CN101616921A - The 1-H-pyrazolo (3,4b) pyrimidine derivatives and as the purposes of mitotic kinase conditioning agent - Google Patents

The 1-H-pyrazolo (3,4b) pyrimidine derivatives and as the purposes of mitotic kinase conditioning agent Download PDF

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CN101616921A
CN101616921A CN200880005962A CN200880005962A CN101616921A CN 101616921 A CN101616921 A CN 101616921A CN 200880005962 A CN200880005962 A CN 200880005962A CN 200880005962 A CN200880005962 A CN 200880005962A CN 101616921 A CN101616921 A CN 101616921A
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pyrimidine
phenyl
pyrazolo
base
dihydro
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斯里尼瓦斯·R·卡西巴特拉
凯文·洪
张琳
马库斯·F·贝姆
范军华
让-伊维斯·勒布拉齐德克
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Biogen Inc
Biogen MA Inc
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Biogen Idec MA Inc
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Abstract

The present invention relates to compound, its polymorphic form, enantiomer, steric isomer, solvate, N-oxide compound or the pharmacy acceptable salt of formula (I), it has restraining effect to one or more protein kinases that relate in cell mitogen.

Description

The 1-H-pyrazolo (3,4b) pyrimidine derivatives and as the purposes of mitotic kinase conditioning agent
Cross reference
The right of priority of the U. S. application that the application requires to submit on January 30th, 2007 U. S. application is submitted to number on January 30th, 60/898,300 and 2007 number 60/898,382.This paper is all incorporated in these two applications by reference into.
Background of invention
Mitotic division is extremely complicated bioprocess, and wherein the duplicate genes group of complete copy accurately is separated to two daughter cells by the microtubule spindle body.Because the existence of cell depends on mitotic tolerance range, so a plurality of fidelity monitoring checkpoint system of having evolved out are coordinated to guarantee this process orthochronous and spatial.Mistake in these mechanism can cause genomic instability---tumorigenic importance.As a result, when comparing with normal cell, these regulation systems often are found unusually in tumour cell, and this is not astonishing.Referring to, Keen for example, N. etc., Nature Rev.Cancer, 4:927-936 (2004); Lengauer, C. etc., Nature.396,643-649 (1998).
Mitotic beginning and termination are closely to regulate by many proteic phosphorylations and dephosphorylation.Mitotic phosphorylation is finished by a plurality of mitotic serine/threonine kinases, such as aurora kinase (Aurora kinase), polo sample kinases (polo-like kinase), cell cycle protein dependent kinase (cyclin-dependent kinase) and MIMA.Referring to, for example, Nigg, E.A., Nature Rev.Mol.Cell Biol., 2:21-32 (2001); Toji, S. etc., Genes toCells, 9:383-397 (2004).
The cell cycle protein dependent kinase (CDKs) of 11 kinds of forms of known existence, and be named as CDK1 to CDK11.Most of CDK is found the participation regulation of Cell Cycle at first.CDKs also participates in transcribing the adjusting of processing with mRNA.CDKs is considered to the potential target of cancer therapy drug.By optionally disturbing CDK to be used for blocking Cycle Regulation in the cancer cells to cause necrocytosis.At present, number of C DK inhibitor is carrying out clinical trial such as Seliciclb.Referring to, Loyer for example, P. etc., Cellular Sgnallng, 17 (9): 1033-51 (2005); Adrano G Rossi, Nature Medicine, 12:1056-1064 (2006).
Aurora kinase is to carry out crucial protein serine/threonine kinase to mitotic.In mammalian cell, aurora kinase family is by three kinds of member compositions, called after aurora A, aurora B and aurora C.Although there are some differences in their Subcellular Localization and mitotic division function, the total conservative catalysis region of these kinases also participates in regulating the mitotic division process.Referring to, Brown for example, J.R. etc., BMC Evol.Biol., 4:39 (2004).Aurora A is positioned to duplication centre body and spindle pole during mitotic division.Functional study shows that it is required that this albumen forms for centrosome maturation, separation and mitotic spindle.Disturb (RNAi) to suppress that aurora A expresses that the mitotic division that postpones in people's cell enters and this kinase whose overexpression infringement spindle body-check point function and suppress division of cytoplasm by RNA.Aurora B is a karyomit(e) passerby albumen, and aurora B is in the mitotic zone, chromosomal kinetochore that is positioned in early days; The anaphase A during, it transfers to spindle body equatorial plate and spindle body intermediate zone, the anaphase transfer to intermediate between B and the division of cytoplasm.Think that this albumen participates in regulating the karyomit(e) arrangement and separating energetically, spindle body-check point function and division of cytoplasm.The chromosomal mitotic spindle that is attached to of the proteic overexpression retardance of the aurora B that kinases lost efficacy, this is the centric strong hint of defectiveness.In addition, the function of being injected the weakening of the aurora B that causes by RNAi or antibody causes the spindle body check point malfunctioning, and this is because cell can not stand mitotic division to be stagnated, but is exposed to promise azoles and taxol with response.Aurora C is the centrosome associated kinase, and it also can work in the generation of cancer and development.Referring to, Jiang N. etc., Mini-Reviews in Medicianl Chemistry, 6:885-895 (2006).The aurora kinase imbalance is expressed with tumour and is closely related.Manyly studies show that aurora A and aurora B gene are by overexpression or amplification in kinds of tumors.Referring to for example Keen, N. etc. see above; Anand, S. etc., Cancer Cell, 3:51 (2003); Warner, S.L. etc., Mol.Cancer Ther., 2:589 (2003).Because therefore the vital role of aurora kinase in mitotic division and tumour generation poured into very big effort and come at the compound exploitation that with these molecules is target.
Polo sample kinases (PLKs) is the family of protein serine/threonine kinase, and is conservative at the eukaryotic cell camber.In Mammals, PLK family is by four member compositions, called after PLK1, PLK2, PLK3 and PLK4.Except that conservative kinases zone, the also total unique motif of PLKs is called Polo box structural domain (PBDs), and it exists in the C-end of this histone.Referring to, Xie for example, S.Q. etc., Oncogene, 24:277 (2005).The multinomial PBDs of studies show that plays a crucial role in the adjusting of Subcellular Localization, may by and vital some phosphorylated protein of on cell proliferation between interact and to carry out.Referring to, Lowery for example, D.M. etc., Oncogene, 24:248 (2005).Regulating in the cell cycle particularly during mitotic division, PLKs has multiple function.Referring to Xie, S.Q. etc. see above.PLKs can activate the Cdk1/cyclinB mixture, and this mixture is to cause the key molecule that mitotic division enters.PLK1 also phosphorylation the anaphase-component of promotion mixture, such as Cdc16 and Cdc27, this show PLK1 be metaphase and the anaphase change important conditioning agent.PLKs also is essential for mitotic finishing, and this is because point mutation or N end brachymemma causing division of cytoplasm failure.Referring to, van Vugt for example, M.A. etc., Oncogene, 24:2844 (2005).In most people's tumour cell and tumor cell line, detect the overexpression of PLK1.Referring to, Eckerdt for example, F. etc., Oncogene, 24,267 (2005); Takai, N. etc., Oncogene, 24:287 (2005).In addition, the metastatic potential of the expression of PLK1 rising and the relatively poor prediction of cancer patients and some tumour is closely related.Therefore, it is believed that PLK1 brings into play etiologic agent in carinogenicity transforms.Referring to Takai, N. etc. see above.
In view of a plurality of mitotic kinases role in tumour cell division and propagation, what can expect is to have such compound, and it can suppress one or more in these a plurality of mitotic kinases, with the treatment cancer.
Summary of the invention
One aspect of the present invention relates to compound, prodrug, polymorphic form, tautomer, enantiomer, steric isomer, solvate, N-oxide compound or its pharmacy acceptable salt of formula (I).
Figure G2008800059629D00031
About formula (I),
R 1Be hydrogen or halogen;
R 2Be-L 1-R a, wherein
L 1Be a key and R aBe thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl; Wherein each in cycloalkyl, Heterocyclylalkyl, aryl and the heteroaryl be replace arbitrarily and have 8 to 16 annular atomses; Perhaps
L 1Be alkyl and R aBe hydrogen, thiazolinyl, alkynyl, amino, hydroxyl, carbalkoxy, alkyl carbonyl oxy, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl; Wherein each in cycloalkyl, Heterocyclylalkyl, aryl and the heteroaryl be replace arbitrarily and have 8 to 16 annular atomses arranged;
R 3Be-R b-L 2-R cWherein
R bBe aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl, and be randomly to replace with 1 to 3 substituting group; Wherein when contiguous, in the substituting group two can form 5 to 16 yuan ring with their connected one or more atoms, and it has 0 to 6 heterocyclic atom,
L 2Be a key ,-(CR xR y) n-,-N=,-O-,-S-,-SO-,-SO 2-,-CO-,-CO-O-,-O-CO-,-NR x-,-NR x-CO-,-NR x-SO 2-,-CO-NR x-,-SO 2-NR x-,-NR x-CO-O-,-NR x-SO 2-O-,-NR x-CO-NR y-,-NR x-SO 2-NR y-,-CO-NR x-NR y-,-SO 2-NR x-NR y-,-NR x-CO-CO-O-,-NR x-SO 2-SO 2-O-,-S (O) 2-N x-CO-R y-,-CO-N x-S (O) 2-R y-or-(NR xR y) C=N-O-;
R cBe hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, cycloalkyl-alkyl, Heterocyclylalkyl-alkyl, cycloalkenyl group-alkyl, heterocycloalkenyl-alkyl, aralkyl or heteroaralkyl; And except hydrogen, it is randomly to replace with 1 to 3 substituting group;
R xAnd R yIn each be independently hydrogen, hydroxyl, alkyl, alkoxyl group, amino ,-the CO-alkyl ,-the CO-aryl ,-SO 2-alkyl ,-SO 2-aryl ,-SO 2-heteroaryl or-P (O) (O-alkyl) 2, wherein at R xPerhaps R yIn alkyl or aryl moiety be randomly to replace with 1 to 3 substituting group; And n is 0,1,2 or 3.
Note the as above L of demonstration 2Direction, just, each Markush member's left side key is connected to R bBe connected to R with right side key cFor example, work as L 2Be-CO-O-, R 3Be-R b-CO-O-R cThe time.
In some embodiments, R bBe randomly to replace with 1 to 3 substituting group, wherein each substituting group be independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, heteroaryl, arylalkyl, heteroarylalkyl ,-OR ,-SR ,-NRR ', oxo ,-C (O)-OR ,-C (O)-NRR ', halogen ,-CN ,-NO 2,-N 3,-C (O) R ,-P (O) (OR) R ' ,-O-P (O) (OR) R ' ,-NR-P (O) (OR ') R " ,-S (O) 2-(OR) ,-O-S (O) 2-(OR) ,-NR-S (O) 2-OR ' ,-NR-C (O)-OR ' ,-NR-C (O)-NR ' R " ,-NR-C (S)-NR ' R " ,-C (S)-NRR ' and alkylthio; Among R and the R ' each is hydrogen, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl independently; And R " be alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl.
In some embodiments, when being hydrogen, R cBe randomly to replace with 1 to 3 substituting group, each substituting group be independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, heteroaryl, arylalkyl, heteroarylalkyl ,-OR ,-SR ,-NRR ', oxo ,-C (O)-OR ,-C (O)-NRR ', halogen ,-CN ,-NO 2,-N 3,-C (O) R ,-P (O) (OR) R ' ,-O-P (O) (OR) R ' ,-NR-P (O) (OR ') R " ,-S (O) 2-(OR) ,-O-S (O) 2-(OR) ,-NR-S (O) 2-OR ' ,-NR-C (O)-OR ' ,-NR-C (O)-NR ' R " ,-NR-C (S)-NR ' R " ,-C (S)-NRR ' and alkylthio; Among R and the R ' each is hydrogen, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl independently; And R " be alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl.
In some embodiments, described R xPerhaps R yIn alkyl or aryl moiety be randomly to replace with 1 to 3 substituting group, each be independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, heteroaryl, arylalkyl, heteroarylalkyl ,-OR ,-SR ,-NRR ', oxo ,-C (O)-OR ,-C (O)-NRR ', halogen ,-CN ,-NO 2,-N 3,-C (O) R ,-P (O) (OR) R ' ,-O-P (O) (OR) R ' ,-NR-P (O) (OR ') R " ,-S (O) 2-(OR) ,-O-S (O) 2-(OR) ,-NR-S (O) 2-OR ' ,-NR-C (O)-OR ' ,-NR-C (O)-NR ' R " ,-NR-C (S)-NR ' R " ,-C (S)-NRR ' and alkylthio; Among R and the R ' each is hydrogen, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl independently; And R " be alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl.
In some embodiments, R 1Be hydrogen.
In some embodiments, L 1It is a key.
In some embodiments, R aBe cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, each has 8 to 12 annular atomses.Except as otherwise noted, these cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl groups can be connected to linker (L at any annular atoms 1) or encircle last nitrogen-atoms and (work as L 1When being a key).Applicable, the shack atom can have R, S or racemize conformation.In some embodiments, R aBe dihydro indenyl (being also referred to as " indanyl ") Tetralyl
Figure G2008800059629D00052
Dihydro-acenaphthylene base Naphthyl
Figure G2008800059629D00054
Tetrahydrochysene-benzo [7] wheel thiazolinyl Quinolyl Isoquinolyl Benzimidazolyl-
Figure G2008800059629D00058
Benzothiazolyl
Figure G2008800059629D00059
Benzoxazolyl
Figure G2008800059629D000510
Phenanthryl
Figure G2008800059629D000511
Perhaps tetrahydrochysene-dibenzo [7] is taken turns thiazolinyl
Figure G2008800059629D000512
As mentioned above, each of these rings can be connected to linker (L at any annular atoms place 1), perhaps work as L 1When being a key, be connected to R on the pyrazoles ring 2The nitrogen-atoms that connects.
In some embodiments, R aBe dihydro indenyl, tetralyl, dihydro-acenaphthylene base or naphthyl.
In some embodiments, R aBe naphthyl or dihydro indenyl (naphthalene-1-base, 1 for example, 2-acenaphthene-1-base, 2,3-dihydro indenes-2-base or 2,3-dihydro indenes-1-yl).
In some embodiments, L 1It is a key.
In some embodiments, R aIt is the tetralyl that replaces arbitrarily with 1-3 substituting group.In any substituting group of 1-3 each can be independently selected from benzyloxy, hydroxyl and sulfonyloxy methyl oxygen base.
In some further embodiments, R aBe 1-benzyloxy-5,6,7,8-naphthane-4-base; 1-hydroxyl-5,6,7,8-naphthane-4-base; Perhaps 1-methanesulfonyloxy group-5,6,7,8-naphthane-4-base.
In some embodiments, R aIt is the dihydro indenyl that randomly replaces with 1 to 3 substituting group.Suitable substituents includes but not limited to hydroxyl, benzoyloxy, dihydro phosphorus acyloxy, alkylidene dioxygen, acetamido, di-t-butyl phosphorus acyloxy, alkoxyalkoxy group (for example methoxyethoxy) and alkoxyl group (for example methoxyl group).
In some further embodiments, R aBe dihydro indenes-1-base, 4-hydroxyl dihydro indenes-1-base, 4-benzoyloxy dihydro indenes-1-base, 4-dihydro phosphorus acyloxy dihydro indenes-1-base, 5,6-dioxy dihydro indenes-1-base, 5-acetamido dihydro indenes-1-base, 5-benzoyloxy dihydro indenes-1-base, 4-benzoyloxy dihydro indenes-1-base, 4-(di-t-butyl phosphorus acyloxy) dihydro indenes-1-base, 5-((2-methoxyethoxy) methyl) dihydro indenes-1-base or 5-melonia indenes-1-base.
In some embodiments, R aIt is the indyl that randomly replaces with 1 to 3 substituting group.Suitable substituents includes but not limited to alkyl (for example methyl) and alkyl carboxyl (for example tertiary butyl carboxyl).
In some further embodiments, R aBe indoles-4-base, indoles-6-base, indoles-5-base, 7-skatole-5-base, 1-tertiary butyl carboxyl-7-skatole-5-base or (1-tertiary butyl carboxyl) indoles-5-base.
In some embodiments, R 2Be 2,3-dihydro-1H-indenes-1-base, (S)-2,3-dihydro-1H-indenes-1-base, (R)-2,3-dihydro-1H-indenes-1-base, 1,2-acenaphthene-1-base, (R)-1,2-acenaphthene-1-base, (S)-1,2-acenaphthene-1-base, phenanthrene-1-base or phenanthrene-4-base.
In some embodiments, L 1Be alkyl and R aBe hydrogen, thiazolinyl, alkynyl, amino, hydroxyl, carbalkoxy, alkyl carbonyl oxy, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl; Wherein each in cycloalkyl, Heterocyclylalkyl, aryl and the heteroaryl be replace arbitrarily with 1-3 substituting group and have 8 to 16 annular atomses.For example, L 1Be methyl, ethyl, propyl group, sec.-propyl or butyl; And R aBe hydrogen, amino, hydroxyl, carbalkoxy, alkyl carbonyl oxy, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl; Wherein each in cycloalkyl, Heterocyclylalkyl, aryl and the heteroaryl replaces arbitrarily with 1-3 substituting group.
In some further embodiments, R 2Be methyl, ethyl, propyl group, sec.-propyl, butyl, 3-aminopropyl, hydroxybutyl, ethoxy carbonyl methyl, methyl carbonyl oxygen Ji Dingji or naphthalene-1-ylmethyl.
In embodiment further, R 3It is the phenyl that replaces arbitrarily with 1-3 substituting group.For example, phenyl can be a para-orientation.The example of this phenyl comprises 4-(piperidines-1-yl) phenyl and 4-(two (methyl sulphonyl) amino) phenyl.
In some embodiments, R bBe phenyl and be randomly to replace with 1 to 3 substituting group.
In some embodiments, L 2Be-O-,-S-,-SO 2-,-CO-,-CO-O-,-NR x-,-NR x-CO-,-NR x-SO 2-,-NR x-CO-O-,-NR x-CO-NR y-or-NR x-CO-CO-O-.
In some embodiments, L 2Be-CO-O-,-NR x-,-NR x-SO 2-,-NR x-CO-O-or-NR x-CO-NR y-, R wherein xBe hydrogen, alkyl ,-the CO-alkyl ,-SO 2-alkyl ,-SO 2-aryl or-SO 2-heteroaryl.
In some embodiments, R cBe hydrogen, alkyl, aryl or heteroaryl.
In some embodiments, R xBe hydrogen, alkyl ,-the CO-alkyl or-SO 2-alkyl; And R cBe hydrogen, alkyl or aryl.
In some embodiments, L 2It is a key; And R cBe cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, (cycloalkyl) alkyl, (Heterocyclylalkyl) alkyl, aralkyl or heteroaralkyl.
In some embodiments, L 2It is a key; And R cBe Heterocyclylalkyl, heteroaryl, Heterocyclylalkyl-alkyl or heteroaralkyl.
In some embodiments, L 2Be a key and R cBe tetrazyl, morpholino or piperazinyl.
In some embodiments, R cBe cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyl-alkyl, Heterocyclylalkyl-alkyl, aralkyl or heteroaralkyl.
In some embodiments, L 1It is a key; R aBe cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl; R bIt is phenyl; L 2Be-O-,-S-,-SO 2-,-CO-,-CO-O-,-NR x-,-NR x-CO-,-NR x-SO 2-,-NR x-CO-O-,-NR x-CO-NR y-or-NR x-CO-CO-O-, wherein R xBe hydrogen, alkyl ,-the CO-alkyl ,-SO 2-alkyl ,-SO 2-aryl or-SO 2-heteroaryl; And R cBe hydrogen, alkyl, aryl or heteroaryl.
In some embodiments, L 1It is a key; R aBe dihydro indenyl, tetralyl, dihydro-acenaphthylene base or naphthyl; R bIt is phenyl; L 2Be-CO-O-,-NR x-,-NR x-SO 2-,-NR x-CO-O-or-NR x-CO-NR y-, R wherein xBe hydrogen, alkyl ,-the CO-alkyl ,-SO 2-alkyl or-SO 2-aryl; And R cBe hydrogen, alkyl or aryl.
In some embodiments, L 1It is a key; R aBe cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl with 8 to 12 annular atomses; R bIt is phenyl; L 2It is a key; And R cBe cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, (cycloalkyl) alkyl, (Heterocyclylalkyl) alkyl, aralkyl or heteroaralkyl.
In some embodiments, L 1It is a key; R aBe dihydro indenyl, tetralyl, dihydro-acenaphthylene base or naphthyl; R bIt is phenyl; L 2It is a key; And R cBe tetrazyl, morpholino or piperazinyl.
In some embodiments, L 2Be a key or-NR x-SO 2-; R xBe hydrogen or-SO 2-alkyl; And R cBe hydrogen, alkyl, Heterocyclylalkyl, heteroaryl, Heterocyclylalkyl-alkyl or heteroaralkyl.
In some embodiments, R xBe-SO 2-alkyl; And R cIt is alkyl.
In some embodiments, R cBe tetrazyl, morpholino or piperazinyl.
In some embodiments, R bBe the phenyl that replaces with 1 to 3 substituting group, each substituting group is independently-NRR ' or-C (O) OR; L 2It is a key; And R cBe hydrogen.
In some embodiments, L 1Be a key and R aIt is also [7] wheel thiazolinyl of dihydro indenyl, tetralyl, dihydro-acenaphthylene base, naphthyl, tetrahydrochysene-benzo [7] wheel thiazolinyl, quinolyl, isoquinolyl, benzimidazolyl-, benzothiazolyl, benzoxazolyl, phenanthryl or tetrahydrochysene-biphenyl.
In some embodiments, R bIt is phenyl.
In some embodiments, L 2Be a key or-NR x-SO 2-, R wherein xBe hydrogen or-SO 2-alkyl; And R cBe hydrogen, alkyl, Heterocyclylalkyl, heteroaryl, Heterocyclylalkyl-alkyl or heteroaralkyl.
In some embodiments, R cBe hydrogen, alkyl, Heterocyclylalkyl, heteroaryl, Heterocyclylalkyl-alkyl or heteroaralkyl.
In some embodiments, R bBe the phenyl that replaces with 1 to 3 substituting group, each substituting group is independently-NRR ' or-C (O) OR; L 2It is a key; And R cBe hydrogen.
In some embodiments, R 1Be hydrogen.
In some embodiments, R bBe usefulness-NRR ' or-phenyl that C (O) OR replaces arbitrarily; L 2Be a key or-NR x-SO 2-, R wherein xBe hydrogen or-SO 2-alkyl; And R cBe tetrazyl, morpholino or piperazinyl.
In some embodiments, R 3Be (4-(1H-tetrazolium-5-yl) phenyl), 3-hydroxyl-4-p-methoxy-phenyl, 4-(4-methylpiperazine-1-yl) phenyl), 4-(piperazine-1-yl) phenyl, 4-aminophenyl, 4 benzoic acid, 4-morpholino phenyl, 4-(N, N-dimethyl methyl acid amides) phenyl or 4-(amsacrine) phenyl.
In some other embodiments, R 3Be two (methane sulfonyl) aminophenyls of 4-; two (ethane alkylsulfonyl) aminophenyls of 4-; 4-(4-methylpiperazine-1-yl) phenyl; two (methane sulfonyl) aminophenyls of 4-; two ((methyl chloride) alkylsulfonyl) aminophenyls of 4-; 4-(methane sulfonyl) aminophenyl; 4-(N '-hydroxyl first miaow base) phenyl; 4-(4-methylpiperazine-1-yl) phenyl; the 4-aminophenyl; 4-(methane sulfonyl carbamyl) phenyl; the 4-cyano-phenyl; 4-(tetrazolium-5-yl) aminophenyl; 2-(4-nitrophenyl) ethyl; 2-(4-aminophenyl) ethyl or 2-(two (methane sulfonyl) aminophenyls of 4-) ethyl.
In going back other embodiment of other, R 3Be two (methane sulfonyl) aminophenyls of 4-.
In some embodiments, described compound is:
N-(methyl sulphonyl)-N-(4-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-methyl-N-(4-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-methyl-N-(4-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
1-(methyl sulphonyl)-N-(4-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N1-(1-(naphthalene-2-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-yl) benzene-1, the 4-diamines,
Ethyl-2-(4-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl amino)-2-fluoroacetic acid,
N-(4-(1-(naphthalene-2-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
3,3,3-three fluoro-N-(4-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) propane-1-sulphonamide,
Methyl-4-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenylcarbamate,
N-(3, the 4-Dimethoxyphenyl)-1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-(4-methylpiperazine-1-yl) phenyl)-1-(naphthalene-2-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
Ethyl-2-hydroxyl-4-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenylcarbamate,
N-(4-(1H-1,2,4-triazol-1-yl) phenyl)-1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
Methyl 3-(4-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl amino)-3-oxygen propionic ester,
N1-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-yl) benzene-1, the 4-diamines,
N-(4-(4-methylpiperazine-1-yl) phenyl)-1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-fluoro-3-p-methoxy-phenyl)-1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-ethoxyl phenenyl)-1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
(S)-1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-(4-methylpiperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
(S)-4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenylformic acid,
(S)-N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
(S)-N 1-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-yl) benzene-1, the 4-diamines,
(S)-1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-morpholino phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
(S)-1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-(4-(sulfonyl propyl base) piperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenylformic acid,
1-(2,3-dihydro-1H-indenes-1-yl)-N-(3-(piperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N 1-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-yl) benzene-1, the 4-diamines,
N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-(4-(sulfonyl propyl base) piperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
(S)-1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-(4-(methyl sulphonyl) piperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
(S)-1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-(piperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) benzamide,
(S)-5-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino)-2-methoxyphenol,
1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-(piperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-morpholino phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
3-(4-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) piperazine-1-yl) propane-1-alcohol,
4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) benzo hydrazides,
2-(4-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) piperazine-1-yl) ethylhexoate,
1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-(4-((4-methoxyl group-3,5-lutidine-2-yl) methyl) piperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
3-(4-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) piperazine-1-yl) propyl-acetic acid ester,
2-(4-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) piperazine-1-yl) ethanol,
1-((S)-2,3-dihydro-1H-indenes-1-yl)-N-(3-(1-((R)-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base oxy)-4-p-methoxy-phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
(S)-ethyl 4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) benzoic ether,
(S)-1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-morpholino phenyl)-1H-pyrazoles [3,4d] pyrimidine-6-amine,
N-(4-(1-(4-hydroxyl-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
(S)-N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(ethylsulfonyl) ethane sulphonamide,
1-(6-(4-(4-methylpiperazine-1-yl) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-alcohol,
1-(6-(4-(N-(methyl sulphonyl) sulfonyloxy methyl amine) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-yl benzoic acid ester,
1-(6-(4-(N-(methyl sulphonyl) sulfonyloxy methyl amine) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-base dihydrogen phosphoric acid,
(S)-1-chloro-N-(chloromethyl alkylsulfonyl)-N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(4-(1-(6,7-dihydro-5H-indeno [5,6-d] [1,3] dioxole-5-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
N-(1-(6-(4-(N-(methyl sulphonyl) sulfonyloxy methyl amine) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-5-yl) ethanamide,
N-(4-(1-(4-hydroxyl-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
1-(6-(4-(N-(methyl sulphonyl) sulfonyloxy methyl amine) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-5-yl benzoic acid ester,
(S, Z)-4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino)-N '-hydroxybenzene azomethine acid amides,
1-(6-(4-(4-methylpiperazine-1-yl) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-yl benzoic acid ester,
1-(6-(4-aminophenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-alcohol,
1-(6-(4-aminophenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-yl benzoic acid ester,
Two-tertiary butyl 1-(6-(4-(N-(methyl sulphonyl) sulfonyloxy methyl amine) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-base phosphoric acid,
(S)-4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino)-N-(methyl sulphonyl) benzamide,
N-(4-(1-(5-((2-methoxy ethoxy) methoxyl group)-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
N-(1-(6-(4-aminophenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-5-yl) ethanamide,
(S)-4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) benzonitrile,
(S)-N-(4-(1H-tetrazolium-5-yl) phenyl)-1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N1-(1-(5-methoxyl group-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-yl) benzene-1, the 4-diamines,
N-(4-(1-(5-methoxyl group-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
1-(2,3-dihydro-1H-indenes-2-yl)-N-(4-morpholino phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-(1-(1H-indoles-4-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
N-(4-(1-(1H-indoles-6-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
N-(4-(1-(1H-indoles-5-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
1-(1H-indoles-4-yl)-N-(4-(4-methylpiperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-(1-(1-Methyl-1H-indole-5-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
1-(7-Methyl-1H-indole-4-yl)-N-(4-(4-methylpiperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
Tertiary butyl 7-methyl-4-(6-(4-(4-methylpiperazine-1-yl) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-1H-indoles-1-carboxylicesters,
Tertiary butyl 4-(6-(4-(4-methylpiperazine-1-yl) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-1H-indoles-1-carboxylicesters,
1-(1,2-acenaphthene-1-yl)-N-(4-(4-methylpiperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-(1-(1,2-acenaphthene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
N 1-(1-(1,2-acenaphthene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-yl) benzene-1, the 4-diamines,
1-(1,2-acenaphthene-1-yl)-N-(4-morpholino phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
4-(1-(1,2-acenaphthene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) benzonitrile,
1-(1,2-acenaphthene-1-yl)-N-(4-(2-(trimethylammonium stannyl)-2H-tetrazolium-5-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
1-(1,2-acenaphthene-1-yl)-N-(4-(piperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-morpholino phenyl)-1-(naphthalene-1-ylmethyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-(1-(4-(benzyloxy)-5,6,7,8-naphthane-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
1-(4-(benzyloxy)-5,6,7,8-naphthane-1-yl)-N-(4-(4-methylpiperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N1-(1-(4-(benzyloxy)-5,6,7,8-naphthane-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-yl) benzene-1, the 4-diamines,
4-(6-(4-aminophenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-5,6,7,8-naphthane-1-alcohol,
Tertiary butyl 4-(1-(4-(benzyloxy)-5,6,7,8-naphthane-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) piperidines-1-carboxylicesters,
4-(6-(4-(N-(methyl sulphonyl) sulfonyloxy methyl amine) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-5,6,7,8-naphthane-1-methylmethane sulphonate,
4-(6-(4-(sulfonyloxy methyl amine) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-5,6,7,8-naphthane-1-methylmethane sulphonate,
N-(4-(1-(4-(benzyloxy)-5,6,7,8-naphthane-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(4-(1-(4-hydroxyl-5,6,7,8-naphthane-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
N-(4-(1-(4-hydroxyl-5,6,7,8-naphthane-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(4-morpholino phenyl)-1-(1,2,3,4-naphthane-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
4-(6-(4-(4-methylpiperazine-1-yl) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-5,6,7,8-naphthane-1-alcohol,
1-(4-(benzyloxy)-5,6,7,8-naphthane-1-yl)-N-(4-morpholino phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine or
4-(6-(4-morpholino phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-5,6,7,8-naphthane-1-alcohol.
