CN101573365A - Compounds useful as protein kinase inhibitors - Google Patents

Abstract

The present invention relates to compounds useful as inhibitors of protein kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

Description

The compound that can be used as kinases inhibitor

Cross reference

[001] preference of the U. S. application submitted to number on October 31st, 60/859,113 and 2007 of the application's U. S. application of requiring to submit on November 15th, 2006 number 60/984,149.

TECHNICAL FIELD OF THE INVENTION

[002] the present invention relates to can be used as the compound of kinases inhibitor.The present invention also provides the pharmaceutically acceptable composition that comprises The compounds of this invention and use these method for compositions in the treatment of various illness.The present invention also provides the process of preparation The compounds of this invention.

Background of invention

[003] in recent years, understand the enzyme relevant and the structure of other biological molecule better, go far towards to seek new therapeutical agent with disease.The important enzyme of a class that has become the theme of broad research is a protein kinase.

[004] protein kinase constitutes structurally involved enzyme of extended familys, they be responsible for controlling intracellular multiple signal transduction process (referring to Hardie, G and Hanks, S.The ProteinKinase Facts Book, I and II, Academic Press, San Diego, CA:1995).Protein kinase is considered to evolve from the common ancestral gene, and reason is to have preserved their structure and catalysis.Nearly all kinases all contains similar 250-300 amino acid catalytic structure function territory.Kinases can be divided into some families (for example protein-tyrosine, protein-serine/threonine, lipid etc.) according to the substrate of their phosphorylations.Differentiated generally sequence motifs corresponding to every kind of kinases family (for example referring to Hanks, S.K., Hunter, T., FASEB J.1995,9,576-596; People such as Knighton, Science 1991,253,407-414; People such as Hiles, Cell 1992,70,419-429; People such as Kunz, Cell 1993,73,585-596; People such as Garcia-Bustos, EMBO J 1994,13,2352-2361).

[005] generally speaking, protein kinase is transferred to the protein receptor that participates in the signal pipeline and signal transmission in the mediated cell by influencing phosphoryl from nucleoside triphosphate.These phosphorylation events serve as molecular switch, can regulate and control or regulate the biological function of target protein.These phosphorylation events finally are in response to the various kinds of cell external stimulus and other stimulations are excited.The example that this class stimulates comprises environment and chemical stress reaction signal (for example osmotic shock, heat shock, uv-radiation, bacterial endotoxin and H ₂O ₂), cytokine (for example il-1 (IL-1) and tumor necrosis factor alpha (TNF-α)) and somatomedin (for example rHuGM-CSF (GM-CSF) and fibroblast growth factor (FGF)).Extracellular stimulus can influence one or more cell responses, relates to cell growth, migration, differentiation, hormone secretion, transcription factor activation, Muscle contraction, carbohydrate metabolism, protein synthesis control, survival and Cycle Regulation.

[006] a lot of diseases are replied relevant with the abnormal cells that is excited by above-mentioned protein kinase mediated incident.These diseases include but not limited to cancer, autoimmune disease, inflammatory diseases, osteopathia, metabolic trouble, neural and neurodegenerative disease, cardiovascular disorder, transformation reactions and asthma, Alzheimer and hormone relative disease.Therefore, medical chemistry circle strives to find as therapeutical agent effective protein proteins kinase inhibitor always.

[007] Polo sample kinases (PLK) belongs to serine/threonine kinase family, they between the different genera from the yeast to the mankind be high conservative (referring to people such as Lowery DM, Oncogene 2005,24,248-259).The PLK kinases is played the part of multiple player in the cell cycle, comprise the control that enters mitotic division and make progress by mitotic division.

[008] PLK1 obtains the member that fullest is differentiated in the PLK family.PLK1 is expressed widely, and is the abundantest in the high tissue of mitotic index.The protein level of PLK1 in mitotic division, rise and reach peak value (Hamanaka, people such as R, J Biol.Chem., 1995,270,21086-21091).The PLK1 substrate of being reported is the molecule that all known adjustings enter mitotic division and make progress by mitotic division, comprises CDC25C, cell periodic protein B, p53, APC, BRCA2 and proteasome.PLK1 in multiple cancer types by incremental adjustments, expression level relevant with severity of disease (Macmillan, people such as J.C., Ann.Surg.Oncol., 2001,8,729-740).PLK1 is a kind of oncogene, can transform the NIH-3T3 cell (Smith, people such as M.R., Biochem.Biophys.Res.Commun.1997,234,397-405).PLK1 lacks or suppresses or understand to the dominance female member of cell transfecting PLK1 propagation and vigor (Guan, people such as R, Cancer Res., 2005,65, the 2698-2704 of external minimizing tumour cell because of siRNA (antibody of antisense, micro-injection); Liu, people such as X, Proc Natl.Acad.Sci.USA, 2003,100,5789-5794, Fan, people such as Y, World J Gastroenterol., 2005,11,4596-4599; Lane, people such as HA, J.Cell Biol., 1996,135,1701-1713).The tumour cell of disappearance PLK1 have the spindle body check point that is activated and spindle body generates, karyomit(e) is arranged with separate with division of cytoplasm on defective.The vigor forfeiture it is reported it is apoptosis inductive result.On the contrary, normal cell it is reported and keep vigor after the disappearance of PLK1.PLK1 is knocked down by siRNA or the use meeting of dominance female member causes that in heteroplastic transplantation model growth of tumor suppresses or disappears in the body.

[009] PLK2 is mainly expressed in the G1 phase of cell cycle, is positioned the centrosome in the interkinesis cell.The mice develop that PLK2 rejects is normal, can give birth to, and has normal survival rate, but littler by about 20% than wild-type mice.From the cell of rejecting animal by the cell cycle progress than normal mouse more slowly (Ma, people such as S, Mol.Cell Biol., 2003,23,6936-6943).PLK2 is because of siRNA disappearance or can block centriole to the mutant that cell transfecting does not have a kinase activity and duplicate.The decrement of PLK2 is regulated and is also made tumour cell be sensitive to taxol, the catastrophe of promoting mitosis, this inhibition of on the part degree, replying by p53 (people such as Burns TF, Mol Cell Biol.2003,23,5556-5571).

[010] PLK3 is expressed in cell cycle whole process, is increased to mitotic division from G1.Be expressed in height proliferative ovarian tumor and the mammary cancer by incremental adjustments, with prognosis relatively poor relevant (Weichert, people such as W, Br.J.Cancer, 2004,90,815-821; Weichert, people such as W, Virchows Arch., 2005,446,442-450).Except mitotic adjusting, PLK3 is believed that the golgi body fragmentation and the DNA-infringement that participate in during the cell cycle reply.PLK3 it is reported by the negative expression inhibiting of dominance and promotes p53-independence apoptosis after the DNA infringement, suppress tumour cell form colony (Li, people such as Z, J.Biol.Chem., 2005,280,16843-16850).

[011] PLK4 structurally more is different from other PLK family members.This kinase whose disappearance cause cancer cells apoptosis (Li, people such as J, Neoplasia., 2005,7,312-323).The mouse that PLK4 rejects stops at E7.5, and most of cell is in the mitotic division, karyomit(e) isolated by part (Hudson, people such as JW, Current Biology 2001,11,441-446).

[012] molecule of protein kinase family implication in growth, propagation and the survival of tumour cell.Therefore, press for the compound that exploitation can be used as kinases inhibitor.There is conclusive evidence to show that the PLK kinases is that cytodifferentiation is necessary.Cell-cycle arrest is through the inhibition tumor cell proliferation of clinical verification and the means of vigor.Therefore, need exploitation to can be used as the compound of PLK family protein kinases (for example PLK1, PLK2, PLK3 and PLK4) inhibitor, they will suppress propagation, reduce tumor cell activity, particularly have the intensive medical need for the new cancer therapy of exploitation.

Summary of the invention

[013] The compounds of this invention can be used as kinases inhibitor.In some embodiment, these compounds are effective as the inhibitor of PLK protein kinase, and are the inhibitor of PLK1 protein kinase in some embodiment.These compounds as defined herein.

[014] these compounds and its pharmacy acceptable salt can be used for treatment or prevent multiple disease, illness or illness, include but not limited to the disease of autoimmunization, inflammatory, propagation or hyperproliferation disease, neurodegenerative disease or immunity-mediation.Study by the kinases that compound provided by the invention (and suitable salt) also can be used in biological and the pathological phenomenon; Research by the intracellular signal transduction approach of this class kinases-mediation; Comparative evaluation with new kinase inhibitor.

The invention detailed content

[015] the present invention describes formula (I), formula (II) and formula (III) compound as herein defined.

[016] The compounds of this invention comprises those of general description above, and kind disclosed herein, group and kind can further be set forth.As used herein, unless otherwise indicated should be suitable for following definition.For purposes of the present invention, chemical element will be identified for the 75th edition according to periodic table of elements CAS version Handbook of Chemistry and Physics.In addition, vitochemical General Principle is described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito:1999 and Advanced OrganicChemistry, the 5th edition, Ed.:Smith, M.B. and March, J., John Wiley ﹠amp; Sons, among the New York:2001, its complete content is quoted at this as a reference.

[017] as described herein, specified atomic quantity scope comprises arbitrary integer wherein.For example, the group with 1-4 atom may have 1,2,3 or 4 atom.

[018] as described herein, The compounds of this invention can be replaced by one or more substituting groups alternatively, and for example above-outlined is set forth, perhaps as specific big class of the present invention, group and kind institute illustration.To be figured out, wording " optional substituted " is used interchangeably with wording " replacement or unsubstituted ".Generally speaking, no matter the front has or not term " optional " to term " replacement ", represents that all rolling into a ball designated substituent atomic group to the hydrogen atom in the fixed structure replaces.Unless indication is arranged in addition, optional substituted group can have substituting group on each commutable position of this group, if substituting group that can be selected from designated groups more than one for arbitrarily in the fixed structure an above position replaces, then substituting group can be identical or different on each position.Those of the stable or chemically feasible compound of substituting group combination preferably can formation that the present invention paid close attention to.

[019] term used herein " stablize " be illustrated in be subjected to being used for their preparations, detect, preferably reclaim, the condition of purifying and constant basically compound when being used for one or more purposes disclosed herein.In some embodiment, stable compound or chemically feasible compound be do not have moisture or other chemical reactivity conditions in the presence of, under 40 ℃ or following temperature, keep at least one week and the compound that do not change basically.

[020] replacement or the unsubstituted hydrocarbon chain of term used herein " aliphatic group " or " aliphatic group " expression straight chain (promptly not branch) or side chain, it is saturated fully or contains one or more unsaturated units that it has the single point that is connected with the molecule rest part.Unless otherwise specified, aliphatic group contains 1-20 aliphatic carbon atom.In some embodiment, aliphatic group contains 1-10 aliphatic carbon atom.In other embodiments, aliphatic group contains 1-8 aliphatic carbon atom.In other embodiments, aliphatic group contains 1-6 aliphatic carbon atom, and in other embodiments, aliphatic group contains 1-4 aliphatic carbon atom.The aliphatic group that is fit to includes but not limited to replacement or unsubstituted alkyl, alkenyl or the alkynyl of straight or branched.Specific examples includes but not limited to methyl, ethyl, sec.-propyl, n-propyl, sec-butyl, vinyl, n-butene base, ethynyl and the tertiary butyl.

[021] term " cyclic aliphatic base " expression monocycle C _3-8Hydrocarbon or two ring C _8-12Hydrocarbon, it is fully saturated or contains one or more unsaturated units, but aromatics whether has the single point that is connected with the molecule rest part, wherein said bicyclic ring be in any discrete ring have 3-7 member.The cycloaliphatic groups that is fit to includes but not limited to cycloalkyl and cycloalkenyl group.Specific examples includes but not limited to cyclohexyl, cyclopropenyl radical and cyclobutyl.

[022] term used herein " assorted aliphatic group " expression aliphatic group, one of them or two carbon atoms are replaced by one or more oxygen, sulphur, nitrogen, phosphorus or silicon independently.Heterolipid family group can be to replace or unsubstituted, branch or ramose not, and ring-type or acyclic comprises " heterocycle ", " heterocyclic radical ", " heterocycle aliphatic series " or " heterocyclic " group.

[023] the monocyclic, bicyclic or tricyclic ring system of the non-aromatics of expression such as term used herein " heterocycle ", " heterocyclic radical " or " heterocyclic ", wherein one or more ring memberses are independent heteroatomss of selecting.In some embodiment, " heterocycle ", " heterocyclic radical " or " heterocyclic " group have three to 14 ring memberses, and wherein one or more ring memberses are the heteroatomss that independently are selected from oxygen, sulphur, nitrogen or phosphorus, and each ring contains 3 to 7 ring memberses in the system.

