CN102459188A - Novel 6-arylamino pyridone sulfonamides and 6-arylamino pyrazinone sulfonamdies as mek inhibitors - Google Patents

Novel 6-arylamino pyridone sulfonamides and 6-arylamino pyrazinone sulfonamdies as mek inhibitors Download PDF

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CN102459188A
CN102459188A CN2010800362746A CN201080036274A CN102459188A CN 102459188 A CN102459188 A CN 102459188A CN 2010800362746 A CN2010800362746 A CN 2010800362746A CN 201080036274 A CN201080036274 A CN 201080036274A CN 102459188 A CN102459188 A CN 102459188A
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group
alkyl
amino
halogen
compound
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校登明
祝力
王世新
梁志
胡伟
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KAIMEILONG (BEIJING) PHARMACEUTICAL TECHNOLOGY Co Ltd
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KAIMEILONG (BEIJING) PHARMACEUTICAL TECHNOLOGY Co Ltd
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Abstract

The invention provides novel substituted 6-arylamino pyridone sulfonamides and 6 arylamino pyrazinone sulfonamides represented by Formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, and a composition comprising these compounds. The compounds provided can be used as inhibitors of MEK and are useful in the treatment of inflammatory diseases, cancer and other hyperproliferative diseases. The invention further provides a method of treatment for inflammatory diseases, cancer and other hyperproliferative diseases in mammals, especially humans.

Description

Novel 6-virtue EL-970 one sulfonamide and the amino pyrazine one sulfonamide mek inhibitor of 6-virtue
Technical field
The present invention relates to the 6-virtue EL-970 one sulfonamide and the amino pyrazine one sulfonamide of 6-virtue of series of substituted, it is for mek inhibitor and can be used for treating diseases associated with inflammation, cancer and other excess proliferative disease.The invention still further relates to the pharmaceutical composition that comprises The compounds of this invention, The compounds of this invention in pharmacy purposes and use the method for the present invention at the excess proliferative disease of treatment Mammals (particularly human).
Background technology
Protein kinase constituted structurally associated, through phosphate group is transferred to the enzyme family that Ser, Thr or the Tyr residue of protein receptor play a role from nucleoside triphosphate.Protein reversible phosphorylation event by protein kinase is received is being regulated and control the various kinds of cell function, comprises dna replication dna, cell cycle progression, energy metabolism and cell growth and differentiation.In addition, the activity of protein kinase and the multiple disease-related that comprises cancer.In known more than 100 main oncogene so far, having much is the known sudden change and/or cross the acceptor and the cytoplasm protein kinases (Blume-Jensen and Hunter, Nature, 411:355-365 (2001)) of expressing in human cancer of coding.Therefore, this year, the protein kinase target attracted most medicament research and development attention, and (relevant summary is referring to Fischer, Curr.Med.Chem., 11:1563 (2004) to have some kinases inhibitors to obtain the approval of supervision department; Dancey and Sausville, Nature Rev.Drug Disc., 2:296 (2003)).
The Ras/Raf/MEK/ERK path is a central signal transduction path, and it is sent to signal the transcription factor of regulate gene expression in the nucleus from a plurality of cell surface receptors.This path often is called as the map kinase path, and MAPK representes MAPK, explains that this path can (Steelman et al., Leukemia 2004,18,189-218) by mitogen, cytokine and factors stimulated growth.This path can transmit according to stimulator and cell type and cause apoptosis or cell cycle progression to be suppressed or the inductive signal.Have now found that the Ras/Raf/MEK/ERK path has important effect in cell proliferation with aspect suppressing to transfer to.In the cell of vicious transformation, usually can observe the abnormal activation of this path.In about 30% human cancer, observe the amplification of Ras proto-oncogene and cause expressing and have the proteic activated mutant of the active Ras of composition (Stirewalt et al., Blood 2001,97,3589-95).(Kohl et al., Science 1993,260,1834-1837) all to have found the Ras of carcinogenic form of sudden change in colorectal cancer 50%, the carcinoma of the pancreas more than 90% and other the multiple cancer.In immortal cell line, proved at present Ras to the effect of propagation and tumour formation (McCubrey et al., Int J Oncol 1995,7,295-310).In the malignant melanoma more than 60%, identified bRaf sudden change (Nature 2002,417 for Davies, H et al., 949954) at present.Because detected high-caliber Ras sudden change, this path is regarded as the important target that carries out therapeutic intervention, and (Chang etal., Leukemia 2003,17,1263-93) always.
Because the constitutively activate of map kinase cascade or excessive activation have keying action in cell proliferation and differentiation, suppress the treatment that this path helps excess proliferative disease beyond doubt.Because be positioned at the downstream of Ras and Raf, MEK is the key members of this path.In addition, MEK is that noticeable treatment target is also because map kinase, ERK1 and ERK2 are the things of only knowing the inside story of MEK phosphorylation.Existing a plurality of at present inhibition MEK that discover have the potential result of treatment.For example have now found that the small molecules mek inhibitor suppresses people's growth of tumor, (Seebolt-Leopold et.al., Nature-Medicine, 1,999 5 (7), 810-816 in a kind of transplantation model of mouse; Trachet et al.AACR April 6-10,2002, Poster & num; 5426) and suppress the growth (Milella et.al., J.Clin.Invest., 2001,108 (6) 851-859) of acute myelocytic leukemia cell.
The compound that is suitable as mek inhibitor also is disclosed in WO 00/41994; WO 00/42022; WO00/42029; WO 00/68201; WO 01/68619; WO 02/06213, and WO 03/077914, WO05/023251, and WO 05/121142; WO07/014011, WO 07/071951, and WO 07/123939, WO08/021389; WO 08/078086, and WO 08/120004, and WO 08/124085, and WO 08/125180; WO09/018233, WO07/044084, WO07/121481 and WO 09/018238.
Summary of the invention
The invention provides the compound of representing by formula I, or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug:
Figure BDA0000135908570000031
Formula I
Wherein, R 0Be H, C 1-C 6Alkyl, C 3-C 6Naphthenic base, C 2-C 6Thiazolinyl, C 5-C 6Cycloalkenyl group or C 2-C 6Alkynyl; Wherein said alkyl, naphthenic base, thiazolinyl, cycloalkenyl group or alkynyl group are optional to be replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, cyanic acid, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed, and said C 3-C 6One or two of naphthenic base becomes optional O, N or the S of replacing with independently of ring carbon atom; And
R 1Be H, C 1-C 4Alkoxyl group, C 1-C 6Alkyl, C 3-C 6Naphthenic base, C 2-C 6Thiazolinyl, C 5-C 6Cycloalkenyl group, C 2-C 6Alkynyl or halogen; Wherein said alkoxyl group, alkyl, naphthenic base, thiazolinyl, thiazolinyl, cycloalkenyl group or alkynyl group are randomly replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyanic acid, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed; Perhaps, R 1Be five yuan or hexavalent saturated heterocyclyl, unsaturated heterocycle base or fragrant heterocyclic radical; Affiliated heterocyclic radical contains 1-5 heteroatoms; Said heteroatoms is independently selected from the group of being made up of O, N or S; And said heterocyclic radical is optional to be replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyanic acid, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed; Or
R 1For-CH 2X, the wherein group of X expression II:
Figure BDA0000135908570000032
Formula II
Wherein, Y 1And Y 2Can be identical or different, represent separately singly-bound ,-CO-,-COO ,-O-,-OCO-,-NR aOr-SO 2-;
Y 3Expression can be by 1-3 the substituted C of group that is represented by Z 1-5Alkyl;
Z can be identical or different, and expression can the substituted C of randomly one or more substituting groups 1-5Alkyl, halogen atom, oxo group ,-OR a,-COOR a,-COOCOR a,-CO-halogen atom ,-OCOR a,-CONR aR b,-SR a,-SO 2R a,-NR aR b,-NR aCOR b,-NR aSO 2R b,-SO 2NR aR b, monocycle or the heterocyclic radical of dicyclo or the heteroaryl of monocycle or dicyclo, said substituting group is selected from by C 1-5Alkyl ,-OR aAnd NR aR bThe group of forming; Each alkyl can be by hydroxyl, C 1-5Alkoxyl group or amino the replacement; Except that oxo group and halogen, above-mentioned substituting group can interconnect and form naphthenic base or heterocyclic radical, and said naphthenic base or heterocyclic radical can have one or more substituting groups, and said substituting group is selected from by-OR a, NR aR bWith can be by-OR aSubstituted C 1-5The group that alkyl is formed;
R aAnd R bCan be identical or different, represent Wasserstoffatoms or can be separately by 1-3 the substituted C of substituting group 1-4Alkyl group, said substituting group is selected from by hydroxyl, C 1-5Alkoxyl group and the amino group of forming;
Symbol " ● " the expression connection site of using among the formula II;
X is C or N;
When X=C, R 2Be H, C 1-C 4Alkoxyl group, C 1-C 6Alkyl, C 3-C 6Naphthenic base, C 2-C 6Thiazolinyl, C 5-C 6Cycloalkenyl group or C 2-C 6Alkynyl; Wherein said alkoxyl group, alkyl, naphthenic base, thiazolinyl, cycloalkenyl group or alkynyl are optional to be replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyanic acid, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed; Perhaps, R 2Be five yuan or hexavalent saturated heterocyclyl, unsaturated heterocycle base or fragrant heterocyclic radical; Wherein, Said heterocyclic radical has 1-5 heteroatoms; Said heteroatoms is selected from the group that O, N and S form, and said heterocyclic radical is optional by 1-3 substituting group replacement, and said substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyanic acid, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed; Perhaps
When X=N, R 2Do not exist; Perhaps
R 1And R 2Common form one five yuan or hexavalent unsaturated heterocycle base or comprise 1-3 heteroatomic fragrant heterocyclic radical; Said heteroatoms is independently selected from the group of being made up of O, N or S; Said heterocyclic radical is optional to be replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyanic acid, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed; And
R 3Be selected from by trifluoromethyl, C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, C 3-C 10Naphthenic base, C 3-C 10Cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heteroaryl ring alkyl, heterocyclic radical and Heterocyclylalkyl; Wherein each alkyl, thiazolinyl, alkynyl, naphthenic base, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical alkyl, hetero-aromatic ring alkyl and heterocyclic radical is not substituted or replaced by 1-3 substituting group, said substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, cyanic acid, trifluoromethyl, difluoro-methoxy, phenyl or have 1-3 substituent substituted-phenyl, the substituting group of said substituted-phenyl independently is selected from halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, cyanic acid, trifluoromethyl, difluoro-methoxy;
R 4, R 5, R 6, R 7And R 8Be independently selected from H, halogen, cyanic acid, nitro, trifluoromethyl, SR 9, OR 9, C (O) R 9, NR 10C (O) OR 12, OC (O) R 9, NR 10S (O) jR 12, S (O) jNR 9R 10, S (O) jNR 10C (O) R 9, C (O) NR 10S (O) jR 12, S (O) jR 12, NR 10C (O) R 9, C (O) NR 9R 10, NR 11C (O) NR 9R 10, NR 11C (NCN) NR 9R 10, NR 9R 10And C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, C 3-C 10Naphthenic base, C 3-C 10Cycloalkylalkyl, S (O) j(C 1-C 6Alkyl), S (O) j(CR 10R 11) m-aryl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical, heterocyclic radical alkyl, O (CR 10R 10) m-aryl, NR 10(CR 10R 11) m-aryl, O (CR 10R 11) m-heteroaryl, NR 10(CR 10R 11) m-heteroaryl, O (CR 10R 11) m-heterocyclic radical, NR 10(CR 10R 11) m-heterocyclic radical and S (C 1-C 2Alkyl), above-mentioned group is optional is replaced by the fluorine atom of 1-5;
R 9Be selected from by hydrogen, trifluoromethyl, C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, C 3-C 10Naphthenic base, C 3-C 10The group that cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical and heterocyclic radical alkyl are formed; Wherein each alkyl, thiazolinyl, alkynyl, naphthenic base, aryl, heteroaryl and heterocyclic radical are not substituted or are replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl, the amino group of forming;
R 10Be selected from by hydrogen or C 1-C 6Alkyl, said alkyl can be not to be substituted or to be replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming; Or
R 9, R 10Form 4-10 first hetero-aromatic ring or heterocycle together with coupled atom, said each ring is not substituted or is replaced by 1-3 substituting group, and said substituting group is free halogen, C independently 1-C 4Alkyl, hydroxyl and the amino group of forming;
R 11Be selected from hydrogen or C 1-C 6Alkyl, wherein alkyl can be not to be substituted or to be replaced by 1-3 substituting group, said substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming; Or
R 10, R 11Form 4-10 first carbocyclic ring, hetero-aromatic ring or heterocycle together with coupled atom, each ring is not substituted or is replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming;
R 12Be selected from by trifluoromethyl, C 1-C 10Alkyl, C 3-C 10The group that naphthenic base, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical and heterocyclic radical alkyl are formed; Wherein each alkyl, naphthenic base, aryl, heteroaryl and heterocycle are not substituted or are replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming;
M is 0,1,2,3,4 or 5; And
J is 1 or 2;
On the other hand, the invention provides the compound of formula I or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug, wherein R 0Be H or C 1-C 6
On the other hand, the invention provides the compound of formula I or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug, wherein R 1Be H or C 1-C 6
On the other hand, the compound or its that the invention provides formula I then do not have R at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug when wherein X is N 2When perhaps X is C, R 2Be H or C 1-C 6Alkoxyl group.
On the other hand, the compound or its that the invention provides formula I be at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug, when wherein X is C, and R 2Be C 1-C 4Alkoxyl group or five yuan or hexavalent saturated heterocyclyl, unsaturated heterocycle base or fragrant heterocyclic radical; Wherein said heterocyclic radical comprises 1-5 the heteroatoms that is independently selected from O, N and S; And said heterocyclic radical is optional to be replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyanic acid, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed.
On the other hand, the invention provides the compound of formula I or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug, wherein R 3Be selected from by following group and form group: randomly by one or more halogens or the substituted C of hydroxyl 1-C 6Alkyl; C 2-C 6Thiazolinyl; Randomly by C 1-C 6Alkyl or C 2-C 6The C of alkenyl substituted 3-C 6Naphthenic base; Have the bicyclic heteroaryl of heteroatoms O, N or S five yuan or single six-membered rings or 9-13 unit, randomly by the bicyclic aryl of substituted five yuan or single six-membered rings or 9-13 unit of one or more substituting groups, wherein said substituting group is selected from by halogen, cyanic acid, C 1-C 6The group that alkoxyl group and hydroxyl, cycloalkyl aryl are formed; Wherein said aryl is five yuan or single six-membered rings or the first bicyclic aryl of 9-13; And what the carbon atom of the 1-6 on the naphthenic base was optional is replaced by one or more substituting groups, and said substituting group is selected from by halogen, cyanic acid, C 1-C 6The group that alkoxyl group and hydroxyl are formed; The heteroaryl ring alkyl, wherein heteroaryl is five yuan or single six-membered rings or the first bicyclic aryl of 9-13, and optional being replaced by one or more substituting groups of the carbon atom of the 1-6 on the naphthenic base, said substituting group is selected from by halogen, cyanic acid, C 1-C 6The group that alkoxyl group and hydroxyl are formed; And C 1-C 6Alkyl C 1-C 6Naphthenic base is optional is obtained a plurality of substituting groups by one and replaces, and said substituting group is selected from by halogen, cyanic acid, C 1-C 6The group that alkoxyl group and hydroxyl are formed.
On the other hand, the invention provides the compound of formula I or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug, wherein R 4, R 5, R 6, R 7And R 8Be independently selected from H or halogen.
On the other hand, the invention provides the compound of formula I or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug, wherein R 4And R 8Be fluorine, and R 6Be iodine.
On the other hand, the invention provides the compound of formula I or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug, wherein R 0Be H or C 1-C 6Alkyl; R 1Be H or C 1-C 6Alkyl; When X is N, R 2Do not exist, when X is C, R 2Be H or C 1-C 6Alkoxyl group; R3 is selected from the group of being made up of following group: optional by one or more halogens or the substituted C of hydroxyl 1-C 6Alkyl; C 2-C 6Thiazolinyl; Randomly by C 1-C 6Alkyl or C 2-C 6The C of alkenyl substituted 3-C 6Naphthenic base, has the bicyclic heteroaryl of heteroatoms O, N or S five yuan or single six-membered rings or 9-13 unit; Randomly by one or more substituting groups substituted five yuan or single six-membered rings or the first bicyclic aryl of 9-13, wherein said substituting group is selected from by halogen, cyanic acid, C 1-C 6The group that alkoxyl group and hydroxyl are formed; Cycloalkyl aryl, wherein aryl is five yuan or single six-membered rings or the first bicyclic aryl of 9-13, naphthenic base has 1-6 carbon atom; And C 1-C 6Alkyl C 1-C 6Naphthenic base; And R 4, R 5, R 6, R 7And R 8Be independently selected from H or halogen.
On the other hand, the invention provides be expressed from the next compound or its at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug:
Figure BDA0000135908570000081
Wherein,
R 0, R 1, R 2, R 4～R 8Definition identical with formula I;
R 13Be selected from by H, C 2-C 6Thiazolinyl and C 1-C 6The group that alkynyl is formed, wherein, said group is carved optional being replaced by one or more substituting groups, and said substituting group is selected from the group of being made up of halogen and hydroxyl;
R 14Be selected from by H, C 1-C 6The bicyclic aryl of alkyl, five yuan or single six-membered rings or 9-13 unit and have heteroatoms O; The group that the bicyclic heteroaryl of N or S five yuan or single six-membered rings or 9-13 unit is formed; Wherein, Said group can randomly be replaced by one or more substituting groups, and said substituting group is selected from by halogen, cyanic acid, hydroxyl, optional by the substituted C of halogen 1-C 6Alkyl, and C 1-C 6Alkoxyl group;
On the other hand, R 0Be H or C 1-C 6Alkyl; R 1Be H, C 1-C 6Or halogen; R 2Be H or C 1-C 6Alkoxyl group; R 3Be selected from the group of forming by following group: randomly by one or more halogens or the substituted C of hydroxyl 1-C 6Alkyl; C 2-C 6Thiazolinyl; Randomly by C 1-C 6Alkyl or C 2-C 6The C of alkenyl substituted 3-C 6Naphthenic base; Has heteroatoms O, five yuan or the bicyclic heteroaryl of single six-membered rings or 9-13 unit of N or S; Randomly by one or more substituting groups substituted five yuan or single six-membered rings or the first bicyclic aryl of 9-13, said substituting group is selected from by halogen, cyanic acid, C 1-C 6Alkoxyl group and hydroxyl; Cycloalkyl aryl, wherein aryl is for having heteroatoms O, five yuan or the bicyclic aryl of single six-membered rings or 9-13 unit of N or S, naphthenic base has 1-6 carbon atom; C 1-C 6Alkyl C 1-C 6Naphthenic base; And R 4, R 5, R 6, R 7And R 8Be independently selected from H or halogen; And
R 13And R 14Definition as above;
Or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
On the other hand, the invention provides be expressed from the next compound or its at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug:
Figure BDA0000135908570000082
Wherein,
R 1Be H, C 1-C 6Alkyl or halogen; R 2Be H or C 1-C 6Alkoxyl group; R 13Be selected from H, C 2-C 6Thiazolinyl and C 1-C 6The group of forming, wherein, said group is selected from by one or more substituting groups and replaces, and said substituting group is selected from the group of being made up of halogen and hydroxyl; R 14Be selected from by H, C 1-C 6The bicyclic aryl of alkyl, five yuan or single six-membered rings or 9-13 unit and have five yuan or the bicyclic heteroaryl of single six-membered rings or 9-13 unit of heteroatoms O, N or S; Wherein, Said group is replaced by one or more substituting groups, and said substituting group is selected from by halogen, cyanic acid, hydroxyl, is chosen wantonly substituted C by halogen 1-C 6Alkyl and C 1-C 6The group that alkoxyl group is formed.
On the other hand, the invention provides be expressed from the next compound or its at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug:
Figure BDA0000135908570000091
Wherein,
R 13Be selected from by H, C 2-C 6Thiazolinyl and C 1-C 6The group that alkyl is formed, wherein, said group is replaced by optional one or more substituting groups, and said substituting group is selected from the group of being made up of halogen and hydroxyl; R 14Be selected from by H, C 1-C 6The bicyclic aryl of alkyl, five yuan or single six-membered rings or 9-13 unit and have five yuan or the bicyclic heteroaryl of single six-membered rings or 9-13 unit of heteroatoms O, N or S; Wherein above-mentioned group is optional to be replaced by one or more substituting groups, and said substituting group is selected from by halogen, cyanic acid, hydroxyl, is chosen wantonly substituted C by halogen 1-C 6Alkyl and C 1-C 6The group that alkoxyl group is formed.
In other embodiments, the present invention provides the compound that following formula is represented:
Figure BDA0000135908570000092
Figure BDA0000135908570000101
Or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
On the other hand, the invention provides be expressed from the next compound or its at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug:
Figure BDA0000135908570000102
Wherein,
R 13For being selected from by H, C 2-C 6Thiazolinyl and C 1-C 6The group that alkyl is formed, wherein, said group is replaced by optional one or more substituting groups, and said group is selected from the group of being made up of halogen and hydroxyl; R 14For being selected from H, C 1-C 6The bicyclic aryl of alkyl, five yuan or single six-membered rings or 9-13 unit and have five yuan or the bicyclic heteroaryl of single six-membered rings or 9-13 unit of heteroatoms O, N or S; Wherein above-mentioned group is optional to be replaced by one or more substituting groups, and said substituting group is selected from halogen, cyanic acid and C 1-C 6Alkoxyl group.
In other embodiments, the present invention provides the compound that following formula is represented:
Figure BDA0000135908570000103
Or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
Compound of the present invention is a mek inhibitor, therefore, can be used for treating cancer and other excess proliferative diseases.
In other respects, the present invention relates to comprise formula I compound or its pharmaceutical composition of significant quantity at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.In some embodiments, said pharmaceutical composition also comprises pharmaceutically acceptable carrier, auxiliary agent and/or vehicle.In some embodiments, this type of combination can comprise at least a as inert fraction of sanitas, absorption delay agent, filler, tackiness agent, sorbent material, buffer reagent, disintegrating agent, solubilizing agent, other carriers and auxiliary agent and/or vehicle.The compound method of this compsn is a technology well known in the art.
Aspect some; The present invention relates to treat the method for the individuality of suffering from said disease; Said method comprises to the said individual pharmaceutical composition that uses the treatment significant quantity, and said pharmaceutical composition comprises formula I compound or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
In other respects; The present invention relates to treat the method for Mammals illness, said method comprises to the formula I compound of said Mammals use treatment significant quantity or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
In other respects, the present invention relates to treat the method for human disorders, said method comprises to the formula I compound of said human patients use treatment significant quantity or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
In other respects; The present invention relates to treat the method for the Mammals diseases associated with inflammation of (comprising the mankind), symptom or illness, said method comprises to the formula I compound of said Mammals use treatment significant quantity or it is at pharmacy acceptable salt, ester, prodrug, solvolyte (comprising hydrate), polymorphic form or tautomer.
In other respects; The present invention relates to treat Mammals (comprising the mankind) and receive the illness of MEK cascade regulation and control or the method for symptom, said method comprises to the formula I compound of said Mammals use treatment significant quantity or it is at pharmacy acceptable salt, ester, prodrug, solvolyte (comprising hydrate), polymorphic form or tautomer.Those skilled in the art can confirm the appropriate dose to particular patient according to currently known methods.
In other respects, the present invention relates to formula I compound or it is in pharmacy acceptable salt, ester, prodrug, solvolyte (comprising hydrate), polymorphic form or the application of tautomer in pharmaceutical compositions.Said pharmaceutical composition can be used for treating illness or the symptom that Mammals (comprising the mankind) receives MEK cascade regulation and control.Said pharmaceutical composition can be used for treating cancer, diseases associated with inflammation and other excess proliferative diseases.
In other respects, the present invention relates to comprise formula I compound or its pharmaceutical composition at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.In some embodiments, said pharmaceutical composition is an oral dosage form.In other embodiments, said pharmaceutical composition is tablet, capsule, pill, pulvis, sustained release preparation, solution and suspension-s.In other embodiments, sterile solution, suspension-s or the emulsion of the injection of said drug regimen inaction parenteral; The ointment or the emulsifiable paste that are used for topical perhaps are used for the suppository of rectal administration.In other embodiments, said pharmaceutical composition is bestowed the unit dosage of exact dosage desired for being fit to single.In other embodiments, the amount of formula I compound is in the scope of about 0.001～about 1000 mg/kg body weight/day.In other embodiments, the amount of formula I compound is in the scope of about 0.5～about 50 mg/kg body weight/day.In other embodiments, the amount of formula I compound is in about 0.001～about 7 gram/skies.In other embodiments, the amount of formula I compound is in about 0.002～about 6 gram/skies.In other embodiments, the amount of formula I compound is in about 0.005～about 5 gram/skies.In other embodiments, the amount of formula I compound is in about 0.01～about 5 gram/skies.In other embodiments, the amount of formula I compound is in about 0.02～about 5 gram/skies.In other embodiments, the amount of formula I compound is in about 0.05～about 2.5 gram/skies.In other embodiments, the amount of formula I compound is in about 0.1～about 1 gram/sky.In other embodiments, the dosage level that is lower than above-mentioned scope lower limit possibly be enough.The dosage level that possibly be higher than in other embodiments, above-mentioned range limit.In other embodiments, use the compound of formula I with single dose, once a day.In other embodiments, use the compound of formula I with multiple doses, every day more than once.In other embodiments, use the compound of quadratic expression I every day.In other embodiments, use the compound of cubic expression tertiary I every day.In other embodiments, use the compound of quarternary quantic I every day.In other embodiments, use compound every day four times with following formula I.In some embodiments, said pharmaceutical composition is applied to Mammals.In other embodiments, said Mammals is the people.In other embodiments, said pharmaceutical composition also comprises pharmaceutical carrier, vehicle and/or auxiliary agent.In other embodiments, said pharmaceutical composition also comprises at least a therapeutical agent.In other embodiments, said therapeutical agent is selected from by the cell toxicant material, anti-angiogenicly forms the group that agent and antineoplastic agent are formed.In other embodiments, antineoplastic agent is selected from the group of being made up of alkylating agent, metabolic antagonist, teniposide (epidophyllotoxin), antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone (mitoxantrones), platinum complex, biological response modifier and growth inhibitor, hormone/hormone antagonist therapeutical agent and hemopoieticgrowth factor.In other embodiments, therapeutical agent be taxol (taxol), Velcade (bortezomib) or both.In other embodiments, the other treatment that is applied to of said pharmaceutical composition is united and is carried out.In other embodiments, said other treatment is radiotherapy, chemotherapy or the combination of the two.In other embodiments, said pharmaceutical composition comprises formula I compound at pharmacy acceptable salt.
In other respects, the present invention relates to suppress the method for MEK enzyme.Said method comprises the compsn that makes said MEK enzyme contact effective inhibitory amount, thereby suppresses the MEK enzyme, and wherein said compsn comprises formula I compound or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.In some embodiments, the present invention relates to the method that selectivity suppresses the MEK enzyme.
In other respects, the present invention relates to formula I compound or its are used for suppressing the pharmaceutical composition of MEK enzyme in vegetation at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug application.
In other embodiments, said enzyme is suppressed at least 1%.In other embodiments, said enzyme is suppressed at least 2%.In other embodiments, said enzyme is suppressed at least 3%.In other embodiments, said enzyme is suppressed at least 4%.In other embodiments, said enzyme is suppressed at least 5%.In other embodiments, said enzyme is suppressed at least 10%.In other embodiments, said enzyme is suppressed at least 20%.In other embodiments, said enzyme is suppressed at least 25%.In other embodiments, said enzyme is suppressed at least 30%.In other embodiments, said enzyme is suppressed at least 40%.In other embodiments, said enzyme is suppressed at least 50%.In other embodiments, said enzyme is suppressed at least 60%.In other embodiments, said enzyme is suppressed at least 70%.In other embodiments, said enzyme is suppressed at least 75%.In other embodiments, said enzyme is suppressed at least 80%.In other embodiments, said enzyme is suppressed at least 90%.In other embodiments, said enzyme is suppressed basically fully.In other embodiments, the MEK enzyme is the MEK kinases.In other embodiments, the MEK enzyme is MEK1.In other embodiments, the MEK enzyme is MEK2.In some embodiments, compound of the present invention optionally suppresses MEK1 enzyme or MEK2 enzyme.In some other embodiments, compound of the present invention possibly not have selectivity between MEK1 enzyme and MEK2 enzyme.In other embodiments, in cell, come in contact.In other embodiments, said cell is a mammalian cell.In other embodiments, said mammalian cell is the human cell.In other embodiments, the MEK enzyme is suppressed at pharmacy acceptable salt by formula I compound or its.
In other respects; The present invention relates to treat the method for the individuality of suffering from the illness that mediates by MEK; Said method comprises the pharmaceutical composition to said individual administering therapeutic significant quantity, and said pharmaceutical composition comprises formula I compound or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
In other respects, the present invention relates to formula I compound or its and be used for suppressing application in preparation by the pharmaceutical composition of the illness of MEK mediation at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
In some embodiments, comprise formula I compound the pharmaceutical composition administered through oral, use through duodenum, parenteral (comprising in intravenously, subcutaneous, intramuscular, the blood vessel or), local (topicaladministration) or the per rectum of using through the infusion mode.In some embodiments, said pharmaceutical composition is an oral dosage form.In other embodiments; In the said embodiment; The formulation of said pharmaceutical composition is oral tablet, capsule, pill, pulvis, slow release formulation, solution and suspension-s; Be used for sterile solution, suspension-s or emulsion that parenteral is injected, be used for the ointment or the emulsifiable paste of topical, perhaps be used for the suppository of rectal administration.In other embodiments, said pharmaceutical composition is the unit dosage that is fit to bestow the single exact dosage desired.In other embodiments, said pharmaceutical composition also comprises pharmaceutical carrier, vehicle and/or auxiliary agent.In other embodiments, the amount of formula I compound is in the scope of about 0.001～about 1000 mg/kg body weight/day.In other embodiments, the scope of the amount of formula I compound is about 0.5～about 50 mg/kg body weight/day.In some embodiments, the amount of formula I compound is in about 0.001～about 7 gram/skies.In other embodiments, the amount of formula I compound is in about 0.01～about 7 gram/skies.In other embodiments, the amount of formula I compound is in about 0.02～about 5 gram/skies.In other embodiments, the amount of formula I compound is in about 0.05～about 2.5 gram/skies.In other embodiments, the amount of formula I compound is in about 0.1～about 1 gram/sky.In other embodiments, the dosage level that is lower than above-mentioned scope lower limit possibly be enough.The dosage level that possibly be higher than in other embodiments, above-mentioned range limit.In other embodiments, bestow formula I compound with single dose, once a day.In other embodiments, bestow formula I compound with multiple doses, every day more than once.In other embodiments, use quadratic expression I compound every day.In other embodiments, use cubic expression tertiary I compound every day.In other embodiments, use quarternary quantic I compound every day.In other embodiments, use four every day with following formula I compound.In some embodiments, the individuality of the illness of the said MEK of suffering from mediation is a Mammals.In other embodiments, said individuality is the people.In some embodiments, comprising using of formula I compound compositions unites with other treatment and to carry out.In other embodiments, said other treatment is radiotherapy, chemotherapy or the combination of the two.In some embodiments, will comprise formula I compound compositions and at least a therapeutical agent combined administration.In some embodiments, said therapeutical agent is selected from the group of cell toxicant material, anti-angiogenic formation agent and antineoplastic agent.In other embodiments, antineoplastic agent is selected from the group of being made up of alkylating agent, metabolic antagonist, teniposide, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum complex, biological response modifier and growth inhibitor, hormone/hormone antagonist therapeutical agent and hemopoieticgrowth factor.In other embodiments, said therapeutical agent be selected from taxol, Velcade or both.In some embodiments, said illness by the MEK mediation is selected from the group of being made up of excess proliferative disease, tumour (tumor), white blood disease, vegetation (neopalsms), cancer (cancer), malignant tumor (carcinoma), metabolic trouble, malignant disease, vascular restenosis, psoriatic, arteriosclerosis, rheumatoid arthritis, osteo-arthritis, heart failure, chronic pain, neuropathic pain, xerophthalmia, angle closure glaucoma and the wide-angle glaucoma of diseases associated with inflammation, infection, autoimmune disorder, apoplexy, ischemic, heart trouble, nervous system disorders, fibrotic disease, proliferative disease, excess proliferative disease, non-cancer.In other embodiments, the disease of said MEK mediation is a diseases associated with inflammation.In other embodiments, the disease of said MEK mediation is an excess proliferative disease.In other embodiments, the disease of said MEK mediation is selected from the group of being made up of tumour, white blood disease, vegetation, cancer, malignant tumor and malignant disease.In other embodiments, said cancer is the cancer of the brain, mammary cancer, lung cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, kidney, colorectal cancer or white blood disease.In other embodiments, said fibrotic disease is scleroderma, polymyositis, systemic lupus erythematous, rheumatoid arthritis, liver cirrhosis, cicatrization, interstitial nephritis or pulmonary fibrosis.In other embodiments, use be significant quantity comprise the compsn of formula I compound at pharmacy acceptable salt.
In other respects; The present invention relates to make the method for cancer cells degeneration (degrade), anticancer growth or kill cancer cell; Said method comprises said cells contacting; Its amount can effectively make the compsn of cancer cells degeneration, anticancer growth or kill cancer cell, and said compsn comprises formula I compound or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
In other respects, the present invention relates to that formula I compound or its are used to make in preparation that cancer cells is degenerated at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug, the application on the pharmaceutical composition of anticancer growth or kill cancer cell.
In some embodiments, said cancer cells comprises brain cancer cell, breast cancer cell, lung carcinoma cell, ovarian cancer cell, prostate cancer cell, kidney cancer cell or colorectal cancer cell.In other embodiments, said compsn uses with at least a therapeutical agent.In other embodiments, said therapeutical agent be taxol, Velcade or both.In other embodiments, said therapeutical agent is selected from by the cell toxicant material, anti-angiogenicly forms the group that agent and antineoplastic agent are formed.In other embodiments, antineoplastic agent is selected from the group of being made up of alkylating agent, metabolic antagonist, teniposide, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum complex, biological response modifier and growth inhibitor, hormone/hormone antagonist therapeutical agent and hemopoieticgrowth factor.In some embodiments, cancer cells is degenerated.In other embodiments, 1% cancer cells is degenerated.In other embodiments, 2% cancer cells is degenerated.In other embodiments, 3% cancer cells is degenerated.In other embodiments, 4% cancer cells is degenerated.In other embodiments, 5% cancer cells is degenerated.In other embodiments, 10% cancer cells is degenerated.In other embodiments, 20% cancer cells is degenerated.In other embodiments, 25% cancer cells is degenerated.In other embodiments, 30% cancer cells is degenerated.In other embodiments, 40% cancer cells is degenerated.In other embodiments, 50% cancer cells is degenerated.In other embodiments, 60% cancer cells is degenerated.In other embodiments, 70% cancer cells is degenerated.In other embodiments, 75% cancer cells is degenerated.In other embodiments, 80% cancer cells is degenerated.In other embodiments, 90% cancer cells is degenerated.In other embodiments, 100% cancer cells is degenerated.In other embodiments, all basically cancer cells are all degenerated.In some embodiments, cancer cells is killed.In other embodiments, 1% cancer cells is killed.In other embodiments, 2% cancer cells is killed.In other embodiments, 3% cancer cells is killed.In other embodiments, 4% cancer cells is killed.In other embodiments, 5% cancer cells is killed.In other embodiments, 10% cancer cells is killed.In other embodiments, 20% cancer cells is killed.In other embodiments, 25% cancer cells is killed.In other embodiments, 30% cancer cells is killed.In other embodiments, 40% cancer cells is killed.In other embodiments, 50% cancer cells is killed.In other embodiments, 60% cancer cells is killed.In other embodiments, 70% cancer cells is killed.In other embodiments, 80% cancer cells is killed.In other embodiments, 90% cancer cells is killed.In other embodiments, 100% cancer cells is killed.In other embodiments, all basically cancer cells all are killed.In some embodiments, the growth of cancer cells is suppressed.In other embodiments, the growth of cancer cells is suppressed 1%.In other embodiments, the growth of cancer cells is suppressed 2%.In other embodiments, the growth of cancer cells is suppressed 3%.In other embodiments, the growth of cancer cells is suppressed 4%.In other embodiments, the growth of cancer cells is suppressed 5%.In other embodiments, the growth of cancer cells is suppressed 10%.In other embodiments, the growth of cancer cells is suppressed 20%.In other embodiments, the growth of cancer cells is suppressed 25%.In other embodiments, the growth of cancer cells is suppressed 30%.In other embodiments, the growth of cancer cells is suppressed 40%.In other embodiments, the growth of cancer cells is suppressed 50%.In other embodiments, the growth of cancer cells is suppressed 60%.In other embodiments, the growth of cancer cells is suppressed 70%.In other embodiments, the growth of cancer cells is suppressed 75%.In other embodiments, the growth of cancer cells is suppressed 80%.In other embodiments, the growth of cancer cells is suppressed 90%.In other embodiments, the growth of cancer cells is suppressed 100%.What use in some embodiments, is to comprise formula I compound or its compsn at pharmacy acceptable salt.
In other respects; The present invention relates to treat or prevent the method for individual proliferative disease; Said method comprises pharmaceutical composition from significant quantity to said individuality that use, and said pharmaceutical composition comprises formula I compound or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
In other respects, the present invention relates to comprise formula I compound or it is used for treating and preventing the application of the pharmaceutical composition of proliferative disease in preparation at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
In some embodiments, said proliferative disease is cancer, psoriatic, restenosis, autoimmune disorder or arteriosclerosis.In other embodiments, said proliferative disease is an excess proliferative disease.In other embodiments, said excess proliferative disease is selected from the group of being made up of tumour, white blood disease, vegetation, cancer, malignant tumor and malignant disease.In other embodiments, said cancer is the cancer of the brain, mammary cancer, lung cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, kidney, colorectal cancer or white blood disease.In other embodiments, said fibrotic disease is scleroderma, polymyositis, male lupus erythematosus, rheumatoid arthritis, liver cirrhosis, cicatrization, interstitial nephritis or pulmonary fibrosis.In other embodiments, said cancer is the cancer of the brain, mammary cancer, lung cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, kidney, colorectal cancer or white blood disease.In other embodiments, said cancer is the cancer of the brain or adrenocortical carcinoma.In other embodiments, said cancer is a mammary cancer.In other embodiments, said cancer is an ovarian cancer.In other embodiments, said cancer is a carcinoma of the pancreas.In other embodiments, said cancer is a prostate cancer.In other embodiments, said cancer is a kidney.In other embodiments, said cancer is a colorectal cancer.In other embodiments, said cancer is a myelocytic leukemia.In other embodiments, said cancer is a glioblastoma multiforme.In other embodiments, said cancer is a follicular lymphoma.In other embodiments, said cancer is the impatient property of a pre B cell white blood disease.In other embodiments, said cancer is a Type B lymphatic chronic leukemia.In other embodiments, said cancer is a mesothelioma.In other embodiments, said cancer is that minicell is a cancer.In some embodiments, will comprise formula I compound compositions to be applied to other treatment linked together.In other embodiments, said other treatment is radiotherapy, chemotherapy or the combination of the two.In other embodiments, will comprise formula I compound compositions and at least a therapeutical agent combined administration.In other embodiments, selected therapeutical agent is selected from the group of cell toxicant material, anti-angiogenic formation agent and antineoplastic agent.In other embodiments; Said antineoplastic agent is selected from the group of being made up of alkylating agent, metabolic antagonist, teniposide, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum complex, biological response modifier and growth inhibitor, hormone/hormone antagonist therapeutical agent and hemopoieticgrowth factor.In other embodiments, said therapeutical agent be selected from taxol, Velcade or both.In some embodiments, administered through oral, use said compsn through duodenum, parenteral (comprise in intravenously, subcutaneous, intramuscular, the blood vessel or pass through infusion), topical application or per rectum.In other embodiments, the scope of the amount of formula I compound is about 0.001～about 1000 mg/kg body weight/day.In other embodiments, the scope of the amount of formula I compound is about 0.05～about 50 mg/kg body weight/day.In other embodiments, the scope of the amount of formula I compound is about 0.001～about 7 gram/kg body weight/sky.In other embodiments, the scope of the amount of formula I compound is about 0.01～about 7 gram/kg body weight/sky.In other embodiments, the scope of the amount of formula I compound is about 0.02～about 5 gram/kg body weight/sky.In other embodiments, the scope of the amount of formula I compound is about 0.05～about 2.5 gram/kg body weight/sky.In other embodiments, the scope of the amount of formula I compound is about 0.1～about 1 gram/kg body weight/sky.In other embodiments, the dosage level that is lower than above-mentioned scope lower limit possibly be enough.In other embodiments, possibly be higher than the dosage level that seems on the above-mentioned scope.In other embodiments, formula I compound is with single dose administration, once a day.In other embodiments, formula I compound is with multiple dose administration, and every day more than once.In other embodiments, use quadratic expression I compound every day.In other embodiments, use cubic expression tertiary I compound every day.In other embodiments, use quarternary quantic I compound every day.In other embodiments, use four every day with following formula I compound.In some embodiments, the individuality of suffering from proliferative disease is a Mammals.In other embodiments, said individuality is the people.In other embodiments, use be significant quantity comprise the compsn of formula I compound at pharmacy acceptable salt.
In other respects; The present invention relates to treat or prevent the method for individual diseases associated with inflammation; Said method comprises pharmaceutical composition from significant quantity to said individuality that use, and said pharmaceutical composition comprises formula I compound or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
In other respects, the present invention relates to comprise formula I compound or its is used for treating or the application of the pharmaceutical composition of preventing inflammation property disease in preparation at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
In other embodiments, diseases associated with inflammation is selected from the group of being made up of chronic inflammation disease, rheumatoid arthritis, SpA, urarthritis, osteo-arthritis, property childhood sacroiliitis, acute rheumatic arthritis, enteropathic arthritis, neurarthropathy, psoriatic arthritis, suppurative arthritis, arteriosclerosis, systemic lupus erythematous, inflammatory intestinal tract disease, irritable bowel syndrome, ulcerative colitis, reflux esophagitis, regional enteritis (Crohn ' s disease), gastritis, asthma, anaphylaxy, respiratory distress syndrome, pancreatitis, chronic obstructive pulmonary disease, pulmonary fibrosis, psoriatic, eczema or scleroderma.In some embodiments, it is linked together to comprise using with other treatment of formula I compound compositions.In other embodiments, will comprise formula I compound compositions and at least a therapeutical agent combined administration.In some embodiments, administered through oral, use composition therefor through duodenum, parenteral (comprise in intravenously, subcutaneous, intramuscular, the blood vessel or pass through infusion), topical application or per rectum.In other embodiments, the scope of the amount of formula I compound is about 0.001～about 1000 mg/kg body weight/day.In other embodiments, the scope of the amount of formula I compound is about 0.05～about 50 mg/kg body weight/day.In other embodiments, the scope of the amount of formula I compound is about 0.001～about 7 gram/kg body weight/sky.In other embodiments, the scope of the amount of formula I compound is about 0.01～about 7 gram/kg body weight/sky.In other embodiments, the scope of the amount of formula I compound is about 0.02～about 5 gram/kg body weight/sky.In other embodiments, the scope of the amount of formula I compound is about 0.05～about 2.5 gram/kg body weight/sky.In other embodiments, the scope of the amount of formula I compound is about 0.1～about 1 gram/kg body weight/sky.In other embodiments, the dosage level that is lower than above-mentioned scope lower limit possibly be enough.In other embodiments, possibly be higher than the dosage level that seems on the above-mentioned scope.In other embodiments, formula I compound is with single dose administration, once a day.In other embodiments, formula I compound is with multiple dose administration, and every day more than once.In other embodiments, use quadratic expression I compound every day.In other embodiments, use cubic expression tertiary I compound every day.In other embodiments, use quarternary quantic I compound every day.In other embodiments, use four every day with following formula I compound.In some embodiments, the individuality of suffering from diseases associated with inflammation is a Mammals.In other embodiments, said individuality is human.In other embodiments, use be significant quantity comprise the compsn of formula I compound at pharmacy acceptable salt.
