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

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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
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校登明
王世新
祝力
梁志
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KAIMEILONG (BEIJING) PHARMACEUTICAL TECHNOLOGY Co Ltd
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Priority to JP2012515317A priority patent/JP2012530079A/en
Priority to KR1020127001106A priority patent/KR20120034736A/en
Priority to PCT/CN2010/000851 priority patent/WO2010145197A1/en
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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-arylaminopyridinone sulfonamide and 6-arylaminopyrazinone sulfonamide MEK inhibitors
Technical Field
The present invention relates to a series of substituted 6-arylaminopyridinone sulfonamides and 6-arylaminopyrazinone sulfonamides that are inhibitors of MEK and are useful in the treatment of inflammatory diseases, cancer and other hyperproliferative diseases. The invention also relates to pharmaceutical compositions comprising the compounds of the invention, to the use of the compounds of the invention in the manufacture of medicaments and to methods of using the compounds of the invention in the treatment of hyperproliferative diseases in mammals, particularly humans.
Background
Protein kinases constitute a family of structurally related enzymes that function by transferring phosphate groups from nucleoside triphosphates to Ser, Thr or Tyr residues of protein receptors. Protein-mediated reversible phosphorylation events of proteins regulate a variety of cellular functions, including DNA replication, cell cycle progression, energy metabolism, and cell growth and differentiation. In addition, the activity of protein kinases is associated with a variety of diseases including cancer. Among the more than 100 major oncogenes known to date, many encode receptor and cytoplasmic protein kinases known to be mutated and/or overexpressed in human cancers (Blume-Jensen and Hunter, Nature, 411: 355-365 (2001)). Thus, protein kinase targets have attracted most drug development attention in recent years, and several protein kinase inhibitors have gained regulatory approval (for review see Fischer, curr. Med. chem., 11: 1563 (2004); Dancey and Sausville, Nature Rev. drug Disc., 2: 296(2003))
The Ras/Raf/MEK/ERK pathway is the major signal transduction pathway that transmits signals from multiple cell surface receptors to transcription factors that regulate gene expression within the nucleus. This pathway is often referred to as the MAP kinase pathway, while MAPK stands for mitogen-activated protein kinase, suggesting that this pathway can be stimulated by mitogens, cytokines, and growth factors (Steelman et al, leukamia 2004, 18, 189218). The pathway may deliver a signal that results in the inhibition or induction of apoptosis or cell cycle progression depending on the stimulus and cell type. The Ras/Raf/MEK/ERK pathway has been found to play an important role in cell proliferation and apoptosis inhibition. Aberrant activation of this pathway is often observed in malignantly transformed cells. Amplification of the Ras proto-oncogene and activating mutations that result in the expression of constitutively active Ras proteins are observed in about 30% of human cancers. Mutated oncogenic forms of Ras are found in 50% of colorectal, more than 90% of pancreatic, and a variety of other cancers (Kohl et a1., Science 1993, 260, 1834-1837). The effects of Ras on proliferation and tumor formation have been demonstrated in immortalized cell lines (McCubrey et al, Int J Oncol 1995, 7, 295-. bRaf mutations have been identified in more than 60% of malignant melanomas (Davies, H et al, Nature2002, 417, 949-. Since high levels of Ras mutations have been detected, this pathway has been considered as an important target for intervention therapy (Chang et al, Leukemia 2003, 17, 1263-93).
Since constitutive activation or overactivation of the MAP kinase cascade has a key role in cell proliferation and differentiation, it is believed that inhibition of this pathway is beneficial for the treatment of hyperproliferative diseases. MEK is a key member of this pathway as it is located downstream of Ras and Raf. In addition, MEK is an attractive therapeutic target also because MAP kinases, ERK1 and ERK2 are the only known substrates for MEK phosphorylation. Numerous studies have now found that inhibition of MEK has potential therapeutic effects. For example, it has been found that small molecule MEK inhibitors inhibit the growth of human tumors in a mouse xenograft model (Seebolt-Leopold et al, Nature Medicine, 19995(7), 810-.
Compounds suitable as MEK inhibitors are also 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.
Disclosure of Invention
The present invention provides a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof:
Figure B200910146822XD0000021
formula I
Wherein
R0Is H, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C2-C6Alkenyl radical, C5-C6Cycloalkenyl or C2-C6An alkynyl group; wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl, and C3-C6One or two ring-forming carbon atoms of the cycloalkyl group are optionally independently replaced with O, N or S;
R1is H, C1-C4Alkoxy radical, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C2-C6Alkenyl radical, C5-C6Cycloalkenyl or C2-C6An alkynyl group; wherein said alkoxy, alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl; or, R1Is a five-or six-membered saturated heterocyclic group, unsaturated heterocyclic group or aromatic heterocyclic group, said heterocyclic group containing 1 to 5 heteroatoms independently selected from the group consisting of O, N and S, and said heterocyclic group being optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl; or
R1is-CH2X, wherein X represents formulaGroup II:
formula II
Wherein
Y1And Y2May be the same or different and each represents a single bond, -CO-, -COO, -O-, -OCO-, -NRaor-SO2-；
Y3Represents C which may be substituted by 1 to 3 groups represented by Z1-5An alkyl group;
z may be the same or different and represents C which may be optionally substituted by one or more substituents1-5Alkyl, halogen atom, oxo group, -ORa、-COORa、-COOCORa-CO-halogen atom, -OCORa、-CONRaRb、-SRa、-SO2Ra、-NRaRb、-NRaCORb、NRaSO2Rb、-SO2NRaRbA monocyclic or bicyclic heterocyclic group, or a monocyclic or bicyclic heteroaryl group, said substituents being selected from the group consisting of C1-5Alkyl, -ORaAnd NRaRbA group of (a); each alkyl group being optionally substituted by hydroxy, C1-5Alkoxy or amino substitution; in addition to the oxygen substituent and halogen, the above substituents may be linked to each other to form a cycloalkyl OR heterocyclic group, which may have one OR more substituents selected from the group consisting of-ORa、NRaRbAnd may be-ORaSubstituted C1-5Alkyl groups;
Raand RbMay be the same or different, each represents a hydrogen atom or C which may be substituted with 1 to 3 substituents1-5An alkyl group, the substituent being selected from the group consisting of hydroxy, C1-5Alkoxy and amino;
the symbol "●" used in formula II represents a linking site;
when X ═ C, R2Is H, C1-C4Alkoxy radical, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C2-C6Alkenyl radical, C5-C6Cycloalkenyl or C2-C6An alkynyl group; wherein said alkoxy, alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl; or, R2Is a five-or six-membered saturated heterocyclic group, unsaturated heterocyclic group or aromatic heterocyclic group, wherein the heterocyclic group has 1 to 5 heteroatoms selected from the group consisting of O, N and S, and the heterocyclic group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl; or
When X is N, R2Is absent; and
R3selected from trifluoromethyl, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, C3-C10Cycloalkyl radical, C3-C10Cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl groups, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl group is unsubstituted or substituted with 1-3 substituents independently selected from halogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, trifluoromethyl, difluoromethoxy, phenyl or substituted phenyl with 1-3 substituents independently selected from hydrogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, trifluoromethyl or difluoromethoxy;
R4、R5、R6、R7and R8Independently selected from hydrogen, halogen, cyano, nitro, trifluoromethyl, SR9、OR9、C(O)R9、NR10C(O)OR12、OC(O)R9、NR10S(O)jR12、S(O)jNR9R10、S(O)jNR10C(O)R9、C(O)NR10S(O)jR12、S(O)jR12、NR10C(O)R9、C(O)NR9R10、NR11C(O)NR9R10、NR11C(NCN)NR9R10、NR9R10And C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, C3-C10Cycloalkyl radical, C3-C10Cycloalkylalkyl, S (O)j(C1-C6Alkyl), S (O)j(CR10R11)mAryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, O (CR)10R10)mAryl, NR10(CR10R11)mAryl, O (CR)10R11)m-heteroaryl, NR10(CR10R11)mHeteroaryl, O (CR)10R11)m-heterocyclic radical, NR10(CR10R11)m-heterocyclyl and S (C)1-C2Alkyl) optionally substituted with 1 to 5 fluorine atoms.
R9Selected from hydrogen, trifluoromethyl, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, C3-C10Cycloalkyl radical, C3-C10Cycloalkylalkyl, aryl, aralkyl, heteroarylAlkyl, heterocyclyl and heterocyclylalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C4Alkyl, hydroxy and amino;
R10selected from hydrogen or C1-C6Alkyl, wherein alkyl may be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C4Alkyl, hydroxy and amino; or
R9、R10And the atoms to which they are attached form a 4-10 membered heteroaromatic or heterocyclic ring, each ring unsubstituted or substituted with 1-3 substituents independently selected from halogen, C1-C4Alkyl, hydroxy and amino;
R11selected from hydrogen or C1-C6Alkyl, wherein alkyl may be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C4Alkyl, hydroxy and amino; or
R10、R11And the atoms to which they are attached form a 4-to 10-membered carbocyclic, heteroaromatic or heterocyclic ring, each ring unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, C1-C4Alkyl, hydroxy and amino;
R12selected from trifluoromethyl, C1-C10Alkyl radical, C3-C10Cycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C4Alkyl, hydroxy and amino;
m is 0, 1, 2, 3, 4 or 5, and
j is 1 or 2; and X is C or N.
In another aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, wherein R is0Is H or C1-C6An alkyl group.
In another aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, wherein R is1Is H or C1-C6An alkyl group.
In another aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, wherein when X is N then no R is present2(ii) a Or R when X is C2Is H or C1-C6An alkoxy group.
In another aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, wherein when X is C, R is2Is C1-C4An alkoxy group, or a five-or six-membered saturated, unsaturated, or aromatic heterocyclic group, wherein the heterocyclic group contains 1-5 heteroatoms independently selected from O, N and S, and the heterocyclic group is optionally substituted with 1-3 substituents independently selected from halogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl.
In another aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, wherein R is3Selected from the group consisting of: c optionally substituted by one or more halogens or hydroxy groups1-C6An alkyl group; c2-C6An alkenyl group;optionally is covered with C1-C6Alkyl or C2-C6Alkenyl-substituted C3-C6A cycloalkyl group; a monocyclic or bicyclic heteroaryl having heteroatom O, N or S; monocyclic or bicyclic aryl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, C1-C6Alkoxy and hydroxy; arylcycloalkyl, wherein aryl is monocyclic or bicyclic aryl, and cycloalkyl has 1 to 6 carbon atoms; and C1-C6Alkyl radical C1-C6A cycloalkyl group.
In another aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, wherein R is4、R5、R6、R7And R8Independently selected from H or halogen.
In another aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, wherein R is4And R8One is fluorine, and R6Is iodine.
In another aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, wherein R is0Is H or C1-C6An alkyl group; r1Is H or C1-C6An alkyl group; is free of R2Or R2Is H or C1-C6An alkoxy group; r3Selected from the group consisting of: c optionally substituted by one or more halogens or hydroxy groups1-C6An alkyl group; c2-C6An alkenyl group; optionally is covered with C1-C6Alkyl or C2-C6Alkenyl-substituted C3-C6A cycloalkyl group; a monocyclic or bicyclic heteroaryl having heteroatom O, N or S; monocyclic or bicyclic aryl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, C1-C6Alkoxy and hydroxy groupsGroup (b); arylcycloalkyl, wherein aryl is monocyclic or bicyclic aryl, and cycloalkyl has 1 to 6 carbon atoms; and C1-C6Alkyl radical C1-C6A cycloalkyl group; and R is4、R5、R6、R7And R8Independently selected from H or halogen.
In another aspect, the present invention provides a compound represented by the formula:
Figure B200910146822XD0000071
wherein
R0Is H or C1-C6An alkyl group; r1Is H or C1-C6An alkyl group; r2Is H or C1-C6An alkoxy group; r3Selected from the group consisting of: c optionally substituted by one or more halogens or hydroxy groups1-C6An alkyl group; c2-C6An alkenyl group; optionally is covered with C1-C6Alkyl or C2-C6Alkenyl-substituted C3-C6A cycloalkyl group; a monocyclic or bicyclic heteroaryl having heteroatom O, N or S; monocyclic or bicyclic aryl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, C1-C6Alkoxy and hydroxy; arylcycloalkyl, wherein aryl is monocyclic or bicyclic aryl, and cycloalkyl has 1 to 6 carbon atoms; c1-C6Alkyl radical C1-C6A cycloalkyl group; and R is4、R5、R6、R7And R8Independently selected from H or halogen;
R13selected from the group consisting of H, C2-C6Alkenyl and C1-C6Alkyl, wherein said group may optionally be substituted by one or more substituents(ii) substituted, said substituents selected from the group consisting of halogen and hydroxy;
R14selected from the group consisting of H, C1-C6Alkyl, monocyclic or bicyclic aryl and monocyclic or bicyclic heteroaryl having heteroatom O, N or S, wherein said group may be optionally substituted with one or more substituents selected from the group consisting of halogen, cyano and C1-C6Alkoxy groups.
In another aspect, the present invention provides a compound represented by the formula:
Figure B200910146822XD0000072
wherein,
R1is H or C1-C6An alkyl group; r2Is H or C1-C6An alkoxy group; r13Selected from the group consisting of H, C2-C6Alkenyl and C1-C6Alkyl, wherein said group may be optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxy; r14Selected from the group consisting of H, C1-C6Alkyl, monocyclic or bicyclic aryl and monocyclic or bicyclic heteroaryl having a heteroatom O, N or S, wherein said groups may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano and C1-C6Alkoxy groups.
In another aspect, the present invention provides a compound represented by the formula:
Figure B200910146822XD0000081
wherein,
R13selected from the group consisting of H, C2-C6Alkenyl and C1-C6Alkyl, wherein said group may be optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxy; r14Selected from the group consisting of H, C1-C6Alkyl, monocyclic or bicyclic aryl and monocyclic or bicyclic heteroaryl having a heteroatom O, N or S, wherein said groups may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano and C1-C6Alkoxy groups.
In other embodiments, the invention provides compounds represented by the formula:
Figure B200910146822XD0000091
or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
In another aspect, the present invention provides a compound represented by the formula:
Figure B200910146822XD0000092
wherein
R13Selected from the group consisting of H, C2-C6Alkenyl and C1-C6Alkyl, wherein said group may be optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxy; r14Selected from the group consisting of H, C1-C6Alkyl, monocyclic or bicyclic aryl and monocyclic or bicyclic heteroaryl having a heteroatom O, N or S, wherein said groups may be optionally substituted by one or more substituents selected from the group consisting of halogen, cyano and C1-C6Alkoxy groups.
In other embodiments, the invention provides compounds represented by the formula:
or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
The compounds of the invention are MEK inhibitors and therefore useful in the treatment of cancer and other hyperproliferative diseases.
In other aspects, the invention relates to pharmaceutical compositions comprising an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. Such compositions may comprise at least one of adjuvants, excipients, preservatives, absorption retarders, fillers, binders, adsorbents, buffers, disintegrants, solubilizers, other carriers, and inert ingredients. Methods of formulating the compositions are well known in the art.
In other aspects, the invention relates to a method of treating a subject suffering from such a disease, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
In other aspects, the invention relates to methods of treating a condition in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
In other aspects, the invention relates to a method of treating a condition in a human patient, comprising administering to the human patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
In other aspects, the invention relates to methods of treating an inflammatory disease, condition, or disorder in a mammal (including a human being) comprising administering to the mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, ester, prodrug, solvate (including hydrate), polymorph or tautomer thereof.
In other aspects, the invention relates to methods of treating a condition or disorder modulated by the MEK cascade in a mammal, including a human, comprising administering to the mammal an amount of a compound of formula I, or a pharmaceutically acceptable salt, ester, prodrug, solvate (including hydrate), polymorph or tautomer thereof, effective to modulate the cascade. One skilled in the art can determine the appropriate dosage for a particular patient according to known methods.
In other aspects, the invention relates to the use of a compound of formula I, or a pharmaceutically acceptable salt, ester, prodrug, solvate (including hydrate), polymorph or tautomer thereof, in the manufacture of a pharmaceutical composition. The pharmaceutical compositions are useful for treating diseases or disorders modulated by the MEK cascade in mammals, including humans. The pharmaceutical compositions are useful for treating cancer, inflammatory diseases, and other hyperproliferative diseases.
In other aspects, the invention relates to pharmaceutical compositions comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. In some embodiments, the pharmaceutical composition is an oral dosage form. In some embodiments, the pharmaceutical composition is in the form of tablets, capsules, pills, powders, sustained release formulations, solutions and suspensions, sterile solutions, suspensions or emulsions for parenteral injection, ointments or creams for topical administration, or suppositories for rectal administration. In other embodiments, the pharmaceutical composition is in unit dosage form suitable for single administration of a precise dose. In other embodiments, the amount of the compound of formula I is in the range of about 0.001mg/kg body weight/day to about 1000mg/kg body weight/day. In other embodiments, the amount of the compound of formula I ranges from about 0.5mg/kg body weight/day to about 50mg/kg body weight/day. In some embodiments, the amount of the compound of formula I is from about 0.001 g/day to about 7 g/day. In other embodiments, the amount of the compound of formula I is from about 0.002 to about 6 g/day. In other embodiments, the amount of the compound of formula I is from about 0.005 g/day to about 5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.01 to about 5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.02 g/day to about 5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.05 g/day to about 2.5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.1 g/day to about 1 g/day. In other embodiments, dosage levels below the lower limit of the above ranges may be sufficient. In other embodiments, dosage levels above the upper limit of the range recited above may be desired. In some embodiments, the compound of formula I is administered in a single dose once daily. In other embodiments, the compound of formula I is administered in multiple doses more than once per day. In some embodiments, the compound of formula I is administered twice daily. In other embodiments, the compound of formula I is administered three times per day. In other embodiments, the compound of formula I is administered four times per day. In other embodiments, the compound of formula I is administered four times per day. In some embodiments, the pharmaceutical composition is administered to a mammal. In other embodiments, the mammal is a human. In other embodiments, the pharmaceutical composition further comprises a pharmaceutical carrier, excipient and/or adjuvant. In other embodiments, the pharmaceutical composition further comprises at least one therapeutic agent. In other embodiments, the therapeutic agent is selected from the group consisting of cytotoxic agents, anti-angiogenic agents, and anti-neoplastic agents. In other embodiments, the antineoplastic agent is selected from the group consisting of alkylating agents, antimetabolites, teniposide (epidophyllotoxin), antineoplastic enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone (mitoxantrones), platinum complexes, biological response modifiers and growth inhibitors, hormone/anti-hormone therapeutics, and hematopoietic growth factors. In other embodiments, the therapeutic agent is paclitaxel (taxol), bortezomib (bortezomib), or both. In other embodiments, the administration of the pharmaceutical composition is performed in combination with other therapies. In other embodiments, the other therapy is radiation therapy, chemotherapy, or a combination of both. In other embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of the compound of formula I.
