CN102134218A - 6-aryl amino pyridone sulfamide and 6-aryl amino pymetrozine sulfamide methyl ethyl ketone (MEK) inihibitor - Google Patents

6-aryl amino pyridone sulfamide and 6-aryl amino pymetrozine sulfamide methyl ethyl ketone (MEK) inihibitor Download PDF

Info

Publication number
CN102134218A
CN102134218A CN200910146822XA CN200910146822A CN102134218A CN 102134218 A CN102134218 A CN 102134218A CN 200910146822X A CN200910146822X A CN 200910146822XA CN 200910146822 A CN200910146822 A CN 200910146822A CN 102134218 A CN102134218 A CN 102134218A
Authority
CN
China
Prior art keywords
group
alkyl
compound
cycloalkyl
halogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN200910146822XA
Other languages
Chinese (zh)
Inventor
校登明
王世新
祝力
梁志
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
KAIMEILONG (BEIJING) PHARMACEUTICAL TECHNOLOGY Co Ltd
Original Assignee
KAIMEILONG (BEIJING) PHARMACEUTICAL TECHNOLOGY Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by KAIMEILONG (BEIJING) PHARMACEUTICAL TECHNOLOGY Co Ltd filed Critical KAIMEILONG (BEIJING) PHARMACEUTICAL TECHNOLOGY Co Ltd
Priority to CN200910146822XA priority Critical patent/CN102134218A/en
Priority to JP2012515317A priority patent/JP2012530079A/en
Priority to PCT/CN2010/000851 priority patent/WO2010145197A1/en
Priority to KR1020127001106A priority patent/KR20120034736A/en
Publication of CN102134218A publication Critical patent/CN102134218A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/14—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Abstract

The invention provides a novel substituted 6-aryl amino pyridone sulfamide and 6-aryl amino pymetrozine sulfamide compound which is represented by a formula I, can be used as a methyl ethyl ketone (MEK) inihibitor and used for treating inflammation diseases, cancers and other hyperproliferative diseases. The invention also provides a pharmaceutical composition containing the compound, application of the compound in pharmacy and a method for treating hyperproliferative diseases of mammalians (especial human) by utilizing the compound. The formula I is shown in the specification.

