CN101146782A - Metasubstituted thiazolidinones, their manufacture and use as a drug - Google Patents

Metasubstituted thiazolidinones, their manufacture and use as a drug Download PDF

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CN101146782A
CN101146782A CNA2005800483966A CN200580048396A CN101146782A CN 101146782 A CN101146782 A CN 101146782A CN A2005800483966 A CNA2005800483966 A CN A2005800483966A CN 200580048396 A CN200580048396 A CN 200580048396A CN 101146782 A CN101146782 A CN 101146782A
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V·K·舒尔策
K·艾斯
L·沃特曼
D·科泽蒙德
O·普里恩
G·西迈斯特
H·赫斯-施通普
U·埃贝施佩歇尔
D·E·A·布里顿
I·伊斯拉姆
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Abstract

Meta-substituted thiazolidinone compounds (I), their solvates, hydrates, diastereomers, enantiomers and salts are new. : Meta-substituted thiazolidinone compounds of formula (I), their solvates, hydrates, diastereomers, enantiomers and salts are new. T1>, T3>-CH= or -N=; T2>T1> or (-CF)=; U1>e.g. -N=; R1>1-3C alkyl or cyclopropyl (both optionally substituted with halo); R2>1-3C alkyl, 3-4C alkenyl, 3-4C alkynyl or cyclopropyl (all optionally substituted with CN, cyclopropyl, ethynyl or halo); R3>e.g. K1>; and K1>1-3C alkyl or 2-4C alkenyl (both optionally substituted). Full definitions are given in the DEFINITIONS - Full Definitions section. Independent claims are also included for: (1) substituted thiazolidinone compounds of formula (II) or (IV), their solvates, hydrates, diastereomers, enantiomers and salts as intermediates for preparing (I); and (2) the preparation of (I). [Image] [Image] - ACTIVITY : Cytostatic; Immunosuppressive; Antipsoriatic; Endocrine-Gen.; Neuroprotective; Cardiovascular-Gen.; Antiarteriosclerotic; Vasotropic; Antimicrobial; Antiparasitic; Nephrotropic; Anticonvulsant; Nootropic; Antiparkinsonian; Virucide; Antiinflammatory; Hepatotropic; Anti-HIV. - MECHANISM OF ACTION : Polo-like kinase inhibitor.

Description

Between the thiazolidinone compound that replaces of position, its preparation method and as the application of medicine
The application that the present invention relates to thiazolidinone compound, its preparation method and make polo sample kinases (PIk) inhibitor for treating various diseases.
Tumour cell is distinguished by untamed cell cycle process.On the other hand, this is based on such as the control of RB, p16, p21, p53 etc. is proteic and loses and so-called promotor---the activation of cell cycle protein dependent kinase (Cdk) of cell cycle process.Cdk has been considered to antineoplastic target albumen in medicine.Except that Cdk, the serine/threonine kinase of regulating to the cell cycle has also been described, so-called polo sample kinases, they not only relate to regulation of Cell Cycle, and and mitotic division and kytoplasm separation period between other processes (form spindle body, chromosome segregation) collaborative.Therefore, this proteinoid has been represented advantage point (Descombes and Nigg.Embo J, 17,1328 ff, 1998 that are used for proliferative disease such as treatment for cancer intervention; People such as Glover, Genes Dev 12,3777 ff, 1998).
At " nonsmall-cell lung cancer " (people Oncogene such as Wolf, 14,543ff, 1997), melanoma (people JAMA such as Strebhardt, 283,479ff, 2000), squamous cell carcinoma (people Cancer Res such as Knecht, 59,2794ff, 1999) and the high expression level rate of having found Plk-1 in the esophageal carcinoma (people Int J Oncol 15 such as Tokumitsu, 687ff, 1999).
Dependency (people such as Strebhardt, JAMA, 283,479ff, 2000 between the prediction of high expression level rate in the tumour patient and difference in most various tumours, have been confirmed; People such as Knecht, Cancer Res, 59,2794ff, 1999; And people such as Tokumitsu, Int J Oncol 15,687ff, 1999).
The constructive expression of Plk-1 in the NIH-3T3 cell caused vicious transformation (proliferation function increases, growth, bacterium colony in the soft agar form and hairless mouse in tumour grow) (people such as Smith, Biochem Biophys ResComm, 234,397ff., 1997).
Micro-injection Plk-1 antibody causes unsuitable mitotic division (people such as Lane in the HeLa cell; Journal cell Biol, 135,1701ff, 1996).
With " 20-mer " antisense scant polymer, can suppress the expression of Plk-1 in the A549 cell, and the ability of their survivals is stopped.In hairless mouse, go back susceptible of proof remarkable antitumor effect (people such as Mundt, BiochemBiophys Res Comm, 269,377ff., 2000).
Compare with the HeLa cell, the anti-Plk antibody of micro-injection demonstrates obviously the more a high proportion of cell that still is in the vegetative rest of G2 phase and shows inappropriate mitotic division sign hardly (people such as Lane: Journal cell Biol in the people Hs68 of non-immortalization cell, 135,1701ff, 1996).
Opposite with tumour cell, the growth of the few molecules in inhibiting primary of antisense people mesangial cell and survival rate people such as (, Biochem Biophys Res Comm, 269,377ff., 2000) Mundt.
In Mammals, except that Plk-1, other three kinds of polo kinases have been described also at present, they be sent out by great waves with the form that mitogenesis is replied and bring into play their effect in the G1 phase of cell cycle.On the other hand, they are so-called Prk/Plk-3 (kinases that people's homologue=fibroblast growth factor of mouse Fnk brings out: people such as Wiest, Genes.Chromosomes ﹠amp; Cancer, 32:384ff, 2001), Snk/Plk-2 (kinases that serum brings out, people such as Liby, DNA Sequence, 11,527-33,2001) and sak/Plk4 (people such as Fode, Proc.Natl.Acad Sci.U.S.A., 91,6388ff; 1994).
Therefore, suppress other kinases such as Plk-2, Plk-3 and the Plk-4 of Plk-1 and polo family, represented a kind of promising method that is used for the treatment of various diseases.
Sequence identity in the Plk territory of polo family makes that one or more other kinases in kinase inhibitor and this family can generating unit divide interaction between 40-60%.But, depend on the structure of described inhibitor, this effect is also alternative or preferentially only take place on a kind of kinases of polo family.
Disclose the thiazolidone compounds in the International Patent Application WO 03/093249 and can suppress polo family kinases.
Therefore, the purpose of this invention is to provide compared with prior art and can suppress the kinase whose compound of polo sample better, and/or this kinases that can be inhibited, the particularly kinase whose alternative compounds of polo sample, and/or provide with prior art in disclosed compound compare compound with better physicochemical property.
First embodiment of the present invention
In first embodiment of the present invention, found that the compound of the general formula I in the claim 1 and solvate, hydrate, diastereomer, enantiomorph and salt are improved compounds aspect inhibition polo sample kinases.
Figure A20058004839600191
Wherein
T 1, T 2And T 3Independently of each other representative-CH=or-N=, and T 2Also can represent in addition (CF)=,
U representative-CR 4=or-N=,
R 1The C that the optional one or many of representative is replaced by halogen identical or differently 1-C 3-alkyl or cyclopropyl,
R 2The C that the optional identical or different by cyano of one or many of representative, cyclopropyl, ethynyl or halogen replace 1-C 3-alkyl, C 3-C 4-thiazolinyl, C 3-C 4-alkynyl or cyclopropyl,
Or represent at least once by methyl substituted hydroxyethyl,
R 3Represent K, L or M, or represent R 15,
The C that the optional one or many of K representative is replaced by X identical or differently 1-C 3-alkyl or C 2-C 4-thiazolinyl, X are represented halogen, hydroxyl or are represented group-OR 6,-NR 10R 11Or represent C 2-C 10-Heterocyclylalkyl, in wherein should encircling
Described Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose the identical or different by cyano of one or many, halogen, hydroxyl, aryl wantonly or by group-(CO)-R 5,-NR 12R 13Or chosen wantonly one or many identical or differently by halogen, hydroxyl or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, and wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces,
L represents group-O-R 7,-O-(CH 2) n-(CO)-NH-R 8,-O-(CH 2) n-(CO)-R 15Or-O-(CH 2) n-(CO)-O-R 8M represents group-NH-R 9,-NH-(CO)-OH) ,-NH-(CO)-O-R 9Or-NR 12-(CO)-R 9,
R 4The methyl of representing the optional one or many of hydrogen, cyano group or halogen or representative to be replaced by halogen identical or differently,
R 5Represent C 1-C 4-alkyl, phenyl or-NR 12R 13,
R 6Representative-SO 2-R 14,
R 7The optional one or many of representative is quilt-NR identical or differently 12R 13Or C 2-C 10The C that-Heterocyclylalkyl replaces 1-C 3-alkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should choose the C that one or many is replaced by halogen by halogen, aryl or optional one or many identical or differently identical or differently wantonly by ring itself 1-C 3-alkyl replaces,
R 8The C that the optional identical or different by cyano of one or many of representative, cyclopropyl or halogen replace 1-C 3-alkyl, C 3-C 4-thiazolinyl or C 3-C 4-alkynyl,
R 9The optional one or many of representative is identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, C 2-C 10-Heterocyclylalkyl, cyano group, cyclopropyl, halogen, hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14The C that replaces 1-C 5-alkyl, C 2-C 4-thiazolinyl, cyclopropyl or C 2-C 10-Heterocyclylalkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or chosen wantonly one or many identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces,
R 10And R 11The optional one or many of representative independently of each other is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3The C that-alkoxyl group replaces 1-C 5-alkyl, C 2-C 10-Heterocyclylalkyl, aryl ,-(CH 2) n-aryl or heteroaryl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys,
R 12And R 13Represent hydrogen or C independently of each other 1-C 4-alkyl,
R 14Represent C 1-C 3-alkyl or represent aryl, and
R 15The optional one or many of representative is identical or differently by C 1-C 3-alkyl or-(CH 2) nThe C that-aryl replaces 2-C 10-Heterocyclylalkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys,
R 16Represent the optional one or many of hydrogen or representative identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, C 2-C 10-Heterocyclylalkyl, cyano group, cyclopropyl, halogen, hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14The C that replaces 2-C 4-thiazolinyl, cyclopropyl or C 2-C 10-Heterocyclylalkyl, or represent one or many identical or differently by C 1-C 4-alkoxyl group, cyano group, cyclopropyl, halogen, hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14The C that replaces 1-C 4-alkyl, or the optional one or many of representative is identical or differently by C 2-C 10The methyl that-Heterocyclylalkyl or heteroaryl replace, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-,-(C=S)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14,-NR 12R 13Or choose wantonly by one or many identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces,
Or represent one or many identical or differently by C 2-C 10The C that-Heterocyclylalkyl replaces 1-C 4-alkyl, or represent one or many identical or differently by C 1-C 4-alkoxy-C 1-C 4The C that-alkoxyl group replaces 2-C 4-alkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should the one or many of ring own identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, and n represents 1-4.
Another variant of the present invention's first embodiment is according to the general formula compound in the claim 2 of claim 1 and solvate, hydrate, diastereomer, enantiomorph and salt, wherein:
R 3Represent K, L or M,
X represents halogen, hydroxyl or represents group-OR 6,-NR 10R 11Or represent C 2-C 10-Heterocyclylalkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose the identical or different by cyano of one or many, halogen, hydroxyl, aryl wantonly or by group-(CO)-R 5Or-NR 12R 13The optional one or many of replacement or quilt is identical or differently by halogen, hydroxyl or C 1-C 3The C that-alkylthio is obtained 1-C 3-alkyl replaces, and wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces,
L represents group-O-R 7,-O-(CH 2) n-(CO)-NH-R 8Or-O-(CH 2) n-(CO)-O-R 8, R 9Represent C 1-C 4-alkyl, C 2-C 4-thiazolinyl, cyclopropyl or C 2-C 10-Heterocyclylalkyl, its optional one or many is identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, C 2-C 10-Heterocyclylalkyl, cyano group, cyclopropyl, halogen or hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14Replace, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkoxyl group replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces,
R 16Represent hydrogen or represent C 2-C 4-thiazolinyl, cyclopropyl or C 2-C 10-Heterocyclylalkyl, its optional one or many is identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, C 2-C 10-Heterocyclylalkyl, cyano group, cyclopropyl, halogen, hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14Replace, or represent C 1-C 4-alkyl, its one or many is identical or differently by C 1-C 4-alkoxyl group, cyano group, cyclopropyl, halogen, hydroxyl or by group-NR 10R 11,-O-(CO) R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14Replace, or represent methylidene, its optional one or many is identical or differently by C 2-C 10-Heterocyclylalkyl replaces, and wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces,
Or represent C 1-C 4-alkyl, its one or many is identical or differently by C 2-C 10-Heterocyclylalkyl replaces, or represents C 2-C 4-alkyl, its one or many is identical or differently by C 1-C 4-alkoxy-C 1-C 4-alkoxyl group replaces, and wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different the former of nitrogen, oxygen or sulphur that be selected from and gives, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces.
Another variant of the present invention's first embodiment is according to the general formula compound in the claim 3 of claim 1 or 2 and solvate, hydrate, diastereomer, enantiomorph and salt, wherein:
R 7The optional one or many of representative is quilt-NR identical or differently 12R 13Or C 2-C 10The C that-Heterocyclylalkyl is obtained 1-C 3-alkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys,
R 9Represent C 1-C 5-alkyl, C 2-C 4-thiazolinyl, cyclopropyl or C 2-C 10-Heterocyclylalkyl, its optional one or many is identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, C 2-C 10-Heterocyclylalkyl, cyano group, cyclopropyl, halogen or hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 12Replace, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose wantonly one or many identical or differently by halogen, cyano group, hydroxyl or optional one or many identical or differently by halogen or C 1-C 3The phenyl that-alkoxyl group replaces replaces, or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces,
R 10And R 11C is represented in choosing independently of each other 1-C 5-alkyl, C 2-C 10-Heterocyclylalkyl, aryl or heteroaryl, its optional one or many is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, and wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys,
R 14Table C 1-C 3-alkyl or represent phenyl, and
N represents 1-4.
Another variant of the present invention's first embodiment is according to the compound of Formula I in the claim 4 of one of claim 1-3 and solvate, hydrate, diastereomer, enantiomorph and salt, wherein:
R 1Represent methylidene, ethyl, sec.-propyl or cyclopropyl, its optional one or many is replaced by halogen identical or differently,
R 2Represent methylidene, ethyl, allyl group or propargyl, the identical or different by cyano of its optional one or many, cyclopropyl, ethynyl or halogen replace, or representative replaced once hydroxyethyl at least by methyl,
X represents halogen, hydroxyl or represents group-OR 6Or-NR 10R 11Or representative azetidinyl, pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl, the octahydro isoquinolyl, the benzopyrrole alkyl, piperazinyl Si Qing oxazolyl, the piperazine ketone group, the thiazolidine base, imidazolidine quinoline ketone group, the benzo morpholinyl, triazine thioketones base (triazinthionyl), tetrahydro isoquinolyl or tetrahydric quinoline group, wherein pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl, the octahydro isoquinolyl, the benzopyrrole alkyl, piperazinyl Si Qing oxazolyl, the piperazine ketone group, the thiazolidine base, imidazolidine quinoline ketone group, the benzo morpholinyl, triazine thioketones base, tetrahydro isoquinolyl, the optional one or many of tetrahydric quinoline group itself is identical or differently by the halogen rope, hydroxyl or optional one or many are identical or differently by halogen or C 1-C 3The phenyl that-alkoxyl group replaces replaces, or by group-(CO)-R 5,-NR 12R 13Or the identical or different by cyano of optional one or many, halogen, hydroxyl or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces,
R 4The methyl of representing the optional one or many of hydrogen or halogen or representative to be replaced by halogen identical or differently,
R 5Represent methylidene, ethyl, the tertiary butyl, phenyl or-NH 2,
R 6Representative-SO 2-methyl,
R 7Represent C 1-C 3-alkyl, its optional one or many is quilt-N (C identical or differently 1-C 3-alkyl) 2, pyrrolidyl, morpholinyl or piperidyl replace,
R 8Represent methylidene, ethyl, allyl group or propargyl, the identical or different by cyano of its optional one or many, cyclopropyl or halogen replace.
R 9Represent methylidene, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, vinyl, cyclopropyl, THP trtrahydropyranyl or tetrahydrofuran base, its optional one or many is identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, pyrrolidyl, piperidyl, piperazinyl, thio-morpholinyl, benzopyrrole alkyl, tetrahydric quinoline group, Si Qing oxazolyl, piperazine ketone group (piperazinonyl), thiazolidine base, imidazolidine quinoline ketone group, benzo morpholinyl, tetrahydrochysene triazolinthione base (tetrahydrotriazolthionyl), morpholinyl, tetrahydro isoquinolyl, octahydro isoquinolyl, cyano group, cyclopropyl, halogen, hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-(SO 2)-C 1-C 3-alkyl replaces, and wherein pyrrolidyl, piperidyl, piperazinyl, thio-morpholinyl, benzopyrrole alkyl, tetrahydric quinoline group, Si Qing oxazolyl, piperazine ketone group, thiazolidine base, imidazolidine quinoline ketone group, benzo morpholinyl, tetrahydrochysene triazolinthione base, morpholinyl, tetrahydro isoquinolyl, the optional one or many of octahydro isoquinolyl itself are identical or differently by halogen, hydroxyl, phenyl or C 1-C 3-alkoxyl group or by group-(CO)-R 5,-(CO)-O-R 5,-(SO 2)-R 14,-N (CH 3) 2Or optional one or many replaces by methyl or the ethyl that halogen, hydroxyl, methylthio group or phenyl replace identical or differently,
R 10And R 11Represent C mutually independently 1-C 5-alkyl, pyrrolidyl, phenyl or pyridyl, its optional one or many is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces,
R 12And R 13Represent hydrogen or methyl, ethyl or sec.-propyl independently of each other,
R 14Represent C 1-C 4-alkyl or represent phenyl, and
N represents 1 or 2.
Another theme of the present invention's first embodiment is according to the compound of Formula I in the claim 5 of one of claim 1-4 and solvate, hydrate, diastereomer, enantiomorph and salt, wherein:
U representative-CH=,-CF=,-C (CH 3)=or-N=,
R 1Represent methylidene, ethyl, sec.-propyl or cyclopropyl, its optional one or many is replaced by fluorine identical or differently,
R 2Represent methylidene, ethyl, allyl group or propargyl, the identical or different by cyano of its optional one or many, cyclopropyl, ethynyl or fluorine replace, or representative replaced once hydroxyethyl at least by methyl,
K represent methylidene, ethyl or vinyl, its optional one or many is replaced by X identical or differently,
X represents halogen, hydroxyl or represents group-O-SO 2-methyl or represent pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl or octahydro isoquinolyl, the methyl substituted that replaced by halogen by halogen, hydroxyl or phenyl or optional one or many of the optional one or many of pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl or octahydro isoquinolyl itself wherein identical or differently identical or differently
L represents group-O-R 7,-O-(CH 2)-(CO)-NH-R 8Or-O-(CH 2)-(CO)-O-R 8,
M represents group-NH-R 9,-NH-(CO)-R 16,-NH-(CO)-O-R 9Or-N (CH 3)-(CO)-R 16,
R 7Represent ethyl, its optional one or many is quilt-N (C identical or differently 1-C 3-alkyl) 2, pyrrolidyl, morpholinyl or piperidyl replace,
R 8Represent methylidene, ethyl, allyl group or propargyl, the identical or different by cyano of its optional one or many, cyclopropyl or fluorine replace,
R 9Represent methylidene, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, vinyl, cyclopropyl, THP trtrahydropyranyl or tetrahydrochysene furan are fed base, and its optional one or many is identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, cyano group, cyclopropyl, halogen, hydroxyl or by group-N (C 1-C 3-alkyl) 2,-O-(CO)-(C 1-C 3-alkyl) or-O-(SO 2)-C 1-C 3-alkyl replaces, and wherein pyrrolidyl, piperidyl, piperazinyl, morpholinyl or thio-morpholinyl itself chosen one or many wantonly identical or differently by halogen or by group-(CO)-C 1-C 4-alkyl ,-(CO)-O-C 1-C 4-alkyl ,-(SO 2)-C 1-C 3-alkyl ,-(SO 2)-phenyl ,-N (C 1-C 3-alkyl) 2Or optional one or many is identical or differently by halogen, hydroxyl or C 1-C 3Methyl that-alkylthio replaces or ethyl replace.
Another theme of the present invention's first embodiment is according to the compound of Formula I in the claim 6 of one of claim 1-5 and solvate, hydrate, diastereomer, enantiomorph and salt, wherein:
R 1Represent ethyl,
X represents iodine or hydroxyl, or represents group-O-SO 2-methyl or represent pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl or octahydro isoquinolyl, wherein pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl or octahydro isoquinolyl itself chosen the methyl substituted that one or many is replaced by halogen by halogen, hydroxyl, phenyl or optional one or many identical or differently identical or differently wantonly
R 7Represent ethyl, its optional one or many is quilt-N (CH identical or differently 3) 2, pyrrolidyl, morpholinyl or piperidyl replace,
R 9Represent methylidene, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, vinyl, cyclopropyl, THP trtrahydropyranyl or tetrahydrofuran base, its optional one or many are identical or differently by methoxyl group, oxyethyl group, butoxy-oxyethyl group, methoxyl group-oxyethyl group, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, cyano group, cyclopropyl, chlorine, fluorine, hydroxyl or by group-N (CH 3) 2,-N (CH 3) (C 2H 5) ,-O-(CO)-(CH 3) or-O-(SO 2)-methyl substituted, wherein the optional one or many of pyrrolidyl, piperidyl, piperazinyl, morpholinyl or thio-morpholinyl itself is identical or differently by fluorine or by group-(CO)-CH 3,-(CO)-C 2H 5,-(CO)-C (CH 3) 3,-(CO)-O-C (CH 3) 3,-(SO 2)-CH 3,-(SO 2)-phenyl ,-N (CH 3) 2Or optional one or many is replaced by methyl or the ethyl that fluorine, hydroxyl or methylthio group replace identical or differently.
Another theme of the present invention's first embodiment is according to the compound of Formula I in the claim 7 of one of claim 1-6 and solvate, hydrate, diastereomer, enantiomorph and salt, wherein:
R 10Represent C 1-C 4-alkyl, its optional one or many is identical or differently by C 1-C 4-alkoxyl group, cyano group, cyclopropyl, halogen or hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14Replace, perhaps represent methylidene, its optional one or many is identical or differently by C 2-C 10-Heterocyclylalkyl replaces, and wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces.
Another variant of the present invention's first embodiment is according to the compound of Formula I in the claim 8 of claim 7 and solvate, hydrate, diastereomer, enantiomorph and salt, wherein:
R 16The optional one or many of representative is identical or differently by group-NR 10R 11The C in generation 1-C 4-alkyl, perhaps the optional one or many of representative is identical or differently by C 2-C 10The methyl that-ore deposit Heterocyclylalkyl replaces, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14,-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces.
According to the compound of the general formula I of one of claim 1-8, the C that replaced by K of the optional one or many of K representative wherein identical or differently 1-C 3-alkyl or C 2-C 4-thiazolinyl is another theme of first embodiment of the invention.
According to the compound of the general formula I of one of claim 1-8, the C that replaced by X of the optional one or many of K representative wherein identical or differently 1-C 3-alkyl or C 2-C 4-thiazolinyl is another theme of first embodiment of the invention.
According to the compound of the general formula I of one of claim 1-8, wherein the methyl, ethyl or the vinyl that are replaced by X of the optional one or many of K representative is another theme of first embodiment of the invention identical or differently.
According to the compound of the general formula I of one of claim 1-8, wherein L represents group-O-R 7,-O-(CH 2) n-(CO)-NH-R 8,-O-(CH 2) n-(CO)-R 15Or-O-(CH 2) n-(CO)-O-R 8, be another theme of first embodiment of the invention.
According to the compound of the general formula I of one of claim 1-8, wherein L represents group-O-R 7,-O-(CH 2) n-(CO)-NH-R 8Or-O-(CH 2) n-(CO)-O-R 8, be another theme of first embodiment of the invention.
According to the compound of the general formula I of one of claim 1-8, wherein L represents group-O-R 7,-O-(CH 2)-(CO)-NH-R 8Or-O-(CH 2)-(CO)-O-R 8, be another theme of first embodiment of the invention.
According to the compound of the general formula I of one of claim 1-8, wherein R 5Represent C 1-C 4-alkyl, phenyl or-NR 12R 13, be another theme of first embodiment of the invention.
According to the compound of the general formula I of one of claim 1-8, wherein R 5Represent methylidene, ethyl, the tertiary butyl, phenyl or-NH2, be another preferred theme of first embodiment of the invention.
Another theme of first embodiment of the invention is the compound of Formula I according to one of claim 1-8, wherein:
R 16Represent hydrogen or represent C 2-C 4-thiazolinyl, cyclopropyl or C 2-C 10-Heterocyclylalkyl, its optional one or many is identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, C 2-C 10-Heterocyclylalkyl, cyano group, cyclopropyl, halogen, hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14Replace, or represent C 1-C 4-alkyl, its one or many is identical or differently by C 1-C 4-alkoxyl group, cyano group, cyclopropyl, halogen, hydroxyl or by group-NR 10R 11,-O-(CO)-R 5Or-(SO 2)-R 14Replace, or represent methylidene, its optional one or many is identical or differently by C 2-C 10-Heterocyclylalkyl or heteroaryl replace, but preferably do not replaced by heteroaryl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group but does not preferably have-(C=S)-group, and optionally in this ring comprises one or more pairs of keys, and should ring itself chooses one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14,-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, but preferably not by C 1-C 3-alkyl replaces,
C 1-C 4-alkyl, its one or many is identical or differently by C 2-C 10-Heterocyclylalkyl replaces, or represents C 2-C 4-alkyl, its one or many is identical or differently by C 1-C 4-alkoxy-C 1-C 4-alkoxyl group replaces, and wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-,-(C=S)-or-SO 2-group but does not preferably have-(C=S)-group, and optionally in this ring comprises one or more pairs of keys, and should ring itself chooses one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl, the optional one or many of wherein said aryl itself is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, and does not also preferably have C 1-C 3-alkyl replaces.
The preferred theme of another of first embodiment of the invention is the compound according to the general formula I of one of claim 1-8, wherein: R 16Represent C 1-C 4-alkyl, its one or many is identical or differently by C 1-C 4-alkoxyl group, cyano group, cyclopropyl, halogen, hydroxyl or by group .NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14The C that replaces 1-C 4-alkyl replaces, or represent methylidene, and its optional one or many is identical or differently by C 2-C 10-Heterocyclylalkyl or heteroaryl replace, but preferably there is not heteroaryl to replace, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group but does not preferably have-(C=S)-group, and optionally in this ring comprises one or more pairs of keys, and should ring itself chooses one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14,-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, but does not also preferably have C 1-C 3-alkyl replaces.
The preferred theme of another of first embodiment of the invention is the compound according to the general formula I of one of claim 1-8, wherein: R 16Represent one or many identical or differently by group-NR 10R 11The C that replaces 1-C 4-alkyl, or represent methylidene, its optional one or many is identical or differently by C 2-C 10-Heterocyclylalkyl or heteroaryl replace, but preferably there is not heteroaryl to replace, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group but does not preferably have-(C=S)-group, and optionally in this ring comprises one or more pairs of keys, and should ring itself chooses one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14, or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, but does not also preferably have C 1-C 3-alkyl replaces.
The preferred theme of another of first embodiment of the invention is the compound according to the general formula I of one of claim 1-8, wherein R 16Represent methylidene, its optional one or many is identical or differently by group-NR 10R 11, C 2-C 10Even-Heterocyclylalkyl, imidazoles benzimidazolyl-replace, but preferably there are not imidazolyl or benzimidazolyl-to replace, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group but does not preferably have-(C=S)-group, and optionally in this ring comprises one or more pairs of keys, and should ring itself chooses one or many wantonly identical or differently by halogen, cyano group, hydroxyl, phenyl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said phenyl itself is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, but does not also preferably have C 1-C 3-alkyl replaces.
The preferred theme of another of first embodiment of the invention is the compound according to the general formula I of one of claim 1-8, wherein R 16Represent methylidene, its optional one or many is born by pyrrolidyl, piperidyl, piperazinyl, thio-morpholinyl, benzopyrrole alkyl, tetrahydric quinoline group, Si Qing oxazolyl, piperazine ketone group, thiazolidine base, imidazolidine quinoline ketone group, benzo morpholinyl, tetrahydrochysene triazolinthione base, morpholinyl, tetrahydro isoquinolyl, octahydro isoquinolyl, imidazoles identical or differently or benzimidazolyl-replaces, even but preferably do not have the imidazoles benzimidazolyl-, or represent very group-NR of quilt 10R 11The methyl that replaces, wherein the optional one or many of pyrrolidyl, piperidyl, piperazinyl, thio-morpholinyl, benzopyrrole alkyl, tetrahydric quinoline group, Si Qing oxazolyl, piperazine ketone group, thiazolidine base, imidazolidine quinoline ketone group, benzo morpholinyl, tetrahydrochysene triazolinthione base, morpholinyl, tetrahydro isoquinolyl, octahydro isoquinolyl itself is replaced by halogen, hydroxyl or phenyl identical or differently, or by group-(CO)-R 5,-(CO)-O-R 5,-(SO 2)-R 14Or-N (CH 3) 2Or optional one or many replaces by methyl or the ethyl that halogen, hydroxyl, methylthio group or phenyl replace identical or differently, and wherein said phenyl itself is chosen one or many wantonly identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, but does not also preferably have C 1-C 3-alkyl replaces.
Second embodiment of the present invention
In second embodiment of the present invention, find, can realize purpose of the present invention according to the compound of Formula I in the claim 9 of claim 1 and solvate, hydrate, diastereomer, enantiomorph and salt, wherein:
The C that on behalf of one or many, K replaced by P identical or differently 1-C 3-alkyl, or the C that represents one or many to be replaced by X identical or differently 2-C 4-thiazolinyl,
P represents group-OR 6,-NR 18R 19, C 2-C 5-Heterocyclylalkyl or represent C 6-C 10Heterocyclylalkyl, the described C in wherein should encircling 2-C 5-Heterocyclylalkyl and C 6-C 10Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group, and in this ring optional one or more pairs of keys and this C of comprising 2-C 5The identical or different by cyano of the one or many of the ring of-Heterocyclylalkyl own, halogen, hydroxyl or aryl or by group-(CO)-R 5Or one or many is identical or differently by halogen or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, and wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces, and described C 6-C 10The ring of-Heterocyclylalkyl itself is chosen the identical or different by cyano of one or many, halogen, hydroxyl, aryl wantonly or by group-(CO)-R 5,-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, and wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces,
L represents group-O-R 7,-O-(CH 2) n-(CO)-NH-R 17,-O-(CH 2) n-(CO)-R 15Or-O-(CH 2) n-(CO)-O-R 8,
R 7The optional one or many of representative is identical or differently by C 6-C 10The C that-Heterocyclylalkyl replaces 1-C 3-alkyl, the described C in wherein should encircling 6-C 10-Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should choose the C that one or many is replaced by halogen by halogen, aryl or optional one or many identical or differently identical or differently wantonly by ring itself 1-C 3-alkyl replaces, or represents one or many identical or differently by C 2-C 5The C that-Heterocyclylalkyl replaces 1-C 3-alkyl, the described C in wherein should encircling 2-C 5-Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should choose the C that one or many is replaced by halogen by halogen, aryl or one or many identical or differently identical or differently wantonly by ring itself 1-C 3-alkyl replaces,
R 16Represent hydrogen, C 2-C 4-thiazolinyl, cyclopropyl, C 2-C 5-Heterocyclylalkyl, C 6-C 10-Heterocyclylalkyl or the methyl that is replaced by heteroaryl, or represent C 1-C 4-alkyl, C 2-C 4-thiazolinyl, cyclopropyl, C 2-C 5-Heterocyclylalkyl or C 6-C 10-Heterocyclylalkyl, its one or many is identical or differently by C 1-C 4-alkoxyl group, C 2-C 5-Heterocyclylalkyl, C 6-C 10-Heterocyclylalkyl, cyano group, cyclopropyl or by group-NR 18R 19,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14Replace the described C in wherein should encircling 2-C 5-Heterocyclylalkyl and C 6-C 10-Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group, and in this ring optional one or more pairs of keys and this C of comprising 2-C 5The optional one or many of the ring of-Heterocyclylalkyl itself is identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or one or many is identical or differently by halogen, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, and this C 6-C 10The optional one or many of the ring of-Heterocyclylalkyl itself is identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces,
R 17Represent one or many identical or differently by the C of halogen or cyano group replacement 1-C 3-alkyl, or the optional one or many of representative is identical or differently by the C of halogen, cyclopropyl or cyano group replacement 3-C 4-thiazolinyl or C 3-C 4-alkynyl,
R 18And R 19Represent C independently of each other 1-C 5-alkyl, C 2-C 10-Heterocyclylalkyl, Fang Mu ,-(CH 2) n-aryl or heteroaryl, its optional one or many is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, and wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and in this ring optional one or more pairs of keys, the wherein R of comprising 18Or R 19Represent C 2-C 10-Heterocyclylalkyl ,-(CH 2) n-aryl or heteroaryl, or represent one or many identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3The C that-alkoxyl group replaces 2-C 10-Heterocyclylalkyl ,-(CH 2) n-aryl or heteroaryl, or represent one or many identical or differently by C 1-C 3The C that-alkoxyl group replaces 1-C 5-alkyl, or represent one or many identical or differently by C 1-C 3-alkyl, C 1-C 3The aryl that-alkoxyl group replaces, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys.