[024] heterocycle of Shi Heing includes but not limited to 3-1H-benzimidazolyl-2 radicals-ketone, 3-(1-alkyl)-benzimidazolyl-2 radicals-ketone, the 2-tetrahydrofuran base, the 3-tetrahydrofuran base, the 2-tetrahydro-thienyl, the 3-tetrahydro-thienyl, 2-morpholino base, 3-morpholino base, 4-morpholino base, the 2-parathiazan is for base, the 3-parathiazan is for base, the 4-parathiazan is for base, the 1-pyrrolidyl, the 2-pyrrolidyl, the 3-pyrrolidyl, 1-tetrahydrochysene piperazinyl, 2-tetrahydrochysene piperazinyl, 3-tetrahydrochysene piperazinyl, piperidino, the 2-piperidyl, the 3-piperidyl, the 1-pyrazolinyl, the 3-pyrazolinyl, the 4-pyrazolinyl, the 5-pyrazolinyl, piperidino, the 2-piperidyl, the 3-piperidyl, the 4-piperidyl, the 2-thiazolidyl, the 3-thiazolidyl, the 4-thiazolidyl, the 1-imidazolidyl, the 2-imidazolidyl, the 4-imidazolidyl, the 5-imidazolidyl, indolinyl, tetrahydric quinoline group, tetrahydro isoquinolyl, the benzo thiacyclopentane, benzo dithiane and 1,3-dihydro-imidazol--2-ketone.

[025] cyclic group (for example cyclic aliphatic base and heterocycle) can be linear condensed, bridging or volution.

[026] one or more oxygen, sulphur, nitrogen, phosphorus or silicon (any oxidised form that comprises nitrogen, sulphur, phosphorus or silicon represented in term " heteroatoms "; Basic nitrogen or heterocycle can replace the quaternized form of nitrogen, for example N (as 3, in the 4-dihydro-2 h-pyrrole base), NH (as in pyrrolidyl) or NR arbitrarily ⁺(in the pyrrolidyl that replaces at N-)).

[027] term used herein " undersaturated " means that this part has one or more unsaturated units.

[028] the saturated or undersaturated ring of part described in term used herein " non-aromatics ".

[029] saturated ring fully described in term used herein " aromatics ".

[030] term used herein " alkoxyl group " or " alkylthio " expression is connected with the main body carbochain by oxygen (" alkoxyl group ") or sulphur (" alkylthio ") atom as the defined alkyl of preamble.

[031] term " haloalkyl ", " halogenated alkenyl " and " halogenated alkoxy " expression are depended on the circumstances by alkyl, alkenyl or alkoxyl group that one or more halogen atoms replace.Term " halogen ", " halogeno-group " and " hal " expression F, Cl, Br or I.

[032] has monocycle, two rings and the three ring ring systems that amount to five to 14 ring memberses separately or as term " aryl " expression that the part of more most of " aralkyl ", " aralkoxy " or " aryloxy alkyl " is used, wherein at least one ring is an aromatics in this system, and wherein in this system each ring contain 3 to 7 ring memberses.Term " aryl " can exchange with term " aryl rings " and use.Term " aryl " also is expressed as follows the heteroaryl ring system of definition.

[033] has monocycle, two rings and the three ring ring systems that amount to five to 14 ring memberses separately or as term " heteroaryl " expression that the part of more most of " heteroaralkyl " or " heteroaryl alkoxyl group " is used, wherein at least one ring is an aromatics in this system, at least one ring contains one or more heteroatomss in this system, and wherein in this system each ring contain 3 to 7 ring memberses.Term " heteroaryl " can exchange with term " heteroaryl ring " or term " heteroaromatic base " and use.The heteroaryl ring that is fit to includes but not limited to the 2-furyl, the 3-furyl, the TMSIM N imidazole base, the 2-imidazolyl, the 4-imidazolyl, the 5-imidazolyl, benzimidazolyl-, the 3-isoxazolyl, the 4-isoxazolyl, the 5-isoxazolyl, the 2-oxazolyl, the 4-oxazolyl, the 5-oxazolyl, the N-pyrryl, the 2-pyrryl, the 3-pyrryl, the 2-pyridyl, the 3-pyridyl, the 4-pyridyl, the 2-pyrimidyl, the 4-pyrimidyl, the 5-pyrimidyl, pyridazinyl (for example 3-pyridazinyl), the 2-thiazolyl, the 4-thiazolyl, the 5-thiazolyl, tetrazyl (for example 5-tetrazyl), triazolyl (for example 2-triazolyl and 5-triazolyl), the 2-thienyl, the 3-thienyl, benzofuryl, benzothienyl, indyl (for example 2-indyl), pyrazolyl (for example 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazole base, 1,2,5-oxadiazole base, 1,2,4-oxadiazole base, 1,2, the 3-triazolyl, 1,2, the 3-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, 1,2, the 5-thiadiazolyl group, purine radicals, pyrazinyl, 1,3, the 5-triazinyl, quinolyl (2-quinolyl for example, the 3-quinolyl, the 4-quinolyl) and isoquinolyl (1-isoquinolyl for example, 3-isoquinolyl or 4-isoquinolyl).

[034] term used herein " blocking group " and " protectiveness group " expression is used for temporarily sealing the composition of the one or more required reactive positions of polyfunctional compound.In some embodiments, blocking group has one or more in the following feature or all preferred: a) with good yield selective reaction, obtain protected substrate, it is stable for the reaction that occurs in one or more other reactive positions; And b) reagent place's selectivity of not attacked regenerated functional group of institute with good yield is removed.Exemplary blocking group sees Greene for details, and people such as T.W. are at Protective Groups in Organic Synthesis, the third edition, JohnWiley ﹠amp; Sons, the description in other versions of New York:1999 and this book, its complete content is quoted at this as a reference.Term used herein " nitrogen-protecting group group " expression is used for temporarily sealing the composition of the reactive position of the one or more required nitrogen of polyfunctional compound.Preferred nitrogen-protecting group is rolled into a ball also possesses above-mentioned feature, and some exemplary nitrogen-protecting group is rolled into a ball also referring to Greene, people's such as T.W. Protective Groups in Organic Synthesis, the third edition, JohnWiley ﹠amp; Sons, the 7th chapter among the New York:1999, its complete content is quoted at this as a reference.

[035] in some embodiment, alkyl or aliphatic chain can be replaced by another atom or group alternatively.The MU (methylene unit) that this means alkyl or aliphatic chain is replaced by described other atoms or group alternatively.This class atom or examples of groups will include but not limited to-NR-,-O-,-S-,-CO ₂-,-OC (O)-,-C (O) CO-,-C (O)-,-C (O) NR-,-C (=N-CN) ,-NRCO-,-NRC (O) O-,-SO ₂NR-,-NRSO ₂-,-NRC (O) NR-,-OC (O) NR-,-NRSO ₂NR-,-SO-or-SO ₂-, wherein R is as defined herein.Unless otherwise specified, optionally replace generating chemically stable compound.Optionally interruption can occur in the chain, also can occur in the end of chain; Just and/or also endways at tie point.Two optional replacements also can be adjacent one another are in chain, as long as cause chemically stable compound.Optionally interruption or replacement also can replace all carbon atoms in the chain fully.For example, C ₃Aliphatic group can be alternatively by-NR-,-C (O)-and-NR-interrupts or replaces generation-NRC (O) NR-(urea).

[036] unless otherwise specified, if replacement or interruption occur in end, replace the H of atomic linkage on end.For example, if-CH ₂CH ₂CH ₃Interrupted by-O-alternatively, the gained compound may be-OCH ₂CH ₃,-CH ₂OCH ₃Or-CH ₂CH ₂OH.

[037] unless otherwise prescribed, the structure that this paper described also means all isomeries (for example enantiomerism, diastereo-isomerism and rotamerism (or conformational isomerism)) form that comprises this structure; The for example R of each asymmetric center and S configuration are (Z) with (E) double bond isomer and (Z) and (E) conformer.Therefore, the single three-dimensional chemical isomer of these compounds and enantiomerism, diastereo-isomerism and rotamerism (or conformational isomerism) mixture all belong to scope of the present invention.

Unless otherwise prescribed, all tautomeric forms of The compounds of this invention all belong to scope of the present invention.

[038] unless otherwise prescribed, substituting group can rotate freely around any rotatable key.For example, be depicted as

Substituting group also represent

In addition, unless otherwise prescribed, the structure that this paper described also means and only comprises compound different in the existence of one or more isotopic enrichment atoms.For example, replaced or the carbon quilt by deuterium or tritium except hydrogen ¹³C-or ¹⁴The compound that has structure of the present invention beyond the carbon of C-enrichment replaces all belongs to scope of the present invention.This compounds for example can be used as analysis tool or the probe in the biological assay.

[039] use following abbreviation:

The PG blocking group

The LG leavings group

The DCM methylene dichloride

The Ac ethanoyl

The DMF dimethyl formamide

The EtOAc ethyl acetate

The DMSO dimethyl sulfoxide (DMSO)

The MeCN acetonitrile

The TCA trichoroacetic acid(TCA)

The ATP adenosine triphosphate

EtOH ethanol

The Ph phenyl

The Me methyl

The Et ethyl

The Bu butyl

The DEAD diethyl azodiformate

HEPES 4-(2-hydroxyethyl)-1-piperazine ethyl sulfonic acid

The BSA bovine serum albumin

The DTT dithiothreitol (DTT)

MOPS 4-morpholine propanesulfonic acid

The NMR nucleus magnetic resonance

The HPLC high performance liquid chromatography

The LCMS liquid chromatography-mass spectrography

The TLC thin-layer chromatography

The Rt retention time

Compound

[040] on the one hand, the invention provides formula (I) compound:

Or its pharmacy acceptable salt.

[041] in formula (I),

Ring A is

Wherein encircle A and go up each commutable carbon atom alternatively by halogeno-group, C _1-6Alkyl, cycloalkyl, aryl or heteroaryl replace, wherein each C _1-6Alkyl, cycloalkyl, aryl or heteroaryl are alternatively by 1-3 J ^AGroup replaces;

Z be S ,-NQ-or O;

Z ₁Be N;

X ¹Be O ,-NR ⁵-, S or-CR ⁵R ⁵'-;

R ¹Be

Or

Condense with ring B alternatively; Perhaps R ¹Be

And alternatively by 1-5

R ⁵Group replaces;

Y is C or N independently of one another;

Ring B is that 3-is saturated to 8-unit, part is unsaturated or aromatic monocyclic, has 1-4 heteroatoms that is selected from nitrogen, oxygen or sulphur independently of one another;

R ²And R ³Be H independently of one another, C _1-4Alkyl, C _3-6Cycloalkyl, 3-is saturated to 8-unit, part is unsaturated or aromatic monocyclic, has 0-4 heteroatoms that is selected from nitrogen, oxygen or sulphur independently of one another; Perhaps 8-is saturated to 12-unit, part is unsaturated or the aromatics dicyclo, has 0-5 heteroatoms that is selected from nitrogen, oxygen or sulphur independently of one another; And R ²And R ³Respectively alternatively by 0-5 J ²A group and 0-5 J ³Group replaces; Perhaps

R ²And R ³With the carbon atom that they connect, form 3-to the saturated or unsaturated monocycle of part of 8-unit, wherein said ring has 0-2 heteroatoms that is selected from nitrogen, oxygen or sulphur independently of one another, and described ring is alternatively by 0-5 J ²³Group replaces;

R ⁵Or R ⁵' be H, T independently of one another ¹, Q or-T ¹-Q;

T ¹Be C independently of one another _1-6Aliphatic group, wherein said C _1-6In the aliphatic group at the most three MU (methylene unit) alternatively by-NR-,-O-,-S-,-C (O)-,-C (=NR)-,-C (=NOR)-,-SO-or-SO ₂-replace; And each T ¹Alternatively by 0-2 J ^TGroup replaces;

Q is H independently of one another, C _1-6Aliphatic group, 3-have 0-4 heteroatoms that is selected from O, N or S independently of one another to 8-unit's aromatics or non-aromatic monocyclic; Perhaps 8-has 0-5 heteroatoms that is selected from O, N or S independently of one another to 12-unit's aromatics or non-aromatics dicyclo ring system; Each Q is alternatively by 0-5 J ^QGroup replaces;

J ^Q, J ^T, J ², J ³And J ²³Be selected from H independently of one another, C _3-6The cyclic aliphatic base, halo (C _1-4Aliphatic group) ,-O (halo C _1-4Aliphatic group), 3-6 unit heterocyclic radical, halogeno-group, NO ₂, CN or C _1-6Aliphatic group, wherein said C _1-6In the aliphatic group at the most three MU (methylene unit) alternatively by-NR-,-O-,-S-,-C (O)-,-C (=NR)-,-C (=NOR)-,-SO-or-SO ₂-replace;

J ^AOr R ^JBe selected from H independently of one another, halogeno-group, NO ₂, CN, C _3-6The cyclic aliphatic base, halo (C _1-4Aliphatic group) ,-O (halo C _1-4Aliphatic group), 3-is to 6-unit heterocyclic radical, and 5-has 0-4 heteroatoms that is selected from nitrogen, oxygen or sulphur independently of one another to 6-unit monocyclic aromatic ring, and 8-has 0-5 heteroatoms that is selected from nitrogen, oxygen or sulphur independently of one another to 12-unit aromatics dicyclo, or C _1-6Aliphatic group, wherein said C _1-6In the aliphatic group at the most three MU (methylene unit) alternatively by-NR-,-O-,-S-,-C (O)-,-C (=NR)-,-C (=NOR)-,-SO-or-SO ₂-replace;

R is H or the C that is unsubstituted independently of one another _1-6Alkyl;

J is halogeno-group, CN, NO independently of one another ₂, C _1-4Aliphatic group, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein each C _1-4Aliphatic group, cycloalkyl, heterocyclic radical, aryl or heteroaryl are alternatively by 1-3 R ^JGroup replaces, perhaps

Two carbon atoms that the J group connects with them, formation 3-is saturated to 8-unit, part is unsaturated or aromatic monocyclic, and wherein said ring has 1-4 heteroatoms that is selected from nitrogen, oxygen or sulphur independently of one another, and described ring is alternatively by 1-3 R ^JGroup replaces; Perhaps

J group and R ²Or R ³The carbon atom that connects them forms that 3-is saturated to 8-unit, part is unsaturated or aromatic monocyclic, and wherein said ring has the individual heteroatoms that is selected from nitrogen, oxygen or sulphur independently of one another of 1-4, and described ring is alternatively by 1-3 R ^JGroup replaces.