Description

6-virtue aminopyridine one sulfonamide and the amino pyrazine one sulfonamide mek inhibitor of 6-virtue
Technical field
The present invention relates to the 6-virtue aminopyridine one sulfonamide and the amino pyrazine one sulfonamide of 6-virtue of a series of replacements, it is for mek inhibitor and can be used for treating diseases associated with inflammation, cancer and other excess proliferative diseases.The invention still further relates to the pharmaceutical composition, the purposes of The compounds of this invention in pharmacy and the method for using the excess proliferative disease of The compounds of this invention treatment Mammals (particularly human) that comprise The compounds of this invention.
Background technology
Protein kinase constituted structurally associated, by phosphate group is transferred to Ser, the Thr of protein receptor or the enzyme family that the Tyr residue plays a role from nucleoside triphosphate.Regulate and control the various kinds of cell function by protein kinase mediated protein reversible phosphorylation event, comprising 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 hitherto known more than 100 main oncogene, 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, the protein kinase target has attracted most medicament research and development attention in recent years, and has some kinases inhibitors to obtain the approval of supervision department (about summarizing referring to Fischer Curr.Med.Chem., 11:1563 (2004); Dancey and Sausville, Nature Rev.Drug Disc., 2:296 (2003))
The Ras/Raf/MEK/ERK path is main signal transduction pathway, 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 represents mitogen activated protein kinase, illustrates that this path can be by mitogen, cytokine and factors stimulated growth (Steelman et al., Leukemia 2004,18,189218).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 aspect cell proliferation and the inhibition apoptosis.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 expression to have the proteic activated mutant of the active Ras of composition.(Kohl et a1., 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 cancers.Now in immortal cell line, proved Ras to the effect of propagation and tumour formation (McCubrey et al., Int J Oncol 1995,7,295-310).Now in the malignant melanoma more than 60%, identified bRaf sudden change (Davies, H et al., Nature2002,417,949-954).Owing to detected high-caliber Ras sudden change, this path is regarded as carrying out the important target of therapeutic intervention always, and (Chang et al., Leukemia 2003,17,1263-93).
Because the constitutively activate of map kinase cascade or excessive activation have keying action in cell proliferation and differentiation, it is believed that and suppress the treatment that this path helps excess proliferative disease.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.Now existing a plurality of 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, 19995 (7), 810-816 in the mouse heteroplastic transplantation model; Trachet et al.AACRApril 6-10,2002, Poster﹠amp; 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, WO00/42022, WO 00/42029, WO 00/68201, WO 01/68619, WO 02/06213, WO03/077914, WO 05/023251, WO 05/121142, WO07/014011, WO 07/071951, WO07/123939, WO 08/021389, WO 08/078086, WO 08/120004, WO 08/124085, WO 08/125180, WO 09/018233, WO07/044084, WO07/121481 and WO 09/018238.
Summary of the invention
The invention provides compound or its pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or the prodrug of formula I:
Figure B200910146822XD0000021
Formula I
Wherein
R 0Be H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 2-C 6Thiazolinyl, C 5-C 6Cycloalkenyl group or C 2-C 6Alkynyl; Wherein said alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group or alkynyl group are optional to be replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyano group, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed, and described C 3-C 6One or two of cycloalkyl becomes optional O, N or the S of replacing with independently of ring carbon atom;
R 1Be H, C 1-C 4Alkoxyl group, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 2-C 6Thiazolinyl, C 5-C 6Cycloalkenyl group or C 2-C 6Alkynyl; Wherein said alkoxyl group, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group or alkynyl group are randomly replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyano group, 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, described heterocyclic radical contains 1-5 heteroatoms, described heteroatoms is independently selected from the group of being made up of O, N and S, and described heterocyclic radical is optional to be replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyano group, 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 3The C that expression can be replaced by the group that 1-3 is represented by Z 1-5Alkyl;
Z can be identical or different, and the expression C that can randomly be replaced by one or more substituting groups 1-5Alkyl, halogen atom, oxo group ,-OR a,-COOR a,-COOCOR a,-CO-halogen atom ,-OCOR a,-CONR aRb ,-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, described 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 cycloalkyl or heterocyclic radical, and described cycloalkyl or heterocyclic radical can have one or more substituting groups, and described substituting group is selected from by-OR a, NR aR bWith can be by-OR aThe C that replaces 1-5The group that alkyl is formed;
R aAnd R bCan be identical or different, represent hydrogen atom or the C that can be replaced by 1-3 substituting group separately 1-5Alkyl group, described 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;
When X=C, R 2Be H, C 1-C 4Alkoxyl group, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 2-C 6Thiazolinyl, C 5-C 6Cycloalkenyl group or C 2-C 6Alkynyl; Wherein said alkoxyl group, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group or alkynyl are optional to be replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyano group, 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, described heterocyclic radical has 1-5 heteroatoms, described heteroatoms is selected from the group of O, N and S composition, and described heterocyclic radical is optional to be replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyano group, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed; Perhaps
When X=N, R 2Do not exist; With
R 3Be selected from by trifluoromethyl, C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, C 3-C 10Cycloalkyl, C 3-C 10The group that cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical and heterocyclic radical alkyl are formed, wherein each alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical are not substituted or are replaced by 1-3 substituting group, and described substituting group is independently selected from halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, cyano group, trifluoromethyl, difluoro-methoxy, phenyl or have 1-3 substituent substituted-phenyl, the substituting group of described substituted-phenyl is independently selected from hydrogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, cyano group, trifluoromethyl or difluoro-methoxy;
R 4, R 5, R 6, R 7And R 8Be independently selected from hydrogen, halogen, cyano group, 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 10Cycloalkyl, 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 1-5 fluorine atom.
R 9Be selected from by hydrogen, trifluoromethyl, C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, C 3-C 10Cycloalkyl, C 3-C 10The group that cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical and heterocyclic radical alkyl are formed, wherein each alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical are not substituted or are replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming;
R 10Be 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, described substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming; Perhaps
R 9, R 10Form the hetero-aromatic ring or the heterocycle of 4-10 unit together with coupled atom, described each ring is not substituted or is replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, C 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, described substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming; Perhaps
R 10, R 11Form carbocyclic ring, hetero-aromatic ring or the heterocycle of 4-10 unit together with coupled atom, each ring is not substituted or is replaced by 1-3 substituting group, and described 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 cycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical and heterocyclic radical alkyl are formed, wherein each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical are not substituted or are replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming;
M be 0,1,2,3,4 or 5 and
J is 1 or 2; And X is C or N.
On the other hand, the invention provides the compound of formula I or it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug, wherein R 0Be H or C 1-C 6Alkyl.
On the other hand, the invention provides the compound of formula I or it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug, wherein R 1Be H or C 1-C 6Alkyl.
On the other hand, the invention provides the compound of formula I or its, then do not have R when wherein X is N at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug 2When perhaps X is C, R 2Be H or C 1-C 6Alkoxyl group.
On the other hand, the invention provides the compound of formula I or its at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug, 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, described heterocyclic radical comprises 1-5 the heteroatoms that is independently selected from O, N and S, and described heterocyclic radical is optional by 1-3 substituting group replacement, and described substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyano group, 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, solvate, polymorphic form, ester, tautomer or prodrug, wherein R 3Be selected from the group of forming by following group: randomly by the C of one or more halogens or hydroxyl replacement 1-C 6Alkyl; C 2-C 6Thiazolinyl; Randomly by C 1-C 6Alkyl or C 2-C 6The C of alkenyl substituted 3-C 6Cycloalkyl; Monocycle or bicyclic heteroaryl with heteroatoms O, N or S; Monocycle or the bicyclic aryl that is replaced by one or more substituting groups randomly, wherein said substituting group is selected from by halogen, cyano group, C 1-C 6The group that alkoxyl group and hydroxyl are formed; Cycloalkyl aryl, wherein aryl is monocycle or bicyclic aryl, cycloalkyl has 1-6 carbon atom; And C 1-C 6Alkyl C 1-C 6Cycloalkyl.
On the other hand, the invention provides the compound of formula I or it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug, wherein R 4, R 5, R 6, R 7And R 8Be independently selected from and be H or halogen.
On the other hand, the invention provides the compound of formula I or it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug, wherein R 4And R 8One of be fluorine, and R 6Be iodine.
On the other hand, the invention provides the compound of formula I or it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug, wherein R 0Be H or C 1-C 6Alkyl; R 1Be H or C 1-C 6Alkyl; There is not R 2Or R 2Be H or C 1-C 6Alkoxyl group; R 3Be selected from the group of forming by following group: randomly by the C of one or more halogens or hydroxyl replacement 1-C 6Alkyl; C 2-C 6Thiazolinyl; Randomly by C 1-C 6Alkyl or C 2-C 6The C of alkenyl substituted 3-C 6Cycloalkyl; Monocycle or bicyclic heteroaryl with heteroatoms O, N or S; Monocycle or the bicyclic aryl that is replaced by one or more substituting groups randomly, wherein said substituting group is selected from by halogen, cyano group, C 1-C 6The group that alkoxyl group and hydroxyl are formed; Cycloalkyl aryl, wherein aryl is monocycle or bicyclic aryl, cycloalkyl has 1-6 carbon atom; And C 1-C 6Alkyl C 1-C 6Cycloalkyl; And R 4, R 5, R 6, R 7And R 8Be independently selected from and be H or halogen.
On the other hand, the invention provides compound that following formula represents or its at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug:
Figure B200910146822XD0000071
Wherein
R 0Be H or C 1-C 6Alkyl; R 1Be H or C 1-C 6Alkyl; R 2Be H or C 1-C 6Alkoxyl group; R 3Be selected from the group of forming by following group: randomly by the C of one or more halogens or hydroxyl replacement 1-C 6Alkyl; C 2-C 6Thiazolinyl; Randomly by C 1-C 6Alkyl or C 2-C 6The C of alkenyl substituted 3-C 6Cycloalkyl; Monocycle or bicyclic heteroaryl with heteroatoms O, N or S; Monocycle or the bicyclic aryl that is replaced by one or more substituting groups randomly, wherein said substituting group is selected from by halogen, cyano group, C 1-C 6The group that alkoxyl group and hydroxyl are formed; Cycloalkyl aryl, wherein aryl is monocycle or bicyclic aryl, cycloalkyl has 1-6 carbon atom; C 1-C 6Alkyl C 1-C 6Cycloalkyl; And R 4, R 5, R 6, R 7And R 8Be independently selected from and be H or halogen;
R 13Be selected from by H, C 2-C 6Thiazolinyl and C 1-C 6The group that alkyl is formed, wherein, described group can randomly be replaced by one or more substituting groups, and described substituting group is selected from the group of being made up of halogen and hydroxyl;
R 14Be selected from by H, C 1-C 6Alkyl, monocycle or bicyclic aryl and have the monocycle of heteroatoms O, N or S or group that bicyclic heteroaryl is formed, wherein, described group can randomly be replaced by one or more substituting groups, and described substituting group is selected from by halogen, cyano group and C 1-C 6The group that alkoxyl group is formed.
On the other hand, the invention provides compound that following formula represents or its at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug:
Figure B200910146822XD0000072
Wherein,
R 1Be H or C 1-C 6Alkyl; R 2Be H or C 1-C 6Alkoxyl group; R 13Be selected from by H, C 2-C 6Thiazolinyl and C 1-C 6The group that alkyl is formed, wherein, described group can randomly be replaced by one or more substituting groups, and described substituting group is selected from the group of being made up of halogen and hydroxyl; R 14Be selected from by H, C 1-C 6Alkyl, monocycle or bicyclic aryl and have the monocycle of heteroatoms O, N or S or group that bicyclic heteroaryl is formed, wherein, described group can randomly be replaced by one or more substituting groups, and described substituting group is selected from by halogen, cyano group and C 1-C 6The group that alkoxyl group is formed.
On the other hand, the invention provides compound that following formula represents or its at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug:
Figure B200910146822XD0000081
Wherein,
R 13Be selected from by H, C 2-C 6Thiazolinyl and C 1-C 6The group that alkyl is formed, wherein, described group can be randomly replaced by one or more substituting groups, and described substituting group is selected from the group of being made up of halogen and hydroxyl; R 14Be selected from by H, C 1-C 6Alkyl, monocycle or bicyclic aryl and have the monocycle of heteroatoms O, N or S or group that bicyclic heteroaryl is formed, wherein, described group can randomly be replaced by one or more substituting groups, and described substituting group is selected from by halogen, cyano group and C 1-C 6The group that alkoxyl group is formed.
In other embodiments, the invention provides the compound that following formula is represented:
Figure B200910146822XD0000091
Or it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug.
On the other hand, the invention provides compound that following formula represents or its at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug:
Figure B200910146822XD0000092
Wherein
R 13Be selected from by H, C 2-C 6Thiazolinyl and C 1-C 6The group that alkyl is formed, wherein, described group can randomly be replaced by one or more substituting groups, and described substituting group is selected from the group of being made up of halogen and hydroxyl; R 14Be selected from by H, C 1-C 6Alkyl, monocycle or bicyclic aryl and have the monocycle of heteroatoms O, N or S or group that bicyclic heteroaryl is formed, wherein, described group can randomly be replaced by one or more substituting groups, and described substituting group is selected from by halogen, cyano group and C 1-C 6The group that alkoxyl group is formed.
In other embodiments, the invention provides the compound that following formula is represented:
Or it is at pharmacy acceptable salt, solvate, 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, solvate, polymorphic form, ester, tautomer or prodrug.In some embodiments, described pharmaceutical composition also comprises pharmaceutically acceptable carrier.This based composition can comprise at least a in auxiliary agent, vehicle, sanitas, absorption delay agent, filler, tackiness agent, sorbent material, buffer reagent, disintegrating agent, solubilizing agent, other carriers and the inert fraction.The compound method of composition is a technology well known in the art.
In other respects, the present invention relates to treat the method for the individuality of suffering from described disease, described method comprises the pharmaceutical composition to described individual administering therapeutic significant quantity, and described pharmaceutical composition comprises the I compound of formula or it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug.
In other respects, the present invention relates to treat the method for Mammals illness, described method comprises to the formula I compound of described administration treatment significant quantity or it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug.
In other respects, the present invention relates to treat the method for human patients illness, described method comprises to the formula I compound of described human patients administering therapeutic significant quantity or it is at pharmacy acceptable salt, solvate, 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, described method comprises to the formula I compound of described administration treatment significant quantity or it is at pharmacy acceptable salt, ester, prodrug, solvate (comprising hydrate), polymorphic form or tautomer.
In other respects, the present invention relates to treat Mammals (comprising the mankind) and be subjected to the symptom of MEK cascade regulation and control or the method for illness, described method comprises to its amount of described administration can effectively regulate and control the formula I compound of described cascade or it is at pharmacy acceptable salt, ester, prodrug, solvate (comprising hydrate), polymorphic form or tautomer.Those skilled in the art can be according to the definite suitable dose to particular patient of currently known methods.
In other respects, the present invention relates to formula I compound or it is in pharmacy acceptable salt, ester, prodrug, solvate (comprising hydrate), polymorph or the application of tautomer in pharmaceutical compositions.Described pharmaceutical composition can be used for treating disease or the illness that Mammals (comprising the mankind) is subjected to MEK cascade regulation and control.Described pharmaceutical composition can be used for treating cancer, diseases associated with inflammation and other excess proliferative disease.
In other respects, the present invention relates to comprise formula I compound or its pharmaceutical composition at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug.In some embodiments, described pharmaceutical composition is an oral dosage form.In some embodiments, the formulation of described pharmaceutical composition is tablet, capsule, pill, pulvis, sustained release preparation, solution and suspension, be used for sterile solution, suspension 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, described 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 0.001mg/kg body weight/day-Yue 1000mg/kg body weight/day.In other embodiments, the scope of the amount of formula I compound is about 0.5mg/kg body weight/day-Yue 50mg/kg body weight/day.In some embodiments, the amount of formula I compound is about 0.001g/ days-Yue 7g/ days.In other embodiments, the amount of formula I compound is the about 6g/ of about 0.002-days.In other embodiments, the amount of formula I compound is about 0.005g/ days-Yue 5g/ days.In other embodiments, the amount of formula I compound is the about 5g/ of about 0.01-days.In other embodiments, the amount of formula I compound is about 0.02g/ days-Yue 5g/ days.In other embodiments, the amount of formula I compound is about 0.05g/ days-Yue 2.5g/ days.In other embodiments, the amount of formula I compound is about 0.1g/ days-Yue 1g/ days.In other embodiments, the dosage level that is lower than above-mentioned scope lower limit may be enough.In other embodiments, may need to be higher than the dosage level of above-mentioned range limit.In some 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 some embodiments, use the compound of twice formula 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, described pharmaceutical composition is applied to Mammals.In other embodiments, described Mammals is the people.In other embodiments, described pharmaceutical composition also comprises pharmaceutical carrier, vehicle and/or auxiliary agent.In other embodiments, described pharmaceutical composition also comprises at least a therapeutical agent.In other embodiments, described therapeutical agent is selected from the group that cell toxicant material, anti-angiogenic formation 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, described therapeutical agent be taxol (taxol), Velcade (bortezomib) or both.In other embodiments, described pharmaceutical composition uses to unite with other treatment and carries out.In other embodiments, described other treatment is radiotherapy, chemotherapy or the combination of the two.In other embodiments, described pharmaceutical composition comprises formula I compound at pharmacy acceptable salt.
In other respects, the present invention relates to suppress the method for MEK enzyme.Described method comprises the composition that makes described MEK enzyme contact effective inhibitory amount, thereby suppresses the MEK enzyme, and wherein said composition comprises formula I compound or it is at pharmacy acceptable salt, hydrate, polymorphic form, ester, tautomer or prodrug.In following embodiment, 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 preparation at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug application.
In some embodiments, described enzyme is suppressed at least about 1%.In other embodiments, described enzyme is suppressed at least about 2%.In other embodiments, described enzyme is suppressed at least about 3%.In other embodiments, described enzyme is suppressed at least about 4%.In other embodiments, described enzyme is suppressed at least about 5%.In other embodiments, described enzyme is suppressed at least about 10%.In other embodiments, described enzyme is suppressed at least about 20%.In other embodiments, described enzyme is suppressed at least about 25%.In other embodiments, described enzyme is suppressed at least about 30%.In other embodiments, described enzyme is suppressed at least about 40%.In other embodiments, described enzyme is suppressed at least about 50%.In other embodiments, described enzyme is suppressed at least about 60%.In other embodiments, described enzyme is suppressed at least about 70%.In other embodiments, described enzyme is suppressed at least about 75%.In other embodiments, described enzyme is suppressed at least about 80%.In other embodiments, described enzyme is suppressed at least about 90%.In other embodiments, described enzyme is suppressed substantially fully.In some embodiments, described MEK enzyme is the MEK kinases.In other embodiments, described MEK enzyme is MEK1.In other embodiments, described 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 can be to not having selectivity between MEK1 enzyme and the MEK2 enzyme.In some embodiments, in cell, come in contact.In some embodiments, described cell is a mammalian cell.In other embodiments, described mammalian cell behaviour cell.In some embodiments, use comprises formula I compound and suppresses the MEK enzyme at the composition of pharmacy acceptable salt.
