 minutes.With solvent evaporation, and, obtained this title compound, be trifluoroacetate (44mg, 15%) the anti-phase preparation HPLC method purifying of resistates by use TFA. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.37(d，J＝6.99Hz，6H)2.84(s，6H)3.30(m，1H)6.50(m，2H)7.13(m，2H)7.20(d，J＝8.46Hz，1H)7.63(dd，J＝8.64，2.39Hz，1H)7.76(m，2H)7.90(m，3H)7.99(d，J＝2.21Hz，1H)8.80(s，1H)9.00(d，J＝8.46Hz，1H)10.53(s，1H)11.67(s，1H)；MS(ESI+)m/z?613?615(M+H)+。

Embodiment 237

4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-styroyl-benzamide

Add 1MNaOH (5 equivalent) in the solution of the product of embodiment 182 in tetrahydrofuran (THF) and water (1:1).60 ℃ of heating 40 minutes, cooling was adjusted to pH6 with 1N hydrochloric acid, and uses ethyl acetate extraction with this solution.With the extraction liquid dried over mgso that merges, filter and vacuum concentration.Crude product by the silica gel chromatography purifying, with the mixture wash-out of 4% methyl alcohol in methylene dichloride, has been obtained this title compound. ¹H?NMR(300MHz，DMSO-d ₆)δppm：1.34(d，J＝6.62Hz，6H)2.82(t，J＝7.17Hz，2H)3.16-3.28(m，1H)3.45(dt，2H)5.58(s，2H)6.62(d，J＝8.46Hz，2H)6.81(d，J＝8.46Hz，1H)7.12(d，J＝8.46Hz，2H)7.16-7.33(m，5H)7.58-7.68(m，2H)7.80(d，J＝1.47Hz，1H)8.51(t，J＝5.15Hz，1H)8.57(s，1H)8.86(d，J＝8.46Hz，1H)10.10(s，1H)。

Embodiment 238

N-[4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-4-fluoro-benzamide

Embodiment 238a

4-fluoro-Benzoyl chloride

In the solution of 4-fluorobenzoic acid (5.0g.35.7mmol) in ethylene dichloride (50mL), drip oxalyl chloride (5.6g, 44.6mmol).Should react and stir 16 hours.Excessive oxalul chloride and solvent decompression are removed.Resistates is handled (chased) with benzene, obtained required product (5.4g, 96%).

Embodiment 238b

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

To 4-chloro-3-nitro-phenyl amine (3.0g, 17.4mmol) add in the solution in methylene dichloride (60mL) diisopropylethylamine (4.5g, 34.8mmol).This solution is cooled to 0 ℃, and the product of adding embodiment 238a (2.75g, 17.4mmol).Remove ice bath, and allow this reaction via being warmed to room temperature in 16 hours.This reaction is poured in the water, and with ethyl acetate extraction (2 *).With organic phase water, the salt water washing that merges, and use dried over sodium sulfate, filter and vacuum concentration, obtained the crude product of this title compound.Resistates by the silica gel chromatography purifying, with hexane/ethyl acetate/methyl alcohol (80:25:5) wash-out, has been obtained required product (3.5g, 63%).

Embodiment 238c

N-[4-(4-amino-phenyl sulfenyl)-3-nitro-phenyl]-4-fluoro-benzamide

(2.5g 8.5mmol) adds CsCO in the solution in DMF (50mL) to the product of embodiment 238b ₃(5.5g, 17.0mmol) and the 4-aminothiophenol (1.0g, 8.5mmol).This mixture was heated 16 hours at 80 ℃.Should react the cooling and pour in the water.With water ethyl acetate extraction (2 *).With organic phase water, the salt water washing that merges, and use dried over sodium sulfate, filter and vacuum concentration, obtained this title compound.Resistates by the silica gel chromatography purifying, with hexane/ethyl acetate/methyl alcohol (60:30:10) wash-out, has been obtained required product (1.5g, 46%).

Embodiment 238d

4-[4-(4-fluoro-benzoyl-amido)-2-nitro-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

To the product of embodiment 238c (0.85g, 2.2mmol) add in the solution in methylene dichloride (40mL) pyridine (0.35g, 4.4mmol) and chloroformic acid 2,2, the 2-trichloro ethyl ester (0.58g, 2.7mmol).With mixture stirring at room 16 hours.This reaction is poured in the water.With water ethyl acetate extraction (2 *).With organic phase water, 5%HC1, the salt water washing that merges, and use dried over sodium sulfate, filter and vacuum concentration, obtained this title compound.Resistates by the silica gel chromatography purifying, with chloroform/methanol (90:10) wash-out, has been obtained required product (0.90g, 75%).

Embodiment 238e

4-[2-amino-4-(4-fluoro-benzoyl-amido)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

(0.88g is 1.6mmol) with Fe and NH with the product of embodiment 238d according to the method for embodiment 9E ₄The Cl reaction has obtained required product (0.50g, 60%).

Embodiment 238f

In sealed tube, product (80mg with embodiment 8E, 0.37mmol) with the product (195mg of embodiment 238e, 0.37mmol) in acetate (10mL), reacted 5 minutes in 125 ℃, obtained the crude product of this title compound,, obtained product by using the HPLC purifying of TFA, be trifluoroacetate (15mg, 7.8%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.34(d，J＝6.99Hz，6H)3.28(q，1H)7.00(dd，J＝8.46，2.21Hz，1H)7.16(d，J＝8.46Hz，2H)7.30-7.40(m，4H)7.45(d，J＝1.84Hz，1H)7.61(d，J＝8.82Hz，2H)7.86(d，J＝8.82Hz，1H)8.02(dd，J＝8.82，5.52Hz，2H)8.88(s，1H)9.01(d，J＝8.82Hz，1H)10.22(s，1H)；MS(ESI+)m/z525(M+H)+。

Embodiment 239

4-[4-(3-dimethylamino-benzoyl-amido)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2-two chloro-ethyl esters

Embodiment 239a

3-dimethylamino-benzoyl chloride hydrochloride salt

(5.6g 44.6mmol), adds the DMF of catalytic amount then to drip oxalyl chloride in the solution of 3-(dimethylamino) phenylformic acid (5.0g.30.0mmol) in ethylene dichloride (50mL).Should react and stir 16 hours.Excessive oxalul chloride and solvent decompression are removed.Resistates is handled (chased) with benzene, obtained required product (6.1g, 92%).

Embodiment 239b

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

To 4-chloro-3-nitro-phenyl amine (5.0g, 28.0mmol) add in the solution in methylene dichloride (60mL) diisopropylethylamine (7.2g, 56.0mmol).This solution is cooled to 0 ℃, and the product of adding embodiment 239a (5.0g, 28.0mmol).Remove ice bath, and allowed this reaction be warmed to room temperature via 16 hours.This reaction is poured in the water, and with ethyl acetate extraction (2 *).With organic phase water, the salt water washing that merges, and, obtained this title compound with dried over sodium sulfate filtration and vacuum concentration.Resistates by the silica gel chromatography purifying, with hexane/ethyl acetate/methyl alcohol (80:15:5) wash-out, has been obtained required product (5.0g, 53%).

Embodiment 239c

N-[4-(4-amino-phenyl sulfenyl)-3-nitro-phenyl]-3-dimethylamino-benzamide

(5.0g 15.6mmol) adds K in the solution in DMF (50mL) to the product of embodiment 239b ₂CO ₃(4.3g, 17.0mmol) and the 4-aminothiophenol (1.9g, 8.5mmol).This mixture was heated 16 hours at 65 ℃.Should react the cooling and pour in the water.With water ethyl acetate extraction (2 *).With organic phase water, the salt water washing that merges, and use dried over sodium sulfate, filter and vacuum concentration, obtained this title compound.Resistates by the silica gel chromatography purifying, with hexane/ethyl acetate/methyl alcohol (50:40:10) wash-out, has been obtained required product (3.4g, 53%).

Embodiment 239d

4-[4-(3-dimethylamino-benzoyl-amido)-2-nitro-phenyl sulfenyl]-phenyl }-carboxylamine 2,2-two chloro-ethyl esters

To the product of embodiment 239c (2.8g, 6.8mmol) add in the solution in methylene dichloride (40mL) pyridine (1.1g, 13.7mmol) and chloroformic acid 2,2, the 2-trichloro ethyl ester (1.7g, 2.8mmol).With mixture stirring at room 72 hours.This reaction is poured in the water.With water ethyl acetate extraction (2 *).With organic phase water, the salt water washing that merges, and use dried over sodium sulfate, filter and vacuum concentration, obtained this title compound.Resistates by the silica gel chromatography purifying, with hexane/ethyl acetate/methyl alcohol (80:15:5) wash-out, has been obtained required product (2.0g, 53%).

Embodiment 239e

4-[2-amino-4-(3-dimethylamino-benzoyl-amido)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2-two chloro-ethyl esters

(2.0g is 3.6mmol) according to method and Fe and the NH of embodiment 9E with the product of embodiment 239d ₄The Cl reaction has obtained required product (1.1g, 58%).

Embodiment 239f

In sealed tube, product (90mg with embodiment 9B, 0.48mmol) with the product (248mg of embodiment 239e, 0.48mmol) in acetate (10mL), reacted 5 minutes in 125 ℃, obtained the crude product of this title compound,, obtained product by using the HPLC purifying of TFA, be trifluoroacetate (40mg, 13%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：2.72 (s，3H)2.96(s，6H)4.54(d，J＝5.15Hz，2H)6.51(t，J＝5.15Hz，1H)6.95(dd，J＝7.35，1.84Hz，1H)7.18-7.24(m，4H)7.30-7.40(m，4H)7.71(dd，J＝8.64，2.39Hz，1H)7.85(d，J＝8.82Hz，1H)8.09(d，J＝2.57Hz，1H)8.87(s，1H)8.93(d，J＝8.46Hz，1H)10.05(s，1H)10.43(s，1H)；MS(ESI+)m/z?662(M+H)+。

Embodiment 240

Thiophene-2-carboxylic acid [4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-acid amides

Embodiment 240a

Thiophene-2-carboxylic acid (4-fluoro-3-nitro-phenyl)-acid amides

This title compound is such synthetic: be dissolved in 4-fluoro-3-nitro-phenyl amine (2.00g among the THF (25ml) with 10 fens clockwise, 12.81mmol) and Hunig ' s alkali (3.312g, 25.62mmol) middle dropping thiophene-2-carbonyl chlorine (1.878g, 12.81mmol).This reaction mixture stirring at room 1 hour, is added entry, collect this title compound, obtained this title compound (3.25g, 95%) by filtering.

Embodiment 240b

Thiophene-2-carboxylic acid [4-(4-hydroxyl-phenyl sulfenyl)-3-nitro-phenyl]-acid amides

(1.50g 5.63mmol) is dissolved among the DMF, adds K with the product of embodiment 240a ₂CO ₃(1.55g, 11.27mmol) and 4-sulfydryl-phenol (711mg, 5.634mmol).Then this reaction mixture was heated 2 hours at 80 ℃.This reaction mixture is cooled to room temperature, and dilute with water, then with ethyl acetate extraction to isolate required compound (1.66g, 79%).

Embodiment 240C

Thiophene-2-carboxylic acid [3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-acid amides

With the product of embodiment 240b according to the method for embodiment 9E with Fe and NH ₄The Cl reduction has obtained this title compound (800mg, 52%).

Embodiment 240d

With the product of embodiment 8E (100mg, 0.462mmol) and the product of embodiment 240C (158mg 0.462mmol) is dissolved among the HOAc, and places 10 minutes in 120 ℃ of oil baths of preheating. then this reaction mixture is cooled to room temperature.Solvent removed in vacuo, and, obtained product with the HPLC purifying of oily crude product by use TFA, be trifluoroacetate (32mg, 13%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.36(d，J＝6.99Hz，6H)，6.70(ddd，J＝9.19，2.94，2.57Hz，2H)，7.13-7.20(m，3H)，7.20-7.25(m，1H)，7.61(dd，J＝8.64，2.39Hz，1H)，7.82-7.90(m，2H)，7.94(s，1H)，8.02(d，J＝2.57Hz，1H)，8.78(s，1H)，8.96(d，J＝8.82Hz，1H)，9.78(s，1H)，10.43(s，1H)；

MS(ESI+)m/z?514(M+TFA+H)+；(ESI-)m/z?512(M+TFA-H)-。

Embodiment 241

5-bromo-thiophene-2-carboxylic acid [4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-acid amides

Embodiment 241a

5-bromo-thiophene-2-carbonyl chlorine

With 5-bromo-thiophene-2-carboxylic acid (2.00g 10.47mmol) is dissolved among the DCM (10mL), add oxalyl chloride (1.99g, 15.71mmol) and the DMF (100 μ L) of catalytic amount.Stirring at room 1 hour, solvent removed in vacuo was directly used in subsequent reaction immediately with this reaction mixture.

Embodiment 241b

5-bromo-thiophene-2-carboxylic acid (4-fluoro-3-nitro-phenyl)-acid amides

With the product of embodiment 241a (2.178g, 10.25mmol) be dissolved in 4-fluoro-3-nitro-phenyl amine among the THF (25mL) (1.60g, 10.25mmol) and Hunig ' s alkali (2.484g, 19.22mmol) reaction.This reaction mixture stirring at room 1 hour, is added entry, and collect this title compound (2.00g, 78%) by filtering.

Embodiment 241c

5-bromo-thiophene-2-carboxylic acid [4-(4-hydroxyl-phenyl sulfenyl)-3-nitro-phenyl]-acid amides

(1.50g 4.34mmol) is dissolved among the DMF, adds K with the product of embodiment 241b ₂CO ₃(1.20g, 8.69mmol) and 4-sulfydryl-phenol (548mg, 4.34mmol).Then this reaction mixture was heated 2 hours at 80 ℃.This reaction mixture is cooled to room temperature, and dilute with water, come together to isolate required compound (1.54g, 78%) with ethyl acetate then.

Embodiment 241d

5-bromo-thiophene-2-carboxylic acid [3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-acid amides

With the product of embodiment 241c according to the method for embodiment 9E with Fe and NH ₄The Cl reduction has obtained this title compound (550mg, 27%).

Embodiment 241e

With the product of embodiment 8E (100mg, 0.462mmol) and the product of embodiment 241d (195mg 0.462mmol) is dissolved among the HOAc, and places 10 minutes in 120 ℃ of oil baths of preheating.Then this reaction mixture is cooled to room temperature, solvent removed in vacuo, and, obtained product with the HPLC purifying of oily crude product by use TFA, be trifluoroacetate (35mg, 14%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.35(d，J＝6.99Hz，6H)，6.65-6.73(m，2H)，7.08-7.20(m，3H)，7.38(d，J＝4.04Hz，1H)，7.57(dd，J＝8.64，2.39Hz，1H)，7.79-7.87(m，2H)，7.90(s，1H)，8.75(s，1H)，8.94(d，J＝8.46Hz，1H)，9.79(s，1H)，10.48(s，1H)；MS(ESI+)m/z?592(M+TFA+H)+；(ESI-)m/z?590(M+TFA-H)-。

Embodiment 242

N-[4-(the 4-tertiary butyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-trifluoromethyl-benzamide

Embodiment 242a

N-(4-fluoro-3-nitro-phenyl)-3-trifluoromethyl-benzamide

This title compound is such synthetic: the 4-fluoro-3-nitro-phenyl amine (2.00g in being dissolved in THF (25ml), 12.81mmol) and Hunig ' s alkali (3.312g, 25.62mmol) in via dripped in 10 minutes 3-trifluoromethyl-Benzoyl chloride (2.672g, 12.81mmol).This reaction mixture stirring at room 1 hour, is added entry then, and collect this title compound (3.11g, 97%) by filtering.

Embodiment 242b

N-[4-(the 4-tertiary butyl-phenyl sulfenyl)-3-nitro-phenyl]-3-trifluoromethyl-benzamide

(600mg 1.828mmol) is dissolved among the DMF (20ml), adds K with the product of embodiment 242a ₂CO ₃(505mg is 3.656mmol) with the 4-tertiary butyl-thiophenol (304mg, 1.828mmol.Then at this moment this reaction mixture is cooled to room temperature with this reaction mixture at 80 ℃ of heating 1hr., dilute with water, and by filtering collection this title compound (311mg, 35%).

Embodiment 242c

N-[3-amino-4-(the 4-tertiary butyl-phenyl sulfenyl)-phenyl]-3-trifluoromethyl-benzamide

With the product of embodiment 242b according to the method for embodiment 9E with Fe and NH ₄The Cl reduction has obtained this title compound (206mg, 70%).

Embodiment 242d

With the product of embodiment 8E (100mg, 0.462mmol) and the product of embodiment 242c (206mg 0.462mmol) is dissolved among the HOAc, and places 10 minutes in 120 ℃ of oil baths of preheating.Then this reaction mixture is cooled to room temperature, and solvent removed in vacuo.The oily crude product by using the HPLC purifying of TFA, has been obtained product, be trifluoroacetate (20mg, 14%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm1.09-1.17(m，9H)，1.34(d，J＝6.99Hz，6H)，7.08-7.18(m，4H)，7.54(d，J＝8.46Hz，1H)，7.73-7.85(m，3H)，8.00(d，J＝7.72Hz，1H)，8.08(s，1H)，8.24-8.32(m，2H)，8.72(s，1H)，8.87(d，J＝8.46Hz，1H)，10.75(s，1H)；MS(ESI+)m/z?616(M+TFA+H)+；(ESI-)m/z?614(M+TFA-H)-。

Embodiment 243

N-[3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-p-methylphenyl sulfenyl-phenyl]-3-trifluoromethyl-benzamide

Embodiment 243a

N-(3-nitro-4-p-methylphenyl sulfenyl-phenyl)-3-trifluoromethyl-benzamide

(600mg 1.828mmol) is dissolved among the DMF (20mL), adds K with the product of embodiment 242b ₂CO ₃(505mg, 3.656mmol) and 4-methyl-thiophenol (227mg, 1.828mmol).Then this reaction mixture was heated 1 hour at 80 ℃.At this moment this reaction mixture is cooled to room temperature, dilute with water, and by filtering collection this title compound (611mg, 77%).

Embodiment 243b

N-(3-amino-4-p-methylphenyl sulfenyl-phenyl)-3-trifluoromethyl-benzamide

With the product of embodiment 243a according to the method for embodiment 9E with Fe and NH ₄The Cl reduction has obtained this title compound (420mg, 73%).

Embodiment 243c

With the product of embodiment 8E (100mg, 0.462mmol) and the product of embodiment 243b (186mg 0.462mmol) is dissolved among the HOAc, and places 10 minutes in 120 ℃ of oil baths of preheating.Then this reaction mixture is cooled to room temperature, and solvent removed in vacuo. the oily crude product by using the HPLC purifying of TFA, has been obtained product, be trifluoroacetate (10mg, 3%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.35(d，J＝6.99Hz，6H)，2.16-2.20(m，3H)，6.96-7.02(m，2H)，7.10(d，J＝8.46Hz，2H)，7.42(d，J＝8.46Hz，1H)，7.72(dd，J＝8.46，2.21Hz，1H)，7.80(t，J＝7.91Hz，2H)，7.99(d，J＝8.09Hz，1H)，8.08(s，1H)，8.22-8.30(m，2H)，8.72(s，1H)，8.89(d，J＝9.56Hz，1H)，10.73(s，1H)；MS(ESI+)m/z?574(M+TFA+H)+；(ESI-)m/z?572(M+TFA-H)-。

Embodiment 244

4-(4-amino-3-methyl-phenoxy group)-N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

This title compound makes like this: carry out Boc method according to embodiment 10A-C, and with product and the product coupling of implementing 100.Crude product by using the HPLC purifying of TFA, has been obtained this title compound, be trifluoroacetate (0.09g, 44%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.34(d，J＝6.62Hz，6H)，2.09(s，3H)，3.12-3.39(m，1H)，6.72-6.90(m，3H)，6.99(d，J＝8.46Hz，1H)，7.49-7.60(m，2H)，7.71-7.78(m，2H)，7.86(d，J＝8.46Hz，1H)，7.98(dd，J＝8.46，2.21Hz，1H)，8.12(d，J＝1.84Hz，1H)，8.88(s，1H)，8.96(d，J＝8.46Hz，1H)，10.37(s，.1H)，11.42(s，1H)；MS(ESI+)m/z?583(M+H)+。

Embodiment 245

4-[4-(3-dimethylamino-benzoyl-amido)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2-two chloro-ethyl esters

Use the 3-dimethylaminobenzoic acid to substitute the 3-bromo-benzoic acid, in sealed tube with the product (80mg of embodiment 8E, 0.37mmol) with the product of embodiment 100 reaction 5 minutes, obtained the crude product of this title compound, by using the HPLC purifying of TFA, obtained product, be trifluoroacetate (30mg, 10%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.35(d，J＝6.99Hz，6H)2.96(s，6H)3.26(q，1H)4.53(d，J＝5.15Hz，2H)6.50(t，J＝5.15Hz，1H)6.94(dd，J＝7.54，2.02Hz，1H)7.18-7.23(m，4H)7.29-7.40(m，4H)7.70(dd，J＝8.64，2.39Hz，1H)7.82(d，J＝8.46Hz，1H)8.06(s，1H)8.77(s，1H)8.91(d，J＝8.46Hz，1H)10.05(s，1H)10.39(s，1H)；MS(ESI+)m/z?690(M+H)+。

Embodiment 246

4-(4-amino-2-methyl-phenoxy group)-N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

This title compound makes like this: carry out the Boc method according to embodiment 10A-C, and substitute the 4-amino-phenol with 4-amino-2-methyl phenol in step 320C.Product with product and embodiment 8E reacts then.Crude product by using the HPLC purifying of TFA, has been obtained this title compound, be trifluoroacetate (0.09g, 44%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.35(d，J＝6.62Hz，6H)，2.00(s，3H)，3.15-3.39(m，1H)，6.60-6.73(m，2H)，6.76(d，J＝8.82Hz，1H)，6.85(d，J＝8.46Hz，1H)，7.44-7.65(m，2H)，7.69-7.80(m，2H)，7.87(d，J＝8.46Hz，1H)，7.95(dd，J＝8.46，2.21Hz，1H)，8.12(d，J＝2.21Hz，1H)，8.88(s，1H)，9.00(d，J＝8.82Hz，1H)，10.36(s，1H)，11.41(s，1H)；MS(ESI+)m/z?583(M+H) ⁺。

Embodiment 247

N-[4-(4-benzyloxy-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-4-bromo-benzamide

Embodiment 247a

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

With 4-fluoro-3-N-methyl-p-nitroaniline (0.5g, 3.2mmol), the 4-bromo-benzoyl chloride (0.702g, 3.2mmol), (0.56ml, 3.2mmol) mixture in methylene dichloride (10mL) was stirring at room 2 hours for diisopropylethylamine.This mixture is diluted with methylene dichloride (50mL), and, use anhydrous sodium sulfate drying then, filter and vacuum concentration, obtained this title compound, be yellow solid (0.89g, 82%) with 10% sodium bicarbonate and the washing of 10% sodium-chlor.

Embodiment 247b

N-[4-(4-benzyloxy-phenoxy group)-3-nitro-phenyl]-4-bromo-benzamide

With the product of embodiment 247a. (0.89g, 2.63mmol) with cesium carbonate (0.85g, 2.63mmol) and 4-benzyloxy phenol (0.53g, 2.63mmol) mixing among DMF (10mL), and stirring at room 60 hours altogether.This reaction mixture with ethyl acetate (100mL) dilution, is handled with 2N HCl (20ml).Isolate organic layer, and use 2N NaOH, anhydrous sodium sulfate drying is used in the washing of 2,10% sodium-chlor. and filter out siccative, and, obtained this title compound, be yellow solid (1.18g, 86%) solvent vacuum-evaporation.

Embodiment 247c

N-[3-amino-4-(4-benzyloxy-phenoxy group)-phenyl]-4-bromo-benzamide

With the product of embodiment 247b (1.18g, 2.27mmol), iron powder (0.51g, 9.1mmol) and ammonium chloride (0.14g, 2.5mmol) reflux 1.5 hours in methyl alcohol (10ml), THF (10ml) and water (5mL) solution.The gained mixture is filtered, and with hot methanol (50ml) washing, and vacuum concentration is to the oily resistates.Resistates is diluted with ethyl acetate (100mL), and water and the washing of 10% sodium-chlor, anhydrous sodium sulfate drying used then.Filter out siccative, and, obtained this title compound (0.81g, 73%) solvent removed in vacuo.

Embodiment 247d

N-[4-(4-benzyloxy-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-4-bromo-benzamide

With the product of embodiment 8E (73.5mg, 0.339mmol) and the product of embodiment 247c (166mg, 0.339mmol) solution in acetate (2mL) is being preheated in 130 ℃ the oil bath and was stirring 10 minutes.Then this mixture is cooled to room temperature, vacuum is removed acetate, and the gained resistates is passed through the silica gel chromatography purifying, from 99:1 CH ₂Cl ₂/ MeOH begins to 97:3CH ₂Cl ₂/ MeOH carries out gradient elution.Merge level part of containing product, vacuum concentration has obtained this title compound, is tawny solid (160mg, 69%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.24-1.36(m，6H)3.13-3.24(m，1H)4.98(s，2H)6.89(s，4H)6.96(d，J＝9.19Hz，1H)7.30-7.45(m，5H)7.54(d，J＝8.82Hz，1H)7.65(dd，J＝9.01，2.02Hz，1H)7.76(d，J＝8.46Hz，2H)7.92(d，J＝8.46Hz，2H)8.04(d，J＝1.84Hz，1H)8.56(s，1H)8.74(d，J＝8.46Hz，1H)9.89(s，1H)10.41(s，1H)；MS(ESI+)m/z?661(M+H)+，(ESI-)m/z?659(M-H)-。

Embodiment 248

N-[4-(4-benzyloxy-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-bromo-benzamide

Embodiment 248a

N-[3-amino-4-(4-benzyloxy-phenoxy group)-phenyl]-3-bromo-benzamide

This title compound is the method for describing according among embodiment 247a, 247b, the 247c, substitutes with the 3-bromo-benzoyl chloride that the 4-bromo-benzoyl chloride makes, and has obtained this title compound (0.62g, 66%).

Embodiment 248b

N-[4-(4-benzyloxy-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-bromo-benzamide

With the product of embodiment 8E (63.8mg, 0.294mmol) and the product of embodiment 248a (144mg, 0.294mmol) solution in acetate (2mL) is being preheated in 130 ℃ the oil bath and was stirring 10 minutes.Then this mixture is cooled to room temperature, vacuum is removed acetate, and the gained resistates is passed through the silica gel chromatography purifying, from 99:1 CH ₂Cl ₂/ MeOH begins to 97:3CH ₂Cl ₂/ MeOH carries out gradient elution.Merge level part of containing product, vacuum concentration is this title compound (150mg, 75%) to yellow solid. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm： 1.30(d，J＝6.99Hz，6H)3.11-3.26(m，1H)4.98(s，2H)6.89(s，4H)6.96(d，J＝8.82Hz，1H)7.28-7.46(m，6H)7.46-7.60(m，2H)7.65(dd，J＝8.82，2.57Hz，1H)7.81(d，J＝6.99Hz，1H)7.97(d，J＝8.09Hz，1H)8.04(d，J＝2.57Hz，1H)8.16(s，1H)8.56(s，1H)8.74(d，J＝8.82Hz，1H)9.89(s，1H)10.44(s，1H)；MS(ESI+)m/z?661(M+H)+，(ESI-)m/z?659(M-H)-。

Embodiment 249

N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-propyl group amino-phenoxy group)-benzamide

To methylene chloride (2mL, 9:1) product of Nei embodiment 10 (57mg, 0.07mmol) and sodium triacetoxy borohydride (32mg, add in 0.15mmol) propionic aldehyde (7.3 μ L, 0.1mmol).With mixture stirring at room 2 hours, and evaporation.Resistates by using the anti-phase preparation HPLC purifying of AA method, has been obtained this title compound (10mg, 23%). ¹H?NMR(300MHz，DMSO-d6)δ?ppm：0.93(t，J＝7.35Hz，3H)1.32(d，J＝6.62Hz，6H)1.54(m，2H)2.92(m，2H)3.21(m，1H)5.55(t，J＝5.52Hz，1H)6.55(m，2H)6.84(m，3H)7.52(m，2H)7.60(d，J＝8.82Hz，1H)7.76(m，2H)7.85(dd，J＝8.82，2.21Hz，1H)8.16(d，J＝2.21Hz，1H)8.62(s，1H)8.83(d，J＝8.46Hz，1H)10.00(s，1H)10.29(s，1H)；MS(ESI+)m/z?611?613(M+H)+。

Embodiment 250

N-(4-bromo-phenyl)-4-(4-dipropyl amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

This title compound (6mg, 13%) is to obtain during purifying derives from the mixture of embodiment 249. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：0.86(t，J＝7.35Hz，6H)1.32(d，J＝6.99Hz，6H)1.48(m，4H)3.16(m，5H)6.60(d，J＝9.19Hz，2H)6.89(m，3H)7.53(m，2H)7.58(d，J＝8.46Hz，1H)7.76(m，2H)7.86(dd，J＝8.46，2.21Hz，1H)8.16(d，J＝1.84Hz，1H)8.61(s，1H)8.80(d，J＝8.46Hz，1H)9.98(s，1H)10.30(s，1H)；MS(ESI+)m/z?653655(M+H)+。

Embodiment 251

N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-[4-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-2-methyl-phenoxy group]-benzamide

This title compound is to be made by the product of embodiment 246 and the product of embodiment 8E according to the method among the embodiment 101.Crude product by using the HPLC purifying of TFA, has been obtained this title compound, be trifluoroacetate (0.02g, 7%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.33(d，J＝6.99Hz，6H)，1.35(d，J＝6.99Hz，6H)，2.16(s，3H)，3.19-3.36(m，2H)，6.93(d，J＝8.82Hz，1H)，7.12(d，J＝8.46Hz，1H)，7.50-7.60(m，2H)，7.61-7.69(m，2H)，7.72-7.80(m，2H)，7.81-7.92(m，2H)，8.01(dd，J＝8.46，2.21Hz，1H)，8.17(d，J＝1.84Hz，1H)，8.85-8.91(m，2H)，8.97(d，J＝8.82Hz，1H)，9.01(d，J＝8.82Hz，1H)，10.40(s，1H)，11.07(s，1H)，11.25(s，1H)；MS(ESI+)m/z?754(M+H) ⁺。

Embodiment 252

N-[4-(4-amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 252a

[4-(4-benzoyl-amido-2-nitro-phenoxy)-phenyl] t-butyl carbamate

With N-(4-fluoro-3-nitrophenyl) benzamide (1.00g, 3.8mmol), N-Boc-4-hydroxyanilines (0.83g, 3.8mmol) and 85% KOH (0.51g, 7.7mmol) mixture in DMSO (20mL) in 80 ℃ the heating 1 hour, under agitation add H then ₂O (100ml).Gained oiliness crystal is extracted with EtOAc.With extraction liquid H ₂MgSO is used in O (3 times) and salt water washing ₄Drying is filtered and vacuum concentration, has obtained the crude product of this title compound, with it by using i-Pr ₂O washs purifying, has obtained required compound, is yellow crystals (1.59g, 92%).

Embodiment 252b

[4-(2-amino-4-benzoyl-amido phenoxy group) phenyl] t-butyl carbamate

With the product of embodiment 252a (1.50g, 3.3mmol), the Fe powder (0.78g, 13.4mmol) and NH ₄(0.71g is 13.4mmol) at THF (7.5mL) and H for Cl ₂Be heated to backflow gradually in the mixture of O (3mL), and refluxed 19 hours.With this reaction mixture at EtOAc and 10%NaHCO ₃Between distribute, filter then in (via diatomite).With organic layer salt water washing, use MgSO ₄Drying is filtered and vacuum concentration, has obtained the crude product of this title compound, and it by silica gel chromatography, with 1:1 normal hexane/EtOAc wash-out, has been obtained this title compound, is yellow foam (1.32g, 94%).

Embodiment 252c

[4-[4-benzoyl-amido-2-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) phenoxy group] phenyl] t-butyl carbamate

With the product of embodiment 252b (0.15g, 0.7mmol) and the product (0.7mmol) of embodiment 8E in HOAc (3mL) under nitrogen in 120 ℃ of heating 5 minutes.Under stirring with this reaction mixture at i-Pr ₂O and 10% NaHCO ₃Between distribute.Collect the gained crystal by filtering, use H ₂O and i-Pr ₂O washing, and vacuum-drying have obtained this title compound, are light brown crystal (0.50g, 100%).

Embodiment 252d

This title compound is the method by embodiment 10E, makes with the product of the product alternate embodiment 10D of embodiment 252c.

Embodiment 253

Pyridine-2-formic acid [4-(4-amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-acid amides

Embodiment 253a

[4-[2-nitro-4-[(pyridine-2-carbonyl) amino] phenoxy group] phenyl] t-butyl carbamate

This title compound is the method according to embodiment 252a, substitutes N-(4-fluoro-3-nitrophenyl) benzamide with pyridine-2-formic acid (4-fluoro-3-nitro-phenyl)-acid amides and makes, and has obtained this title compound, is pale yellow crystals (94%).

Embodiment 253b

[4-[2-amino-4-[(pyridine-2-carbonyl) amino] phenoxy group] phenyl] t-butyl carbamate

The product of embodiment 253a is reacted according to the method for embodiment 252b, obtained this title compound, be light brown crystal (76%).

Embodiment 253c

[4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-[(pyridine-2-carbonyl) amino] phenoxy group] phenyl] t-butyl carbamate

The product of embodiment 253b is reacted according to the method for embodiment 252c, obtained this title compound, be light brown crystal (88%).

Embodiment 253d

(350mg, 0.59mmol) with 4M HCl/1, the 4-dioxane was room temperature reaction 1 hour with the product of embodiment 253c.Solvent removed in vacuo, and crude product washed with EtOAc, this title compound (150mg, 50%) obtained. ¹H NMR (300MHz, DMSO-d ₆) δ ppm:1.32 (d, J=6.7Hz, 6H), 3.20 (septet, J=6.7Hz, 1H), 4.91 (br-s, 2H), 6.50 (d, J=8.1Hz, 2H), 6.71 (d, J=8.1Hz, 2H), 6.81 (d, J=8.9Hz, 1H), 7.57 (d, J=8.4Hz, 1H), 7.62-7.77 (m, 2H), 8.01-8.22 (m, 3H), 8.59 (s, 1H), 8.75 (d, J=3.7Hz, 1H), 8.82 (d, J=8.8Hz, 1H), 9.90 (s, 1H), 10.69 (s, 1H); MS (ESI-) m/z 490 (M-H)-, (ESI+) m/z492 (M+H)+.

Embodiment 254

N-[4-(4-amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3,5-two chloro-benzamide

Embodiment 254a

3,5-two chloro-N-(4-fluoro-3-nitro-phenyl)-benzamide

To 4-fluoro-3-nitro-phenyl amine (3.0g, 20mmol) add in the solution in methylene dichloride (60mL) pyridine (3.2g, 40.0mmol).This solution is cooled to 0 ℃, and adds 3, and the 5-dichlorobenzoyl chloride (4.0g, 20.0mmol).Remove ice bath, and allow this reaction via being warmed to room temperature in 18 hours.This reaction is poured in the water, formed precipitation.Collect solid, and wash with excessive water.Then with this solid 50 ℃ of vacuum-dryings 18 hours.This solid is placed in the ethyl acetate.Ethyl acetate with 5% HCl, water, salt water washing, and is used dried over sodium sulfate, filter and vacuum concentration, obtained this title compound (5.8g, 92%).

Embodiment 254b

{ 4-[4-(3; 5-two chloro-benzoyl-amidos)-2-nitro-phenoxy group]-phenyl }-t-butyl carbamate is to the product (2.0g of embodiment 254a; 6.1mmol) add KOH (1.4g in the solution in DMSO (50mL); 24.3mmol) and the N-Boc-4-amino-phenol (1.3g, 6.1mmol).This mixture was heated 4 hours at 80 ℃.Should react the cooling and pour in the water.With water ethyl acetate extraction (2 *).With organic phase water, the salt water washing that merges, and use dried over sodium sulfate, filter and vacuum concentration, obtained this title compound.Resistates by the silica gel chromatography purifying, with hexane/ethyl acetate/methyl alcohol (80:10:10) wash-out, has been obtained required product (1.6g, 51%).

Embodiment 254c

(1.1g is 2.1mmol) according to method and Fe and the NH of embodiment 9E with the product of embodiment 254b for { 4-[2-amino-4-(3,5-two chloro-benzoyl-amidos)-phenoxy group]-phenyl }-t-butyl carbamate ₄The Cl reaction has obtained required product (0.6g, 58.8%).

Embodiment 254d

In sealed tube, product (70mg with embodiment 8E, 0.32mmol) with the product (162mg of embodiment 254c, 0.32mmol) in acetate (10mL), heated 5 minutes in 125 ℃, obtained the crude product of this title compound,, obtained product by using the HPLC purifying of TFA, be trifluoroacetate (60mg, 27%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.33(d，J＝6.99Hz，6H)3.27(q，1H)6.96(d，2H)7.01-7.09(m，3H)7.69(dd，J＝9.19，2.57Hz，1H)7.81-7.92(m，3H)7.99(d，J＝1.84Hz，2H)8.85(s，1H)893(d，J＝8.82Hz，1H)10.64(s，1H)；MS(ESI+)m/z?559(M+H)+。

Embodiment 255

Furans-2-formic acid [4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-acid amides

Embodiment 255a

Furans-2-formic acid (4-fluoro-3-nitro-phenyl)-acid amides

This title compound is such synthetic: the 4-fluoro-3-nitro-phenyl amine (2.00g in being dissolved in THF (25ml), 12.81mmol) and Hunig ' s alkali (3.312g, 25.62mmol) in via drip to add in 10 minutes furans-2-carbonyl chlorine (1.672g, 12.81mmol).This reaction mixture adds entry then stirring at room 1 hour, and collects this title compound by filtering, and has obtained this title compound (2.90g, 90%).

Embodiment 255b

Furans-2-formic acid [4-(4-hydroxyl-phenyl sulfenyl)-3-nitro-phenyl]-acid amides

(1.00g 2.89mmol) is dissolved among the DMF, to wherein adding K with the product of embodiment 255a ₂CO ₃(801mg, 5.79mmol) and 4-sulfydryl-phenol (366mg, 2.89mmol).Then this reaction mixture was heated 2 hours at 80 ℃.Then this reaction mixture is cooled to room temperature, and dilute with water, then with ethyl acetate extraction to isolate required compound (1.00g, 99%).

Embodiment 255c

Furans-2-formic acid [3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-acid amides

With the product of embodiment 255b according to the method for embodiment 9E with Fe and NH ₄The Cl reduction has obtained this title compound (980mg, 90%).

Embodiment 255d

With the product of embodiment 8E (100mg, 0.462mmol) and the product of embodiment 255c (151mg 0.462mmol) is dissolved among the HOAc, and places 10 minutes in 120 ℃ of oil baths of preheating.Then this reaction mixture is cooled to room temperature, solvent removed in vacuo, and, obtained product with the HPLC purifying of oily crude product by use TFA, be trifluoroacetate (93mg, 45%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.36(d，J＝6.62Hz，6H)，6.64-6.73(m，3H)，7.09-7.20(m，3H)，7.34(d，J＝3.31Hz，1H)，7.63(dd，J＝8.64，2.39Hz，1H)，7.79-7.89(m，1H)，7.93-8.00(m，2H)，8.74-8.80(m，1H)，8.95(d，J＝8.82Hz，1H)，9.77(s，1H)，10.40(s，1H)；MS(ESI+)m/z?498(M+TFA+H)+；(ESI-)m/z?496(M+TFA-H)-。

Embodiment 256

Thiophene-2-carboxylic acid [4-(4-amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-acid amides

Embodiment 256a

Thiophene-2-carboxylic acid (4-fluoro-3-nitro-phenyl)-acid amides

This title compound is such synthetic: the 4-fluoro-3-nitro-phenyl amine (2.00g in being dissolved in THF (25mL), 12.81mmol) and Hunig ' s alkali (3.312g, 25.62mmol) in via drip to add in 10 minutes thiophene-2-carbonyl chlorine (1.878g, 12.81mmol).This reaction mixture adds entry then stirring at room 1 hour, and collects this title compound (3.25g, 95%) by filtering.

Embodiment 256b

(4-{2-nitro-4-[(thiophene-2-carbonyl)-amino]-phenoxy group }-phenyl)-t-butyl carbamate

The product of embodiment 256a is reacted according to the method for embodiment 172c, obtained this title compound (2.053g, 79%).

Embodiment 256c

(4-{2-amino-4-[(thiophene-2-carbonyl)-amino]-phenoxy group }-phenyl)-t-butyl carbamate

With the product of embodiment 256b according to the method for embodiment 9E with Fe and NH ₄The Cl reduction has obtained this title compound (1.25g, 65%).

Embodiment 256d

(4-{2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-[(thiophene-2-carbonyl)-amino]-phenoxy group }-phenyl)-t-butyl carbamate

With the product of embodiment 8E (100mg, 0.462mmol) and the product of embodiment 255c (197mg 0.462mmol) is dissolved among the HOAc, and places 10 minutes in 120 ℃ of oil baths of preheating.Then this reaction mixture is cooled to room temperature, and solvent removed in vacuo, this title compound (276mg, 100%) obtained.

Embodiment 256e

(276mg 0.462mmol) is dissolved in TFA at CH with the product of embodiment 256d ₂Cl ₂In the 1:1 mixture in, and stirring at room 2 hours.Solvent removed in vacuo, and, obtained product with the HPLC purifying of oily crude product by use TFA, be trifluoroacetate (33mg, 12%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.27-1.35(m，6H)，6.80-6.91(m，5H)，6.99(d，J＝9.19Hz，1H)，7.21-7.25(m，1H)，7.63(dd，J＝8.82，2.57Hz，1H)，7.81(d，J＝8.46Hz，1H)，7.87(d，J＝4.04Hz，1H)，8.01-8.03(m，2H)，8.82(s，1H)，8.91(d，J＝8.46Hz，1H)，10.39(s，1H)

MS(ESI+)m/z?497(M+TFA+H)+；(ESI-)m/z?495(M+TFA-H)-。

Embodiment 257

5-bromo-thiophene-2-carboxylic acid [4-(4-amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-acid amides

Embodiment 257a

(4-{4-[(5-bromo-thiophene-2-carbonyl)-amino]-2-nitro-phenoxy group }-phenyl)-t-butyl carbamate

With the product of embodiment 241b (1.50g 4.34mmol) is dissolved among the DMF, add KOH (469mg, 8.69mmol) and (4-hydroxyl-phenyl)-t-butyl carbamate (909mg, 4.34mmol).Then this reaction mixture was heated 2 hours at 80 ℃.This reaction mixture is cooled to room temperature, and dilute with water, ethyl acetate extraction used then.Use Na ₂SO ₄Drying is filtered and vacuum concentration, has obtained this title compound, has obtained this title compound (2.11g, 90%).

Embodiment 257b

(4-{2-amino-4-[(5-bromo-thiophene-2-carbonyl)-amino]-phenoxy group }-phenyl)-t-butyl carbamate

With the product of embodiment 257a according to the method for embodiment 9E with Fe and NH ₄The Cl reduction has obtained this title compound (922mg, 50%).

Embodiment 257c

4-[4-[(5-bromo-thiophene-2-carbonyl)-amino]-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-phenyl }-t-butyl carbamate

Product (100mg with embodiment 8E, 0.462mmol) and the product (233mg of embodiment 257b, 0.462mmol) be dissolved among the HOAc, and in 120 ℃ of oil baths of preheating, placed 10 minutes. then this reaction mixture is cooled to room temperature, and solvent removed in vacuo, obtained this title compound (312mg, 100%).

Embodiment 257d

(mg 0.462mmol) is dissolved in TFA at CH with the product of embodiment 257c ₂Cl ₂In the 1:1 mixture in, and stirring at room 2 hours.Solvent removed in vacuo, and, obtained product with the HPLC purifying of oily crude product by use TFA, be trifluoroacetate (16mg, 6%). ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.32(t，J＝6.99Hz，6H)，3.18-3.33(m，1H)，6.82-6.91(m，4H)，6.99(d，J＝9.19Hz，1H)，7.39(d，J＝4.04Hz，1H)，7.61(dd，J＝8.82，2.57Hz，1H)，7.81(d，J＝8.46Hz，1H)，7.86(d，J＝4.04Hz，1H)，7.99(d，J＝2.57Hz，1H)，8.81(s，1H)，8.91(d，J＝8.09Hz，1H)，10.45(s，1H)；MS(ESI+)m/z?575(M+TFA+H)+；(ESI-)m/z?573(M+TFA-H)-。

Embodiment 258

2-{4-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzoyl-amido]-phenyl }-the ethanimidic acid methyl esters

With N-(4-cyano methyl-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-methoxyl group-phenyl sulfenyl)-benzamide reacts according to the method for embodiment 150, obtained resistates, it is come purifying by development from methyl alcohol, obtained this title compound, be pale solid (15.9mg, 51%).1H?NMR(300MHz，DMSO-D6)δ?ppm：10.13-10.29(m，J＝1.84Hz，2H)，9.95(s，1H)，8.87(d，J＝8.46Hz，1H)，8.59(s，1H)，7.98(s，1H)，7.80(d，J＝8.09Hz，1H)，7.61-7.73(m，J＝8.46Hz，3H)，7.31(d，J＝8.46Hz，2H)，7.22(d，J＝8.46Hz，2H)，6.93(d，J＝9.19Hz，1H)，6.85(d，J＝8.46Hz，2H)，3.64(s，2H)，3.61(s，3H)，3.17-3.28(m，1H)，1.34(d，J＝6.99Hz，6H)；MS(ESI ⁺)m/z?580.2(M+H) ⁺，(ESI ^-)m/z?578.2(M-H) ^-。

Embodiment 259

N-(4-cyano group-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-methoxyl group-phenyl sulfenyl)-benzamide

According to the method for embodiment 137C, substitute 5-amino-ortho-cresol with the 4-aminobenzonitrile, will derive from product and the reaction of 4-aminobenzonitrile of embodiment 137B, after reaction product developed from methyl alcohol, obtained this title compound, be pale solid (20mg, 23%).1H?NMR(300MHz，DMSO-D6)δ?ppm：10.63(s，1H)，8.92(s，1H)，8.69(s，1H)，7.96(d，J＝8.82Hz，2H)，7.66-7.90(m，4H)，7.35-7.46(m，3H)，6.95-7.11(m，3H)，6.55-6.64(m，1H)，3.77(s，3H)，3.18-3.30(m，1H)，1.35(d，J＝6.99Hz，6H)；MS(ESI ⁺)m/z?547.3(M+H) ⁺，(ESI ^-)m/z545.3(M-H) ^-。

Embodiment 260

4-(4-hydroxyl-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-N-(3-trifluoromethyl-phenyl)-benzamide

Embodiment 260A

4-(4-methoxyl group-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-methyl benzoate is according to the method for embodiment 136C, product with the product alternate embodiment 8E of embodiment 29A, the product of embodiment 136B and the product of embodiment 29A are reacted, obtained this title compound.

Embodiment 260B

4-(4-methoxyl group-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-Benzoyl chloride

The product of embodiment 260A is reacted according to the method for embodiment 137A and 137B, obtained this title compound.

Embodiment 260C

4-(4-methoxyl group-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-N-(3-trifluoromethyl-phenyl)-benzamide

Method according to embodiment 137C, substitute 5-amino-ortho-cresol with 3-(trifluoromethyl) aniline, and the product with embodiment 260B substitutes the product that derives from embodiment 137B, product and 3-(trifluoromethyl) aniline reaction with embodiment 260B, after reaction product developed from methyl alcohol, obtained this title compound, be pale solid (43mg, 47%).

Embodiment 260D

According to the method for embodiment 150, use the product of the product alternate embodiment 138 of embodiment 260C, embodiment 260C is reacted, obtain resistates, it has been come purifying by development from methyl alcohol, obtained this title compound, be pale solid (33.3mg, 90%).1HNMR(300MHz，DMSO-D6)δ?ppm：11.74(s，1H)，10.54(s，1H)，10.01(s，1H)，9.19(s，1H)，9.11(d，J＝7.35Hz，1H)，8.90(s，1H)，8.19(s，1H)，7.86-8.08(m，4H)，7.60(t，J＝7.91Hz，1H)，7.46(d，J＝7.72Hz，1H)，7.24-7.38(m，2H)，7.03(d，J＝8.46Hz，1H)，6.73-6.91(m，2H)；MS(ESI ⁺)m/z?534.1(M+H) ⁺，(ESI ^-)m/z?532.2(M-H) ^-。

Embodiment 261

N-(4-fluoro-3-methyl-phenyl)-4-(4-hydroxyl-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 261A

N-(4-fluoro-3-methyl-phenyl)-4-(4-methoxyl group-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

According to the method for embodiment 260C, substitute 3-(trifluoromethyl) aniline with 4-fluoro-3-monomethylaniline, with product and the reaction of 4-fluoro-3-monomethylaniline of embodiment 260B, after reaction product developed from methyl alcohol, obtained this title compound, be pale solid (44mg, 52%).

Embodiment 261B

According to the method for embodiment 150,, the product of embodiment 261A is reacted with the product of the product alternate embodiment 138 of embodiment 261A, obtain resistates, it has been come purifying by development from methyl alcohol, obtained this title compound, be pale solid (30.4mg, 82%).1H?NMR(300MHz，DMSO-D6)δ?ppm：10.22(s，1H)，10.01(s，1H)，9.20(d，J＝3.68Hz，1H)，9.12(d，J＝8.82Hz，1H)，8.92(s，1H)，7.83-8.00(m，4H)，7.64(dd，J＝7.17，2.39Hz，1H)，7.50-7.60(m，1H)，7.29-7.34(m，2H)，7.12(t，J＝9.19Hz，1H)，7.02(d，J＝8.46Hz，1H)，6.80-6.85(m，2H)，2.23(d，J＝1.84Hz，3H)；MS(ESI ⁺)m/z498.1(M+H) ⁺，(ESI-)m/z?496.1(M-H) ^-。

Embodiment 262

N-(4-cyano methyl-phenyl)-4-(4-methoxyl group-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Method according to embodiment 137C, substitute 5-amino-ortho-cresol with 4-aminobenzyl prussiate, and the product with embodiment 260B substitutes the product that derives from embodiment 137B, product and the reaction of 4-aminobenzyl prussiate with embodiment 260B, after reaction product developed from methyl alcohol, obtained this title compound, be pale solid (54.7mg, 64%).1H?NMR(300MHz，DMSO-D6)δ?ppm：10.60(s，1H)，10.26(s，1H)，9.09(s，1H)，8.95(s，1H)，8.65(s，1H)，7.98(s，1H)，7.64-7.89(m，J＝8.46Hz，4H)，7.36-7.47(m，2H)，7.31(d，J＝8.82Hz，2H)，6.91-7.07(m，3H)，3.99(s，2H)，3.78(s，3H)；MS(ESI ⁺)m/z519.4(M+H) ⁺，(ESI ^-)m/z?517.1(M-H) ^-。

Embodiment 263

N-(4-cyano group-phenyl)-4-(4-methoxyl group-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Method according to embodiment 137C, substitute 5-amino-ortho-cresol with the 4-aminobenzonitrile, and the product with embodiment 260B substitutes the product that derives from embodiment 137B, product and the reaction of 4-aminobenzonitrile with embodiment 260B, after reaction product developed from methyl alcohol, obtained this title compound, be pale solid (51.5mg, 62%).1H?NMR(300MHz，DMSO-D6)δ?ppm：11.11(s，1H)，10.62(s，1H)，9.11(s，1H)，9.00(d，J＝5.51Hz，1H)，8.57-8.80(m，1H)，7.97(d，J＝8.82Hz，2H)，7.68-7.90(m，J＝8.82Hz，3H)，7.38-7.52(m，2H)，6.88-7.12(m，3H)，6.45-6.71(m，1H)，3.77(s，3H)。

Embodiment 264

N-(3-dimethylamino-phenyl)-4-(4-methoxyl group-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Method according to embodiment 137C, use N, N-dimethyl-1, the 3-phenylenediamine substitutes 5-amino-ortho-cresol, and the product with embodiment 260B substitutes the product that derives from embodiment 137B, with product and the N of embodiment 260B, N-dimethyl-1, the reaction of 3-phenylenediamine, after reaction product developed from methyl alcohol, obtained this title compound, be pale solid (45mg, 52%).1H?NMR(300MHz，DMSO-D6)δ?ppm：10.33(s，1H)，9.99(s，1H)，9.11(dd，J＝4.41，1.84Hz，1H)，8.96(dd，J＝8.46，1.84Hz，1H)，8.63(s，1H)，8.01(d，J＝1.84Hz，1H)，7.82(dd，J＝8.46，1.84Hz，1H)，7.70(dd，J＝8.09，4.41Hz，1H)，7.36-7.43(m，2H)，7.10-7.20(m，3H)，6.97-7.04(m，3H)，6.48(td，J＝4.50，2.39Hz，1H)，3.77(s，3H)，2.88(s，6H)；MS(ESI ⁺)m/z?523.5(M+H) ⁺，(ESI ^-)m/z?521.2(M-H) ^-。

Embodiment 265

N-[5-(4-hydroxyl-phenyl sulfenyl)-4-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-2-methyl-phenyl]-2-phenyl-ethanamide

Embodiment 265A

N-(5-chloro-2-methyl-4-nitro-phenyl)-2-phenyl-ethanamide

(0.475g, 2.55mmol) (0.394g, 2.55mmol) mixture heating up in toluene (10mL) refluxed 4 hours, was cooled to room temperature then with the phenyl Acetyl Chloride 98Min. with 5-chloro-2-methyl-4-nitrophenyl amine.Under cooling, crystallization has gone out solid from this reaction mixture, separate by vacuum filtration, and dry, obtained this title compound, be yellow solid (0.330g, 43%).

Embodiment 265B

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

With the product of embodiment 265A (0.305g, 1.0mmol), 4-mercapto-phenol (0.151g, 1.2mmol, 1.2eq) and cesium carbonate (0.782g, 2.4mmol, 2.4eq) in dimethyl formamide (10mL) in 110 ℃ the heating 2 hours, be cooled to room temperature, and pour in the frozen water (100mL).(3 * 150mL) extract, and the organic phase that merges is washed with saturated sodium-chloride water solution, use anhydrous magnesium sulfate drying, filter, and evaporate with ethyl acetate with this mixture.Resistates by the silica gel chromatography purifying, with 1:1 hexane/ethyl acetate wash-out, has been obtained this title compound, be yellow solid (0.282g, 72%).

Embodiment 265C

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

With the product of embodiment 265B (0.282g, 0.715mmol), iron powder (0.160g, 2.86mmol, 4.0eq) and ammonium chloride (0.0469g, 0.858mmol 1.2eq) reflux 1.5 hours in tetrahydrofuran (THF) (6mL), methyl alcohol (6mL) and water (2mL) is cooled to room temperature then.Then with this reaction mixture via diatomite filtration, and with diatomite with methyl alcohol (50mL) washing.With filtrate evaporated under reduced pressure, and resistates distributed between ethyl acetate and water.With the organic phase anhydrous magnesium sulfate drying, filter, and evaporation, obtained orange, it is developed with methylene dichloride, obtained this title compound, be yellow powder (0.246g, 94%).

