CN101443334A - Anti-viral compounds - Google Patents
Anti-viral compounds Download PDFInfo
- Publication number
- CN101443334A CN101443334A CNA200680053117XA CN200680053117A CN101443334A CN 101443334 A CN101443334 A CN 101443334A CN A200680053117X A CNA200680053117X A CN A200680053117XA CN 200680053117 A CN200680053117 A CN 200680053117A CN 101443334 A CN101443334 A CN 101443334A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- group
- amino
- carbonyl
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Cephalosporin Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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
The application requires in the right of priority of the 60/752nd, No. 473 U.S. provisional application of submission on December 21st, 2005, and this application is incorporated herein by reference.
Invention field
The present invention relates to effectively to suppress the compound that hepatitis C virus (" HCV ") duplicates.The invention still further relates to the method for the described compound of preparation, comprise described compound compositions, be used for the intermediate of synthetic described compound, and use described compound to treat that HCV infects or the method for the illness/symptom relevant with it.In addition, the present invention relates to described compound and be used for the treatment of application in the medicine that HCV infects in preparation.
Background of invention
HCV, a kind of human pathogen is the RNA viruses that a kind of hepatovirus (Hepacivirus) that belongs to flaviviridae family belongs to.As the every other member of flaviviridae family, HCV has tunicary virion, and described virion contains the positive chain RNA genome, this genome single, be interrupted, all known virus-specific albumen of coding in the open reading frame.Comprise about 9500 Nucleotide in the open reading frame, about 3000 the amino acid whose single big polyproteins of described nucleotide coding.This polyprotein comprises core protein, envelope protein E1 and E2, embrane-associated protein p7, and Nonstructural Protein NS2, NS3, NS4A, NS4B, NS5A and NS5B.The cell protein enzymatic lysis is at the viral protein of NS2-NS3 contact, allows virus protease (NS3 proteolytic enzyme) mediation cracking subsequently.NS3 albumen also shows nucleoside triphosphate and RNA helicase activity.NS2 and NS4A also can participate in proteolytic activity.NS5A is the phosphoric acid albumen that participation is duplicated.NS5B is a RNA-RNA-dependent polysaccharase.The U.S. patent disclosure of announcing on December 30th, 2,004 2004/0265792 has mentioned that the above-mentioned Nonstructural Protein of inhibition can suppress HCV and duplicate.
HCV infects with to carry out the hepatopathy change relevant, comprises liver cirrhosis and hepatocellular carcinoma.The late period hepatopathy relevant with HCV is the most common indication of adult orthotopic liver transplantation.Chronic hepatitis C can come combination therapy with the ribavirin (ribavarin) that gives once every day with injecting a polyoxyethylene glycol interferon-' alpha ' (peginterferon-alpha) weekly.The polyoxyethylene glycol interferon-' alpha ' is to be connected on the polyoxyethylene glycol to slow down the interferon-' alpha ' that medicine is eliminated in the body.Injection of interferon-α compares with every day, and this has brought the raising of compliance and excellent clinically antiviral activity.But still have the restriction of significant effectiveness and tolerance, often insufficient because a lot of user is subjected to the influence and the virus of side effect from intravital elimination.
Carried out making great efforts to design the medicine that can suppress hepatitis C virus specifically.The U.S. patent 6,323,180 of Boehringer Ingelheim has been mentioned tripeptide compound, and described compound is to be suggested as the HCV serpin to be used for the treatment of the HCV infection.
Other method is ISIS-14803 (Isis Pharmaceuticals), a kind of conserved sequence complementary antisense inhibitor of and HCV RNA.This molecule is in conjunction with viral RNA, and suppresses the expression of duplicating desirable proteins.
By can be, and stop itself and the interactional yeast rna of viral internal ribosome entry site (BRES) to suppress the HCV translation to be described in people such as Das, J.VIROLOGY, 72 (7): among the 5638-5647 (1998) in conjunction with cell polypeptide.
The multiple life science related application of fused bicyclic heterogeneous ring compound has been proposed.The example of such heterogeneous ring compound comprise naphthyridine, Pyridopyrimidine, Mi Dingbing pyrimidine, pyrazolopyrimidine and thiazole also/Thienopyrimidine compound.
Assessed the application of naphthyridine type fused bicyclic compound in disease treatment.For example, the WO 93/13097 of the Boots that announces on July 8th, 1993 discloses [1,8] naphthyridine compounds, for example 4-(4-anisole amino)-6-oxyethyl group-7-methyl isophthalic acid, 8-naphthyridine-3-ethyl formate hydrochloride, it is suggested as rheumatism.The WO 95/00511 of the Boots that announces January 5 nineteen ninety-five discloses the ring condensed 4-aminopyridine compound that replaces, 3-oxyethyl group-5-(2-oxyethyl group-5-pyridinylamino)-2-methyl isophthalic acid for example, and the 8-naphthyridine, it is suggested as rheumatism.The WO 98/13350 of the Zeneca that announces on April 2nd, 1998 discloses [1,8] naphthyridine compounds, 2-acetylaminohydroxyphenylarsonic acid 5-(2-fluoro-5-hydroxy-4-methyl phenylamino)-1 for example, and 8-naphthyridine hydrochloride, it is suggested as anti-angiogenic agent.The WO 2004/055004 of the Neurogen that announces on July 1st, 2004 discloses the naphthyridine compounds as the capsicine receptor modulators, particular compound is 5-(4-trifluoromethyl-phenyl amino)-2-(3-trifluoromethyl-pyridine-2-yl)-[1,6] naphthyridine-7-formic acid and 2-methoxymethyl-4-(4-trifluoromethyl-phenyl amino)-7-(3-trifluoromethyl-pyridine-2-yl)-[1,8] naphthyridine-3-formic acid.
After deliberation the application of multiple treatment disease of Pyridopyrimidine type compound.For example, the WO 98/05661 of the Pfizer that announces on February 12nd, 1998 discloses the Pyridopyrimidine compound that replaces, [8-(1-ethyl-propyl group)-2-methyl-5 for example, 6,7,8-tetrahydrochysene-pyrido (2,3-d) pyrimidine-4-yl]-(2,4,6-trimethylammonium-phenyl)-amine, it is suggested as corticotropin releasing factor(CRF) (hormone) CKF (CRH) antagonist and is used for the treatment of alzheimer's disease and obesity.The WO 98/23613 of the Pfizer that announces on June 4th, 1998 discloses condensed bicyclic pyrimidine compound, comprise Pyridopyrimidine base-aminophenyl compound, (3-ethynyl-phenyl)-pyrido [3 for example, 4-d] pyrimidine-4-base-amine, it is suggested and is used for the treatment of for example cancer of high proliferation disease.The U.S. patent 6 of the Glaxo Wellcome that announces January 2 calendar year 2001,169,091 discloses bicyclic heteroaromatic compounds, 4-(4-benzyloxy phenylamino) pyrido [2 for example, 3-d]-pyrimidine, it is suggested as tyrosine kinase inhibitor and is used for the treatment of fibrosis, inflammation, central nervous system disease and cancer.The Eli Lilly WO 01/32632 that announces May 10 calendar year 2001 discloses the pyrimidine compound that 4-replaces, comprise 2-trifluoromethyl-4-[2-(2-(2-chloro-phenyl-) ethylamino] pyrido-[2,3-d] the pyrimidine hydrochloride, it is suggested as the mGluR1 antagonist and is used for the treatment of the nervous disorders relevant with the L-glutamic acid dysfunction, for example convulsions, migraine, psychosis, anxiety disorder and pain.The WO 01/57040 of the Abbott Laboratories that announces August 9 calendar year 2001 discloses 6,7-is dibasic-4-aminopyridine also [2,3-d] pyrimidine compound, 4-amino-6-(4-aminomethyl phenyl)-7-(4-bromophenyl) pyrido [2 for example, 3-d] pyrimidine, it is suggested as adenosine kinase inhibitors and is used for the treatment of pain and inflammation.The WO 2004/055004 of the Neurogen that announces on July 1st, 2004 discloses Pyridopyrimidine base-aminophenyl compound, 2-methyl-2-{4-[2-methyl-7-(3-methyl-pyridine-2-yl)-pyrido [2 for example, 3-d] pyrimidine-4-base amino]-phenyl }-propionic acid, it is as the capsicine receptor modulators.The U.S. patent 6,395,733 of the Pfizer that announces on May 28th, 2002 discloses heterocyclic fused pyrimidine compound, 3-chloro-phenyl-pyrido [2,3-d] pyrimidine-4-base-amine for example, and it is suggested and is used for the treatment of for example cancer of high proliferation disease.
After deliberation the application of Mi Dingbing pyrimidine Type fused bicyclic compound aspect insect control and disease treatment.For example, the U.S. patent 5,350,749 of the Dow Elanco that announces on September 27th, 1994 discloses Mi Dingbing [2, the 3-d] pyrimidine compound that 4-replaces, and it is suggested as mycocide, sterilant and miticide.The WO 95/19774 of the Warner-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 WO01/32632 of the Eli Lilly that announces May 10 calendar year 2001 discloses the pyrimidine compound that 4-replaces, 6-methyl-4-[2 for example, 6-benzyl dichloride sulfenyl) ethylamino] thieno-[2,3-d] the pyrimidine hydrochloride, it is suggested as the mGluR1 antagonist and is used for the treatment of the nervous disorders relevant with the L-glutamic acid dysfunction, for example convulsions, migraine, psychosis, anxiety disorder and pain.
The WO 2004/014852 of the Bristol-Myers Squibb that announces on February 19th, 2004 discloses the imino-thiazolidinone compound, comprise 2-(4-aminophenyl)-5H-thiazole also [2,3-6] the fused bicyclic derivative of quinazoline-3-ketone, it is suggested as the NS5A-protein inhibitor and stops HCV to duplicate.
The WO 2004/014313 of the Bristol-Myers Squibb that announces on February 19th, 2004 discloses the combination therapy that is used for the treatment of virus disease, comprises imino-thiazolidone NS5A-albumen inhibition whose anti-HCV compound and the combination that can disturb other promoting agents of HCV function.
Summary of the invention
The present invention relates to have the compound of formula I, II, III, IV, V, VI, VII or VIII, the tautomer of these compounds and the pharmacologically acceptable salt of these compounds or tautomer.These compounds can use separately or unite to make with other drug or material and be used for suppressing duplicating of HCV or other viruses.These compounds, tautomer or salt can use separately or unite to make with other drug or material and be used for disturbing HCV or other viral functions.
The invention still further relates to the composition that comprises The compounds of this invention, tautomer or salt.The compounds of this invention can comprise one or more The compounds of this invention, tautomer or salt.The present composition also comprises one or more other antiviral or therapeutical agent.
In addition, the composition that the present invention relates to use The compounds of this invention, tautomer or salt or comprise described compound, tautomer or salt suppresses the method for HCV or other virus replications.These methods comprise with HCV or other virus or by the cell of HCV or described other virus infection and contacting with The compounds of this invention, tautomer or the salt of significant quantity, thus the duplicating of inhibition HCV or described other virus.
The invention still further relates to the composition that uses The compounds of this invention, tautomer or salt or comprise described compound, tautomer or salt and suppress the propagation or the infectious method of HCV or other viruses.These methods comprise with HCV or other virus or by the cell of HCV or other virus infection and contacting with The compounds of this invention, tautomer or the salt of significant quantity, thus the propagation or the infection of inhibition HCV or other virus.
In addition, the present invention relates to the combination treatment HCV that uses The compounds of this invention, tautomer or salt or comprise described compound, tautomer or salt or the method for other virus infectiones.These methods comprise needs The compounds of this invention, tautomer or the salt of patient's effective dosage of treatment like this, thereby reduce HCV or other the viral blood among the described patient or organize level.
The invention still further relates to The compounds of this invention, tautomer or salt and be used for the treatment of application in HCV or other medicine for treating viral infections in preparation.
And, the invention still further relates to method for preparing The compounds of this invention, tautomer or salt and the intermediate that in these methods, uses.
Other features of the present invention, target and advantage are conspicuous in the following detailed description.Yet although should be appreciated that and pointed out the preferred embodiment of the invention, providing of this detailed description only is illustrations, rather than restriction.
Detailed Description Of The Invention
Below being described in is illustrative in nature, but not intention the restriction disclosure, application or purposes.
Compound
The present invention relates to have the pharmacologically acceptable salt of compound, its tautomer and described compound or the tautomer of formula I,
Wherein
A and B are selected from carbocylic radical or heterocyclic radical independently of one another, and optional independently of one another by one or more R
18Replace, wherein R
18When each occurs, be independently selected from 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 ') and-L
S-N (R
S) SO
2N (R
S 'R
S ");
W
1And W
2Be selected from N or C (R independently of one another
33);
Z be key ,-CR
41R
41 '-or-NR
41-, R wherein
41And R
41 'Be selected from hydrogen, alkyl, alkenyl and alkynyl independently of one another;
R
10And R
33When each occurs, be selected from independently of one another 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 '-CM
3-M
18Heterocyclic radical);
X be selected from 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 each occurs, be independently selected from 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=C (NR
SR
S ') (NR
SR
S ') ,-L
S-N (R
S) SO
2R
S ',-L
S-SO
2N (R
SR
S ') ,-L
S-N (R
S) SO
2N (R
S 'R
S ") ,-L
E-Q-L
E '-(C
3-C
18Carbocylic radical) and-L
E-Q-L
E '-(M
3-M
18Heterocyclic radical); Perhaps R
22Be alkyl, alkenyl or alkynyl, and optional by one or more R
26Replace; Perhaps R
22Be hydrogen;
Y be selected from key ,-L
S-O-,-L
S-C (O)-,-L
S-S (O)
2-,-L
S-S (O)-,-L
S-OS (O)
2-,-L
S-OS (O)-,-L
S-C (O) O-,-L
S-OC (O)-,-L
S-OC (O) O-,-L
S-C (O) N (R
15)-,-L
S-N (R
15) C (O) ,-L
S-C (O) N (R
15) O-,-L
S-N (R
15) C (O) O-,-L
S-C (O) N (R
15) N (R
15 ')-,-L
S-S-,-L
S-C (S)-,-L
S-C (S) O-,-L
S-OC (S) ,-L
S-N (R
15)-,-L
S-C (S) N (R
15)-,-L
S-N (R
15) C (S)-,-L
S-N (R
15) S (O) ,-L
S-N (R
15) S (O)
2-,-L
S-S (O)
2N (R
15)-,-L
S-S (O) N (R
15)-,-L
S-C (S) N (R
15) O-and-L
S-C (S) N (R
15) N (R
15 ')-, be R wherein
15And R
15 'When occurring, each is selected from hydrogen, alkyl, alkenyl and alkynyl independently of one another;
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, A wherein
1Optional by one or more R
30Replace and R
30When each occurs, be independently selected from 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 each occurs, be independently selected from 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, each is independently selected from key, alkylidene group, alkylene group and alkynylene;
R
S, R
S 'And R
S "When occurring, each is selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, thio alkoxy, alkoxyalkyl, alkoxy alkoxy alkyl, thio alkoxy alkyl, alkyl-carbonyl, alkyl-carbonyl alkyl, alkoxy carbonyl, alkoxy carbonyl alkyl, alkyl-carbonyl oxygen base, alkyl-carbonyl oxygen base alkyl, alkylamino, alkylamino alkyl, alkoxycarbonyl amino and alkoxycarbonyl amino alkyl independently of one another;
L
EAnd L
E 'When occurring, each is selected from key, alkylidene group, alkylene group and alkynylene independently of one another;
Q when each occurs, be independently selected from 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
18, R
26, R
30, R
33, R
38, R
41And R
41 'When each occurs, choose wantonly independently of one another by at least one 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-; 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 is optional independently when each occurs to be 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 pharmacologically acceptable salt of compound, its tautomer and described compound or the tautomer of formula I, wherein:
A and B are selected from C independently of one another
4-C
11Carbocylic radical or M
4-M
11Heterocyclic radical, and optional independently of one another by one or more R
18Replace, wherein R
18When occurring, each is independently selected from 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
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 ') and-L
S-N (R
S) SO
2N (R
S 'R
S ");
W
1And W
2Be selected from N or C (R independently of one another
33);
Z be key ,-CR
41R
41 '-or-NR
41-, R wherein
41And R
41 'Be selected from hydrogen, C independently of one another
1-C
6Alkyl, C
2-C
6Alkenyl and C
2-C
6Alkynyl;
R
10And R
33When occurring, each is selected from hydrogen, halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, azido-, C independently of one another
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);
X be selected from 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 C
4-C
11Carbocylic radical or M
4-M
11Heterocyclic radical, and optional by one or more R
26Replace, wherein R
26When occurring, each is independently selected from 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 ,-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
1-C
6Alkenyl or C
1-C
6Alkynyl, and optional by one or more R
26Replace; Perhaps R
22Be hydrogen;
Y be selected from key ,-L
S-O-,-L
S-C (O)-,-L
S-S (O)
2-,-L
S-S (O)-,-L
S-OS (O)
2-,-L
S-OS (O)-,-L
S-C (O) O-,-L
S-OC (O)-,-L
S-OC (O) O-,-L
S-C (O) N (R
15)-,-L
S-N (R
15) C (O)-,-L
S-C (O) N (R
15) O-,-L
S-N (R
15) C (O) O-,-L
S-C (O) N (R
15) N (R
15 ')-,-L
S-S-,-L
S-C (S)-,-L
S-C (S) O-,-L
S-OC (S)-,-L
S-N (R
15)-,-L
S-C (S) N (R
15)-,-L
S-N (R
15) C (S)-,-L
S-N (R
15) S (O)-,-L
S-N (R
15) S (O)
2,-L
S-S (O)
2N (R
15) ,-L
S-S (O) N (R
15)-,-L
S-C (S) N (R
15) O-and-L
S-C (S) N (R
15) N (R
15 ')-, be R wherein
15And R
15 'When occurring, each is selected from hydrogen, C independently of one another
1-C
6Alkyl, C
2-C
6Alkenyl and C
2-C
6Alkynyl;
R
50Be-L
1-A
1, A wherein
1Be selected from C
4-C
11Carbocylic radical, M
4-M
11Heterocyclic radical, C
1-C
6Alkyl, C
2-C
6Alkenyl and C
2-C
6Alkynyl, and L
1Be selected from 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, each is independently selected from 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 ,-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, each is independently selected from halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, azido-, C
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
6The alkane 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, each is independently selected from key, C
1-C
6Alkylidene group, C
2-C
6Alkylene group and C
2-C
6Alkynylene;
R
S, R
S 'And R
S "When occurring, each is selected from hydrogen, C independently of one another
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
1-C
6Alkoxyl group, C
1-C
6Thio alkoxy, C
1-C
6Sulfo-oxygen base 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, each is selected from key, C independently of one another
1-C
6Alkylidene group, C
2-C
6Alkylene group and C
2-C
6Alkynylene;
Q is independently selected from key, C when each occurs
1-C
6Alkylidene group, C
2-C
6Alkylene group, C
2-C
6Alkynylene ,-S-,-O-,-C (O)-,-N (R
S)-,-N (R
S) C (O)-,-C (O) N (R
S)-,-N (R
S) C (O) O-,-OC (O) N (R
S)-,-N (R
S) C (O) N (R
S ')-,-C (=NR
S) N (R
S ')-,-N (R
S ') C (=NR
S)-,-S (O)-,-SO
2-,-O-SO
2-,-SO
2-O-,-O-S (O)-,-S (O)-O-,-C (O) O-and-OC (O)-;
R
10, R
15, R
15 ', R
18, R
26, R
30, R
33, R
38, R
41And R
41 'When each occurs, choose wantonly independently of one another by at least one 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-; 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 is optional independently when each occurs to be 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 the present embodiment, Y is-L
S-O-,-L
S-S-or-L
S-N (R
15)-, and R
50Be-L
1-A
1, L wherein
1Be key, C
1-C
6Alkylidene group, C
2-C
6Alkylene group or C
2-C
6Alkynylene, and optional by one or more R
38Replace, and A
1Be C
4-C
11Carbocylic radical or M
4-M
11Heterocyclic radical and optional by one or more R
30Replace.
In another example of the present embodiment, Y is a key, and R
50Be-L
1-A
1, L wherein
1Be key, C
2-C
6Alkylidene group, C
2-C
6Alkylene group or C
2-C
6Alkynylene, and optional by one or more R
38Replace, and A
1Be C
4-C
11Carbocylic radical or M
4-M
11Heterocyclic radical and optional by one or more R
30Replace.
In also another example of the present embodiment, Y is a key, and R
50Be-L
1-A
1, L wherein
1Be selected from key, C
1-C
6Alkylidene group, C
2-C
6Alkylene group and C
2-C
6Alkynylene, and optional by one or more R
38Replace, and A
1Be hydrogen or R
18
In also another example of the present embodiment, Y is selected from-L
S-S (O)
2N (R
15)-,-L
S-OS (O)
2-,-L
S-OC (O)-,-L
S-C (O) O-,-L
S-C (O)-and-N (R
15) C (O) O-.
In also another example of the present embodiment, A and B are selected from C independently of one another
5-C
6Carbocylic radical or M
5-M
6Heterocyclic radical, and optional independently of one another by one or more R
18Replace.
In also another example of the present embodiment, W
1And W
2Be N, and Z is-NR
41-.
In also another example of the present embodiment, X is-O-or-S-, and R
22Be C
5-C
6Carbocylic radical or M
5-M
6Heterocyclic radical, and optional by one or more R
26Replace.
In also another example of the present embodiment, part
Be
Wherein:
W
1, W
2, W
3And W
4Be selected from N or C (R independently of one another
33); And
R
10, R
17, R
33And R
35When occurring, each is selected from hydrogen, halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, azido-, C independently of one another
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).
In also another example of the present embodiment, part
Be selected from
With
Wherein:
Q is N or C (R
33); And
R
10, R
17, R
33And R
35When occurring, each is selected from hydrogen, halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, azido-, C independently of one another
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).
In another example of the present embodiment, A and B are selected from C independently of one another
5-C
6Carbocylic radical or M
5-M
6Heterocyclic radical, and optional independently of one another by one or more R
18Replace, wherein:
W
1And W
2Be N;
Z is-NR
41-;
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;
Y be key ,-L
S-O-,-L
S-S-or-L
S-N (R
15)-; And
A
1Be C
5-C
10Carbocylic radical or M
5-M
10Heterocyclic radical, and optional by one or more R
30Replace.
In another example of this embodiment, A and B are selected from C independently of one another
5-C
6Carbocylic radical or M
5-M
6Heterocyclic radical, and optional independently of one another by one or more R
18Replace, wherein:
W
1And W
2Be N;
Z is-NR
41-;
X is-O-or-S-;
R
22Be
Or
, R wherein
48Be hydroxyl, amino, C
1-C
6Alkylamino, C
1-C
6Alkoxyl group, C
1-C
6Alkoxycarbonyl amino or C
1-C
6Alkyl-carbonyl oxygen base, and R
22(R for example
48Or R
22In benzyl ring) optional by one or more R
26Replace;
Y be key ,-L
S-O-,-L
S-S-or-L
S-N (R
15)-; And
A
1Be C
5-C
10Carbocylic radical or M
5-M
10Heterocyclic radical, and optional by one or more R
30Replace.
In also another example of the present embodiment, part
Be selected from
With
Wherein:
Q is N or C (R
33);
R
10, R
17, R
33And R
35When occurring, each is selected from hydrogen, halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, azido-, C independently of one another
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);
A is C
5-C
6Carbocylic radical or M
5-M
6Heterocyclic radical, and optional by one or more R
18Replace;
Z is-NR
41-;
X is-O-or-S-;
R
22Be
Or
R wherein
48Be hydroxyl, amino, C
1-C
6Alkylamino, C
1-C
6Alkoxyl group, C
1-C
6Alkoxycarbonyl amino or C
1-C
6Alkyl-carbonyl oxygen base, and R
22(R for example
48Or R
22In benzyl ring) optional by one or more R
26Replace;
Y be key ,-L
S-O-,-L
S-S-or-L
S-N (R
15)-; And
A
1Be C
5-C
10Carbocylic radical or M
5-M
10Heterocyclic radical, and optional by one or more R
30Replace.
In another embodiment, the present invention relates to a class Pyridopyrimidine base aminophenyl ester cpds, the tautomer of described compound or the pharmacologically acceptable salt of described compound or tautomer, wherein this compounds meets the structure of formula II:
Wherein:
R
6Be selected from hydrogen and cyano group;
R
8Be selected from hydrogen and arylalkyl;
R
25Be selected from hydrogen and alkyl;
R
37Be selected from hydrogen, alkyl, hydroxyalkyl and cycloalkyl;
R
42Be selected from artyl sulfo, heteroaryl sulfenyl and aryloxy; R wherein
42Optional by one or more R that are independently selected from
46Substituting group replace;
R
46Be one or more substituting groups that are selected from hydrogen, hydroxyl, amino, halogen, dialkyl amido and alkoxycarbonyl amino;
R
70Be selected from aryl and heterocyclic radical; R wherein
70Optional by R
75Replace;
R
75Be one or more substituting groups that are independently selected from hydrogen, halogen, alkoxyl group, cyano group, alkyl, haloalkyl and aryl.
In the subclass class of the present embodiment in formula II, R
6Be selected from hydrogen and cyano group;
R
8Be selected from hydrogen and phenyl methyl;
R
25Be selected from hydrogen and methyl;
R
37Be selected from hydrogen, methyl, ethyl, the tertiary butyl, sec.-propyl, hydroxymethyl ethyl and cyclohexyl;
R
42Be selected from phenyl sulfenyl, phenoxy group and pyrimidine-based sulfur-base;
R
46Be selected from hydrogen, hydroxyl, amino, N, N-dimethylamino and tert-butoxycarbonyl amino;
R
70Be selected from phenyl, thiazolyl, pyridyl, tetrahydrofuran base, naphthyl, quinolyl and thienyl;
R
75Be one or more substituting groups that are selected from following groups: hydrogen, methyl, butyl, hydroxyl, methoxyl group, bromine, chlorine, fluorine, cyano group, trifluoromethyl and phenyl.
In going back another embodiment, the present invention relates to a class Pyridopyrimidine base aminophenyl alkylether compounds, the tautomer of described compound or the pharmacologically acceptable salt of described compound or tautomer, wherein this compounds meets the structure of formula III:
R wherein
80Be selected from hydrogen, alkyl-carbonyl and halogenated aryl.
In the subclass class of the present embodiment in formula III, R
80Be selected from hydrogen, methyl carbonyl and bromophenyl.
In going back another embodiment, the invention is characterized in thiazole and pyrimidyl-aminophenyl and Thienopyrimidine base aminophenyl compound, the tautomer of described compound or the pharmacologically acceptable salt of described compound or tautomer, wherein this compounds meets the structure of formula IV:
Wherein:
Q is selected from N and CH;
R
1Be selected from alkyl sulfenyl, cyano group alkyl sulfenyl and alkyl;
R
19Be selected from alkyl and halogenated aryl alkoxyl group;
R
56Be selected from hydrogen, hydroxyl, alkyl and alkyl-carbonyl-amino.
In the subclass class of the present embodiment in formula IV, R
1Be selected from methyl sulfenyl, cyano methyl sulfenyl, propyl group and butyl;
R
19Be selected from methyl and bromophenyl methoxyl group;
R
56Be selected from hydrogen, hydroxyl, methyl and methyl carbonylamino.
In going back another embodiment, the present invention relates to the tautomer of a class Mi Dingbing pyrimidyl-aminophenyl compound, described compound or the pharmacologically acceptable salt of described compound or tautomer, wherein this compounds meets the structure of formula V:
Wherein:
R
5Be selected from hydrogen and alkyl sulfenyl;
R
29Be selected from alkyl, alkoxy aryl, halogen and halogenated aryl alkoxyl group;
R
47Be selected from alkyl, haloalkyl, alkyl sulfenyl, arylalkyl sulfenyl and heterocyclic radical;
R
64Be selected from hydrogen, alkoxyl group and alkyl;
R
66Be selected from hydrogen, hydroxyl, aryloxy, alkyl sulphonyl oxygen base, alkyl-carbonyl-amino aryl sulfonyl oxygen base, halogenated aryl alkylsulfonyl oxygen base, cyano group, alkoxy aryl, alkyl-carbonyl-amino, halogen and alkyl;
R
81Be selected from hydrogen, alkoxyl group and carbonyl.
In the subclass class of the present embodiment in formula V, R
5Be selected from hydrogen and methyl sulfenyl;
R
29Be selected from methyl, ethyl, fluorine, phenyl methoxyl group and bromophenyl methoxyl group;
R
47Be selected from hydrogen, propyl group, sec.-propyl, ethyl sulfenyl, piperidyl, morpholinyl, seven fluoropropyls and phenyl methyl sulfenyl;
R
64Be selected from hydrogen, methoxyl group, hydroxyl and methoxyl group;
R
66Be selected from hydrogen, methyl, hydroxyl, methoxyl group, phenoxy group, phenyl methoxyl group, phenyl sulfenyl oxygen base, sec.-propyl alkylsulfonyl oxygen base, methyl carbonylamino phenyl alkylsulfonyl oxygen base, bromophenyl sulfenyl oxygen base, cyano group, methyl carbonylamino and fluorine;
R
81Be selected from hydrogen, tert.-butoxy and carbonyl.
In another embodiment, the present invention relates to the tautomer of pyrazole and pyrimidinyl-amino phenyl compound, described compound or the pharmacologically acceptable salt of described compound or tautomer, wherein this compounds meets the structure of formula VI:
Wherein:
R
73It is alkyl;
R
76Be selected from hydroxyl, alkyl amino-carbonyl and alkyl-carbonyl-amino.
In the subclass class of the present embodiment in formula VI, R
73Be selected from methyl and butyl;
R
76Be selected from hydroxyl, methylamino carbonyl and methyl carbonylamino.
In going back another embodiment, the present invention relates to the tautomer of a class Pyridopyrimidine base-aminophenyl compound, described compound or the pharmacologically acceptable salt of described compound or tautomer, wherein this compounds meets the structure of formula VII:
Wherein:
A is selected from O and S;
R
21Be selected from hydrogen and hydroxyl;
Perhaps R
21With R
39Form together and contain at least two first heterocycles of heteroatomic 5-12 that are selected from O, N and S; Wherein this heterocycle is optional is replaced by aryl or halogen; Perhaps
R
39Be selected from hydrogen, alkyl, aromatic yl alkenyl, dialkyl amido, heteroaryl, halo heteroaryl, halogenated aryl amino-sulfonyl, aryl sulfonyl oxygen base, alkyl-carbonyl oxygen base, cycloalkyl amino carbonyl, aryl-alkoxy carbonyl amino, halo heteroaryl, alkoxy carbonyl and NH-R
99
R
99Be selected from hydrogen, arylalkyl, cycloalkylalkyl, aryl, heteroaryl, halogenated aryl alkylamino, aryl-alkyl amino and miscellaneous alkyl aryl;
R
67Be selected from hydrogen, alkyl, cycloalkyl and alkyl-cycloalkyl;
R
96Be to be selected from hydrogen, hydroxyl, amino, alkoxyl group, aryl sulfonyl oxygen base, alkyl-carbonyl-amino, alkoxyl group, halogen, alkoxy-carbonyl oxy, halo alkoxy carbonyl amino and alkoxy aryl.
In the subclass class of the present embodiment in formula VII, R
21Be selected from hydrogen and hydroxyl, perhaps work as and R
39Optional when forming benzoxazolyl together by phenyl or bromine replacement; Perhaps
R
39Be selected from hydrogen, methyl, phenyl vinyl, N, N-dipropyl amino, pyrryl, bromophenyl amino-sulfonyl, phenyl sulfonyl oxygen base, tertiary butyl ketonic oxygen base, N-cyclohexyl aminocarboxyl, N-cyclopentyl aminocarboxyl, phenyl methoxycarbonyl amino, methoxycarbonyl amino, methoxycarbonyl and bromobenzene and imidazolyl;
R
67Be selected from hydrogen, methyl, ethyl, sec.-propyl, the tertiary butyl, sec-butyl, cyclopropyl, cyclobutyl and methyl cyclopropyl;
R
96Be selected from hydrogen, hydroxyl, amino, phenyl sulfonyl oxygen base, methyl carbonylamino, methoxyl group, fluorine, tert-butoxycarbonyl amino, trichlorine ethoxy carbonyl amino and phenyl methoxyl group;
R
99Be selected from also [2,3-d] pyrimidyl of hydrogen, phenyl methyl, phenylethyl, cyclopentyl-methyl, furyl, thienyl, naphthyl, bromophenyl methylamino, phenyl methyl amino and picoline.
In going back another embodiment, the present invention relates to a class Pyridopyrimidine base aminophenyl compound, the tautomer of described compound or the pharmacologically acceptable salt of described compound or tautomer, wherein this compounds meets the structure of formula VIII:
Wherein:
R
23Be selected from hydrogen, alkoxy aryl, alkoxy aryl sulfenyl, hydroxyaryl sulfenyl, halogenated aryl alkoxyl group, cyano-aryl alkoxyl group and alkoxy aryl;
R
31Be selected from hydrogen and halogen,
R
49Be selected from hydrogen, alkoxy aryl, halogenated aryl carbonylamino, alkoxy aryl carbonylamino, aromatic yl alkenyl, arylalkyl, halogen, cyano group, halogenated aryl oxygen base alkyl, alkyl, alkoxy aryl sulfenyl, halo heteroaryl and alkoxy carbonyl;
R
52Be selected from hydrogen, halogen, alkyl, hydroxyaryl oxygen base, aryloxy, hydroxyalkyl aryloxy, alkoxy aryl alkyl, alkoxy aryl oxygen base, alkylaryl alkoxy aryl amino, arylalkyl, heteroaryl and aminoaryl oxygen base;
R
77Be selected from hydrogen, alkyl and cycloalkyl.
In the subclass class of the present embodiment in formula VIII, R
23Be selected from hydrogen, p-methoxy-phenyl, p-methoxy-phenyl sulfenyl, hydroxy phenyl sulfenyl, fluorophenyl methoxyl group, difluorophenyl methoxyl group, cyano-phenyl methoxyl group, phenyl methoxyl group, bromophenyl methoxyl group and anisole ylmethoxy;
R
31Be selected from hydrogen, chlorine and fluorine;
R
49Be selected from hydrogen, methyl, phenyl methoxyl group, bromophenyl carbonylamino, fluorophenyl carbonylamino, p-methoxy-phenyl carbonylamino, fluorophenyl carbonylamino, phenyl vinyl, phenylethyl, chlorine, fluorine, bromine, cyano group, bromobenzene oxygen ylmethyl and hydroxy phenyl sulfenyl.
R
52Be selected from hydrogen, fluorine, bromine, methyl, phenoxy group, hydroxyphenoxy, hydroxyethyl phenoxy group, p-methoxy-phenyl ethyl, methoxyl group phenoxy group, N-methyl-N-4-phenyl methoxyl group base amino, phenyl methyl and thibendole base;
R
77Be selected from hydrogen, methyl and sec.-propyl.
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, sulfanilate (sufanilate), cyclohexyl-n-sulfonate, alginic acid (algenic acid), beta-hydroxy-butanoic acid salt, the galacturonic hydrochlorate, adipate, alginate, hydrosulfate, butyrates, camphorate, camsilate, cyclopentane propionate, dodecyl sulfate, gluceptate (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 Trometamol (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, Section E: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
, AND
(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
10, W
1, A, L
1, X or Y) general formula some compounds are described.Except as otherwise noted, each variable in such general formula all is independent of any other variable and defines, and any variable more than occurring once in general formula defines when occurring at every turn independently.If substituting group is described to " being independently selected from " a group, then each substituting group is selected each other independently.Therefore, each substituting group and other substituting groups can be identical or different.
The number of carbon atom can pass through prefix " C in the hydrocarbyl substituent
x-C
y, " indication, wherein x is the minimal number of carbon atom in the substituting group, and y is a maximum number.Therefore, " C for example
1-C
6Alkyl " be meant the alkyl substituent that contains 1-6 carbon atom.Further illustrate C
3-C
6Cycloalkyl is meant the stable hydrocarbon basic ring that contains 3-6 carboatomic ring atom.The prefix that appends on the multicomponent substituting group only is applied to tight first composition after this prefix.Illustrate, term " alkylaryl " contains two compositions: alkyl and aryl.Therefore, C for example
1-C
6Alkylaryl is meant via aryl and is connected to C on the parent molecule part
1-C
6Alkyl.Equally, alkyl C
6-C
10Aryl is meant via C
6-C
10Aryl is connected to the alkyl on the parent molecule part.Similarly, the prefix on the halogenated alkoxy alkyl " halo " is meant that the alkoxyl group composition is replaced by one or more halogens, and the prefix on the halogenated alkoxy alkyl " halo " is meant that the alkyl composition is replaced by one or more halogens
When the connection portion between two other parts of the chemical structure that is used to describe description, the composition that the leftmost side of connection portion is described be with the description structure in left part bonded composition.Illustrate, if chemical structure is X-L-Y, L is described to the methyl aryl ethyl, and then this chemical structure will be X-methyl-aryl-ethyl-Y.
If the connection portion is a key in the structure of describing, then the left part in institute's description scheme directly combines with saying the right side part of describing in the structure.For example, if chemical structure is described to X-L-Y, and L is selected from a key, and then this chemical structure will be X-Y.For another example, if chemical structure is described to-L-X, and L is selected from a key, and then this chemical structure will be-X.For another example, if chemical structure is described to X-L
1-L
2-Y, X-L
1-L
2-L
3-Y or X-L
1-L
2-...-L
N-Y, and L
1, L
2, L
3... L
NBe selected from a key, then this chemical structure will be X-Y.
When using chemical formula to describe substituting group, then the substituent part of free valency represented to have in the dash in chemical formula right side (or left side).
If substituting group is described as " substituted ", then non-hydrogen group has substituted the one or more hydrogen on this substituent carbon, nitrogen or the oxygen.Therefore, for example, the alkyl substituent of replacement is that wherein at least one non-hydrogen group has substituted the alkyl substituent of the hydrogen on this alkyl substituent.Illustrate the alkyl that single fluoroalkyl is replaced by a fluorine, the alkyl that fluoroalkyl is replaced by two fluorine.Will be appreciated that if two or more replacements are arranged, except as otherwise noted, each non-hydrogen group can be identical or different on substituting group.
If comprise carbon, nitrogen or the salt of at least one and one or more hydrogen atom bondings, then substituting group is " can be substituted ".
If substituting group is described to " optional substituted ", then this substituting group can be substituted or unsubstituted.If being described to the optional non-hydrogen group of given number that is up to, substituting group replaces, then but this substituting group can be unsubstituted or is up to the non-hydrogen group replacement that non-hydrogen group replacement of this given number or quilt are up to maximum the position of substitution number on the substituting group, and whichever is less.Therefore, for example, if substituting group is described to the optional heteroaryl that 3 non-hydrogen groups replace that is up to, but but then have any heteroaryl that is less than 3 the position of substitution will choose wantonly only be up to the position of substitution of having with this heteroaryl as many non-hydrogen group of number replace.Illustrate, tetrazyl (but only having a position of substitution) will be chosen wantonly and will be up to 1 non-hydrogen group replacement.Further illustrate, be up to 2 non-hydrogen groups replacements if amino nitrogen is described to choose wantonly, then primary amino nitrogen is chosen wantonly and is up to 2 non-hydrogen groups replacements, and the optional quilt of secondary amino nitrogen is up to 1 non-hydrogen group replacement.
Term " alkenyl " (separately or with other term combination) is meant and contains one or more pairs of keys and 2-20 carbon atom usually, 2-8 carbon atom more generally, even the straight or branched hydrocarbon substituent of 2-6 carbon atom more generally.In the alkenyl part, with respect to the group that replaces on the double key carbon, each carbon-to-carbon double bond can be cis or trans geometry.Substituent limiting examples like this comprises vinyl, 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butylene base, crotyl and 3-butenyl.
Term " alkylene group " (separately or with other term combination) is meant the divalence unsaturated alkyl, and it can be a straight or branched, and has at least one carbon-to-carbon double bond.Alkylene group contains 2-20 carbon atom usually, 2-8 carbon atom more generally, even 2-6 carbon atom more generally.The limiting examples of alkylene group comprises-C (H)=C (H)-,-C (H)=C (H)-CH
2-,-C (H)=C (H)-CH
2-CH
2-,-CH
2-C (H)=C (H)-CH
2-,-C (H)=C (H)-CH (CH
3)-and-CH
2-C (H)=C (H)-CH (CH
2CH
3)-.
Term " alkoxyl group " (separately or with other term combination) is meant the alkyl that partly is connected via oxygen part and parent molecule (promptly-O-alkyl).Substituent limiting examples like this comprises methoxyl group (O-CH
3), oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy.
Term " alkoxyalkyl " (separately or with other term combination) is meant the alkoxyl group that partly is connected via alkylidene group and parent molecule.The limiting examples of alkoxyalkyl comprises tert.-butoxy methyl, 2-ethoxyethyl group, 2-methoxy ethyl and methoxymethyl.
Term " alkoxy carbonyl " (separately or with other term combination) is meant the alkoxyl group that partly is connected via carbonyl and parent molecule (promptly-C (O)-O-alkyl).The representative example of alkoxy carbonyl includes but not limited to methoxycarbonyl, ethoxy carbonyl
And tert-butoxycarbonyl.
Term " alkoxycarbonyl amino " (separately or with other term combination) is meant N (R
AR
B)-, be R wherein
ABe alkyl-O-C (O)-, and R
BBe alkyl-O-C (O)-or hydrogen.R
AAnd R
BCan be identical or different.
Term " alkoxycarbonyl amino alkyl " (separately or with other term combination) is meant N (R
AR
B)-alkylidene group-, R wherein
ABe alkyl-O-C (O)-, and R
BBe alkyl-O-C (O)-or hydrogen.R
AAnd R
BCan be identical or different.
Term " alkoxy carbonyl alkyl " (separately or with other term combination) is meant the alkoxy carbonyl that partly is connected via alkylidene group and parent molecule.The representative example of alkoxy carbonyl alkyl includes but not limited to 2-methoxyl group-2-oxoethyl, 2-oxyethyl group-2-oxoethyl, 3-methoxyl group-3-oxopropyl, 3-oxyethyl group-3-oxopropyl, 4-oxyethyl group-2-(ethoxy carbonyl)-4-oxo butyl, 5-methoxyl group-5-oxo amyl group and 6-methoxyl group-6-oxo-hexyl.
Term " alkyl " (separately or with other term combination) is meant and contains 1-20 carbon atom usually, 1-8 carbon atom more generally, even the straight or branched saturated hydrocarbyl substituting group of 1-6 carbon atom more generally.Substituent limiting examples like this comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, hexyl and octyl group.
Term " alkylamino " (separately or with other term combination) is meant-NR
AR
B, R wherein
ABe alkyl, and R
BIt is hydrogen or alkyl.R
AAnd R
BCan be identical or different.For example, C
1-C
6Alkylamino is meant-NR
AR
B, R wherein
ABe C
1-C
6Alkyl, and R
BBe hydrogen or C
1-C
6Alkyl.
Term " alkylamino alkyl " (separately or with other term combination) is meant N (R
AR
B)-alkylidene group-, R wherein
ABe alkyl, and R
BIt is hydrogen or alkyl.R
AAnd R
BCan be identical or different.Therefore, C
1-C
6Alkylamino C
1-C
6Alkyl is meant N (R
AR
B)-C
1-C
6Alkylidene group-, R wherein
ABe C
1-C
6Alkyl, and R
BBe hydrogen or C
1-C
6Alkyl.
Term " alkyl-carbonyl " (separately or with other term combination) is meant the alkyl that partly is connected via carbonyl and parent molecule (promptly-C (O)-alkyl).The representative example of alkyl-carbonyl includes but not limited to ethanoyl, ethyl carbonyl
1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxo butyl and 1-oxo amyl group.
Term " alkyl-carbonyl alkyl " (separately or with other term combination) is meant the alkyl-carbonyl that partly is connected via alkylidene group and parent molecule.The representative example of alkyl-carbonyl alkyl includes but not limited to 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxo butyl and 3-oxo amyl group.
Term " alkyl-carbonyl oxygen base " (separately or with other term combination) is meant the alkyl-carbonyl that partly is connected via oxygen base section and parent molecule.The representative example of alkyl-carbonyl oxygen base includes but not limited to acetoxyl group, ethyl ketonic oxygen base and tertiary butyl ketonic oxygen base.
Term " alkyl-carbonyl oxygen base alkyl " (separately or with other term combination) is meant the alkyl-carbonyl oxygen base that partly is connected via alkylidene group and parent molecule.The representative example of alkyl-carbonyl oxygen base alkyl includes but not limited to 2-(acetoxyl group) ethyl, 3-(acetoxyl group) propyl group and 3-(propionyloxy) propyl group.
Term " alkylidene group " or " alkylidene group " (separately or with other term combination) be meant by containing 1-20 carbon atom usually, 1-8 carbon atom more generally, even the straight or branched saturated hydrocarbon chain deutero-divalent group of 1-6 carbon atom more generally.The representative example of alkylidene group includes but not limited to-CH
2-,-CH
2CH
2-,-CH
2CH
2CH
2-,-CH
2CH
2CH
2CH
2-and-CH
2CH (CH
3) CH
2-.
Term " alkynyl " (separately or with other term combination) is meant and contains one or more triple bonds and 2-20 carbon atom usually, 2-8 carbon atom more generally, even the straight or branched hydrocarbon substituent of 2-6 carbon atom more generally.Substituent limiting examples like this comprises ethynyl, 1-proyl, 2-propynyl, 3-proyl, decynyl, ethyl acetylene base, 2-butyne base and 3-butynyl.
Term " alkynylene " (separately or with other term combination) is meant the divalence unsaturated alkyl, and it can be a straight or branched, and has at least one carbon-to-carbon triple bond.Representative alkynylene for example comprises-C ≡ C-,-C ≡ C-CH
2-,-C ≡ C-CH
2-CH
2-,-CH
2-C ≡ C-CH
2-,-C ≡ C-CH (CH
3)-and-CH
2-C ≡ C-CH (CH
2CH
3)-.
Term " amino " (separately or with other term combination) is meant-NH
2Term " mono-substituted amino " (separately or with other term combination) is meant amino substituting group, and one of them hydrogen atom is substituted by non-hydrogen substituting group.Term " dibasic amino " (separately or with other term combination) is meant amino substituting group, and wherein two hydrogen atoms are substituted by non-hydrogen substituting group that can be identical or different.
Term " aminocarboxyl " (separately or with other term combination) is meant-C (O)-NH
2, it can also be described to:
Term " aminoalkyl group " (separately or with other term combination) is meant-alkylidene group-NH
2
Term " aminoalkyl group carbonyl " (separately or with other term combination) is meant-C (O)-alkylidene group-NH
2For example, " amino methyl carbonyl " can be described to:
Term " amino-sulfonyl " (separately or with other term combination) is meant-S (O)
2-NH
2, it can also be described to:
Term " aryl " (separately or with other term combination) is meant the aromatic carbocyclyl groups that contains 6-14 carbon atom.The limiting examples of aryl comprises phenyl, naphthyl, anthryl and indenyl.Aryl can partly be connected with parent molecule via any commutable carbon atom of this group.
Term " arylalkyl " (separately or with other term combination) is meant the aryl that partly is connected via alkylidene group and parent molecule.The representative example of substituted/unsubstituted arylalkyl includes but not limited to benzyl, 4-(benzyloxy) benzyl, the 4-methoxy-benzyl, the 4-hydroxybenzyl, 3-(1,3-benzodioxole-5-yl)-the 2-methyl-propyl, 3-(phenoxy group) benzyl, 3-(1,3-benzodioxole-5-yl) propyl group, the 2-phenylethyl, the 3-phenyl propyl, the 2-naphthyl methyl, 3,5-di-t-butyl-2-hydroxybenzyl, the 3-methoxy-benzyl, 3, the 4-dimethoxy-benzyl, 4-(dimethylamino) benzyl, 4-[3-(dimethylamino) propoxy-] benzyl, (6-methoxyl group-2-naphthyl) methyl and 2-naphthalene-2-base ethyl.
Term " aromatic yl alkyl carbonyl " (separately or with other term combination) is meant the arylalkyl that partly is connected via carbonyl and parent molecule (be arylalkyl-C (O)-).The representative example of aromatic yl alkyl carbonyl includes but not limited to 2-naphthyl ethanoyl and phenyl acetyl.
Term " alkoxy aryl " (separately or with other term combination) is meant that the arylalkyl that partly is connected via oxygen base section and parent molecule (is an arylalkyl-O-).The representative example of alkoxy aryl includes but not limited to 2-phenyl ethoxy, 3-naphthalene-2-base propoxy-and 5-phenyl pentyloxy.
Term " alkoxy aryl alkyl " (separately or with other term combination) is meant the alkoxy aryl that partly is connected via alkylidene group and parent molecule.The representative example of alkoxy aryl alkyl includes but not limited to benzyloxymethyl, 2-(benzyloxy) ethyl and (2-phenyl ethoxy) methyl.
Term " aryl-alkoxy carbonyl " (separately or with other term combination) is meant the alkoxy aryl that partly is connected via carbonyl and parent molecule.The representative example of aryl-alkoxy carbonyl includes but not limited to benzyloxycarbonyl and naphthalene-2-ylmethoxy carbonyl.
Term " aryl carbonyl " (separately or with other term combination) is meant the aryl that partly is connected via carbonyl and parent molecule.The representative example of aryl carbonyl includes but not limited to benzoyl and naphthoyl.
Term " aryloxy " (separately or with other term combination) is meant the aryl that partly is connected via oxygen base section and parent molecule.The representative example of substituted/unsubstituted aryloxy includes but not limited to phenoxy group, naphthyloxy, 3-bromine phenoxy group, 4-chlorophenoxy, 4-methylphenoxy and 3,5-dimethoxy phenoxy group.
Term " aryloxy alkyl " (separately or with other term combination) is meant the aryloxy that partly is connected via alkylidene group and parent molecule.The representative example of aryloxy alkyl includes but not limited to 2-phenoxy group ethyl, 3-naphthalene-2-base oxygen base propyl group and phenoxymethyl.
Term " aryloxycarbonyl " (separately or with other term combination) is meant the aryloxy that partly is connected via carbonyl and parent molecule.
Term " artyl sulfo " (separately or with other term combination) is meant that the aryl that partly is connected via sulphur atom and parent molecule (is an aryl-S-).The representative example of artyl sulfo includes but not limited to thiophenyl, naphthalene-1-base sulfenyl and naphthalene-2-base sulfenyl.
Term " artyl sulfo alkyl " (separately or with other term combination) be meant aryl-S-alkylidene group-.The representative example of artyl sulfo alkyl includes but not limited to (thiophenyl) methyl, 2-(thiophenyl) ethyl and 3-(thiophenyl) propyl group.
Term " aryl thio alkoxy " (separately or with other term combination) is meant the artyl sulfo alkyl that partly is connected via oxygen base and parent molecule.
Term " aryl thio alkoxy alkyl " (separately or with other term combination) is meant the aryl thio alkoxy that partly is connected via alkylidene group and parent molecule.
Term " carbocyclic ring " or " carbon ring group " or " carbocylic radical " (separately or with other term combination) are meant saturated (for example " cycloalkyl "), fractional saturation (for example " cycloalkenyl group " or " cycloalkynyl radical ") or unsaturated entirely (for example " aryl ") ring system, wherein contain 0 heteroatomic ring atom and 3-18 carboatomic ring atom usually." annular atoms " or " ring element " is the atom that is combined together to form the ring of cyclic substituents.Carbocylic radical can be but be not limited to monocycle or two or more fused rings or bridge joint ring or volution.It (is C that carbocylic radical can contain 3-14 ring element
3-C
14Carbocylic radical is C for example
3-C
14Cycloalkyl), 3-10 ring element (is C
3-C
10Carbocylic radical is C for example
3-C
10Cycloalkyl), 3-8 ring element (is C
3-C
8Carbocylic radical is C for example
3-C
8Cycloalkyl), 3-6 ring element (is C
3-C
6Carbocylic radical is C for example
3-C
6Cycloalkyl), 4-10 ring element (is C
4-C
10Carbocylic radical is C for example
4-C
10Cycloalkyl and C
4-C
10Cycloalkenyl group), 4-8 ring element (is C
4-C
8Carbocylic radical is C for example
4-C
8Cycloalkyl and C
4-C
8Cycloalkenyl group) or 5-7 ring element (be C
5-C
7Carbocylic radical is C for example
5-C
7Cycloalkyl, C
5-C
7Cycloalkenyl group and phenyl).Substituted carbocylic radical can have cis or trans geometry.The representative example of carbocylic radical includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, cyclopentenyl, cyclopentadienyl, cyclohexadienyl, adamantyl, decahydro naphthyl, octahydro indenyl, cyclohexenyl, phenyl, naphthyl, fluorenyl, indanyl, 1,2,3,4-tetrahydrochysene-naphthyl, indenyl, different indenyl, two ring decyls, anthryl, phenanthrene, benzo naphthyl (also being called " phenalenyl "), naphthane base and norpinanyl.Carbocylic radical can be connected via any commutable carbon atom of this group on the parent molecule part.
Term " carbocylic radical alkyl " (separately or with other term combination) is meant the carbocylic radical that partly is connected via alkylidene group and parent molecule.For example, C
3-C
10Carbocylic radical C
1-C
6Alkyl is meant via C
1-C
6The C that alkylidene group and parent molecule partly are connected
3-C
10Carbocylic radical.Equally, C
5-C
7Carbocylic radical C
1-C
6Alkyl is meant via C
1-C
6The C that alkylidene group and parent molecule partly are connected
5-C
7Carbocylic radical.
Term " carbocylic radical alkoxyl group " (separately or with other term combination) is meant that the carbocylic radical alkyl that partly is connected via oxygen base and parent molecule (is carbocylic radical-alkylidene group-O-).For example, C
3-C
10Carbocylic radical C
1-C
6Alkoxyl group is meant the C that partly is connected via oxygen base and parent molecule
3-C
10Carbocylic radical C
1-C
6Alkyl.Equally, C
5-C
7Carbocylic radical C
1-C
6Alkoxyl group is meant the C that partly is connected via oxygen base and parent molecule
5-C
7Carbocylic radical C
1-C
6Alkyl.
Term " carbocylic radical alkoxyalkyl " (separately or with other term combination) is meant the carbocylic radical alkoxyl group that partly is connected via alkylidene group and parent molecule (be carbocylic radical-alkylidene group-O-alkylidene group-).For example, C
3-C
10Carbocylic radical C
1-C
6Alkoxy C
1-C
6Alkyl is meant via C
1-C
6The C that alkylidene group and parent molecule partly are connected
3-C
10Carbocylic radical C
1-C
6Alkoxyl group.
Term " carbocylic radical alkoxy carbonyl " (separately or with other term combination) is meant the carbocylic radical alkoxyl group that partly is connected via carbonyl and parent molecule (promptly-C (O)-O-alkylidene group-carbocylic radical).For example, C
3-C
10Carbocylic radical C
1-C
6Alkoxy carbonyl is meant the C that partly is connected via carbonyl and parent molecule
3-C
10Carbocylic radical C
1-C
6Alkoxyl group.As limiting examples, " phenyl ethoxy carbonyl " can be described to:
Term " carbocylic radical alkyl-carbonyl " (separately or with other term combination) is meant the carbocylic radical alkyl that partly is connected via carbonyl and parent molecule (promptly-C (O)-alkylidene group-carbocylic radical).For example, " phenylethyl carbonyl " can be described to:
Term " carbocylic radical carbonyl " (separately or with other term combination) is meant the carbocylic radical that partly is connected via carbonyl and parent molecule (be carbocylic radical-C (O)-).For example, " phenylcarbonyl group " can be described to:
Term " carbocylic radical oxygen base " (separately or with other term combination) is meant that the carbocylic radical that partly is connected via oxygen base section and parent molecule (is a carbocylic radical-O-).
Term " carbocylic radical oxygen base alkyl " (separately or with other term combination) is meant the carbocylic radical oxygen base that partly is connected via alkylidene group and parent molecule (be carbocylic radical-O-alkylidene group-).
Term " carbocylic radical oxygen base carbonyl " (separately or with other term combination) is meant the carbocylic radical oxygen base that partly is connected via carbonyl and parent molecule (promptly-C (O)-O-carbocylic radical).For example, " phenyl oxygen base carbonyl " can be described to:
Term " carbocylic radical sulfenyl " (separately or with other term combination) is meant that the carbocylic radical that partly is connected via sulphur atom and parent molecule (is a carbocylic radical-S-).
Term " carbocylic radical thio alkoxy " (separately or with other term combination) is meant carbocylic radical-alkylidene group-S-.
Term " carbocylic radical thio alkoxy alkyl " (separately or with other term combination) be meant carbocylic radical-alkylidene group-S-alkylidene group-.
Term " carbocylic radical sulfenyl alkyl " (separately or with other term combination) is meant the carbocylic radical sulfenyl that partly is connected via alkylidene group and parent molecule (be carbocylic radical-S-alkylidene group-).
Term " carbocylic radical carbocylic radical " (separately or with other term combination) is meant the carbocylic radical that partly is connected via another carbocylic radical and parent molecule (be carbocylic radical-carbocylic radical-).For example, C
3-C
10Carbocylic radical C
5-C
7Carbocylic radical is meant via C
5-C
7The C that carbocylic radical and parent molecule partly are connected
3-C
10Carbocylic radical (is C
3-C
10Carbocylic radical-C
5-C
7Carbocylic radical-).
Term " carbocylic radical carbocylic radical alkyl " (separately or with other term combination) is meant the carbocylic radical carbocylic radical that partly is connected via alkylidene group and parent molecule.
Term " carbocylic radical alkoxyl group carbocylic radical alkyl " (separately or with other term combination) be meant carbocylic radical-alkylidene group-O-carbocylic radical-alkylidene group-.For example, C
3-C
10Carbocylic radical C
1-C
6Alkoxy C
5-C
7Carbocylic radical C
3-C
4Alkyl is meant C
3-C
10Carbocylic radical-C
1-C
6Alkylidene group-O-C
5-C
7Carbocylic radical-C
3-C
4Alkylidene group-.
Term " (carbocylic radical alkyl) carbocylic radical alkyl " (separately or with other term combination) be meant carbocylic radical-alkylidene group-carbocylic radical-alkylidene group-.For example, C
3-C
10Carbocylic radical C
1-C
6Alkyl C
5-C
7Carbocylic radical C
3-C
4Alkyl is meant C
3-C
10Carbocylic radical-C
1-C
6Alkylidene group-C
5-C
7Carbocylic radical-C
3-C
4Alkylidene group-.
Term " carbocylic radical alkoxyl group heterocyclic radical alkyl " (separately or with other term combination) be meant carbocylic radical-alkylidene group-O-heterocyclic radical-alkylidene group-.
Term " carbocylic radical carbonyl heterocyclic radical alkyl " (separately or with other term combination) be meant carbocylic radical-C (O)-heterocyclic radical-alkylidene group-.
Term " carbocylic radical heterocyclic radical alkyl " (separately or with other term combination) be meant carbocylic radical-heterocyclic radical-alkylidene group-.
Term " carbocylic radical carbonyl carbon cyclic group alkyl " (separately or with other term combination) be meant carbocylic radical-C (O)-carbocylic radical-alkylidene group-.For example, C
3-C
10Carbocylic radical carbonyl C
4-C
8Carbocylic radical C
1-C
6Alkyl is meant C
3-C
10Carbocylic radical-C (O)-C
4-C
8Carbocylic radical-C
1-C
6Alkylidene group-.
Term " (carbocylic radical alkyl) heterocyclic radical alkyl " (separately or with other term combination) is meant carbocylic radical-alkylidenyl-heterocyclic base-alkylidene group.
Term " carbonyl " (separately or with other term combination) be meant-C (O)-, it can also be described to:
Term " carboxyl " (separately or with other term combination) is meant-C (O)-OH, and it can also be described to:
Term " carboxyalkyl " (separately or with other term combination) is meant the carboxyl that partly is connected via alkylidene group and parent molecule.The representative example of carboxyalkyl includes but not limited to carboxyl methyl, 2-carboxy ethyl and 3-carboxyl propyl group.
Term " ring amino " (separately or with other term combination) is meant the heterocyclic radical part, wherein comprises at least one azo-cycle atom, and all the other annular atomses are carbon and optional nitrogen or sulphur.The limiting examples of such part comprises piperidyl, piperazinyl and thiazine group.
Term " cycloalkenyl group " (separately or with other term combination) be meant non-aromatics, the undersaturated carbocylic radical substituting group of part, it has 0 heteroatomic ring unit, and 4-18 carbocyclic ring unit usually.The representative example of cycloalkenyl group includes but not limited to cyclobutene base, cyclopentenyl, cyclohexenyl and octahydro naphthyl.
