CN101772500A

CN101772500A - Imidazopyrazines as protein kinase inhibitors

Info

Publication number: CN101772500A
Application number: CN200880101960A
Authority: CN
Inventors: 于涛; D·B·贝兰格; A·D·凯拉奇; 孟昭洋; J·R·塔加特; S·J·伊斯波兹; A·K·曼达; 萧玉玺; B·A·库卡尼; 张永琏; P·J·克伦; R·达尔; M·A·西迪昆
Original assignee: Schering Corp
Current assignee: Merck Sharp and Dohme Corp
Priority date: 2007-06-14
Filing date: 2008-06-11
Publication date: 2010-07-07
Also published as: CA2690557A1; WO2008156614A3; JP2010529195A; WO2008156614A2; MX2009013729A; PE20090365A1; CL2008001745A1; TW200911811A; AR066958A1; EP2170892A2

Abstract

In many embodiments of the present invention, it provides the Imidazopyrazines compound as protein and/or the kinase whose inhibitor of aurora body of new kind, the method for preparing this kind compound, the medical composition that comprises one or more these compounds, preparation comprises the method for the medicine prescription of one or more these compounds, uses this kind compound or medical composition to treat, prevent, suppress or improve the method for one or more and protein or aurora body kinases diseases associated.

Description

Imidazopyrazines as protein kinase inhibitors

Invention field

The present invention relates to imidazo [1,2-a] pyrazine compound, it can be used as protein kinase inhibitors, conditioning agent or modulator and uses, the medical composition that contains this compounds, and the methods of treatment of using this compounds and composition, to treat for example following disease: cancer, inflammation, sacroiliitis, virus disease, neurodegenerative disease for example Ah ear are grown extra large Mo's disease, cardiovascular disorder and fungal disease.The compounds of this invention especially can be used as aurora body kinase inhibitor and uses.

Background technology

Protein kinase is a kind of enzyme family, the hydroxyl of specific tyrosine, Serine or threonine residues in the phosphorylated effect, particularly protein of its meeting catalytic proteins.Protein kinase is the hinge of the adjusting of many kinds of cell processes, and described cell processes comprises metabolism, hyperplasia, cytodifferentiation and cell survival.Uncontrolled hyperplasia is the sign of cancer cells, and one of can be in two ways imbalance by cell division cycle prove-cause pungency gene hyperactivity hyperkinesia or Inhibit Genes inactivation.Protein kinase inhibitors, conditioning agent or modulator can change kinase whose function, for example cyclin-dependent kinase (CDK), mitogen activation of protein kinases (MAPK/ERK), glycogen synthase kinase 3 (GSK3 β), check point (Chk) kinases (for example CHK-1, CHK-2 etc.), AKT kinases, JNK etc.The example of protein kinase inhibitors and by people such as Y.Mettey, in J.Med.Chem., is described among (2003) 46222-236 in WO02/22610 A1.

Cyclin-dependent kinase is a serine/threonine protein matter kinases, and it is cell cycle and hyperplasia motivating force behind.The mistake of CDK function is adjusted in many important noumenal tumours and takes place with high frequency.Indivedual CDK, for example CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK7, CDK8 etc. have given play to unique effect in the cell cycle progress, and can be classified as be G1, S or G2M phase enzyme.CDK2 and CDK4 make us interested especially, because of its activity is regulated by wrong in many kinds of human cancers continually.The CDK2 activity is needed through the process of G1 to the S phase of cell cycle, and CDK2 is one of crucial composition of G1 check point.The check point is in order to the correct order of maintenance cell cycle incident, and the permission cell takes place yet the forfeiture that suitable check point is controlled in the cancer cells can encourage tumour invading or the hyperplasia signal being had response.The CDK2 approach can take place in the level affects tumour of tumor suppressor gene function (for example p52, RB and p27) with oncogene activation (plain E of cycle).Many reports confirm, plain E of the coactivator cycle of CDK2 and inhibitor p27, both excessively or insufficiently are expressed in mastocarcinoma, colorectal carcinoma, nonsmall-cell lung cancer, cancer of the stomach, prostate cancer, bladder cancer, non-Hodgkin lymphomas, ovarian cancer and other cancer respectively.Their expression through changing has been proved with the CDK2 level of activity and the bad overall survival that increase interrelated.This observation makes CDK2 and adjusting approach thereof become noticeable target in the exploitation of cancer therapy medicine.

Competitive little organic molecule of many adenosine 5'-triphosphates (ATP) and peptide are reported the CDK inhibitor as the potential treatment of cancer in the literature.U.S.6,413,974 the 23rd row-Di 15 hurdles the 10th, the 1st hurdle row provide various CDK and with the good description of the relation of various cancer types.Flavones pyridine alcohol (Flavopiridol, hereinafter shown in) is a kind of non-selective CDK inhibitor, and it is carrying out human clinical trial, people such as A.M.Sanderowicz, J.Clin.Oncol. (1998) 16,2986-2999 at present.

The known inhibitor of other of CDK comprises for example olomoucine (olomoucine) (people such as J.Vesely, Eur.J.Biochem., (1994) 224, but 771-786) with Loews Wei Ting (roscovitine) (people such as I.Meijer, Eur.J.Biochem., (1997) 243,527-536).U.S.6,107,305 have described some pyrazolo as the CDK inhibitor [3,4-b] pyridine compounds.The illustrative of compounds of a kind of deriving from ' 305 patents is:

People such as K.S.Kim, J.Med.Chem.45 (2002) 3905-3927 and WO 02/10162 disclose some aminothiazole compounds as the CDK inhibitor.Imidazoles pyrazine class is known.For example, U.S.6,919,341 (it is for reference that its disclosure is incorporated this paper into) disclose various Imidazopyrazines with US2005/0009832.Also can point out have following these: WO2005/047290; US2005/095616; WO2005/039393; WO2005/019220; WO2004/072081; WO2005/014599; WO2005/009354; WO2005/005429; WO2005/085252; US2005/009832; US2004/220189; WO2004/074289; WO2004/026877; WO2004/026310; WO2004/022562; WO2003/089434; WO2003/084959; WO2003/051346; US2003/022898; WO2002/060492; WO2002/060386; WO2002/028860; JP (1986) 61-057587; People such as J.Burke, J.Biological Chem., the 278th (3) volume, 1450-1456 (2003); With people J.Med.Chem. such as F.Bondavalli, the 45th (22) volume, 4875-4887 (2002).

Also can be used as the US 2004/0220189 (on November 4th, 2004 is open) of reference; US2005/0009832 (on January 13rd, 2005 is open); US 2006/0084650 (on April 20th, 2006 open), it is the description kinase inhibitor, and US 2006/0106023 (on May 18th, 2006 is open), its they Imidazopyrazine as the cyclin-dependent kinase inhibitor described.In addition, US2007/0117804 (on May 24th, 2007 is open) has described the conduct Imidazopyrazines of the protein kinase inhibitors of array structure down:

Following formula: compound:

Or its pharmacy acceptable salt, solvate, ester or prodrug, wherein:

R be H, CN ,-NR ⁵R ⁶, cycloalkyl, cycloalkenyl group, heterocycloalkenyl, heteroaryl ,-C (O) NR ⁵R ⁶,-N (R ⁵) C (O) R ⁶, heterocyclic radical, quilt (CH ₂) _1-3NR ⁵R ⁶The heteroaryl that replaces, unsubstituted alkyl or be can be the alkyl that identical or different part group replaces by one or more, the each several part group is independently selected from-OR ⁵, heterocyclic radical ,-N (R ⁵) C (O) N (R ⁵R ⁶) ,-N (R ⁵)-C (O) OR ⁶,-(CH ₂) _1-3-N (R ⁵R ⁶) and-NR ⁵R ⁶

R ¹Be H, halogen, aryl or heteroaryl, wherein respectively this aryl and heteroaryl can not be substituted, or be can be identical or different part group and replace by one or more, the each several part group be independently selected from halogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic radical ,-CH ₂OR ⁵,-C (O) NR ⁵R ⁶,-C (O) OH ,-C (O) NH ₂,-NR ⁵R ⁶(R wherein ⁵With R ⁶And this-NR ⁵R ⁶N form heterocyclic ring together) ,-S (O) R ⁵,-S (O ₂) R ⁵,-CN ,-CHO ,-SR ⁵,-C (O) OR ⁵,-C (O) R ⁵And-OR ⁵

R ²Be H, halogen, aryl, aralkyl or heteroaryl, wherein respectively this aryl, aralkyl and heteroaryl can not be substituted, or optional can be identical or different part group and replace by one or more independently, the each several part group be independently selected from halogen, acid amides, alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl ,-C (O) OH ,-C (O) NH ₂,-NR ⁵R ⁶(R wherein ⁵With R ⁶And this-NR ⁵R ⁶N form heterocyclic ring together) ,-CN, aralkyl ,-CH ₂OR ⁵,-S (O) R ⁵,-S (O ₂) R ⁵,-CN ,-CHO ,-SR ⁵,-C (O) OR ⁵,-C (O) R ⁵, heteroaryl and heterocyclic radical;

R ³Be H, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein:

-above about R ³This shown alkyl can not be substituted, or be can be identical or different part group and replace by one or more, and the each several part group is independently selected from-OR ⁵, alkoxyl group, heteroaryl and-NR ⁵R ⁶

-above about R ³This shown aryl is not substituted, or it is optional by halogen, heteroaryl, heterocyclic radical, cycloalkyl or heteroaralkyl replacement, or optional condense with it, wherein respectively this heteroaryl, heterocyclic radical, cycloalkyl and heteroaralkyl can not be substituted, or optional can be identical or different part group and replace by one or more independently, the each several part group independently be selected from alkyl ,-OR ⁵,-N (R ⁵R ⁶) and-S (O ₂) R ⁵And

-above about R ³This shown heteroaryl can not be substituted, or optional can be identical or different part group and replace by one or more, or optionally condenses with it, wherein the each several part group be independently selected from halogen, amino, carbalkoxy ,-OR ⁵, alkyl ,-CHO ,-NR ⁵R ⁶,-S (O ₂) N (R ⁵R ⁶) ,-C (O) N (R ⁵R ⁶) ,-SR ⁵, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkenyl and heterocyclic radical;

R ⁵Be H, alkyl, aminoalkyl group, aryl, heteroaryl, heterocyclic radical or cycloalkyl; And

R ⁶Be H, alkyl, aryl, aralkyl, heteroaryl, heterocyclic radical or cycloalkyl;

In addition, wherein in formula I, at any-NR ⁵R ⁶In, this R ⁵With R ⁶Can choose wantonly and be somebody's turn to do-NR ⁵R ⁶N combine, to form cyclic rings.

Another serial protein kinase is to play the part of one as those of the key player of check point in cell cycle progress.The check point can prevent that cell cycle from making progress under the inappropriate time, for example respond the DNA injury, and the metabolic balance that when cell is contained, keeps cell, and in some cases, when the requirement condition of check point is not satisfied as yet, can cause apoptosis (apoptosis).Check point control can occur in the G1 phase (before DNA is synthetic) and in G2, in entering mitotic division before.

Genomic integrity can be monitored in a series of check points, and when sensing DNA injured, this type of " DNA injures the check point " can be at G ₁And G ₂Interim blocking-up cell cycle is made progress, and slows down the progress through the S phase.This effect make the DNA mending course can the producer group duplicate and the later separation of this genetic stew is finished its work before to the new daughter cell.The inactivation of CHK1 has been proved and can transduction have injured the signal of feeling mixture from DNA-, with the kinase whose activation of plain B/Cdc2 of inhibition cycle, it can promoting mitosis enters, and eliminates the G that the DNA that the applies injury brought out because of carcinostatic agent or the injury of interior source DNA is caused ₂The containment, and can cause preferentially kill the damaged cell in the check point that forms.Consult, people such as Peng for example, Science 277,1501-1505 (1997); People such as Sanchez, Science 277,1497-1501 (1997), Nurse, Cell, 91,865-867 (1997); Weinert, Science 277,1450-1451 (1997); People such as Walworth, Nature363,368-371 (1993); Reach people such as AI-Khodairy, Molec.Biol.Cell., 5,147-160 (1994).

The selectivity of check point control is controlled in cancer cells, can make to provide in the usage widely in cancer chemotherapeutic and radiotherapy and use, and the common sign of human cancer " genomic instability " can be provided in addition, and it is to desire to be developed the selectivity basis of destroying as cancer cells.The multiple factor is positioned over CHK1 on the maincenter target in the control of DNA-injury check point.This kind and functional go up associated kinase for example CDS1/CHK2 (kinases that the S phase makes progress is regulated in a kind of recent findings meeting and CHK1 cooperation) (consult people such as Zeng, Nature 395,507-510 (1998); Matsuoka, Science282,1893-1897 (1998)) the explanation of inhibitor the cancer therapy entity of valuable novelty can be provided.

Another group kinases is a Tyrosylprotein kinase.Tyrosylprotein kinase can be acceptor type (have born of the same parents outer, stride functional part in film and the born of the same parents) or non-acceptor type (being entirely in the born of the same parents).The acceptor type Tyrosylprotein kinase comprises a large amount of transmembrane receptors, has various biologic activity.In fact, about 20 kinds of different subtribes of acceptor type Tyrosylprotein kinase are identified.A kind of Tyrosylprotein kinase subtribe of the HER of being called subtribe comprises EGFR (HER1), HER2, HER3 and HER4.The ligand of this acceptor subtribe through confirming comprises epidermal growth factor, TGF-α, the two-ways regulation factor, HB-EGF, β cytokine (betacellulin) and heredity plain (heregulin) extremely so far.Another subtribe of this type of acceptor type Tyrosylprotein kinase is the Regular Insulin subtribe, and it comprises INS-R, IGF-IR, IR and IR-R.The PDGF subtribe comprises PDGF-α and beta receptor, CSFIR, c-kit and FLK-II.FLK family comprises that kinases inserts functional part acceptor (KDR), fetus liver kinases-1 (FLK-1), fetus liver kinases-4 (FLK-4) and like fms Tyrosylprotein kinase-1 (flt-1).About going through of acceptor type Tyrosylprotein kinase, can consult people such as Plowman, DN ﹠amp; P 7 (6): 334-339,1994.

It is believed that at least a non-receptor protein tyrosine kinases, meaning is LCK, can mediate from cell surface proteins (Cd4) to resist-transduction of the interactive signal of Cd4 antibody in the T-cell with crosslinked.More going through of nonreceptor tyrosine kinase is provided in Bolen, Oncogene, and 8, among the 2025-2031 (1993).The non-acceptor type of Tyrosylprotein kinase also comprises many subtribes, comprises Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack and LIMK.Each this type of subtribe further is divided into not isoacceptor again.For example, the Src subtribe is a kind of of maximum, and comprises Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.The Src subtribe of enzyme has been linked to and has been tied to the tumour generation.About more going through of the non-acceptor type of Tyrosylprotein kinase, can consult Bolen, Oncogene, 8:2025-2031 (1993).

Except the effect of protein kinase in cell cycle control, it also plays the part of a decisive role in vasculogenesis, and it is for passing through from the existing new microvascular mechanism of vascularization.When needs, this vascular system has the possibility that produces new capillary blood vessel network, to keep the suitable function of tissue and organ.But in the adult, vasculogenesis is considerably limited, occurs over just the process of wound healing, and in the endometrial neovascularity nucleus formation of intermenstrual period.On the other hand, the vasculogenesis of not expecting is the sign of several conditions, described disease for example retinopathy, psoriasis, rheumatoid arthritis, with aging relevant macular degeneration and cancer (noumenal tumour).Be proved the protein kinase that relates to angiogenesis, comprised three members of growth factor receptor tyrosine kinase family; (vascular endothelial growth factor receptor 2 also is called KDR (kinases insert functional part acceptor) and FLK1) to VEGF-R2; FGF-R (fibroblast growth factor acceptor); And TEK (also being called Tie-2).

The VEGF-R2 that only is expressed on the endotheliocyte can be in conjunction with effective blood vessel protogrowth factor VEGF, and through the active activation of its intracellular kinase, the mediation follow-up signal is transduceed.Therefore, the direct inhibition of expection VEGF-R2 kinase activity, will cause the reduction vasculogenesis, even in the presence of exogenous VEGF, also so (consult people such as Strawn, Cancer Research, 56,3540-3545 (1996)), it confirms that with the mutant of VEGF-R2 it fails to mediate signal transduction.People such as Millauer, Cancer Research, 56,1615-1620 (1996).In addition, VEGF-R2 is presented among the adult, except the angiogenic activity of mediation VEGF, does not have function.Therefore, the selective depressant of expection VEGF-R2 kinase activity can show extremely low toxicity.

Similarly, FGFR can be in conjunction with blood vessel protogrowth factor aFGF and bFGF, and mediates follow-up intracellular signal transduction.Recently, existing people points out somatomedin, and for example bFGF can play the part of a pivotal player in causing vasculogenesis in the noumenal tumour that reaches a certain size.People such as Yoshiji, Cancer Research, 57,3924-3928 (1997).But different with VEGF-R2, FGF-R is expressed in the multiple different cell type at whole body, and can or can not play an important role in other normal physiological processes of adult.Even so, the dispensing of the whole body of the micromolecular inhibitor of FGF-R kinase activity is reported that the blocking-up vasculogenesis that bFGF caused does not have tangible toxicity in mouse.People such as Mohammad, EMBO Journal, 17,5996-5904 (1998).

TEK (also being called Tie-2) is the another kind of receptor tyrosine kinase that only is expressed on the endotheliocyte, and it has been proved plays the part of a role in vasculogenesis.The combination of factor angiogenin-1 can cause TEK the kinase function position from the phosphorylated effect, and can cause the signal transduction process, it shows can mediation endotheliocyte and the interaction of endothelium sustenticular cell on every side, thereby helps Neovascularized maturation.On the other hand, factor angiopoietin-2 shows and can generate plain-1 effect for TEK by antagonizing vessel, and disintegrates vasculogenesis.People such as Maisonpierre, Science, 277,55-60 (1997).

Kinases JNK belongs to mitogen activation of protein kinases (MAPK) superfamily.JNK plays the part of a decisive role on inflammatory response, stress response, hyperplasia, apoptosis and tumour take place.The JNK kinase activity can be activated by various stimulations, comprises that costimulatory receptor (CD28 and CD40), DNA-nocuity chemical, radiation and Fas send signal altogether for proinflammatory cytokine (TNF-α and interleukin 1), lymphocyte.The result who derives from the disallowable mouse of JNK shows that JNK relates to apoptosis and brings out with t helper cell and break up.

Pim-1 is little serine/threonine kinase.The high expression level degree of Pim-1 is detected in lymph sample and marrow sample malignant disorders, and recently, Pim-1 is through confirming as the prognostic markers thing in prostate cancer.K.Peltola, " Signaling in Cancer:Pim-1 Kinase and itsPartners ", Annales Universitatis Turkuensis, Sarja-Ser.D Osa-Tom.616, (on August 30th, 2005), Http:// kirjasto.utu.fi/julkaisuralvelut/annaalit/ 2004/D616.htmlPim-1 uses liability factor as, and can prevent the apoptosis in the malignant cell.People such as K.Petersen Shay, Molecular Cancer Research, 3:170-181 (2005).

Kinase whose another group again is aurora body kinases.(aurora body-A, aurora body-B, aurora body-C) are serine/threonine protein matter kinases to aurora body kinases, and for example colorectal carcinoma, mastocarcinoma and other noumenal tumour are relevant with human cancer for they.It is believed that aurora body-A (also being called as AIK sometimes) is relevant with the protein phosphorylated incident of regulating cell cycle.Specifically, aurora body-A can play the part of a role on the chromosomal clean cut separation of control during mitotic division.The mistake of cell cycle is regulated and may be caused hyperplasia and other unusual.In cancerous human colon tumor tissue, found that aurora body-A, aurora body-B, aurora body-C (are consulted people such as Bischoff, EMBO J., 17:3052-3065 (1998) by overexpression; People such as Schumacher, J.Cell Biol.143:1635-1646 (1998); People such as Kimura, J.Biol.Chem., 272:13766-13771 (1997)).

Still need the especially kinase whose effective inhibitor of aurora body of protein kinase, with treatment or prevention and abnormal cells hyperplasia disease states associated.In addition, expect to have especially micromolecular compound of the kinase inhibitor that can easily be synthesized.

Summary of the invention

In many embodiments of the present invention, the imidazo [1 of the novel kind that provides, 2-a] pyrazine compound, the method for preparing this compounds, the medical composition that comprises one or more these compounds, preparation comprises the method for the medicine prescription of one or more these compounds, and uses this compounds or medical composition to treat, prevent, suppress or improve the method for one or more and protein kinase diseases associated.

On the one hand, the invention provides the compound of representing with formula I:

Or its pharmacy acceptable salt, solvate, ester or prodrug, wherein:

R ³Be heterocyclic radical-(CR ⁷R ⁸) _n-X, heterocycloalkenyl-(CR ⁷R ⁸) _n-X, heteroaryl-(CR ⁷R ₈) _n-X or aryl-(CR ⁷R ⁸) _n-X, wherein this R ³Each heterocyclic radical-, heterocycloalkenyl-, heteroaryl-or aryl-part group can not be substituted, or by one or more being independently selected from-CONR ⁵R ⁶,-OR ⁵And the replacement of the part group of alkyl,

N is 1-6,

X is selected from-NR ⁵R ⁶,-OR ⁵,-SO-R ⁵,-SR ⁵, SO ₂R ⁵, heteroaryl, heterocyclic radical and aryl, wherein this heteroaryl or aryl can not be substituted, or by one or more being independently selected from-O-alkyl, alkyl, halogen or NR ⁵R ⁶The part group replace;

R ⁷With R ⁸Be hydrogen, alkyl, heterocyclic radical, aryl, heteroaryl or cycloalkyl independently of one another;

R ⁵Be selected from hydrogen, alkyl, thiazolinyl, alkoxyalkyl ,-alkyl-S-alkyl, aminoalkyl group, aryl, heteroaryl, heterocycloalkenyl, Heterocyclylalkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical alkoxyl group ,-S-alkyl heterocyclic, heterocyclic radical, heterocycloalkenyl, alkyl N (alkyl) ₂, alkyl NH (alkyl), alkyl N (thiazolinyl) ₂,-alkyl N (alkoxyl group) ₂,-alkyl-SH, hydroxyalkyl, three alkylhalide groups, two alkylhalide groups, single alkylhalide group, wherein respectively this alkyl, thiazolinyl, alkoxyalkyl ,-alkyl-S-alkyl, aminoalkyl group, aryl, heteroaryl, heterocycloalkenyl, Heterocyclylalkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical alkoxyl group ,-S-alkyl heterocyclic, heterocyclic radical, heterocycloalkenyl, alkyl N (alkyl) ₂, alkyl NH (alkyl), alkyl N (thiazolinyl) ₂,-alkyl N (alkoxyl group) ₂,-alkyl-SH, hydroxyalkyl, three alkylhalide groups, two alkylhalide groups, single alkylhalide group can not be substituted, or replaced by one or more part groups, this part group be independently selected from alkyl, thiazolinyl, aryl, cycloalkenyl group, cycloalkyl, aralkyl, cycloalkenyl alkyl, cycloalkylalkyl, heteroaryl, heterocycloalkenyl, heterocyclic radical, heteroaralkyl, heterocycloalkenyl alkyl, Heterocyclylalkyl alkyl, alkoxyalkyl ,-alkyl-S-alkyl ,-alkyl SH, alkoxyl group ,-S-alkyl, hydroxyalkyl and aminoalkyl group;

R ⁶Be selected from hydrogen, alkyl, thiazolinyl, aryl, cycloalkenyl group, cycloalkyl, aralkyl, cycloalkenyl alkyl, cycloalkylalkyl, heteroaryl, heterocycloalkenyl, heterocyclic radical, heteroaralkyl, heterocycloalkenyl alkyl, Heterocyclylalkyl alkyl, alkoxyalkyl ,-alkyl-S-alkyl ,-alkyl SH, alkoxyl group ,-S-alkyl, hydroxyalkyl, aminoalkyl group ,-alkyl-OC (O) alkyl ,-alkyl OC (O) cycloalkyl ,-alkyl OC (O) aryl ,-alkyl OC (O) aralkyl ,-alkyl OC (O) NR ⁵Aryl ,-alkyl OC (O) NR ⁵Alkyl ,-alkyl OC (O) NR ⁵Heterocyclic radical ,-alkyl OC (O) NR ⁵Heteroaryl ,-alkyl OC (O) NR ⁵Cycloalkyl ,-alkyl OC (O) heterocyclic radical, alkyl C (O) OH, alkyl C (O) O alkyl ,-alkyl C (O) O cycloalkyl ,-alkyl C (O) O aryl ,-alkyl C (O) O aralkyl ,-alkyl C (O) ONR ⁵Aryl ,-alkyl C (O) ONR ⁵Alkyl ,-alkyl C (O) ONR ⁵Heterocyclic radical ,-alkyl C (O) ONR ⁵Heteroaryl ,-alkyl C (O) ONR ⁵Cycloalkyl ,-alkyl C (O) O heterocyclic radical, alkyl C (O) OH and alkyl C (O) O alkyl, wherein respectively this aryl, cycloalkenyl group, cycloalkyl, aralkyl, cycloalkenyl alkyl, cycloalkylalkyl, heteroaryl, heterocycloalkenyl, heterocyclic radical, heteroaralkyl, heterocycloalkenyl alkyl, Heterocyclylalkyl alkyl ,-alkyl-OC (O) alkyl ,-alkyl OC (O) cycloalkyl ,-alkyl OC (O) aryl ,-alkyl OC (O) aralkyl ,-alkyl OC (O) NR ⁵Aryl ,-alkyl OC (O) NR ⁵Alkyl ,-alkyl OC (O) NR ⁵Heterocyclic radical ,-alkyl OC (O) NR ⁵Heteroaryl ,-alkyl OC (O) NR ⁵Cycloalkyl ,-alkyl OC (O) heterocyclic radical, alkyl C (O) OH, alkyl C (O) O alkyl ,-alkyl C (O) O cycloalkyl ,-alkyl C (O) O aryl ,-alkyl C (O) O aralkyl ,-alkyl C (O) ONR ⁵Aryl ,-alkyl C (O) ONR ⁵Alkyl ,-alkyl C (O) ONR ⁵Heterocyclic radical ,-alkyl C (O) ONR ⁵Heteroaryl ,-alkyl C (O) ONR ⁵Cycloalkyl,-alkyl C (O) O heterocyclic radical, alkyl C (O) OH and alkyl C (O) O alkyl can not be substituted, or by one or more part groups replacements, this part group is independently selected from alkyl, thiazolinyl, aryl, cycloalkenyl group, cycloalkyl, aralkyl, cycloalkenyl alkyl, cycloalkylalkyl, heteroaryl, heterocycloalkenyl, heterocyclic radical, heteroaralkyl, the heterocycloalkenyl alkyl, the Heterocyclylalkyl alkyl, alkoxyalkyl,-alkyl-S-alkyl,-alkyl SH, alkoxyl group,-S-alkyl, hydroxyalkyl, aminoalkyl group, amino, amino dialkyl group, amino cycloalkyl, halogen, three alkylhalide groups, two alkylhalide groups and single alkylhalide group;

In addition, wherein in formula I, at any-NR ⁵R ⁶In, this R ⁵With R ⁶Can choose wantonly and be somebody's turn to do-NR ⁵R ⁶N combine, to form cyclic rings or bridge joint cyclic rings, wherein respectively this cyclic rings or bridge joint cyclic rings can not be substituted, or be can be identical or different part group and replace by one or more, this part group be independently selected from hydroxyl ,-SH, alkyl, thiazolinyl, hydroxyalkyl ,-alkyl-SH, alkoxyl group ,-the S-alkyl ,-CO ₂-alkyl ,-CO ₂-thiazolinyl, aralkyl, cycloalkenyl alkyl, cycloalkylalkyl, heteroaralkyl, heterocycloalkenyl alkyl, Heterocyclylalkyl alkyl, heteroaryl, aryl, cycloalkenyl group, cycloalkyl, spiro heterocyclic radical, spiroheterocyclic thiazolinyl, spiral shell heteroaryl, volution base, volution thiazolinyl, spiral shell aryl, alkoxyalkyl ,-alkyl-S-alkyl, heterocyclic radical, heterocycloalkenyl, halogen, three alkylhalide groups, two alkylhalide groups, CN and single alkylhalide group.

Formula I compound can be used as protein kinase inhibitors and uses.Formula I compound also can be used as aurora body kinase inhibitor and uses.Formula I compound can be used for treatment and prevention proliferative disease, for example cancer, inflammation and sacroiliitis, and neurodegenerative disease for example Ah ear is grown extra large Mo's disease, cardiovascular disorder, virus disease and fungal disease.

Describe in detail

In an embodiment, the invention provides the Imidazopyrazines compound, especially the imidazo of representing with structural formula I [1,2-a] pyrazine compound or its pharmacy acceptable salt, solvate, ester class or prodrug, wherein various part groups are all as above-mentioned.

In another embodiment, the invention provides the compound of representing with formula I:

Or its pharmacy acceptable salt, solvate, ester or prodrug, wherein:

R be H, CN ,-NR ⁵R ⁶, cycloalkenyl group, heterocycloalkenyl ,-C (O) NR ⁵R ⁶,-N (R ⁵) C (O) R ⁶Or by one or more alkyl that can be identical or different part group replacement, the each several part group is independently selected from-OR ⁵With-NR ⁵R ⁶

R ¹Be H, halogen, aryl or heteroaryl, wherein respectively this aryl and heteroaryl can not be substituted, or be can be identical or different part group and replace by one or more, the each several part group be independently selected from halogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic radical ,-C (O) NR ⁵R ⁶And-OR ⁵

R ²Be H, halogen or heteroaryl, wherein this heteroaryl can not be substituted, or be can be identical or different part group and replace by one or more, and the each several part group is independently selected from halogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical;

R ³Be heterocyclic radical-(CR ⁷R ⁸) _n-X, heterocycloalkenyl-(CR ⁷R ⁸) _n-X, heteroaryl-(CR ⁷R ⁸) _n-X or aryl-(CR ⁷R ⁸) _n-X, wherein this R ³Each heterocyclic radical-, heterocycloalkenyl-, heteroaryl-or aryl-part group can not be substituted, or by one or more being independently selected from-CONR ⁵R ⁶,-OR ⁵And the replacement of the part group of alkyl,

N is 1,

X is selected from-NR ⁵R ⁶,-OR ⁵,-SO-R ⁵And-SR ⁵,

R ⁷With R ⁸Be hydrogen or alkyl independently of one another;

R ⁵Be selected from hydrogen, alkyl, thiazolinyl, alkoxyalkyl ,-alkyl-S-alkyl, aminoalkyl group, aryl, heteroaryl, heterocycloalkenyl, Heterocyclylalkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical alkoxyl group ,-S-alkyl heterocyclic, heterocyclic radical, heterocycloalkenyl, alkyl N (alkyl) ₂, alkyl NH (alkyl), alkyl N (thiazolinyl) ₂,-alkyl N (alkoxyl group) ₂-alkyl-SH and hydroxyalkyl, this aryl respectively wherein, heteroaryl, heterocycloalkenyl, Heterocyclylalkyl, cycloalkyl, cycloalkenyl group, the heterocyclic radical alkoxyl group,-S-alkyl heterocyclic, heterocyclic radical, heterocycloalkenyl can not be substituted, or by one or more part groups replacements, this part group is independently selected from alkyl, alkyl, thiazolinyl, aryl, cycloalkenyl group, cycloalkyl, aralkyl, cycloalkenyl alkyl, cycloalkylalkyl, heteroaryl, heterocycloalkenyl, heterocyclic radical, heteroaralkyl, the heterocycloalkenyl alkyl, the Heterocyclylalkyl alkyl, alkoxyalkyl,-alkyl-S-alkyl,-alkyl SH, alkoxyl group,-S-alkyl, hydroxyalkyl and aminoalkyl group;

R ⁶Be selected from hydrogen, alkyl, thiazolinyl, aryl, cycloalkenyl group, cycloalkyl, aralkyl, cycloalkenyl alkyl, cycloalkylalkyl, heteroaryl, heterocycloalkenyl, heterocyclic radical, heteroaralkyl, the heterocycloalkenyl alkyl, the Heterocyclylalkyl alkyl, alkoxyalkyl,-alkyl-S-alkyl,-alkyl SH, alkoxyl group,-S-alkyl, hydroxyalkyl and aminoalkyl group, this aryl respectively wherein, cycloalkenyl group, cycloalkyl, aralkyl, cycloalkenyl alkyl, cycloalkylalkyl, heteroaryl, heterocycloalkenyl, heterocyclic radical, heteroaralkyl, the heterocycloalkenyl alkyl, the Heterocyclylalkyl alkyl can not be substituted, or by one or more part groups replacements, this part group is independently selected from alkyl, alkyl, thiazolinyl, aryl, cycloalkenyl group, cycloalkyl, aralkyl, cycloalkenyl alkyl, cycloalkylalkyl, heteroaryl, heterocycloalkenyl, heterocyclic radical, heteroaralkyl, the heterocycloalkenyl alkyl, the Heterocyclylalkyl alkyl, alkoxyalkyl,-alkyl-S-alkyl,-alkyl SH, alkoxyl group,-S-alkyl, hydroxyalkyl and aminoalkyl group;

In addition, wherein in formula I, at any-NR ⁵R ⁶In, this R ⁵With R ⁶Can choose wantonly and be somebody's turn to do-NR ⁵R ⁶N combine, to form cyclic rings or bridge joint cyclic rings, wherein respectively this cyclic rings or bridge joint cyclic rings can not be substituted, or be can be identical or different part group and replace by one or more, this part group be independently selected from hydroxyl ,-SH, alkyl, thiazolinyl, hydroxyalkyl ,-alkyl-SH, alkoxyl group ,-the S-alkyl ,-CO ₂-alkyl ,-CO ₂-thiazolinyl, aralkyl, cycloalkenyl alkyl, cycloalkylalkyl, heteroaralkyl, heterocycloalkenyl alkyl, Heterocyclylalkyl alkyl, heteroaryl, aryl, cycloalkenyl group, cycloalkyl, spiro heterocyclic radical, spiroheterocyclic thiazolinyl, spiral shell heteroaryl, volution base, volution thiazolinyl, spiral shell aryl, alkoxyalkyl ,-alkyl-S-alkyl, heterocyclic radical and heterocycloalkenyl.

In an embodiment, R, R ¹And R ²Be not H simultaneously entirely.

In another embodiment, in formula I, R ²Be unsubstituted heteroaryl or the heteroaryl that replaced by alkyl.

In another embodiment, in formula I, R ²Be the heteroaryl that is replaced by alkyl.

In another embodiment, in formula I, R ²Be pyrazolyl.

In another embodiment, in formula I, R ²Be the pyrazolyl that is replaced by alkyl.

In another embodiment, in formula I, R ²Be 1-methyl-pyrazoles-4-base.

In another embodiment, in formula I, R is H.

In another embodiment, in formula I, R is CN.

In another embodiment, in formula I, R is-C (O) NR ⁵R ⁶

In another embodiment, in formula I, R is-C (O) NH ₂

In another embodiment, in formula I, R is a heterocycloalkenyl.

In another embodiment, in formula I, R is a tetrahydro pyridyl.

In another embodiment, in formula I, R is 1,2,3, the 6-tetrahydro pyridyl.

In another embodiment, in formula I, R is that the each several part group is independently selected from-OR by one or more alkyl that can be identical or different part group replacement ¹With-NR ⁵R ⁶

In another embodiment, in formula I, R is by one or more-NR ⁵R ⁶The alkyl that replaces.

In another embodiment, in formula I, R is quilt-NH ₂The alkyl that replaces.

In another embodiment, in formula I, R is the alkyl that quilt-NH (methyl) replaces.

In another embodiment, R is unsubstituted alkyl.

In some embodiments, R and R ¹Both are not H simultaneously.

In another embodiment, in formula I, R ³Be heteroaryl-CH ₂-X, wherein X is-OR ⁵,-SOR ⁵,-NR ⁵R ⁶Or-SR ⁵R ⁵For hydrogen ,-alkyl N (alkyl) ₂, heterocyclic radical alkyl or heterocycloalkenyl alkyl; Or R ⁵With R ⁶Can choose wantonly and be somebody's turn to do-NR ⁵R ⁶N combine, to form cyclic rings or bridge joint cyclic rings, wherein this cyclic rings or bridge joint cyclic rings can not be substituted, or be can be identical or different part group and replace by one or more, this part group be independently selected from hydroxyl, alkyl, alkoxyl group, alkoxyalkyl, hydroxyalkyl, aralkyl, aryl, assorted volution base, assorted volution thiazolinyl, assorted spiral shell aryl and-CO ₂Alkyl.

In another embodiment, in formula I, R ³Be heteroaryl-CH ₂-X or heteroaryl-CH methyl-X, wherein X is-NR ⁵R ⁶, R ⁵For-alkyl N (alkyl) ₂, alkyl, alkoxyalkyl, hydroxyalkyl, aralkyl, heterocycloalkenyl alkyl, cycloalkyl, cycloalkylalkyl, heteroaralkyl or-alkyl SH, R ⁶For hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl or-alkyl N (alkyl) ₂Or R ⁵With R ⁶Can choose wantonly and be somebody's turn to do-NR ⁵R ⁶N combine, to form cyclic rings or bridge joint cyclic rings, wherein this cyclic rings or bridge joint cyclic rings can not be substituted, or be can be identical or different part group and replace by one or more, this part group be independently selected from hydroxyl, alkyl, alkoxyl group, alkoxyalkyl, hydroxyalkyl, aralkyl, aryl, assorted volution base, assorted volution thiazolinyl, assorted spiral shell aryl and-CO ₂Alkyl.

In another embodiment, in formula I, R ³Be heteroaryl-CH ₂-X, wherein this heteroaryl-CH ₂The heteroaryl of-X by alkyl or-CONR ⁵R ⁶Replace, wherein X is-NR ⁵R ⁶, R ⁵Be alkyl, R ⁶Be alkyl, or R ⁵With R ⁶Choose wantonly and be somebody's turn to do-NR ⁵R ⁶N combine, to form cyclic rings.

In another embodiment, in formula I, R ³Be aryl-CH ₂-X, wherein this aryl-CH ₂The aryl of-X is replaced by alkyl, and wherein X is a heterocyclic radical.