Another theme of second embodiment of the invention is according to the compound of Formula I in the claim 10 of claim 9 and solvate, hydrate, diastereomer, enantiomorph and salt, wherein:
T 1, T 2And T 3Independently of each other representative-CH=or-N=,
R 3Represent K, L or M,
P represents group-OR 6,-NR 18R 19, C 2-C 5-Heterocyclylalkyl or represent C 6-C 10Heterocyclylalkyl, the described C in wherein should encircling 2-C 5-Heterocyclylalkyl and C 6-C 10Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and in this ring optional one or more pairs of keys and this C of comprising 2-C 5The identical or different by cyano of the one or many of the ring of-Heterocyclylalkyl own, halogen, hydroxyl, aryl or by group-(CO)-R 5Or one or many is identical or differently by halogen or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, and wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces, and described C 6-C 10-Heterocyclylalkyl itself is chosen the identical or different by cyano of one or many, halogen, hydroxyl, aryl wantonly or by group-(CO)-R 5,-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, and wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces,
L represents group-O-R 7,-O-(CH 2) n-(CO)-NH-R 17Or-O-(CH 2) n-(CO)-O-R 8,
R 9Represent C 1-C 4-alkyl, C 2-C 4-thiazolinyl, cyclopropyl or C 2-C 10-Heterocyclylalkyl, its optional one or many is identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, C 2-C 10-Heterocyclylalkyl, cyano group, cyclopropyl, halogen, hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14Replace, wherein the described Heterocyclylalkyl in this ring comprises the atom of the white nitrogen of at least one identical or different choosing, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should the optional one or many of ring itself identical or differently by halogen, cyano group, hydroxyl, basic or by group-(CO)-R in addition 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces,
R 6Represent hydrogen, C 2-C 4-thiazolinyl, cyclopropyl, C 2-C 5-Heterocyclylalkyl, C 6-C 10-Heterocyclylalkyl or quilt are got the heteroaryl methyl in generation, or represent C 1-C 4-alkyl, C 2-C 4-thiazolinyl, cyclopropyl, C 2-C 5-Heterocyclylalkyl or C 6-C 10-Heterocyclylalkyl, its one or many is identical or differently by C 1-C 4-alkoxyl group, C 2-C 5-Heterocyclylalkyl, C 6-C 10-Heterocyclylalkyl, cyano group, cyclopropyl or by group-NR 12R 19,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14Replace the described C in wherein should encircling 2-C 5-Heterocyclylalkyl and C 6-C 10Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and in this ring optional one or more pairs of keys and this C of comprising 2-C 5The one or many of the ring of-Heterocyclylalkyl own is identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12, or-(SO 2)-R 14Or one or many is identical or differently by halogen, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkane very replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces, described C 6-C 10The optional one or many of the ring of-Heterocyclylalkyl itself is identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces.
Another theme of second embodiment of the invention is according to the compound of Formula I in the claim 22 of claim 9 and solvate, hydrate, diastereomer, enantiomorph and ship, wherein:
P represents group-OR 6,-NR 18R 19Or C 2-C 5-Heterocyclylalkyl, or represent C 6-C 10Heterocyclylalkyl, the described C in wherein should encircling 2-C 5-Heterocyclylalkyl and C 6-C 10Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group, and in this ring optional one or more pairs of keys and this C of comprising 2-C 5The repeatedly identical or different by cyano of the ring of-Heterocyclylalkyl itself, halogen, hydroxyl, aryl or by group-(CO)-R 5Or one or many is identical or differently by halogen or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, or described C 2-C 5The ring of-Heterocyclylalkyl itself is by group-(CO)-R 5Replace once, wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces, and described C 6-C 10The ring of-Heterocyclylalkyl itself is chosen the identical or different by cyano of one or many, halogen, hydroxyl, aryl wantonly or by group-(CO)-R 5Or-NR 12R 13Or the optional one or many of optional quilt is identical or differently by halogen, hydroxyl or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, and wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces,
R 5Represent C 1-C 4-alkyl or phenyl,
R 7The optional one or many of representative is identical or differently by C 6-C 10The C that-Heterocyclylalkyl replaces 1-C 3-alkyl, the described C in wherein should encircling 6-C 10-Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should choose the C that one or many is replaced by halogen by halogen, aryl or optional one or many identical or differently identical or differently wantonly by ring itself 1-C 3-alkyl replaces, or the optional one or many of representative is identical or differently by C 2-C 5The C that-Heterocyclylalkyl replaces 1-C 3-alkyl, the described C in wherein should encircling 2-C 5-Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and in this ring optional one or more pairs of keys and this C of comprising 2-C 5-heterocycloalkyl ring itself is replaced by halogen or aryl repeatedly identical or differently, or the C that is replaced by halogen by one or many identical or differently 1-C 3-alkyl replaces,
R 16Represent hydrogen, C 2-C 4-thiazolinyl, cyclopropyl, C 2-C 5-Heterocyclylalkyl, C 6-C 10Heterocyclylalkyl or the methyl that is replaced by heteroaryl, or represent C 1-C 4-alkyl, C 2-C 4-thiazolinyl, cyclopropyl, C 2-C 5-Heterocyclylalkyl or C 6-C 10-Heterocyclylalkyl, its one or many is identical or differently by C 1-C 4-alkoxyl group, C 2-C 5-Heterocyclylalkyl, C 6-C 10-Heterocyclylalkyl, cyano group, cyclopropyl or by group-NR 18R 19,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14Replace the described C in wherein should encircling 2-C 5-Heterocyclylalkyl and C 6-C 10Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group, and in this ring optional one or more pairs of keys and this C of comprising 2-C 5The ring of-Heterocyclylalkyl itself is repeatedly identical or differently by halogen, cyano group, hydroxyl or aryl or by group-(CO)-R 5,-(CO)-O-R 12Or-(SO 2)-R 14Replace, the optional one or many of wherein described in the case aryl itself is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, or this C 2-C 5The ring quilt of-Heterocyclylalkyl-(CO)-O-R 12,-(CO)-R 5Or the aryl replacement once, and the one or many of wherein described in the case aryl own is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, or described C 2-C 5The ring of-assorted bad alkyl by one or many identical or differently by halogen, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and described C 6-C 10The optional one or many of the ring of-Heterocyclylalkyl itself is identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces.
Another theme of second embodiment of the invention is according to the compound of Formula I in the claim 23 of claim 10 and solvate, hydrate, diastereomer, enantiomorph and salt, wherein:
P represents group-OR 6,-NR 18R 19Or C 2-C 5-Heterocyclylalkyl or represent C 6-C 10Heterocyclylalkyl, the described C in wherein should encircling 2-C 5-Heterocyclylalkyl and C 6-C 10Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and in this ring optional one or more pairs of keys and this C of comprising 2-C 5The repeatedly identical or different by cyano of the ring of-Heterocyclylalkyl itself, halogen, hydroxyl, aryl or by group-(CO)-R 5Or one or many is identical or differently by halogen or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, or C 2-C 5-heterocycloalkyl ring itself is by group-(CO)-R 5Replace once, wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces, and C 6-C 10-heterocycloalkyl ring itself is chosen the identical or different by cyano of one or many, halogen, hydroxyl, aryl wantonly or by group-(CO)-R 5,-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, and wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces,
R 5Represent C 1-C 4-alkyl or phenyl,
R 7The optional one or many of representative is identical or differently by C 6-C 10The C that-Heterocyclylalkyl replaces 1-C 3-alkyl, the described C in wherein should encircling 6-C 10-Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should choose the C that one or many is replaced by halogen by halogen, aryl or optional one or many identical or differently identical or differently wantonly by ring itself 1-C 3-alkyl replaces, or represents one or many identical or differently by C 2-C 5The C that-Heterocyclylalkyl replaces 1-C 3-alkyl, the described C in wherein should encircling 2-C 5-Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and in this ring optional one or more pairs of keys and this C of comprising 2-C 5-heterocycloalkyl ring itself is replaced by halogen or aryl repeatedly identical or differently, or the C that is replaced by halogen by one or many identical or differently 1-C 3-alkyl replaces,
R 16Represent hydrogen, C 2-C 4-thiazolinyl, cyclopropyl, C 2-C 5-Heterocyclylalkyl or C 6-C 10-Heterocyclylalkyl or represent C 1-C 4-alkyl, C 2-C 4-thiazolinyl, cyclopropyl, C 2-C 5-Heterocyclylalkyl or C 6-C 10-Duo cycloalkyl, its one or many is identical or differently by C 1-C 4-alkoxyl group, C 2-C 5-Heterocyclylalkyl, C 6-C 10-Heterocyclylalkyl, cyano group, cyclopropyl or by group-NR 18R 19,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14Replace the described C in wherein should encircling 2-C 5-Heterocyclylalkyl and C 6-C 10Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and in this ring optional one or more pairs of keys and this C of comprising 2-C 5The ring of-Heterocyclylalkyl itself is repeatedly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12Or-(SO 2)-R 14Replace, the optional in the case one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces, or this C 2-C 5The ring quilt of-Heterocyclylalkyl-(CO)-O-R 12,-(CO)-R 5Or the aryl replacement once, and the one or many of wherein described in the case aryl own is identical or differently by halogen or C 1-C 3-alkoxyl group replaces, or C 2-C 5The ring one or many of-Heterocyclylalkyl is identical or differently by halogen, C 1-C 3-alkylthio or phenyl replace, and described C 6-C 10The optional one or many of the ring of-cycloalkyl itself is identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR L2R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces.
Another theme of second embodiment of the invention is that wherein P represents group-OR according to compound of Formula I and solvate, hydrate, diastereomer, enantiomorph and salt in claim 9,10,22 or 23 the claim 24 6,-NR 18R 19Or representative azetidinyl, pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl, the octahydro isoquinolyl, the benzopyrrole alkyl, piperazinyl Si Qing oxazolyl, the piperazine ketone group, the thiazolidine base, imidazolidine quinoline ketone group, the benzo morpholinyl, triazine thioketones base, tetrahydro isoquinolyl or tetrahydric quinoline group, wherein pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl, the octahydro isoquinolyl, the benzopyrrole alkyl, piperazinyl Si Qing oxazolyl, the piperazine ketone group, the thiazolidine base, imidazolidine quinoline ketone group, the benzo morpholinyl, triazine thioketones base, tetrahydro isoquinolyl, the one or many of tetrahydric quinoline group own is identical or differently by halogen, hydroxyl, optional one or many own is identical or differently by halogen or C 1-C 3The phenyl that-alkoxyl group replaces or by group-(CO)-R 5Or the identical or different by cyano of one or many, halogen or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces.
Another theme of second embodiment of the invention is according to the compound of Formula I in claim 9,10,22,23 or 24 the claim 25, wherein R 18And R 19Represent C independently of each other 1-C 5-alkyl, pyrrolidyl, phenyl or pyridyl, their optional one or many are identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, wherein R 18And R 19Represent pyrrolidyl or pyridyl or represent one or many identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3Pyrrolidyl or pyridyl that-alkoxyl group replaces.
Another theme of second embodiment of the invention is that wherein K represents the C that one or many is replaced by P identical or differently according to claim 9,10,22,23,24 or 25 compound of Formula I 1-C 3-alkyl, or the C that represents one or many to be replaced by X identical or differently 2-C 4-thiazolinyl.
Another theme of second embodiment of the invention is that wherein K represents the C that one or many is replaced by P identical or differently according to claim 9,10,22,23,24 or 25 compound of Formula I 1-C 3-alkyl.
Another theme of second embodiment of the invention is that wherein P represents group-OR according to claim 9,10,22,23,24 or 25 compound of Formula I 6,-NR 18R 19, C 2-C 5-Heterocyclylalkyl or represent C 6-C 10Heterocyclylalkyl, the described C in wherein should encircling 2-C 5-Heterocyclylalkyl and C 6-C 10-Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group, but preferably do not have-(C=S)-, and in this ring optional one or more pairs of keys and this C of comprising 2-C 5The identical or different by cyano of the one or many of the ring of-Heterocyclylalkyl own, halogen, hydroxyl, aryl or by group-(CO)-R 5Or one or many is identical or differently by halogen or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, and wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces, and C 6-C 10-heterocycloalkyl ring itself is chosen the identical or different by cyano of one or many, halogen, hydroxyl, aryl wantonly or by group-(CO)-R 5,-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, and wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces.
Another theme of second embodiment of the invention is that wherein P represents group-OR according to claim 9,10,22,23,24 or 25 compound of Formula I 6,-NR 18R 19Or C 2-C 5-Heterocyclylalkyl, or represent C 6-C 10Heterocyclylalkyl, the described C in wherein should encircling 2-C 5-Heterocyclylalkyl and C 6-C 10-Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group, but preferably do not have-(C=S)-, and in this ring optional one or more pairs of keys and this C of comprising 2-C 5The identical or different by cyano of the one or many of the ring of-Heterocyclylalkyl own, halogen, hydroxyl, aryl or by group-(CO)-R 5Or one or many is identical or differently by halogen or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, or this C 2-C 5-heterocycloalkyl ring itself is by group-(CO)-R 5Replace once, wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces, and described C 6-C 10-heterocycloalkyl ring itself is chosen the identical or different by cyano of one or many, halogen, hydroxyl, aryl wantonly or by group-(CO)-R 5,-NR 12R 13Optional one or many is identical or differently by halogen, hydroxyl or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, and wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces.
Another theme of second embodiment of the invention is that wherein P represents group-OR according to claim 9,10,22,23,24 or 25 compound of Formula I 6Or-NR 18R L9Perhaps represent azetidinyl, pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl, the octahydro isoquinolyl, the benzopyrrole alkyl, piperazinyl Si Qing oxazolyl, the piperazine ketone group, the thiazolidine base, imidazolidine quinoline ketone group, the benzo morpholinyl, triazine thioketones base, tetrahydro isoquinolyl or tetrahydric quinoline group, wherein pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl, the octahydro isoquinolyl, the benzopyrrole alkyl, piperazinyl Si Qing oxazolyl, the piperazine ketone group, the thiazolidine base, imidazolidine quinoline ketone group, the benzo morpholinyl, triazine thioketones base, tetrahydro isoquinolyl, the one or many of tetrahydric quinoline group own is identical or differently by halogen, hydroxyl, optional one or many is identical or differently by halogen or C 1-C 3The phenyl that-alkoxyl group replaces or by group-(CO)-R 5Or the identical or different by cyano of one or many, halogen or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces.
In preferred embodiments, described pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl, octahydro isoquinolyl, benzopyrrole alkyl, piperazinyl, Si Qing oxazolyl, piperazine ketone group, thiazolidine base, imidazolidine quinoline ketone group, benzo morpholinyl, triazine thioketones base, tetrahydro isoquinolyl, the repeatedly identical or different by cyano of tetrahydric quinoline group itself, halogen, hydroxyl, aryl or by group-(CO)-R 5Or one or many is identical or differently by halogen or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, and wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces.
Another theme of second embodiment of the invention is that wherein L represents group-O-R according to claim 9,10,22,23,24 or 25 compound of Formula I 7,-O-(CH 2) n-(CO)-NH-R 17,-O-(CH 2) n-(CO)-R 15Or-O-(CH 2) n-(CO)-O-R 8L preferably represents group-O-R 7,-O-(CH 2) n-(CO)-NH-R 17Or-O-(CH 2) n-(CO)-O-R 8
Another theme of second embodiment of the invention is according to claim 9,10,22,23,24 or 25 compound of Formula I, wherein R 5Represent C 1-C 4-alkyl, phenyl or-NR 12R 13
Another theme of second embodiment of the invention is according to claim 9,10,22,23,24 or 25 compound of Formula I, wherein R 5Represent C 1-C 4-alkyl or phenyl.
Another theme of second embodiment of the invention is according to claim 9,10,22,23,24 or 25 compound of Formula I, wherein R 5Represent methylidene, ethyl, the tertiary butyl or phenyl.
Another theme of second embodiment of the invention is according to claim 9,10,22,23,24 or 25 compound of Formula I, wherein R 7The optional one or many of representative is identical or differently by C 6-C 10The C that-Heterocyclylalkyl replaces 1-C 3-alkyl, the described C in wherein should encircling 6-C 10Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should choose the C that one or many is replaced by halogen by halogen, aryl or optional one or many identical or differently identical or differently wantonly by ring itself 1-C 3-alkyl replaces, or the optional one or many of representative is identical or differently by C 2-C 5The C that-Heterocyclylalkyl replaces 1-C 3-alkyl, the described C in wherein should encircling 2-C 5-Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and in this ring optional one or more pairs of keys and this C of comprising 2-C 5The C that the one or many of-heterocycloalkyl ring own is replaced by halogen by halogen, aryl or one or many identical or differently identical or differently 1-C 3-alkyl replaces.
Another theme of second embodiment of the invention is according to claim 9,10,22,23,24 or 25 compound of Formula I, wherein R 7Represent C 1-C 3-alkyl, its optional one or many is identical or differently by C 6-C 10-Heterocyclylalkyl replaces, the described C in wherein should encircling 6-C 10Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should choose the C that one or many is replaced by halogen by halogen, aryl or optional one or many identical or differently identical or differently wantonly by ring itself 1-C 3-alkyl replaces, or represents one or many identical or differently by C 2-C 5The C that-Heterocyclylalkyl replaces 1-C 3-alkyl, the described C in wherein should encircling 2-C 5-Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and in this ring optional one or more pairs of keys and this C of comprising 2-C 5The C that the one or many of-heterocycloalkyl ring own is replaced by halogen by halogen or aryl or one or many identical or differently identical or differently 1-C 3-alkyl replaces.
Another theme of second embodiment of the invention is according to claim 9,10,22,23,24 or 25 compound of Formula I, wherein R 16Represent hydrogen, C 2-C 4-thiazolinyl, cyclopropyl, C 2-C 5-Heterocyclylalkyl, C 6-C 10The methyl that-Heterocyclylalkyl or representative are replaced by heteroaryl, but the methyl that preferred representative does not have heteroaryl to replace, or represent C 1-C 4-alkyl, C 2-C 4-thiazolinyl, cyclopropyl, C 2-C 5-Heterocyclylalkyl or C 6-C 10-Heterocyclylalkyl, its one or many is identical or differently by C 1-C 4-alkoxyl group, C 2-C 5-Heterocyclylalkyl, C 6-C 10-Heterocyclylalkyl, cyano group, cyclopropyl or by group-NR 18R 19,-O-(CO)-R 5,-(SO 2)-R 14Or O-(SO 2)-R 14Replace the described C in wherein should encircling 2-C 5-Heterocyclylalkyl and C 6-C 10-Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-CO)-,-(C=S)-or-SO 2-group, but preferably do not have-(C=S)-, and in this ring optional one or more pairs of keys and this C of comprising 2-C 5The one or many of the ring of-Heterocyclylalkyl own is identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or one or many is identical or differently by halogen, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, but does not preferably have C 1-C 3-alkyl replaces, and described C 6-C 10The optional one or many of-heterocycloalkyl ring itself is identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14,-NR L2R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces.
Another theme of second embodiment of the invention is according to claim 9,10,22,23,24 or 25 compound of Formula I, wherein R 16Represent hydrogen, but preferably do not represent hydrogen, represent C 2-C 4Base, C in-thiazolinyl, the ring 2-C 5-Heterocyclylalkyl, C 6-C 10The methyl that-Heterocyclylalkyl or representative are replaced by heteroaryl, but the methyl that preferred representative does not have heteroaryl to replace, or represent C 1-C 4-alkyl, C 2-C 4-thiazolinyl, cyclopropyl, C 2-C 5-Heterocyclylalkyl or C 6-C 10. Heterocyclylalkyl, its one or many is identical or differently by C 1-C 4-alkoxyl group, C 2-C 5-Heterocyclylalkyl, C 6-C 10-Heterocyclylalkyl, cyano group, cyclopropyl or by group-NR 18R 19,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14Replace the described C in wherein should encircling 2-C 5-Heterocyclylalkyl and C 6-C 10-Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group, but preferably do not have-(C=S)-, and in this ring optional one or more pairs of keys and this C of comprising 2-C 5The one or many of the ring of-Heterocyclylalkyl own is identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12Or-(SO 2)-R 14Replace, wherein said aryl itself is chosen one or many wantonly in the case identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, but does not preferably have C 1-C 3-alkyl replaces, or described C 2-C 5The ring quilt of-Heterocyclylalkyl-(CO)-O-R 12,-(CO)-R 5Or aryl replaces once, wherein in the case the one or many of this aryl own identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, but does not preferably have C 1-C 3-alkyl replaces, or place near the steps C 2-C 5The ring of-Heterocyclylalkyl by one or many identical or differently by halogen, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and described C 6-C 10The optional one or many of-heterocycloalkyl ring itself is identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14,-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces.
Another theme of second embodiment of the invention is according to claim 9,10,22,23,24 or 25 compound of Formula I, wherein R 17Represent one or many identical or differently by the C of halogen or cyano group replacement 1-C 3-alkyl, or the optional one or many of representative is identical or differently by the C of halogen, cyclopropyl or cyano group replacement 3-C 4-thiazolinyl or C 3-C 4-alkynyl.
Another theme of second embodiment of the invention is according to claim 9,10,22,23,24 or 25 compound of Formula I, wherein R 18And R 19The optional one or many of representative independently of each other is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3The C that-alkoxyl group replaces 1-C 5The bun of-alkane, C 2-C 10-Heterocyclylalkyl, aryl ,-(CH 2) n-aryl or heteroaryl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and in this ring optional one or more pairs of keys, the wherein R of comprising 18Or R 19Represent C 2-C 10-Heterocyclylalkyl ,-(CH 2) n-aryl or heteroaryl, or represent one or many identical or differently by halogen, C 1-C 3. alkyl or C 1-C 3The C that-alkoxyl group replaces 2-C 10-Heterocyclylalkyl ,-(CH 2) n-aryl or heteroaryl, or represent one or many identical or differently by C 1-C 3The C that-alkoxyl group replaces 1-C 5-alkyl, or represent one or many identical or differently by C 1-C 3-alkyl or C 1-C 3The aryl that-alkoxyl group replaces, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys.
Another theme of second embodiment of the invention is according to claim 9,10,22,23,24 or 25 compound of Formula I, wherein R 18And R 19Represent C independently of each other 1-C 5-alkyl, C 2-C 10-Heterocyclylalkyl, aryl or heteroaryl, its optional one or many is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, and wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and in this ring optional one or more pairs of keys, the wherein R of comprising 18Or R 19Represent C 2-C 10-Heterocyclylalkyl or heteroaryl, its one or many are identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, and wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of key institutes.
Another theme of second embodiment of the invention is according to claim 9,10,22,23,24 or 25 compound of Formula I, wherein R 18And R 19Represent C independently of each other 1-C 5-alkyl, pyrrolidyl, phenyl or pyridyl, its optional one or many is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, wherein R 18And R 19Represent pyrrolidyl or pyridyl respectively or represent one or many identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3Pyrrolidyl or pyridyl that-alkoxyl group replaces.
The 3rd embodiment of the present invention
The purpose of the 3rd embodiment of the present invention provides compared with prior art can suppress the kinase whose compound of polo sample better, and/or provide with prior art in disclosed compound compare compound with better physicochemical property.
In the 3rd embodiment of the present invention, found can realize purpose of the present invention, wherein according to compound and solvate, hydrate, diastereomer, enantiomorph and the salt of the general formula I in the claim 11 of claim 1 and/or 2
R 3Table K or L,
The C that the optional one or many of K representative is replaced by X identical or differently 1-C 3-alkyl, wherein said C 1-C 3The optional one or many of-alkyl is replaced by hydroxyl or halogen identical or differently,
X represents NR 10R 11Or represent C 2-C 10-Heterocyclylalkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose the identical or different by cyano of one or many, halogen, hydroxyl, aryl wantonly or by group-(CO)-R 5,-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, and wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces,
L represents group-O-R 7,
R 7Represent one or many quilt-NR identical or differently 12R 13Or C 2-C 10The C that-Heterocyclylalkyl replaces 1-C 3-alkyl, and the described Heterocyclylalkyl in this ring comprise at least one identical or different be selected from nitrogen, oxygen or sulphur former in, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should choose the C that one or many is replaced by halogen by halogen, aryl or optional one or many identical or differently identical or differently wantonly by ring itself 1-C 3-alkyl replaces.
Another theme of the 3rd embodiment of the present invention is according to the compound of the general formula I in the claim 12 of claim 11 and solvate, hydrate, diastereomer, enantiomorph and salt, wherein
X representative-N (C 1-C 3-alkyl) 2Or representative azetidinyl, pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl, the octahydro isoquinolyl, the benzopyrrole alkyl, piperazinyl Si Qing oxazolyl, the piperazine ketone group, the thiazolidine base, imidazolidine quinoline ketone group, the benzo morpholinyl, triazine thioketones base, tetrahydro isoquinolyl or tetrahydric quinoline group, wherein azetidinyl, pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl, the octahydro isoquinolyl, the benzopyrrole alkyl, piperazinyl Si Qing oxazolyl, the piperazine ketone group, the thiazolidine base, imidazolidine quinoline ketone group, the benzo morpholinyl, triazine thioketones base, the optional one or many of tetrahydro isoquinolyl or tetrahydric quinoline group itself is identical or differently by halogen, hydroxyl, optional one or many is identical or differently by halogen or C 1-C 3The phenyl that-alkoxyl group replaces or by group-(CO)-R 5Or the identical or different by cyano of one or many, halogen or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl,
R 7Represent one or many quilt-N (C identical or differently 1-C 3-alkyl) 2Or C 2-C 10The C that-Heterocyclylalkyl replaces 1-C 3-alkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys.
Another theme of the 3rd embodiment of the present invention is the compound according to the general formula I of claim 11 or 12, wherein R 3Represent K or L.
Another theme of the 3rd embodiment of the present invention is the compound according to the general formula I of claim 11 or 12, wherein the K C that can be replaced by X by one or many identical or differently 1-C 3-alkyl replaces, wherein said C 1-C 3The optional one or many of-alkyl is replaced by hydroxyl or halogen identical or differently.
The preferred theme of another of the 3rd embodiment of the present invention is the compound according to the general formula I of claim 11 or 12, and wherein the K representative is by X replacement C once 1-C 3-alkyl, wherein said C 1-C 3The optional one or many of-alkyl is replaced by hydroxyl or halogen identical or differently.This C 1-C 3-alkyl is preferably only replaced by X.
Another theme of the 3rd embodiment of the present invention is that wherein L represents group-O-R according to the compound of the general formula I of claim 11 or 12 7
Another theme of the 3rd embodiment of the present invention is that wherein X represents NR according to the compound of the general formula I of claim 11 or 12 10R 11Or represent C 2-C 10-Heterocyclylalkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, comprise at least one nitrogen in preferred embodiments, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group, preferably do not have-(C=S)-, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose the identical or different by cyano of one or many, halogen, hydroxyl, aryl wantonly or by group-(CO)-R 5,-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, and wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces.
Another theme of the 3rd embodiment of the present invention is the compound according to the general formula I of claim 11 or 12, wherein X represents azetidinyl, pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl, the octahydro isoquinolyl, the benzopyrrole alkyl, piperazinyl Si Qing oxazolyl, the piperazine ketone group, the thiazolidine base, imidazolidine quinoline ketone group, the benzo morpholinyl, triazine thioketones base, tetrahydro isoquinolyl or tetrahydric quinoline group, wherein azetidinyl, pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl, the octahydro isoquinolyl, the benzopyrrole alkyl, piperazinyl Si Qing oxazolyl, the piperazine ketone group, the thiazolidine base, imidazolidine quinoline ketone group, the benzo morpholinyl, triazine thioketones base, tetrahydro isoquinolyl, the optional one or many of tetrahydric quinoline group itself is identical or differently by halogen, hydroxyl, itself choose one or many wantonly identical or differently by halogen or C 1-C 3The phenyl that-alkoxyl group replaces or by group-(CO)-R 5Or the identical or different by cyano of one or many, halogen or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces.
In preferred embodiments, X represents unsubstituted azetidinyl, pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl, the octahydro isoquinolyl, the benzopyrrole alkyl, piperazinyl Si Qing oxazolyl, the piperazine ketone group, the thiazolidine base, imidazolidine quinoline ketone group, the benzo morpholinyl, triazine thioketones base, tetrahydro isoquinolyl or tetrahydric quinoline group, wherein pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl, the octahydro isoquinolyl, the benzopyrrole alkyl, piperazinyl Si Qing oxazolyl, the piperazine ketone group, the thiazolidine base, imidazolidine quinoline ketone group, the benzo morpholinyl, triazine thioketones base, tetrahydro isoquinolyl or tetrahydric quinoline group.
Another theme of the 3rd embodiment of the present invention is the compound according to the general formula I of claim 11 or 12, wherein X represents pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl or octahydro isoquinolyl, wherein the methyl substituted that replaced by halogen by halogen, hydroxyl or phenyl or optional one or many of the optional one or many of pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl or octahydro isoquinolyl itself identical or differently identical or differently.In preferred embodiments, pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl or octahydro isoquinolyl are not substituted.
Another theme of the 3rd embodiment of the present invention is the compound according to the general formula I of claim 11 or 12, wherein R 7Represent one or many quilt-NR identical or differently 12R 13Or C 2-C 10The C that-Heterocyclylalkyl replaces 1-C 3-alkyl, and the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, comprises at least one nitrogen in preferred embodiments, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should choose the C that one or many is replaced by halogen by halogen, aryl or optional one or many identical or differently identical or differently wantonly by ring itself 1-C 3-alkyl replaces.
Another theme of the 3rd embodiment of the present invention is the compound according to the general formula I of claim 11 or 12, wherein R 7Represent C 1-C 3-alkyl, its one or many is quilt-NR identical or differently 12R 13, preferred-N (C 1-C 3-alkyl) 2Or C 2-C 10-Heterocyclylalkyl replaces, but preferably only by C 2-C 10-Heterocyclylalkyl replaces, and wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, comprises at least one nitrogen in preferred embodiments, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should choose identical or different ground of one or many quilt wantonly by ring itself.
Another theme of the 3rd embodiment of the present invention is the compound according to the general formula I of claim 11 or 12, wherein R 7Represent C 1-C 3-alkyl, its optional one or many is quilt-N (C identical or differently 1-C 3-alkyl) 2, pyrrolidyl, morpholinyl or piperidyl replace.
The preferred theme of another of the 3rd embodiment of the present invention is the compound according to the general formula I of claim 11 or 12, wherein R 7Represent ethyl, its optional one or many is quilt-N (C identical or differently 1-C 3-alkyl) 2, pyrrolidyl, morpholinyl or piperidyl replace.
The preferred theme of another of the 3rd embodiment of the present invention is the compound according to the general formula I of claim 11 or 12, wherein R 7Represent ethyl, its optional one or many is quilt-N (CH identical or differently 3) 2, pyrrolidyl, morpholinyl or piperidyl replace.
The 4th embodiment of the present invention
The purpose of the 4th embodiment of the present invention provides compared with prior art can suppress the kinase whose compound of polo sample better, and/or provide with prior art in disclosed compound compare compound with better physicochemical property.
In the 4th embodiment of the present invention, found can especially easily realize purpose of the present invention, wherein according to compound and solvate, hydrate, diastereomer, enantiomorph and the salt of the general formula I in the claim 13 of claim 1 and/or 2
R 3Represent M,
M represents group-(NR 12-(CO)-R 16,
R 16The methyl of representing one or many to be replaced by following group: C identical or differently 1-C 4-alkoxyl group, C 2-C 10-Heterocyclylalkyl, heteroaryl, cyano group, cyclopropyl, halogen, hydroxyl or group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14, the optional one or many of wherein said methyl itself is identical or differently by C 1-C 3-alkyl replaces, and wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-,-(C=S)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14,-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces.
According to the 4th embodiment of the present invention, wherein R 3Represent M, M to represent group-NR 12-(CO)-R 16, and R 16The compound of Formula I of represent methylidene is particularly suitable for realizing purpose of the present invention, and this methyl is at least by C 2-C 10-Heterocyclylalkyl, heteroaryl or by group-NR 10R 11Replace, and this Heterocyclylalkyl and heteroaryl comprise at least one nitrogen-atoms.
Another theme of the 4th embodiment of the present invention is according to the compound of the general formula I in the claim 14 of claim 13 and solvate, hydrate, diastereomer, enantiomorph and salt, wherein
R 16The methyl of representing one or many to be replaced by following group: C identical or differently 2-C 10-Heterocyclylalkyl, heteroaryl or group-NR 10R 11, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14,-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces.
Another theme of the 4th embodiment of the present invention is the compound according to the general formula I of claim 13 or 14, wherein R 3Represent M.
Another theme of the 4th embodiment of the present invention is that wherein M represents group-NR according to the compound of the general formula I of claim 13 or 14 12-(CO)-R 16
Another theme of the 4th embodiment of the present invention is the compound according to the general formula I of claim 13 or 14, wherein R 16Represent methylidene, its one or many is identical or differently by C 1-C 4-alkoxyl group, C 2-C 10-Heterocyclylalkyl, heteroaryl, cyano group, cyclopropyl, halogen, hydroxyl or by group NR 10R 11,-O-(CO)-R 5, (SO 2)-R 14Or-O-(SO 2)-R 14Replace, preferably do not have heteroaryl to replace, the optional one or many of wherein said methyl itself is identical or differently by C 1-C 3-alkyl replaces, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and comprise at least one nitrogen-atoms in preferred embodiments, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group, preferably do not have-(C=S)-, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14, NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, and does not preferably have C 1-C 3-alkyl replaces.
Another theme of the 4th embodiment of the present invention is the compound according to the general formula I of claim 13 or 14, wherein R 16Represent methylidene, its one or many is identical or differently by C 2-C 10-Heterocyclylalkyl, heteroaryl or by group-NR 10R 11Replace, preferably there is not heteroaryl to replace, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and comprise at least one nitrogen-atoms in preferred embodiments, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group, preferably do not have-(C=S)-, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14,-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, and does not preferably have C 1-C 3-alkyl replaces.In preferred embodiments, the ring of described Heterocyclylalkyl is unsubstituted.