Term " cycloalkyl " (separately or with other term combination) is meant the saturated carbon cyclic group, and it has 0 heteroatomic ring unit, and 3-18 carbocyclic ring unit usually.The limiting examples of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, decahydro naphthyl and norpinanyl.
Term " naphthene base carbonyl " (separately or with other term combination) is meant the cycloalkyl that partly is connected via carbonyl and parent molecule.
Term " cyano group " (separately or with other term combination) is meant-CN that it can also be described to
Term " dialkyl amido " (separately or with other term combination) is meant-NR
AR
B, R wherein
AAnd R
BBe independently selected from alkyl.
Term " dialkyl amino carbonyl " (separately or with other term combination) is meant that the dialkyl amido that partly is connected via carbonyl and parent molecule (is N (R
AR
B)-C (O)-, R wherein
AAnd R
BBe independently selected from alkyl).
Term " formyl radical " (separately or with other term combination) is meant-C (O) H.
Term " halogen " or " halo " (separately or with other term combination) be meant fluorine (it can be described to-F), chlorine (it can be described to-Cl), bromine (it can be described to-Br) or iodine (it can be described to-I).
Prefix " halo " is meant that the substituting group that this prefix connects is replaced by one or more halogens of selecting independently.For example, " haloalkyl " (separately or with other term combination) is meant alkyl substituent, and wherein at least one hydrogen is substituted by halogen.The limiting examples of haloalkyl comprises methyl fluoride, 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, the 2-oxazinyl, 1,3,6-oxazinyl (also being called " pentoxazolyl "), 1,2,6-oxazinyl and 1, the 4-oxazinyl) oxazinyl (comprising Lin Yi oxazinyl and Dui Yi oxazinyl) oxazolidinyl isoxazole alkyl Evil thiazinyl (comprises 1,2,5-Evil thiazinyl or 1,2,6-Evil thiazinyl) oxadiazine base (comprises 1,4,2-oxadiazine base and 1,3,5,2-oxadiazine base), morpholinyl, azepine
Base, oxa-
Base, thia
Base and diaza
Base.
Heterocyclic radical can also include but not limited to condense two or more rings together, for example, phthalazinyl (comprises [1,8] phthalazinyl and [1,6] phthalazinyl), thiazole and pyrimidyl, the Thienopyrimidine base, the Mi Dingbing pyrimidyl, the Pyridopyrimidine base, the pyrazolopyrimidine base, the indolizine base, pyrindine base (pyrindinyl), pyrans and pyrryl, the 4H-quinolizinyl, purine radicals, the pyridopyridine base (comprises pyrido [3,4-b]-pyridyl, pyrido [3,2-b]-pyridyl and pyrido [4,3-b]-pyridyl), Pyridopyrimidine and pteridyl.Other limiting examples of fused rings heterocyclic radical comprise the benzo-fused heterocycle base, indyl for example, pseudoindoyl, pseudoindolyl (also being called " pseudoindolyl "), iso indazolyl (also being called " benzopyrazoles base "), benzo azine group (comprising quinolyl (also being called " 1-benzo azine group ") and isoquinolyl (also being called " 2-benzo azine group ")), phthalazinyl, quinoxalinyl, benzodiazine base (comprising cinnolines base (also being called " 1; 2-benzodiazine base ") and quinazolyl (also being called " 1; 3-benzodiazine base ")), benzopyranyl (comprising " chromenyl " and " heterochromatic thiazolinyl "), benzo thiapyran base (also being called " benzothiopyran base ") benzoxazolyl Yin oxazinyl (indoxazinyl) (also being called " benzoisoxazole base "), the adjacent first lactam group (anthranilyl) of benzene, the benzodioxole base, benzo dioxane base Ben Bing oxadiazole base, benzofuryl (also being called " tonka-bean ketone group "), isobenzofuran-base, benzothienyl (also is called " benzothienyl ", " thianaphthenyl " and " benzothienyl "), isobenzo-thienyl (also is called " isobenzo-thienyl ", " isothianaphthene base " and " isobenzo-thienyl "), benzothiazolyl, the diazosulfide base, benzimidazolyl-, benzotriazole base benzoxazinyl (comprises 1,3, the 2-benzoxazinyl, 1,4, the 2-benzoxazinyl, 2,3,1-benzoxazinyl and 3,1, the 4-benzoxazinyl), Ben Bing Yi oxazinyl (comprises 1,2-Ben Bing Yi oxazinyl and 1,4-Ben Bing Yi oxazinyl), tetrahydro isoquinolyl, carbazyl, xanthenyl and acridyl.
Term " two fused rings " heterocyclic radical (separately or with other term combination) is meant that containing two condenses ring filling, fractional saturation or aromatic heterocyclic radical.The limiting examples of two fused rings heterocyclic radicals comprises that phthalazinyl (comprises [1,8] phthalazinyl and [1,6] phthalazinyl), thiazole and pyrimidyl, the Thienopyrimidine base, the Mi Dingbing pyrimidyl, the Pyridopyrimidine base, the pyrazolopyrimidine base, the indolizine base, pyrindine base (pyrindinyl), pyrans and pyrryl, the 4H-quinolizinyl, purine radicals, the pyridopyridine base, pteridyl, indyl, pseudoindoyl, pseudoindolyl, iso indazolyl, the benzo azine group, phthalazinyl, quinoxalinyl, quinazolyl, the benzodiazine base, benzopyranyl, benzo thiapyran base benzoxazolyl Yin oxazinyl (indoxazinyl), the adjacent first lactam group (anthranilyl) of benzene, the benzodioxole base, benzo dioxane base Ben Bing oxadiazole base, benzofuryl, isobenzofuran-base, benzothienyl, isobenzo-thienyl, benzothiazolyl, the diazosulfide base, benzimidazolyl-, benzotriazole base benzoxazinyl, Ben Bing Yi oxazinyl and tetrahydro isoquinolyl.
Heterocyclic radical can comprise one or more sulphur atoms as ring element; In some cases, sulphur atom is oxidized to SO or SO
2Nitrogen heteroatom in the heterocyclic radical can or cannot be by quaternized, and can maybe cannot be oxidized to the N-oxide compound.In addition, nitrogen heteroatom can maybe cannot be a N-protected.
As used in this article, the number of annular atoms can pass through prefix " M in the heterocyclic radical part
x-M
y, " expression, wherein x is the minimal number of annular atoms in the heterocyclic radical part, y is a maximum number.
Term " heterocyclic radical alkoxyl group " (separately or with other term combination) is meant the heterocyclic radical alkyl that partly is connected via oxygen base and parent molecule.
Term " heterocyclic radical alkoxyalkyl " (separately or with other term combination) is meant the heterocyclic radical alkoxyl group that partly is connected via alkylidene group and parent molecule (be heterocyclic radical-alkylidene group-O-alkylidene group-).
Term " heterocyclic radical alkoxy carbonyl " (separately or with other term combination) is meant the heterocyclic radical alkoxyl group that partly is connected via carbonyl and parent molecule (be heterocyclic radical-alkylidene group-O-C (O)-).
Term " heterocyclic radical alkyl " (separately or with other term combination) is meant the heterocyclic radical that partly is connected via alkylidene group and parent molecule (heterocyclic radical C for example
1-C
6Alkyl).
Term " heterocyclic radical alkyl-carbonyl " (separately or with other term combination) is meant the heterocyclic radical alkyl that partly is connected via carbonyl and parent molecule (promptly-C (O)-alkylidenyl-heterocyclic base).
Term " heterocyclic radical carbonyl " (separately or with other term combination) is meant the heterocyclic radical that partly is connected via carbonyl and parent molecule (promptly-C (O)-heterocyclic radical).
Term " heterocyclyloxy base " or " (heterocyclic radical) oxygen base " (separately or with other term combination) are meant the heterocyclic radical that partly is connected via oxygen base and parent molecule.
Term " (heterocyclic radical) oxygen base alkyl " (separately or with other term combination) is meant the heterocyclyloxy base that partly is connected via alkylidene group and parent molecule (be heterocyclic radical-O-alkylidene group-).
Term " (heterocyclic radical) oxygen base carbonyl " (separately or with other term combination) is meant (heterocyclic radical) oxygen base of partly being connected via carbonyl and parent molecule (be heterocyclic radical-O-C (O)-).
Term " heterocyclic radical sulfenyl " (separately or with other term combination) is meant the heterocyclic radical that partly is connected via-S-and parent molecule.
Term " heterocyclic radical thio alkoxy " (separately or with other term combination) is meant heterocyclic radical-alkylidene group-S-.
Term " heterocyclic radical thio alkoxy alkyl " (separately or with other term combination) be meant heterocyclic radical-alkylidene group-S-alkylidene group-.
Term " heterocyclic radical sulfenyl alkyl " (separately or with other term combination) is meant the heterocyclic radical sulfenyl that partly is connected via alkylidene group and parent molecule (be heterocyclic radical-S-alkylidene group-).
Term " heterocyclic radical carbocylic radical " (separately or with other term combination) is meant the heterocyclic radical that partly is connected via carbocylic radical and parent molecule (be heterocyclic radical-carbocylic radical-).
Term " heterocyclic radical carbocylic radical alkyl " (separately or with other term combination) is meant the heterocyclic radical carbocylic radical that partly is connected via alkylidene group and parent molecule (be heterocyclic radical-carbocylic radical-alkylidene group-).
Term " (heterocyclic radical) alkoxyl group carbocylic radical alkyl " (separately or with other term combination) be meant heterocyclic radical-alkylidene group-O-carbocylic radical-alkylidene group-.
Term " (heterocyclic radical) carbonyl carbon cyclic group alkyl " (separately or with other term combination) be meant heterocyclic radical-C (O)-carbocylic radical-alkylidene group-.
Term " (heterocyclic radical) heterocyclic radical alkyl " (separately or with other term combination) be meant heterocyclic radical-heterocyclic radical-alkylidene group-.
Term " (heterocyclic radical) alkoxyl group heterocyclic radical alkyl " (separately or with other term combination) be meant heterocyclic radical-alkylidene group-O-heterocyclic radical-alkylidene group-.
Term " (heterocyclic radical) carbonyl heterocyclic radical alkyl " (separately or with other term combination) be meant heterocyclic radical-C (O)-heterocyclic radical-alkylidene group-.
Term " (heterocyclic radical alkyl) carbocylic radical alkyl " (separately or with other term combination) be meant heterocyclic radical-alkylidene group-carbocylic radical-alkylidene group-.
Term " (heterocyclic radical alkyl) heterocyclic radical alkyl " (separately or with other term combination) be meant heterocyclic radical-alkylidenyl-heterocyclic base-alkylidene group-.Therefore, for example, (M
3-M
10Heterocyclic radical C
1-C
6Alkyl) M
5-M
6Heterocyclic radical C
1-C
3Alkyl is meant M
3-M
10Heterocyclic radical-C
1-C
6Alkylidene group-M
5-M
6Heterocyclic radical-C
1-C
3Alkylidene group-.
Term " heteroaryl " (separately or with other term combination) is meant the aromatic heterocyclic radical that contains 5-18 annular atoms usually.Heteroaryl can be a monocycle, or two or more fused rings.The limiting examples of 5 yuan of heteroaryls comprises imidazolyl; Furyl; Thienyl (or thienyl or thienyl); Pyrazolyl; Oxazolyl; Isoxazolyl; Thiazolyl; 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,2,5-oxadiazole base and 1,3,4-oxadiazole base; And isothiazolyl.The limiting examples of 6 yuan of heteroaryls comprises pyridyl; Pyrazinyl; Pyrimidyl; Pyridazinyl and 1,3,5-triazines base, 1,2,4-triazinyl and 1,2,3-triazinyl.The limiting examples of 6/5-unit fused ring heteroaryl comprises the adjacent first lactam group (anthranilyl) of benzothienyl, isobenzo-thienyl, benzoisoxazole base, benzoxazolyl, purine radicals and benzene.The limiting examples of 6/6-unit fused ring heteroaryl comprises quinolyl; Isoquinolyl; And benzoxazinyl (comprising cinnolines base and quinazolyl).
Term " heteroaryl alkoxyl group " (separately or with other term combination) is meant that the heteroarylalkyl that partly is connected via oxygen base and parent molecule (is heteroaryl-alkylidene group-O-).The representative example of heteroaryl alkoxyl group includes but not limited to 2-pyridin-3-yl oxyethyl group, 1,3-thiazoles-5-ylmethoxy, 3-quinoline-3-base propoxy-and 5-pyridin-4-yl amyl group oxygen base.
Term " heteroaryl alkoxyalkyl " (separately or with other term combination) is meant the heteroaryl alkoxyl group that partly is connected via alkylidene group and parent molecule (be heteroaryl-alkylidene group-O-alkylidene group-).The representative example of heteroaryl alkoxyalkyl includes but not limited to (2-pyridin-3-yl oxyethyl group) methyl, (3-quinoline-3-base propoxy-) methyl, (1,3-thiazoles-5-ylmethoxy) methyl and 2-(5-pyridin-4-yl amyl group oxygen base) ethyl.
Term " heteroaryl alkoxy carbonyl " (separately or with other term combination) is meant the heteroaryl alkoxyl group that partly is connected via carbonyl and parent molecule (be heteroaryl-alkylidene group-O-C (O)-).The representative example of heteroaryl alkoxy carbonyl includes but not limited to (2-pyridin-3-yl oxyethyl group) carbonyl, (3-quinoline-3-base propoxy-) carbonyl, 2-(1,3-thiazoles-5-ylmethoxy) carbonyl and (5-pyridin-4-yl amyl group oxygen base) carbonyl.
Term " heteroarylalkyl " (separately or with other term combination) is meant the heteroaryl that partly is connected via alkylidene group and parent molecule.The representative example of heteroarylalkyl includes but not limited to 3-quinolyl methyl, 3-pyridylmethyl, 4-pyridylmethyl, 1H-imidazol-4 yl methyl, 1H-pyrroles-2-ylmethyl, pyridin-3-yl methyl and 2-pyrimidine-2-base propyl group.
Term " heteroarylalkyl carbonyl " (separately or with other term combination) is meant the heteroarylalkyl that partly is connected via carbonyl and parent molecule (be heteroaryl-alkylidene group-C (O)-).
Term " heteroaryl carbonyl " (separately or with other term combination) is meant the heteroaryl that partly is connected via carbonyl and parent molecule.The representative example of heteroaryl carbonyl includes but not limited to pyridin-3-yl carbonyl, (1,3-thiazoles-5-yl) carbonyl and quinoline-3-base carbonyl.
Term " heteroaryloxy " (separately or with other term combination) is meant the heteroaryl that partly is connected via oxygen base and parent molecule.The representative example of heteroaryloxy includes but not limited to pyridin-3-yl oxygen base and quinoline-3-base oxygen base.
Term " heteroaryloxy alkyl " (separately or with other term combination) is meant the heteroaryloxy that partly is connected via alkylidene group and parent molecule (be heteroaryl-O-alkylidene group-).
Term " heteroaryloxy carbonyl " (separately or with other term combination) is meant the heteroaryloxy that partly is connected via carbonyl and parent molecule (be heteroaryl-O-C (O)-).
Term " heteroaryl sulfenyl " (separately or with other term combination) is meant the heteroaryl that partly is connected via-S-and parent molecule.
Term " heteroaryl thio alkoxy " (separately or with other term combination) is meant heteroaryl-alkylidene group-S-.
Term " heteroaryl thio alkoxy alkyl " (separately or with other term combination) be meant heteroaryl-alkylidene group-S-alkylidene group-.
Term " heteroaryl sulfenyl alkyl " (separately or with other term combination) is meant the heteroaryl sulfenyl that partly is connected via alkylidene group and parent molecule (be heteroaryl-S-alkylidene group-).
Term " hydrogen " (separately or with other term combination) is meant hydrogen group, and can be described as-H.
Term " hydroxyl " (separately or with other term combination) is meant-OH.
Term " hydroxyalkyl " (separately or with other term combination) is meant alkyl substituent, and wherein one or more hydrogen quilt-OH are alternative.The representative example of hydroxyalkyl includes but not limited to hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and 2-ethyl-4-hydroxyl heptyl.
Term " ketone group " (separately or with other term combination) is meant the oxo base, and can be described to=O.
Term " imino alkyl " (separately or with other term combination) is meant the group of following formula:
, wherein H can choose wantonly by alkyl or hydroxyl and replace, and in this case, substituting group will be alkyl imino alkyl or oxyimino alkyl respectively.
Term " nitro " (separately or with other term combination) is meant-NO
2
Term " oxo base " (separately or with other term combination) is meant=the O part is (promptly
).
Term " oxygen base " (separately or with other term combination) is meant-O-.
Term " propargyl " (separately or with other term combination) is meant and is described to-CH
2The monoradical of-CH ≡ CH.
Term " alkylsulfonyl " (separately or with other term combination) is meant-S (O)
2-, it can also be described to:
Term " sulfinyl " (separately or with other term combination) be meant-S (O)-, it can also be described to:
Term " sulfenyl " or " thia " (separately or with other term combination) are meant-S-.
Term " mercaptan ", " sulfydryl " or " sulfydryl " (separately or with other term combination) are meant the sulfydryl substituting group (promptly-SH).Therefore, for example, mercaptoalkyl is meant alkyl substituent, and wherein one or more hydrogen quilt-SH substitute, and the alkyl sulfenyl is meant alkyl-S-.
Term " thio alkoxy " (separately or with other term combination) is meant the alkyl that partly is connected via-S-and parent molecule.The representative example of thio alkoxy includes but not limited to methyl sulfenyl, ethyl sulfenyl and butyl sulfenyl.
Term " thio alkoxy alkyl " (separately or with other term combination) is meant the thio alkoxy that partly is connected via alkylidene group and parent molecule (be alkyl-S-alkylidene group-).
Term " thiocarbonyl " (separately or with other term combination) is meant carbonyl, and wherein Sauerstoffatom is substituted by sulphur.Such substituting group can be described to-C (S)-, and can be described to:
Term " pharmaceutically acceptable " uses as adjective and is meant that the noun of modification is suitable for use as the part of medicament production or medicament production.
Term " treatment significant quantity " is meant and is enough to show significant patient's benefit, for example the total amount of each active substance of descending of virus load.
Term " prodrug " is meant the derivative of The compounds of this invention, and it has can chemistry or metabolism cracked group, and is transformed into the The compounds of this invention that has pharmacologically active in vivo by solvolysis or under physiological condition.The prodrug of compound be the functional group (for example amino, hydroxyl or carboxyl) by compound reaction and with the ordinary method preparation.The prodrug derivant form often provides following advantage: solvability, histocompatibility or delay release in mammalian organism (referring to, Bungard, H.,
, pp.7-9,21-24, Elsevier, Amsterdam1985).Prodrug comprises the well-known acid derivative of those skilled in the art, for example, and by ester with female acidic cpd and suitable pure prepared in reaction, or the acid amides by female acidic cpd and suitable amine reaction are made.The example of prodrug includes but not limited to the alcohol in the The compounds of this invention or acetic ester or salt, manthanoate or salt, benzoic ether or salt or other acylated derivatives of amine functional group.
Term " solvate " is meant the physics association body of The compounds of this invention and one or more organic or inorganic solvent molecules.This physics associates and often comprises hydrogen bond.In some cases, solvate can be separated, for example, and when one or more solvent molecules are incorporated in the lattice of solid crystal." solvate " comprises solution phase and separable solvate.The exemplary solvent thing includes but not limited to hydrate, ethylate and methylate.
Term " chirality " be meant do not have symmetrical plane and therefore can not with its mirror image eclipsed molecule.Chiral molecules can exist with two kinds of forms, and a kind of is right-hand lay, a kind of be left-hand to.
Term " steric isomer " is meant to have with identical sequence and connects, but the isomer with different three-dimensional arrangement.The term steric isomer comprises for example enantiomorph and diastereomer.
Term " cis-trans isomer " is meant the different steric isomer of stereochemistry around two keys or ring.The cis-trans isomer is also referred to as geometrical isomer.
Term " enantiomorph " is meant the steric isomer of the chiral material with mirror.
Term " diastereomer " is meant the steric isomer that is not enantiomorph or mirror images of each other.
Term " racemic mixture " is meant the mixture by (+) and (-) enantiomorph of the chiral material of equal portions.Though independent molecule is a chirality, racemic mixture does not have optically-active.
Term " tautomer " is meant the isomer that can transform mutually.For example, enol and ketone are tautomers, because by using acid or alkaline purification, they can transform mutually.
Term " positional isomers " is meant two or more composition isomer that the position of specified substituent or group is different.Functional group connects on can be in the structure of the carbon skeleton different position.For example, [1,3] imidazoles is described as
And [1,4] imidazoles, be described as
, be positional isomers.
Term " N-protected base " or " N-protected " are meant can protect the amino group that undesirable reaction does not take place.N-protected base commonly used is described in Greene and Wuts,
(3
RdEd., John Wiley ﹠amp; Sons, among the NY (1999), it is incorporated herein by reference.The limiting examples of N-protected base comprises acyl group for example formyl radical, ethanoyl, propionyl, valeryl, tertiary butyl ethanoyl, 2-acetyl fluoride base, 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-C2H4F2 C2H4F2
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 formula I-VIII compound
Can pass through will
With
Reaction comes synthetic compound of formula i, wherein W
1, W
2, A, B, X, Y, R
10, R
22And R
50Have the implication that provides in top embodiment or the example, and K is Cl or other halogen.Equally, can pass through will
Or
Respectively with
Or
Reaction comes preparation formula II-VIII compound.
The synthesis example of formula I-VIII compound is shown in reaction scheme 1-8.The representative compounds of formula I, wherein
Be
, R
10, R
17And R
35As hereinbefore defined, and Z be NR
41, can prepare with the method for describing in the reaction scheme 1.
Reaction scheme 1
Can in the presence of acid (such as but not limited to acetate), under high temperature (for example about 80 ℃-Yue 150 ℃), incite somebody to action wherein R
41Be the N of formula (2) amine of hydrogen with formula (1), N-dimethyl methyl amidine compound is handled, thus production (3) compound.Acetate can play solvent.Other The suitable solvent also can be used for this reaction.
R wherein
41The N alkylation that is formula (2) compound of hydrogen provides wherein R
41Be formula (2) or (3) compound of alkyl.Can use formula R under the following conditions
41X
1(X wherein
1Be halogen, tosylate, triflate or methanesulfonates) alkylating agent promote this reaction: in the presence of alkali, described alkali such as but not limited to, organic bases is triethylamine or diisopropylamine for example, or mineral alkali for example yellow soda ash, cesium carbonate or salt of wormwood, in The suitable solvent, and under the temperature of about room temperature-Yue 100 ℃.
Reaction scheme 2
The N of formula (1), the preparation of N-dimethyl methyl amidine compound can realize as described in reaction scheme 2.Alkali such as but not limited to sodium hydride or potassium hydride KH (or sodium metal) in the presence of, at about 0 ℃, The suitable solvent such as but not limited to ether in, with the ester reaction of the ketone of formula (4) and formula (5), form the salt of formula (6), wherein M is potassium or sodium.In the presence of Piperidineacetic acid salt, under refluxing approximately, formula (6) is handled acquisition formula (7a) and nitrile (7b) with the 2-malonamide nitrile.Can at this moment regional isomer (7a) be separated with (7b), perhaps later in route of synthesis, use purification technique well known by persons skilled in the art to separate.In The suitable solvent, under refluxing, by handling and formula (7a) compound can be converted into wherein X with phosphoryl chloride
2Be formula (8) compound of Cl, perhaps handle, formula (7a) compound can be converted into wherein X by 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 at for example about 130 ℃ of reactions of high temperature, acquisition formula (9) compound.Formula (9) compound and N, the reaction under solvent is refluxing in such as but not limited to toluene of dinethylformamide dimethyl acetal, the N of acquisition formula (1), N-dimethyl methyl amidine compound.
Reaction scheme 3
Can be according to reaction scheme 3, wherein R
101Be leavings group such as but not limited to halogen, triflate or methanesulfonates (back both can use method known to those skilled in the art prepare by corresponding alcohol), synthetic via two steps, that is, the reduction nitro is replaced R then
101, perhaps replace R
101Reduce nitro then, by formula (10) compound R wherein
41Be that hydrogen and X are formula (2) compounds of O or S.
Can suitable alkali such as but not limited to salt of wormwood, cesium carbonate, yellow soda ash, saleratus, cesium bicarbonate, sodium bicarbonate, sodium hydride or potassium hydride KH in the presence of, and choose wantonly in the presence of 18-hat-6, at high temperature, usefulness wherein X is the R of O or S
22XH replaces R
101This reaction normally at solvent such as but not limited to N, dinethylformamide or methyl-sulphoxide exist down, carry out under the temperature of about room temperature-Yue 180 ℃.This reaction also can be carried out in microwave oven.Should be appreciated that also and can use the previous reaction condition, by inciting somebody to action wherein R
101Be-formula (10) compound of X-H, with X wherein
3Be the formula R of leavings group such as but not limited to halogen, triflate or methanesulfonates
22X
3The compound reaction comes acquisition formula (11) compound.Also can metal catalyst such as but not limited to copper metal, CuI or acid chloride in the presence of, choose wantonly in ligand such as but not limited to 2,2 '-two (diphenylphosphino)-1,1-dinaphthalene or three-tertiary 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, carry out this replacement(metathesis)reaction.This reaction such as but not limited to toluene or N, is carried out in the dinethylformamide at solvent normally in about room temperature-Yue 180 ℃ temperature.
Can in The suitable solvent,, realize the reduction of nitro by nitro-compound is handled such as but not limited to iron powder/ammonium chloride or tin chloride (II) with reductive agent.
Should be appreciated that also and can use above-described condition, at first,, formula (10) compound is converted into formula (2) compound succeeded by replacement(metathesis)reaction with the nitro functions reduction.
Preparation aminophenyl coupling agent (10,11 and 12)
Multiple different aminophenyl coupling agent is possible.Coupling agent in the reaction scheme 4 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 reaction mixture 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 fluoride 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 4
R
9As top definition;
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-replacement-pyrido [2,3-d] pyrimidine compound
7-substituted-4-amino phenyl-replacement-pyrido [2,3-d] the typical case preparation of pyrimidine compound (reaction scheme 6), comprise the linked reaction of aminophenyl coupling agent (describing in the reaction scheme 4) with the 6-replacement-2-amidino groups-3-cyanopyridine compound 9 (reaction scheme 5) of replacement.
Described in reaction scheme 4, multiple aminophenyl coupling agent is possible.
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 realized with multiple coupling agent (some of them are described in reaction scheme 4) coupling.
N, the preparation of N-dimethyl methyl amidine compound 9 can realize as describing in the reaction scheme 5.The alkyl methyl ketone and the ethyl formate that replace are added in the diethyl ether solution of sodium hydride (or sodium metal) with 2 hours in 0 ℃.To react on stirred overnight at room temperature after the adding.Add ether again, and with throw out by the vacuum filtration sharp separation, dry in vacuum drier.This material dissolves in the water that contains the 2-malonamide nitrile.Add the Piperidineacetic acid salts solution, and gained solution was heated 2 hours under refluxing.Mixture is cooled to room temperature, and is adjusted to pH4 with Glacial acetic acid.By isolated by vacuum filtration gained solid, wash with water, drying, and be accredited as 6-replacement-2-oxo-1,2-dihydropyridine-3-formonitrile HCN 24.Can compound 24 be converted into 2-chloro-pyridine with phosphoryl chloride (as shown in reaction scheme 5) or 2-bromopyridine.The 2-bromopyridine is to prepare in 5 hours with Tetrabutylammonium bromide and the reaction under refluxing of five phosphorus oxide by the toluene solution with compound 24.With compound of reaction cooling, add entry, with this mixture in stirring at room 2 hours.With the reaction mixture dilution with toluene, organic layer is separated, use the salt water washing, and use dried over mgso, filter and under vacuum, concentrate, obtain the 2-bromopyridine.The ethanolic soln and the liquefied ammonia of 2-chloropyridine or 2-bromopyridine were reacted about 20 hours down at about 130 ℃ in the high pressure vessel of sealing.Reaction mixture is concentrated under vacuum, resistates is washed with water and drying, obtain 6-replacement-2-amino-cigarette nitrile 25.Compound 25 and N, the dinethylformamide dimethyl acetal is dissolved in the toluene, and reflux 3 hours.Gained solution is cooled to room temperature, and under vacuum, concentrates, obtain 6-replacement-3-cyano group-pyridine-2-base-N, N-dimethyl carbonamidine 9.
Reaction scheme 5
R
7Be selected from hydrogen, alkyl, haloalkyl, alkoxyl group, cycloalkyl, alkoxy carbonyl alkyl, alkoxy carbonyl alkyl amino, cyano alkoxy carbonylic alkyl, cyano group alkyl, hydroxyalkyl, morpholino, diazanyl, alkylamino alkoxyl group, alkoxyalkyl amino and aryl
As described above, 7-substituted-4-amino phenyl-replacement-pyrido [2,3-d] preparation of pyrimidine, can be by 6-replacement-3-cyano group-pyridine-2-base-N with the replacement shown in the reaction scheme 5, N-dimethyl carbonamidine 9 is realized with multiple coupling agent (some of them are described in reaction scheme 4) coupling.This linked reaction is described in reaction scheme 6.
In typical case preparation, with compound 9 be similar to the aminophenyl coupling agent of describing in the reaction scheme 4 and be dissolved in the acetate, and in about 130 ℃ of stir abouts 15 minutes.Mixture is cooled to room temperature, under vacuum, removes acetate, and the gained resistates is passed through the reverse-phase chromatography purifying.Can remove any protective group base for example Boc, Troc or other groups this moment with currently known methods, obtains final product.
Reaction scheme 6
R
7, R
9, X and R define as top
The representative compounds of formula I, wherein
Ring B be 5 yuan of heterocycles, and W
1Be CH, R
10, R
17And R
35As hereinbefore defined, and Z be NR
41, can use the method preparation of describing in the reaction scheme 7, and comprise for example 13 sour and triethyl orthoformate reactions of heterocycle that alkylamino is replaced, and be heated to about 100 ℃ with Meldrum ' s.Reaction mixture is concentrated and, obtained aminomethylene malonic ester 14 by chromatography purification.Then compound 14 is dissolved in the diphenyl ether, and gained solution has obtained 15 about 30 minutes of 230 ℃ of heating.Mixture and phosphoryl chloride (POCl with compound 15
3) mix, and under agitation 50 ℃ of heating 6 hours, and by pouring the cooled on ice stopped reaction into.Be adjusted to pH10 with dense ammonium hydroxide then, and use dichloromethane extraction, use anhydrous sodium sulfate drying, filter and vacuum concentration, obtain 16.In typical case's preparation, with compound 16 be similar to the aminophenyl coupling agent described in the reaction scheme 4 with 2,8,9-triisobutyl-2,5,8, the coupling in solvent (normally toluene etc.) of 9-four azepines-1-phospha-dicyclo [3.3.3] undecane, three (dibenzalacetone)-two palladiums and sodium tert-butoxide obtains 21.
Reaction scheme 7
The representative compounds of formula I, wherein
Ring B be 5 yuan of heterocycles, and W
1Be N, R
10, R
17And R
35As hereinbefore defined, and Z be NR
41, can use in the reaction scheme 8 method of describing to prepare, and comprise the heterocycle of alkylamino-replacements for example 17 is reacted under refluxing with methane amide.Then with pyrimidine product 18 and phosphoryl chloride (POCl
3) reaction, obtain coupling composition (coupling partner) 19.In typical case preparation, with compound 19 be similar to the aminophenyl coupling agent of describing in the reaction scheme 4 and be dissolved in the ethanol, and reflux 12 hours, obtain 20.
Reaction scheme 8
Representative compounds that can preparation formula I, wherein
Ring B be 5 yuan of heterocycles, and W
1Be N, R
10, R
17And R
35As hereinbefore defined, and Z be NR
41
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
4-amino-N-[2-(4-hydroxyl-phenyl sulfenyl)-5-methyl-phenyl]-2-(2-methoxyl group-ethylamino)-pyrimidine-5-carbonamidine
With derive from embodiment 156 product (42mg, 0.1mmol) mixture in 2-methoxyethyl amine (1mL) in microwave reactor in 180 ℃ the heating 2 hours.With solvent evaporation, and with resistates via the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (15mg, 28%).
1H?NMR(300MHz，DMSO-d
6)δ?ppm：2.31(s，3H)3.28(s，3H)3.49(m，4H)6.86(m，3H)7.28(m，4H)8.17(s，br，3H)8.73(s，br，1H)9.75(s，br，2H)11.33(s，br，1H)；MS(ESI+)m/z?425(M+H)+.
Embodiment 2
4-amino-2-butyl amino-N-[2-(4-hydroxyl-phenyl sulfenyl)-5-methyl-phenyl]-pyrimidine-5-carbonamidine
With the product of embodiment 156 (42mg, 0.1mmol) mixture in butylamine (1ml) in microwave reactor in 180 ℃ of heating 2 hours.With solvent evaporation, and with resistates via the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (13mg, 24%).
1HNMR(300MHz，DMSO-d
6)δ?ppm：0.90(t，J＝7.35Hz，3H)1.29(m，2H)1.51(m，2H)2.30(s，3H)3.32(m，2H)6.85(m，3H)7.27(m，4H)8.15(s，br，3H)8.71(s，br，1H)9.55(s，br，1H)9.92(s，br，1H)11.23(s，br，1H)；MS(ESI+)m/z?423(M+H)+.
Embodiment 3
N-{4-[4-methyl-2-(6-propyl group-thieno-[2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide
Embodiment 3a
2-amino-5-propyl group thiophene-3-ethyl formate
The ethyl cyanacetate and the solution of sulphur in dimethyl formamide of equimolar amount are handled with triethylamine (0.5 equivalent) in room temperature, be heated to 50 ℃ then, drip valeral (1 equivalent).After 3 hours, the water stopped reaction, and use ethyl acetate extraction.Organic layer is concentrated, obtain this title compound.
Embodiment 3b
6-propyl group thieno-[2,3-d] pyrimidine-4-alcohol
Product and the excessive methane amide of embodiment 3a were reacted 3 hours under refluxing.Gained reaction mixture water is ended, filtered and collect the gained throw out, wash with water, and dry under vacuum, obtain this title compound.
Embodiment 3c
4-chloro-6-propyl group thieno-[2,3-d] pyrimidine
Product and excessive POCl with embodiment 3b
3Reaction is 3 hours under refluxing, then in room temperature reaction 16 hours.Reaction is poured on ice, and between water and ethyl acetate, distributes.Organic layer is concentrated, obtain this title compound.
Embodiment 3d
N-{4-[4-methyl-2-(6-propyl group-thieno-[2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide
The product of embodiment 3c and the product of embodiment 7b were reacted 16 hours under refluxing in ethanol.To react concentrated, obtain this title compound.
Embodiment 4
(6-butyl-thieno-[2,3-d] pyrimidine-4-yl)-(5-methyl-2-phenyl sulfenyl-phenyl)-amine
According to the method for embodiment 3, in embodiment 3a, replace valeral with hexanal, make this title compound.
Embodiment 5
(5-methyl-2-phenyl sulfenyl-phenyl)-(2-propyl group-thiazole is [5,4-b] pyridine-7-yl also)-amine
Embodiment 5A
Butyrylamino-methyl acetate
To under nitrogen, be cooled to 0 ℃ glycine hydrochloride (1.00g, 7.964mmol) suspension in methylene dichloride (40mL), with triethylamine (4.44mL, 31.86mmol) and butyryl chloride (0.93mL, 8.76mmol) handle, and with compound in stirring at room 2.5 hours.To react with saturated sodium bicarbonate (50mL), water (50mL) and salt water washing.With the organic phase anhydrous sodium sulfate drying, filter and under vacuum, concentrate, obtain this title compound.By flash chromatography on silica gel method purifying, with 25% methyl acetate/methylene dichloride wash-out, obtained this title compound, be colorless oil (0.776g, 4.88mmol, 61%).
Embodiment 5B
Sulfo-butyrylamino-methyl acetate
(0.774g, 4.862mmol) (1.338g 3.209mmol) handles the solution in anhydrous THF (50mL), heating 30 minutes under refluxing under nitrogen then with Lawesson reagent with the product of embodiment 5A.Reaction is cooled to 0 ℃, and slowly drips saturated aqueous solution of sodium bicarbonate (40mL).This mixture is used methyl acetate (100mL) extraction then in stirring at room 15 minutes, and with organic extract liquid with saturated sodium bicarbonate aqueous solution (50mL), water (2 x 25mL) and salt water washing.With the organic phase anhydrous sodium sulfate drying, filter, and under vacuum, concentrate, obtain this title compound.By flash chromatography on silica gel method purifying, with 1% methyl acetate/methylene dichloride wash-out, obtain this title compound, be colorless oil (0.790g, 4.508mmol, 93%).
Embodiment 5C
2-sulfo-butyrylamino-ethanamide
(0.788g, 4.496mmol) solution in methyl alcohol (30mL) is saturated with ammonia, and will be reflected in the flask of jam-pack in stirring at room 17 hours with the product of embodiment 5B.Solvent is concentrated under vacuum, obtain this title compound, this solid by flash chromatography on silica gel method purifying, with 10% ethanol/methylene wash-out, is obtained this title compound, be white solid (500mg, 3.12mmol, 69%).
Embodiment 5D
2-propyl group-thiazole-5-base amine
(395mg, 2.465mmol) (0.189mL 1.972mmol) handles the solution in anhydrous acetic acid methyl esters (12mL), and in stirring at room 20 minutes with phosphorus tribromide under nitrogen with the product of embodiment 5C.Add phosphorus tribromide (0.050mL) again, and stirred 5 minutes.Reaction mixture is diluted with methyl acetate (50mL), and wash with saturated sodium bicarbonate aqueous solution (25mL).Aqueous cleaning solution with methyl acetate (2 x 50mL) extraction, is merged the organic layer extract, use the salt water washing, use anhydrous sodium sulfate drying, filter and under vacuum, concentrate, obtain this title compound.By flash chromatography on silica gel method purifying,, obtain this title compound (175mg, 1.23mmol, 50%) with 3% ethanol/methylene wash-out.
Embodiment 5E
2,2-dimethyl-5-[(2-propyl group-thiazole-5-base is amino)-methylene radical]-[1,3] diox-4,6-diketone
Product (212.7mg with embodiment 5D, 1.496mmol) solution in dehydrated alcohol (5mL) in room temperature with Meldrum ' s acid (237mg, 1.645mmol) and triethyl orthoformate (0.25mL 1.496mmol) handles, and will be reflected in pre-warmed 100 ℃ of oil baths and heat.After 15 minutes, reaction is cooled to room temperature, and under vacuum, removes and desolvate by rotary evaporation.By flash chromatography on silica gel method purifying, with 10%-20% methyl acetate/dichloromethane gradient wash-out, obtain this title compound, be pale solid (240mg, 0.8099mmol, 54%).
Embodiment 5F
2-propyl group-4H-thiazole is [5,4-b] pyridin-7-one also
(230mg 0.7781mmol) is added in the diphenyl ether (5mL) of backflow at following product of embodiment 5E of nitrogen.Reflux after 5 minutes, solution is cooled off in ice bath, and dilute with hexane (50mL).Collect the golden solid of gained by vacuum filtration, obtain this title compound (125mg, 0.644mmol, 83%).
Embodiment 5G
7-chloro-2-propyl group-thiazole is [5,4-b] pyridine also
With the product of embodiment 5F (123mg, 0.6332mmol) and phosphorus oxychloride (2mL) refluxed under nitrogen 1 hour.Solution is cooled off in ice bath, handles with ice, and with the 6N aqueous sodium hydroxide solution with pH regulator to 7.With the organic extract anhydrous sodium sulfate drying of methylene dichloride (3 x 50mL) extraction and merging, filtration also concentrates under vacuum, obtains this title compound, is brown oil (120mg, 0.564mmol, 89%).
Embodiment 5H
4-methyl-2-nitro-1-phenyl sulfenyl-benzene
(3.96g, 30mmol) (2.65mL 20mmol) under agitation heats 2 days to the solution in 60mL DMF with 4-chloro-3-nitrotoluene in 50 ℃ with thiophenols sodium.Be cooled to room temperature and use CH
2Cl
2Dilution.Wash with water, and with organic layer Na
2SO
4Dry.Filter and under vacuum, concentrate, obtain this title compound (4.29g, 87%).
1H?NMR(300MHz，CDCl
3)δ?ppm：2.36(s，3H)6.76(d，J＝8.09Hz，1H)7.16(d，J＝8.46Hz，1H)7.45(m，3H)7.58(m，2H)8.03(s，1H).
Embodiment 5I
5-methyl-2-phenyl sulfenyl-phenyl amine
(1.17g is 7.0mmol) at anhydrous EtOH of 25mL and SnCl with the product of embodiment 5H
2(3.58g, 29.8mmol) solution in was in stirring at room 16 hours.Be adjusted to pH12 with 1N NaOH, and extract with EtOAc.Use Na
2SO
4Drying is filtered and is concentrated under vacuum, obtains this title compound (835mg, 82%).
1H?NMR(300MHz，CDCl
3)δ?ppm：2.30(2，3H)6.62(d，J＝8.83Hz，1H)6.69(s，1H)7.10(m，3H)7.21(m，2H)7.54(d，J＝7.72Hz，2H).
Embodiment 5J
(5-methyl-2-phenyl sulfenyl-phenyl)-(2-propyl group-thiazole is [5,4-b] pyridine-7-yl also)-amine
The flask of exsiccant nitrogen purging is loaded onto 2,8,9-triisobutyl-2,5,8,9-four azepines-1-phospha-two ring [33.3] undecane (38mg, 0.111mmol), three (dibenzalacetone)-two palladiums (25.4mg, 0.0277mmol) and sodium tert-butoxide (82.4mg, 0.8322mmol).The product (118mg, 0.5548mmol) product of solution in dry toluene (2mL) and embodiment 5I (107.5mg, 0.4993mmol) solution in toluene (3mL) that add embodiment 5G by syringe.To be reflected at the heating 18 hours that refluxes down in pre-warmed 120 ℃ of oil baths, being cooled to room temperature, and using three (dibenzalacetone)-two palladiums (25.4mg) to handle again, and under refluxing reheat 2.5 hours.Reaction is cooled to room temperature, and removes by rotary evaporation in a vacuum and desolvate.By flash chromatography on silica gel method purifying, 1%-3% methyl acetate/dichloromethane gradient wash-out has obtained this title compound (29mg, 0.074mmol, 15%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.00(t，J＝7.35Hz，3H)1.71-1.90(m，2H)2.38(s，3H)3.05(t，J＝7.35Hz，2H)6.87(d，J＝5.52Hz，1H)7.07(dd，J＝7.91，1.29Hz，1H)7.12-7.31(m，5H)7.37-7.46(m，2H)8.15(d，J＝5.52Hz，1H)8.52(s，1H)；MS(DCI/NH
3)m/z?392(M+H)
+.
Embodiment 6
4-[4-methyl-2-(2-propyl group-thiazole also [5,4-b] pyridine-7-base is amino)-phenyl sulfenyl]-phenol
Embodiment 6a
Three fluoro-methylsulfonic acid 4-methyl-2-nitro-phenylesters
With 4-methyl-2-nitrophenols (6.0g, 39.1mmol) and Et
3(16.38mL is 117.5mmol) at 100mL CH for N
2Cl
2In solution, at N
2(7.25mL 43.1mmol) handled 30 minutes with trifluoromethanesulfanhydride anhydride in 0 ℃ under the gas.By adding the MeOH stopped reaction.Use 10% citric acid, 0.5m KOH and water washing successively.Use MgSO
4Drying is filtered and is concentrated under vacuum, obtains this title compound, and it by the silica gel column chromatography purifying, is used CH
2Cl
2Wash-out obtains succsinic acid oily matter (11.22g, 100%).
Embodiment 6b
4-(4-methyl-2-nitro-phenyl sulfenyl)-phenol
Will (11.22g, 39.3mmol) (4.96g 39.3mmol) uses Na with the 4-mercapto-phenol at the product of the embodiment 6a among the 100mL EtOH
2CO
3Handle, and under refluxing heated overnight.Be cooled to room temperature, and water is ended.Extract with EtOAc.Use MgSO
4Drying is filtered and is concentrated under vacuum, obtains this title compound, and it by the silica gel column chromatography purifying, with 25%EtOAc/ hexane wash-out, is obtained red oil (8.65g, 85%).
Embodiment 6c
4-(2-amino-4-methyl-phenyl sulfenyl)-phenol
According to the method for embodiment 51, (8.65g 31.3mmol) uses SnCl with the product of embodiment 6b
2Reduction obtains this title compound, is white solid (8.51g, 100%).
Embodiment 6d
4-(4-methyl-2-(2-propyl group thiazole also [5,4-b] pyridine-7-base is amino) thiophenyl) phenol
Exsiccant is loaded onto 2,8 with the flask of nitrogen purging, 9-triisobutyl-2,5,8,9-four azepines-1-phospha-two ring [3.3.3] undecane (40.4mg, 0.118mmol), three (dibenzalacetones), two palladiums (27mg, 0.0295mmol) and sodium tert-butoxide (87.7mg, 0.885mmol).By syringe add embodiment 5G product (125.5mg, the 0.590mmol) solution in dry toluene (5mL), add then embodiment 6c product (136mg, 0.590mmol).To be reflected at refluxes heated 14 hours in pre-warmed 110 ℃ of oil baths down, be cooled to room temperature, use 2 again, 8,9-triisobutyl-2,5,8,9-four azepines-1-phospha-two ring [3.3.3] undecane (40.4mg) and three (dibenzalacetones), two palladiums (27mg) are handled, and under backflow reheat 7 hours.Reaction is cooled to room temperature, and removes by rotary evaporation in a vacuum and desolvate.By flash chromatography on silica gel method purifying, 15%-30% methyl acetate/dichloromethane gradient wash-out obtains impure material.By flash chromatography on silica gel method purifying, with 1%-2% ethanol/methylene gradient elution, obtain required not this title compound, be light yellow solid (20mg, 0.049mmol, 8%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.03(t，J＝7.35Hz，3H)1.76-1.94(m，2H)2.31(s，3H)3.10(t，J＝7.35Hz，2H)5.76(s，1H)6.67-6.73(m，2H)6.96-7.04(m，1H)7.08-7.14(m，1H)7.20(d，J＝8.46Hz，2H)7.29(s，1H)8.14(d，J＝5.52Hz，1H)8.55(s，1H)9.73(s，1H)；MS(DCI/NH
3)m/z?408(M+H)
+.
Embodiment 7
N-{4-[4-methyl-2-(2-propyl group-thiazole also [5,4-b] pyridine-7-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide
Embodiment 7a
N-[4-(4-methyl-2-nitro-phenyl sulfenyl)-phenyl]-ethanamide
According to the method for embodiment 6b, (1g, 3.51mmol) (0.65g, 351mmol) reaction is 18 hours, obtains this title compound (1.04g, 98%) with N-(4-sulfydryl-phenyl)-ethanamide with the product of embodiment 6a.
Embodiment 7b
N-[4-(2-amino-4-methyl-phenyl sulfenyl)-phenyl]-ethanamide
As describing among the embodiment 51, with the product of embodiment 7a (0.30gm, 1mmol) and SnCl
2Reaction obtains this title compound (0.27gm, 100%), for amber oily thing, it is used under the situation that need not be further purified.
Embodiment 7c
N-(4-(4-methyl-2-(2-propyl group thiazole also [5,4-b] pyridine-7-base is amino) thiophenyl) phenyl) ethanamide
Exsiccant is loaded onto 2,8 with the flask of nitrogen purging, 9-triisobutyl-2,5,8,9-four azepines-1-phospha-two ring [3.3.3] undecane (38.6mg, 0.1128mmol), three (dibenzalacetone)-two palladiums (25.8mg, 0.0282mmol) and sodium tert-butoxide (83.8mg, 0.8463mmol).By syringe add embodiment 5G product (120mg, the 0.5642mmol) solution in dry toluene (5mL), add then embodiment 7b product (130mg, 0.4773mmol).To be reflected in pre-warmed 100 ℃ of oil baths and heat 2.5 hours, be cooled to room temperature, use 2 again, 8,9-triisobutyl-2,5,8,9-four azepines-1-phospha-two ring [3.3.3] undecane (38.6mg), three (dibenzalacetone)-two palladiums (25.8mg) and initial aniline (130mg) processing were in 100 ℃ of reheat 18 hours.Reaction is cooled to room temperature, and removes by rotary evaporation in a vacuum and desolvate.By flash chromatography on silica gel method purifying, with 40%-60% methyl acetate/dichloromethane gradient wash-out, obtain required compound, be tawny foam (26mg, 10%).
1H?NMR(300MHz，DMSO-d
6)δ?ppm：1.01(t，J＝7.35Hz，3H)1.73-1.91(m，2H)2.01(s，3H)2.34(s，3H)3.07(t，J＝7.54Hz，2H)6.78(d，J＝5.52Hz，1H)6.97-7.09(m，1H)7.16-7.30(m.3H)7.36(s，1H)7.51(d，J＝8.82Hz，2H)8.15(d，J＝5.52Hz，1H)8.53(s，1H)9.99(s，1H)；MS(DCI/NH
3)m/z?449(M+H)
+.
Embodiment 8
N-{4-[4-methyl-2-(2-methyl-2H-pyrazolo [3,4-b] pyridin-4-yl amino)-phenyl sulfenyl]-phenyl }-ethanamide
Embodiment 8a
2,2-dimethyl-5-[(1-methyl isophthalic acid H-pyrazole-3-yl amino)-methylene radical]-[1,3] diox-4,6-diketone
With 1-methyl isophthalic acid H-pyrazole-3-yl amine (1.05g, 10.8mmol), 2,2-dimethyl-[1,3] dioxs-4, and the 6-diketone (1.71g, 11.9mmol) and triethyl orthoformate (1.60g, 10.8mmol) mixture in the 25mL round-bottomed flask in 100 ℃ of oil baths the heating 15 minutes.Compound is cooled to room temperature, and adds EtOH (10mL).Reaction mixture is heated with the dissolving all solids, and then room temperature is got back in cooling.The solid by filtration that forms is collected and drying, obtain this title compound (1.81g, 66% productive rate).
Embodiment 8b
2-methyl-2,7-dihydro-pyrazolo [3,4-b] pyridine-4-ketone
(1.50g 5.97mmol) and the heating 1 hour under refluxing of the mixture of diphenyl ether (25mL), removes synthetic acetone by distillation simultaneously with the product of embodiment 8a.Be dissolved in methylene dichloride (5mL) then with the solvent decant, and remaining solid, and, use 0-10% MeOH/CH by the silica gel chromatography purifying
2Cl
2Gradient elution obtains this title compound (0.360g, 40% productive rate).
Embodiment 8c
4-chloro-2-methyl-2H-pyrazolo [3,4-b] pyridine
(0.177g 1.19mmol) and the heating 30 minutes under refluxing of the mixture of phosphoryl chloride (3mL), is cooled to room temperature then with the product of embodiment 8b.Reaction mixture on ice, is reached pH8 by adding the 1N aqueous sodium hydroxide solution, and extracts with methylene dichloride (3 x 30mL).With the organic phase anhydrous magnesium sulfate drying that merges, filter, and reduction vaporization, obtain this title compound (0.170g, 88% productive rate).
Embodiment 8d
N-{4-[4-methyl-2-(2-methyl-2H-pyrazolo [3,4-b] pyridin-4-yl amino)-phenyl sulfenyl]-phenyl }-ethanamide
With the product of embodiment 8c (47.3mg, 0.282mmol), the product of embodiment 7b (84.6mg, 0.310mmol), Pd
2(dba)
3(12.9mg, 0.0141mmol), sodium tert-butoxide (67.8mg, 0.706mmol) and 2,8,9-triisobutyl-2,5,8,9-four azepines-1-phospha two rings [3,3,3] undecane (19.3mg, the 0.0564mmol) degassing of the mixture in toluene (4mL), under positive pressure of nitrogen, place, and under refluxing, heated 2 hours.Add Pd again
2(dba)
3(4.0mg, 0.0044mmol) and PN3 (4.5mg, 0.013mmol), and with reaction mixture reheat 2 hours under refluxing.Then mixture is cooled to room temperature, and between methyl acetate (30mL) and water (30mL), distributes.Use the methyl acetate aqueous phase extracted, and, filter the organic phase anhydrous magnesium sulfate drying that merges, and reduction vaporization.Resistates by the silica gel chromatography purifying, is used 5% MeOH/CH
2Cl
2Wash-out obtains this title compound (0.0195g, 17% productive rate).
1H?NMR(300MHz，DMSO-d
6)δ?ppm：2.03(s，3H)，2.29(s，3H)，4.11(s，3H)，5.97(d，H＝5.15Hz，1H)，6.94-7.00(m，1H)，7.05(dd，J＝8.09，1.47Hz，1H)，7.19(s，1H)，7.26(d，J＝8.82Hz，2H)，7.56(d，J＝8.82Hz，2H)，8.09(d，J＝5.15Hz，1H)，8.20(s，1H)，8.80(s，1H)，10.04(s，1H)；MS(ESI
+)m/z?404.1(M+H)
+.
Embodiment 9
4-[4-methyl-2-(2-methyl-2H-pyrazolo [3,4-b] pyridin-4-yl amino)-phenyl sulfenyl]-phenol
With the product of embodiment 8c (62.1mg, 0.371mmol), the product of embodiment 6c (85.7mg, 0.371mmol), Pd
2(dba)
3(16.9mg, 0.0185mmol), sodium tert-butoxide (89.0mg, 0.926mmol) and 2,8,9-triisobutyl-2,5,8,9-four azepines-1-phospha two rings [3,3,3] undecane (25.4mg, the 0.0741mmol) degassing of the mixture in toluene (3mL), under positive pressure of nitrogen, place, and under refluxing, heated 2 hours.Add the Pd of amount in addition
2(dba)
3(7.0mg, 0.0076mmol) and 258,9-triisobutyl-2,5,8,9-four azepines-1-phospha two ring [3,3,3] undecanes (15mg, 0.044mmol), and with reaction mixture reheat 2 hours under refluxing.Then mixture is cooled to room temperature, and between methyl acetate (30mL) and water (30mL), distributes.Use the ethyl acetate extraction water, and, use anhydrous magnesium sulfate drying, filter the organic phase salt water washing that merges, and reduction vaporization.Resistates by the silica gel chromatography purifying, is used 2-5% MeOH/CH
2Cl
2Gradient elution obtains this title compound (0.0279g, 21% productive rate).
1H?NMR(300MHz，DMSO-d
6)δ?ppm：2.27(s，3H)，4.11(s，3H)，5.92(d，J＝5.15Hz，1H)，6.75-6.85(m，3H)，7.02(dd，J＝8.27，0.92Hz，1H)，7.14(s，1H)，7.18-7.27(m，2H)，8.09(d，J＝5.15Hz，1H)，8.20(s，1H)，8.77(s，1H)，9.82(s，1H)；MS(ESI
+)m/z363.0(M+H)
+(ESI
-)m/z?360.9(M-H)
-.
Embodiment 10
4-[4-(4-methoxyl group-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 10A
2-amino-6-methyl-cigarette nitrile
Will the 2-chloro-6-methyl-cigarette nitrile in the 500mL ethanol (25g, 0.164mol) and liquefied ammonia (250mL) the sealing high pressure vessel in 130 ℃ the reaction 20 hours.With the reaction mixture concentrating under reduced pressure, and with resistates water (2 x 50mL) washing, in vacuum chamber dry 24 hours then, obtain this title compound, be light yellow solid (18g, 82%).
1HNMR(300MHz，DMSO-d
6)δ?ppm：2.30(s，3H)，6.52(d，J＝7.7Hz，1H)，6.78(s，2H)，7.73(d，J＝7.7Hz，1H).
Embodiment 10B
N '-(3-cyano group-6-methyl-pyridine-2-yl)-N, N-dimethyl-carbonamidine
With the product of embodiment 10A (10g, 75.19mmol) and N, dinethylformamide dimethyl acetal (11mL, the 82.71mmol) heating 6 hours under refluxing of the solution in toluene (100mL).After being cooled to room temperature, solution decompression is concentrated, obtain this title compound, be yellow solid (13.78g, 98%).
1H?NMR(300MHz，DMSO-d
6)δ?ppm：2.41(s，3H)，3.06(s，3H)，3.14(s，3H)，6.87(d，J＝7.7Hz，1H)，7.89(d，J＝8.1Hz，1H)，8.59(s，1H).
Embodiment 10C
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 the solution, the gained solid by filtration is collected, and dry in vacuum chamber, obtain this title compound (0.812g, 96%).
Embodiment 10D
4-[4-(4-methoxyl group-benzyloxy)-2-nitro-phenyl sulfenyl]-phenol
With the product of embodiment 10C (0.812g, 2.76mmol), 4-hydroxyl sulfenyl phenol (0.419,3.32mmol) and cesium carbonate (2.16g, 6.64mmol) at N, the solution in the dinethylformamide (5mL) be heated to 100 ℃ 16 hours.After being cooled to room temperature, mixture is poured in the frozen water (20mL), and with the 1N aqueous hydrochloric acid acidifying of gained solution.Use methyl acetate (3 x 10mL) to extract this solution then,, filter and under vacuum, concentrate, obtain this title compound (1.06g, 100%) the organic extract dried over mgso that merges.
Embodiment 10E
4-[2-amino-4-(4-methoxyl group-benzyloxy)-phenyl sulfenyl]-phenol
With the product of embodiment 10D (1.06g, 2.76mmol), iron powder (0.63g, 11.04mmol) and ammonium chloride (0.18g, the 3.31mmol) heating 3 hours under refluxing of the solution in methyl alcohol (18mL), tetrahydrofuran (THF) (18mL) and water (6mL).The gained mixture dilutes with methyl alcohol (50mL), and filters by Celite pad.Filtrate decompression is concentrated into volume 10mL, and with solution with water (50mL) dilution, with methyl acetate (2 x 50mL) extraction.With the extract dried over mgso that merges, filter and under vacuum, concentrate, obtain this title compound (0.99g, 100%).
Embodiment 10F
4-[4-(4-methoxyl group-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
With the product of embodiment 10B (28.4mg, 0.151mmol) and the product of embodiment 10E (53.3mg, 0.151mmol) solution in acetate (1mL) stirred 20 minutes in pre-warmed 130 ℃ of oil baths.Then mixture is cooled to room temperature, under vacuum, removes acetate, and gained attended a meeting meet, obtain this title compound, be tawny solid (26.5mg, 35%) with methyl alcohol development.
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 11
3-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxymethyl]-benzonitrile
Embodiment 11A
3-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenoxymethyl]-benzonitrile
Use the condition of describing among the embodiment 10C,, obtain 3-(4-chloro-3-nitro-phenoxymethyl)-benzonitrile, it is handled with the method for embodiment 10D and 10E successively, obtain this title compound 4-chloro-3-nitro-phenol and 3-brooethyl-benzonitrile reaction.
Embodiment 11B
3-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxymethyl]-benzonitrile
With the product of embodiment 11A and the product of embodiment 10B, use the method for embodiment 10F, product with the product alternate embodiment 10E of embodiment 11A, obtain this rough title compound, with it at Waters Symmetry C8 post (25mm x 100mm, 7 μ m size of particles) carry out anti-phase preparation HPLC purifying on, with the 10%-100% acetonitrile/solution of 0.1% trifluoroacetic acid in water via the current gradient wash-out of 8 minutes (10 minute working time) with 40mL/min, obtain this title compound, be trifluoroacetic acid salt form (20mg, 23%).
1H?NMR(300MHz，DMSO-d
6)δ?ppm：11.39(s，1H)，9.70(s，1H)，8.89(d，J＝8.46Hz，1H)，8.77(s，1H)，7.92(s，1H)，7.75-7.86(m，3H)，7.62(t，J＝7.72Hz，1H)，7.18-7.29(m，2H)，7.03-7.14(m，3H)，6.55-6.69(m，2H)，5.18(s，2H)，2.74(s，3H)；MS(ESI+)m/z?492.1(M+H)+(ESI-)m/z?490.2(M-H)-.
Embodiment 12
4-[2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(pyridine-2-ylmethoxy)-phenyl sulfenyl]-phenol
Embodiment 12A
4-[2-amino-4-(pyridine-2-ylmethoxy)-phenyl sulfenyl]-phenol
Use the condition of describing among the embodiment 10C, with 4-chloro-3-nitro-phenol solution and 2-brooethyl-pyridine hydrobromide reactant salt, obtain 2-(4-chloro-3-nitro-phenoxymethyl)-pyridine, it is handled with the method for embodiment 10D and 10E successively, obtain this title compound.
Embodiment 12B
4-[2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(pyridine-2-ylmethoxy)-phenyl sulfenyl]-phenol
Use the method for embodiment 10F, product with the product alternate embodiment 10E of embodiment 12A, the product of embodiment 12A and the product of embodiment 10B are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (15mg, 17%).
