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CN101583616B - Aza-benzothiophenyl compounds and methods of use - Google Patents

Aza-benzothiophenyl compounds and methods of use Download PDF

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CN101583616B
CN101583616B CN2007800391963A CN200780039196A CN101583616B CN 101583616 B CN101583616 B CN 101583616B CN 2007800391963 A CN2007800391963 A CN 2007800391963A CN 200780039196 A CN200780039196 A CN 200780039196A CN 101583616 B CN101583616 B CN 101583616B
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CN101583616A (en
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斯蒂芬·普赖斯
卡伦·威廉斯
帕斯卡尔·P·萨维
黑泽尔·J·戴克
约翰·G·蒙塔纳
马克·S·斯坦利
鲍亮
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Genentech Inc
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Genentech Inc
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Abstract

The invention relates to azabenzothiophenyl compounds of Formula (I) with anti-cancer and/or anti-inflammatory activity and more specifically to azabenzothiophenyl compounds which inhibit MEK kinase activity. The invention provides compositions and methods useful for inhibiting abnormal cell growth or treating a hyperproliferative disorder, or treating an inflammatory disease in a mammal. The invention also relates to methods of using the compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.

Description

Aza-benzothiophenyl compounds and application method
Related application
The application is international patent application, its requirement is filed in August, 2006 U.S. Provisional Application of 21 days 60/839,161st, it is filed in the U.S. Provisional Application 60/871 on December 22nd, 2006,600 and it is filed in the U.S. Provisional Application 60/917 on May 11st, 2007, the content of above-mentioned provisional application, is incorporated herein by reference by 624 priority herein.
Technical field
The present invention relates to the aza-benzothiophenyl with anticancer and/or anti-inflammatory activity (azabenzothiophenyl) compound, relate more specifically to suppress the aza-benzothiophenyl compounds of MEK kinase activities.The invention further relates to be used for the method for external, in situ and in-vivo diagnostic or treatment mammalian cell or associated pathology illness using the compound.
Background technology
In order to understand how Ras transmits extracellular growth signal, occur in that MAP (mitogen-activated protein, mitogen-activated protein) kinases (MAPK) approach is used as the critical path between film combination Ras and nucleus.MAPK approach includes the phosphorylation cascades event for being related to three kinds of Key kinases (i.e. Raf, MEK (map kinase kinases) and ERK (map kinase)).The GTP combinations Ras of activation causes the activation of Raf kinases and indirect phosphorylation.Then Raf carries out phosphorylation (Ahn et al., Methods in Enzymology 2001,332,417-431) on two serine residues (being S218 and S222 for MEK1, be S222 and S226 for MEK2) to MEK1 and MEK2.Then the MEK activated carries out phosphorylation to its only known substrate i.e. map kinase ERK1 and ERK2.For ERK1, phosphorylations of the ERK through MEK is appeared on Y204 and T202, and (Ahn et al., Methods in Enzymology 2001,332,417-431) is appeared on Y185 and T183 for ERK2.The ERK formation dimers of phosphorylation, are then transferred to its nucleus (Khokhlatchevet al., Cell 1998,93,605-615) gathered.In nucleus, it is related to ERK in several important cell functions, these functions include but is not limited to nuclear translocation, signal transduction (signal transduction), DNA reparations, nucleosome assembling and transposition (nucleosome assembly and translocation) and mRNA processing and translation (Ahn et al., Molecular Cell 2000,6,1343-1354).Generally speaking, processing causes ERK1 and ERK2 activation with the cell of growth factor, which results in propagation, and result in differentiation (Lewis et al., Adv.Cancer Res.1998,74,49-139) in some cases.
Strong evidence shows, the genetic mutation of involved protein kinase and/or overexpression cause uncontrolled cell to breed and ultimately result in tumour to be formed in proliferative diseases in map kinase approach.For example, certain cancers, which are included, causes the mutation of the continuous activation as above-mentioned approach caused by the continuously generating of growth factor.Other mutation can cause the inactivation of the GTP combination Ras compounds of activation to lack, and this causes the activation of map kinase approach again.Ras mutation oncogenic form is found (Kohl et al., Science 1993,260,1834-1837) in 50% colon cancer and the cancers of pancreas of ＞ 90% and a variety of other types of cancers.Recently, bRaf mutation (Davies, H.et al., Nature 2002,417,949-954) are identified in more than 60% chromoma.These mutation in bRaf cause composition activating MAP kinases to cascade.The constitutive character activation of map kinase approach or overactivity (Hoshino in cancer of pancreas, colon cancer, lung cancer, oophoroma and kidney (kidney cancer) have also been shown in the research of primary tumor sample and cell line, R.et al., Oncogene 1999,18,813-822).
MEK occurs as attractive therapeutic targets in map kinase cascade pathway.The MEK for being in Ras and Raf downstreams is high degree of specificity to the phosphorylation of map kinase；In fact, the only known substrate of MEK phosphorylations is map kinase ERK1 and ERK2.Had shown that in several researchs and MEK is carried out to suppress that there is potential treatment benefit.For example, have shown that small molecule mek inhibitor suppresses human tumour growth (the Sebolt-Leopold et al. in nude mouse xenograft thing (nude mouse xenograft), Nature-Medicine 1999, 5 (7), 810-816), Trachet et al., AACR Apr.6-10, 2002, Poster#5426 and Tecle, H.IBC 2.sup.nd InternationalConference of Protein Kinases, Sep.9-10, 2002), block the Static allodni (static allodynia) (WO 01/05390 disclosed in 25 days January in 2001) in animal and suppress growth (the Milella et al. of acute myelocytic leukemia (acute myeloid leukemia) cell, J Clin Invest2001, 108 (6), 851-859).
Several small molecule mek inhibitors are discussed in such as WO02/06213, WO 03/077855 and WO03/077914.There are still to being used to treating the various proliferative diseases states such as illness related to MEK hyperactivity hyperkinesias and the need for the new mek inhibitor of the disease of MEK Cascade controls as therapeutic agent effectively and safely.
The content of the invention
The present invention relates generally to the aza-benzothiophenyl compounds (and/or its solvate and salt) with anticancer and/or anti-inflammatory activity and the more specific Formulas I with MEK kinase inhibiting activities.Some excess proliferatives (hyperproliferative) and inflammatory disease are characterised by the regulation to MEK kinase functions, such as mutation or overexpression due to the protein (MEK kinases).Therefore, the compounds of this invention and the composition comprising it can be used for treatment excess proliferative disease (such as cancer) and/or inflammatory disease (such as rheumatoid arthritis).
Figure G2007800391963D00031
Wherein
Z1For CR1Or N；
Z2For CR2Or N；
Z3For CR3Or N；
Z4For CR4Or N；
Wherein Z1、Z2、Z3And Z4In one or two be N；
R1、R2、R3H, halogen, CN, CF are independently selected from R43、-OCF3、-NO2、-(CR14R15)nC (=Y) R11、-(CR14R15)nC (=Y) OR11、-(CR14R15)nC (=Y) NR11R12、-(CR14R15)nNR11R12、-(CR14R15)nOR11、-(CR14R15)nSR11、-(CR14R15)nNR12C (=Y) R11、-(CR14R15)nNR12C (=Y) OR11、-(CR14R15)nNR13C (=Y) NR11R12、-(CR14R15)nNR12SO2R11、-(CR14R15)nOC (=Y) R11、-(CR14R15)nOC (=Y) OR11、-(CR14R15)nOC (=Y) NR11R12、-(CR14R15)nOS(O)2(OR11)、-(CR14R15)nOP (=Y) (OR11)(OR12)、-(CR14R15)nOP(OR11)(OR12)、-(CR14R15)nS(O)R11、-(CR14R15)nS(O)2R11、-(CR14R15)nS(O)2NR11R12、-(CR14R15)nS(O)(OR11)、-(CR14R15)nS(O)2(OR11)、-(CR14R15)nSC (=Y) R11、-(CR14R15)nSC (=Y) OR11、-(CR14R15)nSC (=Y) NR11R12、C1-C12Alkyl, C2-C8Alkenyl, C2-C8Alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl；
W is
Figure G2007800391963D00032
R5And R6It is independently selected from H or C1-C12Alkyl；
X1Selected from R11、-OR11、-NR11R12、-S(O)R11With-S (O)2R11；Work as X1For R11Or-OR11When, R5And X1In R11Or R5And X1In-OR11The nitrogen-atoms being optionally connected with them connects together to form 4-7 members saturation or unsaturation ring with the 0-2 additional heteroatom selected from O, S and N, wherein the ring is optionally selected from following one or more substituent groups：Halogen, CN, CF3、-OCF3、-NO2, oxo ,-Si (C1-C6Alkyl)3、-(CR19R20)nC (=Y ') R16、-(CR19R20)nC (=Y ') OR16、-(CR19R20)nC (=Y ') NR16R17、-(CR19R20)nNR16R17、-(CR19R20)nOR16、-(CR19R20)n-SR16、-(CR19R20)nNR16C (=Y ') R17、-(CR19R20)nNR16C (=Y ') OR17、-(CR19R20)nNR18C (=Y ') NR16R17、-(CR19R20)nNR17SO2R16、-(CR19R20)nOC (=Y ') R16、-(CR19R20)nOC (=Y ') OR16、-(CR19R20)nOC (=Y ') NR16R17、-(CR19R20)nOS(O)2(OR16)、-(CR19R20)nOP (=Y ') (OR16)(OR17)、-(CR19R20)nOP(OR16)(OR17)、-(CR19R20)nS(O)R16、-(CR19R20)nS(O)2R16、-(CR19R20)nS(O)2NR16R17、-(CR19R20)nS(O)(OR16)、-(CR19R20)nS(O)2(OR16)、-(CR19R20)nSC (=Y ') R16、-(CR19R20)nSC (=Y ') OR16、-(CR19R20)nSC (=Y ') NR16R17And R21；
X2Selected from carbocylic radical, heterocyclic radical, aryl and heteroaryl；
R11、R12And R13Stand alone as H, C1-C12Alkyl, C2-C8Alkenyl, C2-C8Alkynyl, carbocylic radical, heterocyclic radical, aryl or heteroaryl；Or
R11And R12Formed together with the nitrogen that they are connected with 0-2 heteroatomic 3-8 members saturated rings, unsaturation ring or aromatic rings selected from O, S and N, wherein the ring is optionally selected from following one or more substituent groups：Halogen, CN, CF3、-OCF3、-NO2、C1-C6Alkyl ,-OH ,-SH ,-O (C1-C6Alkyl) ,-S (C1-C6Alkyl) ,-NH2、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2、-SO2(C1-C6Alkyl) ,-CO2H、-CO2(C1-C6Alkyl) ,-C (O) NH2、-C(O)NH(C1-C6Alkyl) ,-C (O) N (C1-C6Alkyl)2、-N(C1-C6Alkyl) C (O) (C1-C6Alkyl) ,-NHC (O) (C1-C6Alkyl) ,-NHSO2(C1-C6Alkyl) ,-N (C1-C6Alkyl) SO2(C1-C6Alkyl) ,-SO2NH2、-SO2NH(C1-C6Alkyl) ,-SO2N(C1-C6Alkyl)2、-OC(O)NH2、-OC(O)NH(C1-C6Alkyl) ,-OC (O) N (C1-C6Alkyl)2、-OC(O)O(C1-C6Alkyl) ,-NHC (O) NH (C1-C6Alkyl) ,-NHC (O) N (C1-C6Alkyl)2、-N(C1-C6Alkyl) C (O) NH (C1-C6Alkyl) ,-N (C1-C6Alkyl) C (O) N (C1-C6Alkyl)2、-NHC(O)NH(C1-C6Alkyl) ,-NHC (O) N (C1-C6Alkyl)2、-NHC(O)O(C1-C6Alkyl) and-N (C1-C6Alkyl) C (O) O (C1-C6Alkyl)；
R14And R15It is independently selected from H, C1-C12Alkyl, aryl, carbocylic radical, heterocyclic radical and heteroaryl；
Y stands alone as O, NR11Or S；
Wherein R1、R2、R3、R4、R5、R6、X1、X2、R11、R12、R13、R14And R15In each alkyl, alkenyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl is individually optional is independently selected from following one or more substituent group halogens, CN, CF3、-OCF3、-NO2, oxo ,-Si (C1-C6Alkyl)3、-(CR19R20)nC (=Y ') R16、-(CR19R20)nC (=Y ') OR16、-(CR19R20)nC (=Y ') NR16R17、-(CR19R20)nNR16R17、-(CR19R20)nOR16、-(CR19R20)n-SR16、-(CR19R20)nNR16C (=Y ') R17、-(CR19R20)nNR16C (=Y ') OR17、-(CR19R20)nNR18C (=Y ') NR16R17、-(CR19R20)nNR17SO2R16、-(CR19R20)nOC (=Y ') R16、-(CR19R20)nOC (=Y ') OR16、-(CR19R20)nOC (=Y ') NR16R17、-(CR19R20)nOS(O)2(OR16)、-(CR19R20)nOP (=Y ') (OR16)(OR17)、-(CR19R20)nOP(OR16)(OR17)、-(CR19R20)nS(O)R16、-(CR19R20)nS(O)2R16、-(CR19R20)nS(O)2NR16R17、-(CR19R20)nS(O)(OR16)、-(CR19R20)nS(O)2(OR16)、-(CR19R20)nSC (=Y ') R16、-(CR19R20)nSC (=Y ') OR16、-(CR19R20)nSC (=Y ') NR16R17And R21；
Each R16、R17And R18Stand alone as H, C1-C12Alkyl, C2-C8Alkenyl, C2-C8Alkynyl, carbocylic radical, heterocyclic radical, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, carbocylic radical, heterocyclic radical, aryl or heteroaryl are optionally selected from following one or more substituent groups：Halogen, CN ,-OCF3、CF3、-NO2、C1-C6Alkyl ,-OH ,-SH ,-O (C1-C6Alkyl) ,-S (C1-C6Alkyl) ,-NH2、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2、-SO2(C1-C6Alkyl) ,-CO2H、-CO2(C1-C6Alkyl) ,-C (O) NH2、-C(O)NH(C1-C6Alkyl) ,-C (O) N (C1-C6Alkyl)2、-N(C1-C6Alkyl) C (O) (C1-C6Alkyl) ,-NHC (O) (C1-C6Alkyl) ,-NHSO2(C1-C6Alkyl) ,-N (C1-C6Alkyl) SO2(C1-C6Alkyl) ,-SO2NH2、-SO2NH(C1-C6Alkyl) ,-SO2N(C1-C6Alkyl)2、-OC(O)NH2、-OC(O)NH(C1-C6Alkyl) ,-OC (O) N (C1-C6Alkyl)2、-OC(O)O(C1-C6Alkyl) ,-NHC (O) NH (C1-C6Alkyl) ,-NHC (O) N (C1-C6Alkyl)2、-N(C1-C6Alkyl) C (O) NH (C1-C6Alkyl) ,-N (C1-C6Alkyl) C (O) N (C1-C6Alkyl)2、-NHC(O)NH(C1-C6Alkyl) ,-NHC (O) N (C1-C6Alkyl)2、-NHC(O)O(C1-C6Alkyl) and-N (C1-C6Alkyl) C (O) O (C1-C6Alkyl)；Or
R16And R17Formed together with the nitrogen that they are connected with 0-2 heteroatomic 3-8 members saturated rings, unsaturation ring or aromatic rings selected from O, S and N, wherein the ring is optionally selected from following one or more substituent groups：Halogen, CN ,-OCF3、CF3、-NO2、C1-C6Alkyl ,-OH ,-SH ,-O (C1-C6Alkyl) ,-S (C1-C6Alkyl) ,-NH2、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2、-SO2(C1-C6Alkyl) ,-CO2H、-CO2(C1-C6Alkyl) ,-C (O) NH2、-C(O)NH(C1-C6Alkyl) ,-C (O) N (C1-C6Alkyl)2、-N(C1-C6Alkyl) C (O) (C1-C6Alkyl) ,-NHC (O) (C1-C6Alkyl) ,-NHSO2(C1-C6Alkyl) ,-N (C1-C6Alkyl) SO2(C1-C6Alkyl) ,-SO2NH2、-SO2NH(C1-C6Alkyl) ,-SO2N(C1-C6Alkyl)2、-OC(O)NH2、-OC(O)NH(C1-C6Alkyl) ,-OC (O) N (C1-C6Alkyl)2、-OC(O)O(C1-C6Alkyl) ,-NHC (O) NH (C1-C6Alkyl) ,-NHC (O) N (C1-C6Alkyl)2、-N(C1-C6Alkyl) C (O) NH (C1-C6Alkyl) ,-N (C1-C6Alkyl) C (O) N (C1-C6Alkyl)2、-NHC(O)NH(C1-C6Alkyl) ,-NHC (O) N (C1-C6Alkyl)2、-NHC(O)O(C1-C6Alkyl) and-N (C1-C6Alkyl) C (O) O (C1-C6Alkyl)；
R19And R20It is independently selected from H, C1-C12Alkyl, aryl-(CH2)n-, carbocylic radical-(CH2)n-, heterocyclic radical-(CH2)n- and heteroaryl-(CH2)n-；
R21For C1-C12Alkyl, C2-C8Alkenyl, C2-C8Alkynyl, carbocylic radical, heterocyclic radical, aryl or heteroaryl, wherein R21In each member be optionally selected from following one or more substituent groups：Halogen, oxo, CN ,-OCF3、CF3、-NO2、C1-C6Alkyl ,-OH ,-SH ,-O (C1-C6Alkyl) ,-S (C1-C6Alkyl) ,-NH2、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2、-SO2(C1-C6Alkyl) ,-CO2H、-CO2(C1-C6Alkyl) ,-C (O) NH2、-C(O)NH(C1-C6Alkyl) ,-C (O) N (C1-C6Alkyl)2、-N(C1-C6Alkyl) C (O) (C1-C6Alkyl) ,-NHC (O) (C1-C6Alkyl) ,-NHSO2(C1-C6Alkyl) ,-N (C1-C6Alkyl) SO2(C1-C6Alkyl) ,-SO2NH2、-SO2NH(C1-C6Alkyl) ,-SO2N(C1-C6Alkyl)2、-OC(O)NH2、-OC(O)NH(C1-C6Alkyl) ,-OC (O) N (C1-C6Alkyl)2、-OC(O)O(C1-C6Alkyl) ,-NHC (O) NH (C1-C6Alkyl) ,-NHC (O) N (C1-C6Alkyl)2、-N(C1-C6Alkyl) C (O) NH (C1-C6Alkyl) ,-N (C1-C6Alkyl) C (O) N (C1-C6Alkyl)2、-NHC(O)NH(C1-C6Alkyl) ,-NHC (O) N (C1-C6Alkyl)2、-NHC(O)O(C1-C6Alkyl) and-N (C1-C6Alkyl) C (O) O (C1-C6Alkyl)；
Each Y ' stands alone as O, NR22Or S；
R22For H or C1-C12Alkyl；And
M and n are independently selected from 0,1,2,3,4,5 or 6.
The present invention includes the composition (such as pharmaceutical composition) containing compound of formula I (and/or its solvate and salt) and carrier (pharmaceutical acceptable carrier).Present invention additionally comprises the composition (such as pharmaceutical composition) containing compound of formula I (and/or its solvate and salt) and carrier (pharmaceutical acceptable carrier) and another chemotherapeutic agent and/or another anti-inflammatory drug.The present composition can be used for suppressing abnormal cell growth or treatment excess proliferative disease in mammal (such as people).The present composition can be additionally used in the treatment inflammatory disease in mammal (such as people).
Present invention resides in suppressing abnormal cell growth or the method for treating excess proliferative disease in mammal (such as people), methods described includes the composition by the compound of formula I (and/or its solvate and salt) of therapeutically effective amount or comprising it individually or gives the mammal together with another chemotherapeutic agent.
Present invention resides in the method for the treatment of inflammatory disease in mammal (such as people), methods described includes the composition by the compound of formula I (and/or its solvate and salt) of therapeutically effective amount or comprising it individually or gives the mammal together with another anti-inflammatory drug.
The method that the present invention is used for external, in situ and in-vivo diagnostic or treatment mammalian cell, organ or associated pathology illness including the use of the compounds of this invention.
Embodiment
It is additional structure and the embodiment shown by chemical formula now to describe certain embodiments of the present invention in detail.When the present invention is described with listed illustrated embodiments, it should be appreciated that they, which are not intended to, limits the invention to those embodiments.On the contrary, it is contemplated that covering may include having altered, changing and the equivalent form of value in the scope of the invention as defined by the following claims.It will be appreciated by those skilled in the art that a variety of methods similar or of equal value with material with those methods described herein and material, these methods and material can be used in the practice of the present invention.The present invention is never limited to described method and material.If one or more document, patent and similar materials for introducing and the application (term, the usage of term, described technology etc. defined in including but is not limited to) different or contradiction, are defined by the application.
Definition
Term " alkyl " defined herein refers to the saturated straight chain or branched monovalent hydrocarbon group being made up of one to 12 carbon atom.The example of alkyl includes but is not limited to methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), 1- propyl group (n-Pr, n-propyl ,-CH2CH2CH3), 2- propyl group (i-Pr, isopropyl ,-CH (CH3)2), 1- butyl (n-Bu, normal-butyl ,-CH2CH2CH2CH3), 2- methyl isophthalic acids-propyl group (i-Bu, isobutyl group ,-CH2CH(CH3)2), 2- butyl (s-Bu, sec-butyl ,-CH (CH3)CH2CH3), 2- methyl-2-propyls (t-Bu, the tert-butyl group ,-C (CH3)3), 1- amyl groups (n-pentyl ,-CH2CH2CH2CH2CH3), 2- amyl groups (- CH (CH3)CH2CH2CH3), 3- amyl groups (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl isophthalic acids-butyl (- CH2CH2CH(CH3)2), 2-methyl-1-butene base (- CH2CH(CH3)CH2CH3), 1- hexyls (- CH2CH2CH2CH2CH2CH3), 2- hexyls (- CH (CH3)CH2CH2CH2CH3), 3- hexyls (- CH (CH2CH3)(CH2CH2CH3)), 2- methyl -2- amyl groups (- C (CH3)2CH2CH2CH3), 3- methyl -2- amyl groups (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- amyl groups (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- amyl groups (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl groups (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)C(CH3)3, 1- heptyl, 1- octyl groups etc..