Another theme of the 4th embodiment of the present invention is the compound according to the general formula I of claim 13 or 14, wherein R 16Represent methylidene, its one or many is replaced by following group identical or differently: pyrrolidyl, piperidyl, piperazinyl, thio-morpholinyl, benzopyrrole alkyl, tetrahydric quinoline group, four hydrogen oxazolyls, piperazine ketone group, thiazolidine base, imidazolidine quinoline ketone group, benzo morpholinyl, tetrahydrochysene triazolinthione base, morpholinyl, tetrahydro isoquinolyl, octahydro isoquinolyl, imidazolyl or benzimidazolyl-or by group-NR 10R 11Preferably there are not imidazolyl or benzimidazolyl-to replace, wherein the optional one or many of pyrrolidyl, piperidyl, piperazinyl, thio-morpholinyl, benzopyrrole alkyl, tetrahydric quinoline group, Si Qing oxazolyl, piperazine ketone group, thiazolidine base, imidazolidine quinoline ketone group, benzo morpholinyl, tetrahydrochysene triazolinthione base, morpholinyl, tetrahydro isoquinolyl, octahydro isoquinolyl itself is replaced by halogen, hydroxyl or phenyl identical or differently, or by group-(CO)-R 5,-(CO)-O-R 5,-(SO 2)-R 14,-N (CH 3) 2Or optional one or many replaces by methyl or the ethyl that halogen, hydroxyl, methylthio group or phenyl replace identical or differently, and wherein said phenyl itself is chosen one or many wantonly identical or differently by halogen or C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, and does not preferably have C 1-C 3-alkyl replaces.In preferred embodiments, described pyrrolidyl, piperidyl, piperazinyl, thio-morpholinyl, benzopyrrole alkyl, tetrahydric quinoline group, Si Qing oxazolyl, piperazine ketone group, thiazolidine base, imidazolidine quinoline ketone group, benzo morpholinyl, tetrahydrochysene triazolinthione base, morpholinyl, tetrahydro isoquinolyl or described octahydro isoquinolyl are unsubstituted.
The 5th embodiment of the present invention
In the 5th embodiment of the present invention, find that compound and solvate, hydrate, diastereomer, enantiomorph and the salt of general formula I can suppress polo sample kinases better, it can suppress polo sample kinases in the nmole scope,
Figure A20058004839600471
Wherein
T 1, T 2And T 3Independently of each other representative-CH=or-N=,
U representative-CR 4=or-N=,
R 1The C that the optional one or many of representative is replaced by halogen identical or differently 1-C 3-alkyl or cyclopropyl,
R 2The C that the optional identical or different by cyano of one or many of representative, cyclopropyl, ethynyl or halogen replace 1-C 3-alkyl, C 3-C 4-thiazolinyl, C 3-C 4-alkynyl or cyclopropyl, or represent at least once by methyl substituted hydroxyethyl,
R 3Represent K, L or M,
The C that the optional one or many of K representative is replaced by X identical or differently 1-C 3-alkyl or C 2-C 4-thiazolinyl,
X represents halogen, hydroxyl or represents group-OR 6,-NR 10R 11Or represent C 2-C 10-Heterocyclylalkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose the identical or different by cyano of one or many, halogen, hydroxyl, aryl wantonly or by group-(CO)-R 5,-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces,
L represents group-O-R 7,-O-(CH 2) n-(CO)-NH-R 8Or-O-(CH 2) n-(CO)-O-R 8,
M represents group-NH-R 9,-NH-(CO)-O-R 9Or NR 12-(CO)-R 9,
R 4The methyl of representing the optional one or many of hydrogen, cyano group or halogen or representative to be replaced by halogen identical or differently,
R 5Represent C 1-C 4-alkyl, phenyl or-SR 12R 13,
R 6Representative-SO 2-R 14,
R 7The optional one or many of representative is quilt-NR identical or differently 12R 13Or C 2-C 10The C that-Heterocyclylalkyl replaces 1-C 3-alkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should choose the C that one or many is replaced by halogen by halogen, aryl or optional one or many identical or differently identical or differently wantonly by ring itself 1-C 3-alkyl replaces,
R 8The C that the optional identical or different by cyano of one or many of representative, cyclopropyl or halogen replace 1-C 3-alkyl, C 3-C 4-thiazolinyl or C 3-C 4-alkynyl,
R 9Represent hydrogen or represent C 1-C 4-alkyl, C 2-C 4-thiazolinyl, cyclopropyl or C 2-C 10-Heterocyclylalkyl, its optional one or many is identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, C 2-C 10-Heterocyclylalkyl, cyano group, cyclopropyl, halogen, hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14Replace, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14,-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces,
R 10And R 11Represent C independently of each other 1-C 5-alkyl, C 2-C 10-Heterocyclylalkyl, aryl ,-(CH 2) n-aryl or heteroaryl, its optional one or many is identical or differently by halogen, C 1-C 3-alkyl, C 1-C 3-alkoxyl group replaces, and wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys,
R 12And R 13Represent hydrogen or C independently of each other 1-C 4-alkyl,
R 14Represent C 1-C 3-alkyl or represent aryl, and
N represents 1-4.
But do not comprise following compound:
2-[5-[1-(the amino phenyl amino of 3-)-first-(E/Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-2-cyano group-N-ethyl-ethanamide,
2-cyano group-N-ethyl-2-[3-ethyl-5-[1-{3-[2-(2-methoxyl group-oxyethyl group)-acyl amino]-phenyl amino }-first-(E/Z)-subunit]-4-oxo-thiazolidine-(2-(E or Z))-subunit]-ethanamide,
2-cyano group-2-[5-[1-[3-(2,2-dimethyl-propionyl amino)-phenyl amino]-first-(E/Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-N-ethyl-ethanamide,
2-cyano group-N-ethyl-2-[3-ethyl-4-oxo-5-[1-[3-(3-tetramethyleneimine-1-base-propionyl amino)-phenyl amino]-first-(E/Z)-subunit]-thiazolidine-(2-(E or Z))-subunit]-ethanamide,
2-cyano group-2-[5-[1-[3-(2,2-dimethyl-propionyl amino)-phenyl amino]-first-(E/Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-N-(2-hydroxyl-1,1-dimethyl-ethyl)-ethanamide,
2-cyano group-2-[5-[1-[3-(2,2-dimethyl-propionyl tomb amino)-phenyl amino]-first-(E/Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-N-Propargyl-ethanamide,
2-cyano group-2-[3-ethyl-4-oxo-5-[1-[3-(3-tetramethyleneimine-1-base-propionyl amino)-phenyl amino]-first-(E/Z)-subunit]-thiazolidine-(2-(E or Z))-subunit]-N-Propargyl-ethanamide,
2-cyano group-2-[3-ethyl-4-oxo-5-[1-[3-(3-tetramethyleneimine-1-base-propionyl amino)-phenyl amino]-first-(E/Z)-subunit]-thiazolidine-(2-(E or Z))-subunit]-N-(2,2,2-three fluoro-ethyls)-ethanamide,
2-cyano group-N-cyclopropyl methyl-2-[3-ethyl-4-oxo-5-[1-[3-(3-tetramethyleneimine-1-base-propionyl amino)-phenyl amino]-first-(E/Z)-subunit]-thiazolidine-(2-(E or Z))-subunit]-ethanamide,
N-allyl group-2-cyano group-2-[3-ethyl-4-oxo-5-[1-[3-(3-tetramethyleneimine-1-base-propionyl amino)-phenyl amino]-first-(E/Z)-subunit]-thiazolidine-(2-(E or Z))-subunit]-ethanamide,
2-cyano group-2-[5-[1-[3-(2,2-dimethyl-propionyl amino)-phenyl amino]-first-(E/Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-N-methyl-ethanamide
2-cyano group-2-[5-[1-[3-(2,2-dimethyl-propionyl amino)-phenyl amino]-first-(E/Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-N-((S)-2-hydroxyl-1-methyl-ethyl)-ethanamide
2-cyano group-2-[3-ethyl-4-oxo-5-[1-[3-(3-tetramethyleneimine-1-base-propionyl amino)-phenyl amino]-first-(E/Z)-subunit]-thiazolidine-(2-(E or Z))-subunit]-N-(2-methyl-allyl group)-ethanamide
2-cyano group-2-[3-ethyl-4-oxo-5-[1-[3-(3-tetramethyleneimine-1-base-propionyl amino)-phenyl amino]-first-(E/Z)-subunit]-thiazolidine-(2-(E or Z))-subunit]-N-(2-methoxyl group-1-methyl-ethyl)-ethanamide
2-cyano group-2-[3-ethyl-4-oxo-5-[1-[3-(3-tetramethyleneimine-1-base-propionyl amino)-phenyl amino]-first-(E/Z)-subunit]-thiazolidine-(2-(E or Z))-subunit]-N-(2-hydroxyl-propyl group)-ethanamide
2-cyano group-N-cyclopropyl-2-[3-ethyl-4-oxo-5-[1-[3-(3-tetramethyleneimine-1-base-propionyl amino)-phenyl amino]-first-(E/Z)-subunit]-thiazolidine-(2-(E or Z))-subunit]-ethanamide
2-cyano group-2-[3-ethyl-4-oxo-5-[1-[3-(3-tetramethyleneimine-1-base-propionyl amino)-phenyl amino]-first-(E/Z)-subunit]-thiazolidine-(2-(E or Z))-subunit]-N-(2-methoxyl group-ethyl)-ethanamide
2-cyano group-2-[3-ethyl-4-oxo-5-[1-[3-(3-tetramethyleneimine-1-base-propionyl amino)-phenyl amino]-first-(E/Z)-subunit]-thiazolidine-(2-(E or Z))-subunit]-N-propyl group-ethanamide
2-cyano group-2-[3-ethyl-4-oxo-5-[1-[3-(3-tetramethyleneimine-1-base-propionyl amino)-phenyl amino]-first-(E/Z)-subunit]-thiazolidine-(2-(E or Z))-subunit]-N-(2-hydroxyl-1-methyl-ethyl)-ethanamide
2-cyano group-N-(cyano group-dimethyl-methyl)-2-[3-ethyl-4-oxo-5-[1-[3-(3-tetramethyleneimine-1-base-propionyl amino)-phenyl amino]-first-(E/Z)-subunit]-thiazolidine-(2-(E or Z))-subunit]-ethanamide
Particularly preferably be compound and solvate, hydrate, diastereomer, enantiomorph and the salt of following general formula I, wherein
T 1, T 2And T 3Independently of each other representative-CH=or-N=,
U representative-CR 4=or-N=,
R 1The C that the optional one or many of representative is replaced by halogen identical or differently 1-C 3-alkyl or cyclopropyl,
R 2The C that the optional identical or different by cyano of one or many of representative, cyclopropyl, ethynyl or halogen replace 1-C 3-alkyl, C 3-C 4-thiazolinyl, C 3-C 4-alkynyl or cyclopropyl, or represent at least by methyl substituted hydroxyethyl once,
R 3Represent K, L or M,
The C that the optional one or many of K representative is replaced by X identical or differently 1-C 3-alkyl or C 2-C 4-thiazolinyl,
X represents halogen, hydroxyl or represents group-OR 6,-NR 10R 11Or represent C 2-C 10-Heterocyclylalkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-NR 12R 13Or optional one or many is identical or differently by halogen rope, hydroxyl or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, and wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces,
L represents group-O-R 7,-O-(CH 2) n-(CO)-NH-R 8Or-O-(CH 2) n-(CO)-O-R 8, M represents group-NH-R 9,-NH-(CO)-O-R 9Or-NR 12-(CO)-R 9,
R 4Represent hydrogen, cyano group or halogen, or the methyl of representing optional one or many to be replaced by halogen, identical or differently
R 5Represent C 1-C 4-alkyl, phenyl or-NR 12-R 13,
R 6Representative-SO 2-R 14,
R 7The optional one or many of representative is quilt-NR identical or differently 12R 13Or C 2-C 10The C that-Heterocyclylalkyl replaces 1-C 3-alkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys,
R 8The C that the optional identical or different by cyano of one or many of representative, cyclopropyl or halogen replace 1-C 3-alkyl, C 3-C 4-thiazolinyl or C 3-C 4-alkynyl,
R 9Represent hydrogen, or represent C 1-C 4-alkyl, C 2-C 4-thiazolinyl, cyclopropyl or C 2-C 10-Heterocyclylalkyl, its optional one or many is identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, C 2-C 10-Heterocyclylalkyl, cyano group, cyclopropyl, halogen, hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 12Replace, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should the optional one or many of ring itself identical or differently by halogen, cyano group, hydroxyl, choose one or many wantonly identical or differently by halogen or C 1-C 3The phenyl that-alkoxyl group replaces or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14,-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, R 10And R 11Represent C independently of each other 1-C 5-alkyl, C 2-C 10-Heterocyclylalkyl, aryl or heteroaryl, its optional one or many is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, and wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys,
R 12And R 13Represent hydrogen or C independently of each other 1-C 4-alkyl,
R 14Represent C 1-C 3-alkyl or represent phenyl, and
N represents 1-4.
In addition, the compound of the general formula I that is preferably as follows and solvate thereof, hydrate, diastereomer, enantiomorph and salt, wherein
T 1, T 2And T 3Independently of each other representative-CH=or-N=,
U representative-CR 4=or-N=,
R 1Methyl, ethyl, sec.-propyl or cyclopropyl that the optional one or many of representative is replaced by halogen identical or differently,
R 2Methyl, ethyl, allyl group or propargyl that the optional identical or different by cyano of one or many of representative, cyclopropyl, ethynyl or halogen replace, or represent at least by methyl substituted hydroxyethyl once,
R 3Represent K, L or M,
The C that the optional one or many of K representative is replaced by X identical or differently 1-C 3-alkyl or C 2-C 4-thiazolinyl, X are represented halogen, hydroxyl, or represent group-OR 6,-NR 10R 11Or representative azetidinyl, pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl, the octahydro isoquinolyl, the benzopyrrole alkyl, piperazinyl Si Qing oxazolyl, the piperazine ketone group, the thiazolidine base, imidazolidine quinoline ketone group, the benzo morpholinyl, triazine thioketones base, tetrahydro isoquinolyl or tetrahydric quinoline group, wherein pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl, the octahydro isoquinolyl, the benzopyrrole alkyl, piperazinyl Si Qing oxazolyl, the piperazine ketone group, the thiazolidine base, imidazolidine quinoline ketone group, the benzo morpholinyl, triazine thioketones base, the optional one or many of tetrahydro isoquinolyl or tetrahydric quinoline group itself is identical or differently by halogen, hydroxyl or optional one or many itself are identical or differently by halogen or C 1-C 3The phenyl that-alkoxyl group replaces or by group-(CO)-R 5,-NR 12R 13Or the identical or different by cyano of optional one or many, halogen, hydroxyl or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces,
L represents group-O-R 7,-O-(CH 2) n-(CO)-NH-R 8Or-O-(CH 2) n-(CO)-O-R 8-
On behalf of base, M close-NH-R 9,-NH-(CO)-R 9,-NH-(CO)-O-R 9Or-NR 12-(CO)-R 9,
R 4Represent hydrogen or halogen, or the methyl of representing optional one or many to be replaced by halogen, identical or differently
R 5Represent methylidene, ethyl, the tertiary butyl, phenyl or-NH 2,
R 6Representative-SO 2-methyl,
R 7The optional one or many of representative is quilt-N (C identical or differently 1-C 3-alkyl) 2, the C that replaces of pyrrolidyl, morpholinyl or piperidyl 1-C 3-alkyl,
R 8Methyl, ethyl, allyl group or propargyl that the optional identical or different by cyano of one or many of representative, cyclopropyl or halogen replace,
R 9Represent hydrogen or represent methylidene, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, vinyl, cyclopropyl, THP trtrahydropyranyl or tetrahydrofuran base, its optional one or many is identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, pyrrolidyl, piperidyl, piperazinyl, thio-morpholinyl, benzopyrrole alkyl, tetrahydric quinoline group, Si Qing oxazolyl, piperazine ketone group, four oxygen thiazolyls, imidazolidine quinoline ketone group, benzo morpholinyl, tetrahydrochysene triazolinthione base, morpholinyl, tetrahydro isoquinolyl, octahydro isoquinolyl, cyano group, cyclopropyl, halogen, hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-C 1-C 3-alkyl replaces, and wherein the optional one or many of pyrrolidyl, piperidyl, piperazinyl, thio-morpholinyl, benzopyrrole alkyl, tetrahydric quinoline group, Si Qing oxazolyl, piperazine ketone group, thiazolidine base, imidazolidine quinoline ketone group, benzo morpholinyl, tetrahydrochysene triazolinthione base, morpholinyl, tetrahydro isoquinolyl or octahydro isoquinolyl itself is identical or differently by halogen, hydroxyl, phenyl or C 1-C 3-alkoxyl group or by group-(CO)-R 5,-(CO)-O-R 5,-(SO 2)-R 14Or-N (CH 3) 2Or the methyl substituted that replaced by halogen, hydroxyl, methylthio group or phenyl of optional one or many, identical or differently
R 10And R 11Represent C independently of each other 1-C 5-alkyl, pyrrolidyl, phenyl or pyridyl, its optional one or many is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces,
R 12And R 13Represent oxygen or methyl, ethyl or sec.-propyl independently of each other,
R 14Represent C 1-C 4-alkyl or represent phenyl, and
N represents 1 or 2.
In addition, the compound of the general formula I that is preferably as follows and solvate thereof, hydrate, diastereomer, enantiomorph and salt, wherein
T 1, T 2And T 3Independently of each other representative-CH=or-N=,
U representative-CH=,-CF=,-C (CH 3)=or-N=,
R 2Methyl, ethyl, sec.-propyl or cyclopropyl that the optional one or many of representative is replaced by fluorine identical or differently,
R 2Methyl, ethyl, allyl group or propargyl that the optional identical or different by cyano of one or many of representative, cyclopropyl, ethynyl or fluorine replace, or represent at least once by methyl substituted hydroxyethyl,
R 3Represent K, L or M,
Methyl, ethyl or vinyl that the optional one or many of K representative is replaced by X identical or differently,
X represents halogen, hydroxyl or represents group-O-SO 2-methyl or represent pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl or octahydro isoquinolyl, wherein pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl or octahydro isoquinolyl itself chosen the methyl substituted that one or many is replaced by halogen by halogen, hydroxyl, phenyl or optional one or many identical or differently identical or differently wantonly
L represents group-O-R 7,-O-(CH 2)-(CO)-NH-R 8Or-O-(CH 2)-(CO)-O-R 8,
M represents group-NH 2,-NH-R 9,-NH-(CO)-R 9,-NH-(CO)-O-R 9Or-N (CH 3)-(CO)-R 9,
R 7The optional one or many of representative is quilt-N (C identical or differently 1-C 3-alkyl) 2, the ethyl that replaces of pyrrolidyl, morpholinyl or piperidyl,
R 8Methyl, ethyl, allyl group or propargyl that the optional identical or different by cyano of one or many of representative, cyclopropyl or fluorine replace, and
R 9Represent methylidene, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, vinyl, cyclopropyl, THP trtrahydropyranyl or tetrahydrofuran base, its optional one or many is identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, cyano group, cyclopropyl, halogen, hydroxyl or by group-N (C 1-C 3-alkyl) 2,-O-(CO)-(C 1-C 3-alkyl) or-O-(SO 2)-C 1-C 3-alkyl replaces, and wherein pyrrolidyl, piperidyl, piperazinyl, morpholinyl or thio-morpholinyl itself chosen one or many wantonly identical or differently by halogen or by group-(CO)-C 1-C 4-alkyl ,-(CO)-O-C 1-C 4-alkyl ,-(SO 2)-C 1-C 3-alkyl ,-(SO 2)-phenyl ,-N (C 1-C 3-alkyl) 2Or chosen wantonly one or many identical or differently by halogen, hydroxyl or C 1-C 3Methyl that-alkylthio replaces or ethyl replace.
In addition, the compound of the general formula I that is preferably as follows and solvate thereof, hydrate, diastereomer, enantiomorph and salt, wherein
T 1, T 2And T 3Independently of each other representative-CH=or-N=,
U representative-CH=,-CF=,-C (CH 3)=or-N=,
R 1Represent ethyl,
R 2Methyl, ethyl, allyl group or propargyl that the optional identical or different by cyano of one or many of representative, cyclopropyl, ethynyl or fluorine replace, or represent at least by methyl substituted hydroxyethyl at least once,
R 3Represent K, L or M,
Methyl, ethyl or vinyl that the optional one or many of K representative is replaced by X identical or differently,
X represents iodine, hydroxyl or represents group-O-SO 2-methyl or represent pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl or octahydro isoquinolyl, wherein pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl or octahydro isoquinolyl itself chosen the methyl substituted that one or many is replaced by halogen by halogen, hydroxyl, phenyl or optional one or many identical or differently identical or differently wantonly
L represents group-O-R 7,-O-(CH 2)-(CO)-NH-R 8Or-O-(CH 2)-(CO)-O-R 8,
M represents group-NH 2,-NH-R 9,-NH-(CO)-R 9,-NH-(CO)-O-R 9,-N (CH 3)-(CO)-R 9Or-N (CH 3)-R 9,
R 7The optional one or many of representative is quilt-N (CH identical or differently 3) 2, the ethyl that replaces of pyrrolidyl, morpholinyl or piperidyl,
R 8Methyl, ethyl, allyl group or propargyl that the optional identical or different by cyano of one or many of representative, cyclopropyl or fluorine replace, and
R 9Represent methylidene, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, vinyl, cyclopropyl, THP trtrahydropyranyl or tetrahydrofuran base, its optional one or many are identical or differently by methoxyl group, oxyethyl group, butoxy-oxyethyl group, methoxyl group-oxyethyl group, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, cyano group, cyclopropyl, chlorine, fluorine, hydroxyl or by group-N (CH 3) 2,-N (CH 3) (C 2H 5) ,-O-(CO)-(CH 3) or-O-(SO 2)-methyl substituted, wherein the optional one or many ground of pyrrolidyl, piperidyl, piperazinyl, morpholinyl or thio-morpholinyl itself is replaced by fluorine, perhaps can be by group-(CO)-CH 3,-(CO)-C 2H 5,-(CO)-C (CH 3) 3,-(CO)-O-C (CH 3) 3,-(SO 2)-CH 3,-(SO 2)-phenyl ,-N (CH 3) 2Or optional one or many is replaced by methyl or the ethyl that fluorine, hydroxyl or methylthio group replace identical or differently.
In addition, the compound of the general formula I that is preferably as follows and solvate thereof, hydrate, diastereomer, enantiomorph and salt, wherein
T 1, T 2And T 3Independently of each other representative-CH=or-N=, and also additionally representative of T2 (CF)=, and T 1, T 2Or
T 3In at least one substituting group representative-N=,
U representative-CH=,
R 1Represent ethyl,
R 2Methyl, ethyl or propargyl that optional identical or different by cyano of one or many of representative or fluorine replace, or represent at least by methyl substituted hydroxyethyl once,
R 3Represent M,
M represents group-NH-(CO)-R 9,
R 9The optional methyl or the tertiary butyl that is replaced by methoxyl group-oxyethyl group of representative.
In addition, the compound of the general formula I that is preferably as follows and solvate thereof, hydrate, diastereomer, enantiomorph and salt, wherein
T 1, T 2And T 3Representative-CH=,
U representative-N=
R 1Represent ethyl,
R 2Methyl, ethyl or propargyl that optional identical or different by cyano of one or many of representative or fluorine replace, or represent at least by methyl substituted hydroxyethyl once,
R 3Represent M,
M represents group-NH-R 9,
R 9Represent ethyl.
Theme of the present invention also comprises as the general formula I I compound of intermediate product and solvate, hydrate, diastereomer, enantiomorph and salt,
Figure A20058004839600561
Wherein, R 1And R 2Has the definition described in general formula I.
Below statement relates to first and second embodiments of the present invention equally:
Another theme of first and second embodiments of the present invention is the compound of Formula I according to one of claim 1-10, wherein R 3Represent K, L or M or represent R 15, and preferred R wherein 3Represent K, L or M.
Another theme of first and second embodiments of the present invention is the compound of Formula I according to one of claim 1-10, and wherein X represents halogen, hydroxyl or represents group-OR 6Or-NR 10R 11Or represent C 2-C 10-Heterocyclylalkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group, preferably do not have-(C=S)-, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose the identical or different by cyano of one or many, halogen, hydroxyl, aryl wantonly or by group-(CO)-R 5Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, and wherein said aryl itself is optional by cyano group, halogen or C 1-C 3-alkoxyl group replaces.
Another theme of first and second embodiments of the present invention is the compound of Formula I according to one of claim 1-10, and wherein X represents halogen, hydroxyl or represents group-OR 6,-NR 10R 11Or representative azetidinyl, pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl, the octahydro isoquinolyl, the benzopyrrole alkyl, piperazinyl Si Qing oxazolyl, the piperazine ketone group, the thiazolidine base, imidazolidine quinoline ketone group, the benzo morpholinyl, triazine thioketones base, tetrahydro isoquinolyl or tetrahydric quinoline group, pyrrolidyl wherein, morpholinyl, thio-morpholinyl, piperidyl, the octahydro isoquinolyl, the benzopyrrole alkyl, piperazinyl Si Qing oxazolyl, the piperazine ketone group, the thiazolidine base, imidazolidine quinoline ketone group, the benzo morpholinyl, triazine thioketones base, tetrahydro isoquinolyl, or the optional one or many of tetrahydric quinoline group itself is identical or differently by halogen, hydroxyl or optional one or many itself are identical or differently by halogen or C 1-C 3The phenyl that-alkoxyl group replaces or by group-(CO)-R 5Or-NR 12R 13Or the identical or different by cyano of optional one or many, halogen, hydroxyl or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces.
Another theme of first and second embodiments of the present invention is the compound of Formula I according to one of claim 1-10, and wherein X represents halogen, hydroxyl or represents group-O-SO 2-methyl or represent pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl or octahydro isoquinolyl, the wherein methyl substituted that replaced by halogen by halogen, hydroxyl, phenyl or optional one or many of the optional one or many of pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl or octahydro isoquinolyl itself identical or differently identical or differently.
Another theme of first and second embodiments of the present invention is the compound of Formula I according to one of claim 1-10, and wherein X represents iodine or hydroxyl, or represents group-O-SO 2-methyl or represent pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl or octahydro isoquinolyl, the wherein methyl substituted that replaced by halogen by halogen, hydroxyl, phenyl or optional one or many of the optional one or many of pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl or octahydro isoquinolyl itself identical or differently identical or differently.
Another theme of first and second embodiments of the present invention is that wherein M represents group-NH-R according to the compound of Formula I of one of claim 1-10 9,-NH-(CO)-OH ,-NH-(CO)-O-R 9Or-R 12-(CO)-R 16
The preferred theme of another of first and second embodiments of the present invention is that wherein M represents group-NH-R according to the compound of Formula I of one of claim 1-10 9,-NH-(CO)-R 16,-NH-(CO)-O-R 9Or-N (CH 3)-(CO)-R 16
Another theme of first and second embodiments of the present invention is the compound of Formula I according to one of claim 1-10, wherein R 7Represent C 1-C 3-alkyl, its optional one or many is quilt-NR identical or differently 12R 13Or C 2-C 10--Heterocyclylalkyl replaces, wherein the described Heterocyclylalkyl in this ring comprise at least one identical or different be selected from nitrogen, oxygen or sulphur-atom, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should choose the C that one or many is replaced by halogen by halogen, aryl or optional one or many identical or differently identical or differently wantonly by ring itself 1-C 3-alkyl replaces.
Another theme of first and second embodiments of the present invention is the compound of Formula I according to one of claim 1-10, wherein R 7Represent C 1-C 3-alkyl, its optional one or many is quilt-NR identical or differently 12R 13Or C 2-C 10-Heterocyclylalkyl replaces, and wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys.
Another theme of first and second embodiments of the present invention is the compound of Formula I according to one of claim 1-10, wherein R 7The optional one or many of representative is quilt-N (C identical or differently 1-C 3-alkyl) 2, the C that replaces of pyrrolidyl, morpholinyl or piperidyl 1-C 3-alkyl.
The preferred theme of another of first and second embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 7The optional one or many of representative is quilt-N (C identical or differently 1-C 3-alkyl) 2, the ethyl that replaces of pyrrolidyl, morpholinyl or piperidyl.
The preferred theme of another of first and second embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 7The optional one or many of representative is quilt-N (CH identical or differently 3) 2, the ethyl that replaces of pyrrolidyl, morpholinyl or piperidyl.
Below statement relates to third and fourth embodiment of the present invention equally:
Another theme of third and fourth embodiment of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 5Represent C 1-C 4-alkyl, phenyl or-NR 12R 13
The preferred theme of another of third and fourth embodiment of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 5Represent methylidene, ethyl, the tertiary butyl, phenyl or-NH 2
Below statement relates to preceding four embodiments of the present invention equally:
Another theme of preceding four embodiments of the present invention is general formula 1 compound according to one of claim 1-14, wherein T 1, T 2And T 3Independently of each other representative-CH=or-N=, and T 2Also can represent in addition (CF)=.
A theme of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein T 1, T 2And T 3Independently of each other representative-CH=or-N=.
Another theme of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein U representative-CR 4=or-N=.
The preferred theme of another of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein U representative-CH=,-CF=,-C (CH 3)=or-N=.
Another theme of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 1The C that the optional one or many of representative is replaced by halogen identical or differently 1-C 3-alkyl or cyclopropyl.
Another theme of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 1Represent methylidene, ethyl, sec.-propyl or cyclopropyl, its optional one or many is replaced by halogen identical or differently.
The preferred theme of another of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 1Represent methylidene, ethyl, sec.-propyl or cyclopropyl, its optional one or many is replaced by fluorine identical or differently.
The preferred theme of another of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 1Represent ethyl.
Another theme of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 2Represent C 1-C 3-alkyl, C 3-C 4-thiazolinyl, C 3-C 4-alkynyl or cyclopropyl, the identical or different by cyano of its optional one or many, cyclopropyl, ethynyl or halogen replace, or representative is at least by methyl substituted hydroxyethyl once.
Another theme of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 2Represent methylidene, ethyl, allyl group or propargyl, the identical or different by cyano of its optional one or many, cyclopropyl, ethynyl or halogen replace, or representative is at least by methyl substituted hydroxyethyl once.
The preferred theme of another of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 2Represent methylidene, ethyl, allyl group or propargyl, the identical or different by cyano of its optional one or many, cyclopropyl, ethynyl or fluorine replace, or representative is at least by methyl substituted hydroxyethyl once.
A theme of preceding four embodiments of the present invention is that wherein n represents 1-4 according to the compound of Formula I of one of claim 1-14.
Another theme of preceding four embodiments of the present invention is that wherein n represents 1-3 according to the compound of Formula I of one of claim 1-14.
Another theme of preceding four embodiments of the present invention is that wherein n represents 1-2 according to the compound of Formula I of one of claim 1-14.
Preceding four another themes of implementing two schemes of the present invention are that wherein n represents 1 according to the compound of Formula I of one of claim 1-14.
Another theme of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 4Represent hydrogen, cyano group or halogen, or the methyl that one or many is replaced by halogen identical or differently is chosen in representative wantonly.
The preferred theme of another of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 4The methyl of representing the optional one or many of hydrogen or halogen or representative to be replaced by halogen identical or differently.
Another theme of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 6Representative-SO 2-R 14
The preferred theme of another of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 6Representative-SO 2-methyl.
Topic is the compound of Formula I according to one of claim 1-14, wherein R on another of preceding four embodiments of the present invention 8Represent C 1-C 3-alkyl, C 3-C 4-thiazolinyl or C 3-C 4-alkynyl, the identical or different by cyano of its optional one or many, cyclopropyl or halogen replace.
Another theme of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 8Represent methylidene, ethyl, allyl group or propargyl, the identical or different by cyano of its optional one or many, cyclopropyl or halogen replace.
Another theme of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 8Represent methylidene, ethyl, allyl group or propargyl, the identical or different by cyano of its optional one or many, cyclopropyl or fluorine replace.
Another theme of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 9Represent C 1-C 5-alkyl, preferred C 1-C 4-alkyl, C 2-C 4-thiazolinyl, cyclopropyl or C 2-C 10-Heterocyclylalkyl, its optional one or many is identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, C 2-C 10-Heterocyclylalkyl, cyano group, cyclopropyl, halogen, hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14Replace, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces.
Another theme of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 9Represent C 1-C 5-alkyl, preferred C 1-C 4-alkyl, C 2-C 4-thiazolinyl, cyclopropyl or C 2-C 10-Heterocyclylalkyl, its optional one or many is identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, C 2-C 10-Heterocyclylalkyl, cyano group, cyclopropyl, halogen, hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 12Replace, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should the optional one or many of ring itself identical or differently by halogen, cyano group, hydroxyl or itself choose one or many wantonly identical or differently by halogen or C 1-C 3The phenyl that-alkoxyl group replaces replaces, or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces.
The preferred theme of another of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 9Represent methylidene, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, vinyl, cyclopropyl, THP trtrahydropyranyl or tetrahydrofuran base, its optional one or many is identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, pyrrolidyl, piperidyl, piperazinyl, thio-morpholinyl, benzopyrrole alkyl, tetrahydric quinoline group, Si Qing oxazolyl, piperazine ketone group, thiazolidine base, imidazolidine quinoline ketone group, benzo morpholinyl, tetrahydrochysene triazolinthione base, morpholinyl, tetrahydro isoquinolyl, octahydro isoquinolyl, cyano group, cyclopropyl, halogen, hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-C 1-C 3-alkyl replaces, and wherein pyrrolidyl, piperidyl, piperazinyl, thio-morpholinyl, benzopyrrole alkyl, tetrahydric quinoline group, Si Qing oxazolyl, piperazine ketone group, thiazolidine base, imidazolidine quinoline ketone group, benzo morpholinyl, tetrahydrochysene triazolinthione base, morpholinyl, tetrahydro isoquinolyl, the optional one or many of octahydro isoquinolyl itself are identical or differently by halogen, hydroxyl, phenyl or C 1-C 3-alkoxyl group replaces, or by group-(CO)-R 5,-(CO)-O-R 5,-(SO 2)-R 14Or-N (CH 3) 2Or optional one or many is replaced by methyl or the ethyl that halogen, hydroxyl, methylthio group or phenyl replace identical or differently.