1H?NMR(300MHz，DMSO-D6)δ?ppm?2.76(s，3H)5.19(s，2H)6.63(d，J＝8.82Hz，2H)6.98-7.17(m，3H)7.20(d，J＝2.57Hz，1H)7.22-7.30(m，1H)7.38(dd，J＝6.43，4.96Hz，1H)7.53(d，J＝7.72Hz，1H)7.71-7.94(m，2H)8.58(d，J＝4.04Hz，1H)8.82(s，1H)8.93(d，J＝7.72Hz，1H)9.71(brs，1H)11.66(brs，1H)；MS(ESI+)m/z?468(M+H)+.
Embodiment 13
4-[4-(the 4-tertiary butyl-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 13A
4-[2-amino-4-(the 4-tertiary butyl-benzyloxy)-phenyl sulfenyl]-phenol
Use the condition of describing among the embodiment 10C, with 4-chloro-3-nitro-phenol and 1-bromine first and second bases-4-tertiary butyl-benzene reaction, obtain 4-(the 4-tertiary butyl-benzyloxy)-1-chloro-2-nitro-benzene, it is handled with the method for embodiment 10D and 10E successively, obtain this title compound.
Embodiment 13B
4-[4-(the 4-tertiary butyl-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Use the method for embodiment 10F, product with the product alternate embodiment 10E of embodiment 13A, the product of embodiment 13A and the product of embodiment 10B are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (52mg, 36%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.28(s，9H)2.74(s，3H)5.06(s，2H)6.63(d，J＝8.46Hz，2H)7.00-7.12(m，3H)7.15-7.27(m，2H)7.30-7.47(m，5H)7.79(d，J＝8.46Hz，1H)8.77(s，1H)8.89(d，J＝8.46Hz，1H)9.69(s，1H)；MS(ESI+)m/z?523(M+H)+.
Embodiment 14
4-[4-(2-bromo-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 14A
4-[2-amino-4-(2-bromo-benzyloxy)-phenyl sulfenyl]-phenol
Use the condition of describing among the embodiment 10C, with 4-chloro-3-nitro-phenol solution and 1-bromo-2-brooethyl-benzene reaction, obtain 4-(2-bromo-benzyloxy)-1-chloro-2-nitro-benzene, it is handled with the method for embodiment 10D and 10E successively, obtain this title compound.
Embodiment 14B
4-[4-(2-bromo-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
The product of embodiment 14A and the product of embodiment 10B are reacted, use the method for embodiment 10F, product with the product gradient embodiment 10E of embodiment 14A, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (42mg, 39%).
1H?NMR(300MHz；DMSO-D6)δ?ppm：2.68(s，3H)5.13(s，2H)6.67(m，2H)6.96(d，J＝7.68Hz，1H)7.14(m，3H)7.30(m，2H)7.44(m，1H)7.59(m，2H)7.68(d，J＝7.68Hz，1H)8.59(s，1H)8.73(d，J＝8.09Hz，1H)9.66(s，1H)10.27(s，1H)；MS(ESI+)m/z?545，547(M+H)+.
Embodiment 15
4-[4-(3-bromo-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 15A
4-[2-amino-4-(3-bromo-benzyloxy)-phenyl sulfenyl]-phenol
Use the condition of describing among the embodiment 10C, solution and 1-bromo-3-brooethyl-benzene reaction with 4-chloro-3-nitro-phenol, obtain 4-(3-bromo-benzyloxy)-1-chloro-2-nitro-benzene, it is handled with the method for embodiment 10D and 10E successively, obtain this title compound.
Embodiment 15B
4-[4-(3-bromo-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Use the method for embodiment 10F, product with the product alternate embodiment 10E of embodiment 15A, product reaction with the product of the product of embodiment 15A and embodiment 10B, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (25mg, 23%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.72(s，3H)5.13(s，2H)6.65(m，2H)7.11(m，5H)7.40(m，2H)7.54(d，J＝7.72Hz，1H)7.66(s，1H)7.72(d，J＝8.82Hz，1H)8.71(s，1H)8.84(d，J＝8.09Hz，1H)9.68(s，1H)，11.04(m，1H)；MS(ESI+)m/z?545，547(M+H)+.
Embodiment 16
4-[4-(4-bromo-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 16A
4-[2-amino-4-(4-bromo-benzyloxy)-phenyl sulfenyl]-phenol
Use the condition of describing among the embodiment 10C, solution and 1-bromo-4-brooethyl-benzene reaction with 4-chloro-3-nitro-phenol, obtain 4-(4-bromo-benzyloxy)-1-chloro-2-nitro-benzene, it is handled with the method for embodiment 10D and 10E successively, obtain this title compound.
Embodiment 16B
4-[4-(4-bromo-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
The product of embodiment 16A and the product of embodiment 10B are reacted, use the method for embodiment 10F, use the product of the product alternate embodiment 10E of embodiment 16A, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (19mg, 17%).
1H?NMR(300MHz，DMSO-D6)δ?ppm；2.72(s，3H)5.13(s，2H)6.63(m，2H)7.03(dd，J＝8.82，2.57Hz，1H)7.10(m，2H)7.21(d，J＝8.46Hz，2H)7.40(m，2H)7.54(d，J＝8.09Hz，1H)7.66(s，1H)7.73(d，J＝8.46Hz，1H)8.72(s，1H)8.84(d，J＝8.46Hz，1H)9.69(s，1H)11.08(m，1H)；MS(ESI+)m/z?545，547(M+H)+.
Embodiment 17
4-[4-(2-methyl-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 17A
4-[2-amino-4-(2-methyl-benzyloxy)-phenyl sulfenyl]-phenol
Use the condition of describing among the embodiment 10C, with 4-chloro-3-nitro-phenol and 1-brooethyl-2-methyl-benzene reaction, obtain 1-chloro-4-(2-methyl-benzyloxy)-2-nitro-benzene, it is handled with the method for embodiment 10D and 10E successively, obtain this title compound.
Embodiment 17B
4-[4-(2-methyl-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
The product of The embodiment 17A and the reaction of the product of embodiment 10B, use the method for embodiment 10F, product with the product alternate embodiment 10E of embodiment 17A, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (35mg, 36%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.32(s，3H)2.71(s，3H)5.09(s，2H)6.65(m，2H)7.03(dd，J＝8.82，2.57Hz，IH)7.11(m，2H)7.24(m，5H)7.41(d，J＝6.99Hz，1H)7.69(d，J＝8.46Hz，1H)8.69(s，1H)8.82(d，J＝8.82Hz，1H)9.67(s.1H)10.84(s.1H)；MS(ESI+)m/z?481(M+H)+.
Embodiment 18
4-[4-(3-methyl-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 18A
4-[2-amino-4-(3-methyl-benzyloxy)-phenyl sulfenyl]-phenol
The solution and the 1-brooethyl-3-methyl-benzene of 4-chloro-3-nitro-phenol are used the condition of describing among the embodiment 10C, obtain 1-chloro-4-(3-methyl-benzyloxy)-2-nitro-benzene, it is handled with the method for embodiment 10D and 10E successively, obtain this title compound.
Embodiment 18B
4-[4-(3-methyl-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Use the method for embodiment 10F, product with the product alternate embodiment 10E of embodiment 18A, the product of embodiment 18A and the product of embodiment 10B are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (37mg, 39%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.31(s，3H)2.73(s，3H)5.07(s，2H)6.64(m，2H)7.16(m，9H)7.75(d，J＝8.46Hz，1H)8.73(s，1H)8.86(d，J＝8.46Hz，1H)9.69(s，1H)11.16(s，1H)；MS(ESI+)m/z?481(M+H)+.
Embodiment 19
4-[4-(4-methyl-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 19A
4-[2-amino-4-(4-methyl-benzyloxy)-phenyl sulfenyl]-phenol
Use the condition of describing among the embodiment 10C, solution and 1-brooethyl-4-methyl-benzene reaction with 4-chloro-3-nitro-phenol, obtain 1-chloro-4-(4-methyl-benzyloxy)-2-nitro-benzene, it is handled with the method for embodiment 10D and 10E successively, obtain this title compound.
Embodiment 19B
4-[4-(4-methyl-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Use the method for embodiment 10F, product with the product alternate embodiment 10E of embodiment 19A, the product of embodiment 19A and the product of embodiment 10B are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (29mg, 30%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.30(s，3H)2.67(s，3H)5.05(s，2H)6.64(m，2H)6.94(d，J＝7.38Hz，1H)7.17(m，6H)7.33(d，J＝8.09Hz，2H)7.56(d，J＝8.46Hz，1H)8.57(s，1H)8.72(d，J＝8.09Hz，1H)9.63(s，1H)10.12(s，1H)；MS(BSI+)m/z?481(M+H)+.
Embodiment 20
2-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidin-4-yl-amino)-phenoxymethyl]-benzonitrile
Embodiment 20A
2-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenoxymethyl]-benzonitrile
Use the condition of describing among the embodiment 10C, solution and 2-brooethyl-benzonitrile reaction with 4-chloro-3-nitro-phenol, obtain 2-(4-chloro-3-nitro-phenoxymethyl)-benzonitrile, it is handled with the method for embodiment 10D and 10E successively, obtain this title compound.
Embodiment 20B
2-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxymethyl]-benzonitrile
Use the method for embodiment 10F, product with the product alternate embodiment 10E of embodiment 20A, the product of embodiment 20A and the product of embodiment 10B are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (21mg, 16%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：9.93(s，1H)，9.63(s，1H)，8.75(d，J＝8.46Hz，1H)，8.57(s，1H)，7.60(d，J＝8.09Hz，1H)，7.38(d，J＝8.46Hz，2H)，7.27(s，1H)，7.05-7.19(m，3H)，6.85-7.00(m，3H)，6.67(d，J＝8.82Hz，2H)，5.02(s，2H)，3.75(s，3H)，3.14-3.28(m，1H)，1.32(d，J＝6.62Hz，6H)；MS(ESI+)m/z?492.2(M+H)+(ESI-)m/z?490.2(M-H)-.
Embodiment 21
4-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxymethyl]-benzonitrile
Embodiment 21A
4-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenoxymethyl]-benzonitrile
Use the condition of describing among the embodiment 10C, solution and 4-brooethyl-benzonitrile reaction with 4-chloro-3-nitro-phenol, obtain 4-(4-chloro-3-nitro-phenoxymethyl)-benzonitrile, it is handled with the method for embodiment 10D and 10E successively, obtain this title compound.
Embodiment 21B
4-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxymethyl]-benzonitrile
Product with the product alternate embodiment 10E of embodiment 21A, the product of embodiment 21A and the product of embodiment 10B are reacted, use the method for embodiment 10F, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (15mg, 14%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：11.69(s，1H)，9.72(s，1H)，8.94(d，J＝8.46Hz，1H)，8.83(s，1H)，7.78-7.96(m，3H)，7.63(d，J＝8.46Hz，2H)，7.22-7.27(m，1H)，7.18(d，J＝2.57Hz，1H)，7.06-7.13(m，3H)，6.59-6.66(m，2H)，5.23(s，2H)，2.76(s，3H)；MS(ESI+)m/z?492.1(M+H)+(ESI-)m/z?490.1(M-H)-.
Embodiment 22
4-[4-[1-(4-bromo-phenyl)-oxyethyl group]-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 22A
1-bromo-4-(1-bromo-ethyl)-benzene
(4.21g is 20.9mmol) at 15mL CH with 1-(4-bromo-phenyl)-ethanol
2Cl
2In solution and 15mL 1.0M PBr
3At CH
2Cl
2In in room temperature reaction 4 hours.Come stopped reaction in the ice by pouring into, and use 5% NaHCO
3The aqueous solution is adjusted to pH9.Use CH
2Cl
2Extraction, and use Na
2SO
4Drying is filtered and is concentrated under vacuum, obtains this title compound (4.1g, 75%).
Embodiment 22B
4-[1-(4-bromo-phenyl)-oxyethyl group]-1-chloro-2-nitro-benzene
With the product of embodiment 22A (995mg, 3.77mmol) with 4-chloro-3-nitro-phenol (650mg, 3.77mmol) in 15mL DMF with K
2CO
3(10.4g is 3.77mmol) in 80 ℃ of reactions 3 hours.Be cooled to room temperature, and dilute with water.Use CH
2Cl
2Extraction washes with water four times.Use Na
2SO
4Drying is filtered and is concentrated under vacuum, obtains this title compound (1.24g, 92%).
Embodiment 22C
4-{4-[1-(4-bromo-phenyl)-oxyethyl group]-2-nitro-phenyl sulfenyl }-phenol
With the product of embodiment 22B (1.15g, 3.22mmol) with 4-sulfydryl-phenol (403mg, 3.22mmol) and K
2CO
3(890mg 6.44mmol) reacted 18 hours in 80 ℃ in 25mL DMF.Be cooled to room temperature, and pour in the water.Use CH
2Cl
2Extraction, and wash with water several times.Use Na
2SO
4Drying is filtered and is concentrated under vacuum, obtains this title compound (980mg, 68%).
Embodiment 22D
4-[2-amino-4-(1-phenyl-oxyethyl group)-phenyl sulfenyl]-phenol
According to the method for embodiment 10E, with the product of embodiment 22C (560mg, 1.25mmol) with Fe (279mg, 5.0mmol) and NH
4(76mg 1.40mmol) reacts in 5mL MeOH/5mL THF/2.5mL Cl, obtains this title compound, is solid (439mg, 84%).
Embodiment 22E
4-[4-[1-(4-bromo-phenyl)-oxyethyl group]-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Method according to embodiment 10F, product (204mg with embodiment 22D, 0.49mmol) with the product (93mg of embodiment 10B, 0.49mmol) reaction, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (38mg, 12%).
1H?NMR(300MHz，DMSO-d
6)δ?ppm：11.24(br?s，1H)9.70(s，1H)8.83(d，J＝8.09Hz，1H)8.74(s，1H)7.76(d，J＝8.45Hz，1H)7.55(d，J＝8.46Hz，2H)7.37(d，J＝8.46Hz，2H)7.09(m，4H)6.93(dd，J＝6.62Hz，J＝2.20Hz，1H)6.63(d，J＝8.82Hz，2H)5.51(q，J＝6.25Hz，2H)2.73(s，3H)，1.53(d，J＝6.25Hz，3H)；MS(ESI+)m/z，559，561(M+H-TFA)+；(ESI-)m/z，557，559(M-H-TFA)-.
Embodiment 23
4-[4-[1-(4-fluoro-phenyl)-oxyethyl group]-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 23A
4-{2-amino-4-[1-(4-fluoro-phenyl)-oxyethyl group]-the phenyl sulfenyl }-phenol
Use the method for describing among the embodiment 22A, 1-(4-fluoro-phenyl)-alcoholic acid solution is converted into 1-(1-bromo-ethyl)-4-fluoro-benzene, it is handled with the method for embodiment 22B-22D successively, obtain this title compound.
Embodiment 23B
4-[4-[1-(4-fluoro-phenyl)-oxyethyl group]-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Method according to embodiment 10F, product (207mg with embodiment 23A, 0.584mmol) with the product (110mg of embodiment 10B, 0.584mmol) reaction, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (30mg, 35%).
1H?NMR(300MHz，DMSO-d
6)δ?ppm：1.54(d，J＝6.25Hz，3H)2.73(s，3H)5.53(q，J＝6.13Hz，1H)6.63(d，J＝8.82Hz，2H)6.93(dd，J＝8.82，2.57Hz，1H)7.05-7.14(m，4H)7.18(t，J＝9.01Hz，2H)7.41-7.49(m，2H)7，76(d，J＝8.46Hz，1H)8.73(s，1H)8.84(d，J＝8.46Hz，1H)9.71(s，1H)；MS(ESI+)m/z?497(MH)-.
Embodiment 24
4-[4-[1-(3-fluoro-phenyl)-oxyethyl group]-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 24A
4-{2-amino-4-[1-(3-fluoro-phenyl)-oxyethyl group]-the phenyl sulfenyl }-phenol
Use the condition of describing among the embodiment 22A, 1-(3-fluoro-phenyl)-alcoholic acid solution is converted into 1-(1-bromo-ethyl)-3-fluoro-benzene, it is handled with the method for embodiment 22B-22D successively, obtain this title compound.
Embodiment 24B
4-[4-[1-(3-fluoro-phenyl)-oxyethyl group]-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Method according to embodiment 10F, product (226mg with embodiment 24A, 0.637mmol) with the product (120mg of embodiment 10B, 0.637mmol) reaction, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (87mg, 22%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.55(d，J＝6.62Hz，3H)2.72(s，3H)5.54(q，J＝6.13Hz，1H)6.64(d，J＝8.46Hz，2H)6.91(dd，H＝8.82，2.57Hz，1H)7.06-7.15(m，5H)7.20-7.28(m，2H)7.35-7.44(m，1H)7.70(d，J＝8.46Hz，1H)8.68(s，1H)8.81(d，J＝8.46Hz，1H)9.73(s，1H)；M8(ESI+)m/z?499(M+H)+.
Embodiment 25
4-[4-(2-chloro-thiazole-5-ylmethoxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 25A
4-[2-amino-4-(2-chloro-thiazole-5-ylmethoxy)-phenyl sulfenyl]-phenol
With 4-chloro-3-nitro-phenol solution and 5-brooethyl-2-chloro-thiazole (according to Kim, H.-J., Liu, S., Keum, Y.-S., Qing, X.J.Agric.Food Chem.2003,57, the preparation of the method for 1823-1830) condition described among the use embodiment 10C, obtain 2-chloro-5-(4-chloro-3-nitro-phenoxymethyl)-thiazole, it is handled with the method for embodiment 10D and 10E successively, obtain this title compound.
Embodiment 25B
4-[4-(2-chloro-thiazole-5-ylmethoxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Use the method for embodiment 10F, use the product of the product alternate embodiment 10E of embodiment 25A, the product of embodiment 25A and the product of embodiment 10B are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.71(s，3H)5.34(s，2H)6.66(d，J＝8.46Hz，2H)7.01(dd，J＝8.64，2.02Hz，1H)7.06-7.28(m，4H)7.68(d，J＝8.46Hz，1H)7.80(s，1H)8.67(s，1H)8.82(d，J＝8.46Hz，1H)9.70(s，1H)，10.81(bs，1H)；MS(ESI+)m/z?508(M+H)+.
Embodiment 26
4-[2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(3-trifluoromethyl-benzyloxy)-phenyl sulfenyl]-phenol
Embodiment 26A
4-[2-amino-4-(3-trifluoromethyl-benzyloxy)-phenyl sulfenyl]-phenol
Use the condition of describing among the embodiment 10C, solution and 1-chloromethyl-3-trifluoromethyl-benzene reaction with 4-chloro-3-nitro-phenol, obtain 1-chloro-2-nitro-4-(3-trifluoromethyl-benzyloxy)-benzene, it is handled with the method for embodiment 10D and 10E successively, obtain this title compound.
Embodiment 26B
4-[2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(3-trifluoromethyl-benzyloxy)-phenyl sulfenyl]-phenol
Use the method for embodiment 10F, product with the product alternate embodiment 10E of embodiment 26A, the product of embodiment 26A and the product of embodiment 10B are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (9.9mg, 9%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.74(s，3H)，5.22(s，2H)，6.64(d，J＝8.46Hz，2H)，7.10(d，J＝8.82Hz，3H)，7.19-7.30(m，2H)，7.62·7.72(m，J＝7.35Hz，2H)，7.72-7.84(m，4H)，8.75(s，1H)，8.88(d，J＝7.35Hz，1H)，9.69(s，1H)；MS?ESI+m/z?535(M+H)+，ESI-m/z?533(M-H)-.
Embodiment 27
4-[4-benzyloxy-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 27A
4-(2-amino-4-benzyloxy-phenyl sulfenyl)-phenol
Use the condition of describing among the embodiment 10C, solution and brooethyl-benzene reaction with 4-chloro-3-nitro-phenol obtain 4-benzyloxy-1-chloro-2-nitro-benzene, and it is handled with the method for embodiment 10D and 10E successively, obtain this title compound.
Embodiment 27B
4-[4-benzyloxy-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Use the method for embodiment 10F, product with the product alternate embodiment 10E of embodiment 27A, the product of embodiment 27A and the product of embodiment 10B are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (73mg, 25%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.70(s，3H)5.11(s，2H)6.65(d，J＝8.46Hz，2H)6.98(d，J＝7.72Hz，1H)7.10(d，J＝8.46Hz，2H)7.18(d，J＝8.46Hz，1H)7.24(s，1H)7.28-7.51(m，5H)7.63(d，J＝8.82Hz，1H)8.64(s，1H)8.78(d，J＝8.82Hz，1H)9.65(s，1H)10.56(br?s，1H)；MS(ESI+)m/z?467(M+H)+.
Embodiment 28
4-[4-(3-fluoro-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 28A
4-[2-amino-4-(3-fluoro-benzyloxy)-phenyl sulfenyl]-phenol
Use the condition of describing among the embodiment 10C, with 4-chloro-3-nitro-phenol solution and 1-brooethyl-3-fluoro-benzene reaction, obtain 1-chloro-4-(3-fluoro-benzyloxy)-2-nitro-benzene, it is handled with the method for embodiment 10D and 10E successively, obtain this title compound.
Embodiment 28B
4-[4-(3-fluoro-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Use the method for embodiment 10F, product with the product alternate embodiment 10E of embodiment 28A, the product of embodiment 28A and the product of embodiment 10B are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (41mg, 42%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.72(s，3H)5.14(s，2H)6.65(m，2H)7.02(dd，J＝8.64，2.76Hz，1H)7.10(m，2H)7.23(m，5H)7.44(m，1H)7.71(d，J＝8.46Hz，1H)8.69(s，1H)8.83(d，J＝8.46Hz，1H)9.69(s，1H)10.96(s，1H)；MS(ESI+)m/z?485(M+H)+.
Embodiment 29
4-[2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(tetrahydrochysene-furans-2-ylmethoxy)-phenyl sulfenyl-phenol
Embodiment 29A
4-[2-amino-4-(tetrahydrochysene-furans-2-ylmethoxy)-phenyl sulfenyl]-phenol
Use the condition of describing among the embodiment 10C, with 4-chloro-3-nitro-phenol solution and 2-brooethyl-tetrahydrochysene-furans reaction, obtain 2-(4-chloro-3-nitro-phenoxymethyl)-tetrahydrochysene-furans, it is handled with the method for embodiment 10D and 10E successively, obtain this title compound.
Embodiment 29B
4-[2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(tetrahydrochysene-furans-2-ylmethoxy)-phenyl sulfenyl-phenol
Use the method for embodiment 10F, product with the product alternate embodiment 10E of embodiment 29A, the product of embodiment 29A and the product of embodiment 10B are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (29mg, 17%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.55-1.84(m，1H)1.84-2.07(m，1H)2.67(s，3H)3.59-3.71(m，2H)3.73-3.83(m，1H)3.85-4.02(m，2H)4.15(dd，J＝6.43，4.23Hz，2H)6.66(d，J＝8.46Hz，2H)6.87(dd，J＝8.64，2.76Hz，1H)7.02-7.15(m，2H)7.12-7.24(m，2H)7.53(d，J＝8.46Hz，1H)8.56(s，1H)8.71(d，J＝8.46Hz，1H)9.62(s，1H)9.92(s，1H)；MS(ESI+)m/z?461(M+H)+.
Embodiment 30
4-[2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(naphthalene-1-ylmethoxy)-phenyl sulfenyl]-phenol
Embodiment 30A
4-[2-amino-4-(naphthalene-1-ylmethoxy)-phenyl sulfenyl]-phenol
Use the condition of describing among the embodiment 10C, solution and 1-chloromethyl-naphthalene reaction with 4-chloro-3-nitro-phenol obtain 1-(4-chloro-3-nitro-phenoxymethyl)-naphthalene, and it is handled with the method for embodiment 10D and 10E successively, obtain this title compound.
Embodiment 30B
4-[2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(naphthalene-1-ylmethoxy)-phenyl sulfenyl]-phenol
Use the method for embodiment 10F, product with the product alternate embodiment 10E of embodiment 30A, the product of embodiment 30A and the product of embodiment 10B are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (31mg, 25%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.68(s，3H)5.56(s，2H)6.67(d，J＝8.82Hz，2H)7.01-7，16(m，3H)7.16-7.24(m，1H)7.35(s，1H)7.45-7.64(m，4H)7.69(d，J＝6.62Hz，1H)7.87-8.02(m，2H)8.05-8.14(m，1H)8.59(s，1H)8.74(d，J＝8.46Hz，1H)9.65(s，1H)10.23(s，1H)；MS(ESI+)517(M+H)+.
Embodiment 31
4-[4-(3-methoxyl group-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 31A
4-[2-amino-4-(3-methoxyl group-benzyloxy)-phenyl sulfenyl]-phenol
Use the condition of describing among the embodiment 10C, solution and 1-chloromethyl-3-methoxyl group-benzene reaction with 4-chloro-3-nitro-phenol, obtain 1-chloro-4-(3-methoxyl group-benzyloxy)-2-nitro-benzene, it is handled with the method for embodiment 10D and 10E successively, obtain this title compound.
Embodiment 31B
4-[4-(3-methoxyl group-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Use the method for embodiment 10F, use the product of the product alternate embodiment 10E of embodiment 31A, the product of embodiment 31A and the product of embodiment 10B are reacted, obtain solid, it is developed with methyl alcohol, obtain this title compound (24mg, 26%).
1HNMR(300MHz，DMSO-D6)δ?ppm9.93(s，1H)，9.63(s，1H)，8.71(d，J＝8.09Hz，1H)，8.55(s，1H)，7.53(d，J＝8.09Hz，1H)，7.26-7.35(m，2H)，7.15(d，J＝8.46Hz，1H)，7.07-7.13(m，2H)，6.98-7.04(m，J＝5.15Hz，2H)，6.96(s，1H)，6.90(dd，J＝8.09，2.57Hz，1H)，6.62-6.71(m，2H)，5，08(s，2H)，3.75(s，3H)，2.67(s，3H)；MS(ESI+)m/z?497.2(M+H)+(ESI-)m/z?495.2(M-H)-.
Embodiment 32
4-[2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(quinolin-2-ylmethoxy)-phenyl sulfenyl]-phenol
Embodiment 32A
4-[2-amino-4-(quinolin-2-ylmethoxy)-phenyl sulfenyl]-phenol
Use the condition of describing among the embodiment 10C, solution and 2-chloromethyl-quinoline hydrochloride reaction with 4-chloro-3-nitro-phenol, obtain 2-(4-chloro-3-nitro-v phenoxymethyl)-quinoline, it is handled with the method for embodiment 10D and 10E successively, obtain this title compound.
Embodiment 32B
4-[2-(7-methyl-pyridine [2,3-d] pyrimidine-4-base is amino)-4-(quinolin-2-ylmethoxy)-phenyl sulfenyl]-phenol
Use the method for embodiment 10F, product with the product alternate embodiment 10E of embodiment 32A obtains this rough title compound, the product of embodiment 32A and the product of embodiment 10B are reacted, it is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (13mg, 27%).
1H?NMR(500MHz，DMSO-D6)δ?ppm：2.75(s，3H)5.39(s，2H)6.62(d，J＝8.54Hz，2H)7.09(d，J＝8.54Hz，2H)7.14(ddd，J＝8.54，2.44Hz，1H)7.22-7.28(m，2H)7.63(t，J＝7.93Hz，1H)7.68(d，J＝8.54Hz，1H)7.74-7.81(m，1H)7.83(d，J＝8.54Hz，1H)8.00(t，J＝7.93Hz，2H)8.44(d，J＝8.54Hz，1H)8.76(s，1H)8.92(d，J＝8.54Hz，1H)9.68(s，1H)11.64(brs，1H)；MS(ESI+)518(M+H)+.
Embodiment 33
4-[4-(xenyl-4-ylmethoxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Product 16B (free salt form with embodiment, 0.055g, 0.1mmol), phenyl-boron dihydroxide (0.017g, 0.14mmol), cesium carbonate (0.05g, 0.15mmol) and dichloro two (triphenylphosphine) palladium (II) (0.007g, 0.01mmol) at N, mix in the dinethylformamide (1mL), and be heated to 100 ℃ 24 hours.After being cooled to room temperature, mixture is poured in the frozen water (20mL), and with gained solution 1N hcl acidifying.Solution is extracted with methyl acetate (3 x 10mL), and the extract dried over sodium sulfate that merges, filter also concentrated under vacuum.Crude product by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (10mg, 15%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.67(s，3H)，5.16(s，2H)，6.60-6.72(m，2H)，6.98(d，J＝8.09Hz，1H)，7.06-7.22(m，3H)，7.27-7.41(m，2H)，7.47(t，J＝7.54Hz，2H)，7.54(d，J＝8.46Hz，3H)，7.60-7.73(m，4H)，8.58(s，1H)，8.72(d，J＝8.09Hz，1H)，9.64(s，1H)，10.08(s，1H)；MS(ESI+)m/z?543(M+H+)+.
Embodiment 34
4-[4-(5-chloro-thiophene-2-ylmethoxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl] amino)-the phenyl sulfenyl]-phenol
Embodiment 34A
4-[2-amino-4-(5-chloro-thiophene-2-ylmethoxy)-phenyl sulfenyl]-phenol
Use the condition of describing among the embodiment 10C, solution and 2-chloro-5-chloromethyl-thiophene reaction with 4-chloro-3-nitro-phenol, obtain 2-chloro-5-(4-chloro-3-nitro-phenoxymethyl)-thiophene, it is handled with the method for embodiment 10D and 10E successively, obtain this title compound.
Embodiment 34B
4-[4-(5-chloro-thiophene-2-ylmethoxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol phenyl sulfenyl]-phenol
Use the method for embodiment 10F, product with the product alternate embodiment 10E of embodiment 34A, the product of embodiment 34A and the product of embodiment 10B are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (6.6mg, 10%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.72(s，3H)5.25(s，2H)6.65(d，J＝8.46Hz，2H)6.97-7.14(m，4H)7.19(d，J＝8.46Hz，2H)7.72(d，J＝8.09Hz，1H)8.71(s，1H)8.84(d，J＝8.46Hz，1H)9.69(s，1H)11.01(brs，1H)；MS(ESI+)m/z543(M+H)+.
Embodiment 35
4-[4-(4-fluoro-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 35A
4-[2-amino-4-(4-fluoro-benzyloxy)-phenyl sulfenyl]-phenol
Use the condition of describing among the embodiment 10C, solution and 1-brooethyl-4-fluoro-benzene reaction with 4-chloro-3-nitro-phenol, obtain 1-chloro-4-(4-fluoro-benzyloxy)-2-nitro-benzene, it is handled with the method for embodiment 10D and 10E successively, obtain this title compound.
Embodiment 35B
4-[4-(4-fluoro-benzyloxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Use the method for embodiment 10F, product with the product alternate embodiment 10E of embodiment 35A, the product of embodiment 35A and the product of embodiment 10B are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (40mg, 41%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.69(s，3H)5.09(s，2H)6.65(m，2H)6.97(dd，J＝8.64，2.39Hz，1H)7.09(m，2H)7.21(m，4H)7.50.(m，2H)7.61(d，J＝8.46Hz，1H)8.61(s，1H)8.75(d，J＝8.46Hz，1H)9.65(s，1H)10.41(s，1H)；MS(ESI+)m/z?485(M+H)+.
Embodiment 36
3-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxymethyl]-benzonitrile
Embodiment 36A
4-methyl-3-oxo-valeral, sodium salt
Flame-dried flask nitrogen purging that will equipment 25-mL feed hopper, and load onto anhydrous diethyl ether (40mL), add then the sodium bar (1.65g, 0.0725mol).Reaction mixture is cooled to ice/bath temperature, and in 0 ℃ with slowly dripped 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 the cooling ice bath, and with reaction mixture in stirred overnight at room temperature.And then add ether (10mL) dismissing throw out, and with solid by the vacuum filtration sharp separation.Solid is washed with a small amount of ether, in vacuum drier dry 1 hour then, obtain this title compound, be pale solid (5.35g, 54% productive rate).This material is used for next step under situation about not being further purified.
Embodiment 36B
6-sec.-propyl-2-oxo 1,2-dihydro-pyridine-3-formonitrile HCN
With the product of embodiment 36A (5.35g, 0.0393mol) and the 2-malonamide nitrile (3.47g, 0.0413mol) solution in water (35mL) was in stirring at room 10 minutes.In this mixture, add 2.5mL and stock Piperidineacetic acid salts solution (preparing), and solution was heated 2 hours under refluxing by 9.8mL piperidines, 6mL acetate and 10mL water.Then mixture is cooled to room temperature, and is adjusted to pH4 by adding Glacial acetic acid.By isolated by vacuum filtration, water (2 x 30mL) washs with the gained light yellow solid, and is dry under vacuum, obtains this title compound (4.36g, 68%).
Embodiment 36C
2-bromo-6-sec.-propyl-cigarette nitrile
With the product of embodiment 36B (4.35g, 0.0269mol), Tetrabutylammonium bromide (10.4g, 0.0323mol) and five phosphorus oxide (8.01g, the 1.05mol) heating 5 hours under refluxing of the solution in toluene (80mL).Then reaction mixture is cooled to room temperature, adds entry (80mL), and with mixture in stirring at room 2 hours.This reaction mixture dilutes with toluene (20mL), and organic layer is separated.With toluene (50mL) washing water layer, and, use anhydrous magnesium sulfate drying, filter, and under vacuum, concentrate, obtain this title compound, be yellow oil (5.64g, 93%) the organic layer that merges salt solution (50mL) washing.
Embodiment 36D
2-amino-6-sec.-propyl-cigarette nitrile
With the product of embodiment 36C (21g, 0.093mol) with liquefied ammonia (250mL) in 500mL ethanol in the high pressure vessel of sealing in 130 ℃ of reactions 20 hours.Reaction mixture is concentrated under vacuum, and resistates is worn into fine powder, water (2 x 50mL) washing then, and dry in vacuum chamber, obtain this title compound, be beige solid (14g, 93%).
Embodiment 36E
N '-(3-cyano group-6-sec.-propyl-pyridine-2-yl)-N-N '-dimethyl-carbonamidine
(7.1g is 0.044mol) with N-N-dimethyl formamide dimethyl acetal (6.44mL, the 0.0484mol) heating 3 hours under refluxing of the solution in toluene (100mL) with the product of embodiment 36D.Gained solution is cooled to room temperature, and concentrates under vacuum, obtain this title compound (9.5g, 100%), be the thickness brown oil, it is placing after fixing.Though it is seemingly pure that this material is measured by NMR, it contains a small amount of light impurity.Its purifying (methyl acetate/hexane gradient) on silica gel can be obtained yellow oil, it is placing after fixing (reclaiming about 70% by chromatography).
Embodiment 36F
3-(4-chloro-3-nitro-phenoxymethyl)-benzonitrile
According to the method for embodiment 10C, substitute 1-chloromethyl-4-methoxyl group-benzene (0.813g, 98%) with 3-brooethyl-benzonitrile, make this title compound.
Embodiment 36G
3-[4-(4-hydroxyl-phenyl sulfenyl)-3-nitro-phenoxymethyl]-benzonitrile
According to the method for embodiment 10D, substitute 1-chloro-4-(4-methoxyl group-benzyloxy)-2-nitro-benzene (1.07g, 100%) with 3-(4-chloro-3-nitro-phenoxymethyl)-benzonitrile, make this title compound.
Embodiment 36H
3-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenoxymethyl]-benzonitrile
According to the method for embodiment 10E, with 3-[4-(4-hydroxyl-phenyl sulfenyl)-3-nitro-phenoxymethyl]-the alternative 4-[4-(4-methoxyl group-benzyloxy) of benzonitrile-2-nitro-phenyl sulfenyl]-phenol (0.97g, 98%), make this title compound.
Embodiment 36I
3-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxymethyl]-benzonitrile
With the product of embodiment 37E (47.4mg, 0.219mmol) and the product of embodiment 36H (76.3mg, 0.219mmol) solution in acetate (1mL) is preheating to 130 ℃ oil bath and was stirring 15 minutes.Then mixture is cooled to room temperature, under vacuum, remove acetate, and with the gained resistates at Waters Symmetry C8 post (25mm x 100mm, 7 μ m particle sizes) carry out anti-phase preparation HPLC purifying on, use the 10%-100% acetonitrile/solution of 0.1% trifluoroacetic acid in water via the current gradient wash-out of 8 minutes (10 minute working time) with 40mL/min, obtain this title compound, be trifluoroacetic acid salt form (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 37
4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(2-methoxyl group-benzyloxy)-phenyl sulfenyl]-phenol
Embodiment 37A
4-[2-amino-4-(2-methoxyl group-benzyloxy)-phenyl sulfenyl]-phenol
Use the condition of describing among the embodiment 10C, 4-chloro-3-nitro-phenol solution and 1-brooethyl-2-methyl-benzene are obtained 1-chloro-4-(2-methyl-benzyloxy)-2-nitro-benzene reaction, it is handled with the method for embodiment 10D and 10E successively, obtain this title compound.
Embodiment 37B
4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(2-methoxyl group-benzyloxy)-phenyl sulfenyl]-phenol
Use the method for embodiment 36I, use the product of the product alternate embodiment 36H of embodiment 37A, the product of embodiment 37A and the product of embodiment 37E are reacted, obtain solid, it is developed with methyl alcohol, obtain this title compound (31mg, 31%).
1H?NMR(500MHz，DMSO-D6)δ?ppm：9.88(s，1H)，9.57(s，1H)，8.73(d，J＝5.49Hz，1H)，8.56(s，1H)，7.58(d，J＝7.32Hz，1H)，7.40(dd，J＝7.63，1.53Hz，1H)，7.31-7.37(m，1H)，7.30(s，1H)，7.18(d，J＝6.10Hz，1H)，7.11(d，J＝8.54Hz，2H)，7.05(d，J＝7.93Hz，1H)，6.97(t，J＝7.32Hz，1H)，6.93(s，1H)，6.67(d，J＝8.54Hz，2H)，5.06(s，2H)，3.80(s，3H)，3.16-3.25(m，1H)，1.33(d，J＝6.71Hz，6H)；MS(ESI+)m/z?525.2(M+H)+(ESI-)m/z?523.2(M-H)-.
Embodiment 38
4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(4-methoxyl group-benzyloxy)-phenyl sulfenyl]-phenol
According to the method for embodiment 36I, use the product of the product alternate embodiment 36H of embodiment 10E, the product of embodiment 10E and the product of embodiment 36E are reacted, obtain solid, it is developed with methyl alcohol, obtain this title compound (43mg, 49%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：9.93(s，1H)，9.63(s，1H)，8.75(d，J＝8.46Hz，1H)，8.57(s，1H)，7.60(d，J＝8.09Hz，1H)，7.38(d，J＝8.46Hz，2H)，7.27(s，1H)，7.05-7.19(m，3H)，6.85-7.00(m，3H)，6.67(d，J＝8.82Hz，2H)，5.02(s，2H).3.75(s，3H)，3.14-3.28(m，1H)，1.32(d，J＝6.62Hz，6H)；MS(ESI+)m/z?525.3(M+H)+(ESI-)m/z?523.3(M-H)-.
Embodiment 39
4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(1-phenyl-oxyethyl group)-phenyl sulfenyl]-phenol
Embodiment 39A
4-[2-amino-4-(1-phenyl-oxyethyl group)-phenyl sulfenyl]-phenol
Use the condition of describing among the embodiment 22A, 1-(3-fluoro-phenyl)-alcoholic acid solution is converted into 1-(1-bromo-ethyl)-3-fluoro-benzene, it is handled with the method for embodiment 22B-22D successively, obtain this title compound.
Embodiment 39B
4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(1-phenyl-oxyethyl group)-phenyl sulfenyl]-phenol
According to the method for embodiment 36I, use the product of the product 39A alternate embodiment 36H of embodiment to obtain this rough title compound, the product of embodiment 39A and the product of embodiment 36E are reacted, it is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)1.55(d，J＝6.25Hz，3H)3.14-3.29(m，1H)5.49(q，J＝6.37Hz，1H)6.63(d，J＝8.82Hz，2H)6.89(dd，J＝8.82，2.57Hz，1H)7.09(dd，J＝9.01，2.76Hz，3H)7.19-7.48(m，6H)7.75(d，J＝8.82Hz，1H)8.67(s，1H)8.83(d，J＝8.46Hz，1H)9.67(s，1H)10.85(s，1H)；MS?ESI+(m/z)509，ESI-(m/z)507.
Embodiment 40
4-[4-[1-(4-bromo-phenyl)-oxyethyl group]-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl-phenol
Method according to embodiment 36I, product with the product 22D alternate embodiment 36H of embodiment, (211mg is 0.506mmol) with product (109mg, 0.506mmol) reaction of embodiment 36E with the product of embodiment 22D, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (150mg, 42%).
1H NMR (300MHz, DMSO d6) δ ppm:10.87 (br s, 1H) 9.68 (s, 1H) 8.83 (d, J=8.45Hz, 1H) 8.67 (s, 1H) 7.75 (d, J=7.72Hz, 1H) 7.55d, J=8.46Hz, 2H) 7.37 (d, J=8.46Hz, 2H) 7.09 (m, 4H) 6.89 (dd, J=8.46Hz, J=2.20Hz, 1H) 6.66 (d, J=8.82Hz, 2H) 5.50 (q, J=6.25Hz, 2H) 3.25 (septets, J=6.99Hz, 1H) 1.53 (d, J=6.25Hz, 3H) 1.34 (d, J=6.99Hz, 6H) .MS (ESI+) m/z 587,589 (M+H-TFA)+; (ESI-) m/z 585,587 (M-H-TFA)-.
Embodiment 41
4-[4-[1-(3-fluoro-phenyl)-oxyethyl group]-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl-phenol
Method according to embodiment 36I, product with the product 24A alternate embodiment 36H of embodiment, (197mg is 0.555mmol) with product (120mg, 0.555mmol) reaction of embodiment 36E with the product of embodiment 24A, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (100mg, 28%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)1.55(d，J＝6.62Hz，3H)3.19-3.32(m，J＝13.70，6.94，6.94Hz，1H)5.53(q，J＝6.62Hz，1H)6.64(d，J＝8.46Hz，2H)6.91(dd，J＝8.82，2.57Hz，1H)7.09(d，J＝8.46Hz，5H)7.19-7.29(m，2H)7.39(dd，J＝8.09，5.88Hz，1H)7.78(d，J＝8.46Hz，1H)8.68(s，1H)8.85(d，J＝8.46Hz，1H)9.70(s，1H)；MS(ESI+)m/z?527(M+H)+.
Embodiment 42
4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(3-trifluoromethyl-benzyloxy)-phenyl sulfenyl-phenol
Method according to embodiment 36I, product with the product alternate embodiment 36H of embodiment 26A, the product of embodiment 26A and the product of embodiment 36E are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (22mg, 21%).
1H?NMR(300MHz，DMSO-D6)δppm：1.34(d，J＝6.99Hz，6H)，5.22(s，2H)，6.65(d，J＝8.46Hz，2H)，7.01-7.13(m.3H)，7.20(d，J＝8.82Hz，2H)，7.66(d，J＝7.35Hz，1H)，7.70-7.82(m，4H)，8.68(s，1H)，8.87(d，J＝8.46Hz，1H)，9.68(s，1H)；MS?ESI+m/z?563(M+H)+，ESI-m/z?561(M-H)-.
Embodiment 43
4-[4-(3-fluoro-benzyloxy)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Method according to embodiment 36I, product with the product alternate embodiment 36H of embodiment 57D, the product of embodiment 57D and the product of embodiment 36E are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (26mg, 51%).
1H?NMR(300MHz，DMSO-D6)δppm：1.35(d，J＝6.99Hz，6H)3.28(m，1H)5.14(s，2H)6.65(m，2H)7.16(m，8H)7.44(m，1H)7.81(d，J＝8.46Hz，1H)8.73(s，1H)8.90(d，J＝8.46Hz，1H)9.69(s，1H)11.08(s，1H)；MS(ESI+)m/z?513(M+H)+.
Embodiment 44
4-[4-(4-fluoro-benzyloxy)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Method with embodiment 36I, product with the product alternate embodiment 36H of embodiment 35A, the product of embodiment 35A and the product of embodiment 36E are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (23mg, 45%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.99Hz，6H)3.26(m，1H)5.09(s，2H)6.62(m，2H)7.14(m，7H)7.48(m，2H)7.81(d，J＝8.46Hz，1H)8.73(s，1H)8.90(d，J＝8.46Hz，1H)9.68(s，1H)11.12(s，1H)；MS(ESI+)m/z513(M+H)+.
Embodiment 45
4-[4-[1-(4-fluoro-phenyl)-oxyethyl group]-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Method according to embodiment 36I, product with the product alternate embodiment 36H of embodiment 23A, (180mg is 0.510mmol) with product (110mg, 0.510mmol) reaction of embodiment 36E with the product of embodiment 23A, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (35mg, 12%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.99Hz，6H)1.54(d，J＝6.62Hz，3H)3.23-3.34(m，1H)5.52(q，J＝5.88Hz，1H)6.63(d，J＝8.82Hz，2H)6.94(dd，J＝8.82，2.57Hz，1H)7.08(m，J＝8.82Hz，4H)7.14(d，J＝4.78Hz，1H)7.17-7.21(m，1H)7.41-7.49(m，2H)7.86(d，J＝8.82Hz，1H)8.76(s，1H)8.91(d，J＝8.46Hz，1H)；MS(ESI+)m/z?527(M+H)+.
Embodiment 46
4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(3 methoxyl groups-benzyloxy)-phenyl sulfenyl]-phenol
Use the method for embodiment 36I, product with the product alternate embodiment 36H of embodiment 31A, the product of embodiment 31A and the product of embodiment 36E are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (23mg, 45%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：10.98(s，1H)，9.67(s，1H)，8.88(d，J＝8.09Hz，1H)，8.70(s，1H)，7.78(d，J＝8.09Hz，1H)，7.31(t，J＝8.09Hz，1H)，7.15-7.24(m，J＝8.82Hz，2H)，7.06-7.15(m，2H)，6.95-7.05(m，J＝6.62Hz，3H)，6.90(dd，J＝7.72，2.21Hz，1H)，6.54-6.73(m，2H)，5.09(s，2H)，3.75(s，3H)，3.19-3.28(m，1H)，1.34(d，J＝6.99Hz，6H)；MS(ESI+)m/z?525.2(M+H)+(ESI-)m/z?523.2(M-H)-.
Embodiment 47
4-[4-(3-bromo-benzyloxy)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Use the method for embodiment 36I, product with the product alternate embodiment 36H of embodiment 15A, the product of embodiment 15A and the product of embodiment 36E are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (16mg, 28%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.33(d，J＝6.62Hz，6H)3.21(m，1H)5.13(s，2H)6.68(d，J＝8.82Hz，2H)6.95(dd，J＝8.64，2.76Hz，1H)7.12(m，3H)7.34(m，2H)7.50(m，2H)7.60(d，J＝8.82Hz，1H)(s，1H)8.57(s，1H)8.76(d，J＝8.46Hz，1H)9.65(s，1H)9.95(s，1H)；MS(ESI+)m/z?573，575(M+H)+.
Embodiment 48
4-[4-(4-bromo-benzyloxy)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Use the method for embodiment 36I, product with the product alternate embodiment 36H of embodiment 16A, the product of embodiment 16A and the product of embodiment 36E are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (28mg, 49%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.32(d，J＝6.99Hz，6H)3.22(m，1H)5.10(s，2H)6.67(d，J＝8.46Hz，2H)6.94(dd，J＝8.82，2.57Hz，1H)7.12(m，3H)7.28(d，J＝2.57Hz，1H)7.41(d，J＝8.46Hz，2H)7.59(m，3H)8.56(s，1H)8.75(d，J＝8.46Hz，1H)9.65(s，1H)9.94(s，1H)；MS(ESI+)m/z?573，575(M+H)+.
Embodiment 49
4-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxymethyl]-benzonitrile
Use the method for embodiment 36I, product with the product alternate embodiment 36H of embodiment 21A, the product of embodiment 21A and the product of embodiment 36E are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (32mg, 26%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：10.91(s，1H)，9.69(s，1H)，8.87(d，J＝9.19Hz，1H)，8.69(s，1H)，7.88(d，J＝8.09，Hz，2H)，7.77(d，J＝8.46Hz，1H)，7.64(d，J＝8.46Hz，2H)，7.15-7.26(m，J＝8.82Hz，2H)，7.08-7.15(m，2H)，7.01(d，J＝8.82Hz，1H)，6.58-6.72(m，2H)，5.23(s，2H)，3.20-3.31(m，1H)，1.34(d，J＝6.99Hz，6H)；MS(ESI+)m/z?520.2(M+H)+(ESI-)m/z?518.2(M-H)-.
Embodiment 50
2-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxymethyl]-benzonitrile
Use the method for embodiment 36I, product with the product alternate embodiment 36H of embodiment 20A, the product of embodiment 20A and the product of embodiment 36E are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (11mg, 9%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：11.30(s，1H)，9.71(s，1H)，8.93(d，J＝8.82Hz，1H)，8.76(s，1H)，7.92(d，J＝7.35Hz，1H)，7.84(d，J＝8.82Hz，1H)，7.72·7.80(m，2H)，7.59(ddd，J＝7.72，6.25，2.58Hz，1H)，7.19-7.28(m，2H)，7.06-7.17(m，3H)，6.64-6.69(m，2H)，5.25(s，2H)，3.22-3.33(m，1H)，1.35(d，J＝6.99Hz，6H)；MS(ESI+)m/z?520.2(M+H)+(ESI-)m/z?518.2(M-H)-.
Embodiment 51
4-[4-benzyloxy-2-(the 7-sec.-propyl-' pyrido [2,3-d] pyrimidine-4-base is amino)-the phenyl sulfenyl]-phenol
Use the method for embodiment 36I, use the product of the product alternate embodiment 36H of embodiment 27A to obtain solid, the product 27A of embodiment and the product of embodiment 36E are reacted, it is developed with methyl alcohol, obtain this title compound.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.32(d，J＝6.62Hz，6H)3.10-3.30(m，1H)5.11(s，2H)6.67(d，J＝8.82Hz，2H)6.90-6.99(m，1H)7.07-7.19(m，1H)7.11(d，J＝8.82Hz，2H)7.23·7.52(m，6H)7.59(d，J＝8.09Hz，1H)8.56(s，1H)8.75(d，J＝8.09Hz，1H)9.64(s，1H)9.95(s，1H)；MS(DCI/NH3)m/z?495(M+H)+.
Embodiment 52
3-[3-[7-(1-hydroxyl-1-methyl-ethyl)-pyrido [2,3-d] pyrimidine-4-base is amino]-4-(4-hydroxyl-phenyl sulfenyl)-phenoxymethyl]-benzonitrile
Will (45.9mg, 0.212mmol) (73.5mg 0.212mmol) be heated to 130 ℃ with 15 minutes from room temperature gradually in oil bath, then 130 ℃ of reheat 1.5 hours with the product of embodiment 36H at the product of the embodiment 36E in the acetate (1mL).Then mixture is cooled to room temperature, under vacuum, concentrate, obtain this rough title compound, with it at Waters Symmetry C8 post (25mm x 100mm, 7 μ m particle sizes) carry out anti-phase preparation HPLC purifying on, use the 10%-100% acetonitrile/solution of 0.1% trifluoroacetic acid in water via with the current gradient wash-out of 40mL/min, obtaining this title compound 8 minutes (10 minute working time), be trifluoroacetic acid salt form (22mg, 20%).
1H?NMR(300MHz，DMSO-d
6)δ?ppm：11.76(s，1H)，9.72(s，1H)，9.06(d，J＝8.09Hz，1H)，8.83(s，1H)，8.20(d，J＝8.46Hz，1H)，7.92(s，1H)，7.75-7.88(m，2H)，7.63(t，J＝7.72Hz，1H)，7.21-7.26(m，1H)，7.19(d，J＝2.57Hz，1H)，7.07-7.15(m，3H)，6.64(d，J＝8.46Hz，2H)，5.18(s，2H)，1.56(s，6H)；MS(ESI)m/z536.2(M+H)+，(ESI-)m/z?534.2(M-H)-.
Embodiment 53
2-[3-[7-(1-hydroxyl-1-methyl-ethyl)-pyrido [2,3-d] pyrimidine-4-base is amino]-4-(4-hydroxyl-phenyl sulfenyl)-phenoxymethyl]-benzonitrile
Use the method for embodiment 52, product with the product alternate embodiment 36H of embodiment 20A, the product of embodiment 20A and the product of embodiment 36E are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (11mg, 11%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：11.73(s，1H)，9.75(s，1H)，9.05(d，J＝8.46Hz，1H)，8.84(s，1H)，8.20(d，J＝8.82Hz，1H)，7.92(d，J＝7.35Hz，1H)，7.69-7.84(m，2H)，7.54-7.64(m，1H)，7.23-7.27(m，1H)，7.21(d，J＝2.57Hz.1H)，7.10-7.17(m，3H)，6.64-6.69(m，2H)，5.25(s，2H)，1.56(s，6H)；MS(ESI+)m/z?536.2(M+H)+(ESI-)m/z?534.3(M-H).
Embodiment 54
4-[3-[7-(1-hydroxyl-1-methyl-ethyl)-pyrido [2,3-d] pyrimidine-4-base is amino]-4-(4-hydroxyl-phenyl sulfenyl)-phenoxymethyl]-benzonitrile
Use the method for embodiment 52, product with the product 21A alternate embodiment 36H of embodiment, the product of embodiment 21A and the product of embodiment 36E are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (10mg, 10%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：11.64(s，1H)，9.73(s，1H)，9.05(s，1H)，8.82(s，1H)，8.19(d，J＝8.82Hz，1H)，7.88(d，J＝8.09Hz，2H)，7.64(d，J＝8.46Hz，2H)，7.23(d，J＝8.82Hz，1H)，7.18(d，J＝2.57Hz，1H)，7.04-7.15(m，3H)，6.62-6.69(m，2H)，5.23(s，2H)，2.54(s，1H)，1.56(s，6H)；MS(ESI+)m/z?536.2(M+H)+(ESI-)m/z534.2(M-H)-.
Embodiment 55
4-[2-[7-(1-hydroxyl-1-methyl-ethyl)-pyrido [2,3-d] pyrimidine-4-base is amino]-4-(2-methoxyl group-benzyloxy)-phenyl sulfenyl]-phenol
The product of embodiment 37A and the product of embodiment 36E are reacted, use the method for embodiment 52, use the product of the product alternate embodiment 36H of embodiment 37A, obtain solid, it is developed with methyl alcohol, obtain this title compound (8mg, 8%).
1HNMR(300MHz，DMSO-D6)δ?ppm：11.81(s，1H)，9.40-9.95(m，1H)，9.06(d，J＝8.46Hz，1H)，8.85(s，1H)，8.21(d，J＝8.46Hz，1H)，7.31-7.44(m，2H)，7.25(d，J＝8.46Hz，1H)，7.15(d，J＝2.57Hz，1H)，7.02-7.14(m，4H)，6.97(t，J＝7.54Hz，1H)，6.61-6.67(m，2H)，5.05(s，2H)，3.80(s，3H)，2.54(s，1H)，1.56(s，6H)；MS(ESI+)m/z?541.2(M+H)+(ESI-)m/z?539.2(M-H)-.
Embodiment 56
4-{4-(4-bromo-benzyloxy)-2-[7-(1-hydroxyl-1-methyl-ethyl)-pyrido [2,3-d] pyrimidine-4-base is amino]-the phenyl sulfenyl }-phenol
Use the method for embodiment 52, product with the product alternate embodiment 36H of embodiment 16A, the product of embodiment 16A and the product of embodiment 36E are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (8mg, 13%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.55(s，6H)2.08(s，1H)5.10(s，2H)6.65(d，J＝8.46Hz，2H)7.13(m，5H)7.41(d，J＝8.46Hz，2H)7.60(d，J＝8.09Hz，2H)8.15(d，J＝8.46Hz，1H)8.77(s，1H)9.00(d，J＝8.46Hz，1H)9.70(s，1H)11.43(s，1H)；MS(ESI+)m/?z589，591(M+H)+.
Embodiment 57
4-[4-(3-fluoro-benzyloxy)-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 57A
N '-(3-cyano group-pyridine-2-yl)-N, N-dimethyl-carbonamidine
With 2-amino-cigarette nitrile (5g, 42mmol) and N, dinethylformamide dimethyl acetal (6.13mL, the 46.2mmol) heating 3 hours under refluxing of the solution in toluene (20mL).After being cooled to room temperature, solution decompression is concentrated, obtain this title compound (7.3g, 100%).
Embodiment 57B
1-chloro-4-(3-fluoro-benzyloxy)-2-nitro-benzene
According to the method for embodiment 10C, substitute 1-chloromethyl-4-methoxyl group-benzene (0.56g, 100%) with 1-brooethyl-3-fluoro-benzene, make this title compound.
Embodiment 57C
4-[4-(3-fluoro-benzyloxy)-2-nitro-phenyl sulfenyl]-phenol
According to the method for embodiment 10D, substitute 1-chloro-4-(4-methoxyl group-benzyloxy)-2-oil of mirbane (0.57g, 77%) with 1-chloro-4-(3-fluoro-benzyloxy)-2-nitro-benzene, make this title compound.
Embodiment 57D
4-[2-amino-4-(3-fluoro-benzyloxy)-phenyl sulfenyl]-phenol
According to the method for embodiment 10E, 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 (0.501g, 96%), make this title compound.
Embodiment 57E
4-[4-(3-fluoro-benzyloxy)-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
With the product of embodiment 57A (35mg, 0.2mmol) and the product of embodiment 57D (68mg, 0.2mmol) solution in acetate (1mL) was heated to 130 ℃ from room temperature with 15 minutes gradually in oil bath, then 130 ℃ of reheat 1.5 hours.Then mixture is cooled to room temperature, under vacuum, concentrate, obtain this rough title compound, with it at Waters Symmetry C8 post (25mm x 100mm, 7 μ m particle sizes) carry out anti-phase preparation HPLC purifying on, use the 10%-100% acetonitrile/solution of 0.1% trifluoroacetic acid in water via with the current gradient wash-out of 40mL/min, obtaining this title compound 8 minutes (10 minute working time), be trifluoroacetic acid salt form (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 58
4-[4-(2-methyl-benzyloxy)-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Use the method for embodiment 57E, product with the product alternate embodiment 57D of embodiment 17A, the product of embodiment 17A and the product of embodiment 57A are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (50mg, 54%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.31(s，3H)5.09(s，2H)6.66(m，2H)7.01(m，1H)7.19(m，7H)7.42(d，J＝6.99Hz，1H)7.71(dd，J＝7.91，4.23Hz，1H)8.63(s，1H)8.89(d，J＝7.35Hz，1H)9.09(s，1H)9.66(s，1H)10.50(s，1H)；MS(ESI+)m/z?467(M+H)+.
Embodiment 59
4-[4-(4-methyl-benzyloxy)-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Use the method for embodiment 57E, product with the product alternate embodiment 57D of embodiment 19A, with the product of embodiment 19A with the product reaction of embodiment 57A, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (45mg, 48%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.30(s，3H)5.05(s，2H)6.65(m，2H)7.10(m，7H)7.33(d，J＝8.07Hz，2H)7.69(dd，J＝8.27，4.23Hz，1H)8.62(s，1H)8.87(d，J＝7.72Hz，1H)9.07(s，1H)9.64(s，1H)10.42(s，1H)；MS(ESI+)m/z467(M+H)+.
Embodiment 60
4-[4-(2-bromo-benzyloxy)-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Use the method for embodiment 57E, product with the product alternate embodiment 57D of embodiment 14A, the product of embodiment 14A and the product of embodiment 57A are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (40mg, 38%).
1H?NMR(300MHz，DMSO-D6)δ?ppm；5.13(s，2H)6.66(m.2H)6.99(d，J＝8.43Hz，1H)7.15(m，3H)7.35(m，3H)7.64(m，3H)8.60(s，1H)8.85(d，J＝7.32Hz，1H)9.07(s，1H)9.66(s，1H)10.28(s，1H)；MS(ESI+)m/z531，533(M+H)+.
Embodiment 61
3-[4-(4-hydroxyl-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxymethyl]-benzonitrile
According to the method for embodiment 57E, use the product of the product alternate embodiment 57D of embodiment 36H, the product of embodiment 36H and the product of embodiment 57A are reacted, obtain solid, it is developed with methyl alcohol, obtain this title compound (44mg, 44%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：10.08(s，1H)，9.65(s，1H)，9.06(s，1H)，8.86(s，1H)，8.58(s，1H)，7.92(s，1H)，7.77-7.86(m，2H)，7.54-7.70(m，J＝7.72，7.72Hz，2H)，7.28(s，1H)，7.07-7.19(m，3H)，6.97(s，1H)，6.63-6.72(m，2H)，5.18(s，2H)；MS(ESI+)m/z478.2(M+H)+，(ESI-)m/z?476.1(M-H)-.