[042] works as R ²And R ³All be H or all be methyl, X ¹Be CH ₂, and ring A is R so ¹Be not

[043] embodiment of The compounds of this invention comprises that wherein Z is S; Perhaps encircling A is Those.

[044] in some other embodiment, R ¹Be

And alternatively by 1-5 R ⁵Group replaces.In some other embodiment, R ¹Be and ring B condensed six-ring, wherein said six-ring is And ring B is that 3-is saturated to 8-unit, part is unsaturated or aromatic monocyclic, has 1-4 heteroatoms that is selected from nitrogen, oxygen or sulphur independently of one another, and each described 6-unit's ring and ring B are alternatively by 1-5 R ⁵Group replaces.Also in some other embodiment, R ¹Heteroaryl-condensed with 5-to 6-unit

Wherein said condensed pyridine-heteroaryl ring system is alternatively by 1-5 R ⁵Group replaces.In some embodiments, R ¹Be and the pyrrole ring condensed

Wherein said condensed pyridine-pyrroles's ring system is alternatively by 1-5 R ⁵Group replaces.In some embodiments, R ¹Be Er hydrogen benzoxazine (for example, 3,4-dihydro-2H-benzo [b] [1,4] oxazine), alternatively by 1-5 R ⁵Group replaces.In some embodiments, R ¹Be

Wherein said and ring B condensed 5-unit encircles alternatively by 1-5 R ⁵Group replaces.

[045] in some embodiments, X ¹Be NR ⁵, R wherein ⁵Can be-T ¹-Q, wherein T ¹Can be C _1-4Alkyl and Q can be 5-to 6-unit aromatic monocyclic, have 0-4 heteroatoms that is selected from O, N and S independently of one another; Or 9-has 0-5 heteroatoms that is selected from O, N and S independently of one another to 10-unit aromatics dicyclo.In some embodiments, X ¹Be-CR ⁵R ⁵'-.R ⁵And R ⁵' can be H.

[046] in some embodiments, R ²And R ³Can be H or the C that is unsubstituted independently of one another _1-4Alkyl; R ²And R ³All be H; R ²And R ³One of be C _1-4Alkyl; Or R ²And R ³The both can be C _1-4Alkyl.

[047] on the other hand, the present invention relates to formula (II) and formula (III) compound:

(II) and (III), R wherein ¹, R ², R ³, R ⁵With J suc as formula defining in (I) and p is 0,1 or 2.

[048] in yet another aspect, the invention provides following specific compound:

[049], the invention provides and comprise formula (I), (II) or (III) compound compositions and pharmaceutically acceptable carrier, auxiliary agent or media in others.

Aspect another, the invention provides by to patient's giving construction (I), (II) or (III) compound suppress the method for the protein kinase activity among the described patient.

Aspect another, the invention provides by with biological sample and formula (I), (II) or (III) compound contact the method for the protein kinase activity in suppressing described biological sample.Described protein kinase is PLK1.

[050] aspect another, the invention provides by to patient's giving construction (I), (II) or (III) method of the illness of the described patient's of compounds for treating propagation illness, neurodegeneration illness, autoimmunization illness, inflammatory illness or immunology-mediation.This method can comprise described patient is selected from following additional treatment agent: the medicine of the medicine of the medicine of the medicine of chemotherapy or antiproliferative, anti-inflammatory agent, immunoregulation or immunosuppressor, neurotrophic factor, treatment cardiovascular disorder, the destructive bone disorder of treatment, the medicine of treatment hepatopathy, antiviral agent, treatment blood illness, the medicine of treatment diabetes or treatment immune deficiency illness, and wherein: described additional treatment agent is suitable for the disease of being treated; And described additional treatment agent separates a part of administration as polynary formulation with described composition as single formulation administration or with described composition.

On the other hand, the invention provides treatment patient's melanoma, myelomatosis, leukemia, lymphoma, neuroblastoma or be selected from following method for cancer: colon, mammary gland, stomach, ovary, uterine neck, lung, central nervous system (CNS), kidney, prostate gland, bladder or pancreas, wherein said method comprise described patient's giving construction (I), (II) or (III) compound.

[051] aspect another, the invention provides treatment patient's method for cancer, wherein said method comprises described patient's giving construction (I), (II) or (III) compound.

Universal synthesis method

[052] The compounds of this invention generally can by following generalized flowsheet and subsequently those methods of describing of preparation example prepared.Unless indication is arranged in addition, all variablees in the following flow process all are as defined herein.

Flow process 1

[053] above-mentioned flow process 1 expression produces the synthetic route of Compound I-a.According to Bogatskii, A.V., Physicochemical Institute, Academy of Sciences of theUkrainian SSR, Odessa 270080 prepares compd A.Compd A is carried out the Sandmeyer reaction produce compd B.Compd B is through linked reaction (for example, Suzuki (M=B (OR) subsequently ₂), Negishi (M=ZnX) or Stille (M=SnR ³)) generation Compound I-a.About the details of Sandmeyer reaction referring to for example J.K.Kochi, TheMechanism of the Sandmeyer and Meerwein Reactions, J.Am.Chem.Soc., 1957,79 (11): 2942-2948; H.H.Hodgson, The SandmeyerReaction, Chem.Rev., 1947,40 (2): 251-277; Incorporate its all the elements into this paper by reference.As used herein, term " Sandmeyer condition " is meant the condition of carrying out the Sandmeyer reaction.Alternative synthetic method is that M is introduced compd B, produces midbody compound C, and it produces Compound I-a through the reaction with aromatic halide subsequently.Come synthetic compound I-b with the palladium catalyzed coupling reaction between compd B and cyclammonium.

Flow process 2

[054] the general synthetic route of above-mentioned flow process 2 expression preparation The compounds of this invention.The alkylation of Compound D (pressing the WO200064904 preparation) produces compd E.At 2 with M (M=boric acid ester or boric acid (B (OR) ₂), zincate (M=ZnX) or stannane (M=SnR ³)) replace, thereupon with aromatic halide R ¹The X reaction produces compound G.

[055] therefore, the present invention also provides the method for preparing The compounds of this invention.Concrete, the invention provides the method for preparation formula (I) compound:

Described method comprises formula (B) compound and R ¹-CP ₂Reaction forms formula (I) compound under suitable coupling condition.In formula (I), ring A, X ¹, J, R ²And R ³Be

As herein defined; At described compound R ¹-CP ₂In, R ¹Be as herein defined and CP ₂Be CP ₁Suitable coupling partner (partner); And CP ₁Be the coupling partner who suits.This method may further include formula (A) thereby compound reacts under the Sandmeyer condition and forms formula (B) compound.

[056] the invention provides the compound that can be used for treating disease, illness and illness, include but not limited to disease, osteopathia, metabolic trouble, neural and neurodegenerative disease, cardiovascular disorder, hormone relative disease, transformation reactions, asthma and the Alzheimer of autoimmune disease, inflammatory diseases, propagation and hyperproliferation disease, immunology-mediation.Another aspect of the present invention provides the kinases inhibitor compound, thereby can be used for treating disease, illness and illness, and other purposes as herein described.In another aspect of this invention, provide pharmaceutically acceptable composition, wherein these compositions comprise any compound as herein described, comprise pharmaceutically acceptable carrier, auxiliary agent or media alternatively.In some embodiments, these compositions further comprise one or more additional treatment agent alternatively.

[057] also will be figured out, some The compounds of this invention can exist for treatment with free form, perhaps takes the circumstances into consideration to be its pharmacy acceptable salt or pharmaceutically acceptable derivates.

[058] " pharmaceutically acceptable derivates " used herein is adducts or derivative, can directly or indirectly provide The compounds of this invention or its to suppress active metabolite or resistates after to patient's administration that needs are arranged.The example of pharmaceutically acceptable derivates includes but not limited to the salt of ester and this class ester.

[059] salt of term used herein " pharmacy acceptable salt " expression compound, in rational medical judgment scope, they are suitable for contacting with the lower animal tissue with human body, do not have unsuitable toxicity, pungency, transformation reactions etc., match with rational interests/risk ratio.

[060] pharmacy acceptable salt is well known in the art.For example, people such as S.M.Berge are at J.Pharmaceutical Sciences, and 1977,66, describe pharmacy acceptable salt among the 1-19 in detail, quote as a reference at this.The pharmacy acceptable salt of The compounds of this invention comprise from the inorganic and organic acid that is fit to and alkali deutero-those.These salt can be by in-situ preparing during the final separation of compound and purifying.Acid salt can be prepared as follows: 1) make the free alkali form and the organic or inorganic acid-respons that is fit to of the compound of purifying, with 2) separate the salt that is generated.

[061] example of pharmaceutically acceptable non-toxic acid addition salt is the amide that generates with mineral acid or organic acid, mineral acid is hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid and perchloric acid for example, organic acid is acetate, oxalic acid, toxilic acid, tartrate, citric acid, succsinic acid or propanedioic acid for example, perhaps utilize the used additive method in this area, for example the salt of ion-exchange formation.Other pharmacy acceptable salts comprise adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, hydrosulfate, borate, butyrates, camphorate, camsilate, Citrate trianion, cyclopentane propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, glucoheptose salt, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, the 2-isethionate, Lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, maleate, malonate, mesylate, the 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, phosphoric acid salt, picrate, Pivalate, propionic salt, stearate, succinate, vitriol, tartrate, thiocyanate-, right-tosylate, the undecane hydrochlorate, valerate etc.Comprise basic metal, alkaline-earth metal, ammonium and [N (C from suitable alkali deutero-salt _1-4Alkyl) ₄] ⁺Salt.The quaternization of any alkaline nitrogen-containing group of compound is as disclosed herein also contained in the present invention.Can obtain water soluble or the oily product that maybe can be dispersed in water or the oil by this class quaternization.

[062] base addition salt can be prepared as follows: 1) make the sour form and the organic or inorganic alkali reaction that is fit to of the compound of purifying, with 2) separate the salt that is generated.Base addition salt comprises basic metal or alkaline earth salt.Representative basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium etc.In due course, other pharmacy acceptable salts comprise nontoxic ammonium salt, quaternary ammonium salt and amine cationic salts, utilize counter ion to generate, for example halogenide, oxyhydroxide, carboxylate salt, vitriol, phosphoric acid salt, nitrate, low-grade alkane sulfonate and arylsulphonate.Other bronsted lowry acids and bases bronsted lowries although itself be not pharmaceutically acceptable, can be used to prepare the salt that can be used as intermediate when obtaining The compounds of this invention and their pharmaceutically acceptable acid or base addition salt.

[063] as described herein, pharmaceutically acceptable composition of the present invention comprises pharmaceutically acceptable carrier, auxiliary agent or vehicle in addition, just as used herein, they comprise be suitable for required particular dosage form arbitrarily and all solvents, thinner or other liquid excipients, dispersion or suspension aids, tensio-active agent, isotonic agent, thickening or emulsifying agent, sanitas, solid binder, lubricant etc.Remington ' s Pharmaceutical Sciences, the 16 edition, E.W.Martin (Mack Publishing Co., Easton, Pa., 1980) known technology that is used to prepare the various carriers of pharmaceutically acceptable composition and is used for its preparation is disclosed.Except any conventional mounting medium is incompatible with The compounds of this invention, for example produce any worthless biological effect or interact in any other component of pharmaceutically acceptable composition in harmful mode, its use is contained within the scope of the invention.

[064] some examples that can serve as the material of pharmaceutically acceptable carrier include but not limited to ion-exchanger; Aluminum oxide; Aluminum stearate; Yelkin TTS; Serum protein, for example human serum albumin; Buffer substance, for example phosphoric acid salt; Glycine; Sorbic Acid or potassium sorbate; The partial glyceride mixture of saturated vegetable fatty acid; Water; Salt or ionogen, for example protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt; Colloid silica; Magnesium Trisilicate; Polyvinylpyrrolidone; Polyacrylic ester; The wax class; Polyethylene-polyoxytrimethylene-block polymer; Lanolin; Carbohydrate, for example lactose, dextrose plus saccharose; Starch, for example W-Gum and yam starch; Mierocrystalline cellulose and derivative thereof, for example Xylo-Mucine, ethyl cellulose and rhodia; The tragacanth gum of pulverizing; Fructus Hordei Germinatus; Gelatin; Talcum; Vehicle, for example theobroma oil and suppository wax; Oils, for example peanut oil, Oleum Gossypii semen, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soybean oil; Glycol, for example propylene glycol or polyoxyethylene glycol; Ester class, for example ethyl oleate and Laurate ethyl; Agar; Buffer reagent, for example magnesium hydroxide and aluminium hydroxide; Alginic acid; Pyrogen-free water; Isotonic saline solution; Ringer's solution; Ethanol; Phosphate buffer soln; And other nontoxic compatible lubricant, for example Sodium Lauryl Sulphate BP/USP and Magnesium Stearates; According to preparation personnel's judgement, in composition, also can exist toner, releasing agent, Drug coating, sweeting agent, seasonings and spices, sanitas and antioxidant.