In other respects, the present invention relates to treat the method for the individuality of suffering from the illness that mediates by MEK, described method comprises the pharmaceutical composition to described individual administering therapeutic significant quantity, and described pharmaceutical composition comprises formula I compound or it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug.
In other respects, the present invention relates to comprise 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, solvate, polymorphic form, ester, tautomer or prodrug.
In some embodiments, by oral, use through duodenum, parenteral (comprising in intravenously, subcutaneous, intramuscular, the blood vessel or), topical application (topical administration) or per rectum and to comprise formula I compound compositions by the infusion mode.In some embodiments, described pharmaceutical composition is an oral dosage form.In other embodiments, the formulation of described pharmaceutical composition is tablet, capsule, pill, pulvis, slow release formulation, solution and suspension, be used for sterile solution, suspension 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, described pharmaceutical composition is the unit dosage that is fit to bestow the single exact dosage desired.In other embodiments, described 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 0.001mg/kg body weight/day-Yue 1000mg/kg body weight/day.In other embodiments, the scope of the amount of formula I compound is about 0.5mg/kg body weight/day-Yue 50mg/kg body weight/day.In some embodiments, the amount of formula I compound is about 0.001g/ days-Yue 7g/ days.In other embodiments, the amount of formula I compound is about 0.01g/ days-Yue 7g/ days.In other embodiments, the amount of formula I compound is about 0.02g/ days-Yue 5g/ days.In other embodiments, the amount of formula I compound is about 0.05g/ days-Yue 2.5g/ days.In other embodiments, the amount of formula I compound is about 0.1g/ days-Yue 1g/ days.In other embodiments, the dosage level that is lower than above-mentioned scope lower limit may be enough.In other embodiments, may need to be higher than the dosage level of above-mentioned range limit.In other embodiments, bestow the compound of formula I with single dose, once a day.In other embodiments, bestow the compound of formula I with multiple doses, every day more than once.In other embodiments, use the compound of twice formula 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, the individuality of the disease of the described MEK of suffering from mediation is a Mammals.In other embodiments, described 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, described 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, described 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, described therapeutical agent be selected from taxol, Velcade or both.In some embodiments, described disease by the MEK mediation is selected from the group of being made up of following: diseases associated with inflammation, infect, autoimmune disorder, apoplexy, ischemic, heart trouble, nervous system disorders, fibrotic disease, proliferative disease, excess proliferative disease, the excess proliferative disease of non-cancer, tumour (tumor), leukemia, vegetation (neopalsms), cancer (cancer), malignant tumor (carcinoma), metabolic trouble, malignant disease, vascular restenosis, psoriatic, arteriosclerosis, rheumatoid arthritis, osteoarthritis, in heart failure, chronic pain, neuropathic pain, xeropthalmus, angle closure glaucoma and wide-angle glaucoma.In other embodiments, the disease of described MEK mediation is a diseases associated with inflammation.In other embodiments, the disease of described MEK mediation is an excess proliferative disease.In other embodiments, the disease of described MEK mediation is selected from the group of being made up of tumour, leukemia, vegetation, cancer, malignant tumor and malignant disease.In other embodiments, described cancer is the cancer of the brain, mammary cancer, lung cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, kidney, colorectal cancer or leukemia.In other embodiments, described fibrotic disease is scleroderma, polymyositis, systemic lupus erythematous, rheumatoid arthritis, liver cirrhosis, cicatrization, interstitial nephritis or pulmonary fibrosis.In some embodiments, use be significant quantity comprise the composition 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, described method comprises the composition that makes its amount of described cells contacting can effectively make cancer cells degeneration, anticancer growth or kill cancer cell, and described composition comprises formula I compound or it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug.
In other respects, the present invention relates to comprise that formula I compound or its are used to make in preparation that cancer cells is degenerated at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug, the application on the pharmaceutical composition of anticancer growth or kill cancer cell.
In some embodiments, described 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 some embodiments, described composition uses with at least a therapeutical agent.In other embodiments, described therapeutical agent be taxol, Velcade or both.In other embodiments, described 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 substantially 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, 75% 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 all is killed.In other embodiments, all substantially 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 about 1%.In other embodiments, the growth of cancer cells is suppressed about 2%.In other embodiments, the growth of cancer cells is suppressed about 3%.In other embodiments, the growth of cancer cells is suppressed about 4%.In other embodiments, the growth of cancer cells is suppressed about 5%.In other embodiments, the growth of cancer cells is suppressed about 10%.In other embodiments, the growth of cancer cells is suppressed about 20%.In other embodiments, the growth of cancer cells is suppressed about 25%.In other embodiments, the growth of cancer cells is suppressed about 30%.In other embodiments, the growth of cancer cells is suppressed about 40%.In other embodiments, the growth of cancer cells is suppressed about 50%.In other embodiments, the growth of cancer cells is suppressed about 60%.In other embodiments, the growth of cancer cells is suppressed about 70%.In other embodiments, the growth of cancer cells is suppressed about 75%.In other embodiments, the growth of cancer cells is suppressed about 80%.In other embodiments, the growth of cancer cells is suppressed about 90%.In other embodiments, the growth of cancer cells is suppressed about 100%.What use in some embodiments, is to comprise the composition of formula I compound at pharmacy acceptable salt.
In other respects, the present invention relates to treat or prevent the method for individual proliferative disease, described method comprises pharmaceutical composition from significant quantity to described individuality that use, and described pharmaceutical composition comprises formula I compound or it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug.
In other respects, the present invention relates to formula I compound or its is used for the treatment of or prevents application in the pharmaceutical composition of proliferative disease in preparation at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug.
In some embodiments, described proliferative disease is cancer, psoriatic, restenosis, autoimmune disorder or arteriosclerosis.In other embodiments, described proliferative disease is an excess proliferative disease.In other embodiments, described proliferative disease is selected from the group of being made up of tumour, leukemia, vegetation, cancer, malignant tumor and malignant disease.In other embodiments, described cancer is the cancer of the brain, mammary cancer, lung cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, kidney, colorectal cancer or leukemia.In other embodiments, described fibrotic disease is scleroderma, polymyositis, systemic lupus erythematous, rheumatoid arthritis, liver cirrhosis, cicatrization, interstitial nephritis or pulmonary fibrosis.In other embodiments, described cancer is the cancer of the brain, mammary cancer, lung cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, kidney, colorectal cancer or leukemia.In other embodiments, described cancer is the cancer of the brain or adrenocortical carcinoma.In other embodiments, described cancer is a mammary cancer.In other embodiments, described cancer is an ovarian cancer.In other embodiments, described cancer is a carcinoma of the pancreas.In other embodiments, described cancer is a prostate cancer.In other embodiments, described cancer is a kidney.In other embodiments, described cancer is a colorectal cancer.In other embodiments, described cancer is a myelocytic leukemia.In other embodiments, described cancer is a glioblastoma multiforme.In other embodiments, described cancer is a follicular lymphoma.In other embodiments, described cancer is the impatient property of a pre B cell leukemia.In other embodiments, described cancer is a Type B lymphatic chronic leukemia.In other embodiments, described cancer is a mesothelioma.In other embodiments, described 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, described 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, described 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, described therapeutical agent be selected from taxol, Velcade or both.In some embodiments, by oral, through duodenum, parenteral (comprise in intravenously, subcutaneous, intramuscular, the blood vessel or pass through infusion), topical application or per rectum applying said compositions.In other embodiments, the scope of the amount of formula I compound is about 0.001mg/kg body weight/day-Yue 1000mg/kg body weight/day.In other embodiments, the scope of the amount of formula I compound is about 0.5mg/kg body weight/day-Yue 50mg/kg body weight/day.In other embodiments, the amount of formula I compound is about 0.001g/ days-Yue 7g/ days.In other embodiments, the amount of formula I compound is about 0.01g/ days-Yue 7g/ days.In other embodiments, the amount of formula I compound is about 0.02g/ days-Yue 5g/ days.In other embodiments, the amount of formula I compound is about 0.05g/ days-Yue 2.5g/ days.In other embodiments, the amount of formula I compound is about 0.1g/ days-Yue 1g/ days.In other embodiments, the dosage level that is lower than above-mentioned scope lower limit may be enough.In other embodiments, may need to be higher than the dosage level of above-mentioned range limit.In other embodiments, the compound of formula I is with single dose administration, once a day.In other embodiments, the compound of formula I is with multiple dose administration, and every day more than once.In other embodiments, use the compound of twice formula 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, the individuality of suffering from proliferative disease is a Mammals.In other embodiments, described individuality is the people.In some embodiments, use be significant quantity comprise the composition 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, described method comprises pharmaceutical composition from significant quantity to described individuality that use, and described pharmaceutical composition comprises formula I compound or it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug.
In other respects, the present invention relates to comprise formula I compound or its pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug preparation be used for the treatment of or the pharmaceutical composition of preventing inflammation disease in application.
In other embodiments, diseases associated with inflammation is selected from the group of being made up of following: chronic inflammation disease, rheumatoid arthritis, SpA, urarthritis, osteoarthritis, property childhood sacroiliitis, acute rheumatic arthritis, enteropathic arthritis, neurarthropathy, psoriatic arthritis, suppurative arthritis, arteriosclerosis, systemic lupus erythematous, the inflammatory intestinal tract disease, irritable bowel syndrome, ulcerative colitis, reflux esophagitis, regional enteritis (Crohn ' s disease), gastritis, asthma, allergy, 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, by oral, through duodenum, parenteral (comprise in intravenously, subcutaneous, intramuscular, the blood vessel or pass through infusion), topical application or per rectum applying said compositions.In other embodiments, the scope of the amount of formula I compound is about 0.001mg/kg body weight/day-Yue 1000mg/kg body weight/day.In other embodiments, the scope of the amount of formula I compound is about 0.5mg/kg/ days-Yue 50mg/kg/ days.In other embodiments, the amount of formula I compound is about 0.001g/ days-Yue 7g/ days.In his embodiment, the amount of formula I compound is about 0.01g/ days-Yue 7g/ days.In other embodiments, the amount of formula I compound is about 0.02g/ days-Yue 5g/ days.In other embodiments, the amount of formula I compound is about 0.05g/ days-Yue 2.5g/ days.In other embodiments, the amount of formula I compound is about 0.1g/ days-Yue 1g/ days.In other embodiments, the dosage level that is lower than above-mentioned scope lower limit may be enough.In other embodiments, may need to be higher than the dosage level of above-mentioned range limit.In other embodiments, the compound of formula I is with single dose administration, once a day.In other embodiments, the compound of formula I is with multiple dose administration, and every day more than once.In other embodiments, use the compound of twice formula 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, the individuality of suffering from diseases associated with inflammation is a Mammals.In other embodiments, described individuality is the people.In some embodiments, use be significant quantity comprise the composition of formula I compound at pharmacy acceptable salt.
In other respects, the present invention relates to treat or prevent the method for individual cancer, described method comprises pharmaceutical composition from significant quantity to described individuality that use, and described pharmaceutical composition comprises formula I compound or it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug.
In other respects, the present invention relates to comprise formula I compound or its pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug preparation be used for the treatment of or the pharmaceutical composition of preventing cancer in application.
In other embodiments, described cancer is the cancer of the brain, mammary cancer, lung cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, kidney, colorectal cancer or leukemia.In other embodiments, described fibrotic disease is scleroderma, polymyositis, systemic lupus erythematous, rheumatoid arthritis, liver cirrhosis, cicatrization, interstitial nephritis or pulmonary fibrosis.In other embodiments, described cancer is the cancer of the brain, mammary cancer, lung cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, kidney, colorectal cancer or leukemia.In other embodiments, described cancer is the cancer of the brain or adrenocortical carcinoma.In other embodiments, described cancer is a mammary cancer.In other embodiments, described cancer is an ovarian cancer.In other embodiments, described cancer is a carcinoma of the pancreas.In other embodiments, described cancer is a prostate cancer.In other embodiments, described cancer is a kidney.In other embodiments, described cancer is a colorectal cancer.In other embodiments, described cancer is a myelocytic leukemia.In other embodiments, described cancer is a glioblastoma multiforme.In other embodiments, described cancer is a follicular lymphoma.In other embodiments, described cancer is the impatient property of a pre B cell leukemia.In other embodiments, described cancer is a Type B lymphatic chronic leukemia.In other embodiments, described cancer is a mesothelioma.In other embodiments, described 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, described 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, described 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, described therapeutical agent be selected from taxol, Velcade or both.In some embodiments, by oral, through duodenum, parenteral (comprise in intravenously, subcutaneous, intramuscular, the blood vessel or pass through infusion), topical application or per rectum applying said compositions.In other embodiments, in other embodiments, the scope of the amount of formula I compound is about 0.001mg/kg body weight/day-Yue 1000mg/kg body weight/day.In other embodiments, the scope of the amount of formula I compound is about 0.5mg/kg body weight/day-Yue 50mg/kg body weight/day.In other embodiments, the amount of formula I compound is about 0.001g/ days-Yue 7g/ days.In other embodiments, the amount of formula I compound is about 0.01g/ days-Yue 7g/ days.In other embodiments, the amount of formula I compound is about 0.02g/ days-Yue 5g/ days.In other embodiments, the amount of formula I compound is about 0.05g/ days-Yue 2.5g/ days.In other embodiments, the amount of formula I compound is about 0.1g/ days-Yue 1g/ days.In other embodiments, the dosage level that is lower than above-mentioned scope lower limit may be enough.In other embodiments, may need to be higher than the dosage level of above-mentioned range limit.In other embodiments, the compound of formula I is with single dose administration, once a day.In other embodiments, the compound of formula I is with multiple dose administration, and every day more than once.In other embodiments, use the compound of twice formula 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, the individuality of suffering from cancer is a Mammals.In other embodiments, described individuality is the people.In some embodiments, use be significant quantity comprise the composition of formula I compound at pharmacy acceptable salt.
In other respects, the present invention relates to reduce individual in-vivo tumour volume, suppress the method that gross tumor volume increases, reduces tumor proliferation or suppresses tumor proliferation, described method comprises the pharmaceutical composition to described individual administering therapeutic significant quantity, and described pharmaceutical composition comprises formula I compound or it is at pharmacy acceptable salt, solvate, 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, solvate, polymorphic form, ester, tautomer or prodrug, described 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, described tumour is uprooted.In some embodiments, gross tumor volume no longer increases.In some embodiments, tumor proliferation descends.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, described 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, described 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, described therapeutical agent be selected from taxol, Velcade or both.In some embodiments, by oral, through duodenum, parenteral (comprise in intravenously, subcutaneous, intramuscular, the blood vessel or pass through infusion), topical application or per rectum applying said compositions.In other embodiments, in other embodiments, the scope of the amount of formula I compound is about 0.001mg/kg body weight/day-Yue 1000mg/kg body weight/day.In other embodiments, the scope of the amount of formula I compound is about 0.5mg/kg body weight/day-Yue 50mg/kg body weight/day.In other embodiments, the amount of formula I compound is about 0.001g/ days-Yue 7g/ days.In his embodiment, the amount of formula I compound is about 0.01g/ days-Yue 7g/ days.In other embodiments, the amount of formula I compound is about 0.02g/ days-Yue 5g/ days.In other embodiments, the amount of formula I compound is about 0.05g/ days-Yue 2.5g/ days.In other embodiments, the amount of formula I compound was at about 0.1g/ days-Yue 1g/ days.In other embodiments, the dosage level that is lower than above-mentioned scope lower limit may be enough.In other embodiments, may need to be higher than the dosage level of above-mentioned range limit.In other embodiments, the compound of formula I is with single dose administration, once a day.In other embodiments, the compound of formula I is with multiple dose administration, and every day more than once.In other embodiments, use the compound of twice formula 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, the individuality of suffering from cancer is a Mammals.In other embodiments, described individuality is the people.In some embodiments, use be significant quantity comprise the composition 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, described method comprises pharmaceutical composition from significant quantity to described patient that use, and described pharmaceutical composition comprises formula I compound or it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug.In some embodiments, described curative effect is for suppressing multiple cancer.In other embodiments, described curative effect is for suppressing immunological disease.In other embodiments, described curative effect is the inflammation-inhibiting 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, solvate, 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, described 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, by oral, through duodenum, parenteral (comprise in intravenously, subcutaneous, intramuscular, the blood vessel or pass through infusion), topical application or per rectum applying said compositions.In other embodiments, in other embodiments, the scope of the amount of formula I compound is about 0.001mg/kg body weight/day-Yue 1000mg/kg body weight/day.In other embodiments, the scope of the amount of formula I compound is about 0.5mg/kg body weight/day-Yue 50mg/kg body weight/day.In other embodiments, the amount of formula I compound is about 0.001g/ days-Yue 7g/ days.In other embodiments, the amount of formula I compound is about 0.01g/ days-Yue 7g/ days.In other embodiments, the amount of formula I compound is about 0.02g/ days-Yue 5g/ days.In other embodiments, the amount of formula I compound is about 0.05g/ days-Yue 2.5g/ days.In other embodiments, the amount of formula I compound is about 0.1g/ days-Yue 1g/ days.In other embodiments, the dosage level that is lower than above-mentioned scope lower limit may be enough.In other embodiments, may need to be higher than the dosage level of above-mentioned range limit.In other embodiments, the compound of formula I is with single dose administration, once a day.In other embodiments, the compound of formula I is with multiple dose administration, and every day more than once.In other embodiments, use the compound of twice formula 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, the individuality of suffering from cancer is a Mammals.In other embodiments, described individuality is the people.In some embodiments, use be significant quantity comprise the composition of formula I compound at pharmacy acceptable salt.