Embodiment 62
4-[4-(3-methyl-benzyloxy)-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Use the method for embodiment 57E, product with the product alternate embodiment 57D of embodiment 18A, with the product of embodiment 18A with the product reaction of embodiment 57A, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (50mg, 54%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.31(s，3H)5.07(s，2H)6.65(m，2H)7.12(m，9H)7.78(dd，J＝8.10Hz，4.77Hz，1H)8.72(s，1H)8.94(d，J＝7.47Hz，1H)9.12(d，J＝3.15Hz，1H)9.67(s，1H)11.03(s，1H)；MS(ESI+)m/z?467(M+H)+.
Embodiment 63
4-[4-(4-methoxyl group-benzyloxy)-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
According to the method for embodiment 57E, use the product of the product alternate embodiment 57D of embodiment 10E, the product of embodiment 10E and the product of embodiment 57A are reacted, obtain solid, it is developed with methyl alcohol, obtain this title compound (49mg, 55%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：10.07(s，1H)，9.63(s，1H)，9.05(s，1H)，8.83(s，1H)，8.58(s，1H)，7.64(s，1H)，7.38(d，J＝8.46Hz，2H)，7.20-7.29(m，1H)，7.12-7.18(m，1H)，7.06-7.12(m，2H)，6.90-6.99(m，3H)，6.62-6.69(m，2H)，5.02(s，2H)，3.75(s，3H)；MS(ESI+)m/z?483.2(M+H)+，(ESI-)m/z?481.2(M-H)-.
Embodiment 64
4-[4-(2-methoxyl group-benzyloxy)-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Use the method for embodiment 57E, use the product of the product alternate embodiment 57D of embodiment 37A, the product 37A of embodiment and the product of embodiment 57A are reacted, obtain solid, it is developed with methyl alcohol, obtain this title compound (47mg, 56%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：10.08(s，1H)，9.63(s，1H)，9.07(s，1H)，8.85(d，J＝6.62Hz，1H).8.59(s，1H)，7.64(s，1H)，7.41(dd，J＝7.35，1.47Hz，1H)，7.30-7.38(m，1H)，7.24(s，1H)，7.16(d，J＝8.46Hz，1H)，7.08-7.14(m，2H)，7.05(d，J＝8.09Hz，1H)，6.89-7.01(m，J＝7.54，7.54Hz，2H)，6.61-6.71(m，2H)，5.05(s，2H)，3.80(s，3H)；MS(ESI+)m/z?483.2(M+H)+，(ESI-)m/z?481.2(M-H)-.
Embodiment 65
4-[4-(4-hydroxyl-phenyl sulfenyl)-3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxymethyl]-benzonitrile
Use the method for embodiment 57E, product with the product alternate embodiment 57D of embodiment 21A, the product of embodiment 21A and the product of embodiment 57A are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (6mg, 6%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：11.17(s，1H)，9.69(s，1H)，9.09-9.20(m，J＝3.68Hz，1H)，8.97(d，J＝8.82Hz，1H)，8.74(s，1H)，7.78-7.96(m，3H)，7.64(d，J＝8.46Hz，2H)，7.20(d，J＝8.46Hz，2H)，7.07-7.16(m，2H)，7.03(d，J＝6.25Hz，1H)，6.57-6.70(m，zH)，5.23(s，2H)；MS(ESI+)m/z?478.2(M+H)+，(ESI-)m/z?476.2(M-H)-.
Embodiment 66
4-[4-(3-methoxyl group-benzyloxy)-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
According to the method for embodiment 57E, use the product of the product alternate embodiment 57D of embodiment 31A, the product of embodiment 31A and the product of embodiment 57A are reacted, obtain solid, it is developed with methyl alcohol, obtain this title compound (38mg, 45%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：10.07(s，1H)，9.63(s，1H)，9.07(s，1H)，8.86(d，J＝7.72Hz，1H)，8.59(s，1H)，7.64(s，1H)，7.23-7.36(m，2H)，7.16(dd，J＝8.64，1.65Hz，1H)，7.07-7.13(m，2H)，6.93-7.05(m，3H)，6.89(dd，J＝8.27，2.02Hz，1H)，6.61-6.71(m，2H)，5.08(s，2H)，3.75(s，3H)；MS(ESI+)m/z?483.2(M+H)+，(ESI-)m/z?481.2(M-H)-.
Embodiment 67
4-[4-(4-bromo-benzyloxy)-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Method according to embodiment 57E, product with the product alternate embodiment 57D of embodiment 16A, with the product of embodiment 16A and the product of embodiment 57A, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (11mg, 16%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：5.09(s，2H)，6.66(d，J＝8.46Hz，2H)，6.94(s，1H)，7.11(d，J＝8.46Hz，3H)，7.25(s，1H)，7.41(d，J＝8.09Hz，2H)，7.57·7.69(m，3H)，8.59(s，1H)，8.84(s，1H)，9.06(s，1H)，9.64(s，1H)，10.07(s，1H)；MS?ESI+m/z?531(M+H)+，ESI-m/z?529(M-H)-.
Embodiment 68
4-[4-(3-bromo-benzyloxy)-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Method according to embodiment 57E, product with the product alternate embodiment 57D of embodiment 15A, the product of embodiment 15A and the product of embodiment 57A are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (40mg, 16%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：5.12(s，2H)，6.67(d，J＝8.46Hz，2H)，6.94(s，1H)，7.12(d，J＝8.46Hz，3H)，7.26(s，1H)，7.36(t，J＝7.72Hz，1H)，7.45(s，1H)，7.54(d，J＝6.62Hz，1H)，7.66(s，2H)，8.57(s，1H)，8.83(s，1H)，9.04(s，1H)，9.64(s，1H)，10.08(s，1H)；MS?ESI+m/z?531(M+H)+，ESI-m/z?529(M-H)-.
Embodiment 69
4-[4-benzyloxy-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
According to the method for embodiment 57E, use the product of the product alternate embodiment 57D of embodiment 27A, the product reaction of the product of embodiment 27A and embodiment 57A obtains this title compound, and it is (79mg, 48%) as the isolated in form of acetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：5.10(s，3H)，6.61-6.72(m，2H)，6.93(d，J＝9.56Hz，1H)，7.11(d，J＝8.46Hz，4H)，7.24(s，1H)，7.32-7.47(m，5H)，7.59-7.68(m，1H)，8.54(s，1H)，8.83(d，J＝9.56Hz，1H)，9.04(s，1H)；ESI+m/z?453(M+H)+，ESI-m/z?451(M-H)-.
Embodiment 70
4-[4-[1-(4-bromo-phenyl)-oxyethyl group]-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Method according to embodiment 57E, product (153mg with embodiment 22D, 0.367mmol) with the product (63mg of embodiment 57A, 0.367mmol) reaction, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (97mg, 40%).
1H?NMR(300MHz，DMSO-d
6)δ?ppm：10.60(brs，1H)9.67(s，1H)9.09(s，1H)8.88(d，J＝8.46Hz，1H)8.64(s，1H)7.73(m，J＝3.31Hz，1H)7.54(dJ＝8.46Hz，2H)7.36(d，J＝8.46Hz，2H)7.11(m，4H)6.86(d，J＝9.19Hz，1H)6.64(d，J＝8.46Hz，2H)5.51(q，J＝6.62Hz，1H)1.53(d，J＝6.62Ha，3H)；MS(ESI+)m/z，545，547(M+H-TFA)+；(ESI-)m/z，543，545(M-H-TFA)-.
Embodiment 71
4-[4-[1-(4-fluoro-phenyl)-oxyethyl group]-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Method according to embodiment 57E, product (the 180mg of embodiment 23A, 0.803mmol) with the product (140mg of embodiment 57A, 0.803mmol) reaction, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (60mg, 12%).
1H?NMR(500MHz，DMSO-D6)δ?ppm：1.53(d，J＝6.35Hz，3H)5.51(q，1H)6.61(d，J＝8.79Hz，2H)6.74-6.82(m，1H)6.93(dd，J＝8.79，2.44Hz，1H)7.06-7.09(m，3H)7.11-7.19(m，2H)7.44(dd，J＝8.54，5.62Hz，2H)7.83-7.86(m，J＝8.54，5.13Hz，1H)8.75(s，1H)8.96(d，J＝7.32Hz，1H)9.14(d，J＝2.93Hz，1H)；MS(ESI+)m/z?485.
Embodiment 72
4-[4-[1-(3-fluoro-phenyl)-oxyethyl group]-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Method according to embodiment 57E, product (285mg with embodiment 24A, 0.80mmol) with the product (140mg of embodiment 57A, 0.803mmol) reaction, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (150mg, 31%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.55(d，J＝6.25Hz，3H)5.53(q，J＝6.13Hz，1H)6.65(d，J＝8.46Hz，2H)6.85(d，J＝6.99Hz，1H)7.03-7.18(m，4H)7.21-7.29(m，2H)7.37-7.45(m，1H)7.67(dd，J＝8.09，4.41Hz，1H)8.57(s，1H)8.81(s，1H)9.06(s，1H)9.66(s，1H)；MS(ESI+)m/z?485(M+H)+.
Embodiment 73
(5-benzyloxy-4-chloro-2-fluoro-phenyl)-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Embodiment 73A
Carbonic acid 2-chloro-4-fluoro-phenylester ethyl ester
To 2-chloro-4-fluoro-phenol (0.8mL, 7.64mmol) and triethylamine (1.3mL, 9.16mmol) solution in methylene dichloride (10mL) in 0 ℃ drip Vinyl chloroformate (0.9mL, 9.16mmol).Remove ice bath, solution is heated to room temperature, restir 16 hours.Then methylene dichloride (20mL) is added in the mixture, this organic solution with salt solution (50mL) washing, is used anhydrous magnesium sulfate drying, filter, and under vacuum, concentrate this title compound of acquisition, be oily matter (1.65g, 100%).
Embodiment 73B
Carbonic acid 2-chloro-4-fluoro-5-nitro-phenylester ethyl ester
(0.88g, (0.27mL is 6.45mmol) to remain on temperature 0 ℃ 4.03mmol) slowly to add nitrosonitric acid in the solution in the vitriol oil (2mL) to the product of refrigerative embodiment 73A in ice bath.With mixture restir 2 hours, then frozen water (10mL) is added in the solution, the gained solid by filtration is collected, wash with water, and dry in vacuum chamber, obtain this title compound (0.87g, 82%).
Embodiment 73C
2-chloro-4-fluoro-5-nitro-phenol
To the product of embodiment 73B (0.87g, 3.30mmol) add in the solution in methyl alcohol (20mL) and water (1mL) sodium bicarbonate (2.22g, 26.4mmol), and with mixture in stirring at room 16 hours.Remove methyl alcohol then under vacuum, (20mL) is added in the mixture methylene dichloride, and organic solution with salt solution (50mL) washing, is used anhydrous magnesium sulfate drying, filters, and concentrates under vacuum, obtains this title compound (0.62g, 98%).
Embodiment 73D
1-benzyloxy-2-chloro-4-fluoro-5-nitro-benzene
According to the method for embodiment 10C,, make this title compound (0.72g, 79%) with the alternative 1-chloromethyl of the product of bromotoluene and embodiment 73C-4-methoxyl group-benzene and 4-chloro-3-nitro-phenol.
Embodiment 73E
5-benzyloxy-4-chloro-2-fluoro-phenyl amine
According to the method for embodiment 10D,, make this title compound (77mg, 100%) with the alternative 1-chloro-4-(4-methoxyl group-benzyloxy) of the product of embodiment 73D-2-nitro-benzene.
Embodiment 73F
(5-benzyloxy-4-chloro-2-fluoro-phenyl)-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
With the product of embodiment 10B (17mg, 0.0927mmol) and the product of embodiment 73E (28mg, 0.111mmol) solution in acetate (1mL) was preheating to 130 ℃ the oil bath heating 15 minutes.Then mixture is cooled to room temperature, under vacuum, removes acetate, and the gained resistates is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (8.1mg, 17%).
1H?NMR(300MHz，DMSO-d
6)δ?ppm：2.72(s，3H)，5.19(s，2H)，7.28-7.53(m，6H)，7.66(d，J＝9.56Hz，1H)，7.70(d，J＝8.82Hz，1H)，8.73(s，1H)，8.84(d，J＝8.09Hz，1H)，10.85(s，1H)；MS(ESI)m/z?395(M+H)+.
Embodiment 74
(5-benzyloxy-4-chloro-2-fluoro-phenyl)-pyrido [2,3-d] pyrimidine-4-base-amine
According to the method for embodiment 73F, use the product of the product alternate embodiment 10B of embodiment 57A, make this title compound (7.9mg, 19%).
1H?NMR(300MHz，DMSO-d
6)δ?ppm：5.19(s，2H)，7.20-7.54(m，6H)，7.65(d，J＝9.56Hz，1H)，7.78(dd，J＝8.27，4.60Hz，1H)，8.73(s，1H)，8.95(d，J＝8.09Hz，1H)，9.12(d，J＝3.31Hz，1H)，10.82(s，1H)；MS(ESI+)m/z?381(M+H)+.
Embodiment 75
(5-benzyloxy-2,4-two fluoro-phenyl)-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Embodiment 75A
Carbonic acid 2,4-two fluoro-phenylester ethyl esters
According to the method for embodiment 73A, with 2,4-two fluoro-phenol substitute 2-chloro-4-fluoro-phenol (1.48g, 96%), make this title compound
Embodiment 75B
Carbonic acid 2,4-two fluoro-5-nitro-phenylester ethyl esters
Method according to embodiment 73B makes this title compound.
Embodiment 75C
2,4-two fluoro-5-nitro-phenol
According to the method for embodiment 73C, use the product (0.59g, 89%) of the alternative 313B of product of embodiment 73B, make this title compound.
Embodiment 75D
1-benzyloxy-2,4-two fluoro-5-nitro-benzene
According to the method for embodiment 73D, use the product of the alternative 313C of product of embodiment 75C, make this title compound (0.56g, 63%).
Embodiment 75E
5-benzyloxy-2,4-two fluoro-phenyl amine
According to the method for embodiment 73E, use the product of the alternative 313D of product of embodiment 75D, make this title compound (89mg, 100%).
Embodiment 75F
(5-benzyloxy-2,4-two fluoro-phenyl)-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
According to the method for embodiment 73F, use the product of the product alternate embodiment 73E of embodiment 75E, make this title compound.Resistates by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (7.4mg, 16%).
1H?NMR(300MHz，DMSO-d
6)δ?ppm：2.72(s，3H)，5.17(s，2H)，7.19-7.60(m，7H)，7.71(d，J＝8.46Hz，1H)，8.75(s，1H)，8.85(d，J＝8.46Hz，1H)，10.84(s，1H)；MS(ESI)m/z?379(M+H)+.
Embodiment 76
(5-benzyloxy-2,4-two fluoro-phenyl)-pyrido [2,3-d] pyrimidine-4-base-amine
(17mg, 0.099mmol) (28mg, 0.119mmol) solution in acetate (1mL) is preheating and is stirring to 130 ℃ oil bath with the product of embodiment 73E with the product of embodiment 57A.Then mixture is cooled to room temperature, under vacuum, removes acetate, and the gained resistates is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (21.4mg, 45%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：5.17(s，2H)7.19-7.61(m，7H)7.80(dd，J＝8.09，4.41Hz，1H)8.77(s，1H)8.97(d，J＝7.35Hz，1H)9.14(d，J＝2.94Hz，1H)10.88(s，1H)；MS(ESI+)m/z?365(M+H)+.
Embodiment 77
4-{2-benzyl-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amino]-4-benzyloxy-phenyl sulfenyl }-phenol
With the product of embodiment 27 (26.3mg, 0.062mmol), bromotoluene (0.0075mL, 0.062mmol) and salt of wormwood (8.6mg, 0.062mmol) at N, the solution in the dinethylformamide (0.5mL) was in stirring at room 16 hours.Then, mixture is poured in the frozen water (10mL), and with gained solution 1N hcl acidifying.Use ethyl acetate (3 x 10mL) to extract this solution then,, filter and under vacuum, concentrate the extract dried over mgso that merges, obtain this rough title compound it is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (6.7mg, 18%).
1H?NMR(300MH)z，DMSO-D6)δ?ppm：2.74(s，3H)5.10(s，2H)5.69(s，1H)6.65(d，J＝8.82Hz，2H)7.02-7.18(m，2H)7.14-7.26(m，1H)7.26-7.58(m，12H)7.86(s，1H)8.93(s，1H)9.23(s，1H)9.73(s，1H)12.09(s，1H)；MS(ESI+)m/z?557(M+H)+.
Embodiment 78
(5-benzyloxy-2-bromo-phenyl)-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Embodiment 78A
5-benzyloxy-2-bromo-phenyl amine
Make this title compound: Boger in accordance with the following methods, D.L., WysockL, RJ., Ishizaki, T.J.Am.Chem.Soc, 112,1990, p.5230-5240.The amount that obtains is 4.58g, 48%.
Embodiment 78B
(5-benzyloxy-2-bromo-phenyl)-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Will the product of the embodiment 78A in the acetate (15mL) (2.0g, 7.19mmol) and the product of embodiment 10B (1.35g 7.19mmol) was heated to 130 ℃ with 15 minutes from room temperature gradually in oil bath, then 130 ℃ of reheat 1.5 hours.Mixture is cooled to room temperature, under vacuum, concentrates, obtain this rough title compound (3.4g thickness red slurry, 100%), its part by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (81mg).
1H?NMR(300MHz，DMSO-d
6)δ?ppm：2.74(s，3H)，5.14(s，2H)，7.06(dd，J＝8.8，2.9Hz，1H)，7.23(m，1H)，7.41(m，5H)，7.70(d，J＝8.8Hz，1H)，7.78(d，J＝8.5Hz，1H)，8.79(s，1H)，8.91(d，J＝8.8Hz，1H)，11.40(bs，1H)；MS(ESI+)m/z?421/423(M+H)+.
Embodiment 79
2-chloro-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide
Embodiment 79A
N-(3-amino-phenyl)-2-chloro-benzamide
This title compound is prepared as follows: according to the method for embodiment 254A, substitute 4-bromo-Benzoyl chloride with 2-chloro-Benzoyl chloride, then with the method reduction nitro preparation of embodiment 255B, obtain this title compound.
Embodiment 79B
2-chloro-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide
Use the method for embodiment 254C, product with the product alternate embodiment 254B of embodiment 79A, the product of embodiment 79A and the product of embodiment 57A are reacted, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (18mg, 22%).
1H?NMR(300MHz，DMSO-D6)δppm：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 80
2-bromo-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide
Embodiment 80A
N-(3-amino-phenyl)-2-bromo-benzamide
This title compound is prepared as follows: according to the method for embodiment 254A, substitute 4-bromo-Benzoyl chloride with 2-bromo-Benzoyl chloride, the method for using embodiment 255B then obtains this title compound with nitroreduction.
Embodiment 80B
2-bromo-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide
The product of embodiment 80A and the product of embodiment 57A are reacted, use the method for embodiment 254C, product with the product alternate embodiment 254B of embodiment 80A, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (18mg, 22%).
1H?NMR(300MHz，DMSO-D6)δppm：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 81
2-methoxyl group-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide
Embodiment 81A
N-(3-amino-phenyl)-2-methoxyl group-benzamide
This title compound is prepared as follows: according to the method for embodiment 254A, substitute 4-bromo-Benzoyl chloride with 2-methoxyl group-Benzoyl chloride, with the method reduction nitro of embodiment 255B, obtain this title compound then.
Embodiment 81B
2-methoxyl group-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide
Method with embodiment 254C, product with the product alternate embodiment 254B of embodiment 81A, the product of embodiment 81A and the product of embodiment 57A are reacted, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (26mg, 33%).
1H?NMR(300MHz，DMSO-D6)δppm：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 82
3-methoxyl group-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide
Embodiment 82A
N-(3-amino-phenyl)-3-methoxyl group-benzamide
This title compound is prepared as follows: according to the method for embodiment 254A, substitute 4-bromo-Benzoyl chloride with 3-methoxyl group-Benzoyl chloride, the method for using embodiment 255B then obtains this title compound with nitroreduction.
Embodiment 82B
3-methoxyl group-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide
Use the method for embodiment 254C, product with the product alternate embodiment 254B of embodiment 82A, the product of embodiment 82A and the product of embodiment 57A are reacted, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (35mg, 45%).
1H?NMR(300MHz，DMSO-D6)δppm：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 83
3-fluoro-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide
Embodiment 83A
N-(3-amino-phenyl)-3-fluoro-benzamide
This title compound is prepared as follows: according to the method for embodiment 254A, substitute 4-bromo-Benzoyl chloride with 3-fluoro-Benzoyl chloride, the method for using embodiment 255B then obtains this title compound with nitroreduction.
Embodiment 83B
3-fluoro-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide
Use the method for embodiment 254C, product with the product alternate embodiment 254B of embodiment 83A, the product of embodiment 83A and the product of embodiment 57A are reacted, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (21mg, 28%).
1H?NMR(300MHz，DMSO-D6)δppm：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 84
4-[4-benzylamino-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 84A
4-(4-amino-2-nitro-phenyl sulfenyl)-phenol
With 4-chloro-3-N-methyl-p-nitroaniline (1.0g, 5.79mmol), the 4-hydroxythiophenol (0.75g, 6.00mmol), cesium carbonate (3.9g, 12mmol) solution in methyl-sulphoxide (10ml) in 100 ℃ the heating 16 hours.Then frozen water (50mL) is added in this solution, and the gained slurries are handled with methyl acetate (100ml).Layer is separated, and organic layer is washed with 10% sodium bicarbonate and 10% sodium-chlor, use anhydrous sodium sulfate drying then.Siccative is filtered, and under vacuum, remove and desolvate, obtain this title compound, be red solid (1.45g, 92%).
Embodiment 84B
4-(4-benzylamino-2-nitro-phenyl sulfenyl)-phenol
With the product 84A of embodiment (0.63g, 24mmol), phenyl aldehyde (0.24g, 2.3mmol) and sodium cyanoborohydride (0.15g, 2.4mmol) solution in the methyl alcohol that contains 1% acetate (10mL) was in stirring at room 16 hours.Reaction mixture water (20mL) is ended, and gained solution concentrates the acquisition yellow solid under vacuum.This solid is dissolved in the methyl acetate (50mL) water, 10% sodium bicarbonate and the washing of 10% sodium-chlor.With the organic layer anhydrous sodium sulfate drying, filter and under vacuum, remove and desolvate, obtain light yellow oil.This oily matter by the silica gel chromatography purifying, with the solution washing of 1% methyl alcohol in methylene dichloride, is obtained this title compound (0.63g, 77%).
Embodiment 84C
4-(2-amino-4-benzylamino-phenyl sulfenyl)-phenol
With the product 84B of embodiment (0.5g, 1.4mmol), iron powder (0.49g, 8.74mmol) and ammonium chloride (0.50g, 9.3mmol) solution in methyl alcohol (10mL), tetrahydrofuran (THF) (10mL) and water (5mL) is heated to and refluxed 1.5 hours.The gained mixture is diluted with methyl alcohol (50mL), and filter by Celite pad.Filtrate decompression is concentrated into the volume of 10mL,, and extracts with methyl acetate (2 x 50mL) with this solution with water (50mL) dilution.The extract that merges washs with 10% sodium-chlor, uses dried over mgso then, filters and concentrates under vacuum, obtains this title compound (0.30g, 66%).
Embodiment 84D
4-[4-benzylamino-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
With the product of embodiment 10B (30mg, 0.159mmol) and the product of embodiment 84C (56.5mg, 0.17mmol) solution in acetate (2mL) is preheating to 130 ℃ oil bath and was stirring 20 minutes.Then mixture is cooled to room temperature, under vacuum, removes acetate, and the gained resistates is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (12mg, 10%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.71(s，3H)，4.50(s，2H)，6.60-6.69(m，2H)，6.73-6.85(m，2H)，7.04-7.29(m，6H)，7.31-7.40(m，2H)，7.46(d，J＝7.35Hz，2H)，8.54(s，1H)，8.75(s，1H)，9.74(s，1H)；MS(ESI)m/z?466(M+H)+，(ESI-)m/z464(M-H)-.
Embodiment 85
N1-benzyl-4-(4-benzyloxy-phenyl sulfenyl)-N3-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-benzene-1, the 3-diamines
Embodiment 85A
4-(2-amino-4-nitro-phenyl sulfenyl)-phenol
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 the solution, and in the gained slurries, adds methyl acetate (200ml).Layer is separated, and organic layer is used anhydrous sodium sulfate drying with 10% sodium bicarbonate and the washing of 10% sodium-chlor.Siccative is filtered, and under vacuum, remove and desolvate, obtain yellow oil.This oily matter with methylene chloride (97: 3) wash-out, obtains this title compound by the silica gel chromatography purifying, is yellow solid (2.1g, 46%).
Embodiment 85B
2-(4-benzyloxy-phenyl sulfenyl)-5-nitro-phenyl amine
Product (the 0.2g that will contain embodiment 85A, 0.763mmole) and cesium carbonate (0.25g, 0.763mmole) the slurries in dimethyl formamide (5ml) with bromotoluene (0.091ml 0.763mmole) handles, and with the gained slurries in stirring at room 18 hours.Then frozen water (50mL) is added in the solution, and in the gained slurries, adds methyl acetate (50ml).Layer is separated, and organic layer uses layer is separated, and organic layer washs with 10% sodium bicarbonate and 10% sodium-chlor, use anhydrous sodium sulfate drying.Siccative is filtered, and under vacuum, remove and desolvate, obtain this title compound, be yellow solid (0.24g, 89%).
Embodiment 85C
[2-(4-benzyloxy-phenyl sulfenyl)-5-nitro-phenyl]-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
With the product of embodiment 10B (62mg, 0.331mmol) and the product 85B of embodiment (120mg, 0.331mmol) solution in acetate (1mL) is preheating to 130 ℃ oil bath and was stirring 20 minutes.Then mixture is cooled to room temperature, under vacuum, removes acetate, obtain brown oil (0.15g, 92%) as this title compound.This compound is used for next step under situation about not being further purified.
Embodiment 85D
4-(4-benzyloxy-phenyl sulfenyl)-N3-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-benzene-1, the 3-diamines
With the product of embodiment 85C (0.150g, 0.303mmole), iron powder (0.10g, 1.86mmol) and ammonium chloride (0.10g, 1.98mmol) solution in methyl alcohol (2mL), tetrahydrofuran (THF) (2mL) and water (1mL) is heated to and refluxed 1.5 hours.The gained mixture dilutes with methyl alcohol (50mL), and filters by Celite pad.Filtrate decompression is concentrated into the volume of 10mL,, and extracts with methyl acetate (2 x 50mL) with solution with water (50mL) dilution.The extract that merges washs with 10% sodium-chlor, uses dried over mgso then, filters and concentrates under vacuum, obtains this title compound (0.06g, 42%).
Embodiment 85E
N1-benzyl-4-(4-benzyloxy-phenyl sulfenyl)-N3-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-benzene-1, the 3-diamines
With the compound for preparing among the embodiment 85D (0.06g, 0.130mmole), phenyl aldehyde (0.013g, 0.130mmole) and sodium cyanoborohydride (0.0081g, 0.13mmole) at the mixture that contains a methyl alcohol (1ml) in stirring at room 18 hours.Under vacuum, remove and desolvate, and the gained resistates is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (12mg, 17%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.69(s，3H)，4.30(s，2H)，4.96(s，2H)，6.60(dd，J＝8.46，2.57Hz，1H)，6.72-6.89(m，3H)，6.94-7.09(m，2H)，7.19-7.29(m，1H)，7.29-7.46(m，11H)，7.63(d，J＝8.46Hz，1H)，8.61(s，1H)，8.71(d，J＝8.82Hz，1H)，10.69(s，1H).
Embodiment 86
4-[4-[(furans-3-ylmethyl)-amino]-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 86A
4-[2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-nitro-phenyl sulfenyl]-phenol
With the product of embodiment 10B (340mg, 1.80mmol) and the product of embodiment 85A (480mg, 1.80mmol) solution in acetate (10mL) is preheating to 130 ℃ oil bath and was stirring 30 minutes.Then mixture is cooled to room temperature, under vacuum, removes acetate, obtain brown oil (0.65g, 89%) as this title compound.
Embodiment 86B
4-[4-amino-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
With the product of embodiment 86A (0.19g, 0.469mmol) and the slurries of 10% Pd/C (0.025g) in acetate (3ml) under hydrogen in stirring at room 2 hours.Dope filtration, and under vacuum, remove and desolvate, obtain the acetate of this title compound, be brown solid (0.21g, 91%).
Embodiment 86C
4-[4-[(furans-3-ylmethyl)-amino]-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
With the product of embodiment 86B (69.7mg, 0.141mmol), the 3-furtural (13.5mg, 0.141mmol) and sodium cyanoborohydride (8.7mg, 0.141mmol) solution in 2ml methyl alcohol is in stirring at room 18.Vaporising under vacuum desolvates, and the gained resistates is passed through the HPLC purifying, uses the TFA wash-out, obtains this title compound, is trifluoroacetic acid salt form (16mg, 14%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.75(s，3H)，3.85(s，1H)，4.09(s，2H)，6.47(s，1H)，6.53(d，J＝8.82Hz，2H)，6.62-6.75(m，2H)，6.94(d，J＝8.46Hz，3H)，7.21-7.32(m，1H)，7.61(s，1H)，7.83(d，J＝8.46Hz，1H)，8.77(s，1H)，8.88(s，1H)，9.51(s，1H)，11.68(s，1H).
Embodiment 87
4-{2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-[(thiene-3-yl-methyl)-amino]-the phenyl sulfenyl }-phenol
According to the method for embodiment 86C, substitute the 3-furtural with the 3-thiophenecarboxaldehyde, the solution of the product of embodiment 86B is reacted with the 3-thiophenecarboxaldehyde, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (26mg, 37%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.74(s，3H)，3.74(s，1H)，4.26(s，2H)，6.52(d，J＝8.82Hz，3H)，6.64-6.76(m，1H)，6.86-6.99(m，3H)，7.02-7.14(m，1H)，7.19-7.34(m，1H)，7.42-7.54(m，1H)，7.82(d，J＝8.09Hz，1H)，8.76(s，1H)，8.90(s，1H)，9.51(s，1H)，11.65(s，1H).
Embodiment 88
4-{2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-[(naphthalene-1-ylmethyl)-amino]-the phenyl sulfenyl }-phenol
According to the method for embodiment 86C, substitute the 3-furtural with the 1-naphthaldehyde, the solution of the product of embodiment 86B is reacted with the 1-naphthaldehyde, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (18mg, 12%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.73(s，3H)，4.73(s，1H)，6.39(s，1H)，6.45-6.60(m，2H)，6.67-6.80(m，1H)，6.88-6.98(m，2H)，7.17-7.34(m，1H)，7.43-7.54(m，1H)，7.51-7.71(m，4H)，7.71-7.83(m，1H)，7.83(d，J＝8.82Hz，1H)，7.95-8.09(m，2H)，8.10-8.18(m，1H)，8.22(d，J＝8.09Hz，1H)，8.76(s，1H)，8.82-8.89(m，1H)，9.51(s，1H)，11.64(s，1H).
Embodiment 89
4-[4-[(furans-2-ylmethyl)-amino]-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
According to the method for embodiment 86C, substitute the 3-furtural with 2 furan carboxyaldehyde and obtain crude product, the solution of the product of embodiment 86B is reacted with 2 furan carboxyaldehyde, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (18mg, 16%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.69-2.81(m，3H)，4.26(s，2H)，6.27-6.44(m，1H)，6.45-6.59(m，2H)，6.46-6.60(m，3H)，6.68-6.78(m，2H)，6.89-7.00(m，2H)，7.20-7.33(m，1H)，7.59(s，1H)，7.84(d，J＝8.09Hz，1H)，8.77(s，1H)，8.89(s，1H)，11.73(s，1H).
Embodiment 90
4-{2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-[(thiophene-2-ylmethyl)-amino]-the phenyl sulfenyl }-phenol
According to the method for embodiment 86C, substitute the 3-furtural with 2 thiophene carboxaldehyde and obtain crude product, the solution of the product of embodiment 86B is reacted with 2 thiophene carboxaldehyde, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (11mg, 16%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.64-2.86(m，3H)，4.47(s，2H)，6.46-6.57(m，2H)，6.64-6.78(m，3H)，6.87·7.00(m，3H)，7.02-7.13(m，2H)，7.19-7.31(m，2H)，7.32-7.48(m，1H)，7.82(d，J＝8.82Hz，1H)，8.77(s，1H)，8.89(s，1H)，9.50(s，1H)，11.68(s，1H).
Embodiment 91
4-[4-(4-bromo-benzylamino)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 91A
4-[4-(4-bromo-benzylamino)-2-nitro-phenyl sulfenyl]-phenol
Solution and the reaction of 4-bromobenzaldehyde with the product of embodiment 84A, method according to embodiment 84B, obtain crude product with 4-bromobenzaldehyde alternate embodiment 84A, it is passed through the silica gel chromatography purifying, with the eluant solution of 2% methyl alcohol in methylene dichloride, obtain this title compound, be yellow solid (0.11g, 73%).
Embodiment 91B
4-[2-amino-4-(4-bromo-benzylamino)-phenyl sulfenyl]-phenol
The solution of the product of embodiment 91A is reacted according to the method for embodiment 84C, obtain this title compound (0.17g, 76%).
Embodiment 91C
4-[4-(4-bromo-benzylamino)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
With the product of embodiment 10B (50mg, 0.266mmol) and the product of embodiment 91B (110mg, 0.266mmol) solution in acetate (2mL) is preheating to 130 ℃ oil bath and was stirring 20 minutes.Then mixture is cooled to room temperature, under vacuum, removes acetate, and the gained resistates is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (22mg, 15%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.73(s，3H)，4.26(s，2H)，6.53(d，J＝8.46Hz，2H)，6.54-6.69(m，2H)，6.85-7.03(m，2H)，7.23(d，J＝8.46Hz，1H)，7.30(d，J＝8.46Hz，3H)，7.46-7.61(m，2H)，7.78(d，J＝8.46Hz，1H)，8.73(s，1H)，8.89(d，J＝19.12Hz，1H)，9.51(s，1H)，11.46(s，1H).
Embodiment 92
N1-benzyl-4-(4-methoxyl group-phenyl sulfenyl)-N3-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-benzene-1, the 3-diamines
4-(4-methoxyl group-phenyl sulfenyl)-3-nitro-phenyl amine
Embodiment 92A
With 4-chloro-3-N-methyl-p-nitroaniline (1.0g, 5.79mmol), the 4-methoxybenzenethiol (0.84g, 6.00mmol), cesium carbonate (1.95g, 6.00mmol) solution in dimethyl formamide (10ml) in 100 ℃ the heating 16 hours.Then frozen water (50mL) is added in this solution, and the gained slurries are handled with methyl acetate (100ml).Layer is separated, and organic layer is used anhydrous sodium sulfate drying then with 10% sodium bicarbonate and the washing of 10% sodium-chlor.Siccative is filtered, and under vacuum, remove and desolvate, obtain this title compound, be red solid (1.5g, 94%).
Embodiment 92B
Benzyl-[4-(4-methoxyl group-phenyl sulfenyl)-3-nitro-phenyl]-amine
With the product of embodiment 92A (0.50g, 1.81mmol), phenyl aldehyde (0.19g, 1.81mmol) and sodium cyanoborohydride (0.11g, 1.8mmol) solution in the methyl alcohol that contains 1% acetate (10mL) was in stirring at room 16 hours.This reaction mixture water (20mL) is ended, and with gained solution simmer down to yellow solid under vacuum.This solid is dissolved in the methyl acetate (50mL), and water, 10% sodium bicarbonate and the washing of 10% sodium-chlor.The organic layer anhydrous sodium sulfate drying filters and removes under vacuum and desolvate, and obtains light yellow oil.This oily matter with the eluant solution of 1% methyl alcohol in methylene dichloride, obtains this title compound by the silica gel chromatography purifying, is brick-red solid (0.62g, 91%).
Embodiment 92C
N1-benzyl-4-(4-methoxyl group-phenyl sulfenyl)-benzene-1, the 3-diamines
The solution of the product of embodiment 92B is reacted according to the method for embodiment 84C, obtain this title compound (0.49g, 89%).
Embodiment 92D
N1-benzyl-4-(4-methoxyl group-phenyl sulfenyl)-N3-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-benzene-1, the 3-diamines
With the product of embodiment 10B (27.8mg, 0.148mmol) and the product of embodiment 92C (49mg, 0.148mmol) solution in acetate (2mL) is preheating to 130 ℃ oil bath and was stirring 20 minutes.Then mixture is cooled to room temperature, under vacuum, removes acetate, and the gained resistates is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (15mg, 14%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.64-2.81，(m，3H)3.56-3.71，(m，3H)4.29(s，2H)，6.61-6.75(m，3H)，6.95-7.07(m，2H)，7.16-7.45(m，8H)，7.76(d，J＝8.46Hz，1H)，8.69(s，1H)，8.80(d，1H)，11.34(s，1H).
Embodiment 93
N1-benzyl-4-(4-methoxyl group-phenoxy group)-N3-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-benzene-1, the 3-diamines
Embodiment 93A
4-(4-methoxyl group-phenoxy group)-3-nitro-phenyl amine
With 4-chloro-3-N-methyl-p-nitroaniline (1.0g, 5.79mmol), the 4-methoxyphenol (0.74g, 6.00mmol), cesium carbonate (1.95g, 6.00mmol) solution in dimethyl formamide (10ml) in 100 ℃ the heating 16 hours.Then frozen water (50mL) is added in this solution, and the gained slurries are handled with methyl acetate (100ml).Layer is separated, and organic layer is used anhydrous sodium sulfate drying then with 10% sodium bicarbonate and the washing of 10% sodium-chlor.Siccative is filtered, and under vacuum, remove and desolvate, obtain this title compound, be red solid (1.1g, 73%).
Embodiment 93B
N1-benzyl-4-(4-methoxyl group-phenoxy group)-benzene-1, the 3-diamines
According to the method for embodiment 92B, with the product of the product alternate embodiment 92A of embodiment 93A, the solution of the product of embodiment 93A is reacted, according to embodiment 84C with its reduction, obtain this title compound (0.05g, 12%).
Embodiment 93C
N1-benzyl-4-(4-methoxyl group-phenoxy group)-N3-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-benzene-1, the 3-diamines
According to the method for embodiment 92D,, the solution of the product of the embodiment 10B product with embodiment 93B is reacted with the product of the product alternate embodiment 92C of embodiment 93B, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (8mg, 18%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.55-2.68(m，3H)，3.61(s，3H)，4.26(d，J＝5.88Hz，2H)，6.27(t，J＝5.88Hz，1H)，6.50(dd，J＝8.64，2.76Hz，1H)，6.64-6.87(m，6H)，7.18-7.45(m，6H)，8.48(s，1H)，8.57(d，J＝8.46Hz，1H)，9.59(s，1H).
Embodiment 94
N1-benzyl-4-(4-benzyloxy-phenoxy group)-N3-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-benzene-1, the 3-diamines
Embodiment 94A
4-(4-benzyloxy-phenoxy group)-3-nitro-phenyl amine
With 4-chloro-3-N-methyl-p-nitroaniline (2.0g, 11.16mmol), 4-benzyloxy phenol (2.55g, 12.76mmol), powdered potassium hydroxide (0.94g, 16.80mmol) dimethyl formamide (15ml) in 120 ℃ the heating 20 hours.Then frozen water (50mL) is added in this solution, and the gained slurries are handled with methyl acetate (100ml).Layer is separated, and organic layer is used anhydrous sodium sulfate drying then with 10% sodium bicarbonate and the washing of 10% sodium-chlor.Siccative is filtered, and under vacuum, remove and desolvate, obtain dark red solid (2.07g, 53%) as this title compound.
Embodiment 94B
N1-benzyl-4-(4-benzyloxy-phenoxy group)-benzene-1, the 3-diamines
According to the method for embodiment 92B, with the product of the product alternate embodiment 92A of embodiment 94A, the solution of the product of embodiment 94A is reacted, according to the method for embodiment 84C it is reduced, obtain this title compound (0.6g, 91%).
Embodiment 94C
N1-benzyl-4-(4-benzyloxy-phenoxy group)-N3-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-benzene-1, the 3-diamines
According to the method for embodiment 92D,, the solution of the product of the embodiment 10B product with embodiment 94B is reacted with the method for the product alternate embodiment 92C of embodiment 94B, it is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (12mg.10%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.70(s，3H)，4.27(s，2H)，4.94(s，2H)，4.99-5.12(m，1H)，6.64(dd，J＝8.82，2.94Hz，1H)，6.70-6.92(m，9H)，6.90-7.00(m，1H)，7.16-7.29(m，1H)，7.31-7.42(m，5H)，7.70(d，J＝8.46Hz，1H)，8.67-8.86(m，2H)，11.22(s，1H).
Embodiment 95
4-[4-amino-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 95A
4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-nitro-phenyl sulfenyl]-phenol
With the product of embodiment 10B (340mg, 2.31mmol) and the product of embodiment 85A (610mg, 2.30mmol) solution in acetate (10mL) is preheating to 130 ℃ oil bath and was stirring 10 minutes.Then mixture is cooled to room temperature, under vacuum, removes acetate, obtain brown oil (0.92g, 92%) as this title compound.
Embodiment 95B
4-[4-amino-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
With the compound for preparing among the embodiment 95A (0.7g, 1.73mmol) and 10%Pd/C (100
Mg) slurries in acetate (10ml) and methyl alcohol (10mL) place under the hydrogen capsule atmosphere in stirring at room 20 hours.With this dope filtration, and under vacuum, remove and desolvate, obtain this title compound, be acetate form (540mg, 63%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝7.0Hz，6H)，1.91(s，6H)，3.27(m，1H)，6.55(d，J＝8.8Hz，2H)，6.62(m，1H)，6.69(m，1H)，6.95(d，J＝8.8Hz，2H)，7.20(d，J＝8.5Hz，1H)，7.87(d，J＝8.5Hz，1H)，7.95(s，1H)，8.75(s，1H)，8.99(m，1H)，9.52(s，1H)，11.57(bs，1H)；MS(ESI+)m/z?404(M+H)+.
Embodiment 96
4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-styroyl amino-phenyl sulfenyl]-phenol
To contain embodiment 95B product (65mg, 0.124mmole), phenyl acetaldehyde (15mg, 0.124mmole) and sodium cyanoborohydride (10mg, 0.199mmole) solution in 2ml methyl alcohol was in stirring at room 18 hours.Vaporising under vacuum desolvates, and the gained resistates is passed through the HPLC purifying, uses the TFA wash-out, obtains this title compound, is trifluoroacetic acid salt form (25mg, 32%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.28(d，6H)，2.31-2.48(m，1H)，2.78-2.93(m，2H)，3.16-3.35(m，2H)，4.17-4.36(m，2H)，4.73·4.91(m，1H)，6.47-6.59(m，2H)，6.61-6.74(m，1H)，6.86-7.01(m，2H)，7.10(d，J＝6.99Hz，1H)，7.15-7.27(m，1H)，7.19-7.39(m，6H)，7.89(d，J＝8.46Hz，1H)，8.77(s，1H)，8.96(s，1H)，9.50(s，1H)，11.61(s，1H).
Embodiment 97
4-[4-(cyclopentyl-methyl-amino)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
According to the method for embodiment 96, substitute phenyl acetaldehyde with pentamethylene formaldehyde, will contain the solution and the pentamethylene formaldehyde reaction of the product of embodiment 95B, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (11mg, 9%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.26-1.43(m，6H)，1.53(s，4H)，1.75(d，J＝3.31Hz，4H)，2.01-2.19(m，1H)，2.92(d，J＝6.99Hz，2H)，3.20-3.36(m，1H)，6.53(d，J＝8.82Hz，2H)，6.58-6.73(m，1H)，6.87-7.00(m，2H)，6.98-7.13(m，1H)，7.17-7.36(m，1H)，7.89(s，1H)，8.15(s，1H)，8.77(s，1H)，8.95(s，1H)，9.49(s，1H)，10.98(s，1H)，11.68(s，1H).
Embodiment 98
N1-benzyl-N3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-4-(4-methoxyl group-phenyl sulfenyl)-benzene-1, the 3-diamines
With the product of embodiment 36E (40.4mg, 0.187mmol) and the product of embodiment 92C (62.8mg, 0.187mmol) solution in acetate (2mL) is preheating to 140 ℃ oil bath and was stirring 45 minutes.Reaction is cooled to room temperature,, concentrates by rotary evaporation, with dichloromethane/hexane co-evaporated (4x) with hexane (50mL) dilution.Resistates is dry under vacuum, then by flash chromatography on silica gel method purifying, substitute wash-out as eluent with 15%-20% methyl acetate/methylene dichloride, obtain this title compound, be yellow solid (29.6mg, 31%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.31(d，J＝6.99Hz，6H)3.11-3.26(m，1H)3.64(s，3H)4.30(d.J＝5.88Hz，2H)6.53(dd，J＝8.46，2.57Hz，1H)6.66-6.78(m，3H)6.95(d，J＝2.21Hz，1H)7.03(d，J＝8.82Hz，2H)7.12-7.28(m，2H)7.28-7.44(m，4H)7.54(d，J＝8.46Hz，1H)8.50(s，1H)8.65(d，J＝8.46Hz，1H)9.75(s，1H)；MS(DCI/NH
3)m/z?508(M+H)
+.
Embodiment 99
4-[2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-pyrroles-1-base-phenyl sulfenyl]-phenol
To the product of embodiment 86B (50mg, 0.101mmol) and amber dialdehyde (40% in water solution) (0.065mL, 0.303mmol) adding 4A molecular sieve (100mg) in the solution in toluene (5mL) and methyl alcohol (3mL).Then mixture was stirred 7 hours in 60 ℃, be cooled to room temperature, remove under the vacuum and desolvate, add 0.1N aqueous hydrochloric acid (20mL), and mixture is extracted with methylene dichloride (2 x 25mL) and diox (25mL).With the organic extract drying that merges, under vacuum, concentrate, the gained resistates is used the TFA wash-out by the HPLC purifying then, obtains this title compound, is trifluoroacetic acid salt form (14mg, 26%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.68(s，3H)，6.26(m，2H)，6.77(d，J＝8.5Hz，2H)，7.05(d，J＝8.5Hz，1H)，7.24(d，J＝8.5Hz，2H)，7.37(m2H)，7.48(dd，J＝8.6，2.4Hz，1H)，7.57(d，J＝8.5Hz，1H)，7.73(d，J＝2.6Hz，1H)，8.57(s，1H)，8.80(d，J＝8.4Hz，1H)，9.81(s，1H)，10.11(s，1H)；MS(ESI+)m/z?426(M+H)+.
Embodiment 100
4-[2,4-two-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
With the product of embodiment 86B (50mg, 0.101mmol) and the product of embodiment 10B (19mg, 0.101mmol) solution in acetate (1mL) be heated to 120 ℃ 2 hours.After being cooled to room temperature, under vacuum, removing and desolvate, and add methyl alcohol (2mL).Collect the gained solid, and, obtain this title compound, be light brown solid (12mg, 23%) with the methyl alcohol development.
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.67(s，3H)，2.68(m，3H)，6.75(d，J＝8.8Hz，2H)，6.83(m，1H)，7.12(m，1H)，7.21(d，J＝8.8Hz，2H)，7.34(m，1H)，7.58(m，J＝8.8Hz，2H)，8.73(s，1H)，8.81(m，1H)，8.88(m，1H)，9.76(s，1H)，10.13(s，1H)，11.95(bs，1H)；MS(ESI+)m/z?519(M+H)+.
Embodiment 101
4-[4-(4-bromo-benzylamino)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
According to the method for embodiment 96, substitute phenyl acetaldehyde with 4-bromo-phenyl aldehyde, will contain the solution and the reaction of 4-bromo-phenyl aldehyde of the product of embodiment 95B, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (7mg, 3%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.6Hz，6H)，3.30(m，1H)，6.55(d，J＝8.5Hz，2H)，6.68(m，1H)，6.76(d，J＝8.8Hz，2H)，6.91(m，1H)，6.98(d，J＝8.5Hz，2H)，7.27(d，J＝8.8Hz，2H)，7.32(m，1H)，7.56(m，2H)，8.78(s，1H)，9.53(m，1H)；MS(ESI+)m/z?574(M+H)+.
Embodiment 102
4-[4-methyl-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
With the product of embodiment 10B (100mg, 0.575mmol) and the product of embodiment 6c (146mg, 0.632mmol) solution in acetate (1mL) was in 130 ℃ of heating 1 hour.Then mixture is cooled to room temperature, then methyl alcohol (5mL) is added in this solution, collect the gained solid, and use methanol wash, obtain this title compound (120mg, 56%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.29(s，3H)，2.66(s，3H)，6.73(d，J＝8.8Hz，2H)，6.93(m，1H)，7.03(m，1H)，7.18(d，J＝8.5Hz，2H)，7.26，(s，1H)，7.53(d，J＝8.5Hz，1H)，8.53(s，1H)，8.77(m，1H)，9.76(bs，1H)，9.96(bs，1H)；MS(ESI)+m/z?375(M+H)+.
Embodiment 103
(5-methyl-2-phenyl sulfenyl-phenyl)-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
With the product of embodiment 10B (90mg, 0.517mmol) and the product of embodiment 51 (122mg, 0.569mmol) solution in acetate (1mL) was in 130 ℃ of heating 1 hour.Then mixture is cooled to room temperature, collects the gained solid and use methanol wash, then with this material dissolves of 50mg in diox (2mL), and add hydrochloric acid, then under the vacuum except that desolvating, obtain this title compound, be hydrochloride form.
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.37(s，3H)，2.74(s，3H)，7.18(m，5H)，7.24(m，1H)，7.37(m，2H)，7.81(d，J＝8.5Hz，1H)，8.80(s，1H)，8.99(d，J＝8.5Hz，1H)，11.82(bs，1H)；MS(ESI)+m/z?359(M+H)+.
Embodiment 104
[3-(3-bromo-phenoxymethyl)-phenyl]-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Embodiment 104A
1-nitro-3-(3-bromo-phenoxymethyl)-benzene
With the 3-nitrobenzyl chloride (1.0g, 5.83mmol), the 3-bromophenol (1.01g, 5.83mmol) and salt of wormwood (806mg 5.83mmol) is heated at acetone (25mL) and refluxed 23 hours.After the cooling, cross the elimination solid, and filtrate is condensed into yellow residue under vacuum, it is dissolved in the methyl acetate (50mL), and with 1N aqueous sodium hydroxide solution (25mL) and water (25mL) washing, under vacuum, concentrate then, obtain this title compound, be white solid (1.64g, 91%).
Embodiment 104B
3-(3-bromo-phenoxymethyl)-phenyl amine
With the product of embodiment 104A (1.64g, 5.32mmol), iron powder (1.49g, 26.62mmol) and ammonium chloride (430mg, 7.98mmol) solution in the mixture of tetrahydrofuran (THF) (20mL), water (6mL) and ethanol (20mL) is heated to and refluxed 3 hours.Mixture is cooled to room temperature, filters, use washing with alcohol, and gained filtrate is concentrated under vacuum by Celite pad.Then this material dissolves in water (50mL), and,, and under vacuum, concentrate the organic layer drying with methyl acetate (50mL) extraction, obtain this title compound, be yellow oil (1.43g, 97%).
Embodiment 104C
[3-(3-bromo-phenoxymethyl)-phenyl]-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
With the product of embodiment 10C (50mg, 0.266mmol) and the product of embodiment 104B (74mg, 0.266mol) the solution of acetate (3mL) be heated to 130 ℃ 30 minutes.After being cooled to room temperature, solution decompression is concentrated, and, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (62mg, 44%) by the HPLC purifying.
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.71(s，3H)，5.20(s，2H)，7.05(m，1H)，7.16(m，1H)，7.24(m，2H)，7.33(m，1H)，7.49(t，J＝7.7Hz，1H)，7.70(d，J＝8.5Hz，1H)，7.79(m，1H)，7.84(s，1H)，8.83(s，1H)，8.96(d，J＝8.4Hz，1H)，10.75(bs，1H)；MS(ESI)+m/z?421/423(M+H)+.
Embodiment 105
(3 '-methoxyl group-5-methyl-xenyl-3-yl)-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Embodiment 105A
3-bromo-5-methyl-phenyl amine
Use the condition of embodiment 104B, (1.08g 5.0mmol) prepares this title compound, obtains this title compound, is orange (0.8g, 86%) by 3-bromo-5-nitrotoluene.
Embodiment 105B
(3-bromo-5-methyl-phenyl)-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine [0454]
Product (0.8g with embodiment 105A, 4.3mmol) with the reaction of the product of embodiment 10C, use the method for embodiment 104C, product with the product alternate embodiment 104B of embodiment 105A, obtain crude product, it by the silica gel chromatography purifying, is obtained this title compound with the 99:1 methylene chloride, be yellow powder (1.1g, 77%).
Embodiment 105C
(3 '-methoxyl group-5-methyl-xenyl-3-yl)-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Product (0066g with embodiment 105B, 0.2mmol), 3-anisole ylboronic acid (0.043g, 0.28mmol), cesium carbonate (0.1g, 0.3mmol) and dichloro two (triphenylphosphine) palladium (II) (0.014g, 0.02mmol) at N, dinethylformamide (1mL) mixes, and be heated to 100 ℃ 24 hours.After being cooled to room temperature, mixture is poured in the frozen water (20mL), and with gained solution 1N hcl acidifying.With this solution of ethyl acetate extraction (3 x 10mL),, filter and under vacuum, concentrate then, crude product by the HPLC purifying, is used the TFA wash-out, obtain this title compound, trifluoroacetate (12mg, 13%) the extract dried over sodium sulfate that merges.
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.45(s，3H)，2.75(s，3H)，3.83(s，3H)，6.98(dd，J＝7.72，2.21Hz，1H)，7.20(d，J＝2.21Hz，1H)，7.25(d，J＝8.09Hz，1H)，7，41(t，J＝7.91Hz，1H)，7.48(s，1H)，7.56(s，1H)，7.82(d，J＝5.15Hz，1H)，7.83(d，J＝3.31H2，1H)，8.96(s，1H)，9.03(d，J＝8.46Hz，1H)，11.34(s，1H)；MS(ESI)+m/z?357(M+H)+.
Embodiment 106
2-2-(4-methoxyl group-phenyl)-ethyl]-5-methyl-phenyl }-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl) amine
Embodiment 106A
1-[2-(4-methoxyl group-phenyl)-vinyl-4-methyl-2-nitro-benzene
1-bromo-4-methyl-2-nitro-benzene (0.76g, 3.5mmol), 1-methoxyl group-4-vinyl-benzene (0.59g, 4.4mmol), triethylamine (0.88g, 8.8mmol), three-o-tolyl phosphine (0.022g) and acid chloride (0.008g) be at N, the solution in the dinethylformamide (7mL) is inserted in the high pressure pipe and with nitrogen purging 10 minutes.With the seal of tube, and in 120 ℃ the heating hour.With the mixture water be adjusted between the methyl acetate and distribute, regulate pH to 3.Organic layer is filtered with salt water washing, drying (sodium sulfate) and by the tripoli pad.Filtrate is concentrated under vacuum, and resistates is developed with hexane/methyl acetate (9:1), obtain this title compound (0.55g, 58%).
Embodiment 106B
2-[2-(4-methoxyl group-phenyl)-ethyl]-5-methyl-phenyl amine
To the solution of embodiment 106A (164mg, 0.6mmol) and the solution of 10% palladium on carbon (50mg) in ethanol (20ml) with hydrogen capsule hydrogenation three days.Solvent by diatomite filtration, is used washing with alcohol, and dry under vacuum, obtain this title compound (140mg, 97%).
Embodiment 106C
2-2-(4-methoxyl group-phenyl)-ethyl]-5-methyl-phenyl }-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl) amine
Use the method for embodiment 104C, method with the method alternate embodiment 104B of embodiment 106B, the product of embodiment 106B and the product of embodiment 10C are reacted, obtain crude product, it is passed through chromatography purification on silica, obtain this title compound (53mg, 69%) with the 99:1 methylene chloride.
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.30.(s，3H)，2.69(m，7H)，3.64(s，3H)，6.69(d，J＝8.8Hz，2H)，6.89(d，J＝8.8Hz，2H)，7.08(d，J＝7.7Hz，1H)，7.13(s，1H)，7.22(d，J＝7.7Hz，1H)，7.53(d，J＝8.5Hz，1H)，8.50(s，1H)，8.79(d，J＝8.5Hz，1H)，9.83(s，1H)；(ESI+)m/z?385(M+H)+.
Embodiment 107
4-[4-methyl-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Use the method for embodiment 10F, product with the product alternate embodiment 10E of embodiment 6c, and product with the product alternate embodiment 10B of embodiment 57A, product reaction with the product of the product of embodiment 6c and embodiment 57A, obtain thick resistates, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.31(s，3H)，6.61-6.78(m，2H)，7.02(d，J＝8.09Hz，1H)，7.11-7.20(m，3H)，7.24(s，1H)，7.87(dd，J＝8.46，4.41Hz，1H)，8.79(s，1H)，9.03(d，J＝8.46Hz，1H)，9.14-9.19(m，1H)，9.79(s，1H)；MS(ESI+)m/z?361(M+H)+.
Embodiment 108
(5-methyl-2-phenyl sulfenyl-phenyl)-pyrido [2,3-d] pyrimidine-4-base-amine
Use the method for embodiment 10F, product with the product alternate embodiment 10E of embodiment 51, and with the product of the product alternate embodiment 10B of embodiment 57A, the product of embodiment 51 and the product of embodiment 57A are reacted, obtain thick resistates, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.37(s，3H)，7，09-7.27(m，6H)，7.35(d，J＝7.72Hz，2H)，7.83(dd，J＝8.09，4，41Hz，1H)，8.75(s，1H)，8.96(d，J＝7.72Hz，1H)，9.13(d，J＝3.31Hz，1H)；MS(ESI+)m/z?345(M+H)+.
Embodiment 109
N-{4-[4-methyl-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide }
Use the method for embodiment 10F, product with the product alternate embodiment 10E of embodiment 7b, and product with the product alternate embodiment 10B of embodiment 57A, the product of embodiment 7b and the product of embodiment 57A are reacted, obtain thick resistates, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.02(s，3H)，2.34(s，3H)，7.13-7.35(m，5H)，7.46(d，J＝8.46Hz，2H)，7.87(dd，J＝8.09，4.41Hz，1H)，8.80(s，1H)，9.01(d，J＝8.09Hz，1H)，9.15(d，J＝3.31Hz，1H)，9.99(s，1H)；MS(ESI+)m/z?402(M+H)+.
Embodiment 110
4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenol
Use the method for embodiment 36I, use the product of the product alternate embodiment 36H of embodiment 6c, the product of embodiment 6c and the product of embodiment 36E are reacted, obtain thick resistates, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm；1.35(d，J＝6.62Hz，6H)，2.31(s，3H)，3.29(t，J＝6.89Hz，1H)，6.70(d，J＝8.82Hz，2H)，7.01(d，J＝8.09Hz，1H)，7.17(d，J＝8.82Hz，2H)，7.13-7.22(m，2H)，7.23(s，1H)，7.87(d，J＝8.82Hz，1H)，8.79(s，1H)，8.97(d，J＝8.82Hz，1H)，9.80(s，1H)，11.42(s，1H)；MS(ESI+)m/z?403(M+H)+.
Embodiment 111
2-chloro-4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenol
To the product of embodiment 110 (50mg, 0.124mmol) in the solution in acetate (1.5mL) in room temperature drip SULPHURYL CHLORIDE (0.01mL, 0.124mmol).With mixture restir 30 minutes, under vacuum, concentrate then, and, use the TFA wash-out by the HPLC purifying, obtain this title compound, be trifluoroacetic acid salt form (19mg, 28%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.6HZ，6H)，2.34(s，3H)，3.30(m，1H)，6.82(d，J＝8.5Hz，1H)，7.08(dd，J＝8.5，2.2Hz，1H)，7.17(m，1H)，7.24(m，3H)，8.74(s，1H)，8.94(d，J＝8.5Hz，1H)，10.50(s，1H)，11.42(bs，1H)；MS(ESI+)m/z?437(M+H)+.