In the embodiment of going back some, described compound is:
N-(4-(1H-tetrazolium-5-yl) phenyl)-1-((S)-(2,3-dihydro-1H-indenes-1-yl))-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-(1H-tetrazolium-5-yl) phenyl)-1-((R)-(2,3-dihydro-1H-indenes-1-yl))-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-(1H-tetrazolium-5-yl) phenyl)-1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-(1H-tetrazolium-5-yl) phenyl)-1-((S)-(1,2-acenaphthene-1-yl))-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-(1H-tetrazolium-5-yl) phenyl)-1-((R)-(1,2-acenaphthene-1-yl))-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-(1H-tetrazolium-5-yl) phenyl)-1-(1,2-acenaphthene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-(1H-tetrazolium-5-yl) phenyl)-1-(1-naphthyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-(1H-tetrazolium-5-yl) phenyl)-1-(phenanthrene-4-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-morpholino phenyl)-1-((S)-(2,3-dihydro-1H-indenes-1-yl))-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-morpholino phenyl)-1-((R)-(2,3-dihydro-1H-indenes-1-yl))-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-morpholino phenyl)-1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-morpholino phenyl)-1-((S)-(1,2-acenaphthene-1-yl))-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-morpholino phenyl)-1-((R)-(1,2-acenaphthene-1-yl))-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-morpholino phenyl)-1-(1,2-acenaphthene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-morpholino phenyl)-1-(1-naphthyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-morpholino phenyl)-1-(phenanthrene-4-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-(piperazine-1-yl) phenyl)-1-((S)-(2,3-dihydro-1H-indenes-1-yl))-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-(piperazine-1-yl) phenyl)-1-((R)-(2,3-dihydro-1H-indenes-1-yl))-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-(piperazine-1-yl) phenyl)-1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-(piperazine-1-yl) phenyl)-1-((S)-(1,2-acenaphthene-1-yl))-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-(piperazine-1-yl) phenyl)-1-((R)-(1,2-acenaphthene-1-yl))-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-(piperazine-1-yl) phenyl)-1-(1,2-acenaphthene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-(piperazine-1-yl) phenyl)-1-(1-naphthyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-(piperazine-1-yl) phenyl)-1-(phenanthrene-4-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
(S)-4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenylformic acid,
(R)-4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenylformic acid,
4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenylformic acid,
(S)-4-(1-(1,2-acenaphthene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenylformic acid,
(R)-4-(1-(1,2-acenaphthene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenylformic acid,
4-(1-(1,2-acenaphthene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenylformic acid,
4-(1-(1-naphthyl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenylformic acid,
4-(1-(phenanthrene-4-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenylformic acid,
N-(4-aminophenyl)-1-((S)-(2,3-dihydro-1H-indenes-1-yl))-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-aminophenyl)-1-((R)-(2,3-dihydro-1H-indenes-1-yl))-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-aminophenyl)-1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-aminophenyl)-1-((S)-(1,2-acenaphthene-1-yl))-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-aminophenyl)-1-((R)-(1,2-acenaphthene-1-yl))-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-aminophenyl)-1-(1,2-acenaphthene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-aminophenyl)-1-(1-naphthyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-aminophenyl)-1-(phenanthrene-4-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
(S)-N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
(R)-N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
N-(methyl sulphonyl)-N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
(S)-N-(4-(1-(1,2-acenaphthene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
(R)-N-(4-(1-(1,2-acenaphthene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
N-(4-(1-(1,2-acenaphthene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
N-(4-(1-(1-naphthyl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
N-(4-(1-(phenanthrene-4-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
(S)-N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
(R)-N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
(S)-N-(4-(1-(1,2-acenaphthene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
(R)-N-(4-(1-(1,2-acenaphthene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(4-(1-(1,2-acenaphthene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(4-(1-(1-naphthyl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(4-(1-(phenanthrene-4-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-4-(4-methylpiperazine-1-yl) phenyl-1-(S)-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-4-(4-methylpiperazine-1-yl) phenyl-1-(R)-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-4-(4-methylpiperazine-1-yl) phenyl-1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-4-(4-methylpiperazine-1-yl) phenyl-1-(S)-(1,2-acenaphthene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-4-(4-methylpiperazine-1-yl) phenyl-1-(R)-(1,2-acenaphthene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-4-(4-methylpiperazine-1-yl) phenyl-1-(1,2-acenaphthene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-4-(4-methylpiperazine-1-yl) phenyl-1-(1-naphthyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-(1-(phenanthrene-4-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(3-hydroxyl-4-p-methoxy-phenyl)-1-((S)-(2,3-dihydro-1H-indenes-1-yl))-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(3-hydroxyl-4-p-methoxy-phenyl)-1-((R)-(2,3-dihydro-1H-indenes-1-yl))-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(3-hydroxyl-4-p-methoxy-phenyl)-1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(3-hydroxyl-4-p-methoxy-phenyl)-1-((S)-(1,2-acenaphthene-1-yl))-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(3-hydroxyl-4-p-methoxy-phenyl)-1-((R)-(1,2-acenaphthene-1-yl))-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(3-hydroxyl-4-p-methoxy-phenyl)-1-(1,2-acenaphthene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(3-hydroxyl-4-p-methoxy-phenyl)-1-(1-naphthyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine or
N-(3-hydroxyl-4-p-methoxy-phenyl)-1-(phenanthrene-4-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine.
In some further embodiments, described compound is
1-((6-fluoro-4H-benzo [d] [1,3] dioxin-8-yl) methyl)-N-(4-morpholino phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
1-butyl-N-(4-(piperidines-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
Ethyl 2-(6-(4-(piperidines-1-yl) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl) acetic ester,
1-methyl-N-(4-(piperidines-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
1-sec.-propyl-N-(4-(piperidines-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine,
N-(4-(1-(3-aminopropyl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
N-(methyl sulphonyl)-N-(4-(1-propyl group-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(4-(1-butyl-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
N-(4-(1-(4-hydroxybutyl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
4-(6-(4-(N-(methyl sulphonyl) sulfonyloxy methyl amine) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl) butylacetic acid ester,
N-(4-(1-ethyl-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
N-(4-(1-sec.-propyl-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
N-(4-(1-methyl isophthalic acid H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine,
N-(5-(1-(4-hydroxyl-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) pyridine-2-yl) amsacrine,
N-(2, the 3-dihydroxypropyl)-N-(5-(1-(4-hydroxyl-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) pyridine-2-yl) amsacrine,
N-(2, the 3-dihydroxypropyl)-N-(4-(1-(4-hydroxyl-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(5-(1-(4-hydroxyl-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) pyridine-2-yl)-N-(2-morpholino ethyl) amsacrine,
N-(4-(1-(4-hydroxyl-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(2-morpholino ethyl) amsacrine,
N-(4-(1-(4-hydroxyl-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(3-hydroxypropyl) amsacrine,
N-(4-(1-(4-hydroxyl-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(2-hydroxyethyl) amsacrine,
N-(4-(1-(1-hydroxyl-6,7-dihydro-5H-cyclopenta [c] pyridine-5-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(4-(1-(1-hydroxyl-6,7-dihydro-5H-cyclopenta [c] pyridine-5-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(2-hydroxyethyl) amsacrine,
N-(4-(1-(1-hydroxyl-6,7-dihydro-5H-cyclopenta [c] pyridine-5-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(2-morpholino ethyl) amsacrine,
N-(4-(1-(4-hydroxyl-6,7-dihydro-5H-cyclopenta [c] pyridine-7-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(4-(1-(4-hydroxyl-6,7-dihydro-5H-cyclopenta [c] pyridine-7-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(2-hydroxyethyl) amsacrine,
N-(4-(1-(4-hydroxyl-6,7-dihydro-5H-cyclopenta [c] pyridine-7-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(2-morpholino ethyl) amsacrine,
N-(2, the 3-dihydroxypropyl)-N-(4-(1-(1-hydroxyl-6,7-dihydro-5H-cyclopenta [c] pyridine-5-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(2, the 3-dihydroxypropyl)-N-(4-(1-(4-hydroxyl-6,7-dihydro-5H-cyclopenta [c] pyridine-7-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(4-(1-(4-hydroxyl-6,7-dihydro-5H-cyclopenta [b] pyridine-7-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(4-(1-(4-hydroxyl-6,7-dihydro-5H-cyclopenta [b] pyridine-7-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(2-morpholino ethyl) amsacrine,
N-(4-(1-(4-hydroxyl-6,7-dihydro-5H-cyclopenta [b] pyridine-7-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base amino) phenyl)-N-(2-hydroxyethyl) amsacrine or
N-(2, the 3-dihydroxypropyl)-N-(4-(1-(4-hydroxyl-6,7-dihydro-5H-cyclopenta [b] pyridine-7-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine.
Present invention resides in the prodrug in its scope.Generally speaking, these prodrugs will be the functional derivatives of formula (I) compound, and it can easily be converted into required compound in vivo.Therefore, in methods of treatment of the present invention, term administering " should comprise with concrete disclosed compound or with the described various conditions that may not have concrete disclosed compounds for treating and treat, but these compounds are converted into specific compound in vivo after being administered to the patient.At for example " Design of Prodrugs " H.Bundgaard etc., Elsevier has described in 1985 and has selected and the traditional method of the precursor medicine derivative that preparation is fit to, and it all incorporates this paper by reference into.The metabolite of these compounds is included in the reactive specy that produces when being introduced into compound of the present invention in the coenocorrelation.
The N-oxide derivative of formula (I) compound or pharmacy acceptable salt are also within the scope of the invention.For example, the azo-cycle atom of imidazole nucleus thimble or nitrogen heterocyclic ring substituting group are at suitable oxygenant such as metachloroperbenzoic acid or H 2O 2Can form oxide compound under the situation about existing.
Formula (I) compound, it is tart (for example, having carboxyl or phenolic hydroxyl group group) in nature, can form pharmacy acceptable salt, such as sodium, potassium, calcium or golden salt.With pharmaceutically acceptable amine, also within the scope of the invention such as ammonia, alkylamine, hydroxyalkyl amine and the formed salt of N-methyl osamine (N-methylglycamine).Formula (I) compound can adopt acid treatment to form acid salt.The example of this acid comprises hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, methylsulfonic acid, phosphoric acid, to bromobenzene sulfonic acid, carbonic acid, succsinic acid, citric acid, phenylformic acid, oxalic acid, propanedioic acid, salicylic acid, oxysuccinic acid, fumaric acid, xitix, toxilic acid, acetic acid and other inorganic and organic acid well known to those skilled in the art.Can produce acid salt (for example hydrochloride salt) by formula (I) compound that free alkali form is handled in the acid (for example hydrochloric acid) of adopting q.s and prepare acid salt.Handle salt by the alkaline aqueous solution (for example sodium hydroxide, Sodium Hydrogen Carbonate, salt of wormwood or ammonia) that adopts suitable dilution and acid salt can be transformed back into its free alkali form.Formula (I) compound can also be, for example the form of the mixture of non-chiral compound, racemic mixture, activity of optically active compounds, pure diastereomer or diastereomer.
Above-claimed cpd shown the kinase whose restraining effect of one or more proteolytic enzyme, and these protein kinases relate to cell mitotic cycle of tumour cell for example.The example of this protein kinase comprises all existence forms in aurora kinase, cell cycle protein dependent kinase or the Polo sample kinases.
Similarly, the pharmaceutical composition that contains at least one above-claimed cpd and carrier also within the scope of the invention.These pharmaceutical compositions can be used for treating disease or the state of being regulated by the kinases that relates to cell mitogen.
The present invention relates on the other hand treating and suffers from protein kinase-object method of adjusting disease, and wherein this method comprises the pharmaceutically significant quantity of using a kind of above-claimed cpd to described object.
Compound of the present invention also shows restraining effect to one or more kinases relevant with phosphorylation process in the cell.Therefore, the invention further relates to the method that reduces the kinase whose phosphorylation of proteolytic enzyme in the cell, it comprises with a kind of compound exposing cell of the present invention.
Another aspect of the present invention further relates to and suppresses the kinase whose method of proteolytic enzyme in the cell, and it comprises a kind of above-claimed cpd exposing cell of employing.In some embodiments of this method, the proteolytic enzyme kinases relates to one or more proteolytic enzyme kinases of cell mitogen.In some other embodiments, described protein kinase is aurora kinase, cell cycle protein dependent kinase or Polo sample kinases.
The present invention further provides the method that suppresses to comprise the abnormal growth of cells of transformant by the compound of the present invention of using significant quantity.Abnormal growth of cells refers to not rely on the cell growth (for example contact inhibition forfeiture) of normal regulating mechanism.
The present invention also can provide suppress optimum and the virulent hyperplasia (that is) method, because the disease that cell proliferation worsens, described inhibition is finished by compound as herein described to the object of this treatment of needs of using significant quantity.
The present invention further provides pharmaceutical composition---every kind of composition contain just like above put down in writing The compounds of this invention---and the regulation and control of use formula (I) compound relate to the method for cell mitogen protein kinase function.The example of these protein kinases comprises aurora kinase (for example A, B and C), cyclin-dependent kinase (in its 11 kinds of forms any) and polo sample kinases (its any existence form).
The present invention also further provides treatment or prophylaxis of tumours or method for cancer, and it is by give needing formula (I) compound administration the object of this treatment, and for example Mammals (and more particularly people) carries out.Tumour or cancer can be that for example osteocarcinoma is (for example, You Wenshi (the sarcoma of Ewing ' s), osteosarcoma, chondrosarcoma or orthopaedics connect (orthopaedics links)), brain and cns tumor (for example, acoustic tumor, tumor of spinal cord, cerebral tumor (brain tumor ring of hope)), breast cancer, breast cancer, colorectal carcinoma (for example anus cancer), internal secretion cancer (adrenocortical carcinoma for example, the carcinoma of the pancreas carcinoma of the pancreas of exocrine pancreas cancer (for example such as), the hypophysis cancer, thyroid carcinoma, the Parathyroid cancer, thymic carcinoma, multiple endocrine adenomas or other internal secretion cancer), gastrointestinal cancer (cancer of the stomach for example, esophagus cancer, carcinoma of small intestine, carcinoma of gallbladder, liver cancer, cholangiocarcinoma or stomach and intestine innocent tumour), apparatus urogenitalis cancer (carcinoma of testis for example, penile cancer or prostate cancer), gynecological cancer (cervical cancer for example, ovarian cancer, carcinoma of vagina, uterus/carcinoma of endometrium, carcinoma vulvae, gestation trophoderm cancer, carcinoma of fallopian tube or sarcoma of uterus), incidence cancer (oral cavity for example, lip, the glandula cancer, larynx, laryngopharynx portion, the oropharynx cancer, nose, other or the nasopharyngeal carcinoma of nose), leukemia (acute lymphoblastic leukemia for example, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, the hair cell leukemia, acute promyelocyte leukemia, Plasmacytic leukemia), lung cancer (gland cancer for example, small cell lung cancer or nonsmall-cell lung cancer), lymphatic cancer (Huo Qijin (Hodgkin ' s) disease for example, non-Hodgkin (Hodgkin ' s) lymphoma, the lymphoma that AIDS-is relevant), cancer eye (for example retinoblastoma or intraocular melanoma), skin carcinoma (melanoma for example, non-melanoma skin cancer or Merkel cell carcinoma), soft tissue sarcoma's (for example blocking Podbielniak (Kaposi ' s) sarcoma), urinary system cancer (kidney for example, the Wei Er nurse (Wilm ' s) glucagonoma, bladder cancer, urethral carcinoma or transitional cell carcinoma) and other type or relative disease (histiocytosis for example, mesothelioma, metastatic carcinoma, innocent tumour, neurofibroma, germinoma, connective tissue proliferation small circle cell tumour, pernicious shaft-like tumour, the stiff fibre tumour, ataxia-telangiectasia, the Nijmegen syndrome that ruptures, Luo-Tang Er Shi (Rothmund-Thomson) syndrome, Li Fulaomeini (Li-Fraumeni) syndrome, von Hipple-Lindau disease, Beckwith-Wiedemann syndrome, Down ' s syndrome, Denys-Drash syndrome, WAGR syndrome or cervical intraepithelial neoplasia become (CIN cervical intraepithelial neoplasm)).The mode that compound can be fit to is used, for example intravenously, subcutaneous, oral, non-enteron aisle or topical application.
In some other embodiments, the compound and the second therapeutical agent combined administration.The example of this second therapeutical agent comprises that alkylating agent (for example; asaley (Asaley); AZQ; BCNU; busulfan (Busulfan); carboxylic phthalic acid platinum (carboxy phthalatoplatinum); CBDCA; CCNU; CHIP; Chlorambucil (chlorambucil); NSC-178248 (chlorozotocin); cis-platinum; chromium pine (clomesone); the cyano group morphine is for Zorubicin; encircle Song (cyclodisone); dianhydrogalactitol (dianhydrogalactitol); fluorodopan (florodopan); super sulfanilamide (SN) (hepsulfam); hycanthone (hycanthone); melphalan (melphalan); Methyl CCNU; ametycin; rice holder azoles acid amides (mitozolamide); mustargen; PCNU; piperazine; piperazinedione; pipobroman (pipobroman); methylmitomycin (porfiromycin); spiral shell glycolylurea mustard (spirohydantoin mustard); teroxirone (teroxirone); four platinum (tetraplatin); thio-tepa (thio-tepa); triethylenemelamine (triethylenemelamine); uracil mustard or Yoshi-864); antimitotic agent (allocolchicine for example; halichondrin B (HalichondrinB); colchicine; colchicine derivative; aplysiatoxin 10 (dolastatin 10); maytenin (maytansine); Li Suoxin (rhizoxin); taxol; D51-7059; thio-colchicine; the trityl halfcystine; vinblastine sulfate or leucocristine sulfate); topoisomerase I inhibitor (camptothecine for example; camptothecin sodium; amino camptothecin or camptothecin derivative); topoisomerase II inhibitor (Zorubicin for example; amonafide (amonafide); m-AMSA; the anthracene pyrazole derivatives; pyrazoloacridine (pyrazoloacridine); bisantrene hydrochloric acid (bisantrene HCl); daunomycin (daunorubicin); the deoxidation Zorubicin; mitoxantrone; menogaril (menogaril); N; N-dibenzyl daunomycin; oxane thiazole (oxanthrazole); RBZ (rubidazone); VM-26; VP-16); RNA/DNA antimetabolite (L-alanosin for example; 5-nitrogen cytidine (5-azacytidine); 5 FU 5 fluorouracil; U 42126 (acivicin); the aminopterinum derivative; the aminopterinum derivative; the aminopterinum derivative; antifol; Bake solubility antifol (Baker ' s solubleantifol); two chloropropyl 2-hydroxyls-1; 4 naphthoquinones (dichlorallyl lawsone); Bu Kuina (brequinar); fluorofur (ftorafur) (prodrug); 5,6-dihydro-5-nitrogen cytidine; Rheumatrex; Methylamidepterin derivative; N-phosphono ethanoyl)-L-aspartate (PALA); pyrans furans rhzomorph (pyrazofurin) or trimetrexate ((trimetrexate)); DNA antimetabolite (3-HP for example; 2 '-'-Deoxy-5-fluorouridine; 5-HP; α-TGDR; aphidocolin glycine (aphidicolin glycinate); ara-C; 5-azepine-2 '-Deoxyribose cytidine; β-TGDR; cyclotidine; guanazole (guanazole); hydroxyurea; Trophicardyl glycol aldehyde (inosine glycodialdehyde); mark's mycin II (macbecinII); pyrazolyl imidazoles (pyrazoloimidazole); Tioguanine or thio-purine).
For the purposes of the present invention, according to Periodic table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed discerns chemical element.In addition, ThomasSorrell is at Organic Chemistry, and University Science Books is among the Sausalito (1999); And M.B.Smith and J.March are at Advanced Organic Chemistry, 5th Ed., John Wiley﹠amp; Sons, the vitochemical General Principle described in the New York (2001) is incorporated its full content into this paper by reference.
As used herein, term " adjusting " meaning is to increase or reduce for example activity by the amount that can measure.Be called as agonist by increasing their compounds active or effect adjusting proteolytic enzyme kinase function in protein phosphorylation.Be called as antagonist or inhibitor by reducing their compounds active or effect adjusting proteolytic enzyme kinase function in protein phosphorylation.
As described herein, compound of the present invention can be randomly replaces with one or more substituting groups, those of all general remarks as mentioned or by the concrete classification of the present invention, subclass is other and those of the concrete illustration of kind.
As used herein, term " aliphatic " (" alphatic ") comprises alkyl, alkenyl and alkynyl, and wherein each as described belowly randomly is substituted.Except as otherwise noted, it comprises branched group (for example tertiary alkyl, such as the tertiary butyl) or straight aliphatic chain (for example positive alkyl, kiki alkenyl group or alkynyl group).Straight aliphatic chain has-(CH 2) v-basic basic structure, wherein v can be an arbitrary integer, for example from 1 to 12 (such as 1 to 6).Prop up the straight aliphatic chain that aliphatic chain is replaced by one or more aliphatic groups.Prop up aliphatic chain to have-[CQQ '] v-structure, wherein at least one is an aliphatic group among Q and the Q '.
As used herein, " alkyl " group refers to contain the representative examples of saturated aliphatic hydrocarbyl group of 1-8 (for example 1-6 or 1-4) carbon atom.Alkyl can be straight or ramose.The example of alkyl includes but not limited to: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, n-heptyl and 2-ethylhexyl.Alkyl can be (promptly randomly being substituted) that replaces with one or more substituting groups.Substituent example includes but not limited to: (the referring to haloalkyl, such as trifluoromethyl) of halogen; Alicyclic (for example cycloalkyl or cycloalkenyl group); (for example Heterocyclylalkyl or the heterocycloalkenyl) of alicyclic heterocyclic family; Aryl; Heteroaryl; Alkoxyl group; Carbalkoxy; Alkyl carboxyl; Aroyl; 4-hetaroylpyrazol; Acyl group (for example, (aliphatic) carbonyl, (alicyclic) carbonyl or (alicyclic heterocyclic family) carbonyl); Nitro; Cyano group; Amide group (for example, (cycloalkylalkyl) amide group, aryl amido group, arylalkyl amide base, (Heterocyclylalkyl) amide group, (Heterocyclylalkyl alkyl) amide group, heteroaryl amide base, heteroaralkyl amido alkyl amide group, cycloalkyl amide group, Heterocyclylalkyl amide group, aryl amido group or heteroaryl amide base); Amino (for example, aliphatics amino, alicyclic amino or alicyclic heterocyclic family amino); Oxime; Alkylsulfonyl (for example, aliphatics-S (O) 2-); Sulfinyl; Sulfane base (sulfanyl); Sulfoxide (sulfoxy); Urea; Thiocarbamide; Sulphonamide; Sulphamide; Oxo (thereby forms carbonyl, promptly-CO-); Carboxyl; Formamyl; Alicyclic oxygen base; Alicyclic heterocyclic family oxygen base; Aryloxy; Heteroaryloxy; Aralkoxy; The heteroaryl alkoxyl group; Carbalkoxy; Alkyl carbonyl oxy; Hydroxyl or alicyclic (alkoxyl group) phosphorus acyloxy.Without limits, the example of substituted alkyl comprises carboxyalkyl (such as HOOC-alkyl, alkoxycarbonyl alkyl and alkyl carbonyl oxy alkyl); The cyano group alkyl; Hydroxyalkyl; Alkoxyalkyl; The acyl group alkyl; Aralkyl; (alkoxy aryl) alkyl; (sulfonyl amido) alkyl (for example, alkyl-S (O) 2-aminoalkyl group); Aminoalkyl group; Amido alkyl; (alicyclic) alkyl; Silyl (for example trialkylsilkl) and haloalkyl.
As used herein, " alkenyl " group refers to contain the aliphatic carbon group of 2 to 8 (for example, 2 to 6 or 2 to 4) carbon atoms and at least one two key.As alkyl, alkenyl can be straight or ramose.The example of alkenyl includes but not limited to: allyl group, prenyl (isoprenyl), crotyl and 2-hexenyl.Alkenyl can randomly replace with one or more substituting groups, such as halogen; Alicyclic (for example cycloalkyl or cycloalkenyl group); (for example Heterocyclylalkyl or the heterocycloalkenyl) of alicyclic heterocyclic family; Aryl; Heteroaryl; Alkoxyl group; Aroyl; 4-hetaroylpyrazol; Acyl group (for example (aliphatics) carbonyl, (alicyclic) carbonyl or (alicyclic heterocyclic family) carbonyl); Nitro; Cyano group; Amide group (for example (cycloalkylalkyl) amide group, aryl amido group, arylalkyl amide base, (Heterocyclylalkyl) amide group, (Heterocyclylalkyl alkyl) amide group, heteroaryl amide base, heteroaralkyl amido alkyl aminocarboxyl, cycloalkyl amino carbonyl, Heterocyclylalkyl aminocarboxyl, aromatic yl aminocarbonyl or heteroaryl amino carbonyl); Amino (for example, aliphatics amino, alicyclic amino, alicyclic heterocyclic family amino or analiphatic sulphur amide group); Oxime; Alkylsulfonyl (for example, alkyl-S (O) 2-, alicyclic-S (O) 2-or aryl-S (O) 2-); Sulfinyl; The sulfane base; Sulfoxide; Urea; Thiocarbamide; Sulphonamide; Sulphamide; Oxo; Carboxyl; Formamyl; Alicyclic oxygen base; Alicyclic heterocyclic family oxygen base; Aryloxy; Heteroaryloxy; Aralkoxy; Assorted aralkoxy; Carbalkoxy; Alkyl carbonyl oxy; Or hydroxyl.Without limits, some examples of substituted alkenyl base comprise that cyano group alkenyl, alkoxy alkenyl, acyl chain thiazolinyl, hydroxyl alkenyl, aralkenyl, (alkoxy aryl) alkenyl, (sulfonyl amido) alkenyl are (such as (alkyl-S (O) 2-amino alkenyl), amino alkenyl, amide group alkenyl, (alicyclic) alkenyl and halogen alkenyl.
As used herein, " alkynyl " group refers to contain 2 to 8 (for example 2 to 6 or 2 to 4) carbon atoms and has at least one triple-linked aliphatic carbon group.Alkynyl can be straight or ramose.The example of alkynyl includes but not limited to: propargyl and butynyl.Alkynyl can randomly replace with one or more substituting groups, such as: aroyl; 4-hetaroylpyrazol; Alkoxyl group; Cycloalkyloxy; The heterocycle alkoxyl group; Aryloxy; Heteroaryloxy; Aralkoxy; Nitro; Carboxyl; Cyano group; Halogen; Hydroxyl; Sulfo group; Sulfydryl; Sulfane base (for example, aliphatics-S-or alicyclic-S-); Sulfinyl (for example aliphatics-S (O)-or alicyclic-S (O)-); Alkylsulfonyl (aliphatics-S (O) for example 2-, aliphatics amino-S (O) 2-or alicyclic-S (O) 2-); Amide group (for example alkylamidoalkyl, alkylamidoalkyl, cycloalkyl amide group, Heterocyclylalkyl amide group, cycloalkyl amide group, aryl amido group, aryl amido group, arylalkyl amide base, (Heterocyclylalkyl) amide group, (cycloalkylalkyl) amide group, heteroaralkyl amide group, heteroaryl amide base or heteroaryl amide base); Urea; Thiocarbamide; Sulphonamide; Sulphamide; Carbalkoxy; Alkyl carbonyl oxy; Alicyclic; Alicyclic heterocyclic family; Aryl; Heteroaryl; Acyl group (for example, (alicyclic) carbonyl or (alicyclic heterocyclic family) carbonyl); Amino (for example, aliphatics amino); Sulfoxide; Oxo (oxo); Formamyl; (alicyclic) oxygen; (alicyclic heterocyclic family) oxygen or (heteroaryl) alkoxyl group.
As used herein, " amide group " comprises " aminocarboxyl " and " carbonylamino ".Each term wherein is meant the amide group such as-N (R when using endways when using separately or with other moiety combinations X)-C (O)-R YOr-C (O)-N (R X) 2Or when using in inside-C (O)-N (R X)-or-N (R X)-C (O)-, R wherein XAnd R YBe defined as follows.The example of amide group comprises alkylamidoalkyl (such as alkyl-carbonyl-amino or alkyl amino-carbonyl), (alicyclic heterocyclic family) amide group, (heteroaralkyl) amide group, (heteroaryl) amide group, (Heterocyclylalkyl) alkylamidoalkyl, aryl amido group, arylalkyl amide base, (cycloalkyl) alkylamidoalkyl and cycloalkyl amide group.