In other respects, the present invention relates to formula I compound or its preparation method at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug.
Summary of the invention
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.By understanding the features and advantages of the present invention better with reference to following summary of the invention.
Although this paper has described the preferred embodiments of the invention, these embodiments only provide as example.The variant that should understand embodiment of the present invention as herein described also can be used for implementing 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 protection domain that should understand all respects of the present invention determines by claims, 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.
Chapter title used herein only is used to organize the purpose of article, and should not be interpreted as the restriction to described theme.All documents or the literature department branch quoted among the application include but not limited to patent, patent application, article, books, operational manual and paper, and all integral body is incorporated this paper into by reference.
Some technical term of chemistry
Unless otherwise defined, otherwise the connotation that all scientific and technical terminologies of this paper have is identical with the connotation of claim theme one of ordinary skill in the art common sense.Except as otherwise noted, all patents of quoting in full of this paper, patent application, open material by reference 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 information of equal value by internet retrieval or other bibliography channels that is fit to.The availability and the public propagation of the bibliography proof this type of information that is obtained.
Should be understood that above-mentioned summary and being specified as exemplary and only being used for explaining hereinafter, and theme of the present invention is not imposed any restrictions.In this application, unless specify in addition, otherwise also comprise plural number when using odd number.Must be noted that, unless explanation is arranged in the literary composition clearly in addition, used singulative comprises the plural form of indication things in this specification sheets and claims.It shall yet further be noted that except as otherwise noted, otherwise used " or ", " perhaps " expression " and/or ".In addition, used term " comprises " and other forms, for example " comprises ", " containing " and " containing " and non-limiting.
Can be at reference (" the ADVANCED ORGANIC CHEMISTRY 4 that comprises Carey and Sundberg 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 interior ordinary method of art technology scope, as mass spectrum, NMR, IR and UV/Vis spectrography and pharmacological method.Unless 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 use standard technique in the treatment to the patient.For example, can utilize the operation instruction of manufacturer, perhaps implement reaction and carry out purifying according to mode well known in the art or explanation of the present invention to 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 summaries 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 by the conventional chemical formula of writing from left to right, this substituting group comprises the resulting substituting group that chemically is being equal to when writing structural formula 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 form that replaces.For example, " alkyl " used herein comprises the optional alkyl that replaces.
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 form with and corresponding mixture.Be used to the technology that transforms particular stereoisomer or particular stereoisomer is maintained the original state, and the technology that splits stereoisomer mixture is well known in the art, 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 ' S ENCYCLOPEDIA 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 specific fragment or the functional group in the molecule.Chemical part is considered to embed or append to the chemical entities on the molecule usually.
Term " key " or " singly-bound " are meant, by 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 by its effect and reduces the activated energy barrier of reaction, thereby helps catalytic chemical functional group.
Term " optional/any " or " randomly/at random " are meant that incident or the situation described subsequently may take place or may not take place, and this description comprises generation described incident or situation and described incident or situation do not take place.For example, according to definition hereinafter, " the optional alkyl that replaces " is meant " unsubstituted alkyl " (not being substituted the alkyl that base replaces) or " alkyl of replacement " (being substituted the alkyl that base replaces).In addition, the optional group that replaces can be not to be substituted (as CH 2CH 3), replace (as CF fully 2CF 3), single (CH that replaces 2CH 2F) or fully the replacement degree between replacing and singly replacing is (as 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 the optional cycloalkyl that replaces, otherwise, cycloalkyl is defined as comprising the optional alkyl that replaces, so repeatedly).Therefore, described 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, described " 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 described alkyl is selected from methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl.Digital scope herein, 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 hydrogen atom.
The term that this paper is used alone or in combination " 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, described two or more heteroatomss can be mutually the same, and some or all in perhaps described two or more heteroatomss differ from one another.
The term that this paper is used alone or in combination " alkyl " is meant the monovalence stable hydrocarbon of optional straight chain that replaces or the optional side chain that replaces, and it has about 10 carbon atoms of 1-, more preferably about 6 carbon atoms of 1-.Example includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, 2-methyl isophthalic acid-propyl group, 2-methyl-2-propyl group, the 2-methyl-1-butene base, 3-methyl isophthalic acid-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, as heptyl and octyl group etc.The group of this paper definition, as " alkyl " when digital scope occurring, " C for example 1-C 6Alkyl " or " C 1- 6Alkyl " 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.Example 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 straight chain that replaces or the optional side chain that replaces, 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 described two kinds of isomer.Example includes but not limited to vinyl (CH=CH 2), 1-propenyl (CH 2CH=CH 2), pseudoallyl (C (CH 3)=CH 2), butenyl 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.Example includes but not limited to that vinylidene (CH=CH) and propenylidene isomer are (as 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 the optional straight or branched that replaces, and it has one or more C ≡ C triple bonds and has about 10 carbon atoms of 2-, more preferably about 6 carbon atoms of 2-.Example 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.Example 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 the optional straight or branched that replaces, 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 alkyl, thiazolinyl and the alkynyl structure that replaces respectively, as indicated above, wherein one or more skeletal chain carbon atoms (also comprising continuous hydrogen atom in appropriate circumstances) 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 alkyl, thiazolinyl and the alkynyl structure that replaces respectively, as indicated above, wherein one or more hydrogen atoms 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 hydrogen atoms (for example difluoromethyl); Use not identical each other halogen atom to replace two or more hydrogen atoms (for example 1-chloro-1-fluoro-1-iodine ethyl) in other embodiments.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 hydrogen atoms 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 as term " whole haloalkyl " its all hydrogen atoms 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, described chain comprises as core skeleton one or more rings partly, so in order to calculate 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 determine chain length.If described 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 optionally substituted.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, tetrahydrofuran (THF) and thiophene are five-ring.
The term that this paper is used alone or in combination " condenses " and is meant that two or a plurality of ring have the ring structure of one or more keys jointly.
The term that this paper is used alone or in combination " cycloalkyl " is meant the optional monovalence stable hydrocarbon ring that replaces, 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 example of " cycloalkyl " 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] heptyl (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 delocalization electronics that contains 4n+2n electronics and grips system altogether, and wherein n is an integer.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 (as phenyl ring) and contain one or more heteroatomic rings (as pyridine).
The term that this paper is used alone or in combination " aromatic base/aryl " is meant the optional aryl radical that replaces, 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 rings 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 to about 10 fused rings and non-condensed rings that become 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.Example 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 the monovalence aryl of any replacement, it comprises about 5 and becomes annular atoms to about 20 skeletons, wherein one or more become annular atoms is heteroatoms, described 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 described group does not comprise two adjacent O or S atom.Occur in ring in two or more heteroatomic embodiments, described two or more heteroatomss can be mutually the same, and some or all in perhaps described two or more heteroatomss differ from one another.The term heteroaryl comprises the optional heteroaryl with at least one heteroatomic monovalence condensed or non-condensed that replaces.In addition, the 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 by 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 by 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 rings 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 examples of heteroaryl include but not limited to: furyl (furanyl), thienyl (thienyl) oxazolyl (oxazolyl), acridyl (acridinyl), phenazinyl (phenazinyl), benzimidazolyl-(benzimidazolyl), benzofuryl (benzofuranyl) benzoxazolyl (benzoxazolyl), benzothiazolyl (benzothiazolyl), diazosulfide base (benzothiadiazolyl), benzothienyl (benzothiophenyl) Ben Bing oxadiazole base (benzoxadiazolyl), benzotriazole base (benzotriazolyl), imidazolyl (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 (pyrazolyl), purine radicals (purinyl), phthalazinyl (phthalazinyl), pteridyl (pteridinyl), quinolyl (quinolinyl), quinazolyl (quinazolinyl) quinoxalinyl (quinoxalinyl), triazolyl (triazolyl), tetrazyl (tetrazolyl), thiazolyl (thiazolyl), triazinyl (triazinyl) and thiadiazolyl group (thiadiazolyl) etc., and oxide compound, for example pyridyl-N-oxide compound (pyridyl-N-oxide).
The used alone or in combination term " inferior heteroaryl " of this paper is meant the heteroaryl list free radical deutero-diradical by above-mentioned definition.Example includes but not limited to pyridylidene and inferior pyrimidyl.
The term that this paper is used alone or in combination " heterocyclic radical/heterocycle " is being collectively referred to as of aliphatic heterocycle and heteroaryl.(C for example when pointing out the heterocyclic carbon atom number herein 1-C 6Heterocycle), certainly exist at least one non-carbon atom (heteroatoms) in the described 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.As the name of " 4-6 unit heterocycle " is total atom number contained in the finger ring (promptly four, five or six-ring, wherein at least one atom is a carbon atom, and at least one atom is a heteroatoms, and a remaining 2-4 atom is carbon atom or heteroatoms).For having two or more heteroatomic heterocycles, described two or more heteroatomss can be same to each other or different to each other.Heterocycle can be optionally substituted.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 be by heteroatoms or carbon atom and heterocycle combination (being that heterocycle is connected with parent molecule or further replaces).
The term that this paper is used alone or in combination " carbocylic radical " is being collectively referred to as 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 aromatic substance fully.Can form carbocyclic ring by the atom more than 3,4,5,6,7,8,9 or 9.Carbocyclic ring can be optionally substituted.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 term alkyl wherein, fat base and carbocylic radical definition as mentioned.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 " sulfonamido " 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 " the sulfonyl amido is 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, to the active IC of MEK 50Be not more than about 100 μ M or be not more than the compound of about 50 μ M." IC 50" be meant that activity with enzyme (as MEK) is reduced to half inhibitor concentration of 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 IC to MEK 50Be not more than about 10 μ M, be not more than about 5 μ M,, and most preferably be not more than about 200nM more preferably no more than about 1 μ M.
Term used herein " selection ", " selectively ", " selectivity " are meant with other enzymes and compare that compound of the present invention is to the IC of MEK enzyme 50Be worth lower (for example, low at least 2,5,10 or more times).This term also refers to compare with the MEK2 enzyme, and compound of the present invention is to the IC of MEK1 enzyme 50Be worth lower (for example, low 2 times, 5 times, 10 times or more times at least), perhaps, compare with the MEK1 enzyme, compound of the present invention is to the IC of MEK2 enzyme 50Be worth 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 example 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 example of non-human mammal includes but not limited to birds and fish etc.In the embodiment of a method provided herein and composition, described Mammals is behaved.
Term used herein " treatment " and other similar synonyms 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.Described 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 may still be subjected to 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.
Term that this paper uses " significant quantity ", " treatment significant quantity " or " pharmacy effective dose " are meant takes metapedes with at least a medicament of one or more symptoms of alleviating the disease 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 for the treatment of is the amount that comprises the open compound compositions of this paper that provides significant illness remission effect required clinically.Can use technical measurement such as dosage escalation test to be suitable for significant quantity in any individual case.
Term used herein " is taken ", " using ", " administration " etc. are meant the method that compound or composition can 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 composition are by Orally administered.
This paper is meant that at the used term of preparation, composition or 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 (as 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 composition.
Term used herein " pharmaceutical composition " is meant the bioactive compounds that randomly is mixed with at least a pharmaceutically acceptable chemical ingredients, and described 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 compound 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 the target activity, suppresses the target activity, the restriction target is active or prolongs the target activity.
Term used herein " adjusting control agent " is meant and the direct or indirect interactional molecule of target.Described interaction includes but not limited to the interaction of agonist and antagonist.
Term used herein " pharmacy acceptable salt " is meant the free acid that kept appointed compound and the biopotency of free alkali, and at biology or there is not the salt of undesirable action 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 by the 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 by 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 example of pharmacy acceptable salt comprises the salt for preparing by 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, benzoate, benzene sulfonate, hydrosulfate, bisulfite, bromide, butyrates, butine-1, the 4-diacid salt, camphorate, camsilate, hexanoate, octylate, chloro-benzoate, muriate, Citrate trianion, 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, the 2-isethionate, iodide, isobutyrate, lactic acid salt, maleate, malonate, mesylate, mandelate, metaphosphate, methoxybenzoic acid salt, tolyl acid salt, monohydric phosphate, 1-naphthalene sulfonic aicd salt, the 2-naphthalenesulfonate, nicotinate, nitrate, embonate, jelly hydrochlorate (pectinate), persulphate, the 3-phenpropionate, phosphoric acid salt, picrate, pivalate, propionic salt, pyrosulphate, pyrophosphate salt, propynoic acid, phthalate, phenylacetate, benzenebutanoic acid salt, propanesulfonic acid salt, salicylate, succinate, vitriol, sulphite, suberate, sebacate, sulfonate, tartrate, thiocyanate-, tosilate, undecylate (undeconate) and xylenesulfonate.Other acid (as oxalic acid), although itself pharmaceutically is being unacceptable, but can be used as intermediate uses in the preparation process of salt, with obtain compound of the present invention and in pharmaceutically-acceptable acid addition (referring to Berge et al., J.Pharm.Sci.1977,66, the embodiment among the 1-19).In addition, the compound that comprises free acid group as herein described can with suitable alkali reaction (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, potassium hydroxide, hydroxide hydroxyethyl Trimethylamine 99, yellow soda ash and IV ' (C 1-4Alkyl) 4Deng.The representative organic amine that is used to form base addition salt comprises ethamine, diethylamine, quadrol, thanomin, diethanolamine and piperazine etc.Should be understood that the quaternized thing of any alkaline nitrogen-containing group that compound described herein comprises that also it may comprise.Can obtain water-soluble or oil soluble or dispersible products by quaterisation.Referring to, people's such as Berge document above for example.
Term used herein " solvate " is meant by the The compounds of this invention of solvation formation and the combination of solvent molecule.In some cases, " solvate " 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 derivative 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 by being easy to as hydrogen atom migration or proton shifting be obtained by the The compounds of this invention change.
Term that this paper uses " pharmaceutically acceptable derivates or prodrug " is meant any pharmacy acceptable salt, the ester of The compounds of this invention, salt or other derivatives of ester, metabolite or residue that it can provide compound of the present invention or its to have pharmaceutical active directly or indirectly after using to acceptor.Particularly preferred derivative 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, the strange alkali of N-Manny (N-Mannich bases), schiff base (Schiffbase), amino acid conjugates, phosphoric 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 of Prodrugs " 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 Delivery Review, 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 in following group and these materials: amine deutero-prodrug; The hydroxyl prodrug includes but not limited to acyloxy alkyl ester, alkoxy carbonyl yloxy alkyl ester, alkyl ester, aryl ester and contains the ester of disulfide bond.
Term that this paper uses similar vocabulary such as " enhancing/raisings " 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.
Term that this paper uses " amount of reinforced effects (the effectively amount of enhancement) " is meant the amount that is enough to strengthen the effect of other treatment agent in required system.
Term that this paper uses " drug regimen ", " using other treatment ", " using the other treatment agent " etc. be meant by mixing or make up the pharmacological agent that more than a kind of activeconstituents obtains, and it comprises the fixing of activeconstituents and fixed combination not.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 turn, 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 drug cocktail therapy (treatment), 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 the therapeutic strategy of using medicament by identical or different route of administration or identical or different administration number of times.In some embodiments, compound as herein described and other medicaments is co-administered.These terms are contained to animal and are used two or more medicaments so that have described medicament and/or its metabolite in the animal body simultaneously.These terms comprise uses different compositions simultaneously, and different time is used different compositions and/or used a kind of composition that contains the different activities composition.Therefore, in some embodiments,, compound of the present invention and other medicaments use by being blended in a kind of composition.
Term used herein " metabolite " is meant the derivative of this compound that forms when the compound metabolism.
Term used herein " active metabolite " is meant the active derivative that has of this compound of forming when the compound metabolism.
Term used herein " metabolic " is meant that organism transforms all processes (including but not limited to hydrolysis reaction and enzymic catalytic reaction) of predetermined substance.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, 9th Edition, McGraw-Hill (1996).
Compound
This paper described formula I compound, it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug:
Figure B200910146822XD0000371
Formula I
Wherein
R 0Be H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 2-C 6Thiazolinyl, C 5-C 6Cycloalkenyl group or C 2-C 6Alkynyl; Wherein each alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group or alkynyl group are randomly replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyano group, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed, perhaps described 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 6Cycloalkyl, C 2-C 6Thiazolinyl, C 5-C 6Cycloalkenyl group or C 2-C 6Alkynyl; Wherein each alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group or alkynyl group are randomly replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyano group, 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, described 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 described substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyano group, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed; Or