In another embodiment, in formula I, R ³For

Wherein X is selected from-NR ⁵R ⁶,-OR ⁵-SO-R ⁵And-SR ⁵,

In another embodiment, in formula I, R ³Be isothiazole, thiophene or pyrimidine, it is by following replacement:

In another embodiment, in formula I, R ³Be the pyrimidyl that is replaced by heterocyclyl methyl.

In another embodiment, in formula I, R ³For by morpholinyl methyl or the methyl substituted pyrimidyl of pyrrolidyl.

In another embodiment, in formula I, R ³Be the phenyl that is replaced by the heterocyclic radical alkyl, wherein this heterocyclic radical alkyl can not be substituted, or be can be identical or different part group and replace by one or more, and the each several part group is independently selected from alkyl.

In another embodiment, in formula I, R ³Be phenyl-CH methyl-X or phenyl-CH ₂-X, wherein X is piperazinyl, piperidyl, pyrrolidyl, morpholinyl or thio-morpholinyl, wherein this piperazinyl, piperidyl, pyrrolidyl, morpholinyl or thio-morpholinyl can not be substituted, or be can be identical or different part group and replace by one or more, the each several part group is independently selected from alkyl.

In another embodiment, in formula I, R ³Be the phenyl that is replaced by heterocyclyl methyl, wherein this phenyl is further replaced by alkyl.

In another embodiment, in formula I, R ³For by piperidino methyl, morpholinyl methyl or the methyl substituted phenyl of thio-morpholinyl, wherein this phenyl is further by methyl substituted.

In another embodiment, in formula I, R ³For Or

Wherein X is a heterocyclic radical, and wherein this heterocyclic radical can not be substituted, or be can be identical or different part group and replace by one or more, the each several part group be independently selected from hydroxyl, alkyl, hydroxyalkyl, alkoxyl group ,-CO ₂Alkyl, aralkyl, aryl, alkoxyalkyl and heterocyclic radical.

In another embodiment, in formula I, R ³For

Wherein X is a heterocyclic radical, and wherein this heterocyclic radical can not be substituted, or be can be identical or different part group and replace by one or more, and the each several part group is independently selected from alkyl.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be heteroaryl, wherein this heteroaryl can not be substituted, or be can be identical or different part group and replace by one or more, the each several part group be independently selected from halogen, acid amides, alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl ,-C (O) OH ,-C (O) NH ₂,-NR ⁵R ⁶(R wherein ⁵With R ⁶And this-NR ⁵R ⁶N form cyclic amine together) ,-CN, aralkyl ,-CH ₂OR ⁵,-S (O) R ⁵,-S (O ₂) R ⁵,-CN ,-CHO ,-SR ⁵,-C (O) OR ⁵,-C (O) R ⁵, heteroaryl and heterocyclic radical; R is unsubstituted alkyl, or by one or more alkyl that can be identical or different part group replacement, the each several part group is independently selected from-OR ⁵, heterocyclic radical ,-N (R ⁵) C (O) N (R ⁵R ⁶) ,-N (R ⁵)-C (O) OR ⁶,-(CH ₂) _1-3-N (R ⁵R ⁶) and-NR ⁵R ⁶R ¹Be H; R ³Be heteroaryl-CH ₂-X or heteroaryl-CH methyl-X, wherein X is-NR ⁵R ⁶, R ⁵For-alkyl N (alkyl) ₂, alkyl, alkoxyalkyl, hydroxyalkyl, aralkyl, heterocycloalkenyl alkyl, cycloalkyl, cycloalkylalkyl, heteroaralkyl or-alkyl SH, R ⁶For hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl or-alkyl N (alkyl) ₂Or R ⁵With R ⁶Can choose wantonly and be somebody's turn to do-NR ⁵R ⁶N combine, to form cyclic rings or bridge joint cyclic rings, wherein this cyclic rings or bridge joint cyclic rings can not be substituted, or be can be identical or different part group and replace by one or more, this part group be independently selected from hydroxyl, alkyl, alkoxyl group, alkoxyalkyl, hydroxyalkyl, aralkyl, aryl, assorted volution base, assorted volution thiazolinyl, assorted spiral shell aryl and-CO ₂Alkyl; R wherein ⁵With R ⁶All definition as mentioned.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be heteroaryl, wherein this heteroaryl can not be substituted, or be can be identical or different part group and replace by one or more, the each several part group be independently selected from halogen, acid amides, alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl ,-C (O) OH ,-C (O) NH ₂,-NR ⁵R ⁶(R wherein ⁵With R ⁶And this-NR ⁵R ⁶N form cyclic amine together) ,-CN, aralkyl ,-CH ₂OR ⁵,-S (O) R ⁵,-S (O ₂) R ⁵,-CN ,-CHO ,-SR ⁵,-C (O) OR ⁵,-C (O) R ⁵, heteroaryl and heterocyclic radical; R is unsubstituted alkyl, or by one or more alkyl that can be identical or different part group replacement, the each several part group is independently selected from-OR ⁵, heterocyclic radical ,-N (R ⁵) C (O) N (R ⁵R ⁶) ,-N (R ⁵)-C (O) OR ⁶,-(CH ₂) _1-3-N (R ⁵R ⁶) and-NR ⁵R ⁶R ¹Be H; R ³Be heteroaryl-CH ₂-X, wherein this heteroaryl-CH ₂The heteroaryl of-X by alkyl or-CONR ⁵R ⁶Replace, wherein X is-NR ⁵R ⁶, or R ⁵With R ⁶Choose wantonly and be somebody's turn to do-NR ⁵R ⁶N combine, to form heterocyclic radical; R wherein ⁵With R ⁶All definition as mentioned.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be heteroaryl, wherein this heteroaryl can not be substituted, or be can be identical or different part group and replace by one or more, the each several part group be independently selected from halogen, acid amides, alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl ,-C (O) OH ,-C (O) NH ₂,-NR ⁵R ⁶(R wherein ⁵With R ⁶And this-NR ⁵R ⁶N form cyclic amine together) ,-CN, aralkyl ,-CH ₂OR ⁵,-S (O) R ⁵,-S (O ₂) R ⁵,-CN ,-CHO ,-SR ⁵,-C (O) OR ⁵,-C (O) R ⁵, heteroaryl and heterocyclic radical; R is unsubstituted alkyl, or by one or more alkyl that can be identical or different part group replacement, the each several part group is independently selected from-OR ⁵, heterocyclic radical ,-N (R ⁵) C (O) N (R ⁵R ⁶) ,-N (R ⁵)-C (O) OR ⁶,-(CH ₂) _1-3-N (R ⁵R ⁶) and-NR ⁵R ⁶R ¹Be H; R ³Be isothiazole, thiophene or pyrimidine, it is by following replacement:

Or

R wherein ⁵With R ⁶All definition as mentioned.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be heteroaryl, wherein this heteroaryl can not be substituted, or be can be identical or different part group and replace by one or more, the each several part group be independently selected from halogen, acid amides, alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl ,-C (O) OH ,-C (O) NH ₂,-NR ⁵R ⁶(R wherein ⁵With R ⁶And this-NR ⁵R ⁶N form cyclic amine together) ,-CN, aralkyl ,-CH ₂OR ⁵,-S (O) R ⁵,-S (O ₂) R ⁵,-CN ,-CHO ,-SR ⁵,-C (O) OR ⁵,-C (O) R ⁵, heteroaryl and heterocyclic radical; R is unsubstituted alkyl, or by one or more alkyl that can be identical or different part group replacement, the each several part group is independently selected from-OR ⁵, heterocyclic radical ,-N (R ⁵) C (O) N (R ⁵R ⁶) ,-N (R ⁵)-C (O) OR ⁶,-(CH ₂) _1-3-N (R ⁵R ⁶) and-NR ⁵R ⁶R ¹Be H; R ³Be phenyl-CH methyl-X or phenyl-CH ₂-X, wherein this phenyl-CH methyl-X or phenyl-CH respectively ₂The phenyl of-X can not be substituted, or replaced by alkyl, in addition, wherein X is piperazinyl, piperidyl, pyrrolidyl, morpholinyl or thio-morpholinyl, wherein respectively this piperazinyl, piperidyl, pyrrolidyl, morpholinyl or thio-morpholinyl can not be substituted, or are replaced by alkyl; R wherein ⁵With R ⁶All definition as mentioned.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be heteroaryl, wherein this heteroaryl can not be substituted, or be can be identical or different part group and replace by one or more, the each several part group be independently selected from halogen, acid amides, alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl ,-C (O) OH ,-C (O) NH ₂,-NR ⁵R ⁶(R wherein ⁵With R ⁶And this-NR ⁵R ⁶N form cyclic amine together) ,-CN, aralkyl ,-CH ₂OR ⁵,-S (O) R ⁵,-S (O ₂) R ⁵,-CN ,-CHO ,-SR ⁵,-C (O) OR ⁵,-C (O) R ⁵, heteroaryl and heterocyclic radical; R is unsubstituted alkyl, or by one or more alkyl that can be identical or different part group replacement, the each several part group is independently selected from-OR ⁵, heterocyclic radical ,-N (R ⁵) C (O) N (R ⁵R ⁶) ,-N (R ⁵)-C (O) OR ⁶,-(CH ₂) _1-3-N (R ⁵R ⁶) and-NR ⁵R ⁶R ¹Be H; R ³For

Or

Wherein X is selected from-NR ⁵R ⁶,-OR ⁵-SO-R ⁵And-SR ⁵,

R ⁵Be selected from hydrogen, alkyl, thiazolinyl, alkoxyalkyl ,-alkyl-S-alkyl, aminoalkyl group, aryl, heteroaryl, heterocycloalkenyl, Heterocyclylalkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical alkoxyl group ,-S-alkyl heterocyclic, heterocyclic radical, heterocycloalkenyl, alkyl N (alkyl) ₂, alkyl NH (alkyl), alkyl N (thiazolinyl) ₂,-alkyl N (alkoxyl group) ₂,-alkyl-SH and hydroxyalkyl, wherein respectively this aryl, heteroaryl, heterocycloalkenyl, Heterocyclylalkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical alkoxyl group ,-S-alkyl heterocyclic, heterocyclic radical and heterocycloalkenyl can not be substituted, or replaced by one or more alkyl,

R ⁶Be selected from hydrogen, alkyl, thiazolinyl, aryl, cycloalkenyl group, cycloalkyl, aralkyl, cycloalkenyl alkyl, cycloalkylalkyl, heteroaryl, heterocycloalkenyl, heterocyclic radical, heteroaralkyl, the heterocycloalkenyl alkyl, the Heterocyclylalkyl alkyl, alkoxyalkyl,-alkyl-S-alkyl,-alkyl SH, alkoxyl group,-S-alkyl, hydroxyalkyl and aminoalkyl group, this aryl respectively wherein, cycloalkenyl group, cycloalkyl, aralkyl, cycloalkenyl alkyl, cycloalkylalkyl, heteroaryl, heterocycloalkenyl, heterocyclic radical, heteroaralkyl, heterocycloalkenyl alkyl and Heterocyclylalkyl alkyl can not be substituted, or replaced by one or more alkyl

In another embodiment, the invention discloses following formula: compound:

R wherein ⁵With R ⁶All definition as mentioned.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be pyrazolyl, wherein this pyrazolyl can not be substituted, or be can be identical or different part group and replace by one or more, the each several part group be independently selected from halogen, acid amides, alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl ,-C (O) OH ,-C (O) NH ₂,-NR ⁵R ⁶(R wherein ⁵With R ⁶And this-NR ⁵R ⁶N form cyclic amine together) ,-CN, aralkyl ,-CH ₂OR ⁵,-S (O) R ⁵,-S (O ₂) R ⁵,-CN ,-CHO ,-SR ⁵,-C (O) OR ⁵,-C (O) R ⁵, heteroaryl and heterocyclic radical; R is unsubstituted alkyl, or by one or more alkyl that can be identical or different part group replacement, the each several part group is independently selected from-OR ⁵, heterocyclic radical ,-N (R ⁵) C (O) N (R ⁵R ⁶) ,-N (R ⁵)-C (O) OR ⁶,-(CH ₂) _1-3-N (R ⁵R ⁶) and-NR ⁵R ⁶R ¹Be H; R ³Be heteroaryl-CH ₂-X or heteroaryl-CH methyl-X, wherein X is-NR ⁵R ⁶, R ⁵For-alkyl N (alkyl) ₂, alkyl, alkoxyalkyl, hydroxyalkyl, aralkyl, heterocycloalkenyl alkyl, cycloalkyl, cycloalkylalkyl, heteroaralkyl or-alkyl SH, R ⁶For hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl or-alkyl N (alkyl) ₂Or R ⁵With R ⁶Can choose wantonly and be somebody's turn to do-NR ⁵R ⁶N combine, to form cyclic rings or bridge joint cyclic rings, wherein this cyclic rings or bridge joint cyclic rings can not be substituted, or be can be identical or different part group and replace by one or more, this part group be independently selected from hydroxyl, alkyl, alkoxyl group, alkoxyalkyl, hydroxyalkyl, aralkyl, aryl, assorted volution base, assorted volution thiazolinyl, assorted spiral shell aryl and-CO ₂Alkyl, wherein R ⁵With R ⁶All definition as mentioned; R wherein ⁵With R ⁶All definition as mentioned.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be pyrazolyl, wherein this pyrazolyl can not be substituted, or be can be identical or different part group and replace by one or more, the each several part group be independently selected from halogen, acid amides, alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl ,-C (O) OH ,-C (O) NH ₂,-NR ⁵R ⁶(R wherein ⁵With R ⁶And this-NR ⁵R ⁶N form cyclic amine together) ,-CN, aralkyl ,-CH ₂OR ⁵,-S (O) R ⁵,-S (O ₂) R ⁵,-CN ,-CHO ,-SR ⁵,-C (O) OR ⁵,-C (O) R ⁵, heteroaryl and heterocyclic radical; R is unsubstituted alkyl, or by one or more alkyl that can be identical or different part group replacement, the each several part group is independently selected from-OR ⁵, heterocyclic radical ,-N (R ⁵) C (O) N (R ⁵R ⁶) ,-N (R ⁵)-C (O) OR ⁶,-(CH ₂) _1-3-N (R ⁵R ⁶) and-NR ⁵R ⁶R ¹Be H; R ³Be heteroaryl-CH ₂-X, wherein this heteroaryl-CH ₂The heteroaryl of-X by alkyl or-CONR ⁵R ⁶Replace, wherein X is-NR ⁵R ⁶, R ⁵Be alkyl, R ⁶Be alkyl, or R ⁵With R ⁶Choose wantonly and be somebody's turn to do-NR ⁵R ⁶N combine, to form heterocyclic radical; R wherein ⁵With R ⁶All definition as mentioned.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be pyrazolyl, wherein this pyrazolyl can not be substituted, or be can be identical or different part group and replace by one or more, the each several part group be independently selected from halogen, acid amides, alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl ,-C (O) OH ,-C (O) NH ₂,-NR ⁵R ⁶(R wherein ⁵With R ⁶And this-NR ⁵R ⁶N form cyclic amine together) ,-CN, aralkyl ,-CH ₂OR ⁵,-S (O) R ⁵,-S (O ₂) R ⁵,-CN ,-CHO ,-SR ⁵,-C (O) OR ⁵,-C (O) R ⁵, heteroaryl and heterocyclic radical; R is unsubstituted alkyl, or by one or more alkyl that can be identical or different part group replacement, the each several part group is independently selected from-OR ⁵, heterocyclic radical ,-N (R ⁵) C (O) N (R ⁵R ⁶) ,-N (R ⁵)-C (O) OR ⁶,-(CH ₂) _1-3-N (R ⁵R ⁶) and-NR ⁵R ⁶R ¹Be H; R ³Be isothiazole, thiophene or pyrimidine, it is by following replacement:

Or R wherein ⁵With R ⁶All definition as mentioned.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be pyrazolyl, wherein this pyrazolyl can not be substituted, or be can be identical or different part group and replace by one or more, the each several part group be independently selected from halogen, acid amides, alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl ,-C (O) OH ,-C (O) NH ₂,-NR ⁵R ⁶(R wherein ⁵With R ⁶And this-NR ⁵R ⁶N form cyclic amine together) ,-CN, aralkyl ,-CH ₂OR ⁵,-S (O) R ⁵,-S (O ₂) R ⁵,-CN ,-CHO ,-SR ⁵,-C (O) OR ⁵,-C (O) R ⁵, heteroaryl and heterocyclic radical; R is unsubstituted alkyl, or by one or more alkyl that can be identical or different part group replacement, the each several part group is independently selected from-OR ⁵, heterocyclic radical ,-N (R ⁵) C (O) N (R ⁵R ⁶) ,-N (R ⁵)-C (O) OR ⁶,-(CH ₂) _1-3-N (R ⁵R ⁶) and-NR ⁵R ⁶R ¹Be H; R ³Be phenyl-CH methyl-X or phenyl-CH ₂-X, wherein this phenyl-CH methyl-X or phenyl-CH respectively ₂The phenyl of-X can not be substituted, or replaced by alkyl, in addition, wherein X is piperazinyl, piperidyl, pyrrolidyl, morpholinyl or thio-morpholinyl, wherein respectively this piperazinyl, piperidyl, pyrrolidyl, morpholinyl or thio-morpholinyl can not be substituted, or are replaced by alkyl; R wherein ⁵With R ⁶All definition as mentioned.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be pyrazolyl, wherein this pyrazolyl can not be substituted, or be can be identical or different part group and replace by one or more, the each several part group be independently selected from halogen, acid amides, alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl ,-C (O) OH ,-C (O) NH ₂,-NR ⁵R ⁶(R wherein ⁵With R ⁶And this-NR ⁵R ⁶N form cyclic amine together) ,-CN, aralkyl ,-CH ₂OR ⁵,-S (O) R ⁵,-S (O ₂) R ⁵,-CN ,-CHO ,-SR ⁵,-C (O) OR ⁵,-C (O) R ⁵, heteroaryl and heterocyclic radical; R is unsubstituted alkyl, or by one or more alkyl that can be identical or different part group replacement, the each several part group is independently selected from-OR ⁵, heterocyclic radical ,-N (R ⁵) C (O) N (R ⁵R ⁶) ,-N (R ⁵)-C (O) OR ⁶,-(CH ₂) _1-3-N (R ⁵R ⁶) and-NR ⁵R ⁶R ¹Be H; R ³For

R wherein ⁵With R ⁶All definition as mentioned.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be 1-H-pyrazoles-4-base; R is unsubstituted alkyl, or by one or more alkyl that can be identical or different part group replacement, the each several part group is independently selected from-OR ⁵, heterocyclic radical ,-N (R ⁵) C (O) N (R ⁵R ⁶) ,-N (R ⁵)-C (O) OR ⁶,-(CH ₂) _1-3-N (R ⁵R ⁶) and-NR ⁵R ⁶R ¹Be H; R ³Be heteroaryl-CH ₂-X or heteroaryl-CH methyl-X, wherein X is-NR ⁵R ⁶, R ⁵For-alkyl N (alkyl) ₂, alkyl, alkoxyalkyl, hydroxyalkyl, aralkyl, heterocycloalkenyl alkyl, cycloalkyl, cycloalkylalkyl, heteroaralkyl or-alkyl SH, R ⁶For hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl or-alkyl N (alkyl) ₂Or R ⁵With R ⁶Can choose wantonly and be somebody's turn to do-NR ⁵R ⁶N combine, to form cyclic rings or bridge joint cyclic rings, wherein this cyclic rings or bridge joint cyclic rings can not be substituted, or be can be identical or different part group and replace by one or more, this part group be independently selected from hydroxyl, alkyl, alkoxyl group, alkoxyalkyl, hydroxyalkyl, aralkyl, aryl, assorted volution base, assorted volution thiazolinyl, assorted spiral shell aryl and-CO ₂Alkyl; R wherein ⁵With R ⁶All definition as mentioned.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be 1-H-pyrazoles-4-base; R is unsubstituted alkyl, or by one or more alkyl that can be identical or different part group replacement, the each several part group is independently selected from-OR ⁵, heterocyclic radical ,-N (R ⁵) C (O) N (R ⁵R ⁶) ,-N (R ⁵)-C (O) OR ⁶,-(CH ₂) _1-3-N (R ⁵R ⁶) and-NR ⁵R ⁶R ¹Be H; And R ³Be heteroaryl-CH ₂-X, wherein this heteroaryl-CH ₂The heteroaryl of-X by alkyl or-CONR ⁵R ⁶Replace, wherein X is-NR ⁵R ⁶, R ⁵Be alkyl, R ⁶Be alkyl, or R ⁵With R ⁶Choose wantonly and be somebody's turn to do-NR ⁵R ⁶N combine, to form heterocyclic radical;

R wherein ⁵With R ⁶All definition as mentioned.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be 1-H-pyrazoles-4-base; R is unsubstituted alkyl, or by one or more alkyl that can be identical or different part group replacement, the each several part group is independently selected from-OR ⁵, heterocyclic radical ,-N (R ⁵) C (O) N (R ⁵R ⁶) ,-N (R ⁵)-C (O) OR ⁶,-(CH ₂) _1-3-N (R ⁵R ⁶) and-NR ⁵R ⁶R ¹Be H; R ³Be isothiazole, thiophene or pyrimidine, it is by following replacement:

Or

R wherein ⁵With R ⁶All definition as mentioned.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be 1-H-pyrazoles-4-base; R is unsubstituted alkyl, or by one or more alkyl that can be identical or different part group replacement, the each several part group is independently selected from-OR ⁵, heterocyclic radical ,-N (R ⁵) C (O) N (R ⁵R ⁶) ,-N (R ⁵)-C (O) OR ⁶,-(CH ₂) _1-3-N (R ⁵R ⁶) and-NR ⁵R ⁶R ¹Be H; R ³Be phenyl-CH methyl-X or phenyl-CH ₂-X, wherein this phenyl-CH methyl-X or phenyl-CH respectively ₂The phenyl of-X can not be substituted, or replaced by alkyl, in addition, wherein X is piperazinyl, piperidyl, pyrrolidyl, morpholinyl or thio-morpholinyl, wherein respectively this piperazinyl, piperidyl, pyrrolidyl, morpholinyl or thio-morpholinyl can not be substituted, or are replaced by alkyl; R wherein ⁵With R ⁶All definition as mentioned.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be 1-H-pyrazoles-4-base; R is unsubstituted alkyl, or by one or more alkyl that can be identical or different part group replacement, the each several part group is independently selected from-OR ⁵, heterocyclic radical ,-N (R ⁵) C (O) N (R ⁵R ⁶) ,-N (R ⁵)-C (O) OR ⁶,-(CH ₂) _1-3-N (R ⁵R ⁶) and-NR ⁵R ⁶R ¹Be H; R ³For

R wherein ⁵With R ⁶All definition as mentioned.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be 1-H-pyrazoles-4-base; R is unsubstituted alkyl; R ¹Be H; R ³Be heteroaryl-CH ₂-X or heteroaryl-CH methyl-X, wherein X is-NR ⁵R ⁶, R ⁵For-alkyl N (alkyl) ₂, alkyl, alkoxyalkyl, hydroxyalkyl, aralkyl, heterocycloalkenyl alkyl, cycloalkyl, cycloalkylalkyl, heteroaralkyl or-alkyl SH, R ⁶For hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl or-alkyl N (alkyl) ₂Or R ⁵With R ⁶Can choose wantonly and be somebody's turn to do-NR ⁵R ⁶N combine, to form cyclic rings or bridge joint cyclic rings, wherein this cyclic rings or bridge joint cyclic rings can not be substituted, or be can be identical or different part group and replace by one or more, this part group be independently selected from hydroxyl, alkyl, alkoxyl group, alkoxyalkyl, hydroxyalkyl, aralkyl, aryl, assorted volution base, assorted volution thiazolinyl, assorted spiral shell aryl and-CO ₂Alkyl; R wherein ⁵With R ⁶All definition as mentioned.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be 1-H-pyrazoles-4-base; R is unsubstituted alkyl; R ¹Be H; R ³Be heteroaryl-CH ₂-X, wherein this heteroaryl-CH ₂The heteroaryl of-X by alkyl or-CONR ⁵R ⁶Replace, wherein X is-NR ⁵R ⁶, R ⁵Be alkyl, R ⁶Be alkyl, or R ⁵With R ⁶Choose wantonly and be somebody's turn to do-NR ⁵R ⁶N combine, to form heterocyclic radical; R wherein ⁵With R ⁶All definition as mentioned.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be 1-H-pyrazoles-4-base; R is unsubstituted alkyl; R ¹Be H; R ³Be isothiazole, thiophene or pyrimidine, it is by following replacement:

Or

R wherein ⁵With R ⁶All definition as mentioned.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be 1-H-pyrazoles-4-base; R is unsubstituted alkyl; R ¹Be H; R ³Be phenyl-CH methyl-X or phenyl-CH ₂-X, wherein this phenyl-CH methyl-X or phenyl-CH respectively ₂The phenyl of-X can not be substituted, or replaced by alkyl, in addition, wherein X is piperazinyl, piperidyl, pyrrolidyl, morpholinyl or thio-morpholinyl, wherein respectively this piperazinyl, piperidyl, pyrrolidyl, morpholinyl or thio-morpholinyl can not be substituted, or are replaced by alkyl;

R wherein ⁵With R ⁶All definition as mentioned.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be 1-H-pyrazoles-4-base; R is unsubstituted alkyl; R ¹Be H; And R ³For

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be 1-H-pyrazoles-4-base; R is a methyl, R ¹Be H; R ³Be heteroaryl-CH ₂-X or heteroaryl-CH methyl-X, wherein X is-NR ⁵R ⁶, R ⁵For-alkyl N (alkyl) ₂, alkyl, alkoxyalkyl, hydroxyalkyl, aralkyl, heterocycloalkenyl alkyl, cycloalkyl, cycloalkylalkyl, heteroaralkyl or-alkyl SH, R ⁶For hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl or-alkyl N (alkyl) ₂Or R ⁵With R ⁶Can choose wantonly and be somebody's turn to do-NR ⁵R ⁶N combine, to form cyclic rings or bridge joint cyclic rings, wherein this cyclic rings or bridge joint cyclic rings can not be substituted, or be can be identical or different part group and replace by one or more, this part group be independently selected from hydroxyl, alkyl, alkoxyl group, alkoxyalkyl, hydroxyalkyl, aralkyl, aryl, assorted volution base, assorted volution thiazolinyl, assorted spiral shell aryl and-CO ₂Alkyl; R wherein ⁵With R ⁶All definition as mentioned.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be 1-H-pyrazoles-4-base; R is a methyl, R ¹Be H; R ³Be heteroaryl-CH ₂-X, wherein this heteroaryl-CH ₂The heteroaryl of-X by alkyl or-CONR ⁵R ⁶Replace, wherein X is-NR ⁵R ⁶, R ⁵Be alkyl, R ⁶Be alkyl, or R ⁵With R ⁶Choose wantonly and be somebody's turn to do-NR ⁵R ⁶N combine, to form heterocyclic radical; R wherein ⁵With R ⁶All definition as mentioned.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be 1-H-pyrazoles-4-base; R is a methyl, R ¹Be H; R ³Be isothiazole, thiophene or pyrimidine, it is by following replacement:

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be 1-H-pyrazoles-4-base; R is a methyl, R ¹Be H; R ³Be phenyl-CH methyl-X or phenyl-CH ₂-X, wherein this phenyl-CH methyl-X or phenyl-CH respectively ₂The phenyl of-X can not be substituted, or replaced by alkyl, in addition, wherein X is piperazinyl, piperidyl, pyrrolidyl, morpholinyl or thio-morpholinyl, wherein respectively this piperazinyl, piperidyl, pyrrolidyl, morpholinyl or thio-morpholinyl can not be substituted, or are replaced by alkyl.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ²Be 1-H-pyrazoles-4-base; R is a methyl, R ¹Be H; R ³For

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ⁵Be alkyl; R ⁶Be selected from alkoxyalkyl, hydroxyalkyl, cycloalkyl, wherein this cycloalkyl is replaced by hydroxyalkyl; Or R ⁵With R ⁶And this-NR ⁵R ⁶N form cyclic rings together, wherein this cyclic rings is replaced by one or more part groups that are independently selected from alkoxyalkyl, hydroxyalkyl and alkyl.

In another embodiment, the invention discloses following formula: compound:

Or its pharmacy acceptable salt, solvate or ester, wherein R ⁵Be methyl, ethyl or propyl group; R ⁶Be selected from ethoxyethyl group, 1,1-dimethyl hydroxyethyl, cyclopentyl, cyclohexyl, wherein respectively this cyclopentyl and cyclohexyl are replaced by methylol; Or R ⁵With R ⁶And this-NR ⁵R ⁶N form cyclic rings together, wherein this cyclic rings is replaced by one or more part groups that are independently selected from ethoxyl methyl, methoxymethyl, methylol and methyl.

The limiting examples of formula I compound comprises:

Or its pharmacy acceptable salt, solvate, ester or prodrug.

When being used in when above reaching whole present disclosure, following term, unless point out in addition, otherwise should understand to have following meaning, comprise that any of described group or part group may replace:

" patient " comprises human and animal.

Human and other Mammals of " Mammals " expression.

" alkyl " expression aliphatic hydrocarbyl, it can be straight or branched, and comprise about 1 to about 20 carbon atoms in this chain.Preferred alkyl contain have an appointment 1 to about 12 carbon atoms in this chain.Preferred alkyl contain have an appointment 1 to about 6 carbon atoms in this chain.Side chain is represented one or more low alkyl groups, and for example methyl, ethyl or propyl group are connected to linear alkyl chain." low alkyl group " expression have about 1 to the group of about 6 carbon atoms in this chain, it can be straight or branched." alkyl " can not be substituted, or optional can be identical or different substituting group and replace by one or more, each substituting group be independently selected from halogen, alkyl, aryl, cycloalkyl, cyano group, hydroxyl, alkoxyl group, alkylthio, amino, oxime (for example=N-OH) ,-NH (alkyl) ,-NH (cycloalkyl) ,-N (alkyl) ₂,-O-C (O)-alkyl ,-O-C (O)-aryl ,-O-C (O)-cycloalkyl, carboxyl and-C (O) O-alkyl.The suitable limiting examples of alkyl, comprise methyl, ethyl, just-propyl group, sec.-propyl and the tertiary butyl.

" thiazolinyl " expression contains the aliphatic hydrocarbyl of at least one carbon-to-carbon double bond, and it can be straight or branched, and comprise about 2 to about 15 carbon atoms in this chain.Preferred thiazolinyl have about 2 to about 12 carbon atoms in this chain; And be more preferably about 2 to about 6 carbon atoms in this chain.Side chain is represented one or more low alkyl groups, and for example methyl, ethyl or propyl group are connected to linear alkenylene chain." low-grade alkenyl " expression about 2 to about 6 carbon atoms in this chain, it can be straight or branched." thiazolinyl " can not be substituted, or optional can be identical or different substituting group and replace by one or more, each substituting group be independently selected from halogen, alkyl, aryl, cycloalkyl, cyano group, alkoxyl group and-S (alkyl).The suitable limiting examples of thiazolinyl, comprise vinyl, propenyl, just-butenyl, 3-methyl but-2-ene base, just-pentenyl, octenyl and decene base.

" alkylidene group " expression is by removing a difunctionality group that hydrogen atom obtained from defined alkyl above.The limiting examples of alkylidene group comprises methylene radical, ethylidene and propylidene.

" alkynyl " expression contains the aliphatic hydrocarbyl of at least one carbon-to-carbon three key, and it can be straight or branched, and comprise about 2 to about 15 carbon atoms in this chain.Preferred alkynyl have about 2 to about 12 carbon atoms in this chain; And be more preferably about 2 to about 4 carbon atoms in this chain.Side chain is represented one or more low alkyl groups, and for example methyl, ethyl or propyl group are connected to linear alkynyl chain." low-grade alkynyl " expression about 2 to about 6 carbon atoms in this chain, it can be straight or branched.Suitably the limiting examples of alkynyl comprises ethynyl, proyl, 2-butyne base and 3-methyl butynyl." alkynyl " can not be substituted, or optional can be identical or different substituting group and replace by one or more, and each substituting group is independently selected from alkyl, aryl and cycloalkyl.

" aryl " expression aromatic monocyclic shape or polycyclic loop systems comprise about 6 to about 14 carbon atoms, and preferably about 6 to about 10 carbon atoms.Aryl can be chosen wantonly by one or more " loop systems substituting group " and replace, and it can be identical or different, and all as defined herein.Suitably the limiting examples of aryl comprises phenyl and naphthyl.

" bridge joint cyclic rings " is the hydrocarbon ring, for example cycloalkyl, cycloalkenyl group or aryl, or contain heteroatomic ring, for example heterocyclic radical, heterocycloalkenyl or heteroaryl, as described herein, it contains abutment, and it is the not branched chain of the atom of a valence link or an atom or two different pieces that connect this ring.Two tertiary carbon atoms that connect through abutment are called as " end of the bridge ".

" heteroaryl " expression aromatic monocyclic shape or polycyclic loop systems comprise about 5 to about 14 annular atomses, and preferably about 5 to about 10 annular atomses, and wherein one or more annular atomses are the element beyond the carbon, and for example nitrogen, oxygen or sulphur are used separately or also.Preferred heteroaryl contains has an appointment 5 to about 6 annular atomses." heteroaryl " can be chosen wantonly by one or more " loop systems substituting group " and replace, and it can be identical or different, and all as defined herein.Prefix azepine, oxa-or thia before the heteroaryl radical title represent that at least one nitrogen, oxygen or sulphur atom exist as annular atoms respectively.A nitrogen-atoms of heteroaryl can be chosen wantonly and be oxidized to its corresponding N-oxide compound." heteroaryl " also can comprise the heteroaryl of definition as mentioned that defines aryl as mentioned through being fused to.The limiting examples of suitable heteroaryl, comprise pyridyl, pyrazinyl, furyl, thienyl, pyrimidyl, pyridone (comprising the pyridone that N-replaces) isoxazolyl, isothiazolyl oxazolyl, thiazolyl, pyrazolyl, the furazan base, pyrryl, pyrazolyl, triazolyl, 1,2, the 4-thiadiazolyl group, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, the oxindole base, imidazo [1,2-a] pyridyl, imidazo [2,1-b] thiazolyl, benzo furazan base, indyl, azaindolyl, benzimidazolyl-, benzothienyl, quinolyl, imidazolyl, the thienopyridine base, quinazolyl, the Thienopyrimidine base, pyrrolopyridinyl, imidazopyridyl, isoquinolyl, the benzo-aza indyl, 1,2, the 4-triazinyl, benzothiazolyl etc." heteroaryl " speech also finger divides saturated heteroaryl moieties group, for example tetrahydro isoquinolyl, tetrahydric quinoline group etc.

" aralkyl " or " arylalkyl " expression aryl-alkyl-group, wherein aryl and alkyl are all as mentioned before.Preferred aralkyl comprises low alkyl group.Suitably the limiting examples of aralkyl comprises benzyl, 2-styroyl and naphthyl methyl.Being connected with the key of parent fraction group is to pass through alkyl.

" alkylaryl " expression alkyl-aryl-group, wherein alkyl and aryl are all as mentioned before.Preferred alkylaryl comprises low alkyl group.Suitably the limiting examples of alkylaryl is a tolyl.Being connected with the key of parent fraction group is to pass through aryl.

The non-aromatics list of " cycloalkyl " expression-or the polycyclic loop systems, comprise about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms.Preferred cycloalkyl ring contains has an appointment 5 to about 7 annular atomses.Cycloalkyl can be chosen wantonly by one or more " loop systems substituting group " and replace, and it can be identical or different, and all definition as mentioned.Suitably the limiting examples of monocycle shape cycloalkyl comprises cyclopropyl, cyclopentyl, cyclohexyl, suberyl etc.Suitably the limiting examples of polycyclic cycloalkyl comprises 1-decahydro naphthyl, norcamphyl, adamantyl etc.

" cycloalkylalkyl " expression is the cycloalkyl moiety group of definition as mentioned, is linked to the parent core by moieties group (above definition).Suitably the limiting examples of cycloalkylalkyl comprises cyclohexyl methyl, adamantyl methyl etc.

" cycloalkenyl group " non-aromatics list of expression or polycyclic loop systems comprise about 3 to about 10 carbon atoms, and preferably about 5 to about 10 carbon atoms, and it contains at least one carbon-to-carbon double bond.Preferred cyclenes basic ring contains about 5 to about 7 annular atomses.Cycloalkenyl group can be chosen wantonly by one or more " loop systems substituting group " and replace, and it can be identical or different, and all definition as mentioned.Suitably the limiting examples of monocycle shape cycloalkenyl group comprises cyclopentenyl, cyclohexenyl, ring heptan-butadienyl etc.Suitably the limiting examples of polycyclic cycloalkenyl group is a norbornene.

" cycloalkenyl alkyl " expression is the cycloalkenyl group part group of definition as mentioned, is linked to the parent core by moieties group (above definition).Suitably the limiting examples of cycloalkenyl alkyl comprises cyclopentenyl methyl, cyclohexenyl methyl etc.

" halogen " expression fluorine, chlorine, bromine or iodine.Preferably fluorine, chlorine and bromine.

" loop systems substituting group " expression is connected to the substituting group of aromatics or non-aromatics loop systems, and it for example is the available hydrogen in the D-loop system.The loop systems substituting group can be identical or different, respectively is independently selected from alkyl; thiazolinyl; alkynyl; aryl; heteroaryl; aralkyl; alkylaryl; heteroaralkyl; the impure aromatic ene base; the heteroaryl alkynyl; miscellaneous alkyl aryl; hydroxyl; hydroxyalkyl; alkoxyl group; aryloxy; aralkoxy; acyl group; aroyl; halogen; nitro; cyano group; carboxyl; carbalkoxy; aryloxycarbonyl; aromatic alkoxy carbonyl; alkyl sulphonyl; aryl sulfonyl; heteroarylsulfonyl; alkylthio; artyl sulfo; the heteroaryl sulfenyl; aromatic alkylthio; the heteroaralkyl sulfenyl; cycloalkyl; heterocyclic radical; acid amides;-CHO;-O-C (O)-alkyl;-O-C (O)-aryl;-O-C (O)-cycloalkyl;-C (=N-CN)-NH ₂,-C (=NH)-NH ₂,-C (=NH)-NH (alkyl), oxime (for example=N-OH), Y ₁Y ₂N-, Y ₁Y ₂The N-alkyl-, Y ₁Y ₂NC (O)-, Y ₁Y ₂NSO ₂-and-SO ₂NY ₁Y ₂, Y wherein ₁With Y ₂Can be identical or differently, and be independently selected from hydrogen, alkyl, aryl, cycloalkyl and aralkyl." loop systems substituting group " also can represent single part group, and it on two adjacent carbonss of loop systems, replaces two available hydrogens (H on each carbon) simultaneously.This kind part examples of groups be methylene-dioxy, inferior ethylenedioxy ,-C (CH ₃) ₂-etc., its be formation for example with the lower section group:

" heteroaralkyl " expression is the heteroaryl moieties group of definition as mentioned, is linked to the parent core by moieties group (above definition).Suitably the limiting examples of heteroaryl comprises 2-pyridylmethyl, quinolyl methyl etc.