Embodiment 112
2,6-two chloro-4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenol
To the product of embodiment 110 (50mg, 0.124mmol) in the solution in acetate (1.5mL) in room temperature drip SULPHURYL CHLORIDE (0.02mL, 0.248mmol).With mixture restir 30 minutes, under vacuum, concentrate then, and, use the TFA wash-out by the HPLC purifying, obtain this title compound, be trifluoroacetic acid salt form (17mg, 23%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.6Hz，6H)，2.37(s，3H)，3.28(m，1H)，7，12(s，1H)，7.28(m，2H)，7.46(d，J＝8.1Hz，1H)，7.83(d，J＝8.5Hz，1H)，8.70(s，1H)，8.88(d，J＝8.8Hz，1H)，10.38(s，1H)，11.22(bs，1H)；MS(ESI+)m/z?472(M+H)+.
Embodiment 113
4-[4-hydroxymethyl-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 113A
4-(4-hydroxyl-phenyl sulfenyl)-3-nitro-methyl benzoate
With 4-chloro-3-nitro-methyl benzoate (4.0g, 18.55mmol) at anhydrous N, the solution in the dinethylformamide (25mL) in room temperature with the 4-mercapto-phenol (2.34g, 18.55mmol) and cesium carbonate (9.07g, 27.83mmol) processing is 23 hours.Under vacuum, remove then and desolvate, resistates is dissolved in the water (100mL) by rotary evaporation, and with the 1N HCl aqueous solution with pH regulator to 3.The aqueous solution is extracted with methyl acetate (2 x 100mL), and the organic extract that merges washs with salt solution (50mL).The organic layer dried over mgso is filtered, and concentrates by rotary evaporation, obtains the product as orange, and it contains N, dinethylformamide (7.28g) impurity.
Embodiment 113B
3-amino-4-(4-hydroxyl-phenyl sulfenyl)-methyl benzoate
Product (as the DMF adducts) (7.25g with embodiment 113A, 19.23mmol), ammonium chloride (1.54g, 28.8mmol) and iron powder (5.37g, the 96.15mmol) heating 3 hours under refluxing of the suspension in tetrahydrofuran (THF) (75mL), water (25mL) and ethanol (75mL).Reaction is cooled to room temperature, and mixture filters by Celite pad, then it used methanol wash, and under vacuum with filtrate simmer down to solid.Then resistates is dissolved in the water (100mL), and extracts with methylene dichloride (2 x 50mL).The organic extract that merges is used dried over mgso with salt solution (25mL) washing, filters, and concentrates under vacuum, obtains this title compound, is white solid (4.2g, 79%).
Embodiment 113C
4-(2-amino-4-hydroxy methyl-phenyl sulfenyl)-phenol
In the product of the embodiment 113B in tetrahydrofuran (THF) (50mL) (500mg, 1.82mmol) in room temperature drip solutions of lithium aluminium hydride (solution of 1.0M in THF, 1.8mL, 1.82mmol), then with mixture heating up to 70 ℃ 4 hours.Then water (25mL) is added in this solution carefully, and organic layer is separated, dry and concentrated under vacuum, obtain this title compound (295mg, 66%).
Embodiment 113D
4-[4-hydroxymethyl-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl] amino)-the phenyl sulfenyl]-phenol
Use the method for embodiment 36I, product with the product alternate embodiment 36H of embodiment 113C, the product of embodiment 113C and the product of embodiment 36E are reacted, obtain thick resistates, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (30mg, 31%).
1H?NMR(300MHz，DMSO-D6)δppm：1.36(d，J＝7.0Hz，6H)，3.30(m，1H)，4.50(s，2H)，6.72(d，J＝8.5Hz，2H)，7.05(d，J＝8.1Hz，1H)，7.19(d，J＝8.5Hz，2H)，7.27(m，1H)，7.35(s，1H)，7.87(d，J＝8.5Hz，1H)，8.79(s，1H)，8.98(m，1H)，9.82(s，1H)，11.43(bs，1H)；MS(ESI+)m/z?419(M+H)+.
Embodiment 114
Acetate 4-(4-hydroxyl-phenyl sulfenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzyl ester
Use the method for embodiment 36I, product with the product alternate embodiment 36H of embodiment 113C, the product of embodiment 113C and the product of embodiment 36E are reacted, obtain thick resistates, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (12mg, 11%).
1H?NMR(300MHz，DMSO-D6)δppm：1.36(d，J＝6.6Hz，6H)，2.05(s，3H)，3.30(m，1H)，5.07(s，2H)，6.71(d，J＝8.5Hz，2H)，7.03(d，J＝8.1Hz，1H)，7.19(d，J＝8.5Hz，2H)，7.27(m，1H)，7.40(m，1H)，7.95(d，J＝8.8Hz，1H)，8.89(s，1H)，9.02(d，J＝8.8Hz，1H)，9.75(bs，1H)，11.79(bs，1H)；MS(ESI+)m/z?461(M+H)+.
Embodiment 115
N-{4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenyl }-ethanamide
Use the method for embodiment 36I, use the product of the product alternate embodiment 36H of embodiment 7b, the product of embodiment 7b and the product of embodiment 36E are reacted, obtain thick resistates, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.99Hz，6H)，2.02(s，3H)，2.33(s，3H)，3.28(t，J＝6.89Hz，1H)，7.18(s，1H)，7.20(d，J＝8.46Hz，2H)，7.28(s，1H)，7.46(d，J＝8.46Hz，2H)，7.86(d，J＝8.46Hz，1H，)8.79(s，1H)，8.93(d，J＝8.82Hz，1H)，9.99(s，1H)，11.46(s，1H)；MS(ESI+)m/z?444(M+H)+.
Embodiment 116
(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-[2-(4-methoxyl group-phenoxy group)-5-methyl-phenyl]-amine
Embodiment 116A
1-(4-methoxyl group-phenoxy group)-4-methyl-2-nitro-benzene
According to the method for embodiment 122a, substitute quinhydrones with 4-methoxyl group-phenol, with 4-methoxyl group-phenol and 1-fluoro-4-methyl-2-oil of mirbane reaction, obtain this title compound.
Embodiment 116B
2-(4-methoxyl group-phenoxy group)-5-methyl-phenyl amine
According to the method for embodiment 104B, use the method for the product alternate embodiment 104A of embodiment 116A, the product reduction with embodiment 116A obtains this title compound.
Embodiment 116C
(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-[2-(4-methoxyl group-phenoxy group)-5-methyl-phenyl]-amine
Use the method for embodiment 36I, use the product of the product alternate embodiment 36H of embodiment 116B, obtain thick resistates, the product of embodiment 116B and the product of embodiment 36E are reacted, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.33(d，J＝6.99Hz，6H)，2.33(s，3H)，3.26(dt，J＝13.74，6.85Hz，1H)，3.67(s，3H)，6.77-6.96(m，5H)，7.18(dd，J＝8.46，2.21Hz，1H)，7.33(d，J＝1.84Hz，1H)，7.83(d，J＝8.46Hz，1H)，8.84(s，1H)，8.91(d，J＝8.82Hz，1H)，11.33(s，1H)；MS(ESI)+m/z?401(M+H)+.
Embodiment 117
4-[2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-methyl-phenoxy group]-phenol
Use the method for embodiment 36I, use the product of the product alternate embodiment 36H of embodiment 122b, the product of embodiment 122b and the product of embodiment 36E are reacted, obtain thick resistates, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.33(d，J＝6.99Hz，6H)，2.32(s，3H)，3.27(t，J＝6.89Hz，1H)，6.67(m，2H)，6.75-6.85(m，3H)，7.16(dd，J＝8.46，1.84Hz，1H)，7.31(d，J＝1.47Hz，1H)，7.84(d，J＝8.46Hz，1H)，8.85(s，1H)，8.94(d，J＝8.46Hz，1H)，9.28(s，1H)；MS(ESI)+m/z?387(M+H)+.
Embodiment 118
(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-[2-(4-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl]-amine
Method according to embodiment 6b, with the product of embodiment 6a (5.0g, 175mmol) with 4-methoxyl group-thiophenol (2.45g, 175mmol) reaction is 18 hours, obtain 1-(4-methoxyl group-phenyl sulfenyl)-4-methyl-2-nitro-benzene, with it according to embodiment 51 method SnCl
2Reduction obtains 2-(4-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl amine.
Use the method for embodiment 36I, product with 2-(4-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl amine alternate embodiment 36H, product reaction with 2-(4-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl amine and embodiment 36E, obtain thick resistates, it is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.62Hz，6H)，2.33(s，3H)，3.28(t，J＝6.89Hz，1H)，3.69(s，3H)，6.81(d，J＝9.19Hz，2H)，7.06-7.20(m，2H)，7.23(d，J＝8.82Hz，2H)，7.26(s，1H)，7.85(d，J＝8.46Hz，1H)，8.76(s，1H)，8.94(d，J＝8.46Hz，1H)，11.36(s，1H)；MS(ESI)+m/z?417(M+H)+.
Embodiment 119
(7-cyclopropyl-pyrido [2,3-d] pyrimidine-4-yl)-(5-methyl-2-phenyl sulfenyl-phenyl)-amine
Embodiment 119A
N '-(3-cyano group-6-cyclopropyl-pyridine-2-yl)-N, N-dimethyl-carbonamidine
Cyclopropyl Methyl Ketone is reacted according to the method for describing among the 36A-36E, obtain this title compound.
Embodiment 119B
(7-cyclopropyl-pyrido [2,3-d] pyrimidine-4-yl)-(5-methyl-2-phenyl sulfenyl-phenyl)-amine
Use the method for embodiment 102, product with the product alternate embodiment 6c of embodiment 51, and product with the product alternate embodiment 10B of embodiment 119A, the product of embodiment 51 and the product of embodiment 119A are reacted, obtain thick resistates, it by carrying out purifying with the methyl alcohol development, is obtained this title compound.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.05-1.19(m，4H)，2.22-2.41(m，1H)，2.35(s，3H)，7.05-7.31(m，7H)，7.37(s，1H)，，7.58(d，J＝8.46Hz，1H)，8.50(s，1H)，8.65(d，J＝8.46Hz，1H)，10.21(s，1H)；MS(ESI)+m/z?385(M+H)+.
Embodiment 120
4-[2-(7-cyclopropyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenol
With the product reaction of the product embodiment 119A of embodiment 6c, use the method for embodiment 102, the product with the product alternate embodiment 10B of embodiment 119A obtains thick resistates, and it by developing purifying with methyl alcohol, is obtained this title compound.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.05-1.22(m，J＝1.84Hz，4H)，2.24-2.39(m，1H)，2.29(s，3H)，6.73(d，J＝8.82Hz，2H)，6.91(d，J＝8.09Hz，1H)，7.04(dd，J＝8.09，1.47Hz，1H)，7.17(d，J＝8.82Hz，2H)，7.25(s，1H)，7.57(d，J＝8.82Hz，1H)，8.49(s，1H)，8.71(d，J＝8.46Hz，1H)，9.74(s，1H)，9.92(s，1H)；MS(ESI)+m/z?401(M+H)+.
Embodiment 121
N-{4-[2-(7-cyclopropyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenyl }-ethanamide
Use the method for embodiment 102, product with the product alternate embodiment 6c of embodiment 7b, and product with the product alternate embodiment 10B of embodiment 119A, the product of embodiment 7b and the product of embodiment 119A are reacted, obtain thick resistates, it by carrying out purifying with the methyl alcohol development, is obtained this title compound.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.13(d，J＝6.25Hz，4H)，2.02(s，3H)，2.22-2.38(m，1H)，2.31(s，3H)，7.07(s，2H)，7.20(d，J＝8.82Hz，2H)，7.30(s，1H)，7.50(d，J＝8.82Hz，2H)，7.56(d，J＝8.46Hz，1H)，8.49(s，1H)，8.68(d，J＝8.82Hz，1H)，9.99(s，2H)；MS(ESI+)m/z?442(M+H)+.
Embodiment 122
4-[2-(7-cyclopropyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-methyl-phenoxy group]-phenol
Embodiment 122a
4-(4-methyl-2-nitro-phenoxy) phenol
Under agitation with quinhydrones (3.2g, 29.0mmol) and K
2CO
3(8.0g, 54.0mmol) (3.0g 19.3mmol) one arises from 100 ℃ of stirrings 24 hours for the solution in 40mL DMF and 1-fluoro-4-methyl-2-oil of mirbane.Be cooled to room temperature and dilute with EtOAc.Wash with water and with organic layer MgSO
4Dry.Filter and under vacuum, concentrate, obtain this title compound, it by the silica gel column chromatography purifying, with 5% EtOAc/ hexane wash-out, is obtained orange (1.89g, 40%).
Embodiment 122b
4-(2-amino-4-methylphenoxy) phenol
(1.89g 7.71mmol) uses SnCl with the product of embodiment 122a according to the method for embodiment 51
2Reduction obtains this title compound, is white solid (1.42g, 86%).
Embodiment 122c
4-(2-(7-cyclopropyl pyrido [2,3-d] pyrimidine-4-base is amino)-4-methylphenoxy) phenol
Use the method for embodiment 102, product with the product alternate embodiment 6c of embodiment 122b, and with the product of the product alternate embodiment 10B of embodiment 119A, the product of embodiment 122b and the product of embodiment 119A are reacted, obtain thick resistates, it by carrying out purifying with the methyl alcohol development, is obtained this title compound.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.03-1.18(m，J＝6.25Hz，4H)，2.20-2.35(m，1H)，2.30(s，3H)，6.57-6.85(m，5H),7.03(dd，J＝8.27，1.65Hz，1H)，7.36(d，J＝1.84Hz，1H)，7.52(d，J＝8.46Hz，1H)，8.50(s，1H)，8.65(d，J＝8.46Hz，1H)，9.18(s，1H)，9.70(s，1H)；MS(ESI)+m/z?385(M+H)+.
Embodiment 123
(7-cyclopropyl-pyrido [2,3-d] pyrimidine-4-yl)-[2-(4-methoxyl group-phenoxy group)-5-methyl-phenyl]-amine
Use the method for embodiment 102, product with the product alternate embodiment 6c of embodiment 116B, and with the product of the product alternate embodiment 10B of embodiment 119A, the product of embodiment 116B and the product of embodiment 119A are reacted, obtain thick resistates, it by carrying out purifying with the methyl alcohol development, is obtained this title compound.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.02-1.20(m，J＝6.25Hz，4H)，2.21-2.37(m，1H)，2.31(s，3H)，3.66(s，3H)，6.75-6.92(m，5H)，7.06(dd，J＝8.64，0.92Hz，1H)，7.37(s，1H)，7.51(d，J＝8.46Hz，1H)，8.49(s，1H)，8.63(d，J＝8.82Hz，1H)，9.74(s，1H)；MS(ESI)+?m/z399(M+H)+.
Embodiment 124
(7-cyclopropyl-pyrido [2,3-d] pyrimidine-4-yl)-[2-(4-fluoro-phenyl sulfenyl)-5-methyl-phenyl]-amine
Method according to embodiment 5H, product (5.00g with embodiment 6a, 17.53mmol) with the 4-fluoro thiophenol (2.24g of alternative thiophenol, 17.53mmol) reacted 18 hours, obtain 1-(4-fluoro-phenyl sulfenyl)-4-methyl-2-nitro-benzene, it by the silica gel column chromatography purifying, is used 5%EtOAc/ hexane wash-out, obtain solid (3.39g, 74%).According to the method for embodiment 51 with 1-(4-fluoro-phenyl sulfenyl)-4-methyl-2-nitro-benzene SnCl
2Reduction obtains 2-(4-fluoro-phenyl sulfenyl)-5-methyl-phenyl amine.
Use the method for embodiment 102, product with 2-(4-fluoro-phenyl sulfenyl)-5-methyl-phenyl amine alternate embodiment 6c, and with the product of the product alternate embodiment 10B of embodiment 119A, product reaction with 2-(4-fluoro-phenyl sulfenyl)-5-methyl-phenyl amine and embodiment 119A, obtain thick resistates, it by carrying out purifying with the methyl alcohol development, is obtained this title compound.
1H?NMR(300MHz，DMSO-D6)δ?ppm：0.96-1.19(m，J＝6.25Hz，4H)，2.22-2.42(m，1H)，2.33(s，3H)，7.02-7.28(m，6H)，7.33(s，1H)，7.56(d，J＝8.46Hz，1H)，8.46(s，1H)，8.66(d，J＝8.09Hz，1H)，10.03(s，1H)；MS(ESI)+?m/z403(M+H)+.
Embodiment 125
(7-cyclopropyl-pyrido [2,3-d] pyrimidine-4-yl)-[2-(4-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl]-amine
Use the method for embodiment 102, product with 2-(4-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl amine alternate embodiment 6c, and with the product of the product alternate embodiment 10B of embodiment 119A, with of the product reaction of 2-(4-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl amine (embodiment 118) with embodiment 119A, obtain thick resistates, it by developing purifying with methyl alcohol, is obtained this title compound.
1H?NMR(300MHz，DMSO-D6)δ?ppm：0.96-1.30(m，J＝5.52Hz，4H)，2.21-2.42(m，1H)，2.31(s，3H)，3.71(s，3H)，6.85(d，J＝8.82Hz，2H)，6.99-7.12(m，2H)，7.24(d，J＝8.82Hz，2H)，7.63(d，J＝8.46Hz，1H)，8.53(s，1H)，8.72(d，J＝8.46Hz，1H)，10.33(s，1H)；MS(ESI)+m/z?415(M+H)+.
Embodiment 126
[2-(4-methoxyl group-phenoxy group)-5-methyl-phenyl]-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Use the method for embodiment 104C, use the product of the product alternate embodiment 104B of embodiment 116B, the product of embodiment 116B and the product of embodiment 10C are reacted, obtain thick resistates, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.33(s，3H)，2.72(s，3H)，3.68(s，3H)，6.80-6.95(m，5H)，7.18(dd，J＝8.46，2.21Hz，1H)，7.34(d，J＝1.84Hz，1H)，7.76(d，J＝8.46Hz，1H)，8.85(s，2H)，11.32(s，1H).
Embodiment 127
4-[2-(the 7-tertiary butyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenol
Embodiment 127A
N '-(the 6-tertiary butyl-3-cyano group-pyridine-2-yl)-N, N-dimethyl-carbonamidine
With 3,3-dimethyl-2-butanone reacts according to the method for describing among the embodiment 36A-36E, obtains this title compound.
Embodiment 127B
4-[2-(the 7-tertiary butyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenol
Use the method for embodiment 36I, product with the product alternate embodiment 36H of embodiment 6c, and substitute the product of 276E with embodiment 127A product, the product of embodiment 6c and the product of embodiment 127A are reacted, obtain thick resistates, it is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (40mg, 29%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.44(s，9H)，2.31(s，3H)，6.71(d，J＝8.5Hz，2H)，7.00(d，J＝8.1Hz，1H)，7.16(m，1H)，7.18(d，J＝8.8Hz，2H)，7.23(s，1H)，8.01d，J＝7.6Hz，1H)，8.75(s，1H)，8.97(d，J＝8.8Hz，1H)，9.79(s，1H)，11.22(bs，1H)；MS(ESI)+m/z?417(M+H)+.
Embodiment 128
(5-methyl-2-phenyl sulfenyl-phenyl)-(7-propyl group-pyrido [2,3-d] pyrimidine-4-yl)-amine
Use the method for embodiment 36A, substitute methyl isopropyl Ketone, obtain intermediate, then its sequential grammar according to embodiment 36A-36E is reacted, make this title compound with 2 pentanone.
Embodiment 128A
N '-(3-cyano group-6-propyl group-pyridine-2-yl)-N, N-dimethyl-carbonamidine
Use the method for embodiment 36A, substitute methyl isopropyl Ketone, obtain intermediate,, make this title compound its sequential grammar reaction according to embodiment 36A-36E with 2 pentanone.
Embodiment 128B
(5-methyl-2-phenyl sulfenyl-phenyl)-(7-propyl group-pyrido [2,3-d] pyrimidine-4-yl)-amine
With the product (49mg0.231mmol) of embodiment 51 and the product of 128A (50mg 0.231mmol) is dissolved in the acetate (1mL), and be heated to 130 ℃ 1.5 hours.After being cooled to room temperature, solid in acetic acid solvent, occurs, it is collected by filtering, obtain this title compound, be acetate (68mg, 62%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：0.94(t，J＝7.4Hz，3H)，1.79(m，2H)，1.88(s，6H)，2.35(s，3H)，2.88(t，J＝7.6Hz，2H)，7.18(m，5H)，7.23(m，2H)，7.37(s，1H)，7.51(d，J＝8.1Hz，1H)，8.48(s，1H)，8.69(d，J＝8.5Hz，1H)；MS(ESI)+m/z?387(M+H)+.
Embodiment 129
3-[4-methyl-2-(7-propyl group-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Method according to embodiment 6b, product (10.14g with embodiment 6a, 35.6mmol) and 3-(4-methyl-2-nitro-phenyl sulfenyl)-phenol (4.48g, 35.6mmol) reacted 18 hours, obtain 3-(4-methyl-2-nitro-phenyl sulfenyl)-phenol (7.88g, 85%), it is used SnCl according to the method for embodiment 51
2Reduction obtains 3-(2-amino-4-methyl-phenyl sulfenyl)-phenol.
The product of 3-(2-amino-4-methyl-phenyl sulfenyl)-phenol (49mg 0.231mmol) and embodiment 128A (50mg 0.231mmol) is dissolved in the acetate (1mL), and be heated to 130 ℃ 1.5 hours.After being cooled to room temperature, solid in acetic acid solvent, occurs, it is collected by filtering, obtain this title compound, be acetate (78mg, 68%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：0.95(t，J＝7.3Hz，3H)，1.79(m，2H)，1.88(s，6H)，2.40(s，3H)，2.88(t，J＝7.6Hz，2H)，6.57(m，3H)，7.00(t，J＝7.7Hz，1H)，7.13(m，1H)，7.26(d，J＝7.7Hz，1H)，7.38(s，1H)，7.51(d，J＝8.5Hz，1H)，8.50(s，1H)，8.70(d，J＝8.5Hz，1H)；MS(ESI)+m/z?403(M+H)+.
Embodiment 130
N-{4-[4-methyl-2-(7-propyl group-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-ethanamide
The product of the product of embodiment 7b (49mg 0.231mmol) and embodiment 128A (50mg 0.231mmol) is dissolved in the acetate (1mL), and be heated to 130 ℃ 1.5 hours.After being cooled to room temperature, remove acetic acid solvent under vacuum, methyl alcohol (3mL) is added in this oily matter, it causes that solid forms, and it is developed with methyl alcohol, obtains this title compound (80mg, 78%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：0.95(t，J＝7.4Hz，3H)，1.89(m，2H)，2.02(s，3H)，2.32(s，3H)，2.89(t，J＝7.5Hz，2H)，7.06(s，2H)，7.21(t，J＝8.5Hz，2H)，7.30(s，1H)，7.50(d，J＝8.8Hz，2H)，7.52(m，1H)，8.52(s，1H)，8.74(d，J＝7.7Hz，1H)，10.00(s，1H)；MS(ESI)+m/z?444(M+H)+.
Embodiment 131
4-[4-methyl-2-(7-propyl group-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
The product of the product of embodiment 6c (49mg 0.231mmol) and embodiment 128A (50mg 0.231mmol) is dissolved in the acetate (1mL), and be heated to 130 ℃ 1.5 hours.After being cooled to room temperature, solid in acetic acid solvent, occurs, it is collected by filtering, obtain this title compound, be acetate (77mg, 68%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：0.96(t，J＝7.4Hz，3H)，1.80(m，2H)，1.88(s，6H)，2.40(s，3H)，2.90(t，J＝7.6Hz，2H)，6.74(d，J＝8.5Hz，2H)，6.90(d，J＝8.1Hz，1H)，7.03(m，1H)，7.18(d，J＝8.8Hz，2H)，7.22(s，1H)，7.54(d，J＝8.1Hz，1H)，8.53(s，1H)，8.78(d，J＝8.5Hz，1H)；MS(ESI)+m/z?403(M+H)+.
Embodiment 132
N-{4-[5-hydroxyl-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenyl }-ethanamide
With 2-methyl-4-nitro-5-chlorophenol (1.5g, 8.0mmol), 4-kharophen thiophenol (1.6g, 8.8mmol) and cesium carbonate (5.74g, 17.6mmol) mixture in DMF (10mL) in 100 ℃ the heating 2.5 hours.With the mixture cooling,, and, use anhydrous sodium sulfate drying then with organic layer water and the washing of 10% sodium chloride aqueous solution with methyl acetate (100mL) dilution.Siccative is filtered, and under vacuum, removes and desolvate, obtain N-[4-(5-hydroxy-4-methyl-2-nitro-phenyl sulfenyl)-phenyl]-ethanamide, be solid (2.5g, 81%).With N-[4-(5-hydroxy-4-methyl-2-nitro-phenyl sulfenyl)-phenyl]-ethanamide (2.5g, 6.45mmol), iron powder (1.79g, 32mmol) and ammonium chloride (0.514g, 9.6mmol) solution in methyl alcohol (10mL), tetrahydrofuran (THF) (10mL) and water (5mL) is heated to and refluxed 1.5 hours.The gained mixture dilutes with methyl alcohol (50mL), and filters by Celite pad.Filtrate decompression is concentrated into the volume of 10mL, this solution with water (50mL) dilution, and extract with methyl acetate (2 x 50mL).The extract that merges washs with 10% sodium-chlor, uses dried over mgso then, filters and concentrates under vacuum, obtains N-[4-(2-amino-5-hydroxy-4-methyl phenyl sulfenyl)-phenyl]-ethanamide (1.7g, 91%).
Use the method for embodiment 36I, with N-[4-(2-amino-5-hydroxy-4-methyl-phenyl sulfenyl)-phenyl]-product of ethanamide alternate embodiment 36H, with N-[4-(the amino 5-hydroxy-4-methyl of 2--phenyl sulfenyl)-phenyl]-ethanamide reacts with the product of embodiment 36E, obtain thick resistates, it is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)，2.03(s，3H)，2.11(s，3H)，3.27(s，1H)，6.63(s，1H)，7.12(s，1H)，7.25(d，J＝8.82Hz，2H)，7.51(d，J＝8.82Hz，2H)，7.85(d，J＝8.46Hz，1H)，8.80(s，1H)，8.94(d，J＝8.46Hz，1H)，9.75(s，1H)，10.02(s，1H)，11.36(s，1H)；MS(ESI)+m/z?460(M+H)+.
Embodiment 133
N
1-(4-benzyloxy-phenyl)-N
2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-4, N
1-dimethyl-benzene-1, the 2-diamines
Embodiment 133A
(4-benzyloxy-phenyl)-(4-methyl-2-nitro-phenyl)-amine
With 4-methyl-2-N-methyl-p-nitroaniline (1.006g, 6.612mmol), 4-benzyloxy bromobenzene (5.794g, 22.02mmol), cuprous iodide (62.9mg, 0.3306mmol), salt of wormwood (0.914g, 6.612mmol) and the mixture of anhydrous o-Xylol (18mL) in 150 ℃ of heating 24 hours.Add cuprous iodide (30mg) again, and in 160 ℃ of reheat 6 hours.Reaction is cooled to room temperature, and under vacuum, removes and desolvate by rotary evaporation.Resistates by flash chromatography on silica gel method purifying, as solvent, is obtained this title compound with 1: 1 dichloromethane/hexane, be red oil, its slow crystallization (1.23g, 56%).
Embodiment 133B
(4-benzyloxy-phenyl)-methyl-(4-methyl-2-nitro-phenyl)-amine
In the product (229.4mg of room temperature at following embodiment 133A of nitrogen, 0.6861mmol) at anhydrous N, the solution in the dinethylformamide (3mL) is added to sodium hydride (60% dispersion in mineral oil, 55mg, 1.372mmol) at N, in the suspension in the dinethylformamide (3mL).To react on stirring at room 1 hour, add then methyl-iodide (0.171mL, 2.744mmol), and in stirring at room 2 hours.Under vacuum, remove and desolvate via rotary evaporation.Resistates is dissolved in the water (30mL), and extracts with methylene dichloride (50mL).With organic phase water (30mL) washing, use anhydrous magnesium sulfate drying, filter, and under vacuum, concentrate by rotary evaporation, obtain this title compound, be chestnut color solid (239mg, 100%).
Embodiment 133C
(4-benzyloxy-phenyl)-methyl-(4-methyl-2-amino-phenyl)-amine
With the product of embodiment 133B (129.4mg, 0.3714mmol), iron powder (128mg, 2.284mmol), (130mg, 2.433mmol) mixture in water (1mL) and ethanol (2mL) is in 70 ℃ of heating 1 hour under nitrogen for ammonium chloride.Reaction is cooled to room temperature, and vacuum filtration, the methanol wash resistates used.Filtrate is concentrated under vacuum, and with toluene (50mL) azeotropic.Resistates by flash chromatography on silica gel method purifying, as eluent, is obtained this title compound with methylene dichloride, be waxy solid (85mg, 72%).
Embodiment 133D
N
1-(4-benzyloxy-phenyl)-N
2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-4, N
1-dimethyl-benzene-1, the 2-diamines
With the product of embodiment 36E (28mg, 0.1297mmol) and the product of embodiment 133C (41.3mg, 0.1297mmol) solution in acetate (1mL) is preheating to 140 ℃ oil bath and was stirring 1 hour.Reaction is cooled to room temperature,, under vacuum, concentrates via rotary evaporation with hexane (50mL) dilution, and with dichloromethane/hexane (4x) co-evaporated.With the resistates drying, via flash chromatography on silica gel method purifying, as eluent, obtain this title compound then with 20% methyl acetate/methylene dichloride, be yellow solid (35mg, 55%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.27(d，J＝6.62Hz，6H)，2.34(s，3H)，3.08(s，3H)，3.06-3.22(m，1H)，4.79(s，2H)，6.50(d，J＝9.19Hz，2H)，6.60(d，J＝8.82Hz，2H)，7.05-7.17(m，2H)，7.25-7.37(m，5H)，7.41(d，J＝8.46Hz，1H)，7.47(s，1H)，8.42(d，J＝8.46Hz，1H)，8.52(s，1H)，9.33(s，1H)；MS(DCI/NH
3)m/z?490(M+H)
+.
Embodiment 134
(2-benzyl-5-methyl-phenyl)-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Embodiment 134A
2-benzyl-5-methyl-phenyl amine
(2.54mmol) solution in is added to via syringe and contains aluminum chloride (534ing in flask 4.005mmol), and cools off in 0 ℃ bath for 1.0M, 2.54mL at tetrahydrofuran (THF) with lithium aluminum hydride under nitrogen.After mixture was cooled 5 minutes, slowly drip 2-amino-4-methyldiphenyl ketone (200mg, 0.9467mmol) solution in tetrahydrofuran (THF) (4mL) in 0 ℃.To react on 50 ℃ of heating 30 minutes minutes then.Reaction is cooled to room temperature, and adds moisture ether (5mL).Reaction is poured in the water (20mL) carefully, and extract with ether (2 x 50mL).The ethereal extract that merges is washed with salt solution (20mL), use anhydrous sodium sulfate drying, filter also concentrated via rotary evaporation under vacuum.By flash chromatography on silica gel method purifying, as eluent, obtain this title compound with the 40:60 hexanes/ch, be oily matter (94mg, 50%).
Embodiment 134B
(2-benzyl-5-methyl-phenyl)-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
With the product of embodiment 36E (34.6mg, 0.160mmol) and the product of embodiment 134A (31.6mg, 0.160mmol) solution in acetate (1mL) is preheating to 140 ℃ oil bath and was stirring 1 hour.Reaction is cooled to room temperature,, under vacuum, concentrates via rotary evaporation with hexane (50mL) dilution, and with dichloromethane/hexane (4x) co-evaporated.With the resistates drying, via flash chromatography on silica gel method purifying, as eluent, obtain this title compound then with 2% ethanol/methylene, be light yellow solid (50mg, 85%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.32(d，J＝6.99Hz，6H)2.30(s，3H)3.12-3.28(m，1H)3.87(s，2H)6.95-7.20(m，8H)7.57(s，1H)8.47(s，1H)8.74(d，J＝8.46Hz，1H)9.81(s，1H)；MS(DCI/NH
3)m/z?369(M+H)
+.
Embodiment 135
(7-cyclohexyl-pyrido [2,3-d] pyrimidine-4-yl)-(5-methyl-2-phenyl sulfenyl-phenyl)-amine
Embodiment 135A
N '-(3-cyano group-6-cyclohexyl-pyridine-2-yl)-N, N-dimethyl-carbonamidine
1-cyclohexyl-ethyl ketone is reacted according to the method for describing among the embodiment 36A-36E, obtain this title compound.
Embodiment 135B
(7-cyclohexyl-pyrido [2,3-d] pyrimidine-4-yl)-(5-methyl-2-phenyl sulfenyl-phenyl)-amine
(56.0mg, (50.0mg 0.2322mmol), and stirs mixture 15 minutes preheating to 130 ℃ oil bath 0.2322mmol) to add the product of embodiment 51 in the solution in acetate (4mL) to the product of embodiment 135A.Then mixture is cooled to room temperature, under vacuum, removes acetate, and the gained resistates is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (20mg, 20%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.38-1.51(m，2H)，1.57-1.69(m，2H)，1.70-1.80(m，2H)，1.80-1.99(m，6H)，2.33-2.40(m，3H)，7.12-7.17(m，1H)，7.12-7.26(m，3H)，7.30-7.33(m，1H)，7.33-7.38(m，2H)，8.68-8.75(m，1H)，8.82-8.90(m，1H)；MS(DCI/NH3)m/z?427(M+H)+.
Embodiment 136
4-[2-(7-cyclohexyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenol
According to the method for embodiment 135B, use the product of the product alternate embodiment 51 of embodiment 6c, the product of embodiment 135A and the product of embodiment 6c are reacted, obtain this title compound, be trifluoroacetic acid salt form (20mg, 20%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.38-1.52(m，2H)，1.55-1.80(m，3H)，1.80-1.91(m，2H)，1.91-2.03(m，3H)，2.30(s，3H)，3.26-3.47(m，1H)，6.66-6.74(m，2H)，6.74-6.81(m，1H)，6.96-7.03(m，1H)，7.10-7.14(m，1H)，7.14·7.21(m，3H)，7.21-7.26(m，1H)，8.72-8.80(m，1H)，8.90-8.97(m，1H)，9.78(s，1H)；MS(DCI/NH3)m/z?443(M+H)+.
Embodiment 137
N-{4-[2-(7-cyclohexyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenyl }-ethanamide
According to the method for embodiment 135B, use the product of the product alternate embodiment 51 of embodiment 7b, the product of embodiment 135A and the product of embodiment 7b are reacted, obtain this title compound, be trifluoroacetic acid salt form (21mg, 25%).
1HNMR(300MHz，DMSO-D6)δ?ppm：1.28-1.52(m，3H)，1.53-1.79(m，3H)，1.79-1.97(m，4H)，2.02(s，3H)，2.32(s，3H)，2.79-2.94(m，1H)，7.03-7.12(m，1H)，7.20(d，J＝8.46Hz，2H)，7.31(s，1H)，7.50(d，J＝8.82Hz，2H)，7.56(d，J＝8.46Hz，1H)，8.54(s，1H)，8.76(d，J＝8.82Hz，1H)，9.99(s，2H)；MS(DCI/NH3)m/z?484(M+H)+.
Embodiment 138
N-{4-[2-(7-cyclobutyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenyl }-ethanamide
Embodiment 138A
N '-(3-cyano group-6-cyclobutyl-pyridine-2-yl)-N, N-dimethyl-carbonamidine
1-cyclobutyl-ethyl ketone is reacted according to the method for describing among the embodiment 36A-36E, obtain this title compound.
Embodiment 138B
N-{4-[2-(7-cyclobutyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenyl }-ethanamide
Method according to embodiment 135B, product with the product alternate embodiment 51 of embodiment 7b, and with the product of the product alternate embodiment 135A of embodiment 138A, the product of embodiment 138A and the product of embodiment 7b are reacted, obtain this title compound, be trifluoroacetic acid salt form (30mg, 36% productive rate).
1HNMR(500MHz，DMSO-D6)δ?ppm：0.86(t，J＝7.02Hz，1H)，1.86-1.98(m，1H)，2.02(s，3H)，2.06-2.18(m，1H)，2.34(s，3H)，2.37-2.47(m，4H)，3.80-4.02(m，1H)，7.13-7.25(m，4H)，7.29(s，1H)，7.45(d，J＝8.54Hz，2H)，7.78(d，J＝8.54Hz，1H)，8.80(s，1H)，8.92(d，J＝8.54Hz，1H)，9.98(s，1H)；MS(DCI/NH
4)m/z?456(M+H)+.
Embodiment 139
4-[2-(7-cyclobutyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenol
Method according to embodiment 135, product with the product alternate embodiment 51 of embodiment 6c, and with the product of the product alternate embodiment 135A of embodiment 138A, the product of embodiment 138A and the product of embodiment 6c are reacted, obtain this title compound, be trifluoroacetic acid salt form (30mg, 33%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.85-2.01(m，1H)，2.03-2.24(m，1H)，2.31(s，3H)，2.36-2.46(m，4H)，3.81-4.13(m，2H)，6.70(d，J＝8.46Hz，2H)，7.02(d，J＝8.09Hz，1H)，7.17(d，J＝8.46Hz，3H)，7.24(s，1H)，7.82(d，J＝8.46Hz，1H)，8.82(s，1H)，8.97(d，J＝8.46Hz，1H)，9.72-9.93(m，1H)；MS(DCI/NH
4)m/z?415(M+H)+.
Embodiment 140
(the 7-second month in a season-butyl-pyrido [2,3-d] pyrimidine-4-yl)-(5-methyl-2-phenyl sulfenyl-phenyl)-amine
Embodiment 140A
N '-(6-sec-butyl-3-cyano group-pyridine-2-yl)-N, N-dimethyl-carbonamidine
3-methyl-penta-2-ketone is reacted according to the method for describing among the embodiment 36A-36E, obtain this title compound.
Embodiment 140B
(7-sec-butyl-pyrido [2,3-d] pyrimidine-4-yl)-(5-methyl-2-phenyl sulfenyl-phenyl)-amine
According to the method for embodiment 135B, use the product of the product alternate embodiment 135A of embodiment 140A, the product of embodiment 140A and the product of embodiment 51 are reacted, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：0.83(t，J＝7.35Hz，3H)，1.32(d，J＝6.99Hz，3H)，1.59-1.75(m，1H)，1.75-1.95(m，1H)，2.37(s，3H)，2.95-3.12(m，2H)，7.11-7.22(m，5H)，7.25(d，J＝6.62Hz，1H)，7.31-7.46(m，2H)，7.81(d，J＝8.82Hz，1H)，8.76(s，1H)，8.91(d，J＝8.46Hz，1H)；MS(DCI/NH
4)M/Z?401(M+H)+.
Embodiment 141
N-{4-[2-(7-sec-butyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenyl }-ethanamide
Method according to embodiment 135B, product with the product alternate embodiment 51 of embodiment 7b, and with the product of the product alternate embodiment 135A of embodiment 140A, the product of embodiment 140A and the product of embodiment 7b are reacted, obtain this title compound, be trifluoroacetic acid salt form (37mg, 45%).
1H?NMR(500MHz，DMSO-D6)δ?ppm：0.84(t，J＝7.32Hz，3H)，1.33(d，J＝6.71Hz，3H)，1.62-1.76(m，1H)，1.77-1.91(m，1H)，2.34(s，3H)，2.49(s，3H)，2.96-3.14(m，1H)，7.11-7.25(m，4H)，7.28(s，1H)，7.46(d，J＝9.16Hz，2H)，7.83(d，J＝8.54Hz，1H)，8.79(s，1H)，8.94(d，J＝7.93Hz，1H)，9.97(s，1H)，11.31-11.69(m，1H)；MS(DCI/NH
4)m/z?458(M+H)+.
Embodiment 142
N-(4-{4-methyl-2-[7-(1-methyl-cyclopropyl)-pyrido [2,3-d] pyrimidine-4-base is amino]-the phenyl sulfenyl }-phenyl)-ethanamide
Embodiment 142A
N '-[3-cyano group-6-(1-methyl-cyclopropyl)-pyridine-2-yl]-N, N-dimethyl-carbonamidine
1-(1-methyl-cyclopropyl)-ethyl ketone is reacted according to the method for describing among the embodiment 36A-36E, obtain this title compound.
Embodiment 142B
N-(4-{4-methyl-2-[7-(1-methyl-cyclopropyl)-pyrido [2,3-d] pyrimidine-4-base is amino]-the phenyl sulfenyl }-phenyl)-ethanamide
Method according to embodiment 135B, product with the product alternate embodiment 51 of embodiment 7b, and with the product of the product alternate embodiment 135A of embodiment 142A, the product of embodiment 142A and the product of embodiment 7b are reacted, obtain this title compound, be trifluoroacetic acid salt form (30mg, 50%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：0.79-0.91(m，1H)，1.08-1.19(m，2H)，1.19-1.30(m，1H)，1.37-1.50(m，2H)，1.61(s，3H)，2.02(s，1H)，2.33(s，3H)，7.10-7.24(m，4H)，7.28(s，1H)，7.45(d，J＝8.82Hz，2H)，7.85(d，J＝8.46Hz，1H)，8.78(s，1H)，8.89(d，J＝9.19Hz，1H)，9.99(s，1H)；MS(DCI/NH
4)m/z?456(M+H)+.
Embodiment 143
4-{4-methyl-2-[7-(1-methyl-cyclopropyl)-pyrido [2,3-d] pyrimidine-4-base is amino]-the phenyl sulfenyl }-phenol
Method according to embodiment 135B, product with the product alternate embodiment 51 of embodiment 6c, and with the product of the product alternate embodiment 135A of embodiment 142A, the product of embodiment 142A and the product of embodiment 6c are reacted, obtain this title compound, be trifluoroacetic acid salt form (20mg, 37%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：0.77-0.91(m，1H)，1.07-1.18(m，2H)，1.38-1.52(m，2H)，1.61(s，3H)，2.31(s，3H)，6.70(d，J＝8.46Hz，2H)，7.02(d，J＝8.09Hz，1H)，7.10-7.21(m，J＝8.46Hz，3H)，7.23(s，1H)，7.86(d，J＝8.82Hz，1H)，8.78(s，1H)，8.93(d，J＝8.82Hz，1H)，9.82(s，1H)；MS(DCI/NH
4)m/z?415(M+H)+.
Embodiment 144
3-{4-methyl-2-[7-(1-methyl-cyclopropyl)-pyrido [2,3-d] pyrimidine-4-base is amino]-the phenyl sulfenyl }-phenol
Product and 3-(2-amino-4-methyl-phenyl sulfenyl)-phenol (embodiment 129) reaction with embodiment 142A, method according to embodiment 135B, product with 3-(2-amino-4-methyl-phenyl sulfenyl)-phenol alternate embodiment 51, and with the product of the product alternate embodiment 135A of embodiment 142A, obtain this title compound, be trifluoroacetic acid salt form (20mg, 37%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：0.77-0.92(m，1H)，1.35-1.48(m，2H)，1.60(s，3H)，2.36(s，3H)，6.41-6.68(m，3H)，6.90-7.05(m，1H)，7.23(d，J＝6.62Hz，1H)，7.29-7.42(m，2H)，7.77(d，J＝9.56Hz，1H)，8.68(s，1H)，8.82(d，J＝7.72Hz，1H)，9.52(s，1H)；MS(DCI/NH
4)m/z?415(M+H)+.
Embodiment 145
(7-ethyl-pyrido [2,3-d] pyrimidine-4-yl)-(5-methyl-2-phenyl sulfenyl-phenyl)-amine
Embodiment 145A
N '-(3-cyano group-6-ethyl-pyridine-2-yl)-N, N-dimethyl-carbonamidine
(0.942g, 5.0mmol) solution in anhydrous tetrahydro furan (50mL) is cooled to-78 ℃ under nitrogen with the product of embodiment 10B.Slow dropping diisopropylaminoethyl lithium solution in this solution (solution of 3.0mL 2.0M in toluene/hexane/hexane, 6.0mmol, 1.2eq).Add finish after, reaction mixture was stirred 1 hour in-78 ℃, drip then methyl-iodide (1.42g, 10.0mmol, 2.0eq).With reaction mixture in-78 ℃ of restir 1.5 hours, all solids dissolving during this period.Reaction flask shifts out cooling bath then, and is saturated with aqueous ammonium chloride solution (25mL), and adds entry (25mL).Reaction mixture is extracted with methyl acetate (3 x 100mL), and, use anhydrous magnesium sulfate drying, filter the organic layer salt water washing that merges, and vaporising under vacuum.By the silica gel chromatography purifying, use 3/2 hexane: the methyl acetate wash-out obtains this title compound (0.87g, 86% productive rate) with resistates.
Embodiment 145B
(7-ethyl-pyrido [2,3-d] pyrimidine-4-yl)-(5-methyl-2-phenyl sulfenyl-phenyl)-amine
According to the method for embodiment 135B, use the product of the product alternate embodiment 135A of embodiment 145A, the product of embodiment 145A and the product of embodiment 51 are reacted, obtain this title compound, be trifluoroacetic acid salt form (20mg, 33%).
1H?NMR(500MHz，DMSO-D6)δ?ppm：1.34(t，J＝7.93Hz，3H)，2.35(s，3H)，3.01(q，J＝7.93Hz，2H)，7.09-7.29(m，6H)，7.36(s，1H)，7.78(d，J＝8.54Hz，1H)，8.75(s，1H)，8.88(d，J＝8.54Hz，1H)；MS(DCI/NH
4)m/z?373(M+H)+.
Embodiment 146
N-{4-[2-(7-ethyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenyl }-ethanamide
Method according to embodiment 135B, product with the product alternate embodiment 51 of embodiment 7b, and with the product of the product alternate embodiment 135A of embodiment 145A, the product reaction of the product of embodiment 145A and embodiment 7b, obtain this title compound, be trifluoroacetic acid salt form (20mg, 29%).
1H?NMR(500MHz，DMSO-D6)δ?ppm：1.34(m，3H)，2.37(s，3H)，3.01(q，J＝7.93Hz，2H)，7.12-7.28(m，5H)，7.35(s，1H)，7.36(s，1H)，7.78(d，J＝8.54Hz，1H)，8.75(s，1H)，8.88(d，J＝8.54Hz，1H)；MS(DCI/NH
4)m/z?430(M+H)+.
Embodiment 147
4-[4-(6-bromo-1H-benzimidazolyl-2 radicals-yl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-phenol
Embodiment 147A
4-(4-benzyloxy-phenoxy group)-3-nitro-phenyl aldehyde
With 4-chloro-3-nitrobenzaldehyde (1.00g, 5.389mmol), 4-(benzyloxy) phenol (1.187g, 5.928mmol) and salt of wormwood (0.744g, 5.389mmol) mixture in anhydrous pyridine (10mL) under nitrogen in reflux 30 minutes.Reaction is cooled to room temperature, and under vacuum, removes and desolvate via rotary evaporation.Resistates is dissolved in methyl acetate (100mL), and washs with 1N aqueous hydrochloric acid (2 x 50mL), water (50mL) and salt solution (50mL).With the organic phase anhydrous sodium sulfate drying, filter and under vacuum, concentrate.By flash chromatography on silica gel method purifying, as eluent, obtain this title compound with methylene dichloride, be yellow solid (1.625g, 86%).
Embodiment 147B
2-[4-(4-benzyloxy-phenoxy group)-3-nitro-phenyl]-6-bromo-1H-benzoglyoxaline
With 4-bromo-1, (214mg is 1.145mmol) at the N that contains water (0.4mL) for the 2-phenylenediamine, solution in the dinethylformamide (12mL) product (400mg of embodiment 147A, 1.145mmol) and OXONE (458mg, 0.7443mmol) processing, and will react on stirring at room 30 minutes.Add entry (40mL) then, and will react and stir 10 minutes.With the mixture vacuum filtration, and solid washed with water, dry under the vacuum then.Via the silica gel chromatography purifying, as the eluent gradient elution, obtain this title compound with 3%-4% methyl acetate/methylene dichloride, be yellow solid (305mg, 51%).
Embodiment 147C
2-(4-benzyloxy-phenoxy group)-5-(6-bromo-1H-benzimidazolyl-2 radicals-yl)-phenyl amine
With the product of embodiment 147B (374mg, 0.723mmol), iron powder (248mg, 4.45mmol) and ammonium chloride (253mg, 4.74mmol) mixture in water (5mL) and ethanol (10mL) was in 80 ℃ of heating 45 minutes.Reaction mixture is cooled to room temperature, with methyl acetate (100mL) dilution, water (2 x 50mL) and salt solution (50mL) washing.With the organic phase anhydrous sodium sulfate drying, filter, and under vacuum, concentrate by rotary evaporation, obtain this title compound, be golden solid (327mg, 93%).
Embodiment 147D
[2-(4-benzyloxy-phenoxy group)-5-(6-bromo-1H-benzimidazolyl-2 radicals-yl)-phenyl]-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
With the product of embodiment 36E (26.7mg, 0.123mmol) and the product of embodiment 147C (60mg, 0.123mmol) solution in acetate (2mL) is preheating to 140 ℃ oil bath and was stirring 30 minutes.Reaction is cooled to room temperature,, under vacuum, concentrates via rotary evaporation with hexane (50mL) dilution, and with dichloromethane/hexane (4x) co-evaporated.Resistates is dry under vacuum, then via the silica gel chromatography purifying, as eluent, obtain this title compound with 3% ethanol/methylene, be pale solid (59mg, 73%).
Embodiment 147E
4-[4-(6-bromo-1H-benzimidazolyl-2 radicals-yl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-phenol
With the product of embodiment 147D (38.8mg, 0.059mmol) and pentamethylbenzene (87mg, 0.5901mmol) solution in trifluoroacetic acid (5mL) was in stirring at room 2 hours.Under vacuum, remove and desolvate by rotary evaporation, and with dichloromethane/hexane (2x) co-evaporated.The gained solid is developed with hexane (3x), and by the HPLC purifying, uses the TFA wash-out, obtains this title compound, is trifluoroacetic acid salt form (22mg, 47%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.99Hz，6H)，3.20-3.39(m，1H)，6.78(d，J＝8.82Hz，2H)，6.95(d，J＝9.19Hz，2H)，7.02(d，J＝8.82Hz，1H)，7.36(dd，J＝8.64，2.02Hz，1H)，7.55(d，J＝8.46Hz，1H)，7.78(d，J＝1.47Hz，1H)，7.91(d，J＝8.82Hz，1H)，8.11(dd，J＝8.64，2.02Hz，1H)，8.35(d，J＝1.84Hz，1H)，8.94(s，1H)，9.03(d，J＝8.82Hz，1H)，9.46(drs，1H)，11.63(br?s，1H)；MS(APCI+)m/z?567/569(M+H)
+.
Embodiment 148
4-[4-(6-bromo-1H-benzimidazolyl-2 radicals-yl)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-phenol
Use the method for describing among the embodiment 147D, product with the product alternate embodiment 36E of embodiment 10B, the product of embodiment 147C and the product of embodiment 10B are reacted, obtain [2-(4-benzyloxy-phenoxy group)-5-(6-bromo-1H-benzimidazolyl-2 radicals-yl)-phenyl]-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine, it is sloughed benzyl according to the method for describing among the embodiment 147E, obtain crude product, it is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δppm：2.74(s，3H)，6.77(d，J＝9.19Hz，2H)，6.95(d，J＝8.82Hz，2H)，7.01(d，J＝8.82Hz，1H)，7.35(dd，J＝8.46，1.84Hz，1H)，7.54(d，J＝8.82Hz，1H)，7.74-7.85(m，2H)，8.10(dd，J＝8.82，2.21Hz，1H)，8.36(d，J＝2.21Hz，1H)，8.90(s，1H)，8.95(d，J＝8.46Hz，1H)，9.45(ds，1H)，11.35(bs，1H)；MS(ESI+)m/z?539/541(M+H)+.
Embodiment 149
4-(4-amino-phenyl sulfenyl)-N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzsulfamide
Embodiment 149A
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 methyl acetate (100mL), and water (2 x 25mL) and salt solution (25mL) washing.With the organic phase anhydrous sodium sulfate drying, filter and under vacuum, concentrate, this oily matter and dichloromethane/hexane co-evaporated.Via the silica gel chromatography purifying, use 5% methyl acetate/methylene dichloride as eluent then with methylene dichloride, obtain this title compound, be yellow solid (2.038g, 52%).
Embodiment 149B
4-(4-amino-phenyl sulfenyl)-N-(4-bromo-phenyl)-3-nitro-benzsulfamide
With the product 149A of embodiment (500mg, 1.277mmol), the 4-aminothiophenol (240mg, 1.915mmol) and anhydrous sodium acetate (524mg, 6.384mmol) mixture in dehydrated alcohol (9mL) under nitrogen in reflux 1 hour.Reaction is cooled to room temperature, and under vacuum, removes ethanol by rotary evaporation.Resistates is dissolved in methyl acetate (100mL), water (2 x 50mL) and salt solution (50mL) washing.With the organic phase anhydrous sodium sulfate drying, filter and under vacuum, concentrate, with this oily matter and dichloromethane/hexane co-evaporated, obtain this title compound, be orange foam (613mg, 100%).
Embodiment 149C
4-[4-(4-bromo-phenyl sulfamoyl)-2-nitro-phenyl sulfenyl]-phenyl }-t-butyl formate
With the product of embodiment 149B (613mg, 1.277mmol) anhydrous 1, the solution in the 4-diox (10mL) in room temperature with tert-Butyl dicarbonate (418mg 1.92mmol) handles, then under nitrogen in reflux 3 hours.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 via rotary evaporation.Resistates via the silica gel chromatography purifying, as eluent, is obtained this title compound with 3% methyl acetate/methylene dichloride, be yellow solid (512mg, 69%)
Embodiment 149D
{ 4-[2-amino-4-(4-bromo-phenyl sulfamoyl)-phenyl sulfenyl]-phenyl }-t-butyl formate is with the product 149C (510mg of embodiment, 0.879mmol), iron powder (302mg, 5.40mmol) and ammonium chloride (308mg, 5.76mmol) mixture in water (4mL) and ethanol (8mL) in 80 ℃ the heating minute.Reaction is cooled to room temperature, with methyl acetate (100mL) dilution, and water (2 x 50mL) and salt solution (50mL) washing.With the organic phase anhydrous sodium sulfate drying, filter, and under vacuum, concentrate via rotary evaporation, obtain this title compound, be white foam shape thing (436mg, 90%).
Embodiment 149E
4-[4-(4-bromo-phenyl sulfamoyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenyl }-t-butyl formate
With the product of embodiment 36E (59mg, 0.2725mmol) and the product of embodiment 149D (150mg, 0.2725mmol) solution in acetate (4mL) is preheating to 140 ℃ oil bath and was stirring 25 minutes.Reaction is cooled to room temperature,, under vacuum, concentrates via rotary evaporation with hexane (100mL) dilution, and with dichloromethane/hexane (4x) co-evaporated.Resistates is dry under vacuum, then via the silica gel chromatography purifying, as eluent, obtain this title compound with 4% ethanol/methylene, be tawny solid (67mg, 34%).
Embodiment 149F
4-(4-amino-phenyl sulfenyl)-N-(4-bromo-phenyl)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzsulfamide
With the product of embodiment 149E (44mg, 0.061mmol) with trifluoroacetic acid (2mL) in methylene dichloride (2mL) in room temperature reaction 30 minutes.Under vacuum, remove and desolvate by rotary evaporation, and remaining oily matter is dry under high vacuum.Via the silica gel chromatography purifying, as eluent, obtaining this title compound is trifluoroacetic acid salt form (25mg, 48%) with 5% ethanol/methylene.
1H?NMR(300MHz，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 150
4-(4-amino-phenyl sulfenyl)-N-(4-bromo-phenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzsulfamide
The product of embodiment 149D and the product of embodiment 10B are reacted; use the method for describing among the embodiment 149E; product with the product alternate embodiment 36E of embodiment 10B; obtain { 4-[4-(4-bromo-phenyl sulfamoyl)-2-(7-methyl-pyrido [2; 3-d] pyrimidine-4-base amino)-the phenyl sulfenyl]-phenyl }-t-butyl formate, it according to the method deprotection of describing among the embodiment 149F, 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)+.
Embodiment 151
4-[4-chloro-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-phenol
Embodiment 151A
4-(4-chloro-2-nitro-phenoxy group)-phenol
With quinhydrones (1.21g, 0.011mol) and potassium hydroxide (0.894g, 0.0159mol) solution in anhydrous dimethyl sulfoxide (7mL) under nitrogen in 120 ℃ the heating 30 minutes.Dripped 2 in 120 ℃ with 30 minutes, (1.90g, the 0.0099mol) solution in methyl-sulphoxide (3mL) will be reflected at uniform temp and stir 1 hour the 5-dichloronitrobenzene then.To be reflected in the ice bath then and cool off, and pour in the 30mL frozen water.Mixture is acidified to pH1 with concentrated hydrochloric acid, and extracts with ether (2 x 50mL).With ethereal extract water (the 3 x 150mL) washing that merges, use anhydrous sodium sulfate drying, filter and under vacuum, concentrate via rotary evaporation.Resistates by the silica gel chromatography purifying, as eluent, is obtained this title compound with methylene dichloride, be tawny solid (1.34g, 51%).
Embodiment 151B
4-(2-amino-4-chloro-phenoxy group)-phenol
With the product of embodiment 151A (400mg, 1.506mmol) and iron powder (336mg, 6.02mmol) mixture in acetate (10mL) and ethanol (10mL) under nitrogen in reflux 25 minutes.Reaction is cooled to room temperature, and water (50mL) dilution is handled to pH6 with solid sodium carbonate.With methyl acetate (2 x 50mL) extraction, and, use anhydrous sodium sulfate drying, filter also concentrated via rotary evaporation under vacuum organism salt solution (50mL) washing.With gained oily matter and dichloromethane/hexane co-evaporated, obtain this title compound, be tawny solid (355mg, 100%).
Embodiment 151C
4-[4-chloro-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-phenol is the product (38mg of embodiment 36E, 0.177mmol) (42mg, 0.177mmol) solution in acetate (2mL) is preheating to 140 ℃ oil bath and stirring 1.5 hours with the product of embodiment 151B.Reaction is cooled to room temperature,, under vacuum, concentrates via rotary evaporation with hexane (100mL) dilution, and with dichloromethane/hexane (4x) co-evaporated.Resistates is dry under high vacuum, by coming purifying, obtain this title compound then with 40% methyl acetate/methylene dichloride development, be beige solid (49mg, 65%).
1HNMR(300MHz，DMSO-D6)δ?ppm：1.31(d，J＝6.99Hz，6H)，3.10-3.29(m，1H)，6.70(d，J＝8.82Hz，2H)，6.76-6.90(m，3H)，7.24(dd，J＝8.64，2.39Hz，1H)，7.55(d，J＝8.82Hz，1H)，7.71(bs，1H)，8.59(bs，1H)，8.73(d，J＝8.09Hz，1H)，9.31(bs，1H)，9.89(bs，1H)；MS(DCI/NH
3)m/z407(M+H)+.
Embodiment 152
4-(4-hydroxyl-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzonitrile
Embodiment 152A
4-(4-hydroxyl-phenoxy group)-3-nitro-benzonitrile
With quinhydrones (1.21g, 0.011mol) and potassium hydroxide (0.894g, 0.0159mol) solution in anhydrous dimethyl sulfoxide (8mL) under nitrogen in 90 ℃ the heating 30 minutes.(1.806g, the 0.0099mol) solution in methyl-sulphoxide (8mL) will react on uniform temp then and stir 1 hour to drip 4-chloro-3-nitrobenzonitrile in 90 ℃ with 30 minutes.To be reflected in the ice bath then and cool off, and pour in the 30mL frozen water.Mixture is acidified to pH3 with concentrated hydrochloric acid, and extracts with ether (3 x 100mL).With ethereal extract water (3 x 150mL) and salt solution (50mL) washing that merges, use anhydrous sodium sulfate drying, filter and under vacuum, concentrate via rotary evaporation.Via the silica gel chromatography purifying, be eluent with 4% methyl acetate/METHYLENE CHLORIDE, obtain orange solids product (0.984g, 39%).
Embodiment 152B
3-amino-4-(4-hydroxyl-phenoxy group)-benzonitrile
Will (500mg be 1.952mmol) with hydrogen (1 normal atmosphere, air bag) and 10% palladium on carbon (50mg) hydrogenation 30 minutes at the product of the embodiment 152A in the methyl alcohol (20mL).To react by 0.45 PTFE film vacuum filtration, and with the catalyzer methanol wash.Filtrate is concentrated via rotary evaporation under vacuum, obtain this title compound, be peachiness-beige solid (437mg, 99%).