The preferred theme of another of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 9Represent methylidene, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, vinyl, cyclopropyl, THP trtrahydropyranyl or tetrahydrofuran base, its optional one or many is identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, cyano group, cyclopropyl, halogen, hydroxyl or by group-N (C 1-C 3-alkyl) 2,-O-(CO)-(C 1-C 3-alkyl) or-O-(SO 2)-C 1-C 3-alkyl replaces, wherein pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thio-morpholinyl itself is chosen one or many wantonly identical or differently by halogen or by group-(CO)-C 1-C 4-alkyl ,-(CO)-O-C 1-C 4-alkyl ,-(SO 2)-C 1-C 3-alkyl ,-(SO 2)-phenyl ,-N (C 1-C 3-alkyl) 2Or optional one or many is identical or differently by halogen, hydroxyl or C 1-C 3Methyl that-alkylthio replaces or ethyl replace.
The preferred theme of another of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 9Represent methylidene, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, vinyl, cyclopropyl, THP trtrahydropyranyl or tetrahydrofuran base, its optional one or many are identical or differently by methoxyl group, oxyethyl group, butoxy-oxyethyl group, methoxyl group-oxyethyl group, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, cyano group, cyclopropyl, chlorine, fluorine, hydroxyl or by group-N (CH 3) 2,-N (CH 3) (C 2H 5) ,-O-(CO)-(CH 3) or-O-(SO 2)-methyl substituted, wherein the optional one or many of pyrrolidyl, piperidyl, piperazinyl, morpholinyl or thio-morpholinyl itself is identical or differently by fluorine or by group-(CO)-CH 3,-(CO)-C 2H 5,-(CO)-C (CH 3) 3,-(CO)-O-C (CH 3) 3,-(SO 2)-CH 3,-(SO 2)-phenyl ,-N (CH 3) 2Or optional one or many is replaced by methyl or the ethyl that fluorine, hydroxyl or methylthio group replace identical or differently.
Another theme of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 10And R 11The optional one or many of representative independently of each other is identical or differently by halogen, C 1-C 3-alkyl, C 1-C 3The C that-alkoxyl group replaces 1-C 5-alkyl, C 2-C 10-Heterocyclylalkyl, aryl ,-(CH 2) n-aryl or heteroaryl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys.
Another theme of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 10And R 11The optional one or many of representative independently of each other is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3The C that-alkoxyl group replaces 1-C 5-alkyl, C 2-C 10-Heterocyclylalkyl, aryl or heteroaryl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys.
The preferred theme of another of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 10And R 11Represent C independently of each other 1-C 5-alkyl, pyrrolidyl, phenyl or pyridyl, its optional one or many is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces.
Another theme of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 12And R 13Represent hydrogen or C independently of each other 1-C 4-alkyl.
The preferred theme of another of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 12And R 13Represent hydrogen or methyl, ethyl or sec.-propyl independently of each other.
Another theme of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 14Represent C 1-C 3-alkyl or represent aryl.
Another theme of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 14Represent C 1-C 3-alkyl or represent phenyl.
The preferred theme of another of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 14Represent C 1-C 4-alkyl or represent phenyl.
Another theme of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 15The optional one or many of representative is identical or differently by C 1-C 3-alkyl or-(CH 2) nThe C that-aryl replaces 2-C 10-Heterocyclylalkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys.
The preferred theme of another of preceding four embodiments of the present invention is the compound of Formula I according to one of claim 1-14, wherein R 15The optional one or many of representative is identical or differently by C 1-C 3-alkyl or-(CH 2) nThe C that-phenyl replaces 2-C 5-Heterocyclylalkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur.
Another theme of preceding four embodiments of the present invention is general formula I I in the claim 15 or compound and solvate, hydrate, diastereomer, enantiomorph and the salt of IV, and it is as the intermediate product of preparation compound of Formula I,
Figure A20058004839600631
R wherein 1, R 2, R 3, U, T 2, T 2And T 3Has the definition described in general formula I.
Another theme of preceding four embodiments of the present invention is according to the compound of the general formula I I in the claim 16 of claim 15 and solvate, hydrate, diastereomer, enantiomorph and salt, and it is used as the intermediate product of preparation compound of Formula I:
2-cyano group-N-ethyl-2-[3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-ethanamide,
2-cyano group-2-[3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-N-(2,2,2-three fluoro-ethyls)-ethanamide,
2-cyano group-2-[3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-N-Propargyl-ethanamide or
2-cyano group-N-cyano methyl-2-[3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-ethanamide
2-cyano group-N-(2-2-two fluoro-ethyls)-2-[3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-ethanamide
2-cyano group-2-[3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-N-(2-hydroxyl-1,1-dimethyl-ethyl)-ethanamide
2-cyano group-2-[3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-N-(2-fluoro-ethyl)-ethanamide.
Another theme of preceding four embodiments of the present invention is according to the general formula (II) of claim 15 or 16 or the compound in the claim 17 (IV) or according to the compound of claim 16, it is as the intermediate product of preparation compound of Formula I.
Another theme of preceding four embodiments of the present invention is according to the general formula in the claim 18 of claim 15 (II) or compound (IV) or according to the compound of claim 16, as the application of intermediate product in the preparation compound of Formula I.
Another theme of preceding four embodiments of the present invention is the medicine in the claim 19, and it comprises at least a compound according to one of claim 1-14.
Another theme of preceding four embodiments of the present invention is according to the application in the preparation medicine of the compound of Formula I of one of claim 1-14 in the claim 20.
Another theme of preceding four embodiments of the present invention is according to the compound of one of claim 1-14 or according to medicine and the appropriate formulation material and the carrier of claim 19 in the claim 21.
A theme of preceding four embodiments of the present invention is methods of the compound of the preparation general formula I in the claim 22, wherein the compound of the compound of general formula I I and following general formula III reacts in the formic acid ortho ester with alkoxyl group three identical or different, optional bridge joints or that halogen replaces or aryloxy, they are chosen wantonly and heat with polar solvent
R wherein 3, U, T 1, T 2And T 3Have with one of claim 1-14 in R 3, U, T 1, T 2And T 3Identical definition,
Perhaps
The compound of general formula I V and allyl acceptor and catalyzer react in non-protonic solvent,
Figure A20058004839600642
R wherein 3, U, T 1, T 2And T 3Have with one of claim 1-14 in R 3, U, T 1, T 2And T 3Identical definition, and after first part reaction is finished in non-protonic solvent with coupling agent, alkali and R 2-NH 2Reaction, wherein R 2Have with one of claim 1-14 in R 2Identical definition, the compound of formation general formula I.
Another theme of preceding four embodiments of the present invention is according to the method in the claim 23 of claim 22, wherein is the compound of preparation general formula I I, and the compound of general formula V and allyl acceptor and catalyzer react in non-protonic solvent,
Figure A20058004839600643
R wherein 1Have with one of claim 1-14 in R 1Identical definition, and after first part reaction is finished in non-protonic solvent with coupling agent, alkali and R 2-NH 2Reaction, wherein R 2Have with one of claim 1-14 in R 2Identical definition, the compound of formation general formula I.
Described in claim 22 or 23 have alkoxyl group three identical or different, optional bridge joints or that halogen replaces or the formic acid ortho ester of aryloxy is preferably the triethyl ortho-formiate.Other formic acid ortho ester be those skilled in the art oneself know.
Be applicable to that the polar solvent of implementing the method described in the claim 22 is C 1-C 5Alcohol or glycol are as ethylene glycol; Be preferably C 1-C 3Alcohol is by special preferred alcohol or 1-propyl alcohol.If the excessive existence of described formic acid ortho ester does not then need polar solvent when forming the compound of general formula I in the reaction of the compound of compound that carries out general formula I I and general formula III.
For implementing according to the general formula I I compound of claim 22 and the reaction of compound of Formula I, heating is essential.In preferred embodiments, this is reflected at least 70 ℃, preferably between 70 ℃-150 ℃, and more preferably carries out under the temperature between 100 ℃-150 ℃.This reaction also can be carried out under higher temperature, but is known that for those skilled in the art this will need to use more high boiling solvent and/or pressurized vessel.In a preferred embodiment of the invention, reacting by heating was carried out 2-24 hour.
" catalyzer " that can be used in the method for claim 22 or 23 is well known by persons skilled in the art, preferably uses palladium catalyst.
" non-protonic solvent " that can be used in the method for claim 22 or 23 is well known by persons skilled in the art.Tetrahydrofuran (THF) and methylene dichloride are suitable and the non-protonic solvent of preferred use.In the linked reaction described in claim 22 or 23 (second section reaction), also preferred use dimethyl formamide is as non-protonic solvent.Yet be known that for those skilled in the art other non-protonic solvents such as N,N-DIMETHYLACETAMIDE (DMA) or N-Methyl pyrrolidone (NMP) also can be used for implementing the method described in claim 22 or 23.
1,3-dimethyl barbituric acid, barbituric acid and/or silane are corresponding to the present invention and according to the preferred allyl acceptor of claim 22 or 23.Other allyl acceptor is known to those skilled in the art, and can be used for implementing described method.
" coupling agent " that can be used in the method for claim 22 or 23 is well known by persons skilled in the art.The preferred coupling agent that uses is O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-URONIUM a tetrafluoro borate (TBTU) and/or O-(7-AZA benzotriazole-1-yl)-N, N, N ', N-tetramethyl-URONIUM phosphofluoric acid ship (HATU).
" alkali " that can be used in the method for claim 22 or 23 is well known by persons skilled in the art.The preferred alkali that uses is triethylamine, Hiinig alkali or sodium bicarbonate.
Preferably under the temperature between O ℃-500 ℃, carry out with the reaction with the compound of the compound formation general formula I I of general formula V in the reaction of the compound of the compound formation general formula I of general formula I V and the claim 23 in the claim 22, more preferably at room temperature carry out.
Below explanation relates to all embodiments of the present invention:
Alkyl is defined as from chain or branched-chain alkyl, as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, hexyl, heptyl, octyl group, nonyl and decyl.
Alkoxyl group is defined as the straight or branched alkoxyl group, for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, isopentyloxy, hexyloxy, heptan oxygen base, octyloxy, the ninth of the ten Heavenly Stems oxygen base or the last of the ten Heavenly stems oxygen base.But C in the present invention, 1-C 6-alkoxyl group is preferred, C 1-C 3-alkoxyl group is particularly preferred, and methoxyl group is particularly preferred.
Alkenyl group for example is the following group of straight or branched: vinyl, propylene-1-base, propylene-2-base, but-1-ene-1-base, but-1-ene-2-base-but-2-ene-1-base, but-2-ene-2-base ,-2-methyl-third-2-alkene-1-base-2-methyl-third-1--alkene-1-base, but-1-ene-3-Ji-Ding-3-alkene-1-base and allyl group.
Alkynyl is defined as the straight or branched alkynyl that comprises individual, preferred 2-4 the carbon atom of 2-6, for example can be following group: ethynyl, propine-1-base, propine-3-base, fourth-1-alkynes-1-base, fourth-1-alkynes-4-base, fourth-2-alkynes-1-base, fourth-1-alkynes-3-base etc.
C 2-C 10The representative of-Heterocyclylalkyl comprises 2- 10The alkyl ring of individual carbon atom, preferred 3-10 carbon atom, preferred especially 5-6 carbon atom, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this Heterocyclylalkyl optional insert one or more-(CO)-,-(C=S)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly and be substituted identical or differently, perhaps can be condensed.
As Heterocyclylalkyl; for example can be: Oxyranyle; oxethanyl; two oxa-s, penta cyclic groups (diox01anyl); dithia penta cyclic group (dithianyl) alkyl dioxin; aziridinyl; azetidinyl; tetrahydrofuran base; THP trtrahydropyranyl Si Qing oxazolyl; the thiazolidine base; tetrahydro isoquinolyl; the octahydro isoquinolyl; tetrahydric quinoline group; the octahydro quinolyl; imidazolidine quinoline ketone group; pyrazolidyl; pyrrolidyl; pyrrolidone-base; piperidyl; piperazinyl; the piperazine ketone group; N-methylpyrrole alkyl; 2-hydroxymethyl-pyrrolidine base; 3-hydroxyl pyrrolidine base; the N methyl piperazine base; N-is the acyl piperazine base; N-methyl sulphonyl piperazinyl; 4-hydroxy piperidine base; 4-aminocarboxyl piperidyl; 2-hydroxyethyl piperidyl; 4-hydroxymethyl piperidyl; imidazolidyl; imidazolidine quinoline ketone group; morpholinyl; thio-morpholinyl; 1; 1-dioxo-thio-morpholinyl; the trithian base; tetrahydrotriazine thioketones base; triazine thioketones base; quinuclidinyl; nortropine base etc.; perhaps benzo-fused above-mentioned ring is as the benzopyrrole alkyl; benzo morpholinyl etc.
Substituting group on this heterocycloalkyl ring for example can be: cyano group, halogen, hydroxyl, C 1-C 6-alkyl, C 1-C 6-alkoxyl group, C 1-C 6-alkoxyalkyl, C 1-C 6-hydroxyalkyl, C 3-C 6-cycloalkyl or aryl, or C 1-C 6-alkyl, its optional one or many is identical or differently by halogen, hydroxyl or C 1-C 6-alkylthio or by group-(CO)-C 1-C 6-alkyl ,-(CO)-O-C 1-C 6-alkyl ,-(SO 2)-C 1-C 6-alkyl ,-(SO 2)-phenyl ,-NH 2,-N (C 1-C 6-alkyl) 2,-NH (C 1-C 6-alkyl) replacement such as.
Cycloalkyl is defined as the mononaphthene basic ring, as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or suberyl, but also can be two ring or tricyclic alkyl rings, as adamantyl.It is benzo-fused that this cycloalkyl also can be chosen wantonly, for example tetralyl etc.
Halogen is defined as fluorine, chlorine, bromine or iodine.
Under the various situations, heteroaryl comprises 5-16, preferred 5-10, preferred especially 5-7 annular atoms, except that carbon atom, in ring, also can comprise one or more identical or different heteroatoms, as oxygen, nitrogen or sulphur, and this group can be single, two or three rings, and can be benzo-fused in addition.
For example, this heteroaryl can be: thienyl, furyl, pyrrolidyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazole base, triazolyl, thiadiazolyl group, and benzo derivative, as benzofuryl, benzothienyl, benzoxazolyl, benzimidazolyl-, indazolyl, indyl, pseudoindoyl etc.; Or pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl etc., and benzo derivative, as quinolyl, isoquinolyl etc.; Or oxepinyl, azocine base, indolizine base, indyl, indolinyl, pseudoindoyl, indazolyl, benzimidazolyl-, purine radicals etc. and benzo derivative thereof; Or quinolyl, isoquinolyl, cinnolines base, 2 base, quinazolyl, quinoxaline, naphthyridine base, pteridyl, carbazyl, acridyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthyl, tetralyl etc.
Preferred heteroaryl for example is 5 yuan of assorted aromatic compounds, as thiophene, furans, oxazole, thiazole, imidazoles and benzo derivative thereof, and 6 yuan of assorted aromatic compounds, as pyridine, pyrimidine, triazine, quinoline, isoquinoline 99.9 and benzo derivative thereof.
All comprise 3-12 carbon atom under the various situations of aryl, and can be that replace or benzo-fused.
For example, aryl can be cyclopropenyl radical, cyclopentadienyl, phenyl, tropyl, cyclooctadiene base, indenyl, naphthyl, camomile cyclic group, xenyl, fluorenyl, anthryl, tetralyl, tolyl etc.
Therefore, in the present invention, for example with " C 1-C 5-alkyl " " the C that uses of contact 1-C 5" be meant alkyl with 1-5 carbon atom, promptly, have an alkyl of 1,2,3,4 or 5 carbon atom.In addition, definition " C 1-C 5" explanation should be arbitrarily the zone, also can comprise C 1-C 5, C 2-C 5, C 3-C 5, C 4-C 5, C 1-C 2, C 1-C 3, C 1-C 4, C 1-C 5
The present invention refers to that the scope that does not specify also is similar to above-mentioned " C 1-C 5" scope define.
Isomer is defined as has identical total formula but the different compound of chemical structure.Usually, divide into constitutional isomer and steric isomer.
Constitutional isomer has identical total formula, and difference is the mode of connection of their atoms or atomic group.It comprises function isomer, positional isomers, tautomer or valence isomer.
In principle, steric isomer has identical structure (structure), and therefore has identical total formula, arranges but difference is atoms in space.
Generally, configurational isomer and conformer are distinguishing.Configurational isomer is the steric isomer that only can be converted into another compound by bond rupture.It comprises enantiomer, diastereomer and E/Z (cis/trans) isomer.
Enantiomer foot shows as image and mirror image each other but does not have the steric isomer of any symmetrical plane.All are not that the steric isomer of enantiomer is called as diastereomer.The E/Z of two keys (cis/trans) isomer is Special Circumstances.
Conformer is the steric isomer that can be converted into another compound by single bonded rotation.
Be difference isomer type each other, can be referring to IUPAC rules, Section E (Pure Appl.Chem.45,11-30,1976).
Also comprise possible tautomeric forms and comprise E or Z isomer according to compound of Formula I of the present invention, perhaps,, also comprise racemic modification and enantiomer if there is chiral centre.In the latter, also comprise double bond isomer.
Form that also can solvate, particularly hydrate according to compound of the present invention exists, and wherein therefore comprises polar solvent, the particularly water structural element as the crystal lattices of The compounds of this invention according to compound of the present invention.The ratio of polar solvent, particularly water can the water chemistry metered amount or or even not enough stoichiometry.When the solvate of stoichiometry and hydrate, also can comprise half, list, sesquialter, two, three, four, five etc. solvate or hydrate.
If comprise acidic-group, organic and physiology compatible salt mineral alkali is suitable, for example easily molten an alkali metal salt and alkaline earth salt and N-methyl-glycosamine, dimethyl-glycosamine, ethyl-glycosamine, Methionin, 1,6-hexanediamine, thanomin, glycosamine, sarkosine, serinol, trishydroxymethyl-amino-methane, aminopropane glycol, Sovak alkali and 1-amino-2,3, the 4-trihydroxybutane.
If comprise basic group, organic and physiology compatible salt mineral acid is suitable, for example hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartrate, toxilic acid, fumaric acid etc.
Suppress polo sample kinases according to compound of Formula I of the present invention, and based on this have the treatment following disease effect: cancer such as solid carcinoma and leukemia, autoimmune disorders such as psoriasis, alopecia and multiple sclerosis, alopecia that chemotherapeutics brings out and mucositis, cardiovascular disorder such as narrow, arteriosclerosis and restenosis, transmissible disease such as those are by such as trypanosome, the communicable disease that toxoplasma gondii or plasmodial unicellular parasite or fungi cause, kidney disease such as glomerulonephritis, chronic neurodegenerative disease such as Huntington disease, the muscular dystrophy lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer, acute neurodegenerative disease such as cerebral ischemia and neurotrauma, infect with virus infection such as giant cells, bleb, B-mode and hepatitis C, and HIV disease.
In addition, the compound of general formula I I and solvate thereof, hydrate, diastereomer, enantiomorph and salt also are themes of the present invention as the application of intermediate product.
For using according to compound of Formula I of the present invention with the form of medicine, compound of the present invention can be mixed with pharmaceutical preparation, can comprise suitable organic or inorganic pharmaceutical carrier medium when wherein being used for enteron aisle or parenteral administration, as water, gelatin, gum arabic, lactose, starch, stearic acid enzymes, talcum, vegetables oil, polyoxyethylene glycol etc. except activeconstituents is external.This pharmaceutical preparation can be solid form, as tablet, coated tablet, suppository or capsule, or liquid form, as solution, suspensoid or emulsion.In addition, they can randomly comprise assistant agent, as sanitas, stablizer, wetting agent or lubricant, be used to change the salt or the buffer reagent of osmotic pressure.
These pharmaceutical preparations also are themes of the present invention.
When parenteral administration, specially suitable is injection liquid or suspension, the especially active compound aqueous solution in many hydroxyethoxylations Viscotrol C.
As carrier system, also can use the surfactivity assistant agent, as salt or animal phosphatide or the plant phosphatide and their mixture of cholic acid, and liposome or their moiety.
When oral administration, specially suitable is tablet, coated tablet or capsule, and they can contain talcum and/or hydrocarbon carrier or tackiness agent, as lactose, corn or yam starch.Also can the liquid form administration, as the optional juice that adds sweeting agent.
Enteron aisle, parenteral route and oral administration also are themes of the present invention.
The dosage of activeconstituents can according to the type of medication, patient's age and body weight, disease to be treated and severity and similarly factor change.Per daily dose is 0.5-1000mg, is preferably 50-200mg, and wherein this dosage can the disposable administration of single dosage or is divided into two or more a plurality of per daily dose.
Theme of the present invention comprises that also compound of Formula I is used for the treatment of application in the medicine of following disease in preparation: cancer, autoimmune disorders, cardiovascular disorder, the alopecia of chemotherapy induction and mucositis, transmissible disease, the kidney disease, chronic and acute neurodegenerative disease, and virus infection, wherein cancer is defined as solid carcinoma and leukemia, autoimmune disorders is defined as psoriasis, alopecia and multiple sclerosis, cardiovascular disorder is defined as narrow, arteriosclerosis and restenosis, transmissible disease is defined as those communicable diseases that is caused by unicellular parasite, the kidney disease is defined as glomerulonephritis, chronic neurodegenerative disease is defined as Huntington disease, the muscular dystrophy lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer, the acute neurodegenerative disease is defined as cerebral ischemia and neurotrauma, and virus infection is defined as the giant cells infection, bleb, B-mode and hepatitis C, and HIV disease.
Theme of the present invention also comprises and is used for the treatment of comprising of above-mentioned disease of at least a medicine according to compound of Formula I, and the medicine that also comprises appropriate formulation material and carrier.
According to compound of Formula I of the present invention for example is the excellent inhibitor of polo sample kinases such as Plk1, Plk2, Plk3 and Plk4.
If do not describe the preparation of initial compounds, then this compound is known or can prepares similarly according to known compound described here or method.Also can be in parallel reactor or implement institute described here and respond by making up each operation steps.If isomer is not in equilibrium state each other, can as crystallization, chromatogram or salt forming method, isomer mixture be separated into isomer according to the method for routine use, for example be separated into enantiomorph, diastereomer or E/Z isomer.
According to the method for routine, with solution and the equivalent or the excessive alkali or sour mixing of formula I compound, this alkali or acid can randomly be the solution form, and sediment separate out or treatment soln then in a conventional manner can prepare heat thus.
Synthetic route 1:
Figure A20058004839600711
A) ester fracture; B) linked reaction
R A=ethyl, allyl group
R wherein 1, R 2, R 3, U, T 1, T 2And T 3Have the definition identical with general formula I.
Synthetic route 2:
Improvement with general formula (I) of above-mentioned definition
Figure A20058004839600721
A) deprotection; B) linked reaction; C) replace; D) 1, the 4-addition; E) alcohol is converted into leavings group;
The PG=protecting group
Spacer=C 1-C 3-alkyl or SR 12-(CO)-C 1-C 3-alkyl
R x=-NR 10R 11Or represent C 2-C 10-Heterocyclylalkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and optionally in this Heterocyclylalkyl insert one or more-(CO)-,-(C=S)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose the identical or different by cyano of one or many, halogen, hydroxyl, aryl wantonly or by group-(CO)-R 5Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, and wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces,
Wherein U, T 1, T 2, T 3, R 1, R 2, R 3, R 9, R 12, R 5, R 14, R 13, R 10, and R 11Have the definition identical with general formula I.
The route 1 that is used for synthetic aniline compound:
Figure A20058004839600731
A) replace; B) reduction;
Wherein U, T 1, T 2And T 3Have the definition identical with general formula I, and R xHas the definition described in synthetic route 2.
The route 2 that is used for synthetic aniline compound:
Figure A20058004839600732
B) reduction;
Wherein U, T 1, T 2And T 3Have the definition identical with general formula I.
The route 3 that is used for synthetic aniline compound:
Figure A20058004839600741
A) 1, the 4-addition; B) reduction;
Wherein U, T 1, T 2And T 3Have the definition identical with general formula I, and R xHas the definition described in synthetic route 2.
The route 4 that is used for synthetic aniline compound:
A) reduction;
Wherein U, T 1, T 2And T 3Have the definition identical with general formula I.
The route 6 that is used for synthetic aniline compound:
A) coupling agent; B) deprotection;
Wherein U, T 1, T 2, T 3And R 9Have the definition identical with general formula I.
The route 7 that is used for synthetic aniline compound:
Figure A20058004839600751
A) coupling agent;
Wherein U, T 1, T 2, T 3And R 9Have the definition identical with general formula I.
The route 8 that is used for synthetic aniline compound:
Figure A20058004839600752
A) replace; B) reduction;
Wherein U, T 1, T 2And T 3Have the definition identical with general formula I, and R XHas the definition described in synthetic route 2.
The route 9 that is used for synthetic aniline compound:
Figure A20058004839600753
A) replace; B) reduction;
R wherein 9Has the definition described in general formula I.
The route 10 that is used for synthetic aniline compound:
Figure A20058004839600761
A) reduction;
Wherein U, T 1, T 2And T 3Have the definition identical with general formula I, and R xHas the definition described in synthetic route 2.
The route 11 that is used for synthetic aniline compound:
Figure A20058004839600762
A) reduction;
Wherein U, T 1, T 2, T 3, R 9And R 12Have the definition identical with general formula I.
The route 12 that is used for synthetic aniline compound:
Figure A20058004839600763
A) reductive amination; B) reduction;
Wherein U, T 1, T 2, T 3And R 9Have the definition identical with general formula I.
Route 13 is used for synthetic aniline compound:
Figure A20058004839600771
A) replace; B) reduction;
Wherein U, T 1, T 2, T 3And R 9Have the definition identical with general formula I.
1. synthetic aniline composition
Intermediate compound INT1
1-(2-iodo-ethyl)-3-nitro-benzene
Figure A20058004839600772
The 3-nitrophenyl ethanol of 5g, the triphenylphosphine of 9.4g and the imidazoles of 3.1g are dissolved among the THF of 250ml, mix with the iodine of 9.1g in batches, at room temperature stirred then 15 hours.Reaction mixture mixes with ammonium chloride solution and uses dichloromethane extraction.Organic phase is sequentially used hypo solution and water washing, and is dry on sodium sulfate then.After carry out chromatographically pure system on the silica gel, obtain the 7.51g title compound.
1H-NMR(DMSO-d6)：δ＝3.31(t，2H)；3.41(t，2H)；7.46-7.60(m，2H)；8.09(s，1H)；8.16(d，lH)：ppm．
Intermediate compound INT2
1-[2-(3-nitro-phenyl)-ethyl]-tetramethyleneimine
Figure A20058004839600773
With 1.88g at intermediate compound INT1) compound dissolution described down in the dimethyl formamide of 10 ml, mix with the tetramethyleneimine of 0.85ml lentamente, at room temperature stirred then 15 hours.Evaporating solvent under the high vacuum, residue are put into ethyl acetate and are washed with water 3 times.Organic phase is dry on sodium sulfate.After carry out chromatographically pure system on the silica gel, obtain the 350mg title compound.
1H-NMR(CDCl3)：δ＝1.81(m，4H)；2.57(m，4H)；2.74(t，2H)；2.93(t，2H)；7.45(t，1H)；7.56(d，1H)；8.03-8.13(m，2H)ppm．
Intermediate compound INT3
3-(2-tetramethyleneimine-1-base-ethyl)-phenyl amine
Figure A20058004839600781
With 650mg at INT2) compound dissolution described down in the ethanol of 250ml, mix with the palladium on carbon (10%) of 130mg then.Under room temperature and nitrogen atmosphere, stirred 15 hours.After filtering on the diatomite and in rotatory evaporator, concentrating solvent, obtain the 540mg title compound.
1H-NMR(DMSO-d6)：δ＝1.78(m，4H)；2.65(t，2H)；2.70-2.92(m，6H)；4.99(s，2H)；6.31-6.45(m，3H)；6.92(t，1H)ppm。
Intermediate compound INT4
N-(3-amino-phenyl)-2,2-dimethyl-propionic acid amide
Figure A20058004839600782
With 1 of 5.0g, the 3-diaminobenzene is dissolved in the methylene dichloride of 50ml and mixes with the diisopropyl ethyl amine of 24ml and the PIVALIC ACID CRUDE (25) acid anhydride of 10.4ml down at 0 ℃.It stirred 2 hours down at 0 ℃, at room temperature stirred then 18 hours.Reaction mixture mixes with half saturated sodium hydrogen carbonate solution, uses ethyl acetate extraction then.Organic solution is washed with saturated nacl aqueous solution, and is dry on sodium sulfate, evaporation concentration, and after carry out chromatographically pure system on the silica gel, obtain the 5.7g title compound.
1H-NMR(DMSO-d6)：δ＝1.20(s，9H)；4.98(s，2H)；6.24(d，1?H)；6.70(d，1H)；6.83-6.96(m，2H)ppm。
Intermediate compound INT5
1-(2-iodo-ethyl)-3-nitro-benzene
Figure A20058004839600783
2-hydroxy-2-methyl-propionic acid of 1.5g is mixed with the thionyl chloride of 1.05ml down in-10 ℃ in the N,N-DIMETHYLACETAMIDE of 50ml, stirred 30 minutes down at-10 ℃ then.At-10 ℃ of 3-N-methyl-p-nitroaniline solution in the 10ml N,N-DIMETHYLACETAMIDE that drip 2g down, sequentially stirred 1 hour down then at-10 ℃, stir 1 hour down, and at room temperature stirred 15 hours at 0 ℃.Evaporating solvent under the high vacuum, residue are put into the mixture of ethyl acetate and methylene dichloride (1: 3), then with half saturated sodium hydrogen carbonate solution washing 2 times.Organic phase is dry on sodium sulfate.After carry out chromatographically pure system on the silica gel, obtain the 2.42g title compound.
1H-NMR(CDCl3)：δ＝1.49(s，6H)；2.35(s，1H)；7.50(t，1H)；7.98(d，2H)；8.49(s，1H)；8.98(s，b，1H)ppm。
Intermediate compound INT6
N-(3-amino-phenyl)-2-hydroxy-2-methyl-propionic acid amide
With 1.92g at INT5) compound dissolution described down in the ethanol of 400ml, mix with the Raney nickel of 50mg then.Under nitrogen atmosphere and room temperature, stirred 18 hours.After filtering on the brick algae soil and in rotatory evaporator, concentrating solvent, obtain the 1.9g title compound.
lH-NMR(CDCl3)：δ＝1.51(s，6H)；2.68(s，1H)；3.71(s，b，2H)；6.42(d，1H)；7.08(t，1H)；7.20(s，1H)；8.60(s，b，1H)ppm。
Intermediate compound INT7
2-(2-methoxyl group-oxyethyl group)-N-(3-nitro-phenyl)-ethanamide
(2-methoxy ethoxy) with 5g. acetate is dissolved in the tetrahydrofuran (THF) of 500ml.Add the triethylamine of 9.7ml and the chloroformic acid isobutyl of 5.6ml down at 0 ℃, and stirred 30 minutes down at 0 ℃.The 3-N-methyl-p-nitroaniline of carbonyl 5.0g, and restir 15 hours at room temperature.Reaction mixture with mix half saturated sodium hydrogen carbonate solution, use ethyl acetate extraction then.Organic solution is washed with saturated nacl aqueous solution, and is dry on sodium sulfate, and evaporation concentration and after carry out chromatographically pure system on the silica gel obtains the 7.5g title compound.
lH-NMR(DMSO-d6)：δ＝3.30(s，3H)；3.53(m，2H)；3.70(m，2H)；4.04(s，1H)；7.62(t，1H)；7.93(d，1H)；8.02(d，1H)；8.69(s，1H)；10.20(s，b，1H)ppm。
Intermediate compound INT8
N-(3-amino-phenyl)-2-(2-methoxyl group-oxyethyl group)-ethanamide
Figure A20058004839600801
With 7.5g at INT7) compound dissolution described down in the ethanol of 150ml, mix with the palladium on carbon (10%) of 1.3g then.Under nitrogen atmosphere and room temperature, stirred 15 hours.After filtering on the diatomite and in rotatory evaporator, concentrating solvent, obtain the 6.5g title compound.
1H-NMR(DMSO-d6)：δ＝3.31(s，3H)；3.51(m，2H)；3.65(m，2H)；4.02(s，2H)；6.10(s，2H)；6.28(d，1H)；6.70(d，1H)；6.87-6.98(m，2H)；9.27(s，1H)ppm。
Intermediate compound INT9
N-(6-amino-pyridine-2-yl)-2, the 2-dimethyl. propionic acid amide
With 2 of 10g, the 6-diamino adjoins in the tetrahydrofuran (THF) that pyridine is dissolved in 150ml.Add the diisopropyl ethyl amine of 48ml and the PIVALIC ACID CRUDE (25) acid anhydride of 20.8ml, at room temperature stirred then 15 hours.Concentrated solvent in rotatory evaporator.After carry out chromatographically pure system on the silica gel, obtain the 10.6g title compound.
1H-NMR(DMSO-d6)：δ＝1.20(s，9H)；5.72(s，2H)；6.07(d，1H)；7.18(d，1H)；7.33(t，1H)；8.93(s，1H)ppm。
Intermediate compound INT10
N-(6-amino-pyridine-2-yl)-2-(2-methoxyl group-oxyethyl group)-ethanamide
Figure A20058004839600803
(2-methoxy ethoxy)-acetate of 4.9ml is dissolved in the tetrahydrofuran (THF) of 500ml.Add the triethylamine of 9.7ml and the chloroformic acid isobutyl of 5.6ml down at 0 ℃, stirred 30 minutes down at 0 ℃ then.Add 2 of 3.96g, 6-diamino-pyridine, and restir 4 hours at room temperature.Reaction mixture mixes with half saturated sodium hydrogen carbonate solution, uses ethyl acetate extraction then.Organic solution is washed with saturated nacl aqueous solution, and is dry on sodium sulfate, and after carry out chromatographically pure system on the silica gel, obtain the 5.04g title compound.
1H-NMR(DMSO-d6)：δ＝3.31(s，3H)；3.50(m，2H)；3.67(m，2H)；4.07(s，2H)；5.88(s，2H)；6.19(d，1H)；7.21(d，1H)；7.36(t，1H)；9.13(s，1H)ppm。
Intermediate compound INT11
Ethyl-(4-nitro-1-oxygen base-pyridine-2-yl)-amine
Figure A20058004839600811
With 2-chloro-4-nitro-pyridine 1-oxide dissolution of 2.0g really in the ethanol of 20ml.Add the triethylamine of 11.5ml, and under refluxing, stirred 4 hours.Concentrated solvent in rotatory evaporator.After carry out chromatographically pure system on the silica gel, obtain the 1.5g title compound.