In other aspects, the invention relates to methods of inhibiting MEK enzymes. The method comprises contacting the MEK enzyme with an effective inhibitory amount of a composition, thereby inhibiting the MEK enzyme, wherein the composition comprises a compound of formula I, or a pharmaceutically acceptable salt, hydrate, polymorph, ester, tautomer, or prodrug thereof. In the following embodiments, the invention relates to methods of selectively inhibiting MEK enzymes.
In other aspects, the invention relates to the use of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, for the preparation of a pharmaceutical composition for the inhibition of MEK enzymes.
In some embodiments, the enzyme is inhibited by at least about 1%. In other embodiments, the enzyme is inhibited by at least about 2%. In other embodiments, the enzyme is inhibited by at least about 3%. In other embodiments, the enzyme is inhibited by at least about 4%. In other embodiments, the enzyme is inhibited by at least about 5%. In other embodiments, the enzyme is inhibited by at least about 10%. In other embodiments, the enzyme is inhibited by at least about 20%. In other embodiments, the enzyme is inhibited by at least about 25%. In other embodiments, the enzyme is inhibited by at least about 30%. In other embodiments, the enzyme is inhibited by at least about 40%. In other embodiments, the enzyme is inhibited by at least about 50%. In other embodiments, the enzyme is inhibited by at least about 60%. In other embodiments, the enzyme is inhibited by at least about 70%. In other embodiments, the enzyme is inhibited by at least about 75%. In other embodiments, the enzyme is inhibited by at least about 80%. In other embodiments, the enzyme is inhibited by at least about 90%. In other embodiments, the enzyme is substantially completely inhibited. In some embodiments, the MEK enzyme is a MEK kinase. In other embodiments, the MEK enzyme is MEK 1. In other embodiments, the MEK enzyme is MEK 2. In some embodiments, the compounds of the invention can selectively inhibit MEK1 enzyme or MEK2 enzyme. In some other embodiments, the compounds of the invention may not be selective for the MEK1 enzyme and the MEK2 enzyme. In some embodiments, the contacting occurs within a cell. In some embodiments, the cell is a mammalian cell. In other embodiments, the mammalian cell is a human cell. In some embodiments, MEK enzymes are inhibited using compositions comprising a pharmaceutically acceptable salt of a compound of formula I.
In other aspects, the invention relates to a method of treating a subject having a disorder mediated by MEK comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
In other aspects, the invention relates to the use of a compound comprising formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, for the preparation of a pharmaceutical composition for the inhibition of a condition mediated by MEK.
In some embodiments, the composition comprising the compound of formula I is administered orally, intraduodenally, parenterally (including intravenously, subcutaneously, intramuscularly, intravascularly or by infusion), topically (topical administration), or rectally. In some embodiments, the pharmaceutical composition is an oral dosage form. In other embodiments, the pharmaceutical composition is in the form of tablets, capsules, pills, powders, sustained release formulations, solutions and suspensions, sterile solutions, suspensions or emulsions for parenteral injection, ointments or creams for topical administration, or suppositories for rectal administration. In other embodiments, the pharmaceutical composition is in unit dosage form suitable for administration of a single precise dose. In other embodiments, the pharmaceutical composition further comprises a pharmaceutical carrier, excipient and/or adjuvant. In other embodiments, the amount of the compound of formula I is in the range of about 0.001mg/kg body weight/day to about 1000mg/kg body weight/day. In other embodiments, the amount of the compound of formula I ranges from about 0.5mg/kg body weight/day to about 50mg/kg body weight/day. In some embodiments, the amount of the compound of formula I is from about 0.001 g/day to about 7 g/day. In other embodiments, the amount of the compound of formula I is from about 0.01 g/day to about 7 g/day. In other embodiments, the amount of the compound of formula I is from about 0.02 g/day to about 5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.05 g/day to about 2.5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.1 g/day to about 1 g/day. In other embodiments, dosage levels below the lower limit of the above ranges may be sufficient. In other embodiments, dosage levels above the upper limit of the range recited above may be desired. In other embodiments, the compound of formula I is administered in a single dose once daily. In other embodiments, the compound of formula I is administered in multiple doses more than once per day. In other embodiments, the compound of formula I is administered twice daily. In other embodiments, the compound of formula I is administered three times per day. In other embodiments, the compound of formula I is administered four times per day. In other embodiments, the compound of formula I is administered four times per day. In some embodiments, the subject having a MEK mediated disease is a mammal. In other embodiments, the individual is a human. In some embodiments, administration of a composition comprising a compound of formula I is performed in combination with other therapies. In other embodiments, the other therapy is radiation therapy, chemotherapy, or a combination of both. In some embodiments, a composition comprising a compound of formula I is administered in combination with at least one therapeutic agent. In some embodiments, the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenic agents, and anti-neoplastic agents. In other embodiments, the antineoplastic agent is selected from the group consisting of alkylating agents, antimetabolites, teniposide, antineoplastic enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone, platinum complexes, biological response modifiers and growth inhibitors, hormone/anti-hormone therapeutics, and hematopoietic growth factors. In other embodiments, the therapeutic agent is selected from paclitaxel, bortezomib, or both. In some embodiments, the disease mediated by MEK is selected from the group consisting of: inflammatory diseases, infections, autoimmune diseases, stroke, ischemia, heart diseases, neurological diseases, fibrotic diseases, proliferative diseases, hyperproliferative diseases, non-cancerous hyperproliferative diseases, tumors (tumors), leukemia, neoplasms (neoplasms), cancer (cancer), malignant tumors (carcinoma), metabolic diseases, malignant diseases, vascular restenosis, psoriasis, atherosclerosis, rheumatoid arthritis, osteoarthritis, heart failure, chronic pain, neuropathic pain, dry eye, angle closure glaucoma and wide angle glaucoma. In other embodiments, the MEK mediated disease is an inflammatory disease. In other embodiments, the MEK mediated disease is a hyperproliferative disease. In other embodiments, the MEK mediated disease is selected from the group consisting of a tumor, leukemia, neoplasm, cancer, malignancy, and malignant disease. In other embodiments, the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer, or leukemia. In other embodiments, the fibrotic disease is scleroderma, polymyositis, systemic lupus erythematosus, rheumatoid arthritis, liver cirrhosis, scarring, interstitial nephritis, or pulmonary fibrosis. In some embodiments, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered.
In other aspects, the invention relates to a method of degenerating (degrade) a cancer cell, inhibiting the growth of a cancer cell, or killing a cancer cell, the method comprising contacting the cell with a composition comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof, in an amount effective to degenerate, inhibit the growth of, or kill a cancer cell.
In other aspects, the invention relates to the use of a compound comprising formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof for the preparation of a pharmaceutical composition for the regression, inhibition of growth or killing of cancer cells.
In some embodiments, the cancer cell comprises a brain cancer cell, a breast cancer cell, a lung cancer cell, an ovarian cancer cell, a prostate cancer cell, a renal cancer cell, or a colorectal cancer cell. In some embodiments, the composition is used with at least one therapeutic agent. In other embodiments, the therapeutic agent is paclitaxel, bortezomib, or both. In other embodiments, the therapeutic agent is selected from the group consisting of cytotoxic agents, anti-angiogenic agents, and anti-neoplastic agents. In other embodiments, the antineoplastic agent is selected from the group consisting of alkylating agents, antimetabolites, teniposide, antineoplastic enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone, platinum complexes, biological response modifiers and growth inhibitors, hormone/anti-hormone therapeutics, and hematopoietic growth factors. In some embodiments, the cancer cells are degenerated. In other embodiments, 1% of the cancer cells are degenerated. In other embodiments, 2% of the cancer cells are degenerated. In other embodiments, 3% of the cancer cells are degenerated. In other embodiments, 4% of the cancer cells are degenerated. In other embodiments, 5% of the cancer cells are degenerated. In other embodiments, 10% of the cancer cells are degenerated. In other embodiments, 20% of the cancer cells are degenerated. In other embodiments, 25% of the cancer cells are degenerated. In other embodiments, 30% of the cancer cells are degenerated. In other embodiments, 40% of the cancer cells are degenerated. In other embodiments, 50% of the cancer cells are degenerated. In other embodiments, 60% of the cancer cells are degenerated. In other embodiments, 70% of the cancer cells are degenerated. In other embodiments, 75% of the cancer cells are degenerated. In other embodiments, 80% of the cancer cells are degenerated. In other embodiments, 90% of the cancer cells are degenerated. In other embodiments, 100% of the cancer cells are degenerated. In other embodiments, substantially all of the cancer cells are degenerated. In some embodiments, the cancer cells are killed. In other embodiments, 1% of the cancer cells are killed. In other embodiments, 2% of the cancer cells are killed. In other embodiments, 3% of the cancer cells are killed. In other embodiments, 4% of the cancer cells are killed. In other embodiments, 5% of the cancer cells are killed. In other embodiments, 10% of the cancer cells are killed. In other embodiments, 20% of the cancer cells are killed. In other embodiments, 25% of the cancer cells are killed. In other embodiments, 30% of the cancer cells are killed. In other embodiments, 40% of the cancer cells are killed. In other embodiments, 50% of the cancer cells are killed. In other embodiments, 60% of the cancer cells are killed. In other embodiments, 70% of the cancer cells are killed. In other embodiments, 75% of the cancer cells are killed. In other embodiments, 80% of the cancer cells are killed. In other embodiments, 90% of the cancer cells are killed. In other embodiments, 100% of the cancer cells are killed. In other embodiments, substantially all of the cancer cells are killed. In some embodiments, the growth of cancer cells is inhibited. In other embodiments, the growth of cancer cells is inhibited by about 1%. In other embodiments, the growth of cancer cells is inhibited by about 2%. In other embodiments, the growth of cancer cells is inhibited by about 3%. In other embodiments, the growth of cancer cells is inhibited by about 4%. In other embodiments, the growth of cancer cells is inhibited by about 5%. In other embodiments, the growth of cancer cells is inhibited by about 10%. In other embodiments, the growth of cancer cells is inhibited by about 20%. In other embodiments, the growth of cancer cells is inhibited by about 25%. In other embodiments, the growth of cancer cells is inhibited by about 30%. In other embodiments, the growth of cancer cells is inhibited by about 40%. In other embodiments, the growth of cancer cells is inhibited by about 50%. In other embodiments, the growth of cancer cells is inhibited by about 60%. In other embodiments, the growth of cancer cells is inhibited by about 70%. In other embodiments, the growth of cancer cells is inhibited by about 75%. In other embodiments, the growth of cancer cells is inhibited by about 80%. In other embodiments, the growth of cancer cells is inhibited by about 90%. In other embodiments, the growth of cancer cells is inhibited by about 100%. In some embodiments, a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered.
In other aspects, the present invention relates to a method of treating or preventing a proliferative disease in a subject, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
In other aspects, the invention relates to the use of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, for the preparation of a pharmaceutical composition for the treatment or prevention of a proliferative disease.
In some embodiments, the proliferative disease is cancer, psoriasis, restenosis, an autoimmune disease, or atherosclerosis. In other embodiments, the proliferative disease is a hyperproliferative disease. In other embodiments, the proliferative disease is selected from the group consisting of a tumor, leukemia, neoplasm, cancer, malignancy, and malignant disease. In other embodiments, the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer, or leukemia. In other embodiments, the fibrotic disease is scleroderma, polymyositis, systemic lupus erythematosus, rheumatoid arthritis, liver cirrhosis, scarring, interstitial nephritis, or pulmonary fibrosis. In other embodiments, the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer, or leukemia. In other embodiments, the cancer is brain cancer or adrenocortical cancer. In other embodiments, the cancer is breast cancer. In other embodiments, the cancer is ovarian cancer. In other embodiments, the cancer is pancreatic cancer. In other embodiments, the cancer is prostate cancer. In other embodiments, the cancer is renal cancer. In other embodiments, the cancer is colorectal cancer. In other embodiments, the cancer is a myeloid leukemia. In other embodiments, the cancer is glioblastoma. In other embodiments, the cancer is follicular lymphoma. In other embodiments, the cancer is pre-B cell acute leukemia. In other embodiments, the cancer is a B-lymphocytic chronic leukemia. In other embodiments, the cancer is mesothelioma. In other embodiments, the cancer is a small cell line cancer. In some embodiments, administration of a composition comprising a compound of formula I is combined with other therapies. In other embodiments, the other therapy is radiation therapy, chemotherapy, or a combination of both. In other embodiments, a composition comprising a compound of formula I is administered in combination with at least one therapeutic agent. In other embodiments, the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenic agents, and anti-neoplastic agents. In other embodiments, the antineoplastic agent is selected from the group consisting of alkylating agents, antimetabolites, teniposide, antineoplastic enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone, platinum complexes, biological response modifiers and growth inhibitors, hormone/anti-hormone therapeutics, and hematopoietic growth factors. In other embodiments, the therapeutic agent is selected from paclitaxel, bortezomib, or both. In some embodiments, the composition is administered orally, intraduodenally, parenterally (including intravenously, subcutaneously, intramuscularly, intravascularly or by infusion), topically, or rectally. In other embodiments, the amount of the compound of formula I ranges from about 0.001mg/kg body weight/day to about 1000mg/kg body weight/day. In other embodiments, the amount of the compound of formula I ranges from about 0.5mg/kg body weight/day to about 50mg/kg body weight/day. In other embodiments, the amount of the compound of formula I is from about 0.001 g/day to about 7 g/day. In other embodiments, the amount of the compound of formula I is from about 0.01 g/day to about 7 g/day. In other embodiments, the amount of the compound of formula I is from about 0.02 g/day to about 5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.05 g/day to about 2.5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.1 g/day to about 1 g/day. In other embodiments, dosage levels below the lower limit of the above ranges may be sufficient. In other embodiments, dosage levels above the upper limit of the range recited above may be desired. In other embodiments, the compound of formula I is administered in a single dose once daily. In other embodiments, the compound of formula I is administered in multiple doses more than once per day. In other embodiments, the compound of formula I is administered twice daily. In other embodiments, the compound of formula I is administered three times per day. In other embodiments, the compound of formula I is administered four times per day. In other embodiments, the compound of formula I is administered four times per day. In some embodiments, the subject having a proliferative disease is a mammal. In other embodiments, the individual is a human. In some embodiments, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered.
In other aspects, the present invention relates to a method of treating or preventing an inflammatory disease in a subject, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
In other aspects, the invention relates to the use of a compound comprising formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof for the preparation of a pharmaceutical composition for the treatment or prevention of an inflammatory disease.
In other embodiments, the inflammatory disease is selected from the group consisting of: chronic inflammatory diseases, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis, acute rheumatic arthritis, enteropathic arthritis, neuroarthritis, psoriatic arthritis, suppurative arthritis, atherosclerosis, systemic lupus erythematosus, inflammatory bowel disease, irritable bowel syndrome, ulcerative colitis, reflux esophagitis, Crohn's disease, gastritis, asthma, allergy, respiratory distress syndrome, pancreatitis, chronic obstructive pulmonary disease, pulmonary fibrosis, psoriasis, eczema, or scleroderma. In some embodiments, administration of a composition comprising a compound of formula I is combined with other therapies. In other embodiments, a composition comprising a compound of formula I is administered in combination with at least one therapeutic agent. In some embodiments, the composition is administered orally, intraduodenally, parenterally (including intravenously, subcutaneously, intramuscularly, intravascularly or by infusion), topically, or rectally. In other embodiments, the amount of the compound of formula I ranges from about 0.001mg/kg body weight/day to about 1000mg/kg body weight/day. In other embodiments, the amount of the compound of formula I ranges from about 0.5 mg/kg/day to about 50 mg/kg/day. In other embodiments, the amount of the compound of formula I is from about 0.001 g/day to about 7 g/day. In other embodiments, the amount of the compound of formula I is from about 0.01 g/day to about 7 g/day. In other embodiments, the amount of the compound of formula I is from about 0.02 g/day to about 5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.05 g/day to about 2.5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.1 g/day to about 1 g/day. In other embodiments, dosage levels below the lower limit of the above ranges may be sufficient. In other embodiments, dosage levels above the upper limit of the range recited above may be desired. In other embodiments, the compound of formula I is administered in a single dose once daily. In other embodiments, the compound of formula I is administered in multiple doses more than once per day. In other embodiments, the compound of formula I is administered twice daily. In other embodiments, the compound of formula I is administered three times per day. In other embodiments, the compound of formula I is administered four times per day. In other embodiments, the compound of formula I is administered four times per day. In some embodiments, the subject having an inflammatory disease is a mammal. In other embodiments, the individual is a human. In some embodiments, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered.
In other aspects, the present invention relates to a method of treating or preventing cancer in a subject, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
In other aspects, the invention relates to the use of a compound comprising formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof for the preparation of a pharmaceutical composition for the treatment or prophylaxis of cancer.