In other respects, the present invention relates to treat or prevent the method for individual cancers.Said method comprises pharmaceutical composition from significant quantity to said individuality that use, and said pharmaceutical composition comprises formula I compound or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
In other respects, the present invention relates to comprise formula I compound or its is used for treating or the application of the pharmaceutical composition of preventing cancer in preparation at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
In other embodiments, said cancer is the cancer of the brain, mammary cancer, lung cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, kidney, colorectal cancer or white blood disease.In other embodiments, affiliated fibrotic disease is scleroderma, polymyositis, systemic lupus erythematous, rheumatoid arthritis, liver cirrhosis, cicatrization, interstitial nephritis or pulmonary fibrosis.In other embodiments, said cancer is the cancer of the brain, mammary cancer, lung cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, kidney, colorectal cancer or white blood disease.In other embodiments, said cancer is the cancer of the brain or adrenocortical carcinoma.In other embodiments, said cancer is a mammary cancer.In other embodiments, said cancer is an ovarian cancer.In other embodiments, said cancer is a carcinoma of the pancreas.In other embodiments, said cancer is a prostate cancer.In other embodiments, said cancer is a kidney.In other embodiments, said cancer is a colorectal cancer.In other embodiments, said cancer is a myelocytic leukemia.In other embodiments, said cancer is a glioblastoma multiforme.In other embodiments, said cancer follicular lymphoma.In other embodiments, said cancer is the impatient property of a pre B cell white blood disease.In other embodiments, said cancer is a Type B lymphatic chronic leukemia.In other embodiments, said cancer is a mesothelioma.In other embodiments, said cancer is that minicell is a cancer.In some embodiments, it is linked together to comprise using with other treatment of formula I compound compositions.In other embodiments, said other treatment is radiotherapy, chemotherapy or the combination of the two.In other embodiments, will comprise formula I compound compositions and at least a therapeutical agent combined administration.In other embodiments, selected therapeutical agent is selected from the group of cell toxicant material, anti-angiogenic formation agent and antineoplastic agent.In other embodiments; Said antineoplastic agent is selected from the group of being made up of alkylating agent, metabolic antagonist, teniposide, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum complex, biological response modifier and growth inhibitor, hormone/hormone antagonist therapeutical agent and hemopoieticgrowth factor.In other embodiments, said therapeutical agent be selected from taxol, Velcade or both.In some embodiments, administered through oral, use said compsn through duodenum, parenteral (comprise in intravenously, subcutaneous, intramuscular, the blood vessel or pass through infusion), topical application or per rectum.In other embodiments, the scope of the amount of formula I compound is about 0.001～about 1000 mg/kg body weight/day.In other embodiments, the scope of the amount of formula I compound is about 0.05 about 50 mg/kg body weight/day.In other embodiments, the scope of the amount of formula I compound is about 0.001～about 7 gram/kg body weight/sky.In other embodiments, the scope of the amount of formula I compound is about 0.01～about 7 gram/kg body weight/sky.In other embodiments, the scope of the amount of formula I compound is about 0.02 about 5 gram/kg body weight/sky.In other embodiments, the scope of the amount of formula I compound is about 0.05 about 2.5 gram/kg body weight/sky.In other embodiments, the scope of the amount of formula I compound is about 0.1～about 1 gram/kg body weight/sky.In other embodiments, the dosage level that is lower than above-mentioned scope lower limit possibly be enough.In other embodiments, possibly be higher than the dosage level that seems on the above-mentioned scope.In other embodiments, formula I compound is with single dose administration, once a day.In other embodiments, formula I compound is with multiple dose administration, and every day more than once.In other embodiments, use quadratic expression I compound every day.In other embodiments, use cubic expression tertiary I compound every day.In other embodiments, use quarternary quantic I compound every day.In other embodiments, use four every day with following formula I compound.In some embodiments, the individuality of suffering from proliferative disease is a Mammals.In other embodiments, said individuality is the people.In other embodiments, use be significant quantity comprise the compsn of formula I compound at pharmacy acceptable salt.
In other respects; The present invention relates to reduce gross tumor volume in the individual's body, suppress the method that gross tumor volume increases, reduces tumor proliferation or suppresses tumor proliferation; Said method comprises the pharmaceutical composition to said individual administering therapeutic significant quantity, and said pharmaceutical composition comprises formula I compound or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
In other respects; The present invention relates to formula I compound or its in the application in pharmaceutical compositions of pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug, said pharmaceutical composition is used to reduce gross tumor volume, suppress gross tumor volume increases, reduces tumor proliferation or suppress tumor proliferation.
In some embodiments, gross tumor volume reduces.In other embodiments, gross tumor volume reduces at least 1%.In other embodiments, gross tumor volume reduces at least 2%.In other embodiments, gross tumor volume reduces at least 3%.In other embodiments, gross tumor volume reduces at least 4%.In other embodiments, gross tumor volume reduces at least 5%.In other embodiments, gross tumor volume reduces at least 10%.In other embodiments, gross tumor volume reduces at least 20%.In other embodiments, gross tumor volume reduces at least 25%.In other embodiments, gross tumor volume reduces at least 30%.In other embodiments, gross tumor volume reduces at least 40%.In other embodiments, gross tumor volume reduces at least 50%.In other embodiments, gross tumor volume reduces at least 60%.In other embodiments, gross tumor volume reduces at least 70%.In other embodiments, gross tumor volume reduces at least 75%.In other embodiments, gross tumor volume reduces at least 80%.In other embodiments, gross tumor volume reduces at least 85%.In other embodiments, gross tumor volume reduces at least 90%.In other embodiments, gross tumor volume reduces at least 95%.In other embodiments, said tumour is uprooted.In some embodiments, gross tumor volume no longer increases.In some embodiments, tumor proliferation descends at least 1%.In some embodiments, tumor proliferation descends at least 2%.In some embodiments, tumor proliferation descends at least 3%.In some embodiments, tumor proliferation descends at least 4%.In some embodiments, tumor proliferation descends at least 5%.In some embodiments, tumor proliferation descends at least 10%.In some embodiments, tumor proliferation descends at least 20%.In some embodiments, tumor proliferation descends at least 25%.In some embodiments, tumor proliferation descends at least 30%.In some embodiments, tumor proliferation descends at least 40%.In some embodiments, tumor proliferation descends at least 50%.In some embodiments, tumor proliferation descends at least 60%.In some embodiments, tumor proliferation descends at least 70%.In some embodiments, tumor proliferation descends at least 75%.In some embodiments, tumor proliferation descends at least 80%.In some embodiments, tumor proliferation descends at least 90%.In some embodiments, tumor proliferation descends at least 95%.In some embodiments, tumor proliferation is prevented from.In some embodiments, it is linked together to comprise using with other treatment of formula I compound compositions.In other embodiments, said other treatment is radiotherapy, chemotherapy or the combination of the two.In other embodiments, will comprise formula I compound compositions and at least a therapeutical agent combined administration.In other embodiments, selected therapeutical agent is selected from the group of cell toxicant material, anti-angiogenic formation agent and antineoplastic agent.In other embodiments; Said antineoplastic agent is selected from the group of being made up of alkylating agent, metabolic antagonist, teniposide, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum complex, biological response modifier and growth inhibitor, hormone/hormone antagonist therapeutical agent and hemopoieticgrowth factor.In other embodiments, said therapeutical agent be selected from taxol, Velcade or both.In some embodiments, administered through oral, use said compsn through duodenum, parenteral (comprise in intravenously, subcutaneous, intramuscular, the blood vessel or pass through infusion), topical application or per rectum.In other embodiments, the scope of the amount of formula I compound is about 0.001～about 1000 mg/kg body weight/day.In other embodiments, the scope of the amount of formula I compound is about 0.05～about 50 mg/kg body weight/day.In other embodiments, the scope of the amount of formula I compound is about 0.001～about 7 gram/kg body weight/sky.In other embodiments, the scope of the amount of formula I compound is about 0.01～about 7 gram/kg body weight/sky.In other embodiments, the scope of the amount of formula I compound is about 0.02～about 5 gram/kg body weight/sky.In other embodiments, the scope of the amount of formula I compound is about 0.05～about 2.5 gram/kg body weight/sky.In other embodiments, the scope of the amount of formula I compound is about 0.1～about 1 gram/kg body weight/sky.In other embodiments, the dosage level that is lower than above-mentioned scope lower limit possibly be enough.In other embodiments, possibly be higher than the dosage level that seems on the above-mentioned scope.In other embodiments, formula I compound is with single dose administration, once a day.In other embodiments, formula I compound is with multiple dose administration, and every day more than once.In other embodiments, use quadratic expression I compound every day.In other embodiments, use cubic expression tertiary I compound every day.In other embodiments, use quarternary quantic I compound every day.In other embodiments, use four every day with following formula I compound.In some embodiments, the individuality of suffering from cancer is a Mammals.In other embodiments, said individuality is the people.In other embodiments, use be significant quantity comprise the compsn of formula I compound at pharmacy acceptable salt.
In other respects; The present invention relates to the patient is produced the method for curative effect; Wherein said curative effect is selected from and suppresses multiple cancer, inhibition immunological disease and/or diseases associated with inflammation; Said method comprises pharmaceutical composition from significant quantity to said patient that use, and said pharmaceutical composition comprises formula I compound or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.In some embodiments, said curative effect is for suppressing multiple cancer.In other embodiments, said curative effect is for suppressing immunological disease.In other embodiments, said curative effect is an inflammation-inhibiting property disease.
In other respects, the present invention relates to comprise formula I compound or its are used for suppressing the pharmaceutical composition of multiple cancer, immunological disease and/or diseases associated with inflammation in preparation at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug application.
In some embodiments, it is linked together to comprise using with other treatment of formula I compound compositions.In other embodiments, said other treatment is radiotherapy, chemotherapy or the combination of the two.In other embodiments, will comprise formula I compound compositions and at least a therapeutical agent combined administration.In some embodiments, administered through oral, use said compsn through duodenum, parenteral (comprise in intravenously, subcutaneous, intramuscular, the blood vessel or pass through infusion), topical application or per rectum.In other embodiments, the scope of the amount of formula I compound is about 0.001～about 1000 mg/kg body weight/day.In other embodiments, the scope of the amount of formula I compound is about 0.05 about 50 mg/kg body weight/day.In other embodiments, the scope of the amount of formula I compound is about 0.001～about 7 gram/kg body weight/sky.In other embodiments, the scope of the amount of formula I compound is about 0.01～about 7 gram/kg body weight/sky.In other embodiments, the scope of the amount of formula I compound is about 0.02 about 5 gram/kg body weight/sky.In other embodiments, the scope of the amount of formula I compound is about 0.05～about 2.5 gram/kg body weight/sky.In other embodiments, the scope of the amount of formula I compound is about 0.1～about 1 gram/kg body weight/sky.In other embodiments, the dosage level that is lower than above-mentioned scope lower limit possibly be enough.In other embodiments, possibly be higher than the dosage level that seems on the above-mentioned scope.In other embodiments, formula I compound is with single dose administration, once a day.In other embodiments, formula I compound is with multiple dose administration, and every day more than once.In other embodiments, use quadratic expression I compound every day.In other embodiments, use cubic expression tertiary I compound every day.In other embodiments, use quarternary quantic I compound every day.In other embodiments, use four every day with following formula I compound.In some embodiments, use be significant quantity comprise formula I compound or its compsn at pharmacy acceptable salt.
In other respects, the present invention relates to formula I compound or its preparation method at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
Specify
Claims of the present invention have been stated new feature of the present invention especially.Stated the exemplary of utilizing the principle of the invention in the detailed Description Of The Invention hereinafter.Through understanding feature and advantage of the present invention better with reference to summary of the invention once.
Although this paper has described the preferred embodiments of the invention, these embodiments only provide as an example.The variant that should understand embodiment of the present invention as herein described also can be used for embodiment of the present invention.Those of ordinary skills should be understood that and multiple variant, variation and replacement can occur and do not depart from the scope of the present invention.The claim decision of having the right of the protection domain that should understand all respects of the present invention, and the method and structure in these claim scopes with and method and structure of equal value all within the scope that these claims are contained.
Sub-section titles used herein only is used to organize the purpose of article, and should not be interpreted as the restriction to said main body.All documents or the literature department branch quoted among the application include but not limited to patent, patented claim, article, books, operational manual and paper, and all mode integral body is incorporated this paper into by reference.
Some technical term of chemistry
Only if definition is arranged in addition, otherwise the connotation that this paper reason scientific and technical terminology has is identical with the connotation of claim main body one of ordinary skill in the art common sense.Except as otherwise noted, all patents of quoting in full of this paper, patented claim, open material by reference mode integral body incorporate this paper into.If this paper has a plurality of definition to term, be as the criterion with the definition of this chapter.When quoting URL or other this class identifiers or address, should understand this class identifier and can change also and can exchange with the specifying information on the internet, also can obtain corresponding information through internet retrieval or other bibliography channels that is fit to.The availability and the public propagation property of the bibliography proof this type of information that is obtained.
Should be understood that above-mentioned summary and close being specified as of hereinafter exemplary and only be used for explaining, and main body of the present invention is not done any restriction.In this application,, otherwise also comprise plural number when using odd number, must be noted that only if clearly explanation is arranged in the literary composition in addition, otherwise used singulative comprises the plural form of indication things in this specification sheets and claims only if specify in addition.It shall yet further be noted that except as otherwise noted, otherwise all " or ", " perhaps " expression " and/or ".In addition, used term " comprises " and other forms, for example " comprises ", " containing " and " containing " and non-limiting.
Can (comprise Carey and Sundberg " ADVANCED ORGANICCHEMISTRY 4 at reference THED. " Vols.A (2000) and B (2001), Plenum Press, New York.) in find definition to the standard chemical term.Except as otherwise noted, otherwise adopt the ordinary method in the art technology scope, like mass spectrum, NMR, IR and UV/Vis spectrography and pharmacological method.Only if propose concrete definition, otherwise the term of this paper employing in analytical chemistry, Synthetic Organic Chemistry and medicine and pharmaceutical chemical relevant the description is known in the art.Can and send at chemosynthesis, chemical analysis, medication preparation, preparation, and the standard technique of using in the treatment to the patient.For example, manufacturer capable of using perhaps implements reaction and carries out purifying according to mode well known in the art or explanation of the present invention the operation instruction of test kit.Usually can implement above-mentioned technology and method according to ordinary method well known in the art according to the description in a plurality of outlined quoting in this specification sheets and discuss and the more concrete document.In this manual, can select group and substituting group thereof so that stable structure part and compound to be provided by those skilled in the art.
When describing substituting group through the conventional chemical formula of writing from left to right, the resulting substituting group that chemically is being equal to when this substituting group comprises the structural formula of writing from right to left too.For example, CH 2O is equal to OCH 2
Except as otherwise noted, otherwise used universalization technics, such as but not limited to, " alkyl ", " amine ", " aryl " are equal to its optional substituted form.For example, " alkyl " used herein comprises optional substituted alkyl.
Compound described herein can have one or more stereogenic centres, and each isomery center can exist with the form of R or S configuration or its combination.Similarly, compound described herein can have one or more pairs of keys, and each pair key can exist with the form of E (trans) or Z (cis) configuration or its combination.Specific steric isomer, constitutional isomer (regioisomer), diastereomer, enantiomer or an epimer should be understood to include all possible steric isomer, constitutional isomer, diastereomer, enantiomer or epimer and composition thereof.Therefore, compound described herein comprise steric isomers different on all configurations, constitutional isomer, diastereomer, enantiomer or epimer with and corresponding mixture.Be used to the technology that transforms particular stereoisomer or particular stereoisomer is maintained the original state, and it is well known in the art to split the technological thing of stereoisomer mixture, those skilled in the art can select the method that is fit to regard to particular case.Referring to, Fumiss et al. (eds.) for example, VOGEL ' SENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991,809-816; And Heller, Acc.Chem.Res.1990,23,128.
Term used herein " part ", " structure division ", " chemical part ", " group ", " chemical group " are meant particular segment or the functional group in the molecule.Chemical part is considered to embed or append to the chemical formula body on the molecule usually.
Term " key " or " singly-bound " are meant, through key two atoms or two parts are linked to each other and obtain the more chemical bond of macrostructure part.
Term " catalytic group " is meant through its effect and reduces the activated energy barrier of reaction, thereby helps catalytic chemical functional group.
Term " optional/arbitrarily " or " randomly/at random " are meant that incident or situation that the institute back is described possibly take place or possibly not take place, and this description comprises generation said incident or situation and said incident and situation do not take place.For example according to the definition of hereinafter, " optional substituted alkyl " is meant " unsubstituted alkyl " (not being substituted basic substituted alkyl) or " substituted alkyl " (being substituted basic substituted alkyl).In addition, optional substituted group can be not to be substituted (like CH 2CH 3), replace (like CF fully 3CF 3), single (CH that replaces 2CH 2F) or fully the replacement degree between replacing and singly replacing is (like CH 2CHF 2, CF 2CH 3, CFHCHF 2Deng).Those skilled in the art can understand; For comprising one or more substituent any groups; Can not be introduced into any spatially can not exist and/or can not synthetic replace or substitute mode (for example, substituted alkyl comprises optional substituted naphthenic base, otherwise; Naphthenic base is defined as and comprises optional substituted alkyl, so repeatedly).Therefore, said substituting group should be understood that usually maximum molecular weight is about 1,000 dalton, more generally, and the most about 500 dalton (except that obviously needing the substituent situation of macromole, for example polypeptide, polysaccharide, polyoxyethylene glycol, DNA and RNA etc.).
C used herein 1-C nComprise C 1-C 2, C 1-C 3... C 1-C nFor example, said " C 1-C 4" group is meant to have 1-4 carbon atom in this part, promptly group comprises 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.Scope C 1-C 2And C 1-C 3Definition similarly.Therefore, " C for example 1-C 4Alkyl " be meant that at the alkyl that 1-4 carbon atom arranged promptly said alkyl is selected from methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec.-butyl and the tertiary butyl.Digital scope among this paper; For example " 1-10 " is meant each integer in the given range, and for example " 1-10 carbon atom " is meant that this group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
The term that this paper is used alone or in combination " hydrocarbon " is meant compound or the chemical group that only comprises carbon atom and Wasserstoffatoms.
This paper makes up separately or combination is used term " heteroatoms " or " mixing " are meant the atom outside de-carbon and the hydrogen.Heteroatoms is independently selected from oxygen, nitrogen, sulphur, phosphorus, silicon, selenium and tin, but is not limited to these atoms.In two or more heteroatomic embodiments occurring, said two or more heteroatomss can be mutually the same, perhaps under in two or more heteroatomss some or all differ from one another.
The term that this paper is used alone or in combination " alkyl " is meant the monovalence stable hydrocarbon of optional substituted straight chain or optional substituted side chain, and it has about 10 carbon atoms of 1-, more preferably about 6 carbon atoms of 1-.Instance includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, 2-methyl isophthalic acid-propyl group, 2-methyl-2-propyl group, 2-methyl-1-butene base, 3-methyl-butyl, 2-methyl-3-butyl, 2; 2-dimethyl--1-propyl group, 2-methyl-1-pentene base, 3-methyl-1-pentene base, 4-methyl-1-pentene base, 2-methyl-2-amyl group, 3-methyl-2-amyl group, 4-methyl-2-amyl group, 2; 2-dimethyl--1-butyl, 3; 3-dimethyl--1-butyl, 2-ethyl-1-butyl, normal-butyl, isobutyl-, sec.-butyl, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, tert-pentyl and hexyl; And longer alkyl group, like heptyl and octyl group etc.The group of this paper definition, like " alkyl " when digital scope occurring, " C for example 1-C6 alkyl " or " C 1-6 alkyl " being meant can be by 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 alkyl that carbon atom constitutes, and the alkyl of this paper also comprises the not situation of designation number scope.
The term that this paper is used alone or in combination " alkylidene group " is meant the univalent alkyl deutero-divalent group by above-mentioned definition.Instance includes but not limited to methylene radical (CH 2), ethylidene (CH 2CH 2), propylidene (CH 2CH 2CH 2) and isopropylidene (CH (CH 3) CH 2) etc.
The term that this paper is used alone or in combination " thiazolinyl " is meant the monovalence alkyl of optional substituted straight chain or optional substituted side chain, and it has the two keys of one or more C=C and has about 10 carbon atoms of 2-, more preferably about 6 carbon atoms of 2-.Two keys in these groups can be cis or transoid conformation, and should be understood that to comprise said two kinds of isomer.Instance includes but not limited to vinyl (CH=CH 2), 1-propenyl (CH 2CH=CH 2), pseudoallyl (C (CH 3)=CH 2), crotonyl and 1,3-butadiene base etc.When digital scope appears in the thiazolinyl of this paper definition, " C for example 2-C 6Thiazolinyl " or " C 2-6Thiazolinyl " being meant can be by 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 thiazolinyl that carbon atom constitutes, and the thiazolinyl of this paper is also contained the not situation of designation number scope.
The term that this paper is used alone or in combination " alkenylene " is meant the monovalence thiazolinyl deutero-divalent group by above-mentioned definition.Instance includes but not limited to that vinylidene (CH=CH) and propenylidene isomer are (like CH 2CH=CH and C (CH 3)=CH) etc.
The term that this paper is used alone or in combination " alkynyl " is meant the monovalence alkyl of optional substituted straight or branched, and it has one or more C ≡ C keys and has about 10 carbon atoms of 2-, more preferably about 6 carbon atoms of 2-.Instance includes but not limited to ethynyl, 2-propynyl, 2-butyne base and 1,3-diacetylene base etc.When digital scope appears in the alkynyl of this paper definition, " C for example 2-C 6Alkynyl " or " C 2-6Alkynyl " being meant can be by 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 alkynyl group that carbon atom constitutes, and the alkynyl of this paper is also contained the not situation of designation number scope.
The term that this paper is used alone or in combination " alkynylene " is meant the monovalence alkynyl deutero-divalent group by above-mentioned definition.Instance includes but not limited to ethynylene (C ≡ C-) and inferior proyl (CH 2C ≡ C-) etc.
The term that this paper is used alone or in combination " aliphatics " be meant optional substituted straight or branched, non-annularity, saturated, part is unsaturated or complete undersaturated non-aromatic hydrocarbon.Therefore, this term comprises alkyl, thiazolinyl and alkynyl group on the whole.
The term that this paper is used alone or in combination " assorted alkyl ", " assorted thiazolinyl " and " assorted alkynyl " refer to optional substituted alkyl, thiazolinyl and alkynyl structure respectively; As indicated above; Wherein one or more skeletal chain carbon atoms (under suitable situation, also comprising continuous Wasserstoffatoms) are replaced by heteroatoms (promptly respectively independently; Other atoms outside the de-carbon are such as but not limited to oxygen, nitrogen, sulphur, silicon, phosphorus, tin or its combination).
The term that this paper is used alone or in combination " haloalkyl ", " haloalkenyl group ", " halo alkynyl " refer to optional substituted alkyl, thiazolinyl and alkynyl structure respectively; As indicated above, wherein one or more Wasserstoffatomss are replaced by fluorine, chlorine, bromine, iodine atom or its combination.In some embodiments, use mutually the same halogen atom to replace two or more Wasserstoffatomss (for example difluoromethyl); In other embodiments, use not identical each other halogen atom to replace two or more Wasserstoffatomss (for example 1-chloro-1-fluoro-1-iodine ethyl).The non-limiting example of haloalkyl is methyl fluoride and bromotrifluoromethane.The non-limiting example of haloalkenyl group is a bromo vinyl.The non-limiting example of halo alkynyl is the chloroethene alkynyl.
The term that this paper is used alone or in combination " perhalogeno " is meant that its all Wasserstoffatomss all are replaced by the group of fluorine, chlorine, bromine, iodine atom or its combination.Therefore, according to the definition of this paper, be meant that like term " whole haloalkyl " its all Wasserstoffatomss all are replaced by the alkyl group of fluorine, chlorine, bromine, iodine atom or its combination.The non-limiting example of whole haloalkyl is a bromine chlorine methyl fluoride.The non-limiting example of perhalogeno alkenyl group is a trichloro-vinyl.The non-limiting example of perhalogeno alkynyl group is the tribromo proyl.
The term that this paper is used alone or in combination " carbochain " is meant any alkyl, thiazolinyl, alkynyl, assorted alkyl, assorted thiazolinyl or assorted alkynyl group, and it can be wire, ring-type or its arbitrary combination.If being joint and this joint, said chain comprises one or more rings as the core skeleton part; So for calculating chain length; Should " chain " only comprise and constitute those carbon atoms of specifying ring bottom or top but not the two all comprises; Under the situation about being uneven in length of ring upper and lower, should use short distance to confirm chain length.If said chain comprises the heteroatoms as the skeleton part, these heteroatomss are not counted in carbon chain lengths.
The term that this paper is used alone or in combination " ring ", " ring-type " and " ... unit's ring " are meant any covalence closed structure as described herein, and it comprises alicyclic ring, heterocycle, aromatic ring, hetero-aromatic ring and encircle more and condenses ring system or encircle the non-condensed ring system more.Ring can be by any replacement.Ring can form fused rings pastern branch.Term " unit " is meant the number of the skeletal atom of makeup ring.Therefore, for example, hexanaphthene, pyridine, pyrans and pyrimidine are six-ring, and pentamethylene, pyrroles, THF and thiophene are five-ring.
The term that this paper is used alone or in combination " condenses " and is meant that its two or more rings have the ring structure of one or more keys jointly.
The term that this paper is used alone or in combination " naphthenic base " is meant optional substituted monovalence stable hydrocarbon ring; It comprises about 15 of 3-and becomes ring carbon atom or about 10 of 3-to become ring carbon atom; Also can comprise as substituent other non-one-tenth ring carbon atoms (for example, methyl cyclopropyl).
The instance of " naphthenic base " includes but not limited to azine group (azinyl), azetidinyl (azetidinyl), oxa-cyclobutyl (oxetanyl), thia cyclobutyl (thietanyl), homopiperidinyl (homopiperidinyl), oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1; 2; 3; 6-tetrahydro pyridyl (1; 2; 3; 6-tetrahydropyridinyl), 2-pyrrolinyl (2-pyrrolinyl), 3-pyrrolinyl (3-pyrrolinyl), indyl (indolinyl), 2H-pyranyl (2H-pyranyl), 4H-pyranyl (4H-pyranyl), dioxacyclohexyl (dioxanyl), 1; The 3-dioxolanyl (1,3-dioxolanyl), pyrazolinyl (pyrazolinyl), two sulphur cyclohexyl (dithianyl), two sulphur cyclopentyl (dithiolanyl), dihydro pyranyl (dihydropyranyl), dihydro-thiophene base (dihydrothienyl), dihydrofuran-base (dihydrofuranyl), pyrazolidyl (pyrazolidinyl), imidazolinyl (imidazolinyl), imidazolidine base (imidazolidinyl), 3-azabicyclic [3.1.0] hexyl (3-azabicyclo [3.1.0] hexyl), 3-azabicyclic [4.1.0] hexyl (3-azabicyclo [4.1.0] heptyl), 3H-indyl (3H-indolyl) and quinolyl (quinolizinyl) etc.This term also comprises all annular form of carbohydrate, includes but not limited to monose, disaccharides and oligosaccharides.
The term that this paper is used alone or in combination " aromatic series/aromatics " is meant the loop section of a ring of planar or a plurality of rings, and it has the electron conjugated system of the delocalizationization that contains 4n+2n electronics, and wherein n is a certificate.Aromatic ring can be formed by the atom more than 5,6,7,8,9 or 9.Aromatic substance can randomly be replaced, and can be many rings of monocycle or fused rings.Term aromatic compound comprises that all contain carbocyclic ring (like phenyl ring) and contain one or more heteroatomic rings (like pyridine).
The term that this paper is used alone or in combination " aromatic base/aryl " is meant optional substituted aryl radical, and it has about 20 of 6-and becomes ring carbon atom, and comprises fused rings and non-condensed aromatic ring.Fused-aryl comprises 2-4 aromatic ring condensed ring, and other free ring can be alicyclic ring, heterocycle, aromatic ring, aromatic heterocycle or its arbitrary combination.In addition, term aryl also comprises and contains 6 to about 12 fused rings and non-condensed rings that become ring carbon atoms, and contains 6 fused rings and non-condensed rings to about 10 one-tenth ring carbon atoms.The non-limiting example of monocyclic aryl comprises phenyl; The fused rings aryl comprises naphthyl, phenanthryl, anthryl, Azulene base; Two aryl of non-condensed comprise xenyl.
The used alone or in combination term " arylidene " of this paper is meant the monovalence aryl deutero-divalent aryl by above-mentioned definition.Instance includes but not limited to 1,2-phenylene, 1,3-phenylene, 1,4-phenylene and 1,2-naphthylidene etc.
The term that this paper is used alone or in combination " heteroaryl " is meant any substituted monovalence aryl; It comprises about 5 and becomes annular atoms to about 20 skeletons; Wherein one or more become annular atoms is heteroatoms; Said heteroatoms is independently selected from the heteroatoms in oxygen, nitrogen, sulphur, phosphorus, silicon, selenium and the tin, but is not limited thereto; Its prerequisite is that the ring of said group does not comprise two adjacent O or S atom.In ring, occur in two or more heteroatomic embodiments, affiliated two or more heteroatomss can be mutually the same, some in perhaps said two each or the more heteroatomss or all differ from one another.Term heteroaryl comprises optional substituted have at least one heteroatomic monovalence condensed or non-condensed heteroaryl.In addition, term heteroaryl comprises that also containing 5 becomes the condensed of annular atoms and the heteroaryl of non-condensed to about 12 skeletons, and contains 5 and become the condensed of annular atoms and the heteroaryl of non-condensed to about 10 skeletons.Can combine with heteroaryl through carbon atom or heteroatoms.Therefore, for example, imidazoles can carbon atom (imidazoles-2-base, imidazol-4 yl or imidazoles-5-yl) or its nitrogen-atoms (imidazoles-1-base or imidazo-3-yl) link to each other with parent molecule arbitrarily through it.Similarly, can pass through its any or whole carbon atoms and/or the further substituted heteroaryl group of any or whole heteroatoms.The condensed heteroaryl can comprise 2-4 aromatic heterocycle phase condensed fused rings, and other free ring can be alicyclic ring, heterocycle, aromatic ring, aromatic heterocycle or its arbitrary combination.The non-limiting example of bicyclic heteroaryl comprises pyridyl; Fused ring heteroaryl comprises benzimidazolyl-(benzimidazolyl), quinolyl (quinolinyl), acridyl (acridinyl), and two heteroaryls of non-condensed comprise bipyridyl (bipyridinyl).Other instance of heteroaryl includes but not limited to: furyl (furanyl), thienyl (thienyl) 、 oxazolyl (oxazolyl), acridyl (acridinyl), phenazinyl (phenazinyl), benzimidazolyl-(benzimidazolyl), benzofuryl (benzofuranyl), benzoxazolyl (benzoxazolyl), benzothiazolyl (benzothiazolyl), diazosulfide base (
Figure BDA0000135908570000331
), benzothienyl (benzothiophenyl), Ben Bing oxadiazole base (benzoxadiazolyl), benzotriazole base (benzotriazolyl), imidazolyl ( ), indyl (indolyl) 、 isoxazolyl (isoxazolyl), isoquinolyl (isoquinolinyl), indyl (indolizinyl), isothiazolyl (isothiazolyl), pseudoindolyl (isoindolyl) 、 oxadiazole base (oxadiazolyl), indazolyl (indazolyl), pyridyl (pyridyl), pyridazinyl (pyridazyl), pyrimidyl (pyrimidyl), pyrazinyl (pyrazinyl), pyrryl (pyrrolyl), pyrazolyl (
Figure BDA0000135908570000333
), purine radicals (purinyl), phthalazinyl (phthalazinyl), pteridyl (pteridinyl), quinolyl (quinolinyl), quinazolyl (quinazolinyl) 、 quinoxalinyl (quinoxalinyl), triazolyl (triazolyl), tetrazyl (tetrazolyl), thiazolyl (thiazolyl), triazinyl (triazinyl) He thiadiazolyl group (thiadiazolyl) etc.; And oxide compound, such as pyridyl-N-oxide compound (pyridyl-N-oxide).
The used alone or in combination term " inferior heteroaryl " of this paper is meant the heteroaryl list radical deutero-diradical by above-mentioned definition.Instance includes but not limited to pyridylidene and inferior pyrimidyl.
The term that this paper is used alone or in combination " heterocyclic radical/heterocycle " is the title that closes of aliphatic heterocycle and heteroaryl.(C for example when this paper middle finger goes out the heterocyclic carbon atom number 1-C 6Heterocycle), certainly exist at least one non-carbon atom (heteroatoms) in the said ring." C for example 1-C 6Heterocycle " name only relate to the number of carbon atom in the ring, and do not relate to the sum of atom in the ring.Contained total atom number in the name essence ring like " 4-6 unit heterocycle " (promptly four, five or six-ring, wherein at least one atom is a carbon atom, and at least one atom is a heteroatoms, and remaining-4 atoms are carbon atom or heteroatoms).For having two or more heteroatomic heterocycles, affiliated two or more heteroatomss can be same to each other or different to each other.Heterocycle can be by any replacement.The non-aromatic heterocyclic group comprises the group that only has 3 atoms in the ring, and aromatic heterocyclic group must have at least 5 atoms in ring.All the other groups can combine (being that heterocycle is connected with parent molecule or further replaces) through heteroatoms or carbon atom with heterocycle.
This paper alone or in combination or the term " carbocylic radical " that uses be the title that closes of alicyclic radical and aryl; Just all are by the structure of carbon covalently closed circle, its can for saturated, part is unsaturated, unsaturated or rent compound fully.Can form carbocyclic ring by the atom more than 3,4,5,6,7,8,9 or 9.Carbocyclic ring can be by any replacement.The term carbocyclic ring is that with difference between the heterocycle heterocyclic ring skeleton comprises at least one atom different with carbon.
The term that this paper is used alone or in combination " halogen ", " halo " or " halogenide " are meant fluorine, chlorine, bromine and iodine.
The term that this paper is used alone or in combination " alkoxyl group " is meant alkylether radicals O-alkyl; It comprises O-fat base and O-carbocylic radical; Wherein alkyl, fat base and carbon ring group can randomly be replaced, and the definition of term alkyl wherein, fat base and carbocylic radical such as preceding text.The non-limiting example of alkoxyl group comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy and tert.-butoxy etc.
The term that this paper is used alone or in combination " sulfinyl " is meant that divalent group-S (O).
The term that this paper is used alone or in combination " sulphonyl " is meant that divalent group-S (O) 2
The term that this paper is used alone or in combination " sulphonamide " and " sulfoamido " are meant that divalent group-S (O) 2-NH-and-NH-S (=O) 2
The term that this paper is used alone or in combination " sulphamide " and " sulfonyl amido " are meant divalent group NHS (O) 2NH.
The some drugs term
Term used herein " mek inhibitor " is meant the measurement according to MEK1 kinase assay described herein, and the active IC50 of MEK is not more than about 100 μ M or is not more than the compound of about 50 μ M." IC50 " is meant that the activity with enzyme (like MEK) is reduced to the inhibitor concentration the maximum horizontal.Have now found that the restraining effect of compound described herein to MEK.According to the measurement of MEK1 kinase assay described herein, compound of the present invention preferably shows the active IC50 of MEK is not more than 10 μ M, is not more than about 5 μ M, more preferably no more than about 1 μ M, and most preferably is not more than about 200nM.
Term used herein " selection ", " selectively ", " selectivity " are meant with other enzymes and compare that compound of the present invention is to the IC50 value of MEK enzyme lower (for example, hanging down 2 times, 5 times, 10 times or more times) at least.This term also refers to compare with the MEK2 enzyme; Compound of the present invention is lower (for example to the IC50 value of MEK1 enzyme; At least low 2 times, 5 times, 10 times or more times), perhaps, compare with the MEK1 enzyme; Compound of the present invention is to the IC50 value of MEK2 enzyme lower (for example, hanging down 2 times, 5 times, 10 times or more times) at least.
Relational term used herein " experimenter ", " patient " or " individuality " be meant suffer from disease, the individuality of illness or patient's condition etc., comprise Mammals and nonmammalian.Mammiferous instance includes but not limited to any member of class of mammals: the mankind, inhuman primate (for example chimpanzee and other apes and monkey); Domestic animal, for example ox, horse, sheep, goat, pig; Domestic animal, for example rabbit, dog and cat; Laboratory animal comprises rodent, for example rat, mouse and cavy etc.The instance of non-human mammal includes but not limited to birds and fish etc.In the method that provides at this paper and the embodiment of compsn, said Mammals is behaved.
Term used herein " treatment " and other similar synonym comprise alleviation, alleviate or improve disease or condition symptoms, prevent other symptoms, improve or prevent to cause the potential metabolism reason of symptom; Suppress disease or illness, for example stop the development of disease or illness, alleviate disease or illness; Disease or illness are taken a turn for the better, alleviate the symptom that causes by disease or illness, perhaps end the symptom of disease or illness; In addition, this term comprises the purpose of prevention.This term also comprises acquisition result of treatment and/or preventive effect.Said result of treatment is meant cures or improves the potential disease of being treated.In addition, to the healing of one or more physiological signs relevant or to improve also be result of treatment,, observe patient's condition improved although for example the patient possibly still receive the influence of potential disease with potential disease.With regard to preventive effect, can be to having patient's applying said compositions of suffering from the specified disease risk, even if perhaps do not make medical diagnosis on disease as yet, but to patient's applying said compositions of the one or more physiological signs that this disease occurs.
Use a technical term " significant quantity ", " treatment significant quantity " or " pharmacy effective dose " of this paper is meant and takes metapedes with at least one medicament of one or more symptoms of alleviating the disease of being treated or illness to a certain extent or the amount of compound.Its result can be the subduing and/or alleviate of sign, symptom or the cause of disease, or any other required variation of biosystem.For example, " significant quantity " that is used to treat is the amount that comprises the open compound compositions of this paper that provides significant illness remission effect required clinically.Can use technical measurement to be suitable for the significant quantity in any individual case such as the dosage escalation test.
Term used herein " is taken ", " using ", " administration " etc. are meant the method that can compound or compsn be delivered to the required site of carrying out biological action.These methods include but not limited to oral route, through duodenum approach, parenteral injection (comprising intravenously, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), topical and per rectum administration.Those skilled in the art know the application technique that can be used for Compounds and methods for described herein, for example at Goodman and Gilman, and The Pharmacological Basis of Therapeutics, current ed.; Pergamon; And Remington ' s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, those that discuss among the Pa..In preferred embodiments, the compound of this paper discussion and compsn administered through oral are used.
This paper is meant that to preparation, compsn or the used term of composition " acceptable " the subject experimenter's of butt joint general health situation does not have secular harmful effect.
Term used herein " pharmaceutically acceptable " is meant the biological activity that do not influence The compounds of this invention or the material (like carrier or thinner) of character; And nontoxic relatively, promptly this material can be applied to individuality and not cause bad biological respinse or any component interaction to comprise in bad mode and the compsn.
Term used herein " pharmaceutical composition " is meant the bioactive compounds that randomly is mixed with at least a pharmaceutically acceptable chemical ingredients, and said pharmaceutically acceptable chemical ingredients includes but not limited to carrier, stablizer, thinner, dispersion agent, suspension agent, thickening material and/or vehicle.
Term used herein " carrier " is meant nontoxic relatively chemical cpd or reagent, and it helps compound is incorporated in the cell or tissue.
Term used herein " agonist " is meant activity or the active molecule of acceptor site, for example compound, medicine, zymoexciter or the hormone regulating and controlling agent that strengthens other molecules.
Term used herein " antagonist " is meant elimination or suppresses the activity of other molecules or the active molecule of acceptor site, for example compound, medicine, enzyme inhibitors or hormone regulating and controlling agent.
Term used herein " regulation and control " thus be meant and target directly or indirectly interacts and changes the activity of target that for example, it comprises and strengthens that target is active, to suppress target active or to prolong target active.
Term used herein " adjusting control agent " is meant and the direct or indirect interactional molecule of target.Said interaction includes but not limited to that agonist and antagonist must interact.
Term used herein " pharmacy acceptable salt " is the biopotency that has kept the free acid and the free alkali of appointed compound, and does not have the salt of undesirable action at biology or on aspect other.Compound as herein described can have acidity or basic group, therefore can with multiple mineral alkali or organic bases and mineral acid and organic acid reaction arbitrarily, thereby form pharmacy acceptable salt.These salt can prepare through following method: in the final separation and the purge process made acid-stable in situ of The compounds of this invention, perhaps the free alkali form through The compounds of this invention reacts separately with the organic acid or the mineral acid that are fit to, and separates the salt that forms thus.The instance of pharmacy acceptable salt comprises the salt for preparing through the reaction between compound described herein and mineral acid or organic acid or mineral alkali or the organic bases.These salt comprise acetate, acrylate, adipate, alginates, aspartate, phenylformic acid eye, benzene sulfonate, hydrosulfate, bisulfite, bromide, butyrates, butine-1; 4-diacid salt, camphorate, camsilate, hexanoate, octylate, chloro-benzoate, chloro thing, Acidum Citricum salt, cyclopentane propionate, caprate, gluconate, dihydrogen phosphate, dinitro-benzoate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, glycollate, Hemisulphate, enanthate, hexin-1; The 6-diacid salt (hexyne-1,6-dioate), hydroxy benzoate, y-hydroxybutyric acid salt, hydrochloride, hydrobromate, hydriodate, 2-isethionate, iodide, isobutyrate, lactic acid salt, PHENRAMINE MALEATE, malonate, mesylate, mandelate, metaphosphate, the basic formate of methoxy, tolyl acid salt, monohydric phosphate, 1-naphthalene sulfonic aicd salt, 2-naphthalenesulfonate, nicotinate, nitrate salt, embonate, jelly hydrochlorate (pectinate), persulphate, 3-phenpropionate, phosphoric acid salt, picrate, pivalate, propionic salt, pyrosulphate, pyrophosphate salt, propynoic acid, phthalate, phenylacetate, benzenebutanoic acid salt, propanesulfonic acid salt, salicylate, SUMATRIPTAN SUCCINATE, vitriol, sulphite, suberate, sebacate, sulphonate, tartrate, thiocyanate-, tosilate, undecylate (undeconate) and xylenesulfonate.Other acid (like oxalic acid); Although itself pharmaceutically is being unacceptable; Use in the preparation process of salt but can be used as intermediate, with obtain compound of the present invention and in pharmaceutically-acceptable acid addition (referring to Berge et al., J.Pharm.Sci.1977; 66, the instance among the 1-19.).In addition, the compound that comprises free acid group as herein described can with suitable alkali reaction (the for example oxyhydroxide of pharmaceutically acceptable metallic cation, carbonate or supercarbonate).With ammonia react, or with pharmaceutically acceptable organic primary amine, secondary amine or reactive tertiary amine.Representational an alkali metal salt or alkaline earth salt comprise lithium salts, sodium salt, sylvite, calcium salt, magnesium salts and aluminium salt etc.The illustrative example of alkali comprises sodium hydroxide, Pottasium Hydroxide, hydroxide hydroxyethyl Trimethylamine 99, yellow soda ash and IV ' (C 1-4Alkyl) 4 etc.The representative organic amine that is used to form base addition salt comprises ethamine, diethylamine, quadrol, thanomin, diethylolamine and piperazine etc.Should be understood that the quaternized thing of any alkaline nitrogen-containing group that compound described herein comprises that also it possibly comprise.Can obtain water-soluble or oil soluble or product dispersedly through quaterisation.Referring to, people's such as preceding text Berge document for example.