Embodiment 265D

With the product of embodiment 265C (0.071g, 0.19mmol) and the product of embodiment 8E (0.0463g, 0.21mmol) mixture in Glacial acetic acid (1mL) heated 15 minutes in 135 ℃ of oil baths.Then solvent is evaporated under nitrogen gas stream, and resistates is passed through the silica gel chromatography purifying,, obtained this title compound, be beige solid (0.0502g, 48%) with ethanol/methylene gradient (0-5% MeOH) wash-out.1H?NMR(300MHz，DMSO-D6)δ?ppm：9.95(s，1H)，9.77(s，1H)，9.51(s，1H)，8.81(d，J＝8.46Hz，1H)，8.52(s，1H)，7.59(d，J＝8.46Hz，1H)，7.20-7.39(m，6H)，7.13-7.20(m，2H)，7.05(s，1H)，6.73(d，J＝8.82Hz，2H)，3.61(s，2H)，3.14-3.27(m，1H)，2.11(s，3H)，1.32(d，J＝6.62Hz，6H)；MS(ESI ⁺)m/z?536.2(M+H) ⁺，(ESI ^-)m/z?534.2(M-H) ^-。

Embodiment 266

3-bromo-N-[5-(4-hydroxyl-phenyl sulfenyl)-4-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-2-methyl-phenyl]-benzamide

Embodiment 266A

3-bromo-N-(5-chloro-2-methyl-4-nitro-phenyl)-benzamide

(0.373g, 2.00mmol) (0.439g, 2.00mmol) mixture heating up in toluene (10mL) refluxed 1.5 hours, and was cooled to room temperature with the 4-bromo-benzoyl chloride with 5-chloro-2-methyl-4-nitrophenyl amine.Under cooling, crystallization has gone out solid from this reaction mixture, separate by vacuum filtration, and dry, obtained this title compound, be gray solid (0.241g, 33%).

Embodiment 266B

3-bromo-N-[5-(4-hydroxyl-phenyl sulfenyl)-2-methyl-4-nitro-phenyl]-benzamide

Method according to embodiment 265B, product with the product alternate embodiment 265A of embodiment 266A, the product of embodiment 266A is reacted, obtained resistates, it by the silica gel chromatography purifying, with ethanol/methylene gradient (0-5% methyl alcohol) wash-out, has been obtained this title compound, be yellow solid (0.204g, 71%).

Embodiment 266C

N-[4-amino-5-(4-hydroxyl-phenyl sulfenyl)-2-methyl-phenyl]-3-bromo-benzamide

According to the method for embodiment 265C, with the product of the product alternate embodiment 265B of embodiment 266B, the product of embodiment 266B is reacted, obtained this title compound, be brown solid (0.164g, 86%).This product need not directly use by the silica gel chromatography purifying.

Embodiment 266D

Method according to embodiment 265D, product with the product alternate embodiment 265C of embodiment 266C, the product of embodiment 266C is reacted, obtained resistates, it by the silica gel chromatography purifying, is carried out wash-out with ethanol/methylene gradient (0-5% methyl alcohol), obtained this title compound, be yellow solid (0.0356g, 52%).1H?NMR(300MHz，DMSO-D6)δ?ppm：10.03(s，1H)，10.01(s，1H)，9.76(s，1H)，8.84(d，J＝8.46Hz，1H)，8.56(s，1H)，8.10(s，1H)，7.93(d，J＝8.09Hz，1H)，7.80(dd，J＝8.09，1.10Hz，1H)，7.61(d，J＝8.82Hz，1H)，7.48(t，J＝7.91Hz，1H)，7.33(s，1H)，7.17-7.24(m，2H)，6.97(s，1H)，6.70-6.76(m，J＝8.46Hz，2H)，3.17-3.28(m，1H)，2.19(s，3H)，1.34(d，J＝6.62Hz，6H)；MS(ESI ⁺)m/z?600.2(M+H) ⁺，602.2(M+H) ⁺，(ESI ^-)m/z?598.1(M-H) ^-?600.1(M-H) ^-。

Embodiment 267

N-[5-(4-hydroxyl-phenyl sulfenyl)-4-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-2-methyl-phenyl]-benzamide

Embodiment 267A

N-(5-chloro-2-methyl-4-nitro-phenyl)-benzamide

With 5-chloro-2-methyl-4-nitrophenyl amine (0.560g, 3.00mmol) and Benzoyl chloride (0.422g, 3.00mmol) mixture heating up in toluene (15mL) refluxed 1.5 hours, and was cooled to room temperature.Under the cooling, crystallization has gone out solid from this reaction mixture, separate by vacuum filtration, and dry, obtained this title compound, be gray solid (0.276g, 32%).

Embodiment 267B

N-[5-(4-hydroxyl-phenyl sulfenyl)-2-methyl-4-nitro-phenyl is foretold benzamide

Method according to embodiment 265B, product with the product alternate embodiment 265A of embodiment 267A, the product of embodiment 267A is reacted, obtained resistates, it by the silica gel chromatography purifying, with ethyl acetate/hexane gradient (0-50% ethyl acetate) wash-out, has been obtained this title compound, be yellow solid (0.120g, 37%).

Embodiment 267C

N-[4-amino-5-(4-hydroxyl-phenyl sulfenyl)-2-methyl-phenyl]-benzamide

According to the method for embodiment 265C, with the product of the product alternate embodiment 265B of embodiment 267B, the product of embodiment 267B is reacted, obtained this title compound, be brown solid (0.11g, 100%).This product need not directly use by the silica gel chromatography purifying.

Embodiment 267D

Method according to embodiment 265D, product with the product alternate embodiment 265C of embodiment 267C, the product of embodiment 267C is reacted, obtained resistates, it by the silica gel chromatography purifying, is carried out wash-out with ethanol/methylene gradient (0-5% methyl alcohol), obtained this title compound, be yellow solid (0.0212g, 33%).1H?NMR(300MHz，DMSO-D6)δ?ppm：10.02(s，1H)，9.90(s，1H)，9.77(s，1H)，8.84(d，J＝8.46Hz，1H)，8.56(s，1H)，7.93(d，J＝6.99Hz，2H)，7.55-7.65(m，2H)，7.51(t，J＝7.35Hz，2H)，7.33(s，1H)，7.15-7.25(m，2H)，6.99(s，1H)，6.65-6.79(m，2H)，3.14-3.27(m，1H)，2.20(s，3H)，1.33(d，J＝6.62Hz，6H)；MS(ESI ⁺)m/z?522.2(M+H) ⁺，(ESI ^-)m/z?520.2(M-H) ^-。

Embodiment 268

Morpholine-4-formic acid 4-[4-(4-bromo-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-phenyl }-acid amides

Embodiment 268A

4-(4-amino-phenoxy group)-N-(4-bromo-phenyl)-3-nitro-benzamide

Product (3.55g with embodiment 10A, 10mmol), 4-amino-phenol (1.09g, 10mmol) and potassium hydroxide (1.12g, mixture 20mmol) is dissolved in the methyl-sulphoxide (15mL), and in CEM Discover microwave oven, heated 25 minutes in 100 ℃, then this mixture is cooled to room temperature, pour in the water (300mL), with the pH regulator to 6 of 1N hydrochloric acid with this solution, with gained solution stirring 30 minutes, collect gained solid and drying, obtained this title compound, be yellow solid (4.2g, 98%).

Embodiment 268B

4-[4-(4-bromo-phenyl amino formyl radical)-2-nitro-phenoxy group]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

The product of embodiment 268A in being dissolved in methylene dichloride (100mL) (4.2g, add in 9.8mmol) pyridine (1.62mL 20mmol), drips chloroformic acid 2,2 then, the 2-trichloro ethyl ester (2.29g, 10.8mmol).With gained solution stirring 4 hours, vacuum concentration then.Then this mixture is poured into (200mL) in the water,,, collected gained solid and drying, obtained this title compound (6.0g, 100%) gained solution stirring 30 minutes with the pH regulator to 5 of 1N hydrochloric acid with this solution.

Embodiment 268C

4-[2-amino-4-(4-bromo-phenyl amino formyl radical)-phenoxy group]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

With the product of embodiment 268B (6.0g, 10mmol), iron powder (2.8g, 50mmol) and ammonium chloride (0.81g, 15mmol) reflux 5 hours in the mixture of ethanol (60mL), tetrahydrofuran (THF) (60mL) and water (20mL) is cooled to room temperature then.With this reaction mixture via diatomite filtration, and with ethanol (100mL) washing leaching cake.With filtrate evaporated under reduced pressure, obtained resistates, it with hexane/ethyl acetate 4/1 development, has been obtained this title product (2.39g, 42%), be the tawny solid.

Embodiment 268D

4-[4-(4-bromo-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

With the product of embodiment 268C (2.39g, 4.2mmol) and the product of embodiment 8E (0.91g, 4.2mmol) mixture in Glacial acetic acid (10mL) heated 15 minutes in 130 ℃ of oil baths.Then this reaction mixture is cooled to room temperature, and, has obtained this title product, be brown ceramic powder solvent removed under reduced pressure.

Embodiment 268E

With the product of embodiment 268D (74mg, 0.1mmol), 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (30mg, 0.2mmol) and morpholine (87mg, 1.0mmol) mixture in tetrahydrofuran (THF) (2ml) in sealed tube in 65 ℃ of heating 1 hour.Then this mixture is cooled to room temperature, vacuum concentration, and, obtained this title compound with the HPLC purifying of gained resistates by use TFA, be trifluoroacetate (50mg, 63%).1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)，3.19-3.32(m，1H)，3.35-3.44(m，4H)，3.57-3.63(m，4H)，6.95-7.03(m，3H)，7.47(d，J＝9.19Hz，2H)，7.54(d，J＝8.82Hz，2H)，7.75(d，J＝8.82Hz，2H)，7.82(d，J＝8.46Hz，1H)，7.98(dd，J＝8.64，2.02Hz，1H)，8.14(d，J＝1.84Hz，1H)，8.56(s，1H)，8.85(s，1H)，8.94(d，J＝8.46Hz，1H)，10.38(s，1H)；MS(ESI+)m/z?682/684(M+H)+。

Embodiment 269

N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-[4-(3-methyl-urea groups)-phenoxy group]-benzamide

Use the method for embodiment 268E, substitute morpholine, the product of embodiment 268D is reacted, obtained crude product,, obtained this title compound, be trifluoroacetate by using the HPLC purifying of TFA with methylamine.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)，2.63(d，J＝4.41Hz，3H)，3.14-3.32(m，1H)，5.99(q，J＝4.78Hz，1H)，6.91-7.04(m，3H)，7.40(d，J＝9.19Hz，2H)，7.54(d，J＝8.82Hz，2H)，7.75(d，J＝8.82Hz，2H)，7.82(d，J＝8.82Hz，1H)，7.97(dd，J＝8.64，2.02Hz，1H)，8.14(d，J＝1.84Hz，1H)，8.54(s，1H)，8.85(s，1H)，8.94(d，J＝8.82Hz，1H)，10.37(s，1H)，11.21(s，1H)；MS(ESI+)m/z?626/628(M+H)+。

Embodiment 270

N-(4-bromo-phenyl)-4-[4-(3,3-dimethyl-urea groups)-phenoxy group]-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 268E, substitute morpholine, the product of embodiment 268D is reacted, obtained crude product,, obtained this title compound, be trifluoroacetate by using the HPLC purifying of TFA with dimethyl amine.1H?NMR(300MHz，DMSO-D6)δppm：1.34(d，J＝6.99Hz，6H)，2.91(s，6H)，3.12-3.35(m，1H)，6.93-7.02(m，3H)，7.47(d，J＝9.19Hz，2H)，7.53-7.56(m，2H)，7.73-7.78(m，2H)，7.82(d，J＝8.82Hz，1H)，7.98(dd，J＝8.82，2.21Hz，1H)，8.14(d，J＝2.21Hz，1H)，8.31(s，1H)，8.85(s，1H)，8.94(d，J＝8.46Hz，1H)，10.38(s，1H)，11.23(s，1H)；MS(ESI+)m/z?640/642(M+H)+。

Embodiment 271

N-(4-bromo-phenyl)-4-[4-(3-ethyl-urea groups)-phenoxy group]-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 268E, substitute morpholine, the product of embodiment 268D is reacted, obtained crude product,, obtained this title compound, be trifluoroacetate by using the HPLC purifying of TFA with ethamine.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.04(t，J＝7.17Hz，3H)，1.34(d，J＝6.62Hz，6H)，3.01-3.17(m，2H)，3.21-3.32(m，1H)，6.09(t，J＝5.52Hz，1H)，6.93-7.05(m，J＝9.01，3.49Hz，3H)，7.40(d，J＝8.82Hz，2H)，7.54(d，J＝9.19Hz，2H)，7.75(d，J＝9.19Hz，2H)，7.81(d，J＝8.82Hz，1H)，7.96(dd，J＝8.46，2.21Hz，1H)，8.14(d，J=2.21Hz，1H)，8.47(s，1H)，8.84(s，1H)，8.94(d，J＝8.82Hz，1H)，10.37(s，1H)，11.19(s，1H)；MS(ESI+)m/z640/642(M+H)+。

Embodiment 272

Piperidines-1-formic acid 4-[4-(4-bromo-phenyl amino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-phenyl }-acid amides

Use the method for embodiment 268E, substitute morpholine, the product of embodiment 268D is reacted, obtained crude product,, obtained this title compound, be trifluoroacetate by using the HPLC purifying of TFA with piperidines.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.62Hz，6H)，1.42-1.66(m，6H)，3.22-3.32(m，1H)，3.36-3.43(m，4H)，6.98(t，J＝9.01Hz，3H)，7.47(d，J＝9.19Hz，2H)，7.54(d，J＝8.82Hz，2H)，7.75(d，J＝8.82Hz，2H)，7.83(d，J＝8.46Hz，1H)，7.98(dd，J＝8.46，2.21Hz，1H)，8.14(d，J＝2.21Hz，1H)，8.47(s，1H)，8.86(s，1H)，8.95(d，J＝8.46Hz，1H)，10.38(s，1H)，11.30(s，1H)；MS(ESI+)m/z?680/682(M+H)+。

Embodiment 273

N-(4-bromo-phenyl)-4-[4-(3-cyclopentyl-urea groups)-phenoxy group]-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 268E, substitute morpholine, the product of embodiment 268D is reacted, obtained crude product,, obtained this title compound, be trifluoroacetate by using the HPLC purifying of TFA with cyclopentyl amine.1H?NMR(300MHz，DMSO-D6)δppm：1.34(d，J＝6.99Hz，6H)，1.34-1.43(m，2H)，1.46-1.71(m，4H)，1.74-1.92(m，2H)，3.12-3.31(m，1H)，3.78-4.00(m，1H)，6.14(d，J＝7.35Hz，1H)，6.93-7.02(m，J＝9.01，2.76Hz，3H)，7.38(d，J＝9.19Hz，2H)，7.54(d，J＝8.82Hz，2H)，7.75(d，J＝9.19Hz，2H)，7.81(d，J＝8.46Hz，1H)，7.96(dd，J＝8.82，2.21Hz，1H)，8.14(d，J＝2.21Hz，1H)，8.31(s，1H)，8.84(s，1H)，8.94(d，J＝8.82Hz，1H)，10.37(s，1H)，11.18(s，1H)；MS(ESI+)m/z?680/682(M+H)+。

Embodiment 274

N-(4-bromo-phenyl)-4-[4-(3-cyclopropyl-urea groups)-phenoxy group]-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 268E, substitute morpholine, the product of embodiment 268D is reacted, obtained crude product,, obtained this title compound, be trifluoroacetate by using the HPLC purifying of TFA with cyclopropylamine.1H?NMR(300MHz，DMSO-D6)δppm：0.30-0.45(m，2H)，0.57-0.68(m，2H)，1.34(d，J＝6.99Hz，6H)，3.15-3.37(m，2H)，6.37(d，J＝2.21Hz，1H)，6.97(dd，J＝9.01，2.02Hz，3H)，7.41(d，J＝9.19Hz，2H)，7.54(d，J＝8.82Hz，2H)，7.75(d，J＝8.82Hz，2H)，7.79(d，J＝8.82Hz，1H)，7.96(d，J＝10.66Hz，1H)，8.14(s，1H)，8.33(s，1H)，8.83(s，1H)，8.93(d，J＝9.56Hz，1H)，10.36(s，1H)，11.08(s，1H)；MS(ESI+)m/z?652/654(M+H)+。

Embodiment 275

N-(4-bromo-phenyl)-4-[4-(3-butyl-3-methyl-urea groups)-phenoxy group]-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 268E, substitute morpholine, the product of embodiment 268D is reacted, obtained crude product,, obtained this title compound, be trifluoroacetate by using the HPLC purifying of TFA with N-butyl methyl amine.1H?NMR(300MHz，DMSO-D6)δ?ppm：0.90(t，J＝7.35Hz，3H)，1.10-1.31(m，2H)，1.33(d，J＝6.62Hz，6H)，1.40-1.53(m，3H)，2.91(s，3H)，3.17-3.32(m，3H)，6.91-7.03(m，3H)，7.47(d，J＝9.19Hz，2H)，7.54(d，J＝8.82Hz，2H)，7.73-7.83(m，3H)，7.96(dd，J＝8.46，2.21Hz，1H)，8.14(d，J＝1.84Hz，1H)，8.23(s，1H)，8.82(s，1H)，8.93(d，J＝8.46Hz，1H)，10.37(s，1H)；MS(ESI+)m/z?682/684(M+H)+。

Embodiment 276

N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-[4-(3-amyl group-urea groups)-phenoxy group]-benzamide

Use the method for embodiment 268E, substitute morpholine, the product of embodiment 268D is reacted, obtained crude product,, obtained this title compound, be trifluoroacetate by using the HPLC purifying of TFA with the 1-aminopentane.1H?NMR(300MHz，DMSO-D6)δppm：0.85-0.90(m，3H)，1.23-1.31(m，4H)，1.33(d，J＝6.99Hz，6H)，1.38-1.47(m，2H)，2.99-3.10(m，2H)，3.19-3.29(m，1H)，6.09(t，J＝5.52Hz，1H)，6.96(dd，J＝9.01，3.13Hz，3H)，7.39(d，J＝8.82Hz，2H)，7.54(d，J＝8.82Hz，2H)，7.75(d，J＝9.19Hz，2H)，7.79(d，J＝8.82Hz，1H)，7.96(dd，J＝8.82，1.84Hz，1H)，8.13(s，1H)，8.43(s，1H)，8.82(s，1H)，8.92(d，J＝8.46Hz，1H)，10.36(s，1H)，11.08(s，1H)；MS(ESI+)m/z?682/684(M+H)+。

Embodiment 277

N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-{4-[3-(2-methoxyl group-ethyl)-urea groups]-phenoxy group }-benzamide

Use the method for embodiment 268E, substitute morpholine, the product of embodiment 268D is reacted, obtained crude product,, obtained this title compound, be trifluoroacetate by using the HPLC purifying of TFA with the 2-methoxyethyl amine.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)，3.20-3.31(m，5H)，3.27(s，3H)，6.17(t，J＝5.88Hz，1H)，6.92-7.01(m，3H)，7.38(d，J＝8.82Hz，2H)，7.54(d，J＝8.82Hz，2H)，7.75(d，J＝8.82Hz，2H)，7.80(d，J＝9.19Hz，1H)，7.96(dd，J＝8.64，2.02Hz，1H)，8.14(d，J＝1.47Hz，1H)，8.56(s，1H)，8.83(s，1H)，8.93(d，J＝9.93Hz，1H)，10.36(s，1H)，11.13(s，1H)；MS(ESI+)m/z?670/672(M+H)+。

Embodiment 278

N-(4-bromo-phenyl)-4-{4-[3-(2-oxyethyl group-ethyl)-urea groups]-phenoxy group }-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 268E, substitute morpholine, the product of embodiment 268D is reacted, obtained crude product,, obtained this title compound, be trifluoroacetate by using the HPLC purifying of TFA with the 2-ethoxy ethyl amine.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.13(t，J＝6.99Hz，3H)，1.33(d，J＝6.99Hz，6H)，3.17-3.27(m，3H)，3.40-3.54(m，4H)，6.15(t，J＝5.70Hz，1H)，6.94-7.03(m，3H)，7.38(d，J＝9.19Hz，2H)，7.54(d，J＝8.82Hz，2H)，7.71-7.83(m，3H)，7.95(dd，J＝8.64，2.02Hz，1H)，8.14(d，J＝1.47Hz，1H)，8.59(s，1H)，8.80(s，1H)，8.91(d，J＝8.46Hz，1H)，10.36(s，1H)，11.01(s，1H)；MS(ESI+)m/z?684/686(M+H)+。

Embodiment 279

4-[4-(3-benzyl-3-methyl-urea groups)-phenoxy group]-N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 268E, substitute morpholine, the product of embodiment 268D is reacted, obtained crude product,, obtained this title compound, be trifluoroacetate by using the HPLC purifying of TFA with N-benzyl methylamine.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.62Hz，6H)，2.91(s，3H)，3.22-3.31(m，1H)，4.54(s，2H)，7.00(dd，J=9.01，4.23Hz，3H)，7.20-7.40(m，4H)，7.47-7.61(m，4H)，7.72-7.84(m，3H)，7.97(dd，J＝8.64，2.02Hz，1H)，8.14(d，J＝2.21Hz，1H)，8.46(s，1H)，8.84(s，1H)，8.94(d，J＝8.82Hz，1H)，10.38(s，1H)，11.19(s，1H)；MS(ESI+)m/z?716/718(M+H)+。

Embodiment 280

4-[4-(3-benzyl-urea groups)-phenoxy group]-N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 268E, substitute morpholine, the product of embodiment 268D is reacted, obtained crude product,, obtained this title compound, be trifluoroacetate by using the HPLC purifying of TFA with benzyl amine.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)，3.18-3.35(m，1H)，4.29(d，J＝5.88Hz，2H)，6.61(t，J＝6.07Hz，1H)，6.98(d，J＝8.82Hz，3H)，7.17-7.38(m，5H)，7.42(d，J＝8.82Hz，2H)，7.52-7.56(m，2H)，7.75(d，J＝8.82Hz，2H)，7.81(d，J＝8.46Hz，.1H)，7.97(dd，J＝8.82，2.21Hz，1H)，8.14(d，J＝2.21Hz，1H)，8.62(s，1H)，8.84(s，1H)，8.94(d，J＝8.82Hz，1H)，10.37(s，1H)，11.21(s，1H)；MS(ESI+)m/z?702/704(M+H)+。

Embodiment 281

N-(4-bromo-phenyl)-4-[4-(3,3-di-isopropyl-urea groups)-phenoxy group]-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Use the method for embodiment 268E, substitute morpholine, the product of embodiment 268D is reacted, obtained crude product,, obtained this title compound, be trifluoroacetate by using the HPLC purifying of TFA with diisopropylamine.1H?NMR(300MHz，DMSO-D6)δppm：1.24(d，J＝6.62Hz，12H)，1.34(d，J＝6.99Hz，6H)，3.22-3.34(m，1H)，3.76-3.87.(m，2H)，6.92-7.02(m，3H)，7.46(d，J＝9.19Hz，2H)，7.54(d，J＝8.82Hz，2H)，7.75(d，J＝8.82Hz，2H)，7.83(d，J＝8.46Hz，1H)，7.98(dd，J＝8.82，2.21Hz，1H)，8.07(s，1H)，8.14(d，J＝2.21Hz，1H)，8.86(s，1H)，8.96(d，J＝8.46Hz，1H)，10.38(s，1H)，11.28(s，1H)；MS(ESI+)m/z?696/698(M+H)+。

Embodiment 282

N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-{4-[3-(1-phenyl-ethyl)-urea groups]-phenoxy group }-benzamide

Use the method for embodiment 268E, substitute morpholine, the product of embodiment 268D is reacted, obtained crude product,, obtained this title compound, be trifluoroacetate by using the HPLC purifying of TFA with (R)-(+)-α-Jia Jibianji amine.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.33(d，J＝6.99Hz，6H)，1.38(d，J＝6.99Hz，3H)，3.12-3.30(m，1H)，4.73-4.89(m，1H)，6.61(d，J＝8.09Hz，1H)，6.96(d，J＝9.19Hz，3H)，7.19-7.29(m，1H)，7.31-7.40(m，5H)，7.54(d，J＝8.82Hz，2H)，7.74(d，J＝8.82Hz，2H)，7.80(d，J＝8.09Hz，1H)，7.95(dd，J＝8.64，2.02Hz，1H)，8.13(d，J＝1.84Hz，1H)，8.44(s，1H)，8.83(s，1H)，8.93(d，J＝8.09Hz，1H)，10.36(s，1H)，11.17(s，1H)；MS(ESI+)m/z?716/718(M+H)+。

Embodiment 283

Use the method for embodiment 268E, substitute morpholine, the product of embodiment 268D is reacted, obtained crude product,, obtained this title compound, be trifluoroacetate by using the HPLC purifying of TFA with (S)-(-)-α-Jia Jibianji amine.1H?NMR(300MHz，DMSO-D6)d?ppm?1.33(d，J＝6.99Hz，6H)，1.38(d，J＝6.99Hz，3H)，3.12-3.30(m，1H)，4.73-4.89(m，1H)，6.61(d，J＝8.09Hz，1H)，6.96(d，J＝9.19Hz，3H)，7.19-7.29(m，1H)，7.31-7.40(m，5H)，7.54(d，J＝8.82Hz，2H)，7.74(d，J＝8.82Hz，2H)，7.80(d，J＝8.09Hz，1H)，7.95(dd，J＝8.64，2.02Hz，1H)，8.13(d，J＝1.84Hz，1H)，8.44(s，1H)，8.83(s，1H)，8.93(d，J＝8.09Hz，1H)，10.36(s，1H)，11.17(s，1H)；MS(ESI+)m/z?716/718(M+H)+。

Embodiment 284

N-(4-bromo-phenyl)-4-(4-ethylamino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

In the product of the embodiment in 9/1 methylene chloride 10 and sodium triacetoxy borohydride, add acetaldehyde.With mixture stirring at room 2 hours, and evaporation.Resistates by using the anti-phase preparation HPLC purifying of AA method, has been obtained this title compound. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.14(t，J＝7.17Hz，3H)1.32(d，J＝6.62Hz，6H)2.98(m，2H)3.21(m，1H)5.50(t，J＝5.15Hz，1H)6.55(d，J＝8.82Hz，2H)6.84(m，3H)7.53(d，J＝8.82Hz，2H)7.60(d，J＝8.82Hz，1H)7.75(d，J＝9.19Hz，2H)7.85(dd，J＝8.46，1.84Hz，1H)8.16(d，J＝1.84Hz，1H)8.62(s，1H)8.83(d，J＝8.46Hz，1H)9.99(s，1H)10.29(s，1H)；MS(ESI+)m/z?597/599(M+H)+。

Embodiment 285

N-(4-bromo-phenyl)-4-(4-diethylamino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

This title compound is to obtain during purifying derives from the mixture of embodiment 284.1HNMR(300MHz，DMSO-D6)δ?ppm：1.04(t，J＝6.99Hz，6H)1.32(d，J＝6.99Hz，6H)3.26(m，5H)6.63(m，2H)6.89(m，3H)7.54(m，2H)7.58(d，J＝8.46Hz，1H)7.76(m，2H)7.86(m，1H)8.16(s，1H)8.61(s，1H)8.80(d，J＝8.46Hz，1H)9.99(s，1H)10.30(s，1H)；MS(ESI+)m/z?625/627(M+H)+。

Embodiment 286

N-(4-bromo-phenyl)-4-[4-(2,2-dimethyl-propyl group amino)-phenoxy group]-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

In the product of the embodiment in 9/1 methylene chloride 10 and sodium triacetoxy borohydride, add trimethyl-acetaldehyde.With mixture stirring at room 2 hours, and evaporation.Resistates by using the anti-phase preparation HPLC purifying of AA method, has been obtained this title compound.1H?NMR(300MHz，DMSO-D6)δ?ppm：0.94(s，9H)1.32(d，J＝6.99Hz，6H)2.77(d，J＝5.88Hz，2H)3.20(m，1H)5.41(t，J＝5.88Hz，1H)6.63(d，J＝9.19Hz，2H)6.84(m，3H)7.53(d，J＝8.82Hz，2H)7.60(d，J＝8.82Hz，1H)7.75(d，J＝8.82Hz，2H)7.86(m，1H)8.16(d，J＝1.84Hz，1H)8.62(s，1H)8.83(d，J＝8.46Hz，1H)9.99(s，1H)10.29(s，1H)；MS(ESI+)m/z?639/641(M+H)+。

Embodiment 287

N-(4-bromo-phenyl)-4-[4-(cyclopropyl methyl-amino)-phenoxy group]-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

In the product of the embodiment in 9/1 methylene chloride 10 and sodium triacetoxy borohydride, add cyclopanecarboxaldehyde.With mixture stirring at room 2 hours, and evaporation.Resistates by using the anti-phase preparation HPLC purifying of AA method, has been obtained this title compound.1H?NMR(300MHz，DMSO-D6)δ?ppm：0.20(m，2H)0.45(m，2H)1.01(m，1H)1.32(d，J＝6.62Hz，6H)2.84(t，J＝6.07Hz，2H)3.21(m，1H)5.63(t，J＝5.85Hz，1H)6.57(d，J＝8.82Hz，2H)6.84(m，3H)7.53(d，J＝8.82Hz，2H)7.60(d，J＝8.82Hz，1H)7.75(d，J＝8.82Hz，2H)7.84(m，1H)8.16(d，J＝1.47Hz，1H)8.61(s，1H)8.83(d，J＝8.46Hz，1H)10.00(s，1H)10.29(s，1H)；MS(ESI+)m/z?623/625(M+H)+。

Embodiment 288

N-(4-bromo-phenyl)-4-(4-dimethylamino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

In the product of the embodiment in 9/1 methylene chloride 10 and sodium triacetoxy borohydride, add excess formaldehyde (solution of 37%wt in water).With mixture stirring at room 2 hours, and evaporation.Resistates by using the anti-phase preparation HPLC purifying of AA method, has been obtained this title compound.1H?NMR(300MHz，DMSO-D6)δ?ppm：1-32(d，J＝6.62Hz，6H)2.84(s，6H)3.20(m，1H)6.70(d，J＝9.19Hz，2H)6.88(d，J＝8.46Hz，1H)6.92(d，J＝9.19Hz，2H)7.53(d，J＝8.82Hz，2H)7.59(d，J＝8.46Hz，1H)7.75(d，J＝9.19Hz，2H)7.86(dd，J＝8.82，2.21Hz，1H)8.16(d，J＝2.21Hz，1H)8.61(s，1H)8.81(d，J＝8.46Hz，1H)10.01(s，1H)10.30(s，1H)；MS(ESI+)m/z?597/599(M+H)+。

Embodiment 289

N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-piperidines-1-base-phenoxy group)-benzamide

In the product of the embodiment in 9/1 methylene chloride 10 and sodium triacetoxy borohydride, add glutaraldehyde.With mixture stirring at room 2 hours, and evaporation.Resistates by using the HPLC purifying of TFA, has been obtained this title compound.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)1.52(m，2H)1.57(m，4H)3.07(m，4H)3.26(m，1H)6.96(s，4H)7.05(d，J＝8.46Hz，1H)7.55(d，J＝8.82Hz，2H)7.75(d，J＝8.82Hz，2H)7.83(d，J＝8.82Hz，1H)7.99(d，J＝8.82Hz，1H)8.12(s，1H)8.85(s，1H)8.92(d，J＝8.46Hz，1H)10.38(s，1H)11.29(s，1H)；MS(ESI+)m/z?637/639(M+H)+。

Embodiment 290

N-(5-bromo-pyridine-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-propyl group amino-phenyl sulfenyl)-benzamide

In the product of the embodiment in 9/1 methylene chloride 17 and sodium triacetoxy borohydride, add propionic aldehyde.With mixture stirring at room 2 hours, and evaporation.Resistates by using the anti-phase preparation HPLC purifying of AA method, has been obtained this title compound.1H?NMR(300MHz，DMSO-D6)δ?ppm：0.95(t，J＝7.35Hz，3H)1.34(d，J＝6.99Hz，6H)1.57(m，2H)2.99(m，2H)3.24(m，1H)6.16(t，J＝5.16Hz，1H)6.64(d，J＝8.82Hz，2H)6.83(d，J＝8.46Hz，1H)7.20(d，J＝8.82Hz，2H)7.63(d，J＝8.46Hz，1H)7.86(d，J＝8.46Hz，1H)8.04(d，J＝2.57Hz，1H)8.07(d，J＝2.57Hz，1H)8.16(m，1H)8.49(d，J＝2.57Hz，1H)8.58(s，1H)8.87(d，J＝8.46Hz，1H)10.13(s，1H)10.91(s，1H)；MS(ESI+)m/z?628/630(M+H)+。

Embodiment 291

N-(5-bromo-pyridine-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-[4-(methyl-propyl group-amino)-phenyl sulfenyl]-benzamide

In the product of the embodiment in 9/1 methylene chloride 290 and sodium triacetoxy borohydride, add excess formaldehyde (37% in water solution).With mixture stirring at room 2 hours, and evaporation.Resistates by using the anti-phase preparation HPLC purifying of AA method, has been obtained this title compound.1H?NMR(300MHz，DMSO-D6)δ?ppm：0.88(t，J＝7.35Hz，3H)1.34(d，J＝6.99Hz，6H)1.54(m，2H)2.93(s，3H)3.25(m，3H)6.75(d，J＝9.19Hz，2H)6.85(d，J＝7.72Hz，1H)7.27(d，J＝8.82Hz，2H)7.63(d，J=8.46Hz，1H)7.87(d，J＝8.46Hz，1H)8.04(d，J＝2.57Hz，1H)8.07(d，J＝2.21Hz，1H)8.17(m，1H)8.49(d，J＝2.21Hz，1H)8.58(s，1H)8.88(d，J＝8.82Hz，1H)10.13(s，1H)10.91(s，1H)；MS(ESI+)m/z?642/644(M+H)+。

Embodiment 292

N-(5-bromo-pyridine-2-yl)-4-[4-(ethyl-propyl group-amino)-phenyl sulfenyl]-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

In the product of the embodiment in 9/1 methylene chloride 290 and sodium triacetoxy borohydride, add excessive acetaldehyde.With mixture stirring at room 2 hours, and evaporation.Resistates by using the anti-phase preparation HPLC purifying of AA method, has been obtained this title compound.1H?NMR(300MHz，DMSO-D6)δ?ppm：0.90(t，J＝7.35Hz，3H)1.09(t，J＝6.99Hz，3H)1.34(d，J＝6.99Hz，6H)1.55(m，2H)3.24(m，3H)3.38(q，J＝6.99Hz，2H)6.71(d，J＝8.82Hz，2H)6.87(d，J＝8.82Hz，1H)7.26(d，J＝8.82Hz，2H)7.63(d，J＝8.46Hz，1H)7.88(d，J＝8.46Hz，1H)8.04(d，J＝2.57Hz，1H)8.07(d，J＝2.21Hz，1H)8.17(m，1H)8.49(d，J＝1.84Hz，1H)8.58(s，1H)8.89(d，J＝8.46Hz，1H)10.13(s，1H)10.91(s，1H)；MS(ESI+)m/z?656/658(M+H)+。

Embodiment 293

N-(5-bromo-pyridine-2-yl)-4-(4-dipropyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

In the product of the embodiment in 9/1 methylene chloride 17 and sodium triacetoxy borohydride, add excessive propionic aldehyde.With mixture stirring at room 2 hours, and evaporation.Resistates by using the anti-phase preparation HPLC purifying of AA method, has been obtained this title compound.1HNMR(300MHz，DMSO-D6)δ?ppm：0.89(t，J＝7.35Hz，6H)，1.34(d，J＝6.99Hz，6H)，1.45-1.69(m，4H)，3.11-3.30(m，5H)，6.70(d，J＝8.82Hz，2H)，6.87(d，J＝8.46Hz，1H)，7.25(d，J＝8.82Hz，2H)，7.64(d，J＝8.82Hz，1H)，7.87(dd，J＝8.46，1.84Hz，1H)，8.00-8.09(m，2H)，8.12-8.20(m，1H)，8.49(d，J＝2.57Hz，1H)，8.58(s，1H)，8.88(d，J＝8.46Hz，1H)，10.12(s，1H)，10.91(s，1H)；MS(ESI+)m/z?670/672(M+H)+。

Embodiment 294

4-(4-amino-phenoxy group)-N-(3-fluoro-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 294A

{ 4-[2-amino-4-(3-fluoro-phenyl amino formyl radical)-phenoxy group is foretold phenyl }-t-butyl carbamate

According to the method for embodiment 172b, substitute of product and the 3-fluoroaniline reaction of 4-trifluoromethyl-phenyl amine with the 3-fluoroaniline with embodiment 172a, react according to the method for embodiment 172c and 172d then, obtained this title product.

Embodiment 294B

Method according to embodiment 172e; product with the product alternate embodiment 172d of embodiment 294A; the product of embodiment 294A and the product of embodiment 8E are reacted; it is used the method deprotection of embodiment 172f; obtained crude product; by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δppm：1.34(d，J＝6.62Hz，6H)3.16-3.37(m，1H)6.84-7.04(m，6H)7.34-7.47(m，1H)7.55(d，J＝8.46Hz，1H)7.74(d，J＝11.77Hz，1H)7.87(d，J＝8.46Hz，1H)8.00(dd，J＝8.82，2.21Hz，1H)8.14(d，J＝1.84Hz，1H)8.88(s，1H)8.98(d，J＝8.46Hz，1H)10.45(s，1H)；MS(ESI+)m/z?509.3(M+H)+。

Embodiment 295

4-(4-amino-phenoxy group)-N-(4-bromo-3-fluoro-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 295A

4-[2-amino-4-(4-bromo-3-fluoro-phenyl amino formyl radical)-phenoxy group]-phenyl }-t-butyl carbamate

According to the method for embodiment 172b, substitute 4-trifluoromethyl-phenyl amine with 4-bromo-3-fluoroaniline, with product and the reaction of 4-bromo-3-fluoroaniline of embodiment 172a, react according to the method for embodiment 172c and 172d then, obtained this title product.

Embodiment 295B

Method according to embodiment 172e; product with the product alternate embodiment 172d of embodiment 295A; the product of embodiment 295A and the product of embodiment 8E are reacted; it is used the method deprotection of embodiment 172f; obtained crude product; by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δppm：1.34(d，J＝6.99Hz，6H)3.20-3.35(m，1H)6.83-7.02(m，5H)7.54(dd，J＝8.82，2.21Hz，1H)7.69(t，J＝8.46Hz，1H)7.86(d，J＝8.46Hz，1H)7.91(dd，J＝11.58，2.39Hz，1H)7.99(dd，J＝8.82，2.21Hz，1H)8.14(d，J＝2.21Hz，1H)8.87(s，1H)8.98(d，J＝8.46Hz，1H)10.55(s，1H)；MS(ESI+)m/z?589.2(M+H)+。

Embodiment 296

4-(4-amino-phenoxy group)-N-(3-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 296A

4-[2-amino-4-(3-bromine+phenyl amino formyl radical)-phenoxy group]-phenyl }-t-butyl carbamate

According to the method for embodiment 172b, substitute 4-trifluoromethyl-phenyl amine with the 3-bromaniline, with product and the reaction of 3-bromaniline of embodiment 172a, react according to the method for embodiment 172c and 172d then, obtained this title product.

Embodiment 296B

Method according to embodiment 172e; product with the product alternate embodiment 172d of embodiment 296A; the product of embodiment 296A and the product of embodiment 8E are reacted; it is used the method deprotection of embodiment 172f; obtained crude product; by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δppm：1.34(d，J＝6.62Hz，6H)3.22-3.36(m，1H)6.82-7.02(m，5H)7.27-7.37(m，2H)7.72-7.78(m，1H)7.86(d，J＝8.82Hz，1H)7.99(dd，J＝8.46，2.21Hz，1H)8.09(s，1H)8.14(d，J＝1.84Hz，1H)8.87(s，1H)8.97(d，J＝8.82Hz，1H)10.39(s，1H)；MS(ESI+)m/z?569.2(M+H)+。

Embodiment 297

4-[2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(5-methyl-thiazol-2-yl formamyl)-phenoxy group]-phenyl }-t-butyl carbamate

Embodiment 297A

4-[2-amino-4-(5-methyl-thiazol-2-yl formamyl)-phenoxy group]-phenyl }-t-butyl carbamate

Method according to embodiment 172b, substitute 4-trifluoromethyl-phenyl amine with 5-methyl-thiazol-2-yl amine, with product and the 5-methyl-thiazol-2-yl amine reaction of embodiment 172a, react according to the method for embodiment 172c and 172d then, obtained this title product.

Embodiment 297B

Method according to embodiment 172e, product with the product alternate embodiment 172d of embodiment 297A, and product with the product alternate embodiment 8E of embodiment 9B, the product of embodiment 297A and the product of embodiment 9B are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.47(s，9H)2.37(s，3H)2.66(s，3H)6.89(d，J＝8.46Hz，1H)6.99(d，J＝9.19Hz，2H)7.21(d，J＝1.10Hz，1H)7.45(d，J＝9.19Hz，2H)7.53(d，J＝8.46Hz，1H)8.01(dd，J＝8.46，2.21Hz，1H)8.34(d，J＝2.21Hz，1H)8.62(s，1H)8.77(d，J＝8.46Hz，1H)9.37(s，1H)10.00(s，1H)12.40(s，1H)。

Embodiment 298

4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(5-methyl-thiazol-2-yl formamyl)-phenoxy group]-phenyl }-t-butyl carbamate

According to the method for embodiment 172e, use the product of the product alternate embodiment 172d of embodiment 297A, the product of embodiment 297A and the product of embodiment 9B are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.32(d，J＝6.99Hz，6H)1.47(s，9H)2.37(s，3H)3.09-3.28(m，1H)6.89(d，J＝8.46Hz，1H)6.99(d，J＝8.82Hz，2H)7.21(s，1H)7.44(d，J＝8.82Hz，2H)7.59(d，J＝8.46Hz，1H)8.02(dd，J＝8.82，1.84Hz，1H)8.32(s，1H)8.62(s，1H)8.81(d，J＝8.46Hz，1H)9.37(s，1H)10.02(s，1H)12.40(s，1H)。

Embodiment 299

4-(4-amino-phenoxy group)-N-(the 5-tertiary butyl-thiazol-2-yl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 299A

4-[2-amino-4-(the 5-tertiary butyl-thiazol-2-yl formamyl)-phenoxy group]-phenyl }-t-butyl carbamate

Method according to embodiment 172b, substitute 4-trifluoromethyl-phenyl amine with the 5-tertiary butyl-thiazol-2-yl amine, with product and the 5-tertiary butyl-thiazol-2-yl amine reaction of embodiment 172a, react according to the method for embodiment 172c and 172d then, obtained this title product.

Embodiment 299B

Method according to embodiment 172e; product with the product alternate embodiment 172d of embodiment 299A; and product with the product alternate embodiment 8E of embodiment 9B; the product of embodiment 299A and the product of embodiment 9B are reacted; with its method deprotection that uses embodiment 172f, obtained crude product, by using the HPLC purifying of TFA; obtain this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.29(s，9H)2.75(s，3H)4.85(s，2H)6.81(s，1H)6.97(d，J＝8.82Hz，1H)7.03(s，4H)7.83(d，J＝8.82Hz，1H)8.18(dd，J＝8.46，2.21Hz，1H)8.30(d，J＝2.21Hz，1H)8.94(s，1H)8.97(d，J＝8.46Hz，1H)11.66(s，1H)12.57(s，1H)。

Embodiment 300

4-(4-amino-phenoxy group)-N-(the 5-tertiary butyl-thiazol-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Method according to embodiment 172e; product with the product alternate embodiment 172d of embodiment 299A; the product of embodiment 299A and the product of embodiment 8E are reacted; it is used the method deprotection of embodiment 172f; obtained crude product; by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δppm：1.29(s，9H)1.32(d，J＝6.99Hz，6H)3.12-3.28(m，1H)5.06(s，2H)6.58(d，J＝8.82Hz，2H)6.73-6.87(m，3H)7.61(d，J＝8.46Hz，1H)8.02(dd，J＝8.82，2.21Hz，1H)8.33(d，J＝2.21Hz，1H)8.64(s，1H)8.86(d，J＝8.46Hz，1H)9.97(s，1H)12.43(s，1H)。

Embodiment 301

2,3-two fluoro-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 301A

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-2,3-two fluoro-benzamide

This title compound is such synthetic: according to the method for embodiment 255a, with 2, the 3-difluoro benzoyl chloride substitutes furans-2-carbonyl chlorine, with 4-fluoro-3-nitro-phenyl amine and 2, the reaction of 3-difluoro benzoyl chloride, then products therefrom is reacted according to the method for embodiment 255b and 255c, obtained this title product.

Embodiment 301B

According to the method for embodiment 255d, use the product of the product alternate embodiment 255c of embodiment 301A, the product of embodiment 301A and the product of embodiment 8E are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-d6)δ?ppm：1.33(d，J＝7.0Hz，6H)，3.22(seven，J＝7.0Hz，1H)，6.74(d，J＝8.8Hz，2H)，7.08(d，J＝8.5Hz，1H)，7.18(d，J＝8.8Hz，2H)，7.30-7.39(m，1H)，7.44-7.68，(m，4H)，7.91(br-s，1H)，8.57(s，1H)，8.83(d，J＝8.5Hz，1H)，9.75(s，1H)，10.10(s，1H)，10.70(s，1H)；MS(ESI+)m/z?544(M+H)+。

Embodiment 302

2,4-two fluoro-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 302A

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-2,4-two fluoro-benzamide

This title compound is such synthetic: according to the method for embodiment 255a, with 2, the 4-difluoro benzoyl chloride substitutes furans-2-carbonyl chlorine, with 4-fluoro-3-nitro-phenyl amine and 2, the reaction of 4-difluoro benzoyl chloride, then products therefrom is reacted according to the method for embodiment 255b and 255c, obtained this title product.

Embodiment 302B

According to the method for embodiment 255d, use the product of the product alternate embodiment 255c of embodiment 302A, the product of embodiment 302A and the product of embodiment 8E are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H NMR (300MHz, DMSO-d6) δ ppm:1.33 (d, J=7.0Hz, 6H), 3.22 (gas, J=7.0Hz, 1H), 6.73 (d, J=8.8Hz, 2H), 7.08 (d, J=8.5Hz, 1H), 7.18 (d, J=8.8Hz, 2H), 7.24 (dd, J=8.5,2.2Hz, 1H), 7.43 (td, J=10.0,2.3Hz, 1H), 7.53 (br-d, J=8.1Hz, 1H), 7.62 (d, J=8.5Hz, 1H), 7.54 (dd, J=15.1,8.5Hz, 1H), 7.90 (br-s, 1H), 8.56 (s, 1H), 8.82 (d, J=8.5Hz, 1H), 9.73 (s, 1H), 10.09 (s, 1H), 10.56 (s, 1H); MS (ESI+) m/z 544 (M+H)+.

Embodiment 303

3,5-two fluoro-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 303A

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-3,5-two fluoro-benzamide

This title compound is such synthetic: according to the method for embodiment 255a, with 3, the 5-difluoro benzoyl chloride substitutes furans-2-carbonyl chlorine, with 4-fluoro-3-nitro-phenyl amine and 3, the reaction of 5-difluoro benzoyl chloride, then products therefrom is reacted according to the method for embodiment 255b and 255c, obtained this title product.

Embodiment 303B

According to the method for embodiment 255d, use the product of the product alternate embodiment 255c of embodiment 303A, the product of embodiment 303A and the product of embodiment 8E are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-d6)δ?ppm：1.33(d，J＝7.0Hz，6H)，3.22(seven，J＝7.0Hz，1H)，6.74(d，J＝8.5Hz，2H)，7.07(br-d，J＝8.8Hz，1H)，7.20(d，J＝8.5Hz，2H)，7.47-7.74(m，5H)，7.94(br-s，1H)，8.56(s，1H)，8.83(br-d，J＝8.1Hz，1H)，9.75(s，1H)，10.09(s，1H)，10.48(s，1H)；MS(ESI+)m/z?544(M+H)+。

Embodiment 304

3-fluoro-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-4-methoxyl group-benzamide

Embodiment 304A

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-3-fluoro-4-methoxyl group-benzamide

This title compound is such synthetic: according to the method for embodiment 255a, substitute furans-2-carbonyl chlorine with 3-fluoro-4-methoxy benzoyl chloride, with 4-fluoro-3-nitro-phenyl amine and the reaction of 3-fluoro-4-methoxy benzoyl chloride, then products therefrom is reacted according to the method for embodiment 255b and 255c, obtained this title product.

Embodiment 304B

According to the method for embodiment 255d, use the product of the product alternate embodiment 255c of embodiment 304A, the product of embodiment 304A and the product of embodiment 8E are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.99Hz，6H)3.20-3.33(m，1H)3.92(s，3H)6.71(d，2H)7.13(d，1H)7.17(d，2H)7.32(t，J＝8.64Hz，1H)7.62(dd，J＝8.64，2.02Hz，1H)7.77(d，1H)7.83(d，2H)7.98(s，1H)8.71(s，1H)8.92(d，J＝8.46Hz，1H)9.77(s，1H)10.33(s，1H)；(ESI+)m/z?556(M+H)+。

Embodiment 305

3,4-two chloro-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 305A

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-3,4-two chloro-benzamide

This title compound is such synthetic: according to the method for embodiment 255a, with 3, the 4-dichlorobenzoyl chloride substitutes furans-2-carbonyl chlorine, with 4-fluoro-3-nitro-phenyl amine and 3, the reaction of 4-dichlorobenzoyl chloride, then products therefrom is reacted according to the method for embodiment 255b and 255c, obtained this title product.

Embodiment 305B

According to the method for embodiment 255d, use the product of the product alternate embodiment 255c of embodiment 305A, the product of embodiment 305A and the product of embodiment 8E are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.62Hz，6H)3.20-3.33(m，1H)6.71(d，2H)7.08-7.21(m，3H)7.61(dd，J＝8.46Hz，1H)7.80(d，J＝9.19Hz，2H)7.94(dd，1H)7.97(s，1H)8.20(s，1H)8.72(s，1H)8.92(d，J＝8.46Hz，1H)9.78(s，1H)10.58(s，1H)；MS(ESI+)m/z?576(M+H)+。

Embodiment 306

2,5-two fluoro-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 306A

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

This title compound is such synthetic: according to the method for embodiment 255a, with 2, the 5-difluoro benzoyl chloride substitutes furans-2-carbonyl chlorine, with 4-fluoro-3-nitro-phenyl amine and 2, the reaction of 5-difluoro benzoyl chloride, then products therefrom is reacted according to the method for embodiment 255b and 255c, obtained this title product.

Embodiment 306B

Method according to embodiment 255d, product with the product alternate embodiment 255c of embodiment 306A, the product of embodiment 306A and the product of embodiment 8E are reacted, obtained crude product, by using the HPLC purifying of TFA, neutralization then, and adding hydrochloric acid, obtain this title product, be hydrochloride.1H NMR (300MHz, DMSO-d6) δ ppm:1.37 (d, J=7.0Hz, 6H), 3.31 (septet, J=7.0Hz, 1H), 6.70 (d, J=8.5Hz, 2H), 7.17 (d, J=8.5Hz, 2H), 7.20 (d, J=8.5Hz, 1H), 7.38-7.60 (m, 4H), 7.96 (d, J=8.8Hz, 1H), 7.98 (d, J=2.2Hz, 1H), 8.89 (s, 1H), 9.16 (d, J=8.8Hz, 1H), 9.83 (br-s, 1H), 10.79 (s, 1H), 12.12 (br-s, 1H); MS (ESI+) m/z 544 (M+H)+.

Embodiment 307

2-fluoro-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 307A

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-2-fluoro-benzamide

This title compound is such synthetic: according to the method for embodiment 255a, substitute furans-2-carbonyl chlorine with the 2-fluorobenzoyl chloride, with 4-fluoro-3-nitro-phenyl amine and the reaction of 2-fluorobenzoyl chloride, then products therefrom is reacted according to the method for embodiment 255b and 255c, obtained this title product.

Embodiment 307B

According to the method for embodiment 255d, use the product of the product alternate embodiment 255c of embodiment 307A, the product of embodiment 307A and the product of embodiment 8E are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H NMR (300MHz, DMSO-d ₆) δ ppm:1.33 (d, J=7.0Hz, 6H), 3.22 (septet, J=7.0Hz, 1H), 6.73 (d, J=8.8Hz, 2H), 7.08 (d, J=8.5Hz, 1H), 7.18 (d, J=8.8Hz, 2H), 7.28-7.40 (m, 2H), 7.48-7.70 (m, 4H), 7.92 (s, 1H), 8.56 (s, 1H), 8.82 (d, J=8.5Hz, 1H), 9.73 (s, 1H), 10.12 (s, 1H), 10.57 (s, 1H); MS (ESI+) m/z 526 (M+H)+.

Embodiment 308

1H-pyrroles-2-formic acid [4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-acid amides

Embodiment 308A

1H-pyrroles-2-formic acid [3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-acid amides

This title compound is such synthetic: according to the method for embodiment 255a, substitute furans-2-carbonyl chlorine with 1H-pyrroles-2-carbonyl chlorine, with 4-fluoro-3-nitro-phenyl amine and 1H-pyrroles-2-carbonyl chlorine reaction, then products therefrom is reacted according to the method for embodiment 255b and 255c, obtained this title product.

Embodiment 308B

According to the method for embodiment 255d, use the product of the product alternate embodiment 255c of embodiment 308A, the product of embodiment 308A and the product of embodiment 8E are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.62Hz，6H)，6.09-6.19(m，1H)，6.68(d，J＝8.82Hz，2H)，6.97(s，1H)，7.06(s，1H)，7.11-7.19(m，3H)，7.61-7.67(m，1H)，7.86(d，J＝8.46Hz，1H)，7.95(s，1H)，8.79(s，1H)，8.96(d，J＝9.56Hz，1H)，9.74(s，1H)，9.95(s，1H)，11.65(d，J＝1.47Hz，1H)；MS(ESI+)m/z?497(M+H)+。

Embodiment 309

4-hydroxy-n-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 309A

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-4-hydroxyl-benzamide

This title compound is such synthetic: according to the method for embodiment 255a, substitute furans-2-carbonyl chlorine with the 4-hydroxybenzoyl chloride, with 4-fluoro-3-nitro-phenyl amine and the reaction of 4-hydroxybenzoyl chloride, then products therefrom is reacted according to the method for embodiment 255b and 255c, obtained this title product.

Embodiment 309B

According to the method for embodiment 255d, use the product of the product alternate embodiment 255c of embodiment 309A, the product of embodiment 309A and the product of embodiment 8E are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.99Hz，6H)3.27-3.34(m，1H)6.68(d，2H)6.85(d，2H)7.18(m，3H)7.63(dd，J＝8.64，2.39Hz，1H)7.84(m，3H)8.02(s，1H)8.79(s，1H)8.98(d，1H)9.76(s，1H，)10.15(s，1H)，10.21(s，1H)；MS(ESI+)m/z?524(M+H)+。

Embodiment 310

N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-2-methoxyl group-benzamide

Embodiment 310A

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-2-methoxyl group-benzamide

This title compound is such synthetic: with 4-fluoro-3-nitro-phenyl amine and the reaction of 2-methoxy benzoyl chloride, method according to embodiment 255a, substitute furans-2-carbonyl chlorine with the 2-methoxy benzoyl chloride, then products therefrom is reacted according to the method for embodiment 255b and 255c, obtained this title product.

Embodiment 310B

According to the method for embodiment 255d, use the product of the product alternate embodiment 255c of embodiment 310A, the product of embodiment 310A and the product of embodiment 8E are reacted, obtained this title product, be acetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.33(d，J＝6.99Hz，6H)，3.23(dd，J＝12.87，6.62Hz，1H)，3.87(s，3H)，6.72(d，J＝8.46Hz，2H)，7.05(t，J＝7.91Hz，2H)，7.16(dd，J＝8.64，2.39Hz，3H)，7.47-7.62(m，4H)，7.93(s，1H)，8.55(s，1H)，8.82(d，J＝8.09Hz，1H)，9.71(s，1H)，10.09(s，1H)，10.25(s，1H)。

Embodiment 311

3-hydroxy-n-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 311A

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-3-hydroxyl-benzamide

This title compound is such synthetic: according to the method for embodiment 255a, substitute furans-2-carbonyl chlorine with the 3-hydroxybenzoyl chloride, with 4-fluoro-3-nitro-phenyl amine and the reaction of 3-hydroxybenzoyl chloride, then products therefrom is reacted according to the method for embodiment 255b and 255c, obtained this title product.