In other embodiments, the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer, or leukemia. In other embodiments, the fibrotic disease is scleroderma, polymyositis, systemic lupus erythematosus, rheumatoid arthritis, liver cirrhosis, scarring, interstitial nephritis, or pulmonary fibrosis. In other embodiments, the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer, or leukemia. In other embodiments, the cancer is brain cancer or adrenocortical cancer. In other embodiments, the cancer is breast cancer. In other embodiments, the cancer is ovarian cancer. In other embodiments, the cancer is pancreatic cancer. In other embodiments, the cancer is prostate cancer. In other embodiments, the cancer is renal cancer. In other embodiments, the cancer is colorectal cancer. In other embodiments, the cancer is a myeloid leukemia. In other embodiments, the cancer is glioblastoma. In other embodiments, the cancer is follicular lymphoma. In other embodiments, the cancer is pre-B cell acute leukemia. In other embodiments, the cancer is a B-lymphocytic chronic leukemia. In other embodiments, the cancer is mesothelioma. In other embodiments, the cancer is a small cell line cancer. In some embodiments, administration of a composition comprising a compound of formula I is combined with other therapies. In other embodiments, the other therapy is radiation therapy, chemotherapy, or a combination of both. In other embodiments, a composition comprising a compound of formula I is administered in combination with at least one therapeutic agent. In other embodiments, the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenic agents, and anti-neoplastic agents. In other embodiments, the antineoplastic agent is selected from the group consisting of alkylating agents, antimetabolites, teniposide, antineoplastic enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone, platinum complexes, biological response modifiers and growth inhibitors, hormone/anti-hormone therapeutics, and hematopoietic growth factors. In other embodiments, the therapeutic agent is selected from paclitaxel, bortezomib, or both. In some embodiments, the composition is administered orally, intraduodenally, parenterally (including intravenously, subcutaneously, intramuscularly, intravascularly or by infusion), topically, or rectally. In other embodiments, the amount of the compound of formula I ranges from about 0.001mg/kg body weight/day to about 1000mg/kg body weight/day. In other embodiments, the amount of the compound of formula I ranges from about 0.5mg/kg body weight/day to about 50mg/kg body weight/day. In other embodiments, the amount of the compound of formula I is from about 0.001 g/day to about 7 g/day. In other embodiments, the amount of the compound of formula I is from about 0.01 g/day to about 7 g/day. In other embodiments, the amount of the compound of formula I is from about 0.02 g/day to about 5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.05 g/day to about 2.5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.1 g/day to about 1 g/day. In other embodiments, dosage levels below the lower limit of the above ranges may be sufficient. In other embodiments, dosage levels above the upper limit of the range recited above may be desired. In other embodiments, the compound of formula I is administered in a single dose once daily. In other embodiments, the compound of formula I is administered in multiple doses more than once per day. In other embodiments, the compound of formula I is administered twice daily. In other embodiments, the compound of formula I is administered three times per day. In other embodiments, the compound of formula I is administered four times per day. In other embodiments, the compound of formula I is administered four times per day. In some embodiments, the individual having cancer is a mammal. In other embodiments, the individual is a human. In some embodiments, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered.
In other aspects, the invention relates to a method of reducing tumor volume, inhibiting an increase in tumor volume, reducing tumor proliferation, or inhibiting tumor proliferation in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof.
In other aspects, the invention relates to the use of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, for the preparation of a pharmaceutical composition for reducing tumor volume, inhibiting tumor volume increase, reducing tumor proliferation or inhibiting tumor proliferation.
In some embodiments, the tumor volume is decreased. In other embodiments, the tumor volume is reduced by at least 1%. In other embodiments, the tumor volume is reduced by at least 2%. In other embodiments, the tumor volume is reduced by at least 3%. In other embodiments, the tumor volume is reduced by at least 4%. In other embodiments, the tumor volume is reduced by at least 5%. In other embodiments, the tumor volume is reduced by at least 10%. In other embodiments, the tumor volume is reduced by at least 20%. In other embodiments, the tumor volume is reduced by at least 25%. In other embodiments, the tumor volume is reduced by at least 30%. In other embodiments, the tumor volume is reduced by at least 40%. In other embodiments, the tumor volume is reduced by at least 50%. In other embodiments, the tumor volume is reduced by at least 60%. In other embodiments, the tumor volume is reduced by at least 70%. In other embodiments, the tumor volume is reduced by at least 75%. In other embodiments, the tumor volume is reduced by at least 80%. In other embodiments, the tumor volume is reduced by at least 85%. In other embodiments, the tumor volume is reduced by at least 90%. In other embodiments, the tumor volume is reduced by at least 95%. In other embodiments, the tumor is eradicated. In some embodiments, the tumor volume is no longer increased. In some embodiments, tumor proliferation is decreased. In some embodiments, tumor proliferation is reduced by at least 1%. In some embodiments, tumor proliferation is reduced by at least 2%. In some embodiments, tumor proliferation is reduced by at least 3%. In some embodiments, tumor proliferation is reduced by at least 4%. In some embodiments, tumor proliferation is reduced by at least 5%. In some embodiments, tumor proliferation is reduced by at least 10%. In some embodiments, tumor proliferation is reduced by at least 20%. In some embodiments, tumor proliferation is reduced by at least 25%. In some embodiments, tumor proliferation is reduced by at least 30%. In some embodiments, tumor proliferation is reduced by at least 40%. In some embodiments, tumor proliferation is reduced by at least 50%. In some embodiments, tumor proliferation is reduced by at least 60%. In some embodiments, tumor proliferation is reduced by at least 70%. In some embodiments, tumor proliferation is reduced by at least 75%. In some embodiments, tumor proliferation is reduced by at least 80%. In some embodiments, tumor proliferation is reduced by at least 90%. In some embodiments, tumor proliferation is reduced by at least 95%. In some embodiments, tumor proliferation is prevented. In some embodiments, administration of a composition comprising a compound of formula I is combined with other therapies. In other embodiments, the other therapy is radiation therapy, chemotherapy, or a combination of both. In other embodiments, a composition comprising a compound of formula I is administered in combination with at least one therapeutic agent. In other embodiments, the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenic agents, and anti-neoplastic agents. In other embodiments, the antineoplastic agent is selected from the group consisting of alkylating agents, antimetabolites, teniposide, antineoplastic enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone, platinum complexes, biological response modifiers and growth inhibitors, hormone/anti-hormone therapeutics, and hematopoietic growth factors. In other embodiments, the therapeutic agent is selected from paclitaxel, bortezomib, or both. In some embodiments, the composition is administered orally, intraduodenally, parenterally (including intravenously, subcutaneously, intramuscularly, intravascularly or by infusion), topically, or rectally. In other embodiments, the amount of the compound of formula I ranges from about 0.001mg/kg body weight/day to about 1000mg/kg body weight/day. In other embodiments, the amount of the compound of formula I ranges from about 0.5mg/kg body weight/day to about 50mg/kg body weight/day. In other embodiments, the amount of the compound of formula I is from about 0.001 g/day to about 7 g/day. In other embodiments, the amount of the compound of formula I is from about 0.01 g/day to about 7 g/day. In other embodiments, the amount of the compound of formula I is from about 0.02 g/day to about 5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.05 g/day to about 2.5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.1 g/day to about 1 g/day. In other embodiments, dosage levels below the lower limit of the above ranges may be sufficient. In other embodiments, dosage levels above the upper limit of the range recited above may be desired. In other embodiments, the compound of formula I is administered in a single dose once daily. In other embodiments, the compound of formula I is administered in multiple doses more than once per day. In other embodiments, the compound of formula I is administered twice daily. In other embodiments, the compound of formula I is administered three times per day. In other embodiments, the compound of formula I is administered four times per day. In other embodiments, the compound of formula I is administered four times per day. In some embodiments, the individual having cancer is a mammal. In other embodiments, the individual is a human. In some embodiments, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered.
In other aspects, the present invention relates to a method of producing a therapeutic effect in a patient, wherein the therapeutic effect is selected from inhibiting a plurality of cancers, inhibiting immune diseases and/or inflammatory diseases, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. In some embodiments, the therapeutic effect is inhibition of a plurality of cancers. In other embodiments, the therapeutic effect is suppression of an immune disease. In other embodiments, the therapeutic effect is inhibition of an inflammatory disease.
In other aspects, the invention relates to the use of a compound comprising formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, in the manufacture of a pharmaceutical composition for the inhibition of various cancers, immune and/or inflammatory diseases.
In some embodiments, administration of a composition comprising a compound of formula I is combined with other therapies. In other embodiments, the other therapy is radiation therapy, chemotherapy, or a combination of both. In other embodiments, a composition comprising a compound of formula I is administered in combination with at least one therapeutic agent. In some embodiments, the composition is administered orally, intraduodenally, parenterally (including intravenously, subcutaneously, intramuscularly, intravascularly or by infusion), topically, or rectally. In other embodiments, the amount of the compound of formula I ranges from about 0.001mg/kg body weight/day to about 1000mg/kg body weight/day. In other embodiments, the amount of the compound of formula I ranges from about 0.5mg/kg body weight/day to about 50mg/kg body weight/day. In other embodiments, the amount of the compound of formula I is from about 0.001 g/day to about 7 g/day. In other embodiments, the amount of the compound of formula I is from about 0.01 g/day to about 7 g/day. In other embodiments, the amount of the compound of formula I is from about 0.02 g/day to about 5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.05 g/day to about 2.5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.1 g/day to about 1 g/day. In other embodiments, dosage levels below the lower limit of the above ranges may be sufficient. In other embodiments, dosage levels above the upper limit of the range recited above may be desired. In other embodiments, the compound of formula I is administered in a single dose once daily. In other embodiments, the compound of formula I is administered in multiple doses more than once per day. In other embodiments, the compound of formula I is administered twice daily. In other embodiments, the compound of formula I is administered three times per day. In other embodiments, the compound of formula I is administered four times per day. In other embodiments, the compound of formula I is administered four times per day. In some embodiments, the individual having cancer is a mammal. In other embodiments, the individual is a human. In some embodiments, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered.
In other aspects, the invention relates to processes for the preparation of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
Disclosure of Invention
The claims hereof set forth the features of the invention believed to be novel. Exemplary embodiments utilizing the principles of the present invention are set forth in the following detailed description of the invention. The features and advantages of the present invention may be better understood by reference to the following summary.
While preferred embodiments of the present invention are described herein, these embodiments are provided by way of example only. It is to be understood that variations of the embodiments of the invention described herein may also be used in the practice of the invention. Those skilled in the art will appreciate that various modifications, changes, and substitutions can be made without departing from the scope of the invention. It should be understood that the scope of the various aspects of the invention is defined by the claims and that methods and structures within the scope of these claims and their equivalents are intended to be covered thereby.
The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.
Certain chemical terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated. If there are multiple definitions of terms herein, the definition in this section controls. When referring to a URL or other such identifier or address, it is understood that such identifier can be transformed and exchanged with specific information on the internet, and equivalent information can be obtained through internet retrieval or other suitable reference data channels. The obtained reference demonstrates the availability and public dissemination of such information.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter claimed. In this application, the use of the singular also includes the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the term "comprising" as well as other forms, such as "includes," "including," and "containing," are used without limitation.
Can be found in the reference (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4)THED. "Vols.A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR and UV/Vis spectroscopy, and pharmacological methods. Unless specific definitions are set forth, analytical chemistry, organic synthesis are used hereinThe terminology used in chemistry and the related description of pharmaceutical and pharmaceutical chemistry is known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the instructions of the kit from the manufacturer, or according to the methods known in the art or the instructions of the present invention. The techniques and methods described above can generally be practiced according to conventional methods well known in the art, as described in various general and more specific documents referred to and discussed in this specification. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds.
When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left. For example, CH2O is equivalent to OCH2。
Unless otherwise indicated, the use of general chemical terms such as, but not limited to, "alkyl", "amine", "aryl" is equivalent to their optionally substituted forms. For example, "alkyl" as used herein includes optionally substituted alkyl.
The compounds described herein may have one or more stereogenic centers, and each stereogenic center may exist in the R or S configuration or a combination thereof. Similarly, the compounds described herein may have one or more double bonds, and each double bond may exist in either the E (trans) or Z (cis) configuration, or a combination thereof. A particular stereoisomer, structural isomer (regioisomer), diastereoisomer, enantiomer or epimer is understood to include all possible stereoisomers, structural isomers, diastereomers, enantiomers or epimers and mixtures thereof. Thus, the compounds described herein include all configurationally different stereoisomers, structural isomers, diastereomers, enantiomers, or epimers, as well as the corresponding mixtures thereof. Techniques for converting or leaving intact a particular stereoisomer, as well as techniques for resolving mixtures of stereoisomers, are well known in the art and those skilled in the art will be able to select appropriate methods for a particular situation. See, e.g., Fumiss et al (eds.), VOGEL' S ENCYCOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5. TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; and Heller, acc, chem, res, 1990, 23, 128.
The terms "moiety," "structural moiety," "chemical moiety," "group," "chemical group" as used herein refer to a specific fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded in or attached to a molecule.
The term "bond" or "single bond" refers to a chemical bond that connects two atoms or two moieties by a bond resulting in a larger moiety.
The term "catalytic group" refers to a chemical functional group that, through its action, lowers the activation energy barrier of a reaction, thereby aiding catalysis.
The terms "optionally/any" or "optionally/optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, an "optionally substituted alkyl" refers to an "unsubstituted alkyl" (alkyl unsubstituted by a substituent) or a "substituted alkyl" (alkyl substituted by a substituent), as defined below. Furthermore, the optionally substituted group may be unsubstituted (e.g. CH)2CH3) Completely substituted (e.g. CF)2CF3) Monosubstituted (CH)2CH2F) Or the degree of substitution between fully and mono-substituted (e.g. CH)2CHF2、CF2CH3、CFHCHF2Etc.). It will be understood by those skilled in the art that, for any group containing one or more substituents, no substitution or substitution pattern is introduced that would not be sterically impossible and/or synthetically possible (e.g., substituted alkyl includes optionally substituted cycloalkyl, whereas cycloalkyl is defined as including optionally substituted alkylRepeating the above steps). Thus, the substituent is generally understood to mean a maximum molecular weight of about 1,000 daltons, more typically, up to about 500 daltons (except where macromolecular substituents are obviously required, e.g., polypeptides, polysaccharides, polyethylene glycols, DNA and RNA, etc.).
As used herein C1-CnComprising C1-C2、C1-C3、......C1-Cn. For example, the "C" is1-C4By "group" is meant a moiety having 1 to 4 carbon atoms, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Range C1-C2And C1-C3Is defined similarly. Thus, for example, "C1-C4Alkyl "means an alkyl group having 1 to 4 carbon atoms, i.e., the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Herein, a numerical range, such as "1 to 10" refers to each integer in the given range, such as "1 to 10 carbon atoms" means that the group may 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 "hydrocarbon" as used herein, alone or in combination, refers to a compound or chemical group that contains only carbon and hydrogen atoms.
The term "heteroatom" or "hetero", as used herein, alone or in combination, refers to atoms other than carbon and hydrogen. The heteroatoms are independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but are not limited to these atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other.
The term "alkyl" as used herein, alone or in combination, refers to an optionally substituted straight or optionally substituted branched chain monovalent saturated hydrocarbon having from 1 to about 10 carbon atoms, more preferably from 1 to about 6 carbon atoms. Fruit of Chinese wolfberryExamples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-dimethyl-1-butyl, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1, N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and hexyl, and also longer alkyl groups such as heptyl and octyl, etc. When a group as defined herein, such as "alkyl" appears in a numerical range, e.g. "C1-C6Alkyl "or" C1-6Alkyl "means an alkyl group that can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and the alkyl group herein also encompasses instances where no numerical range is specified.
The term "alkylene" as used herein, alone or in combination, refers to a divalent group derived from a monovalent alkyl group as defined above. Examples include, but are not limited to, methylene (-CH)2) Ethylene (-CH)2CH2) Propylene (-CH)2CH2CH2) And isopropylidene (-CH (CH)3)CH2) And the like.
The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight or optionally substituted branched chain monovalent hydrocarbon radical having one or more C ═ C double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The double bond in these groups may be in either the cis or trans conformation and should be understood to encompass both isomers. Examples include, but are not limited to, ethenyl (CH ═ CH)2) 1-propenyl (CH)2CH＝CH2) Isopropenyl (C (CH)3)＝CH2) Butenyl, 1, 3-butadienyl and the like. When a numerical range is present for alkenyl as defined herein, e.g. "C2-C6Alkenyl "or" C2-6Alkenyl "means an alkenyl group that can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atomsAlkenyl groups herein also encompass instances where numerical ranges are not specified.
The term "alkenylene", as used herein, alone or in combination, refers to a divalent radical derived from a monovalent alkenyl radical as defined above. Examples include, but are not limited to, ethenylene (CH ═ CH) and propenylene isomers (e.g., CH)2CH ═ CH and C (CH)3) CH), and the like.
The term "alkynyl", as used herein, alone or in combination, refers to an optionally substituted straight or branched chain monovalent hydrocarbon radical having one or more C ≡ C triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl, and the like. When a numerical range occurs for alkynyl as defined herein, for example "C2-C6Alkynyl "or" C2-6Alkynyl "refers to an alkynyl group that can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and alkynyl groups herein also encompass instances where no numerical range is specified.
The term "alkynylene" as used herein, alone or in combination, refers to a divalent radical derived from a monovalent alkynyl group as defined above. Examples include, but are not limited to, ethynylene (-C ≡ C-) and propynyl (-CH)2C.ident.C-), and the like.
The term "aliphatic", as used herein, alone or in combination, refers to optionally substituted straight or branched chain, acyclic, saturated, partially unsaturated, or fully unsaturated nonaromatic hydrocarbons. Thus, the term includes alkyl, alkenyl and alkynyl groups as a whole.