Term used herein " solvolyte " is meant through the The compounds of this invention of solvation formation and the combination of solvent molecule.In some cases, " solvolyte " is " hydrate ", and promptly solvent molecule is a water molecules, The compounds of this invention and water be combined to form hydrate.
Term used herein " polymorphic form " or " polymorph " are meant the The compounds of this invention that exists with different form crystal lattices.
Term used herein " ester " is meant the verivate by oxygen acid group and oh group deutero-The compounds of this invention, both can exist the oxygen acid group also can have oh group in the The compounds of this invention.
Term used herein " tautomer " is meant the isomer through being easy to like Wasserstoffatoms migration or protolysis reaction obtained by the The compounds of this invention change.
Term used herein " pharmaceutically acceptable derivates or prodrug " is meant any pharmacy acceptable salt, the ester of The compounds of this invention, salt or other verivates of ester, metabolite or residue that it can provide compound of the present invention or its to have pharmacy Mars directly or indirectly after using to acceptor.Preferred especially verivate or prodrug be when being applied to the patient, can improve the The compounds of this invention bioavailability those compounds (for example; Can make oral compound be easier to be absorbed in the blood), perhaps promote those compounds that parent compound is sent to biologic-organ or action site (for example brain or lymphsystem).
The pharmaceutically acceptable prodrug of compound described herein includes but not limited to quaternary ammonium derivative, N-Ma Niqi alkali (N-Mannich bases), schiff base (Schiff bases), amino acid conjugates, SULPHOSUCCINIC ACID ESTER, metal-salt and the sulphonate of ester, carbonate, thiocarbonate, N-acyl derivative, N-acyloxy alkyl derivative, tertiary amine.Various prodrug forms are well known in the art.Referring to, Design of Prodrugs for example, Bundgaard, A.Ed., Elseview, 1985 and Method in Enzymology, Widder, K.et al., Ed.; Academic, 1985, vol.42, p.309-396; Bundgaard, H. " Design and Application ofProdrugs " in A Textbook of Drug Design and Development, Krosgaard-Larsen and H.Bundgaard, Ed., 1991, chapter 5,113-191 page or leaf; And Bundgaard, H., Advanced Drug DeliveryReview, 1992,8,1-38, above document is incorporated this paper by reference into.Prodrug described herein includes but not limited to the combination of material and these materials in following group: amine deutero-prodrug; The hydroxyl prodrug includes but not limited to acyloxy alkyl ester, alkoxy carbonyl yloxy alkyl ester, alkyl ester, aromatic ester and contains the ester of disulfide bond.
This paper similar vocabulary such as " enhancing/raisings " that uses a technical term is meant the effectiveness that increases required effect or prolongs the time length of required effect.Therefore, when expression strengthened the therapeutical agent effect, term " enhancing " was meant and increases or prolong the other treatment agent to the effectiveness of systemic effect or the ability of time length.
This paper use a technical term " amount of reinforced effects (the effectively amount of enhancement) " be meant the amount that is enough to strengthen the effect of other treatment agent in required system.
Use a technical term " drug regimen ", " using other treatment ", " using the other treatment agent " etc. of this paper are meant through mixing or make up the pharmacological agent that more than a kind of activeconstituents obtains, the fixing and fixed combination not of its activeconstituents.Term " fixed combination " is meant with the form with single entity or single formulation uses at least a compound as herein described and at least a collaborative medicament simultaneously to the patient.Term " not fixed combination " is meant with the form of separate entity and uses simultaneously, share or to use at least a compound as herein described and at least a collaborative preparation variable pitch time in order, wherein this type of is applied in two or more compounds that level of significance is provided in patient's body to the patient.These also are applied in the HAART, for example use three kinds or more kinds of activeconstituents.
Term used herein " co-administered ", " with ... combined administration " and its synonym etc. are to point to same patient to use selected therapeutical agent, and are intended to contain and use medicament through identical or different route of administration or identical or different administration number of times and get therapeutic strategy.In some embodiments, compound as herein described and other medicament is co-administered.These terms contain to animal use two kinds or more the multiple medicines agent so that have said medicament and/or its metabolite in the animal body simultaneously.These terms comprise uses the different combinations thing simultaneously, and different time is used different groups and thing and/or used a kind of compsn that contains the different activities composition.Therefore, in some embodiments,, compound of the present invention and other medicaments use through being blended in a kind of compsn.
Term used herein " metabolite " is meant the verivate of this compound that when the compound metabolism, forms.
Term used herein " active metabolite " is meant the active verivate that has of this compound of when the compound metabolism, forming.
Term used herein " metabolic " is meant that all processes of organism conversion predetermined substance " include but not limited to hydrolysis reaction and enzymic catalytic reaction ".Therefore, enzyme can make compound produce special structural changes.For example, the multiple redox reaction of Cytochrome P450 catalysis, and the glucal acid molecule of UDPglucuronyl transferase catalytic activation is to the transfer of aromatic alcohol, Fatty Alcohol(C12-C14 and C12-C18), carboxylic acid, amine and free thiohydroxy group.Can be about metabolic more information referring to The Pharmacological Basis of Therapeutics, 9thEdition, McGraw-Hill (1996).
Compound
This paper described formula I compound, it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug:
Figure BDA0000135908570000401
Formula I
Wherein
R 0Be H, C 1-C 6Alkyl, C 3-C 6Naphthenic base, C 2-C 6Thiazolinyl, C 5-C 6Cycloalkenyl group or C 2-C 6Alkynyl; Wherein each alkyl, naphthenic base, thiazolinyl, cycloalkenyl group or alkynyl group randomly are independently selected from by halogen, hydroxyl, C by 1-3 substituting group 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyanic acid, trifluoromethyl, difluoro-methoxy and phenyl are formed, perhaps said C 3-C 6One or two carbon atom in the group of naphthene base is by optional O, N or the S of replacing with independently; With
R 1Be H, C 1-C 4Alkoxyl group, C 1-C 6Alkyl, C 3-C 6Naphthenic base, C 2-C 6Thiazolinyl, C 5-C 6Cycloalkenyl group or C 2-C 6Alkynyl; Wherein each alkyl, naphthenic base, thiazolinyl, cycloalkenyl group or alkynyl group are randomly replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyanic acid, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed; Perhaps,
R 1For having saturated, the unsaturated or fragrant heterocyclic radical of 5 or 6 atoms; Wherein, Said heterocyclic group comprises 1-5 the heteroatoms that is independently selected from the group of being made up of O, N and S, and it is randomly by 1-3 substituting group replacement, and said substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, cyanic acid, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl; Perhaps,
R 1For-CH 2X ', the wherein group of X ' expression II:
Figure BDA0000135908570000402
Formula II
Wherein
Y 1And Y 2Can be identical or different, represent separately singly-bound ,-CO-,-COO ,-O-,-OCO-,-NR nOr-SO 2-;
Y 3Expression can be by 1-3 the substituted C of group that is represented by Z 1-5Alkyl;
Z can be identical or different, and expression can be randomly by the substituted C of one or more substituting groups 1-5Alkyl, halogen atom, oxo group ,-OR a,-COOR a,-COOCOR a,-CO-halogen atom ,-OCOR a,-CONR aR b,-SR a,-SO 2R n,-NR aR b,-NR aCOR b, NR aSO 2R b,-SO 2NR aR b, monocyclic heterocycles group or the heterocyclic radical of dicyclo or the heteroaryl of monocycle or dicyclo, said substituting group is selected from by C 1-5Alkyl group ,-OR aAnd NR aR bThe group of forming; Said each alkyl can be by hydroxyl, C 1-5Alkoxyl group or amino the replacement; Except that oxo group and halogen, above-mentioned substituting group can interconnect and form naphthenic base or heterocyclic radical, and said alkyl or heterocyclic radical can have one or more substituting groups, and said substituting group is selected from by-OR a, NR aR bWith can be by-OR aSubstituted C 1-5The group that alkyl is formed;
R aAnd R bCan be identical or different, represent Wasserstoffatoms or can be separately by 1-3 the substituted C of substituting group 1-5Alkyl group, said substituting group is selected from by hydroxyl, C 1-5Alkoxyl group and the amino group of forming;
Symbol " ● " the expression connection site of using among the formula II;
X is C or N;
When X=C, R 2Be H, C 1-C 4Alkoxyl group, C 1-C 6Alkyl, C 3-C 6Naphthenic base, C 2-C 6Thiazolinyl, C 5-C 6Cycloalkenyl group or C 2-C 6Alkynyl; Wherein each alkyl, naphthenic base, thiazolinyl, cycloalkenyl group or alkynyl are optional is replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyanic acid, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed; Perhaps, R 2Be five yuan or hexavalent saturated heterocyclyl, unsaturated heterocycle base or fragrant heterocyclic radical; Wherein, Said heterocyclic radical has 1-5 heteroatoms; Said heteroatoms is independently selected from the group of being made up of O, N and S, and said heterocyclic radical is optional by 1-3 substituting group replacement, and said substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyanic acid, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed; Perhaps
When X=N, R 2Do not exist; Perhaps
R 1And R 2Common form one five yuan or hexavalent unsaturated heterocycle base or comprise 1-3 heteroatomic fragrant heterocyclic radical; Said heteroatoms is independently selected from the group of being made up of O, N or S; Said heterocyclic radical is optional to be replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyanic acid, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed; And
R 3Be selected from by trifluoromethyl, C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, C 3-C 10Naphthenic base, C 3-C 10Cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heteroaryl ring alkyl, heterocyclic radical and Heterocyclylalkyl; Wherein each alkyl, thiazolinyl, alkynyl, naphthenic base, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical alkyl, hetero-aromatic ring alkyl and heterocyclic radical is not substituted or replaced by 1-3 substituting group, said substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, cyanic acid, trifluoromethyl, difluoro-methoxy, phenyl or have 1-3 substituent substituted-phenyl, the substituting group of said substituted-phenyl independently is selected from halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, cyanic acid, trifluoromethyl or difluoro-methoxy; And
R 4, R 5, R 6, R 7And R 8Be independently selected from hydrogen, halogen, cyanic acid, nitro, trifluoromethyl, SR 9, OR 9, C (O) R 9, NR 10C (O) OR 12, OC (O) R 9, NR 10S (O) jR 12, S (O) jNR 9R 10, S (O) jNR 10C (O) R 9, C (O) NR 10S (O) jR 12, S (O) jR 12, NR 10C (O) R 9, C (O) NR 9R 10, NR 11C (O) NR 9R 10, NR 11C (NCN) NR 9R 10, NR 9R 10And C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, C 3-C 10Naphthenic base, C 3-C 10Cycloalkylalkyl, S (O) j(C 1-C 6Alkyl), S (O) j(CR 10R 11) m-aryl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical, heterocyclic radical alkyl, O (CR10R10) m-aryl, NR 10(CR 10R 11) m-aryl, O (CR 10R 11) m-heteroaryl, NR 10(CR 10R 11) m-heteroaryl, O (CR 10R 11) m-heterocyclic radical, NR 10(CR 10R 11) m-heterocyclic radical and S (C 1-C 2Alkyl), above-mentioned group is optional is replaced by the fluorine atom of 1-5;
R 9Be selected from by hydrogen, trifluoromethyl, C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, C 3-C 10Naphthenic base, C 3-C 10The group that cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical and heterocyclic radical alkyl are formed; Wherein each alkyl, thiazolinyl, alkynyl, naphthenic base, aryl, heteroaryl and heterocyclic radical are not substituted or are replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl, the amino group of forming;
R 10Be selected from by hydrogen and C 1-C 6Alkyl, wherein said alkyl can be not to be substituted or to be replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming; Or
R 9, R 10Form 4-10 first hetero-aromatic ring or heterocycle together with coupled atom, said each ring is not substituted or is replaced by 1-3 substituting group, and said substituting group is free halogen, C independently 1-C 4Alkyl, hydroxyl and the amino group of forming;
R 11Be selected from hydrogen or C 1-C 6Alkyl, wherein alkyl can be not to be substituted or to be replaced by 1-3 substituting group, said substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming; Or
R 10, R 11Form 4-10 first carbocyclic ring, hetero-aromatic ring or heterocycle together with coupled atom, each ring is not substituted or is replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming;
R 12Be selected from by trifluoromethyl, C 1-C 10Alkyl, C 3-C 10The group that naphthenic base, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical and heterocyclic radical alkyl are formed; Wherein each alkyl, naphthenic base, aryl, heteroaryl and heterocycle are not substituted or are replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming;
M is 0,1,2,3,4 or 5; And
J is 1 or 2;
The invention provides the compound method of above-claimed cpd.In some embodiments, can prepare compound as herein described through following method.Following flow process and instance are for these methods are described.These flow processs and instance should not be interpreted as limitation of the present invention by any way.Also can use standard synthetic technology well known by persons skilled in the art to synthesize compound as herein described, perhaps means known in the art and methods described herein are used in combination.
Embodiment
Compound method and instance
Below be the schema of formula I compound:
Route 1
Figure BDA0000135908570000441
Above route 1 has shown the preparation of pyridone sulfone amide derivative 10.Can pass through chlorine monoxide pyridine 1, the two-step reaction of chloride oxidation pyridine 2 prepares dichloropyridine verivate 3 subsequently.Nitrated dichloropyridine 3 carries out SN with aniline 5 then ArReaction, thus intermediate product 6 formed.Pyridione derivatives 7 alkylations that can hydrolysis chloropyridine 6 be obtained, thus nitropyridine 8 is provided.After the reduction reaction, use SULPHURYL CHLORIDE to handle EL-970 9, thereby obtain required pyridone sulphonamide 10.
Route 2
Figure BDA0000135908570000442
Route 2 has been described the preparation of Trimetylene SULPHURYL CHLORIDE 17.Trimetylene SULPHURYL CHLORIDE 11 reacts under the existence condition of alkali (like pyridine) with alkyl alcohol 12, thereby obtains sulphonate 13.Through lithiumation and the alkanisation that utilizes haloalkane 14 to carry out substituted Trimetylene sulphonate 15 is provided subsequently.Use KSCN to handle compound 15, thus preparation sylvite 16.Through the reaction acquisition SULPHURYL CHLORIDE 17 of sylvite 16 with THIONYL CHLORIDE 97.
Route 3
Figure BDA0000135908570000451
Route 3 has been described the preparation of dihydroxypropyl cyclopropyl base SULPHURYL CHLORIDE 23.Use epoxide 19 to handle sec.-propyl Trimetylene sulphonate 18 after the lithiumation, thereby obtain hydroxypropyl sulphonate 20.Protection secondary hydroxy group and hydrolysis sulphonate 21, thus sulphonate 22 obtained.Use THIONYL CHLORIDE 97 to handle compound 22, thereby obtain shielded dihydroxypropyl cyclopropyl base SULPHURYL CHLORIDE 23.
Route 4
Figure BDA0000135908570000452
Route 4 has been described the preparation of the Trimetylene SULPHURYL CHLORIDE 27 that receives the protection of dioxane pentanone.Utilize CDI or two (trichloromethyl) carbonic ether that the dihydroxypropyl Trimetylene sulphonate 24 that is obtained by shielded hydroxypropyl Trimetylene sulphonate 20 (route 3) deprotection is handled, thereby form dioxane pentanone propyl group Trimetylene sulphonate 25.Under mild conditions (like NaI/ acetone or Bu 4NI) hydrolysis compound 25 under, thus sulphonate 26 obtained.There is use THIONYL CHLORIDE 97 processing compound 26 under the condition of PPh3, thereby obtaining to receive the Trimetylene SULPHURYL CHLORIDE 27 of dioxane pentanone protection.
The method A that is used for synthetic sulphonamide
Method A: at 0 ℃-5 ℃, in the anhydrous pyridine that contains amine 9 (1 equivalent) (1 milliliter) solution that stirs, add SULPHURYL CHLORIDE (2-3 equivalent), add Dimethylamino pyridine (DMAP, 0.1 equivalent) subsequently.Mixture was stirred 1-2 hour at 0 ℃-5 ℃.The concentrating under reduced pressure reaction solution adds methylene dichloride then, the water washed mixture, and organic phase is carried out drying with sal epsom, filters, and filtrating is carried out concentrating under reduced pressure.Through quick purification by silica gel column chromatography residue, thereby obtain the purpose product.
Embodiment 1
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene sulphonamide
Figure BDA0000135908570000461
Steps A: 2-chloro-5-picoline 1-oxide compound
Figure BDA0000135908570000462
At 0 ℃; (200 grams are 1.57mol) with hydrogen peroxide urea addition compound (310 grams, the anhydrous trifluoroacetic acid of dropping (679 grams in methylene dichloride 3.29mol) (2 liters) mixture containing 2-chloro-5-picoline; 5.96mol), and this mixture stirred 1 hour at 0 ℃.Stir after simultaneously temperature of reaction rose to room temperature in 48 hours, add V-Brite B (326 grams, aqueous solution 3.14mol), and reaction mixture stirred 4 hours.Using the sodium hydroxide neutralization reaction, by dichloromethane extraction, is to clean with salt solution, uses dried over mgso by organic phase, filters, and filtrate decompression concentrates, thereby obtains the title compound (189 grams, 84%) of brown solid shape. 1H?NMR(400MHz，CDCl 3)δ8.21(s，1H)，7.39(d，J＝8.4Hz，1H)，7.06(d，J＝8.4Hz，1H)，2.32(s，3H)；m/z＝144[M+1] +。
Step B:2,6-two chloro-3-picolines
Figure BDA0000135908570000463
At 0 ℃, to contain 2-chloro-5-picoline 1-oxide compound (130 grams, 905mmol) with triethylamine (110 restrain, add in methylene dichloride 1087mmol) (1.5 liters) mixture phosphoryl chloride (100 milliliters, methylene dichloride 1087mmol) (500 milliliters) solution., at room temperature stirred again 24 hours after 2 hours 0 ℃ of stirring, add water, and use the sodium hydroxide solution neutralization reactant.Use saturated brine solution to clean organic layer; Use the ethyl acetate extraction water layer and use saturated brine solution to clean.The organic layer that uses dried over mgso to merge filters and concentrating under reduced pressure filtrating, thereby obtains 2,6-two chloro-3-methyl-pyridines and 2,4-two chloro-5-methyl-pyridines (138 grams, 94%, according to 1H NMR measures, ratio 3: 1) the garnet solid mixture. 1H?NMR(400MHz，CDCl 3)δ7.50(d，J＝8.0Hz，1H)，7.17(d，J＝8.4Hz，1H)，2.33(s，3H)；m/z＝161[M+1] +.
Step C:2,6-two chloro-3-methyl-5-nitro pyridines
Figure BDA0000135908570000471
Reach under lasting the stirring at 0 ℃, with 2,6-two chloro-3-methyl-pyridines and 2, the mixture of 4-two chloro-5-methyl-pyridines (26 grams, 160mmol, 1 equivalent) slowly adds in the vitriol oil (294 grams, 3mol, 18 equivalents).In this solution, slowly add nitric acid (95.0%, 74 gram, 1.17mol, 7 equivalents), simultaneously temperature of reaction was kept 0.5 hour at 0 ℃.After add accomplishing, with gained mixture heating up to 100 ℃ and continue 3.5 hours.Reaction mixture is cooled to 50 ℃, and in the impouring frozen water.Filtering gained throw out and water cleans.Dry gained yellow solid, thus above-mentioned title compound (17.6 grams, 51%) obtained. 1H?NMR(400MHz，CDCl 3)δ8.14(s，1H)，2.47(s，3H)。
Step D:6-chloro-N-(2-fluoro-4-iodo-phenyl)-5-methyl-3-nitro pyridine-2-amine
At room temperature, in THF (THF, the 500 milliliters) mixture that contains sodium hydride (3.55 grams, 148mmol, 3 equivalents), add 2-fluoro-4-iodo-aniline (11.68 grams, 49.3mmol, 1 equivalent).Stir after 30 minutes, add 2,6-two chloro-3-methyl-5-nitro pyridines (10.2 grams, 49.3mmol, 1 equivalent), and with this mixture heating up backflow 0.5 hour.After being cooled to room temperature, slowly add entry, use this solution of ethyl acetate extraction, and use saturated brine solution to clean.Use the dried over mgso organic layer, filter, and removal of solvent under reduced pressure, thereby the above-mentioned title compound of acquisition brown solid shape, it can be used for next step reaction and need not further purifying. 1H?NMR(400MHz，CDCl 3)δ10.24(br，1H)，8.40(s，1H)，8.18(t，J＝8.4Hz，1H)，7.50-7.54(m，2H)，2.37(s，3H)；
Step e: 6-(2-fluoro-4-iodophenyl is amino)-3-methyl-5-nitro pyridine-2 (1H)-ketone
(20 grams 49.1mmol) are dissolved into EtOH (400 milliliters), slowly add Pottasium Hydroxide (55 grams, 980mmol the is dissolved in 200 ml waters) aqueous solution subsequently, mixture are refluxed 4 hours again with 6-chloro-N-(2-fluoro-4-iodophenyl)-5-methyl-3-nitro pyridine-2-amine.Mixture is cooled to room temperature, and filters yellow suspension, water cleans and is dry, thereby obtains purpose product (11.3 grams, 59%). 1H?NMR(400MHz，DMSO)δ11.61(s，1H)，8.84(t，J＝8.8Hz，1H)，7.61-7.66(m，2H)，7.50(d，J＝8.8Hz，1H)，1.85(s，3H)；
Step F: 6-(2-fluoro-4-iodophenyl is amino)-1,3-dimethyl--5-nitropyridine-2 (1H)-ketone
Figure BDA0000135908570000482
At room temperature; To (0.2mol/L) interpolation 6-(2-fluoro-4-iodophenyl is amino)-3-methyl-5-nitro pyridine-2 (1H)-ketone (1 equivalent) in the solution and stirring 35 minutes of the dry N (DMF) of sodium hydride (1.2 equivalent), in this garnet mixture, add methyl iodide (1.05 equivalent) subsequently.After at room temperature stirring 1 hour, use saturated ammonium chloride cancellation reaction, and use the ethyl acetate extraction mixture.Water and salt solution clean organic phase, use dried over mgso subsequently.Filter, remove desolvate and with eluent (DCM: PE=1: 1 to DCM) through the purification by silica gel column chromatography residue, thereby acquisition purpose product (productive rate=63%).1HNMR(400MHz，CDCl3)δ10.35(s，1H)，8.10(d，J＝1.2Hz，1H)，7.54(dd，J＝1.6&9.6Hz，1H)，7.47-7.50(m，1H)，6.71(t，J＝8.0Hz，1H)，3.22(s，3H)，2.16(s，3H)；
Step G:5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone
With 6-(2--fluoro-4-iodophenyl is amino)-1,3-dimethyl--5-nitropyridine-2 (1H)-ketone (510 milligrams) and sodium sulfate (1.96 grams, 8 equivalents) are dissolved in dioxane and water (30 milliliters, 1: 1), subsequently, at room temperature add volatile caustic (1 milliliter).After 2 hours 40 minutes, use 100 milliliters of ETHYLE ACETATE diluted mixture things, water and salt solution clean.Use ethyl acetate extraction water layer twice, and clean with salt solution.Merge organic layer, use dried over mgso, filter removal of solvent under reduced pressure.With eluent (PE: EA (and sherwood oil: ETHYLE ACETATE)=1: 1 to DCM: MeOH (methylene dichloride: methyl alcohol)=20: 1) through the purification by silica gel column chromatography residue, thereby obtain the above-mentioned title compound (378 milligrams, productive rate=80%) of greyish-green solid-like. 1H?NMR(400MHz，CDCl 3)δ7.40(dd，J＝2.0&10.8Hz，1H)，7.25(d，J＝6.8Hz，1H)，7.02(s，1H)，6.18(t，J＝8.4Hz，1H)，5.45(br，1H)，3.43(s，3H)，2.85(br，2H)，2.18(s，3H)；m/z＝373[M+1] +。
Step H:N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene alkylsulfonyl
Figure BDA0000135908570000492
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and the reaction of Trimetylene SULPHURYL CHLORIDE, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.44(dd，J＝1.6Hz&10.8Hz，1H)，7.28-7.29(m，2H)，7.14(s，1H)，6.13(t，J＝8.4Hz，1H)，6.02(s，1H)，3.44(s，3H)，2.42(m，1H)，2.17(s，3H)，1.15-1.17(m，2H)，1.00-1.02(m，2H)；m/z＝478[M+1] +。
Embodiment 2
1-allyl group-N-(2-(2-fluoro-4-iodo-phenyl amino) 1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene sulphonamide
Steps A: 1-butyl Trimetylene sulphonate
Figure BDA0000135908570000501
Trimetylene SULPHURYL CHLORIDE (25 grams, 178mmol, 1 equivalent) is dissolved in excessive n-BuOH (80 milliliters) and reaction mixture is cooled to 0 ℃, drip pyridine (13.3 milliliters, 160mmol, 0.9 equivalent) subsequently.This mixture slowly is heated to room temperature and stirred 36 hours.Removal of solvent under reduced pressure, and the gained white solid is dissolved in chloroform.Water, salt solution clean organic phase, and dry (sal epsom) concentrates subsequently and obtains oil (24.5 grams, 77%). 1H?NMR(400MHz，CDCl 3)δ4.25(t，J＝6.4Hz，2H)，2.47(heptet，2H)，1.74(quintet，2H)，1.43(sextet，2H)，1.24(m，2H)，1.08(m，2H)，0.96(t，J＝7.6Hz，3H)；
Step B:1-allyl group Trimetylene-1-sulfonic acid butyl ester
Figure BDA0000135908570000502
In-78 ℃, nitrogen atmosphere; (60 grams slowly add butyllithium (150 milliliters contain the hexane solution of 2.5M butyllithium in THF 337mmol) (500 milliliters) solution to 1-butyl Trimetylene sulphonate; 404mmol); Stir after 15 minutes, add contain allyl group iodate thing (31 milliliters, THF 337mmol) (100 milliliters).Reaction mixture stirred 2 hours and stirring at room 30 minutes at-78 ℃.The reduction vaporization volatile matter, and use the dichloromethane extraction residue.Water cleans extract, and dry (sal epsom) filters, and removes and desolvates.(eluent: PE/EA=10: 1) purifying residue, (50 restrain productive rate: water white oil 68%) thereby obtain above-mentioned title compound through silica gel column chromatography. 1H?NMR(400MHz，CDCl 3)δ5.71-5.81(m，1H)，5.09-5.14(m，2H)，4.22(t，J＝6.4Hz，2H)，2.65(d，J＝7.2Hz，2H)，1.74(m，2H)，1.42(m，4H)，0.91(m，5H)；
Step C:1-allyl group Trimetylene-1-potassium sulfonate
Figure BDA0000135908570000511
(50 grams, 229mmol) (23.4 grams, the backflow of dme 240mmol) (DME, 350 milliliters) and water (350 milliliters) mixture heating up is spent the night with Rhocya will to contain 1-allyl group Trimetylene-1-sulfonic acid butyl ester.Use the ethyl acetate extraction mixture, and the reduction vaporization water, thereby obtaining crude product, it can be used for next step reaction and need not further purifying. 1H?NMR(400MHz，DMSO)δ5.83-5.90(m，1H)，4.90-4.94(m，2H)，2.45(d，J＝7.6Hz，2H)，0.82(dd，J＝3.6Hz&6.0Hz，2H)，0.36(dd，J＝3.2Hz&6.4Hz，2H)；
Step D:1-allyl group Trimetylene-1-SULPHURYL CHLORIDE
Figure BDA0000135908570000512
(44 grams, 220mmol) solution, THIONYL CHLORIDE 97 (500 milliliters) and DMF (5 milliliters) vlil are 1.5 hours with 1-allyl group Trimetylene-1-potassium sulfonate.The reduction vaporization volatile matter, and slowly add water.Use the ethyl acetate extraction mixture, use dried over mgso, filter and concentrating under reduced pressure.Through silica gel column chromatography (eluent: PE/EA=10: 1) purifying residue, thereby obtain above-mentioned title compound (33 gram, 83%). 1HNMR(400MHz，CDCl 3)δ5.69-5.78(m，1H)，5.17-5.23(m，2H)，2.89(d，J＝7.6Hz，2H)，1.71-1.75(m，2H)，1.18-1.21(m，2H)；
Step e: 1-allyl group-N-(2-(2-fluoro-4-iodo-phenyl amino)-1,5-dimethyl--6 oxo-1,6-dichloropyridine-3-yl) Trimetylene sulphonamide
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 1-allyl group Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.44(dd，J＝2.0Hz?&?10.0Hz，1H)，7.26(m，1H)，7.09(s，1H)，6.10(t，J＝8.4Hz，1H)，5.88(s，1H)，5.73-5.79(m，1H)，5.14-5.19(m，2H)，3.43(s，3H)，2.67(d，J＝7.2Hz，2H)，2.17(s，3H)，1.25(m，2H)，0.83-0.87(m，2H)；m/z＝517[M+1] +；
Embodiment 3
2,2,2-three fluoro-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) ethyl sulfonamide
Figure BDA0000135908570000521
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 2,2, the reaction of 2-trifluoro ethyl sulfonyl chloride, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.45(dd，J＝2.0Hz?&?6.4Hz，1H)，7.28(d，J＝8.4Hz，1H)，7.23-7.26(m，1H)，7.01(s，1H)，6.62(s，1H)，6.13(t，J＝8.4Hz，1H)，3.79(q，J＝8.8Hz，2H)，3.44(s，3H)，2.18(s，3H)；m/z＝520[M+1] +。
Embodiment 4
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) propane-2-sulphonamide
Figure BDA0000135908570000522
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and propane-2-SULPHURYL CHLORIDE reaction, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.44(dd，J＝2.0Hz?&?9.6Hz，1H)，7.28(m，1H)，7.18(m，2H)，6.11(t，J＝8.4Hz，1H)，5.30(s，1H)，3.44(s，3H)，3.22(m，1H)，2.18(s，3H)，1.26(m，2H)；m/z＝452[M+1] +。
Embodiment 5
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) ethyl sulfonamide
Figure BDA0000135908570000531
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and ethyl sulfonyl chloride reaction, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.44(dd，J＝1.2Hz?&?10.0Hz，1H)，7.28(m，1H)，7.15(d，J＝9.2Hz，2H)，6.12(t，J＝8.4Hz，1H)，5.30(s，1H)，3.09(q，J＝7.2Hz，2H)，2.18(s，3H)，1.43(t，J＝7.6Hz，3H)；m/z＝464[M+1] +。
Embodiment 6
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) hexanaphthene sulphonamide
According to method A, 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and the reaction of hexanaphthene SULPHURYL CHLORIDE, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.44(dd，J＝2.0Hz?&?10.4Hz，1H)7.26(m，1H)，7.18(m，1H)，6.11(t，J＝8.8Hz，1H)，5.73(s，1H)，3.44(s，3H)，2.90(m，1H)，2.18(s，3H)，1.20-2.14(m，10H)；m/z＝520[M+1] +。
Embodiment 7
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) butane-1-sulphonamide
Figure BDA0000135908570000541
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and butane-SULPHURYL CHLORIDE reaction, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.44(dd，J＝1.2Hz?&?10.0Hz，1H)，7.29(m，1H)，7.16(m，1H)，6.12(t，J＝8.4Hz，1H)，5.75(s，1H)，3.45(s，3H)，3.04(t，J＝7.6Hz，2H)，2.19(s，3H)，1.79-1.81(m，2H)，1.42-1.48(m，2H)，0.95(t，J＝7.22Hz，3H)；m/z＝494[M+1] +。
Embodiment 8
3-chloro-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) propane-1-sulphonamide
Figure BDA0000135908570000542
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 3-chloropropane-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.45(dd，J＝1.6Hz?&?9.6Hz，1H)，7.30(m，1H)，7.23(m，1H)，7.04(s，1H)，6.13(t，J＝8.4Hz，1H)，5.77(s，1H)，3.68(t，J＝6.4Hz，2H)，3.45(s，3H)，3.25(t，J＝8.0Hz，2H)，2.31-2.36(m，2H)，2.18(m，3H)；m/z＝514[M+1] +。
Embodiment 9
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Toluidrin
Figure BDA0000135908570000551
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and methylsulfonyl chloride reaction, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.44(dd，J＝1.6Hz?&?10.0Hz，1H)，7.29(m，1H)，7.21(m，1H)，7.12(s，1H)，6.13(t，J＝8.8Hz，1H)，5.91(s，1H)，3.45(s，3H)，2.99(s，3H)，2.18(s，3H)；m/z＝452[M+1] +。
Embodiment 10
1-chloro-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Toluidrin
Figure BDA0000135908570000552
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and the reaction of methyl chloride SULPHURYL CHLORIDE, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.45(dd，J＝1.2Hz?&?10.0Hz)，7.30(m，2H)，6.90(s，1H)，6.13(m，2H)，4.51(s，2H)，3.44(s，3H)，2.19(m，3H)；m/z＝486[M+1] +。
Embodiment 11
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) pentamethylene sulphonamide
Figure BDA0000135908570000561
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and the reaction of pentamethylene SULPHURYL CHLORIDE, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.44(dd，J＝1.6Hz?&?10.0Hz，1H)，7.30(m，2H)，7.17(s，1H)，6.11(t，J＝8.4Hz，1H)，5.77(s，1H)，3.51(quintet，1H)，3.44(s，3H)，2.18(s，3H)，2.00-2.15(m，4H)，1.82-1.85(m，2H)，1.65-1.68(m，2H)；m/z＝506[M+1] +。
Embodiment 12
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) thiophene-2-sulphonamide
Figure BDA0000135908570000562
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and thiophene-2-SULPHURYL CHLORIDE reaction, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.65(dd，J＝1.2Hz?&?4.8Hz，1H)，7.50(dd，J＝1.6Hz?&?4.0Hz，1H)，7.42-7.45(dd，J＝1.6Hz?&?10.0Hz，1H)，7.250-7.27(m，2H)，7.09(m，1H)，6.79(s，1H)，6.65(s，1H)，6.01(t，J＝4.0Hz，1H)，3.41(s，3H)，2.05(s，3H)；m/z＝520[M+1] +。
Embodiment 13
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) benzsulfamide
Figure BDA0000135908570000571
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and benzene sulfonyl chloride reaction, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.73(d，J＝7.6Hz，2H)，7.62(m，1H)，7.49(t，J＝8.0Hz，2H)，7.43(dd，J＝1.6Hz&?10.0Hz，1H)，7.20(d，J＝8.0Hz，1H)，6.71(s，1H)，6.65(s，1H)，5.98(m，1H)，3.39(s，3H)，2.05(s，3H)；m/z＝514[M+1] +。
Embodiment 14
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-4-methyl benzenesulfonamide
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 4-aminomethyl phenyl-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.58(d，J＝8.4Hz，2H)，7.41(dd，J＝1.6Hz?&?9.6Hz，1H)，7.23-7.26(m，2H)，7.18(d，J＝8.4Hz，1H)，6.80(s，1H)，6.64(s，1H)，5.99(s，1H)，5.94(t，J＝8.8Hz，1H)，3.38(s，3H)，2.44(s，3H)，2.04(s，3H)；m/z＝528[M+1] +。
Embodiment 15
4-fluoro-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) benzsulfamide
Figure BDA0000135908570000581
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 4-fluorophenyl-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.73-7.76(m，2H)，7.43(dd，J＝1.6Hz?&?10.0Hz，1H)，7.21(d，J＝8.4Hz，1H)，7.13(t，J＝8.4Hz，2H)，6.76(d，J＝6.0Hz，2H)，6.16(s，1H)，5.96(t，J＝8.8Hz，1H)，3.40(s，1H)，2.04(s，3H)；m/z＝532[M+1] +。
Embodiment 16
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) thiophene-3-sulphonamide
Figure BDA0000135908570000582
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and thiophene-3-SULPHURYL CHLORIDE reaction, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.85(dd，J＝1.2Hz?&?6.8Hz，1H)，7.41-7.45(m，2H)，7.22-7.26(m，2H)，6.77(s，2H)，6.16(s，1H)，6.01(t，J＝8.4Hz，1H)，3.40(s，3H)，2.05(s，3H)；m/z＝520[M+1] +。
Embodiment 17
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-sec.-propyl-Trimetylene-1-sulphonamide
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 2-sec.-propyl-Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.43(dd，J＝1.6Hz?&?10.0Hz，1H)，7.26(m，2H)，7,16(s，1H)，6.12(t，J＝8.4Hz，1H)，5.84(s，1H)，3.44(s，3H)，2.19-2.22(m，1H)，2.18(s，3H)，1.22-1.26(m，1H)，1.17-1.21(m，2H)，0.96(m，6H)，0.84-0.99(m，1H)；m/z＝520[M+1] +。
Embodiment 18
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-isobutyl--Trimetylene-1-sulphonamide
Figure BDA0000135908570000591
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 2-isobutyl--Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.45(dd，J＝1.2Hz?&?10.0Hz，1H)，7.28-7.30(m，2H)，7.17(s，1H)，6.14(t，J＝8.8Hz，1H)，5.81(s，1H)，3.47(s，3H)，2.21(s，3H)，2.16-2.19(m，1H)，1.67-1.73(m，1H)，1.33-1.38(m，2H)，1.27-1.31(m，1H)，1.08-1.15(m，6H)，0.93-0.95(m，1H)；m/z＝534[M+1] +。
Embodiment 19
2-(4-ethoxyl phenenyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-Trimetylene-1-sulphonamide
Figure BDA0000135908570000592
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 2-(4-ethoxyl phenenyl)-Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.44(dd，J＝1.6Hz?&?10.0Hz，1H)，7.24-7.26(m，2H)，7.09(s，1H)，6.85(q，J＝8.8Hz，4H)，6.76(s，1H)，6.08(t，J＝8.4Hz，1H)，5.81(s，1H)，4.01(q，6.8Hz，2H)，3.39(s，3H)，2.57-2.59(m，1H)，2.50(m，1H)，2.01(s，3H)，1.70-1.73(m，1H)，1.38-1.43(m，4H)；m/z＝598[M+1] +。
Embodiment 20
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-phenyl-Trimetylene-1-sulphonamide
Figure BDA0000135908570000601
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 2-phenyl-Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.42(dd，J＝1.6Hz?&?10.0Hz，1H)，7.24-7.35(m，4H)，7.07(s，1H)，6.96(d，J＝7.2Hz，2H)，6.82(s，1H)，6.08(t，J＝8.8Hz，1H)，6.01(s，1H)，3.38(s，3H)，2.62-2.65(m，1H)，2.53-2.55(m，1H)，2.04(s，3H)，1.75-1.77(m，1H)，1.45(m，1H)；m/z＝554[M+1] +。
Embodiment 21
2-(3, the 4-difluorophenyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-Trimetylene-1-sulphonamide
Figure BDA0000135908570000602
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 2-(3, the 4-difluorophenyl)-Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.44(dd，J＝2.0Hz?&?10.0Hz，1H)，7.29(m，1H)，7.11-7.13(m，1H)，7.07(s，1H)，6.74-6.77(m，1H)，6.12(t，J＝8.4Hz，1H)，5.30(s，1H)，3.43(s，3H)，2.57-2.63(m，2H)，2.05(s，3H)，1.73-1.75(m，1H)，1.38-1.42(m，1H)；m/z＝590[M+1] +。
Embodiment 22
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(thiophene-2-yl)-Trimetylene-1-sulphonamide
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 2-(thiophene-2-yl)-Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.43(dd，J＝2.0Hz?&?10.4Hz，1H)，7.23(d，J＝5.6Hz，2H)，7.16(d，J＝5.2Hz，1H)，6.98(s，1H)，6.94(dd，J＝3.6Hz?&?5.2Hz，1H)，6.75(d，J＝3.2HZ，1H)，6.09(t，J＝8.4Hz，1H)，3.41(s，3H)，2.67-2.80(m，1H)，2.63-2.66(m，1H)，2.04(d，J＝2.0Hz，3H)，1.76-1.81(m，1H)，1.39-1.44(m，1H)；m/z＝560[M+1] +。
Embodiment 23
2-(2,4 difluorobenzene base)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-Trimetylene-1-sulphonamide
Figure BDA0000135908570000612
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 2-(2,4 difluorobenzene base)-Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.43(dd，J＝1.6Hz?&?10.0Hz，1H)，7.26(m，1H)，7.09(s，1H)，7.04(s，1H)，6.82-6.89(m，3H)，6.12(t，J＝8.8Hz，1H)，5.94(s，1H)，3.43(s，3H)，2.68-2.74(m，2H)，2.01(s，3H)，1.72-1.78(m，1H)，1.47-1.49(m，1H)；m/z＝590[M+1] +。
Embodiment 24
2-(4-cyano-phenyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-Trimetylene-1-sulphonamide
Figure BDA0000135908570000621
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 2-(4-cyano-phenyl)-Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.62(d，J＝8.4HZ，2H)，7.44(dd，J＝1.6Hz?&?10.0Hz，1H)，7.29(m，1H)，7.10(d，J＝8.4Hz，2H)，7.03(s，1H)，6.91(s，1H)，6.12(t，J＝8.4Hz，1H)，5.84(s，1H)，3.43(s，3H)，2.64-2.71(m，2H)，2.01(s，3H)，1.78-1.84(m，1H)，1.46-1.49(m，1H)；m/z＝579[M+1] +。
Embodiment 25
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-1-methyl cyclopropane-1-sulphonamide
Steps A: Trimetylene sulphonyl isopropyl ester
Trimetylene SULPHURYL CHLORIDE (21.6 grams, 154mmol, 1 equivalent) is dissolved in excessive i-PrOH (50 milliliters), and with 0 ℃ of reaction mixture cooling.Drip pyridine (12.15 grams, 154mmol, 1 equivalent), mixture slowly is heated to room temperature, and stirred 94 hours.Removal of solvent under reduced pressure, and the gained white solid is dissolved in methylene dichloride.Water, salt solution clean organic phase, and dry (sal epsom) filters and concentrated filtrate obtains oily matter (17.8 grams, 71%). 1H?NMR(400MHz，CDCl 3)δ4.91-4.97(m，1H)，2.42-2.48(m，1H)，1.41-1.44(m，6H)，1.24-1.28(m，2H)，1.04-1.10(m，2H)；
Step B:1-methyl-Trimetylene-1-sulfonic acid isopropyl ester
Figure BDA0000135908570000631
Under-78 ℃, nitrogen atmosphere, (2 grams slowly add butyllithium (6.1 milliliters contain the hexane of 2.5M butyllithium, 15.22mmol) in THF 12.18mmol) (40 milliliters) solution to Trimetylene sulfonic acid isopropyl ester.Stir after 30 minutes, add methyl iodide (1.44 grams, THF 10.15mmol) (5 milliliters) solution.Reaction mixture was stirred 2 hours at-60 ℃.Water cancellation solution, and be warming up to room temperature.The reduction vaporization volatile matter, and use the ethyl acetate extraction residue.Water cleans organic phase, and dry (sal epsom) filters, and evaporation removes and desolvates.Through silica gel column chromatography (eluent: PE/EA=5: 1) purifying residue, thereby the acquisition above-mentioned title compound of yellow oily (830 milligrams, productive rate 46%). 1H?NMR(400MHz，CDCl 3)δ4.91-4.96(m，1H)，1.54-1.56(m，2H)，1.41-1.48(m，2H)，0.83-0.88(m，2H)；
Step C:1-methyl-Trimetylene-1-potassium sulfonate
Figure BDA0000135908570000632
To contain 1-methyl-Trimetylene-1-sulfonic acid isopropyl ester (810 milligrams, 4.54mmol) and Rhocya (442 milligrams, DME 4.54mmol) (12.5 milliliters) and water (12.5 milliliters) mixture heating up reflux and spend the night.Use the ethyl acetate extraction residue, and the reduction vaporization water, thereby obtaining crude product, it can be used for next step reaction and need not further purifying.
