CN1950345A

CN1950345A - Morpholinylanilinoquinazoline derivatives for use as antiviral agents

Info

Publication number: CN1950345A
Application number: CN 200580013829
Authority: CN
Inventors: 基思·斯宾塞; 海伦娜·丹尼森; 尼尔·马修; 米歇尔·巴恩斯; 苏恩德尔·沙纳
Original assignee: Arrow Therapeutics Ltd
Current assignee: Arrow Therapeutics Ltd
Priority date: 2004-04-28
Filing date: 2005-04-28
Publication date: 2007-04-18
Also published as: GB0409494D0

Abstract

Compounds of formula (Ia) are found to be active in inhibiting replication of flaviviridae viruses, wherein R1, R2, R3 and R4 are as defined in the claims.

Description

Morpholinyl anilinoquinazoline derivatives as antiviral agent

The present invention relates to a series of being used for the treatment of or quinazoline derivant that prevention of flavivirus section (flaviviridae) infects.

The virus of flaviviridae is to contain the young waiter in a wineshop or an inn of adopted rna gene group decahedron enveloped virus is arranged.This section is made up of three genus, is respectively Flavivirus (flavivirus), pestivirus (pestivirus) and Hepacivirus (hepacivirus).

Many yellow jack coe viruses are human important pathogenic agent.In fact, Hepacivirus comprises hepatitis C virus.Yet, so far still there is not the i.e. treatment of safety effectively again in flaviviridae infections.

WO 98/02434 discloses the inhibitor that quinazoline makes to represent protein tyrosine kinase.In the document, specifically be not disclosed in the compound that has morpholino-aniline group on the 6-position.

Now the quinazoline derivant of discoverable type (Ia) has the activity that the inhibition flaviviridae duplicates surprisingly, therefore can effectively treat or prevention of flavivirus infections.Therefore the present invention provides quinazoline derivant or its pharmaceutically acceptable salt of formula (Ia),

R wherein ₁Represent hydrogen, halogen, C ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₁-C ₄Alkoxyl group, C ₁-C ₄Halogenated alkoxy ,-CO ₂R ^/,-CONR ^/R ^//,-A ,-A-L-A ^/,-Z-L-A or-A-L-Z-L-A, wherein R ^/And R ^//Identical or different, represent hydrogen or C separately ₁-C ₄Alkyl;

R ₂Represent hydrogen, halogen, C ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₁-C ₄Alkoxyl group or C ₁-C ₄Halogenated alkoxy;

R ₃Represent hydrogen, C ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₁-C ₄Alkoxyl group or C ₁-C ₄Halogenated alkoxy; And

R ₄Represent hydrogen, C ₁-C ₆Alkyl or C ₁-C ₆Haloalkyl,

Wherein:

-A represents C ₆-C ₁₀Aryl, 5-to 10-unit's heteroaryl or 5-to 10-unit heterocyclic radical group;

-each L is identical or different, and is direct key or C ₁-C ₄Alkylidene group;

-A/ is 5-to 10-unit's heteroaryl or 5-to 10-unit heterocyclic group;

And

-Z is-S-,-O-,-NR ^/-,-CO ₂-,-C (O) NR ^/-,-OC (O)-,-NR ^/C (O)-,-OCO ₂-,-NR ^/CO ₂-,-OC (O) NR ^/-or-NR ^/C (O) NR ^//-, R wherein ^/And R ^//Identical or different, and represent hydrogen or C ₁-C ₄Alkyl,

R ₁Middle aryl, heteroaryl and heterocyclic radical part are not substituted or are selected from halogen, C by 1,2 or 3 ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₁-C ₄Halogenated alkoxy, hydroxyl, thiol ,-NH ₂, C ₁-C ₄Hydroxyalkyl, C ₁-C ₄Sulfane base, C ₁-C ₄Aminoalkyl group, cyano group, nitro ,-COR ^/,-CO ₂R ^/,-S (O) R ^/,-S (O) ₂R ^/,-CONR ^/R ^//With-L ^/-X-L ^//The substituting group of-Y replaces, wherein each R ^/And R ^//Identical or different, and be selected from hydrogen and C ₁-C ₄Alkyl, L ^/Be direct key or C ₁-C ₄Alkylidene group, X be-S-,-O-or-NR ^/-, R wherein ^/Define as above L ^//Be direct key or C ₁-C ₄Alkylidene group, and Y be hydrogen ,-COR _/,-CO ₂R _/,-S (O) ₂R _/Or-S (O) R _/, R wherein _/Be hydrogen or C ₁-C ₄Alkyl.

For avoiding doubt, the orientation of Z part is such, promptly the left-hand side of the group of describing connection quinazoline group or-the A-L-part.Therefore, for example working as Z is-C (O) NR ^/-and R ¹During for-Z-L-A, R ¹For-C (O) NR ^/-L-A.

In one embodiment, the quinazoline derivant of formula (Ia) is the quinazoline derivant of formula (I),

R wherein ₁Represent hydrogen, halogen, C ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₁-C ₄Alkoxyl group, C ₁-C ₄Halogenated alkoxy ,-A or-A-L-A ^/, and R ₂Represent hydrogen, halogen, C ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₁-C ₄Alkoxyl group or C ₁-C ₄Halogenated alkoxy, wherein:

-A represents C ₆To C ₁₀Aryl, 5-to 10-unit's heteroaryl or 5-to 10-unit heterocyclic radical group;

-L is direct key or C ₁-C ₄Alkylidene group; And

-A/ is 5-to 10-unit's heteroaryl or heterocyclic radical group;

R ₁Middle aryl, heteroaryl and heterocyclic radical part are not substituted or are selected from halogen, C by 1,2 or 3 ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₁-C ₄Halogenated alkoxy, hydroxyl, thiol ,-NH ₂, C ₁-C ₄Hydroxyalkyl, C ₁-C ₄Sulfane base, C ₁-C ₄Aminoalkyl group, cyano group, nitro ,-COR ^/,-CO ₂R ^/,-CONR ^/R ^//,-SOR ^/,-S (O) ₂R ^/With-L ^/-X-L ^//The substituting group of-Y replaces, wherein each R ^/And R ^//Identical or different, and be selected from hydrogen and C ₁-C ₄Alkyl, L ^/Be direct key or C ₁-C ₄Alkylidene group, X be-S-,-O-or-NR ^/-, R wherein ^/Define as above L ^//Be C ₁-C ₄Alkylidene group, and Y be hydrogen ,-COR _/,-CO ₂R _/,-S (O) ₂R _/Or-S (O) R _/, R wherein _/Be hydrogen or C ₁-C ₄Alkyl.

Usually, the R of formula (I) ₁Middle aryl, heteroaryl and heterocyclic radical be not partly for being substituted or being selected from halogen, C by 1,2 or 3 ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₁-C ₄Halogenated alkoxy, hydroxyl, mercaptan ,-NH ₂, C ₁-C ₄Hydroxyalkyl, C ₁-C ₄Sulfane base, C ₁-C ₄Aminoalkyl group, cyano group, nitro ,-COR ^/,-CO ₂R ^/,-CONR ^/R ^//With-L ^/-X-L ^//The substituting group of-Y replaces, wherein each R ^/And R ^//Identical or different, and be selected from hydrogen and C ₁-C ₄Alkyl, L ^/Be direct key or C ₁-C ₄Alkylidene group, X be-S-,-O-or-NR ^/-, R wherein ^/Define as above L ^//Be C ₁-C ₄Alkylidene group, and Y be hydrogen ,-COR _/,-CO ₂R _/,-S (O) ₂R _/Or-S (O) R _/, R wherein _/Be hydrogen or C ₁-C ₄Alkyl.

C used herein ₁-C ₆Alkyl group or part are alkyl group or the part that contains the straight or branched of 1-6 carbon atom.Usually, C ₁-C ₆Alkyl group or part are C ₁-C ₄Alkyl group or part.C ₁-C ₄Alkyl group or part are alkyl group or the part that contains the straight or branched of 1-4 carbon atom.C ₁-C ₆The example of alkyl group or part comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl and 3-methyl butyl.C ₁-C ₄The example of alkyl group and part comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-and the tertiary butyl.For avoiding doubt, when two moieties appeared in the group, moieties can be identical or different.

C used herein ₁-C ₄Alkylidene group or part are the alkylidene group or the part of straight or branched.Example comprises methylene radical, ethylidene and inferior n-propyl group or part.

C used herein ₆-C ₁₀Aryl is generally phenyl or naphthyl, preferred phenyl.

Halogen used herein is generally chlorine, fluorine, bromine or iodine, preferred chlorine, bromine or fluorine.

C used herein ₁-C ₄Alkoxyl group is generally the described C that is connected to Sauerstoffatom ₁-C ₄Alkyl.Haloalkyl or halogenated alkoxy are generally described alkyl or the alkoxyl group that is replaced by one or more described halogen atoms.Generally replaced by 1,2 or 3 described halogen atom.Preferred haloalkyl and halogenated alkoxy comprise whole haloalkyl and perhalogeno alkoxyl group, as-CX ₃With-OCX ₃, wherein X is described halogen atom, for example chlorine and fluorine.Particularly preferred haloalkyl is-CF ₃With-CCl ₃Particularly preferred halogenated alkoxy is-OCF ₃With-OCCl ₃

C used herein ₁-C ₄The C of hydroxyalkyl for being replaced by one or more hydroxyls ₁-C ₄Alkyl.Generally by one, two or three hydroxyls replacements.Preferably replaced by single hydroxyl.Preferred hydroxyalkyl is-CH ₂-OH.

C used herein ₁-C ₄The sulfane base is by one or more sulfydryls (SH) C of Qu Daiing ₁-C ₄Alkyl.Generally by one, two or three sulfydryls replacements.Preferably replaced by single sulfydryl.

C used herein ₁-C ₄Aminoalkyl group is by one or more-NH ₂The C that group replaces ₁-C ₄Alkyl.Generally by one, two or three-NH ₂Replace.Preferably by single-NH ₂Replace.

5-to 10-unit's heteroaryl groups used herein or part are monocycle 5-to 10-unit aromatic nucleus, as 5-or 6-unit ring, contain at least one heteroatoms, for example 1,2 or 3 heteroatoms that is selected from O, S and N.Example comprises pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, furyl, thienyl, pyrazolidyl, pyrryl, oxadiazole Ji, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl group, imidazolyl, pyridazolyl and pyrazolyl groups.Preferred examples comprises pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, furyl, thienyl, pyrazolidyl, pyrryl, oxadiazole Ji, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl group, imidazolyl and pyrazolyl groups.Preferred furyl, thienyl, pyridazolyl, pyrazolyl, pyrimidyl and thiazolyl group.More preferably furyl, thienyl, pyrimidyl and thiazolyl group.Further preferred thienyl and thiazolyl group.

5-to 10-unit's heterocyclic radical group used herein or part are monocyclic non-aromaticity, saturated or undersaturated C ₅-C ₁₀Carbocyclic ring, wherein one or more, for example 1,2 or 3 carbon atom is selected from N, O, S, S (O) and S (O) ₂Heteroatoms replace.Be generally 5-to 6-unit ring.

Heterocyclic radical group that is fit to and part comprise pyrazolidyl, piperidyl, piperazinyl, thio-morpholinyl, S-oxygen-thio-morpholinyl, S, S-dioxy-thio-morpholinyl, morpholinyl, pyrrolidyl, pyrrolinyl, imidazolidyl, imidazolinyl, 1,3-dioxolanyl, dioxolyl and pyrazolinyl group and part.Preferred piperazinyl, thio-morpholinyl, S, S-dioxy thio-morpholinyl, morpholinyl and 1,3-dioxolanyl group and part.

Usually, R ₁Middle aryl, heteroaryl and heterocyclic radical be not partly for being substituted or being selected from halogen, C by 1,2 or 3 ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₁-C ₄Halogenated alkoxy, C ₁-C ₄Hydroxyalkyl, cyano group ,-COR ^/,-CO ₂R ^/,-S (O) R ^/,-S (O) ₂R ^/With-L ^/-X-L ^//The substituting group of-Y replaces, here R ^/, L ^/, X, L ^//Define as above with Y.

Usually, L ^/Be direct key or C ₁-C ₄Alkylidene group.Usually, X be-O-or-NR ^/-, R wherein ^/Definition as above.Usually, L ^//Be direct key or C ₁-C ₂Alkylidene group, preferred C ₁-C ₂Alkylidene group.Usually, Y be hydrogen ,-COR _/,-CO ₂R _/,-S (O) ₂R _/Or-S (O) R _/, R wherein _/Be C ₁-C ₄Alkyl.Preferably, Y be hydrogen ,-COR _/,-C (O) ₂R _/Or-S (O) R _/, R wherein _/Be C ₁-C ₄Alkyl.

R ₁Aryl, heteroaryl and heterocyclic radical partly are preferably and are not substituted or are selected from halogen, C by 1 or 2 in the substituting group ₁-C ₂Alkyl, C ₁-C ₂Haloalkyl, C ₁-C ₂Hydroxyalkyl, cyano group ,-COR ^/,-CO ₂R ^/,-S (O) R ^/,-S (O) ₂R ^/,-(C ₁-C ₂Alkyl)-NR ^/R ^//, C ₁-C ₂Alkoxyl group ,-NR ^/-COR ^/, NR ^/-CO ₂R _/,-(C ₁-C ₂Alkyl)-NR ^/-CO ₂R _/,-NR ^/-S (O) ₂-R _/With-(C ₁-C ₂Alkyl)-NR ^/-(C ₁-C ₂Alkyl)-S (O) ₂-R ^//Substituting group replace each R wherein ^/, R ^//And R _/Identical or different, and represent hydrogen or C ₁-C ₂Alkyl.