The terms "heteroalkyl," "heteroalkenyl," and "heteroalkynyl" as used herein, alone or in combination, refer to optionally substituted alkyl, alkenyl, and alkynyl structures, respectively, as described above, wherein one or more backbone chain carbon atoms (also including, where appropriate, the attached hydrogen atom) are each independently replaced with a heteroatom (i.e., an atom other than carbon, such as, but not limited to, oxygen, nitrogen, sulfur, silicon, phosphorus, tin, or combinations thereof).
The terms "haloalkyl", "haloalkenyl", "haloalkynyl" and "haloalkynyl" as used herein, alone or in combination, refer to optionally substituted alkyl, alkenyl and alkynyl structures, respectively, as described above, wherein one or more hydrogen atoms are replaced with fluorine, chlorine, bromine, iodine atoms, or combinations thereof. In some embodiments, two or more hydrogen atoms are replaced with halogen atoms that are the same as each other (e.g., difluoromethyl); in other embodiments, two or more hydrogen atoms are replaced with halogen atoms that are not exactly the same as each other (e.g., 1-chloro-1-fluoro-1-iodoethyl). Non-limiting examples of haloalkyl groups are fluoromethyl and bromoethyl. A non-limiting example of a haloalkenyl group is bromovinyl. A non-limiting example of a haloalkynyl group is chloroethynyl.
The term "perhalo" as used herein, alone or in combination, refers to a group wherein all of the hydrogen atoms have been replaced with fluorine, chlorine, bromine, iodine atoms, or combinations thereof. Thus, as defined herein, the term "perhaloalkyl" refers to an alkyl group having all of its hydrogen atoms replaced with fluorine, chlorine, bromine, iodine atoms, or combinations thereof. A non-limiting example of a perhaloalkyl group is bromochlorofluoromethyl. A non-limiting example of a perhaloalkenyl group is trichloroethenyl. A non-limiting example of a perhaloalkynyl group is tribromopropynyl.
The term "carbon chain" as used herein, alone or in combination, refers to any alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl group, which may be linear, cyclic, or any combination thereof. If the chain is a linker and the linker contains one or more rings as part of the core backbone, then to calculate the chain length, the "chain" includes only those carbon atoms that make up the lower or upper part of the designated ring, rather than both, and in the case of unequal lengths of the upper and lower ring parts, a shorter distance should be used to determine chain length. If the chain contains heteroatoms as part of the backbone, these heteroatoms are not counted as carbon chain length.
The terms "ring," "cyclic," and ". multidrug" as used herein, alone or in combination, mean any covalently closed structure as described herein, including alicyclic, heterocyclic, aromatic, heteroaromatic, and polycyclic fused or polycyclic non-fused ring systems. The ring may be optionally substituted. The rings may form part of a fused ring system. The term "member" refers to the number of backbone atoms that make up the ring. Thus, for example, cyclohexane, pyridine, pyran and pyrimidine are six-membered rings, while cyclopentane, pyrrole, tetrahydrofuran and thiophene are five-membered rings.
The term "fused" as used herein, alone or in combination, refers to a ring structure wherein two or more rings have one or more bonds in common.
The term "cycloalkyl" as used herein, alone or in combination, refers to an optionally substituted monovalent saturated hydrocarbon ring containing from 3 to about 15 ring-forming carbon atoms or from 3 to about 10 ring-forming carbon atoms, and may also include as substituents other non-ring-forming carbon atoms (e.g., methylcyclopropyl).
Examples of "cycloalkyl" include, but are not limited to, azine (azinyl), azetidinyl (azidinyl), oxetanyl (oxolanyl), thietanyl (thietanyl), homopiperidinyl (homopiperidyl), oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1, 2, 3, 6-tetrahydropyridinyl (1, 2, 3, 6-tetrahydropyridinyl), 2-pyrrolinyl (2-pyrrolinyl), 3-pyrrolinyl (3-pyrrolinyl), indolyl (indolinyl), 2H-pyranyl (2H-pyranyl), 4H-pyranyl (4H-pyranyl), dioxacyclohexyl (dioxanyl), 1, 3-dioxolanyl (1, 3-dioxolanyl), pyrazolinyl (pyrazolinyl), cyclohexyl (dithiodiyl), dithiodiaminyl (dithiofuranyl), dithiofuranyl (dihydrofuranyl), pyrazolinyl (dihydrofuranyl), dithiofuranyl (dithiofuranyl), dithiofuranyl, imidazolinyl (imidazolinyl), imidazolinyl (imidazolinidinyl), 3-azabicyclo [3.1.0] hexyl (3-azabicyclo [3.1.0] hexyl), 3-azabicyclo [4.1.0] heptyl (3-azabicyclo [4.1.0] hexyl), 3H-indolyl (3H-indolyl) and quinolyl (quinolizinyl), and the like. The term also includes all cyclic forms of saccharides, including but not limited to monosaccharides, disaccharides, and oligosaccharides.
The term "aromatic/aromatic" as used herein, alone or in combination, refers to a planar ring portion of a ring or rings having a delocalized electron-conjugated system of 4n +2n electrons, where n is an integer. The aromatic ring may be formed of 5, 6, 7, 8, 9 or more atoms. The aromatic compound may be optionally substituted and may be monocyclic or fused-ring polycyclic. The term aromatic compound includes all carbon-containing rings (e.g., benzene rings) and rings containing one or more heteroatoms (e.g., pyridine).
The term "aryl/aryl" as used herein, alone or in combination, refers to an optionally substituted aromatic hydrocarbon group having from 6 to about 20 ring-forming carbon atoms and including fused rings and non-fused aromatic rings. Fused aryl groups comprise 2 to 4 aromatic ring fused rings, and other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic, or any combination thereof. In addition, the term aryl also includes fused and non-fused rings containing from 6 to about 12 ring-forming carbon atoms, as well as fused and non-fused rings containing from 6 to about 10 ring-forming carbon atoms. Non-limiting examples of monocyclic aryl groups include phenyl; the fused ring aryl comprises naphthyl, phenanthryl, anthryl and azulenyl; non-fused bisaryl groups include biphenyl groups.
The term "arylene" as used herein, alone or in combination, refers to a divalent aromatic radical derived from a monovalent aromatic radical as defined above. Examples include, but are not limited to, 1, 2-phenylene, 1, 3-phenylene, 1, 4-phenylene, 1, 2-naphthylene, and the like.
The term "heteroaryl", as used herein, alone or in combination, refers to an optionally substituted monovalent aryl group comprising from about 5 to about 20 backbone ring-forming atoms, wherein one or more of the ring-forming atoms is a heteroatom independently selected from the group consisting of heteroatoms of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, but is not limited thereto; with the proviso that the ring of the group does not contain two adjacent O or S atoms. In embodiments where two or more heteroatoms are present in the ring, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other. The term heteroaryl includes optionally substituted monovalent fused or non-fused heteroaryl groups having at least one heteroatom. In addition, the term heteroaryl also includes fused and non-fused heteroaryl groups containing from 5 to about 12 backbone ring atoms, and fused and non-fused heteroaryl groups containing from 5 to about 10 backbone ring atoms. The heteroaryl group may be bonded through a carbon atom or a heteroatom. Thus, for example, an imidazole may be attached to the parent molecule through any of its carbon atoms (imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl) or its nitrogen atom (imidazol-1-yl or imidazol-3-yl). Similarly, heteroaryl groups may be further substituted by any or all of their carbon atoms and/or any or all of their heteroatoms. The fused heteroaryl group may comprise 2 to 4 fused rings fused with aromatic heterocycles, and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic, or any combination thereof. Non-limiting examples of monocyclic heteroaryl groups include pyridyl; fused ring heteroaryls include benzimidazolyl (benzimidazolyl), quinolyl (quinolyl), acridinyl (acridinyl), and non-fused bis-heteroaryls include bipyridyl (bipyridinyl). Other examples of heteroaryl groups include, but are not limited to: furyl (furanyl), thienyl (thienyl), oxazolyl (oxazolyl), acridinyl (acridinyl), phenazinyl (phenazinyl), benzimidazolyl (benzimidazolyl), benzofuranyl (benzofuranyl), benzoxazolyl (benzoxazolyl), benzothiazolyl (benzothiazolyl), benzothiadiazolyl (benzothiazolyl), benzothiophenyl (benzothiophenyl), benzoxadiazolyl (benzoxadiazolyl), benzotriazolyl (triazolyl), imidazolyl (imidiazolyl), indolyl (indolyl), isoxazolyl (isoxazolyl), isoquinolyl (isoquinolinyl), indolizinyl (indolizinyl), isothiazolyl (isothiazolyl), isoindolinyl (isoindolinyl), quinazolinyl (pyrazolinyl), quinazolinyl (pyrazinyl), quinazolinyl (pyridyl), pyrazinyl (pyridyl), quinazolinyl (pyridyl), benzothiazolyl (pyridyl), benzoxazolyl (pyridyl), benzoxazinyl (pyridyl) (pyridyl), quinazolinyl) (pyridyl) (pyridyl), pyridyl (pyridyl) (pyridyl), pyridyl) (pyridyl) (, Triazolyl (triazolyl), tetrazolyl (tetrazolyl), thiazolyl (thiazoyl), triazinyl (triazinyl), and thiadiazolyl (thiadiazolyl), and the like, and oxides thereof, such as pyridyl-N-oxide (pyridil-N-oxide).
The term "heteroarylene" as used herein, alone or in combination, refers to a diradical derived from a heteroaryl diradical as defined above. Examples include, but are not limited to, pyridinylene and pyrimidinylene.
The term "heterocyclyl" as used herein, alone or in combination, is a generic term for aliphatic heterocycles and heteroaryls. When the number of carbon atoms of the heterocyclic ring is indicated herein (e.g. C)1-C6Heterocyclic ring), at least one non-carbon atom (heteroatom) necessarily being present in the ring. E.g. "C1-C6The designation "heterocyclic" relates only to the number of carbon atoms in the ring and not to the total number of atoms in the ring. The nomenclature as "4-6 membered heterocyclic ring" refers to the total number of atoms contained in the ring (i.e., a four, five or six membered ring wherein at least one atom is a carbon atom, at least one atom is a heteroatom, and the remaining 2-4 atoms are carbon atoms or heteroatoms). For heterocycles having two or more heteroatoms, the two or more heteroatoms may be the same or different from each other. The heterocyclic ring may be optionally substituted. Non-aromatic heterocyclic groups include groups having only 3 atoms in the ring, whereas aromatic heterocyclic groups must have at least 5 atoms in the ring. The remaining groups may be attached to the heterocycle via a heteroatom or carbon atom (i.e., the heterocycle is attached to the parent molecule or further substituted).
The term "carbocyclyl" as used herein, alone or in combination, is a combination of alicyclic and aromatic groups; that is, all structures covalently closed by carbon, which may be saturated, partially unsaturated, fully unsaturated, or aromatic. A carbocyclic ring may be formed by more than 3, 4, 5, 6, 7, 8, 9, or 9 atoms. The carbocycle may be optionally substituted. The term carbocycle differs from heterocycle in that the ring backbone of the heterocycle contains at least one atom other than carbon.
The terms "halogen", "halo" or "halide", as used herein, alone or in combination, refer to fluorine, chlorine, bromine and iodine.
The term "alkoxy" as used herein, alone or in combination, refers to an alkylether group, O-alkyl, which includes O-aliphatic and O-carbocyclic groups, wherein the alkyl, aliphatic and carbocyclic groups may be optionally substituted, and wherein the terms alkyl, aliphatic and carbocyclic are as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
The term "sulfinyl" as used herein, alone or in combination, refers to a divalent group-S (-O).
The term "sulfonyl", as used herein, alone or in combination, refers to a divalent group-S (-O)2。
The terms "sulfonamide" and "sulfonamido", as used herein, alone or in combination, refer to the divalent group-S (-O)2-NH-and-NH-S (═ O)2。
The terms "sulfamide" and "sulfamide group" as used herein, alone or in combination, refer to the divalent group NHS (-O)2NH。
Certain pharmaceutical terms
The term "MEK inhibitor" as used herein refers to the IC to MEK activity as measured according to the MEK1 kinase assay described herein50No greater than about 100 μ M or no greater than about 50 μ M of the compound. ' IC50By "is meant a concentration of inhibitor that reduces the activity of an enzyme (e.g., MEK) to half of the maximum level. The inhibitory effect of the compounds described herein on MEK has now been found. The compounds of the invention preferably exhibit an IC for Mek activity as measured by the Mek1 kinase assay described herein50Not greater than about 10 μ M, not greater than about 5 μ M, more preferably not greater than about 1 μ M, and most preferably not greater than about 200 nM.
The terms "selective", "selectively", "selectivity" and "selectivity" as used herein refer to the IC of a compound of the invention for a MEK enzyme as compared to other enzymes50Lower values (e.g., at least 2, 5, 10 or more times lower). The term also refers to the IC of a compound of the invention for the MEK1 enzyme as compared to the MEK2 enzyme50Lower values (e.g., at least 2-fold, 5-fold, 10-fold or more lower), or IC of a compound of the invention against a MEK2 enzyme as compared to a MEK1 enzyme50Lower values (e.g., at least 2, 5, 10 or more times lower)。
As used herein, reference to the term "subject", "patient" or "individual" refers to an individual suffering from a disease, disorder or condition, and the like, including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment related to the methods and compositions provided herein, the mammal is a human.
As used herein, the term "treating" and other similar synonyms include alleviating, or ameliorating a symptom of a disease or disorder, preventing other symptoms, ameliorating, or preventing an underlying metabolic cause of a symptom, inhibiting a disease or disorder, e.g., arresting the development of a disease or disorder, alleviating a disease or disorder, ameliorating a disease or disorder, alleviating a symptom of a disease or disorder, or discontinuing a symptom of a disease or disorder, and further, the term encompasses prophylactic purposes. The term also includes obtaining a therapeutic effect and/or a prophylactic effect. The therapeutic effect refers to curing or ameliorating the underlying disease being treated. In addition, a cure or amelioration of one or more physiological symptoms associated with the underlying disease is also a therapeutic effect, e.g., an improvement in the condition of the patient is observed, although the patient may still be affected by the underlying disease. For prophylactic effect, the composition can be administered to a patient at risk of developing a particular disease, or to a patient presenting with one or more physiological symptoms of the disease, even if a diagnosis of the disease has not yet been made.
The terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein, refer to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is clinically necessary to provide a significant remission effect of the condition. An effective amount suitable in any individual case can be determined using techniques such as a dose escalation assay.
The terms "administering," "administration," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, via the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Administration techniques useful for The compounds and methods described herein are well known to those skilled in The art, for example, in Goodman and Gilman, The pharmaceutical Basis of Therapeutics, current ed.; pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
The term "acceptable" as used herein with respect to a formulation, composition or ingredient means that there is no long-term deleterious effect on the general health of the subject being treated.
The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.
The term "pharmaceutical composition" as used herein refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical ingredient including, but not limited to, carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and/or excipients.
The term "carrier" as used herein refers to a relatively non-toxic chemical compound or agent that facilitates the introduction of the compound into a cell or tissue.
The term "agonist" as used herein refers to a molecule that enhances the activity of other molecules or receptor sites, such as a compound, a drug, an enzyme activator, or a hormone modulator.
The term "antagonist" as used herein refers to a molecule that abrogates or inhibits the activity of other molecules or receptor sites, such as a compound, drug, enzyme inhibitor, or hormone modulator.
The term "modulate" as used herein refers to interacting with a target directly or indirectly to alter the activity of the target, including, for example, enhancing target activity, inhibiting target activity, limiting target activity, or prolonging target activity.
The term "modulator" as used herein refers to a molecule that interacts directly or indirectly with a target. The interaction includes, but is not limited to, an agonist and antagonist interaction.
The term "pharmaceutically acceptable salt" as used herein refers to salts that retain the biological potency of the free acid and free base of the specified compound, and that are biologically or otherwise non-adverse. The compounds described herein may have acidic or basic groups and thus may react with any of a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. These salts can be prepared by the following method: prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting the free base form of the compounds of the invention with a suitable organic or inorganic acid and isolating the salt thus formed. Examples of pharmaceutically acceptable salts include salts prepared by reaction between a compound described herein and an inorganic or organic acid or base. These salts include acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1-yl acetate4-dioate, camphorate, camphorsulfonate, hexanoate, octanoate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, gluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexyne-1, 6-dioate (hexyne-1, 6-dioate), hydroxybenzoate, y-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-isethionate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, mandelate, metaphosphate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, caprylate, caprate, citrate, cyclopentanepropionate, caprate, gluconate, dihydrogenate, dinitrobenzoate, dodecylsulfate, glycolate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, jellylate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolic acid, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, suberate, sebacate, sulfonate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate (undeconate), and xylenesulfonate. Other acids (such as oxalic acid), although not pharmaceutically acceptable per se, may be used as intermediates in the preparation of the salts to obtain the compounds of the invention and their pharmaceutically acceptable acid addition salts (see, e.g., Berge et al, j.pharm.sci.1977, 66, 1-19). Further, the compounds described herein that can include a free acid group can be reacted with a suitable base (e.g., a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation), with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali metal salts or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, hydroxyethyltrimethylamine hydroxide, sodium carbonate and IV' (C)1-4Alkyl radical)4And the like. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, and mixtures thereof,Diethanolamine, piperazine and the like. It is to be understood that the compounds described herein also include quats of any basic nitrogen-containing group that they may contain. Water-or oil-soluble or dispersible products can be obtained by quaternization. See, e.g., Berge et al, supra.
The term "solvate" as used herein refers to a combination of a compound of the invention formed by solvation with a solvent molecule. In some instances, a "solvate" is a "hydrate," i.e., the solvent molecule is a molecule of water, and the combination of the compound of the invention with water forms a hydrate.
The term "polymorph" or "polymorph" as used herein refers to a compound of the invention in the form of different crystal lattices.
The term "ester" as used herein refers to derivatives of the compounds of the present invention derived from oxo acid groups and hydroxy groups, both oxo acid groups and hydroxy groups being present in the compounds of the present invention.