Embodiment 152C
4-(4-hydroxyl-phenoxy group)-3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-benzonitrile
With the product of embodiment 36E (41mg, 0.1896mmol) and the product of embodiment 152B (42.9mg, 0.1896mmol) solution in acetate (2mL) is preheating to 140 ℃ oil bath and was stirring 1.5 hours.Reaction is cooled to room temperature,, under vacuum, concentrates via rotary evaporation with hexane (100mL) dilution, and with dichloromethane/hexane (4x) co-evaporated.Resistates is dry under high vacuum.Via the silica gel chromatography purifying, as eluent, obtain this title compound with 30% methyl acetate/methylene dichloride, be white solid (16mg, 21%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.31(d，J＝6.99Hz，6H)，3.11-3.28(m，1H)，6.77(d，J＝8.82Hz，2H)，6.85(d，J＝8.46Hz，1H)，6.93(d，J＝8.46Hz，2H)，7.64(dd，J＝17.28，8.46Hz，2H)，8.12(s，1H)，8.66(s，1H)，8.81(d，J＝8.09Hz，1H)，9.47(s，1H)，9.99(s，1H)；MS(DCI/NH
3)m/z?398(M+H)+.
Embodiment 153
(5-bromo-2-phenoxy group-phenyl)-pyrido [2,3-d] pyrimidine-4-base-amine
Use the method for describing among the embodiment 57E, with the product of 5-bromo-2-phenoxybenzamine alternate embodiment 57D, with the product reaction of 5-bromo-2-phenoxybenzamine and embodiment 57A, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：6.94-7.03(m，J＝8.09，5.88Hz，3H)，7.07(t，J＝7.35Hz，1H)，7.24-7.36(m，2H)，7.54(dd，J＝8.82，2.21Hz，1H)，7.77(dd，J＝8.46，4.41Hz，1H)，7.83(d，J＝2.21Hz，1H)，8.82(s，1H)，8.89(d，J＝7.35Hz，1H)，9.10(d，J＝2.57Hz，1H)；MS(ESI)+m/z?394(M+2)+.
Embodiment 154
(5-chloro-2-phenoxy group-phenyl)-pyrido [2,3-d] pyrimidine-4-base-amine
Use the method for describing among the embodiment 57E, product with 5-chloro-2-phenoxy group-phenyl amine alternate embodiment 57D, product reaction with 5-chloro-2-phenoxy group-phenyl amine and embodiment 57A, obtain crude product, it is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：6.97(d，J＝7.72Hz，2H)，7.00-7.11(m，2H)，7.24-7.34(m，J＝8.09，8.09Hz，2H)，7.41(dd，J＝8.82，2.57Hz，1H)，7.69-7.77(m，2H)，8.77(s，1H)，8.85(d，J＝8.46Hz，1H)，9.08(d，J＝3.31Hz，1H)；MS(ESI)+m/z?349(M+H)+.
Embodiment 155
1-{3-[4-chloro-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-phenyl }-ethanol
Method according to embodiment 152C, with 1-[4-(2-amino-4-chloro-phenoxy group)-phenyl]-product of ethanol alternate embodiment 152B, with 1-[4-(2-amino-4-chloro-phenoxy group)-phenyl]-the product reaction of ethanol and embodiment 36E, obtain crude product, it is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetate.
1HNMR(300MHz，DMSO-D6)δ?ppm：1.16(d，J＝6.62Hz，3H)，1.31(d，J＝6.99Hz，6H)，3.17-3.28(m，1H)，4.60(q，1H)，6.81(m，1H)，6.94(s，1H)，7.01(d，J＝7.72Hz，1H)，7.06(d，J＝8.82Hz，1H)，7.23(t，J＝7.91Hz，1H)，7.43(dd，J＝8.82，2.57Hz，1H)，7.72(m，1H)，7.76(s，1H)，8.79(s，1H)，8.82(s，1H)；MS(ESI-)m/z?433(M-H)-.
Embodiment 156
4-[2-(7-ethyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenol
Embodiment 156A
4-amino-2-ethyl sulfenyl-pyrimidine-5-formonitrile HCN
With 2-ethyl-2-sulfo-pseudo-urea hydrobromate (1.52g, 8.19mmol), (oxyethyl group methylene radical) propane dinitrile (1.0g, 8.19mmol) and N, (3.57mL, 20.05mmol) solution in ethanol (20mL) was in stirring at room 3.5 hours for the N-diisopropyl ethyl amine.Collect the gained solid, use washing with alcohol, and dry under vacuum, obtain this title compound, be light yellow solid (580mg, 39%).
Embodiment 156B
N '-(5-cyano group-2-ethyl sulfenyl-pyrimidine-4-yl)-N, N-dimethyl-carbonamidine
(200mg, 1.11mmol) and N, (0.15mL, 1.11mmol) solution in toluene (10mL) refluxed 2.5 hours the dinethylformamide dimethyl acetal with the product of embodiment 156A.After being cooled to room temperature, solution decompression is concentrated, obtain this title compound, be colorless solid (260mg, 100%).
Embodiment 156C
4-[2-(7-ethyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenol
With the product 54mg of embodiment 6c, 0.234mmol) and the product of embodiment 156B (50mg, 0.213mmol) solution in acetate (2mL) was in 130 ℃ of heating 1.5 hours.Then solution is cooled to room temperature, under vacuum, removes acetate, and the gained resistates is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (51mg, 45%).
1H?NMR(300MHz，DMSO-d
6)δ?ppm：1.38(t，J＝7.4Hz，3H)，2.30(s，3H)，3.23(q，J＝7.3Hz，2H)，6.72(d，J＝8.8Hz，2H)，6.98(d，J＝8.1Hz，1H)，7.10(m，1H)，7.18(d，J＝8.7Hz，2H)，7.21(s，tH)，8.62(s，1H)，9.70(s，1H)，9.78(bs，1H)，10.85(s，1H)；MS(ESI)+m/z?422(M+H)+.
Embodiment 157
(7-ethyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-yl)-[5-methyl-2-(4-phenoxy group-phenyl sulfenyl)-phenyl]-amine
Embodiment 157a
5-methyl-2-(4-phenoxy group-phenyl sulfenyl)-phenyl amine
The product of embodiment 6c (0.500g, 1.91mmol) with phenyl-boron dihydroxide (0.701g, 5.74mmol), venus crystals (II) (0.659g, 3.83mmol) and triethylamine (0.387g 3.83mmol) is dissolved in CH together
2Cl
2In.In stirring at room 48 hours, add each above reagent of 2 equivalents at this moment.In room temperature restir 16 hours, add each reagent of 2eq at this moment again.In room temperature restir 16 hours.To react dilute with water, and extract with methyl acetate.Use Na
2SO
4Drying is filtered and is concentrated under vacuum, obtains crude product, it is passed through the silica gel column chromatography purifying, with 20% EtOAc/ hexane (0.100g, 15%) wash-out.According to the method for describing among the embodiment 51 with this product SnCl
2Reduction obtains this title compound (90mg, 98%).
Embodiment 157b
7-(ethylmercapto group)-N-(5-methyl-2-(4-phenoxy group thiophenyl) phenyl) Mi Dingbing [4,5-d] pyrimidine-4-amine
Method according to embodiment 156C, product with the product alternate embodiment 6c of embodiment 157a, solution reaction with the product of the product of embodiment 156B and embodiment 157a, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (16mg, 21%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.37(t，J＝7.35Hz，3H)，2.34(s，3H)，3.22(q，J＝7.35Hz，2H)，6.82(m，2H)，6.93(m，2H)，7.29(m，8H)，8.57(s，1H)，9.64(s，1H)，10.66(s，1H)；MS(ESI+)m/z?498(M+H)+.
Embodiment 158
4-[4-methyl-2-(7-piperidines-1-base-Mi Dingbing [4,5-fiT pyrimidine-4-base is amino)-the phenyl sulfenyl]-phenol
(42mg, 0.1mmol) solution in piperidines (1ml) was in 180 ℃ of microwave irradiations (CEM Discover microwave) 2 hours with the product of embodiment 156C.This solution concentrates under vacuum, and resistates uses the TFA purifying by the HPLC purifying, obtains this title compound, is trifluoroacetic acid salt form (17mg, 38%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.64(m，6H)，2.30(s，3H)，3.96(m，4H)，6.72(m，2H)，7.01(d，J＝7.72Hz，1H)，7.17(m，4H)，8.59(s，1H)，9.53(s，1H)，9.83(s，1H)，11.43(s，1H)；(ESI+)m/z?445(M+H)+.
Embodiment 159
Third-2-sulfonic acid 4-[2-(7-ethyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenylester
Product (0.042g with embodiment 156C, 0.1mmol), sec.-propyl SULPHURYL CHLORIDE (0.014g, 0.105mmol), 4-dimethylaminopyridine (0.002g, 0.01mmol) and diisopropyl ethyl amine (0.04g, 0.3mmol) 1, mixture in the 2-ethylene dichloride (2.0mL) stirred 1 hour, poured in the water (20mL), and extracted with methyl acetate (3 x 10mL).The extract that merges dried over sodium sulfate, filtration also concentrate under vacuum.Crude product by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (15mg, 23%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.27-1.46(m，9H)，2.37(s，3H)，3.20(q，J＝7.35Hz，2H)，3.56-3.70(m，1H)，7.09-7.20(m，2H)，7.19-7.29(m，3H)，7.34(s，1H)，7.39(d，J＝8.09Hz，2H)，8.56(s，1H)，9.61(s，1H)，10.72(s，1H)；MS(ESI)+m/z?528(M+H)+.
Embodiment 160
4-acetylamino-Phenylsulfonic acid 4-[2-(7-ethyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenylester
Method according to embodiment 159; substitute the sec.-propyl SULPHURYL CHLORIDE with 4-acetylamino-benzene sulfonyl chloride; product and 4-acetylamino-benzene sulfonyl chloride reaction with embodiment 156C; obtain crude product; it by the HPLC purifying, is used the TFA wash-out, obtain this title compound; be trifluoroacetic acid salt form (31mg, 50%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(t，J＝7.35Hz，3H)，2.10(s，3H)，2.35(s，3H)，3.20(q，J＝7.35Hz，2H)，6.85(d，J＝8.82Hz，2H)，7.13(d，J＝8.82Hz，2H)，7.26(m，3H)，7.71(m，2H)，7.81(m，2H)，8.52(s，1H)，9.59(s，1H)，10.48(s，1H)，10.71(s，1H)；MS(ESI+)m/z?619(M+H)+.
Embodiment 161
4-[4-methyl-2-(7-morpholine-4-base-Mi Dingbing [4,5-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
With the solution of product in morpholine (1ml) of embodiment 156C in 180 ℃ of microwave irradiations (CEMDiscover microwave) 2 hours.This solution concentrates under vacuum, and resistates uses the TFA wash-out by the HPLC purifying, obtains this title compound, is trifluoroacetic acid salt form (29mg, 65%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.30(s，3H)，3.73(t，J＝4.41Hz，4H)，3.94(bs，4H)，6.72(d，J＝8.82Hz，2H)，7.02(d，J＝8.09Hz，1H)，7.18(m，4H)，8.61(s，1H)，9.57(s，1H)，9.85(s，1H)，11.47(s，1H)；MS(ESI+)m/z?447(M+H)+.
Embodiment 162
Phenylsulfonic acid 4-[2-(7-ethyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenylester
According to the method for embodiment 159, substitute the sec.-propyl SULPHURYL CHLORIDE with benzene sulfonyl chloride, with product and the benzene sulfonyl chloride reaction of embodiment 156C, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (27mg, 48%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(t，J＝7.35Hz，3H)，2.36(s，3H)，3.20(q，J＝7.35Hz，2H)，6.85(m，2H)，7.11(m，2H)，7.20(d，J＝7.72Hz，1H)，7.35(m，2H)，7.65(m，2H)，7.86(m，3H)，8.51(s，1H)，9.58(s，1H)，10.65(s，1H)；MS(ESI+)562(M+H)+.
Embodiment 163
4-bromo-Phenylsulfonic acid 4-[2-(7-ethyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenylester
According to the method for embodiment 159, substitute the sec.-propyl SULPHURYL CHLORIDE with 4-bromo-benzene sulfonyl chloride, with embodiment 156C and the reaction of 4-bromo-benzene sulfonyl chloride, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(t，J＝7.35Hz，3H)，2.37(s，3H)，3.20(q，J＝7.35Hz，2H)，6.87(m，2H)，7.12(m，2H)，7.19(d，J＝7.05Hz，1H)，7.36(m，2H)，7.71(m，2H)，7.87(m，2H)，8.51(s，1H)，9.60(s，1H)，10.61(s，1H)；MS(ESI+)m/z?640/642(M+H)+.
Embodiment 164
(7-ethyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-yl)-[2-(4-hydroxyl-phenyl sulfenyl)-5-methyl-phenyl]-t-butyl carbamate
With the product of embodiment 156C and tert-Butyl dicarbonate and triethylamine in tetrahydrofuran (THF) in room temperature reaction 16 hours.Then mixture is poured in the water (10mL), and with gained solution with methyl acetate (3 x 10mL) extraction, merging with the extract dried over mgso, filter also concentratedly under vacuum, obtain this title compound.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.52(t，J＝7.35Hz，3H)，1.62(s，9H)，2.50(s，3H)，3.35(q，J＝7.35Hz，2H)，7.21(d，J＝8.46Hz，2H)，7.41(m，5H)，8.71(s，1H)，9.80(s，1H)，10.72(s，1H)；MS(ESI+)m/z?522(M+H)+.
Embodiment 165
4-[2-(7-ethyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenoxy group }-acetonitrile
With the product of embodiment 164 (52mg, 0.1mmol), the bromo-acetonitrile (0.008ml, 0.12mmol), cesium carbonate (0.065g, 0.2mmol) and tetrabutylammonium iodide (0.001g) at N, the mixture in the dinethylformamide (2ml) was in stirring at room 2 hours.This mixture distributes between water and methyl acetate.Organic layer salt water washing, dry (sodium sulfate) filters and vaporising under vacuum.In resistates, add methylene dichloride (2.5ml) and trifluoroacetic acid (2.5ml), then in stirring at room 1 hour.Vaporising under vacuum desolvates, and resistates is passed through the HPLC purifying, uses the TFA wash-out, obtains this title compound (9mg, 20%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.42(t，J＝7.35Hz，3H)，2.24(s，3H)，3.29(q，J＝7.35Hz，2H)，5.25(s，2H)，6.81(m，5H)，7.20(d，J＝8.46Hz，2H)，8.34(s，1H)，9.25(s，1H)，9.75(s，1H)；MS(ESI+)m/z?461(M+H)+.
Embodiment 166
[2-(4-benzyloxy-phenyl sulfenyl)-5-methyl-phenyl]-(7-ethyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-yl)-amine
According to the method for embodiment 165, substitute the bromo-acetonitrile with bromotoluene, with product and the bromotoluene reaction of embodiment 164, obtain crude product, with it by the silica gel chromatography purifying, with 98/2 methylene chloride as eluent, obtain this title compound (15mg, 29%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.20(t，J＝7.35Hz，3H)，2.27(s，3H)，3.08(q，J＝7.35Hz，2H)，5.44(s，2H)，6.74(d，J＝8.46Hz，2H)，6.95(m，3H)，7.20(d，J＝8.46Hz，2H)，7.35(m，5H)，8.77(s，1H)，9.42(s，1H)，9.81(s，1H)；MS(ESI+)m/z?512(M+H)+.
Embodiment 167
4-[4-(3-bromo-benzyloxy)-2-(2-methyl sulfenyl-thiazole is [4,5-d] pyrimidin-7-yl amino also)-phenyl sulfenyl]-phenol
Embodiment 167A
N '-(5-cyano group-2-methyl sulfenyl-thiazole-4-yl)-N, N-dimethyl-carbonamidine
This title compound is prepared as follows: use the method for embodiment 156B, with 4-amino-2-methyl sulfenyl-thiazole-5-formonitrile HCN and N, the reaction of dinethylformamide dimethyl acetal obtains this title compound, is white foam shape thing (0.132, g, 99%).
Embodiment 167B
4-[4-(3-bromo-benzyloxy)-2-(2-methyl sulfenyl-thiazole is [4,5-d] pyrimidin-7-yl amino also)-phenyl sulfenyl-phenol
With the product of embodiment 167A (66.0mg, 0.29mmol) and the product of embodiment 15A (118mg, 0.29mmol) solution in acetate (1mL) is preheating to 140 ℃ oil bath and was stirring 20 minutes.With the mixture cooling, and under vacuum, concentrate.Then the gained resistates is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (34mg, 17%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.75(s，3H)，5.12(s，2H)，6.70(d，J＝8.82Hz，1H)，6.96-7.05(m，2H)，7.07-7.16(m，3H)，7.33(t，J＝7.72Hz，1H)，7.41-7.46(m，1H)，7.51(d，J＝7.72Hz，1H)，7.63(s，1H)，8.47(s，1H)，9.73(s，2H)；MS(ESI)+m/z?583/585(M+H)+.
Embodiment 168
4-[4-(4-bromo-benzyloxy)-2-(2-methyl sulfenyl-thiazole is [4,5-d] pyrimidin-7-yl amino also)-phenyl sulfenyl]-phenol
Method according to embodiment 167B, product with the product alternate embodiment 15A of embodiment 16A, solution reaction with the product of the product of embodiment 167A and embodiment 16A, obtain roughage, with it by carry out purifying with methyl alcohol development, obtain this title compound, be white solid (46mg, 27%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.76(s，3H)，5.09(s，2H)，6.70(d，J＝8.46Hz，2H)，6.91-7.24(m，5H)，7.38(d，J＝8.09Hz，2H)，7.56(d，J＝8.09Hz，2H)，8.46(s，1H)，9.71(s，2H)；MS(ESI)+m/z583/585(M+H)+.
Embodiment 169
4-[4-methyl-2-(2-methyl sulfenyl-thiazole is [4,5-d] pyrimidin-7-yl amino also)-phenyl sulfenyl]-phenol
Method according to embodiment 167B, product with the product alternate embodiment 15A of embodiment 6c, solution reaction with the product of the product of embodiment 167A and embodiment 6c, obtain roughage, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (17mg, 11%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.27(s，3H)，2.76(s，3H)，6.76(d，J＝8.46Hz，2H)，6.82(d，J＝8.09Hz，1H)，7.06-7.22(m，4H)，8.49(s，1H)，9.86(s，2H)；MS(ESI)+m/z?413(M+H)+.
Embodiment 170
N-{4-[4-methyl-2-(2-methyl sulfenyl-thiazole is [4,5-d] pyrimidin-7-yl amino also)-phenyl sulfenyl]-phenyl }-ethanamide
According to the method for embodiment 167B,, the solution of the product of the embodiment 167A product with embodiment 7b is reacted with the product of the product alternate embodiment 15A of embodiment 7b, obtain roughage, it by carrying out purifying with the methyl alcohol development, is obtained this title compound (110mg, 83%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.03(s，3H)，2.29(s，3H)，2.76(s，3H)，6.96(d，J＝8.09Hz，1H)，7.14(d，J＝8.09Hz，1H)，7.18-7.26(m，J＝8.82Hz，3H)，7.54(d，J＝8.46Hz，2H)，8.45(s，1H)，9.74(s，1H)，10.04(s，1H)；MS(ESI)+m/z?454(M+H)+.
Embodiment 171
N-{4-[2-(the 1-tertiary butyl-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenyl }-ethanamide
Embodiment 171A
N '-(the 2-tertiary butyl-4-cyano group-2H-pyrazole-3-yl)-N, N-dimethyl-carbonamidine
This title compound is prepared as follows: use the method for embodiment 156B, with 5-amino-1-tertiary butyl-1H-pyrazoles-4-formonitrile HCN and N, the reaction of dinethylformamide dimethyl acetal obtains this title compound.
Embodiment 171B
N-{4-[2-(the 1-tertiary butyl-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenyl }-ethanamide
Method according to embodiment 167B, product with the product alternate embodiment 15A of embodiment 7b, and with the product of the product alternate embodiment 167A of embodiment 171A, product reaction with the solution and the embodiment 7b of the product of embodiment 171A obtains roughage, with it by the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (54mg, 32%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.74(s，9H)，2.03(s，3H)，2.41(s，3H)，7.13(d，J＝8.82Hz，2H)，7.49(m，4H)，7.62(s，1H)，8.41(s，1H)，8.47(s，1H)，8.76(s，1H)，10.06(s，1H)，10.39(s，1H)；MS(ESI+)m/z?447(M+H)+.
Embodiment 172
4-[2-(the 1-tertiary butyl-1H-pyrazolo [354-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenol
Method according to embodiment 167B, product with the product alternate embodiment 15A of embodiment 6c, and with the product of the product alternate embodiment 167A of embodiment 171A, the solution of embodiment 171A and the product of embodiment 6c are reacted, obtain roughage, it is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (40mg, 25%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.76(s，9H)，2.38(s，3H)，6.67(d，J＝8.82Hz，2H)，7.07(d，J＝8.82Hz，2H)，7.34(d，J＝8.09Hz，1H)，7.50(d，J＝8.09Hz，1H)，7.58(s，1H)，8.43(s，1H)，8.49(s，1H)，8.75(s，1H)，9.91(s，1H)，10.40(s，1H)；MS(ESI+)m/z?406(M+H)+.
Embodiment 173
4-[2-(7-sec.-propyl-Mi Dingbing [4,5-d] pyrimidine-4-base is amino)-4-aminomethyl phenyl sulfenyl]-phenol
Embodiment 173A
N '-(5-cyano group-2-sec.-propyl-pyrimidine-4-yl)-N, N-dimethyl-carbonamidine
This title compound is prepared as follows: use the method for embodiment 156B, with 4-amino-2-sec.-propyl-pyrimidine-5-formonitrile HCN and N, the dinethylformamide dimethyl acetal obtains this title compound.
Embodiment 173B
4-[2-(7-sec.-propyl-Mi Dingbing [4,5-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenol
Method according to embodiment 167B, product with the product alternate embodiment 15A of embodiment 6c, and with the product of the product alternate embodiment 167A of embodiment 173A, product reaction with the solution and the embodiment 6c of the product of embodiment 173A obtains roughage, with it by the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (39mg, 38%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.62Hz，6H)，2.30(s，3H)，3.29(m，1H)，6.70(d，J＝8.46Hz，2H)，6.98(d，J＝8.09Hz，1H)，7.17(m，4H)，8.72(s，1H)，9.76(s，1H)，9.90(s，1H)，11.13(s，1H)；MS(ESI+)m/z?404(M+H)+.
Embodiment 174
4-[4-benzyloxy-2-(7-sec.-propyl-Mi Dingbing [4,5-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Method according to embodiment 167B, product with the product alternate embodiment 15A of embodiment 27A, and with the product of the product alternate embodiment 167A of embodiment 173A, product reaction with the solution and the embodiment 27A of the product of embodiment 173A obtains roughage, with it by the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (10mg, 20%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.99Hz，6H)，3.27(m，1H)，5.11(s，2H)，6.64(d，J＝8.46Hz，2H)，7.06(m，5H)，7.40(m，5H)，8.64(s，1H)，9.65(s，1H)，9.84(s，1H)，10.88(s，1H)；MS(ESI+)m/z?496(M+H)+.
Embodiment 175
N-{4-[2-(7-ethyl sulfenyl-5-methyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenyl }-ethanamide
Embodiment 175A
N '-(5-cyano group-2-ethyl sulfenyl-6-methyl sulfenyl-pyrimidine-4-yl)-N, N-dimethyl-carbonamidine
This title compound is prepared as follows: use embodiment 156B method, with 4-amino-2-ethyl sulfenyl-6-methyl sulfenyl-pyrimidine-5-formonitrile HCN and N, the reaction of dinethylformamide dimethyl acetal obtains this title compound.
Embodiment 175B
N-{4-t2-(7-ethyl sulfenyl-5-methyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl-phenyl }-ethanamide
Method according to embodiment 167B, product with the product alternate embodiment 15A of embodiment 7b, and with the product of the product alternate embodiment 167A of embodiment 175A, product reaction with the solution and the embodiment 7b of the product of embodiment 175A obtains roughage, with it by the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (23mg, 35%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(t，J＝7.35Hz，3H)，2.03(s，3H)，2.24(s，3H)，2.40(s，3H)，3.18(q，J＝7.35Hz，2H)，6.84(m，3H)，7.19(d，J＝8.46Hz，2H)，7.49(d，J＝8.46Hz，2H)，7.82(s，1H)，9.97(s，1H)，12.25(s，1H)；MS(ESI+)m/z?509(M+H)+.
Embodiment 176
4-[2-(7-ethyl sulfenyl-5-methyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenol
Product reaction with the solution and the embodiment 6c of the product of embodiment 175A, method according to embodiment 167B, product with the product alternate embodiment 15A of embodiment 6c, and with the product of the product alternate embodiment 167A of embodiment 175A, obtain roughage, with it by the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (19mg, 31%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(t，J＝7.35Hz，3H)，2.21(s，3H)，2.44(s，3H)，3.19(q，J＝7.11Hz，2H)，6.70(m，5H)，7.18(d，J＝8.46Hz，2H)，7.84(s，1H)，9.67(s，1H)，12.24(s，1H)；MS(ESI+)m/z?468(M+H)+.
Embodiment 177
N-{4-[2-(2-cyano methyl sulfenyl-thiazole is [4,5-d] pyrimidin-7-yl amino also)-4-methyl-phenyl sulfenyl]-phenyl }-ethanamide
Embodiment 177A
N '-(5-cyano group-2-cyano methyl sulfenyl-thiazole-4-yl)-N, N-dimethyl-carbonamidine
This title compound is prepared as follows: use the method for embodiment 156B, with 4-amino-2-cyano methyl sulfenyl-thiazole-5-formonitrile HCN and N, the reaction of dinethylformamide dimethyl acetal obtains this title compound.
Embodiment 177B
N-{4-[2-(2-cyano methyl sulfenyl-thiazole is [4,5-d] pyrimidin-7-yl amino also)-4-methyl-phenyl sulfenyl]-phenyl }-ethanamide
Method according to embodiment 167B, product with the product alternate embodiment 15A of embodiment 7b, and with the product of the product product alternate embodiment 167A of embodiment 177A, solution reaction with the product of the product of embodiment 177A and embodiment 7b obtains roughage, with it by the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (64mg, 52%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.03(s，3H)，2.30(s，3H)，4.54(s，2H)，6.95(d，J＝8.09Hz，1H)，7.15(d，J＝8.09Hz，1H)，7.23(m，3H)，7.55(d，J＝8.46Hz，2H)，8.51(s，1H)，9.91(s，1H)，10.04(s，1H)；MS(ESI+)m/z?479(M+H)+.
Embodiment 178
7-[2-(4-hydroxyl-phenyl sulfenyl)-5-methyl-phenyl amino]-thiazole [4,5-d] pyrimidine-2-base sulfenyl also }-acetonitrile
Method according to embodiment 167B, product with the product alternate embodiment 15A of embodiment 6c, and with the product of the product alternate embodiment 167A of embodiment 177A, the solution of the product of the product of embodiment 177A and embodiment 6c is reacted, obtains roughage, with it by the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (62mg, 56%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.27(s，3H)，4.54(s，2H)，6.77(m，3H)，7.18(m，4H)，8.53(s，1H)，9.85(s，1H)，9.97(s，1H)；MS(ESI+)m/z?438(M+H)+.
Embodiment 179
4-[4-benzyloxy-2-(7-seven fluoropropyls-Mi Dingbing [4,5-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 179A
N '-(5-cyano group-2-seven fluoropropyls-pyrimidine-4-yl)-N, N-dimethyl-carbonamidine
This title compound is prepared as follows: with the method for embodiment 156B, with 4-amino-2-seven fluoropropyls-pyrimidine-5-formonitrile HCN and N, the reaction of dinethylformamide dimethyl acetal obtains this title compound.
Embodiment 179B
4-[4-benzyloxy-2-(7-seven fluoropropyls-Mi Dingbing [4,5-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Method according to embodiment 167B, product with the product alternate embodiment 15A of embodiment 27A, and with the product of the product alternate embodiment 167A of embodiment 179A, solution reaction with the product of the product of embodiment 179A and embodiment 27A obtains roughage, with it by the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (24mg, 39%).
1H?NMR(300MHz，DMSO.D6)δ?ppm：5.11(s，2H)，6.61(d，J＝8.46Hz，2H)，7.04(dd，J＝8.82，2.57Hz，1H)，7.10(d，J＝8.46Hz，2H)，7.17(d，J＝2.57Hz，1H)，7.23(d，J＝8.82Hz，1H)，7.40(m，5H)，8.79(s，1H)，9.63(s，1H)，10.12(s，1H)，11.01(s，1H)；MS(ESI+)m/z?622(M+H)+.
Embodiment 180
(7-sec.-propyl-Mi Dingbing [4,5-d] pyrimidine-4-yl)-[5-methyl-2-(4-phenoxy group-phenyl sulfenyl)-phenyl]-amine
Method according to embodiment 167B, product with the product alternate embodiment 15A of embodiment 157a, and with the product of the product alternate embodiment 167A of embodiment 173A, the solution of the product of the product of embodiment 173A and embodiment 157a is reacted, obtain roughage, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)，2.34(s，3H)，3.24(m，1H)，6.81(d，J＝8.82Hz，2H)，6.94(d，J＝7.72Hz，2H)，7.28(m，8H)，8.63(s，1H)，9.83(s，1H)，10.78(s，1H)；MS(ESI+)m/z?480(M+H))+.
Embodiment 181
(7-ethyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-yl)-[3-(4-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl]-amine embodiment
Embodiment 181A
1-(4-methoxyl group-phenyl sulfenyl)-3-methyl-5-nitro-benzene
With the cuprous (0.94g of 4-methoxybenzenethiol, 4.63mmol) (its spend the night by excessive 4-methoxybenzenethiol and cupric oxide are refluxed in ethanol and by the preparation of filtering separation products therefrom) and 3-bromo-5-nitrotoluene (1.0g, 4.63mmol) (as J.Am.Chetn.Soc.Vol.78, pp1992, described in 1956, in two steps, make by 3-nitro-4-phenylmethylamine) in the mixture of quinoline (5mL) and pyridine (1mL), be heated to 165 ℃ 2 hours.After the termination of the HCI aqueous solution, required product by chromatography purification on silica, as eluent, is obtained this title compound (0.96g, 75%) with methyl acetate/hexane.
Embodiment 181B
3-(4-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl amine
According to the method for embodiment 147C, use the product of the product alternate embodiment 147B of embodiment 181A, the method reduction with embodiment 181A obtains this title compound.
Embodiment 181C
(7-ethyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-yl)-[3-(4-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl]-amine
According to the method for embodiment 156C, use the product of the product alternate embodiment 6c of embodiment 181B, the product of embodiment 181B and the product of embodiment 156B are reacted, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(500MHz，DMSO-D6)δ?ppm：1.37(t，J＝7.32Hz，3H)，2.28(s，3H)，3.21(q，J＝7.32Hz，2H)，3.79(s，3H)，6.83(s，1H)，7.03(d，J＝9.16Hz，2H)，7.42-7.53(m，4H)，8.71(s，1H)，9.72(s，1H)，10.39(s，1H)；MS(ESI+)m/z?436(M+H)+.
Embodiment 182
(7-ethyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-yl)-[3-(3-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl]-amine
Embodiment 182A
3-(3-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl amine
Method according to embodiment 181A, cuprous with the cuprous alternative 4-methoxybenzenethiol of 3-methoxybenzenethiol, cuprous and the 3-bromo-5-nitrotoluene reaction with the 3-methoxybenzenethiol, obtain 1-(3-methoxyl group-phenyl sulfenyl)-3-methyl-5-nitro-benzene, with its method reduction, obtain this title compound according to embodiment 181B.
Embodiment 182B
(7-ethyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-yl)-[3-(3-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl]-amine
According to the method for embodiment 156C, use the product of the product alternate embodiment 6c of embodiment 182A, the product of embodiment 182A and the product of embodiment 156B are reacted, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.37(t，J＝7.35Hz，3H)，2.33(s，3H)，3.21(q，J＝7.11Hz，2H)，3.74(s，3H)，6.84-6.96(m，J＝1.10Hz，3H)，7.05(s，1H)，7.32(dd，J＝9.01，7.17Hz，1H)，7.60(s，1H)，7.65(s，1H)，8.74(s，1H)，9.74(s，1H)，10.47(s，1H)；MS(ESI+)m/z?436(M+H)+.
Embodiment 183
(7-benzyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-yl)-(5-ethyl-2-phenyl sulfenyl-phenyl)-amine
Embodiment 183A
5-ethyl-2-phenyl sulfenyl-phenyl amine
According to embodiment 5H method, substitute 4-chloro-3-nitrotoluene with 1-chloro-4-ethyl-2-nitro-benzene, sodium salt and 1-chloro-4-ethyl-2-nitro-benzene reaction with thiophenol obtain 4-ethyl-2-nitro-1-phenyl sulfenyl-benzene, with its method reduction, obtain this title compound according to embodiment 51.
Embodiment 183B
4-amino-2-benzyl sulfenyl-pyrimidine-5-formonitrile HCN
With 2-benzyl-2-sulfo-pseudo-urea hydrochloride (5.0g, 24.67mmol), (oxyethyl group methylene radical) propane dinitrile (3.01g, 24.67mmol) and N, (10.75mL, 61.68mmol) solution in ethanol (50mL) was in stirring at room 18 hours for the N-diisopropyl ethyl amine.Collect the gained solid, use washing with alcohol, and dry under vacuum, obtain this title compound (2.69g.45%).
Embodiment 183C
N '-(2-benzyl sulfenyl-5-cyano group-pyrimidine-4-yl)-N, N-dimethyl-carbonamidine
According to the method for embodiment 156B, with the product of the product alternate embodiment 156B of embodiment 183B, with the solution and the N of the product of embodiment 183B, the reaction of dinethylformamide dimethyl acetal obtains this title compound.
Embodiment 183D
(7-benzyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-yl)-(5-ethyl-2-phenyl sulfenyl-phenyl)-amine
Method according to embodiment 156C, use the product of alternate embodiment 6c with the product of embodiment 183A, and with the product of the product alternate embodiment 156B of embodiment 183C, the product of embodiment 183A and the product of embodiment 183C are reacted, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.MS(ESI+)m/z482(M+H)+。
Embodiment 184
(7-benzyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-yl)-[2-(4-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl]-amine
Method according to embodiment 156C, product with 2-(4-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl amine alternate embodiment 6c, and with the product of the product alternate embodiment 156B of embodiment 183C, product and 2-(4-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl amine (embodiment 118) reaction with embodiment 183C, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.MS(ESI+)m/z?498(M+H)+。
Embodiment 185
(7-benzyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-yl)-(5-fluoro-2-phenyl sulfenyl-phenyl)-amine
Embodiment 185A
5-fluoro-2-phenyl sulfenyl-phenyl amine
According to the method that is similar to described in embodiment 6a, 6b and the 6c, substitute the 4-mercapto-phenol with thiophenol, and, 4-fluoro-2-nitrophenols is reacted with the alternative 4-methyl of 4-fluoro-2-nitrophenols-2-nitrophenols, obtain this title compound.
Embodiment 185B
(7-benzyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-yl)-(5-fluoro-2-phenyl sulfenyl-phenyl)-amine
Method according to embodiment 156C, product with the product alternate embodiment 6c of embodiment 203A, and with the product of the product alternate embodiment 156B of embodiment 185A, the product of embodiment 185A and the product of embodiment 203A are reacted, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.MS(ESI+)m/z?472(M+H)+。
Embodiment 186
(7-benzyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-yl)-[2-(4-fluoro-phenyl sulfenyl)-5-methyl-phenyl]-amine
Method according to embodiment 156C, product with 2-(4-fluoro-phenyl sulfenyl)-5-methyl-phenyl amine alternate embodiment 6c, and with the product of the product alternate embodiment 156B of embodiment 183C, product and 2-(4-fluoro-phenyl sulfenyl)-5-methyl-phenyl amine (embodiment 124) reaction with embodiment 183C, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.MS(ESI+)m/z?486(M+H)+。
Embodiment 187
(7-benzyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-yl)-(tolyl sulfenyl-phenyl between 5-methyl-2-)-amine
Method according to embodiment 156C, product with tolyl sulfenyl between 5-methyl-2--phenyl amine alternate embodiment 6c, and with the product of the product alternate embodiment 156B of embodiment 183C, with tolyl sulfenyl between the product of embodiment 183C and 5-methyl-2--phenyl amine reaction, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.MS(ESI+)m/z?482(M+H)+。
Embodiment 188
(7-benzyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-yl)-(5-methyl-2-phenyl sulfenyl-phenyl)-amine
Method according to embodiment 156C, product with the product alternate embodiment 6c of embodiment 51, and with the product of the product alternate embodiment 156B of embodiment 183C, the product of embodiment 183C and the product of embodiment 51 are reacted, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.MS(ESI+)m/z?468(M+H)+。
Embodiment 189
3-[2-(7-benzyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-base is amino)-4-methyl-phenyl sulfenyl]-phenol
Method according to embodiment 156C, product with 3-(2-amino-4-methyl-phenyl sulfenyl)-phenol alternate embodiment 6c, and with the product of the product alternate embodiment 156B of embodiment 183C, product and 3-(2-amino-4-methyl-phenyl sulfenyl)-phenol (embodiment 129) reaction with embodiment 183C, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.MS(ESI+)m/z?484(M+H)+。
Embodiment 190
(7-benzyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-yl)-[3-(3-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl]-amine
Method according to embodiment 156C, product with the product alternate embodiment 6c of embodiment 182A, and with the product of the product alternate embodiment 156B of embodiment 183C, the product of embodiment 183C and the product of embodiment 182A are reacted, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.34(s，3H)，3.74(s，3H)，4.52(s，2H)，6.34-6.97(m，J＝1.10Hz，3H)，7.05(s，1H)，7.21-7.39(m，4H)，7.46-7.53(m，2H)，7.61(s，1H)，7.66(s，1H)，8.76(s，1H)，9.77(s，1H)，10.47(s，1H)；MS(ESI+)m/z＝498(M+H)+.
Embodiment 191
(7-benzyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-yl)-[3-(4-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl]-amine
Method according to embodiment 156C, product with embodiment 181B alternate embodiment 6c, and with the product of the product alternate embodiment 156B of embodiment 183C, the product of embodiment 183C and the product of embodiment 181B are reacted, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.28(s，3H)，3.79(s，3H)，4.52(s，2H)，6.83(s，1H)，7.04(d，J＝8.82Hz，2H)，7.19-7.38(m，2H)，7.41-7.55(m，5H)，8.74(s，1H)，9.75(s，1H)，10.42(s，1H)；MS(ESI+)m/z?497(M+H)+.
Embodiment 192
(7-benzyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-yl)-[2-(4-methoxyl group-phenoxy group)-5-methyl-phenyl]-amine
Method according to embodiment 156C, product with the product alternate embodiment 6c of embodiment 116B, and with the product of the product alternate embodiment 156B of embodiment 183C, the product of embodiment 183C and the product of embodiment 116B are reacted, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.MS(ESI+)m/z?482(M+H)+。
Embodiment 193
(7-benzyl sulfenyl-Mi Dingbing [4,5-d] pyrimidine-4-yl)-(5-methyl-2-p-methylphenyl sulfenyl-phenyl)-amine
Method according to embodiment 156C, product with 5-methyl-2-p-methylphenyl sulfenyl-phenyl amine alternate embodiment 6c, and with the product of the product alternate embodiment 156B of embodiment 183C, the product of embodiment 183C is reacted with 5-methyl-2-p-methylphenyl sulfenyl-phenyl amine, obtain crude product, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.MS(ESI+)m/z?482(M+H)+。
Embodiment 194
4-[4-(3-bromo-benzyloxy)-2-(Mi Dingbing [4,5-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 194A
N '-(5-cyano group-pyrimidine-4-yl)-N, N-dimethyl-carbonamidine
This title compound is prepared as follows: use the method for embodiment 156B, with 4-amino-5-pyrimidine formonitrile HCN (Aldrich) and N, the reaction of dinethylformamide dimethyl acetal obtains this title compound.
Embodiment 194B
4-[4-(3-bromo-benzyloxy)-2-(Mi Dingbing [4,5-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
According to the method for embodiment 156C, with the product of the product alternate embodiment 6c of embodiment 15A, and with the product of the product alternate embodiment 156B of embodiment 194A, the product of embodiment 194A and the product of embodiment 15A are reacted, obtain crude product, it by the HPLC purifying, is used NH
4The OAc wash-out obtains this title compound.
1H?NMR(300MHz，DMSO-D6)δ?ppm：5.12(s，2H)，6.64(d，J＝8.82Hz，2H)，6.93-7.04(m，1H)，7.10(d，J＝8.82Hz，2H)，7.14-7.23(m，2H)，7.36(t，J＝7.72Hz，1H)，7.43-7.49(m，1H)，7.54(dt，J＝7.81，1.61Hz，1H)，7.65(d，J＝1.47Hz，1H)，9.04(m，1H)，9.63(s，1H)，10.29(m，1H)；MS(ESI-)m/z?531(M-H)-.
Embodiment 195
4-[4-benzyloxy-2-(Mi Dingbing [4,5-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
According to the method for embodiment 156C, with the product of the product alternate embodiment 6c of embodiment 27A, and with the product of the product alternate embodiment 156B of embodiment 194A, the product of embodiment 194A and the product of embodiment 27A are reacted, obtain crude product, it by the HPLC purifying, is used NH
4The OAc wash-out obtains this title compound.
1H?NMR(300MHz，DMSO-D6)δ?ppm：5.10(s，2H)，6.63(d，J＝8.46Hz，2H)，6.94-7.05(m，1H)，7.10(d，J＝8.82Hz，2H)，7.18(d，J＝7.72Hz，2H)，7.29-7.51(m，5H)，9.05(m，1H)，9.63(s，1H)，9.92(s，1H)，10.66(s，1H)；MS(ESI-)m/z?452(M-H)-.
Embodiment 196
(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-[3-(4-methoxyl group-phenyl sulfenyl)-5-methyl-phenyl]-amine
Use the method for embodiment 36I, use the product of the product alternate embodiment 36H of embodiment 181B, the product of embodiment 181B and the product of embodiment 36E are reacted, obtain roughage, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(500MHz，DMSO-D6)δ?ppm：1.33(d，J＝6.71Hz，6H)，2.29(s，3H)3.25(qq，J＝7.02，6.90Hz，1H)，3.79(s，3H)，6.88(s，1H)，7.03(d，J＝9.16Hz，2H)，7.42(d，J＝7.93Hz，2H)，7.45(d，J＝8.54Hz，2H)，7.77(d，J＝8.54Hz，1H)，8.81(s，1H)，8.95(d，J＝8.54Hz，1H)，10.74(s，1H)；MS(ESI+)m/z?417(M+H)+.
Embodiment 197
4-[3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-5-methyl-phenyl sulfenyl]-phenol
Embodiment 197A
4-(3-amino-5-methyl-phenyl sulfenyl)-phenol
(0.5g 2.0mmol) handled 1 hour with boron tribromide (10mmol) in room temperature the product of embodiment 181B that will be in methylene dichloride.Water extracts this solution, and is then that organic solution is dry and concentrated, obtains this title compound.
Embodiment 197B
4-[3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-5-methyl-phenyl sulfenyl]-phenol
Use the method for embodiment 36I, use the product of the product alternate embodiment 36H of embodiment 197A, the product reaction of the product of embodiment 197A and embodiment 36E, obtain roughage, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(s，3H)，1.33(s，3H)，2.28(s，3H)，3.27(qq，J＝6.86Hz，1H)，6.79-6.91(m，1H)，6.86(d，J＝8.82Hz，2H)，7.30(s，1H)，7.36(d，J＝8.46Hz，2H)，7.35(s，1H)，7.83(d，J＝8.46Hz，1H)，8.87(s，1H)，8.98(d，J＝8.82Hz，1H)，9.92(s，1H)，11.06(s，1H)；MS(ESI-)m/z?403(M+H)+.
Embodiment 198
4-[5-(3-fluoro-benzyloxy)-2-(4-hydroxyl-phenyl sulfenyl)-phenyl amino]-7-methyl-pyrido [2,3-d] pyrimidine-6-formonitrile HCN
Embodiment 198A
N '-(3,5-dicyano-6-methyl-pyridine-2-yl)-N, N-dimethyl-carbonamidine
With 2-amino-6-methyl-pyridine-3, and the 5-dimethoxy nitrile (0.158g, 1.0mmol) and N, dinethylformamide dimethyl acetal (0.119g, the 1.0mmol) heating 6 hours under refluxing of the solution in toluene (10mL).After being cooled to room temperature, solution decompression is concentrated, obtain this title compound, be brown solid (0.2g, 94%).
Embodiment 198B
4-[5-(3-fluoro-benzyloxy)-2-(4-hydroxyl-phenyl sulfenyl)-phenyl amino]-7-methyl-pyrido [2,3-d] pyrimidine-6-formonitrile HCN
Use the method for embodiment 10F, use the product of the product alternate embodiment 10E of embodiment 198A, the product of embodiment 198A and the product of embodiment 10B are reacted, obtain roughage, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (18mg, 29%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.82(s，3H)，5.13(s，2H)，6.64(d，J＝8.46Hz，2H)，6.99(d，J＝9.56Hz，1H)，7.09(d，J＝8.82Hz，2H)，7.12-7.21(m，3H)，7.29(d，J＝7.72Hz，2H)，7.39-7.53(m，1H)，8.63(s，1H)，9.36(s，1H)，9.64(s，1H)，10.33(s，1H).
Embodiment 199
[3-(3-fluoro-benzyloxy)-phenyl]-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Embodiment 199A
(3-fluoro-benzyloxy)-3-nitro-benzene
With 3-nitro-phenol (0.278g, 2.0mmol), 1-brooethyl-3-fluoro-benzene (0.258ml, 2.1mmol), salt of wormwood (0.553g, 4.0mmol) and tetrabutylammonium iodide (0.001g) 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 chamber, obtain with quantitative yield and get this title compound.
Embodiment 199B
(3-fluoro-benzyloxy)-3-amino-benzene
With the product of embodiment 199A (0.494g, 2.0mmol), iron powder (0.56g, 10.0mmol) and ammonium chloride (0.54g, 10.0mmol) solution in methyl alcohol (20mL), tetrahydrofuran (THF) (20mL) and water (10mL) is heated to and refluxed 2 hours.The gained mixture filters by Celite pad, and filtrate is concentrated.Add methyl acetate then, stirred 30 minutes, filter and under vacuum, concentrate, obtain this title compound (0.405g, 93%).
Embodiment 199C
[3-(3-fluoro-benzyloxy)-phenyl]-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Use the method for embodiment 10F, product with the product 199B alternate embodiment 10E of embodiment, the product of embodiment 199B and the product of embodiment 10B are reacted, obtain roughage, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (32mg, 89%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.74(s，3H)，5.18(s，2H)，6.98(m，1H)，7.18(m，1H)，7.42(m，6H)，7.79(d，J＝8.46Hz，1H)，8.92(s，1H)，9.00(d，J＝8.82Hz，1H)，11.16(s，1H)；MS(ESI+)m/z?361(M+H)+.
Embodiment 200
[3-(3-fluoro-benzyloxy)-phenyl]-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Use the method for embodiment 36I, use the product of the product alternate embodiment 36H of embodiment 199B, the product of embodiment 199B and the product of embodiment 36E are reacted, obtain roughage, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)，3.26(m，1H)，5.18(s，2H)，6.93(m，1H)，7.17(m，1H)，7.42(m，6H)，7.79(d，J＝8.46Hz，1H)，8.85(s，1H)，9.00(d，J＝8.46Hz，1H)，10.76(s，1H)；MS(ESI+)m/z?389(M+H)+.
Embodiment 201
[3-(3-fluoro-benzyloxy)-phenyl]-pyrido [2,3-d] pyrimidine-4-base-amine
Use the method for embodiment 57E, use the product of the product 199B alternate embodiment 57D of embodiment, the product of embodiment 199B and the product of embodiment 57A are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：5.18(s，2H)，6.98(m，1H)，7.18(m，1H)，7.42(m，6H)，7.87(dd，J＝8.27，4.60Hz，1H)，8.93(s，1H)，9.14(m，2H)，11.12(s，1H)；MS(ESI+)m/z?347(M+H)+.
Embodiment 202
[3-(4-fluoro-benzyloxy)-phenyl]-pyrido [2,3-d] pyrimidine-4-base-amine
Embodiment 202A
3-(4-fluoro-benzyloxy)-phenyl amine
According to the method for embodiment 199A, substitute 1-brooethyl-3-fluoro-benzene with 1-brooethyl-4-fluoro-benzene, with 3-nitro-phenol and 1-brooethyl-4-fluoro-benzene reaction, according to the method reduction of embodiment 199B, obtain this title compound then.
Embodiment 202B
[3-(4-fluoro-benzyloxy)-phenyl]-pyrido [2,3-d] pyrimidine-4-base-amine
Use the method for embodiment 57E, product with the product alternate embodiment 57D of embodiment 202A, the product of embodiment 202A and the product of embodiment 57A are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (20mg, 58%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：5.13(s，2H)，6.92(m，1H)，7.24(m，2H)，7.38(m，2H)，7.55(m，3H)，7.80(dd，J＝8.27，4.60Hz，1H)，8.87(s，1H)，9.07(dd，J＝8.27，1.65Hz，1H)，9.12(dd，J＝4.41，1.84Hz，1H)，10.69(s，1H)；MS(ESI+)m/z?347(M+H)+.
Embodiment 203
[3-(3,5-two fluoro-benzyloxies)-phenyl]-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Embodiment 203A
3-(3,5-two fluoro-benzyloxies)-phenyl amine
According to the method for embodiment 199A, with 1-brooethyl-3,5-two fluoro-benzene substitute 1-brooethyl-3-fluoro-benzene, and with 3-nitro-phenol and 1-brooethyl-3, the reaction of 5-two fluoro-benzene according to the method reduction of embodiment 199B, obtains this title compound then.
Embodiment 203B
[3-(3,5-two fluoro-benzyloxies)-phenyl]-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Use the method for embodiment 36I, product with the product alternate embodiment 36H of embodiment 203A, the product of embodiment 203A and the product of embodiment 36E are reacted, obtain roughage, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (26mg, 67%).
1H?NMR(300MHz，DMSO-D6)δppm：1.35(d，J＝6.99Hz，6H)，3.26(m，1H)，5.19(s，2H)，6.95(m，1H)，7.20(m，3H)，7.38(m，2H)，7.54(s，1H)，7.82(d，J＝8.46Hz，1H)，8.86(s，1H)，9.02(d，J＝8.46Hz，1H)，10.89(s，1H)；MS(ESI+)m/z?407(M+H)+.
Embodiment 204
[3-(3,5-two fluoro-benzyloxies)-phenyl]-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Use the method for embodiment 10F, use the product of the product alternate embodiment 10E of embodiment 203A, the product of embodiment 203A and the product of embodiment 10B are reacted, obtain roughage, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.73(s，3H)，5.19(s，2H)，6.95(m，1H)，7.21(m，3H)，7.38(m，2H)，7.55(s，1H)，7.75(d，J＝8.46Hz，1H)，8.87(s，1H)，8.98(d，J＝8.46Hz，1H)，10.90(s，1H)；MS(ESI+)m/z?379(M+H)+.
Embodiment 205
[3-(3,5-two fluoro-benzyloxies)-phenyl]-pyrido [2,3-d] pyrimidine-4-base-amine
Use the method for embodiment 57E, use the product of the product alternate embodiment 57D of embodiment 203A, the product of embodiment 203A and the product of embodiment 57A are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：5.19(s，2H)，6.94(m，1H)，7.21(m，3H)，7.39(d，J＝5.15Hz，2H)，7.58(s，1H)，7.81(dd，J＝8.09，4.41Hz，1H)，8.87(s，1H)，9.10(m，2H)，10.79(s，1H)；MS(ESI+)m/z?365(M+H)+.
Embodiment 206
4-[3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxymethyl]-benzonitrile
Embodiment 206A
4-(3-amino-phenoxymethyl)-benzonitrile
According to the method for embodiment 199A, substitute 1-brooethyl-3-fluoro-benzene with 4-brooethyl-benzonitrile, with 3-nitro-phenol and 4-brooethyl-benzonitrile reaction, according to the method reduction of embodiment 199B, obtain this title compound then.
Embodiment 206B
4-[3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxymethyl]-benzonitrile
Use the method for embodiment 10F, use the product of the product alternate embodiment 10E of embodiment 206A, the product of embodiment 206A and the product of embodiment 10B are reacted, obtain roughage, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.71(s，3H)，5.27(s，2H)，6.92(m，1H)，7.38(m，2H)，7.59(s，1H)，7.68(m，3H)，7.89(d，J＝8.46Hz，2H)，8.83(s，1H)，8.95(d，J＝8.82Hz，1H)，10.64(s，1H)；MS(ESI+)m/z?368(M+H)+.
Embodiment 207
4-[3-(pyridine [2,3-d] pyrimidine-4-base is amino)-phenoxymethyl]-benzonitrile
Use the method for embodiment 57E, use the product of the product alternate embodiment 57D of embodiment 206A, the product of embodiment 206A and the product of embodiment 57A are reacted, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：5.27(s，2H)，6.93(m，1H)，7.38(m，2H)7.60(s，1H)，7.67(d，J＝8.46Hz，2H)，7.80(dd，J＝8.46，4.41Hz，1H)，7.90(d，J＝8.46Hz，2H)，8.86(s，1H)，9.07(dd，J＝8.46，1.65Hz，1H)，9.13(dd，J＝4.41，1.65Hz，1H)，10.72(s，1H)；MS(ESI+)m/z?354(M+H)+.
Embodiment 208
3-[3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxymethyl]-benzonitrile
Embodiment 208A
3-(3-amino-phenoxymethyl)-benzonitrile
According to the method for embodiment 199A, substitute 1-brooethyl-3-fluoro-benzene with 3-brooethyl-benzonitrile, with 3-nitro-phenol and 3-brooethyl-benzonitrile reaction, according to the method reduction of embodiment 199B, obtain this title compound then.
Embodiment 208B
3-[3-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxymethyl]-benzonitrile
Use the method for embodiment 36I,, the product of embodiment 208A and the product of embodiment 36E are reacted with the product of embodiment 208A alternate embodiment 36H, obtain roughage, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (22mg, 56%).
1H?NMR(300MHz，DMSO-D6)δppm：1.34(d.J＝6.99Hz，6H)，3.26(m，1H)，5.22(s，2H)，6.93(m，1H)，7.38(m，2H)，7.62(m，2H)，7.77(d，J＝8.46Hz，1H)，7.84(m，2H)，7.95(s，1H)，8.83(s，1H)，8.99(d，J＝8.46Hz，1H)，10.67(s，1H)；MS(ESI+)m/z?396(M+H)+.
Embodiment 209
2-[3-(pyridine [2,3-d] pyrimidine-4-base is amino)-phenoxymethyl]-benzonitrile
Embodiment 209A
2-(3-amino-phenoxymethyl)-benzonitrile
According to the method for embodiment 199A, substitute 1-brooethyl-3-fluoro-benzene with 2-brooethyl-benzonitrile, with 3-nitro-phenol and 2-brooethyl-benzonitrile reaction, according to the method reduction of embodiment 199B, obtain this title compound then.
Embodiment 209B
2-[3-(pyridine [2,3-d] pyrimidine-4-base is amino)-phenoxymethyl]-benzonitrile
Use the method for embodiment 36I, use the product of the product alternate embodiment 36H of embodiment 209A, the product of embodiment 209A and the product of embodiment 36E are reacted, obtain roughage, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：5.30(s，2H)，7.02(m，1H)，7.42(m，2H)，7.59(m，2H)，7.78(m，2H)，7.85(dd，J＝8.46，4.41Hz，1H)，7.94(d，J＝7.72Hz，1H)，8.92(s，1H)，9.14(m，2H)，11.03(s，1H)；MS(ESI+)m/z?354(M+H)+.
Embodiment 210
(3-benzyloxy-phenyl)-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Embodiment 210A
3-benzyloxy-phenyl amine
According to the method for embodiment 199A, substitute 1-brooethyl-3-fluoro-benzene with brooethyl-benzene, with 3-nitro-phenol and brooethyl-benzene reaction, according to the method reduction of embodiment 199B, obtain this title compound then.
Embodiment 210B
(3-benzyloxy-phenyl)-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Use the method for embodiment 36I, product with the product alternate embodiment 36H of embodiment 210A, the product of embodiment 210A and the product of embodiment 36E are reacted, obtain roughage, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (5mg, 10%).
1H?NMR(500MHz，DMSO-D6)δppm：1.33(d，J＝6.84Hz，6H)，3.25(qt，J＝6.84Hz，1H)，5.13(s，2H)，6.89-6.94(m，J＝2.20，2.20Hz，1H)，7.33-7.41(m，5H)，7.45-7.48(m，J＝7.32Hz，2H)，7.54-7.58(m，J＝2.44，2.44Hz，1H)，7.76(d，J＝8.30Hz，1H)，8.84(s，1H)，9.02(d，J＝8.30Hz，1H)；MS?ESI+m/z?371(M+H)+，ESI-m/z?369(M-H)-.
Embodiment 211
[3-(3-bromo-benzyloxy)-phenyl]-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Embodiment 211A
3-(3-bromo-benzyloxy)-phenyl amine
According to the method for embodiment 199A, substitute 1-brooethyl-3-fluoro-benzene with 1-bromo-3-brooethyl-benzene, with 3-nitro-phenol and 1-bromo-3-brooethyl-benzene reaction, according to the method reduction of embodiment 199B, obtain this title compound then.
Embodiment 211B
[3-(3-bromo-benzyloxy)-phenyl]-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Use the method for embodiment 36I, product with the product alternate embodiment 36H of embodiment 211A, the product of embodiment 211A and the product of embodiment 36E are reacted, obtain roughage, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (1mg, 1%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.34(d，J＝6.99Hz，6H)，5.16(s，2H)，6.94(td，J＝4.50，2.39Hz，1H)，7.39(td，J＝7.63，3.86Hz，3H)，7.46-7.51(m，1H)，7.53-7.57(m，2H)，7.69(s，1H)，7.80(d，J＝8.46Hz，1H)，8.86(s，1H)，9.01(d，J＝8.46Hz，1H)，10.84(s，1H)；MS?ESI+m/z?451(M+H)+，ESI-m/z?449(M-H)-.
Embodiment 212
(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-[3-(3-methoxyl group-benzyloxy)-phenyl]-amine
Embodiment 212A
3-(3-methoxyl group-benzyloxy)-phenyl amine
According to the method for embodiment 199A, substitute 1-brooethyl-3-fluoro-benzene with 1-brooethyl-3-methoxyl group-benzene, with 3-nitro-phenol and 1-brooethyl-3-methoxyl group-benzene reaction, the back obtains this title compound according to the method reduction of embodiment 199B.
Embodiment 212B
(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-[3-(3-methoxyl group-benzyloxy)-phenyl]-amine
Use the method for embodiment 36I,, the product of embodiment 212A and the product of embodiment 36E are reacted with the product of embodiment 212A alternate embodiment 36H, obtain roughage, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (8mg, 9%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.99Hz，6H)，3.76(s，3H)，5.12(s，2H)，6.87-6.98(m，2H)，7.00-7.06(m，2H)，7.36(dt，J＝19.85，8.09Hz，3H)，7.52(s，1H)，7.82(d，J＝8.82Hz，1H)，8.88(s，1H)，9.02(d，J＝8.46Hz，1H)，10.94(s，1H)；MS?ESI+m/z?40I(M+H)+，ESI-m/z?399(M-H)-.
Embodiment 213
[3-(4-bromo-benzyloxy)-phenyl]-pyrido [2,3-d] pyrimidine-4-base-amine
Embodiment 213A
3-(4-bromo-benzyloxy)-phenyl amine
According to the method for embodiment 199A, substitute 1-brooethyl-3-fluoro-benzene with 1-bromo-4-brooethyl-benzene, with 3-nitro-phenol and 1-bromo-4-brooethyl-benzene reaction, according to the method reduction of embodiment 199B, obtain this title compound then.
Embodiment 213B
[3-(4-bromo-benzyloxy)-phenyl]-pyrido [2,3-d] pyrimidine-4-base-amine
Use the method for embodiment 36I, use the product of the product alternate embodiment 36H of embodiment 213A, the product of embodiment 213A and the product of embodiment 36E are reacted, obtain roughage, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：5.13(s，2H)，6.82(dd，J＝8.09，1.84Hz，1H)，7.32(t，J＝8.09Hz，1H)，7.45(d，J＝8.46Hz，3H)，7.61(d，J＝8.46Hz，2H)，7.64-7.71(m，2H)，9.01(dd，J＝8.46，1.84Hz，1H)，9.08(dd，J＝4.23，1.65Hz，1H)，10.01(s，1H)；MS?ESI+m/z?407(M+H)+，ESI+m/z?429(M+Na)+，ESI-m/z?405(M-H)-.