[065] one aspect of the present invention provides treatment to be selected from following disease or alleviates the method for its seriousness: disease, osteopathia, metabolic trouble, nerve or neurodegenerative disease, cardiovascular disorder, transformation reactions, asthma, Alzheimer or the hormone relative disease of autoimmune disease, inflammatory diseases, propagation or hyperproliferation disease (for example cancer), immunology-mediation comprise and give the compound of significant quantity or the pharmaceutically acceptable composition of inclusion compound to the curee that these needs are arranged.Term " cancer " includes but not limited to following cancer: mammary gland; Ovary; Uterine neck; Prostate gland; Testis, urogenital tract; Esophagus; Larynx, glioblastoma; Neuroblastoma; Stomach; Skin, keratoacanthoma; Lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, adenocarcinoma of lung; Bone; Colon, adenoma; Pancreas, gland cancer; Tiroidina, follicular carcinoma, undifferentiated cancer, papillary carcinoma; Spermocytoma; Melanoma; Sarcoma; Bladder cancer; Liver cancer and biliary tract; Kidney; Marrow sample illness; Lymph sample illness, Hokdkin disease, hair cell; Oral cavity and pharynx (mouth), lip, tongue, mouth, pharynx; Small intestine; Colon-rectum, large intestine, rectum; Brain and central nervous system; And leukemia.

[066] in some embodiments, " significant quantity " of compound or pharmaceutically acceptable composition is effectively to measure in order to treat described disease.Can utilize according to the compound of the inventive method and composition and just to treat described disease or to alleviate with regard to its seriousness effective any amount and in addition administration of route of administration arbitrarily.In some embodiment, described disease is selected from the illness of propagation illness, neurodegeneration illness, autoimmunization illness, inflammatory illness and immunology-mediation.In some embodiment, described disease is the propagation illness.In some embodiment, be cancer.

[067] in other embodiments of the present invention, described disease is protein kinase mediated illness.In some embodiment, described protein kinase is PLK.

[068] known protein kinases any disease or other harmful illnesss of figure therein represented in term used herein " illness of protein kinase-mediation ".This class illness comprises disease, osteopathia, metabolic trouble, neural and neurodegenerative disease, cardiovascular disorder, hormone relative disease, transformation reactions, asthma and the Alzheimer of autoimmune disease, inflammatory diseases, propagation and hyperproliferation disease, immunology-mediation without limitation.

[069] PLK any disease or other harmful illnesss of figure therein represented in term used herein " illness of PLK-mediation ".This class illness comprises the illness of propagation illness (for example cancer), neurodegeneration illness, autoimmunization illness, inflammatory illness and immunology-mediation without limitation.

[070] in some embodiment, compound of the present invention and composition are the inhibitor of protein kinase.As the inhibitor of protein kinase, compound of the present invention and composition are particularly useful for treatment a kind of like this disease, illness or illness or alleviate its seriousness, wherein protein kinase implication in this disease, illness or illness.On the one hand, the invention provides the method for the treatment of disease, illness or illness or alleviating its seriousness, wherein protein kinase implication in this morbid state.On the other hand, the invention provides treatment disease, illness or illness or alleviate the method for its seriousness, wherein enzymic activity is suppressed at implication in this treatment of diseases.On the other hand, the invention provides with compounds for treating disease, illness or illness or alleviate the method for its seriousness, this compound is by combining and inhibitory enzyme activity with protein kinase.In some embodiment, described protein kinase is PLK.

[071] can or be measured in the clone in external, body as the activity of the compound of kinases inhibitor in the present invention.The external test method comprises the restraining effect of mensuration to the kinase activity or the atpase activity of activated protein kinase.But optionally external test method quantitative assay inhibitor and protein kinase bonded ability.The combination of inhibitor can be measured like this, radio-labeling inhibitor before combination separates inhibitor/kinase complex, measures the radiolabeled amount of institute's bonded again, the experiment that perhaps is at war with is wherein with novel inhibitors with known radioligand bonded kinases incubation.

[072] kinases inhibitor or its drug salts can be formulated into pharmaceutical composition, to animal or human's administration.These pharmaceutical compositions comprise the kinases inhibitor and the pharmaceutically acceptable carrier of effective treatment or prevention kinases-mediation illness amount, are another embodiment of the invention.In some embodiment, the illness of described protein kinase-mediation is the illness of PLK-mediation.It in some embodiment the illness of PLK1-mediation.

[073] the definite amount of treatment required compound will be different because of the curee, depend on seriousness, the certain drug of curee's kind, age and general state, infection, the mode of its administration etc.The compounds of this invention preferably is formulated into dosage unit form, and the consistence of administration of being easy to and dosage is arranged.The drug unit that phraseology used herein " dosage unit form " expression is physically discrete is suitable for the patient who is treated.But will be appreciated, total every day of the consumption of The compounds of this invention and composition will reasonably determined in the medical judgment scope by the attending doctor.The concrete effective dose level of any specific patient or organism will depend on multiple factor, comprise the illness of being treated and the seriousness of illness; The activity of the particular compound that is adopted; The concrete composition that is adopted; Patient's age, body weight, general health situation, sex and diet; The discharge rate of the approach of time of administration, administration and the particular compound that is adopted; The time length of treatment; With particular compound associating of being adopted or the medicine that uses simultaneously; Other factors of knowing with field of medicaments.Term used herein " patient " expression animal, preferred mammal, optimum is chosen.

[074] pharmaceutically acceptable composition of the present invention can be oral to people and other animals, in the rectum, parenteral, brain pond, intravaginal, intraperitoneal, part (with pulvis, ointment or drops), oral cavity, with mouth with or mode administration such as nasal spray, this depends on the seriousness that infection is treated by institute.In some embodiments, The compounds of this invention can be by oral or administered parenterally, dosage level be every day about 0.01mg/kg to about 50mg/kg, preferred about 1mg/kg about 25mg/kg curee's body weight extremely, once a day or repeatedly, to obtain required result of treatment.

[075] liquid dosage form of oral administration includes but not limited to pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.Except active compound, liquid dosage form can contain this area inert diluent commonly used, for example water or other solvents, solubilizing agent and emulsifying agent, for example ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, phenylformic acid benzyl ester, propylene glycol, 1,3-butyleneglycol, dimethyl formamide, oil (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, wheat germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol, polyoxyethylene glycol and the fatty acid ester of anhydro sorbitol and their mixture.Except inert diluent, oral compositions also can comprise auxiliary agent, for example wetting agent, emulsification and suspension agent, sweeting agent, correctives and spices.

[076] uses dispersion or wetting agent and the suspension agent that is fit to, can prepare the injectable prepared product according to known technique, for example the water-based of sterile injectable or oiliness suspension.The sterile injectable prepared product also can be at nontoxic parenteral acceptable diluent or sterile injectable solution, suspension or the emulsion in the solvent, for example solution in 1,3 butylene glycol.Acceptable carrier that can adopt and solvent have water, Ringer's solution, U.S.P. and isotonic sodium chlorrde solution.In addition, routine adopts aseptic fixed oil as solvent or suspension medium.For this reason, can adopt the fixed oil of any gentleness, comprise synthetic list-or two-glyceryl ester.In addition, in the preparation of injection, also can use lipid acid, for example oleic acid.

[077] injectable formulation can be sterilized like this, for example filters by the bacterium property held back filter, perhaps mixes the disinfectant of aseptic solid composite form, can be before use with its dissolving be dispersed in aseptic water or other sterile injectable medium in.

[078] in order to prolong the effect of The compounds of this invention, often need delay the absorption of compound after subcutaneous or intramuscularly.This can utilize the crystallinity of poorly water-soluble or the liquid suspension of amorphous substance to realize.The uptake rate of compound depends on its dissolution rate, and the latter may be depended on crystallographic dimension and crystal formation.Select as an alternative, with compound dissolution or be suspended in the oils carrier, realize that the delay of administered parenterally compound form absorbs.Injectable depot forms is like this preparation, and in Biodegradable polymeric, polylactide-polyglycolide for example generates the microencapsulation matrix of compound.According to the ratio of compound and polymkeric substance and the attribute of the particular polymers that adopts, can control the rate of release of compound.The example of other biological degradable polymer comprises poly-(ortho ester) and poly-(acid anhydrides).The depot injectable formulation also can prepare the compound inclusion in liposome compatible with body tissue or micro emulsion.

[079] rectum or vagina administration composition suppository preferably, they can prepare like this, The compounds of this invention is mixed with the nonirritant excipient or the carrier that are fit to, for example theobroma oil, polyoxyethylene glycol or suppository wax, they are solid at ambient temperature, but under body temperature, be liquid, therefore in rectum or vaginal canal, melt, discharge active compound.

[080] solid dosage of oral administration comprises capsule, tablet, pill, pulvis and granule.In this class solid dosage, active compound is mixed with pharmaceutically acceptable vehicle of at least a inert or carrier, for example Trisodium Citrate or Lin Suanergai, and/or a) weighting agent or expanding material, starch for example, lactose, sucrose, glucose, mannitol and silicic acid, b) tackiness agent, carboxymethyl cellulose for example, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) wetting agent, glycerine for example, d) disintegrating agent, for example agar, lime carbonate, potato or tapioca (flour), alginic acid, some silicate and yellow soda ash, e) dissolving retarding agent, paraffin for example, f) absorption enhancer, for example quaternary ammonium compound, g) wetting agent, for example hexadecanol and Zerol, h) absorption agent, for example kaolin and wilkinite, and i) lubricant, for example talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sodium Lauryl Sulphate BP/USP and composition thereof.Under the situation of capsule, tablet and pill, described formulation also can comprise buffer reagent.

[081] solids composition that also can adopt similar type is as the weighting agent in the gelatine capsule agent of soft or hard filling, and the capsule used excipient is lactose or toffee and high molecular weight polyethylene glycol etc. for example.Solid dosages such as tablet, lozenge, capsule, pill and granule can have dressing and shell, for example other dressings of knowing of enteric coating and medicine formulation art.They can contain opalizer alternatively, also can be only or preferentially at the composition of a part of release of active ingredients of enteron aisle, alternatively the mode for postponing.The example of operable embedding composition comprises polymeric material and wax class.The solids composition that also can adopt similar type is as the weighting agent in the gelatine capsule agent of soft and hard filling, and the capsule used excipient is lactose or toffee and macromolecule polyethylene glycol etc. for example.

[082] active compound also can be the form of microencapsulation, wherein contains one or more above-mentioned vehicle.Solid dosages such as tablet, lozenge, capsule, pill and granule can have dressing and shell, for example enteric coating, discharge other dressings that controlled dressing and medicine formulation art are known.In this class solid dosage, active compound can be mixed with at least a inert diluent, for example sucrose, lactose or starch.Under normal circumstances, this class formulation also can comprise other materials except that inert diluent, for example compressing tablet lubricant and other compression aids, for example Magnesium Stearate and Microcrystalline Cellulose.Under the situation of capsule, tablet and pill, formulation also can comprise buffer reagent.They can contain opalizer alternatively, also can be only or preferentially at the composition of a part of release of active ingredients of enteron aisle, alternatively the mode for postponing.The example of operable embedding composition comprises polymeric material and wax class.

[083] part of The compounds of this invention or transdermal administration formulation comprise ointment, paste, creme, lotion, gelifying agent, pulvis, solution, sprays, inhalation or patch.Active ingredient is mixed with pharmaceutically acceptable carrier and any essential sanitas or buffer reagent under aseptic condition, decide as required.Ophthalmic preparation, ear drop and eye drops also covered in the scope of the present invention.In addition, the use of transdermal patch is contained in the present invention, and they have the attendant advantages that the control compound is sent to body.This class formulation can be by with compound dissolution or be dispersed in the appropriate medium and prepare.Also can use absorption enhancer to increase the flux that compound passes skin.Can control speed by rate controlling membranes being provided or compound being dispersed in polymeric matrix or the gel.

Except compound of the present invention, in treatment or prevent also can adopt in the composition of above-mentioned illness the pharmaceutically acceptable derivates or the prodrug of The compounds of this invention.

[084] salt or other derivatives of any pharmacy acceptable salt of " pharmaceutically acceptable derivates or prodrug " expression The compounds of this invention, ester, ester can directly or indirectly provide The compounds of this invention or its to suppress active metabolite or resistates after to recipient's administration.Desirable especially derivative and prodrug are such, they increase the bioavailability (for example allowing the easier absorption of compound of oral administration to enter blood) of The compounds of this invention during to the Mammals administration at this compounds, perhaps strengthen send (for example brain or the lymphsystem) of parent compound to body cavity of organism with respect to the parent kind.