The term "tautomer" as used herein refers to an isomer that is readily interconverted from the compounds of the present invention by, for example, hydrogen atom migration or proton migration.
The term "pharmaceutically acceptable derivative or prodrug" as used herein refers to any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the invention which, upon administration to a subject, is capable of providing, directly or indirectly, a compound of the invention or a pharmaceutically active metabolite or residue thereof. Particularly preferred derivatives or prodrugs are those compounds which, when administered to a patient, enhance the bioavailability of the compounds of the invention (e.g., may allow an orally administered compound to be more readily absorbed into the blood), or facilitate delivery of the parent compound to a biological organ or site of action (e.g., the brain or lymphatic system).
Pharmaceutically acceptable prodrugs of the compounds described herein include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternized derivatives of tertiary amines, N-Mannich bases (N-Mannich bases), Schiff bases (Schiffbase), amino acid conjugates, phosphates, metal salts, and sulfonates. Various prodrug forms are well known in the art. See, e.g., Design of produgs, Bundgaard, a.ed., Elseview, 1985 and Method in Enzymology, Widder, k.et al, ed.; academy, 1985, vol.42, p.309-396; bundgaard, H. "Design and Application of precursors" in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 113 and 191; and Bundgaard, h., Advanced Drug Delivery Review, 1992, 8, 1-38, which are incorporated herein by reference. The prodrugs described herein include, but are not limited to, the following groups of materials and combinations of these materials: an amine-derived prodrug; hydroxy prodrugs include, but are not limited to, acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, and esters containing a disulfide bond.
As used herein, the term "enhance/improve" and the like refers to increasing the effectiveness of a desired effect or extending the duration of a desired effect. Thus, in referring to enhancing the effect of a therapeutic agent, the term "enhance" refers to the ability to increase or prolong the efficacy or duration of the effect of the other therapeutic agent on the system.
The term "effect-enhancing amount (an amount effective to enhance effect)" as used herein refers to an amount sufficient to enhance the effect of other therapeutic agents in a desired system.
The terms "pharmaceutical combination", "administering other therapy", "administering other therapeutic agent" and the like as used herein refer to a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, including both fixed and unfixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form. The term "non-fixed combination" refers to the administration of at least one compound described herein and at least one synergistic formulation to a patient simultaneously, in combination, or sequentially at variable intervals as separate entities, wherein such administration provides effective levels of the two or more compounds in the body of the patient. These also apply to cocktail therapy, for example the administration of three or more active ingredients.
As used herein, the terms "co-administration," with. In some embodiments, the compounds described herein are administered in combination with other agents. These terms encompass the administration of two or more agents to an animal such that the agents and/or metabolites thereof are present simultaneously within the animal. These terms include the simultaneous administration of different compositions, the administration of different compositions at different times and/or the administration of one composition containing different active ingredients. Thus, in some embodiments, administration is by mixing a compound of the invention and other agents in one composition.
The term "metabolite" as used herein refers to a derivative of a compound that is formed upon metabolism of the compound.
The term "active metabolite" as used herein refers to an active derivative of a compound that is formed upon metabolism of the compound.
The term "metabolic" as used herein refers to all processes (including but not limited to hydrolysis reactions and enzyme-catalyzed reactions) in which an organism converts a particular substance. Thus, enzymes can produce specific structural changes to a compound. For example, cytochrome P450 catalyzes a variety of redox reactions, while uridine diphosphate glucuronosyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. For more information on metabolism, see The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996).
Compound (I)
Described herein are compounds of formula I, pharmaceutically acceptable salts, solvates, polymorphs, esters, tautomers, or prodrugs thereof:
Figure B200910146822XD0000371
formula I
Wherein
R0Is H, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C2-C6Alkenyl radical, C5-C6Cycloalkenyl or C2-C6An alkynyl group; wherein each alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl, or C3-C6One or both carbon atoms in the cycloalkyl group are optionally independently replaced with O, N or S; and
R1is H, C1-C4Alkoxy radical, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C2-C6Alkenyl radical, C5-C6Cycloalkenyl or C2-C6An alkynyl group; wherein each alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl; or, R1Is a saturated, unsaturated or aromatic heterocyclic group having 5 or 6 atoms, wherein the heterocyclic group comprises 1-5 heteroatoms independently selected from the group consisting of O, N and S, and which is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyanoMethyl, trifluoromethyl, difluoromethoxy and phenyl; or
R1is-CH2X, wherein X represents a group of formula II:
Figure B200910146822XD0000381
formula II
Wherein
R0Is H, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C2-C6Alkenyl radical, C5-C6Cycloalkenyl or C2-C6An alkynyl group; wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl, and C3-C6One or two ring-forming carbon atoms in a cycloalkyl group is optionally independently replaced with O, N or S;
R1is H, C1-C4Alkoxy radical, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C2-C6Alkenyl radical, C5-C6Cycloalkenyl or C2-C6An alkynyl group; wherein said alkoxy, alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl, or
R1Is a five-membered or six-membered saturated heterocyclic group, unsaturated heterocyclic group or aromatic heterocyclic group, wherein the heterocyclic group contains 1 to 5 hetero atomsThe heteroatoms are independently selected from the group consisting of O, N and S, and the heterocyclyl is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl; or
R1is-CH2X, wherein X represents a group of formula II:
Figure B200910146822XD0000391
formula II
Wherein
Y1And Y2May be the same or different and each represents a single bond, -CO-, -COO, -O-, -OCO-, -NRaor-SO2-；
Y3Represents C which may be substituted by 1 to 3 groups represented by Z1-5An alkyl group;
z may be the same or different and represents C which may be optionally substituted by one or more substituents1-5Alkyl, halogen atom, oxo group, -ORa、-COORa、-COOCORa-CO-halogen atom, -OCORa、-CONRaRb、-SRa、-SO2Ra、-NRaRb、-NRaCORb、NRaSO2Rb、-SO2NRaRbA monocyclic heterocyclic group or a bicyclic heterocyclic group or a monocyclic or bicyclic heteroaryl group, said substituents being selected from the group consisting of1-5Alkyl radical, -ORaAnd NRaRbA group of (a); each of the alkyl groups may be substituted by hydroxy, C1-5Alkoxy or amino substitution; in addition to the oxygen substituent and halogen, the above substituents may be linked to each other to form a cycloalkyl group or a heterocyclic group, which may have one or more substituentsA substituent selected from the group consisting of-ORa、NRaRbAnd may be-ORaSubstituted C1-5Alkyl groups;
Raand RbMay be the same or different, each represents a hydrogen atom or C which may be substituted with 1 to 3 substituents1-5An alkyl group, the substituent being selected from the group consisting of hydroxy, C1-5Alkoxy and amino;
the symbol "●" used in formula II represents a linking site;
when X ═ C, R2Is H, C1-C4Alkoxy radical, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C2-C6Alkenyl radical, C5-C6Cycloalkenyl or C2-C6An alkynyl group; wherein said alkoxy, alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl, or R2Is a five-or six-membered saturated, unsaturated or aromatic heterocyclic group, wherein the heterocyclic group has 1 to 5 heteroatoms selected from the group consisting of O, N and S, wherein the heterocyclic group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl; or
When X is N, R2Is absent; and
R3selected from trifluoromethyl, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, C3-C10Cycloalkyl radical, C3-C10Cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclylAnd heterocyclylalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is unsubstituted or substituted with 1-3 substituents independently selected from halogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, trifluoromethyl, difluoromethoxy, phenyl or substituted phenyl with 1-3 substituents independently selected from hydrogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, trifluoromethyl or difluoromethoxy;
R4、R5、R6、R7and R8Independently selected from hydrogen, halogen, cyano, nitro, trifluoromethyl, SR9、OR9、C(O)R9、NR10C(O)OR12、OC(O)R9、NR10S(O)jR12、S(O)jNR9R10、S(O)jNR10C(O)R9、C(O)NR10S(O)jR12、S(O)jR12、NR10C(O)R9、C(O)NR9R10、NR11C(O)NR9R10、NR11C(NCN)NR9R10、NR9R10And C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, C3-C10Cycloalkyl radical, C3-C10Cycloalkylalkyl, S (O)j(C1-C6Alkyl), S (O)j(CR10R11)mAryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, O (CR)10R10)mAryl, NR10(CR10R11)mAryl, O (CR)10R11)m-heteroaryl, NR10(CR10R11)mHeteroaryl, O (CR)10R11)m-heterocyclic radical, NR10(CR10R11)m-heterocyclyl and S (C)1-C2Alkyl) optionally substituted with 1 to 5 fluorine atoms.
R9Selected from hydrogen, trifluoromethyl, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, C3-C10Cycloalkyl radical, C3-C10Cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl groups, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl group is unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C4Alkyl, hydroxy and amino;
R10selected from hydrogen or C1-C6Alkyl, wherein alkyl may be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C4Alkyl, hydroxy and amino; or
R9And R10May form a 4-to 10-membered heteroaromatic or heterocyclic ring together with the atoms to which they are attached, wherein each ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, C1-C4Alkyl, hydroxy and amino;
R11selected from hydrogen or C1-C6Alkyl, wherein alkyl may be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C4Alkyl, hydroxy and amino; or
R10、R11And the atoms to which they are attached form a 4-to 10-membered carbocyclic, heteroaromatic or heterocyclic ring, each ring unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, C1-C4Alkyl, hydroxy and amino;
R12selected from trifluoromethyl, C1-C10Alkyl radical, C3-C10Cycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl groups, wherein each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl group is unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C4Alkyl, hydroxy and amino;
m is 0, 1, 2, 3, 4 or 5, and
j is 1 or 2; and X is C or N.
The invention provides a synthetic method of the compound. In some embodiments, the compounds described herein can be prepared by the following methods. The following methods and examples are intended to illustrate these methods. These schemes and examples should not be construed as limiting the invention in any way. The compounds described herein can also be synthesized using standard synthetic techniques known to those skilled in the art, or using methods known in the art in combination with those described herein.
Detailed Description
Synthetic methods and examples
The following is a scheme for the preparation of compounds of formula I:
route 1
Figure B200910146822XD0000421
Scheme 1 above shows the preparation of pyridone sulfonamide derivatives 10. Dichloropyridine derivative 3 may be prepared by a two-step reaction of chloropyridine 1 oxide followed by pyridine 2 oxide chloride. Nitrating dichloropyridine 3, then SN with Aniline 5ArReacting to form intermediate 6. Pyridone derivatives obtained by hydrolyzing chloropyridine 6Organism 7 alkylates, providing nitropyridine 8. After the reduction reaction, aminopyridine 9 was treated with sulfonyl chloride to obtain the desired pyridone sulfonamide 10.
Route 2
Figure B200910146822XD0000422
Scheme 2 describes the preparation of cyclopropanesulfonyl chloride 17. Cyclopropanesulfonyl chloride 11 is reacted with an alkyl alcohol 12 in the presence of a base such as pyridine, thereby obtaining a sulfonic acid ester 13. Followed by lithiation and alkylation with an alkyl halide 14 provides a substituted cyclopropane sulfonate 15. Compound 15 was treated with KSCN to prepare potassium salt 16. The sulfonyl chloride 17 is obtained by reaction of the potassium salt 16 with thionyl chloride.
Route 3
Figure B200910146822XD0000431
Scheme 3 describes the preparation of dihydroxypropylcyclopropylsulfonyl chloride 23. After lithiation isopropyl cyclopropane sulfonate 18 is treated with epoxide 19 to obtain hydroxypropyl sulfonate 20. Protecting the secondary hydroxyl group and hydrolyzing the sulfonate 21 to obtain sulfonate 22. Compound 22 is treated with thionyl chloride to obtain the protected dihydroxypropylcyclopropanesulfonyl chloride 23.
Route 4
Figure B200910146822XD0000441
Scheme 4 describes the preparation of cyclopropanesulfonyl chloride 27 protected with dioxolanone. Deprotection of protected hydroxypropyl cyclopropanesulfonate 20 (scheme 3) with CDI or bis (trichloromethyl) carbonateThe resulting dihydroxypropylcyclopropanesulfonate 24 was treated to form a dioxolanone propylcyclopropanesulfonate 25. Under mild conditions (e.g. NaI/acetone or Bu)4NI) compound 25 was hydrolyzed to obtain sulfonate 26. In the presence of PPh3Compound 26 is treated with thionyl chloride under the conditions of (a) to obtain cyclopropanesulfonyl chloride 27 protected by dioxolanone.
Process A for the synthesis of sulfonamides
The method A comprises the following steps: to a stirred solution of amine 9(1 eq) in anhydrous pyridine (1m) was added sulfonyl chloride (2-3 eq) at 0 ℃ to 5 ℃, followed by dimethylaminopyridine (DMAP, 0.1 eq). The mixture is stirred at 0 ℃ to 5 ℃ for 1 to 2 hours. Concentrating the reaction under reduced pressure, adding dichloromethane, washing the mixture with water, and purifying the organic phase with MgSO4Drying, filtering, and concentrating the filtrate under reduced pressure. The residue was purified by flash silica gel column chromatography to obtain the desired product.