" heterocyclic radical " non-aromatics saturated mono ring-type of expression or polycyclic loop systems, comprise about 3 to about 10 annular atomses, preferably about 5 to about 10 annular atomses, and wherein the one or more atoms in this loop systems are the element beyond the carbon, for example nitrogen, oxygen or sulphur are used separately or also.There are not adjacent oxygen and/or sulphur atom to be present in this loop systems.Preferred heterocyclic radical contains has an appointment 5 to about 6 annular atomses.Prefix azepine, oxa-or thia before heterocyclic radical radical title represent that at least one nitrogen, oxygen or sulphur atom exist as annular atoms respectively.Any-NH in the heterocyclic ring can protected precedent as-N (Boc) ,-N (CBz) ,-N (Tos) etc. and existing; This kind protection also is regarded as a part of the present invention.Heterocyclic radical can be chosen wantonly by one or more " loop systems substituting group " and replace, and it can be identical or different, and all as defined herein.The nitrogen of heterocyclic radical or sulphur atom can be chosen wantonly and be oxidized to its corresponding N-oxide compound, S-oxide compound or S, the S-dioxide.Suitably the limiting examples of monocyclic heterocycle basic ring comprises piperidyl, pyrrolidyl, piperazinyl, morpholinyl, thio-morpholinyl, thiazolidyl, 1,4-dioxane base, tetrahydrofuran base, tetrahydro-thienyl, lactan, lactone etc." heterocyclic radical " also can represent single part group (for example carbonyl), and it is two available hydrogens on the identical carbon atoms of D-loop system simultaneously.This kind part examples of groups is a pyrrolidone:

" heterocyclic radical alkyl " expression is the heterocyclic radical part group of definition as mentioned, is linked to the parent core by moieties group (above definition).Suitably the limiting examples of heterocyclic radical alkyl comprises piperidino methyl, piperazinyl methyl etc.

" heterocycloalkenyl " expression non-aromatic monocyclic shape or polycyclic loop systems, comprise about 3 to about 10 annular atomses, preferably about 5 to about 10 annular atomses, wherein the one or more atoms in this loop systems are the element beyond the carbon, for example nitrogen, oxygen or sulphur atom, separately or and usefulness, and it contains at least one carbon-to-carbon double bond or the two keys of carbon-nitrogen.There are not adjacent oxygen and/or sulphur atom to be present in this loop systems.Preferred heterocycloalkenyl ring contains has an appointment 5 to about 6 annular atomses.Prefix azepine, oxa-or thia before heterocycloalkenyl radical title represent that at least one nitrogen, oxygen or sulphur atom exist as annular atoms respectively.Heterocycloalkenyl can be chosen wantonly by one or more loop systems substituting groups and replace, and wherein " loop systems substituting group " defines as mentioned.The nitrogen of heterocycloalkenyl or sulphur atom can be chosen wantonly and be oxidized to its corresponding N-oxide compound, S-oxide compound or S, the S-dioxide.The limiting examples of suitable heterocycloalkenyl, comprise 1,2,3,4-tetrahydro pyridyl, 1,2-dihydropyridine base, 1,4-dihydropyridine base, 1,2,3,6-tetrahydro pyridyl, 1,4,5,6-tetrahydro-pyrimidine base, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, glyoxalidine base, dihydro-oxazole base, Er Qing oxadiazole base, dihydro-thiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuran base, fluorine dihydrofuran base, 7-oxabicyclo be [2.2.1] heptenyl, dihydro-thiophene base, dihydrogen phosphorothioate pyranyl etc. also." heterocycloalkenyl " also can represent single part group (for example carbonyl), and it is two available hydrogens on the identical carbon atoms of D-loop system simultaneously.This kind part examples of groups is a pyrrolidone:

" heterocycloalkenyl alkyl " expression is the heterocycloalkenyl part group of definition as mentioned, is linked to the parent core by moieties group (above definition).

It should be noted, contain in the heteroatomic loop systems do not have hydroxyl on the carbon atom of contiguous N, O or S, and do not have N or S group on contiguous another heteroatomic carbon in the present invention.Therefore, for example in following ring:

Do not have-OH is connected directly to and is denoted as 2 and 5 carbon.

Also it should be noted, tautomeric form, for example with the lower section group:

In certain embodiments of the invention, be considered to equate.

" alkynyl alkyl " expression alkynyl-alkyl-group, wherein alkynyl and alkyl are all as mentioned before.Preferred alkynyl alkyl contains low-grade alkynyl and low alkyl group.Being connected with the key of parent fraction group is to pass through alkyl.Suitably the limiting examples of alkynyl alkyl comprises the propargyl methyl.

" heteroaralkyl " expression heteroaryl-alkyl-group, wherein heteroaryl and alkyl are all as mentioned before.Preferred heteroaralkyl contains low alkyl group.Suitably the limiting examples of aralkyl comprises pyridylmethyl and quinoline-3-ylmethyl.Being connected with the key of parent fraction group is to pass through alkyl.

" volution system " has by the two or more rings of common atom institute's banded.Preferred spiro system turnkey is drawn together spiral shell heteroaryl, spiroheterocyclic thiazolinyl, spiro heterocyclic radical, spiro cycloalkyl group, volution thiazolinyl and spiral shell aryl.The volution system can choose wantonly by one or more loop systems substituting groups and replace, and wherein " loop systems substituting group " defines as mentioned.Suitably the limiting examples of volution system comprises

Spiral shell [4.5] decane,

8-azaspiro [4.5] last of the ten Heavenly stems-2-alkene and

Spiral shell [4.4] ninth of the ten Heavenly Stems-2, the 7-diene.

" hydroxyalkyl " expression HO-alkyl-group, wherein alkyl such as preamble define.Preferred hydroxyalkyl contains low alkyl group.Suitably the limiting examples of hydroxyalkyl comprises methylol and 2-hydroxyethyl.

" acyl group " expression H-C (O)-, alkyl-C (O)-or cycloalkyl-C (O)-group, wherein various groups are all as mentioned before.Being connected with the key of parent fraction group is to pass through carbonyl.Preferred acyl group contains low alkyl group.Suitably the limiting examples of acyl group comprises formyl radical, ethanoyl and propionyl.

" aroyl " expression aryl-C (O)-group, wherein aryl as mentioned before.Being connected with the key of parent fraction group is to pass through carbonyl.Suitably the limiting examples of group comprises benzoyl and 1-naphthoyl.

" alkoxyl group " expression alkyl-O-group, wherein alkyl as mentioned before.The suitable limiting examples of alkoxyl group, comprise methoxyl group, oxyethyl group, just-propoxy-, isopropoxy and just-butoxy.Being connected with the key of parent fraction group is by ether oxygen.

" aryloxy " expression aryl-O-group, wherein aryl as mentioned before.Suitably the limiting examples of aryloxy comprises phenoxy group and naphthyloxy.Being connected with the key of parent fraction group is by ether oxygen.

" aralkoxy " expression aralkyl-O-group, wherein aralkyl as mentioned before.Suitably the limiting examples of aralkoxy comprises benzyloxy and 1-or 2-naphthalene methoxyl group.Being connected with the key of parent fraction group is by ether oxygen.

" alkylthio " expression alkyl-S-group, wherein alkyl as mentioned before.Suitably the limiting examples of alkylthio comprises methylthio group and ethylmercapto group.Being connected with the key of parent fraction group is to pass through sulphur.

" artyl sulfo " expression aryl-S-group, wherein aryl as mentioned before.Suitably the limiting examples of artyl sulfo comprises thiophenyl and naphthyl sulfenyl.Being connected with the key of parent fraction group is to pass through sulphur.

" aromatic alkylthio " expression aralkyl-S-group, wherein aralkyl as mentioned before.Suitably the limiting examples of aromatic alkylthio is a benzylthio-.Being connected with the key of parent fraction group is to pass through sulphur.

" carbalkoxy " expression alkyl-O-CO-group.Suitably the limiting examples of carbalkoxy comprises methoxycarbonyl and ethoxycarbonyl.Being connected with the key of parent fraction group is to pass through carbonyl.

" aryloxycarbonyl " expression aryl-O-C (O)-group.Suitably the limiting examples of aryloxycarbonyl comprises phenyloxycarbonyl and naphthyloxy carbonyl.Being connected with the key of parent fraction group is to pass through carbonyl.

" aromatic alkoxy carbonyl " expression aralkyl-O-C (O)-group.Suitably the limiting examples of aromatic alkoxy carbonyl is a carbobenzoxy-(Cbz).Being connected with the key of parent fraction group is to pass through carbonyl.

" alkyl sulphonyl " expression alkyl-S (O ₂)-group.Preferred group is the low alkyl group person for alkyl wherein.Being connected with the key of parent fraction group is to pass through alkylsulfonyl.

" aryl sulfonyl " expression aryl-S (O ₂)-group.Being connected with the key of parent fraction group is to pass through alkylsulfonyl.

" be substituted " vocabulary and be shown in one or more hydrogen on the specified atom and be selected from indicated group and replace, its condition is, can not surpass specified atom at the normal valence link that exists under the situation, and this replaces and can produce stable compound.The combination of substituting group and/or variable only can produce under the stable compound in this kind combination and just can allow.So-called " stable compound " or " rock steady structure " is meant that compound is enough strong and retaining from reaction mixture, is separated to useful purity, and is deployed into effective therapeutical agent.

" optional being substituted " vocabulary shows with special groups, atomic group or the optional of part group to be selected generation.

About " purifying ", " being purified form " or " be and separate and purified form " term of compound, be meant that this compound is in the physical condition after synthetic method (for example reaction mixture) or natural origin or its combination separation.Therefore, " purifying ", " being purified form " or " being the isolation and purification form " term about compound, be meant this compound derive from purification process described herein or well known to a person skilled in the art method (for example chromatography, recrystallization etc.) after physical condition, its enough purity can be by described or well known to a person skilled in the art the standard analytical techniques characterized herein.

Also it should be noted that in the context of this article, flow process, embodiment and form, any carbon and heteroatoms that has less than the full price key is assumed that the hydrogen atom with enough numbers, to satisfy this valence link.

When the functional group in the compound was called as " protection ", this represented that this group is modified form, with when the compound acceptable response, get rid of this protection the position do not want side reaction.The due care base will be by those skilled in the art and reference standard textbook and is understood, people such as T.W.Greene for example, Protective Groups in organic Synthesis (1991), Wiley, NewYork.

As any parameter (for example aryl, heterocycle, R ²Deng) when occurring surpassing one time in any composition or formula I, its definition and its definition in each other existence place in each existence place is irrelevant.

" composition " speech of Shi Yonging in this article is intended to contain and a kind ofly comprises the product of specific composition with specified quantitative, and directly or indirectly makes up formed spawn by specific composition with specified quantitative.

The prodrug of The compounds of this invention and solvate also are intended to be included in this paper.The discussion of prodrug is provided in T.Higuchi and V.Stella, 14 of Pro-drugs as Novel DeliverySystems (1987) A.C.S. analects series, and at Bioreversible Carriers inDrug Design, (1987) Edward B.Roche writes, American Medical Association and Pergamon press." prodrug " vocabulary shows and can in vivo change and the compound (for example prodrug) of pharmaceutically-acceptable salts, hydrate or the solvate of production (I) compound or this compound.This transformation can take place by various mechanism (for example by metabolism or chemical process), for example process hydrolytic action in blood.The discussion of prodrug purposes, by T.Higuchi and W.Stella, " Pro-drugsas Novel Delivery Systems ", A.C.S. the 14th of analects series the roll up, and at Bioreversible Carriers in Drug Design, Edward B.Roche writes, and American Medical Association and Pergamon press provide in 1987.

For example, if pharmaceutically-acceptable salts, hydrate or the solvate of formula (I) compound or this compound contain the carboxylic-acid functional base, then prodrug can comprise that by with the formed ester of a kind of hydrogen atom of this acidic group of group displacement, this group is (C for example ₁-C ₈) alkyl, (C ₂-C ₁₂) alkanoyloxymethyl, 1-(alkanoyloxy) ethyl with 4 to 9 carbon atoms, 1-methyl isophthalic acid-(alkanoyloxy)-ethyl with 5 to 10 carbon atoms, alkoxy carbonyl yloxy ylmethyl with 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy) ethyl with 4 to 7 carbon atoms, 1-methyl isophthalic acid-(alkoxycarbonyloxy) ethyl with 5 to 8 carbon atoms, N-(carbalkoxy) amino methyl with 3 to 9 carbon atoms, 1-(N-(carbalkoxy) amino) ethyl with 4 to 10 carbon atoms, the 3-phthalidyl, 4-crotons lactone group, gamma-butyrolactone-4-base, two-N, N-(C ₁-C ₂) alkylamino (C ₂-C ₃) alkyl (for example β-dimethylaminoethyl), carbamyl-(C ₁-C ₂) alkyl, N, N-two (C ₁-C ₂) alkylcarbamoyl group-(C ₁-C ₂) alkyl, and piperidines also-, tetramethyleneimine also-or morpholine (C also ₂-C ₃) alkyl etc.

Similarly, if formula (I) compound contains alcohol functional group, then prodrug can form by the hydrogen atom with a kind of this alcohol radical of group displacement, and this group is (C for example ₁-C ₆) alkanoyloxymethyl, 1-((C ₁-C ₆) alkanoyloxy) ethyl, 1-methyl isophthalic acid-((C ₁-C ₆) alkanoyloxy) ethyl, (C ₁-C ₆) alkoxy carbonyl yloxy ylmethyl, N-(C ₁-C ₆) alkoxycarbonyl ammonia ylmethyl, succinyl, (C ₁-C ₆) alkyloyl, alpha-amino group (C ₁-C ₄) alkyl, aryl-acyl and α-aminoacyl or α-aminoacyl-α-aminoacyl, wherein each α-aminoacyl independently be selected from natural generation L-amino acids, P (O) (OH) ₂,-P (O) (O (C ₁-C ₆) alkyl) ₂Or glycosyl (owing to removing the formed group of hydroxyl of carbohydrate hemiacetal form) etc.

If formula (I) compound incorporates the amine functional group into, then prodrug can be by forming with the hydrogen atom in this amine groups of a kind of group displacement, and this group is R-carbonyl, RO-carbonyl, NRR '-carbonyl for example, wherein R and R ' each independently be (C ₁-C ₁₀) alkyl, (C ₃-C ₇) cycloalkyl, benzyl, or the R-carbonyl be natural α-aminoacyl or natural α-aminoacyl ,-C (OH) C (O) OY ¹, Y wherein ¹Be H, (C ₁-C ₆) alkyl or benzyl ,-C (OY ²) Y ³, Y wherein ²Be (C ₁-C ₄) alkyl, and Y ³Be (C ₁-C ₆) alkyl, carboxyl (C ₁-C ₆) alkyl, amino (C ₁-C ₄) alkyl or list-N-or two-N, N-(C ₁-C ₆) alkyl amino alkyl ,-C (Y ⁴) Y ⁵, Y wherein ⁴Be H or methyl, and Y ⁵Be list-N-or two-N, N-(C ₁-C ₆) alkylamino morpholinyl, piperidines-1-base or tetramethyleneimine-1-base etc.

One or more The compounds of this invention not solvent chemical combination form exist, and exist with solvent chemical combination form, have pharmaceutically acceptable solvent for example water, ethanol etc., and this invention is intended to comprise solvent chemical combination and solvent chemical combination form not.The physics association of " solvate " expression The compounds of this invention and one or more solvent molecules.This physics association relates to ionic and covalent bonding in various degree, comprises hydrogen bond.In some cases, solvate can separate, for example, and when one or more solvent molecules are impregnated in the lattice of crystalline solid." solvate " contains solution and separable solvate.The limiting examples of appropriate solvent compound comprises ethanol compound, methyl alcohol compound etc." hydrate " is solvate, and wherein solvent molecule is H ₂O.

One or more The compounds of this invention can be chosen wantonly and be converted to solvate.The preparation of solvate generally is known.Therefore, people such as M.Caira for example, J.Pharmaceutical Sci., 93 (3), 601-611 (2004) describes the anti-mycotic agent fluconazole and prepare solvate in ethyl acetate and from water.The similar preparation of solvate, half solvate, hydrate etc., by people such as E.C.van Tonder, AAPS PharmSciTech., 5 (1), paper 12 (2004); With people such as A.L.Bingham, Chem.Commun., 603-604 (2001) describes.The unrestricted method of a kind of typical case relates in the required solvent (organic or water or its mixture) that makes The compounds of this invention be dissolved in aequum under being higher than envrionment temperature, and solution is cooled off being enough to form under the crystalline speed, separates by standard method then.Analytical technology, for example I.R. spectroscopy shows that solvent (or water) is present in the crystallization as solvate (or hydrate).

" significant quantity " or " significant quantity in the treatment " is intended to describe The compounds of this invention or composition effectively suppresses the above amount of indication disease, and therefore produces needed treatment, improvement, inhibition or prophylactic effect.

Formula I compound can form salt, and it also within the scope of the invention.This paper is to the denotion of formula I compound, and what should understand is, unless point out in addition, otherwise comprise and censure its salt.When adopting in this article, " salt " vocabulary shows the acid-salt that forms with inorganic and/or organic acid, and the basic salt that forms with inorganic and/or organic bases.In addition, when formula I compound contains the basic moiety group such as but not limited to pyridine or imidazoles, and the acidic moiety group such as but not limited to carboxylic acid both the time, then can form zwitter-ion (" inner salt "), and be included in as used in this article in " salt " speech.The salt of pharmaceutically acceptable (meaning is can accept on nontoxicity, the physiology) is for preferred, although other salt also can use.The salt of formula I compound can be for example by making formula I compound and certain a certain amount of acid or alkali, equivalent for example, and in medium, for example salt can be deposited in wherein those, or reacts in aqueous medium, then lyophilize and forming.

Acid salt for example, comprise acetate, ascorbate salt, benzoate, benzene sulfonate, hydrosulphate, borate, butyrates, Citrate trianion, camphorate, camsilate, fumarate, hydrochloride, hydrobromate, hydriodate, lactic acid salt, maleic acid salt, methane sulfonates, naphthalenesulfonate, nitrate, oxalate, phosphoric acid salt, propionic salt, salicylate, succinate, vitriol, tartrate, thiocyanate-, tosylate (toluenesulfonate) (also being called tosylate (tosylate)) etc.In addition, it is generally acknowledged and be applicable to the acids that pharmaceutically can use salt from alkaline pharmaceutical compound formation, be for example by people such as P.Stahl, Camille G. (writing) Handbook of Pharmaceutical Salts.Properties, Selection and Use. (2002) Zurich:Wiley-VCH; People such as S.Berge, Journal of PharmaceuticalSciences (1977) 66 (1) 1-19; P.Gould, International J.of Pharmaceutics (1986) 33 201-217; People such as Anderson, The Practice of Medicinal Chemistry (1996), university press, New York; And discussed at The Orange Book (D.C. is on its website for food and drug administration, Washington).It is for reference that this type of disclosure is incorporated this paper into.

Basic salt for example, comprise ammonium salt, an alkali metal salt, for example sodium, lithium and sylvite, alkaline earth salt, for example calcium and magnesium salts, and the salt of organic bases (for example organic amine), this bases is dicyclohexyl amine, tertiary butyl amine for example, and and amino acid whose salt, this amino acid is arginine, Methionin etc. for example.The alkalescence nitrogen-containing group is can reagent quaternized, and this reagent is elementary alkyl halide (for example muriate of methyl, ethyl and butyl, bromide and iodide), sulfuric acid dialkyl (for example sulfuric ester of dimethyl, diethyl and dibutyl), long-chain halogenide (for example muriate of decyl, lauryl and stearyl, bromide and iodide), aralkyl halide (for example benzyl and styroyl bromination thing) and other for example.

All these type of hydrochlorates and alkali salt are intended to be the pharmaceutically-acceptable salts in the scope of the invention, and for the purposes of this invention, all acid and alkali salt are considered to be equivalent to the free form of respective compound.

The pharmaceutically acceptable ester class of The compounds of this invention comprises following group: (1) is by the carboxylic acid esters that esterification obtained of hydroxyl; wherein the non-carbonyl moiety group of ester group group's carboxylic moiety be selected from the straight or branched alkyl (for example ethanoyl, just-propyl group, the tertiary butyl or normal-butyl), alkoxyalkyl (for example methoxymethyl), aralkyl (for example benzyl), aryloxy alkyl (for example phenoxymethyl), aryl (for example; phenyl, it is optional by for example halogen, C _1-4Alkyl or C _1-4Alkoxyl group or amino replacement the); (2) sulfonic acid esters, for example alkyl-or aralkyl alkylsulfonyl (for example methane sulfonyl); (3) amino acid esters (for example different valerian aminoacyl of L-or L-isoleucyl base); (4) phosphonic acid ester, and (5) single-, two-or triguaiacyl phosphate class.Phosphoric acid ester can be further by for example C _1-20Alcohol or its reactive derivatives, or by 2,3-two (C _6-24) the acylglycerol esterification.

Formula I compound, with and salt, solvate, ester and prodrug, can its tautomeric form have (for example as acid amides or imido ether).All this kind tautomeric forms are intended to covered in herein, as a part of the present invention.

Formula (I) compound can contain asymmetric or chiral centre, therefore exists with different stereoisomeric forms in any ratio.Desirablely be, all stereoisomeric forms in any ratio of formula (I) compound with and composition thereof comprise that racemic mixture constitutes a part of the present invention.In addition, the present invention includes all geometry and positional isomerss.For example, if formula (I) compound is incorporated two keys or fused rings into, cis-within the scope of the invention involved then with trans-form and mixture.

The diastereo-isomerism mixture can its physical chemistry difference be the basis, by well known to a person skilled in the art method, for example by chromatography and/or fractional crystallization, is separated into its each diastereomer.Enantiomer can be separated by making enantiomeric mixture change into non-enantiomer mixture, its mode is and suitable optically active compound (chiral adjuvant for example, for example chiral alcohol or MosherShi chlorination acyl) reaction, separate diastereomer, make each diastereomer transform (for example hydrolysis) again and become its corresponding pure enantiomer.Some formulas (I) compound also can be atropisomer (for example biaryl base class of Qu Daiing), and is considered to a part of the present invention.Enantiomer also can utilize chirality HPLC post to separate.

Formula (I) compound can also different tautomeric forms exist, and all these type of forms are within the scope of the invention involved.For example, all keto-enols of compound and imines-enamine form, also in the present invention involved.

The compounds of this invention (the salt that comprises this compound, solvate, ester and prodrug, and the salt of this prodrug, solvate and ester) all steric isomers (geometrical isomer for example, optical isomer etc.), for example can owing to exist due to the asymmetric carbon on the different substituents those, comprise enantiomerism form (itself even can exist in the presence of not) at asymmetric carbon, the rotational isomeric form, atropisomer and diastereomeric form, be intended to covered in the scope of the present invention, for example positional isomers (for example 4-pyridyl and 3-pyridyl) (for example, if formula (I) compound is incorporated two keys or fused rings into, cis-within the scope of the invention involved then with trans-form and mixture.For example, all keto-enols of this compound and imines-enamine form, also in the present invention involved).Each steric isomer of The compounds of this invention can for example not contain other isomer in fact, or can be for example through being mixed into racemoid, or with all other or other steric isomer through selecting mixes.Chiral centre of the present invention can have as advising defined S or R configurations by IUPAC 1974.The use of term " salt ", " solvate ", " ester ", " prodrug " etc. is intended to similarly be applicable to salt, solvate, ester and the prodrug of enantiomer, steric isomer, rotational isomer, tautomer, positional isomers, racemoid or the prodrug of The compounds of this invention.

The present invention also comprises the The compounds of this invention that identifies in the isotropic substance mode, it is with described herein those are identical, but except the following situation, promptly one or more atoms are had by one that atomic mass or total mass number are different from usually the atomic mass found on natural or the atom of total mass number is replaced.Can be merged in the isotropic substance example in the The compounds of this invention, comprise the isotropic substance of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example be respectively ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl.

Some formula that identifies in the isotropic substance mode (I) compound (for example with ³H with ¹⁴The C sign) can be used in compound and/or the detection of substrate tissue distribution.(meaning promptly in tritiate ³H) and carbon-14 (meaning promptly ¹⁴C) isotropic substance is particularly preferred, but is easy to preparation and the bolt property surveyed because of it.In addition, with than the heavy isotropic substance for example deuterium (meaning promptly ²H) replace, can provide because some that higher metabolic stability caused treated interests (for example, increasing in vivo half life or reduction dosage requirement), therefore in some cases may be preferred.Generally can make according to disclosed program in similar hereinafter flow process and/or the example with formula (I) compound that the isotropic substance mode identifies, its mode is to replace the reagent that does not identify in the isotropic substance mode with the reagent that suitable isotropic substance mode identifies.

The polycrystalline form of formula I compound, and the polycrystalline form of the salt of formula I compound, solvate, ester class and prodrug will comprise in the present invention.

Can have pharmacological property according to compound of the present invention; Particular words, formula I compound can be inhibitors of protein kinases, conditioning agent or modulator.Can be suppressed, the limiting examples of adjusting or synthetic protein kinase, comprise cyclin-dependent kinase (CDK), CDK1 for example, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK7, CDK8, mitogen activation of protein kinases (MAPK/ERK), glycogen synthase kinase 3 (GSK3 β), the Pim-1 kinases, Chk kinases (for example Chk1 and Chk2), Tyrosylprotein kinase, for example the HER subtribe (comprises for example EGFR (HER1), HER2, HER3 and HER4), the Regular Insulin subtribe (comprises for example INS-R, IGF-IR, IR and IR-R), the PDGF subtribe (comprises for example PDGF-α and beta receptor, CSFIR, c-kit and FLK-II), FLK family (comprises that for example kinases inserts functional part acceptor (KDR), fetus liver kinases-1 (FLK-1), fetus liver kinases-4 (FLK-4) reaches like fms Tyrosylprotein kinase-1 (flt-1)), non-receptor protein tyrosine kinases, LCK for example, Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack and LIMK, growth factor receptor tyrosine kinase, for example VEGF-R2, FGF-R, TEK, the AKT kinases, aurora body kinases (aurora body A, aurora body B, aurora body C) etc.

Formula I compound can be inhibitors of protein kinases, for example check point kinases, for example inhibitor of Chk1, Chk2 etc.Preferred compound can show the IC that is lower than about 5 μ M ₅₀Value, preferably about 0.001 to about 1.0 μ M, and are more preferably about 0.001 to about 0.1 μ M.Detection method is described in hereinafter described the example.

Formula I compound can be used for the therapy of proliferative disease, and this disease is cancer, autoimmune disease, virus disease, fungal disease, neuropathy/neurodegenerative disorders, sacroiliitis, inflammation, anti-hyperplasia (for example eye retinopathy), neurone, baldness and cardiovascular disorder for example.Many these type of diseases and illness are shown in the U.S.6 of preamble citation, in 413,974, and for reference at this paper.

Say that more clearly formula I compound can be used for treating multiple cancer, includes, but is not limited to following:

The tumour of bladder cancer, mastocarcinoma (comprising BRCA-sudden change breast cancer), colorectal carcinoma, colorectal carcinoma, renal cancer, liver cancer, lungs cancer, small cell lung cancer, nonsmall-cell lung cancer, head and neck cancer, esophagus cancer, bladder cancer, carcinoma of gallbladder, ovarian cancer, cancer of pancreas, cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer and skin comprises squamous cell carcinoma;

Leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphomas, non-Hodgkin lymphomas, galley proof cell lymphoma, adventitial cell lymphoma, bone marrow cell carcinoma and Burkett lymphomas;

Lymphocytic leukemia (" CLL "),

Acute and chronic lymphocytic leukemia, myelodysplastic syndrome and progranulocyte leukemia;

Fibrosarcoma, rhabdosarcoma;

Head and deroncus, adventitial cell lymphoma, bone marrow cell carcinoma;

Astrocytoma, neuroblastoma, neurospongioma, neuroglia blastoma, pernicious neuroglial tumor, astrocytoma, hepatocellular carcinoma, gastrointestinal stromal tumor (" GIST ") and schwannoma;

Melanoma, multiple myeloma, spermatoblastoma, teratocarcinoma, osteosarcoma, different skin painted (xenoderoma pigmentosum), molluscum pseudocarcinomatosum (keratoctanthoma), Tiroidina follicular carcinoma and Kaposi sarcoma.

Because kinases is prevailingly in the vital role of regulating in the hyperplasia, so inhibitor can be useed reversible cytostatics as, it can be used for treatment and is characterized as the outgrowth any lysis of abnormal cells, for example restenosis, loose scar formation, inflammatory bowel disease, transplant rejection, endotoxin shock and the fungi infestation after benign prostatic hyperplasia, familial adenhomatosis polyposis, neurofibroma generation, atherosclerosis, pnemnofibrosis, sacroiliitis, psoriasis, glomerulonephritis, angioplasty or the vascular surgery.

Formula I compound also can be used for treating Ah ear and grows extra large Mo's disease, as the recent findings that participates in the effect of tau protein matter phosphorylated by CDK5 pointed (J.Biochem, (1995) 117,741-749).

Formula I compound can bring out or suppress apoptosis.Apoptosis is replied superstition in multiple human diseases.Formula I compound as apoptotic modulator will can be used for treating cancer (including but not limited to type referred to above), virus infection (includes but not limited to simplexvirus (herpevirus), poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), the AIDS development of the individual philtrum that prevention HIV infects, autoimmune disease (includes but not limited to systemic lupus erythematosus, systemic lupus erythematosus (erythematosus), the glomerulonephritis that autoimmunization mediated, rheumatoid arthritis, psoriasis, inflammatory bowel disease and autoimmune diabetes), neurodegenerative disorders (includes but not limited to that Ah ear grows extra large Mo's disease, the dementia that AIDS is relevant, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellum degeneration), myelodysplastic syndrome, aplastic anemia, form relevant ischemia injury with myocardial infarction, apoplexy and reperfusion injury, irregularity of pulse, atherosclerosis, the hepatopathy that toxin brings out or alcohol is relevant, blood disease (including but not limited to chronic anaemia and aplastic anemia), the degenerative disease of musculoskeletal system (including but not limited to osteoporosis and sacroiliitis), the aspirin sensitive sinusitis paranasal sinusitis, the gall-bladder fibrosis, multiple sclerosis, kidney disease and cancer pain.

Formula I compound as kinase whose inhibitor, can be modulated cell RNA and DNA synthetic level.Therefore, this type of medicament can be used for treating virus infection (including but not limited to HIV, Human papilloma virus HPV, simplexvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus).

Formula I compound also can be used for the chemoprophylaxis of cancer.It is by blocking initial mutagenesis incident that chemoprophylaxis is defined as, or the progress of the preceding malignant cell of having been invaded by blocking-up, and suppresses the development of invasive cancer, or suppresses tumor recurrence.

Formula I compound also can be used for suppressing tumor-blood-vessel growth and transfer.

Formula I compound also can be used as cyclin-dependent kinase and other inhibitors of protein kinases, for example protein kinase C, her2, raf1, MEK1, map kinase, EGF acceptor, pdgf receptor, IGF acceptor, PI3 kinases, wee1 kinases, Src, Abl, and therefore effective treatment and other protein kinase diseases associated.

Another aspect of the invention is a kind of treatment and suffer from method with the Mammals (for example human) of kinases (for example CDK, CHK and aurora body kinases) diseases associated or symptom, its mode is this Mammals to be thrown give at least a formula I compound that significant quantity is gone up in treatment, or the pharmaceutically-acceptable salts of this compound, solvate, ester or prodrug.

Preferred dosage is the formula I compound in about 0.001 to 1000mg/ kg body weight/sky.Particularly preferred dosage is the formula I compound in about 0.01 to 25mg/ kg body weight/sky, or the pharmaceutically-acceptable salts of this compound, solvate, ester or prodrug.

The compounds of this invention also can and with (together or dispensing) in succession one or more anticancer therapy methods, radiotherapy for example, and/or one or more are different from the carcinostatic agent of formula I compound.The compounds of this invention can be present in the same dose unit as carcinostatic agent, or in isolating dose unit.

Another aspect of the invention is the method for one or more and kinases (for example CDK, CHK and aurora body) diseases associated of treatment, it comprises the Mammals of this kind of needs treatment thrown and gives a certain amount of first compound that it is compound or its pharmacy acceptable salt, solvate, ester or the prodrug of formula 1; And a certain amount of at least a second compound, this second compound is the carcinostatic agent that is different from the compound of formula 1, wherein the amount of first compound and second compound can produce result of treatment.

Suitably the limiting examples of carcinostatic agent (for example is selected from cytostatic agent, cis-platinum, Zorubicin, liposome Zorubicin

), taxotere (taxotere), taxol, Etoposide, Rinotecan, camptostar, Hycamtin, taxol (paclitaxel), docetaxel (docetaxel), Ai Boxi ketone (epothilone), tamoxifen, 5 FU 5 fluorouracil, Rheumatrex (methoxtrexate), Temozolomide, endoxan, SCH 66336,

The antibody of EGFR, the antibody of IGFR (comprise and being delivered among the US 2005/0136063 of bulletin on June 23rd, 2005 for example), KSP inhibitor (are for example announced among WO 2006/098962 and the WO 2006/098961; Ispinesib, SB-743921 derive from Cytokinetics), centrosome related protein E (" CENP-E ") inhibitor (for example GSK-923295),

Intron, ara-C, Zorubicin, endoxan, gemcitabine, uracil mustard, mustargen, ifosfamide (Ifosfamide), L-PAM, Chlorambucil, pipobroman (Pipobroman), Persistol, triethylene sulfo-phosphamidon, busulfan, carmustine, lomustine, streptozocin, dacarbazine, fluorodeoxyuridine, cytosine arabinoside, Ismipur, 6-sulfenyl guanine, fludarabine phosphate, oxaliplatin, formyl tetrahydrofolic acid (leucovirin), ELOXATIN ^TMPentostatine, vinealeucoblastine(VLB), vincristine(VCR), vindesine, bleomycin, gengshengmeisu, daunorubicin, Hydroxydaunomycin, epirubicin, idarubicin (Idarubicin), mithramycin, deoxidation is formycin altogether, Mitomycin-C, the altheine enzyme, teniposide (Teniposide), 17 alpha-acetylenes estradiol, stilboestrol, testosterone, prednisone, FL, dromostanolone propionate, testolactone, the acetate megestrol, medrat, methyltestosterone, Prednisolone Acetate, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimidium (Aminoglutethimide), Emcyt (Estramustine), the Zytron acetic ester, Leuprolide, Drogenil (Flutamide), toremifene, goserelin, cis-platinum, carboplatin, hydroxyurea, Amsiacrine (Amsacrine), procarbazine, mitotane (Mitotane), mitoxantrone, L-tetramisole, nvelbine (Navelbene), Anastrazole, Letrazole, capecitabine, raloxifene, droloxifene, hexamethyl melamine, Avastin, herceptin, Bexxar, rich for left side rice (bortezomib) (" Velcade "), Zevalin, white arsenic (Trisenox), xeloda (Xeloda), vinorelbine, porfimer (Porfimer), Erbitux, liposome (Liposomal), thio-tepa, hexamethyl melamine, L-PAM, trastuzumab, Lerozole, fulvestrant, Exemestane, fulvestrant, Ifosfomide, Rituximab;

Satriplatin, mylotarg, Avastin, B cell monoclonal antibody (rituxan), panitubimab, Sutent, sorafinib, Sprycel (dastinib), nilotinib, Tykerb (lapatinib) and Campath.

If be deployed into fixed dosage, then this kind combination product adopts the The compounds of this invention in dosage range described herein, and another kind of pharmaceutical active or medicine in its dosage range.For example, found that CDC2 inhibitor Ou Luomuxin (olomucine) can bring out on the apoptosis, produced synergy (J Cell Sci., (1995) 108,2897) with known cytotoxic agent.When combination formula was inappropriate, formula I compound also can be offerd medicine in succession with known anticancer agents or cytotoxic agent.The present invention does not limit the order of dispensing; Formula I compound can the preceding of known anticancer agents or cytotoxic agent dispensing or back dispensing.For example, the cytotoxic activity of cyclin-dependent kinase inhibitor flavones pyridine alcohol (flavopiridol) is subjected to influencing with the order that carcinostatic agent is offerd medicine.CancerResearch，(1997) 57，3375。This kind technology is in those skilled in the art and working doctor's technical scope.

Therefore, on the one hand, the present invention includes combination, it comprises a certain amount of at least a formula I compound or its pharmacy acceptable salt, solvate, ester and prodrug, and a certain amount of one or more anticancer therapy method and carcinostatic agents of above enumerating, wherein the amount of compound/therapeutics can produce the result of treatment that needs.

Another aspect of the invention is a kind of kinase whose method of one or more aurora bodies that suppresses in the patient who needs is arranged, it comprises this patient thrown and gives at least a formula 1 compound or its pharmacy acceptable salt, solvate, ester or the prodrug that significant quantity is gone up in treatment.

Another aspect of the invention is a kind of treatment or slow down method with one or more aurora body kinases diseases associated progress in the patient who needs is arranged, it comprises throwing and gives at least a formula 1 compound or its pharmacy acceptable salt, solvate, ester or the prodrug that significant quantity is gone up in treatment.

Of the present inventionly be a kind of method for the treatment of one or more and aurora body kinases diseases associated again on the other hand, it comprises the Mammals of this kind of needs treatment thrown and gives a certain amount of first compound that it is compound or its pharmacy acceptable salt, solvate, ester or the prodrug of formula 1; And a certain amount of at least a second compound, this second compound is a carcinostatic agent, wherein the amount of first compound and second compound can produce result of treatment.

Another aspect of the invention is a kind of treatment or slow down method with one or more aurora body kinases diseases associated progress in the patient who needs is arranged, it comprises throwing and gives a kind of medical composition that significant quantity is gone up in treatment, and it comprises and with at least a pharmaceutically acceptable carrier and at least a compound or its pharmacy acceptable salt, solvate, ester or prodrug according to formula 1.