In one embodiment, the quinazoline derivant of formula (Ia) is the quinazoline derivant of formula (I), usually, and R ₁Aryl, heteroaryl and heterocyclic radical be not partly for being substituted or being selected from halogen, C by 1,2 or 3 in the substituting group ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₁-C ₄Halogenated alkoxy, C ₁-C ₄Hydroxyalkyl ,-COR ^/,-CO ₂R ^/,-S (O) R ^/,-S (O) ₂R ^/With-L ^/-X-L ^//The substituting group of-Y replaces, wherein R ^/, L ^/, X, L ^//Define as above with Y.R ₁Aryl, heteroaryl and heterocyclic radical partly are preferably and are not substituted or are selected from halogen, C by 1,2 or 3 in the substituting group ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₁-C ₄Halogenated alkoxy, C ₁-C ₄Hydroxyalkyl ,-COR ^/With-L ^/-X-L ^//-Y substituting group replaces, wherein R ^/, L ^/, X, L ^//With Y as defined above.More preferably, R ₁Aryl, heteroaryl and heterocyclic radical be not partly for being substituted or being selected from halogen, C by 1 or 2 in the substituting group ₁-C ₂Alkyl, C ₁-C ₂Alkoxyl group, C ₁-C ₂Haloalkyl, C ₁-C ₂Hydroxyalkyl ,-COR ^/,-CO ₂R ^/,-S (O) R ^/,-S (O) ₂R ^/,-(C ₁-C ₂Alkyl)-NR ^/R ^//With-(C ₁-C ₂Alkyl)-NR ^/-(C ₁-C ₂Alkyl)-S (O) ₂-R ^//Substituting group replace each R wherein ^/And R ^//Identical or different, and represent hydrogen or C ₁-C ₂Alkyl.More preferably R also ₁Aryl, heteroaryl and heterocyclic radical be not partly for being substituted or being selected from halogen, C by 1 or 2 in the substituting group ₁-C ₂Alkyl, C ₁-C ₂Haloalkyl, C ₁-C ₂Hydroxyalkyl ,-COR ^/,-(C ₁-C ₂Alkyl)-NR ^/R ^//With-(C ₁-C ₂Alkyl)-NR ^/-(C ₁-C ₂Alkyl)-S (O) ₂-R ^//Substituting group replace each R wherein ^/And R ^//Identical or different, and represent hydrogen or C ₁-C ₂Alkyl.

Usually, A is phenyl, 5-to 6-unit's heteroaryl or 5-to 6-unit heterocyclic radical.A is preferably phenyl or 5-to 6-unit heteroaryl.A is phenyl, furyl, thienyl, pyrimidyl, thiazolyl or pyridazolyl group more preferably.A is more preferably phenyl, furyl, thienyl, pyrimidyl or thiazolyl group also.A is phenyl, furyl, thienyl or thiazolyl group most preferably.

Usually, L is direct key or C ₁-C ₂Alkylidene group.

Generally, A ^/Be 5-to 6-unit's heteroaryl or 5-to 6-unit heterocyclic radical.Work as A ^/During for 5-to 6-unit heteroaryl, preferred pyrazolyl.

A ^/More preferably 5-to 6-unit heterocyclic radical or heteroaryl, it is not substituted or is selected from halogen, C by 1,2 or 3 ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl and C ₁-C ₄The substituting group of halogenated alkoxy replaces.A ^/Most preferably be morpholinyl, thio-morpholinyl, piperazinyl, 1,3-dioxolanyl, S, S-dioxy thio-morpholinyl or pyrazolyl groups, it is not substituted or is selected from C by 1 or 2 ₁-C ₂Alkyl, halogen and C ₁-C ₂The substituting group of haloalkyl replaces.

In one embodiment, the quinazoline derivant of formula (Ia) is the quinazoline derivant of formula (I), and A ^/Be preferably 5-to 6-unit heterocyclic radical.A ^/More preferably be not substituted or be selected from halogen, C by 1,2 or 3 ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl and C ₁-C ₄The 5-to 6-that substituting group the replaced unit heterocyclic radical of halogenated alkoxy.A ^/Most preferably be morpholinyl, thio-morpholinyl, piperazinyl, 1,3-dioxolanyl or S, S-dioxy thio-morpholinyl, it is not substituted or is selected from C by 1 or 2 ₁-C ₂Alkyl, halogen and C ₁-C ₂The substituting group of haloalkyl replaces.

Usually, Z be-O-,-CONR ^/-,-NR ^/C (O)-or-NR ^/CO ₂-, R wherein ^/As defined above.Z is preferably-O-,-CONH-,-CON (C ₁-C ₂Alkyl)-,-NHC (O)-or-NHCO ₂-.

Usually, R ₁Be halogen, C ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₁-C ₄Alkoxyl group, C ₁-C ₄Halogenated alkoxy ,-CO ₂R ^/,-CONR ^/R ^//,-A ,-A-L-A ^/,-Z-L-A or-A-L-Z-L-A, wherein R ^/, R ^//, A, L, A ^/With Z as defined above.R ₁Be preferably halogen, C ₁-C ₂Alkoxyl group, C ₁-C ₂Halogenated alkoxy ,-CONR ^/R ^//,-A ,-Ar-L-A ^/,-Z-L-A or-Ar-Z-L-Ar, wherein R ^/And R ^//Identical or different, and represent hydrogen or C ₁-C ₂Alkyl, A and A ^/As defined above, Ar is unsubstituted furyl or unsubstituted phenyl, and L is direct key or methylene radical, and Z be-O-,-C (O) NR ^/-,-NR ^/C (O)-or-NR ^/CO ₂-, R wherein ^/As defined above.

In one embodiment, the quinazoline derivant of formula (Ia) is the quinazoline derivant of formula (I), and usually, R ₁Be halogen, C ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₁-C ₄Alkoxyl group, C ₁-C ₄Halogenated alkoxy ,-A or-A-L-A ^/, wherein A, L and A ^/As defined above.R ₁Be preferably halogen, C ₁-C ₂Alkoxyl group, C ₁-C ₂Halogenated alkoxy ,-A or-Ar-L-A ^/, wherein A and A ^/As defined above, Ar is unsubstituted furyl, and L is direct key or alkylidene group.

Usually, R ₂Be hydrogen, C ₁-C ₄Alkyl or C ₁-C ₄Alkoxyl group.R ₂Be preferably hydrogen or C ₁-C ₂Alkoxyl group.

Usually, R ₃Be hydrogen, C ₁-C ₂Alkyl, C ₁-C ₂Haloalkyl or C ₁-C ₂Alkoxyl group.R ₃Be preferably hydrogen, methyl, trifluoromethyl or methoxyl group.

Usually, R ₄Be hydrogen or C ₁-C ₆Alkyl.

In the preferred compound of the present invention:

-R ₁Be halogen, C ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₁-C ₄Alkoxyl group, C ₁-C ₄Halogenated alkoxy ,-CO ₂R ^/,-CONR ^/R ^//,-A ,-A-L-A ^/,-Z-L-A or-A-L-Z-L-A;

-R ₂Be hydrogen, C ₁-C ₄Alkyl or C ₁-C ₄Alkoxyl group;

-R ₃Be hydrogen, C ₁-C ₂Alkyl, C ₁-C ₂Haloalkyl or C ₁-C ₂Alkoxyl group;

-R ₄Be hydrogen or C ₁-C ₆Alkyl;

-A is phenyl, 5-to 6-unit's heteroaryl or 5-to 6-unit heterocyclic radical;

-L is direct key or C ₁-C ₂Alkylidene group;

-A ^/Be 5-to 6-unit's heteroaryl or heterocyclic radical; And

-Z is-O-,-CONR ^/-,-NR ^/C (O)-or-NR ^/CO ₂-, R wherein ^/Be hydrogen or C ₁-C ₄Alkyl,

R ₁Aryl in the substituting group, heteroaryl and heterocyclic radical part are not substituted or are selected from halogen, C by 1,2 or 3 ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₁-C ₄Halogenated alkoxy, C ₁-C ₄Hydroxyalkyl, cyano group ,-COR ^/,-CO ₂R ^/,-S (O) R ^/,-S (O) ₂R ^/With-L ^/-X-L ^//The substituting group of-Y replaces, wherein R ^/, L ^/, X, L ^//With Y as defined above.

In the preferred compound of the present invention, the quinazoline derivant of formula (Ia) is the quinazoline derivant of formula (I), wherein:

-R ₁Be halogen, C ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₁-C ₄Alkoxyl group, C ₁-C ₄Halogenated alkoxy ,-A or-A-L-A ^/

-R ₂Be hydrogen, C ₁-C ₄Alkyl or C ₁-C ₄Alkoxyl group;

-A is phenyl, 5-to 6-unit's heteroaryl or 5-to 6-unit heterocyclic radical;

-L is direct key or C ₁-C ₄Alkylidene group; And

-A ^/Be 5-to 6-unit's heteroaryl or heterocyclic radical,

R ₁Aryl in the substituting group, heteroaryl and heterocyclic radical part are not substituted or are selected from halogen, C by 1,2 or 3 ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₁-C ₄Halogenated alkoxy, C ₁-C ₄Hydroxyalkyl ,-COR ^/,-CO ₂R ^/,-S (O) R ^/,-S (O) ₂R ^/With-L ^/-X-L ^//The substituting group of-Y replaces, wherein R ^/, L ^/, X, L ^//With Y as defined above.

-R ₂Be hydrogen, C ₁-C ₄Alkyl or C ₁-C ₄Alkoxyl group;

-A is phenyl, 5-to 6-unit's heteroaryl or 5-to 6-unit heterocyclic radical;

-L is direct key or C ₁-C ₄Alkylidene group; And

-A ^/Be 5-to 6-unit's heteroaryl or heterocyclic radical,

R ₁Aryl in the substituting group, heteroaryl and heterocyclic radical part are not substituted or are selected from halogen, C by 1,2 or 3 ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₁-C ₄Halogenated alkoxy, C ₁-C ₄Hydroxyalkyl ,-COR ^/With-L ^/-X-L ^//The substituting group of-Y replaces, wherein R ^/, L ^/, X, L ^//With Y as defined above.

In the preferred compound of the present invention:

-R ₁Be halogen, C ₁-C ₂Alkoxyl group, C ₁-C ₂Halogenated alkoxy ,-CONR ^/R ^//,-A ,-Ar-L-A ^/,-Z-L-A or-Ar-Z-L-Ar, wherein R ^/And R ^//For identical or different, represent hydrogen or C separately ₁-C ₂Alkyl;

-R ₂Be hydrogen or C ₁-C ₂Alkoxyl group;

-A is phenyl or 5-to a 6-unit heteroaryl, for example furyl, thienyl, pyrimidyl and thiazolyl, and it is not substituted or is selected from halogen, C by 1 or 2 ₁-C ₂Alkyl, C ₁-C ₂Haloalkyl, C ₁-C ₂Hydroxyalkyl, cyano group ,-COR ^/,-CO ₂R ^/,-S (O) R ^/,-S (O) ₂R ^/,-(C ₁-C ₂Alkyl)-NR ^/R ^//, C ₁-C ₂Alkoxyl group ,-NR ^/-COR _/, NR ^/-CO ₂R _/,-(C ₁-C ₂Alkyl)-NR ^/-CO ₂R _/,-NR ^/-S (O) ₂-R _/With-(C ₁-C ₂Alkyl)-NR ^/-(C ₁-C ₂Alkyl)-S (O) ₂-R ^//Substituting group replace each R wherein ^/And R ^//Identical or different, and represent hydrogen or C ₁-C ₂Alkyl;

-Ar is unsubstituted furyl or unsubstituted phenyl;

-L is direct key or methylene radical;

-A ^/Be 5-to 6-unit's heterocyclic radical or heteroaryl, for example morpholinyl, thio-morpholinyl, piperazinyl, 1,3-dioxolanyl, S, S-dioxy thio-morpholinyl and pyrazolyl, it is not substituted or is selected from C by 1 or 2 ₁-C ₂Alkyl, halogen and C ₁-C ₂The substituting group of haloalkyl replaces; And

-Z is-O-,-CONH-,-CON (C ₁-C ₂Alkyl)-or-NHC (O)-.

-R ₁Be halogen, C ₁-C ₂Alkoxyl group, C ₁-C ₂Halogenated alkoxy ,-A or-Ar-L-A ^/

-R ₂Be hydrogen or C ₁-C ₂Alkoxyl group;

-A is phenyl or 5-to a 6-unit heteroaryl, for example furyl, thienyl, pyrimidyl and thiazolyl, and it is not substituted or is selected from halogen, C by 1 or 2 ₁-C ₂Alkyl, C ₁-C ₂Alkoxyl group, C ₁-C ₂Haloalkyl, C ₁-C ₂Hydroxyalkyl ,-COR ^/,-CO ₂R ^/,-S (O) R ^/,-S (O) ₂R ^/,-(C ₁-C ₂Alkyl)-NR ^/R ^//With-(C ₁-C ₂Alkyl)-NR ^/-(C ₁-C ₂Alkyl)-S (O) ₂-R ^//Substituting group replace each R wherein ^/And R ^//Identical or different, and represent hydrogen or C ₁-C ₂Alkyl;

-Ar is a unsubstitued furyl;

-L is direct key or methylene radical; And

-A ^/Be 5-to 6-unit heterocyclic radical, for example morpholinyl, thio-morpholinyl, piperazinyl, 1,3-dioxolanyl and S, S-dioxy thio-morpholinyl, it is not substituted or is selected from C by 1 or 2 ₁-C ₂Alkyl, halogen and C ₁-C ₂The substituting group of haloalkyl replaces.