[085] the pharmaceutically acceptable prodrug of The compounds of this invention comprises ester, amino acid ester, phosphoric acid ester, metal-salt and sulphonate without limitation.

[086] the pharmaceutically acceptable carrier that can be used in these compositions includes but not limited to ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein (for example human serum albumin), buffer substance (for example phosphoric acid salt), glycine, Sorbic Acid, potassium sorbate, the partial glyceride mixture of saturated vegetable fatty acid, water, salt or ionogen (for example protamine sulfate), Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloid silica, Magnesium Trisilicate, polyvinylpyrrolidone, cellulose substances, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, the wax class, polyethylene-polypropylene-block polymer, polyoxyethylene glycol and lanolin.

[087] administration of the present composition can be oral, parenteral, suction spraying, part, rectum, nose, cheek, vagina or via implanting bank.That term used herein " parenteral " comprises is subcutaneous, in the intravenously, intramuscular, intraarticular, synovial membrane, in the breastbone, in the sheath, in the liver, in the damage location and intracranial injection or infusion techniques.Preferably, composition is oral, intraperitoneal or intravenous administration.

[088] the sterile injectable formulation of the present composition can be water-based or oiliness suspension.These suspensions can use suitable dispersion or wetting agent and suspension agent to be prepared according to technology known in the art.Sterile injectable preparation also can be at nontoxic parenteral acceptable diluent or sterile injectable solution or the suspension in the solvent, for example solution in 1,3 butylene glycol.Acceptable carrier that can adopt and solvent have water, Ringer's solution and isotonic sodium chlorrde solution.In addition, routine adopts aseptic fixed oil as solvent or suspension medium.For this reason, can adopt the fixed oil of any gentleness, comprise synthetic list-or two-glyceryl ester.Lipid acid, for example oleic acid and glyceride derivative thereof can be used for preparing injection, because they are natural pharmaceutically acceptable oil, and for example sweet oil or Viscotrol C, especially their polyoxy ethylization form.These oil solutions or suspension also can contain long-chain alcohol thinner or dispersion agent, for example carboxymethyl cellulose or similar dispersion agent, and they are usually used in preparing pharmaceutically acceptable formulation, comprise emulsion and suspension.For the purpose of preparation, also can use other tensio-active agents commonly used, for example Tweens, spans and other emulsifying agents or bioavailability toughener, they are usually used in making pharmaceutically acceptable solid, liquid or other formulations.

[089] pharmaceutically acceptable composition of the present invention can be taken orally, and any oral acceptable forms includes but not limited to capsule, tablet, aqueous suspensions or solution.With under the situation of tablet, carrier commonly used comprises lactose and W-Gum at mouth.Usually also add lubricant, for example Magnesium Stearate.With regard to the oral capsule administration, useful thinner comprises lactose and exsiccant W-Gum.Very moment mixes activeconstituents during with the needs aqueous suspensions with emulsifying and suspending agent.If necessary, also can add some sweeting agent, correctives or tinting material.

[090] select as an alternative, pharmaceutical composition of the present invention can be with the suppository form administration, for rectal administration.They can prepare like this, and medicine is mixed with the nonirritant excipient that is fit to, and the latter at room temperature is a solid, but is liquid under rectal temperature, therefore will melt at internal rectum, discharges medicine.This class material comprises theobroma oil, beeswax and polyoxyethylene glycol.

[091] pharmaceutical composition of the present invention also can topical, especially when therapeutic goal comprises local application easy to reach position or organ, comprises the disease of eye, skin or lower intestinal tract.The topical formulations that is fit to is prepared according to each these position or organ easily.

[092] lower intestinal tract local application can utilize rectal suppository (on seeing) or suitable enema to carry out.Also can use the topical transdermal patch.

[093] with regard to local application, pharmaceutical composition can be formulated in the suitable ointment, wherein contain to suspend or be dissolved in-kind or variety carrier in active ingredient.The topical carrier of The compounds of this invention includes but not limited to mineral oil, petrosio, white vaseline, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.Select as an alternative, pharmaceutical composition can be formulated into suitable lotion or creme, wherein contains to suspend or be dissolved in active ingredient in one or more pharmaceutically acceptable carriers.The carrier that is fit to includes but not limited to mineral oil, Arlacel-60, polysorbate60, spermaceti ester type waxes, cetostearyl alcohol, 2-Standamul G, benzyl alcohol and water.

[094] with regard to eye with regard to, pharmaceutical composition can be formulated into micronization suspension or the solution in the Sterile Saline of isoosmotic pH regulator preferably in the Sterile Saline of isoosmotic pH regulator, the two all contains or does not have sanitas, for example a benzalkonium chloride.Select as an alternative, with regard to eye was used, pharmaceutical composition can be formulated in the ointment, for example vaseline.

[095] pharmaceutical composition of the present invention also can pass through nose aerosol or inhalation administration.This based composition is to prepare according to the technology that field of pharmaceutical preparations is known, can make salt brine solution, adopt absorption enhancer, fluorocarbon and/or other the conventional solubilizing agent or the dispersion agent of phenylcarbinol or other sanitass that is fit to, raising bioavailability.

Can merge the amount of the kinase inhibitor make single formulation with solid support material will be different because of the host that treated, specific administering mode.Preferably, composition should be preparation like this, so that can give the inhibitor of dosage between the 0.01-100mg/kg body weight/day to the patient who accepts these compositions.

[096] also is to be understood that, concrete dosage and treatment system with regard to any particular patient will depend on multiple factor, comprise activity, age, body weight, general health situation, sex, diet, administration time, discharge rate, drug regimen, attending doctor's judgement and the seriousness of the specified disease for the treatment of of the particular compound that is adopted.The amount of inhibitor also will depend on the specific compound in the composition.

[097] in other embodiments, the invention provides the method for treatment or prophylaxis of protein kinase-mediation illness (in some embodiment, being PLK-mediation illness), comprise the step that the patient is given one of aforementioned pharmaceutical compositions.Term used herein " patient " expression animal, preferred people.

[098] preferably, this method is used for the treatment of or prevents to be selected from following illness: cancer, and for example the cancer of mammary gland, colon, prostate gland, skin, pancreas, brain, urogenital tract, lymphsystem, stomach, larynx and lung comprises adenocarcinoma of lung and small cell lung cancer; Apoplexy, diabetes, melanoma, hepatomegaly, megalocardia, Alzheimer, cystic fibrosis and virus disease, perhaps above-mentioned any specific disease or illness.

[099] another aspect of the present invention relates to the protein kinase activity that suppresses among the patient, and this method comprises this patient is given The compounds of this invention or comprises described compound compositions.

[100] depend on the specific protein kinase-mediation illness that to treat or to prevent, under normal circumstances drug treatment or prevent the medication of this illness can be with inhibitor administration of the present invention.For example, chemotherapeutics or other anti-proliferating agents can with kinases inhibitor combination therapy hyperplasia of the present invention.

[101] these medications can with compound that contains kinases inhibitor or composition separate administration, as the part of polynary dosage regimen.Select as an alternative, these medicines can be the parts of single formulation, are mixed together in the single composition with kinases inhibitor.

[102] in some embodiment, described kinases inhibitor is the PLK kinase inhibitor.In other embodiments, described kinases inhibitor is the PLK1 kinase inhibitor.

[103] the present invention also can be used in those methods that do not involve patient's administration.

[104] one aspect of the present invention relates to the protein kinase activity that suppresses among biological sample or the patient, and this method comprises to be made described biological sample contact The compounds of this invention or comprise described compound compositions.The sample of external or ex vivo represented in term used herein " biological sample ", comprises cell culture and extract thereof without limitation; Biopsy material from Mammals or the acquisition of its extract; With blood, saliva, urine, ight soil, seminal fluid, tear or other body fluid or its extract.

[105] protein kinase activity that suppresses in the biological sample can be used for multiple purpose well known by persons skilled in the art.This classification example include but not limited to that blood transfusion, organ transplantation and biological specimen store.

[106] another aspect of the present invention relates to the protein kinase research in biological and the pathological phenomenon; Research by the kinase mediated intracellular signal transduction approach of this proteinoid; Comparative evaluation with new kinases inhibitor.The example of this class purposes includes but not limited to bioassay method, for example enzyme assay and cell class assay method.

[107] The compounds of this invention generally can be prepared by method known to those skilled in the art.These compounds can include but not limited to LCMS (liquid chromatography mass) and NMR (nucleus magnetic resonance) by the currently known methods analysis.The compounds of this invention also can be tested according to these embodiment.Should be appreciated that down and show that actual conditions only is example, does not represent to limit the scope that can be used in preparation, analyzes or test the condition of The compounds of this invention.On the contrary, the present invention comprises that also those skilled in the art become known for preparing, analyzing and test the condition of The compounds of this invention.

[108] term used herein " Rt (min) expression HPLC retention time, in minute, relevant with compound.Unless indication is arranged in addition, the HPLC method that is used to obtain the retention time reported is as follows:

Pillar: ACE C8 post, 4.6 * 150mm

Gradient: 0-100% acetonitrile+methyl alcohol 60: 40 (20mM Tris phosphoric acid salt)

Flow velocity: 1.5mL/ minute

Detect: 225nm

[109] on MicroMass Quattro Micro mass spectrograph, analyze mass spectrum sample, work in the single MS pattern of using electro-spray ionization.Utilize chromatography to introduce sample to mass spectrograph.

[110] utilize Bruker DPX 400 instruments record under 400MHz ¹H-NMR spectrum.Be prepared as follows and analyze following formula (I) compound.

Embodiment 1:5,6,7,8-tetrahydrochysene-7,7-dimethyl-2-(pyridin-4-yl) thiazole is [5,4-c] azepine also

-4-ketone (I-1).

Step 1:2-amino-5,6,7,8-tetrahydrochysene-7,7-dimethylthiazole is [5,4-c] azepine also

-4-ketone.

[111] according to Bogatskii, A.V., Physicochemical Institute, Academy of Sciences of the Ukrainian SSR, Odessa 270080 prepares.Translation is from Khimiya Geterotsiklicheskikh Soedinenii, No2, p277,1989.Isolating title compound, is cream powder (3.78g, yield 73%); ¹H (DMSO-D ₆): 1.0 (6H, s), 2.6 (2H, s), 2.9 (2H, d), 7.3 (2H, brs), 7.5-7.6 (1H, br t); LC/MS M+1 (obs.) 212.3; LC/MS M-1 (obs.) 210.4.

Step 2:2-bromo-5,6,7,8-tetrahydrochysene-7,7-dimethylthiazole be [5,4-c] azepine also

-4-ketone.

[112] with CuBr ₂(4.76g, 21.30mmol, 1.2eq.) and nitrite tert-butyl (3.05g, 3.5mL, 26.62mmol, purity 90%, 1.5 equivalent) anhydrous CH suspends/is dissolved in ₃Cool off among the CN (100mL) and with ice bath.In about 17 minutes, slowly add 2-amino-5,6,7 in batches, 8-tetrahydrochysene-7,7-dimethylthiazole be [5,4-c] azepine also

-4-ketone (3.75g, 17.75mmol, 1 equivalent).Stirred down institute's suspension that obtains about 2 minutes at 0 ℃, stir about is 30 minutes under the room temperature, and 40 ℃ are stirred down and spend the night.The concentrating under reduced pressure reaction mixture is removed CH ₃CN is dissolved in EtOAc/ salt solution again, filters by C salt.The filtrate phase-splitting is with EtOAc (3 * 200mL) aqueous phase extracted.(organic phase that 1 * 200mL) washing merges is at Na with salt solution ₂SO ₄Last dry, filter concentrating under reduced pressure.Produce the greenish orange look solid of 4.02g by column chromatography purifying (50%EtOAc/ hexane).It is used pentane/Et ₂O grinds, and uses pentane (3 * 10mL) washing gained solids again.50 ℃ of following high vacuum dry are spent the night, and produce 3.65g greenish orange toner end (yield 75%); 1H (DMSO) 1.0 (6H, s), 2.9 (2H, s), 3.0 (2H, d), 8.3 (br m); LC/MS M+1 (obs.) 277.1; LC/MS M-1 (obs.) 275.4

Step 3:5,6,7,8-tetrahydrochysene-7,7-dimethyl-2-(pyridin-4-yl) thiazole is [5,4-c] azepine also

-4-ketone (I-1).