In aforesaid method, the repressed aurora body of desire kinases can be aurora body A, aurora body B and/or aurora body C.

Another aspect of the invention is a kind of kinase whose method in one or more check points that suppresses in the patient who needs is arranged, it comprises this patient thrown and gives at least a formula 1 compound or its pharmacy acceptable salt, solvate, ester or the prodrug that significant quantity is gone up in treatment.

Another aspect of the invention is a kind of treatment or slow down one or more and the method for check point kinases diseases associated progress in the patient who needs is arranged, it comprises throwing and gives treatment upward at least a formula 1 compound or its pharmacy acceptable salt, solvate, ester or the prodrug of significant quantity.

Of the present inventionly be a kind of method for the treatment of one or more and check point kinases diseases associated again on the other hand, it comprises the Mammals of this kind of needs treatment thrown and gives a certain amount of first compound that it is compound or its pharmacy acceptable salt, solvate, ester or the prodrug of formula 1; And a certain amount of at least a second compound, this second compound is a carcinostatic agent, wherein the amount of first compound and second compound can produce result of treatment.

Another aspect of the invention is a kind of treatment or slow down method with one or more check point kinases diseases associated progress in the patient who needs is arranged, it comprises throwing and gives a kind of medical composition that significant quantity is gone up in treatment, and it comprises and with at least a pharmaceutically acceptable carrier and at least a compound or its pharmacy acceptable salt, solvate, ester or prodrug according to formula 1.

In aforesaid method, the repressed check point of desire kinases can be Chk1 and/or Chk2.

Another aspect of the invention is a kind of method that suppresses one or more cyclin-dependent kinases in the patient who needs is arranged, it comprises this patient thrown and gives at least a formula 1 compound or its pharmacy acceptable salt, solvate, ester or the prodrug that significant quantity is gone up in treatment.

Another aspect of the invention is a kind of treatment or slow down one or more and the method for cyclin-dependent kinase diseases associated progress in the patient who needs is arranged, it comprises throwing and gives treatment upward at least a formula 1 compound or its pharmacy acceptable salt, solvate, ester or the prodrug of significant quantity.

Of the present inventionly be the method for one or more and cyclin-dependent kinase diseases associated of treatment again more on the other hand, it comprises the Mammals of this kind of needs treatment thrown and gives a certain amount of first compound that it is formula 1 compound or its pharmacy acceptable salt, solvate, ester or prodrug; And a certain amount of at least a second compound, this second compound is a carcinostatic agent, wherein the amount of first compound and second compound can produce result of treatment.

Another aspect of the invention is a kind of treatment or slow down method with one or more cyclin-dependent kinase diseases associated progress in the patient who needs is arranged, it comprises throwing and gives a kind of medical composition that significant quantity is gone up in treatment, and it comprises and with at least a pharmaceutically acceptable carrier and at least a compound or its pharmacy acceptable salt, solvate, ester or prodrug according to formula 1.

Another aspect of the invention is a kind of method that suppresses one or more Tyrosylprotein kinases in the patient who needs is arranged, it comprises this patient thrown and gives at least a formula 1 compound or its pharmacy acceptable salt, solvate, ester or the prodrug that significant quantity is gone up in treatment.

Of the present inventionly be a kind of treatment or slow down method with one or more Tyrosylprotein kinase diseases associated progress in the patient who needs is arranged again more on the other hand, it comprises throwing and gives at least a formula 1 compound or its pharmacy acceptable salt, solvate, ester or the prodrug that significant quantity is gone up in treatment.

Another aspect of the invention is the method for one or more and Tyrosylprotein kinase diseases associated of treatment, it comprises the Mammals of this kind of needs treatment thrown and gives a certain amount of first compound that it is formula 1 compound or its pharmacy acceptable salt, solvate, ester or prodrug; And a certain amount of at least a second compound, this second compound is a carcinostatic agent, wherein the amount of first compound and second compound can produce result of treatment.

Another aspect of the invention is a kind of treatment or slow down method with one or more Tyrosylprotein kinase diseases associated progress in the patient who needs is arranged, it comprises throwing and gives a kind of medical composition that significant quantity is gone up in treatment, and it comprises and with compound or its pharmacy acceptable salt, solvate, ester or the prodrug of at least a pharmaceutically acceptable carrier and at least a formula 1.

In aforesaid method, Tyrosylprotein kinase can be VEGFR (VEGF-R2), EGFR, HER2, SRC, JAK and/or TEK.

Another aspect of the invention is a kind of kinase whose method of one or more Pim-1 that suppresses in the patient who needs is arranged, it comprises this patient thrown and gives compound or its pharmacy acceptable salt, solvate, ester or the prodrug that at least a formula 1 of significant quantity is gone up in treatment.

Of the present inventionly be a kind of treatment or slow down method with one or more Pim-1 kinases diseases associated progress in the patient who needs is arranged again more on the other hand, it comprises throwing and gives at least a formula 1 compound or its pharmacy acceptable salt, solvate, ester or the prodrug that significant quantity is gone up in treatment.

Another aspect of the invention is a kind of method for the treatment of one or more and Pim-1 kinases diseases associated, it comprises the Mammals of this kind of needs treatment thrown and gives a certain amount of first compound that it is formula 1 compound or its pharmacy acceptable salt, solvate, ester or prodrug; And a certain amount of at least a second compound, this second compound is a carcinostatic agent, wherein the amount of first compound and second compound can produce result of treatment.

Another aspect of the invention is a kind of treatment or slow down method with one or more Pim-1 kinases diseases associated progress in the patient who needs is arranged, it comprises throwing and gives a kind of medical composition that significant quantity is gone up in treatment, and it comprises and with at least a pharmaceutically acceptable carrier and at least a formula 1 compound or its pharmacy acceptable salt, solvate, ester or prodrug.

The pharmacological property of The compounds of this invention can be confirmed by multiple pharmacology detection method.Hereinafter the pharmacology detection method of the illustrative of Miao Shuing has been used according to compound of the present invention and salt, solvate, ester or prodrug and has been carried out.

The invention still further relates to medical composition, it comprises at least a formula I compound, or the pharmacy acceptable salt of this compound, solvate, ester or prodrug, and at least a pharmaceutically acceptable carrier.

For for compound medical composition of the present invention, it is solid or liquid that inert, pharmaceutically acceptable carrier can be.But the solid form preparation comprises powder, tablet discrete particles, capsule, cachet and suppository.Powder and tablet can comprise about 5 active ingredients to about 95 per-cents.Suitably solid carrier is known in the art, for example magnesiumcarbonate, Magnesium Stearate, talcum, sugar or lactose.Tablet, powder, cachet and capsule can be used as the solid dosage that is suitable for oral administration medicine supplying and use.The example of pharmaceutically acceptable carrier and the method for making of various compositions can be consulted A.Gennaro (ed.), Remington ' s Pharmaceutical Sciences, 18 ^ThEdition, (1990), Mack Publishing Co., Easton, Pennsylvania.

Liquid form preparation comprises solution, suspension and emulsion.With as an example following, it is non-through enteral administration to point out that water or water-propylene glycol solution are used for, or adds sweetener and opalizer, to be used for oral liquid, suspension and emulsion.Liquid form preparation also can comprise the solution for interanasal administration.

The aerosol preparations that is applicable to suction can comprise solution and be the solid of powder type, its can and with pharmaceutically acceptable carrier, for example inertia pressurized gas, for example nitrogen.

Also comprise the solid form preparation, it is intended to be converted to liquid form preparation using not long ago, offers medicine through intestines for oral or non-.This kind liquid form comprises solution, suspension and emulsion.

The compounds of this invention can also transmit through the skin mode.Transdermal composition can be taked the form of emulsifiable paste, lotion, aerosol and/or emulsion, and can be comprised in the transdermal patch of matrix or reservoir type, and it is this area usual manner for this purpose.

The compounds of this invention can also subcutaneous mode transmit.

Compound is preferably offerd medicine with per os mode or intravenously mode.

Also contain in the present invention be transmission method, it is the above combination of indication transmission method.This kind method is determined by those skilled in the art usually.

This pharmaceutical preparation preferably is unit dosage.In this kind form, preparation is subdivided into the unitary dose of suitable size, and it contains the active ingredient of appropriate amount, for example reaches the significant quantity of required purpose.

The amount of active compound in unit dose formulations decided according to application-specific, can change or be adjusted into about 1mg to about 100mg, and preferably about 1mg is more preferably about 1mg to about 25mg to about 50mg.

The actual dose that is adopted can change according to patient's requirement and by the seriousness of treatment symptom.Determine that the suitable dosage instructions about how to take medicine for particular condition are in the skill of this area.For simplicity, can as required total day clothes dosage be distinguished, and the gradation throwing is given in during one day.

The dosage of The compounds of this invention and/or its pharmaceutically-acceptable salts and frequency adjust according to doctor in charge's judgement, wherein consider some factors, for example the seriousness of patient's age, symptom and size and quilt treatment symptom.Typical case to oral administration medicine supplying advises that every day, the dosage instructions about how to take medicine can contain from about 1mg/ days to about 500mg/ days scope, preferably 1mg/ days to 200mg/ days, and in two to four parts of divided doses.

Another aspect of the invention is a kind of medicine box, it comprises at least a formula I compound that significant quantity is gone up in treatment, or the pharmacy acceptable salt of this compound, solvate, ester or prodrug, and pharmaceutically acceptable carrier, medium or thinner.

Of the present invention is again a kind of medicine box on the other hand, at least a formula I compound of its packet content, or the pharmacy acceptable salt of this compound, solvate, ester or prodrug, and a certain amount of at least a anti-cancer therapies and/or carcinostatic agent of above enumerating, wherein the amount of these two or more compositions can produce the result of treatment that needs.

Embodiment

Disclosed in this article the present invention comes for example with following preparation and embodiment, and it should not be interpreted as the scope of limit publicity content.Alternate mechanism pathway and similar structures will be that those skilled in the art institute is apparent.

Proposing under the NMR data conditions, ¹H spectrum be Varian VXR-200 (200MHz, ¹H), Varian Gemini-300 (300MHz) or XL-400 (400MHz) go up and obtain, and with distance Me ₄The ppm of Si downfield gives a report, and wherein proton number, multiplicity and coupling constant (representing with hertz) are to indicate in the bracket mode.Proposing under the LC/MS data conditions, analyzing and use AppliedBiosystems API-100 mass spectrograph and Shimadzu SCL-10A LC post to carry out: Altech platinum C18,3 microns, 33 millimeters * 7 millimeters internal diameters; Gradient flow quantity: 0 minute-10%CH ₃CN, 5 minutes-95%CH ₃CN, 7 minutes-95%CH ₃CN, 7.5 minutes-10%CH ₃CN, 9 minutes-stop.Provide and protect retention time and the parent ion of being observed.

Following solvent and reagent can be censured by its abbreviation in bracket:

Tlc: TLC

Methylene dichloride: CH ₂Cl ₂

Ethyl acetate: AcOEt or EtOAc

Methyl alcohol: MeOH

Trifluoro-acetate: TFA

Triethylamine: Et ₃N or TEA

Butoxy carbonyl: n-Boc or Boc

Nuclear magnetic resonance spectrometry: NMR

Liquid chromatography-mass spectrometry: LCMS

High resolution mass spectrometry method: HRMS

Milliliter: mL

Milli rubs: mmol

Microlitre: μ l

Gram: g

Milligram: mg

Room temperature or rt (environment): about 25 ℃

Glycol dimethyl ether: DME

The synthetic of The compounds of this invention is illustrated in hereinafter.Should be noted also that the U.S.6 that holds jointly, 919,341 with the disclosure of Application No. 11/598186 to incorporate this paper into for reference.

Embodiment 1

Part A: make according to US20060106023 (A1).

Part B: to the compound that derives from embodiment 1 part A (2.00g, 8.19mmol) add in the solution in DMF (50mL) N-iodosuccinimide (1.84g, 8.19mmol).Reaction mixture was stirred 16 hours down at 60 ℃.Make mixture be cooled to 25 ℃, reconcentration.Resistates is dissolved among the DCM with small amount of methanol, fills on the post then.By column chromatography purifying (SiO ₂, 40% ethyl acetate/hexane), obtain compound 4, be white solid 2.30g (76%). ¹H-NMR (400MHz, DMSO-d ₆) δ 8.3 (s, 1H), 7.8 (s, 1H), 2.6 (s, 3H) .HPLC-MSt _R=1.87 minutes (UV ₂₅₄Nm).To the Mass Calculation value 370.01 of formula C7H5BrIN3S, measured value LC/MS m/z 370.9 (M+H).

Portion C: bromide (45.6g), the Pd (PPh that will derive from part B ₃) ₄(10.8g), salt of wormwood (77.4g), trimethylboroxin (46.9g) and the suspension of salt of wormwood (77.4g) in DMF (410mL), in nitrogen and 105 ℃ of following heated overnight.After the cooling, with ethyl acetate (1L) diluted mixture thing, with salt solution (2x500mL) washing, dry (sal epsom) filters, and concentrates, and passes through chromatography purification again on silica gel.Obtain title compound, be faint yellow solid (21.4g, 64%).

Part D: in the DMF of the compound that derives from embodiment 1 portion C (21.8g) (400mL) solution, add N-iodosuccinimide (26.9g), and with formed mixture 60 ℃ of following heated overnight.Mixture is concentrated, and add water (400mL).After at room temperature stirring 1 hour, add saturated sodium carbonate (250mL), then restir 30 minutes at room temperature.Mixture is filtered,, make filter cake dried overnight under vacuum with water, methyl alcohol (100mL) washing.Obtain brown solid (31.4g, 87%).

Part E: in flask, filling derives from iodide (1.00 equivalent), Bpin-compound 5a (1.3 equivalent), the PdCl of part D ₂(dppf) (0.1 equivalent) and potassiumphosphate monohydrate (3.0 equivalent).After flask purged with argon, add 1,4-dioxane (50mL) and water (5), and with formed mixture in 80 ℃ of following heated overnight (23 hours).Make reactant be cooled to room temperature.EtOAc is added in the reaction mixture, and through diatomite filtration.After concentrating, make resistates pass through column chromatography purifying (silica gel, 25%EtOAc/ hexane), obtain title compound.

Part F: in the solution of the compound that derives from embodiment 1 part E (1.0 equivalent) in DCM (10mL), add m-CPBA (2.05 equivalent) with portion.Formed mixture was at room temperature stirred 30 minutes.Mixture is concentrated, between EtOAc and water, make separatory then and handle.With organic layer with NaHCO ₃(saturated aqueous solution, twice), salt water washing, dry (Na ₂SO ₄).After concentrating, obtain title compound, directly be used in next step, need not to be further purified.

Embodiment 2

To 1 ¹(1.04g 5.98mmol) adds K in the solution in 20mL DMF ₂CO ₃(2.48g, 17.9mmol) with MeI (1.27g, 8.96mmol).Reactant at room temperature stirred spend the night.It is diluted with 200mL 50%EtOAc/ hexane, and with water (200mL) and salt solution (100mL) washing.Organic substance is concentrated.In resistates, add the 20mL hexane.By solid collected by filtration, obtain 2.Filtrate is concentrated, by column purification, with 25%EtOAc/ hexane wash-out, measured in addition 2.2 merging output is 1.05g. ¹H?NMR(400MHz，CDCl ₃)δ8.37(s，1H)，4.05(s，3H)。

Embodiment 3

To 2 (260mg, 1.38mmol) add in the solution in 6mL AcOH iron powder (774mg, 13.8mmol).Reaction mixture was heated 12 minutes down at 70-75 ℃.Make mixture be cooled to room temperature, add 20mL MeOH then.Make formed mixture through diatomite (with the MeOH flushing of diatomite) filtration with other amount.Concentrated filtrate is to remove most of AcOH.In resistates, add 15mL 20%MeOH/CH ₂Cl ₂, then be the saturated NaHCO of 20mL ₃The aqueous solution.Mixture is stirred, up to stopping foaming.By EtOAc (60mLx2) extraction mixture, with Na ₂SO ₄Drying concentrates then.In resistates, add 5mL ether, then be the 5mL hexane.By solid collected by filtration, it is rough 3 to obtain 160mg, and it contains a small amount of acylations amine, but enough pure, for the sulfone replacement(metathesis)reaction.Make filtrate pass through post, with 20%AcOEt/CH ₂Cl ₂Purifying obtains 3 of other 30mg. ¹H?NMR(400MHz，CDCl ₃)δ6.85(s，1H)，4.61(brs，2H)，3.92(s，3H)。

Example 4

To compound 3 (89mg; 0.56mmol) and 6-bromo-8-methane sulfonyl-3-[1-(2-TMS-ethoxyl methyl)-1H-pyrazoles-4-yl]-imidazo [1; 2-a] pyrazine (258mg; 0.55mmol) add NaH (60% dispersion liquid in oil in the solution in 2mL DMF; 44mg, 1.1mmol).Reactant was at room temperature stirred 15 minutes.With the saturated NH of 5mL ₄The Cl aqueous solution makes its cancellation, and dilutes with 30mL water.By solid collected by filtration, with water and MeOH washing.Make it dry under vacuum, obtain 255mg compound 4. ¹H?NMR(400MHz，DMSO-d ₆)δ8.85(s，1H)，8.22(s，1H)，8.15(s，1H)，7.96(s，1H)，7.62(s，1H)，5.50(s，2H)，3.85(s，3H)，3.60(t，2H)，1.83(t，2H)，0.00(s，9H)。

Embodiment 5

Steps A: (76mg 0.14mmol) adds Pd (PPh in the solution in 6mL THF to 4 ₃) ₄(16mg, 0.014mmol) with 0.35mL MeZnCl (the 2M solution in THF, 0.69mmol).Reactant was stirred 20 minutes down at 80 ℃.Make it be cooled to room temperature, and make the reaction cancellation by adding 0.5mL MeOH.With it with 30mL CH ₂Cl ₂Dilution is with 20mL 0.5NHCl solution washing.Move down in vacuum and to desolventize.Make resistates pass through purified by flash chromatography, with 5%MeOH/CH ₂Cl ₂Wash-out, 5-{6-methyl-3-[1-(2-TMS-ethoxyl methyl)-1H-pyrazoles-4-yl of acquisition 50mg]-imidazo [1,2-a] pyrazine-8-base is amino }-isothiazole-3-carboxylate methyl ester, by a small amount of triphenyl phosphine oxide contaminant.

Step B: above-mentioned crude material is dissolved among the 5mL THF.In this solution, add 0.5mLLiBHEt ₃(the 1M solution in THF).Reactant was at room temperature stirred 30 minutes.By adding the saturated NH of 5mL ₄The Cl aqueous solution makes its cancellation.By 30mL CH ₂Cl ₂The extraction mixture.Organic substance is concentrated, and by purified by flash chromatography, with 5%MeOH/CH ₂Cl ₂Wash-out obtains 25mg compound 5.NMR(400MHz，CDCl ₃)δ7.90(s，1H)，7.82(s，1H)，7.60(s，1H)，7.48(s，1H)，6.90(s，1H)，5.55(s，2H)，4.75(brs，2H)，3.65(t，2H)，2.50(s，3H)，1.00(t，2H)，0.00(s，9H)。

Embodiment 6

To compound 5 (200mg, 0.438mmol) add in the solution in 20mL THF triethylamine (0.21mL, 1.5mmol) with methylsulfonyl chloride (0.10mL, 1.3mmol).Reactant was at room temperature stirred 30 minutes.Make its cancellation by adding 1mL MeOH.Solution is passed through 30mL CH ₂Cl ₂Dilution is with the 15mL 2N HCl aqueous solution, water and salt solution continuous washing.Move down in vacuum and to desolventize, obtain 230mg crude compound 6, it is used in further transformation, need not to be further purified.

Embodiment 7

Steps A: (17mg, 0.032mmol) (15mg, the 0.23mmol) mixture in 1mL DMF heated 3 hours down at 70 ℃ with sodiumazide with compound 6.Make it be cooled to room temperature, and add 10mL water.Collect formed solid by filtering, by purified by flash chromatography, with 5%MeOH/CH ₂Cl ₂Wash-out, (the 3-azido methyl-isothiazole-5-yl) of acquisition 12mg-6-methyl-3-[1-(2-TMS-ethoxyl methyl)-1H-pyrazoles-4-yl]-imidazo [1,2-a] pyrazine-8-yl }-amine.

Step B: above-mentioned substance is dissolved among the 3mL MeOH.In this solution, add the 10 weight %Pd/C of 15mg.With mixture at H ₂(1 normal atmosphere) stirred 1 hour down.Make it through diatomite filtration.Concentrated filtrate under vacuum obtains 12mg compound 7.NMR(400MHz，CDCl ₃)δ7.88(s，1H)，7.80(s，1H)，7.60(s，1H)，7.47(s，1H)，6.86(s，1H)，5.55(s，2H)，4.00(brs，2H)，3.65(t，2H)，2.50(s，3H)，1.00(t，2H)，0.00(s，9H)。

Embodiment 8

(12mg 0.026mmol) adds the 4N HCl of 0.5mL in dioxane in 70 ℃ of solution that heat down in 2mL THF to compound 7.In formed mixture, add MeOH, till it becomes evenly.Reactant was stirred 1 hour down at 70 ℃, be cooled to room temperature then.By solid collected by filtration, and, obtain 9mg compound 8, be its HCl salt form with the ether washing.NMR (400MHz, CD ₃OD) δ 8.23 (s, 1H), 8.20 (s, 2H), 8.03 (s, 1H), 7.20 (s, 1H), 4.22 (s, 2H), 2.59 (s, 3H) .HPLC-MS t _R=1.82 minutes (UV ₂₅₄Nm).To formula C ₁₄H ₁₄N ₈The Mass Calculation value 326.1 of S; Measured value MH ⁺(LCMS) 327.2 (m/z).

Embodiment 9

Steps A: (9mg is 0.02mmol) at 1mL MeOH/CH to compound 7 ₂Cl ₂Interpolation formaldehyde in the solution in (1: 1) (40 weight %, in water, 6mg, 0.2mmol).When adding NaBH with two parts ₄(16mg in the time of 0.4mmol), at room temperature stirred it 15 minutes.Make mixture pass through purified by flash chromatography, with NH ₄Cl (aqueous solution)/MeOH/CH ₂Cl ₂(1: 5: 190) wash-out, (the 3-dimethylamino methyl-isothiazole-5-yl) of acquisition 5mg-6-methyl-3-[1-(2-TMS-ethoxyl methyl)-1H-pyrazoles-4-yl]-imidazo [1,2-a] pyrazine-8-yl }-amine.

Step B: then, above-mentioned substance is dissolved among the 2mL THF.When adding the 4N HCl of 0.5mL in dioxane, with formed solution 70 ℃ of heating down.In formed mixture, add 1mL MeOH.Reactant was stirred 1 hour down at 70 ℃, then be cooled to room temperature.Under vacuum, remove most of solvent.In resistates, add 5mL ether.By solid collected by filtration, and, obtain 5mg compound 9, be its HCl salt form with the ether washing.NMR (400MHz, CD ₃OD) δ 8.21 (s, 1H), 8.18 (s, 2H), 8.08 (s, 1H), 7.30 (s, 1H), 4.42 (s, 2H), 2.95 (s, 6H), 2.59 (s, 3H) .HPLC-MS t _R=2.04 minutes (UV ₂₅₄Nm).To formula C ₁₆H ₁₈N ₈The Mass Calculation value 354.1 of S; Measured value MH ⁺(LCMS) 355.2 (m/z).

Embodiment 10

To compound 5 (2.50g 5.47mmol) adds 0.3mL water in the solution in 100mL THF, then for Dess-Martin cross iodine alkane (6.96g, 16.4mmol).Reactant was at room temperature stirred 30 minutes.Leach solid.With filtrate with 200mL CH ₂Cl ₂Dilution, and with the saturated NH of 100mL ₄The Cl solution washing.Make organic substance with anhydrous Na ₂SO ₄Drying concentrates then.In resistates, add the 30mL acetonitrile.By solid collected by filtration, obtain 2.05g compound 10.NMR(400MHz，DMSO-d ₆)δ12.38(s，1H)，9.84(s，1H)，8.60(s，1H)，8.11(s，1H)，7.96(s，1H)，7.91(s，1H)，7.55(s，1H)，5.50(s，2H)，3.60(t，2H)，2.45(s，3H)，1.83(t，2H)，0.00(s，9H)。

Embodiment 11

Steps A: (100mg, 0.220mmol) (156mg is 2.20mmol) at 14mL CH with tetramethyleneimine with compound 10 ₂Cl ₂In solution, at room temperature stirred 20 minutes.In this solution, add two acetate, then be NaBH ₄(67mg, 1.8mmol).When adding 3mL MeOH, formed mixture was at room temperature stirred 5 minutes.Continue again to stir 20 minutes.By adding the saturated NaHCO of 15mL ₃The aqueous solution makes the reaction cancellation.With 20mL CH ₂Cl ₂After the dilution, separating organic substances.Move down in vacuum and to desolventize.Make resistates pass through purified by flash chromatography, with NH ₄Cl (aqueous solution)/MeOH/CH ₂Cl ₂(1: 10: 190) wash-out, acquisition 98mg 6-methyl-3-[1-(2-TMS-ethoxyl methyl)-1H-pyrazoles-4-yl]-imidazo [1,2-a] pyrazine-8-yl }-(3-tetramethyleneimine-1-ylmethyl-isothiazole-5-yl)-amine.NMR(400MHz，CDCl ₃)δ7.88(s，1H)，7.81(s，1H)，7.60(s，1H)，7.48(s，1H)，6.96(s，1H)，5.55(s，2H)，3.80(s，2H)，3.65(t，2H)，2.70(brs，4H)，2.50(s，3H)，1.85(brs，4H)，0.96(t，2H)，0.00(s，9H)。

Step B: to 6-methyl-3-[1-(2-TMS-ethoxyl methyl)-1H-pyrazoles-4-yl]-imidazo [1,2-a] pyrazine-8-yl }-(98mg 0.19mmol) adds the 4N HCl of 2mL in dioxane to (3-tetramethyleneimine-1-ylmethyl-isothiazole-5-yl)-amine in 70 ℃ of solution that heat down in 8mL THF.In formed mixture, add MeOH, till it becomes evenly.Reactant was stirred 1 hour down at 70 ℃, be cooled to room temperature then.In mixture, add 3mL ether.By solid collected by filtration, and, obtain 79mg compound 11, be its HCl salt form with the ether washing.NMR (400MHz, CD ₃OD) δ 8.18 (s, 2H), 8.13 (s, 1H), 8.00 (s, 1H), 7.22 (s, 1H), 4.50 (s, 2H), 3.62-3.68 (m, 2H), 3.06-3.15 (m, 2H), 2.58 (s, 3H), 1.95-2.22 (m, 4H) .HPLC-MS t _R=2.03 minutes (UV ₂₅₄Nm).To formula C ₁₈H ₂₀N ₈The Mass Calculation value 380.2 of S; Measured value MH ⁺(LCMS) 381.2 (m/z).

Embodiment 12

Basically by the same program described in the embodiment 11, only in steps A, replace tetramethyleneimine, make the compound shown in table 1 the 2nd hurdle with other each aliphatic amine.

Table 1

Embodiment 13

Basically by the same program described in the embodiment 4; only with 8-methane sulfonyl-3-[1-(2-TMS-ethoxyl methyl)-1H-pyrazoles-4-yl]-imidazo [1; 2-a] pyrazine displacement 6-bromo-8-methane sulfonyl-3-[1-(2-TMS-ethoxyl methyl)-1H-pyrazoles-4-yl]-imidazo [1; 2-a] pyrazine, make compound 13.NMR(400MHz，DMSO-d ₆)δ8.66(s，1H)，8.22(d，1H)，8.21(s，1H)，8.03(s，1H)，7.82(d，1H)，5.58(s，2H)，3.96(s，3H)，3.69(t，2H)，3.40(s，1H)，0.95(t，2H)，0.02(s，9H)。

Embodiment 14

(830mg is 1.76mmol) at 50mL CH to compound 13 ₂Cl ₂In in 0 ℃ of solution that stirs down, add 7.05mL LiBHEt ₃(the 1M solution in THF).Reactant was at room temperature stirred 10 minutes.By adding saturated NH ₄The Cl aqueous solution makes its cancellation.Separating organic substances, and with saturated NaHCO ₃Solution washing.Move down in vacuum and to desolventize.In resistates, add 10mLMeOH.By solid collected by filtration, obtain 530mg compound 14.NMR(400MHz，CD ₃OD)δ8.38(s，1H)，7.98(s，1H)，7.97(d，2H)，7.78(s，1H)，7.69(d，2H)，7.15(s，1H)，5.55(s，2H)，4.62(s，2H)，3.66(t，2H)，0.92(t，2H)，0.00(s，9H)。

Embodiment 15

To compound 14 (258mg 0.582mmol) adds 0.05mL water in the solution in 20mL THF, then for Dess-Martin cross iodine alkane (740mg, 1.75mmol).Reactant was at room temperature stirred 1.5 hours.Leach solid.With 100mL CH ₂Cl ₂Dilution filtrate, and Yi Shui and salt water washing.Move down in vacuum and to desolventize, make resistates pass through purified by flash chromatography, with 5%MeOH/CH ₂Cl ₂Wash-out obtains 230mg compound 15.

Embodiment 16

Basically by the same program described in the embodiment 11, the compound shown in table 2 the 2nd hurdle is by with compound 15 displacement compounds 10, in steps A, with other each aliphatic amine displacement tetramethyleneimine and make.

Table 2

1)Walsh?R.J.A.；Wooldridge，K.R.H.J.Chem.Soc.Perkin?Trans.1972，1247.

Embodiment 17

Part A: at room temperature, with ester (2.38g, 4.91mmol, 1 equivalent) solution in DMF (40mL) was handled 20 minutes with NaH (60% dispersion liquid in oil, 1.5 equivalents), at this moment, make reaction mixture be cooled to-10 ℃, and 2-(TMS) oxyethyl group chloromethane (0.87mL, 1 equivalent) is added in the reaction mixture.Make formed solution be warmed to room temperature at leisure, at room temperature continue again to stir 1 hour.LC-MS analyzes the demonstration reaction and finishes.(15mL) makes the reaction cancellation with methyl alcohol, with ethyl acetate (300mL) dilution, and with saturated sodium bicarbonate, water, salt water washing, dry (sodium sulfate), reconcentration.By column chromatography purifying (SiO ₂, 40% ethyl acetate/hexane), the product that acquisition needs is yellow solid 1.2g (40%).HPLC-MS t _R=2.79 minutes (UV ₂₅₄Nm).To the Mass Calculation value 615.25 of formula C27H41N7O4SSi2, measured value LC/MS m/z 616.2 (M+H).

Part B: at room temperature, in the solution of the compound that derives from part A (1.2g, 1.90mmol, 1 equivalent) in THF (100mL), add super hydride (superhydride) solution (4 equivalent).Formed solution was at room temperature stirred 30 minutes, and at this moment, LC-MS analyzes the demonstration reaction and finishes.Make the reaction cancellation with saturated aqueous ammonium chloride, then with dichloromethane extraction (x2).Make the organic layer drying (sodium sulfate) of merging, reconcentration.By column chromatography purifying (SiO ₂, 60% ethyl acetate/hexane), obtain alcohol, be clean oil (47%).HPLC-MS t _R=2.49 minutes (UV ₂₅₄Nm).To the Mass Calculation value 587.25 of formula C26H41N7O3SSi2, measured value LC/MSm/z 588.3 (M+H).

Portion C: under 0 ℃ (ice bath), will derive from the solution of alcohol (0.52g, 0.88mmol, 1 equivalent) in DCM (15mL) of part B, handled 15 minutes with triethylamine (1.5 equivalent), be added into methylsulfonyl chloride (1.2 equivalent) in the reactant this moment under 0 ℃.Make formed solution be warmed to room temperature at leisure, and at room temperature continue again to stir 3 hours.LC-MS analyzes the demonstration reaction and finishes.With reaction mixture with ethyl acetate (100mL) dilution, Yi Shui, salt water washing, dry (anhydrous sodium sulphate), reconcentration obtains methane sulfonates, is redness/brown oil 0.59g (100%), uses it and need not to be further purified.HPLC-MS t _R=2.66 minutes (UV ₂₅₄Nm).To the Mass Calculation value 665.23 of formula C27H43N7O5S2Si2, measured value LC/MS m/z 666.1 (M+H).

Part D: at room temperature, with the solution of each alcohol (3 equivalent) in THF (1.5mL), with NaH (60% dispersion liquid in oil, 2 equivalents) handled 15 minutes, at this moment, will derive from the methane sulfonates (40mg of portion C, 0.06mmol, 1 equivalent) be added in the reaction mixture.After at room temperature stirring 1 hour, LC-MS analyzes the demonstration reaction and finishes.Make the reaction cancellation with saturated aqueous ammonium chloride, then with ethyl acetate extraction (twice).Make the organic layer drying (sodium sulfate) of merging, reconcentration obtains rough ether, uses it and need not to be further purified.

Part E: the compound that will derive from part D is 1, the solution in the 4-dioxane (1mL), and under 60 ℃, with 1, the 4N HCl (1mL) in the 4-dioxane solution handled 10 minutes, and this moment, HPLC-MS showed that reaction finishes.Remove solvent, and make resistates by preparation type LC purifying.Change into hydrochloride, the compound of being enumerated in the acquisition table 3.

Table 3

Embodiment 18

Basically by the same program shown in the preparation embodiment 17, can be made into the compound shown in the table 4.

Table 4

Embodiment 19

Embodiment 19 makes in the mode that is similar to embodiment 4. ¹H?NMR(300MHz，DMSO-d ₆)δ12.4(bs，1H)，7.81(s，1H)，7.75(s，1H)，7.59(s，1H)，3.85(s，3H)，2.49(s，3H)。

Embodiment 20

Embodiment 20 makes in the mode that is similar to embodiment 17 part A. ¹H?NMR(300MHz，CDCl ₃)δ7.81(s，1H)，7.73(s，1H)，7.63(s，1H)，6.61(s，2H)，3.98(s，3H)，3.74(t，J＝8Hz，2H)，2.62(s，3H)，0.94(t，J＝8Hz，2H)，-0.83(s，9H)。

Embodiment 21

To ester (2.40g, 4.40mmol) in tetrahydrofuran (THF) (96mL) just in stirred solution, under-78 ℃, dropwise add DIBAL-H (1M, in methylene dichloride, 11.0mL, 11.0mmol).Mixture was stirred 3 hours down at-78 ℃, and at this moment, tlc (30% ethyl acetate/hexane) shows to react to be finished.Mixture is promptly poured in the saturated sodium tartrate aqueous solutions of potassium of stirring, and at room temperature stirred 14 hours.Mixture with ethyl acetate (2x250mL) extraction, is merged organic layer,,, filter, under reduced pressure concentrate, obtain compound 21, be yellow solid 2.20g (97%) with dried over mgso with salt solution (100mL) washing. ¹H?NMR(300MHz，CDCl ₃)δ9.99(s，1H)，7.74(s，1H)，7.73(s，1H)，7.65(s，1H)，6.60(s，2H)，3.74(t，J＝8Hz，2H)，2.64(s，3H)，0.94(t，J＝8Hz，2H)，-0.07(s，9H)。

Embodiment 22

To aldehyde (1.30g, 2.52mmol), piperidines (257mg, 3.02mmol) and acetate (150 μ L, 2.52mmol) 1, in the 2-ethylene dichloride (17mL) just in stirred solution, at room temperature, with portion add sodium triacetoxy borohydride (801mg, 3.78mmol).Mixture was at room temperature stirred 2 hours, and at this moment, tlc (40% ethyl acetate/hexane) shows to react to be finished.(25mL) makes the reaction cancellation with 1N sodium hydroxide, and stirs 20 minutes.Mixture with chloroform (3x20mL) extraction, is merged organic layer,, filter, under reduced pressure concentrate with dried over sodium sulfate.Obtain compound 22, be yellow solid 1.35g (92%). ¹H?NMR(300MHz，CDCl ₃)δ7.70(s，1H)，7.59(s，1H)，7.23(s，1H)，6.58(s，2H)，3.72(t，J＝8Hz，2H)，3.62(s，2H)，2.58(s，3H)，2.47(m，4H)，1.58(m，6H)，0.93(t，J＝8Hz，2H)，-0.086(s，9H)。

Embodiment 23

Embodiment 23 is to be similar to the mode of embodiment 22, to make with 3-methyl piperidine substituted piperidine. ¹H?NMR(300MHz，CDCl ₃)δ7.70(s，1H)，7.59(s，1H)，7.23(s，1H)，6.58(s，2H)，3.72(t，J＝8Hz，2H)，3.62(s，2H)，2.85(m，2H)，2.59(s，3H)，1.98(m，1H)，1.65(m，6H)，0.93(t，J＝8Hz，2H)，0.84(d，J＝6Hz，3H)，-0.076(s，9H)。

Embodiment 24

Embodiment 24 is to be similar to the mode of embodiment 23, to make with the tetramethyleneimine substituted piperidine. ¹H?NMR(300MHz，CDCl ₃)δ7.70(s，1H)，7.59(s，1H)，7.23(s，1H)，6.58(s，2H)，3.77(s，2H)，3.72(t，J＝8Hz，2H)，2.61(m，4H)，2.59(s，3H)，1.81(m，4H)，0.92(t，J＝8Hz，2H)，-0.90(s，9H)。

Embodiment 25

With derive from embodiment 24 iodide (20mg, 0.035mmol) 1, the solution in the 4-dioxane (1mL), with 1,4N HCl (1mL) in the 4-dioxane handles.Make mixture sonication at room temperature 2.5 hours, this moment, HPLC demonstration reaction was finished.Enriched mixture under reduced pressure, and make formed resistates by the preparation HPLC purifying, and change into its hydrochloride, obtain compound 25, be white solid 15mg (83%). ¹H NMR (300MHz, CD ₃OD) δ 7.88 (s, 1H), 7.79 (s, 1H), 7.17 (s, 1H), 4.51 (s, 2H), 3.71 (m, 2H), 3,22 (m, 2H), 2.57 (s, 3H), 2.07 (m, 4H) .HPLC t _R=4.83 minutes (UV ₂₅₄Nm).To formula C ₁₅H ₁₇IN ₆The Mass Calculation value 440.03 of S; Measured value MH ⁺(MS) 441.5 (m/z).