Embodiment 311B

Method according to embodiment 255d, product with the product alternate embodiment 255c of embodiment 311A, the product of embodiment 311A and the product of embodiment 8E are reacted, obtained crude product, by using the HPLC purifying of TFA, neutralization then, and adding Hydrogen bromide, obtain this title product, be hydrobromate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.39(d，J＝6.62Hz，6H)，3.29-3.38(m，1H)，6.69(d，J＝8.46Hz，2H)，6.96-7.04(m，1H)，7.17(d，J＝8.46Hz，2H)，7.25(d，J＝8.82Hz，1H)，7.29-7.41(m，3H)，7.70(dd，J＝8.82，2.57Hz，1H)，7.96(d，J＝8.82Hz，1H)，8.05-8.15(m，1H)，8.93(s，1H)，9.09(d，J＝8.46Hz，1H)；MS(ESI+)m/z?524(M+H)+。

Embodiment 312

4-acetylamino-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 312A

4-acetylamino-N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-benzamide

This title compound is such synthetic: according to the method for embodiment 255a; substitute furans-2-carbonyl chlorine with 4-acetylamino Benzoyl chloride; with 4-fluoro-3-nitro-phenyl amine and the reaction of 4-acetylamino Benzoyl chloride; then products therefrom is reacted according to the method for embodiment 255b and 255c, obtained this title product.

Embodiment 312B

According to the method for embodiment 255d, use the product of the product alternate embodiment 255c of embodiment 312A, the product of embodiment 312A and the product of embodiment 8E are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.99Hz，6H)2.08(s，3H)3.24-3.34(m，1H)6.67(d，2H)7.18(m，3H)7.63(dd，J＝8.64，2.39Hz，1H)7.71(d，J＝9.19Hz，2H)7.91(m，3H)8.02(s，1H)8.80(s，1H)8.98(d，1H)9.97(s，1H)10.23(s，1H)，10.34(s，1H)；MS(ESI+)m/z?556(M+H)+。

Embodiment 313

2-chloro-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-4-trifluoromethyl-benzamide

Embodiment 313A

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-2-chloro-4-trifluoromethyl-benzamide

This title compound is such synthetic: according to the method for embodiment 255a, substitute furans-2-carbonyl chlorine with 2-chloro-4-trifluoromethyl benzoyl chloride, with 4-fluoro-3-nitro-phenyl amine and the reaction of 2-chloro-4-trifluoromethyl benzoyl chloride, then products therefrom is reacted according to the method for embodiment 255b and 255c, obtained this title product.

Embodiment 313B

According to the method for embodiment 255d, use the product of the product alternate embodiment 255c of embodiment 313A, the product of embodiment 313A and the product of embodiment 8E are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.99Hz，6H)3.20-3.33(m，1H)6.70(d，2H)7.18(m，3H)7.53(dd，J＝8.64，2.02Hz，1H)7.82-7.91 (m，3H)7.98(s，1H)8.04(s，1H)8.84(s，1H)8.92(d，J＝8.46Hz，1H)9.80(s，1H)10.89(s，1H)；MS(ESI+)m/z?610(M+H)+。

Embodiment 314

N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-4-methoxyl group-benzamide

Embodiment 314A

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-4-methoxyl group-benzamide

This title compound is such synthetic: according to the method for embodiment 255a, substitute furans-2-carbonyl chlorine with the 4-methoxy benzoyl chloride, with 4-fluoro-3-nitro-phenyl amine and the reaction of 4-methoxy benzoyl chloride, then products therefrom is reacted according to the method for embodiment 255b and 255c, obtained this title product.

Embodiment 314B

According to the method for embodiment 255d, use the product of the product alternate embodiment 255c of embodiment 314A, the product of embodiment 314A and the product of embodiment 8E are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.16(d，J＝6.99Hz，6H)1.36(d，J＝6.99Hz，6H)2.76-2.89(m，1H)3.22-3.37(m，1H)3.83(s，3H)6.55(d，J＝7.72Hz，1H)6.68(d，J＝8.82Hz，2H)7.06(d，J＝9.19Hz，2H)7.16(d，J＝8.82Hz，2H)7.20(s，1H)7.65(dd，J＝8.64，2.39Hz，1H)7.77(d，J＝7.72Hz，1H)7.90(s，1H)7.95(d，J＝9.19Hz，2H)8.04(d，J＝2.21Hz，1H)8.84(s，1H)9.00(d，J＝8.46Hz，1H)9.78(s，1H)10.33(s，1H)11.70(s，1H)；MS(ESI+)m/z?538(M+H)+。

Embodiment 315

N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-4-methoxyl group-benzamide

Method according to embodiment 255d, product with the product alternate embodiment 255c of embodiment 314A, and product with the product alternate embodiment 8E of embodiment 9B, the product of embodiment 314A and the product of embodiment 9B are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：2.73(s，3H)3.83(s，3H)6.69(d，J＝8.82Hz，2H)7.06(d，J＝9.19Hz，2H)7.16(d，J＝8.82Hz，2H)7.63(dd，J＝8.64，2.39Hz，1H)7.74(d，J＝8.46Hz，1H)7.94(d，J＝8.82Hz，2H)8.02(d，J＝1.47Hz，1H)8.73(s，1H)8.89(d，J＝8.46Hz，1H)9.75(s，1H)10.28(s，1H)11.13(s，1H)；MS(ESI+)m/z?510(M+H)+。

Embodiment 316

N-[4-(3-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-4-methoxyl group-benzamide

Embodiment 316A

N-[3-amino-4-(3-hydroxyl-phenyl sulfenyl)-phenyl]-4-methoxyl group-benzamide

This title compound is such synthetic: according to the method for embodiment 255a, substitute furans-2-carbonyl chlorine with the 4-methoxy benzoyl chloride, with 4-fluoro-3-nitro-phenyl amine and the reaction of 4-methoxy benzoyl chloride, then according to the method for embodiment 255b, substitute 4-sulfydryl-phenol with 3-sulfydryl-phenol, and,, obtained this title product with the products therefrom reaction according to the method for embodiment 255c.

Embodiment 316B

According to the method for embodiment 255d, use the product of the product alternate embodiment 255c of embodiment 316A, the product of embodiment 316A and the product of embodiment 8E are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.99Hz，6H)3.22-3.35(m，1H)3.84(s，3H)6.45-6.60(m，3H)6.94(t，J＝7.91Hz，1H)7.08(d，J＝8.82Hz，2H)7.52(d，J＝8.46Hz，1H)7.76(dd，J＝8.64，2.39Hz，1H)7.85(d，J＝8.82Hz，1H)7.97(d，J＝9.19Hz，2H)8.14(d，J＝2.21Hz，1H)8.77(s，1H)8.92(d，J＝8.46Hz，1H)9.51(s，1H)10.42(s，1H)11.55(s，1H)；MS(ESI+)m/z?538(M+H)+。

Embodiment 317

N-[4-(3-hydroxyl-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-4-methoxyl group-benzamide

Method according to embodiment 255d, product with the product alternate embodiment 255c of embodiment 316A, and product with the product alternate embodiment 8E of embodiment 29A, the product of embodiment 316A and the product of embodiment 29A are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：3.84(s，3H)6.42-6.64(m，3H)6.95(t，J＝7.91Hz，1H)7.08(d，J＝8.82Hz，2H)7.52(d，J＝8.46Hz，1H)7.75(dd，J＝8.64，2.39Hz，1H)7.84(dd，J＝8.27，4.60Hz，1H)7.97(d，J＝8.82Hz，2H)8.15(d，J＝1.84Hz，1H)8.77(s，1H)8.98(dd，J＝8.27，1.29Hz，1H)9.14(dd，J＝4.41，1.47Hz，1H)9.52(s，1H)10.41(s，1H)11.47(s，1H)；MS(ESI+)m/z?496(M+H)+。

Embodiment 318

N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-methoxyl group-benzamide

Embodiment 318A

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-3-methoxyl group-benzamide

This title compound is such synthetic: according to the method for embodiment 255a, substitute furans-2-carbonyl chlorine with the 3-methoxy benzoyl chloride, with 4-fluoro-3-nitro-phenyl amine and the reaction of 3-methoxy benzoyl chloride, then products therefrom is reacted according to the method for embodiment 255b and 255c, obtained this title product.

Embodiment 318B

According to the method for embodiment 255d, use the product of the product alternate embodiment 255c of embodiment 318A, the product of embodiment 318A and the product of embodiment 8E are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.62Hz，6H)3.22-3.36(m，1H)3.83(s，3H)6.70(d，J＝8.82Hz，2H)7.12-7.21(m，4H)7.40-7.55(m，3H)7.64(dd，J＝8.64，2.39Hz，1H)7.84(d，JJ＝8.46Hz，1H)8.01(d，J＝2.21Hz，1H)8.77(s，1H)8.96(d，J＝8.46Hz，1H)9.78(s，1H)10.43(s，1H)11.35(s，1H)；MS(ESI+)m/z?538(M+H)+。

Embodiment 319

N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-methoxyl group-benzamide

Method according to embodiment 255d, product with the product alternate embodiment 255c of embodiment 318A, and product with the product alternate embodiment 8E of embodiment 9B, the product of embodiment 318A and the product of embodiment 9B are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)?δ?ppm：2.75(s，3H)3.83(s，3H)6.69(d，J＝8.46Hz，2H)7.12-7.21(m，4H)7.41-7.54(m，3H)7.64(dd，J＝8.46，2.21Hz，1H)7.80(d，J＝8.46Hz，1H)8.03(d，J＝1.84Hz，1H)8.80(s，1H)8.93(d，J＝8.09Hz，1H)9.77(s，1H)10.43(s，1H)11.45(s，1H)；MS(ESI+)m/z?510(M+H)+。

Embodiment 320

N-[4-(3-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-methoxyl group-benzamide

Embodiment 320A

N-[3-amino-4-(3-hydroxyl-phenyl sulfenyl)-phenyl]-3-methoxyl group-benzamide

This title compound is such synthetic: according to the method for embodiment 255a, substitute furans-2-carbonyl chlorine with the 3-methoxy benzoyl chloride, with 4-fluoro-3-nitro-phenyl amine and the reaction of 3-methoxy benzoyl chloride, then products therefrom is reacted according to the method for embodiment 255b, substitute 4-sulfydryl-phenol with 3-sulfydryl-phenol, and the method according to embodiment 255c is reacted, and has obtained this title product.

Embodiment 320B

According to the method for embodiment 255d, use the product of the product alternate embodiment 255c of embodiment 320A, the product of embodiment 320A and the product of embodiment 8E are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.16(d，J＝6.99Hz，2H)1.35(d，J＝6.62Hz，4H)2.75-2.87(m，1H)3.22-3.36(m，1H)3.84(s，3H)6.46-6.61(m，3H)6.95(t，J＝7.91Hz，1H)7.16-7.23(m，1H)7.42-7.57(m，3H)7.74-7.80(m，1H)7.87(d，J＝8.46Hz，1H)8.14(d，J＝2.21Hz，1H)8.80(s，1H)8.94(d，J＝8.46Hz，1H)10.56(s，1H)11.65(s，1H)；MS(ESI+)m/z?538(M+H)+。

Embodiment 321

5-chloro-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-2-methoxyl group-benzamide

Embodiment 321A

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-5-chloro-2-methoxyl group-benzamide

This title compound is such synthetic: according to the method for embodiment 255a, substitute furans-2-carbonyl chlorine with 5-chloro-2-methoxy benzoyl chloride, with 4-fluoro-3-nitro-phenyl amine and the reaction of 5-chloro-2-methoxy benzoyl chloride, then products therefrom is reacted according to the method for embodiment 255b and 255c, obtained this title product.

Embodiment 321B

According to the method for embodiment 255d, use the product of the product alternate embodiment 255c of embodiment 321A, will execute the product reaction of product and the embodiment 8E of routine 321A, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1HNMR(300MHz，DMSO-D6)δ?ppm：1.35(t，J＝6.07Hz，6H)3.20-3.35(m，1H)3.86(s，3H)6.65-6.72(m，2H)7.07-7.29(m，4H)7.51-7.59(m，3H)7.85(d，J＝8.82Hz，1H)7.97(s，1H)8.78(s，1H)8.96(d，J＝8.46Hz，1H)9.77(s，1H)10.41(s，1H)；MS(ESI+)m/z?572(M+H)+。

Embodiment 322

3-hydroxyl-pyridine-2-formic acid [4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-acid amides

Embodiment 322A

3-hydroxyl-pyridine-2-formic acid [3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-acid amides

This title compound is such synthetic: according to the method for embodiment 255a, substitute furans-2-carbonyl chlorine with 3-hydroxyl-pyridine-2-carbonyl chlorine, with 4-fluoro-3-nitro-phenyl amine and 3-hydroxyl-pyridine-2-carbonyl chlorine reaction, then products therefrom is reacted according to the method for embodiment 255b and 255c, obtained this title product.

Embodiment 322B

According to the method for embodiment 255d, use the product of the product alternate embodiment 255c of embodiment 322A, the product of embodiment 322A and the product of embodiment 8E are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.62Hz，6H)3.23-3.34(m，1H)6.73(d，J＝8.46Hz，2H)7.11(d，J＝8.82Hz，1H)7.21(d，JJ＝8.82Hz，2H)7.49(dd，J＝8.46，1.47Hz，1H)7.59(d，J＝4.41Hz，1H)7.62(d，J＝4.41Hz，1H)7.73(dd，J＝8.82，2.21Hz，1H)7.86(d，J＝8.46Hz，1H)8.05(s，1H)8.26(d，J＝3.31Hz，1H)8.79(s，1H)8.97(d，J＝8.46Hz，1H)9.83(s，1H)11.10(s，1H)；MS(ESI+)m/z?525(M+H)+。

Embodiment 323

2-hydroxy-n-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-niacinamide

Embodiment 323A

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-2-hydroxyl-niacinamide

This title compound is such synthetic: according to the method for embodiment 255a, substitute furans-2-carbonyl chlorine with 2-hydroxyl-nicotinoyl chlorine, with 4-fluoro-3-nitro-phenyl amine and 2-hydroxyl-nicotinoyl chlorine reaction, then products therefrom is reacted according to the method for embodiment 255b and 255c, obtained this title product.

Embodiment 323B

According to the method for embodiment 255d, use the product of the product alternate embodiment 255c of embodiment 323A, the product of embodiment 323A and the product of embodiment 8E are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.62Hz，6H)3.23-3.40(m，1H)6.58(t，J＝6.25Hz，1H)6.66-6.74(m，2H)7.14-7.22(m，3H)7.56(dd，J＝8.64，2.39Hz，1H)7.79-7.86(m，1H)7.92(d，J＝8.46Hz，1H)7.97(d，J＝2.21Hz，1H)8.43(dd，J＝6.99，2.21Hz，1H)8.85(s，1H)9.00(d，J＝8.46Hz，1H)9.80(d，1H)11.71(d，1H)12.34(s，1H)12.79(d，J＝6.62Hz，1H)；MS(ESI+)m/z?525(M+H)+。

Embodiment 324

N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-methyl-benzamide

Embodiment 324A

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-3-methyl-benzamide

This title compound is such synthetic: according to the method for embodiment 255a, substitute furans-2-carbonyl chlorine with the 3-methyl benzoyl chloride, with 4-fluoro-3-nitro-phenyl amine and the reaction of 3-methyl benzoyl chloride, then products therefrom is reacted according to the method for embodiment 255b and 255c, obtained this title product.

Embodiment 324B

According to the method for embodiment 255d, use the product of the product alternate embodiment 255c of embodiment 324A, the product of embodiment 324A and the product of embodiment 8E are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.MS(ESI+)m/z?522(M+H)+。

Embodiment 325

4-dimethylamino-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Embodiment 325A

N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-4-dimethylamino-benzamide

This title compound is such synthetic: according to the method for embodiment 255a, substitute furans-2-carbonyl chlorine with 4-dimethylamino-Benzoyl chloride, with 4-fluoro-3-nitro-phenyl amine and 4-dimethylamino-Benzoyl chloride reaction, then products therefrom is reacted according to the method for embodiment 255b and 255c, obtained this title product.

Embodiment 325B

According to the method for embodiment 255d, use the product of the product alternate embodiment 255c of embodiment 325A, the product of embodiment 325A and the product of embodiment 8E are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.99Hz，6H)3.00(s，6H)3.24-3.37(m，1H)6.67(d，2H)6.75(d，J＝9.19Hz，2H)7.13(d，2H)7.21(d，J＝8.46Hz，1H)7.65(dd，J＝8.64，2.39Hz，1H)7.85(d，J＝9.19Hz，2H)7.91(d，J＝8.46Hz，1H)8.05(d，J＝2.21Hz，1H)8.83(s，1H)9.01(d，J＝8.82Hz，1H)10.10(s，1H)。(ESI+)m/z?551(M+H)+。

Embodiment 326

4-dimethylamino-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Method according to embodiment 255d, product with the product alternate embodiment 255c of embodiment 325A, and product with the product alternate embodiment 8E of embodiment 9B, the product of embodiment 325A and the product of embodiment 9B are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：2.73(s，3H)2.94(s，6H)6.61(d，J＝8.82Hz，2H)6.70(d，J＝9.19Hz，2H)7.08(d，J＝8.46Hz，2H)7.16(d，J＝8.82Hz，1H)7.60(dd，J＝8.46，2.21Hz，1H)7.79(m，4H)8.01(d，J＝1.84Hz，1H)8.78(s，1H)8.91(d，J＝8.46Hz，1H)10.06(s，1H)；MS(ESI-)m/z522(M-H)-。

Embodiment 327

3,4-two chloro-N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Will be according to the method for embodiment 255d, product with the product alternate embodiment 255c of embodiment 305A, and product with the product alternate embodiment 8E of embodiment 29A, obtained crude product, the product reaction of the product of embodiment 305A and embodiment 29A, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：6.69(d，2H)7.16-7.20(m，3H)7.62(dd，J＝8.46，2.21Hz，1H)7.82(d，1H)7.89-7.94(m，J＝8.36，1.88，1.88Hz，2H)8.03(s，1H)8.21(s，1H)8.84(s，1H)9.05(d，1H)9.17(d，1H)10.61(s，1H)。)；MS(ESI+)m/z?535(M+H)+。

Embodiment 328

4-bromo-N-[4-(4-hydroxyl-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Method according to embodiment 43F, product with the product alternate embodiment 43F of embodiment 247d, product and the pentamethylbenzene of embodiment 247d are reacted in trifluoroacetic acid, obtained crude product, it is passed through silica gel chromatography, use ethanol/methylene as eluent, obtained this title product.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.24-1.40(m，6H)3.17-3.28(m，1H)6.60-6.72(m，2H)6.75-6.88(m，2H)6.91(d，J＝8.82Hz，1H)7.62(dd，J=9.19，2.57Hz，1H)7.71-7.83(m，3H)7.91(d，J=8.46Hz，2H)8.05(d，J=2.21Hz，1H)8.77(s，1H)8.89(d，J=8.46Hz，1H)9.26(s，1H)10.44(s，1H)，10.94(bs，1H)；MS(ESI+)m/z570/572(M+H)+。

Embodiment 329

3-bromo-N-[4-(4-hydroxyl-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide

Product and the pentamethylbenzene of embodiment 248b are reacted in trifluoroacetic acid, method according to embodiment 43F, product with the product alternate embodiment 43F of embodiment 248b, obtained crude product, it is passed through silica gel chromatography, use ethanol/methylene as eluent, obtained this title product.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.31(d，J=6.99Hz，6H)3.14-3.26(m，1H)6.59-6.74(m，2H)6.75-6.85(m，2H)6.83-6.94(m，1H)7.51(t，J=7.91Hz，1H)7.57-7.69(m，2H)7.79(s，1H)7.96(d，J＝8.09Hz，1H)8.03(s，1H)8.15(s，1H)8.61(s，1H)8.79(d，J=8.82Hz，1H)9.21(s，1H)10.07(s，1H)10.42(s，1H)；MS(ESI+)m/z?570/572(M+H)+。

Embodiment 330

N-[4-(4-hydroxyl-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-trifluoromethyl-benzamide

Embodiment 330A

N-[3-amino-4-(4-hydroxyl-phenoxy group)-phenyl]-3-trifluoromethyl-benzamide

The solution of quinhydrones is heated under nitrogen atmosphere.Drip the solution of the product of embodiment 114A.Then this mixture is stirred, cooling is poured in the water, and regulates pH.With this mixture extraction, washing, and concentrate, obtained N-[4-(4-hydroxyl-phenoxy group)-3-nitro-phenyl]-3-trifluoromethyl-benzamide, with its reduction, obtained this title product.

Embodiment 330B

According to the method for embodiment 255d, use the product of the product alternate embodiment 255c of embodiment 330A, the product of embodiment 330A and the product of embodiment 8E are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)，3.28(dt，J＝13.70，6.94Hz，1H)，6.66-6.74(m，2H)，6.82-6.86(m，2H)，6.95(d，J＝8.82Hz，1H)，7.65(dd，J＝8.82，2.57Hz，1H)，7.77-7.89(m，2H)，7.99(d，J＝7.72Hz，1H)，8.08(d，J＝2.57Hz，1H)，8.24-8.31(m，2H)，8.89(s，1H)，8.96(d，J＝8.46Hz，1H)，9.32(s，1H)，10.63(s，1H)，11.47(s，1H)；MS(ESI+)m/z?560(M+H)+。

Embodiment 331

N-[4-(4-hydroxyl-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-4-methoxyl group-benzamide

Embodiment 331A

N-[3-amino-4-(4-hydroxyl-phenoxy group)-phenyl]-4-methoxyl group-benzamide

Method according to embodiment 330A, with N-(4-fluoro-3-nitro-phenyl)-4-methoxyl group-benzamide (deriving from embodiment 314A) and reacted with hydroquinone, obtained N-[4-(4-hydroxyl-phenoxy group)-3-nitro-phenyl]-4-methoxyl group-benzamide, with its reduction, obtained this title product.

Embodiment 331B

According to the method for embodiment 255d, use the product of the product alternate embodiment 255c of embodiment 331A, the product of embodiment 331A and the product of embodiment 8E are reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.33(d，J＝6.99Hz，6H)3.21-3.34(m，1H)3.84(s，3H)6.67(d，J＝9.19Hz，2H)6.82(d，J＝9.19Hz，2H)6.92(d，J＝8.82Hz，1H)7.07(d，J＝8.82Hz，2H)7.63(dd，J＝8.82，2.57Hz，1H)7.81(d，J＝8.82Hz，1H)7.96(d，J＝8.82Hz，2H)8.06(d，J＝2.57Hz，1H)8.83(s，1H)8.92(d，J＝8.46Hz，1H)9.27(s，1H)10.23(s，1H)11.23(s，1H)；MS(ESI+)m/z?522(M+H)+。

Embodiment 332

Product and two-(t-butyl carbamate)-thiocarbamide, mercury chloride and the triethylamine of embodiment 17B are reacted in dimethyl formamide, obtained crude product, by the fast silica gel chromatogram purifying, use dichloromethane/ethyl acetate it, obtained this title product as eluent.1HNMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)1.41(s，9H)1.51(s，9H)3.16-3.29(m，1H)7.10(d，J＝8.46Hz，1H)7.41(d，J＝8.82Hz，2H)7.63(d，J＝8.82Hz，3H)7.92(dd，J＝8.46，1.84Hz，1H)8.02-8.10(m，1H)8.12(d，J＝1.84Hz，1H)8.15-8.22(m，1H)8.50(d，J＝2.57Hz，1H)8.59(s，1H)8.85(d，J＝8.46Hz，1H)10.06(s，1H)10.23(s，1H)11.00(s，1H)11.30(s，1H)。

Embodiment 333

N-(5-bromo-pyridine-2-yl)-4-(4-guanidine radicals-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

In room temperature with the product of embodiment 332 and the solution reaction of 50% trifluoroacetic acid in methylene dichloride 2 hours.After the solvent removed in vacuo,, use methyl alcohol/chloroform, obtained this title product as eluent by fast silica gel chromatogram purifying resistates.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)3.18-3.30(m，1H)7.20(d，J＝8.46Hz，1H)7.26(d，J＝8.46Hz，2H)7.46(d，J＝8.46Hz，2H)7.58(s，4H)7.65(d，J＝8.46Hz，1H)7.92(dd，J＝8.46，1.10Hz，1H)8.07(dd，1H)8.13-8.24(m，2H)8.51(d，J＝2.21Hz，1H)8.59(s，1H)8.86(d，J＝8.46Hz，1H)9.91(s，1H)10.27(s，1H)11.02(s，1H)；MS(ESI+)m/z?628(M+H)+。

Embodiment 334

N-[4-(4-amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-methyl-benzamide

Embodiment 334A

4-[2-amino-4-(3-methyl-benzoyl-amido)-phenoxy group]-phenyl }-t-butyl carbamate

Method according to embodiment 256a, substitute thiophene-2-carbonyl chlorine with the 3-methyl benzoyl chloride, with 4-fluoro-3-nitro-phenyl amine and the reaction of 3-methyl benzoyl chloride, obtained N-(4-fluoro-3-nitro-phenyl)-3-methyl-benzamide, its method according to embodiment 256b and 256c is reacted, obtained this title product.

Embodiment 334B

Method according to embodiment 256d; product with the product alternate embodiment 256c of embodiment 334A; the product of embodiment 334A and the product of embodiment 8E are reacted; obtained { 4-[2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-4-(3-methyl-benzoyl-amido)-phenoxy group]-phenyl }-t-butyl carbamate; with its method deprotection according to embodiment 256e; obtained crude product; by using the HPLC purifying of TFA; obtain this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.33(d，J＝6.99Hz，6H)，2.40(s，3H)，3.19-3.34(m，1H)，6.89-6.99(m，4H)，7.03(d，J＝8.82Hz，1H)，7.42(d，J＝5.52Hz，2H)，7.67-7.78(m，3H)，7.83(d，J＝8.46Hz，1H)，8.10(d，J＝2.57Hz，1H)，8.83(s，1H)，8.92(d，J＝8.46Hz，1H)，10.40(s，1H)；MS(ESI+)m/z?505(M+H)+。

Embodiment 335

N-[4-(4-amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-4-methoxyl group-benzamide

Embodiment 335A

4-[2-amino-4-(4-methoxyl group-benzoyl-amido)-phenoxy group]-phenyl }-t-butyl carbamate

Method according to embodiment 256a, substitute thiophene-2-carbonyl chlorine with the 4-methoxy benzoyl chloride, with 4-fluoro-3-nitro-phenyl amine and the reaction of 4-methoxy benzoyl chloride, obtained N-(4-fluoro-3-nitro-phenyl)-4-methoxyl group-benzamide, its method according to embodiment 256b and 256c is reacted, obtained this title product.

Embodiment 335B

Method according to embodiment 256d; product with the product alternate embodiment 256c of embodiment 335A; the product of embodiment 335A and the product of embodiment 8E are reacted; obtained { 4-[2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-4-(4-methoxyl group-benzoyl-amido)-phenoxy group]-phenyl }-t-butyl carbamate; with its method deprotection according to embodiment 256e; obtained crude product; by using the HPLC purifying of TFA; obtain this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.33(d，J＝6.99Hz，6H)3.20-3.33(m，1H)3.84(s，3H)6.91-6.97(m，2H)7.02(d，J＝7.35Hz，1H)7.08(d，J＝9.19Hz，2H)7.70(dd，J＝8.82，2.57Hz，1H)7.84(d，J＝8.46Hz，1H)7.97(d，J＝9.19Hz，2H)8.10(d，J＝2.57Hz，1H)8.85(s，1H)8.92(d，J＝8.46Hz，1H)10.30(s，1H)；MS(ESI+)m/z?521(M+H)+。

Embodiment 336

N-[4-(4-amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-methoxyl group-benzamide

Embodiment 336A

4-[2-amino-4-(3-methoxyl group-benzoyl-amido)-phenoxy group]-phenyl }-t-butyl carbamate

Method according to embodiment 256a, substitute thiophene-2-carbonyl chlorine with the 3-methoxy benzoyl chloride, with 4-fluoro-3-nitro-phenyl amine and the reaction of 3-methoxy benzoyl chloride, obtained N-(4-fluoro-3-nitro-phenyl)-3-methoxyl group-benzamide, its method according to embodiment 256b and 256c is reacted, obtained this title product.

Embodiment 336B

Method according to embodiment 256d; product with the product alternate embodiment 256c of embodiment 336A; the product of embodiment 336A and the product of embodiment 8E are reacted; obtained { 4-[2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-4-(3-methoxyl group-benzoyl-amido)-phenoxy group]-phenyl }-t-butyl carbamate; with its method deprotection according to embodiment 256e; obtained crude product; by using the HPLC purifying of TFA; obtain this title product, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.33(d，J＝6.99Hz，6H)3.21-3.34(m，1H)3.84(s，3H)6.90-7.22(m，6H)7.38-7.58(m，4H)7.70(dd，J＝8.82，2.57Hz，1H)7.84(d，J＝8.46Hz，1H)8.09(d，J＝2.57Hz，1H)8.24(dd，J＝21.69，2.57Hz，1H)8.84(s，1H)8.92(d，J＝8.46Hz，1H)10.41(s，1H)11.44(s，1H)；MS(ESI+)m/z?521(M+H)+。

Embodiment 337

N-[4-(4-amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-2,5-two fluoro-benzamide

Embodiment 337A

4-[2-amino-4-(2,5-two fluoro-benzoyl-amidos)-phenoxy group]-phenyl }-t-butyl carbamate

Method according to embodiment 256a, with 2, the 5-difluoro benzoyl chloride substitutes thiophene-2-carbonyl chlorine, with 4-fluoro-3-nitro-phenyl amine and 2, the reaction of 5-difluoro benzoyl chloride has obtained 2,5-two fluoro-N-(4-fluoro-3-nitro-phenyl)-benzamide, its method according to embodiment 256b and 256c is reacted, obtained this title product.

Embodiment 337B

Method according to embodiment 256d; product with the product alternate embodiment 256c of embodiment 337A; the product of embodiment 337A and the product of embodiment 8E are reacted, obtained { 4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(2; 5-two fluoro-benzoyl-amidos)-phenoxy group]-phenyl }-t-butyl carbamate; with its method deprotection according to embodiment 256e, obtained crude product, it is passed through the silica gel chromatography purifying; obtain this title product, be hydrochloride.1H NMR (300MHz, DMSO-d6) δ ppm:1.34 (d, J=7.0Hz, 6H), 3.28 (septet, J=7.0Hz, 1H), 7.05 (d, J=8.8Hz, 2H), 7.12 (d, J=8.8Hz, 1H), 7.26 (d, J=8.8Hz, 2H), 7.41-7.50 (m, 2H), 7.52-7.61 (m, 1H), 7.69 (dd, J=8.8,2.6Hz, 1H), 7.88 (d, J=8.8Hz, 1H), 8.03 (d, J=2.6Hz, 1H), 8.88 (s, 1H), 9.19 (d, J=8.8Hz, 1H), 10.80 (s, 1H), 12.16 (br-s, 1H); MS (ESI+) m/z 527 (M+H)+.

Embodiment 338

N-[4-(4-amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-2-fluoro-benzamide

Embodiment 338A

4-[2-amino-4-(2-fluoro-benzoyl-amido)-phenoxy group]-phenyl }-t-butyl carbamate

Method according to embodiment 256a, substitute thiophene-2-carbonyl chlorine with the 2-fluorobenzoyl chloride, with 4-fluoro-3-nitro-phenyl amine and the reaction of 2-fluorobenzoyl chloride, obtain 2-fluoro-N-(4-fluoro-3-nitro-phenyl)-benzamide, its method according to embodiment 256b and 256c is reacted, obtained this title product.

Embodiment 338B

Method according to embodiment 256d; product with the product alternate embodiment 256c of embodiment 338A; the product of embodiment 338A and the product of embodiment 8E are reacted; obtained 4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(2-fluoro-benzoyl-amido)-phenoxy group]-phenyl }-t-butyl carbamate, with its method deprotection according to embodiment 256e; obtained crude product; it by the silica gel chromatography purifying, is obtained this title product, be hydrochloride.1H NMR (300 MHz, DMSO-d6) δ ppm:1.34 (d, J=7.0Hz, 6H), 3.27 (septet, J=7.0Hz, 1H), 7.03 (d, J=8.8Hz, 2H), 7.11 (d, J=9.2Hz, 1H), 7.20 (d, J=8.8Hz, 2H), 7.31-7.42 (m, 2H), 7.55-7.73 (m, 3H), 7.87 (d, J=8.5Hz, 1H), 8.05 (d, J=2.5Hz, 1H), 8.87 (s, 1H), 9.11 (d, J=8.5Hz, 1H), 10.69 (s, 1H), 11.97 (br-s, 1H); MS (ESI+) m/z 509 (M+H)+.

Embodiment 339

N-[4-(4-amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3,5-di-trifluoromethyl-benzamide

Embodiment 339A

4-[2-amino-4-(3,5-di-trifluoromethyl-benzoyl-amido)-phenoxy group]-phenyl }-t-butyl carbamate

Method according to embodiment 256a, with 3,5-di-trifluoromethyl-Benzoyl chloride substitutes thiophene-2-carbonyl chlorine, with 4-fluoro-3-nitro-phenyl amine and 3,5-di-trifluoromethyl-Benzoyl chloride reaction has obtained N-(4-fluoro-3-nitro-phenyl)-3,5-di-trifluoromethyl-benzamide, its method according to embodiment 256b and 256c is reacted, obtained this title product.

Embodiment 339B

Method according to embodiment 256d; product with the product alternate embodiment 256c of embodiment 339A; the product of embodiment 339A and the product of embodiment 8E are reacted; obtained 4-[4-(3,5-di-trifluoromethyl-benzoyl-amido)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-phenyl }-t-butyl carbamate; with its method deprotection according to embodiment 256e; obtained crude product, it by the silica gel chromatography purifying, has been obtained this title product.1H NMR (300MHz, DMSO-d6) δ ppm:1.32 (d, J=7.0Hz, 6H), 3.20 (septets, J=7.0Hz, 1H), 4.91 (s, 2H), 6.52 (d, J=8.8Hz, 2H), 6.74 (d, J=8.8Hz, 2H), 6.86 (d, J=9.2Hz, 1H), 7.58 (d, J=8.5Hz, 1H), 7.60 (dd, J=9.2,2.6Hz, 1H), 8.04 (d, J=2.6Hz, 1H), 8.38 (br-s, 1H), 8.60 (s, 1H), 8.62 (br-s, 2H), 8.82 (d, J=8.5Hz, 1H), 9.88 (s, 1H), 10.70 (s, 1H); MS (ESI+) m/z 627 (M+H)+.

Embodiment 340

N-[4-(4-amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-fluoro-5-trifluoromethyl-benzamide

Embodiment 340A

4-[2-amino-4-(3-fluoro-5-trifluoromethyl-benzoyl-amido)-phenoxy group]-phenyl }-t-butyl carbamate

Method according to embodiment 256a, substitute thiophene-2-carbonyl chlorine with 3-fluoro-5-trifluoromethyl-Benzoyl chloride, with 4-fluoro-3-nitro-phenyl amine and 3-fluoro-5-trifluoromethyl-Benzoyl chloride reaction, obtained N-(4-fluoro-3-nitro-phenyl)-3-fluoro-5-trifluoromethyl-benzamide, its method according to embodiment 256b and 256c is reacted, obtained this title product.

Embodiment 340B

Method according to embodiment 256d; product with the product alternate embodiment 256c of embodiment 340A; the product of embodiment 340A and the product of embodiment 8E are reacted; obtained { 4-[4-(3-fluoro-5-trifluoromethyl-benzoyl-amido)-2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine 4-base amino)-phenoxy group]-phenyl }-t-butyl carbamate, with its method deprotection, obtained crude product according to embodiment 256e; it by the silica gel chromatography purifying, has been obtained this title product.1H NMR (300MHz, DMSO-d6) δ ppm:1.32 (d, J=7.0Hz, 6H), 3.20 (septets, J=7.0Hz, 1H), 4.90 (s, 2H), 6.51 (d, J=8.8Hz, 2H), 6.73 (d, J=8.8Hz, 2H), 6.84 (d, J=8.8Hz, 1H), 7.58 (d, J=8.5Hz, 1H), 7.59 (dd, J=8.8,2.6Hz, 1H), 7.98 (br-d, J=8.4Hz, 1H), 8.03 (d, J=2.6Hz, 1H), 8.13 (br-d, J=8.8Hz, 1H), 8.18 (s, 1H), 8.60 (s, 1H), 8.82 (d, J=8.5Hz, 1H), 9.88 (s, 1H), 10.55 (s, 1H); MS (ESI+) m/z 577 (M+H)+.

Embodiment 341

4,4 '-(4,4 '-carbonyl diurethane (azane two bases) two (4, the 1-phenylene) two (sulfane two bases)) two (N-(5-bromopyridine-2-yl)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) benzamide)

The product (1 equivalent) of embodiment 17B was heated 3 hours in 60 ℃ in THF with triphosgene [two (trichloromethyl) carbonic ether, 0.33 equivalent].Solvent removed in vacuo has obtained gained isocyanic ester crude product then, it is dissolved among the THF, and adds the product (1 equivalent) of embodiment 17B.Gained solution was heated 3 hours at 60 ℃, then solvent removed in vacuo.Resistates by using the HpLC purifying of TFA, is obtained this title product, be trifluoroacetate.1HNMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.99Hz，12H)，3.19-3.34(m，J＝6.99Hz，2H)，7.03(d，J＝7.72Hz，2H)，7.42(d，J＝8.46Hz，4H)，7.52-7.59(m，4H)，7.83(d，J＝8.09Hz，2H)，7.95(d，J＝7.72Hz，2H)，8.04-8.10(m，4H)，8.12-8.21(m，2H)，8.51(d，J＝2.57Hz，2H)，8.79(s，2H)，8.97(d，J＝5.88Hz，2H)，9.12(s，2H)，10.99(s，2H)，11.29(s，2H)；MS(ESI+)m/z?1199(M+H)+。

Embodiment 342

Piperidines-1-formic acid 4-[4-(5-bromo-pyridine-2-base formamyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-acid amides

Embodiment 342A

4-[2-amino-4-(5-bromo-pyridine-2-base formamyl)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

Mixture and 5-bromo-pyridine-2-base amine reaction with 4-chloro-3-nitrobenzoyl chloride, generated N-(4-bromo-phenyl)-4-chloro-3-nitro-benzamide, according to the method for embodiment 10A, use the method for embodiment 13A, 268B and 268C to handle successively it, obtained this title product.

Embodiment 342B

4-[4-(5-bromo-pyridine-2-base formamyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

The product of embodiment 342A and the mixture of product in Glacial acetic acid of embodiment 8E were heated 15 minutes in 130 ℃ of oil baths.Then this reaction mixture is cooled to room temperature, and, has obtained this title product solvent vacuum-evaporation.

Embodiment 342C

With the product (1 equivalent), 1 of embodiment 342B, 8-diazabicylo [5.4.0] 11 carbon-7-alkene (2 equivalent) and the mixture of piperidines (10 equivalent) in tetrahydrofuran (THF) (2ml) heated 2 hours in 65 ℃ in sealed tube.Then this mixture is cooled to room temperature, vacuum concentration, and, obtained this title compound with the HPLC purifying of gained resistates by use TFA, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.99Hz，6H)，1.43-1.64(m，6H)，3.22-3.37(m，5H)，6.97(d，J＝8.46Hz，1H)，7.35(d，J＝8.82Hz，2H)，7.56(d，J＝8.82Hz，2H)，7.82(d，J＝9.56Hz，1H)，7.93(d，J＝9.19Hz，1H)，8.07(dd，J＝8.82，2.57Hz，2H)，8.14-8.18(m，1H)，8.50(d，J＝2.21Hz，1H)，8.68(s，1H)，8.78(s，1H)，8.96(d，J＝8.82Hz，1H)，10.98(s，1H)，11.24(s，1H)；MS(ESI+)m/z?697(M+H)+。

Embodiment 343

-[4-(3-benzyl-urea groups)-phenyl sulfenyl]-N-(5-bromo-pyridine-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

According to the method for embodiment 342C, substitute piperidines with benzyl amine, the product of embodiment 342B is reacted, obtained crude product, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.62Hz，6H)，3.18-3.38(m，1H)，4.31(d，J＝5.88Hz，2H)，6.75(t，J＝5.88Hz，1H)，6.96(d，J＝8.09Hz，1H)，7.20-7.40(m，7H)，7.52(d，J＝8.82Hz，2H)，7.84(d，J＝8.46Hz，1H)，7.93(d，J＝8.82Hz，1H)，8.05(d，J＝2.57Hz，1H)，8.08(d，J＝2.57Hz，1H)，8.14-8.20(m，1H)，8.50(d，J＝2.57Hz，1H)，8.79(s，1H)，8.88(s，1H)，8.97(d，J＝9.19Hz，1H)，10.99(s，1H)，11.36(s，1H)；MS(ESI+)m/z?719/721(M+H)+。

Embodiment 344

N-(5-bromo-pyridine-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-[4-(3-amyl group-urea groups)-phenyl sulfenyl]-benzamide

According to the method for embodiment 342C, substitute piperidines with the 1-aminopentane, the product of embodiment 342B is reacted obtain crude product, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：0.83-0.92(m，3H)，1.21-1.32(m，4H)，1.35(d，J＝6.62Hz，6H)，1.39-1.51(m，2H)，3.08(q，J＝6.62Hz，2H)，3.20-3.35(m，1H)，6.24(t，J＝5.70Hz，1H)，6.95(d，J＝8.46Hz，1H)，7.35(d，J＝8.82Hz，2H)，7.47-7.52(m，2H)，7.82(d，J＝8.09Hz，1H)，7.93(d，J＝8.82Hz，1H)，8.06(dd，J＝9.01，2.39Hz，2H)，8.13-8.19(m，1H)，8.50(d，J＝2.57Hz，1H)，8.70(s，1H)，8.77(s，1H)，8.96(d，J＝9.19Hz，1H)，10.98(s，1H)，11.25(s，1H)；MS(ESI+)m/z?699/701(M+H)+。

Embodiment 345

N-[4-(4-dimethylamino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-trifluoromethyl-benzamide

Embodiment 345A

N-[3-amino-4-(4-dimethylamino-phenyl sulfenyl)-phenyl]-3-trifluoromethyl-benzamide

According to the method for embodiment 114B, substitute the 4-hydroxythiophenol with 4-dimethylamino-thiophenol, the product of embodiment 114A is reacted, then according to the method for embodiment 114C with nitroreduction, obtained this title product.

Embodiment 345B

The product of embodiment 345A and the mixture of product in Glacial acetic acid of embodiment 8E were heated 15 minutes in 130 ℃ of oil baths.Then this reaction mixture is cooled to room temperature, and, has obtained resistates,, obtained this title compound, be trifluoroacetate by using the HPLC purifying of TFA with solvent vacuum-evaporation.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)，2.88(s，6H)，3.17-3.28(m，1H)，6.65(d，J＝8.82Hz，2H)，7.02(d，J＝8.82Hz，1H)，7.20(d，J＝8.82Hz，2H)，7.61(d，J＝8.82Hz，2H)，7.78(t，J＝7.72Hz，1H)，7.91(d，J＝2.21Hz，1H)，7.97(d，J＝6.99Hz，1H)，8.18-8.33(m，2H)，8.55(s，1H)，8.84(d，J＝8.46Hz，1H)，10.05(s，1H)，10.57(s，1H)；MS(ESI+)m/z699/701(M+H)+。

Embodiment 346

N-(5-bromo-pyridine-2-yl)-4-(4-dimethylamino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 346A

3-amino-N-(5-bromo-pyridine-2-yl)-4-(4-dimethylamino-phenyl sulfenyl)-benzamide

Method according to embodiment 10A, mixture and 5-bromo-pyridine-2-base amine reaction with 4-chloro-3-nitrobenzoyl chloride, generated N-(4-bromo-phenyl)-4-chloro-3-nitro-benzamide, then according to the method for embodiment 114B, substituting the 4-hydroxythiophenol with 4-dimethylamino-thiophenol reacts, afterwards according to the method for embodiment 114C with nitroreduction, obtained this title product.

Embodiment 346B

The product of embodiment 346A and the mixture of product in Glacial acetic acid of embodiment 8E were heated 15 minutes in 130 ℃ of oil baths.Then this reaction mixture is cooled to room temperature, and, has obtained resistates, it by silica gel chromatography, has been obtained this title product solvent vacuum-evaporation.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)2.95(s，6H)3.24(m，1H)6.77(d，J＝9.19Hz，2H)6.85(d，J＝8.82Hz，1H)7.29(d，J＝8.82Hz，2H)7.65(d，J＝8.82Hz，1H)7.88(d，J＝8.82Hz，1H)8.10(m，3H)8.49(d，J＝2.57Hz，1H)8.54(s，1H)8.89(d，J＝8.82Hz，1H)10.13(s，1H)10.92(s，1H)；MS(ESI+)m/z?614/616(M+H)+。

Embodiment 347

N-(5-bromo-pyridine-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-[4-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-benzamide

The product of embodiment 17B and the mixture of product in Glacial acetic acid of embodiment 8E were heated 15 minutes in 130 ℃ of oil baths.Then this reaction mixture is cooled to room temperature, and, has obtained resistates, it by silica gel chromatography, has been obtained this title product solvent vacuum-evaporation.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.33(d，J＝6.26Hz，6H)1.34(d，J＝6.98Hz，6H)3.10-3.32(m，2H)7.02-7.15(m，1H)7.37-7.44(m，1H)7.51(d，J＝8.46Hz，2H)7.66(d，J＝8.46Hz，2H)7.93(dd，J＝7.17，1.65Hz，1H)8.01(d，J＝8.82Hz，2H)8.06(dd，J＝9.19，2.20Hz，1H)8.12(s，1H)8.18(d，J＝8.82Hz，2H)8.50(d，J＝2.21Hz，1H)8.54-8.66(m，1H)8.76(s，1H)8.83-8.91(m，1H)8.94(d，J＝8.46Hz，1H)10.07(s，1H)10.24(s，1H)10.99(s，1H)；MS(ESI+)m/z757/759(M+H)+。

Embodiment 348

N-(5-bromo-pyridine-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-pyrroles-1-base-phenyl sulfenyl)-benzamide

To add in the product (1 equivalent) of embodiment 17B and the mixture of suceinic aldehyde (40% aqueous solution) (3 equivalent) in toluene and methanol 1/1 mixture Molecular sieve and acetate (0.05 equivalent).This mixture 75 ℃ of heating 30 hours, is removed under vacuum then Molecular sieve and solvent have obtained resistates, by using the HPLC purifying of TFA, have obtained this title compound, are trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.6Hz，6H)，3.24(m，1H)，6.29(t，J＝2.2Hz，2H)，7.25(d，J＝8.1Hz，1H)，7.36(t，J＝2.2Hz，2H)，7.49(d，J＝8.5Hz，2H)，7.60(d，J＝8.9Hz，2H)，7.85(d，J＝8.5Hz，1H)，8.01(m，1H)，8.09(m，2H)，8.18(d，J＝8.8Hz，1H)，8.51(m，1H)，8.80(bs，1H)，8.96(d，J＝7.5Hz，1H)，11.04(s，1H)；MS(ESI+)m/z?636/638(M+H)+。

Embodiment 349

4-[6-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-2-thiazol-2-yl-benzoxazoles-5-base sulfenyl]-phenol

Embodiment 349A

5-chloro-6-nitro-2-thiazol-2-yl-benzoxazoles

In the flask that is equipped with the vigreux post, add 2-amino-4-chloro-5-nitro-phenol, thiazole-2-formaldehyde, Darco KB and dimethylbenzene.Then this mixture is refluxed and spend the night, and, filter this mixture cooling, and solvent removed in vacuo.With the gained solid from Et ₂Recrystallization among the O has obtained 4.76g (63%) yellow solid.

Embodiment 349B

4-(6-amino-2-thiazol-2-yl-benzoxazoles-5-base sulfenyl)-phenol

The product, 4-mercapto-phenol, salt of wormwood and the ethanol that in the flask that is equipped with magnetic stirring bar and vigreux post, add embodiment 349A.This mixture was refluxed 2 hours, add tindichloride then, add tindichloride then, simultaneously this mixture is remained on 70 ℃.After the heated overnight, filter, use 10% CH then with this mixture cooling, and via silicon-dioxide ₃OH/CHCl ₃Wash-out.(3% to 100%CH then with the organic layer vacuum concentration, and via anti-phase (C-18) column chromatography ₃CN/ contains the H of 0.1%TFA ₂O) purifying has obtained this title product.

Embodiment 349C

The product of embodiment 349B and the mixture of product in Glacial acetic acid of embodiment 8E were heated 5 minutes in 130 ℃ of oil baths.Then this reaction mixture is cooled to room temperature, and, has obtained resistates,, obtained this title compound, be trifluoroacetate by using the HPLC purifying of TFA with solvent vacuum-evaporation. ¹H?NMR(300MHz，DMSO-D ₆)δ?ppm：1.18(d，J＝6.99Hz，6H)2.79-2.91(m，1H)6.58(d，J＝7.72Hz，2H)6.79(d，J＝8.82Hz，1H)7.29(d，J＝8.82Hz，1H)7.47(s，1H)7.80(d，J＝8.09Hz，2H)7.99(d，J＝8.82Hz，1H)8.07(s，1H)8.22(s，1H)8.90(s，1H)9.09(d，J＝8.46Hz，1H)；MS(ESI+)m/z?513(M+H)+。

Embodiment 350

4-[6-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-2-phenyl-benzoxazoles-5-base sulfenyl]-phenol

Embodiment 350A

4-(6-amino-2-phenyl-benzoxazoles-5-base sulfenyl)-phenol

In the flask that is equipped with the vigreux post, add 2-amino-4-chloro-5-nitro-phenol, phenyl aldehyde, Darco KB and dimethylbenzene.Then this mixture is refluxed and spend the night, and, filter this mixture cooling, and solvent removed in vacuo.With the gained solid from Et ₂Recrystallization among the O has obtained 5-chloro-6-nitro-2-phenyl-benzoxazoles, and it is imposed the method for embodiment 349B, and the product with 5-chloro-6-nitro-2-phenyl-benzoxazole alternate embodiment 349A has obtained this title product.

Embodiment 350B

The product of embodiment 350A and the mixture of product in Glacial acetic acid of embodiment 8E were heated 5 minutes in 130 ℃ of oil baths.Then this reaction mixture is cooled to room temperature, and, has obtained resistates,, obtained this title compound, be trifluoroacetate by using the HPLC purifying of TFA with solvent vacuum-evaporation.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.99Hz，6H)3.20-3.30(m，1H)6.80(d，J＝8.82Hz，2H)7.28(d，J＝8.46Hz，2H)7.58-7.68(m，5H)7.75(d，J＝7.35Hz，1H)7.95(s，1H)8.18(dd，J＝7.72，1.84Hz，2H)8.66(s，1H)8.91(s，1H)9.89(s，1H)；MS(ESI+)m/z?506(M+H)+。

Embodiment 351

5-(4-hydroxyl-phenyl sulfenyl)-4-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-thiophene-2-carboxylic acid (3-bromo-phenyl)-acid amides

Embodiment 351A

5-chloro-4-nitro-thiophene-2-carboxylic acid ethyl ester

Nitrosonitric acid solution (75mL) is cooled to 10 ℃, add then 5-chloro-thiophene-2-carboxylic acid ethyl ester (15g, 78.7mmol).The gained mixture was stirred 30 minutes at 10 ℃, add frozen water then.With this solution ethyl acetate extraction, and dry, vacuum concentration then, and, obtained this title product of 10.29g (55%) by using the column chromatography purifying of silica gel.

Embodiment 351B

5-(4-hydroxyl-phenyl sulfenyl)-4-nitro-thiophene-2-carboxylic acid ethyl ester

Product (1 equivalent) and the 4-mercapto-phenol (1 equivalent) of embodiment 351A are dissolved in the dimethyl formamide, add cesium carbonate (5 equivalent).The gained mixture was stirred 2.5 hours at 80 ℃, be cooled to room temperature, and add entry.With this solution ethyl acetate extraction, dry and vacuum concentration has obtained this title product with organic extract liquid.

Embodiment 351C

5-(4-hydroxyl-phenyl sulfenyl)-4-nitro-thiophene-2-carboxylic acid

The product (1 equivalent) of embodiment 351B is dissolved in methanol 3/1 mixture, adds lithium hydroxide (5 equivalent) then.Gained solution was stirring at room 24 hours, and adding 1N hydrochloric acid then is 2 until the pH of solution.With this mixture ethyl acetate extraction, dry and vacuum concentration has obtained this title product with organic extract liquid then.

Embodiment 351D

5-(4-hydroxyl-phenyl sulfenyl)-4-nitro-thiophene-2-carboxylic acid (3-bromo-phenyl)-acid amides

The product of embodiment 351C is dissolved in the methylene dichloride, adds the solution of the dimethyl formamide of oxalyl chloride and catalytic amount then.This solution stirring at room 3 hours, is added 3-bromaniline and pyridine then.Gained solution adds entry then stirring at room 20 hours, and with this solution ethyl acetate extraction, dry and vacuum concentration has obtained crude product with organic extract liquid, and it by the silica gel chromatography purifying, has been obtained this title product.

Embodiment 351E

4-amino-5-(4-hydroxyl-phenyl sulfenyl)-thiophene-2-carboxylic acid (3-bromo-phenyl)-acid amides

With reflux in product (1 equivalent), iron powder (5 equivalent) and the solution of ammonium chloride (3 equivalent) in tetrahydrofuran (THF), water and alcoholic acid mixture of embodiment 351D 3 hours.This mixture is cooled to room temperature, filters, it is used washing with alcohol via Celite pad, and with gained filtrate vacuum concentration.Then resistates is dissolved in the water, and uses ethyl acetate extraction, with the organic layer drying, and vacuum concentration, obtained this title product.

Embodiment 351F

The product of embodiment 351E and the mixture of product in Glacial acetic acid of embodiment 8E were heated 20 minutes in 130 ℃ of oil baths of preheating.Then this reaction mixture is cooled to room temperature, and, has obtained resistates,, obtained this title compound, be trifluoroacetate by using the HPLC purifying of TFA with solvent vacuum-evaporation.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.99Hz，6H)3.28(qq，1H)6.75(d，J＝8.82Hz，2H)7.23-7.42(m，4H)7.61-7.72(m，J＝2.94Hz，1H)7.84(d，J＝8.46Hz，1H)7.96-8.01(m，1H)8.10(s，1H)8.85(s，1H)8.94(d，J＝8.46Hz，1H)9.93(s，1H)10.42(s，1H)11.13(s，1H)；MS(ESI+)m/z?594(M+H)+。

Embodiment 352

5-(4-hydroxyl-phenyl sulfenyl)-4-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-thiophene-2-carboxylic acid (3-bromo-phenyl)-acid amides

The product of embodiment 351E and the mixture of product in Glacial acetic acid of embodiment 9B were heated 20 minutes in 130 ℃ of oil baths of preheating.Then this reaction mixture is cooled to room temperature, and, has obtained resistates,, obtained this title compound, be trifluoroacetate by using the HPLC purifying of TFA with solvent vacuum-evaporation.1H?NMR(300MHz，DMSO-D6)δ?ppm：2.72(s，3H)6.75(d，J＝8.82Hz，2H)7.25-7.37(m，4H)7.62-7.76(m，2H)8.00(s，1H)8.12(s，1H)8.78(s，1H)8.86(d，J＝8.09Hz，1H)9.91(s，1H)10.38(s，1H)10.82(s，1H)；MS(ESI+)m/z?565(M+H)+。

Embodiment 353

5-(4-hydroxyl-phenyl sulfenyl)-4-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-thiophene-2-carboxylic acid phenyl amide

Embodiment 353A

4-amino-5-(4-hydroxyl-phenyl sulfenyl)-thiophene-2-carboxylic acid phenyl amide

According to the method for embodiment 351D, substitute the 3-bromaniline with aniline, with product and the aniline reaction of embodiment 351C, then according to the method for embodiment 351E with nitroreduction, obtained this title product.