-R ₂Be hydrogen or C ₁-C ₂Alkoxyl group;

-A is phenyl or 5-to a 6-unit heteroaryl, for example furyl, thienyl and thiazolyl, and it is not substituted or is selected from halogen, C by 1 or 2 ₁-C ₂Alkyl, C ₁-C ₂Haloalkyl, C ₁-C ₂Hydroxyalkyl ,-COR ^/,-(C ₁-C ₂Alkyl)-NR ^/R ^//And-(C ₁-C ₂Alkyl)-NR ^/-(C ₁-C ₂Alkyl)-S (O) ₂-R ^//Substituting group replace each R wherein ^/And R ^//Identical or different, and represent hydrogen or C ₁-C ₂Alkyl;

-Ar is unsubstituted furyl;

-L is direct key or methylene radical; And

The particularly preferred compound of formula (Ia) comprising:

(6-bromo-quinazoline-4-yl)-(4-morpholine-4-base-phenyl)-amine;

(6-iodo-quinazoline-4-yl)-(4-morpholine-4-base-phenyl)-amine;

(6,7-dimethoxy-quinazoline-4-yl)-(4-morpholine-4-base-phenyl)-amine;

(6-trifluoromethoxy-quinazoline-4-yl)-(4-morpholine-4-base-phenyl)-amine;

(6-furans-2-base-quinazoline-4-yl)-(4-morpholine-4-base-phenyl)-amine;

[6-(5-[1,3] dioxolane-2-base-furans-2-yl)-quinazoline-4-yl]-(4-morpholine-4-base-phenyl)-amine;

5-[4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-yl]-furans-2-formaldehyde;

5-[4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-yl]-furans-2-yl }-methyl alcohol;

(6-{5-[(2-methylsulfonyl-ethylamino)-methyl]-furans-2-yl }-quinazoline-4-yl)-(4-morpholine-4-base-phenyl)-amine;

6-[5-(1,1-dioxy-1-λ-6-thiomorpholine-4-ylmethyl)-furans-2-yl]-quinazoline-4-yl }-(4-morpholine-4-base-phenyl)-amine;

6-[5-(4-methyl-piperazine-1-ylmethyl)-furans-2-yl]-quinazoline-4-yl }-(4-morpholine-4-base-phenyl)-amine;

[6-(5-morpholine-4-ylmethyl-furans-2-yl)-quinazoline-4-yl]-(4-morpholine-4-base-phenyl)-amine;

[6-(5-dimethylaminomethyl-furans-2-yl)-quinazoline-4-yl]-(4-morpholine-4-base-phenyl)-amine;

[6-(5-methylamino methyl-furans-2-yl)-quinazoline-4-yl]-(4-morpholine-4-base-phenyl)-amine;

(4-morpholine-4-base-phenyl)-(6-thiophene-2-base-quinazoline-4-yl)-amine;

(6-chloro-quinazoline-4-yl)-(4-morpholine-4-base-phenyl)-amine;

(4-morpholine-4-base-phenyl)-(6-o-tolyl-quinazoline-4-yl)-amine;

(4-morpholine-4-base-phenyl)-(6-thiazolyl-2-base-quinazoline-4-yl)-amine;

(4-morpholine-4-base-phenyl)-[6-(3-pyrazol-1-yl-phenyl)-quinazoline-4-yl]-amine;

4-[4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-yl]-benzonitrile;

[6-(2-methoxyl group-pyrimidine-5-yl)-quinazoline-4-yl]-(4-morpholine-4-base-phenyl)-amine;

[6-(4-methyl-thiophene-2-yl) quinazoline-4-yl]-(4-morpholine-4-base-phenyl)-amine;

5-[4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-yl]-thiophene-2-carboxylic acid;

[6-(4-methylsulfonyl-phenyl)-quinazoline-4-yl]-(4-morpholine-4-base-phenyl)-amine;

Furans-2-carboxylic acid [4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-yl]-acid amides;

4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-carboxylic acid 4-methoxyl group-benzyl acid amides;

3-{[4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-carbonyl] amino }-ethyl benzoate;

4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-carboxylic acid 3-methoxyl group-benzyl acid amides;

4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-carboxylic acid 4-methyl-benzyl acid amides;

4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-carboxylic acid methyl acid amides;

4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-carboxylic acid dimethylformamide;

4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-carboxylic acid buserelin;

N-{3-[4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-yl]-phenyl }-ethanamide;

4-[4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-yl]-phenyl }-the carboxylamine benzene methyl;

N-{4-[4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-yl]-phenyl } ethanamide;

4-[4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-yl]-phenyl }-t-butyl carbamate;

3-[4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-yl] benzyl }-t-butyl carbamate;

N-{3-[4-(4-morpholine-4-base-phenyl amino-quinazoline-6-yl]-phenyl }-Toluidrin;

(6-iodo-quinazoline-4-yl)-(4-morpholine-4-base-2-trifluoromethyl-phenyl)-amine;

(4-morpholine-4-base-2-trifluoromethyl-phenyl)-(6-thiophene-2-base-quinazoline-4-yl)-amine;

(6-iodo-quinazoline-4-yl)-(3-methoxyl group-4-morpholine-4-base-phenyl)-amine;

(3-methoxyl group-4-morpholine-4-base-phenyl)-(6-thiophene-2-base-quinazoline-4-yl)-amine;

(2-methyl-4-morpholine-4-base-phenyl)-(6-thiophene-2-base-quinazoline-4-yl)-amine;

(3-methyl-4-morpholine-4-base-phenyl-(6-thiophene-2-base-quinazoline-4-yl)-amine;

Ethyl-(4-morpholine-4-base-phenyl)-(6-thiophene-2-base-quinazoline-4-yl)-amine;

(6-iodo-quinazoline-4-yl)-methyl-(4-morpholine-4-base-phenyl)-amine;

(6-iodo-quinazoline-4-yl)-(3-methyl-butyl)-(4-morpholine-4-base-phenyl)-amine;

Sec.-propyl-(4-morpholine-4-base-phenyl)-(6-thiophene-2-base-quinazoline-4-yl)-amine;

(3-methyl-butyl-(4-morpholine-4-base-phenyl)-(6-thiophene-2-base-quinazoline-4-yl)-amine;

[6-(2-benzyloxy-phenyl)-quinazoline-4-yl]-(4-morpholine-4-base-phenyl)-amine;

[6-(4-benzyloxy-phenyl)-quinazoline-4-yl]-(4-morpholine-4-base-phenyl)-amine; And pharmaceutically acceptable salt.

The compound that contains the formula (Ia) of one or more chiral centres can use with the pure form on enantiomorph or the diastereomer, perhaps uses with the form of isomer mixture.For avoiding doubt, if necessary, the compound of formula (Ia) can solvate forms use.Further, for avoiding doubt, the form that compound of the present invention can any tautomer is used.

Used herein, pharmaceutically acceptable salt is the salt of pharmaceutically acceptable acid or alkali.Pharmaceutically acceptable acid had both comprised mineral acid, example hydrochloric acid, sulfuric acid, phosphoric acid, bisphosphate, Hydrogen bromide or nitric acid, also comprise organic acid, as citric acid, fumaric acid, toxilic acid, oxysuccinic acid, xitix, succsinic acid, tartrate, M-nitro benzoic acid, acetic acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid or tosic acid.Pharmaceutically acceptable alkali comprises basic metal (for example sodium or potassium) and alkaline-earth metal (for example calcium or magnesium) oxyhydroxide and organic bases such as alkylamine, aralkylamine and heterocyclic amine.

R ₁The The compounds of this invention that is not hydrogen or halogen for example can be according to following reaction scheme preparation.

Scheme 1a

In one embodiment, scheme 1a is by scheme 1 expression.

Scheme 1

X is suitable leavings group in the above-mentioned reaction, halogen for example, and this is apparent to those skilled in the art.

Reference scheme 1a and 1, with organometallic reagent (V) handle respectively formula (IIa) and compound (II) can be easily in suitable solvent (as tetrahydrofuran (THF), dimethyl formamide or toluene) and under heating up (for example from 50 ℃ to refluxing) carry out.Easily, in the presence of organic bases (for example triethylamine) or the mineral alkali (for example yellow soda ash or potassiumphosphate), under palladium katalysis (for example 20mol% three (dibenzalacetone) two palladiums (II) or 20mol% dichloro two (triphenylphosphine) palladiums (0)), react.When reagent (V) is organic stannane (M=SnBu for example ₃) time, one skilled in the art will recognize that this reaction for Stille coupled example, wherein extra additive may be useful, for example lithium chloride, silver suboxide, this is reflected in the toluene and under reflux temperature and carries out easily.When reagent (V) when being boric acid derivatives, one skilled in the art will recognize that this reaction is Suzuki-Miyaura coupled example, it can carry out in tetrahydrofuran (THF) under 60 ℃ easily.

Reference scheme 1a and 1, by use reagent such as thionyl chloride as solvent, add catalyst activator such as dimethyl formamide, make the 4-hydroxyl of formula (III) compound be converted into suitable leavings group, chlorine for example, subsequently suitable solvent for example in the acetonitrile with 4-morpholinyl aniline reaction, the compound of realization formula (III) is separately converted to formula (IIa) and compound (II).

Reference scheme 1a and 1, formula (IV) compound is converted into formula (III) and is well known to those skilled in the art, and can react as solvent with under heating up as refluxing at methane amide easily.

Obviously, can use the compound of X, the compound of formula (IV) is converted into compound corresponding to aforesaid formula (III) as the formula (IV) of hydrogen or halogen, and respectively with aforesaid formula (VIa) or the reaction of compound (VI), prepare R ₁Formula (Ia) or compound (I) for hydrogen or halogen.R ₁Be the formula (Ia) or the compound (I) of alkyl, haloalkyl, alkoxyl group and halogenated alkoxy, also available certainly similar method prepares.

The starting raw material of above reaction scheme is that known compound maybe can be analogized from currently known methods and prepared.Particularly, the compound of formula (VIa) can be with known method preparation, as the method for describing in scheme 2.

Scheme 2

Compound of the present invention is gone up effectively for treatment.Therefore, the invention provides quinazoline derivant or its pharmaceutically acceptable salt of the formula as defined above (Ia) of treatment human or animal body.The present invention also provides the quinazoline derivant of the formula (Ia) that comprises as defined above or the pharmaceutical composition of its pharmaceutically acceptable salt and pharmaceutically acceptable carrier or thinner.

Described pharmaceutical composition generally contains the The compounds of this invention up to 85wt%.More generally, it contains the The compounds of this invention up to 50wt%.Preferred pharmaceutical composition is aseptic and pyrogen-free.Further, pharmaceutical composition provided by the invention contains the The compounds of this invention that is essentially pure optically active isomer usually.

As mentioned above, The compounds of this invention has the activity that anti-flavivirus section infects.Therefore, the invention provides the quinazoline derivant or the purposes of its drug acceptable salt in the medicine of preparation treatment or the infection of prevention of flavivirus section of formula (Ia) as defined above.The present invention provides treatment to be subjected to flaviviridae infections simultaneously or easily has been the patient's of flaviviridae infections method, and this method comprises that the quinazoline derivant of the formula (Ia) with significant quantity or its drug acceptable salt are to described patient's administration.

Flaviviridae comprises three genus.They are Hepacivirus, Flavivirus and pestivirus.Compound of the present invention has activity on treatment or the infection of prevention of hepatitis C genus, Flavivirus infection or pestivirus infection.

Can infect with the typical pestivirus of The compounds of this invention treatment and comprise bovine viral diarrhea virus, Pestivirus suis (classical swine fever virus) and border disease virus (border diseasevirus).

Can infect with the typical Flavivirus of The compounds of this invention treatment and comprise yellow fever virus, dengue fever virus, japanese encephalitis virus and tick-borne encephalitis.

Can infect with the Hepacivirus of The compounds of this invention treatment and comprise hepatitis C virus.

Compound of the present invention is effective especially to hepatitis C.Therefore described Flavivirus is generally hepatitis C virus.

The compounds of this invention can be with multiple dose of shape administration.Therefore, they can for example pass through oral administration as tablet, lozenge, lozenge, water-based or oiliness suspension agent, dispersible powder or granule.The compounds of this invention also can be without enterally administering, and by administration in subcutaneous administration, intravenous administration, intramuscular administration, the breastbone, percutaneous dosing, perhaps by the infusion techniques administration.The compounds of this invention also can be used as suppository and comes administration.

For administration, The compounds of this invention is generally with pharmaceutically acceptable carrier or thinner preparation.For example, solid orally ingestible can also comprise thinner except active substance, for example lactose, glucose, sucrose, Mierocrystalline cellulose, W-Gum or yam starch; Slipping agent, for example silica, talcum, stearic acid, Magnesium Stearate or calcium and/or polyoxyethylene glycol; Tackiness agent; For example starch, Sudan Gum-arabic, gelatin, methylcellulose gum, carboxymethyl cellulose or Polyvinylpyrolidone (PVP); Decomposition agent, for example starch, alginic acid, alginate or sodium starch glycolate; The effervesce mixture; Tinting material; Sweeting agent; Wetting agent is as Yelkin TTS, polysorbate, dodecyl sulfate (laurylsulphate); And generally speaking be used for non-activity material on the nontoxic and pharmacology on the pharmaceutical preparation.These pharmaceutical preparations can be with known method preparation, for example by mixing, granulation, film-making, sugar coating or film coating procedure.

The liquid dispersion that is used for oral administration can be syrup, emulsion and suspension agent.Syrup can for example contain sucrose or contain the sucrose of glycerine and/or N.F,USP MANNITOL and/or sorbyl alcohol as carrier.

Suspension agent and emulsion can for example contain natural gum, agar, Sodium Alginate, pectin, methylcellulose gum, carboxymethyl cellulose or polyvinyl alcohol as carrier.Be used for the suspension agent of intramuscular injection or solution except active compound, can also contain pharmaceutically acceptable carrier, sterilized water, sweet oil, ethyl oleate, glycol propylene glycol for example for example, and if necessary together with an amount of Xylotox.

Be used to inject or the solution of infusion can for example contain sterilized water as carrier, or preferably they can be the forms of aseptic normal isotonic saline solution.

Compound of the present invention can be united use with known antiviral agent.In this respect, preferred known antiviral agent is Interferon, rabbit and ribavirin and derivative thereof, they treatment on the hepatitis C be known (Clinical Microbiology Reviews, Jan.2000,67-82).Therefore described medicine generally further comprises Interferon, rabbit or derivatives thereof and/or ribavirin or derivatives thereof.Further, the invention provides pharmaceutical composition, it comprises:

(a) quinazoline derivant of formula as defined above (Ia) or its pharmaceutically acceptable salt;

(b) Interferon, rabbit or derivatives thereof and/or ribavirin or derivatives thereof; And

(c) pharmaceutically acceptable carrier or thinner.

Product is provided simultaneously, and it comprises:

(a) (Ia) quinazoline derivant of formula as defined above or its pharmaceutically acceptable salt; And

(b) Interferon, rabbit or derivatives thereof and/or ribavirin or derivatives thereof are used for, simultaneously or in a sequence use independent in the treatment of human or animal body.

Interferon derivative is preferably the PEG-Interferon, rabbit.The ribavirin glycoside derivates is preferably Wella rice fixed (viramidine).