Embodiment 214
[2-(4-amino-phenyl sulfenyl)-5-benzyloxy-phenyl]-(7-methyl-pyridine [2,3-d] pyrimidine-4-yl)-amine
Embodiment 214A
4-benzyloxy-1-chloro-2-nitro-benzene
Solution (2.0g with 4-chloro-3-nitro-phenol, 11.5mmol), 1-brooethyl-benzene (2.01g, 11.5mmol), salt of wormwood (1.65g, 12.0mmol) 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 chamber, obtain this title compound (3.0g, 99%).
Embodiment 214B
4-(4-benzyloxy-2-nitro-phenyl sulfenyl)-phenyl amine
With the compound for preparing among the embodiment 214A (1.0g, 3.80mmol), the 4-aminothiophenol (0.5g, 4.00mmol), (1.3g, 4mmol) solution in dimethyl formamide (10ml) was in 40 ℃ of heating 16 hours for cesium carbonate.Then, (50mL) is added in this solution frozen water, and the gained slurries are handled with methyl acetate (100ml).Layer is separated, and organic layer is used anhydrous sodium sulfate drying then with 10% sodium bicarbonate and the washing of 10% sodium-chlor.Siccative is filtered, and under vacuum, removes and desolvate, obtain this title compound, be orange (1.1g, 83%).
Embodiment 214C
[4-(4-benzyloxy-2-nitro-phenyl sulfenyl)-phenyl]-t-butyl carbamate
(1.1g, (0.9g 4.00mmole) handles, and heating under refluxing 3.1mmole) to be used in Boc acid anhydrides in the diox (15ml) with the compound of embodiment 214B.Next day, under vacuum, remove and desolvate, obtain this title compound, be light brown oily thing (1.4g, 100%).
Embodiment 214D
[4-(2-amino-4-benzyloxy-phenyl sulfenyl)-phenyl]-t-butyl carbamate
With the product 214C of embodiment (1.4g, 3.09mmol), iron powder (0.70g, 12mmol) and ammonium chloride (0.18g, 3.41mmol) solution in methyl alcohol (10mL), tetrahydrofuran (THF) (10mL) and water (5mL) is heated to and refluxed 1.5 hours.The gained mixture is diluted with methyl alcohol (50mL), and filter by Celite pad.Filtrate decompression is concentrated into the volume of 10mL,, and extracts with methyl acetate (2 x 50mL) with solution with water (50mL) dilution.The extract that merges washs with 10% sodium-chlor, uses dried over mgso then, filters and concentrates under vacuum, obtains this title compound (1.1g, 90%).
Embodiment 214E
[2-(4-amino-phenyl sulfenyl)-5-benzyloxy-phenyl]-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
With the product of embodiment 10B (67mg, 0.355mmol) and embodiment 214D (150mg, 0.355mmol) solution in acetate (1mL) is preheating to 130 ℃ oil bath and was stirring 10 minutes.Then mixture is cooled to room temperature, under vacuum, removes acetate, and with the gained resistates in room temperature with 50% TFA at CH
2Cl
2Solution-treated (2ml) 30 minutes.Vaporising under vacuum desolvates, and the gained resistates is passed through the HPLC purifying, uses the TFA wash-out, obtains this title compound, is trifluoroacetic acid salt form (25mg, 12%).
1HNMR(300MHz，DMSO-D6)δ?ppm：2.76(s，3H)，5.10(s，2H)，6.46-6.61(m，2H)，6.97-7.12(m，3H)，7.10-7.22(m，2H)，7.29-7.51(m，6H)，7.85(d，J＝8.46Hz，1H)，8.80-8.90(m，2H)，8.95(d，J＝8.46Hz，1H)，11.70(s，1H).
Embodiment 215
[2-(4-amino-phenyl sulfenyl)-5-benzyloxy-phenyl]-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
With the product of embodiment 36E (80mg, 0.368mmol) and the product of embodiment 214D (160mg, 0.368mmol) solution in acetate (2mL) is preheating to 130 ℃ oil bath and was stirring 10 minutes.Then mixture is cooled to room temperature, under vacuum, removes acetate, and with resistates in room temperature with 50% TFA at CH
2Cl
2Solution-treated (2ml) 30 minutes.Vaporising under vacuum desolvates, and the gained resistates is passed through the HPLC purifying, uses the TFA wash-out, obtains this title compound, is trifluoroacetic acid salt form (22mg, 10%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.62Hz，6H)，3.19-3.38(m，1H)，5.10(s，2H)，6.41-6.61(m，2H)，6.92-7.18(m，5H)，7.27-7.52(m，6H)，7.91(d，J＝8.46Hz，1H)，8.84(s，1H)，9.01(s，1H)，11.64(s，2H).
Embodiment 216
[2-(4-amino-phenyl sulfenyl)-5-(1-phenyl-oxyethyl group)-phenyl]-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Embodiment 216A
1-chloro-2-nitro-4-(1-phenyl-oxyethyl group)-benzene
With the solution of 4-chloro-3-nitro-phenol (2.0g, 11.5mmol), 1-bromotrifluoromethane-benzene (3.2g, 17.3mmol), yellow soda ash (1.80g, 17.0mmol) heating 18 hours under the solution of acetone (20ml) is refluxing.With reaction mixture cooling, cross the elimination solid, and under vacuum, filtrate is condensed into dense thick slurries.Resistates is dissolved in the ether (80ml), water (20ml) and 30% KOH solution (2 X 20ml) washing, and solvent is concentrated under vacuum, obtain this title compound, be oily resistates (3.01g, 94%).
Embodiment 216B
4-[2-nitro-4-(1-phenyl-oxyethyl group)-phenyl sulfenyl]-phenyl amine
With the compound of embodiment 216A (1.86g, 6.95mmol), the 4-aminothiophenol (0.88g, 7.00mmol), (2.3g, 7.00mmol) solution in dimethyl formamide (10ml) was in 40 ℃ of heating 16 hours for cesium carbonate.Then, (50mL) is added in this solution frozen water, and the gained slurries are handled with methyl acetate (100ml).Layer is separated, and organic layer washs with 10% sodium bicarbonate and 10% sodium-chlor, and uses anhydrous sodium sulfate drying.Siccative is filtered, and under vacuum, remove and desolvate, obtain this title compound, be orange (2.35g, 92%).
Embodiment 216C
4-[2-nitro-4-(1-phenyl-oxyethyl group)-phenyl sulfenyl]-phenyl }-t-butyl formate
(2.35g, 6.4mmole) (1.7g 7.70mmole) handles the solution in Zai diox (20ml), and heats 18 hours under refluxing with the Boc acid anhydrides with embodiment 216B compound.Next day, under vacuum, remove and desolvate, obtain this title compound, be light brown oily thing (1.78g, 60%).
Embodiment 216D
4-[2-amino-4-(1-phenyl-oxyethyl group)-phenyl sulfenyl]-phenyl }-t-butyl formate
With the compound of embodiment 216C (1.78g, 3.80mmol), iron powder (0.85g, 15.3mmol) and ammonium chloride (0.25g, 4.57mmol) solution in methyl alcohol (10mL), tetrahydrofuran (THF) (10mL) and water (5mL) is heated to and refluxed 1.5 hours.The gained mixture dilutes with methyl alcohol (50mL), and filters by Celite pad.Filtrate decompression is concentrated into the volume of 10mL,, and extracts with methyl acetate (2 x 50mL) with solution with water (50mL) dilution.The extract that merges washs with 10% sodium-chlor, uses dried over mgso then, filters and concentrates under vacuum, obtains this title compound (0.53g, 32%).
Embodiment 216E
[2-(4-amino-phenyl sulfenyl)-5-(1-phenyl-oxyethyl group)-phenyl]-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
With the product of embodiment 36E (57mg, 0.265mmol) and the product of embodiment 216D (116mg, 0.265mmol) solution in acetate (2mL) is preheating to 130 ℃ oil bath and was stirring 10 minutes.Then mixture is cooled to room temperature, under vacuum, removes acetate, and with resistates in room temperature with 50% TFA at CH
2Cl
2Solution-treated (2ml) 30 minutes.Vaporising under vacuum desolvates, and the gained resistates is passed through the HPLC purifying, uses the TFA wash-out, obtains this title compound, is trifluoroacetic acid salt form (18mg, 11%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.30(m，3H)，1.31(d，6H)，3.18-3.34(m，1H)，5.48(s，1H)，6.50(s，1H)，6.86-7.08(m，3H)，7.10(d，J＝5.15Hz，2H)，7.22-7.50(m，5H)，7.86(s，1H)，8.37(s，1H)，8.48(s，1H)，8.78(s，1H)，8.94(s，1H)，11.19(s，1H).
Embodiment 217
[2-(2-amino-6-chloro-pyrimidine-4-base sulfenyl)-5-benzyloxy-phenyl]-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Embodiment 217A
4-benzyloxy-2-nitro-phenyl amine
To contain the 4-amino-3-nitro phenol (1.09g, 7.07mmole), bromotoluene (1.28g, 7.5mmole) and cesium carbonate (2.43g, solution 7.5mmole) was in stirring at room 4 days.After reaction is finished, reaction mixture is poured in the frozen water (500ml), stirred 1 hour, with the gained solid filtering, and dry under vacuum, obtain this title compound (1.1g, 64%).
Embodiment 217B
4-benzyloxy-2-oil of mirbane diazonium tetrafluoroborate
The product of embodiment 217A (0.5g 2.05mmole) is dissolved among the THF (10ml), and with dripped in 5 minutes contain boron-trifluoride etherate (1.1ml, 8.20mmole) and nitrite tert-butyl (0.6ml, cold (20 ℃) solution 4.92mmole).The gained mixture stirred 2 hours in 10 ℃ then in-20 ℃ of stirrings 10 minutes.Then reaction mixture is poured in the hexane (100ml), and with solid filtering, with the ether washing, and dry under vacuum, obtain this title compound (0.61g, 87%).
Embodiment 217C
4-(4-benzyloxy-2-nitro-phenyl sulfenyl)-6-chloro-pyrimidine-2-base amine
(0.1g, 0.290mmol) drips of solution in methyl-sulphoxide (1ml) is added to thioacetic acid potassium (0.04g is 0.350mmol) in the solution in methyl-sulphoxide (1ml) with the product of embodiment 217B.This reaction mixture begins bubbling immediately.When bubbling is calmed down with reaction mixture in stirring at room 90 minutes.Then gained blackish green mixture is handled with 3M potassium hydroxide aqueous solution (0.1ml), and restir 80 minutes, then, added solid 4,6-two chloro-2-aminopyrimidines, and with mixture restir 60 minutes.Reaction mixture is diluted with methyl acetate (50ml), and dried over sodium sulfate is used in water (20ml), 10% sodium bicarbonate and the washing of 10% sodium chloride solution, filters also to remove under vacuum and desolvates, and obtains this title compound, is brown solid (0.1g, 88%).
Embodiment 217D
4-(2-amino-4-benzyloxy-phenyl sulfenyl)-6-chloro-pyrimidine-2-base amine
With the product of embodiment 217C (0.1g, 0.257mmol), iron powder (0.058g, 1.03mmol) and ammonium chloride (0.017g, 0.310mmol) solution in methyl alcohol (5mL), tetrahydrofuran (THF) (5mL) and water (2mL) is heated to and refluxed 1.5 hours.The gained mixture filters with methyl alcohol (50mL) dilution with by Celite pad.Filtrate decompression is concentrated into the volume of 10mL, and, extracts with methyl acetate (2 x 50mL) with solution with water (50mL) dilution.The extract that merges washs with 10% sodium-chlor, uses dried over mgso then, filters and concentrates under vacuum, obtains this title compound (0.04g, 43%).
Embodiment 217E
[2-(2-amino-6-chloro-pyrimidine-4-base sulfenyl)-5-benzyloxy-phenyl]-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
With the product of embodiment 10B (21mg, 0.112mmol) and the product of embodiment 217D (40mg, 0.112mmol) solution in acetate (1mL) is preheating to 130 ℃ oil bath and was stirring 10 minutes.Then mixture is cooled to room temperature, under vacuum, removes acetate, and with the gained resistates in room temperature with 50% TFA at CH
2Cl
2Solution-treated (2ml) 30 minutes.Vaporising under vacuum desolvates, and the gained resistates is passed through the HPLC purifying, uses the TFA wash-out, obtains this title compound, is trifluoroacetic acid salt form (5mg, 7%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：2.66(s，J＝6.25Hz，3H)，5.21(s，2H)，6.53(s，1H)，7.07(s，1H)，7.14(dd，J＝8.64，2.76Hz，1H)，7.25-7.61(m，6H)，7.62-7.72(m，1H)，8.52(s，1H)，8.66(d，J＝8.82Hz，1H)，8.71(s，1H)，8.88(d，J＝8.46Hz，1H)，10.05(s，1H).
Embodiment 218
4-[4-(3-bromo-benzyloxy)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-phenol
Embodiment 218A
4-[4-(3-bromo-benzyloxy)-2-nitro-phenoxy group]-phenol
Heated 30 minutes in 120 ℃ with quinhydrones (276.4mg is 2.510mmol) at anhydrous 3.64mmol) and under nitrogen.(774mg, the 2.259mmol) solution in methyl-sulphoxide (4mL) stir mixture 1 hour in this temperature then to drip 4-(3-bromo-benzyloxy)-1-chloro-2-nitro-benzene (deriving from embodiment 15A) with 30 minutes with other funnel in 120 ℃.To be reflected in the ice bath and cool off, pour into then in the frozen water (20mL), and with concentrated hydrochloric acid with pH regulator to 2.This mixture extracts with ether (3 x 100mL), and anhydrous sodium sulfate drying is used in ethereal extract water of merging (3 x 100mL) and salt solution (50mL) washing, filters also to concentrate via rotary evaporation under vacuum.Resistates by flash chromatography on silica gel method purifying, as eluent, is obtained this title compound with 3% methyl acetate/methylene dichloride, be blackyellow solid (386mg, 0.927mmol, 41%).
Embodiment 218B
4-[2-amino-4-(3-bromo-benzyloxy)-phenoxy group]-phenol
With the product of embodiment 218A (384.6mg, 0.924mmol), iron powder (317.4mg, 5.683mmol) and ammonium chloride (323.7mg, 6.052mmol) mixture in water (3mL) and ethanol (6mL) is in 70 ℃ of heating 1 hour under nitrogen.Reaction is cooled to room temperature, and vacuum filtration, the methanol wash resistates used.Filtrate is concentrated under vacuum, and with toluene (50mL) azeotropic.Resistates by flash chromatography on silica gel method purifying, as the eluent gradient elution, is obtained this title compound with 7%-10% methyl acetate/methylene dichloride, be beige solid (272mg, 0.704mmol, 76%).
Embodiment 218C
4-[4-(3-bromo-benzyloxy)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-phenol
With the product of embodiment 36E (25mg, 0.116mmol) and the product of embodiment 218B (44.6mg, 0.116mmol) solution in acetate (1mL) is preheating to 140 ℃ oil bath and was stirring 1 hour.Reaction is cooled to room temperature,, concentrates by rotary evaporation with hexane (50mL) dilution, and with dichloromethane/hexane (4x) co-evaporated.With resistates dried overnight under high vacuum, via flash chromatography on silica gel method purifying, as eluent, obtain this title compound then with 3% ethanol/methylene, be light yellow solid (34mg, 0.0613mmol, 53%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.30(d，J＝6.62Hz，6H)，3.09-3.28(m，1H)，5.12(s，2H)，6.62(d，J＝9.20Hz，2H)，6.76(d，J＝8.82Hz，2H)，6.82-6.97(m，2H)，7.32-7.36(m，1H)，7.39(d，J＝7.72Hz，1H)，7.45-7.58(m，3H)，7.68(s，1H)，8.57(s，1H)，8.72(d，J＝8.82Hz，1H)，9.14(s，1H)，9.75(s，1H)；MS(ESI+)m/z?557/559(M+H)+.
Embodiment 219
4-[4-(4-bromo-benzyloxy)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-phenol
Embodiment 219A
4-[2-amino-4-(4-bromo-benzyloxy)-phenoxy group]-phenol
With 4-(4-bromo-benzyl oxygen base)-1-chloro-2-nitro-benzene (deriving from embodiment 16A) and reacted with hydroquinone, and, obtain this title compound according to the method for embodiment 39A according to the method reduction of embodiment 39B.
Embodiment 219B
4-[4-(4-bromo-benzyloxy)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-phenol
According to the method for embodiment 39C, use the product of the product alternate embodiment 218B of embodiment 219A, the product of embodiment 219A and the product of embodiment 36E are reacted, the silica gel chromatography purifying obtains this title compound (38mg, 59%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.30(d，J＝6.99Hz，6H)，3.10-3.27(m，1H)，5.09(s，2H)，6.56-6.66(m，2H)，6.70-6.79(m，2H)，6.81-6.97(m，2H)，7.32(d，J＝2.57Hz，1H)，7.43(d，J＝8.46Hz，2H)，7.53(d，J＝8.46Hz，1H)，7.60(d，J＝8.46Hz，2H)，8.57(s，1H)，8.72(d，J＝8.46Hz，1H)，9.14(s，1H)，9.74(s，1H)；MS(ESI+)m/z?557/559(M+H)+.
Embodiment 220
4-[4-benzyloxy-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-phenol
Embodiment 220A
4-(2-amino-4-benzyloxy-phenoxy group)-phenol
According to the method for embodiment 39A,, and, obtain this title compound according to the reduction of the method for embodiment 39B with 4-benzyloxy-1-chloro-2-nitro-benzene (deriving from embodiment 27A) and reacted with hydroquinone.
Embodiment 220B
4-[4-benzyloxy-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenoxy group]-phenol
According to the method for embodiment 39C, use the method for the product alternate embodiment 218B of embodiment 220A, the product of embodiment 220A and the product of embodiment 36E are reacted, obtain this title compound (58mg, 65%) behind the silica gel chromatography purifying.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.30(d，J＝6.99Hz，6H)，3.08-3.27(m，1H)，5.10(s，2H)，6.62(d，J＝9.2Hz，2H)，6.74(d，J＝9.2Hz，2H)，6.81-6.98(m，2H)，7.26-7.61(m，7H)，8.57(s，1H)，8.72(d，J＝8.46Hz，1H)，9.13(s，1H)，9.75(s，1H)；MS(DCI/NH
3)m/z?479(M+H)+.
Embodiment 221
4-[4-benzyloxy-2-(7-ethyl-pyrido [233-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Use the method for embodiment 10F,, and, the product of embodiment 27A and the product of embodiment 145A are reacted, obtain this title compound with the product of the product alternate embodiment 10B of embodiment 145A with the product of the product alternate embodiment 10E of embodiment 27A.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.32(t，J＝7.72Hz，3H)，2.95(q，J＝7.72Hz，2H)，5.11(s，2H)，6.65(d，J＝8.82Hz，2H)，6.91-7.05(m，1H)，7.10(d，J＝8.46Hz，2H)，7.32-7.50(m，6H)，8.12(d，J＝6.99Hz，1H)，8.66-8.77(m，1H)，9.04(d，J＝8.82Hz，1H)，9.63(s，1H)，10.28(s，1H)；MS(APCI)m/z?481(M+H)+.
Embodiment 222
4-[4-benzyloxy-2-(7-cyclohexyl-pyrido [233-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Use the method for embodiment 10F,, and, the product of embodiment 27A and the product of embodiment 135A are reacted, obtain this title compound with the product of the product alternate embodiment 10B of embodiment 135A with the product of the product alternate embodiment 10E of embodiment 27A.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.23-1.51(m，4H)，1.53-1.79(m，4H)，1.80-2.00(m，2H)，2.77-3.02(m，1H)，5.10(s，2H)，6.67(d，J＝8.46Hz，2H)，6.88-7.01(m，1H)，7.11(d，J＝8.82Hz，2H)，7.22-7.31(m，1H)，7.32-7.49(m，6H)，7.56(d，J＝7.72Hz，1H)，8.55(s，1H)，8.73(d，J＝8.09Hz，1H)，9.94(s，1H)；MS(APCI)m/z?535(M+H)+.
Embodiment 223
4-[4-benzyloxy-2-(7-sec-butyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Use the method for embodiment 10F,, and, the product of embodiment 27A and the product of embodiment 140A are reacted, obtain this title compound with the product of the product alternate embodiment 10B of embodiment 140A with the product of the product alternate embodiment 10E of embodiment 27A.
1H?NMR(300MHz，DMSO-D6)δ?ppm：0.82(t，J＝7.35Hz，3H)，1.30(d，J＝6.62Hz，3H)，1.58-1.73(m，1H)，1.75-1.87(m，1H)，2.89-3.08(m，1H)，5.11(s，2H)，6.67(d，J＝8.82Hz，2H)，6.85-7.03(m，1H)，7.11(d，J＝8.46Hz，2H)，7.30-7.50(m，6H)，7.56(d，J＝8.82Hz，1H)，8.56(s，1H)，8.75(d，J＝8.46Hz，1H)，9.64(s，1H)，9.95(s，1H)；MS(APCI)m/z
Embodiment 224
4-[4-(2-chloro-thiazole-5-ylmethoxy)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 224A
4-[2-amino-4-(2-chloro-thiazole-5-ylmethoxy)-phenyl sulfenyl]-phenol
Substitute bromotoluene with 2-chloro-5-brooethyl thiazole, described in embodiment 16A, prepare this title compound, obtain this title compound (0.38g, 64%).
Embodiment 224b
4-[4-(2-chloro-thiazole-5-ylmethoxy)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
With the product of embodiment 37E (40.4mg, 0.187mmol) and the product of embodiment 224A (68mg, 0.187mmol) solution in acetate (1mL) is preheating to 130 ℃ oil bath and was stirring 10 minutes.Then mixture is cooled to room temperature, under vacuum, removes acetate, and the gained resistates is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (31mg, 30%).
1H?NMR(300MHz，DMSO-d
6)δ?ppm：1.35(d，J＝6.99Hz，6H)3.17-3.36(m，1H)5.35(s，2H)6.55(d，J＝7.72Hz，1H)6.58-6.74(m，2H)7.00-7.30(m，4H)7.68-7.95(m，2H)8.76(s，1H)8.94(d，J＝8.46Hz，1H)9.73(s，1H)11.34(s，1H)；MS(ESI+)m/z?536(M+H)+，(ESI-)m/z?534(M-H)-.
Embodiment 225
4-[4-(6-chloro-pyridine-2-ylmethoxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 225a
4-[2-amino-4-(6-chloro-pyridine-2-ylmethoxy)-phenyl sulfenyl]-phenol
Substitute bromotoluene with 2-chloro-5-bromo methyl cycloheptapyridine, described in embodiment 16A, prepare this title compound, obtain this title compound (0.63g, 73%).
Embodiment 225b
4-[4-(6-chloro-pyridine-2-ylmethoxy)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
With the product of embodiment 10B (37mg, 0.197mmol) and the product of embodiment 225a (70.7mg, 0.197mmol) solution in acetate (2mL) is preheating to 130 ℃ oil bath and was stirring 20 minutes.Then mixture is cooled to room temperature, under vacuum, removes acetate, and the gained resistates is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (20mg, 20%).
1H?NMR(300MHz，DMSO-d
6)δ?ppm：2.70(s，3H)5.18(s，2H)6.65(d，J＝8.82Hz，2H)7.02(d，J＝8.09Hz，1H)7.11(d，J＝8.82Hz，2H)7.19(d，J＝8.82Hz，1H)7.25(s，1H)7.52(dd，J＝13.60，7.72Hz，2H)7.67(d，J＝8.09Hz，1H)7.93(t，J＝7.72Hz，2H)8.65(s，1H)8.80(d，J＝8.09Hz，1H)9.68(s，1H)；MS(ESI+)m/z?502(M+H)+，(ESI-)m/z?500(M-H)-.
Embodiment 226
4-[4-(6-chloro-pyridine-2-ylmethoxy)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
With the product of embodiment 37E (36mg, 0.168mmol) and the product of embodiment 225a (60mg, 0.168mmol) solution in acetate (1mL) is preheating to 130 ℃ oil bath and was stirring 10 minutes.Then mixture is cooled to room temperature, under vacuum, removes acetate, and the gained resistates is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (31mg, 30%).
1H?NMR(300MHz，DMSO-d
6)δ?ppm：1.16(d，J＝6.99Hz，3H)1.36(d，J＝6.62Hz，3H)3.20-3.40(m，1H)5.18(s，1H)6.55(d，J＝7.72Hz，1H)6.64(d，J＝8.82Hz，2H)6.77(s，1H)7.04-7.18(m，2H)7.15-7.29(m，2H)7.52(dd，J＝10.48，7.91Hz，2H)7.77(d，J＝7.72Hz，1H)7.93(t，J＝7.72Hz，2H)8.82(s，1H)8.97(s，1H)9.72(s，1H)11.66(s，1H)；MS(ESI+)m/z?530(M+H)+，(ESI-)m/z?528(M-H)-.
Embodiment 227
4-[2-(the 7-tertiary butyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(3-fluoro-benzyloxy)-phenyl sulfenyl]-phenol
(110mg, 0.478mmol) (164mg 0.48mmol) reacted in the 1mL Glacial acetic acid, 120 ℃ of heating 13 minutes with the product of embodiment 28A with the product of embodiment 127A.Be cooled to room temperature and under vacuum, remove acetate.Crude product by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (134mg, 44%).
1H?NMR(300MHz，DMSO-d
6)δ?ppm：1.43(s，9H)5.14(s，2H)6.65(d，J＝8.45Hz，2H)7.17(m，4H)7.29(d，J＝8.45Hz，2H)7.44(d，J＝8.45Hz，2H)7.99(d，J＝7.80Hz，1H)8.72(s，1H)8.93(d，J＝8.45Hz，1H)9.68(s，1H)10.90(br?s，1H)；MS(ESI+)m/z，527(M+H-TFA)+；(ESI-)m/z，525(M-H-TFA)-.
Embodiment 228
4-[4-[1-(3-bromo-phenyl)-oxyethyl group]-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 228a
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).This mixture was in stirring at room 16 hours.Reaction is poured on ice/waterborne, makes water be alkalescence with sodium bicarbonate.Use the dichloromethane extraction water.Dried over sodium sulfate is used in organic layer water, salt water washing, filters and concentrates under vacuum, obtains this title compound (7.8g, 80%).
Embodiment 228b
4-[1-(3-bromo-phenyl)-oxyethyl group]-1-chloro-2-nitro-benzene
To the embodiment 228a 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 in 80 ℃ of heating 16 hours.Reacting cooling and pouring in the water.With ethyl acetate (2x) aqueous phase extracted, and phase water that will merge and salt water washing, dried over sodium sulfate used.With the organic phase concentrating under reduced pressure.Resistates with (hexane/methyl acetate 90:10) wash-out, obtains this title compound (7.0g, 66%) by the silica gel chromatography purifying.
Embodiment 228c
4-{4-[1-(3-bromo-phenyl)-oxyethyl group]-2-nitro-phenyl sulfenyl }-phenol
To the embodiment 228b 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 in 80 ℃ of heating 16 hours.Reacting cooling and pouring in the water.With ethyl acetate (2x) aqueous phase extracted, and the phase water that will merge, salt water washing, dried over sodium sulfate used.With the organic phase concentrating under reduced pressure.Resistates with (hexane/methyl acetate/methanol 75:15:5) wash-out, obtains this title compound (5.2g, 83%) by the silica gel chromatography purifying.
Embodiment 228d
4-{2-amino-4-[1-(3-bromo-phenyl)-oxyethyl group]-the phenyl sulfenyl }-phenol
Described in embodiment 10E, (5.4g is 12.2mmol) with Fe and NH with the product of embodiment 228c
4The Cl reaction obtains this title compound (3.6g, 76%).
Embodiment 228e
4-[4-[1-(3-bromo-phenyl)-oxyethyl group]-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
In 125 ℃ of product (125mg in sealed tube with embodiment 57A, 0.72mmol) and embodiment 228d (298mg, 0.72mmol) acetate (10mL) reaction 5 minutes, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain the formula product (120mg, 31%) of trifluoroacetic acid shape.
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 229
4-[4-[1-(3-bromo-phenyl)-oxyethyl group]-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
In 125 ℃ of product (110mg in the pipe of sealing with embodiment 10B, 0.58mmol) and embodiment 228d (243mg, 0-58mmol) in acetate (10mL), reacted 5 minutes, obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain the product (100mg, 30%) of trifluoroacetic acid form.
1H?NMR(300MHz，DMSO-d
6)δ?ppm：1.33(d，J＝6.25Hz，3H)2.53(s，3H)5.31(q，J＝6.43Hz，1H)6.44(d，J＝8.82Hz，2H)6.68(dd，J＝8.82，2.57Hz，1H)6.85-6.92(m，3H)6.95(d，J＝2.57Hz，1H)7.11(t，J＝7.72Hz，1H)7.19-7.27(m，2H)7.40(s，1H)7.44(d，J＝8.46Hz，1H)8.44(s，1H)8.56(d，J＝8.46Hz，1H)；MS(ESI+)m/z?560(M+H)+.
Embodiment 230
4-[4-[1-(3-bromo-phenyl)-oxyethyl group]-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
In 125 ℃ of product (130mg in the pipe of sealing with embodiment 36E, 0.60mmol) and embodiment 228d (250mg, 0.60mmol) reaction in acetate (10mL), obtain this rough title compound, it is passed through the HPLC purifying, use the TFA wash-out, obtain the product (140mg, 39%) of trifluoroacetic acid form.
1H?NMR(300MHz，DMSO-d
6)δ?ppm：1.34(d，J＝6.99Hz，6H)1.54(d，J＝6.25Hz，3H)3.26(q，1H)5.52(q，J＝6.62Hz，1H)6.65(d，J＝8.46Hz，2H)6.92(dd，J＝8.82，2.94Hz，1H)7.10(m，4H)7.32(t，J＝7.72Hz，1H)7.39-7.50(m，2H)7.60(s，1H)7.79(d，J＝8.46Hz，1H)8.70(s，1H)8.86(d，J＝8.46Hz，1H)9.72(s，1H)；MS(ESI+)m/z?588(M+H)+.
Embodiment 231
4-[4-(3-bromo-benzyloxy)-2-(the 7-tertiary butyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
With the product of embodiment 127A (147mg, 0.63mmol) with the product of embodiment 15A (256mg, 0.63mmol) in the 2mL Glacial acetic acid in 120 ℃ of heating 15min.Be cooled to room temperature and under vacuum, remove acetate.Crude product by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate (45mg, 10%).
1H?NMR(300MHz，DMSO-d
6)δ?ppm：1.43(s，9H)5.139(s，2H)6.66(d，J＝8.83Hz，2H）7.01(d，J＝6.62Hz，1H)7.11(d，J＝8.83Hz，2H)7.19(m，1H)7.37(m，1H)7.46(d，J＝7.72Hz，1H)7.54(D，J＝6.62Hz，1H)7.66(s，1H)7.95(d，J＝8.09Hz，1H)8.69(s，1H)8.88(D，J＝8.83Hz，1H)9.68(s，1H)；MS(ESI+)m/z，587，589(M+H-TFA)+；(ESI-)m/z，585，587(M-H-TFA)-.
Embodiment 232
4-[4-(3-bromo-phenoxymethyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl-phenol
Embodiment 232A
4-[2-amino-4-(3-bromo-phenoxymethyl)-phenyl sulfenyl]-phenol
With 4-[4-(3-bromo-phenoxymethyl)-2-nitro-phenyl sulfenyl]-phenol (325mg, 0.752mmol), iron powder (210mg, 3.76mmol) and ammonium chloride (60mg, the 1.13mmol) heating 2.5 hours under refluxing of the solution in tetrahydrofuran (THF) (5mL), water (1.5mL) and ethanol (5mL).After being cooled to room temperature, this solution filters by Celite pad, and it is used methanol wash.Filtration concentrates under vacuum then, is dissolved in then in the water (20mL), and extracts with methyl acetate (2 x 20mL).Organic extract is dry and concentrated under vacuum, obtain this title compound, be light yellow solid (240mg, 79%).
Embodiment 232B
4-[4-(3-bromo-phenoxymethyl)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
With the product of embodiment 232A (85mg, 0.211mmol) and the product of embodiment 36E (46mg, 0.211mmol) solution in acetate (3mL) was in 130 ℃ of heating 15 minutes.Then solution is cooled to room temperature, under vacuum, removes acetate, and the gained resistates is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (63mg, 43%).
1H?NMR(300MHz，DMSO-d
6)δ?ppm：1.35(d，J＝7.0Hz，6H)，3.25(m，1H)，5.13(s，2H)，6.77(d，J＝8.8Hz，2H)，7.02(d，J＝8.1Hz，2H)，7.15(m，1H)，7.23(m，4H)，7.36(m1H)，7.46(s，1H)，7.83(d，J＝8.8Hz，1H)，8.76(s，1H)，8.95(d，J＝8.8Hz，1H)，9.88(s，1H)，11.22(bs，1H)；MS(ESI)+m/z?573/575(M+H)+.
Embodiment 233
4-[4-(3-bromo-phenoxymethyl)-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
With the product of embodiment 232A (60mg, 0.149mmol) and the product of embodiment 10B (28mg, 0.149mmol) solution in acetate (3mL) was in 130 ℃ of heating 15 minutes.Then solution is cooled to room temperature, under vacuum, removes acetate, and the gained resistates is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (46mg, 47%).
1H?NMR(300MHz，DMSO-d
6)δ?ppm：2.72(s，3H)，5.12(s，2H)，6.77(d，J＝8.5Hz，2H)，7.02(m，2H)，7.16(m，1H)，7.23(m，4H)，7.36(m1H)，7.47(s，1H)，7.70(d，J＝8.8Hz，1H)，8.70(s，1H)，8.86(d，J＝8.5Hz，1H)，9.87(s，1H)，10.95(bs，1H)；MS(ESI)+m/z?545/547(M+H)+.
Embodiment 234
4-[4-(2,5-two fluoro-benzyloxies)-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 234a
2-brooethyl-1,4-two fluoro-benzene
Phase (2,5-two fluoro-phenyl)-methyl alcohol (4.8g, 33.6mmol) drip in the solution in methylene dichloride (40mL) phosphorus tribromide (94g, 33.6mmol).This mixture was in stirring at room 16 hours.Reaction is poured on ice/waterborne.Make water be alkalescence with sodium bicarbonate.Use the dichloromethane extraction water.With the organic phase concentrating under reduced pressure.Resistates with (hexane/methyl acetate 90:10) wash-out, obtains this title compound (3.5g, 50%) by the silica gel chromatography purifying.
Embodiment 234b
1-chloro-4-(2,5-fluoro-benzyloxy)-2-nitro-benzene
To the embodiment 234a in DMF (50mL) (2.2g, add in 10.4mmol) 4-chloro-3-nitro-phenol (1.8g, 10.4mmol) and K
2CO
3(2.87g, 20.8mmol).This mixture was in 80 ℃ of heating 16 hours.To react and concentrate and pour in the water.With ethyl acetate (2x) aqueous phase extracted, and the phase water that will merge, salt water washing, dried over sodium sulfate used.With the organic phase concentrating under reduced pressure.Resistates with (hexane/methyl acetate 90:10), obtains this title compound (2.48g, 66%) by the silica gel chromatography purifying.
Embodiment 234c
4-[4-(2,5-two fluoro-benzyloxies)-2-nitro-phenyl sulfenyl]-phenol
Embodiment 234b in DMF (50mL) (2.5g, add in 8.3mmol) the 4-mercapto-phenol (1.0g, 8.3mmol) and K
2CO
3(2.3g, 16.5mmol).This mixture was in 80 ℃ of heating 16 hours.Reaction is concentrated and pours in the water.With ethyl acetate (2X) aqueous phase extracted, and the phase water that will merge, salt water washing, dried over sodium sulfate used.With the organic phase concentrating under reduced pressure.Resistates with (hexane/methyl acetate/methanol 75:15:5) wash-out, obtains this title compound (1.7g, 52%) by purified by flash chromatography.
Embodiment 234d
4-[2-amino-4-(2,5-two fluoro-benzyloxies)-phenyl sulfenyl]-phenol
Described in embodiment 10E, (1.70g is 4.2mmol) with Fe and NH with the product of embodiment 234c
4The Cl reaction obtains this title compound (1.3g, 84%).
Embodiment 234e
4-[4-(2,5-two fluoro-benzyloxies)-2-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
In 125 ℃ of pipes that sealing, product (100mg with embodiment 57A, 0.57mmol) and embodiment 234d (206mg, 0.57mmol) in acetate (10mL), reacted 5 minutes, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain the product (140mg, 39%) of trifluoroacetic acid form.
1H?NMR(300MHz，DMSO-d
6)δ?ppm：5.13(s，2H)6.67(d，J＝8.46Hz，2H)6.93-7.01(m，1H)7.10-7.16(m，3H)7.22-7.37(m，4H)7.41-7.52(m，J＝5.79，5.79，2.76Hz，1H)7.64(dd，J＝8.09，4.41Hz，1H)8.53(s，1H)8.84(d，J＝7.72Hz，1H)9.05(s，1H)；MS(ESI+)m/z?489(M+H)+.
Embodiment 235
4-[4-(2,5-two fluoro-benzyloxies)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
In 125 ℃ of pipes that sealing, product (100mg with embodiment 36E, 0.46mmol) and embodiment 234d (206mg, 0.46mmol) in acetate (10mL), reacted 5 minutes, obtain this rough title compound, it by the HPLC purifying, is used the TFA wash-out, obtain the product (140mg, 39%) of trifluoroacetic acid form.
1H?NMR(300MHz，DMSO-d
6)δ?ppm：1.34(d，J＝6.62Hz，6H)5.14(s，2H)6.66(d，J＝8.46Hz，2H)7.06(d，J＝2.57Hz，1H)7.12(d，J＝8.46Hz，2H)7.21-7.35(m，4H)7.44(s，1H)7.77(d，J＝8.46Hz，1H)8.69(s，1H)8.88(d，J＝8.46Hz，1H)9.70(s，1H)；MS(ESI+)m/z?531(M+H)+.
Embodiment 236
4-[4-(2-chloro-5-fluoro-benzyloxy)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl-phenol
Embodiment 236a
2-brooethyl-1-chloro-4-fluoro-benzene
To (2-fluoro-5-fluoro-phenyl)-methyl alcohol (5.0g, 31.1mmol) drip in the solution in methylene dichloride (40mL) phosphorus tribromide (87g, 31.1mmol).This mixture was in stirring at room 16 hours.Reaction is poured on ice/waterborne.Make water be alkalescence with sodium bicarbonate.Use the dichloromethane extraction water.With the organic phase concentrating under reduced pressure.Resistates with (hexane/methyl acetate 90:10), obtains this title compound (5.75g, 82.5%) by the silica gel chromatography purifying.
Embodiment 236b
1-chloro-4-(2-chloro-5-fluoro-benzyloxy)-2-nitro-benzene
To the embodiment 236a in DMF (50mL) (5.7g, add in 25.7mmol) 4-chloro-3-nitro-phenol (4.46g, 25.7mmol) and K
2CO
3(7.10g, 51.4mmol).This mixture was in 80 ℃ of heating 16 hours.Reaction is concentrated and pours in the water.With ethyl acetate (2x) aqueous phase extracted, and the phase water that will merge, salt water washing, dried over sodium sulfate used.With the organic phase concentrating under reduced pressure.Resistates with (hexane/methyl acetate 90:10), obtains this title compound (7.0g, 86%) by the silica gel chromatography purifying.
Embodiment 236c
4-[4-(2-chloro-5-fluoro-benzyloxy)-2-nitro-phenyl sulfenyl]-phenol
To the embodiment 236b in DMF (50mL) (2.5g, add in 8.3mmol) the 4-mercapto-phenol (1.0g, 8.3mmol) and K
2CO
3(2.3g, 16.5mmol).This mixture was in 80 ℃ of heating 16 hours.Reaction is concentrated and pours in the water.With ethyl acetate (2X) aqueous phase extracted, and the phase water that will merge, salt water washing, dried over sodium sulfate used.With the organic phase concentrating under reduced pressure.Resistates is by the silica gel chromatography purifying, with (hexane/methyl acetate/methanol (70:25:5) wash-out obtains this title compound (5.0g, 78%).
Embodiment 236d
4-[2-amino-4-(2-chloro-5-fluoro-benzyloxy)-phenyl sulfenyl]-phenol
Described in embodiment 10E, (4.2g is 10.2mmol) with Fe and NH with the product of embodiment 236c
4The Cl reaction obtains this title compound (3.0g, 77%).
Embodiment 236e
4-[4-(2-chloro-5-fluoro-benzyloxy)-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
In 125 ℃ in sealed tube, product (125mg with embodiment 36E, 0.72mmol) and embodiment 236d (298mg, 0.72mmol) in acetate (10mL), reacted 5 minutes, obtain this rough title compound, it is carried out purifying by ether is added in resistates, obtain required product, be acetate form (225mg, 66%).
1H?NMR(300MHz，DMSO-d
6)δ?ppm：1.32(d，J＝6.99Hz，6H)3.21(q，1H)5.15(s，2H)6.69(d，J＝8.46Hz，2H)6.99(dd，1H)7.13(d，J＝8.46Hz，4H)7.25-7.35(m，2H)7.49(dd，J＝9.38，3.13Hz，1H)7.54-7.62(m，J＝8.82，5.15Hz，3H)8.55(1H，s)(18.74(s，1H)9.66(s，1H)9.98(s，1H)；MS(ESI-)m/z?547(M+H)+.
Embodiment 237
4-[5-benzyloxy-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 237A
4-benzyloxy-2-fluoro-1-nitro-benzene
With 3-fluoro-4-nitrophenols (0.30g, 1.91mmol), bromotoluene (0.36g, 2.10mmol, 1.1eq), salt of wormwood (0.792g, 5.73mmol, 3.0eq) and tetrabutylammonium iodide (0.007eq) mixture in dimethyl formamide (5mL) was in stirring at room 16 hours for 5.0mg, 0.014mmol.(20mL) is added in the reaction mixture water, and comes separating obtained solid sediment and dry by vacuum filtration, obtains this title compound (0.455g, 96%), is yellow solid.
Embodiment 237B
4-(5-benzyloxy-2-nitro-phenyl sulfenyl)-phenol
With the product of embodiment 237A (0.301g, 1.22mmol), 4-mercapto-phenol (0.184g, 1.46mmol, 1.2eq) and cesium carbonate (0.952g, 2.92mmol, 2.4eq) in dimethyl formamide (10mL), in 100 ℃ oil bath, heated 3 hours, be cooled to room temperature then.Add (20mL), mixture in stirring at room 2 hours, is come separating obtained solid and dry by vacuum filtration, obtaining this title compound (0.405g, 94%) is yellow solid.
Embodiment 237C
4-(2-amino-5-benzyloxy-phenyl sulfenyl)-phenol
Product 237B (0.390g with embodiment, 1.10mmol), iron powder (0.248g, 4.41mmol, 4.0eq) and ammonium chloride (0.071g, 1.32mmol, 1.2eq) heating 16 hours under refluxing of mixture in tetrahydrofuran (THF) (6mL), methyl alcohol (6mL) and water (2mL), be cooled to room temperature then.This reaction mixture is used methanol wash, and with filtrate evaporated under reduced pressure, is obtained this title compound (0.340g, 95%) by diatomite filtration, is gray powder powder thing, it need not be further purified be used for subsequent reaction.
Embodiment 237D
4-[5-benzyloxy-2-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
With the product of embodiment 237C (0.0908g, 0.281mmol) and the product of embodiment 36E (0.0607g, 0.281mmol) mixture in Glacial acetic acid (2mL) heated 10 minutes in 140 ℃ of oil baths, was cooled to room temperature, and reduction vaporization.By the silica gel column chromatography purifying, with 5% ethanol/methylene wash-out, obtaining this title compound (0.0368g, 27%) is brown solid with resistates.
1H?NMR(300MHz，DMSO-D6)δ?ppm：9.88(s，2H)，8.82(d，J＝8.46Hz，1H)，8.52(s，1H)，7.58(d，J＝8.46Hz，1H)，7.28-7.42(m，5H)，7.19-7.28(m，3H)，6.87(dd，J＝8.64，2.76Hz，1H)，6.75-6.84(m，2H)，6.38(d，J＝2.57Hz，1H)，4.99(s，2H)，3.14-3.27(m，1H)，1.32(d，J＝6.99Hz，6H)；MS(ESI
+)m/z495.2(M+H)
+，(ESI
-)m/z?493.2(M-H)
-.
Embodiment 238
4-[2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-styryl-phenyl sulfenyl]-phenol
Embodiment 238A
4-(4-bromo-2-nitro-phenyl sulfenyl)-phenol
With 4-bromo-1-fluoro-2-oil of mirbane (0.44g, 2.0mmol), the 4-mercapto-phenol (0.303g, 2.4mmol) and cesium carbonate (1.56g, 4.8mmol, 2.4eq) mixture in dimethyl formamide (10mL) heated 3 hours in 100 ℃ of oil baths, was cooled to room temperature then.Reaction mixture is poured on the frozen water (50mL), is adjusted to pH3 by adding 1N hydrochloric acid, and extracts with methyl acetate (3 x 100mL).The organic layer anhydrous magnesium sulfate drying that merges filters and evaporation, obtains this title compound, is dense thick yellow oil (0.70g,〉100%), it is used under situation about not being further purified.
Embodiment 238B
4-(2-amino-4-bromo-phenyl sulfenyl)-phenol
Product (0.302g with embodiment 238A, 0.926mmol), iron powder (0.208g, 3.7mmol, 4.0eq) and ammonium chloride (0.059g, 1.11mmol, 1.2eq) in the mixture of methyl alcohol (6mL), tetrahydrofuran (THF) (6mL) and water (2mL), under refluxing, heated 5 hours, be cooled to room temperature then.This reaction mixture passes through diatomite filtration, and filter plate is washed with methyl alcohol (25mL).With filtrate evaporated under reduced pressure, obtain amber glass shape solid (0.27g, 99%), it is used under the situation that need not be further purified.
Embodiment 238C
4-[4-bromo-2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
With the product of embodiment 238B (0.158g, 0.533mmol) and the product of embodiment 10B (0.100g, 0.533mmol) mixture in Glacial acetic acid (2mL) heated 30 minutes in 130 ℃ of oil baths.Reenter embodiment 10B product (0.060g, 0.319mmol), and again with reaction mixture in 130 ℃ the heating 30 minutes.Then reaction mixture is cooled to room temperature, and with solvent removed under reduced pressure.Resistates is developed with the 2-propyl alcohol, and come separating obtained solid and dry, obtain this title compound (0.083g, 36% productive rate), be beige solid by vacuum filtration.
Embodiment 238D
4-[2-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-styryl-phenyl sulfenyl]-phenol
Product (0.0791g with embodiment 238C, 0.180mmol), vinylbenzene (0.176g, 1.69mmol, 9.4eq), acid chloride (II) (6.2mg, 0.0276mmol, 0.15eq), three-o-tolyl phosphine (13.3mg, 0.0437mmol, 0.24eq) and two-sec.-propyl ethylamine (3.0eq) mixture in dimethyl formamide (2mL) heated 98 hours in 130 ℃ of oil baths for 0.697g, 0.539mmol.Then mixture is cooled to room temperature, solvent is evaporated under nitrogen gas stream.Resistates is distributed between ethyl acetate and water, and with the further aqueous layer extracted of ethyl acetate.The organic layer anhydrous magnesium sulfate drying that merges filters and evaporation.Resistates is used the TFA wash-out by the HPLC purifying, obtains this title compound, is trifluoroacetic acid salt form (6.1mg, 10% productive rate).
1H?NMR(300MHz，DMSO-D6)δ?ppm：11.27(s，1H)，9.89(s，1H)，8.93(d，J＝8.09Hz，1H)，8.79(s，1H)，7.78(d，J＝8.82Hz，1H)，7.66(s，1H)，7.58(d，J＝7.35Hz，2H)，7.52(dd，J＝8.09，1.47Hz，1H)，7.37(t，J＝7.35Hz，2H)，7.19-7.31(m，5H)，7.00(d，J＝8.09Hz，1H)，6.73-6.81(m，2H)，2.75(s，3H).
Embodiment 239
(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-(2-phenyl sulfenyl-5-styryl-phenyl)-amine
Embodiment 239A
(5-bromo-2-phenyl sulfenyl-phenyl)-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
According to embodiment 6a, 6b and 6c in the similar approach described, substitute the 4-mercapto-phenol with thiophenol, and, make 5-bromo-2-(thiophenyl) aniline with the alternative 4-methyl of 4-bromo-2-nitrophenols-2-nitrophenols.
(0.188g, 1.0mmol) (0.280g, 1.0mmol) mixture in Glacial acetic acid (2mL) heated 30 minutes in 130 ℃ of oil baths with 5-bromo-2-(thiophenyl) aniline with the product of embodiment 10B.Then reaction mixture is cooled to room temperature, and with solvent removed under reduced pressure.Resistates is developed with methyl alcohol, and come separating obtained solid and dry, obtain this title compound (0.276g, 65% productive rate), be beige solid by vacuum filtration.
Embodiment 239B
(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-(2-phenyl sulfenyl-5-styryl-phenyl)-amine
Product (0.127g with embodiment 239A, 0.30mmol), vinylbenzene (0.133g, 1.27mmol, 4.3eq), acid chloride (H) (5.3mg, 0.0236mmol, 0.08eq), three-o-tolyl phosphine (17.7mg, 0.058mmol, 0.19eq) and triethylamine (3.0eq) mixture in dimethyl formamide (3mL) heated 98 hours in 130 ℃ of oil baths for 0.0913g, 0.90mmol.Then mixture is cooled to room temperature, solvent is evaporated under nitrogen gas stream.Resistates is distributed between ethyl acetate and water, and with the further aqueous layer extracted of ethyl acetate.The organic layer anhydrous magnesium sulfate drying that merges filters and evaporation.Resistates is used the TFA wash-out by the HPLC purifying, obtains this title compound, is trifluoroacetic acid salt form (4.0mg, 2.4%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：11.21(s，1H)，8.85(d，J＝8.46Hz，1H)，8.74(s，1H)，7.68-7.78(m，2H)，7.55-7.65(m，J＝7.35Hz，3H)，7.19-7.46(m，11H)，2.72(s，3H)；MS(ESI
+)m/z447.2(M+H)
+，(ESI
-)m/z?445.2(M-H)
-.
Embodiment 240
(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-(3-styryl-phenyl)-amine
Embodiment 240A
(3-bromo-phenyl)-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
(0.206g, 1.09mmol) (0.188g, 1.09mmol) mixture in Glacial acetic acid (1mL) heated 15 minutes in 130 ℃ of oil baths with the 3-bromaniline with the product of embodiment 10B.Then reaction mixture is cooled to room temperature, and with solvent removed under reduced pressure.Resistates is developed with methyl alcohol, and come separating obtained solid and dry, obtain this title compound (0.126g, 37%), be beige solid by vacuum filtration.
Embodiment 240B
(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-(3-styryl-phenyl)-amine
Product (0.063g with embodiment 240A, 0.20mmol), vinylbenzene (0.0412g, 0.40mmol, 2.0eq), acid chloride (II) (0.9mg, 0.004mmol, 0.02eq), three-o-tolyl phosphine (2.4mg, 0.008mmol, 0.04eq) and triethylamine (3.0eq) mixture in dimethyl formamide (2mL) heated 4 hours in 120 ℃ of oil baths for 0.0607g, 0.60mmol.Then mixture is cooled to room temperature, solvent is evaporated under nitrogen gas stream.Resistates is distributed between ethyl acetate and water, and water is further extracted with methyl acetate.The organic layer anhydrous magnesium sulfate drying that merges filters and evaporation.With resistates recrystallize methyl alcohol and dry from methyl alcohol, obtain this title compound, be yellow crystals (11.8mg, 17%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：10.01(s，1H)，8.89(d，J＝8.46Hz，1H)，8.72(s，1H)，8.03(s，1H)，7.72-7.85(m，J＝6.07，2.76Hz，1H)，7.64(d，J＝6.99Hz，2H)，7.57(d，J＝8.82Hz，1H)，7.35-7.49(m，4H)，7.24-7.35(m，3H)，2.63-2.74(m，3H)；MS(ESI
+)m/z?339.1(M+H)
+，(ESI
-)m/z?337.1(M-H)
-.
Embodiment 241
(2-methyl-5-styroyl-phenyl)-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Embodiment 241A
1-methyl-2-nitro-4-vinylbenzene-benzene
With 4-bromo-2-nitrotoluene (0.432g, 2.0mmol), vinylbenzene (0.250g, 2.40mmol, 1.2eq), acid chloride (II) (4.5mg, 0.020mmol, 0.01eq), three-o-tolyl phosphine (12.2mg, 0.04mmol, 0.02eq) and triethylamine (2.0eq) mixture in dimethyl formamide (2mL) heated 4 hours in 120 ℃ of oil baths for 0.405g, 4.0mmol.Then mixture is cooled to room temperature, solvent is evaporated under nitrogen gas stream.Resistates is distributed between ethyl acetate and water, and with the further aqueous layer extracted of ethyl acetate.The organic layer anhydrous magnesium sulfate drying that merges filters and evaporation.Resistates by the silica gel chromatography purifying, with hexane/methyl acetate gradient elution, is obtained this title compound, be yellow solid (166mg, 35% productive rate).
Embodiment 241B
2-methyl-5-styroyl-phenyl amine
(0.166g, 0.694mmol) (18.4mg, 0.025eq) mixture in ethanol (10mL) stirred 16 hours under a normal atmosphere hydrogen with 10% palladium on carbon with the product of embodiment 241A.Then reaction mixture is filtered by Celite, and, obtain this title compound, be incarnadine oily matter (0.141g, 96% productive rate) solvent removed under reduced pressure.
Embodiment 241C
(2-methyl-5-styroyl-phenyl)-(7-methyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
With the product of embodiment 10B (0.041g, 0.22mmol) and the product of embodiment 241B (0.046g, 0.22mmol) mixture in Glacial acetic acid (1mL) heated 15 minutes in 130 ℃ of oil baths.Then reaction mixture is cooled to room temperature, and solvent removed under reduced pressure.Resistates is developed with methyl alcohol, and come separating obtained solid and dry, obtain this title compound (0.0121g, 16% productive rate), be the light orange solid by vacuum filtration.
1H?NMR(300MHz，CHCl
3-d)δ?ppm：8.84(s，1H)，8.23(d，J＝8.46Hz，1H)，7.44(s，1H)，7.15-7.37(m，8H)，7.07(dd，J＝7.72，1.47Hz，1H)，2.93(s，4H)，2.78(s，3H)，2.28(s，3H)；MS(ESI
+)m/z?355.3(M+H)
+，(ESI
-)m/z?353.2(M-H)
-.
Embodiment 242
(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-(2-methyl-5-styroyl-phenyl)-amine
With the product of embodiment 241B (46.2mg, 0.219mmol) and the product of embodiment 36E (47.3mg, 0.219mmol) mixture in Glacial acetic acid (1mL) heated 15 minutes in 130 ℃ of oil baths.Then reaction mixture is cooled to room temperature, and with solvent removed under reduced pressure.Resistates is used the TFA wash-out by the HPLC purifying, obtains this title compound, is trifluoroacetic acid salt form (0.0131g, 10%).
1H?NMR(300MHz，DMSO-D6)δ?ppm：11.09(s，1H)，8.94(d，J＝8.46Hz，1H)，8.74(s，1H)，7.82(d，J＝8.46Hz，1H)，7.12-7.35(m，8H)，3.21-3.33(m，1H)，2.89(s，4H)，2.15(s，3H)，1.35(d，J＝6.62Hz，6H)；MS(ESI
+)m/z?383.2(M+H)
+，(ESI
-)m/z381.3(M-H)
-.
Embodiment 243
(5-methyl-2-phenyl sulfenyl-phenyl)-(7-propyl group-pteridine-4-yl)-amine
Embodiment 243A
N '-(3-cyano group-6-propyl group pyrazine-2-yl)-N, N-dimethyl carbonamidine
With 3-amino-5-propyl group pyrazine-2-formonitrile HCN (0.140g, 0.863mmol) (according to Taylor and LaMattina, JOC 1977,47,1523 method preparation) and dimethyl formamide dimethyl acetal (0.123g, 1.04mmol 1.2eq) mixture in toluene (10mL) heated 2 hours under refluxing.Mixture is cooled to room temperature, and, obtains this title compound (0.188mg, 100%), be dense thick oily matter solvent removed under reduced pressure.
Embodiment 243B
(5-methyl-2-phenyl sulfenyl-phenyl)-(7-propyl group-pteridine-4-yl)-amine
With the product of embodiment 243A (38.2mg, 0.176mmol) and the product of embodiment 5I (41.6mg, 0.193mmol, the 1.1eq) heating 1.5 hours under refluxing of the mixture in acetate (1mL).Reaction mixture is cooled to room temperature, and with solvent removed under reduced pressure.The gained resistates is developed with methyl alcohol, obtains this title compound (19mg, 28% productive rate), is beige solid.
1H?NMR(300MHz，DMSO-D6)δ?ppm：0.97(t，J＝7.35Hz，3H)，1.76-1.90(m，2H)，2.42(s，3H)，2.94-3.05(m，2H)，7.08-7.28(m，6H)，7.55(d，J＝8.09Hz，1H)，8.45(s，1H)，8.81(s，1H)，8.89(s，1H)，10.32(s，1H).MS(ESI
+)m/z?388.1(M+H)
+(ESI
-)m/z?386.1(M-H)
-.
Embodiment 244
4-[4-benzyloxy-2-(7-sec.-propyl-pteridine-4-base is amino)-phenyl sulfenyl]-phenol
Embodiment 244A
3-amino-5-sec.-propyl-4-oxygen base-pyrazine-2-formonitrile HCN
With 2-hydroxyl imide base-3-methyl butyraldehyde (1.93g, 16.8mmol) (pass through Nakamura, Agric.Biol.Chem.1961,25, the preparation of the method for 665-670) and 2-amino propane dinitrile benzene methanesulfonic acid salt (4.25g, 16.8mmol) mixture in Virahol (40mL) was in stirring at room 18 hours.The gained solid by isolated by vacuum filtration, with washed with isopropyl alcohol and dry air, is obtained this title compound (0.525g, 18% productive rate), be white solid.
Embodiment 244B
3-amino-5-sec.-propyl-pyrazine-2-formonitrile HCN
(0.525g, 2.95mmol) solution in tetrahydrofuran (THF) (30mL) stirs under the ice-water bath temperature with the product of embodiment 244A.Quick dropping phosphorus trichloride in this solution (4.0g, 2.6mL, 29.5mmol, 10eq).With reaction mixture in stirring at room 16 hours, then with solvent and excess reagent evaporation.The gained resistates distributes between methyl acetate and half saturated sodium bicarbonate aqueous solution.With ethyl acetate collection (3 x 100mL) water intaking phase, and, filter the organic layer anhydrous magnesium sulfate drying that merges, and evaporation, obtain this title compound (0.370g, 77% productive rate), be light brown solid.
Embodiment 244C
N '-(3-cyano group-6-sec.-propyl-pyrazine-2-yl)-N, N-dimethyl-carbonamidine
With the product of embodiment 244B (0.37g, 2.28mmol) and dimethyl formamide dimethyl acetal (0.30g, 2.5mmol, the 1.1eq) heating 1.75 hours under refluxing of the mixture in toluene (25mL).Then reaction mixture is cooled to room temperature, and, obtains this title compound (0.50g, 100%),, it is used for subsequent reaction under situation about not being further purified for dense thick redness/brown oil with solvent removed under reduced pressure.
Embodiment 244D
4-[4-benzyloxy-2-(7-sec.-propyl-pteridine-4-base is amino)-phenyl sulfenyl]-phenol
With the product of embodiment 244C (56.2mg, 0.259mmol) and the heating 2 hours under refluxing of the mixture of product in acetate (1mL) of embodiment 27A.Reaction mixture is cooled to room temperature, and reduction vaporization.The gained resistates is developed with methyl alcohol, obtained this title compound (55.5mg, 53% productive rate), be beige solid.
1HNMR(300MHz，DMSO-D6)δ?ppm：10.37(s，1H)，9.65(s，1H)，9.03(s，1H)，8.80(s，1H)，8.31(s，1H)，7.38(d，J＝8.09Hz，1H)，7.21(d，J＝8.82Hz，2H)，7.03(dd，J＝8.09，1.47Hz，1H)，6.68(d，J＝8.82Hz，2H)，3.35-3.46(m，1H)，2.37(s，3H)，1.38(d，J＝6.62Hz，6H).MS(ESI
+)m/z?404.2(M+H)
+(ESI
-)m/z?402.3(M-H)
-.