Term " alkenyl " refers to there is at least one unsaturated site i.e. carbon carbon sp by what one to 12 carbon atom was constituted2The straight or branched univalence hydrocarbyl of double bond, wherein the alkenyl includes the group with " cis " and " trans " orientation (or " E " and " Z " is orientated).Example includes but is not limited to vinyl (ethylenyl or vinyl) (- CH=CH2), pi-allyl (- CH2CH=CH2) etc..
Term " alkynyl " refers to there is at least one the unsaturated site i.e. straight or branched univalence hydrocarbyl of the keys of carbon carbon sp tri- by what one to 12 carbon atom was constituted.Example includes but is not limited to acetenyl (- C ≡ CH), propinyl (propargyl ,-CH2C ≡ CH) etc..
Term " carbocyclic ring (carbocycle) ", " carbocylic radical (carbocyclyl) ", " carbocyclic ring (carbocyclic ring) " and " cyclic hydrocarbon radical (cycloalkyl) " refer to have 3 to 12 carbon atoms as monovalent non-aromatic saturation or the ring of fractional saturation of monocyclic or 7 to 12 carbon atoms as two rings.Bicyclic carbocycle with 7 to 12 atoms can be arranged as such as two rings [4,5], [5,5], [5,6] or [6,6] system, the bicyclic carbocycle with 9 or 12 annular atoms can be arranged as two rings [5,6] or [6,6] system, or it is arranged as bridge system (bridged system) such as two rings [2.2.1] heptane, two rings [2.2.2] octane and two rings [3.2.2] nonane.The example of monocycle carbocyclic ring includes but is not limited to the amyl- 1- alkenyls of cyclopropyl, cyclobutyl, cyclopenta, 1- rings, the amyl- 2- alkenyls of 1- rings, the amyl- 3- alkenyls of 1- rings, cyclohexyl, 1- hexamethylene -1- alkenyls, 1- hexamethylene -2- alkenyls, 1- hexamethylene -3- alkenyls, cyclohexadienyl, suberyl, cyclooctyl, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl etc..
" aryl " is represented by removing the monovalent aromatic alkyl being made up of 6-18 carbon atom that a hydrogen atom is obtained from the single carbon atom in Parent Aromatic loop system.Some aryl are represented as " Ar " in example arrangement.Aryl is included containing the bicyclic groups with saturation, the ring of fractional saturation or aromatic carbocyclic or heterocyclic fused aromatic ring.Typical aryl includes but is not limited to the group obtained by benzene (phenyl), benzene, naphthalene, anthracene, indenyl (indenyl), indanyl (indanyl), 1,2- dihydronaphthalene, 1,2,3, the 4- tetralyls of substitution etc..
Term " heterocycle (heterocycle) ", " heterocyclic radical (heterocyclyl) " and " heterocycle (heterocyclicring) " are used interchangeably in this application, refer to the carbon ring group for the saturation or fractional saturation (there are one or more double bonds and/or three keys i.e. in ring) being made up of 3 to 18 annular atoms, wherein at least one annular atom is the hetero atom selected from nitrogen, oxygen and sulphur, remaining annular atom is C, and wherein one or more annular atoms are optionally independent to be replaced by one or more substituents as described below.Heterocycle can be monocyclic with 3 to 7 ring memberses (2 to 6 carbon atoms and 1 to 4 hetero atom selected from N, O, P and S) or two rings with 7 to 10 ring memberses (4 to 9 carbon atoms and 1 to 6 hetero atom) selected from N, O, P and S, such as two rings [4,5], [5,5], [5,6] or [6,6] system.Heterocycle is described in Paquette, Leo A.；" Principles of Modern Heterocyclic Chemistry " (W.A.Benjamin, New York, 1968) (particularly the 1st, 3,4,6,7 and 9 chapters)；" The Chemistryof Heterocyclic Compounds, A series of Monographs " (John Wiley＆Sons, NewYork, 1950 to present) (the particularly the 13rd, 14,16, volume 19 and 28)；And J.Am.Chem.Soc. (1960) 82：In 5566." heterocyclic radical " also includes heterocyclic group and saturation, the ring of fractional saturation or aromatic carbocyclic or heterocyclic fused group.The example of heterocycle includes but is not limited to pyrrolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidino (piperidino), morpholino (morpholino), thiomorpholine generation (thiomorpholino), thia oxacyclohexyl (thioxanyl), piperazinyl, homopiperazine base (homopiperazinyl), azetidinyl, oxetanyl, Thietane base, homopiperidinyl (homopiperidinyl), oxepane alkyl (oxepanyl), thia cycloheptyl alkyl (thiepanyl), oxa-
Figure G2007800391963D00091
Base (oxazepinyl), diaza
Figure G2007800391963D00092
Base (diazepinyl), thia
Figure G2007800391963D00093
Base (thiazepinyl), 2- pyrrolinyls, 3- pyrrolinyls, indolinyl, 2H- pyranoses, 4H- pyranoses, dioxane base, 1,3- dioxolyls, pyrazolinyl, dithia cyclohexyl (dithianyl), dithia cyclopenta (dithiolanyl), dihydro pyranyl, dihydro-thiophene base, dihydrofuran base, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3- azabicyclics [3.1.0] hexyl, 3- azabicyclics [4.1.0] heptane base and azabicyclic [2.2.2] hexyl.Spiral shell part is also included within the range of this definition.Annular atom is pyrimidine ketone group (pyrimidinonyl) and 1,1- dioxo-thiomorpholin base by the example of oxo (=O) partially substituted heterocyclic radical.
Term " heteroaryl " refers to the monovalent aromatic group being made up of 5 or 6 yuan of rings, and including by 5-18 former molecular fused ring systems (wherein at least one ring is aromatics), it contains the one or more hetero atoms for being independently selected from nitrogen, oxygen and sulphur.The example of heteroaryl is pyridine radicals (including such as 2 hydroxy pyrimidine base), imidazole radicals, imidazopyridyl, pyrimidine radicals (including such as 4- hydroxy pyrimidines base), pyrazolyl, triazolyl, pyrazinyl, tetrazole radical, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrole radicals, quinolyl, isoquinolin is just, indyl, benzimidazolyl, benzofuranyl, cinnolines base, indazolyl, indolizine base, phthalazinyl, pyridazinyl, triazine radical, isoindolyl, pteridyl, purine radicals, oxadiazolyl, triazolyl, thiadiazolyl group, furazanyl, benzofuraxan base, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolyl, quinoxalinyl, phthalazinyl and furopyridyl.
Heterocycle or heteroaryl it is suitable when attached can carbon (carbon connection) or (nitrogen joins) connection.Unrestricted by way of example, the heterocycle or heteroaryl of bond with carbon are bonded in following position：Pyridine 2,3,4,5 or 6, pyridazine 3,4,5 or 6, pyrimidine 2,4,5 or 6, pyrazine 2,3,5 or 6, furans, tetrahydrofuran, thiophene, the 2 of pyrroles or nafoxidine, 3,4 or 5 oxazoles, the 2 of imidazoles or thiazole, 4 or 5 isoxazoles, the 3 of pyrazoles or isothiazole, 4 or 5,2 or 3 of aziridine, azetidine 2,3 or 4, quinoline 2,3,4,5,6,7 or 8, or isoquinolin 1,3,4,5,6,7 or 8.
Unrestricted by way of example, the heterocycle or heteroaryl of nitrogen bonding are bonded in following position：Aziridine, azetidine, pyrroles, pyrrolidines, 2- pyrrolins, 3- pyrrolins, imidazoles, imidazolidine, 2- imidazolines, 3- imidazolines, pyrazoles, pyrazoline, 2- pyrazolines, 3- pyrazolines, piperidines, piperazine, indoles, indoline, 1 of 1H- indazoles, 2 of iso-indoles or isoindoline, 4 of morpholine, and 9 of carbazole or B-carboline.
Term " halogen " refers to F, Cl, Br or I.Hetero atom present in heteroaryl or heterocyclic radical includes oxidised form such as N+→O-, S (O) and S (O)2。
Term " treatment (treating) " or " treatment (treatment) " refer to therapeutic disposal and preventive measure, and wherein purpose is prevention or slows down (mitigation) undesirable physiology change or the development or diffusion of obstacle such as cancer.For purposes of the present invention, beneficial or desired clinical effectiveness include but is not limited to relief of symptoms, reduce lesion degree, stably (i.e. be not deteriorate) morbid state, postpone or slow down progression of disease, improve or relax morbid state and take a turn for the better (part takes a turn for the better or improvement completely), no matter these results are detectable or undetectable." treatment (treating) " can also represent the survival with extending compared with the expected survival for not receiving treatment.Need the object for the treatment of to include object with illness or obstacle and be susceptible to suffer from the object that the object or the illness or obstacle of the illness or obstacle should be prevented.
Term " therapeutically effective amount " represents that (i) treats or prevents the amount of the compounds of this invention of disease specific described herein, illness or obstacle, (ii) amount of the compounds of this invention of the one or more symptoms weaken, improved or eliminate disease specific described herein, illness or obstacle, or (iii) prevent or postponed the amount of the compounds of this invention of the breaking-out of one or more symptoms of disease specific described herein, illness or obstacle.In the case of cancer, the medicine of therapeutically effective amount can reduce the quantity of cancer cell；Reduce tumor size；Suppress and (to a certain extent slow down and preferably stop) cancer cell to penetrate into peripheral organs；Suppress tumour growth to a certain extent；And/or alleviate the one or more symptoms related to cancer to a certain extent.If medicine can prevent the growth of cancer cell and/or kill existing cancer cell, it is probably cell growth inhibiting (cytostatic) and/or cytotoxicity.For treatment of cancer, effect for example can be measured by evaluating disease developing time (TTP) and/or determining response rate (RR).
Term " abnormal cell growth " and " excess proliferative disease " are used interchangeably in this application.Unless otherwise indicated, " abnormal cell growth " used in this application refers to the cell growth independent of normal regulator mechanisms (for example contact inhibition lacks (loss of contact inhibition)).This includes the misgrowth of for example following cell：(1) tumour cell (tumour) by expressing the EGFR-TK or overexpression receptor tyrosine kinase of mutation and breeding；(2) there is the benign and malignant cell in other proliferative diseases of aberrant tyrosine kinase activation；(3) any tumour that its propagation is influenceed by receptor tyrosine kinase；(4) any tumour that its propagation is influenceed by aberrant serine/threonine kinase activation；And there is the benign and malignant cell in other proliferative diseases of aberrant serine/threonine kinase activation in (5).
Term " cancer (cancer) " and " (cancerous) of cancer " refer to or described the physiological conditions that feature in mammal is typically unadjusted cell growth." tumour " includes one or more cancer cells.The example of cancer includes but is not limited to carcinoma (carcinoma), lymthoma, blastoma, sarcoma and lymph or lymphoid malignancies.The more specifically example of the cancer includes squamous cell carcinoma (such as epithelial squamous cell cancer), lung cancer, including ED-SCLC, non-small cell lung cancer (" NSCLC "), adenocarcinoma of lung (adenocarcinoma of the lung) and squamous cell lung carcinoma (squamous carcinoma of thelung), peritoneal cancer, hepatocellular carcinoma, stomach cancer (gastric or stomach cancer), including human primary gastrointestinal cancers, cancer of pancreas, spongioblastoma, cervix cancer, oophoroma, liver cancer (liver cancer), carcinoma of urinary bladder, hepatoma (hepatoma), breast cancer (breast cancer), colon cancer, the carcinoma of the rectum, colorectal cancer, carcinoma of endometrium or uterine cancer, salivary-gland carcinoma, kidney or renal cancer, prostate cancer, carcinoma of vulva (vulvalcancer), thyroid cancer, liver cancer (hepatic carcinoma), cancer of anus, carcinoma of penis, acute leukemia, and head/cancer of the brain and neck cancer.
" chemotherapeutic agent " is the compound available for treating cancer.The example of chemotherapeutic agent includes Erlotinib (TARCEVA
Figure G2007800391963D00111
Genentech/OSI Pharm.), bortezomib (Bortezomib) (VELCADEMillennium Pharm.), fulvestrant (FASLODEX
Figure G2007800391963D00113
AstraZeneca), Sutent (SU11248, Pfizer), Letrozole (FEMARANovartis), imatinib mesylate (GLEEVEC
Figure G2007800391963D00115
Novartis), PTK787/ZK 222584 (Novartis), oxaliplatin (Eloxatin
Figure G2007800391963D00116
Sanofi), 5-FU (5 FU 5 fluorouracil), formyl tetrahydrofolic acid (Leucovorin), rapamycin (Sirolimus, RAPAMUNE
Figure G2007800391963D00117
Wyeth), Lapatinib (Lapatinib) (TYKERB
Figure G2007800391963D00118
GSK572016, Glaxo Smith Kline), Lonafarnib (SCH 66336), Sorafenib (Sorafenib, BAY43-9006, Bayer Labs) and Gefitinib (IRESSA
Figure G2007800391963D00119
AstraZeneca)、AG1478、AG1571(SU 5271；Sugen)；Alkylating agent such as phosphinothioylidynetrisaziridine (thiotepa) and CYTOXAN
Figure G2007800391963D00121
Endoxan；Alkyl sulfonate esters (alkyl sulfonate) such as busulfan, Improsulfan and piposulfan (piposulfan)；Aziridine such as benzodopa, carboquone, meturedopa and uredopa；Ethylenimine (ethylenimine) and methylaminacrine (methylamelamine), including hexamethyl melamine, tretamine (triethylenemelamine), triethylenephosphoramide (triethylenephosphoramide), triethylenethiophosphoramide (triethylenethiophosphoramide) and trimethylomelamine；Annona lactone (acetogenin) (especially Bradley its pungent (bullatacin) and Bradley its octanone (bullatacinone))；Camptothecine (including synthetic analog Hycamtin (topotecan))；Bryostatin (bryostatin)；callystatin；CC-1065 (including its Adozelesin (adozelesin), Carzelesin (carzelesin) and Bizelesin (bizelesin) synthetic analog)；Cryptophycins (particularly cryptophycin 1 and cryptophycin 8)；Dolastatin (dolastatin)；Duocarmycin (including synthetic analog KW-2189 and CB1-TM1)；eleutherobin；pancratistatin；sarcodictyin；spongistatin；Mustargen such as Chlorambucil, Chlornaphazine, chlorine phosphamide (chlorophosphamide), Estramustine, ifosfamide, chlormethine (mechlorethamine), mustron (mechlorethamine oxide hydrochloride), melphalan, novoembichin (novembichin), phenesterin (phenesterine), prednimustine (prednimustine), Trofosfamide (trofosfamide), uracil mastard (uracil mustard)；Nitrourea such as BCNU, chlorozotocin (chlorozotocin), Fotemustine, lomustine, Buddhist nun not STING and Ranimustine；Antibiotic such as enediyne (enediyne) antibiotic (such as calicheamycin (calicheamicin) especially calicheamycin γ 1I and calicheamycin ω I1 (Angew Chem.Intl.Ed.Engl. (1994) 33：183-186)；Anthracycline antibiotic (dynemicin), including dynemicin A；Diphosphonate (bisphosphonate) such as clodronate (clodronate)；Ai Sipeila mycins (esperamicin)；And neocarzinostatin chromophore (neocarzinostatin chromophore) and related chromoprotein enediyne antibiotic chromophore (enediyne antibiotic chromophore), aclacinomysin, D actinomycin D (actinomycin), authramycin, azaserine (azaserine), bleomycin, act-C (cactinomycin), carabicin, carminomycin (carminomycin), carzinophillin (carzinophilin), chromomycin (chromomycin), actinomycin D (dactinomycin), daunorubicin (daunorubicin), floor mop is than star (detorubicin), 6- diazo -5- oxn-l-norieucins (6-diazo-5-oxo-L-norleucine), ADRIAMYCIN(Doxorubicin), morpholino-Doxorubicin, Cyanomorpholino-Doxorubicin, 2- pyrrolins subbase-Doxorubicin and deoxidation Doxorubicin, epirubicin (epirubicin), esorubicin, idarubicin, marcellomycin (marcellomycin), mitomycin such as mitomycin C, Mycophenolic Acid (mycophenolic acid), nogalamycin (nogalamycin), olivomycin (olivomycins), Peplomycin (peplomycin), porfiromycin (porfiromycin), Puromycin (puromycin), triferricdoxorubicin (quelamycin), rodorubicin (rodorubicin), broneomycin (streptonigrin), streptozotocin (streptozocin), tubercidin (tubercidin), ubenimex (ubenimex), Zinostatin (zinostatin), zorubicin；Antimetabolite such as methopterin and 5 FU 5 fluorouracil (5-FU)；Folacin such as denopterin, methopterin, sieve purine (pteropterin) of talking endlessly, Trimetrexate (trimetrexate)；Purine analogue such as fludarabine (fludarabine), 6-MP, thiapurine (thiamiprine), thioguanine (thioguanine)；Pyrimidine analogue such as ancitabine (ancitabine), azacitidine (azacitidine), 6- nitrogen guanosine (6-azauridine), Carmofur (carmofur), cytarabine (cytarabine), di-deoxyuridine (dideoxyuridine), doxifluridine (doxifluridine), Yi Nuota shores (enocitabine), floxuridine (floxuridine)；Androgen such as Calusterone (calusterone), dromostanolone propionate (dromostanolone propionate), epithioandrostanol (epitiostanol), Mepitiostane (mepitiostane), Testolactone (testolactone)；Antiadrenergic drug (anti-adrenal) such as aminoglutethimide (aminoglutethimide), mitotane (mitotane), Trilostane (trilostane)；Folic acid supplement (folic acid replenisher) such as folinic acid (frolinic acid)；Aceglatone (aceglatone)；Aldophosphamideglycoside (aldophosphamide glycoside)；Amino-laevulic acid (aminolevulinic acid)；Eniluracil (eniluracil)；Amsacrine (amsacrine)；bestrabucil；Bisantrene (bisantrene)；She kills (edatraxate) up to song；Defosfamide (defofamine)；Demecolcine (demecolcine)；Diaziquone (diaziquone)；elfornithine；Elliptinium Acetate (elliptinium acetate)；Epothilones (epothilone)；Ethoglucid (etoglucid)；Gallium nitrate (gallium nitrate)；Hydroxycarbamide (hydroxyurea)；Lentinan (lentinan)；Lonidamine (lonidainine)；Maytansinol (maytansinoid) such as maytansine (maytansine) and ansamitocin (ansamitocin)；Mitoguazone (mitoguazone)；Mitoxantrone (mitoxantrone)；mopidanmol；Nitragin (nitraerine)；Pentostatin (pentostatin)；Phenamet (phenamet)；THP (pirarubicin)；Losoxantrone (losoxantrone)；Podophyllic acid (podophyllinic acid)；2- ethyl hydrazines；Procarbazine (procarbazine)；PSK
Figure G2007800391963D00131
Polysaccharide compound (JHS Natural Products, Eugene, OR)；Razoxane (razoxane)；Rhizomycin (rhizoxin)；Sizofiran (sizofiran)；Spirogermanium (spirogermanium)；Tenuazonic acid (tenuazonic acid)；Triethyleneiminobenzoquinone (triaziquone)；2,2 ', 2 "-trichlorotriethylamine；Trichothecene (trichothecene) (especially T-2 toxin, verracurin A, Roridine A and anguidine)；Urethane；Eldisine；Dacarbazine (dacarbazine)；Mannomustine (mannomustine)；Dibromannitol (mitobronitol)；Mitolactol (mitolactol)；Pipobroman (pipobroman)；gacytosine；Cytarabine (arabinoside) (" Ara-C ")；Endoxan；Phosphinothioylidynetrisaziridine；Taxane such as TAXOL
Figure G2007800391963D00141
(taxol；Bristol-Myers Squibb Oncology, Princeton, N.J.), albumin engineering Nanoparticulate formulations (albumin-engineered nanoparticle formulations ofpaclitaxel) (American Pharmaceutical Partners of ABRAXANETM (Cremophor-free), taxol, Schaumberg, Illinois) and TAXOTERE
Figure G2007800391963D00142
(doxetaxel；
Figure G2007800391963D00143
- Poulenc Rorer, Antony, France)；chloranmbucil；GEMZAR(gemcitabine)；6-thioguanine；Mercaptopurine；Methopterin；Platinum analogs such as cis-platinum and carboplatin；Vincaleukoblastinum；Etoposide (VP-16)；Ifosfamide；Mitoxantrone；Vincristine；NAVELBINE
Figure G2007800391963D00145
(vinorelbine)；Novantrone (novantrone)；Teniposide (teniposide)；She kills (edatrexate) up to song；Daunorubicin；Aminopterin-induced syndrome；Capecitabine (XELODA
Figure G2007800391963D00146
)；Ibandronate (ibandronate)；CPT-11；Topoisomerase enzyme inhibitor RFS2000；DFMO (difluoromethylornithine) (DMFO)；Retinoids (retinoid) such as retinoic acid (retinoic acid)；And officinal salt, acid and the derivative of any of the above described material.