R 1For-CH 2X, the wherein group of X expression II:
Figure B200910146822XD0000381
Formula II
Wherein
R 0Be H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 2-C 6Thiazolinyl, C 5-C 6Cycloalkenyl group or C 2-C 6Alkynyl; Wherein said alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group or alkynyl group are optional to be replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyano group, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed, and described C 3-C 6In the cycloalkyl one or two becomes ring carbon atom by optional O, N or the S of replacing with independently;
R 1Be H, C 1-C 4Alkoxyl group, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 2-C 6Thiazolinyl, C 5-C 6Cycloalkenyl group or C 2-C 6Alkynyl; Wherein said alkoxyl group, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group or alkynyl group are randomly replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyano group, 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, wherein, described heterocyclic radical contains 1-5 heteroatoms, described heteroatoms is independently selected from the group of being made up of O, N and S, and described heterocyclic radical is optional to be replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyano group, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed; Or
R 1For-CH 2X, the wherein group of X expression II:
Figure B200910146822XD0000391
Formula II
Wherein
Y 1And Y 2Can be identical or different, represent separately singly-bound ,-CO-,-COO ,-O-,-OCO-,-NR aOr-SO 2-;
Y 3The C that expression can be replaced by the group that 1-3 is represented by Z 1-5Alkyl;
Z can be identical or different, and the expression C that can randomly be replaced by 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, monocyclic heterocycles group or the heterocyclic radical of dicyclo or the heteroaryl of monocycle or dicyclo, described substituting group is selected from by C 1-5Alkyl group ,-OR aAnd NR aR bThe group of forming; Described 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 cycloalkyl or heterocyclic radical, and described cycloalkyl or heterocyclic radical can have one or more substituting groups, and described substituting group is selected from by-OR a, NR aR bWith can be by-OR aThe C that replaces 1-5The group that alkyl is formed;
R aAnd R bCan be identical or different, represent hydrogen atom or the C that can be replaced by 1-3 substituting group separately 1-5Alkyl group, described 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;
When X=C, R 2Be H, C 1-C 4Alkoxyl group, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 2-C 6Thiazolinyl, C 5-C 6Cycloalkenyl group or C 2-C 6Alkynyl; Wherein said alkoxyl group, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group or alkynyl are optional to be replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyano group, 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, described heterocyclic radical has 1-5 heteroatoms, described heteroatoms is selected from the group of O, N and S composition, wherein said heterocyclic radical is optional to be replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyano group, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed; Or
When X=N, R 2Do not exist; With
R 3Be selected from by trifluoromethyl, C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, C 3-C 10Cycloalkyl, C 3-C 10The group that cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical and heterocyclic radical alkyl are formed, wherein each alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical be not for being substituted or being replaced by 1-3 substituting group, and described substituting group is independently selected from halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, cyano group, trifluoromethyl, difluoro-methoxy, phenyl or have 1-3 substituent substituted-phenyl, the substituting group of described substituted-phenyl is independently selected from hydrogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, cyano group, trifluoromethyl or difluoro-methoxy;
R 4, R 5, R 6, R 7And R 8Be independently selected from hydrogen, halogen, cyano group, 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 10Cycloalkyl, 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 1-5 fluorine atom.
R 9Be selected from by hydrogen, trifluoromethyl, C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, C 3-C 10Cycloalkyl, C 3-C 10The group that cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical and heterocyclic radical alkyl are formed, wherein each alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical be not for replacing or being replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming;
R 10Be 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, described substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming; Perhaps
R 9And R 10Can form the hetero-aromatic ring or the heterocycle of 4-10 unit with coupled atom together, wherein said each ring is not by being substituted or being replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, C 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, described substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming; Perhaps
R 10, R 11Form carbocyclic ring, hetero-aromatic ring or the heterocycle of 4-10 unit together with coupled atom, each ring is replaced for replacement or by 1-3 substituting group, and described 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 cycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical and heterocyclic radical alkyl are formed, wherein each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical be not by replacing or being replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming;
M be 0,1,2,3,4 or 5 and
J is 1 or 2; And X is C or N.
The invention provides the synthetic method of above-claimed cpd.In some embodiments, can prepare compound as herein described by following method.Following method and embodiment are for these methods are described.These flow processs and embodiment 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 be used in combination means known in the art and methods described herein.
Embodiment
Synthetic method and embodiment
Below be the schema of formula I compound:
Route 1
Figure B200910146822XD0000421
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 derivative 3 subsequently.Nitrated dichloropyridine 3 carries out SN with aniline 5 then ArReaction, thus intermediate product 6 formed.Pyridione derivatives 7 alkylations that hydrolysis chloropyridine 6 can be obtained, thus nitropyridine 8 is provided.After the reduction reaction, use SULPHURYL CHLORIDE to handle aminopyridine 9, thereby obtain required pyridone sulphonamide 10.
Route 2
Figure B200910146822XD0000422
Route 2 has been described the preparation of cyclopropane SULPHURYL CHLORIDE 17.Cyclopropane SULPHURYL CHLORIDE 11 is reacted under the existence condition of alkali (as pyridine) with alkyl alcohol 12, thereby obtains sulphonate 13.The cyclopropane sulphonate 15 of replacement is provided by lithiumation and the alkanisation that utilizes haloalkane 14 to carry out subsequently.Use KSCN to handle compound 15, thus preparation sylvite 16.By the reaction acquisition SULPHURYL CHLORIDE 17 of sylvite 16 with thionyl chloride.
Route 3
Figure B200910146822XD0000431
Route 3 has been described the preparation of dihydroxypropyl cyclopropyl base SULPHURYL CHLORIDE 23.Use epoxide 19 to handle sec.-propyl cyclopropane sulphonate 18 after the lithiumation, thereby obtain hydroxypropyl sulphonate 20.Protection secondary hydroxy group and hydrolysis sulphonate 21, thus sulfonate 22 obtained.Use thionyl chloride to handle compound 22, thereby obtain shielded dihydroxypropyl cyclopropane SULPHURYL CHLORIDE 23.
Route 4
Figure B200910146822XD0000441
Route 4 has been described the preparation of the cyclopropane SULPHURYL CHLORIDE 27 that is subjected to the protection of dioxane pentanone.Utilize CDI or two (trichloromethyl) carbonic ether that the dihydroxypropyl cyclopropane sulphonate 24 that is obtained by shielded hydroxypropyl cyclopropane sulphonate 20 (route 3) deprotection is handled, thereby form dioxane pentanone propyl group cyclopropane sulphonate 25.At mild conditions (as NaI/ acetone or Bu 4NI) hydrolysis compound 25 under, thus sulfonate 26 obtained.There is PPh 3Condition under use thionyl chloride to handle compound 26, thereby obtain to be subjected to the cyclopropane SULPHURYL CHLORIDE 27 of dioxane pentanone protection.
The method A that is used for synthetic sulphonamide
Method A: at 0 ℃-5 ℃, in anhydrous pyridine (1m) solution that contains amine 9 (1 equivalent) 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, water washed mixture, organic phase MgSO 4Carry out drying, filter, filtrate is carried out concentrating under reduced pressure.By quick purification by silica gel column chromatography residue, thereby obtain the purpose product.
Embodiment 1
N-(2-(2-fluoro-4-iodophenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) cyclopropane sulphonamide
Figure B200910146822XD0000451
Steps A: 2-chloro-5-picoline 1-oxide compound
Figure B200910146822XD0000452
At 0 ℃, (200g is 1.57mol) with hydrogen peroxide urea addition compound (310g, the anhydrous trifluoroacetic acid (679g of dropping in methylene dichloride 3.29mol) (2L) mixture to 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 (326g, aqueous solution 3.14mol), and reaction mixture stirred 4 hours.Use the sodium hydroxide neutralization reaction, by dichloromethane extraction, use salt solution to clean, by the organic phase dried over mgso, filter, filtrate decompression concentrates, thereby obtains the title compound (189g, 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 B200910146822XD0000453
At 0 ℃, to contain 2-chloro-5-picoline 1-oxide compound (130g, 905mmol) and triethylamine (110g adds phosphoryl chloride (100mL, methylene dichloride 1087mmol) (500ml) solution in methylene dichloride 1087mmol) (1.5L) mixture., 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 filtrate, thereby obtains 2,6-two chloro-3-methyl-pyridines and 2,4-two chloro-5-methyl-pyridines (138g, 94%, according to 1H NMR measures, and ratio is 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 B200910146822XD0000461
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 (26g, 160mmol, 1 equivalent) slowly adds in the vitriol oil (294g, 3mol, 18 equivalents).In this solution, slowly add nitric acid (95.0%, 74g, 1.17mol, 7 equivalents), simultaneously temperature of reaction was kept 0.5 hour at 0 ℃.Add finish after, 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 (17.6g, 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, (tetrahydrofuran (THF) 500ml) adds 2-fluoro-4-iodo-aniline (11.68g, 49.3mmol, 1 equivalent) in the mixture to the THF that contains NaH (3.55g, 148mmol, 3 equivalents).Stir after 30 minutes, add 2,6-two chloro-3-methyl-5-nitro pyridines (10.2g, 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 amino)-3-methyl-5-nitro pyridine-2 (1H)-ketone
Figure B200910146822XD0000471
(20g 49.1mmol) is dissolved among the EtOH (400ml), slowly adds KOH (55g, 980mmol the are dissolved in 200ml water) aqueous solution subsequently, mixture is 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 (11.3g, 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 amino)-1,3-dimethyl-5-nitropyridine-2 (1H)-ketone
Figure B200910146822XD0000472
At room temperature, (0.2mol/L) add 6-(2-fluoro-4-iodophenyl amino)-3-methyl-5-nitro pyridine-2 (1H)-ketone (1 equivalent) in the solution and stirred 35 minutes to the dry dimethyl formamide (DMF) of NaH (1.2 equivalent), in this garnet mixture, add methyl iodide (1.05 equivalent) subsequently.After at room temperature stirring 1 hour, use saturated NH 4Cl 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) by the purification by silica gel column chromatography residue, thereby acquisition purpose product (productive rate=63%). 1H?NMR(400MHz，CDCl 3)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 amino)-1,3-lutidine-2 (1H)-ketone
Figure B200910146822XD0000481
With 6-(2-fluoro-4-iodophenyl amino)-1,3-dimethyl-5-nitropyridine-2 (1H)-ketone (510mg) and Na 2S 2O 4(1.96g, 8 equivalents) are dissolved in dioxane and water (30mL, 1: 1), subsequently, at room temperature add NH 4OH (1mL).After 2 hours 40 minutes, use 100mL ethyl acetate diluted mixture thing, 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: ethyl acetate)=1: 1 to DCM: MeOH (methylene dichloride: methyl alcohol)=20: 1) by the purification by silica gel column chromatography residue, thereby obtain the above-mentioned title compound (378mg, productive rate=80%) of greyish-green solid state. 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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3- Base) cyclopropane sulphonamide
Figure B200910146822XD0000482
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-1,3-lutidine-2 (1H)-ketone and the reaction of cyclopropane 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-oxo-1,6-dihydropyridine-3-yl) cyclopropane sulphonamide
Steps A: 1-butyl cyclopropane sulphonate
Figure B200910146822XD0000491
Cyclopropane SULPHURYL CHLORIDE (25g, 178mmol, 1 equivalent) is dissolved in excessive n-BuOH (80ml) and reaction mixture is cooled to 0 ℃, drip pyridine (13.3ml, 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, dry (MgSO 4), concentrate subsequently and obtain oil (24.5g, 77%) 1H NMR (400MHz, CDCl 3) δ 4.25 (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 cyclopropane-1-sulfonic acid butyl ester
Figure B200910146822XD0000492
In-78 ℃, nitrogen atmosphere, (60g, (150ml contains the hexane solution of 2.5M butyllithium, 404mmol) slowly to add butyllithium in THF 337mmol) (500ml) solution to 1-butyl cyclopropane sulphonate.Stir after 15 minutes, interpolation contains allyl group iodate thing (31ml, THF 337mmol) (100ml).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, dry (MgSO 4), filter, remove and desolvate.By silica gel column chromatography (eluent: PE/EA=10: 1) purifying residue, thereby obtain above-mentioned title compound (50g, productive rate: water white oil 68%). 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 cyclopropane-1-potassium sulfonate
To contain 1-allyl group cyclopropane-1-sulfonic acid butyl ester (50g, 229mmol) and potassium sulfocyanate (23.4g, 240mmol) dme (DME, 350ml) and water (350ml) mixture heating up reflux and to spend the night.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 cyclopropane-1-SULPHURYL CHLORIDE
(44g, 220mmol) solution, thionyl chloride (500ml) and DMF (5ml) vlil are 1.5 hours with 1-allyl group cyclopropane-1-potassium sulfonate.The reduction vaporization volatile matter, and slowly add water.Use the ethyl acetate extraction mixture, use MgSO 4Drying is filtered and concentrating under reduced pressure.By silica gel column chromatography (eluent: PE/EA=10: 1) purifying residue, thereby obtain above-mentioned title compound (33g, 83%). 1H?NMR(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)-15-dimethyl-6-oxo-1,6-dihydro Pyridin-3-yl) cyclopropane sulphonamide
Figure B200910146822XD0000503
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-1,3-lutidine-2 (1H)-ketone and 1-allyl group cyclopropane-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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) ethyl sulfonamide
Figure B200910146822XD0000511
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl 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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) propane-2-sulphonamide
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl 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 amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) encircles ethyl sulfonamide
Figure B200910146822XD0000521
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl 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 amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) hexanaphthene sulphonamide
Figure B200910146822XD0000522
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl 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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) butane-1-sulphonamide
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-1,3-lutidine-2 (1H)-ketone and butane-1-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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) propane-1-sulphonamide
Figure B200910146822XD0000532
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl 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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) Toluidrin
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl 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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) Toluidrin
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl 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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) pentamethylene sulphonamide
Figure B200910146822XD0000551
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl 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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) thiophene-2-sulphonamide
Figure B200910146822XD0000552
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl 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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) benzsulfamide
According to universal method A, make 5-amino-6-(2-fluoro-4-iodophenyl 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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-4-methyl benzenesulfonamide
Figure B200910146822XD0000562
According to universal method A, make 5-amino-6-(2-fluoro-4-iodophenyl 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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) benzsulfamide
Figure B200910146822XD0000571
According to universal method A, make 5-amino-6-(2-fluoro-4-iodophenyl 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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) thiophene-3-sulphonamide
Figure B200910146822XD0000572
According to universal method A, make 5-amino-6-(2-fluoro-4-iodophenyl 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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-2-sec.-propyl-cyclopropane-1-sulphonamide
Figure B200910146822XD0000581
According to universal method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-1,3-lutidine-2 (1H)-ketone and 2-sec.-propyl-cyclopropane-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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-2-isobutyl--cyclopropane-1-sulphonamide
Figure B200910146822XD0000582
According to universal method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-1,3-lutidine-2 (1H)-ketone and 2-isobutyl--cyclopropane-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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-cyclopropane-1-sulphonamide
Figure B200910146822XD0000591
According to universal method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-1,3-lutidine-2 (1H)-ketone and 2-(4-ethoxyl phenenyl)-cyclopropane-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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-2-phenyl-cyclopropane-1-sulphonamide
Figure B200910146822XD0000592
According to universal method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-1,3-lutidine-2 (1H)-ketone and 2-phenyl-cyclopropane-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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-cyclopropane-1-sulphonamide
Figure B200910146822XD0000601
According to universal method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-1,3-lutidine-2 (1H)-ketone and 2-(3, the 4-difluorophenyl)-cyclopropane-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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-2-(thiophene-2-yl)-cyclopropane-1-sulphonamide
Figure B200910146822XD0000602
According to universal method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-1,3-lutidine-2 (1H)-ketone and 2-(thiophene-2-yl)-cyclopropane-1-SULPHURYL CHLORIDE reaction, thus obtain the purpose product. 1HNMR(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 amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-cyclopropane-1-sulphonamide
Figure B200910146822XD0000611
According to universal method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-1,3-lutidine-2 (1H)-ketone and 2-(2,4 difluorobenzene base)-cyclopropane-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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-cyclopropane-1-sulphonamide
Figure B200910146822XD0000612
According to universal method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-1,3-lutidine-2 (1H)-ketone and 2-(4-cyano-phenyl)-cyclopropane-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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-1-methyl-cyclopropane-1-sulphonamide
Steps A: Cyclopropane sulfonic acid isopropyl ester
Figure B200910146822XD0000621
Cyclopropane SULPHURYL CHLORIDE (21.6g, 154mmol, 1 equivalent) is dissolved in excessive i-PrOH (50ml), and reaction mixture is cooled to 0 ℃.Drip pyridine (12.15g, 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, dry (MgSO 4), filtering, concentrated filtrate obtains oily matter (17.8g, 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-cyclopropane-1-sulfonic acid isopropyl ester
Figure B200910146822XD0000622
In-78 ℃, nitrogen atmosphere, (2g, (6.1ml contains the hexane of 2.5M butyllithium, 15.22mmol) slowly to add butyllithium in THF 12.18mmol) (40ml) solution to cyclopropane sulfonic acid isopropyl ester.Stir after 30 minutes, add methyl iodide (1.44g, THF 10.15mmol) (5ml) 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, dry (MgSO 4), to filter, evaporation removes and desolvates.By silica gel column chromatography (eluent: PE/EA=5: 1) purifying residue, thereby the acquisition above-mentioned title compound of yellow oily (830mg, productive rate 46%). 1HNMR(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-cyclopropane-1-potassium sulfonate
Figure B200910146822XD0000623
To contain 1-methyl-cyclopropane-1-sulfonic acid isopropyl ester (810mg, 4.54mmol) and potassium sulfocyanate (442mg, DME 4.54mmol) (12.5ml) and water (12.5ml) 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-cyclopropane-1-SULPHURYL CHLORIDE
Figure B200910146822XD0000631
To contain 1-methyl-cyclopropane-1-potassium sulfonate (349mg, thionyl chloride 2mmol) (5ml) and DMF (5) vlil 1.5 hours.The reduction vaporization volatile matter, and slowly add water.Use the ethyl acetate extraction residue, use MgSO 4Drying, 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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3- Base)-1-methyl-cyclopropane-1-sulphonamide
According to method A, make 5-amino-6-(2-fluoro-4-iodo-phenyl amino)-1,3-lutidine-2 (1H)-ketone and 1-methyl-cyclopropane-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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-tetramethylene sulphonamide
Steps A: The tetramethylene SULPHURYL CHLORIDE
Figure B200910146822XD0000633
To containing Mg bits (0.405g, the iodine of interpolation 0.3g bromo tetramethylene and catalytic amount in the anhydrous THF suspension of 5ml 16.67mmol).Use the electric blower heated mixt.After solution becomes colorless, slowly add the 1.2g bromo tetramethylene that is dissolved in 15ml THF.Mixture heating up was refluxed 1 hour, be cooled to room temperature subsequently, (4.5g is in the ice-cold solution of 10ml anhydrous methylene chloride 33.3mmol) to containing sulfuryl chloride with the supernatant liquor portion-wise addition.After interpolation is finished, suspension is heated to room temperature, and removes volatile matter in a vacuum.Residue is dissolved in hexane (25ml).Also evaporating solns is to obtain yellow oily crude product (1.55g, 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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydro pyrrole Pyridine-3- Base)-the tetramethylene sulphonamide