1H-NMR(DMSO-d6)：δ＝1.19(t，3H)；3.39(pentuplet，2H)；7.39(dd，1H)；7.47(d，1H)；7.64(t，1H)；8.35(d，1H)ppm。
Intermediate compound INT12
4-amino-2-ethylamino-pyridine
Figure A20058004839600812
With 800mg at INT11) compound dissolution described down in the ethanol of 50ml, mix with the Raney nickel of 50mg then.Hydrogenation is 5 hours under 3.5bar hydrogen pressure and room temperature.After filtering on the diatomite and in rotatory evaporator, concentrating solvent, obtain the 610mg title compound.
1H-NMR(DMSO-d6)：δ＝1.09(t，3H)；3.11(m，2H)；5.48(s，2H)；5.52(d，1H)；5.7l(t，1H)；5.78(dd，1H)；7.49(d，1H)ppm。
Intermediate compound INT13
2-chloro-N-(3-nitro-phenyl)-ethanamide
Figure A20058004839600813
The 3-N-methyl-p-nitroaniline of 13.8g is dissolved in the tetrahydrofuran (THF) of 500ml.Add the triethylamine of 30.5ml and the chloromethane acid anhydrides of 19.4g down at 0 ℃.At room temperature stirred 12 hours.Reaction mixture mixes with half saturated sodium hydrogen carbonate solution, uses ethyl acetate extraction then.Organic solution is washed with saturated nacl aqueous solution, and is dry on sodium sulfate, and evaporation concentration and after carry out chromatographically pure system on the silica gel obtains the 20.0g title compound.
1H-NMR(DMSO-d6)：δ＝4.31(s，2H)；7.64(t，1H)；7.89-8.00(m，2H)；8.61(s，1H)；10.79(b，1H)ppm。
Intermediate compound INT14
N-(3-nitro-phenyl)-2-piperidines-1-base-ethanamide
Figure A20058004839600821
With 2.14g at INT13) compound dissolution described down is in the dimethyl formamide of 100ml.Add the piperidines of triethylamine, 248mg potassiumiodide and the 1.48ml of 2.0ml.At room temperature stirred 4 hours.Reaction mixture mixes with half saturated sodium hydrogen carbonate solution, uses ethyl acetate extraction then.Organic solution is washed with saturated nacl aqueous solution, and is dry on sodium sulfate, evaporation concentration, and after carry out chromatographically pure system on the silica gel, obtain the 1.97g title compound.
1H-NMR(DMSO-d6)：δ＝1.34-1.48(m，2H)；1.51-1.63(m，4H)；2.45(m，4H)；3.12(s，2H)；7.60(t，1H)；7.91(d，1H)；8.02(d，1H)；8.70(s，1H)；10.18(s，1H)ppm。
Intermediate compound INT15
Acetate (3-nitro-phenylamino formyl radical)-methyl ester
Figure A20058004839600822
With 5.0g at INT13) compound dissolution described down is in the dimethyl formamide of 200ml.Add the potassium acetate of 19.1g and the potassiumiodide of 350mg.At room temperature stirred 24 hours.Reaction mixture mixes with water, uses ethyl acetate extraction then.Organic solution is with half saturated sodium chloride solution washing 3 times, and is dry on sodium sulfate, evaporation concentration, and after carry out chromatographically pure system on the silica gel, obtain the 4.7g title compound.
1H-NMR(DMSO-d6)：δ＝2.14(s，3H)；4.70(s，2H)；7.62(t，1H)；7.87-7.98(m，2H)；8.60(s，1H)；10.57(b，1H)ppm。
Intermediate compound INT16
4-[2-(2-methyl-5-nitro-phenoxy group)-ethyl]-morpholine
Figure A20058004839600823
Make 4-(2-the chloroethyl)-morpholine of 2-methyl-5-nitro phenol, 12g of 10g and the suspension returning of 27.1g salt of wormwood in 200ml acetone 15 hours.From reactant, remove under the vacuum and desolvate, and residue is put into ethyl acetate.With aqueous NaOH (1N, 3 * 200ml) extractions, and the organic phase that merges is dry on yellow soda ash, distills solvent in rotatory evaporator, obtains 4-[2-(2-methyl-5-nitro-phenoxy group)-ethyl then]-morpholine, productive rate is 62% (10.8g).
1H-NMR(300MHz，CDCl 3)：δ＝2.30(s，3H)；2.61(m，4H)；2.86(m，2H)；3.71(m，4H)；4.20(m，2H)；7.22(d，1H)；7.68(d，1H)；7.75(dd，1E)ppm。
Intermediate compound INT17
4-methyl-3-(2-morpholine-4-base-oxyethyl group)-phenyl amine
Figure A20058004839600831
15.9g at INT16) compound described down and palladium on carbon hydrogenation under low pressure and room temperature in the methyl alcohol of 300ml of 2g.After oxygen uptake is finished, filter out catalyzer, and in rotatory evaporator, desolvate by removing in the crude product.Obtain title compound with quantitative yield.The not further pure system of this crude product promptly is used for next step.
1H-NMR(300MHz，CDCl 3)：δ＝2.10(s，3H)；2.62(m，4H)；2.85(m，2H)；3.77(m，4H)；4.10(m，2H)；6.21(m，2H)；6.90(d，1H)ppm。
Be similar to the following compound of method for preparing.
Figure A20058004839600841
Figure A20058004839600851
Figure A20058004839600861
Figure A20058004839600871
Figure A20058004839600881
Intermediate compound INT49
N-methyl-N-(3-nitro-phenyl)-ethanamide
Figure A20058004839600882
0.43g sodium hydride (60% mineral oil suspensoid) in round-bottomed flask under shielding gas with normal hexane washing (3x), then it is suspended among a spot of THF.The solution of 3-nitro monoacetylaniline in the THF of 15ml of 1.3g is dropped in this suspension lentamente.After the gas generation stops, in this reaction mixture, dripping the methyl iodide of 4.5ml.At room temperature stirred 2 hours.Distillation is removed this solvent to very large degree.Optional some water that add destroy unreacted sodium hydride thus.The residue of gained is put into ethyl acetate.Organic phase is water and saturated nacl aqueous solution washing sequentially, and is dry on sal epsom then.The oily matter of gained after the evaporation concentration on silica gel pure system.Obtain 1.23g glassy yellow buttery title compound.
1H-NMR(CDCl 3)：δ＝1.93(s，3H)；3.31(s，3H)；7.56-7.64(m，2H)；8.09(s，1H)；8.18-8.20(m，1H)ppm．MS(ESB[M+1] +：195。
Intermediate compound INT50
2-(3-nitro-phenyl amino)-ethanol
Figure A20058004839600891
The glacial acetic acid of glycollic aldehyde (glycoaldehyde), 195mg sodium cyanoborohydride and the 0.08ml of 195mg is added in the solution of 200mg3-N-methyl-p-nitroaniline in the methyl alcohol of 10ml, is cooled to 0 ℃.At room temperature stirred 5 hours.During aftertreatment, mix with the sodium hydrogen carbonate solution of 150ml and use ethyl acetate extraction.Organic phase is washed with saturated nacl aqueous solution, and is dry on sal epsom then.The oily matter of gained carries out pure system on silica gel after evaporation.Obtain the 224mg title compound, it is orange crystal.
1H-NMR(DMSO-d 6)：δ＝3.15(q，2H)；3.56(q，2H)；4.76(t，1H)；6.39(t，1H)；6.97-6.99(m，1H)；7.28-7.34(m，3H)ppm．MS(ESI)[M+I] +：183。
Intermediate compound INT51
N-(2-methoxyl group-ethyl)-benzene-1, the 3-diamines
Figure A20058004839600892
By 1 of 5g, the mixture that the 2-methoxy ethyl chlorine of 3-phenylenediamine, 4.2ml, the yellow soda ash (anhydrous) of 4.9g and 30ml water are formed refluxed 12 hours.Then, its water (600ml) dilution is filtered then.Filtrate is used ethyl acetate extraction.Organic phase is water and saturated nacl aqueous solution washing sequentially, and is dry on sal epsom then.The oily matter of gained is carrying out pure system on silica gel after the evaporation concentration.Obtain 1.85g buttery title compound.
1H-NMR(DMSO-d6)：δ＝3.09(q，2H)；3.25(s，3H)；3.43(t，2H)；4.68(s，2H)；5.10(t，1H)；5.78-5.81(m，3H)；6.69(t，1H)ppm.MS(ESI)[M+1]+：167。
Intermediate compound INT52
2-(3-nitro-phenyl)-oxyethane
Figure A20058004839600901
2-bromo-1-(3-nitro-phenyl)-ethane ketone of 10g is dissolved in the ethanol of 200ml, mixes, at room temperature stirred then 1 hour with the sodium borohydride of 1.55g.Add the potassium hydroxide of 2.1g, and restir 15 hours at room temperature.Add the ethyl acetate of 1000ml, then at every turn with the semi-saturation ammonium chloride solution washing of 300ml 2 times, then with the water washing of 100ml 1 time.Organic phase is dry on sodium sulfate.After carry out chromatographically pure system on the silica gel, obtain the 7.48g title compound.
1H?NMR(CDCl 3)：δ＝2.79(dd，1H)；3.19(dd，1H)；3.93(dd，1H)；7.50(t，1H)；7.60(d，1H)；8.08-8.16(m，2H)ppm．
Intermediate compound INT53
1-(3-nitro-phenyl)-2-piperidines-1-base-ethanol
Figure A20058004839600902
The compound dissolution that 1.68g is described in INT52 mixes with the piperidines of 1.5ml in the tetrahydrofuran (THF) of 10ml then, then stirs 15 hours under refluxing.In rotatory evaporator, distill solvent and after carry out chromatographically pure system on the silica gel, obtain the 1.4g title compound.
1H?NMR(CDCl 3)：δ＝1.40-1.80(m，6H)；2.23-2.49(m，3H)；2.59(dd，1H)；2.71(b，2H)；4.35(b，1H)；4.80(dd，1H)；7.51(t，1H)；7.73(d，1H)；8.13(d，1H)；8.28(s，1H)ppm。
Intermediate compound INT54
1-(3-amino-phenyl)-2-piperidines-1-base-ethanol
Figure A20058004839600911
The compound dissolution that 2.0g is described in INT53 mixes in the ethanol of 250ml and with 200mg palladium carbon (10%).Under nitrogen atmosphere and room temperature, stirred 15 hours.After concentrating solvent, obtain the 1.76g title compound by diatomite filtration and in rotatory evaporator.
1H?NMR(CDCl 3)：δ＝1.40-1.70(m，6H)；2.28-2.55(m，4H)；2.58-2.77(m，2H)；3.65(b，2H)；4.63(dd，1H)；6.52-6.62(m，1H)；6.72(d，1H)；6.75(s，lH)；7.11(t，1H)ppm。
Intermediate compound INT55
1-(3-nitro-phenyl)-2-(4aR, 8aS)-octahydro-isoquinoline 99.9-2-base-ethanol (non-enantiomer mixture)
Figure A20058004839600912
The compound dissolution that 5.0g is described in INT52 mixes in the tetrahydrofuran (THF) of 50ml and with trans-Decahydroisoquinolinpreparation of 7.3g, stirs 20 hours under refluxing then.In rotatory evaporator, distill solvent and after carry out chromatographically pure system on the silica gel, obtain the 5.75g title compound.
1H?NMR(CDCl 3)：δ＝0.72-1.45(m，7H)；1.45-1.85(m，6H)；1.95-3．20(m，5H)；4.43(b，1H)；4.75-4.86(m，1H)；7.51(t，1H)；7.72(d，1H)；8.13(d，1H)；8.25(s，1H)ppm。
Intermediate compound INT56
Acetate (4aR, 8aS)-1-(3-nitro-phenyl)-2-octahydro-isoquinoline 99.9-2-base-ethyl ester
Figure A20058004839600913
The compound dissolution that 5.75g is described in INT55 and mixes with the triethylamine of 5.4ml and the diacetyl oxide of 3.6ml down at 0 ℃ in the tetrahydrofuran (THF) of 100ml, then at room temperature stirs 48 hours.In rotatory evaporator, distill the solvent of half, add the half saturated sodium hydrogen carbonate solution of 100ml, use the dichloromethane extraction 3 times of 150ml then at every turn.The organic phase that merges is dry on sodium sulfate.Carry out drying on the silica gel by chromatogram and subsequently behind the recrystallization, obtaining the 4.07g title compound.
1H NMR (CDCl 3Main isomer): δ=0.72-1.05 (m, 3H); 1.06-1.35 (m, 4H); 1.40-1.89 (m, 6H); 2.00-2.22 (m, 4H); 2.55 (dd, 1H); 2.64-2.96 (m, 3H); 5.97 (dd, 1H); 7.51 (t, 1H); 7.68 (d, 1H); 8.14 (d, 1H); 8.22 (s, 1H) ppm.
Intermediate compound INT57
3-[(4aR, 8aS)-2-(octahydro-isoquinoline 99.9-2-yl)-ethyl]-phenyl amine
Figure A20058004839600921
With 4.07g at INT56) in the compound dissolution described in the glacial acetic acid of the ethyl acetate of 400ml and 100ml, mix with 400mg palladium carbon (10%) then.Hydrogenation is 15 hours under the hydrogen of 100bar and room temperature.Add the palladium carbon (10%) of other 1000mg, and hydrogenation 15 hours again under the hydrogen of 100bar and room temperature.Distilling the solvent of half in rotatory evaporator, add the 2N sodium hydroxide solution of about 1L, is 9.5 until the pH of solution.This solution is sequentially used the mixture extraction of being made up of chloroform and methyl alcohol (10: 1) of the ethyl acetate of 300ml and 500ml.Organic phase water (100ml) that merges and the washing of saturated salt solution (100ml), dry on sodium sulfate then.Filter solvents and in rotatory evaporator, concentrate this solvent after, obtain the 2.57g title compound.
1H?NMR(CDCl 3)：δ＝0.69-1.03(m，3H)；1.03-1.33(m，4H)；1.39-1.73(m，6H)；1.86.2，00(m，1H)；2.41-2.53(m，2H)；2.61-2.71(m，2H)；2.75-2.83(m，1H)；2.88-3.00(m，1H)；3.37-3.70(b，2H)；6.40-6.50(m，2H)；6.54(d，1H)；7.00(t，1H)ppm。
Intermediate compound INT58
2-chloro-N-(2-fluoro-5-nitro-phenyl)-ethanamide
Figure A20058004839600922
2-fluoro-5-nitro-phenyl amine of 10g is dissolved in the tetrahydrochysene furan food in one's mouth of 330ml, and mixes with the triethylamine of 19.5ml, the pyridine of 0.5ml and the chloracetyl chlorine of 5.6ml down, at room temperature stirred then 24 hours at 0 ℃.Distill solvent in rotatory evaporator, add the ethyl acetate of 1L, the half saturated sodium hydrogen carbonate solution with 200ml washs then.Organic phase is dry on sodium sulfate.After carry out chromatographically pure system on the silica gel, obtain the 5.4g title compound.
1H?NMR(CDCl 3)：δ＝4.27(s，2H)；7.21-7.38(m，IH)；7.97-8.31(m，1H)；8.66(s，b，1H)；9.19-9.32(m，1H)ppm。
Intermediate compound INT59
N-(2-fluoro-5-nitro-phenyl)-2-morpholine-4-base-ethanamide
Figure A20058004839600931
The compound dissolution that 3.0g is described in INT58 is in the dimethyl formamide of 50ml, and with 4 of the triethylamine that mixes 2.68ml, 330mg potassiumiodide and 1.18ml, the 4-morpholine mixes, and at room temperature stirs then 15 hours.Distill solvent in rotatory evaporator, add the ethyl acetate of 500ml, use the water washing of 50ml then, then each semi-saturation sodium hydrogen carbonate solution with 50ml washs 2 times.Organic phase is dry on sodium sulfate.After carry out chromatographically pure system on the silica gel, obtain the 2.7g title compound.
1H?NMR(CDCl 3)：δ＝2.66(t，4H)；3.23(s，2H)；3.79(t，4H)；7.18-7.33(m，1H)；7.92-8.05(m，1H)；9.27-9.39(m，1H)；9.73(s，b，1H)ppm。
Intermediate compound INT60
N-(5-amino-2-fluoro-phenyl)-2-morpholine-4-base-ethanamide
Figure A20058004839600932
The compound dissolution that 2.7g is described in INT59 mixes with 270mg palladium carbon (10%) in the ethanol of 500ml then.Under nitrogen atmosphere and room temperature, stirred 15 hours.After filtering on the diatomite and in rotatory evaporator, concentrating solvent, obtain the 2.4g title compound.
1H?NMR(CDCl 3)：δ＝2.62(t，4H)；3.15(s，2H)；3.35-3.70(b，2H)；3.77(t，4H)；6.25-6.39(m，1H)；6.81-6.95(m，1H)；7.70-7.84(m，1H)；9.44(s，b，1H)ppm。
Intermediate compound INT61
2-(4,4-two fluoro-piperidines-1-yl)-N-(2-fluoro-5-nitro-phenyl)-ethanamide
Figure A20058004839600941
The compound dissolution that 1.41g is described in INT58 is in the dimethyl formamide of 25ml, and with 4 of triethylamine, 155mg potassiumiodide and the 1.0g of 1.26ml, 4-difluoro piperidines mixes, and at room temperature stirs then 15 hours.Distillation is at room temperature added the mixture that 500ml is made up of methylene dichloride and methyl alcohol (100: 1) after removing and desolvating, and uses the semi-saturation sodium hydrogen carbonate solution of 50ml to wash then 2 times at every turn.Organic phase is dry on sodium sulfate.After carry out chromatographically pure system on the silica gel, obtain the 1.1g title compound.
1H?NMR(CDCl 3)：δ＝2.00-2.21(m，4H)；2.78(t，4H)；3.28(s，2H)；7.18-7.34(m，1H)；7.91-8.52(m，1H)；9.25-9.38(m，1H)；9.62(s，b，1H)ppm。
Intermediate compound INT62
N-(5-amino-2-fluoro-phenyl)-2-(4,4-two fluoro-piperidines-1-yl)-ethanamide
Figure A20058004839600942
The compound dissolution that 1.1g is described in INT61 mixes with 110mg palladium carbon (10%) in the ethanol of 200ml then.Under nitrogen atmosphere and room temperature, stirred 15 hours.After concentrating solvent, obtain the 0.99g title compound by diatomite filtration and in rotatory evaporator.
1H?NMR(CDCl 3)：δ＝1.93-2.20(m，4H)；2.73(t，4H)；3.20(s，2H)；3.60(b，2H)；6.24-6.44(m，1H)；6.87(t，1H)；7.65-7.85(m，1H)；9.36(s，b，1H)ppm。
Intermediate compound INT63
(5-bromo-2-chloro-pyrimidine-4-yl)-(2-methoxyl group-ethyl)-amine
Figure A20058004839600943
With the 5-bromo-2 of 5.0g, the 4-dichloro pyrimidine is dissolved in the acetonitrile of 100ml, mixes with the triethylamine of 5.2ml and the 2-methoxy ethyl amine of 1.85ml, at room temperature stirs then 15 hours.Add the ethyl acetate of 100ml, use the water washing 2 times of 50ml then at every turn, then each saturated nacl aqueous solution washing with 50ml 2 times.Organic phase is dry on sodium sulfate.After carry out chromatographically pure system on the silica gel, obtain the 4.97g title compound.
1H?NMR(CDCl 3)：δ＝3.46(s，3H)；3.62(t，2H)；3.77(m，2H)；5.98(s，b，1H)；8.18(s，1H)ppm。
Intermediate compound INT64
5-bromo-N *4 *-(2-methoxyl group-ethyl)-pyrimidine-2, the 4-diamines
Figure A20058004839600951
The compound dissolution that 2.97g is described in INT63 is in the methyl alcohol of 80ml.This solution is saturated with ammonia under 8bar, and the autoclave of sealing stirred 20 hours down at 80 ℃ then.In rotatory evaporator, distill solvent.The methanol mixed of residue and 10ml is put into the chloroform of 100ml, uses the water washing 2 times of 20ml then at every turn.After carry out chromatographically pure system on the silica gel, obtain the 1.4g title compound.
1H?NMR(CDCl 3)：δ＝3.39(s，3H)；3.54(t，2H)；3.61(m，2H)；4.82(s，b，2H)；5.54(s，b，1H)；7.86(s，1H)ppm。
Intermediate compound INT65
N *4 *-(2-methoxyl group-ethyl)-pyrimidine-2, the 4-diamines
Figure A20058004839600952
The compound dissolution that 1.1g is described in INT64 mixes with 110mg palladium carbon (10%) in the ethanol of 250ml then.Under nitrogen atmosphere and room temperature, stirred 15 hours.After concentrating solvent by diatomite filtration and in rotatory evaporator, obtain the title compound of 0.99g, it is a HBr salt.
1(DMSO-d6 is with K for H NMR 2CO 3Store together): δ=3.27 (s, 3H); 3.43-3.58 (m, 4H); 6.12 (d, 1H); 7.64 (d, 1H); 7.73 (s, b, 2H); 8.81 (s, b, 1H); 11.57 (s, b, 1H) ppm.
Intermediate compound INT66
(R)-2-(5-bromo-2-chloro-pyrimidine-4-base is amino)-3-methyl-Ding-1-alcohol
Figure A20058004839600961
Be similar to the preparation of intermediate compound INT63, by initial 5-bromo-2,4-dichloro pyrimidine and (R)-2-amino-3-methyl-Ding-1-alcohol obtains title compound.
Molecular weight/MS (ESI) [M+1] +: 294.58/294; 296 (100%); 298.
Intermediate compound INT67
(R)-2-(2-amino-5-bromo-pyrimidine-4-base is amino)-3-methyl-Ding-1-alcohol
Figure A20058004839600962
The compound dissolution that 1.0g is described in INT66 is in the methyl alcohol of 100ml.This solution is saturated with ammonia under 8bar, and the autoclave of sealing stirred 20 hours down at 80 ℃ then.In rotatory evaporator, distill solvent.The methanol mixed of residue and 5ml is put into the chloroform of 50ml, uses the water washing 2 times of 20ml then at every turn.After carry out chromatographically pure system on the silica gel, obtain the 640mg title compound.
1(DMSO-d6 is with K for H NMR 2CO 3Store together): δ=0.90-1.04 (m, 6H); 1.91-2.08 (m, 1H); 3.00 (s, b, 1H); 3.70 (dd, 1H); 3.80 (dd, 1H); 3.95 (m, 1H); 4.89 (s, 2H); 5.33 (d, 1H); 7.89 (s, 1H) ppm.
Intermediate compound INT68
(6-bromo-pyridine-2-yl)-two fluoro-acetate ethyl esters
Figure A20058004839600963
With 2 of 6.75g, the 6-dibromo pyridine is dissolved in the dimethyl sulfoxide (DMSO) of 40ml.Add the copper powder of 4.1g and the Bromodifluoroacetic acid ethyl ester of 7.51g, and stirred 4 hours down at 50 ℃.Reaction mixture mixes with the ethyl acetate of 200ml and the 1.3M potassium dihydrogen phosphate of 200ml, and at room temperature stirs 30 minutes.Cross filter solid, separate organic phase, the semi-saturation salt solution with 50ml washs 3 times at every turn, and is dry on sodium sulfate then.After carry out chromatographically pure system on the silica gel, obtain the 4.1g title compound.
1(DMSO-d6 is with K for H NMR 2CO 3Store together): δ=1.24 (t, 3H); 4.38 (q, 2H); 7.88-7.97 (m, 2H); 8.03 (t, 1H) ppm.
Intermediate compound INT69
2-(6-bromo-pyridine-2-yl)-2,2-two fluoro-ethanol
Figure A20058004839600971
The compound dissolution that 7.75g is described in INT68 mixes with the sodium borohydride of 785mg down at 0 ℃ in the ethanol of 130ml, at room temperature stirs then 4 hours.Add the 2M hydrochloric acid of 15ml with the ice bath cooling down.At room temperature stirred 10 minutes, then with sodium hydroxide solution with pH regulator to 10.Reaction mixture mixes with the methylene dichloride of 500ml and the semi-saturation salt solution of 100ml, separates organic phase and drying on sodium sulfate.After carrying out pure system by filtered through silica gel, obtain the 6.3g title compound.
1(DMSO-d6 is with K for H NMR 2CO 3Store together): δ=3.93 (t, 2H); 5.59 (s, 1H); 7.70 (d, 1H); 7.9 (d, 1H); 7.90 (t, 1H) ppm.
Intermediate compound INT70
2-bromo-6-[2-(tertiary butyl-dimethyl one silanyloxy base)-1,1-two fluoro-ethyls]-pyridine
6.9g the compound dissolution of describing in INT69 in the dimethyl formamide of 60ml, mixes with the imidazoles of 3.77g and the tert-butyldimethylsilyl chloride of 5.27g, at room temperature stirs then 15 hours.Add the semi-saturation sodium hydrogen carbonate solution of 300ml, the ethyl acetate extraction of then each usefulness 150ml 3 times.The organic phase that merges is dry on sodium sulfate.After carrying out pure system by filtered through silica gel, obtain the 9.2g title compound.
1(DMSO-d6 is with K for H NMR 2CO 3Store together): δ=-0.07 (s, 6H); 0.70 (s, 9H); 4.16 (t, 2H); 7.72 (d, 1H); 7.80 (d, 1H); 7.91 (t, 1H) ppm.
Intermediate compound INT71
6-[2-(tertiary butyl-dimethyl-silanyloxy base)-1,1-two fluoro-ethyls]-pyridine-2-yl }-(2,4-dimethoxy-benzyl)-amine
Figure A20058004839600981
The compound dissolution that 2.5g is described in INT70 25ml two uh in the alkane, with 2 of 2.7ml, the sodium tert-butoxide of the acid chloride of 4-dimethyl benzyl amine, 168mg, the BINAP of 218mg and 950mg mixes, and stirs 3 hours down at 80 ℃ then.Add the water of 100ml, use the ethyl acetate extraction 3 times of 50ml then at every turn.The organic phase that merges is dry on sodium sulfate.After carry out chromatographically pure system on the silica gel, obtain the 2.3g title compound.
1(DMS0-d6 is with K for H NMR 2CO 3Store together): δ=-0.07 (s, 6H); 0.75 (s, 9H); 3.69 (s, 3H); 3.77 (s, 3H); 4.06 (t, 2H); 4.30 (d, 2H); 6.39 (d, 2H); 6.48-6.58 (m, 2H); 6.69 (d, 1H); 6.97 (t, 1H); 7.20 (d, 1H); 7.41 (t, 1H) ppm.
Intermediate compound INT72
2-[6-(2,4-dimethoxy one benzylamino)-pyridine-2-yl]-2,2-two fluoro-ethanol
Figure A20058004839600982
The compound dissolution that 2.3g is described in INT71 mixes with the 1M tetrabutyl ammonium fluoride tetrahydrofuran solution of 13ml in the tetrahydrofuran (THF) of 100ml then, at room temperature stirs then 1 hour.Add the half saturated sodium hydrogen carbonate solution of 100ml, the ethyl acetate extraction of then each usefulness 100ml 3 times.The organic phase that merges is dry on sodium sulfate.After carry out chromatographically pure system on the silica gel, obtain the 1.42g title compound.
1(DMSO-d6 is with K for H NMR 2CO 3Store together): δ=3.70 (s, 3H); 3.77 (s, 3H); 3.87 (t, 2H); 4.30 (d, 2H); 5.37 (s, b, 1H); 6.41 (d, 1H); 6.50-6.59 (m, 2H); 6.70 (d, 1H); 6.95 (t, 1H); 7.13 (d, 1H); 7.41 (t, 1H) ppm.
Intermediate compound INT73
Methanesulfonic 2-[6-(2,4-dimethoxy-benzylamino)-pyridine-2-yl]-2,2-two fluoro-ethyl esters
The compound dissolution that 1.37g is described in INT72 mixes with the triethylamine of 1.47ml and the methane sulfonyl chloride of 0.49ml down at 0 ℃ in the tetrahydrofuran (THF) of 100ml then, then at room temperature stirs 2 hours.Add the water of 100ml, use 50ml ethyl acetate extraction 3 times then at every turn.The organic phase that merges is dry on sodium sulfate.After carry out chromatographically pure system on the silica gel, 1.56g obtains title compound.
1(DMSO-d6 is with K for H NMR 2CO 3Store together): δ=3.19 (s, 3H); 3.70 (s, 3H); 3.77 (s, 3H); 4.31 (d, 2H); 4.79 (t, 2H); 6.41 (d, 1H); 6.52 (s, 1H); 6.62 (d, 1H); 6.79 (d, 1H); 7.08-7.19 (m, 2H); 7.49 (t, 1H) ppm.
Intermediate compound INT74
[6-(1,1-two fluoro-2-tetramethyleneimine-1-base-ethyls)-pyridine-2-yl]-(2,4-dimethoxy-benzyl)-amine
Figure A20058004839600992
The compound dissolution that 2.0g is described in INT73 is in the dimethyl formamide of 40ml, and with the salt of wormwood of 1.38g, 120mg potassiumiodide, the tetramethyleneimine of and2.1ml mixes, and stirs 24 hours down at 120 ℃ then.Add the ethyl acetate of 200ml, water (50ml) washing then, and then each with the half saturated sodium chloride solution washing of 50ml 3 times.Organic phase is dry on sodium sulfate.After carry out chromatographically pure system on the silica gel, obtain the 1.35g title compound.
1(DMSO-d6 is with K for H NMR 2CO 3Store together): δ=1.54 (b, 4H); 2.40 (b, 4H); 3.14 (t, 2H); 3.70 (s, 3H); 3.77 (s, 3H); 4.30 (d, 2H); 6.39 (d, 1H); 6.48-6.57 (m, 2H); 6.68 (d, 1H); 7.00 (t, 1H); 7.10 (d, 1H); 7.42 (t, 1H) ppm.
Intermediate compound INT75
6-(1,1-two fluoro-2-tetramethyleneimine-1-base-ethyls)-pyridine-2-base amine
Figure A20058004839600993
The compound dissolution that 1.34g is described in INT74 mixes with the trifluoroacetic acid of 14ml in the methylene dichloride of 70ml, at room temperature stirs then 1 hour.Add the sodium hydrogen carbonate solution of 50ml, use the dichloromethane extraction 3 times of 50ml then at every turn.The organic phase that merges is dry on sodium sulfate.Obtain the title compound crude product of 520mg, its not further pure system is promptly reacted.
1(DMSO-d6 is with K for H NMR 2CO 3Store together): δ=1.58 (b, 4H); 2.49 (b, 4H); 3.14 (t, 3H); 6.15 (s, 2H); 6.46 (d, 1H); 6.69 (d, 1H); 7.42 (t, 1H) ppm.
Intermediate compound INT76
4-[2-(3-nitro-phenoxy group)-ethanoyl]-piperazine-1-formic acid tertiary butyl ester
Figure A20058004839601001
(9.3g 50mmol) is dissolved in the N,N-DIMETHYLACETAMIDE (200ml), is dripping SOCl under argon gas and the room temperature in 5 minutes time then with 3-nitro-phenoxy acetate 2(7.4ml, 102mmol).At room temperature stirred 30 minutes, (19.1g 102mmol), and uses ice-cooled portion-wise addition Boc-piperazine simultaneously then.Under argon gas and room temperature, stirred 50 minutes, and reaction mixture is poured in the water (500ml),, use ethyl acetate extraction (3 * 100ml) then with the yellow soda ash neutralization.(3 * 100ml) washings, dry on sodium sulfate, vacuum distilling removes and desolvates the organic phase water that merges then.Obtain the title compound of dark oil with quantitative yield, it is crystallization fully lentamente.This crude product promptly is used for next step reaction without pure system.
1H-NMR(CDCl 3，)：δ＝1.49(s，9H)；3.42(m，4H)；3.50(m，4H)；4.82(s，2H)；7.32(dd，1H)；7.48(t，1H)；7.77(m，1H)；.88(dd，1H)ppm。
Intermediate compound INT77
4-[2-(3-amino-phenoxy group)-ethanoyl]-piperazine-1-formic acid tertiary butyl ester
Figure A20058004839601002
The compound dissolution that 22g (50mmol) is described in INT76 is in methyl alcohol (600ml).Add Pd/C (4g) under argon gas, it is complete to be hydrogenated to absorption of hydrogen then.Filter out catalyzer, vacuum distilling removes and desolvates then.Obtain the brown buttery title compound of heavy-gravity with quantitative yield.This crude product promptly is used for next step reaction without pure system.
1H-NMR(CDCl 3,)：δ＝1.48(s，9H)；3.41(m，4H)；3.59(m，4H)；4.68(s，2H)；6.31(m，3H)；7.07(t，1H)ppm。
Intermediate compound INT78
3-(3-nitrophenyl 1-propionic aldehyde
Figure A20058004839601011
The Dess-Martin periodinane of 2.81g is added in 3-(3-the nitrophenyl)-solution of 1-propyl alcohol (ref.J.Med.Chem., 1989,32,2104) in the 100ml methylene dichloride of 0.80g.At room temperature stirred 2 hours.Add 10% hypo solution of 50ml and the saturated sodium bicarbonate solution of 50ml, at room temperature stirred 10 minutes, in rotatory evaporator, distill out methylene dichloride then.Residue is used the ethyl acetate extraction 2 times of 100ml at every turn, and the water washing of the organic phase 100ml of merging is dry on sodium sulfate then.Concentrate in rotatory evaporator except that after desolvating, obtain the title compound crude product of 780mg, it does not carry out the i.e. further reaction of extra pure system.
1H-NMR(CDCl 3)：δ＝2.86(t，2H)；3.06(t，2H)；7.44-7.49(m，1H)；7.55(d，1H)；8.08(m，2H)；9.83(s，1H)ppm。
Intermediate compound INT79
1-[3-(3-nitro-phenyl)-propyl group]-piperidines
Figure A20058004839601012
The sodium cyanoborohydride of the piperidines of 1.27ml and 0.16g is added in the solution of compound in the methyl alcohol of 10ml that 0.46g makes in INT78.At room temperature stirred 3 hours, and added the ethyl acetate of water and the 40ml of 50ml then.Separate each phase, and contain the ethyl acetate extraction 2 times that water is used 40ml at every turn.The organic phase that merges is with the saturated common salt solution washing of 40ml, and is dry on sodium sulfate then.After carry out chromatographically pure system on the silica gel, obtain the 635mg title compound.