Embodiment 353B

The product of embodiment 353A and the mixture of product in Glacial acetic acid of embodiment 8E were heated 20 minutes in 130 ℃ of oil baths of preheating.Then this reaction mixture is cooled to room temperature, and, has obtained resistates,, obtained this title compound, be trifluoroacetate by using the HPLC purifying of TFA with solvent vacuum-evaporation.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.99Hz，6H)3.28(qq，1H)6.75(d，J＝8.82Hz，2H)7.23-7.42(m，4H)7.61-7.72(m，J＝2.94Hz，1H)7.84(d，J＝8.46Hz，1H)7.96-8.01(m，1H)8.10(s，1H)8.85(s，1H)8.94(d，J＝8.46Hz，1H)9.93(s，1H)10.42(s，1H)11.13(s，1H)；MS(ESI+)m/z?514(M+H)+。

Embodiment 354

4-[7-(1-hydroxyl-1-methyl-ethyl)-pyrido [2,3-d] pyrimidine-4-base is amino]-5-(4-hydroxyl-phenyl sulfenyl)-thiophene-2-carboxylic acid phenyl amide

The product of embodiment 353A and the mixture of product in Glacial acetic acid of embodiment 8E are heated (through 20 minutes) to 130 ℃ of oil baths lentamente from room temperature, under this temperature, kept 20 minutes then.Then this reaction mixture is cooled to room temperature, and, has obtained resistates,, obtained this title compound, be trifluoroacetate by using the HPLC purifying of TFA with solvent vacuum-evaporation.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.56(s，6H)6.75(d，J＝8.46Hz，2H)7.11(t，J＝7.35Hz，1H)7.26-7.44(m，4H)7.68(d，J＝7.72Hz，2H)8.10(s，1H)8.15(d，J＝8.46Hz，1H)8.88(s，1H)9.02(d，J＝8.82Hz，1H)9.93(s，1H)10.30(s，1H)11.26(s，1H)；MS(ESI+)m/z?530(M+H)+。

Embodiment 355

5-(3-hydroxyl-phenyl sulfenyl)-4-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-thiophene-2-carboxylic acid (3-bromo-phenyl)-acid amides

Embodiment 355A

4-amino-5-(3-hydroxyl-phenyl sulfenyl)-thiophene-2-carboxylic acid (3-bromo-phenyl)-acid amides

According to the method for embodiment 351C, substitute the 4-mercapto-phenol with the 3-mercapto-phenol, with product and the reaction of 3-mercapto-phenol of embodiment 351B, react according to the method for embodiment 351D and 828E then, obtained this title product.

Embodiment 355B

The product of embodiment 355A and the mixture of product in Glacial acetic acid of embodiment 8E were heated 20 minutes in 130 ℃ of oil baths of preheating.Then this reaction mixture is cooled to room temperature, and, has obtained resistates,, obtained this title compound, be trifluoroacetate by using the HPLC purifying of TFA with solvent vacuum-evaporation.1H?NMR(300?MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)3.26(m，1H)6.66(m，3H)7.08(t，J＝7.91Hz，1H)7.32(m，2H)7.72(m，2H)8.02(s，1H)8.24(s，1H)8.76(s，1H)8.85(d，j＝8.46Hz，1H)9.67(s，1H)10.50(s，1H)10.82(s，1H)；MS(ESI+)m/z?592/594(M+H)+。

Embodiment 356

4-[5-(3-bromo-phenyl amino formyl radical)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-thiophene-2-base sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

Embodiment 356A

5-chloro-4-nitro-thiophene-2-carboxylic acid

The product (1 equivalent) of embodiment 351A is dissolved in methanol 3/1 mixture, adds lithium hydroxide (5 equivalent) then.Gained solution was stirring at room 24 hours, and adding 1N hydrochloric acid then is 2 until the pH of solution.With this mixture ethyl acetate extraction, dry and vacuum concentration has obtained this title product with organic extract liquid then.

Embodiment 356B

5-chloro-4-nitro-thiophene-2-carboxylic acid (3-bromo-phenyl)-acid amides

The product of embodiment 356A is dissolved in the methylene dichloride, adds the dimethyl formamide of thionyl chloride and catalytic amount then.With this solution in stirring at room 3 hours, solvent removed in vacuo then.Then resistates is dissolved in the toluene, and adds the 3-bromaniline.With gained vlil 2 hours, add hexane then, and, with the filtrate vacuum concentration, obtained this title product then via filter paper filtering.

Embodiment 356C

5-(4-amino-phenyl sulfenyl)-4-nitro-thiophene-2-carboxylic acid (3-bromo-phenyl)-acid amides

The product of embodiment 356B is dissolved in the dimethyl formamide, adds the 4-amino-phenol, add cesium carbonate then.Gained solution stirring 3 hours, with this solution with water dilution, adding 1N hydrochloric acid afterwards is 3 until the pH of this solution then.Collect formed solid by filtering, and dry in vacuum drying oven, obtained this title product.

Embodiment 356D

4-[3-amino-5-(3-bromo-phenyl amino formyl radical)-thiophene-2-base sulfenyl]-phenyl }-carboxylamine 2,2,2-three chloro-ethyl esters

Add pyridine in the product of embodiment 356C in being dissolved in methylene dichloride, drip chloroformic acid 2,2 then, the 2-trichloro ethyl ester.With gained solution stirring 4 hours, vacuum concentration then.Then this mixture is poured in the water,,, is collected gained solid and drying gained solution stirring 30 minutes with 1N hydrochloric acid pH regulator to 5 with this solution, then according to the method for describing among the embodiment 356E with nitroreduction, obtained this title product.

Embodiment 356E

The product of embodiment 356D and the mixture of product in Glacial acetic acid of embodiment 8E were heated 20 minutes in 130 ℃ of oil baths of preheating.Then this reaction mixture is cooled to room temperature, and, has obtained this title compound, be acetate solvent vacuum-evaporation.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.33(d，J＝6.62Hz，6H)3.13-3.28(m，1H)4.93(s，2H)7.35(d，J＝8.82Hz，2H)7.32(d，J＝6.25Hz，2H)7.47(d，2H)7.63(d，J＝8.46Hz，1H)7.70(dt，J＝4.50，2.39Hz，1H)8.02(s，1H)8.23(s，1H)8.67(s，1H)8.83(d，J＝8.46Hz，1H)10.12(s，1H)10.28(s，1H)10.42(s，1H)11.96(s，2H)。

Embodiment 357

5-(4-amino-phenyl sulfenyl)-4-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-thiophene-2-carboxylic acid (3-bromo-phenyl)-acid amides

The product (1 equivalent) of embodiment 356E is dissolved in the THF/ water, adds 1N aqueous sodium hydroxide solution (3 equivalent) then, this mixture 60 ℃ of heating 2 hours, is added entry then, and uses ethyl acetate extraction.With the organic extract liquid drying, and vacuum concentration, obtained resistates, by using the HPLC purifying of TFA, obtained this title compound, be trifluoroacetate.1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.62Hz，6H)3.30(dq，J＝6.89Hz，1H)6.57(d，J＝8.82Hz，2H)7.20(d，J＝8.46Hz，2H)7.25-7.37(m，2H)7.67(dt，J＝4.32，2.39Hz，1H)7.90(d，J＝8.46Hz，1H)7.99(s，1H)8.05(s，1H)8.92(s，1H)8.99(d，J＝8.82Hz，1H)10.39(s，1H)11.39(s，1H)。

Embodiment 358

N-(5-bromo-pyridine-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-{4-[4-(3,7,12-trihydroxy--10,13-dimethyl-16 hydrogen-cyclopenta [a] phenanthrene-17-yl)-pentanoyl amino]-the phenyl sulfenyl }-benzamide

Embodiment 358A

4-(3,7,12-three methanoyies-10,13-dimethyl-16 hydrogen-cyclopenta [a] phenanthrene-17-yl)-valeric acid

According to JACS 57Method in 1393 (1935) is prepared.(5.00g, 12.24mmol) solution in 96% formic acid (10mL) is in 55 ℃ of heating 5 hours, then by being evaporated to dried at 55 ℃ of rotary evaporations with cholic acid.This white foam is placed 95% ethanol (50mL) that is boiling, and water (60mL) is to keep the velocity process of solution.This solution magnetic is stirred, allow it be cooled to room temperature simultaneously, then with this mixture standing over night.Collect this white solid by vacuum filtration, and wash with the mixture of 95% ethanol (10mL) and water (8.3mL); To wash and repeat once.In vacuum drying oven,, obtained this title compound (4.683g, 9.51mmol, 78%) in 80 ℃ of dryings 2 hours.

Embodiment 358B

Formic acid 17-(3-{4-[4-(5-bromo-pyridine-2-base formamyl)-2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-the phenyl sulfenyl]-the phenyl amino formyl radical }-1-methyl-propyl group)-3; 7-two methanoyies-10,13-dimethyl-16 hydrogen-cyclopenta [a] phenanthrene-12-base ester

(200mg, 0.406mmol) (0.40mL 4.588mmol) handles the solution in dry-out benzene (4mL), and this was reflected at stirring at room 2 hours with the oxalyl chloride that drips with the product of embodiment 358A under nitrogen.Remove by rotary evaporation and to desolvate, with the methylene dichloride coevaporation, and vacuum-drying, obtained white foam shape thing.With the solution of this acyl chlorides in anhydrous tetrahydro furan (2.5mL) be added to implement 17B product (158.7mg, 0.2706mmol) and pyridine (0.20mL is 2.47mmol) in the suspension in tetrahydrofuran (THF) (2.5mL).With this solution under nitrogen in stirring at room 3 hours, evaporate by rotary evaporation then.By the fast silica gel chromatogram purifying, carry out gradient elution with 3% to 4% ethanol/methylene, obtained this title compound, be yellow solid (167mg, 0.157mmol, 58%).

Embodiment 358C

(162mg 0.1527mmol) is suspended in the methyl alcohol (2mL), and handles with the solution (2mL) of 10% sodium hydroxide in methyl alcohol, and of short duration supersound process to be promoting dissolving, and stirring at room 1 hour with the product of embodiment 358B.Remove by rotary evaporation in vacuo and to desolvate, and resistates is placed ethyl acetate (150mL) and water (50mL).With water layer pH regulator to 5, and separate each layer with 1N hydrochloric acid.Organic phase with washing water (50mL) and salt solution (50mL), is used anhydrous sodium sulfate drying then, filter, and concentrate by rotary evaporation.By the fast silica gel chromatogram purifying, carry out gradient elution with 8% to 10% ethanol/methylene, obtained this title compound (137mg, 0.140mmol, 92%). ¹H?NMR(300MHz，DMSO-D6)δppm：0.60(s，3H)0.81(s，3H)0.98(d，J＝5.88Hz，3H)1.12-2.52(m，24H)1.33(d，J＝6.99Hz，6H)3.12-3.31(m，2H)3.55-3.69(m，1H)3.75-3.87(m，1H)4.02(d，J＝3.31Hz，1H)4.13(d，J＝3.68Hz，1H)4.32(d，J＝4.41Hz，1H)6.89-7.05(m，1H)7.40(d，J＝8.46Hz，2H)7.57-7.66(m，1H)7.68(d，J＝8.46Hz，2H)7.81-7.95(m，1H)8.01-8.12(m，2H)8.16(d，J＝8.82Hz，1H)8.50(d，J＝2.57Hz，1H)8.53-8.67(m，1H)8.76-8.96(m，1H)10.09(s，1H)10.21(br?s，1H)10.97(br?s，1H)；MS(ESI+)m/z?977/979(M+H) ⁺。

Embodiment 359

4-(3-{4-[-(5-bromo-pyridine-2-base formamyl)-2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-the phenyl sulfenyl]-phenyl amino formyl radical oxygen base }-7; 12-dihydroxyl-10,13-dimethyl-16 hydrogen-cyclopenta [a] phenanthrene-17-yl)-methyl valerate

Under nitrogen atmosphere, product (100mg with embodiment 17B, 0.1705mmol) suspension in anhydrous tetrahydro furan (2.5mL) is with anhydrous pyridine (0.041mL, 0.512mmol) and 7 α, 12 alpha-dihydroxy-s-3 α-chloroformyl oxygen base-5 α-ursodeoxycholic acid-(24)-methyl ester (124mg, 0.256mmol, according to JACS 119Method in (4) 640 (1997) makes) solution-treated in tetrahydrofuran (THF) (0.5mL).This was reflected at stirring at room 16 hours, and removes by rotary evaporation in vacuo and to desolvate.By the fast silica gel chromatogram purifying, carry out gradient elution with 3% to 4% ethanol/methylene, obtained this title compound, be yellow solid (108mg, 0.104mmol, 61%). ¹H?NMR(300?MHz，DMSO-D6)δ?ppm：0.60(s，3H)0.86(s，3H)0.92(d，J＝6.25Hz，3H)0.96-2.64(m，24H)1.34(d，J＝6.62Hz，6H)3.15-3.32(m，1H)3.57(s，3H)3.61-3.68(m，1H)3.76-3.88(m，1H)4.12(d，J＝3.31Hz，1H)4.16(d，J＝3.31Hz，1H)4.35-4.55(m，1H)6.94(d，J＝8.09Hz，1H)7.34-7.44(m，2H)7.54(d，J＝8.82Hz，2H)7.64(d，J＝8.46Hz，1H)7.88(dd，J＝7.72，1.47Hz，1H)8.02-8.11(m，2H)8.13-8.22(m，1H)8.49(d，J＝2.21Hz，1H)8.59(s，1H)8.86(d，J＝8.46Hz，1H)9.82(s，1H)10.20(s，1H)10.97(s，1H)；MS(ESI+)m/z1035/1037(M+H) ⁺。

Embodiment 360

4-trifluoromethyl-naphthenic acid [4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-acid amides

Embodiment 360A

4-trifluoromethyl-naphthenic acid [3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-acid amides

This title compound is such synthetic: according to the method for embodiment 255a, substitute furans-2-carbonyl chlorine with 4-trifluoromethyl-hexanaphthene carbonyl chlorine, with 4-fluoro-3-nitro-phenyl amine and 4-trifluoromethyl-hexanaphthene carbonyl chlorine reaction, then products therefrom is reacted according to the method for embodiment 255b and 255c, obtained this title product.

Embodiment 360B

The product of embodiment 360A and the product of embodiment 8E are reacted,, use the product of the product alternate embodiment 255c of embodiment 360A, obtained crude product, it by silica gel chromatography, has been obtained this title product according to the method for embodiment 255d.1H NMR (300MHz, DMSO-d6) δ ppm:1.33 (d, J=7.0Hz, 6H), 1.51-1.80 (m, 6H), and 1.90-2.04 (m, 2H), 2.20-2.41 (m, 1H), 2.64 (br-t, J=4.0Hz, 1H), 3.21 (septet, J=7.0Hz, 1H), 6.70 (d, J=8.8Hz, 2H), 7.05 (d, J=8.5Hz, 1H), 7.14 (d, J=8.8Hz, 2H), 7.41 (dd, J=8.5,1.8Hz, 1H), 7.60 (d, J=8.4Hz, 1H), 7.83 (d, J=1.8Hz, 1H), 8.54 (s, 1H), 8.80 (d, J=8.4Hz, 1H), 9.69 (s, 1H), 9.97 (s, 1H), 10.04 (s, 1H); MS (ESI+) m/z2 (M+H)+.

Embodiment 361

Embodiment 361C

4-(4-amino-phenoxy group)-N-(4-bromo-phenyl)-3-nitro-benzamide

With 4-(4-amino-benzene oxygen)-N-(4-bromophenyl)-3-nitrobenzamide (3.55g, 0.01mol), 4-amino-phenol (1.09g, 0.01mol), potassium hydroxide (1.12g, 0.02mol) and the mixture of 10mL DMSO in the microwave tube of sealing by microwave in 100 ℃ of heating 25 minutes, then with this reaction mixture cooling, pour in the 300mL water, being adjusted to pH with 1M HCl is 6.This mixture was stirred 30 minutes, filter, and, obtained this title compound (4.2g, 98%) the solid vacuum-drying of collecting.

Embodiment 361D

To the product of embodiment 361C (4.2g, 9.8mmol) and pyridine (1.6g, 1.62mL, 20mmol) in the mixture in methylene dichloride (100mL) via dripping chloroformic acid 2,2 in 30 minutes, the 2-trichloro ethyl ester (2.29g, 10.8mmol).This reaction mixture was stirred 4 hours, concentrate, and resistates is poured in the 200mL water, being adjusted to pH with 1M HCl is 5.This mixture was stirred 30 minutes, filter, and, obtained this title compound (6.0g, 98%) the solid vacuum-drying of collecting.

Embodiment 361E

Product (6.0g with embodiment 361D, 10.0mmol), iron powder (2.8g, 50mmol, 5equiv., derive from Acros, electrolytic reduction, reagent, powder) and the mixture heating up of ammonium chloride (0.81g, 15.0mmol, 1.5 equivalents) in tetrahydrofuran (THF)/ethanol/water (60/60/20mL) refluxed 5 hours.This reaction mixture is cooled to room temperature, and via diatomite filtration, with 50mL washing with alcohol Celite pad.With the gained filtrate evaporated under reduced pressure, and resistates distributed between ethyl acetate (100mL) and water (100mL).(2 * 100mL) extract with ethyl acetate with water.The organic phase that merges is washed with salt solution (50mL), use anhydrous magnesium sulfate drying, filter, and reduction vaporization, obtained this title compound (4.71g, 83%), be the tawny solid.

Embodiment 361F

Product (2.39g with embodiment 361E, 4.2mmol) and the product of embodiment 8E (N '-(3-cyano group-6-sec.-propyl-pyridine-2-yl)-N, N-dimethyl-carbonamidine) (0.91g, 4.2mmol) mixture in the 10mL Glacial acetic acid heated 45 minutes in the oil bath of 140 ℃ of preheatings.With the cooling of this reaction mixture, vacuum-evaporation, and resistates distributed between ethyl acetate (250mL) and water (100mL).Organic phase is used saturated sodium bicarbonate aqueous solution and salt water washing successively, use anhydrous magnesium sulfate drying, filter, and reduction vaporization.The gained resistates is developed with methyl alcohol, filtered, and vacuum-drying, obtained this title compound (2.0g, 64%), be beige solid.MS(ESI+)m/z?743/745(M+H) ⁺； ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.31(d，J＝6.62Hz，6H)，3.10-3.27(m，1H)，4.93(s，2H)，6.93-7.05(m，3H)，7.39-7.62(m，5H)，7.77(d，J＝8.82Hz，2H)，8.17(s，1H)，8.60(s，1H)，8.78(d，J＝8.09Hz，1H)，10.08(s，1H)，10.16(s，1H)，10.35(s，2H)。

Embodiment 361G

Will be at the product (74mg of the embodiment 361F in the tetrahydrofuran (THF) (1mL), 0.1mmol) with 1, and 8-diazabicylo [5.4.0] 11 carbon-7-alkene (30 μ L, 0.2mmol) and piperidines (85mg, 1.0mmol) handle, and in sealed tube, heated 1 hour in 60 ℃.With this reaction mixture cooling, concentrate and with crude product by at Waters Symmetry C8 post (25mm * 100mm, 7 μ m particle diameters) the anti-phase preparation HPLC purifying that carries out on, use 10% to 100% acetonitrile/0.1% trifluoroacetic acid aqueous solution via 8 minutes (10 minute working time) with 40mL/ minute current gradient wash-out.Obtained this title compound, be trifluoroacetate (0.04g, 59%). ¹H?NMR(300MHz，DMSO-D ₆)δ?ppm：1.34(d，J＝6.62Hz，6H)，1.42-1.66(m，6H)，3.22-3.32(m，1H)，3.36-3.43(m，4H)，6.98(t，J＝9.01Hz，3H)，7.47(d，J＝9.19Hz，2H)，7.54(d，J＝8.82Hz，2H)，7.75(d，J＝8.82Hz，2H)，7.83(d，J＝8.46Hz，1H)，7.98(dd，J＝8.46，2.21Hz，1H)，8.14(d，J＝2.21Hz，1H)，8.47(s，1H)，8.86(s，1H)，8.95(d，J＝8.46Hz，1H)，10.38(s，1H)，11.30(s，1H)；(ESI+)m/z?680/682(M+H)+。

Embodiment 362

This title compound is according to the method among the embodiment 361G, and (85mg 1.0mmol) substitutes piperidines and makes, and has obtained trifluoroacetate (42mg, 62%) with cyclopentyl amine.(ESI+)m/z?680/682(M+H)+；1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)，1.34-1.43(m，2H)，1.46-1.71(m，4H)，1.74-1.92(m，2H)，3.12-3.31(m，1H)，3.78-4.00(m，1H)，6.14(d，J＝7.35Hz，1H)，6.93-7.02(m，J＝9.01，2.76Hz，3H)，7.38(d，J＝9.19Hz，2H)，7.54(d，J＝8.82Hz，2H)，7.75(d，J＝9.19Hz，2H)，7.81(d，J＝8.46Hz，1H)，7.96(dd，J＝8.82，2.21Hz，1H)，8.14(d，J＝2.21Hz，1H)，8.31(s，1H)，8.84(s，1H)，8.94(d，J＝8.82Hz，1H)，10.37(s，1H)，11.18(s，1H)。

Embodiment 363

This title compound is according to the method among the embodiment 361G, and (107mg 1.0mmol) substitutes piperidines and makes, and has obtained trifluoroacetate (45mg, 64%) with benzyl amine.(ESI+)m/z?702/704(M+H)+； ¹H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)，3.18-3.35(m，1H)，4.29(d，J＝5.88Hz，2H)，6.61(t，J＝6.07Hz，1H)，6.98(d，J＝8.82Hz，3H)，7.17-7.38(m，5H)，7.42(d，J＝8.82Hz，2H)，7.52-7.56(m，2H)，7.75(d，J＝8.82Hz，2H)，7.81(d，J＝8.46Hz，1H)，7.97(dd，J＝8.82，2.21Hz，1H)，8.14(d，J＝2.21Hz，1H)，8.62(s，1H)，8.84(s，1H)，8.94(d，J＝8.82Hz，1H)，10.37(s，1H)，11.21(s，1H)。

Embodiment 364

Embodiment 364A

N-(5-bromo-pyridine-2-yl)-4-chloro-3-nitro-benzamide

(22.0g, 0.1mol) (17.3g, 0.1mol) mixture in toluene (250mL) refluxed 4 hours, allowed HCl gas overflow from reaction vessel via the water-cooled condenser of opening with 2-amino-5-bromopyridine with 4-chloro-3-nitrobenzoyl chloride.This reaction mixture is cooled to room temperature,, has obtained this title compound (33.9g, 95%) with hexane (200mL) dilution and filtration.

Embodiment 364B

4-(4-amino-phenyl sulfenyl)-N-(5-bromo-pyridine-2-yl)-3-nitro-benzamide

Product (24.2g with embodiment 364A, 0.0678mol), 4-amino-thiophenol (12.7g, 0.102mol, 1.5 equivalents) and sodium acetate trihydrate (46.1g, 0.339mol, 5.0 equivalents) and mixture reflux 2 hours under nitrogen under agitation in 500mL ethanol.Then this reaction mixture is cooled to room temperature, and adds 200mL water.This mixture was stirred 30 minutes, filter, and vacuum-drying, this title compound (29.8g, 99%) obtained.

Embodiment 364C

With the product of embodiment 364B (27.5g, 0.0618mol) and the mixture of pyridine (7.73g, 7.50mL, 0.0927mol, 1.5 equivalents) in methylene dichloride (500mL) in stirring at room.In this mixture via dripping chloroformic acid 2,2,2-trichloro ethyl ester (17.0g, 10.8mL, 0.0803mol, 1.3 equivalents) in 30 minutes lentamente.With this reaction mixture stirring at room 2 hours, during be settled out product, be yellow solid.This mixture is filtered, and just filter cake washs with methylene dichloride (100mL), vacuum-drying has obtained this title compound (35.3g, 92%), is yellow solid.

Embodiment 364D

Product (1.63g with embodiment 364C, 2.63mmol), iron powder (0.737g, 13.1mmol, 5 equiv. derive from Acros, electrolytic reduction, reagent, powder) and the mixture heating up of ammonium chloride (0.211g, 3.94mmol, 1.5 equivalents) in tetrahydrofuran (THF)/ethanol/water (30/30/10mL) refluxed 2.5 hours.This reaction mixture is cooled to room temperature, and via diatomite filtration, with 50mL washing with alcohol Celite pad.With the gained filtrate evaporated under reduced pressure, and resistates distributed between ethyl acetate (100mL) and water (100mL).(2 * 100mL) wash with ethyl acetate with water.The organic phase that merges is washed with salt solution (50mL), use anhydrous magnesium sulfate drying, filter, and reduction vaporization, obtained this title compound (1.48g, 95%), be faint yellow solid.

Embodiment 364E

Product (3.05g with embodiment 364D, 5.16mmol) and the product of embodiment 8E (N '-(3-cyano group-6-sec.-propyl-pyridine-2-yl)-N, N-dimethyl-carbonamidine) (1.34g, 6.20mmol, 1.2 equivalents) and mixture in the 25mL Glacial acetic acid heated 45 minutes in the oil bath of 140 ℃ of preheatings.With the cooling of this reaction mixture, vacuum-evaporation, and resistates distributed between ethyl acetate (250mL) and water (100mL).Then organic phase is used successively saturated sodium bicarbonate aqueous solution and salt water washing, used anhydrous magnesium sulfate drying, filter, and reduction vaporization.The gained resistates is developed with methyl alcohol, filtered, and vacuum-drying, obtained this title compound (3.10g, 79%), be beige solid.MS(ESI+)m/z?762/764(M+H) ⁺； ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.33(d，J＝6.99Hz，6H)，3.16-3.26(m，1H)，4.97(s，2H)，6.96(s，1H)，7.43(d，J＝8.82Hz，2H)，7.59(s，2H)，7.86(s，1H)，8.01-8.10(m，3H)，8.15-8.20(m，1H)，8.50(d，J＝2.57Hz，1H)，8.57(s，1H)，8.84(s，1H)，10.23(s，1H)，10.40(s，1H)，10.94(s，1H)。

Embodiment 365

N-(5-bromo-pyridine-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base ammonia

Base)-4-{4-[3-((R)-1-phenyl-ethyl)-urea groups]-the phenyl sulfenyl }-benzamide

Product (152mg with embodiment 364E, 0.2mmol) at tetrahydrofuran (THF) (2mL) with 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (60 μ L, 0.4mml) and (R)-(+)-α-Jia Jibianji amine (121mg, 1.0mmol) handle, and in sealed tube, heated 1 hour in 60 ℃.With this reaction mixture cooling, concentrate, and resistates is passed through at Waters Symmetry C8 post (40mm * 100mm, 7 μ m particle diameters) the preparation HPLC purifying that carries out on, use 10% to 100% acetonitrile/ammonium acetate solution (10mM) via 12 minutes (15 minute working time) with 70mL/ minute current gradient wash-out, obtained this title compound (21mg, 14%). ¹H?NMR(300MHz，DMS0-D ₆)δ?ppm：1.33(d，J＝6.99Hz，6H)1.40(d，J＝6.62Hz，3H)3.22(m，1H)4.82(m，1H)6.73(d，J＝8.09Hz，1H)6.90(s，br，1H)7.24(m，1H)7.35(m，6H)7.48(m，2H)7.63(s，br，1H)7.86(s，br，1H)8.04(d，J＝2.57Hz，1H)8.07(d，J＝2.57Hz，1H)8.17(m，1H)8.49(d，J＝2.57Hz，1H)8.60(s，1H)8.66(s，1H)8.86(s，br，1H)10.28(s，1H)10.95(s，1H)；(ESI+)m/z?733?735(M+H)+。

Embodiment 366

N-(5-bromo-pyridine-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-{4-[3-((S)-1-phenyl-ethyl)-urea groups]-the phenyl sulfenyl }-benzamide

This title compound is the method according to embodiment 365, and (121mg 1.0mmol) substitutes (R)-(+)-α-Jia Jibianji amine and makes, and has obtained yellow solid (29mg, 20%) with (S)-(-)-α-Jia Jibianji amine. ¹H?NMR(300MHz，DMSO-D ₆)δ?ppm：1.34(d，J＝6.99Hz，6H)1.40(d，J＝6.99Hz，3H)3.22(m，1H)4.82(m，1H)6.72(d，J＝7.72Hz，1H)6.90(d，J＝8.46Hz，1H)7.25(m，1H)7.34(m，6H)7.48(d，J＝8.82Hz，2H)7.64(d，J＝8.46Hz，1H)7.86(d，J＝8.46Hz，1H)8.04(d，J＝2.57Hz，1H)8.07(d，J＝2.57Hz，1H)8.16(m，1H)8.49(d，J＝2.21Hz，1H)8.59(s，1H)8.66(s，1H)8.87(d，J＝8.09Hz，1H)10.20(s，1H)10.95(s，1H)；(ESI+)m/z?733，735(M+H)+。

Embodiment 367

N-(5-bromo-pyridine-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-[4-(3-thiophene-2-ylmethyl-urea groups)-phenyl sulfenyl]-benzamide

This title compound is the method according to embodiment 365, and (113mg 1.0mmol) substitutes (R)-(+)-α-Jia Jibianji amine and makes, and has obtained yellow solid (57mg, 39%) with 2-thenyl amine. ¹H?NMR(300MHz，DMSO-D ₆)δ?ppm：1.34(d，J＝6.62Hz，6H)3.21(m，1H)4.47(d，J＝5.88Hz，2H)6.78(t，J＝6.07Hz，1H)6.95(m，3H)7.37(m，3H)7.52(d，J＝8.82Hz，2H)7.64(d，J＝7.35Hz，1H)7.87(d，J＝8.82Hz，1H)8.04(d，J＝2.57Hz，1H)8.07(d，J＝2.57Hz，1H)8.17(m，1H)8.49(d，J＝2.21Hz，1H)8.59(s，1H)8.86(m，2H)10.19(s，1H)10.96(s，1H)；(ESI+)m/z?725，727(M+H)+。

Embodiment 368

N-(5-bromo-pyridine-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-[4-(3-thiene-3-yl-methyl-urea groups)-phenyl sulfenyl]-benzamide

This title compound is the method according to embodiment 365, and (113mg 1.0mmol) substitutes (R)-(+)-α-Jia Jibianji amine and makes, and has obtained yellow solid (31mg, 21%) with 3-thenyl amine. ¹H?NMR(300?MHz，DMSO-D ₆)δ?ppm：1.33(d，J＝6.99Hz，6H)3.22(m，1H)4.29(d，J＝5.52Hz，2H)6.66(t，J＝5.70Hz，1H)6.93(d，J＝8,82Hz，1H)7.07(dd，J＝4.80Hz，1.47Hz，1H)7.35(m，3H)7.50(m，3H)7.63(d，J＝8.82Hz，1H)7.87(d，J＝8.82Hz，1H)8.04(d，J＝2.57Hz，1H)8.07(d，J＝2.57Hz，1H)8.17(m，1H)8.49(d，J＝2.21Hz，1H)8.59(s，1H)8.80(s，1H)8.88(d，J＝8.46Hz，1H)10.19(s，1H)10.96(s，1H)；(ESI+)m/z?725?727(M+H)+。

Embodiment 369

N-(5-bromo-pyridine-2-yl)-4-[4-(3-furans-2-ylmethyl-urea groups)-phenyl sulfenyl]-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

This title compound is the method according to embodiment 365, and (97mg 1.0mmol) substitutes (R)-(+)-α-Jia Jibianji amine and makes, and has obtained yellow solid (19mg, 13%) with 2-chaff amine. ¹H?NMR(300MHz，DMSO-D ₆)δ?ppm：1.34(d，J＝6.99Hz，6H)3.22(m，1H)4.30(d，J＝5.52Hz，2H)6.26(d，J＝2.57Hz，1H)6.40(dd，J＝3.31，1.84Hz，1H)6.65(t，J＝5.70Hz，1H)6.93(d，J＝8.46Hz，1H)7.36(d，J＝8.82Hz，2H)7.50(d，J＝8.82Hz，2H)7.59(dd，J＝1.84Hz，0.99Hz，1H)7.64(d，J＝8.46Hz，1H)7.89(d，J＝8.46Hz，1H)8.04(d，J＝2.21Hz，1H)8.07(d，J＝2.57Hz，1H)8.16(m，1H)8.49(d，J＝2.21Hz，1H)8.59(s，1H)8.80(s，1H)8.87(d，J＝8.46Hz，1H)10.19(s，1H)10.96(s，1H)；(ESI+)m/z?709，711(M+H)+。

Embodiment 370

N-(5-bromo-pyridine-2-yl)-4-[4-(3-furans-3-ylmethyl-urea groups)-phenyl sulfenyl]-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

This title compound is the method according to embodiment 365, and (97mg 1.0mmol) substitutes (R)-(+)-α-Jia Jibianji amine and makes, and has obtained yellow solid (58mg, 41%) with 3-chaff amine. ¹H?NMR(300MHz，DMSO-D ₆)δ?ppm?1.33(d，J＝6.99Hz，6H)3.22(m，1H)4.13(d，J＝5.52Hz，2H)6.46(m，1H)6.52(t，J＝5.88Hz，1H)6.90(d，J＝8.46Hz，1H)7.36(d，J＝8.82Hz，2H)7.51(d，J＝8.82Hz，2H)7.61(m，3H)7.87(d，J＝8.46Hz，1H)8.04(d，J＝2.57Hz，1H)8.07(d，J＝2.57Hz，1H)8.17(m，1H)8.49(d，J＝2.57Hz，1H)8.58(s，1H)8.76(s，1H)8.87(d，J＝8.46Hz，1H)10.19(s，1H)10.96(s，1H)；(ESI+)m/z?709，711(M+H)+。

Embodiment 371

N-(5-bromo-pyridine-2-yl)-4-{4-[3-(2-oxyethyl group-ethyl)-urea groups]-the phenyl sulfenyl }-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

This title compound is the method according to embodiment 365, and (89mg 1.0mmol) substitutes (R)-(+)-α-Jia Jibianji amine and makes with 2-oxyethyl group-ethamine.Crude product is passed through at WatersSymmetry C8 post (25mm * 100mm, 7 μ m particle diameters) the anti-phase preparation HPLC purifying that carries out on, use 10% to 100% acetonitrile/0.1% trifluoroacetic acid aqueous solution via 8 minutes (10 minute working time) with 40mL/ minute current gradient wash-out, obtained this title compound, be trifluoroacetate (60mg, 37%). ¹H?NMR(300MHz，DMSO-D ₆)δ?ppm：1.14(t，J＝6.99Hz，3H)1.36(d，J＝6.99Hz，6H)3.26(m，3H)3.46(m，4H)6.29(t，J＝5.52Hz，1H)6.96(d，J＝8.46Hz，1H)7.35(d，J＝8.82Hz，2H)7.48(d，J＝8.82Hz，2H)7.84(d，J＝8.46Hz，1H)7.93(d，J＝8.46Hz，1H)8.05(d，J＝2.57Hz，1H)8.08(d，J＝2.21Hz，1H)8.17(m，1H)8.50(d，J＝2.57Hz，1H)8.78(s，1H)8.84(s，1H)8.97(d，J＝8.82Hz，1H)10.99(s，1H)11.34(s，1H)；(ESI+)m/z?701，703(M+H)+。

Embodiment 372

4-[4-(5-bromo-pyridine-2-base formamyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-benzyl carbamate

This title compound is the method according to embodiment 365, and (108mg 1.0mmol) substitutes (R)-(+)-α-Jia Jibianji amine and makes with benzyl alcohol.Crude product is passed through at WatersSymmetry C8 post (25mm * 100mm, 7 μ m particle diameters) the anti-phase preparation HPLC purifying that carries out on, use 10% to 100% acetonitrile/0.1% trifluoroacetic acid aqueous solution via 8 minutes (10 minute working time) with 40mL/ minute current gradient wash-out, obtained this title compound, be trifluoroacetate (26mg, 16%). ¹H?NMR(300MHz，DMSO-D ₆)δ?ppm：1.35(d，J＝6.99Hz，6H)3.26(m，1H)5.17(s，2H)6.99(d，J＝8.46Hz，1H)7.40(m，7H)7.54(m，2H)7.79(d，J＝8.46Hz，1H)7.93(d，J＝8.46Hz，1H)8.05(d，J＝2.57Hz，1H)8.08(d，J＝2.21Hz，1H)8.16(m，1H)8.50(d，J＝1.84Hz，1H)8.74(s，1H)8.92(d，J＝8.46Hz，1H)10.04(s，1H)10.98(s，1H)11.16(s，1H)；(ESI+)m/z?720，722(M+H)+。

Embodiment 373

4-[4-(5-bromo-pyridine-2-base formamyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine thiophene-2-ylmethyl ester

This title compound is the method according to embodiment 365, and (114mg 1.0mmol) substitutes (R)-(+)-α-Jia Jibianji amine and makes with the 2-thiophen(e)alcohol.Crude product is passed through at WatersSymmetry C8 post (25mm * 100mm, 7 μ m particle diameters) the anti-phase preparation HPLC purifying that carries out on, use 10% to 100% acetonitrile/0.1% trifluoroacetic acid aqueous solution via 8 minutes (10 minute working time) with 40mL/ minute current gradient wash-out, obtained this title compound, be trifluoroacetate (33mg, 20%). ¹H?NMR(300MHz，DMSO-D ₆)δ?ppm：1.36(d，J＝6.99Hz，6H)3.28(m，1H)5.34(s，2H)7.04(m，2H)7.22(m，1H)7.41(d，J＝8.82Hz，2H)7.53(d，J＝8.82Hz，2H)7.58(dd，J＝5.13，1.83Hz，1H)7.86(d，J＝8.46Hz，1H)7.93(d，J＝8.46Hz，1H)8.05(d，J＝2.57Hz，1H)8.08(d，J＝2.57Hz，1H)8.16(m，1H)8.51(d，J＝2.57Hz，1H)8.83(s，1H)8.96(d，J＝8.46Hz，1H)10.03(s，1H)11.01(s，1H)11.50(s，1H)；(ESI+)m/z?726，728(M+H)+。

Embodiment 374

4-[4-(5-bromo-pyridine-2-base formamyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-butyl carbamate

This title compound is the method according to embodiment 365, and (74mg 1.0mmol) substitutes (R)-(+)-α-Jia Jibianji amine and makes with the 1-butanols.Crude product is passed through at Waters SymmetryC8 post (25mm * 100mm, 7 μ m particle diameters) the anti-phase preparation HPLC purifying that carries out on, use 10% to 100% acetonitrile/0.1% trifluoroacetic acid aqueous solution via 8 minutes (10 minute working time) with 40mL/ minute current gradient wash-out, obtained this title compound, be trifluoroacetate (42mg, 26%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm：0.92(t，J＝7.35Hz，3H)1.37(m，8H)1.61(m，2H)3.26(m，1H)4.10(t，J＝6.62Hz，2H)7.00(d，J＝8.09Hz，1H)7.40(d，J＝8.46Hz，2H)7.54(d，J＝8.46Hz，2H)7.81(d，J＝8.46Hz，1H)7.92(d，J＝8.46Hz，1H)8.05(d，J＝2.21Hz，1H)8.08(d，J＝2.57Hz，1H)8.16(m，1H)8.50(d，J＝2.57Hz，1H)8.74(s，1H)8.93(d，J＝8.46Hz，1H)9.87(s，1H)10.99(s，1H)11.20(s，1H)；(ESI+)m/z?686，688(M+H)+。

Embodiment 375

4-[4-(5-bromo-pyridine-2-base formamyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine tetrahydrochysene-furans-2-ylmethyl ester

This title compound is the method according to embodiment 365, and (101mg 1.0mmol) substitutes (R)-(+)-α-Jia Jibianji amine and makes with tetrahydrofuran (THF)-2-base-methyl alcohol.Crude product is passed through at Waters Symmetry C8 post (25mm * 100mm, 7 μ m particle diameters) the anti-phase preparation HPLC purifying that carries out on, use 10% to 100% acetonitrile/0.1% trifluoroacetic acid aqueous solution via 8 minutes (10 minute working time) with 40mL/ minute current gradient wash-out, obtained this title compound, be trifluoroacetate (89mg, 52%). ¹H?NMR(300MHz，DMSO-D ₆)δppm：1.35(d，J＝6.99Hz，6H)1.60(m，1H)1.82(m，2H)1.94(m，1H)3.26(m，1H)3.66(m，1H)3.77(m，1H)4.05(m，3H)6.99(d，J＝8.09Hz，1H)7.40(d，J＝8.46Hz，2H)7.54(d，J＝8.46Hz，2H)7.78(d，J＝8.82Hz，1H)7.90(d，J＝8.82Hz，1H)8.05(d，J＝2.21Hz，1H)8.08(d，J＝2.57Hz，1H)8.16(m，1H)8.50(d，J＝2.57Hz，1H)8.72(s，1H)8.91(d，J＝8.46Hz，1H)9.98(s，1H)10.98(s，1H)；(ESI+)m/z?714，716(M+H)+。

Embodiment 376

4-[4-(5-bromo-pyridine-2-base formamyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 2-(2-methoxyl group-oxyethyl group)-ethyl ester

This title compound is the method according to embodiment 365, and (72mg 0.6mmol) substitutes (R)-(+)-α-Jia Jibianji amine and makes with 2-(2-methoxyl group-oxyethyl group)-ethanol.Crude product is passed through at Waters Symmetry C8 post (25mm * 100mm, 7 μ m particle diameters) the anti-phase preparation HPLC purifying that carries out on, use 10% to 100% acetonitrile/0.1% trifluoroacetic acid aqueous solution via 8 minutes (10 minute working time) with 40mL/ minute current gradient wash-out, obtained this title compound, be trifluoroacetate (38mg, 45% productive rate). ¹H?NMR(300MHz，DMSO-D ₆)δ?ppm：1.34(d，J＝6.62Hz，6H)，3.13-3.27(m，1H)，3.25(s，3H)，3.42-3.48(m，2H)，3.53-3.59(m，2H)，3.62-3.68(m，2H)，4.19-4.24(m，2H)，6.94(d，J＝8.09Hz，1H)，7.40(d，J＝8.82Hz，2H)，7.56(d，J＝8.82Hz，2H)，7.67(d，J＝8.46Hz，1H)，7.87(d，J＝6.25Hz，1H)，8.06(dd，J＝9.19，2.57Hz，2H)，8.12-8.20(m，1H)，8.50(d，J＝1.84Hz，1H)，8.61(s，1H)，8.86(d，J＝7.72Hz，1H)，10.02(s，1H)，10.56(s，1H)，10.96(s，1H)；MS(ESI+)m/z?732，734(M+H)。

Embodiment 377

This title compound is the method according to embodiment 365, and (120mg 0.2mmol) substitutes (R)-(+)-α-Jia Jibianji amine and makes the product of usefulness embodiment 17.Crude product is passed through at Waters Symmetry C8 post (25mm * 100mm, 7 μ m particle diameters) the anti-phase preparation HPLC purifying that carries out on, use 10% to 100% acetonitrile/0.1% trifluoroacetic acid aqueous solution via 8 minutes (10 minute working time) with 40mL/ minute current gradient wash-out, obtained this title compound, be two-trifluoroacetate (30mg, 45% productive rate). ¹H?NMR(300MHz，DMSO-D ₆)δppm：1.35(d，J＝6.99Hz，12H)，3.19-3.34(m，J＝6.99Hz，2H)，7.03(d，J＝7.72Hz，2H)，7.42(d，J＝8.46Hz，4H)，7.52-7.59(m，4H)，7.83(d，J＝8.09Hz，2H)，7.95(d，J＝7.72Hz，2H)，8.04-8.10(m，4H)，8.12-8.21(m，2H)，8.51(d，J＝2.57Hz，2H)，8.79(s，2H)，8.97(d，J＝5.88Hz，2H)，9.12(s，2H)，10.99(s，2H)，11.29(s，2H)；MS(ESI+)m/z?1199(M+H) ⁺

Embodiment 378

To methylene chloride (50mL, 9:1) product of Nei embodiment 17B (586mg, 1.0mmol) and sodium triacetoxy borohydride (844mg, add in 4.0mmol) propionic aldehyde (218 μ L, 3.0mmol).With this reaction mixture stirring at room 2 days, and evaporation.Resistates is distributed between saturated sodium carbonate solution and ethyl acetate.Wash organic layer with water dried over mgso, filter and evaporation.Resistates by the silica gel chromatography purifying, with methylene chloride (99:1) wash-out, has been obtained this title compound (207mg, 33%). ¹H?NMR(300MHz，DMSO-D ₆)δ?ppm：0.95(t，J＝7.35Hz，3H)1.34(d，J＝6.99Hz，6H)1.57(m，2H)2.99(m，2H)3.24(m，1H)6.16(t，J＝5.16Hz，1H)6.64(d，J＝8.82Hz，2H)6.83(d，J＝8.46Hz，1H)7.20(d，J＝8.82Hz，2H)7.63(d，J＝8.46Hz，1H)7.86(d，J＝8.46Hz，1H)8.04(d，J＝2.57Hz，1H)8.07(d，J＝2.57Hz，1H)8.16(m，1H)8.49(d，J＝2.57Hz，1H)8.58(s，1H)8.87(d，J＝8.46Hz，1H)10.13(s，1H)10.91(s，1H)；(ESI+)m/z628，630(M+H)+。

Embodiment 379

N-(5-bromo-pyridine-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-[4-(ethyl-propyl group-amino)-phenyl sulfenyl]-benzamide

To methylene chloride (5mL, 9:1) product of Nei embodiment 378 (31mg, 0.05mmol) and sodium triacetoxy borohydride (414mg, add in 2.0mmol) acetaldehyde (112 μ L, 2.0mmol).With mixture stirring at room 16 hours, and evaporation.Resistates is distributed between saturated sodium carbonate solution and ethyl acetate.Wash organic layer with water dried over mgso, filter and evaporation.Resistates by the silica gel chromatography purifying, with methylene chloride (99:1) wash-out, has been obtained this title compound (25mg, 77%). ¹H?NMR(300MHz，DMSO-D ₆)δ?ppm：0.90(t，J＝7.35Hz，3H)1.09(t，J＝6.99Hz，3H)1.34(d，J＝6.99Hz，6H)1.55(m，2H)3.24(m，3H)3.38(q，J＝6.99Hz，2H)6.71(d，J＝8.82Hz，2H)6.87(d，J＝8.82Hz，1H)7.26(d，J＝8.82Hz，2H)7.63(d，J＝8.46Hz，1H)7.88(d，J＝8.46Hz，1H)8.04(d，J＝2.57Hz，1H)8.07(d，J＝2.21Hz，1H)8.17(m，1H)8.49(d，J＝1.84Hz，1H)8.58(s，1H)8.89(d，J=8.46Hz，1H)10.13(s，1H)10.91(s，1H)；(ESI+)m/z656，658(M+H)+。

Embodiment 380

4-[4-benzoyl-amido-phenyl sulfenyl]-N-(5-bromo-pyridine-2-yl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

To the product of embodiment 17B (117mg, 0.2mmol) and phenylformic acid (28mg 0.22mmol) adds 3-(diethoxy phosphoryl oxy)-1 in the solution in tetrahydrofuran (THF) (4ml), 2,3-phentriazine-4 (3H)-ketone (72mg, 0.22mmol) and triethylamine (0.14ml, 1.0mmol).Mixture stirring at room 16 hours, is poured in the saturated sodium carbonate solution then, and used ethyl acetate extraction.With the organic layer dried over mgso, filter and evaporation.Resistates is passed through chromatogram purification on WatersSymmetry C8 post, with the aqueous solution/methyl alcohol (90/10) of 0.1% trifluoroacetic acid the aqueous solution/methyl alcohol (5/95) wash-out to 0.1% trifluoroacetic acid, obtained this title compound, be trifluoroacetate (24mg, 15%). ¹H?NMR(300MHz，DMSO-D ₆)δ?ppm：1.35(d，J＝6.62Hz，6H)3.29(m，1H)7.16(d，J＝8.09Hz，1H)7.46(d，J＝8.82Hz，2H)7.57(m，3H)7.84(d，J＝8.82Hz，2H)7.94(m，3H)8.01(dd，J＝8.46，1.84Hz，1H)8.06(d，J＝2.57Hz，1H)8.09(d，J＝2.21Hz，1H)8.17(m，1H)8.51(d，J＝2.21Hz，1H)8.89(s，1H)9.01(d，J＝8.46Hz，1H)10.41(s，1H)11.04(s，1H)11.74(s，1H)；ESI+)m/z?690，692(M+H)+。

Embodiment 381

N-(5-bromo-pyridine-2-yl)-4-[4-(2-oxyethyl group-acetylamino)-phenyl sulfenyl]-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

This title compound is the method according to embodiment 380, and (23mg 0.22mmol) substitutes phenylformic acid and makes, and has obtained trifluoroacetate (40mg, 25%) with ethoxyacetic acid. ¹H?NMR(300MHz，DMSO-D ₆)δ?ppm：1.19(t，J＝6.99Hz，3H)1.35(d，J＝6.99Hz，6H)3.28(m，1H)3.57(q，J＝6.99Hz，2H)4.04(s，2H)7.04(d，J＝8.09Hz，1H)7.42(d，J＝8.82Hz，2H)7.73(d，J＝8.82Hz，2H)7.82(d，J＝8.46Hz，1H)7.94(d，J＝8.46Hz，1H)8.06(m，2H)8.16(m，1H)8.51(d，J＝2.21Hz，1H)8.76(s，1H)8.95(d，J＝8.46Hz，1H)9.92(s，1H)11.00(s，1H)11.25(s，1H)；(ESI+)m/z?672，674(M+H)+。

Embodiment 382

N-(5-bromo-pyridine-2-yl)-4-{4-[2-(2,4-dimethoxy-phenyl)-acetylamino]-the phenyl sulfenyl }-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

This title compound is the method according to embodiment 380, and with 2, (43mg 0.22mmol) substitutes phenylformic acid and makes 4-dimethoxy benzene guanidine-acetic acid, has obtained trifluoroacetate (21mg, 12%). ¹H?NMR(300MHz，DMSO-D ₆)δ?ppm：1.35(d，J＝6.62Hz，6H)3.26(m，1H)3.56(s，2H)3.75(s，3H)3.76(s，3H)6.49(dd，J＝8.09，2.57Hz，1H)6.55(d，J＝2.21Hz，1H)7.00(d，J＝8.46Hz，1H)7.11(d，J＝8.09Hz，1H)7.41(d，J＝8.82Hz，2H)7.69(d，J＝8.82Hz，2H)7.77(d，J＝8.46Hz，1H)7.90(d，J＝8.46Hz，1H)8.05(d，J＝2.57Hz，1H)8.08(d，J＝2.21Hz，1H)8.18(m，1H)8.50(d，J＝1.84Hz，1H)8.71(s，1H)8.93(d，J＝8.46Hz，1H)10.21(s，1H)10.98(s，1H)；(ESI+)m/z764?766(M+H)+。

Embodiment 383

N-(5-bromo-pyridine-2-yl)-4-{4-[2-(4-hydroxymethyl-phenyl)-acetylamino]-the phenyl sulfenyl }-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

This title compound is the method according to embodiment 380, and (37mg 0.22mmol) substitutes phenylformic acid and makes, and has obtained this title compound, is trifluoroacetate (19mg, 11%) with 4-hydroxymethyl phenylacetic acid. ¹H?NMR(300MHz，DMSO-D ₆)δ?ppm：1.35(d，J＝6.99Hz，6H)3.26(m，1H)3.63(s，2H)4.47(s，2H)7.01(d，J＝8.46Hz，1H)7.28(m，4H)7.41(d，J＝8.82Hz，2H)7.68(d，J＝8.46Hz，2H)7.79(d，J＝8.46Hz，1H)7.90(d，J＝8.46Hz，1H)8.05(d，J＝2.57Hz，1H)8.08(d，J＝2.57Hz，1H)8.16(m，1H)8.50(d，J＝2.57Hz，1H)8.75(s，1H)8.92(d，J＝8.46Hz，1H)10.36(s，1H)10.99(s，1H)；(ESI+)m/z?734，736(M+H)+。

Embodiment 384

5-bromo-pyridine-2-formic acid [4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-acid amides

Embodiment 384A

5-bromo-pyridine-2-carbonyl chlorine

To 5-bromo-pyridine-2-formic acid (1.5g, 7.42mmol) THF (20mL) in interior solution, add cat.DMF (2 drip) and oxalyl chloride (0.64mL, 8.16mmol).This reaction mixture was stirred 0.5 hour, refluxed then 0.5 hour.Should react cooling, and the solvent decompression was removed, obtain acyl chloride hydrochloride (1.85g, 97%).Acyl chloride hydrochloride need not be further purified and directly use.

Embodiment 384B

5-bromo-pyridine-2-formic acid (4-fluoro-3-nitro-phenyl)-acid amides

To 4-fluoro-3-nitro-phenyl amine (0.82g, 5.23mmol) and N, the N-diisopropylethylamine (1.5g, 12.0mmol) product of disposable adding embodiment 384A in the solution in DMF (25mL) (1.0g, 5.23mmol).This solution is spent the night 40 ℃ of stirrings.This reaction is poured in the water, and collect this yellow mercury oxide by filtering.Precipitation is washed with water (2 *), and spend the night, obtained required product (1.0,68%) 60 ℃ of vacuum-dryings.

Embodiment 384C

(4-(4-[(5-bromo-pyridine-2-carbonyl)-amino]-2-nitro-phenyl sulfenyl }-phenyl)-carboxylamine 9H-fluorenes-9-ylmethyl ester

In room temperature, in round-bottomed flask, with derive from front embodiment 384B product (0.42gm 0.95mmol) is suspended among the THF (12ml), to wherein add pyridine (0.24mL, 2.85mmol).To disposable adding 9-fluorenyl methoxy carbonyl chlorine wherein (0.304gm, 1.17mmol), and flask beyond the Great Wall with diaphragm of rubber.With this reaction mixture in stirred overnight at room temperature.By dilute separated product (50mL) and vacuum filtration with ether.Filter cake is washed with other ether, and vacuum-drying has then obtained this title compound (0.526gm, 82%).

Embodiment 384D

(4-{2-amino-4-[(5-bromo-pyridine-2-carbonyl)-amino]-the phenyl sulfenyl }-phenyl)-carboxylamine 9H-fluorenes-9-ylmethyl ester

(0.20gm 0.30mmol) is suspended in 4/1v-v Glacial acetic acid and the alcoholic acid mixture (8ml) with the product of embodiment 384C.(0.215gm 3.85mmol), and heats the gained mixture in 100 ℃ of oil baths disposable adding iron powder in the suspension that this vigorous stirring under nitrogen.19.5 after hour, with this reaction mixture cooling, vacuum concentration is suspended in it in water to mashed prod then, and collects solid product by vacuum filtration. filter cake is washed with water, then in room temperature vacuum-drying (0.204gm, quantitative yield).

Embodiment 384E

4-[4-[(5-bromo-pyridine-2-carbonyl)-amino]-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-carboxylamine 9H-fluorenes-9-ylmethyl ester

(0.10gm, 0.157mmol) (0.045gm 0.21mmol) merges in Glacial acetic acid (2ml), and this mixture in 120 ℃ oil bath, was heated 35 minutes in sealed tube with the product of embodiment 8E with the product of embodiment 384D.(0.055gm 0.25mmol), and reheat 22 minutes, at this moment measures and finds that the amine raw material runs out of to add the amidine of second sample aliquot.With this reaction mixture cooling, then these two batches similar reactions are merged, and with its vacuum concentration.Resistates water and methylene dichloride are distributed, and the gained water is extracted repeatedly with methylene dichloride (100ml altogether).With the organic phase MgSO that merges ₄Drying, vacuum concentration has obtained green foam shape thing then.Crude product is dissolved in the methylene dichloride, and is applied on the Biotage KPSil samplet (25mm) in batches, between sample applies in vacuum drying oven in drying at room temperature.With sample and 25mm column coupling, with ethyl acetate-hexane (1/10-1/1v-v) wash-out, use methylene chloride-methanol (95/5v-v) wash-out then, go out product (0.15gm, 47%) with wash-out.