[113] with 2-bromo-5,6,7,8-tetrahydrochysene-7,7-dimethylthiazole be [5,4-c] azepine also

-4-ketone (200mg, 1.0 equivalents), 4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) pyridine (224mg, 1.5 equivalents), Pd (DBA) ₂In (42mg, 0.1 equivalent) and yellow soda ash (2M aq., 1090 μ l, the 3.0 equivalents) dioxane (4mL) that suspends/be dissolved in.With vacuum/N ₂Circulate and make this system degassing for three times.Add subsequently P ( ^tBu) ₃(42mg, 0.1 equivalent) spends the night at 80 ℃ of following stirred reaction mixtures.Make reaction mixture be cooled to room temperature.At EtOAc/H ₂Distribute above-mentioned reaction mixture among the O, filter, use EtOAc/H by C salt ₂The O thorough washing.The filtrate phase-splitting is with EtOAc (3 * 20mL) aqueous phase extracted.Use saturated Na ₂CO ₃(organic phase that 1 * 20mL) washing merges is at Na for the aqueous solution ₂SO ₄Last dry, filter concentrating under reduced pressure.By column chromatography (5%MeOH/95%EtOAc) purifying, recrystallization produces title compound from the EtOAc/ hexane subsequently, is brown powder (19.6mg, yield 10%); 1H NMR (DMSO-D ₆) 1.0 (6H, s), 3.0 (4H, m), 7.7-7.8 (2H, d), 8.3 (1H, br m), 8.7-8.8 (2H, d); LC/MS M+1 (obs.) 274.60; LC/MS M-1 (obs.) 272.80.

Embodiment 2:N-benzenesulfonyl-5,6,7,8-tetrahydrochysene-7,7-dimethyl-2-(1H-pyrrolo-[2,3-b] pyridin-4-yl) thiazole is [5,4-c] azepine also

-4-ketone (I-2).

Step 1:N-benzenesulfonyl-4-bromo-1H-pyrrolo-[2,3-b] pyridine

[114] 4-bromo-1H-pyrrolo-[2,3-b] pyridine (1g, 1 equivalent) is dissolved in anhydrous THF and in ice bath, cools off.Add NaH (60% dispersion in the mineral oil, 305mg, 1.2 equivalents) in batches.Stir the gained mixture 45 minutes down at 0 ℃, slowly drip benzene sulfonyl chloride (1.076g, 1.2 equivalents).In 0 ℃ of following restir gained mixture 75 minutes, removal of solvent under reduced pressure subsequently.At the saturated NH of EtOAc/ ₄Distribute resistates among the Cl, with EtOAc (3 * 50mL) extractions.Use saturated Na ₂CO ₃The aqueous solution (1 * 20mL), (organic phase that 1 * 20mL) washing merges is at Na for salt solution ₂SO ₄Last dry, filter concentrating under reduced pressure.Realize purifying, recrystallization from the EtOAc/ hexane subsequently with column chromatography (20%EtOAc/80% hexane).Filtration product with the pentane washing, obtains title compound subsequently, is white powder (1.24g, yield 73%). ¹H-NMR(DMSO-D ₆)：6.8(1H，d)，7.6-7.66(3H，m)，7.72-7.76(1H，m)，8.0(1H，d)，8.1(2H，m)，8.24-8.26(1H，m)；LC/MS?M+1；(obs.)339.1；LC/MS?M-1(obs.)337.1。

Step 2:N-benzenesulfonyl-5,6,7,8-tetrahydrochysene-7,7-dimethyl-2-(1H-pyrrolo-[2,3-b] pyridin-4-yl) thiazole is [5,4-c] azepine also

-4-ketone (I-2).

[115] with 2-bromo-5,6,7,8-tetrahydrochysene-7,7-dimethylthiazole be [5,4-c] azepine also

-4-ketone (200mg, 1.33 equivalents) is dissolved in anhydrous THF (3mL) and cools off in ice bath.Once add NaH (60% dispersion in the mineral oil, 35mg, 1.6 equivalents).0 ℃ of following stirred reaction mixture 30 minutes, at room temperature stirred 15 minutes, stirred 10 minutes down at 45 ℃.Cool off gained solution down at-78 ℃, and slowly drip BuLi (2.5M hexane solution, 377uL, 1.73 equivalents).-78 ℃ of following stirred reaction mixtures 15 minutes.Add ZnCl ₂(134mg, 1.8 equivalents) stirred gained solution 30 minutes down at-78 ℃, at room temperature stirred 1 hour.Add Pd ₂(DBA) ₃(7mg, 0.01 equivalent), 2-(dicyclohexylphosphontetrafluoroborate)-2 ', 4 '; 6 '-three-sec.-propyl-1,1 '-biphenyl (X-PHOS, 14mg; 0.04 equivalent) and N-benzenesulfonyl-4-bromo-1H-pyrrolo-[2,3-b] pyridine (184mg, 1.0 equivalents) and stir down the gained mixture overnight at 70 ℃.Make reaction mixture be cooled to room temperature, at the saturated NH of EtOAc/ ₄Distribute between the Cl aqueous solution, be extracted into EtOAc (3 * 20mL).In anhydrous Na ₂SO ₄The last dry organic layer that merges filters concentrating under reduced pressure.Finish purifying with column chromatography (90%EtOAc/10% hexane), subsequently at Et ₂O grinds.Use the pentane washing precipitation subsequently.Obtaining title compound, is buff powder (51.5mg, yield 21%); ¹H-NMR (DMSO-D ₆): 1.0 (6H, s), 3.0 (4H, m), 7.4 (1H, d), 7.64 (2H, m), 7.74 (1H, m), 7.8 (1H, m), 8.1 (3H, m), 8.36 (1H, br m), 8.5 (1H, m); LC/MS M+1; (obs.) 453.2; LC/MS M-1 (obs.) 451.2.

Embodiment 3:5,6,7,8-tetrahydrochysene-7,7-dimethyl-2-(1H-pyrrolo-[2,3-b] pyridin-4-yl) thiazole is [5,4-c] azepine also

-4-ketone (I-3).

[116] with N-benzenesulfonyl-5,6,7,8-tetrahydrochysene-7,7-dimethyl-2-(1H-pyrrolo-[2,3-b] pyridin-4-yl) thiazole is [5,4-c] azepine also

-4-ketone (embodiment 2) (79mg, 1.0 equivalents) suspends/is dissolved among the EtOH (4.5mL), adds NaOH (15 weight %, 0.5mL, ≈ 11 equivalents).Reaction mixture refluxed 4 hours.Make reaction mixture be cooled to room temperature, removal of solvent under reduced pressure then.At the saturated NH of EtOAc/ ₄Distribute mixture between the Cl aqueous solution, be extracted into EtOAc (3 * 20mL).With the NaOH of 15 weight % (1 * 10mL), (organic layer that 1 * 10mL) washing merges is at Na for salt solution ₂SO ₄Last dry, filter concentrating under reduced pressure.(5%MeOH/95%DCM) finishes purifying with column chromatography, subsequently at Et ₂O grinds.Use the pentane washing precipitation subsequently.Obtaining title compound, is orange solid (27.8mg, yield 52%); ¹H NMR (DMSO-D ₆) 1.1 (6H, s), 3.0 (4H, m), 7.0 (1H, m), 7.6 (1H, m), 7.7 (1H, m), 8.3 (2H, m), 12.1 (1H, br s); LC/MS M+1 (obs.) 313.20; LC/MSM-1 (obs.) 311.40.

Embodiment 4:2-(2-chloropyridine-4-yl)-5,6,7,8-tetrahydrochysene-7,7-dimethylthiazole be [5,4-c] azepine also

-4-ketone (I-4)

[117] with 2-bromo-5,6,7,8-tetrahydrochysene-6,6-dimethylthiazole be [5,4-c] azepine also

-4-ketone (200mg, 1.0 equivalents), 2-chloropyridine-4-boric acid (126mg, 1.1 equivalents), Pd ₂(DBA) ₃(27mg, 0.04 equivalent), K ₃PO ₄H suspends/is dissolved in (341mg mg, 2.2 equivalents) ₂In the O/ dioxane (0.5mL/2.5mL), and the degassing (vacuum/N ₂Circulation * 5).(20mg 0.1Eq.), spends the night at 60 ℃ of following stirred reaction mixtures to add tricyclohexyl phosphine subsequently.Make reaction mixture be cooled to room temperature, at EtOAc/H ₂Distribute between O, filter by C salt subsequently.Use saturated Na ₂CO ₃The solution dilution water layer is extracted into EtOAc (3 * 50mL).(organic layer that 1 * 50mL) washing merges is at Na with salt solution ₂SO ₄Last dry, filter concentrating under reduced pressure.(100%EtOAc) finishes purifying with column chromatography, subsequently at Et ₂O grinds.Use the pentane washing precipitation subsequently.Obtaining title compound, is light yellow solid (74.1mg, yield 33%); ¹H NMR (DMSO-D ₆) 1.0 (6H, s), 3.0 (4H, m), 7.9 (1H, m), 8.0 (1H, s), 8.8 (1H, br m), 9.1 (1H, m); LC/MS M+1; (obs.) 308.1; LC/MSM-1 (obs.) 306.3.

Embodiment 5:4-(4-(5,6,7,8-tetrahydrochysene-7,7-dimethyl-4-oxo-4H-thiazole is [5,4-c] azepine also -2-yl) pyridine-2-base is amino)-N-methyl-benzamide (I-5)

[118] with 2-(2-chloropyridine-4-yl)-5,6,7,8-tetrahydrochysene-7,7-dimethylthiazole be [5,4-c] azepine also

-4-ketone (70mg, 1.0 equivalents), 4-amino-N-methyl-benzamide (41mg, 1.2 equivalents), NaOtBu (61mg, 2.8 equivalents), Pd (OAc) ₂(5mg, 0.1 equivalent) suspends/be dissolved in the dry toluene, and the degassing (vacuum/N ₂Circulation * 5).Add 2-(di-t-butyl phosphino-) biphenyl (143mg, 0.2 equivalent) subsequently.Gained mixture overnight subsequently refluxes.Add a part of NaOtBu (61mg, 2.8 equivalents), Pd (OAc) again ₂(5mg, 0.1 equivalent) and 2-(di-t-butyl phosphino-) biphenyl (14mg, 0.2 equivalent) add anhydrous dioxane (0.5mL) subsequently.Backflow gained mixture is after a night.Make reaction mixture be cooled to room temperature, at EtOAc/MeOH (3: 1)/NH ₄Distribute between Cl, be extracted into EtOAc/MeOH (3: 1) (3 * 50mL) subsequently.(organic layer that 1 * 20mL) washing merges is at Na with salt solution ₂SO ₄Last dry, filter concentrating under reduced pressure.(10%MeOH/90%DCM) finishes purifying with column chromatography, obtains title compound, is glassy yellow powder (18.6mg, yield 19%); ¹H-NMR (DMSO-D ₆) 1.0 (6H, s), 2.8 (3H, d), 3.0 (2H, s), 3.0 (2H, m), 7.3 (1H, m), 7.5 (1H, s), 7.8 (4H, s), 8.2 (1H, m), 8.3 (2H, m), 9.6 (1H, s); LC/MS M+1 (obs.) 422.20; LC/MS M-1 (obs.) 420.30.

Embodiment 6:5,6,7,8-tetrahydrochysene-2-(2, and 3-dihydrobenzo [b] [1,4] oxazine-4-yl)-7, the 7-dimethylthiazole is [5,4-c] azepine also

-4-ketone (I-6)

[119] with 2-bromo-5,6,7,8-tetrahydrochysene-7,7-dimethylthiazole be [5,4-c] azepine also

-4-ketone (200mg, 1 equivalent), 3,4-dihydro-2H-benzo [b] [1,4] oxazine (118mg, 1.2 equivalents), NaOtBu (196mg, 2.8 equivalents), Pd (OAc) ₂(6mg, 0.04 equivalent) suspends/is dissolved in the dry toluene (3mL).With the reaction mixture degassing (vacuum/N ₂Circulation * 5).Adding 2-(di-t-butyl phosphino-) biphenyl (18mg, 0.08 equivalent) is heated to 100 ℃ with reaction mixture and spends the night.Make reaction mixture be cooled to room temperature, at the saturated NH of EtOAc/ ₄Distribute in the Cl aqueous solution, with EtOAc (3 * 20ml) extractions.(1 * 200mL) washing merges extract, at Na with salt solution ₂SO ₄Last dry, filter removal of solvent under reduced pressure.

Finish purifying with column chromatography (70/30 EtOAc/ hexane), grind subsequent filtration with ether.Use ether, pentane washed product then, spend the night at 50 ℃ of following drying under reduced pressure.Isolate 5,6,7,8-tetrahydrochysene-2-(2, and 3-dihydrobenzo [b] [1,4] oxazine-4-yl)-7, the 7-dimethylthiazole is [5,4-c] azepine also

-4-ketone is buff powder, yield 22%; ¹H-NMR (DMSO-D ₆): 1.0 (6H, s), 2.8 (2H, 2), 2.9-3.0 (2H, d), 4.0 (2H, m), 4.3 (2H, m), 6.9-7.0 (2H, m), 7.0-7.1 (1H, m), 7.8-7.9 (1H, br m), 8.0-8.1 (1H, d); LC/MS M+1 (obs.) 330.20; LC/MS M-1 (obs.) 328.50.

Embodiment 7:1-[1-(2-chloro-phenyl)-ethyl]-7-imidazo [1,2-a] pyridin-3-yl-1,2,3,4-tetrahydrochysene-thieno-[3,2-e] [1,4] diaza

-5-ketone (I-7).

Step 1:1,2,3,4-tetrahydrochysene-thieno-[3,2-e] [1,4] diaza

-5-ketone.