1H-NMR(CDCl 3)：δ＝1.41-1.48(m，2H)；1.57-1.65(m，4H)；1.87(q，2H)；2.32-2.44(m，6H)；2.75(t，2H)；7.43(t，1H)；7.52(d，1H)；8.06(m，2H)ppm。
Intermediate compound INT80
6-fluoro-pyridine-2-base amine
Figure A20058004839601021
2 of 13g, 25% ammonium hydroxide aqueous solution of 6-difluoro pyridine and 15ml stirred 24 hours in bomb tube under 125 ℃.Reaction mixture is cooled to 0 ℃ and stirred 2 hours under this temperature.The solid filtering that is settled out is also dry under 40 ℃ and vacuum.Obtain the 5.0g title compound.
Molecular weight/MS (ESI) [M+1] +: 112.107/113.
1H?NMR(CDCl 3)：δ＝4.52，(bs，2H)，6.24(dd，1H)；6.35(dd，1H)；7.50(q，1H)ppm。
Intermediate compound INT81
(6-fluoro-pyridine-2-yl)-carboxylamine tertiary butyl ester
Figure A20058004839601022
The compound dissolution that 0.5g is described in INT80 mixes with the dimethyl aminopyridine of 10mg, the diisopropyl ethyl amine of 1.57ml and the di-tert-butyl dicarbonic acid ester of 0.97g in the tetrahydrofuran (THF) of 10ml, at room temperature stirs then 4 hours.Add the ethyl acetate of 100ml, and water (50ml) washing.Organic phase is dry on sodium sulfate.After carry out chromatographically pure system on the silica gel, obtain the 100mg title compound.
Molecular weight/MS (ESI) [M+1] +: 212.226/213.
1H?NMR(CDCl 3)：δ＝1.54，(s，9H)，6.56(dd，1H)；7.08(bs，1H)；7.74(m，2H)ppm。
Intermediate compound INT82
[6-(2-methoxyl group-ethylamino)-pyridine-2-yl]-carboxylamine tertiary butyl ester
1.0g 2-oxygen base-ethylamine of compound of describing in INT81 and 5.0ml stirred 48 hours down at 80 ℃.Reaction mixture vacuum-evaporation concentrates.Residue is put into the ethyl acetate of 100ml, sequentially extracts with the water of 50ml and the saturated common salt solution of 50ml then, and is then dry on sodium sulfate.After carry out chromatographically pure system on the silica gel, obtain the 500mg title compound.
Molecular weight/MS (ESI) [M+1] +: 267.331/268.
1H?NMR(CDCl 3)：1.50，(s，9H)；3.32(s，3H)；3.42(m，2H)；3.52(m，2H)；4.64(t，1H)；6.08(d，1H)；6.90(s，1H)；7.18(d，1H)；7.34(t，1H)ppm。
Intermediate compound INT83
N-(2-methoxyl group-ethyl)-pyridine-2, the 6-diamines
Figure A20058004839601031
The compound dissolution that 0.51g is described in INT82 mixes with the 4M HCl dioxane solution of 4.0ml in the methylene dichloride of 5ml then.At room temperature stirred 48 hours.Vacuum distilling removes and desolvates, and residue is put into the ethyl acetate of 100ml, and is sequentially with the 1N sodium hydrogen carbonate solution of 50ml, the water of 50ml and the saturated common salt solution washing of 50ml, then dry on sodium sulfate then.Distillation obtains the 300mg title compound after removing and desolvating.
Molecular weight/MS (ESI) [M+1] +: 167.212/168.
1H NMR (DMSO-d6 stores with K2CO3): δ=3.36 (s, 3H); 3.42 (m, 2H); 3.54 (m, 2H); 4.16 (s, 2H); 4.60 (s, 1H); 5.80 (m, 2H); 7.18 (t, 1H) ppm.
Intermediate compound INT84
3,5,6-three fluoro-pyridine-2-base amine
5.0g 2,3,5,25% ammonium hydroxide aqueous solution of the tetrahydrofuran (THF) of 6-ptfe pyridine, 140ml and 25ml stirred in bomb tube 48 hours under 60 ℃.Reaction mixture mixes with the water of 100ml, uses the Anaesthetie Ether of 150ml to extract then 3 times at every turn.Obtain the title compound crude product of 3.5g in dry also distillation on the sodium sulfate except that after desolvating, it does not carry out extra pure system and promptly further reacts.
Molecular weight/MS (EsI) [M+1] +: 148.088/149.
Be similar to the following compound of method for preparing.
Figure A20058004839601041
Figure A20058004839601051
Figure A20058004839601061
Figure A20058004839601071
Figure A20058004839601081
Figure A20058004839601091
Figure A20058004839601101
Figure A20058004839601111
2. template is synthetic
Intermediate compound INTT1)
Cyano group-ethylenebis dithiocarbamate carbamyl-acetate ethyl ester
Figure A20058004839601121
Isothiocyanic acid ethyl ester with 4.25ml under 25 ℃ is added in the mixture of being made up of 5g ethyl cyanacetate and 5ml triethylamine.Make it 50 ℃ of following restir 6 hours.Reaction mixture is followed vacuum-evaporation and is concentrated.Residue is put into ethanol, is poured over 150ml then in ice-cooled 1N hydrochloric acid.Make it 25 ℃ of following restir 3 hours, filter out residue then.The solid of gained washes with water again, obtains the product of 7g.
Molar mass=200.261; MS (ESD:[M+1] +=201.
Intermediate compound INTT2)
(E or Z)-cyano group-(3-ethyl-4-oxo-thiazolidin-2-ylidene)-acetate ethyl ester
With 7.82g at intermediate compound INTTl) in the compound dissolution described in the tetrahydrofuran (THF) of 100ml.Slowly add the bromoacetyl chloride of 3.9ml, make it then 25 ℃ of following restir 8 hours.Then reaction mixture is poured in the saturated sodium bicarbonate aqueous solution.Restir 1 hour is used ethyl acetate extraction then.Organic phase is washed with saturated nacl aqueous solution, and is dry on sodium sulfate, and vacuum-evaporation concentrates then.The crude product of gained obtains the product of 7.7g by recrystallization in the mixture of ethyl acetate/diisopropyl ester.
1H-NMR(CDCl3)：δ＝1.36(6H)；3.70(2H)；4.32(4H)ppm。
Intermediate compound INTT3)
(E or Z)-cyano group-(5-(E/Z)-oxyethyl group methylene radical-3-ethyl-4-oxo-thiazolidin-2-ylidene)-acetate ethyl ester
Figure A20058004839601123
By 1.54g at intermediate compound INTT2) in the triethyl orthoformate of the compound, the 2.5ml that describe and mixture backflow that the 3.5ml diacetyl oxide is formed 8 hours.Then reaction mixture is poured in the frozen water, makes its restir 3 hours, filter out residue then.The solid of gained washes with water again, obtains the product of 1.28g.
1H-NMR(CDCl3)：δ＝1.38(9H)；4.20-4.40(6H)；7.72(1H)ppm。
Intermediate compound INTT4)
(E or Z)-cyano group-(3-ethyl-4-oxo-thiazolidin-2-ylidene)-allyl acetate
Figure A20058004839601131
Under 0 ℃ the solution of 37.6ml cyanoacetic acid allyl ester in the 60ml dimethyl formamide is being added in the suspensoid of 12.8g sodium hydride (60%) in the 200ml dimethyl formamide.0 ℃ of following restir 10 minutes, add the solution of isothiocyanic acid ethyl ester in the 60ml dimethyl formamide of 28.0ml then.Then 25 ℃ of following restir 2 hours.Add down the solution of 32ml bromoacetyl chloride in the 60ml dimethyl formamide at 0 ℃, and 25 ℃ of following restir 15 hours.Reaction mixture is poured in the saturated sodium bicarbonate solution.Use ethyl acetate extraction, organic phase is washed with saturated nacl aqueous solution, and is dry on sodium sulfate, and vacuum-evaporation concentrates then.Crude product carries out pure column chromatography system by the mixture that uses hexane/ethyl acetate on silica gel, obtain the product of 33.9g.
1H-NMR(CDCl3)：δ＝1.23(3H)；4.11(2H)；4.71(2H)；5.25(1H)；5.37(1H)；5.90-6.04(1H)ppm。
Intermediate compound INTT5)
(E or Z)-cyano group-(5-(E/Z)-oxyethyl group methylene radical-3-ethyl-4-oxo-thiazolidin-2-ylidene)-allyl acetate
Figure A20058004839601132
Be similar to intermediate compound INTT3), by 12.8g at intermediate compound INTT4) in the diacetyl oxide of the triethyl orthoformate of the compound, the 20.9ml that describe and 29.4ml obtain the product of 14.8g.
1H-NMR(CDCl3)：δ＝1.32-1.45(6H)；4.23(2H)；4.38(2H)；4.73(2H)；5.29(1H)；5.41(1H)；5.92-6.05(1H)；7.72(1H)ppm。
Intermediate compound INTT6)
Cyano group-[3-ethyl-4-oxo-thiazolidine-(2-(E or z))-subunit]-acetate
With 5.04g at intermediate compound INTT4) in the compound dissolution described in the tetrahydrofuran (THF) of 300ml.Add 1 of 3.42g, four of 3-dimethyl barbituric acid and 1.17g-(triphenylphosphine)-palladium.At room temperature stirred 30 minutes, reaction mixture is evaporated to dried in rotatory evaporator then.The not further pure system of the crude product that obtains thus can be used.
1H-NMR (DMSO-d6, the signal of selection) δ=1.21 (t, 3H); 3.89 (s, 2H); 4.10 (q, 2H); 13.24 (s, b, 1H) ppm.
Intermediate compound INTT7) 2-cyano group-N-ethyl-2-[3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit] ethanamide
Figure A20058004839601142
With about 4.15g at intermediate compound INTT6) in the compound (crude product, it is to be obtained by the compound that 2.5g describes in intermediate compound INTT4) described be dissolved in the dimethyl formamide of 100ml.Add 3.34g sodium bicarbonate, 6.0ml ethylamine in the tetrahydrochysene furan is fed solution (c=2.0M) and the TBTU of 3.88g.At room temperature stirred 3 hours.Reaction mixture mixes with water, uses ethyl acetate extraction then.Organic solution is washed with saturated nacl aqueous solution, and is dry on sodium sulfate, then evaporation concentration.After carrying out pure system, obtain the 1.47g title compound by ethyl alcohol recrystallization.
1H-NMR(DMSO-d6)：δ＝1.05(t，3H)；1.21(t，3H)；3.18(pentuplet，2H)；3.70(s，2H)；4.10(q，2[I)；7.81(t，1H)ppm。
Be similar to the following compound of method for preparing.
Figure A20058004839601161
3. ethyl ester and allyl ester intermediate product is synthetic
Intermediate compound INTE1
Cyano group-[3-ethyl-4-oxo-5-[1-[3-(2-tetramethyleneimine-1-base-ethyl)-phenyl amino] first-(E/Z)-subunit]-thiazolidine-(2-(E or Z))-subunit]-sour ethyl ester
Figure A20058004839601171
With 740mg at intermediate compound INT3) in the compound dissolution described in the ethanol of 50ml.Add 1.1g at intermediate compound INTT3) in the compound described, and the stirring 5 hours that refluxes.Concentrated solvent in rotatory evaporator.After carry out chromatographically pure system on the silica gel, obtain the title compound of 540mg, it is the dependent 5-of pH (E/Z)-isomer mixture.
1H-NMR (CDCl3, main isomer): δ=1.38 (t, 3H); 1.42 (t, 3H); 1.83 (m, 4H); 2.60 (m, 4H); 2.72 (m, 2H); 2.86 (m, 2H); 4.31 (q, 2H); 4.43 (q, 2H); 6.87-6.97 (m, 2H); 7.00 (d, 1H); 7.29 (t, 1H); 7.62 (d, 1H); 10.56 (d, 1H) ppm.
Intermediate compound INTE2
Cyano group-[3-ethyl-4-oxo-5-[1-[3-(2-tetramethyleneimine-1-base-ethyl)-phenyl amino]-first-(E/Z)-subunit]-thiazolidine-(2-(E or Z))-subunit]-allyl acetate
Figure A20058004839601172
With 1.35g at intermediate compound INT3) in the compound dissolution described in the ethanol of 400ml.Add 2.19g at intermediate compound INTT5) in the compound described, and the stirring 4 hours that refluxes.Concentrated solvent in rotatory evaporator.After carry out chromatographically pure system on the silica gel, obtain the title compound of 2.2g, it is the dependent 5-of pH (E/Z)-isomer mixture.
1H-NMR (DMSO-d6 stores with K2CO3, main isomer): δ=1.24 (t, 3H); 1.69 (m, 4H); 2.50 (m, 4H); 2.66 (m, 2H); 2.76 (m, 2H); 4.25 (q, 2H); 4.71 (d, 2H); 5.26 (d, 1H); 5.38 (d, 1H); 5.90-6.08 (m, 1H); 6.96 (d, 1H); 7.12 (d, 1H); 7.22 (s, 1H); 7.26 (t, 1H); 8.22 (s, 1H); 10.53 (s, b, 1H) ppm.
Intermediate compound INTE3
Cyano group-[3-ethyl-5-[1-[3-(2-base-2-methyl-propionyl amino)-phenyl amino]-first-(E/Z)-subunit]-4-oxo-thiazolidine-(2-(E or Z))-subunit]-allyl acetate
Figure A20058004839601181
With 1.26g at intermediate compound INT6) in the compound dissolution described in the ethanol of 400ml.Add 2.0g at intermediate compound INTT5) in the compound described, stirring 6 hours under refluxing then.After the cooling, reaction mixture filters, and the solid of gained obtains the title compound of 1.4g by recrystallization in the ethanol, and it is the dependent 5-of pH (E/Z)-isomer mixture.The solution that obtains during filtration evaporation concentration in rotatory evaporator.After carry out chromatographically pure system on the silica gel, residue forms the title compound of other 1.1g, and it is the dependent 5-of pH (E/Z)-isomer mixture.
1H-NMR (DMSO-d6 stores with K2CO3, main isomer): δ=1.28 (t, 3H); 1.38 (s, 6H); 4.26 (q, 2H); 4.72 (d, 2H); 5.27 (d, 1H); 5.39 (d, 1H); 5.76 (s, 1H); 5.90-6.08 (m, 1H); 6.99 (d, 1H); 7.27 (t, 1H); 7.46 (d, 1H); 7.89 (s, 1H); 8.16 (s, 1H); 9.67 (s, 1H); 10.63 (s, 1H) ppm.
Intermediate compound INTE4
Cyano group-[3-ethyl-5-[1-(2-ethylamino-pyridin-4-yl amino)-first-(E/Z)-subunit]-4-oxo-thiazolidine-(2-(E or Z))-subunit]-allyl acetate
Figure A20058004839601182
With 0.94g at intermediate compound INT12) in the compound dissolution described in the 1-of 50ml propyl alcohol.Add 1.85g at intermediate compound INTT5) in the compound described, and the stirring 4 hours that refluxes.After the cooling, reaction mixture filters.After carry out chromatographically pure system on the silica gel, the solid of gained forms the title compound of 1.48g, and it is the dependent 5-of pH (E/Z)-isomer mixture.
1H-NMR (DMSO-d6 stores with K2CO3, main isomer): δ=1.13 (t, 3H); 1.26 (t, 3H); 3.24 (pentuplet, 2H); 4.25 (q, 2H); 4.72 (d, 1H); 5.28 (d, 1H); 5.39 (d, 1H); 5.90-6.07 (m, 1H); 6.25 (d, 1H); 6.44 (dd, 1H); 6.49 (t, 1H); 7.85 (d, 1H); 8.13 (s, 1H); 10.47 (s, 1H) ppm.
Intermediate compound INTE5
Cyano group-[5-[1-[6-(2,2-dimethyl-propionyl amino)-pyridine-2-base is amino]-first-(E/Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-allyl acetate
Figure A20058004839601191
With 1.35g at intermediate compound INT9) in the compound dissolution described in the 1-of 50ml propyl alcohol.Add 2.0g at intermediate compound INTT5) in the compound described, and stirring 3 hours under refluxing.After the cooling, reaction mixture filters, and the solid of gained obtains the title compound of 2.47g by recrystallization in the ethanol, and it is the dependent 5-of pH (E/Z)-isomer mixture.
1H-NMR pMSO-d6 stores with K2CO3, main isomer): δ=1.20-1.31 (m, 12H); 4.27 (q, 2H); 4.72 (d, 2H); 5.28 (d, 2H); 5.39 (d, 2H); 5.91-6.06 (m, 1H); 6.29 (d, 2H); 7.68-7.80 (m, 2H); 8.86 (s, 1H); 9.71 (s, 1H); 10.94 (s, 1H) ppm.
Be similar to the following compound of method for preparing.
Figure A20058004839601201
Figure A20058004839601211
Figure A20058004839601231
Figure A20058004839601261
Figure A20058004839601271
Figure A20058004839601281
Figure A20058004839601291
Figure A20058004839601301
Figure A20058004839601311
Figure A20058004839601321
Figure A20058004839601331
Figure A20058004839601341
Figure A20058004839601351
Figure A20058004839601361
Figure A20058004839601371
Figure A20058004839601381
Figure A20058004839601391
Figure A20058004839601401
Figure A20058004839601411
Figure A20058004839601431
Figure A20058004839601441
Figure A20058004839601451
Figure A20058004839601471
Intermediate compound INTE77
4-[2-(3-{[2-[1-allyl group oxygen base carbonyl-1-cyano group-first-(E or Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(5-(E/Z))-ylidenylmethyl]-amino }-phenoxy group)-ethanoyl] piperazine-1-formic acid tertiary butyl ester
The compound dissolution that compound that 4.8g is described in INT77 and 4.4g describe in INTT5 stirred 3 hours under the gentle argon gas of 95 ℃ bath in ethanol (140ml) then.Formed throw out suction filtration is also used washing with alcohol.Obtain title compound (5.7g), productive rate is 67%.The not extra pure system of crude product promptly is used for next step.
1H-NMR (DMSO-d6 stores with K2CO3, main isomer): δ=1.26 (t, 3H); 1.40 (s, 2H); 3.32 (m, 4H); 3.45 (m, 4H); 4.28 (m, 2H); 4.72 (d, 2H); 4.89 (s, 2H); 5.29 (dd, 1H); 5.40 (dd, 1H); 5.99 (m, 1H); 6.68 (dd, 1H); 6.90 (s, 1H); 6.93 (d, 1H); 7.28 (t, 1H); 8.21 (d, 1H); 10.47 (d, 1H) ppm.
Intermediate compound INTE78
Cyano group-[3-ethyl-4-oxo-5-[1-[3-(2-oxo-2-piperazine-1-base-oxyethyl group)-phenyl amino]-first-(E/Z)-subunit]-thiazolidine-(2-(E or Z))-subunit] allyl acetate
Figure A20058004839601483
The compound dissolution that 2.99g is described in INTE77 at room temperature slowly adds trifluoroacetic acid (10ml) then in methylene dichloride (100ml).Under room temperature and argon gas, stirred 2.5 hours, add 10% aqueous sodium carbonate (about 170ml) then, make thus to react completely.(3 * 100ml) extractions, (1 * 100ml) washs the organic phase of merging reaction mixture, dry on sodium sulfate then with sodium chloride solution with methylene dichloride.Distill solvent in rotatory evaporator after, obtain title compound (2g), productive rate is 80%.This not extra pure system promptly is used for next step.
1H-NMR (DMSO-d6 stores with K2C03, main isomer): δ=1.23 (m, 3H); 2.68 (m, 2H); 2.71 (m, 2H); 4.25 (m, 2H); 4.73 (m, 2H); 4.82 (s, 2H); 5.29 (dd, 1H); 5.39 (dd, 1H); 5.99 (m, 1H); 6.64 (dd, 1H); 6.88 (s, 1H); 6.91 (d, 1H); 7.27 (t, 1H); 8.22 (s, 1H) ppm.
Intermediate compound INTE79
[5-[1-{3-[2-(4-benzyl-piperazine-1-yl)-2-oxo-oxyethyl group]-phenyl amino }-first-(E/Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-cyano group-allyl acetate
Figure A20058004839601491
Compound that 2.9g is described in INTE78 and the phenyl aldehyde of 0.92ml are suspended in the methyl alcohol (240ml), at room temperature add acetate (24ml) and sodium cyanoborohydride (0.7g) then.This reactant stirred 5 hours under room temperature and argon gas, and reaction mixture neutralizes by adding yellow soda ash, then the throw out of suction filtration formation.Obtain title compound (2.54g), productive rate is 71%.The not extra pure system of this product promptly is used for next step.
1H-NMR (DMSO-d6 stores with K2CO3, main isomer): 1H-NMR δ=1.29 (m, 3H); 2.32 (m, 2H); 2.41 (m, 2H); 3.43 (m, 4H); 4.26 (m, 2H); 4.72 (d, 2H); 4.86 (s, 2H); 5.29 (d, 1H); 5.40 (d, 1H); 6.00 (m, 1H); 6.68 (dd, 1H); 6.89 (s, 1H); 6.92 (d, 1H); 7.30 (m, 6H); 8.21 (d, 1H); 10.50 (d, 1H) ppm.
4. synthetic sour intermediate compound
Intermediate compound INTA1
The preparation method 1
Cyano group-[3-ethyl-4-oxo-5-[1-[3-(2-tetramethyleneimine-1-base-ethyl) phenyl amino]-first-(E/Z)-subunit]-thiazolidine-(2-(E or Z))-subunit]-acetate
Figure A20058004839601492
Under 0 ℃ the 1.1g potassium tert.-butoxide is introduced in the tetrahydrofuran (THF) of 50ml, the water with 45 μ l mixes then.Add 540mg at intermediate compound INTE1) in the compound described, and 0 ℃ of stirring 30 minutes down, restir 20 hours at room temperature then.Add the triethylamine of 0.25ml and the 2M hydrochloric acid diethyl ether solution of 10.5ml down at 0 ℃, and at room temperature stirred 1 hour.Concentrated solvent under the high vacuum, and the not extra pure system of residue promptly is used for further reaction.
MW：412.51；MS(EsI)[M+1] +：413
The preparation method 2
Figure A20058004839601501
With 300mg at intermediate compound INTE2) in the compound, the Pd (PPh of 80mg described 3) 4Be dissolved in the tetrahydrofuran (THF) of 18ml with the morpholine of 0.6ml and stirred 15 hours.After adding the ether of 40ml, filter resulting solid, vacuum-drying is dissolved in the dimethyl formamide of 10ml then.This solution is added in the suspension of PL-MIA resin (Polymer Laboratories GmbH Company) in the 5ml dimethyl formamide of 770mg, at room temperature stirred then 15 hours.Reaction mixture filters, and under high vacuum concentrated solvent.Obtain the title compound of 280mg as crude product.
1H-NMR (DMSO-d6 stores with K2CO3): δ=1.20 (t, 3H); 1.88 (m, 4H); 2.50 (m, 4H); 3.09 (m, 2H); 3.20 (m, 2H); 4.20 (q, 2H); 6.93 (d, 1H); 7.04-7.12 (m, 2H); 7.23 (t, 1H); 7.88 (s, 1H); 9.97 (s, 1H) ppm.
Intermediate compound INTA2
Cyano group-[3-ethyl-5-[1-(2-ethylamino-pyridin-4-yl amino)-first-(E/Z)-subunit] 4-oxo-thiazolidine-(2-(E or Z))-subunit]-acetate
With 1.2g at intermediate compound INTE4) in the compound, the Pd (PPh of 350mg described 3) 4Be dissolved in the tetrahydrofuran (THF) of 60ml with the morpholine of 2.6ml and at room temperature stirred 1 hour.After adding the hexane of 40ml, the solid of gained filters, and vacuum-drying is dissolved in the dimethyl formamide of 20ml then.This solution is added in the suspension of PL-MIA resin (Polymer Laboratories GmbH Company) in the 30ml dimethyl formamide of 6.0g, at room temperature stirred then 15 hours.Reaction mixture filters, and under high vacuum concentrated solvent.Obtain the title compound of 970mg as crude product.
MW：359.41；MS(EsI)[M+1] +：360
1H-NMR (DMSO-d6 stores with K2CO3): δ=1.11 (t, 3H); 1.22 (t, 3H); 3.23 (m, 2H); 4.22 (q, 2H); 6.25 (s, 1H); 6.42 (d, 1H); 6.54 (s, b, 1H); 7.81 (d, 1H); 7.95 (s, 1H); 10.20 (s, 1H) ppm.
Intermediate compound INTA3
Cyano group-[5-[1-[6-(2,2-dimethyl-propionyl amino)-pyridine-2-base is amino] first-(E/Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-acetate
Figure A20058004839601511
With 2.2g at intermediate compound INTE5) in the compound, the Pd (PPh of 560mg described 3) 4Be dissolved in the tetrahydrofuran (THF) of 110ml with the morpholine of 4.2ml and at room temperature stirred 1 hour.After adding the hexane of 50ml, the solid that is settled out carries out suction filtration, and vacuum-drying is dissolved in the dimethyl formamide of 25ml then.This solution is added in the suspension of PL-MIA resin (Polymer Laboratories GmbH Company) in the 50ml dimethyl formamide of 9.6g, at room temperature stirred then 15 hours.Reaction mixture filters, and under high vacuum concentrated solvent.Obtain the title compound of 2.1g as crude product.
MW：415.47；MS(ESI)[M+1] +：416
1H-NMR (DMSO-d6 stores with K2CO3): δ=1.15-1.30 (m, 12H); 4.23 (q, 2H); 6.80 (m, 1H); 7.64-7.74 (m, 2H); 8.73 (d, 1H); 9.68 (s, 1H); 10.68 (d, 1H) ppm.
Be similar to the following compound of method for preparing.
Figure A20058004839601521
Figure A20058004839601531
Figure A20058004839601541
Figure A20058004839601551
Figure A20058004839601561
Figure A20058004839601571
Intermediate compound INTA23
[5-[1-{3-[2-(4-benzyl-piperazine-1-yl)-2-oxo-oxyethyl group] phenyl amino }-first-(E/Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-cyano group-acetate
The compound that 2.5g is described in INTE79 is suspended among the THF (320ml), adds barbituric acid (0.6g) and Pd (PPh then 3) 4(0.49g).Reaction mixture stirs and spends the night, and evaporation concentration is until precipitation occurring in rotatory evaporator for reaction mixture, and formed then throw out carries out suction filtration, obtains title compound (522mg), and productive rate is 23%.The not extra pure system of this product promptly is used for next step.
EI-MS＝548。
Be similar to the following compound of method for preparing.
Figure A20058004839601573
Figure A20058004839601581
Figure A20058004839601591
Figure A20058004839601601
5. synthesizing amide compound
Embodiment 1
2-cyano group-2-[3-ethyl 4-oxo-5-[1-[3-(2-tetramethyleneimine-1-base-ethyl)-phenyl amino]-first-(E/Z)-subunit]-thiazolidine-(2-(E or Z))-subunit]-N-(2-hydroxyl-1,1-dimethyl-ethyl)-ethanamide
Figure A20058004839601621
With 170mg at intermediate compound INTA1) in the crude product (about 0.42mmol) described be dissolved in the dimethyl formamide of 10ml, mix with the sodium bicarbonate of 248mg, 2-amino-2-methyl-third-1-alcohol of 62 μ l and the TBTU of 200mg, at room temperature stirred then 18 hours.Reaction mixture mixes with half saturated sodium hydrogen carbonate solution and uses dichloromethane extraction.Organic solution is washed with saturated nacl aqueous solution, and is dry on sodium sulfate, and evaporation concentration and after carry out chromatographically pure system on the silica gel obtains the title compound of 61mg, and it is the dependent 5-of pH (E/Z)-isomer mixture.
1H-NMR (DMSO-d6 stores with K2CO3, main isomer): δ=1.30 (t, 3H); 1.36 (s, 6H); 1.74 (m, 4H); 2.54 (m, 4H); 2.69 (m, 2H); 2.79 (m, 2H); 3.43 (d, 2H); 4.27 (q, 2H); 5.27 (t, 1H); 6.74 (s, 1H); 7.00 (d, 1H); 7.18 (d, 1H); 7.25-7.35 (m, 2H); 8.19 (s, 1H); 10.31 (s, 1H) ppm.
Embodiment 2
Tetrahydropyrans-4-formic acid (3-{[2-[1-cyano group-1-ethyl carbamyl-first-(E or Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(5-(E/Z))-ylidenylmethyl]-amino }-phenyl)-acid amides
Tetrahydropyrans-4-formic acid of 42mg is dissolved in the tetrahydrofuran (THF) of 10ml.Under 0 ℃, add the chloroformic acid isobutyl of triethylamine and the 42 μ l of 80 μ l.At room temperature stirred 30 minutes.Add 100mg at embodiment 6) in the compound of description.At room temperature stirred 12 hours.Reaction mixture mixes with half saturated sodium hydrogen carbonate solution and uses dichloromethane extraction.Organic solution is washed with saturated nacl aqueous solution, and is dry on sodium sulfate, and evaporation concentration and after carry out chromatographically pure system on the silica gel obtains the title compound of 49mg, and it is the dependent 5-of pH (E/Z)-isomer mixture.
(DMSO-d6 stores with K2CO3, main isomer): δ=1.07 (t, 3H); 1.2 (t, 3H); 1.68 (m, 4H); 2.58 (m, 2H); 3.19 (pentuplet, 2H); 3.39 (m, 1H); 3.90 (m, 1H); 4.21 (q, 2H); 6.90 (s, 1H); 7.12-7.31 (m, 2H); 7.50-7.80 (m, 2H); 8.04 (s, 1H); 9.81-9.99 (s, b, 1H); 10.39 (s, 1H) ppm.
Embodiment 3
2-cyano group-N-ethyl-2-[3-ethyl-5-[1-{3-[3-(4-hydroxymethyl-piperidines-1-yl)-propionyl amino]-phenyl amino }-first-(E/Z)-subunit] 4-oxo-thiazolidine-(2-(E or Z))-subunit]-ethanamide
Figure A20058004839601631
With 150mg at embodiment 19) in the compound dissolution described in the tetrahydrofuran (THF) of 5ml.Add the triethylamine of 0.25ml and piperidin-4-yl-methyl alcohol of 62mg.Refluxed 12 hours.Reaction mixture mixes with half saturated sodium hydrogen carbonate solution and uses dichloromethane extraction.Organic solution is washed with saturated nacl aqueous solution, and is dry on sodium sulfate, and evaporation concentration and after carry out chromatographically pure system on the silica gel obtains the title compound of 37mg, and it is the dependent 5-of pH (E/Z)-isomer mixture.
(DMSO-d6 stores with K2CO3, main isomer): δ=0.97-1.40 (m, 9H); 1.64 (d, 2H); 1.90 (t, 2H); 2.45 (m, 2H); 2.60 (t, 2H); 2.89 (m, 2H); 3.11-3.29 (m, 4H); 4.21 (q, 2H); 4.49 (t, 1H); 6.92 (s, 1H); 7.13 (d, 1H); 7.24 (t, 1H); 7.56-7.80 (m, 2H); 8.02 (s, 1H); 10.18 (s, 1H); 10.40 (s, 1H) ppm.
Embodiment 4
2-cyano group-2-[3-ethyl-5-[1-(3-hydroxymethyl-phenyl amino)-first-(E/Z)-subunit]-4-oxo-thiazolidine-(2-(E or Z))-subunit]-N-Propargyl-ethanamide
Figure A20058004839601632
With 50mg at intermediate compound INT9) in the compound dissolution described in the ethanol of 5ml.Add the pure and mild 100 μ l triethyl orthoformates of 3-aminobenzyl of 148mg.Under refluxing, stirred 3 hours.After the reaction mixture cooling, the product that is settled out carries out suction filtration.After carrying out pure system by recrystallization in the ethanol, obtain the 56mg title compound.
1H-NMR (DMSO-d6 stores with K2CO3, main isomer): δ=1.24 (t, 3H); 3.07 (s, b, 1H); 3.92 (m, 2H); 4.23 (q, 2H); 4.49 (d, 2H); 5.25 (t, 1H); 7.00 (d, 1H); 7.13 (d, 1H); 7.21-7.35 (m, 2H); 7.95-8.20 (m, 2H); 10.40 (s, 1H) ppm.
Embodiment 5
2-cyano group-N-ethyl-2-[3-ethyl-4-oxo-5-[1-[3-(2-piperidines-1-base-acetylamino)-phenyl amino]-first-(E/Z)-subunit]-thiazolidine-(2-(E or Z))-subunit]-ethanamide
With 50mg at intermediate compound INTT7) in the compound dissolution described in the ethanol of 10ml.Add 140mg at intermediate compound INT20) in the compound of description and the triethyl orthoformate of 100 μ l.Under refluxing, stirred 3 hours.The reaction mixture evaporation concentration.After carrying out pure system by recrystallization in the ethanol, obtain the title compound of 26mg, it is the dependent 5-of pH (E/Z)-isomer mixture.
1H-NMR (DMSO-d6 stores with K2CO3, main isomer): δ=1.07 (t, 1H); 1.25 (t, 3H); 1.41 (m, 2H); 1.59 (m, 4H); 2.44 (m, 4H); 3.06 (s, 2H); 3.20 (pentuplet, 2H); 4.23 (q, 2H); 6.96 (d, 1H); 7.20-7.33 (m, 2H); 7.60-7.77 (m, 2H); 8.03 (s, 1H); 9.70 (s, 1H); 10.39 (s, 1H) ppm.
Embodiment 6
2-[5-[1-(3-amino-phenyl amino)-first-(E/Z)-subunit] 3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-2-cyano group-N-ethyl-ethanamide
Figure A20058004839601642
With 7.75g at embodiment 79) in the preparation compound be suspended in the methylene dichloride of 120ml.Add the trifluoroacetic acid of 70ml.At room temperature stirred 1 hour.The reaction mixture evaporation concentration is mixed with methylene dichloride and hexane, and then evaporation concentration.Under vacuum, after the thorough drying, obtain the title compound of 11.2g trifluoroacetic acid form.The not further pure system of this product promptly is used for following reaction.