Embodiment 245
[2-(4-amino-phenoxy group)-5-(6-bromo-1H-benzimidazolyl-2 radicals-yl)-phenyl]-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Embodiment 245A
[4-(4-formyl radical-2-nitro-phenoxy group)-phenyl]-t-butyl carbamate
The mixture of 4-chloro-3-nitrobenzaldehyde and (4-hydroxyl-phenyl)-t-butyl carbamate reacting, is obtained this title compound in the DMSO of KOH.
Embodiment 245B
4-[2-amino-4-(6-bromo-1H-benzimidazolyl-2 radicals-yl)-phenoxy group]-phenyl }-t-butyl formate
The product of embodiment 245A is reacted according to the method for embodiment 147B and 147C, obtain this title compound.
Embodiment 245C
[2-(4-amino-phenoxy group)-5-(6-bromo-1H-benzimidazolyl-2 radicals-yl)-phenyl]-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
The product of embodiment 245B and the product of embodiment 36E are reacted in HOAc, and be placed on and preheat to 120 ℃ oil bath.At N
2Air-flow removes down and desolvates.With product by being dissolved in the 1:1 mixture of TFA in DCM, and in stirring at room.Roughage by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.35(d，J＝6.99Hz，6H)3.21-3.39(m，1H)6.87-7.04(m，4H)7.09(d，J＝8.46Hz，1H)7.36(dd，J＝8.82，1.84Hz，1H)7.56(d，J＝8.46Hz，1H)7.78(d，J＝1.47Hz，1H)7.89(d，J＝8.46Hz，1H)8.14(dd，J＝8.82，1.84Hz，1H)8.37(d，J＝1.84Hz，1H)8.90(s，1H)9.00(d，J＝8.09Hz，1H)；MS(ESI+)m/z?568.2(M+H)+.
Embodiment 246
4-[4-benzyloxy-2-(the 7-tertiary butyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl sulfenyl]-phenol
The product of embodiment 27A arises from 130 ℃ of heating 15 minutes with the product one of embodiment 127A in acetate, then mixture is cooled to room temperature, remove and desolvate, and with resistates by the silica gel column chromatography purifying, obtain this title compound.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.38(s，9H)5.11(s，2H)6.60-6.74(m，2H)6.94(d，J＝7.35Hz，1H)7.06-7.19(m，3H)7.27-7.50(m，6H)7.78(d，J＝8.09Hz，1H)8.56(s，1H)8.75(s，1H)9.64(s，1H)9.95(s，1H)；MS(ESI+)m/z?509(M+H)+.
Embodiment 247
2-(4-amino-phenyl sulfenyl)-5-(2-chloro-thiazole-5-ylmethoxy)-phenyl]-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Embodiment 247A
4-[2-amino-4-(2-chloro-thiazole-5-ylmethoxy)-phenyl sulfenyl]-phenyl }-t-butyl carbamate
Under nitrogen, 2-chloro-5-(4-chloro-3-nitro-phenoxymethyl)-thiazole (deriving from embodiment 25A) and 4-aminothiophenol are reacted under refluxing in dehydrated alcohol.Reaction is cooled to room temperature, and removes ethanol by rotary evaporation.Resistates is dissolved in the water, and extracts with methyl acetate.With the organic extract salt water washing that merges, use anhydrous sodium sulfate drying, filter and concentrate in a vacuum.Solid with 4% methyl acetate/methylene dichloride development, is obtained 4-(4-((2-diuril azoles-5-yl) methoxyl group)-2-nitrophenylsulfenyl) aniline.1, the mixture in the 4-diox is heating under refluxing under nitrogen, and then adds the Boc acid anhydrides, and reaction is heated to backflow with 4-(4-((2-diuril azoles-5-yl) methoxyl group)-2-nitrophenylsulfenyl) aniline and tert-Butyl dicarbonate.Reaction is cooled to room temperature, and removes by rotary evaporation in a vacuum and desolvate.The gained solid obtains 4-(4-((2-diuril azoles-5-yl) methoxyl group)-2-nitrophenylsulfenyl) the phenylcarbamic acid tert-butyl ester with 2.5% methyl acetate/methylene dichloride development.With the suspension heating in water and ethanol of 4-(4-((2-diuril azoles-5-yl) methoxyl group)-2-nitrophenylsulfenyl) phenylcarbamate, iron powder and ammonium chloride.Reaction is cooled to room temperature.This mixture dilutes with methyl acetate, and water and salt water washing.With the organic phase drying, filter and under vacuum, concentrate, obtain this title compound.
Embodiment 247B
[2-(4-amino-phenyl sulfenyl)-5-(2-chloro-thiazole-5-ylmethoxy)-phenyl]-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
The product of embodiment 247A is arised from 130 ℃ of heating 15 minutes with the product one of embodiment 36E in acetate, then mixture is cooled to room temperature, under vacuum, remove and desolvate, the mixture that adds methylene dichloride/trifluoroacetic acid 1/1, then with resistates in stirring at room 2 hours, under vacuum, remove then and desolvate, and with resistates by the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝6.99Hz，6H)3.20-3.37(m，1H)3.75(s，2H)5.33(s，2H)6.53(d，J＝8.46Hz，2H)6.99-7.12(m，5H)7.14(s，1H)7.80(s，1H)7.92(d，J＝8.82Hz，1H)8.83(s，1H)9.01(s，1H)11.62(s，1H)；MS(ESI+)m/z?535(M+H)+.
Embodiment 248
4-[2-(the 7-tertiary butyl-pyrido [2,3-d] pyrimidine-4-base is amino)-4-(2-chloro-thiazole-5-ylmethoxy)-phenyl sulfenyl]-phenyl }-t-butyl formate
The product of embodiment 247A is arised from 130 ℃ of heating 15 minutes with the product one of embodiment 127A in acetate, then mixture is cooled to room temperature, remove and desolvate, and with resistates by the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.43(d，J＝11.40Hz，15H)2.73(s，1H)5.36(s，2H)7.00(d，1H)7.13(d，J＝8.46Hz，2H)7.25(d，1H)7.33(d，J＝8.46Hz，3H)7.81(s，2H)8.62(s，1H)8.78(s，1H)9.39(s，1H)10.49(bs，1H)；MS(ESI+)m/z?649(M+H)+.
Embodiment 249
[2-(4-amino-phenyl sulfenyl)-5-(2-chloro-thiazole-5-ylmethoxy)-phenyl]-(the 7-tertiary butyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
The product of embodiment 248 is added in the mixture of methylene dichloride/trifluoroacetic acid 1/1, and with this solution in stirring at room 2 hours, under vacuum, remove then and desolvate, and with the gained resistates by the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δppm：1.44(s，6H)2.51-2.59(m，1H)3.72(s，2H)5.33(s，2H)6.24(dd，J＝8.82，2.94Hz，1H)6.42(d，J＝2.94Hz，1H)6.53(d，J＝8.46Hz，2H)6.98-7.12(m，3H)7.14(s，1H)7.74-7.85(m，1H)8.09(d，J＝8.46Hz，1H)8.83(s，1H)9.03(s，1H)11.65(s，1H)；MS(ESI+)m/z?549(M+H)+.
Embodiment 250
[2-(4-amino-phenyl sulfenyl)-5-(6-bromo-1H-benzimidazolyl-2 radicals-yl)-phenyl]-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Embodiment 250A
[4-(4-methane amide-2-nitro-phenyl sulfenyl)-phenyl]-t-butyl carbamate
According to the method for embodiment 216B, the product with 4-chloro-3-nitrobenzaldehyde alternate embodiment 216A with the mixture reaction of 4-chloro-3-nitrobenzaldehyde and 4-aminothiophenol, with its operation of carrying out embodiment 216C, obtains this title compound then.
Embodiment 250B
[2-(4-amino-phenyl sulfenyl)-5-(6-bromo-1H-benzimidazolyl-2 radicals-yl)-phenyl]-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
The product of embodiment 250A is reacted according to embodiment 147B, 147C and 147C, obtain thick resistates, it by the HPLC purifying, is used the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMMSO-D6)δ?ppm：1.38(d，J＝6.62Hz，6H)3.26-3.40(m，1H)6.64(d，J＝8.46Hz，2H)7.03(d，J＝8.46Hz，1H)7.17(d，J＝8.46Hz，2H)7.35(dd，J＝8.46，1.84Hz，1H)7.54(d，J＝8.82Hz，1H)7.77(d，J＝1.84Hz，1H)7.94(d，J＝8.46Hz，1H)8.03(dd，J＝8.46，1.84Hz，1H)8.18(s，1H)8.89(s，1H)9.05(d，J＝8.82Hz，1H)；MS(ESI+)m/z?584(M+H)+.
Embodiment 251
[2-(4-amino-phenyl sulfenyl)-5-(3-fluoro-benzyloxy)-phenyl]-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Embodiment 251A
(4-[2-amino-4-(3-fluoro-benzyloxy)-phenyl sulfenyl]-phenyl }-t-butyl formate
Resistates and the 4-aminothiophenol of embodiment 57B are reacted according to the method for embodiment 214B, according to the method reaction of embodiment 214C and 214D, obtain this title compound then.
Embodiment 251B
[2-(4-amino-phenyl sulfenyl)-5-(3-fluoro-benzyl oxygen base)-phenyl]-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
The product of embodiment 251A is arised from 130 ℃ of heating 15 minutes with the product one of embodiment 36E in acetate, then mixture is cooled to room temperature, under vacuum, remove and desolvate, the mixture that adds methylene dichloride/trifluoroacetic acid 1/1, with resistates in stirring at room 2 hours, under vacuum, remove then and desolvate, and resistates is passed through the silica gel column chromatography purifying, obtain this title compound.
1HNMR(300MHz，DMSO-D6)δ?ppm：1.26-1.44(d，6H)3.23-3.37(m，1H)5.13(s，2H)6.44-6.61(m，2H)6.96-7.10(m，，3H)7.10-7.22(m，2H)7.24-7.35(m，3H)7.35(d，J＝6.25Hz，1H)7.43(dd，J＝7.91，5.70Hz，2H)7.92(s，1H)8.18(d，J＝8.82Hz，1H)8.83(s，1H)9.03(s，1H)；MS(ESI+)m/z?512(M+H)+.
Embodiment 252
[2-(4-amino-phenyl sulfenyl)-5-(3-fluoro-benzyloxy)-phenyl]-(the 7-tertiary butyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
The product of embodiment 251A is arised from 130 ℃ of heating 15 minutes with the product one of embodiment 127A in acetate, then mixture is cooled to room temperature, under vacuum, remove and desolvate, the mixture that adds methylene dichloride/trifluoroacetic acid 1/1 in stirring at room 2 hours, removes resistates then and desolvates under vacuum, and with resistates by the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetate.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.38-1.50(m，，9H)5.12(s，2H)6.44-6.61(m，3H)6.96-7.12(m，3H)7.19(s，3H)7.23-7.33(m，3H)7.38-7.50(m，2H)8.00(s，1H)8.76(s，1H)8.96(s，1H)；MS(ESI+)m/z?526(M+H)+.
Embodiment 253
[5-benzyloxy-2-(4-dimethylamino-phenyl sulfenyl)-phenyl]-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
Embodiment 253A
5-benzyloxy-2-(4-dimethylamino-phenyl sulfenyl)-phenyl amine
(1.0g, 0.284mmol) (5mL), diox (5mL) and 37% formalin (5mL) are inserted in the test tube with formic acid with the product of embodiment 214B.With test tube sealing and be heated to 110 ℃ 20 minutes.Mixture is cooled to room temperature, removes and to desolvate, and with gained resistates silica gel column chromatography purifying, then according to the method for embodiment 214D with nitroreduction, obtain this title compound (411mg, 43%).
Embodiment 253B
[5-benzyloxy-2-(4-dimethylamino-phenyl sulfenyl)-phenyl]-(7-sec.-propyl-pyrido [2,3-d] pyrimidine-4-yl)-amine
The product of embodiment 253A was being preheated to 130 ℃ the oil bath heating 20 minutes with the mixture of product in Glacial acetic acid of embodiment 36E.Then reaction mixture is cooled to room temperature, and vaporising under vacuum desolvates, obtain this title compound, be the acetate form.
1H?NMR(300MHz，DMSO-D6)δ?ppm：1.36(d，J＝7.0Hz，6H)，2.81(s，6H)，3.30(m，1H)，5.10(s，2H)，6.45(d，J＝9.2Hz，2H)，7.07(d，J＝8.8Hz，2H)，7.12(m，2H)，7.25(d，J＝8.8Hz，1H)，7.40(m，5H)，7.94(m，1H)，8.78(s，1H)，8.99(m，1H)，11.70(bs，1H)；MS(ESI)m/z?522(M+H)+.
Embodiment 254
4-bromo-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide
Embodiment 254A
4-bromo-N-(3-nitro-phenyl)-benzamide
Substitute 4-fluoro-3-nitro-aniline with 3-nitro-phenyl amine, and with the alternative 3-trifluoromethyl-Benzoyl chloride of 4-bromo-Benzoyl chloride, prepare this title compound, obtain this title compound (3.373g, 90%) according to the method for embodiment 255A.
Embodiment 254B
4-bromo-N-(3-amino-phenyl)-benzamide
With the product of the product alternate embodiment 255A of embodiment 254A, prepare this title compound according to the method for embodiment 255B, obtain this title compound (1.8g, 80%).
Embodiment 254C
4-bromo-N-[3-(pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-benzamide
With the product of embodiment 57A (40.0mg, 0.212mmol) and the product of embodiment 254B (61.0mg, 0.212mmol) solution in acetate (1mL) is preheating to 130 ℃ oil bath and was stirring 20 minutes.Then mixture is cooled to room temperature, under vacuum, removes acetate, and the gained resistates is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (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 255
N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-trifluoromethyl-benzamide
Embodiment 255A
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,, obtains this title compound (3.3Hg, 97%) by filtration collection gained solid and dry in vacuum chamber.
Embodiment 255B
N-[4-(4-hydroxyl-phenyl sulfenyl)-3-nitro-phenyl]-3-trifluoromethyl-benzamide
With the product 255A of embodiment (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) be heated to 80 ℃ 2 hours.After being cooled to room temperature, mixture is poured in the frozen water (100mL).Then this solution is extracted with ethyl acetate (3 x 150mL), the extract dried over mgso of merging, filtration also concentrates under vacuum, obtains this title compound (2.52g, 100%).
Embodiment 255C
N-[3-amino-4-(4-hydroxyl-phenyl sulfenyl)-phenyl]-3-trifluoromethyl-benzamide
With the product 255B of embodiment (0.660g, 1.52mmol), iron powder (0.339g, 6.07mmol) and ammonium chloride (0.099g, 1.82mmol), the solution in tetrahydrofuran (THF) (18mL) and the water (6mL) is heated to and refluxed 3 hours.The gained mixture is diluted with methyl alcohol (50mL), and filter by Celite pad.Filtrate water (50mL) is diluted, and extract with methylene dichloride (2x100mL).With the extract dried over mgso that merges, filter and under vacuum, concentrate, obtain this title compound (0.60g, 97%).
Embodiment 255D
N-[4-(4-hydroxyl-phenyl sulfenyl)-3-(7-methyl-pyrido [2,3-d] pyrimidine-4-base is amino)-phenyl]-3-trifluoromethyl-benzamide
With the product of embodiment 10B (40.0mg, 0.212mmol) and the product of embodiment 255C (86.0mg, 0.212mmol) solution in acetate (1mL) is preheating to 130 ℃ oil bath and was stirring 20 minutes.Then mixture is cooled to room temperature, under vacuum, removes acetate, and the gained resistates is passed through the HPLC purifying, use the TFA wash-out, obtain this title compound, be trifluoroacetic acid salt form (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/z?548.2(M+H)+，(ESI-)m/z?546.2(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 TM of DMEM Dulbecco
RNA Yeast Nucleic Acid
The RT-PCR reverse transcriptase-polymerase chain reaction
SEAP excretory alkaline phosphatase
The polyprotein that the hepatitis c virus gene group coding is big, after processing, polyprotein produces synthon for the necessary functional component of RNA.The optional cell that produces the subgene group HCV RNA (replicon) of high and lasting level is a derived from human hepatoma cells (Huh7), as people such as Ikeda, and J.
, 76 (6): people such as 2997-3006 (2002) and Blight,
, described in the 290:1972-1974 (2000).In the clone mechanism of rna replicon be considered to the liver cell that infects in total length HCV duplicate identical.The compounds of this invention is the HCV rna replicon inhibitor in the following replicon mensuration system.
The assessment of HCV inhibitor in the HCV replicon
Assess the restraining effect of representative compounds of the present invention for HCV genotype 1a and 1b replicon.Also measure and assessed the cytotoxicity of representative compounds of the present invention for host cell by MTT.By people such as Yi,
, 304 (2): the method for describing among the 197-210 (2002) keeps clone.
A.RNA measures and SEAP measures
The purpose of these mensuration is the effectiveness that the assessment compound duplicates at vitro inhibition HCV genotype 1a and 1b.
With genotype 1a and/or 1b replicon cell in containing the DMEM substratum of 5% foetal calf serum with 3-5 * 10
3Individual cells/well is layered in the flat board of 96-hole.Second day, take out substratum, and replace with the fresh culture of the compound that contains 8 serial dilutions.Untreated control cultures is handled in the same manner, but in substratum, do not added inhibitor.With flat board at CO
2In the incubator in 37 ℃ of cultivations.At the 4th day, behind the taking-up substratum, in each hole, add 100 μ l lysis buffers (RTL) (Qiagen).Introduction (Qiagen RNAeasy) according to the manufacturer comes purifying RNA, and in 200 μ l water wash-out.By the real-time RT-PCR method, come quantitative assay HCV rna level from a part (5 μ l in the middle of the 200 μ l) purifying RNA.Primer and the source probe specific sequence in 5 '-untranslated zone (5 ' UTR).RT-PCR is reflected at 48 ℃ to carry out 30 minutes, carried out 40 following cycles then and set: 95 ℃, and 15s; 54 ℃, 30s; With 72 ℃, 40s.Perhaps, cultivate 4 days with compound after, measure the activity of SEAP in each culture supernatants according to manufacturer's specification sheets.Calculate HCV RNA or the minimizing per-cent of SEAP in the presence of compound, (San Diego CA), calculates 50% inhibition concentration (IC50) by nonlinear regression analysis for 4.0 versions, GraphPad software to use Prism program.
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.#M 2128) of tetrazolium salts MTT with 25 μ l/ holes.Flat board was further cultivated 4 hours, added 0.02N 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, II, III, IV, V, VI, VII or VIII compound.Preferably, each compound is independently selected from the compound of embodiment 1-255.
The invention still further relates to the pharmaceutical composition of the pharmacologically acceptable salt, solvate or the prodrug that comprise The compounds of this invention.Pharmacologically acceptable salt can be a zwitter-ion or can be derived from pharmaceutically acceptable inorganic or organic acid or alkali.Preferably, the pharmacologically acceptable salt of The compounds of this invention keeps the biological effectiveness of the compound of free acid or alkali form, there are not unsuitable toxicity, pungency or anaphylaxis simultaneously, have rational profit/danger than, using for its purpose is effectively, and does not have disadvantageous biotic influence or other undesirable influences.The limiting examples of pharmacologically acceptable salt includes but not limited to following: acetate, adipate, alginate, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulphite, butyrates, camphorate, camsilate, digluconate, cyclopentane propionate, dodecyl sulfate, esilate, gluceptate, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, 2-isethionate (isethionate), lactic acid salt, maleate, mesylate, nicotinate, the 2-naphthalenesulfonate, oxalate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, thiocyanate-, tosilate and hendecoic acid salt.The alkalescence nitrogen-containing group can also be with for example following reagent is quaternized: elementary alkyl halide (for example methyl, ethyl, propyl group or butyl muriate, bromide or iodide), dialkyl sulfate (for example dimethyl, diethyl, dibutyl or diamyl vitriol), long-chain halogenide (for example decyl, lauryl, myristyl or stearyl chlorination thing, bromide or iodide), aralkyl halide (for example benzyl or styroyl bromination thing).Can be used for other salt of the present invention and comprise and basic metal or the alkaline-earth metal salt that forms of sodium, potassium, calcium or magnesium for example, perhaps the salt that forms with organic bases.The example that can be used for forming the acid of pharmaceutically acceptable acid additive salt includes but not limited to hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, succsinic acid, citric acid or other suitable inorganic or organic acids.
The invention still further relates to the pharmaceutical composition that comprises The compounds of this invention (or its salt, solvate or prodrug) and another therapeutical agent.In limiting examples, pharmaceutical composition of the present invention comprises a kind of, two kinds, three kinds or more kinds of The compounds of this invention (or its salt, solvate or prodrug) and a kind of, two kinds, three kinds or more kinds of other treatment agent.Such as but not limited to, these other treatment agent can be selected from antiviral agent (for example anti-HIV agent or other whose anti-HCV agent), immunomodulator, carcinostatic agent or chemotherapeutics or anti-inflammatory agent.The specific examples of these other treatment agent includes but not limited to ribavirin; Interferon, rabbit (for example IFN α 2a or 2b); Proteinase inhibitor; Immunosuppressor; Antibody (for example therapeutic monoclonal antibodies or chimeric antibody); Antisense or siRNA; Hiv inhibitor; Hepatitis B (HBV) inhibitor; The medicine that is used for the treatment of liver cirrhosis and liver inflammation; Omega IFN (BioMedicines Inc., Emeryville, CA); The BILN-2061 serpin (Boehringer Ingelheim Pharma KG, Ingelheim, Germany); The Summetrel antiviral agent (Endo Pharmaceuticals Holdings Inc., Chadds Ford, PA); Roferon AIFN-α 2a (F.Hoffmann-La Roche LTD, Basel, Switzerland); PegasysPEGylated IFN-α 2a (F.Hoffmann-La Roche LTD, Basel, Switzerland); Pegasys and ribavirin PEGylated IFN-α 2a/ ribavirin (F.Hoffmann-La RocheLTD, Basel, Switzerland); CellCept HCV IgG immunosuppressor (F.Hoffmann-LaRoche LTD, Basel, Switzerland); Wellferon lymphoblastoid IFN-α n1 (GlaxoSmithKline plc, Uxbridge, UK); Albuferon-α albumin IFN-α 2b (Human Genome Sciences Inc., Rockville, MD); The Levovirin ribavirin (ICNPharmaceuticals, Costa Mesa, CA); IDN-6556 caspase inhibitor (IdunPharmaceuticals Inc., San Diego, CA); The agent of IP-501 fibrosis (IndevusPharmaceuticals Inc., Lexington, MA); Actimmune INF-γ (InterMune Inc., Brisbane, CA); Infergen A IFN alfacon-1 (InterMune Pharmaceuticals Inc., Brisbane, CA); ISIS 14803 antisenses (ISIS Pharmaceuticals Inc., Carlsbad, CA/Elan Pharmaceuticals Inc., New York, NY); JTK-003 RdRp inhibitor (Japan Tobacco Inc., Tokyo, Japan); Pegasys and Ceplene PEGylated IFN-α 2a/ immunomodulator (Maxim Pharmaceuticals inc., San Diego, CA); The Ceplene immunomodulator (Maxim Pharmaceuticals Inc., San Diego, CA); Civacir HCV IgG immunosuppressor (Nabi Biopharmaceuticals Inc., Boca Raton, FL); Intron A and Zadaxin IFN-α 2b/ α 1-thymosin (RegeneRx Biopharmiceuticals Inc., Bethesda, MD/SciClone Pharmaceuticals Inc., San Mateo, CA); Levovirin IMPDH inhibitor (Ribapharm Inc., Costa Mesa, CA); Viramidine IMPDH inhibitor (Ribapharm Inc., Costa Mesa, CA); The Heptazyme ribozyme (RibozymePharmaceuticals Inc., Boulder, CO); Intron A IFN-α 2b (Schering-PloughCorporation, Kenilworth, NJ); PEG-Intron PEGylated IFN-α 2b (Schering-Plough Corporation, Kenilworth, NJ); Rebetron IFN-α 2b/ ribavirin (Schering-Plough Corporation, Kenilworth, NJ); Ribavirin (Schering-Plough Corporation, Kenilworth, NJ); PEG-Intron/ ribavirin PEGylated IFN-α 2b/ ribavirin (Schering-Plough Corporation, Kenilworth, NJ); The Zadazim immunomodulator (SciClone Pharmaceuticals Inc., San Mateo, CA); Rebif IFN-β 1a (Serono, Geneva, Switzerland); IFN-β and EMZ701 IFN-β and EMZ701 (Transition Therapeutics Inc., Ontario, Canada); T67 'beta '-tubulin inhibitor (Tularik Inc., South San Francisco, CA); VX-497 IMPDH inhibitor (Vertex Pharmaceuticals Inc., Cambridge, MA); The VX-950/LY-570310 serpin (Vertex Pharmaceuticals Inc., Cambridge, MA/Eli Lillyand Co., Inc., Indianapolis, IN); The natural IFN-α of Omniferon (Viragen Inc., Plantation, FL); XTL-002 monoclonal antibody (XTL Biopharmaceuticals);
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, II, III, IV, V, VI, VII or VIII compound or embodiment 1-255, 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, II, III, IV, V, VI, VII or VIII compound or embodiment 1-255.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, II, III, IV, V, VI, VII or VIII compound or embodiment 1-255.
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, II, III, IV, V, VI, VII or VIII compound or embodiment 1-255.
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, II, III, IV, V, VI, VII or VIII compound or embodiment 1-255.
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, II, III, IV, V, VI, VII or VIII compound or embodiment 1-255.
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, II, III, IV, V, VI, VII or VIII compound or embodiment 1-255.
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, II, III, IV, V, VI, VII or VIII compound or embodiment 1-255 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, II, III, IV, V, VI, VII or VIII compound or embodiment 1-255 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, II, III, IV, V, VI, VII or VIII compound or embodiment 1-255 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, II, III, IV, V, VI, VII or VIII compound or embodiment 1-255 compound.
Pharmaceutical composition of the present invention comprises pharmaceutically acceptable carrier or vehicle usually.The limiting examples of suitable pharmaceutically acceptable carrier/vehicle comprises sugar (lactose for example, glucose or sucrose), starch (for example W-Gum or yam starch), Mierocrystalline cellulose or derivatives thereof (Xylo-Mucine for example, ethyl cellulose or cellulose acetate), oils (peanut oil for example, Oleum Gossypii semen, Thistle oil, sesame oil, sweet oil, Semen Maydis oil or soybean oil), glycols (for example propylene glycol), buffer reagent (for example magnesium hydroxide or aluminium hydroxide), agar, alginic acid, tragacanth gum powder, Fructus Hordei Germinatus, gelatin, talcum powder, theobroma oil, the water that does not contain pyrogen, isotonic saline solution, Ringer's solution, ethanol or phosphate buffered saline buffer.As skilled in the art to understand, pharmaceutical composition of the present invention can also comprise lubricant, tinting material, releasing agent, Drug coating, sweeting agent, correctives or spices, sanitas or antioxidant.
Pharmaceutical composition of the present invention can be via number of ways, for example oral, parenteral, hypogloeeis, rectum, part or introduce spraying and come patient's administration to there being this to need.Topical can comprise that the use percutaneous dosing is for example through skin patch or Iontophoretic device.That parenteral admin includes but not limited to is subcutaneous, intravenously, intramuscular or breastbone inner injection, and infusion techniques.
Pharmaceutical composition of the present invention can use method well-known in the art to prepare based on its route of administration.For example, can use suitable dispersion agent or wetting agent and suspension agent aseptic injection preparation to be made the form of sterile injectable water or oil suspension.The suppository that is used for rectal administration can make like this: for example theobroma oil or polyoxyethylene glycol mix with medicine and suitable non-irritating excipient, described vehicle is solid at normal temperatures, but in rectal temperature is liquid, will and discharge medicine in the internal rectum fusing thus.The solid dosage that is used for oral administration can be capsule, tablet, pill, pulvis or granula.I in such solid dosage can for example sucrose, lactose or starch mix with at least a inert diluent with active compound.Handle beyond the inert diluent, solid dosage can also comprise for example lubricant of other materials.For capsule, tablet and pill, formulation can also comprise buffer reagent.Tablet and pill also can be used the enteric coating dressing.The liquid dosage form that is used for oral administration can comprise pharmaceutical acceptable emulsion, solution, suspension, syrup or elixir, and it contains this area inert diluent commonly used.Liquid dosage form can also comprise wetting agent, emulsifying agent, suspension agent, sweeting agent, correctives or fragrance material.Pharmaceutical composition of the present invention can also be with the liposome form administration as describing in U.S. patent 6,703,403.Be applied to pharmaceutical preparation of the present invention generally at for example Hoover, John E.,
(Mack Publishing Co., Easton, PA:1975), and and Lachman, L., eds.,
Discuss in (Marcel Decker, New York, N.Y., 1980).
The invention still further relates to and use The compounds of this invention (or its salt, solvate or prodrug) to suppress the method that HCV duplicates.In one embodiment, the inventive method comprises HCV virus is contacted with the The compounds of this invention (or its salt, solvate or prodrug) of significant quantity, suppresses duplicating of HCV virus thus.In another embodiment, the inventive method comprises and contacting with the The compounds of this invention of significant quantity (or its salt, solvate or prodrug) having infected the cell of HCV virus, suppresses HCV virus duplicating in cell thus.In another embodiment, the inventive method comprises that the cell with HCV virus or infection contacts with two or more The compounds of this invention (or its salt, solvate or prodrug) of significant quantity, suppresses duplicating of HCV virus thus." inhibition " used herein is meant remarkable reduction or eliminates repressed activity (for example virus replication).Under many circumstances, representative compounds of the present invention can reduce at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more with duplicate (for example in aforesaid HCV replicon is measured) of HCV virus.
The compounds of this invention can suppress all HCV hypotypes.The example of the HCV hypotype that can suppress by the present invention includes but not limited to HCV hypotype 1,2,3,4,5 and 6, comprises HCV genotype 1a, 1b, 2a, 2b, 2c or 3a.In one embodiment, use The compounds of this invention (or its salt, solvate or prodrug) to suppress duplicating of HCV genotype 1a.In another embodiment, use The compounds of this invention (or its salt, solvate or prodrug) to suppress duplicating of HCV genotype 1b.In another embodiment, use The compounds of this invention (or its salt, solvate or prodrug) to suppress duplicating of HCV genotype 1a and 1b.
The invention still further relates to and use The compounds of this invention (or its salt, solvate or prodrug) to treat the method that HCV infects.These methods generally include to the The compounds of this invention of HCV patient's administering therapeutic significant quantity (or its salt, solvate or prodrug), to reduce the HCV virus levels in blood samples of patients or the liver thus.Term used herein " treatment " is meant reverse, alleviate, suppress this term at disease or one or more symptoms of illness or disease or illness, the progress that suppresses one or more symptoms of disease or illness or disease or illness, perhaps one or more symptoms of preventing disease or illness or disease or illness.Term " treatment " is meant therapeutic action.In one embodiment, in one embodiment, these methods comprise to two or more The compounds of this invention of HCV patient's administering therapeutic significant quantity (or its salt, solvate or prodrug), to reduce the HCV virus levels in blood samples of patients or the liver thus.Preferably, the compound that uses in these methods is selected from the compound of formula I, II, III, IV, V, VI, VII or VIII compound or embodiment 1-255, 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, II, III, IV, V, VI, VII or VIII compound or embodiment 1-255 compound, with at least a other whose anti-HCV agent, described other whose anti-HCV agent are selected from HCV RNA RNA-dependent AG14361, HCV proteinase inhibitor or HCV helicase inhibitor.In another embodiment, the pharmaceutical composition of using comprises at least a The compounds of this invention or its salt, solvate or the prodrug that is selected from formula I, II, III, IV, V, VI, VII or VIII compound or embodiment 1-255 compound, with a kind of, two or more HCV RNA RNA-dependent AG14361 (for example those that describe among WO0190121 (A2), US6348587B1, WO0160315, WO0132153, EP1162196A1 and the WO0204425).In another embodiment, the pharmaceutical composition of using comprises at least a The compounds of this invention or its salt, solvate or the prodrug that is selected from formula I, II, III, IV, V, VI, VII or VIII compound or embodiment 1-255 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, II, III, IV, V, VI, VII or VIII compound or embodiment 1-255 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, II, III, IV, V, VI, VII or VIII compound or embodiment 1-255 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, II, III, IV, V, VI, VII or VIII compound or embodiment 1-255 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, II, III, IV, V, VI, VII or VIII compound or embodiment 1-255 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, II, III, IV, V, VI, VII or VIII compound or embodiment 1-255 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, II, III, IV, V, VI, VII or VIII 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, II, III, IV, V, VI, VII or VIII 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 formula I, II, III, IV, V, VI, VII or the VIII compound or pharmaceutically acceptable salt thereof to patient's administering therapeutic significant quantity of this treatment of needs.
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, II, III, IV, V, VI, VII or the VIII compound or pharmaceutically acceptable salt thereof of treatment significant quantity.
In another embodiment, the present invention relates to the method for the infection treating or prevent to cause by the virus that contains RNA, described method comprises to co-administered one or more of the patient of this treatment of needs and is selected from interferon-' alpha ', Pegylation (pegylated)-interferon-' alpha ', interferon-beta, interferon-, cytokine, vaccine and comprises antigen and the therapeutical agent of the vaccine of adjuvant and second antiviral agent or its combination, with formula I, II, III, IV, V, VI, VII or the VIII compound or pharmaceutically acceptable salt thereof of treatment significant quantity.
In another embodiment, the present invention relates to the method for the infection treating or prevent to be caused by the virus that contains RNA, described method comprises to co-administered one or more of the patient of this treatment of needs and is selected from the host immune conditioning agent and suppresses second antiviral agent that HCV duplicates or the therapeutical agent and formula I, II, III, IV, V, VI, VII or the VIII 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, II, III, IV, V, VI, VII or the VIII 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, II, III, IV, V, VI, VII or the VIII 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, II, III, IV, V, VI, VII or the VIII 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, II, III, IV, V, VI, VII or VIII 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, II, III, IV, V, VI, VII or VIII 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, II, III, IV, V, VI, VII or VIII 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 IngelheimPharma KG, Ingelheim, Germany); The Summetrel antiviral agent (EndoPharmaceuticals Holdings Inc., Chadds Ford, PA); Roferon A IFN-α 2a (F.Hoffmann-La Roche LTD, Basel, Switzerland); Pegasys PEGylated IFN-o2a (F.Hoffmann-La Roche LTD, Basel, Switzerland); Pegasys and ribavirin PEGylated IFN-α 2a/ ribavirin (F.Hoffmann-La Roche LTD, Basel, Switzerl and); CellCept HCV IgG immunosuppressor (F.Hoffmann-La Roche LTD, Basel, Switzerland); Wellferon lymphoblastoid IFN-α n1 (GlaxoSmithKlineplc, Uxbridge, UK); Albuferon-α albumin IFN-α 2b (Human GenomeSciences Inc., Rockville, MD); The Levovirin ribavirin (ICN Pharmaceuticals, Costa Mesa, CA); IDN-6556 caspase inhibitor (Idun Pharmaceuticals Inc., SanDiego, CA); The agent of IP-501 fibrosis (Indevus Pharmaceuticals Inc., Lexingtor, MA); Actimmure 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 CeplenePEGylated IFN-α 2a/ immunomodulator (MaximPharmaceuticals inc., San Diego, CA); The Ceplene immunomodulator (MaximPharmaceuticals Inc., San Diego, CA); Civacir HCV IgG immunosuppressor (NabiBiopharmaceuticals Inc., Boca Raton, FL); Intron A and Zadaxin IFN-α 2b/ α 1-thymosin (RegeneRx Biopharmiceuticals Inc., Bethesda, MD/SciClonePharmaceuticals Inc., San Mateo, CA); Levovirin IMPDH inhibitor (Ribapharm Inc., Costa Mesa, CA); Viramidine IMPDH inhibitor (RibapharmInc., Costa Mesa, CA); The Heptazyme ribozyme (Ribozyme Pharmaceuticals Inc., Boulder, CO); Intron A IFN-α 2b (Schering-Plough Corporation, Kenilworth, NJ); PEG-Intron PEGylated IFN-α 2b (Schering-Plough Corporation, Kenilworth, NJ); Rebetron IFN-α 2b/ ribavirin (Schering-PloughCorporation, 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 (TransitionTherapeutics Inc., Ontario, Canada); T67 'beta '-tubulin inhibitor (Tularik Inc., South San Francisco, CA); VX-497 IMPDH inhibitor (Vertex PharmaceuticalsInc., Cambridge, MA); The VX-950/LY-570310 serpin (VertexPharmaceuticals Inc., Cambridge, MA/EliLilly and Co., Inc., Indianapolis, IN); The natural IFN-α of Omniferon (Viragen Inc., Plantation, FL); XTL-002 monoclonal antibody (XTL Biopharmaceuticals); Compound VX-950 (VertexPharmaceuticals Inc.); Compound S CH503034 (Schering-Plough Co.); With compound GS9137 (Gilead Sciences, Inc., Foster City, CA).
In another embodiment, the present invention relates at least a The compounds of this invention (or its salt, solvate or prodrug) and at least a other antiviral agent and be used for the treatment of application in the medicine for treating viral infections in preparation.Preferably, The compounds of this invention is selected from formula I, II, III, IV, V, VI, VII or VIII 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, II, III, IV, V, VI, VII or VIII compound (or its salt, solvate or prodrug) and at least a other whose anti-HCV agent and be used for the treatment of application in the medicine that HCV infects in preparation.The limiting examples of whose anti-HCV agent comprises HCV RNA RNA-dependent AG14361 (for example nucleosides or non-nucleosides type AG14361) or HCV proteinase inhibitor.In another example, relate at least a be selected from the The compounds of this invention of formula I, II, III, IV, V, VI, VII or VIII 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, II, III, IV, V, VI, VII or VIII 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, II, III, IV, V, VI, VII or VIII 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, II, III, IV, V, VI, VII or VIII 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 (20)
1. the pharmacologically acceptable salt of the tautomer of compound, described compound or described compound or tautomer, wherein said compound has formula I,
Wherein:
A and B are selected from carbocylic radical or heterocyclic radical independently of one another, and optional independently of one another by one or more R
18Replace, wherein R
18When each occurs, be independently selected from 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 (CR
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 ");
W
1And W
2Be selected from N or C (R independently of one another
33);
Z be key ,-CR
41R
41 '-or-NR
41-, R wherein
41And R
41 'Be selected from hydrogen, alkyl, alkenyl and alkynyl independently of one another;
R
10And R
33When each occurs, be selected from independently of one another 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 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 each occurs, be independently selected from 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 ") ,-LS-N=C (NR
SR
S ') (NR
SR
S ') ,-L
S-N (R
S) SO
2R
S ',-L
S-SO
2N (R
SR
S ') ,-L
S-N (R
S) SO
2N (R
S 'R
S ") ,-L
E-Q-L
E '-(C
3-C
18Carbocylic radical) and-L
E-Q-L
E '-(M
3-M
18Heterocyclic radical); Perhaps R
22Be alkyl, alkenyl or alkynyl, and optional by one or more R
26Replace; Perhaps R
22Be hydrogen;
Y be selected from key ,-L
S-O-,-L
S-C (O)-,-L
S-S (O)
2-,-L
S-S (O)-,-L
S-OS (O)
2-,-L
S-OS (O)-,-L
S-C (O) O-,-L
S-OC (O)-,-L
S-OC (O) O-,-L
S-C (O) N (R
15)-,-L
S-N (R
15) C (O)-,-L
S-C (O) N (R
15) O-,-L
S-N (R
15) C (O) O-,-L
S-C (O) N (R
15) N (R
15)-,-L
S-S-,-L
S-C (S)-,-L
S-C (S) O-,-L
S-OC (S)-,-L
S-N (R
15)-,-L
S-C (S) N (R
15)-,-L
S-N (R
15) C (S)-,-L
S-N (R
15) S (O) ,-L
S-N (R
15) S (O)
2-,-L
S-S (O)
2N (R
15)-,-L
S-S (O) N (R
15)-,-L
S-C (S) N (R
15) O-and-L
S-C (S) N (R
15) N (R
15 ')-, be R wherein
15And R
15 'When occurring, each is selected from hydrogen, alkyl, alkenyl and alkynyl independently of one another;
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 A
1Optional by one or more R
30Replace, and R
30When each occurs, be independently selected from 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 each occurs, be independently selected from 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, each is independently selected from key, alkylidene group, alkylene group and alkynylene;
R
S, R
S 'And R
S "When occurring, each is selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxyl group, thio alkoxy, alkoxyalkyl, alkoxy alkoxy alkyl, thio alkoxy alkyl, alkyl-carbonyl, alkyl-carbonyl alkyl, alkoxy carbonyl, alkoxy carbonyl alkyl, alkyl-carbonyl oxygen base, alkyl-carbonyl oxygen base alkyl, alkylamino, alkylamino alkyl, alkoxycarbonyl amino and alkoxycarbonyl amino alkyl independently of one another;
L
EAnd L
E 'When occurring, each is selected from key, alkylidene group, alkylene group and alkynylene independently of one another;
Q when each occurs, be independently selected from 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
18, R
26, R
30, R
33, R
38, R
41And R
41 'When each occurs, choose wantonly independently of one another by at least one 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-; 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 is optional independently when each occurs to be 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.
2. the compound of claim 1, tautomer or salt, wherein:
A and B are selected from C independently of one another
4-C
11Carbocylic radical or M
4-M
11Heterocyclic radical, and optional independently of one another by one or more R
18Replace, wherein R
18When occurring, each is independently selected from 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
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 ') and-L
S-N (R
S) SO
2N (R
S 'R
S ");
W
1And W
2Be selected from N or C (R independently of one another
33);
Z be key ,-CR
41R
41 '-or-NR
41-, R wherein
41And R
41 'Be selected from hydrogen, C independently of one another
1-C
6Alkyl, C
2-C
6Alkenyl and C
2-C
6Alkynyl;
R
10And R
33When occurring, each is selected from hydrogen, halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, azido-, C independently of one another
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);
X be selected from 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 C
4-C
11Carbocylic radical or M
4-M
11Heterocyclic radical, and optional by one or more R
26Replace, wherein R
26When occurring, each is independently selected from 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 ,-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
1-C
6Alkenyl or C
1-C
6Alkynyl, and optional by one or more R
26Replace; Perhaps R
22Be hydrogen;
Y be selected from key ,-L
S-O-,-L
S-C (O)-,-L
S-S (O)
2-,-L
S-S (O)-,-L
S-OS (O)
2-,-L
S-OS (O)-,-L
S-C (O) O-,-L
S-OC (O)-,-L
S-OC (O) O-,-L
S-C (O) N (R
15)-,-L
S-N (R
15) C (O)-,-L
S-C (O) N (R
15) O-,-L
S-N (R
15) C (O) O-,-L
S-C (O) N (R
15) N (R
15 ')-,-L
S-S-,-L
S-C (S)-,-L
S-C (S) O-,-L
S-OC (S)-,-L
S-N (R
15)-,-L
S-C (S) N (R
15)-,-L
S-N (R
15) C (S)-,-L
S-N (R
15) S (O)-,-L
S-N (R
15) S (O)
2-,-L
S-S (O)
2N (R
15) ,-L
S-S (O) N (R
15) ,-L
S-C (S) N (R
15) O-and-L
S-C (S) N (R
15) N (R
15 '), R wherein
15And R
15 'Be selected from hydrogen, C independently of one another
1-C
6Alkyl, C
2-C
6Alkenyl and C
2-C
6Alkynyl;
R
50Be-L
1-A
1, A wherein
1Be selected from C
4-C
11Carbocylic radical, M
4-M
11Heterocyclic radical, C
1-C
6Alkyl, C
2-C
6Alkenyl and C
2-C
6Alkynyl, and L
1Be selected from 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, each is independently selected from 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 ,-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
SS (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, each is independently selected from halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, azido-, C
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, each is independently selected from key, C
1-C
6Alkylidene group, C
2-C
6Alkylene group and C
2-C
6Alkynylene;
R
S, R
S 'And R
S "When occurring, each is selected from hydrogen, C independently of one another
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, each is selected from key, C independently of one another
1-C
6Alkylidene group, C
2-C
6Alkylene group and C
2-C
6Alkynylene;
Q is independently selected from key, C when each occurs
1-C
6Alkylidene group, C
2-C
6Alkylene group, C
2-C
6Alkynylene ,-S-,-O-,-C (O)-,-N (R
S)-,-N (R
S) C (O)-,-C (O) N (R
S)-,-N (R
S) C (O) O-,-OC (O) N (R
S)-,-N (R
S) C (O) N (R
S ')-,-C (=NR
S) N (R
S ')-,-N (R
S ') C (=NR
S)-,-S (O)-,-SO
2-,-O-SO
2-,-SO
2-O-,-O-S (O)-,-S (O)-O-,-C (O) O-and-OC (O)-;
R
10, R
15, R
15 ', R
18, R
26, R
30, R
33, R
38, R
41And R
41 'When each occurs, choose wantonly independently of one another by at least one 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-; 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 is optional independently when each occurs to be 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.
3. compound, tautomer or the salt of each claim among the claim 1-2, wherein:
Y is-L
S-O-,-L
S-S-or-L
S-N (R
15)-; And
A
1Be C
4-C
11Carbocylic radical or M
4-M
11Heterocyclic radical, and optional by one or more R
30Replace.
4. compound, tautomer or the salt of each claim among the claim 1-3, wherein A and B are selected from C independently of one another
5-C
6Carbocylic radical or M
5-M
6Heterocyclic radical, and optional independently of one another by one or more R
18Replace.
5. compound, tautomer or the salt of each claim, wherein W among the claim 1-4
1And W
2Be N, and Z is-NR
41-.
6. compound, tautomer or the salt of each claim among the claim 1-5, wherein X be-O-or-S-, and R
22Be C
5-C
6Carbocylic radical or M
5-M
6Heterocyclic radical, and optional by one or more R
26Replace.
7. compound, tautomer or the salt of each claim, wherein part among the claim 1-6
Be selected from
With
Wherein Q is N or C (R
33), and R wherein
10, R
17, R
33And R
35When occurring, each is selected from hydrogen, halogen, oxo base, thio group, hydroxyl, sulfydryl, nitro, cyano group, amino, carboxyl, formyl radical, phosphoric acid ester, azido-, C independently of one another
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).
8. compound, tautomer or the salt of each claim, wherein R among the claim 1-7
22Be
Or
And it is optional by one or more R
26Replace, and R wherein
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.
9. the pharmacologically acceptable salt of the tautomer of compound, described compound or described compound or tautomer, wherein said compound has formula II:
Wherein:
R
6Be selected from hydrogen and cyano group;
R
8Be selected from hydrogen and arylalkyl;
R
25Be selected from hydrogen and alkyl;
R
37Be selected from hydrogen, alkyl, hydroxyalkyl and cycloalkyl;
R
42Be selected from artyl sulfo, heteroaryl sulfenyl and aryloxy; R wherein
42Optional by one or more R that are independently selected from
46Substituting group replace;
R
46Be one or more substituting groups that are selected from hydrogen, hydroxyl, amino, halogen, dialkyl amido and alkoxycarbonyl amino;
R
70Be selected from aryl and heterocyclic radical; R wherein
70Optional by R
75Replace;
R
75Be one or more substituting groups that are independently selected from hydrogen, halogen, alkoxyl group, cyano group, alkyl, haloalkyl and aryl.
10. the pharmacologically acceptable salt of the tautomer of compound, described compound or described compound or tautomer, wherein said compound has formula III:
R wherein
80Be selected from hydrogen, alkyl-carbonyl and halogenated aryl.
11. the pharmacologically acceptable salt of the tautomer of compound, described compound or described compound or tautomer, wherein said compound has formula IV:
Wherein:
Q is selected from N and CH;
R
1Be selected from alkyl sulfenyl, cyano group alkyl sulfenyl and alkyl;
R
19Be selected from alkyl and halogenated aryl alkoxyl group;
R
56Be selected from hydrogen, hydroxyl, alkyl and alkyl-carbonyl-amino.
12. the pharmacologically acceptable salt of the tautomer of compound, described compound or described compound or tautomer, wherein said compound has formula V:
Wherein:
R
5Be selected from hydrogen and alkyl sulfenyl;
R
29Be selected from alkyl, alkoxy aryl, halogen and halogenated aryl alkoxyl group;
R
47Be selected from alkyl, haloalkyl, alkyl sulfenyl, arylalkyl sulfenyl and heterocyclic radical;
R
64Be selected from hydrogen, alkoxyl group and alkyl;
R
66Be selected from hydrogen, hydroxyl, aryloxy, alkyl sulphonyl oxygen base, alkyl-carbonyl-amino aryl sulfonyl oxygen base, halogenated aryl alkylsulfonyl oxygen base, cyano group, alkoxy aryl, alkyl-carbonyl-amino, halogen and alkyl;
R
81Be selected from hydrogen, alkoxyl group and carbonyl.
13. the pharmacologically acceptable salt of the tautomer of compound, described compound or described compound or tautomer, wherein said compound has formula VI:
Wherein:
R
73It is alkyl;
R
76Be selected from hydroxyl, alkyl amino-carbonyl and alkyl-carbonyl-amino.
14. the pharmacologically acceptable salt of the tautomer of compound, described compound or described compound or tautomer, wherein said compound has formula VII:
Wherein:
A is selected from O and S;
R
21Be selected from hydrogen and hydroxyl;
Perhaps R
21With R
39Form together and contain at least two first heterocycles of heteroatomic 5-12 that are selected from O, N and S; Wherein said heterocycle is optional to be replaced by aryl or halogen; Perhaps
R
39Be selected from hydrogen, alkyl, alkyl chain thiazolinyl, dialkyl amido, heteroaryl, halo heteroaryl, halogenated aryl amino-sulfonyl, aryl sulfonyl oxygen base, alkyl-carbonyl oxygen base, cycloalkyl amino carbonyl, aryl-alkoxy carbonyl amino, halo heteroaryl, alkoxy carbonyl and NH-R
99
R
99Be selected from hydrogen, arylalkyl, cycloalkylalkyl, aryl, heteroaryl, halogenated aryl alkylamino, aryl-alkyl amino and miscellaneous alkyl aryl;
R
67Be selected from hydrogen, alkyl, cycloalkyl and alkyl-cycloalkyl;
R
96Be selected from hydrogen, hydroxyl, amino, alkoxyl group, aryl sulfonyl oxygen base, alkyl-carbonyl-amino, alkoxyl group, halogen, alkoxy-carbonyl oxy, halo alkoxy carbonyl amino and alkoxy aryl.
15. the pharmacologically acceptable salt of the tautomer of compound, described compound or described compound or tautomer, wherein said compound has formula VIII:
Wherein:
R
23Be selected from hydrogen, alkoxy aryl, alkoxy aryl sulfenyl, hydroxyaryl sulfenyl, halogenated aryl alkoxyl group, cyano-aryl alkoxyl group and alkoxy aryl;
R
31Be selected from hydrogen and halogen;
R
49Be selected from hydrogen, alkoxy aryl, halogenated aryl carbonylamino, alkoxy aryl carbonylamino, aromatic yl alkenyl, arylalkyl, halogen, cyano group, halogenated aryl oxygen base alkyl, alkyl, alkoxy aryl sulfenyl, halo heteroaryl and alkoxy carbonyl;
R
52Be selected from hydrogen, halogen, alkyl, hydroxyaryl oxygen base, aryloxy, hydroxyalkyl aryloxy, alkoxy aryl alkyl, alkoxyl group aryloxy, alkylaryl alkoxy aryl amino, arylalkyl, heteroaryl and amino aryloxy;
R
77Be selected from hydrogen, alkyl and cycloalkyl.
16. contain the pharmaceutical composition of compound, tautomer or the salt of each claim among the claim 1-15.
17. suppress the method for HCV virus replication, described method comprises that compound, tautomer or the salt with each claim among the claim 1-15 of HCV virus and significant quantity contacts, thereby suppresses duplicating of described virus.
18. the method that treatment HCV infects, described method comprises compound, tautomer or the salt of each claim in the claim 1-15 of HCV patient's effective dosage, thereby reduces the HCV virus levels in blood samples of patients or the liver.
19. the compound of each claim, tautomer or salt are used for the treatment of that HCV infects or suppress application in the medicine that HIV duplicates in preparation among the claim 1-15.
20. the method for the compound of each claim among the preparation claim 1-15, described method comprises described step of reaction scheme among the reaction scheme 1-8.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US75247305P | 2005-12-21 | 2005-12-21 | |
| US60/752,473 | 2005-12-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101443334A true CN101443334A (en) | 2009-05-27 |
Family
ID=39830150
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200680053117XA Pending CN101443334A (en) | 2005-12-21 | 2006-12-20 | Anti-viral compounds |
| CNA2006800532079A Pending CN101384592A (en) | 2005-12-21 | 2006-12-20 | Anti-viral compounds |
| CNA2006800531964A Pending CN101384591A (en) | 2005-12-21 | 2006-12-20 | Anti-viral compounds |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800532079A Pending CN101384592A (en) | 2005-12-21 | 2006-12-20 | Anti-viral compounds |
| CNA2006800531964A Pending CN101384591A (en) | 2005-12-21 | 2006-12-20 | Anti-viral compounds |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JP2009521460A (en) |
| CN (3) | CN101443334A (en) |
| CA (1) | CA2633752A1 (en) |
| ES (1) | ES2348557T3 (en) |
| RU (1) | RU2441010C2 (en) |
| ZA (2) | ZA200805418B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020156512A1 (en) * | 2019-02-02 | 2020-08-06 | 华东理工大学 | Aromatic (hetero)cyclic ether compound having insecticidal activity, preparation method therefor, and application thereof |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2505540C2 (en) * | 2008-12-23 | 2014-01-27 | Эббви Инк. | Antiviral compounds |
| WO2010111436A2 (en) * | 2009-03-25 | 2010-09-30 | Abbott Laboratories | Antiviral compounds and uses thereof |
| RU2644351C1 (en) * | 2016-11-15 | 2018-02-09 | Федеральное государственное бюджетное учреждение науки Институт органического синтеза им. И.Я. Постовского Уральского отделения Российской академии наук (ИОС УрО РАН) | -4-[6-(purine-6-ylamino)hexanoyl]-3,4-dihydro-3-methyl-7,8-difluor-2h-[1,4]benzoxazine and (3r)-4-[6-(purine-6-ylamino)hexanoyl]-3,4-dihydro-3-methyl-7,8-difluor-2h-[1,4]benzoxazine with antiviral activity |
| CN113582842A (en) * | 2021-07-26 | 2021-11-02 | 苏州求索生物科技有限公司 | Preparation process of methyl glycolate |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003321472A (en) * | 2002-02-26 | 2003-11-11 | Takeda Chem Ind Ltd | Grk inhibitor |
| WO2004065392A1 (en) * | 2003-01-24 | 2004-08-05 | Smithkline Beecham Corporation | Condensed pyridines and pyrimidines and their use as alk-5 receptor ligands |
| JP2006521398A (en) * | 2003-03-28 | 2006-09-21 | サイオス・インコーポレーテツド | Bicyclic pyrimidine inhibitors of TGFβ |
| WO2005003100A2 (en) * | 2003-07-03 | 2005-01-13 | Myriad Genetics, Inc. | 4-arylamino-quinazolines as activators of caspases and inducers of apoptosis |
| BRPI0413861A (en) * | 2003-08-29 | 2006-10-24 | Vernalis Cambridge Ltd | pyrimidothiophene compounds |
| GB0326168D0 (en) * | 2003-11-10 | 2003-12-17 | Arrow Therapeutics Ltd | Chemical compounds |
| CA2564175A1 (en) * | 2004-04-28 | 2005-11-10 | Arrow Therapeutics Limited | Chemical compounds |
| WO2006019831A1 (en) * | 2004-07-14 | 2006-02-23 | Ptc Therapeutics, Inc. | Methods for treating hepatitis c |
| GB0416168D0 (en) * | 2004-07-20 | 2004-08-18 | Vernalis Cambridge Ltd | Pyrmidothiophene compounds |
| TW200626157A (en) * | 2004-09-30 | 2006-08-01 | Tibotec Pharm Ltd | HCV inhibiting bi-cyclic pyrimidines |
| AR054122A1 (en) * | 2005-05-12 | 2007-06-06 | Tibotec Pharm Ltd | PIRIDO [2,3-D] USEFUL PYRIMIDES AS HCV INHIBITORS, AND METHODS FOR THE PREPARATION OF THE SAME |
| DE602005018972D1 (en) * | 2005-09-23 | 2010-03-04 | Equispharm Co Ltd | 5,6-DIMETHYLTHIENOE2,3-DIETYRIMIDIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITION CONTAINING THEREOF FOR THE FIGHT AGAINST VIRUSES |
-
2006
- 2006-12-20 CN CNA200680053117XA patent/CN101443334A/en active Pending
- 2006-12-20 JP JP2008547521A patent/JP2009521460A/en not_active Withdrawn
- 2006-12-20 CN CNA2006800532079A patent/CN101384592A/en active Pending
- 2006-12-20 CA CA002633752A patent/CA2633752A1/en not_active Abandoned
- 2006-12-20 ES ES06848056T patent/ES2348557T3/en active Active
- 2006-12-20 RU RU2008129782/04A patent/RU2441010C2/en not_active IP Right Cessation
- 2006-12-20 CN CNA2006800531964A patent/CN101384591A/en active Pending
-
2008
- 2008-06-20 ZA ZA2008/05418A patent/ZA200805418B/en unknown
-
2011
- 2011-10-19 ZA ZA2011/07667A patent/ZA201107667B/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020156512A1 (en) * | 2019-02-02 | 2020-08-06 | 华东理工大学 | Aromatic (hetero)cyclic ether compound having insecticidal activity, preparation method therefor, and application thereof |
| CN111518022A (en) * | 2019-02-02 | 2020-08-11 | 华东理工大学 | Aromatic (hetero) cyclic ether compound with insecticidal activity and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2009521460A (en) | 2009-06-04 |
| ES2348557T3 (en) | 2010-12-09 |
| RU2441010C2 (en) | 2012-01-27 |
| CA2633752A1 (en) | 2007-07-19 |
| CN101384591A (en) | 2009-03-11 |
| RU2008129782A (en) | 2010-01-27 |
| ZA201107667B (en) | 2012-07-25 |
| ZA200805418B (en) | 2011-12-28 |
| CN101384592A (en) | 2009-03-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102702193A (en) | Anti-viral compounds | |
| TWI399380B (en) | Anti-viral compounds | |
| CN107207505B (en) | Treat and prevent hepatitis b virus infected 2- oxo -6,7- dihydrobenzo [a] quinolizine -3- formic acid derivates | |
| CN106467541B (en) | Substituted quinolone analog derivative or its pharmaceutically acceptable salt or stereoisomer and its Pharmaceutical composition and application | |
| CN110511209B (en) | Indole carboxamide compounds useful as kinase inhibitors | |
| US7915411B2 (en) | Anti-viral compounds | |
| RU2467007C2 (en) | [1,8]naphthyridine derivatives, useful as inhibitors of hcv virus replication | |
| WO2021087018A1 (en) | Pyridazinones as parp7 inhibitors | |
| JP5730281B2 (en) | Poly (ADP-ribose) polymerase (PARP) inhibitor | |
| CA2683557C (en) | Inhibitors of histone deacetylase | |
| WO2002032872A1 (en) | Nitrogenous aromatic ring compounds | |
| CN105189505A (en) | Tricyclic gyrase inhibitors for use as antibacterial agents | |
| JP6797923B2 (en) | ALK and SRPK inhibitors and how to use | |
| CN101443334A (en) | Anti-viral compounds | |
| CN109810110A (en) | A kind of compound with 2- aminopyrimidine structure, preparation method and use | |
| TWI392677B (en) | Anti-viral compounds,process for preparation and uses thereof | |
| JPH11152275A (en) | Nitrogen-containing condensed ring compound, its production and agent | |
| KR101122376B1 (en) | Novel 5,6-dimethylpyrimidine derivatives and processes for the preparation thereof | |
| JP2023545452A (en) | Compounds and compositions for the treatment of cryptosporidiosis | |
| WO2023250165A1 (en) | Salts of sos1 inhibitors | |
| JP2022550393A (en) | Substituted 3,4-dihydroquinazolines for the treatment and prevention of hepatitis B virus infection | |
| JP2001199889A (en) | Collunarium comprising annulated pyridazine derivative | |
| MX2008008161A (en) | Anti-viral compounds | |
| UA81271C2 (en) | 2-pyridone derivatives as inhibitors of neutrophile elastase, process for the preparation thereof and pharmaceutical composition based thereon | |
| BRPI0620440A2 (en) | antiviral compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| ASS | Succession or assignment of patent right |
Owner name: ABBVIE COMPANY Free format text: FORMER OWNER: ABBOTT GMBH. + CO. KG Effective date: 20130619 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20130619 Address after: Illinois State Applicant after: ABBVIE company Address before: Illinois State Applicant before: Abbott GmbH. & Co. Kg |
|
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20090527 |