Example 1
N- (2- (2-fluoro-4-iodophenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) cyclopropanesulphonamide
Figure B200910146822XD0000451
Step A:2-chloro-5-methylpyridine 1-oxide
Figure B200910146822XD0000452
To a mixture of 2-chloro-5-methylpyridine (200g, 1.57mol) and urea hydroperoxide addition compound (310g, 3.29mol) in dichloromethane (2L) was added dropwise anhydrous trifluoroacetic acid (679g, 5.96mol) at 0 ℃ and the mixture was stirred at 0 ℃ for 1 hour. Stirring for 48 hours while the reaction temperature is raised to room temperature, and adding dithioniteAn aqueous solution of sodium salt (326g, 3.14mol) and the reaction mixture was stirred for 4 hours. The reaction was neutralized with sodium hydroxide, extracted with dichloromethane, washed with brine, dried from the organic phase over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound as a brown solid (189g, 84%).1H NMR(400MHz，CDCl3)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]+。
And B:2, 6-dichloro-3-methylpyridine
Figure B200910146822XD0000453
To a mixture of 2-chloro-5-methylpyridine 1-oxide (130g, 905mmol) and triethylamine (110g, 1087mmol) in dichloromethane (1.5L) was added a solution of phosphoryl chloride (100mL, 1087mmol) in dichloromethane (500mL) at 0 ℃. After stirring at 0 ℃ for 2 hours, at room temperature for a further 24 hours, water is added and the reaction is neutralized with sodium hydroxide solution. Washing the organic layer with a saturated saline solution; the aqueous layer was extracted with ethyl acetate and washed with saturated brine solution. The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2, 6-dichloro-3-methyl-pyridine and 2, 4-dichloro-5-methyl-pyridine (138g, 94%, according to1H NMR determination of a dark red solid mixture in a ratio of 3: 1).1H NMR(400MHz，CDCl3)δ7.50(d，J＝8.0Hz，1H)，7.17(d，J＝8.4Hz，1H)，2.33(s，3H)；m/z＝161[M+1]+。
And C:2, 6-dichloro-3-methyl-5-nitropyridine
Figure B200910146822XD0000461
2, 6-dichloro-3-methyl is added at 0 ℃ with continuous stirringA mixture of-pyridine and 2, 4-dichloro-5-methyl-pyridine (26g, 160mmol, 1 eq.) was slowly added to concentrated sulfuric acid (294g, 3mol, 18 eq.). To this solution was slowly added nitric acid (95.0%, 74g, 1.17mol, 7 eq.) while maintaining the reaction temperature at 0 ℃ for 0.5 h. After the addition was complete, the resulting mixture was heated to 100 ℃ for 3.5 hours. The reaction mixture was cooled to 50 ℃ and poured into ice water. The resulting precipitate was filtered and washed with water. The resulting yellow solid was dried to obtain the above title compound (17.6g, 51%).1H NMR(400MHz，CDCl3)δ8.14(s，1H)，2.47(s，3H)。
Step D:6-chloro-N- (2-fluoro-4-iodo-phenyl) -5-methyl-3-nitropyridin-2-amine
To a mixture of NaH (3.55g, 148mmol, 3 equiv.) in THF (tetrahydrofuran, 500ml) at room temperature was added 2-fluoro-4-iodo-aniline (11.68g, 49.3mmol, 1 equiv.). After stirring for 30 min, 2, 6-dichloro-3-methyl-5-nitropyridine (10.2g, 49.3mmol, 1 eq) was added and the mixture was heated at reflux for 0.5 h. After cooling to room temperature, water was slowly added, and the solution was extracted with ethyl acetate and washed with a saturated saline solution. The organic layer was dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the above title compound as a brown solid, which was used for the next reaction without further purification.1H NMR(400MHz，CDCl3)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-iodophenylamino) -3-methyl-5-nitropyridin-2 (1H) -one
Figure B200910146822XD0000471
6-chloro-N- (2-fluoro-4-iodophenyl) -5-methyl-3-nitropyridin-2-amine (20g, 49.1mmol) was dissolved in EtOH (400ml) followed by slow addition of aqueous KOH (55g, 980mmol, dissolved in 200ml water) and the mixture refluxed for 4 h. The mixture was cooled to room temperature, and the yellow suspension was filtered, washed with water and dried to obtain the desired 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-iodophenylamino) -1, 3-dimethyl-5-nitropyridin-2 (1H) -one
Figure B200910146822XD0000472
To a solution of NaH (1.2 eq) in dry Dimethylformamide (DMF) (0.2mol/L) was added 6- (2-fluoro-4-iodophenylamino) -3-methyl-5-nitropyridin-2 (1H) -one (1 eq) at room temperature and stirred for 35 min, followed by the addition of iodomethane (1.05 eq) to the dark red mixture. After stirring at room temperature for 1 hour, saturated NH was used4The reaction was quenched with Cl and the mixture was extracted with ethyl acetate. The organic phase was washed with water and brine and then dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue by column chromatography on silica gel with eluent (DCM: PE ═ 1: 1 to DCM) gave the desired product (yield ═ 63%).1H NMR(400MHz，CDCl3)δ10.35(s，1H)，8.10(d，J＝1.2Hz，1H)，7.54(dd，J＝1.6&9.6Hz，1H)，7.47-7.50(m，1H)，6.71(t，J＝8.0Hz，1H)，3.22(s，3H)，2.16(s，3H)。
Step G:5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one
Figure B200910146822XD0000481
6- (2-fluoro-4-iodophenylamino) -1, 3-dimethyl-5-nitropyridin-2 (1H) -one (510mg) and Na2S2O4(1.96g, 8 equivalents) was dissolved in dioxane and water (30mL, 1: 1) and NH was added at room temperature4OH (1 mL). After 2 hours and 40 minutes, the mixture was diluted with 100mL of ethyl acetate and washed with water and brine. The aqueous layer was extracted twice with ethyl acetate and washed with brine. The organic layers were combined, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel with eluent (PE: EA (petroleum ether: ethyl acetate) ═ 1: 1 to DCM: MeOH (dichloromethane: methanol) ═ 20: 1) to give the above title compound (378mg, yield ═ 80%) as a pale green solid.1H NMR(400MHz，CDCl3)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-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridine-3- Yl) cyclopropanesulfonamides
Figure B200910146822XD0000482
According to method a, 5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with cyclopropanesulfonyl chloride to obtain the desired product.1H NMR(400MHz，CDCl3)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]+。
Example 2
1-allyl-N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) cyclopropanesulfonamide
Step A:1-butylcyclopropane sulfonate
Figure B200910146822XD0000491
Cyclopropanesulphonyl chloride (25g, 178mmol, 1 equiv) was dissolved in excess n-BuOH (80ml) and the reaction mixture was cooled to 0 ℃ followed by the dropwise addition of pyridine (13.3ml, 160mmol, 0.9 equiv). The mixture was slowly warmed to room temperature and stirred for 36 hours. The solvent was removed under reduced pressure and the resulting white solid was dissolved in chloroform. The organic phase was washed with water, brine and dried (MgSO)4) And then concentrated to give an oil (24.5g, 77%)1H NMR(400MHz，CDCl3)δ4.25(t，J＝6.4Hz，2H)，2.47(heptet，2H)，1.74(quintet，2H)，1.43(sextet，2H)，1.24(m，2H)，1.08(m，2H)，0.96(t，J＝7.6Hz，3H)。
And B:1-allylcyclopropane-1-sulfonic acid butyl ester
Figure B200910146822XD0000492
Butyllithium (150ml, 2.5M butyllithium in hexane, 404mmol) was slowly added to a solution of 1-butylcyclopropanesulfonate (60g, 337mmol) in THF (500ml) at-78 deg.C under a nitrogen atmosphere. After stirring for 15 min, allyl iodide (31ml, 337mmol) in THF (100ml) was added. The reaction mixture was stirred at-78 ℃ for 2 hours and at room temperature for 30 minutes. The volatiles were evaporated under reduced pressure and the residue was extracted with dichloromethane. The extract was washed with water and dried (MgSO)4) And filtering to remove the solvent. The residue was purified by silica gel column chromatography (eluent: PE/EA ═ 10: 1) to obtain the above title compound (50g, yield: 68%) as a colorless oil.1H NMR(400MHz，CDCl3)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)。
And C:1-allylcyclopropane-1-sulfonic acid potassium salt
A mixture of dimethyl ether (DME, 350ml) containing 1-allylcyclopropane-1-sulfonic acid butyl ester (50g, 229mmol) and potassium thiocyanate (23.4g, 240mmol) and water (350ml) was heated to reflux overnight. The mixture was extracted with ethyl acetate and the aqueous phase was evaporated under reduced pressure to give the crude product, which was used for the next reaction without further purification.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-allylcyclopropane-1-sulfonyl chloride
A solution of potassium 1-allylcyclopropane-1-sulfonate (44g, 220mmol), thionyl chloride (500ml) and a solution of DMF (5ml) were heated under reflux for 1.5 hours. The volatiles were evaporated under reduced pressure and water was slowly added. The mixture was extracted with ethyl acetate and MgSO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: PE/EA ═ 10: 1) to obtain the above title compound (33g, 83%).1H NMR(400MHz，CDCl3)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-N- (2- (2-fluoro-4-iodo-phenylamino) -15-dimethyl-6-oxo-1, 6-dihydro Pyridin-3-yl) cyclopropanesulfonamides
Figure B200910146822XD0000503
According to method A, 5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with 1-allylcyclopropane-1-sulfonyl chloride to obtain the desired product.1H NMR(400MHz，CDCl3)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]+。
Example 3
2, 2, 2-trifluoro-N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) ethanesulfonamide
Figure B200910146822XD0000511
According to method A, 5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with 2, 2, 2-trifluoroethanesulfonyl chloride to obtain the desired product.1H NMR(400MHz，CDCl3)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]+。
Example 4
N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) propane-2-sulfonamide
According to method a, 5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with propane-2-sulfonyl chloride to obtain the desired product.1H NMR(400MHz，CDCl3)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]+。
Example 5
N- (2- (2-fluoro-4-iodophenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) ethanesulfonamide
Figure B200910146822XD0000521
According to method a, 5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with ethanesulfonyl chloride to obtain the desired product.1H NMR(400MHz，CDCl3)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]+。
Example 6
N- (2- (2-fluoro-4-iodophenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) cyclohexanesulfonamide
Figure B200910146822XD0000522
According to method A, 5-amino-6- (2-fluoro-4-iodophenylamino) is reactedThe radical) -1, 3-dimethyl pyridine-2 (1H) -ketone reacts with cyclohexane sulfonyl chloride to obtain the target product.1H NMR(400MHz，CDCl3)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]+。
Example 7
N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) butane-1-sulfonamide
According to method A, 5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with butane-1-sulfonyl chloride to obtain the desired product.1H NMR(400MHz，CDCl3)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]+。
Example 8
3-chloro-N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) propane-1-sulfonamide
Figure B200910146822XD0000532
According to method a, 5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with 3-chloropropane-1-sulfonyl chloride to obtain the desired product.1H NMR(400MHz，CDCl3)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]+。
Example 9
N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) methanesulfonamide
According to method a, 5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with methanesulfonyl chloride to obtain the desired product.1H NMR(400MHz，CDCl3)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]+。
Example 10
1-chloro-N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) methanesulfonamide
According to method A, 5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with chloromethanesulfonyl chloride to obtain the desired product.1H NMR(400MHz，CDCl3)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]+。
Example 11
N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) cyclopentanesulfonamide
Figure B200910146822XD0000551
According to method A, 5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with cyclopentanesulfonyl chloride to obtain the desired product.1H NMR(400MHz，CDCl3)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]+。
Example 12
N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) thiophene-2-sulfonamide
Figure B200910146822XD0000552
According to method a, 5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with thiophene-2-sulfonyl chloride to obtain the desired product.1H NMR(400MHz，CDCl3)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]+。
Example 13
N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide
According to general procedure a, 5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with benzenesulfonyl chloride to give the desired product.1H NMR(400MHz，CDCl3)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]+。
Example 14
N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -4-methylbenzenesulfonamide
Figure B200910146822XD0000562
According to general procedure a, 5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with 4-methylphenyl-1-sulfonyl chloride to obtain the desired product.1H NMR(400MHz，CDCl3)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]+。
Example 15
4-fluoro-N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide
Figure B200910146822XD0000571
According to general procedure a, 5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with 4-fluorophenyl-1-sulfonyl chloride to obtain the desired product.1H NMR(400MHz，CDCl3)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]+。
Example 16
N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) thiophene-3-sulfonamide
Figure B200910146822XD0000572
According to general procedure a, 5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with thiophene-3-sulfonyl chloride to obtain the desired product.1H NMR(400MHz，CDCl3)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]+。
Example 17
N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -2-isopropyl-cyclopropane-1-sulfonamide
Figure B200910146822XD0000581
According to general procedure A, 5-amino-6- (2-fluoro-4-iodo)Phenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with 2-isopropyl-cyclopropane-1-sulfonyl chloride to obtain the desired product.1H NMR(400MHz，CDCl3)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]+。
Example 18
N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -2-isobutyl-cyclopropane-1-sulfonamide
Figure B200910146822XD0000582
According to general procedure a, 5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with 2-isobutyl-cyclopropane-1-sulfonyl chloride to obtain the desired product.1H NMR(400MHz，CDCl3)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]+.
Example 19
2- (4-ethoxyphenyl) -N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -cyclopropane-1-sulfonamide
Figure B200910146822XD0000591
According to general procedure A, 5-amino-6- (2-fluoro-4-iodophenylamino) is reacted) -1, 3-dimethylpyridin-2 (1H) -one is reacted with 2- (4-ethoxyphenyl) -cyclopropane-1-sulfonyl chloride to obtain the desired product.1H NMR(400MHz，CDCl3)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]+。
Example 20
N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -2-phenyl-cyclopropane-1-sulfonamide
Figure B200910146822XD0000592
According to general procedure a, 5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with 2-phenyl-cyclopropane-1-sulfonyl chloride to obtain the desired product.1H NMR(400MHz，CDCl3)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]+。
Example 21
2- (3, 4-difluorophenyl) -N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -cyclopropane-1-sulfonamide
Figure B200910146822XD0000601
According to the general methodA, reacting 5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one with 2- (3, 4-difluorophenyl) -cyclopropane-1-sulfonyl chloride to obtain the objective product.1H NMR(400MHz，CDCl3)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]+。
Example 22
N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -2- (thiophen-2-yl) -cyclopropane-1-sulfonamide
Figure B200910146822XD0000602
According to general procedure a, 5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with 2- (thiophen-2-yl) -cyclopropane-1-sulfonyl chloride to obtain the desired product.1HNMR(400MHz，CDCl3)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]+。
Example 23
2- (2, 4-difluorophenyl) -N- (2- (2-fluoro-4-iodophenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -cyclopropane-1-sulfonamide
Figure B200910146822XD0000611
According to general procedure a, 5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with 2- (2, 4-difluorophenyl) -cyclopropane-1-sulfonyl chloride to obtain the desired product.1H NMR(400MHz，CDCl3)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]+。
Example 24
2- (4-cyanophenyl) -N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -cyclopropane-1-sulfonamide
Figure B200910146822XD0000612
According to general procedure a, 5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with 2- (4-cyanophenyl) -cyclopropane-1-sulfonyl chloride to give the desired product.1H NMR(400MHz，CDCl3)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]+。
Example 25
N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -1-methyl-cyclopropane-1-sulfonamide
Step A:cyclopropanesulfonic acid isopropyl ester
Figure B200910146822XD0000621
Cyclopropanesulfonyl chloride (21.6g, 154mmol, 1 eq) was dissolved in excess i-PrOH (50ml) and the reaction mixture was cooled to 0 ℃. Pyridine (12.15g, 154mmol, 1 eq) was added dropwise and the mixture was slowly warmed to room temperature and stirred for 94 hours. The solvent was removed under reduced pressure and the resulting white solid was dissolved in dichloromethane. The organic phase was washed with water, brine and dried (MgSO)4) Filtration and concentration of the filtrate gave an oil (17.8g, 71%).1H NMR(400MHz，CDCl3)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)。
And B:1-methyl-cyclopropane-1-sulfonic acid isopropyl ester
Figure B200910146822XD0000622
Butyllithium (6.1ml, 2.5M butyllithium in hexane, 15.22mmol) was slowly added to a solution of isopropyl cyclopropanesulfonate (2g, 12.18mmol) in THF (40ml) at-78 deg.C under a nitrogen atmosphere. After stirring for 30 min, a solution of methyl iodide (1.44g, 10.15mmol) in THF (5ml) was added. The reaction mixture was stirred at-60 ℃ for 2 hours. The solution was quenched with water and warmed to room temperature. The volatiles were evaporated under reduced pressure and the residue was extracted with ethyl acetate. The organic phase was washed with water and dried (MgSO)4) Filtered and the solvent evaporated. The residue was purified by silica gel chromatography (eluent: PE/EA 5: 1) to obtain the above title compound (830mg, yield 46%) as a yellow oil.1HNMR(400MHz，CDCl3)δ4.91-4.96(m，1H)，1.54-1.56(m，2H)，1.41-1.48(m，2H)，0.83-0.88(m，2H)。
And C:1-methyl-cyclopropane-1-sulfonic acid potassium salt
Figure B200910146822XD0000623
A mixture of 1-methyl-cyclopropane-1-sulfonic acid isopropyl ester (810mg, 4.54mmol) and potassium thiocyanate (442mg, 4.54mmol) in DME (12.5ml) and water (12.5ml) was heated at reflux overnight. The residue was extracted with ethyl acetate and the aqueous phase was evaporated under reduced pressure to give the crude product, which was used in the next reaction without further purification.
Step D:1-methyl-cyclopropane-1-sulfonyl chloride
Figure B200910146822XD0000631
A solution of potassium 1-methyl-cyclopropane-1-sulfonate (349mg, 2mmol) in thionyl chloride (5ml) and DMF (5 drops) was heated at reflux for 1.5 h. The volatiles were evaporated under reduced pressure and water was slowly added. The residue was extracted with ethyl acetate, MgSO4Dried, filtered and evaporated to give the crude product as a yellow oil which was used for the next reaction without further purification.
Step E:n- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridine-3- 1-methyl-cyclopropane-1-sulfonamide
According to method a, 5-amino-6- (2-fluoro-4-iodo-phenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with 1-methyl-cyclopropane-1-sulfonyl chloride to obtain the desired product.1H NMR(400MHz，CDCl3)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]+。
Example 26
N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -cyclobutanesulfonamide
Step A:cyclobutanesulfonyl chloride
Figure B200910146822XD0000633
To a suspension of Mg turnings (0.405g, 16.67mmol) in 5ml of anhydrous THF were added 0.3g of bromocyclobutane and a catalytic amount of iodine. The mixture was heated using an electric blower. After the solution became colorless, 1.2g of bromocyclobutane dissolved in 15ml of THF was slowly added. The mixture was heated to reflux for 1 hour, then cooled to room temperature, and the supernatant was added portionwise to a 10ml anhydrous ice-cold dichloromethane solution containing sulfuryl chloride (4.5g, 33.3 mmol). After the addition was complete, the suspension was warmed to room temperature and the volatiles were removed in vacuo. The residue was dissolved in hexane (25 ml). The suspension was filtered and the solution was evaporated to give the crude product as a yellow oil (1.55g, 90%) which was used for the next reaction without further purification.
And B:n- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropir-zine Pyridine-3- Yl) -cyclobutanesulfonamides
Figure B200910146822XD0000641
According to method a, 5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with cyclobutanesulfonyl chloride to obtain the desired product.1H NMR(400MHz，CDCl3)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]+。
Example 27
1- (2, 3-dihydroxypropyl) -N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -cyclopropane-1-sulfonamide
Step A:1-allyl-cyclopropanesulfonyl (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6- Oxo-1, 6-dihydropyridin-3-yl) carbamic acid tert-butyl ester
Figure B200910146822XD0000651
To a solution of 1-allyl-N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -cyclopropanesulfonamide (182mg, 0.352mmol) and di-tert-butyl dicarbonate (84mg, 0.387mmol, 1.1 equivalents) in 3mL anhydrous THF at 0 deg.C was added NaH (60% wt, 31mg, 2.2 equivalents), followed by stirring at room temperature overnight (14 h). After quenching with water, ethyl acetate was added. The organic phase was washed with water and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluent PE: EA ═ 2: 1) to give the title compound (138mg, yield ═ 63%) as a pale yellow oil.1H NMR(400MHz，CDCl3)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]+。
And B:1- (2, 3-dihydroxypropyl) -cyclopropanesulfonyl (2- (2-fluoro-4-iodophenylamino) -1, 5-dimethyl Yl-6-oxo-1, 6-dihydropyridin-3-yl) carbamic acid tert-butyl ester
To a solution of tert-butyl 1-allylcyclopropanesulphonyl (2- (2-fluoro-4-iodophenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) carbamate (100mg, 0.162mmol) at 0 ℃ was added N-methylmorpholine N-oxide (19mg, 0.162mmol) followed by osmium (VIII) oxide (4% wt, 103mg, 0.1 equiv) at 0 ℃. The mixture was stirred at room temperature for 18 hours, followed by Na2S2O4The aqueous solution was quenched, extracted with dichloromethane, dried over magnesium sulfate and filtered. The solvent was removed from the filtrate, and the residue was purified by flash silica gel column chromatography (eluent: DCM: MeOH ═ 10: 1) to obtain the above title compound (96mg, 91%) as a gray solid.1H NMR(400MHz，CDCl3)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]+。
And C:1- (2, 3-dihydroxypropyl) -N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo -1, 6-dihydropyridin-3-yl) cyclopropane-1-sulfonamide
Figure B200910146822XD0000661
To a solution of tert-butyl 1- (2, 3-dihydroxypropyl) cyclopropanesulfonyl (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) carbamate (43mg, 0.066mmol) in 1mL of dichloromethane was added trifluoroacetic acid (0.5mL) at room temperature and stirred for 1 hour. With saturated Na2CO3The solution was quenched and stirred for 0.5 h. After extraction with dichloromethane (3 ×), sodium chloride was added to the aqueous phase and extracted with dichloromethane (3 ×). Using MgSO4The combined organic layers were dried and filtered. The solvent was removed from the filtrate under reduced pressure, and the residue was purified by flash silica gel column chromatography (eluent: DCM: MeOH ═ 10: 1), whereby the above title compound (24mg, yield 66%) was obtained as a gray solid.1H NMR(400MHz，CDCl3)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]+。
Example 28
(R) -1- (2, 3-dihydroxypropyl) -N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -cyclopropane-1-sulfonamide
Step A:(R) -1- (3- (benzyloxy) -2-hydroxypropyl) -cyclopropane-1-sulfonic acid isopropyl ester
Figure B200910146822XD0000672
At-78 ℃ for 25 min (ethyl acetate/N)2Bath), n-butyllithium (2.5M, 91mL, 228mmol) was added to anhydrous THF (450mL) containing isopropyl cyclopropanesulfonate (30g, 183mmol) and HMPA (hexamethylphosphoramide, 50mL) and stirred for 30 min. Followed by heating at-40 deg.C (acetonitrile/N)2Bath) stirring the black solution, (R) -2- (benzyloxymethyl) was added) Ethylene oxide (25g, 152mmol) in THF (50mL) and stirred at-40 deg.C for 3 hours. The reaction was quenched with water, extracted with ethyl acetate (2 ×), washed with saturated NaCl solution, and washed with MgSO4Dried and filtered. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate: 5: 1 to 2: 1), whereby the above-mentioned title compound (37.9g, yield: 76%) was obtained as a brown oil.1H NMR(400MHz，CDCl3)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]+。
And B:(R) -1- (2, 3-bis (benzyloxy) propyl) -cyclopropane-1-sulfonic acid isopropyl ester
Figure B200910146822XD0000673
(R) -1- (3- (benzyloxy) -2-hydroxypropyl) -cyclopropane-1-sulfonic acid isopropyl ester (1.38g, 4.2mmol) was added to a DMF mixture containing NaH (60% wt, 210mg, 5.25mmol) at 0 deg.C and stirred for 30 min. To the reaction mixture was added benzyl bromide (0.75mL, 6.3mmol) at 0 ℃, and stirred at room temperature overnight (13 hours), followed by quenching with water, extraction with ethyl acetate, washing with water (2 ×) and saturated brine, washing with Mg2SO4Dried and filtered. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate: 10: 1 to 5: 1), whereby the above title compound (1.145g, yield: 65%) was obtained as a brown oil.1H NMR(400MHz，CDCl3)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]+。
And C:(R) -1- (2, 3-bis (benzyloxy) propyl) cyclopropane-1-sulfonic acid potassium salt
Figure B200910146822XD0000681
(R) -1- (2, 3-bis (benzyloxy) propyl) cyclopropane-1-sulfonic acid isopropyl ester (450mg, 1.075mmol) and potassium thiocyanate (115mg, 1.183mmol) were dissolved in a solution of dimethyl ether and water (10mL, 2: 1 by volume). The reaction mixture was heated to reflux overnight, and the mixture was then evaporated under reduced pressure. The residue was washed with diethyl ether to obtain the above title compound as a viscous solid.