Following material is also included within the definition of " chemotherapeutic agent "：(i) it is used for the antihormones medicine of regulation or inhibitory hormone to the effect of tumour, such as antiestrogen (anti-estrogen) and SERM (selective estrogen receptor modulator, SERM), including for example TAM (including NOLVADEX
Figure G2007800391963D00147
Tamoxifen citrate), Raloxifene, Droloxifene, 4-hydroxytamoxifen, Trioxifene (trioxifene), Lei Luoxifen (keoxifene), LY117018, Onapristone (onapristone) and FARESTON
Figure G2007800391963D00148
(citric acid Toremitene (toremifine citrate))；(ii) aromatase inhibitor of aromatase enzyme (estrogen is produced in regulation adrenal gland), such as 4 (5)-imidazoles, aminoglutethimide, MEGASE are suppressed
Figure G2007800391963D00149
(megestrol acetate (megestrol acetate)), AROMASIN
Figure G2007800391963D001410
(Exemestane (exemestane)；Pfizer), formestanie, Fadrozole (fadrozole), RIVISOR(Vorozole (vorozole)), FEMARA
Figure G2007800391963D001412
(Letrozole；) and ARIMIDEX Novartis
Figure G2007800391963D001413
(Anastrozole (anastrozole)；AstraZeneca)；(iii) antiandrogen medicine (anti-androgen), such as Flutamide, Nilutamide (nilutamide), Bicalutamide (bicalutamide), leuprorelin acetate (leuprolide) and Goserelin (goserelin) and troxacitabine (troxacitabine) (1,3- dioxolane nucleosides analogue of cytosine)；(iv) kinases inhibitor；(v) lipid kinase inhibitors；(vi) ASON, particularly suppresses those ASONs of the gene expression in the signal transduction pathway involved by abnormal cell proliferation, such as PKC- α, Ralf and H-Ras；(vii) ribozyme such as vegf expression inhibitor (such as ANGIOZYME
Figure G2007800391963D001414
) and HER2 expression inhibiting agent；(viii) vaccine such as gene therapeutic vaccine, such as ALLOVECTIN
Figure G2007800391963D001415
LEUVECTIN
Figure G2007800391963D001416
And VAXID
Figure G2007800391963D001417
PROLEUKIN
Figure G2007800391963D001418
rIL-2；The inhibitor of topoisomerase 1 such as LURTOTECAN
Figure G2007800391963D00151
ABARELIX
Figure G2007800391963D00152
rmRH；(ix) anti-angiogenic medicaments such as bevacizumab (AVASTIN
Figure G2007800391963D00153
Genentech)；And the officinal salt, acid and derivative of (x) any of the above described material.Other anti-angiogenic medicaments include MMP-2 (MMP2) inhibitor, MMP-9 (GELB) inhibitor, COX-II (cyclooxygenase II) inhibitor and vegf receptor tyrosine kinase inhibitor.It can be described with the example of above-mentioned useful NMPI associated with the compounds of this invention/composition in WO 96/33172, WO 96/27583, EP 818442, EP 1004578, WO 98/07697, WO 98/03516, WO 98/34918, WO 98/34915, WO 98/33768, WO 98/30566, EP 606, 046, EP 931, 788, WO 90/05719, WO 99/52910, WO 99/52889, WO 99/29667, WO 99/07675, EP 945864, United States Patent (USP) 5, 863, 949, United States Patent (USP) 5, 861, 510 and EP 780, in 386, all these entireties are incorporated herein by reference.The example of vegf receptor tyrosine kinase inhibitor includes 4- (the bromo- 2- fluoroanilinos of 4-) -6- methoxyl groups -7- (1- methyl piperidine -4- ylmethoxies) quinazoline (ZD6474；Embodiment 2 in WO 01/32651), 4- (the fluoro- 2 methyl indole -5- bases epoxides of 4-) -6- methoxyl groups -7- (3- pyrrolidin-1-yls propoxyl group)-quinazoline (AZD2171；Embodiment 240 in WO 00/47212), vatalanib (PTK787；WO 98/35985) and SU11248 ((Sutents (sunitinib)；) and the compound disclosed in compound such as PCT Publication WO 97/22596, WO 97/30035, WO97/32856 and WO 98/13354 WO01/60814.
The compound reported in PI3K (PI-3 kinase) inhibitor, such as documents below can be included with other examples of chemotherapeutic agent associated with the compounds of this invention：Yaguchi et al(2006)Jour.ofthe Nat.Cancer Inst.98(8)：545-556；US 7173029；US 7037915；US 6608056；US 6608053；US 6838457；US 6770641；US 6653320；US 6403588；WO2006/046031；WO 2006/046035；WO 2006/046040；WO 2007/042806；WO2007/042810；WO 2004/017950；US 2004/092561；WO 2004/007491；WO2004/006916；WO 2003/037886；US 2003/149074；WO 2003/035618；WO2003/034997；US 2003/158212；EP 1417976；US 2004/053946；JP 2001247477；JP 08175990；JP 08176070；US 6703414；With WO 97/15658, all these entireties are incorporated herein by reference.The instantiation of the PI3K inhibitor includes SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis, Inc.).
Term " inflammatory disease " used herein includes but is not limited to rheumatoid arthritis, atherosclerosis, congestive heart failure, IBD (includes but is not limited to Crohn disease (Crohn ' sdisease) and ulcerative colitis), chronic obstructive pulmonary disease (chronic obstructive pulmonarydisease in the lung), liver kidney fibrosis disease (fibrotic disease in the liver and kidney), Crohn disease, skin disease (such as psoriasis, eczema and chorionitis (scleroderma)), osteoarthritis, multiple sclerosis, asthma, the disease related to diabetic complication and obstacle, organ such as lung, liver, the fibrosis organ failure (fibrotic organ failure) of kidney and the inflammatory complication such as acute coronary syndrome (acute coronary syndrome) of cardiovascular system.
" anti-inflammatory drug " is the compound available for treatment inflammation.The example of anti-inflammatory drug includes injectable protein for treatment agent such as Enbrel
Figure G2007800391963D00161
Remicade
Figure G2007800391963D00162
Humira
Figure G2007800391963D00163
And Kineret
Figure G2007800391963D00164
Other examples of anti-inflammatory drug include nonsteroidal anti-inflammatory agent (NSAID), such as brufen or aspirin (it reduces swelling and pain of alleviation)；Alleviate the antirheumatic drug (DMARD) of disease, such as methopterin；5-aminosalicylic acid ester (medicine of SASP (sulfasalazine) and non-sulfanilamide (SN))；Cortin；Immunomodulator such as 6-MP (" 6-MP "), imuran (" AZA "), cyclosporin and biological response modifier (biological responsemodifier) such as Remicade.RTM. (infliximab (infliximab)) and Enbrel.RTM. (Etanercept (etanercept))；Fibroblast growth factor (fibroblast growth factor)；Platelet-derived growth factor (platelet derived growth factor)；Enzyme retarding agent such as Arava.RTM. (leflunomide)；And/or chondroprotective drugs such as hyaluronic acid, aminoglucose and chondroitin.
Term " prodrug " used in this application is to refer to precursor or derivative form through enzyme or hydrolytic activation or the compounds of this invention for being converted into more active parent fo.See, for example, Wilman, " Prodrugs in Cancer Chemotherapy " Biochemical Society Transactions, 14, pp.375-382,615th Meeting Belfast (1986) and Stella et al., " Prodrugs：A ChemicalApproach to Targeted Drug Delivery, " Directed Drug Delivery, Borchardt et al., (ed.), pp.247-267, Humana Press (1985).The prodrug of the present invention includes but is not limited to amino acid modified prodrug, glycosylated prodrug, the prodrug containing beta-lactam, the prodrug containing optionally substituted phenoxy-acetamide, the prodrug containing optionally substituted phenyl-acetamides, 5-flurocytosine and the other 5 FU 5 fluorouracil prodrugs of the prodrug containing ester, the prodrug of phosphate ester-containing, the prodrug containing thiophosphate, the prodrug of sulfur-bearing acid esters, the prodrug containing peptide, D-, and these prodrugs can be converted into the medicine of more active no cytotoxicity.The example that can derive as the cytotoxic drug of the prodrug forms for the present invention includes but is not limited to the compounds of this invention and chemotherapeutic agent as described above.
" metabolin " is the product produced by the metabolism in vivo of particular compound or its salt.The metabolin of routine techniques authenticating compound known in the art can be used, and their activity is determined using experiment as described in the present application.The product can be due to the oxidation such as the compound being administered, hydroxylating, reduction, hydrolysis, amidatioon, desamidization, esterification, de- esterification, enzymatic cleavage.Therefore, the present invention includes the metabolin of the compounds of this invention, including the compound produced by following methods, and methods described includes making the compounds of this invention be enough to produce the time of its metabolite with mammalian animal.
The vesicles that " liposome " is made up of various types of lipids, phosphatide and/or surfactant, it can be used for medicine (mek inhibitor and optional chemotherapeutic agent such as disclosed in the present application) being delivered to mammal.With the fat homotaxis of biomembrane, the component of liposome is generally arranged with bilayer formation.
Term " package insert (package insert) " refers to be typically included in the specification in the commercially available back for the treatment of product, it, which contains, is related to indication, usage, dosage, administration, contraindication and/or the information for warning item, and these information are related to the use of above-mentioned treatment product.
Term " chirality " refers to the molecule with mirror image gametophyte (mirror image partner) non-overlapping property, and term " achirality " refer to can be overlapping with its mirror image gametophyte molecule.
Term " stereoisomer " refers to that the orientation with identical chemical composition and link situation but their atoms spatially Bu Tong therefore can not be by the compound that is mutually converted around singly-bound rotation.
" diastereoisomer " refers to have two or more chiral centres and its molecule not stereoisomer of mirror image each other.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral quality and reactivity.The mixture of diastereoisomer can split analysis operation by height and be separated such as crystallization, electrophoresis and chromatogram.
" enantiomter " refers to two kinds of stereoisomers of the compound of non-overlapping mirror image each other.
Stereochemical definitions used in this application and routine are generally according to S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York and Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley＆Sons, Inc., New York, 1994.The compounds of this invention can contain asymmetric or chiral centre, therefore exist with different stereoisomeric forms in any ratio.It is contemplated that all stereoisomeric forms in any ratio of the compounds of this invention, including but not limited to diastereoisomer, enantiomter and atropisomer (atropisomers) and their mixture such as racemic mixture, forms the part of the present invention.A variety of organic compounds exist with optical active forms, i.e., they have the ability of the plane of Plane of rotation polarised light.When description has optically active compound, represent that molecule surrounds the absolute configuration of one or more chiral centre using prefix D and L or R and S.Prefix d and l or (+) and (-) are used for the symbol that given plane polarised light rotates as caused by compound, wherein (-) or l represent that compound is left-handed.Prefix is dextrorotation for (+) or d compound.For given chemical constitution, in addition to these stereoisomers each other mirror image, these stereoisomers are identicals.Specific stereoisomer is alternatively referred to as enantiomter, and the mixture of the isomers is commonly referred to as enantiomeric mixture.50: 50 mixtures of enantiomter are referred to as racemic mixture or racemic modification, and such case is may occur in which when not having stereoselectivity or stereocpecificity in chemical reaction or method.Term " racemic mixture " and " racemic modification " refer to the equimolar mixture of two kinds of enantiomter materials, and it does not have optical activity.
Term " dynamic isomer " or " tautomeric form " refer to that the constitutional isomer of the different-energy of (low energybarrier) mutual inversion of phases can be built by low energy.For example, proton tautomer (protontautomer) (also referred to as proton migration dynamic isomer (prototropic tautomer)) includes migrating the mutual inversion of phases carried out, such as keto-enol isomerization and imine-enamine isomerizations by proton.Valence tautomerism body (valence tautomer) includes the mutual inversion of phases carried out by the restructuring of some bonding electrons.
Phrase " officinal salt " used in this application refers to the pharmaceutically acceptable organic or inorganic salt of the compounds of this invention.Exemplary salt includes but is not limited to sulfate, citrate, acetate, oxalates, chloride, bromide, iodide, nitrate, disulfate, phosphate, acid phosphate, isonicotinic acid salt, lactate, salicylate, acid citrate, tartrate, oleate, tannate (tannate), pantothenate (pantothenate), biatrate, ascorbate, succinate, maleate, gentisate (gentisinate), fumarate, gluconate, glucuronate, saccharate (saccharate), formates, benzoate, glutamate, mesylate (mesylate (mesylate)), esilate, benzene sulfonate, tosilate, pamoate (i.e. 1, 1 '-methylene-two-(2- hydroxyl -3- naphthoates)), alkali metal (such as sodium and potassium) salt, alkaline-earth metal (such as magnesium) salt and ammonium salt.Officinal salt can relate to the inclusion compound (inclusion) of another molecule such as acetate ion, succinate ion or other counter ion counterionsl gegenions.Counter ion counterionsl gegenions can be any organic or inorganic part of stable matrix compound electric charge.In addition, officinal salt can have more than one charge atom in its structure.Multiple charge atoms can have multiple counter ion counterionsl gegenions for the situation of the part of officinal salt.Therefore, officinal salt can have one or more charge atoms and/or one or more counter ion counterionsl gegenions.
If the compounds of this invention is alkali, then desired officinal salt can be prepared by the available any appropriate method in this area, for example with inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid etc.) or with organic acid (such as acetic acid, maleic acid, butanedioic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic, salicylic acid, pyranose acid (pyranosidyl acid) such as glucuronic acid or galacturonic acid, 'alpha '-hydroxy acids such as citric acid or tartaric acid, amino acid such as aspartic acid or glutamic acid, aromatic acid such as benzoic acid or cinnamic acid, sulfonic acid such as p-methyl benzenesulfonic acid or ethyl sulfonic acid etc.) processing free alkali.
If the compounds of this invention is acid, then desired officinal salt can be prepared by any appropriate method, such as with inorganic or organic base (as amine (primary amine, secondary amine or tertiary amine), alkali metal hydroxide or alkaline earth metal hydroxide) handle free acid.The illustrative examples of acceptable acid addition salts include but is not limited to the organic salt obtained from following material：Amino acid such as glycine and arginine, ammonia, primary amine, secondary amine and tertiary amine and cyclic amine such as piperidines, morpholine and piperazine；And the inorganic salts obtained from following material：Sodium, calcium, potassium, magnesium, iron, copper, zinc, aluminium and lithium.
Other compositions and/or be in chemistry and/or in toxicology compatible with its mammal treated that " pharmaceutically useful " the expression material of phrase or composition must be included with preparation.
" solvate " refers to the combination or complexing of one or more solvent molecules and the compounds of this invention.The example for forming the solvent of solvate includes but is not limited to water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and monoethanolamine.Term " hydrate " refers to the complex compound when solvent molecule is water.
The substituent of specific functional group is prevented or protected when other functional groups that term " protection group " refers to be generally used in compound react.For example, " amino protecting group " is the substituent of amino functionality in the prevention or protection compound being connected with amino.Suitable amino protecting group includes acetyl group, trifluoroacetyl group, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9- fluorenylmethoxycarbonyl groups (Fmoc).Similarly, " hydroxyl protecting group " refer to prevent or protect hydroxy functionality hydroxyl substituent.Suitable protection group includes acetyl group and silicyl." carboxyl-protecting group " refer to prevent or protect carboxyl functionality carboxyl substituent.Common carboxyl-protecting group includes phenylsulfonylethyl, cyano ethyl, 2- (trimethyl silyl) ethyl, 2- (trimethyl silyl) ethoxyl methyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino)-ethyl, nitro-ethyl etc..General description for protection group and application thereof, referring to T.W.Greene, Protective Groups inOrganic Synthesis, John Wiley＆Sons, New York, 1991.
Unless otherwise indicated, term " the compounds of this invention (compound of this invention) " and " the compounds of this invention (compounds of the present invention) " and " compound of formula I " include compound of formula I and its stereoisomer, geometric isomer, dynamic isomer, solvate, metabolin, salt (such as officinal salt) and prodrug.
The invention provides can be used as the aza-benzothiophenyl compounds that kinase inhibitor especially can be used as the Formulas I as described above of MEK kinase inhibitors.The present invention includes Formulas I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, II-i, III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h and III-i compound, and all other variable is as defined in Formulas I.
Figure G2007800391963D00201
Figure G2007800391963D00211
In one embodiment of the invention, compound is Formulas I-b, I-f, I-g, I-h, II-b, II-f, II-g, II-h, III-b, III-f, III-g and III-h compound, and all other variable is as defined in Formulas I.
In one embodiment of the invention, compound is formula III-c compound, and all other variable is as defined in Formulas I.
In one embodiment of the invention, R1For H, halogen, CN, CF3、-NR11R12、-OR11、-SR11,-C (=O) NR11R12Or C1-C6Alkyl, and all other variable is as defined in Formulas I, I-a, I-b, I-d, I-f, I-g, II-a, II-b, II-d, II-f, II-g, III-a, III-b, III-d, III-f or III-g.
In another embodiment of the present invention, R1For H, halogen, CN, CF3、C1-C6Alkyl ,-NR11R12(wherein R11And R12Stand alone as H or C1-C6Alkyl) ,-OR11(wherein R11For H or C1-C6Alkyl) or-SR11(wherein R11For H or C1-C6Alkyl)；And all other variable is as defined in Formulas I, I-a, I-b, I-d, I-f, I-g, II-a, II-b, II-d, II-f, II-g, III-a, III-b, III-d, III-f or III-g.
In another embodiment of the present invention, R1For H, Cl, CN, CF3, methyl ,-NH2、-NH(CH3)、-N(CH3)2,-OH or-OCH3；And all other variable is as defined in Formulas I, I-a, I-b, I-d, I-f, I-g, II-a, II-b, II-d, II-f, II-g, III-a, III-b, III-d, III-f or III-g.
In another embodiment of the present invention, R1For H；And all other variable is as defined in Formulas I, I-a, I-b, I-d, I-f, I-g, II-a, II-b, II-d, II-f, II-g, III-a, III-b, III-d, III-f or III-g.
In one embodiment of the invention, R2For H, halogen, CN, CF3、-NR11R12、-OR11、-SR11,-C (=O) NR11R12Or C1-C6Alkyl, and all other variable is as defined in Formulas I, I-a, I-c, I-d, I-e, I-i, II-a, II-c, II-d, II-e, II-i, III-a, III-c, III-d, III-e or III-i or as hereinbefore defined.
In another embodiment of the present invention, R2For H, halogen, CN, CF3、C1-C6Alkyl ,-NR11R12(wherein R11And R12Stand alone as H or C1-C6Alkyl) ,-OR11(wherein R11For H or C1-C6Alkyl) or-SR11(wherein R11For H or C1-C6Alkyl)；And all other variable is as defined in Formulas I, I-a, I-c, I-d, I-e, I-i, II-a, II-c, II-d, II-e, II-i, III-a, III-c, III-d, III-e or III-i or as hereinbefore defined.
In another embodiment of the present invention, R2For H, Cl, CN, CF3, methyl ,-NH2、-NH(CH3)、-N(CH3)2,-OH or-OCH3；And all other variable is as defined in Formulas I, I-a, I-c, I-d, I-e, I-i, II-a, II-c, II-d, II-e, II-i, III-a, III-c, III-d, III-e or III-i or as hereinbefore defined.
In one embodiment of the invention, R3For H, halogen, CN, CF3、-NR11R12、-OR11、-SR11,-C (=O) NR11R12Or C1-C6Alkyl, and all other variable is as defined in Formulas I, I-a, I-c, I-d, I-e, I-i, II-a, II-c, II-d, II-e, II-i, III-a, III-c, III-d, III-e or III-i or as hereinbefore defined.
In another embodiment of the present invention, R3For H, halogen, CF3Or C1-C6Alkyl；And all other variable is as defined in Formulas I, I-a, I-c, I-d, I-e, I-i, II-a, II-c, II-d, II-e, II-i, III-a, III-c, III-d, III-e or III-i or as hereinbefore defined.
In another embodiment of the present invention, R3For H, F, CF3Or methyl；And all other variable is as defined in Formulas I, I-a, I-c, I-d, I-e, I-i, II-a, II-c, II-d, II-e, II-i, III-a, III-c, III-d, III-e or III-i or as hereinbefore defined.
In another embodiment of the present invention, R3For H, F, Cl, CF3, methyl or CN；And all other variable is as defined in Formulas I, I-a, I-c, I-d, I-e, I-i, II-a, II-c, II-d, II-e, II-i, III-a, III-c, III-d, III-e or III-i or as hereinbefore defined.
In one embodiment of the invention, R4For H, halogen, CN, CF3、-NR11R12、-OR11、-SR11,-C (=O) NR11R12Or C1-C6Alkyl, and all other variable is as defined in Formulas I, I-a, I-b, I-c, I-e, I-g, I-h, II-a, II-b, II-c, II-e, II-g, II-h, III-a, III-b, III-c, III-e, III-g or III-h or as hereinbefore defined.
In another embodiment of the present invention, R4For H, halogen, CN, CF3、-NR11R12,-C (=O) NR11R12(wherein R11And R12Stand alone as H or C1-C6Alkyl) ,-OR11(wherein R11For H or C1-C6Alkyl) or-SR11(wherein R11For H or C1-C6Alkyl)；And all other variable is as defined in Formulas I, I-a, I-b, I-c, I-e, I-g, I-h, II-a, II-b, II-c, II-e, II-g, II-h, III-a, III-b, III-c, III-e, III-g or III-h or as hereinbefore defined.
In another embodiment of the present invention, R4For H, Br, CN, CF3、-NH2、-NH(CH3)、-N(CH3)2、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2,-OH or-OCH3；And all other variable is as defined in Formulas I, I-a, I-b, I-c, I-e, I-g, I-h, II-a, II-b, II-c, II-e, II-g, II-h, III-a, III-b, III-c, III-e, III-g or III-h or as hereinbefore defined.
In another embodiment of the present invention, R4For H, Br, Cl, CN, CF3、-NH2、-NH(CH3)、-N(CH3)2、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2,-OH or-OCH3；And all other variable is as defined in Formulas I, I-a, I-b, I-c, I-e, I-g, I-h, II-a, II-b, II-c, II-e, II-g, II-h, III-a, III-b, III-c, III-e, III-g or III-h or as hereinbefore defined.
In another embodiment of the present invention, R4For halogen ,-OH or the C being optionally optionally substituted by halogen1-C6Alkyl；And all other variable is as defined in Formulas I, I-a, I-b, I-c, I-e, I-g, I-h, II-a, II-b, II-c, II-e, II-g, II-h, III-a, III-b, III-c, III-e, III-g or III-h or as hereinbefore defined.
In another embodiment of the present invention, R4Stand alone as Cl, Br, Me, Et, F, CHF2、CF3Or-OH；And all other variable is as defined in Formulas I, I-a, I-b, I-c, I-e, I-g, I-h, II-a, II-b, II-c, II-e, II-g, II-h, III-a, III-b, III-c, III-e, III-g or III-h or as hereinbefore defined.