To the The compounds of this invention administration of patient with the treatment significant quantity.According to the activity of specific compound, the age of individuality to be treated, body weight and situation, the type of disease and severity, and the frequency of administration and approach, general dosage is about 0.01 to 100 milligram of every kg body weight.Dosage level is preferably about 0.05 to 16 milligram of every kg body weight, about 0.05 to 1.25 milligram of more preferably every kg body weight.

The following example explanation the present invention.Yet they do not limit the present invention in any way.In this, importantly understand the indication that the particular assay method that is used in the embodiment part only aims to provide antiviral activity.Many test method(s)s can be used for determining this activity, the therefore negative findings in any one particular assay and indecisive.

Embodiment

All temperature are with a ℃ expression.On the plastic plate that Si 60G applies, carry out thin-layer chromatography (TLC) with uv254 telltale (Polygram).Except as otherwise noted, all NMR spectrum are under 250MHz, at d ⁶Obtain among-the DMSO.

The LC-MS condition

Use electrospray and detect positively charged ion-negatively charged ion, working sample on MicroMass ZMD simultaneously.

Pillar: Synergi Hydro-RP, 30 * 4.6mm I.D, 4 μ m.

Gradient: 4.0min 95: 5 to 5: 95v/v H ₂O/CH ₃CN+0.05% formic acid keeps 3min, gets back to 95 at 0.2min: 5v/v H ₂O/CH ₃CN+0.05% formic acid also keeps 95: 5v/v H ₂O/CH ₃CN+0.05% formic acid 3min.

Detect: PDA 250-340nm.

Flow velocity: 1.5ml/min

Embodiment 1:(6-bromo-quinazoline-4-yl)-(4-morpholine-4-base-phenyl)-amine

(5g 23.1mmol) is suspended in the methane amide (5eq), at N with 5-bromo-2-benzaminic acid ₂Under be heated to 155 ℃ 16 hours.Allow mixture cooling and adding in the water.The throw out that obtains obtains 6-bromine quinazoline-4-alcohol intermediate by filtering separation and dry.The part of this material (1g) is dissolved in thionyl chloride (10ml), adds DMF (0.3ml), refluxes subsequently 5 hours.Remove and desolvate, (3 * 10ml) form azeotropic mixture to remove the thionyl chloride of trace for resistates and toluene.The material that obtains is dissolved in MeCN (10ml), add 4-morpholinyl aniline (1.1eq, Lancaster), and heating reflux reaction mixture 24 hours.The cooling back obtains the solid-state target compound of beige (867mg) by the filtering separation throw out.

δ(DMSO)11.5(1H，br s)；9.17(1H，d，J2.5Hz)；8.9(1H，s)；8.22(1H，dd，J 8.8，1.9Hz)；7.88(1H，d，J 8.8Hz)；7.61(2H，d，J 8.8Hz)；7.06(2H，d，J 8.8Hz)；3.78(4H，m)；3.18(4H，m)

LC-MS ES+＝385，rt 3.89

Embodiment 2:(6-iodo-quinazoline-4-yl)-(4-morpholine-4-base-phenyl)-amine

Adopt method similar to Example 1, use 5-iodo-2-benzaminic acid, obtain orange solid-state target compound (568mg) as starting material.

δ(DMSO)11.5(1H，br s)；9.17(1H，d，J2.5Hz)；8.89(1H，s)；8.22(1H，dd，J 8.8，1.9Hz)；7.88(1H，d，J 8.8Hz)；7.62(2H，d，J 8.8Hz)；7.07(2H，d，J 8.8Hz)；3.78(4H，m)；3.18 4H，m)

LC-MS ES+＝433，rt 3.97

Embodiment 3:(6,7-dimethoxy-quinazoline-4-yl)-(4-morpholine-4-base-phenyl)-amine

Adopt method similar to Example 1, use 4,5-dimethoxy-2-benzaminic acid obtains target compound as starting material.

LC-MS ES+＝367rt 3.76

Embodiment 4:(6-trifluoromethoxy-quinazoline-4-yl)-(4-morpholine-4-base-phenyl)-amine

Adopt method similar to Example 1, use 5-trifluoromethoxy-2-benzaminic acid, obtain target compound (110mg) as starting material.

δ(DMSO)10.0(1H，s)；8.66(1H，s)；8.62(1H，s)；7.91(2H，s)；7.68(2H，d，J 8.85Hz)；7.0(2H，d，J 8.85Hz)；3.80(2H，m)；3.10(2H，m)

LC-MS 391rt.4.89

Embodiment 5:(6-furans-2-base-quinazoline-4-yl)-(4-morpholine-4-base-phenyl)-amine

(embodiment 2 with (6-iodo-quinazoline-4-yl)-(4-morpholine-4-base-phenyl)-amine, 0.23mmol) be dissolved in toluene (5ml), with tributyl stannyl furans (Aldrich, 1.1eq), lithium chloride (5eq) and two (triphenyl phosphine) palladium chloride (5mol%) handle, and under nitrogen reflux 24 hours.Water treatment is after column chromatography obtains target compound (22mg).

δ(DMSO)9.92(1H，s)；8.89(1H，s)；8.55(1H，s)；8.23(1H，dd，J8.85，1.89Hz)；7.95(1H，d，1.26Hz)；7.84(1H，d，8.85Hz)；7.72(2H，d，J8.85Hz)；7.19(1H，d，J 1.89Hz)；7.07(2H，d，9.48Hz)；6.77(1h，dd，J3.16Hz，1.89Hz)；3.83(4H，m)；3.18(4H，m)

LC-MS ES+＝373rt 4.31

Embodiment 6:[6-(5-[1,3] dioxolane-2-base-furans-2-yl)-quinazoline-4-yl]-(4-morpholine 4-base-phenyl)-amine

The method of embodiment 5 is used 5-[1,3] dioxolane-2-base-2-tributyl stannyl furans obtains target compound (30mg).

LC-MS ES+＝373 Rt 4.31

Embodiment 7:5-[4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-yl] furans-2-formaldehyde

Heating is down with [6-(5-[1,3] dioxolane-2-base-furans-2-yl)-quinazoline-4-yl]-(4-morpholine-4-base-phenyl)-amine (100mg) is dissolved in THF (10ml), add 2M HCl (2ml) and add entry (10ml) then, and heat up to TLC (SiO down at 75 ℃ ₂, CH ₂Cl ₂/ iPrOH 20%) show and finish protection.The refrigerative reaction mixture alkalizes to pH 8 with 2M NaOH, arrives yellow solid-state target compound (45mg) by filtering separation.

δ(DMSO)10.07(1H，br s)；9.72(1H，s)；9.04(1H，s)；8.56(1H，s)，8.32(1H，d，J 8.21Hz)；7.87(1H，d，J 8.84Hz)；7.79(1H，d，J 3.79Hz)；7.67(2H，d 8.84Hz)，7.46(1H，d J 3.16Hz)；7.05(2H，d J 8.84Hz)；3.81(4H，m)；3.17(4H，m)

LC-MS ES+＝401 rt 4.16

Embodiment 8:{5-[4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-yl]-furans-2-yl }-methyl alcohol

At CH ₂Cl ₂(15ml) and in the acetate (1ml) with sodium triacetoxy borohydride (0.477g, 2eq) reduction 5-[4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-yl]-furans-2-formaldehyde (450mg) 2 hours, with after water treatment obtains target compound.

δ(DMSO)9.86(1H，br)；8.77(1H，d，J 1.26Hz)；8.47(1H，s)；8.13(1H，dd J 8.85，1.89Hz)；7.76(1H，d，8.85Hz)；7.65(2H，d，J 8.85Hz)；7.05(1H，d J 3.16Hz)；7.0(2H，d J 8.85Hz)；6.50(1H，d，3.16Hz)，5.76(1H，s)；5.34(1H，br)；4.53(2H，s)；3.70(4H，m)；3.10(4H，m)

LC-MS ES+＝403 rt 4.66

Embodiment 9:(6-{5-[(2-methylsulfonyl-ethylamino)-methyl]-furans-2-yl }-quinazoline-4-yl)-(4-morpholine-4-base-phenyl)-amine

Under 40 ℃ at CH ₂Cl ₂(46mg is by Bioorganic ﹠amp with 2-methylsulfonyl ethamine (15ml); Medicinal Chemistry Letters 14,1,, the preparation of the method for p111-114 Yue-Mei Zhang etc.) and the formaldehyde (150mg) of 5A molecular sieve (300mg) Processing Example 75 hours.(139mg 2eq), at room temperature stirs and spends the night to add acetate (2ml) and sodium triacetoxy borohydride.Enriched mixture obtains target compound (70mg) to dry with the absorption purification by chromatography.

δ(CDCl ₃)8.60(1H，br)；8.29(1H，d，1.42Hz)；7.88 91H，dd，J 8.68，1.74Hz)；7.78(1H，d，8.86Hz)；7.60(2H，d，9.0Hz)；6.91(2H，d，9.10Hz)；6.62(1H，d，3.32Hz)；6.25(1H，d，3.30Hz)；3.86(2H，s)；3.81(4H，m)；3.22(4H，s)，3.10(4H，m)；2.83(3H，s)

LC-MS ES+＝508 rt 4.95

Embodiment 10:{6-[5-(1,1-dioxy-1-λ-6-thiomorpholine-4-ylmethyl)-furans-2-yl]-quinazoline-4-yl }-(4-morpholine-4-base-phenyl)-amine

According to the method for embodiment 9, obtain yellow solid-state target compound (25mg).

δ(DMSO)9.82(1H，s)；8.76(1H，s)；8.48(1H，s)；8.14(1H，dd，J8.85，1.89Hz)；7.79(1H，d，J 8.85Hz)；7.64(2H，d，J 8.85Hz)；7.08(1H，d，J 3.16Hz)；7.01(2H，d，J 8.85Hz)；6.59(1H，d，J 3.16Hz)；3.85(2H，s)；3.8(4H，m)；3.15(8H，m)；3.0(4H，m)

LC-MS ES+＝520 rt 4.85

Embodiment 11:{6-[5-(4-methyl-piperazine-1-ylmethyl)-furans-2-yl]-quinazoline-4-yl }-(4-morpholine-4-base-phenyl)-amine

According to the method for embodiment 9, obtain yellow solid-state target compound (30mg).

δ(DMS)9.75(1H，s)；8.64(1H，d，J 1.26Hz)；8.37(1H，s)；8.03(1H，dd，J 8.85，1.26Hz)；7.86(1H，s)；7.67(1H，d，J 8.21Hz)；7.54(2H，d，8.85Hz)；6.96(1H，d，J 3.16Hz)；6.91(2H，d，J 9.48Hz)；6.40(1H，d，J3.16Hz)；3.67(4H，m)；3.50(2H，s)；3.27(8H，b)；3.02(4H，m)；2.03(3H，s)

LC-MS m/z 485 rt 4.48

Embodiment 12:[6-(5-morpholine-4-ylmethyl-furans-2-yl)-quinazoline-4-yl]-(4-morpholine-4-base-phenyl)-amine

According to the method for embodiment 9, obtain light yellow solid-state target compound (20mg).

δ(DMSO)9.92(1H，s)；8.80(1H，s)；8.49(1H，s)；8.15(1H，d，J8.21Hz)；7.79(1H，d，J 8.85Hz)；7.65(2H，d，J 8.85Hz)；7.09(1H，d，J3.16Hz)；7.01(2H，d，J 8.85Hz)；6.57(1H，d，J 3.16Hz)；6.53(1H，s)；3.80(10H，m)；；3.33(4H，m)；3.20(4H，m)

LC-MS m/z 472 rt 4.12

Embodiment 13:[6-(5-dimethylaminomethyl-furans-2-yl)-quinazoline-4-yl]-(4-morpholine-4-base-phenyl)-amine

δ(DMSO)9.93(1H，s)；8.85(1H，s)；8.56(1H，s)；8.22(1H，dd，J8.85，1.26Hz)；7.86(1H，d，J 8.85Hz)；7.73(2H，d，J 9.48Hz)；7.16(1H，d，J 3.16Hz)；7.09(2H，d，J 8.85Hz)；6.63(1H，d，J 3.16Hz)；3.86(4H，m)；3.73(2H，s)；3.21(4H，m)；2.37(6H，s)

LC-MS 430 rt 4.51

Embodiment 14:[6-(5-methylamino methyl-furans-2-yl)-quinazoline-4-yl]-(4-morpholine 4-base-phenyl)-amine

According to the method for embodiment 9, obtain light yellow solid-state target compound (8mg).

δ(DMSO)9.69(1H，s)；8.63(1H，s)；8.35(1H，s)；8.02(1H，d，J8.85Hz)；7.64(1H，d，J 8.85Hz)；7.53(2H，d，J 8.21Hz)；6.90(3H，m)；6.35(1H，m)；3.65(6H，m)；3.10(4H，m)；2.23(3H，s)

LC-MS m/z 4.16

Embodiment 15:(4-morpholine-4-base-phenyl)-(6-thiophene-2-base-quinazoline-4-yl)-amine

With triethylamine (2.6ml, 3eq.) (6-iodo-quinazoline-4-yl)-(4-morpholine-4-base-phenyl)-(embodiment 2 for amine in processing, 2.66g) and thiophene-2-boric acid (Lancaster, 1.18g, 1.5eq) suspension in THF (26ml), (282mg) be heated to 60 ℃ before at adding three (dibenzalacetones), two palladiums (0), continue heating 18 hours then.The throw out that obtains separates from the refrigerative reaction mixture by filtering, and washs with THF (10ml).Before dilute with water this solid is dissolved in DMSO (40ml) also by the diatomite sheet, throw out passes through filtering separation, and dry in a vacuum, obtains yellow solid-state target compound (1.2g, 50%).

δ(DMSO)10.75(1H，br s)；8.9(1H，s)；8.61(1H，s)；8.20(1H，dd，J8.85，1.89Hz)；7.8(2H，d，8.85Hz)；7.76(1H，s)；7.66(1H，d，J 4.42Hz)；7.58(2H，d，J 8.85Hz)，7.21(1H，t，3.79Hz)；7.0(2H，d，J 8.85Hz)；3.70(4H，m)；3.10(4H，m)

LC-MS ES+＝389 rt 4.32

Embodiment 16:(6-chloro-quinazoline-4-yl)-(4-morpholine-4-base-phenyl)-amine

According to method similar to Example 15, obtain target compound (42mg).