Step D:(R) -1- (23-bis (benzyloxy) propyl) cyclopropane-1-sulfonyl chloride
Figure B200910146822XD0000682
(R) -1- (2, 3-bis (benzyloxy) propyl) -cyclopropane-1-sulfonic acid potassium was dissolved in sulfur dichloride (7mL) and DMF (1 mL). The reaction mixture was heated to reflux for 1 hour, and then the mixture was evaporated under reduced pressure. The yellow residue was purified by silica gel column chromatography gradient elution (eluent: ethyl acetate: petroleum ether ═ 1: 5) to obtain the above title compound as a yellow oil (250mg, two-step total yield 60%).1H NMR(400MHz，CDCl3)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, 3-bis (benzyloxy) propyl) -N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl 6-oxo-1, 6-dihydropyridin-3-yl-cyclopropane-1-sulfonamide
Figure B200910146822XD0000691
According to method a, 5-amino-6- (2-fluoro-4-iodophenylamino) -1, 3-dimethylpyridin-2 (1H) -one is reacted with (R) -1- (2, 3-bis (benzyloxy) propyl) cyclopropane-1-sulfonyl chloride to obtain the desired product.1H NMR(400MHz，CDCl3)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, 3-dihydroxypropyl) -N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl Radical-6- Oxo-1, 6-dihydropyridin-3-yl) cyclopropane-1-sulfonamides
Figure B200910146822XD0000692
Boron trichloride (1M boron trichloride in dichloromethane, 0.8mL) was added to 8mL dichloromethane containing (R) -1- (2, 3-bis (benzyloxy) propyl) -N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -cyclopropane-1-sulfonamide (61mg, 0.083mmol) at 0 ℃. After stirring at room temperature for 10 minutes, 1N HCl was added and the mixture was extracted with dichloromethane. With saturated NaHCO3The organic phase was washed with saturated NaCl solution and MgSO4And (5) drying. The solvent was removed from the filtrate by filtration and the residue was subjected to silica gel column chromatography (eluent: dichloromethane: methanol 15: 1) to obtain the above title compound (41mg, 90%) as a gray solid.1HNMR(400MHz，CDCl3)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，CDCl3+2drops of DMSO-d6)δ8.64(s，1H)，7.68(s，1H)，7.49(s，CDCl3)，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]+。
Example 29
(S) -1- (2, 3-dihydroxypropyl) -N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -cyclopropane-1-sulfonamide
Step A:(S) -1- (3- (benzyloxy) -2-hydroxypropyl) -cyclopropane-1-sulfonic acid isopropyl ester
Figure B200910146822XD0000701
The title compound was obtained according to step a of the method in example 28 above.1HNMR(400MHz，CDCl3)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]+。
And B:(S) -1- (2, 3-bis (benzyloxy) propyl) -cyclopropane-1-sulfonic acid isopropyl ester
Figure B200910146822XD0000711
The title compound was obtained according to step B of the method in example 28 above.1HNMR(400MHz，CDCl3)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]+。
And C:(S) -1- (2, 3-bis (benzyloxy) propyl) -cyclopropane-1-sulfonic acid potassium salt
Figure B200910146822XD0000712
The title compound was obtained according to step C of the method in example 28 above.
Step D:(S) -1- (2, 3-bis (benzyloxy) propyl) -cyclopropane-1-sulfonyl chloride
Figure B200910146822XD0000713
The title compound was obtained according to step D of the procedure in example 28 above.1HNMR(400MHz，CDCl3)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, 3-bis (benzyloxy) propyl) -N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl 6-oxo-1, 6-dihydropyridin-3-yl-cyclopropane-1-sulfonamide
Figure B200910146822XD0000721
The title compound was obtained according to step E of the procedure in example 28 above.1HNMR(400MHz，CDCl3)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, 3-dihydroxypropyl) -N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo Substituted-1, 6-dihydropyridin-3-yl) -cyclopropane-1-sulfonamides
Figure B200910146822XD0000722
The title compound was obtained according to step F of the method in example 28 above.1HNMR(400MHz，CDCl3)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]+。
Example 30
N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -1- (3-hydroxypropyl) cyclopropane-1-sulfonamide
Figure B200910146822XD0000731
A mixture of tert-butyl 1-allylcyclopropanesulphonyl (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) carbamate (100mg, 0.162mmol) and THF (2ml) in a three-necked round-bottomed flask was stirred under a nitrogen atmosphere. Using a syringe to administer BH3THF (1ml, 1mmol) was slowly added to the reaction flask. The reaction was stirred at room temperature for 48 hours, cooled in an ice bath and aqueous NaOH (3M, 1ml) and 30% H were added to the reaction flask2O2Aqueous solution (3 ml). After the addition was completed, the mixture was stirred at room temperature for 2 hours, followed by extraction with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate) to obtain the above-mentioned title product 1-OH (66mg, 64%) and by-product 2-OH (27mg, 26%). The 1-OH product (60mg, 0.094mmol) was dissolved in 2ml dichloromethane and excess TFA (trifluoroacetic acid, 0.5ml) was added slowly. The mixture was stirred at room temperature for 2 hours and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography (eluent dichloromethane: methanol 20: 1) to obtain the desired product (44mg, 87%).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]+。
Example 31
N- (2- (2-fluoro-4-iodo-phenylamino) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -1- (2-hydroxypropyl) -cyclopropane-1-sulfonamide
Figure B200910146822XD0000741
The objective product was obtained in the same manner as in example 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]+。
Example 32
N- (2- (2-fluoro-4-iodo-phenylamino) -4-methoxy-1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) butane-1-sulfonamide
Step A: 2-chloro-4-nitropyridine 1-oxide
Figure B200910146822XD0000742
To a mixture of 2-chloro-5-methylpyridine, a urea hydrogen peroxide addition compound and dichloromethane was added dropwise anhydrous trifluoroacetic acid at 0 ℃, and the mixture was stirred at 0 ℃ for 1 hour. After stirring for 3 days and raising the reaction temperature to room temperature, an aqueous solution (250mL) of sodium dithionite (45g) was added and the reaction mixture was stirred for 15 minutes. Hydrochloric acid (0.5N, 400mL) was added and the mixture was extracted with dichloromethane (400mL)A compound (I) is provided. The organic phase was washed with sodium bicarbonate solution, dried over magnesium sulfate, filtered and the solvent was removed from the filtrate under reduced pressure to give the above title compound as a yellow solid which was used for the next reaction without further purification. The yield was 90%.1H NMR(400MHz，CDCl3)：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 B2-chloro-4-methoxypyridine 1-oxide
Figure B200910146822XD0000751
A sodium methoxide solution prepared by dissolving sodium (21g) in anhydrous MeOH (1000ml) was quickly poured into a stirred solution of 2-chloro-4-nitropyridine-1-oxide (151g) in MeOH (1000 ml). Dissolution was complete in 5 minutes and the reaction was stirred overnight in a stoppered flask. The yellow solution was concentrated in one portion, a precipitate was formed, which was filtered off and washed with MeOH (2X 100 mL). The filtrate and washings were evaporated to dryness and the remaining solid was extracted with boiling dichloromethane to obtain (after filtration and concentration) a tan solid which was reacted further without further purification. The yield was 95%.1H NMR(400MHz，CDCl3)：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)。
And C: 2, 6-dichloro-4-methoxypyridine
Figure B200910146822XD0000752
To a mixture of 2-chloro-4-methoxypyridine 1-oxide (130g) and triethylamine (151ml) in dichloromethane (1000ml) was added a solution of phosphorus oxychloride (151g) in dichloromethane (250ml) at 0 ℃. Stirring at 0 deg.CAfter stirring at room temperature for 2 hours and 1 hour, water was added and the mixture was neutralized with sodium hydroxide solution (6N), and the separated organic layer was washed with a saturated saline solution. The aqueous layer of the reaction solution was extracted with ethyl acetate and washed with a saturated saline solution. With Na2SO4The combined organic layers were dried, filtered and the filtrate was concentrated in vacuo to give the crude product which was purified by silica gel column (petroleum ether/ethyl acetate 10/1) to give the desired compound. The yield was 38.3%.1H NMR(400MHz，CDCl3)：δ＝6.794(s，2H)，3.877(s，3H)；m/z＝178(M+1)。
Step D: 2, 6-dichloro-4-methoxy-3-nitropyridine
Figure B200910146822XD0000761
Concentrated nitric acid (95%) was added to a concentrated sulfuric acid solution of 2, 6-dichloro-4-methoxypyridine (40g) at 0 ℃. The mixture was heated at 100 ℃ for 3.5 hours. After cooling to 50 ℃, the mixture was poured into ice. The resulting precipitate was filtered and washed with water. Dissolve the white solid in dichloromethane and add Na2SO4Drying, filtration and concentration of the filtrate under reduced pressure gave the title compound as a white solid which was used without further purification. The yield was 82%.1H NMR(400MHz，CDCl3)：δ＝6.994(s，1H)，4.023(s，3H)；m/z＝223(M+1)。
Step E: 6-chloro-N- (2-fluoro-4-iodophenyl) -4-methoxy-3-nitropyridin-2-amine
To a THF mixture containing NaH (3.0 equivalents) was added 2-fluoro-4-iodoaniline (1.0 equivalent) at room temperature. The mixture was heated at 60 ℃ for 15 minutes, followed by the addition of 2, 6-dichloro-4-methoxy-3-nitropyridine. After heating to reflux for 0.5 h, the reaction was cooled and water was added. The suspension was filtered and dried to obtain the title compound. The yield was 50%.1H NMR(400MHz，CDCl3)：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-phenylamino) -4-methoxy-5-nitropyridin-2 (1H) -one
Figure B200910146822XD0000763
To an aqueous KOH solution (52 ml water containing 14.4g KOH) was added the compound 6-chloro-N- (2-fluoro-4-iodophenyl) -4-methoxy-3-nitropyridin-2-amine (2g) followed by MeOH (150 ml). The mixture was heated to reflux for 1.5 hours. Cold water was added, the yellow suspension was filtered and dried to yield the title compound. The filtrate was adjusted to pH7 using concentrated hydrochloric acid to obtain a yellow precipitate which was filtered and dried to obtain the above title compound as a red solid which was used for the next reaction without further purification. The yield was 99%.1H NMR(400MHz，CDCl3)：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-phenylamino) -4-methoxy-1-methyl-5-nitropyridin-2 (1H) -one
Figure B200910146822XD0000771
To a solution of NaH (2.5 equivalents) in anhydrous DMF (0.2mol/L) was added 6- (2-fluoro-4-iodophenylamino) -4-methoxy-5-nitropyridin-2 (1H) -one (1 equivalent) at room temperature. After stirring for 25 minutes, methyl iodide (1) was added to the dark red mixture3 equivalents) and stirring continued for 1 hour, then saturated NH was added4And (4) Cl solution. The mixture was extracted with ethyl acetate and washed with water and brine. Using MgSO4The organic layer was dried, filtered, and the filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (from 100% petroleum ether to-1/2 petroleum ether/ethyl acetate) to afford the title compound as a yellow solid. The yield was 50%.1H NMR(400MHz，CDCl3)：δ＝8.799(brs，1H)，7.525～7.268(dd，2H，J＝10&7.6Hz)，6.593～6.551(t，1H，J＝8.4Hz)，5.810(s，1H)，3.912(s，3H)，3.230(s，3H)；m/z＝420(M+1)。
Step H: 5-amino 6- (2-fluoro-4-iodo-phenylamino) -4-methoxy-1-methylpyridin-2 (1H) -one
Figure B200910146822XD0000772
6- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methyl-5-nitropyridin-2 (1H) -one (220mg) and Na2S2O4(1.96g, 16 equivalents) was dissolved in dioxane and water (30mL, 1: 1) followed by addition of NH at room temperature4OH (1 mL). After 1 hour, the mixture was diluted with 100mL of ethyl acetate and washed with water and brine. Extract the aqueous layer with ethyl acetate (2 ×), wash with brine, and wash with Na2SO4Drying, filtration and concentration of the filtrate in vacuo afforded the crude product which was purified by preparative TLC to afford the title compound. The yield was 50%.1H NMR(400MHz，CDCl3)：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-phenylamino) -4-methoxy-1-methyl-6-oxo-1, 6-dihydro Pyridine compound -3-yl) butane-1-sulfonamide
Figure B200910146822XD0000781
According to the method A, 5-amino-6- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methylpyridin-2 (1H) -one is reacted with butane-1-sulfonyl chloride to obtain the objective compound. The yield was 76.6%.1H NMR(400MHz，CDCl3)：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]。
Example 33
N- (2- (2-fluoro-4-iodo-phenylamino) -4-methoxy-1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide
Figure B200910146822XD0000782
According to the method A, 5-amino-6- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methylpyridin-2 (1H) -one is reacted with benzenesulfonyl chloride to obtain the objective compound. The yield was 25%.1H NMR(400MHz，CDCl3)：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]。
Example 34
N- (2- (2-fluoro-4-iodo-phenylamino) -4-methoxy-1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) cyclohexanesulfonamide
Figure B200910146822XD0000791
According to method a, 5-amino-6- (2-fluoro-4-iodo-phenylamino) -4-methoxy-1-methylpyridin-2 (1H) -one is reacted with cyclohexanesulfonyl chloride to obtain the objective compound. The yield was 9.45%.1H NMR(400MHz，CDCl3)：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]。
Example 35
N- (2- (2-fluoro-4-iodo-phenylamino) -4-methoxy-1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) cyclopropanesulfonamide
Figure B200910146822XD0000792
According to method a, 5-amino-6- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methylpyridin-2 (1H) -one is reacted with cyclopropanesulfonyl chloride to give the desired compound. The yield was 19.72%.1H NMR(400MHz，CDCl3)：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]。
Example 36
N- (2- (2-fluoro-4-iodo-phenylamino) -4-methoxy-1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) thiophene-3-sulfonamide
Figure B200910146822XD0000801
According to the method a, 5-amino-6- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methylpyridin-2 (1H) -one is reacted with thiophene-3-sulfonyl chloride to obtain the objective compound. The yield was 34.1%.1H NMR(400MHz，CDCl3)：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]。
Example 37
3-chloro-N- (2- (2-fluoro-4-iodo-phenylamino) -4-methoxy-1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) propane-1-sulfonamide
Figure B200910146822XD0000802
According to method a, 5-amino-6- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methylpyridin-2 (1H) -one was reacted with 3-chloropropane-1-sulfonyl chloride to obtain the desired compound in 29.8% yield.1H NMR(400MHz，CDCl3)：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]。
Example 38
N- (2- (2-fluoro-4-iodo-phenylamino) -4-methoxy-1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) propane-2-sulfonamide
Figure B200910146822XD0000811
According to the method A, 5-amino-6- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methylpyridin-2 (1H) -one is reacted with propane-2-sulfonyl chloride to obtain the objective compound. The yield was 50%.1HNMR(400MHz，CDCl3)：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]。
Example 39
N- (2- (2-fluoro-4-iodo-phenylamino) -4-methoxy-1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) thiophene-2-sulfonamide
Figure B200910146822XD0000812
According to the method a, 5-amino-6- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methylpyridin-2 (1H) -one is reacted with thiophene-2-sulfonyl chloride to obtain the objective compound. The yield was 17.89%.1H NMR(400MHz，CDCl3)：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]。
Example 40
1-chloro-N- (2- (2-fluoro-4-iodo-phenylamino) -4-methoxy-1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) methanesulfonamide
Figure B200910146822XD0000821
According to the method a, 5-amino-6- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methylpyridin-2 (1H) -one is reacted with chloromethanesulfonyl chloride to obtain the objective compound. The yield was 29.8%.1H NMR(400MHz，CDCl3)：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]。
EXAMPLE 41
4-fluoro-N- (2- (2-fluoro-4-iodo-phenylamino) -4-methoxy-1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide
Figure B200910146822XD0000822
According to method a, 5-amino-6- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methylpyridin-2 (1H) -one is reacted with 4-fluoro-benzene-1-sulfonyl chloride to obtain the objective compound. The yield was 27.3%.1H NMR(400MHz，CDCl3)：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]。
Example 42
N- (2- (2-fluoro-4-iodo-phenylamino) -4-methoxy-1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) methanesulfonamide
According to the method A, 5-amino-6- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methylpyridin-2 (1H) -one is reacted with methanesulfonyl chloride to obtain the objective compound. The yield was 30%.1H NMR(400MHz，CDCl3)：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]。
Example 43
2, 2, 2-trifluoro-N- (2- (2-fluoro-4-iodo-phenylamino) -4-methoxy-1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) ethanesulfonamide
Figure B200910146822XD0000832
According to the method a, 5-amino-6- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methylpyridin-2 (1H) -one is reacted with 2, 2, 2-trifluoroethanesulfonyl chloride to obtain the objective compound. The yield was 48.7%.1H NMR(400MHz，CDCl3)：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]。
Example 44
N- (2- (2-fluoro-4-iodo-phenylamino) -4-methoxy-1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -2-phenyl-cyclopropane-1-sulfonamide