In one embodiment of the invention, R5For H or C1-C6Alkyl；And all other variable such as Formulas I, I-a to I-i or II-a is to defined in II-i or as hereinbefore defined.
In another embodiment of the present invention, R5For H or methyl；And all other variable such as Formulas I, I-a to I-i or II-a is to defined in II-i or as hereinbefore defined.
In another embodiment of the present invention, R5For H；And all other variable such as Formulas I, I-a to I-i or II-a is to defined in II-i or as hereinbefore defined.
In another embodiment of the present invention, R5For methyl；And all other variable such as Formulas I, I-a to I-i or II-a is to defined in II-i or as hereinbefore defined.
In one embodiment of the invention, R6For H or C1-C6Alkyl；And all other variable such as Formulas I, I-a to I-i, II-a to II-i or III-a is to defined in III-i or as hereinbefore defined.
In another embodiment of the present invention, R6For H or methyl；And all other variable such as Formulas I, I-a to I-i, II-a to II-i or III-a is to defined in III-i or as hereinbefore defined.
In another embodiment of the present invention, R6For H；And all other variable such as Formulas I, I-a to I-i, II-a to II-i or III-a is to defined in III-i or as hereinbefore defined.
In another embodiment of the present invention, R6For methyl；And all other variable such as Formulas I, I-a to I-i, II-a to II-i or III-a is to defined in III-i or as hereinbefore defined.
In one embodiment of the invention, X1For OR11(i.e. Formula II-a to II-i)；And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined.
In one embodiment of the invention, X1For OR11, wherein R11For H；And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined.
In another embodiment of the present invention, X1For OR11, wherein R11To be independently selected from the C of following one or more substituent groups1-C12Alkyl (such as C1-C6Alkyl)：Halogen, CN, CF3、-OCF3、-NO2, oxo ,-Si (C1-C6Alkyl)3、-(CR19R20)nC (=Y ') R16、-(CR19R20)nC (=Y ') OR16、-(CR19R20)nC (=Y ') NR16R17、-(CR19R20)nNR16R17、-(CR19R20)nOR16、-(CR19R20)n-SR16、-(CR19R20)nNR16C (=Y ') R17、-(CR19R20)nNR16C (=Y ') OR17、-(CR19R20)nNR18C (=Y ') NR16R17、-(CR19R20)nNR17SO2R16、-(CR19R20)nOC (=Y ') R16、-(CR19R20)nOC (=Y ') OR16、-(CR19R20)nOC (=Y ') NR16R17、-(CR19R20)nOS(O)2(OR16)、-(CR19R20)nOP (=Y ') (OR16)(OR17)、-(CR19R20)nOP(OR16)(OR17)、-(CR19R20)nS(O)R16、-(CR19R20)nS(O)2R16、-(CR19R20)nS(O)2NR16R17、-(CR19R20)nS(O)(OR16)、-(CR19R20)nS(O)2(OR16)、-(CR19R20)nSC (=Y ') R16、-(CR19R20)nSC (=Y ') OR16、-(CR19R20)nSC (=Y ') NR16R17And R21；And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined.
In another embodiment of the present invention, X1For
And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined.
In another embodiment of the present invention, X1For
Figure G2007800391963D00261
And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined.
In another embodiment of the present invention, X1For
Figure G2007800391963D00262
And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined.
In another embodiment of the present invention, X1For
Figure G2007800391963D00263
Figure G2007800391963D00271
And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined.
In another embodiment of the present invention, X1For
Figure G2007800391963D00272
And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined.
In another embodiment of the present invention, X1For OR11, wherein R11To be optionally independently selected from the heterocyclic radical (such as 4 to 6 circle heterocycles bases) of following one or more substituent groups：Halogen, CN, CF3、-OCF3、-NO2, oxo ,-Si (C1-C6Alkyl)3、-(CR19R20)nC (=Y ') R16、-(CR19R20)nC (=Y ') OR16、-(CR19R20)nC (=Y ') NR16R17、-(CR19R20)nNR16R17、-(CR19R20)nOR16、-(CR19R20)n-SR16、-(CR19R20)nNR16C (=Y ') R17、-(CR19R20)nNR16C (=Y ') OR17、-(CR19R20)nNR18C (=Y ') NR16R17、-(CR19R20)nNR17SO2R16、-(CR19R20)nOC (=Y ') R16、-(CR19R20)nOC (=Y ') OR16、-(CR19R20)nOC (=Y ') NR16R17、-(CR19R20)nOS(O)2(OR16)、-(CR19R20)nOP (=Y ') (OR16)(OR17)、-(CR19R20)nOP(OR16)(OR17)、-(CR19R20)nS(O)R16、-(CR19R20)nS(O)2R16、-(CR19R20)nS(O)2NR16R17、-(CR19R20)nS(O)(OR16)、-(CR19R20)nS(O)2(OR16)、-(CR19R20)nSC (=Y ') R16、-(CR19R20)nSC (=Y ') OR16、-(CR19R20)nSC (=Y ') NR16R17And R21；And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined.
In another embodiment of the present invention, X1For OR11, wherein R11For 4 to the 6 circle heterocycles bases with 1 nitrogen ring atom, wherein the heterocyclic radical is optionally independently selected from following one or more substituent groups：Halogen, CN, CF3、-OCF3、-NO2, oxo ,-Si (C1-C6Alkyl)3、-(CR19R20)nC (=Y ') R16、-(CR19R20)nC (=Y ') OR16、-(CR19R20)nC (=Y ') NR16R17、-(CR19R20)nNR16R17、-(CR19R20)nOR16、-(CR19R20)n-SR16、-(CR19R20)nNR16C (=Y ') R17、-(CR19R20)nNR16C (=Y ') OR17、-(CR19R20)nNR18C (=Y ') NR16R17、-(CR19R20)nNR17SO2R16、-(CR19R20)nOC (=Y ') R16、-(CR19R20)nOC (=Y ') OR16、-(CR19R20)nOC (=Y ') NR16R17、-(CR19R20)nOS(O)2(OR16)、-(CR19R20)nOP (=Y ') (OR16)(OR17)、-(CR19R20)nOP(OR16)(OR17)、-(CR19R20)nS(O)R16、-(CR19R20)nS(O)2R16、-(CR19R20)nS(O)2NR16R17、-(CR19R20)nS(O)(OR16)、-(CR19R20)nS(O)2(OR16)、-(CR19R20)nSC (=Y ') R16、-(CR19R20)nSC (=Y ') OR16、-(CR19R20)nSC (=Y ') NR16R17And R21；And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined.
In another embodiment of the present invention, X1For
Figure G2007800391963D00281
And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined.
In another embodiment of the present invention, X1For
Figure G2007800391963D00282
And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined.
In another embodiment of the present invention, X1For
And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined.
In one embodiment of the invention, X1For R11, and X1And R5The nitrogen-atoms being connected with them connects together to form 5-7 members saturation or unsaturation ring with the 0-2 additional heteroatom selected from O, S and N, wherein the ring is optionally selected from following one or more substituent groups：Halogen, CN, CF3、-OCF3、-NO2, oxo ,-Si (C1-C6Alkyl)3、-(CR19R20)nC (=Y ') R16、-(CR19R20)nC (=Y ') OR16、-(CR19R20)nC (=Y ') NR16R17、-(CR19R20)nNR16R17、-(CR19R20)nOR16、-(CR19R20)n-SR16、-(CR19R20)nNR16C (=Y ') R17、-(CR19R20)nNR16C (=Y ') OR17、-(CR19R20)nNR18C (=Y ') NR16R17、-(CR19R20)nNR17SO2R16、-(CR19R20)nOC (=Y ') R16、-(CR19R20)nOC (=Y ') OR16、-(CR19R20)nOC (=Y ') NR16R17、-(CR19R20)nOS(O)2(OR16)、-(CR19R20)nOP (=Y ') (OR16)(OR17)、-(CR19R20)nOP(OR16)(OR17)、-(CR19R20)nS(O)R16、-(CR19R20)nS(O)2R16、-(CR19R20)nS(O)2NR16R17、-(CR19R20)nS(O)(OR16)、-(CR19R20)nS(O)2(OR16)、-(CR19R20)nSC (=Y ') R16、-(CR19R20)nSC (=Y ') OR16、-(CR19R20)nSC (=Y ') NR16R17And R21；And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined.
In another embodiment of the present invention, X1For R11, and X1And R5The nitrogen-atoms being connected with them connects together to form the 5-6 member saturated rings with the 0-2 additional heteroatom selected from O, S and N, wherein the ring is optionally selected from following one or more substituent groups：Halogen, CN, CF3、-OCF3、-NO2, oxo ,-Si (C1-C6Alkyl)3、-(CR19R20)nC (=Y ') R16、-(CR19R20)nC (=Y ') OR16、-(CR19R20)nC (=Y ') NR16R17、-(CR19R20)nNR16R17、-(CR19R20)nOR16、-(CR19R20)n-SR16、-(CR19R20)nNR16C (=Y ') R17、-(CR19R20)nNR16C (=Y ') OR17、-(CR19R20)nNR18C (=Y ') NR16R17、-(CR19R20)nNR17SO2R16、-(CR19R20)nOC (=Y ') R16、-(CR19R20)nOC (=Y ') OR16、-(CR19R20)nOC (=Y ') NR16R17、-(CR19R20)nOS(O)2(OR16)、-(CR19R20)nOP (=Y ') (OR16)(OR17)、-(CR19R20)nOP(OR16)(OR17)、-(CR19R20)nS(O)R16、-(CR19R20)nS(O)2R16、-(CR19R20)nS(O)2NR16R17、-(CR19R20)nS(O)(OR16)、-(CR19R20)nS(O)2(OR16)、-(CR19R20)nSC (=Y ') R16、-(CR19R20)nSC (=Y ') OR16、-(CR19R20)nSC (=Y ') NR16R17And R21；And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined.
In another embodiment of the present invention, W is
Figure G2007800391963D00301
And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined.
In another embodiment of the present invention, W is
Figure G2007800391963D00302
And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined.
In another embodiment of the present invention, W is
Figure G2007800391963D00303
And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined.
In one embodiment of the invention, X1For R11, and X1And R5The nitrogen-atoms being connected with them connects together to form 4 yuan of saturations or unsaturation ring with the 0-1 additional heteroatom selected from O, S and N, wherein the ring is optionally selected from following one or more substituent groups：Halogen, CN, CF3、-OCF3、-NO2, oxo ,-Si (C1-C6Alkyl)3、-(CR19R20)nC (=Y ') R16、-(CR19R20)nC (=Y ') OR16、-(CR19R20)nC (=Y ') NR16R17、-(CR19R20)nNR16R17、-(CR19R20)nOR16、-(CR19R20)n-SR16、-(CR19R20)nNR16C (=Y ') R17、-(CR19R20)nNR16C (=Y ') OR17、-(CR19R20)nNR18C (=Y ') NR16R17、-(CR19R20)nNR17SO2R16、-(CR19R20)nOC (=Y ') R16、-(CR19R20)nOC (=Y ') OR16、-(CR19R20)nOC (=Y ') NR16R17、-(CR19R20)nOS(O)2(OR16)、-(CR19R20)nOP (=Y ') (OR16)(OR17)、-(CR19R20)nOP(OR16)(OR17)、-(CR19R20)nS(O)R16、-(CR19R20)nS(O)2R16、-(CR19R20)nS(O)2NR16R17、-(CR19R20)nS(O)(OR16)、-(CR19R20)nS(O)2(OR16)、-(CR19R20)nSC (=Y ') R16、-(CR19R20)nSC (=Y ') OR16、-(CR19R20)nSC (=Y ') NR16R17And R21；And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined.
In another embodiment of the present invention, W is
Figure G2007800391963D00311
And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined.
In one embodiment of the invention, X1For-OR11, and X1- OR11And R5The nitrogen-atoms being connected with them connects together to form 4-7 members saturation or unsaturation ring with the 0-2 additional heteroatom selected from O, S and N, wherein the ring is optionally selected from following one or more substituent groups：Halogen, CN, CF3、-OCF3、-NO2, oxo ,-Si (C1-C6Alkyl)3、-(CR19R20)nC (=Y ') R16、-(CR19R20)nC (=Y ') OR16、-(CR19R20)nC (=Y ') NR16R17、-(CR19R20)nNR16R17、-(CR19R20)nOR16、-(CR19R20)n-SR16、-(CR19R20)nNR16C (=Y ') R17、-(CR19R20)nNR16C (=Y ') OR17、-(CR19R20)nNR18C (=Y ') NR16R17、-(CR19R20)nNR17SO2R16、-(CR19R20)nOC (=Y ') R16、-(CR19R20)nOC (=Y ') OR16、-(CR19R20)nOC (=Y ') NR16R17、-(CR19R20)nOS(O)2(OR16)、-(CR19R20)nOP (=Y ') (OR16)(OR17)、-(CR19R20)nOP(OR16)(OR17)、-(CR19R20)nS(O)R16、-(CR19R20)nS(O)2R16、-(CR19R20)nS(O)2NR16R17、-(CR19R20)nS(O)(OR16)、-(CR19R20)nS(O)2(OR16)、-(CR19R20)nSC (=Y ') R16、-(CR19R20)nSC (=Y ') OR16、-(CR19R20)nSC (=Y ') NR16R17And R21；And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined.
In another embodiment of the present invention, X1For-OR11, and X1- OR11And R5The nitrogen-atoms being connected with them connects together to form 5-7 members saturation or unsaturation ring with the 0-2 additional heteroatom selected from O, S and N, wherein the ring is optionally selected from following one or more substituent groups：Halogen, CN, CF3、-OCF3、-NO2, oxo ,-Si (C1-C6Alkyl)3、-(CR19R20)nC (=Y ') R16、-(CR19R20)nC (=Y ') OR16、-(CR19R20)nC (=Y ') NR16R17、-(CR19R20)nNR16R17、-(CR19R20)nOR16、-(CR19R20)n-SR16、-(CR19R20)nNR16C (=Y ') R17、-(CR19R20)nNR16C (=Y ') OR17、-(CR19R20)nNR18C (=Y ') NR16R17、-(CR19R20)nNR17SO2R16、-(CR19R20)nOC (=Y ') R16、-(CR19R20)nOC (=Y ') OR16、-(CR19R20)nOC (=Y ') NR16R17、-(CR19R20)nOS(O)2(OR16)、-(CR19R20)nOP (=Y ') (OR16)(OR17)、-(CR19R20)nOP(OR16)(OR17)、-(CR19R20)nS(O)R16、-(CR19R20)nS(O)2R16、-(CR19R20)nS(O)2NR16R17、-(CR19R20)nS(O)(OR16)、-(CR19R20)nS(O)2(OR16)、-(CR19R20)nSC (=Y ') R16、-(CR19R20)nSC (=Y ') OR16、-(CR19R20)nSC (=Y ') NR16R17And R21；And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined
In another embodiment of the present invention, X1For-OR11, and X1- OR11And R5The nitrogen-atoms being connected with them connects together to form the 5-6 member saturated rings with the 0-2 additional heteroatom selected from O, S and N, wherein the ring is optionally selected from following one or more substituent groups：Halogen, CN, CF3、-OCF3、-NO2, oxo ,-Si (C1-C6Alkyl)3、-(CR19R20)nC (=Y ') R16、-(CR19R20)nC (=Y ') OR16、-(CR19R20)nC (=Y ') NR16R17、-(CR19R20)nNR16R17、-(CR19R20)nOR16、-(CR19R20)n-SR16、-(CR19R20)nNR16C (=Y ') R17、-(CR19R20)nNR16C (=Y ') OR17、-(CR19R20)nNR18C (=Y ') NR16R17、-(CR19R20)nNR17SO2R16、-(CR19R20)nOC (=Y ') R16、-(CR19R20)nOC (=Y ') OR16、-(CR19R20)nOC (=Y ') NR16R17、-(CR19R20)nOS(O)2(OR16)、-(CR19R20)nOP (=Y ') (OR16)(OR17)、-(CR19R20)nOP(OR16)(OR17)、-(CR19R20)nS(O)R16、-(CR19R20)nS(O)2R16、-(CR19R20)nS(O)2NR16R17、-(CR19R20)nS(O)(OR16)、-(CR19R20)nS(O)2(OR16)、-(CR19R20)nSC (=Y ') R16、-(CR19R20)nSC (=Y ') OR16、-(CR19R20)nSC (=Y ') NR16R17And R21；And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined.
In another embodiment of the present invention, W is
Figure G2007800391963D00321
And all other variable such as Formulas I or I-a are to defined in I-i or as hereinbefore defined.
In one embodiment of the invention, X1For R11；And all other variable is as defined in Formulas I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h or I-i or as hereinbefore defined.
In another embodiment of the present invention, X1For R11, wherein R11For H；And all other variable is as defined in Formulas I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h or I-i or as hereinbefore defined.
In another embodiment of the present invention, X1For R11, wherein R11To be independently selected from the C of following one or more substituent groups1-C12Alkyl (such as C1-C6Alkyl)：Halogen, CN, CF3、-OCF3、-NO2, oxo ,-Si (C1-C6Alkyl)3、-(CR19R20)nC (=Y ') R16、-(CR19R20)nC (=Y ') OR16、-(CR19R20)nC (=Y ') NR16R17、-(CR19R20)nNR16R17、-(CR19R20)nOR16、-(CR19R20)n-SR16、-(CR19R20)nNR16C (=Y ') R17、-(CR19R20)nNR16C (=Y ') OR17、-(CR19R20)nNR18C (=Y ') NR16R17、-(CR19R20)nNR17SO2R16、-(CR19R20)nOC (=Y ') R16、-(CR19R20)nOC (=Y ') OR16、-(CR19R20)nOC (=Y ') NR16R17、-(CR19R20)nOS(O)2(OR16)、-(CR19R20)nOP (=Y ') (OR16)(OR17)、-(CR19R20)nOP(OR16)(OR17)、-(CR19R20)nS(O)R16、-(CR19R20)nS(O)2R16、-(CR19R20)nS(O)2NR16R17、-(CR19R20)nS(O)(OR16)、-(CR19R20)nS(O)2(OR16)、-(CR19R20)nSC (=Y ') R16、-(CR19R20)nSC (=Y ') OR16、-(CR19R20)nSC (=Y ') NR16R17And R21；And all other variable is as defined in Formulas I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h or I-i or as hereinbefore defined.
In another embodiment of the present invention, X1For
Figure G2007800391963D00331
Figure G2007800391963D00341
And all other variable is as defined in Formulas I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h or I-i or as hereinbefore defined.
In another embodiment of the present invention, X1For
Figure G2007800391963D00351
And all other variable is as defined in Formulas I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h or I-i or as hereinbefore defined.
In another embodiment of the present invention, X1For-S (O)2R11, and all other variable is as defined in Formulas I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h or I-i or as hereinbefore defined.
In another embodiment of the present invention, X1For-S (O)2R11, wherein R11For H or methyl；And all other variable is as defined in Formulas I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h or I-i or as hereinbefore defined.
In one embodiment of the invention, W is-OR11(i.e. formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h or III-i), wherein W R11For H or C1-C12Alkyl；And all other variable is as hereinbefore defined.
In another embodiment of the present invention, W is-OR11(i.e. formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h or III-i), wherein W R11For H；And all other variable is as hereinbefore defined.
In another embodiment of the present invention, W is-OR11(i.e. formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h or III-i), wherein W R11For C1-C6Alkyl；And all other variable is as hereinbefore defined.
In one embodiment of the invention, X2For aryl (such as phenyl), wherein the aryl is optionally independently selected from following one or more substituent groups：Halogen, CN, CF3、-OCF3、-NO2, oxo ,-Si (C1-C6Alkyl)3、-(CR19R20)nC (=Y ') R16、-(CR19R20)nC (=Y ') OR16、-(CR19R20)nC (=Y ') NR16R17、-(CR19R20)nNR16R17、-(CR19R20)nOR16、-(CR19R20)n-SR16、-(CR19R20)nNR16C (=Y ') R17、-(CR19R20)nNR16C (=Y ') OR17、-(CR19R20)nNR18C (=Y ') NR16R17、-(CR19R20)nNR17SO2R16、-(CR19R20)nOC (=Y ') R16、-(CR19R20)nOC (=Y ') OR16、-(CR19R20)nOC (=Y ') NR16R17、-(CR19R20)nOS(O)2(OR16)、-(CR19R20)nOP (=Y ') (OR16)(OR17)、-(CR19R20)nOP(OR16)(OR17)、-(CR19R20)nS(O)R16、-(CR19R20)nS(O)2R16、-(CR19R20)nS(O)2NR16R17、-(CR19R20)nS(O)(OR16)、-(CR19R20)nS(O)2(OR16)、-(CR19R20)nSC (=Y ') R16、-(CR19R20)nSC (=Y ') OR16、-(CR19R20)nSC (=Y ') NR16R17And R21；And all other variable such as Formulas I, I-a to I-i, II-a to II-i or III-a is to defined in III-i or as hereinbefore defined.
In another embodiment of the present invention, X2For
Figure G2007800391963D00361
And all other variable such as Formulas I, I-a to I-i, II-a to II-i or III-a is to defined in III-i or as hereinbefore defined.
In another embodiment of the present invention, X2For
Figure G2007800391963D00371
And all other variable such as Formulas I, I-a to I-i, II-a to II-i or III-a is to defined in III-i or as hereinbefore defined.
In another embodiment of the present invention, X2For
And all other variable such as Formulas I, I-a to I-i, II-a to II-i or III-a is to defined in III-i or as hereinbefore defined.
In another embodiment of the present invention, X2For
Figure G2007800391963D00381
And all other variable such as Formulas I, I-a to I-i, II-a to II-i or III-a is to defined in III-i or as hereinbefore defined.
In another embodiment of the present invention, X2For
Figure G2007800391963D00382
And all other variable such as Formulas I, I-a to I-i, II-a to II-i or III-a is to defined in III-i or as hereinbefore defined.
In another embodiment of the present invention, X2For by C1-C4Alkyl-substituted C6-C10Aryl；And all other variable such as Formulas I, I-a to I-i, II-a to II-i or III-a is to defined in III-i or as hereinbefore defined.