δ(DMSO)11.86(1H，s)；9.26(1H，s)；8.97(1H，s)；8.5(1H，dd，J8.85，1.9Hz)；8.06(2H，d 8.85Hz)；7.73(2H，d，J 8.85Hz)；7.67(2H，d，J8.85Hz)；7.28(1H，d，J 8.85Hz)；7.16(1H，d，J 9.48Hz)；7.11(1H，d，J9.48Hz)；3.81(4H，m)；3.2(4H，m)

LC-MS ES+＝417.5 rt 4.4

Embodiment 17:(4-morpholine-4-base-phenyl)-(6-o-tolyl-quinazoline-4-yl)-amine

According to method similar to Example 15, obtain target compound (25mg).

δ(MeOD)8.58(1H，s)；8.44(1H，d，J 1.26Hz)；7.93(1H，d，J1.89Hz)；7.91(1H，s)；7.65(2H，d，J 8.85Hz)；7.39(4H，m)；7.10(2H，d，J8.85Hz)；6.96(2H，s)；3.92(2H，m)；3.24(4H，m)；2.39(3H，s)

LC-MS ES+＝397 rt 4.26

Embodiment 18:(4-morpholine-4-base-phenyl)-(6-thiazol-2-yl-quinazoline-4-yl)-amine

According to method similar to Example 5, obtain target compound (5.3mg).

δ(DMSO)10.16(1H，s)，9.17(1H，s)，8.61(1H，s)，8.5(1H，d)，8.48(1H，d，J 8.8Hz)，8.10(1H，d，J 3Hz)，7.98(1H，d，J 3Hz)，7.91(1H，d，8.8Hz)，7.72(2H，d，J 8.8Hz)，7.09(2H，d，J 8.8Hz)，3.85(4H，m)，3.2(4H，m)

LC-MS m/z 390 rt 3.31

Embodiment 19:[6-(2-methoxyl group-pyrimidine-5-yl)-quinazoline-4-yl]-(4-morpholine-4-base-phenyl)-amine

According to method similar to Example 15, obtain yellow solid-state target compound (120mg).

δ(DMSO)9.75(1H，s)，9.15(2H，s)，8.86(1H，s)，8.53(1H，s)，8.23(1H，d，J 8.85Hz)，7.83(1H，d，J 8.85Hz)，7.64(2H，d，J 8.85Hz)，6.996(2H，d，J 8.85Hz)，4.0(3H，s)，3.76(4H，m)，3.11(4H，m)

LC-MS m/z 415

Embodiment 20:[6-(4-methyl-thiophene-2-yl)-quinazoline-4-yl]-(4-morpholine-4-base-phenyl)-amine

According to method similar to Example 15, obtain red solid-state target compound.

δ(DMSO)11.8(1H，br s)，9.18(1H，s)，8.83(1H，s)，8.31(1H，d，J8.85Hz)，7.97(1H，d，J 8.2Hz)，7.77(1H，s)，7.61(2H，d，J 8.85Hz)，7.32(1H，s)，7.08(1H，s)，3.78(4H，m)，3.19(4H，m)，2.3(3H，s)

LC-MS m/z 403

Embodiment 21:5-[4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-yl]-thiophene-2-carboxylic acid

According to method similar to Example 15, obtain the solid-state target compound of reddish-brown.

δ(DMSO)11.97(1H，br s)，9.36(1H，s)，8.86(1H，s)，8.43(1H，d，J8.2Hz)，7.99(2H，m)，7.82(1H，d，J 3.8Hz)，7.61(2H，d，J 8.85Hz)，7.08(2H，d，J 9.5Hz)，3.77(4H，m)，3.18(4H，m)

LC-MS m/z 433

Embodiment 22:[6-(4-methylsulfonyl-phenyl)-quinazoline-4-yl]-(4-morpholine-4-base-phenyl)-amine

According to method similar to Example 15, obtain yellow solid-state target compound.

δ(DMSO)9.91(1H，br s)，8.91(1H，s)，8.53(1H，s)，8.15(4H，m)，7.86(1H，d，J 8.85Hz)，7.64(2H，d，J 8.85Hz)，6.99(2H，d，J 8.85Hz)，3.76(4H，m)，3.29(3H，s)，3.11(4H，m)

LC-MS M/z 461

Embodiment 23:(4-morpholine-4-base-phenyl)-[6-(3-pyrazol-1-yl-phenyl)-quinazoline-4-yl]-amine

According to method similar to Example 15, use preparation LC-MS to be separated to brown solid-state target compound (5mg), δ (DMSO) 3.12 (s, 4H) 3.75 (s, 4H) 6.25 (s, 1H) 7.01 (d, 2H) 7.54 (m, 4H) 7.65 (d, 2H) 7.89 (d, 1H) 8.11 (m, 2H) 8.55 (s, 1H) 8.72 (s, 1H) 9.99 (s, 1H), LC/MS RT=3.62min Found ES+=449.4

Embodiment 24:4-[4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-yl]-benzonitrile

According to method similar to Example 15, use preparation LC-MS to be separated to brown solid-state target compound (5mg).δ(DMSO)3.12(s，4H)3.77(s，4H)7.01(d，2H)7.62(d，2H)7.82(d，2H)8.03-8.24(m，5H)8.50(s，1H)8.90(s，1H)9.91(bs，1H)，LC/MS RT＝2.50min Found ES+＝408.5

Embodiment 25: furans-2-carboxylic acid [4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-yl]-acid amides

Step 1: (method according to embodiment 1 prepares with (4-morpholine-4-base-phenyl)-(6-nitro-quinazoline-4-yl)-amine, 3.60LC-MS ES+ 352ES-350 0.5g) joins the THF of stirring: MeOH solution (1: 1,25ml) in, add Raney Ni (2 flat spoons, excessive) then.Heated mixt to 50 ℃ adds hydrazine (1ml) in this stage, and stirs 5 hours under this temperature.Allow mixture cool off diatomite filtration.Obtain solid except that desolvating under the vacuum, use 2.5-5%MeOH: DCM on silicagel column, to pass through purification by chromatography.Output 0.16g (35%).

LCMS：RT 2.01，ES ⁺322，ES-320

δ(DMSO)9.28(1H，s)；8.25(1H，s)；7.67(2H，d，J8.85Hz)；7.50(1H，d，J8.85Hz)；7.34(1H，d，1.90Hz)，7.22(1H，dd，J8.85Hz，1.90Hz)；6.96(2H，d，J8.85Hz)；5.53(2H，s)；3.77(4H，m)，3.09(4H，m).

Step 2: (0.033g 1.2eq) joins in pyridine (4ml) solution of a part of amine (50mg), stirs 4 hours with the 2-furoyl chloride.Remove pyridine in the vacuum, obtain target compound by the purification by chromatography resistates.

δ(DMSO)8.77(1H，s)；8.43(1H，s)；8.01(1H，d，J8.5Hz)；7.97(1H，s)；7.72(1H，d，J8.85Hz)；7.64(2H，d，J8.85Hz)；7.42(1H，d，J3.16Hz)；6.96(2H，d，J8.85Hz)；6.73(1H，m)；3.75(4H，m)；3.08(4H，m)，LC-MSm/z 416Rt 2.22

Embodiment 26:4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-carboxylic acid 4-methoxyl group-benzyl acid amides

Step 1:4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-carboxylic acid

With embodiment 2 (2.0g, 4.6mMol), salt of wormwood (1.4g, 11.6mMol), four (triphenyl phosphine)-palladium (O) (0.27g, 0.23mMol) and dichloro two-(triphenyl phosphine)-palladium (II) (0.16g, 0.23mMol) at 4: 1 dimethyl formamides: the solution of water (75ml) places carbon monoxide atmosphere, and be heated to 100 ℃ 6 hours.After the cooling, remove reaction solvent under the vacuum, resistates places water.To pH2, form orange throw out with the 1M hcl acidifying.Leach and in methyl alcohol, form pulpous state.Filter the suspension of acquisition and, obtain yellow solid-state 4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-carboxylic acid at air drying.Output=0.56g (1.6mMol, 35%).

LC/MS：RT-2.05，MH ⁺@351，δ(DMSO)10.37(1H，s)；9.46(1H，s)；8.79(1H，s)；8.49(1H，dd，J 8.4Hz，1.2Hz)；8.01(1H，d，J 8.2Hz)；7.87(2H，d，J 8.8Hz)；7.21(2H，d，J 8.8Hz)；3.98(4H，t，J 4.4Hz)；3.33(4H，t，J 4.4Hz)

Step 2: handle 4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-carboxylic acid (50mg with the 4-methoxybenzylamine, 0.14mMol), O-(7-azepine benzotriazole-1-yl)-N-N '-N '-tetramethyl-urea phosphofluoric acid ester (55mg, 0.14mMol) and triethylamine (45 μ l, 0.32mMol) solution in dimethyl formamide (2ml), and stir and spend the night.To reaction mixture, form throw out adding entry.By filtering collection and, obtaining target compound at air drying.

δ(DMSO)10.06(1H，s)；9.20(1H，s)；9.16(1H，s)；8.36(1H，d，J8.2Hz)；7.92(1H，d，J 8.8Hz)；7.78(2H，d，J 8.8Hz)；7.45(2H，d，J 8.8Hz)；7.12(2H，d，J 8.8Hz)；7.05(2H，d，J 8.2Hz)；4.62(2H，d，J 5.1Hz)；3.85-3.94(7H，m)；3.24(4H，t，J 3.6Hz)，LC-MS m/z 470Rt 2.46

Use suitable amine (1.2eq) in step 2, perhaps pure or as the solution (if feasible) in tetrahydrofuran (THF), use with embodiment 26 similar modes to prepare:

Embodiment 27:3-{[4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-carbonyl]-amido }-ethyl benzoate

δ(DMSO)10.68(1H，s)；10.00(1H，s)；9.13(1H，s)；8.57(1H，s)；8.47(1H，s)；8.30(1H，dd，J 8.8Hz，1.3Hz)；8.13(1H，d，J 8.2Hz)；7.84(1H，d，J 8.8Hz)；7.72(1H，d，J 8.2Hz)；7.67(2H，d，J 8.8Hz)；7.50-7.59(1H，m)；6.99(2H，d，J 8.8Hz)；4.33(2H，q，J 7.2Hz)；3.75(4H，t，J 4.4Hz)；3.10(4H，t，J 4.4Hz)，1.33(3H，t，J 6.9Hz)，LC-MS m/z 498Rt 2.70

Embodiment 28:4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-carboxylic acid 3-methoxyl group-benzyl acid amides

δ(DMSO)9.75(1H，s)；8.93(1H，t，J 5.7Hz)；8.85(1H，s)；8.35(1H，s)；8.05(1H，d，J 8.2Hz)；7.76(1H，s)；7.60(1H，d，J 8.2Hz)；7.46(2H，d，J 8.2Hz)；7.07(1H，t，J 7.6Hz)；6.72-6.82(3H，m)；6.63(1H，d，J 8.8Hz)；4.34(2H，d，J 5.1Hz)；3.11-3.17(7H，m)；2.87-2.94(3H，m)，LC-MS m/z470Rt 2.48

Embodiment 29:4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-carboxylic acid 4-methyl-benzyl acid amides

δ(DMSO)10.14(1H，s)；9.30(1H，t，J 6.1Hz)；9.24(1H，s)；8.76(1H，s)；8.44(1H，dd，J 8.8Hz，1.3Hz)；8.00(1H，d，J 8.8Hz)；7.87(2H，d，J8.8Hz)；7.47(2H，d，J 8.2Hz)；7.36(2H，d，J 7.6Hz)；7.20(2H，d，8.8Hz)；4.73(2H，d，J 5.7Hz)；3.94-4.00(4H，m)；3.29-3.35(4H，m)；2.49(3H，s)LC-MS m/z 454 rt 2.58

Embodiment 30:4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-carboxylic acid methane amide

δ(DMSO)9.81(1H，s)；8.86(1H，s)；8.39-8.45(2H，m)；8.04(1H，dd，J 8.8Hz，1.9Hz)；7.65(1H，d，J 8.2Hz)；7.53(2H，d，J 8.8Hz)；6.86(2H，d，J 8.8Hz)；3.59-3.67(4H，m)；2.95-3.01(4H，m)；2.73(3H，d，J 4.4Hz)，LC-MS rt 2.08，m/z 364

Embodiment 31:4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-carboxylic acid diformamide

δ(DMSO)9.60(1H，s)；8.43(1H，s)；8.35(1H，s)；7.63(1H，dd，J8.2Hz，1.3Hz)；7.57(2H，d，J 8.8Hz)；6.79(2H，d，J 8.8Hz)；3.53-3.59(4H，m)；2.89-2.94(4H，m)；2.86(3H，s)；2.79(3H，s)，LC-MS rt 2.09，m/z 378

Embodiment 32:4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-carboxylic acid ethanamide

δ(DMSO)9.96(1H，s)；9.01(1H，s)；8.63(1H，t，J 5.4Hz)；8.57(1H，s)；8.21(1H，dd，J 8.8Hz，1.9Hz)；7.80(1H，d，J 8.8Hz)；7.69(2H，d，J9.5Hz)；7.02(2H，d，J 8.8Hz)；3.75-3.82(4H，m)；3.38(2H，q，J 6.9Hz)；3.11-3.17(4H，m)；1.21(3H，t，J 6.9Hz)，LC-MS rt 2.15，m/z 378

Embodiment 33:N-{3-[4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-yl]-phenyl }-ethanamide

According to method similar to Example 15, LC-MS is separated to brown solid-state target compound (5mg) by preparation.