As used herein, " amino " group refers to-NR XR Y, R wherein XAnd R YIn each be hydrogen (or hereinafter sometimes for " H ") independently; alkyl; alicyclic; (alicyclic) aliphatics; aryl; virtue aliphatic (araliphatic); alicyclic heterocyclic family; (alicyclic heterocyclic family) aliphatics; heteroaryl; carboxyl; the sulfane base; sulfinyl; alkylsulfonyl; (aliphatics) carbonyl; (alicyclic) carbonyl; ((alicyclic) aliphatics) carbonyl; aryl carbonyl; (fragrant aliphatics) carbonyl; (alicyclic heterocyclic family) carbonyl; ((alicyclic heterocyclic family) aliphatics) carbonyl; (heteroaryl) carbonyl or (assorted fragrant aliphatics) carbonyl, wherein each is in this paper definition and randomly replacement.The example of amino group comprises alkylamino, dialkyl amido, arylamino and ammonia diaryl base.When term " amino " was not end group (for example alkyl-carbonyl-amino), it was by-NR X-expression, wherein R XHave the meaning identical with above-mentioned definition.
As used herein, " aryl "---uses separately or as major part such as the part in " aralkyl ", " aralkoxy " or " aryloxy alkyl "---and refers to monocyclic (for example phenyl); (for example indenyl, naphthyl, tetralyl, benzoglyoxaline, benzothiazole or the tetrahydro indenyl) of dicyclo; And trinucleated (for example fluorenyl tetrahydrofluorenyl, tetrahydrochysene anthryl or anthryl) member ring systems, wherein monocyclic member ring systems is that at least one ring is fragrant in fragrance or dicyclo or the trinucleated member ring systems.Dicyclo comprise benzo-fused 2-or 3-unit carbocyclic ring with the trinucleated group.For example, benzo-fused group (benzofused group) comprises and two or more C 4-8Isocyclic part condensed phenyl.Aryl randomly replaces with one or more substituting groups.This substituent example includes but not limited to: aliphatic (for example alkyl, alkenyl or alkynyl); (for example arylalkyl) of aromatic yl aliphat, alicyclic; (alicyclic) is aliphatic; Alicyclic heterocyclic family; (alicyclic heterocyclic family) is aliphatic; Aryl; Heteroaryl; Heteroaryl aliphatic (for example heteroarylalkyl); Alkoxyl group; (alicyclic) oxygen base; (alicyclic heterocyclic family) oxygen base; Aroyl; 4-hetaroylpyrazol; (virtue is aliphatic) oxygen; (assorted virtue is aliphatic) oxygen; Aroyl; 4-hetaroylpyrazol; Amino; Oxygen base (on the non-aromatic carbocyclic of benzo-fused dicyclo or three cyclophane bases); Trinitride (promptly-N 3), nitro; Carboxyl (for example, alkoxy-C (O)-); Amide group; Amide group amino (for example-NR-C (O)-NRR '); The thioamides base (for example-C (S)-NRR '); Thioamides base amino (for example-NR-C (S)-NRR '); The alkoxyl group amide group (for example-NR-C (O)-alkoxyl group or-C (O)-NR-alkoxyl group); Acyl group (for example aliphatic carbonyl, (alicyclic) carbonyl, ((alicyclic) is aliphatic) carbonyl, (virtue is aliphatic) carbonyl, (alicyclic heterocyclic family) carbonyl, ((alicyclic heterocyclic family) is aliphatic) carbonyl or (assorted virtue is aliphatic) carbonyl); Sulfonyl (for example, aliphatic-S (O) 2-, (aliphatic-O)-S (O) 2-O-or amino-S (O) 2-); The sulfonyl amido (for example-NR-S (O) 2-OR '); Sulfinyl (for example aliphatic-S (O)-or alicyclic-S (O)-); Sulfinyl amino; The sulfane base (for example aliphatic-S-); Cyano group; Halogen; Hydroxyl; Sulfydryl; Sulfoxide; Urea; Thiocarbamide; Sulphonamide; Sulphamide; Formamyl; Phosphino-(phosphinio) (for example-P (O) (OR) R '); Phosphino-(for example-O-P (O) (OR) R '); Phosphino-amino (for example-NR-P (O) (OR ') R ") or phosphino-amino (for example-NR-P (O) (OR) (OR ')).R, R ' and R " in each in the example of mentioning just now, can be aliphatic independently.Alternatively, aryl can not be substituted.
The unrestricted example of substituted aryl comprise halogenated aryl (for example, single-, two-(for example right ,-dihalo aryl) and (three halos) aryl); (carboxyl) aryl (for example (carbalkoxy) aryl, ((aralkyl) carbonyl oxygen base) aryl and (carbalkoxy) aryl); (amide group) aryl (for example (aminocarboxyl) aryl, (((alkylamino) alkyl) aminocarboxyl) aryl, (alkyl-carbonyl) aminoaryl, (aromatic yl aminocarbonyl) aryl and (((heteroaryl) amino) carbonyl) aryl); Aminoaryl (for example ((alkyl sulfonyl) amino) aryl or ((dialkyl group) amino) aryl); (cyano group alkyl) aryl; (alkoxyl group) aryl; (sulphonamide) aryl (for example (amino sulfonyl) aryl); (alkyl sulfonyl) aryl; (cyano group) aryl; (hydroxyalkyl) aryl; ((alkoxyl group) alkyl) aryl; (hydroxyl) aryl, ((carboxyl) alkyl) aryl; (((dialkyl group) amino) alkyl) aryl; (4-nitro alkyl) aryl; (((alkyl sulfonyl) amino) alkyl) aryl; ((alicyclic heterocyclic family) carbonyl) aryl; ((alkyl sulphonyl) alkyl) aryl; (cyano group alkyl) aryl; (hydroxyalkyl) aryl; (alkyl-carbonyl) aryl; Alkylaryl; (three alkylhalide groups) aryl; Right-amino--the carbalkoxy aryl; Right-amino--cyano-aryl; Right-halogen--aminoaryl and (-(alicyclic heterocyclic family)-adjacent-(alkyl)) aryl.
As used herein, " virtue aliphatic " such as " aralkyl " group aliphatic group of referring to replace (C for example with aryl 1-4Alkyl)." aliphatic ", " alkyl " and " aryl " are as defined herein.The aliphatic example such as aralkyl of virtue is a benzyl.
As used herein, " aralkyl " group alkyl of referring to replace (C for example with aryl 1-4Alkyl)." alkyl " and " aryl " is defined hereinbefore.The example of aralkyl is a benzyl.Aralkyl randomly replaces with one or more substituting groups.
One or more substituent each can be independently: for example aliphatic (for example alkyl, alkenyl or alkynyl, it comprises that carboxyalkyl, hydroxyalkyl or alkylhalide group are such as trifluoromethyl); Alicyclic (for example cycloalkyl or cycloalkenyl group); (cycloalkyl) alkyl; Heterocyclylalkyl; (Heterocyclylalkyl) alkyl; Aryl; Heteroaryl; Alkoxyl group; Cycloalkyloxy; The heterocycle alkoxyl group; Aryloxy; Heteroaryloxy; Aralkoxy; Assorted aralkoxy; Aroyl; 4-hetaroylpyrazol; Nitro; Carboxyl; Carbalkoxy; Alkyl carbonyl oxy; Amide group (for example alkylamidoalkyl, cycloalkyl amide group, (cycloalkylalkyl) amide group, aryl amido group, arylalkyl amide base, (Heterocyclylalkyl) amide group, (Heterocyclylalkyl alkyl) amide group, heteroaryl amide base or heteroaralkyl amide group); Cyano group; Halogen; Hydroxyl; Acyl group; Sulfydryl; Alkyl alkylthio base; Sulfoxide; Urea; Thiocarbamide; Sulphonamide; Sulphamide; Oxo or formamyl.
As used herein, " member ring systems of dicyclo " comprises the structure of 8-to 12-(for example 9-, 10-or the 11-) unit that forms two rings, and wherein two rings have at least one total atom (for example 2 total atoms).The member ring systems of dicyclo comprises dicyclo aliphatic (for example bicyclic alkyl or bicyclic alkenyl), dicyclo assorted aliphatics, bicyclic aryl and bicyclic heteroaryl.
As used herein, " alicyclic " group comprises " cycloalkyl " group and " cycloalkenyl group " group, wherein each randomly replacement as described below.
As used herein, " cycloalkyl " group refers to the list or the two-ring (condense or bridging) of the saturated carbon ring of 3 to 10 (for example 5 to 10) carbon atoms.The example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, adamantyl (adamantly), norcamphyl (norbornyl)), Ku Ji (cubyl), octahydro indenyl, decahydro naphthyl, dicyclo [3.2.1] octyl group, dicyclo [2.2.2] octyl group, dicyclo [3.3.1] nonyl, dicyclo [3.3.2.] decyl, dicyclo [2.2.2] octyl group, adamantyl, azacycloalkyl or ((aminocarboxyl) cycloalkyl) cycloalkyl.
As used herein, " cycloalkenyl group " group refers to have the non-fragrant isocyclic ring of 3-10 (for example 4-8) carbon atom of one or more pairs of keys.The example of cycloalkenyl groups comprises cyclopentenyl, 1,4-ring six-two-thiazolinyl, cycloheptenyl, cyclooctene base, six hydrogen-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, dicyclo [2.2.2] octenyl or dicyclo [3.3.1] nonene base.
Cycloalkyl or cycloalkenyl group can randomly replace described substituting group such as aliphatics (for example alkyl, alkenyl or alkynyl) with one or more substituting groups; Alicyclic; (alicyclic) is aliphatic; Alicyclic heterocyclic family; (alicyclic heterocyclic family) is aliphatic; Aryl; Heteroaryl; Alkoxyl group; (alicyclic) oxygen base; (alicyclic heterocyclic family) oxygen base; Aryloxy; Heteroaryloxy; (virtue is aliphatic) oxygen base; (assorted virtue is aliphatic) oxygen base; Aroyl; 4-hetaroylpyrazol; Amino; Amide group (for example, (aliphatic) carbonylamino, (alicyclic) carbonylamino, ((alicyclic) is aliphatic) carbonylamino, (aryl) carbonylamino, (virtue is aliphatic) carbonylamino, (alicyclic heterocyclic family) carbonylamino, ((alicyclic heterocyclic family) is aliphatic) carbonylamino, (heteroaryl) carbonylamino or (assorted virtue is aliphatic) carbonylamino); Nitro; Carboxyl (for example HOOC-, carbalkoxy or alkyl carbonyl oxy); Acyl group (for example (alicyclic) carbonyl, ((alicyclic) is aliphatic) carbonyl, (virtue is aliphatic) carbonyl, (alicyclic heterocyclic family) carbonyl, ((alicyclic heterocyclic family) is aliphatic) carbonyl or (assorted virtue is aliphatic) carbonyl); Cyano group; Halogen; Hydroxyl; Sulfydryl; Sulfonyl (alkyl-S (O) for example 2-and aryl-S (O) 2-); Sulfinyl (for example alkyl-S (O)-); Sulfane base (alkyl-S-) for example; Sulfoxide; Urea; Thiocarbamide; Sulphonamide; Sulphamide; Oxo or formamyl.
As used herein, " circular part " comprises alicyclic, alicyclic heterocyclic family, aryl or heteroaryl, and wherein each formerly is defined.
As used herein, term " alicyclic heterocyclic family " comprises Heterocyclylalkyl and heterocycloalkenyl, and wherein each quilt as described below randomly replaces.
As used herein, " Heterocyclylalkyl " group refers to (condensed or bridging) (for example 5 to 10 yuan list or dicyclo) saturated rings structure of the list or the dicyclo of 3-10 unit, and wherein one or more annular atomses are heteroatoms (for example N, O, S or its combination).The example of Heterocyclylalkyl comprises piperidyl, piperazinyl, THP trtrahydropyranyl, tetrahydrofuran base, 1,4-dioxolanyl (1,4-dioxolanyl), 1,4-dithiane base (1,4-dithianyl), 1, the 3-dioxolanyl, oxazolidyl, isoxazolidyl, the morphine base, thio-morpholinyl, the octahydro benzofuryl, octahydrochromenyl, octahydrothiochromenyl, the octahydro indyl, octahydropyrindinyl, decahydroquinolyl, octahydro benzo [b] thienyl, 2-Evil-dicyclo [2.2.2] octyl group, 1-aza-bicyclo [2.2.2] octyl group, 3-aza-bicyclo [3.2.1] octyl group and 2,6-Er Evil-three encircles [3.3.1.03,7] nonyl.Monocyclic Heterocyclylalkyl can condense such as tetrahydroisoquinoline with phenyl moiety.
As used herein, " heterocycloalkenyl " group refers to have (for example 5 to 10 yuan list or dicyclo) non-aromatic ring structure of the list of one or more pairs of keys or dicyclo, and wherein one or more annular atomses are heteroatoms (for example N, O or S).Monocycle and dicyclo heterolipid fat are numbered according to the standard chemical nomenclature.
Heterocyclylalkyl or heterocycloalkenyl group can randomly replace with one or more substituting groups.These substituent examples include but not limited to: aliphatic (for example alkyl, alkenyl or alkynyl); (for example arylalkyl) of aromatic yl aliphat, alicyclic; (alicyclic) is aliphatic; Alicyclic heterocyclic family; (alicyclic heterocyclic family) is aliphatic; Aryl; Heteroaryl; Heteroaryl aliphatic (for example heteroarylalkyl); Alkoxyl group; (alicyclic) oxygen base; (alicyclic heterocyclic family) oxygen base; Aryloxy; Heteroaryloxy; (virtue is aliphatic) oxygen base; (assorted virtue is aliphatic) oxygen base; Aroyl; 4-hetaroylpyrazol; Amino; Oxo (on the non-aromatic carbocyclic of benzo-fused dicyclo or three cyclophane bases); Trinitride (promptly-N 3), nitro; Carboxyl (for example alkoxy-C (O)-); Amide group; Amide group amino (for example-NR-C (O)-NRR '); The thioamides base (for example-C (S)-NRR '); Thioamides base amino (for example-NR-C (S)-NRR '); The alkoxyl group amide group (for example-NR-C (O)-alkoxyl group or-C (O)-NR-alkoxyl group); Acyl group (for example aliphatic carbonyl, (alicyclic) carbonyl, ((alicyclic) is aliphatic) carbonyl, (virtue is aliphatic) carbonyl, (alicyclic heterocyclic family) carbonyl, ((alicyclic heterocyclic family) is aliphatic) carbonyl or (assorted virtue is aliphatic) carbonyl); Sulfonyl (for example aliphatic-S (O) 2-, (aliphatic-O)-S (O) 2-O-or amino-S (O) 2-); The sulfonyl amido (for example-NR-S (O) 2-OR '); Sulfinyl (for example aliphatic-S (O)-or alicyclic-S (O)-); Sulfinyl amino; The sulfane base (for example aliphatic-S-); Cyano group; Halogen; Hydroxyl; Sulfydryl; Sulfoxide; Urea; Thiocarbamide; Sulphonamide; Sulphamide; Formamyl; Phosphino-(for example-P (O) (OR) R '); Phosphorus base (for example-O-P (O) (OR) R '); Phosphino-amino (for example-NR-P (O) (OR ') R "); Or phosphorus base amino (for example-NR-P (O) (OR) (OR ')).The R of R, R ' " each in the example of mentioning just now, can be aliphatic independently.
As used herein, " heteroaryl " group refers to have monocyclic, dicyclo or the trinucleated member ring systems of 4 to 15 annular atomses, wherein at least one annular atoms be heteroatoms (for example N, O, S or its combination) and wherein monocyclic member ring systems be fragrance or dicyclo or the trinucleated member ring systems at least one ring be fragrant.Heteroaryl comprises the benzo-fused member ring systems with 2 to 3 rings.For example, benzo-fused group comprises benzo-fused (for example indolizyl, indyl, pseudoindoyl, 3H-indyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl, quinolyl or the isoquinolyl) with one or two alicyclic heterocyclic family of 4 to 8 yuan part.Some examples of heteroaryl are azetidinyl, pyridyl, the 1H-indazolyl, furyl, pyrryl, thienyl, thiazolyl oxazolyl, imidazolyl, tetrazyl, benzofuryl, isoquinolyl, benzothiazolyl, xanthene, the sulfo-xanthene, thiodiphenylamine (phenothiazine), indoline, benzo [1,3] dioxole, benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzimidazolyl-, benzothiazolyl, puryl, the cinnolines base, quinolyl, quinazolyl, the cinnolines base, phthalazines (phthalazyl), quinazolyl, quinoline is held the quinoline base, isoquinolyl, 4H-quinolizyl, phendioxin, 2,5-thiadiazolyl group and 1,8-naphthyridinyl (naphthyridyl).
Without limits, the example of bicyclic heteroaryl comprises furyl, thiophenyl, 2H-pyrryl, pyrryl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl group, 2H-pyranyl, 4-H-pranyl, pyridyl, pyridazinyl (pyridazyl), pyrimidyl, pyrazolyl, pyrazolyl and 1,3,5-triazolyl (triazyl).Bicyclic heteroaryl is numbered according to standardized denomination.
Without limits, the example of bicyclic heteroaryl comprises indolizyl, indyl, pseudoindoyl, 3H-indyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl, quinolyl, isoquinolyl, indolizyl, pseudoindoyl, indyl, benzo [b] furyl, bexo[b] thiophenyl, indazolyl, benzoglyoxaline, benzothiazolyl, purine radicals, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolines base, phthalazines, quinazolyl, quinoline hold quinoline base, 1,8-naphthyridinyl and pteridyl.Bicyclic heteroaryl is numbered according to standardized denomination.
Heteroaryl randomly replaces with one or more substituting groups.This substituent example includes but not limited to: aliphatic (for example alkyl, alkenyl or alkynyl); (for example arylalkyl) of aromatic yl aliphat, alicyclic; (alicyclic) is aliphatic; Alicyclic heterocyclic family; (alicyclic heterocyclic family) is aliphatic; Aryl; Heteroaryl; Heteroaryl aliphatic (for example, heteroarylalkyl); Alkoxyl group; (alicyclic) oxygen; (alicyclic heterocyclic family) oxygen; Aryloxy; Heteroaryloxy; (virtue is aliphatic) oxygen; (assorted virtue is aliphatic) oxygen; Aroyl; 4-hetaroylpyrazol; Amino; Oxo (on the non-aromatic carbocyclic of benzo-fused dicyclo or three cyclophane bases); Trinitride (promptly-N 3), nitro; Carboxyl (for example alkoxy-C (O)-); Amide group; Amide group amino (for example-NR-C (O)-NRR '); The thioamides base (for example-C (S)-NRR '); Thioamides base amino (for example-NR-C (S)-NRR '); The alkoxyl group amide group (for example-NR-C (O)-alkoxyl group or-C (O)-NR-alkoxyl group); Acyl group (for example aliphatic carbonyl, (alicyclic) carbonyl, ((alicyclic) is aliphatic) carbonyl, (virtue is aliphatic) carbonyl, (alicyclic heterocyclic family) carbonyl, ((alicyclic heterocyclic family) is aliphatic) carbonyl or (assorted virtue is aliphatic) carbonyl); Sulfonyl (for example aliphatic-S (O) 2-, (aliphatic-O)-S (O) 2-O-or amino-S (O) 2-); The sulfonyl amido (for example-NR-S (O) 2-OR '); Sulfinyl (for example aliphatic-S (O)-or alicyclic-S (O)-); Sulfinyl amino; The sulfane base (for example aliphatic-S-); Cyano group; Halogen; Hydroxyl; Sulfydryl; Sulfoxide; Urea; Thiocarbamide; Sulphonamide; Sulphamide; Formamyl; Phosphino-(for example ,-P (O) (OR) R '); Phosphorus base (for example-O-P (O) (OR) R '); Phosphino-amino (for example-NR-P (O) (OR ') R "); Or phosphorus base amino (for example-NR-P (O) (OR) (OR ')).R, R ' and R " in each in the example of mentioning just now, can be aliphatic independently.Selectively, heteroaryl can be unsubstituted.
The unrestricted example of substituted heteroaryl comprises (halo) heteroaryl (for example single and two (halo) heteroaryl); (carboxyl) heteroaryl (for example (carbalkoxy) heteroaryl); cyanoheteroaryl; aminoheteroaryl (for example ((alkyl sulfonyl) amino) heteroaryl and ((dialkyl group) amino) heteroaryl); (amide group) heteroaryl (aminocarboxyl heteroaryl for example; ((alkyl-carbonyl) amino) heteroaryl; ((((alkyl) amino) alkyl) aminocarboxyl) heteroaryl; (((heteroaryl) amino) carbonyl) heteroaryl; ((alicyclic heterocyclic family) carbonyl) heteroaryl or ((alkyl-carbonyl) amino) heteroaryl); (cyano group alkyl) heteroaryl; (alkoxyl group) heteroaryl; (sulphonamide) heteroaryl (for example (amino sulfonyl) heteroaryl); (sulfonyl) heteroaryl (for example (alkyl sulfonyl) heteroaryl); (hydroxyalkyl) heteroaryl; (alkoxyalkyl) heteroaryl; (hydroxyl) heteroaryl; ((carboxyl) alkyl) heteroaryl; (((dialkyl group) amino) alkyl) heteroaryl; (alicyclic heterocyclic family) heteroaryl; (alicyclic) heteroaryl; (4-nitro alkyl) heteroaryl; (((alkyl sulfonyl) amino) alkyl) heteroaryl; ((alkyl sulfonyl) alkyl) heteroaryl; (cyano group alkyl) heteroaryl; (acyl group) heteroaryl (for example, (alkyl-carbonyl) heteroaryl); (alkyl) heteroaryl and (alkylhalide group) heteroaryl (for example three alkylhalide group heteroaryls).
As used herein, " assorted virtue aliphatic " group (for example heteroaralkyl) aliphatic group of referring to be replaced (C for example by heteroaryl 1-4Alkyl group)." aliphatic ", " alkyl " and " heteroaryl " above are being defined.
As used herein, " heteroaralkyl " group refers to alkyl (for example, the C that replaced by heteroaryl 1-4Alkyl)." alkyl " and " heteroaryl " is in above definition.Heteroaralkyl randomly replaces with one or more substituting groups.This type of substituent example includes but not limited to: aliphatic (for example alkyl, alkenyl or alkynyl); (for example arylalkyl) of aromatic yl aliphat, alicyclic; (alicyclic) is aliphatic; Alicyclic heterocyclic family; (alicyclic heterocyclic family) is aliphatic; Aryl; Heteroaryl; Heteroaryl aliphatic (for example heteroarylalkyl); Alkoxyl group; (alicyclic) oxygen; (alicyclic heterocyclic family) oxygen; Aryloxy; Heteroaryloxy; (virtue is aliphatic) oxygen; (assorted virtue is aliphatic) oxygen; Aroyl; 4-hetaroylpyrazol; Amino; Oxo (on the non-aromatic carbocyclic of benzo-fused dicyclo or three cyclophane bases); Trinitride (promptly-N 3), nitro; Carboxyl (for example alkoxy-C (O)-); Amide group; Amide group amino (for example-NR-C (O)-NRR '); The thioamides base (for example-C (S)-NRR '); Thioamides base amino (for example-NR-C (S)-NRR '); The alkoxyl group amide group (for example-NR-C (O)-alkoxyl group or-C (O)-NR-alkoxyl group); Acyl group (for example aliphatic carbonyl, (alicyclic) carbonyl, ((alicyclic) is aliphatic) carbonyl, (virtue is aliphatic) carbonyl, (alicyclic heterocyclic family) carbonyl, ((alicyclic heterocyclic family) is aliphatic) carbonyl or (assorted virtue is aliphatic) carbonyl); Alkylsulfonyl (for example aliphatic-S (O) 2-, (aliphatic-O)-S (O) 2-O-or amino-S (O) 2-); The sulfonyl amido (for example-NR-S (O) 2-OR '); Sulfinyl (for example aliphatic-S (O)-or alicyclic-S (O)-); Sulfinyl amino; The sulfane base (for example aliphatic-S-); Cyano group; Halogen; Hydroxyl; Sulfydryl; Sulfoxide; Urea; Thiocarbamide; Sulphonamide; Sulphamide; Formamyl; Phosphino-(for example-P (O) (OR) R '); Phosphorus base (for example-O-P (O) (OR) R '); Phosphino-amino (for example-NR-P (O) (OR ') R "); Or phosphorus base amino (for example-NR-P (O) (OR) (OR ')).R, R ' and R " in each in the example of mentioning just now, can be aliphatic independently.
As used herein, " acyl group " group nail acyl group or R X-C (O)-(such as-alkyl-C (O)-, be also referred to as " alkyl-carbonyl "), R wherein X" alkyl " formerly is defined.Ethanoyl and valeryl are the example of acyl group.
As used herein, " aroyl " or " 4-hetaroylpyrazol " group refer to aryl-C (O)-or heteroaryl-C (O)-.The aryl of aroyl or 4-hetaroylpyrazol and heteroaryl moieties be being substituted as previously defined randomly.
As used herein, " alkoxyl group " base refers to alkyl-O-group, and wherein " alkyl " formerly is defined.
As used herein, " formamyl " group (O)-NR that refers to have structure-O-C XR YOr-NR X-C (O)-O-R ZGroup, R wherein XAnd R YAs hereinbefore defined and R ZCan be that aliphatic, aryl, virtue are aliphatic, alicyclic heterocyclic family, heteroaryl or assorted virtue be aliphatic.
As used herein, " carboxyl " group refer to when when the end group-COOH ,-COOR X,-OC (O) H ,-OC (O) R XMaybe when when the inner group-OC (O)-or-C (O) O-.
As used herein, " halogen is aliphatic " group refers to by the aliphatic group of 1-3 halogen atom replacement.For example, the term alkylhalide group comprises group-CF 3
As used herein, " sulfydryl " group refers to-SH.
As used herein, " sulfonic " group refer to when with endways the time-S (O) 2OH or-S (O) 2OR X
As used herein, " sulphamide " group refers to the structure-NR when using endways X-S (O) 2-NR YR Z, and when being used in inside-NR X-S (O) 2-NR Y-, R wherein X, R YAnd R ZAbove be defined.
As used herein, " sulphonamide " group refers to the structure-S (O) when using endways 2-NR XR YOr-NR X-S (O) 2-R ZMaybe when being used in inside-S (O) 2-NR X-or-NR X-S (O) 2-, wherein Rx, Ry and R ZAbove be defined.
As used herein, " sulfane base " group refer to when with endways the time-S-R X, and when being used in inside-S-, wherein R XAbove be defined.The example of sulfane base comprises aliphatic-S-, alicyclic-S-, aryl-S-or analogue.
As used herein, " sulfinyl " group refer to when with endways the time-S (O)-R X, and when being used in inside-S (O)-, R wherein XAbove be defined.Exemplary sulfinyl group comprise aliphatic-S (O)-, aryl-S (O)-, (alicyclic (aliphatic))-S (O)-, cycloalkyl-S (O)-, alicyclic heterocyclic family-S (O)-, heteroaryl-S (O)-or analogue.
As used herein, " alkylsulfonyl " group refer to when with endways the time-S (O) 2-R X, and when being used in inside-S (O) 2-, R wherein XAbove be defined.Exemplary alkylsulfonyl group comprises aliphatic-S (O) 2-, aryl-S (O) 2-, (alicyclic (aliphatic))-S (O) 2-, alicyclic-S (O) 2-, alicyclic heterocyclic family-S (O) 2-, heteroaryl-S (O) 2-, (alicyclic (amide group (aliphatic)))-S (O) 2-or analogue.
As used herein, " sulfoxide " group refer to when with endways the time-O-SO-R XOr-SO-O-R X, and when being used in inside-O-S (O)-or-S (O)-O-, wherein R XAbove be defined.
As used herein, " halogen " or " halo " group refers to fluorine, chlorine, bromine or iodine.
As used herein, " carbalkoxy "---it is comprised by the term carboxyl, uses separately or in conjunction with other group---refer to such as alkyl-O-C (O)-group.
As used herein, " alkoxyalkyl " refer to such as alkyl-O-alkyl-alkyl, wherein alkyl above is being defined.
As used herein, " carbonyl " refer to-C (O)-.
As used herein, " oxo " refers to=O.
As used herein, " aminoalkyl group " refers to (R X) 2N-alkyl-structure.
As used herein, " cyano group alkyl " refers to (NC)-alkyl-structure.
As used herein, " urea " group refers to-NR X-CO-NR YR ZStructure and " thiocarbamide " group refer to when with endways the time-NR X-CS-NR YR ZStructure and when being used in inside-NRX-CO-NR Y-or-NR X-CS-NR Y-, R wherein X, R YAnd R ZAbove be defined.
As used herein, " guanidine " group refers to-N=C (N (R XR Y)) N (R XR Y) or-N (R X) C=(N (R X)) N (R XR Y) structure, wherein R XAnd R YAbove be defined.
As used herein, term " amidino groups " group refers to structure-C=(NR X) N (R XR Y), R wherein XAnd R YAbove be defined.
Generally speaking, term " vicinal " (" vicinal ") refers to that wherein this substituting group is connected to contiguous carbon atom in the substituent location that comprises on the group of two or more carbon atoms.
Generally speaking, term " geminal " (" geminal ") refers to that wherein substituting group is connected to identical carbon atom in the substituent location that comprises on the group of two or more carbon atoms.