In another embodiment of the present invention, X2For
Figure G2007800391963D00383
And all other variable such as Formulas I, I-a to I-i, II-a to II-i or III-a is to defined in III-i or as hereinbefore defined.
In another embodiment of the present invention, X2For
Figure G2007800391963D00384
And all other variable such as Formulas I, I-a to I-i, II-a to II-i or III-a is to defined in III-i or as hereinbefore defined.
In another embodiment of the present invention, X2For
Figure G2007800391963D00391
And all other variable such as Formulas I, I-a to I-i, II-a to II-i or III-a is to defined in III-i or as hereinbefore defined.
In another embodiment of the present invention, X2For carbocylic radical (such as C4-C6Carbocylic radical) or heterocyclic radical (such as 4 to 6 circle heterocycles bases), wherein the carbocylic radical or heterocyclic radical are optionally independently selected from following one or more substituent groups：Halogen, CN, CF3、-OCF3、-NO2, oxo ,-Si (C1-C6Alkyl)3、-(CR19R20)nC (=Y ') R16、-(CR19R20)nC (=Y ') OR16、-(CR19R20)nC (=Y ') NR16R17、-(CR19R20)nNR16R17、-(CR19R20)nOR16、-(CR19R20)n-SR16、-(CR19R20)nNR16C (=Y ') R17、-(CR19R20)nNR16C (=Y ') OR17、-(CR19R20)nNR18C (=Y ') NR16R17、-(CR19R20)nNR17SO2R16、-(CR19R20)nOC (=Y ') R16、-(CR19R20)nOC (=Y ') OR16、-(CR19R20)nOC (=Y ') NR16R17、-(CR19R20)nOS(O)2(OR16)、-(CR19R20)nOP (=Y ') (OR16)(OR17)、-(CR19R20)nOP(OR16)(OR17)、-(CR19R20)nS(O)R16、-(CR19R20)nS(O)2R16、-(CR19R20)nS(O)2NR16R17、-(CR19R20)nS(O)(OR16)、-(CR19R20)nS(O)2(OR16)、-(CR19R20)nSC (=Y ') R16、-(CR19R20)nSC (=Y ') OR16、-(CR19R20)nSC (=Y ') NR16R17And R21；And all other variable such as Formulas I, I-a to I-i, II-a to II-i or III-a is to defined in III-i or as hereinbefore defined.
In another embodiment of the present invention, X2For C4-C6Carbocylic radical, wherein the carbocylic radical is by-C (=Y ') R16Substitution；And all other variable such as Formulas I, I-a to I-i, II-a to II-i or III-a is to defined in III-i or as hereinbefore defined.
In another embodiment of the present invention, X2ForAnd all other variable such as Formulas I, I-a to I-i, II-a to II-i or III-a is to defined in III-i or as hereinbefore defined.
Another embodiment of the present invention includes the compound and following compounds described in embodiment 5-12：
Figure G2007800391963D00402
Figure G2007800391963D00411
The compounds of this invention is operation according to described in following scheme and embodiment or prepared by methods known in the art.Initiation material and various intermediates can be obtained from commercial source, be prepared from commercial compound, or be prepared using well known synthetic method (such as those methods described in WO02/06213, WO 03/077855 and WO03/077914).
For example, the route of synthesis summarized in scheme 1,2 and 3 can be used to prepare for the 5- azepines benzothiophene of formula (I-b), (II-b) or (III-b).
Scheme 1
The disclosed method described in document can be used to prepare for formula (IV) compound.Formula (IV) compound and methyl thioglycolate or ethyl thioglycolate can be made, in the presence of alkali such as sodium hydride, in suitable solvent such as N, dinethylformamide or 1, in 2- dimethoxy-ethanes, at -50 DEG C to reacting at room temperature, formula (VI) compound is obtained.
Formula (VI) compound can be converted into formula (VII) compound in the following manner：Make formula (VI) compound and halogenating agent such as pure phosphoryl bromide (phosphorus oxybromide) or its solution in suitable solvent such as toluene, reacted in room temperature to 140 DEG C.Alternatively, formula (VI) compound and nine fluorine butyl sulfuryl fluorides (nonafluorobutane sulphonyl fluoride) can be made, in alkali such as diisopropylethylamine and catalyst such as N, in the presence of N- dimethyl -4-aminopyridine, in solvent such as dichloromethane, in room temperature reaction；Or with N- phenyl trifluoromethanesulfonate methylsulfonimides (N-phenyltrifluoromethanesulfonimide, Tf2NPh), in the presence of alkali such as diisopropylethylamine, in suitable solvent such as 1,2- dimethoxy-ethanes, reacted in the reflux temperature of room temperature to solvent.Furthermore, it is possible to which with trifluoromethanesulfanhydride anhydride in the presence of alkali such as pyridine, in solvent such as dichloromethane, formula (VI) compound is handled at -20 DEG C to environment temperature.
Formula (VIII) compound can be obtained from formula (VII) compound as follows：Make formula (VII) compound and aniline (introducing appropriate substituent R 1), in the palladium (0) of catalyst such as three (dibenzalacetone) two or palladium, alkali such as potassium phosphate, sodium tert-butoxide, 1, carbon -7- the alkene of 8- diazabicylos [5.4.1] 11 or cesium carbonate, part such as 9, 9 '-dimethyl -4, 5- bis- (diphenylphosphino) xanthene, 2, 2 '-two (diphenylphosphinos) -1, 1 '-dinaphthalene, 2- (dicyclohexyl phosphino-) -2 '-(N, N- dimethylaminos) biphenyl, 2- (dicyclohexyl phosphino-) -2 ', in the presence of 6 '-dimethoxy-biphenyl or tributylphosphine, in suitable solvent such as toluene, 1, 2- dimethoxy-ethanes, in tetrahydrofuran or dioxane, reacted in the reflux temperature of room temperature to solvent, or under microwave irradiation, in 70 DEG C to 150 DEG C reactions.
Alternatively, formula (VIII) compound can be obtained from formula (VI) compound as follows：Formula (VI) compound is set (to be prepared with formula (IX) compound using the disclosed method described in document), in suitable solvent such as toluene or 1, in 2- dimethoxy-ethanes, reacted in the reflux temperature of room temperature to solvent, or under microwave irradiation, in 100 DEG C to 180 DEG C reactions.
Formula (X) compound can be obtained from formula (VIII) compound as follows：Make formula (VIII) compound and alkali such as sodium hydroxide, in proton solvent such as ethanol or methanol, reacted in room temperature to reflux temperature.
The azanol (commercially available or prepared according to scheme 6) or amine of the functionalization of formula (X) compound and formula (XII) can be made, and suitable coupling agent such as O- (7- azepine benzos triazol-1-yl)-N, N, N ', N '-tetramethyl
Figure G2007800391963D00421
Hexafluorophosphate, N- (3- (dimethylamino) propyl group)-N '-ethyl-carbodiimide hydrochlorides or N, N '-dicyclohexylcarbodiimide, in N- hydroxyls -1, in the presence of 2,3- BTAs, in the presence of suitable alkali such as diisopropylethylamine or triethylamine, in atent solvent such as tetrahydrofuran, N, in dinethylformamide or dichloromethane, about reacting at room temperature, obtaining formula (XI) compound.Alternatively, formula (XI) compound can be obtained directly from formula (VIII) compound as follows：Make formula (VIII) compound and amine or azanol DNHR, in the presence of lewis acid (Lewis acid) such as trimethyl aluminium, in solvent such as DCM (dichloromethane), reacted in room temperature to reflux temperature.
Alternatively, formula (VIII) compound can be prepared according to scheme 2 from formula (XIII) compound.
Scheme 2
Figure G2007800391963D00431
Formula (XIII) compound can be used to be prepared using the disclosed method described in document.The method just described above from formula (IV) preparation of compounds of formula (VI) compound can be used in the compound of formula (XIV), is prepared from formula (XIII) compound.
Formula (VIII) compound can be prepared from formula (XIV) compound as follows：Using the method just described above from formula (VI) preparation of compounds of formula (VIII) compound, make formula (XIV) compound and formula (XV) compound (introducing appropriate substituent R 1) reaction.Alternatively, formula (VIII) compound is prepared from formula (XIV) compound as follows：Make formula (XIV) compound and formula (XVI) compound (introducing appropriate substituent R 1), in the presence of alkali such as sodium hydride or hexamethl disilamine base lithium (lithium hexamethyldisilazane), in suitable solvent such as tetrahydrofuran or N, in dinethylformamide, in room temperature to 150 DEG C of reactions.
Alternatively, formula (X) compound can also be prepared according to scheme 3 from formula (VII) compound.
Scheme 3
The method just described above from formula (VIII) preparation of compounds of formula (X) compound can be used, formula (VII) compound is converted into formula (XVII) compound.The method just described above from formula (X) preparation of compounds of formula (XI) compound can be used, formula (XVII) compound and amine such as 2-amino-2-methyl-1-propanol are coupled, then with reagent such as pure thionyl chloride or its solution in suitable solvent such as dichloromethane, chloroform or ether or pure phosphoryl chloride phosphorus oxychloride or its solution in suitable solvent such as dichloromethane, chloroform or ether, reacted in the reflux temperature of room temperature to solvent, obtain formula (XVIII) compound.
Formula (XIX) compound can be obtained from formula (XVIII) compound as follows：Make formula (XVIII) compound and aniline (introducing appropriate substituent R 1), in the palladium (0) of catalyst such as three (dibenzalacetone) two or palladium, alkali such as potassium phosphate, sodium tert-butoxide, 1, carbon -7- the alkene of 8- diazabicylos [5.4.1] 11 or cesium carbonate, part such as 9, 9 '-dimethyl -4, 5- bis- (diphenylphosphino) xanthene, 2, 2 '-two (diphenylphosphinos) -1, 1 '-dinaphthalene, 2- (dicyclohexyl phosphino-) -2 '-(N, N- dimethylaminos) biphenyl, 2- (dicyclohexyl phosphino-) -2 ', in the presence of 6 '-dimethoxy-biphenyl or tributylphosphine, in suitable solvent such as toluene, 1, 2- dimethoxy-ethanes, in tetrahydrofuran or dioxane, reacted in the reflux temperature of room temperature to solvent, or under microwave irradiation, in 70 DEG C to 150 DEG C reactions.
Alternatively, formula (XIX) compound can be obtained from formula (XVIII) compound as follows：Make formula (XVIII) compound and aniline compound (introducing appropriate substituent R 1), in the presence of alkali such as sodium hydride or hexamethl disilamine base lithium, in suitable solvent such as tetrahydrofuran or DMF, in room temperature to 150 DEG C of reactions.Formula (X) compound can be obtained from formula (XIX) compound as follows：Make formula (XIX) compound and acid such as hydrochloric acid or acetic acid, in suitable solvent such as water, reacted in the reflux temperature of room temperature to solvent.
The route of synthesis summarized in scheme 4 can be used to prepare for Formulas I-c, II-c or III-c 6- azepines benzothiophene.
Scheme 4
Figure G2007800391963D00451
The disclosed method described in document can be used to prepare for formula (XX) compound.Formula (XX) compound and glycolic methyl esters or ethyl glycolate can be made, in phosphine such as triphenylphosphine, in the presence of azodicarboxy acid alkyl ester such as diethylazodicarboxylate or diisopropyl azo-2-carboxylic acid, in aprotic solvent such as tetrahydrofuran or ether, reacted in the reflux temperature of room temperature to solvent, obtain formula (XXI) compound.
Formula (XXI) compound can be made in the presence of alkali such as sodium hydride, in suitable solvent such as DMF or 1,2- dimethoxy-ethane, at -50 DEG C to reacting at room temperature, formula (XXII) compound is obtained.
Formula (XXII) compound can be converted into formula (XXIII) compound in the following manner：Make formula (XXIII) compound and halogenating agent such as pure phosphoryl bromide or its solution in suitable solvent such as toluene, reacted in room temperature to 140 DEG C.Alternatively, formula (XXII) compound can be made with nine fluorine butyl sulfuryl fluorides in the presence of alkali such as diisopropylethylamine and catalyst such as N, N- dimethyl -4-aminopyridine, in solvent such as dichloromethane, in room temperature reaction；Or with N- phenyl trifluoromethanesulfonates methylsulfonimide in the presence of alkali such as diisopropylethylamine, in suitable solvent such as 1,2- dimethoxy-ethanes, reacted in the reflux temperature of room temperature to solvent.Furthermore, it is possible to trifluoromethanesulfanhydride anhydride in the presence of alkali such as pyridine, in solvent such as dichloromethane, at -20 DEG C to environment temperature processing formula (XXII) compound.
Formula (XXIV) compound can be obtained from formula (XXIII) compound as follows：Make formula (XXIII) compound and aniline (introducing appropriate substituent R 1), in the palladium (0) of catalyst such as three (dibenzalacetone) two or palladium, alkali such as potassium phosphate, sodium tert-butoxide, 1, carbon -7- the alkene of 8- diazabicylos [5.4.1] 11 or cesium carbonate, part such as 9, 9 '-dimethyl -4, 5- bis- (diphenylphosphino) xanthene, 2, 2 '-two (diphenylphosphinos) -1, 1 '-dinaphthalene, 2- (dicyclohexyl phosphino-) -2 '-(N, N- dimethylaminos) biphenyl, 2- (dicyclohexyl phosphino-) -2 ', in the presence of 6 '-dimethoxy-biphenyl or tributylphosphine, in suitable solvent such as toluene, 1, 2- dimethoxy-ethanes, in tetrahydrofuran or dioxane, reacted in the reflux temperature of room temperature to solvent, or under microwave irradiation, in 70 DEG C to 150 DEG C reactions.
Alternatively, formula (XXIV) compound can be obtained from formula (XXII) compound as follows：Formula (XXII) compound is set (to be prepared with formula (IX) compound using the disclosed method described in document), in suitable solvent such as toluene or 1, in 2- dimethoxy-ethanes, reacted in the reflux temperature of room temperature to solvent, or under microwave irradiation, in 100 DEG C to 180 DEG C reactions.
Formula (XXVI) compound can be obtained from formula (XXIV) compound as follows：Make formula (XXIV) compound and alkali such as sodium hydroxide, in proton solvent such as ethanol or methanol, reacted in room temperature to reflux temperature.
The azanol (commercially available or prepared according to scheme 6) or amine of the functionalization of formula (XXVI) compound and formula (XII) can be made, and suitable coupling agent such as O- (7- azepine benzos triazol-1-yl)-N, N, N ', N '-tetramethyl
Figure G2007800391963D00461
Hexafluorophosphate, N- (3- (dimethylamino) propyl group)-N '-ethyl-carbodiimide hydrochlorides or N, N '-dicyclohexylcarbodiimide, in N- hydroxyls -1, in the presence of 2,3- BTAs, in the presence of suitable alkali such as diisopropylethylamine or triethylamine, in atent solvent such as tetrahydrofuran, N, in dinethylformamide or dichloromethane, about reacting at room temperature, obtaining formula (XXVII) compound.Alternatively, formula (XXII) compound can be obtained directly from formula (XXIV) compound as follows：Make formula (XXIV) compound with amine or azanol DNHR in the presence of lewis acid such as trimethyl aluminium, in solvent such as DCM, reacted in room temperature to reflux temperature.
The route of synthesis summarized in scheme 5 can be used to prepare for Formulas I-f, II-f or III-f thieno [2,3-d] pyrimidine.
Scheme 5
Figure G2007800391963D00471
Formula (XXVIII) compound can be according to described in document method prepare.Formula (XXVIII) compound and halogenating agent such as pure phosphoryl chloride phosphorus oxychloride or its solution in suitable solvent such as toluene can be made, in room temperature to reflux temperature reaction, formula (XXIX) compound is obtained.
Formula (XXXVI) compound can be used, from the method that the method for formula (IV) preparation of compounds of formula (XI) compound is similar, to be obtained with as shown in scheme 5 from formula (XXIX) compound.
The route of synthesis summarized in method or scheme 6 described in document can be used to prepare for the azanol of formula (XII).
Scheme 6
Figure G2007800391963D00472
The method described in document can be used to prepare for the primary alconol or secondary alcohol of formula (XXXVII).Phosphine and coupling agent such as diethylazodicarboxylate can be used, the primary alconol or secondary alcohol and 1- hydroxyphthalimides that make formula (XXXVII) react the compound for obtaining formula (XXXVIII).Hydrazine or methyl hydrazine can be used to be deprotected for the compound of formula (XXXVIII), and obtain formula (XII-a) azanol.Formula (XII-a) compound can be modified further below：Using reducing agent such as sodium triacetoxy borohydride, sodium cyanoborohydride or borane-pyridine, in solvent such as dichloroethanes, reproducibility ammonification is carried out in environment temperature to reflux temperature and aldehydes or ketones.In addition, formula (XII-a) compound can be modified further below：In the presence of alkali such as triethylamine, it is alkylated in solvent such as dichloromethane with alkyl halide (alkyl halide), obtains formula (XII-b) azanol.
The aniline of the formula (XXXIX) used in above-described cross-coupling reaction can be prepared by the method described in document or according to scheme 7.
Scheme 7
Figure G2007800391963D00481
Catalyst such as tetrakis triphenylphosphine palladium can be used, makes the chloro- nitrobenzene of substituted 4- with hexamethyldisilane (hexamethyldisilane) in solvent such as dimethylbenzene, is reacted in room temperature to reflux temperature.The method reduction described in document can be used in nitro, such as in a hydrogen atmosphere, under the pressure of 1 to 5 atmospheric pressure, in the presence of catalyst such as palladium/carbon, in solvent such as ethanol or ethyl acetate, in room temperature reaction.
The triflate of the formula (XL) used in above-described cross-coupling reaction can be used method described in document or be prepared according to scheme 8.
Scheme 8
Figure G2007800391963D00482
The halogenated phenol and two equivalent alkyl lithium reagents such as n-BuLis of formula (XLI) can be made to be reacted in solvent such as THF (tetrahydrofuran), then trialkylsilkl phenol (XLII) is obtained as trimethylsilyl chloride is quenched with trialkylsilyl halide (trialkylsilyl halide).Usable literature procedures further make trialkylsilkl phenol react, and obtain the triflate or nine fluorine fourth sulphonic acid esters (nonaflate) of formula (XL).
It should be appreciated that, in the presence of appropriate functional group, formula (I), (II), the compound of (III) or any intermediate for being used in their preparation can by one or more Standard synthetic methods using substitution, oxidation, reduction or cracking reaction come further derivatization.Specific substitution technique includes conventional alkylation, arylation, heteraryl, acylation, sulfonylation, halogenation, nitrification, formylated and COUPLING PROCEDURE.
For example, aryl bromide or aryl cl radical can be converted into aryl iodide as follows：Using Finkelstein reaction (Finkelstein reaction) i.e. in solvent such as 1, in 4- dioxanes, using propiodal such as sodium iodide, catalyst such as cuprous iodide, with for example trans-N of part, N '-dimethyl -1,2- cyclohexanediamine, then heats reactant mixture in reflux temperature.Aryltrialkylphosphonium monosilane can be converted into aryl iodide as follows：With propiodal such as iodine monochloride, in the solvent such as dichloromethane with or without lewis acid such as silver tetrafluoroborate, at -40 DEG C to the reflux temperature processing monosilane.
In another embodiment, primary amine (- NH2) group can be carried out as follows alkylation：Using reductive alkylation process on glycopeptides i.e. in solvent such as halogenated hydrocarbons such as 1,2- dichloroethanes, or in alcohol such as ethanol, if necessary in the presence of acid such as acetic acid, in environment temperature or so, aldehydes or ketones, and boron hydride such as sodium triacetoxy borohydride or sodium cyanoborohydride are used.Secondary amine (- NH-) group is alkylated as aldehydes can be used.
In another embodiment, primary amine or secondary amine group can be converted into amide group (- NHCOR ' or-NRCOR ') by acylated.Acylation can be implemented as described below：With appropriate acyl chlorides in the presence of alkali such as triethylamine, reacted in suitable solvent such as dichloromethane；Or with appropriate carboxylic acid suitable coupling agent such as HATU (O- (7- azepine benzos triazol-1-yl)-N, N, N ', N '-tetramethyl
Figure G2007800391963D00491
Hexafluorophosphate) in the presence of, reacted in suitable solvent such as dichloromethane.Similarly, amine groups can be converted into sulfuryl amine group (- NHSO as follows2R ' or-NR " SO2R’)：Make amine groups with appropriate sulfonic acid chloride in the presence of suitable alkali such as triethylamine, reacted in suitable solvent such as dichloromethane.Primary amine or secondary amine group can be converted into urea groups (- NHCONR ' R " or-NRCONR ' R ") as follows：Make primary amine or secondary amine group with appropriate isocyanates in the presence of suitable alkali such as triethylamine, reacted in suitable solvent such as dichloromethane.
Amine (- NH2) can be obtained as below：Reduce nitro (- NO2), such as hydrogen in solvent such as ethyl acetate or alcohol such as methanol, is for example used i.e. in the presence of metallic catalyst (such as palladium/carrier (such as carbon)) by catalytic hydrogenation.Alternatively, the conversion can be carried out using such as metal (such as tin or iron) in the presence of acid such as hydrochloric acid by electronation.
In another embodiment, amine (- CH2NH2) group can be obtained as below：Nitrile (- CN) is reduced, for example by catalytic hydrogenation i.e. in the presence of metallic catalyst (such as palladium/carrier (such as carbon) or Raney Ni (Raneynickel)), in solvent such as ether (such as cyclic ethers such as tetrahydrofuran), such as hydrogen is used in -78 DEG C to solvent of reflux temperatures.
In another embodiment, amine (- NH2) group can be as follows from hydroxy-acid group (- CO2H) obtain：By hydroxy-acid group (- CO2H) it is converted into corresponding acid azide (- CON3), Ku Ertisi rearrangements (Curtiusrearrangement) are carried out, then the isocyanates (- N=C=O) of formation is hydrolyzed.