Figure B200910146822XD0000641
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl 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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-cyclopropane-1-sulphonamide
Steps A: 1-allyl group-cyclopropane alkylsulfonyl (2-(2-fluoro-4-iodo-phenyl amino)-1,5-dimethyl-6- Oxo-1,6-dihydropyridine-3-yl) t-butyl carbamate
Figure B200910146822XD0000651
At 0 ℃, to containing 1-allyl group-N-(2-(2-fluoro-4-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-and the cyclopropane sulphonamide (182mg, 0.352mmol) and tert-Butyl dicarbonate (84mg, 0.387mmol, 1.1 add NaH (60%wt in 3mL anhydrous THF solution equivalent), 31mg, 2.2 equivalents), at room temperature stir subsequently spend the night (14 hours).After the water cancellation, add ethyl 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 filtrate.By quick silica gel column chromatography (eluent is PE: EA=2: 1) purifying residue, thereby obtain the light yellow oil of above-mentioned title compound (138mg, 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)-cyclopropane alkylsulfonyl (2-(2-fluoro-4-iodophenyl amino)-1,5-diformazan Base-6-oxo-1,6-dihydropyridine-3-yl) t-butyl carbamate
At 0 ℃; to 1-allyl group cyclopropane alkylsulfonyl (2-(2-fluoro-4-iodophenyl amino)-1; 5-dimethyl-6-oxo-1; 6-dihydropyridine-3-yl) t-butyl carbamate (100mg; 0.162mmol) (19mg 0.162mmol), adds osmium oxide (VIII) (4%wt at 0 ℃ subsequently to add N-methylmorpholine N-oxide compound in the solution; 103mg, 0.1 equivalent).Mixture stirring at room 18 hours, is used Na subsequently 2S 2O 4Dichloromethane extraction is used in aqueous solution cancellation, with dried over mgso and filtration.Remove the solvent in the filtrate, and by quick silica gel column chromatography (eluent: DCM: MeOH=10: 1) purifying residue, thereby obtain the gray solid of above-mentioned title compound (96mg, 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-iodo-phenyl amino)-1,5-dimethyl-6-oxo -1,6-dihydropyridine-3-yl) cyclopropane-1-sulphonamide
Figure B200910146822XD0000661
At room temperature; to containing 1-(2; the 3-dihydroxypropyl) cyclopropane alkylsulfonyl (2-(2-fluoro-4-iodo-phenyl amino)-1; 5-dimethyl-6-oxo-1; 6-dihydropyridine-3-yl) (43mg adds trifluoroacetic acid (0.5mL) and stirred 1 hour t-butyl carbamate in 1mL dichloromethane solution 0.066mmol).Use saturated Na 2CO 3Solution cancellation reaction was also stirred 0.5 hour.After using methylene dichloride (3 *) extraction, add sodium-chlor, and use methylene dichloride (3 *) extraction to water.Use MgSO 4The dry organic layer that merges, and filter.The solvent in the filtrate is removed in decompression, and by quick silica gel column chromatography (eluent: DCM: MeOH=10: 1) purifying residue, thereby the acquisition above-mentioned title compound of gray solid shape (24mg, 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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)--cyclopropane-1-sulphonamide
Steps A: (R)-1-(3-(benzyloxy)-2-hydroxypropyl)-cyclopropane-1-sulfonic acid isopropyl ester
Figure B200910146822XD0000672
At-78 ℃, 25 minutes (ethyl acetate/N 2Bathe) in, with the n-butyllithium (2.5M, 91mL, 228mmol) add to contain cyclopropane sulfonic acid isopropyl ester (30g, anhydrous THF (450mL) 183mmol) and HMPA (hexamethylphosphoramide, 50mL) in and stirred 30 minutes.Subsequently at-40 ℃ of (acetonitrile/N 2Bathe) the stirring dark solution, interpolation (R)-2-(benzyloxymethyl) oxyethane (25g, THF 152mmol) (50mL), and-40 ℃ of stirrings 3 hours.Use the shrend reaction of going out, with ethyl acetate (2 *) extraction, with saturated NaCl solution cleaning, by MgSO 4Dry also filtration.Removal of solvent under reduced pressure is by purification by silica gel column chromatography residue (eluent: sherwood oil: ethyl acetate=5: 1 to 2: 1), thereby obtain the above-mentioned title compound of brown oily (37.9g, 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-)-cyclopropane-1-sulfonic acid isopropyl ester
Figure B200910146822XD0000673
At 0 ℃, (1.38g 4.2mmol) adds to and contains NaH (60%wt, 210mg in DMF mixture 5.25mmol), and stirred 30 minutes with (R)-1-(3-(benzyloxy)-2-hydroxypropyl)-cyclopropane-1-sulfonic acid isopropyl ester.At 0 ℃, (0.75mL 6.3mmol), and at room temperature stirs and spends the night (13 hours), uses shrend to go out subsequently, uses ethyl acetate extraction, cleans with water (2 *) and saturated brine, by Mg to add bromobenzyl in reaction mixture 2SO 4Dry also filtration.Removal of solvent under reduced pressure is by purification by silica gel column chromatography residue (eluent: sherwood oil: ethyl acetate=10: 1 to 5: 1), thereby obtain the above-mentioned title compound (1.145g, 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-) cyclopropane-1-potassium sulfonate
Figure B200910146822XD0000681
With (R)-1-(2,3-two (benzyloxy) propyl group) cyclopropane-1-sulfonic acid isopropyl ester (450mg, 1.075mmol) and potassium sulfocyanate (115mg 1.183mmol) is dissolved in the solution (10mL, 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-(two (benzyloxy) propyl group of 23-) cyclopropane-1-SULPHURYL CHLORIDE
Figure B200910146822XD0000682
(R)-1-(2, two (benzyloxy) propyl group of 3-)-cyclopropane-1-potassium sulfonate is dissolved in sulfur dichloride (7mL) and DMF (1mL).With reaction mixture reflux 1 hour, subsequently with the mixture reduction vaporization.By silica gel column chromatography gradient elution (eluent: ethyl acetate: purifying xanchromatic residue sherwood oil=1: 5), thereby the above-mentioned title compound of acquisition yellow oily (250mg, 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-iodo-phenyl amino)-1,5-diformazan Base-6-oxo-1,6-dihydropyridine-3-yl)-cyclopropane-1-sulphonamide
Figure B200910146822XD0000691
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 (benzyloxy) propyl group) cyclopropane-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-iodo-phenyl amino)-1,5-diformazan Base-6- Oxo-1,6-dihydropyridine-3-yl) cyclopropane-1-sulphonamide
Figure B200910146822XD0000692
At 0 ℃, with the boron trichloride (dichloromethane solution that contains the 1M boron trichloride, 0.8mL) add to and contain (R)-1-(2, two (benzyloxy) propyl group of 3-)-N-(2-(2-fluoro-4-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-(61mg is in 8mL methylene dichloride 0.083mmol) for cyclopropane-1-sulphonamide.After 10 minutes, add 1N HCl in stirring at room, and use the dichloromethane extraction mixture.Use saturated NaHCO 3Solution, saturated NaCl solution clean organic phase, and use MgSO 4Dry.Filter, remove the solvent in the filtrate and pass 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 (41mg, 90%). 1HNMR(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+2drops?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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-cyclopropane-1-sulphonamide
Steps A: (S)-1-(3-(benzyloxy)-2-hydroxypropyl)-cyclopropane-1-sulfonic acid isopropyl ester
Figure B200910146822XD0000701
Steps A according to method in the foregoing description 28 obtains above-mentioned title compound. 1HNMR(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-)-cyclopropane-1-sulfonic acid isopropyl ester
Figure B200910146822XD0000711
Step B according to method in the foregoing description 28 obtains above-mentioned title compound. 1HNMR(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-)-cyclopropane-1-potassium sulfonate
Figure B200910146822XD0000712
Step C according to method in the foregoing description 28 obtains above-mentioned title compound.
Step D: (S)-1-(2, two (benzyloxy) propyl group of 3-)-cyclopropane-1-SULPHURYL CHLORIDE
Figure B200910146822XD0000713
Step D according to method in the foregoing description 28 obtains above-mentioned title compound. 1HNMR(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-iodo-phenyl amino)-1,5-diformazan Base-6-oxo-1,6-dihydropyridine-3-yl)-cyclopropane-1-sulphonamide
Figure B200910146822XD0000721
Step e according to method in the foregoing description 28 obtains above-mentioned title compound. 1HNMR(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-iodo-phenyl amino)-1,5-dimethyl-6-oxygen Generation-1,6-dihydropyridine-3-yl)-cyclopropane-1-sulphonamide
Figure B200910146822XD0000722
Step F according to method in the foregoing description 28 obtains above-mentioned title compound. 1HNMR(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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-1-(3-hydroxypropyl) cyclopropane-1-sulphonamide
Figure B200910146822XD0000731
Under nitrogen atmosphere, stir 1-allyl group cyclopropane alkylsulfonyl (2-(2-fluoro-4-iodo-phenyl amino)-1 in three mouthfuls of round-bottomed flasks; 5-dimethyl-6-oxo-1; 6-dihydropyridine-3-yl) the carboxylamine tertiary butyl ester (100mg, 0.162mmol) and the mixture of THF (2ml).Use syringe with BH 3(1ml 1mmol) slowly joins in the reaction flask-THF.At room temperature stirring reaction is 48 hours, carries out refrigerative simultaneously with ice bath, and in reaction flask, add the NaOH aqueous solution (3M, 1ml) and 30%H 2O 2The aqueous solution (3ml).After interpolation is finished, 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 filtrate.By silica gel column chromatography (eluent: ethyl acetate) purifying residue, thereby obtain above-mentioned title product 1-OH (66mg, 64%) and by product 2-OH (27mg, 26%).With the 1-OH product (60mg 0.094mmol) is dissolved in the 2ml methylene dichloride, and slowly add excessive TFA (trifluoroacetic acid, 0.5ml).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 (44mg, 87%) by silica gel column chromatography. 1HNMR(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-iodo-phenyl amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-1-(2-hydroxypropyl)-cyclopropane-1-sulphonamide
Figure B200910146822XD0000741
Obtain the purpose product according to the method identical with embodiment 31. 1H?NMR(400MHz，DMSO)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-iodo-phenyl amino)-4-methoxyl group-1-methyl-6-oxo-1,6-dihydropyridine-3-yl) butane-1-sulphonamide
Steps A: 2-chloro-4-nitropyridine 1-oxide compound
Figure B200910146822XD0000742
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 the aqueous solution (250mL) of V-Brite B (45g), and reaction mixture was stirred 15 minutes.Add hydrochloric acid (0.5N, 400mL) and use methylene dichloride (400mL) extraction mixture.Use sodium hydrogen carbonate solution to clean organic phase, by dried over mgso, filter, the solvent in the filtrate 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 B200910146822XD0000751
To be dissolved in anhydrous MeOH (1000ml) and the quick impouring of the sodium methoxide solution that makes contains in MeOH (1000ml) stirred solution of 2-chloro-4-nitropyridine-1-oxide compound (151g) by sodium (21g).In 5 minutes, finish dissolving, and stirring reaction spends the night in the flask of jumping a queue.Yellow solution is concentrated a part, have throw out to produce, this throw out is leached, and (2 * 100mL) clean with MeOH.Filtrate and washing lotion are evaporated to dried,, thereby obtain (filtering and concentrate the back) pale brown look solid with the remaining solid of dichloromethane extraction that boils, but its 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 B200910146822XD0000752
At 0 ℃, in methylene dichloride (1000ml) mixture that contains 2-chloro-4-methoxypyridine 1-oxide compound (130g) and triethylamine (151ml), add methylene dichloride (250ml) solution of phosphoryl chloride (151g).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.Use Na 2SO 4The dry organic layer that merges filters, and concentrated filtrate in the vacuum obtains crude product, by 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 B200910146822XD0000761
At 0 ℃,, add concentrated nitric acid (95%) in the concentrated sulfuric acid solution of 6-two chloro-4-methoxypyridines (40g) 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 Na 2SO 4Drying is filtered, concentrating under reduced pressure filtrate, 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 NaH (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, will react cooling 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-iodo-phenyl amino)-4-methoxyl group-5-nitropyridine-2 (1H)-ketone
Figure B200910146822XD0000763
In the KOH aqueous solution (the 52ml water that contains 14.4gKOH), successively add compound 6-chloro-N-(2-fluoro-4-iodophenyl)-4-methoxyl group-3-nitropyridine-2-amine (2g) and MeOH (150ml).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 that filtrate is transferred to pH 7, thereby obtain yellow mercury oxide, this yellow mercury oxide is filtered and drying, thereby obtain the above-mentioned title compound of 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-iodo-phenyl amino)-4-methoxyl group-1-methyl-5-nitro pyridine-2 (1H)-ketone
Figure B200910146822XD0000771
At room temperature, in dry DMF (0.2mol/L) solution of NaH (2.5 equivalent), add 6-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-5-nitropyridine-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 NH then 4Cl solution.Use the ethyl acetate extraction mixture, water and salt solution clean.Use MgSO 4Dry organic layer filters, and concentrated filtrate in the vacuum obtains crude product, and by 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)。
The amino 6-(2-fluoro-4-iodo-phenyl amino) of step H:5--4-methoxyl group-1-picoline-2 (1H)-ketone
Figure B200910146822XD0000772
With 6-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-1-methyl-5-nitro pyridine-2 (1H)-ketone (220mg) and Na 2S 2O 4(1.96g, 16 equivalents) are dissolved in dioxane and water (30mL, 1: 1), at room temperature add NH subsequently 4OH (1mL).After 1 hour, use 100mL ethyl acetate diluted mixture thing, water and salt solution clean.With ethyl acetate (2 *) aqueous layer extracted, clean with salt solution, with Na 2SO 4Drying is filtered, concentrated filtrate in the vacuum, thus obtain crude product, by 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-iodo-phenyl amino)-4-methoxyl group-1-methyl-6-oxo-1,6-dihydro Pyridine -3-yl) butane-1-sulphonamide
Figure B200910146822XD0000781
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl 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-iodo-phenyl amino)-4-methoxyl group-1-methyl-6-oxo-1,6-dihydropyridine-3-yl) benzsulfamide
Figure B200910146822XD0000782
According to method A, make the reaction of 5-amino-6-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and benzene sulfonyl chloride, 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-iodo-phenyl amino)-4-methoxyl group-1-methyl-6-oxo-1,6-dihydropyridine-3-yl) hexanaphthene sulphonamide
Figure B200910146822XD0000791
According to method A, make the reaction of 5-amino-6-(2-fluoro-4-iodo-phenyl amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 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-iodo-phenyl amino)-4-methoxyl group-1-methyl-6-oxo-1,6-dihydropyridine-3-yl) cyclopropane sulphonamide
Figure B200910146822XD0000792
According to method A, make the reaction of 5-amino-6-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and cyclopropane SULPHURYL CHLORIDE, thereby obtain required 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-iodo-phenyl amino)-4-methoxyl group-1-methyl-6-oxo-1,6-dihydropyridine-3-yl) thiophene-3-sulphonamide
Figure B200910146822XD0000801
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and thiophene-3-SULPHURYL CHLORIDE reaction, thereby 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-iodo-phenyl amino)-4-methoxyl group-1-methyl-6-oxo-1,6-dihydropyridine-3-yl) propane-1-sulphonamide
Figure B200910146822XD0000802
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 3-chloropropane-1-SULPHURYL CHLORIDE reaction, thereby obtain 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-iodo-phenyl amino)-4-methoxyl group-1-methyl-6-oxo-1,6-dihydropyridine-3-yl) propane-2-sulphonamide
Figure B200910146822XD0000811
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and propane-2-SULPHURYL CHLORIDE reaction, thereby obtain the purpose compound.Productive rate=50%. 1HNMR(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-iodo-phenyl amino)-4-methoxyl group-1-methyl-6-oxo-1,6-dihydropyridine-3-yl) thiophene-2-sulphonamide
Figure B200910146822XD0000812
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and thiophene-2-SULPHURYL CHLORIDE reaction, thereby 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-iodo-phenyl amino)-4-methoxyl group-1-methyl-6-oxo-1,6-dihydropyridine-3-yl) Toluidrin
Figure B200910146822XD0000821
According to method A, make the reaction of 5-amino-6-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and methyl chloride SULPHURYL CHLORIDE, thereby 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-iodo-phenyl amino)-4-methoxyl group-1-methyl-6-oxo-1,6-dihydropyridine-3-yl) benzsulfamide
Figure B200910146822XD0000822
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 4-fluoro-benzene-1-SULPHURYL CHLORIDE reaction, thereby 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-iodo-phenyl amino)-4-methoxyl group-1-methyl-6-oxo-1,6-dihydropyridine-3-yl) Toluidrin
According to method A, make the reaction of 5-amino-6-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and methylsulfonyl chloride, thereby 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-iodo-phenyl amino)-4-methoxyl group-1-methyl-6-oxo-1,6-dihydropyridine-3-yl) ethyl sulfonamide
Figure B200910146822XD0000832
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl 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-iodo-phenyl amino)-4-methoxyl group-1-methyl-6-oxo-1,6-dihydropyridine-3-yl)-2-phenyl-cyclopropane-1-sulphonamide
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-phenyl-cyclopropane-1-SULPHURYL CHLORIDE reaction, thereby 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 amino)-4-methoxyl group-1-methyl-6-oxo-1,6-dihydropyridine-3-yl) cyclopropane-1-sulphonamide
Figure B200910146822XD0000842
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-(4-ethoxyl phenenyl)-cyclopropane-1-SULPHURYL CHLORIDE reaction, thereby 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-iodo-phenyl amino)-4-methoxyl group-1-methyl-6-oxo-1,6-dihydropyridine-3-yl) cyclopropane-1-sulphonamide
Figure B200910146822XD0000851
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-(3, the 4-difluorophenyl)-cyclopropane-1-SULPHURYL CHLORIDE reaction, thereby 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-iodo-phenyl amino)-4-methoxyl group-1-methyl-6-oxo-1,6-dihydropyridine-3-yl)-2-sec.-propyl-cyclopropane-1-sulphonamide
Figure B200910146822XD0000852
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-sec.-propyl-cyclopropane-1-SULPHURYL CHLORIDE reaction, thereby obtain the purpose compound.Productive rate=40%. 1H?NMR(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 amino)-4-methoxyl group-1-methyl-6-oxo-1,6-dihydropyridine-3-yl)-2-isobutyl--cyclopropane-1-sulphonamide
Figure B200910146822XD0000861
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-isobutyl--cyclopropane-1-SULPHURYL CHLORIDE reaction, thereby obtain the purpose compound.Productive rate=35.4%. 1H?NMR(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-iodo-phenyl amino)-4-methoxyl group-1-methyl-6-oxo-1,6-dihydropyridine-3-yl)-2-(thiophene-2-yl)-cyclopropane-1-sulphonamide
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-(thiophene-2-yl)-cyclopropane-1-SULPHURYL CHLORIDE reaction, thereby obtain the purpose compound.Productive rate=6.76%. 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 amino)-4-methoxyl group-1-methyl-6-oxo-1,6-dihydropyridine-3-yl) cyclopropane-1-sulphonamide
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-(2,4 difluorobenzene base)-cyclopropane-1-SULPHURYL CHLORIDE reaction, thereby 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-iodo-phenyl amino)-4-methoxyl group-1-methyl-6-oxo-1,6-dihydropyridine-3-yl) cyclopropane-1-sulphonamide
Figure B200910146822XD0000881
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-(3, the 5-difluorophenyl)-cyclopropane-1-SULPHURYL CHLORIDE reaction, thereby 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-cyano-phenyl)-N-(2-(2-fluoro-4-iodo-phenyl amino)-4-methoxyl group-1-methyl-6-oxo-1,6-dihydropyridine-3-yl) cyclopropane-1-sulphonamide
Figure B200910146822XD0000882
According to method A, make 5-amino-6-(2-fluoro-4-iodophenyl amino)-4-methoxyl group-1-picoline-2 (1H)-ketone and 2-(4-cyano-phenyl)-cyclopropane-1-SULPHURYL CHLORIDE reaction, thereby 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]。
Biological activity test
Material and reagent:
Kinase Glo Plus test kit is available from Promega.Substrate, APT, DTT and dimethyl sulfoxide (DMSO) are available from Sigma-Aldrich.
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﹠amp; 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 DMSO mother liquor that will contain compound is diluted to 1 * buffer reagent (20mM MOPS (PH7.4), 5mM MgCl 2, 0.5mM MnCl 2, 100uM sodium orthovanadate, 0.01%Triton X-100,1mM DTT) in.Common reaction reagent comprises 0.01nmol MEK1 kinases, 0.01nmol ATP and 10ng substrate.Shaker test mainly comprises four steps.The diluted compounds branch of 2ul is added in the 384 holes test blank.Subsequently, in each hole, add 6ul kinases-substrate mixture.Subsequently, in each hole, add 2ul 5x ATP to start reaction.Plate is sealed, and it was hatched 60 minutes 22 ℃ of following lucifuges.At last, in each hole, add 10ulKinase Glo Plus reagent with stopped reaction.At room temperature the lucifuge incubation is 10 minutes.Remove the closedtop on the plate, use the standard light-emitting procedure that plate is carried out reading by 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 by the Prism program 50
Kinases is in conjunction with active mensuration
The DMSO mother liquor that will contain compound is diluted to buffer reagent (20mM MOPS (PH7.4), 5mM MgCl 2, 0.5mM MnCl 2, 100uM sodium orthovanadate, 0.01%Triton X-100,1mM DTT) in.Common reaction reagent comprises 3 * 10 -4Nmol MEK1 kinases, 3 * 10 -5Nmol europium labeling antibody, 1.5 * 10 -3Nmol tracer agent 236.Shaker test 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 1 * buffer A.The 5ul 3x tracer agent 236 that adds in each hole again by the dilution of 1 * buffer A 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 by EnVision 2104 multiple labeling plate readers (PerkinElmer).Quantitative to fluorescence signal intensity, and use these data to produce dose response curve, and calculate IC50 by the Prism program.
IC based on cell 50Data
By 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, use 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 described plate was hatched 2 hours 25 ℃ of following lucifuges.Remove closedtop, use the AlphaScreen program of optimizing that plate is carried out reading by EnVision 2104 multiple labeling plate readers (PerkinElmer).The intensity of quantitative signal, and use this data to produce dose response curve, and calculate IC by the Prism program 50
The biological data of selected compounds
According to biological method as herein described the selected compounds of above-mentioned preparation is tested.It the results are shown in following table:
Figure B200910146822XD0000911
Figure B200910146822XD0000921
Figure B200910146822XD0000931
Figure B200910146822XD0000941
Figure B200910146822XD0000951
Figure B200910146822XD0000961
Figure B200910146822XD0000971
Figure B200910146822XD0000981
Figure B200910146822XD0000991
Figure B200910146822XD0001001