Term " endways " and " in inside " refer to the position of group in the substituting group.When group is present in substituent end and when further not being connected to the chemical structure other parts, group is terminal.Carboxyalkyl, i.e. R XO (O) C-alkyl is the example that C-terminal uses.When group exists in substituent centre, be connected with the other parts of chemical structure at this substituent end, this group is inner.Alkyl carboxyl (for example alkyl-C (O) O-or alkyl-OC (O)-) and alkyl carboxyl aryl (for example alkyl-C (O) O-aryl-or alkyl-O (CO)-aryl-) are the examples of the use of carboxyl inside.
As used herein, term " cyclic group " comprises single, double and trinucleated member ring systems, and it comprises alicyclic, alicyclic heterocyclic family, aryl or heteroaryl, and wherein each formerly is defined.
As used herein, term " member ring systems of the dicyclo of bridging " refers to (heterocyclicalipahtic) member ring systems of alicyclic heterocyclic family of dicyclo or the alicyclic member ring systems of dicyclo, and wherein said ring has at least two shared atoms.The example of the bicyclic system of bridging includes but not limited to: adamantyl, norbornanyl, dicyclo [3.2.1] octyl group, dicyclo [2.2.2] octyl group, dicyclo [3.3.1] nonyl, dicyclo [3.2.3] nonyl, 2-Evil dicyclo [2.2.2] octyl group, 1-azabicyclo [2.2.2] octyl group, 3-azabicyclo [3.2.1] octyl group and 2,6-Er Evil three ring [3.3.1.03,7] nonyls.The bicyclic system of bridging can randomly replace with one or more substituting groups, (comprises carboxyalkyl such as alkyl; hydroxyalkyl and alkylhalide group are such as trifluoromethyl); alkenyl; alkynyl; cycloalkyl; (cycloalkyl) alkyl; Heterocyclylalkyl; (Heterocyclylalkyl) alkyl; aryl; heteroaryl; alkoxyl group; cycloalkyloxy; the heterocycle alkoxyl group; aryloxy; heteroaryloxy; aralkoxy; assorted aralkoxy; aroyl; 4-hetaroylpyrazol; nitro; carboxyl; carbalkoxy; alkyl carbonyl oxy; aminocarboxyl; alkyl-carbonyl-amino; cycloalkyl amino carbonyl; (cycloalkylalkyl) carbonylamino; aryl-amino-carbonyl; aromatic alkyl carbonyl amino; (Heterocyclylalkyl) carbonylamino; (Heterocyclylalkyl alkyl) carbonylamino; the heteroaryl carbonylamino; the heteroaralkyl carbonylamino; cyano group; halogen; hydroxyl; acyl group; sulfydryl; alkyl alkylthio base; sulfoxide; urea; thiocarbamide; sulphonamide; sulphamide; oxo or formamyl.
Phrase " randomly replaces " with phrase and " replaces or do not replace " use alternately.As described herein, compound of the present invention can randomly be replaced by one or more substituting groups, those of all general remarks as mentioned or by the concrete classification of the present invention, subclass not and those of kind illustration.As described herein, variable R 1, R 2Or R 3, and other variable that contains in the formula (I) comprises concrete group, such as alkyl and aryl.Except as otherwise noted, for variable R 1, R 2And R 3, and other variable that wherein contains, each concrete group can randomly be replaced by one or more substituting groups as herein described.The substituting group of each concrete group is further randomly replaced by one to three halogen, cyano group, oxo alkoxyl group, hydroxyl, amino, nitro, aryl, haloalkyl and alkyl.For example, alkyl can be replaced by alkyl alkylthio base and alkyl alkylthio base can randomly be replaced by one to three halogen, cyano group, oxo alkoxyl group, hydroxyl, amino, nitro, aryl, haloalkyl and alkyl.As another example, the cycloalkyl moiety of (cycloalkyl) carbonylamino can randomly be replaced by one to three halogen, cyano group, alkoxyl group, hydroxyl, nitro, haloalkyl and alkyl.The atom that is connected to identical atom or vicinity when two alkoxyl groups is that these two alkoxyl groups can form ring with the atom that their connect.
Generally speaking, at term " randomly " before whether term " replacement " showed in the fixed structure with concrete substituent free radical replacement hydroperoxyl radical.Concrete substituting group is described in above-mentioned definition neutralizes the description of following compound and embodiment.Except as otherwise noted, randomly substituted radical can have the substituting group in each commutable position of group, and when a more than position in any given structure can be replaced by more than one substituting group that is selected from concrete group, substituting group can be identical or different on each position.Cyclic substituents---such as Heterocyclylalkyl, can be connected to another ring---such as cycloalkyl to form the spiral shell bicyclic system, for example, two shared shared atoms of ring.It should be appreciated by one skilled in the art that the substituting group combination by the present invention's anticipation is that those produce stable or chemically feasible combination of compounds.
As used herein, phrase " stable or chemically feasible " refers to when standing such condition: be used for their production, detection, preferably, their recovery, purifying and when being used for one or more purpose disclosed herein, indeclinable in fact compound.In some embodiments, stable compound or chemically feasible compound are when under 40 ℃ or lower temperature, under the situation that does not have moisture or other chemical reaction condition, keep indeclinable in fact compound of at least one week.
As used herein, " object " of treatment is common indication and therefore can exchanges with " patient ", such as animal (for example Mammals is such as the people).
As used herein, " significant quantity " is defined as the aequum of the patient treatment effect for the treatment of, and determines according to patient's age, surface-area, weight and state usually.Freireich etc., CancerChemother.Rep., 50:219 (1966) have described animal and human's dosage mutual relationship (according to the every body surface of milligram square metre).Body surface area can be approximately definite by patient's height and weight.Referring to, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970).
Except as otherwise noted, the implication of structure as herein described also comprises all of this structure isomeric (for example enantiotopic, diastereoisomeric and how much (or conformation)) forms; For example, the R of each asymmetric center and S configuration, (Z) and (E) double bond isomer and (Z) and (E) conformer.Therefore, the single three-dimensional chemical isomer of this compound and enantiotopic, diastereoisomeric and how much (or conformation) mixture within the scope of the invention.Except as otherwise noted, the tautomeric form of all of The compounds of this invention within the scope of the invention.In addition, except as otherwise noted, the implication of structure as herein described only also comprises one or more and is rich in isotopic atom and has different compounds.For example, the compound that has this structure---the hydrogen that removes deuterium or tritium replaces or is rich in 13C or 14Outside the carbon of the carbon of C replaces---within the scope of the invention.These compounds are as analysis tool or probe in the biological example test.
Detailed Description Of The Invention
Generally speaking, feature of the present invention is formula (I) compound, and above-claimed cpd is regulated the function of one or more protein kinases.
Figure G2008800059629D00371
(I)
Relevant formula (I),
R 1Be hydrogen or halogen;
R 2Be-L 1-R a, wherein
L 1Be a key and R aBe thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl; Wherein each in cycloalkyl, Heterocyclylalkyl, aryl and the heteroaryl be replace arbitrarily and have 8 to 16 annular atomses; Perhaps L 1Be alkyl and R aBe hydrogen, thiazolinyl, alkynyl, amino, hydroxyl, carbalkoxy, alkyl carbonyl oxy, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl; Wherein each in cycloalkyl, Heterocyclylalkyl, aryl and the heteroaryl be replace arbitrarily and have 8 to 16 annular atomses arranged;
R 3Be-R b-L 2-R cWherein
R bBe aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl, and be randomly to replace with 1 to 3 substituting group; Wherein when contiguous, in the substituting group two can form 5 to 16 yuan ring with their connected one or more atoms, and it has 0 to 6 heterocyclic atom,
L 2Be a key ,-(CR xR y) n-,-N=,-O-,-S-,-SO-,-SO 2-,-CO-,-CO-O-,-O-CO-,-NR x-,-NR x-CO-,-NR x-SO 2-,-CO-NR x-,-SO 2-NR x-,-NR x-CO-O-,-NR x-SO 2-O-,-NR x-CO-NR y-,-NR x-SO 2-NR y-,-CO-NR x-NR y-,-SO 2-NR x-NR y-,-NR x-CO-CO-O-,-NR x-SO 2-SO 2-O-,-S (O) 2-N x-CO-R y-,-CO-N x-S (O) 2-R y-or-(NR xR y) C=N-O-;
R cBe hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, cycloalkyl-alkyl, Heterocyclylalkyl-alkyl, cycloalkenyl group-alkyl, heterocycloalkenyl-alkyl, aralkyl or heteroaralkyl; And except hydrogen, it is randomly to replace with 1 to 3 substituting group;
R xAnd R yIn each be independently hydrogen, hydroxyl, alkyl, alkoxyl group, amino ,-the CO-alkyl ,-the CO-aryl ,-SO 2-alkyl ,-SO 2-aryl ,-SO 2-heteroaryl or-P (O) (O-alkyl) 2, wherein at R xPerhaps R yIn alkyl or aryl moiety be randomly to replace with 1 to 3 substituting group; And n is 0,1,2 or 3.
In formula (I), R bBe randomly to replace with 1 to 3 substituting group, wherein each substituting group be independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, heteroaryl, arylalkyl, heteroarylalkyl ,-OR ,-SR ,-NRR ', oxo ,-C (O)-OR ,-C (O)-NRR ', halogen ,-CN ,-NO 2,-N 3,-C (O) R ,-P (O) (OR) R ' ,-O-P (O) (OR) R ' ,-NR-P (O) (OR ') R " ,-S (O) 2-(OR) ,-O-S (O) 2-(OR) ,-NR-S (O) 2-OR ' ,-NR-C (O)-OR ' ,-NR-C (O)-NR ' R " ,-NR-C (S)-NR ' R " ,-C (S)-NRR ' and alkylthio; Among R and the R ' each is hydrogen, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl independently; And R " be alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl.
When being hydrogen, R cBe randomly to replace with 1 to 3 substituting group, each substituting group be independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, heteroaryl, arylalkyl, heteroarylalkyl ,-OR ,-SR ,-NRR ', oxo ,-C (O)-OR ,-C (O)-NRR ', halogen ,-CN ,-NO 2,-N 3,-C (O) R ,-P (O) (OR) R ' ,-O-P (O) (OR) R ' ,-NR-P (O) (OR ') R " ,-S (O) 2-(OR) ,-O-S (O) 2-(OR) ,-NR-S (O) 2-OR ' ,-NR-C (O)-OR ' ,-NR-C (O)-NR ' R " ,-NR-C (S)-NR ' R " ,-C (S)-NRR ' and alkylthio; Among R and the R ' each is hydrogen, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl independently; And R " be alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl.
R xPerhaps R yIn alkyl or aryl moiety be randomly to replace with 1 to 3 substituting group, each be independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, heteroaryl, arylalkyl, heteroarylalkyl ,-OR ,-SR ,-NRR ', oxo ,-C (O)-OR ,-C (O)-NRR ', halogen ,-CN ,-NO 2,-N 3,-C (O) R ,-P (O) (OR) R ' ,-O-P (O) (OR) R ' ,-NR-P (O) (OR ') R " ,-S (O) 2-(OR) ,-O-S (O) 2-(OR) ,-NR-S (O) 2-OR ' ,-NR-C (O)-OR ' ,-NR-C (O)-NR ' R " ,-NR-C (S)-NR ' R " ,-C (S)-NRR ' and alkylthio; Among R and the R ' each is hydrogen, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl independently; And R " be alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl.
Synthesizing of formula (I) compound
By known method, from buying or known starting raw material can synthesis type (I) compound.The exemplary synthetic route of formula (I) compound is provided in following scheme 1-5.General scheme is not restrictive, and it can be applied to other compound, and these other compounds comprise and are different from the following variable that clearly shows.
A kind of method of preparation formula (I) compound has been described in scheme 1.
Scheme 1
Figure G2008800059629D00391
Reference scheme 1, for example using, diisobutyl aluminium hydride (DIBAL) becomes corresponding alcohol 2 with 1 reduction of pyrimidine ester.Use Manganse Dioxide for example to provide corresponding aldehyde 3 to 2 oxidation.Aldehyde 3 can with hydrazine reaction to provide formula 6 compounds, R wherein 1Be H.Alternatively, aldehyde 3 can with for example Grignard reagent (Grignard reagent) R 1The MgX reaction is to provide intermediate product alcohol 4, wherein R 1It is the group except that H.4 oxidation provides ketone 5, ketone 5 can with hydrazine reaction so that pyrazolopyrimidine 6 to be provided.For example use haloalkane such as R 2X comes alkanisation 6 that intermediate 7 is provided.Alternatively, for example use aryl boric acid such as R 2B (OH) 2At Cu (OAc) 2Exist processing 6 to provide intermediate 7 (R 2=aryl).Use for example Oxone
Figure G2008800059629D00392
Come oxidizing sulfur ether 7 that sulfone 8 is provided.8 with amine R 3NH 2Reaction formula (I) compound is provided.
Scheme 2 has illustrated the another kind of method of preparation formula (I) compound, wherein R 1Be H.
Scheme 2
Figure G2008800059629D00401
Reference scheme 2, cyanoacrylate 10 provides amino-pyrazol 12 with the reaction of hydrazine 11.Amino-pyrazol 12 provides benzoyl thiourea 13 with the reaction of Benzoyl chloride and potassium sulfocyanate, provides pyrazolopyrimidine 14 with the described benzoyl thiourea 13 of sodium-hydroxide treatment in methyl alcohol.Under the situation that sodium hydroxide exists, use iodomethyl to come alkanisation pyrazolopyrimidine 14 that thioether intermediate 15 is provided.Thioether intermediate 15 provides Chloropyrimide 16 with phosphorus oxychloride (phosphorousoxychloride) reaction, and under the situation that acetate exists, zinc becomes pyrazolopyrimidine 17 with Chloropyrimide 16 reduction.Use Oxone
Figure G2008800059629D00402
Come oxidation pyrazolopyrimidine 17 that sulfone 18 is provided, sulfone 18 and amine R 3NH 2Reaction provides compound of the present invention, just formula (I) compound, wherein R 1Be H.
In some embodiments, R wherein 3Be for example amino aryl that replaces, the other example of formula (I) compound can be as be prepared in the scheme 3 illustratedly.
Scheme 3
Reference scheme 3, amino-substituted compounds 19 can with formula Rc-L 3The reaction of-Q compound, wherein L 3Be-C (O)-,-SO 2-or-P (OR X) 2-and Q represent halogenide, perhaps Rc-L 3-Q represents acid anhydrides, with the single substitution compound that formula 20 is provided or the bisubstituted compound of formula 21.
Scheme 4 has illustrated the another kind of method of preparation I compound, wherein, and R for example 3It is the amino aromatic base that replaces.
Scheme 4
Reference scheme 4, amino-substituted compounds 19 can with formula R 2The compound reaction of OH is to provide formula I. compound.
In further embodiment, can come preparation formula (I) compound as the explanation in the scheme 5, wherein R 3It is aryl-tetrazolium.
Scheme 5
Reference scheme 5, itrile group substitution compound 22 and trialkyltin trinitride for example tin trimethyl trinitride react so that intermediate tin-tetrazolium 23 to be provided.Under the mineral acid situation that for example hydrochloric acid exists, the hydrolysis of compound 23 provides formula 24 compounds.
Contain using of formula (I) compound compositions
As above definition, significant quantity are the aequums that the patient who treats is had result of treatment.For formula (I) compound, the scope of significant quantity can be for example from about 1mg/kg to about 150mg/kg (for example from about 1mg/kg to about 100mg/kg).Recognize as those of ordinary skills, significant quantity also can according to route of administration, vehicle use and with comprise that using therapeutical agent and/or radiocurable other treatment method to share changes.
For the composition of manufacture order dosage form, can be according to the main body (host treated) of treatment with the amount of other support material bonded The compounds of this invention, concrete method of application and changing.For example, composition can be prepared, so that the conditioning agent of the dosage of body weight/day can be administered to the patient who is just accepting these compositions between 0.01-100mg/kg.
Also be understood that, any concrete patient's concrete application dosage and treatment plan can change according to various factors, and it comprises particular compound activity, age, body weight, general health, sex, diet, time of application, discharge rate, drug regimen and treatment doctor's the judgement of use and the seriousness of the disease specific of being treated.The amount of The compounds of this invention also depends on the particular compound in the composition simultaneously in composition.
According to the concrete situation or the disease of being treated or preventing, other therapeutical agent---is applied usually to treat or to prevent this situation---and also may reside in the present composition.Therapeutical agent as used herein, other---it is applied usually with treatment or prevention disease specific or situation---is known as " be suitable for just treated disease or situation ".
Formula (I) compound can be used with any method of application that is suitable for pharmaceutical compound, and it includes but not limited to: pill, tablet, capsule, spraying, suppository, be used for suction or injection liquid preparations or as eyes or ear drops, dietary supplement and topical formulations.Pharmaceutically acceptable composition comprises the aqueous solution of promoting agent, and it oozes in physiological saline, 5% glucose or other the pharmaceutically acceptable vehicle of knowing waiting.Solubilizing agent for example other solubilizing agent of knowing of cyclodextrin or this area ordinary person vehicle of can be used as the pharmacy that is used for the delivery treatments compound uses.About route of administration, composition can be oral, in the nose, in skin, intracutaneous, vagina, ear, intraocular, oral cavity, rectum, per mucous membrane use, perhaps through sucking, implant (for example surgically) or intravenous administration.Composition can be applied to animal (for example Mammals, such as the mankind, inhuman primates, horse, dog, ox, pig, sheep, goat, cat, mouse, rat, cavy, rabbit, hamster, gerbil jird or ferret or bird or Reptilia such as lizard).
The sustained release of therapeutical agent can utilize various technology.Known devices has monolithic layer (monolithic layer) or coating, it has comprised heterogeneous solution and/or the dispersion of promoting agent in the polymeric material, wherein the diffusion of promoting agent is a rate limiting, and promoting agent process polymer diffusion is to polymkeric substance circulation interface and be released into surrounding fluid.In some devices, soluble substance also is dissolved or is dispersed in the polymeric material, so that after the material dissolves, stay additional hole or passage.Matrix device also is diffusional limitation usually, but other inner geometry body of itself and passage or device also plays a role in that promoting agent is discharged in the fluid.Passage can be passage that is pre-existing in or the passage that is stayed by releasing agent or other soluble substance.
Easily lose or degradable device has the promoting agent that physically is fixed in the polymkeric substance usually.Promoting agent can and/or disperse by the polymer materials dissolving.By the key of hydrolytically unstable, polymer materials is degraded in time often with being hydrolyzed, makes the polymkeric substance corrosion become fluid, and release bioactive agent enters fluid.Hydrophilic polymer has the usually very fast erosion rate with respect to hydrophobic polymer.Hydrophobic polymer is considered to have almost entirely promoting agent surface diffusion, it has the corrosion inside from the surface.Hydrophilic polymer be considered to make water osmopolymer surface, make subsurface labile bond hydrolysis, can cause polymkeric substance evenly or the bulk corrosion.
The coating of implantable device can comprise the adulterant of polymkeric substance, and wherein every kind of polymkeric substance has different therapeutical agent rates of release.For example, coating can comprise poly(lactic acid)/polyethylene oxide (PLA-PEO) multipolymer and poly(lactic acid)/polycaprolactone (PLA-PCL) multipolymer.With respect to poly(lactic acid)/polycaprolactone (PLA-PCL) multipolymer, poly(lactic acid)/polyethylene oxide (PLA-PEO) multipolymer can show higher therapeutical agent rate of release.Relative quantity that therapeutical agent is sent in time and dose rates can be controlled with respect to the relative quantity of putting the very fast release polymers of polymkeric substance than slow release by control.For higher initial rate of release, can increase very fast polymer phase for the ratio of putting polymkeric substance than slow release.If expectation is that most dosage is released through long-time section, so most polymkeric substance can be the polymkeric substance of putting than slow release.Can be coated with support (stent) by spraying support with the solution of polymkeric substance, promoting agent and solvent or dispersion.Solvent can be evaporated, and stays the coating of polymkeric substance and promoting agent.Promoting agent can dissolve in polymkeric substance and/or disperse.In some embodiments, multipolymer can be extruded through stake body.
The purposes of formula (I) compound
At cell mitogen, for example find in the abnormal growth of cells of tumor cell proliferation: The compounds of this invention has one or more (for example aurora kinase, polo sample kinases or the cyclin-dependent kinases) in for example multiple mitotic kinase of pair protein kinase inhibited.
Therefore, the significant quantity of the application of the invention compound, The compounds of this invention can be used for suppressing the misgrowth of cell, comprises transformant.The misgrowth of cell is meant the cell growth (for example losing contact inhibition) that does not rely on normal regulating mechanism.This has comprised following misgrowth: (1) expresses the tumour cell (tumour) of activated ras oncogene (ras oncogene); (2) tumour cell, wherein said ras albumen is activated, it is the result of the Cancer-causing mutation of another gene; (3) the optimum and malignant cell of other proliferative disease, wherein unusual ras activation takes place.In addition, shown that in the literature ras oncogene not only facilitates intravital tumor growth by direct effect tumour cell, and facilitate intravital tumor growth indirectly, for example the vasculogenesis by promoting tumor inducing is (referring to Rak.J. etc., CancerResearch, 55:4575-4580,1995).Therefore, pharmacological target sudden change ras oncogene may partly stop the solid tumor growth in vivo by the vasculogenesis that suppresses tumor inducing convincingly.
Can be included but not limited to by the example that The compounds of this invention suppresses: lung cancer (as gland cancer), carcinoma of the pancreas is (as pancreatic neoplasm, exocrine pancreas tumour for example), colorectal carcinoma (as the colorectum tumour, such as for example adenocarcinoma of colon and adenoma of colon), the hematopoiesis tumour of drenching system is (as acute lymphoblastic leukemia, B cell lymphoma, Burkitt lymphoma), marrow series leukemia (for example acute myeloid leukemia (AML)), thyroid follcular carcinoma, myelodysplastic syndrome (MDS), the tumour (for example fibrosarcoma and rhabdosarcoma) in mesenchymal cell source, melanoma, the deformity cancer, neuroblastoma, neurospongioma, benign tumour of skin (as keratoacanthoma), mammary cancer, kidney, ovarian cancer, bladder cancer and epidermal carcinoma.Compound can be in a suitable manner for example vein, subcutaneous, oral, parenteral or topical application.
The present invention also provides the method that suppresses optimum and virulent proliferative disease, and wherein ras albumen is to be activated singularly, and this is the result of Cancer-causing mutation in the gene.By using the significant quantity of compound described herein for the object that needs treatment like this, can finish described inhibition.For example, The compounds of this invention can suppress optimum proliferative disease neurofibroma or tumour, and wherein sudden change or the mistake expression owing to Tyrosylprotein kinase oncogene is activated ras.
All reference that this document is quoted are all incorporated this paper by reference into.
The embodiment of the following stated is for invention as herein described can more easily be understood.These embodiment only are used for the illustrative purpose, and should not be interpreted as limiting by any way the present invention.
Common experiment
On Bruker 400 MHz equipment, measure 1H-NMR spectrum.On Agilent ESI-TOF mass spectrograph, write down mass spectrum.On Agilent 1100 equipment, carry out HPLC.The HPLC method that is used for these compounds is as follows:
Post: Agilent Zorbax 300 SB C18,4.6 * 150mm, 5 μ m;
Column temperature: envrionment temperature;
Flow velocity: 1.0ml/min,
Gradient: in 7 minutes, the 5% acetonitrile * (0.05%TFA) of (0.1%TFA) kept 100% acetonitrile (0.05%TFA) 2 minutes to 100% acetonitrile (0.05%TFA) in the water.
The general method of preparation pyrazoles [3,4-d] pyrimidine
Synthesizing of general method 1-1:1-alkyl-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine
Figure G2008800059629D00451
Carry out the synthetic of this compound according to J.Adams in method described in the WO03/029209A2.Particularly, with diisopropyl azodiformate (diisopropylazodicarboxylate, DIAD) under condition of nitrogen gas at-78 ℃ of triphenyl phosphorus solution that drop among the THF.At pure R 2OH (R 2Be alkyl) add before, reaction mixture was stirred 5 minutes.With mixture restir 5 minutes, add 6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine subsequently.The reaction mixture that produces was at room temperature stirred 2 hours.The rotary evaporation solvent adds ether, filtering mixt, and rotary evaporation filtrate.With flash chromatography (EtOAc/ hexane) purifying coarse raw materials to provide title described compound.
Synthesizing of general method 1-2:1-suberyl-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine
Figure G2008800059629D00461
(2.36g 11.6mmol) drops to triphen phosphorus (3.05g, 11.6mmol) solution in-78 ℃ 20mL THF solution under condition of nitrogen gas with diisopropyl azodiformate (DIAD).(1.34g 11.7mmol) before, stirs reaction mixture 5 minutes adding suberyl alcohol.Mixture stirred 5 minutes, add subsequently 6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine (1.6g, 9.6mmol).Reaction mixture was stirring at room 2 hours.(10% EtOAc/ hexane) uses the chromatography separate reacted mixture on silica gel, and 1-suberyl-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine of 2.32g solid (90.6% productive rate) is provided.
Rf (25% EtOAc/ hexane): 0.5.
HPLC tR:7.69 minute.
Synthesizing of general method 1-3:1-aryl-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine
Figure G2008800059629D00462
According to P.Y.S.Lam at Tetrahedron Lett., 1998,39, method described in 2941 is carried out the synthetic of this compound.Particularly, DCM, neutralized verdigris and pyridine are added to activated molecular sieve
Figure G2008800059629D00463
With mixture in stirring at room after 15 minutes, with 6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine and R 2B (OH) 2(R 2Be aryl) join mixture.In stirring at room after 2 days, filter reaction mixture, the mixture washing of water, bittern (Brine) and oxyammonia, and use dried over sodium sulfate subsequently.With flash chromatography (ethyl acetate or acetone/hexane) purifying coarse raw materials to produce the described compound of title.
Synthesizing of general method 1-4:5-amino-1-replacement-1H-pyrazoles-4-carboxylicesters
Figure G2008800059629D00464
According to M.Kopp at J.Heteroryclic Chem., 2001,38, method described in the 1045-1050 is carried out the synthetic of this compound.Particularly, the hydrazonium salt acid that will replace arbitrarily in ethanol and triethylamine joins round-bottomed flask.Be heated to 90 ℃ and add (Z)-2-cyano group-3-ethoxy carboxylate ethyl ester before, with reaction mixture stirring at room 15 minutes.Therefore, the reaction mixture of acquisition was 90 ℃ of heating 1 hour, and cool to room temperature subsequently.Filtering precipitate also cleans with ether, and dry to produce the described compound of title under high vacuum subsequently.
General method 1-5:5-(3-benzoyl thiourea base)-1-replacement-1H-pyrazoles-4-carboxylicesters
Figure G2008800059629D00471
According to F.Carraro etc. at J.Med.Chem., 2006,49, method described in the 1549-1561 is synthesized the described compound of title.Particularly, the potassium sulfocyanate in acetone is added to round-bottomed flask, then add Benzoyl chloride in room temperature.Before 5-amino-1-replacement-1H-pyrazoles-4-carboxylicesters joins mixture, reaction mixture was stirred 10 minutes.The mixture heating up that produces is spent the night and cool to room temperature to refluxing.Remove solvent by rotary evaporation.Clean with ethyl acetate extraction residue and water, bittern, use MgSO 4Dry and concentrated to produce the described compound of title.
Synthesizing of general method 1-6:6-sulfydryl-1-replacement-1H-pyrazoles [3,4-d] pyrimidine-4-alcohol
Figure G2008800059629D00472
According to F.Carraro etc. at J.Med.Chem., 2006,49, method described in the 1549-1561 is carried out the synthetic of the described compound of title.Particularly, the 5-in the methyl alcohol (3-benzoyl thiourea base)-1-replacement-1H-pyrazoles-4-carboxylicesters is joined sodium hydroxide in water in room temperature, and with the reaction mixture reflux that generates 3 hours.Subsequently with the reaction mixture cool to room temperature and with saturated NH 4The Cl acidifying.The precipitation of filtering generation is to produce the described compound of title.
Synthesizing of general method 1-7:1-replacement-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine-4-alcohol
Figure G2008800059629D00473
According to F.Carraro etc. at the Journal of Medicinal Chemistry, 2006,49, method described in the 1549-1561 is carried out the synthetic of the described compound of title.Particularly, the NaOH in the water and alkyl iodide (for example methyl-iodide) are at room temperature joined 6-sulfydryl-1-replacement-1H-pyrazoles [3,4-d] pyrimidine-4-alcohol among the DMF.Reaction mixture was stirred 1 hour, use saturated NH then 4The Cl neutralization.The precipitation of filtering generation is to produce the described compound of title.
Synthesizing of general method 1-8:4-chloro-1 replacement-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine
According to F.Carraro etc. at Journal of Medicinal Chemistry, 2006,49, method described in the 1549-1561 is carried out the synthetic of title compound.Particularly, with POCl 3Heating is 1 hour under room temperature joins in 1-replacement-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine-4-alcohol and the mixture that produces refluxed.With the reaction mixture cool to room temperature, formation precipitates and it is filtered to produce the described compound of title.
Synthesizing of general method 1-9:6-(methylthio group)-1-replacement-1H-pyrazoles [3,4-d] pyrimidine
Figure G2008800059629D00482
Rieke zinc (Rieke zinc) is at room temperature joined 4-chloro-1-replacement-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine in tetrahydrofuran (THF) and acetate.With reaction mixture 80 ℃ of heating 20 minutes, and cool to room temperature subsequently.Pass through diatomite filtration reaction mixture and concentrated filtrate subsequently, and use ethyl acetate extraction filtrate, water, bittern clean and are dry and concentrated to produce thick product.With flash chromatography (EtOAc/ hexane) purifying coarse raw materials to produce the described compound of title.