Aldehyde radical (- CHO) can be converted into amine groups (- CH as follows2NR’R”)：Reproducibility ammonification is i.e. in solvent such as halogenated hydrocarbons (such as dichloromethane) or alcohol (such as ethanol), if necessary in the presence of acid such as acetic acid, amine and boron hydride (such as sodium triacetoxy borohydride or sodium cyanoborohydride) are used in environment temperature or so.
In another embodiment, aldehyde radical can be converted into alkenyl (- CH=CHR ') as follows：Under standard conditions well known by persons skilled in the art witig reaction (Wittig reaction) or Wadsworth-Emmons reaction are carried out using appropriate phosphine alkane (phosphorane) or phosphonate ester (phosphonate).
Aldehyde radical can be obtained as below：Using diisobutyl aluminium hydride to ester group (such as-CO in suitable solvent such as toluene2) or nitrile (- CN) is reduced Et.Alternatively, aldehyde radical can be obtained as below：Alcohol radical (alcohol group) is aoxidized using any suitable oxidizers well known by persons skilled in the art.
Depending on R property, ester group (- CO2R ') corresponding acid groups (- CO can be converted into by acid-catalyzed hydrolysis or alkali catalyzed hydrolysis2H).If R is the tert-butyl group, acid-catalyzed hydrolysis can be implemented as described below：For example handled, or handled with inorganic acid such as hydrochloric acid in aqueous solvent in aqueous solvent with organic acid such as trifluoroacetic acid.
Hydroxy-acid group (- CO2H) acid amides (CONHR ' or-CONR ' R ") can be converted into by the presence of suitable coupling agent such as HATU, being reacted with appropriate amine in suitable solvent such as dichloromethane.
In another embodiment, carboxylic acid can add a carbon atom (be homologated by onecarbon) (i.e.-CO as follows2H is changed into-CH2CO2H)：Carboxylic acid is converted into corresponding acyl chlorides (- COCl), Arndt-Esther synthesis (Arndt-Eistert synthesis) is then carried out.
In another embodiment ,-OH groups can be as follows from corresponding ester (such as-CO2R ') or aldehyde (- CHO) generation：Reduced using such as complex metal hydride (solution or sodium borohydride solution in solvent such as methanol of such as lithium aluminium hydride reduction in ether or tetrahydrofuran).Alternatively, corresponding the acid (- CO of solution reduction that alcohol can be by using solution of such as lithium aluminium hydride reduction in solvent such as tetrahydrofuran or use borine in solvent such as tetrahydrofuran2H) prepare.
Condition well known by persons skilled in the art can be used to be converted into leaving group such as halogen atom or sulfonyl epoxide (such as alkyl sulphonyl epoxide (such as trifluoromethyl sulfonyl epoxide) or aryl sulfonyl epoxide (such as p-toluenesulfonyl epoxide)) for alcohol radical.For example, can make alcohol, the reaction in halogenated hydrocarbons (such as dichloromethane) obtains corresponding chloride with thionyl chloride.Alkali (such as triethylamine) can also be used in the reaction.
In another embodiment, alcohol, phenol or amide group can be carried out as follows alkylation：Make phenol or acid amides with alcohol in solvent such as tetrahydrofuran, be coupled in the presence of phosphine such as triphenylphosphine and activator such as diethylazodicarboxylate, diisopropyl azo-2-carboxylic acid or azodicarboxy dimethyl phthalate.Alternatively, alkylation can be implemented as described below：Deprotonation is carried out using suitable alkali such as sodium hydride, alkylating reagent such as alkyl halide is subsequently added into.
Aromatic halogen substituents in compound can be carried out as follows halogen-metal exchange：Aromatic halogen substituents in compound are with alkali (such as lithium alkali such as n-BuLi or tert-butyl lithium), and optionally in such as -78 DEG C or so of low temperature, processing, is then quenched to introduce desired substituent with electrophilic reagent in solvent such as tetrahydrofuran.Thus, for example formoxyl can be introduced by using DMF as electrophilic reagent.Alternatively, aromatic halogen substituents can enter the reaction of row metal (such as palladium or copper) catalysis to introduce such as acid groups, ester group, cyano group, amide group, aryl, heteroaryl, alkenyl, alkynyl, thio or amino-substituent.Workable proper operation includes being operated by those that Heck, Suzuki, Stille, Buchwald or Hartwig are described.
Aromatic halogen substituents also can be with carrying out nucleophilic displacement after appropriate nucleopilic reagent such as amine or alcohol reaction.It is advantageous that above-mentioned reaction can be in the presence of microwave irradiation in the progress of elevated temperature.
As described below, test the compounds of this invention suppress MEK activity and activation ability (primary determine) and they to growing the biological action (secondary measure) of cell.Following compound can be used as mek inhibitor, and the compound has the IC for being less than 10 μM (more preferably less than 5 μM, even more preferably less than 1 μM, more preferably less than most 0.5 μM) in embodiment 1a or 1b MEK determinations of activity50, there is the IC for being less than 5 μM (more preferably less than 0.1 μM, more preferably less than 0.01 μM) in the MEK activation determinations of embodiment 250, there is the IC for being less than 10 μM (more preferably less than 5 μM, more preferably less than 0.5 μM) in the cell proliferating determining of embodiment 350, and/or there is the IC for being less than 10 μM (more preferably less than 1 μM, more preferably less than 0.1 μM) in the ERK phosphorylation assay of embodiment 450。
The present invention includes the composition (such as pharmaceutical composition) containing compound of formula I (and/or its solvate and salt) and carrier (pharmaceutical acceptable carrier).Present invention additionally comprises containing compound of formula I (and/or its solvate and salt) and carrier (pharmaceutical acceptable carrier) and also containing the composition (such as pharmaceutical composition) such as another chemotherapeutic agent described herein and/or another anti-inflammatory drug.The present composition can be used for suppressing abnormal cell growth or treatment excess proliferative disease in mammal (such as people).The present composition can be additionally used in the treatment inflammatory disease in mammal (such as people).
The compounds of this invention and composition can be additionally used in treatment autoimmune disease, destructive bone disease (destructive bone disorder), proliferative diseases, infectious diseases (infectious disease), virus disease, fibrotic disease or neurodegenerative disease in mammal (such as people).The example of above-mentioned diseases/disorders includes but is not limited to diabetes and diabetic complication, diabetic retinopathy (diabeticretinopathy), retinopathy of prematurity (retinopathy of prematurity), age related macular degeneration (age-related macular degeneration), hemangioma, idiopathic pulmonary fibrosis (idiopathicpulmonary fibrosis), rhinitis and atopic dermatitis (atopic dermatitis), nephrosis and kidney failure, POLYCYSTIC KIDNEY DISEASE (polycystic kidney disease), congestive heart failure, neurofibromatosis (neurofibromatosis), organ-graft refection, cachexia, apoplexy, septic shock, heart failure, organ-graft refection, alzheimer disease, chronic ache or neuropathic pain, and virus infection such as HIV, hepatitis type B virus (HBV), HPV (human papilloma virus, HPV), cytomegalovirus (CMV) and Epstein-Barr virus (Epstein-Barr virus, EBV).For purposes of the present invention, chronic ache includes but is not limited to idiopathic pain (idiopathic pain) and the pain related to chronic alcoholism, hypovitaminosis, uremia, hypothyroidism (hypothyroidism), inflammation, arthritis, and postoperative pain (post-operative pain).Neuropathic pain is related to various disease conditions, these illnesss include but is not limited to inflammation, postoperative pain, phantom limb pain (phantom limb pain), burn pain (burnpain), gout, trigeminal neuralgia (trigeminal neuralgia), acute herpes pain and post herpetic neuralgia (acute herpetic and postherpetic pain), cusalgia (causalgia), diabetic neuropathy, desmachyme avulsion (plexus avulsion), neuroma, vasculitis (vasculitis), virus infection, crush injury (crush injury), constriction injury (constriction injury), tissue damage (tissue injury), amputation (limb amputation), neurotrosis between arthritis ache and peripheral neverous system and central nervous system.
The compounds of this invention and composition can be additionally used in treatment pancreatitis or kidney trouble (nephrosis for including proliferative glomerulonephritis (proliferative glomerulonephritis) and diabetes-induced) in mammal (such as people).
The compounds of this invention and composition can also be used to prevent blastocyte to be implanted into (blastocyte implantation) in mammal (such as people).
Present invention resides in abnormal cell growth or the method for treating excess proliferative disease is suppressed in mammal (such as people), methods described includes the compound of formula I (and/or its solvate and salt) or the composition containing it for giving the mammalian therapeutic effective dose.Present invention additionally comprises the method for the treatment inflammatory disease in mammal (such as people), methods described includes the compound of formula I (and/or its solvate and/or salt) or the composition containing it for giving the mammalian therapeutic effective dose.
Present invention resides in suppress abnormal cell growth or the method for treating excess proliferative disease in mammal (such as people), methods described includes the compound of formula I (and/or its solvate and salt) or the composition containing it for giving the mammalian therapeutic effective dose, and such as another chemotherapeutic agent described in this application.Present invention additionally comprises the method for the treatment inflammatory disease in mammal (such as people), methods described includes the compound of formula I (and/or its solvate and/or salt) or the composition containing it for giving the mammalian therapeutic effective dose, and such as another anti-inflammatory drug described in this application.
Present invention resides in the method that autoimmune disease, destructive bone disease, proliferative diseases, infectious diseases, virus disease, fibrotic disease or neurodegenerative disease are treated in mammal (such as people), methods described includes the compound of formula I (and/or its solvate and salt) or the composition containing it for giving the mammalian therapeutic effective dose, and optionally also gives another medicine.The example of above-mentioned diseases/disorders includes but is not limited to diabetes and diabetic complication, diabetic retinopathy, retinopathy of prematurity, age related macular degeneration, hemangioma, idiopathic pulmonary fibrosis, rhinitis and atopic dermatitis, nephrosis and kidney failure, POLYCYSTIC KIDNEY DISEASE, congestive heart failure, neurofibromatosis, organ-graft refection, cachexia, apoplexy, septic shock, heart failure, organ-graft refection, alzheimer disease, chronic ache or neuropathic pain, and virus infection, such as HIV, hepatitis type B virus (HBV), HPV (HPV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV).
Present invention resides in the method for the treatment of pancreatitis or kidney trouble (nephrosis for including proliferative glomerulonephritis and diabetes-induced) in mammal (such as people), methods described includes the compound of formula I (and/or its solvate and salt) or the composition containing it for giving the mammalian therapeutic effective dose, and optionally also gives another medicine.
Present invention resides in the method for preventing that blastocyte is implanted into mammal (such as people), methods described includes the compound of formula I (and/or its solvate and salt) or the composition containing it for giving the mammalian therapeutic effective dose, and optionally also gives another medicine.
The method that the present invention is used for external, in situ and in-vivo diagnostic or treatment mammalian cell, organ or associated pathology illness including the use of the compounds of this invention.
Also believe, the compounds of this invention may be such that abnormal cell is more sensitive to the radiotherapy carried out for the purpose for killing and/or suppressing these cell growths.Therefore, the invention further relates to make the method that the abnormal cell in mammal (such as people) is sensitive to radiotherapy, methods described includes giving a certain amount of compound of formula I of the mammal (and/or its solvate and salt) or the composition containing it, and the amount is effective for making abnormal cell be sensitive to radiotherapy.
The administration of the compounds of this invention (hereinafter referred to as " reactive compound ") can be carried out by that can deliver the compound to any method of action site.These methods include oral route, intraduodenal route, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), part, suction and rectally.
The amount for the reactive compound being administered may depend on disposition (disposition) and the judgement for the doctor that prescribes of the severity, medicine-feeding rate, compound of treated subject, disease or illness.However, the scope of effective dose is about 0.001 to about 100mg/ kg body weights/day preferably from about 1 to about 35mg/kg/ days, it is single dose or broken dose.For 70kg people, effective dose can add up to about 0.05 to 7g/ days, preferably from about 0.05 to about 2.5g/ days.In some cases, dosage level less than the lower limit of above range can be much enough, and in other cases, bigger dosage can be used without causing any harmful side effect, condition is that the bigger dosage is divided into some low dose of for being administered in one day first.
Reactive compound can be used as monotherapy, or be combined with one or more chemotherapeutic agents those chemotherapeutic agents for example described herein.The therapeutic alliance can be realized by simultaneously, successively or separately giving each therapeutic component.
Pharmaceutical composition can be for example in the form suitable for oral administration, and it is tablet, capsule, pill, powder agent, extended release preparation, solution, supensoid agent；Suitable for the form of parenteral injection, it is sterile solution agent, supensoid agent or emulsion；Suitable for the form of local administration, it is ointment or cream；Or the form suitable for rectally, it is suppository.Pharmaceutical composition can be in the unit dosage form suitable for single-dose exact dose.Pharmaceutical composition can be comprising conventional pharmaceutical carrier or excipient, and is used as the compounds of this invention of active component.In addition, it can include other pharmaceutical reagents, carrier, auxiliary material etc..
Exemplary parenteral administration forms include reactive compound solution or supensoid agent in aseptic aqueous solution (such as aqueous solution of propylene glycol or aqueous dextrose).If desired, appropriate buffering can be carried out to above-mentioned formulation.
Suitable pharmaceutical carrier includes inert diluent or filler, water and various organic solvents.If desired, pharmaceutical composition can contain extra composition, such as flavouring, adhesive, excipient.Thus, for oral administration, the tablet containing various excipient such as citric acid can be used together with various disintegrants (such as starch, alginic acid and some composition silicates (complex silicate)) and adhesive (such as sucrose, gelatin and Arabic gum).In addition, lubricant (such as magnesium stearate, lauryl sodium sulfate and talcum) is generally used for tablet purpose.The solid composite of similar type can also be used by the form of soft-filled gelatin capsule agent and hard-filled gelatin capsule agent.Accordingly, it is preferred that material includes lactose (lactose or milksugar) and high molecular weight polyethylene glycol., can be by reactive compound therein and following material mixing when aqueous suspensions or elixir are expected to be used to be administered orally：Various sweeteners or flavouring, colouring agent or dyestuff, and emulsifying agent or suspending agent (if it is desire to), and diluent such as water, ethanol, propane diols, glycerine or combinations thereof.
To those skilled in the art, the method for preparing the various pharmaceutical compositions of the reactive compound containing Specific amounts is known or obvious.For example, with reference to Remington ' sPharmaceutical Sciences, Mack Publishing Company, Ester, Pa., 15.sup.thEdition (1975).
Embodiment
Abbreviation
Carbon -7- the alkene of DBU 1,8- diazabicylo [5.4.0] 11
DCM dichloromethane
DIPEA diisopropylethylamine
DMAP DMAPs
DMF dimethylformamides
EDCI 1- ethyls -3- (3 '-dimethylamino-propyl) carbodiimide
HATU O- (7- azepine benzos triazol-1-yl)-N, N, N ', N '-tetramethyl
Figure G2007800391963D00551
Hexafluorophosphate
HCl hydrochloric acid
HM-N     Isolute
Figure G2007800391963D00552
HM-N can effectively absorb the diatomite of aqueous sample for improved form
HOBt I-hydroxybenzotriazoles
LDA lithium diisopropylamines
MeOH methanol
NaHCO3Sodium acid carbonate
NaOH sodium hydroxides
Pd(PPh3)4Tetrakis triphenylphosphine palladium (0)
Pd2dba3Three (dibenzalacetone) two palladium (0)
PdCl2(PPh3)2Two (triphenylphosphine) palladium chlorides (II)
Isolute pre-filled Si-SPE
Figure G2007800391963D00553
Flash chromatography on silica gel post
THF tetrahydrofurans
Xantphos 9,9- dimethyl -4,5- bis- (diphenylphosphino) xanthene
Common experimental conditions
Varian Unity Inova (400MHz) spectrometer popped one's head in triple resonant 5mm is used to record in environment temperature1H NMR spectras.Chemical shift is expressed as the ppm relative to tetramethylsilane.Use following abbreviation：Br=bandwidth signals, s=is unimodal, d=doublets, dd=double doublets, t=triplets, q=quartets, m=multiplets.
Carry out high pressure liquid chromatography-mass spectrum (LCMS) experiment to determine retention time (R using one of following methodT) and correlated quality ion (mass ion).
Method A：Tested on the Waters Micromass ZQ quadrupole mass spectrometers being connected with the Hewlett Packard HP1100LC systems with PDAD.Use 5 microns of 100 × 3.0mm of C18 posts of HigginsClipeus and the flow velocity of 1ml/ minutes.Initial solvent system was 95% water (solvent orange 2 A) containing 0.1% formic acid and 5% acetonitrile (solvent B) containing 0.1% formic acid in first minute, and 14 minutes gradients are then lasted again and rise to 5% solvent orange 2 A and 95% solvent B.Final solvent system keeps constant and continues 5 minutes again.
Method B：Tested on the Waters Platform LC quadrupole mass spectrometers being connected with the HewlettPackard HP1100LC systems with PDAD and 100 automatic samplers, use the 30 × 4.6mm posts of Phenomenex Luna C18 (2) and the flow velocity of 2ml/ minutes.Solvent system is 95% solvent orange 2 A and 5% solvent B in 0.50 minute of beginning, and 4 minutes gradients are then lasted again and rise to 5% solvent orange 2 A and 95% solvent B.Final solvent system keeps constant and continues 0.50 minute again.
Use Personal Chemistry Emrys InitiatorTMOr OptimizerTMMicrowave experiment is carried out, described device both can be reappeared and be controlled using single mode resonator and aerodynamic field tuning (dynamic field tuning).40-250 DEG C of temperature can be achieved, and can reach the pressure of up to 20 bars.
Embodiment 1a：MEK determines (MEK determinations of activity)
The people for the composition activation expressed using in insect cell is mutated MEK1 as the source of enzymatic activity, and its ultimate density in kinase assays is 62.5nM.
The measure is carried out 30 minutes in the presence of 50 μM of ATP, and the restructuring GST-ERK1 produced using in Escherichia coli (E.Coli) is used as substrate.Using the phosphorylation by the Cisbio HTRF reagent detection substrates provided and quantitatively.Anti- phosphoric acid (Thr202/Tyr204) ERK antibody that above-mentioned HTRF reagents are combined by the anti-GST antibody that is combined with allophycocyanin (allophycocyanin) (XL665) and with europium cryptate (europium-cryptate) is constituted.The ERK1 of antiphosphotyrosine antibody identification Dual phosphorylation on Thr202 and Tyr204.When both antibody are all combined with ERK1 (i.e. when substrate is phosphorylated), after 340nm is excited, transfer of the energy from cryptate to allophycocyanin is there occurs, causes to launch the fluorescence proportional to the amount of produced phosphorylated substrate.Fluorescence is detected using porous fluorescence photometer (multiwellfluorimeter).
Compound is diluted in DMSO, then added in measure buffer solution, the final DMSO concentration in measure is 1%.
IC50It is defined as concentration when given compound realizes 50% suppression control.IC is calculated using XLfit software kits (2.0.5 versions)50Value.
Embodiment 1b：MEK determines (MEK determinations of activity)
The people for the composition activation expressed using in insect cell is mutated MEK1 as the source of enzymatic activity, and its ultimate density in kinase assays is 15nM.
The measure is carried out 30 minutes in the presence of 50 μM of ATP, and the restructuring GST-ERK1 produced using in Escherichia coli (E.Coli) is used as substrate.Using the phosphorylation by the Cisbio HTRF reagent detection substrates provided and quantitatively.Anti- phosphoric acid (Thr202/Tyr204) ERK antibody that above-mentioned HTRF reagents are combined by the anti-GST antibody that is combined with allophycocyanin (XL665) and with europium cryptate is constituted.Above-mentioned antibody is used in 4 μ g/ml and 0.84 μ g/ml ultimate density respectively.The ERK1 of antiphosphotyrosine antibody identification Dual phosphorylation on Thr202 and Tyr204.When both antibody are all combined with ERK1 (i.e. when substrate is phosphorylated), after 340nm is excited, transfer of the energy from cryptate to allophycocyanin is there occurs, causes to launch the fluorescence proportional to the amount of produced phosphorylated substrate.Fluorescence is detected using porous fluorescence photometer.
Compound is diluted in DMSO, then added in measure buffer solution, the final DMSO concentration in measure is 1%.
IC50It is defined as concentration when given compound realizes 50% suppression control.IC is calculated using XLfit software kits (2.0.5 versions)50Value.
In measure described in embodiment 1a or 1b, embodiment 5-8 and 10-12 compound show the IC less than 10 μM50, most of IC shown less than 5 μM in these compounds50。
Embodiment 2：BRaf determines (MEK activation determinations)
The bRaf mutant for the composition activation expressed using in insect cell is used as the source of enzymatic activity.
The measure is carried out 30 minutes in the presence of 200 μM of ATP, and the restructuring GST-ERK1 produced using in Escherichia coli (E.Coli) is used as substrate.Using the phosphorylation of HTRF detection substrates and quantitative, these reagents are provided by Cisbio.Anti- phosphoric acid (Ser217/Ser221) MEK antibody that above-mentioned HTRF reagents are combined by the anti-GST antibody that is combined with allophycocyanin (XL665) and with europium cryptate is constituted.Antiphosphotyrosine antibody identification on Ser217 and Ser221 Dual phosphorylation or on Ser217 independent phosphorylation MEK.When both antibody are all combined with MEK (i.e. when substrate is phosphorylated), after 340nm is excited, transfer of the energy from cryptate to allophycocyanin is there occurs, causes to launch the fluorescence proportional to the amount of produced phosphorylated substrate.Fluorescence is detected using porous fluorescence photometer.
Compound is diluted in DMSO, then added in measure buffer solution, the final DMSO concentration in measure is 1%.
IC50It is defined as concentration when given compound realizes 50% suppression control.IC is calculated using XLfit software kits (2.0.5 versions)50Value.
In this measure, embodiment 5-7 and 10 compound shows the IC less than 5 μM50。
Embodiment 3：Cell proliferating determining
Compound is tested using following cell line in cell proliferating determining：
HCT116 human colorectal cancers (ATCC)
A375 people's chromoma (ATCC)
At 37 DEG C in 5%CO2Both cell lines are all maintained in humidified incubator and are supplemented with 10%FCS DMEM/F12 (1: 1) culture medium (Gibco).