Step D:1-methyl-Trimetylene-1-SULPHURYL CHLORIDE
Figure BDA0000135908570000633
To contain 1-methyl-Trimetylene-1-potassium sulfonate (349 milligrams, THIONYL CHLORIDE 97 2mmol) (5 milliliters) and DMF (5) vlil 1.5 hours.The reduction vaporization volatile matter, and slowly add water.Be to use the ethyl acetate extraction residue, use dried over mgso, filtration and evaporation are to obtain the crude product of yellow oily, and it can be used for next step reaction and need not to be further purified.
Step e: N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-1-methyl-Trimetylene-1-sulphonamide
Figure BDA0000135908570000641
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 1-methyl-Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.43(dd，J＝2.0Hz?&?10.4Hz，1H)，7.28(m，1H)，7.08(s，1H)，6.11(t，J＝8.4Hz，1H)，5.73(s，1H)，3.44(s，3H)，2.05(s，3H)，1.58(s，3H)，1.26-1.32(m，2H)，0.78-0.80(m，2H)；m/z＝492[M+1] +。
Embodiment 26
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) tetramethylene sulphonamide
Steps A: tetramethylene SULPHURYL CHLORIDE
Figure BDA0000135908570000642
To containing magnesium chips (0.405 gram, the iodine of interpolation 0.3 gram bromo tetramethylene and catalytic amount in 5 milliliters of anhydrous THF suspensions 16.67mmol).Use the electric blower heated mixt.After solution becomes colorless, slowly add the 1.2 gram bromo tetramethylene that are dissolved in 15 milliliters of THF.To mix no reflux 1 hour, and be cooled to room temperature subsequently, (4.5 grams are in 10 milliliters of ice-cold solution of anhydrous methylene chloride 33.3mmol) to containing sulfuryl chloride with the supernatant portion-wise addition.After adding completion, suspension is heated to room temperature, and removes volatile matter in a vacuum.Residue is dissolved in hexane (25 milliliters).Also evaporating solns is to obtain yellow oily crude product (1.55 grams, 90%) with the suspension filtration, and it can be used for next step reaction and need not to be further purified.
Step B:N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-tetramethylene sulphonamide
Figure BDA0000135908570000643
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and the reaction of tetramethylene SULPHURYL CHLORIDE, thus obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.44(dd，J＝2.0Hz?&?10.0Hz，1H)，7.28(m，1H)，7.20(s，1H)，7.08(s，1H)，6.11(t，J＝8.4Hz，1H)，5.61(s，1H)，3.84-3.88(m，1H)，3.43(s，3H)，2.52-2.57(m，2H)，2.29-2.35(m，2H)，2.17(s，3H)，2.03-2.08(m，2H)；m/z＝492[M+1] +。
Embodiment 27
1-(2, the 3-dihydroxypropyl)-N-(2-(2-fluoro-4-iodophenyl is amino) 1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-Trimetylene-1-sulphonamide
Steps A: 1-allyl group-Trimetylene alkylsulfonyl (2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) t-butyl carbamate
Figure BDA0000135908570000651
At 0 ℃, to containing 1-allyl group-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1; 6-dihydropyridine-3-yl)-the Trimetylene sulphonamide (182 milligrams, 0.352mmol) with and the dimethyl dicarbonate butyl ester (84 milligrams, 0.387mmol; 1.1 add NaH (60%wt in 3 milliliters of anhydrous THF solutions equivalent); 31 milligrams, 2.2 equivalents), stirred overnight (14 hours) at room temperature subsequently.After the water cancellation, add ETHYLE ACETATE.Water cleans organic phase and uses the ethyl acetate extraction water.Clean the organic layer that merges with salt solution, use dried over mgso, filter, and concentrating under reduced pressure filtrating.Through quick silica gel column chromatography (eluent is PE: EA=2: 1) purifying residue, thereby obtain the light yellow oil of above-mentioned title compound (138 milligrams, productive rate=63%). 1H?NMR(400MHz，CDCl 3)δ7.45-7.50(m，2H)，7.32(s，1H)，7.12(t，J＝8.4Hz，1H)，5.68-5.78(m，1H)，5.54(s，1H)，5.08-5.15(m，2H)，3.39(s，3H)，2.68(d，J＝7.6Hz，2H)，2.16(s，3H)，1.15(s，9H)，1.30-1.35(m，1H)，1.23-1.27(m，1H)，0.85-0.92(m，2H)；m/z＝618[M+1] +。
Step B:1-(2, the 3-dihydroxypropyl)-N-(2-(2-fluoro-4-iodophenyl is amino) 1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) t-butyl carbamate
At 0 ℃, to 1-allyl group Trimetylene alkylsulfonyl (2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1; 6-dihydropyridine-3-yl) t-butyl carbamate is (100 milligrams; 0.162mmol) add N-methylmorpholine-N-oxide compound (19 milligrams 0.162mmol), are added osmium oxide (VIII) (4%wt at 0 ℃ subsequently in the solution; 103 milligrams, 0.1 equivalent).Stirring at room 18 hours, is to use the aqueous sodium persulfate solution cancellation with mixture subsequently, uses dichloromethane extraction, with dried over mgso and filter.Remove the solvent in the filtrating, and through quick silica gel column chromatography (eluent: DCM: MeOH=10: 1) purifying residue, thereby obtain the gray solid of above-mentioned title compound (96 milligrams, 91%). 1H?NMR(400MHz，CDCl 3)δ7.46-7.48(m，2H)，7.35(s，1H)，7.16(t，J＝8.4Hz，1H)，6.31(d，J＝5.2Hz，1H)，4.00(m，1H)，3.59(d，J＝11.2Hz，1H)，3.41(s，3H)，3.40-3.49(m，1H)，3.23(s，1H)，2.26(dd，J＝15.6&9.6Hz，1H)，2.16(s，3H)，1.77(dd，J＝15.6&45.2Hz，1H)，1.15(s，9H)，1.25(m，2H)，1.00(m，2H)；m/z＝652[M+1] +。
Step C:1-(2, the 3-dihydroxypropyl)-N-(2-(2-fluoro-4-iodophenyl is amino) 1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-Trimetylene-1-sulphonamide
Figure BDA0000135908570000662
At room temperature; To containing 1-(2, the 3-dihydroxypropyl)-N-(2-(2-fluoro-4-iodophenyl is amino) 1,5-dimethyl--6-carbonyl-1; 6-dihydropyridine-3-yl) t-butyl carbamate (43 milligrams are added trifluoroacetic acid (0.5 milliliter) and stirred 1 hour in 1 milliliter of dichloromethane solution 0.066mmol).With saturated sodium carbonate solution cancellation reaction and stirred 0.5 hour.After using methylene dichloride (3x) extraction, add sodium-chlor to water, and be to extract with methylene dichloride (3x).Be the organic layer that merges with dried over mgso, and filter.The solvent in the filtrating is removed in decompression, and through quick silica gel column chromatography (eluent: DCM: MeOH=10: 1) purifying residue, thereby the acquisition above-mentioned title compound of gray solid shape (24 milligrams, productive rate 66%). 1H?NMR(400MHz，CDCl 3)δ7.49(s，1H)，7.39-7.42(dd，J＝1.6&11.2Hz，1H)，7.42(s，1H)，7.24-7.26(m，2H)，6.10(t，J＝8.0Hz，1H)，3.92(m，1H)，3.66(s，1H)，3.57-3.60(m，1H)，3.42-3.46(m，1H)，3.42(s，3H)，2.72(s，1H)，2.25(dd，J＝9.6&15.2Hz，1H)，2.15(s，3H)，1.63(d，J＝14.4Hz，1H)，1.37-1.42(m，1H)，1.22-1.33(m，1H)，0.81-0.90(m，2H)；m/z＝552[M+1] +。
Embodiment 28
(R)-1-(2, the 3-dihydroxypropyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
Figure BDA0000135908570000671
Steps A: (R)-1-(3-(benzyloxy)-2-hydroxypropyl)-Trimetylene-1-sulfonic acid isopropyl ester
At-78 ℃, 25 minutes (ETHYLE ACETATE/N 2Bathe) in, (2.5M, 228mmol) adds to and contains Trimetylene sulfonic acid isopropyl ester (30 grams are among anhydrous THF 183mmol) (450 milliliters) and the HMPA (hexamethylphosphoramide, 50 milliliters) and stirred 30 minutes, subsequently at-40 ℃ of (acetonitrile/N by 91 milliliters with the n-butyllithium 2Bathe) the stirring dark solution, interpolation (R)-2-(benzyloxymethyl) oxyethane (25 grams, THF 152mmol) (50 milliliters), and-40 ℃ of stirrings 3 hours.Be water cancellation reaction, with ETHYLE ACETATE (2x) extraction, saturated nacl aqueous solution cleans, by dried over mgso and filtration.Removal of solvent under reduced pressure is through purification by silica gel column chromatography residue (eluent: sherwood oil: ETHYLE ACETATE=5: 1 to 2: 1), thereby obtain the above-mentioned title compound of brown oily (37.9 grams, productive rate=76%). 1H?NMR(400MHz，CDCl 3)δ7.30-7.37(m，5H)，4.95(sept，6.0Hz，1H)，4.55(s，2H)，4.16-4.20(m，1H)，3.51(dd，J＝9.6Hz&4.8Hz，1H)，3.42(dd，J＝9.6Hz&6.0Hz，1H)，2.70(d，J＝4.0Hz，1H)，2.08(dd，J＝15.6Hz&3.6Hz，1H)，1.88(dd，J＝15.2Hz&8.8Hz，1H)，1.44-1.46(m，2H)，1.43(d，J＝6.0Hz，3H)，1.15-1.18(m，1H)，0.93-0.97(m，1H)；m/z＝329[M+1] +。
Step B: (R)-1-(2, two (benzyloxy) propyl group of 3-)-Trimetylene-1-sulfonic acid isopropyl ester
Figure BDA0000135908570000681
At 0 ℃, (1.38 grams 4.2mmol) add to and contain NaH (60%wt, in DMF mixture 5.25mmol), and stirred 30 minutes by 210 milligrams with (R)-1-(3-(benzyloxy)-2-hydroxypropyl)-Trimetylene-1-sulfonic acid isopropyl ester.At 0 ℃, in reaction mixture, add bromobenzyl (0.75 milliliter, 6.3mmol), and stirred overnight (13 hours) at room temperature, follow by the water cancellation, use ethyl acetate extraction, clean with water (2x) and saturated brine, by dried over mgso and filter.Removal of solvent under reduced pressure is through purification by silica gel column chromatography residue (eluent: sherwood oil: ETHYLE ACETATE=10: 1 to 5: 1), thereby obtain the above-mentioned title compound (1.145 grams, productive rate=65%) of brown oil. 1H?NMR(400MHz，CDCl 3)δ7.26-7.34(m，10H)，4.89(sept，J＝6.0Hz，1H)，4.63(dd，J＝36.4Hz&11.2Hz，2H)，4.55(s，3H)，4.13-4.16(m，1H)，4.15(dd，J＝8.4Hz&4.4Hz，2H)，3.56(dd，J＝4.4Hz，&1.2Hz，1H)，2.32(dd，J＝15.6Hz&4.4Hz，1H)，1.40-1.45(m，2H)，1.37(dd，J＝8.0Hz&6.0Hz，6H)，1.18-1.22(m，1H)，0.87-0.92(m，1H)；m/z＝419[M+1] +。
Step C: (R)-1-(2, two (benzyloxy) propyl group of 3-)-Trimetylene-1-potassium sulfonate
Figure BDA0000135908570000682
With (R)-1-(2,3-two (benzyloxy) propyl group)-Trimetylene-1-sulfonic acid isopropyl ester (450 milligrams, 1.075mmol) and Rhocya (115 milligrams 1.183mmol) are dissolved in the solution (10 milliliters, volume ratio is 2: 1) of dme and water.The reaction mixture reflux is spent the night, subsequently with the mixture reduction vaporization.Use the ether wash residue, thereby obtain the above-mentioned title compound of sticky solid shape.
Step D: (R)-1-(2, two (benzyloxy) propyl group of 3-) Trimetylene-1-SULPHURYL CHLORIDE
(R)-1-(2, two (benzyloxy) propyl group of 3-)-Trimetylene-1-potassium sulfonate is dissolved in sulfur dichloride (7 milliliters) and DMF (1 milliliter).With reaction mixture reflux 1 hour, subsequently with the mixture reduction vaporization.Through silica gel column chromatography gradient elution (eluent: ETHYLE ACETATE: purifying xanchromatic residue sherwood oil=1: 5), thereby the above-mentioned title compound of acquisition yellow oily (250 milligrams, two step overall yields 60%). 1H?NMR(400MHz，CDCl 3)δ7.29-7.37(m，10H)，4.60(dd，J＝57.6Hz&11.6Hz，2H)4.56(s，2H)，4.14-4.20(m，1H)，3.54-3.62(m，2H)，2.63(dd，J＝16.4Hz&3.6Hz，1H)，2.17(s，3H)，2.02(dd，J＝16.4Hz&9.2Hz.1H)，1.75-1.81(m，1H)，1.65-1.71(m，1H)，1.52-1.57(m，1H)，1.14-1.19(m，1H)。
Step e: (R)-1-(2, two (benzyloxy) propyl group of 3-)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-Trimetylene-1-sulphonamide
Figure BDA0000135908570000692
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-1,3-lutidine-2 (1H)-ketone with (R)-1-(2, two (benzyloxy) propyl group of 3-) Trimetylene-1-SULPHURYL CHLORIDE reaction, thereby obtain the purpose product. 1H?NMR(400MHz，CDCl 3)δ7.22-7.41(m，11H)，7.00(s，1H)，6.87(s，1H)，6.55(s，1H)，5.99(t，J＝8.8Hz，1H)，4.57(dd，J＝72.4Hz&10.8Hz，2H)，4.52(s，2H)，3.89-3.92(m，1H)，3.60(dd，J＝9.6Hz&4.0Hz，1H)，3.50(dd，J＝9.6Hz&5.6Hz，1H)，3.31(s，3H)，2.18-2.20(m，2H)，2.08(s，3H)，1.38-1.42(m，1H)，1.24-1.30(m，1H)，0.84-0.97(m，1H)，0.84-0.87(m，1H)；m/z＝732[M+1] +。
Step F: (R)-1-(2, the 3-dihydroxypropyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-Trimetylene-1-sulphonamide
At 0 ℃; With the boron trichloride (dichloromethane solution that contains the 1M boron trichloride; 0.8 milliliter) add to and contain (R)-1-(2,3-two (benzyloxy) propyl group)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1; 6-dihydropyridine-3-yl)-and Trimetylene-1-sulphonamide (61 milligrams, in 8 milliliters of methylene dichloride 0.083mmol).After 10 minutes, add 1M HCl in stirring at room, and use the dichloromethane extraction mixture.Use saturated sodium bicarbonate solution, saturated nacl aqueous solution to clean organic phase, and use dried over mgso.The solvent that removes by filter in the filtrating is sick through silica gel column chromatography (eluent: methylene dichloride: methyl alcohol=15: 1) handle residue, thereby obtain the above-mentioned title compound of gray solid shape (41 milligrams, 90%). 1H?NMR(400MHz，CDCl 3)δ7.43(d，J＝10.4Hz，1H)，7.35(s，1H)，7.26(s，1H)，7.12(s，1H)，6.84(s，1H)，6.10(t，J＝8.8Hz，1H)，3.96(m，1H)，3.65(m，1H)，3.50(m，1H)，3.44(s，3H)，3.16(s，1H)，2.34(dd，J＝10.0&15.6Hz，1H)，2.18(s，3H)，1.97(s，1H)，1.67(d，J＝15.6Hz，1H)，1.46-1.49(m，1H)，1.26-1.30(m，1H)，0.88-0.95(m，2H)； 1H?NMR(400MHz，CDCl 3+2?drops?of?DMSO-d6)δ8.64(s，1H)，7.68(s，1H)，7.49(s，CDCl 3)，7.37(s，1H)，7.32(dd，J＝10.4&2.0Hz，1H)，7.17(d，J＝8.4Hz，1H)，6.05(t，J＝8.8Hz，1H)，4.04(m，1H)，3.90(m，1H)，3.72(m，1H)，3.31(s，3H)，3.22-3.34(m，1H)，2.50(DMSO-d6)，1.68-1.80(m，2H)，1.10-1.18(m，1H)，0.99-1.03(m，1H)，0.80-0.82(m，1H)，0.73-0.76(m，1H)；m/z＝552[M+1] +。
Embodiment 29
(S)-1-(2, the 3-dihydroxypropyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-Trimetylene-1-sulphonamide
Steps A: (S)-1-(3-(benzyloxy)-2-hydroxypropyl)-Trimetylene-1-sulfonic acid isopropyl ester
Steps A according to method in the foregoing description 28 obtains above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.30-7.37(m，5H)，4.95(sept，6.0Hz，1H)，4.55(s，2H)，4.16-4.20(m，1H)，3.51(dd，J＝9.6Hz&4.8Hz，1H)，3.42(dd，J＝9.6Hz&6.0Hz，1H)，2.70(d，J＝4.0Hz，1H)，2.08(dd，J＝15.6Hz&3.6Hz，1H)，1.88(dd，J＝15.2Hz&8.8Hz，1H)，1.44-1.46(m，2H)，1.43(d，J＝6.0Hz，3H)，1.15-1.18(m，1H)，0.93-0.97(m，1H)；m/z＝329[M+1] +。
Step B: (S)-1-(2, two (benzyloxy) propyl group of 3-) Trimetylene-1-sulfonic acid isopropyl ester
Figure BDA0000135908570000712
Step B according to method in the foregoing description 28 obtains above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.26-7.34(m，10H)，4.89(sept，J＝6.0Hz，1H)，4.63(dd，J＝36.4Hz&11.2Hz，2H)，4.55(s，3H)，4.13-4.16(m，1H)，4.15(dd，J＝8.4Hz&4.4Hz，2H)，3.56(dd，J＝4.4Hz，&1.2Hz，1H)，2.32(dd，J＝15.6Hz&4.4Hz，1H)，1.40-1.45(m，2H)，1.37(dd，J＝8.0Hz&6.0Hz，6H)，1.18-1.22(m，1H)，0.87-0.92(m，1H)；m/z＝419[M+1] +。
Step C: (S)-1-(2, two (benzyloxy) propyl group of 3-) Trimetylene-1-potassium sulfonate
Figure BDA0000135908570000713
According to the step C of 28 kinds of methods of the foregoing description, obtain above-mentioned title compound.
Step D: (S)-1-(2, two (benzyloxy) propyl group of 3-) Trimetylene-1-sulphonic acid chloride
According to the step D of 28 kinds of methods of the foregoing description, obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.29-7.37(m，10H)，4.60(dd，J＝57.6Hz&11.6Hz，2H)4.56(s，2H)，4.14-4.20(m，1H)，3.54-3.62(m，2H)，2.63(dd，J＝16.4Hz&3.6Hz，1H)，2.17(s，3H)，2.02(dd，J＝16.4Hz&9.2Hz，1H)，1.75-1.81(m，1H)，1.65-1.71(m，1H)，1.52-1.57(m，1H)，1.14-1.19(m，1H)。
Step e: (S)-1-(2, two (benzyloxy) propyl group of 3-)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
Figure BDA0000135908570000722
Step e according to method in the foregoing description 28 obtains above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.22-7.41(m，11H)，7.00(s，1H)，6.87(s，1H)，6.55(s，1H)，5.99(t，J＝8.8Hz，1H)，4.57(dd，J＝72.4Hz&10.8Hz，2H)，4.52(s，2H)，3.89-3.92(m，1H)，3.60(dd，J＝9.6Hz&4.0Hz，1H)，3.50(dd，J＝9.6Hz&5.6Hz，1H)，3.31(s，3H)，2.18-2.20(m，2H)，2.08(s，3H)，1.38-1.42(m，1H)，1.24-1.30(m，1H)，0.84-0.97(m，1H)，0.84-0.87(m，1H)；m/z＝732[M+1] +。
Step F: (S)-1-(2, the 3-dihydroxypropyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
Step F according to method in the foregoing description 28 obtains above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.43(d，J＝10.4Hz，1H)，7.35(s，1H)，7.26(s，1H)，7.12(s，1H)，6.84(s，1H)，6.10(t，J＝8.8Hz，1H)，3.96(m，1H)，3.65(m，1H)，3.50(m，1H)，3.44(s，3H)，3.16(s，1H)，2.34(dd，J＝10.0&15.6Hz，1H)，2.18(s，3H)，1.97(s，1H)，1.67(d，J＝15.6Hz，1H)，1.46-1.49(m，1H)，1.26-1.30(m，1H)，0.88-0.95(m，2H)；m/z＝552[M+1] +。
Embodiment 30
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-1-(3-hydroxypropyl) Trimetylene-1-sulphonamide
Under nitrogen atmosphere, stir (the 2-(2-fluoro-4-iodophenyl is amino)-1 of 1-allyl group Trimetylene alkylsulfonyl in three mouthfuls of round-bottomed flasks; 5-dimethyl--6-carbonyl-1; 6-dihydropyridine-3-yl) the carboxylamine tertiary butyl ester (100 milligrams, 0.162mmol) and the mixture of THF (2 milliliters).Use syringe with BH 3-THF (1 milliliter 1mmol) slowly joins in the reaction flask.At room temperature stirring reaction is 48 hours, carries out refrigerative simultaneously with ice bath, and in reaction flask, adds aqueous sodium hydroxide solution (3M, 1 milliliter) and 30%H 2O 2The aqueous solution (3 milliliters).After adding completion, mixture was at room temperature stirred 2 hours, use ethyl acetate extraction subsequently.Clean organic phase with salt solution, use dried over mgso, filter and concentrating under reduced pressure filtrating.Through silica gel column chromatography (eluent: purifying residue ETHYLE ACETATE), thereby obtain above-mentioned title product 1-OH (66 milligrams, 64%) and by product 2-OH (27 milligrams, 26%).With 1-OH product (60 milligrams 0.094mmol) are dissolved in 2 milliliters of methylene dichloride, and slowly add excessive TFA (trifluoroacetic acid, 0.5 milliliter).Mixture is at room temperature stirred 2 hours, and remove volatile matter in a vacuum.(eluent is a methylene dichloride: purifying residue methyl alcohol=20: 1), thereby acquisition purpose product (44 milligrams, 87%) through silica gel column chromatography. 1H?NMR(400MHz，DMSO)δ8.86(s，1H)，7.98(s，1H)，7.58(dd，J＝1.6Hz?&?10.8Hz，1H)，7.33-7.36(m，2H)，6.27(t，J＝8.8Hz，1H)，4.18(br，1H)，3.22-3.33(m，5H)，2.03(s，3H)，1.61-1.65(m，2H)，1.28-1.32(m，2H)，0.86-0.92(m，2H)，0.63-0.66(m，2H)；m/z＝535[M+1] +。
Embodiment 31
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-1-(2-hydroxypropyl) Trimetylene-1-sulphonamide
Figure BDA0000135908570000741
According to obtaining the purpose product with embodiment 30 identical methods. 1H?NMR(400MHz，DMSO-D6)δ8.82(br，1H)，7.94(s，1H)，7.57(dd，J＝2.0Hz?&?10.8Hz，1H)，7.39(s，1H)，7.31(d，J＝8.4Hz，1H)，6.25(t，J＝8.4Hz，1H)，4.45(d，J＝5.6Hz，1H)，3.60(br，1H)，3.26(s，3H)，2.00(s，3H)，1.78-1.83(m，1H)，1.52-1.58(m，1H)，0.81-0.94(m，5H)；m/z＝535[M+1] +。
Embodiment 32
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) butane-1-sulphonamide
Steps A: 2-chloro-4-nitropyridine 1-oxide compound
Figure BDA0000135908570000742
At 0 ℃, in the mixture of 2-chloro-5-picoline, hydrogen peroxide urea addition compound and methylene dichloride, drip anhydrous trifluoroacetic acid, and mixture was stirred 1 hour at 0 ℃.After stirring 3 days and temperature of reaction risen to room temperature, add and connect and the aqueous solution (250 milliliters) of S-WAT (45 gram), and cry reaction mixture stirring 15 minutes.Add hydrochloric acid (0.5N, 400 milliliters) and use methylene dichloride (400 milliliters) extraction mixture.Use sodium hydrogen carbonate solution to clean organic phase, by dried over mgso, filter, the solvent in the filtrating is removed in decompression, thereby obtains the above-mentioned title compound of yellow solid shape, and it can be used for next step reaction and need not to be further purified.Productive rate=90%. 1H?NMR(400MHz，CDCl 3)：δ＝8.422-8.404(t，1H，J＝3.6Hz)，8.399-8.375(t，1H，J＝4.8Hz)，8.067-8.049(t，1H，J＝3.6Hz)。
Step B:2-chloro-4-methoxypyridine 1-oxide compound
Figure BDA0000135908570000751
To be dissolved in anhydrous methanol (1000 milliliters) and the quick impouring of the sodium methoxide solution that makes contains in methyl alcohol (1000 milliliters) stirred solution of 2-chloro-4-nitropyridine 1-oxide compound (151 gram) by sodium (21 gram).In 5 minutes, accomplish dissolving, and stirring reaction spends the night in the flask of jumping a queue.Yellow solution is concentrated a part, produce, this throw out is leached, and clean with methyl alcohol (2x100 milliliter) by throw out.To filtrate and washing lotion is evaporated to driedly, and with the remaining solid of dichloromethane extraction that boils, thereby obtain (filtering and concentrate the back) pale brown look solid, it can be used for next step reaction and need not to be further purified.Productive rate=95%. 1H?NMR(400MHz，CDCl 3)：δ＝8.256-8.237(d，1H，J＝7.6Hz)，7.026-7.018(d，1H，J＝3.2Hz)，6.804-6.777(dd，1H，J＝3.6?&?3.2Hz)，3.875(s，3H)。
Step C:2,6-two chloro-4-methoxypyridines
Figure BDA0000135908570000752
At 0 ℃,, add methylene dichloride (250 milliliters) solution of phosphoryl chloride (151 gram) in methylene dichloride (1000 milliliters) mixture of 6-two chloro-4-methoxypyridine 1-oxide compounds (130 gram) and triethylamine (151 milliliters) to 2.Stir 2 hours again in stirring at room after 1 hour at 0 ℃, add entry and use sodium hydroxide solution (6N) this mixture that neutralizes, and use saturated brine solution to clean isolating organic layer.With the water layer of ethyl acetate extraction reaction soln, and clean with saturated brine solution.Organic layer with dried over sodium sulfate merges filters, and concentrated filtrate in the vacuum obtains crude product, through silicagel column (petrol ether/ethyl acetate=10/1) this crude product of purifying, thereby obtains required compound.Productive rate=38.3%. 1H?NMR(400MHz，CDCl 3)：δ＝6.794(s，2H)，3.877(s，3H)；m/z＝178[M+1] +。
Step D:2,6-two chloro-4-methoxyl group-3-nitropyridines
Figure BDA0000135908570000761
At 0 ℃,, add concentrated nitric acid (95%) in the concentrated sulfuric acid solution of 6-two chloro-4-methoxypyridines (40 gram) to 2.Mixture was heated 3.5 hours at 100 ℃.After being cooled to 50 ℃, in mixture impouring ice.Filtering gained throw out and water cleans.White solid is dissolved in methylene dichloride, uses dried over sodium sulfate, filter, concentrating under reduced pressure filtrating, thus obtaining the above-mentioned title compound of white solid, it can use without being further purified.Productive rate=82%. 1H?NMR(400MHz，CDCl 3)：δ＝6.994(s，1H)，4.023(s，3H)；m/z＝223[M+1] +。
Step e: 6-chloro-N-(2-fluoro-4-iodophenyl)-4-methoxyl group-3-nitropyridine-2-amine
At room temperature, in the THF mixture that contains sodium hydride (3.0 equivalent), add 2-fluoro-4-Iodoaniline (1.0 equivalent).This mixture 60 ℃ of heating 15 minutes, is added 2,6-two chloro-4-methoxyl group-3-nitropyridines subsequently.After the reflux 0.5 hour, with reaction cooled and add entry.Filter suspension and dry, thereby obtain above-mentioned title compound.Productive rate=50%. 1H?NMR(400MHz，CDCl 3)：δ＝9.529(brs，1H)，8.032-7.998(t，1H，J＝8.8Hz)，7.493-7.463(m，2H)，6.523(s，1H)，3.974(s，3H)；m/z＝424[M+1] +。
Step F: 6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-5-nitropyridine-2 (1H)-ketone
Figure BDA0000135908570000763
In potassium hydroxide aqueous solution (14.4 gram Pottasium Hydroxide are dissolved in 52 ml waters), successively add compound 6-chloro-N-(2-fluoro-4-iodophenyl)-4-methoxyl group-3-nitropyridine-2-amine (2 gram) and methyl alcohol (150 milliliters).Mixture heating up was refluxed 1.5 hours.Add cold water, filter yellow suspension and dry, obtain above-mentioned title compound.Use concentrated hydrochloric acid to filtrate and modulate pH7, thereby obtain yellow mercury oxide, with this yellow mercury oxide filtration and dry, thus the above-mentioned title compound of acquisition red solid shape, it can be used for next step reaction and need not to be further purified.Productive rate=99%. 1H?NMR(400MHz，CDCl 3)：δ＝10.257(brs，1H)，7.564-7.490(m，2H)，7.174-7.133(t，1H，J＝8.4Hz)，6.523(s，1H)，3.974(s，3H)；m/z＝405[M+1] +。
Step G:6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-5-nitro pyridine-2 (1H)-ketone
Figure BDA0000135908570000771
At room temperature, in dry DMF (0.2mol/L) solution of sodium hydride (2.5 equivalent), add 6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-5-nitro pyridine-2 (1H)-ketone (1 equivalent).Stir after 25 minutes, in the garnet mixture, add methyl iodide (1.3 equivalent), and continue to stir 1 hour, add saturated ammonium chloride solution then.Use the ethyl acetate extraction mixture, water and salt solution clean.Use the dried over mgso organic layer, filter, concentrated filtrate in the vacuum obtains crude product, and through silica gel column chromatography (by sherwood oil 100% to petrol ether/ethyl acetate～1/2) purifying crude product, thereby obtain the above-mentioned title compound of yellow solid shape.Productive rate=50%. 1H?NMR(400MHz，CDCl 3)：δ＝8.799(brs，1H)，7.525-7.268(dd，2H，J＝10?&?7.6Hz)，6.593-6.551(t，1H，J＝8.4Hz)，5.810(s，1H)，3.912(s，3H)，3.230(s，3H)；m/z＝420[M+1] +。
Step H:5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone
6-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-1-methyl-5-nitro pyridine-2 (1H)-ketone (220 milligrams) and Sodium Persulfate (1.96 restrain 16 equivalents) are dissolved in dioxane and water (30 milliliters, 1: 1), subsequently sky-high price volatile caustic (1 milliliter) at room temperature.After 1 hour, use 100 milliliters of ETHYLE ACETATE diluted mixture things, water and salt solution clean.With ETHYLE ACETATE (2x) aqueous layer extracted, clean with salt solution, with dried over sodium sulfate, filter, concentrated filtrate in the vacuum, thus obtain crude product, through this crude product of preparation TLC purifying, obtain above-mentioned title compound.Productive rate=50%. 1H?NMR(400MHz，CDCl 3)：δ＝7.525-7.268(dd，2H，J＝10?&?7.6Hz)，6.593-6.551(t，1H，J＝8.4Hz)，5.810(s，1H)，3.912(s，3H)，3.230(s，3H)；m/z＝390[M+1] +。
Step I:N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) butane-1-sulphonamide
Figure BDA0000135908570000781
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and butane-1-SULPHURYL CHLORIDE reaction, thereby obtain the purpose compound.Productive rate=76.6%. 1H?NMR(400MHz，CDCl 3)：δ＝7.750(brs，1H)，7.424-7.420(d，1H，J＝1.6Hz)，7.399-7.395(d，1H，J＝1.6Hz)，6.511(brs，1H)，6.226-6.183(t，1H，J＝8.6Hz)，5.926(s，1H)，3.849(s，3H)，3.299(s，1H)，3.048-3.008(t，3H，J＝8.6Hz)，1.866-1.809(m，2H)，1.455-1.399(m，2H)，0.994-0.960(t，3H，J＝6.8Hz)；m/z＝509.92[M+1] +。
Embodiment 33
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) benzsulfamide
Figure BDA0000135908570000782
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and benzene sulfonyl chloride reaction, thereby obtain the purpose compound.Productive rate=25%. 1H?NMR(400MHz，CDCl 3)：δ＝7.749-7.713(t，3H，J＝7.2Hz)，7.598-7.561(t，1H，J＝5.8Hz)，7.472-7.424(t，3H，J＝9.6Hz)，6.239-6.196(t，1H，J＝8.6Hz)，5.602(s，1H)，3.340(s，3H)，3.162(s，3H)；m/z＝529.79[M+1] +。
Embodiment 34
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) hexanaphthene sulphonamide
Figure BDA0000135908570000791
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and the reaction of hexanaphthene SULPHURYL CHLORIDE, thereby obtain the purpose compound.Productive rate=9.45%. 1H?NMR(400MHz，CDCl 3)：δ＝7.828(brs，1H)，7.451-7.422(d，1H，J＝2Hz)，7.289-7.269(d，1H，J＝8Hz)，6.203-6.168(t，1H，J＝7Hz)，5.903(s，1H)，5.722(brs，1H)，3.826(s，3H)，3.339(s，1H)，2.895(m，1H)，2.245-2.216(brd，2H，J＝11.6Hz)，1.933-1.920(m，2H)，1.724-1.714(br，1H)，1.614-1.555(m，3H)，1.277-1.218(m，2H)；m/z＝535.95[M+1] +。
Embodiment 35
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene sulphonamide
Figure BDA0000135908570000792
According to method A, 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and the reaction of Trimetylene SULPHURYL CHLORIDE, thus obtain the purpose compound.Productive rate=19.72%. 1H?NMR(400MHz，CDCl 3)：δ＝7.663(brs，1H)，7.434-7.409(d，1H，J＝10Hz)，7.289-7.273(d，1H，J＝6.4Hz)，6.218-6.178(t，1H，J＝8.4Hz)，5.913(s，1H)，3.865(s，3H)，3.324(s，1H)，2.437(brs，1H)，1.116(brs，2H)，0.946(brs，2H)；m/z＝493.96[M+1] +。
Embodiment 36
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) thiophene-3 sulphonamide
Figure BDA0000135908570000801
According to method A, 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and thiophene-3-SULPHURYL CHLORIDE reaction, thus obtain the purpose compound.Productive rate=34.1%. 1H?NMR(400MHz，CDCl 3)：δ＝7.897-7.880(d，1H，J＝6.8Hz)，7.719-7.699(d，1H，J＝8Hz)，7.497-7.391(m，2H)，7.333-7.264(m，2H)，6.238-6.216(d，1H，J＝8.8Hz)，5.689-5.666(d，1H，J＝9.2Hz)，3.392-3.375(q，6H，J＝4Hz)；m/z＝535.95[M+1] +
Embodiment 37
3-chloro-N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) propane-1-sulphonamide
Figure BDA0000135908570000802
According to method A, 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 3-chloropropane-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose compound.Productive rate=29.8%. 1H?NMR(400MHz，CDCl 3)：δ＝7.678(brs，1H)，7.462-7.432(dd，1H，J＝1.6?&?2Hz)，7.306-7.267(dd，1H，J＝8.4?&?0.4Hz)，6.227-6.185(t，1H，J＝8.4Hz)，5.916(s，1H)，5820(brs，1H)，3.895(s，3H)，3.687-3.657(t，2H，J＝6Hz)，3.337(s，3H)，3.262-3.224(t，2H，J＝7.6Hz)，2.366-2.297(m，2H)；m/z＝529.75[M+1] +。
Embodiment 38
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) propane-2-sulphonamide
Figure BDA0000135908570000811
According to method A, 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and propane-2-SULPHURYL CHLORIDE reaction, thus obtain the purpose compound.Productive rate=10.21%. 1H?NMR(400MHz，CDCl 3)：δ＝7.850(brs，1H)，7.455-7.426(dd，1H，J＝1.6?&?2Hz)，7.292-7.264(dd，1H，J＝8.4?&?0.4Hz)，6.202-6.159(t，1H，J＝8.8Hz)，5.895(s，1H)，5.716(brs，1H)，3.873(s，3H)，3.340(s，3H)，3.231-3.196(m，1H)，1.439-1.413(t，6H，J＝7.2Hz)；m/z＝495.96[M+1] +
Embodiment 39
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) thiophene-2 sulphonamide
Figure BDA0000135908570000812
According to method A, 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and thiophene-2-SULPHURYL CHLORIDE reaction, thus obtain the purpose compound.Productive rate=17.89%. 1H?NMR(400MHz，CDCl 3)：δ＝7.648-7.633(q，1H，J＝1.6Hz)，7.511-7.499(q，1H，J＝1.2Hz)，7.479-7.449(dd，1H，J＝2?&?2Hz)，7.314-7.293(d，2H，J＝8.4Hz)，7.090-7.078(t，1H，J＝4Hz)，6.242-6.199(t，1H，J＝8.4Hz)，5.667(s，1H)，3.364-3.360(d，6H，J＝1.6Hz)；m/z＝535.93[M+1] +。
Embodiment 40
1-chloro-N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) Toluidrin
Figure BDA0000135908570000821
According to method A, 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and the reaction of methyl chloride SULPHURYL CHLORIDE, thus obtain the purpose compound.Productive rate=29.8%. 1H?NMR(400MHz，CDCl 3)：δ＝7.463-7.433(dd，1H，J＝1.6?&?2Hz)，7.318-7.266(dd，1H，J＝8.4?&?0.4Hz)，6.260-6.218(t，1H，J＝8.4Hz)，5.991(s，1H)，4.252(s，2H)，3.887(s，3H)，3.323(s，3H)；m/z＝501.91[M+1] +。
Embodiment 41
4-fluoro-N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) benzsulfamide
Figure BDA0000135908570000822
According to method A, 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 4-fluoro-benzene-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose compound.Productive rate=27.3%. 1H?NMR(400MHz，CDCl 3)：δ＝7.790-7.760(m，2H)，7.677(s，1H)，7.485-7.460(d，1H，J＝10Hz)，7.319-7.299(d，1H，J＝8Hz)，7.185-7.146(t，2H，J＝8Hz)，6.241-6.199(t，1H，J＝8.4Hz)，5.911(brs，1H)，5.623(s.1H)，3.358(s，3H)，3.279(s，3H)；m/z＝547.99[M+1] +。
Embodiment 42
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) Toluidrin
Figure BDA0000135908570000831
According to method A, 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and methylsulfonyl chloride reaction, thus obtain the purpose compound.Productive rate=30%. 1H?NMR(400MHz，CDCl 3)：δ＝7.660(brs，1H)，7.454-7.429(d，1H，J＝10Hz)，7.304-7.270(dd，1H，J＝8.4?&?1.2Hz)，6.236-6.194(t，1H，J＝8.4Hz)，5.922(s，1H)，3.889(s，3H)，3.332(s，3H)；m/z＝464.97[M+1] +。
Embodiment 43
2,2,2-three fluoro-N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) ethyl sulfonamide
Figure BDA0000135908570000832
According to method A, 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2,2, the reaction of 2-trifluoro ethyl sulfonyl chloride, thus obtain the purpose compound.Productive rate=48.7%. 1H?NMR(400MHz，CDCl 3)：δ＝7.446-7.416(dd，1H，J＝2?&?1.6Hz)，7.310-7.291(d，2H，J＝7.6Hz)，6.264-6.221(t，1H，J＝8.6Hz)，5.940(s，1H)，3.873(s，3H)，3.398(s，3H)；m/z＝535.95[M+1] +。
Embodiment 44
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-2-benzyl ring propane-1-sulphonamide
Figure BDA0000135908570000841
According to method A, 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-benzyl ring propane-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose compound.Productive rate=44%. 1H?NMR(400MHz，CDCl 3)：δ＝7.661(brs，1H)，7.450-7.424(dd，1H，J＝1.6?&?2Hz)，7.321-7.219(m，4H)，6.934-6.913(t，1H，J＝8.4Hz)，6.206-6.213(t，1H，J＝8.4Hz)，5.971(brs，1H)，5.617(s，1H)，3.357(s，3H)，3.109(s，3H)，2.724-2.678(m，1H)，2.527-2.475(m，1H)，1.782-1.729(m，1H)，1.424-1.372(m，1H)；m/z＝569.96[M+1] +。
Embodiment 45
2-(4-ethoxyl phenenyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
Figure BDA0000135908570000842
According to method A, 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-(4-ethoxyl phenenyl) Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose compound.Productive rate=13.32%. 1H?NMR(400MHz，CDCl 3)：δ＝7.673(brs，1H)，7.460-7.430(dd，1H，J＝1.6?&?2Hz)，7.297-7.235(dd，1H，J＝8.8?&?2.8Hz)，6.206-6.163(t，1H，J＝8.6Hz)，5.648(s，1H)，4.028-3.975(q，2H，J＝7.1Hz)，3.488(s，3H)，3.202(s，3H)，2.632-2.612(m，1H)，2.473-2.463(m，1H)，1.719-1.681(m，1H)，1.358-1.3337(m，1H)，1.251-1.241(t，3H，J＝7.1Hz)；m/z＝614.05[M+1] +。
Embodiment 46
2-(3, the 4-difluorophenyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
Figure BDA0000135908570000851
According to method A, 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-(3, the 4-difluorophenyl) Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose compound.Productive rate=5.79%. 1H?NMR(400MHz，CDCl 3)：δ＝7.619(brs，1H)，7.438-7.408(dd，1H，J＝1.6?&?2Hz)，7.290-7.226(dd，1H，J＝8.8?&?2.8Hz)，7.101-7.077(t，1H，J＝8.6Hz)，6.811-6.806(d，1H，J＝2Hz)，6.221-6.178(t，1H，J＝8.6Hz)，5.736(s，1H)，3.387(s，3H)，3.333(s，3H)，2.674-2.663(m，1H)，2.549-2.525(m，1H)，1.752-1.698(m，1H)，1.347-1.310(m，1H)；m/z＝605.99[M+1] +。
Embodiment 47
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-2-sec.-propyl-Trimetylene-1-sulphonamide
According to method A, 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-sec.-propyl-Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose compound.Productive rate=40%. 1HNMR(400MHz，CDCl 3)：δ＝7.743(brs，1H)，7.445-7.415(dd，1H，J＝1.6&2Hz)，7.291-7.269(dd，1H，J＝8.8?&?2.8Hz)，6.209-6.166(t，1H，J＝8.6Hz)，5.896(brs，2H)，3.876(s，3H)，3.336(s，3H)，2.237-2.193(m，1H)，1.499-1.438(m，1H)，1.198-1.152(m，1H)，0.997-0.981(d，3H，J＝6.4Hz)，0.943-0.926(d，3H，J＝6.8Hz)，0.819-0.783(m，1H)；m/z＝536.02[M+1] +。
Embodiment 48
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-2-isobutyl--Trimetylene-1-sulphonamide
Figure BDA0000135908570000861
According to method A, 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-isobutyl--Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose compound.Productive rate=35.4%. 1HNMR(400MHz，CDCl 3)：δ＝7.752(brs，1H)，7.444-7.4154(dd，1H，J＝1.6&?2Hz)，7.291-7.270(dd，1H，J＝8.8?&?2.8Hz)，6.209-6.166(t，1H，J＝8.6Hz)，5.958(brs，1H)，5.914(s，1H)，3.878(s，3H)，3.332(s，3H)，2.169-2.126(m，1H)，1.694-1.627(m，1H)，1.559-1.516(m，1H)，1.327-1.229(m，2H)，1.053-0.999(m，1H)，0.919-0.900(m，6H)，0.943-0.926(d，3H，J＝6.8Hz)，0.774-0.724(m，1H)；m/z＝550.06[M+1] +。
Embodiment 49
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-2-(thiophene-2-yl) Trimetylene-1-sulphonamide
Figure BDA0000135908570000862
According to method A, 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-(thiophene-2-yl) Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose compound.Productive rate=6.67%.