Claims (13)

1. the compound of representing by formula I, or it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug,
Formula I
Wherein
R 0Be H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 2-C 6Thiazolinyl, C 5-C 6Cycloalkenyl group or C 2-C 6Alkynyl; Wherein said alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group or alkynyl group are optional to be replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyano group, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed, and described C 3-C 6In the cycloalkyl one or two becomes ring carbon atom by optional O, N or the S of replacing with independently;
R 1Be H, C 1-C 4Alkoxyl group, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 2-C 6Thiazolinyl, C 5-C 6Cycloalkenyl group or C 2-C 6Alkynyl; Wherein said alkoxyl group, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group or alkynyl group are randomly replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyano group, 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, wherein, described heterocyclic radical contains 1-5 heteroatoms, described heteroatoms is independently selected from the group of being made up of O, N and S, and described heterocyclic radical is optional to be replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyano group, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed; Or
R 1For-CH 2X, the wherein group of X expression II:
Figure F200910146822XC0000021
Formula II
Wherein
Y 1And Y 2Can be identical or different, represent separately singly-bound ,-CO-,-COO ,-O-,-OCO-,-NR aOr-SO 2-;
Y 3The C that expression can be replaced by the group that 1-3 is represented by Z 1-5Alkyl;
Z can be identical or different, and the expression C that can randomly be replaced by 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, monocyclic heterocycles group or the heterocyclic radical of dicyclo or the heteroaryl of monocycle or dicyclo, described substituting group is selected from by C 1-5Alkyl group ,-OR aAnd NR aR bThe group of forming; Described 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 cycloalkyl or heterocyclic radical, and described cycloalkyl or heterocyclic radical can have one or more substituting groups, and described substituting group is selected from by-OR a, NR aR bWith can be by-OR aThe C that replaces 1-5The group that alkyl is formed;
R aAnd R bCan be identical or different, represent hydrogen atom or the C that can be replaced by 1-3 substituting group separately 1-5Alkyl group, described 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;
When X=C, R 2Be H, C 1-C 4Alkoxyl group, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 2-C 6Thiazolinyl, C 5-C 6Cycloalkenyl group or C 2-C 6Alkynyl; Wherein said alkoxyl group, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group or alkynyl are optional to be replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyano group, 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, described heterocyclic radical has 1-5 heteroatoms, described heteroatoms is selected from the group of O, N and S composition, wherein said heterocyclic radical is optional to be replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4The group that alkoxyl group, cyano group, cyanogen methyl, trifluoromethyl, difluoro-methoxy and phenyl are formed; Or
When X=N, R 2Do not exist; With
R 3Be selected from by trifluoromethyl, C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, C 3-C 10Cycloalkyl, C 3-C 10The group that cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical and heterocyclic radical alkyl are formed, wherein each alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical be not for being substituted or being replaced by 1-3 substituting group, and described substituting group is independently selected from halogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, cyano group, trifluoromethyl, difluoro-methoxy, phenyl or have 1-3 substituent substituted-phenyl, the substituting group of described substituted-phenyl is independently selected from hydrogen, hydroxyl, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, cyano group, trifluoromethyl or difluoro-methoxy;
R 4, R 5, R 6, R 7And R 8Be independently selected from hydrogen, halogen, cyano group, 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 10Cycloalkyl, 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 1-5 fluorine atom;
R 9Be selected from by hydrogen, trifluoromethyl, C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, C 3-C 10Cycloalkyl, C 3-C 10The group that cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical and heterocyclic radical alkyl are formed, wherein each alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical be not for replacing or being replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming;
R 10Be 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, described substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming; Perhaps
R 9And R 10Can form the hetero-aromatic ring or the heterocycle of 4-10 unit with coupled atom together, wherein said each ring is not by being substituted or being replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, C 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, described substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming; Perhaps
R 10, R 11Form carbocyclic ring, hetero-aromatic ring or the heterocycle of 4-10 unit together with coupled atom, each ring is replaced for replacement or by 1-3 substituting group, and described 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 cycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical and heterocyclic radical alkyl are formed, wherein each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical be not by replacing or being replaced by 1-3 substituting group, and described substituting group is independently selected from by halogen, C 1-C 4Alkyl, hydroxyl and the amino group of forming;
M be 0,1,2,3,4 or 5 and
J is 1 or 2; And X is C or N.
2. compound as claimed in claim 1, or it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug, wherein
R 0Be H or C 1-C 6Alkyl; R 1Be H or C 1-C 6Alkyl; R 2Do not exist or R 2Be H or C 1-C 6Alkoxyl group; R 3Be selected from the group of forming by following group: optional by the C of one or more halogens or hydroxyl replacement 1-C 6Alkyl; Randomly by the C of one or more halogens or hydroxyl replacement 2-C 6Thiazolinyl; Optional by C 1-C 6Alkyl or C 2-C 6The C of alkenyl substituted 3-C 6Cycloalkyl; Heteroatoms is monocycle or the bicyclic heteroaryl of one or more O, N or S; Monocycle or the bicyclic aryl that is replaced by one or more substituting groups randomly, wherein said substituting group is selected from by halogen, cyano group, C 1-C 6The group that alkoxyl group and hydroxyl are formed; Cycloalkyl aryl, wherein aryl is monocycle or bicyclic aryl, cycloalkyl is the group with 1-6 carbon atom; And C 1-C 6Alkyl C 1-C 6Cycloalkyl; With
R 4, R 5, R 6, R 7And R 8Be independently selected from and be H or halogen.
3. compound as claimed in claim 1 or 2, or it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug, and it has the structure of following formula
Figure F200910146822XC0000041
Wherein
R 0Be H or C 1-C 6Alkyl; R 1Be H or C 1-C 6Alkyl; R 2Do not exist or R 2Be H or C 1-C 6Alkoxyl group; R 3Be selected from the group of forming by following group: optional by the C of one or more halogens or hydroxyl replacement 1-C 6Alkyl; Randomly by the C of one or more halogens or hydroxyl replacement 2-C 6Thiazolinyl; Optional by C 1-C 6Alkyl or C 2-C 6The C of alkenyl substituted 3-C 6Cycloalkyl; Heteroatoms is monocycle or the bicyclic heteroaryl of one or more O, N or S; Monocycle or the bicyclic aryl that is replaced by one or more substituting groups randomly, wherein said substituting group is selected from by halogen, cyano group, C 1-C 6The group that alkoxyl group and hydroxyl are formed; Cycloalkyl aryl, wherein aryl is monocycle or bicyclic aryl, cycloalkyl is the group with 1-6 carbon atom; And C 1-C 6Alkyl C 1-C 6Cycloalkyl; With
R 4, R 5, R 6, R 7And R 8Be independently selected from and be H or halogen.
R 13Be selected from by H, C 2-C 6Thiazolinyl and C 1-C 6The group that alkyl is formed, wherein said group can randomly be replaced by one or more substituting groups, and described substituting group is selected from by halogen or hydroxyl; With
R 14Be selected from by H, C 1-C 6Alkyl, monocycle or bicyclic aryl and heteroatoms are the monocycle of one or more O, N or S or the group that bicyclic heteroaryl is formed, and wherein said group is randomly replaced by one or more substituting groups, and described substituting group is selected from by halogen, cyano group and C 1-C 6The group that alkoxyl group is formed.
4. compound as claimed in claim 3, or it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug, and it has the structure of following formula
Figure F200910146822XC0000051
Wherein,
R 1, R 2, R 13And R 14Definition as claimed in claim 3.
5. compound as claimed in claim 4, or it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug, and it has the structure of following formula
Wherein
R 13And R 14Definition as claimed in claim 4.
6. compound as claimed in claim 5, or it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug, and it is selected from following compound:
Figure F200910146822XC0000061
7. compound as claimed in claim 4, or it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug, and it has the structure of following formula
Figure F200910146822XC0000062
Wherein
R 13And R 14Definition as claimed in claim 4.
8. compound as claimed in claim 7, or it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug, and it is selected from following compound:
Figure F200910146822XC0000071
9. pharmaceutical composition, it comprises compound any among the claim 1-8 or it is at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug and pharmaceutically acceptable carrier.
10. any one compound or its are used for suppressing the application of the pharmaceutical composition of MEK enzyme among the claim 1-8 in preparation at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug.
11. any one compound or its are used for the treatment of or prevent application in the pharmaceutical composition of the disease of MEK mediation or illness in preparation at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug among the claim 1-8.
12. any one compound or its are used for the treatment of or prevent application in the pharmaceutical composition of proliferative disease in preparation at pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug among the claim 1-8.
13. purposes as claimed in claim 12, wherein said proliferative disease is selected from diseases associated with inflammation or cancer.
CN200910146822XA 2009-06-15 2009-06-15 6-aryl amino pyridone sulfamide and 6-aryl amino pymetrozine sulfamide methyl ethyl ketone (MEK) inihibitor Pending CN102134218A (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CN200910146822XA CN102134218A (en) 2009-06-15 2009-06-15 6-aryl amino pyridone sulfamide and 6-aryl amino pymetrozine sulfamide methyl ethyl ketone (MEK) inihibitor
JP2012515317A JP2012530079A (en) 2009-06-15 2010-06-13 Novel 6-arylaminopyridonesulfonamides and 6-arylaminopyridonesulfonamides as MEK inhibitors
PCT/CN2010/000851 WO2010145197A1 (en) 2009-06-15 2010-06-13 Novel 6-arylamino pyridone sulfonamides and 6-arylamino pyrazinone sulfonamdies as mek inhibitors
KR1020127001106A KR20120034736A (en) 2009-06-15 2010-06-13 Novel 6-arylamino pyridone sulfonamides and 6-arylamino pyrazinone sulfonamdies as mek inhibitors