Cell is inoculated in 96 orifice plates with 2,000 cells/wells, solution of the compound of various concentrations in 0.83%DMSO is exposed to after 24 hours.Make the long 72h of cytothesis, then isometric CellTiter-Glo reagents (Promega) are added in every hole.This make cell dissolve and produce the ATP to being discharged amount proportional (therefore proportional with cell number in hole) luminous signal, porous luminometer (multiwell luminometer) can be used to detect for the luminous signal.
EC50It is defined as concentration when given compound realizes 50% suppression control.EC is calculated using XLfit software kits (2.0.5 versions)50Value.
In this measure, the compound of embodiment 5 and 10 all shows the EC less than 10 μM in any cell line50。
Embodiment 4：Phosphoric acid-ERK based on cell is determined
Compound is tested using following cell line in the phosphoric acid-ERK ELISA based on cell：
HCT116 human colorectal cancers (ATCC)
A375 people's chromoma (ATCC)
At 37 DEG C in 5%CO2Both cell lines are all maintained in humidified incubator and are supplemented with 10%FCS DMEM/F12 (1: 1) culture medium (Gibco).
Cell is inoculated in 96 orifice plates with 2,000 cells/wells, solution of the compound of various concentrations in 0.83%DMSO is exposed to after 24 hours.Make cytothesis long 2h or 24h, it is fixed with formaldehyde (2% ultimate density), then use methanol crossover.After being closed with TBST-3%BSA, fixed cell is incubated overnight together with first antibody (the anti-phosphoric acid ERK from rabbit) at 4 DEG C.Cell is incubated together with propidium iodide (Propidium Iodide) (DNA fluorescent dyes), then uses the anti-rabbit secondary antibody combined with the dyestuffs of fluorescence AlexaFluor 488 (molecular probe) to detect cell p-ERK.Fluorescence is analyzed using Acumen Explorer (TTP Labtech) laser scanning micro plate cell counters (laser-scanningmicroplate cytometer), is then PI signals (proportional to cell number) by the signal normalizations of Alexa Fluor 488.
EC50It is defined as the concentration that given compound realizes half signal between baseline and peak response.EC is calculated using XLfit software kits (2.0.5 versions)50Value.
In this measure, embodiment 5 and 10-12 compound all show the EC less than 10 μM in any cell line50。
Embodiment 5
The chloro- pyridine-3-carboxylic acids of 4-
Figure G2007800391963D00591
According to Guillier et al. (1995) J.Org.Chem.60 (2)：Operation in 292-6, adds 4- chloropyridines (5.0g, 33.3mmol) into solution of cold (- 78 DEG C) LDA (21ml, 1.6M hexane solution, 33.3mmol) in anhydrous THF (70ml) under an argon atmosphere.After -78 DEG C are reacted 1 hour, solution is quickly poured on to the solid CO in 250ml conical flasks2On bed.Reaction solution is warmed to after environment temperature, solution is quenched with water (30ml).Volatile organic solvent is removed in vacuum, then extracts remaining aqueous suspension with ether (3 × 100ml).Aqueous phase is cooled to 0 DEG C, then adjusted by adding concentrated hydrochloric acid to pH 4.The sediment to be formed is aged (age) 30 minutes, be then collected by filtration.Solid is washed with cold ether (10ml), title compound is obtained, it is white solid (3.2g, 61%).
The chloro- pyridine-3-carboxylic acid ethyl esters of 4-
Suspension of the chloro- pyridine-3-carboxylic acids of 4- (3.0g, 19.0mmol) in thionyl chloride (50ml) is heated at reflux 90 minutes.It is cooled to after environment temperature, solution is concentrated to dryness, then with toluene (2 × 50ml) azeotropic, obtains solid.In the solution that the solid of formation is added to (0 DEG C) ethanol (25ml) of cooling and DIPEA (15ml) in batches.Reactant mixture is stirred at room temperature 4 hours, is then concentrated in vacuo, water (75ml) is subsequently added into.Solution is extracted with ethyl acetate (2 × 75ml), and the organic phase being then combined with is dried over sodium sulfate, then concentrates, obtains title compound, and it is brown oil (3.3g, 94%).1HNMR(CDCl3, 400MHz) and 9.03 (s, 1H), 7.58 (d, J=5.4Hz, 1H), 7.41 (dd, J=5.4Hz, 0.5Hz, 1H), 4.45 (q, J=7.3Hz, 2H), 1.43 (t, J=7.3Hz, 3H).
3- Hydroxy-thiophenes simultaneously [3,2-c] pyridine-2-carboxylic acids ethyl ester
Figure G2007800391963D00601
The chloro- pyridine-3-carboxylic acid ethyl ester (1.55g of 4- of (5 DEG C) stirrings to cooling in 20 minutes are lasted under an argon atmosphere, 8.4mmol) with ethyl thioglycolate (2.6ml, sodium hydride (21.7mmol 23.4mmol) is added portionwise in the solution in dry DMF (30ml), 60% oil dispersion liquid, 868mg).Continue to stir 10 minutes at 5 DEG C, be then stirred at room temperature 1.5 hours.Then reactant mixture is quenched by adding water (5ml), is acidified by adding acetic acid (1ml), is then concentrated, obtain residue.Residue is distributed between ethyl acetate (150ml) and water (100ml).Each layer is separated, aqueous phase is extracted with DCM (100ml).The organic phase of merging is dried over sodium sulfate, filters and evaporates, obtains solid.By solid ether: pentane (1: 1,15ml) is ground, and obtains title compound, it is yellow solid (1.5g, 81%).LCMS (method B)：RT=2.21 minutes, M+H+=224.
3- (nine fluorine butyl- 1- sulfonyls epoxides)-thieno [3,2-c] pyridine-2-carboxylic acids ethyl ester
Figure G2007800391963D00602
In 0 DEG C of 3- Hydroxy-thiophene to stirring simultaneously [3,2-c] pyridine-2-carboxylic acids ethyl ester (1.3g, 5.82mmol) with DMAP (35mg, DIPEA (2.5ml 0.29mmol) are added in the solution in DCM (10ml), 14.0mmol) with nine fluorine butyl sulfuryl fluorides (1.36ml, 7.56mmol).After 10 minutes, reactant mixture is warmed to room temperature, is then stirred for 20 hours.Reactant mixture is diluted with DCM (50ml), then washed with water (30ml).Organic phase is separated, it is dried over sodium sulfate, filter and evaporate, obtain brown oil.Grease (Si-SPE, pentane: ether, gradient 100: 0 to 70: 30) purifies through flash chromatography, obtains title compound, it is colorless oil, the grease crystallizes (420mg, 14%) when standing.LCMS (method B)：RT=4.46 minutes, M+H+=508.
3- (the bromo- 2- fluoro-phenyls amino of 4-)-thieno [3,2-c] pyridine-2-carboxylic acids ethyl ester
Figure G2007800391963D00603
Make 3- (nine fluorine butyl- 1- sulfonyls epoxides)-thieno [3,2-c] pyridine-2-carboxylic acids ethyl ester (422mg, 0.83mmol), the bromo- 2- fluoroanilines (206mg, 1.08mmol) of 4-, the Pd of degassing2dba3(38mg, 0.04mmol), Xantphos (48mg, 0.08mmol) and the solution of DBU (316 μ l, 2.08mmol) in toluene (1ml) receive microwave irradiation 10 minutes at 150 DEG C.Reactant mixture is cooled to environment temperature, then diluted with ethyl acetate (30ml).The solution of formation is washed with water (20ml), dried over sodium sulfate, is then concentrated in vacuo, is obtained solid residue.Solid residue (Si-SPE, pentane: ether, gradient 90: 10 to 70: 30) purifies through flash chromatography, obtains title compound, it is white solid (210mg, 64%).LCMS (method B)：RT=3.78 minutes, M+H+=395/397.
3- (the iodo- phenyl aminos of the fluoro- 4- of 2-)-thieno [2,3-c] pyridine-2-carboxylic acids ethyl ester
Figure G2007800391963D00611
Under an argon atmosphere by 3- (the bromo- 2- fluoro-phenyls amino of 4-)-thieno [3,2-c] pyridine-2-carboxylic acids ethyl ester (209mg, 0.53mmol), cuprous iodide (I) (5mg, 0.026mmol), sodium iodide (159mg, 1.06mmol) with trans-N, N '-dimethyl -1,2- cyclohexanediamine (8.5 μ l, 0.053mmol) mixture in Isosorbide-5-Nitrae-dioxane (1.0ml) is heated 24 hours at 105 DEG C.Cuprous iodide (I) (5mg, 0.026mmol) and trans-N, N '-dimethyl -1,2- cyclohexanediamine (8.5 μ l, 0.053mmol) are added, is then further continued for heating 24h.Once reactant mixture is cooled into room temperature, mixture is distributed between ethyl acetate (30ml) and the ammonia waters of 10%v/v 0.880 (20ml).Each layer is separated, aqueous phase is extracted with DCM (30ml).The organic layer of merging is dried over sodium sulfate, filters and evaporates, and then residue is through flash chromatography (Si-SPE, with pentane: ether is eluted, gradient 90: 10 to 70: 30) purify, obtain title compound, it is yellow solid (174mR, 74%).LCMS (method B)：RT=3.97 minutes, M+H+=443.
3- (the iodo- phenyl aminos of the fluoro- 4- of 2-)-thieno [3,2-c] pyridine-2-carboxylic acids (((R) -2,2- dimethyl-[1,3] Dioxolane -4- bases) methoxyl group)-acid amides
Figure G2007800391963D00612
By 3- (the iodo- phenyl aminos of the fluoro- 4- of 2-)-thieno [2,3-c] pyridine-2-carboxylic acids ethyl ester (50mg, 0.11mmol), the mixture of the 1N NaOH aqueous solution (0.12ml, 0.12mmol) and ethanol (2ml) is heated 45 minutes at 65 DEG C.Reactant mixture is concentrated, then with toluene (2 × 2ml) azeotropic, solid residue is obtained.Solid residue is dissolved in anhydrous THF (2ml), then O- (((R) -2 is added, 2- dimethyl-[1,3] dioxolane -4- bases) methyl) azanol (27mg, 0.23mmol), EDCI (27mg, 0.14mmol), HOBt (21mg, 0.16mmol) and DIPEA (59 μ l, 0.34mmol).After stirring 19 hours, then evaporation solvent distributes residue between ethyl acetate (30ml) and water (20ml).Organic layer is dried over sodium sulfate, filters and evaporates, obtains yellow oil.Grease (Si-SPE, pentane: ethyl acetate, gradient 80: 20 to 50: 50) purifies through flash chromatography, obtains title compound, it is yellow solid (18mg, 30%).LCMS (method B)：RT=3.09 minutes, M+H+=544.
3- (the iodo- phenyl aminos of the fluoro- 4- of 2-)-thieno [3,2-c] pyridine-2-carboxylic acids ((R) -2,3--the third oxygen of dihydroxy Base)-acid amides
Figure G2007800391963D00621
By 3- (the iodo- phenyl aminos of the fluoro- 4- of 2-)-thieno [3,2-c] pyridine-2-carboxylic acids (((R) -2,2- dimethyl-[1,3] dioxolane -4- bases) methoxyl group)-acid amides (18mg, 0.03mmol) it is dissolved in methanol (1ml), then adds concentrated hydrochloric acid (1 drop).Stir the mixture for 2 hours, be then evaporated to dryness and obtain residue.By residue in saturation NaHCO3Distributed between the aqueous solution (10ml), water (20ml) and DCM (20ml).Organic layer is separated, it is dried over sodium sulfate, filter and evaporate, obtain yellow solid.Solid (Si-SPE, DCM: MeOH, gradient 98: 2 to 92: 8) purifies through flash chromatography, obtains title compound, it is yellow solid (8mg, 50%).LCMS (method A)：RT=6.32 minutes, M+H+=504.1HNMR(d4- MeOH, 400MHz) 8.56 (s, 1H), 8.34 (d, J=5.7Hz, 1H), 7.87 (d, J=5.7Hz, 1H), 7.45 (dd, J=10.5Hz, 1.8Hz, 1H), 7.27 (d, J=8.5Hz, 1H), 6.61 (dd, J=8.5Hz, 8.5Hz, 1H), 3.89-3.94 (m, 1H), 3.76-3.85 (m, 2H), 3.45-3.54 (m, 2H).
Embodiment 6
3- (the bromo- 2- fluoro-phenyls amino of 4-)-thieno [3,2-c] pyridine-2-carboxylic acids (((R) -2,2- dimethyl-[1,3] Dioxolane -4- bases) methoxyl group)-acid amides
Figure G2007800391963D00622
By 3- (the bromo- 2- fluoro-phenyls amino of 4-)-thieno [3,2-c] pyridine-2-carboxylic acids ethyl ester (36mg, 0.09mmol), the mixture of the 1N NaOH aqueous solution (0.10ml, 0.10mmol) and methanol (2ml) is heated 45 minutes at 65 DEG C.Reactant mixture is concentrated in vacuo, then with toluene (2 × 2ml) azeotropic, solid residue is obtained.Solid residue is dissolved in anhydrous THF (2ml), then O- (((R) -2 is added, 2- dimethyl-[1,3] dioxolane -4- bases) methyl) azanol (22mg, 0.18mmol), EDCI (22mg, 0.12mmol), HOBt (17mg, 0.13mmol) and DIPEA (48 μ l, 0.28mmol).After environment temperature is stirred overnight, reactant mixture is concentrated in vacuo, yellow residue is obtained.The residue of formation is dissolved in ethyl acetate (30ml), successively with water (20ml) and salt water washing (10ml), organic layer is then separated, it is then dried over sodium sulfate and be concentrated in vacuo, obtain yellow oil.Grease (Si-SPE, pentane: ethyl acetate, gradient 90: 10 to 50: 50) purifies through flash chromatography, obtains title compound, it is yellow oil (18mg, 41%).LCMS (method B)：RT=3.03 minutes, M+H+=496/498.
3- (the bromo- 2- fluoro-phenyls amino of 4-)-thieno [3,2-c] pyridine-2-carboxylic acids ((R) -2,3--the third oxygen of dihydroxy Base)-acid amides
Figure G2007800391963D00631
By 3- (the bromo- 2- fluoro-phenyls amino of 4-)-thieno [3,2-c] pyridine-2-carboxylic acids (((R) -2,2- dimethyl-[1,3] dioxolane -4- bases) methoxyl group) the solution stowage of-acid amides (18mg, 0.036mmol) in methanol (1ml) be in Isolute
Figure G2007800391963D00632
On SCX-2 posts (5g).Then post is washed with methanol (15ml), then desired product is eluted with the MeOH solution of 2M ammonia, the eluent being collected into then is concentrated, obtains residue.Residue (Si-SPE, DCM: MeOH, gradient 100: 0 to 94: 6) purifies through flash chromatography, obtains title compound, it is pale solid (9mg, 53%)：LCMS (method A)：RT=5.59 minutes, M+H+=456/458.1H NMR(d4- MeOH, 400MHz) 8.60 (s, 1H), 8.40 (d, J=5.7Hz, 1H), 7.94 (d, J=5.7Hz, 1H), 7.39 (dd, J=10.6Hz, 2.2Hz, 1H), 7.16 (d, J=8.5Hz, 1H), 6.80 (dd, J=8.5Hz, 8.5Hz, 1H), 4.01-4.10 (m, 1H), 3.89-4.00 (m, 2H), 3.57-3.67 (m, 2H).
Embodiment 7
The chloro- Pyridine-4-carboxylic acid ethyl esters of 3-
Figure G2007800391963D00633
Suspension of the chloro- Pyridine-4-carboxylic acids of 3- (1.0g, 6.35mmol) in thionyl chloride (10ml) is heated at reflux 2.5 hours.It is cooled to after environment temperature, solution is concentrated to dryness, then with toluene (10ml) azeotropic, obtains grease.10 minutes are lasted to be added drop-wise to the grease of formation in (0 DEG C) ethanol (15ml) of cooling and DIPEA (5ml) solution.Reactant mixture is stirred at room temperature 18 hours, is then concentrated in vacuo, water (20ml) is subsequently added into.Solution is extracted with ethyl acetate (30ml), organic phase is dried over sodium sulfate, then concentrates, obtains title compound, it is orange (1.1g, 94%).1HNMR(CDCl3, 400MHz) and 8.72 (s, 1H), 8.59 (d, J=4.9Hz, 1H), 7.63 (dd, J=4.9Hz, 0.5Hz, 1H), 4.44 (q, J=7.3Hz, 2H), 1.42 (t, J=7.3Hz, 3H).
3- Hydroxy-thiophenes simultaneously [2,3-c] pyridine-2-carboxylic acids ethyl ester
Figure G2007800391963D00641
Under an argon atmosphere to (5 DEG C) of the cooling chloro- Pyridine-4-carboxylic acid ethyl ester (1.11g of 3- stirred, 6.0mmol) with ethyl thioglycolate (1.8ml, 16.7mmol) 20 minutes being lasted in the solution in dry DMF (20ml), sodium hydride (15.6mmol is added portionwise, 60% oil dispersion liquid, 622mg).Continue to stir 20 minutes at 5 DEG C, be then stirred at room temperature 18 hours.Then reactant mixture is quenched by adding water (5ml), is acidified by adding acetic acid (1ml), then concentrates, obtain residue.Residue is distributed between ethyl acetate (150ml) and water (50ml).Organic phase is separated, it is dried over sodium sulfate, filter and evaporate, obtain yellow oil.Grease (Si-SPE, pentane: ethyl acetate, gradient 80: 20 to 30: 70) purifies through flash chromatography, obtains title compound, it is yellow solid (1.33g, 99%).LCMS (method B)：RT=2.57 minutes, M+H+=224.
3- (nine fluorine butyl- 1- sulfonyls epoxides)-thieno [2,3-c] pyridine-2-carboxylic acids ethyl ester
Figure G2007800391963D00642
In 0 DEG C of 3- Hydroxy-thiophene to stirring simultaneously [2,3-c] pyridine-2-carboxylic acids ethyl ester (950mg, 4.26mmol) with DMAP (26mg, DIPEA (1.8ml 0.21mmol) are added in the solution in DCM (12ml), 10.2mmol) with nine fluorine butyl sulfuryl fluorides (0.99ml, 5.53mmol).After 10 minutes, reactant mixture is warmed to room temperature, is then stirred for 20 hours.Reactant mixture is diluted with DCM (30ml), then washed with water (20ml).Organic phase is dried over sodium sulfate, filters and evaporates, obtains yellow oil.Grease (Si-SPE, pentane: ether, gradient 90: 10 to 65: 35) purifies through flash chromatography, obtains title compound, it is colorless oil, the grease crystallizes (678mg, 31%) when standing：LCMS (method B)：RT=4.49 minutes, M+H+=508.
3- (the bromo- 2- fluoro-phenyls amino of 4-)-thieno [2,3-c] pyridine-2-carboxylic acids ethyl ester
Figure G2007800391963D00651
Make 3- (nine fluorine butyl- 1- sulfonyls epoxides)-thieno [2,3-c] pyridine-2-carboxylic acids ethyl ester (678mg, 1.33mmol), the bromo- 2- fluoroanilines (329mg, 1.73mmol) of 4-, the Pd of degassing2dba3(61mg, 0.07mmol), Xantphos (78mg, 0.14mmol) and the solution of DBU (509 μ l, 3.35mmol) in toluene (3ml) receive microwave irradiation 10 minutes at 150 DEG C.Reactant mixture is cooled to environment temperature, then diluted with ethyl acetate (70ml).The solution of formation is washed with water (20ml), it is dried over sodium sulfate and be concentrated in vacuo, obtain orange.Grease (Si-SPE, pentane: ether, gradient 90: 10 to 50: 50) is purified, then from ethyl acetate: recrystallized in pentane, obtain title compound, it is white solid (353mg, 67%) through flash chromatography.LCMS (method B)：RT=4.08 minutes, M+H+=395/397.
3- (the iodo- phenyl aminos of the fluoro- 4- of 2-)-thieno [2,3-c] pyridine-2-carboxylic acids ethyl ester
Figure G2007800391963D00652
By 3- (the bromo- 2- fluoro-phenyls amino of 4-)-thieno [2,3-c] pyridine-2-carboxylic acids ethyl ester (288mg, 0.73mmol), cuprous iodide (I) (7mg, 0.036mmol), sodium iodide (219mg, 1.46mmol) with trans-N, N '-dimethyl -1,2- cyclohexanediamine (10.4mg, 0.073mmol) mixture in Isosorbide-5-Nitrae-dioxane (1.0ml) is heated 24 hours at 105 DEG C under an argon atmosphere.Cuprous iodide (I) (7mg, 0.036mmol) and trans-N, N '-dimethyl -1,2- cyclohexanediamine (10.4mg, 0.073mmol) are added, heating 24 hours is then further continued for.Reactant mixture is cooled to room temperature, then distributed compound between DCM (30ml), concentrated ammonia solution (2ml) and water (13ml).Organic layer is separated, it is dried over sodium sulfate, filter and evaporate, then residue is purified through flash chromatography (Si-SPE, DCM), obtains title compound, it is yellow solid (275mg, 85%).LCMS (method B)：RT=4.23 minutes, M+H+=443.
3- (the iodo- phenyl aminos of the fluoro- 4- of 2-)-thieno [2,3-c] pyridine-2-carboxylic acids (((R) -2,2- dimethyl-[1,3] Dioxolane -4- bases) methoxyl group)-acid amides
Figure G2007800391963D00653
By 3- (the iodo- phenyl aminos of the fluoro- 4- of 2-)-thieno [2,3-c] pyridine-2-carboxylic acids ethyl ester (50mg, 0.11mmol), the mixture of the 1N NaOH aqueous solution (0.12ml, 0.12mmol) and ethanol (2ml) is heated 45 minutes at 65 DEG C.Reactant mixture is concentrated, then solid residue is obtained with toluene (2 × 2ml) azeotropic.Solid residue is dissolved in anhydrous THF (4ml), then O- (((R) -2 is added, 2- dimethyl-[1,3] dioxolane -4- bases) methyl) azanol (27mg, 0..23mmol), EDCI (27mg, 0.14mmol), HOBt (21mg, 0.16mmol) and DIPEA (59 μ l, 0.34mmol).After stirring 19 hours, then evaporation solvent distributes residue between ethyl acetate (20ml) and water (15ml).Organic layer is separated, it is dried over sodium sulfate, filter and evaporate, obtain brown oil.Grease (Si-SPE, pentane: ethyl acetate, gradient 80: 20 to 0: 100) purifies through flash chromatography, obtains title compound, it is orange (40mg, 66%).LCMS (method B)：RT=3.30 minutes, M+H+=544.