[120] method according to report among the WO 2000/64904 prepares title compound 1,2,3,4-tetrahydrochysene-thieno-[3,2-e] [1,4] diaza

-5-ketone.

[121] isolating title compound, is beige solid (2.52g, 15.0mmol, 56%); ¹H-NMR (DMSO-D ₆): 3.22-3.25 (2H, m), 3.28-3.31 (4H, m), 6.48 (1H, d), 7.01-7.05 (1H, m), 7.42 (1H, d), 7.53-7.56 (1H, m); LC/MS M+1 (obs.) 169.0, LC/MS M-1 (obs.) 167.1.

Step 2:1-[1-(2-chloro-phenyl)-ethyl]-1,2,3,4-tetrahydrochysene-thieno-[3,2-e] [1,4] diaza -5-ketone.

[122] under nitrogen with 1-(2-chloro-phenyl)-ethanol (1.0g, 6.39mmol, 3.6 equivalents) and Et ₃N (1.16mL, 8.30mmol, 4.7 equivalents) is dissolved in anhydrous DCM (20mL) and is cooled to 0 ℃.Add MsCl (645 μ L, 8.30mmol, 4.7 equivalents) in batches.3.5 after hour, will react impouring 1M HCl (20mL), layering.(2 * 30mL) aqueous layer extracted are washed the organic extract that merges with salt solution (30mL), dry (MgSO with EtOAc ₄), concentrating under reduced pressure.Resistates is dissolved in dioxane (6mL), adds 1,2,3,4-tetrahydrochysene-thieno-[3,2-e] [1,4] diaza

-5-ketone (300mg, 1.78mmol, 1.0 equivalents), the reflux reaction is spent the night.Reaction is cooled to envrionment temperature, removal of solvent under reduced pressure.By column chromatography (ISCOTM Companion

The 40g post, the MeOH/DCM of 0-10%) the purifying resistates, produce title compound, be pale solid (178mg, 0.06mmol, 33%); ¹H-NMR (DMSO-D ₆): 1.50 (3H, d), 2.92-2.99 (1H, m), 3.13 (1H, m), 3.20-3.25 (2H, m), 5.32 (1H, dd), 6.91 (1H, d), 7.25-7.35 (2H, m), 7.36-7.41 (2H, m), 7.58 (1H, d), 7.61-7.63 (1H, m); LC/MSM+1 (obs.) 307.0.

Step 3:1-[1-(2-chloro-phenyl)-ethyl]-7-(4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane-2-yl)-1,2,3,4-tetrahydrochysene-thieno-[3,2-e] [1,4] diaza

-5-ketone.

[123] with HN (i-Pr) ₂(246 μ L, 1.74mmol, 3.0 equivalents) are dissolved in anhydrous THF (10mL), are cooled to-78 ℃ under nitrogen.Drip the BuLi hexane solution (700 μ L, 1.74mmol, 3.0 equivalents) of 2.5M,, be warmed to 0 ℃ subsequently, continue 30 minutes-78 ℃ of following stirring reactions 15 minutes.Reaction is cooled to-78 ℃, drips 1-[1-(2-chloro-phenyl)-ethyl]-1,2,3,4-tetrahydrochysene-thieno-[3,2-e] [1,4] diaza

Anhydrous THF (5mL) solution of-5-ketone (178mg, 0.58mmol, 1.0 equivalents).-78 ℃ of following stirring reactions 2 hours.Add 2-isopropoxy-4,4,5,5-tetramethyl--1,3, anhydrous THF (5mL) solution of 2-two oxa-s-ring pentaborane (355 μ L, 1.74mmol, 3.0 equivalents)-78 ℃ of following stirring reactions 20 minutes, is warmed to envrionment temperature, lasting 1.5 hours subsequently.Add 1M HCl (20mL), (3 * 40mL) extract this mixture with EtOAc.With the organic extract that salt solution (40mL) washing merges, dry (MgSO ₄), concentrating under reduced pressure.Obtain yellow oil, do not add with being further purified and use; ¹H-NMR (DMSO-D ₆): 1.28 (12H, s), 1.51 (3H, d), 2.93-2.99 (1H, m), 3.03-3.13 (2H, m), 3.20-3.26 (1H, m), 5.32 (1H, dd), 6.19 (1H, br s), 7.20-7.28 (3H, m), 7.33-7.36 (2H, m); LC/MS M+1 (obs.) 433.4.

Step 4:1-[1-(2-chloro-phenyl)-ethyl]-7-imidazo [1,2-a] pyridin-3-yl-1,2,3,4-tetrahydrochysene-thieno-[3,2-e] [1,4] diaza

-5-ketone (I-7).

[124] with 1-[1-(2-chloro-phenyl)-ethyl]-7-(4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane-2-yl)-1,2,3,4-tetrahydrochysene-thieno-[3,2-e] [1,4] diaza

-5-ketone (251mg, 0.58mmol, 1.3 equivalents), 3-iodo-imidazo [1,2-a] pyridine (109mg, 0.45mmol, 1.0 equivalents) and Pd (PPh ₃) 4 (52mg, 0.045mmol, 0.1 equivalents) are dissolved in toluene (1.6mL)/EtOH (0.4mL).Add 2M K ₂CO ₃(0.45mL, 0.89mmol, 2.0 equivalents), under microwave condition in 140 ℃ of following reacting by heating 15 minutes.Add entry (10mL) and EtOAc (15mL), layering.(3 * 10mL) aqueous layer extracted are washed the organic layer that merges with salt solution (15mL), dry (MgSO with EtOAc ₄), concentrating under reduced pressure.By the chromatography purification crude product, produce title compound, be faint yellow solid (66mg, 0.16mmol, 35%); ¹H-NMR (DMSO-D ₆): 1.57 (3H, d), 2.92-3.00 (1H, m), 3.10-3.18 (1H, m), 3.29-3.33 (2H, m), 5.51 (1H, q), 7.12 (1H, t), 7.36-7.46 (4H, m), 7.52 (1H, d), 7.59 (1H, d), 7.69-7.75 (2H, m), 7.95 (1H, s), 8.62 (1H, d); LC/MS M+1 (obs.) 423.1, LC/MS M-1 (obs.) 421.3.

Embodiment 8:PLK assay method

[125] utilize following assay method, The compounds of this invention can be evaluated as people PLK kinase inhibitor.

PLK1 restraining effect assay method:

[126] utilize radiophosphorus hydrochlorate binding assay SCREENED COMPOUND to suppress the ability of PLK1.At 25mM HEPES (pH 7.5), 10mM MgCl ₂With test in the mixture of 1mM DTT.Final concentration of substrate is 50 μ m[γ-33P] ATP (136mCi 33P ATP/mmolATP, Amersham Pharmacia Biotech/Sigma Chemicals) and 10 μ M peptides (SAM68 albumen Δ 332-443).Under 25 ℃, in the presence of 15nM PLK1 (A20-K338), measure.Formation determination deposit buffered soln wherein contains whole reagent of as above enumerating, except ATP and the relevant test compound.30 μ L stock solutions are placed 96 hole flat boards,, wherein contain the serial dilutions (starting from the ultimate density of 10 μ M usually) of test compound, duplicate (final DMSO concentration 5%) by 2 times of serial dilutions succeeded by adding 2 μ L DMSO storing solutions.Flat board 25 ℃ of following preincubation 10 minutes, is added 8 μ L[γ-33P] ATP (ultimate density 50 μ M) initiation reaction.

Add 100 μ L 0.14M phosphoric acid, termination reaction after [127] 60 minutes.To sieve phosphorylated cotton filters 96 hole flat boards (Millipore Cat.No.MAPHN0B50) with 100 μ L0.2M phosphoric acid pre-treatment, adds 125 μ L institute terminated then and measures mixtures more.Each described dull and stereotyped four times with 200 μ L0.2M phosphoric acid washings.After the drying, add 100 μ L Optiphase ' SuperMix ' liquid scintillation cocktail reagents (Perkin Elmer) to aperture, then scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).

[128] remove the average background value of all data point after, utilize Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California is USA) from nonlinear regression analysis calculating K i (app) data of initial rate data.

PLK1 restraining effect assay method:

[129] utilize radiophosphorus hydrochlorate binding assay SCREENED COMPOUND to suppress the ability of PLK1.At 25mM HEPES (pH 7.5), 10mM MgCl ₂, 0.1%BSA and 2mM DTT mixture in measure.Final concentration of substrate is 100 μ M[γ-33P] ATP (115mCi 33PATP/mmol ATP, Amersham Pharmacia Biotech/Sigma Chemicals) and 300 μ M peptides (KKKISDELMDATFADQEAK) (SEQ ID NO:1).In the presence of 25nM PLK1, under 25 ℃, measure.Formation determination deposit buffered soln wherein contains whole reagent of as above enumerating, except ATP and the relevant test compound.30 μ L stock solutions are placed 96 hole flat boards,, wherein contain the serial dilutions (starting from the ultimate density of 10 μ M usually) of test compound, duplicate (final DMSO concentration 5%) by 2 times of serial dilutions succeeded by adding 2 μ L DMSO storing solutions.Flat board 25 ℃ of following preincubation 10 minutes, is added 8 μ L[γ-33P] ATP (ultimate density 100 μ M) initiation reaction.

Add 100 μ L 0.14M phosphoric acid, termination reaction after [130] 90 minutes.To sieve phosphorylated cotton filters 96 hole flat boards (Millipore Cat.No.MAPHNOB50) with 100 μ L0.2M phosphoric acid pre-treatment, adds 125 μ L institute terminated then and measures mixtures more.Each described dull and stereotyped four times with 200 μ L0.2M phosphoric acid washings.After the drying, add 100 μ L Optiphase ' SuperMix ' liquid scintillation cocktail reagents (Perkin Elmer) to aperture, then scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).

[131] remove the average background value of all data point after, utilize Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California is USA) from nonlinear regression analysis calculating K i (app) data of initial rate data.

PLK2 restraining effect assay method:

[132] utilize radiophosphorus hydrochlorate binding assay SCREENED COMPOUND to suppress the ability of PLK2.In the mixture of 25mM HEPES (pH 7.5), 10mM MgCl2,0.1%BSA and 2mM DTT, measure.Final concentration of substrate is 200 μ M[γ-33P] ATP (57mCi 33PATP/mmol ATP, Amersham Pharmacia Biotech/Sigma Chemicals) and 300 μ M peptides (KKKISDELMDATFADQEAK) (SEQ ID NO:1).Under 25 ℃, in the presence of 25nM PLK2, measure.Formation determination deposit buffered soln wherein contains whole reagent of as above enumerating, except ATP and the relevant test compound.30 μ L stock solutions are placed 96 hole flat boards,, wherein contain the serial dilutions (starting from the ultimate density of 10 μ M usually) of test compound, duplicate (final DMSO concentration 5%) by 2 times of serial dilutions succeeded by adding 2 μ L DMSO storing solutions.Flat board 25 ℃ of following preincubation 10 minutes, is added 8 μ L[γ-33P] ATP (ultimate density 200 μ M) initiation reaction.

Add 100 μ L 0.14M phosphoric acid, termination reaction after [133] 90 minutes.To sieve phosphorylated cotton filters 96 hole flat boards (Millipore Cat.No.MAPHN0B50) with 100 μ L0.2M phosphoric acid pre-treatment, adds 125 μ L institute terminated then and measures mixtures more.Each described dull and stereotyped four times with 200 μ L0.2M phosphoric acid washings.After the drying, add 100 μ L Optiphase ' SuperMix ' liquid scintillation cocktail reagents (Perkin Elmer) to aperture, then scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).

[134] remove the average background value of all data point after, utilize Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California is USA) from nonlinear regression analysis calculating K i (app) data of initial rate data.

PLK3 restraining effect assay method:

[135] utilize radiophosphorus hydrochlorate binding assay SCREENED COMPOUND to suppress the ability of PLK3.At 25mM HEPES (pH 7.5), 10mM MgCl ₂With test in the mixture of 1mM DTT.Final concentration of substrate is 75 μ M[γ-33P] ATP (60mCi 33P ATP/mmolATP, Amersham Pharmacia Biotech/Sigma Chemicals) and 10 μ M peptides (SAM68 albumen Δ 332-443).Under 25 ℃, in the presence of 5nM PLK3 (S38-A340), measure.Formation determination deposit buffered soln wherein contains whole reagent of as above enumerating, except ATP and the relevant test compound.30 μ L stock solutions are placed 96 hole flat boards,, wherein contain the serial dilutions (starting from the ultimate density of 10 μ M usually) of test compound, duplicate (final DMSO concentration 5%) by 2 times of serial dilutions succeeded by adding 2 μ L DMSO storing solutions.Flat board 25 ℃ of following preincubation 10 minutes, is added 8 μ L[γ-33P] ATP (ultimate density 75 μ M) initiation reaction.

Add 100 μ L 0.14M phosphoric acid, termination reaction after [136] 60 minutes.To sieve phosphorylated cotton more and filter 96 hole flat boards (Millipore, Cat No.MAPHN0B50), and add 125 μ L institute terminated then and measure mixture with 100 μ L0.2M phosphoric acid pre-treatment.Each described dull and stereotyped four times with 200 μ L0.2M phosphoric acid washings.After the drying, add 100 μ L Optiphase ' SuperMix ' liquid scintillation cocktail reagents (Perkin Elmer) to aperture, then scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).