1H-NMR (DMSO-d6 stores with K2CO3, main isomer): δ=1.07 (t, 3H); 1.26 (t, 3H); 3.20 (m, 2H); 4.22 (q, 2H); 6.80 (d, 1H); 7.01 (s, 1H); 7.05 (d, 1H); 7.30 (t, 1H); 7.74 (t, 1H); 8.01 (d, 1H); 9.20 (s, b, 3H); 10.35 (d, 1H) ppm.
Embodiment 7
2-[5-[1-[3-(2-chloro-acetylamino)-phenyl amino]-first-(E/Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-2-cyano group-N-ethyl-ethanamide
Figure A20058004839601651
Will about 16.9mmol at embodiment 6) in during the crude product of compound (11.2g) of the preparation tetrahydrochysene furan that is suspended in 500ml feeds.At room temperature add the triethylamine of 5.15ml,, and at room temperature stirred 2 hours then at the sym-dichloroacetic anhydride of 15 ℃ of following portion-wise addition 3.28g.Reaction mixture mixes with half saturated sodium hydrogen carbonate solution, uses ethyl acetate extraction then.Organic solution is washed with saturated nacl aqueous solution, and dry on sodium sulfate, evaporation concentration after recrystallization carries out pure system in by ethanol then, obtains the title compound of 5.26g, and it is the dependent 5-of pH (E/Z)-isomer mixture.
1H-NMR (DMSO-d6 stores with K2CO3, main isomer): δ=1.09 (t, 3H); 1.26 (t, 3H); 3.21 (pentuplet, 2H); 4.21 (q, 2H); 4.28 (s, 2H); 7.00 (d, 1H); 7.20 (d, 1H); 7.29 (t, 1H); 7.58-7.77 (m, 1H); 8.01 (s, 1H); 10.35 (s, 1H); 10.41 (s, 1H) ppm.
Embodiment 8
2-cyano group-N-ethyl-2-[3-ethyl-5-[1-{3-[2-(4-methyl-piperidines-1-yl)-acetylamino]-phenyl amino }-first-(E/Z)-subunit]-4-oxo-thiazolidine-(2-(E or Z))-subunit]-ethanamide
Figure A20058004839601652
With 100mg at embodiment 7) in the compound dissolution described in the dimethyl formamide of 5ml.Add the 4-methyl piperidine of triethylamine, 6mg potassiumiodide and the 38 μ l of 0.15ml.At room temperature stirred 4 hours.Reaction mixture mixes with half saturated sodium hydrogen carbonate solution and uses ethyl acetate extraction.Organic solution is washed with saturated nacl aqueous solution, and is dry on sodium sulfate, evaporation concentration, and after carry out chromatographically pure system on the silica gel, obtain the title compound of 62mg, it is the dependent 5-of pH (E/Z)-isomer mixture.
1H-NMR (DMSO-d6 stores with K2CO3, main isomer): δ=0.91 (d, 3H); 1.08 (t, 3H); 1.14-1.40 (m, 6H); 1.59 (d, 2H); 2.12 (t, 2H); 2.83 (d, 2H); 3.09 (s, 2H); 3.21 (m, 2H); 4.22 (q, 4H); 6.96 (d, 2H); 7.20-7.33 (m, 2H); 7.58-7.78 (m, 2H); 8.04 (s, 1H); 9.69 (s, 1H); 10.40 (s, 1H) ppm.
Embodiment 9
2-[5-[1-{3-[2-(4-ethanoyl-piperazine-1-yl)-acetylamino]-phenyl amino }-first-(E/Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit] 2-cyano group-N-ethyl-ethanamide
With 94mg at embodiment 80) in the preparation compound be suspended in the methylene dichloride of 5ml.Add the trifluoroacetic acid of 2.5ml.At room temperature stirred 30 minutes.The reaction mixture evaporation concentration is mixed with methylene dichloride and hexane, and then evaporation concentration.Under vacuum, after the thorough drying, the residue that obtains thus is suspended in the dimethyl formamide of 5ml.Add the acetate of 50 μ l, the sodium bicarbonate of 67mg and the TBTU of 62mg.At room temperature stirred 12 hours.Reaction mixture mixes with half saturated sodium hydrogen carbonate solution and uses ethyl acetate extraction.Organic solution is washed with saturated nacl aqueous solution, and dry on sodium sulfate, evaporation concentration after recrystallization carries out pure system in by ethanol then, obtains the title compound of 48mg, and it is the dependent 5-of pH (E/Z)-isomer mixture.
1H-NMR (DMSO-d6 stores with K2CO3, main isomer): δ=1.07 (t, 3H); 1.25 (t, 3H); 2.00 (s, 3H); 2.41-2.60 (m, 4H); 3.14-3.28 (m, 4H); 3.50 (m, 4H); 4.22 (q, 2H); 6.98 (m, 1H); 7.21-7.31 (m, 2H); 7.63-7.76 (m, 2H); 8.00 (s, 1H); 9.81 (s, 1H); 10.40 (s, 1H) ppm.
Embodiment 10
2-cyano group-N-ethyl-2-[3-ethyl-5-[1-{3-[2-(4-methane sulfonyl-piperazine-1-yl)-acetylamino] phenyl amino }-first-(E/Z)-subunit]-4-oxo-thiazolidine-(2-(E or Z))-subunit]-ethanamide
With 120mg at embodiment 80) in the preparation compound be suspended in the methylene dichloride of 5ml.Add the trifluoroacetic acid of 2.5ml, and at room temperature stirred 30 minutes.The reaction mixture evaporation concentration is mixed with methylene dichloride and hexane, and revaporization concentrates.After the thorough drying, the residue that obtains thus is suspended in the tetrahydrofuran (THF) of 5ml under vacuum.Add the triethylamine of 150 μ l and the methanesulfonic of 20 μ l, and at room temperature stirred 3 hours.Reaction mixture is with half saturated sodium hydrogen carbonate solution, mix with ethyl acetate then.Organic solution is washed with saturated nacl aqueous solution, and dry on sodium sulfate, evaporation concentration after recrystallization carries out pure system in by ethanol then, obtains the title compound of 46mg, and it is the dependent 5-of pH (E/Z)-isomer mixture.
1H-NMR (DMSO-d6 stores with K2C03, main isomer): δ=1.08 (t, 3H); 1.24 (t, 3H); 2.63 (m, 4H); 2.91 (s, 3H); 3.10-3.28 (m, 8H); 4.22 (q, 2H); 6.95 (s, 1H); 7.20-7.30 (m, 2H); 7.56-7.75 (m, 2H); 8.05 (s, 1H); 9.80 (s, 1H); 10.40 (s, 1H) ppm.
Embodiment 11
2-cyano group-N-cyano methyl-2-[3-ethyl-5-[1-[3-(2-hydroxyl-acetylamino)-phenyl amino] first-(E/Z)-subunit]-4-oxo-thiazolidine-(2-(E or Z))-subunit] ethanamide
Figure A20058004839601671
With 100mg at embodiment 95) in the preparation compound dissolution in the methyl alcohol of 10ml.Add the water of 1ml and the salt of wormwood of 30mg.At room temperature stirred 2 hours.Reaction mixture mixes with water and uses ethyl acetate extraction.Organic solution is washed with saturated nacl aqueous solution, and dry on sodium sulfate, evaporation concentration after recrystallization carries out pure system in by ethanol then, obtains the title compound of 72mg, and it is the dependent 5-of pH (E/Z)-isomer mixture.
1H-NMR (DMSO-d6 stores with K2CO3, main isomer): δ=1.26 (t, 3H); 4.01 (d, 1H); 4.17 (d, 2H); 4.25 (q, 2H); 5.70 (t, 1H); 6.99 (d, 2H); 7.28 (t, 1H); 7.40 (d, 1H); 7.81 (s, 1H); 8.09 (s, 1H); 8.35 (s, 1H); 9.73 (s, 1H); 10.53 (s, 1H) ppm.
Embodiment 12 methanesulfonic 2-(3-{[2-[1-cyano group-1-(cyano methyl-carbamyl)-first-(E or Z)-subunit] 3-ethyl-4-oxo-thiazolidine-(5-(E/Z))-ylidenylmethyl] amino }-phenyl)-ethyl ester
Figure A20058004839601672
With 1.0g at embodiment 71) in the compound dissolution of preparation in the tetrahydrofuran (THF) of the dimethyl formamide of 10ml and 200ml.Under-100C, add the triethylamine of 0.9ml and the methane sulfonyl chloride of 0.31ml, and at room temperature stirred 1 hour.Reaction mixture mixes with half saturated sodium hydrogen carbonate solution and uses ethyl acetate extraction.Organic solution is washed with saturated nacl aqueous solution, and is dry on sodium sulfate, and evaporation concentration.The solid of gained mixes with methylene dichloride, at room temperature stirs 1 hour, filters then.Obtain the title compound of 1.0g, it is the dependent 5-of pH (E/Z)-isomer mixture.
1H-NMR (DMSO-d6 stores with K2CO3, main isomer): δ=1.26 (t, 3H); 3.00 (t, 2H); 3.11 (s, 3H); 4.17 (m, 2H); 4.24 (q, 2H); 4.45 (t, 2H); 7.01 (d, 1H); 7.19 (d, 1H); 7.25-7.36 (m, 2H); 8.19 (s, 1H); 8.34 (t, 1H); 10.41 (s, 1H) ppm.
Embodiment 13
2-cyano group-N-cyano methyl-2-[3-ethyl-5-[1-[3-(2-iodo-ethyl)-phenyl amino]-first-(E/z)-subunit]-4-oxo-thiazolidine-(2-(E or Z))-subunit 1-ethanamide
Figure A20058004839601681
With 4.5g at embodiment 12) in the preparation compound dissolution in the butanone of 400ml.Add the sodium iodide of 1.72g, under refluxing, stirred 8 hours then.Reaction mixture mixes with water and uses ethyl acetate extraction.By containing the initiator that aqueous phase reclaims 1.6g.Organic solution is dry and evaporation concentration on sodium sulfate, obtains the title compound of 3.0g, and it is the dependent 5-of pH (E/Z)-isomer mixture.
1H-NMR (DMSO-d6 stores with K2CO3, main isomer): δ=1.27 (t, 3H); 3.12 (t, 2H); 3.50 (t, 2H); 4.16 (d, 2H); 4.24 (q, 2H); 6.98 (d, 1H); 7.18 (d, 1H); 7.22-7.34 (m, 2H); 8.20 (d, 1H); 8.35 (t, 1H); 10.41 (d, 1H) ppm.
Embodiment 14
2-cyano group-N-cyano methyl-2-[3-ethyl-5-[1-[3-(2-morpholine-4-base-ethyl)-phenyl amino]-first-(E/Z)-subunit]-4-oxo-thiazolidine-(2-(E or Z))-subunit] ethanamide
Figure A20058004839601682
With 120mg at embodiment 13) in the preparation compound dissolution in the dimethyl formamide of 5ml.Add the morpholine of 42mg and the salt of wormwood of 65mg, and at room temperature stirred 12 hours.Reaction mixture mixes with water and uses ethyl acetate extraction.Organic solution is washed with saturated nacl aqueous solution, and is dry on sodium sulfate, evaporation concentration, and after carry out chromatographically pure system on the silica gel, obtain the title compound of 40mg, it is the dependent 5-of pH (E/Z)-isomer mixture.
1H-NMR (DMSO-d6 stores with K2CO3, main isomer):: δ=1.27 (t, 3H); 2.43 (m, 4H); 2.52 (m, 2H); 2.74 (m, 2H); 3.59 (m, 4H); 4.17 (m, 2H); 4.23 (q, 2H); 6.95 (d, 1H); 7.11 (d, 1H); 7.19-7.30 (m, 2H); 8.18 (s, 1H); 8.32 (s, 1H); 10.39 (s, 1H) ppm.
Be similar to the following compound of method for preparing.
Figure A20058004839601691
Figure A20058004839601701
Figure A20058004839601711
Figure A20058004839601731
Figure A20058004839601751
Figure A20058004839601761
Figure A20058004839601771
Figure A20058004839601791
Figure A20058004839601801
Figure A20058004839601811
Figure A20058004839601821
Figure A20058004839601841
Figure A20058004839601851
Figure A20058004839601871
Figure A20058004839601881
Figure A20058004839601891
Figure A20058004839601901
Figure A20058004839601911
Figure A20058004839601921
Figure A20058004839601931
Figure A20058004839601941
Figure A20058004839601951
Figure A20058004839601961
Figure A20058004839601981
Figure A20058004839601991
Figure A20058004839602001
Figure A20058004839602011
Figure A20058004839602021
Figure A20058004839602041
Figure A20058004839602051
Figure A20058004839602061
Figure A20058004839602081
Figure A20058004839602111
Figure A20058004839602121
Figure A20058004839602131
Figure A20058004839602151
Figure A20058004839602161
Figure A20058004839602171
Figure A20058004839602191
Figure A20058004839602201
Figure A20058004839602211
Figure A20058004839602221
Figure A20058004839602231
Figure A20058004839602241
Figure A20058004839602251
Figure A20058004839602261
Figure A20058004839602271
Figure A20058004839602281
Figure A20058004839602291
Figure A20058004839602301
Figure A20058004839602311
Figure A20058004839602321
Figure A20058004839602331
Figure A20058004839602341
Figure A20058004839602351
Figure A20058004839602361
Figure A20058004839602371
Figure A20058004839602381
Figure A20058004839602391
Figure A20058004839602401
Figure A20058004839602421
Figure A20058004839602431
Figure A20058004839602441
Figure A20058004839602451
Figure A20058004839602461
Figure A20058004839602471
Embodiment 198
Acetate (3-{[2-[1-cyano group-1-Propargyl carbamyl-first-(E or Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(5-(E/z))-ylidenylmethyl] amino }-the phenylamino formyl radical)-methyl ester
The compound dissolution that 2.5g is described in intermediate compound INTE44 in the tetrahydrofuran (THF) of 160ml, with the N of 1.66g, the Pd (PPh of N-dimethyl barbituric acid and 614mg 3) 4Mix, at room temperature stirred then 2 hours.Add triethylamine, the propargyl amine of 1.09ml and the TBTU of 5.12g of 3.68ml, and restir 15 hours at room temperature.Add the ethyl acetate of 250ml, use the water washing 1 time of 100ml then.Organic phase is dry on sodium sulfate.After carrying out pure system, obtain the title compound of 1.68g with the methylene dichloride recrystallization and with ethyl alcohol recrystallization.
1(DMSO-d6 is with K for H NMR 2CO 3Store main isomer together):
δ＝1.25(t，3H)；2.14(s，3H)；3.07(t，1H)；3.88-4.00(m，2H)；4.24(q，2H)；4.66(s，2H)；7.02(d，1H)；7.20(d，1H)；7.29(t，1H)；7.67(s，1H)；8.02(d，1H)；8,11(t，1H)；10.16(s，1H)；10.46(d，1H)ppm。
Embodiment 199
2-cyano group-2-[3-ethyl-5-[1-[3-(2-hydroxyl-acetylamino)-phenyl amino]-first-(E/Z)-subunit]-4-oxo-thiazolidine-(2-(E or Z))-subunit]-N-Propargyl-ethanamide
Figure A20058004839602482
The compound dissolution that 2.6g is described in embodiment 198 mixes with the methyl alcohol of 40ml and the water of 40ml in the dimethyl formamide of 80ml then.Add the salt of wormwood of 1.15g, and at room temperature stirred 2 hours.Add the ethyl acetate of 1000ml, separate organic phase, use the semi-saturation sodium chloride solution of 75ml to wash then at every turn 3 times.Organic phase is dry on sodium sulfate.Obtain the title compound of 2.19g.
(DMSO-d6 is with K 2CO 3Store main isomer together):
δ＝1.21(t，3H)；3.2(b，1H)；3.83-3,93(m，2H)；3.96(d，2H)；4.19(q，2H)；5.67(t，1H)；6.94(d，1H)；7.22(t，1H)；7.35(d，1H)；7.77(s，1H)；7.94-8.12(m，2H)；9.70(s，1H)；10.40(d，b，1H)ppm。
Embodiment 200
Methylsulfonic acid (3-{[2-[1-cyano group-1-Propargyl carbamyl-first-(E or z)-subunit]-3-ethyl-4-oxo-thiazolidine-(5-(E/Z))-ylidenylmethyl]-amino }-the phenylamino formyl radical)-methyl ester
Figure A20058004839602491
The compound dissolution that 2.18g is described in embodiment 199 mixes with the tetrahydrofuran (THF) of 320ml in the dimethyl formamide of 18ml then.Under 0 ℃, add the triethylamine of 1.78ml and the methylsulfonyl chloride of 0.60ml, and at room temperature stirred 1 hour.Add the ethyl acetate of 500ml and the water of 200ml, separate organic phase, use the semi-saturation sodium chloride solution of 75ml to wash then at every turn 3 times.Organic phase is dry on sodium sulfate.Solid stirs with methylene dichloride, carries out pure system thus, and obtains the title compound of 2.02g.
(DMSO-d6 is with K 2CO 3Store main isomer together): δ=1.24 (t, 3H); 3.06 (b, 1H); 3.31 (s, 3H); 3.86-3.99 (m, 2H); 4.22 (q, 2H); 4.85 (s, 2H); 7.04 (d, 1H); 7.22 (d, 1H); 7.30 (t, 1H); 7.68 (s, 1H); 8.03 (d, 1H); 8.10 (t, 1H); 10.24 (s, 1H); 10.47 (d, b, 1H) ppm.
Embodiment 201
2-cyano group-N-cyano methyl-2-[5-[1-{3-[2-(4,4-two fluoro-piperidines-1-yl)-acetylamino]-4-fluoro-phenyl amino }-first-(E/Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-ethanamide
Figure A20058004839602492
The compound that 60mg is described in INTT10 is suspended in the 1-propyl alcohol of 3ml, and compound of describing in INT62 with 138mg and the triethyl orthoformate of 0.16ml mix then.Under 140 ℃, in bomb tube, stirred 4 hours.This reaction mixture slowly cools to room temperature, and at room temperature stirs 15 hours.The solid filtering that is settled out is then sequentially with ethanol and ether washing.By filtered through silica gel and after carrying out pure system with ethyl alcohol recrystallization subsequently, obtain the title compound of 106mg.
(DMSO-d6 is with K 2CO 3Store main isomer together):
δ＝1.20(t，3H)；1.83-2.10(m，4H)；2.66(m，4H)；3.26(s，2H)；4.11(d，2H)；4.19(q，2H)；6.95-7.12(m，1H)；7.22(t，1H)；7.93(s，b，1H)；8.02(s，1H)；8.27(s，b，1H)；9.62(s，1H)；10.50(s，b，1H)ppm。
Embodiment 202
2-[5-[1-(3-amino-phenyl amino)-first-(E/Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-2-cyano group-N-(2,2,2-three fluoro-ethyls)-ethanamide
Figure A20058004839602501
The compound that 1.6g is described in embodiment 204 is suspended in the methylene dichloride of 40ml.Add the trifluoroacetic acid of 24ml, and at room temperature stirred 1 hour.This reaction mixture evaporation concentration is mixed with methylene dichloride and hexane, and revaporization concentrates.After the thorough drying, obtain the title compound of 1.7g trifluoroacetic acid salt form under the vacuum.The not further pure system of this crude product promptly is used for following reaction.
Embodiment 203
2-[5-[1-[3-(2-chloro-acetylamino)-phenyl amino]-first-(E/Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit] 2-cyano group-N-(2,2,2-three fluoro-ethyls)-ethanamide
Figure A20058004839602502
The trifluoroacetate of the compound that 3.1mmol is described in embodiment 202 is dissolved in the tetrahydrofuran (THF) of 45ml.Under 0 ℃, add the pyridine of 0.64ml and the sym-dichloroacetic anhydride of 0.60mg, at room temperature stirred then 30 minutes.Add the ethyl acetate of 200ml and the water of 100ml, separate organic phase, and dry on sodium sulfate.After carrying out pure system by recrystallization in the ethanol, obtain the title compound of 1.12g.
(DMSO-d6 is with K 2CO 3Store main isomer together):
δ＝1.27(t，3H)；3.98(m，2H)；4.19-4.31(m，4H)；7.04(d，1H)；7.22(d，1H)；7.31(t，1H)；7.70(s，1H)；8.06(b，1H)；8.21(b，1H)；10.40(s，1H)；10.54(s，b，1H)ppm。
Embodiment 204
N-allyl group-2-[5-[1-{3-[2-(4-benzyl-piperazine-1-yl)-2-oxo-oxyethyl group]-phenyl amino)-first-(E/Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit 1-2-cyano group-ethanamide
Figure A20058004839602511
The compound dissolution that 95mg is described in INTA23 adds HATU (194mg) and allyl amine (34 μ l) then in the DMF of 3ml.Reactant stirs under room temperature and argon gas and spends the night, and water (about 20ml) dilution is adjusted to alkalescence by adding sodium carbonate solution, uses ethyl acetate (3 * 10ml) extractions then.The organic phase that merges is dry on sodium sulfate, distills solvent then in rotatory evaporator.Crude product carry out chromatographically pure system on Flashmaster, obtain title compound (45mg), and productive rate is 45%.
1H-NMR (CDCl 3, main isomer): δ=1.39 (m, 3H); 2.49 (m, 4H); 3.61 (m, 4H); 3.69 (m, 2H); 3.97 (m, 2H); 4.38 (m, 2H); 4.80 (s, 2H); 5.21 (m, 2H); 5.88 (m, 1H); 6.38 (t, 1H); 6.58 (m, 3H); 7.12 (t, 1H); 7.50 (m, 2H); 7.68 (m, 1H); 8.00 (d, 1H); 8.65 (d, 1H); 10.40 (d, 1H) ppm.
Be similar to the following compound of method for preparing.
Figure A20058004839602521
Figure A20058004839602531
Figure A20058004839602541
Figure A20058004839602551
Figure A20058004839602561
Figure A20058004839602581
Figure A20058004839602591
Figure A20058004839602601
Figure A20058004839602611
Figure A20058004839602621
Figure A20058004839602631
Figure A20058004839602641
Figure A20058004839602651
Figure A20058004839602661
Figure A20058004839602671
Figure A20058004839602681
Figure A20058004839602691
Figure A20058004839602701
Figure A20058004839602711
Figure A20058004839602721
Figure A20058004839602731
Figure A20058004839602741
Figure A20058004839602751
Figure A20058004839602761
Figure A20058004839602771
Figure A20058004839602801
Figure A20058004839602831
Figure A20058004839602841
Figure A20058004839602851
Figure A20058004839602861
Figure A20058004839602871
Figure A20058004839602881
Figure A20058004839602891
Figure A20058004839602901
Figure A20058004839602911
Figure A20058004839602931
Figure A20058004839602941
Figure A20058004839602951
Figure A20058004839602961
Figure A20058004839602971
Figure A20058004839602981
Figure A20058004839603001
Figure A20058004839603011
Figure A20058004839603021
Figure A20058004839603031
Figure A20058004839603041
Figure A20058004839603061
Figure A20058004839603071
Figure A20058004839603081
Figure A20058004839603091
Figure A20058004839603101
Figure A20058004839603111
Figure A20058004839603121
Figure A20058004839603131
Figure A20058004839603141
Figure A20058004839603151
Figure A20058004839603181
Figure A20058004839603191
Figure A20058004839603211
Figure A20058004839603231
Figure A20058004839603241
Figure A20058004839603261
Figure A20058004839603271
Figure A20058004839603281
Figure A20058004839603291
Figure A20058004839603301
Embodiment 370
(3-{[2-[1-cyano group-1-(2,2,2-three fluoro-ethyl carbamyls)-first-(E or Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(5-(E/Z))-ylidenylmethyl] amino }-phenyl)-the carboxylamine tertiary butyl ester
Figure A20058004839603311
The trifluoroethyl amine of 2.6g, the TBTU of 8.4g and the triethylamine of 3.6ml are added in the l solution of intermediate compound INTA37 in DMF (360ml).This reaction mixture at room temperature stirred 12 hours.Distillation removes and desolvates, and the crude product of gained mixes, and uses then by ethyl acetate and saturated NaHCO 3The mixture extraction of solution composition.The organic phase that merges is dry on sodium sulfate, distills solvent then in rotatory evaporator.Crude product carry out chromatographically pure system, obtains the title compound of 7.9g.
MW：511；MS(ESI)[M+1] +：512
Embodiment 371
(3-{[2-[1-cyano group-1-Propargyl carbamyl-first-(E or Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(5-(E/Z))-ylidenylmethyl]-amino }-phenyl)-the carboxylamine tertiary butyl ester
The propargyl amine of 1.3ml, the TBTU of 6.2g and the triethylamine of 2.7ml are added in the solution of intermediate compound INTA37 in DMF (285ml).This reaction mixture at room temperature stirred 12 hours.Distillation removes and desolvates, and the crude product of gained mixes, and uses then by ethyl acetate and saturated NaHCO 3The mixture extraction of solution composition.The organic phase that merges is dry on sodium sulfate, distills solvent then in rotatory evaporator.Crude product carry out chromatographically pure system, obtains the title compound of 7.8g.
MW：467；MS(ESI)[M+1] +：468
Embodiment 372
2-cyano group-2-[3-ethyl-5-[1-(3-methylamino-phenyl amino)-first-(E/Z)-subunit]-4-oxo-thiazolidine-(2-(E or z))-subunit]-N-(2,2,2-three fluoro-ethyls)-ethanamide
Figure A20058004839603321
The compound that 7.9g is described in embodiment 370 is suspended in the methylene dichloride of 175ml.Add the trifluoroacetic acid of 19ml, and at room temperature stirred 2.5 hours.This reaction mixture is added into 400ml carefully in refrigerative 1MNaOH solution.Then mix, and with methylene dichloride and ethyl acetate extraction.Organic phase is at Na 2SO 4Last dry.Obtain the title compound of 7g trifluoroacetic acid salt form.The not further pure system of this crude product promptly is used for following reaction.
Embodiment 373
2-cyano group-2-[3-ethyl-5-[1-(3-methylamino-phenyl amino)-first-(E/Z)-subunit]-4-oxo-thiazolidine-(2-(E or Z))-subunit]-N-Propargyl-ethanamide
Figure A20058004839603322
The compound that 5.8g is described in embodiment 371 is suspended in the methylene dichloride of 140ml.Add the trifluoroacetic acid of 15.4ml, and at room temperature stirred 4 hours.This reaction mixture is added into 300ml carefully in refrigerative 1M NaOH solution.Then mix, and with methylene dichloride and ethyl acetate extraction.Organic phase is at Na 2SO 4Last dry.Obtain the title compound of 3g trifluoroacetic acid salt form.The not further pure system of this crude product promptly is used for following reaction.
Embodiment 374
2-[5-[1-{3-[(2-chloro-ethanoyl)-methyl-amino]-phenyl amino }-first-(E/Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-2-cyano group-N-(2,2,2-three fluoro-ethyls)-ethanamide
Figure A20058004839603323
The trifluoroacetate of the compound that 0.71mmol is described in embodiment 372 is dissolved in the tetrahydrofuran (THF) of 9ml.After adding the sym-dichloroacetic anhydride of 113 μ l, three pyridines and 157mg, at room temperature stirred 2.5 hours.Add the ethyl acetate of 20ml and the saturated sodium bicarbonate solution of 10ml, separate organic phase, and dry on sodium sulfate.Obtain the title compound of 0.4g.
MW：501；MS(ESI)[M+1] +：502
Embodiment 375
2-[5-[1-{3-[(2-chloro-ethanoyl)-and methyl-amino] phenyl amino }-first-(E/Z)-subunit] 3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-2-cyano group-N-Propargyl-ethanamide
Figure A20058004839603331
The trifluoroacetate of the compound that 8mmol is described in embodiment 373 is dissolved in the tetrahydrofuran (THF) of 50ml.After adding the 1.3ml pyridine and 2g sym-dichloroacetic anhydride among the THF that is dissolved in 50ml, at room temperature stirred 4 hours.Add the ethyl acetate of 200ml and the saturated sodium bicarbonate solution of 100ml.Separate organic phase and drying on sodium sulfate.Obtain the title compound of 3.1g.
MW：457；MS(ESI)[M+1] +：458
Parallel synthetic method 1 (PSM1):
Embodiment 376
2-cyano group-2-[5-[1-[3-(2-2,3-dihydro-benzo [1,4] oxazine-4-base-acetylamino)-phenyl amino] first-(E/Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-N-Propargyl-ethanamide
Figure A20058004839603332
In argon atmospher; with 3 of 270mg (0.38mmol); 4-dihydro-2H-benzo [solution of 1,4] oxazine in 0.5ml DMF is added into 2-[5-[1-[3-(2-chloro-acetylamino)-phenyl amino of 67mg (0.15mmol)]-first-(E/Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-2-cyano group-N-Propargyl-ethanamide and the solution of 6.5mg (0.04mmol) potassiumiodide in 1.5ml DMF in.After adding 170 μ l (1.22mmol) triethylamines, this mixture at room temperature stirred 12 hours.Desolvate by removing in this reaction mixture.The crude product that obtains thus carries out pure system by HPLC.Obtain the desirable product of 5.1mg (9%).
HPLC-MS (analysis) through the product of pure system
(detect: UV=254nmol; Post: Purospher STAR RPl8e, 125 * 4mm, 5 μ (Merck KgGa, Darmstadt); Flowing agent: A:H 2O/0.1%TFA, B:CH 3CN/0.1%TFA, gradient: 5 to 95%B, in 10 minutes; Flow velocity: 1ml/min):
Retention time=the 9.25min of product; The MS:m/z=560 of product ([M+H] +)
Parallel synthetic method 2 (PSM2):
Embodiment 377
2-cyano group-N-cyano methyl-2-[3-ethyl-5-[1-{3-[2-(2-methyl-tetramethyleneimine-1-yl)-acetylamino] phenyl amino }-first-(E/Z)-subunit]-4-oxo-thiazolidine-(2-(E or z))-subunit]-ethanamide
Figure A20058004839603341
In argon atmospher; with 3 of 278mg (0.37mmol); 4-dihydro-2H-benzo [solution of 1,4] oxazine in 0.5ml DMF be added into 76mg (0.15mmol) methylsulfonic acid (3-{[2-[1-cyano group-1-(cyano methyl-carbamyl)-first-(E or Z)-subunit]-3-ethyl-4-oxo-thiazolidine-(5-(E/Z))-ylidenylmethyl]-amino-the phenylamino formyl radical)-methyl ester and the solution of 6.5mg (0.04mmol) potassiumiodide in 1.5mlDMF in.After adding the diisopropyl ethyl amine of 213 μ l (1.22mmol), this mixture at room temperature stirred 12 hours.Desolvate by removing in this reaction mixture.The crude product that obtains thus carries out pure system by HPLC.Obtain the desirable product of 30mg (37%).
HPLC-MS (analysis) through the product of pure system
(detect: UV=254nmol; Post: Purospher STAR RP18e, 125 * 4mm, 5 μ (Merck KgGa, Darmstadt); Flowing agent: A:H 2O/0.1%TFA, B:CH 3CN/0.1%TFA, gradient: 5 to 95%B, in 10 minutes; Flow velocity: 1ml/min):
Retention time=the 9.09min of product; The MS:m/z=548 of product ([M+H] +)
Figure A20058004839603361
Figure A20058004839603371
Figure A20058004839603381
Figure A20058004839603391
Figure A20058004839603401
Figure A20058004839603411
Figure A20058004839603421
Figure A20058004839603441
Figure A20058004839603451
Figure A20058004839603461
Figure A20058004839603471
Figure A20058004839603481
Figure A20058004839603491
Figure A20058004839603501
Figure A20058004839603511
Figure A20058004839603521
Figure A20058004839603531
Figure A20058004839603551
Figure A20058004839603561
Figure A20058004839603571
Figure A20058004839603581
Figure A20058004839603591
Figure A20058004839603601
Figure A20058004839603631
Figure A20058004839603641
6.Additional acid amides s
The?follOwing?compounds?can?be?produced?analogously：
Table: acid amides s (2)
Figure A20058004839603651
Figure A20058004839603661
Figure A20058004839603671
Figure A20058004839603681
Figure A20058004839603691
Figure A20058004839603711
Figure A20058004839603721
Figure A20058004839603731
Figure A20058004839603741
Experimental example 1
Following examples have been described the biological action of The compounds of this invention.
The experiment of PLK enzyme
By pure system recombinant human Plk-1 (6xHis) in the insect cell (Hi5) of baculovirus infection.
10ng (by recombination form preparation and through pure system) PLK enzyme at room temperature be 15 μ l with volume through biotinylated casein and as the 33P-γ-ATP of substrate in 384 hole Greiner small volume microtiter plates incubation (ultimate density in the damping fluid was: the PLK of 660ng/ml in 90 minutes; 0.7 the casein of μ mol, the ATP of 0.5 μ mol comprises 33P-γ-ATP of 400nCi/ml; The MgCl2 of 10mmol, the MnCl2 of 1mmol; 0.01%NP40; The DTT of 1mmol, proteinase inhibitor; 0.1mmol Na2VO3, in the HEPES of 50mmol, pH7.5).For finishing reaction, that adds 5 μ l stops the solution (ATP of 500 μ mol; The EDTA of 500mmol; 1%Triton X100; 100mg/ml is coated with the SPA pearl of streptavidin in PBS).Behind the diaphragm seal microtiter plate, by centrifugal (10 minutes, 1500rpm) make described pearl precipitation.By the incorporation of 33P-γ-ATP in the beta counting measurement casein, as measuring of enzymic activity.The size of inhibitor activity is with reference to solvent control (=untamed enzymic activity=0% suppress) and the mean value (=complete downtrod enzymic activity=100% suppresses) that comprises several experiments of 300 μ mol wortmannins.
Use the test substances (in 0 μ mol and the 0.01-30 μ mol scope) of various concentration.The ultimate density of solvent dimethyl sulfoxide (DMSO) all is 1.5% in all experiments.