1H?NMR(400MHz，CDCl 3)：δ＝7.763(brs，1H)，7.456-7.426(dd，1H，J＝1.6?&?2Hz)，7.299-7.269(d，1H，J＝8.4Hz)，7.130-7.128(d，1H，J＝8.4Hz)，6.929-6.907(d，1H，J＝8.4Hz)，6.216-6.273(t，1H，J＝8.4Hz)，5.737(s，1H)，3.379(s，3H)，3.337(s，3H)，2.780-2.716(m，2H)，1.796-1.782(m，1H)，1.396-1.375(m，1H)；m/z＝575.91[M+1] +。
Embodiment 50
2-(2,4 difluorobenzene base)-N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
According to method A, 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-(2,4 difluorobenzene base)-Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose compound.Productive rate=41.8%. 1H?NMR(400MHz，CDCl 3)：δ＝7.662(brs，1H)，7.456-7.426(dd，1H，J＝1.6?&?2Hz)，7.300-7.273(dd，1H，J＝8.8?&?2.8Hz)，6.850-6.804(m，3H)，6.226-6.184(t，1H，J＝8.6Hz)，5.665(s，1H)，3.386(s，3H)，3.351(s，3H)，2.785-2.751(m，1H)，2.694-2.665(m，1H)，1.742-1.703(m，1H)，1.486-1.448(m，1H)；m/z＝605.99[M+1] +。
Embodiment 51
2-(3, the 5-difluorophenyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
Figure BDA0000135908570000872
According to method A, 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-(3, the 5-difluorophenyl)-Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose compound.Productive rate=28.9%. 1H?NMR(400MHz，CDCl 3)：δ＝7.607(brs，1H)，7.455-7.425(dd，1H，J＝1.6?&?2Hz)，7.300-7.265(dd，1H，J＝8.8?&?2.8Hz)，6.738-6.685(m，1H)，6.553-6.516(m，2H，J＝8.6Hz)，6.219-6.177(t，1H，J＝8.6Hz)，5.752(s，1H)，3.420(s，3H)，3.323(s，3H)，2.742-2.709(m，1H)，2.695-2.543(m，1H)，1.798-1.745(m，1H)，1.391-1.338(m，1H)；m/z＝605.99[M+1] +。
Embodiment 52
2-(4-benzonitrile base)-N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
Figure BDA0000135908570000881
According to method A, 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-(4-benzonitrile base)-Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose compound.Productive rate=2%. 1H?NMR(400MHz，CDCl 3)：δ＝7.630-7.593(t，3H，J＝7.4Hz)，7.472-7.443(dd，1H，J＝1.6?&?1.6Hz)，7.312-7.270(m，1H)，7.083-7.083(d，2H，J＝8Hz)，6.219-6.176(t，1H，J＝8.6Hz)，5.781(s，1H)，5.664(s，1H)，3.357(s，3H)，3.236(s，3H)，2.768-2.735(m，1H)，2.612-2.592(m，1H)，1.866-1.828(m，1H)，1.460-1.423(m，1H)；m/z＝594.96[M+1] +。
Embodiment 53
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-1-(2-hydroxyethyl) Trimetylene-1-sulphonamide
Steps A: tertiary butyl 2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-base (1-(2-oxoethyl)) cyclopropyl alkylsulfonyl) carbamate
Figure BDA0000135908570000882
With tertiary butyl 1-(2, the 3-dihydroxypropyl) cyclopropyl alkylsulfonyl (2-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) and carbamate (230 milligrams, THF 0.353mmol): H 2O (1: 1,3 milliliters) solution is used NaIO 4(151 milligrams 0.706mmol) are handled at 0 ℃.Stirred overnight subsequently, dilute with water also uses the dichloromethane extraction water.With the dried over mgso organic phase and concentrate and to obtain the above-mentioned title compound of gray solid shape it can be used for next step reaction and need not to be further purified.m/z＝620[M+1] +。
Step B: tertiary butyl 2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-base (1-(2-hydroxyethyl)) cyclopropyl alkylsulfonyl) carbamate
Figure BDA0000135908570000891
With steps A gained aldehyde (210 milligrams 0.339mmol) are dissolved in 3 ml methanol, and add NaBH 4(33 milligrams).With this mixture stirred overnight.Add entry and use the ethyl acetate extraction mixture, use dried over mgso, and concentratedly obtain above-mentioned title compound it can be used for next step reaction and need not to be further purified.m/z＝622[M+1] +。
Step C:N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-1-(2-hydroxyethyl) Trimetylene-1-sulphonamide
Figure BDA0000135908570000892
With 1-OH product (150 milligrams 0.241mmol) are dissolved in 2 milliliters of methylene dichloride, and slowly add excessive TFA (0.8 milliliter).This mixture is at room temperature stirred 2 hours, and remove volatile matter in a vacuum.Obtain above-mentioned title compound (85 milligrams, 68%) through silica gel column chromatography column purification residue. 1H?NMR(400MHz，DMSO-D6)δ8.86(s，1H)，7.93(s，1H)，7.59(dd，J＝2.0?&?10Hz)，7.31-7.35(m，2H)，6.25(t，J＝8.8Hz，1H)，4.45(br，1H)，3.16-3.26(m，5H)，2.01(s，3H)，1.81(t，J＝7.2Hz，2H)，0.87-0.89(m，2H)，0.77-0.78(m，2H)；m/z＝522[M+1] +。
Embodiment 54
N-(2-(2-chloro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene sulphonamide
Figure BDA0000135908570000901
According to method A, make 5-amino-6-(2-chloro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and the reaction of Trimetylene SULPHURYL CHLORIDE obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.71(d，J＝1.6Hz，1H)，7.27(dd，J＝1.6?&?9.6Hz，1H)，7.26(m，2H)，6.05(d，J＝8.4Hz，1H)，5.70(s，1H)，3.42(s，3H)，2.45(m，1H)，2.19(s，3H)，1.17-1.19(m，2H)，1.03-1.05(m，2H)；m/z＝494[M+1] +。
Embodiment 55
N-(2-(4-bromo-2-chloro-phenyl-is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene sulphonamide
Figure BDA0000135908570000902
According to method A, make 5-amino-6-(4-bromo-2-chloro-phenyl-is amino)-1,3-lutidine-2 (1H)-ketone and the reaction of Trimetylene SULPHURYL CHLORIDE obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.55(d，J＝2.4Hz，1H)，7.29(m，2H)，7.19-7.22(m，1H)，6.18(dd，J＝2.4&?8.4Hz，1H)，5.73(s，1H)，3.41(d，J＝2.0Hz，3H)，2.43-2.46(m，1H)，2.19(s，3H)，1.18-1.19(m，2H)，1.03-1.05(m，2H)；m/z＝446[M+1] +。
N-(2-(4-bromo-2-fluorophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene sulphonamide
According to method A, make 5-amino-6-(4-bromo-2-fluorophenyl is amino)-1,3-lutidine-2 (1H)-ketone and the reaction of Trimetylene SULPHURYL CHLORIDE obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.30(d，J＝2.4Hz，1H)，7.27(m，1H)，7.26(dd，J＝2.4?&?4.0Hz，1H)，7.08-7.11(m，1H)，6.26(t，J＝8.8Hz，1H)，5.66(s，1H)，5.30(s，1H)，3.45(s，3H)，2.44-2.48(m，1H)，2.19(s，3H)，1.17-1.19(m，2H)，1.04-1.08(m，2H)；m/z＝430[M+1] +。
Embodiment 57
N-(2-(the 2,4 difluorobenzene base is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene sulphonamide
Figure BDA0000135908570000912
According to method A, make 5-amino-6-(the 2,4 difluorobenzene base is amino)-1,3-lutidine-2 (1H)-ketone and the reaction of Trimetylene SULPHURYL CHLORIDE obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ6.89-6.94(m，2H)，6.73(m，1H)，6.35-6.41(m，1H)，5.68(s，1H)，3.42(s，3H)，2.45-2.49(m，1H)，2.18(s，3H)，1.17-1.20(m，2H)，1.04-1.08(m，2H)；m/z＝370[M+1] +。
Embodiment 58
N-(2-(2-chloro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) allyl group-Trimetylene-1-sulphonamide
Figure BDA0000135908570000913
According to method A, make 5-amino-6-(the 2,4 difluorobenzene base is amino)-1,3-lutidine-2 (1H)-ketone and 1-allyl group Trimetylene-1-SULPHURYL CHLORIDE reaction obtains above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.70(d，J＝2.0Hz，1H)，7.36(dd，J＝2.0?&?8.4Hz，1H)，7.23(s，1H)，6.02(d，J＝8.4Hz，1H)，5.76-5.82(m，1H)，5.61(s，1H)，5.17-.521(m，2H)，3.41(s，3H)，2.69(d，J＝7.6Hz，2H)，2.19(s，3H)，1.24-1.29(m，2H)，0.85-0.87(m，2H)；m/z＝534[M+1] +。
Embodiment 59
N-(2-(4-bromo-2-chloro-phenyl-is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) allyl group-Trimetylene-1-sulphonamide
According to method A, make 5-amino-6-(4-bromo-2-chloro-phenyl-is amino)-1,3-lutidine-2 (1H)-ketone and 1-allyl group Trimetylene-1-SULPHURYL CHLORIDE reaction obtains above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.54(d，J＝2.4Hz，1H)，7.18-7.26(m，2H)，6.15(d，J＝8.8Hz，1H)，5.76-5.80(m，1H)，5.63(s，1H)，5.18(dd，J＝2.0?&?9.6Hz，2H)，3.41(s，3H)，2.69(d，J＝7.2Hz，2H)，2.19(s，3H)，1.26-1.30(m，2H)，0.86-0.88(m，2H)；m/z＝488[M+1] +。
Embodiment 60
N-(2-(4-bromo-2-fluorophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) allyl group-Trimetylene-1-sulphonamide
Figure BDA0000135908570000922
According to method A, make 5-amino-6-(4-bromo-2-fluorophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 1-allyl group Trimetylene-1-SULPHURYL CHLORIDE reaction obtains above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.30(d，J＝2.4Hz，1H)，7.27(m，1H)，7.09-7.12(m，1H)，7.08(m，1H)，6.23(t.，J＝8.8Hz，1H)，5.76-5.79(m，1H)，5.62(s，1H)，5.17-5.21(m，2H)，3.44(s，3H)，2.69(d，J＝7.2Hz，2H)，2.19(s，3H))，1.27-1.30(m，2H)，0.86-0.89(m，2H)；m/z＝470[M+1] +。
Embodiment 61
N-(2-(the 2,4 difluorobenzene base is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) allyl group-Trimetylene-1-sulphonamide
Figure BDA0000135908570000931
According to method A, make 5-amino-6-(the 2,4 difluorobenzene base is amino)-1,3-lutidine-2 (1H)-ketone and 1-allyl group Trimetylene-1-SULPHURYL CHLORIDE reaction obtains above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.25-7.26(m，1H)，6.90-6.94(m，2H)，6.71-6.73(m，1H)，6.32-6.37(m，1H)，5.77-5.81(m，1H)，5.63(s，1H)，5.17-5.21(m，2H)，3.41(s，3H)，2.70(d，J＝7.2Hz，2H)，2.18(s，3H)，1.25-1.30(m，2H)，0.86-0.89(m，2H)；m/z＝410[M+1] +。
Embodiment 62
N-(2-(4-bromo-2-chloro-phenyl-is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) benzsulfamide
Figure BDA0000135908570000932
According to method A, make 5-amino-6-(4-bromo-2-chloro-phenyl-is amino)-1,3-lutidine-2 (1H)-ketone and benzene sulfonyl chloride reaction obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.74(dd，J＝1.2?&?8.4Hz，2H)，7.61-7.63(m，1H)，7.48-7.53(m，3H)，7.13(dd，J＝2.0?&?8.4Hz，1H)，6.79(s，1H)，6.74(s，1H)，6.03(d，J＝8.4Hz，1H)，5.83(s，1H)，3.35(s，3H)，2.03(s，3H)；m/z＝484[M+1] +。
Embodiment 63
N-(2-(4-bromo-2-chloro-phenyl-is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) butane-1-sulphonamide
Figure BDA0000135908570000941
According to method A, make 5-amino-6-(4-bromo-2-chloro-phenyl-is amino)-1,3-lutidine-2 (1H)-ketone and butane-1-SULPHURYL CHLORIDE reaction obtains above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.55(d，J＝2.0Hz，1H)，7.29(s，1H)，7.19-7.22(m，2H)，6.17(d，J＝8.8Hz，1H)，5.65(s，1H)，3.41(s，3H)，3.04(t，J＝7.6Hz，2H)，2.19(s，3H)，1.80-1.83(m，2H)，1.45-1.47(m，2H)，0.95(t，J＝7.6Hz，3H)；m/z＝464[M+1] +。
Embodiment 64
(R)-N-(2-(2-chloro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-1-(2, the 3-dihydroxypropyl) Trimetylene-1-sulphonamide
According to method A, make 5-amino-6-(2-chloro-4-iodophenyl amino)-1,3-lutidine-2 (1H)-ketone with (R)-1-(2, the 3-dihydroxypropyl) Trimetylene-1-SULPHURYL CHLORIDE reaction obtains above-mentioned title compound. 1HNMR(400MHz，DMSO-D6)δ8.98(s，1H)，7.77(d，J＝2.0Hz，2H)，7.44-7.48(m，2H)，6.18(d，J＝8.8Hz，1H)，4.56-4.59(m，2H)，3.47(br，1H)，3.18-3.23(m，5H)，2.10-2.13(m，1H)，2.09(s，3H)，1.60-1.63(m，1H)，0.93-1.00(m，4H)；m/z＝568[M+1] +。
Embodiment 65
(S)-N-(2-(2-chloro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-1-(2, the 3-dihydroxypropyl) Trimetylene-1-sulphonamide
Figure BDA0000135908570000951
According to method A, make 5-amino-6-(2-chloro-4-iodophenyl amino)-1,3-lutidine-2 (1H)-ketone with (S)-1-(2, the 3-dihydroxypropyl) Trimetylene-1-SULPHURYL CHLORIDE reaction obtains above-mentioned title compound. 1HNMR(400MHz，DMSO-D6)δ8.98(s，1H)，7.77(d，J＝2.0Hz，2H)，7.44-7.48(m，2H)，6.18(d，J＝8.4Hz，1H)，4.56-4.60(m，2H)，3.47(br，1H)，3.18-3.22(m，5H)，2.10-2.13(m，1H)，2.09(s，3H)，1.60-1.63(m，1H)，0.93-0.99(m，4H)；m/z＝568[M+1] +。
Embodiment 66
N-(2-(2-chloro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) benzsulfamide
According to method A, make 5-amino-6-(2-chloro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and benzene sulfonyl chloride reaction obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.74(d，J＝2.0Hz，2H)，7.72(d，J＝1.2Hz，1H)，7.68-7.69(m，1H)，7.53(t，J＝7.6Hz，2H)，7.29(dd，J＝2.0?&?8.4Hz，1H)，6.80(s，1H)，6.77(s，1H)，5.94(s，1H)，5.89(d，J＝8.4Hz，1H)，3.35(s，3H)，2.04(d，J＝5.6Hz，3H)；m/z＝530[M+1] +。
Embodiment 67
N-(2-(2-chloro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) butane-1-sulphonamide
Figure BDA0000135908570000961
According to method A, make 5-amino-6-(2-chloro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and butane-1-SULPHURYL CHLORIDE reaction obtains above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.71(d，J＝2.0Hz，2H)，7.37(dd，J＝2.0?&?8.4Hz，1H)，7.31(s，1H)，7.20(s，1H)，6.05(d，J＝8.8Hz，1H)，5.77(s，1H)，3.41(s，3H)，3.03(t，J＝8.0Hz，2H)，2.19(s，3H)，1.80-1.84(m，2H)，1.42-1.47(m，2H)，0.95(t，J＝7.2Hz，3H)；m/z＝510[M+1] +。
Embodiment 68
N-(2-(2-chloro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) tetramethylene sulphonamide
Figure BDA0000135908570000962
According to method A, make 5-amino-6-(2-chloro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and the reaction of tetramethylene SULPHURYL CHLORIDE obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.71(d，J＝2.0Hz，2H)，7.37(m，1H)，7.35(d，J＝2.0Hz，1H)，7.10(s，1H)，6.03(d，J＝8.4Hz，1H)，5.63(s，1H)，3.83-3.88(m，1H)，3.40(s，3H)，2.52-2.57(m，2H)，2.31-2.34(m，2H)，2.18(s，3H)，2.03-2.08(m，2H)；m/z＝508[M+1] +
Embodiment 69
N-(2-(2-chloro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) hexanaphthene sulphonamide
Figure BDA0000135908570000971
According to method A, make 5-amino-6-(2-chloro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and the reaction of hexanaphthene SULPHURYL CHLORIDE obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.70(d，J＝2.0Hz，2H)，7.37(dd，J＝2.0?&?8.4Hz，1H)，7.28(s，1H)，7.20(s，1H)，6.04(d，J＝8.8Hz，1H)，5.64(s，1H)，3.41(s，3H)，2.86-2.92(m，1H)，2.19(s，3H)，2.14(m，2H)，1.85-1.91(m，2H)，1.55-1.72(m，2H)，1.21-1.26(m，3H)；m/z＝536[M+1] +。
Embodiment 70
N-(2-(2-chloro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-isobutyl--Trimetylene-1-sulphonamide
According to method A, make 5-amino-6-(2-chloro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 2-isobutyl--Trimetylene-1-SULPHURYL CHLORIDE reaction obtains above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.70(d，J＝2.0Hz，2H)，7.36(dd，J＝2.0?&?8.4Hz，1H)，7.32(s，1H)，7.26(s，1H)，6.05(d，J＝8.4Hz，1H)，5.68(s，1H)，3.42(s，3H)，2.20(s，3H)，2.15-2.17(m，1H)，1.62-1.69(m，1H)，1.24-1.33(m，3H)，1.12(m，1H)，0.92-0.94(m，6H)，0.82-0.86(m，1H)；m/z＝550[M+1] +。
Embodiment 71
N-(2-(2-chloro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(2,4 difluorobenzene base)-Trimetylene-1-sulphonamide
Figure BDA0000135908570000981
According to method A, make 5-amino-6-(2-chloro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 2-(2,4 difluorobenzene base)-Trimetylene-1-SULPHURYL CHLORIDE reaction obtains above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.69(d，J＝2.0Hz，2H)，7.35(dd，J＝2.0?&?8.4Hz，1H)，7.18(s，1H)，7.12(s，1H)，6.82-6.90(m，3H)，6.04(d，J＝8.4Hz，1H)，5.88(s，1H)，4.10-4.15(m，1H)，3.40(s，3H)，2.72(t，J＝7.2Hz，1H)，2.04(s，3H)，1.73-1.78(m，1H)，1.48-1.52(m，1H)；m/z＝606[M+1] +。
Embodiment 72
N-(2-(2-chloro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) thiophene-2-sulphonamide
Figure BDA0000135908570000982
According to method A, make 5-amino-6-(2-chloro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and thiophene-2-SULPHURYL CHLORIDE reaction obtains above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.69(d，J＝2.0Hz，1H)，7.65(dd，J＝1.6?&?8.8Hz，1H)，7.50(dd，J＝2.0?&?4.0Hz，1H)，7.27-7.34(m，1H)，7.09(dd，J＝3.6?&?9.2Hz，1H)，6.82-6.84(m，2H)，5.93-5.97(m，2H)，3.37(s，3H)，2.07(s，3H)；m/z＝536[M+1] +。
Embodiment 73
N-(2-(2-chloro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) thiophene-3-sulphonamide
Figure BDA0000135908570000991
According to method A, make 5-amino-6-(2-chloro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and thiophene-3-SULPHURYL CHLORIDE reaction obtains above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.88(dd，J＝1.6?&?3.2Hz，1H)，7.70(d，J＝1.6Hz，1H)，7.44(dd，J＝3.2?&?8.8Hz，1H)，7.32(m，1H)，7.25-7.26(m，1H)，6.88(s，1H)，6.80(d，J＝1.6Hz，1H)，5.94-5.96(m，2H)，3.37(s，3H)，2.06(s，3H)；m/z＝536[M+1] +。
Embodiment 74
N-(2-(2-chloro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) propane-2-sulphonamide
Figure BDA0000135908570000992
According to method A, make 5-amino-6-(2-chloro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and propane-2-SULPHURYL CHLORIDE reaction obtains above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.70(d，J＝2.0Hz，1H)，7.35-7.38(m，2H)，7.20(s，1H)，6.03(d，J＝7.2Hz，1H)，5.66(s，1H)，3.41(s，3H)，3.21-3.24(m，1H)，2.18(s，3H)，1.42(d，J＝7.2Hz，6H)；m/z＝496[M+1] +。
Embodiment 75
3-chloro-N-(2-(2-chloro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) propane-1-sulphonamide
Figure BDA0000135908570001001
According to method A, make 5-amino-6-(2-chloro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 3-chloropropane-2-SULPHURYL CHLORIDE reaction obtains above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.17(d，J＝2.0Hz，1H)，7.37(dd，J＝2.0?&?8.4Hz，1H)，7.23-7.26(m，2H)，6.05(d，J＝8.4Hz，1H)，5.86(s，1H)，3.67(t，J＝6.0Hz，2H)，3.42(s，3H)，3.24(t，J＝7.6Hz，2H)，2.30-2.34(m，2H)，2.19(s，3H)；m/z＝530[M+1] +。
Embodiment 76
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(3, the 5-difluorophenyl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001002
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 2-(3, the 5-difluorophenyl)-Trimetylene-1-SULPHURYL CHLORIDE reaction obtains above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.43-7.46(m，1H)，7.26-7.27(m，1H)，7.05(s，1H)，6.91(m，1H)，6.71-6.74(m，1H)，6.54(dd，J＝2.0?&?8.0Hz，2H)，6.12(t，J＝8.8Hz，1H)，5.77(s，1H)，3.42(s，3H)，2.66-2.68(m，1H)，2.58-2.61(m，1H)，2.04(s，3H)，1.77-1.79(m，1H)，1.42-1.46(m，1H)；m/z＝590[M+1] +。
Embodiment 77
N-(2-(2-chloro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) ethyl sulfonamide
Figure BDA0000135908570001011
According to method A, make 5-amino-6-(2-chloro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and ethyl sulfonyl chloride reaction obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.71(d，J＝1.6Hz，1H)，7.37(dd，J＝2.0&8.4Hz，1H)，7.32(s，1H)，7.19(s，1H)，6.04(d，J＝8.4Hz，1H)，5.73(s，1H)，3.41(s，3H)，3.06-3.10(m，2H)，2.19(s，1H)，1.43(t，J＝7.2Hz，3H)；m/z＝482[M+1] +。
Embodiment 78
(R)-N-(2-(4-bromo-2-chloro-phenyl-is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-1-(2, the 3-dihydroxypropyl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001012
According to method A, step e and F, embodiment 28, make 5-amino-6-(4-bromo-2-chloro-phenyl-is amino)-1, and 3-lutidine-2 (1H)-ketone obtains above-mentioned title compound with identical SULPHURYL CHLORIDE reaction. 1H?NMR(400MHz，CDCl 3)δ7.52(d，J＝4.4Hz，1H)，7.29(s，1H)，7.20(dd，J＝2.4&8.8Hz，1H)，6.96(br，1H)，6.15(d，J＝8.8Hz，1H)，3.99(br，1H)，3.64-3.70(m，1H)，3.48-3.52(m，1H)，3.41(s，3H)，3.17(br，1H)，2.35-2.41(m，1H)，2.19(s，3H)，1.98(m，1H)，1.63-1.67(m，1H)，1.47-1.51(m，1H)，1.31-1.35(m，1H)，0.88-0.97(m，2H)；m/z＝522[M+1] +。
Embodiment 79
(R)-N-(2-(the 2,4 difluorobenzene base is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-1-(2, the 3-dihydroxypropyl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001021
According to method A, step e and F, embodiment 28, make 5-amino-6-(the 2,4 difluorobenzene base is amino)-1, and 3-lutidine-2 (1H)-ketone obtains above-mentioned title compound with identical SULPHURYL CHLORIDE reaction. 1H?NMR(400MHz，CDCl 3)δ7.34(s，1H)，7.00(s，1H)，6.74-6.88(m，2H)，6.70-6.72(m，1H)，6.32(t，J＝5.6Hz，1H)，3.99(br，1H)，3.65-3.66(m，1H)，3.48-3.53(m，1H)，3.41(s，3H)，2.32-2.39(m，1H)，2.18(s，3H)，1.46-1.50(m，2H)，1.28-1.33(m，2H)，0.84-0.97(m，3H)；m/z＝444[M+1] +。
Embodiment 80
(R)-N-(2-(4-bromo-2-fluorophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-1-(2, the 3-dihydroxypropyl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001022
According to method A, step e and F, embodiment 28, make 5-amino-6-(4-bromo-2-fluorophenyl is amino)-1, and 3-lutidine-2 (1H)-ketone obtains above-mentioned title compound with identical SULPHURYL CHLORIDE reaction. 1H?NMR(400MHz，CDCl 3)δ7.35(s，1H)，7.29(s，1H)，7.08-7.11(m，2H)，6.85(s，1H)，6.23(t，J＝8.8Hz，1H)，3.97(br，1H)，3.65-3.68(m，1H)，3.47-3.53(m，1H)，3.44(s，3H)，3.16(d，J＝4.0Hz，1H)，2.32-2.38(m，1H)，2.19(s，3H)，1.97(t，J＝5.2Hz，1H)，1.65-1.68(m，1H)，1.45-1.51(m，1H)，1.26-1.32(m，2H)，0.86-0.97(m，2H)；m/z＝506[M+1] +。
Embodiment 81
N-(2-(4-bromo-2-chloro-phenyl-is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) thiophene-2-sulphonamide
Figure BDA0000135908570001031
According to method A, make 5-amino-6-(4-bromo-2-chloro-phenyl-is amino)-1,3-lutidine-2 (1H)-ketone and thiophene-2-SULPHURYL CHLORIDE reaction obtains above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.64(dd，J＝1.2?&?5.2Hz，1H)，7.51(dd，J＝1.2?&?6.0Hz，1H)，7.50(t，J＝1.6Hz，1H)，7.15(dd，J＝2.0?&?8.4Hz，1H)，7.08-7.09(m，1H)，6.85-6.87(m，2H)，6.15(s，1H)，6.06(d，J＝8.8Hz，1H)，3.37(s，3H)，2.06(s，3H)；m/z＝490[M+1] +。
Embodiment 82
N-(2-(4-bromo-2-chloro-phenyl-is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) thiophene-3-sulphonamide
Figure BDA0000135908570001032
According to method A, make 5-amino-6-(4-bromo-2-chloro-phenyl-is amino)-1,3-lutidine-2 (1H)-ketone and thiophene-3-SULPHURYL CHLORIDE reaction obtains above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.88(d，J＝1.2Hz，1H)，7.54(d，J＝2.4Hz，1H)，7.44-7.46(m，1H)，7.17(dd，J＝2.0&8.4Hz，1H)，6.89(s，1H)，6.79(s，1H)，6.08(d，J＝8.8Hz，1H)，5.93(s，1H)，3.37(s，3H)，2.06(s，3H)；m/z＝490[M+1] +。
Embodiment 83
N-(2-(4-bromo-2-chloro-phenyl-is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-4-fluorobenzene sulphonamide
Figure BDA0000135908570001041
According to method A, make 5-amino-6-(4-bromo-2-chloro-phenyl-is amino)-1,3-lutidine-2 (1H)-ketone and the reaction of 4-fluorobenzene SULPHURYL CHLORIDE obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.73-.77(m，2H)，7.53(d，J＝2.4Hz，1H)，7.12-7.16(m，3H)，6.91(s，1H)，6.17(s，1H)，6.00(d，J＝8.8Hz，1H)，3.36(s，3H)，2.05(d，J＝1.2Hz，3H)；m/z＝502[M+1] +。
Embodiment 84
N-(2-(2-chloro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-4-fluorobenzene sulphonamide
According to method A, make 5-amino-6-(2-chloro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and the reaction of 4-fluorobenzene SULPHURYL CHLORIDE obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.73-7.76(m，2H)，7.69(d，J＝2.0Hz，1H)，7.30(dd，J＝2.0?&?8.4Hz，1H)，7.14(t，J＝8.8Hz，2H)，6.88(s，1H)，6.81(s，1H)，6.10(s，1H)，5.88(d，J＝8.8Hz，1H)，3.36(s，3H)，2.05(s，3H)；m/z＝502[M+1] +。
Embodiment 85
N-(2-(2-chloro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(methylol) Trimetylene-1-sulphonamide
Figure BDA0000135908570001043
According to method A, make 5-amino-6-(2-chloro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone obtains corresponding sulphonamide with (2-(chlorosulfonyl) cyclopropyl) methyl trimethoxy guanidine-acetic acid reactant salt, and it can be used for next step reaction and need not to carry out purifying.Use this midbody of LiOH hydrogenation.Solvent is removed in decompression, through silica gel column chromatography purifying residue (eluent: methylene dichloride: methyl alcohol=15: 1) obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.68(s，1H)，7.43(dd，J＝2.0?&?10.4Hz，1H)，7.39(s，1H)，7.25-7.26(m，1H)，6.11(t，J＝8.8Hz，1H)，4.06(dd，J＝4.0?&?11.2Hz，1H)，3.42(s，3H)，3.15(dd，J＝8.8?&?11.2Hz，1H)，2.42-2.44(m，1H)，2.17(s，3H)，1.72-1.73(m，1H)，1.40-1.44(m，2H)，0.99(dd，J＝2.0?&?6.0Hz，1H)；m/z＝508[M+1] +。
Embodiment 86
N-(2-(4-bromo-2-fluorophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(methylol) Trimetylene-1-sulphonamide
According to method A, make 5-amino-6-(4-bromo-2-fluorophenyl is amino)-1,3-lutidine-2 (1H)-ketone obtains corresponding sulphonamide with (2-(chlorosulfonyl) cyclopropyl) methyl trimethoxy guanidine-acetic acid reactant salt, and it can be used for next step reaction and need not to carry out purifying.Use this midbody of LiOH hydrogenation.Solvent is removed in decompression, through silica gel column chromatography purifying residue (eluent: methylene dichloride: methyl alcohol=15: 1) obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.49(s，1H)，7.28(dd，J＝2.0?&?11.2Hz，1H)，7.25-7.26(m，1H)，7.09-7.11(m，1H)，6.24(t，J＝8.8Hz，1H)，5.83(br，1H)，4.05(dd，J＝4.4?&?11.2Hz，1H)，3.42(s，3H)，3.18(dd，J＝8.4?&?11.2Hz，1H)，2.42-2.46(m，1H)，2.17(s，3H)，1.73-1.76(m，1H)，1.41-1.44(m，1H)，0.98-1.03(m，1H)；m/z＝460[M+1] +。
Embodiment 87
N-(2-(the 2,4 difluorobenzene base is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(methylol) Trimetylene-1-sulphonamide
Figure BDA0000135908570001061
According to method A, make 5-amino-6-(the 2,4 difluorobenzene base is amino)-1,3-lutidine-2 (1H)-ketone obtains corresponding sulphonamide with (2-(chlorosulfonyl) cyclopropyl) methyl trimethoxy guanidine-acetic acid reactant salt, and it can be used for next step reaction and need not to carry out purifying.Use this midbody of LiOH hydrogenation.Solvent is removed in decompression, through silica gel column chromatography purifying residue (eluent: methylene dichloride: methyl alcohol=15: 1) obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.50(s，1H)，7.16(s，1H)，6.89-6.95(m，1H)，6.71-6.75(m，1H)，6.30-6.36(m，1H)，4.03(dd，J＝4.4?&?11.2Hz，1H)，3.41(s，3H)，3.20-3.25(m，1H)，2.44-2.48(m，1H)，2.17(s，3H)，1.73-1.79(m，1H)，1.39-1.43(m，1H)，1.00-1.05(m，1H)；m/z＝400[M+1] +。
Embodiment 88
N-(2-(2-chloro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(methylol) Trimetylene-1-sulphonamide
Figure BDA0000135908570001062
According to method A, make 5-amino-6-(2-chloro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone obtains corresponding sulphonamide with (2-(chlorosulfonyl) cyclopropyl) methyl trimethoxy guanidine-acetic acid reactant salt, and it can be used for next step reaction and need not to carry out purifying.Use this midbody of LiOH hydrogenation.Solvent is removed in decompression, through silica gel column chromatography purifying residue (eluent: methylene dichloride: methyl alcohol=15: 1) obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.70(d，J＝2.0Hz，1H)，7.51(d，J＝7.2Hz，2H)，7.36(dd，J＝2.0?&?8.8Hz，1H)，6.04(d，J＝8.8Hz，1H)，5.82(br，1H)，4.03-4.07(m，1H)，3.39(s，3H)，3.15-3.18(m，1H)，2.44-2.47(m，1H)，2.17(s，3H)，1.55(m，1H)，1.38-1.41(m，1H)，0.98-1.01(m，1H)；m/z＝524[M+1] +。
Embodiment 89
N-(2-(4-bromo-2-chloro-phenyl-is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(methylol) Trimetylene-1-sulphonamide
Figure BDA0000135908570001071
According to method A, make 5-amino-6-(4-bromo-2-chloro-phenyl-is amino)-1,3-lutidine-2 (1H)-ketone obtains corresponding sulphonamide with (2-(chlorosulfonyl) cyclopropyl) methyl trimethoxy guanidine-acetic acid reactant salt, and it can be used for next step reaction and need not to carry out purifying.Use this midbody of LiOH hydrogenation.Solvent is removed in decompression, through silica gel column chromatography purifying residue (eluent: methylene dichloride: methyl alcohol=15: 1) obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.55(d，J＝2.0Hz，1H)，7.51(s，2H)，7.20(dd，J＝2.0?&?8.4Hz，1H)，6.16(d，J＝8.4Hz，1H)，5.90(br，1H)，4.06(dd，J＝4.0?&?11.2Hz，1H)，3.39(s，3H)，3.12-3.17(m，1H)，2.44-2.48(m，1H)，2.17(s，3H)，1.70-1.72(m，1H)，1.37-1.42(m，1H)，0.98-1.01(m，1H)；m/z＝478[M+1] +。
Embodiment 90
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-butyl-Trimetylene-1-sulphonamide
Figure BDA0000135908570001072
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-1,3-lutidine-2 (1H) thereby-ketone reacts with 1-butyl Trimetylene-1-SULPHURYL CHLORIDE and obtains above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.43(dd，J＝2.0?&?10.0Hz，1H)，7.25-7.27(m，2H)，7.05(s，1H)，6.11(t，J＝8.4Hz，1H)，5.69(s，1H)，3.44(s，3H)，2.18(s，3H)，1.89(t，J＝8.8Hz，2H)，1.24-1.54(m，7H)，0.88-0.92(t，J＝7.2Hz，3H)，0.81-0.84(m，2H)；m/z＝534[M+1] +。
Embodiment 91
(S)-N-(2-(the 2,4 difluorobenzene base is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-1-(2, the 3-dihydroxypropyl) Trimetylene-1-sulphonamide
According to method A, step e and F, embodiment 28, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-1,3-lutidine-2 (1H)-ketone with (S)-1-(2,3 dihydroxypropyl) Trimetylene-1-SULPHURYL CHLORIDE reaction, use BBr 3Remove phenyl group, thereby obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.58(s，1H)，7.39(s，1H)，7.15(s，1H)，6.86-6.91(m，1H)，6.69-6.73(m，1H)，6.31-6.37(m，1H)，3.96(m，1H)，3.76(s，1H)，3.58-3.61(m，1H)，3.43-3.47(m，1H)，3.39(s，3H)，2.25(dd，J＝9.6?&?15.6Hz，1H)，2.14(s，3H)，1.84(s，1H)，1.66(d，J＝15.2Hz，1H)，1.37-1.40(m，1H)，1.22-1.30(m，1H)，0.84-.090(m，2H)；m/z＝444[M+1] +。
Embodiment 92
(S)-N-(2-(4-bromo-2-fluorophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-1-(2, the 3-dihydroxypropyl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001082
According to method A, step e and F, embodiment 28, make 5-amino-6-(4-bromo-2-fluorophenyl amino)-1,3-lutidine-2 (1H)-ketone with (S)-1-(2,3 dihydroxypropyl) Trimetylene-1-SULPHURYL CHLORIDE reaction, use BCl 3Remove phenyl group, thereby obtain above-mentioned title compound. 1H?NMR(400MHz，DMSO-D6)δ8.81(s，1H)，7.92(s，1H)，7.49(dd，J＝2.0?&?10.8Hz，1H)，7.16(dd，J＝1.6?&?9.6Hz，1H)，6.39(t，J＝9.2Hz，1H)，4.55(s，2H)，3.45(s，1H)，3.25(s，3H)，3.15(m，2H)，2.04(dd，J＝2.0?&?15.2Hz，1H)，2.00(s，3H)，1.56(dd，J＝9.6&14.8Hz，1H)，0.84-.097(m，4H)；m/z＝504[M+1] +。
Embodiment 93
1-allyl group-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(3-fluorophenyl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001091
According to method A, make 5-amino-6-(4-bromo-2-fluorophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 1-allyl group-2-(3-fluorophenyl) Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.44(dd，J＝1.6?&?10.4Hz，1H)，7.24-7.31(m，3H)，7.09(s，1H)，7.00(dd，J＝6.4?&?8.4Hz，1H)，6.93(d，J＝6.4Hz，1H)，6.78(d，J＝9.6Hz，1H)，6.12(t，J＝6.4Hz，1H)，5.75-5.85(m，2H)，5.04-5.11(m，2H)，3.46(s，3H)，3.00(dd，J＝8.0?&?10.0Hz，1H)，2.64(dd，J＝6.4?&?15.6Hz，1H)，2.20(s，3H)，2.12(dd，J＝7.6?&?15.6Hz，1H)，1.77(dd，J＝6.4?&?10.0Hz，1H)，1.39(t，J＝6.8Hz，1H)；m/z＝612[M+1] +。
Embodiment 94
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-2-(3-fluorophenyl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001101
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-(3-fluorophenyl) Trimetylene-1-SULPHURYL CHLORIDE reaction, thereby obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.64(s，1H)，7.45(dd，J＝1.6?&?10.0Hz，1H)，7.26-7.30(m，2H)，6.96(t，J＝8.4Hz，1H)，6.77(d，J＝8.0Hz，1H)，6.42(d，J＝10.0Hz，1H)，6.19(t，J＝8.0Hz，1H)，5.81(s，1H)，5.67(s，1H)，3.36(s，3H)，3.27(s，3H)，2.68-2.72(m，1H)，2.53-2.56(m，1H)，1.75-1.81(m，1H)，1.36-1.42(m，1H)；m/z＝588[M+1] +。
Embodiment 95
1-(2,3 dihydroxypropyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(3-p-methoxy-phenyl) Trimetylene-1-sulphonamide
Steps A: 1-allyl group-N-(2-(2-fluoro-4-iodophenyl is amino)-1,3-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(3-p-methoxy-phenyl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001102
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 1-allyl group-(3-p-methoxy-phenyl) Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.43(d，J＝10.4Hz，1H)，7.22-7.28(m，2H)，7.07(s，1H)，6.82(dd，J＝2.4?&?8.4Hz，1H)，6.65(d，J＝8.4Hz，1H)，6.61(s，1H)，6.09(t，J＝8.8Hz，1H)，5.76-5.87(m，1H)，5.75(s，1H)，5.06-5.10(m，2H)，3.80(s，3H)，3.46(s，3H)，2.99(dd，J＝7.6?&?10.0，1H)，2.63(dd，J＝7.2?&?16.0Hz，1H)，2.20(s，3H)，2.13(dd，J＝7.6?&?16.0Hz，1H)，1.74(dd，J＝6.0?&?9.6Hz，1H)，1.39(t，J＝6.8Hz，1H)；m/z＝624[M+1] +。
Step B:1-(2,3 dihydroxypropyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(3-p-methoxy-phenyl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001111
Obtain the compound of above-mentioned title according to embodiment 27 described same procedure. 1H?NMR(400MHz，DMSO-D6，two?isomer?1∶1)δ8.95(s，1H)，8.93(s，1H)，7.91(s，2H)，7.52-7.56(m，2H)，7.40(s，1H)，7.35(s，1H)，7.15-7.21(m，3H)，7.03(d，J＝8.0Hz，1H)，6.81-6.85(m，2H)，6.58-6.60(m，2H)，6.52(s，1H)，6.48(d，J＝7.6Hz，1H)，6.14(t，J＝8.8Hz，1H)，5.88(t，J＝8.8Hz，1H)，4.64(d，J＝4.8Hz，1H)，4.54(J＝5.2Hz，1H)，4.43-4.48(m，2H)，3.71(s，3H)，3.70(s，3H)，3.26(s，3H)，3.22(s，3H)，2.00(s，6H)，1.27-3.90(m，16H)；m/z＝658[M+1] +。
Embodiment 96
2-(4-chloro-phenyl-)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001112
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 2-(4-chloro-phenyl-)-Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.44(dd，J＝1.6?&?10.0Hz，1H)，7.25-7.31(m，3H)，7.05(s，1H)，6.91-6.93(m，2H)，6.12(s，1H)，6.10(t，J＝8.4Hz，1H)，5.91(s，1H)，3.41(s，3H)，2.54-2.63(m，2H)，2.01(s，3H)，1.72-1.77(m，1H)，1.40-1.43(m，1H)；m/z＝588[M+1] +。
Embodiment 97
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(2-fluoro-4-p-methoxy-phenyl)-Trimetylene-1-sulphonamide
Figure BDA0000135908570001121
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 2-(2-fluoro-4-p-methoxy-phenyl)-Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.44(d，J＝10.0Hz，1H)，7.25-7.27(m，1H)，7.09(s，1H)，6.88-6.92(m，2H)，6.70-6.73(m，2H)，6.10(t，J＝8.4Hz，1H)，5.98(s，1H)，3.88(s，3H)，3.42(s，3H)，2.50-2.60(m，2H)，2.03(s，3H)，1.70-1.72(m，1H)，1.35-1.39(m，1H)；m/z＝602[M+1] +。
Embodiment 98
2-(2,4 dichloro benzene base)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001122
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 2-(2,4 dichloro benzene base)-Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.41-7.44(m，2H)，7.21-7.27(m，2H)，7.09(s，1H)，7.01(s，1H)，6.82(d，J＝8.4Hz，1H)，6.12(t，J＝8.4Hz，1H)，5.87(s，1H)，3.43(s，3H)，2.91-2.97(m，1H)，2.58-2.63(m，1H)，2.02(s，3H)，1.77-1.82(m，1H)，1.42-1.48(m，1H)；m/z＝622[M+1] +。
Embodiment 99
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(3-fluoro-4-p-methoxy-phenyl)-Trimetylene-1-sulphonamide
Figure BDA0000135908570001131
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 2-(3-fluoro-4-p-methoxy-phenyl)-Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.43(dd，J＝1.6?&?10.0Hz，1H)，7.25-7.27(m，1H)，7.10(s，1H)，6.99(s，1H)，6.80(t，J＝8.8Hz，1H)，6.61-6.67(m，2H)，6.11(t，J＝8.8Hz，1H)，5.84(s，1H)，3.80(s，3H)，3.42(s，3H)，2.67(t，J＝7.2Hz，2H)，1.74(dd，J＝7.2?&?13.6Hz，1H)，1.50(dd，J＝7.2?&?13.6Hz，1H)；m/z＝602[M+1] +。
Embodiment 100
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(3-fluorophenyl)-Trimetylene-1-sulphonamide
Figure BDA0000135908570001132
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 2-(3-fluorophenyl)-Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.43(d，J＝10.4Hz，1H)，7.25-7.32(m，2H)，7.06(s，1H)，6.96-7.00(m，1H)，6.93(s，1H)，6.77(d，J＝8.0Hz，1H)，6.68(d，J＝10.0Hz，1H)，6.10(t，J＝8.4Hz，1H)，6.02(s，1H)，3.41(s，3H)，2.63-2.68(m，1H)，2.55-2.59(m，1H)，1.99(s，3H)，1.74-1.80(m，1H)，1.40-1.46(m，1H)；m/z＝572[M+1] +。
Embodiment 101
(R)-1-(2-fluoro-3-hydroxypropyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
Steps A: (R)-sec.-propyl 1-(3-(benzyl)-2-fluoropropyl) Trimetylene-1-sulphonate
Figure BDA0000135908570001141
Under 0 ℃, with (S)-sec.-propyl 1-((3-benzyl)-2-hydroxypropyl) Trimetylene-1-sulphonate (2.0 grams 6.7mmol) stir and to be dissolved in 30 milliliters of THF, and slowly add diethylaminosulfurtrifluoride (1.806 milliliters, 14.57mmol).This mixture at room temperature stirred add saturated sodium bicarbonate solution after 1.5 hours.Make the ethyl acetate extraction mixture, with dried over mgso, filtration, concentrate, and use chromatography purification (eluent: sherwood oil: ETHYLE ACETATE=8: 1) thus obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.29-7.37(m，5H)，5.54-5.59(m，0.5H)，5.02-5.06(m，0.5H)，4.94(sept.，J＝6.4Hz，1H)，4.50-4.61(m，2H)，3.58-4.13(m，2H)，2.36-2.48(m，1H)，1.96-2.05(m，1H)，1.42-1.46(m，2H)，1.40(d，J＝6.0Hz，6H)，1.13-1.20(m，1H)，0.86-0.94(m，1H)。
Step B: (R)-1-(3-(benzyl)-2-fluoropropyl) Trimetylene-1-sulphonate potassium
With (R)-sec.-propyl 1-(3-(benzyl)-2-fluoropropyl) Trimetylene-1-sulphonate (682 milligrams, 2.27mmol) and potassium thiocyanate (232 milligrams, the mixture heating up of (6 milliliters) solution of DME 2.38mmol) and water (6 milliliters) refluxes and spends the night.Use the ethyl acetate extraction residue, thereby and the reduction vaporization water obtain crude product, it can be used for next step reaction and need not to be further purified.