[137] remove the average background value of all data point after, utilize Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California is USA) from nonlinear regression analysis calculating K i (app) data of initial rate data.

PLK4 restraining effect assay method:

[138] utilize radiophosphorus hydrochlorate binding assay SCREENED COMPOUND to suppress the ability of PLK4.At 8mM MOPS (pH 7.5), 10mM MgCl ₂, 0.1%BSA and 2mM DTT mixture in measure.Final concentration of substrate is 15 μ M[γ-33P] ATP (227mCi 33PATP/mmol ATP, Amersham Pharmacia Biotech/Sigma Chemicals) and 300 μ M peptides (KKKMDATFADQ) (SEQ ID NO:2).Under 25 ℃, in the presence of 25nM PLK4, measure.Formation determination deposit buffered soln wherein contains whole reagent of as above enumerating, except ATP and the relevant test compound.30 μ L stock solutions are placed 96 hole flat boards,, wherein contain the serial dilutions (starting from the ultimate density of 10 μ M usually) of test compound, duplicate (final DMSO concentration 5%) by 2 times of serial dilutions succeeded by adding 2 μ L DMSO storing solutions.Flat board 25 ℃ of following preincubation 10 minutes, is added 8 μ L[γ-33P] ATP (ultimate density 15 μ M) initiation reaction.

Add 100 μ L 0.14M phosphoric acid, termination reaction after [139] 180 minutes.To sieve phosphorylated cotton filters 96 hole flat boards (Millipore Cat.no.MAPHN0B50) with 100 μ L0.2M phosphoric acid pre-treatment, adds 125 μ L institute terminated then and measures mixtures more.Each described dull and stereotyped four times with 200 μ L0.2M phosphoric acid washings.After the drying, add 100 μ L Optiphase ' SuperMix ' liquid scintillation cocktail reagents (Perkin Elmer) to aperture, then scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).

After removing the average background value of all data point, utilize Prism software package (GraphPadPrism version 3.0cx for Macintosh, GraphPad Software, San DiegoCalifornia is USA) from nonlinear regression analysis calculating K i (app) data of initial rate data.

Sequence table

<110>Vertex?Pharmaceuticals?Incorporated

＜120〉can be used as the compound of kinases inhibitor

<130>125805/00387

<160>2

<170>PatentIn?version?3.3

<210>1

<211>19

<212>PRT

＜213〉artificial sequence

<220>

＜223〉SAM68 peptide

<400>1

Lys?Lys?Lys?Ile?Ser?Asp?Glu?Leu?Met?Asp?Ala?Thr?Phe?Ala?Asp?Gln

1 5 10 15

Glu?Ala?Lys

<210>2

<211>11

<212>PRT

＜213〉artificial sequence

<220>

＜223〉SAM68 peptide

<400>2

Lys?Lys?Lys?Met?Asp?Ala?Thr?Phe?Ala?Asp?Gln

1 5 10

Claims (34)

1. formula (I) compound:

Or its pharmacy acceptable salt; Wherein

Ring A is

Wherein encircle A and go up each commutable carbon atom alternatively by halogeno-group, C _1-6Alkyl, cycloalkyl, aryl or heteroaryl replace, wherein each C _1-6Alkyl, cycloalkyl, aryl or heteroaryl are alternatively by 1-3 J ^AGroup replaces;

Z be S ,-NQ-or O;

Z ₁Be N;

X ¹Be O ,-NR ⁵-, S or-CR ⁵R ⁵'-;

R ¹Be 6-unit ring, be selected from

And condense with ring B alternatively; Perhaps R ¹Be

With

R ¹Alternatively by 1-5 R ⁵Group replaces;

Y is C or N independently of one another;

Ring B is that 3-is saturated to 8-unit, part is unsaturated or aromatic monocyclic, has 1-4 heteroatoms that is selected from nitrogen, oxygen or sulphur independently of one another;

R ²And R ³Be H independently of one another, C _1-4Alkyl, C _3-6Cycloalkyl, 3-is saturated to 8-unit, part is unsaturated or aromatic monocyclic, has 0-4 heteroatoms that is selected from nitrogen, oxygen or sulphur independently of one another; Perhaps 8-is saturated to 12-unit, part is unsaturated or the aromatics dicyclo, has 0-5 heteroatoms that is selected from nitrogen, oxygen or sulphur independently of one another; And R ²And R ³Respectively alternatively by 0-5 J ²A group and 0-5 J ³Group replaces; Perhaps

R ²And R ³With the carbon atom that they connect, form 3-to the saturated or unsaturated monocycle of part of 8-unit, wherein said ring has 0-2 heteroatoms that is selected from nitrogen, oxygen or sulphur independently of one another, and described ring is alternatively by 0-5 J ²³Group replaces;

R ⁵Or R ⁵' be H, T independently of one another ¹, Q or-T ¹-Q;

T ¹Be C independently of one another _1-6Aliphatic group, wherein said C _1-6In the aliphatic group at the most three MU (methylene unit) alternatively by-NR-,-O-,-S-,-C (O)-,-C (=NR)-,-C (=NOR)-,-SO-or-SO ₂-replace; And each T ¹Alternatively by 0-2 J ¹Group replaces;

Q is H independently of one another, C _1-6Aliphatic group, 3-have 0-4 heteroatoms that is selected from O, N or S independently of one another to 8-unit's aromatics or non-aromatic monocyclic; Perhaps 8-has 0-5 heteroatoms that is selected from O, N or S independently of one another to 12-unit's aromatics or non-aromatics dicyclo ring system; Each Q is alternatively by 0-5 J ^QGroup replaces;

J ^Q, J ^T, J ², J ³And J ²³Be selected from H independently of one another, C _3-6The cyclic aliphatic base, halo (C _1-4Aliphatic group) ,-O (halo C _1-4Aliphatic group), 3-6 unit heterocyclic radical, halogeno-group, NO ₂, CN or C _1-6Aliphatic group, wherein said C _1-6In the aliphatic group at the most three MU (methylene unit) alternatively by-NR-,-O-,-S-,-C (O)-,-C (=NR)-,-C (=NOR)-,-SO-or-SO ₂-replace;

J ^AOr R ^JBe selected from H independently of one another, halogeno-group, NO ₂, CN, C _3-6The cyclic aliphatic base, halo (C _1-4Aliphatic group) ,-O (halo C _1-4Aliphatic group), 3-is to 6-unit heterocyclic radical, and 5-has 0-4 heteroatoms that is selected from nitrogen, oxygen or sulphur independently of one another to 6-unit monocyclic aromatic ring, and 8-has 0-5 heteroatoms that is selected from nitrogen, oxygen or sulphur independently of one another to 12-unit aromatics dicyclo, or C _1-6Aliphatic group, wherein said C _1-6In the aliphatic group at the most three MU (methylene unit) alternatively by-NR-,-O-,-S-,-C (O)-,-C (=NR)-,-C (=NOR)-,-SO-or-SO ₂-replace;

R is H or the C that is unsubstituted independently of one another _1-6Alkyl;

J is halogeno-group, CN, NO independently of one another ₂, C _1-4Aliphatic group, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein each C _1-4Aliphatic group, cycloalkyl, heterocyclic radical, aryl or heteroaryl are alternatively by 1-3 R ^JGroup replaces, perhaps

Two carbon atoms that the J group connects with them, formation 3-is saturated to 8-unit, part is unsaturated or aromatic monocyclic, and wherein said ring has 1-4 heteroatoms that is selected from nitrogen, oxygen or sulphur independently of one another, and described ring is alternatively by 1-3 R ^JGroup replaces; Perhaps

J group and R ²Or R ³The carbon atom that connects them forms that 3-is saturated to 8-unit, part is unsaturated or aromatic monocyclic, and wherein said ring has the individual heteroatoms that is selected from nitrogen, oxygen or sulphur independently of one another of 1-4, and described ring is alternatively by 1-3 R ^JGroup replaces;

Condition is to work as R ²And R ³All be H or all be methyl, X ¹Be CH ₂, and ring A is The time, R so ¹Be not

2. the compound of claim 1, wherein Z is S.

3. the compound of claim 1 or claim 2 wherein encircles A and is

4. the compound of claim 1 or claim 2 wherein encircles A and is

5. the compound of claim 3 or claim 4, wherein Z is S.

6. each compound of claim 1-5, wherein R ¹Be

And alternatively by 1-5 R ⁵Group replaces.

7. the compound of claim 6, wherein R ¹Be

And alternatively by 1-5 R ⁵Group replaces.

8. each compound of claim 1-5, wherein R ¹Be and ring B condensed six-ring, wherein said six-ring is

Or And ring B is that 3-is saturated to 8-unit, part is unsaturated or aromatic monocyclic, has 1-4 heteroatoms that is selected from nitrogen, oxygen or sulphur independently of one another, and each described 6-unit's ring and ring B are alternatively by 1-5 R ⁵Group replaces.

9. the compound of claim 8, wherein R ¹Heteroaryl-condensed with 5-to 6-unit

Wherein said condensed pyridine-heteroaryl ring system is alternatively by 1-5 R ⁵Group replaces.

10. the compound of claim 9, wherein R ¹Be and the pyrrole ring condensed

Wherein said condensed pyridine-pyrroles's ring system is alternatively by 1-5 R ⁵Group replaces.

11. the compound of claim 8, wherein R ¹Be alternatively by 1-5 R ⁵The Er hydrogen benzoxazine that group replaces.

12. each compound of claim 1-5, wherein R ¹Be

Wherein said and ring B condensed 5-unit encircles alternatively by 1-5 R ⁵Group replaces.

13. each compound of claim 1-8, wherein X ¹Be NR ⁵

14. the compound of claim 13, wherein R ⁵Be-T ¹-Q.

15. the compound of claim 14, wherein T ¹Be C _1-4Alkyl.

16. the compound of claim 14, wherein Q is 5-to 6-unit aromatic monocyclic, has 0-4 heteroatoms that is selected from O, N and S independently of one another; Or 9-has 0-5 heteroatoms that is selected from O, N and S independently of one another to 10-unit aromatics dicyclo.

17. each compound of claim 1-8, wherein X ¹Be-CR ⁵R ⁵'-.

18. the compound of claim 17, wherein R ⁵And R ⁵' all be H.

19. each compound of claim 1-18, wherein R ²And R ³Be H or the C that is unsubstituted independently of one another _1-4Alkyl.

20. the compound of claim 19, wherein R ²And R ³All be H.

21. the compound of claim 19, wherein R ²And R ³One of be C _1-4Alkyl.

22. the compound of claim 19, wherein R ²And R ³All be C _1-4Alkyl.

23. the compound of claim 1, by formula (II) or formula (III) representative,

Wherein p is 0,1 or 2.

24. the compound of claim 1 is selected from:

25. composition comprises any one compound of claim 1-24 and pharmaceutically acceptable carrier, auxiliary agent or media.

26. the method for arrestin kinase activity in the patient of needs comprises and gives claim 1-24 each compound to described patient.

27. the method for the protein kinase activity in the inhibition biological sample comprises each compound of described biological sample and claim 1-24 is contacted.

28. the method for claim 26 or 27, wherein said protein kinase is PLK1.

29. the method for the illness of treatment propagation illness, neurodegeneration illness, autoimmunization illness, inflammatory illness or immunology-mediation in the patient of needs treatments comprises and gives claim 1-24 each compound to described patient.

30. the method for claim 29, further comprise described patient is selected from following additional treatment agent: the medicine of the medicine of the medicine of the medicine of chemotherapy or antiproliferative, anti-inflammatory agent, immunoregulation or immunosuppressor, neurotrophic factor, treatment cardiovascular disorder, the destructive bone disorder of treatment, the medicine of treatment hepatopathy, antiviral agent, treatment blood illness, the medicine of treatment diabetes or treatment immune deficiency illness, wherein said additional treatment agent is suitable for described disease of being treated; And described additional treatment agent separates a part of administration as polynary formulation with described composition as single formulation administration or with described composition.

31. in the patient of needs treatments, treat melanoma, myelomatosis, leukemia, lymphoma, neuroblastoma or be selected from the method for cancer of colon, mammary gland, stomach, ovary, uterine neck, lung, central nervous system (CNS), kidney, prostate gland, bladder or pancreas, comprise and give claim 1-24 each compound to described patient.

32. in the patient of needs treatments, treat method for cancer, comprise and give claim 1-24 each compound to described patient.

33. the method for preparation formula (I) compound:

Comprise formula (B) compound and formula R ¹-CP ²Compound reaction under suitable coupling condition forms formula (I) compound,

Wherein

At formula (among the A), ring A, X ¹, J, R ²And R ³Each defines as claim 1-24;

In formula (B), ring A, X ¹, J, R ²And R ³Such as claim 1 definition, CP ¹Be the coupling partner who suits; With

At compound R ¹-CP ²In, R ¹Such as claim 1 definition, CP ²Be CP ¹Suitable coupling partner.

34. the method for claim 33 further is included in reaction formula under the Sandmeyer condition (A) compound:

Form the step of formula (B) compound.