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN200910146822XA CN102134218A (en) 2009-06-15 2009-06-15 6-aryl amino pyridone sulfamide and 6-aryl amino pymetrozine sulfamide methyl ethyl ketone (MEK) inihibitor

Publications (1)

Publication Number Publication Date
CN102134218A true CN102134218A (en) 2011-07-27

Family

ID=43355726

Family Applications (1)

Application Number Title Priority Date Filing Date
CN200910146822XA Pending CN102134218A (en) 2009-06-15 2009-06-15 6-aryl amino pyridone sulfamide and 6-aryl amino pymetrozine sulfamide methyl ethyl ketone (MEK) inihibitor

Country Status (4)

Country Link
JP (1) JP2012530079A (en)
KR (1) KR20120034736A (en)
CN (1) CN102134218A (en)
WO (1) WO2010145197A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104011039A (en) * 2011-12-19 2014-08-27 住友化学株式会社 Method for producing sulfonate
WO2015058589A1 (en) * 2013-10-25 2015-04-30 上海恒瑞医药有限公司 Pyridic ketone derivatives, method of preparing same, and pharmaceutical application thereof

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5844727B2 (en) * 2009-03-27 2016-01-20 アルデア バイオサイエンシズ，インコーポレイティド Dihydropyridinesulfonamide and dihydropyridinesulfamide as MEK inhibitors
BR112012008599A2 (en) 2009-10-13 2019-09-24 Allostem Therapeutics Llc compound of formula (i), compound of formula (ia), compound of formula (ic), compound of formula (ii), compound of formula (iia), compound, method for treating a hyperproliferative disorder in a mammal, which includes a human, method for treating a inflammatory disease, condition, or disorder in a mammal, which includes a human, method for treating a disorder or condition that is modulated by the meik cascade in a mammal, which includes a hyman, method for treating or prevent cancer, pharmaceutical composition and method to inhibit a mek enzyme
AU2012265844A1 (en) * 2009-12-08 2013-05-02 Novartis Ag Heterocyclic sulfonamide derivatives
CN102020651B (en) * 2010-11-02 2012-07-18 北京赛林泰医药技术有限公司 6-aryl amino pyridone formamide MEK (methyl ethyl ketone) inhibitor
AU2012264884B2 (en) * 2011-05-27 2017-03-09 Bayer Intellectual Property Gmbh Chiral synthesis of N-{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl}-1-[2,3-dihydroxy-propyl]cyclopropanesulfonamides
CN103748085A (en) 2011-06-09 2014-04-23 诺华股份有限公司 Heterocyclic sulfonamide derivatives
PT2855434T (en) * 2012-05-30 2016-10-04 Merck Patent Gmbh Solid state forms of n-((s)-2,3-dihydroxy-propyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide
CN109320513B (en) * 2018-11-09 2021-03-16 安庆奇创药业有限公司 Method for synthesizing trametinib
WO2020188015A1 (en) 2019-03-21 2020-09-24 Onxeo A dbait molecule in combination with kinase inhibitor for the treatment of cancer
AU2020378630A1 (en) 2019-11-08 2022-05-26 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of cancers that have acquired resistance to kinase inhibitors
WO2021148581A1 (en) 2020-01-22 2021-07-29 Onxeo Novel dbait molecule and its use

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2354182T3 (en) * 2006-04-18 2011-03-10 Ardea Biosciences, Inc. PIRIDONA SULFONAMIDS AND PIRIDONA SULFAMIDS AS MEK INHIBITORS.
WO2008024725A1 (en) * 2006-08-21 2008-02-28 Genentech, Inc. Aza-benzofuranyl compounds and methods of use

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104011039A (en) * 2011-12-19 2014-08-27 住友化学株式会社 Method for producing sulfonate
WO2015058589A1 (en) * 2013-10-25 2015-04-30 上海恒瑞医药有限公司 Pyridic ketone derivatives, method of preparing same, and pharmaceutical application thereof
CN104936945A (en) * 2013-10-25 2015-09-23 上海恒瑞医药有限公司 Pyridic ketone derivatives, method of preparing same, and pharmaceutical application thereof
CN104936945B (en) * 2013-10-25 2017-11-03 上海恒瑞医药有限公司 Pyridinone derivatives, its preparation method and its in application pharmaceutically
US9914703B2 (en) 2013-10-25 2018-03-13 Shanghai Hengrui Pharmaceutical Co., Ltd. Pyridic ketone derivatives, method of preparing same, and pharmaceutical application thereof
US10064848B2 (en) 2013-10-25 2018-09-04 Shanghai Hengrui Pharmaceutical Co., Ltd. Pyridic ketone derivatives, method of preparing same, and pharmaceutical application thereof

Also Published As

Publication number Publication date
WO2010145197A8 (en) 2011-03-03
KR20120034736A (en) 2012-04-12
JP2012530079A (en) 2012-11-29
WO2010145197A1 (en) 2010-12-23

Similar Documents

Publication Publication Date Title
CN102134218A (en) 6-aryl amino pyridone sulfamide and 6-aryl amino pymetrozine sulfamide methyl ethyl ketone (MEK) inihibitor
CN102020651B (en) 6-aryl amino pyridone formamide MEK (methyl ethyl ketone) inhibitor
CN104837825B (en) Shandong tyrosine kinase inhibitor
CN102093364B (en) 2,4-diamido-6,7-dihydro-5H-pyrrolo [2,3] pyrimidine derivative as focal adhesion kinase/pyruvate kinase 2 (FAK/Pyk2) inhibitor
TWI632134B (en) Heterocyclic compounds and uses thereof
ES2879645T3 (en) PDE1 inhibitor
CN102459187B (en) Janus kinase inhibitor compounds and methods
CN103974954B (en) Regulate kinase whose compound, containing combinations thereof thing and application thereof
CN103476776B (en) 2,4-diaminourea-6,7-dihydro-5H-pyrrolo-[2,3] pyrimidine derivatives as FAK/Pyk2 inhibitor
CN105189514A (en) Pyrrolo- and pyrazolo-triazolodiazepines as bet-protein inhibitors for treating hyperproliferative diseases
CN103304572A (en) 3-cyanoquinoline compound as well as pharmaceutical composition and application thereof
CN105906631A (en) Compounds and methods for kinase modulation, and indications therefor
CN103261167A (en) Substituted 6,6-used nitrogenous heterocyclic compounds and uses thereof
CN103261198A (en) 2-arylimidazo[1,2-]pyridazine, 2-phenylimidazo[1,2-a]pyridine, and 2-phenylimidazo[1,2-a]pyrazine derivatives
CN105555786A (en) Substituted dihydropyrido[3,4-b]pyrazinones as dual inhibitors of bet proteins and polo-like kinases
CN105085474A (en) Bruton tyrosine kinase inhibitor
KR20140072037A (en) Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
CN102947272A (en) 2 -aminopyridine derivatives useful as inhibitors of atr kinase
CN104220070A (en) Heterocyclic inhibitors of glutaminase
CN104302647A (en) Novel pyridopyrimidine derivatives and use thereof
JP2010524962A (en) Drug discovery for aurora kinase inhibitors
CN104379597A (en) Methods for improving diaphragm function
CN103102349B (en) Kinases inhibitor and combinations thereof and purposes
CN103596952A (en) Substituted pyridopyrazines as novel Syk inhibitors
CN101821279A (en) Some chemical entity, composition and method

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20110727