Embodiment 384F

(0.179gm 0.22mmol) is dissolved among the THF (12ml) product of describing in embodiment 384E in room temperature.Via syringe in this solution, drip 1.0M fluoridize the solution of tetra-n-butyl ammonium in THF (0.225ml, 0.225mmol).This mixture was stirred 30 minutes, use ethyl acetate and water dispenser then.Organic phase is washed with water (3 *), be concentrated into small volume then, and by coming dry with benzene azeotropic.Remove volatile matter then, and resistates is suspended in the ether, collect the gained solid by vacuum filtration.1H NMR shows and has the quaternary ammonium material, therefore filter cake is dissolved among the minimum THF again, with the ethyl acetate dilution, and washes (cumulative volume of washing is 140ml) with water 8 times.The gained organic phase is concentrated, and drying has obtained product as noted above (0.077gm, 60%) light yellow solid. ¹H?NMR(300MHz，DMSO-d ₆)δ?ppm：1.34(d，J＝6.99Hz，6H)3.15-3.29(m，1H)5.46(s，2H)6.56(d，J＝8.46Hz，2H)6.90(d，J＝8.82Hz，1H)7.08(d，J＝8.46Hz，2H)7.62(d，J＝8.46Hz，1H)7.68(dd，J＝8.82，2.21Hz，1H)8.00-8.11(m，2H)8.32(dd，J＝8.46，2.21Hz，1H)8.56(s，1H)8.81-8.91(m，2H)10.07(s，1H)10.77(s，1H)。

Embodiment 385

(S)-4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(1-phenyl-ethyl)-benzamide

Embodiment 385A

4-(4-amino-phenyl sulfenyl)-3-nitro-methyl benzoate

With 4-chloro-3-nitrobenzoic acid methyl esters (15.0g, 68mmol), the 4-aminothiophenol (8.8g, 68mmol) and K ₂CO ₃(11.8g, 85mmol) mixture in DMF (150mL) is cooled to room temperature in 90 ℃ of heating 1.5 hours, under agitation adds H then ₂O (450mL).This aqueous mixture is extracted with AcOEt (400mL).With extraction liquid H ₂MgSO is used in O (3 times) and salt water washing ₄Drying, and evaporation have obtained crude product, are orange crystal.Crude product is suspended in 150mL i-Pr ₂Among the O, and stirring at room 1 hour.Collect crystal by filtering, use i-Pr ₂O washing, and, obtained this title compound of purifying 60 ℃ of drying under reduced pressure 3 days, be orange crystal (18.6g, 90%).

Embodiment 385B

4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-nitro-methyl benzoate

With 4-(4-amino-phenyl sulfenyl)-3-nitro-methyl benzoate (18.5g, 61mmol) and Boc ₂(26.8g, 122mmol) solution in para-dioxane (280mL) was in 90 ℃ of heating 3 hours for O.Add Boc again ₂O (26.8g, 122mmol), and with this mixture 90 ℃ the heating 3 hours.Add second section Boc ₂O (13.4g, 61mmol), and with this mixture 90 ℃ the heating 4 hours.This reaction mixture is cooled to room temperature, then evaporation.With resistates i-Pr ₂O (250mL) dilution, and with mixture stirring at room 1 hour.Collect the gained crystal by filtering, use i-Pr ₂The O washing is spent the night at 60 ℃ of drying under reduced pressure, has obtained this title compound, is yellow crystals (22.8g, 93%).

Embodiment 385C

3-amino-4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-methyl benzoate

With 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-nitro-methyl benzoate (22.8g, 56mmol), the Fe powder (16.4g, 282mmol) and NH ₄Cl (15.1g, 282mmol) at the EtOH aqueous solution [by EtOH (228mL) and H ₂O (228mL) makes] in suspension be heated to backflow gradually, and gentle reflux 2 hours. this reaction mixture is cooled to room temperature, and filters via Celite pad.Filtrate is evaporated.With aqueous residue at AcOEt and H ₂Distribute between the O, use K ₂CO ₃Alkalize to pH9, filter then (via Celite pad).Isolate organic layer, use H ₂MgSO is used in O and salt water washing ₄Drying, and evaporation.With the oily resistates by using i-Pr ₂O (200mL) handled crystallization, stirring at room 30 minutes.Collect the gained crystal by filtering, use i-Pr ₂O washs, and spends the night at 60 ℃ of drying under reduced pressure, has obtained this title compound, is clear crystal (13.9g, 66%).

Embodiment 385D

4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-methyl benzoate

With N '-(3-cyano group-6-sec.-propyl-pyridine-2-yl)-N, N-dimethyl-carbonamidine (2.00g, 9.3mmol) and 3-amino-4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-methyl benzoate (3.46g, 9.3mmol) suspension in AcOH (40mL) under nitrogen in 120 ℃ the heating 20 minutes.After being cooled to room temperature, with this reaction mixture at AcOEt (150mL) and H ₂Distribute between the O (200mL), under agitation use K then ₂CO ₃Alkalize to pH9. and isolate organic layer, with 10%NaHCO3, H ₂MgSO is used in O and salt water washing ₄Drying, and evaporation have obtained light brown oily thing.By this oily resistates of silica gel column chromatography (AcOEt/n-hexane=5/1) purifying, obtained yellow crystals.By being further purified with cold AcOEt (15mL) washing, obtained this title compound, be pale yellow crystals (3.27g, 65%).

Embodiment 385E

4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid

In room temperature to 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-methyl benzoate (3.25g, 6.0mmol) drip in the solution in THF (32.5mL) the LiOH aqueous solution [by the LiOH monohydrate (1.02g, 24mmol) and H ₂O (10mL) makes].With mixture stirring at room 26 hours, evaporation then.With this aqueous mixture 100mL H ₂The O dilution with AcOEt (50mL) washing, carefully is acidified to pH4-5 with 10%HCl at 5 ℃ then under stirring.Collect the gained solid by filtering, use H ₂0 washs, and spends the night at 60 ℃ of drying under reduced pressure, has obtained this title compound, is pale yellow crystals (3.09g, 98%). ¹H-NMR (300MHz, DMSO-d6) δ ppm:1.34 (d, J=7.0Hz, 6H), 1.48 (s, 9H), 3.22 (septets, J=7.0Hz, 1H), 6.93 (d, J=8.5Hz, 1H), 7.36 (d, J=8.8Hz, 2H), 7.54 (d, J=8.8Hz, 2H), 7.63 (d, J=8.5Hz, 1H), 7.75 (dd, J=8.5,1.8Hz, 1H), 7.89 (d, J=1.8Hz, 1H), 8.58 (s, 1H), 8.84 (d, J=8.5Hz, 1H), 9.61 (s, 1H), 10.16 (s, 1H), 12.98 (br-s, 1H).

Embodiment 385F

(S)-4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(1-phenyl-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

In room temperature, under nitrogen to 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenylformic acid (100mg, 0.19mmol) with O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate [TBTU] (68mg, 0.21mmol) drip in the suspension in DMSO (1mL) S-(-)-α-Jia Jibianji amine (25 μ L, 0.19mmol) and N, the N-diisopropylethylamine (67 μ L, 0.38mmol).Mixture is stirred 1 dilution in room temperature under nitrogen, under agitation add H then ₂O (20mL).The gained precipitation is extracted with AcOEt (20mL).With organic layer H ₂O (3 times) and 10% NaHCO ₃MgSO is used in washing ₄Drying, and evaporation have obtained yellow amorphous substance.Separate this oily resistates by silica gel column chromatography (AcOEt/n-hexane=10/1), obtained light yellow amorphous substance, with it by using i-Pr ₂O handles and solidifies.Collect the gained solid by filtering, use i-Pr ₂O washing, and, obtained this title compound 40 ℃ of drying under reduced pressure 3 days, be pale yellow crystals (92mg, 77%).1H-NMR (300MHz, DMSO-d6) δ ppm:1.33 (d, J=7.0Hz, 6H), 1.45 (d, J=7.3Hz, 3H), 1.47 (s, 9H), 3.22 (septets, J=7.0Hz, 1H), 5.16 (quintet, J=7.3Hz, 1H), 6.97 (d, J=8.4Hz, 1H), 7.17-7.25 (m, 1H), 7.26-7.40 (m, 4H), 7.32 (d, J=8.8Hz, 2H), 7.51 (d, J=8.8Hz, 2H), 7.63 (d, J=8.5Hz, 1H), 7.74 (br-d, J=8.4Hz, 1H), 7.93 (br-s, 1H), 8.57 (s, 1H), 8.81 (d, J=7.3Hz, 1H), 8.84 (d, J=8.5Hz, 1H), 9.58 (s, 1H), 10.19 (s, 1H) MS ESI+m/z:635 (M+H).

Embodiment 385G

In room temperature to (S)-{ 4-[2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base is amino)-4-(1-phenyl-ethylamino formyl radical)-phenyl sulfenyl]-phenyl-drip trifluoroacetic acid [TFA] (0.40mL) in the solution of t-butyl carbamate (80mg) in methylene dichloride (1.6mL), and with mixture stirring at room 1 hour.With this reaction mixture at AcOEt and K ₂CO ₃Distribute between the aqueous solution.Isolate organic layer, use H ₂MgSO is used in O and salt water washing ₄Drying, and evaporation have obtained light yellow amorphous substance, and it is passed through at i-Pr ₂Development is solidified among the O.Collect the gained solid by filtering, use i-Pr ₂O washs, and spends the night at 40 ℃ of drying under reduced pressure, has obtained this title compound, is yellow crystals (57mg, 85%).1H-NMR (300MHz, DMSO-d6) δ ppm:1.34 (d, J=7.0Hz, 6H), 1.45 (d, J=7.3Hz, 3H), 3.23 (septet, J=7.0Hz, 1H), 5.15 (quintet, J=7.3Hz, 1H), 5.58 (s, 2H), 6.62 (d, J=8.4Hz, 2H), 6.84 (d, J=8.5Hz, 1H), 7.12 (d, J=8.4Hz, 2H), 7.16-7.25 (m, 1H), and 7.25-7.40 (m, 4H), 7.63 (d, J=8.4Hz, 1H), 7.71 (dd, J=8.5,1.8Hz, 1H), 7.88 (d, J=1.8Hz, 1H), 8.57 (s, 1H), 8.75 (d, J=7.3Hz, 1H), 8.87 (d, J=8.5Hz, 1H), 10.12 (s, 1H) MSESI+m/z:535 (M+H).

Embodiment 386

(R)-4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(1-phenyl-ethyl)-benzamide

Embodiment 386A

(R)-4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(1-phenyl-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, use 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid (in embodiment 385E, making) and R-(+)-α-Jia Jibianji amine to make this title compound: productive rate 72%.

Embodiment 386B

According to the method among the embodiment 385G; made this title compound by (R)-{ 4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-4-(1-phenyl-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 386A, preparing): productive rate 81%.1H-NMR (300MHz, DMSO-d6) δ ppm:1.34 (d, J=7.0Hz, 6H), 1.45 (d, J=7.0Hz, 3H), 3.23 (septets, J=7.0Hz, 1H), 5.15 (quintet, J=7.0Hz, 1H), 5.58 (s, 2H), 6.62 (d, J=8.5Hz, 2H), 6.84 (d, J=8.5Hz, 1H), 7.12 (d, J=8.5Hz, 2H), 7.17-7.25 (m, 1H), 7.26-7.39 (m, 4H), 7.63 (d, J=8.5Hz, 1H), 7.71 (dd, J=8.5,1.8Hz, 1H), 7.88 (d, J=1.8Hz, 1H), 8.57 (s, 1H), 8.75 (d, J=7.3Hz, 1H), 8.87 (d, J=8.5Hz, 1H), 10.12 (s, 1H) MS ESI+m/z:535 (M+H) ESI-m/z:533 (M-H).

Embodiment 387

(S)-4-(4-amino-phenyl sulfenyl)-N-[1-(4-fluoro-phenyl)-ethyl]-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 387A

(S)-4-[4-[1-(4-fluoro-phenyl)-ethylamino formyl radical]-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

According to the method among the embodiment 385F, use 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid (in embodiment 385E, preparing) and S-(-)-1-(4-fluorophenyl) ethylamine to make this title compound: productive rate 95%.

Embodiment 387B

According to the method among the embodiment 385G, by (S)-4-[4-[1-(4-fluoro-phenyl)-ethylamino formyl radical]-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenyl sulfenyl]-phenyl-t-butyl carbamate (preparing in embodiment 387A) made this title compound: productive rate 87%.1H-NMR (300MHz; DMSO-d6) δ ppm:1.34 (d, J=6.62Hz, 6H) 1-44 (d; J=7-35Hz; 3H) 3-15-3-28 (m, 1H) 5-09-5-21 (m, 1H) 5-58 (s; 2H) 6-61 (d; J=8-46Hz, 2H) 6-83 (d, J=8-46Hz; 1H) 7-07-7-18 (m; 4H) 7-34-7-44 (m, 2H) 7.63 (d, J=8.46Hz; 1H) 7.70 (dd; J=8.46,1.84Hz, 1H) 7.87 (d; J=1.84Hz; 1H) 8.57 (s, 1H) 8.74 (d, J=7.72Hz; 1H) 8.86 (d; J=8.46Hz, 1H) 10.12 (s, 1H) MS ESI+m/z 553 (M+H).

Embodiment 388

(S)-4-(4-amino-phenyl sulfenyl)-N-[1-(4-chloro-phenyl)-ethyl]-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 388A

(S)-4-[4-[1-(4-chloro-phenyl)-ethylamino formyl radical]-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

According to the method among the embodiment 385F, use 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid (in embodiment 385E, preparing) and S-(-)-1-(4-chloro-phenyl-) ethylamine to make this title compound: productive rate 76%.

Embodiment 388B

According to the method among the embodiment 385G; by (S)-4-[4-[1-(4-chloro-phenyl)-ethylamino formyl radical]-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenyl sulfenyl]-phenyl-t-butyl carbamate (preparing in embodiment 388A) made this title compound: productive rate 85%.1H-NMR(300MHz，DMSO-d6)δ?ppm：1.33(d，J＝6.99Hz，6H)1.43(d，J＝6.99Hz，3H)3.18-3.27(m，1H)5.06-5.18(m，1H)5.58(s，2H)6.61(d，J＝8.82Hz，2H)6.83(d，J＝8.46Hz，1H)7.11(d，J＝8.46Hz，2H)7.32-7.41(m，4H)7.64(d，J＝8.46Hz，1H)7.70(d，J＝8.46Hz，1H)7.87(s，1H)8.58(s，1H)8.75(d，J＝8.82Hz，1H)8.87(d，J＝8.82Hz，1H)10.17(s，1H)MS?ESI+m/z：569(M+H)。

Embodiment 389

(S)-4-(4-amino-phenyl sulfenyl)-N-[1-(4-bromo-phenyl)-ethyl]-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 389A

(S)-4-[4-[1-(4-bromo-phenyl)-ethylamino formyl radical]-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

According to the method among the embodiment 385F, use 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid (in embodiment 385E, preparing) and S-(-)-1-(4-bromophenyl) ethylamine to make this title compound: productive rate 95%.

Embodiment 389B

According to the method among the embodiment 385G; by (S)-4-[4-[1-(4-bromo-phenyl)-ethylamino formyl radical]-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenyl sulfenyl]-phenyl-t-butyl carbamate (preparing in embodiment 389A) made this title compound: productive rate 93%.1H-NMR(300MHz，DMSO-d6)δ?ppm：1.34(d，J＝6.62Hz，6H)1.43(d，J＝6.99Hz，3H)3.16-3.28(m，1H)5.04-5.15(m，1H)5.58(s，2H)6.61(d，J＝8.46Hz，2H)6.83(d，J＝8.46Hz，1H)7.11(d，J＝8.46Hz，2H)7.31(d，J＝8.09Hz，2H)7.50(d，J＝8.46Hz，2H)7.63(d，J＝8.82Hz，1H)7.70(dd，J＝8.27，1.65Hz，1H)7.86(d，J＝1.80Hz，1H)8.57(s，1H)8.77(d，J＝7.72Hz，1H)8.86(d，J＝8.46Hz，1H)10.13(s，1H)MS?ESI+m/z：613，615(M+H)。

Embodiment 390

(S)-4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(1-p-methylphenyl-ethyl)-benzamide

Embodiment 390A

(S)-4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(1-p-methylphenyl-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

According to the method among the embodiment 385F, use 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenylformic acid (in embodiment 385E, preparing) and S-(-)-α, the 4-dimethyl benzyl amine has made this title compound: productive rate 84%.

Embodiment 390B

According to the method among the embodiment 385G; made this title compound by (S)-{ 4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-4-(1-p-methylphenyl-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 390A, preparing): productive rate 89%.1H-NMR (300MHz, DMSO-d6) δ ppm:1.34 (d, J=7.0Hz, 6H), 1.42 (d, J=7.0Hz, 3H), 2.25 (s, 3H), 3.23 (septets, J=6.6Hz, 1H), 5.11 (dq, J=8.1,7.0Hz, 1H), 5.58 (s, 2H), 6.62 (d, J=8.5Hz, 2H), 6.83 (d, J=8.5Hz, 1H), 7.11 (d, J=8.1Hz, 2H), 7.12 (d, J=8.5Hz, 2H), 7.24 (d, J=8.1Hz, 2H), 7.63 (d, J=8.5Hz, 1H), 7.70 (dd, J=8.5,1.9Hz, 1H), 7.87 (d, J=1.9Hz, 1H), 8.57 (s, 1H), 8.69 (d, J=8.1Hz, 1H), 8.87 (d, J=8.5Hz, 1H), 10.12 (s, 1H) MS ESI+m/z:549 (M+H) ESI-m/z:547 (M-H).

Embodiment 391

(S)-4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-[1-(3-methoxyl group-phenyl)-ethyl]-benzamide

Embodiment 391A

(S)-(4-{2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-[1-(4-methoxyl group-phenyl)-ethylamino formyl radical]-the phenyl sulfenyl }-phenyl)-t-butyl carbamate

According to the method among the embodiment 385F, use 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid (in embodiment 385E, preparing) and S-(-)-1-(4-p-methoxy-phenyl) ethylamine to make this title compound: productive rate 96%.

Embodiment 391B

(S)-4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-[1-(4-methoxyl group-phenyl)-ethyl]-benzamide

According to the method among the embodiment 385G; use (S)-(4-{2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-[1-(4-methoxyl group-phenyl)-ethylamino formyl radical]-the phenyl sulfenyl }-phenyl)-t-butyl carbamate (preparing in embodiment 391A) made this title compound: productive rate 52%.1H-NMR (300MHz, DMSO-d6) δ ppm:1.34 (d, J=7.0Hz, 6H), 1.42 (d, J=7.0Hz, 3H), 3.23 (septet, J=7.0Hz, 1H), 3.71 (s, 3H), 5.03-5.18 (m, 1H), 5.58 (s, 2H), 6.62 (d, J=8.5Hz, 2H), 6.83 (d, J=8.5Hz, 1H), 6.87 (d, J=8.5Hz, 2H), 7.12 (d, J=8.5Hz, 2H), 7.28 (d, J=8.5Hz, 2H), 7.63 (d, J=8.5Hz, 1H), 7.70 (dd, J=8.5,1.8Hz, 1H), 7.86 (d, J=1.8Hz, 1H), 8.57 (s, 1H), 8.67 (d, J=8.1Hz, 1H), 8.87 (d, J=8.5Hz, 1H), 10.12 (s, 1H) MSESI+m/z:565 (M+H) ESI-m/z:565 (M-H).

Embodiment 392

(S)-4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-[1-(3-trifluoromethyl-phenyl)-ethyl]-benzamide

Embodiment 392A

(S)-(4-{2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-[1-(3-trifluoromethyl-phenyl)-ethylamino formyl radical]-the phenyl sulfenyl }-phenyl)-t-butyl carbamate

According to the method among the embodiment 385F, use 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid (in embodiment 385E, preparing) and S-(-)-1-(3-trifluoromethyl) ethylamine to make this title compound: productive rate 85%.

Embodiment 392B

According to the method among the embodiment 385G; by (S)-(4-{2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-4-[1-(3-trifluoromethyl-phenyl)-ethylamino formyl radical]-the phenyl sulfenyl-phenyl)-t-butyl carbamate (preparing in embodiment 392A) made this title compound: productive rate 96%.1H-NMR (300MHz, DMSO-d6) δ ppm:1.34 (d, J=7.0Hz, 6H), 1.48 (d, J=7.3Hz, 3H), 3.22 (septet, J=7.0Hz, 1H), 5.22 (quintet, J=7.3Hz, 1H), 5.58 (s, 2H), 6.62 (d, J=8.8Hz, 2H), 6.85 (d, J=8.4Hz, 1H), 7.12 (d, J=8.8Hz, 2H), 7.52-7.75 (m, 5H), 7.64 (d, J=8.5Hz, 1H), 7.88 (d, J=1.8Hz, 1H), 8.57 (s, 1H), 8.86 (d, J=7.3Hz, 1H), 8.87 (d, J=8.5Hz, 1H), 10.13 (s, 1H) MS ESI+m/z:603 (M+H) ESI-m/z:601 (M-H).

Embodiment 393

Embodiment 393A

(S)-(4-{2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-[1-(3-methoxyl group-phenyl)-ethylamino formyl radical]-the phenyl sulfenyl }-phenyl)-t-butyl carbamate

According to the method among the embodiment 385F, use 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid (in embodiment 385E, preparing) and S-(-)-1-(3-p-methoxy-phenyl) ethylamine to make this title compound: productive rate 85%.

Embodiment 393B

According to the method among the embodiment 385G; by (S)-(4-{2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-4-[1-(3-methoxyl group-phenyl)-ethylamino formyl radical]-the phenyl sulfenyl-phenyl)-t-butyl carbamate (preparing in embodiment 393A) made this title compound: productive rate 85%.1H-NMR (300MHz, DMSO-d6) δ ppm:1.34 (d, J=7.0Hz, 6H), 1.43 (d, J=7.0Hz, 3H), 3.23 (septet, J=7.0Hz, 1H), 3.72 (s, 3H), 5.02-5.21 (m, 1H), 5.58 (s, 2H), 6.62 (d, J=8.5Hz, 2H), 6.78 (dd, J=8.1,1.8Hz, 1H), 6.84 (d, J=8.5Hz, 1H), and 6.88-6.96 (m, 2H), 7.12 (d, J=85Hz, 2H), 7.22 (t, J=8.1Hz, 1H), 7.64 (d, J=8.5Hz, 1H), 7.71 (dd, J=8.5,1.8Hz, 1H), 7.88 (br-s, 1H), 8.57 (s, 1H), 8.72 (d, J=8.1Hz, 1H), 8.87 (d, J=8.5Hz, 1H), 10.13 (s, 1H) MS ESI+m/z:565 (M+H) ESI-m/z:563 (M-H).

Embodiment 394

(S)-4-(4-amino-phenyl sulfenyl)-N-[1-(2-bromo-phenyl)-ethyl]-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 394A

(S)-1-(1-azido-ethyl)-2-bromobenzene

To (R)-(+)-2-bromo-methylbenzyl alcohol (402mg, 2.0mmol) and the diphenylphosphine acylazide (0.692ml 3.2mmol) adds 1 in the solution in THF (10mL), 8-diazabicylo [5.4.0] 11 carbon-7-alkene (0.466ml, 3.2mmol).This mixture 50 ℃ of heated overnight, is used H ₂O and AcOEt distribute, and are adjusted to pH7 by adding 1MHCl then.With organic layer MgSO ₄Drying is filtered and evaporation.Resistates by silica gel chromatography [with normal hexane/AcOEt=95/5 wash-out], has been obtained this title compound (381mg, 84%).

Embodiment 394B

(S)-(-)-1-(2-bromophenyl) ethylamine

To (S)-1-(1-azido-ethyl)-(45mg is 0.2mmol) at EtOH/H for the 2-bromobenzene ₂Add NH in the adding in the O (5mL/5mL) ₄Cl (108mg, 2.0mmol) and indium (91mg, 0.8mmol).This mixture backflow is spent the night.This reaction mixture is filtered, with the EtOH washing, and evaporation.Resistates is developed and filtered with AcOEt.With the filtrate evaporation, obtained this title compound (35mg, 88%).

Embodiment 394C

(S)-4-[4-[1-(2-bromo-phenyl)-ethylamino formyl radical]-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

According to the method among the embodiment 385F, use 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid (in embodiment 385E, preparing) and S-(-)-1-(2-bromophenyl) ethamine (in embodiment 394B, preparing) to make this title compound: productive rate 30%.

Embodiment 394D

According to the method among the embodiment 385G; by (S)-4-[4-[1-(2-bromo-phenyl)-ethylamino formyl radical]-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenyl sulfenyl]-phenyl-t-butyl carbamate (preparing in embodiment 394C) made this title compound: productive rate 89%.1H-NMR(300MHz，DMSO-d6)δ?ppm：1.34(d，J＝6.99Hz，6H)1.41(d，J＝6.99Hz，3H)3.16-3.28(m，1H)5.31-5.41(m，1H)5.58(s，2H)6.62(d，J＝8.82Hz，2H)6.84(d，J＝8.46Hz，1H)7.08-7.20(m，3H)7.35(t，J＝7.35Hz，1H)7.48(dd，J＝7.71Hz，1.47Hz，1H)7.57(d，J＝8.09Hz，1H)7.64(d，J＝8.46Hz，1H)7.72(dd，J＝8.46，1.47Hz，1H)7.90(d，J＝1.47Hz，1H)8.58(s，1H)8.78-9.00(m，2H)10.14(s，1H)MS?ESI+m/z：613，615(M+H)。

Embodiment 395

(S)-4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-[1-(2-trifluoromethyl-phenyl)-ethyl]-benzamide

Embodiment 395A

(S)-(4-{2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-[1-(2-trifluoromethyl-phenyl)-ethylamino formyl radical]-the phenyl sulfenyl }-phenyl)-t-butyl carbamate

According to the method among the embodiment 385F, use 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid (in embodiment 385E, preparing) and S-(-)-1-(2-trifluoromethyl) ethylamine to make this title compound: productive rate 68%.

Embodiment 395B

According to the method among the embodiment 385G; by (S)-(4-{2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-4-[1-(2-trifluoromethyl-phenyl)-ethylamino formyl radical]-the phenyl sulfenyl-phenyl)-t-butyl carbamate (preparing in embodiment 395A) made this title compound: productive rate 83%.1H-NMR(300MHz，DMSO-d6)δ?ppm：1.34(d，J＝6.99Hz，6H)1.44(d，J＝6.99Hz，3H)3.14-3.28(m，1H)5.38-5.49(m，1H)5.59(s，2H)6.62(d，J＝8.82Hz，2H)6.83(d，J＝8.46Hz，1H)7.12(d，J＝8.46Hz，2H)7.43(t，J＝7.54Hz，1H)7.61-7.73(m，4H)7.79(d，J＝8.09Hz，1H)7.89(s，1H)8.58(s，1H)8.77-8.99(m，2H)10.13(s，1H)MSESI+m/z：603(M+H)。

Embodiment 396

(S)-4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(1-naphthalene-2-base-ethyl)-benzamide

Embodiment 396A

(S)-4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(1-naphthalene-2-base-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

According to the method among the embodiment 385F, use 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid (in embodiment 385E, preparing) and S-(-)-1-naphthalene-2-base-ethylamine to make this title compound: productive rate 72%.

Embodiment 396B

According to the method among the embodiment 385G; made this title compound by (S)-{ 4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-4-(1-naphthalene-2-base-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 396A, preparing): productive rate 64%.1H-NMR(300MHz，DMSO-d6)δ?ppm：1.33(d，J＝6.62Hz，6H)1.59(d，J＝6.99Hz，3H)3.12-3.30(m，1H)5.58(s，2H)5.89-6.01(m，1H)6.61(d，J＝8.46Hz，2H)6.83(d，J＝8.46Hz，1H)7.11(d，J＝8.46Hz，2H)7.43-7.65(m，5H)7.70-7.77(dd，J＝8.46，1.47Hz，1H)7.82(d，J＝8.09Hz，1H)7.88-7.98(m，2H)8.18(d，J＝8.09Hz，1H)8.56(s，1H)8.85(d，J＝8.46Hz，1H)8.90(d，J＝7.72Hz，1H)10.12(s，1H)MS?ESI+m/z：585(M+H)。

Embodiment 397

(RS)-4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(1-thiophene-2-base-ethyl)-benzamide

Embodiment 397A

(RS)-4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(1-thiophene-2-base-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

According to the method among the embodiment 385F, use 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid (in embodiment 385E, preparing) and (RS)-1-thiophene-2-base-ethylamine to make this title compound: productive rate 92%.

Embodiment 397B

According to the method among the embodiment 385G; by (RS)-{ 4-[2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-4-(1-thiophene-2-base-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate (preparing in embodiment 397A) has made this title compound, is two-trifluoroacetate: productive rate 31%.1H-NMR(300MHz，DMSO-d6)δ?ppm：1.36(d，J＝6.62Hz，6H)1.56(d，J＝6.99Hz，3H)3.23-3.41(m，1H)4.03(s，2H)5.31-5.56(m，1H)6.62(d，J＝8.82Hz，2H)6.85-7.06(m，3H)7.13(d，J＝8.46Hz，2H)7.33-7.42(m，1H)7.80(dd，J＝8.46，1.84Hz，1H)7.88(s，1H)7.93(d，J＝8.46Hz，1H)8.87-8.94(m，2H)9.03(d，J＝8.46Hz，1H)11.72(s，1H)MS?ESI+m/z：541(M+H)

Embodiment 398

(RS)-4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(1-pyridine-2-base-ethyl)-benzamide

Embodiment 398A

(RS)-4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(1-pyridine-2-base-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

According to the method among the embodiment 385F, use 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid (in embodiment 385E, preparing) and (RS)-1-pyridine-2-base-ethylamine to make this title compound: productive rate 93%.

Embodiment 398B

According to the method among the embodiment 385G; made this title compound by (RS)-{ 4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-4-(1-pyridine-2-base-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 398A, preparing): productive rate 95%.1H-NMR(300MHz，DMSO-d6)δ?ppm：1.34(d，J＝6.62Hz，6H)1.47(d，J＝7.35Hz，3H)3.12-3.28(m，1H)5.17(qt，1H)5.58(s，2H)6.62(d，J＝8.46Hz，2H)6.84(d，J＝8.46Hz，1H)7.12(d，J＝8.46Hz，2H)7.24(dd，J＝6.62，4.78Hz，1H)7.37(d，J＝8.09Hz，1H)7.63(d，J＝8.09Hz，1H)7.69-7.83(m，2H)7.91(s，1H)8.50(d，J＝4.04Hz，1H)8.57(s，1H)8.78(d，J＝7.72Hz，1H)8.87(d，J＝8.82Hz，1H)10.13(s，1H)MS?ESI+m/z：536(M+H)。

Embodiment 399

(RS)-4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(1-pyridin-3-yl-ethyl)-benzamide

Embodiment 399A

(RS)-4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(1-pyridin-3-yl-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

According to the method among the embodiment 385F, use 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid (in embodiment 385E, preparing) and (RS)-1-pyridin-3-yl-ethylamine to make this title compound: productive rate 79%.

Embodiment 399B

According to the method among the embodiment 385G; made this title compound by (RS)-{ 4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-4-(1-pyridin-3-yl-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 399A, preparing): productive rate 98%.1H-NMR(300MHz，DMSO-d6)δ?ppm：1.34(d，J＝6.99Hz，6H)1.48(d，J＝6.99Hz，3H)3.14-3.27(m，1H)5.12-5.28(m，1H)5.58(s，2H)6.61(d，J＝8.82Hz，2H)6.80-6.86(m，J＝8.46Hz，1H)7.11(d，J＝8.82Hz，2H)7.34(dd，J＝7.91，4.23Hz，1H)7.63(d，J＝8.46Hz，1H)7.68-7.78(m，2H)7.87(d，J＝1.47Hz，1H)8.43(dd，J＝4.78，1.47Hz，1H)8.55-8.59(m，2H)8.82(d，J＝7.72Hz，1H)8.86(d，J＝8.46Hz，1H)10.12(s，1H)MS?ESI+m/z：536(M+H)。

Embodiment 400

(RS)-4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(1-pyridin-4-yl-ethyl)-benzamide

Embodiment 400A

(RS)-4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(1-pyridin-4-yl-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

According to the method among the embodiment 385F, use 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid (in embodiment 385E, preparing) and (RS)-1-pyridin-4-yl-ethylamine to make this title compound: productive rate 41%.

Embodiment 400B

According to the method among the embodiment 385G; made this title compound by (RS)-{ 4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-4-(1-pyridin-4-yl-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 400A, preparing): productive rate 83%.1H-NMR(300MHz，DMSO-d6)δ?ppm：1.34(d，J＝6.99Hz，6H)1.45(d，J＝6.99Hz，3H)3.13-3.27(m，1H)5.02-5.23(m，1H)5.58(s，2H)6.62(d，J＝8.82Hz，2H)6.84(d，J＝8.09Hz，1H)7.12(d，J＝8.46Hz，2H)7.34(d，J＝6.25Hz，2H)7.63(d，J＝8.46Hz，1H)7.72(dd，J＝8.27，1.65Hz，1H)7.89(d，J＝1.47Hz，1H)8.49(d，J＝5.88Hz，2H)8.58(s，1H)8.85(t，J＝8.27Hz，2H)10.13(s，1H) MS ESI+m/z：536(M+H)。

Embodiment 401

(S)-4-(4-amino-phenyl sulfenyl)-N-(1-cyclohexyl-ethyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 401A

(S)-4-[4-(1-cyclohexyl-ethylamino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenylformic acid (in embodiment 385E, making) and S-(+)-1-cyclohexylethylamine, make this title compound: productive rate 73%.

Embodiment 401B

Method according to embodiment 385G; by (S)-{ 4-[4-(1-cyclohexyl-ethylamino formyl radical)-2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-the phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 401A, making), make this title compound: productive rate 90%.1H-NMR(300MHz，DMSO-d6)δ?ppm：0.86-0.97(m，2H)1.04-1.16(m，6H)1.28-1.40(m，7H)1.54-1.76(m，5H)3.16-3.28(m，1H)3.77-3.86(m，1H)5.57(s，2H)6.61(d，J＝8.46Hz，2H)6.83(d，J＝8.46Hz，1H)7.11(d，J＝8.46Hz，2H)7.57-7.72(m，2H)7.83(d，J＝1.47Hz，1H)8.05(d，J＝8.46Hz，1H)8.57(s，1H)8.86(d，J＝8.46Hz，1H)10.12(s，1H)MS?ESI+m/z：541(M+H)。

Embodiment 402

(S)-4-(4-amino-phenyl sulfenyl)-N-indane-1-base-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 402A

(S)-4-[4-(indane-1-base formamyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenylformic acid (in embodiment 385E, making) and S-(+)-1-aminoidan, make this title compound: productive rate 71%.

Embodiment 402B

Method according to embodiment 385G; by (S)-{ 4-[4-(indane-1-base formamyl)-2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-the phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 402A, making), make this title compound: productive rate 92%.1H-NMR(300MHz，DMSO-d6)δ?ppm：1.33(d，J＝6.99Hz，6H)1.88-1.98(m，1H)2.37-2.46(m，1H)2.76-2.88(m，1H)2.90-3.02(m，1H)3.16-3.27(m，1H)5.47-5.66(m，3H)6.62(d，J＝8.46Hz，2H)6.82(d，J＝8.09Hz，1H)7.12(d，J＝8.46Hz，2H)7.16-7.28(m，4H)7.63(d，J＝8.46Hz，1H)7.74(d，J＝8.46Hz，1H)7.90(s，1H)8.57(s，1H)8.72(d，J＝8.46Hz，1H)8.86(d，J＝8.46Hz，1H)10.12(s，1H)MS?ESI+m/z：547(M+H)。

Embodiment 403

(S)-4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(1-phenyl-propyl group)-benzamide

Embodiment 403A

(S)-4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(1-phenyl-propyl group formamyl)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenylformic acid (in embodiment 385E, making) and S-(-)-1-phenyl propyl amine, make this title compound: productive rate 90%.

Embodiment 403B

Method according to embodiment 385G; by (S)-{ 4-[2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-4-(1-phenyl-propyl group formamyl)-phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 403A, making), make this title compound: productive rate 89%.1H-NMR (300MHz, DMSO-d6) δ ppm:0.88 (d, J=7.3Hz, 3H), 1.34 (d, J=7.0Hz, 6H), 1.68-1.90 (m, 2H), 3.23 (septets, J=7.0Hz, 1H), 4.89 (dt, J=8.1,7.3Hz, 1H), 5.58 (s, 2H), 6.62 (d, J=8.5Hz, 2H), 6.84 (d, J=8.4Hz, 1H), 7.12 (d, J=8.5Hz, 2H), 7.21 (t, J=7.0Hz, 1H), 7.30 (t, J=7.0Hz, 2H), 7.36 (d, J=7.0Hz, 2H), 7.64 (d, J=8.5Hz, 1H), 7.71 (dd, J=8.4,1.8Hz, 1H), 7.88 (d, J=1.8Hz, 1H), 8.57 (s, 1H), 8.68 (d, J=8.1Hz, 1H), 8.87 (d, J=8.5Hz, 1H), 10.13 (s, 1H) MS ESI+m/z:549 (M+H) ESI-m/z:547 (M-H).

Embodiment 404

(R)-4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(1-phenyl-propyl group)-benzamide

Embodiment 404A

(R)-4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(1-phenyl-propyl group formamyl)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenylformic acid (in embodiment 385E, making) and R-(+)-1-phenyl propyl amine, make this title compound: productive rate 88%.

Embodiment 404B

Method according to embodiment 385G; by (R)-{ 4-[2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-4-(1-phenyl-propyl group formamyl)-phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 404A, making), make this title compound: productive rate 89%.1H-NMR (300MHz, DMSO-d6) δ ppm:0.88 (d, J=7.3Hz, 3H), 1.34 (d, J=7.0Hz, 6H), 1.67-1.92 (m, 2H), 3.23 (septets, J=7.0Hz, 1H), 4.89 (dt, J=8.1,7.3Hz, 1H), 5.57 (s, 2H), 6.62 (d, J=8.5Hz, 2H), 6.84 (d, J=8.5Hz, 1H), 7.11 (d, J=8.5Hz, 2H), 7.21 (t, J=7.0Hz, 1H), 7.30 (t, J=7.0Hz, 2H), 7.36 (d, J=7.0Hz, 2H), 7.64 (d, J=8.5Hz, 1H), 7.71 (dd, J=8.5,1.8Hz, 1H), 7.88 (d, J=1.8Hz, 1H), 8.57 (s, 1H), 8.68 (d, J=8.1Hz, 1H), 8.87 (d, J=8.5Hz, 1H), 10.13 (s, 1H) MS ESI+m/z:549 (M+H) ESI-m/z:547 (M-H).

Embodiment 405

(R)-4-(4-amino-phenyl sulfenyl)-N-(2-hydroxyl-1-phenyl-ethyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 405A

(R)-4-[4-(2-hydroxyl-1-phenyl-ethylamino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenylformic acid (in embodiment 385E, making) and R-(-)-2-phenyl glycinol, make this title compound: productive rate 70%.

Embodiment 405B

Method according to embodiment 385G; by (R)-{ 4-[4-(2-hydroxyl-1-phenyl-ethylamino formyl radical)-2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-the phenyl sulfenyl]-phenyl }-t-butyl carbamate, make this title compound (in embodiment 405A, making): productive rate 59%.1H-NMR (300MHz, DMSO-d6) δ ppm:1.34 (d, J=7.0Hz, 6H), 3.22 (septets, J=7.0Hz, 1H), 3.52-3.75 (m, 2H), 4.92 (t, J=5.1Hz, 1H), 4.98-5.13 (m, 1H), 5.64 (br-s, 2H), 6.62 (d, J=8.5Hz, 2H), 6.83 (br-d, 1H), 7.12 (d, J=8.5Hz, 2H), 7.21 (t, J=7.0Hz, 1H), 7.30 (t, J=7.0Hz, 2H), 7.36 (d, J=7.0Hz, 2H), 7.64 (br-d, J=8.5Hz, 1H), 7.72 (br-d, 1H), 7.90 (br-s, 1H), 8.58 (br-s, 1H), 8.65 (br-d, J=8.1Hz, 1H), 8.87 (br-d, J=8.5Hz, 1H), 10.19 (br-s, 1H) MS ESI+m/z:551 (M+H) ESI-m/z:549 (M-H).

Embodiment 406

(S)-4-(4-amino-phenyl sulfenyl)-N-(3-hydroxyl-1-phenyl-propyl group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 406A

(S)-4-[4-(3-hydroxyl-1-phenyl-propyl group formamyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid (in embodiment 385E, making) and (S)-3-amino-3-phenyl third-1-alcohol, make this title compound: productive rate 81%.

Embodiment 406B

Method according to embodiment 385G; by (S)-{ 4-[4-(3-hydroxyl-1-phenyl-propyl group formamyl)-2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-the phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 406A, making), make this title compound: productive rate 80%.1H-NMR (300MHz, DMSO-d6) δ ppm:1.34 (d, J=7.0Hz, 6H), 1.78-2.08 (m, 2H), 3.23 (septet, J=7.0Hz, 1H), 3.33-3.48 (m, 2H), 4.55 (t, J=4.8Hz, 1H), and 5.05-5.22 (m, 1H), 5.58 (s, 2H), 6.62 (d, J=8.8Hz, 2H), 6.84 (d, J=8.5Hz, 1H), 7.11 (d, J=8.8Hz, 2H), 7.16-7.42 (m, 5H), 7.63 (d, J=8.5Hz, 1H), 7.70 (dd, J=8.5,1.8Hz, 1H), 7.86 (d, J=1.8Hz, 1H), 8.57 (s, 1H), 8.71 (d, J=8.1Hz, 1H), 8.87 (d, J=8.5Hz, 1H), 10.13 (s, 1H) MS ESI+m/z:565 (M+H) ESI-m/z:563 (M-H).

Embodiment 407

(R)-[4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzoyl-amido]-phenyl-acetic acid methyl esters

Embodiment 407A

(R)-[4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzoyl-amido]-phenyl-acetic acid methyl esters

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenylformic acid (in embodiment 385E, making) and R-(-)-2-phenylglycocoll first methyl esters (hydrochloride), make this title compound: productive rate 91%.

Embodiment 407B

(R)-[4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine 4-base is amino)-benzoyl-amido]-phenyl-acetic acid methyl esters

Method according to embodiment 385G; by (R)-[4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-benzoyl-amido]-phenyl-acetic acid methyl esters (in embodiment 407A, making), make this title compound: productive rate 80%.1H-NMR (300MHz, DMSO-d6) δ ppm:1.33 (d, J=7.0Hz, 6H), 3.22 (septets, J=7.0Hz, 1H), 3.64 (s, 3H), 5.59 (s, 2H), 5.65 (d, J=7.0Hz, 1H), 6.62 (d, J=8.5Hz, 2H), 6.82 (d, J=8.5Hz, 1H), 7.12 (d, J=8.5Hz, 2H), 7.30-7.49 (m, 5H), 7.63 (d, J=8.5Hz, 1H), 7.74 (dd, J=8.5,1.8Hz, 1H), 7.94 (d, J=1.8Hz, 1H), 8.56 (s, 1H), 8.86 (d, J=8.5Hz, 1H), 9.13 (d, J=7.0Hz, 1H), 10.12 (s, 1H) MS ESI+m/z:579 (M+H) ESI-m/z:577 (M-H).

Embodiment 408

(S)-4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-methyl-N-(1-phenyl-ethyl)-benzamide

Embodiment 408A

(S)-(4-{2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-[methyl-(1-phenyl-ethyl)-formamyl]-the phenyl sulfenyl }-phenyl)-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid (in embodiment 385E, making) and (S)-N, α-Er Jiajibianji amine makes this title compound: productive rate 54%.

Embodiment 408B

Method according to embodiment 385G; by (S)-(4-{2-(7-sec.-propyl-pyrido [2 as two-trifluoroacetate; 3-d] pyrimidine-4-base amino)-4-[methyl-(1-phenyl-ethyl)-formamyl]-the phenyl sulfenyl }-phenyl)-t-butyl carbamate (in embodiment 408A, making), make this title compound: productive rate 67%.1H-NMR(300MHz，DMSO-d6)δ?ppm：1.36(d，J＝6.99Hz，6H)1.55(d，J＝6.99Hz，3H)2.62(s，3H)3.15-3.38(m，1H)3.20-3.80(m，4H)6.63(d，J＝8.46Hz，2H)6.91(d，J＝8.09Hz，1H)7.15(d，J＝8.46Hz，2H)7.25-7.45(m，5H)7.50(s，1H)7.93(d，J＝8.46Hz，1H)8.86(s，1H)9.03(d，J＝8.82Hz，1H) MS ESI+m/z：549(M+H)。

Embodiment 409

(S)-N-allyl group-4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(1-phenyl-ethyl)-benzamide

Embodiment 409A

(S)-4-[4-[allyl group-(1-phenyl-ethyl)-formamyl]-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid (in embodiment 385E, making) and (S)-N-allyl group-α-Jia Jibianji amine, make this title compound: productive rate 36%.

Embodiment 409B

(S)-N-allyl group-4-(4-cyano group-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(1-phenyl-ethyl)-benzamide

Method according to embodiment 385G; by (S) that prepare among the embodiment 409A-4-[4-[allyl group-(1-phenyl-ethyl)-formamyl]-2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-the phenyl sulfenyl]-phenyl }-t-butyl carbamate, make this title compound: productive rate 88%.1H-NMR(300MHz，DMSO-d6)δ?ppm：1.33(d，J＝6.99Hz，6H)1.57(d，J＝6.99Hz，3H)3.11-3.28(m，1H)3.39-3.53(m，1H)3.93-4.03(m，1H)4.85-5.15(m，3H)5.48-5.73(m，3H)6.61(d，J＝8.46Hz，2H)6.83(d，J＝8.09Hz，1H)7.13(d，J＝8.09Hz，2H)7.22-7.38(m，6H)7.47(s，1H)7.62(d，J＝8.46Hz，1H)8.52(s，1H)8.86(d，J＝8.82Hz，1H)10.04(s，1H)MS?ESI+m/z：575(M+H)

Embodiment 410

(S)-4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(1-phenyl-ethyl)-benzamide

Embodiment 410A

4-(4-hydroxyl-phenyl sulfenyl)-3-nitro-methyl benzoate

(4.00g, 18mmol) (2.37g 18mmol) adds Cs in room temperature in the solution in acetone (60mL) with the 4-mercapto-phenol to 4-chloro-3-nitrobenzoic acid methyl esters ₂CO ₃(5.93g 18mmol), refluxes compound 30 minutes then.After being cooled to room temperature, compound is filtered, and filtrate is evaporated.Resistates is used H with AcOEt (30mL) dilution ₂MgSO is used in O (3 times) and salt water washing ₄Dry also evaporation obtains brown oil.(normal hexane/AcOEt=4/3), obtain this title compound is the armorphous thing of yellow (5.60g) to this oily resistates by the silica gel column chromatography separation.

Embodiment 410B

3-amino-4-(4-hydroxyl-phenyl sulfenyl)-methyl benzoate

With 4-(4-hydroxyl-phenyl sulfenyl)-3-nitro-methyl benzoate (5.60g, 18mmol), iron powder (5.34g, 92mmol) and NH ₄Cl (4.91g, 92mmol) at the EtOH aqueous solution [by EtOH (50mL) and H ₂O (50mL) makes] in suspension be heated to gradually and reflux and refluxed 45 minutes.Reaction mixture is diluted with AcOEt (50mL), and filter by Celite pad.With filtrate evaporation, and with aqueous residue at AcOEt and 10% NaHCO ₃Between distribute.Organic layer is separated, use H ₂MgSO is used in O and salt water washing ₄Dry also evaporation obtains light yellow solid.Gained solid i-Pr ₂O washing, and, obtain this title compound in 40 ℃ of drying under reduced pressure 3 days, be pale yellow crystals (4.50g, 90% by 2 steps).

Embodiment 410C

4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-methyl benzoate

With N '-(3-cyano group-6-sec.-propyl-pyridine-2-yl)-N, N-dimethyl-carbonamidine (0.75g, 3.5mmol) and 3-amino-4-(4-hydroxyl-phenyl sulfenyl)-methyl benzoate (0.96g, 3.5mmol) suspension in AcOH (15mL) under nitrogen in 120 ℃ the heating 10 minutes.With reaction mixture at AcOEt (10mL) and H ₂Distribute between the O (150mL), and under agitation use K ₂CO ₃Alkalize to pH9.Filter and collect the gained solid, use H ₂O and AcOEt wash, and spend the night in 50 ℃ of drying under reduced pressure, obtain this title compound, are light brown crystal (1.27g, 82%).

Embodiment 410D

4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid is to 4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-methyl benzoate (0.50g, 1.1mmol) THF (5mL) in suspension in drip the LiOH aqueous solution [by LiOH monohydrate (0.15g) and H in room temperature ₂O (1.5mL) makes].With mixture stirring at room 24 hours.Add the LiOH aqueous solution again [by LiOH monohydrate (0.15g) and H in room temperature ₂O (1.5mL)].With mixture stirring at room 23 hours, evaporation then.With aqueous mixture 50mL H ₂The O dilution with the AcOEt washing, and is used activated carbon treatment.Compound is filtered, and filtrate under agitation is acidified to pH4-5 with 10%HCl carefully.Filter and collect the gained solid, use H ₂O washing, and, obtain this title compound in 40 ℃ of drying under reduced pressure 3 days, be pale yellow crystals (0.35g, 73%).1H-NMR (300MHz, DMSO-d6) δ ppm:1.33 (d, J=7.0Hz, 6H), 3.22 (septets, J=7.0Hz, 1H), 6.81-6.90 (m, 1H), 6.85 (d, J=8.5Hz, 2H), 7.30 (d, J=8.5Hz, 2H), 7.63 (br-d, J=8.4Hz, 1H), 7.73 (br-d, J=8.1Hz, 1H), 7.85 (br-s, 1H), 8.57 (s, 1H), 8.86 (d, J=8.4Hz, 1H), 10.14 (s, 1H).

Embodiment 410E

Method according to embodiment 385F, with 4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenylformic acid (in embodiment 410D, making) and S-(-)-α-Jia Jibianji amine, make this title compound productive rate 39%.1H-NMR (300MHz, DMSO-d6) δ ppm:1.34 (d, J=7.0Hz, 6H), 1.45 (d, J=7.4Hz, 3H), 3.23 (septet, J=7.0Hz, 1H), 5.15 (quintet, J=7.4Hz, 1H), 6.83 (d, J=8.4Hz, 2H), 6.90 (d, J=8.1Hz, 1H), 7.16-7.40 (m, 5H), 7.28 (d, J=8.4Hz, 2H), 7.63 (d, J=8.4Hz, 1H), 7.73 (br-d, J=8.1Hz, 1H), 7.91 (br-s, 1H), 8.57 (s, 1H), 8.78 (d, J=7.3Hz, 1H), 8.86 (d, J=8.4Hz, 1H), 9.93 (s, 1H), 10.16 (s, 1H) MS ESI+m/z:536 (M+H) ES1-m/z:534 (M-H).

Embodiment 411

(S)-4-(4-amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(1-phenyl-ethyl)-benzamide

Embodiment 411A

4-(4-tert-butoxycarbonyl amino-phenoxy group)-3-nitro-methyl benzoate

With 4-chloro-3-nitrobenzoic acid methyl esters (15.0g, 68mmol), (4-hydroxyl-phenyl)-t-butyl carbamate (14.7g, 68mmol) and K ₂CO ₃(18.9g, 136mmol) mixture in DMF (300mL) heated 1 hour under nitrogen in 110 ℃, was cooled to room temperature, under agitation poured ice-H then into ₂Among the O (1200mL).Aqueous mixture is extracted with AcOEt (600mL).With extraction liquid H ₂MgSO is used in O (3 times) and salt water washing ₄Dry and evaporation obtains light brown crystal, with it by using i-Pr ₂Purifying is carried out in the O washing, and spends the night in 40 ℃ of drying under reduced pressure, obtains this title compound, is pale yellow crystals (18.5g, 70%).

Embodiment 411B

3-amino-4-(4-tert-butoxycarbonyl amino-phenoxy group)-methyl benzoate

With 4-(4-tert-butoxycarbonyl amino-phenoxy group)-3-nitro-methyl benzoate (18.0g, 46mmol), iron powder (13.5g, 232mmol) and NH ₄Cl (12.4g, 232mmol) at the EtOH aqueous solution [by EtOH (180mL) and H ₂O (180mL) preparation] in suspension be heated to gradually and reflux and refluxed 1.5 hours.Reaction mixture filters by Celite pad, and filtrate is evaporated.This aqueous residue is at AcOEt and 5% NaHCO ₃Between distribute, filter by Celite pad then.Organic layer is separated, use H ₂MgSO is used in O and salt water washing ₄And evaporation, obtain light brown oily matter, it is used i-Pr ₂O (100mL) dilution, and in stirring at room 1 hour.Filter and collect the gained crystal, use i-Pr ₂O washs, and spends the night in 40 ℃ of drying under reduced pressure, obtains this title compound, is clear crystal (10.5g, 63%).

Embodiment 411C

4-(4-tert-butoxycarbonyl amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-methyl benzoate

With N '-(3-cyano group-6-sec.-propyl-pyridine-2-yl)-N, N-dimethyl-carbonamidine (2.00g, 9.3mmol) and 3-amino-4-(4-tert-butoxycarbonyl amino-phenoxy group)-methyl benzoate (3.31g, 9.3mmol) suspension in AcOH (40mL) in 120 ℃ under nitrogen the heating 10 minutes.Reaction mixture is at AcOEt (30mL) and H ₂Distribute between the O (250mL), and under agitation use K ₂CO ₃Alkalize to pH9.Filter and collect the gained solid, wash with cold AcOEt, and spend the night, obtain this title compound, be pale yellow crystals (4.31g, 88%) in 40 ℃ of drying under reduced pressure.

Embodiment 411D

4-(4-tert-butoxycarbonyl amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid

To 4-(4-tert-butoxycarbonyl amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-(4.30g 8.1mmol) drips the LiOH aqueous solution [by LiOH monohydrate (1.08g) and H in room temperature in the suspension in THF (43mL) to methyl benzoate ₂O (11mL) makes].With mixture stirring at room 21 hours.Add the LiOH aqueous solution again [by LiOH monohydrate (0.70g) and H in room temperature ₂O (7mL) preparation].This mixture stirred evaporation then 6 hours in 35 ℃.This aqueous mixture 150mL H ₂The O dilution with the AcOEt washing, and is used activated carbon treatment.Compound is filtered, and filtrate under agitation is acidified to pH4-5 with 1N HCl carefully.Filter and collect the gained solid, use H ₂O washing, and, obtain this title compound in 40 ℃ of drying under reduced pressure 1 day, be pale yellow crystals (4.06g, 97%).

Embodiment 411E

(S)-4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(1-phenyl-ethylamino formyl radical)-phenoxy group]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenylformic acid (in embodiment 411D, making) and S-(-)-α-Jia Jibianji amine, make this title compound: productive rate 75%.