General method 1-10:3-replaces arbitrarily-6-(methyl sulphonyl)-1-replacement-1H-pyrazoles [3,4-d] pyrimidine synthetic
Figure G2008800059629D00483
Oxone that will be in water
Figure G2008800059629D00484
(5 eq.) joins 6-(methylthio group)-1-replacement-1H-pyrazoles [3, the 4-d] pyrimidine in methyl alcohol, and at room temperature stirs and spend the night.Concentrated reaction mixture and subsequently with EtOAc extraction, water, bittern clean, and is dry and concentrate.With flash chromatography (ethyl acetate/hexane) purifying coarse raw materials to produce the described compound of title.
General method 1-11: formula (I) compound synthetic
1-replacement-6-(methyl sulphonyl)-1H-pyrazoles [3,4-d] pyrimidine and any aniline (5 eq.) that replaces in DMSO at room temperature are added in the sealing test tube.Reaction mixture is heated to about 110 ℃, and it continues 30 minutes to the time of spending the night, and cool to room temperature subsequently.Water termination mix and with EtOAc extraction, water, bittern washing, dry and concentrate to produce crude product.With flash chromatography (ethyl acetate/hexane or DCM/MeOH) purified feed stock with production (I) compound.
Synthesizing of general method 1-12:N-(4-(1-replacement-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine
Methane sulfonyl chloride (1 eq.) or methanesulfonic acid anhydride and DIEA (1.5 eq.) are at room temperature joined at CHCl 3In N1-(1-replacement-1H-pyrazoles [3,4-d] pyrimidine-6-yl) benzene-1,4 diamines.Stirring at room 15 minutes, and use flash chromatography (ethyl acetate/hexane or DCM/MeOH) purifying subsequently reaction mixture to produce the described compound of title.
General method 1-13:N-(4-(1-replacement-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine.
Figure G2008800059629D00493
Methane sulfonyl chloride (5 eq.) or methanesulfonic acid anhydride and DIEA (7.5 eq.) are at room temperature joined at CHCl 3In N1-(1-replacement-1H-pyrazoles [3,4-d] pyrimidine-6-yl) benzene-1,4 diamines methane sulfonyl chloride (5 eq.).Stirring at room 15 minutes, and use flash chromatography (ethyl acetate/hexane or DCM/MeOH) purifying subsequently reaction mixture to produce the described compound of title.
Synthesizing of general method 1-14:4-(1-suberyl-1H-pyrazoles [3,4-d] pyrimidine-6-amido)-N-(replacement-alkylsulfonyl) benzamide
Figure G2008800059629D00501
At Tetrahedron Lett., method described in 1998,39,5891 is carried out the synthetic of the described compound of title according to C.F.Sturino etc.Particularly, N-(3-dimethylamino-propyl)-N '-ethyl-carbodiimide hydrochloride (5 eq.), DMAP (10 eq.) and S-replacement-sulphonamide (10 eq.) are joined the trimethyl carbinol/1 1/1/1/, 4-in 2-ethylene dichloride/DMF mixture (1-suberyl-1H-pyrazoles [3,4-d] pyrimidine-6-amido) phenylformic acid.With reaction mixture in stirring at room after 2 hours, to wherein adding 2.0M HCl.The reaction mixture ethyl acetate extraction that produces washes and uses dried over sodium sulfate with water, and under reduced pressure concentrates to produce crude product.After in DCM, pulverizing crude product, the described compound of title is separated with white solid.
Synthesizing of general method 1-15:N-(4-(1H-tetrazolium-5-yl) phenyl)-1-replacement-1H-pyrazoles [3,4-d] pyrimidine-6-amine
Figure G2008800059629D00502
According to J.V.Duncia at J.Org.Chem., 1991,56, method described in the 2395-2400 is carried out the synthetic of the described compound of title.Particularly, will be at (1-replacement-1H-the pyrazoles [3 of the 4-in the 5mL toluene, 4-d] pyrimidine-6-amido) suspension of phenyl cyanide (1.0mmol) and trimethyl tin trinitride (2.00mmol) under refluxad heated in nitrogen environment 40-60 hour, produced thick tin trimethyl intermediate.Thick intermediate is dissolved to 5mL De diox (dioxane), and when 4.0M HCl exists, stirs 30 minutes to produce the described compound of title.
Preparation 1H-indoles-4-ylboronic acid and 5,6,7, the general method of 8-naphthane-1-ylboronic acid
Synthesizing of general method 2-1:7-replacement-1H-indoles-4-base-boric acid
According to L.Li at Tetrahedron Lett., 2003,44, method described in the 5987-5990 is carried out the synthetic of the described compound of title.Particularly, handle the solution of 6-replacement-3-bromo-oil of mirbane with vinyl bromination magnesium to produce the 7-substituted indole, with the 7-substituted indole of purified by flash chromatography generation.Then 7-substituted indole and two (tetramethyl ethylene ketone closes) two boron (bis (pinacolato) diboron) are reacted when existing so that 7-replacement-4-(4 to be provided at palladium (0), 4,5,5-tetramethyl--1,3, the assorted oxygen pentaborane of 2-two-2-yls)-and the 1H-indoles, use sodium periodate in acetic acid/water/tetrahydrofuran (THF), its hydrolysis to be become the described compound of title.
General method 2-2:4-(benzyloxy)-5,6,7,8-naphthane-1-ylboronic acid synthetic
Figure G2008800059629D00512
According to John A.Lowe, III is at J.Med.Chem., and 2004,47, the method described in the 1575-1586 is carried out the synthetic of the described compound of title.Particularly, by handling, prepare 4-bromo-1-naphthols from the 1-naphthols with 1 normal tetrabutyl tribromide.Subsequently it is dissolved in acetonitrile, handles with bromotoluene and salt of wormwood, and under refluxad heat 14 hours so that 4-bromo-1-benzyloxy naphthalene to be provided.Subsequently with compound 4-bromo-1-benzyloxy naphthalene and n-Butyl Lithium and triethyl borate reaction so that title compound to be provided.
Preparation 3, the general method of 4-substituted aniline
Synthesizing general method 3-1:(4-((4-methylpiperazine-1-yl) methyl) aniline)
Figure G2008800059629D00521
According to carrying out the synthetic of the described compound of title described in the U.S. Patent Application Publication No. 2006058341 (2006.03.16).Particularly, the 1-methylpiperazine is joined 4-nitrobenzyl chlorine solution in tetrahydrofuran (THF) in room temperature.Solution was being stirred 3 hours, at this moment between after, with the crude reaction thing with ethyl acetate dilution and water repetitive scrubbing.The organism of concentrate drying is directly to produce 4-nitrobenzyl amine adduct.Be used in Raney Ni in the tetrahydrofuran (THF) (Rainey Nickel) subsequently and handled 12 hours, produce the described compound of title at 75PSI.
Synthesizing of general method 3-2:2-(4-aminophenyl)-2 Methylpropionic acid ethyl ester analogue
Figure G2008800059629D00522
According to Lawrence etc. at J.Org.Chem., 2002,67, method described in the 457-464 is carried out the synthetic of title compound.Drips of solution in DMF adds to the sodium hydride suspension in 0 ℃ of DMF with 2-chloropropionate and oil of mirbane.Stirred 30 minutes postheating to 25 ℃ at 0 ℃.Subsequently methyl-iodide is joined in this solution, and mixture was stirred more than 2 hour.With 1 M HCl termination reaction solution and with methylene dichloride dilution.Wash organic phase and use dried over sodium sulfate with saturated sodium bicarbonate solution.Concentrated organic phase is produced as the described compound of the title that does not need purifying, and it is the stickiness brown oil.When R was chlorine, flash chromatography was necessary.
General method 3-3: ethyl 2-(4-amino-2-chloro-phenyl-) acetic ester synthetic
Figure G2008800059629D00523
According to G.Nannini at Arzneimittel-Forschung, 1973,23, method described in the 1090-1100 is carried out the synthetic of the described compound of title.Particularly, 2-chloro-4-nitrobenzoic acid is put into pure thionyl chloride and refluxed 1 hour.Remove under reduced pressure and desolvate to produce 2-chloro-4-nitrobenzoyl chloride, it is a yellow oil.It is used in trimethyl silicane diazomethane in the ether in room temperature treatment.The amber oily thing that produces is through purification by flash chromatography, and to produce diazo ketone, it is the crystalline yellow solid.Put it in wet ethanol (wet ethanol) solution, and handle with dry oxidation silver (II).Behind filtration catalizer, the dilute with water mother liquor is also used ethyl acetate extraction.Use the dried over sodium sulfate organic phase, do not need to carry out the title compound of chromatographic separation by concentrating generation subsequently, it is a viscous yellow oil.
Synthesizing of general method 3-4:4-(sulfonyloxy methyl methyl) aniline (4-(methylsulfonylmethyl) anline) analogue
Figure G2008800059629D00531
According to G.Huiping at Bioorganic﹠amp; Medicinal Chemistry Letters, 2004,14, the method described in the 187-190 is carried out the synthetic of the described compound of title.Particularly, 4-nitro-benzyl chloride is put into THF, add methyl-sulfinic acid sodium therein.With microwave 150 ℃ of radioreactions 5 minutes.The former reaction soln of dilute with water is also used ethyl acetate extraction.Organic phase behind the concentrate drying replaces adducts to produce the tawny solid.In THF with this latter's raw material with drawing Buddhist nun's nickel (RaineyNickel) to handle 12 hours to produce the described compound of tawny solid title at 75PSI.
Preparation 1-(4-aminophenyl)-2-(dialkyl amido) ethanol and 1-(3-aminophenyl)-2-(dialkyl group Amino) the alcoholic acid general method
Figure G2008800059629D00541
Step 1: Synthetic 2-(4-nitrophenyl) oxyethane
According to K.Takai at Angewandte Chemie, 1981,93 (8), method described in 707 is carried out the synthetic of the described compound of title.Will be in chloroform (21.0ml) right-nitrostyrolene (1.40g, 9.4mmol) and the metachloroperbenzoic acid phenylformic acid (2.50g, 11.2mmol) solution refluxed in oil bath 4 hours, monitored with TLC (solution of 40% ethyl acetate in hexane).With reaction mixture cool to room temperature and filtration.The reject white precipitate also concentrates remaining solution, absorption and through purified by flash chromatography on 3.0 gram silica gel, with the eluant solution of 25% ethyl acetate in hexane with the described compound 2-of the title that produces 43% productive rate (4-nitro-phenyl)-oxyethane (2.20g).
Step 2:1-(4-nitrophenyl)-2-(piperidines-1-yl) alcoholic acid is synthetic
According to U.M.Teotino at Farmaco, Edizione Scientifica 1962,17, method described in the 252-65 is carried out the synthetic of the described compound of title.Will the 2-in the straight alcohol (100.0ml) (4-nitrophenyl)-oxyethane (0.80g, 3.0mmol.) and piperidines (1.00ml, 10.1mmol.) solution refluxed in oil bath 4 hours, with TLC monitoring (solution of 5% methyl alcohol in methylene dichloride).With the reaction soln cool to room temperature, be adsorbed on the 1.50 gram silica gel and through purified by flash chromatography, with title compound 1-(4-nitro-phenyl)-2-piperidines-1-base-ethanol (0.65g) of the eluant solution of 2% and 4% methyl alcohol in methylene dichloride to produce 86% productive rate.
Step 3:1-(4-aminophenyl)-2-(piperidines-1-yl) alcoholic acid is synthetic
(0.60g 2.4mmol.) is added in Raney Ni (raney-nickel) the pulpous state solution of (2.5ml) in the water and carried out hydrogenation 12 hours at 75psi in the solution to the 1-in tetrahydrofuran (THF) (25.0ml) (4-nitro-phenyl)-2-piperidines-1-base-ethanol.Residue also is evaporated to dry title compound 1-(4-amino-phenyl)-2-piperidines-1-base-ethanol (0.47g) to produce 90% productive rate subsequently through diatomite filtration carefully.
The general method for preparing other intermediate
General method 5-1:(4-chloro-2-(methylthio group) pyrimidine-5-yl) methyl alcohol
Figure G2008800059629D00551
Under nitrogen environment, with DIBAL (185mL, 1M is in the tetrahydrochysene furan, Aldrich catalog number (Cat.No.): 214981,185mmol) through 30 minutes dropwise (through the pressure equalization dropping funnel) joins 4-chloro-2-(methylthio group) pyrimidine-5-carboxylic acid ester (10.7g, 46mmol) solution among the exsiccant THF (50mL) on ice bath.It is being transferred to exsiccant erlenmeyer flask (Erlenmeyer flask) before, the yellow transparent solution that generates was being stirred 30 minutes in addition.Subsequently on ice bath, with saturated Na 2SO 4Solution dropwise adds, and the termination reaction mixture is to produce warm yellow gelatinous solid mixture carefully.Ethyl acetate (200mL) is joined in this solid mixture, dropwise add the 6.0 N HCl aqueous solution subsequently, with the aqueous solution of solid dissolving becoming pH 3-4.Collect the EtOAc layer.Water layer is extracted (2 times, each 200mL) with EtOAc again.The EtOAc layer that merges is washed with water (2 times, each 200mL), use MgSO 4Dry and concentrate to produce white solid, be suspended in white solid in the 75mL sherwood oil and refluxed 10 minutes.Mixture is cooled to envrionment temperature and the subsequent filtration generation described compound of title (4.67g, 53%, HPLC:97% purity).
HPLC?Rt：4.72min。
1H-NMR(CDCl 3)：δ8.54(s，1H)，4.74(d，2H)，2.57(s，3H)，2.10(t，1H)。
General method 5-2:4-chloro-2-(methylthio group) pyrimidine-5-formaldehyde
(9.0g is 47mmol) with activated MnO with (4-chloro-2-(methylthio group) pyrimidine-5-yl) methyl alcohol 2(the Aldrich catalog number (Cat.No.): mixture 217646) is at 120mLCH for 70g, 800mmol 2Cl 2Middle stirring at room 24 hours.With mixture through diatomite (Acros Celite 521, catalog number (Cat.No.): 206350010) filter.Use CH 2Cl 2Washing leaching cake is up to cannot see the ultraviolet activated feedstock.Concentrate the CH that merges 2Cl 2Solution also uses 25% EtOAc/ hexane with its process thin-layer silicon plug (thin silicagel plug).Concentrating filtrate is to produce pale solid (6.37g, 71.6% productive rate).
HPLC?Rt：5.53min。
1H-NMR(CDCl 3)：δ10.32(s，1H)，8.88(s，1H)，2.65(s，3H)。
Below explanation is used to prepare the method for some intermediates of The compounds of this invention and embodiment.Below also be provided for testing and use The compounds of this invention to suppress the method for mitotic kinase and treatment and these kinases diseases related.These embodiment only are used for illustration purpose, rather than attempt to limit the scope of the invention by any way.
Embodiment 1:6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine
Figure G2008800059629D00561
Adding hydrazine (1.8g, 56mmol, Alfa Aesar P/N 32728) before, will (6.6g, 52mmol) (6.3g, 33mmol) solution cools off on ice bath 5 minutes 4-chloro-2-(methylthio group) pyrimidine-5-formaldehyde at 160mLEtOH and DIEA.Subsequently, reaction being positioned in 50 ℃ of oil baths before another hour, reaction is stayed 0 ℃ stirred in addition 1 hour.Except that desolvating and washing residue with water, dry to produce former product (5.05g, 91% productive rate) under high vacuum subsequently.Can be from the mixture of methanol-water recrystallization compound.
HPLC?Rt：3.91min。
1H-NMR(CDCl 3)：δ10.95(br，s，1H)，9.00(s，1H)，8.10(s，1H)，2.66(s，3H)。
Embodiment 2:1-(1,2-acenaphthene-1-yl)-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine
According to general method 1-1, by 1,2-acenaphthene-1-alcohol (1,2-dihydroacenaphthylen-1-ol) and the Mitsunobu coupling between 6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine synthesize the described compound of title.
HPLC?Rt：7.47min。
1H-NMR(CDCl 3)：δ8.93(s，1H)，7.99(s，1H)，7.77(m，2H)，7.47(m，1H)，7.40(m，1H)，7.17(d，1H)，6.95(m，1H)，4.99(m，1H)，4.11(m，1H)，3.92(m，1H)，2.3(s，3H)。
Embodiment 3:1-(1,2-acenaphthene-1-yl)-6-(methyl sulphonyl)-1H-pyrazoles [3,4-d] pyrimidine
According to general method 1-10, by oxidation 1-(1,2-acenaphthene-1-yl)-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine synthesising title compound.
HPLC?Rt：6.36min。
1H-NMR(DMSO-d 6)：δ9.35(s，1H)，8.30(s，1H)，7.78(d，1H)，7.75(d，1H)，7.61(t，1H)，7.44(m，2H)，7.09(m，2H)，4.18(m，1H)，3.86(m，1H)，3.24(s，3H)。
Embodiment 4:6-(methylthio group)-1-(2-nitrobenzyl)-1H-pyrazoles [3,4-d] pyrimidine
According to general method 1, synthesize the described compound of title by Mitsunobu coupling (Mitsunobu coupling) between 2-nitro-benzyl alcohol and 6-(methylthio group)-1H-pyrazoles [3, the 4-d] pyrimidine.
HPLC?Rt：6.79min。
LC/MS：302(M+1)。
Embodiment 5:6-(methyl sulphonyl)-1-(2-nitrobenzyl)-1H-pyrazoles [3,4-d] pyrimidine
According to general method 1-10, by the synthetic described compound of title of oxidation 6-(methylthio group)-1-(2-nitrobenzyl)-1H-pyrazoles [3,4-d] pyrimidine.
HPLC?Rt：5.79min。
LC/MS：334(M+1)。
Embodiment 6:6-(methylthio group)-1-(4-nitrobenzyl)-1H-pyrazoles [3,4-d] pyrimidine
According to general method 1-1, come synthesising title compound by Mitsunobu coupling between 4-nitro-benzyl alcohol and 6-(methylthio group)-1H-pyrazoles [3, the 4-d] pyrimidine.
HPLC?Rt：6.81min。
LC/MS：302(M+1)。
Embodiment 7:6-(methyl sulphonyl)-1-(4-nitrobenzyl)-1H-pyrazoles [3,4-d] pyrimidine
According to general method 1-10, by oxidation 6-(methyl sulphonyl)-1-(4-nitrobenzyl)-1H-pyrazoles [3,4-d] pyrimidine synthesising title compound.
HPLC?Rt：5.854min。
LC/MS：334(M+1)。
Embodiment 8:(S)-6-(methylthio group)-1-(1-phenylethyl)-1H-pyrazoles [3,4-d] pyrimidine
According to general method 1-1, synthesize the described compound of title by the Mitsunobu coupling between (S)-1-phenylethyl alcohol and 6-(methylthio group)-1H-pyrazoles [3, the 4-d] pyrimidine.
HPLC?Rt：6.98min。
1H-NMR(CDCl 3)：δ8.89(s，1H)，8.02(s，1H)，7.36(m，5H)，6.18(q，1H)，2.64(s，3H)，2.01(d，3H)。
Embodiment 9:(S)-6-(methyl sulphonyl)-1-(1-phenylethyl)-1H-pyrazoles [3,4-d] pyrimidine
According to general method 1-10, synthesize the described compound of title by oxidation (S)-6-(methylthio group)-1-(1-phenylethyl)-1H-pyrazoles [3,4-d] pyrimidine.
HPLC?Rt：5.79min。
1H-NMR(CDCl 3)δ9.30(s，1H)，8.34(s，1H)，7.35(m，5H)，6.35(q，1H)，3.43(s，3H)，2.06(d，3H)。
Embodiment 10:1-(6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-yl benzoic acid ester
According to general method 1-1, by 1-hydroxyl-2, the described compound of title is synthesized in the Mitsunobu coupling between 3-dihydro-1H-indenes-4-yl benzoic acid ester and 6-(methylthio group)-1H-pyrazoles [3, the 4-d] pyrimidine.
HPLC?Rt：8.21min。
LC/MS is 403 (M+1).
Embodiment 11:1-(6-(methyl sulphonyl)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-yl benzoic acid ester
According to general method 1-10, by oxidation 1-(6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-yl benzoic acid ester synthesizes the described compound of title.
HPLC?Rt：7.20min。
LC/MS：435(M+1)。
Embodiment 12:N-(1-(6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-yl) ethanamide
According to general method 1-1, by the synthetic described compound of title of Mitsunobu coupling between N-(1-hydroxyl-2,3-dihydro-1H-indenes-4-yl) ethanamide and 6-(methylthio group)-1H-pyrazoles [3, the 4-d] pyrimidine.
HPLC?Rt：6.10min。
LC/MS：340(M+1)。
Embodiment 13:N-(1-(6-(methyl sulphonyl)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-yl) ethanamide
According to general method 1-10, by the synthetic described compound of title of oxidation N-(1-(6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-yl) ethanamide.
HPLC?Rt：5.22min。
LC/MS：372(M+1)。
Embodiment 14:1-(4-methoxy-benzyl)-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine
According to general method 1-1, synthesize the described compound of title by Mitsunobu coupling between 4-methoxyl group-benzyl alcohol and 6-(methylthio group)-1H-pyrazoles [3, the 4-d] pyrimidine.
HPLC?Rt：6.55min。
1H-NMR(CDCl 3)：δ8.90(s，1H)，7.99(s，1H)，7.32(m，2H)，6.84(d，2H)，5.53(s，2H)，3.77(s，3H)，2.66(s，3H)。
Embodiment 15:1-(4-methoxy-benzyl)-6-(methyl sulphonyl)-1H-pyrazoles [3,4-d] pyrimidine
According to general method 1-10, by the synthetic described compound of title of oxidation 1-(4-methoxy-benzyl)-6-(methyl sulphonyl)-1H-pyrazoles [3,4-d] pyrimidine.
HPLC?Rt：5.54min。
1H-NMR(CDCl 3)δ9.32(s，1H)，8.32(s，1H)，7.38(m，2H)，6.88(d，2H)，5.70(s，2H)，3.80(s，3H)，3.48(s，3H)。
Embodiment 16:(S)-1-(2,3-dihydro-1H-indenes-1-yl)-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine
According to general method 1-1, by (R)-2, the described compound of title is synthesized in the Mitsunobu coupling between the 3-dihydro-pure and mild 6-of 1H-indenes-1-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine.
HPLC?Rt：7.15min。
1H-NMR(CDCl 3)：δ8.95(s，1H)，8.01(s，1H)，7.36(d，1H)，7.28(q，1H)，7.16(t，1H)，7.01(d，1H)，6.55(t，1H)，3.39(m，1H)，3.10(m，1H)，2.76(m，1H)，2.66(m，1H)，2.63(s，3H)。
Embodiment 17:(S)-1-(2,3-dihydro-1H-indenes-1-yl)-6-(methyl sulphonyl)-1H-pyrazoles [3,4-d] pyrimidine
According to general method 1-10, synthesize the described compound of title by oxidation (S)-1-(2,3-dihydro-1H-indenes-1-yl)-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine.
HPLC?Rt：5.99min。
1H-NMR(CDCl 3)：δ9.34(s，1H)，8.31(s，1H)，7.39(d，1H)，7.31(q，1H)，7.17(t，1H)，7.00(d，1H)，6.69(t，1H)，3.45(s，1H)，3.43(m，3H)，3.13(m，1H)，2.80(m，1H)，2.66(m，1H)。
Embodiment 18:6-(methylthio group)-1-(3-nitrobenzyl)-1H-pyrazoles [3,4-d] pyrimidine
According to general method 1.1, synthesize the described compound of title by Mitsunobu coupling between 3-nitro-benzyl alcohol and 6-(methylthio group)-1H-pyrazoles [3, the 4-d] pyrimidine.
HPLC?Rt：6.63min。
1H-NMR(CDCl 3)：δ8.93(s，1H)，8.27(m，1H)，8.16(m，1H)，8.05(s，1H)，7.69(d，1H)，7.52(t，1H)，5.70(s，2H)，2.65(s，3H)。
Embodiment 19:6-(methyl sulphonyl)-1-(3-nitrobenzyl)-1H-pyrazoles [3,4-d] pyrimidine
According to general method 1-10, synthesize the described compound of title by oxidation 6-(methylthio group)-1-(3-nitrobenzyl)-1H-pyrazoles [3,4-d] pyrimidine.
HPLC?Rt：5.83min。
LC/MS：334(M+1)。
Embodiment 20:1-(5-methoxyl group-2,3-dihydro-1H-indenes-1-yl)-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine
According to general method 1-1, by 5-methoxyl group-2, the described compound of title is synthesized in the Mitsunobu coupling between the 3-dihydro-pure and mild 6-of 1H-indenes-1-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine.
HPLC?Rt：7.41min。
LC/MS：313(M+1)。
Embodiment 21:1-(5-methoxyl group-2,3-dihydro-1H-indenes-1-yl)-6-(methyl sulphonyl)-1H-pyrazoles [3,4-d] pyrimidine
According to general method 1-10, synthesize the described compound of title by oxidation 1-(5-methoxyl group-2,3-dihydro-1H-indenes-1-yl)-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine.
HPLC?Rt：6.32min。
LC/MS：345.0(M+1)。
Embodiment 22: ethyl 5-amino-1-(3-p-methoxy-phenyl)-1H-pyrazoles-4-carboxylicesters
According to general method 1-4, obtain the described compound of title by condensation (3-p-methoxy-phenyl) hydrazine and (Z)-2-cyano group-3-ethoxy-c olefin(e) acid second fat.
LC Rt:6.10 minute.
1H-NMR(DMSO-D 6)：δ7.71(s?1H)，7.45(t，1H)，7.1
Figure G2008800059629D00601
m，2H)，6.95(m?1H)，6.35(s，2H)，4.22(q，2H)，3.82(s，3H)，1.28(t，3H)。
Embodiment 23:5-amino-1-(4-p-methoxy-phenyl)-1H-pyrazoles-4-carboxylicesters
According to the general 1-4 that crosses, by condensation (4-p-methoxy-phenyl) hydrazine and (Z)-2-cyano group-3-ethoxy-c olefin(e) acid second fat obtains the described compound of title
HPLC?Rt：5.96min。
1H-NMR(DMSO-D 6)：δ7.77(s?1H)，7.45(d，2H)，7.0
Figure G2008800059629D00602
d，2H)，5.20(s，2H)，4.22(q，2H)，3.82(s，3H)，1.28(t，3H)。
Embodiment 24:5-amino-1-(naphthalene-1-yl)-1H-pyrazoles-4-carboxylicesters
According to general method 1-4, by condensation naphthalene-1-base hydrazine and (Z)-2-cyano group-3-ethoxy-c olefin(e) acid second fat obtains the described compound of title.
HPLC?Rt：6.53min。
1H-NMR(DMSO-D 6)：δ8.03(d，2H)，7.86(s，1H)，7.53(d，2H)，7.37(d，2H)，6.71(s，1H)，4.22(q，2H)，1.28(t，3H)。
Embodiment 25: ethyl 5-(3-benzoyl thiourea base)-1-(3-p-methoxy-phenyl)-1H-pyrazoles-4-carboxylicesters
According to general method 1-5, obtain the described compound of title from 5-amino-1-(3-p-methoxy-phenyl)-1H-pyrazoles-4-carboxylicesters.
HPLC?Rt：7.14min。
LC/MS：425.0(M+1)。
Embodiment 26: ethyl 5-(3-benzoyl thiourea base)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-4-carboxylicesters
According to general method 1-5, obtain the described compound of title from 5-amino-1-(4-p-methoxy-phenyl)-1H-pyrazoles-4-carboxylicesters.
HPLC?Rt：7.02min。
1H-NMR(CDCl 3)：δ12.15(s，3H)，1.35(t，3H)。
Embodiment 27:5-(3-benzoyl thiourea base)-1-(naphthalene-1-yl)-1H-pyrazoles-4-carboxylicesters
According to general method 1-5, obtain the described compound of title from 5-amino-1-(naphthalene-1-yl)-1H-pyrazoles-4-carboxylicesters.
HPLC?Rt：7.51min。
1H-NMR(DMSO)：δ12.08(s，1H)，11.86(s，1H)，8.28(s，1H)，7.89(m，3H)，7.64(m，3H)，7.40(m，6H)，4.24(q，2H)，1.28(t，3H)。
Embodiment 28:6-sulfydryl-1-(3-p-methoxy-phenyl)-1H-pyrazoles [3,4-d] pyrimidine-4-alcohol
According to general method 1-6, obtain the described compound of title by cyclase 25 under alkaline condition-(3-benzoyl thiourea base)-1-(3-p-methoxy-phenyl)-1H-pyrazoles-4-carboxylicesters.
HPLC?Rt：4.96min。
LC/MS：275.0(M+1)。
Embodiment 29:6-sulfydryl-1-(4-p-methoxy-phenyl)-1H-pyrazoles [3,4-d] pyrimidine-4-alcohol
According to general method 1-6, obtain describedization of title by cyclase 25 under alkaline condition-(3-benzoyl thiourea base)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-4-carboxylicesters.
HPLC?Rt：4.89min。
1H-NMR(DMSO)：δ10.25(s，1H)，8.11(d，2H)，7.82(s，1H)，7.0
Figure G2008800059629D00611
d，2H)，3.80(s，3H)。
Embodiment 30:6-sulfydryl-1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-4-alcohol
According to general method 1-6, obtain the described compound of title by cyclase 25 under alkaline condition-(3-benzoyl thiourea base)-1-(naphthalene-1-yl)-1H-pyrazoles-4-carboxylicesters.