δ(DMSO)2.10(s，3H)3.13(s，4H)3.77(s，4H)7.01(d，2H)7.54(m，2H)7.67(d，2H)7.85(d，1H)8.03(m，2H)8.53(s，1H)8.79(s，1H)9.89(s，1H)10.15(s，1H)

LC/MS RT＝3.62min Found ES+＝449.4

Embodiment 34:{4-[4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-yl]-phenyl }-the carboxylamine benzene methyl

According to the method for embodiment 15, and δ (DMSO) 3.10-3.14 (t, 2H), 3.75-3.93 (t, 2H), 5.19 (s, 2H), 6.99-7.03 (d, 2H, J=9Hz), 7.36-7.48 (m, 5H), 7.64-7.68 (t, 3H), 7.78-7.87 (m, 3H), and 8.13-8.16 (dd, 1H), 8.33-8.35 (d, 1H), 8.50 (s, 1H), 8.77 (s, 1H), 9.82 (s, 1H), 9.97 (s, 1H); LC-MS m/z 533, rt 2.81

Embodiment 35:N-{4-[4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-yl]-phenyl }-ethanamide

According to the method for embodiment 15, and δ (DMSO) 2.17-2.19 (s, 3H), 3.21-3.24 (t, 4H), 3.85-3.89 (t, 4H), 7.10-7.13 (d, 2H), 7.75-7.79 (d, 2H), 7.84-7.98 (m, 5H), 8.24-8.27 (d, 1H), 8.60 (s, 1H), 8.88 (s, 1H), 9.92 (s, 1H), 10.23 (s, 1H), LC-MS m/z 440, rt 2.44

Embodiment 36:{4-[4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-yl]-phenyl }-t-butyl carbamate

According to the method for embodiment 15, and δ 1.47 (s, 9H), 3.06-3.10 (t, 4H), and 3.71-3.74 (t, 4H), 6.95-6.99 (d, 2H), and 7.57-7.64 (m, 4H), 7.76-7.79 (t, 3H), and 8.10-8.12 (d, 1H), 8.45 (s, 1H), 8.75 (s, 1H), 9.50 (s, 1H), 9.75 (s, 1H); LC-MS m/z 498, rt 2.86

Embodiment 37:{3-[4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-yl]-benzyl }-t-butyl carbamate

According to the method for embodiment 15, and δ 1.17 (s, 3H), 2.87-2.90 (t, 4H), 3.51-3.55 (t, 4H), and 4.01-4.03 (d, 2H), 6.75-6.79 (d, 2H), 7.27-7.31 (d, 2H), and 7.41-7.44 (t, 2H), 7.49-7.51 (d, 1H), 7.58-7.62 (d, 1H), 7.87 (d, 1H), 7.9 (d, 1H), 8.2 (s, 1H), 8.28 (s, 1H), 8.56 (s, 1H), 9.65 (s, 1H), LC-MS m/z 514, rt 2.18

Embodiment 38:N-{3-[4-(4-morpholine-4-base-phenyl amino)-quinazoline-6-yl]-phenyl }-sulfonyloxy methyl amine

Method according to embodiment 15

δ(DMSO，)2.86-2.89(s，3H)，2.95-2.98(t，4H)，3.53-3.57(t，4H)，6.86-6.89(d，2H)，7.07-7.10(d，1H)，7.31-7.45(m，5H)，7.88(d，1H)，8.07-8.10(d，1H)，8.65(s，1H)，9.05(s，1H)，9.35(s(broad)，1H)，9.78(s，1H)，11.79(s，1H)，LC-MS m/z 476 tt 2.54

Embodiment 39:(6-iodo-quinazoline-4-yl)-(4-morpholine-4-base-2-trifluoromethyl-phenyl)-amine

Step 1: with morpholine (1.74ml, 20mMol) handle 5-fluoro-2-nitro-trifluoromethyl toluene (2.1g, 10mM) and triethylamine (2.50ml, 24mMol) solution in acetonitrile (35ml).The solution that heating obtains, backflow is spent the night.After the cooling, under vacuum, remove reaction solvent, and between methylene dichloride and 10% (w/v) citric acid solution, distribute thick resistates.Separation of organic substances is used dried over mgso, and concentrating under reduced pressure obtains 4-(4-nitro-3-trifluoromethyl-phenyl)-morpholine (2.63g, 95%), LC/MS:RT-3.69, no ionization under the vacuum

δ(CDCl ₃)8.04(1H，d，J 8.8Hz)；7.17(1H，d，J 3.2Hz)；6.96(1H，dd，J 8.8Hz，2.5Hz)；3.89(4H，t，J 4.5Hz)；3.40(4H，t，J 4.5Hz)

Step 2: use standard method, with 4-(4-nitro-3-trifluoromethyl-phenyl)-morpholine (2.63g, 0.95mMol) and 10% palladium-carbon catalyst (263mg) at 2: 1 toluene: the suspension in the ethanol (75ml) places under the hydrogen atmosphere, up to finishing reaction.By diatomite sheet filter reaction mixture, use washing with alcohol then.Concentrating under reduced pressure filtrate obtains the solid-state 4-morpholine of beige-4-base-2-trifluoromethyl-aniline under the vacuum.(1.25g, 53%), LC/MS:RT-2.40, no ionization, δ (CDCl ₃) 7.05-7.12 (2H, m); (6.83 1H, d, J 8.8Hz); (3.96 4H, t, J 4.4Hz); 3.14 (4H, t, 4.4Hz)

Step 3: with the product (280mg) of 4-chloro-6-iodo-quinazoline (300mg, 1.1 mMol) treatment step 2, backflow is spent the night, and obtains throw out in acetonitrile (4ml).The cooling reaction leaches throw out.Throw out then at air drying, obtains target compound with 1M sodium hydroxide solution and water washing.δ(DMSO)9.79(1H，s)；8.85(1H，s)；8.27(1H，d，J12.0Hz)；8.03(1H，d，J 7.0Hz)；7.17-7.43(4H，m)；3.72-3.78(4H，m)；3.16-3.23(4H，m)，LC/MS：RT-2.80，MH ⁺@501，

Embodiment 40:(4-morpholine-4-base-2-trifluoromethyl-phenyl)-(6-thiophene-2-base-quinazoline-4-yl)-amine

Heating embodiment 39 (170mg, 0.4mMol), the 2-thienyl boric acid (50mg, 0.4mMol), triethylamine (120 μ l, 1.0mMol) and three (dibenzalacetone)-two palladium (0) (50mg, 15Mol%) the solution in anhydrous tetrahydro furan (3ml), backflow is spent the night.After the cooling, reaction mixture concentrates on tripoli, obtains the solid-state target compound of yellow through flash chromatography (wash-out under with the dichloromethane gradient of methylene dichloride-contain 2.5% methyl alcohol).

δ(DMSO)9.84(1H，s)；8.71(1H，s)；8.31(1H，s)；8.09(1H，d，J8.2Hz)；7.73(1H，d，J 8.8Hz)；7.65(1H，d，J 3.2Hz)；7.60(1H，d，J 5.1Hz)；7.14-7.36(4H，m)；3.67-3.77(4H，m)；3.13-3.19(4H，m).LC/MS：RT-2.80，MH ⁺@457

Embodiment 41:(6-iodo-quinazoline-4-yl)-(3-methoxyl group-4-morpholine-4-base-phenyl)-amine

Step 1: 2-bromo-5-nitro-methyl-phenoxide (0.5g) and morpholine (1.92g) are heated together, under 130 ℃, spend the night.The refrigerative reaction mixture is added in the ice, and the precipitation of acquisition obtains required 4-(2-methoxyl group-4-nitro-phenyl)-morpholine (91%, m/z 239) with water washing and dry

Step 2: (76%, 0.159g), it can use and need not to be further purified to use palladium-carbon catalyst hydrogenation nitro to obtain the solid-state 3-methoxyl group of brown-4-morpholine-4-base-aniline in ethanol under the room temperature.

Step 3: heating 3-methoxyl group-4-morpholine-4-base-aniline (136mg) and 4-chloro-6-iodine quinazoline (186mg) in acetonitrile (10ml), backflow is spent the night, after the cooling, by filtering to isolate throw out, wash with water, use 1N NaOH slurrying then, further wash with water and drying.Obtain target compound (263mg, 88%)

δ(DMSO)11.01(1H，br s)；9.20(1H，s)；8.83(1H，s)；8.29(1H，d，J8.85Hz)；7.67(1H，d，J8.85Hz)；7.40(2H，m)；6.98(1H，d，J8.85Hz)；8.83(3H，s)；3.76(4H，m)；3.01(4H，m).，LC-MS rt 2.74，m/z E+463

Embodiment 42:(3-methoxyl group-4-morpholine-4-base-phenyl)-(6-thiophene-2-base-quinazoline-4-yl)-amine

Method similar to Example 15 uses embodiment 41 to obtain target compound (14mg, 11%) as starting raw material

δ(DMSO)9.96(1H，s)；8.86(1H，s)；8.61(1H，s)；8.22(1H，d，J8.85Hz)；7.87(1H，d，J8.85Hz)；7.83(1H，d，J3.79Hz)；7.76(1H，d，J5.06Hz)；7.48(2H，m)；7.33(1H，t J5.05，3.79Hz)；7.03(1H，d，J8.85Hz)；3.92(3H，s)；3.84(4H，m)；3.07(4H，m)，LC-MS rt 3.63，m/z E+419

Embodiment 43:(2-methyl-4-morpholine-4-base-phenyl)-(6-thiophene-2-base-quinazoline-4-yl)-amine

Step 1: with morpholine (1.74ml, 20mMol) handle 5-fluoro-2-nitrotoluene (1.22ml, 10mM) and triethylamine (2.10ml, 20mMol) solution in acetonitrile (30ml).The solution that heating obtains, backflow is spent the night.After the cooling, remove reaction solvent under the vacuum, between methylene dichloride and 10% (w/v) citric acid solution, distribute thick resistates.Isolate organism, use dried over mgso, concentrating under reduced pressure obtains 4-(3-methyl-4-nitrophenyl)-morpholine (1.96g, 88%) LC/MS:RT-2.76, no ionization under the vacuum.

Step 2: use standard method, the suspension in toluene (30ml) places under the hydrogen atmosphere with 4-(3-methyl-4-nitrophenyl)-morpholine 1.96g (8.9mMol) and 10% palladium carbon (100mg), up to finishing reaction.By the diatomite filtration reaction mixture, liquid concentrating under reduced pressure under vacuum obtains the solid-state 2-methyl of dun-4-morpholine-4-base-aniline.(1.07g，63％)，LC/MS：RT-0.71，MH ⁺@193；δ(CDCl ₃)6.74(1H，s)；6.64-6.70(2H，m)；3.88(4H，t，J 4.5Hz)；3.06(4H，t，J 4.5Hz)；1.99(3H，s)

Step 3: heating 4-chloro-6-iodo-quinazoline (500mg, 1.8mMol) (spend the night, and produces throw out therebetween for 360mg, the 1.9mMol) suspension in acetonitrile (10ml) with 2-methyl-4-morpholine-4-base-aniline by backflow.The cooling reaction, filtering precipitate.Before air drying,, obtain (6-iodo-quinazoline-4-yl)-(2-methyl-4-morpholine-4-base-phenyl)-amine (738mg, 95%) with 1M NaOH solution and water washing.LC/MS：RT-3.55，MH ⁺@447δ(DMSO)10.35(1H，br s)；9.04(1H，d，1.3Hz)；8.55(1H，s)；8.20(1H，dd，J 8.8Hz，1.3Hz)；7.60(1H，d，J 8.8Hz)；7.14(1H，d，J 8.8Hz)；6.92(1H，d，J 2.5)；6.87(1H，dd，J 8.2Hz，1.9Hz)；3.77(4H，t，4.4Hz)；3.15(4H，t，4.4Hz)；2.15(3H，s)

Step 4: heating (6-iodo-quinazoline-4-yl)-(2-methyl-4-morpholine-4-base-phenyl)-amine (250mg, 0.6mMol), 2-thienyl boric acid (75mg, 0.6mMol), triethylamine (150 μ l, 1.2mMol) and three (dibenzalacetones), two palladiums (0) (50mg, 10Mol%) the solution in anhydrous tetrahydro furan (10ml), backflow is spent the night.After the cooling, reaction mixture concentrates on silica gel, through flash chromatography (with 200: 8: 1 methylene dichloride: ethanol: the ammonia water mixture wash-out), obtain solid-state (2-methyl-4-morpholine-4-base-phenyl)-(6-thiophene-2-base-quinazoline-4-the yl)-amine of yellow.LC/MS：RT-3.54，MH ⁺@403；δ(DMSO)9.89(1H，s)；8.89(1H，d，J 1.9Hz)；8.46(1H，s)；8.25(1H，dd，J 8.8Hz，1.9Hz)；7.89(1H，d，J 8.8Hz)；7.84(1H，3.8Hz)，7.78(1H，d，J 5.0Hz)；7.36(1H，dd，J 5.0Hz，3.8Hz)；7.30(1H，d，8.2Hz)；7.05(1H，d，1.9Hz)；6.98(1H，dd，J 8.8Hz，3.2Hz)；3.90(4H，t，J4.4Hz)；3.28(4H，t，J 4.4Hz)；2.29(3H，s)

Embodiment 44:(3-methyl-4-morpholine-4-base-phenyl)-(6-thiophene-2-base-quinazoline-4-yl)-amine

Step 1: heating 2-fluoro-5-nitrotoluene (1.65g, 10.6mMol), triethylamine (2.96ml, 21.2mMol) and morpholine (backflow is spent the night for 1.86ml, the 21.2mMol) solution in acetonitrile (30ml).After the cooling, concentrating under reduced pressure reaction solvent under the vacuum, resistates adds in the morpholine.Heat this solution down at 100 ℃, finish reaction up to detecting by TLC.Reaction mixture washs with the methylene dichloride dilution and with the 1M citric acid solution.Use the dried over mgso organism, concentrating under reduced pressure obtains oily matter under the vacuum.Further (with gasoline-9: 1 gasoline: the ethyl acetate gradient elution) purifying obtains orange solid-state 4-(2-methyl-4-nitro-phenyl)-morpholine by flash chromatography.(0.53g, 22%), LC/MS:RT-3.76 does not have ionization; δ (CDCl ₃) 7.99-8.02 (2H, m); (6.94 1H, d, J 9.5Hz); (3.81 4H, t, J 4.5Hz); (2.95 4H, t, J 4.5Hz); 2.31 (3H, s)