Embodiment 411F

Method according to embodiment 385G; by (S)-{ 4-[2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-4-(1-phenyl-ethylamino formyl radical)-phenoxy group]-phenyl }-t-butyl carbamate (in embodiment 411E, preparing), make this title compound: productive rate 78%.1H-NMR (300MHz, DMSO-d6) δ ppm:1.32 (d, J=7.0Hz, 6H), 1.47 (d, J=7.3Hz, 3H), 3.20 (septet, J=7.0Hz, 1H), 4.99 (s, 2H), 5.17 (quintet, J=7.3Hz, 1H), 6.55 (d, J=8.8Hz, 2H), 6.75 (d, J=8.8Hz, 2H), 6.78 (d, J=8.8Hz, 1H), 7.21 (br-t, J=7.0Hz, 1H), 7.32 (t, J=7.0Hz, 2H), 7.38 (d, J=7.0Hz, 2H), 7.59 (d, J=8.5Hz, 1H), 7.78 (dd, J=8.8,2.2Hz, 1H), 8.07 (d, J=2.2Hz, 1H), 8.59 (s, 1H), 8.74 (d, J=7.3Hz, 1H), 8.82 (d, J=8.5Hz, 1H), 9.96 (s, 1H) MS ESI+m/z:519 (M+H) ESI-m/z:517 (M-H).

Embodiment 412

(R)-4-(4-amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(1-phenyl-ethyl)-benzamide

Embodiment 412A

(R)-4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(1-phenyl-ethylamino formyl radical)-phenoxy group]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenylformic acid (in embodiment 411D, making) and R-(+)-α-Jia Jibianji amine, make this title compound: productive rate 84%.

Embodiment 412B

Method according to embodiment 385G; by (R)-{ 4-[2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-4-(1-phenyl-ethylamino formyl radical)-phenoxy group]-phenyl }-t-butyl carbamate (in embodiment 412A, making), make this title compound: productive rate 71%.1H-NMR (300MHz, DMSO-d6) δ ppm:1.32 (d, J=7.0Hz, 6H), 1.47 (d, J=7.3Hz, 3H), 3.20 (septet, J=7.0Hz, 1H), 5.00 (s, 2H), 5.17 (quintet, J=7.3Hz, 1H), 6.55 (d, J=8.8Hz, 2H), 6.75 (d, J=8.8Hz, 2H), 6.78 (d, J=8.5Hz, 1H), 7.22 (br-t, J=7.0Hz, 1H), 7.32 (t, J=7.0Hz, 2H), 7.38 (d, J=7.0Hz, 2H), 7.59 (d, J=8.5Hz, 1H), 7.78 (dd, J=8.5,2.2Hz, 1H), 8.07 (d, J=2.2Hz, 1H), 8.59 (s, 1H), 8.75 (d, J=7.3Hz, 1H), 8.82 (d, J=8.5Hz, 1H), 9.96 (s, 1H).

Embodiment 413

(S)-4-(4-amino-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(1-phenyl-ethyl)-benzamide

Embodiment 413A

4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-methyl benzoate

With N '-(3-cyano group-6-methyl-pyridine-2-yl)-N, N-dimethyl-carbonamidine (1.00g, 5.3mmol) and 3-amino-4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-methyl benzoate (in embodiment 385C, making) (1.99g, 5.3mmol) suspension in AcOH (20mL) under nitrogen in 120 ℃ the heating 30 minutes.After being cooled to room temperature, with reaction mixture at AcOEt (250mL) and H ₂Distribute between the O (200mL), under agitation use K then ₂CO ₃Alkalize to pH9.Organic layer is separated, use 10% NaHCO ₃, H ₂MgSO is used in O and salt water washing ₄Dry also evaporation obtains light brown oily matter.This oily resistates by silica gel column chromatography purifying (AcOEt), is obtained yellow amorphous thing, with it by using i-Pr ₂O handles and is cured.Filter and collect the gained solid, use i-Pr ₂O washs, and spends the night in 40 ℃ of drying under reduced pressure, obtains this title compound, is pale yellow crystals (1.70g, 62%).

Embodiment 413B

4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid

To 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base amino)-methyl benzoate (1.50g, 2.9mmol) in the suspension in THF (15mL) in room temperature drip the LiOH aqueous solution [by the LiOH monohydrate (0.39g, 9.0mmol) and H ₂O (3.9mL) preparation].With mixture stirring at room 21 hours.Add the LiOH aqueous solution again [by LiOH monohydrate (0.25g) and H in room temperature ₂O (2.5mL) preparation].With mixture stirring at room 24 hours, evaporation then.With aqueous mixture 50mL H ₂The O dilution with the AcOEt washing, and is used activated carbon treatment.Compound is filtered, and filtrate under agitation is acidified to pH4-5 with 1N HCl carefully.With mixture (comprising the oily throw out) ultrasonication 1 hour, and, obtain light yellow solid in stirring at room 1 hour.Filter and collect the gained solid, wash with H2O, and spend the night, obtain this title compound, be pale yellow crystals (1.36g, 93%) in 60 ℃ of drying under reduced pressure.1H-NMR(300MHz，DMSO-d6)δ?ppm：1.48(s，9H)，2.68(s，3H)，6.93(d，J＝8.5Hz，1H)，7.37(d，J＝8.5Hz，2H)，7.55(d，J＝8.5Hz，2H)，7.57(d，J＝8.5Hz，1H)，7.75(br-d，J＝8.5Hz，1H)，7.89(br-s，1H)，8.58(s，1H)，8.80(d，J＝8.5Hz，1H)，9.62(s，1H)，10.15(s，1H)，12.97(br-s，1H)

Embodiment 413C

(S)-4-[2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(1-phenyl-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenylformic acid (in embodiment 413B, making) and S-(-)-α-Jia Jibianji amine, make this title compound: productive rate 88%.

Embodiment 413D

Method according to embodiment 385G; by (S)-{ 4-[2-(7-methyl-pyrido [2; 3-d] pyrimidine-4-base amino)-4-(1-phenyl-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 413C, making), make this title compound: productive rate 84%.1H-NMR (300MHz, DMSO-d6) δ ppm:1.45 (d, J=7.3Hz, 3H), 2.68 (s, 3H), 5.15 (quintet, J=7.3Hz, 1H), 5.58 (s, 2H), 6.62 (d, J=8.5Hz, 2H), 6.84 (d, J=8.5Hz, 1H), 7.12 (d, J=8.5Hz, 2H), 7.16-7.25 (m, 1H), 7.26-7.39 (m, 4H), 7.57 (d, J=8.5Hz, 1H), 7.71 (dd, J=8.5,1.8Hz, 1H), 7.90 (d, J=1.8Hz, 1H), 8.57 (s, 1H), 8.74 (d, J=7.3Hz, 1H), 8.82 (d, J=8.5Hz, 1H), 10.11 (s, 1H) MS ESI+m/z:507 (M+H).

Embodiment 414

(S)-4-(4-amino-phenyl sulfenyl)-3-(the 7-tertiary butyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(1-phenyl-ethyl)-benzamide

Embodiment 414A

4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(the 7-tertiary butyl-pyrido [2,3-d] pyrimidine-4-base is amino)-methyl benzoate

With N '-(the 6-tertiary butyl-3-cyano group-pyridine-2-yl)-N, N-dimethyl-carbonamidine (0.46g, 2.0mmol) and 3-amino-4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-methyl benzoate [in embodiment 385C, making] (0.75g, 2.0mmol) suspension in AcOH (10mL) in 120 ℃ under nitrogen the heating 30 minutes.After being cooled to room temperature, with reaction mixture at AcOEt and H ₂Distribute between the O, under agitation use K then ₂CO ₃Alkalize to pH9.Organic layer is separated, use 10% NaHCO ₃, H ₂MgSO is used in O and salt water washing ₄Dry also evaporation obtains light brown oily matter.This oily resistates is passed through silica gel column chromatography purifying (CH ₂Cl ₂/ MeOH=98/2) separate, obtain this title compound, be pale powder (0.53g, 47%).

Embodiment 414B

4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(the 7-tertiary butyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid

To 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(the 7-tertiary butyl-pyrido [2,3-d] pyrimidine-4-base amino)-methyl benzoate (0.53g, 0.1mmol) in the solution in the mixture of THF (9mL) and MeOH (3mL) in room temperature drip the LiOH aqueous solution [by the LiOH monohydrate (0.21g, 5.0mmol) and H ₂O (3mL) makes].Mixture in 50 ℃ of stirrings, is evaporated then.With this aqueous mixture H ₂The O dilution with the AcOEt washing, is acidified to pH4-5 with 10% HCl in 5 ℃ in stirring then carefully.Filter and collect the gained solid, use H ₂O washs, and spends the night in 60 ℃ of drying under reduced pressure, obtains this title compound, is yellow powder (0.53g, 99%).

Embodiment 414C

(S)-4-[2-(the 7-tertiary butyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(1-phenyl-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(the 7-tertiary butyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenylformic acid (in embodiment 414B, making) and S-(-)-α-Jia Jibianji amine, make this title compound: productive rate 99%.

Embodiment 414D

Method according to embodiment 385G; by (S)-{ 4-[2-(the 7-tertiary butyl-pyrido [2; 3-d] pyrimidine-4-base amino)-4-(1-phenyl-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 414C, making), make this title compound: rate 88%.1H-NMR(300?MHz，DMSO-d6)δ?ppm：1.42(s，9H)1.45(d，J＝7.35Hz，3H)5.09-5.21(m，1H)5.58(s，2H)6.62(d，J＝8.46Hz，2H)6.83(d，J＝8.09Hz，1H)7.11(d，J＝8.46Hz，2H)7.17-7.39(m，5H)7.71(d，J＝8.82Hz，1H)7.82(d，J＝8.46Hz，1H)7.88(s，1H)8.57(s，1H)8.75(d，J＝8.09Hz，1H)8.88(d，J＝8.82Hz，1H)10.13(s，1H)MSESI+m/z：549(M+H)。

Embodiment 415

4-(4-amino-phenyl sulfenyl)-N-benzyl-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 415A

4-[4-benzylamino formyl radical-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenylformic acid (in embodiment 385E, making) and benzyl amine, make this title compound: productive rate 79%.

Embodiment 415B

Method according to embodiment 385G; by { 4-[4-benzylamino formyl radical-2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-the phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 415A, making), make this title compound: productive rate 79%.1H-NMR (300MHz, DMSO-d6) δ ppm:1.34 (d, J=7.0Hz, 6H), 3.22 (septets, J=7.0Hz, 1H), 4.45 (d, J=5.9Hz, 2H), 5.59 (s, 2H), 6.62 (d, J=8.5Hz, 2H), 6.83 (d, J=8.5Hz, 1H), 7.13 (d, J=8.5Hz, 2H), 7.18-7.35 (m, 5H), 7.63 (d, J=8.5Hz, 1H), 7.72 (dd, J=8.5,1.8Hz, 1H), 7.87 (d, J=1.8Hz, 1H), 8.57 (s, 1H), 8.87 (d, J=8.5Hz, 1H), 9.00 (t, J=5.9Hz, 1H), 10.11 (s, 1H) MS ESI+m/z:521 (M+H) ESI-m/z:519 (M-H).

Embodiment 416

4-(4-amino-phenyl sulfenyl)-N-(2-bromo-benzyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 416A

4-[4-(2-bromo-benzylamino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

According to the method for embodiment 385F,, make this title compound with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid (in embodiment 385E, making) and neighbour-bromobenzyl amine.

Embodiment 416B

Method according to embodiment 385G; by { 4-[4-(2-bromo-benzylamino formyl radical)-2-(7-sec.-propyl-pyrido [2 as two-trifluoroacetate; 3-d] pyrimidine-4-base amino)-the phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 416A, making), make this title compound.1H-NMR(500MHz，DMSO-d6)δ?ppm：1.37(d，J＝6.71Hz，6H)3.27-3.38(m，1H)4.50(s，2H)6.64-6.74(m，2H)7.01(d，J＝8.54Hz，1H)7.14-7.20(m，2H)7.21-7.26(m，1H)7.29-7.34(m，1H)7.34-7.41(m，1H)7.63(d，J＝7.93Hz，1H)7.84(dd，J＝8.24，1.83Hz，1H)7.90(d，J＝1.83Hz，1H)7.93(d，J＝8.85Hz，1H)8.86(s，1H)9.01(d，J＝8.54Hz，1H)MS?ESI+m/z：599，601(M+H)。

Embodiment 417

4-(4-amino-phenyl sulfenyl)-N-(4-bromo-benzyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 417A

4-[4-(4-bromo-benzylamino formyl radical)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

According to the method for embodiment 385F,, make this title compound with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid (in embodiment 385E, making) and p-bromobenzyl amine.

Embodiment 417B

Method according to embodiment 385G; by { 4-[4-(4-bromo-benzylamino formyl radical)-2-(7-sec.-propyl-pyrido [2 as two-trifluoroacetate; 3-d] pyrimidine-4-base amino)-the phenyl sulfenyl]-phenyl }-t-butyl carbamate (preparing) at embodiment 417A, make this title compound.1H-NMR(500MHz，DMSO-d6)δ?ppm：1.37(d，J＝6.00Hz，1H)3.28-3.39(m，1H)4.42(s，2H)6.64-6.76(m，2H)6.99(d，J＝8.54Hz，1H)7.14-7.21(m，2H)7.27(d，J＝8.54Hz，2H)7.49-7.56(m，2H)7.80(dd，J＝8.39，1.98Hz，1H)7.87(d，J＝1.83Hz，1H)7.93(d，J＝8.85Hz，1H)8.85(s，1H)9.01(d，J＝8.54Hz，1H)MS?ESI+m/z：599，601(M+H)

Embodiment 418

4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(2-methyl-benzyl)-benzamide

Embodiment 418A

4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(2-methyl-benzylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenylformic acid (in embodiment 385E, making) and neighbour-methyl-benzyl amine, make this title compound.

Embodiment 418B

Method according to embodiment 385G; by { 4-[2-(7-sec.-propyl-pyrido [2 as two-trifluoroacetate; 3-d] pyrimidine-4-base amino)-4-(2-methyl-benzylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 418A, making), make this title compound.1H-NMR (500MHz, DMSO-d6) δ ppm:1.37 (d, J=7.0Hz, 6H), 2.31 (s, 3H), 3.32 (septet, J=7.0Hz, 1H), 4.44 (s, 2H), 6.68 (d, J=8.5Hz, 2H), 6.99 (d, J=8.5Hz, 1H), and 7.11-7.24 (m, 4H), 7.17 (d, J=8.5Hz, 2H), 7.82 (dd, J=8.5,1.8Hz, 1H), 7.89 (d, J=1.8Hz, 1H), 7.93 (d, J=8.8Hz, 1H), 8.85 (s, 1H), 9.01 (d, J=8.8Hz, 1H) MSESI+m/z:535 (M+H) ESI-m/z:533 (M-H).

Embodiment 419

4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(3-methyl-benzyl)-benzamide

Embodiment 419A

4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(3-methyl-benzylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid (in embodiment 385E, making) and-methyl-benzyl amine, make this title compound.

Embodiment 419B

Method according to embodiment 385G; by { 4-[2-(7-sec.-propyl-pyrido [2 as two-trifluoroacetate; 3-d] pyrimidine-4-base amino)-4-(3-methyl-benzylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 419A, making), make this title compound.1H-NMR (500MHz, DMSO-d6) δ ppm:1.37 (d, J=7.0Hz, 6H), 2.28 (s, 3H), 3.32 (septet, J=7.0Hz, 1H), 4.42 (s, 2H), 6.68 (d, J=8.5Hz, 2H), 6.99 (d, J=8.5Hz, 1H), and 7.04-7.13 (m, 3H), 7.17 (d, J=8.5Hz, 2H), 7.21 (t, J=7.5Hz, 1H), 7.81 (dd, J=8.5,1.8Hz, 1H), 7.88 (d, J=1.8Hz, 1H), 7.93 (d, J=8.5Hz, 1H), 8.85 (s, 1H), 9.01 (d, J=8.5Hz, 1H) MS ESI+m/z:535 (M+H) ESI-m/z:533 (M-H).

Embodiment 420

4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(4-methyl-benzyl)-benzamide

Embodiment 420A

4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-methyl-benzylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenylformic acid (in embodiment 385E, making) and right-methyl-benzyl amine, make this title compound.

Embodiment 420B

Method according to embodiment 385G; by { 4-[2-(7-sec.-propyl-pyrido [2 as two-trifluoroacetate; 3-d] pyrimidine-4-base amino)-4-(4-methyl-benzylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 420A, making), make this title compound.1H-NMR (500MHz, DMSO-d6) δ ppm:1.37 (d, J=7.0Hz, 6H), 2.27 (s, 3H), 3.32 (septet, J=7.0Hz, 1H), 4.41 (s, 2H), 6.68 (d, J=8.5Hz, 2H), 6.99 (d, J=8.5Hz, 1H), 7.13 (d, J=8.0Hz, 2H), 7.17 (d, J=8.5Hz, 2H), 7.19 (d, J=8.0Hz, 2H), 7.80 (dd, J=8.5,2.0Hz, 1H), 7.87 (d, J=2.0Hz, 1H), 7.93 (d, J=8.5Hz, 1H), 8.85 (s, 1H), 9.01 (d, J=8.5Hz, 1H) MS ESI+m/z:535 (M+H) ESI-m/z:533 (M-H).

Embodiment 421

4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(3-trifluoromethyl-benzyl)-benzamide

Embodiment 421A

4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(3-trifluoromethyl-benzylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenylformic acid (in embodiment 385E, making) and (m-trifluoromethyl) benzyl amine, make this title compound: productive rate 64%.

Embodiment 421B

Method according to embodiment 385G; by { 4-[2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-4-(3-trifluoromethyl-benzylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 421A, making), make this title compound: productive rate 80%.1H-NMR (300MHz, DMSO-d6) δ ppm:1.34 (d, J=7.0Hz, 6H), 3.22 (septet, J=7.0Hz, 1H), 4.54 (d, J=5.9Hz, 2H), 5.59 (s, 2H), 6.63 (d, J=8.8Hz, 2H), 6.84 (d, J=8.4Hz, 1H), 7.13 (d, J=8.8Hz, 2H), and 7.52-7.67 (m, 5H), 7.72 (dd, J=8.4,1.5Hz, 1H), 7.86 (d, J=1.5Hz, 1H), 8.57 (s, 1H), 8.87 (d, J=8.9Hz, 1H), 9.09 (t, J=5.9Hz, 1H), 10.12 (s, 1H) MS ESI+m/z:589 (M+H) ESI-m/z:587 (M-H)

Embodiment 422

4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(4-trifluoromethyl-benzyl)-benzamide

Embodiment 422A

4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-trifluoromethyl-benzylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenylformic acid (in embodiment 385E, making) and (p-trifluoromethyl) benzyl amine, make this title compound.

Embodiment 422B

Method according to embodiment 385G; by { 4-[2-(7-sec.-propyl-pyrido [2 as two-trifluoroacetate; 3-d] pyrimidine-4-base amino)-4-(4-trifluoromethyl-benzylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 422A, making), make this title compound.1H-NMR(500MHz，DMSO-d6)δ?ppm：1.37(d，J＝7.02Hz，6H)3.25-3.39(m，1H)4.54(s，2H)6.60-6.77(m，2H)7.01(d，J＝8.24Hz，1H)7.14-7.22(m，2H)7.52(d，J＝7.93Hz，2H)7.69(d，J＝7.93Hz，2H)7.82(dd，J＝8.54，1.83Hz，1H)7.88(d，J＝2.14Hz，1H)7.94(d，J＝8.54Hz，1H)8.82-8.89(m，1H)9.01(d，J＝8.54Hz，1H)MS?ESI+m/z：589(M+H)。

Embodiment 423

4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-thiophene-2-ylmethyl-benzamide

Embodiment 423A

(4-{2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-[(thiophene-2-ylmethyl)-formamyl]-the phenyl sulfenyl }-phenyl)-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenylformic acid (in embodiment 385E, making) and 2-thienyl methyl amine, make this title compound.

Embodiment 423B

Method according to embodiment 385G; by (4-{2-(7-sec.-propyl-pyrido [2 as two-trifluoroacetate; 3-d] pyrimidine-4-base amino)-4-[(thiophene-2-ylmethyl)-formamyl]-the phenyl sulfenyl }-phenyl)-t-butyl carbamate (in embodiment 423A, making), make this title compound.1H-NMR(500MHz，DMSO-d6)δ?ppm：1.37(d，J＝6.71Hz，6H)3.27-3.39(m，1H)4.50(s，2H)6.61-6.75(m，2H)7.01(d，J＝8.54Hz，1H)7.14-7.21(m，2H)7.21-7.27(m，1H)7.29-7.33(m，1H)7.37(t，J＝7.48Hz，1H)7.63(d，J＝7.93Hz，1H)7.84(dd，J＝8.24，1.83Hz，1H)7.90(d，J＝1.83Hz，1H)7.93(d，J＝8.85Hz，1H)8.86(s，1H)9.01(d，J＝8.54Hz，1H)MS?ESI+m/z：527(M+H)。

Embodiment 424

4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(tolyl-ethyl between 2-)-benzamide

Embodiment 424A

4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(tolyl between 2--ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenylformic acid (in embodiment 385E, making) and 2-(tolyl) ethylamine, make this title compound.

Embodiment 424B

Method according to embodiment 385G; by { 4-[2-(7-sec.-propyl-pyrido [2 as two-trifluoroacetate; 3-d] pyrimidine-4-base amino)-4-(tolyl between 2--ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 424A, making), make this title compound.1H-NMR(500MHz，DMSO-d6)δ?ppm：1.36(t，J＝7.32Hz，6H)2.26(s，3H)2.76-2.84(m，2H)3.28-3.38(m，1H)3.42-3.52(m，2H)6.62-6.76(m，2H)6.96(d，J＝8.24Hz，1H)7.00-7.08(m，3H)7.11-7.24(m，3H)7.72(dd，J＝8.54，1.83Hz，1H)7.81(d，J＝1.83Hz，1H)7.93(d，J＝8.54Hz，1H)8.85(s，1H)9.01(d，J＝8.54Hz，1H)MS?ESI+m/z：549(M+H)。

Embodiment 425

4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(2-p-methylphenyl-ethyl)-benzamide

Embodiment 425A

4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(2-p-methylphenyl-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenylformic acid (in embodiment 385E, making) and 2-(p-methylphenyl) ethylamine, make this title compound.

Embodiment 425B

Method according to embodiment 385G; by { 4-[2-(7-sec.-propyl-pyrido [2 as two-trifluoroacetate; 3-d] pyrimidine-4-base amino)-4-(2-p-methylphenyl-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 425A, making), make this title compound.1H-NMR(500MHz，DMSO-d6)δ?ppm：1.37(d，J＝6.71Hz，6H)2.25(s，3H)2.74-2.83(m，2H)3.28-3.37(m，1H)3.45(t，J＝7.48Hz，2H)6.61-6.71(m，2H)6.96(d，J＝8.54Hz，1H)7.06-7.14(m，4H)7.14-7.21(m，2H)7.71(dd，J＝8.39，1.98Hz，1H)7.81(d，J＝1.83Hz，1H)7.93(d，J＝8.54Hz，1H)8.86(s，1H)9.01(d，J＝8.54Hz，1H)MSESI+m/z：549(M+H)。

Embodiment 426

4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(1-methyl isophthalic acid-phenyl-ethyl)-benzamide

Embodiment 426A

4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(1-methyl isophthalic acid-phenyl-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenylformic acid (in embodiment 385E, making) and cumyl amine, make this title compound productive rate 81%.

Embodiment 426B

Method according to embodiment 385G; by { 4-[2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-4-(1-methyl isophthalic acid-phenyl-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 426A, making), make this title compound: productive rate 26%.1H-NMR (300MHz, DMSO-d6) δ ppm:1.34 (d, J=7.0Hz, 6H), 1.64 (s, 6H), 3.22 (septet, J=7.0Hz, 1H), 5.57 (s, 2H), 6.62 (d, J=8.8Hz, 2H), 6.83 (d, J=8.1Hz, 1H), 7.12 (d, J=8.8Hz, 2H), 7.15 (t, J=7.3Hz, 1H), 7.26 (t, J=7.3Hz, 2H), 7.35 (d, J=7.3Hz, 2H), 7.63 (d, J=8.5Hz, 1H), 7.67 (dd, J=8.1,0.7Hz, 1H), 7.84 (d, J=0.7Hz, 1H), 8.36 (s, 1H), 8.58 (s, 1H), 8.87 (d, J=8.5Hz, 1H), 10.12 (s, 1H) MS ESI+m/z:549 (M+H) ESI-m/z:547 (M-H)

Embodiment 427

(RS)-4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(1-phenyl-ethyl)-benzamide

Embodiment 427A

(Rs)-4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(1-phenyl-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid (in embodiment 385E, making) and (RS)-α-Jia Jibianji amine, make this title compound: productive rate 78%.

Embodiment 427B

Method according to embodiment 385G; by (RS)-{ 4-[2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-4-(1-phenyl-ethylamino formyl radical)-phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 427A, making), make this title compound: productive rate 70%.1H-NMR (300MHz, DMSO-d6) δ ppm:1.34 (d, J=7.0Hz, 6H), 1.45 (d, J=7.4Hz, 3H), 3.23 (septets, J=7.0Hz, 1H), 5.15 (quintet, J=7.4Hz, 1H), 5.58 (s, 2H), 6.62 (d, J=8.4Hz, 2H), 6.84 (d, J=8.5Hz, 1H), 7.12 (d, J=8.4Hz, 2H), 7.16-7.25 (m, 1H), 7.25-7.40 (m, 4H), 7.63 (d, J=8.4Hz, 1H), 7.71 (dd, J=8.5,1.8Hz, 1H), 7.88 (d, J=1.8Hz, 1H), 8.57 (s, 1H), 8.75 (d, J=7.3Hz, 1H), 8.87 (d, J=8.5 Hz, 1H), 10.12 (s, 1H) MS ESI+m/z:535 (M+H) ESI-m/z:533 (M-H)

Embodiment 428

(RS)-4-(4-amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-N-(1-phenyl-propyl group)-benzamide

Embodiment 428A

(RS)-4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(1-phenyl-propyl group formamyl)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid (in embodiment 385E, making) and (RS)-1-phenyl propyl amine, make this title compound: productive rate 90%.

Embodiment 428B

Method according to embodiment 385G; by (RS)-{ 4-[2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-4-(1-phenyl-propyl group formamyl)-phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 428A, making), make this title compound: productive rate 88%.1H-NMR (300MHz, DMSO-d6) δ ppm:0.88 (d, J=7.3Hz, 3H), 1.34 (d, J=7.0Hz, 6H), 1.68-1.91 (m, 2H), 3.22 (septets, J=7.0Hz, 1H), 4.89 (dt, J=8.1,7.3Hz, 1H), 5.57 (s, 2H), 6.62 (d, J=8.5Hz, 2H), 6.83 (br-d, J=8.5Hz, 1H), 7.12 (d, J=8.5Hz, 2H), 7.21 (t, J=7.0Hz, 1H), 7.30 (t, J=7.0Hz, 2H), 7.36 (d, J=7.0Hz, 2H), 7.63 (br-d, J=8.5Hz, 1H), 7.70 (br-d, J=8.5Hz, 1H), 7.86 (br-s, 1H), 8.56 (br-s, 1H), 8.67 (br-d, J=8.1Hz, 1H), 8.86 (br-d, J=8.5Hz, 1H), 10.13 (br-s, 1H) MS ESI+m/z:549 (M+H) ESI-m/z:547 (M-H).

Embodiment 429

(RS)-4-(4-amino-phenyl sulfenyl)-N-[1-(2-fluoro-phenyl)-ethyl]-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzamide

Embodiment 429A

(RS)-4-[4-[1-(2-fluoro-phenyl)-ethylamino formyl radical]-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

Method according to embodiment 385F, with 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenylformic acid (in embodiment 385E, making) and (RS)-1-(2-fluorophenyl) ethylamine, make this title compound: productive rate 84%.

Embodiment 429B

Method according to embodiment 385G; by (RS)-4-[4-[1-(2-fluoro-phenyl)-ethylamino formyl radical]-2-(7-sec.-propyl-pyrido [2; 3-d] pyrimidine-4-base amino)-the phenyl sulfenyl]-phenyl }-t-butyl carbamate (in embodiment 429A, making), make this title compound: productive rate 88%.1H-NMR(300MHz，DMSO-d6)δ?ppm：1.34(d，J＝6.99Hz，6H)1.44(d，J=7.35Hz，3H)3.11-3.28(m，1H)5.37(t，J＝7.17Hz，1H)5.58(s，2H)6.62(d，J＝8.82Hz，2H)6.84(d，J＝8.46Hz，1H)7.09-7.19(m，4H)7.23-7.33(m，1H)7.36-7.46(m，1H)7.63(d，J＝8.46Hz，1H)7.71(dd，J＝8.46，1.47Hz，1H)7.89(d，J＝1.47Hz，1H)8.57(s，1H)8.81(d，J＝7.72Hz，1H)8.86(d，J＝8.82Hz，1H)10.13(s，1H)MSESI+m/z：553(M+H)

Embodiment 430

(S)-5-(4-aminophenyl sulfenyl)-4-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino)-N-(2-phenyl propyl) thiophene-2-carboxamide derivatives

Embodiment 430A

5-chloro-4-nitrothiophene-2-ethyl formate

To in ice bath, being cooled in 5 ° the nitrosonitric acid (50mL) so that temperature of reaction the speed below 10 ° of remaining on drip pure 5-chloro-2-thiophene-2-carboxylic acid ethyl ester (10g, 0.0524mol).To react on 5-10 ° and stir 30 minutes, and add ice (200g) then, and (2 * 100mL) extract with ethyl acetate.The organic extract liquid water that merges (2 * 100mL) and salt solution (50mL) washing, then with dried over mgso and filtration.Filtrate is concentrated by rotation, and resistates is passed through the fast silica gel chromatogram purifying,, obtained this title compound, be crystalline light yellow solid (7.6g, 0.0322mol, 62%) with 10:90 ethyl acetate/hexane wash-out. ¹H?NMR(300MHz，DMSO-D6)δ?ppm?1.31(t，J＝7.17Hz，3H)4.35(q，J＝7.23Hz，2H)8.17(s，1H)。

Embodiment 430B

5-(4-aminophenyl sulfenyl)-4-nitrothiophene-2-ethyl formate

With the product of embodiment 430A (1.0g, 4.244mmol), the 4-aminothiophenol (0.797g, 6.366mmol) and anhydrous sodium acetate (1.74g, 21.22mmol) heating 30 minutes under refluxing under the nitrogen in dehydrated alcohol (40mL).Reaction is cooled to room temperature, distributes, layer is separated with ethyl acetate (100mL) and water (50mL), and with the organic phase water (2 * 50mL) and salt solution (50mL) wash.With the organic extract liquid dried over sodium sulfate, filter, and concentrate by rotary evaporation.(2 * 30mL) developments have obtained this title compound, are aureus solid (1.167g, 3.598mmol, 85%) with ether with the gained solid.1H?NMR(300MHz，DMSO-D6)δ?ppm?1.24(t，J＝7.17Hz，3H)4.24(q，J＝7.23Hz，2H)5.94(s，2H)6.71(d，J＝8.82Hz，2H)7.35(d，J＝8.46Hz，2H)8.08(s，1H)；MS(ESI+)m/z?325(M+H) ⁺，MS(ESI-)m/z?323(M-H) ^-。

Embodiment 430C

5-(4-(((9H-fluorenes-9-yl) methoxyl group) carbonylamino) phenyl sulfenyl)-4-nitrothiophene-2-ethyl formate

Product (0.500g with embodiment 430B, 1.541mmol) and 9-fluorenyl methoxy carbonyl chlorine (0.478g, 1.849mmol) suspension in methylene dichloride (10mL) under nitrogen atmosphere with pyridine (0.25mL 3.083mmol) handles, and with gained solution in stirring at room 18 hours.This reaction is diluted with methylene dichloride (50mL), and washs with the 1N HCl aqueous solution (50mL), water (50mL) washing then.With the organism dried over mgso, filter, and concentrate by rotary evaporation.By flash chromatography on silica gel method purifying, use the methylene dichloride wash-out, obtained this title compound, be aureus solid (0.842g, quantitative). ¹H?NMR(300MHz，DMSO-D6)δ?ppm1.23(t，J＝7.17Hz，3H)4.24(q，J＝7.23Hz，2H)4.35(t，J＝6.43Hz，1H)4.57(d，J＝6.25Hz，2H)7.29-7.50(m，4H)7.69(s，4H)7.77(d，J＝7.35Hz，2H)7.92(d，J＝7.35Hz，2H)8.11(s，1H)10.15(s，1H)；MS(ESI+)m/z?564(M+NH ₄) ⁺，569(M+Na) ⁺。

Embodiment 430D

5-(4-(((9H-fluorenes-9-yl) methoxyl group) carbonylamino) phenyl sulfenyl)-4-aminothiophene-2-ethyl formate

Product (0.918g with embodiment 430C, 1.679mmol) solution in ethanol (14mL) and tetrahydrofuran (THF) (14mL) is with iron powder (0.577g, 10.33mmol) and ammonium chloride (0.588g, the 10.99mmol) solution-treated in water (7mL) refluxed 1 hour then.To react cooling, with ethyl acetate (100mL) dilution, water (3 * 25mL) and salt solution (25mL) wash.With the organic extract liquid dried over sodium sulfate, filter, and concentrate by rotary evaporation, obtained this title compound, be yellow solid (0.698g, 1.351mmol, 80%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm?1.27(t，J＝6.99Hz，3H)4.19-4.36(m，3H)4.48(d，J＝6.62Hz，2H)5.56(s，2H)7.10(d，J＝8.09Hz，2H)7.28-7.55(m，7H)7.74(d，J＝7.35Hz，2H)7.90(d，J＝7.35Hz，2H)9.73(s，1H)；MS(ESI+)m/z?517(M+H) ⁺，539(M+Na) ⁺。

Embodiment 430E

5-(4-(((9H-fluorenes-9-yl) methoxyl group) carbonylamino) phenyl sulfenyl)-4-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) thiophene-2-carboxylic acid ethyl ester

With the product of embodiment 8E (0.105g, 0.484mmol) and the product of embodiment 430D (0.250g, product 0.484mmol) in acetate (5mL) in reaction 30 minutes in pre-warmed 140 ° of oil baths under the nitrogen atmosphere.To react cooling, and remove by rotary evaporation and to desolvate.Resistates and dichloromethane/hexane (1:1v/v) are concentrated four times jointly, and the gained solid is dry under high vacuum.By flash chromatography on silica gel method purifying,, obtained this title compound (0.247g, 0.359mmol, 74%) with 3:97 ethanol/methylene wash-out. ¹H?NMR(300MHz，DMSO-D6)δ?ppm?1.27(t，J＝6.99Hz，3H)1.32(d，J＝6.99Hz，6H)3.13-3.26(m，1H)4.18-4.38(m，3H)4.50(d，J＝6.25Hz，2H)7.29-7.50(m，8H)7.62(d，J＝8.82Hz，1H)7.74(d，J＝7.35Hz，2H)7.90(d，J＝7.72Hz，2H)7.92(d，J＝2.21Hz，1H)8.65(s，1H)8.79(d，J＝8.46Hz，1H)9.85(s，1H)10.07(s，1H)；MS(ESI+)m/z?688(M+H) ⁺。

Embodiment 430F

5-(4-aminophenyl sulfenyl)-4-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) thiophene-2-carboxylic acid

Product (0.245g with embodiment 430E, 0.356mmol) 1, (0.0747g, 1.78mmol) solution in water (1.5mL) heats the gained mixture 25 minutes at 60 ° in room temperature treatment with lithium hydroxide monohydrate in the 4-dioxane (3mL).With the reaction mixture cooling, water (10mL) dilution is regulated pH to 3 with the 1N HCl aqueous solution.With a small amount of 1, the washing of 4-dioxane has obtained this title compound (0.113g, 0.258mmol, 72%) with crude product.MS(ESI+)m/z?438(M+H) ⁺，MS(ESI-)m/z?436(M-H)。

Embodiment 430G

Product (62mg with embodiment 430F, 0.142mmol) in methyl-sulphoxide (2mL) under nitrogen atmosphere in room temperature with (S)-(-)-Beta-methyl phenylethylamine (23mg, 0.170mmol), N, N-diisopropylethylamine (0.123mL, 0.708mmol) and O-benzotriazole-1-base-N, N, N ', (55mg 0.170mmol) handled 20 hours N '-tetramethyl-urea a tetrafluoro borate.Reaction mixture water (10mL) is diluted, and extract with ethyl acetate (50mL).With organic extract liquid water successively (3 * 10mL), the washing of saturated sodium bicarbonate aqueous solution (20mL) and salt solution (20mL), use dried over mgso, filter, and concentrated by rotary evaporation.By fast silica gel chromatogram purifying resistates,, obtained this title compound (67mg, 0.121mmol, 85%) with 4:96 ethanol/methylene wash-out. ¹H?NMR(300MHz，DMSO-D6)δ?ppm?1.19(d，J＝6.99Hz，3H)1.33(d，J＝6.99Hz，6H)2.91-3.07(m，1H)3.14-3.29(m，1H)5.50(s，2H)6.51(d，J＝8.46Hz，2H)7.12(d，J＝8.82Hz，2H)7.16-7.34(m，5H)7.63(d，J＝8.46Hz，1H)7.77(s，1H)8.50(t，J＝5.88Hz，1H)8.62(s，1H)8.82(d，J＝8.82Hz，1H)9.97(s，1H)；MS(ESI+)m/z?555(M+H) ⁺，1109(2M+H) ⁺，MS(ESI-)m/z?553(M-H) ^-。

Embodiment 431

(S)-4-(4-aminophenyl sulfenyl)-3-(7-sec.-propyl quinazoline-4-base is amino)-N-(1-phenylethyl) benzamide

Embodiment 431A

1-bromo-4-sec.-propyl-2-oil of mirbane

In being cooled to 5 ° nitrosonitric acid (5mL) so that temperature of reaction the speed below 10 ° of remaining on drip pure 4-bromine isopropyl benzene (1.0g, 5.023mmol).To react on 5-10 ° and stir 2 hours, end with ice (50g), with ethyl acetate (50mL) extraction, and with the organic extract liquid water (2 * 25mL) and salt solution (25mL) wash, use dried over mgso then.Filter and concentrate by rotary evaporation.Resistates by the fast silica gel chromatogram purifying, with 5:95 ethyl acetate/hexane wash-out, has been obtained this title compound, be light yellow solid (1.03g, 4.22mmol, 84%). ¹H NMR (300MHz, the δ ppm 1.27 of chloroform-D) (d, J=6.99Hz, 6H) 2.75-3.23 (m, 1H) 7.29 (dd, J=8.82,2.21Hz, 1H) 7.63 (d, J=8.09Hz, 1H) 7.69 (d, J=2.21Hz, 1H); MS (DCI) m/z 261/263 (M+NH ₄) ⁺

Embodiment 431B

4-sec.-propyl-2-nitrobenzonitrile

With the product of embodiment 431A (0.581g, 2.380mmol) and cupric cyanide (I) (0.426g, 4.760mmol) at N, heating 1.5 hours in 160 ° of oil baths under nitrogen in the dinethylformamide (5mL).With the reaction mixture cooling, handle with the molten and concentrated hydrochloric acid (0.62mL) of iron(ic) chloride (III) hexahydrate (2.48g) in water (3.72mL), then in 65 ° of heating 20 minutes.(2 * 50mL) extract with ether with cold reaction mixture.The ether extraction liquid that merges is used the 1NHCl aqueous solution (25mL), 3N aqueous sodium hydroxide solution (25mL), water (25mL) and salt solution (25mL) washing successively, use dried over mgso then, filter, and concentrate by rotary evaporation.Resistates by the fast silica gel chromatogram purifying, with 20:80 ethyl acetate/hexane wash-out, has been obtained this title compound, be yellow liquid (0.351g, 1.845mmol, 58%). ¹H NMR (300MHz, the δ ppm 1.33 of chloroform-D) (d, J=6.99Hz, 6H) 2.82-3.47 (m, 1H) 7.66 (dd, J=7.91,1.29Hz, 1H) 7.83 (d, J=7.72Hz, 1H) 8.18 (d, J=1.47Hz, 1H); MS (DCI) m/z 208 (M+NH ₄) ⁺

Embodiment 431C

4-sec.-propyl-2-nitrobenzoic acid

(1.746g, 9.1798mmol) reflux is 3 days will to be dissolved in the product of the embodiment 431B in the 2:1:1v/v/v mixture of water/acetate/vitriol oil (24mL).To react cooling, arrive on frozen water (80mL), and be adjusted to pH12 with the 6N aqueous sodium hydroxide solution.To react with ether (3 * 50mL) washings.Water is acidified to pH2 with concentrated hydrochloric acid, and (2 * 75mL) extract with ether.With the ether extraction liquid dried over mgso, filter, and concentrate by rotary evaporation.Resistates and methylene dichloride (5mL)/hexane (100mL) are concentrated three times jointly, and dry under high vacuum, obtained this title compound, be pale solid (1.402g, 6.702mmol, 73%). ¹H?NM[R(300MHz，DMSO-D6)δ?ppm?1.23(d，J＝6.62Hz，6H)2.88-3.23(m，1H)7.66(dd，J＝8.09，1.84Hz，1H)7.80(d，J＝7.72Hz，1H)7.83(d，J＝1.47Hz，1H)13.70(br?s，1H)。

Embodiment 431D

2-amino-4-isopropyl acid

With the product of embodiment 431C (0.697g, 3.332mmol) in methyl alcohol (30mL) with 10% palladium on carbon (70mg) (air bag) hydrogenation 2 hours under 1 hydrogen pressure.To react by 0.45 micron PTFE membrane filtration, and catalyzer will thoroughly be washed with methyl alcohol.Filtrate is concentrated by rotary evaporation, obtain this title compound (0.585g, 3.264mmol, 98%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm?1.15(d，J＝6.62Hz，6H)2.61-2.92(m，1H)6.41(dd，J＝8.46，1.47Hz，1H)6.58(d，J＝1.84Hz，1H)7.60(d，J＝8.46Hz，1H)8.46(br?s，2H)；MS(ESI+)m/z?180(M+H) ⁺。

Embodiment 431E

7-sec.-propyl quinazoline-4 (3H)-ketone

With the product of embodiment 431D (0.579g, 3.231mmol) with methane amide (1.3mL) under nitrogen atmosphere microwave (Personal Chemistry Emrys Creator, 300W) in 150 ℃ of reactions 30 minutes.This cold reaction produces solid, with its recrystallize from straight alcohol (2mL), has obtained this title compound, is pale solid (0.208g, 1.105mmol, 34%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm1.26(d，J＝6.99Hz，6H)2.91-3.21(m，1H)7.44(dd，J＝8.27，1.65Hz，1H)7.50(d，J＝1.84Hz，1H)8.02-8.07(m，2H)12.15(s，1H)；MS(APCI)m/z?189(M+H) ⁺，211(M+Na) ⁺。

Embodiment 431F

4-chloro-7-sec.-propyl quinazoline

With the product of embodiment 431E (100mg, 0.5313mmol) heating 1 hour under refluxing under the nitrogen atmosphere in phosphoryl chloride (2mL).To react cooling, and concentrate by rotary evaporation.Resistates is dissolved in the ethyl acetate (50mL), and use successively saturated sodium bicarbonate aqueous solution (2 * 25mL), the washing of water (25mL) and salt solution (25mL).With the organic extract liquid dried over sodium sulfate, filter, and concentrate by rotary evaporation, obtained this title compound, be yellow oil (107mg, 0.5177mmol, 97%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm1.33(d，J＝6.99Hz，6H)3.14-3.29(m，1H)7.86(dd，J＝8.64，1.65Hz，1H)7.93(s，1H)8.22(d，J＝8.46Hz，1H)9.07(s，1H)。

Embodiment 431G

(S)-4-(2-(7-sec.-propyl quinazoline-4-base is amino)-4-(1-phenylethyl formamyl) phenyl sulfenyl) the phenylcarbamic acid tert-butyl ester

With (S)-4-(2-amino-4-(1-phenylethyl formamyl) phenyl sulfenyl)-phenylcarbamic acid tert-butyl ester (50mg; 0.1078mmol) and the product of embodiment 431F (24.5mg, 0.1186mmol) heating 1 hour under nitrogen atmosphere in dehydrated alcohol (2mL) under refluxing.To react cooling, and concentrate by rotary evaporation.Resistates by the fast silica gel chromatogram purifying, with 3:97 ethanol/methylene wash-out, has been obtained this title compound, be pale solid (51mg, 0.0805mmol, 68%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm1.31(d，J＝6.99Hz，6H)1.45(d，J＝7.35Hz，3H)1.47(s，9H)3.03-3.21(m，1H)5.01-5.29(m，1H)6.96(d，J＝8.46Hz，1H)7.16-7.25(m，1H)7.26-7.43(m，3H)7.32(d，J＝8.09Hz，2H)7.51(d，J＝8.82Hz，2H)7.55-7.63(m，2H)7.72(dd，J＝8.46，1.47Hz，1H)7.94(d，J＝1.47Hz，1H)8.41(d，J＝8.82Hz，1H)8.44(s，1H)8.80(d，J＝8.09Hz，1H)9.58(s，1H)9.95(s，1H)；MS(ESI+)m/z?634(M+H) ⁺；MS(ESI-)m/z?632(M-H) ^-。

Embodiment 431H

With the product of embodiment 431d (36mg, 0.0568mmol) with 1:1v/v methylene dichloride/trifluoroacetic acid (3mL) in room temperature treatment 1 hour, concentrate by rotary evaporation then.Resistates is dissolved in the ethyl acetate (50mL),, uses dried over mgso then, filter, and concentrate by rotary evaporation with saturated sodium bicarbonate aqueous solution (25mL), water (25mL) and salt solution (25mL) washing.By flash chromatography on silica gel method purifying, with 3:97 ethanol/methylene wash-out, obtained this title compound, be white solid (22mg, 0.0412mmol, 73%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm1.31(d，J＝6.99Hz，6H)1.45(d，J＝7.35Hz，3H)3.01-3.20(m，1H)5.07-5.26(m，1H)5.57(s，2H)6.61(d，J＝8.46Hz，2H)6.83(d，J＝8.46Hz，1H)7.11(d，J＝8.82Hz，2H)7.17-7.43(m，5H)7.54-7.64(m，2H)7.69(dd，J＝8.46，1.10Hz，1H)7.89(d，J＝1.47Hz，1H)8.43(t，J＝4.23Hz，2H)8.74(d，J＝7.72Hz，1H)9.88(s，1H)；MS(ESI+)m/z?534(M+H) ⁺，1067(2M+H) ⁺；MS(ESI-)m/z?532(M-H) ^-。

Embodiment 432

(R)-4-(4-aminophenyl sulfenyl)-N-(2,3-dihydro-1H-indenes-1-yl)-3-(7-sec.-propyl quinazoline-4-base is amino) benzamide

Embodiment 432A

4-(4-aminophenyl sulfenyl)-3-nitrobenzoic acid methyl esters

With 4-chloro-3-nitrobenzoic acid methyl esters (1.00g, 4.638mmol) solution in dehydrated alcohol (40mL) is with 4-aminothiophenol (0.813g, 6.494mmol) and anhydrous sodium acetate (1.90g 23.19mmol) handles under nitrogen atmosphere in room temperature, refluxes then 2 hours.With reaction mixture cooling, with ethyl acetate (100mL) dilution, and water (3 * 50mL) and salt solution (50mL) wash.With the organic phase dried over mgso, filter, and concentrate by rotary evaporation.(1:1v/v, 3 * 30mL) develop, and dry in a vacuum, have obtained this title compound (1.36g, 4.469mmol, 96%) with ether/hexane with the gained orange solids. ¹H?NMR(300MHz，DMSO-D6)δ?ppm?3.87(s，3H)5.80(s，2H)6.70(d，J＝8.46Hz，2H)7.00(d，J＝8.46Hz，1H)7.23(d，J＝8.46Hz，2H)8.05(dd，J＝8.46，1.84Hz，1H)8.64(d，J＝1.84Hz，1H)。MS(ESI+)m/z?305(M+H) ⁺。

Embodiment 432B

4-(4-tert-butoxycarbonyl amino) phenyl sulfenyl)-3-nitrobenzoic acid methyl esters

Product (1.36g with 432A, 4.469mmol) 1, (1.46g is 6.703mmol) 1 with tert-Butyl dicarbonate in room temperature under nitrogen atmosphere in the 4-dioxane (25mL), solution-treated in the 4-dioxane (5mL) refluxed 3.5 hours then.With the reaction mixture cooling, add tert-Butyl dicarbonate (1.46g) again, and refluxed again 3.5 hours.To react cooling again, and handle with tert-Butyl dicarbonate (1.46g), and refluxed 16 hours.Reaction is cooled to room temperature, and concentrates by rotary evaporation, dry then.Resistates is developed with ethyl acetate (30mL), and vacuum filtration, obtain this title compound, be yellow solid (1.56g, (3.857mmol, 86%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm?1.50(s，9H)3.87(s，3H)6.95(d，J＝8.46Hz，1H)7.47-7.57(d，J＝8.82Hz，2H)7.67(d，J＝8.82Hz，2H)8.05(dd，J＝8.64，2.02Hz，1H)8.66(d，J＝1.84Hz，1H)9.77(s，1H)。MS(ESI+)m/z?422(M+NH ₄) ⁺，427(M+Na) ⁺。

Embodiment 432C

3-amino-4-(4-tert-butoxycarbonyl amino) phenyl sulfenyl) methyl benzoate

Product (1.56g with embodiment 432B, 3.857mmol) usefulness iron powder (1.32g in ethanol (20mL) and tetrahydrofuran (THF) (20mL), 23.72mmol) and ammonium chloride (1.351g, the 25.26mmol) solution-treated in water (10mL), then in 80 ° the heating hour.With reaction mixture cooling, with ethyl acetate (150mL) dilution, and water (3 * 50mL) and salt solution (50mL) wash.With the organic extract liquid dried over mgso, filter, and concentrate by rotary evaporation.By flash chromatography on silica gel method purifying, with 3:97 ethanol/methylene wash-out, obtained this title compound, be yellow solid (0.920g, 2.46mmol, 64%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm?1.46(s，9H)3.80(s，3H)5.53(s，2H)7.05-7.14(m，2H)7.19(d，J＝8.82Hz，2H)7.36(d，J＝1.84Hz，1H)7.44(d，J＝8.82Hz，2H)9.46(s，1H)。MS(ESI-)m/z?373(M-H) ^-。

Embodiment 432D

4-(4-(tert-butoxycarbonyl amino) phenyl sulfenyl)-3-(7-sec.-propyl quinazoline-4-base is amino) methyl benzoate

Product (0.572g with embodiment 431F, 2.768mmol) and the product of 3-amino-4-(4-(tert-butoxycarbonyl amino) phenyl sulfenyl) methyl benzoate embodiment 385C or embodiment 432C (0.902g, 2.409mmol) reaction 30 minutes under refluxing under the nitrogen atmosphere in dehydrated alcohol (25mL).With the reaction mixture cooling, and concentrated by rotary evaporation.Resistates is dissolved in the methylene dichloride (50mL), and washs with saturated sodium bicarbonate aqueous solution (25mL) and water (25mL).With the organic phase dried over mgso, filter, and concentrate by rotary evaporation.By flash chromatography on silica gel method purifying, with 3:97 ethanol/methylene wash-out, obtained this title compound, be white solid (0.505g, 0.927mmol, 33%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm?1.32(d，J＝6.99Hz，6H)1.48(s，9H)2.99-3.21(m，1H)3.83(s，3H)6.93(d，J＝8.46Hz，1H)7.37(d，J＝8.82Hz，2H)7.55(d，J＝8.82Hz，2H)7.55-7.64(m，2H)7.75(dd，J＝8.46，1.84Hz，1H)7.91(d，J＝1.84Hz，1H)8.41(d，J＝8.46Hz，1H)8.45(s，1H)9.62(s，1H)9.92(s，1H)。MS(ESI+)m/z?545(M+H) ⁺。

Embodiment 432E

4-(4-(tert-butoxycarbonyl amino) phenyl sulfenyl)-3-(7-sec.-propyl quinazoline-4-base is amino) phenylformic acid

The product of embodiment 432D (0.505g 0.927mmol) is suspended in 1, in the 4-dioxane (6mL), with lithium hydroxide monohydrate (0.078g, 1.85mmol) at the solution of water (3mL) in room temperature treatment, then in 50 ° of heating 1 hour.To react water (25mL) dilution, and be adjusted to pH1 with the 1N HCl aqueous solution, and extract with ethyl acetate (50mL).With organic extract liquid water (25mL) and salt solution (25mL) washing, use dried over mgso, filter, and obtained this title compound by rotary evaporation is concentrated, be light yellow solid (0.433g, 0.816mmol, 88%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm1.31(d，J＝6.99Hz，6H)1.48(s，9H)2.98-3.23(m，1H)6.92(d，J＝8.09Hz，1H)7.36(d，J＝8.46Hz，2H)7.54(d，J＝8.82Hz，2H)7.59(d，J＝11.77Hz，1H)7.73(d，J＝8.09Hz，1H)7.89(s，1H)8.34-8.49(m，2H)9.61(s，1H)9.94(s，1H)。MS(ESI+)m/z?531(M+H) ⁺。

Embodiment 432F

(45mg 0.0848mmol) is dissolved in the methylene dichloride (2mL), handles 1 hour with trifluoroacetic acid (2mL) in room temperature the product of embodiment 432E.To react concentrated by rotary evaporation, and again from methylene dichloride/ethane (25mL, 1:1v/v) middle azeotropic.Dry under high vacuum; obtained the compound of deprotection, be yellow powder, it has been dissolved in methyl-sulphoxide (2mL) under nitrogen atmosphere; and with (R)-(-)-1-aminoidan (13.6mg; 0.102mmol), N, the N-diisopropylethylamine (0.074mL, 0.424mmol) and O-benzotriazole-1-base-N; N; N ', (32.7mg is 0.102mmol) in room temperature treatment 2 hours for N '-tetramethyl-urea a tetrafluoro borate.To react water (10mL) dilution, with ethyl acetate (50mL) extraction, and with the organic extract liquid water (3 * 10mL), saturated sodium bicarbonate aqueous solution (20mL) and salt solution (20mL) washs.With the organic phase dried over mgso, filter, and concentrate by rotary evaporation.By flash chromatography on silica gel method purifying, with 4:96 ethanol/methylene wash-out, obtained this title compound, be white solid (22mg, 0.0403mmol, 48%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm1.31(d，J＝6.99Hz，6H)1.85-2.09(m，1H)2.35-2.47(m，1H)2.75-3.03(m，2H)3.04-3.18(m，1H)5.50-5.60(m，1H)5.57(s，2H)6.62(d，J＝8.46Hz，2H)6.82(d，J＝8.46Hz，1H)7.12(d，J＝8.46Hz，2H)7.15-7.29(m，4H)7.57(dd，J＝8.46，1.47Hz，1H)7.60(s，1H)7.73(dd，J＝8.46，1.84Hz，1H)7.91(d，J＝1.84Hz，1H)8.42(t，J＝4.41Hz，2H)8.72(d，J=8.09Hz，1H)9.83(s，1H)。MS(ESI+)m/z?546(M+H) ⁺，1091(2M+H) ⁺。

Embodiment 433

4-(4-aminophenyl sulfenyl)-N-(1-hydroxyl-2-phenyl third-2-yl)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) benzamide