HPLC?Rt：5.59min。
1H-NMR(DMSO-D 6)：δ10.21(s，1H)，8.09(t，2H)，8.05(s，1H)，7.96(t?1H)，7.63(m，2H)，7.50(m，1H)，7.3
Figure G2008800059629D00621
d，1H)。
Embodiment 31:1-(3-p-methoxy-phenyl)-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine-4-alcohol
According to general method 1-7, obtain the described compound of title from 6-sulfydryl-1-(3-p-methoxy-phenyl)-1H-pyrazoles [3,4-d] pyrimidine-4-alcohol.
HPLC?Rt：6.14min。
1H-NMR(DMSO-D 6)：δ8.23(s?1H)，7.95(s，2H)，7.87s，1H)，7.79(d，1H)，7.46(t，1)，6.95(d，1H)，3.82(s，3H)，2.56(s，3H)。
Embodiment 32:1-(4-p-methoxy-phenyl)-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine-4-alcohol
According to general method 1-7, obtain the described compound of title from 6-sulfydryl-1-(4-p-methoxy-phenyl)-1H-pyrazoles [3,4-d] pyrimidine-4-alcohol.
HPLC?Rt：6.00min。
1H-NMR(DMSO-D 6)：δ8.10(d，2H)，7.72(s，1H)，7.0
Figure G2008800059629D00622
d，2H)，3.78(s，3H)，2.39(s，3H)。
Embodiment 33:1-(naphthalene-1-yl)-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine-4-alcohol
According to general method 1-7, obtain the described compound of title from 6-sulfydryl-1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-4-alcohol.
HPLC?Rt：6.39min。
1H-NMR(DMSO-D 6)：δ12.65(s?1H)，8.34(s，1H)，8.13(dd，2H)，7.67(m，2H)，7.57(m，1H)，7.3
Figure G2008800059629D00623
m，2H)，2.23(s，3H)。
Embodiment 34:4-chloro-1-(3-p-methoxy-phenyl)-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine
According to general method 1-8, use POCl 3Obtain the described compound of title from 1-(3-p-methoxy-phenyl)-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine-4-alcohol.
HPLC?Rt：8.26min。
1H-NMR(DMSO-D 6)：δ8.61(s?1H)7.85(s，1H)，7.7
Figure G2008800059629D00624
d，1H)，7.50(t，1H)，6.98(d，1H)，3.85(s，3H)，2.67(s，3H)。
Embodiment 35:4-chloro-1-(4-p-methoxy-phenyl)-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine
According to general method 1-8, use POCl 3Obtain the described compound of title from 1-(4-p-methoxy-phenyl)-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine-4-alcohol.
HPLC?Rt：8.06min。
1H-NMR(DMSO)：δ8.59(s?1H)，8.02(d，2H)，7.18(d，2H)，3.82(s，3H)，2.67(s，3H)。
Embodiment 36:4-chloro-1-(naphthalene-1-yl)-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine
According to general method 1-8, use POCl 3Obtain the described compound of title from 1-(naphthalene-1-yl)-6-(methylthio group)-1H-pyrazoles [3,4-d] pyrimidine-4-alcohol.
HPLC?Rt：8.27min。
1H-NMR(DMSO)：δ8.73(s?1H)，8.21(d，1H)，8.13(d，1H)，7.78(m，3H)，7.55(m，2H)，2.39(s，3H)。
Embodiment 37:N-(4-(1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine
Figure G2008800059629D00631
According to R.N.Misra at Bioorg.Med.Chem.Lett.EN, 2006,13 (6), method described in the 1133-1136 is carried out the synthetic of the described compound of title.Particularly; with N-(4-(1-(4-methoxy-benzyl)-1H-pyrazoles [3; 4-d] pyrimidine-6-base amino) phenyl)-(0.34g 0.68mmol) is dissolved among the 5mlTFA N-(methyl sulphonyl) amsacrine, and solution was under refluxad heated 16 hours.Under reduced pressure, remove TFA subsequently to produce viridant oily residue, after the adding frozen water this oily residue is transformed into solid product.Cross filter solid, before it is once more with the ether washing,, produce the described product of title of 0.248g (96% productive rate) with a large amount of DCM washings.
Following table 1-4 provides formula (I) compound other specific embodiment, and it is according to being prepared at aforesaid method and testing by the method for describing after this.
Table 1 contains R in the formula (I) 2Be naphthyl or the tetrahydrochysene compound of group how
The embodiment numbering The compound title HPLC RT (minute) ??LC/MS ?? 1H-NMR(CDCl 3, unless otherwise noted)
??38 N-(methyl sulphonyl)-N-(4-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine ??6.95 ??509??(M+1)
39 N-methyl-N-(4-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine 6.89 443 (M-1)
40 N-(4-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) cyclopropane sulphonamide 6.71 457 (M+1)
41 1-(methyl sulphonyl)-N-(4-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine 6.53 509 (M+1)
42 N-(4-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine 6.47 2.94 (s, 3H), 6.20 (s, 1H), 7.04 (d, J=8.67Hz, 2H), 7.28 (s, 1H), 7.53 (m, 5H), 7.70 (t, J=8.66Hz, 2H), 8.18 (t, J=8.66Hz, 2H), 8.28 (s, 1H), 9.01 (s, 1H).
43 N 1-(1-(naphthalene-2-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-yl) benzene-1, the 4-diamines 6.84 353 (M+1)
44 Ethyl 2-(4-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl amino)-2-fluoroacetic acid 6.89 (DMSO-d6) 1.30 (t, J=5.68Hz, 3H), 4.31 (dd, 2H), 7.47-7.67 (m, 9H), 8.15 (t, J=8.52Hz, 2H), 8.46 (s, 1H), 9.16 (s, 1H), 9.95 (s, 1H), 10.60 (s, 1H).
45 N-(4-(1-(naphthalene-2-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine 7.09 431 (M+1)
46 3,3,3-three fluoro-N-(4-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) propane-1-sulphonamide 7.16 535 (M+23)
47 Methyl 4-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenylcarbamate 6.69 3.78 (s, 3H), 6.50 (s, 1H), 7.19 (t, J=8.67Hz, 2H), 7.36 (s, 1H), 7.48-7.59 (m, 5H), 7.64 (d, J=8.67Hz, 1H), 7.66 (d, J=8.67Hz, 1H), 8.01 (t, J=8.67Hz, 2H), 8.25 (s, 1H), 8.98 (s, 1H).
48 N-(3, the 4-Dimethoxyphenyl)-1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 6.92 398 (M+1)
49 N-(4-(4-methylpiperazine-1-yl) phenyl)-1-(naphthalene-2-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 6.07 436 (M+1)
50 Ethyl 2-hydroxyl-4-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenylcarbamate 6.72 439 (M-1)
51 N-(4-(1H-1,2,4-triazol-1-yl) phenyl)-1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 7.80 403 (M-1)
52 Methyl 3-(4-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl amino)-3-oxygen propionic ester 6.41 451 (M-1)
53 N 1-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-yl) benzene-1, the 4-diamines 5.36 6.52 (d, J=8.52Hz, 2H), 7.28 (d, J=8.52Hz, 2H), 7.31 (t, J=8.55Hz, 1H), and 7.50-7.64 (m, 3H), 7.79 (d, J=8.64Hz, 1H), 7.81 (d, J=8.64Hz, 1H), 8.01 (t, J=8.66Hz, 2H), 8.21 (s, 1H), 8.93 (s, 1H).
54 N-(4-(4-methylpiperazine-1-yl) phenyl)-1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 5.64 434.9 (M+1) 2.40 (t, J=5.64Hz, 4H), 2.64 (s, 3H), 3.16 (t, J=5.64Hz, 4H), 6.77 (d, J=8.56Hz, 2H), 7.02 (s, 1H), 7.28-7.64 (m, 5H), 7.78 (d, J=8.65Hz, 1H), 7.98 (d, J=8.65Hz, 1H), 8.03 (t, J=8.55Hz, 2H), 8.23 (s, 1H), 8.96 (s, 1H).
55 N-(4-fluoro-3-p-methoxy-phenyl)-1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 7.52 384 (M-1)
56 N-(4-ethoxyl phenenyl)-1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 7.52 1.30 (t, J=5.42Hz, 3H), 4.06 (dd, J=5.42Hz, 2H), 6.75 (d, J=8.46Hz, 2H), 7.19 (s, 1H), 7.41-7.81 (m, 7H), 8.03 (t, J=8.64Hz, 2H), 8.24 (s, 1H), 8.97 (s, 1H).
57 3-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenol 6.55 4.07 (s, 1H), 6.44 (d, J=8.46Hz, 1H), 6.75 (d, J=8.46Hz, 1H), 7.06 (t, J=8.52Hz, 1H), 7.34 (d, J=8.52Hz, 2H), 7.57～7.76 (m, 4H), 7.85 (d, J=8.52Hz, 1H), 8.01 (t, J=8.52Hz, 2H), 8.28 (s, 1H), 9.01 (s, 1H).
58 2-(4-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) ethanol 6.42 382 (M-1)
59 2-methyl-5-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenol 6.84 366 (M-1)
60 2-methoxyl group-5-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenol 6.46 384.9 (M+1) 3.85 (s, 3H), 5.50 (s, 1H), 6.70 (d, J=8.45Hz, 1H), 7.00 (d, J=8.45Hz, 1H), 7.20 (s, 2H), 7.45～7.80 (m, 5H), 8.00 (t, J=8.75Hz, 2H), 8.25 (s, 1H), 8.92 (s, 1H).
61 N-(4-p-methoxy-phenyl)-1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 7.19 3.77 (s, 3H), 6.80 (d, J=8.76Hz, 2H), 7.20 (s, 1H), 7.50 (d, J=8.76Hz, 2H), 7.60～7.80 (m, 5H), 8.01 (t, J=8.24Hz, 2H), 8.24 (s, 1H), 8.96 (s, 1H).
62 N-(3-chloro-4-p-methoxy-phenyl)-1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 7.62 402 (M+1)
63 N-(4-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) ethanamide 6.20 (D6-DMSO) 2.19 (s, 3H), 7.27 (d, J=8.46Hz, 2H), 7.50～7.77 (m, 7H), 8.16 (t, J=8.55Hz, 2H), 8.43 (s, 1H), 9.14 (s, 1H), 9.73 (s, 1H), 9.84 (s, 1H).
64 4-(1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenol 6.23 354 (M+1)
65 2-methoxyl group-5-(1-(naphthalene-2-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenol 7.21 384 (M+1)
66 N-(4-methoxyl group-3-(trifluoromethyl) phenyl)-1-(naphthalene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 7.78 436 (M+1)
67 N-(4-(1-(4-(benzyloxy)-5,6,7,8-naphthane-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine 8.151 619 (M+1)
68 1-(4-(benzyloxy)-5,6,7,8-naphthane-1-yl)-N-(4-(4-methylpiperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 6.882 560 (M+1)
??69 N1-(1-(4-(benzyloxy)-5,6,7,8-naphthane-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-yl) benzene-1, the 4-diamines ??6.699 ??463??(M+1)
??70 4-(6-(4-aminophenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-5,6,7,8-naphthane-1-alcohol ??5.145 ??373??(M+1)
??71 Tertiary butyl 4-(1-(4-(benzyloxy)-5,6,7,8-naphthane-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) piperidines-1-carboxylicesters ??8.537 ??555??(M+1)
??72 4-(6-(4-(N-(methyl sulphonyl) sulfonyloxy methyl amine) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-5,6,7,8-naphthane-1-methylmethane sulphonate ??6.967 ??629??(M+23)
??73 4-(6-(4-(sulfonyloxy methyl amine) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-5,6,7,8-naphthane-1-methylmethane sulphonate ??6.572 ??529??(M+1)
??74 N-(4-(1-(4-(benzyloxy)-5,6,7,8-naphthane-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine ??7.780 ??619??(M+1)
??75 N-(4-(1-(4-hydroxyl-5,6,7,8-naphthane-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine ??6.572 ??551??(M+23)
??76 N-(4-(1-(4-hydroxyl-5,6,7,8-naphthane-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine ??6.052 ??451??(M+1)
??77 4-(6-(4-(4-methylpiperazine-1-yl) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-5,6,7,8-naphthane-1-alcohol ??5.262 ??456??(M+1)
??78 1-(4-(benzyloxy)-5,6,7,8-naphthane-1-yl)-N-(4-morpholino phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine ??7.515 ??533??(M+1)
??79 4-(6-(4-morpholino phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-5,6,7,8-naphthane-1-alcohol ??5.660 ??443??(M+1)
Figure G2008800059629D00681
Table 2 contains R in the formula (I) 2Compound for dihydro indenyl group
The embodiment numbering The compound title The HPLC data (Rt: minute) LC/MS 1H-NMR (CDCl3)
81 (S)-1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-(4-methylpiperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 5.24 426 (M+1)
82 (S)-4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenylformic acid 6.2 12.63 (s, 1H), 10.33 (s, 1H), 9.07 (s, 1H), 7.84 (m, 2H), 7.67 (d, 1H), 7.26 (t, 1H), 7.15 (t, 1H), 6.94 (d, 1H), 6.44 (t, 1H), 3.27 (m, 1H), 3.07 (m, 1H), 2.65 (m, 1H), 2.55 (m, 1H).
83 (S)-N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine 6.61 499.8 (M+1)
84 (S)-N1-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-yl) benzene-1.4-diamines 5.11 343.0 (M+1) 8.80 (s, 1H), 7.89 (s, 1H), 7.42 (d, 2H), 7.35 (d, 1H), 7.30 (m, 1H), 7.15 (t, 1H), 7.03 (d, 1H) 6.67 (d, 2H), 6.44 (t, 1H), 3.61 (b, 2H), 3.37 (m, 1H), 3.07 (m, 1H), 2.65 (m, 2H).
85 (S)-1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-morpholino phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 5.79 8.79 (s, 1H), 7.88 (s, 1H), 7.56 (m, 2H), 7.36 (s, 1H), 7.29 (m, 2H), 7.14 (t, 1H), 7.02 (d, 1H), 6.92 (d, 2H), 6.41 (t, 1H), 3.88 (t, 4H), 3.35 (m, 1H), 3.14 (t, 4H), 3.05 (m, 1H), 2.68 (m, 2H).
86 (S)-1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-(4-(sulfonyl propyl) piperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 6.72 8.82 (s, 1H), 7.92 (s, 1H), 7.58 (m, 2H), 7.39 (m, 2H), 7.29 (m, 1H), 7.14 (t, 1H), 7.02 (d, 1H), 6.97 (d, 2H), 6.41 (t, 1H), 3.47 (t, 4H), 3.35 (m, 1H), 3.22 (t, 4H), 3.05 (m, 1H), 2.97 (m, 2H), 2.71 (m, 2H), 1.95 (m, 2H), 1.1 (t, 3H).
87 4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenylformic acid 6.21 10.33 (s, 1H), 9.07 (s, 1H), 8.12 (s, 1H), 7.87 (m, 4H), 7.42 (d, 1H), 7.29 (t, 1H), 7.12 (t, 1H), 6.92 (d, 1H), 6.41 (t, 1H), 3.25 (m, 1H), 3.05 (m, 1H), 2.68 (m, 1H), 2.56 (m, 1H).
88 1-(2,3-dihydro-1H-indenes-1-yl)-N-(3-(piperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 5.57 8.90 (s, 1H), 7.92 (s, 1H), 7.60 (t, 1H), 7.42 (s, 1H), 7.35 (d, 1H), 7.30 (m, 1H), 7.22 (m, 1H), 7.15 (m, 2H), 7.03 (d, 1H) 6.67 (dd, 1H), 6.44 (t, 1H), (3.37 (m, 1H), 3.19 (t, 4H), 3.07 (m, 1H), 2.974 (t, 4H), 2.65 (m, 2H).
89 N1-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-yl) benzene-1, the 4-diamines 5.06 8.80 (s, 1H), 7.89 (s, 1H), 7.42 (d, 2H), 7.35 (d, 1H), 7.30 (m, 1H), 7.15 (t, 1H), 7.03 (d, 1H) 6.67 (d, 2H), 6.44 (t, 1H), 3.61 (b, 2H), 3.37 (m, 1H), 3.07 (m, 1H), 2.65 (m, 2H).
90 N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine 6.13 8.83 (s, 1H), 7.93 (s, 1H), 7.67 (d, 2H), 7.56 (s, 1H), 7.35 (d, 1H), 7.30 (m, 1H), 7.23 (d, 2H), 7.15 (t, 1H), 7.01 (d, 1H), 6.66 (s, 1H), 6.44 (t, 1H), 3.37 (m, 1H), 3.07 (m, 1H), 3.00 (s, 3H), 2.65 (m, 2H).
91 1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-(4-(sulfonyl propyl) piperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 6.74 8.81 (s, 1H), 7.90 (s, 1H), 7.57 (m, 2H), 7.54 (s, 1H), 7.44 (d, 1H), 7.29 (t, 1H), 7.16 (t, 1H), 7.05 (d, 1H), 6.96 (m, 2H), 6.43 (t, 1H), 3.44 (m, 4H), 3.39 (m, 1H), 3.28 (m, 4H), 3.28 (t, 4H), 3.11 (m, 1H), 2.97 (m, 2H), 2.72 (m, 2H), 1.93 (m, 2H), 1.12 (t, 3H)
92 (S)-1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-(4-(methyl sulphonyl) piperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 6.24 8.81 (s, 1H), 7.90 (s, 1H), 7.57 (m, 2H), 7.54 (s, 1H), 7.38 (d, 1H), 7.29 (t, 1H), 7.16 (t, 1H), 7.05 (d, 1H), 6.96 (m, 2H), 6.43 (t, 1H), 3.44 (m, 4H), 3.39 (m, 1H), 3.28 (m, 4H), 3.28 (t, 4H), 3.11 (m, 1H), 2.85 (s, 3H), 2.72 (m, 2H).
93 (S)-1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-(piperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 5.31 411.9 (M+1)
94 N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) benzamide 7.74 11.65 (s, 1H), 8.73 (s, 1H), 8.14 (s, 1H), 7.89 (s, 2H), 7.87 (s, 1H), 7.65 (m, 4H), 7.52 (m, 1H), 7.50 (m, 2H), 7.34 (t, 1H), 7.18 (t, 1H), 7.02 (d, 1H), 6.38 (t, 1H), 3.36 (m, 1H), 3.13 (m, 1H), 2.78 (m, 1H).
95 (S)-5-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino)-2-methoxyphenol 6.14 374 (M+1)
96 1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-(piperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 5.22 411.9 (M+1) 8.81 (s, 1H), 7.90 (s, 1H), 7.57 (m, 2H), 7.54 (s, 1H), 7.38 (d, 1H), 7.29 (t, 1H), 7.16 (t, 1H), 7.05 (d, 1H), 6.96 (m, 2H), 6.43 (t, 1H), 3.32 (m, 1H), 3.13 (m, 4H).
97 1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-morpholino phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 5.79 8.79 (s, 1H), 7.88 (s, 1H), 7.56 (m, 2H), 7.36 (s, 1H), 7.29 (m, 2H), 7.14 (t, 1H), 7.02 (d, 1H), 6.92 (d, 2H), 6.41 (t, 1H), 3.88 (t, 4H), 3.35 (m, 1H), 3.14 (t, 4H), 3.05 (m, 1H), 2.68 (m, 2H).
98 3-(4-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) piperazine-1-yl) propane-1-alcohol 5.34 8.79 (s, 1H), 7.88 (s, 1H), 7.56 (m, 2H), 7.36 (m, 2H), 7.26 (m, 1H), 7.14 (t, 1H), 7.02 (d, 1H), 6.92 (d, 2H), 6.41 (t, 1H), 5.10 (b, 1H), 3.84 (t, 2H), 3.35 (m, 1H), 3.14 (t, 4H), 3.05 (m, 2H), 2.72 (m, 8H), 1.78 (m, 2H).
99 4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) hydrazides 5.12 384.4 (M-1)
100 2-(4-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) piperazine-1-yl) ethyl acetate 5.6 497.9 (M+1)
101 1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-(4-((4-methoxyl group-3,5-lutidine-2-yl) methyl) piperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 6.07 8.79 (s, 1H), 8.20 (s, 1H), 7.88 (s, 1H), 7.56 (d, 2H), 7.35 (d, 1H), 7.27 (m, 2H), 7.13 (t, 1H), 7.02 (d, 1H), 6.89 (d, 2H), 6.38 (t, 1H), 3.77 (s, 3H), 3.66 (s, 2H), 3.33 (m, 1H), 2.70 (t, 4H), 3.20 (s, 3H), 2.25 (s, 3H).
102 3-(4-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) piperazine-1-yl) propyl group acetic ester 5.68 8.79 (s, 1H), 7.88 (s, 1H), 7.56 (m, 2H), 7.43 (s, 1H), 7.36 (d, 1H), 7.29 (m, 1H), 7.14 (t, 1H), 7.02 (d, 1H), 6.92 (d, 2H), 6.41 (t, 1H), 4.16 (m, 3H), 3.35 (m, 1H), 3.17 (t, 4H), 3.05 (m, 1H), 2.62 (m, 6H), 2.48 (t, 2H), 2.05 (s, 3H), 1.83 (t, 2H).
103 2-(4-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) piperazine-1-yl) ethanol 5.27 8.79 (s, 1H), 7.88 (s, 1H), 7.56 (m, 2H), 7.36 (m, 1H), 7.29 (m, 2H), 7.14 (t, 1H), 7.02 (d, 1H), 6.92 (d, 2H), 6.41 (t, 1H), 3.77 (t, 2H), 3.35 (m, 1H), 3.14 (t, 4H), 3.05 (m, 1H), 2.71 (m, 6H), 2.61 (t, 2H).
104 1-((S)-2,3-dihydro-1H-indenes-1-yl)-N-(3-(1-((R)-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base oxygen)-4-p-methoxy-phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 7.46 608.2 (M+1)
105 (S)-ethyl 4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) benzoic ether 7.6 8.89 (s, 1H), 8.22 (d, 2H), 7.97 (s, 1H), 7.67 (d, 2H), 7.56 (s, 1H), 7.45 (d, 1H), 7.35 (m, 1H), 7.15 (t, 1H), 7.01 (d, 1H), 6.44 (t, 1H), 4.41 (m, 2H), 3.52 (m, 1H), 3.37 (m, 1H), 3.07 (m, 1H), 3.00 (s, 3H), 2.65 (m, 2H), 1.38 (t, 3H).
106 (S)-1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-morpholino phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 5.79 8.79 (s, 1H), 7.88 (s, 1H), 7.56 (m, 2H), 7.36 (s, 1H), 7.29 (m, 2H), 7.14 (t, 1H), 7.02 (d, 1H), 6.92 (d, 2H), 6.41 (t, 1H), 3.88 (t, 4H), 3.35 (m, 1H), 3.14 (t, 4H), 3.05 (m, 1H), 2.68 (m, 2H).
107 1-(2,3-dihydro-1H-indenes-2-yl)-N-(4-morpholino phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 5.94 8.79 (s, 1H), 7.89 (s, 1H), 7.29 (m, 5H), 6.89 (d, 2H), 5.71 (m, 1H), 3.88 (t, 4H), 3.66 (m, 2H), 3.48 (m, 2H), 3.11 (m, 1H).
108 N-(4-(1-(4-hydroxyl-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine 6.159 515 (M+1)
109 (S)-N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(ethyl sulphonyl) ethane sulphonamide 7.301 527 (M+1)
??110 1-(6-(4-(4-methylpiperazine-1-yl) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-alcohol ??4.896 ??442??(M+1)
??111 1-(6-(4-(N-(methyl sulphonyl) sulfonyloxy methyl amine) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-yl benzoic acid ester ??7.507 ??619??(M+1)
??112 1-(6-(4-(N-(methyl sulphonyl) sulfonyloxy methyl amine) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-base dihydrogen phosphoric acid ester ??4.830 ??595??(M+1)
??113 (S)-1-chloro-N-(chloromethyl sulphonyl)-N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine ??7.228 ??8.89(s，1H)；7.98(s，1H)，7.76(d，??2H)，7.55(s，1H)，7.44(d，2H)，7.39??(d，1H)，7.31(t，1H)，7.17(t，1H)，??7.03(d，1H)，5.06(s，4H)，3.36(m，??1H)，3.13(m，1H)，2.76(m，2H)
??114 N-(4-(1-(6,7-dihydro-5H-indeno [5,6-d] [1,3] dioxole-5-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine ??6.771 ??543??(M+1)
??115 N-(1-(6-(4-(N-(methyl sulphonyl) sulfonyloxy methyl amine) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-5-yl) ethanamide ??6.023 ??556??(M+1)
??116 N-(4-(1-(4-hydroxyl-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine ??5.762 ??437??(M+1)
??117 1-(6-(4-(N-(methyl sulphonyl) sulfonyloxy methyl amine) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-5-yl benzoic acid ester ??6.543 ??619??(M+1)
??118 (S, Z)-4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino)-N '-hydroxybenzene azomethine acid amides ??6.402 ??386??(M+1)
??119 1-(6-(4-(4-methylpiperazine-1-yl) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-yl benzoic acid ester ??6.415 ??546??(M+1)
??120 1-(6-(4-aminophenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-alcohol ??4.729 ??359??(M+1)
??121 1-(6-(4-aminophenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-yl benzoic acid ester ??6.286 ??463??(M+1)
??122 Two-tertiary butyl 1-(6-(4-(N-(methyl sulphonyl) sulfonyloxy methyl amine) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-base phosphoric acid ester ??7.446 ??707??(M+1)
??123 (S)-4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino)-N-(methyl sulphonyl) benzamide ??6.567 ??449??(M+1)
??124 N-(4-(1-(5-((2-methoxy ethoxy) methoxyl group)-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine ??6.637 ??8.87(s，1H)；7.97(s，1H)，7.81(d，??2H)，7.52(s，1H)，7.34(d，2H)，??7.09(s，1H)，6.97(d，1H)，6.87(dd，??1H)，6.42(t，1H)，5.28(s，2H)，3.84??(m，2H)，3.58(m，2H)，3.44(s，6H)，??3.39(s，3H)，3.32(m，1H)，3.10(m，??1H)，2.76(m，1H)，2.72(m，1H)
??125 N-(1-(6-(4-aminophenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-5-yl) ethanamide ??4.703 ??400??(M+1)
??126 (S)-4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl cyanide ??7.04 ??8.00(s，1H)；7.70(s，1H)，7.68(s，??1H)，8.60(m，3H)，7.44(d，1H)，??7.34(t，1H)，7.19(t，1H)，7.04(d，??1H)，6.47(t，1H)，3.36(m，1H)，3.13??(m，1H)，2.76(m，2H)
??127 (S)-N-(4-(1H-tetrazolium-5-yl) phenyl)-1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine ??.39 ??396??(M+1)
??128 N1-(1-(5-methoxyl group-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-yl) benzene-1, the 4-diamines ??5.090 ??373??(M+1)
??129 N-(4-(1-(5-methoxyl group-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine ??6.856 ??529??(M+1)
??130 (S)-1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-oil of mirbane ethyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine ??6.939 ??401??(M+1)
??131 (S)-N-(4-amino-benzene ethyl)-1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine ??5.251 ??371??(M+1)
??132 (S)-N-(4-(2-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) ethyl) phenyl)-N-(methyl sulphonyl) amsacrine ??6.583 ??527??(M+1)
The R2 that table 3 contains in the formula (I) is the compound of dihydro acetyl naphthylidene group
133 The compound title HPLC data (Rt:Mins) LC/MS 1H-NMR (CDCl3)
134 1-(1,2-acenaphthene-1-yl)-N-(4-(4-methylpiperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 5.6 8.80 (s, 1H), 7.89 (s, 1H), 7.76 (t, 2H), 7.56 (t, 1H), 7.45 (t, 1H), 7.40 (s, 1H), 7.38 (m, 3H), 7.20 (d, 1H), 6.89 (m, 1H), 6.75 (d, 2H), 4.02 (m, 2H), 3.18 (t, 4H), 2.60 (m, 4H), 2.38 (s, 3H).
135 N-(4-(1-(1,2-acenaphthene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine 6.84 8.89 (s, 1H), 7.89 (s, 1H), 7.76 (t, 2H), 7.56 (t, 1H), 7.45 (t, 1H), 7.40 (s, 1H), 7.38 (m, 3H), 7.20 (d, 1H), 7.03 (d, 2H), 6.89 (m, 1H), 4.02 (m, 2H), 3.41 (s, 6H).
136 N1-(1-(1,2-acenaphthene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-yl) benzene-1, the 4-diamines 5.31 379 (M+1)
137 1-(1,2-acenaphthene-1-yl)-N-(4-morpholino phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 6.09 8.80 (s, 1H), 7.89 (s, 1H), 7.76 (t, 2H), 7.56 (t, 1H), 7.45 (t, 1H), 7.40 (s, 1H), 7.38 (m, 3H), 7.20 (d, 1H), 6.89 (m, 1H), 6.75 (d, 2H), 4.02 (m, 2H), 3.87 (t, 4H), 3.09 (t, 4H).
138 4-(1-(1,2-acenaphthene-1-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl cyanide 7.3 10.27 (s, 1H), 9.08 (s, 1H), 8.12 (s, 1H), 7.79 (m, 6H), 7.65 (t, 1H), 7.49 (d, 2H), 7.18 (d, 1H), 6.95 (m, 1H), 4.15 (m, 2H).