Step 2: use standard method, with 4-(2-methyl-4-nitro-phenyl)-morpholine (0.53g, 2.4mMol) and 10% palladium carbon (55mg) at 1: 1 toluene: the suspension in the ethanol (25ml) places under the hydrogen atmosphere, up to finishing reaction.By diatomite sheet filter reaction mixture, use washing with alcohol then.Concentrating under reduced pressure filtrate obtains the solid-state 3-methyl of tawny-4-morpholine-4-base-aniline under the vacuum.(0.47g，100％)，LC/MS：RT-2.66，MH ⁺@193；δ(CDCl ₃)6.82(1H，d，J 8.2Hz)；6.48-6.54(2H，m)；3.76(4H，t，J 4.4Hz)；2.76(4H，t，J 4.4Hz)；2.18(3H，s)

Step 3: heating 4-chloro-6-iodo-quinazoline (300mg) and the 3-methyl-4-morpholine-suspension of 4-base-aniline (240mg) in acetonitrile (4ml), backflow is spent the night, and produces throw out therebetween.The cooling reaction, filtering precipitate.Before air drying,, obtain (6-iodo-quinazoline-4-yl)-(3-methyl-4-morpholine-4-base-phenyl)-amine with 1M NaOH solution and water washing.LC/MS：RT-2.81，MH ⁺@447；δ(DMSO)9.82(1H，s)；9.03(1H，d，J 1.9Hz)；8.59(1H，s)；8.12(1H，dd，J 8.8Hz，1.9Hz)；7.60-7.70(2H，m)；7.58(1H，d，J8.8Hz)；7.09(1H，d，J 8.8Hz)；3.78(4H，t，J 4.1Hz)；2.87(4H，t，J 4.1Hz)；2.32(3H，s)

Step 4: heating (6-iodo-quinazoline-4-yl)-(3-methyl-4-morpholine-4-base-phenyl)-amine (170mg, 0.4mMol), 2-thienyl boric acid (50mg, 0.4mMol), triethylamine (120 μ l, 1.0mMol) and three (dibenzalacetones), two palladiums (0) (50mg, 10Mol%) the solution in anhydrous tetrahydro furan (3ml), backflow is spent the night.During cooling, reaction mixture concentrates on tripoli, obtains solid-state (3-methyl-4-morpholine-4-base-phenyl)-(6-thiophene-2-base-quinazoline-4-the yl)-amine of yellow through flash chromatography (wash-out under with the dichloromethane gradient of methylene dichloride-contain 2.5% methyl alcohol).

LC/MS：RT-2.76，MH ⁺@403；δ(DMSO)10.05(1H，s)；8.97(1H，d，J 1.9Hz)；8.71(1H，s)；8.32(1H，dd，J 8.8Hz，1.9Hz)；7.99(1H，d，J8.8Hz)；7.93(1H，dd，J 3.8Hz，1.3Hz)；7.87(1H，dd，J 5.1Hz，1.3Hz)；7.75-7.85(3H，m，)；7.44(1H，dd，J 5.1Hz，3.2Hz)；7.29(1H，d，J 8.8Hz)；3.96(4H，t，J 4.4Hz)；3.06(4H，t，J 4.4Hz)；2.51(3H，s)

Embodiment 45: ethyl-(4-morpholine-4-base-phenyl)-(6-thiophene-2-base-quinazoline-4-yl)-amine

Step 1: (0.5g 2.80mmol), adds Et then to add N-(4-amino-benzene) morpholine in the stirred solution of dry DMF (10ml) ₃N (0.70g, 7.0mmol).(0.24g 3.10mmol), at room temperature stirs the mixture and spends the night slowly to add Acetyl Chloride 98Min..Add entry (50ml), with ethyl acetate (2 * 20ml) extraction mixtures.Be associated with machine washing liquid and dry (Na ₂SO ₄), obtain solid-state N-(4-morpholine-4-base-phenyl)-4-ethanamide except that desolvating under the vacuum.Output 0.29g (47%).δ(DMSO)9.71(1H，bs)；7.42(2H，d，J8.85Hz)；6.87(2H，d，J9.48Hz)；3.72(4H，m)；3.01(4H，m)；1.98(3H，s)，LCMS：RT 1.97，ES ⁺221

Step 2: to handle N-(4-morpholine-4-base-phenyl)-4-ethanamide (1g) with the similar mode of embodiment 46 steps 2, obtain half crude product ethyl-(4-morpholine-4-base-phenyl)-amine (0.92g,), according to embodiment 46 steps 3 itself and 4-chloro-6-iodine quinazoline are reacted, obtain target compound (104mg according to the reaction of embodiment 44 steps 4 then, 61%) δ (DMSO) 8.61 (1H, s); 8.18 (1H, s); 7.93 (1H, d, J8.85Hz); 7.70 (2H, d, J8.85Hz); 7.50 (1H, d, J4.42Hz); 7.14 (5H, m); 4.11 (2H, m); 3.76 (4H, m); 3.19 (4H, m); 1.22 (3H, t, J6.31Hz), LC-MS rt 2.67, m/z E+417

Embodiment 46:(6-iodo-quinazoline-4-yl)-methyl-(4-morpholine-4-base-phenyl)-amine

Step 1: in diacetyl oxide (0.75g), adding formic acid (0.41g) under 0 ℃ of stirring, be heated to then 50 ℃ 2 hours.With dry THF (5ml) dilution refrigerative mixture, add 4-morpholinyl aniline (0.5g), mixture recovered 3 hours.Removing under the vacuum desolvates obtains yellow solid-state N-(4-morpholine-4-base-phenyl) 4-methane amide (450mg, 77%), δ (DMSO) 8.72 (1H, s), 7.90 (1H, d, J8.85Hz); 7.51 (1H, d, J8.85Hz); 7.15 (5H, m); 3.81 (4H, m); 3.56 (3H, s); 3.21 (4H, m), LC-MS rt 2.62, m/z E+447.

Step 2: handle the solution of N-(4-morpholine-4-base-phenyl) 4-methane amide (0.29g) in dry THF (2ml) with sodium borohydride (160mg) down at 0 ℃, and stirred 30 minutes.In 10 minutes, add BF ₃/ Et ₂The solution of O (0.67ml), and 0 ℃ of following restir 1 hour.The reflux mixture is 5 hours then.Cooling mixture also drips water (3ml) with the excessive sodium borohydride of hydrolysis.With diethyl ether (2 * 10ml) extraction mixtures.Organic washes merges dry (Na ₂SO ₄), remove methyl-(4-morpholine-4-base-phenyl)-amine that desolvates and obtain white solid state under the vacuum.Output 43mg (16%) δ (DMSO) 6.76 (2H, d, J8.85Hz); 6.47 (2H, d, J8.85Hz); 5.17 (1H, bs); 3.69 (4H, m); 2.87 (4H, m); 2.60 (3H, s), LCMS:RT 2.35, ES ⁺193

Step 3: heating methyl-(4-morpholine-4-base-phenyl)-amine (37mg) and the solution of 4-chloro-6-iodine quinazoline (52mg) in acetonitrile (6ml), backflow is spent the night, after the cooling, obtain throw out by filtering separation, wash with water,, further wash with water and drying with 1N NaOH slurrying.Obtain target compound (22mg, 28%) δ (DMSO) 8.72 (1H, s), 7.90 (1H, d, J8.85Hz); 7.51 (1H, d, J8.85Hz); 7.15 (5H, m); 3.81 (4H, m); 3.56 (3H, s); 3.21 (4H, m), LC-MS rt 2.62, m/z E+447

Embodiment 47:(6-iodo-quinazoline-4-yl)-(3-methyl-butyl)-(4-morpholine-4-base-phenyl)-amine

Step 1: in swivel pipe (carousel tube), add N-(4-aminophenyl) morpholine (0.25g, 1.40mmol), DCM (exsiccant, 15ml), molecular sieve 3a (excessive, 0.2g) and 3-methyl-butyraldehyde (0.14g, 1.4mmol).At room temperature stirred the mixture 1 hour, and stirred 2 hours down at 45 ℃ then.Cooling mixture adds acetate (1ml), and (0.60g 2.80mmol), allows mixture at room temperature stir and spends the night to add triacetoxy borohydride hydrogen sodium then.Remove under the vacuum and desolvate, on silicagel column, obtain (3-methyl-butyl)-(4-morpholine-4-base-phenyl)-amine, output 0.20g (57%) through the column chromatography purification crude product by using 2.5%MeOH: DCM.δ(DMSO)6.75(2H，d，J8.85Hz)；6.50(2H，d，J8.85Hz)；3.71(4H，m)；3.17(2H，m)；2.89(4H，m)；1.66(1H，m)；1.39(2H，m)；0.91(6H，d，J6.32Hz)，LCMS：RT 2.22，ES ⁺249

Step 2: handle (3-methyl-butyl)-(4-morpholine-4-base-phenyl)-amine (210mg) according to embodiment 47 steps 3, obtain target compound (294mg, 71%), δ (DMSO) 8.69 (1H, s); 7.89 (1H, dd, J8.85Hz, 1.9Hz); 7.50 (1H, d, J8.85Hz); 7.16 (4H, AB, J8.85Hz); 7.06 (1H, d, J1.90Hz); 4.12 (2H, t, J7.58Hz); 3.80 (4H, m); 3.23 (4H, m); 1.62 (2H, m); 1.37 (1H, m); 0.94 (6H, d, 6.32Hz), LC-MS rt 3.11, m/z E+503

Embodiment 48: sec.-propyl-(4-morpholine-4-base-phenyl)-(6-thiophene-2-base-quinazoline-4-yl)-amine

According to embodiment 47 similar methods, then according to embodiment 45 step 4 similar methods obtain target compound (4.5mg) δ (DMSO) 8.61 (1H, s); 7.90 (1H, d, J7.58Hz); 7.67 (1H, d, J8.85Hz); 7.51 (1H, d, J4.42Hz); 7.09 (7H, m); 5.51 (1H, m); 3.77 (4H, m); 3.23 (4H, m); 1.18 (J6.32Hz), LC-MSrt 2.74, m/z E+431 for 6H, d

Embodiment 49:(3-methyl-butyl)-(4-morpholine-4-base-phenyl)-(6-thiophene-2-base-quinazoline-4-yl)-amine

According to obtaining target compound (12.5mg) δ (DMSO) 8.63 (1H) with embodiment 44 step 4 similar methods; 8.21 (1H, s); 7.94 (1H d, J8.85Hz); 7.72 (2H, m); 7.52 (1H, d, J5.06Hz); 7.12 (5H, m); 4.13 (2H, m); 3.78 (4H, m); 3.20 (4H, m); 3.0 (3H, m); 1.15 (6H, t, J7.58Hz), LC-MS rt 2.98, m/z E+459

Embodiment 50:[6-(2-benzyloxy-phenyl)-quinazoline-4-yl]-(4-morpholine-4-base-phenyl)-amine

According to obtaining target compound LC-MS m/z 489.4rt 2.82 with embodiment 15 similar methods

Embodiment 51:[6-(4-benzyloxy-phenyl)-quinazoline-4-yl]-(4-morpholine-4-base-phenyl)-amine

According to embodiment 15 similar methods obtain target compound (DMSO, δ) 3.07-3.10 (t, 4H), 3.71-3.75 (t, 4H), 5.18 (s, 2H), 6.95-6.99 (d, 2H), and 7.14-7.18 (d, 2H), 7.28-7.48 (m, 5H), and 7.60-7.64 (d, 2H), 7.74-7.83 (m, 3H), and 8.08-8.12 (d, 1H), 8.45 (s, 1H), 8.71 (s, 1H), LC-MS m/z 490 rt 2.89

Active embodiment

The cell that uses:

HCV replicon cell Huh 9B (ReBlikon) contains the HCV polyprotein that fluorescence Luci-ubiquitin-neomycin phosphotransferase fused protein and EMCV-IRES drive, and has the cell cultures adaptive mutation.

Cell culture condition:

Cell is under 37 ℃, cultivate under 5% carbon dioxide environment, and first day with 2 * 10E6 cell/flask inoculation, after 3 days with 1 * 10E6 inoculation, weekly at twice.In substratum, add the G418 (the every 25ml of 125ul) of about 0.25mg/ml, do not add and measure in the medium.

Substratum by the DMEM that contains 4500g/l glucose and add 1 * non-essential amino acid glutamax (Gibco 61965-026), penicillin (100IU/ml)/Streptomycin sulphate (100 μ g/ml), FCS (10%, 50ml) and 1mg/ml G418 (Invitrogen cat no 10131-027) ﹠amp; 10% foetal calf serum is formed.

The mensuration process:

With the cell in the trypsin treatment flask and carry out cell counting.Cell dilution to 100,000 cell/ml, and per 7 compounds that are used for test I C50 are got 100 μ l inoculate opaque and white 96 orifice plates (being used for replicon measures) and a flat transparent panel (being used for toxicity test).The hole G12 of transparent panel and H12 are vacant as blank.Then plate was being hatched 24 hours under 37 ℃, under 5% carbon dioxide environment.

Second day, the concentration of target final concentration twice with them in transparent round bottom plate was prepared diluted chemical compound liquid in medium.All diluent has 1% final DMSO concentration.

In case the dilution plate is made, and will contrast with compound and be transferred to assay plate (containing cell), plate double with 100 μ l/ holes.

Other item: in white (replicon) plate, hole A1 and A2 do not add any compound, add the 1%DMSO of 100 μ l as an alternative.In transparent (toxicity) plate, hole E12 and F12 only contain the DMSO contrast.Then plate was being hatched 72 hours under 37 ℃, under 5% carbonic acid gas.

When incubation period finished, the cell in the white flat board was collected by temperature (37 ℃) the PBS washing with 200 μ l/ holes, and with 20 μ l cell culture lysis buffer (Promega) cracking.After at room temperature hatching 5 minutes, in luciferase assay damping fluid (LARB), add luciferin solution with the every 10ml LARB of 200 μ l.The M syringe of microwell plate photometer (Lmax, Molecular Devices) is with the injection liquid initialize of 4 * 300l.Plate is inserted in the photometer, and add the luciferase assay reagent of 100 μ l by the syringe on the photometer.Use the program that postponed to measure in 4 seconds then in 1 second to come measurement signal.The replicon level is reduced by 50% required drug level with respect to undressed cell control value, and promptly IC50 can calculate from uciferase activity minimizing per-cent drug level being mapped.