Embodiment 26

Embodiment 26 makes in the mode that is similar to embodiment 25. ¹H NMR (300MHz, CD ₃OD) δ 7.87 (s, 1H), 7.79 (s, 1H), 7.22 (s, 1H), 4.39 (s, 2H), 3.52 (m, 2H), 2.96 (m, 1H), 2.70 (m, 1H), 2.57 (s, 3H), 1.90 (m, 4H), 1.21 (m, 1H), 0.99 (d, J=6Hz, 3H) .HPLC t _R=5.06 minutes (UV ₂₅₄Nm).To C ₁₇H ₂₁IN ₆The Mass Calculation value 468.3 of S; Measured value MH ⁺(MS) 469.7 (m/z).

Embodiment 27

Compound shown in table 5 the 2nd hurdle is made by following:

To contain Manufactured aryl iodide skeleton and (derive from the compound of embodiment 22,23 or 24,1 equivalent), it is commercially to get or easily make with 1 to 3 step, aryl/hetaryl/alkyl dihydroxyl borine/ester/boroxin or aryl/hetaryl/alkyl magnesium bromide or aryl/hetaryl/alkyl zinc chloride (1.5-3 equivalent), potassiumphosphate or salt of wormwood (2-3 equivalent) and Pd (PPh ₃) ₄Or PdCl ₂The flask of dppf (0.05-0.10 equivalent) is bled, and with the nitrogen backfill, and repeats.Add 1,4-dioxane or N, dinethylformamide or 1,2-glycol dimethyl ether (1-3mL), and with mixture stirring under 50-130 ℃, till reaction has been finished, as judging by tlc (ethyl acetate/hexane) or HPLC.Mixture is diluted with water (3-10mL), and extract with ethyl acetate (2-3x10-30mL).Merge organic layer,,, filter, concentrate, by column chromatography purifying (SiO with dried over mgso with salt solution (15-30mL) washing ₂, ethyl acetate/hexane).Make the product of gained be dissolved in 1, in the 4-dioxane (1mL), and with 1, the 4N HCl (1mL) in the 4-dioxane handles, and at room temperature sonication 1-5 hour, this moment, HPLC demonstration reaction was finished.Enriched mixture under reduced pressure, and make formed resistates by the preparation HPLC purifying, change into its hydrochloride again, obtain compound 27-1 to 27-7.

Table 5

Embodiment 28

Make iodide (60mg, 0.103mmol), trimethylammonium (trifluoromethyl) silane (44mg, 0.308mmol), cupric iodide (73mg, 0.385mmol), Potassium monofluoride (15mg, 0.257mmol) and the mixture of dry DMF (1.0mL) outgas with nitrogen, then in sealed tube, 80 ℃ of following heated overnight.Make mixture be cooled to room temperature, dilute, and extract with ethyl acetate (100mL) with water (30mL).Make organic layer with dried over sodium sulfate, filter, under reduced pressure concentrate.Again by column chromatography purifying (SiO ₂, 90: 10: 0.25 methylene chloride/dense ammonium hydroxide).It is anhydrous 1 that formed resistates is dissolved in, and in the 4-dioxane (1mL), and adds 4M HCl (1mL) in the dioxane.Make formed solution sonication at room temperature 2 hours, under reduced pressure be concentrated into drying.By the preparation HPLC purifying, and change into its hydrochloride, obtain title compound, be pale solid 3.1mg (6%). ¹H NMR (300MHz, CD ₃OD) δ 8.07 (s, 1H), 7.85 (s, 1H), 7.24 (s, 1H), 4.40 (s, 2H), 3.61 (d, J=12.3Hz, 2H), 3.07 (t, J=12.3Hz, 2H), 2.55 (s, 3H), 1.75-2.03 (m, 5H), 1.56 (m, 1H) .HPLC t _R=7.19 minutes.To formula C ₁₇H ₁₉F ₃N ₆The Mass Calculation value 396.13 of S; Measured value MH ⁺397.2 (m/z).

Embodiment 29

Make iodide (100mg, 0.171mmol) mixture in anhydrous THF (2.0mL) is cooled to-78 ℃, and dropwise add n-Butyl Lithium (the 2.5M solution in hexane, 89 μ L, 0.222mmol).After stirring 15 minutes, dropwise add hexachloroethane (45mg, 0.188mmol) solution in THF (1.0mL).Reactant after stirring 30 minutes under-78 ℃, is made the solution cancellation with saturated aqueous ammonium chloride (3.0mL), and is warmed to room temperature.Reactant is under reduced pressure concentrated,, and make organic layer, filter, under reduced pressure concentrate, by column chromatography purifying (SiO with dried over sodium sulfate with ethyl acetate (50mL) extraction ₂, 90: 10: 0.25 methylene chloride/dense ammonium hydroxide).It is anhydrous 1 that formed resistates is dissolved in, and in the 4-dioxane (1mL), and adds 4MHCl (1mL) in the dioxane.Make formed solution sonication at room temperature 2 hours, under reduced pressure be concentrated into drying.By the preparation HPLC purifying, and change into its hydrochloride, obtain title compound, be pale solid 30mg (40%). ¹H NMR (300MHz, CD ₃OD) δ 7.80 (s, 1H), 7.73 (s, 1H), 7.22 (s, 1H), 4.39 (s, 2H), 3.59 (d, J=12.3Hz, 2H), 3.08 (t, J=12.3Hz, 2H), 2.55 (s, 3H), 1.75-2.03 (m, 5H), 1.56 (m, 1H) .HPLC t _R=4.79 minutes.To formula C ₁₆H ₁₉ClN ₆The Mass Calculation value 362.11 of S; Measured value MH ⁺363.7 (m/z).

Example 30

Embodiment 30 makes as the similar fashion of embodiment 29. ¹H NMR (300MHz, CD ₃OD) δ 7.77 (s, 1H), 7.68 (s, 1H), 7.20 (s, 1H), 4.39 (s, 2H), 3.47-3.67 (m, 2H), 2.97 (m, 1H), 2.71 (m, 1H), 2.55 (s, 3H), 1.77-2.01 (m, 4H), 1.20 (m, 1H), 1.00 (d, J=6.4Hz, 3H) .HPLC t _R=4.98 minutes.To formula C ₁₇H ₂₁ClN ₆The Mass Calculation value 376.12 of S; Measured value MH ⁺377.6 (m/z).

Embodiment 31

Embodiment 31 is the modes with similar compound 29, replaces hexachloroethane and makes with the tetrachloro ethylene dibromide. ¹H NMR (300MHz, CD ₃OD) δ 7.84 (s, 1H), 7.83 (s, 1H), 7.25 (s, 1H), 4.41 (s, 2H), 3.61 (d, J=12.3Hz, 2H), 3.08 (t, J=12.3Hz, 2H), 2.57 (s, 3H), 1.77-2.03 (m, 5H), 1.55 (m, 1H) .HPLC t _R=5.19 minutes.To formula C ₁₆H ₁₉BrN ₆The Mass Calculation value 406.06 of S; Measured value MH ⁺407.4 (m/z).

Embodiment 32

To aminopyrimidine (100mg, 0.452mmol) add in the solution in anhydrous pyridine (2.0mL) chlorination 3-fluorobenzoyl (72mg, 0.452mmol).After at room temperature stirring is spent the night, reactant is under reduced pressure concentrated, dilute with water (30mL), and extract with methylene dichloride (100mL).Make organic layer with dried over sodium sulfate, filter, reconcentration obtains title compound, is pale solid 124mg (80%). ¹H?NMR(300MHz，CDCl ₃)δ8.95(s，2H)，8.72(s，1H)，7.66-7.72(m，2H)，7.49(m，2H)，1.36(s，12H)。

Embodiment 33

Similar fashion as compound 31 is made, and obtains title compound, is pale solid 131mg (80%). ¹H?NMR(300MHz，CDCl ₃)δ8.93(s，2H)，8.65(s，1H)，7.83(m，1H)，7.69(m，1H)，7.30(m，1H)，1.34(s，12H)。

Embodiment 34

Make iodide (60mg, 0.103mmol), three-normal-butyl (pyridyl) tin (57mg, 0.154mmol), dichloro [1,1 '-two (diphenylphosphino) Dicyclopentadiene (DCPD) iron] palladium (II) methylene dichloride affixture (8mg, 0.0103mmol) and Potassium monofluoride (18mg, 0.309mmol) anhydrous 1, the mixture in the 4-dioxane (1.0mL) outgases with nitrogen, then in sealed tube, 85 ℃ of following heated overnight.Make mixture be cooled to room temperature, dilute, and extract with ethyl acetate (2x100mL) with water (30mL).Then separate organic layer,, filter, under reduced pressure be condensed into resistates, by column chromatography purifying (SiO with dried over sodium sulfate ₂, 90: 10: 0.25 methylene chloride/dense ammonium hydroxide).Then, it is anhydrous 1 that formed resistates is dissolved in, and in the 4-dioxane (1mL), and adds 4M HCl (1mL) in the dioxane.Make formed solution sonication at room temperature 2 hours, then under reduced pressure be concentrated into drying.By the preparation HPLC purifying, and change into its hydrochloride, obtain to be pale solid through the product 3.2mg of dehalogenation (10%): ¹H NMR (300MHz, CD ₃OD) δ 8.23 (s, 1H), 8.13 (s, 2H), 7.29 (s, 1H), 4.55 (s, 2H), 3.72 (brs, 2H), 3.29 (m, 2H), 2.61 (s, 3H), 2.05-2.18 (m, 4H) .HPLC t _R=3.49 minutes.To formula C ₁₅H ₁₆N ₆The Mass Calculation value 314.13 of S; Measured value MH ⁺315.2 (m/z).

Also obtain the product 5.0mg (10%) of coupling, be pale solid: ¹H NMR (300MHz, CD ₃OD) δ 8.95 (s, 1H), 8.86 (d, J=5.1Hz, 1H), 8.50 (s, 1H), 8.28 (t, J=7.5Hz, 1H), 8.18 (d, J=7.8Hz, 1H), 7.70 (t, J=6.3Hz, 1H), 7.26 (s, 1H), 4.54 (s, 2H), 3.74 (m, 2H), 3.29 (m, 2H), 1.99-2.30 (m, 4H) .HPLCt _R=4.80 minutes.To formula C ₂₀H ₂₁N ₇The Mass Calculation value 391.16 of S; Measured value MH ⁺392.5 (m/z).

Embodiment 35

(3mg 0.073mmol) is added in the room temperature suspension of iodide (15mg, 0.037) in methyl alcohol (1mL) with sodium borohydride.Reactant was stirred 30 minutes, make the reaction cancellation with water (20mL) then.Mixture is diluted with ether (20mL), and with liquid phase separation.Make organic layer drying (sodium sulfate), filter reconcentration, the intermediate of the dehalogenation that is protected.Make that (7mg 0.017mmol) accepts the previous acidic conditions of summarizing, and obtains title compound, is yellow solid 2mg (17%) through the reductive product. ¹H NMR (300MHz, CD ₃OD) δ 7.94 (s, 1H), 7.90 (s, 1H), 7.74 (s, 1H), 7.55 (s, 1H), 3.94 (s, 3H), 2.50 (s, 3H) .HPLC t _R=4.67 minutes (UV ₂₅₄Nm).To formula C ₁₂H ₁₁N ₅O ₂The Mass Calculation value 289.06 of S; Measured value MH ^-(ESIMS) 288.0 (m/z).

Embodiment 36

Embodiment 36 makes in the mode that is similar to embodiment 31. ¹H NMR (300MHz, CD ₃OD) δ 7.72 (s, 1H), 7.69 (s, 1H), 7.15 (s, 1H), 4.38 (s, 2H), 3.69-3.52 (m, 2H), 3.17-2.96 (m, 2H), 2.54 (s, 3H), 2.06-1.70 (m, 5H), 1.65-1.44 (m, 1H) .HPLC t _R=5.00 minutes (UV ₂₅₄Nm).To formula C ₁₆H ₁₉IN ₆The Mass Calculation value 454.04 of S; Measured value MH ⁺(ESI MS) 455.0 (m/z).

Embodiment 37

With Pd ₂(dba) ₃(5mg, (6mg 0.103mmol) at N, in the solution at room temperature among the N '-dimethyl formamide (1mL), and stirred 10 minutes 0.005mmol) to be added into DPPF.Then, with mixture be added into iodide (60mg, 0.103mmol), Zn (CN) ₂(12mg is 0.103mmol) at N, in the solution among the N '-dimethyl formamide (4mL).Reactant in microwave oven, is heated to 150 ℃, went through 30 minutes, be cooled to room temperature, then be concentrated into drying.Formed resistates is by purified by flash chromatography (SiO ₂12g; 10% methyl alcohol is in methylene dichloride), obtain impure nitrile, be yellow solid.(22mg 0.045mmol) is dissolved among the 2N HCl (4mL), need not to be further purified to make impure nitrile.Make formed solution 45 ℃ of following sonications 2 hours.When finishing, make reactant be concentrated into drying.Formed resistates obtains title compound by the preparation HPLC purifying, is white solid 8mg (18%). ¹H NMR (300MHz, CD ₃OD) δ 8.22 (s, 1H), 7.93 (s, 1H), 7.22 (s, 1H), 4.40 (s, 2H), 3.73-3.52 (m, 2H), 3.20-2.97 (m, 2H), 2.55 (s, 3H), 2.06-1.71 (m, 5H), 1.66-1.42 (m, 1H) .HPLC t _R=4.50 minutes (UV ₂₅₄Nm).To formula C ₁₇H ₁₉N ₇The Mass Calculation value 353.14 of S; Measured value MH ⁺(ESI MS) 354.3 (m/z).

Embodiment 38

With iodide (70mg, 0.12mmol), Pd (dppf) Cl ₂(9mg, 0.012mmol), sodium tert-butoxide (35mg, 0.36mmol) and the sulfo-sodium methylate (17mg, mixture 0.24mmol) washes with nitrogen, is dissolved in 1 then, in the 4-dioxane (5mL).Solution is heated to 95 ℃ in microwave oven, went through 90 minutes.Make reactant be cooled to room temperature, with ethyl acetate (100mL) dilution, and through diatomite filtration.With water (50mL) and salt solution (50mL) washing, then dry (sodium sulfate) filters with organic layer, and reconcentration is to dry.Formed resistates obtains the sulfenyl methyl ether of protection by the preparation HPLC purifying.(35mg 0.07mmol) accepts the reaction conditions summarized among the embodiment 110, obtains title compound, is white solid 6mg (11%) to make the sulfenyl methyl ether. ¹H NMR (300MHz, CD ₃OD) δ 8.28 (s, 1H), 8.25 (s, 1H), 7.34 (s, 1H), 4.43 (s, 2H), 3.68-3.52 (m, 2H), 3.18-2.98 (m, 2H), 2.67 (s, 3H), 2.49 (s, 3H), 2.05-1.71 (m, 5H), 1.65-1.44 (m, 1H) .HPLC t _R=4.74 minutes (UV ₂₅₄Nm).To formula C ₁₇H ₂₂N ₆S ₂Mass Calculation value 374.13; Measured value MH ⁺(ESI MS) 375.3 (m/z).

Embodiment 39

With iodide (70mg, 0.12mmol), the sulfo-sodium ethylate (20mg, 0.24mmol), Pd (dppf) Cl ₂(9mg, 0.012mmol) and sodium tert-butoxide (35mg, combined mixture 0.36mmol) then are dissolved in 1 with nitrogen wash, in the 4-dioxane (5mL).Reactant is heated to 95 ℃, and stirred 72 hours.Then, make reactant be cooled to room temperature, with ethyl acetate (100mL) dilution, and through diatomite filtration.With water (50mL) and salt solution (50mL) washing, then dry (sodium sulfate) filters with filtrate, and reconcentration is to dry.Formed resistates is by purified by flash chromatography (SiO ₂12g; 0% to 10% methyl alcohol is in methylene dichloride), obtain sulphur ethyl ether intermediate, be yellow solid.(10mg 0.019mmol) accepts the reaction conditions summarized among the embodiment 110, obtains title compound, is white solid 2mg (4%) to make the sulphur ethyl ether. ¹H NMR (300MHz, CD ₃OD) δ 8.32 (s, 1H), 8.28 (s, 1H), 7.35 (s, 1H), 4.43 (s, 2H), 3.68-3.55 (m, 2H), 3.17-3.01 (m, 2H), 2.90 (q, J=7.3Hz, 2H), 2.67 (s, 3H), and 2.07-1.71 (m, 5H), 1.65-1.42 (m, 1H), 1.28 (t, J=7.3Hz, 3H) .HPLC t _R=5.27 minutes (UV ₂₅₄Nm).To formula C ₁₈H ₂₄N ₆S ₂Mass Calculation value 388.15; Measured value MH ⁺(ESI MS) 389.7 (m/z).

Embodiment 40

Part A: to 2-bromo-thiazole-5-carboxylic acid (2.0g, 9.615mmol) at the trimethyl carbinol (30mL) and triethylamine (15mL, 10.57mmol) in the solution of stirring in add azide phenylbenzene phosphinylidyne (2.9g, 10.57mmol), and reaction mixture is heated to 80 ℃, stirred 12 hours, LCMS shows the initial substance completely dissolve.Make reaction mixture be cooled to room temperature, move down in vacuum and desolventize, add water (100mL), and extract with ethyl acetate (3x100mL).With organic layer Yi Shui, salt water washing, with dried over sodium sulfate, reconcentration makes crude material by little silicagel pad, and with formed (2-bromo-thiazole-5-yl)-aminomethyl tert-butyl acrylate (solid) itself to be used in the next step output 2.5g (90%). ¹H?NMR(400MHz，DMSO-d ₆)δ7.10(s，1H)，7.05(s，1H)，1.51(s，9H)。To formula C ₈H ₁₁BrN ₂O ₂The Mass Calculation value 277.97 of S; Measured value MH ⁺(LCMS) 279.0 (m/z).

Part B: to (2-bromo-thiazole-5-yl)-aminomethyl tert-butyl acrylate (2.5g, 8.9928mmol) 1, add tributyl (vinyl) tin (2.9mL in the solution of the stirring in the 4-dioxane (20.0mL), 9.892mmol), 2,6-two-tertiary butyl-4-sylvan (catalytic amount) and four (triphenyl phosphine) palladiums (0) (506.0mg, 0.4496mmol).Reaction mixture is heated to 100 ℃, and stirred 12 hours, LCMS shows the initial substance completely dissolve.Make reaction mixture be cooled to room temperature, filter, and solid is washed with ethyl acetate, under vacuum, remove the filtrate (organic solvent) of merging, crude material is used biotage HPLC purifying, use hexane/ethyl acetate gradient liquid 0.0 to 100%, to produce (2-vinyl-thiazole-5-yl)-aminomethyl tert-butyl acrylate (solid) 1.1g (54%). ¹H?NMR(400MHz，CDCl ₃)δ7.27(d，J＝12.7Hz，2H)，7.19(brs，1H)，6.84-6.77(m，1H)，6.87(d，J＝17.0Hz，1H)，5.43(d，J＝10.5Hz，1H)，1.52(s，9H)。To formula C ₁₀H ₁₄N ₂O ₂The Mass Calculation value 226.08 of S; Measured value MH ⁺(LCMS) 227.1 (m/z).

Portion C: to (2-vinyl-thiazole-5-yl)-aminomethyl tert-butyl acrylate (0.76g, 2.857mmol) 1,4-dioxane: water (30: add sodium periodate (2.5g in the solution of the stirring 9mL), 11.43mmol), perosmic anhydride (2.5% solution in the 2-propyl alcohol) (0.5mL) and 2,6-lutidine (0.663mL, 5.714mmol), and with reaction mixture stirring 4 hours, LCMS showed that initial substance almost disappears.Reaction mixture is diluted with water (100mL), and,, with dried over sodium sulfate, under high vacuum, concentrate again, and produce aldehyde 710mg (92%) organic layer Yi Shui, salt water washing with ethyl acetate extraction.With crude product with itself be used in next the reaction in. ¹H?NMR(400MHz，DMSO-d ₆)δ11.45(s，1H)，9.76(s，1H)，7.58(s，1H)，1.40(s，9H)。To formula C ₉H ₁₂N ₂O ₃The Mass Calculation value 228.06 of S; Measured value MH ⁺(LCMS) 229.1 (m/z).

Part D: to (2-formyl thiazole-5-yl)-aminomethyl tert-butyl acrylate (0.76g; 2.857mmol) 1; add morpholine (250mg in the solution of the stirring in the 2-ethylene dichloride (10mL); 1.1135mmol), sodium triacetoxy borohydride (472mg; 2.227mmol) and the acetate (three) of catalytic amount, and at room temperature stirred two hours.(126mg 3.3405mmol), and stirred one hour to add sodium borohydride in reaction mixture.LCMS shows that initial substance disappears.Reaction mixture is diluted with water (100mL), and with dichloromethane extraction, with organic layer Yi Shui, salt water washing, with dried over sodium sulfate, under high vacuum, concentrate, and produce (2-morpholine-4-ylmethyl-thiazole-5-yl)-aminomethyl tert-butyl acrylate 298mg (91%).With crude product with itself be used in next the reaction in.Mass Calculation value 315.43 to formula C14H25N3O3S; Measured value MH ⁺(LCMS) 300.3 (m/z).

Part E: (80.0mg, (44 μ L 0.321mmol), and stirred 10 minutes 0.268mmol) to add the iodo trimethyl silane in the solution of the stirring in methylene dichloride (5mL) to (2-morpholine-4-ylmethyl-thiazole-5-yl)-aminomethyl tert-butyl acrylate.LCMS shows that initial substance disappears.Reaction mixture is diluted with water (10mL), the 1N NaOH aqueous solution (5mL), and extract with the 10%2-propyl alcohol (3x25mL) among the DCM, and make organic layer with dried over sodium sulfate, under high vacuum, concentrate, and produce 2-morpholine-4-ylmethyl-thiazole-5-base amine 30.0mg (56%).With crude product with itself be used in next the reaction in.Mass Calculation value 199.27 to formula C8H13N3OS; Measured value MH ⁺(LCMS) 200.1 (m/z).

Part F: to 2-morpholine-4-ylmethyl-thiazole-5-base amine (30.0mg; 0.151mmol) add 8-methane sulfonyl-6-methyl-3-(1H-pyrazoles-4-yl)-imidazo [1 in the solution of stirring in DMSO (2.5mL); 2-a] pyrazine (25.0mg; 0.09045mmol); then be the NaH60% (48mg in the Dormant oils; 1.206mmol), and stirred 30 minutes.LCMS shows that initial substance disappears.1: 1 mixture (10mL) with acetonitrile and saturated ammonium chloride makes the reaction mixture cancellation, and extract with the 10%2-propyl alcohol (3x25mL) among the DCM, organic layer is concentrated under high vacuum, rough [6-methyl-3-(1H-pyrazoles-4-yl)-imidazo [1 and produce, 2-a] pyrazine-8-yl]-(2-morpholine-4-ylmethyl-thiazole-5-yl)-amine, subsequently, it is passed through the Agilent reversed-phase HPLC, use formic acid method purifying, and produce 10mg (28%).HPLC-MS (10 fens clock methods) t _R=2.06 minutes (UV ₂₅₄Nm).Mass Calculation value 396.47 to formula C18H20N8OS; Measured value MH ⁺(LCMS) 397.5 (m/z).

Series of compounds shown in the table 6 uses the program described in the embodiment 40 to make.

Table 6

Embodiment 41

To 5-nitrothiophene-3-carboxylic acid (5.00g, 28.88mmol) add in the solution in dimethyl formamide (40mL) salt of wormwood (11.98g, 86.71mmol) with methyl iodide (2.70mL, 43.37mmol).Reaction mixture was at room temperature stirred 16 hours.After initial substance consumes, reactant is diluted with 50% ethyl acetate/hexane (350mL), and with H ₂O (350mL) extraction.With salt solution (150mL) washing organic layer, reconcentration.(50mL) is added in the solid with hexane, and concentrates again, and produces 5.456g (99%) product. ¹H?NMR(400MHz)CDCl ₃δ8.30(s，1H)，8.25(s，1H)，3.93(s，3H)。To formula C ₆H ₅NO ₄The Mass Calculation value 187.17 of S; Measured value M4H ⁺(MS) 191.15 (m/z)

Embodiment 42

(1.006g, 5.375mmol) in the solution in TFA (15mL), (15135g 27.10mmol) slowly is added in the round-bottomed flask with the Fe powder to nitro-ester.Reactant is heated to 60 ℃, went through 45 minutes, TLC this moment (1: 1, ethyl acetate is to hexane) shows initial substance consumption.Reactant is diluted with ethyl acetate, and leach Fe.With Na ₂CO ₃The aqueous solution makes the filtrate neutralization, and it was stirred 1 hour.With the EtOAc aqueous layer extracted.With salt water washing organic layer, with Na ₂SO ₄Drying, reconcentration obtains 0.701g (83%) yellow solid. ¹H?NMR(400MHz)CD ₃ODδ7.29(s，1H)，6.44(s，1H)，3.79(s，3H)。To formula C ₆H ₇NO ₂The Mass Calculation value 157.19 of S; Measured value MH ⁺(LCMS) 158.1 (m/z).

Embodiment 43

At room temperature, with sulfone (1.27g, 3.11mmol) and 2-aminothiophene-4-carboxylate methyl ester (0.701g, 4.46mmol) solution in DMF (35mL), with NaH (60% dispersion liquid in oil, 0.402g, 10.05mmol) handle, up to mass spectroscopy and tlc (50% ethyl acetate/hexane) show react finished till.Saturated ammonium chloride (15mL) and water (50mL) are added in the reactant.Reactant was stirred 10 minutes.Collect settled solid by filtering, and produce the product that needs. ¹H?NMR(400MHz)CDCl ₃δ8.78(s，1H)，7.88(s，1H)，7.82(s，3H)，7.68(s，1H)，7.58(s，1H)，7.44(s，1H)，7.16(s，3H)，5.54(s，2H)，3.87(s，3H)，3.67(t，2H)，2.46(s，3H)，0.97(t，2H)，0.01(s，9H)。To formula C ₂₂H ₂₈N ₆O ₃The Mass Calculation value 484.65 of SSi; Measured value MH ⁺(MS) 485.1 (m/z).

Embodiment 44

(0.565g, the 1.17mmol) solution in THF (10mL) and MeOH (3mL) is with solid NaOH (9 pills), then with H with the ester made among the embodiment 43 ₂O (5mL) handles.Reactant was at room temperature stirred fierce 16 hours.Remove THF and MeOH in a vacuum, and resistates is extracted with EtOAc (3x20mL).Making water reach the pH value with the HCl aqueous solution is 3-4.The acidifying water with EtOAc (5x20mL) extraction, is concentrated in a vacuum, obtain the carboxylic acid that 0.393g (71%) needs.

Embodiment 45

With carboxylic acid (in embodiment 4, making) (0.054g, the 0.115mmol) solution in DMF (3mL), with amine (0.03mL, 0.262mmol), NMM (0.07mL, 0.637mmol), then HATU (0.141g 0.372mmol) handles.Reactant was at room temperature stirred 16 hours.Add water (15mL), and reactant was stirred 10 minutes.Collect settled solid by filtering, and produce the acid amides that 0.038g (60%) needs. ¹H?NMR(400MHz)CDCl ₃δ9.13(s，1H)，7.86(s，1H)，7.80(s，3H)，7.54(s，1H)，7.41(s，1H)，7.31(s，1H)，7.08(s，3H)，5.83(d，1H)，5.53(s，2H)，3.93(m，1H)，3.67(t，2H)，2.44(s，3H)，1.70(m，10H)，0.96(t，2H)，0.00(s，9H)。To formula C ₂₇H ₃₇N ₇O ₂The Mass Calculation value 551.78 of SSi; Measured value MH ⁺(MS) 552.1 (m/z).

Basically by the same program described in the embodiment 45, only replace the amine shown in table 7 the 2nd hurdle, make the compound in the 3rd hurdle:

Table 7

Embodiment 46

(0.038g, (0.029g is 0.775mmol) with ether (0.8mL) 0.069mmol) to add lithium aluminium hydride in the solution in methylene dichloride (4mL) to acid amides.Reaction mixture was at room temperature stirred 10 minutes, refluxed 5 hours down at 40 ℃ then.Reaction is to monitor by mass spectroscopy.When initial acid amides consumes, make reactant be cooled to room temperature, and with H ₂O (2mL) makes the reaction cancellation.Reactant is diluted with DCM, and filter.With H ₂O (≤8mL) wash filtrate.Organic layer is concentrated, obtain 0.019g (52%) amine.Above-mentioned amine among the THF under 60 ℃, was further handled 1 hour with 4N HCl/ dioxane.When being cooled to room temperature, add Et ₂O, and with mixture stirring 10 minutes.Collect settled solid, obtain the amine that 13.9mg (96% productive rate) needs.

Basically by the same program described in the embodiment 46, make the following compounds shown in table 8 the 2nd hurdle:

Table 8

Embodiment 47

With 4-chloro-ethyl 3-oxobutanoate (14.15g, 86mmol), cyanoacetic acid (8.00g, 86mmol), NH ₄OAc (1.32g, 17.2mmol), (2.46mL 43mmol) and benzene (40mL), uses the Dean-Stark trap to AcOH, stirs under refluxing and spends the night.Make mixture be cooled to room temperature, with the EtOAc dilution, with saturated NaHCO ₃, the salt water washing, with Na ₂SO ₄Drying, reconcentration obtains crude product 1 (9.29g, 58%).HPLC-MS t _R=1.67 minutes (UV ₂₅₄Nm).To the Mass Calculation value 187.0 of M+, measured value LC/MS m/z 188.1 (M+H).

Embodiment 48

(580 μ L, (622mg, 3.33mmol) (116mg is 3.63mmol) in the mixture in EtOH (5mL) with the S-thin slice 6.65mmol) dropwise to be added into 3-(chloro methyl)-4-cyano group fourth-3-olefin(e) acid ethyl ester with morpholine.Reactant at room temperature stirred spend the night.Mixture is concentrated.Mixture is diluted with EtOAc, with the salt water washing, with Na ₂SO ₄Drying, reconcentration obtains crude product.By preparation type LC purifying, obtain title compound (182mg, 20%).HPLC-MS t _R=0.80 minute (UV ₂₅₄Nm).To the Mass Calculation value 270.1 of M+, measured value LC/MS m/z 271.1 (M+H).

Embodiment 49

At room temperature, (61.0mg, 0.225mmol) ((60% dispersion liquid in oil, 20.9mg 0.521mmol) handle with NaH for 71.0mg, the 0.173mmol) solution in DMF (2mL) with sulfone with 5-amino-3-(morpholinyl methyl) thiophene-2-carboxylic acid ethyl ester.Mixture is at room temperature stirred, till LCMS shows that reaction has been finished.With the EtOAc diluted reaction mixture, with saturated NH ₄The Cl washing is with Na ₂SO ₄Drying, reconcentration obtains title compound.HPLC-MS t _R=1.79 minutes (UV ₂₅₄Nm).To the Mass Calculation value 597.2 of M+, measured value LC/MS m/z 598.3 (M+H).

Embodiment 50

Under-20 ℃, (0.78 μ L, (104.2mg, 0.173mmol) (91 μ L are 0.782mmol) in the solution in THF (3mL) with diethylamine 1.56mmol) dropwise to be added into the crude compound that derives from embodiment 49 with the solution of i-PrMgCl in THF.Make mixture be warmed to room temperature at leisure, and under this temperature, stir, till LCMS shows that reaction has been finished.Make reaction mixture be cooled to 0 ℃, and with saturated NH ₄Cl makes the reaction cancellation.Reaction mixture is extracted with EtOAc, and make organic layer with Na ₂SO ₄Drying, reconcentration obtains crude product 4.HPLC-MS t _R=1.81 minutes (UV ₂₅₄Nm).To the Mass Calculation value 624.3 of M+, measured value LC/MS m/z 625.3 (M+H).

Embodiment 51

Under 0 ℃, with the 4N HCl (1mL) in the dioxane be added into crude compound 4 (17mg, 0.027mmol) in.Make mixture be warmed to room temperature, and under this temperature, stir, till LCMS shows that reaction has been finished.Concentrate, and by preparation type LC purifying, and change into hydrochloride, obtain title compound.HPLC-MS t _R=1.14 minutes (UV ₂₅₄Nm).To the Mass Calculation value 494.2 of M+, measured value LC/MS m/z 495.2 (M+H).

Basically by same program, can be made into the compound shown in table 9 the 2nd hurdle.

Table 9

Embodiment 52

With thiophene-2, the 5-dicarboxylic acid (2.73g, 15.84mmol), azide phenylbenzene phosphinylidyne (3.41mLg, 15.84mmol) and triethylamine (heating is 5 hours under refluxing for 4.4mL, the 31.68mmol) solution in the trimethyl carbinol (80mL).Make reaction mixture be cooled to room temperature, then concentrate, obtain rough title compound.HPLC-MS t _R=1.52 minutes (UV ₂₅₄Nm).To the Mass Calculation value 243.0 of M+, measured value LC/MS m/z 244.1 (M+H).

Embodiment 53

With Et ₃N (1261.6 μ L, 9.05mmol) under 0 ℃, be added into 5-t-butoxycarbonyl amino-thiophene-2-carboxylic acid (550mg, 2.26mmol), EDCI (1086mg, 5.65mmol) and piperidines (447 μ L are 4.52mmol) in the mixture in DMF (6mL).Make reaction mixture be warmed to room temperature, and under this temperature, stir and spend the night.Mixture is diluted with EtOAc, with salt water washing (2x), with Na ₂SO ₄Drying, reconcentration obtains rough resistates.By the Biotage purifying, obtain compound 2 (368mg, 53%).HPLC-MS t _R=1.89 minutes (UV ₂₅₄Nm).To the Mass Calculation value 310.1 of M+, measured value LC/MS m/z 311.2 (M+H) .HPLC-MS t _R=2.4 minutes (UV ₂₅₄Nm).

Embodiment 54

(90mg is 0.29mmol) at 20%TFA/CH with the compound that derives from embodiment 53 ₂Cl ₂In the solution (5mL), at room temperature stirred 1.5 hours.Reaction mixture is concentrated, to obtain compound 3.Use this crude product, need not to be further purified.HPLC-MS t _R=1.16 minutes (UV ₂₅₄Nm).To the Mass Calculation value 210.0 of M+, measured value LC/MS m/z 211.1 (M+H).

Embodiment 55

At room temperature, ((60% dispersion liquid in oil, 29.0mg 0.725mmol) handle with NaH for 98.0mg, the 0.241mmol) solution in DMF (2mL) with deriving from the crude material of embodiment 54 and sulfone.Mixture is stirred, till LCMS shows that reaction has been finished.With the EtOAc diluted reaction mixture, with saturated NH ₄The Cl washing is with Na ₂SO ₄Drying, reconcentration obtains crude product 4.By the Biotage purifying, obtain title compound (82mg, 63%).HPLC-MSt _R=2.30 minutes (UV ₂₅₄Nm).To the Mass Calculation value 537.2 of M+, measured value LC/MS m/z538.2 (M+H).

Embodiment 56

(47.6mg, (39.9mg is 1.0mmol) with ether (1mL) 0.089mmol) to add lithium aluminium hydride in the solution in methylene dichloride (5mL) to acid amides.Reaction mixture was at room temperature stirred 10 minutes, reflux down at 40 ℃ then, till LCMS shows that reaction has been finished.Make reactant be cooled to room temperature, and with H ₂O (0.5mL) makes the reaction cancellation.Reactant is diluted with methylene dichloride, with Na ₂SO ₄Drying, reconcentration obtains rough title compound.HPLC-MS t _R=1.52 minutes (UV ₂₅₄Nm).To the Mass Calculation value 523.2 of M+, measured value LC/MS m/z 524.2 (M+H).

Embodiment 57

Under 0 ℃, the 4N HCl (2mL) in the dioxane is added in the crude compound that derives from embodiment 56.Make mixture be warmed to room temperature, and under this temperature, stir, till LCMS shows that reaction has been finished.Concentrate, obtain rough title compound.By preparation type LC purifying, and change into hydrochloride, obtain title compound.HPLC-MS t _R=0.91 minute (UV ₂₅₄Nm).To the Mass Calculation value 393.1 of M+, measured value LC/MS m/z 394.1 (M+H).

Basically by same program, make the compound in the table 10.

Table 10

Embodiment 58

To 8-methane sulfonyl-6-methyl-3-thiazol-2-yl-imidazo [1,2-a] pyrazine (0.070g; 0.24mmol) and 5-amino-3-methoxycarbonyl-isothiazole (0.039g; 0.25mmol) at dimethyl formamide (DMF; 0.8mL) in solution in add sodium hydride (NaH; 60%, in oil; 0.024g).Reaction mixture was at room temperature stirred 0.5 hour, then, with saturated aqueous ammonium chloride (NH ₄Cl) make the reaction cancellation.With more water dilutions, and filter.With filter cake with water and hexane wash.Make filter cake dry in a vacuum,, be yellow solid (0.078g to obtain title compound; 87%). ¹H?NMR(400MHz，DMSO-d ₆)：8.85(s，1H)，8.42(s，1H)，8.1(s，1H)，7.9(s，1H)，7.65(s，1H)，3.85(s，3H)2.5(s，3H).HPLC-MS?t _R＝4.35(UV ₂₅₄nm)。To C ₁₅H ₁₂N ₆O ₂S ₂Mass Calculation value 372.04; Measured value MH ⁺(LCMS) 373.2 (m/z).

Embodiment 59

Solution (super hydride with lithium triethylborohydride; 1M is in THF; 0.32mL) dropwise be added into methyl esters (0.03g; 0.08mmol) in the solution in dry THF (0.8mL).After at room temperature stirring 1.5 hours, with saturated NH ₄The Cl aqueous solution (8mL) makes the reaction mixture cancellation, and dilutes with water.Filter a small amount of settled yellow solid, again with water and ether washing.Make solid dry in a vacuum, the alcohol of acquisition～10mg (36%). ¹H?NMR(400MHz，DMSO-d ₆)：8.8(s，1H)，8.4(s，1H)，8.1(s，1H)，7.9(s，1H)，7.2(s，1H)，5.4(t，1H).4.5(d，2H)，2.5(s，3H).HPLC-MS?t _R＝2.98(UV ₂₅₄nm)。To C ₁₄H ₁₂N ₆OS ₂Mass Calculation value 344.05; Measured value MH ⁺(LCMS) 345.2 (m/z).