3- (the iodo- phenyl aminos of the fluoro- 4- of 2-)-thieno [2,3-c] pyridine-2-carboxylic acids ((R) -2,3--the third oxygen of dihydroxy Base)-acid amides
Figure G2007800391963D00661
By 3- (the iodo- phenyl aminos of the fluoro- 4- of 2-)-thieno [2,3-c] pyridine-2-carboxylic acids (((R) -2,2- dimethyl-[1,3] dioxolane -4- bases) methoxyl group)-acid amides (40mg, 0.07mmol) it is dissolved in methanol (1ml), then adds concentrated hydrochloric acid (1 drop).Stir the mixture for 2 hours, be then evaporated to dryness and obtain residue.By residue in saturation NaHCO3Distributed between the aqueous solution (3ml), water (20ml) and DCM (20ml).Organic layer is separated, it is dried over sodium sulfate, filter and evaporate, obtain yellow solid.Solid (Si-SPE, DCM: MeOH, gradient 99: 1 to 92: 8) purifies through flash chromatography, obtains title compound, it is yellow solid (21mg, 57%).LCMS (method A)：RT=7.12 minutes, M+H+=504.1HNMR(d4- MeOH, 400MHz) 9.15 (s, 1H), 8.38 (d, J=5.7Hz, 1H), 7.52 (dd, J=10.6Hz, 2.0Hz, 1H), 7.44 (dd, J=5.7Hz, 1.0Hz, 1H), 7.32 (ddd, J=8.5Hz, 2.0Hz, 1.0Hz, 1H), 6.56 (dd, J=8.5Hz, 8.5Hz, 1H), 4.00-4.13 (m, 1H), 3.85-3.95 (m, 2H), 3.54-3.65 (m, 2H).
Embodiment 8
3- (the bromo- 2- fluoro-phenyls amino of 4-)-thieno [2,3-c] pyridine-2-carboxylic acids (((R) -2,2- dimethyl-[1,3] Dioxolane -4- bases) methoxyl group)-acid amides
Figure G2007800391963D00662
By 3- (the bromo- 2- fluoro-phenyls amino of 4-)-thieno [2,3-c] pyridine-2-carboxylic acids ethyl ester (63mg, 0.16mmol), the mixture of the 1N NaOH aqueous solution (0.17ml, 0.17mmol) and ethanol (2ml) is heated 45 minutes at 65 DEG C.The reactant mixture of formation is concentrated in vacuo, then makes residue and toluene (2 × 2ml) azeotropic, obtains solid residue.The solid residue of formation is suspended in anhydrous THF (2ml), it is subsequently added into O- (((R) -2,2- dimethyl-[1,3] dioxolane -4- bases) methyl) azanol (38mg, 0.32mmol), EDCI (38mg, 0.20mmol), HOBt (30mg, 0.22mmol) and DIPEA (83 μ l, 0.48mmol).After environment temperature is stirred 66 hours, reactant mixture is concentrated in vacuo, yellow residue is obtained.The residue of formation is dissolved in ethyl acetate (50ml), is then washed with water (20ml), then separates organic layer, it is dried over sodium sulfate, then it is concentrated in vacuo, obtains yellow oil.Grease (Si-SPE, pentane: ethyl acetate, gradient 60: 40 to 0: 100) purifies through flash chromatography, obtains title compound, it is yellow foam (61mg, 77%).LCMS (method B)：RT=3.02 minutes, M+H+=496/498.
3- (the bromo- 2- fluoro-phenyls amino of 4-)-thieno [2,3-c] pyridine-2-carboxylic acids ((R) -2,3--the third oxygen of dihydroxy Base)-acid amides
Figure G2007800391963D00671
By 3- (the bromo- 2- fluoro-phenyls amino of 4-)-thieno [2,3-c] pyridine-2-carboxylic acids (((R) -2,2- dimethyl-[1,3] dioxolane -4- bases) methoxyl group) solution of-acid amides (61mg, 0.12mmol) and the 1 dense HCl of drop in methanol (2ml) stirs 2 hours in environment temperature.Vacuum evaporating solvent, then by the residue of formation in dichloromethane (20ml), water (10ml) and saturation NaHCO3Distributed between solution (3ml).Organic phase is dried over sodium sulfate and is concentrated in vacuo, and obtains yellow oil.The yellow oil of formation (Si-SPE, DCM: MeOH, gradient 99: 1 to 92: 8) purifies through flash chromatography, is then ground with methanol/acetonitrile, obtain title compound, it is light yellow solid (15mg, 26%)：LCMS (method A)：RT=6.01 minutes, M+H+=456/458.1H NMR(d4- MeOH, 400MHz) 9.16 (d, J=0.8Hz, 1H), 8.38 (d, J=5.8Hz, 1H), 7.37-7.46 (m, 2H), 7.17 (ddd, J=8.6Hz, 2.3Hz, 2.2Hz, 1H), 6.72 (dd, J=8.7Hz, 8.7Hz, 1H), 4.00-4.05 (m, 1H), 3.84-3.96 (m, 2H), 3.53-3.64 (m, 2H).
Embodiment 9
3- (the iodo- phenyl aminos of the fluoro- 4- of 2-)-thieno [3,2-c] pyridine-2-carboxylic acids (2- (vinyl epoxide)-ethoxy Base)-acid amides
Figure G2007800391963D00681
By 3- (the iodo- phenyl aminos of the fluoro- 4- of 2-)-thieno [3,2-c] pyridine-2-carboxylic acids ethyl ester (124mg, 0.28mmol), the mixture of the 1N NaOH aqueous solution (0.30ml, 0.30mmol) and ethanol (4ml) is heated 45 minutes at 65 DEG C.Reactant mixture is concentrated in vacuo, then by the residue of formation and toluene (2 × 2ml) azeotropic, solid residue is obtained.Solid residue is dissolved in anhydrous THF (4ml), it is subsequently added into O- (2- (vinyl epoxide)-ethyl)-azanol (58mg, 0.56mmol), EDCI (67mg, 0.35mmol), HOBt (53mg, 0.39mmol) with DIPEA (147 μ l, 0.84mmol).After environment temperature is stirred 18 hours, then evaporation solvent dilutes the residue of formation with (20ml), is then successively extracted with ethyl acetate (30ml) and dichloromethane (30ml).The organic layer of merging is dried over sodium sulfate, filters and evaporates, obtains yellow oil.The yellow oil of formation (Si-SPE, dichloromethane: methanol, gradient 100: 0 to 98: 2) purifies through flash chromatography, obtains title compound, it is yellow solid (91mg, 65%).LCMS (method B)：RT=3.05 minutes, M+H+=500.
Embodiment 10
3- (the iodo- phenyl aminos of the fluoro- 4- of 2-)-thieno [3,2-c] pyridine-2-carboxylic acids (2- hydroxyl-oxethyls)-acid amides
Figure G2007800391963D00682
By 3- (the iodo- phenyl aminos of the fluoro- 4- of 2-)-thieno [3,2-c] pyridine-2-carboxylic acids (2- (vinyl epoxide)-ethyoxyl)-acid amides (91mg, 0.18mmol) it is dissolved in ethanol (2ml), then adds 1M hydrochloric acid (0.5ml).Stir the mixture for 2 hours, be then evaporated to dryness, obtain residue.By the residue of formation in saturation NaHCO3Distributed between the aqueous solution (3ml), water (20ml) and DCM (20ml).Organic layer is separated, it is dried over sodium sulfate, filter and evaporate, obtain yellow solid.Through flash chromatography (Si-SPE after obtained yellow solid elder generation, DCM: MeOH, gradient 100: 0 to 98: 2) with reversed-phase HPLC (5 phenyl of PhenomenexLuna/hexyl, the 0.1%TFA aqueous solution/methanol, gradient is 95: 5 to 40: 60) is purified, title compound is obtained, it is yellow solid (34mg, 40%).LCMS (method A)：RT=6.00 minutes, M+H+=474.1H NMR(d4- MeOH, 400MHz) 8.68 (s, 1H), 8.44 (d, J=5.7Hz, 1H), 7.98 (dd, J=5.7Hz, 0.8Hz, 1H), 7.55 (dd, J=10.5Hz, 1.8Hz, 1H), 7.35-7.40 (m, 1H), 6.7 (dd, J=8.5Hz, 8.5Hz, 1H), 3.98 (t, J=Hz, 2H), 3.74 (t, J=Hz, 2H).
Embodiment 11
Figure G2007800391963D00691
The fluoro- thienos of 3- amino -7- [3,2-c] pyridine-2-carboxylic acids ethyl ester
Figure G2007800391963D00692
Ethyl thioglycolate (0.73mL, 6.7mmol) is added dropwise in 0 DEG C of mixture to the fluoro- pyridine -3- formonitrile HCNs (1.0g, 6.4mmol) of the chloro- 5- of 4- and potassium carbonate (4.4g, 32mmol) in DMF (15mL).Reactant mixture is stirred 10 minutes at 0 DEG C, is stirred at room temperature 20 minutes, is then stirred 30 minutes at 40 DEG C.Reactant mixture is cooled to room temperature, distributed between water and ethyl acetate.Separate organic layer, then priority water and salt water washing are dried over sodium sulfate and be concentrated in vacuo, and obtain title compound, it is yellow solid (1.5g, quantitatively).LCMS (method B)：RT=3.41 minutes, M+H+=241.
The fluoro- 3- of 7- (the fluoro- 4- of 2- (trimethyl silyl)-phenyl amino)-thieno [3,2-c] pyridine-2-carboxylic acids Ethyl ester
Figure G2007800391963D00693
Make 3- amino -7- fluoro- thieno [3,2-c] pyridine-2-carboxylic acids ethyl ester (360mg, 1.5mmol), the fluoro- 4- of trifluoromethanesulfonic acid 2- (trimethyl silyl)-phenyl ester (411mg, 1.3mmol), Pd2dba3(69mg, 0.075mmol), Xantphos (86mg, 0.15mmol) and Cs2CO3The mixture of (685mg, 2.1mmol) in toluene (6ml) receives microwave irradiation 20 minutes at 160 DEG C.Reactant mixture is filtered by Celite pad.Filtrate decompression is concentrated, residue is obtained, it is carried out flash chromatography and (Si-SPE, pentane: ether, gradient 100: 0 to 90: 10), obtains title compound, it is yellow solid (338mg, 55%).LCMS (method B)：RT=5.20 minutes, M+H+=407。
The fluoro- 3- of 7- (the iodo- phenyl aminos of the fluoro- 4- of 2-)-thieno [3,2-c] pyridine-2-carboxylic acids ethyl ester
Figure G2007800391963D00694
To the fluoro- 3- of (0 DEG C) 7- (the fluoro- 4- of 2- (trimethyl silyl)-phenyl amino)-thieno [3 of cooling, 2-c] pyridine-2-carboxylic acids ethyl ester (330mg, iodine monochloride (1M DCM solution 0.81mmol) is added dropwise in the solution in DCM (10mL), 1.6mL, 1.6mmol).After addition terminates, mixture is stirred 1 hour at 0 DEG C, is then quenched by adding saturated sodium thiosulfate solution (10mL).Mixture is stirred vigorously 10 minutes, then distributed between ethyl acetate and water.Organic layer is separated, then priority saturated sodium bicarbonate solution and salt water washing, dried over sodium sulfate, filters and concentrates, obtains title compound, it is yellow solid (358mg, 54%).LCMS (method B)：RT=4.72 minutes, M+H+=461.
The fluoro- 3- of 7- (the iodo- phenyl aminos of the fluoro- 4- of 2-)-thieno [3,2-c] pyridine-2-carboxylic acids (2- (vinyl epoxide)- Ethyoxyl)-acid amides
To the fluoro- 3- of 7- (the iodo- phenyl aminos of the fluoro- 4- of 2-)-thieno [3,2-c] pyridine-2-carboxylic acids ethyl ester (175mg, 1.0M sodium hydrate aqueous solutions (0.5mL, 0.5mmol) 0.38mmol) are added in the solution in IMS (industrial methylated spirit) (4mL).Reactant mixture is heated to 65 DEG C and kept for 1 hour, room temperature is then cooled to and is concentrated in vacuo.The residue of formation and toluene (3 × 10mL) azeotropic, are then suspended in THF (5mL).Then O- (2- (vinyl epoxide)-ethyl)-azanol (78mg is successively added, 0.76mmol), N, N- diisopropylethylamine (0.26mL, 1.52mmol), EDCI (146mg, 0.76mmol) with HOBt (103mg, 0.76mmol), then reactant mixture is stirred at room temperature 18 hours.Reactant mixture is concentrated in vacuo, then distributed residue between water and ethyl acetate.Separate organic layer, then saturated sodium bicarbonate solution and salt water washing are used, it is dried over sodium sulfate, filter and concentrate, obtain residue, the residue is through column chromatography (Si-SPE, gradient 0-2% methanol/DCM) purifying, title compound is obtained, it is light yellow solid (106mg, 54%).LCMS (method B)：RT=3.92 minutes, M+H+=518.
The fluoro- 3- of 7- (the iodo- phenyl aminos of the fluoro- 4- of 2-)-thieno [3,2-c] pyridine-2-carboxylic acids (2- Hydroxy-ethoxies)- Acid amides
Figure G2007800391963D00702
By the fluoro- 3- of 7- (the iodo- phenyl aminos of the fluoro- 4- of 2-)-thieno [3,2-c] pyridine-2-carboxylic acids (2- (vinyl epoxide)-ethyoxyl)-acid amides (100mg, 0.19mmol) solution stowage in methanol and DCM mixture is successively eluted on SCX-2 posts (5g) with the methanol solution of methanol and 2M ammonia.Merge appropriate cut, be then concentrated under reduced pressure.Remaining solid is purified through column chromatography (Si-SPE, gradient 0-40% fert-butyidimethylsilyl ether/DCM followed by 10% methanol/DCM), obtains title compound, and it is yellow solid (50mg, 53%).LCMS (method A)：RT=9.60 minutes, M+H+=492.1H NMR(CD3OD, 400MHz) 3.58 (2H, t, J=4.89Hz), 3.84 (2H, t, J=4.91Hz), 6.89 (1H, t, J=8.76Hz), 6.98 (1H, dd, J=8.41,2.15Hz), 7.21-7.26 (1H, m), 8.02 (1H, d, J=5.61Hz), 8.45 (1H, dd, J=8.25,5.61Hz), and 8.53-8.59 (1H, m).
Embodiment 12
Figure G2007800391963D00711
3- (the fluoro- 4- of 2- (methylsulfany)-phenyl amino)-thieno [3,2-c] pyridine-2-carboxylic acids ethyl ester
Figure G2007800391963D00712
By 3- (nine fluorine butyl- 1- sulfonyls epoxides)-thieno [3 of degassing; 2-c] pyridine-2-carboxylic acids ethyl ester (0.74g; 1.5mmol), the fluoro- 4- of 2- (methylsulfany)-phenyl amine (0.12g, 0.76mmol), Pd2dba3(0.035g, 0.038mmol), Xantphos (0.044g, 0.076mmol) and K3PO4The solution of (0.32g, 1.5mmol) in toluene (10ml) is heated at reflux 18 hours.Reactant mixture is cooled to environment temperature, then filtered through Hyflo pads (being washed with ethyl acetate).Filter vacuum is concentrated, the residue to be formed is carried out flash chromatography (Si-SPE, gradient 0-10% ethyl acetate/dichloromethane), obtains title compound, it is yellow solid (0.16g, 57%).LCMS (method B)：RT=3.84 minutes, M+H+363。
3- (the fluoro- 4- of 2- (methylsulfany)-phenyl amino)-thieno [3,2-c] pyridine-2-carboxylic acids
Figure G2007800391963D00713
By 3- (the fluoro- 4- of 2- (methylsulfany)-phenyl amino)-thieno [3,2-c] pyridine-2-carboxylic acids ethyl ester (0.19g, 0.52mmol) sodium hydroxide (the 1M aqueous solution of the suspension in IMS (10ml), 0.63ml) handle, then heat reactant mixture 3 hours at 60 DEG C.The mixture to be formed is cooled down, is then concentrated in vacuo.By thick residue water process, then mixture is adjusted to pH 5 with acetic acid.The suspension of formation is filtered, residue is collected, is then dried in vacuo, obtains title compound, it is green solid (0.107g, 56%), it is just used for next step without further purification.
3- (the fluoro- 4- of 2- (methylsulfany)-phenyl amino)-thieno [3,2-c] pyridine-2-carboxylic acids (2- (vinyl oxygen Base)-ethyoxyl)-acid amides
Figure G2007800391963D00721
By 3- (the fluoro- 4- of 2- (methylsulfany)-phenyl amino)-thieno [3,2-c] pyridine-2-carboxylic acids (0.107g, 0.32mmol) suspension in anhydrous methylene chloride (5ml) is cooled to 0 DEG C in a nitrogen atmosphere, then handled with DMF (1 drop) and oxalyl chloride (0.081ml, 0.96mmol).Reactant mixture is stirred 1 hour, then solvent in vacuo is removed.The residue to be formed is set to be suspended in again in anhydrous methylene chloride (1ml), then O- (2- (vinyl epoxide)-ethyl)-azanol (0.066g is used, 0.64mmol) with DIPEA (0.167ml, 0.96mmol) solution in anhydrous methylene chloride (4ml) is handled dropwise, is followed by stirring for 18 hours.Reactant mixture is washed (water and salt solution), dry (MgSO4), filter and be concentrated in vacuo.The residue to be formed is carried out flash chromatography (Si-SPE, gradient 0-30% ethyl acetate/dichloromethane), obtain title compound, it is yellow solid (0.024g, 18%).LCMS (method B)：RT=3.17 minutes, M+H+420。
3- (the fluoro- 4- of 2- (methylsulfany)-phenyl amino)-thieno [3,2-c] pyridine-2-carboxylic acids (2- hydroxyls-ethoxy Base)-acid amides
By 3- (the fluoro- 4- of 2- (methylsulfany)-phenyl amino)-thieno [3,2-c] pyridine-2-carboxylic acids (2- (vinyl epoxide)-ethyoxyl)-acid amides (20mg, 0.048mmol) it is dissolved in methanol (1ml), then concentrated hydrochloric acid (0.01ml is used, 0.12mmol) handle, be then stirred at room temperature 2 hours.Reactant mixture is concentrated in vacuo, the residue to be formed is carried out reversed-phase HPLC (0.1%HCO2Gradient of the H aqueous solution based on acetonitrile).Merge appropriate cut, be then freeze-dried, obtain title compound (9mg, 47%).LCMS (method A)：RT=6.36 minutes, M+H+394。1HNMR(DMSO-d6, 400MHz) and 3.58 (2H, t, J=4.89Hz), 3.84 (2H, t, J=4.91Hz), 6.89 (1H, t, J=8.76Hz), 6.98 (1H, dd, J=8.41,2.15Hz), 7.21-7.26 (1H, m), 8.02 (1H, d, J=5.61Hz), 8.45 (1H, dd, J=8.25,5.61Hz), and 8.53-8.59 (1H, m).

Claims (18)

1. the compound or its salt of Formulas I：
Figure FSB00000722429000011
Wherein
Z1For CR1；
Z2For N；
Z3For CR3；
Z4For CR4；
R1、R3And R4It is independently selected from H, halogen, CN, CF3、-OCF3、-NO2、C1-12Alkyl or C1-12Alkoxy；
W is
Figure FSB00000722429000012
R5And R6It is independently selected from H or C1-C12Alkyl；
X1For-OR11；
X2To be optionally substituted with the phenyl that one or more is selected from following group：Halogen and C1-12Alkyl sulfenyl；
R11There is the C of one or more hydroxyls for substitution1-12Alkyl.
2. the compound of claim 1, wherein X1It is selected from：
Figure FSB00000722429000013
3. the compound of claim 1, wherein X2For
Figure FSB00000722429000021
4. the compound of claim 1, wherein R1Selected from H, CH3、CF3, CN and Cl.
5. the compound of claim 1, wherein R3Selected from H, CH3, F or CF3。
6. the compound of claim 1, wherein R4Selected from CF3, Br, Cl or CN.
7. the compound of claim 1, wherein R4Selected from Cl, Br, Me, Et, F or CF3。
8. the compound of claim 1, wherein R5For H or methyl.
9. the compound of claim 1, wherein R6For H or methyl.
10. a kind of compound, it is selected from：
Figure FSB00000722429000022
11. a kind of pharmaceutical composition, its compound comprising any one of claim 1-10 and pharmaceutical acceptable carrier.
12. the pharmaceutical composition of claim 11, it also includes another chemotherapeutic agent.
13. the pharmaceutical composition of claim 11, it also includes another anti-inflammatory drug.
14. any one of claim 1-10 compound is preparing the purposes in being used to treat the medicine of the kinase mediated cancers of MEK in mammal.
15. any one of claim 1-10 compound is preparing the purposes in being used to treat the medicine of the kinase mediated diseases associated with inflammation of MEK in mammal.
16. the pharmaceutical composition of claim 11 or 12 is preparing the purposes in being used to treat the medicine of the kinase mediated cancers of MEK in mammal.
17. the pharmaceutical composition of claim 11 or 13 is preparing the purposes in being used to treat the medicine of the kinase mediated diseases associated with inflammation of MEK in mammal.
18. the pharmaceutical composition of claim 11 is being prepared for treating the purposes in the kinase mediated autoimmune diseases of MEK, cancer or the medicine of infectious diseases in mammal.
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CN1652792A (en) * 2002-03-13 2005-08-10 阵列生物制药公司 N3 alkylated benzimidazole derivatives as MEK inhibitors
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