Product (205mg at the following embodiment 454 of nitrogen atmosphere, 0.3104mmol) be dissolved in methyl-sulphoxide (4mL), and in room temperature and 2-amino-2-phenyl third-1-alcohol hydrochloride (70mg, 0.3725mmol), N, the N-diisopropylethylamine (0.27mL, 1.552mmol) and O-benzotriazole-1-base-N, N, N ', (120mg, 0.3725mmol) reaction is 15 hours for N '-tetramethyl-urea a tetrafluoro borate.To react water (20mL) dilution, with ethyl acetate (3 * 50mL) extractions, then water (3 * 20mL), saturated sodium bicarbonate aqueous solution (40mL) and salt solution (40mL) washs.With the organic phase dried over mgso, filter, and concentrate by rotary evaporation.By flash chromatography on silica gel method purifying, with 5:95 ethanol/methylene wash-out, obtained this title compound, be light yellow solid (69mg, 0.122mmol, 39%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm1.34(d，J＝6.62Hz，6H)1.69(s，3H)3.13-3.29(m，1H)3.51(dd，J＝11.03，6.25Hz，1H)3.73(dd，J＝10.85，5.70Hz，1H)5.09(t，J＝6.07Hz，1H)5.57(s，2H)6.61(d，J＝8.46Hz，2H)6.85(d，J＝8.09Hz，1H)7.11(d，J＝8.46Hz，2H)7.12-7.37(m，5H)7.63(d，J＝8.82Hz，1H)7.64-7.69(m，1H)7.84(d，J＝1.47Hz，1H)8.03(s，1H)8.58(s，1H)8.87(d，J＝8.46Hz，1H)10.14(s，1H)。MS(ESI+)m/z?565(M+H) ⁺。MS(ESI-)m/z?563(M-H) ^-。

Embodiment 434

4-(4-aminophenyl sulfenyl)-N-(1-(hydroxymethyl)-2,3-dihydro-1H-indenes-1-yl)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) benzamide

Embodiment 434A

1-amino-2,3-dihydro-1H-indenes-1-ethyl formate

Thionyl chloride (0.617mL 8.465mmol) is added drop-wise in the dehydrated alcohol (6mL) that is cooled to-30 °, the adding 1-amino-2 that continues, (0.300g 1.693mmol), will react and reflux 4 hours 3-dihydro-1H-indenes-1-formic acid then.To react concentrated by rotary evaporation, water (5mL) dilutes, and regulates pH to 9 with the 6N aqueous sodium hydroxide solution.Solution is extracted with ethyl acetate (2 x25mL), and organic extract liquid is washed with salt solution (25mL), use dried over sodium sulfate, filter, and concentrate, obtained this title compound, be oily matter (0.293g, 1.43mmol, 84%) by rotary evaporation. ¹H?NMR(300MHz，DMSO-D6)δ?ppm?1.12(t，J＝7.17Hz，3H)1.85-2.07(m，1H)2.31(s，2H)2.51-2.66(m，1H)2.93(t，J＝6.99Hz，2H)3.90-4.21(m，2H)7.13-7.34(m，4H)。MS(DCI)m/z206(M+H) ⁺，223(M+NH ₄) ⁺。

Embodiment 434B

(1-amino-2,3-dihydro-1H-indenes-1-yl) methyl alcohol

With the product of embodiment 434A (0.292g, 1.423mmol) and sodium borohydride (0.275g, 7.113mmol) reaction 4 hours under refluxing in 1:3v/v water/ethanol (7mL).To react concentrated, and between water (5mL), ether (20mL), 1N aqueous sodium hydroxide solution (0.712mL), distribute by rotary evaporation.Add solid sodium chloride with saturated water, and will be separated.(2 * 25mL) extract with ether with water.The ether extraction liquid that merges is used the salt of wormwood drying with salt solution (25mL) washing, filters, and concentrates by rotary evaporation, has obtained this title compound (0.197g, 1.209mmol, 85%).1H?NMR(300MHz，DMSO-D6)δ?ppm?1.64-1.80(m，1H)1.85(s，2H)2.16-2.31(m，1H)2.63-2.91(m，2H)3.30(d，J＝5.52Hz，2H)4.74(t，J＝5.52Hz，1H)6.80-7.63(m，4H)。MS(DCI)m/z?164(M+H) ⁺，181(M+NH ₄) ⁺。

Embodiment 434C

Product (57mg with embodiment 454,0.0865mmol) with the product (16.9mg of embodiment 434B, 0.104mmol), N, N-diisopropylethylamine (0.075mL, 0.433mmol) and O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (33mg, 0.104mmol) in methyl-sulphoxide (2mL) under nitrogen atmosphere in room temperature reaction 1 hour.To react water (10mL) dilution, with ethyl acetate (50mL) extraction.With organic extract liquid in succession water (3 * 10mL), the washing of saturated sodium bicarbonate aqueous solution (20mL) and salt solution (20mL), use dried over mgso then, filter, and concentrate by rotary evaporation.With 5:95 ethanol/methylene wash-out, obtained this title compound by fast silica gel chromatogram purifying resistates, be light yellow solid (28mg, 0.0486mmol, 56%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm?1.33(d，J＝6.99Hz，6H)2.19-2.38(m，1H)2.49-2.63(m，1H)2.76-2.90(m，1H)2.91-3.07(m，1H)3.16-3.28(m，1H)3.53(dd，J＝11.03，5.88Hz，1H)3.73(dd，J＝11.03，5.88Hz，1H)5.09(t，J＝6.07Hz，1H)5.57(s，2H)6.61(d，J＝8.46Hz，2H)6.81(d，J＝8.09Hz，1H)7.05-7.22(m，3H)7.10(d，J＝8.46Hz，2H)7.27(d，J＝7.35Hz，1H)7.55-7.71(m，2H)7.80(d，J＝1.84Hz，1H)7.94(s，1H)8.56(s，1H)8.86(d，J＝8.46Hz，1H)10.10(s，1H)。MS(ESI+)m/z?577(M+H) ⁺。MS(ESI-)m/z?575(M-H) ^-。

Embodiment 435

4-(4-aminophenyl sulfenyl)-N-(1-hydroxyl-2-phenyl fourth-2-yl)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) benzamide

Embodiment 435A

2-amino-2-phenyl fourth-1-alcohol

With 2-amino-2-phenylbutyrate (0.162g, 0.782mmol) solution in 1:3v/v water/ethanol (4mL) and sodium borohydride (0.151g, 3.908mmol) reaction hour under refluxing.To react and concentrate water (5mL), ether (10mL) and 1N aqueous sodium hydroxide solution (0.39mL) distribution.Add solid sodium chloride with saturated water, and will be separated.With aqueous phase separation, and with ether (2 * 20mL) again the extraction.The ether extraction liquid that merges is washed with salt solution (25mL), use the salt of wormwood drying, filter, and concentrate, obtained this title compound, be oily matter (0.116g, 0.702mmol, 90%) by rotary evaporation. ¹H?NMR(300MHz，DMSO-D6)δppm?0.59(t，J＝7.54Hz，3H)1.49-1.80(m，4H)3.44(d，J＝5.15Hz，2H)4.63(t，J＝5.52Hz，1H)6.89-7.76(m，5H)。MS(DCI)m/z?166(M+H) ⁺。

Embodiment 435B

Product (58mg with embodiment 454,0.0884mmol) with the product (17.5mg of embodiment 435A, 0.106mmol), N, N-diisopropylethylamine (0.077mL, 0.442mmol) and O-benzotriazole-1-base-N, N, N ', (34mg 0.106mmol) reacted 1 hour in 60 ° under nitrogen atmosphere at methyl-sulphoxide (2mL) N '-tetramethyl-urea a tetrafluoro borate.Reaction is diluted in the water (10mL), with ethyl acetate (50mL) extraction, and with organic extract liquid in succession water (2 * 10mL), saturated sodium bicarbonate aqueous solution (20mL) and salt solution (20mL) washs, and uses dried over mgso, filter, and concentrate by rotary evaporation.By fast silica gel chromatogram purifying resistates,, obtained this title compound (11mg, 0.019mmol, 22%) with 5:95 ethanol/methylene wash-out. ¹H?NMR(300MHz，DMSO-D6)δ?ppm?0.74(t，J＝7.17Hz，3H)1.34(d，J＝6.99Hz，6H)1.93-2.28(m，2H)3.13-3.28(m，1H)3.71-4.03(m，2H)4.90(t，J＝5.70Hz，1H)5.57(s，2H)6.61(d，J＝8.46Hz，2H)6.85(d，J＝8.46Hz，1H)7.08-7.2t(m，1H)7.11(d，J＝8.46Hz，2H)7.21-7.34(m，4H)7.63(d，J＝8.46Hz，1H)7.67(dd，J＝8.46，1.84Hz，1H)7.81-7.90(m，2H)8.58(s，1H)8.87(d，J＝8.46Hz，1H)10.13(s，1H)。MS(ESI+)m/z?579(M+H) ⁺，1157(2M+H) ⁺，1179(2M+Na) ⁺。MS(ESI-)m/z?577(M-H) ^-。

Embodiment 436

(S)-and 2-(4-(4-(2-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino)-4-(1-phenylethyl formamyl) phenyl sulfenyl) phenyl sulfenyl)-2-methyl-4-oxo fourth-2-yl)-3,5-3,5-dimethylphenyl sodium phosphate

Embodiment 436A

4,4,5,7-tetramethyl-benzo dihydropyrane-2-ketone

3, (5.00g, 0.0409mol) with 3, (5.14g 0.045mol) is added in the methylsulfonic acid (5mL) in room temperature the 3-methyl methacrylate 5-xylenol, then in 70 ° of heating 17 hours.With reaction mixture cooling, water (750mL) dilution, with ethyl acetate (2 * 200mL) extractions, and with the organic extract liquid that merges with saturated sodium bicarbonate aqueous solution (2 * 100mL) and salt solution (50mL) wash.With the organic phase dried over mgso, filter, and concentrate by rotary evaporation.By flash chromatography on silica gel method purifying, use the methylene dichloride wash-out, obtained this title compound, be beige solid (7.73g, 0.0378mol, 92%). ¹H NMR (300MHz, the δ ppm 1.43 of chloroform-D) (s, 6H) 2.27 (s, 3H) 2.46 (s, 3H) 2.59 (s, and 2H) 6.74 (s, 2H).MS(DCI)m/z?205(M+H) ⁺，222(M+NH ₄) ⁺。

Embodiment 436B

2-(4-hydroxy-2-methyl fourth-2-yl)-3, the 5-xylenol

The product (4.00g of the embodiment 436A in tetrahydrofuran (THF) (75mL), 0.0196mol) in room temperature with being added drop-wise to the lithium aluminum hydride (solution of 1.0M in tetrahydrofuran (THF) in 30 minutes, 20.6mL, 0.0206mol) in the solution in tetrahydrofuran (THF) (105mL), then in stirring at room 1 hour.After 15 minutes, the reaction of stirring is passed through to drip saturated aqueous ammonium chloride (5mL) stopped reaction, vacuum filtration disgorging.Filtrate is concentrated by rotary evaporation, and resistates is passed through the fast silica gel chromatogram purifying,, obtained this title compound, be white solid (2.94g, 0.014 mol, 72%) with 4:96 ethanol/methylene wash-out. ¹H?NMR(300MHz，DMSO-D6)δ?ppm?1.44(s，6H)2.00-2.07(m，2H)2.08(s，3H)2.36(s，3H)3.11-3.28(m，2H)4.09(t，J＝4.78Hz，1H)6.29(s，1H)6.42(s，1H)8.95(s，1H)。MS(ESI+)m/z?209(M+H) ⁺，226(M+NH ₄) ⁺。

Embodiment 436C

2-(4-t-butyldimethylsilyl oxygen base)-2-methyl fourth-2-yl)-3, the 5-xylenol

With the product of embodiment 436B (2.938g, 0.0141mol) with tert-butyldimethylsilyl chloride (2.63g, 0.0169mol) and imidazoles (2.40g, 0.0353mol) at N, in the dinethylformamide (30mL) under nitrogen atmosphere in room temperature treatment 2 hours.Under high vacuum, remove and desolvate by rotary evaporation.Resistates by the fast silica gel chromatogram purifying, with 30:70 ethyl acetate/hexane wash-out, has been obtained this title compound, be white solid (4.295g, 0.0133mol, 94%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm?-0.07(s，6H)0.80(s，9H)1.45(s，6H)2.00-2.17(m，5H)2.37(s，3H)3.34-3.44(m，2H)6.30(s，1H)6.43(s，1H)9.00(s，1H)。MS(DCI)m/z?323(M+H) ⁺，340(M+NH ₄) ⁺。

Embodiment 436D

2-(4-(t-butyldimethylsilyl oxygen base)-2-methyl fourth-2-yl)-3,5-3,5-dimethylphenyl phosphate dibenzyl ester

(1.70g, 5.272mmol) (0.685g 5.799mmol) handled 5 minutes in 60 ° in tetrahydrofuran (THF) (90mL), and then (3.123g, 5.799mmol) processing is 1 hour with tetra-sodium four benzyl esters with solid sodium tert-butoxide with the product of embodiment 436C.After the dense thick white reaction mixture cooling of gained, with hexane (125mL) dilution, vacuum filtration is also concentrated by rotary evaporation with filtrate.By fast silica gel chromatogram purifying resistates, with 20:80 ethyl acetate/hexane wash-out, obtained this title compound, for colorless oil (3.07g, 5.27mmol, quantitatively). ¹H NMR (300MHz, δ ppm-0.07 (s, 6H) 0.82 (s of chloroform-D), 9H) 1.51 (s, 6H) 2.07 (t, J=7.35Hz 2H), 2.16 (s, 3H) 2.49 (s, 3H) 3.47 (t, J=7.35Hz, 2H) 5.10 (d, J=8.09Hz, 4H) 6.70 (s, 1H) 7.08 (s, 1H) 7.27-7.38 (m, 10H).MS(ESI+)m/z?583(M+H) ⁺，605(M+Na) ⁺。

Embodiment 436E

3-(2-two (benzyloxy) phosphoryl oxygen base)-4, the 6-3,5-dimethylphenyl)-3 Methylbutanoic acid

With the product of embodiment 436D (0.732g, 1.256mmol) with Potassium monofluoride (0.0803g, 1.382mmol) in acetone (10mL) in 0 ° of reaction, (1.04mL was according to Fieser and Fieser with 20 minutes dropping Jones reagent then 1, p.142 make).After 2 hours, add Jones reagent (0.50mL) again, use isopropyl alcohol (1mL) to handle then 20 minutes.Reaction mixture is concentrated by rotary evaporation, be dissolved in the water (25mL), (3 * 50mL) extract, and with the organic layer that merges salt solution (25mL) washing, use dried over mgso with ethyl acetate.The filtrate filtration is concentrated by rotary evaporation, obtained this title compound, be oily matter (0.544g, 1.127mmol, 90%). ¹H NMR (300MHz, the δ ppm 1.61 of chloroform-D) (s, 6H) 2.12 (s, 3H) 2.51 (s, 3H) 2.84 (s, 2H) 5.11 (d, J=8.09Hz, 4H) 6.73 (s, 1H) 6.97 (s, 1H) 7.28-7.42 (m, 10H).MS(ESI+)m/z?483(M+H) ⁺，505(M+Na) ⁺。MS(ESI-)m/z?481(M-H) ^-。

Embodiment 436F

(S)-and 2-(4-(2-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino)-4-(1-phenylethyl formamyl) phenyl sulfenyl) phenyl amino)-2-methyl-4-oxo fourth-2-yl)-3,5-3,5-dimethylphenyl phosphate dibenzyl ester

Product (0.235g with embodiment 436E, 0.4863mmol) and N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (0.129g, 0.6733mmol) and 4-dimethylaminopyridine (7mg, 0.056mmol) at N, dinethylformamide (3.7mL) was handled 15 minutes in 0 ° under nitrogen atmosphere, (0.200g is 0.374mmol) in 0 °-room temperature treatment 20 hours to use the product of embodiment 385G then.To be reflected under the high vacuum and concentrate by rotary evaporation.By flash chromatography on silica gel method purifying, with 3:97 ethanol/methylene wash-out, obtained this title compound, be yellow solid (0.151g, 0.151mmol, 40%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm?1.33(d，J＝6.99Hz，6H)1.45(d，J＝6.99Hz，3H)1.56(s，6H)2.10(s，3H)2.48(s，3H)2.89(s，2H)3.14-3.27(m，1H)5.14(d，J＝8.09Hz，4H)6.73(s，1H)6.92(s，1H)6.97(d，J＝8.82Hz，1H)7.15-7.43(m，17H)7.53(d，J＝8.46Hz，2H)7.62(d，J＝8.09Hz，1H)7.71(d，J＝8.46Hz，1H)7.93(s，1H)8.58(s，1H)8.81(t，J＝8.46Hz，2H)9.89(s，1H)10.23(s，1H)。MS(ESI+)m/z?999(M+H) ⁺。MS(ESI-)m/z997(M-H) ^-。

Embodiment 436G

In room temperature with the product of embodiment 436F (0.149g, 0.1491mmol) acetonitrile (3mL) under nitrogen atmosphere with sodium iodide (0.0894g 0.5965mmol) handles, drip then the chlorine trimethyl silyl (0.076mL, 0.5965mmol).After 3 hours, water (3mL) stopped reaction is regulated pH to 9 with saturated sodium bicarbonate aqueous solution, adds entry till the solution muddiness, adds enough methyl alcohol then so that regain clear soln.Injection of solution is arrived C ₁₈On the HPLC post (Biotage 40S cartridge), and water (5 minutes) wash-out, use 0%-100% methyl alcohol via 25 minutes gradient elutions then.The product merga pass rotary evaporation that will contain the fraction that goes out at 21-26 minute wash-out concentrates, and with methyl alcohol, methylene dichloride and hexane co-evaporated.Dried overnight under high vacuum has obtained this title compound, is yellow solid (0.055g, 0.0637mmol, 43%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm?1.28(d，J＝6.99Hz，6H)1.43(d，J＝6.99Hz，3H)1.63(s，6H)2.07(s，3H)2.33(s，3H)2.80(s，2H)2.98-3.13(m，1H)5.02-5.23(m，1H)6.36(s，1H)7.09-7.47(m，10H)7.58(d，J＝8.82Hz，2H)7.93(s，1H)8.59(brs，2H)11.70(s，1H)。MS(ESI+)m/z?819(M+H) ⁺，862(M+2Na) ⁺。MS(ESI-)m/z?817(M-H) ^-。

Embodiment 437

4-(4-aminophenyl sulfenyl)-N-(1-hydroxyl-2-(thiophene-2-yl)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) benzamide

Embodiment 437A

2-amino-2-(thiophene-2-yl) ethyl propionate

In 0 ° thionyl chloride (1mL, 14.6mmol) be added drop-wise to 2-amino-2-(thiophene-2-yl) propionic acid of being suspended in the dehydrated alcohol (10mL) (0.500g, 2.92mmol) in, will react reflux then 22 hours.To react concentrated by rotary evaporation, water (5mL) dilution is regulated pH to 9 with the 6N aqueous sodium hydroxide solution, and (2 * 25mL) extract with ethyl acetate.The organic extract liquid that merges is washed with salt solution (25mL), use dried over sodium sulfate, filter, and concentrate, obtained this title compound, be oily matter (0.498g, 2.499mmol, 86%) by rotary evaporation. ¹H?NMR(300MHz，DMSO-D6)δ?ppm?1.17(t，J＝7.17Hz，3H)1.60(s，3H)2.53(s，2H)4.11(q，J＝7.23Hz，2H)6.91-6.98(m，1H)7.00(dd，J＝3.68，1.10Hz，1H)7.37(dd，J＝5.15，1.10Hz，1H)。MS(DCI)m/z200(M+H) ⁺，217(M+NH ₄) ⁺。

Embodiment 437B

2-amino-2-(thiophene-2-yl) third-1-alcohol

With the product of embodiment 437A (0.497g, 2.494mmol) in 1:3v/v water/ethanol (12mL) with sodium borohydride (0.481g, 12.47mmol) reaction 4 hours under refluxing.To react by rotary evaporation and concentrate distribution between water (5mL), ether (25mL) and 1N aqueous sodium hydroxide solution (1.25mL).Solid sodium chloride be added to saturated isolating mutually in.Water is extracted with ether (25mL) again.The ether extraction liquid that merges is washed with salt solution (25mL), use the salt of wormwood drying, filter, and concentrate, obtained this title compound, be oily matter (0.330g, 2.099mmol, 84%) by rotary evaporation. ¹H?NMR(300MHz，DMSO-D6)δ?ppm1.35(s，3H)1.96(s，2H)3.33-3.42(m，2H)4.91(t，J＝5.70Hz，1H)6.89-6.95(m，2H)7.28(dd，J＝3.49，2.76Hz，1H)。MS(DCI)m/z?158(M+H) ⁺。

Embodiment 437C

Product (1.00g with embodiment 454,1.5199mmol) with the product (0.287g of embodiment 437B, 1.824mmol), N, N-diisopropylethylamine (1.32mL, 7.599mmol) and O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (0.586g, 1.824mmol) in methyl-sulphoxide (15mL) under nitrogen atmosphere in room temperature reaction 15 hours.Reaction is diluted in the water (75mL), with ethyl acetate (100mL) extraction, and with the organic extract liquid water (3 * 50mL), saturated sodium bicarbonate aqueous solution (50mL) and salt solution (50mL) washs.With the organism dried over mgso, filter, and concentrate by rotary evaporation.By flash chromatography on silica gel method purifying, with 6:94 ethanol/methylene wash-out, obtained this title compound, be light yellow solid (0.464g, 0.813mmol, 53%). ¹H?NMR(300MHz，DMSO-D6)δ?ppm?1.34(d，J＝6.99Hz，6H)1.73(s，3H)3.12-3.27(m，1H)3.56(dd，J＝11.03，6.62Hz，1H)3.86(dd，J＝11.21，6.07Hz，1H)5.19(t，J＝6.07Hz，1H)5.57(s，2H)6.61(d，J＝8.46Hz，2H)6.84(d，J＝8.46Hz，1H)6.91(d，J＝3.31Hz，2H)7.11(d，J＝8.46Hz，2H)7.25-7.33(m，1H)7.63(d，J＝8.46Hz，2H)7.81(s，1H)8.08(s，1H)8.58(s，1H)8.87(d，J＝8.46Hz，1H)10.13(s，1H)。MS(ESI+)m/z?571(M+H) ⁺，1141(2M+H) ⁺。MS(ESI-)m/z?569(M-H) ^-，1139(2M-H) ^-。

Embodiment 438

2-(4-(4-aminophenyl sulfenyl)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) benzoylamino)-2-methyl-propyl sodium phosphate

Embodiment 438A

1-hydroxy-2-methyl third-2-aminocarbamic acid benzyl ester

With 2-amino-2-methyl third-1-alcohol (1.0g, 11.2mmol), triethylamine (1.7mL, 12.2mmol) and N-(benzyloxycarbonyloxy base)-succinimide (3.1g, 12.4mmol) in THF (100mL) in 0 ℃ of reaction 0.5 hour, and then in room temperature reaction 1 hour.To react concentrated, and extract with ethyl acetate (100mL).With organic extract liquid water successively, salt water washing, use MgSO ₄Drying, and vacuum concentration.Resistates by the silica gel column chromatography purifying, with the solution gradient wash-out of ethyl acetate in methylene dichloride (0-20%), is obtained this title compound, be colorless oil (2.5g, quantitative).

Embodiment 438B

1-(two-tert.-butoxy phosphoryl oxygen base)-2-methyl-prop-2-aminocarbamic acid benzyl ester

Product (0.80g with embodiment 438A, 3.8mmol), diethyl phosphamic acid di tert butyl carbonate (di-tert-butyl diethylphosphoramidite) (1.07mL, 3.8mmol) and the 1-H-tetrazolium (0.63g, 8.99mmol) in THF (35mL) in room temperature reaction 12 hours.To react with methylene dichloride (35mL) dilution, and be cooled to-45 ℃, (0.90g 4.0mmol) handled 0.5 hour, used ethyl acetate (100mL) dilution then with mCPBA.Organism with 10% Na2CO3 (2 *), salt water washing, is used MgSO ₄Drying, and concentrate.Resistates by the silica gel column chromatography purifying, with solution (0-25%) gradient elution of ethyl acetate in methylene dichloride, is obtained this title compound, be colorless oil (0.926g, 62%).

Embodiment 438C

Phosphoric acid 2-amino-2-methyl propyl diester di-t-butyl ester

With the product of embodiment 438B (0.40g, 0.96mmol) and 20% palladium hydroxide be the stirring 0.5 hour under nitrogen atmosphere in ethyl acetate (10mL) and methyl alcohol (1mL) of the palladium hydroxide (0.21g) of carrier with carbon.To react by Celite pad and filter and concentrate, obtain this title product (0.256g).

Embodiment 438D

4-(4-(1-(two-tert.-butoxy phosphoryl oxygen base)-2-methyl-prop-2-base formamyl)-2-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) phenyl sulfenyl) the phenylcarbamic acid tert-butyl ester

To embodiment 385E (100mg, 0.19mmol), O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate [TBTU] (72mg, 0.22mmol), (65mg 0.23mmol) drips N in room temperature in the solution in DMSO (1mL) under nitrogen for the product of embodiment 438C, the N-diisopropylethylamine (0.065mL, 0.37mmol).With mixture under nitrogen stirring at room 12 hours.To react with the ethyl acetate dilution, and, use MgSO water layer water successively (3 *) and salt water washing ₄Drying, and concentrate.Resistates by the silica gel column chromatography purifying, with the eluant solution of ethyl acetate in methylene dichloride (0-100%), is obtained this title compound (93mg, 62%).

Embodiment 438E

With the product of embodiment 438D (90mg, 0.11mmol) in methylene dichloride (0.5mL) with the trifluoroacetic acid [TFA] that dropwise adds (0.5mL) in room temperature reaction, stirred then 1 hour.To react and concentrate, and be dissolved in again in the first alcohol and water, to wherein add sodium bicarbonate (0.10g, 1.19mmol).With resistates purifying on anti-phase C18 post, with the mixture gradient elution of methyl alcohol in water (0-100%), this title compound is yellow solid (62.5mg, 88%).1H?NMR(300MHz，DMSO-D6)δ?ppm?1.29(d，J＝6.99Hz，6H)1.32(s，6H)3.03-3.20(m，1H)3.54(d，J＝11.40Hz，2H)5.45(s，2H)6.50-6.53(m，1H)6.62(d，J＝8.46Hz，2H)7.11(d，J＝8.46Hz，2H)7.34(s，1H)7.60(s，1H)7.87(s，1H)8.29(s，1H)8.74(s，1H)9.82(s，1H)。

Embodiment 439

4-(4-(1-hydroxyl-2-phenyl third-2-base formamyl)-2-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) phenyl sulfenyl) phenylcarbamic acid methyl esters

Product (30mg to embodiment 441D, 0.061mmol), O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate [TBTU] (25mg, 0.078mmol) (11mg 0.073mmol) drips N in room temperature in the solution in DMSO (0.3mL) under nitrogen with 2-amino-2-phenyl third-1-alcohol, the N-diisopropylethylamine (0.020mL, 0.115mmol).Mixture was stirred 0.25 hour under nitrogen in room temperature.Mixture is diluted with ethyl acetate.With organic layer water (3 *) and salt water washing in succession, use MgSO ₄Drying, and concentrate.Resistates by the silica gel column chromatography purifying, with the solution gradient wash-out of ethyl acetate in methylene dichloride (0-100%), is obtained this title compound (15.6mg, 41%).1H?NMR(300MHz，DMSO-D6)δppm?1.33(d，J＝6.99Hz，6H)1.70(s，3H)3.15-3.28(m，1H)3.52(dd，J＝10.66，5.88Hz，1H)3.67(s，3H)3.70-3.78(m，1H)5.10(t，J＝6.07Hz，1H)7.02(d，J＝8.46Hz，1H)7.14-7.39(m，8H)7.50(d，J＝8.46Hz，2H)7.62(d，J＝8.46Hz，1H)7.70(d，J＝8.09Hz，1H)7.90(s，1H)8.10(s，1H)8.58(s，1H)8.84(d，J＝8.46Hz，1H)9.86(s，1H)10.20(s，1H)。

Embodiment 440

(S)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino)-4-(4-(sulfonyloxy methyl amine o) phenyl sulfenyl)-N-(1-phenylethyl) benzamide

With the product of embodiment 385G (50mg, 0.094mmol) and triethylamine (0.030mL, 0.215mmol) (0.008mL 0.103mmol) handles, then in room temperature reaction 1 hour with dripping methylsulfonyl chloride under nitrogen in 0 ℃ in THF (1.0mL).Reaction is cooled to 0 ℃, and then (0.004mL is 0.052mmol) and in room temperature reaction 0.5 hour to drip methylsulfonyl chloride.Mixture is diluted with ethyl acetate (20mL), and with the saturated NaHCO of organic layer ₃With the salt water washing, use MgSO ₄Drying, and concentrate.By the silica gel column chromatography purifying, elder generation is with using ethyl acetate (25mg, 44%) gradient elution behind the methylene dichloride with resistates.1H?NMR(300MHz，DMSO-D6)δ?ppm?1.33(d，J＝6.99Hz，6H)1.46(d，J＝6.99Hz，3H)3.03(s，3H)3.15-3.28(m，1H)5.04-5.31(m，1H)7.09(d，J＝8.09Hz，2H)7.13-7.27(m，3H)7.26-7.45(m，7H)7.62(d，J＝8.46Hz，1H)7.77(dd，J＝8.27，1.65Hz，1H)7.95(s，1H)8.57(s，1H)8.82(d，J＝8.46Hz，2H)10.00(s，1H)10.20(s，1H)。

Embodiment 441

2-(3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino)-4-(4-(methoxycarbonyl amino) phenyl sulfenyl) benzoylamino)-2-methyl-propyl sodium phosphate

Embodiment 441A

4-(4-(methoxycarbonyl amino) phenyl sulfenyl)-3-nitrobenzoic acid methyl esters

With the product of embodiment 385A (5.0g., 16.4mmol), pyridine (2.7ml., 32.8mmol) and methyl-chloroformate (1.3ml. is 16.4mmol) at CH ₂Cl ₂(130ml.) in room temperature reaction 1 hour.To react and use CH ₂Cl ₂(500ml.) dilution, and use saturated NaHCO in succession ₃(100ml.), 1 NHCl (100ml.) and salt solution (100ml.) washing.With organic phase MgSO ₄Dry and concentrated, obtain this title compound (6g., 100%).

Embodiment 441B

3-amino-4-(4-(methoxycarbonyl amino) phenyl sulfenyl) methyl benzoate

By the method for embodiment 385C, use the product of the product alternate embodiment 385B of embodiment 441A, make this title compound.To react by silica gel chromatography purifying (ethyl acetate/CHCl ₃=1/9), obtains this title compound (productive rate 88%).

Embodiment 441C

3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino)-4-(4-(methoxycarbonyl amino) phenyl sulfenyl) phenylformic acid

By the method for embodiment 385D, use the product of the product alternate embodiment 385C of embodiment 441B, make this title compound (productive rate 88%).

Embodiment 441D

By the method for embodiment 385E, use the product of the product alternate embodiment 385D of embodiment 441C, make this title compound (productive rate 92%).

Embodiment 441E

4-(4-(1-(two-tert.-butoxy phosphoryl oxygen base)-2-methyl-prop-2-base formamyl)-2-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) phenyl sulfenyl) phenylcarbamic acid methyl esters

Product (200mg to embodiment 441D, 0.41mmol) and 0-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate [TBTU] (187mg, 0.57mmol) product (178mg of adding embodiment 438C in the suspension in DMSO (2mL), 0.57mmol), under nitrogen, drip N in room temperature then, and the N-diisopropylethylamine (0.220mL, 1.10mmol).After 2 hours, reaction water (20mL) is ended, and extract with ethyl acetate (75mL).With organic layer water (3 *) and saturated NaHCO in succession ₃MgSO is used in washing ₄Drying, and concentrate.Resistates by the silica gel column chromatography purifying, is used eluent ethyl acetate, obtain this title compound, be light yellow amorphous solid (245mg., 79%).

Embodiment 441F

(240mg. is 0.32mmol) at CH with the product of embodiment 441E ₂Cl ₂(1.6ml.) with TFA (1.6ml.) in room temperature reaction 30 minutes.To react concentrated, and be dissolved in again in the water (4mL), and under agitation use solid NaHCO ₃(270mg. 3.2mmol) handles.With solution purifying on the C-18 post, with the mixture gradient elution of methyl alcohol in water (0-100%).Obtain this title compound (202mg., 92%).1H?NMR(300MHz，DMSO-D6)δ?ppm?1.17-1.40(m，12H)2.98-3.11(m，1H)3.66(s，3H)6.65(s，1H)7.18-7.27(m，1H)7.32(d，J＝8.09Hz，2H)7.48(d，J＝8.09Hz，2H)7.51-7.62(m，1H)7.94(s，1H)8.18-8.29(s，1H)8.77(s，1H)9.84(s，1H)。

Embodiment 442

2-(3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino)-4-(4-(methoxycarbonyl amino) phenyl sulfenyl) benzoylamino)-2-phenyl propyl sodium sulfate

Embodiment 442A

1-hydroxyl-2-phenyl third-2-aminocarbamic acid benzyl ester

With 2-amino-2-phenyl third-1-alcohol hydrochloride (0.5g, 2.7mmol) and N-(benzyloxycarbonyloxy base)-succinimide (0.73g, 2.9mmol) and triethylamine (0.82mL, 5.9mmol) in THF (25mL) in 0 ℃ of reaction 1.0 hours, then in room temperature reaction 1 hour.To react concentrated, and extract with ethyl acetate (25mL).With extraction liquid water (2 *) and salt water washing, use MgSO ₄Drying, and concentrate obtains rough title compound and uses under situation about not being further purified.

Embodiment 442B

1-(two-tert.-butoxy phosphoryl oxygen base)-2-phenyl third-2-aminocarbamic acid benzyl ester

Product (2.7mmol), diethyl phosphamic acid di tert butyl carbonate (di-tert-butyl diethylphosphoramidite) (0.80mL with embodiment 442A, 2.7mmol) and the 1-H-tetrazolium (0.50g, 6.8mmol) in THF (25mL) in room temperature reaction 12 hours.To react then with methylene dichloride (25mL) dilution, and be cooled to-45 ℃, (0.66g 3.0mmol) handled 0.5 hour to use metachloroperbenzoic acid then.To react with ethyl acetate (70mL) extraction, and with organic extract liquid with 10% yellow soda ash (2 *) and salt water washing, use MgSO ₄Drying, and concentrate.Resistates by the silica gel column chromatography purifying, with the solution gradient wash-out of ethyl acetate in methylene dichloride (0-25%), is obtained this title compound, be colorless oil (0.99g, 78%).

Embodiment 442C

Phosphoric acid 2-amino-2-phenyl propyl ester di-t-butyl ester

With the product of embodiment 442B (0.10g, 0.21mmol) and 20% be that the palladium hydroxide (0.02g) of carrier stirred 18 hours under nitrogen atmosphere in ethyl acetate (1mL) and methyl alcohol (1mL) with carbon.To react by Celite pad and filter and concentrate, obtain this title compound, it need not be further purified use (0.073g).

Embodiment 442D

4-(4-(1-(two-tert.-butoxy phosphoryl oxygen base)-2-phenyl third-2-base formamyl)-2-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) phenyl sulfenyl) phenylcarbamic acid methyl esters

By the method for embodiment 441E, use the product of the product alternate embodiment 441D of embodiment 442C, make this title compound (productive rate 43%).

Embodiment 442E

2-(3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino)-4-(4-(methoxycarbonyl amino) phenyl sulfenyl) benzoylamino)-2-phenyl propyl sodium phosphate

By the method for embodiment 441F, use the product of the product alternate embodiment 441E of embodiment 442D, make this title compound (productive rate 76%).1H?NMR(300MHz，DMSO-D6)δ?ppm?1.25(d，J＝6.99Hz，6H)1.77(s，3H)2.93-3.08(m，1H)3.68(s，3H)3.71-3.82(m，1H)6.48(s，1H)6.98-7.33(m，6H)7.39(d，J＝8.09Hz，2H)7.52(d，J＝8.09Hz，2H)7.56-7.68(m，1H)7.92-8.10(m，2H)8.56(s，1H)9.82(s，1H)10.42(s，1H)。

Embodiment 443

2-(4-(4-aminophenyl sulfenyl)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) benzoylamino)-2-phenyl propyl sodium phosphate

Embodiment 443A

4-(4-(1-(two-tert.-butoxy phosphoryl oxygen base)-2-phenyl third-2-base formamyl)-2-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) phenyl sulfenyl) the phenylcarbamic acid tert-butyl ester

Product (100mg with embodiment 385E, 0.19mmol), O-benzotriazole-1-base-N, N, N ', and N '-tetramethyl-urea a tetrafluoro borate [TBTU] (79mg, 0.24mmol) and the product (90mg. of embodiment 442C, 0.26mmol) in DMSO (1.0mL), dropwise use N in room temperature, (100 μ L 0.57mmol) handle the N-diisopropylethylamine, and stir 2 hours under nitrogen.To react water (10mL) dilution under agitation.With ethyl acetate (50mL) extraction gained throw out.With the saturated NaHCO of organic layer water (3 *) ₃Solution washing is used the salt water washing then, uses MgSO ₄Drying, and concentrate.(ethyl acetate: chloroform=4:1) obtain this title compound is light yellow amorphous solid (112mg, 69%) by the silica gel column chromatography purifying with resistates.

Embodiment 443B

Phosphoric acid 2-(4-(4-aminophenyl sulfenyl)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) hexamethylene-1,5-diene formamido-)-2-phenyl propyl ester

By the method for embodiment 441F, use the product of the product alternate embodiment 441E of embodiment 443A, make this title compound (productive rate 74%).1H?NMR(500MHz，DMSO-D6)δ?ppm?1.26(d，J＝6.84Hz，6H)1.75(s，3H)3.00-3.11(m，1H)3.73-3.85(m，2H)5.39(s，2H)6.55-6.63(m，3H)7.00-7.34(m，8H)7.58-7.70(m，1H)7.91(s，1H)8.81(s，1H)。

Embodiment 444

2-(4-(4-aminophenyl sulfenyl)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) benzoylamino)-2-phenylpropionic acid ethyl ester

Embodiment 444A

2-(4-(4-(tert-butoxycarbonyl amino) phenyl sulfenyl)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) benzoylamino)-2-phenylpropionic acid ethyl ester

Product (90mg with embodiment 385E, 0.17mmol), O-benzotriazole-1-base-N, N, N ', (60mg is 0.19mmol) with 2-amino-2-phenylpropionic acid ethyl ester (39mg for N '-tetramethyl-urea a tetrafluoro borate [TBTU], 0.20mmol) in DMSO (0.9mL) with the N that dropwise adds, the N-diisopropylethylamine (0.060mL, 0.34mmol) stirred 18 hours under nitrogen in room temperature then by reaction.Under agitation mixture is poured in the water (10mL).The gained throw out is extracted with ethyl acetate (50mL), and with organic layer water (3 *), saturated NaHCO ₃Solution washing is used the salt water washing then, uses MgSO ₄Drying, and concentrate.With resistates by silica gel chromatography purifying (ethyl acetate: chloroform 4:1) obtain this title compound, be light yellow amorphous solid (93mg, 78%).

Embodiment 444B

With the product (93mg) of embodiment 444A and trifluoroacetic acid [TFA] (0.60mL) in the methylene dichloride (0.60mL) that dropwise adds in room temperature reaction, then in stirring at room 1 hour.Reaction mixture is concentrated, and at ethyl acetate and saturated NaHCO ₃Distribute between the aqueous solution.With organic layer salt water washing, use MgSO ₄Drying, and concentrate.With resistates purifying on C-18 HPLC post, with the solution gradient wash-out of acetonitrile in 0.1% TFA water (0-100%).Required fraction is merged, concentrate, be dissolved in the ethyl acetate, use saturated NaHCO ₃Solution washing is used the salt water washing then, uses MgSO ₄Dry and concentrated, obtain light yellow amorphous solid (67mg, 84%).1H?NMR(300MHz，DMSO-D6)δ?ppm?1.07(t，J＝6.99Hz，3H)1.34(d，J＝6.62Hz，6H)1.84(s，3H)3.15-3.29(m，1H)4.03(q，J＝7.35Hz，2H)5.59(s，2H)6.62(d，J＝8.46Hz，2H)6.84(d，J＝8.46Hz，1H)7.12(d，J＝8.46Hz，2H)7.24-7.41(m，4H)7.52(d，J＝7.35Hz，2 H)7.63(d，J＝8.46Hz，1H)7.73(dd，J＝8.46，1.84Hz，1H)7.90(d，J＝1.84Hz，1H)8.57(s，1H)8.83(s，1H)8.86(d，J＝8.46Hz，2H)10.13(s，1H)。

Embodiment 445

(S)-4-(4-aminophenyl sulfenyl)-N-(1-hydroxyl-2-phenyl third-2-yl)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) benzamide

Embodiment 445A

(RS)-2-formamido--2-phenylpropionic acid

With (RS)-2-amino-2-phenylpropionic acid (20g, 0.12mol) in 88% formic acid (220mL) with so that internal temperature remains on diacetyl oxide (100mL) reaction that 60-65 ℃ speed adds.After adding is finished, will react to stir and reduce to till 35 ℃, concentrate then up to internal temperature.With solid residue by with the methylbenzene azeotropic drying.Solid residue is dissolved in the hot ethanol (70mL), handles, and filter with gac (0.5g).Under agitation hot water (210mL) is added in the filtrate of heat.With mixture refrigerator and cooled but 3 days.Filter to collect the gained crystal, wash, and, obtain this title compound, be clear crystal (17.8g, 76%) in 60 ℃ of dryings 4 hours with cold EtOH/ water (1:3).

Embodiment 445B

(S)-2-formamido--2-phenylpropionic acid

By J.Chem.Soc., the chiral separation method of describing in 1912,101,390 makes this title compound.

Embodiment 445C

(S)-2-amino-2-phenylpropionic acid ethyl ester

The product (1.25g, 7.6mmol)) of embodiment 445B was refluxed 1 hour in 1N HCl (12.5mL).Reaction mixture is concentrated, and, obtain (S)-2-amino-2-phenylpropionic acid hydrochloride, be light brown crystal (1.53g) in 40 ℃ of dried overnight under vacuum.Intermediate amino acid (1.5g.7.5mmol) is dissolved among the EtOH (30mL), and (2.7ml. 37.5mmol) in room temperature reaction, refluxed 23 hours then with the thionyl chloride that dropwise adds.To react and concentrate, and with resistates at saturated NaHCO ₃Distribute between solution and the ethyl acetate.With organic layer water (3 * 15mL) and 10% NaHCO ₃(MgSO is used in 1 * 15mL) washing to the aqueous solution ₄Drying concentrates, and obtains this title compound (1.28g, 90%).

Embodiment 445D

(S)-2-amino-2-phenyl third-1-alcohol

With the product (1.28g, 6.6mmol prepare in embodiment 445C) of embodiment 445C and sodium borohydride (1.25g, 33mmol) reaction 1 hour under refluxing in 75% moisture EtOH (32mL).To react concentrated, water (20mL) dilutes, and (3 * 75mL) extract with ethyl acetate.With organic layer 10% NaHCO ₃(MgSO is used in 2 * 10mL) washings to solution ₄Drying, and concentrate this title compound of acquisition, be colourless viscosity oily matter (1.09g., 100%).

Embodiment 445E

Product (50mg. with embodiment 454,0.12mmol), O-benzotriazole-1-base-N, N, N ', and N '-tetramethyl-urea a tetrafluoro borate [TBTU] (42mg, 0.13mmol) and the product (21mg. of embodiment 445D, 0.13mmol) in DMSO (0.6mL) with the N that dropwise adds, (0.040mL 0.24mmol) reacted 2 hours under nitrogen in room temperature the N-diisopropylethylamine, under agitation poured into then in the water (10mL).With ethyl acetate (40mL) extraction gained throw out.With organic layer water (3 *) and saturated NaHCO ₃Solution washing is used MgSO ₄Drying, and concentrate.With resistates purifying on the C-18 post, with the solution gradient wash-out of acetonitrile in 0.1% TFA water (0-100%).The fraction that will contain product merges, and concentrates and is dissolved in the ethyl acetate again, uses saturated NaHCO ₃Solution washing is used the salt water washing then, uses MgSO ₄Dry and concentrated, obtain this title compound (13mg, 20%).1H?NMR(300MHz，DMSO-D6)δ?ppm1.34(d，J＝6.99Hz，6H)1.69(s，3H)3.13-3.27(m，1H)3.51(dd，J＝10.85，6.43Hz，1H)3.73(dd，J＝10.85，6.07Hz，1H)5.10(t，J＝6.07Hz，1H)5.57(s，2H)6.62(d，J＝8.46Hz，2H)6.85(d，J＝8.46Hz，1H)7.07-7.22(m，3H)7.22-7.37(m，4H)7.57-7.72(m，2H)7.85(d，J＝1.84Hz，1H)8.04(s，1H)8.58(s，1H)8.87(d，J＝8.46Hz，1H)10.14(s，1H)。

Embodiment 446

(R)-4-(4-aminophenyl sulfenyl)-N-(2,3-dihydro-1H-indenes-1-yl)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) benzamide

Embodiment 446A

(R)-4-(4-(2,3-dihydro-1H-indenes-1-base formamyl)-2-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) phenyl sulfenyl) the phenylcarbamic acid tert-butyl ester

With embodiment 385F method, by with the product of embodiment 385E and R-(-)-1-aminoidan reaction, make this title compound (productive rate 84%).1H-NMR(300MHz，DMSO-d6)δ?ppm：1.33(d，J＝6.6Hz，6H)，1.48(s，9H)，1.87-2.04(m，1H)，2.35-2.50(m，1H)，2.75-3.04(m，2H)，3.13-3.28(m，1H)，5.55(q，J＝8.1Hz，1H)，6.96(d，J＝8.4Hz，1H)，7.12-7.29(m，4H)，7.33(d，J＝8.8Hz，2H)，7.52(d，J＝8.8Hz，2H)，7.62(d，J＝8.5Hz，1H)，7.77(br-d，J＝8.4Hz，1H)，7.95(br-s，1H)，8.57(s，1H)，8.78(d，J＝8.5Hz，1H)，8.83(d，J＝8.5Hz，1H)，9.58(s，1H)，10.17(s，1H)。MS?ESI+m/z：647(M+H)，ESI-m/z：645(M-H)。

Embodiment 446B

By the method for embodiment 385G, use the product of the product alternate embodiment 385F of embodiment 446A, make this title compound (productive rate 89%).1H-NMR (300MHz, DMSO-d6) δ ppm:1.33 (d, J=7.0Hz, 6H), 1.86-2.04 (m, 1H), and 2.33-2.53 (m, 1H), 2.74-3.03 (m, 2H), 3.22 (septet, J=7.0Hz, 1H), 5.48-5.62 (m, 1H), 5.58 (s, 2H), 6.62 (d, J=8.5Hz, 2H), 6.83 (d, J=8.1Hz, 1H), 7.11-7.28 (m, 4H), 7.13 (d, J=8.5Hz, 2H), 7.63 (d, J=8.5Hz, 1H), 7.75 (dd, J=8.1,1.5Hz, 1H), 7.90 (d, J=1.5Hz, 1H), 8.56 (s, 1H), 8.73 (d, J=8.1Hz, 1H), 8.86 (d, J=8.5Hz, 1H), 10.11 (s, 1H).MS?ESI+m/z：547(M+H)，ESI-m/z：545(M-H)。

Embodiment 447

(R)-4-(4-aminophenyl sulfenyl)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino)-N-(2,2,2-three fluoro-1-phenylethyls) benzamide

Embodiment 447A

(R)-1-phenyl-N-(2,2,2-three fluoro-1-phenyl ethylidene) ethamine

With 2,2,2-trifluoroacetyl benzene (7.0g, 40mmol), R-(+)-α-Jia Jibianji amine (7.75mL, 60mmol) and the tosic acid monohydrate (0.77g, 4.0mmol) solution in toluene (40mL) refluxed 18 hours with Dean Rodney Stark couch water trap.After the cooling, with reaction mixture with toluene (50mL) dilution, with 5%NaOH (1 * 50mL), saturated NH ₄Cl (4 * 30mL) and the salt water washing, use MgSO ₄Drying, concentrated and dry in a vacuum in room temperature, obtain this title compound, be light yellow liquid (11.1g).

Embodiment 447B

(R)-2,2,2-three fluoro-1-phenyl-N-((R)-1-phenylethyl) ethamine

(11.1g, 40mmol) (5.3g, 80mmol) solution in THF (30mL) was handled 15 minutes in 5 ℃, handled 3 hours in 5 ℃ then, and in room temperature treatment 3 days with the sodium cyanoborohydride that dropwise adds in THF (60mL) with the product of embodiment 447A.With 1N HCl (to pH 1) stopped reaction, and, use K in stirring at room 3 hours ₂CO ₃Be adjusted to pH11, use ethyl acetate (100mL) extraction then.With the organic layer water (3 * 50mL) and the salt water washing, use MgSO ₄Drying, concentrated and dry in a vacuum in room temperature, obtain crude product (10.2g), be colourless liquid.The crude product of acquisition is diluted with i-PrOH (71mL), and (7.05g 37mmol) handles, and then mixture heating up is extremely refluxed with the tosic acid monohydrate.(71mL) is added in the hot solution normal hexane, then solution is cooled to room temperature gradually, and in stirring at room 2 hours.Filter and collect the gained crystal, with the mixture washing of i-PrOH and normal hexane (1:1), and in 40 ^℃Vacuum-drying is spent the night, and obtains this title compound, and (clear crystal, 9.3g): from 2,2,2-trifluoroacetyl benzene begins productive rate 52% for tosylate.

Embodiment 447C

R-(-)-2,2,2-three fluoro-1-phenyl-ethyl amines

With (R)-2,2, and 2-three fluoro-1-phenyl-N-((R)-1-phenylethyl) ethamine tosylates (10.2g, 23mmol prepare in embodiment 447B), tetrahydrobenzene (11.6mL, 113mmol) and 20%Pd (OH) ₂The mixture of/C (0.31g) in EtOH (204mL) refluxed 8 hours.After the cooling, reaction mixture is filtered by Celite pad.Filtrate is concentrated, obtain colorless solid.With resistates water (50mL) dilution, use K ₂CO ₃Be adjusted to pH11, and use CH ₂Cl ₂(3 * 50mL) extractions.With organic layer salt water washing, use MgSO ₄Drying concentrates, and obtains light brown liquid (3.9g).With the resistates underpressure distillation, obtain this title compound, be colourless liquid (3.2g): productive rate 81%.B.p.106-108℃/37mmHg?[α] _D ²³：-23.1°(c＝0.97，EtOH)1H-NMR(300MHz，CDCl3)δ?ppm：1.78(br-s，2H)，4.40(q，J＝7.4Hz，1H)，7.32-7.47(m，5H)。MS?ESI+m/z：176(M+H)。

Embodiment 447D

(R)-4-(2-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino)-4-(2,2,2-three fluoro-1-phenylethyl formamyls) phenyl sulfenyl) the phenylcarbamic acid tert-butyl ester

To 4-(4-tert-butoxycarbonyl amino-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base amino)-phenylformic acid (120mg, 0.23mmol, in embodiment 385E, make) and O-(7-azepine benzo triazol-1-yl)-N, N, N ', (97mg 0.25mmol) in the suspension in DMSO (1.2mL), drips R-(-) 2 in room temperature to N '-tetramethyl-urea hexafluorophosphate [HATU] under nitrogen, 2,2-three fluoro-1-phenyl-ethyl amines (42mg, 0.24mmol prepare in embodiment 447C) and N, the N-diisopropylethylamine (0.079mL, 0.45mmol).Mixture stirred under nitrogen in room temperature spend the night, under agitation pour into then in the water (20mL).The gained throw out is extracted with ethyl acetate (20mL).With organic layer water (3 * 15mL) and 10% NaHCO ₃(MgSO is used in 1 * 15mL) washing ₄Dry and concentrated, obtain yellow amorphous thing.This oily resistates is separated by silica gel chromatography purifying (ethyl acetate/normal hexane=3/1), obtains light yellow amorphous thing, with it by using i-Pr ₂O handles and is cured.Filter and collect the gained solid, use i-Pr ₂O washing, and, obtain this title compound in a vacuum in 60 ℃ of dryings 5 hours, be yellow crystals (93mg, 60%).1H-NMR (300MHz, DMSO-d6) δ ppm:1.34 (d, J=7.0Hz, 6H), 1.48 (s, 9H), 3.23 (septet, J=7.0Hz, 1H), 6.05 (quintets, J=8.8Hz, 1H), 6.99 (d, J=8.4Hz, 1H), 7.30-7.48 (m, 3H), 7.34 (d, J=8.8Hz, 2H), 7.52 (d, J=8.8Hz, 2H), 7.60-7.71 (m, 2H), 7.64 (d, J=8.8Hz, 1H), 7.77 (br-d, J=8.4Hz, 1H), 7.98 (br-s, 1H), 8.58 (s, 1H), 8.84 (d, J=8.8Hz, 1H), 9.49 (d, J=9.2Hz, 1H), 9.59 (s, 1H), 10.22 (s, 1H).MS?ESI+m/z：689(M+H)，ESI-m/z：687(M-H)。

Embodiment 447E

By the method for embodiment 385G, use the product of the product alternate embodiment 385F of embodiment 447D, make this title compound (productive rate 88%).

By the method for embodiment 385G, use the product of the product alternate embodiment 385F of embodiment 447D, make this title compound (productive rate 88%).1H-NMR (300MHz, DMSO-d6) δ ppm:1.34 (d, J=7.0Hz, 6H), 3.23 (septets, J=7.0Hz, 1H), 5.60 (br-s, 2H), 6.05 (quintets, J=9.2Hz, 1H), 6.63 (d, J=8.5Hz, 2H), 6.86 (d, J=8.4Hz, 1H), 7.12 (d, J=8.5Hz, 2H), 7.36-7.47 (m, 3H), 7.60-7.71 (m, 2H), 7.64 (d, J=8.5Hz, 1H), 7.75 (br-d, J=8.4Hz, 1H), 7.95 (br-s, 1H), 8.57 (s, 1H), 8.87 (d, J=8.5Hz, 1H), 9.42 (d, J=9.5Hz, 1H), 10.16 (s, 1H).MS?ESI+m/z：589(M+H)。

Embodiment 448

(R)-4-(4-aminophenyl sulfenyl)-N-(2-fluoro-1-phenylethyl)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) benzamide

Embodiment 448A

(R)-2-fluoro-1-phenyl-ethyl amine

By the method for embodiment 447A-C, in embodiment 447A, substitute 2,2 with 2-acetyl fluoride benzene (J.Fluorine Chem.2001,112,357), 2-trifluoroacetyl benzene makes this title compound.1H-NMR(300MHz，CDCl3)δ?ppm：1.83(br-s，2H)，4.22-4.61(m，3H)，7.24-7.42(m，5H)MS?ESI+m/z：140(M+H)。

Embodiment 448B

(R)-4-(4-(2-fluoro-1-phenylethyl formamyl)-2-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) phenyl sulfenyl) the phenylcarbamic acid tert-butyl ester

By the method for embodiment 447D, use the product of the product alternate embodiment 447C of embodiment 448A, make this title compound (productive rate 63%).1H-NMR (300MHz, DMSO-d6) δ ppm:1.34 (d, J=7.0Hz, 6H), 1.48 (s, 9H), 3.23 (septet, J=7.0Hz, 1H), 4.50-4.80 (m, 2H), and 5.33-5.50 (m, 1H), 6.99 (d, J=8.1Hz, 1H), and 7.24-7.40 (m, 3H), 7.33 (d, J=8.8Hz, 2H), 7.44 (d, J=7.0Hz, 2H), 7.52 (d, J=8.8Hz, 2H), 7.63 (d, J=8.4Hz, 1H), 7.76 (br-d, J=8.1Hz, 1H), 7.95 (br-s, 1H), 8.58 (s, 1H), 8.84 (d, J=8.4Hz, 1H), 9.06 (d, J=8.1Hz, 1H), 9.58 (s, 1H), 10.21 (s, 1H).MS?ESI+m/z：653(M+H)，ESI-m/z：651(M+H)。

Embodiment 448C

By the method for embodiment 385G, use the product of the product alternate embodiment 385F of embodiment 448B, make this title compound (productive rate 71%).1H-NMR (300MHz, DMSO-d6) δ ppm:1.34 (d, J=7.0Hz, 6H), 3.23 (septets, J=7.0Hz, 1H), 4.48-4.79 (m, 2H), 5.32-5.49 (m, 1H), 6.62 (d, J=8.5Hz, 2H), 6.86 (d, J=8.4Hz, 1H), 7.13 (d, J=8.5Hz, 2H), 7.28 (t, J=7.0Hz, 1H), 7.35 (t, J=7.0Hz, 2H), 7.43 (d, J=7.0Hz, 2H), 7.68 (d, J=8.1Hz, 1H), 7.73 (br-d, J=8.4Hz, 1H), 7.88 (br-s, 1H), 8.61 (br-s, 1H), 8.89 (d, J=8.1Hz, 1H), 9.00 (d, J=8.1Hz, 1H), 10.45 (br-s, 1H).MS?ESI+m/z：553(M+H)，ESI-m/z：551(M+H)。

Embodiment 449

(RS)-4-(4-amino-3-fluorophenyl sulfenyl)-N-(1-hydroxyl-2-phenyl third-2-yl)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) benzamide

Embodiment 449A

4-amino-3-fluoro thiophenol hydrochloride

With the 2-fluoroaniline (9.8mL, 0.1mol) and Sodium Thiocyanate 99 (24.9g, 0.3mol) (5.7mL, 0.11mol) cold soln in saturated NaBr-MeOH (50mL) solution was handled 2 hours in-5-0 ℃ with bromine in MeOH (55mL).After the adding, under agitation reaction mixture is poured in the cold water (200mL), used NaHCO ₃(10g) be adjusted to pH8-9, and stirred 30 minutes in 5 ℃.Filter and collect the gained crystal, use cold water washing, and spend the night, obtain crude product 2-fluoro-4-sulphur cyanato-aniline (14.5g), be light brown crystal in room temperature vacuum-drying.Mixture in EtOH (15mL) refluxed 8 hours with thick 2-fluoro-4-sulphur cyanato-aniline (14.5g) and concentrated hydrochloric acid (58mL).With the reaction mixture cooling and in stirred overnight at room temperature.Filter and collect the gained crystal, with cold EtOH and i-Pr ₂The O washing is spent the night in room temperature vacuum-drying, obtains this title compound, is hydrochloride (pale yellow crystals, 10.1g, 56%).