Embodiment 60

With ester (0.113g; 0.3mmol) solution in DMF (1.5mL), with NaH (60%, in oil; 0.03g; 0.76mmol), then with 2-(TMS) oxyethyl group chloromethane (SEM-Cl; 0.1mL; 0.61mmol) handle.Reaction mixture was at room temperature stirred 3 hours, and with saturated NH ₄The Cl aqueous solution and water make the reaction cancellation.Collect settled yellow solid by filtering, with water washing, drying.Obtain title compound, be yellow solid (0.142g; 92%). ¹HNMR(400MHz，CDCl ₃)：9.1(s，1H)，8.1(s，1H)，7.98(s，1H)，7.8(s，1H)，7.4(s，1H)，6.65(s，2H)，4.0(s，3H)，3.78(t，2H)，2.65(s，3H)，1.0(t，2H)，0.0(s，9H).HPLC-MS?t _R＝5.98(UV ₂₅₄nm)。To C ₂₁H ₂₆N ₆O ₃S ₂The Mass Calculation value 502.13 of Si; Measured value MH ⁺(LCMS) 503.3 (m/z).

Embodiment 61

Solution (super hydride with lithium triethylborohydride; 1M is in THF; 1mL) dropwise be added in the solution of methyl esters 2 in dry THF.After at room temperature stirring 1 hour, with saturated NH ₄The Cl aqueous solution (8mL) makes the reaction mixture cancellation with saturated Luo Seer salt brine solution.With organic product with methylene dichloride (CH ₂Cl ₂) extraction, Yi Shui and salt water washing.Concentrate the alcohol of acquisition～120mg (100%) in a vacuum.HPLC-MS?t _R＝4.22(UV ₂₅₄nm)。To C ₂₀H ₂₆N ₆O ₂S ₂The Mass Calculation value 474.13 of Si; Measured value MH ⁺(LCMS) 475.3 (m/z).

Embodiment 62

Dess-Martin is crossed iodine alkane (0.147g; 0.35mmol) be added into alcohol (0.11g; 0.23mmol) in the solution in dry THF, and at room temperature stirred 40 minutes.With 30mL CH ₂Cl ₂Diluted reaction mixture is with saturated sodium bicarbonate (NaHCO ₃) solution, water washing, drying.Concentrate, yellow solid is provided, make it be dissolved in CH again ₂Cl ₂In, and filter.Make filtrate concentrating, obtain the rough title compound of 120mg, be yellow solid, it is used in the next step with itself. ¹H?NMR(400MHz，CDCl ₃)：10(s，1H)，9.1(s，1H)，8.1(s，1H)，7.98(s，1H)，7.78(s，1H)，7.4(s，1H)，6.6(s，2H)，3.78(t，2H)，2.65(s，3H)，1.0(t，2H)，0.0(s，9H).HPLC-MS?t _R＝6.14(UV ₂₅₄nm)。To C ₂₀H ₂₄N ₆O ₂S ₂The Mass Calculation value 472.12 of Si; Measured value MH ⁺(LCMS) 473.3 (m/z).

Embodiment 63

With aldehyde (0.05g; 0.1mmol) and piperidines (0.05mL; 0.5mmol) at CH ₂Cl ₂Solution (1mL) is with glacial acetic acid (AcOH; 1) handle, and stirred 3 hours down in room temperature (RT).Add solid sodium borohydride (NaBH ₄0.016g; 0.42mmol), and reaction mixture is cooled off in ice/brine bath (5 ℃), dropwise add methyl alcohol (0.2mL).After stirring 30 minutes at low temperatures, with saturated NH ₄Cl makes the reaction cancellation, and at CH ₂Cl ₂Middle extraction.With organic extract liquid with saturated NH ₄Cl, water and salt water washing.Remove solvent, obtain crude product, it by preparative thin-layer chromatography (preparation type TLC), is used to have 4%CH ₃The CH of OH and 1% ammonium hydroxide ₂Cl ₂Purifying.Title compound is separated into yellow film (25mg; 45%). ¹H?NMR(400MHz，CDCl ₃)：9.1(s，1H)，8.1(s，1H)，7.98(s，1H)，7.4(s，1H)，7.3(s，1H)，6.6(s，2H)，3.8(t，2H)，3.6(s，2H)，2.65(s，3H)，2.5(br-s，4H)，1.7(br-s，4H)，1.45(br-s，2H)，0.98(t，2H)，0.0(s，9H).HPLC-MS?t _R＝3.82(UV ₂₅₄nm)。To C ₂₅H ₃₅N ₇OS ₂The Mass Calculation value 541.21 of Si; Measured value MH ⁺(LCMS) 542.3 (m/z).

Embodiment 64

Compound (the 0.013g of embodiment 63 will be derived from; 0.02mmol) solution in 0.5mL THF, with the HCl (4M in the dioxane; 0.5mL) handle, and place oil bath under 70 ℃.Heat after 30 minutes, throw out forms, and when adding 0.5mL methyl alcohol, makes its dissolving.With reaction mixture reheat 1 hour under 70 ℃ bath temperature.Make reaction content be cooled to room temperature, on rotatory evaporator, remove all volatile matter.Resistates is suspended among the THF, and develops with ether.By filtration collecting precipitation thing, with～washing of 10mL ether, in air drying (0.5 hour), (16 hours) in a vacuum provide 10mg (93%) title compound, are yellow solid. ¹H?NMR(400MHz，CD ₃OD)：9.0(s，1H)，8.3(s，1H)，8.05(s，1H)，7.7(s，1H)，7.25(s，1H)，4.4(s，2H)，3.6(d，2H)，3.1(t，2H)，2.6(s，3H)，2.0(d，2H)，1.85(t，4H)，1.6(t，1H).HPLC-MS?t _R＝2.96(UV ₂₅₄nm)。To C ₁₉H ₂₁N ₇S ₂Mass Calculation value 411.13; Measured value MH ⁺(LCMS) 412.2 (m/z).

Compound in the table 11 is to make according to embodiment above:

Table 11

Embodiment 65

Part A: at room temperature, (1M is in THF with hexamethyl two silicon lithium nitrides; 0.18mL) be added into 4-morpholine-4-ylmethyl phenyl amine (0.013g; 0.068mmol) and 8-methane sulfonyl-6-methyl-3-[1-(2-TMS-ethoxyl methyl)-1H-pyrazoles-4-yl]-imidazo [1,2-a] pyrazine (0.025g; 0.061mmol) in the amber solution in 2mL THF, cause red grape wine and women-sensual pursuits solution.After at room temperature stirring 20 minutes, with saturated NH ₄The Cl aqueous solution makes the reaction mixture cancellation.Content is diluted with ethyl acetate, and Yi Shui and salt water washing.Make crude material from organic extraction liquid by preparation type TLC purifying (5% methyl alcohol-CH ₂Cl ₂), to obtain title compound, be light yellow oil (0.025g; 80%). ¹H?NMR(400MHz，CDCl ₃)：8(s，1H)，7.9(d，2H)，7.85(s，1H)，7.8(s，1H)，7.5(s，1H)，7.4(s，1H)，7.35(d，2H)，5.55(s，2H)，3.75(br-s，4H)，3.7(t，2H)，3.5(br-s，2H)，2.5(br-s，2H)，2.4(s，3H)，1.6(br-s，2H)，0.95(t，2H)，0.0(s，9H).HPLC-MS?t _R＝3.05(UV ₂₅₄nm)。To C ₂₇H ₃₇N ₇O ₂The Mass Calculation value 519.27 of Si; Measured value MH ⁺(LCMS) 520.3 (m/z).

Part B: feasible compound (0.025g from part A; 0.048mmol) be suspended in the dry THF, and with the HCl (4M in the dioxane; 1mL) handle, when forming white depositions, heating is 15 minutes in being set to 70 ℃ oil bath.Add methyl alcohol, so that the dissolving of a part of solid continues heating more than 45 minutes with reaction mixture.After being cooled to room temperature, on rotatory evaporator, remove volatile matter.Resistates is suspended among the THF, and collects settled solid, with ether washing, dried overnight in a vacuum by filtering.Title compound is separated into beige solid (14mg; 78%).All analogues in the table 12 are to make in a similar manner.

Table 12

Embodiment 66

Part A: at room temperature, with 4-amino-2-methyl-methyl benzoate (0.33g; 2mmol; System is from the commercial 4-nitro-2-methyl-phenylformic acid that gets) and 8-methane sulfonyl-6-bromo-3-[1-(2-TMS-ethoxyl methyl)-1H-pyrazoles-4-yl]-imidazo [1,2-a] pyrazine (0.472g; 1.0mmol) solution, (1M is in THF with LiHMDS; 2mL) handle.Formed red grape wine and women-sensual pursuits solution was at room temperature stirred 20 minutes, then, with saturated NH ₄The Cl aqueous solution makes the reaction cancellation.By handling about embodiment 65 described standards, (25%EtOAc is at CH to reach the fast silica gel chromatogram method ₂Cl ₂In), title compound is provided, be weak yellow foam thing (0.48g; 86%).NMR(400MHz，CDCl ₃)：8.18(s，1H)，8(d，1H)，7.9(s，1H)，7.85(d，1H)，7.78(s，1H)，7.7(s，1H)，7.62(s，1H)，7.58(s，1H)，5.5(s，2H)，3.9(s，3H)，3.65(t，2H)，2.6(s，3H)，0.98(t，2H)，0.0(s，9H)。To C ₂₄H ₂₉BrN ₆O ₃The Mass Calculation value 556.13 of Si; Measured value MH ⁺(CI-MS) 557/559 (m/z).

Part B: the compound (0.48g that will derive from part A; 0.86mmol) solution in the 2mL dry THF, with the solution (2M of zinc methide; 4mL) dropwise handle.After foaming stops, adding solid Pd (PPh ₃) ₄, and reactant washed with nitrogen, load onto reflux condensing tube, heat in the oil bath under 65-70 ℃.0.5 after hour, reaction mixture is transformed into scarlet from yellow orange, after 4 hours, it has become opaque black again.TLC (25%EtOAc-CH ₂Cl ₂) show to form a little more luminous point of salience(-cy).Make reactant be cooled to room temperature, with saturated NH ₄The Cl aqueous solution makes the reaction cancellation, and extracts with EtOAc.Crude material is carried out the fast silica gel chromatogram method, obtains 6-methyl title compound, is yellow solid (0.38g; 90%).NMR(400MHz，CDCl ₃)：8.1(s，1H)，8(d，1H)，7.9(d，1H)，7.85(s，1H)，7.8(s，1H)，7.7(s，1H)，7.58(s，1H)，7.4(s，1H)，5.5(s，2H)，3.9(s，3H)，3.65(t，2H)，2.65(s，3H)，2.4(s，3H)，0.98(t，2H)，0.0(s，9H)。To C ₂₅H ₃₂N ₆O ₃The Mass Calculation value 492.23 of Si; Measured value MH ⁺(CI-MS) 493.11 (m/z).

Embodiment 67

Part A: at first, at room temperature use the LiBEt among the THF ₃H makes ester be reduced into alcohol, then by aforementioned, use Dess-Marin to cross the iodine alcoxyl and changes into aldehyde.Carry out the reduction amination effect of aldehyde with various secondary amine classes, SEM-is provided the title compound of protection.Removing of SEM protecting group is to carry out subject to the foregoing.In a similar manner, other tertiary amines that is listed in the table 13 also by similar reaction process, is used its corresponding secondary amine class, then makes for removing of SEM protecting group.

Table 13

Embodiment 68

(1g 5.07mmol) is dissolved in THF:H to make substrate ₂O (12mL, 1: 1, v/v) in, and at room temperature, with K ₂CO ₃(1.4g 10.15mmol) handles.Slowly add then chloroformic acid benzyl ester among the THF (2mL) (0.79mL, 5.58mmol).Mixture was stirred 16 hours.It is diluted with ethyl acetate (25mL).Separate two liquid layers, and with ethyl acetate (2x25mL) aqueous layer extracted.The organic layer that merges is washed dry (Na with salt solution (1x30mL) ₂SO ₄), filtering, vapourisation under reduced pressure obtains crude product, makes it pass through column chromatography purifying (SiO ₂), with ethyl acetate-hexane wash-out.

Embodiment 69

(1.2g 3.64g) is dissolved in the acetone (20mL), and at room temperature, handles with the 1N HCl aqueous solution (2mL), and mixture was stirred 7 hours to make the substrate acetal.Evaporate acetone then, again with saturated NaHCO ₃The aqueous solution (30mL) dilution resistates.With ethyl acetate (2x30mL) aqueous layer extracted.The organic layer that merges is washed dry (Na with salt solution (1x30mL) ₂SO ₄), filtering, vapourisation under reduced pressure obtains crude product, is solid, and it is used in next step, does not carry out any being further purified.

Embodiment 70

With 1, the substrate in the 2-ethylene dichloride (1 equivalent), amine (4 equivalent), catalysis AcOH, NaB (OAc) ₃H (2 equivalent) at room temperature stirred 2 hours.Add sodium borohydride (3 equivalent) then, and mixture was stirred 30 minutes, at this moment, LC-MS analyzes and shows that the initial substance completely consumed becomes product.Then make the reaction cancellation with the 2N NaOH aqueous solution, and with the mixture high degree of agitation, till two transparent layers separate.With organic layer Yi Shui, salt water washing, dry (Na ₂SO ₄), filter, under reduced pressure concentrate, obtain product.

Make crude product in ethyl acetate, use 10%Pd/C, hydrogenation under 1 atmospheric hydrogen pressure.Leach catalyzer, and the vapourisation under reduced pressure solvent, crude product obtained.

Embodiment 71

Part A: with 1, the substrate in the 2-ethylene dichloride (1 equivalent), amine (4 equivalent), catalysis AcOH, NaB (OAc) ₃H at room temperature stirred 2 hours.Add sodium borohydride (3 equivalent) then, and mixture was stirred 30 minutes, at this moment, LC-MS analyzes and shows that the initial substance completely consumed becomes product.Then make the reaction cancellation with the 2N NaOH aqueous solution, and with the mixture high degree of agitation, till two transparent layers separate.With organic layer Yi Shui, salt water washing, dry (Na ₂SO ₄), filter, under reduced pressure concentrate, obtain product.

Part B: make crude product in ethyl acetate, use 10%Pd/C, hydrogenation under 1 atmospheric hydrogen pressure.Leach catalyzer, and the vapourisation under reduced pressure solvent, crude product obtained.

Embodiment 72

Embodiment 73

Part A: under argon gas, substrate (1 equivalent) and amine (1.5-2 equivalent) are dissolved among the DMSO, and handle with NaH (5 equivalents, 60% dispersion liquid in oil).After 30 minutes, LC-MS analyzes and shows the initial substance completely consumed.By adding saturated NH ₄The Cl aqueous solution-acetonitrile (1: 1, v/v) make the reaction cancellation.Separate two liquid layers, with the ethyl acetate extraction water layer.With the organic layer that the salt water washing merges, dry (Na ₂SO ₄), filter, under reduced pressure concentrate, obtain crude product.

Part B: substrate is dissolved in the 4N HCl in the dioxane, and at room temperature stirred 30 minutes.Evaporating solvent makes resistates by preparation type LC purifying then.Change into hydrochloride, obtain product, be solid.

Table 14

Embodiment 74

Part A: basically by as about embodiment 1 and 13 described same programs.

Part B: (0.16g 0.57mmol) adds Dess-Martin and crosses iodine alkane (3 equivalent) in the solution in THF (20mL) and water (0.025mL) to the compound that derives from embodiment 74 part A.Formed solution was at room temperature stirred 1.5 hours, and LC-MS analysis this moment shows to react to be finished.Reaction mixture is diluted with methylene dichloride (75mL), with water washing, dry (sodium sulfate), reconcentration.By column chromatography purifying (SiO ₂, 10% methyl alcohol/DCM), obtain title compound is yellow solid 0.08g (49%).HPLC-MS t _R=1.59 minutes (UV ₂₅₄Nm).To the Mass Calculation value 285.07 of formula C13H11N5OS, measured value LC/MS m/z 286.1 (M+H).

Portion C: to the compound that derives from part B (30mg, 0.105mmol, 1 equivalent), 3-methyl piperidine (10 equivalent) at methylene dichloride: add acetate (1) in the solution of methyl alcohol (5: 1) in (3mL).Formed solution was at room temperature stirred 30 minutes, then, sodium borohydride (8 equivalent) is added in the reactant.Reaction mixture was at room temperature stirred 1 hour, and LC-MS analysis this moment shows to react to be finished.Make the reaction cancellation with saturated sodium bicarbonate aqueous solution, then with dichloromethane extraction (x2).Make the organic layer drying (sodium sulfate) of merging, reconcentration.By preparation type LC purifying, and change into hydrochloride, obtain title compound.HPLC-MS t _R=3.73 minutes (UV ₂₅₄Nm).To the Mass Calculation value 368.18 of formula C19H24N6S, measured value LC/MS m/z 369.2 (M+H).

Embodiment 75

Part A: to compound 1 (30mg, 0.105mmol, 1 equivalent), piperidines (10 equivalent) at methylene dichloride: add acetate (1) in the solution of methyl alcohol (5: 1) in (3mL).Formed solution was at room temperature stirred 30 minutes, then, sodium borohydride (8 equivalent) is added in the reactant.Reaction mixture was at room temperature stirred 1 hour, and LC-MS analysis this moment shows to react to be finished.Make the reaction cancellation with saturated sodium bicarbonate aqueous solution, then with dichloromethane extraction (x2).Make the organic layer drying (sodium sulfate) of merging, reconcentration.By preparation type LC purifying, and change into hydrochloride, obtain compound 2.HPLC-MS t _R=3.47 minutes (UV ₂₅₄Nm).To formula C ₁₈H ₂₂N ₆The Mass Calculation value 354.16 of S, measured value LC/MS m/z 355.1 (M+H).

Embodiment 76

Steps A: at room temperature (by room-temperature water bath), with sodium hydride (60% dispersion liquid in Dormant oils, 6.68g, 3.40 equivalent) slowly be added into compound sulfone (20.0g with portion, 1.00 equivalent) with aminoisothiazoles (11.5g, 1.20 equivalent, for example HCl salt) in the stirring the mixture in DMF (490mL).Reactant was stirred 1 hour, and HPLC analysis this moment shows to react to be finished.(200mL) makes the reaction cancellation carefully with saturated sodium bicarbonate aqueous solution, dilutes with water (1L) then.This mixture was at room temperature stirred 20 minutes, then, collect formed throw out by filtering, with water (200mL) washing, drying is 16 hours under high vacuum.Make formed waxy solid be dissolved in 1: 1 chloroform of 1.8L: in the methyl alcohol,, to filter, under reduced pressure concentrate, obtain title compound (22.3g, 93%), be the dark yellow solid with dried over sodium sulfate. ¹H?NMR(300MHz，DMSO-d ₆)δ12.3(bs，1H)，8.60(s，1H)，8.10(s，1H)，7.88(s，2H)，7.59(s，1H)，5.51(s，2H)，3.85(s，3H)，3.63(d，J＝8Hz，2H)，2.48(s，3H)，0.88(d，J＝8Hz，2H)，-0.026(s，9H)。To formula C ₂₁H ₂₇N ₇O ₃The Mass Calculation value 485.63 of SSi; Measured value MH ⁺(MS) 486.6 (m/z).

Step B: make that (4.27g, mixture 3.73mmol) is dissolved among the 180mL THF for compound from steps A.Make formed solution be cooled to 0 ℃, and carefully add LiAlH ₄Powder (2.6g, 68.5mmol).Remove cooling bath, and with reactant at room temperature and N ₂Atmosphere stirred 1.5 hours down.Make reactant be cooled to 0 ℃, again by adding 2.6mL H in succession ₂O; 2.6mL 15%NaOH (aqueous solution); 7.8mL H ₂O makes the reaction cancellation carefully.After stirring 10 minutes, make reactant filter (with THF, EtOAc and DCM flushing) through diatomaceous pad as thin as a wafer.Concentrated filtrate produces faint yellow solid.By obtaining pure alcohol (2.66g, 66% productive rate), and directly be used in step C with MeOH development.

Step B (alternative program; Embodiment 76-39 for example): to 4,4-difluoro piperidine hydrochlorate (25.1mg, 0.16mmol) add in the solution in THF (2.0mL) NaH (60% dispersion liquid in Dormant oils, 12mg, 0.30mmol).With mixture at N ₂Stirred 10 minutes under atmosphere and the room temperature, then, (31.4mg, 0.06mmo1) (4mg 0.03mmol) is added in the reaction flask with NaI with methane sulfonates.With reactant at N ₂Atmosphere and 80 ℃ of following heating 8 hours.Make reactant be cooled to room temperature, and add the saturated NH of 15mL ₄Cl (aqueous solution) solution.Reactant with methylene dichloride (20mL) dilution, is separated liquid layer.With methylene dichloride (2x20mL) aqueous layer extracted.With organic phase with the saturated NaHCO of 15mL ₃(aqueous solution) then washs with salt solution (15mL).Make organic phase with Na ₂SO ₄Drying concentrates in a vacuum.By preparation type TLC purifying (10%MeOH/CH ₂Cl ₂), obtain 19.7mg (60% productive rate) title compound.

Step C: will derive from step B compound (2.40g, 4.49mmol), amine (1.57g, 13.46mmol) and NaI (63.0mg, the 0.449mmol) mixture in 45mL THF is 80 ℃ of down heating 12 hours.With it with 200mL CH ₂Cl ₂Dilution, and with the saturated NaHCO of 100mL ₃The aqueous solution then washs with salt solution (100mL).Move down in vacuum and to desolventize.Make resistates pass through purified by flash chromatography, with 5% to 10%MeOH/CH ₂Cl ₂Wash-out obtains the 1.68g title compound. ¹H?NMR(400MHz，CDCl ₃)δ9.49(brs，1H)，7.89(s，1H)，7.82(s，1H)，7.60(s，1H)，7.49(s，1H)，6.86(s，1H)，5.54(s，2H)，3.79(brs，3H)，3.67(t，J＝8.3Hz，2H)，3.36(s，2H)，2.65-2.80(m，2H)，2.50(s，3H)，1.11(s，6H)，1.02(t，J＝7.1Hz，2H)，0.96(t，J＝8.2Hz，H)，0.01(s，9H)。(2.0g is 3.6mmol) at 36mL MeOH/CH to the compound of Sem-protection ₂Cl ₂In 80 ℃ of solution that stir down, add the 4N HCl of 36mL in dioxane in (1: 1).Reactant was stirred 30 minutes down at 80 ℃.After making it be cooled to room temperature, add 120mL ether.By solid collected by filtration, dry under vacuum with the ether washing, obtain the 2.0g title compound, be its HCl salt form.To formula C ₂₀H ₂₆N ₈The Mass Calculation value 426.2 of OS; Measured value MH ⁺(LCMS) 427.2 (m/z).

Use as about embodiment 76 described same programs, is made following compounds basically.

Table 15

Embodiment 76-1: ¹H NMR (400MHz, CD ₃OD) δ 8.24 (s, 1H), 8.23 (s, 2H), 8.07 (s, 1H), 7.35 (s, 1H), 4.57 (d, J=12.8Hz, 2H), 3.81 (t, J=4.8,2H), 3.57 (q, J=14.0,6.8Hz, 2H), 3.52 (m, 2H), 3.41 (m, 2H), 2.60 (s, 3H), 1.38 (t, J=7.2Hz, 3H), 1.21 (t, J=6.8Hz, 3H) .HPLC-MS t _R=2.28 minutes (UV ₂₅₄Nm).To formula C ₂₀H ₂₆N ₈The Mass Calculation value 426.2 of OS; Measured value MH ⁺(LCMS) 427.2 (m/z).

Embodiment 76-2: ¹H NMR (400MHz, CD ₃OD) δ 8.31 (s, 1H), 8.29 (s, 2H), 7.32 (s, 1H), 4.88 (d, 1H), 4.46 (d, J=16.1Hz, 1H), 3.82 (d, J=12.3Hz, 1H), 3.71 (d, J=12.3Hz, 1H), 3.64 (m, 1H), 2.65 (s, 3H), 1.42 (s, 3H), 1.40 (s, 3H), 1.31 (t, J=7.1Hz, 3H) .HPLC-MS t _R=2.26 minutes (UV ₂₅₄Nm).

Embodiment 76-3: ¹H NMR (400MHz, CD ₃OD) δ 8.16 (s, 2H), 8.13 (s, 1H), 7.99 (s, 1H), 7.25 (s, 1H), 4.72 (d, J=15.6Hz, 1H), 4.53 (t, J=15.6,1H), 3.66 (s, 2H), 3.61 (m, 1H), 3.40 (m, 1H), 2.57 (s, 3H), 1.33-0.95 (8H), 1.17 (t, J=6.8Hz, 3H) .HPLC-MS t _R=2.26 minutes (UV ₂₅₄Nm).To formula C ₂₀H ₂₆N ₈The Mass Calculation value 452.2 of OS; Measured value MH ⁺(LCMS) 453.2 (m/z).

Embodiment 76-4: ¹H NMR (400MHz, CD ₃OD) δ 8.16 (s, 2H), 8.15 (s, 1H), 8.00 (s, 1H), 7.21 (s, 1H), 4.95 (d, J=16.0Hz, 1H), 4.35 (d, J=16.8Hz, 1H), 4.07 (d, J=12.4Hz, 1H), 3.82 (d, J=12.8Hz, 1H), 3.52 (m, 2H), 2.57 (s, 3H), 1.96-1.58 (10H), 1.26 (t, J=6.8Hz, 3H) .HPLC-MS t _R=2.48 minutes (UV ₂₅₄Nm).To formula C ₂₀H ₂₆N ₈The Mass Calculation value 466.3 of OS; Measured value MH ⁺(LCMS) 467.3 (m/z).

Embodiment 76-5: ¹H NMR (400MHz, CD ₃OD) δ 8.28 (s, 1H), 8.25 (s, 2H), 8.10 (s, 1H), 7.39 (s, 1H), 4.65 (d, J=14.0Hz, 1H), 4.52 (d, J=10.8Hz, 1H), 4.24 (d, J=14.0Hz, 1H), 3.85 (d, J=18.0Hz, 1H), 3.65-3.44 (4H), 2.65 (s, 3H), 1.97-1.58 (6H), 1.29 (t, J=7.2Hz, 3H) .HPLC-MS t _R=2.35 minutes (UV ₂₅₄Nm).To formula C ₂₀H ₂₆N ₈The Mass Calculation value 452.2 of OS; Measured value MH ⁺(LCMS) 453.2 (m/z).

Embodiment 76-6: ¹H NMR (400MHz, CD ₃OD) δ 8.21 (s, 3H), 8.03 (s, 1H), 7.23 (s, 1H), 4.38 (d, J=5.6Hz, 1H), 3.79 (d, J=5.4Hz, 1H), 3.63 (d, J=12.4Hz, 1H), 3.53 (m, 1H), 3.10 (m, 1H), 2.58 (s, 3H), 1.34 (s, 6H), 0.87 (t, J=6.2Hz, 3H) .HPLC-MS t _R=2.39 minutes (UV ₂₅₄Nm).To formula C ₂₀H ₂₆N ₈The Mass Calculation value 440.2 of OS; Measured value MH ⁺(LCMS) 441.2 (m/z).

Embodiment 76-7: ¹H-NMR (400MHz, CD ₃OD) δ 8.33m (3H), 8.15s (1H), 7.41s (1H), 4.80 (d, 2H), 4.15 (d, 2H), 4.06 (d, 2H), 3.62 (d, 2H), 3.58 (m, 1H), 2.68 (d, 3H), 2.21 (m, 1H), 1.81 (m, 6H) and 1.45 (s, 3H) .HPLC-MSt _R=1.80 minutes (UV ₂₅₄Nm).To the Mass Calculation value 438.55 of formula C21H26N8OS, measured value LC/MS m/z 439.1 (M+H).

Embodiment 76-8: ¹H-NMR (400MHz, DMSO-d ₆) δ 12.73bs (1H), 9.2bs (1H), 8.28s (2H), 8.09s (1H), 8.08s (1H), 7.36s (1H), 4.71m (1H), 4.05m (1H), 3.82m (1H), 3.63m (1H), 3.25m (2H), 1.97m (1H), 1.65m (6H) and 1.30s (3H).

Embodiment 76-9: ¹H-NMR (400MHz, DMSO-d ₆) δ 8.28 (1H), 8.25 (2H), 8.08 (1H), 7.32 (1H), 4.71 (1H), 4.08 (1H), 3.84 (1H), 3.52 (3H), 3.46 (1H), 2.63 (3H), 2.17 (2H), 1.87-1.73 (6H), 1.45 (3H).

Embodiment 76-10: ¹H-NMR (400MHz, DMSO-d ₆) δ 8.28 (1H), 8.25 (2H), 8.08 (1H), 7.32 (1H), 4.71 (1H), 4.08 (1H), 3.84 (1H), 3.52 (3H), 3.46 (1H), 2.63 (3H), 2.17 (2H), 1.87-1.73 (6H), 1.45 (3H).

Embodiment 76-11: ¹H NMR (400MHz, CD ₃OD) δ 8.20 (s, 2H), 8.14 (s, 1H), 8.03 (s, 1H), 7.25 (s, 1H), 4.48 (d, 1H), 4.37 (d, 1H), 3.46 (s, 3H), 2.91-3.60 (m, 6H), 2.62 (s, 3H), 1.40-1.89 (m, 4H), 0.92. (s, 3H).

Embodiment 76-12: ¹H NMR (400MHz, CD ₃OD) δ 8.20 (s, 2H), 8.14 (s, 1H), 8.03 (s, 1H), 7.25 (s, 1H), 4.48 (d, 1H), 4.37 (d, 1H), 3.46 (s, 3H), 2.91-3.60 (m, 6H), 2.62 (s, 3H), 1.40-1.89 (m, 4H), 0.92 (s, 3H).

Embodiment 76-40: ¹H NMR (400MHz, CD ₃OD) δ 8.28 (s, 1H), 8.25 (s, 2H), 8.10 (s, 1H), 7.38 (s, 1H), 4.59 (s, 2H), 3.3-3.9 (m, 4H), 2.64 (s, 3H), 2.3-2.5 (m, 4H).

Embodiment 76-42: ¹H NMR (400MHz, CD ₃OD) δ 8.13 (broad s, 2H), 7.85 (s, 1H), 7.78 (s, 1H), 7.15 (s, 1H), 4.10 (d, J～14Hz, 1H), 3.96 (d, J～14Hz, 1H), 3.54-3.66 (m, 1H), 3.07-3.17 (m, 1H), 2.62-2.72 (m, 1H), 2.53 (s, 3H), 1.82-2.21 (m, 4H).

Embodiment 77

(52.5g, 336.5mmol) (30.0g, mixture 336.5mmol) stirred 15 minutes down at 60 ℃ with 2-amino-2-methyl-1-propanol with ethyl iodide.It is diluted with 500mL ether, and by adding the alkalization of the 5N NaOH aqueous solution, till it reaches pH=10.Separate organic layer.With ether (500mLx3) aqueous layer extracted.With the organic substance that merges in succession with 100mL water and the water washing of 100mL salt, then with anhydrous Na ₂SO ₄Dry.Remove solvent, 20g is provided crude product, make it pass through recrystallization in the 150mL hexane and purifying obtains the 13g white solid.The sublimation of solid by under reduced pressure is further purified, obtains the 12g title compound. ¹H?NMR(400MHz，CDCl ₃)δ3.28(s，2H)，2.54(qt，J＝7.1Hz，2H)，1.09(t，J＝7.0Hz，3H)，1.07(s，6H)。

Embodiment 78

Steps A: substrate (10g) is suspended among the THF (200mL).Slowly add lithium aluminium hydride solution (110mL, 2M is in THF) then.Mixture was at room temperature stirred 12 hours.Make solution be cooled to 0 ℃, and slowly add saturated Na ₂SO ₄The aqueous solution (200mL).Make mixture through diatomite filtration, with ethyl acetate (400mL) washing leaching cake.Organic layer is washed with water (200mL) and salt solution (200mL).Make organic layer drying (anhydrous Na ₂SO ₄), to filter, evaporation obtains amino alcohol (6.9g).At room temperature, amino alcohol (6.9g) is dissolved in THF (80mL) and the water (80mL).Add salt of wormwood (14.76g).Then dropwise add the chloroformic acid benzyl ester (8.28mL) among the THF (40mL).Mixture was at room temperature stirred 30 minutes.Vapourisation under reduced pressure goes out solvent, and adds ethyl acetate (100mL).Separates two is with ethyl acetate (2x100mL) aqueous layer extracted.The organic layer that merges is washed dry (Na with salt solution (200mL) ₂SO ₄), filtering, vapourisation under reduced pressure obtains crude product, makes it pass through the column chromatography purifying.Racemic amino alcohol is passed through SFC HPCL method chiral separation.Then, continue respectively to adopt corresponding to the enantiomer of absorption peak 1, to prepare its corresponding structure unit with absorption peak 2.

Step B: feasible alcohol (1.936g) from steps A is dissolved in the methylene dichloride (80mL), and at room temperature, handles with proton sponge (8.32g).Add trimethylammonium oxygen a tetrafluoro borate (5.69g) then.Mixture was stirred 1 hour.(100mL) makes the reaction cancellation with saturated aqueous ammonium chloride.Separate two liquid layers, with methylene dichloride (2x100mL) aqueous layer extracted.With the organic layer that merges in succession with hydrochloric acid (200mL, 1N), saturated sodium bicarbonate solution (200mL), salt solution (200mL) washing, dry (Na ₂SO ₄), filtering, vapourisation under reduced pressure obtains crude product, makes it pass through the column chromatography purifying.

Step C: with the methyl ether of the enantiomer-pure that derives from step B among the EtOH, with Pd (OH) ₂/ carbon (20 weight %) is handled, and in nitrogen atmosphere, stirs 2 hours under barometric point and room temperature.Leach mixture, make the filtrate vapourisation under reduced pressure, obtain amine.

Embodiment 79

Steps A: under-78 ℃, with the ester among the THF (50mL) (6359mg, 24.7mmol) dropwise be added into LDA among the THF (200mL) (1.8M, in THF, 27.5mL, 49.4mmol) in.Make reaction mixture be warmed to room temperature at leisure, and under this temperature, stir and spend the night.Make reactant be cooled to 0 ℃, and with saturated NH ₄Cl solution makes the reaction cancellation.With H ₂O diluted mixture thing is with EtOAc extraction (x2).The organic layer that makes merging is with anhydrous Na ₂SO ₄Drying, reconcentration.By the column chromatography purifying, obtain title compound (6221mg, 93%).LCMS t _R=2.27 minutes. to the Mass Calculation value 271.1 of M+, measured value LC/MS m/z 216.1 (M+H-C ₄H ₈).(4659mg 17.2mmol) adds LiBHEt in the solution in THF (300mL) to ester ₃(69mL, 1M is in THF).Reactant was at room temperature stirred 30 minutes.By adding saturated NH ₄Cl makes its cancellation.With mixture with CH ₂Cl ₂Extraction.The organic layer that makes merging is with anhydrous Na ₂SO ₄Drying, reconcentration.By the column chromatography purifying, obtain title compound (3032mg, 77%).LCMSt _R=1.82 minutes. to the Mass Calculation value 229.1 of M+, measured value LC/MS m/z 174.1 (M+H-C ₄H ₈).

Step B: under 0 ℃, (33.1mmol) gradation is added into the compound that derives from steps A and MeI (3.3mL is 52.9mmol) in the mixture in DMF (66mL) for 1324mg, 60% dispersion liquid in Dormant oils with NaH.Make reaction mixture be warmed to room temperature at leisure, and under this temperature, stir and spend the night.Make reactant be cooled to 0 ℃, and with saturated NH ₄Cl solution makes the reaction cancellation.With H ₂O diluted mixture thing is with EtOAc extraction (x2).The organic layer that makes merging is with anhydrous Na ₂SO ₄Drying, reconcentration.By the column chromatography purifying, obtain title compound (2633mg, 82%).LCMSt _R=2.32 minutes. to the Mass Calculation value 243.1 of M+, measured value LC/MS m/z 188.1 (M+H-C ₄H ₈).Under 0 ℃, (901mg, solution 3.71mmol) is at CH with compound 4 ₂Cl ₂In 20%TFA (20mL) in stirred 30 minutes, room temperature is 15 minutes then.Reaction mixture is concentrated.Rough resistates is used in embodiment, need not to be further purified.LCMS t _R=0.26 minute. to the Mass Calculation value 143.1 of M+, measured value LC/MS m/z 144.1 (M+H).

Step C: under 0 ℃, (604 μ L 4.08mmol) are added into compound and the K that derives from step B with the CbzCl among the THF (1mL) ₂CO ₃(1125mg is 8.15mmol) at THF (20mL) and H ₂In the mixture among the O (20mL).After at room temperature stirring 30 minutes, reaction mixture is extracted (x2) with EtOAc.The organic layer that makes merging is with anhydrous Na ₂SO ₄Drying, reconcentration.By the column chromatography purifying, obtain title compound (965mg, 94%).LCMS t _R=2.28 minutes (UV ₂₅₄Nm).To the Mass Calculation value 277.1 of M+, measured value LC/MS m/z 278.1 (M+H).The Gilson GX-281 liquid processing system chiral separation that the utilization of title amine is had the HPLC ability.Separating is to use following condition to finish: chiral technology Chiral PAK AD post (5x50cm; 20 μ); Flow rate=50mL/ minute; 7.5% Virahol is (constant composition) in hexane; Under 210nm, observe.

Step D: make isomer from the enantiomer-pure of step C be dissolved among the EtOH (6mL) (1mmol, 277mg) in, with 20%Pd (OH) ₂(51mg) mix, and at H ₂Stirred 2 hours under gas cylinder and the room temperature.Through diatomite filtration, reconcentration, obtain title compound, it is used in next step, need not to be further purified.LCMS t _R=0.26 minute. to the Mass Calculation value 143.1 of M+, measured value LC/MS m/z 144.1 (M+H).

Embodiment 80

Steps A: parent compound is to use chlorination acyl, acids, ureas and isocyanic ester, uses the standard reaction condition to make from embodiment 76-2.

Step B: make the material of protecting from the Sem-of steps A be dissolved in 1, in the 4-dioxane (1mL), and with 1, the 4N HCl (1mL) in the 4-dioxane handles.Heated 1 hour down at 60 ℃ then.Under reduced pressure enriched mixture makes formed resistates by the preparation HPLC purifying, and changes into its hydrochloride, obtains title compound, is colorless solid.