139 1-(1,2-acenaphthene-1-yl)-N-(4-(2-(trimethylammonium stannyl)-2H-tetrazolium-5-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 6.4 8.91 (s, 1H), 8.02 (s, 1H), 7.83 (m, 2H), 7.65 (t, 1H), 7.51 (s, 1H), 7.40 (t, 1H), 7.35 (m, 3H), 7.20 (d, 1H), 6.89 (m, 1H), 4.15 (m, 2H), 3.88 (1H).
140 1-(1,2-acenaphthene-1-yl)-N-(4-(piperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 5.42 447.9 (M+1) 8.78 (s, 1H), 7.88 (s, 1H), 7.63 (d, 2H), 7.34 (s, 1H), 7.00 (d, 2H), 4.85 (m, 1H), 3.23 (t, 4H), 2.64 (t, 4H), 2.38 (s, 3H), 2.21 (m, 2H), 1.90 (m, 2H), 1.74 (m, 6H).
It is the compound of indyl group that table 4 contains the middle R2 of formula (I)
The embodiment numbering The compound title HPLC (Rt, Min) LC/MS 1H-NMR (CDCl3, unless otherwise noted)
141 N-(4-(1-(1H-indoles-4-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine 6.28 498 (M+1)
142 N-(4-(1-(1H-indoles-6-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine 6.61 498 (M+1)
143 N-(4-(1-(1H-indoles-5-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine 6.38 498 (M+1)
144 1-(1H-indoles-4-yl)-N-(4-(4-methylpiperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 5.14 425 (M+1)
145 N-(4-(1-(1-Methyl-1H-indole-5-yl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine 6.80 512 (M+1)
146 1-(7-Methyl-1H-indole-4-yl)-N-(4-(4-methylpiperazine-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 5.23 439 (M+1)
147 Tertiary butyl 7-methyl-4-(6-(4-(4-methylpiperazine-1-yl) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-1H-indoles e-1-carboxylicesters 6.71 8.88 (s, 1H), 8.13 (s, 1H), 7.69 (d, 1H), 7.55 (m, 3H), 7.34 (s, 1H), 7.24 (d, 1H), 6.87 (d, 2H), 6.82 (d, 1H), 3.17 (m, 4H), 2.70 (s, 3H), 2.61 (m, 4H), 2.37 (s, 3H), 1.65 (s, 9H).
148 Tertiary butyl 4-(6-(4-(4-methylpiperazine-1-yl) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl)-1H-indoles e-1-carboxylicesters 6.60 8.89 (s, 1H), 8.23 (d, 1H), 8.14 (s, 1H), 7.88 (d, 1H), 7.63 (d, 1H), 7.57 (d, 2H), 7.46 (t, 1H), 7.32 (s, 1H), 6.945 (d, 1H), 6.88 (d, 2H), 3.18 (m, 4H), 2.63 (m, 4H), 2.38 (s, 3H), 1.69 (s, 9H).
149 1-((6-fluoro-4H-benzo [d] [1,3] dioxin-8-yl) methyl)-N-(4-morpholino phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 5.47 8.80 (s, 1H), 7.93 (s, 1H), 7.60 (d, 2H), 7.20 (s, 1H), 6.96 (d, 2H), 6.65 (m, 2H), 5.51 (s, 2H), 5.27 (s, 2H), 4.88 (s, 2H), 3.89 (t, 3H), 3.15 (t, 4H).
Table 5 contains the compound of the middle R2 of formula (I) for other group
The embodiment numbering The compound title The HPLC data (Rt, Min) LC/MS 1H-NMR (CDCl3)
150 N-(4-morpholino phenyl)-1-(naphthalene-1-ylmethyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 5.73 8.80 (s, 1H), 8.44 (m, 1H), 7.92 (s, 1H), 7.90 (m, 1H), 7.84 (s, 1H), 7.67 (d, 2H), 7.57 (d, 1H), 7.51 (m, 3H), 7.38 (s, 1H), 6.97 (d, 2H), 5.97 (s, 2H), 3.91 (t, 4H), 3.18 (t, 4H).
151 1-butyl-N-(4-(piperidines-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 5.34 8.78 (s, 1H), 7.89 (s, 1H), 7.60 (d, 2H), 7.20 (s, 1H), 7.00 (d, 2H), 4.37 (t, 2H), 3.15 (t, 4H), 1.95 (m, 2H), 1.60 (m, 6H), 1.38 (m, 2H), 0.98 (t, 3H).
152 Ethyl 2-(6-(4-(piperidines-1-yl) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl) acetic ester 4.78 8.80 (s, 1H), 7.93 (s, 1H), 7.55 (d, 2H), 7.25 (d, 1H), 6.96 (d, 2H), 5.11 (s, 2H), 4.27 (m, 2H), 3.15 (t, 4H), 1.76 (t, 4H), 1.60 (m, 2H), 1.31 (m, 5H)
153 1-methyl-N-(4-(piperidines-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 4.62 1.30 (t, J=7.12Hz, 2H, CH2), 1.75 (m, 4H, 2CH2), 3.15 (t, J=5.30Hz, 4H, 2CH2), 4.00 (s, 3H, CH3), 6.99 (d, J=8.50Hz, 2H, CH), 7.20 (s, 1H, NH7.17 (d, J=8.50Hz, 2H, 2CH), 7.89 (s, 1H, CH), 8.79 (s, 1H, CH).
154 1-sec.-propyl-N-(4-(piperidines-1-yl) phenyl)-1H-pyrazoles [3,4-d] pyrimidine-6-amine 4.94 8.78 (s, 1H), 7.89 (s, 1H), 7.60 (d, 2H), 7.20 (s, 1H), 7.00 (d, 2H), 5.01 (m, 1H), 3.15 (t, 4H), 2.04 (s, 6H), 1.78 (m, 4H), 1.58 (m, 6H).
155 N-(4-(1-(3-aminopropyl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine 4.660 440 (M+1)
156 N-(methyl sulphonyl)-N-(4-(1-propyl group-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine 6.301 425 (M+1)
157 N-(4-(1-butyl-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine 6.522 439 (M+1)
158 N-(4-(1-(4-hydroxybutyl)-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine 5.403 455 (M+1) 8.80 (s, 1H), 7.93 (s, 1H), 7.60 (d, 2H), 7.40 (s, 1H), 7.35 (m, 2H), 7.30 (m, 2H), 6.96 (d, 2H), 6.09 (q, 1H), 3.95 (t, 3H), 3.19 (t, 4H), 2.03 (d, 3H).
159 4-(6-(4-(N-(methyl sulphonyl) sulfonyloxy methyl amine) phenyl amino)-1H-pyrazoles [3,4-d] pyrimidine-1-yl) butylacetic acid ester 6.120 497 (M+1) 8.80 (s, 1H), 7.93 (s, 1H), 7.60 (d, 2H), 7.20 (s, 1H), 6.96 (d, 2H), 6.65 (m, 2H), 5.51 (s, 2H), 5.27 (s, 2H), 4.88 (s, 2H), 3.89 (t, 3H), 3.15 (t, 4H).
160 N-(4-(1-ethyl-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine 5.929 411 (M+1)
161 N-(4-(1-sec.-propyl-1H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine 6.241 425 (M+1) 8.80 (s, 1H), 7.93 (s, 1H), 7.66 (d, 2H), 7.39 (d, 1H), 7.34 (s, 1H), 6.96 (d, 2H), 6.43 (d, 1H), 6.36 (m, 1H), 5.51 (s, 2H), 3.17 (t, 3H), 3.09 (t, 4H).
162 N-(4-(1-methyl isophthalic acid H-pyrazoles [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methyl sulphonyl) amsacrine 5.697 397 (M+1)
Embodiment 127: the kinases analysis of aurora kinase A (AKA)
Analyze and press Toji, S. etc. are at Genes to Cells, and 9:383-397 carries out described in (2004), and it all incorporates this paper by reference into.
The Lats2 substrate of 6His-mark (5ug/mL in PBS) be coated in advance on the 96-hole HisGrab plate with the TBST sealing that contains 5% BSA and 1% milk powder (catalog number (Cat.No.): 5142, PierceChemical, Rockford, Illinois, USA).At kinase reaction damping fluid (20mM HEPES, 1mM DTT, 50mM MgCl 2, 50uM ATP, pH 7.5) in aurora kinase A (MBLInternational, Woburn, Massachusetts, USA, #CY-E 1165-1) dilution (1: 200) and make it 30 ℃ of auto-activations 60 minutes.Add compound of the present invention subsequently, and in 30 ℃ of incubation mixtures 60 minutes.Behind the incubation, aurora kinase A is joined the HisGrab plate of Lats2 bag quilt, and 30 ℃ of incubations 1 hour, subsequently with PBS (PBST) washed twice that contains 0.05% Tween-20.(TBST that contains 5% BSA and 1% milk powder) is with Anti-Phospho-Lats2-Ser83 monoclonal antibody (MBL International in antibody dilution buffer, #ST-3B11) dilute (1: 500), join each hole, and subsequently room temperature incubation 30 minutes.Each hole PBST washed twice then.In the TBST that contains BSA and milk with sheep anti-mouse igg (the Jackson Immunoresearch of coupling horseradish peroxidase (HRP), West Grove, Pennsylvania, USA, #115-035-003) dilute (1: 4000), be added to each hole, and subsequently room temperature incubation 30 minutes.Each hole is with PBST washing 5 times, add then 100uL TMB Ultra HRP substrate (Pierce Chemical, #34028), and with mixture room temperature incubation 5 minutes.In each hole, add 100uL 1N H then 2SO 4, and use the absorption value of spectrophotometric card reader measurement at the 450nM wavelength.To be defined as 100% activity as the aurora kinase (contrast) of inhibitor incubation with DMSO.EC 50Be defined as and have aurora kinase 50% inhibiting compound concentration.
The compound exhibits of most of test goes out the IC less than 2 μ M 50Value, some are less than 0.2 μ M, and some are less than 0.08 μ M and some even less than 0.01 μ M.
The result shows the high restraining effect of formula (I) compound exhibits of test to aurora kinase A.
Embodiment 78: the kinases analysis of aurora kinase A (AKA)
This analysis classes is similar to as above embodiment 77 described analyses.Particularly, use the Z-lysokinase to analyze serine/threonine 1 peptide reagent box (Z-Lyte Kinase Assay Ser/Thr 1 Peptide Kit) (Invitrogen, # PV3174) and synthetic peptide substrate Ser-Thr 1 peptide (Invitrogen, #PV3196), described synthetic peptide substrate Ser-Thr 1 peptide is with forming right donor fluorophore (tonka bean camphor) of FRET and acceptor fluorescence group (fluorescein) mark.All dilution 1X reaction buffers (50mM HEPES-pH 7.5,10mM MgCl2,1 mM EGTA, 0.01% Brij-35 comes from 5X stock solution (Invitrogen, PV3189)) and carries out.
Elementary 10uL reaction relates to laser kinase b (Invitrogen # PV3970), 64uM ATP (PV3227), 2uM Ser-Th 1 peptide and compound of the present invention (1%, in DMSO).Be reflected at the room temperature incubation 1 hour.
Also use 0% contrast, it is made up of 64uM ATP, 2uM Ser-Thr1 peptide, does not contain aurora kinase B; And use 100% contrast, it is made up of 64uM ATP, 2uM P phosphoric acid Ser-Thr 1 peptide (Invitrogen # PV3211), does not contain aurora kinase B.
In secondary reaction, the locus specificity proteolytic enzyme of 5uL (the Development Reagent A, Invitrogen, # PV3295) is added to dilution in 1: 2048 damping fluid (Development Buffer) (Invotrigen takes place, # P3127), continue 1 hour in room temperature.Proteolytic cleavage non-phosphorylating polypeptide, the FRET that has destroyed two fluorophores interacts; And the phosphorylation polypeptide is not sheared, and has kept the FRET interaction.Be reflected on the M5 spectrophotometer, exciting 400nm and emission 445nm and 520nm reading.
Emission ratio (Em)=tonka bean camphor (C) (at 445nm)/fluorescein (F) transmit (at 520nm) that transmits.
Phosphorylation per-cent=[1-((Em ratio * F100%)-C100%)/((C0%-C100%)+(Em ratio X (F100%-F0%)))].
Test compounds has also shown the restraining effect to aurora kinase B.Most of test compounds has shown the IC less than 2.0 μ M 50Value, some are less than 0.6 μ M, and some are less than 0.2 μ M and some even less than 0.005 μ M.
Embodiment 128:CDK1 kinases is analyzed
Use the Z-lysokinase to measure serine/threonine 18 peptide reagent boxes (Z-Lyte Kinase AssaySer/Thr 18 Peptide Kit) (Invitrogen, Carlsbad, California, USA, #PV4319) be used for this analysis, and analyze according to the operational guidance of manufacturers.This is analyzed and uses synthetic peptide substrate (Ser-Thr18 polypeptide, Invitrogen # PV4320), and described synthetic peptide substrate is with forming right donor fluorophore (tonka bean camphor) of FRET and acceptor fluorescence group (fluorescein) mark.All dilutions are carried out with the 1X reaction buffer, and the 1X reaction buffer is by 50mM HEPES-pH 7.5,10mMMgCl 2,, 1mM EGTA, 0.01% Brij-35 form.
Elementary 10 μ l reaction relate to 0.62ug/ml CDK1/ cell periodic protein B (Invitrogen, #PV3292), 34uM ATP, 2uM Ser-Thr 18 polypeptide.Compound of the present invention is dissolved to 1% in DMSO.0% contrast comprises 34uM ATP, 2uM Ser-Thr18 polypeptide, does not contain enzyme; And 100% contrast contains 34uM ATP, (Invitrogen #PV4321), does not contain enzyme to 2uM phosphorylation Ser-Thr18 polypeptide.Be reflected at the room temperature incubation 1 hour.
In secondary reaction, the locus specificity proteolytic enzyme of 5uL (the Development Reagent A, Invitrogen, # PV3295) dilutes (1: 1024) in damping fluid (#3127) takes place, and continues 1 hour in room temperature.Proteolytic cleavage non-phosphorylating polypeptide, the FRET that has destroyed two fluorophores interacts, and the phosphorylation polypeptide is not sheared, and has kept the FRET interaction.Reaction mixture on the M5 spectrophotometer, is being excited 400nm and emission 445nm and 520nm reading.
Emission ratio (Em)=tonka bean camphor (C) (at 445nm)/fluorescein (F) transmit (at 520nm) that transmits.
Phosphorylation per-cent=[1-((Em ratio * F100%)-C100%)/((C0%-C100%)+(Em ratio * (F100%-F0%)))].
IC50 is defined as has the compound concentration that CDK1 kinase activity 50% suppresses.
The result shows that the compound exhibits of test is to the high restraining effect of CDK1 kinase activity.Most of test compounds has shown the IC less than 2 μ M 50Value, some are less than 0.4 μ M, and some are less than 0.1 μ M and some even less than 0.01 μ M.
The embodiment 129:G2M cell cycle stops analysis
In containing the Dulbecco improvement Eagle substratum of 10% FBS in 96 orifice plates of (Dulbecco ' sModified Eagle Media), at 37 ℃ and 10% CO 2With the The compounds of this invention that increases concentration (0-0.001-0.003-0.01-0.03uM or 0.1-0.3-1-3-30-100uM) 100,000 K562 leukemia cells of 200uL volume of culture incubation 24 hours.With the DPBS washed cell once, and subsequently in 70% ice-cold ethanol, fix 30 minutes at 4 ℃.After DPBS washing 1 time, with cell suspension in the DPBS that contains 0.2% Tween-20 30 minutes.Use the DPBS washed cell once more once, cell is resuspended in the solution of 25ug/mL propidium iodide, 0.002% NP-40 and 12.5ug/mL RNAse A.Measure cell DNA content being equipped with on the FACSCALIBUR flow cytometer of argon laser, the 488nm light that argon laser sends 15mW is used to excite the fluorescence of DNA intercalative dye propidium iodide.Minimum effective concentration is defined as the cell per-cent that is in G2M and surpasses the inhibitor concentration of removing the cell per-cent that is in G1.
The result who in table, shows G2M, and show that the minimum effective concentration scope carries out the G2M cell cycle with the K562 in the leukemia cell and stop from 0.03nM to 100uM.
The compound exhibits of most of test less than the IC of 10 μ M 50Value, some are less than 3 μ M and some even less than 0.3 μ M.
Embodiment 130:HCT116 growth-inhibiting is analyzed
HCT116 (colon) cancer cells is dispersed to 96 orifice plates (each hole 100uL, every milliliter of 20000 cells), and uses the standard cell lines culture condition to make cell adhesion spend the night.Then under the type culture condition with compound incubation culture of the present invention 5 days.With 3-(4,5-dimethylthiazole-2-yl)-5-(3-carboxyl p-methoxy-phenyl)-2-(4-sulfonic group phenyl)-2H-tetrazolium inner salt (MTS)--new tetrazole compound (Promega, Madison, Wisconsin, USA, G1111) add with 2mg/mL concentration, and to mix the phenazine methosulfate of 50ug/mL at 20: 1, join the mixture of 20uL in the culture then and make its growth several hrs.Use color change on 96-orifice plate spectrophotometric plate reader, to measure survival rate with OD490nm.
IC 50Be defined as and have HCT116 tumor cell line 50% growth inhibiting compound concentration.
The compound of test usually shows the IC50 value less than 6.0 μ M, and some are less than 0.8 μ M, and some are less than 0.2 μ M and some even less than 0.08 μ M.
Embodiment 131: the in-vivo procedures method
Obtain the 6-8 Balb/C and the nu/nu athymic mouse in age in week from Charles River Laboratories.Having 12 hours day and night in the room in cycle, mouse is incubated in the airy cage.Food and water arbitrarily are provided.Discern animal by using the barcode chip.Experimentize under the guidance suitable and that the mankind use of animal according to Biogen Idec IACUC working method SD34-07 and in the research that laboratory animal institute (ILAR) sets up.
Embodiment 132: mouse tumor research
A left side or right side abdomen subcutaneous vaccination tumor fragment (about 2mm animal 3) or 5 * 10 6Tumour cell.Select establiss tumour (50-200mm 3) mouse be used for research (n=7-10/ treatment group).Use calipers to measure tumor size, and use ellipsoidal equation (l * w 2)/2=mm 3Calculate gross tumor volume, wherein l and w are meant the big and reduced size in each is measured.
Preparation test compounds and Orally administered (p.o.) perhaps use with the dose volume of 10mL/kg through peritonaeum inner chamber (IP).Vehicle is administered to control group separately.Animal is administration (the week) in 5 days weekly, continuous 4 to 6 weeks.Weigh for twice weekly animal and measure the tumour size.
Follow the tracks of the gross tumor volume of mouse in control group and reach about 1000mm 3, use CO then 2Euthanasia is put to death mouse.Calculate every group mean tumour volume.With the change of mean treatment gross tumor volume change divided by the average control gross tumor volume, multiply by 100 and take advantage of and from 100%, deduct, the tumor growth that has obtained every group suppresses.Use standard t check is also used GraphPad Prism
Figure G2008800059629D00811
Software carries out statistical study.The result shows that the compound of test has reduced gross tumor volume effectively.
Other embodiment
Should be understood that, be described that the description intention of carrying out previously is explanation rather than limits the scope of the invention that scope of the present invention defines by appended claim though the present invention has made up by the description detailed with it.Others, beneficial effect and modification should be in the scopes of following claim.

Claims (72)

1. the compound of formula (I), prodrug, polymorphic form, tautomer, enantiomer, steric isomer, solvate, N-oxide compound or its pharmacy acceptable salt:
Figure A2008800059620002C1
Wherein:
R 1Be hydrogen or halogen;
R 2Be-L 1-R a, wherein
L 1Be a key and R aBe thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl; Wherein each in cycloalkyl, Heterocyclylalkyl, aryl and the heteroaryl be replace arbitrarily and have 8 to 16 annular atomses; Perhaps
L 1Be alkyl and R aBe hydrogen, thiazolinyl, alkynyl, amino, hydroxyl, carbalkoxy, alkyl carbonyl oxy, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl; Wherein each in cycloalkyl, Heterocyclylalkyl, aryl and the heteroaryl be replace arbitrarily and have 8 to 16 annular atomses arranged;
R 3Be-R b-L 2-R cWherein
R bBe aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl, and be randomly to replace with 1 to 3 substituting group; Wherein when contiguous, in the substituting group two can form 5 to 16 yuan ring with their connected one or more atoms, and it has 0 to 6 heterocyclic atom,
L 2Be a key ,-(CR xR y) n-,-N=,-O-,-S-,-SO-,-SO 2-,-CO-,-CO-O-,-O-CO-,-NR x-,-NR x-CO-,-NR x-SO 2-,-CO-NR x-,-SO 2-NR x-,-NR x-CO-O-,-NR x-SO 2-O-,-NR x-CO-NR y-,-NR x-SO 2-NR y-,-CO-NR x-NR y-,-SO 2-NR x-NR y-,-NR x-CO-CO-O-,-NR x-SO 2-SO 2-O-,-S (O) 2-N x-CO-R y-,-CO-N x-S (O) 2-R y-or-(NR xR y) C=N-O-;
R cBe hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, cycloalkyl-alkyl, Heterocyclylalkyl-alkyl, cycloalkenyl group-alkyl, heterocycloalkenyl-alkyl, aralkyl or heteroaralkyl; And except hydrogen, it is randomly to replace with 1 to 3 substituting group;
R xAnd R yIn each be independently hydrogen, hydroxyl, alkyl, alkoxyl group, amino ,-the CO-alkyl ,-the CO-aryl ,-SO 2-alkyl ,-SO 2-aryl ,-SO 2-heteroaryl or-P (O) (O-alkyl) 2, wherein at R xPerhaps R yIn alkyl or aryl moiety be randomly to replace with 1 to 3 substituting group; And n is 0,1,2 or 3.
2. compound according to claim 1, wherein
R bBe randomly to replace with 1 to 3 substituting group, wherein each substituting group be independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, heteroaryl, arylalkyl, heteroarylalkyl ,-OR ,-SR ,-NRR ', oxo ,-C (O)-OR ,-C (O)-NRR ', halogen ,-CN ,-NO 2,-N 3,-C (O) R ,-P (O) (OR) R ' ,-O-P (O) (OR) R ' ,-NR-P (O) (OR ') R " ,-S (O) 2-(OR) ,-O-S (O) 2-(OR) ,-NR-S (O) 2-OR ' ,-NR-C (O)-OR ' ,-NR-C (O)-NR ' R " ,-NR-C (S)-NR ' R " ,-C (S)-NRR ' and alkylthio;
Among R and the R ' each is hydrogen, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl independently; And R " be alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl.
3. compound according to claim 1, wherein
When being hydrogen, R cBe randomly to replace with 1 to 3 substituting group, each substituting group be independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, heteroaryl, arylalkyl, heteroarylalkyl ,-OR ,-SR ,-NRR ', oxo ,-C (O)-OR ,-C (O)-NRR ', halogen ,-CN ,-NO 2,-N 3,-C (O) R ,-P (O) (OR) R ' ,-O-P (O) (OR) R ' ,-NR-P (O) (OR ') R " ,-S (O) 2-(OR) ,-O-S (O) 2-(OR) ,-NR-S (O) 2-OR ' ,-NR-C (O)-OR ' ,-NR-C (O)-N R ' R " ,-NR-C (S)-NR ' R " ,-C (S)-NRR ' and alkylthio;
Among R and the R ' each is hydrogen, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl independently; And
R " be alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl.
4. compound according to claim 1, wherein
Described R xPerhaps R yIn alkyl or aryl moiety be randomly to replace with 1 to 3 substituting group, each be independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, heteroaryl, arylalkyl, heteroarylalkyl ,-OR ,-SR ,-NRR ', oxo ,-C (O)-OR ,-C (O)-NRR ', halogen ,-CN ,-NO 2,-N 3,-C (O) R ,-P (O) (OR) R ' ,-O-P (O) (OR) R ' ,-NR-P (O) (OR ') R " ,-S (O) 2-(OR) ,-O-S (O) 2-(OR) ,-NR-S (O) 2-OR ' ,-NR-C (O)-OR ' ,-NR-C (O)-NR ' R " ,-NR-C (S)-NR ' R " ,-C (S)-NRR ' and alkylthio;
Among R and the R ' each is hydrogen, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl independently; And
R " be alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl.
5. compound according to claim 1, wherein L 2It is a key.
6. compound according to claim 1, wherein R 3Be two (methane sulfonyl) aminophenyls of 4-; two (ethane alkylsulfonyl) aminophenyls of 4-; 4-(4-methylpiperazine-1-yl) phenyl; two (methane sulfonyl) aminophenyls of 4-; two ((methyl chloride) alkylsulfonyl) aminophenyls of 4-; 4-(methane sulfonyl) aminophenyl; 4-(N '-hydroxyl first miaow base) phenyl; 4-(4-methylpiperazine-1-yl) phenyl; the 4-aminophenyl; 4-(methane sulfonyl carbamyl) phenyl; the 4-cyano-phenyl; 4-(tetrazolium-5-yl) aminophenyl; 2-(4-nitrophenyl) ethyl; 2-(4-aminophenyl) ethyl or 2-(two (methane sulfonyl) aminophenyls of 4-) ethyl.
7. compound according to claim 1, wherein L 1It is a key.
8. compound according to claim 7, wherein R aBe cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl.
9. compound according to claim 8, wherein R aIt is also [7] wheel thiazolinyl of dihydro indenyl, tetralyl, dihydro-acenaphthylene base, naphthylidene, tetrahydrochysene-benzo [7] wheel thiazolinyl, quinolyl, isoquinolyl, benzimidazolyl-, benzothiazolyl, benzoxazolyl, phenanthryl or tetrahydrochysene-biphenyl; And R aWith 1-3 substituting group is to replace arbitrarily.
10. according to the described compound 9 of claim, wherein R aBe dihydro indenyl, tetralyl, dihydro-acenaphthylene base or naphthyl; And R aBe to replace arbitrarily with 1-3 substituting group.
11. compound according to claim 10, wherein R aBe naphthyl, dihydro-acenaphthylene base or dihydro indenyl.
12. compound according to claim 11, wherein R aBe naphthalene-1-base, 1,2-acenaphthene-1-base, 2,3-dihydro indenes-2-base or 2,3-dihydro indenes-1-base.
13. compound according to claim 8, wherein R aIt is the dihydro indenyl that randomly replaces with 1 to 3 substituting group.
14. compound according to claim 13, wherein R aBe dihydro indenes-1-base, 4-hydroxyl dihydro indenes-1-base, 4-benzoyloxy dihydro indenes-1-base, 4-dihydro phosphorus acyloxy dihydro indenes-1-base, 5,6-dioxy dihydro indenes-1-base, 5-acetamido dihydro indenes-1-base, 5-benzoyloxy dihydro indenes-1-base, 4-benzoyloxy dihydro indenes-1-base, 4-(di-t-butyl phosphorus acyloxy) dihydro indenes-1-base, 5-((2-methoxyethoxy) methyl) dihydro indenes-1-base or 5-melonia indenes-1-base.
15. compound according to claim 14, wherein R 3Be two (methane sulfonyl) aminophenyls of 4-; two (ethane alkylsulfonyl) aminophenyls of 4-; 4-(4-methylpiperazine-1-yl) phenyl; two (methane sulfonyl) aminophenyls of 4-; two ((methyl chloride) alkylsulfonyl) aminophenyls of 4-; 4-(methane sulfonyl) aminophenyl; 4-(N '-hydroxyl first miaow base) phenyl; 4-(4-methylpiperazine-1-yl) phenyl; the 4-aminophenyl; 4-(methane sulfonyl carbamyl) phenyl; the 4-cyano-phenyl; 4-(tetrazolium-5-yl) aminophenyl; 2-(4-nitrophenyl) ethyl; 2-(4-aminophenyl) ethyl or 2-(two (methane sulfonyl) aminophenyls of 4-) ethyl.
16. compound according to claim 8, wherein R aIt is the indyl that randomly replaces with 1 to 3 substituting group.
17. compound according to claim 16, wherein R aBe indoles-4-base, indoles-6-base, indoles-5-base, 7-skatole-5-base, 1-tertiary butyl carboxyl-7-skatole-5-base or (1-tertiary butyl carboxyl) indoles-5-base.
18. compound according to claim 17, wherein R 3Be two (methane sulfonyl) aminophenyls of 4-.
19. compound according to claim 10, wherein R aIt is the tetralyl that replaces arbitrarily with 1-3 substituting group.
20. compound according to claim 19, each in the individual substituting group arbitrarily of wherein said 1-3 is independently selected from benzyloxy, hydroxyl and sulfonyloxy methyl oxygen base.
21. compound according to claim 20, wherein R aBe 1-benzyloxy-5,6,7,8-naphthane-4-base, 1-hydroxyl-5,6,7,8-naphthane-4-base or 1-methanesulfonyloxy group-5,6,7,8-naphthane-4-base.
22. compound according to claim 21, wherein L 1Be alkyl and R aBe hydrogen, thiazolinyl, alkynyl, amino, hydroxyl, carbalkoxy, alkyl carbonyl oxy, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl; Wherein each in cycloalkyl, Heterocyclylalkyl, aryl and the heteroaryl be replace arbitrarily with 1-3 substituting group and have 8 to 16 annular atomses.
23. compound according to claim 22, wherein L 1Be methyl, ethyl, propyl group, sec.-propyl or butyl; And R aBe hydrogen, amino, hydroxyl, carbalkoxy, alkyl carbonyl oxy, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl; Wherein each in cycloalkyl, Heterocyclylalkyl, aryl and the heteroaryl replaces arbitrarily with 1-3 substituting group.
24. compound according to claim 23, R 2Be methyl, ethyl, propyl group, sec.-propyl, butyl, 3-aminopropyl, hydroxybutyl, ethoxy carbonyl methyl, methyl carbonyl oxygen Ji Dingji or naphthalene-1-ylmethyl.