Step C: (R)-1-(3-(benzyl)-2-fluoropropyl) Trimetylene-1-SULPHURYL CHLORIDE
With sulphonate (670 milligrams, 2.26mmol), THIONYL CHLORIDE 97 (5 milliliters) and N, the mixture heating up of dinethylformamide (5) refluxed 15 minutes.The reduction vaporization volatile matter slowly adds entry simultaneously.Use ETHYLE ACETATE (2x) extraction leftover, dried over mgso blended organic phase is filtered and the evaporation back obtains the yellow oily crude product.Through silica gel column chromatography (eluent: sherwood oil: the compound of the above-mentioned title of acquisition behind purifying ETHYLE ACETATE=8: 1). 1H?NMR(400MHz，CDCl 3)δ7.30-7.38(m，5H)，5.17-5.19(m，0.5H)，5.05-5.07(m，0.5H)，4.54-4.62(m，2H)，3.49-3.74(m，2H)，2.64-2.76(m，1H)，2.17-2.27(m，1H)，1.83-1.88(m，1H)，1.72-1.78(m，1H)，1.51-1.57(m，1H)，1.20-1.26(m，1H)。
Step D: (R)-1-(3-(benzyl)-2-fluoropropyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001152
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-1,3-lutidine-2 (1H)-ketone with (R)-1-(3-(benzyl)-2-fluoropropyl) Trimetylene-1-SULPHURYL CHLORIDE reaction, thereby obtain above-mentioned title compound.
Step e: (R)-1-(2-fluoro-3-hydroxypropyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001153
With (R)-1-(3-(benzyl)-2-fluoropropyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide (61 milligrams 0.095mmol) are dissolved in anhydrous methylene chloride (2 milliliters).Slowly add BCl at 0 ℃ 3(16.66 milligrams, 0.142mmol, 1.5 equivalents).Mixture stirring at room 2 hours, and is added entry.Separate organic phase and use the dichloromethane extraction water.Use salt solution to clean and mix organic phase, dried over mgso is filtered and concentrating under reduced pressure.Through silica gel column chromatography (eluent: ETHYLE ACETATE) thus the purifying residue obtains above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.44(d，J＝10.0Hz，1H)，7.26-7.30(m，2H)，7.02(s，1H)，6.11(t，J＝8.4Hz，1H)，6.06(s，1H)，4.84-5.04(m，1H)，3.64-3.86(m，2H)，3.44(s，3H)，2.18(s，3H)，2.11-2.40(m，2H)，1.93(s，1H)，1.38-1.43(m，1H)，1.23-1.33(m，1H)，1.04-1.13(m，1H)，0.94-1.00(m，1H)；m/z＝554[M+1] +。
Embodiment 102
(R)-1-(2,3-two fluoropropyls)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
Steps A: (S)-1-(2,3-two fluoropropyls) Trimetylene-1-sulphonyl isopropyl ester
Figure BDA0000135908570001161
At 0 ℃, with BCl 3(12.7 milliliters, (3.2 restrain, 9.74mol) 12.67mmol) to add (S)-sec.-propyl 1-(3-(benzyl)-2-hydroxypropyl) Trimetylene-1-sulfonyl ester.This mixture, is reacted with the sodium hydrogencarbonate cancellation of a great deal of after 0.5 hour in stirring at room.By the dichloromethane extraction mixture and use salt solution hydrogen, use dried over sodium sulfate, filtration, solvent is removed in decompression, and pass through chromatography (silica gel, eluent: ETHYLE ACETATE: purifying gained residue sherwood oil=10: 1), thus obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ4.98(sept，J＝6.4Hz，1H)，4.11-4.14(m，1H)，3.66(dd，J＝10.8Hz&4.0Hz，1H)，3.49(dd，J＝10.8Hz&6.0Hz，1H)，1.90-1.94(m，2H)，1.49-1.51(m，2H)，1.44(d，J＝6.4Hz，6H)，1.09-1.12(m，1H)，0.93-0.96(m，1H)。
Step B: (R)-1-(2,3-two fluoropropyls) Trimetylene-1-sulfonyl ester
Figure BDA0000135908570001171
At 0 ℃, the diethylin sulfur trifluoride is slowly added glycol in the stirring (1.75 grams, 30 milliliters of THF solution 7.34mmol).This mixture is at room temperature added saturated sodium bicarbonate solution after the stirred overnight.Separate organic phase and use the ethyl acetate extraction water.Mix organic phase, and clean, use dried over sodium sulfate, filter with sodium chloride brine, except that desolvating, through chromatography (silica gel, eluent: ETHYLE ACETATE: purifying residue sherwood oil=8: 1), thus obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ5.06-5.29(m，1H)，4.96(sept.，J＝6.0Hz，1H)，4.01-4.74(m，2H)，2.31-2.42(m，1H)，2.00-2.10(m，1H)，1.49-1.53(m，2H)，1.43(d，J＝6.0Hz，6H)，1.14-1.22(m，1H)，0.94-1.00(m，1H)。
Step C: (R)-1-(2,3-two fluoropropyls) Trimetylene-1-sulfonyl ester potassium
Figure BDA0000135908570001172
According to step B, the same procedure of embodiment 101 obtains above-mentioned title compound, and it can directly be used for next step reaction.
Step D: (R)-1-(2,3-two fluoropropyls) Trimetylene-1-SULPHURYL CHLORIDE
Figure BDA0000135908570001173
According to step C, the same procedure of embodiment 101 obtains above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ5.11-5.32(m，1H)，4.42-4.78(m，2H)，2.63-2.75(m，1H)，2.17-2.27(m，1H)，1.90-1.96(m，1H)，1.78-1.84(m，1H)，1.54-1.60(m，1H)，1.23-1.29(m，1H)。
Step e: (R)-1-(2,3-two fluoropropyls)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001181
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-1,3-lutidine-2 (1H)-ketone with (R)-1-(2,3-two fluoropropyls) Trimetylene-1-SULPHURYL CHLORIDE reaction, thereby obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.45(dd，J＝2.0?&?10.0Hz，1H)，7.25-7.29(m，2H)，6.94(s，1H)，6.11(t，J＝8.4Hz，1H)，5.79(s，1H)，4.96-5.20(m，1H)，4.40-4.70(m，2H)，3.45(s，3H)，2.22-2.42(m，2H)，2.18(s，3H)，1.40-1.44(m，1H)，1.28-1.34(m，1H)，1.09-1.14(m，1H)，0.92-0.96(m，1H)；m/z＝556[M+1] +。
Embodiment 103
(R)-1-(2,3-two fluoropropyls)-N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-1-picoline-2 (1H)-ketone with (R)-1-(2,3-two fluoropropyls) Trimetylene-1-SULPHURYL CHLORIDE reaction, thereby obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.59(s，1H)，7.44(d，J＝10.0Hz，1H)，7.29(d，J＝8.4Hz，1H)，6.18(t，J＝8.4Hz，1H)，5.90(s，1H)，5.84(s，1H)，4.95-5.18(m，1H)，4.404.72(m，2H)，3.88(s，3H)，3.34(s，3H)，2.21-2.48(m，2H)，1.40-1.46(m，1H)，1.25-1.32(m，1H)，1.01-1.12(m，1H)，0.87-0.92(m，1H)；m/z＝572[M+1] +。
Embodiment 104
1-(2,2-two fluoro-3-hydroxypropyls)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
Steps A: 1-(3-(benzyl)-2-oxopropyl) Trimetylene-1-sulphonyl isopropyl ester
Figure BDA0000135908570001191
(5.29 grams 14.27mmol) add (S)-1-(3-(benzyl)-2-oxopropyl) Trimetylene-1-sulphonyl isopropyl ester (2.05 grams, 50 milliliters of dichloromethane solutions 6.24mmol), and the gained mixture at room temperature stirred 3.5 hours with Dai Si-Martin's oxygenant.With saturated sodium bicarbonate solution cancellation reaction, drying, concentrating under reduced pressure.Through silica gel column chromatography (sherwood oil: ETHYLE ACETATE: methylene dichloride=2: 1: 1) the concentrating residues thing is carried out purifying, obtain the compound (1.788 grams, 88%) of the above-mentioned title of yellow oily. 1H?NMR(400MHz，CDCl 3)δ7.31-7.36(m，5H)，4.91(sept.，J＝6.0Hz，1H)，4.60(s，2H)，4.16(s，2H)，2.90(s，2H)，1.51-1.54(m，2H)，1.38(d，J＝6.0Hz，6H)，1.14-1.18(m，2H)。
Step B:1-(3-(benzyl)-2,2-two fluoropropyls) Trimetylene-1-sulphonyl isopropyl ester
Figure BDA0000135908570001192
(0.96 gram 2.94mmol) is dissolved in 10 milliliters of anhydrous methylene chlorides, and is cooled to 0 ℃ with ketone.Under the nitrogen environment to solution drip DAST (1 milliliter, 7.76mmol) and stirred 6 hours, add again DAST (1 milliliter, 7.76mmol).After this solution at room temperature stirred 3 days, in the impouring sodium carbonate solution.Separate organic phase, concentrate and through silica gel column chromatography (sherwood oil: ETHYLE ACETATE=10: 1) thus the purifying residue obtains above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.31-7.36(m，5H)，4.94(sept.，J＝6.0Hz，1H)，4.61(s，2H)，3.68(t，J＝12.4Hz，2H)，2.65(t，J＝17.6Hz，2H)，1.51-1.54(m，2H)，1.39(d，J＝6.0Hz，6H)，1.23-1.26(m，2H)。
Step C:1-(3-(benzyl)-2,2-two fluoropropyls) Trimetylene-1-sulfonyl ester potassium
According to step B, the same procedure that embodiment 101 describes obtains above-mentioned title compound and directly is used for next step.
Step D:1-(3-(benzyl)-2,2-two fluoropropyls) Trimetylene-1-SULPHURYL CHLORIDE
Figure BDA0000135908570001202
According to step C, the same procedure that embodiment 101 describes obtains above-mentioned title compound and directly is used for next step. 1H?NMR(400MHz，CDCl 3)δ7.26-7.38(m，5H)，4.62(s，2H)，3.68(t，J＝12.4Hz，2H)，2.92(t，J＝17.6Hz，2H)，1.84-1.86(m，2H)，1.57-1.60(m，2H)。
Step e: 1-(3-(benzyl)-2,2-two fluoropropyls)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonyl ammonia
Figure BDA0000135908570001203
According to method A: make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1; 3-lutidine-2 (1H)-ketone and 1-(3-(benzyl)-2; 2-two fluoropropyls) Trimetylene-1-SULPHURYL CHLORIDE reaction, thus above-mentioned title compound obtained, and it can be used for next step reaction and need not purifying.
Step F: 1-(2,2-two fluoro-3-hydroxypropyls)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonyl ammonia
Figure BDA0000135908570001211
At-10 ℃, 1-(3-(benzyl)-2,2-two fluoropropyls)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonyl ammonia is dissolved in 3 milliliters of anhydrous methylene chlorides and in this solution and adds BCl 3(0.45 milliliter, 1mol/L 0.45mmol), at room temperature stirred 2 hours.Stir after 15 minutes, add-10 ℃ BCl again 3(0.9 milliliter, 0.9mmol) and water.Separate organic phase, and use the dichloromethane extraction water, and wash with saturated sodium bicarbonate solution.Clean the organic phase that merges with saturated brine, use dried over mgso, filter concentrating under reduced pressure.Through silica gel column chromatography (methylene dichloride: purifying residue methyl alcohol=20: 1), the compound (56 milligrams, 65%) of the above-mentioned title of acquisition yellow crystals shape. 1H?NMR(400MHz，acetone-D6)δ7.54(dd，J＝2.0?&?10.8Hz，1H)，7.52(s，1H)，7.48(s，1H)，7.39(d，J＝8.4Hz，1H)，6.38(t，J＝8.4Hz，1H)，3.72(t，J＝13.6Hz，2H)，3.40(s，3H)，2.76(t，J＝18.0Hz，2H)，2.09(s，3H)，1.24-1.27(m，2H)，1.19-1.21(m，2H)；m/z＝572[M+1] +。
Embodiment 105
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(3-p-methoxy-phenyl) Trimetylene-1-sulphonyl ammonia
Figure BDA0000135908570001212
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 2-(3-p-methoxy-phenyl) Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain above-mentioned title compound. 1HNMR(400MHz，CDCl 3)δ7.43(d，J＝10.0Hz，1H)，7.23-7.27(m，2H)，7.07(s，1H)，6.81(dd，J＝2.0?&?8.0Hz，1H)，6.69(s，1H)，6.55(d，J＝8.0Hz，1H)，6.51(t，J＝2.0Hz，1H)，6.08(t，J＝8.4Hz，1H)，5.77(s，1H)，3.80(s，3H)，3.38(s，3H)，2.66-2.69(m，1H)，2.49-2.51(m，1H)，1.99(s，3H)，1.74-1.79(m，1H)，1.43-1.48(m，1H)；m/z＝584[M+1] +。
Embodiment 106
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-2-(3-p-methoxy-phenyl) Trimetylene-1-sulphonyl ammonia
Figure BDA0000135908570001221
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-(3-p-methoxy-phenyl) Trimetylene-1-SULPHURYL CHLORIDE reaction, thereby obtain above-mentioned title compound. 1HNMR(400MHz，CDCl 3)δ7.66(s，1H)，7.45(d，J＝10.0Hz，1H)，7.29(d，J＝8.8Hz，1H)，7.21(t，J＝8.0Hz，1H)，6.78(d，J＝8.0Hz，1H)，6.51(d，J＝8.0Hz，1H)，6.47(s，1H)，6.18(t，J＝8.8Hz，1H)，5.76(s，1H)，5.65(s，1H)，3.79(s，3H)，3.36(s，3H)，3.20(s，3H)，2.68-2.72(m，1H)，2.46-2.53(m，1H)，1.72-1.78(m，1H)，1.37-1.42(m，1H)；m/z＝600[M+1] +。
Embodiment 107
2-(3-fluoro-4-hydroxy phenyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonyl ammonia
Figure BDA0000135908570001222
Use BBr 3Handle N-(2-(2-fluoro-4-iodophenyl is amino)-1,3-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(3-fluoro-4-p-methoxy-phenyl) Trimetylene-1-sulphonyl ammonia, thereby obtain above-mentioned title compound.
1H?NMR(400MHz，DMSO-D6)δ9.85(s，1H)，8.92(s，1H)，7.95(s，1H)，7.60(d，J＝10.8Hz，1H)，7.31(d，J＝8.0Hz，1H)，7.23(s，1H)，6.50-6.62(m，3H)，6.34(t，J＝8.8Hz，1H)，3.27(s，3H)，2.64-2.67(m，1H)，2.41-2.45(m，1H)，1.91(s，3H)，1.32-1.34(m，1H)，0.99-1.03(m，1H)；m/z＝588[M+1] +。
Embodiment 108
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(3-hydroxy phenyl) Trimetylene-1-sulphonyl ammonia
Figure BDA0000135908570001231
Use BBr 3Handle N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(3-p-methoxy-phenyl) Trimetylene-1-sulphonyl ammonia, thereby obtain above-mentioned title compound. 1HNMR(400MHz，DMSO-D6)δ9.37(s，1H)，8.88(s，1H)，7.91(s，1H)，7.58(dd，J＝1.6?&?10.8Hz，1H)，7.31(d，J＝7.6Hz，1H)，7.17(s，1H)，7.05(t，J＝7.6Hz，1H)，6.60(dd，J＝2.0?&?8.0Hz，1H)，6.47(s，1H)，6.32(t，J＝8.8Hz，1H)，6.29(d，J＝8.0Hz，1H)，3.26(s，3H)，2.59-2.62(m，1H)，2.31-2.33(m，1H)，1.86(s，3H)，1.34-1.37(m，1H)，1.02-1.05(m，1H)；m/z＝570[M+1] +。
Embodiment 109
2-(4-fluoro-3-p-methoxy-phenyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonyl ammonia
Figure BDA0000135908570001241
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 2-(4-fluoro-3-p-methoxy-phenyl) Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain above-mentioned title compound. 1H?NMR(400MHz，DMSO-D6)δ8.92(s，1H)，7.93(s，1H)，7.57-7.61(dd，J＝1.6?&?10.8Hz，1H)，7.30-7.32(d，J＝8.4Hz，1H)，7.20(s，1H)，7.06-7.12(dd，J＝8.4?&?11.6Hz，1H)，6.83-6.85(d，J＝6.8Hz，1H)，6.49-6.50(d，J＝6.4Hz，1H)，6.32-6.36(t，J＝8.8Hz，1H)，3.81(s，3H)，3.28(s，3H)，2.78-2.83(m，1H)，2.43-2.46(m，1H)，1.86(s，3H)，1.36-1.39(m，1H)，1.04-1.07(m，1H)；m/z＝602[M+1] +。
Embodiment 110
2-(4-chloro-2-fluorophenyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonyl ammonia
Figure BDA0000135908570001242
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 2-(4-chloro-2-fluorophenyl) Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain above-mentioned title compound. 1HNMR(400MHz，DMSO-D6)δ8.98(s，1H)，7.94(s，1H)，7.56-7.59(dd，J＝1.6?&?10.6Hz，1H)，7.40-7.41(d，J＝2.0Hz，1H)，7.38-7.39(d，J＝2.0Hz，1H)，7.31(s，1H)，7.28-7.29(d，J＝1.6Hz，1H)，7.21-7.23(d，J＝8.4Hz，1H)，6.89-6.93(t，J＝8.4Hz，1H)，6.32-6.36(t，J＝8.4Hz，1H)，3.28(s，3H)，2.86-2.90(m，1H)，2.46-2.48(m，1H)，1.88(s，3H)，1.40-1.46(m，1H)，1.11-1.16(m，1H)；m/z＝607[M+1] +。
Embodiment 111
2-(4-fluoro-3-p-methoxy-phenyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonyl ammonia
Figure BDA0000135908570001251
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-(4-fluoro-3-p-methoxy-phenyl) Trimetylene-1-SULPHURYL CHLORIDE reaction, thereby obtain above-mentioned title compound. 1H?NMR(400MHz，DMSO-D6)δ8.75(s，1H)，7.89(s，1H)，7.56-7.61(d，J＝11.2Hz，1H)，7.36-7.38(d，J＝8.0Hz，1H)，7.07-7.12(dd，J＝8.4&?11.2Hz，1H)，6.86-6.88(d，J＝7.2Hz，1H)，6.61(s，1H)，6.37-6.41(t，J＝8.4Hz，1H)，5.60(s，1H)，3.82(s，3H)，3.24(s，3H)，3.23(s，3H)，2.85-2.89(m，1H)，2.35-2.39(m，1H)，1.33-1.44(m，2H)；m/z＝618[M+1] +。
Embodiment 112
2-(4-chloro-2-fluorophenyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonyl ammonia
Figure BDA0000135908570001252
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-(4-chloro-2-fluorophenyl) Trimetylene-1-SULPHURYL CHLORIDE reaction, thereby obtain above-mentioned title compound. 1HNMR(400MHz，DMSO-D6)δ8.81(s，1H)，7.91(s，1H)，7.57-7.59(dd，J＝1.6?&?10.8Hz，1H)，7.39-7.40(d，J＝2.0Hz，1H)，7.35-7.37(d，J＝8.4Hz，1H)，7.23-7.25(d，J＝8.4Hz，1H)，7.07-7.11(t，J＝8.4Hz，1H)，6.37-6.42(t，J＝8.8Hz，1H)，5.64(s，1H)，3.26(s，3H)，3.24(s，3H)，2.94-2.98(m，1H)，2.42-2.46(m，1H)，1.41-1.50(m，2H)；m/z＝623[M+1] +。
Embodiment 113
2-(4-fluoro-2-hydroxy phenyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonyl ammonia
Figure BDA0000135908570001261
Use BBr 3Handle 2-(4-fluoro-2-p-methoxy-phenyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonyl ammonia, thereby obtain above-mentioned title compound. 1H?NMR(400MHz，DMSO-D6)δ9.86(s，1H)，8.93(s，1H)，7.96(s，1H)，7.68-7.71(d，J＝13.6Hz，1H)，7.59-7.61(d，J＝10.4Hz，1H)，7.30-7.32(d，J＝8.0Hz，1H)，7.24(s，1H)，6.50-6.62(m，3H)，6.32-6.36(t，J＝8.6Hz，1H)，3.28(m，3H)，2.63-2.65(m，1H)，2.42-2.45(m，1H)，1.91(s，3H)，1.34-1.36(m，1H)，1.04-1.06(m，1H)；m/z＝588[M+1] +。
Embodiment 114
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-2-(3-hydroxy phenyl) Trimetylene-1-sulphonyl ammonia
At-15 ℃, N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-2-(3-p-methoxy-phenyl) Trimetylene-1-sulphonyl ammonia is dissolved in 3 milliliters of methylene dichloride and adds BBr 3Reaction finishes back (by the TLC monitoring), and water cancellation solution cleans with ethyl acetate extraction and with salt solution.Use the dried over mgso organic phase, filter, thereby remove solvent and obtain above-mentioned title compound through silica gel column chromatography column purification residue. 1H?NMR(400MHz，DMSO-D6)δ9.39(s，1H)，8.74(s，1H)，7.91(s，1H)，7.60(d，J＝10.8Hz，1H)，7.37(d，J＝8.0Hz，1H)，7.06(t，J＝8.0Hz，1H)，6.62(d，J＝8.0Hz，1H)，6.45-6.48(m，1H)，6.37-6.42(t，J＝8.8Hz，1H)，5.65(s，1H)，3.25(s，3H)，3.23(s，3H)，2.70-2.73(m，1H)，2.29-2.33(m，1H)，1.38-1.40(m，1H)，1.27-1.29(m，1H)；m/z＝586[M+1] +。
Embodiment 115
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(4-p-methoxy-phenyl) Trimetylene-1-sulphonyl ammonia
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 2-(4-p-methoxy-phenyl) Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain above-mentioned title compound. 1HNMR(400MHz，CDCl 3)δ7.41-7.44(dd，J＝2.0?&?10.0Hz，1H)，7.24-7.26(m，1H)，7.10(s，1H)，6.83-6.90(m，5H)，6.06-6.11(t，J＝8.6Hz，1H)，5.98(s，1H)，3.80(s，3H)，3.39(s，3H)，2.47-2.58(m，2H)，2.00(s，3H)，1.68-1.73(m，1H)，1.36-1.40(m，1H)；m/z＝584[M+1] +。
Embodiment 116
2-(4-chloro-3-(trifluoromethyl) phenyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonyl ammonia
Figure BDA0000135908570001272
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 2-(4-chloro-3-(trifluoromethyl) phenyl) Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.48(s，1H)，7.43-7.46(dd，J＝1.6&?10.0Hz，1H)，7.34-7.35(d，J＝2.4Hz，1H)，7.25-7.28(m，1H)，7.08-7.13(m，2H)，7.01(s，1H)，6.12-6.14(t，J＝8.2Hz，1H)，6.08(s，1H)，3.43(s，3H)，2.66-2.69(m，2H)，2.03(s，3H)，1.75-1.80(m，1H)，1.40-1.45(m，1H)；m/z＝656[M+1] +。
Embodiment 117
2-(3, the 4-Dimethoxyphenyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonyl ammonia
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone and 2-(3, the 4-Dimethoxyphenyl) Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.42-7.44(d，J＝10.0Hz，1H)，7.24-7.27(d，J＝9.2Hz，1H)，7.13(s，1H)，6.81-6.83(d，J＝8.0Hz，1H)，6.72(s，1H)，6.49-6.51(d，J＝10.0Hz，1H)，6.47(s，1H)，6.06-6.11(t，J＝8.6Hz，1H)，5.93-5.94(d，J＝2.4Hz，1H)，3.87(s，3H)，3.86(s，3H)，3.38(s，3H)，2.60-2.62(m，1H)，2.50-2.52(m，1H)，2.03(s，3H)，1.70-1.72(m，1H)，1.38-1.40(m，1H)；m/z＝614[M+1] +。
Embodiment 118
2-(4-fluoro-3-hydroxy phenyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonyl ammonia
Figure BDA0000135908570001282
Use BBr 3Handle 2-(4-fluoro-3-p-methoxy-phenyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonyl ammonia, thereby obtain above-mentioned title compound. 1H?NMR(400MHz，DMSO-D6)δ9.81(s，1H)，8.90(s，1H)，7.92(s，1H)，7.58-7.61(dd，J＝1.6?&?10.8Hz，1H)，7.32-7.34(d，J＝8.4Hz，1H)，7.19(s，1H)，6.99-7.05(dd，J＝8.6?&?11.4Hz，1H)，6.37-6.70(dd，J＝2.0?&?8.4Hz，1H)，6.32-6.37(t，J＝8.8Hz，1H)，6.30-6.32(m，1H)，3.30(s，3H)，2.64-2.67(m，1H)，2.36-2.38(m，1H)，1.88(s，3H)，1.34-1.37(m，1H)，1.03-1.05(m，1H)；m/z＝588[M+1] +
Embodiment 119
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(4-hydroxy phenyl) Trimetylene-1-sulphonyl ammonia
Figure BDA0000135908570001291
Use BBr 3Handle N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(4-p-methoxy-phenyl)-Trimetylene-1-sulphonyl ammonia, thereby obtain above-mentioned title compound. 1HNMR(400MHz，DMSO-D6)δ9.33(s，1H)，8.88(s，1H)，7.98(s，1H)，7.62(d，J＝8.8Hz，1H)，7.34(d，J＝8.8Hz，1H)，7.22(s，1H)，6.72-6.74(m，2H)，6.65-6.67(m，2H)，6.33(t，J＝9.2Hz，1H)，3.31(s，3H)，2.44-2.51(m，1H)，2.29-2.39(m，1H)，1.90(s，3H)，1.22-1.36(m，1H)，0.88-0.95(m，1H)；m/z＝570[M+1] +。
Embodiment 120
2-(3, the 4-dihydroxy phenyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonyl ammonia
Use BBr 3Handle 2-(3, the 4-Dimethoxyphenyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonyl ammonia, thereby obtain above-mentioned title compound. 1H?NMR(400MHz，DMSO-D6)δ9.03(s，1H)，8.90(s，1H)，8.86(s，1H)，8.12(s，1H)，7.60(d，J＝8.4Hz，1H)，7.33(d，J＝8.4Hz，1H)，7.24(s，1H)，6.65(d，J＝8.0Hz，1H)，6.49(s，1H)，6.33(t，J＝8.8Hz，1H)，6.08(d，J＝8.0Hz，1H)，3.27(s，3H)，2.30-2.43(m，1H)，2.22-2.30(m，1H)，1.91(s，3H)，1.24-1.36(m，1H)，0.86-0.92(m，1H)；m/z＝586[M+1] +。
Embodiment 121
N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino)-2-(2-fluoro-4-p-methoxy-phenyl) Trimetylene-1-sulphonyl ammonia
According to method A, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl is amino) benzene-1,2-diamines and 2-(2-fluoro-4-p-methoxy-phenyl) Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.39-7.42(m，2H)，7.07-7.17(m，2H)，6.76-6.80(m，1H)，6.72(s，1H)，6.34-6.57(m，2H)，6.15(t，J＝8.4Hz，1H)，5.67(s，1H)，3.79(s，3H)，2.67-2.71(m，2H)，1.68-1.72(m，1H)，1.42-1.50(m，1H)，m/z＝592[M+1] +
Embodiment 122
N-(5-fluoro-2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene sulphonyl ammonia
Under-10 ℃; With N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1; 6-dihydropyridine-3-yl) (190 milligrams, 0.385mmol) (177 milligrams, mixture 0.501mmol) stirred 15 minutes Trimetylene sulphonyl ammonia with the selectivity fluorine reagent that is dissolved in 5 milliliters of MeCN.Concentrating under reduced pressure gained solution, and through silica gel column chromatography (sherwood oil: ETHYLE ACETATE=3: 1 is to ETHYLE ACETATE) purifying residue, thereby above-mentioned title compound obtained. 1H?NMR(400MHz，CDCl 3)δ7.55(s，1H)，7.43(d，J＝8.4Hz，1H)，7.28(d，J＝8.4Hz，1H)，6.12(t，J＝8.4Hz，1H)，5.93(s，1H)，4.30(s，3H)，3.40(s，3H)，2.43-2.47(m，1H)，1.14-1.20(m，2H)，0.92-1.10(m，2H)；m/z＝496[M+1] +。
Embodiment 123
2-(2,4 dichloro benzene base)-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl) Trimetylene-1-sulphonyl ammonia
Figure BDA0000135908570001312
According to method A, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl is amino) phenyl-1,2-diamines and 2-(2,4 dichloro benzene base) Trimetylene-1-SULPHURYL CHLORIDE reaction, thus obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.36-7.41(m，3H)，7.16-7.20(m，2H)，7.06-7.12(m，1H)，6.78-6.83(m，2H)，6.19(t，J＝8.4Hz，1H)，5.80(s，1H)，2.91-2.97(m，1H)，2.61-2.91(m，1H)，1.60-1.79(m，1H)，1.36-1.41(m，1H)；m/z＝613[M+1] +。
Embodiment 124
N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl)-2-(2-fluoro-4-hydroxy phenyl) Trimetylene-1-sulphonyl ammonia
Figure BDA0000135908570001321
According to embodiment 114, use BBr 3Handle N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl)-2-(2-fluoro-4-hydroxy phenyl) Trimetylene-1-sulphonyl ammonia, thereby obtain the compound of above-mentioned title. 1H?NMR(400MHz，CDCl 3)δ7.38-7.41(m，2H)，7.17(d，J＝8.8Hz，1H)，7.07(d，J＝8.8Hz，1H)，6.80(s，1H)，6.69-6.74(m，1H)，6.55-6.58(m，2H)，6.15-6.18(m，2H)，5.75(s，1H)，2.60-2.69(m，2H)，1.64-1.72(m，1H)，1.40-1.48(m，1H)；m/z＝579[M+1] +。
Embodiment 125
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-1-(3-hydroxyl-2-oxopropyl) Trimetylene-1-sulphonamide
Steps A: (S)-1-(benzyloxy)-3-(1-(isopropoxy alkylsulfonyl) cyclopropyl) propyl group-2-base educt
With (S)-1-(3-(benzyloxy)-2-hydroxypropyl) Trimetylene-1-sulfonyl ester (5.0 the gram, 15.22mmol), pivaloyl chloride (2.25 milliliters, 18.27mmol), Et 3N (2.64 milliliters, 18.87mmol) and DMAP (186 milligrams 1.522mmol), are dissolved in 40 milliliters of methylene dichloride, reflux 15.5 hours.Water cancellation reaction mixture is used ethyl acetate extraction, and water (2x) cleans.Use dried over sodium sulfate, filter, and concentrating under reduced pressure.Through silica gel column chromatography (sherwood oil: purifying residue ETHYLE ACETATE=8: 1 to 5: 1), thereby the compound of the above-mentioned title of acquisition colorless oil (4.75 grams, 76%). 1H?NMR(400MHz，CDCl 3)δ7.28-7.36(m，5H)，5.34-5.37(m，1H)，4.95-5.00(sept.，J＝6.0Hz，1H)，4.52(s，2H)，3.55-3.63(m，2H)，2.37(dd，J＝4.8?&?15.2Hz，1H)，2.04(dd，J＝8.4?&?15.2Hz，1H)，1.40(dd，J＝6.4?&?11.2Hz，6H)，1.24-1.26(m，2H)，1.20(s，9H)，1.02-1.05(m，1H)，0.92-0.96(m，1H)。
Step B: (S)-1-(3-(benzyloxy)-2-(pivaloyl oxygen base) propyl group) Trimetylene-1-sulfonyl ester
Figure BDA0000135908570001331
(S)-1-(benzyloxy)-3-(1-(the different third oxygen acyl group) cyclopropyl) propane-2-base educt (4.75 grams; 11.51mmol) and Soiodin (2.07 grams; 13.81mmol) be dissolved in 60 milliliters of acetone reflux after 64 hours; Concentrating under reduced pressure is also dry with Vanadium Pentoxide in FLAKES, restrains yellow viscous substance and can be used for next step reaction and need not to be further purified thereby obtain 4.758. 1H?NMR(400MHz，DMSO-D6)δ7.28-7.35(m，5H)，5.50(m，1H)，4.40-4.49(m，2H)，3.56-3.64(m，2H)，1.82-1.93(m，2H)，1.11(s，9H)，0.87(m，2H)，0.45(m，2H)。
Step C: (S)-1-(benzyloxy)-3-(1-(the different third oxygen acyl group) cyclopropyl) propane-2-base pivalate
Figure BDA0000135908570001332
(1.48 grams 3.58mmol) are dissolved in 5 milliliters of SOCl with sodium salt 2, add 4 N, dinethylformamide.Concentrating under reduced pressure after this mixture heating up refluxed 1.5 hours.With ETHYLE ACETATE dilution residue and water flushing, with ETHYLE ACETATE (2x) aqueous phase extracted.Merge organic phase and, use dried over mgso, filter and concentrating under reduced pressure with the saturated nacl aqueous solution cleaning.Through silica gel column chromatography (sherwood oil: purifying residue ETHYLE ACETATE=8: 1), thereby obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.29-7.38(m，5H)，5.33-5.37(m，1H)，4.53(s，2H)，3.57-3.62(m，2H)，2.61(dd，J＝4.0?&?16.0Hz，1H)，2.31(dd，J＝9.2?&?16.0Hz，1H)，1.73-1.80(m，2H)，1.33-1.36(m，1H)，1.21-1.25(m，1H)，1.21(s，9H)。
Step D: (S)-1-(benzyloxy)-3-(1-(N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3 base) alkylsulfonyl) cyclopropyl) propane-2-base pivalate
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-1,3-lutidine-2 (1H)-ketone with (S)-1-(benzyloxy)-3-(1-(chlorosulfonyl) cyclopropyl) propane-2-base pivalate, thereby obtain above-mentioned title compound. 1H?NMR(400MHz，CDCl 3)δ7.39(dd，J＝2.0?&10.4Hz，1H)，7.24-7.36(m，7H)，7.10(s，1H)，6.74(s，1H)，6.10(t，J＝8.8Hz，1H)，5.36-5.39(m，1H)，4.48-4.56(m，2H)，3.66(dd，J＝4.0?&?10.8Hz，1H)，3.52(dd，J＝4.0?&?10.8Hz，1H)，3.42(s，3H)，2.16(s，3H)，2.14-2.16(m，2H)，1.32-1.36(m，1H)，1.22-1.28(m，1H)，1.18(s，9H)，0.85-0.89(m，1H)，0.78-0.82(m，1H)。
Step e: (S)-1-(benzyloxy)-3-(1-(N-(tertbutyloxycarbonyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3 base) alkylsulfonyl) cyclopropyl) propane-2-base pivalate
With (S)-1-(benzyloxy)-3-(1-(N-(2-(2-fluoro-4-iodophenyl amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3 base) alkylsulfonyl) cyclopropyl) propane-2-base pivalate with (Boc) 2O is dissolved in 15 milliliters of THF, at-45 ℃, adds sodium hydride successively, and in stirred overnight at room temperature (17 hours).With frozen water cancellation mixture, and use ethyl acetate extraction.Clean with saturated ammonium chloride solution, use dried over sodium sulfate, filter and concentrating under reduced pressure obtains 1.379 and restrains the brown solid crude products and can be used for next step reaction and need not to be further purified.
Step F: (S)-1-(3-(benzyloxy)-2-hydroxypropyl) cyclopropyl alkylsulfonyl (2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) tertiary butyl carbamate
Figure BDA0000135908570001351
With (175 milligrams of Lithium Hydroxide Monohydrates; 4.17mmol) thick (the S)-1-(benzyloxy) of adding-3-(1-(N-(tertbutyloxycarbonyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1; 5-dimethyl--6-carbonyl-1; 6-dihydropyridine-3 base) cyclopropyl alkylsulfonyl)) propane-2-base pivalate (689 milligrams, by step e gained 92% purity, methyl alcohol 0.768mmol) (6 milliliters) and the turbid solution of water (2 milliliters).At room temperature stir and obtained solution clearly in 3 hours.Be heated to 60 ℃ and spend the night (17 hours), add again Lithium Hydroxide Monohydrate (156 milligrams, 3.72mmol), and with mixture heating up 4 hours.Concentrating under reduced pressure gained solution by ethyl acetate extraction, is cleaned by water and salt solution, and drying is filtered and pressurization concentrates and obtains 505 milligrams of yellow solid crude products (89%) and can be used for next step reaction and need not to be further purified.
Step G: (S)-1-(3-(benzyloxy)-2-oxopropyl) cyclopropyl alkylsulfonyl (2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) tertiary butyl carbamate
Figure BDA0000135908570001352
(S)-1-(3-(benzyloxy)-2-hydroxypropyl) cyclopropyl alkylsulfonyl (2-(2-fluoro-4-iodophenyl is amino)-1; 5-dimethyl--6-carbonyl-1; 6-dihydropyridine-3-yl) tertiary butyl carbamate (500 milligrams, 0.674mmol) be dissolved in 7 milliliters of methylene dichloride, add (572 milligrams of Dai Si-Martin's oxygenant; 1.348mmol), and at room temperature stirred this mixture 16.5 hours.By saturated sodium bicarbonate solution cancellation mixture, use dichloromethane extraction, drying is filtered and concentrating under reduced pressure.(sherwood oil: purifying residue ETHYLE ACETATE=1: 1) obtains the compound (181 milligrams, 36%) of the above-mentioned title of yellow crystals solid-like through silica gel column chromatography. 1H?NMR(400MHz，CDCl 3)δ7.44-7.47(m，2H)，7.31-7.40(m，6H)，7.18(t，J＝8.4Hz，1H)，6.23(s，1H)，4.57(s，2H)，4.08(s，2H)，3.46(s，3H)，3.15(d，J＝15.6Hz，1H)，2.96(d，J＝15.6Hz，1H)，2.15(s，3H)，1.52-1.55(m，1H)，1.47(s，9H)，1.41-1.47(m，1H)，0.97-1.08(m，2H)。
Step H:N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-1-(3-hydroxyl-2-oxopropyl) Trimetylene-1-sulphonamide
Under 0 ℃; With (S)-1-(3-(benzyloxy)-2-oxopropyl) cyclopropyl alkylsulfonyl (2-(2-fluoro-4-iodophenyl is amino)-1; 5-dimethyl--6-carbonyl-1; 6-dihydropyridine-3-yl) tertiary butyl carbamate (175 milligrams 0.237mmol) are dissolved in 5 milliliters of methylene dichloride, and in this solution, add 1 milliliter of BCl 3(1M) stirred 10 minutes.Go out by shrend afterwards, and, clean, use dried over mgso with saturated brine by methylene dichloride (x3) extraction.(methylene dichloride: purifying residue methyl alcohol=20: 1) obtains the compound of the above-mentioned title of yellow solid shape of 64 grams (49%) through silica gel column chromatography. 1H?NMR(400MHz，CDCl 3)δ7.42-7.45(m，2H)，7.26-7.28(m，1H)，7.04(s，1H)，6.63(s，1H)，6.11(t，J＝8.4Hz，1H)，4.31(s，2H)，3.44(s，3H)，2.98(s，2H)，2.90(s，1H)，2.19(s，3H)，2.46-2.52(m，2H)，0.94-1.04(m，2H)；m/z＝550[M+1] +。
Embodiment 126
(S)-1-(3-fluoro-2-hydroxy phenyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
Steps A: (S)-1-hydroxyl-3-(1-(isopropoxy alkylsulfonyl) cyclopropyl) propane-special valerate of 2-base
Figure BDA0000135908570001371
(S)-1-(benzyloxy)-3-(1-(isopropoxy alkylsulfonyl) cyclopropyl) propane-(1.5 grams 3.92mmol) are dissolved in anhydrous methylene chloride (30 milliliters) to the special valerate of 2-base.In ice bath with BCl 3(5.1 milliliters, 1mol/L 5.10mmol) slowly adds solution, at room temperature stirs 2 hours, adds entry again.Use dichloromethane extraction,, use dried over mgso, filter and concentrating under reduced pressure with the salt solution extraction.(eluent: sherwood oil: purifying residue ETHYLE ACETATE=4: 1) obtains the compound (1.04 gram, 91%) of above-mentioned title through silica gel column chromatography. 1H?NMR(400MHz，CDCl 3)δ5.25-5.28(m，1H)，5.00(sept.，J＝6.4Hz，1H)，3.80(dd，J＝3.2?&?12.0Hz，1H)，3.70(dd，J＝4.4&?12.0Hz，1H)，2.32(dd，J＝5.6?&?15.6Hz，1H)，1.99(dd，J＝8.0?&?15.6Hz，1H)，1.46-1.50(m，2H)，1.42(dd，J＝6.4?&?6.8Hz，6H)，1.22(s，9H)，1.03-1.06(m，1H)，0.97-1.00(m，1H)。
Step B: (S)-1-fluoro-3-(1-(isopropoxy alkylsulfonyl) cyclopropyl) propane-special valerate of 2-base
With alcohol (1.04 grams 3.56mmol) stir and to be dissolved in 20 milliliters of THF, under 0 ℃, slowly add DAST (1.26 grams, 0.958 milliliter, 7.83mmol).At room temperature mixture was stirred 24 hours, add saturated sodium bicarbonate solution again.Use the ethyl acetate extraction organic phase, use dried over mgso, filter and concentrating under reduced pressure.Through silica gel column chromatography column purification residue, obtain the compound of above-mentioned title. 1H?NMR(400MHz，CDCl 3)δ5.21-5.23(m，0.5H)，5.09-5.11(m，0.5H)，4.96(sept.，J＝6.4Hz，1H)，4.12-4.29(m，2H)，2.37-2.49(m，1H)，1.63-1.96(m，1H)，1.48-1.51(m，2H)，1.42(d，J＝6.4Hz，6H)，1.19-1.22(m，10H)，0.88-0.92(m，1H)。
Step C: (S)-1-(3-fluoro-2-(special pentyloxy) propyl group) Trimetylene-1-sulphonate sodium
Figure BDA0000135908570001381
(S)-the special valerate of 1-fluoro-3-(1-(isopropoxy alkylsulfonyl) cyclopropyl) propane-2-base (295 milligrams, 1.00mmol) and Soiodin (165 milligrams, 1.10mmol) be dissolved in 10 milliliters in acetone, backflow is spent the night.Use the ethyl acetate extraction residue, the reduction vaporization water obtains crude product, can be used for next step reaction and need not to be further purified.