Use as about embodiment 80 described same programs, is made following compounds basically.

Table 16

Embodiment 81

Steps A: initial sulfone is to make by the same program described in the embodiment 6 basically, and difference is to use ethyl dihydroxyl borine or cyclopropyl dihydroxyl borine.The final product that is listed in the table 17 is to utilize embodiment 76 described programs to obtain.

Table 17

Embodiment 82

Steps A: title compound is to use as described in embodiment 7 and makes, and difference is to use tert-butylamine.

Step B: at room temperature, in the solution of product (1 equivalent) in THF (3mL) of steps A, add DIEA (3 equivalent) and each trifluoro-methanyl sulfonate (1.2 equivalent).With reactant heating under refluxing, up to analyze the consumption of discovery initial substance by LC-MS till.Make solution be cooled to room temperature, under reduced pressure concentrate.By column chromatography purifying (SiO ₂, 30% ethyl acetate/dichloromethane), the intermediate of the acquisition coupling of wanting.Make this material be dissolved in 1, in the 4-dioxane, add HCl (4N is in dioxane), and make the mixture sonication, when HPLC shows that no initial substance is residual till.Under reduced pressure enriched mixture by the preparation HPLC purifying, and changes into its hydrochloride, obtains the title compound in the table 18, is pale solid.

Table 18

Embodiment 83

Steps A: at room temperature, sulfo-sodium methylate (39mg, 3.00 equivalents) is added in the methane sulfonates (100mg, 1.00 equivalents) made among the embodiment 7 and sodium iodide (14mg, 0.50 equivalent) the stirring the mixture in DMF (6mL).Formed mixture was stirred 2.5 hours, and LC-MS analysis this moment shows to react to be finished.(30mL) makes the reaction cancellation with saturated sodium bicarbonate aqueous solution, extracts with methylene dichloride (2x70mL) then.The organic substance that makes merging filters with anhydrous sodium sulfate drying, under reduced pressure concentrates, and obtains title compound, is yellow solid 100mg (＞99%).

Step B: at room temperature, will between-chlorine peroxybenzoic acid (66mg, 2.05 equivalents) be added into derive from steps A compound (91mg, 1.00 equivalents) in methylene dichloride (3mL) just in stirred solution.Mixture was stirred 2 hours, and at this moment, tlc shows to react to be finished.Mixture with ethyl acetate (40mL) dilution, with saturated sodium bicarbonate aqueous solution (15mL) and salt solution (10mL) washing, with anhydrous sodium sulfate drying, is filtered then, under reduced pressure concentrate.Make this material be dissolved in 1, in the 4-dioxane, add HCl (4N is in dioxane), and make the mixture sonication, when HPLC shows that no initial substance is residual till.Under reduced pressure enriched mixture by the preparation HPLC purifying, and changes into its hydrochloride, obtains title compound, is pale solid 18mg (27%). ¹H NMR (300MHz, DMSO-d ₆) δ 12.19 (s, 1H), 8.24 (s, 2H), 7.96 (s, 1H), 7.83 (s, 1H), 7.28 (s, 1H), 4.61 (s, 2H), 3.01 (s, 3H), 2.53 (s, 3H) .HPLC t _R=4.04 minutes (UV ₂₅₄Nm).To C ₁₅H ₁₅N ₇O ₂S ₂Mass Calculation value 389.1; Measured value MH ⁺(MS) 390.7 (m/z).

Embodiment 84

Steps A: with EtN (iPr) ₂(10.55mL, 60.69mmol) under 0 ℃, be added into acid among the DMF (100mL) (2953mg, 20.23mmol is according to Bioorganic ﹠amp; MedicinalChemistry, 11 (20), 4333-4340; 2003 make), EDCI (5817mg, 30.34mmol), HOBT (4100mg, 30.34mmol) and piperidines (2398 μ L, 24.28mmol) in.After at room temperature stirring is spent the night, rough reactive material is diluted with EtOAc, and with salt water washing (2x).Make organic layer with Na ₂SO ₄Drying is filtered, and reconcentration obtains crude product, makes its chromatography, obtains the product acid amides.HPLC-MS t _R=1.57 minutes (UV ₂₅₄Nm).To the Mass Calculation value 213.0 of formula M+, measured value LC/MS m/z 214.1 (M+H).

Step B: under 0 ℃, with Powdered KNO ₃(1100.8mg, 10.89mmol) gradation is added into acid amides (927.6mg is 4.356mmol) at dense H ₂SO ₄In the solution of the stirring (20mL).After stirring 30 minutes under 0 ℃, reaction mixture is poured on ice.With CH ₂Cl ₂Extraction, and with the organic layer that merges with H ₂The O washing is with Na ₂SO ₄Drying, reconcentration.By the column chromatography purifying, at first obtain the nitrification product 545.5mg (48.5%) do not expect, HPLC-MS t _R=1.79 minutes (UV ₂₅₄Nm).To the Mass Calculation value 258.0 of M+, measured value LC/MS m/z 259.1 (M+H), ¹H NMR (400MHz, CDCl ₃) δ 7.58 (d, 1H, J=0.4Hz), 3.67 (m, 4H), 1.73 (m, 6H), then nitrification product 435.6mg (38.8%), HPLC-MS t for needing _R=1.68 minutes (UV ₂₅₄Nm).To the Mass Calculation value 258.0 of M+, measured value LC/MS m/z 259.1 (M+H). ¹H NMR (400MHz, CDCl ₃) δ 8.37 (d, 1H, J=3.2Hz), 3.67 (m, 4H), 1.71 (m, 6H).

Step C: to the nitro acid amides (435.6mg, 1.69mmol) add in the solution in HOAc (20mL) iron powder (471.5mg, 8.44mmol).Reaction mixture was heated 30 minutes down at 70 ℃.Make mixture be cooled to room temperature, reconcentration is to dry.In resistates, add 30mL 20%MeOH/CH ₂Cl ₂, then be the saturated NaHCO of 20mL ₃The aqueous solution.Mixture is stirred, up to stopping foaming.Mixture is extracted (x2) by EtOAc, with Na ₂SO ₄Drying concentrates then.Rough amine is used in replacement(metathesis)reaction, need not to be further purified.HPLC-MS t _R=1.32 minutes (UV ₂₅₄Nm).To the Mass Calculation value 228.0 of M+, measured value LC/MS m/z 229.1 (M+H).

Step D: at room temperature, (491.5mg, 2.156mmol) ((60% dispersion liquid in oil, 172.5mg 4.312mmol) handle with NaH for 292mg, the 0.719mmol) solution in DMSO (10mL) with sulfone with the rough amine that derives from step C.Mixture is stirred, till LCMS shows that reaction has been finished.With the EtOAc diluted reaction mixture, with saturated NH ₄The Cl washing is with Na ₂SO ₄Drying, reconcentration obtains crude product 4.Purifying obtains compound 4.HPLC-MSt _R=2.503 minutes (UV ₂₅₄Nm).To the Mass Calculation value 555.2 of M+, measured value LC/MS m/z556.3 (M+H).

Step e: under 0 ℃, (120mg, (86.4mg is 2.162mmol) with ether (3mL) 0.216mmol) to add lithium aluminium hydride in the solution in methylene dichloride (12mL) to the acid amides that derives from step D.Reaction mixture is at room temperature stirred, till LCMS shows that reaction has been finished.With H ₂O (86 μ L), 3N NaOH (86 μ L) and H ₂O (264 μ L) makes the reaction cancellation.The filtering reaction thing, reconcentration obtains crude compound 5.HPLC-MS t _R=1.738 minutes (UV ₂₅₄Nm).To the Mass Calculation value 541.2 of M+, measured value LC/MS m/z 542.2 (M+H).

Step F: under 0 ℃, the 4N HCl (3mL) in the dioxane is added in the crude product that derives from step e.Mixture is at room temperature stirred, till LCMS shows that reaction has been finished.Concentrate and obtain crude product.By preparation type LC purifying, and change into hydrochloride, obtain title compound.HPLC-MS t _R=0.923 minute (UV ₂₅₄Nm).To the Mass Calculation value 411.1 of M+, measured value LC/MS m/z 412.2 (M+H).

Embodiment 85

Basically by the same program shown in the embodiment 84, can be made into title compound.HPLC-MS t _R=1.005 minutes (UV ₂₅₄Nm).To the Mass Calculation value 425.1 of M+, measured value LC/MS m/z 426.2 (M+H).

Embodiment 86

Steps A: to nitro ester (2285mg, 12.22mmol) add in the solution in HOAc (55mL) iron powder (6825mg, 122.20mmol).Reaction mixture was heated 10 minutes down at 75 ℃.Make mixture be cooled to room temperature, add the MeOH of 200mL then.Make formed mixture through diatomite (with the MeOH flushing of diatomite) filtration with other amount.Concentrated filtrate is to remove most of AcOH.In resistates, add 50mL 20%MeOH/CH ₂Cl ₂, then be saturated NaHCO ₃The aqueous solution is up to stopping foaming.Mixture is extracted (x2) by EtOAc, with Na ₂SO ₄Drying concentrates then.Use rough amine, need not to be further purified.HPLC-MS t _R=1.07 minutes (UV ₂₅₄Nm).To the Mass Calculation value 157.0 of M+, measured value LC/MS m/z 158.1 (M+H).

Step B: at room temperature, (850mg, 5.414mmol) (3.609mmol) solution in DMSO (36mL) is with NaH (60% dispersion liquid in oil, 14.43mmol, 577mg) gradation processing for 1 equivalent, 1469mg with the sulfone that derives from embodiment 1 with amino ester.After 10 minutes, the LC-MS of reaction analyzes the demonstration reaction and finishes.When cooling off, dropwise with saturated NH by water-bath ₄Cl (5mL) makes the reaction cancellation, adds H then ₂O (160mL) is with ethyl acetate extraction (2x).With the organic layer that merges with the salt water washing, dry (sodium sulfate).Evaporation by column chromatography purifying (0 to 100%EtOAc/ hexane), obtains title compound (1492mg, 85%).HPLC-MS t _R=2.41 minutes (UV ₂₅₄Nm).To the Mass Calculation value 484.1 of M+, measured value LC/MS m/z 485.2 (M+H).

Step C: under-78 ℃, (206mg, 0.4271mmol) solution in THF (8mL) is dropwise used DIBAL (1.0M is at CH to the product of step B ₂Cl ₂In, 2.56mL) handle.Stirring is after 4.5 hours down at-78 ℃, and LCMS shows that a small amount of initial substance exists.Add 2 equivalent DIBAL (0.85mL) again.After 0.5 hour, under-78 ℃, salt solution (6mL) is added in gradation, so that the excess reagent cancellation at-78 ℃ of following restir.With CH ₂Cl ₂Extraction (3x) reaction mixture.Evaporating solvent by column chromatography purifying (0-＞100%2%MeOH is in the EtOAc/ hexane), obtains alcohol (153mg, 79%).HPLC-MS t _R=2.01 minutes (UV ₂₅₄Nm).To the Mass Calculation value 456.1 of M+, measured value LC/MS m/z 457.1 (M+H).

Step D: under 0 ℃, (537mg 1.17mmol) adds H in the solution in THF (26mL) to the alcohol that derives from step C ₂O (0.078mL), then for Dess-Martin cross iodine alkane (599mg, 1.41mmol).Reactant is at room temperature stirred, till LCMS shows that reaction has been finished.With CH ₂Cl ₂Diluted reaction mixture, and with saturated NH ₄The Cl solution washing.Make organic substance with anhydrous Na ₂SO ₄Drying concentrates then.By the column chromatography purifying, obtain aldehyde (237.1mg, 44%).HPLC-MS t _R=2.15 minutes (UV ₂₅₄Nm).To the Mass Calculation value 454.1 of M+, measured value LC/MS m/z 455.1 (M+H).

Step e: (94mg, 0.21mmol) (58mg, (144 μ L 0.828mmol), then are NaBH (OAc) 0.41mmol) to add DIEA in the mixture in DCE (10mL) with 4-fluorine piperidine hydrochlorate to aldehyde ₃(139mg, 0.62mmol).Reaction mixture at room temperature stirred spend the night, then with CH ₂Cl ₂Dilution, and with saturated NaHCO ₃Solution washing.Make organic substance with anhydrous Na ₂SO ₄Drying then concentrates.This crude product is used in next step, need not purifying.HPLC-MS t _R=1.57 minutes (UV ₂₅₄Nm).To the Mass Calculation value 541.2 of M+, measured value LC/MS m/z 542.2 (M+H).

Step F: under 0 ℃, the 4N HCl (5mL) in the dioxane is added in the rough amine.Mixture is at room temperature stirred, till LCMS shows that reaction has been finished.Concentrate, and, obtain title compound by preparation type LC purifying.HPLC-MS t _R=0.89 minute (UV ₂₅₄Nm).To the Mass Calculation value 411.1 of M+, measured value LC/MS m/z 412.1 (M+H).

Embodiment 87

Basically by same program, can be made into title compound as embodiment 86.HPLC-MSt _R=0.97 minute (UV ₂₅₄Nm).To the Mass Calculation value 429.1 of M+, measured value LC/MS m/z430.1 (M+H).

Embodiment 88

Basically by same program, can be made into title compound as embodiment 86.HPLC-MSt _R=0.99 minute (UV ₂₅₄Nm).To the Mass Calculation value 443.1 of M+, measured value LC/MS m/z444.1 (M+H).

Embodiment 89

Part A: make the 6-bromine-based compound (4562mg, 10.39mmol), PdCl ₂Dppf (424.3mg, 0.519mmol), CuI (296.9mg, 1.56mmol) and tributyl (1-vinyl ethyl ether base) tin (5617 μ L are 16.627mmol) at CH ₃Mixture among the CN (100mL) refluxes, till LCMS shows that reaction has been finished.Add 1N HCl (15mL), and mixture is stirred, till the LCMS demonstration changes into ketone.With the EtOAc diluted reaction mixture, with saturated NH ₄The Cl washing is with Na ₂SO ₄Drying, reconcentration.Purifying obtains ketone (3200mg, 76%).HPLC-MS t _R=2.32 minutes (UV ₂₅₄Nm).To the Mass Calculation value 403.1 of M+, measured value LC/MS m/z 404.2 (M+H).

Part B: under 0 ℃, (2745 μ L 14.89mmol) dropwise are added into CH with two (2-methoxy ethyl) amino sulfur trifluorides ₂Cl ₂The ketone that derives from part A (1mL) (600mg, 1.489mmol) in.Mixture was at room temperature stirred for 1 week, dropwise be added into saturated NaHCO then carefully ₃In the solution.With CH ₂Cl ₂The extraction mixture, and make organic layer with Na ₂SO ₄Drying, reconcentration.Purifying obtains two-fluorine cpd.HPLC-MS t _R=2.52 minutes (UV ₂₅₄Nm).To the Mass Calculation value 425.1 of M+, measured value LC/MS m/z 426.2 (M+H).

Portion C: (1515.7mg, (1307mg is 3.07mmol) at CH 6.76mmol) to be added into the product of part B with m-CPBA ₂Cl ₂In the solution (31mL).After at room temperature stirring 2 hours, with the EtOAc diluted reaction mixture, with saturated NaHCO ₃Washing is with Na ₂SO ₄Drying, reconcentration.Directly use sulfone (5-A), need not to be further purified.HPLC-MS t _R=2.17 minutes (UV ₂₅₄Nm).To the Mass Calculation value 457.1 of M+, measured value LC/MS m/z 458.0 (M+H).

Part D: at room temperature, (400mg, 2.53mmol) ((60% dispersion liquid in oil, 4.64mmol 186mg) handle with NaH for 964mg, the 2.11mmol) solution in DMF (13mL) with the sulfone that derives from portion C with aminoisothiazoles.Mixture is stirred, till LCMS shows that reaction has been finished.With the EtOAc diluted reaction mixture, with saturated NH ₄The Cl washing is with Na ₂SO ₄Drying, reconcentration.Purifying obtains substitution product (438.5mg, 39%).HPLC-MSt _R=2.22 minutes (UV ₂₅₄Nm).To the Mass Calculation value 535.1 of M+, measured value LC/MS m/z536.1 (M+H).

Part E: (406.5mg 0.759mmol) adds LiBHEt in the solution in THF (39mL) to ester ₃(3.79mL, the 1M solution in THF).Reactant was at room temperature stirred 30 minutes.By adding saturated NH ₄The Cl aqueous solution (15mL) makes its cancellation.Mixture is passed through 30mL CH ₂Cl ₂Extraction.Organic substance is concentrated, and crude alcohol is used in next step, need not to be further purified.HPLC-MS t _R=1.99 minutes (UV ₂₅₄Nm).To the Mass Calculation value 507.1 of M+, measured value LC/MS m/z 508.1 (M+H).

Part F: in the solution (40mL) of the crude alcohol that derives from part E in THF, add triethylamine (365 μ L, 2.62mmol) with methylsulfonyl chloride (173 μ L, 2.23mmol).Reactant was at room temperature stirred 30 minutes.Make its cancellation by adding MeOH.Solution is passed through 30mL CH ₂Cl ₂Dilution is with the 2N HCl aqueous solution, water and the salt solution continuous washing of 15mL.Move down in vacuum and to desolventize, obtain rough methane sulfonates, it is used in during next changes, need not to be further purified.HPLC-MSt _R=2.35 minutes (UV ₂₅₄Nm).To the Mass Calculation value 585.1 of M+, measured value LC/MS m/z586.1 (M+H).

Part G: with crude compound (30mg, 0.051mmol), the 3-methyl piperidine (24 μ L, 0.205mmol), EtN (iPr) ₂(54 μ L, 0.307mmol) and the mixture of NaI (1mg) in THF (2mL), 80 ℃ of heating 1 hour 10 minutes again down.Mixture is at room temperature cooled off, then concentrate.Under 0 ℃, the 4N HCl (3mL) in the dioxane is added in the rough substitution product.Mixture is at room temperature stirred, till LCMS shows that reaction has been finished.Concentrate and purifying acquisition compound 5-1.HPLC-MS t _R=1.27 minutes (UV ₂₅₄Nm).To the Mass Calculation value 458.1 of M+, measured value LC/MS m/z 459.1 (M+H).

Basically by the same program shown in the embodiment 89, the compound that can be made in the table 19 to be enumerated.

Table 19

Embodiment 90

Steps A: to methane sulfonates (1.1g, 1.65mmol) in the solution in DMSO (20mL), at room temperature add NaI (280mg, 1.88mmol) with NaCN (300mg, 6.12mmol).Mixture was stirred 1 hour down at 60 ℃.It is diluted with 200mL EtOAc, and wash with water (200mLx2).Move down in vacuum and to desolventize.Make resistates pass through column chromatography purifying (SiO ₂, the 60%EtOAc/ hexane), obtain the 980mg title compound. ¹H?NMR(400MHz，CDCl ₃)δ7.90(s，1H)，7.82(s，1H)，7.63(s，1H)，7.58(s，1H)，7.20(s，1H)，6.61(brs，2H)，5.56(s，2H)，3.88(s，2H)，3.75(t，2H)，3.65(t，2H)，2.53(s，3H)，0.95(m，4H)，0.02(s，9H)，-0.07(s，9H)。

Step B: (530mg is 0.889mmol) at 30mL CH to make compound from steps A ₂Cl ₂In solution be cooled to 0 ℃.(1M is at CH to wherein slowly adding DIBAL-H solution ₂Cl ₂In, 3.56mL, 3.56mmol).Reactant was stirred 20 minutes down at 0 ℃.Make its cancellation with 1mL MeOH, and formed solution was at room temperature stirred 2 hours with the saturated Luo Seer salts solution of 50mL.Separate organic layer, move down in vacuum and desolventize.Make resistates pass through column chromatography purifying (SiO ₂, 10%7N NH ₃At MeOH/CH ₂Cl ₂In), obtain the 450mg title compound. ¹HNMR(400MHz，CDCl ₃)δ7.90(s，1H)，7.83(s，1H)，7.63(s，1H)，7.58(s，1H)，7.05(s，1H)，6.65(brs，2H)，5.55(s，2H)，3.75(t，2H)，3.65(t，2H)，3.16(t，2H)，2.95(t，2H)，2.52(s，3H)，0.95(m，4H)，0.02(s，9H)，-0.08(s，9H)。

Step C: (400mg, 0.667mmol) (400mg, the 4.88mmol) solution in 20mL AcOH stir down at 60 ℃ with NaOAc will to derive from the compound of step B.To wherein slowly add nitrite tert-butyl (1.40mL, 11.8mmol).Reactant was stirred 20 minutes down at 60 ℃.Make it be cooled to room temperature, and add 20mL CH ₂Cl ₂Leach solid, under vacuum, remove the solvent in the filtrate.With resistates with 100mL CH ₂Cl ₂Dilution, and with the saturated NaHCO of 50mL ₃Solution washing.Concentrate organic moiety.Resistates is dissolved among the 10mL MeOH.In this solution, add the solution of NaOH (200mg) in 1mL water.After at room temperature stirring 30 minutes, with it with 100mL CH ₂Cl ₂Dilution is with the water washing of 100mL salt.Move down in vacuum and to desolventize.Make resistates pass through column chromatography purifying (SiO ₂, the 75%EtOAc/ hexane), obtain the 240mg title compound. ¹H?NMR(400MHz，CDCl ₃)δ7.90(s，1H)，7.81(s，1H)，7.63(s，1H)，7.58(s，1H)，7.05(s，1H)，6.65(brs，2H)，5.57(s，2H)，4.03(t，2H)，3.75(t，2H)，3.65(t，2H)，3.01(t，2H)，2.52(s，3H)，0.95(m，4H)，0.02(s，9H)，-0.10(s，9H)。

Embodiment 91

Steps A: (200mg 0.333mol) adds NEt in the solution in 10mL THF to embodiment 90 ₃(84mg, 0.830mmol), then for methylsulfonyl chloride (76.4mg, 0.667mmol).Reactant was at room temperature stirred 20 minutes.Make its cancellation by adding 10mL water, and with 50mLCH ₂Cl ₂Dilution.With the 0.5N HCl solution washing of mixture with 20mL.Make organic substance with anhydrous Na ₂SO ₄Dry.Move down in vacuum and to desolventize.Make resistates pass through column chromatography purifying (SiO ₂, the 70%EtOAc/ hexane), obtain the 180mg title compound.

Step B: will derive from steps A methane sulfonates (42mg, 0.062mmol), thiomorpholine (16mg, 0.16mmol), K ₂CO ₃(8.5mg 0.062mmol) and the mixture of micro-NaI in 1.5mLTHF, stirred 24 hours down at 80 ℃.Make it be cooled to room temperature.Move down in vacuum and to desolventize.Make resistates pass through column chromatography purifying (SiO ₂, 5%7N NH ₃At MeOH/CH ₂Cl ₂In), obtain the 37mg title compound. ¹H?NMR(400MHz，CDCl ₃)δ7.88(s，1H)，7.81(s，1H)，7.64(s，1H)，7.57(s，1H)，7.05(s，1H)，6.64(brs，2H)，5.55(s，2H)，3.75(t，2H)，3.65(t，2H)，2.64-3.08(m，8H)，2.52(s，3H)，0.95(m，4H)，0.02(s，9H)，-0.10(s，9H)。

Step C: (37mg 0.054mmol) adds the 4NHCl of 0.5mL in dioxane solution in 80 ℃ of solution that stir down in 2mL THF/MeOH (1: 1) to the product that derives from step B.Reactant was stirred 30 minutes down at 80 ℃.Make it be cooled to room temperature, and with 2mL THF and the dilution of 1mL ether.By solid collected by filtration, with the ether washing, obtain the 26mg title compound again, be its HCl salt form.HPLC-MS t _R=2.21 minutes (UV ₂₅₄Nm).To formula C ₁₉H ₂₀N ₈The Mass Calculation value 426.1 of OS; Measured value MH ⁺(LCMS) 427.2 (m/z).

Basically by the same program described in the embodiment 91, only in step B, replace thiomorpholine, make the compound shown in table 20 the 2nd hurdle with other each aliphatic amine.

Table 20

Embodiment 92

Steps A: (170mg is 0.512mmol) at 4mL CH to carbon tetrabromide ₂Cl ₂In in 0 ℃ of solution that stirs down, add PPh ₃(267mg, 1.02mmol).(200mg in the time of 0.341mmol), stirs reactant 15 minutes down at 0 ℃ when adding aldehyde.With formed solution 0 ℃ of following restir 15 minutes.With the saturated NaHCO of 10mL ₃The aqueous solution makes its cancellation.By 20mL CH ₂Cl ₂The extraction mixture.Water is passed through CH ₂Cl ₂(10mLx2) further extraction.The organic substance of merging is concentrated, be further purified (SiO by column chromatography ₂, the 50%EtOAc/ hexane), obtain the 150mg title compound.

Step B: (40mg, 0.054mmol) (30mg, 0.43mmol) solution of the stirring in 0.6mL DMSO and 0.15mL water is 100 ℃ of down stirrings 3 hours with tetramethyleneimine will to derive from the compound of steps A.Make it be cooled to room temperature, and with 15mL CH ₂Cl ₂Dilution.With content with water, saturated NaHCO ₃The aqueous solution and salt solution continuous washing.Organic substance is concentrated, by column chromatography purifying (SiO ₂, 3.5%7N NH ₃At MeOH/CH ₂Cl ₂In), obtain the 20mg title compound. ¹H?NMR(400MHz，CDCl ₃)δ7.88(s，1H)，7.81(s，1H)，7.64(s，1H)，7.57(s，1H)，7.18(s，1H)，6.62(brs，2H)，5.55(s，2H)，3.90(s，2H)，3.75(t，2H)，3.67(t，2H)，3.45-3.62(m，4H)，2.52(s，3H)，1.35-1.63(m，6H)，0.95(m，4H)，0.02(s，9H)，-0.08(s，9H)。

Step C: (20mg, the 0.029mmol) solution in 1mL THF and 2mL TFA stirred 2 hours down at 60 ℃ will to derive from the compound of part B.Move down in vacuum and to desolventize.Resistates is dissolved among the 2mL THF.In the solution that stirs, add the 1M HCl of 1mL in ether.By solid collected by filtration, and, obtain the 10mg title compound, be its HCl salt form with the ether washing.HPLC-MS t _R=2.55 minutes (UV ₂₅₄Nm).To formula C ₁₉H ₂₀N ₈The Mass Calculation value 408.2 of OS; Measured value MH ⁺(LCMS) 409.2 (m/z).

Basically by the same program described in the embodiment 92, only in step B, replace tetramethyleneimine, make the compound shown in table 21 the 2nd hurdle with other each aliphatic amine.

Table 21

Embodiment 93

Steps A: to methane sulfonates (560mg, 0.841mmol) add in the solution in 16mL acetone LiBr (730mg, 8.41mmol).Mixture was at room temperature stirred 1.5 hours.With it with 100mL CH ₂Cl ₂Dilute, and wash with salt solution (100mL).Move down in vacuum and to desolventize.Make resistates pass through column chromatography purifying (SiO ₂, the 40%EtOAc/ hexane), obtain the 506mg title compound.δ7.88(s，1H)，7.81(s，1H)，7.65(s，1H)，7.58(s，1H)，7.30(s，1H)，6.70(brs，2H)，5.57(s，2H)，4.55(s，2H)，3.78(t，2H)，3.68(t，2H)，2.56(s，3H)，0.95(m，4H)，0.02(s，9H)，-0.08(s，9H)。

Step B: (40mg, (45mg is 0.12mmol) with Pd (PPh 0.061mmol) to add 2-three-normal-butyl stannane yl pyridines in the solution in 1.5mL THF to the compound that derives from steps A ₃) ₄(17mg, 0.015mmol).Reactant in the little glass bottle of sealing, was stirred 16 hours down at 80 ℃.Move down in vacuum and to desolventize.Make resistates pass through column chromatography purifying (SiO ₂, 3%7N NH ₃At MeOH/CH ₂Cl ₂In), obtain 32mg by the rough title compound of triphenyl phosphine oxide contaminant.This material is used in step C, need not to be further purified.

Step C: under 80 ℃, the product of step B is dissolved among the 2mL MeOH/THF (1: 1).In this solution, add the 4N HCl of 0.5mL in dioxane.Reactant was stirred 30 minutes down at 80 ℃.Make it be cooled to room temperature, and dilute with 1mL THF.By solid collected by filtration, with THF and ether washing, obtain the 15mg title compound again, be its HCl salt form.δ 8.8 (d, 1H), 8.86 (t, 1H), 8.10 (s, 3H), 7.92-8.08 (m, 3H), 7.22 (s, 1H), 4.60 (s, 2H), 2.58 (s, 3H) .HPLC-MS t _R=2.00 minutes (UV ₂₅₄Nm).To formula C ₁₉H ₁₆N ₈The Mass Calculation value 388.1 of S; Measured value MH ⁺(LCMS) 389.2 (m/z).

Basically by the same program described in the embodiment 93, only in step B,, make the compound shown in table 22 the 2nd hurdle with other each stannane base reagent displacement 2-three-normal-butyl stannane yl pyridines.

Table 22

Embodiment 94

Steps A: in the mixture of 10mL THF/DMF (1: 1), add NaH (39.3mg, 1.64mmol).Make it be cooled to-10 ℃, slowly add iodate trimethylsulfonium (334mg, 1.64mmol) solution in 5mL DMSO then.In formed mixture, add aldehyde.Reactant was at room temperature stirred 40 minutes.Make its cancellation with frozen water, and with 50mL CH ₂Cl ₂Dilution.With mixture Yi Shui and salt water washing.Move down in vacuum and to desolventize.Make resistates pass through column chromatography purifying (SiO ₂, the 40%EtOAc/ hexane), obtain the 390mg title compound.δ7.90(s，1H)，7.82(s，1H)，7.67(s，1H)，7.59(s，1H)，7.10(s，1H)，6.80(brd，1H)，6.56(brd，1H)，5.57(s，2H)，4.02-4.10(m，1H)，3.78(t，2H)，3.69(t，2H)，3.07-3.25(m，2H)，2.58(s，3H)，0.95(m，4H)，0.02(s，9H)，-0.08(s，9H)。

Step B: (270mg, 0.450mmol) (100mg 1.43mmol) handles the solution in 4mL DMF with methyl mercaptan sodium will to derive from the compound of steps A.Reactant was at room temperature stirred 30 minutes.It is diluted with 15mL water.With EtOAc (20mLx3) extraction mixture.The organic substance that merges is washed with salt solution (20mL), then concentrate.Make resistates pass through column chromatography purifying (SiO ₂, the 70%EtOAc/ hexane), obtain the 220mg title compound.δ7.90(s，1H)，7.82(s，1H)，7.65(s，1H)，7.58(s，1H)，7.21(s，1H)，6.76(brd，1H)，6.56(brd，1H)，5.57(s，2H)，4.94(m，1H)，3.40-3.80(m，5H)，2.80-3.15(m，2H)，2.58(s，3H)，2.12(s，3H)，0.95(m，4H)，0.02(s，9H)，-0.10(s，9H)。

Step C: (30mg 0.046mol) adds NEt in the solution in 1mL THF to the compound that derives from step B ₃(14mg, 0.14mmol), then for methylsulfonyl chloride (16mg, 0.14mmol).Reactant was at room temperature stirred 15 minutes.Make its cancellation by adding 2mL water, and with 15mL CH ₂Cl ₂Dilution.With the 0.2N HCl solution washing of mixture with 10mL.Make organic substance with anhydrous Na ₂SO ₄Drying concentrates then.(10mg, 0.071mmol) (13mg 0.15mmol) handles in 1mL THF with piperidines with NaI with resistates.Formed mixture was stirred 12 hours down at 80 ℃.With it with 15mL CH ₂Cl ₂Dilution, and with the saturated NaHCO of 15mL ₃Solution washing.Move down in vacuum and to desolventize, make resistates pass through column chromatography purifying (SiO ₂, 3%7NNH ₃At MeOH/CH ₂Cl ₂In), obtain the 12mg title compound.

Step D: (12mg 0.017mmol) adds the 4N HCl of 0.5mL in dioxane in the solution in 1mLTHF/MeOH (1: 1) to the compound that derives from step C.Reactant was stirred 1 hour down at 80 ℃.Make it be cooled to room temperature, and dilute with 10mL ether.By solid collected by filtration, with the ether washing, obtain the 8mg title compound, be its HCl salt form.HPLC-MSt _R=2.88 minutes (UV ₂₅₄Nm).To formula C ₂₁H ₂₆N ₈S ₂Mass Calculation value 454.2; Measured value MH ⁺(LCMS) 455.3 (m/z).

Basically by the same program described in the embodiment 94, only in step B, replace piperidines, make the compound shown in table 23 the 2nd hurdle with other each aliphatic amine.

Table 23

Embodiment 95

Basically by the same program described in the embodiment 94, only in steps A,, in step B, adopt each aliphatic amine, make the compound shown in table 24 the 2nd hurdle with the displacement piperidines with benzenethiol sodium displacement methyl mercaptan sodium.

Table 24

Embodiment 96

At room temperature, (281mg, 2.99mmol) (287mg 2.99mmol) handled 5 minutes the solution of the stirring in 5mL DMF with sodium tert-butoxide with dimethyl sulfone.Add aldehyde then.Reactant was at room temperature stirred 15 minutes.With saturated NH ₄The Cl aqueous solution (5mL) makes its cancellation.With 50mL water diluted mixture thing, and, then extract with 25mL EtOAc with 50mL EtOAc/ hexane (1: 1).The organic phase that merges with the salt water washing, is concentrated then.Make resistates pass through column chromatography purifying (SiO ₂, the 50%EtOAc/ hexane), obtain the 270mg title compound.δ7.90(s，1H)，7.82(s，1H)，7.68(s，1H)，7.60(s，1H)，7.20(s，1H)，6.67(brs，2H)，5.55(s，2H)，5.34-5.47(brs，1H)，3.90-3.98(brs，1H)，3.78(t，2H)，3.68(t，2H)，3.10(s，3H)，2.58(s，3H)，0.95(m，4H)，0.02(s，9H)，-0.10(s，9H)。

Basically by the same program described in embodiment 96 step B and the step C, make the compound shown in table 25 the 2nd hurdle.

Table 25

Embodiment 97

Compound shown in table 24 the 2nd hurdle is an above reaction process of basis, and adopts following general procedure to make.

Steps A: to compound alcohol (1.00g, 1.70mmol) add in the solution of the stirring in 20mL THF Dess-Martin cross iodine alkane (1.84g, 4.26mmol) and minor amount of water.Reactant was at room temperature stirred 40 minutes.With it with 200mL CH ₂Cl ₂Dilution, and Yi Shui and salt water washing.Make organic substance with anhydrous Na ₂SO ₄Dry.Move down in vacuum and to desolventize.Make resistates pass through column chromatography purifying (SiO ₂, the 40%EtOAc/ hexane), obtain the 250mg title compound.

Step B: to the compound that derives from steps A (0.05mmol) at 1mL CH ₂Cl ₂Add each amine (5 equivalent) and micro-trifluoroacetic acid in the solution among/the MeOH (1: 1).When adding NaBH ₄When (10 equivalent), mixture was at room temperature stirred 30 minutes.Continue again to stir 10 minutes.With saturated NH ₄The Cl aqueous solution makes the reaction cancellation.With CH ₂Cl ₂The extraction mixture.Organic substance is concentrated, and make resistates pass through column chromatography purifying (SiO ₂, 5%7N NH ₃, at MeOH/CH ₂Cl ₂In), obtain title compound.

Step C: in the solution of the compound that derives from step B (0.05mmol) in 1mL THF/MeOH (1: 1), add the 4N HCl of 1mL in dioxane.Reactant was stirred 30 minutes down at 80 ℃.Make it be cooled to room temperature, and dilute with 10mL ether.By solid collected by filtration, obtain compound 97-1 and 97-2 respectively.

Table 26

Embodiment 98

Part A: at room temperature, to isothiazole-aldehyde (534mg; 0.9mmol) add methylmagnesium-bromide (3M in the solution in anhydrous THF (9mL); 1.8mL).After stirring 20 minutes, with the saturated NH of 5mL ₄The Cl aqueous solution makes the reaction mixture cancellation, and with CH ₂Cl ₂Dilution.Yi Shui and salt water washing organic layer.With water layer with CH ₂Cl ₂Counterextraction.The organic layer that makes merging is with dried over sodium sulfate, and reconcentration obtains crude product.Through fast silica gel chromatogram method (EtOAc: CH ₂Cl ₂=2: 1), the methyl alcohol (carbinol) that acquisition needs is white solid (460mg; 84%), and unreacted aldehyde (50mg) arranged. ¹H-NMR(CDCl ₃)：7.9(s，1H)；7.8(s，1H)；7.65(s，1H)；7.55(s，1H)；7.1(s，1H)；6.75-6.65(br-dd，2H)；5.55(s，2H)；4.95(t，J＝3Hz，1H)；3.8(t，J＝6Hz，2H)；3.7(t，J＝6Hz，2H)；2.55(s，3H)；1.6(d，J＝3Hz，3H)；1.0(m，2H)；0.05(s，9H)；-0.05(s，9H)。

Part B: at room temperature, with triethylamine (136mg; 1.35mmol) and methylsulfonyl chloride (88mg; 0.77mmol) be added into the methyl alcohol (232mg that derives from part A; 0.39mmol) in the solution in 12mL THF.After 10 minutes, make the reaction cancellation with water, and with CH ₂Cl ₂Dilution.With organic layer Yi Shui and salt water washing, with Na ₂SO ₄Drying, reconcentration obtains crude product.With CH ₂Cl ₂: EtOAc (2: 1) is from the quick quick wash-out of silicagel column, and the methane sulfonates that acquisition needs is white solid (268mg; 100%). ¹H-NMR(CDCl ₃)：7.9(s，1H)；7.8(s，1H)；7.65(s，1H)；7.55(s，1H)；7.3(s，1H)；6.7(br-s，2H)；5.85(q，J＝4Hz，1H)；5.55(s，2H)；3.8(t，J＝6Hz，2H)；3.7(t，J＝6Hz，2H)；2.95(s，3H)；2.6(s，3H)；1.85(d，J＝4Hz，3H)；1.0(m，2H)；0.05(s，9H)；-0.05(s，9H)。

Portion C: with methane sulfonates (40mg; 0.06mmol) solution in the anhydrous THF of 2mL, with hexamethylene imine (15mg; 0.15mmol) add that the NaI of catalytic amount handles, and with mixture under refluxing, heating is (80 ℃ in oil bath; 20 hours).Make reaction mixture be cooled to room temperature, with water and CH ₂Cl ₂Dilution.With organic layer Yi Shui, salt water washing, again with Na ₂SO ₄Dry.Concentrate in a vacuum, obtain crude product.Purifying is to carry out on the silicagel column fast, making product to contain the CH of the 7N-ammonia of 2-4% in methyl alcohol ₂Cl ₂Wash-out.The amine product that the two-SEM that obtains to need protects is colorless film (31mg; 75%). ¹H-NMR(CDCl ₃)：7.9(s，1H)；7.8(s，1H)；7.65(s，1H)；7.55(s，1H)；7.3(s，1H)；6.6(br-s，2H)；5.55(s，2H)；4.0(br-s，1H)；3.8(t，J＝6Hz，2H)；3.7(t，J＝6Hz，2H)；2.8(br-s，4H)；2.6(s，3H)；1.75-1.5(m，11H)；1.0(m，2H)；0.05(s，9H)；-0.05(s，9H)。

Part D: to the amine (31mg of the above-mentioned two-SEM protection that derives from portion C; 0.045mmol) at 0.2mL THF and 0.2mL CH ₃Add the 4N-HCl (0.2mL) in the dioxane in the solution among the OH.In oil bath, 80 ℃ of following heating 30 minutes, then, make it be cooled to room temperature in formed mixture.THF (2mL) is added in the reaction mixture, and collects settled product by filtering.Filter cake is with THF and ether washing, dry under vacuum, to obtain title product, be white solid (23mg).