Embodiment 449B

4-(4-amino-3-fluorophenyl sulfenyl)-3-nitrobenzoic acid methyl esters

With 4-chloro-3-nitrobenzoic acid methyl esters (3.0g, 14mmol), the product of embodiment 449A (2.8g, 16mmol) and Cs ₂CO ₃(8.9g, 27mmol) mixture in DMF (30mL) was in 90 ℃ of heating 3 hours.Reaction mixture is cooled off, under agitation pour in the water (90mL), and extract with ethyl acetate (100mL).With the organic extract liquid water (3 * 40mL) and the salt water washing, use MgSO ₄Dry and concentrated, obtain crude product, be yellow crystals.Crystalline resistates is suspended in 30mL i-Pr ₂Among the O, and in stirring at room 30 minutes.Filter and collect crystal, use i-Pr ₂O washs, and spends the night in 40 ℃ of vacuum-dryings, obtains this title compound, is pale yellow crystals (3.6g, 82%).

Embodiment 449C

4-(3-fluoro-4-((2,2,2-three chloroethoxies) carbonylamino) phenyl sulfenyl)-3-nitrobenzoic acid methyl esters

With execute routine 449B product (2.0g, 6.2mmol) and pyridine (0.55mL is 6.8mmol) at CH ₂Cl ₂With the chloroformic acid 2,2 that dropwise adds, (0.92mL is 6.5mmol) in 5 ℃ of reactions for the 2-trichloro ethyl ester (20mL).Mixture was stirred 30 minutes and concentrated in 5 ℃.Resistates water (50mL) is diluted.Filter the gained crystal, water and i-Pr ₂O washs, and spends the night in room temperature vacuum-drying, obtains this title compound, is yellow crystals (2.9g, 93%).

Embodiment 449D

3-amino-4-(3-fluoro-4-((2,2,2-three chloroethoxies) carbonylamino) phenyl sulfenyl) methyl benzoate with the product of embodiment 449C (2.8g, 5.6mmol), iron powder (1.6g, 28mmol) and NH ₄(1.5g's Cl lenitively 28mmol) at EtOH (28mL), refluxed 1 hour in the mixture in THF (14mL) and the water (28mL).Filter with the reaction mixture cooling and by Celite pad.Filtrate is concentrated.Aqueous residue is distributed between ethyl acetate and water, and use NaHCO ₃Be adjusted to pH8-9.Organic layer is separated, and MgSO is used in water and salt water washing ₄Dry and concentrated.The oily resistates is separated (SiO by column chromatography ₂, n-hexane/ethyl acetate=3/1), obtain this title compound, be pale yellow crystals (1.3g, 48%).

Embodiment 449E

4-(3-fluoro-4-((2,2,2-three chloroethoxies) carbonylamino) phenyl sulfenyl)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) methyl benzoate

With the product of embodiment 8E (0.50g, 2.3mmol) and the suspension of product in AcOH (10mL) of embodiment 449D in 120 ℃ of heating 1 hour under nitrogen.This reaction mixture is cooled to room temperature, between ethyl acetate (50mL) and water (50mL), distributes, and under agitation use K ₂CO ₃Be adjusted to pH9-10.With the organic layer water (1 * 30mL) and the salt water washing, use MgSO ₄Drying, and concentrate.The oily resistates is separated (SiO2, n-hexane/ethyl acetate=1/3) by column chromatography, will contain the product i-Pr of fraction ₂O handles and is cured.Filter and collect the gained solid, use i-Pr ₂O washs, and spends the night in 40 ℃ of vacuum-dryings, obtains this title compound, is yellow crystals (1.26g, 85%).

Embodiment 449F

4-(4-amino-3-fluorophenyl sulfenyl)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) phenylformic acid

With the product of embodiment 449E (1.25g, 2.0mmol) in THF (12.5mL) with the LiOH aqueous solution that dropwise adds [by the LiOH monohydrate (0.42g, 10mmol) and water (8.4mL) make] in stirring at room.Mixture in 40 ℃ of stirrings 16 hours, is concentrated then.Aqueous mixture is diluted with 50mL water, and (1 * 40mL) washing under agitation is acidified to pH5-6 with 1N HCl then carefully with ethyl acetate.After 30 minutes, filter and collect the gained throw out, use cold water washing, and, obtain this title compound, be light brown crystal (0.77g, 87%) in 40 ℃ of vacuum-dryings 3 days.1H-NMR (300MHz, DMSO-d6) δ ppm:1.34 (d, J=7.0Hz, 6H), 3.23 (septets, J=7.0Hz, 1H), 5.67 (s, 2H), 7.15-7.30 (m, 2H), 6.81 (dd, J=9.2,8.4Hz, 1H), 6.91 (d, J=8.4Hz, 1H), 7.02 (dd, J=8.4,1.8Hz, 1H), 7.11 (dd, J=11.4,1.8Hz, 1H), 7.64 (d, J=8.5Hz, 1H), 7.76 (dd, J=8.4,1.9Hz, 1H), 7.86 (d, J=1.9Hz, 1H), 8.57 (s, 1H), 8.85 (d, J=8.5Hz, 1H), 10.12 (s, 1H).MS?ESI+m/z：450(M+H)，ESI-m/z：448(M-H)。

Embodiment 449G

(RS)-2-amino-2-phenylpropionic acid methyl esters

This title compound is by J.Med.Chem., and the method for describing in 1995,38,4446 is by the preparation of 2-phenylglycocoll methyl ester hydrochloride.

Embodiment 449H

(RS)-2-amino-2-phenyl third-1-alcohol

With the product of embodiment 449G (0.58g, 3.2mmol) and sodium borohydride (0.12g 3.2mmol) refluxed 1.5 hours in 75% moisture EtOH (7.6mL).Reaction mixture is concentrated, and with resistates water (15mL) washing, with ethyl acetate (2 * 25mL) extractions.With the organic layer water (2 * 10mL) and the salt water washing, use MgSO ₄Drying concentrates, and obtains this title compound, is colourless viscosity oily matter, and it is at crystallization after a while (0.27g, 55%).1H-NMR(300MHz，CDCl3)δ?ppm：1.46(s，3H)，1.86(br-s，2H)，3.59(d，J＝10.7Hz，1H)，3.65(d，J＝10.7Hz，1H)，7.22-7.30(m，1H)，7.31-7.41(m，2H)，7.41-7.49(m，2H)。MS?ESI+m/z：152(M+H)。

Embodiment 449I

Product (150mg to embodiment 449F, 0.31mmol) and O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate [HATU] (132mg, 0.21mmol) product (49mg of adding embodiment 449H in the mixture in DMSO (1.5mL), 0.32mmol), and under nitrogen, drip N in room temperature, and the N-diisopropylethylamine (0.11mL, 0.61mmol).Mixture stirring at room 2 hours, is under agitation poured in the water (30mL) then.(1 * 30mL) extracts with ethyl acetate with the gained throw out.With organic layer water (3 * 15mL) and 10% NaHCO ₃(MgSO is used in 1 * 15mL) washing ₄Drying, and concentrate.Resistates by column chromatography purifying (SiO2, ethyl acetate/MeOH=98/2-95/5 gradient elution), is obtained yellow solid.The product that will contain fraction is developed with ethyl acetate, obtains this title compound, is pale yellow crystals (86mg, 48%).1H-NMR (300MHz, DMSO-d6) δ ppm:1.34 (d, J=7.0Hz, 6H), 1.69 (s, 3H), 3.23 (septet, J=7.0Hz, 1H), 3.52 (dd, J=11.0,6.3Hz, 1H), 3.74 (dd, J=11.0,5.9Hz, 1H), 5.09 (dd, J=6.3,5.9Hz, 1H), 5.61 (s, 2H), 6.79 (dd, J=9.2,8.4Hz, 1H), 6.95 (d, J=8.5Hz, 1H), 6.99 (dd, J=8.4,1.8Hz, 1H), 7.08 (dd, J=11.4,1.8Hz, 1H), 7.17 (br-t, J=7.0Hz, 1H), 7.27 (t, J=7.0Hz, 2H), 7.33 (br-d, J=7.0Hz, 2H), 7.64 (d, J=8.4Hz, 1H), 7.69 (dd, J=8.5,1.8Hz, 1H), 7.87 (d, J=1.8Hz, 1H), 8.07 (s, 1H), 8.58 (s, 1H), 8.86 (d, J=8.4Hz, 1H), 10.17 (s, 1H).MS?ESI+m/z?583(M+H)，ESI-m/z：581(M-H)。

Embodiment 450

(R)-4-(4-aminophenyl sulfenyl)-N-(1-hydroxyl-2-phenyl third-2-yl)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) benzamide

Embodiment 450A

(R)-2-formamido--2-phenylpropionic acid

This title compound is by J.Chem.S ℃., the method for describing in 1912,101,390 is by the product preparation of embodiment 445A.

Embodiment 450B

(R)-2-amino-2-phenylpropionic acid ethyl ester

By the method for embodiment 445C, use the product of the product alternate embodiment 445B of embodiment 450A, make this title compound (1.12g, 76%).

Embodiment 450C

(R)-2-amino-2-phenyl third-1-alcohol

By the method for embodiment 445D, use the product of the product alternate embodiment 445C of embodiment 450B, prepare this title compound, obtain colourless viscosity oily matter (0.57g, 67%).[α] _D ²³：-13.8°(c＝1.05，EtOH)。1H-NMR(300MHz，DMSO-d6)δ?ppm：1.28(s，3H)，1.76(br-s，2H)，3.39(d，J＝5.2Hz，2H)，4.72(t，J＝5.2Hz，1H)，7.12-7.20(m，1H)，7.22-7.32(m，2H)，7.44-7.54(m，2H)。MS?ESI+m/z：152(M+H)。

Embodiment 450D

By the method for embodiment 445E, use the product of the product alternate embodiment 445D of embodiment 450C, prepare this title compound (productive rate 58%). ¹H-NMR (300 MHz, DMSO-d6) δ ppm 1.34 (d, J=7.0Hz, 6H), 1.69 (s, 3H), 3.23 (septet, J=7.0Hz, 1H), 3.51 (dd, J=11.0,6.3Hz, 1H), 3.73 (dd, J=11.0,5.8Hz, 1H), 5.09 (dd, J=6.3,5.8Hz, 1H), 5.57 (br-s, 2H), 6.62 (d, J=8.4Hz, 2H), 6.85 (d, J=8.1Hz, 1H), 7.12 (d, J=8.4Hz, 1H), 7.17 (br-t, J=7.0Hz, 1H), 7.27 (t, J=7.0Hz, 2H), 7.32 (br-d, J=7.0Hz, 2H), 7.64 (d, J=8.9Hz, 1H), 7.67 (dd, J=8.1,1.8Hz, 1H), 7.85 (d, J=1.8Hz, 1H), 8.03 (s, 1H), 8.58 (s, 1H), 8.87 (d, J=8.9Hz, 1H), 10.13 (s, 1H).MS?ESI+m/z：565(M+H)，ESI-m/z：563(M-H)。

Embodiment 451

(RS)-4-(4-aminophenyl sulfenyl)-3-(6-fluoro-7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino)-N-(1-hydroxyl-2-phenyl third-2-yl) benzamide

Embodiment 451A

N '-(3-cyano group-5-fluoro-6-isopropyl pyridine-2-yl)-N, N-dimethyl methyl imines acid amides

To N '-(3-cyano group-6-sec.-propyl-pyridine-2-yl)-N, (3.0g is 14mmol) at anhydrous CH for N-dimethyl-carbonamidine ₃In the solution among the CN (139mL), add 1-(chloromethyl)-4-fluoro-1,4-diaza-bicyclo [2.2.2] octane two (a tetrafluoro borate) [SELECTFLUOR in room temperature ^TM] (5.4g, 15mmol).Mixture was stirred 18 hours under nitrogen in room temperature, concentrate then.With resistates with ethyl acetate (100mL) dilution, water (5 * 40mL) and the salt water washing, use MgSO ₄Drying, and concentrate.With oily resistates ketone column chromatography purifying (SiO ₂, n-hexane/ethyl acetate=3/1) and obtain this title compound, be clear crystal (0.63g, 19%). ¹H-NMR (300MHz, CDCl3) δ ppm:1.26 (d, J=7.0Hz, 6H), 3.15 (s, 3H), 3.16 (s, 3H), 3.29 (septet-d, J=7.0,1.9Hz, 1H), 7.41 (d, J=8.8Hz, 1H), 8.55 (s, 1H).MS?ESI+m/z：235(M+H)。

Embodiment 451B

4-(4-(tert-butoxycarbonyl amino) phenyl sulfenyl)-3-(6-fluoro-7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) methyl benzoate

By the method for embodiment 385D, use the product of the product alternate embodiment 8E of embodiment 451A, make this title compound (productive rate 62%).

Embodiment 451C

4-(4-(tert-butoxycarbonyl amino) phenyl sulfenyl)-3-(6-fluoro-7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) phenylformic acid

By the method for embodiment 385E, use the product of the product alternate embodiment 385D of embodiment 451B, make this title compound (productive rate 84%). ¹H-NMR(300?MHz，DMSO-d6)δ?ppm：1.34(d，J＝7.0Hz，6H)，1.48(s，9H)，3.43-3.58(m，1H)，6.95(d，J＝8.4Hz，1H)，7.36(d，J＝8.8Hz，2H)，7.54(d，J＝8.8Hz，2H)，7.76(dd，J＝8.4，1.8Hz，1H)，7.89(d，J＝1.8Hz，1H)，8.59(s，1H)，8.71(d，J＝10.3Hz，1H)，9.61(s，1H)，10.11(s，1H)，12.99(br-s，1H)。MS?ESI+m/z：550(M+H)ESI-m/z：548(M-H)。

Embodiment 451D

4-(4-aminophenyl sulfenyl)-3-(6-fluoro-7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) phenylformic acid

(0.23g is 0.4mmo) at CH with the product of embodiment 451C ₂Cl ₂Use the trifluoroacetic acid [TFA] that dropwise adds (1.15mL) in room temperature treatment (4.6mL), stirred then 1 hour.Reaction mixture is concentrated.With residue diluted with water, use K ₂CO ₃Alkalization is in stirred overnight at room temperature.With 1N HCl with pH regulator to pH5-6, in stirring at room 1 hour, filter and collect gained throw out, water and i-Pr ₂O washs, and spends the night in 40 ℃ of vacuum-dryings, obtains this title compound, is yellow crystals (0.13g, 71%). ¹H-NMR(300MHz，DMSO-d6)δ?ppm：1.34(d，J＝7.0Hz，6H)，3.42-3.60(m，1H)，5.64(br-s，2H)，6.64(d，J＝8.4Hz，2H)，6.84(d，J＝7.7Hz，1H)，7.14(d，J＝8.4Hz，2H)，7.73(br-d，J=7.7Hz，1H)，7.83(br-s，1H)，8.58(s，1H)，8.65-8.80(m，1H)，10.10(s，1H)，12.91(br-s，1H)。MS?ESI+m/z：450(M+H)，ESI-m/z：448(M-H)。

Embodiment 451E

By the method for embodiment 449I, use the product of the product alternate embodiment 449H of embodiment 451D, make this title compound (productive rate 30%). ¹H-NMR(300MHz，DMSO-d6)δ?ppm：1.34(d，J＝7.0Hz，6H)，1.69(s，3H)，3.43-3.58(m，2H)，3.74(dd，J＝10.7，5.9Hz，1H)，5.09(t，J＝5.9Hz，1H)，5.57(br-s，2H)，6.62(d，J＝8.5Hz，2H)，6.86(d，J＝8.5Hz，1H)，7.12(d，J＝8.5Hz，2H)，7.17(br-t，J＝7.0Hz，1H)，7.27(t，J＝7.0Hz，2H)，7.33(br-d，J＝7.0Hz，2H)，7.68(dd，J＝8.5，1.5Hz，1H)，7.83(d，J＝1.5Hz，1H)，8.04(s，1H)，8.60(s，1H)，8.76(d，J＝10.3Hz，1H)，10.10(s，1H)。MS?ESI+m/z：583(M+H)，ESI-m/z：581(M-H)。

Embodiment 452

(R)-4-(4-amino-3-fluorophenyl sulfenyl)-N-(1-hydroxyl-2-phenyl third-2-yl)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) benzamide

By the method for embodiment 449I, use the product of the product alternate embodiment 449H of embodiment 450C, make this title compound (productive rate 61%). ¹H-NMR (300MHz, DMSO-d6) δ ppm:1.34 (d, J=7.0Hz, 6H), 1.69 (s, 3H), 3.23 (septet, J=7.0Hz, 1H), 3.52 (dd, J=11.0,6.2Hz, 1H), 3.74 (dd, J=11.0,5.5Hz, 1H), 5.09 (dd, J=6.2,5.5Hz, 1H), 5.61 (s, 2H), 6.79 (dd, J=9.2,8.4Hz, 1H), 6.95 (d, J=8.5Hz, 1H), 6.99 (dd, J=8.4,1.8Hz, 1H), 7.08 (dd, J=11.4,1.8Hz, 1H), 7.17 (br-t, J=7.0Hz, 1H), 7.27 (t, J=7.0Hz, 2H), 7.33 (br-d, J=7.0Hz, 2H), 7.64 (d, J=8.5Hz, 1H), 7.70 (br-d, J=8.5Hz, 1H), 7.86 (br-s, 1H), 8.07 (br-s, 1H), 8.58 (s, 1H), 8.86 (d, J=8.5Hz, 1H), 10.18 (s, 1H).MS?ESI+m/z：583(M+H)，ESI-m/z：581(M-H)。

Embodiment 453

(S)-4-(4-aminophenyl sulfenyl)-3-(6-fluoro-7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino)-N-(1-phenylethyl) benzamide

Embodiment 453A

(S)-4-(2-(6-fluoro-7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino)-4-(1-phenylethyl formamyl) phenyl sulfenyl) the phenylcarbamic acid tert-butyl ester

By the method for embodiment 385F, use the product of the product alternate embodiment 385E of embodiment 451C, make this title compound.1H-NMR(300MHz，DMSO-d6)δ?ppm：1.34(d，J＝7.0Hz，6H)，1.45(d，J＝7.3Hz，3H)，1.47(s，9H)，3.42-3.57(m，1H)，5.07-5.22(m，1H)，7.00(d，J＝8.1Hz，1H)，7.21(br-t，J＝7.0Hz，1H)，7.31(t，J＝7.0Hz，2H)，7.31(d，J＝8.8Hz，2H)，7.37(d，J＝7.0Hz，2H)，7.49(d，J＝8.8Hz，2H)，7.75(dd，J＝8.1， 1.5Hz，1H)，7.92(d，J＝1.5Hz，1H)，8.58(s，1H)，8.70(d，J＝10.3Hz，1H)，8.81(d，J＝8.1Hz，1H)，9.57(s，1H)，10.13(s，1H)。MS?ESI+m/z：653(M+H)，ESI-m/z：651(M-H)。

Embodiment 453B

By the method for embodiment 385G, use the product of the product alternate embodiment 385F of embodiment 453A, make this title compound (70%).1H-NMR(300MHz，DMSO-d6)δppm：1.34(d，J＝7.0Hz，6H)，1.45(d，J＝7.0Hz，3H)，3.43-3.58(m，1H)，5.07-5.22(m，1H)，5.58(s，2H)，6.62(d，J＝8.4Hz，2H)，6.84(d，J＝8.5Hz，1H)，7.12(d，J＝8.4Hz，2H)，7.21(br-t，J＝7.0Hz，1H)，7.30(t，J＝7.0Hz，2H)，7.36(br-d，J＝7.0Hz，2H)，7.72(dd，J＝8.5，1.8Hz，1H)，7.87(d，J＝1.8Hz，1H)，8.58(s，1H)，8.75(d，J＝10.0Hz，1H)，8.75(d，J＝7.3Hz，1H)，10.08(s，1H)。MS?ESI+m/z：553(M+H)，ESI-m/z：551(M-H)。

Embodiment 454

4-(4-aminophenyl sulfenyl)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) phenylformic acid two-trifluoroacetate

(808mg 1.52mmol) is dissolved in the methylene dichloride (8mL), handles with trifluoroacetic acid (8mL), and in stirring at room 1 hour the product of embodiment 385E.Remove by rotary evaporation and to desolvate, and with the oily resistates be dissolved in dichloromethane/hexane (25mL, 1:1v/v) in and reconcentration.Dry under high vacuum, obtained this title compound, be blackyellow powder (1.01g, quantitative). ¹H?NMR(300MHz，DMSO-D6)δ?ppm?1.37(d，J＝6.62Hz，6H)3.21-3.43(m，1H)6.65(d，J＝8.46Hz，2H)6.92(d，J＝8.09Hz，1H)7.15(d，J＝8.46Hz，2H)7.83(dd，J＝8.27，1.65Hz，1H)7.90(d，J＝1.84Hz，1H)7.95(d，J＝8.46Hz，1H)8.92(s，1H)9.05(d，J＝8.82Hz，1H)；MS(ESI+)m/z?432(M+H) ⁺，MS(ESI-)m/z?430(M-H) ^-。

Embodiment 455

4-(4-aminophenyl sulfenyl)-N-(1-hydroxy-2-methyl third-2-yl)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) benzamide

To the product of the embodiment 454 in DMSO (4ml) ((0.238g, 0.55mmol) in, add 2-amino-2-methyl third-1-alcohol (0.059g, 0.66mmol), add N then, and N-diisopropyl ethyl amine (Hunigs alkali) (0.192ml, 1.10mmol), add O-benzotriazole-1-base-N at last, N, N ', N '-tetramethyl-urea a tetrafluoro borate [TBTU] (0.195g, 0.606mmol), and under nitrogen, in room temperature the gained mixture was stirred 2 hours.(0.184g, 0.572mmol) (0.190ml 1.10mmol), and continues to stir 30 minutes the TBTU of second equal portions of adding again, and will be reflected between ethyl acetate and the water this moment distributes with Hunigs alkali.With water ethyl acetate extraction twice, and with the organic extract liquid merging, and wash with water 3 times, use dried over mgso then, and vacuum concentration.Crude product by silicagel column purified by flash chromatography (ethyl acetate-hexane-methyl alcohol), is used preparation (C then ₁₈) HPLC (methyl alcohol is at the solution gradient wash-out of 0.1%TFA/ water) purifying.The fraction vacuum concentration that will contain product, and dilute with 5% sodium hydrogen carbonate solution.The gained throw out by isolated by vacuum filtration, is washed with water, and vacuum-drying, obtain required product (0.0766g, 28%), be light yellow solid.1H?NMR(300MHz，DMSO-D6)δ?ppm?1.28(s，6H)1.34(d，J＝6.62Hz，6H)3.16-3.29(m，1H)3.48(d，J＝5.88Hz，2H)4.88(t，J＝5.88Hz，1H)5.57(s，2H)6.61(d，J＝8.46Hz，2H)6.81(d，J＝8.46Hz，1H)7.11(d，J＝8.46Hz，2H)7.47(s，1H)7.61-7.64(m，2H)7.79(s，1H)8.57(s，1H)8.87(d，J＝8.46Hz，1H)10.10(s，1H)。(ESI+)m/z?503.3(M+H)+(ESI-)m/z?501.3(M-H)-。

Embodiment 456

4-(4-aminophenyl sulfenyl)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino)-N-(2-methyl isophthalic acid-phenoxy group third-2-yl) benzamide

Embodiment 456A

4-(2-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino)-4-(2-methyl isophthalic acid-phenoxy group third-2-base formamyl) phenyl sulfenyl) the phenylcarbamic acid tert-butyl ester

By the method for embodiment 385F, use according to JACS, 2-methyl isophthalic acid-phenoxy group third-2-amine hydrochlorate of preparation substitutes S-(-)-α-Jia Jibianji amine described in 73,2584 (1951), makes this title compound (productive rate 100%).

Embodiment 456B

By the method for embodiment 385G, use the product of the product alternate embodiment 385F of embodiment 456B, make this title compound (productive rate 100%).1H?NMR(300MHz，DMSO-D6)δ?ppm?1.31(d，J＝6.99Hz，6H)1.43(s，6H)3.16(s，1H)4.15(s，2H)5.53(s，2H)6.61(d，J＝8.46Hz，2H)6.65-6.72(m，1H)6.90(t，J＝7.35Hz，3H)7.11(d，J＝8.46Hz，2H)7.17-7.36(m，2H)7.46(s，2H)7.70(s，1H)7.82(s，1H)8.38(s，1H)8.75(s，1H)10.05-10.32(m，1H)。(ESI+)m/z?579.4(M+H) ⁺，(ESI-)m/z?577.4(M-H) ^-。

Embodiment 457

4-(4-aminophenyl sulfenyl)-N-(4-hydroxyl-2-phenyl fourth-2-yl)-3-(7-isopropyl pyridine also [2,3-d] pyrimidine-4-base is amino) benzamide

Embodiment 457A

4-(t-butyldimethylsilyl oxygen base) fourth-2-ketone

With 4-hydroxyl fourth-2-ketone (1.0g, 11.35mmol), (1.16g, 17mmol) (1.7g is 11.35mmol) in room temperature reaction 3 hours with tert-butyldimethylsilyl chloride in DMF (15ml) for imidazoles.Reaction ether and water dispenser.With water several times with extracted with diethyl ether.The organism that merges is washed with water several times, with dried over mgso and vacuum concentration, obtain this title compound then, be clarification oily matter (2.16g, 94%).

Embodiment 457B

4-(t-butyldimethylsilyl oxygen base)-2-phenyl fourth-2-alcohol

With the product of embodiment 457A (2.0g, 9.88mmol) in anhydrous THF (50ml) in 0 ℃ under nitrogen with the phenylmagnesium bromide that drips via syringe at ether (5.0ml, 15mmol) the 0.3M solution reaction in and stirring 1 hour.To react by dripping saturated ammonium chloride solution and end, and will react with ether and water dispenser.With the organism dried over mgso that merges, and vacuum concentration, obtain required product, be clarification oily matter (2.71g, quantitative).

Embodiment 457C

3-phenyl fourth-1, the 3-glycol

With the product of embodiment 457B (2.71g, 9.66mmol) in THF (50ml) with fluoridize four-normal-butyl ammonium (TBAF) at THF (10.6ml, 10.6mmol) the 1.0M solution reaction in and stirring 0.5 hour.To react with ethyl acetate and salt water dispenser.With the water ethyl acetate extraction.With the extraction liquid that merges with dried over mgso and vacuum concentration.Resistates by silicagel column purified by flash chromatography (ethyl acetate-hexane), is obtained required glycol, be clarification oily matter (1.38g, 86%).

Embodiment 457D

2,4-dimethyl-4-phenyl-5,6-dihydro-4H-1,3-oxazine

Under nitrogen, stir fast and cooling under so that internal temperature remains on 6 ℃ or following speed, acetonitrile (2.6ml, 50mmol) product of the embodiment 457C in (0.994,5.98mmol) be added drop-wise in the vitriol oil (7ml).After the adding, with reaction mixture in 0 ° of restir 45 minutes, then by being poured on stopped reaction on ice.With dichloromethane extraction 3 times of gained solution.Water with ice-cooled, with the NaOH alkalization, and is used extracted with diethyl ether.The extraction liquid that merges is washed with water once, use dried over mgso, and vacuum concentration, obtain required product, be clarification oily matter (0.886g, 78%).

Embodiment 457E

3-amino-3-phenyl fourth-1-alcohol

With the product of embodiment 457D (0.886g, 4.68mmol) at methyl alcohol (15ml) in room temperature and 6N NaOH (15ml) reaction, and with the gained mixture under nitrogen in 80 ℃ of heated overnight.With methyl alcohol vacuum-evaporation, and with aqueous residue by separating with dichloromethane extraction.With the extraction liquid dried over sodium sulfate that merges, and vacuum concentration, obtain this title compound (0.717g, 93%), be light yellow solid, it is used under the situation that need not be further purified.

Embodiment 457F

To the product of the embodiment 454 in DMSO (800ul) (0.050g, 0.117mmol) in, add 3-amino-3-phenyl fourth-1-alcohol (0.023g, 0.140mmol), add N then, and N-diisopropyl ethyl amine (Hunigs alkali) (41ul, 0.233mmol), add O-benzotriazole-1-base-N at last, N, N ', N '-tetramethyl-urea a tetrafluoro borate [TBTU] (0.045g, 0.142mmol), and with the gained mixture under nitrogen in stirring at room 1 hour.To react with ethyl acetate and water dispenser.Water with ethyl acetate extraction twice, is merged organism, and washes with water three times, use dried over mgso then, and vacuum concentration.Crude product is passed through preparation (C ₁₈) HPLC purifying (methyl alcohol-0.1% TFA/ water).The fraction vacuum concentration that will contain product with the dilution of 5% sodium hydrogen carbonate solution, and is used ethyl acetate extraction.With the extraction liquid dried over mgso that merges, and vacuum concentration is to doing.The gained yellow solid is developed with ether, and collected, obtain required product (0.0112g, 17%) by vacuum filtration.1H?NMR(300MHz，DMSO-D6)δ?ppm?1.33(d，J＝6.99Hz，6H)1.77(s，3H)1.90-2.16(m，2H)3.14-3.28(m，1H)3.46-3.57(m，J＝5.88Hz，1H)4.98(t，J＝4.23Hz，1H)5.57(s，2H)6.62(d，J＝8.46Hz，2H)6.82(d，1H)7.06-7.22(m，3H)7.22-7.35(m，5H)7.56-7.67(m，2H)7.76(s，1H)8.57(s，1H)8.72(s，1H)8.85(d，1H)10.12(s，1H)。(ESI+)m/z?579.3(M+H)+，(ESI-)m/z?577.3(M-H)-。

Embodiment 458

4-(4-amino-phenyl sulfenyl)-N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzsulfamide

Embodiment 458A

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

With 4-chloro-3-nitrobenzene sulfonyl chloride (2.561g, 10mmol) solution in acetate (20mL) with the 4-bromaniline (1.72g, 10mmol) and anhydrous sodium acetate (1.23g 15mmol) handles, and heats 30 minutes in 100 ° then.Reaction is cooled to room temperature, and under vacuum, removes acetate by rotary evaporation.Resistates is dissolved in the ethyl acetate (100mL), and water (2 * 25mL) and salt solution (25mL) washing.With the organic phase anhydrous sodium sulfate drying, filter, and vacuum concentration, with this oily matter dichloromethane/hexane co-evaporated.By the silica gel chromatography purifying, use 5% ethyl acetate/dichloromethane as eluent then with methylene dichloride, obtained this title compound, be yellow solid (2.038g, 52%).

Embodiment 458B

4-(4-amino-phenyl sulfenyl)-N-(4-bromo-phenyl)-3-nitro-benzsulfamide

With the product of embodiment 458A (500mg, 1.277mmol), the 4-aminothiophenol (240mg, 1.915mmol) and anhydrous sodium acetate (524mg, the 6.384mmol) heating 1 hour under refluxing under the nitrogen atmosphere of the mixture in dehydrated alcohol (9mL).Reaction is cooled to room temperature, and under vacuum, removes ethanol by rotary evaporation.Resistates is dissolved in the ethyl acetate (100mL) and water (2 * 50mL) and salt solution (50mL) wash.With the organic phase anhydrous sodium sulfate drying, filter, and vacuum concentration, with this oily matter dichloromethane/hexane co-evaporated, obtain this title compound, be orange foam (613mg, 100%).

Embodiment 458C

4-[4-(4-bromo-phenyl sulfamoyl)-2-nitro-phenyl sulfenyl]-phenyl }-t-butyl carbamate

(613mg, 1.277mmol) anhydrous 1, (418mg 1.92mmol) in room temperature treatment, will be reflected under the nitrogen atmosphere under refluxing heating 3 hours to the solution in the 4-dioxane (10mL) then with tert-Butyl dicarbonate with the product of embodiment 458B.Reaction is cooled to room temperature, adds tert-Butyl dicarbonate (500mg) again, and will react and reflux 17 hours.Reaction is cooled to room temperature, and under vacuum, removes and desolvate by rotary evaporation.Resistates by the silica gel column chromatography purifying, as eluent, has been obtained this title compound with 3% ethyl acetate/dichloromethane, be yellow solid (512mg, 69%).

Embodiment 458D

4-[2-amino-4-(4-bromo-phenyl sulfamoyl)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

With the product of embodiment 458C (510mg, 0.879mmol), iron powder (302mg, 5.40mmol) and ammonium chloride (308mg, 5.76mmol) in water (4mL) and ethanol (8mL) in 80 ° of heating 40 minutes.Reaction is cooled to room temperature, with ethyl acetate (100mL) dilution, and water (2 * 50mL) and salt solution (50mL) wash.With the organic phase anhydrous sodium sulfate drying, filter, concentrate by rotary evaporation in vacuo, obtained this title compound, be white foam shape thing (436mg, 90%).

Embodiment 458E

4-[4-(4-bromo-phenyl sulfamoyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-t-butyl carbamate

With the product of embodiment 8E (59mg, 0.2725mmol) and the product of embodiment 458D (150mg, 0.2725mmol) solution in acetate (4mL) is being preheated in 140 ℃ the oil bath and was stirring 25 minutes.Reaction is cooled to room temperature,, concentrates by rotary evaporation in vacuo with hexane (100mL) dilution, and with dichloromethane/hexane (4 *) co-evaporated.With resistates vacuum-drying, by the silica gel chromatography purifying, 4% ethanol/methylene has obtained this title compound as eluent, is brown solid (67mg, 34%) then.

Embodiment 458F

With the product of embodiment 458E (44mg, 0.061mmo1) with trifluoroacetic acid (2mL) in methylene dichloride (2mL) in room temperature treatment 30 minutes.Remove by rotary evaporation in vacuo and to desolvate, and remaining oily matter is dry under high vacuum.By the silica gel chromatography purifying, as eluent, obtained this title compound with 5% ethanol/methylene, be trifluoroacetate (25mg, 48%). ¹H?NMR(300?MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.62Hz，6H)，3.13-3.38(m，1H)，6.63(d，J＝8.46Hz，2H)，6.87(d，J＝7.72Hz，1H)，7.01-7.09(d，J＝8.82Hz，2H)，7.12(d，J＝8.46Hz，2H)，7.44(d，J＝8.82Hz，2H)，7.61(dd，J＝7.72，1.47Hz，1H)，7.71(s，1H)，7.81(dd，J＝6.62，1.47Hz，1H)，8.66-8.80(m，1H)，8.90(d，J＝6.99Hz，1H)，10.55(s，1H)；MS(ESI+)m/z?621/623(M+H) ⁺。

Embodiment 459

4-(4-amino-phenyl sulfenyl)-N-(4-bromo-phenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzsulfamide

Use the method for describing among the embodiment 458E; product with the product alternate embodiment 8E of embodiment 9B; the product of embodiment 458D and the product of embodiment 9B are reacted; obtain { 4-[4-(4-bromo-phenyl sulfamoyl)-2-(7-methyl-pyrido [2; 3-d] pyrimidine-4-base amino)-the phenyl sulfenyl]-phenyl }-t-butyl carbamate, it according to the method deprotection of describing among the embodiment 458F, is passed through the silica gel chromatography purifying then; obtain this title compound, be trifluoroacetate. ¹H?NMR(300MHz，DMSO-D6)δ?ppm：2.74(s，3H)，6.64(d，J＝8.46Hz，2H)，6.89(d，J＝8.09Hz，1H)，7.05(d，J＝9.19Hz，2H)，7.12(d，J＝8.82Hz，2H)，7.44(d，J＝8.82Hz，2H)，7.63(dd，J＝7.72，0.74Hz，1H)，7.74(s，1H)，7.79(dd，J＝7.72，1.10Hz，1H)，8.70-8.83(m，1H)，8.88(d，J＝8.09Hz，1H)，10.55(s，1H)；MS(ESI+)m/z?593/595(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 divide must 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 HCVRNA (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 (QiagenRNAeasy) 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 HCVRNA 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 0.3nM 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.# M2128) 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 TC of representative compounds of the present invention ₅₀Value 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, I (a), I (b), I (c), I (d), I (e), I (f), I (g) or I (h) compound.Preferably, each compound is independently selected from the compound of embodiment 1-457.

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; OmegaIFN (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 A IFN-α 2a (F.Hoffmann-La Roche 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 LDD, Basel, Switzerland); CellCept HCV IgG immunosuppressor (F.Hoffmann-La Roche LTD, Basel, Switzerland); Wellferonlymphoblastoid IFN-α n1 (GlaxoSmithKline plc, Uxbridge, UK); Albuferon-α albumin IFN-α 2b (Human Genome Sciences Inc., Rockville, MD); The Levovirin ribavirin (ICN Pharmaceuticals, Costa Mesa, CA); IDN-6556 caspase inhibitor (Idun Pharmaceuticals Inc., San Diego, CA); The agent of IP-501 fibrosis (Indevus Pharmaceuticals Inc., Lexington, MA); Actimmune INF-γ (InterMune Inc., Brisbane, CA); Infergen A IFNalfacon-I (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 (MaximPharmaceuticals inc., San Diego, CA); The Ceplene immunomodulator (MaximPharmaceuticals Inc., San Diego, CA); Civacir HCV IgG immunosuppressor anti-(NabiBiopharmaceuticals 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); Levovi rin 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 Lilly and Co., Inc., Indianapolis, IN); The natural IFN-α of Omniferon (Viragen Inc., Plantation, FL); XTL-002 monoclonal antibody (XTLBiopharmaceuticals);

(compound VX-950 hereinafter, Vertex Pharmaceuticals 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, I (a), I (b), I (c), I (d), I (e), I (f), I (g) or I (h) compound or embodiment 1-457, and each other whose anti-HCV agent is independently selected from HCV RNA 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), I (c), I (d), I (e), I (f), I (g) or I (h) compound or embodiment 1-457.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 HCV RNA 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), I (c), I (d), I (e), I (f), I (g) or I (h) compound or embodiment 1-457.

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), I (c), I (d), I (e), I (f), I (g) or I (h) compound or embodiment 1-457.

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), I (c), I (d), I (e), I (f), I (g) or I (h) compound or embodiment 1-457.

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), I (c), I (d), I (e), I (f), I (g) or I (h) compound or embodiment 1-457.

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), I (c), I (d), I (e), I (f), I (g) or I (h) compound or embodiment 1-457.

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, I (a), I (b), I (c), I (d), I (e), I (g), I (g) or I (h) compound or embodiment 1-457 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, I (a), I (b), I (c), I (d), I (e), I (f), I (g) or I (h) compound or embodiment 1-457 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, I (a), I (b), I (c), I (d), I (e), I (f), I (g) or I (h) compound or embodiment 1-457 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, I (a), I (b), I (c), I (d), I (e), I (f), I (g) or I (h) compound or embodiment 1-457 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 be based on its route of administration, use method well-known in the art to prepare. 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 (MarcelDecker, 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), I (c), I (d), I (e), I (f), I (g) or I (h) compound or embodiment 1-457, 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), I (c), I (d), I (e), I (f), I (g) or I (h) compound or embodiment 1-457 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 formula I (a), I (b), I (c), the I (d) of being selected from, The compounds of this invention or its salt, solvate or the prodrug of I (e), I (f), I (g) or I (h) compound or embodiment 1-457 compound are with a kind of, two or more HCV RNA RNA-dependent AG14361 (for example those that describe among WO0190121 (A2), US6348587B1, WO0160315, WO0132153, EPI162196A1 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), I (c), I (d), I (e), I (f), I (g) or I (h) compound or embodiment 1-457 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), I (c), I (d), I (e), I (f), I (g) or I (h) compound or embodiment 1-457 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), I (c), I (d), I (e), I (f), I (g) or I (h) compound or example I-457 compound, and the other treatment agent of using comprises that one 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), I (c), I (d), I (e), I (f), I (g) or I (h) compound or embodiment 1-457 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), I (c), I (d), I (e), I (f), I (g) or I (h) compound or embodiment 1-457 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), I (c), I (d), I (e), I (f), I (g) or I (h) compound or embodiment 1-457 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, I (a), I (b), I (c), I (d), I (e), I (f), I (g) or I (h) 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, I (a), I (b), I (c), I (d), I (e), I (f), I (g) or I (h) 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 formula I, the I (a) of patient's administering therapeutic significant quantity of this treatment of needs, I (b), I (c), I (d), I (e), I (f), I (g) or I (h) 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, I (a), I (b), I (c), I (d), I (e), I (f), I (g) or I (h) 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 comprise the vaccine of antigen and adjuvant and the therapeutical agent of second antiviral agent or its combination is with the formula I that treats significant quantity, I (a), I (b), I (c), I (d), I (e), I (f), I (g) or I (h) 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 host immune conditioning agent and suppresses second antiviral agent that HCV duplicates or the therapeutical agent and formula I, I (a), I (b), I (c), I (d), I (e), I (f), I (g) or I (h) 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, I (a), I (b), I (c), I (d), I (e), I (f), I (g) or I (h) 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, I (a), I (b), I (c), I (d), I (e), I (f), I (g) or I (h) 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, I (a), I (b), I (c), I (d), I (e), I (f), I (g) or I (h) 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, I (a), I (b), I (c), I (d), I (e), I (f), I (g) or I (h) 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, I (a), I (b), I (c), I (d), I (e), I (f), I (g) or I (h) 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, I (a), I (b), I (c), I (d), I (e), I (f), I (g) or I (h) 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 Pharmaceuticals Holdings Inc., Chadds Ford, PA); Roferon A IFN-α 2a (F.Hoffmann-La Roche 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); Wellferonlymphoblastoid IFN-α n1 (GlaxoSmithKline plc, Uxbridge, UK); Albuferon-α albumin IFN-α 2b (Human Genome Sciences Inc., Rockville, MD); The Levovirin ribavirin (ICN Pharmaceuticals, Costa Mesa, CA); IDN-6556 caspase inhibitor (Idun Pharmaceuticals Inc., San Diego, 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/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 Cbrporation, 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 Lilly and Co., Inc., Indianapolis, IN); The natural IFN-α of Omniferon (Viragen Inc., Plantation, FL); XTL-002 monoclonal antibody (XTLBiopharmaceuticals); Compound VX-950 (Vertex Pharmaceuticals Inc.); Compound S CH503034 (Sche ring-Plough Co.); With compound GS9137 (GileadSciences, 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), I (c), I (d), I (e), I (f), I (g) or I (h) 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), I (c), I (d), I (e), I (f), I (g) or I (h) 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 HCVRNA 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), I (c), I (d), I (e), I (f), I (g) or I (h) 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 HCV RNA 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, I (a), I (b), I (c), I (d), I (e), I (f), I (g) or I (h) 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, I (a), I (b), I (c), I (d), I (e), I (f), I (g) or I (h) 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, I (a), I (b), I (c), I (d), I (e), I (f), I (g) or I (h) 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, compound or compound or tautomer, wherein said compound has formula I,

Wherein:

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, azido-, phosphoric acid ester, 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 ³³And R ³⁵When occurring, be independently selected from respectively at every turn hydrogen, halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, azido-, phosphoric acid ester, 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 '}-(carbocylic radical) and-L _E-Q-L _{E '}-(heterocyclic radical);

R ²²Be carbocylic radical or heterocyclic radical, 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, azido-, phosphoric acid ester, 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=C (NR _SR _{S '}) (NR _SR _{S '}) ,-LS-N (R _S) SO ₂R _{S '},-LS-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 ,-O-,-C (O)-,-S (O) ₂-,-S (O)-,-OS (O) ₂-,-OS (O)-,-C (O) O-,-OC (O)-,-OC (O) O-,-C (O) N (R ¹⁵)-,-N (R ¹⁵) C (O)-,-C (O) N (R ¹⁵) O-,-N (R ¹⁵) C (O) O-,-C (O) N (R ¹⁵) N (R ^{15 '})-,-S-,-C (S)-,-C (S) O-,-OC (S)-,-C (S) N (R ¹⁵)-,-N (R ¹⁵) C (S)-,-N (R ¹⁵)-,-N (R ¹⁵) S (O)-,-N (R ¹⁵) S (O) ₂-,-S (O) ₂N (R ¹⁵)-,-S (O) N (R ¹⁵)-,-C (S) N (R ¹⁵) O-and-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, azido-, phosphoric acid ester, 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, azido-, phosphoric acid ester, 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 _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; azido-; phosphoric acid ester; 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 and alkoxycarbonyl amino alkyl.

2. the compound of claim 1, tautomer or pharmacologically acceptable salt, wherein: W ₁, W ₂, W ₃And W ₄Be independently selected from N or C (R respectively ³³);

R ¹⁰, R ¹⁷, R ³³And R ³⁵When 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 or heterocyclic radical 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-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=C (NR _SR _{S '}) (NR _SR _{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); 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;

R ⁵⁰Be-L ¹-A ¹, wherein A1 is 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 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;

3. each compound, tautomer or pharmacologically acceptable salt of claim 1-2, wherein: W ₁, W ₂And W ₃Be N;

W ₄Be C (R ³³);

Z is-NR ⁴¹-;

R ⁴¹Be selected from hydrogen or C ₁-C ₆Alkyl;

R ¹⁰Be hydrogen;

R ¹⁷Be C ₁-C ₆Alkyl;

X is-S-or-O-;

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 ²²Optional by one or more R ²⁶Replace;

R ⁵⁰Be-L ¹-A ¹, wherein:

L ¹Be a key, A ¹Be C ₄-C ₁₂Carbocylic radical or M ₄-M ₁₂Heterocyclic radical, and optional by one or more R ³⁰Replace; Perhaps

L ¹Be a key, and A ¹Be two rings, described two rings have 6-12 annular atoms, and optional by one or more R ³⁰Replace.

4. the compound of claim 1, tautomer or pharmacologically acceptable salt, wherein said compound has the structural formula that is selected from formula I (a), I (b), I (c) and I (d)

Wherein:

R ⁴¹Be selected from hydrogen or C ₁-C ₆Alkyl;

X is-S-or-O-;

R ²²Be C ₄-C ₁₂Carbocylic radical or M ₄-M ₁₂Heterocyclic radical, and optional by one or more R ²⁶Replace;

R ⁵⁰Be-L ¹-A ¹, wherein:

L ¹Be a key, A ¹Be C ₄-C ₁₂Carbocylic radical or M ₄-M ₁₂Heterocyclic radical, and optional by one or more R ³⁰Replace;

L ¹Be a key, and A ¹Be two rings, described two rings have 6-12 annular atoms, and optional by one or more R ³⁰Replace; Perhaps

L ¹Be optional by one or more R ³⁸The C that replaces ₁-C ₆Alkyl, and A ¹Be or optional by one or more R ³⁰The C that replaces ₁-C ₆Alkyl;

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, C ₁-C ₆Haloalkyl ,-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=C (NR _SR _{S '}) (NR _SR _{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 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, C ₁-C ₆Haloalkyl ,-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 ¹⁵, R ¹⁷, R ¹⁸, R ²⁶, R ³⁰, 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 and azido-by at least one;-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: 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 ₆Haloalkyl, 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 and C ₁-C ₆Alkoxycarbonyl amino C ₁-C ₆Alkyl;

M is 0,1,2 or 3;

N is 0 or 1;

P is 0,1,2 or 3; And

U is-CH ₂-or-CH ₂-CH ₂-, and optional by one or more R ¹⁸Replace.

5. each compound, tautomer or pharmacologically acceptable salt of claim 1-4, wherein: R ²²Be

Y is-C (O) N (R ¹⁵)-or-N (R ¹⁵) C (O)-, R wherein ¹⁵Be hydrogen, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl or C ₂-C ₆Alkynyl; And R ⁵⁰Be-L ¹-A ¹, L wherein ¹Be C ₁-C ₆Alkylidene group, and optional by one or more R ³⁸Replace A ¹Be C ₄-C ₁₂Carbocylic radical or M ₄-M ₁₂Heterocyclic radical, and optional by one or more R ³⁰Replace.

6. claim 3 or 5 compound, tautomer or pharmacologically acceptable salt, wherein R ⁴⁸Be amino, and optional by at least one R ²⁶Replace.

7. each compound, tautomer or pharmacologically acceptable salt of claim 3 or 5-6, wherein R ⁴⁸By at least one R ²⁶Replace R ²⁶Be selected from-C (O)-O-C ₁-C ₆Alkyl ,-SO ₂-C ₁-C ₆Alkyl ,-C (O)-C ₁-C ₆Alkylidene group-C ₃-C ₁₈Carbocylic radical or-C (O)-C ₁-C ₆Alkylidene group-M ₃-M ₁₈Heterocyclic radical, wherein said-C (O)-C ₁-C ₆Alkylidene group-C ₃-C ₁₈C in the carbocylic radical ₃-C ₁₈Carbocylic radical and described-C (O)-C ₁-C ₆Alkylidene group-M ₃-M ₁₈M in the heterocyclic radical ₃-M ₁₈Heterocyclic radical is that replace or unsubstituted, and is optionally replaced by at least one phosphoric acid ester.

8. each compound, tautomer or pharmacologically acceptable salt of claim 1-7, wherein R ¹⁷Be C ₁-C ₆Alkyl, R ⁴¹, R ³³And R ³⁵Be hydrogen or halogen independently, Y is-C (O) N (R ¹⁵)-, and A ¹Be C ₅-C ₆Carbocylic radical or M ₅-M ₆Heterocyclic radical, and optional by one or more R ³⁰Replace.

9. the compound of claim 8, tautomer or pharmacologically acceptable salt, wherein R ⁴⁸By at least one R ²⁶Replace R ²⁶Be selected from-C (O)-O-C ₁-C ₆Alkyl ,-SO ₂-C ₁-C ₆Alkyl ,-C (O)-C ₁-C ₆Alkylidene group-C ₃-C ₁₈Carbocylic radical or-C (O)-C ₁-C ₆Alkylidene group-M ₃-M ₁₈Heterocyclic radical, wherein said-C (O)-C ₁-C ₆Alkylidene group-C ₃-C ₁₈C in the carbocylic radical ₃-C ₁₈Carbocylic radical and described in-C (O)-C ₁-C ₆Alkylidene group-M ₃-M ₁₈Heterocyclic radical M ₃-M ₁₈Heterocyclic radical is that replace or unsubstituted, and is optionally replaced by at least one phosphoric acid ester.

10. each compound, tautomer or pharmacologically acceptable salt of claim 1-9, wherein: R ²²Be

R ⁵⁰Be-A ¹, A wherein ¹Be two rings, described two rings have 6-12 annular atoms, and optional by one or more R ³⁰Replace.

11. the compound of claim 10, tautomer or pharmacologically acceptable salt, wherein A ¹Be two rings with 9-11 annular atoms, and optional by one or more R ³⁰Replace R ⁴⁸Be amino, and optional by one or more R ²⁶Replace, Y is-C (O) N (R ¹⁵)-, R ¹⁷Be C ₁-C ₆Alkyl, and R ⁴¹, R ³³And R ³⁵Be hydrogen or halogen independently.

12. each compound, tautomer or pharmacologically acceptable salt of claim 1-9, wherein: R ¹⁷Be C ₁-C ₆Alkyl;

R ³³And R ³⁵Be hydrogen;

R ⁴¹Be hydrogen;

R ²²Be

R wherein ⁴⁸Be amino, and R ²²Optional by one or more R ²⁶Replace;

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

R ⁵⁰Be-L ¹-A ¹, wherein:

L ¹Be C ₁-C ₆Alkylidene group, and optional by one or more R ³⁸Replace, wherein A ¹Be phenyl, pyridyl, thiazolyl, thienyl, furyl, tetrahydrofuran base, pyrryl, pyrazinyl, cyclobutyl, cyclohexyl or naphthyl, and optional by one or more R ³⁰Replace, perhaps

L ¹Be a key, and A ¹Be two rings, described two rings have 9-11 annular atoms, and optional by one or more R ³⁰Replace.

13. the compound of claim 1, tautomer or pharmacologically acceptable salt, wherein said compound has the structural formula that is selected from formula I (e)

Wherein:

R ⁴¹Be selected from hydrogen or C ₁-C ₆Alkyl;

A is C ₅-C ₁₂Carbocylic radical or M ₅-M ₁₂Heterocyclic radical, and optional by one or more R ¹⁸Replace;

X is-S-or-O-;

R ⁵⁰Be-L ¹-A ¹, wherein:

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);

R ¹⁵, R ¹⁷, R ¹⁸, R ²⁶, R ³⁰, 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 and azido-by at least one;-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: 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 ₆Haloalkyl, 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 and C ₁-C ₆Alkoxycarbonyl amino C ₁-C ₆Alkyl.

14. the compound of claim 1, tautomer or pharmacologically acceptable salt, wherein said compound has the structural formula that is selected from formula I (f)

Wherein:

X is selected from O and S;

R ⁵⁰Be selected from

With

Wherein HET is optional by R ³⁰The heterocyclic radical that replaces;

R ²⁰Be selected from hydrogen and alkyl;

M is selected from 0 and 1 integer;

R ¹⁷Be selected from hydrogen and alkyl;

15. the compound of claim 1, tautomer or pharmacologically acceptable salt, wherein said compound has the structural formula that is selected from formula I (g)

Wherein:

R ²⁷Be selected from hydrogen and alkyl;

16. the compound of claim 1, tautomer or pharmacologically acceptable salt, wherein said compound has the structural formula that is selected from formula I (h)

Wherein:

R ⁵⁷Be selected from alkyl and hydroxyalkyl;

R ⁷⁴Be selected from hydrogen and hydroxyl;

R ⁹⁰Be selected from halogenated aryl and aryl.

17. comprise each the pharmaceutical composition of compound, tautomer or salt of claim 1-16.

18. each compound, tautomer or salt of claim 1-16 is used for suppressing the application of the medicine of HCV virus replication in preparation.

19. each compound, tautomer or salt of claim 1-16 is used for the treatment of application in the medicine that HCV infects in preparation.

20. each the method for compound of preparation claim 1-16, described method are included in the step of describing among among the reaction scheme 1-12 one.