According to method A, 5-amino-6- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methylpyridin-2 (1H) -one is reacted with 2-phenyl-cyclopropane-1-sulfonyl chloride, thereby obtaining the objective compound. The yield was 44%.1H NMR(400MHz，CDCl3)：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]。
Example 45
2- (4-ethoxyphenyl) -N- (2- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) cyclopropane-1-sulfonamide
Figure B200910146822XD0000842
According to method a, 5-amino-6- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methylpyridin-2 (1H) -one is reacted with 2- (4-ethoxyphenyl) -cyclopropane-1-sulfonyl chloride to obtain the objective compound. The yield was 13.32%.1H NMR(400MHz，CDCl3)：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]。
Example 46
2- (3, 4-difluorophenyl) -N- (2- (2-fluoro-4-iodo-phenylamino) -4-methoxy-1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) cyclopropane-1-sulfonamide
Figure B200910146822XD0000851
According to the method a, 5-amino-6- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methylpyridin-2 (1H) -one is reacted with 2- (3, 4-difluorophenyl) -cyclopropane-1-sulfonyl chloride, thereby obtaining the objective compound. The yield was 5.79%.1H NMR(400MHz，CDCl3)：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]。
Example 47
N- (2- (2-fluoro-4-iodo-phenylamino) -4-methoxy-1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -2-isopropyl-cyclopropane-1-sulfonamide
Figure B200910146822XD0000852
According to method a, 5-amino-6- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methylpyridin-2 (1H) -one is reacted with 2-isopropyl-cyclopropane-1-sulfonyl chloride to obtain the objective compound. The yield was 40%.1H NMR(400MHz，CDCl3)：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]。
Example 48
N- (2- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -2-isobutyl-cyclopropane-1-sulfonamide
Figure B200910146822XD0000861
According to method a, 5-amino-6- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methylpyridin-2 (1H) -one is reacted with 2-isobutyl-cyclopropane-1-sulfonyl chloride to obtain the target compound. The yield was 35.4%.1H NMR(400MHz，CDCl3)：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]。
Example 49
N- (2- (2-fluoro-4-iodo-phenylamino) -4-methoxy-1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -2- (thiophen-2-yl) -cyclopropane-1-sulfonamide
According to method a, 5-amino-6- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methylpyridin-2 (1H) -one is reacted with 2- (thiophen-2-yl) -cyclopropane-1-sulfonyl chloride to obtain the objective compound. The yield was 6.76%.1H NMR(400MHz，CDCl3)：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]。
Example 50
2- (2, 4-difluorophenyl) -N- (2- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) cyclopropane-1-sulfonamide
According to the method a, 5-amino-6- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methylpyridin-2 (1H) -one is reacted with 2- (2, 4-difluorophenyl) -cyclopropane-1-sulfonyl chloride, thereby obtaining the objective compound. The yield was 41.8%.1H NMR(400MHz，CDCl3)：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]。
Example 51
2- (3, 5-difluorophenyl) -N- (2- (2-fluoro-4-iodo-phenylamino) -4-methoxy-1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) cyclopropane-1-sulfonamide
Figure B200910146822XD0000881
According to the method a, 5-amino-6- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methylpyridin-2 (1H) -one is reacted with 2- (3, 5-difluorophenyl) -cyclopropane-1-sulfonyl chloride, thereby obtaining the objective compound. The yield was 28.9%.1H NMR(400MHz，CDCl3)：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]。
Example 52
2- (4-cyanophenyl) -N- (2- (2-fluoro-4-iodo-phenylamino) -4-methoxy-1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) cyclopropane-1-sulfonamide
Figure B200910146822XD0000882
According to method a, 5-amino-6- (2-fluoro-4-iodophenylamino) -4-methoxy-1-methylpyridin-2 (1H) -one is reacted with 2- (4-cyanophenyl) -cyclopropane-1-sulfonyl chloride to obtain the objective compound. The yield was 2%.1H NMR(400MHz，CDCl3)：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 assay
Materials and reagents:
the Kinase Glo Plus kit was purchased from Promega. Substrate, APT, DTT and dimethyl sulfoxide were purchased from Sigma-Aldrich.
MEK1 kinase, europium-labeled antibody, tracer 236 and binding buffer a were purchased from Invitrogen.
Recombinant human Epidermal Growth Factor (EGF) was purchased from R & D System.
The SureFire Phospho-ERK1/2 test kit and the AlphaScreen General IgG (protein A) test kit were purchased from Perkinelmer.
Obtaining an IC50Data of
Determination of enzyme Activity:
the DMSO stock containing the compound was diluted to 1 Xbuffer (20mM MOPS (pH7.4), 5mM MgCl2、0.5mM MnCl2100uM sodium orthovanadate, 0.01% Triton X-100, 1mM DTT). Typical reagents contain 0.01nmol MEK1 kinase, 0.01nmol ATP and 10ng substrate. The screening assay essentially comprises four steps. 2ul of the diluted compound was added to a 384 well test white plate. Subsequently, 6ul of the kinase-substrate mixture was added to each well. Subsequently, 2ul 5x ATP was added to each well to initiate the reaction. The plates were sealed and incubated at 22 ℃ for 60 minutes in the absence of light. Finally, 10ul of Kinase Glo Plus reagent was added to each well to stop the reaction. Incubate at room temperature in the dark for 10 minutes. The tip seal on the plate was removed and the plate was read by EnVision 2104 multimark plate reader (PerkinElmer) using standard luminescence procedure. The intensity of the luminescence signal was quantified and this data was used to generate a dose response curve and the IC calculated by the Prism program50。
Determination of kinase binding Activity
The DMSO stock containing the compound was diluted to buffer (20mM MOPS (pH7.4), 5mM MgCl2、0.5mM MnCl2100uM sodium orthovanadate, 0.01% Triton X-100, 1mM DTT). Typical reagents comprise 3X 10-4nmol MEK1 kinase, 3X 10-5nmol europium-labeled antibody, 1.5X 10-3nmol tracer 236. The screening assay essentially comprises three steps. 5ul of the diluted compound was dispensed into 384 well assay blackboards. Subsequently, 5ul of 3x kinase-antibody mixture diluted in 1 x buffer a was added to each well. To each well was added 5ul of 3x tracer 236 diluted in 1 x buffer a to start the reaction. The plates were sealed and incubated at 22 ℃ for 60 minutes in the absence of light. Removing deviceThe plates were decapsulated and read by an EnVision 2104 multimarker plate reader (PerkinElmer) using the TR-FRET program. The intensity of the fluorescent signal was quantified and this data was used to generate a dose response curve and the IC50 was calculated by the Prism program.
Cell-based IC50Data of
The effect of compounds on phosphorylated ERK in cells was determined by AlphaScreen assay. MCF-7 breast cancer cells were plated at a density of 80,000 cells per well in 96-well plates and humidified CO at 37 ℃2Growing in an incubator. The next day, growth medium (DMEM + 10% fetal bovine serum) was removed and replaced with starvation medium (DMEM only). Cells were incubated overnight in starvation medium and subsequently treated with a range of concentrations of compound for 60 minutes at 37 ℃. After incubation with compound, cells were stimulated with EGF for 10 minutes. Subsequently, the cells were lysed and each lysate (4ul) was transferred to a 384-well reaction whiteboard. In the dark, a freshly prepared mixture of AlphaScreen bead and buffer was added to each well. Plates were sealed and incubated at 25 ℃ for 2 hours in the dark. The tip seal was removed and the plate was read by EnVision 2104 multi-label plate reader (PerkinElmer) using an optimized AlphaScreen program. The intensity of the signal was quantified and this data was used to generate a dose response curve and the IC calculated by the Prism program50。
Biological data of selected compounds
Selected compounds prepared as described above were tested according to the biological methods described herein. The results are shown in the 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. A compound represented by formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof,
formula I
Wherein
R0Is H, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C2-C6Alkenyl radical, C5-C6Cycloalkenyl or C2-C6An alkynyl group; wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl, and C3-C6One or two ring-forming carbon atoms in a cycloalkyl group is optionally independently replaced with O, N or S;
R1is H, C1-C4Alkoxy radical, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C2-C6Alkenyl radical, C5-C6Cycloalkenyl or C2-C6An alkynyl group; wherein said alkoxy, alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl, or
R1Is a five-or six-membered saturated heterocyclic group, unsaturated heterocyclic group or aromatic heterocyclic group, wherein the heterocyclic group contains 1 to 5 heteroatoms independently selected from the group consisting of O, N and S, and the heterocyclic group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl; or
R1is-CH2X, wherein X represents a group of formula II:
Figure F200910146822XC0000021
formula II
Wherein
Y1And Y2May be the same or different and each represents a single bond, -CO-, -COO, -O-, -OCO-, -NRaor-SO2-；
Y3Represents C which may be substituted by 1 to 3 groups represented by Z1-5An alkyl group;
z may be the same or different and represents C which may be optionally substituted by one or more substituents1-5Alkyl, halogen atom, oxo group, -ORa、-COORa、-COOCORa-CO-halogen atom, -OCORa、-CONRaRb、-SRa、-SO2Ra、-NRaRb、-NRaCORb、NRaSO2Rb、-SO2NRaRbA monocyclic heterocyclic group or a bicyclic heterocyclic group or a monocyclic or bicyclic heteroaryl group, said substituents being selected from the group consisting of1-5Alkyl radical, -ORaAnd NRaRbA group of (a); each of the alkyl groups may be substituted by hydroxy, C1-5Alkoxy or amino substitution; in addition to the oxygen substituent and halogen, the above substituents may be linked to each other to form a cycloalkyl OR heterocyclic group, which may have one OR more substituents selected from the group consisting of-ORa、NRaRbAnd may be-ORaSubstituted C1-5Alkyl groups;
Raand RbMay be the same or different, each represents a hydrogen atom or C which may be substituted with 1 to 3 substituents1-5An alkyl group, the substituent being selected from the group consisting of hydroxy, C1-5Alkoxy and amino;
the symbol "●" used in formula II represents a linking site;
when X ═ C, R2Is H, C1-C4Alkoxy radical, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C2-C6Alkenyl radical, C5-C6Cycloalkenyl or C2-C6An alkynyl group; wherein said alkoxy, alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl is optionally substituted with 1-3 substituents, said substitutionThe radicals are independently selected from the group consisting of halogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl, or R2Is a five-or six-membered saturated, unsaturated or aromatic heterocyclic group, wherein the heterocyclic group has 1 to 5 heteroatoms selected from the group consisting of O, N and S, wherein the heterocyclic group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl; or
When X is N, R2Is absent; and
R3selected from trifluoromethyl, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, C3-C10Cycloalkyl radical, C3-C10Cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl groups, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl group is unsubstituted or substituted with 1-3 substituents independently selected from halogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, trifluoromethyl, difluoromethoxy, phenyl or substituted phenyl with 1-3 substituents independently selected from hydrogen, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy, cyano, trifluoromethyl or difluoromethoxy;
R4、R5、R6、R7and R8Independently selected from hydrogen, halogen, cyano, nitro, trifluoromethyl, SR9、OR9、C(O)R9、NR10C(O)OR12、OC(O)R9、NR10S(O)jR12、S(O)jNR9R10、S(O)jNR10C(O)R9、C(O)NR10S(O)jR12、S(O)jR12、NR10C(O)R9、C(O)NR9R10、NR11C(O)NR9R10、NR11C(NCN)NR9R10、NR9R10And C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, C3-C10Cycloalkyl radical, C3-C10Cycloalkylalkyl, S (O)j(C1-C6Alkyl), S (O)j(CR10R11)mAryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, O (CR)10R10)mAryl, NR10(CR10R11)mAryl, O (CR)10R11)m-heteroaryl, NR10(CR10R11)mHeteroaryl, O (CR)10R11)m-heterocyclic radical, NR10(CR10R11)m-heterocyclyl and S (C)1-C2Alkyl) optionally substituted with 1 to 5 fluorine atoms;
R9selected from hydrogen, trifluoromethyl, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, C3-C10Cycloalkyl radical, C3-C10Cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl groups, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl group is unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C4Alkyl, hydroxy and amino;
R10selected from hydrogen or C1-C6Alkyl, wherein alkyl may be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C4Alkyl, hydroxy and amino; or
R9And R10May form a 4-to 10-membered heteroaromatic or heterocyclic ring together with the atoms to which they are attached, wherein each ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, C1-C4Alkyl, hydroxy and amino;
R11selected from hydrogen or C1-C6Alkyl, wherein alkyl may be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C4Alkyl, hydroxy and amino; or
R10、R11And the atoms to which they are attached form a 4-to 10-membered carbocyclic, heteroaromatic or heterocyclic ring, each ring unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, C1-C4Alkyl, hydroxy and amino;
R12selected from trifluoromethyl, C1-C10Alkyl radical, C3-C10Cycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl groups, wherein each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl group is unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C4Alkyl, hydroxy and amino;
m is 0, 1, 2, 3, 4 or 5, and
j is 1 or 2; and X is C or N.
2. A compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, wherein
R0Is H or C1-C6An alkyl group; r1Is H or C1-C6An alkyl group; r2Is absent or R2Is H or C1-C6An alkoxy group; r3Selected from the group consisting of: c optionally substituted by one or more halogens or hydroxy groups1-C6An alkyl group; optionally substituted by one or more halogensOr hydroxy-substituted C2-C6An alkenyl group; optionally is covered with C1-C6Alkyl or C2-C6Alkenyl-substituted C3-C6A cycloalkyl group; monocyclic or bicyclic heteroaryl wherein the heteroatom is one or more of O, N or S; monocyclic or bicyclic aryl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, C1-C6Alkoxy and hydroxy; arylcycloalkyl, wherein aryl is monocyclic or bicyclic aryl and cycloalkyl is a group having 1 to 6 carbon atoms; and C1-C6Alkyl radical C1-C6A cycloalkyl group; and
R4、R5、R6、R7and R8Independently selected from H or halogen.
3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, having the structure of formula
Figure F200910146822XC0000041
Wherein
R0Is H or C1-C6An alkyl group; r1Is H or C1-C6An alkyl group; r2Is absent or R2Is H or C1-C6An alkoxy group; r3Selected from the group consisting of: c optionally substituted by one or more halogens or hydroxy groups1-C6An alkyl group; c optionally substituted by one or more halogens or hydroxy groups2-C6An alkenyl group; optionally is covered with C1-C6Alkyl or C2-C6Alkenyl-substituted C3-C6A cycloalkyl group; monocyclic or bicyclic heteroaryl wherein the heteroatom is one or more of O, N or S; monocyclic or bicyclic aryl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, C1-C6Alkoxy and hydroxy; arylcycloalkyl, wherein aryl is monocyclic or bicyclic aryl and cycloalkyl is a group having 1 to 6 carbon atoms; and C1-C6Alkyl radical C1-C6A cycloalkyl group; and
R4、R5、R6、R7and R8Independently selected from H or halogen.
R13Selected from the group consisting of H, C2-C6Alkenyl and C1-C6Alkyl, wherein said group may be optionally substituted with one or more substituents selected from the group consisting of halogen or hydroxy; and
R14selected from the group consisting of H, C1-C6Alkyl, monocyclic or bicyclic aryl and monocyclic or bicyclic heteroaryl wherein the heteroatom is one or more of O, N or S, wherein said group is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano and C1-C6Alkoxy groups.
4. The compound of claim 3, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, having the structure of formula
Figure F200910146822XC0000051
Wherein,
R1、R2、R13and R14As defined in claim 3.
5. The compound of claim 4, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, having the structure of formula
Wherein
R13And R14As defined in claim 4.
6. The compound of claim 5, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, selected from the group consisting of:
Figure F200910146822XC0000061
7. the compound of claim 4, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, having the structure of formula
Figure F200910146822XC0000062
Wherein
R13And R14As defined in claim 4.
8. A compound of claim 7, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, selected from the group consisting of:
Figure F200910146822XC0000071
9. a pharmaceutical composition comprising a compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, and a pharmaceutically acceptable carrier.
10. Use of a compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, for the preparation of a pharmaceutical composition for the inhibition of MEK enzymes.
11. Use of a compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, for the manufacture of a pharmaceutical composition for the treatment or prevention of a MEK mediated disease or disorder.
12. Use of a compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, for the preparation of a pharmaceutical composition for the treatment or prevention of a proliferative disease.
13. The use of claim 12, wherein the proliferative disease is selected from an inflammatory disease or cancer.
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