In said procedure, utilize suitable Grignard reagent in first step and the suitable amine in the 3rd step, all purpose compounds that listed in preparation and the evaluation table 1.

Table 27

Embodiment 99

Substrate (500mg) is suspended among the t-BuOH (30mL), and at room temperature adds Et continuously ₃N (0.45mL) and DPPA (0.73mL).Then, with mixture 85 ℃ of following heated overnight.Make reaction mixture be cooled to room temperature, the vapourisation under reduced pressure solvent.Resistates is dissolved in the ethyl acetate (50mL), and adds water (50mL).Two-phase mixture was stirred 15 minutes.Follow separates two, with ethyl acetate (2x50mL) aqueous layer extracted.The organic layer that merges is washed dry (Na with salt solution (50mL) ₂SO ₄), filtering, vapourisation under reduced pressure obtains crude product, makes it pass through column chromatography purifying (SiO ₂).HPLC-MS t _R=1.70. is to C ₁₁H ₁₅NO ₃The Mass Calculation value 241.08 of S; Measured value MH ⁺(LCMS) 242.2 (m/z) (UV ₂₅₄Nm).

Embodiment 100

Part A: make diacid (3g) be suspended in CH ₂Cl ₂(50mL), and at room temperature add N continuously, O-dimethyl hydroxyl amine hydrochlorate (1.69g), HATU (6.6g) and diisopropylethylamine (12.12mL).The reaction mixture stirring is spent the night, and make the reaction cancellation by adding water (100mL).Separate two liquid layers.Make water layer be acidified to pH4.0, and with CHCl ₃(5x100mL) extraction.Merge organic layer, dry (Na ₂SO ₄), filtering, vapourisation under reduced pressure obtains product.HPLC-MSt _R=1.14. is to C ₈H ₉NO ₄The Mass Calculation value 215.03 of S; Measured value MH ⁺(LCMS) 216.1 (m/z) (UV ₂₅₄Nm).

Part B: feasible substrate (3.2g) from part A is suspended among the t-BuOH (100mL), and at room temperature adds Et continuously ₃N (2.27mL) and DPPA (3.64mL).Then, with mixture 85 ℃ of following heated overnight.Make reaction mixture be cooled to room temperature, and the vapourisation under reduced pressure solvent.Resistates is dissolved in the ethyl acetate (100mL), and adds water (100mL).Two-phase mixture was stirred 15 minutes.Follow separates two, with ethyl acetate (2x100mL) aqueous layer extracted.The organic layer that merges is washed dry (Na with salt solution (150mL) ₂SO ₄), filtering, vapourisation under reduced pressure obtains crude product, makes it pass through column chromatography purifying (SiO ₂).HPLC-MS t _R=1.55. is to C ₁₂H ₁₈N ₂O ₄The Mass Calculation value 286.1 of S; Measured value MH ⁺(LCMS) 287.2 (m/z) (UV ₂₅₄Nm).

Portion C: feasible substrate (191mg) from part B is dissolved in THF/Et ₂Among the O (3mL/6mL), and be cooled to 0 ℃.Dropwise add methylmagnesium-bromide (0.83mL, 2.0M solution) then.Make reaction mixture be warmed to room temperature, and stirred 12 hours, make the reaction cancellation by adding saturated ammonium chloride (10mL).Separate two liquid layers, and water layer is extracted with ethyl acetate (10mL).With the organic layer that salt solution (30mL) washing merges, dry (Na ₂SO ₄), filtering, vapourisation under reduced pressure obtains crude product, makes it pass through column chromatography purifying (SiO ₂).

Part D: feasible substrate (10mg) from portion C is dissolved in CH ₂Cl ₂In 30%TFA (2mL) in, and mixture stirred 30 minutes.The vapourisation under reduced pressure solvent makes resistates dry in a vacuum then.This crude product is used in the next step, need not to be further purified.

Part E: under argon gas, sulfone (574.19mg) and amine trifluoroacetate (514mg) are dissolved among the DMF (15mL), and handle with NaH (432mg, 60% dispersion liquid in oil).LCMS show initial substance change into product fully after, (15mL) makes the reaction mixture cancellation with saturated ammonium chloride solution.Add ethyl acetate (25mL) then.Separate two liquid layers, and with ethyl acetate (25mL) aqueous layer extracted.The organic layer that merges is washed dry (Na with salt solution (30mL) ₂SO ₄), filtering, vapourisation under reduced pressure obtains crude product, makes it pass through column chromatography purifying (SiO ₂).HPLC-MSt _R=2.31. is to C ₂₂H ₂₈N ₆O ₂The Mass Calculation value 468.2 of SSi; Measured value MH ⁺(LCMS) 469.1 (m/z) (UV ₂₅₄Nm).

Part F: make ketone (25mg) be suspended in Ti (O-i-Pr) ₄(1mL), and under argon gas, handle with piperidines (0.2mL).Mixture at room temperature stirred spend the night.Add methyl alcohol (2mL) then, then be NaBH ₄(10mg).With reaction mixture restir 30 minutes, and make the reaction cancellation by adding the 2M NaOH aqueous solution (5mL).With its filtration, and ethyl acetate (5mL) is added in the filtrate.Separate two liquid layers, with ethyl acetate (5mL) aqueous layer extracted.Make the organic layer drying (Na of merging ₂SO ₄), filtering, vapourisation under reduced pressure obtains crude product, and it is taken to next step, need not to be further purified.

Part G: substrate is dissolved in the 4N HCl in the dioxane, and stirred 30 minutes.What LCMS showed initial substance changes into product fully.The vapourisation under reduced pressure solvent makes crude material pass through the reversed-phase HPLC purifying then.HPLC-MS t _R=1.28. is to C ₂₁H ₂₅N ₇The Mass Calculation value 407.2 of S; Measured value (M-84) ⁺(LCMS) 323 (m/z) (UV ₂₅₄Nm).

Compound in the table 28 is made according to similar program.

Table 28

Embodiment 101

Steps A: to the 2-ethoxy ethyl amine (2.0g, 22.4mmol) in the solution in ether (40mL), under 0 ℃, dropwise add trifluoroacetic anhydride (4.7g, 22.4mmol).Reactant was at room temperature stirred 1 hour.(10g) is added in the reaction soln with salt of wormwood.Reactant was at room temperature stirred 1 hour.Through the diatomite filtration mixture, and make organic filtrate concentrating, obtain 1.5g (36% productive rate) title compound.

Step B: (1.5g is 8.1mmol) at Et will to derive from (trifluoromethyl) ethanamide of steps A ₂Solution among the O (20mL) is added into Et is housed ₂(0.92g is in flask 24.3mmol) for lithium aluminium hydride among the O (20mL).Reactant was at room temperature stirred 30 minutes under refluxing 12 hours then.Make reactant be cooled to room temperature, and make the reaction cancellation, stop up to foaming with MeOH.With reactant with Et ₂O (30mL) dilution is filtered through Celite pad.Make filtrate pass through distillation and concentrate, obtain 0.5g (36% productive rate) title compound, be colourless liquid.Use this amine to need not to be further purified.

Embodiment 102

Steps A: to the 2-ethoxy ethyl amine (1.0g, 11.2mmol) in the solution in methylene dichloride (50mL), 0 ℃ add down pyridine (2.2g, 28.1mmol).Then, (2.3g 13.5mmol) slowly is added in the reaction soln with the difluoroacetic acid acid anhydride.With reactant 0 ℃ of following restir 15 minutes, then at room temperature 2.5 hours.With methylene dichloride (50mL) and H ₂O (20mL) diluting reaction thing.With reactant in succession with 1N HCl (aqueous solution); Saturated NaHCO ₃(aqueous solution); The salt water washing.Make organic phase with NaSO ₄Drying concentrates in a vacuum, obtains 1.03g (55% productive rate) (difluoromethyl) ethanamide, is colourless liquid.

Step B: under 0 ℃, simultaneously at N ₂Under the atmosphere, (1.04g is 6.20mmol) at Et with (difluoromethyl) ethanamide of deriving from steps A ₂Solution among the O (21mL) is added into Et is housed ₂(0.47g is in flask 12.39mmol) for lithium aluminium hydride among the O (25mL).With reactant at N ₂Stirred 2 hours under atmosphere and the room temperature.By adding the H of 0.47mL in succession ₂O; 0.47mL 15%NaOH (aqueous solution) solution; 1.4mL H ₂O makes the reaction cancellation.Reactant was at room temperature stirred 15 minutes, filter through Celite pad then.Make filtrate pass through distillation and concentrate, obtain 0.79g (83% productive rate) title compound, be colourless liquid.Use this amine to need not to be further purified.

Embodiment 103

Steps A: to 1-amino-1-pentamethylene methyl alcohol (1.0g, 8.68mmol) in the solution in methylene dichloride (35mL), 0 ℃ add down pyridine (2.4g, 30.4mmol).Then, (4.6g 21.7mmol) slowly is added in the reaction soln with trifluoroacetic anhydride.With reactant 0 ℃ of following restir 15 minutes, then at room temperature 16 hours.With reactant in succession with 1N HCl (aqueous solution); Saturated NaHCO ₃(aqueous solution); The salt water washing.Make organic phase with NaSO ₄Drying concentrates in a vacuum, obtains 1.07g (60% productive rate) title compound, is filbert liquid.Title compound directly is used in next reaction (step B), need not to be further purified.

Step B: under 0 ℃, simultaneously at N ₂Under the atmosphere, (0.64g is 3.06mmol) at Et with (trifluoromethyl) ethanamide of deriving from steps A ₂Solution among the O (10mL) is added into Et is housed ₂(0.35g is in flask 9.1mmol) for lithium aluminium hydride among the O (30mL).With reactant at N ₂Atmosphere and 0 ℃ of following stirring 30 minutes, then at room temperature 19 hours.Make reactant be cooled to room temperature, and stirred 3 days.Then, make reactant be cooled to 0 ℃, by adding the H of 0.35mL in succession ₂O; 0.35mL 15%NaOH (aqueous solution) solution; 1.05mL H ₂O makes the reaction cancellation.Reactant was at room temperature stirred 20 minutes, then filter through Celite pad.With filter cake with Et ₂The O washing concentrates in a vacuum, obtains 0.39g (65% productive rate) title compound, is white solid.Use this amine to need not to be further purified.

Embodiment 104

Steps A: to 2-amino-2-methyl-1-propanol (1.0g, 11.2mmol) in the solution in methylene dichloride (100mL), 0 ℃ add down pyridine (3.1g, 39.6mmol).Then, (5.9g 28.1mmol) slowly is added in the reaction soln with trifluoroacetic anhydride.With reactant 0 ℃ of following restir 15 minutes, then at room temperature 16 hours.With reactant in succession with 1N HCl (aqueous solution); Saturated NaHCO ₃(aqueous solution); The salt water washing.Make organic phase with NaSO ₄Drying concentrates in a vacuum, obtains 0.79g (38% productive rate) title compound, is white solid.

Step B: under 0 ℃, simultaneously at N ₂Under the atmosphere, (0.79g is 4.29mmol) at Et with (trifluoromethyl) ethanamide of deriving from steps A ₂Solution among the O (43mL) is added into Et is housed ₂(0.49g is in flask 12.91mmol) for lithium aluminium hydride among the O (13mL).With reactant at N ₂Atmosphere and 0 ℃ stirred 30 minutes down, under refluxing 4 hours then.Make reactant be cooled to room temperature, and stirred 3 days.Then, make reactant be cooled to 0 ℃, by adding the H of 0.49mL in succession ₂O; 0.49mL 15%NaOH (aqueous solution) solution; 1.47mL H ₂O makes the reaction cancellation.Reactant was at room temperature stirred 20 minutes, filter through Celite pad then.With Et ₂The O washing leaching cake concentrates in a vacuum, obtains 0.67g (92% productive rate) title compound, is white solid.Use this amine to need not to be further purified.

Embodiment 105

Steps A: to 2-amino-2-methyl-1-propanol (1.0g, 11.2mmol) in the solution in methylene dichloride (50mL), 0 ℃ add down pyridine (2.7g, 33.7mmol).Then, (3.9g 22.4mmol) slowly is added in the reaction soln with the difluoroacetic acid acid anhydride.With reactant 0 ℃ of following restir 15 minutes, then at room temperature 2 hours.With methylene dichloride (50mL) and H ₂O (20mL) diluting reaction thing.With reactant in succession with 1N HCl (aqueous solution); Saturated NaHCO ₃(aqueous solution); The salt water washing.Make organic phase with NaSO ₄Drying concentrates in a vacuum, obtains 2.04g (74% productive rate) title compound, is colourless liquid.

Step B: under 0 ℃, simultaneously at N ₂Under the atmosphere, (2.04g is 8.31mmol) at Et with (difluoromethyl) ethanamide of deriving from steps A ₂Solution among the O (17mL) is added into Et is housed ₂(0.95g is in flask 24.92mmol) for lithium aluminium hydride among the O (50mL).With reactant at N ₂Stirred 2 hours under atmosphere and the room temperature.By adding the H of 0.95mL in succession ₂O; 0.95mL 15%NaOH (aqueous solution) solution; 2.85mL H ₂O makes the reaction cancellation.Reactant was at room temperature stirred 15 minutes, filter through Celite pad then.With Et ₂The O washing leaching cake concentrates in a vacuum, obtains 1.23g (97% productive rate) title compound, is the white needles thing.Use this amine to need not to be further purified.

Embodiment 106

Steps A: Dess-Martin is crossed iodine alkane reagent (13g; 3.1mmol) be added into isothiazole-alcohol (450mg; 1mmol) in the solution in containing the 30mL THF of 0.06mL water, and reaction mixture at room temperature stirred 45 minutes.With ether diluting reaction thing, filter, again with more polyether washing.With filtrate with saturated NaHCO ₃Solution, salt water washing, drying.Concentrate in a vacuum, obtain isothiazole aldehyde (418mg; 93%). ¹H-NMR(CDCl ₃)：10(s，1H)；7.68(s，1H)；7.65(s，1H)；7.4(s，1H)；7.3(s，1H)；6.65(s，2H)；3.7(t，J＝6Hz，2H)；2.6(s，3H)；1.95(m，1H)；1.1(q，J＝2，6Hz，2H)；1.0(t，J＝6Hz，2H)；0.8(q，J＝2，6Hz，2H)；-0.05(s，9H)。

Step B: to sodium hydride (60%, in Dormant oils; 169mg; 4.2mmol) in the mixture of 3.6mL DMSO and 3.6mL THF, be cooled in-10 ℃ the solution, dropwise add iodate trimethylsulfonium (863mg; 4.2mmol) solution in 3.6mL DMSO.Then the mode of adding with portion is added aldehyde (363mg; 0.84mmol) solution in the anhydrous THF of 5.6mL.After at room temperature stirring one hour, make the reaction mixture cancellation with frozen water.With EtOAc extraction organic product.With the water layer that merges with the ethyl acetate counterextraction.Compile all organic extract liquids, and Yi Shui, salt water washing, with Na ₂SO ₄Drying, reconcentration obtains crude product.From the main spot of quick silica gel wash-out, use the 25%EtOAc in the hexane, obtain the isothiazole epoxide (316mg that needs; 85%). ¹H-NMR(CDCl ₃)：7.7(s，1H)；7.35(s，1H)；7.05(s，1H)；6.8(d，J＝4Hz，1H)；6.5(d，J＝4Hz，1H)；4.05(t，J＝2Hz，1H)；3.7(t，J＝6Hz，2H)；3.2(t，J＝4Hz，1H)；3.05(t，J＝2Hz，1H)；2.6(s，3H)；1.95(m，1H)；1.1(q，J＝2，6Hz，2H)；0.95(t，J＝6Hz，2H)；0.8(q，J＝2，6Hz，2H)；-0.05(s，9H)。

Step C: with solution (25% weight of sodium methylate in methyl alcohol; 4.5mmol; 1mL) be added into epoxide (201mg; 0.45mmol) in the solution in 1: 1 mixture (4mL) of DMF-methyl alcohol.Formed solution was heated 3.5 hours down at 60 ℃, be cooled to room temperature then, and make the reaction cancellation with water.With EtOAc extraction organic product, Yi Shui and salt water washing organic extract liquid are again with Na ₂SO ₄Dry.Concentrate and obtain crude product.By the fast silica gel chromatogram method, use CH ₂Cl ₂With 1: 1 mixture of EtOAc, provide the methyl cellosolve (180mg that needs; 84%), is water white oil. ¹H-NMR(CDCl ₃)：7.7(s，1H)；7.35(s，1H)；7.2(s，1H)；6.7(d，J＝4Hz，1H)；6.58(d，J＝4Hz，1H)；5.0(d，J＝2Hz，1H)；3.7(m，3H)；3.5(s，3H)；2.95(d，J＝14Hz，1H)；2.6(s，3H)；1.95(m，1H)；1.05(d，J＝4Hz，2H)；0.95(t，J＝6Hz，2H)；0.8(d，J＝4Hz，2H)，-0.05(s，9H)。

Step D-F: the order of this step is carried out as described in embodiment 76, and the overall yield of going through 3 sequence of steps is 64%.HPLC-MS t _R=2.85. is to C ₂₁H ₂₇FN ₆Mass Calculation value=430.2 of OS; Measured value (M-H) ⁺(LCMS) 431.2 (m/z) (UV ₂₅₄Nm).

Detect:

Aurora body enzyme detects

Develop and a kind ofly in vitro detect, it utilizes reorganization aurora body A or aurora body B as enzyme source, and a kind of peptide based on PKA is as substrate.

Aurora body A detects

Aurora body A kinase assay is to carry out in lower protein bonded 384-orifice plate (Corning company).Whole reagent are being melted on ice.Compound is diluted to the concentration that needs in 100%DMSO.Each reactant comprises 8nM enzyme (aurora body A, Upstate catalogue #14-511), 100nMTamra-PKAtide (molecular device, 5TAMRA-GRTGRRNSICOOH), 25 μ M ATP (Roche), 1mM DTT (Pierce) and kinase buffer agent (10mM Tris, 10mM MgCl2,0.01%Tween 20).For each reaction, will contain 14 μ L of TAMRA-PKAtide, ATP, DTT and kinase buffer agent, with the compound merging of 1 μ L dilution.By adding the enzyme of 5 μ L dilution, kinase reaction is begun.Reaction was at room temperature carried out 2 hours.By adding 60 μ L IMAP beads (bead was at incremental (94.7% buffer reagent A:5.3% buffer reagent B) 1X buffer reagent, among the 24mM NaCl in 1: 400) reaction is stopped.Behind other 2 hours, operational analysis device AD (molecular device company) measures the fluorescence polarization.

Aurora body B detects

Aurora body A kinase assay is to carry out in lower protein bonded 384-orifice plate (Corning company).Whole reagent are being melted on ice.Compound is diluted to the concentration that needs in 100%DMSO.Each reactant comprises 26nM enzyme (aurora body B, Invitrogen catalogue #pv3970), 100nMTamra-PKAtide (molecular device, 5TAMRA-GRTGRRNSICOOH), 50 μ M ATP (Roche), 1mM DTT (Pierce) and kinase buffer agent (10mM Tris, 10mM MgCl2,0.01%Tween 20).For each reaction, will contain 14 μ L of TAMRA-PKAtide, ATP, DTT and kinase buffer agent, with the compound merging of 1 μ L dilution.By adding the enzyme of 5 μ L dilution, kinase reaction is begun.Reaction was at room temperature carried out 2 hours.By adding 60 μ L IMAP beads (bead was at incremental (94.7% buffer reagent A:5.3% buffer reagent B) 1X buffer reagent, among the 24mM NaCl in 1: 400) reaction is stopped.Behind other 2 hours, operational analysis device AD (molecular device company) measures the fluorescence polarization.

IC ₅₀ Measure

Dose-response curve is from suppressing 8 serial dilutions of compound, from the inhibition data mapping that respectively repeats to produce.Facing to the kinase activity mapping, this kinase activity is to calculate by fluorescence polarization degree to get with compound concentrations.In order to produce IC ₅₀Value then makes dose-response curve fit to standard S shape curve, and derives IC by nonlinear regression analysis ₅₀Value.

Compound exhibits aurora body A IC of the present invention ₅₀Value is that about 4nM is to about 3000nM, aurora body B IC ₅₀Value is extremely about 3000nM of about 13nM, and p-HH3IC ₅₀Value is extremely about 10 for about 1nM, 000nM.

Though the present invention is described in conjunction with above particular, many alternative, correction and other variation will be understood to those skilled in the art.All these type of alternative, correction and variation all will fall within spirit of the present invention and the scope.

Claims

1. formula I compound or its pharmacy acceptable salt, solvate, ester or prodrug:

Formula I

Wherein:

N is 1-6,

2. compound as claimed in claim 1, wherein R ²Be unsubstituted heteroaryl or the heteroaryl that replaced by alkyl.

3. compound as claimed in claim 1, wherein R ²Be the heteroaryl that is replaced by alkyl.

4. compound as claimed in claim 1, wherein R ²Be pyrazolyl.

5. compound as claimed in claim 1, wherein R ²Be the pyrazolyl that is replaced by alkyl.

6. compound as claimed in claim 1, wherein R ²Be 1-methyl-pyrazoles-4-base.

7. compound as claimed in claim 1, wherein R is H.

8. compound as claimed in claim 1, wherein R is CN.

9. compound as claimed in claim 1, wherein R is-C (O) NR ⁵R ⁶

10. compound as claimed in claim 1, wherein R is-C (O) NH ₂

11. compound as claimed in claim 1, wherein R is a heterocycloalkenyl.

12. compound as claimed in claim 1, wherein R is a tetrahydro pyridyl.

13. compound as claimed in claim 1, wherein R is 1,2,3, the 6-tetrahydro pyridyl.

14. compound as claimed in claim 1, wherein R is that the each several part group is independently selected from-OR by one or more alkyl that can be identical or different part group replacement ¹With-NR ⁵R ⁶

15. compound as claimed in claim 1, wherein R is by one or more-NR ⁵R ⁶The alkyl that replaces.

16. compound as claimed in claim 1, wherein R is quilt-NH ₂The alkyl that replaces.

17. compound as claimed in claim 1, wherein R is the alkyl that quilt-NH (methyl) replaces.

18. compound as claimed in claim 1, wherein R ³Be the heteroaryl that is replaced by heterocyclyl methyl.

19. compound as claimed in claim 1, wherein R ³Be heteroaryl-CH ₂-X, wherein X is-OR ⁵,-SOR ⁵,-NR ⁵R ⁶Or-SR ⁵R ⁵For hydrogen ,-alkyl N (alkyl) ₂, heterocyclic radical alkyl or heterocycloalkenyl alkyl; R ⁶For or R ⁵With R ⁶Can choose wantonly and be somebody's turn to do-NR ⁵R ⁶N combine, to form cyclic rings or bridge joint cyclic rings, wherein this cyclic rings or bridge joint cyclic rings can not be substituted, or be can be identical or different part group and replace by one or more, this part group be independently selected from hydroxyl, alkyl, alkoxyl group, alkoxyalkyl, hydroxyalkyl, aralkyl, aryl, assorted volution base, assorted volution thiazolinyl, assorted spiral shell aryl and-CO ₂Alkyl.

20. compound as claimed in claim 1, wherein R ³Be heteroaryl-CH ₂-X or heteroaryl-CH methyl-X, wherein X is-NR ⁵R ⁶, R ⁵For-alkyl N (alkyl) ₂, alkyl, alkoxyalkyl, hydroxyalkyl, aralkyl, heterocycloalkenyl alkyl, cycloalkyl, cycloalkylalkyl, heteroaralkyl or-alkyl SH, wherein respectively this aralkyl, heterocycloalkenyl alkyl, cycloalkyl, cycloalkylalkyl or heteroaralkyl can not be substituted, or are replaced by hydroxyalkyl, alkoxyalkyl, alkyl or hydroxyl; R ⁶For hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl or-alkyl N (alkyl) ₂Or R ⁵With R ⁶Can choose wantonly and be somebody's turn to do-NR ⁵R ⁶N combine, to form cyclic rings or bridge joint cyclic rings, wherein this cyclic rings or bridge joint cyclic rings can not be substituted, or be can be identical or different part group and replace by one or more, this part group be independently selected from hydroxyl, alkyl, alkoxyl group, alkoxyalkyl, hydroxyalkyl, aralkyl, aryl, assorted volution base, assorted volution thiazolinyl, assorted spiral shell aryl and-CO ₂Alkyl.

21. compound as claimed in claim 1, wherein R ³Be heteroaryl-CH ₂-X, wherein this heteroaryl-CH ₂The heteroaryl of-X by alkyl or-CONR ⁵R ⁶Replace, wherein X is-NR ⁵R ⁶, R ⁵Be alkyl, R ⁶Be alkyl, or R ⁵With R ⁶Choose wantonly and be somebody's turn to do-NR ⁵R ⁶N be combined together to form cyclic rings.

22. compound as claimed in claim 1, wherein R ³Be aryl-CH ₂-X, wherein this aryl-CH ₂The aryl of-X is not substituted, or is replaced by alkyl, and wherein X is a heterocyclic radical.

23. compound as claimed in claim 1, wherein R ³Be isothiazole, thiophene or pyrimidine, it is replaced by following group:

24. compound as claimed in claim 1, wherein R ³For Wherein X is selected from-NR ⁵R ⁶,-OR ⁵-SO-R ⁵And-SR ⁵,

R ⁵Be selected from hydrogen, alkyl, thiazolinyl, alkoxyalkyl ,-alkyl-S-alkyl, aminoalkyl group, aryl, heteroaryl, heterocycloalkenyl, Heterocyclylalkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical alkoxyl group ,-S-alkyl heterocyclic, heterocyclic radical, heterocycloalkenyl, alkyl N (alkyl) ₂, alkyl NH (alkyl), alkyl N (thiazolinyl) ₂,-alkyl N (alkoxyl group) ₂,-alkyl-SH and hydroxyalkyl, wherein respectively this aryl, heteroaryl, heterocycloalkenyl, Heterocyclylalkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical alkoxyl group ,-S-alkyl heterocyclic, heterocyclic radical and heterocycloalkenyl can not be substituted, or replaced by one or more part groups that are independently selected from alkyl, alkoxyalkyl and hydroxyalkyl;

In addition, wherein in formula I, at any-NR ⁵R ⁶In, this R ⁵With R ⁶Choose wantonly and be somebody's turn to do-NR ⁵R ⁶N be combined together to form cyclic rings or bridge joint cyclic rings, wherein respectively this cyclic rings or bridge joint cyclic rings can not be substituted, or be can be identical or different part group and replace by one or more, this part group be independently selected from hydroxyl ,-SH, alkyl, thiazolinyl, hydroxyalkyl ,-alkyl-SH, alkoxyl group ,-the S-alkyl ,-CO ₂-alkyl ,-CO ₂-thiazolinyl, aralkyl, cycloalkenyl alkyl, cycloalkylalkyl, heteroaralkyl, heterocycloalkenyl alkyl, Heterocyclylalkyl alkyl, heteroaryl, aryl, cycloalkenyl group, cycloalkyl, spiro heterocyclic radical, spiroheterocyclic thiazolinyl, spiral shell heteroaryl, volution base, volution thiazolinyl, spiral shell aryl, alkoxyalkyl ,-alkyl-S-alkyl, heterocyclic radical and heterocycloalkenyl.

25. compound of representing with following formula:

Or its pharmacy acceptable salt, solvate, ester or prodrug.

26. compound as claimed in claim 1 or its pharmacy acceptable salt, solvate, ester or prodrug, it is the form of purifying.

27. compound as claimed in claim 1 or its pharmacy acceptable salt, solvate, ester or prodrug, it is isolating form.

28. a pharmaceutical composition, it comprises compound or its pharmacy acceptable salt, solvate, ester or prodrug and at least a pharmaceutically acceptable carrier of at least a claim 1 for the treatment of significant quantity.

29. as the pharmaceutical composition of claim 28, it further comprises one or more carcinostatic agents that is different from claim 2 compound.

30. as the pharmaceutical composition of claim 29, wherein one or more carcinostatic agents are selected from cytostatic agent, cis-platinum, Zorubicin, liposome Zorubicin (Caelyx for example, Myocet, Doxil), taxotere (taxotere), taxol, Etoposide, Rinotecan, camptostar, Hycamtin, taxol (paclitaxel), docetaxel (docetaxel), Ai Boxi ketone (epothilone), tamoxifen, 5 FU 5 fluorouracil, Rheumatrex (methoxtrexate), Temozolomide, endoxan, SCH 66336, R115777

, L778,123 , BMS 214662

, Iressa

, Tarceva

, EGFR antibody (comprise and being delivered among the US 2005/0136063 of bulletin on June 23rd, 2005 for example), the KSP inhibitor of antibody, IGFR (for example announced among WO2006/098962 and the WO2006/098961; Ispinesib, SB-743921 derive from Cytokinetics), centrosome related protein E (" CENP-E ") inhibitor (for example GSK-923295), Gleevec

Intron, ara-C, Zorubicin, endoxan, gemcitabine, uracil mustard, mustargen, ifosfamide (Ifosfamide), L-PAM, Chlorambucil, pipobroman (Pipobroman), Persistol, triethylene sulfo-phosphamidon, busulfan, carmustine, lomustine, streptozocin, dacarbazine, fluorodeoxyuridine, cytosine arabinoside, Ismipur, 6-sulfenyl guanine, fludarabine phosphate, oxaliplatin, formyl tetrahydrofolic acid (leucovirin), ELOXATIN ^TMPentostatine, vinealeucoblastine(VLB), vincristine(VCR), vindesine, bleomycin, gengshengmeisu, daunorubicin, Hydroxydaunomycin, epirubicin, idarubicin (Idarubicin), mithramycin, deoxidation is formycin altogether, Mitomycin-C, the altheine enzyme, teniposide (Teniposide), 17 alpha-acetylenes estradiol, stilboestrol, testosterone, prednisone, FL, dromostanolone propionate, testolactone, the acetate megestrol, medrat, methyltestosterone, Prednisolone Acetate, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimidium (Aminoglutethimide), Emcyt (Estramustine), the Zytron acetic ester, Leuprolide, Drogenil (Flutamide), toremifene, goserelin, cis-platinum, carboplatin, hydroxyurea, Amsiacrine (Amsacrine), procarbazine, mitotane (Mitotane), mitoxantrone, L-tetramisole, nvelbine (Navelbene), Anastrazole, Letrazole, capecitabine, raloxifene, droloxifene, hexamethyl melamine, Avastin, herceptin, Bexxar, rich for left side rice (bortezomib) (" Velcade "), Zevalin, white arsenic (Trisenox), xeloda (Xeloda), vinorelbine, porfimer (Porfimer), Erbitux, liposome (Liposomal), thio-tepa, hexamethyl melamine, L-PAM, trastuzumab, Lerozole, fulvestrant, Exemestane, fulvestrant, Ifosfomide, Rituximab, C225

, satriplatin, mylotarg, Avastin, B cell monoclonal antibody (rituxan), panitubimab, Sutent, sorafinib, Sprycel (dastinib), nilotinib, Tykerb (lapatinib) and Campath.

31. one kind is suppressed the kinase whose method of one or more aurora bodies, it comprises compound or its pharmacy acceptable salt, solvate, ester or the prodrug of the patient being thrown at least a claim 1 of giving the treatment significant quantity.

32. one kind by suppressing aurora body kinases to treat the method for one or more diseases, it comprises compound or its pharmacy acceptable salt, solvate, ester or the prodrug of the patient being thrown at least a claim 1 of giving the treatment significant quantity.

33. one kind by suppressing aurora body kinases treating the method for one or more diseases, it comprises the Mammals of this kind of needs treatment thrown and gives:

A certain amount of first compound, it is compound or its pharmacy acceptable salt, solvate, ester or the prodrug of claim 1; With

A certain amount of at least a second compound, this second compound is the carcinostatic agent that is different from the compound of claim 1;

Wherein the amount of first compound and second compound can produce result of treatment.

34. as each method in the claim 31,32 or 33, wherein aurora body kinases is aurora body A.

35. as each method in the claim 31,32 or 33, wherein aurora body kinases is aurora body B.

36. as each method in claim 32 or 33, wherein disease is selected from:

Lymphocytic leukemia (" CLL "),

Fibrosarcoma, rhabdosarcoma;

Head and deroncus, adventitial cell lymphoma, bone marrow cell carcinoma;

37. as each method in the claim 31,32 or 33, it further comprises radiotherapy.

38. method as claim 33, wherein carcinostatic agent is selected from cytostatic agent, cis-platinum, Zorubicin, taxotere (taxotere), taxol, Etoposide, Rinotecan, camptostar, Hycamtin, taxol (paclitaxel), docetaxel (docetaxel), Ai Boxi ketone (epothilone), tamoxifen, 5 FU 5 fluorouracil, Rheumatrex (methoxtrexate), Temozolomide, endoxan, SCH 66336, R115777, L778,123, BMS 214662, Iressa, Tarceva, the antibody of EGFR, Gleevec, intron, ara-C, Zorubicin, endoxan, gemcitabine, uracil mustard, mustargen, ifosfamide (Ifosfamide), L-PAM, Chlorambucil, pipobroman (Pipobroman), Persistol, triethylene sulfo-phosphamidon, busulfan, carmustine, lomustine, streptozocin, dacarbazine, fluorodeoxyuridine, cytosine arabinoside, Ismipur, 6-sulfenyl guanine, fludarabine phosphate, oxaliplatin, formyl tetrahydrofolic acid (leucovirin), ELOXATIN ^TMPentostatine, vinealeucoblastine(VLB), vincristine(VCR), vindesine, bleomycin, gengshengmeisu, daunorubicin, Hydroxydaunomycin, epirubicin, idarubicin (Idarubicin), mithramycin, deoxidation is formycin altogether, Mitomycin-C, the altheine enzyme, teniposide (Teniposide), 17 alpha-acetylenes estradiol, stilboestrol, testosterone, prednisone, FL, dromostanolone propionate, testolactone, the acetate megestrol, medrat, methyltestosterone, Prednisolone Acetate, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimidium (Aminoglutethimide), Emcyt (Estramustine), the Zytron acetic ester, Leuprolide, Drogenil (Flutamide), toremifene, goserelin, cis-platinum, carboplatin, hydroxyurea, Amsiacrine (Amsacrine), procarbazine, mitotane (Mitotane), mitoxantrone, L-tetramisole, nvelbine (Navelbene), Anastrazole, Letrazole, capecitabine, raloxifene, droloxifene, hexamethyl melamine, Avastin, herceptin, Bexxar, Velcade, Zevalin, white arsenic (Trisenox), xeloda (Xeloda), vinorelbine, porfimer (Porfimer), Erbitux, liposome (Liposomal), thio-tepa, hexamethyl melamine, L-PAM, trastuzumab, Lerozole, fulvestrant, Exemestane, fulvestrant, Ifosfomide, Rituximab, C225, Campath, Clofarabine, CldAdo (cladribine), aphidicolon, B cell monoclonal antibody (rituxan), sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP and MDL-101,731.

39. one kind is suppressed one or more kinase whose methods, wherein this kinases is selected from cyclin-dependent kinase, check point kinases, Tyrosylprotein kinase and Pim-1 kinases, and this method comprises gives compound at least a as claimed in claim 1 or its pharmacy acceptable salt, solvate, ester or the prodrug that significant quantity is gone up in treatment to patient's throwing of this kind of needs inhibition.

40. one kind by suppressing one or more kinases to treat the method for one or more diseases, wherein this kinases is selected from cyclin-dependent kinase, check point kinases, Tyrosylprotein kinase and Pim-1 kinases, and this method comprises gives compound at least a as claimed in claim 1 or its pharmacy acceptable salt, solvate, ester or the prodrug that significant quantity is gone up in treatment to patient's throwing of this kind of needs treatment.

41. as the method for claim 39 or 40, wherein this cyclin-dependent kinase is selected from CDK1 or CDK2, this check point kinases is selected from CHK-1 or CHK-2, and this Tyrosylprotein kinase is selected from VEGF-R2, EGFR, HER2, SRC, JAK and TEK.

42. a treatment method for cancer, it comprises throwing to give treats upward compound or its pharmacy acceptable salt, solvate, ester or the prodrug of at least a claim 1 of significant quantity.

43. one kind is suppressed one or more kinase whose methods, wherein this kinases is selected from cyclin-dependent kinase, check point kinases, Tyrosylprotein kinase and Pim-1 kinases, and this method comprises gives compound or its pharmacy acceptable salt, solvate, ester or the prodrug that at least a claim 25 of significant quantity is gone up in treatment to patient's throwing of this kind of needs inhibition.

44. one kind by suppressing aurora body kinases treating the method for one or more diseases, it comprises the Mammals of this kind of needs treatment thrown and gives

A certain amount of first compound, it is compound or its pharmacy acceptable salt, solvate, ester or the prodrug of claim 25; With

A certain amount of at least a second compound, this second compound is the carcinostatic agent that is different from the compound of claim 25;

45. a pharmaceutical composition, it comprises compound or its pharmacy acceptable salt, solvate, ester or prodrug and at least a pharmaceutically acceptable carrier of at least a claim 25 for the treatment of significant quantity.