25. compound according to claim 24, wherein R 3It is the phenyl that replaces arbitrarily with 1-3 substituting group.
26. compound according to claim 25, wherein R 3It is the phenyl of para-orientation.
27. compound according to claim 26, wherein R 3It is 4-(piperidines-1-yl) phenyl or 4-(two (methyl sulphonyl) amino) phenyl.
28. compound according to claim 1, R bBe phenyl and be randomly to replace with 1 to 3 substituting group.
29. compound according to claim 28, wherein L 2Be-O-,-S-,-SO 2-,-CO-,-CO-O-,-NR x-,-NR x-CO-,-NR x-SO 2-,-NR x-CO-O-,-NR x-CO-NR y-or-NR x-CO-CO-O-.
30. compound according to claim 29, wherein R xAnd R Among the yEach be hydrogen, alkyl ,-the CO-alkyl or-SO 2-alkyl.
31. compound according to claim 30, wherein R cBe hydrogen, alkyl or aryl.
32. compound according to claim 29, wherein L 2Be-CO-O-,-NR x-,-NR x-SO 2-,-NR x-CO-O-or-NR x-CO-NR y-, R wherein xAnd R yIn each be hydrogen, alkyl ,-the CO-alkyl ,-SO 2-alkyl ,-SO 2-aryl or-SO 2-heteroaryl.
33. compound according to claim 32, wherein R cBe hydrogen, alkyl, aryl or heteroaryl.
34. compound according to claim 32, wherein L 2It is a key; And R cBe cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, (cycloalkyl) alkyl, (Heterocyclylalkyl) alkyl, aralkyl or heteroaralkyl.
35. compound according to claim 28, wherein L 2It is a key; And R cBe Heterocyclylalkyl, heteroaryl, Heterocyclylalkyl-alkyl or heteroaralkyl.
36. compound according to claim 28, wherein L 2Be a key and R cBe tetrazyl, morpholino or piperazinyl.
37. compound according to claim 1, wherein R cBe cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyl-alkyl, Heterocyclylalkyl-alkyl, aralkyl or heteroaralkyl.
38. compound according to claim 1, wherein R bBe the phenyl that replaces with 1 to 3 substituting group, wherein each substituting group be independently selected from-NRR ' and-C (O) OR; L 2It is a key; And R cBe hydrogen.
39. compound according to claim 1, wherein R 1Be hydrogen.
40. according to the described compound of claim 39, wherein L 1It is a key; R aBe cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl; R bIt is phenyl; L 2Be-O-,-S-,-SO 2-,-CO-,-CO-O-,-NR x-,-NR x-CO-,-NR x-SO 2-,-NR x-CO-O-,-NR x-CO-NR y-or-NR x-CO-CO-O-, wherein R xBe hydrogen, alkyl ,-the CO-alkyl ,-SO 2-alkyl ,-SO 2-aryl or-SO 2-heteroaryl; And R cBe hydrogen, alkyl, aryl or heteroaryl.
41. according to the described compound of claim 39, wherein L 1It is a key; R aBe dihydro indenyl, tetralyl, dihydro-acenaphthylene base or naphthyl; R bIt is phenyl; L 2Be-CO-O-,-NR x-,-NR x-SO 2-,-NR x-CO-O-or-NR x-CO-NR y-, R wherein xBe hydrogen, alkyl ,-the CO-alkyl ,-SO 2-alkyl or-SO 2-aryl; And R cBe hydrogen, alkyl or aryl.
42. according to the described compound of claim 39, wherein L 1It is a key; R aBe cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl; R bIt is phenyl; L 2It is a key; And R cBe cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, (cycloalkyl) alkyl, (Heterocyclylalkyl) alkyl, aralkyl or heteroaralkyl.
43. according to the described compound of claim 43, wherein L 1It is a key; R aBe dihydro indenyl, tetralyl, dihydro-acenaphthylene base or naphthyl; R bIt is phenyl; L 2It is a key; And R cBe tetrazyl, morpholino or piperazinyl.
44. according to the described compound of claim 44, wherein L 1Be alkyl and R aBe hydrogen, thiazolinyl, alkynyl, amino, hydroxyl, carbalkoxy, alkyl carbonyl oxy, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl; Wherein each in cycloalkyl, Heterocyclylalkyl, aryl and the heteroaryl be replace arbitrarily with 1-3 substituting group and have 8 to 16 annular atomses.
45. according to the described compound of claim 45, wherein L 1Be methyl, ethyl, propyl group, sec.-propyl or butyl; And R aCan be hydrogen, amino, hydroxyl, carbalkoxy, alkyl carbonyl oxy, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl; Wherein each in cycloalkyl, Heterocyclylalkyl, aryl and the heteroaryl replaces arbitrarily with 1-3 substituting group.
46. according to the described compound of claim 45, R 2Be methyl, ethyl, propyl group, sec.-propyl, butyl, 3-aminopropyl, hydroxybutyl, ethoxy carbonyl methyl, methyl carbonyl oxygen Ji Dingji or naphthalene-1-ylmethyl.
47. according to the described compound of claim 46, wherein R 3It is the phenyl that replaces arbitrarily with the 1-3 substituting group.
48. according to the described compound of claim 47, wherein R 3It is 4-(piperidines-1-yl) phenyl or 4-(two (methyl sulphonyl) amino) phenyl.
49. compound according to claim 1, wherein R bIt is the phenyl that randomly replaces with 1 to 3 substituting group; L 2Be a key or-NR x-SO 2-; R xBe hydrogen or-SO 2-alkyl; And R cBe hydrogen, alkyl, Heterocyclylalkyl, heteroaryl, Heterocyclylalkyl-alkyl or heteroaralkyl.
50. according to the described compound of claim 49, wherein R xBe-SO 2-alkyl; And R cIt is alkyl.
51. compound according to claim 1, wherein R bIt is the phenyl that randomly replaces with 1 to 3 substituting group.
52. according to the described compound of claim 51, wherein R cBe tetrazyl, morpholino or piperazinyl.
53. compound according to claim 1, wherein R bBe the phenyl that replaces with 1 to 3 substituting group, wherein each substituting group be independently-NRR ' or-C (O) OR; L 2It is a key; And R cBe hydrogen.
54. compound according to claim 1, wherein L 1Be a key and R aIt is also [7] wheel thiazolinyl of dihydro indenyl, tetralyl, dihydro-acenaphthylene base, naphthyl, tetrahydrochysene-benzo [7] wheel thiazolinyl, quinolyl, isoquinolyl, benzimidazolyl-, benzothiazolyl, benzoxazolyl, phenanthryl or tetrahydrochysene-biphenyl.
55. according to the described compound of claim 39, wherein R bBe the phenyl that replaces with 1 to 3 substituting group, wherein each substituting group be independently-NRR ' or-C (O) OR.
56. according to the described compound of claim 55, wherein R bBe the phenyl that replaces with 1 to 3 substituting group, each substituting group is independently-NRR ' or-C (O) OR; L 2It is a key; And R cBe hydrogen.
57. according to the described compound of claim 54, wherein L 2Be a key or-NR x-SO 2-, R xBe hydrogen or-SO 2-alkyl; And R cBe hydrogen, alkyl, Heterocyclylalkyl, heteroaryl, Heterocyclylalkyl-alkyl or heteroaralkyl.
58. according to the described compound of claim 54, wherein R cBe hydrogen, alkyl, Heterocyclylalkyl, heteroaryl, Heterocyclylalkyl-alkyl or heteroaralkyl.
59. according to the described compound of claim 58, wherein R 1Be hydrogen.
60. according to the described compound of claim 59, R bBe usefulness-NRR ' or-phenyl that C (O) OR replaces arbitrarily; L 2Be a key or-NR x-SO 2-, R wherein xBe hydrogen or-SO 2-alkyl; And R cBe tetrazyl, morpholino or piperazinyl.
61. compound according to claim 1, wherein R 2Be 2,3-dihydro-1H-indenes-1-base, (S)-2,3-dihydro-1H-indenes-1-base, (R)-2,3-dihydro-1H-indenes-1-base, 1,2-acenaphthene-1-base, (R)-1,2-acenaphthene-1-base, (S)-1,2-acenaphthene-1-base, phenanthrene-1-base or phenanthrene-4-base.
62. compound according to claim 1, R wherein 3Be 4-(1H-tetrazolium-5-yl) phenyl, 3-hydroxyl-4-p-methoxy-phenyl, 4-(4-methylpiperazine-1-yl) phenyl), 4-(piperazine-1-yl) phenyl, 4-aminophenyl, 4 benzoic acid, 4-morpholino phenyl, 4-(N, N-dimethyl methyl acid amides) phenyl or 4-(amsacrine) phenyl.
63. compound according to claim 1, wherein said compound is
N-(methylsulfonyl)-N-(4-(1-(naphthalene-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-methyl-N-(4-(1-(naphthalene-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-methyl-N-(4-(1-(naphthalene-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
1-(methylsulfonyl)-N-(4-(1-(naphthalene-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N 1-(1-(naphthalene-2-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-yl) benzene-1, the 4-diamines,
Ethyl-2-(4-(1-(naphthalene-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl amino)-2-fluoroacetic acid,
N-(4-(1-(naphthalene-2-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
3,3,3-three fluoro-N-(4-(1-(naphthalene-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) propane-1-sulphonamide,
Methyl-4-(1-(naphthalene-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenylcarbamate,
N-(3, the 4-Dimethoxyphenyl)-1-(naphthalene-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-(4-methylpiperazine-1-yl) phenyl)-1-(naphthalene-2-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
Ethyl-2-hydroxyl-4-(1-(naphthalene-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenylcarbamate,
N-(4-(1H-1,2,4-triazol-1-yl) phenyl)-1-(naphthalene-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
First 3-(4-(1-(naphthalene-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base amino) phenyl amino)-3-contain the oxygen propionic ester,
N 1-(1-(naphthalene-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-yl) benzene-1, the 4-diamines,
N-(4-(4-methylpiperazine-1-yl) phenyl)-1-(naphthalene-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-fluoro-3-p-methoxy-phenyl)-1-(naphthalene-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-ethoxyl phenenyl)-1-(naphthalene-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
(S)-1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-(4-methylpiperazine-1-yl) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
(S)-4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenylformic acid,
(S)-N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine,
(S)-N 1-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-yl) benzene-1, the 4-diamines,
(S)-1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-morpholino phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
(S)-1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-(4-(sulfonyl propyl) piperazine-1-yl) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenylformic acid,
1-(2,3-dihydro-1H-indenes-1-yl)-N-(3-(piperazine-1-yl) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N 1-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-yl) benzene-1, the 4-diamines,
N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-(4-(sulfonyl propyl) piperazine-1-yl) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
(S)-1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-(4-(methylsulfonyl) piperazine-1-yl) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
(S)-1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-(piperazine-1-yl) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) benzamide,
(S)-5-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino)-2-methoxyphenol,
1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-(piperazine-1-yl) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-morpholino phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
3-(4-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) piperazine-1-yl) third-1-alcohol,
4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) benzo hydrazides,
2-(4-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) piperazine-1-yl) ethylhexoate,
1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-(4-((4-methoxyl group-3,5-lutidine-2-yl) methyl) piperazine-1-yl) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
3-(4-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) piperazine-1-yl) propyl-acetic acid ester,
2-(4-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) piperazine-1-yl) ethanol,
1-((S)-2,3-dihydro-1H-indenes-1-yl)-N-(3-(1-((R)-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base oxygen)-4-p-methoxy-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
(S)-ethyl 4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) benzoic ether,
(S)-1-(2,3-dihydro-1H-indenes-1-yl)-N-(4-morpholino phenyl)-1H-pyrazolo [3,4d] pyrimidine-6-amine,
N-(4-(1-(4-hydroxyl-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine,
(S)-N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(ethyl sulphonyl) ethane sulphonamide,
1-(6-(4-(4-methylpiperazine-1-yl) phenyl amino)-1H-pyrazolo [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-alcohol,
1-(6-(4-(N-(methylsulfonyl) methyl sulfonamido) phenyl amino)-1H-pyrazolo [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-yl benzoic acid ester,
1-(6-(4-(N-(methylsulfonyl) methyl sulfonamido) phenyl amino)-1H-pyrazolo [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-base dihydrogen phosphoric acid ester,
(S)-1-chloro-N-(chloromethane alkylsulfonyl)-N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(4-(1-(6,7-dihydro-5H-indeno [5,6-d] [1,3] dioxole-5-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine,
N-(1-(6-(4-(N-(methylsulfonyl) methyl sulfonamido) phenyl amino)-1H-pyrazolo [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-5-yl) ethanamide,
N-(4-(1-(4-hydroxyl-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
1-(6-(4-(N-(methylsulfonyl) methyl sulfonamido) phenyl amino)-1H-pyrazolo [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-5-yl benzoic acid ester,
(S, Z)-4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino)-N '-hydroxy benzo Orazamide,
1-(6-(4-(4-methylpiperazine-1-yl) phenyl amino)-1H-pyrazolo [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-yl benzoic acid ester,
1-(6-(4-aminophenyl amino)-1H-pyrazolo [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-alcohol,
1-(6-(4-aminophenyl amino)-1H-pyrazolo [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-yl benzoic acid ester,
Di-t-butyl 1-(6-(4-(N-(methylsulfonyl) methyl sulfonamido) phenyl amino)-1H-pyrazolo [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-4-base phosphoric acid ester,
(S)-4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino)-N-(methylsulfonyl) benzamide,
N-(4-(1-(5-((2-methoxy ethoxy) methoxyl group)-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine,
N-(1-(6-(4-aminophenyl amino)-1H-pyrazolo [3,4-d] pyrimidine-1-yl)-2,3-dihydro-1H-indenes-5-yl) ethanamide,
(S)-4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) benzonitrile,
(S)-N-(4-(1H-tetrazolium-5-yl) phenyl)-1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N1-(1-(5-methoxyl group-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-yl) benzene-1, the 4-diamines,
N-(4-(1-(5-methoxyl group-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine,
1-(2,3-dihydro-1H-indenes-2-yl)-N-(4-morpholino phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-(1-(1H-indoles-4-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine,
N-(4-(1-(1H-indoles-6-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine,
N-(4-(1-(1H-indoles-5-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine,
1-(1H-indoles-4-yl)-N-(4-(4-methylpiperazine-1-yl) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-(1-(1-Methyl-1H-indole-5-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine,
1-(7-Methyl-1H-indole-4-yl)-N-(4-(4-methylpiperazine-1-yl) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
Tertiary butyl 7-methyl-4-(6-(4-(4-methylpiperazine-1-yl) phenyl amino)-1H-pyrazolo [3,4-d] pyrimidine-1-yl)-1H-indoles-1-carboxylicesters,
Tertiary butyl 4-(6-(4-(4-methylpiperazine-1-yl) phenyl amino)-1H-pyrazolo [3,4-d] pyrimidine-1-yl)-1H-indoles e-1-carboxylicesters,
1-(1,2-acenaphthene-1-yl)-N-(4-(4-methylpiperazine-1-yl) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-(1-(1,2-acenaphthene-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine,
N 1-(1-(1,2-acenaphthene-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-yl) benzene-1, the 4-diamines,
1-(1,2-acenaphthene-1-yl)-N-(4-morpholino phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
4-(1-(1,2-acenaphthene-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) benzonitrile,
1-(1,2-acenaphthene-1-yl)-N-(4-(2-(trimethylammonium stannyl)-2H-tetrazolium-5-yl) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
1-(1,2-acenaphthene-1-yl)-N-(4-(piperazine-1-yl) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-morpholino phenyl)-1-(naphthalene-1-ylmethyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine or
N-(4-morpholino phenyl)-1-(naphthalene-1-ylmethyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine.
64. compound according to claim 1, wherein said compound is
N-(4-(1H-tetrazolium-5-yl) phenyl)-1-((S)-(2,3-dihydro-1H-indenes-1-yl))-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-(1H-tetrazolium-5-yl) phenyl)-1-((R)-(2,3-dihydro-1H-indenes-1-yl))-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-(1H-tetrazolium-5-yl) phenyl)-1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-(1H-tetrazolium-5-yl) phenyl)-1-((S)-(1,2-dihydro-acenaphthylene base-1-yl))-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-(1H-tetrazolium-5-yl) phenyl)-1-((R)-(1,2-dihydro-acenaphthylene base-1-yl))-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-(1H-tetrazolium-5-yl) phenyl)-1-(1,2-dihydro-acenaphthylene base-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-(1H-tetrazolium-5-yl) phenyl)-1-(1-naphthyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-(1H-tetrazolium-5-yl) phenyl)-1-(phenanthrene-4-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-morpholino phenyl)-1-((S)-(2,3-dihydro-1H-indenes-1-yl))-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-morpholino phenyl)-1-((R)-(2,3-dihydro-1H-indenes-1-yl))-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-morpholino phenyl)-1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-morpholino phenyl)-1-((S)-(1,2-dihydro-acenaphthylene base-1-yl))-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-morpholino phenyl)-1-((R)-(1,2-dihydro-acenaphthylene base-1-yl))-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-morpholino phenyl)-1-(1,2-dihydro-acenaphthylene base-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-morpholino phenyl)-1-(1-naphthyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-morpholino phenyl)-1-(phenanthrene-4-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-(piperazine-1-yl) phenyl)-1-((S)-(2,3-dihydro-1H-indenes-1-yl))-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-(piperazine-1-yl) phenyl)-1-((R)-(2,3-dihydro-1H-indenes-1-yl))-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-(piperazine-1-yl) phenyl)-1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-(piperazine-1-yl) phenyl)-1-((S)-(1,2-dihydro-acenaphthylene base-1-yl))-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-(piperazine-1-yl) phenyl)-1-((R)-(1,2-dihydro-acenaphthylene base-1-yl))-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-(piperazine-1-yl) phenyl)-1-(1,2-dihydro-acenaphthylene base-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-(piperazine-1-yl) phenyl)-1-(1-naphthyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-(piperazine-1-yl) phenyl)-1-(phenanthrene-4-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
(S)-4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenylformic acid,
(R)-4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenylformic acid,
4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenylformic acid,
(S)-4-(1-(1,2-dihydro-acenaphthylene base-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenylformic acid,
(R)-4-(1-(1,2-dihydro-acenaphthylene base-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenylformic acid,
4-(1-(1,2-dihydro-acenaphthylene base-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenylformic acid,
4-(1-(1-naphthyl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenylformic acid,
4-(1-(phenanthrene-4-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenylformic acid,
N-(4-aminophenyl)-1-((S)-(2,3-dihydro-1H-indenes-1-yl))-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-aminophenyl)-1-((R)-(2,3-dihydro-1H-indenes-1-yl))-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-aminophenyl)-1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-aminophenyl)-1-((S)-(1,2-dihydro-acenaphthylene base-1-yl))-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-aminophenyl)-1-((R)-(1,2-dihydro-acenaphthylene base-1-yl))-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-aminophenyl)-1-(1,2-dihydro-acenaphthylene base-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-aminophenyl)-1-(1-naphthyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-aminophenyl)-1-(phenanthrene-4-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
(S)-N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine,
(R)-N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine,
N-(methylsulfonyl)-N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
(S)-N-(4-(1-(1,2-dihydro-acenaphthylene base-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine,
(R)-N-(4-(1-(1,2-dihydro-acenaphthylene base-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine,
N-(4-(1-(1,2-dihydro-acenaphthylene base-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine,
N-(4-(1-(1-naphthyl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine,
N-(4-(1-(phenanthrene-4-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine,
(S)-N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
(R)-N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(4-(1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
(S)-N-(4-(1-(1,2-dihydro-acenaphthylene base-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
(R)-N-(4-(1-(1,2-dihydro-acenaphthylene base-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(4-(1-(1,2-dihydro-acenaphthylene base-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(4-(1-(1-naphthyl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(4-(1-(phenanthrene-4-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-4-(4-methylpiperazine-1-yl) phenyl-1-(S)-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-4-(4-methylpiperazine-1-yl) phenyl-1-(R)-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-4-(4-methylpiperazine-1-yl) phenyl-1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-4-(4-methylpiperazine-1-yl) phenyl-1-(S)-(1,2-dihydro-acenaphthylene base-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-4-(4-methylpiperazine-1-yl) phenyl-1-(R)-(1,2-dihydro-acenaphthylene base-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-4-(4-methylpiperazine-1-yl) phenyl-1-(1,2-dihydro-acenaphthylene base-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-4-(4-methylpiperazine-1-yl) phenyl-1-(1-naphthyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-(1-(phenanthrene-4-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(3-hydroxyl-4-p-methoxy-phenyl)-1-((S)-(2,3-dihydro-1H-indenes-1-yl))-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(3-hydroxyl-4-p-methoxy-phenyl)-1-((R)-(2,3-dihydro-1H-indenes-1-yl))-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(3-hydroxyl-4-p-methoxy-phenyl)-1-(2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(3-hydroxyl-4-p-methoxy-phenyl)-1-((S)-(1,2-dihydro-acenaphthylene base-1-yl))-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(3-hydroxyl-4-p-methoxy-phenyl)-1-((R)-(1,2-dihydro-acenaphthylene base-1-yl))-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(3-hydroxyl-4-p-methoxy-phenyl)-1-(1,2-dihydro-acenaphthylene base-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(3-hydroxyl-4-p-methoxy-phenyl)-1-(1-naphthyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(3-hydroxyl-4-p-methoxy-phenyl)-1-(phenanthrene-4-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-(1-(4-(benzyloxy)-5,6,7,8-naphthane-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine,
1-(4-(benzyloxy)-5,6,7,8-naphthane-1-yl)-N-(4-(4-methylpiperazine-1-yl) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N1-(1-(4-(benzyloxy)-5,6,7,8-naphthane-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-yl) benzene-1, the 4-diamines,
N-(4-morpholino phenyl)-1-(1,2,3,4-naphthane-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
4-(6-(4-aminophenyl amino)-1H-pyrazolo [3,4-d] pyrimidine-1-yl)-5,6,7,8-naphthane-1-alcohol,
Tertiary butyl 4-(1-(4-(benzyloxy)-5,6,7,8-naphthane-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) piperidines-1-carboxylicesters,
4-(6-(4-(N-(methylsulfonyl) methyl sulfonamido) phenyl amino)-1H-pyrazolo [3,4-d] pyrimidine-1-yl)-5,6,7,8-naphthane-1-methylmethane sulphonate,
4-(6-(4-(methyl sulfonamido) phenyl amino)-1H-pyrazolo [3,4-d] pyrimidine-1-yl)-5,6,7,8-naphthane-1-methylmethane sulphonate,
N-(4-(1-(4-(benzyloxy)-5,6,7,8-naphthane-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(4-(1-(4-hydroxyl-5,6,7,8-naphthane-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine,
N-(4-(1-(4-hydroxyl-5,6,7,8-naphthane-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
4-(6-(4-(4-methylpiperazine-1-yl) phenyl amino)-1H-pyrazolo [3,4-d] pyrimidine-1-yl)-5,6,7,8-naphthane-1-alcohol,
1-(4-(benzyloxy)-5,6,7,8-naphthane-1-yl)-N-(4-morpholino phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
4-(6-(4-morpholino phenyl amino)-1H-pyrazolo [3,4-d] pyrimidine-1-yl)-5,6,7,8-naphthane-1-alcohol,
1-((6-fluoro-4H-benzo [d] [1,3] dioxin-8-yl) methyl)-N-(4-morpholino phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
1-butyl-N-(4-(piperidines-1-yl) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
Ethyl 2-(6-(4-(piperidines-1-yl) phenyl amino)-1H-pyrazolo [3,4-d] pyrimidine-1-yl) acetic ester,
1-methyl-N-(4-(piperidines-1-yl) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
1-sec.-propyl-N-(4-(piperidines-1-yl) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-amine,
N-(4-(1-(3-aminopropyl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine,
N-(methylsulfonyl)-N-(4-(1-propyl group-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(4-(1-butyl-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine,
N-(4-(1-(4-hydroxybutyl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine,
4-(6-(4-(N-(methylsulfonyl) methyl sulfonamido) phenyl amino)-1H-pyrazolo [3,4-d] pyrimidine-1-yl) butylacetic acid ester,
N-(4-(1-ethyl-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine,
N-(4-(1-sec.-propyl-1H-pyrazolo [3,4-d] pyrimidine-6-base amino) phenyl)-N-(methylsulfonyl) amsacrine or
N-(4-(1-methyl isophthalic acid H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(methylsulfonyl) amsacrine.
65. compound according to claim 1, wherein said compound is
N-(5-(1-(4-hydroxyl-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) pyridine-2-yl) amsacrine,
N-(2, the 3-dihydroxypropyl)-N-(5-(1-(4-hydroxyl-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) pyridine-2-yl) amsacrine,
N-(2, the 3-dihydroxypropyl)-N-(4-(1-(4-hydroxyl-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(5-(1-(4-hydroxyl-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) pyridine-2-yl)-N-(2-morpholino ethyl) amsacrine,
N-(4-(1-(4-hydroxyl-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(2-morpholino ethyl) amsacrine,
N-(4-(1-(4-hydroxyl-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(3-hydroxypropyl) amsacrine,
N-(4-(1-(4-hydroxyl-2,3-dihydro-1H-indenes-1-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(2-hydroxyethyl) amsacrine,
N-(4-(1-(1-hydroxyl-6,7-dihydro-5H-cyclopenta [c] pyridine-5-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(4-(1-(1-hydroxyl-6,7-dihydro-5H-cyclopenta [c] pyridine-5-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(2-hydroxyethyl) amsacrine,
N-(4-(1-(1-hydroxyl-6,7-dihydro-5H-cyclopenta [c] pyridine-5-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(2-morpholino ethyl) amsacrine,
N-(4-(1-(4-hydroxyl-6,7-dihydro-5H-cyclopenta [c] pyridine-7-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(4-(1-(4-hydroxyl-6,7-dihydro-5H-cyclopenta [c] pyridine-7-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(2-hydroxyethyl) amsacrine,
N-(4-(1-(4-hydroxyl-6,7-dihydro-5H-cyclopenta [c] pyridine-7-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(2-morpholino ethyl) amsacrine,
N-(2, the 3-dihydroxypropyl)-N-(4-(1-(1-hydroxyl-6,7-dihydro-5H-cyclopenta [c] pyridine-5-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(2, the 3-dihydroxypropyl)-N-(4-(1-(4-hydroxyl-6,7-dihydro-5H-cyclopenta [c] pyridine-7-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(4-(1-(4-hydroxyl-6,7-dihydro-5H-cyclopenta [b] pyridine-7-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine,
N-(4-(1-(4-hydroxyl-6,7-dihydro-5H-cyclopenta [b] pyridine-7-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl)-N-(2-morpholino ethyl) amsacrine,
N-(4-(1-(4-hydroxyl-6,7-dihydro-5H-cyclopenta [b] pyridine-7-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base amino) phenyl)-N-(2-hydroxyethyl) amsacrine or
N-(2, the 3-dihydroxypropyl)-N-(4-(1-(4-hydroxyl-6,7-dihydro-5H-cyclopenta [b] pyridine-7-yl)-1H-pyrazolo [3,4-d] pyrimidine-6-base is amino) phenyl) amsacrine.
66. pharmaceutical composition, it comprises compound and carrier in any one of the claim 1 to 66.
67. the method that the treatment protein kinase is regulated disease object, it comprises the significant quantity of using the compound in any one of the claim 1 to 65 to described object.
68. the method for protein kinase in the inhibition cell, it comprises with compound and described cells contacting in any one of the claim 1 to 65.
69. according to the described method of claim 68, wherein said protein kinase is one or more protein kinases that relate in cell mitogen.
70. according to the described method of claim 68, wherein said protein kinase is aurora kinase, cell cycle protein dependent kinase or polo-sample kinases.
71. treatment tumour or method for cancer in object, it comprises to object uses compound in any one of the claim 1 to 65 of its needs.
72. according to the described method of claim 71, wherein said tumour is osteocarcinoma, brain and cns tumor, breast cancer, breast cancer, colorectal cancer, internal secretion cancer, gastrointestinal cancer, apparatus urogenitalis cancer, gynecological cancer, incidence cancer, leukemia, lung cancer, lymphatic cancer, cancer eye, skin carcinoma, soft tissue sarcoma, urinary system cancer and other type or relative disease.
CN200880005962A 2007-01-30 2008-01-30 The 1-H-pyrazolo (3,4b) pyrimidine derivatives and as the purposes of mitotic kinase conditioning agent Pending CN101616921A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102746307A (en) * 2012-07-09 2012-10-24 四川大学 1-N-benzyl allopurinol derivative as well as preparation method and application thereof
CN114008051A (en) * 2019-06-18 2022-02-01 豪夫迈·罗氏有限公司 Pyrazolopyrimidine sulfone inhibitors of JAK kinases and uses thereof
WO2022247641A1 (en) * 2021-05-28 2022-12-01 江苏天士力帝益药业有限公司 Wee1 inhibitor and use thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102746307A (en) * 2012-07-09 2012-10-24 四川大学 1-N-benzyl allopurinol derivative as well as preparation method and application thereof
CN102746307B (en) * 2012-07-09 2013-07-31 四川大学 1-N-benzyl allopurinol derivative as well as preparation method and application thereof
CN114008051A (en) * 2019-06-18 2022-02-01 豪夫迈·罗氏有限公司 Pyrazolopyrimidine sulfone inhibitors of JAK kinases and uses thereof
WO2022247641A1 (en) * 2021-05-28 2022-12-01 江苏天士力帝益药业有限公司 Wee1 inhibitor and use thereof

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