Be dissolved in 50% alcoholic acid methylene blue to transparent panel dyeing 1 hour, the methylene blue that solvation absorbs in 100 μ l, 1% Sarkosyl L of every hole then with 100 μ l 0.5% under the room temperature.Go up the absorption of measuring plate at microwell plate spectrophotometer (Molecular Devices), and the absorption of each concentration of compound is represented with the ratio of relative DMSO contrast.Total cell area is reduced by 50% required drug level with respect to the DMSO contrast, and promptly TD50 can calculate by with the absorption at 620nm place drug level being mapped.

Table 1

	Replicon IC50 (＜1uM= ^*；＜5uM＝ ^；＜25uM＝ ^* )	Replicon TD50 (＞25uM= ^* ；＞10uM＝ ^；＞1uM＝ ^*)
	Replicon IC50 (＜1uM= ^*；＜5uM＝ ^；＜25uM＝ ^* )	Replicon TD50 (＞25uM= ^* ；＞10uM＝ ^；＞1uM＝ ^*)	Embodiment	uM	uM
1	**	***	Embodiment	uM	uM
1	**	***	2	***	**

3	*	***
3	*	***	4	*	***
5	***	*	4	*	***
5	***	*	6	**	**
7	***	**	6	**	**
7	***	**	8	***	***
9	***	**	8	***	***
9	***	**	10	**	***
11	**	***	10	**	***
11	**	***	12	***	***
13	**	**	12	***	***
13	**	**	14	*	***
15	***	***	14	*	***
15	***	***	16	**	***
17	**	***	16	**	***
17	**	***	18	***	***
19	***	***	18	***	***
19	***	***	20	**	***
21	*	***	20	**	***
21	*	***	22	***	***
23	***	**	22	***	***
23	***	**	24	**	***
25	*	***	24	**	***
25	*	***	26	**	***
27	**	***	26	**	***
27	**	***	28	**	***

29	**	***
29	**	***	30	**	***
31	**	***	30	**	***
31	**	***	32	**	***
33	**	***	32	**	***
33	**	***	34	***	***
35	***	***	34	***	***
35	***	***	36	***	***
37	**	**	36	***	***
37	**	**	38	**	***
39	***	***	38	**	***
39	***	***	40	***	**
41	**	**	40	***	**
41	**	**	42	***	***
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Claims

1. compound, described compound is quinazoline derivant or its pharmaceutically acceptable salt of formula (Ia),

R wherein ₁Represent hydrogen, halogen, C ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₁-C ₄Alkoxyl group, C ₁-C ₄Halogenated alkoxy ,-CO ₂R ^/,-CONR ^/R ^//,-A ,-A-L-A ^/,-Z-L-A or-A-L-Z-L-A, wherein R ^/And R ^//Identical or different, and represent hydrogen or C separately ₁-C ₄Alkyl;

R ₄Represent hydrogen, C ₁-C ₆Alkyl or C ₁-C ₆Haloalkyl,

Wherein:

-A ^/Be 5-to 10-unit's heteroaryl or 5-to 10-unit heterocyclic radical group;

And

R ₁Described in aryl, heteroaryl and heterocyclic radical part be not substituted or be selected from halogen, C by 1,2 or 3 ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₁-C ₄Halogenated alkoxy, hydroxyl, mercaptan ,-NH ₂, C ₁-C ₄Hydroxyalkyl, C ₁-C ₄Sulfane base, C ₁-C ₄Aminoalkyl group, cyano group, nitro ,-COR ^/,-CO ₂R ^/,-S (O) R ^/,-S (O) ₂R ^/,-CONR ^/R ^//With-L ^/-X-L ^//The substituting group of-Y replaces, wherein each R ^/And R ^//Identical or different, and be selected from hydrogen and C ₁-C ₄Alkyl, L ^/Be direct key or C ₁-C ₄Alkylidene group, X be-S-,-O-or-NR ^/-, R wherein ^/Define as above L ^//Be direct key or C ₁-C ₄Alkylidene group, and Y be hydrogen ,-COR _/,-CO ₂R _/,-S (O) ₂R _/Or-S (O) R _/, R wherein _/Be hydrogen or C ₁-C ₄Alkyl.

2. compound as claimed in claim 1, wherein L ^/Be direct key or C ₁-C ₂Alkylidene group.

3. compound as claimed in claim 1 or 2, wherein X be-O-or-NR ^/-, R wherein ^/As defined in claim 1.

4. each described compound, wherein L in the claim as described above ^//Be direct key or C ₁-C ₂Alkylidene group.

5. each described compound in the claim as described above, wherein Y be hydrogen ,-COR ^/,-CO ₂R ^/,-S (O) R ^/Or-S (O) ₂R ^/, R wherein ^/Be hydrogen or C ₁-C ₄Alkyl group.

6. each described compound in the claim as described above, the aryl in the wherein said R1 substituting group, heteroaryl and heterocyclic radical part are not substituted or are selected from halogen, C by 1,2 or 3 ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₁-C ₄Halogenated alkoxy, C ₁-C ₄Hydroxyalkyl, cyano group ,-COR ^/,-CO ₂R ^/,-S (O) R ^/,-S (O) ₂R and-L ^/-X-L ^//The substituting group of-Y replaces, wherein R ^/, L ^/, X, L ^//Each defines in the claim as described above with Y.

7. each described compound in the claim as described above, wherein said R ₁Aryl in the substituting group, heteroaryl and heterocyclic radical part are not substituted or are selected from halogen, C by 1 or 2 ₁-C ₂Alkyl, C ₁-C ₂Haloalkyl, C ₁-C ₂Hydroxyalkyl, cyano group ,-COR ^/,-CO ₂R ^/,-S (O) R ^/,-S (O) ₂R ^/,-(C ₁-C ₂Alkyl)-NR ^/R ^//, C ₁-C ₂Alkoxyl group ,-NR ^/-COR ^/, NR ^/-CO ₂R ^/,-(C ₁-C ₂Alkyl)-NR ^/-CO ₂R ^/,-NR ^/-S (O) ₂-R ^/With-(C ₁-C ₂Alkyl)-NR ^/-(C ₁-C ₂Alkyl)-S (O) ₂-R ^//Substituting group replace each R wherein ^/, R ^//And R ^/Identical or different, and represent hydrogen or C ₁-C ₂Alkyl.

8. each described compound in the claim as described above, wherein A is phenyl, 5-to 6-unit's heteroaryl or 5-to 6-unit heterocyclic radical group.

9. each described compound in the claim as described above, wherein A is phenyl, furyl, thienyl, pyrimidyl, thiazolyl or pyridazolyl group.

10. each described compound in the claim as described above, wherein L is direct key or C ₁-C ₂Alkylidene group.

11. each described compound, wherein A in the claim as described above ^/Be 5-to 6-unit's heterocyclic radical or heteroaryl groups, it is not substituted or is selected from halogen, C by 1,2 or 3 ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl and C ₁-C ₄The substituting group of halogenated alkoxy replaces.

12. each described compound, wherein A in the claim as described above ^/Be morpholinyl, thio-morpholinyl, piperazinyl, 1,3-dioxolanyl, S, S-dioxy thio-morpholinyl or pyrazolyl groups, it is not substituted or is selected from C by 1 or 2 ₁-C ₂Alkyl, halogen and C ₁-C ₂The substituting group of haloalkyl replaces.

13. each described compound in the claim as described above, wherein Z be-O-,-CONR ^/-,-NR ^/C (O)-or-NR ^/CO ₂-, R wherein ^/Each defines in the claim as described above.

14. each described compound in the claim as described above, wherein Z be-O-,-CONH-,-CON (C ₁-C ₂Alkyl)-,-NHC (O)-or-NHCO ₂-.

15. each described compound, wherein R in the claim as described above ₁Be halogen, C ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₁-C ₄Alkoxyl group, C ₁-C ₄Halogenated alkoxy ,-CO ₂R ^/,-CONR ^/R ^//,-A ,-A-L-A ^/,-Z-L-A or-A-L-Z-L-A, wherein R ^/, R ^//, A, L, A ^/Each defines in the claim as described above with Z.

16. each described compound, wherein R in the claim as described above ₁Be halogen, C ₁-C ₂Alkoxyl group, C ₁-C ₂Halogenated alkoxy ,-CONR ^/R ^//,-A ,-Ar-L-A ^/,-Z-L-A or-Ar-Z-L-Ar, wherein R ^/And R ^//Identical or different, and represent hydrogen or C separately ₁-C ₂Alkyl group, A and A ^/Each defines in the claim as described above, and Ar is unsubstituted furyl or unsubstituted phenyl group, and L is direct key or methylene group, and Z be-O-,-C (O) NR ^/-,-NR ^/C (O)-or-NR ^/CO ₂-, R wherein ^/Be hydrogen or C ₁-C ₄Alkyl group.

17. each described compound, wherein R in the claim as described above ₂Be hydrogen, C ₁-C ₄Alkyl or C ₁-C ₄Alkoxyl group.

18. each described compound, wherein R in the claim as described above ₃Be hydrogen, C ₁-C ₂Alkyl, C ₁-C ₂Haloalkyl or C ₁-C ₂Alkoxyl group.

19. each described compound, wherein R in the claim as described above ₄Be hydrogen or C ₁-C ₆Alkyl.

20. each described compound in the claim as described above, the described quinazoline derivant of its Chinese style (Ia) is the quinazoline derivant of formula (I),

Wherein:

-R ₂Be hydrogen or C ₁-C ₂Alkoxyl group;

-A is phenyl or 5-to a 6-unit heteroaryl groups, for example furyl, thienyl, pyrimidyl and thiazolyl, and it is not substituted or is selected from halogen, C by 1 or 2 ₁-C ₂Alkyl, C ₁-C ₂Alkoxyl group, C ₁-C ₂Haloalkyl, C ₁-C ₂Hydroxyalkyl ,-COR ^/,-CO ₂R ^/,-S (O) R ^/,-S (O) ₂R ^/,-(C ₁-C ₂Alkyl)-NR ^/R ^//With-(C ₁-C ₂Alkyl)-NR ^/-(C ₁-C ₂Alkyl)-S (O) ₂-R ^//Substituting group replace each R wherein ^/And R ^//Identical or different, and represent hydrogen or C ₁-C ₂Alkyl;

-Ar is unsubstituted furyl;

-L is direct key or methylene group; And

-A ^/Be 5-to 6-unit heterocyclic radical group, for example morpholinyl, thio-morpholinyl, piperazinyl, 1,3-dioxolanyl and S, S-dioxy thio-morpholinyl, it is not substituted or is selected from C by 1 or 2 ₁-C ₂Alkyl, halogen and C ₁-C ₂The substituting group of halogenated alkyl group replaces.

21. compound as claimed in claim 20, wherein:

-R ₂Be hydrogen or C ₁-C ₂Alkoxyl group;

-A is phenyl or 5-to a 6-unit heteroaryl groups, for example furyl, thienyl and thiazolyl, and it is not for being substituted or being selected from halogen, C by 1 or 2 ₁-C ₂Alkyl, C ₁-C ₂Haloalkyl, C ₁-C ₂Hydroxyalkyl ,-COR ^/,-(C ₁-C ₂Alkyl)-NR ^/R ^//With-(C ₁-C ₂Alkyl)-NR ^/-(C ₁-C ₂Alkyl)-S (O) ₂-R ^//Substituting group replace each R wherein ^/And R ^//Identical or different, and represent hydrogen or C ₁-C ₂Alkyl;

-Ar is unsubstituted furyl group;

-L is direct key or methylene group; And

-A ^/Be 5-to 6-unit heterocyclic radical group, for example morpholinyl, thio-morpholinyl, piperazinyl, 1,3-dioxolanyl and S, S-dioxy thio-morpholinyl, it is not substituted or is selected from C by 1 or 2 ₁-C ₂Alkyl, halogen and C ₁-C ₂The substituting group of haloalkyl replaces.

22. the purposes of the quinazoline derivant of each described formula (Ia) in the treatment human or animal body in the aforementioned claim.

23. pharmaceutical composition, it comprises the quinazoline derivant of each described formula (Ia) among the claim 1-21, or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier or thinner.

24. the quinazoline derivant of each described formula (Ia) or its pharmaceutically acceptable salt purposes in the medicine of preparation treatment or the infection of prevention of flavivirus section among the claim 1-21.

25. being pestivirus, purposes as claimed in claim 24, wherein said flaviviridae infections infect.

26. purposes as claimed in claim 25, wherein said pestivirus infects the infection that causes for bovine viral diarrhea virus, Pestivirus suis or border disease virus.

27. being Flavivirus, purposes as claimed in claim 24, wherein said flaviviridae infections infect.

28. purposes as claimed in claim 27, wherein said Flavivirus infects the infection that causes for yellow fever virus, dengue fever virus, japanese encephalitis virus or tick-borne encephalitis.

29. being Hepaciviruses, purposes as claimed in claim 24, wherein said flaviviridae infections infect.

30. purposes as claimed in claim 29, wherein said Hepacivirus infects the infection that causes for hepatitis C virus.

31. purposes as claimed in claim 30, wherein said medicine further comprise (a) Interferon, rabbit or derivatives thereof and/or (b) ribavirin or derivatives thereof.

32. purposes as claimed in claim 31, wherein said interferon derivative are that PEG-Interferon, rabbit and/or described ribavirin glycoside derivates are fixed for Wella rice.

33. product comprises:

(a) quinazoline derivant of each described formula (Ia) among the claim 1-21, or its pharmaceutically acceptable salt; And

(b) claim 31 or 32 described Interferon, rabbit or interferon derivative and/or claim 31 or 32 described ribavirins or ribavirin glycoside derivates;

Wherein said (a) and (b) component in the treatment of human or animal body simultaneously, independence or use in order.

34. treatment is subjected to or is easy to be subjected to the method for the patient of each described flaviviridae infections among the claim 24-30, described method to comprise quinazoline derivant or its pharmaceutically acceptable salt administration with each described formula (I) among the claim 1-21 of significant quantity to described patient.