Step D: (S)-1-(1-(chlorosulfonyl) cyclopropyl)-3-fluoro-propane-special valerate of 2-base
Figure BDA0000135908570001382
With sodium salt (260 milligrams 0.948mmol) are dissolved in THIONYL CHLORIDE 97 (5 milliliters) and N, dinethylformamide (5) backflow 1 hour.The reduction vaporization volatile matter also slowly adds entry.Use the ethyl acetate extraction residue, use dried over mgso, and evaporation obtains yellow oil.(eluent: sherwood oil: purifying residue ETHYLE ACETATE=10: 1) obtains the compound (216 milligrams, 79%) of above-mentioned title through silica gel column chromatography. 1H?NMR(400MHz，CDCl 3)δ5.24-5.26(m，0.5H)，5.11-5.14(m，0.5H)，4.25-4.28(m，1H)，4.21-4.23(m，1H)，2.75(dd，J＝16.4?&?34.8Hz，1H)，2.00-2.11(m，1H)，1.88-1.94(m，1H)，1.76-1.82(m，1H)，1.56-1.60(m，1H)，1.19-1.25(m，10H)。
Step e: (S)-1-fluoro-3-(1-(N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1, the 6-dihydropyridine-3-yl) alkylsulfonyl) cyclopropyl) propane-special valerate of 2-base
Figure BDA0000135908570001383
According to method A, 5-amino-6-(2-fluoro-4-iodophenyl amino)-1,3-lutidine-2 (1H)-ketone with (S)-1-(1-(chlorosulfonyl) Trimetylene)-3-fluoro-propane-special valerate of 2-base, thereby obtain the compound of above-mentioned title.
Step F: (S)-1-(3-fluoro-2-hydroxypropyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-2-sulphonamide
Figure BDA0000135908570001391
With (S)-1-fluoro-3-(1-(N-(2-(2-fluoro-4-iodophenyl is amino)-1; 5-dimethyl--6-carbonyl-1; 6-dihydropyridine-3-yl) cyclopropyl alkylsulfonyl)) the basic special valerate of propane-2-is (163 milligrams; 0.256mmol) with Lithium Hydroxide Monohydrate (53.6 milligrams, 1.278mmol) be dissolved in 4 ml methanol-water (volume ratio: 3/1) and be heated to 60 ℃ 2 hours, concentrating under reduced pressure afterwards.(eluent: sherwood oil: purifying residue ETHYLE ACETATE=1: 1 to 1: 3) obtains the compound (65 milligrams, 46%) of above-mentioned title through silica gel column chromatography. 1H?NMR(400MHz，CDCl 3)δ7.43-7.46(m，1H)，7.25-7.30(m，2H)，6.13(s，1H)，6.11(t，J＝8.8Hz，1H)，5.28-5.40(m，2H)，3.68-3.83(m，2H)，3.44(s，3H)，2.05-2.36(m，5H)，1.31-1.43(m，2H)，1.25-1.31(m，2H)，1.06-1.09(m，1H)，0.92-0.98(m，1H)；m/z＝554[M+1] +。
Embodiment 127
N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(3-p-methoxy-phenyl)-N-methyl cyclopropane-1-sulphonamide
Figure BDA0000135908570001392
At 0 ℃; With N-(2-(2-fluoro-4-iodophenyl is amino)-1; 5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-and 2-(3-p-methoxy-phenyl)-N-methyl cyclopropane-1-sulphonamide (100 milligrams, 0.171mmol) and (0.012 milliliter of methyl iodide; 0.188mmol) be dissolved in 2 milliliters of THF and add salt of wormwood (36 milligrams, 0.26mmol).Stirring reaction water cancellation and use ethyl acetate extraction after 2.5 hours.Clean organic phase with salt solution, use dried over mgso, filter concentrating under reduced pressure.(sherwood oil: purifying residue ETHYLE ACETATE=1: 1) obtains the compound of above-mentioned title through silica gel column chromatography. 1H?NMR(400MHz，CDCl 3)δ7.42-7.45(m，1H)，7.25-7.28(m，1H)，6.94-7.00(m，2H)，6.78-6.88(m，1H)，6.42-6.70(m，2H)，6.14(t，J＝8.4Hz，1H)，3.80(s，3H)，3.45(s，3H)，3.08(s，3H)，2.60-2.74(m，1H)，2.40-2.50(m，1H)，1.95(s，3H)，1.70-1.80(m，1H)，1.40-1.50(m，1H)；m/z＝598[M+1] +。
Embodiment 128
N-(5-chloro-2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-2-(3-p-methoxy-phenyl) Trimetylene-1-sulphonamide
At 0 ℃, N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-2-(3-p-methoxy-phenyl) Trimetylene-1-sulphonamide (77 milligrams, 0.128 mmole) is dissolved in 2 milliliters of CH 3Among the CN, then add N-chlorosuccinimide (20.6 milligrams, 0.154 mmole).Stir after two hours, decompression is enriched mixture down, and residue is with silica gel column chromatography column purification (sherwood oil: ETHYLE ACETATE=2: 1), obtain the compound (50 milligrams, 61%) of above-mentioned title. 1H?NMR(400MHz，CDCl 3)δ7.61(s，1H)，7.44(d，J＝8.4Hz，1H)，7.20-7.31(m，2H)，6.79(d，J＝5.6Hz，1H)，6.51-6.55(m，2H)，6.18(t，J＝8.4Hz，1H)，6.00(s，1H)，3.91(s，3H)，3.79(s，3H)，3.43(s，3H)，2.60-2.68(m，1H)，2.51-2.59(m，1H)，1.60-1.71(m，1H)，1.43-1.45(m，1H)；m/z＝634[M+1] +。
Embodiment 129
N-(4-fluoro-5-(2-fluoro-4-iodophenyl is amino)-1-methyl isophthalic acid H-benzo [d] imidazoles-6-yl)-2-(3-fluorophenyl) encircles third-sulphonamide
Figure BDA0000135908570001411
Handle 1-(2-fluoro-4-iodophenyl is amino)-8-fluoro-5-methyl-benzoglyoxaline [6 at-78 ℃ with LiHMDS; 5-d] imidazoles (WO2008089459 A1; Embodiment 1), add 2-(3-fluorophenyl) Trimetylene-1-SULPHURYL CHLORIDE according to step K (WO2008089459 A1, embodiment 1) again at 0 ℃ subsequently; And use trimethyl silane alkyd potassium (step I), obtain the compound of above-mentioned title. 1H?NMR(400MHz，CDCl 3)δ7.89(s，1H)，7.57(s，1H)，7.38-7.41(d，J＝10.4Hz，1H)，7.19-7.25(m，1H)，7.04-7.06(d，J＝8.8Hz，1H)，6.92-6.96(t，1H)，6.62-6.64(d，1H)，6.55-6.58(d，J＝8.8Hz，1H)，5.95-5.99(t，J＝8.8Hz，1H)，5.39(s，1H)，4.30-4.32(m，1H)，4.12-4.16(m，1H)，3.86(s，3H)，2.62-2.66(s，3H)；m/z＝599[M+1] +。
Embodiment 130
2-(6-chloropyridine-3-yl)-N-(2-(2-fluoro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-1,3-lutidine-2 (1H)-ketone and thiophene-3-SULPHURYL CHLORIDE obtains the compound of above-mentioned title. 1H?NMR(400MHz，DMSO-D6)δ8.95(s，1H)，8.17(s，1H)，7.90(s，1H)，7.51-7.54(d，J＝10.4Hz，1H)，7.38(s，2H)，7.28-7.30(d，J＝8.4Hz，1H)，7.14(s，1H)，6.30-6.32(t，1H)，3.24(s，3H)，2.91-2.93(m，2H)，1.82(s，3H)，1.42-1.45(m，2H)；m/z＝589[M+1] +。
Embodiment 131
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(3-fluorophenyl) Trimetylene-1-sulphonamide
Steps A: 2-methyl-3-keto-glutaric acid diethyl ester
Figure BDA0000135908570001421
(2.32 grams 11.48mmol) are dissolved in 10 milliliters of THF, and (60%, 0.48 restrains, 1.045mmol) to add sodium hydride with 3-keto-glutaric acid diethyl ester.Added after stirring the mixture under the room temperature 30 minutes methyl iodide (0.715 milliliter, 11.48mmol).The mixture stirring was gone out with shrend after 2 days, and ethyl acetate extraction is arranged.Clean organic phase with salt solution, and, filter and concentrating under reduced pressure by dried over mgso.Through silica gel column chromatography column purification residue, obtain the compound (1.01 grams, 41%) of above-mentioned title. 1H?NMR(400MHz，CDCl 3)δ4.18-4.24(m，4H)，3.36-3.75(m，3H)，1.25-1.40(m，9H)。
Step B:1-(2-fluoro-4 iodophenyls)-3-methyl urea
With N, N-carbonyl dimidazoles (30 gram) is dissolved in 150 milliliters of N, and dinethylformamide also adds triethylamine (26 milliliters), is dissolved in 30 milliliters of N 0 ℃ of dropping afterwards, the 2-fluoro-4-Iodoaniline of dinethylformamide (38 gram).After dosing completion, at room temperature stirred the mixture 5 hours, subsequently at 0 ℃ of methanol solution that drips 30 milliliter of 30% methylamine.After the stirred overnight at room temperature, water-dilution with toluene white depositions filters, and drying obtains the compound (92%) of the above-mentioned title of white solid. 1H?NMR(400MHz，DMSO-D6)δ8.39(s，1H)，7.90-7.94(t，J＝8.6Hz，1H)，7.52-7.55(dd，J＝1.8?&?10.6Hz，1H)，7.38-7.40(d，J＝10.4Hz，1H)，6.46-6.48(d，J＝4.8Hz，1H)，2.62(s，3H)。
Step C:2-fluoro-4-iodo-N-((methylene imine) methylene radical) aniline
Figure BDA0000135908570001423
With urea (0.8mmol), PPh 3(420 milligrams, 1.6mmol) and Et 3N (0.45 milliliter, 3.20mmol) be dissolved in methylene dichloride (8.0 milliliters), 0 ℃ add CBr4 (530 milligrams, methylene dichloride 1.6mmol) (2.0 milliliters) solution.At room temperature stirred reaction mixture is 30 minutes, and is concentrated into drying.(sherwood oil: purifying residue ETHYLE ACETATE=10: 1) obtains the compound of above-mentioned title through silica gel column chromatography. 1HNMR(400MHz，CDCl 3)δ7.34-7.41(m，2H)，6.76-6.81(t，J＝8.6Hz，1H)，3.17(s，3H)。
Step D:2-(2-fluoro-4-iodophenyl is amino)-4-hydroxyl-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-ETHYLE ACETATE
Figure BDA0000135908570001431
2-methyl-3-keto-glutaric acid diethyl ester (1.0 equivalent) stirring is dissolved in anhydrous THF, at 0 ℃, adds sodium hydride (1.1 equivalents, 60%) in batches.THF solution with 2-fluoro-4-iodo-N-((methylene imine) methylene radical) aniline (1.1 equivalent) at room temperature slowly adds through funnel, and with gained mixture stirred overnight.Water cancellation reaction, and by the ETHYLE ACETATE washed mixture, separate water layer and also neutralize with 2N hydrochloric acid.Use the ethyl acetate extraction water.Clean the organic phase that merges with saturated nacl aqueous solution, carry out drying, filter with sal epsom, and concentrating under reduced pressure.Through silica gel column chromatography column purification residue, obtain the compound of above-mentioned title. 1HNMR(400MHz，CDCl 3)δ11.21(s，1H)，8.28(s，1H)，7.48-7.51(dd，J＝1.8?&?10.2Hz，1H)，7.35-7.37(d，J＝8.4Hz，1H)，6.31-6.35(t，J＝8.6Hz，1H)，4.38-4.43(m，2H)，3.35(s，3H)，2.05(s，3H)，1.32-1.38(m，3H)。
Step e: 2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-carboxylic acid, ethyl ester.
Figure BDA0000135908570001432
With the alcohol (6.54mmol) of a last step gained, (0.37 milliliter, 3.93mmol) (1.085 restrain methyl-sulfate, 7.85mmol) are dissolved in acetone and reflux 17 hours with salt of wormwood.Water cancellation reaction extracts with ETHYLE ACETATE.By the dried over mgso organic phase, filter and concentrating under reduced pressure.(sherwood oil: purifying residue ETHYLE ACETATE=3: 1 to 1: 1) obtains the compound (50%) of above-mentioned title through silica gel column chromatography. 1H?NMR(400MHz，CDCl 3)δ8.87(s，1H)，7.46(d，J＝8.4Hz，1H)，7.33(d，J＝8.4Hz，1H)，6.35(t，J＝8.4Hz，1H)，4.31(q，J＝7.2Hz，2H)，3.78(s，3H)，3.32(s，3H)，2.09(s，3H)，1.35(t，J＝7.2Hz，3H)
Step F: 2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-carboxylic acid
Figure BDA0000135908570001441
(120 milligrams, 2.86mmol), the reflux mixture is concentrating under reduced pressure after 1.5 hours in the solution of methanol-water-THF of ester (1.908mmol) (14 milliliters, 5: 1: 1), to add Lithium Hydroxide Monohydrate.(methylene dichloride: purifying residue methyl alcohol=6: 1) obtains the compound (11%) of above-mentioned title through silica gel column chromatography. 1H?NMR(400MHz，DMSO-D6)δ7.60(d，J＝8.0Hz，1H)，7.35(d，J＝8.0Hz，1H)，6.39(t，J＝9.2Hz，1H)，3.72(s，3H)，3.20(s，3H)，1.90(s，3H)。
Step G:3-(2-fluoro-4-iodophenyl is amino)-7-methoxyl group-4, and 6-dimethyl--1H-imidazoles [4,5-b] pyridine-2,5 (3H, 4H)-diketone
Figure BDA0000135908570001442
(0.1 milliliter, (100 milligrams, 0.23mmol) (0.14 milliliter, 5 milliliters of N 0.93mmol), dinethylformamide solution at room temperature stir 2.25 hours (after 1.5 hours just muddiness), spend the night being heated to 50 ℃ with triethylamine 0.46mmol) to add acid with DPPA.After adding ETHYLE ACETATE, water (x3) washed mixture is used the ethyl acetate extraction water again.Merge organic phase, and use dried over mgso, filter, and concentrating under reduced pressure.(ETHYLE ACETATE to methylene dichloride: purifying residue methyl alcohol=15: 1) obtains the compound (40 milligrams, 40%) of the above-mentioned title of gray solid shape through silica gel column chromatography. 1H?NMR(400MHz，CDCl 3)δ9.24(s，1H)，7.67-7.71(m，2H)，7.19(t，J＝8.0Hz，1H)，3.97(s，3H)，3.21(s，3H)，2.10(s，3H)。
Step H:3-(2-fluoro-4-iodophenyl is amino)-1-(2-(3-fluorophenyl) cyclopropyl alkylsulfonyl)-7-methoxyl group-4, and 6-dimethyl--1H-imidazoles [4,5-b] pyridine-2,5 (3H, 4H)-diketone
Figure BDA0000135908570001451
At-78 ℃, with LiHMDS (0.1 milliliter, 1M; 0.1mmol) adding 3-(2-fluoro-4-iodophenyl is amino)-7-methoxyl group-4,6-dimethyl--1H-imidazoles [4,5-b] pyridine-2; 5 (3H, 4H)-diketone (37 milligrams, THF solution 0.086mmol) was above 20 minutes; Add afterwards 2-(3-fluorophenyl) Trimetylene-1-SULPHURYL CHLORIDE (30 milligrams, 0.129mmol).In stirring at room after 4 hours, with saturated ammonium chloride solution cancellation mixture, with ethyl acetate extraction and use dried over mgso.Filter, remove and desolvate, and (sherwood oil: purifying residue ETHYLE ACETATE=2: 1) obtains the compound (17 milligrams, 32%) of above-mentioned title through silica gel column chromatography. 1H?NMR(400MHz，CDCl 3)δ7.65-7.71(m，2H)，7.18(t，J＝8.0Hz，1H)，7.12(t，J＝8.0Hz，1H)，6.89-6.99(m，2H)，6.78-6.84(m，1H)，4.00(s，3H)，3.47-3.52(m，1H)，3.17(s，3H)，3.06-3.12(m，1H)，2.13(s，3H)，2.07-2.12(m，1H)，1.60-1.67(m，1H)。
Step I:N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-2-(3-fluorophenyl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001461
With 3-(2-fluoro-4-iodophenyl is amino)-1-(2-(3-fluorophenyl) cyclopropyl alkylsulfonyl)-7-methoxyl group-4; 6-dimethyl--1H-imidazoles [4; 5-b] and pyridine-2,5 (3H, 4H)-diketone (17 milligrams) is dissolved in (0.3 milliliter of aqueous sodium hydroxide solution; 1H) and dioxane (1 milliliter), be heated to 50 ℃ 15 minutes.With saturated ammonium chloride solution cancellation mixture, use the ethyl acetate extraction water.Merge organic phase, and clean, use dried over mgso, filter and concentrating under reduced pressure with saturated brine.Through silica gel column chromatography column purification residue, obtain the compound (50%) of above-mentioned title. 1H?NMR(400MHz，CDCl 3)δ7.41-7.44(m，2H)，7.22-7.28(m，2H)，6.92-6.96(m，1H)，6.74-6.76(d，J＝8.0Hz，1H)，6.64-6.67(dd，J＝1.8?&?11.4Hz，1H)，6.12-6.16(t，J＝8.6Hz，1H)，6.04(s，1H)，4.09-4.15(q，1H)，3.41(s，3H)，2.69-2.74(m，H)，2.53-2.58(m，1H)，1.98(s，3H)，1.67-1.72(m，1H)，1.34-1.40(m，1H)；m/z＝602[M+1] +。
Embodiment 132
N-(6-(2-fluoro-4-iodophenyl is amino)-5-methyl-4-carbonyl-4,5-dihydro fluorine [3,2-c] pyridine-7-yl)-2-(3-fluorophenyl) Trimetylene-1-sulphonamide
Steps A: 2-(the 2-4-iodophenyl is amino)-4-hydroxyl-1-methyl-6-1,6-dihydropyridine-3-carboxylic acid, ethyl ester
At 0 ℃; With sodium hydride (1.1 equivalents; 60%) adds the anhydrous THF solution of 3-keto-glutaric acid diethyl ester (1.0 equivalent) in batches, and, at room temperature slowly add said mixture through funnel with the THF solution of 2-fluoro-4-iodo-N-((methylene imine) methylene radical) aniline (1.1 equivalent).With gained mixture stirred overnight.After the water cancellation reaction, use the ETHYLE ACETATE washed mixture, water phase separated also neutralizes with 2N HCl.Use the ethyl acetate extraction water, and merge organic phase.After saturated sodium sulphite cleaning, use dried over mgso, filter and concentrating under reduced pressure.Through silica gel column chromatography column purification residue, obtain the compound of above-mentioned title. 1H?NMR(400MHz，CDCl 3)δ10.96(s，1H)，8.75(s，1H)，7.52(dd，J＝2.0?&?10.0Hz，1H)，7.41(d，J＝8.4Hz，1H)，6.44(t，J＝8.4Hz，1H)，5.84(s，1H)，4.43(q，J＝7.2Hz，2H)，3.28(s，3H)，1.38(t，J＝7.2Hz，3H)。
Step B:6-(2-fluoro-4-iodophenyl is amino)-5-methyl-4-carbonyl-4,5-dihydro fluorine [3,2-c] pyridine-7-carboxylic acid ethyl ester
Figure BDA0000135908570001471
With 2-(the 2-4-iodophenyl is amino)-4-hydroxyl-1-methyl-6-1, (0.720 gram 5.21mmol) is dissolved in 20 milliliters of acetone, and (0,409 restrains, 5.21mmol) at room temperature to add the 2-monochloroacetaldehyde for 6-dihydropyridine-3-carboxylic acid, ethyl ester (3.47mmol) and salt of wormwood.Mixture is at room temperature stirred after 30 minutes with 1N hydrochloric acid cancellation reaction, and extract with ETHYLE ACETATE.Use the dried over mgso organic phase, dry and concentrating under reduced pressure.Through silica gel column chromatography column purification residue, obtain the compound (66%) of the above-mentioned title of white solid. 1H?NMR(400MHz，CDCl 3)δ9.85(s，1H)，7.53(d，J＝2.4Hz，1H)，7.49(dd，J＝2.0?&?10.0Hz，1H)，7.37(d，J＝8.4Hz，1H)，6.96(d，J＝2.0Hz，1H)，6.44(t，J＝8.4Hz，1H)，4.41(q，J＝7.2Hz，2H)，3.36(s，3H)，1.43(t，J＝7.2Hz，3H)。
Step C:6-(2-fluoro-4-iodophenyl is amino)-5-methyl-4-carbonyl-4,5-dihydro fluorine [3,2-c] pyridine-7-carboxylic acid acetate
Figure BDA0000135908570001472
According to step F, the same procedure of embodiment 131 obtains the compound of above-mentioned title. 1H?NMR(400MHz，DMSO-D6)δ7.82(d，J＝2.0Hz，1H)，7.65(dd，J＝2.0?&?10.8Hz，1H)，7.38(d，J＝8.4Hz，1H)，6.90(d，J＝2.0Hz，1H)，6.57(t，J＝8.4Hz，1H)，3.20(s，3H)。
Step D:3-(2-fluoro-4-iodophenyl is amino)-4-methyl isophthalic acid H-fluorine [2,3-d] imidazoles [4,5-b] pyridine-2,5 (3H, 4H)-diketone
Figure BDA0000135908570001481
According to step G, the same procedure of embodiment 131 obtains the compound of above-mentioned title. 1H?NMR(400MHz，CDCl 3)δ8.28(s，1H)，7.71(d，J＝8.8Hz，1H)，7.69(d，J＝10.4Hz，1H)，7.45(d，J＝1.6Hz，1H)，7.23(t，J＝8.4Hz，1H)，7.04(d，J＝1.6Hz，1H)，3.27(s，3H)。
Step e: 3-(2-fluoro-4-iodophenyl is amino)-1-(2-(3-fluorophenyl) cyclopropyl alkylsulfonyl)-4-methyl isophthalic acid H-fluorine [2,3-d] imidazoles [4,5-b] pyridine-2,5 (3H, 4H)-diketone
Figure BDA0000135908570001482
According to step H, the same procedure of embodiment 131 obtains the compound of above-mentioned title. 1H?NMR(400MHz，CDCl 3)δ7.68-7.74(m，2H)，7.54(d，J＝2.4Hz，1H)，7.17-7.28(m，2H)，7.03(d，J＝2.0Hz，1H)，6.93-6.98(m，1H)，6.89(d，J＝7.6Hz，1H)，6.80(d，J＝7.6Hz，1H)，3.35-3.39(m，1H)，3.23(s，3H)，3.10-3.23(m，1H)，2.10-2.19(m，1H)，1.65-1.69(m，1H)。
Step F: N-(6-(2-fluoro-4-iodophenyl is amino)-5-methyl-4-carbonyl-4,5-dihydro fluorine [3,2-c] pyridine-7-yl)-2-(3-fluorophenyl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001491
According to step I, the same procedure of embodiment 131 obtains the compound of above-mentioned title. 1H?NMR(400MHz，CDCl 3)δ7.46-7.47(m，2H)，7.17-7.22(m，1H)，6.98-6.99(d，J＝3Hz，1H)，6.90-6.93(m，1H)，6.64-6.66(d，J＝3.6Hz，1H)，6.55-6.66(m，1H)，6.12-6.17(m，2H)，2.75-2.79(m，2H)，2.54-2.59(m，2H)，1.73-1.78(m，2H)，1.26-1.41(m，2H)；m/z＝598[M+1] +。
Embodiment 133
N-(2-(4-bromo-2-fluorophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) butane-1-sulphonamide
According to method A, make 5-amino-6-(4-bromo-2-fluorophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and butane-1-SULPHURYL CHLORIDE reaction, obtain the compound of above-mentioned title.Productive rate=76.6%. 1H?NMR(400MHz，CDCl 3)δ＝7.76(brs，1H)，7.297-7.266(dd，1H，J＝2.0?&?2.4Hz)，7.123-7.102(d，1H，J＝8.4Hz)，6.356-6.313(t，1H，J＝8.6Hz)，5.909-5.875(brs，2H)，3.875(s，3H)，3.316(s，1H)，3.058-3.018(t，3H，J＝8.6Hz)，1.882-1.805(m，2H)，1.474-1.415(m，2H)，0.997-0.965(t，3H，J＝6.8Hz)；m/z＝463.33[M+1] +。
Embodiment 134
N-(2-(2-chloro-2-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) butane-1-sulphonamide
Figure BDA0000135908570001501
According to method A, make 5-amino-6-(2-chloro-2-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and butane-1-SULPHURYL CHLORIDE reaction, obtain the compound of above-mentioned title.Productive rate=35.5%. 1H?NMR(400MHz，CDCl 3)δ＝7.948(brs，1H)，7.709-7.704(d，1H，J＝2.0Hz)，7.390-7.394(dd，1H，J＝2?&?2.0Hz)，6.118-6.097(d，1H，J＝8.4Hz)，5.926(s，1H)，5.842(brs，1H)，3.880(s，3H)，3.296(s，1H)，3.054-3.015(t，3H，J＝7.8Hz)，1.866-1.827(m，2H)，1.474-1.418(m，2H)，1.274-1.240(t，3H，J＝7.2Hz)；m/z＝525.79[M+1] +。
Embodiment 135
N-(2-(2-chloro-2-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) thiophene-3-sulphonamide
Figure BDA0000135908570001502
According to method A, make 5-amino-6-(2-chloro-2-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and thiophene-3-SULPHURYL CHLORIDE reaction, obtain the compound of above-mentioned title.Productive rate=34.1%. 1H?NMR(400MHz，CDCl 3)δ＝7.920-7.879(dd，2H，J＝6.0?&?6.0Hz)，7.738-7.733(d，1H，J＝2.0Hz)，7.409-7.379(m，2H)，7.285-7.275(m，1H)，6.129-6.108(d，1H，J＝4.4Hz)，5.684(s，1H)，3.375(s，3H)，3.331(s，3H)；m/z＝551.92[M+1] +。
Embodiment 136
N-(2-(2-chloro-2-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) benzsulfamide
Figure BDA0000135908570001511
According to method A, make 5-amino-6-(2-chloro-2-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and benzene sulfonyl chloride reaction, obtain the compound of above-mentioned title.Productive rate=25%. 1H?NMR(400MHz，CDCl 3)δ＝7.945(brs，1H)，7.768-7.732(m，3H)，7.620-7.583(t，1H，J＝7.4Hz)，7.501-7.462(t，2H，J＝7.8Hz)，7.403-7.377(t，1H，J＝8.6Hz)，6.130-6.109(d，1H，J＝8.4Hz)，5.933(brs，1H)，5.609(s，1H)，3.332(s，3H)，3.187(s，3H)；m/z＝545.78[M+1] +。
Embodiment 137
N-(2-(2-chloro-2-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-2,2,2-trifluoromethane sulphonamide
Figure BDA0000135908570001512
According to method A, make 5-amino-6-(2-chloro-2-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2,2, the 2-trifluoromethanesulfonyl chloride reacts, and obtains the compound of above-mentioned title.Productive rate=48.7%. 1HNMR(400MHz，CDCl 3)δ＝7.727-7.720(dd，1H，J＝1.2?&?1.2Hz)，7.484(s，1H)，7.411-7.386(dd，1H，J＝1.2?&?1.2Hz)，6.142-6.120(d，1H，J＝8.8Hz)，5.945(s，1H)，3.898-3.848(m，5H)，3.299(s，3H)；m/z＝551.94[M+1] +。
Embodiment 138
N-(2-(2-chloro-2-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene sulphonamide
Figure BDA0000135908570001521
According to method A, make 5-amino-6-(2-chloro-2-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and the reaction of ring methane sulfonyl chloride, obtain the compound of above-mentioned title.Productive rate=19.72%. 1H?NMR(400MHz，CDCl 3)δ＝7.868(brs，1H)，7.714-7.709(d，1H，J＝2.0Hz)，7.398-7.372(dd，1H，J＝2?&?2.0Hz)，6.120-6.099(d，1H，J＝8.4Hz)，5.928(s，1H)，3.890(s，3H)，3.22(s，1H)，2.467-2.427(m，1H)，1.166-1.143(m，2H)，0.984-0.957(m，2H)；m/z＝510.75[M+1] +。
Embodiment 139
N-(2-(2-chloro-2-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-4-fluorobenzene sulphonamide
Figure BDA0000135908570001522
According to method A, make 5-amino-6-(2-chloro-2-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and the reaction of 4-fluorobenzene SULPHURYL CHLORIDE, obtain the compound of above-mentioned title.Productive rate=27.3%. 1H?NMR(400MHz，CDCl 3)δ＝7.885(s，1H)，7.798-7.764(m，2H)，7.734-7.729(d，1H，J＝2.0Hz)，7.404-7.378(dd，1H，J＝2?&?2.0Hz)，7.197-7.136(m，2H)，6.128-6.107(d，2H，J＝3.6Hz)，5.648(s，1H)，3.319(s，3H)，3.280(s，3H)；m/z＝563.96[M+1] +。
Embodiment 140
N-(2-(2-chloro-2-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-1-methyl chloride sulphonamide
According to method A, make 5-amino-6-(2-chloro-2-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and the reaction of 1-methyl chloride SULPHURYL CHLORIDE, obtain the compound of above-mentioned title.Productive rate=27.3%. 1H?NMR(400MHz，CDCl 3)δ＝7.710-7.705(d，1H，J＝2.0Hz)，7.477(s，1H，)，7.406-7.380(dd，1H，J＝1.6?&?2.0Hz)，6.154-6.133(t，1H，J＝8.4Hz)，5.936(s，1H)，4.529(s，2H)，3.886(s，3H)，3.278(s，3H)；m/z＝517.91[M+1] +。
Embodiment 141
N-(2-(2-chloro-2-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) NSC-249992
Figure BDA0000135908570001532
According to method A, make 5-amino-6-(2-chloro-2-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and methane sulfonyl chloride reaction, obtain the compound of above-mentioned title.Productive rate=30%. 1H?NMR(400MHz，CDCl 3)δ＝7.849(brs，1H)，7.713-7.708(d，1H，J＝2.0Hz)，7.399-7.373(dd，1H，J＝2?&?2.0Hz)，6.135-6.114(d，1H，J＝8.4Hz)，5.938(brs，2H)，3.895(s，3H)，3.297(s，3H)，2.973(s，3H)；m/z＝483.95[M+1] +。
Embodiment 142
N-(2-(2-chloro-2-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) ethane sulphonamide
Figure BDA0000135908570001533
According to method A, make 5-amino-6-(2-chloro-2-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and ethanesulfonyl chloride reaction, obtain the compound of above-mentioned title.Productive rate=35.5%. 1H?NMR(400MHz，CDCl 3)δ＝7.931(brs，1H)，7.704-7.699(d，1H，J＝2.0Hz)，7.389-7.363(dd，1H，J＝2?&?2.0Hz)，6.122-6.100(d，1H，J＝8.8Hz)，5.923(s，1H)，3.875(s，3H)，3.286(s，3H)，3.098-3.043(q，2H，J＝7.2Hz)，1.437-1.399(t，3H，J＝7.6Hz)；m/z＝526.00[M+1] +。
Embodiment 143
N-(2-(2-chloro-2-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) thiophene-2-sulphonamide
Figure BDA0000135908570001541
According to method A, make 5-amino-6-(2-chloro-2-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and thiophene-2-SULPHURYL CHLORIDE reaction, obtain the compound of above-mentioned title.Productive rate=17.89%. 1H?NMR(400MHz，CDCl 3)δ＝7.868(brs，1H)，7.738-7.733(d，1H，J＝2.0Hz)，7.652-7.636(dd，1H，J＝1.2?&?1.6Hz)，7.521-7.508(dd，1H，J＝2?&?1.6Hz)，7.409-7.382(dd，1H，J＝2?&?2.0Hz)，7.095-7.073(t，1H，J＝4Hz)，6.135-6.114(t，1H，J＝8.4Hz)，5.687(s，1H)，3.364-3.360(d，6H，J＝1.6Hz)；m/z＝551.92[M+1] +。
Embodiment 144
N-(2-(4-bromo-2-fluorophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) thiophene-3-sulphonamide
Figure BDA0000135908570001542
According to method A, make 5-amino-6-(4-bromo-2-fluorophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and thiophene-3-SULPHURYL CHLORIDE reaction, obtain the compound of above-mentioned title.Productive rate=34.1%. 1H?NMR(400MHz，CDCl 3)δ＝7.887-7.876(d，1H，J＝4.4Hz)，7.680(brs，1H)，7.413-7.392(d，1H，J＝8.4Hz)，7.329-7.298(m，1H)，7.149-7.119(m，2H)，6.382-6.338(t，1H，J＝8.8Hz)，5.670(s，1H)，3.378-3.346(d，6H，J＝12.8Hz)；m/z＝489.35[M+1] +。
Embodiment 145
N-(2-(4-bromo-2-fluorophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) benzsulfamide
Figure BDA0000135908570001551
According to method A, make 5-amino-6-(4-bromo-2-fluorophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and benzene sulfonyl chloride reaction, obtain the compound of above-mentioned title.Productive rate=25%. 1H?NMR(400MHz，CDCl 3)δ＝7.768-7.741(t，3H，J＝5.4Hz)，7.621-7.580(t，1H，J＝2?&?2.4Hz)，7.502-7.463(t，2H，J＝7.8Hz)，7.327-7.296(dd，1H，J＝8.6Hz)，7.145-7.115(d，1H，J＝12.0Hz)，6.381-6.337(t，1H，J＝8.8Hz)，5.590(s，1H)，3.358(s，3H)，3.162(s，3H)；m/z＝483.32[M+1] +。
Embodiment 146
N-(2-(4-bromo-2-fluorophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-2,2,2-trifluoromethane sulphonamide
Figure BDA0000135908570001552
According to method A, make 5-amino-6-(4-bromo-2-fluorophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2,2, the 2-trifluoromethanesulfonyl chloride reacts, and obtains the compound of above-mentioned title.Productive rate=48.7%. 1HNMR(400MHz，CDCl 3)δ＝7.312-7.281(dd，1H，J＝2?&?2.0Hz)，7.146-7.125(d，1H，J＝8.4Hz)，6.397-6.354(t，1H，J＝8.6Hz)，5.922(s，1H)，3.733-3.661(t，2H，J＝14.4Hz)，3.497(s，3H)，3.308(s，3H)；m/z＝489.25[M+1] +。
Embodiment 147
N-(2-(4-bromo-2-fluorophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene sulphonamide
Figure BDA0000135908570001561
According to method A, make 5-amino-6-(4-bromo-2-fluorophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and the reaction of Trimetylene SULPHURYL CHLORIDE, obtain the compound of above-mentioned title.Productive rate=19.72%. 1H?NMR(400MHz，CDCl 3)δ＝7.643(brs，1H)，7.291-7.261(d，1H，J＝12.0Hz)，7.126-7.096(d，1H，J＝12.0Hz)，6.356-6.313(t，1H，J＝8.6Hz)，5.910(s，1H)，3.875(s，3H)，3.329(s，3H)，2.437-2.410(m，1H)，1.155-1.116(m，2H)，0.997-0.929(m，2H)；m/z＝447.29[M+1] +。
Embodiment 148
N-(2-(4-bromo-2-fluorophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-4-fluorobenzene sulphonamide
Figure BDA0000135908570001562
According to method A, make 5-amino-6-(4-bromo-2-fluorophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and the reaction of 4-fluorobenzene SULPHURYL CHLORIDE, obtain the compound of above-mentioned title.Productive rate=27.3%. 1H?NMR(400MHz，CDCl 3)δ＝7.798-7.760(m，2H)，7.655(s，1H)，7.328-7.297(d，1H，J＝12.4Hz)，7.184-7.118(m，3H)，6.381-6.337(t，1H，J＝8.4Hz)，5.623(s.1H)，3.350(s，3H)，3.267(s，3H)；m/z＝501.31[M+1] +。
Embodiment 149
N-(2-(4-bromo-2-fluorophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) ethane sulphonamide
Figure BDA0000135908570001571
According to method A, make 5-amino-6-(4-bromo-2-fluorophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and ethanesulfonyl chloride reaction, obtain the compound of above-mentioned title.Productive rate=48.7%. 1H?NMR(400MHz，CDCl 3)δ＝7.744(brs，1H)，7.297-7.267(dd，1H，J＝2?&?2.0Hz)，7.127-7.098(d，1H，J＝11.6Hz)，6.360-6.317(t，1H，J＝8.8Hz)，5.905(s，1H)，3.875(s，3H)，3.310(s，3H)，3.104-3.048(q，2H，J＝7.6Hz)，1.440-1.402(t，3H，J＝7.6Hz)；m/z＝435.29[M+1] +。
Embodiment 150
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) tetramethylene sulphonamide
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and the reaction of tetramethylene SULPHURYL CHLORIDE, obtain the compound of above-mentioned title.Productive rate=36.6%. 1H?NMR(400MHz，CDCl 3)δ＝7.852(brs，1H)，7.462-7.432(d，1H，J＝16Hz)，7.296-7.263(d，1H，J＝13.2Hz)，6.204-6.162(t，1H，J＝8.4Hz)，5.890(s，1H)，3.875(s，3H)，3.330(s，1H)，2.577-2.523(m，2H)，2.299-2.232(m，2H)，2.074-2.011(m，2H)；m/z＝508.32[M+1] +。
Embodiment 151
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) ethane sulphonamide
Figure BDA0000135908570001581
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and ethanesulfonyl chloride reaction, obtain the compound of above-mentioned title.Productive rate=26.6%. 1H?NMR(400MHz，CDCl 3)δ＝7.767(brs，1H)，7.458-7.428(d，1H，J＝12.0Hz)，6.221-6.179(d，1H，J＝8.4Hz)，5.930(s，1H)，3.878(s，3H)，3.332(s，1H)，3.104-3.048(q，2H，J＝7.6Hz)，1.443-1.409(t，3H，J＝7.6Hz)；m/z＝482.28[M+1] +。
Embodiment 152
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-3-chloropropane sulphonamide
Figure BDA0000135908570001582
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and the reaction of 3-chloropropane SULPHURYL CHLORIDE, obtain the compound of above-mentioned title.Productive rate=29.8%. 1H?NMR(400MHz，CDCl 3)：δ＝7.868(brs，1H)，7.720-7.716(d，1H，J＝2.0Hz)，7.402-7.376(dd，1H，J＝2?&?1.6Hz)，6.126-6.105(d，1H，J＝4.4Hz)，5.933(s，1H)，5620(brs，1H)，3.903(s，3H)，3.692-3.662(t，2H，J＝6Hz)，3.307(s，3H)，3.263-3.226(t，2H，J＝7.6Hz)，2.372-2.304(m，2H)；m/z＝545.94[M+1] +。
Embodiment 153
N-(2-(4-bromo-2-fluorophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-3-chloropropane sulphonamide
Figure BDA0000135908570001591
According to method A, make 5-amino-6-(4-bromo-2-fluorophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and the reaction of 3-chloropropane SULPHURYL CHLORIDE, obtain the compound of above-mentioned title.Productive rate=29.8%. 1H?NMR(400MHz，CDCl 3)：δ＝7.666(brs，1H)，7.311-7.283(dd，1H，J＝2?&?1.2Hz)，7.140-7.116(dd，1H，J＝3.2?&?3.6Hz)，6.369-6.325(t，1H，J＝8.8Hz)，5.918(brs，2H)，3.900(s，3H)，3.692-3.662(t，2H，J＝6Hz)，3.337(s，3H)，3.268-3.230(t，2H，J＝7.6Hz)，2.371-2.303(m，2H)；m/z＝483.75[M+1] +。
Embodiment 154
N-(2-(4-bromo-2-fluorophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-1-monochloroethane sulphonamide
According to method A, make 5-amino-6-(4-bromo-2-fluorophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and the reaction of 1-monochloroethane SULPHURYL CHLORIDE, obtain the compound of above-mentioned title.Productive rate=10.1%. 1H?NMR(400MHz，CDCl 3)δ＝7.337-7.304(d，1H，J＝2.4Hz)，7.173-7.164(dd，1H，J＝1.6&?2.0Hz)，6.455-6.411(t，1H，J＝8.8Hz)，5.925(s，1H)，4.439(s，2H)，3.869(s，3H)，3.371(s，3H)；m/z＝517.91[M+1] +。
Embodiment 155
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-2-(hydroxymethyl)-Trimetylene-1-sulphonamide
Steps A: fourth-3-alkene-1-sulfonyl ester sodium
Figure BDA0000135908570001601
4-bromine but-1-ene and S-WAT are water-soluble and 70 ℃ of heated overnight.After being cooled to room temperature, decompression is removed solvent and is obtained crude product and can be used for next step and need not to be further purified.Productive rate=100%.