The proliferation function experiment
People MaTu breast tumor cell through cultivating spreads in the many titer plates in 96 holes with the density of 5000 cell/measurement point, and the volume of corresponding growth medium is 200 μ l.After 24 hours, dye, use fresh substratum (200 μ l) to replace the substratum of other plates simultaneously, and the test substances of adding various concentration is (in 0 μ m and the 0.01-30 mu m range with the cell of Viola crystallina (as follows) to a plate (plate at zero point); The ultimate density of solvent dimethyl sulfoxide (DMSO) is 0.5%).Culturing cell is 4 days under the situation that has test substances to exist.By measure the proliferation function of cell with the violet staining cell: at room temperature each measurement point is added 11% glutaraldehyde solution totally 15 minutes of 20 μ l, makes cell fixation thus.Wash with water after 3 circulations of fixed cell, described plate is at room temperature dry.Each measurement point is added 0.1% crystal violet solution (pH being set at 3 by adding acetate) of 100 μ l, makes cell dyeing thus.After washing 3 circulations of dyed cell with water, described plate is at room temperature dry.Each measurement point is added 10% acetic acid solution of 100 μ l, makes the dyestuff dissolving thus.Under 595nm, measure delustring by photometry.Make the observed value stdn of the delustring of the extinction value of plate at zero point (=0%) and (the 0 μ m) cell (=100%) that is untreated, calculate the variation (%) of cell growth thus.
The results are shown in the following table of experiment of PLK enzyme and tumor cell proliferation:
Figure A20058004839603761
Table 2: the contrast of prior art
Figure A20058004839603771
Table 3: the contrast of prior art
As can be seen from Table 1, the compound of general formula I of the present invention suppresses PLK.In addition, those skilled in the art from table 2 and 3 as can be seen, material of the present invention also has better effect than immediate prior art.
Accompanying drawing is described
Fig. 1 has shown the function of Plk-1.This:
1, enters mitotic division: Plk-1 activatory CDC25 C.This causes the activation of CDK/ cell periodic protein B mixture, and cell is converted into the M state by G2.
2, mitotic initiation: Plk1 is in division of cytoplasm, particularly playing the part of important role in the formation of bipolar spindle body device and mitotic division chromosome segregation in late period.Also need Plk-1 at the centrosome ripening period, and in conjunction with so-called " kinesin motor (kinesin motors) ".
3, mitotic finishing: Plk-1 activation APC/C mixture (anaphase promote mixture/cyclosome; People such as Kotani 1998).APC/C is as many ubiquitinization (polyubiquitinylation) of E3 enzyme catalysis specific substrates such as cell periodic protein B.Proteic these many ubiquitinization only cause them to be degraded to proteasome.This causes the Cycle Regulation agent to be reduced to below the threshold value again, and breaks away from m period (M → G1 changes) in so-called G1 attitude cell.

Claims (23)

1. the compound of general formula I and solvate thereof, hydrate, diastereomer, enantiomorph and salt,
Figure A2005800483960002C1
Wherein
T 1, T 2And T 3Independently of each other representative-CH=or-N=, and T 2Also can represent in addition (CF)=, U representative-CR 4=or-N=,
R 1The C that the optional one or many of representative is replaced by halogen identical or differently 1-C 3-alkyl or cyclopropyl,
R 2The C that the optional identical or different by cyano of one or many of representative, cyclopropyl, ethynyl or halogen replace 1-C 3-alkyl, C 3-C 4-thiazolinyl, C 3-C 4-alkynyl or cyclopropyl,
Or represent at least once by methyl substituted hydroxyethyl,
R 3Represent K, L or M, or represent R 15,
The C that the optional one or many of K representative is replaced by X identical or differently 1-C 3-alkyl or C 2-C 4-thiazolinyl, X are represented halogen, hydroxyl or are represented group-OR 6,-NR 10R 11Or represent C 2-C 10-Heterocyclylalkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose the identical or different by cyano of one or many, halogen, hydroxyl, aryl wantonly or by group-(CO)-R 5,-NR 12R 13Or chosen wantonly one or many identical or differently by halogen, hydroxyl or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, and wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces,
L represents group-O-R 7,-O-(CH 2) n-(CO)-NH-R 8,-O-(CH 2) n-(CO)-R 15Or-O-(CH 2) n-(CO)-O-R 8, M represents group-NH-R 9,-NH-(CO)-OH) ,-NH-(CO)-O-R 9Or-NR 12-(CO)-R 9,
R 4The methyl of representing the optional one or many of hydrogen, cyano group or halogen or representative to be replaced by halogen identical or differently,
R 5Represent C 1-C 4-alkyl, phenyl or-NR 12R 13,
R 6Representative-SO 2-R 14,
R 7The optional one or many of representative is quilt-NR identical or differently 12R 13Or C 2-C 10The C that-Heterocyclylalkyl replaces 1-C 3-alkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one
Individual or a plurality of pairs of keys, and should the optional one or many of ring itself identical or differently by halogen, aryl or optional
The C that one or many is replaced by halogen identical or differently 1-C 3-alkyl replaces, R 8The C that the optional identical or different by cyano of one or many of representative, cyclopropyl or halogen replace 1-C 3-alkyl, C 3-C 4-thiazolinyl or C 3-C 4-alkynyl,
R 9The optional one or many of representative is identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, C 2-C 10-Heterocyclylalkyl, cyano group, cyclopropyl, halogen, hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14The C that replaces 1-C 5-alkyl, C 2-C 4-thiazolinyl, cyclopropyl or C 2-C 10-Heterocyclylalkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or chosen wantonly one or many identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces, R 10And R 11The optional one or many of representative independently of each other is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3The C that-alkoxyl group replaces 1-C 5-alkyl, C 2-C 10-Heterocyclylalkyl, aryl ,-(CH 2) n-aryl or heteroaryl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys,
R 12And R 13Represent hydrogen or C independently of each other 1-C 4-alkyl,
R 14Represent C 1-C 3-alkyl or represent aryl, and
R 15The optional one or many of representative is identical or differently by C 1-C 3-alkyl or-(CH 2) nThe C that-aryl replaces 2-C 10-Heterocyclylalkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys,
R 16Represent the optional one or many of hydrogen or representative identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, C 2-C 10-Heterocyclylalkyl, cyano group, cyclopropyl, halogen, hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14The C that replaces 2-C 4-thiazolinyl, cyclopropyl or C 2-C 10-Heterocyclylalkyl, or represent one or many identical or differently by C 1-C 4-alkoxyl group, cyano group, cyclopropyl, halogen, hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14The C that replaces 1-C 4-alkyl, or the optional one or many of representative is identical or differently by C 2-C 10The methyl that-Heterocyclylalkyl or heteroaryl replace, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-,-(C=S)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14,-NR 12R 13Or choose wantonly by one or many identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces,
Or represent one or many identical or differently by C 2-C 10The C that-Heterocyclylalkyl replaces 1-C 4-alkyl, or represent one or many identical or differently by C 1-C 4-alkoxy-C 1-C 4The C that-alkoxyl group replaces 2-C 4-alkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should the one or many of ring own identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, and n represents 1-4.
2. according to general formula compound and solvate, hydrate, diastereomer, enantiomorph and the salt of claim 1, wherein:
T 1, T 2And T 3Independently of each other representative-CH=or-N=,
R 3Represent K, L or M,
X represents halogen, hydroxyl or represents group-OR 6,-NR 10R 11Or represent C 2-C 10-Heterocyclylalkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose the identical or different by cyano of one or many, halogen, hydroxyl, aryl wantonly or by group-(CO)-R 5Or-NR 12R 13The optional one or many of replacement or quilt is identical or differently by halogen, hydroxyl or C 1-C 3The C that-alkylthio is obtained 1-C 3-alkyl replaces, and wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces,
L represents group-O-R 7,-O-(CH 2) n-(CO)-NH-R 8Or-O-(CH 2) n-(CO)-O-R 8, R 9The optional one or many of representative is identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, C 2-C 10-Heterocyclylalkyl, cyano group, cyclopropyl, halogen or hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14The C that replaces 1-C 4-alkyl, C 2-C 4-thiazolinyl, cyclopropyl or C 2-C 10-Heterocyclylalkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkoxyl group replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces, R 16Represent the optional one or many of hydrogen or representative identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, C 2-C 10-Heterocyclylalkyl, cyano group, cyclopropyl, halogen, hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14The C that replaces 2-C 4-thiazolinyl, cyclopropyl or C 2-C 10-Heterocyclylalkyl, or represent one or many identical or differently by C 1-C 4-alkoxyl group, cyano group, cyclopropyl, halogen, hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14The C that replaces 1-C 4-alkyl, or the optional one or many of representative is identical or differently by C 2-C 10The methyl that-Heterocyclylalkyl replaces, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces, or represents one or many identical or differently by C 2-C 10The C that-Heterocyclylalkyl replaces 1-C 4-alkyl, or represent one or many identical or differently by C 1-C 4-alkoxy-C 1-C 4The C that-alkoxyl group replaces 2-C 4-alkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces.
3. according to general formula compound and solvate, hydrate, diastereomer, enantiomorph and the salt of claim 1 or 2, wherein:
R 7The optional one or many of representative is quilt-NR identical or differently 12R 13Or C 2-C 10The C that-Heterocyclylalkyl is obtained 1-C 3-alkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys,
R 9The optional one or many of representative is identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, C 2-C 10-Heterocyclylalkyl, cyano group, cyclopropyl, halogen or hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 12The C that replaces 1-C 5-alkyl, C 2-C 4-thiazolinyl, cyclopropyl or C 2-C 10-Heterocyclylalkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose wantonly one or many identical or differently by halogen, cyano group, hydroxyl or optional one or many identical or differently by halogen or C 1-C 3The phenyl that-alkoxyl group replaces replaces, or by group-(CO)-R 5,-(CO)-O-R 12,-SO 2)-R 14Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, R 10And R 11The optional one or many of optional representative independently of each other is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3The C that-alkoxyl group replaces 1-C 5-alkyl, C 2-C 10-Heterocyclylalkyl, aryl or heteroaryl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and in this ring optional one or more pairs of keys, the R of comprising 14Represent C 1-C 3-alkyl or represent phenyl, and
N represents 1-4.
4. according to compound of Formula I and solvate, hydrate, diastereomer, enantiomorph and the salt of one of claim 1-3, wherein:
R 1Methyl, ethyl, sec.-propyl or cyclopropyl that the optional one or many of representative is replaced by halogen identical or differently, R 2Methyl, ethyl, allyl group or propargyl that the optional identical or different by cyano of one or many of representative, cyclopropyl, ethynyl or halogen replace, or representative replaced once hydroxyethyl at least by methyl, and X represents halogen, hydroxyl or represents group-OR 6Or-NR 10R 11Or representative azetidinyl, pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl, the octahydro isoquinolyl, the benzopyrrole alkyl, piperazinyl Si Qing oxazolyl, the piperazine ketone group, the thiazolidine base, imidazolidine quinoline ketone group, the benzo morpholinyl, triazine thioketones base, tetrahydro isoquinolyl or tetrahydric quinoline group, wherein pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl, the octahydro isoquinolyl, the benzopyrrole alkyl, piperazinyl Si Qing oxazolyl, the piperazine ketone group, the thiazolidine base, imidazolidine quinoline ketone group, the benzo morpholinyl, triazine thioketones base, tetrahydro isoquinolyl, the optional one or many of tetrahydric quinoline group itself is identical or differently by halogen, hydroxyl or optional one or many are identical or differently by halogen or C 1-C 3The phenyl that-alkoxyl group replaces replaces, or by group-(CO)-R 5,-NR 12R 13Or the identical or different by cyano of optional one or many, halogen, hydroxyl or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, R 4The methyl of representing the optional one or many of hydrogen or halogen or representative to be replaced by halogen identical or differently,
R 5Represent methylidene, ethyl, the tertiary butyl, phenyl or-NH 2,
R 6Representative-SO 2-methyl,
R 7The optional one or many of representative is quilt-N (C identical or differently 1-C 3-alkyl) 2, the C that replaces of pyrrolidyl, morpholinyl or piperidyl 1-C 3-alkyl,
R 8Methyl, ethyl, allyl group or propargyl that the optional identical or different by cyano of one or many of representative, cyclopropyl or halogen replace,
R 9Represent methylidene, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, vinyl, cyclopropyl, THP trtrahydropyranyl or tetrahydrofuran base, its optional one or many is identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, pyrrolidyl, piperidyl, piperazinyl, thio-morpholinyl, benzopyrrole alkyl, tetrahydric quinoline group, Si Qing oxazolyl, piperazine ketone group, thiazolidine base, imidazolidine quinoline ketone group, benzo morpholinyl, tetrahydrochysene triazolinthione base, morpholinyl, tetrahydro isoquinolyl, octahydro isoquinolyl, cyano group, cyclopropyl, halogen, hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-C 1-C 3-alkyl replaces, and wherein pyrrolidyl, piperidyl, piperazinyl, thio-morpholinyl, benzopyrrole alkyl, tetrahydric quinoline group, Si Qing oxazolyl, piperazine ketone group, thiazolidine base, imidazolidine quinoline ketone group, benzo morpholinyl, tetrahydrochysene triazolinthione base, morpholinyl, tetrahydro isoquinolyl, the optional one or many of octahydro isoquinolyl itself are identical or differently by halogen, hydroxyl, phenyl or C 1-C 3-alkoxyl group replaces, or by group-(CO)-R 5,-(CO)-O-R 5,-(SO 2)-R 14,-N (CH 3) 2Or optional one or many is substituted methyl or the ethyl that halogen, hydroxyl, methylthio group or phenyl replace identical or differently and replaces,
R 10And R 11The optional one or many of representative independently of each other is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3The C that-alkoxyl group replaces 1-C 5-alkyl, pyrrolidyl, phenyl or pyridyl,
R 12And R 13Represent hydrogen or methyl, ethyl or sec.-propyl independently of each other,
R 14Represent C 1-C 4-alkyl or represent phenyl, and
N represents 1 or 2.
5. according to compound of Formula I and solvate, hydrate, diastereomer, enantiomorph and the salt of one of claim 1-4, wherein:
U representative-CH=,-CF=,-C (CH 3)=or-N=,
R 1Methyl, ethyl, sec.-propyl or cyclopropyl that the optional one or many of representative is replaced by fluorine identical or differently,
R 2Methyl, ethyl, allyl group or propargyl that the optional identical or different by cyano of one or many of representative, cyclopropyl, ethynyl or fluorine replace, or representative replaced once hydroxyethyl at least by methyl,
Methyl, ethyl or vinyl that the optional one or many of K representative is replaced by X identical or differently,
X represents halogen, hydroxyl or represents group-O-SO 2-methyl or represent pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl or octahydro isoquinolyl, the methyl substituted that replaced by halogen by halogen, hydroxyl or phenyl or optional one or many of the optional one or many of pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl or octahydro isoquinolyl itself wherein identical or differently identical or differently
L represents group-O-R 7,-O-(CH 2)-(CO)-NH-R 8Or-O-(CH 2)-(CO)-O-R 8,
M represents group-NH-R 9,-NH-(CO)-R 16,-NH-(CO)-O-R 9Or-N (CH 3)-(CO)-R 16,
R 7The optional one or many of representative is quilt-N (C identical or differently 1-C 3-alkyl) 2, the ethyl that replaces of pyrrolidyl, morpholinyl or piperidyl,
R 8Methyl, ethyl, allyl group or propargyl that the optional identical or different by cyano of one or many of representative, cyclopropyl or fluorine replace,
R 9Represent methylidene, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, vinyl, cyclopropyl, THP trtrahydropyranyl or tetrahydrofuran base, its optional one or many is identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, cyano group, cyclopropyl, halogen, hydroxyl or by group-N (C 1-C 3-alkyl) 2,-O-(CO)-(C 1-C 3-alkyl) or-O-(SO 2)-C 1-C 3-alkyl replaces, and wherein pyrrolidyl, piperidyl, piperazinyl, morpholinyl or thio-morpholinyl itself chosen one or many wantonly identical or differently by halogen or by group-(CO)-C 1-C 4-alkyl ,-(CO)-O-C 1-C 4-alkyl ,-(SO 2)-C 1-C 3-alkyl ,-(SO 2)-phenyl ,-N (C 1-C 3-alkyl) 2Or optional one or many is identical or differently by halogen, hydroxyl or C 1-C 3Methyl that-alkylthio replaces or ethyl replace.
6. according to compound of Formula I and solvate, hydrate, diastereomer, enantiomorph and the salt of one of claim 1-5, wherein:
R 1Represent ethyl,
X represents iodine or hydroxyl, or represents group-O-SO 2-methyl or represent pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl or octahydro isoquinolyl, wherein pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl or octahydro isoquinolyl itself chosen the methyl substituted that one or many is replaced by halogen by halogen, hydroxyl, phenyl or optional one or many identical or differently identical or differently wantonly
R 7The optional one or many of representative is quilt-N (CH identical or differently 3) 2, the ethyl that replaces of pyrrolidyl, morpholinyl or piperidyl,
R 9Represent methylidene, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, vinyl, cyclopropyl, THP trtrahydropyranyl or tetrahydrofuran base, its optional one or many are identical or differently by methoxyl group, oxyethyl group, butoxy-oxyethyl group, methoxyl group-oxyethyl group, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, cyano group, cyclopropyl, chlorine, fluorine, hydroxyl or by group-N (CH 3) 2,-N (CH 3) (C 2H 5) ,-O-(CO)-(CH 3) or-O-(SO 2)-methyl substituted, wherein the optional one or many of pyrrolidyl, piperidyl, piperazinyl, morpholinyl or thio-morpholinyl itself is identical or differently by fluorine or by group-(CO)-CH 3,-(CO)-C 2H 5,-CO)-C (CH 3) 3.-(CO)-O-C (CH 3) 3,-(SO 2)-CH 3,-(SO 2)-phenyl ,-N (CH 3) 2Or optional one or many is replaced by methyl or the ethyl that fluorine, hydroxyl or methylthio group replace identical or differently.
7. according to compound of Formula I and solvate, hydrate, diastereomer, enantiomorph and the salt of one of claim 1-6, wherein:
R 16The optional one or many of representative is identical or differently by C 1-C 4-alkoxyl group, cyano group, cyclopropyl, halogen or hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14The C that replaces 1-C 4-alkyl, perhaps the optional one or many of representative is identical or differently by C 2-C 10The methyl that-Heterocyclylalkyl replaces, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces.
8. according to compound of Formula I and solvate, hydrate, diastereomer, enantiomorph and the salt of claim 7, wherein:
R 16The optional one or many of representative is identical or differently by group-NR 10R 11The C that replaces 1-C 4-alkyl, perhaps the optional one or many of representative is identical or differently by C 2-C 10The methyl that-Heterocyclylalkyl replaces, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14,-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces.
9. according to compound of Formula I and solvate, hydrate, diastereomer, enantiomorph and the salt of claim 1, wherein:
The C that on behalf of one or many, K replaced by P identical or differently 1-C 3-alkyl, or the C that represents one or many to be replaced by X identical or differently 2-C 4-thiazolinyl,
P represents group-OR 6,-NR 18R 19, C 2-C 5-Heterocyclylalkyl or represent C 6-C 10Heterocyclylalkyl, the described C in wherein should encircling 2-C 5-Heterocyclylalkyl and C 6-C 10Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group, and in this ring optional one or more pairs of keys and this C of comprising 2-C 5The identical or different by cyano of the one or many of the ring of-Heterocyclylalkyl own, halogen, hydroxyl or aryl or by group-(CO)-R 5Or one or many is identical or differently by halogen or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, and wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces, and described C 6-C 10The ring of-Heterocyclylalkyl itself is chosen the identical or different by cyano of one or many, halogen, hydroxyl, aryl wantonly or by group-CO)-R 5,-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, and wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces,
L represents group-O-R 7,-O-(CH 2) n-(CO)-NH-R 17,-O-(CH 2) n-(CO)-R 15Or-O-(CH 2) n-(CO)-O-R 8,
R 7The optional one or many of representative is identical or differently by C 6-C 10The C that-Heterocyclylalkyl replaces 1-C 3-alkyl, the described C in wherein should encircling 6-C 10-Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should choose the C that one or many is replaced by halogen by halogen, aryl or optional one or many identical or differently identical or differently wantonly by ring itself 1-C 3-alkyl replaces, or
Represent one or many identical or differently by C 2-C 5The C that-Heterocyclylalkyl replaces 1-C 3-alkyl, the described C in wherein should encircling 2-C 5-Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should choose the C that one or many is replaced by halogen by halogen, aryl or one or many identical or differently identical or differently wantonly by ring itself 1-C 3-alkyl replaces,
R 16Represent hydrogen, C 2-C 4-thiazolinyl, cyclopropyl, C 2-C 5-Heterocyclylalkyl, C 6-C 10-Heterocyclylalkyl or the methyl that is replaced by heteroaryl, or represent one or many identical or differently by C 1-C 4-alkoxyl group, C 2-C 5-Heterocyclylalkyl, C 6-C 10-Heterocyclylalkyl, cyano group, cyclopropyl or by group-NR 18R 19,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14The C that replaces 1-C 4-alkyl, C 2-C 4-thiazolinyl, cyclopropyl, C 2-C 5-Heterocyclylalkyl or C 6-C 10-Heterocyclylalkyl, the described C in wherein should encircling 2-C 5-Heterocyclylalkyl and C 6-C 10-Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group, and in this ring optional one or more pairs of keys and this C of comprising 2-C 5The optional one or many of the ring of-Heterocyclylalkyl itself is identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or one or many is identical or differently by halogen, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces, and this C 6-C 10The optional one or many of the ring of-Heterocyclylalkyl itself is identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces,
R 17Represent one or many identical or differently by the C of halogen or cyano group replacement 1-C 3-alkyl, or the optional one or many of representative is identical or differently by the C of halogen, cyclopropyl or cyano group replacement 3-C 4-thiazolinyl or C 3-C 4-alkynyl,
R 18And R 19The optional one or many of representative independently of each other is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3The C that-alkoxyl group replaces 1-C 5-alkyl, C 2-C 10-Heterocyclylalkyl, aryl ,-(CH 2) n-aryl or heteroaryl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and in this ring optional one or more pairs of keys, the wherein R of comprising 18Or R 19Represent C 2-C 10-Heterocyclylalkyl ,-(CH 2) n-aryl or heteroaryl, or represent one or many identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3The C that-alkoxyl group replaces 2-C 10-Heterocyclylalkyl ,-(CH 2) n-aryl or heteroaryl, or represent one or many identical or differently by C 1-C 3The C that-alkoxyl group replaces 1-C 5-alkyl, or represent one or many identical or differently by C 1-C 3-alkyl, C 1-C 3The aryl that-alkoxyl group replaces, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys.
10. according to compound of Formula I and solvate, hydrate, diastereomer, enantiomorph and the salt of claim 9, wherein:
T 1, T 2And T 3Independently of each other representative-CH=or-N=,
R 3Represent K, L or M,
P represents group-OR 6,-NR 18R 19, C 2-C 5-Heterocyclylalkyl or represent C 6-C 10Heterocyclylalkyl, the described C in wherein should encircling 2-C 5-Heterocyclylalkyl and C 6-C 10Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and in this ring optional one or more pairs of keys and this C of comprising 2-C 5The identical or different by cyano of the one or many of the ring of-Heterocyclylalkyl own, halogen, hydroxyl, aryl or by group-(CO)-R 5Or one or many is identical or differently by halogen or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, and wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces, and described C 6-C 10-Heterocyclylalkyl itself is chosen the identical or different by cyano of one or many, halogen, hydroxyl, aryl wantonly or by group-(CO)-R 5,-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, and wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces,
L represents group-O-R 7,-O-(CH 2) n-(CO)-NH-R 17Or-O-(CH 2) n-(CO)-O-R 8, R 9Represent C 1-C 4-alkyl, C 2-C 4-thiazolinyl, cyclopropyl or C 2-C 10-Heterocyclylalkyl, its optional one or many is identical or differently by C 1-C 4-alkoxyl group, C 1-C 4-alkoxy-C 1-C 4-alkoxyl group, C 2-C 10-Heterocyclylalkyl, cyano group, cyclopropyl, halogen, hydroxyl or by group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14Replace, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces,
R 16Represent hydrogen, C 2-C 4-thiazolinyl, cyclopropyl, C 2-C 5-Heterocyclylalkyl or C 6-C 10-Heterocyclylalkyl, or represent one or many identical or differently by C 1-C 4-alkoxyl group, C 2-C 5-Heterocyclylalkyl, C 6-C 10-Heterocyclylalkyl, cyano group, cyclopropyl or by group-NR 18R 19,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14The C that replaces 1-C 4-alkyl, C 2-C 4-thiazolinyl, cyclopropyl, C 2-C 5-Heterocyclylalkyl or C 6-C 10-Heterocyclylalkyl, the described C in wherein should encircling 2-C 5-Heterocyclylalkyl and C 6-C 10Heterocyclylalkyl comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and in this ring optional one or more pairs of keys and this C of comprising 2-C 5The one or many of the ring of-Heterocyclylalkyl own is identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12Or-(SO 2)-R 14Or one or many is identical or differently by halogen, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces, and described C 6-C 10The optional one or many of the ring of-Heterocyclylalkyl itself is identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14Or-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen or C 1-C 3-alkoxyl group replaces.
11. according to compound and solvate, hydrate, diastereomer, enantiomorph and the salt of the general formula I of claim 1 and/or 2, wherein
R 3Represent K or L,
The C that the optional one or many of K representative is replaced by X identical or differently 1-C 3-alkyl, wherein said C 1-C 3-alkyl is optional
One or many identical or differently by hydroxyl or halogen replace,
X represents NR 10R 11Or represent C 2-C 10-Heterocyclylalkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-,-(C=S)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose the identical or different by cyano of one or many, halogen, hydroxyl, aryl wantonly or by group-(CO)-R 5,-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces, and wherein said aryl itself is chosen the identical or different by cyano of one or many, halogen or C wantonly 1-C 3-alkoxyl group replaces,
L represents group-O-R 7,
R 7Represent one or many quilt-NR identical or differently 12R 13Or C 2-C 10The C that-Heterocyclylalkyl replaces 1-C 3-alkyl, and the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should choose the C that one or many is replaced by halogen by halogen, aryl or optional one or many identical or differently identical or differently wantonly by ring itself 1-C 3-alkyl replaces.
12. according to compound and solvate, hydrate, diastereomer, enantiomorph and the salt of the general formula I of claim 11, wherein
X representative-N (C 1-C 3-alkyl) 2Or representative azetidinyl, pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl, the octahydro isoquinolyl, the benzopyrrole alkyl, piperazinyl Si Qing oxazolyl, the piperazine ketone group, the thiazolidine base, imidazolidine quinoline ketone group, the benzo morpholinyl, triazine thioketones base, tetrahydro isoquinolyl or tetrahydric quinoline group, wherein azetidinyl, pyrrolidyl, morpholinyl, thio-morpholinyl, piperidyl, the octahydro isoquinolyl, the benzopyrrole alkyl, piperazinyl Si Qing oxazolyl, the piperazine ketone group, the thiazolidine base, imidazolidine quinoline ketone group, the benzo morpholinyl, triazine thioketones base, the optional one or many of tetrahydro isoquinolyl or tetrahydric quinoline group itself is identical or differently by halogen, hydroxyl, optional one or many is identical or differently by halogen or C 1-C 3The phenyl that-alkoxyl group replaces replaces, or by group-(CO)-R 5Or the identical or different by cyano of one or many, halogen or C 1-C 3The C that-alkylthio replaces 1-C 3-alkyl replaces,
R 7Represent one or many quilt-N (C identical or differently 1-C 3-alkyl) 2Or C 2-C 10The C that-Heterocyclylalkyl replaces 1-C 3-alkyl, wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring optional insert one or more-(CO)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys.
13. according to compound and solvate, hydrate, diastereomer, enantiomorph and the salt of the general formula I of claim 1 and/or 2, wherein
R 3Represent M,
M represents group-NR 12-(CO)-R 16,
R 16The methyl of representing one or many to be replaced by following group: C identical or differently 1-C 4-alkoxyl group, C 2-C 10-Heterocyclylalkyl, heteroaryl, cyano group, cyclopropyl, halogen, hydroxyl or group-NR 10R 11,-O-(CO)-R 5,-(SO 2)-R 14Or-O-(SO 2)-R 14, the optional one or many of wherein said methyl itself is identical or differently by C 1-C 3Alkyl replaces, and wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-,-(C=S)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14,-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, and the optional one or many of wherein said aryl itself is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces.
14. according to compound and solvate, hydrate, diastereomer, enantiomorph and the salt of the general formula I of claim 13, wherein
R 16Represent one or many identical or differently by C 2-C 10-Heterocyclylalkyl, heteroaryl or group-NR 10R 11The methyl that replaces, the optional one or many of wherein said methyl itself is identical or differently by C 1-C 3Alkyl replaces, and wherein the described Heterocyclylalkyl in this ring comprises at least one identical or different atom that is selected from nitrogen, oxygen or sulphur, and in this ring, choose wantonly insertion one or more-(CO)-,-(C=S)-or-SO 2-group, and optionally in this ring comprise one or more pairs of keys, and should ring itself choose one or many wantonly identical or differently by halogen, cyano group, hydroxyl, aryl or by group-(CO)-R 5,-(CO)-O-R 12,-(SO 2)-R 14,-NR 12R 13Or optional one or many is identical or differently by halogen, hydroxyl, C 1-C 3The C that-alkylthio or phenyl replace 1-C 3-alkyl replaces, wherein
The optional one or many of described aryl itself is identical or differently by halogen, C 1-C 3-alkyl or C 1-C 3-alkoxyl group replaces.
15. the compound of general formula I I or IV and solvate thereof, hydrate, diastereomer, enantiomorph and salt,
Figure A2005800483960015C1
R wherein 1, R 2, R 3, U, T 1, T 2And T 3Have according to the definition described in the general formula I of one of claim 1-14, it is as the intermediate product of preparation compound of Formula I.
16. according to compound and solvate, hydrate, diastereomer, enantiomorph and the salt of the general formula I I of claim 15, it is as the intermediate product of preparation general formula (I) compound:
2-cyano group-N-ethyl-2-[3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-ethanamide,
2-cyano group-2-[3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-N-(2,2,2-three fluoro-ethyls)-ethanamide,
2-cyano group-2-[3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-N-Propargyl-ethanamide or,
2-cyano group-N-cyano methyl-2-[3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-ethanamide,
2-cyano group-N-(2,2-two fluoro-ethyls)-2-[3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-ethanamide,
2-cyano group-2-[3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-N-(2-hydroxyl-1,1-dimethyl-ethyl)-ethanamide,
2-cyano group-2-[3-ethyl-4-oxo-thiazolidine-(2-(E or Z))-subunit]-N-(2-fluoro-ethyl)-ethanamide.
17. according to the general formula (II) of claim 15 or compound (IV) or according to the compound of claim 16, it is as the intermediate product of preparation general formula (I) compound.
18. according to the general formula (II) of claim 15 or compound (IV) or according to the compound of claim 16 as the application of intermediate product in preparation general formula (I) compound.
19. a medicine, it comprises at least a compound according to one of claim 1-14.
20. the application of compound of Formula I in the preparation medicine according to one of claim 1-14.
21. according to the compound of one of claim 1-14 or according to the medicine of claim 19, it comprises appropriate formulation material and carrier.
22. the method for the compound of preparation general formula I, wherein the compound of the compound of general formula I I and following general formula III reacts in having three formic acid ortho ester identical or different, that choose alkoxyl group bridge joint or that replaced by halogen or aryloxy wantonly, they are chosen wantonly and heat with polar solvent
R wherein 3, U, T 1, T 2And T 3Have with one of claim 1-14 in R 3, U, T 1, T 2And T 3Phase
Definition together,
Perhaps
The compound of general formula I V and allyl acceptor and catalyzer react in non-protonic solvent,
Figure A2005800483960016C2
R wherein 3, U, T 1, T 2And T 3Have with one of claim 1-14 in R 3, U, T 1, T 2And T 3Identical definition, and after first part reaction is finished in non-protonic solvent with coupling agent, alkali and R 2-NH 2Reaction, wherein R 2Have with one of claim 1-14 in R 2Identical definition, the compound of formation general formula I.
23. according to the method for claim 22, wherein be the compound of preparation general formula I I, the compound of general formula V and allyl acceptor and catalyzer react in non-protonic solvent,
Figure A2005800483960016C3
R wherein 1Have with one of claim 1-14 in R 1Identical definition, and after first part reaction is finished in non-protonic solvent with coupling agent, alkali and R 2-NH 2Reaction, wherein R 2Have with one of claim 1-14 in R 2Identical definition, the compound of formation general formula I.
CNA2005800483966A 2004-12-15 2005-12-12 Metasubstituted thiazolidinones, their manufacture and use as a drug Pending CN101146782A (en)

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CN104402830A (en) * 2014-11-27 2015-03-11 太仓运通生物化工有限公司 Synthesis method of 2-chloropyrimidine
CN114907288A (en) * 2022-05-13 2022-08-16 中国医学科学院医药生物技术研究所 Application of nitrobenzene compounds in preparation of pseudomonas aeruginosa quorum sensing inhibitor

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EP2065039A1 (en) 2007-11-27 2009-06-03 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Selective inhibition of Polo-like kinase 1

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RU2004135533A (en) * 2002-05-03 2005-07-20 Шеринг Акциенгезельшафт (De) THIAZOLIDINONES AND THEIR APPLICATION AS POLO-LIKE KINASE INHIBITORS
DE10351744A1 (en) * 2003-10-31 2005-06-16 Schering Ag Thiazolidinones, their preparation and use as pharmaceuticals

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104402830A (en) * 2014-11-27 2015-03-11 太仓运通生物化工有限公司 Synthesis method of 2-chloropyrimidine
CN114907288A (en) * 2022-05-13 2022-08-16 中国医学科学院医药生物技术研究所 Application of nitrobenzene compounds in preparation of pseudomonas aeruginosa quorum sensing inhibitor
CN114907288B (en) * 2022-05-13 2023-12-08 中国医学科学院医药生物技术研究所 Application of nitrobenzene compounds in preparation of pseudomonas aeruginosa quorum sensing inhibitor

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