Step B: fourth-3-alkene-1-SULPHURYL CHLORIDE
Figure BDA0000135908570001602
3-butylene sulfonyl ester sodium (8.3 gram) and phosphoryl chloride (16 milliliters) are put into one 100 ml flasks and are constantly stirred down 115 ℃ of heating 1.5 hours.With the muddy 100 milliliters of frozen water of thing impouring of gained grey and leave standstill 20 minutes, thus the not reacted phosphoryl chloride of hydrolysis.Separate two and also use the dichloromethane extraction water mutually.Obtain brown oily crude product with dried over sodium sulfate organic phase and vacuum concentration.Productive rate=33%. 1H?NMR(400MHz，CDCl 3)δ＝5.860-5.792(m，1H)，5.303-5.194(m，2H)，3.762-3.737(t，2H，J＝5.6Hz)，2.826-2.763(m，2H)。
Step C: fourth-3-alkene-1-sulphonyl ethyl ester
Figure BDA0000135908570001603
(0.65 gram 6.47mmol) adds fourth-3-alkene-1-SULPHURYL CHLORIDE (1 gram, ethanolic soln 6.47mmol) (30 milliliters) that stirs with TEtOAc.Gained solution at room temperature stirred 2 hours.Water (10 milliliters) washed mixture is also used the dichloromethane extraction water.Merge organic phase and use sodium sulfate to carry out drying, under vacuum, concentrate and obtain crude product.Through silica gel column chromatography (petrol ether/ethyl acetate=20/1) purifying, obtain the compound of above-mentioned title.Productive rate=37.7%. 1H?NMR(400MHz，CDCl 3)δ＝5.839-5.797(m，1H)，5.178-5.111(m，1H)，4.332-4.278(m，1H)，3.191-3.151(m，2H)，2.635-2.576(m，2H)，1.435-1.374(m，3H)。
Step D:2-(oxyethane-2-yl) ethane sulphonyl ethyl ester
At room temperature, (0.4 gram, (0.72 restrains, 2.92mmol) to add m-CPBA in dichloroethane solution 2.43mmol) to fourth-3-alkene-1-sulphonyl ethyl ester.This mixture was at room temperature stirred 72 hours.Add in the S-WAT and excessive acid.Separate organic phase, and clean, carry out drying with sodium sulfate with 5% sodium hydrogen carbonate solution.Vacuum is removed the volumetrical residue, through silica gel column chromatography (petrol ether/ethyl acetate=2/1) purifying, obtains the compound of above-mentioned title.Productive rate=80%. 1H?NMR(400MHz，CDCl 3)δ＝4.350-4.296(m，2H)，3.279-3.232(m，1H)，3.116-3.083(m，1H)，2.857-2.836(t，1H，J＝4.4Hz)，2.589-2.572(m，1H)，2.319-2.254(m，1H)，1.959-1.905(m，1H)，1.453-1.406(m，3H)。
Step e: 2-(hydroxymethyl) Trimetylene-1-sulphonyl ethyl ester
Figure BDA0000135908570001612
At-30 ℃, under the nitrogen environment, (0.32 gram, anhydrous THF 1.7mmol) (22 milliliters) adds LiHMDS (4.1 milliliters, 1.06M is dissolved in THF) to 2-(oxyethane-2-yl) ethane sulphonyl ethyl ester.React after 3 hours, reaction mixture is warming up to room temperature also reacts with the aqueous ammonium chloride solution cancellation.Use the ethyl acetate extraction reaction mixture, use the dried over sodium sulfate organic phase and under vacuum, concentrate to obtain residue.Through silica gel column chromatography (petrol ether/ethyl acetate=1/1) purifying, obtain the compound of above-mentioned title.Productive rate=65.6%. 1H?NMR(400MHz，CDCl 3)δ＝4.366-4.309(m，2H)，3.839-3.798(m，1H)，3.586-3.538(m，1H)，2.501-2.048(m，1H)，1.955-1.901(m，1H)，1.445-1.403(m，3H)，1.181-1.129(m，1H)。
Step F: (2-(ethoxy alkylsulfonyl) cyclopropyl) special pentyl ester of methyl
Under 0 ℃, (0.15 gram, 0.772mmol) (0.1 gram, 0.1mmol) (0.01 restrains, and (0.11 restrains, 0.1mmol) to add SULPHURYL CHLORIDE in 5 milliliters of dichloromethane solutions 0.07mmol) with DMAP with TEtOAc to 2-(hydroxymethyl) Trimetylene-1-sulphonyl ethyl ester.The yellow mixture solution of reaction gained is stirred overnight at room temperature.After using sodium hydrogencarbonate cancellation mixture, separate dichloromethane be harmonious saturated sodium bicarbonate and salt solution.Use the crude product that falls of dried over sodium sulfate organic phase and vacuum concentration.Through silica gel column chromatography (from petrol ether/ethyl acetate=30/1 to ETHYLE ACETATE 100%) purifying, obtain the compound of above-mentioned title.Productive rate=61%. 1H?NMR(400MHz，CDCl 3)δ＝4.348-4.298(q，2H，J＝7.2Hz)，4.216-4.113(q，1H，J＝6.4Hz)，3.960-3.912(q，1H，J＝7.6Hz)，2.516-2.471(m，1H)，2.007-1.973(m，1H)，1.516-1.465(m，1H)，1.435-1.229(m，3H)，1.227-1.192(m，10H)，1.164-1.112(m，1H)。
Step G: (2-(chlorosulfonyl) cyclopropyl) methyl-special pentyl ester
Figure BDA0000135908570001621
In the acetone soln of (2-(ethoxy alkylsulfonyl) cyclopropyl) the special pentyl ester of methyl, add Bu 4NI.With mixture refluxing and stirring 2 days.After the cooling, vacuum is removed solvent and is obtained crude product and can be used for next step and need not to be further purified.At 0 ℃, sulfur dichloride is added PPh 3Dichloromethane solution.Stir after 15 minutes, with methylene dichloride (5 milliliters) the solution adding reaction mixture of above-mentioned salt.Institute is obtained reactant at room temperature stirred 6 hours.Solvent is removed in decompression, and residue through silica gel column chromatography (petrol ether/ethyl acetate=30/1) purifying, is obtained the compound of above-mentioned title.Productive rate=44.8%. 1H?NMR(400MHz，CDCl 3)δ＝4.292-4.250(q，1H，J＝4.8Hz)，3.968-3.919(q，1H，J＝7.6Hz)，3.331-3.288(m，1H)，2.314-2.263(m，1H)，1.840-1.787(m，1H)，1.427-1.366(m，1H)，1.227-1.192(m，10H)。
Step H: (2-(N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) alkylsulfonyl) cyclopropyl) methyl-special pentyl ester
Figure BDA0000135908570001622
According to method A, make 5-amino-6-(4-iodo-2-fluorophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and (2-(chlorosulfonyl) cyclopropyl) methyl-special pentyl ester reaction, obtain the compound of above-mentioned title.
Step I:N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-2-(hydroxymethyl) Trimetylene-1-sulphonamide
As aforementioned, use Lithium Hydroxide MonoHydrate hydrolysis (2-(N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) alkylsulfonyl) cyclopropyl) methyl-special pentyl ester.Solvent is removed in decompression, and (eluent: methylene dichloride: purifying methyl alcohol=15: 1) obtains the compound of above-mentioned title through silica gel column chromatography with residue.Productive rate=2.9%. 1H?NMR(400MHz，CDCl 3)δ＝7.508-7.477(dd，1H，J＝1.6?&?2.0Hz)，7.382-7.361(d，1H，J＝8.4Hz)，6.388-6.355(t，1H，J＝8.8Hz)，5.956(s，1H)，3.917(s，3H)，3.577-3.536(dd，1H，J＝4.8?&?4.8Hz)，3.432-3.389(dd，1H，J＝5.6?&?6.0)，3.336(s，3H)，2.481-2.448(dd，1H，J＝4?&?4.8Hz)；1.627-1.616(br，1H)，1.141-1.093(m，1H)，1.003-0.966(m，1H)；m/z＝524.32[M+1] +。
Embodiment 156
N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino)-6-p-methoxy-phenyl)-2-(2,4 difluorobenzene base) Trimetylene-1-sulphonamide
Figure BDA0000135908570001632
According to method A, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl amino)-3-p-methoxy-phenyl-1,2-diamines and-(2,4 difluorobenzene base) Trimetylene-1-SULPHURYL CHLORIDE reaction obtain the compound of above-mentioned title. 1H?NMR(400MHz，CDCl 3)δ7.38(dd，J＝2.0?&?10.4Hz，1H)，7.27(d，J＝8.0Hz，1H)，6.75-6.82(m，3H)，6.43-6.48(m，1H)，6.26(dd，J＝6.4?&?7.6Hz，1H)，6.15(s，1H)，3.42(s，3H)，2.80-2.83(m，1H)，2.52-2.55(m，1H)，1.66-1.71(m，1H)，1.39-1.44(m，1H)；m/z＝611[M+1] +。
Embodiment 157
(S)-1-(2, the 3-dihydroxy phenyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
Steps A: (S)-1-(2, the 3-dihydroxy phenyl) Trimetylene-1-sulphonyl isopropyl ester
Figure BDA0000135908570001641
(37.9 grams add 10% palladium carbon (3.8 gram) in the solution of i-PrOH 115mmol) (250 milliliters) to (S)-1-(3-(benzyloxy)-2-hydroxypropyl) Trimetylene-1-sulphonyl isopropyl ester.Under hydrogen (0.5MPa) with the mixture stirred overnight.After using diatomite filtration, will filter gained and evaporate, clarified, the compound (24.4 restrain 89%) of the colourless above-mentioned title of oily. 1H?NMR(400M?Hz，CDCl 3)δ4.98(sept，J＝6.4Hz，1H)，4.11-4.14(m，1H)，3.66(dd，J＝10.8Hz&4.0Hz，1H)，3.49(dd，J＝10.8Hz&6.0Hz，1H)，1.90-1.94(m，2H)，1.49-1.51(m，2H)，1.44(d，J＝6.4Hz，6H)，1.09-1.12(m，1H)，0.93-0.96(m，1H)。
Step B: (S)-1-((2-carbonyl-1,3-dioxa penta ring-4-yl) methyl) Trimetylene-1-sulphonyl isopropyl ester
Figure BDA0000135908570001642
Under 0 ℃, to (S)-1-(2, the 3-dihydroxypropyl) Trimetylene-1-sulphonyl isopropyl ester (500 milligrams were pursued crowd a small amount of N of adding, N-carbonyl dimidazoles (374 milligrams 2.31mmol), and were stirred 1 hour in 9 minutes in the solution of methylene dichloride 2.1mmol) (16 milliliters).In 9 minutes, add N on a small quantity once more, N-carbonyl dimidazoles (170 milligrams 1.05mmol) are also continued stirring and use TLC (UV) to monitor reaction process simultaneously by criticizing.Use independent funnel to add ETHYLE ACETATE (40 milliliters) diluting reaction.Water and salt solution clean crude product.After the separation, use dried over sodium sulfate organic phase and concentrated.Crude product through silica gel column chromatography (ethyl acetate/petroleum ether=2/1) purifying, is clarified, the compound of the colourless above-mentioned title of oily, and productive rate is 81%. 1H?NMR(400M?Hz，CDCl 3)δ5.17-5.21(m，1H)，4.96(sept，J＝6.4Hz，1H)，4.65(dd，J＝8.8Hz&8.0Hz，1H)，4.14(dd，J＝8.8Hz&7.2Hz，1H)，2.54(dd，J＝16.0Hz&5.2Hz，1H)，1.94(dd，J＝15.6Hz&8.0Hz，1H)，1.52-1.54(m，2H)，1.43(d，J＝6.4Hz，6H)，1.21-1.24(m，1H)，0.94-0.98(m，1H)。
Step C: (S)-1-((2-carbonyl-1,3-dioxa penta ring-4-yl) methyl) Trimetylene-1-sulfonyl ester sodium
Figure BDA0000135908570001651
With (S)-1-((2-carbonyl-1,3-dioxa penta ring-4-yl) methyl) Trimetylene-1-sulphonyl isopropyl ester (930 milligrams, 3.52mmol) and Soiodin (670 milligrams 4.47mmol) are mixed in acetone (35 milliliters) and refluxed 4 days.Behind the vacuum concentration, obtain 1.0 gram yellow solids and (80% purity comprises 20% Soiodin) can directly be used for next step and need not to be further purified. 1H?NMR(400M?Hz，DMSO-D6)δ5.22(m，1H)，4.57(dd，J＝8.4Hz&8.4Hz，1H)，4.29(dd，J＝8.4Hz&7.2Hz，1H)，2.07(dd，J＝14.4Hz&7.6Hz，1H)，1.90(dd，J＝14.4Hz&5.6Hz，1H)，0.86-0.88(m，2H)，0.48-0.51(m，2H)。
Step D: (S)-1-((2-carbonyl-1,3-dioxa penta ring-4-yl) methyl) Trimetylene-1-SULPHURYL CHLORIDE
The resulting yellow solid of step C was dissolved in 5 milliliters of THIONYL CHLORIDE 97s and reflux 1 hour.Underpressure distillation slowly adds entry after removing volatile matter.Use the ethyl acetate extraction residue, and use dried over sodium sulfate, filter, and carry out concentrating under reduced pressure.Residue through silica gel column chromatography (ethyl acetate/petroleum ether=1/1) purifying, is obtained the compound (669 milligrams, 79% liang of step productive rate) of above-mentioned title. 1H?NMR(400M?Hz，CDCl 3)δ5.24-5.30(m，1H)，4.69(dd，J＝8.4Hz&8.4Hz，1H)，4.15(dd，J＝8.8Hz&7.6Hz，1H)，2.88(dd，J＝16.0Hz&2.8Hz，1H)，2.07(dd，J＝16.0Hz&8.8Hz，1H)，1.94-2.00(m，1H)，1.79-1.85(m，1H)，1.60-1.67(m，1H)，1.23-1.29(m，1H)。
Step e: (S)-N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-1-((2-carbonyl-1,3-dioxa penta ring-4-yl) methyl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001661
According to method A; Make 5-amino-6-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-1-picoline-2 (1H)-ketone with (S)-1-((2-carbonyl-1; 3-dioxa penta ring-4-yl) Trimetylene-1-SULPHURYL CHLORIDE reaction methyl), the compound that obtains above-mentioned title is directly used and next step reaction.
Step F: (S)-1-(2, the 3-dihydroxy phenyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001662
At room temperature; With (S)-N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1; 6-dihydropyridine-3-yl)-methanol (5/1) solution stirring of 1-((2-carbonyl-1,3-dioxa penta ring-4-yl) methyl) Trimetylene-1-sulphonamide and Lithium Hydroxide MonoHydrate (2 equivalent) spends the night.This mixture of concentrating under reduced pressure.Through silica gel column chromatography (ETHYLE ACETATE) purifying, obtain the compound of above-mentioned title.Productive rate=22.3%. 1H?NMR(400MHz，CDCl 3)δ＝7.552(br，1H)，7.432-7.402(dd，1H，J＝1.6&?2.0Hz)，7.285(br，1H)，6.190-6.174(t，1H，8.4Hz)，5.903(s，1H)，3.993(br，1H)，3.858(s，3H)，3.569-3.561(d，1H，J＝3.2Hz)，3.459-3.443(m，1H)，3.335(s，3H)，2.395-2.302(m，2H)，1.678-1.640(d，2H，J＝15.2Hz)，1.377(br，1H)，1.300(br，1H)；m/z＝568.37[M+1] +。
Embodiment 158
N-(2-(4-bromo-2-fluorophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-2-(hydroxymethyl) Trimetylene-1-sulphonamide
According to method A, the step H of embodiment 155 and I make the special pentyl ester reaction of 5-amino-6-(4-bromo-2-fluorophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and (2-(chloro-acid amide base) cyclopropyl) methyl, use the Lithium Hydroxide MonoHydrate hydrolysis afterwards.After solvent was removed in decompression, (eluent: methylene dichloride: purifying methyl alcohol=15: 1) obtained the compound of above-mentioned title through silica gel column chromatography with residue. 1H?NMR(400MHz，CDCl 3)δ＝7.337-7.305(dd，1H，J＝2.0?&?2.0Hz)，7.175-7.150(dd，1H，J＝1.6?&?1.2Hz)，6.438-6.394(t，1H，J＝8.8Hz)，5.945(s，1H)，3.883(s，3H)，3.574-3.532(dd，1H，J＝5.2?&?5.2Hz)，3.362-3.336(dd，1H，J＝4.4?&?6.4)，3.293(s，3H)，2.375-2.330(m，1H)，1.574-1.527(br，1H)，1.077-1.042(m，1H)，1.029-0.827(m，1H)；m/z＝476.32[M+1] +。
Embodiment 159
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-2-(hydroxymethyl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001681
According to embodiment 53 same procedure of describing, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone obtain the compound of above-mentioned title. 1H?NMR(400MHz，CDCl 3)δ＝7.457-7.426(dd，1H，J＝2.0?&?2.4Hz)，7.326-7.302(dd，1H，J＝7.6?&?1.2Hz)，6.246-6.203(t，1H，8.4Hz)，5.918(s，1H)，3.869(s，3Hz)，3.762-3.726(t，2H，J＝6.4Hz)，3.306(s，3H)，2.169-2.135(t，2H，J＝6.8Hz)，1.086-1.058(dd，2H，J＝4.8?&?4.4Hz)，0.712-0.683(dd，2H，J＝4.8?&?4.8Hz)；m/z＝538.34[M+1] +。
Embodiment 160
2-(4-chloro-phenyl-)-N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001682
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-(4-chloro-phenyl-) Trimetylene-1-SULPHURYL CHLORIDE reaction, obtain the compound of above-mentioned title. 1H?NMR(400MHz，CDCl 3)δ7.63(s，1H)，7.45(dd，J＝2.0?&?10.0Hz，1H)，7.26-7.30(m，3H)，6.88(d，J＝8.8Hz，2H)，6.19(t，J＝8.8Hz，1H)，5.75(s，1H)，5.66(s，1H)，3.36(s，3H)，3.25(s，3H)，2.65-2.69(m，1H)，2.48-2.53(m，1H)，1.74-1.79(m，1H)，1.34-1.39(m，1H)；m/z＝604[M+1] +。
Embodiment 161
2-(4-chloro-3-p-methoxy-phenyl)-N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001691
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-(4-chloro-3-p-methoxy-phenyl) Trimetylene-1-SULPHURYL CHLORIDE reaction, obtain the compound of above-mentioned title. 1H?NMR(400MHz，CDCl 3)δ7.68(s，1H)，7.44(d，J＝10.4Hz，1H)，7.24-7.31(m，2H)，6.73(dd，J＝3.2?&?8.8Hz，1H)，6.28(d，J＝2.8Hz，1H)，6.19(t，J＝8.4Hz，1H)，5.78(s，1H)，5.65(s，1H)，3.77(s，3H)，3.38(s，3H)，3.35(s，3H)，2.92-2.98(m，1H)，2.68-2.71(m，1H)，1.78-1.81(m，1H)，1.37-1.43(m，1H)；m/z＝634[M+1] +。
Embodiment 162
2-(2,4 dichloro benzene base)-N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001692
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-(2,4 dichloro benzene base) Trimetylene-1-SULPHURYL CHLORIDE reaction, obtain the compound of above-mentioned title. 1H?NMR(400MHz，CDCl 3)δ7.67(s，1H)，7.45(dd，J＝2.0?&?10.0Hz，1H)，7.43(d，J＝2.4Hz，1H)，7.29(d，J＝9.6Hz，1H)，7.20(dd，J＝2.4?&?8.8Hz，1H)，6.73(d，J＝8.0Hz，1H)，6.20(t，J＝8.8Hz，1H)，5.79(s，1H)，5.69(s，1H)，3.43(s，3H)，3.35(s，3H)，2.92-2.98(m，1H)，2.66-2.70(m，1H)，1.77-1.82(m，1H)，1.34-1.40(m，1H)；m/z＝638[M+1] +。
Embodiment 163
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-2-(2-fluoro-4-p-methoxy-phenyl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001701
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-(2-fluoro-4-p-methoxy-phenyl) Trimetylene-1-SULPHURYL CHLORIDE reaction, obtain the compound of above-mentioned title. 1H?NMR(400MHz，CDCl 3)δ7.68(s，1H)，7.43-7.46(dd，J＝2.0?&?10.0Hz，1H)，7.23-7.29(d，1H)，6.69-6.71(d，1H)，6.60-6.65(m，2H)，6.17-6.22(t，J＝8.6Hz，1H)，5.79(s，1H)，5.64(s，1H)，3.78(s，3H)，3.36(s，3H)，3.33(s，3H)，2.71-2.75(m，1H)，2.62-2.64(m，1H)，1.67-1.73(m，1H)，1.42-1.47(m，1H)；m/z＝618[M+1] +。
Embodiment 164
N-(2-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-methyl-6-carbonyl-1,6-dihydropyridine-3-yl)-2-(3-fluoro-4-p-methoxy-phenyl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001702
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl is amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-(3-fluoro-4-p-methoxy-phenyl) Trimetylene-1-SULPHURYL CHLORIDE reaction, obtain the compound of above-mentioned title. 1H?NMR(400MHz，CDCl 3)δ7.66(s，1H)，7.44-7.47(dd，J＝1.6?&?10.0Hz，1H)，7.28-7.31(d，1H)，6.87-6.92(t，1H)，6.71-6.73(d，1H)，6.63-6.67(dd，J＝2.0?&?8.0Hz，1H)，6.17-6.21(t，J＝8.4Hz，1H)，5.77(s，1H)，5.70(s，1H)，3.88(s，3H)，3.36(s，3H)，3.34(s，3H)，2.61-2.65(m，1H)，2.49-2.53(m，1H)，1.70-1.75(m，1H)，1.29-1.34(m，1H)；m/z＝618[M+1] +。
Embodiment 165
N-(2-(2-chloro-4-iodophenyl is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-1-(2-hydroxyethyl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001711
According to embodiment 2, step e; Embodiment 27, steps A and B; Embodiment 53, the described same procedure of steps A and B and C.Make 5-amino-6-(2-chloro-4-iodophenyl is amino)-1,3-lutidine-2 (1H)-ketone (from embodiment 54, step D) obtains the compound of above-mentioned title as parent material. 1H?NMR(400MHz，CDCl 3)δ7.69(d，J＝2.0Hz，1H)，7.35(dd，J＝1.6?&?8.4Hz，1H)，7.32(s，2H)，7.06(s，br，1H)，6.02(d，J＝8.8Hz，1H)，3.88(t，J＝5.2Hz，2H)，3.40(s，3H)，2.40(s，br，1H)，2.19(s，3H)，2.12(t，J＝5.2Hz，2H)，1.37(m，2H)，0.88(m，2H)；m/z＝538[M+1] +。
Embodiment 166
N-(2-(4-bromo-2-chloro-phenyl-is amino)-1,5-dimethyl--6-carbonyl-1,6-dihydropyridine-3-yl)-1-(2-hydroxyethyl) Trimetylene-1-sulphonamide
Figure BDA0000135908570001712
According to embodiment 2, step e; Embodiment 27, steps A and B; Embodiment 53, the described same procedure of steps A and B and C.Make 5-amino-6-(4-bromo-2-chloro-phenyl-is amino)-1,3-lutidine-2 (1H)-ketone (from embodiment 55, step D) obtains the compound of above-mentioned title as parent material. 1H?NMR(400MHz，CDCl 3)δ7.53(d，J＝2.4Hz，1H)，7.31(s，1H)，7.29(s，1H)，7.19(dd，J＝2.0?&?8.8Hz，1H)，6.90(s，1H)，6.15(d，J＝8.8Hz，1H)，3.90(t，J＝5.4Hz，2H)，3.40(s，3H)，2.19(s，4H，CH 3+OH)，2.14(t，J＝5.4Hz，2H)，1.39(m，2H)，0.89(m，2H)；m/z＝490[M+1] +。
Biological activity test
Material and reagent:
Kinase Glo Plus test kit is available from Promega.Substrate, APT, DTT and DMSO 99.8MIN. are available from Sigma-Aldrich.
MAP2K1 (MEK1) kinases, europium traget antibody, tracer agent 236 and binding buffer liquid A are available from Invitrogen.
Recombinant human epidermal growth factor (EGF) is available from R&D System.
SureFire Phospho-ERK1/2 test kit and AlphaScreen General IgG (albumin A) detection kit are all available from PerkinElmer.
Obtain IC 50Data
The mensuration of enzymic activity:
The DSMO mother liquor that will contain compound is diluted to 1 * buffer reagent (20mM MOPS (pH7.4), 5mMMgCl 2, 0.5mM MnCl 2, 100uM Trisodium vanadate, 0.01%Triton X-100,1mM DTT) in.Common reaction reagent comprises 0.01nmolMEK1,0.01nmolATP and 10ng substrate.Shaker test mainly comprises four steps.The enforcement compound of 2ul is added to respectively in the 384 holes test blank.Subsequently, to each aerial 6ul kinases-substrate mixture of adding.Subsequently, in each hole, add 2ul 5x ATP to start reaction.Plate is sealed, and it was hatched 60 minutes 22 ℃ of following lucifuges.In each hole, add 10ul KinaseGlo Plus reagent at last with stopped reaction.At room temperature the lucifuge incubation is 10 minutes.Remove closedtop on the plate, use the standard light-emitting procedure that plate is carried out reading through EnVision 2104 multiple labeling plate readers (PerkinElmer).To the quantification of intensities of luminous signal, and use these data to produce dose response curve, and calculate IC through the Prism program 50
Kinases combines active mensuration
The DMSO mother liquor that will contain compound is diluted to buffer reagent (20mM MOPS (PH 7.4), 5mMMgCl 2, 0.5mM MnCl 2, 100uM Trisodium vanadate, 0.01%Triton X-100,1mM DTT) in.Common reaction reagent comprises 3 * 10 -4Nmol MEK kinases, 3 * 10 -5Nmol europium labeling antibody, 1.5 * 10 -3Nmol tracer agent 236.Screening reagent mainly comprises three steps.The compound branch of 5ul dilution is installed in the 384 holes test blackboard.Subsequently, in each hole, add the 5ul 3x kinases-mixtures of antibodies that dilutes by the 1x buffer A.The 5ul 3x tracer agent 236 that in each hole, adds again by the dilution of 1x damping fluid reacts to start.Seal up flat board, and it was hatched 60 minutes 22 ℃ of following lucifuges.Remove closedtop, use the TR-FRET program that plate is carried out reading through EnVision 2104 multiple labeling plate readers (PerkinElmer).Quantitative to fluorescence signal intensity, and use these data to produce dose response curve, and calculate IC through the Prism program 50
IC based on cell 50Data
Through the effect to phosphorylation ERK in cell of AlphaScreen test determination compound.With the density of every hole 80,000 cells the MCF-7 breast cancer cell is tiled in 96 orifice plates, and at 37 ℃ of humidification CO 2Grow in the incubator.Next day, remove growth medium (DMEM+10% foetal calf serum) and replace to hungry substratum (only DMEM).Cell is incubated overnight in hungry substratum, handled 60 minutes at 37 ℃ with the compound of a series of concentration subsequently.Behind compound incubation together, with EGF irritation cell 10 minutes.Subsequently, lysing cell is transferred to every part of lysate (4ul) in the 384 holes reaction blank.In the darkroom, the AlphaScreen bead of preparation newly and the mixture branch of damping fluid are added in each hole.Seal up flat board, and said plate was hatched 2 hours 25 ℃ of following lucifuges.Remove closedtop, use the AlphaScreen program of optimizing that plate is carried out reading through EnVision 2104 multiple labeling plate readers (PerkinElmer).The quantitatively intensity of signal, and the dose response curve that uses these data to produce, and through Prism program calculating IC 50
The biological data of selected compounds
Make an experiment according to the said compound of biological method as herein described to above-mentioned preparation.Its result is shown in following table:
Figure BDA0000135908570001751
Figure BDA0000135908570001761
Figure BDA0000135908570001781
Figure BDA0000135908570001791
Figure BDA0000135908570001801
Figure BDA0000135908570001811
Figure BDA0000135908570001821
Figure BDA0000135908570001831
Figure BDA0000135908570001841
Figure BDA0000135908570001851
Figure BDA0000135908570001871
Figure BDA0000135908570001901
Figure BDA0000135908570001911
Figure BDA0000135908570001931
Figure BDA0000135908570001941
Figure BDA0000135908570001951
Figure BDA0000135908570001961
Figure BDA0000135908570001981
Figure BDA0000135908570001991
Figure BDA0000135908570002001

Claims (24)

1. the compound of representing by formula I, or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug:
Formula I
Wherein, R 0Be H, C 1-C 6Alkyl, C 3-C 6Naphthenic base, C 2-C 6Thiazolinyl, C 5-C 6Cycloalkenyl group or C 2-C 6Alkynyl; Wherein said alkyl, naphthenic base, thiazolinyl, cycloalkenyl group or alkynyl group are optional to be replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyanic acid, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed, and said C 3-C 6One or two of naphthenic base becomes optional O, N or the S of replacing with independently of ring carbon atom; And
R 1Be H, C 1-C 4Alkoxyl group, C 1-C 6Alkyl, C 3-C 6Naphthenic base, C 2-C 6Thiazolinyl, C 5-C 6Cycloalkenyl group, C 2-C 6Alkynyl or halogen; Wherein said alkoxyl group, alkyl, naphthenic base, thiazolinyl, thiazolinyl, cycloalkenyl group or alkynyl group are randomly replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyanic acid, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed; Perhaps, R 1Be five yuan or hexavalent saturated heterocyclyl, unsaturated heterocycle base or fragrant heterocyclic radical; Affiliated heterocyclic radical contains 1-5 heteroatoms; Said heteroatoms is independently selected from the group of being made up of O, N or S; And said heterocyclic radical is optional to be replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyanic acid, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed; Or
R 1For-CH 2X, the wherein group of X expression II:
Formula II
Wherein, Y 1And Y 2Can be identical or different, represent separately singly-bound ,-CO-,-COO ,-O-,-OCO-,-NR aOr-SO 2-;
Y 3Expression can be by 1-3 the substituted C of group that is represented by Z 1-5Alkyl;
Z can be identical or different, and expression can be randomly by the substituted C of one or more substituting groups 1-5Alkyl, halogen atom, oxo group ,-OR a,-COOR a,-COOCOR a,-CO-halogen atom ,-OCOR a,-CONR aR b,-SR a,-SO 2R a,-NR aR b,-NR aCOR b,-NR aSO 2R b,-SO 2NR aR b, monocycle or the heterocyclic radical of dicyclo or the heteroaryl of monocycle or dicyclo, said substituting group is selected from by C 1-5Alkyl ,-OR aAnd NR aR bThe group of forming; Each alkyl can be by hydroxyl, C 1-5Alkoxyl group or amino the replacement; Except that oxo group and halogen, above-mentioned substituting group can interconnect and form naphthenic base or heterocyclic radical, and said naphthenic base or heterocyclic radical can have one or more substituting groups, and said substituting group is selected from by-OR a, NR aR bWith can be by-OR aSubstituted C 1-5The group that alkyl is formed;
R aAnd R bCan be identical or different, represent Wasserstoffatoms or can be separately by 1-3 the substituted C of substituting group 1-5Alkyl group, said substituting group is selected from by hydroxyl, C 1-5Alkoxyl group and the amino group of forming;
Symbol " ● " the expression connection site of using among the formula II;
X is C or N;
When X=C, R 2Be H, C 1-C 4Alkoxyl group, C 1-C 6Alkyl, C 3-C 6Naphthenic base, C 2-C 6Thiazolinyl, C 5-C 6Cycloalkenyl group or C 2-C 6Alkynyl; Wherein said alkoxyl group, alkyl, naphthenic base, thiazolinyl, cycloalkenyl group or alkynyl are optional to be replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyanic acid, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed; Perhaps,
R 2Be five yuan or hexavalent saturated heterocyclyl, unsaturated heterocycle base or fragrant heterocyclic radical; Wherein, Said heterocyclic radical has 1-5 heteroatoms; Said heteroatoms is selected from the group that O, N and S form, and said heterocyclic radical is optional by 1-3 substituting group replacement, and said substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyanic acid, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed; Perhaps
When X=N, R 2Do not exist; Perhaps
R 1And R 2Common form one five yuan or hexavalent unsaturated heterocycle base or comprise 1-3 heteroatomic fragrant heterocyclic radical; Said heteroatoms is independently selected from the group of being made up of O, N or S; Said heterocyclic radical is optional to be replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyanic acid, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed; And
R 3Be selected from by trifluoromethyl, C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, C 3-C 10Naphthenic base, C 3-C 10Cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heteroaryl ring alkyl, heterocyclic radical and Heterocyclylalkyl; Wherein each alkyl, thiazolinyl, alkynyl, naphthenic base, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical alkyl, hetero-aromatic ring alkyl and heterocyclic radical is not substituted or replaced by 1-3 substituting group, said substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, cyanic acid, trifluoromethyl, difluoro-methoxy, phenyl or have 1-3 substituent substituted-phenyl, the substituting group of said substituted-phenyl independently is selected from halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, cyanic acid, trifluoromethyl or difluoro-methoxy;
R 4, R 5, R 6, R 7And R 8Be independently selected from H, halogen, cyanic acid, nitro, trifluoromethyl, SR 9, OR 9, C (O) R 9, NR 10C (O) OR 12, OC (O) R 9, NR 10S (O) jR 12, S (O) jNR 9R 10, S (O) jNR 10C (O) R 9, C (O) NR 10S (O) jR 12, S (O) jR 12, NR 10C (O) R 9, C (O) NR 9R 10, NR 11C (O) NR 9R 10, NR 11C (NCN) NR 9R 10, NR 9R 10And C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, C 3-C 10Naphthenic base, C 3-C 10Cycloalkylalkyl, S (O) j(C 1-C 6Alkyl), S (O) j(CR 10R 11) m-aryl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical, heterocyclic radical alkyl, O (CR 10R 10) m-aryl, NR 10(CR 10R 11) m-aryl, O (CR 10R 11) m-heteroaryl, NR 10(CR 10R 11) m-heteroaryl, O (CR 10R 11) m-heterocyclic radical, NR 10(CR 10R 11) m-heterocyclic radical and S (C 1-C 2Alkyl), above-mentioned group is optional is replaced by the fluorine atom of 1-5;
R 9Be selected from by hydrogen, trifluoromethyl, C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, C 3-C 10Naphthenic base, C 3-C 10The group that cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical and heterocyclic radical alkyl are formed; Wherein each alkyl, thiazolinyl, alkynyl, naphthenic base, aryl, heteroaryl and heterocyclic radical are not substituted or are replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl, the amino group of forming;
R 10Be selected from by hydrogen or C 1-C 6Alkyl, said alkyl can be not to be substituted or to be replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming; Or
R 9, R 10Form 4-10 first hetero-aromatic ring or heterocycle together with coupled atom, said each ring is not substituted or is replaced by 1-3 substituting group, and said substituting group is free halogen, C independently 1-C 4Alkyl, hydroxyl and the amino group of forming;
R 11Be selected from hydrogen or C 1-C 6Alkyl, wherein alkyl can be not to be substituted or to be replaced by 1-3 substituting group, said substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming; Or
R 10, R 11Form 4-10 first carbocyclic ring, hetero-aromatic ring or heterocycle together with coupled atom, each ring is not substituted or is replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming;
R 12Be selected from by trifluoromethyl, C 1-C 10Alkyl, C 3-C 10The group that naphthenic base, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical and heterocyclic radical alkyl are formed; Wherein each alkyl, naphthenic base, aryl, heteroaryl and heterocycle are not substituted or are replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming;
M is 0,1,2,3,4 or 5; And
J is 1 or 2;
Or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
2. compound according to claim 1, wherein R 0Be H or C 1-C 6Alkyl; Or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
3. compound according to claim 1, wherein R 1Be H or C 1-C 6Alkyl; Or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
4. compound according to claim 1 does not then have R when wherein X is N 2When perhaps X is C, R 2Be H or C 1-C 6Alkoxyl group; Or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
5. compound as claimed in claim 1, when wherein X is C, R 2Be C 1-C 4Alkoxyl group or five yuan or hexavalent saturated heterocyclyl, unsaturated heterocycle base or fragrant heterocyclic radical; Wherein said heterocyclic radical comprises 1-5 the heteroatoms that is independently selected from O, N and S; And said heterocyclic radical is optional to be replaced by 1-3 substituting group, and said substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyanic acid, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed; Or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
6. compound according to claim 1, wherein R3 is selected from by following group and forms group: randomly by one or more halogens or the substituted C of hydroxyl 1-C 6Alkyl; C 2-C 6Thiazolinyl; Randomly by C 1-C 6Alkyl or C 2-C 6The C of alkenyl substituted 3-C 6Naphthenic base; Have the bicyclic heteroaryl of heteroatoms O, N or S five yuan or single six-membered rings or 9-13 unit, randomly by the bicyclic aryl of substituted five yuan or single six-membered rings or 9-13 unit of one or more substituting groups, wherein said substituting group is selected from by halogen, cyanic acid, C 1-C 6The group that alkoxyl group and hydroxyl, cycloalkyl aryl are formed; Wherein said aryl is five yuan or single six-membered rings or the first bicyclic aryl of 9-13; And what the carbon atom of the 1-6 on the naphthenic base was optional is replaced by one or more substituting groups, and said substituting group is selected from by halogen, cyanic acid, C 1-C 6The group that alkoxyl group and hydroxyl are formed; The heteroaryl ring alkyl, wherein heteroaryl is five yuan or single six-membered rings or the first bicyclic aryl of 9-13, and optional being replaced by one or more substituting groups of the carbon atom of the 1-6 on the naphthenic base, said substituting group is selected from by halogen, cyanic acid, C 1-C 6The group that alkoxyl group and hydroxyl are formed; And C 1-C 6Alkyl C 1-C 6What naphthenic base was optional is replaced by one or more substituting groups, and said substituting group is selected from by halogen, cyanic acid, C 1-C 6The group that alkoxyl group and hydroxyl are formed; Or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
7. compound according to claim 1, wherein R 4, R 5, R 6, R 7And R 8Be independently selected from H or halogen; Or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
8. compound according to claim 1, wherein R 0Be H or C 1-C 6Alkyl; R 1Be H or C 1-C 6Alkyl; When X is N, R 2Do not exist, when X is C, R 2Be H or C 1-C 6Alkoxyl group; R3 is selected from the group of being made up of following group: optional by one or more halogens or the substituted C of hydroxyl 1-C 6Alkyl; C 2-C 6Thiazolinyl; Randomly by C 1-C 6Alkyl or C 2-C 6The C of alkenyl substituted 3-C 6Naphthenic base, has the bicyclic heteroaryl of heteroatoms O, N or S five yuan or single six-membered rings or 9-13 unit; Randomly by one or more substituting groups substituted five yuan or single six-membered rings or the first bicyclic aryl of 9-13, wherein said substituting group is selected from by halogen, cyanic acid, C 1-C 6The group that alkoxyl group and hydroxyl are formed; Cycloalkyl aryl, wherein aryl is five yuan or single six-membered rings or the first bicyclic aryl of 9-13, naphthenic base has 1-6 carbon atom; And C 1-C 6Alkyl C 1-C 6Naphthenic base; And
R 4, R 5, R 6, R 7And R 8Be independently selected from H or halogen;
Or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
9. compound according to claim 1, it has formula:
Figure FDA0000135908560000061
Wherein, R 0, R 1, R 2, R 4～R 8Definition identical with formula I;
R 13Be selected from by H, C 2-C 6Thiazolinyl and C 1-C 6The group that alkynyl is formed, wherein, said group is optional to be replaced by one or more substituting groups, and said substituting group is selected from the group of being made up of halogen and hydroxyl;
R 14Be selected from by H, C 1-C 6The bicyclic aryl of alkyl, five yuan or single six-membered rings or 9-13 unit and have heteroatoms O; The group that the bicyclic heteroaryl of N or S five yuan or single six-membered rings or 9-13 unit is formed; Wherein, Said group can randomly be replaced by one or more substituting groups, and said substituting group is selected from by halogen, cyanic acid, hydroxyl, optional by the substituted C of halogen 1-C 6Alkyl, and C 1-C 6Alkoxyl group;
Or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
10. compound according to claim 9, wherein R 0Be H or C 1-C 6Alkyl; R 1Be H, C 1-C 6Alkyl or halogen; R 2Be H or C 1-C 6Alkoxyl group; R 3Be selected from the group of forming by following group: randomly by one or more halogens or the substituted C of hydroxyl 1-C 6Alkyl; C 2-C 6Thiazolinyl; Randomly by C 1-C 6Alkyl or C 2-C 6The C of alkenyl substituted 3-C 6Naphthenic base; Has heteroatoms O, five yuan or the bicyclic heteroaryl of single six-membered rings or 9-13 unit of N or S; Randomly by one or more substituting groups substituted five yuan or single six-membered rings or the first bicyclic aryl of 9-13, said substituting group is selected from by halogen, cyanic acid, C 1-C 6The group that alkoxyl group and hydroxyl are formed; Cycloalkyl aryl, wherein aryl is for having heteroatoms O, five yuan or the bicyclic aryl of single six-membered rings or 9-13 unit of N or S, naphthenic base has 1-6 carbon atom; C 1-C 6Alkyl C 1-C 6Naphthenic base; With
R 4, R 5, R 6, R 7And R 8Be independently selected from H or halogen;
Or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug:
11. compound according to claim 9, it has formula:
Wherein, R 1, R 2, R 13And R 14Definition is with claim 9;
Or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
12. compound according to claim 11, it has formula:
Figure FDA0000135908560000072
Wherein, R 13, R 14Definition is with claim 9;
Or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
13. compound according to claim 12, it has formula:
Figure FDA0000135908560000081
Or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
14. compound according to claim 11, it has formula:
Figure FDA0000135908560000082
Wherein, R 13, R 14Definition is with claim 9;
Or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
15. compound according to claim 14, it has formula:
Figure FDA0000135908560000091
Or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
16. a pharmaceutical composition, it comprises pharmaceutically any compound of the claim 1 to 15 of significant quantity, or it is at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug and pharmaceutically acceptable carrier.
17. any compound of claim 1 to 15, or it is used for suppressing the application of the pharmaceutical composition of MEK enzyme in preparation at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
18. any compound of claim 1 to 15, or it is used for treating or prevents the application of pharmaceutical composition of disease or the illness of MEK mediation in preparation at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
19. any compound of claim 1 to 15, or it is used for treating or preventing the application of the pharmaceutical composition of proliferative disease in preparation at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug.
20. purposes according to claim 19, wherein said proliferative disease is selected from diseases associated with inflammation or cancer.
21. any compound of claim 1 to 15, thereby or its be enough to suppress to be in contact with it under the MEK enzyme amount at pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug and reaching the method that suppresses it.
22. any compound of claim 1 to 15, or it treats or prevents disease or the illness of the MEK mediation method to the adjusting of individuality at the synthetics that pharmacy acceptable salt, solvolyte, polymorphic form, ester, tautomer or prodrug are formed under significant quantity.
23. method according to claim 22, wherein said disease or illness are proliferative disease.
24. method according to claim 23, wherein said proliferative disease is selected from the group of being made up of diseases associated with inflammation and cancer.
CN2010800362746A 2009-06-15 2010-06-13 Novel 6-arylamino pyridone sulfonamides and 6-arylamino pyrazinone sulfonamdies as mek inhibitors Pending CN102459188A (en)

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Application publication date: 20120516